<%BANNER%>

Synthetic Application in Thioacylation, Acylation, and Sulfonylation

xml version 1.0 encoding UTF-8
REPORT xmlns http:www.fcla.edudlsmddaitss xmlns:xsi http:www.w3.org2001XMLSchema-instance xsi:schemaLocation http:www.fcla.edudlsmddaitssdaitssReport.xsd
INGEST IEID E20110217_AAAACC INGEST_TIME 2011-02-17T18:57:06Z PACKAGE UFE0015000_00001
AGREEMENT_INFO ACCOUNT UF PROJECT UFDC
FILES
FILE SIZE 33789 DFID F20110217_AABSWH ORIGIN DEPOSITOR PATH tao_h_Page_085.pro GLOBAL false PRESERVATION BIT MESSAGE_DIGEST ALGORITHM MD5
9b6f040a5fede4ab8c06c8d51ea2de14
SHA-1
55f3ae44acad1b128d1149619a50efe03f76f338
8423998 F20110217_AABTAZ tao_h_Page_102.tif
63d4be2fd473ad37ca58c391b0453095
0e6627692e0bffe77ff2374fd6794710e93bfaae
F20110217_AABSVS tao_h_Page_075.tif
cce4263a74b37fc142b3dbf074d5a200
0581844dbddb6504cadaa313b6eb037405170501
1999 F20110217_AABTCB tao_h_Page_024.txt
0ca7e909cce7f0955ad665596f766809
b49ceef5cda216a61e5a2aa80bc0d42caa3abed5
2379 F20110217_AABTBN tao_h_Page_009.txt
f2461eff3d8ff7a35575af05642ab4de
765fa0750f53a34f8aef899b894b09ce72003242
825 F20110217_AABSWI tao_h_Page_008.txt
ce74de617e891e2c69075a5ae7553447
03a1eafa903fa32731e697bda523fdaa6016d75e
959667 F20110217_AABSVT tao_h_Page_069.jp2
0e04844609b292d9454c04c1c9ee4a8d
c48cb98daf10913ecaade451cffe5d0ff572770a
1881 F20110217_AABTCC tao_h_Page_025.txt
4e13c372868b858e151aa168b906838e
6ce9c00889acda5bdd7e11c46697a010b34e42e1
891 F20110217_AABTBO tao_h_Page_011.txt
f10dae5106fefb958d432348f210e437
726ce3f7a566c4f49a536edbc17cac2c02d8c594
1051977 F20110217_AABSWJ tao_h_Page_045.jp2
17649e969e04fbf67002212a1de8d7a9
ff25f7a998696c56046802aa477ac65aeaa78f48
50460 F20110217_AABSVU tao_h_Page_045.pro
509add88a2f3ae6606653597a7e2f05b
d984dae0e1281d3f2d4737cb1b8ffa827c22a5a2
1686 F20110217_AABTCD tao_h_Page_026.txt
582fc9c1d2b44eab4988bb9777973efb
7f9196dc8d0195c7578f7c37d56a6611c6f20764
1474 F20110217_AABTBP tao_h_Page_012.txt
994aee3008f331bde379aea36cc29635
ce1706d8f02978123913222d89ed5d3cf2403d0f
7147 F20110217_AABSWK tao_h_Page_056thm.jpg
202b78ac1ab6633b81bdbacbf3911041
b3a57c7478fd8b79e4c1b7c1425a516ed6471d1b
F20110217_AABSVV tao_h_Page_028.tif
4ad2e1ddb2c8264bf14b2b473ab77c8d
efcea7726273dafc469f307cb6aa1463fc0b7ce2
1993 F20110217_AABTCE tao_h_Page_027.txt
30fa2c2ec130ad3fb07fe9ee3efcbf94
a1fd85deb800fe12610ec0b3bc7a3ea758327a23
1747 F20110217_AABTBQ tao_h_Page_013.txt
f52074a16241aebcc1ded8173d660aa9
fad1cac2a65165ceb73d2984f5a38628c8d0e8bf
994119 F20110217_AABSWL tao_h_Page_043.jp2
b3247ca26852ac31efb40ad909d036e8
edfcd43122f92e1ff424146a7e933ac6c068e17b
35733 F20110217_AABSVW tao_h_Page_088.pro
8a253ff31dcd702fcd1987284228aae9
b93f74baa75c447ec8667be91e9665c47b943c9a
1811 F20110217_AABTCF tao_h_Page_028.txt
e3ceabb2f07b3f8207d661daa69338f7
63fceb3e920f8615cd536c484eba4ed77bc37ce7
1902 F20110217_AABTBR tao_h_Page_014.txt
4dfee94db3784afe4b0d44dc64dbd0d1
f0f4c6a52428a01f05bf554dba3414f88f15f967
F20110217_AABSWM tao_h_Page_094.tif
ba5c4d93b190b508013d09eaeda85590
dd5909262a28fb8fac57c410f8a7b427decf75d8
44805 F20110217_AABSVX tao_h_Page_089.pro
853eabbbd5b1daf15fa2af72b82cde2d
6a7ceb69f753439cc8b347384094064a616ac6a8
1816 F20110217_AABTCG tao_h_Page_029.txt
fec4afbd55d236ca473e1de50c892a3a
3ba10e5c73739e38e7d9e26f35f4736405d09a14
353444 F20110217_AABSXA tao_h_Page_062.jp2
5057564ef4277189b80fdeed2855f2cd
0777cdf7c45a17ab0c1c466d331f1a242caea13a
1636 F20110217_AABTBS tao_h_Page_015.txt
c0374cbde9fc4d10cdfbc918e592365d
5d7ac02b63cde2feca4021c07db073be7c4dfac2
1020823 F20110217_AABSWN tao_h_Page_010.jp2
6cf8019cf21d3e53087851cca0174e50
9517908e0c72bbf857c2dd356496ab22ea391fff
1036194 F20110217_AABSVY tao_h_Page_014.jp2
c0eebb61f2e7f0ec195e68ef030bb0ae
23bbc367e4e3175b090f9d0594716fdc2a1615e7
1746 F20110217_AABTCH tao_h_Page_030.txt
63729205bd5dc1c7cd5b2557fd7db500
680f15dc182da7702bd8a5bf50cdc4c0d0f26a4d
55821 F20110217_AABSXB tao_h_Page_073.jpg
a1a03d5b25518d2798101f854f0163e5
d899440a8ddb13e3c5793be1d254a75eb0e45561
1668 F20110217_AABTBT tao_h_Page_016.txt
4b4c673852b6dab7d22a68df0c5017ca
77424f7f6486c382b07f04cdb12e0996097cb7f1
1801 F20110217_AABSWO tao_h_Page_053.txt
dd3c95f871f778bb2096698a1bd6c147
1ccea058138d0073678bf018541d5b329770f1bf
F20110217_AABSVZ tao_h_Page_043.tif
d4d8d51909b41e42e9cc84c152070a82
2ce4dbe5909d74dd89ca9379b4c140c604bfbd1d
1752 F20110217_AABTCI tao_h_Page_031.txt
a46aceb10c28b68e0896c38aa58b8adb
d52065e0581a4cdf390943a9542f03862b9eecba
6839 F20110217_AABSXC tao_h_Page_025thm.jpg
75c310e2f65939eed57dd09ca6957744
a55160bdd717bc32cb02243825f385df71d00ff7
1435 F20110217_AABTBU tao_h_Page_017.txt
3724b5cf5fbddbafcd55dc10cb1e72c1
2438c60accc864affb0dd0c8932fc9e72fcff799
16601 F20110217_AABSWP tao_h_Page_006.QC.jpg
ee47827821bd3e2bcdc264619231b0c2
1c604d8cec0698d81aefa1a8c1dbd16ed3686abf
667 F20110217_AABTCJ tao_h_Page_032.txt
d92f12004a3f491c22f9606665dbc57d
54b8302f5996fe3d46cada3d7125f4f7bc3b26ed
76885 F20110217_AABSXD tao_h_Page_053.jpg
2297eb3ce625ab9a388d0e54ee26d6d3
9e4b037674fbf5180b4381ea16d928716cecbcca
1723 F20110217_AABTBV tao_h_Page_018.txt
5c0cfdebc4aa6453ccbadd99945b5bdc
dc3562a697e1cb860a045bc6192f09530fd0532f
19848 F20110217_AABSWQ tao_h_Page_005.QC.jpg
eca836d334ae6be1f7fa0c3153bb9e03
a2ae79303db989c827cd19609f0913295f43b911
1620 F20110217_AABTCK tao_h_Page_033.txt
60e5da85b2328450c35678942dd11891
905928769cbff67ab402c9fa7458113382fd056b
92945 F20110217_AABSXE tao_h_Page_030.jpg
b686e51f4576ed92e6ab0e2db228ee10
43bff5190bf9a52e68d52874e00a3baf06263b8b
628 F20110217_AABTBW tao_h_Page_019.txt
52bd7c2f205745402db961a5bfc393af
214d05384137743b555fc3848aa7a0f9bb5d856c
83154 F20110217_AABSWR tao_h_Page_056.jpg
47e1fb61bdd0e974817db19b9ed77f31
286a198525f80f53b2cd8388a7b752dde9467b50
1901 F20110217_AABTCL tao_h_Page_034.txt
39f0ea85dbb6be13b9404ae92461ab54
35f358017b9abff2f9ce095583ab87e77bfbc10e
F20110217_AABSXF tao_h_Page_056.tif
d32e621fee6229c9434953eefefb1786
da51acb6de906ea24bf2415bfb076ee78bf7e8b2
1765 F20110217_AABTBX tao_h_Page_020.txt
e57b5086952e95028f08b775b27d4574
67c2d4b8a4cf5a1f7b3260580055bfe756fb20e8
1829 F20110217_AABTDA tao_h_Page_055.txt
7d9c15ac85c6a42607ee5a98928d1d07
1bf38cbdfe7a3bd346f4220990e57a6360c3514d
1918 F20110217_AABTCM tao_h_Page_035.txt
88bde6575f7fc56dd439a03fdc3c201c
97a51b94b8f1d68599e6dc35e7c504e360a57320
1633 F20110217_AABSXG tao_h_Page_097.txt
4d185d0892ba77ad8933b13cc87af970
9b0bcea21c55cb21e15f5ae7e4c61357fec1ec00
1959 F20110217_AABTBY tao_h_Page_021.txt
e4e89299d7e7ba8e7ed61ae96b0db945
5282b0037974777f2db1fc1a5895cb57bc21245f
F20110217_AABSWS tao_h_Page_088.tif
750554e80a3af96d58a3e6a88707dcae
6804183e38be93d11ed5678654b1a85d874ad8b3
2148 F20110217_AABTDB tao_h_Page_056.txt
dc683f26b52f6c4dd5fc09127b631490
874c22bb6a71fa5ce5d0851a4c635576267186a9
1844 F20110217_AABTCN tao_h_Page_036.txt
06cd9ca808f11dc2d284dc604075a5ef
5a7db4ae0c195a6f8e198e0f7cc10bac4b54afea
8173 F20110217_AABSXH tao_h_Page_102thm.jpg
735211aaf24740b3107f54d1fef3d9b8
b61d4344a76cae8b15003962357e4ee5a02dad6c
1739 F20110217_AABTBZ tao_h_Page_022.txt
a49f01b59cee6cfe8364ef432b26cd9a
7055b3f41658f8580abd557b1511ea3eb9b8a917
37474 F20110217_AABSWT tao_h_Page_084.pro
59ad28a3a92bb76d1c862b3889859894
b54cd547b230d7988eabe3eb13b6e8726a019543
1872 F20110217_AABTDC tao_h_Page_057.txt
3e1cbd2fbc3b22cc4ca28250743ae362
14c15428681a58d71859fd75934841835ce35d07
2095 F20110217_AABTCO tao_h_Page_037.txt
56ffc6743f4cb13e5fd4735e16d4ced7
28c33d048977b21cc3478eb9aec24758d2410978
1841 F20110217_AABSXI tao_h_Page_044.txt
8a2584a275d18a18d158ef868540ccf5
5ccde5e35b36162feb2dd202707ec292c8e49c92
F20110217_AABSWU tao_h_Page_020.tif
7a68c297ac9d99dbc7137264556740cf
be076e8d841693f505cea8d862531748948b3153
1830 F20110217_AABTDD tao_h_Page_058.txt
cf560d78c6bf50d071d5b3099838796c
7addcd1178694d276cf2c97f66f02c4625539fe1
1855 F20110217_AABTCP tao_h_Page_038.txt
43819857c005f229b567534f0c0d2a8b
82719f8ea7996a253d9ee841a9c105b7392dd9df
F20110217_AABSXJ tao_h_Page_038.tif
c01fe23cadd1ab6065bb8c4069fabd69
999761381d84cb7e95527e545d82c7fb32ce2e4d
101063 F20110217_AABSWV tao_h_Page_064.jpg
d7cec477a5970cc74e6f5fd1d2ef2c2b
ea8f9641aaa25118c3abde72a7db275da9b6499c
1873 F20110217_AABTDE tao_h_Page_059.txt
958bef520cd17a4cb271c320540ba4d8
5984eac5572193e9597eba35c3bf413222901c7e
1871 F20110217_AABTCQ tao_h_Page_040.txt
91f6580136631837bd6062d56cff9cd5
253a77a17360668391873ee8078a7015d4fd6943
F20110217_AABSXK tao_h_Page_071.tif
43a4bf36f97c3e710190879b32e488ec
74c9849a1d2a6fb35f0449e89f2ee28d6607e6ae
1771 F20110217_AABSWW tao_h_Page_048.txt
7604beba3e6e804e97861ca3ab2f4924
6c553215de7c06fd490c8bfba27edaa7df1d5a59
1762 F20110217_AABTDF tao_h_Page_060.txt
0edf1fc573962c2254d76ee494e88d6c
972cadae382d2e931ecc2af81f3ecd464f51dab6
1975 F20110217_AABTCR tao_h_Page_041.txt
d3eece2993cd61baa65552211a8aae58
0249d9459c45619bb0a5dd1fc454cede128ad1ed
1884 F20110217_AABSXL tao_h_Page_076.txt
ff6e6e36521afe6654cc1d1ce1615344
f90b07bbbea0d9b183bebba27c3d7139ddbbf93c
1051946 F20110217_AABSWX tao_h_Page_037.jp2
1658819801e6d968ff2b4addfbfd432f
a344ca9fe1590367fbdbd3f1d9712d74e74150d7
1947 F20110217_AABTDG tao_h_Page_061.txt
2f2bff500d3b9b2f6d87e6726ed62dc8
d15ea2eb733905b1417b26b5eb94f503437cae83
F20110217_AABSYA tao_h_Page_003.tif
03173577282e65492716eaa3bbe3a5d1
8fd87c5cd76228ca69c47f34b065dcb8e19c1b07
1735 F20110217_AABTCS tao_h_Page_042.txt
553ec8c6697b6dfdce5ccb3c4de01192
3f17901ee8dfe073464c772226818cea64d050b2
72096 F20110217_AABSXM tao_h_Page_004.jpg
e017babfc4113c0167388f392b9db5c7
729f503ad74c9a63ce515ba2f2e5195485209434
8166 F20110217_AABSWY tao_h_Page_104thm.jpg
9a3720d1091a25b8714269d892132634
f4cc29932a67c639c6a3c8c8c4015d5c30c55419
647 F20110217_AABTDH tao_h_Page_062.txt
e7480decbb28c4559a002540ced2a533
1136ff2d7ee8630b834f4200fc8bc5e2614eefa2
F20110217_AABSYB tao_h_Page_004.tif
5411f3cd2db63df299ca5fd7519de910
3150b0c374e16dd302cba80ff7be9fbcccc540ad
1994 F20110217_AABTCT tao_h_Page_045.txt
9631c12fadaa87e01de435355c5fa91a
ce6ead86fc80ea50ca573933513e8fdfde849052
F20110217_AABSXN tao_h_Page_048.tif
80c897bea8db92e7710149b81a100f88
8208584258ee7c046151d83ab816cde4563f2d93
23981 F20110217_AABSWZ tao_h_Page_095.QC.jpg
e11daeb6a09c4c723062ea25af8176a7
480db5170201f662fa9d1171b3454675abc22e70
1812 F20110217_AABTDI tao_h_Page_063.txt
c7ef44a1f22ffdbbae235e4d0b2bf96a
1f857b09100e085fc5d96f87c968e389955aa1ee
F20110217_AABSYC tao_h_Page_005.tif
7738f17df7ce92839bb90961680459db
6d9131f9fc5359adfa27decae65ed8123810b593
1860 F20110217_AABTCU tao_h_Page_046.txt
2cc6ac88978bca461a532f2fd46b70aa
c0ad47334c79ecccc21b29a06f14d3a75a4f77e1
8387 F20110217_AABSXO tao_h_Page_100thm.jpg
6a4bec5089ca2e9815151290de4a2eb5
bb0ded1ae4c4e1ff8b1b8f953db9878b2d7263b0
1914 F20110217_AABTDJ tao_h_Page_064.txt
41da5bfe5afee648f45bfeab2bb03985
ce6eb989c3c4738203a967e6cbcf483faf247344
F20110217_AABSYD tao_h_Page_006.tif
76778816963af026ece1ed812a4529ad
6bdba874258b57ef7aede0fa97cda46659e9da21
1296 F20110217_AABTCV tao_h_Page_049.txt
09f61dc52947422b39064adeebc21eda
6679c97fbb9349c433be17728e4d9a3668fb372d
6637 F20110217_AABSXP tao_h_Page_068thm.jpg
a8c026e743fa983dd3a740ea3d953aff
494adc1de6c80e3854dbdadd8946942f1174b0da
F20110217_AABTDK tao_h_Page_065.txt
4eaca2e7ab8bbf9fbbd82319ea41bffb
1467e896f10d503b0c14f9ac4ca502a055cf5dbd
F20110217_AABSYE tao_h_Page_007.tif
8115559b6d6253ec9a7e9d57fe5d1055
f83c44aad484a10bffb794d1d946a23de21ed92e
2546 F20110217_AABTCW tao_h_Page_050.txt
cf302f61ea9c9d8d5e42c8e95d319c15
35343a215642863aa6c4c87c02a19b3b138dd6ee
93640 F20110217_AABSXQ tao_h_Page_060.jpg
118afb048c28425e64e4a1ac680ea7b8
fa01094349e4f59d40aae285a7515fde643c7bc2
1470 F20110217_AABTDL tao_h_Page_066.txt
06054cfde649f3a78bd0264820929c46
afb315eecd7fb80547c3ea41ee2c6dcfd2a1de90
F20110217_AABSYF tao_h_Page_008.tif
9a6064fc76e465e10d1ae7ef4819a35d
74961c2341652496e37d8b8bbbab72fa98ea7029
2159 F20110217_AABTCX tao_h_Page_051.txt
a6325bcdf6380f13a8dab9073b2c72a9
d454a1d80b33a2362262fa7ff5e0f3ef181ad37a
47039 F20110217_AABSXR tao_h_Page_090.pro
83a510d549a6fc1ad6612db7cfc8b719
2b92476df03434e557477a9a413324b19c5fee97
1817 F20110217_AABTDM tao_h_Page_067.txt
85a54e4111b53d9190aff04d425bc30b
35b7c23b340891215f251dec909f7eac8272f5d5
F20110217_AABSYG tao_h_Page_009.tif
e96cc4cd7a450cd81ec32e6516b713c0
5631164180913c4cf626697f1183c3c814d9c768
2353 F20110217_AABTCY tao_h_Page_052.txt
2f92c42cd99f9c68501dd6a64bdbbfd8
224729fde4290451b4f4b1c4cfc408c8534ae142
F20110217_AABSXS tao_h_Page_002.tif
caab8ad6b367e5940c3a05d9a6471c92
fd0a926d94cbb51e52ddd116e12b73f4ad65624e
2025 F20110217_AABTEA tao_h_Page_086.txt
2639b65c9edf312cc6b1a6a01fc5135f
291fe71fc8799107a462a47be16d33095fb50f20
1886 F20110217_AABTDN tao_h_Page_069.txt
61c99d6ab9bdd01f2300e721ddb71c3d
f3fd0da874d921b0ed5f1b89b43a0eba825caeed
F20110217_AABSYH tao_h_Page_010.tif
b91a711d3298a8bd44393715c8e829dc
f60d6af6fb24d1a2f4281719028411ff09548612
1849 F20110217_AABTCZ tao_h_Page_054.txt
4ead5680b462e2c58668a6fdf7f36b9c
f05a7754590ce5db685ccacd4bf790fda1e0aa4f
1837 F20110217_AABTEB tao_h_Page_089.txt
5af080a586efd9de55731140ba5574c9
14648315b61b1d06b3b3729c6eac4fd647405da2
1768 F20110217_AABTDO tao_h_Page_070.txt
35310dc197b61a68722b9fffdfc09cbc
8e89b97abf236b7e90a5ef23de0f1645001dcb1c
F20110217_AABSYI tao_h_Page_011.tif
ea4c40696e5e3cdd63f744dc65c4c1bd
d1ab9fb1eb1cdbcdcd9ca3e7cdc90358eeef0199
6096 F20110217_AABSXT tao_h_Page_004thm.jpg
0deac1c7d58e7aa6a2e8109b76fcac78
f78f5d9e532f25fa3f5c4fa95772b6168527c73b
1877 F20110217_AABTEC tao_h_Page_090.txt
0ed02c54937b47a57793b7e51768b69f
333648395ba07d2d8959f8aea9cea2cf0ddca0a9
1741 F20110217_AABTDP tao_h_Page_071.txt
996fcb04d2b4111e8d3cd2d70fc6d9f9
7bb0f590bbd5e66fab15b161462f1f193b776b51
F20110217_AABSYJ tao_h_Page_013.tif
4477d25cfda7a107e57f5f4e09a83054
a4fe0a88bc36966a0bf98a8b8dd31f4c5bc9a71d
573906 F20110217_AABSXU tao_h_Page_066.jp2
9e0ff3934bba607e377ffe51e2169584
2b68024f37a7c88759d2c929c97f54c675a9256c
1861 F20110217_AABTED tao_h_Page_091.txt
8cad3818c87a3d84227d664f2ab416a0
5f8b0660f9066af9b0c236289a98f50abb826db7
1685 F20110217_AABTDQ tao_h_Page_072.txt
7fd35e171572b16e23d594a8c6402c3e
b0cce4d36ded0fd752c14a5ae74d01709d7318f3
F20110217_AABSYK tao_h_Page_014.tif
f887db7d4f897182535fc5547ca050f9
4f939ffb8dcb812430945bd4b311562811e7db23
6624 F20110217_AABSXV tao_h_Page_015thm.jpg
595d3013a3ee22f59ea0428701c04a36
f06230b05bee85a89329bf65801ea965f6184a94
1607 F20110217_AABTEE tao_h_Page_092.txt
7a381f819a0636df26b589f9e0afce68
92a0f944c695176b3b61bad3b5d99cb06874d608
1803 F20110217_AABTDR tao_h_Page_073.txt
bdfdba5b57a070c7c5f11e03db423bf9
14e839c9abd6cf4f0e280b6ee7a3347aaabf3f48
F20110217_AABSYL tao_h_Page_015.tif
14d00d20cb055e6f735bdef7c32af39b
0351adbf8af22ab95b02dd4bb3737721e8e23572
174146 F20110217_AABSXW UFE0015000_00001.xml FULL
43847abbcebdd8923debdc8ba3026d45
b99a730fc63fb447ebbbca2610fd297e28c5ef7f
F20110217_AABTEF tao_h_Page_093.txt
ad8102144a7524c8f9d719e566b6c9aa
2d2cf39f122a3d4ff5febd391bc8498fe45c43ea
F20110217_AABSZA tao_h_Page_035.tif
6191e7a88878d55449bc892865e37697
a09bf312684c89300d07de0a8cbbceed7091fa74
1826 F20110217_AABTDS tao_h_Page_075.txt
dd59d1f9c2c208de5dc80280c54cc807
816aac2c5dde6505ed48870b2888c816d4c0d16d
F20110217_AABSYM tao_h_Page_016.tif
fff277050fe53aa941ad34b94a7c2de9
a5d0c304af21a88bf70750b43fbeda4a4df8c2e6
1581 F20110217_AABTEG tao_h_Page_094.txt
702c1d8cf6e6598ea9c584ef40dd0ba4
fe1f93acdcf55141d09550c741d8e8c2ab7df9ee
F20110217_AABSZB tao_h_Page_036.tif
3f23714934602c6348445240a06f8316
5850a8998473ed6c050ee0854d838f15d8f834f9
1958 F20110217_AABTDT tao_h_Page_077.txt
27dc4b6773b7329d1d8e8552085d4ab5
344b0be538d8b7d14d84b4d85f1ef6f346dd1471
F20110217_AABSYN tao_h_Page_018.tif
e9a502d6bf4413fa40c3f6c3f4f148af
d42354ed74c217409fe1761e0105b68959f2f70c
1702 F20110217_AABTEH tao_h_Page_096.txt
e6984dc0ba87e167ff99b5e6f22949bd
95416bc00c15e482a807224c228e26ec3957902a
1876 F20110217_AABTDU tao_h_Page_079.txt
e24e3568f7187adfa340d99f9e404077
485613e62d3de7895220d21a609c3b78db9ea809
F20110217_AABSYO tao_h_Page_019.tif
4d517a8e72ddf52aabd936a036b6d468
0a6c76906f0ccae7dd3b00e41a7174f775a67535
F20110217_AABSXZ tao_h_Page_001.tif
73f5a7f3db6f74f495b67149e6116924
a5be99ff7c2487095fad3a6fa4a51d0e3ab253f6
1789 F20110217_AABTEI tao_h_Page_098.txt
631a2d5fe78c225603dba43b5c459ed6
7a7fa0423de02cb95384044915bd8e79ce29bad7
F20110217_AABSZC tao_h_Page_037.tif
f798e96c91f2d36df1dfbe40f47f7b05
058b0da1b7fbbe9b12fd4fddd4987d4d39b997c6
1828 F20110217_AABTDV tao_h_Page_080.txt
27963daa1f4d22b3268d8a70cb4a1be8
c1bd29d48dcf3578c19799ba9b49f3df055ddb0a
F20110217_AABSYP tao_h_Page_021.tif
1b19f88f23ffca57227077647c11c8d5
0cdb863e9dd4e759f15bb458f3dca830f9f0f053
F20110217_AABTEJ tao_h_Page_099.txt
f37e5648a56bdf941d9f42610328505a
1f6e004b6314c82f02eb0a3c26488f0de1347f0d
F20110217_AABSZD tao_h_Page_039.tif
866fc72fca0f50d5f79a3376fd67fd39
da4da00592ce2c8eefb8e0c1c25e4bb63b215410
F20110217_AABTDW tao_h_Page_081.txt
001af06a8a465632e7032bad23088c2e
1253eee3f0954eb61d1dc66c6342c45a434f0040
F20110217_AABSYQ tao_h_Page_022.tif
56d0dd12ca8eece4b56af4475a450733
4334206e7a23eefe7b12b12ea52f631d4d1dc4b8
1945 F20110217_AABTEK tao_h_Page_101.txt
6dbd949e10f970e7a449743551205a03
05c70be8861694d0c20c5b0f183122105de3db13
F20110217_AABSZE tao_h_Page_040.tif
8f06629a7d10b3585274891cce669003
1fd3a519ccef200464c8f6bcfbf146fcf325fc23
1889 F20110217_AABTDX tao_h_Page_082.txt
3f31057f87db089bf39cba49d7bbd169
6765f63dd3d38e711d89bf6bb499f69a4947a194
F20110217_AABSYR tao_h_Page_025.tif
5cbf2759ba8b3db0005ea4b4eafa8745
a9161b21c2f14eb93947b4aa52900c4019dbbc4e
1745 F20110217_AABTEL tao_h_Page_102.txt
b6a58d23b91c2b2c44fc5898e6aa61cf
2a863f5ba566d9ad4a0b606297c27f0be0eb605b
F20110217_AABSZF tao_h_Page_041.tif
8878368d95c32d20eeabd14d7fde83b0
6d20d6cfa92b90fc7900b4643d700b01a3d1e733
1773 F20110217_AABTDY tao_h_Page_083.txt
1beabf621209d41eaab459cd8ffc4485
fc72e2aa9c2cbb4eb898a8f31ea23f10fc03733a
F20110217_AABSYS tao_h_Page_026.tif
4e9efdbbb3ec5c842f4ce9d1d3838a93
b0a6dd40878d7166001f004fd75925703247ed8a
66774 F20110217_AABTFA tao_h_Page_010.pro
8e4926155166537722a6614af9902409
ac2e481b89d312d6d2dc6f0af668478d819a7c36
1806 F20110217_AABTEM tao_h_Page_103.txt
a2bb106e619582ac2aa13bc4def810e0
5ea63f6854a9e4c68fd99d56db410c0ebf61d2ed
F20110217_AABSZG tao_h_Page_042.tif
106420ced2cb3b363dedc5b9cbeb9e78
73b111cb054b4545a34c39830c6a52981a74d33d
1939 F20110217_AABTDZ tao_h_Page_085.txt
bcc14bc4396b482d15bec30aedf042f9
774a35be1857003612e0b58f16d39dd5fd90b6a8
F20110217_AABSYT tao_h_Page_027.tif
c422ae35a098c413386890214a826183
794200e8ffcd92acbd582794759e22730f655d07
22085 F20110217_AABTFB tao_h_Page_011.pro
c08ad24a8b38b11564b1e37a8f5502b2
f76e7e1265596c928e3bf81faa85218f52fe1048
1697 F20110217_AABTEN tao_h_Page_104.txt
7e67e818f135030ae264372f5a988359
c1837671fa62b478fbd3f8919450e6dbcb448029
F20110217_AABSZH tao_h_Page_044.tif
8c83cfb839ee96e539417c125ec8ef66
9e54d36af876b30b7e332f7ee60ec7d8418558c7
31766 F20110217_AABTFC tao_h_Page_012.pro
e58530d8bd10635b05b2a1262e64e944
2084fb1ddbd4a75bce07cdbd6ee37b40edc82f3c
1774 F20110217_AABTEO tao_h_Page_105.txt
b80a6246fd90ea423e7316f11a319de8
ce2727dd57b3ddd1b1fe7474e1b6b1a5a8bc483b
F20110217_AABSZI tao_h_Page_045.tif
98c400af8b88004426783b75131cbd04
7dea7b73b5dfcb978d3383280fb431c27dc5f061
F20110217_AABSYU tao_h_Page_029.tif
86029b01b335d71815c36280b09ec7b6
e12454680ae44fd521dbb080146eaeec683e5b84
43769 F20110217_AABTFD tao_h_Page_013.pro
6ea9b9be0723e96e8735511e2bd3e622
f742f637768af1e89e19aa9457960bdae62cf9de
1728 F20110217_AABTEP tao_h_Page_106.txt
97fc8c0944f0596109f112653fb56825
be9a58a3b37763e649dac7277a47de4ff78d9837
F20110217_AABSZJ tao_h_Page_047.tif
b8073225e9d8c3c20e13f201307927ee
4a2d1c011ecac585501294add5878cdc674bca5b
F20110217_AABSYV tao_h_Page_030.tif
a8082d8651e62c0e6af130a62b6cd88f
9c7d45bc9f384d3b80048046f2a2d42207fb5786
46555 F20110217_AABTFE tao_h_Page_014.pro
71f7cdb54a5046904e15e5c3cfa8adda
a7b3ee03a0574fa9eba7827b9086d45e0f662309
1758 F20110217_AABTEQ tao_h_Page_107.txt
f8f3947c6272eb645ef6effe13e46252
4b4b10c043429fa5f87c25405ebf9e5b9e1ccfc0
F20110217_AABSZK tao_h_Page_049.tif
6404e6495c1931a42776d7ecbb869be9
64637d5c282320fbbf84b05ce3efcbb7f4a8b30e
F20110217_AABSYW tao_h_Page_031.tif
9df89c4de433256a0925bba43f59b54e
6887943a198ddec10033fa860d98a4736e322dc3
39326 F20110217_AABTFF tao_h_Page_015.pro
244b0bb90a1e4d29f7c7158894127ab5
4d8c015b8feb0fe8948b16aeb1c83903bd75b82a
1558 F20110217_AABTER tao_h_Page_108.txt
dc753a739d336216b0c9cfc25e9791f8
c934d7dee572dbf4121189654c6916ddca390b52
F20110217_AABSZL tao_h_Page_050.tif
3fbf013ead3af2643233ac3e9623a5a7
1683f6f735dfdc38d2e9676c019ffc318934f716
F20110217_AABSYX tao_h_Page_032.tif
54f95dd400a1d0b462fb0bd03c6ea63b
7df60fa9df2acb7a520c2d62e8ded301a95231f2
29325 F20110217_AABTFG tao_h_Page_017.pro
7e0cbf8bb9e6e1246450c35965f814e1
47d7641955c10fb9f61dd484cccd8e680a75455f
7638 F20110217_AABTES tao_h_Page_001.pro
69290b4a1aa575ceb388163e7a95d52e
5cb0a7e724ac0eb07bec8bbca25bfcf8a31751a7
F20110217_AABSZM tao_h_Page_051.tif
525c7ea082b2cd6db2c8783b6f4bdbc2
1e49515135295ed816fa6b91ffa11c6fa2cb50ca
F20110217_AABSYY tao_h_Page_033.tif
e33a735a40ca001a1f98896bed341375
5456642638ba585fd2e5feb74bdf13a3a1d9f304
34473 F20110217_AABTFH tao_h_Page_018.pro
bb3dc8e4a739a9e45cb0fc46cf193789
8f2170094cc8bada5b36369ae614cfa3cda55e08
963 F20110217_AABTET tao_h_Page_002.pro
11e849729c52450e4f2544b15ba434ae
9287f86f5cc9f5a5f40117fe363202df7664e8f2
F20110217_AABSZN tao_h_Page_052.tif
03c46d1b0339feb5944dd98b5130f466
b272b3282c0cbee576353b54f52122bebee78e31
F20110217_AABSYZ tao_h_Page_034.tif
14c3937f17ce371953f666b7b6eee335
9d7ea3073ffbed941d8a3140389c9863fc0e9c88
14579 F20110217_AABTFI tao_h_Page_019.pro
82155f1fe0f4d49ab3fd00c5984d8f5c
6b22926235e0fe496e7be4c008c3471ad3d0299f
2742 F20110217_AABTEU tao_h_Page_003.pro
a5485e0f631bc7bcc19c5c72b4cc3768
3d47ed273191087340a64fe43f0ee3536beb1d38
F20110217_AABSZO tao_h_Page_053.tif
df8e3ee368a486e1fed22e9dd758ecf7
4b25daf78e59965db7aa3eb44b883c922dfb1b1f
42538 F20110217_AABTFJ tao_h_Page_020.pro
d4c4845518945dc9c62c3133fb636032
0d9ffabf03dd122d70508a8e87ccf233ca1cee11
67598 F20110217_AABTEV tao_h_Page_005.pro
8d9079e000851dc6574d2777a4c7c7ce
1a12ac8f3cda9ff8ac65003258465c9dff797e64
F20110217_AABSZP tao_h_Page_054.tif
914f3bbe0304c58e3835aefefbb8a896
6d1128c2c2c35c9d1e5d3d01fad3c0c9a917c532
49619 F20110217_AABTFK tao_h_Page_021.pro
5cb1557b7bf7945e15f53ccb0532a267
f203d93e9d0996df48727410dd1a5da7d1290934
57589 F20110217_AABTEW tao_h_Page_006.pro
9aa8d50c7de9cf44f000b9597a83fd06
8ba850d4535bb7dcb7f502993ecd4d5b6d08fc7a
F20110217_AABSZQ tao_h_Page_057.tif
1d9604e7fbb1542183400faeb0146342
af461e8077dd619587e149e8bf4507e0e98686b4
36374 F20110217_AABTFL tao_h_Page_022.pro
5560ee61084b862a9326e0ccaba9c133
1a2ebdd67775ee56c83ebc6b57146cfb5faf47bf
43665 F20110217_AABTEX tao_h_Page_007.pro
d0dfd8700bb62f5b14599a7fbfdb224f
60f212a22573d7ad520550995781c0c62362aff8
F20110217_AABSZR tao_h_Page_058.tif
7d0ca3ca7d57fd9cd18c36c335e4160c
4bae1704ef252342b3557032fc0cdfc454447f08
49483 F20110217_AABTGA tao_h_Page_041.pro
e9147114f37c2c00e3007a0df4bacf07
d7e374bbd30c97d76f6bbcbf33a2e896936e2d59
33782 F20110217_AABTFM tao_h_Page_023.pro
41ed22abcac4fd26e5100317a7e80b64
c4a9bfc5afb1db37bcb6e790762a01ab084cf915
19516 F20110217_AABTEY tao_h_Page_008.pro
5f0091a2ba41b2a7255306e3318adff8
94fe229bf6ccb55096931e06f83639ba6c85155b
F20110217_AABSZS tao_h_Page_059.tif
5ccb590aa53e2c93ae274ce7ee88ee2d
caaa4e4f62c4c96e52a3ed7df1d4c32da14898e1
48109 F20110217_AABTFN tao_h_Page_024.pro
8da70fb3319a266b07ecfd7d225bfbb9
cec1ff096932960bba4e668f5a44de20f0138236
59267 F20110217_AABTEZ tao_h_Page_009.pro
bafe67f4f320a182d3b3333c4edcf2a0
a511430936f2ad0b72ac0b8060c1dafd634e2576
F20110217_AABSZT tao_h_Page_060.tif
6bd130eb91d1413ec44f1b985c79755f
712eb0239fe1faa2b51218b54c8cccda7eb08b4f
43431 F20110217_AABTGB tao_h_Page_042.pro
8a2881ccd4fcdf8af9cb05618a82ce53
205fa80bfcf64e8e47a07148dc36ea41599198b4
38220 F20110217_AABTFO tao_h_Page_025.pro
e564812342a538631afe6bfe34fb4f1e
8a0e5e5d732ac97620f320d79f099a3280fae90f
F20110217_AABSZU tao_h_Page_061.tif
8835fe65db80d75a760448d476ffc90a
d26cf351a66e45d175f4c31dd34a063d4d6ff8b1
45129 F20110217_AABTGC tao_h_Page_043.pro
8af84129049e0f8bc461d9a242c20582
4fc779c6eea55b66b94f25ae7d50b5d10cb2e43f
36025 F20110217_AABTFP tao_h_Page_026.pro
4ead67c1b0e0855bafd45ada262d4c72
968624d8fdfc4e6c8618b48425f4b8a1f93e4d2a
46017 F20110217_AABTGD tao_h_Page_044.pro
79fe66d1fefa40fd733a549a59269048
806f14c6851616f1f9aaf9d18106fe9b4b1d19f1
45835 F20110217_AABTFQ tao_h_Page_027.pro
7effa37f8e613c6eb1edff228fc43133
ace5db9b8b3cba09b4712421e5c63bff76537eba
F20110217_AABSZV tao_h_Page_062.tif
0c0f28c3e3aa08e6961e72ea6279ddec
ce8d540cb2f5e93102d639e1c9a1f4316938a25e
6399 F20110217_AABTGE tao_h_Page_047.pro
e370ff7974b50e26a10931141cbdd2dc
bd53c8589529e4591d006eedd5de98264cccbc88
45525 F20110217_AABTFR tao_h_Page_029.pro
05a661581d9efcc733a08ceba10527b6
0605c5da365e787f79cbedb7b13b9cd456c74938
F20110217_AABSZW tao_h_Page_063.tif
4dea036c01a5cec29f2418b0b85f1f93
da8c1c4007234c87119694579684ffd8804d9f38
42834 F20110217_AABTGF tao_h_Page_048.pro
4d2fba38e58ebd62154f7fad67da82d5
79cc643a266e1fe3671dfa17d5670b0f4a1d597c
43004 F20110217_AABTFS tao_h_Page_031.pro
6a65703c7aaa9cc486d79b2b07a5c1bf
8b78c8c8164ee3db6fe8ed91a14c62aa7c452a68
F20110217_AABSZX tao_h_Page_065.tif
b65552ebd8f59dd9f139799720e0cd1a
803956be96d666739abb181d6eedd0645a835aef
22996 F20110217_AABTGG tao_h_Page_049.pro
d78d186e8cb709b3e4004050609435cd
b6392dcb2d5c6b2748d0f7f5e6b8ea82f36e81e4
16215 F20110217_AABTFT tao_h_Page_032.pro
6a685030278d633dc0a4da2613a6c53a
0a5a63fd3a396ddae89f55309e31608262a77dd3
F20110217_AABSZY tao_h_Page_066.tif
75cc13997cf8df4ae0f4804c9215de67
a1bdea314188e8076da3709bf4badd3780f9118b
54069 F20110217_AABTGH tao_h_Page_050.pro
c01c99e340acc2ef63473efb23709548
8402597773a1a51f1eac84a8f012e1058fd55797
36925 F20110217_AABTFU tao_h_Page_033.pro
83ae9b63d8c629f21b578ef1c6d4cae0
9e6136e5af7297f9a468e74c2decbbbd055d3089
F20110217_AABSZZ tao_h_Page_067.tif
c3a959053ff3b938f5c5c7fe5930e262
e6d8015f16edf91262151c66b023730cac1c2613
39884 F20110217_AABTGI tao_h_Page_051.pro
fa436c95b5d22f26b3f7867c728fa998
450008d7a710b3a9dd0ad2fc685dad2c4f004580
41852 F20110217_AABTFV tao_h_Page_034.pro
33cdd7ddd7b9c3e6c2ed114fd4e649d9
ff6ad83b90d6dd1264c996cfbd5efaf72c2bcbc7
44237 F20110217_AABTGJ tao_h_Page_052.pro
f41ced5d086583d19a842bab9d0a41c2
9a4734aa3014f5fd4540be27c4c4efb6cabfc6db
42867 F20110217_AABTFW tao_h_Page_035.pro
d6f347e9ccdfe547bfec3e98fd71f1f3
1e1e625ce571a9ef33f62f1a774f58f01237ffc8
38647 F20110217_AABTGK tao_h_Page_053.pro
eca8dbfa16b74e98432e26f38758f134
27a71932c8b98bef0e388a8233453d50414349d6
39257 F20110217_AABTFX tao_h_Page_036.pro
84e673e61d938c94e79ae4b3faee9980
47209928cdb0989119eed4af0a71bc4afce3a622
39289 F20110217_AABTHA tao_h_Page_071.pro
9081c82ebffe1058af22a3522b9eeb46
22dc0f508079caddc430ca2a41b147c2159fd5e4
42072 F20110217_AABTGL tao_h_Page_054.pro
d5ce0ae7b781baeb1928a71280c61d76
1aa33bddb5058d75d26b2d7ff545ae4e1a160684
48994 F20110217_AABTFY tao_h_Page_037.pro
328db285839a7bb5d8d2187e8b493ffe
e8a96ad71f26ed95fbb72ce9b6a4f49bab2d7d74
39530 F20110217_AABTHB tao_h_Page_072.pro
1a60f59e7b84a35a1f1474a5c8d199c8
97d9a249ecdf4eb03a2fc60565a52034bd7f9e9c
42042 F20110217_AABTGM tao_h_Page_056.pro
964e223eb2c1305980a028a96aeaa186
cffce70daa0df499651d8bd9e36ed7b1d2a746c1
46410 F20110217_AABTFZ tao_h_Page_040.pro
1f6aea62e4750ff598775369e0b3267c
90c77b62c24571275d2d1b4a77dc31c0eb3918b2
46739 F20110217_AABTGN tao_h_Page_057.pro
27c0d7f2fa59e04ec653ca6301341983
edc31f7faf539a802eddfdf11e362a9bd78bc4b2
29703 F20110217_AABTHC tao_h_Page_073.pro
b26c3efb356e5c33a088ecaa5cb47d3c
bdbbb2c1987d55fb05d9027dc3291459819e83eb
46162 F20110217_AABTGO tao_h_Page_058.pro
87b0cd4cbb019a127979292b1c01477d
b9ba7e57e7e7eb0be1d6ee840946e45994ffb42f
46374 F20110217_AABTHD tao_h_Page_074.pro
7358e0a161fc4068d2bfbd1b3faa697e
1fe1beb8bca3ad7a17659c2b0a3e674379921121
47206 F20110217_AABTGP tao_h_Page_059.pro
d293ae412da2867be09b1a82b9be4da1
d566f81d82c2ad3aefadb822678528f8bbe57546
45853 F20110217_AABTHE tao_h_Page_075.pro
b736887ac8542969e2416e77bf38d6a8
95f6a0558861902fc02bae0bf2c8cff4aa624272
44290 F20110217_AABTGQ tao_h_Page_060.pro
2ff95d3a26d5d6907e91150b630b3db1
c7cb35fd3dbae85eebbe632b3dbc731a44c53bfa
47683 F20110217_AABTHF tao_h_Page_076.pro
099258333dadf74950192a9e71d88130
ccb3d6b0aee58a2d51dc82b340990a485f098372
49274 F20110217_AABTGR tao_h_Page_061.pro
6dcc45aa0a9fddbfbdc2d2c8d080d167
fa87516170746ff011bff68971990a7b93fcde72
49493 F20110217_AABTHG tao_h_Page_077.pro
e7bbfb3d8dcbbd95995b5cbe70d6f12a
9457219cb4fe6b64b6a6d8ec2fd667ce08079831
16091 F20110217_AABTGS tao_h_Page_062.pro
1344f98541dfc5e2e52752c21cdaebd7
9afa6b7e84dfdb8ac2ff4fda58b3a3b1737a4fd2
46400 F20110217_AABTHH tao_h_Page_078.pro
39efc30d798b06baea7d3026c4755bd6
0977b2640b83433131f6afc318258d1a219ba049
43987 F20110217_AABTGT tao_h_Page_063.pro
43a7ca707098d8455b3cc402bd03116b
0b4450192d273f216b5ab3dfee24e3e1f4703385
47505 F20110217_AABTHI tao_h_Page_079.pro
08a83f47ffafaec0da8b34cfae2205b9
688e6ecb5bc32311198d8a59b03fbb196e95d960
48537 F20110217_AABTGU tao_h_Page_064.pro
bb265da4f5d9acd7c8c670368c7169c3
3cb522a92f5ae093af0f5212c10560fc547951f0
47269 F20110217_AABTHJ tao_h_Page_081.pro
88cc19f74359ce5c9df04b84aa435ff2
c087054ed561c1017ac4eaa41c5a39502d45c52f
44691 F20110217_AABTGV tao_h_Page_065.pro
c32b8c56c4a4f9804be269c38723ca53
e45a5f0c2cfc58f777c1669b7a047a3edbf25fa0
42416 F20110217_AABTHK tao_h_Page_083.pro
000a86fcc0131a1336831c04c8872abe
ceede25387f14eec8e6edcddcda9420916139991
29886 F20110217_AABTGW tao_h_Page_066.pro
5405cc7139cef50c5ee38a601214d56c
b14033061b9e570b3060838e74e41a24871ea6ec
43119 F20110217_AABTIA tao_h_Page_107.pro
7fb0d9177e55cb129672dcda1edaa70f
08d30b5469d24e8d0214f672b6b939d945deda92
50641 F20110217_AABTHL tao_h_Page_086.pro
dbd0262c4ad33259a9c80edc92b15d95
e2dbf8d9a382029211ef73a2652554f845732167
34457 F20110217_AABTGX tao_h_Page_067.pro
ce53ab8519a4b6bd2b14558f809aa0cb
d772288ddfe92df40c092fb3688391bd3349b720
37935 F20110217_AABTIB tao_h_Page_108.pro
bd5696fcc4a75294c157a34a1c5f8a1c
de9b2dedd6af582de07d14d5cce765e99eeed6e3
46894 F20110217_AABTHM tao_h_Page_091.pro
2acb5ffd8034d7130730d8b8a8a645af
783f2854130adb7638b495b2ca5b3b1fe8bba22d
43721 F20110217_AABTGY tao_h_Page_069.pro
bb3ab2749281765e597b045c7288ceaf
349e067862dc3cbebcbefe180d6c98569247716e
18307 F20110217_AABTIC tao_h_Page_109.pro
b35181eeaa8247b47ca800245c653d33
475f2b38a229cebf73dce9dfaf115cfd6f3946d1
40061 F20110217_AABTHN tao_h_Page_092.pro
2f9a39fb5df1491f0a1eb233ce60c1d3
83cbdd75bf4d32e0d47b6c0d2690680c9a80ab31
37415 F20110217_AABTGZ tao_h_Page_070.pro
bb96ffde605cd663ebd2486f45ac1fe6
52a5d6d1f0101b28e0c0ce9343f6cac60e0b2fd6
42639 F20110217_AABTHO tao_h_Page_093.pro
2f097cd6132b2a9c78cb21cb528e86f9
eb48ce32dbf9fc2c60225181843bbdb2234d4c6d
25211 F20110217_AABTID tao_h_Page_001.jpg
2a5612e95a409b5853943fbcd106aa0c
5b95f578180dc5e314eeb49e549e35d18d50e802
39502 F20110217_AABTHP tao_h_Page_094.pro
b794b3a5249136e5d8963408d5426dcc
acf8199709c85ee327ffe4a260efd02243fa817a
7607 F20110217_AABTIE tao_h_Page_001.QC.jpg
5a58bcdd27990d573c4e28834dc77fa5
b9c42b9a5d27dc91ac11c31625064b28cb3ef757
46636 F20110217_AABTHQ tao_h_Page_095.pro
2a96ec8f6d046447c616e63b86cd751a
a09f6c9812b34081adc073ce592c2f93f4a9e5b2
4215 F20110217_AABTIF tao_h_Page_002.jpg
d0046fbf7917ee4a1a178fd03e1b1338
6a41337616cdcff91c38f3628b0ead61a040e102
41707 F20110217_AABTHR tao_h_Page_096.pro
b08d67348def10dfba1543321a3c0d23
70ce804983e545f6039523686672a179b797e659
1394 F20110217_AABTIG tao_h_Page_002.QC.jpg
2441c238442b259eb9ab668f70499afc
44dbfbdd942932f50eb6beb85f722985f468ec71
39857 F20110217_AABTHS tao_h_Page_097.pro
36b4cbe0480bb9611029740f6a898310
eeb727f568af9fb01ae91687f6ed199f373b5481
8620 F20110217_AABTIH tao_h_Page_003.jpg
31a428fe612e880ab4b839c52561b554
67c26cc77cebc85bb549365c3fb8863e131c0db9
43950 F20110217_AABTHT tao_h_Page_098.pro
fcc34db30ee70333e11ef856df613cf5
4a4ddf5b577c12c82e019b010a6dd418a6e2beaa
2149 F20110217_AABTII tao_h_Page_003.QC.jpg
fb3c20b3b4f869f74077b87fde877937
a679679f0e21acf287612613b4ea7b157b98c86f
44769 F20110217_AABTHU tao_h_Page_099.pro
274fe4312955c3300da66381e7f2a3a4
c45f2b70c696693d5c9626700cf8cbe161d3dd32
23308 F20110217_AABTIJ tao_h_Page_004.QC.jpg
5368c1e6327f70181399f2dae864b150
a19713a87b58083dbf77073bab0b469cb8fc6816
46521 F20110217_AABTHV tao_h_Page_100.pro
903a8542f3fd88928e62aa61df9f0b99
68c8f8a440aa2bd170f77082837027bf91b56bb2
80317 F20110217_AABTIK tao_h_Page_005.jpg
58fb0039821f0cff7b0cbaa66fe8e7fb
c014d88e91e44a2c9732a7176144c9b4040a1f2d
48298 F20110217_AABTHW tao_h_Page_101.pro
12ff5ac5643c8a5b0a2f9d1240bd722b
63b856810e0e55f1238c17123afe50018d5fb11e
70197 F20110217_AABTIL tao_h_Page_006.jpg
29d4baecc0ac424fe95180ba48660eae
88555f12afce26dbd21810b7838071929e389ee3
42920 F20110217_AABTHX tao_h_Page_102.pro
ad0412dcafe919c39e451838f8865df8
f7de5f84bc87363a46392929e71f4fafe027aaa3
95054 F20110217_AABTJA tao_h_Page_014.jpg
3cbfaf220175b1d8fcf8b61c34c05e94
a644d150e33d2a7959764bec56449347a648f39f
67179 F20110217_AABTIM tao_h_Page_007.jpg
fba9c9216e107c87d5e4de59452a568b
e5524d15a04fe36e80b8d3dce78877ccfc999078
44437 F20110217_AABTHY tao_h_Page_103.pro
0bffe52ca7b04024ae8c4335c763e64d
24132e6db89641b1d8842db0db8f77551538a588
31111 F20110217_AABTJB tao_h_Page_014.QC.jpg
74b92943c8d44f80e6e7342bf1f978e0
733b81c07d658c71e190e5f01f546ec1a17d14d7
19091 F20110217_AABTIN tao_h_Page_007.QC.jpg
2263d929eabaf2483e8435a0c74e7487
8f6aa9fadbf063f56caf74f0de9c0bfd0c6139c4
43607 F20110217_AABTHZ tao_h_Page_105.pro
79788cdeb81860baa7c0120cc85b11d3
5666475459cabfe0e299862fe126d761cd0b4391
80005 F20110217_AABTJC tao_h_Page_015.jpg
20d109905605cd7848178d2024c43507
69cef19fca04455af23670fae8fa558a36d520af
30871 F20110217_AABTIO tao_h_Page_008.jpg
8c11e1bbd3317fde5fb05a7332f5333b
b222275bc4c55238776c76aeacece665d090c15b
25028 F20110217_AABTJD tao_h_Page_015.QC.jpg
b889c5cf69ea83ccfcef28347887bb23
3c8dc964ccda591615a8d1aac59eb30e3e1694a5
9509 F20110217_AABTIP tao_h_Page_008.QC.jpg
48f40536ffabb07196bbe7d092438fdd
6ec0394a92fbf5c405a1baa705e878718f0d8908
90279 F20110217_AABTIQ tao_h_Page_009.jpg
4bf8dc639c9d6f0840740840b940fb34
b02631a0b5e1c0939b9062f20451dcb95fae2bd8
74781 F20110217_AABTJE tao_h_Page_016.jpg
db7131e6340f79786df5dcff3ec9915e
9e40ef12356418859ffa011237e9bf8cb6d961e9
26394 F20110217_AABTIR tao_h_Page_009.QC.jpg
e4cd5963122334de7b63da54ad9835af
65f12b6ac31adc570a0e5aa829c9d42430236bef
24615 F20110217_AABTJF tao_h_Page_016.QC.jpg
522e8fdc6b386e6717c1c88bbc0111cf
102474cc6c92887dbffa27a54506360a0604ad20
98129 F20110217_AABTIS tao_h_Page_010.jpg
9985c8710ad722039d3e69bafa67a5e2
c64670c7f680896fa09f4e0672a8f59c92717cff
64813 F20110217_AABTJG tao_h_Page_017.jpg
055a7f8d4247294efa3d476732d2d95c
6dc0c511edbae2dc793511d2be451a87292bf1c4
28157 F20110217_AABTIT tao_h_Page_010.QC.jpg
741adaa20dfe6f0f995cc5f8554d3470
ef8f9146f5bc205f4813875aaff8b5bb9275262e
21008 F20110217_AABTJH tao_h_Page_017.QC.jpg
ee69bfe45d56e92ae7aeb2524f952595
b2a96971047fd11350ea812f6f58f9342d10fb8d
32653 F20110217_AABTIU tao_h_Page_011.jpg
3d08d0067049ae27693ab60c619ab725
63dc2b0918fa7ff889af320a36dce39408ad48f3
63049 F20110217_AABTJI tao_h_Page_018.jpg
55f8d948750a4c3709cabdc70c8e82d9
b0afeb652c991c819ebfb81dbd545f99889eff41
9473 F20110217_AABTIV tao_h_Page_011.QC.jpg
50e309d7f7d4a562eed08bc0a6a12757
b74cc79dc95bf607ed638d9dfc82f437c7f83daa
10774 F20110217_AABTJJ tao_h_Page_019.QC.jpg
0fb377bf8c3a0ea5ddf164f39c066e2c
5f6049d5e25a29a040f834d2d4f955adccf3c88e
69029 F20110217_AABTIW tao_h_Page_012.jpg
be8d26ddf896c083690be03871f3c518
88b96ed7f960ec0663696015f39ed7050d728160
93557 F20110217_AABTJK tao_h_Page_020.jpg
a40186c058b983050012ccc6de54b58f
fbc1a02095086af98891cf874cd9a53c603e9a6e
21869 F20110217_AABTIX tao_h_Page_012.QC.jpg
6b17f19edef72ea1cee26592404d2bc4
403476c742dfc951a4f8b4be698ef7ba95eb90b9
96365 F20110217_AABTKA tao_h_Page_028.jpg
07c42e32c904bc67e68292c476276bee
715283a08c3ce1612d864b1c4fb0711c5cf84ee4
29914 F20110217_AABTJL tao_h_Page_020.QC.jpg
22010c022d2026e4dc6906f2626d78e7
a6e2daa66fe69c7165e432a4549837db701af7ab
31102 F20110217_AABTKB tao_h_Page_028.QC.jpg
7ab2cbc86a1e35e728238f0d8bcada9b
b40ec30d764a2a772c6c879eb1b2abee561120cf
104637 F20110217_AABTJM tao_h_Page_021.jpg
70406695c38e490d9d003f453d377b92
42486cbe13dae4eefbe4318465c41c5874b5ebc9
90301 F20110217_AABTIY tao_h_Page_013.jpg
74069783816bf700c81f6c4fbc1801ba
4699044cc310e687420e44c2eccb6a5abeb6e054
99368 F20110217_AABTKC tao_h_Page_029.jpg
b07dadc1516e62381bf4c8019d685da3
33f341d1841f53b7ab69244ae351b452c77f8907
33465 F20110217_AABTJN tao_h_Page_021.QC.jpg
950f3288c4dee54071013494df44d14c
ab3fb870a4741832b78ae5b667e304145e1e590b
29350 F20110217_AABTIZ tao_h_Page_013.QC.jpg
b5318c6a0bdbebf594f2d38e59b0fe85
e0d698778e5d754f2c6d47b0bc2736e7ea159f99
30447 F20110217_AABTKD tao_h_Page_030.QC.jpg
5cf4633ac9e144143ffaa35ef509888a
51c372592f1c9f7f91a9fe35f3302a88e624ac12
73721 F20110217_AABTJO tao_h_Page_022.jpg
82a42efd093f9229c531a78392605d1a
b84ee535b7b550468a18f6f5c94f2aa1a54dadb0
31684 F20110217_AABTKE tao_h_Page_031.QC.jpg
c54c7fe41878347222f0e2b0a09f3675
561fbf2a6d9d96c59c29883d1e68963bcc1803f3
25004 F20110217_AABTJP tao_h_Page_022.QC.jpg
f12e5ac42a85fb7a4263bc20e91c9132
ae881d84d9299cf2c858ff983bd5ae65ae21fe62
67608 F20110217_AABTJQ tao_h_Page_023.jpg
f4d147d72a2854ba90ac3e5dbd1e9c79
ddfd3b40f097b8dc590dc5f521c14b0ef0a66297
38683 F20110217_AABTKF tao_h_Page_032.jpg
5a78708d20428944330c5479c217812b
b4d31fd7cbc482627204700d7de5206893abb613
22104 F20110217_AABTJR tao_h_Page_023.QC.jpg
134faac39c4308491e2787dbe753ac48
f8e9303c0b09590c8f59139c1c66554a7a95be3c
12486 F20110217_AABTKG tao_h_Page_032.QC.jpg
a6f176f87833cae62c196c37f5db3ddf
495b559f60ae157474ea43c5bb8d43297f4a7a0d
102082 F20110217_AABTJS tao_h_Page_024.jpg
3dfeb165d9ed735864f37dec4ba6eb72
0621f41132078dfb6666cf9361981f5da3c17cbc
79982 F20110217_AABTKH tao_h_Page_033.jpg
ea98b1a0df58dcaf2c0fc6ae503f6e85
d8f8aee0aec877ddaaca4fd5ba597e40e6aa8a26
32436 F20110217_AABTJT tao_h_Page_024.QC.jpg
a47e98671f750f83ac51b803c356d790
fbb0d73b7e2a860fc25678e5b2e2b32cb1eb0514
83507 F20110217_AABTKI tao_h_Page_034.jpg
715d322aad6a5be4f93f9b8f1a4931b1
52a715f29008a04ccd6bfe7069d95daad49f26d8
76838 F20110217_AABTJU tao_h_Page_025.jpg
d6325699651135bdd0c87e2774052548
024cbfd808f0ce8aad815e7160fd06ae3c213fa9
26827 F20110217_AABTKJ tao_h_Page_034.QC.jpg
0fc53aa5d874e8030b2388f094c00e21
07988ffc1d38a5468c0f242432cd2bd8c04eb869
26191 F20110217_AABTJV tao_h_Page_025.QC.jpg
74f69a09fd68a165bb0e7e88f3f2b271
d726f6642605074f07b6f8162f0bacf7e584ca33
91571 F20110217_AABTKK tao_h_Page_035.jpg
6ee5ad8a81d687827e21d0cc4a9f99b4
b0eac45a581c06db3d14a4dc29a9f4b470a2ea2f
75153 F20110217_AABTJW tao_h_Page_026.jpg
24a28a4b1a4c05d56351474e6b523b91
2992ea5bd19675639d2a75c38c1c89a3a6ed89cc
29407 F20110217_AABTKL tao_h_Page_035.QC.jpg
21158ed9c73c866873c2d31d86ec2aa5
7d8db01f25beef530e0ca76439c28826da099856
24349 F20110217_AABTJX tao_h_Page_026.QC.jpg
eddd7eaeab8af490bbc9d4aa69d8f977
c83b98432b365e9b764c411a5d5e06f579eb19fe
32914 F20110217_AABTLA tao_h_Page_044.QC.jpg
6f0d087eda33285a176ff16c3e2e88f2
f88139a105e500ba07bafa01e782e6aab8c53602
79465 F20110217_AABTKM tao_h_Page_036.jpg
fb41ef606ba2f7a7747a8d51b81b210d
a88ff805eab59d0f3e51c2aab2d8143b989697fe
90420 F20110217_AABTJY tao_h_Page_027.jpg
a981a615478c55378ed79291d16d5f74
a3b7f7953939b15dd38a8a10cfe8a5bbecb3ce9f
105342 F20110217_AABTLB tao_h_Page_045.jpg
17ac8eec4c0bd44eef53c4e68ba356ca
e4ac9725b1d404a824b82aa44d568eb5f3140308
25708 F20110217_AABTKN tao_h_Page_036.QC.jpg
964b494081a517cbb716845c03a99775
7d7658af834615da6b5ea7f934900924a644f9ad
29231 F20110217_AABTJZ tao_h_Page_027.QC.jpg
dcd944ef96eda2e533c3e9444c20a27c
91e1b6c854d55c848fee71d9a0e4bad957d2f966
36907 F20110217_AABTLC tao_h_Page_045.QC.jpg
8a81c25664b56b4cf9b453e21011890f
21f55815b03c560f1497e1fcaba034770dd5a3fd
104591 F20110217_AABTKO tao_h_Page_037.jpg
85e08edd90fbfa6527e712b25eabcc23
1ec446ae4d6e647cdb14574693d9902bc875bfb3
100167 F20110217_AABTLD tao_h_Page_046.jpg
ef445c2baebe9133a9ea19c26ea7cc40
a7ac395ae9f975c75f3d5fa6f97fc77c202ab45d
32361 F20110217_AABTKP tao_h_Page_037.QC.jpg
42596352e31729c76b9df79fec50b756
c1dc6dae5912cca4ccb51bc94da4da27accf2756
32958 F20110217_AABTLE tao_h_Page_046.QC.jpg
b9643419d660d21d2194093805a4dcb2
bfd0aba67eb9f4639a2f7aee532abe9d359caf91
100326 F20110217_AABTKQ tao_h_Page_038.jpg
2824a524b6e76f0f11bc9cae40a0048f
224380825518f56cf35a90d72dbf2bb2fe42a26c
16495 F20110217_AABTLF tao_h_Page_047.jpg
9ff0f6b4ef3d534e39be8005c6660557
fce4f14ffd30eaf15835cd9acaedacdca2fd9ca8
33049 F20110217_AABTKR tao_h_Page_038.QC.jpg
f283b7019d92d446333b657e2610744b
bbca6078e8ac4dbbff59082861c1ed03d2b38ea8
99250 F20110217_AABTKS tao_h_Page_039.jpg
ee3b95c7f5a1b2ac2d69428650526d2a
9b1c8bdec5d9ba092724fbd642c590ed261a8a1d
6403 F20110217_AABTLG tao_h_Page_047.QC.jpg
e5a5fa7b294028fdbb2b3c1564b77403
67c3a96ee478df37f6368ce95e96710f34d99ddc
32655 F20110217_AABTKT tao_h_Page_039.QC.jpg
6b9c33fa60054ba7c8476baa9d9e05ef
bc1a5ce18aff07e2b2c4dd3404bd2c6c5f045918
92757 F20110217_AABTLH tao_h_Page_048.jpg
2241b75c07f70a7e69577af2902b2681
0fbbf5a4c628079e6214b23b338f44bad841072d
31449 F20110217_AABTKU tao_h_Page_040.QC.jpg
f1c02048026a2b6dd83ddcefcb85f6ee
3a68471301547a2063d50601f4e549274837bcac
29102 F20110217_AABTLI tao_h_Page_048.QC.jpg
12ae1e153fa85874fed5468e8651552d
db1d9d81fed752243aeac0a57c5ef3e5323864ef
34874 F20110217_AABTKV tao_h_Page_041.QC.jpg
7dfdd492b99a0903603a0e4d9d47be3c
8b4b72071395ee45ee5b2c24c4d9875e4898962a
64617 F20110217_AABTLJ tao_h_Page_049.jpg
58ad1977c09a2022b41c7451a55dc3ad
7f7e965bca64cdb7f79ccf425d3830abdde5c827
31240 F20110217_AABTKW tao_h_Page_042.QC.jpg
93f5eddb861a3f7a1f1133a90b652527
597fb2ab7f331af1f4c84ab5ccb0528240cd49de
22063 F20110217_AABTLK tao_h_Page_049.QC.jpg
802e3a7d82f2d22ba5ad1b23db54e870
6da6972e3b1338a84cd70f35fd60227946a85620
94986 F20110217_AABTKX tao_h_Page_043.jpg
0ab60c05f2847be32477b735d10436b7
a905fd4849cfb53c90c6696c5d6845d1ef907f9d
34328 F20110217_AABTMA tao_h_Page_059.QC.jpg
8f9af952db4ff1f4465c7e9776f868fe
1ced12aef6fb9ebf6bf775be2f7879113037dc65
97062 F20110217_AABTLL tao_h_Page_050.jpg
096f8c8d469ec5118e23edff35dd3fb9
96a063668bbf35c5030ecc0748ea5a4fd3b8dbc0
32661 F20110217_AABTKY tao_h_Page_043.QC.jpg
f2f624fb9d8136d5c6d607bf9ea991e3
0bc9ea03615f93359020c6d867c080fb377c4238
31548 F20110217_AABTMB tao_h_Page_060.QC.jpg
661f418e86b350fed7a665c23792f16e
26b5fdd0066aa09067d21996dd8ad4feff0acfe8
72859 F20110217_AABTLM tao_h_Page_051.jpg
e3f51d96ab78df534366a5ca3628e662
66636a1cce8d9259f6ff01b09f9cb65c5ea350b1
98383 F20110217_AABTKZ tao_h_Page_044.jpg
c93979728f3e5c189696e9030a95be3b
0965b335f492b12843031c845b03e64e4c02a980
34783 F20110217_AABTMC tao_h_Page_061.QC.jpg
c566e3c10562a83a62596b29c4580402
80e12fcb94a7a5edaff22e8f3ed30a1581da64e2
79809 F20110217_AABTLN tao_h_Page_052.jpg
e5583a48039cbfcbb759d47e72d0c8ab
0d6c4f8a5ef6fe730d02f6e9c30da39b85821ee4
38255 F20110217_AABTMD tao_h_Page_062.jpg
281270eecdece78c89fc2b8f831f96e7
88d2b1c51301242bc40ea94b6574000384ba6ca5
25898 F20110217_AABTLO tao_h_Page_052.QC.jpg
6a23aebbe32e87fb67dc59a53629af13
499ede83545956ba1d0c8410ae5cf7483ce7bcf2
13357 F20110217_AABTME tao_h_Page_062.QC.jpg
9a25d4ce874c085152163116ecec1159
716c6b653d60ec44e8a69ba2b2e2da005686b0db
24837 F20110217_AABTLP tao_h_Page_053.QC.jpg
0f45ce4b82ef0b9db55923ebd976cbfb
d9a6ed1603e0f9d8d070a537beed8dcfacbec223
96522 F20110217_AABTMF tao_h_Page_063.jpg
34e714e290edb50273d1add327164cd5
5aae149ca473d3de5665ffba06ee06b13fc6e967
88090 F20110217_AABTLQ tao_h_Page_054.jpg
b92ac6a65811b7923853321cf8c35ae4
12191180ac95d86800ed677115304b0c75bc7c39
31423 F20110217_AABTMG tao_h_Page_063.QC.jpg
e9df100ef83f20a8d949218a3d5de2e2
0b3dfd19c72749ad6c4acc99a0c8d15541d36277
27112 F20110217_AABTLR tao_h_Page_054.QC.jpg
14a38b11f204dba1ca8c8ee43ab7b20f
34bc193ca00be3fe2e35c535ba1285a5390eb698
87503 F20110217_AABTLS tao_h_Page_055.jpg
6a27729a9f097755b98b0d156113bd15
227db235e239f4430e5e1900e975847fbdcf8c19
32826 F20110217_AABTMH tao_h_Page_064.QC.jpg
cc6f75016ebad448fb66e11411277905
43a11c7aadd6f780e18434dfcbe99fb5ae4b8195
29490 F20110217_AABTLT tao_h_Page_055.QC.jpg
b48c446f77c502cdd268e57d49b575c7
d09d7fa1f66a297c16702fc64a758c6e2e0ed5e1
91443 F20110217_AABTMI tao_h_Page_065.jpg
838a6b2e0a63b7f26b2624ce28b9c66d
1a33056b44609f49cc50f1c7e4f7ac94a78f8e85
28158 F20110217_AABTLU tao_h_Page_056.QC.jpg
9b87369555d8d0f09b5d69742279d981
a7bd40e5d62ebf3016ce5594e8a60b081e7966c2
31024 F20110217_AABTMJ tao_h_Page_065.QC.jpg
ac4f97cb79a150b365d8545f5419d023
24c78131cdb9f09894bc4cd030883542a086ae16
97112 F20110217_AABTLV tao_h_Page_057.jpg
a14f247c0a89de18d0c537f13adcadad
e8266a968e575868259aac3cc0ef7f557512b629
55185 F20110217_AABTMK tao_h_Page_066.jpg
16c97536a0f8a2d6d8b66934a2126eba
b84c34f1f9997f90afb2724e2175190aaad6a000
33163 F20110217_AABTLW tao_h_Page_057.QC.jpg
a6a0fb8266fee002a7bb448f9758d8a3
39e63a2674fd78370f9904a81eb7cd3679e3aa88
106249 F20110217_AABTNA tao_h_Page_077.jpg
a6cc373f56c5fbeb1c93755d6430581d
5bb67d1852995f43847f757fd28a75d823dc93eb
18959 F20110217_AABTML tao_h_Page_066.QC.jpg
259a30303264f56a5d92b60bfa4bffa2
488640825da409b5e227bd4f26811bd594a0a682
99036 F20110217_AABTLX tao_h_Page_058.jpg
730a14011484ad01d4c1cb1050045cd8
f46d5633e5dd6448d90f6d94a975fd12417883b0
35396 F20110217_AABTNB tao_h_Page_077.QC.jpg
bf47a6cc682c59fa02bbf23efde2a510
2e205b71e2181ecc653920a5fb7e74ce0062ee75
23087 F20110217_AABTMM tao_h_Page_067.QC.jpg
6fdff473ba6f09a3242d9b6b50dfc934
489168bf64cd78459c905f7e431c5cec851d1d7f
F20110217_AABTLY tao_h_Page_058.QC.jpg
9081cf4f4f72c4499f1fed48d95fc485
155e3fabeec72c2be55ebf0931773b19dac93000
99238 F20110217_AABTNC tao_h_Page_078.jpg
abeba735745df431bca50d4d87a038ab
34638c5c34f065a8661cd757c966e84b5d6c738d
25460 F20110217_AABTMN tao_h_Page_068.QC.jpg
30b344b6c62ac9f6b4e4694f5291711a
86c47bc8b64ba204204826e3b3c59910489b4867
102602 F20110217_AABTLZ tao_h_Page_059.jpg
1549dcdcb2a897dd988186d8f41a353a
fda23152d4a4a5b82603c731a78fc10a8bc57b2c
34649 F20110217_AABTND tao_h_Page_078.QC.jpg
6a50b7be63ccf1b4f33c81a4a01d960c
ab860ec54716cb0cd66b13aaa5ceaa4d726e920b
87715 F20110217_AABTMO tao_h_Page_069.jpg
9addd24cf775798d89db089bad47c59f
78e4b242d49f72dc275ec1e0559a450a2da94951
102778 F20110217_AABTNE tao_h_Page_079.jpg
58868c6f3744d757f6feef532ab2d4e2
334087445cbb8a4782ee7ff4d8901e0e12dc8d15
76061 F20110217_AABTMP tao_h_Page_070.jpg
66df07933daffdad0388b54bb7f58c57
8f0baee399dbb73b4dd11017ce57795fb05eef6c
34902 F20110217_AABTNF tao_h_Page_079.QC.jpg
9d35cd23d0293d719751514c8b3e9592
90529e12925ab61bd9ddee3078321b956cb7a8e8
24658 F20110217_AABTMQ tao_h_Page_070.QC.jpg
fa86a2309f08ec80181305c7ed8b7ab2
6f43643491da2ed9a4711bd68b7b721e0d448c74
98311 F20110217_AABTNG tao_h_Page_080.jpg
1badf9e77460c7433c5591f72c350862
8f47de89ade36910d87fa11cd127f00c88c0c48c
76579 F20110217_AABTMR tao_h_Page_071.jpg
59cd1e6680a5dadf1ba643cf415931f4
c22fd7b9c4aec615a6f211c4e222f64682f0b7a2
31613 F20110217_AABTNH tao_h_Page_080.QC.jpg
9d24dcaf11c155f0fa771112847da294
f281b5ddde982c07c77f2f9408b64586b3920f13
25540 F20110217_AABTMS tao_h_Page_071.QC.jpg
8424e4d7f589066e1e54fba0e6374540
6ee2c261cf42fc4a80c5df70124151fad5de304c
83281 F20110217_AABTMT tao_h_Page_072.jpg
9e5c61232dcf3ab16b73518abd5107a0
6c2cb8e544388b613d0d5e444d624a68cf1d8f5b
101221 F20110217_AABTNI tao_h_Page_081.jpg
816ce5930b1ddb86f340d898c14d3612
476f2904e6cd29a063ae773b3f34f7dd4fbceafb
26279 F20110217_AABTMU tao_h_Page_072.QC.jpg
552e63def57767b72db7b7b474a4a89e
48b0dc602c1c864c52d712feef144a37d33cfcc8
34108 F20110217_AABTNJ tao_h_Page_081.QC.jpg
78fa64d711f2ad1492e63425132a9d63
060d8383f8cab28f5655ff00d76119b756c78225
19375 F20110217_AABTMV tao_h_Page_073.QC.jpg
ff1ee90af9014b9e82f40f972a41f3f3
f57da42ed879b31b8dd22a913827a987abbcce59
35256 F20110217_AABTNK tao_h_Page_082.QC.jpg
a20978e553ab7b02d890face377b3acf
0a47467db052909be83b76998b956c7a76ecacbc
100502 F20110217_AABTMW tao_h_Page_074.jpg
87949d063781ee89eb93e8c5c61fe9c3
2cda3ffc5c12b9dbf18f2a72ad7ac8ed88a22358
92706 F20110217_AABTNL tao_h_Page_083.jpg
e9c20af1a3d0f04469e921de3c759fe3
d7ff1a9546c7f46fa0243c9854fce97b26db5728
32072 F20110217_AABTMX tao_h_Page_074.QC.jpg
5e6f1ff6f7975d508c128ab7b2d65232
74d66e3a01a369ca45cf91a8c73556974dd3d7b5
34394 F20110217_AABTOA tao_h_Page_091.QC.jpg
938cddddadb7863f699dc39661110b06
3a4d74ca08d3e1ce603bc2d7e3d8ae183a1fb151
29900 F20110217_AABTNM tao_h_Page_083.QC.jpg
6baf370ba8e1f0b6eb8294c17a27169c
1197d1888ea50368dd977b403caf4f5703148f80
32875 F20110217_AABTMY tao_h_Page_075.QC.jpg
0f33779aeec2fb8f11388f83e1c00192
c4c74126dff4b231b9292595c0f902c4e3e0c6b7
88012 F20110217_AABTOB tao_h_Page_092.jpg
8bb579bd622bc6765172dab20d34b6ba
6ce0cd694f2990c914404d2250f5c925f94f42c9
27570 F20110217_AABTNN tao_h_Page_084.QC.jpg
9cc642b7d2b704b9f3dfcfd2df2915f4
48f270ad92ceb175f0165921b6cdda0b722c647f
35041 F20110217_AABTMZ tao_h_Page_076.QC.jpg
faec8e0e36adea690b48e3c7adfad981
9218a23aaca9230806f50261c8be5426e48462a0
80869 F20110217_AABTOC tao_h_Page_094.jpg
01c3d44dbdebdbca0135082494836f9e
00e08b6ead4ca67deeaa14792f8045c62b41ab3f
75972 F20110217_AABTNO tao_h_Page_085.jpg
bace1e69b247a7d9a5addcaef115d2aa
280ef5830e34a9435f3c9ca5ac5f4c10c989275d
92098 F20110217_AABTOD tao_h_Page_096.jpg
b9be8ffcb1d8dbd791e939c8d2a4518b
f519aa19b300e26e144e870b8b05e0ba4f579d9c
25564 F20110217_AABTNP tao_h_Page_085.QC.jpg
6cac4fcfec1b5b6276ed389966f3a647
1e4dfc10791879ee8db4a8f70e8fb7f6d6509b0c
30152 F20110217_AABTOE tao_h_Page_096.QC.jpg
caa7f28b67241454842e1b7cfc74eba7
716516e3e375b94d37877372d991e253d84d66bf
103374 F20110217_AABTNQ tao_h_Page_086.jpg
c218150e2aee1fe0f8e1c3284bd5e083
d0ef1c4486bccba74d2bf826d3c6325d14ba0b4b
86308 F20110217_AABTOF tao_h_Page_097.jpg
631badaf9d3fa6be90e21ec508a9c389
e8a2bc6f1ee6b7b1fa46a9049c7768ebae6b92e1
33372 F20110217_AABTNR tao_h_Page_086.QC.jpg
cfd7399e8ca231a1d192994e277de670
aefe0c8939581c6f546f66521340c49cba819b83
28532 F20110217_AABTOG tao_h_Page_097.QC.jpg
79d08a1631ce4b5d9128678f6466e33f
0da8a714cea30c13e480ce1669baf6ac2a088c4d
76984 F20110217_AABTNS tao_h_Page_087.jpg
698a41b0cc3b23291d9c97ad2586d967
8d906a04037bd5fa32af98a05fa7f249000c487c
91981 F20110217_AABTOH tao_h_Page_098.jpg
6b87283272885a6e400d625dfd51684f
393da21ad6f25b70212b2aa02c4236eed93fd5ce
25821 F20110217_AABTNT tao_h_Page_087.QC.jpg
b14fc23b621a45387758a671eca5c2d9
f0e993650944b70188cecf39e13b5fce34fd796d
29729 F20110217_AABTOI tao_h_Page_098.QC.jpg
50695206d376875d2e59b2d6551bac88
19ec88603d8e479cf9c586303705b30ee3ee3768
75129 F20110217_AABTNU tao_h_Page_088.jpg
97c05ac40292e0db001b0a2af06208fa
e98330943a0aeed76e3b92b72472404a9998d700
93591 F20110217_AABTOJ tao_h_Page_099.jpg
6b2caeff82eec335bd1dfb9d3a48498e
1b6556c977bcd8405e0e4d9df3e1a1f55119202c
24443 F20110217_AABTNV tao_h_Page_088.QC.jpg
c8a288e3d5dd0d33418ad7c26202e69a
e000f7474676b0b22e5babef9d3572be7acb5198
29596 F20110217_AABTOK tao_h_Page_099.QC.jpg
9068358002e8c4b88167b513cbce1ede
d51ce27aa655a6fc4eee8b695b74e8fb8cf27b1f
30356 F20110217_AABTNW tao_h_Page_089.QC.jpg
e2d2f99bf7d497ae062523548bcf87ff
60f5bac19b92d904d7b6e1a78f64502267deb290
81213 F20110217_AABTPA tao_h_Page_108.jpg
0661e232f3e48f3beb2321444ecaf680
a11236fda7905bfa50dbaa6740394a0f4b15bf0c
96226 F20110217_AABTOL tao_h_Page_100.jpg
2dc8add6defabd355ecd3870e68a57cc
fc6db01ad389ed0869fa0b6d480a3842ef06efe1
97380 F20110217_AABTNX tao_h_Page_090.jpg
42d82cb13b189891393a70df3427ae7b
318317256e70f46cb553a76b5ef54182a8afd080
26841 F20110217_AABTPB tao_h_Page_108.QC.jpg
c1b70d30bbf739e950e7e41fd73de2ee
b28953adc8e99a613c9244418c3a244dec3db796
30103 F20110217_AABTOM tao_h_Page_100.QC.jpg
f956b912363fd3a1817e4dd23daa681a
b2121f2e51f7828d0037dc96921f689ca3f9841c
33139 F20110217_AABTNY tao_h_Page_090.QC.jpg
f1cdc685b0279e1e53251a7224ae7e93
6330744f213fbf9aaac33aaca2e1b53e57640c38
41884 F20110217_AABTPC tao_h_Page_109.jpg
01a7c92cb4ff1cdcd1879646ce6573a4
a40549d8c22331f97c32cfae19d4c68015f4e2db
100622 F20110217_AABTON tao_h_Page_101.jpg
7d1274bc228396c9809a209db9f50fe5
2cc6b4893f02053146e62c924391379504241787
98751 F20110217_AABTNZ tao_h_Page_091.jpg
4b72cac3975ddebb8f9e8393828d75af
2064400c06a0aeac2abdd439ede695f737fcc51c
13668 F20110217_AABTPD tao_h_Page_109.QC.jpg
652b648cdc4d1e85f95357055fb61b50
08e63728c101607bc61471c2c951e591eff7a904
30892 F20110217_AABTOO tao_h_Page_101.QC.jpg
fe184cbb8406d1932543fd9aeada1953
a44eb68d9433759c57b27232c347cce9842846a9
222892 F20110217_AABTPE tao_h_Page_001.jp2
3bf664c0ee1717defae740e33939129b
e165c44df6d874ac7b60300f1faa2d64e81be101
29328 F20110217_AABTOP tao_h_Page_102.QC.jpg
c143ea26639af44dff8bc2535a844110
ac4edb8d3689545bf4e739070682bb4d4e9920a7
22030 F20110217_AABTPF tao_h_Page_002.jp2
94d991d19a071ff7e33ad6f44b75ce1f
29352710f6b7154c6351a751785d666fc800dee3
93285 F20110217_AABTOQ tao_h_Page_103.jpg
5d077cb562a175d408e6feb7c5c616f8
6f4dd81e6109e5a7d22a5c7b9b23a642cef08c6c
63554 F20110217_AABTPG tao_h_Page_003.jp2
debbab1eb1c504d85d3d65b8d4a49cc5
41a74893c588ac32a9a938bccebefda3ab5a620d
29632 F20110217_AABTOR tao_h_Page_103.QC.jpg
4cdcaab5c6dbf9bbe6638fbc95344443
62457eb314ba22fda4a8271769e331c51785ba97
766386 F20110217_AABTPH tao_h_Page_004.jp2
dd79b5563c6ae8c70175763c2b5641b4
e50d6faf9c0a9d5f7bc2e014e3be4a13cebf4b36
87878 F20110217_AABTOS tao_h_Page_104.jpg
ffe89795066ce70594874385fbadf0b9
eed1a5254a24c5dbae6d5da7e84a09166c71d398
788996 F20110217_AABTPI tao_h_Page_005.jp2
d04928f36f9cd7f3d9ffda128a624a18
a3900fb28e7474a162e3f1d74740bbd315017a6c
28525 F20110217_AABTOT tao_h_Page_104.QC.jpg
ad4878489b0d2101f9dcb4abeac88fa0
e23f9bb387d92b00fbdfb6a9f65c9967fd199b30
683937 F20110217_AABTPJ tao_h_Page_006.jp2
ba3451a2d5e7eb8d35d7c39433aa9646
6352a9df07aeb1b82e02e74f3e665c654391964f
91420 F20110217_AABTOU tao_h_Page_105.jpg
57904e6e48a20467993f80bf0661b672
78d56cfad8d0ddd61dbb185a03efc66238a7788b
29918 F20110217_AABTOV tao_h_Page_105.QC.jpg
fb77743adb59750c1ba46adf802d8ab3
de0046e2ff518b1a3d5e1abcd939f54dad881c58
690152 F20110217_AABTPK tao_h_Page_007.jp2
cf1caaa230f20af3debf77d345a9c6cd
40c76293218c74ede65fae763b192c376451a91d
91289 F20110217_AABTOW tao_h_Page_106.jpg
6f79658701110a815d0de5fa97ce7f50
14626bcf639eb5e8dde9d293df59af81eb24d381
300031 F20110217_AABTPL tao_h_Page_008.jp2
3880a70c1556ccde988bad134a3f125f
3d87153a3c5e67a4cf0341d1f79b37455ca9129a
29235 F20110217_AABTOX tao_h_Page_106.QC.jpg
330a4908beac0ef9a9ae2b46716bf882
42941a8df74ed87063d5c85dd51f5a433e497ea4
1003777 F20110217_AABTQA tao_h_Page_029.jp2
1de15642ead720f67fcd7dddf77123c8
8c97af7ae1b101c0c168d94beb5705bf17a2d2c5
979090 F20110217_AABTPM tao_h_Page_009.jp2
daa206300bcb9bd1d0f4a5e4c07fed4f
648248133249ad04ce6d242098134cfa17505183
92406 F20110217_AABTOY tao_h_Page_107.jpg
29f399315a90b409ff2564c3701fc37e
03d2e8e057175214f58ca84f6cee48e0d9f69e80
967321 F20110217_AABTQB tao_h_Page_030.jp2
cf1a297487ff61ca19743a1f51f6e0f0
9ba3ab26527f233b8f69970f3a131bb1d719440a
327682 F20110217_AABTPN tao_h_Page_011.jp2
1663a7017a25666784f1187dca351673
cf481de424c580c2c0cef5facb42cffa2d745818
29509 F20110217_AABTOZ tao_h_Page_107.QC.jpg
6a46af34280fd9d9b6ac6fd24cfb17b2
dbaef90bd492c7124d52a4cdd4f03bcaeaa2e809
988269 F20110217_AABTQC tao_h_Page_031.jp2
c091bf9d16c96cebc0c382364a3f7400
e012010c7e27351229fcb991e2ed95acfad7e8af
734261 F20110217_AABTPO tao_h_Page_012.jp2
a8a9248e1c3846b24109102840bd95ef
e93d1c54726589254ee5089149f37ac71c6645e1
853336 F20110217_AABTQD tao_h_Page_033.jp2
c148ca42d22bd03258109cd0c1a05130
fdd635c9b30a09ca4e48a75af3b440f278020148
980995 F20110217_AABTPP tao_h_Page_013.jp2
fe89caf6016c53f091534bca2523fbc8
ba6cf76be9fa8c13124569adc3681ae8fce17d91
877209 F20110217_AABTQE tao_h_Page_034.jp2
d7816616bf737389636363696cbb882f
05d4c507505191be03a7f7d8f0028750135f5a05
844348 F20110217_AABTPQ tao_h_Page_015.jp2
813a604d2e79413c93b050a454c02bc8
2f68ee5045ff57556760abfcae768beaadfebd0c
1051933 F20110217_AABTQF tao_h_Page_038.jp2
b6b3cf4aad3ae129ba331377777d1e09
529794f3c66f960909633650ba5c1a2a38ea238b
781689 F20110217_AABTPR tao_h_Page_016.jp2
7fcad14d3616df54c67c781b1ce2e593
843cf235350a76d23aee6440b1bb4f5bdc5962b3
1038029 F20110217_AABTQG tao_h_Page_039.jp2
93c4e913c27210b5462b83955892b785
4c78384f2b322a0ad95470da5a81f023bc12c663
650400 F20110217_AABTPS tao_h_Page_018.jp2
eeceb1163b1a64f7ab0a139f1f78260d
66c08cc72db80ae6e522a59d10577fcdc13b498d
1051953 F20110217_AABTQH tao_h_Page_040.jp2
01aadb6c379daa3b3f90fee5711a12e3
8f21dad8f1595062c0da635d5f3e0a93161d3683
326867 F20110217_AABTPT tao_h_Page_019.jp2
f9736980160abc22ca627218528a7cf8
451d70e39c6fbe2ee35d800bc9be51b3a08881b8
1051942 F20110217_AABTQI tao_h_Page_041.jp2
eb21b23b64706e34765b8d7f794d9d40
75dec791965acca0e7bbe2c64767c8a308cfb438
1011010 F20110217_AABTPU tao_h_Page_020.jp2
6ab30bb56d014c87983daa5d3b2c7064
f16da886f6cfaa7d5def39805d44966aa4ff9e19
931074 F20110217_AABTQJ tao_h_Page_042.jp2
4c195a1f045fdb3b50bcf7a4ff84a4d3
2b5a0f5b39e1bc72f07069d32a2883f602d977bc
1051976 F20110217_AABTPV tao_h_Page_021.jp2
977f90b5c28ec0db83243345e1e38805
caec13d9ac2285052a67d16dc3c60ecb7dce1976
1015680 F20110217_AABTQK tao_h_Page_044.jp2
43bd138bd80325d40d10e4338d6f3a27
8b69f59d948b37118728bd48915d493b57a21b83
767160 F20110217_AABTPW tao_h_Page_022.jp2
ccca114f3ef6da6eb91b272e74129005
8b306b841ae3aeacf32198641a2a9010df952c67
1051929 F20110217_AABTPX tao_h_Page_024.jp2
c7679c9b49e11138d80aab6a348966b3
ea4f357c66ce30a9d053e978704bba2a7dde1893
736938 F20110217_AABTRA tao_h_Page_067.jp2
f02d43dabbaf59637781c90bcd19bdd3
936684b651201a58092b0e922d93c05dab0baced
1001263 F20110217_AABTQL tao_h_Page_046.jp2
38e1559746800cbc07eddaa83a49a7cb
15b15d9109543cdf2c91be820877241fb855aefd
803365 F20110217_AABTPY tao_h_Page_025.jp2
344337b9863de474ee2b7e58ad78c56f
63fce62be7580da8d6dba2893015dd637c63ee58
793506 F20110217_AABTRB tao_h_Page_068.jp2
46015df06ad802aa8b4c85b9c766234a
a1ea3b8b57ef20b587708f6088cbc97f7a825ff6
133132 F20110217_AABTQM tao_h_Page_047.jp2
4dc0b0490e4f38ff48a572736377ad02
70e527f851a514925e65cf218a412bcb9eb95380
757023 F20110217_AABTPZ tao_h_Page_026.jp2
b5bbb76724b8a8479c45db3ce3f552aa
c8e7eed7d1556581a8ed9b0987af036e425e733b
788533 F20110217_AABTRC tao_h_Page_070.jp2
75aaafa8e5fa022849c0aebe2710e020
b963ac682bf128d2c4c6fe0e76afb1820a5572bb
656745 F20110217_AABTQN tao_h_Page_049.jp2
0229d2b7e957af5e68c185d19e06c550
217826b54af85a104c7dd0e4d325b7a223e950bf
873725 F20110217_AABTRD tao_h_Page_072.jp2
1816b322fccc2822e5ae02784c357bdc
ab0fe3e1f3b79dcf23d9dbb224531028e2a72a1d
1015282 F20110217_AABTQO tao_h_Page_050.jp2
29e251f1850b1896d998b69710c2048e
6bba70f428cef8046be9ef7b11c65bbba8e1c004
1051982 F20110217_AABTRE tao_h_Page_074.jp2
965ec4a88ba3a537e487d8eb13421a76
3874ed1bd33433fa8e0cb2b127fe2514e6a4ba17
828805 F20110217_AABTQP tao_h_Page_052.jp2
f486bab28b2d16be41983b4d507ccc64
4a5232c4ee4b446c5c166998daef3d4ae9154278
1026768 F20110217_AABTRF tao_h_Page_075.jp2
2992d74f289dbc1fcb79a64c7e93e863
3ff233150de934e462de314f742f17b03538df1c
800557 F20110217_AABTQQ tao_h_Page_053.jp2
2a5e03af97c44be222155da06b29abe7
efb0a3c2892bdde1ad180ea83d852d1d783cd92a
1029643 F20110217_AABTRG tao_h_Page_076.jp2
b9b109d4c19730498aebb831063727d1
22112b4038987b2fecf229b97150bd615b58734b
899881 F20110217_AABTQR tao_h_Page_054.jp2
a20c18cc79f296429a0413a43b9b0665
e89fa3275d9f95d08ec39bbacfd0ea9ceb5ca07e
1039511 F20110217_AABTRH tao_h_Page_077.jp2
711269f197abb6c4a2881aba93478fcc
592596eef5f29966055902fb0031e543b303a98e
924458 F20110217_AABTQS tao_h_Page_055.jp2
42c2a1f90dad347e8b4304616aa56bf1
b6e91dac674179bece9609ea773c89670e42f41f
1028148 F20110217_AABTRI tao_h_Page_078.jp2
a3d73f469c20612546262c14c3b7f2b7
d2e9a3e9d8f726eb942b35da2ce1f9eb835da351
874181 F20110217_AABTQT tao_h_Page_056.jp2
3a77ebae9d07c85db85d8f0f0084ab97
7b510aba0d7800c2f7debc892b6f6cb36806f73c
1041717 F20110217_AABTRJ tao_h_Page_079.jp2
6f73f39d25ec8708c0023e609b3b9654
510d96dd288bb9b483858c230e82507954e201c5
F20110217_AABTQU tao_h_Page_057.jp2
32e7373664048cf02f38dbb8bb667931
81fae36900fbbf3b43dfef551ae5dfbed0b2ebc2
1016259 F20110217_AABTRK tao_h_Page_080.jp2
cd19b84a1c7d601bf58b4bfc998d1137
4823bf92f4f249d73dab2359cacacb6c2338f4e2
1014407 F20110217_AABTQV tao_h_Page_059.jp2
fea6d0013a62f82c727bc0c845ea94a0
f11ef6068d33a62215772c63d4e6cdb13b5d19b7
1019049 F20110217_AABTRL tao_h_Page_082.jp2
52a87e85fb3183d6cc40c185edeaed1c
5374081641c089d2b34b9b23e2177a42bc72ea8d
971830 F20110217_AABTQW tao_h_Page_060.jp2
4551a1b3043394dd5247eb25dcbb3fae
36587c6df86f2a522d3de8a6c0ae5ad05a93403d
977106 F20110217_AABTSA tao_h_Page_099.jp2
8f3d6bf40e740fb8e7378cd0a37bf563
0ae88cf22883c357f5b0ee4e938e74a45c8e0d43
1051968 F20110217_AABTQX tao_h_Page_061.jp2
f83ff864e029b9dd1adc46169e952180
db52d3b9dcd7aba8d22d9344276e334c91338d91
1010345 F20110217_AABTSB tao_h_Page_100.jp2
9ed0216f7962dbd47d089e64c65827b4
cdf1c4e20e8fbc5ab39bd5d29d799e77fb41c1cc
983276 F20110217_AABTRM tao_h_Page_083.jp2
9d3cad4dd5b704cc75d45fe050641b09
46f5df100045b29842f2d6cfe5a8d511ac7bfd03
1034054 F20110217_AABTQY tao_h_Page_063.jp2
f937a22d1cf76b175fb4202a849e4da3
40cca247cb11caa4477112af20e8d8d2abab01a9
1042724 F20110217_AABTSC tao_h_Page_101.jp2
d6a11aab5210762a91fbb30b41442323
772f958d607a73f9a3522a7b53085269fcb90f4b
888610 F20110217_AABTRN tao_h_Page_084.jp2
8efc6b392f0d8a512e546c9a9589d9fc
bc71f20bb9d2299204ec390fddfb3d0eb2783165
1051980 F20110217_AABTQZ tao_h_Page_064.jp2
44f1a815778c7c4773f0e057526bbef1
0cec05be6be9e0640f33a658dbcdc3f33acfe5f0
923906 F20110217_AABTSD tao_h_Page_104.jp2
73a18251791dcffbc219689c48caedcc
fb977bdcdea75976a3a2571e4bc2a0a2801a00bd
771665 F20110217_AABTRO tao_h_Page_085.jp2
c2a672a04e59e52d8e96982eaaf2e925
124525ef78abb306fcabb7b3244071bb02919a8e
971662 F20110217_AABTSE tao_h_Page_105.jp2
b2d25c6c3164aeb5b22196fd03102dc8
fb98602db59442ca73f089ff0e1ac27ccce6a6cf
1051949 F20110217_AABTRP tao_h_Page_086.jp2
ddd90ee4cea5ffc9af85b18a02b21b41
411a48805400382c6b9238d93992f56c69c2caf6
965857 F20110217_AABTSF tao_h_Page_106.jp2
c8e86354b4f41634bf7db6022b6a8d3b
0adb53c156bdb3ea65fc938fdbb90083e9f98e85
796768 F20110217_AABTRQ tao_h_Page_087.jp2
5244043d07e237c246156ba560bddc30
2bb68be109f71a78d761d0922921636742f77e6f
963386 F20110217_AABTSG tao_h_Page_107.jp2
13a3669d21f3220ca2338d639c9c0589
57faa55442abd89407503c6ff88c2a1b1295e0bb
790203 F20110217_AABTRR tao_h_Page_088.jp2
0a76669c8acb0f63e497ba9e78675445
3b6b8287539870791d474abdc1954739b74f0308
859995 F20110217_AABTSH tao_h_Page_108.jp2
c355f0de2381074618f619f4eaaa6af9
b53a2fd9f927415a27588e03d959d0c96fade28d
1048901 F20110217_AABTRS tao_h_Page_090.jp2
85ea208c764845e5ee14095fc4d0f67d
b7130813758ce2dbdbab47d0ed207e2ffe5fa8b8
430750 F20110217_AABTSI tao_h_Page_109.jp2
ebc963400f998c87bf3c2b8a0ce108c0
9e18b9102514d82fcaa2c10d35cb46d524938446
1017399 F20110217_AABTRT tao_h_Page_091.jp2
2420c7ec00059526a8b3ef19b19603d2
4f88ebde2b1a73d5ccc35940e6bb9a9808fdd68f
F20110217_AABTSJ tao_h_Page_001thm.jpg
64f57f05042daef4755e3c7e43481a2a
4351145dbf3acbe0b2a4e5d816ab7c5e874734f2
874732 F20110217_AABTRU tao_h_Page_092.jp2
9d9f1d4bdc28a325d2785d668bac0f06
867cc3b7afe28e772a98d2687be60819a2646d4a
560 F20110217_AABTSK tao_h_Page_002thm.jpg
409ff689d892ebd6ee20497cff4bd5d4
d4ac8a14d538dbcc09d775eb9ad7cd1eb965cc70
962662 F20110217_AABTRV tao_h_Page_093.jp2
e8821b08938c9281cc28129e6a6107ff
1df757a318ea245a3c46a0e81785612fe1202da4
889 F20110217_AABTSL tao_h_Page_003thm.jpg
49464d56feb6290af2d00ad882037f63
f6459834ea298a57422226087dfbd3b7b6ea83a8
878152 F20110217_AABTRW tao_h_Page_094.jp2
06ae72ddcde5fe94b41e24b38f1479b2
cc825bcb1f21d7c45a4a64ac12c445cb57b3cbf4
4747 F20110217_AABTSM tao_h_Page_005thm.jpg
826cd70eebd1fcc0dc36959252c038ed
624200144a8cdb6897896f0cb990d751af88c6f9
945018 F20110217_AABTRX tao_h_Page_096.jp2
48e5695f5da23d4a3ab2cf7dc706580e
63cbcacb503fc65c8012d700cf3a729e6244859f
6243 F20110217_AABTTA tao_h_Page_023thm.jpg
68b4fa9b3d8b166cc6a5b7c8377aa09d
c9606adafd515742a1279c1970c33d2d9c60a924
893169 F20110217_AABTRY tao_h_Page_097.jp2
5634492b916f9cc3a58fd4cc3cbb58ef
d30bc9bb2f08137a1f5409912ec45343973d0433
7975 F20110217_AABTTB tao_h_Page_024thm.jpg
b69ecff1abff8be73d9f17a952dddcd0
137bb21ec7e532df13d49a23ae1ea434725113d3
4155 F20110217_AABTSN tao_h_Page_006thm.jpg
fc8e512d7525db1abf17e8ce93636d55
efef36bf345263761715bf358faeecc95254fca5
972914 F20110217_AABTRZ tao_h_Page_098.jp2
d4dc4ca1658eaccd2a92c6d685a6ebd0
19571689bf3da786f411bee92b1881514d036168
7756 F20110217_AABTTC tao_h_Page_028thm.jpg
f4cf3f4eec7112b57dcddcb0881d6e00
087f85b70a70354d73fc3c93d8be6b9680fc318a
5016 F20110217_AABTSO tao_h_Page_007thm.jpg
0db99e834e218c569febf930e38682fb
06245ea8f7d98873914abf100a714ffda72483d2
8245 F20110217_AABTTD tao_h_Page_029thm.jpg
7ec8cb2d3af47319b1c69f49d9ff8c69
ea4aed49bd23f578453fce29fac3bfcf74afe0d0
2518 F20110217_AABTSP tao_h_Page_008thm.jpg
47120d7437cca61e16c8a0aaf7b29d20
cb4c82d8c2aab92ad6e41590c83fa2e178eb6687
7465 F20110217_AABTTE tao_h_Page_030thm.jpg
f48924b4590d63c4ee3aa796be0e822d
c8c8730eaa4f8e7b53d37a7e705162b072df4036
6428 F20110217_AABTSQ tao_h_Page_009thm.jpg
3b77638138730547c691bff052ebf534
086441d88864452b9028d820ed356e1c7047f77c
8110 F20110217_AABTTF tao_h_Page_031thm.jpg
174458884a107c84d633d83baab79227
0969b3d3f7891dfbc4677f3208b8aaa98bbf9168
7095 F20110217_AABTSR tao_h_Page_010thm.jpg
0d2e839858303597065bd4673edd5c42
f5bb41b626f27ce20c90549e4f828fa56b5560fa
3331 F20110217_AABTTG tao_h_Page_032thm.jpg
99e54f80ed113e9c76de33c0eafbdf4d
0ec3f2f3fca856c329deb1dc6de45a8f2e23573d
7359 F20110217_AABTTH tao_h_Page_035thm.jpg
6b30b990319a99ef2c010dfaae364c83
7e96ffa62f1cb2eee6d7bc7decf912a456c24592
2621 F20110217_AABTSS tao_h_Page_011thm.jpg
3eeb91688c8e0a6ed20bed33a15349ff
4e4d44655ddf64d4083b81c6f523441dea600d9f
F20110217_AABTTI tao_h_Page_036thm.jpg
569801b73249e302e1fc241f3449c4b2
cc10711dd1cd44f3ff0908de47d780c7832a6b56
5786 F20110217_AABTST tao_h_Page_012thm.jpg
a4fdeea558a038e97fc7a17c2063c6f8
beff5c29a49fc44736c42e283645eb6fa457c0d7
8039 F20110217_AABTTJ tao_h_Page_038thm.jpg
bc2871215d6e7192e35b488890038432
646b921d9988d0ecd7b44700d659e36383f2a093
6978 F20110217_AABTSU tao_h_Page_013thm.jpg
49caab1d7c07d213f8ccf715cc97634d
b8270a3ca6b35a3fbc6829e88cbecdab60d4e593
7528 F20110217_AABTTK tao_h_Page_039thm.jpg
a75b9eaab7f0fe4ec1887f0689f1196b
77961d527339a6a08f34e58526bd8052b3d2cf06
7411 F20110217_AABTSV tao_h_Page_014thm.jpg
519be372819b6b735b03bea300a38127
41c8820ca6d824dd9b8c27e3ecd730fdf952614b
7787 F20110217_AABTTL tao_h_Page_040thm.jpg
3c0a2fe4604e28d061255bbc194a3357
cbf080eea20331b190a691b4aa2658ff55f15b9d
6782 F20110217_AABTSW tao_h_Page_016thm.jpg
0af617c443b2d37c4450181c9debbb5e
fa0b04244fef375685ceae977357afc8e09d1e9e
7501 F20110217_AABTUA tao_h_Page_063thm.jpg
f58d184e8724cba6d745a383e24fcfd4
ca69ed06cd959738dd9427230a9e47b82ee9a442
8497 F20110217_AABTTM tao_h_Page_041thm.jpg
68a9703d433a14529eef6fb7b7add8b9
5da90fc5191e65161cddb4efa14c0a2dab980813
6103 F20110217_AABTSX tao_h_Page_017thm.jpg
2c4fca18f4d7f76c2317b5fac94d2ba8
9168190cd65b253a4cfc1054dc6c0196c49a1c65
7998 F20110217_AABTUB tao_h_Page_064thm.jpg
c42f9dc1d63c6b6cf17f8d8cb2c2be33
aebb13393b57713a72e39c17712fa84c9dcde381
7763 F20110217_AABTTN tao_h_Page_042thm.jpg
b1cf1f85dafefe6b440d12a74a722dc1
30dac5e7849a75445aaea9353a6da5bdebee80d6
6150 F20110217_AABTSY tao_h_Page_018thm.jpg
220c03c7dfe4c1da2ec947322219a046
1adc1768853193ff1df859be323ab1ab4bb771d0
7593 F20110217_AABTUC tao_h_Page_065thm.jpg
963e30a355e5ee5ac59c8bb8c2084a7e
a541211c87e4526e9b076509ee19ed5c41982bdf
7292 F20110217_AABTSZ tao_h_Page_020thm.jpg
08d8b328ce3b5adaa1b8db844df2a396
662d29619465e63214711985c4978bf23e1b516f
5511 F20110217_AABTUD tao_h_Page_066thm.jpg
b503b60899f2804ec503b0e70d6dfd46
3c80e17bd5255205189c3e87490b438bcb1f01d4
8201 F20110217_AABTTO tao_h_Page_043thm.jpg
2f085695e662f6def563824aacd64161
f2ccdc0e9fa2cda2d06cb0f5be337b57b815d7b7
6391 F20110217_AABTUE tao_h_Page_067thm.jpg
565d874cc0e2394381cf1612d0de4e87
80d2ea9a844fdee36ec2926ffc84e49bcc1cb946
1585 F20110217_AABTTP tao_h_Page_047thm.jpg
4c8726c9c01d6c1c1b1b2ba780d9238a
df2a5e513b593b73a27d939dd926695679ce179d
7636 F20110217_AABTUF tao_h_Page_069thm.jpg
da32fe26f561ffd77c0ef44ddad0d82d
e1bf0109bc9b2b4d95b73acd7346337a8d4a5973
6022 F20110217_AABTTQ tao_h_Page_049thm.jpg
98d8279482a9316cd7ccda3681d5249f
77193c7a1aec1dc610154ed12ac1b6229bf4faf2
F20110217_AABTUG tao_h_Page_071thm.jpg
b3ce8373b549859319c3dbf773cb23e9
2a4dc119bc9712771f120319992098aa7ca3a22f
8211 F20110217_AABTTR tao_h_Page_050thm.jpg
7ad70f332b26bed8a59a4c011abe591c
7e621842dd48cdf4d08826523cb4de36585ae481
5753 F20110217_AABTUH tao_h_Page_073thm.jpg
9574b9f8206a2a0cfd97ec22090dab2b
bfa2683d1fbbabecaefaa9624443ad609412eb37
6674 F20110217_AABTTS tao_h_Page_051thm.jpg
e5592a68fbd91d1f3cc06b9a00946570
4ebbe83eafe40fe0f640bde7eaa792cb5c8651f4
7825 F20110217_AABTUI tao_h_Page_074thm.jpg
19e25b29a25d5c544d3a41206381c63e
0846b984064ae2f0cfef15d3e78a6e949972ea8b
7311 F20110217_AABTTT tao_h_Page_052thm.jpg
af98a06ed9881532de45cfb33c9a7e03
068a75de6f3e93e0902e4536f9fa9107627e7a29
8359 F20110217_AABTUJ tao_h_Page_075thm.jpg
7b85cc17bbb75800ba6201ce4d305dbe
d978ba680b5319fa09ffcb3ae557cea04dba8d0f
7213 F20110217_AABTTU tao_h_Page_053thm.jpg
b800dd7793574da5566237a2ce11d383
fea3ef0c0e26115db95b18ecc30445248ac3e01d
8664 F20110217_AABTUK tao_h_Page_076thm.jpg
26ff4f1808bbb0837b5459a2f4843852
d39e67df1e6645dffdad8fa5b00a8cb62417ac9b
7260 F20110217_AABTTV tao_h_Page_055thm.jpg
10a16bac1284d6cdf5582dbbf31b30cf
a4126969e5270f4cc034c060a3292de1731a6fdd
8350 F20110217_AABTUL tao_h_Page_078thm.jpg
032fb0c489677bbe5e0802381462601a
483013c0261baf9cfddda8cb8206cf56b8ccfa9a
8303 F20110217_AABTTW tao_h_Page_057thm.jpg
422ef52be86fc437bcea3126b0317b93
490483b1a9be3f7e85df540f02f648fbf04f4838
8634 F20110217_AABTUM tao_h_Page_079thm.jpg
d8a581596853dcb23fea84f9530c1d63
0e37d9dfb6611d3a82fc4e64fd750ea4947bebe1
8017 F20110217_AABTTX tao_h_Page_058thm.jpg
9836c2123e3dc6bc31d6800ba5c67143
a9e2007a3856f7e5eb533a074f548ecf9ba5000a
8240 F20110217_AABTVA tao_h_Page_098thm.jpg
64b129bae92be1c0faa9317c996c9274
6a2ea44db9358486bb5781432c5a06a3901f2b56
8104 F20110217_AABTUN tao_h_Page_080thm.jpg
c462cd4f46c3a6ea93c6e25fcb97c754
01a597e2b6944605abd7068018af6b0e2f051896
8079 F20110217_AABTTY tao_h_Page_059thm.jpg
561c44a8635a7e8dde32ffde758befa3
f0c461e0bfb4700ef7946a482cd6fabc0202e270
8016 F20110217_AABTVB tao_h_Page_099thm.jpg
628985464a7ba2d84e75c55998d901a0
3a929b69a0a60618a1b144cb89721ca466915657
8278 F20110217_AABTUO tao_h_Page_081thm.jpg
5c7a3b14e90eb41c51b174a9bb9b7574
4a80fa033ef3fcad133e0c863877cd0263d5aeb7
3162 F20110217_AABTTZ tao_h_Page_062thm.jpg
46f74ca4b994ebef7605bf894fa21735
6a13fdd6a298df45f43c8b2bce59ff6197d054a3
25797 F20110217_AABSSA tao_h_Page_033.QC.jpg
de6bc384f3ca882a8eaaa6d41e8ae493
667319cd278b230f6bb7b46dbb9e3083cf874478
8428 F20110217_AABTVC tao_h_Page_101thm.jpg
29b91ccd0d5a0a1288845ed918a0e3f1
610a0f89b4034ea60330bceead96aa45e89147dc
989975 F20110217_AABSSB tao_h_Page_065.jp2
1bf7abd2be22294dde3a1f5109f9b432
7f10af5400a98cff56a4dacc34707e474b2d5f0c
8216 F20110217_AABTVD tao_h_Page_103thm.jpg
6e4d585a73ee9f148b7c7ea05f8e5edb
7ebeebd163035a971d632ac0725c780fa9312064
8292 F20110217_AABTUP tao_h_Page_082thm.jpg
809ac6e3f7a49c41e486023380f7f083
7cab2f4a93eb9277330600096855bde810920fba
8072 F20110217_AABSSC tao_h_Page_021thm.jpg
5f665848a781765be7397c79dbf27706
7c2fdd38546abf711540bc21347bd3da21c45ab3
8145 F20110217_AABTVE tao_h_Page_105thm.jpg
be0ce72290e5d6f9daa6a51420395c1c
c5cb4e1d07853445122bf3771d7890dd4f9066f0
7312 F20110217_AABTUQ tao_h_Page_083thm.jpg
52ec7fe5d4cd5861857265fa8992d26c
30376a5ce76496a082137a8f74dcb03691ecf3a4
21245 F20110217_AABSSD tao_h_Page_018.QC.jpg
55af9ef3f8f359aec9dbba68e3a39482
c03204e21ea72ff7ca0fa15549100b5607f42799
8043 F20110217_AABTVF tao_h_Page_106thm.jpg
8d1c250aa34dd942f062527d9d63d807
4e213b39d85123868f9ce45a7992a7109fd2af4d
7324 F20110217_AABTUR tao_h_Page_084thm.jpg
61a726ebe3ce2eaab0fe1ec4a5e10f15
c845776efaf459a3532608b74248985001028d41
6384 F20110217_AABSSE tao_h_Page_095thm.jpg
1d13253541c7fb87e2d0d869aea0d871
c8f6f8a80b336c85977aaa3c1967fd78d9aab8ab
8316 F20110217_AABTVG tao_h_Page_107thm.jpg
9bc582f4d6e92817c3ccd96ade9350e0
ec978b6b1ba77696b5bb05b6754fc3a317abd1a6
7099 F20110217_AABTUS tao_h_Page_085thm.jpg
b3354f345e430f787a16cab21e7a80fa
5136abbed536da8c6ede4ecea4f2db4fc98e31bf
32874 F20110217_AABSSF tao_h_Page_087.pro
445e343ae5d45808c9834447ded17efb
44d420511b3d40ad8eff7951865f1270952a7a2c
7271 F20110217_AABTVH tao_h_Page_108thm.jpg
c0b0344a57acfecf34bc108fcf4236c1
3983df082a99a86fd66f61d5d626042f91895e64
7045 F20110217_AABTUT tao_h_Page_087thm.jpg
606f9bc90d135e244dae6f86d0f9b9ff
5cf59e6c2f81e576a18b125426c283276e6e70d1
F20110217_AABSSG tao_h_Page_023.tif
885b9084e30f940ba72cc4dd080e3042
9a438950759e1b6635e21c594aa0d75609eafdfd
3705 F20110217_AABTVI tao_h_Page_109thm.jpg
2c30017768e72998769863f0172cdf22
19f94480e1be3185d35613a93b5634970925ab5b
6633 F20110217_AABTUU tao_h_Page_088thm.jpg
a62ebb8e009d171c6e29f3d1f5967903
fea41084d7ac9758edce88c1cbaf038929a216f1
2632 F20110217_AABSSH tao_h_Page_010.txt
444a058110614ac6564c567bcb3bdfb6
bae1cbe4c3d420932fd670479e57483eea88d885
528830 F20110217_AABTVJ tao_h.pdf
fadf8b9e8e15b9e600bdcd880d7c527d
f84593aaa5d47525788db2154fc8ee2e86f0d99b
7740 F20110217_AABTUV tao_h_Page_092thm.jpg
dd1f51bf9aae3ba61b9361efab541045
f748c1a316ce1615a44025d9659af9096f96a073
F20110217_AABSSI tao_h_Page_055.tif
93ef1d84f893553c387b4b5a7277bf8a
67a13a8b892441d395a6b3488b957c37fb99eb20
127475 F20110217_AABTVK UFE0015000_00001.mets
d0577d7b5d4cbed5e6438b61f64445f8
038d2438b4dbdf1bb8b9a084f12b2b7b7a7098e3
7114 F20110217_AABTUW tao_h_Page_093thm.jpg
e1e6dc86409c52cef2dfbbe9a7c2b0eb
92ad7223f7cbbb299b004136b9c1fcd47c1ba2ee
41572 F20110217_AABSSJ tao_h_Page_104.pro
6defcb7a0e0211f55553e394e092422a
10c06780d688efcfbf1a8721e61953be7dd60c7d
6620 F20110217_AABTUX tao_h_Page_094thm.jpg
eeb0c4e89b5b22b87ab022987294b54c
4234df023af479b835c3b726719c68ad04142521
6718 F20110217_AABSSK tao_h_Page_072thm.jpg
02891417a27e3ef118d6a3e8927fbefa
509f4548de30b9718c50bcf66bdb978cc2c14e1e
8164 F20110217_AABTUY tao_h_Page_096thm.jpg
8978283b1bca4fe94df0ff13a716ca2a
52fd1dc253886ebff0c33bce5cc5bacd665f0d3b
7089 F20110217_AABSSL tao_h_Page_034thm.jpg
5d44a636469c6fa747df1d22faae0b1f
ce940d76fd8f85221c6ea3622242cfd7e8c962e2
27128 F20110217_AABSRX tao_h_Page_094.QC.jpg
e9600235f523925c9def1e4b35aaa7db
744a35d4e822ae9ff3371549f76ba0555fd9c102
7969 F20110217_AABTUZ tao_h_Page_097thm.jpg
68c8d4f0a4d9947eaeff4c30276c256a
80a2a2b580321aa82c5721ad188ecc988907c825
90473 F20110217_AABSTA tao_h_Page_102.jpg
051b485eddcb50aee2a4c57602f0bbf1
64ac14275d9143c2d2fdffc7d39722b90c142c43
6309 F20110217_AABSSM tao_h_Page_026thm.jpg
202d272c2b6825aed83b1538aee116aa
5ca180e209065d32d2a7808d87fbfed27257617b
32282 F20110217_AABSRY tao_h_Page_019.jpg
67b1226fd3b188bae85d5ca2dd2fe543
320003df0c609f047fe5bd4e70d8409b42e245c0
7815 F20110217_AABSTB tao_h_Page_044thm.jpg
4221c190895f85bbe118b3b113a404d1
61ed8113be3991f00d6abfda4884de7548d70402
1843 F20110217_AABSSN tao_h_Page_078.txt
7cde3d18a4eab547fd23772f7551abdd
b9f633b4bdee84e6a2272b824d8ebb591692d9a2
7791 F20110217_AABSRZ tao_h_Page_027thm.jpg
d816cd4ac446817a389d5b66f53bfdf2
0c816c7eea37eeb114c56dd7feb1f222655cbb10
6858 F20110217_AABSTC tao_h_Page_070thm.jpg
897299c878f5b103b1510f70b3269180
eae1dc7435ded738a3f03dd7a5f18c6ad91060d6
F20110217_AABSTD tao_h_Page_076.tif
96f5793d7cbd996f45f898377a29038d
fdd8fbc26d5dcea98179f3212bf25f76e69b5bcc
1998 F20110217_AABSSO tao_h_Page_039.txt
248e3ff1a3327df43556273b42d89069
70ca37c78e4cd3b824d74b1b2a566fa472ad413a
1048620 F20110217_AABSTE tao_h_Page_028.jp2
4706fc6556ecc20314a17d9d83710a48
c91b10cffa299c044bb14bd052075c369e7d8961
32734 F20110217_AABSSP tao_h_Page_029.QC.jpg
2960519d94f3ca67d482ccb9174a04e2
85d73de1fcb0f4a5313889dfad3e4f67118c6088
97857 F20110217_AABSTF tao_h_Page_040.jpg
01e305633620502e49b58092db84c18b
3bad4945ecb11e0d13b9725c400001867a17ced0
42823 F20110217_AABSSQ tao_h_Page_055.pro
3a9399e017b86c8e027989a93dd1e84b
227fa49c89a8939eb8dead7210f1af5a1e762d60
80867 F20110217_AABSTG tao_h_Page_068.jpg
1ad63f3a60091131e465d0a735434f7a
7044ce0296abb388437b0b883a55d68587a1a290
F20110217_AABSSR tao_h_Page_043.txt
8c1fc28f5eaf0db44b94d5c0cd6fca5c
6553fd84dec209aa96e69017baddc825fe3ae4cb
28965 F20110217_AABSTH tao_h_Page_069.QC.jpg
91ce07c1916538388b717334d03d90e6
1dd24a56bd57d02387fc5619f3f6e8a4f9fc0d44
7458 F20110217_AABSSS tao_h_Page_060thm.jpg
cb7c63482b5205e5d65d4afc4a27abe0
9174d234eea20be19c09f71613af1cf4247f3bf0
7353 F20110217_AABSTI tao_h_Page_048thm.jpg
84b729c00ca28bae16623e9936dd7c30
36d50c0286eea43e58a2140d92f30005725f3968
42387 F20110217_AABSST tao_h_Page_106.pro
3512cf19e72acbe067c6e9ad1103ca71
15a693cadcfc08180b9d8fe3747e9bed8db3f2ff
101485 F20110217_AABSTJ tao_h_Page_076.jpg
247d1f1ee3c0b1f09fd76b8f172b5e39
f250a396dbeb348f2f6dcf2ae7853158b95ad658
47009 F20110217_AABSSU tao_h_Page_038.pro
c2cb605272b87e770f752733d8981f7f
b4d217359937afe06b3b433bec41682751a48bf5
849186 F20110217_AABSTK tao_h_Page_036.jp2
15d7b2acf574cb0a0971e630c4e9bc41
1abd98be86d28e2e3f78aadbd288a96c53163c73
1909 F20110217_AABSSV tao_h_Page_095.txt
b9f9d47f7c9e974565234a8cdfb427cd
4d5d829e00c1356e187bd868685513cd35969a1c
F20110217_AABSTL tao_h_Page_064.tif
103aaaaf4d308db80326e7c022f0a2f6
e7b9b76a29ce228fad23777e3f91434a3c0ad3a7
715873 F20110217_AABSSW tao_h_Page_023.jp2
381f17018b1a9d70a2973264b4a5812c
4886a04bfb6539c166dae35ba65ae277934c8a5a
46163 F20110217_AABSUA tao_h_Page_080.pro
a015cd9be8fc89a8dd5785d79f8dc919
8263283d2054549b7bef8621c3e7b6cab071e48c
23724 F20110217_AABSTM tao_h_Page_051.QC.jpg
0027c9095c4e094698b06051d1fa18de
253dfcf0c5fdc3f324456a52659eaf7cea2b7607
7847 F20110217_AABSSX tao_h_Page_037thm.jpg
2f979c8c58caa841bd585b9d418a2aa8
3fe7729c1fc0147df21ed664f6a268f42695a6c2
8433 F20110217_AABSUB tao_h_Page_061thm.jpg
aa938722593032e6671f823408805f32
39c515e25944639c5848e8b531bc57e17182734f
83320 F20110217_AABSTN tao_h_Page_084.jpg
411ab9a37c947aa68227a09e62061225
6581c7d3cb50fbc3a03860eb04100ce850c22e93
1017065 F20110217_AABSSY tao_h_Page_089.jp2
90ab695929eeff121adb91d3e18f72a9
f3c2b59c27e520571b2d9833fe1cadf8d601a034
30117 F20110217_AABSUC tao_h_Page_092.QC.jpg
51ed3ad89ac0deafffa89dc45fdd62f0
ce5867efd3d8e2fcda223f20584b729a658eabc5
35979 F20110217_AABSTO tao_h_Page_068.pro
9fe1de327328766f146f69e665492bd9
d210e5e625ae92c876ae25163c4c811df30f194e
1903 F20110217_AABSSZ tao_h_Page_100.txt
f802420ef7a9310403c459f92b756548
b358efb343626d31d0f5276dccfd603196c073d7
8405 F20110217_AABSUD tao_h_Page_086thm.jpg
dde9439692ef0c85d74dc5ee58b431ee
fe5193af8798facb5bf5f34facc006b646789704
371575 F20110217_AABSUE tao_h_Page_032.jp2
8e234788d8602cbff1983e3d71525808
8c972166adcbc85d634215990951339eba1e9926
F20110217_AABSTP tao_h_Page_078.tif
dd83c3a5676adcfe4daf28ec18244720
ae8711778060ed8e5f04a89505c9110c381b3b89
810299 F20110217_AABSTQ tao_h_Page_071.jp2
a4e727c8d67225ae17a7a86c0ade6a24
d5ec83ab4827769d33f6c709234361ebdab588c1
106293 F20110217_AABSUF tao_h_Page_061.jpg
f13b741234824a2ea387daddcb0ce242
eef9a08b4c31827bcf6a6932af98465163fdf005
6521 F20110217_AABSTR tao_h_Page_033thm.jpg
f0c19259c66370363665cd02ca096633
7388c834168251a273bd7ea63fbb3fd30d0a3541
F20110217_AABTAA tao_h_Page_068.tif
ce05ac69587b7abd89b7f588dc780439
4170a786c656a52a42ddef0ad02d4f5771300b42
1046737 F20110217_AABSUG tao_h_Page_081.jp2
bd564ec93a71560b0c84117322c31b43
dcd33628a4529c61ca38b0061ee758457e52b658
F20110217_AABSTS tao_h_Page_024.tif
cf6895719afe014df1f4082a9298c8a8
d3c4c6df9dcb3bde602b8e9ad45b1e0d270386b9
F20110217_AABTAB tao_h_Page_069.tif
fe94743548e5ea7c6ee6b9e7ef2cc13b
f3d6ef3fbd4a03c0c32f36d0d912c2f4a382a4ad
7848 F20110217_AABSUH tao_h_Page_089thm.jpg
6bf2724636deec2ca195523b0dc8f858
941f1b5ef986c34f32a4f6ccc60eee224df79df4
873549 F20110217_AABSTT tao_h_Page_095.jp2
cee07822d8684022c57333552f80402a
44166b898ef24a2d930f64da4aa6c36f5ee503f3
F20110217_AABTAC tao_h_Page_070.tif
a562dd7ffae7f9e0bbacf8cf11f76ccd
b4268d5ca2b22475cfffe1775db77323c7e2882a
F20110217_AABSUI tao_h_Page_088.txt
25a5c72d07c4720c04d7dbc9d8d8fe57
a95a294d32ef5a4f34e0be48007dada47fc5243b
38282 F20110217_AABSTU tao_h_Page_016.pro
1f3579fd8ad39e05df0871a41a95e5bb
44a7aa5b7c7f157c792450cab3149b2d537af4a3
F20110217_AABTAD tao_h_Page_072.tif
d6d6e0e2aeec16b3ed106383b12360a6
195b34b2a5a66042660749abd2bdb8993351c3d2
F20110217_AABSUJ tao_h_Page_012.tif
7dcb96c4e76de0ded2b1db4b1150854d
103fe78c1e6ece48196eb36f72c63743688cb269
103795 F20110217_AABSTV tao_h_Page_041.jpg
78667a27e94541b20c4dbb6689d84eb5
e580f994ab8760460fe5aef0e57a69b7864ad6de
F20110217_AABTAE tao_h_Page_073.tif
2b8ae83afddf32a422f2fdb5b9979774
baf06d0455c3b5ec4a47b454e4839016263bd7e4
8204 F20110217_AABSUK tao_h_Page_090thm.jpg
126dc460520f5a4e83d39f89e8bf2579
e8f65e0dcd112082d3e30de21796c592a7e773aa
46650 F20110217_AABSTW tao_h_Page_046.pro
fdbb04d5549086c42468a9cb2d769f7d
78efe3a6dacec151d3f4241019859e5252ba6253
F20110217_AABTAF tao_h_Page_074.tif
25e5c3970d809b7d5b0fd547d991f30a
c6b9fdad8b21a798ee2b778150ee805eb649c2dc
786 F20110217_AABSUL tao_h_Page_109.txt
12117029f60a86b636c69cd8118bc378
2e9dea17887ded5f99fcabdf2c059c69c32de042
43506 F20110217_AABSTX tao_h_Page_030.pro
6c83510f0c887ba0a5c356abd990c5e3
6dc4354a44355fbb2ded6e21fd15209154d4db65
F20110217_AABTAG tao_h_Page_077.tif
1b0c8dd34b2f8a87ae759ec706d859b4
afe9fab98fd379465004f7738feff082d5afb794
8505 F20110217_AABSVA tao_h_Page_046thm.jpg
7cd28c85f9800f205a71c328c9382b85
a1cbe3432b06058e2915439e34bcb5ee6f155069
8512 F20110217_AABSUM tao_h_Page_077thm.jpg
353fbc2115276d7a870554b569925bfe
221e7666341f36db3013f50b2b4c7c21c012a5a8
984863 F20110217_AABSTY tao_h_Page_103.jp2
9936d6958b1c68c243c46eb5ab20a03f
c9c59827bb439e4046622a57adf964c407706f0f
F20110217_AABTAH tao_h_Page_081.tif
0083043984bc5daa4e989ecc3bbe6205
f018498a402b03743a56b7fab089e48a95765980
46543 F20110217_AABSVB tao_h_Page_039.pro
932e2d18be9c957ba6235691a7fcae73
56b973d3b9e20cfbb0ef4d0cbdbe72928ff1e4c0
1786 F20110217_AABSUN tao_h_Page_084.txt
6061c0a061d643beb01a5c6ef729e1be
2ba1f16a6dbe892cd72a40bc082ab54d039dfafa
290 F20110217_AABSTZ tao_h_Page_047.txt
eeb09f0f2db7da085ee7e2111cb512c8
48c59b70b1ac9dbb1c243e0197da3b14bc6f7957
F20110217_AABTAI tao_h_Page_082.tif
227b0c803cd3b563915e1e8f50802538
ec4526938c31cde64d0d49d9822fa2339b54560b
962054 F20110217_AABSVC tao_h_Page_027.jp2
0a13dcec5eba96a41debd90b28b48a19
9fc865f09f4a0429ee03f7763e5862300e06e561
759603 F20110217_AABSUO tao_h_Page_051.jp2
b99b50e27fa68172da7310dd2569e84e
2adedf69982ee7f61a2570ddbb0f9f3777a94132
F20110217_AABTAJ tao_h_Page_083.tif
cf5eb2404163f1728a0b2695dbd41cd9
848dbe6d5f9b08254413c14ba6e3e9f923a264c0
98906 F20110217_AABSVD tao_h_Page_075.jpg
7eb526087e7195a601fbab488bcf7933
12a853eafa614c38ff948037a0bc6afec6f34178
998390 F20110217_AABSUP tao_h_Page_048.jp2
417b41d6855bf58300ecdf51b7cf29a2
d74644b7f029d5dcdc62f555516240b5c3f61258
F20110217_AABTAK tao_h_Page_084.tif
3780b29b578a0583201e94ad9f3f8309
5bdd47212dbc3ac229412673c1a6921036a3d9b5
555181 F20110217_AABSVE tao_h_Page_073.jp2
7ef71f7b1f660b4e5d72caf2852c678f
7351f8bedf856265b882c04afd6dbf334e880f00
F20110217_AABTAL tao_h_Page_085.tif
97fd25c5fa1279c8cce84a0a445aa595
116d4bf75c70ccdc842ca2ac3a2e37f5416b1ffe
94549 F20110217_AABSVF tao_h_Page_042.jpg
65ccaee162ce2facf8a6acf8ddcc4aa8
b1454de78dbcf69a8bf902ce84657af286a9a09f
1017205 F20110217_AABSUQ tao_h_Page_058.jp2
704c65f04d5c6ec76d62a1f990fec28b
ec667aa8c1073e8d33d27377fcfd672f5da47d8f
F20110217_AABTBA tao_h_Page_103.tif
82ee89e6d2558c3f700b974a71c58679
6e124fbb520de7d61cf4fab1561f89f60bec6285
F20110217_AABTAM tao_h_Page_087.tif
8882683572741775ea5456ac59d98ab6
8105310c521b02b75485f742021243237d801599
F20110217_AABSVG tao_h_Page_079.tif
7e859dddb4da7c9405487cc1255ce6e4
6784c96305c53631c648eba2074e3d546de278b7
78785 F20110217_AABSUR tao_h_Page_095.jpg
b4364bf9087e75baa8c8415afe05fcd3
bf81353d09b4b8e7f1372f14b9aab8027a309dee
F20110217_AABTBB tao_h_Page_104.tif
3d93c95ec56c425f01e206e52dadca58
8bb3e47a0821b4d8ff95a057054f0cb76215d999
F20110217_AABTAN tao_h_Page_089.tif
51067ee7229ee02c5a3d15ba8abf9ef2
c7c094c1d23420e5440d2c7dde76d00d64791233
87524 F20110217_AABSVH tao_h_Page_093.jpg
bd603628e44e1a8f18675255195adc1f
b73e501c101ed490e2d502811faeca3b9e2b4ab5
2671 F20110217_AABSUS tao_h_Page_019thm.jpg
73577dbaa7d14b0f47653e16c2c2f77c
476fd9a223ce231d082a0f7a7ff8bfbcac00790c
F20110217_AABTAO tao_h_Page_090.tif
2e39f9dc7a2bbed3aa4cc96b4810050f
fa9a2f6d253fe340265a12e64e738a760c06449f
656532 F20110217_AABSVI tao_h_Page_017.jp2
8a79338c4b354e7b06f22efe1a741e19
b1c57d871b1673485cef57e83549c2d5225961a4
8733 F20110217_AABSUT tao_h_Page_045thm.jpg
68c81a96df5c5c81971f928c390c7498
3111ca1b36774fc3aa969aefcdb9f31b8dcc106c
F20110217_AABTBC tao_h_Page_105.tif
f2d8099cc92ac04a4a5f0e4b5d518504
bf0fcc054c74665f166eb1a2e9ba4c267fd9e333
F20110217_AABTAP tao_h_Page_091.tif
09c52dab8fbcd00ef0d91dd109dce269
759e3b72881e595c6783031aa1a3f71bbbbee46f
47474 F20110217_AABSVJ tao_h_Page_082.pro
ba03f2ef2f3555bfef19e744c4064ff8
ffd6b50b9eadf4bd5c58b2f51fa1a78bbfe635d9
32039 F20110217_AABSUU tao_h_Page_050.QC.jpg
1f20fab180db10f22f6c22adb3b2a586
60248532227547e9ba47bf5fdd60fa94fcfd074d
F20110217_AABTBD tao_h_Page_106.tif
fdd34351eb0b2b720c76a0405fab2c7a
85203185210bff5b75f1b3ad6253d70bccbe9901
F20110217_AABTAQ tao_h_Page_092.tif
4a87f951880a6c2eb80b41fdf1e33f07
139a5efa254f97b73f665087c940c3a75990bea7
944669 F20110217_AABSVK tao_h_Page_035.jp2
bf4d12e7a854f88264b6d9e34524ed34
79d5fc912cdbd5a174cad22891e71edc1d5d5e3d
103649 F20110217_AABSUV tao_h_Page_082.jpg
f7e479b1d45feb974ad27de2ebda7df6
5ab6e1fe73ff100de9c4c205ea60b189a0ae949b
F20110217_AABTBE tao_h_Page_107.tif
e94469a6d7c8230f8defa3ae619d256d
30be91b64a37eccf4152dd4324b28cb7a2241f0b
F20110217_AABTAR tao_h_Page_093.tif
ac85b89cdad9a74782b4270d91373fd3
b943c81b2fd623322857613f9acc1fc5a702d143
F20110217_AABSVL tao_h_Page_017.tif
1ba509e15fe12a6ba6f6b8949abaca1f
4796998bbae88d8d72c7cede9e42aa8ff9b77659
7141 F20110217_AABSUW tao_h_Page_054thm.jpg
6317de5265eeeaab824da4bba826fae5
93b163bc290ea5234bd36c59b546e9c1306a7270
F20110217_AABTBF tao_h_Page_108.tif
02af53ac5319973c56730452b406eecc
95906e83c9b2712db12cf411bf8c544701e1777a
1878 F20110217_AABSWA tao_h_Page_074.txt
bfe1f1c47daccd24801736f425fc0409
7bcd6e9bc91c16f0b10a58568120ff1cca6a607f
F20110217_AABTAS tao_h_Page_095.tif
5b7f1eaabe47f4253cebb653db3b0603
02e0a700c73ce0ef72e927869af36a6ebf6d2b4b
1720 F20110217_AABSVM tao_h_Page_087.txt
c69bcfa442d2c853039f5a72bbe40f8b
2baed183861adfce5517d529b0ab26910de4d3e8
44739 F20110217_AABSUX tao_h_Page_028.pro
784626c3254c63f2eee91993f0fec4d5
39020e879c4813c690618ea249ceb41fcc22ab78
F20110217_AABTBG tao_h_Page_109.tif
77af3f6533c136393b93dad1434f73a6
a2ac9b835e94fa124e0c251fe15507b9a2b5d560
73862 F20110217_AABSWB tao_h_Page_067.jpg
0097db95a8ed5154ad9b3230e33b6efe
fa1523ebcca7a7f9952b7e6d82905a8b4311298d
F20110217_AABTAT tao_h_Page_096.tif
20cf44f298d2cc8b9748abec08328340
656c0d9ff565b1edea245ea205126221a7477de4
2303 F20110217_AABSVN tao_h_Page_006.txt
b4cd266617c654c41f8333b48386c765
047e5b1d4771a88b394ae55ed2a4b876ec368d0c
6789 F20110217_AABSUY tao_h_Page_022thm.jpg
d63efb9166c794ef55a0c16f7cbcea33
2a68d7f7147b15c6a9b95db6a96e96e247cc2ea0
463 F20110217_AABTBH tao_h_Page_001.txt
4bf95fd67df8e610d8333fba8f4ef803
5e8fe832a309789e456c91f2f1207130295b9285
F20110217_AABSWC tao_h_Page_086.tif
d0faf258cdb61875a3b7fa01ea19688e
732061e6e4e913ba1bf66f3a783ee079a15e1c98
F20110217_AABTAU tao_h_Page_097.tif
81b9beb5ef306eb65f1ae842813d950f
3aa87f122e9c79a5a9b8e5ce5b7ba00915361959
94431 F20110217_AABSVO tao_h_Page_089.jpg
c4d377b766dc7ec80757a31f84d16ea9
e05b9e4a5c09b7b47b99fb9a276d3fc445fd79a3
F20110217_AABSUZ tao_h_Page_068.txt
67aa7f08f8c34fabefb7b5152b90bdeb
cd695322f7491d2cda975b47443b4b474010f3f7
106 F20110217_AABTBI tao_h_Page_002.txt
b2a1d49ed431b5d1f736ff9fe8ef0ee8
add69e0062e467cfb3acbfe03b5fc1101036e3bd
F20110217_AABSWD tao_h_Page_080.tif
6b66b2baf616ccc9f62e1893d8ebcef7
c2e285c60922224d4bff09343d1a6cc828593123
F20110217_AABTAV tao_h_Page_098.tif
62ca8c91b22b0dbe73fd01875ba54927
b80ad09d748710e867abee9b49f5ebcb0c8e582c
950338 F20110217_AABSVP tao_h_Page_102.jp2
ac4363e41db7c43644c4fe19d4d61b0b
be188f4afb788431739bf8dca2e094bee554eb7c
196 F20110217_AABTBJ tao_h_Page_003.txt
3306ba585aec80da12ac98cb60b9bc83
98f1f231835cf84d77ab317aa8e375c78eb8903b
F20110217_AABSWE tao_h_Page_046.tif
a41fc0aca3513d6f16637a5fe49a83eb
4fe1af59afead8ad9e7fd7f9b9cde393d6e88967
F20110217_AABTAW tao_h_Page_099.tif
47c53f60d1127234ff150caccc3516b7
70820faf022562c17a974cf818f1c4f43c2ec9f9
33376 F20110217_AABSVQ tao_h_Page_004.pro
645a465796513387db7b89251327ae3d
25d6222b8ac677f001db0f9285878d006e0946f3
1380 F20110217_AABTBK tao_h_Page_004.txt
693954543de89197239960e9084d9cc7
83e3962a272cd193bb97f687b179fd1245b8dd7c
96164 F20110217_AABSWF tao_h_Page_031.jpg
34284e238a88f57750f45597d3657b45
b4881020fae15faecdd5331b824c7c408504d072
F20110217_AABTAX tao_h_Page_100.tif
fb538562abcec072eb746dd067275651
2a9e5cd5abb742c7a723704b30b5927df28ed44a
2680 F20110217_AABTBL tao_h_Page_005.txt
bfdd71e3f75c4e874893ad4887428200
5f6c49941278eb83360629e9ec21a2d83cb5f237
27899 F20110217_AABSWG tao_h_Page_093.QC.jpg
c3fb30ac4ec70a7e1107abff490e1232
f582eb6dfe81d3dae5e61a219b2a2d6a90fa9df4
F20110217_AABTAY tao_h_Page_101.tif
92d87d72410771e15e100031e25b148d
36d3b0e242c5c8d1310840654aef5aa2d09341e0
8144 F20110217_AABSVR tao_h_Page_091thm.jpg
cec8d6f3e6bf7589555c9a3045cffb33
eedd831c2695e4eef7b6ace6454035af7cb0fb9b
1810 F20110217_AABTCA tao_h_Page_023.txt
dd6b8888f9a06f8e6388f9299fb42933
c99476712f0426a16c84c7042e5bb8c4ffecfd8c
1790 F20110217_AABTBM tao_h_Page_007.txt
a6b7e98fea4af3a26daedacaadd24821
03a79686d0b77e63702493d8b4e642d4d233fb9f



PAGE 1

SYNTHETIC APPLICATION IN THIOACYLATION, ACYLATION AND SULFONYLATION By HUI TAO A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006

PAGE 2

Copyright 2006 By Hui Tao

PAGE 3

Dedicated to my family, my fa ther Banghe Tao, my mother Pingf en Li and my twin sister Yong Tao

PAGE 4

iv ACKNOWLEDGMENTS It is a great pleasure to acknowledge th e support and assistance I have received from people around me. I would not have ach ieved my Ph.D. wit hout their guidance, support and encouragement. My deepest gratitude goes to my superv isor, Professor Alan R. Katritzky, whose supervision, guidance and support are essential in my chemis try journey. I greatly thank my committee members, Dr. William R. Dolbier, Dr. Lisa McElwee-White, Dr. Daniel R. Talham and Dr. Kenneth Sloan, for their time and help. Particularly, I thank Dr. Dolbier for excellent teaching in physical organic ch emistry and the organic bull session he holds every semester, which brought my understandi ng of organic chemistry to a new level, and Dr. Kenneth Sloan, who opened the door of medicinal chemistry for me and led me to a new world where I can fully apply the knowledge and skills I learned and challenge my potential in a different way. I also want to express my deepest appr eciation to my colleagues in the Katritzky group for their collaboration and friendship. My special thanks are given to Dr. Chunming Cai, Dr. Kostyantyn Kirichenko and Dr. Sanjay Singh for their constant help and encouragement, carefully checking my thes is and shaping my approaches to research.

PAGE 5

v TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES............................................................................................................vii LIST OF FIGURES.........................................................................................................viii LIST OF SCHEMES..........................................................................................................ix ABSTRACT......................................................................................................................x ii CHAPTER 1 GENERAL INTRODUCTION....................................................................................1 2 SYNTHESIS OF N -MONO AND N N -DISUBSTITUTED THIOUREAS FROM (BENZOTRIAZOL-1-YL)CARBOXIMIDAMIDES..................................................7 2.1 Introduction.............................................................................................................7 2.2 Results and Discussion.........................................................................................11 2.3 Conclusion............................................................................................................14 2.4 Experimental Section............................................................................................15 3 EFFICIENT C-SULFONYLATION OF NITRILES AND SULFONES WITH 1SULFONYLBENZOTRIAZOLES............................................................................20 3.1 Introduction...........................................................................................................20 3.2 Results and Discussion.........................................................................................21 3.2.1 Preparation of Sulfonylbenzotriazoles 3.1.................................................21 3.2.2 Synthesis of -Cyano Sulfones..................................................................22 3.2.3 Synthesis of -Sulfonyl Sulfones...............................................................25 3.3 Conclusion............................................................................................................26 3.4 Experimental Section............................................................................................27 4 NOVEL SYNTHESES OF -AMINO ACID DERIVATIVES UTILIZING N PROTECTED AMINOACYLBENZOTRIAZ OLES FROM GLUTAMIC ACID...35 4.1 Introduction...........................................................................................................35 4.2 Results and Discussion.........................................................................................39

PAGE 6

vi 4.2.1 Preparation of 1-( N -Tfa-Aminoacyl)benzotriazoles 4.10.......................39 4.2.2 Syntheses of -Keto-amino Esters 4.11...................................................40 4.2.3 Preparation of -Aryl-amino Esters 4.12 and -Aryl-amino Acids 4.13 by Reduction of -Keto-amino Esters 4.11...........................................41 4.2.4 Configuration Study of -Aryl-amino Acids 4.13...................................42 4.3 Conclusion............................................................................................................43 4.4 Experimental Section............................................................................................44 5 MICROWAVE MEDIATED SYNTHESIS OF -ENAMINO THIOIC ACID DERIVATIVES FROM DIBENZ OTRIAZOLYLMETHANETHIONE..................50 5.1 Introduction...........................................................................................................50 5.2 Results and Discussion.........................................................................................52 5.3 Conclusion............................................................................................................60 5.4 Experimental Section............................................................................................61 6 THE GENERATION AND REACTIVITY OF POLYANION DERIVED FROM 1,1-DIBENZOTRIAZOLYLETHANE......................................................................70 6.1 Introduction...........................................................................................................70 6.2 Results and Discussion.........................................................................................73 6.3 Conclusion............................................................................................................76 6.4 Experimental Section............................................................................................76 7 CONCLUSION...........................................................................................................80 LIST OF REFERENCES...................................................................................................82 BIOGRAPHICAL SKETCH.............................................................................................96

PAGE 7

vii LIST OF TABLES Table page 2-1 Preparation of N -Monoand N,N -Disubstituted Thioureas 2.3a–e from 1Benzotriazole-1-carbothioamide 2.2........................................................................10 2-2 Preparation of Monoand N,N -Disubstituted Thioureas 2.3a–d,f–j........................13 3-1 Synthesis of 1-Sulfonylbenzotriazoles 3.1a–i from Correspondi ng Alkyl or Aryl Sulfonyl Chlorides 3.2 or Or ganolithium Reagents 3.3...........................................22 3-2 Preparation of -Cyano Sulfones 3.5a i via C -Sulfonylation of Nitriles 3.4a–f with Sulfonylbenzotriazoles 3.1a-f..........................................................................24 3-3 Preparation of -Sulfonyl Sulfones 3.7a g via C -Sulfonylation of Sulfones 3.6a–d with Sulfonylbenzotriazoles 3.1a,b,d,e,g......................................................26 4-1 Syntheses of -Keto-Amino Esters 4.11................................................................41 4-2 Preparation of -Aryl-amino Esters 4.12e,f..........................................................41 4-3 Preperation of -Aryl-amino Acids 4.13...............................................................42 4-4 The Comparison of Chiral HPLC Results of 4.13b ( L ) with Corresponding DL Mixtures 4.13g.........................................................................................................43 5-1 The Synthesis of Benzotriazolyl -Enaminothiones 5.5..........................................54 5-2 Microwave-mediated Synthesis of -Enamino Thioic Acid Derivatives 5.6–5.8....55 5-3 C -Thioacylation of Ketimines 5.2a w ith Thioacylbenzotriazoles 5.9a–c................57

PAGE 8

viii LIST OF FIGURES Figure page 1-1 Benzotriazole Intermediate 1.1..................................................................................2 1-2 New Types of Benzotriazole Intermediates 1.2–1.6..................................................3 2-1 The Tautomarization of N -Aryl(benzotriazol-1-yl) carboximidamides 2.4a,d,j.......14 3-1 Sulfonyl Group, a Termporary Transf ormer of Chemical Reactivity......................20 4-1 Known Biologically Active Co mpounds Containing Fragments of -Amino Acids Derivatives.....................................................................................................36 5-1 The Structure of ZnBr2-Thioacylbenzotriazole Complex 5.12................................59

PAGE 9

ix LIST OF SCHEMES Scheme page 1-1 Classical Prototype of Benzotriazole-mediated -Hetero-alkylations.......................2 1-2 The Synthesis of Monoand N,N -Disubstituted Thioureas from (Benzotriazol-1yl)carboximidamides 1.2............................................................................................3 1-3 N -Sulfonylbenzotriazoles as Advantageous Reagents for C -Sulfonylation...............4 1-4 Novel Syntheses of Chiral -Amino Acid Derivatives Utilizing N -(Protected aminoacyl)benzotriazoles from L -Glutamic Acid......................................................4 1-5 The Synthesis of -Enaminothiones 1.8 from Thioacylbenzotriazoles 1.5...............5 1-6 The Synthesis of Benzotriazolyl -Enaminothiones 1.6............................................5 1-7 The Synthesis of -Enamino Thioic Acid Derivatives...............................................6 2-1 Well-known Routes to Substituted Thioureas............................................................9 2-2 Attempted Synthesis of 1-Be nzotriazole-1-Carbothioamide 2.2 from 1Cyanobenzotriazole 2.1 via Benzotriazole-1-carboxylic Acid Amide ....................10 2-3 NMonoand N,N -Disubstituted Thioureas 2.3a–e from 1-Cyanobenzotriazole 2.1 via 1-Benzotriazole-1-carbothioamide 2.2.........................................................10 2-4 Preparation of (Benzotriazo l-1-yl)carboximidamides 2.4a–d,f–j............................12 2-5 Previous Study on Nucleophilic Displacement of Benzotriazole in (Benzotriazol-1-yl)carboximidamides 2.4...............................................................13 2-6 The Proposed Mechanism for the Reaction of (Benzotriazol-1yl)carboximidamides with Hydrogen Sulfide..........................................................14 3-1 1-Sulfonylbenzotriazoles 3.1 as Activating Reagents in N -Acylation of Benzotriazole and Benzotriazolylalk ylation of Aromatic Compounds....................21 3-2 1-Sulfonylbenzotriazoles 3.1 as Effec tive Reagents for N-Sulfonylation of Amines and O-Sulfonylation of Phenols..................................................................21 3-3 Preparation of 1-Sulf onylbenzotriazoles 3.1a–i.......................................................22

PAGE 10

x 3-4 Known Approaches to -Cyano Sulfones................................................................23 3-5 A Novel Approach to -Cyano Sulfones 3.5a–i......................................................24 3-6 A Novel Approach to -Sulfonyl Sulfones..............................................................26 4-1 Literature Methods of Synthesis of -Amino Acids from -Amino Acids..............37 4-2 -Amino Acids from Glutamic Acid........................................................................38 4-3 Novel Syntheses of -amino Acid Derivatives, -Aryl-amino Acids 4.6.............39 4-4 Preparation of N -(Tfa-aminoacyl)benzotriazoles, Tfa-Glu(OMe)-Bt 4.10...........39 4-5 Chiral N -Protected ( -Aminoacyl)benzotriazoles as Acylating Reagents in Friedel-Craft Acylation............................................................................................40 4-6 Syntheses of -Keto-amino Esters 4.11.................................................................40 4-7 Preparation of -Aryl-amino Esters 4.12e,f by the Reduction of -Ketoamino Esters 4.11e,f.................................................................................................41 4-8 Preparation of -Aryl-amino Acids 4.13a,b by the Reduction of -Ketoamino Esters 4.11a,b................................................................................................42 4-9 Synthesis of Compounds 4.13g ( DL ).......................................................................43 5-1 Novel Approach to Dibenzotriazolylmethanethione 5.1..........................................52 5-2 Known Reactions of Benzotriazole and Related Derivatives with Thiphosgene.....53 5-3 The Reactivity of Dibenzotriazoly lmethanethione 5.1 toward Ketimines, Aldimines and Enamines..........................................................................................54 5-4 Novel Approach to -Enamino Thioic Acid Derivatives 5.6–5.8............................55 5-5 Plausible Mechanism for the Reaction of Benzotriazolyl -Enaminothiones 5.5 with Nucleophiles.....................................................................................................56 5-6 Published Benzotriazole-Mediated Thioacylation...................................................57 5-7 Novel Approach to -Enaminothiones 5.10.............................................................57 5-8 Attempts to Obtain -Enaminothiones 5.10 from Diverse Ketimines.....................58 5-9 Ketimine with High Reactivity Reacts Through the Enamino Form with the Complex 5.12...........................................................................................................60

PAGE 11

xi 5-10 Ketimine with Low Reactivity Reacts through Imino Form with the Complex 5.12........................................................................................................................... 60 6-1 The Generation of Dianion 6.2 from 1Vinylbenzotriazole 6.1 and its Reactivity toward Diverse Electrophiles...................................................................................71 6-2 The Generation of Polyanion 6.7 from Dibenzotriazolylmethane 6.6 and its Reactivity toward Different Electrophiles................................................................72 6-3 The Generation of Dianion 6.15 and its Reactivity towa rd a Range of Electrophiles.............................................................................................................74 6-4 Attempted Trapping of Dian ion 6.15 with 1,3-Dielectrophiles...............................75

PAGE 12

xii Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SYNTHETIC APPLICATIONS IN THIOACYLATION, ACYLATION AND SULFONYLATION By Hui Tao August, 2006 Chair: Alan R. Katritzky Major Department: Chemistry Novel synthetic applications of benz otriazole methodology in thioacylation, acylation and sulfonylation have been deve loped to synthesize a wide range of biologically and syntheti cally useful compounds. Chapter 2 describes the r eaction of (benzotriazol-1yl)carboximidamides with hydrogen sulfide, which provide N -mono and N N -disubstituted thioureas under mild conditions in 21–99% yields. 1-Sulfonylbenzotriazoles, as advantage ous sulfonylating reagents, have been applied in N -sulfonylation and O -sulfonylation. In a logical sequel, C -sulfonylation with 1-sulfonylbenzotriazoles was investigated, which is discussed in Chapter 3. The subsequent investigation led to novel syntheses of -cyano sulfones and -sulfonyl sulfones, which are not easy to synthesize by known methods (i.e., via classic sulfonylation of nitriles and sulfones) in synt hetic useful yields.

PAGE 13

xiii Recently, katritzky group has extensively studied 1-acylbenzotriazoles as powerful neutral acylating reagents. In a further exte nsion of this methodology, a novel approach to -amino acid derivatives utilizing N -protected aminoacylbenzotriazoles was achieved and described in Chapter 4. Friedel-Cr afts reactions of readily available N -protected aminoacylbenzotriazoles with hetero and benzenoidaromatics give -amino ketones which can be reduced by either triethyl silane or sodium borohydride to form corresponding -amino acid derivatives. The preser vation of chirality throughout this process was confirmed by chiral HPLC results. In Chapter 5, the synthesis of air and mo isture stable benzotriazole derivatives, benzotriazolyl -enaminothiones, from dibenzotri azolylmethanethione is discussed. Subsequent investigation of thei r synthetic utilities led to a simple and efficient approach to -enamino thioic acid derivatives, including thioamides, thioesters and dithioesters via microwave mediated nucleophlic substituti on of the benzotriazolyl moiety in benzotriazolyl -enaminothiones in 74–99% yields. C -Thioacylation with 1thioacylbenzotriazoles has also b een studied in this chapter. At the end, continuing efforts to develop new routes to heterocycles led to the generation of polyanion from 1,1dibenzotriazolylethane and th e subsequent investigation of the reactivity of polyanions toward a variety of mono-, dia nd trielectrophiles was described in Chapter 6. In one case, wh en the generated polyanion reacted with dielectrophile diethyl oxalat e, the heterocyclization t ook place to give a novel triazoloquinolinone in high yield.

PAGE 14

1 CHAPTER 1 GENERAL INTRODUCTION Benzotriazole has found wide application as an efficient synt hetic auxiliary in organic chemistry. Its derivatives are employed in the photographic, dye and pharmaceutical industries. Diverse applications of benzotriazole as a synthetic auxiliary are due to its unique properties, which allow be nzotriazole to (i) be easily introduced at the beginning of a synthetic se quence; (ii) activate attached functionali ty; (iii) be easily substituted with various nucleophi les; (iv) be recycled at the end of a reaction sequence by simple washing with a weak aqueous ba sic solution, such as sodium carbonate or bicarbonate (benzotriazole is an aci d of appreciable strength with pKa 8.2). The benzotriazole ring system is stable under di verse reaction conditions, and the presence of both pyrrole and pyridine-like nitrogen atoms as well as the aromatic system endows benzotriazole with either electron donor or electron acceptor properties, depending on the nature of the attached substituent, and the reaction conditions. The above special chemical dichotomy gives benzotriazole unique chemical characteristics: the ability to act as a nucleofuge and the ability to activate the -CH toward proton loss are close to those of cyano and phenylsulfonyl groups, and bett er than both phenyl and vinyl groups. The applications of benzotriazole met hodology as a versatile synthetic tool and chemical properties of benzotriazole deriva tives have been periodically reviewed [91T2683, 94S445, 94AA31, 98CR409, 98AA35, 03CEJ4586, 05T2555]. Readily available benzotriazole intermediates of type 1.1 (Fig. 1-1) can react with a variety of nucleophiles providing access to products of s ubstitution of the benzotriazolyl moiety.

PAGE 15

2 Extensive exploration of the util ity of benzotriazole derivatives 1.1 resulted in development of highly important pro cesses of amino-alkylation (X = NR2), amidoalkylation (X = NHCOR), thio amido-alkylation (X = NHCSR ), sulfonamide-alkylation (X = NHSO2R), alkoxy-alkylation (X = OR), alkylth io-alkylation (X = SR) and silylalkylation (X = SiR3) (Scheme1-1). Typical nucleophile s utilized in these reactions [91T2683, 94S445, 94AA31, 98CR409, 98AA35, 03CEJ4586, 05T2555] include Grignard, organozinc, organolithium, organos amarium and tin reagents, enolates, silyl enol ethers, allyl trimethyl silane, active me thylenes, amines, thiols, alcohols, phosphates, and metal hydrides. R1 X Bt Bt = benzotriazol-1-yl X = NR2, NHCOR, NHCSR, NHSO2R, OR, SR, SiR3R1 = alkyl, aryl 1.1 Figure 1-1. Benzotriazole Intermediate 1.1. R X Bt 1.1 + NuR X Nu + Bt-X = NR2, NHCOR, NHCSR, NHSO2R, OR, SR, SiR3 Scheme 1-1. Classical Protot ype of Benzotriazole-mediated -Hetero-alkylations. Further effort to develop new benzotriazole interm ediates and investigate their synthetic applications is of great importa nce. In the present thesis, new types of benzotriazole intermediates, including (benzotriazol-1-yl)carboximidamides 1.2 1sulfonylbenzotriazoles 1.3 1-acylbenzotriazoles 1.4 1-thioacylbenzotriazoles 1.5 and benzotriazolyl -enaminothiones 1.6 have been developed and utilized for the synthesis

PAGE 16

3 of various synthetically useful compounds (Fi g. 1-2). Novel and useful aspects of these benzotriazole intermedia tes are investigated. NH Bt N S O O Bt R R = alkyl, aryl, heteroaryl, R' = H, alkyl, aryl, R1 = Bu, R2 = H, alkyl, R3 = alkyl, aryl 1.21.3 Bt O R Bt' S R 1.41.5 Bt S 1.6 HN R3 R1 R2 Bt' = N N N O2N R R' Figure 1-2. New Types of Benz otriazole Intermediates 1.2–1.6. The results of studies on transformations of (benzotriazol-1-yl)carboximidamides 1.2 to N -monoand N,N -disubstituted thioureas are discussed in Chapter 2. (Benzotriazol-1-yl)carboximidamides 1.2 reacted with hydrogen sulfide in THF giving the corresponding monoand N,N -disubstituted thioureas in moderate to high yields under mild conditions (Scheme 1-2). The po ssible mechanism and potential synthetic advantages are discussed. Bt NH N R'R H2S THF R N S NH2R' 1.2 Scheme 1-2. The Synthesis of Monoand N,N -Disubstituted Thioureas from (Benzotriazol-1-yl)carboximidamides 1.2. In Chapter 3, a novel approach to -functionalized sulfones is discussed. Reactions of readily available N -(alkyl-, aryl-, and hetero arylsulfonyl)benzotriazoles 1.3 with anions, generated from n itriles or sulfones, produce cyanoalkyl sulfones and sulfonylalkyl sulfones respect ively, in moderate to high yields (Scheme 1-3).

PAGE 17

4 In Chapter 4, novel syntheses of chiral -amino acid derivatives, utilizing N protected aminoacylbenzotriazoles, prepared from L -glutamic acid is discussed. The preservation of chirality th roughout this process is conf irmed by chiral HPLC tests (Scheme 1-4). R1CN R2 R1CN R2RO2S S O O Bt R 1.3 n-BuLi THF R1O2S R2 R1O2S R2SO2R n-BuLi THF Scheme 1-3. N -Sulfonylbenzotriazoles as Advantageous Reagents for C -Sulfonylation. Et3SiH N H O Ar TFA OMe O TiCl4N H O Bt TFA OMe O NaBH4CF3COOH N H Ar TFA OH O N H Ar TFA OMe O 46-88% Aromatics TFA-Glu(OMe)-Bt DMF/H2O 1.4 Scheme 1-4. Novel Syntheses of Chiral -Amino Acid Derivatives Utilizing N -Protected aminoacylbenzotriazoles from L -Glutamic Acid. In Chapter 5, the syntheses and synthe tic applications of two benzotriazole derivatives, 1-thioacylbenzotriazoles 1.5 and benzotriazolyl -enaminothiones 1.6 are discussed. The reactivity of thioacylbenzotriazoles 1.5 toward various nucleophiles is investigated and it is found that the reactive ketimines 1.7 reacted with

PAGE 18

5 thioacylbenzotriazoles 1.5 smoothly to give -enaminothiones 1.8 in moderate to good yields (Scheme 1-5). Inspired by the results obtained in the synthesis of -enaminothiones 1.8 this methodology is extended to the synthesis of novel benzotriazole intermediates, benzotriazolyl -enaminothiones 1.6 from dibenzotriazolylmethanethione 1.9 and ketimines 1.7 (Scheme 1-6). R1N R3R2 N N N R4S O2N ZnBr2THF, r.t. R1NHS R4R3R2 + 1.7 R1 = Ph, R2 = H R3 = Bu 1.5 1.8 Scheme 1-5. The Synthesis of -Enaminothiones 1.8 from Thioacylbenzotriazoles 1.5. S Bt Bt THF R1NH R3Bt S R2 R1N R3R2 r.t. 6h 1.7 1.9 + 1.6 Scheme 1-6. The Synthesis of Benzotriazolyl -Enaminothiones 1.6. Further investigations support benzotriazolyl -enaminothiones 1.6 as effective synthetic precursors to -enamino thioic acid derivatives 1.10 including thioamides, thioesters (thiocarboxylicO -esters) and dithioes ters (thiocarboxylicS -esters) (Scheme 17). R1NH R3Bt S R2 + HXR4X = O, S, NR4microwave irradiation base R1NH R3XR4S R2 1.6 1.10

PAGE 19

6 Scheme 1-7. The Synthesis of -Enamino Thioic Acid Derivatives. As mentioned previously, besides acting as a leaving group, a benzotriazolyl group also activates the deprotonation of -H. Futhermore, treatment of some benzotriazole derivatives by excess base leads to deprot onation of the benzotri azolyl group at the 7position giving a polyanion. The reactivit y of polyanions, generated from 1,1dibenzotriazolylethane, toward electrophiles, including reactions with a variety of mono-, di-, and trielectrophiles, is discussed in Chapter 6.

PAGE 20

7 CHAPTER 2 SYNTHESIS OF N -MONO AND N N -DISUBSTITUTED THIOUREAS FROM (BENZOTRIAZOL-1-YL)CARBOXIMIDAMIDES 2.1 Introduction Thiourea-containing compounds are important because of their numerous chemical and pharmaceutical applications. For exampl e, thiourea derivatives are efficient guanylating agents both in solution [86JOC1882, 98S460] and on solid support [98T15063, 98TL2663, 02EJOC3909]. Thermal decomposition of N -arylthioureas gives aryl isothiocyanates [56J CS659, 56OS56]. Oxidation of arylthioureas with lead tetraacetate [51OS19] or iodi c acid [30JA3647] affords arylcyanamides. Thioureas are also widely used as building blocks to c onstruct libraries of small heterocyclic ring systems that have potential utility in pharmaceu tical applications and related areas. Solidphase Biginelli pyrimidine synthesis [03A RK(iv)93] and synthesis of imidazolone derivatives [99OL1351] usi ng resin-bound thioureas were recently reported. Thioureas also condense with -halocarbonyl compounds to afford 2-amino-1,3-thiazoles [96CL1409, 98JOC196, 98ACIE1402, 99JC SP(1)11363, 01ARK(v)119, 02ARK(x)72], which are potential drug candidates for the treatment of a llergies [83JMC1158], hypertension [92JMC2562], inflammati on [88JMC1719], bacterial infections [94BMCL1601], and HIV [95JMC4929]. Benz othiazoles can be prepared from arylthioureas in the presence of bromine [84J OC997]. The utility of thioureas to prepare 1,3-thiazines [97S573], 1,3-di azines [86S1041], 1,3-quinazo lines [00JCC378] and 1,2,4triazin-5-ones [01TL4433] was also described recently. In pa rticular, 1,2,4-triazin-5-ones

PAGE 21

8 have exhibited anticancer [88CL29], antiu lcer [86JP61134389] and anti-inflammatory [73RC2199] activities. Commerci ally, thioureas are used in industries as diverse as dye products, photographic films, elastomers, plas tics and textiles. Some thiourea derivatives are insecticides, preservatives, rodenticides and pharmaceuticals [55CR181]. Furthermore, the ability of thioureas to form crystalline complexes with branched hydrocarbons and cycloaliphatic structures has le d to their use in th e characterization and separation of mixtures of or ganic compounds [51USP2520715]. Synthetic approaches to thioureas have been investigated extensively [55CR181, 95COFGT569]. Well-known routes to substi tuted thioureas (Scheme 2-1) involve reactions of (i) anilines w ith sodium [72JMC1024] or am monium thiocyanate [63OS180] in the presence of strong acids (TFA or concentrated HCl); (i i) aroyl isothiocyanates with amines followed by basic hydrolysis [ 34JA1408, 55OS735, 88S456]; most recently, mono and N N -disubstituted thioureas were also pr epared on solid support using Fmocisothiocyanate followed by subsequent deprotection [99OL1351]; (iii) silicon tetraisothiocyanate with primary or seconda ry amines [73OS801]; (iv) unsubstituted thioureas with primary alkyl amines at 170–180 oC [56JOC483]; (v) isothiocyanates with ammonia or amines [55OS617, 01ARK(iii)33, 02 ARK(i)7]; (vi) primary amines with carbon disulfide in the presence of mercur y acetate and aqueous ammonia [51JACS906]; (vii) disubstituted cyanamides with hydr ogen chloride and LiAlHSH [01TL6333] or hydrogen sulfide and ammonia [55OS609]. Although these synthetic approaches have prove n to be of great utility for specific classes of the title compounds, method (i) was limited to monos ubstituted thioureas; methods (ii), (iii), (v) and (vii) require aroyl isothiocyanates, silicon tetraisothiocyanate,

PAGE 22

9 isothiocyanates and disubstituted cyanamides respectively; methods (iv) and (vi) need either harsh reaction conditions (170–180 oC) or the presence of mercury salt while method (vi) was also limited to the prep aration of monosubstituted thioureas. LiAlHSH or H2S/NH3PhCONCS R1NH2Si(NCS)4R1N R2N N S R1R2N H S NH2H2N R1NH2R1R2NH CS2R3NCS Hg(OAc)2NH3R1NH2R1 =Aryl MSCN 1. R1R2NH 2. OH-1. R1R2NH 2. H+R3 = H(i) (ii)(iii)(iv) (v) (vi) (vii)M = Na, NH4 R3 R2, R3 = H R3 = H R2, R3 = H R3 = PhCO R2, R3 = H Scheme 2-1. Well-known Routes to Substituted Thioureas. Inspired by the wide applications of thi ourea, new approaches to the synthesis of thioureas were attempted. The synthesis of mono and N N -disubstituted thioureas from (benzotriazol-1-yl)carboximidamides is addressed in this chapter. Recently, a new and efficient reagent, benz otriazole-1-carboxylic acid amide, for the preparation of mono and N N -disubstituted ureas (Scheme 2-2) [03ARK(viii)8] was developed. Attempts to prepare 1-benzotriazole-1 -carbothioamide from the previously described benzotriazole-1-carboxylic acid amide [03ARK(viii)8] with Lawesson’s reagent gave only benzotriazole (Scheme 2-2). Reactions of benzotriazole or 1-

PAGE 23

10 trimethylsilyl benzotriazole with sodium thiocyanate, sodium hydrogen sulfide or trimethylsilyl isothiocyanate failed under various condi tions. Finally, the desired 1benzotriazole-1-carbothioamide 2.2 was prepared by Nataliya Kirichenko in 84% yield from 1-cyanobenzotriazole 2.1 in DME under hydrogen sulfide gas flow (Scheme 2-3). BtN Bt O NH2 R1N O NH2R2 2.1 R1R2NH THF 30% H2O2(n-C4H9)4N+HSO4 CH2Cl2, r.t. Bt S NH2 Lawesson's reagent 2.2 Scheme 2-2. Attempted Synthesis of 1-Benzotriazole-1Carbothioamide 2.2 from 1Cyanobenzotriazole 2.1 via Benzotriazole-1-carboxylic Acid Amide Nataliya Kirichenko in the Katritzky rese arch group found that 1-benzotriazole-1carbothioamide 2.2 was unreactive toward amines in THF at 20 oC and only reacted sluggishly under reflux. Treatment of 2.2 with amines in refluxing toluene gave the corresponding thioureas 2.3a – e in moderate yields (39–71%) (Scheme 2-3, Table 2-1) [04S1799]. BtN H2S Bt S NH2 R1N S NH2R2 2.1 2.2 2.3a-e R1R2NH toluene reflux DME, r. t. Scheme 2-3. Monoand N,N -Disubstituted Thioureas 2.3a–e from 1-Cyanobenzotriazole 2.1 via 1-Benzotriazole-1-carbothioamide 2.2.

PAGE 24

11 Table 2-1. Preparation of Monoand N,N-Disubstituted Thioureas 2.3a–e from 1Benzotriazole-1-carbothioamide 2.2. Entry Prodcut R1 R2 Yield (%) 1 2.3a 4-CH3O-C6H4H 54 2 2.3b Benzyl Benzyl67 3 2.3c pyrrolidinyl 54 4 2.3d Phenyl H 71 5 2.3e PhNH H 39 2.2 Results and Discussion The moderate yields of thioureas 2.3a–e (Table 2.1), under rela tively harsh reaction conditions make it necessary to find an alternative approach via (benzotriazol-1yl)carboximidamides 2.4 (Benzotriazol-1-yl)carboximidamides 2.4a–d,f–j (Scheme 2-4) were prepared from di(benzotriazolyl)methanimine 2.5 available as mixture of isomers 2.5 and 2.5 (Scheme 2-4), and primary or secondary amines in 56-82% yield [00JOC8080]. The displacement of the first benzotriazole moiety was affected by the addition of an amine of choice to a solution of isomers 2.5 and 2.5 in THF. Compounds 2.4a–d,f–j were obtained exclusively as pure Bt1 isomers, probably due to the preferential displacement of the Bt2 group in the 2.5 isomer. Furthermore, compared to the previous approach via 1-cyanobenzotriazole 2.1 di(benzotriazolyl)methanimine 2.5 is more air and moisture stable, more crystalline-like (1-cyanobenzotriazole 2.1 amorphous mp 73–75 oC [67JA4760]; di(benzotriazolyl)methanimine 2.5 white microneedles, mp 162–163 oC [00JOC8080]), and is prepared under mild conditions (no NaH required). These chemical and physical properties make di(benzotriazolyl)methanimine 2.5 a better starting material for the synthesis of thioureas. Nucleophilic displacement of benz otriazole in (benzotriazol-1yl)carboximidamides 2.4a–d f–j by a variety of amines with the formation of triand tetrasubstituted guanidines has been reported previously [00JOC8080]. Previous reports

PAGE 25

12 [91RRC573, 00JOC8080] also indicate that mono-subst ituted (benzotriazol-1yl)carboximidamides 2.4a d h i j are stable compounds which are resistant to displacement of benzotriazole by amines [00J OC8080] and to elimination in highly basic conditions (Scheme 2-5) [91RRC573]. N N N Bt = Bt1 = Bt1NH Bt1 THF Bt NH N R1R2 2.4a-d,f-j 2.5' r. t. Bt2 = N N N Bt1NH Bt2 2.5" + 2 BtH BrCN 2.5 '& 2.5" mixture + R1HN R2 H2S THF R1N S NH2R2 2.3a-d, f-j Scheme 2-4. Preparation of (Benzotr iazol-1-yl)carboximidamides 2.4a–d,f–j. Continuing the efforts in benzotri azole methodology, the reactivity of (benzotriazol-1-yl)carboximidamides 2.4 toward substitution of benzotriazolyl group with hydrogen sulfide has investigate d. (Benzotriazol-1-yl)carboximidamides 2.4b c f–i reacted with hydrogen sulfide smoothly in THF at 20 oC and gave the desired mono and N,N-disubstituted thioureas 2.3b c f–i (method A). However, N-aryl(benzotriazol-1yl)carboximidamides 2.4a d j did not react with hydrogen su lfide at room temperature. In refluxing THF, rapid desorption of hydr ogen sulfide from the reaction mixture apparently occurred resulting in no reaction. He ating the reaction mixture in a sealed tube at 90 oC in THF saturated with hydrogen sulfide, results in successful conversion of N-

PAGE 26

13 aryl substituted compounds 2.4a d j into the desired thioureas 2.3a d j in 21–78% isolated yields (method B) (Scheme 2-4, Table 2-2). Bt NH N R1R2 2.4 + R3HN R4 R1 = alkyl, aryl R2 = alkyl THF, reflux THF, reflux R2 = H KOH/MeOH no reaction N NH N R1R2 R3 R4 R2 = H R2 = alkyl PhCl, heat NCN R1 R 2 Scheme 2-5. Previous Study on Nucleophi lic Displacement of Benzotriazole in (Benzotriazol-1-yl)carboximidamides 2.4. Table 2-2. Preparation of Monoand N,N -Disubstituted Thioureas 2.3a–d,f–j. Entry Prodcut R1 R2 MethodaYield (%) 1 2.3a 4-CH3O-C6H4H B 59 2 2.3b Benzyl BenzylA 86 3 2.3c pyrrolidinyl A 85 4 2.3d Phenyl H B 78 5 2.3f (CH2)2O(CH2)2 A 99 6 2.3g Ethyl Ethyl A 92 7 2.3h Benzyl H A 76 8 2.3i n-Butyl H A 94 9 2.3j 4-Cl-C6H4 H B 21 a: Method A: THF, rt; Method B: THF, sealed tube, 90 C. These reaction results suggest a plausible mechanism of substitution, which involves initial formation of the cationic carbodiimide 2.4 followed by the nucleophilic addition of hydrogen sulfide and tautomarization to afford 2.3 as final product (Scheme 2-6). This mechanism was also supported by previous research results (Scheme 2-5) [91RRC573, 00JOC8080].

PAGE 27

14 BtNHN R1R2 THF R1N S NH2R2 NH C N R1 R2 Bt-SH2 R1N NH SH2R2 2.4 2.3 Scheme 2-6. The Proposed Mechanism for the Reaction of (Benzotriazol-1yl)carboximidamides with Hydrogen Sulfide. As depicted in Scheme 2-6, the fo rmation of the cationic carbodiimide 2.4 would be facilitated by aliphati c chains on the quarternary nitrogen. These cationic carbodiimides readily re act with hydrogen sulfide followed by tautomerization to give the desired thioureas, in a total eff ect of benzotriazole substitution. However, in the presence of an aromatic substitutent on the nitrogen, st ructural tautomers play an important role. Compounds 2.4a d j prefer to exist in the more conjugated tautomeric form 2.4 a d j (Figure 2-1). This fact is s upported by the NMR spectra of ar yl substituted (benzotriazol1-yl)carboximidamides 2.4a d j where a 2-proton broad signal, corresponding to NH2 in the range of 5.76–5.80 ppm is observed. The form ation of cationic carbodiimide requires higher energy. Bt NH NH R1 2.4"a,d,j R1 = aryl Bt NH2N R1 2.4a,d,j Figure 2-1. The Tautomerization of N -Aryl(benzotriazol-1-yl) carboximidamides 2.4a,d,j. 2.3 Conclusion In summary, di(benzotriazolyl)methanimine 2.5 [00JOC8080] readily reacts with primary and secondary amines to give (benzotriazol-1-yl)carboximidamides 2.4a–d f–j which are easily converted into mono and N N -disubstituted thioureas 2.3a–d f–j with hydrogen sulfide under mild reaction conditions. The present procedure is advantageous in comparison to literature methods by avoiding the use of strong acids [63OS180,

PAGE 28

15 72JMC1024], strong bases [34JA1408, 55OS735, 88S456], difficult to handle reagents (such as silicon tetraisothiocyanate [73OS 801] or LiAlHSH [01TL6333]), high reaction temperatures [56JOC483] and environmenta lly hazardous heavy metal salts [51JA906]. Furthermore, since the preparation of (benzotriazol-1-yl)carboximidamides [02JCC285, 02JCC290] on solid su pport has been described, the development of this protocol could be valuable in combinatorial synthesis. 2.4 Experimental Section General. All reactions were carried out unde r nitrogen atmosphere. THF and DME were freshly distilled over sodium / benzophenone; toluen e was distilled over sodium before use. Other materials were used as supplied. Melting points were determined by using a capillary melting point apparatus equipped with a digital thermometer and Bristoline hot-stage micros cope and were uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a Varian Gemini 300 spectrometer in CDCl3 (with TMS for 1H and CDCl3 for 13C as the internal referenc e), unless otherwise stated. The elemental analyses were performed on a Carlo Erba EA–1108 instrument. Column chromatography was conducted on silica gel 200 425 mesh. Di(benzotriazolyl)methanimine 2.5 was prepared according to published procedure [00JOC8080] as off-white microcrystals (62%), mp 162 163 C, (lit. mp 162-163 C [00JOC8080]). Compounds 2.4a–d,f–j were prepared according to the published procedures[00JOC8080, 01S897]: be nzotriazol-1-yl(tetrahydro-1 H -pyrrol-1yl)methanimine ( 2.4c ), yellow oil [00JOC8080] (70%); N -phenyl benzotriazole-1carboximidamide ( 2.4d ), white prisms from methanol (56%), mp 123–124 C (lit. mp

PAGE 29

16 123–124 C [00JOC8080]); benzot riazol-1-yl(tetrahydro-4 H -1,4-oxazin-4yl)methanimine ( 2.4f ) light yellow oil [00JOC8080] (65%); N N -diethyl-1 H benzotriazole-1-carboximidamide ( 2.4g ), yellow oil [01S897] (60%); N (benzyl)benzotriazole-1-carboximidamide ( 2.4h ), colorless needle s (82%), mp 97–98 C (lit. mp 97–98 C [00JOC8080]). N’ -(4-Methoxyphenyl)-1 H -1,2,3-benzotriazole-1-carboximidamide (2.4a). Light yellow microcrystals (87%); mp 140–141 C; 1H NMR 3.82 (s, 3H), 5.80 (br s, 2H), 6.93–6.97 (m, 2H), 7.04–7.07 (m, 2H), 7.43–7.49 (m, 1H), 7.57–7.62 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H); 13C NMR 55.5, 115.0, 115.4, 119.7, 122.8, 125.2, 129.3, 131.2, 139.5, 144.4, 146.7, 156.2. Anal. Calcd for C14H13N5O: C, 62.91; H, 4.90; N, 26.20. Found: C, 63.14; H, 4.75; N, 26.56. N,N -Dibenzyl-1 H -1,2,3-benzotriazole-1-carboximidamide (2.4b). Colorless oil (55%); 1H NMR 4.49 (s, 4H), 7.25–7.36 (m, 11H), 7.40–7.50 (m, 1H), 7.53–7.59 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H); 13C NMR 51.7, 111.0, 120.3, 124.9, 127.7, 127.9, 128.7, 129.2, 132.1, 136.2, 145.7, 152.0. Anal. Calcd for C21H19N5: C, 73.88; H, 5.61; N, 20.51. Found: C, 74.16; H, 5.77; N, 20.97. N -Butyl-1 H -1,2,3-benzotriazole-1-carboximidamide (2.4i) Off-white microcrystals (92%), mp 56–58 C; 1H NMR (DMSOd6) 0.98 (t, J = 7.1 Hz, 3H), 1.50–1.52 (m, 2H), 1.66–1.70 (m, 2H), 3.33 (t, J = 6.8 Hz, 2H), 7.06 (br s, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.67 (d, J = 7.3 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H); 13C NMR (DMSOd6) 13.9, 20.3, 33.0, 46.3, 115.2, 119.2, 124.9, 128.7, 131.0, 144.8, 145.8. Anal. Calcd for C11H15N5: C, 60.81; H, 6.96; N, 32.23. Found: C, 61.25; H, 7.13; N, 32.49.

PAGE 30

17 N’ -(4-Chlorophenyl-1 H -1,2,3-benzotriazole-1-ca rboximidamide (2.4j). Offwhite microcrystals (45%), mp 146–148 C; 1H NMR 5.76 (br s, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 8.1 Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.51 (d, J = 8.1 Hz, 1H); 13C NMR 115.3, 119.8, 123.2, 125.3, 129.1, 129.5, 129.7, 131.2, 144.2, 145.2, 146.7. Anal. Calcd for C13H10ClN5: C, 57.47; H, 3.71; N, 25.78. Found: C, 57.93; H, 3.64; N, 25.56. General Procedure for the Preparation of Compounds 2.3a–d f–j from 2.4a– d f–j. Hydrogen sulfide was bubbled into THF (40 mL) for 2 minutes under dry conditions. The (benzotri azol-1-yl)carboximidamide 2.4 (2.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 h (for 2.3b–c f–i ) under a flow of hydrogen sulfide. Completion of the reaction was monitored by TLC. For compounds 2.3a d j the reaction was very slow at room temperature. After bubbling hydrogen sulfide into the reaction mi xture for 1 h at room temperature, the hydrogen sulfide flow was stopped and the reacti on mixture was allowed to react at 90 C for 4 h in a sealed tube. The solvent was re moved under reduced pressure and the residue was dissolved in dichloromethane and washed with 10 % aqueous Na2CO3. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under reduced pressure. For thioureas 2.3b c g no further purifica tion was required; 2.3d f h–j were purified by gradient column chromatography on silica gel with ethyl acetate/hexanes from 1/6 to 1/1. Compound 2.3a precipitated from the reaction mi xture, was filtered and washed with hexanes.

PAGE 31

18 p -Methoxyphenylthiourea (2.3a). Off-white microcrystals (59%), mp 209–210 C (lit. mp 210–210 C [60JOC770]); 1H NMR (DMSOd6) 3.74 (s, 3H), 6.90 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.24–7.62 (m, 2H, NH2), 9.48 (s, 1H, NH); 13C NMR (DMSOd6) 55.2, 114.0, 125.6, 131.7, 156.6, 181.1. N,N -Dibenzylthiourea (2.3b). White microcrystals (86%), mp 137–138 C (lit. mp 138–139 C [79CB1956]); 1H NMR 4.92 (br s, 4H), 5.84 (br s, 2H), 7.26–7.39 (m, 10H); 13C NMR 54.6, 126.9, 127.9, 129.0, 135.2, 183.8. 1-Thiocarbamoylpyrrolidine (2.3c). Off-white microcrystals (54%), mp 194– 196 C (lit. mp 193–197 C [56AC545]); 1H NMR (DMSOd6) 1.80–1.92 (m, 4H), 3.27–3.38 (m, 2H), 3.54–3.60 (m, 2H), 7.09 (br s, 2H); 13C NMR (DMSOd6) 24.6, 25.9, 47.5, 51.4, 178.3. Phenylthiourea (2.3d). White microcrystals (71%), mp 153–154 C (lit. mp 154– 154 C [60JOC770]); 1H NMR (acetoned6) 6.90–7.10 (m, 4H), 7.20 (t, J = 7.2 Hz, 1H), 7.35–7.46 (m, 4H), 9.16 (br s, 1H); 13C NMR (acetoned6) 124.8, 126.3, 130.0, 139.7, 183.3. 4-Thiocarbamoylmorpholine (2.3f). White microcrystals (99%), mp 159–161 C (lit. mp 160–161 C [72USP3700664]); 1H NMR (DMSOd6) 3.55–3.58 (m, 4H), 3.70– 3.73 (m, 4H), 7.50 (br s, 2H); 13C NMR (DMSOd6) 47.9, 66.0, 182.7. 1,1-Diethylthiourea (2.3g). Light-yellow microcrystals (92%), mp 82–84 C (lit. mp 98–101 C [01TL6333]); 1H NMR 1.18 (t, J = 7.1 Hz, 6H), 3.58 (br s, 4H), 5.91 (br s, 2H); 13C NMR 12.3, 46.0, 180.3. Benzylthiourea (2.3h). Colorless microcrystals (76%), mp 154–155 C (lit. mp 155–156C [88LAC983]); 1H NMR (DMSOd6) 4.66 (s, 2H), 6.60 (s, 1H), 7.11 (br s,

PAGE 32

19 1H), 7.28–7.39 (m, 5H), 8.03 (br s, 1H); 13C NMR (DMSOd6) 47.5, 127.0, 127.4, 128.4, 139.3, 183.5. Butylthiourea (2.3i). White microcrystals (94%), mp 67–69 C (lit. mp 71–72 C [71P3155]); 1H NMR 0.94 (t, J = 7.3 Hz, 3H), 1.36–1.43 (m, 2H), 1.55–1.65 (m, 2H), 3.20 (br s, 2H), 5.88 (br s, 2H), 6.39 (br s, 1H); 13C NMR 13.5, 19.9, 30.5, 44.2, 44.9, 180.4, 182.8 (mixture of rotamers). (4-Chlorophenyl)thiourea (2.3j). Off-white microcrystals (21%), mp 178–179 C (lit. mp 180–181 C [00JMC2362]); 1H NMR (DMSOd6) 7.37–7.51 (m, 6H), 9.78 (s, 1H); 13C NMR (DMSOd6) 124.6, 128.1, 128.5, 138.2, 181.2.

PAGE 33

20 CHAPTER 3 EFFICIENT C-SULFONYLATION OF NITRILES AND SULFONES WITH 1SULFONYLBENZOTRIAZOLES 3.1 Introduction Sulfones are one of the fundamental classe s of intermediates in organic synthesis [88MI, 93MI, 97CL1023] and have wide a pplicability in fields as diverse as agrochemicals [88USP4780127], pharm aceuticals [90JOC955, 03USP6525042] and polymers [93USP5260489]. Sulfones have been described as “chemical chameleons” and therefore have sustained the interest of chemists all ove r the world. The sulfonyl group has the ability to serv e as a temporary transformer of chemical reactivity [84JA7260], it can function as an electrophile via the sulfur atom or as a leaving group (Figure 3-1) [94TL6017]. This, coupled with its powerful stabilizing properties for the adjacent carbanions in carbon-carbon bond form ing reactions [94JOC2014, 97CL1025, 97JCSCC1210, 97T307], gives sufficient driving force to the intramolecular nucleophilic substitution in the formation of cyclopropanes [69JOC3085, 75JCSP(1)897]. R1C R2 RO2S H = R1C R2 Figure 3-1. Sulfonyl Group, a Termporary Tr ansformer of Chemical Reactivity. 1-Sulfonylbenzotriazoles have been prev iously used in the preparation of N acylbenzotriazoles [00J OC8210]. They also act as an ac tivating moiety of aldehydes in the benzotriazolylalkylation of aroma tic compounds (Scheme 3-1) [94H345].

PAGE 34

21 RCO2H, Et3N THF, r.t. PhSO2Bt 3.1a Ar1CHO Ar2H Ar1 Ar2 Bt RCOBt Scheme 3-1. 1-Sulfonylbenzotriazole s 3.1 as Activating Reagents in N -Acylation of Benzotriazole and Benzotriazolyla lkylation of Aromatic Compounds. 1-Sulfonylbenzotriazoles have al so been used as effective N -sulfonylation agents of amines and O -sulfonylation agents of phenols to give the corresponding sulfonamides and sulfonates, respectively (Scheme 3-2) [94SC205, 04JOC1849]. THF R1SO2Bt + NHR2R3r.t. R1 = aryl, alkyl, heteroaryl THF R1SO2Bt + NHR2R3r.t. 15 examples (yield: 51 99%) THF R1SO2Bt + ArOH R1SO3Ar r.t. 10 examples (yield: 51 99%) R1 = aryl, alkyl 3.1 3.1 R1SO2NR2R3R1SO2NR2R3 Scheme 3-2. 1-Sulfonylbenzotriazole s 3.1 as Effective Reagents for N -Sulfonylation of Amines and O -Sulfonylation of Phenols. Using this approach, C -sulfonylation with 1-sulf onylbenzotriazoles was investigated. Novel syntheses of -cyano sulfones and -sulfonyl sulfones, which are not easily available by known methods i.e. via classic sulfonylation of nitriles and sulfones, are developed in this chapter. 3.2 Results and Discussion 3.2.1 Preparation of Sulfonylbenzotriazoles 3.1 Sulfonylbenzotriazoles 3.1 were prepared according to the literature procedures [92T7817]. The reaction of alkyl or aryl sulf onyl chlorides with benzotriazole in the presence of pyridine afforded the corres ponding alkyland aryl sulfonylbenzotriazoles 3.1a–e while the reaction of organolithium r eagents with sulfur dioxide at –78 oC gave

PAGE 35

22 lithium sulfinates that reacted with N -chlorobenzotriazole in the presence of triethylamine to give heteroarylsulfonylbenzotriazoles 3.1f–i (Scheme 3-3, Table 3-1) [04JOC1849]. RSO2ClBtSO2RRLi BtH, C5H5N R = alkyl or aryl 3.2 3.1a-g i) SO2ii) BtCl, NEt3R = heteroaryl 3.3 method A method B Scheme 3-3. Preparation of 1Sulfonylbenzotriazoles 3.1a–i. Table 3-1. Synthesis of 1-Sulfonylbenzotri azoles 3.1a–i from Corresponding Alkyl or Aryl Sulfonyl Chlorides 3.2 or Organolithium Reagents 3.3. Prodcut R MethodYield (%) 3.1a Methyl A 97 3.1b 4-Tolyl A 78 3.1c Phenyl A 81 3.1d Butyl A 81 3.1e 4-NO2C6H4 A 87 3.1f 2-Thienyl B 82 3.1g 2-Pyridinyl B 71 3.1h 3-Pyridinyl B 52 3.1i Benzofur-2-yl B 81 3.2.2 Synthesis of -Cyano Sulfones -Cyano sulfones are important precurso rs in synthetic chemistry [77S690, 80S565, 92S552, 94JOC1518, 95SL645, 96SL1067, 97JOC 4562]. They are utilized in the preparation of numerous com pounds, including pyr idones [99S1169], 4aminopyrimidines [84S1045], 5,6-dihydro-4 H -pyrans [75S260], tetrahydrofurans, [98JOC3067] tetrasubstituted cylcobutanes [75S260], and cyclopropanes [85JOC2806, 03CC536]. In addition, they are also valu able building blocks for constructing biologically active compounds such as -amido sulfones [39JA3386] and L -indospicines [96BMCL111]. Published synthetic routes to -cyano sulfones include (S cheme 3-4): (i) oxidation of the corresponding sulfides [ 87S453]; (ii) alkylation of ben zenesulfinate salts with -

PAGE 36

23 halo nitriles either under the conditions of anionic activation [77S690, 84JOC1125] or heat in two-phase system (so lid-liquid) in the presence of phase-transfer catalyst [87S56] or alkylation of phenyl sulfonyl chloride with -halo acetonitriles in the presence of sodium diethylphosphorotellu rite [90SC2291]; (iii) Cp2TiCl2-catalyzed addition of Reformatsky reagents to geminal cya nosulfonylalkenes [01SC2089] and (iv) sulfonylation of nitriles w ith phenyl tosylate [95SC4063] Although these synthetic approaches are of great util ity for specific classes of the title compounds, there are drawbacks. Method (i) suffers from foul sme lling starting material while approaches (ii) and (iii) require -halo nitriles and geminal cyanosul fonylalkenes which are not usually readily available. They are also limited by th eir functional tolerance. The method (iv) was reported for the tosylation of arylacetonitriles only. R1CN RSO3Ph R S R1CN R S O O R1CN RSO2 R 3R2CN R1CN Hal RSO2Cl or RSO2Na Oxidation (i) + (ii) (iii) R = p -tolyl (iv) + R4ZnX R1 = CR2 R3R4 R = aryl, R1 = H R2 = R3 Scheme 3-4. Known Approaches to -Cyano Sulfones. With the objective to develop a general and efficient route to -cyano sulfones, the reactions of nitriles 3.4 with 1-sulfonylbenzotriazoles 3.1 were investigated. It was found that 1-sulfonylbenzotriazoles 3.1 reacted with nitriles 3.4 smoothly in the presence of

PAGE 37

24 either n -BuLi or t -BuOK to afford the desired -cyano sulfones in good to high yields (Scheme 3-5, Table 3-2). R1CN 2) BtSO2R 3.4a-f A) n-BuLi, THF, -78 0C B) t-BuOK, DMSO, r.t. 3.5a-i R2 R1CN R2 RO2S 1) Base Scheme 3-5. A Novel Approach to -Cyano Sulfones 3.5a–i. Table 3-2. Preparation of -Cyano Sulfones 3.5a i via C -Sulfonylation of Nitriles 3.4a–f with Sulfonylbenzotriazoles 3.1a–f. Product R R1 R2 MethodYield (% ) 3.5a Phenyl Phenyl H A 76 3.5b Phenyl H H A 50 3.5c 2-Thienyl 2,4-Cl2C6H3H A 90 3.5d 2-Pyridinyl n -Hexyl H A 54 3.5e 3-Pyridinyl Phenyl MethylA 73 3.5f Methyl 4-BrC6H4 H B 82 3.5g* Methyl 2,4-Cl2C6H3 H B 87 3.5h* 4-Tolyl 4-BrC6H4 H A 93 3.5i* 4-Tolyl 2,4-Cl2C6H3H B 97 *: compounds 3.5f,g,h,i were prepared by Dr. Ashraf A. A. Abdel-Fattah, which were not included in experimental part. Spectroscopic and analytical data of these compounds are available in the correspondi ng published paper [05JOC9191]. Initially, 4-bromophenyl acetonitrile 3.4f was successively tr eated with 1.2 molar equivalents n -butyllithium and 1-(4-tol yl)sulfonyl benzotriazole 3.1b at –78 oC in THF. The reaction mixture was allowe d to stir at room temperat ure overnight. Aqueous workup gave 4-bromophenyl(toluene -4-sulfonyl)acetonitrile 3.5h in 43% yield along with about 50% of the starting material nitrile 3.4a The yield of 3.5h was improved to 93% by using two-fold excess of n -butyllithium. To simplify the procedure, the reaction of nitrile 3.4f with 3.1b was examined in the presence of of t -BuOK in DMSO (2 eq.) at room temperature. This reaction proceeded smoothly and provided -cyano sulfone 3.5h in 88% yield. The use of a two-fold excess of either n -BuLi in THF at –78 oC or t -BuOK in

PAGE 38

25 DMSO at room temperature proved effectiv e for the sulfonylation of nitriles. The reactions of 1-sulfonylbenzotriazoles 3.1a–f with nitriles 3.4a f were performed under these optimized conditions. In all cases, th e reaction proceeded smoothly to give the corresponding -cyano sulfones 3.5a i (Scheme 3-5 and Table 3-1). Success with a wide range of 1-sulfonylbenzotriazole s and nitriles demonstrates th e general app licability of this procedure. It can be used for alky lsulfonylbenzotriazoles for preparation of cyanoalkyl sulfones 3.5f g in 82% and 87% yields, respectively. Arylsulfonylbenzotriazoles were also used to convert acetonitrile itself or arylacetonitriles into the corre sponding sulfonylated products 3.5a b h i in 50 97% yields. Heterocyclic sulfonylating reagen ts, 1-(2-thienyl, 2-pyridinyl-, or 3pyridinyl)sulfonylbenzotriazoles 3.1d–f reacted with a variety of nitriles to give the desired products 3.5c e in 54 90% yields. The structures of compounds 3.5a i were supported by NMR spectral data and elemental analyses. The 1H NMR and 13C NMR spectra of -cyano sulfones 3.5a i showed characteristic signals in the regions 4.10 5.85 ppm and 45.7 62.5 ppm which were assigned to the proton and carbon alpha to the cyano group. 3.2.3 Synthesis of -Sulfonyl Sulfones -Sulfonyl methyl sulfones are valuable intermediates in the synthesis of carbocycles [02JOC922, 02JOC5197, 04AGIE2402] and heterocycles [97JCS(P1)695]. They are also reactive substrates in Ramberg-Backlund olefinations [86JA2358, 87JOC1703], Knoevenagel condensation [91S1205] and metal-catalyzed cross-coupling reactions [98JOC9608, 03EJOC 1064]. In addition, some -sulfonyl sulfones are useful for the synthesis of -aryl propanoic acids, ibupr ofen analogs [03JMC3].

PAGE 39

26 In spite of these applications, approaches to their syntheses are scarce: the wellknown route to -sulfonyl sulfones involves the oxidati on of the corresponding disulfides [00T8263] or -sulfonyl sulfides [89JA 779]. The lack of available methods prompts us to study the generality of the benzotriazole-mediated C -sulfonylation methodology. A high yielding and general method to a diverse range of target molecules is herein reported. Treatment of sulfones 3.6 with 2 molar equivalents of nBuLi at –78 oC followed by the addition of 1-sulfonyl]benzotriazole 3.1 gave the corresponding -sulfonyl sulfones in moderate to excellent yields (Scheme 3-6 and Table 3-3). R3 SO2R4 2) BtSO2R 3.1a,b,d,e,g 1) n-BuLi, THF 3.6a-d R3 SO2R4 RO2S 3.7a-g Scheme 3-6. A Novel Approach to -Sulfonyl Sulfones. Table 3-3 Preparation of -Sulfonyl Sulfones 3.7a g via C -Sulfonylation of Sulfones 3.6a–d with Sulfonylbenzotriazoles 3.1a,b,d,e,g. Product R R3 R4 Yield (%) 3.7a Phenyl MethylEthyl 91 3.7b 2-Pyridinyl MethylEthyl 87 3.7c Benzofur-2-yl (-CH2-)3 67 3.7d 2-Thienyl Ethyl Ethyl 71 3.7e* 4-Tolyl Phenyl Phenyl96 3.7f* 4-Tolyl H Phenyl87 3.7g* 4-Tolyl (-CH2-)3 78 *: compounds 3.7e f g were prepared by Dr. Ashraf A. A. Abdel-Fattah, which were not included in experimental part. Spectroscopic and analytic al data of these compounds are available in the correspondi ng published paper [05JOC9191]. 3.3 Conclusion A high yielding and convenient method fo r the syntheses of two classes of C sulfonylated products has been developed by the treatment of 1-su lfonylbenzotriazoles with appropriate nitriles and sulfones. In general, the use of 1-sulfonylbenzotriazoles as

PAGE 40

27 C -sulfonylating agents compared with sulfonyl halides is advantageous because of their neutral character, easy accessibility and high st ability. In addition, the approach offers a general protocol for the pr eparation of a variety of -cyano sulfones and -sulfonyl sulfones where the corresponding sulfonyl halides or sulfides are not readily available. The present procedure, combining readily av ailable reagents, simp le manipulations and high yields, should be valuable for obtaining th e targeted sulfone derivatives. The present work provides additional evidence for the good leaving ability of a benzotriazole group. 3.4 Experimental Section General. Melting points were determined by a capillary melting point apparatus equipped with a digital thermometer and Br istoline hot-stage microscope and were uncorrected. NMR spectra were recorded in CDCl3 or DMSOd6 with tetramethylsilanes as internal standard for 1H (300 MHz) or as the internal standard for 13C (75 MHz). The elemental analyses were performed on a Carlo Erba EA–1108 instrument.. Anhydrous THF was freshly distilled over sodium /benzophenone before use. Column chromatography was conducted on silica gel 200-245 mesh. General procedure for the preparation of sulfonylbenzotriazole s 3.1. Method A: The mixture of benzotriazole (20 mmol), alkyl or aryl sulphonyl chloride (20 mmol) and pyridine (28 mmol) in methylene chloride (50 mL) was stirred at room temperature for 10 h. After quenching the reaction by adding water (50 mL), the product was extracted with ethyl acetate (330 mL). The combined organic layer was dried over anhydrous MgSO4. After evaporation of solven t under reduced pressure, the residue was recrystallized from et hyl acetate to give pure products 3.1a–e

PAGE 41

28 Method B: A solution of heteroaryl com pound (35 mmol) in anhydrous THF (120 mL) was cooled to -78 oC under nitrogen and then treated dropwise with n -BuLi (21.8 mL of 1.55 M in hexanes, 35 mmol) to afford a clear solution, which was stirred at this temperature for 15 minutes, and then at room temperature for 1 h. Sulfur dioxide was bubbled into the react ion mixture at -78 oC and stirred at this te mperature for 15 minutes, and then at room temperature for 1 h. N -Chlorobenzotriazole (5.4 g, 35 mmol) was added in one portion at room temperature. The mi xture was stirred for 2 h. Triethylamine (5.3 mL, 40 mmol) was added followed by stirring at room temperature for 10 h. Water (300 mL) was added to the reaction mixture, and the product was extracted with ethyl acetate (3300 mL). The combined organic layers we re washed with water and brine and dried over anhydrous MgSO4. After evaporation of solvent unde r reduced pressure, the residue was recrystallized from ethyl acetate to give pure products 3.1f–i 1-(Methylsulfonyl)-1 H -1,2,3-benzotriazole (3.1a). Colorless microcrystals (97%), mp 109 111 oC (Lit. mp 110-112 oC [00JOC8210]); 1H NMR 8.15 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 3.52 (s, 3H). 13CNMR 145.2, 131.6, 130.5, 126.0, 120.6, 111.9, 42.8. 1-(4-Methylbenzenesulfonyl)-1 H -1,2,3-benzotriazole (3.1b). Colorless microcrystals (78%), mp 126 129 oC (Lit. mp 128-129 oC [92T7817]); 1H NMR 8.138.06 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.66 (dt, J = 7.8, 0.8 Hz, 1 H), 7.47 (dt, J = 7.8, 0.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H). 13CNMR 146.8, 145.5, 134.0, 131.6, 130.3, 130.2, 128.0, 125.8, 120.6, 112.1, 21.8. 1-(Benzensulfonyl)-1 H -1,2,3-benzotriazole (3.1c). Colorless microcrystals (81%), mp 124 125 oC (Lit. mp 123-126 oC [92T7817]); 1H NMR 8.07-8.14 (m, 4H), 7.64-

PAGE 42

29 7.70 (m, 2H), 7.46-7.57 (m, 3H). 13CNMR 145.4, 139.4, 137.0, 135.2, 130.3, 129.7, 127.9, 125.9, 120.6, 112.0. 1-(Butane-1-sulfonyl)-1 H -1,2,3-benzotriazole (3.1d). Yellow microcrystals (78%), mp 32 34 oC (Lit. yellow oil [04JOC1849]); 1H NMR 8.17 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.56-7.51 (m, 1H), 3.65-3.6-0 (m, 2H), 1.77-1.69 (m, 2H), 1.45-1.37 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13CNMR 145.1, 132.2, 130.4, 125.9, 120.6, 111.9, 55.4, 24.7, 21.1, 13.2. 1-(4-Nitrobenzenesulfonyl)-1 H -1,2,3-benzotriazole (3.1e). Yellow microcrystals (87%), mp 172 174 oC; 1H NMR 8.40-8.32 (m, 4H), 8.11 (d, J = 8.3 Hz, 2H), 7.75-7.70 (m, 1H), 7.57-7.51 (m, 1H). 13CNMR 151.3, 145.4, 142.2, 131.4, 130.9, 129.4, 126.4, 124.9, 120.9, 111.7. Anal. Calcd. For C12H8N4O4S: C, 47.37; H, 2.65; N, 18.41. Found: C, 47.65; H, 2.53; N, 18.34. 1-(2-Thienylsulfonyl)-1 H -1,2,3-benzotriazole (3.1f). Purple microcrystals (82%), mp 143 144 oC (Lit. mp 143-144 oC [04JOC1849]); 1H NMR 8.12-8.11 (m, 1H), 8.098.08 (m, 1H), 7.96 (dd, J = 3.8, 1.4 Hz, 1H), 7.75 (dd, J = 5.0, 1.4 Hz, 1H), 7.72-7.67 (m, 1H), 7.54-7.49 (m, 1H), 7.14-7.11 (m, 1H). 13CNMR 145.4, 138.5, 136.2, 135.8, 131.3, 130.4, 128.2, 126.0, 120.6, 112.0. 1-(2-Pyridinylsulfonyl)-1 H -1,2,3-benzotriazole (3.1g). Light red microcrystals (71%), mp 132 133 oC (Lit. mp 133-135 oC [04JOC1849]); 1H NMR 8.59 (d, J = 4.7 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.02 (td, J = 7.9, 1.8Hz, 1H), 7.73-7.67 (m, 1H) 7.59-7.49 (m, 2H). 13CNMR 154.6, 150.7, 145.3, 138.7, 132.6, 130.4, 128.7, 125.9, 123.3, 120.3, 112.6.

PAGE 43

30 1-(3-Pyridinylsulfonyl)-1 H -1,2,3-benzotriazole (3.1h). Colorless microcrystals (52%), mp 128 129 oC (Lit. mp 129 oC [04JOC1849]); 1H NMR 9.30 (d, J = 2.0 Hz, 1H), 8.87 (d, J =3.8Hz, 1H), 8.42 (d, J = 8.2 Hz, 1H), 8.14-8.10 (m, 2H), 7.71 (t, J = 5.5 Hz, 1H), 7.55-7.50 (m, 1H). 13CNMR 155.5, 148.4, 145.4, 135.7, 134.0, 131.5, 130.8, 126.3, 124.1, 120.8, 111.8. 1-(Benzofuran-2-ylsulfonyl)-1 H -1,2,3-benzotriazole (3.1i). Colorless microcrystals (81%), mp 147 148 oC; 1H NMR 8.16 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.75 7.70 (m, 2H), 7.56 7.46 (m, 3H), 7.38-7.32 (m, 1H). 13CNMR 156.5, 145.5, 131.6, 130.7, 129.4, 126.2, 125.2, 124.9, 123.6, 120.7, 116.9, 112.7, 112.2. Anal. Calcd. For C14H9N3O3S: C, 56.18; H, 3.03; N, 14.04. Found: C, 56.4; H, 2.83; N, 14.12. General procedure for the preparation of -cyano sulfones 3.5a-f. Method A: A solution of the nitrile 3.4 (2 mmol) in anhydrous THF (15 mL) was cooled to -78 oC under nitrogen and then treated dropwise with n -BuLi (2.6 mL of 1.55 M in hexanes 4 mmol) to afford a clear soluti on, which was stirred at this temperature for 1 h. A solution of 1-sulfonylbenzotriazole 3.1 in anhydrous THF (5–10 ml) was added dropwise to the stirred mixtur e. The reaction mixture was allowed to warm to room temperature while stirring overnight. Af ter quenching the reaction by addition of saturated aqueous NH4Cl, the product was extracted w ith ethyl acetate. The organic extract was washed with 10 % aqueous Na2CO3 and brine, and dried over anhydrous MgSO4. After evaporation of solvent under redu ced pressure, the residue was purified by flash chromatography (hexanes/ethyl acetat e, 5/1) to afford the desired product 3.5

PAGE 44

31 Method B: A mixture of nitrile 3.4 (2 mmol) and t -BuOK (0.45 g, 4 mmol) in DMSO (10 mL) was stirrred below 10 oC for 10 minutes. After addition of 1sulfonylbenzotriazole 3.3 (2 mmol) in DMSO (5 mL), the mixture was allowed to warm to room temperature and stirred for 8 h. The mixture was poured into water (40 mL), acidified with NH4Cl and then extracted with ethyl ace tate (330 mL). The extracts were washed with water, dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. The residue was purified by flash ch romatography (hexanes/e thyl acetate, 5/1) on silica gel to give the pure product 3.5 Benzenesulfonyl-phenyl-acetonitrile (3.5a). Colorless crystals (76%), mp 148 150 oC (Lit. mp 147.0-148 oC [03JOC8003]); 1H NMR 7.73 7.70 (m, 3H), 7.55 7.26 (m, 7H), 5.14 (s, 1H). 13CNMR 135.2, 134.3, 130.5, 130.1, 129.7, 129.2, 129.0, 125.3, 113.4, 63.1. Anal. Calcd. For C14H11NO2S: N, 5.44. Found: N, 5.71. Benzenesulfonyl acetonitrile (3.5b). Colorless crystals (50%), mp 87 88 C (lit. mp 88 C [70CB2775]); 1H NMR 8.06 8.02 (m, 2H), 7.82 7.77 (m, 1H), 7.69 7.64 (m, 2H), 4.10 (s, 2H). 13CNMR 136.6, 135.4, 129.8, 128.8, 110.4, 45.7. Anal. Calcd. For C8H7NO2S: C, 53.03; H, 3.89; N, 7.73. Found: C, 53.09; H, 3.81; N, 7.62. 2,4-Dichlorophenyl(thiophene-2-sul fonyl)acetonitrile (3.5c). Pale yellow plates (90%), mp 142 144 oC; 1H NMR 7.91 (d, J = 4.9 Hz, 1H), 7.73 (d, J = 3.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.4, 1.9 Hz, 1H), 7.25 (dd, J = 4.9, 3.3 Hz, 1H), 5.85 (s, 1H). 13C NMR 137.9, 137.8, 137.5, 135.9, 134.6, 131.8, 130.1, 128.6, 128.1, 122.7, 112.8, 59.4. Anal. Calcd. For C12H7Cl2NO2S: C, 43.38; H, 2.12; N, 4.22. Found: C, 43.43; H, 2.01; N, 4.07.

PAGE 45

32 2-Methyl-2-(2-pyridinylsulf onyl)hexanenitrile (3.5d). Red oil (54%); 1H NMR 8.82 8.80 (m, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.06 (td, J = 7.8, 1.6 HZ, 1H), 7.67(dd, J = 7.7, 4.8 Hz, 1H), 4.64 (dd, J = 10.2, 5.0 Hz, 1H), 2.25 2.13 (m, 2H), 1.76 1.50 (m, 2H), 1.45 1.21 (m, 6H), 0.90 (t, J = 6.6 Hz, 3H). 13C NMR 154.5, 150.5, 138.6, 128.5, 123.6, 113.4, 63.1, 31.0, 28.2, 26.4, 25.0, 22.2, 13.8. Anal. Calcd. For C13H18N2O2S: C, 58.62; H, 6.81; N, 10.52. Found: C, 59.39; H, 7.13; N, 10.48. 2-Phenyl-2-(3-pyridinylsulfo nyl)propanenitrile (3.5e). Colorless microcrystals (73%), mp 121 122 oC; 1H NMR 8.85 (dd, J = 4.9, 1.7 Hz, 1H), 8.57 (d, J = 2.2Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.46 7.37 (m, 6H), 2.28 (s, 3H). 13C NMR 155.1, 150.8, 138.3, 130.6, 130.1, 129.5, 129.0, 128.1, 123.4, 116.8, 67.2, 19.2. Anal. Calcd. For C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.77; H, 4.44; N, 10.05. 4-Bromophenyl methanesulfonyl acetonitrile (3.5f). Colorless plates (82%), mp 111 113 oC; 1H NMR 7.64 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 5.07 (s, 1H), 3.07 (s, 3H). 13C NMR 132.8, 131.1, 125.7, 123.4, 113.0, 60.5, 38.1. Anal. Calcd. For C9H8BrNO2S: C, 39.43; H, 2.94; N, 5.11. Found: C, 39.60; H, 2.84; N, 5.00. General procedure for the preparation of -sulfonyl sulfones 3.7a-d. A solution of the sulfone 3.6 (2 mmol) in anhydrous THF (15 mL) was cooled to -78 oC under nitrogen and thereafter treated dropwise with n -BuLi (2.6 mL of 1.55 M in hexane, 4 mmol) to afford a clear solution, which was stirred at this temperature for 1h. Then sulfonylbenzotriazole 3.1 (dissolved in 5–10 mL anhydrous THF) was added dropwise. The reaction mixture was allowed to warm to room temperature while stirring overnight. After the reaction was quenched by addition of saturated aqueous NH4Cl, the reaction mixture was extracted with ethyl acetate. Th e organic extracts were combined, washed

PAGE 46

33 with 10% aqueous Na2CO3 and brine, and dried over anhydrous MgSO4. After cencetration under vacuum, the residue was purified by flash chromatography (hexanes/ethyl acetate, 5/1) to afford the desired product 3.7 (1-Ethanesulfonyl-ethanesulfonyl)benzene (3.7a). Colorless crystals (91%), mp 96 97 oC (Lit. mp 93 94 oC [74LAC1315]); 1H NMR 7.97 (d, J = 7.4 Hz, 2H), 7.76 7.71 (m, 1H), 7.63 7.58 (m, 2H), 4.38 (q, J = 7.4 Hz, 1H), 3.67 3.47 (m, 2H), 1.69 (d, J = 7.3 Hz, 3H), 1.49 (t, J = 7.4 Hz, 3H). 13C NMR 135.7, 134.9, 130.1, 129.1, 76.0, 48.2, 9.5, 6.2. Anal. Calcd. For C10H14O4S2: C, 45.78; H, 5.38. Found: C, 45.73; H, 5.37. 2-(1-Ethanesulfonyl-ethane sulfonyl)-pyridine (3.7b). Red microcrystals (87%), mp 118 120 oC; 1H NMR 8.77 (br d, J = 4.5 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.04 7.99 (m, 1H), 7.64 7.60 (m, 1H), 5.14 (q, J = 7.6 Hz, 1H), 3.60 3.33 (m, 2H), 1.86 (d, J = 7.5 Hz, 3H), 1.45 (t, J = 7.6 Hz, 3H). 13C NMR 155.8, 150.2, 138.3, 128.0, 123.4, 72.4, 46.7, 8.8, 5.5. Anal. Calcd. For C9H13NO4S2: C, 41.05; H, 4.98; N, 5.32. Found: C, 41.20; H, 4.94; N, 5.17. 2-(1-Benzofuran-2-ylsulfonyl)tetra hydrothiophene-1,1-dione (3.7c). Colorless crystals (67%), mp 147 148 C; 1H NMR 7.97 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 5.42 (t, J = 8.5 Hz, 1H), 3.42 3.35 (m, 1H), 3.28 3.18 (m, 1H), 2.54 2.46 (m, 2H), 2.25 2.17 (m, 1H), 2.07 1.99 (m, 1H). 13CNMR 155.8, 148.3, 129.1, 125.6, 124.0, 117.1, 112.6, 76.7, 52.4, 25.3, 19.0. Anal. Calcd. For C12H12O5S2: C, 47.99; H, 4.03. Found: C, 47.58; H, 4.15. Ethyl 1-(2-thienylsulfony l)ethyl sulfone (3.7d). Yellow oil (71%); 1H NMR 7.87 (dd, J = 4.9, 1.2 Hz, 1H), 7.83 (dd, J = 3.8, 1.2 Hz 1H), 7.22 (dd, J = 4 .8, 4.0 Hz,

PAGE 47

34 1H), 4.50 (q, J = 7.3 Hz, 1H), 3.62-3.46 (m, 2H), 1.75 (d, J = 7.3 Hz, 3H), 1.47 (t, J = 7.4 Hz, 3H). 13C NMR 137.4, 136.4, 135.5, 128.0, 76.1, 48.3, 9.5, 6.0. Anal. Calcd. For C8H12O4S3: C, 35.80; H, 4.51. Found: C, 35.95; H, 4.37.

PAGE 48

35 CHAPTER 4 NOVEL SYNTHESES OF -AMINO ACID DERIVATIVES UTILIZING N PROTECTED AMINOACYLBENZOTRIAZOLES FROM GLUTAMIC ACID 4.1 Introduction Non-natural -amino acids have gained considerable attention due to their important roles in design and synthesis of bi oactive molecules as well as in the study of biomimetic polymers that contain both sec ondary and tertiary st ructural analogous to those of natural proteins. Typically, -amino acids play an importa nt part in the structure of natural products with antitumor activ ity such as hapalosin [94JOC7219, 99SL1118, 99TL9309], dolastatin [94JOC6287], caliculin s [86JA2780, 91Tl5983], and of various enzyme inhibitor GABA-analogues (Figure 4-1) [97TL5503]. In addition, they are attractive starting materials for the forma tion of peptides with helical secondary structures [98HCA983, 98JA8569]. Given this significance of -amino acids, the development of efficient methods for the synthesis of enantiomerically pure -amino acids is important. Four methods for the synthesis of -amino acids from natural -amino acids have been reported (Scheme 4-1). (i) Double Arndt-Eistert homologation [ 69RC299, 77HCA2747]. However, the ArndtEistert homologation protocol is not suitable for large scale s ynthesis due to the high cost of the silver catalyst and difficult handling of the hazardous reagent CH2N2 [02T7991]. Although Longobarbo’s modification provided a method to avoid us ing the silver catalyst and CH2N2, the procedure took four steps [95T12337]. (ii) W ittig reaction of Ph3P=CHCO2Et with aldehydes ava ilable from natural -amino acids followed by

PAGE 49

36 reduction, which is limited to -alkyl -amino acid derivatives [97TL163]. (iii) Reaction of diethyl potassiomalonate with N -tosylaziridines generated in situ from N,O -ditosyl protected -amino alcohols derived from -amino acids [77CPB29]. However, removal of N-tosyl group requires harsh reaction condi tions (reflux in 47% aqueous HBr), which may be incompatible with sensitiv e functionalities [ 77CPB29]. Smreina et al reported the synthesis of -substituted -amino acid via N -Boc-5-substituted pyrrolidinones (Scheme 4-1, route iv), but the decarboxylative ring closure requires hi gh temperature (77 to 110 C) [97T12867]. N H N N N O NH O MeO S N OMe O O Dolastatin O N O O HO n C7H15 O O Hapalosin MeO N H N O OH O O O P OH HO O OMe OH OH R1 R2 R3 OH OH O N Calyculins Figure 4-1. Known Biologically Active Compounds Containing Fragments of -Amino Acid Derivatives.

PAGE 50

37 O OH N H PG R N H PG R OH O 1) SOCl22) CH2N23) H2O/Ag2O 2) CH2N2 N H PG RO N2 cat. Ag+ N H PG R OH O R1 OMe O NH 1) DIBALH, then Ph3P=CHCO2R2 2) Pd/C, H2, MeOH R1 NH OR2 O Base R1 NH OR2 O E PG PG PG E+/THF R1 = Bn, iPr, Me, iBu O OH H2N Ph H2N Ph OTs HN Ph OH Ts TsCl Pyridine N Ph Ts K2CO3 NH2 OH O 1) diethyl potassiomalonate 2) 47% HBr, reflux, 17 hr Ph (i) (ii) (iii) O OH BocHN R O O O BocHN R O O O O BocHN R O O BocN R O BocHN R OH O a b c d (iv) a) Meldrum's acid, DCC, DMAP; b) NaBH4, AcOH; c) Toluene, reflux; d) NaOH, acetone/water. 1) SOCl2 Scheme 4-1 Literature Methods of Synthesis of -Amino Acids from -Amino Acids. Other reported synthe ses of optically pure -amino acids from glutamic acid are (Scheme 4-2): (i) the nucleophilic substitution of iodo derivatives of glutamic acid with organocuprates [92S1104] and (ii) coupling of organozinc reag ent of glutamic acid with aryl iodides in the presence of Pd [99J OC7579]. However, a major limitation of using organometallic reagents is the incompa tibility with many functionalities [92S1104, 97T12867, 99JOC7579]. The Katritzky research group has investigat ed 1-acylbenzotriaz oles as efficient acylating agents for N -acylation [98S153, 00JOC8210, 02ARK(viii)134, 02BMC1809, 04ARK(xii)14, 04S2645], C -acylation [00JOC3679, 03JOC1443, 03JOC4932, 03JOC5720, 04CCA175, 04JOC6617], O -acylation [96LA881, 99JHC777, 04JOC6617] and S-acylation reactions [04S1806]. In part icular, 1-acylbenzotriazoles, which are advantageously stable toward moisture a nd storable for a long period of time, are efficient for the C -acylation of electron rich hetero cycles, such as indole, pyrrole [03JOC5720], furan, and thiophene [04CCA175] in the presence of Lewis acids, such as

PAGE 51

38 AlCl3. Recently, the preparation of N -TFAand Fmoc-amino ketones by C -acylation of pyrroles and indoles with chiral N -protected -aminoacylbenzotriazoles [02ARK(viii)134, 04S2645, 05S297] was successfu lly achieved in the presence of AlCl3 with preservation of chirality, as demonstrat ed by configurational analysis [05JOC4993]. Subsequently, Dr. Rong Jiang and Dr. Kost yantyn Kiricheko in Katritzky’s group developed a novel synthesis of -aryl-amino acids 4.6 from L -aspartic acid via ( N protected) aminoacylbenzotriazoles 4.5 (Scheme 4-3) [1475]. HO OR1 O O NH PG i) ClCO2Et ii) NaBH4 HO OR1 O NH PG i) TsCl/Py ii) NaI I OR1 O NH PG R2Cu/THF R2 OR1 O NH PG i) Hydrolysis ii) Deprotection R2 OH O NH2 HO OR1 O O NH PG NHS, DCC O OR1 O O NH PG N O O NaBH4HO OR1 O NH PG I2, PPh3, imidazole I OR1 O NH PG i) Zn, Pd2(dba)3, Ar-I, (o-Tol)3P Ar OH O NH2 ii) Hydrolysis ii) Deprotection i) ii) Scheme 4-2. -Amino Acids from Glutamic Acid. Here, a novel and practical method for the synthesis with preservation ( 99%) of the chirality of -amino acid derivatives, -aryl-amino esters 4.12 and acids 4.13 by the Friedel-Crafts acylation of aromatics with chiral N -protected ( -aminoacyl)benzotriazoles

PAGE 52

39 4.10 readily available from L -glutamic acid, followed by the reduction of formed -keto-amino esters 4.11 is presented. N H O OMe O TFA OH TFA-Asp(OMe)-Bt ( 4.4 ) H2N O OH O OH SOCl2MeOH H3N O OMe O OH Cl CF3COOEt Et3N, MeOH BtH, SOCl2 CH2Cl2N H O OMe O TFA Bt 80% 87% 91% 4.1 4.2 4.3 TiCl4TFA N H O OMe O Ar Aromatics 4.5 (45-89%) reduction TFA N H OX O Ar X = H or Me 4.6 TFA = CF3CO Scheme 4-3. Novel Syntheses of -amino Acid Derivatives, -Aryl-amino Acids 4.6. 4.2 Results and Discussion 4.2.1 Preparation of 1-( N -Tfa-Aminoacyl)benzotriazoles 4.10 L -Glutamic acid 4.7 reacted with methanol and th ionyl chloride to form the -mono methyl amino ester 4.8 in 80% yield (Scheme 4-4) [01CC1710]. Amino ester 4.8 was protected with N -trifluoroacetyl (TFA) group using ethyl trifluoroacetate in the presence of Et3N (2 eq.) in methanol to generate N -TFA-glutamic monoester 4.9 [72JOC2805] On treatment with a mixture of thionyl chloride (4 eq.) and benzotriazole (4 eq.), N -Tfaglutamic ester 4.9 gave the corresponding acylben zotriazole TFA-Glu(OMe)-Bt 4.10 in 93% yield (overall yield: 66%). N H O TFA OH TFA-Glu(OMe)-Bt ( 4.10 ) H2N O OH SOCl2MeOH H3N O OH Cl CF3COOEt Et3N, MeOH BtH, SOCl2 CH2Cl2N H O TFA Bt OH O OMe O OMe O OMe O 80% 89% 93% 4.7 4.8 4.9 Scheme 4-4. Preparation of N -(TFA-aminoacyl)benzotriazoles, TFA-Glu(OMe)-Bt 4.10.

PAGE 53

40 4.2.2 Syntheses of -Keto-amino Esters 4.11 Previously, the synthesis of -amino ketones by Friedel-Craft acylation of N heterocycles utilizing chiral N -protected -aminoacylbenzotriazoles in presence of AlCl3 had been achieved by Katritzky’s res earch group (Scheme 4-5) [05JOC4993]. PG N H OH R O BtH, SOCl2 PG N H Bt R O N-Heterocycles AlCl3PG N H Het R O PG = TFA, Fmoc; R = H, phenyl, indol-3-yl, CH2SMe Scheme 4-5. Chiral N -Protected -Aminoacylbenzotriazoles as Acylating Reagents in Friedel-Craft Acylation. Unfortunately, efforts to extend th is method to the preparation of -keto-amino esters 4.11 by acylation of aromatics with TFA-Glu(OMe)-Bt 4.10 under the same reaction conditions failed. The starting material 4.10 was decomposed in one hour, and no desired product formed. The results fr om Lewis acids screening led to TiCl4 as a promising catalyst (starting materials were recovered when BF3 or ZnBr2 was used). The reaction of Tfa-Glu(OMe)-Bt 4.10 with aromatics (1.1 eq.) in the presence of TiCl4 (1.5 eq.) at room temperature fo r 1 h gave the corresponding -keto-amino esters 4.11a f in 46 88% yield (Scheme 4-6, Table 4-1). N H O Bt OMe O TFA Tfa-Glu(OMe)-Bt 4.10 TiCl4Aromatics N H O Ar OMe O TFA 4.11a-f Scheme 4-6. Syntheses of -Keto-amino Esters 4.11.

PAGE 54

41 Table 4-1. Syntheses of -Keto-Amino Esters 4.11. Entry Aromatics -Keto-amino esters 4.11 (%) 1 Indole 4.11a (80) 2 N-Methylindole 4.11b (88) 3* N-Methylpyrrole 4.11c (69) 4* Pyrrole 4.11d (50) 5 1,3-(MeO)2C6H4 4.11e (48) 6 1,3,5-(MeO)3C6H3 4.11f (46) *: compounds 4.11c,d were prepared by Dr. Rong Jiang which were not included in experimental part. Spectroscopi c and analytical data of th ese compounds are available in Dr. Rong Jiang’s Ph. D. dissertation. 4.2.3 Preparation of -Aryl-amino Esters 4.12 and -Aryl-amino Acids 4.13 by Reduction of -Keto-amino Esters 4.11. The reduction of -keto-amino esters 4.11e f by triethylsilane in trifluoroacetic acid at room temperature gave the corresponding -aryl-amino esters 4.12e f in 84% and 88% yield respectively (Sch eme 4-7, Table 4-2) [73JOC2675]. Et3SiH N H O Ar OMe O TFA CF3COOH N H Ar OMe O TFA 4.11e,f 4.12e,f Scheme 4-7. Preparation of -Aryl-amino Esters 4.12e,f by the Reduction of -Ketoamino Esters 4.11e,f. Table 4-2. Preparation of -Aryl-amino Esters 4.12e,f. Entry Aromatics -Aryl-amino esters 4.12 (%) 1 1,3-(MeO)2C6H4 4.12e (84) 2 1,3,5-(MeO)3C6H3 4.12f (88) However, the attempts to reduce -keto-amino esters 4.11a b with triethyl silane in trifluoroacetic acid were unsuc cessful. Unlike their phenyl analogs, 4.11e f carbonyl group in 4.11a,b could not be reduced to methylene under these conditions. On the other

PAGE 55

42 hand, when -keto-amino esters 4.11a b were treated with 4 molar equivalents sodium borohydride in DMF/H2O (v/v = 5/1) mixture for two hours, the corresponding -arylamino acids 4.13a b were isolated in 87% and 73 % yield, respectively (Scheme 4-8, Table 4-3) [03TL8229]. N H O Ar OMe O TFA N H Ar OH O TFA NaBH4DMF/H2O 4.11a,b 4.13a,b Scheme 4-8. Preparation of -Aryl-amino Acids 4.13a,b by the Reduction of -Ketoamino Esters 4.11a,b. Table 4-3. Preparation of -Aryl-amino Acids 4.13. Entry Aromatics -Aryl-amino acids 4.13 (%) 1 Indole 4.13a (87) 2 NMethylindole 4.13b (73) 4.2.4 Configuration Study of -Aryl-amino Acids 4.13. Since the key feature of bi ologically active amino acid derivatives is associated with the absolute configuration of the -carbon to the amino group, total control of chirality represents a major goal in the synt hesis of amino acid derivatives. To evaluate the chiral integrity of these reactions, ( DL )-5-(1-methyl-1 H -indole-3-yl)-4-[(2,2,2trifluoroacetyl)amino]pentanoic acid 4.13g was prepared starting from DL -glutamic acid, following the procedure for 4.13b (Scheme 4-9). The chiral resolution of 4.13g ( DL ) by chiral HPLC [CHIROBIOTIC T column ; eluted with 60/40 (v/v) 0.1% TEAA (triethylamine acetate) methanol solution/ water; flow rate 0.4 mL/min at room temperature; UV detection at 210 nm] gave two distinct signals with equal intensity at 13.22 min and 13.68 min, while 4.13b ( L ) gave only one signal at 13.7 min under same

PAGE 56

43 conditions that demonstrated the complete chiral preservation (>99%) of synthesis of aryl-amino acid derivitaives 4.12 and 4.13 (Table 4-4). N H O Bt OMe O TFA DL -TFA-Glu(OMe)-Bt ( 4.10g ) TiCl4N -methyl indole 83% N H O OMe O TFA N N H OH O TFA N 4.13g ( DL ) NaBH4DMF/H2O 71% 4.11g ( DL ) Scheme 4-9. Synthe sis of Compounds 4.13g ( DL ). Table 4-4. The Comparison of Ch iral HPLC Results of 4.13b ( L ) with Corresponding DL -Mixtures 4.13g. Retention Time (min) Entry Compound L D 1 4.13b ( L ) 13.7 -a 2 4.13g ( DL ) 13.7 13.2 ano peak detected. The complete preservation of chirality of this process is due to the mild reaction condition and the avoidance of the formation of hydrogen chloride, which is a typical side product of classic Fr iedel-Crafts acylation. 4.3 Conclusion A novel and efficient approach to -amino acids from glutamic acid through their corresponding benzotriazole intermediates has been developed. Complete preservation of chirality of this process was supported by ch iral HPLC results. Compared with other published methods, the present benzotriazole methodology advantageously uses mild reaction conditions (no strong acid or base needed) at low reaction temperatures (room temperature). In addition, th e easy accessibility and high st ability of th e corresponding benzotriazole intermediates offer an alternat ive route for the preparations of a variety

PAGE 57

44 aromatic and heteroaromatic analogs of -amino acids. The present procedures, combining readily available re agents, simple manipulations and synthetic useful yields, should be valuable fo r obtaining certain -amino acid derivatives with specific synthetic requirements and biologi cal activity concerns. 4.4 Experimental Section General. Melting points were determined by using a capillary melting point apparatus equipped with a digi tal thermometer and Bristoline hot-stage microscope and were uncorrected. NMR spectra were recorded in CDCl3 or DMSOd6 with tetramethylsilane as the internal standard for 1H (300 MHz) or solvent as the internal standard for 13C (75 MHz). Elemental analyses we re performed on a Carlo Erba-1106 instrument. HPLC analyses were perform ed on Beckman system gold programmable solvent module 126 using Chirobiotic T column (4.6 250 mm), detection at 210 nm, flow rate of 0.4 mL/min and 0.1% TEAA [triet hylamine acetate: it is a mixture of triethylamine and glacial acetic acid (1/1; v/ v)] methanol solution/water as an eluting solvent. Amino acids purchased from Acros and DL -glutamic acid from TCI, were used without further purification. TH F was distilled over sodium /benzophenone prior to use. All of the reactions were carried out under N2. Column chromatography was conducted on silica gel 200 425 mesh. Procedure for the preparation of N -Tfa-(aminoacyl)benzotriazoles 4.10. To a solution of benzotriazole (0.95 g, 8 mmol) in CH2Cl2, SOCl2 (0.24 g, 2 mmol) was added, and the reaction mixture was refluxed for 30 min. Then, the reaction mixture was cooled to 0 C, and Tfa-Glu(OMe)-OH (0.516 g, 2 mmol) in CH2Cl2 (10 mL) was added dropwise. The reaction mixture was stirred at 23 C for 2 h, and then it was washed with

PAGE 58

45 10% aqueous Na2CO3 until BtH was completely rem oved. The oganic layer was dried over anhydrous MgSO4. After removing the solvent, the white residue was recrystallized from CHCl3/hexanes to give the desi red product Tfa-Glu(OMe)-Bt ( 4.10 ) in 93% yield. Methyl (4 S )-5-(1 H -1,2,3-benzotriazol1-yl)-5-oxo-4-[(2,2,2trifluoroacetyl)amino] pentanoate (4.10). Colorless needles (93%), mp 90 92 C; [ ]23 D = 49.04 o ( c 6.67, CHCl3); 1H NMR 8.27 8.16 (m, 3H), 7.75 7.70 (m, 1H), 7.60 7.55 (m, 1H), 6.03 5.98 (m, 1H), 3.71 (s, 3H), 2.65 2.43 (m, 4H); 13C NMR 173.9, 168.8, 157.4 (q, J = 38.9 Hz), 146.0, 131.2, 130.9, 126.9, 120.5, 115.6 (q, J = 287.4 Hz), 114.2, 53.4, 52.4 30.1, 26.4. Anal. Calcd for C14H13F3N4O4: C, 46.93; H, 3.66; N, 15.64. Found: C, 46.95; H, 3.64; N, 14.91. General procedure for the preparation of -keto-amino esters 4.11. To a solution of Tfa-Glu(OMe)-Bt ( 4.10 ) (0.34 g, 1 mmol) and aromatics (1.1 mmol) in anhydrous CH2Cl2 (10 mL) was added TiCl4 (1.5 mL, 1.5 mmol) at 0 C. The mixture was stirred at room temperature for 1 h and purified by flash chromatography (dry loading method, hexanes/ethyl acetate, 3/1). Methyl (4 S )-5-(1 H -indol-3-yl)-5-oxo-4-[(2,2,2trifluoroacetyl)amino]pentanoate (4.11a). Colorless microcrystals (80%), mp 132 133 C; [ ]23 D = 4.50 o ( c 2.00, CHCl3); 1H NMR 1.92 1.97 (m, 1H), 2.42 2.54 (m, 3H), 3.72 (s, 3H), 5.49 5.55 (m, 1H), 7.31 7.36 (m, 2H), 7.43 7.46 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 8.32 8.35 (m, 2H), 9.26 (br s, 1H); 13C NMR 190.5, 173.7, 157.6 (q, J = 37.6 Hz), 136.4, 133.5, 125.5, 124.4, 123.4, 122.1, 115.8 (q, J = 285.8 Hz), 114.2, 111.8, 54.1, 52.0, 30.2, 29.4. Anal. Calcd for C16H15F3N2O4: C, 53.94; H, 4.24; N, 7.86; Found: C, 54.22; H, 4.27; N, 7.69.

PAGE 59

46 Methyl (4 S )-5-(1-methyl-1 H -indol-3-yl)-5-oxo-4-[(2,2,2-trifluoroacetyl)amino] pentanoate (4.11b). Colorless needles (88%), mp 137 139 C; [ ]23 D = 15.30 o ( c 2.00, CHCl3); 1H NMR 8.32 8.35 (m, 1H), 8.21 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.33 7.36 (m, 3H), 5.45 5.51 (m, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 2.40 2.55 (m, 3H), 1.93 2.01 (m, 1H); 13C NMR 190.2, 173.6, 157.5 (q, J = 37.1 Hz), 137.8, 137.6, 126.6, 124.2, 123.5, 122.5, 116.0 (q, J = 286.3 Hz), 112.9, 110.2, 54.3, 52.1, 34.0, 30.3, 29.6. Anal. Calcd for C17H17F3N2O4: C, 55.14; H, 4.63; N, 7.56. Found: C, 55.04; H, 4.61; N, 7.44. Methyl (4S)-5-(2,4-dimethoxyphenyl)-5 -oxo-4-[(2,2,2-trifluoroacetyl)amino] pentanoate (4.11e). White microcrystals (48%), mp 136–137 C; [ ]23 D = 7.29 o ( c 1.40, CHCl3); 1H NMR 7.94 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 6.59 (dd, J = 8.8, 2.2 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 5.71–5.67 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.64 (s, 3H), 2.43–2.25 (m, 3H), 1.96–1.86 (m, 1H); 13C NMR 194.5, 173.0, 166.1, 161.2, 156.9 (q, J = 37.8 Hz), 134.1, 116.4, 115.8 (q, J = 287.4 Hz), 106.3, 98.3, 57.5, 55.8, 55.7, 51.8, 29.8, 27.2. Anal. Calcd for C16H18F3NO6: C, 50.93; H, 4.81; N, 3.71. Found: C, 50.97; H, 4.77; N, 3.70. Methyl (4S)-5-(2,4,6-trimethoxyphenyl)-5 -oxo-4-[(2,2,2-trifluoroacetyl)amino] pentanoate (4.11f). White microcrystals (46%), mp 99–100 C; [ ]23 D = 5.02 o ( c 16.01, CHCl3); 1H NMR 7.55 (d, J = 7.5 Hz, 1H), 6.13 (s, 2H), 5.36-5.30 (m, 1H), 3.84 (s, 3H), 3.80 (s, 6H), 3.64 (s, 3H), 2.372.27 (m, 3H), 2.03 – 1.90 (m, 1H). 13C NMR 198.4, 173.0, 163.7, 159.3, 156.7 (q, J = 37.0 Hz), 115.6 (q, J = 285.7Hz), 108.1, 90.5, 58.5, 55.7 (2C), 55.3, 51.5, 29.2, 26.1. Anal. Calcd for C17H20F3NO7: C, 50.13; H, 3.44; N, 4.95. Found: C, 50.13; H, 3.40; N, 4.93.

PAGE 60

47 General procedure for the preparation of of -aryl-amino esters 4.12. To keto-amino esters 4.11e f (1mmol) in trifluoroacetic aci d (0.45 mL) was added triethyl silane (0.4 mL, 2.5 mmol). After stirring at room temperature for 4 h, water was added and the mixture was extracted with ether. The ether layer was dried over anhydrous MgSO4. Solvent was then removed under reduce d pressure. The residue was purified by flash chromatography (hexanes/ethyl acetate, 6/1). Methyl (4S)-5-(2,4-dimet hoxyphenyl)4-[(2,2,2trifluoroacetyl)amino]pentanoate (4.12e). White microcrystals(84%), mp 85–86 C; [ ]23 D = 8.33 o ( c 1.92, CHCl3); 1H NMR 7.06–7.00 (m, 2H), 6.46–6.43 (m, 2H), 4.16–4.04 (m, 1H), 3.83 (s, 3H), 3.80 (s, 3H ), 3.67 (s, 3H), 2.83–2.80 (m, 2H), 2.51–2.31 (m, 2H), 2.01–1.77 (m, 2H); 13C NMR (CDCl3) 173.7, 160.1, 157.9, 157.0 (q, J = 36.4 Hz), 131.7, 117.3, 115.9 (q, J = 288.3 Hz), 104.6, 98.6, 55.4, 55.2, 51.8, 51.7, 33.8, 30.6, 29.1. Anal. Calcd for C16H20F3NO5: C, 52.89; H, 5.55; N, 3.85; Found: C, 53.78; H, 5.71; N, 3.72. Methyl (4S)-5-(2,4,6-trimethoxyphenyl)4-[(2,2,2trifluoroacetyl)amino]pentanoate (4.12f). White microcrystals (88%), mp 88–89 C; [ ]23 D = 3.12 o ( c 3.08, CHCl3); 1H NMR 7.15 (d, J = 7.0 Hz, 1H), 6.13 (s, 2H), 4.04– 3.98 (m, 1H), 3.81 (s, 3H), 3.80 (s, 6H), 3.68 (s, 3H), 2.87 (dd, J = 3.9, 13.9 Hz, 1H), 2.76 (dd, J = 9.5, 13.9 Hz, 1H), 2.55–2.35 (m, 2H), 2.04– 1.84 (m, 2H); 13C NMR (CDCl3) 160.2, 158.6, 157.1 (q, J = 36.5 Hz), 174.0, 115.9 (q, J = 286.9 Hz), 105.5, 90.4, 55.5 (2C), 55.3, 51.7, 51.6, 30.6, 29.5, 26.4. Anal. Calcd for C16H20F3NO5: C, 51.91; H, 5.64; N, 3.56. Found: C, 51.72; H, 5.61; N, 3.44.

PAGE 61

48 General procedure for the preparation of -aryl-amino acids 4.13. NaBH4 (0.05 g, 1.3 mmol) was added to -keto-amino esters 4.11a b (0.33 mmol) in DMF/H2O (5 mL/1 mL). The mixture was stirred at r oom temperature for 2 h and quenched with 15 mL water. Then the reaction mixture was acidi fied with 1N HCl aqueous solution to PH = 4, followed by extraction with EtOAc (4 30 mL). The organic layers were combined and washed with water (30 mL) and dried over anhydrous Na2SO4. After removing solvent, the product was purified by recrystallization from CHCl3/hexane. (4S)-5-(1 H -Indol-3-yl)-4-[(2,2,2-trifluoroacetyl )amino]pentanoic acid (4.13a). White microcrystals (87%), mp 127–130 C; [ ]23 D = + 14.48 o ( c 0.67, CHCl3); 1H NMR (DMSOd6) 12.10 (br s, 1H), 10.85 (s, 1H), 9.27 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.12–6.96 (m, 3H), 4.14–3.98 (m, 1H), 2.91 (d, J = 7.0 Hz, 2H), 2.31–2.16 (m, 2H), 1.92–1.73 (m, 2H); 13C NMR (DMSOd6) 174.1, 156.1 (q, J = 36.0 Hz), 136.2, 127.4, 123.3, 121.0, 118.4, 118.3, 116.0 (q, J = 288.6 Hz), 111.4, 110.5, 50.5, 30.5, 29.8, 28.5. Anal. Calcd for C15H15F3N2O3: C, 54.88; H, 4.61; N, 5.83. Found: C, 54.64; H, 4.71; N, 8.35. (4S)-5-(1-Methyl-1 H -indol-3-yl)-4-[2,2,2-trifluoroacet yl)amino]pentanoic acid (4.13b). Light brown microcrystals (73%), mp 185-186 C; [ ]23 D = 12..24 o ( c 0.67, CHCl3); 1H NMR (DMSOd6) 12.09 (br s, 1H), 9.27 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.16–7.09 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 4.04– 3.99 (m, 1H), 3.72 (s, 3H), 2.89 (d, J = 6.9Hz, 2H), 2.25–2.18 (m, 2H), 1.85–1.75 (m, 2H); 13C NMR (DMSO) 174.0, 156.1 (q, J = 36.1 Hz), 136.6, 127.8, 127.7, 121.1, 118.5, 118.4, 116.0 (q, J = 288.6 Hz), 109.8, 109.6, 50.6, 32.3, 30.5, 29.7, 28.3. Anal. Calcd for C16H17F3N2O3: C, 56.04; H, 5.01. Found: C, 56.01; H, 5.22.

PAGE 62

49 5-(1-Methyl-1 H -indol-3-yl)-4-[2,2,2-trifluoroa cetyl)amino]pentanoic acid (4.13g). Light brown microcrystals (71%), mp 148-150 C; 1H NMR (DMSO) 12.10 (br s, 1H), 9.28 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.16– 7.10 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 4.10–3.94 (m, 1H), 3.73 (s, 3H), 2.90–2.88 (m, 2H), 2.25–2.17 (m, 2H), 1.87–1.72 (m, 2H); 13C NMR (DMSO) 174.0, 156.1 (q, J = 36.1 Hz), 136.6, 127.8, 127.7, 121.1, 118.5, 118.4, 116.0 (q, J = 288.6 Hz), 109.8, 109.6, 50.6, 32.3, 30.5, 29.7, 28.3. Anal. Calcd for C16H17F3N2O3: C, 56.04; H, 5.01. Found: C, 55.93; H, 5.03.

PAGE 63

50 CHAPTER 5 MICROWAVE MEDIATED SYNTHESIS OF -ENAMINO THIOIC ACID DERIVATIVES FROM DIBENZ OTRIAZOLYLMETHANETHIONE 5.1 Introduction Organosulfur compounds are of considerable in terest both for thei r rich and varied chemistry, and for their diverse biol ogical properties [77TL4037, 82T2857, 96BMC1493, 96MI]. Among them, -enamino thioic acid derivatives are important building blocks for the construction of a variety of hete rocyclic compounds including pyrazoles [96JHC1243], 4-aminoquinolines [97T2931] dihydrothiopyrans [00T3909, 01MFC947], thiazolines [85H1225], thazolin -4-ones [85H1225], 1,3-thia zolin-4-ones [85H1225], 6 H 1,3-thiazines [80S453], as we ll as precursors for liquid crystals [95JOC3074] and -keto thioic acid derivatives [88JCSP(I)1739]. They have been reported as good 1-thia-1,3dienes [81TL3175, 93JOC1702,01M947] a nd Michael acceptors [01T8705]. Unsaturated carbodithioic esters generally show good reactivity as heterodienes in thermally or Lewis acid induced cycloadditi ons with various dienophiles [99CC1001]. -Unsaturated thioamides form C-C bonds in reaction with C-nucleophiles such as alkyllithiums, alkylmagnesiums [78JA5221, 81TL3409], lithium enolates [79JA1316] and nitromethane in the presence of base [96SL1117]. Characteristi c reactivities of the thiocarbonyl group are also Known: thiophi lic addition of nucleophiles, cycloaddition reaction with dienes, easy thio-Claisen rea rrangement and high reactivity with 1,3-dipoles [92S1185]. Apart from their wide use as intermediates in or ganic synthesis, thioamides have also attracted attention in the field of peptide chemistry [00B387, 00TL2797,

PAGE 64

51 03TL3551]. These modified peptides have of ten retained biological activity, sometimes associated with significant selectivity betw een different cellular receptors [94JOC1257]. Partial resistance toward proteases ha s been observed [82JA5221]. Thioamide substitution in a peptide has been used as a tool to determine the possible involvement of an individual peptides bond in receptor in teraction (structure-activity relationships) [90JMC2323]. Furthermore, dithioesters have attracted the attention of polymer chemists for their ability to control radical polymeri zation: indeed the RAFT (Reversible Addition Fragmentation Chain Transfer) radical polymerization of such monomers as N acryloylmorpholine, styrene and methacrylates is based on the use of dithioesters as transfer agents [00M243, 01M7849, 02M8271]. Recen tly, the influence of thionoesters as effective chain transfer agents in the polym erization of styrene, methyl acrylate, and related olefins was reported [92MC369]. Despite the importance and interest in this class of derivatives, existing methods for the preparation of -enamino thioic acid derivatives are limited to: i) the reaction of enaminones with phosphorus pentasulfide or other O/S exchange reagents, such as Lawesson’s reagents [79S942, 80T3047, 85T5061]; ii) the cycloadditi on of unactivated 2-aza-1,3-dienes with isothiocyanate s followed by the reduction of the 1,2dihydropyrimidin-4(3 H )-thiones with LiAlH4 to provide -enamino thioamides [88JCSP(1)1739]; iii) the reaction of -enaminones with aryl isothiocyanates at 90 C [94S898, 98BMCL2203]; and iv) cyclopenta nones and 2-substituted cyclopentanones with carbon disulphide and ammonia at 0 C [83S605]. The first method is plagued by the foul smell of the starting material, while other methods are limited to specific substrates.

PAGE 65

52 The need for an efficient and general approach to -enamino thioic derivatives stimulates considerable interest. A novel a nd efficient procedure of the synthesis of enamino thioic acid derivatives from dibenz otriazolylmethanethione is discussed herein. 5.2 Results and Discussion Unlike the reported reaction of thiophosgene with benzotriazole (2 eq.) in dioxane giving 1-(benzothiazol-2-yl)benzotriazole (S cheme 5-2) [65JHC486], the straightforward reaction of thiophosgene with four equivalents of benzotriazole in methylene chloride at 0 C gave dibenzotriazolylmethanethione 5.1 in 87% yield (Scheme 5-1). S Bt Bt 5.1 4 BtH + S Cl Cl CH2Cl287% 0 C Scheme 5-1. Novel Approach to Dibenzotriazolylmethanethione 5.1. The use of two-fold excess of benzotriazole advantageously avoids the use of either 1-trimethylsilylbenzotriazole [78JOC337] or sodium salt of benzotriazole (no yield of 5.1 is reported) (Scheme 5-2) [ 65JHC486], required in the pr eviously available methods. Excess benzotriazole and low reaction temperat ure appear to be essential for successful preparation of 5.1 Dibenzotriazolylmethanethione 5.1 reacted with equimolar ketimines 5.2a–f in THF at 20 C to give benzotriazolyl -enaminothiones 5.5a–f (78–97%). The treatment of 5.2 with two equivalents of ketimine 5.2a–f aiming to substitute both benzotriazolyl groups in 5.1 however resulted in exclusiv e formation of benzotriazolyl enaminothiones 5.5a–f Unfortunately, under the same r eaction conditions, treatment of 5.1 with aldimines 5.3 and 1-cyclohexenylpyrrolidine 5.4 caused the decomposition of dibenzotriazolylmethanethione 5.1 (Scheme 5-3).

PAGE 66

53 + S Cl Cl dioxane 25 C-reflux 50% N N N N S 1-(2-benzothiazolyl)benzotriazole 2 BtH i) BtH + H N Me3Si SiMe3 BtSiMe3BtSiMe3+ S Cl Cl S Bt Bt 90% 93% (NH4)2SO4 reflux, 18h 1,1,2-trichloroethane r.t. ii) 5.1 iii) + S Cl Cl 2 BtNa S Bt Bt 5.1 benzene reflux-r.t. Scheme 5-2. Known Reactions of Benzot riazole and Related Derivatives with Thiophosgene. Structures of compounds 5.5a–f were supported by 1H and 13C NMR spectra, and elemental analyses (see Experimental Section). In the 1H NMR spectra of benzotriazolyl -enaminothiones 5.5a–f the broad singlet signal in the range 13.21–15.24 ppm and the singlet signal at 7.16–7.2 1 ppm (for compounds 5.5a,b,e ) corresponding to NH and CH of the enamine fragment, respectively, conf irmed the exclusive formation of the in Z enamine form resulting from NHS chelation. Further effort to prove the Z-enamine form by X-ray crystallography will be done in the near future.

PAGE 67

54 THF N S Bt Bt THF THF R1NH R3Bt S R2 H N R3R2 R1N R3R2 5.3a: R2 = vinyl, R3 = Ph 5.3b: R2 = Et, R3 = Bn r.t. 6h r.t. 6h r.t. 10 mins decomposition decomposition 5.2 5.4 5.1 5.3 5.5 Scheme 5-3. The Reactivity of Dibenzotri azolylmethanethione 5.1 toward Ketimines, Aldimines and Enamines. Table 5-1. The Synthesis of Benzotriazolyl -Enaminothiones 5.5. 5.5 R1 R2 R3 Yield (%) 5.5a Phenyl H Butyl 97 5.5b 4-Pyridinyl H Butyl 94 5.5c Phenyl Methyl Butyl 83 5.5d -(CH2)4Butyl 78 5.5e Ethyl H Butyl 78 5.5f -(CH2)4Benzyl95 Treatment of compound 5.5a,b under microwave irradi ation at 80 C with secondary amines gave -enamino thioamides 5.6a–c (92–95%). Similar treatments of 5.5a,b with alcohols or thiols in the presence of sodium or potassium hydroxide afforded thioesters 5.7a–c (74–99%) and dithioesters 5.8a–c (85–92%), respectively (Scheme 5-4, Table 5-2). Similarly to compounds 5.5 1H NMR spectra of products 5.6–5.8 showed the presence of the broad singlet signal in the range 11.44–13.16 ppm corresponding to NH proton and suggesting exclusive Z -enaminothione configuration of the products (Scheme 5-4).

PAGE 68

55 NH R3R1Bt S R2 ROH, NaOH R1SR S R2R3NH R4NH R1N S R2R5 R3R1OR S NH R2 RSH, KOH Microwave irradiation 5.6 5.8 5.5a,b 5.7 secondary amine Microwave irradiation Microwave irradiation R3 Scheme 5-4. Novel Approach to -Enamino Thioic Acid Derivatives 5.6–5.8. Table 5-2. Microwave-mediated Synthesis of -Enamino Thioic Acid Derivatives 5.6– 5.8. Entry R1 R2 R3 R4 R5 R Product Yield (%) 1 Phenyl H ButylC2H4OC2H4-5.6a 93 2 Phenyl H Butyl-(CH2)55.6b 95 3 4-Pyridinyl H ButylC2H4OC2H4-5.6c 92 4 Phenyl H ButylMethyl 5.7a 99 5 Phenyl H ButylPropyl 5.7b 98 6 4-Pyridinyl H ButylMethyl 5.7c 74 7 Phenyl H Butyln -Hexyl 5.8a 85 8 Phenyl H ButylPhenyl 5.8b 87 9 4-Pyridinyl H ButylPhenyl 5.8c 92 However, under the same conditions, treatment of benzotriazolyl -enaminothiones 5.5c–e with alcohols, thiols or amines resulted in the recovery of 5.5c–e The attempted reaction of 5.5c–e with sodium methoxide in metha nol under microwave irradiation as well as stirring at room temperature for 48 h gave the same results. The reaction results, suggest that the nucleophilic substitution undergoes addition-elimination mechanism, which is shown in Scheme 5-5.

PAGE 69

56 When R1 group is aryl or he teroaryl group (compounds 5.5a b ), which behaves as electron withdrawing group, th e electrophilicity of thioacyl group increases, making the benzotriazolyl -enaminothione reactive toward sec ondary amines, alcohols and thiols. However, when R1 group is alkyl group (compounds 5.5d e ), which behaves as electron donating group, the electrophilicity of thioacy l group decreases, resu lting in no reaction observed under same reac tion conditions. Compound 5.5c also appears to be unreactive toward secondary amines, alcohols and thio ls, probably due to the steric hindrance. Further efforts to activate le ss reactive benzotriazolyl -enaminothiones by Lewis acid will be attempted in the future. NH R3R1Bt S R2 5.5 NuNH R3R1Bt S R2 Nu NH R3R1Nu S R2 + Bt-5.6-5.8 Nu = secondary amines, alcohols & thiols Scheme 5-5. Plausible Mechanism for the Reaction of Benzotriazolyl -Enaminothiones 5.5 with Nucleophiles. The reaction of benzotriazolyl -enaminothione 5.5a with hydrazine under microwave irradiation at 80 C failed and re sulted in a complex set of polar products. Treatment of 5.5a with nitromethane or acetonitrile at 80 C under microwave irradiation in the presence of sodium hydroxide gave no reaction. Meanwhile, the reactivity of 1-thioacylbenzotriazoles 5.9 toward ketimines 5.2 were investigated, which le d to a novel approach to -enaminothiones 5.10 The Katritzky research group has devel oped efficient thioacylating agents, 1thioacylbenzotriazoles, for N -, O -, and S -thioacylation (Scheme 5-6) [05JOC7866]. In

PAGE 70

57 particular, 1-thioacylbenzotriazoles are advantageously stable toward moisture and storable for a long period of time. As a logical sequel, the C -thioacylation potential of 1-thioacylbenzotriazoles was studied. After careful screening of a series of nucleophiles, including Grignard, organozinc, organolithium reagents enolates, silyl enol ethers allyl trimethyl silane, and active methylenes, enamines and aldimine s, only ketimines stood out as effective nucleophiles to be thioacylated by 1-thioacylbenzotriazoles. R = alkyl, aryl, heteroaryl R1 = alkyl R2 = alkyl, H R3 = aryl Bt S R 5.9 R1R2NH R3XH N S R R3X S R R1 R2 X = O, S Scheme 5-6. Published Benzotriazole-Mediated Thioacylation. 1-Thioacylbenzotriazoles 5.9a–c reacted with ketimine 5.2a in the presence of ZnBr2 in THF at room temperature for 3 days, to give the desired -enaminothiones 5.10a–c in moderate to good yield (Scheme 5-7, Table 5-3). Scheme 5-7. Novel Approach to -Enaminothiones 5.10 R1N R3R2 N N N R4S O2N ZnBr2THF, r.t. + 5.2 5.9a-c 5.10a-c R1NHS R4R3R2 Table 5-3. C -Thioacylation of Ketimines 5.2a wi th Thioacylbenzotriazoles 5.9a–c. Product R1 R2 R3 R4 Yield (%) 5.10a Phenyl H Butyl4-ClC6H491 5.10b Phenyl H Butyl2-thienyl 76 5.10c Phenyl H Butyl2-furyl 45

PAGE 71

58 To broaden the scope of this methodology, the reactivity of 1thioacylbenzotriazoles 5.9a with ketimines 5.2f–g was examined Unfortunately, all the attempts failed to give -enaminothiones corresponding to 5.10a–c and resulted in either a low yield of thioamide 5.11a (35%) or complex mixtures of products (Scheme 5-8 ) We have observed that the order of a ddition has remarkable influence on the chemical yield of compound 5.10a–c Thus, the best results were obtained when a THF solution of thioacylbenzotriazole 5.9 was allowed to react firstly with ZnBr2, followed by slow addition of the appropriate ketimine 5.2 By contrast, reactions carried out by initial addition of the Lewis acid to a THF solution of ketimine 5.2 were less efficient and resulted in a marked decrease in the yield. N N N N R4S O2N ZnBr2THF, r.t. N H S R4Ph + 5.2g 5.9a 5.11a Ph N R1Ph R2 N N N R4S O2N ZnBr2THF, r.t. + 5.9a complex mixture 5.2f: R1, R2 = -(CH2)45.2h: R1= Et, R2 = H Scheme 5-8. Attempts to Obtain -Enaminothiones 5.10 from Diverse Ketimines. We presume that the initial formation of the complex 5.12 can take place in two different ways: either via a benzotriazolium intermediate 5.12a or through the coordination of the zinc at om with the carbonyl sulfur 5.12b in a similar way as in the case of carbonyl compounds (Figure 5-1).

PAGE 72

59 N N N O2N R4Br2Zn S N O2N R4ZnBr2N N S 5.12a 5.12b Figure 5-1. The Structure of ZnBr2-Thioacylbenzotriazole Complex 5.12. In both cases the electrophilicity of the thioacyl carbon increases, permitting the thioacylbenzotriazole to become reactive to ward ketimines. Depending on their nature, ketimines 5.2 react with the complex 5.12 through the enamino forms (Scheme 5-9) or imino forms (Scheme 5-10) in an addition-elimination process, involving the formation of a new carbon-carbon bond in 5.13 (Scheme 5-9) or carbon-nitrogen bond in 5.14 (Scheme 5-10), followed by the elimination of benzotriazole. As result, the reaction proceeds by either of these two competitive mechanisms or by both of them with low regioselectivity. With more reactive ketimine 5.2a [03JA15114], enamino pathway is predominant. The reaction pathway involves nucleophilic addition of enamine tautomer 5.2 to thioacyl group, followed by elimination of benzotriazole from intermediate 5.13 to give ompounds 5.10 in the more stable enamino tautomeric form 5.10 (Scheme 5-9) In contrast, the less reactive to ketimine 5.2g [03JA15114], imino pathway is predominant. Compounds 5.11a was isolated as the major product, possibly via reaction sequence depicted in Scheme 5-10. When the ketimine’ s reactivity is moderate, such as ketimines 5.2f h [03JA15114], the reaction proceeds by both pathways to provide complex mixtures of products.

PAGE 73

60 5.10' 5.10" R1N R3R2 R1NH R3R2 R1NHS R4N N N O2N R2R3 R1N R3S R2R4 R1NH R3S R2R4 5.2 complex 5.12 addition elimination 5.13 5.2' Scheme 5-9. Ketimine with High Reactivity Reacts Through the Enamino Form with the Complex 5.12. R1N R3R2 R1N S R4N N N NO2R2R3 H2O R1R2O N H S R4R3 H N N N NO2 5.2 complex 5.12 addition basic work-up ++ 5.11 Scheme 5-10. Ketimine with Low Reactivity Reacts through Imino Form with the Complex 5.12. 5.3 Conclusion In conclusion, novel approach to the -enamino thioic acid derivatives has been developed. The described procedure appears to be an efficient and simple route to enamino thioic acid derivatives. We also investigated the reaction of 1thioacylbenzotriazoles with ketimines, and pr ovided a plausible explanation for related results.

PAGE 74

61 5.4 Experimental Section General. Melting points were determined by a capillary melting point apparatus equipped with a digital thermometer and Br istoline hot-stage microscope and were uncorrected. NMR spectra were recorded in CDCl3 or DMSOd6 with tetramethylsilane as the internal standard for 1H (300 MHz) or solvent as the internal standard for 13C (75 MHz). The elemental analyses were perf ormed on a Carlo Erba EA–1108 instrument. Anhydrous THF was used freshly distilled over sodium/benzophenone. Column chromatography was conducted on silica gel 200-245 mesh. Ketimines 5.2 were prepared according to th e published procedures [83JA4396, 90T6715]: butyl (1-phenylethylidene)amine ( 5.2a ), colorless oil [83JA4396] (91%); butyl (1-pyridin-4-yl-ethylidene)amine ( 5.2b ), colorless oil [83JA4396 ] (78%); butyl (1phenylpropylidene)amine ( 5.2c ), colorless oil [83J A4396] (88%); butyl cyclohexylideneamine ( 5.2d ), colorless oil [90T6715] (83% ); butyl (butylidene)amine ( 5.2e ), colorless oil [90T6715] (88%); benzyl cyclohexylidene-amine ( 5.2f ), colorless oil [90T6715] (85%); benzyl (butylidene)amine ( 5.2h ), colorless oil [90T6715] (78%). Aldimines 5.3 were prepared according to the published procedures: [90T6715, 01JOC7051] N -[(E)-3-butenylidene]aniline ( 5.3a ), colorless oil [90T6715] (73%); benzyl propylideneamine ( 5.3b ), colorless oil [01JOC7051] (84%). 1-Thioacylbenzotriazoles 5.9a-c were prepared according to the published procedures: [05JOC7866] (6 -nitrobenzotriazol-1-yl) (2-thienyl)methanethione ( 5.9b ), gray green microcrystals (40%), mp 132 134 C (lit. mp 133 134 C [05JOC7866]); (6nitrobenzotriazol-1-yl) (2-furyl)methanethione ( 5.9c ), red orange microcrystals (80%), mp 162 163 C (lit. mp 161 162 C [05JOC7866]).

PAGE 75

62 (6-Nitrobenzotriazol-1-yl)-4-chl orophenylmethanethione (5.9a). Pink microcrystals (93%), mp 161 163 C; 1H NMR 9.49 (d, J = 1.9 Hz, 1H), 8.47 (dd, J = 8.9, 2.1 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H); 13C NMR 199.4, 149.1, 140.2, 132.9, 132.1, 128.7, 121.9, 121.4, 112.2. Anal. Calcd for C13H7ClN4O2S: C, 48.99; H, 2.21; N, 17.58. Found: C, 49.11; H, 2.19; N, 16.22. Procedure for the preparation of dibenzotriaolylmethanethione 5.1 Thiophogene (10 mmol.) was added dropwise to a solution of benzotriazole (40 mmol) in CH2Cl2 (50 mL) at 0 C. The reaction mixture was stirred at the same temperature for 3 h. After filtration, the residue was washed with CH2Cl2 (330 mL). The combined filtrate was washed with 5% aqueous Na2CO3 (350 mL). After removing solvent under vacuum, the residue was recrystallized from CH2Cl2 to give pure product di-(1 H -1,2,3benzotriaol-1-yl)methanethione in 87% yield as yellow microcrystals. Di(1 H -1,2,3-benzotriazol-1-yl)methanethione (5.1). Yellow microcrystals (87%), mp 171 171 C (lit. mp 170 172 C [78JOC337]); 1H NMR 8.27 (d, J = 8.2 Hz, 2H), 8.21 (d, J = 8.2 Hz, 2H), 7.76 7.71 (m, 2H), 7.62 7.57 (m, 2H); 13C NMR 169.6, 146.8, 133.1, 130.6, 126.9, 121.0, 113.9. General procedure for the preparation of benzotriazolyl -enaminothiones 5.5 from dibenzotriaolylmethanethione 5.1. To a solution of dibenzotriazolylmethanethione (1 mmol) in THF (50 mL), the appropriate ketimine (1 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 6 h, and then concentrated under vacuum. The resi due was dissolved in ethyl acetate (50 mL), and wa s washed with 5% aqueous Na2CO3 (330 mL), followed

PAGE 76

63 by brine (30 mL). The organic la yer was dried over anhydrous Na2SO4. After removing the solvent under vacuum, the residue was either recrystallized from CH2Cl2/hexanes or was purified by flash chromatography (hexanes/et hyl acetate, 5/1) on silica gel to give the pure product 5.5 ( Z )-1-(1 H -1,2,3-Benzotriazol-1-yl)-3-(butyl amino)-3-phenyl-2-propene-1thione (5.5a) Yellow microcrystals (95%), mp 94 96 C; 1H NMR 13.36 (br s, 1H), 8.82 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.58 7.38 (m, 7H), 7.21 (s, 1H), 3.45 3.40 (m, 2H), 1.73 1.64 (m, 2H), 1.53 1.41 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR 179.3, 169.4, 147.0, 135.1, 132.5, 130.3, 128.8, 128.5, 127.3, 124.7, 119.8, 115.7, 106.5, 45.7, 32.1, 19.9, 13.5. Anal. Calcd for C19H20N4S: C, 67.83; H, 5.99; N, 16.65. Found: C, 67.80; H, 6.04; N, 16.74. ( Z )-1(1 H -1,2,3-Benzotriazol-1-yl)-3-(butylam ino)-3-(4-pyridinyl)-2-propene1-thione (5.5b) Yellow microcrystals (94%), mp 100 102 C; 1H NMR 13.21 (br s, 1H), 8.85 8.80 (m, 3H), 8.07 (d, J = 8.3 Hz, 1H), 7.61 7.55 (m, 1H), 7.46 7.38 (m, 3H), 7.19 (s, 1H), 3.40 3.34 (m, 2H), 1.73 1.64 (m, 2H), 1.54 1.42 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR 181.5, 165.8, 150.6, 147.0, 142.8, 132.5, 129.0, 125.0, 121.7, 120.0, 115.7, 104.8, 45.6, 32.1, 19.9, 13.5. Anal. Calcd for C18H19N5S: C, 64.07; H, 5.68; N, 20.75. Found: C, 64.33; H, 5.69; N, 20.72. ( Z )-1-(1 H -1,2,3-Benzotriazol-1-yl)-3-(butyl amino)-2-methyl-3-phenyl-2propene-1-thione (5.5c). Red yellow oil (83%); 1H NMR 15.22 (br s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.56 7.39 (m, 4H), 7.37 7.27 (m, 3H), 3.28 3.22 (m, 2H), 1.71 1.60 (m, 2H), 1.51 1.35 (m, 5H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR 175.0, 172.6, 145.3, 133.2, 132.0, 129.5, 129.0, 127.4, 125.9, 123.7, 119.1, 115.5, 112.1,

PAGE 77

64 46.2, 31.4, 19.7, 19.2, 13.2. Anal. Calcd for C20H22N4S: C, 68.54; H, 6.33; N, 15.99. Found: C, 68.68; H, 6.40; N, 15.62. 1 H -1,2,3-Benzotriazol-1-yl [2-(butylamin o)-1-cylohexen-1-y l]methanethione (5.5d) Thick red oil (78%); 1H NMR 14.95 (br s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.39 7.34 (m, 1H), 3.57 3.50 (m, 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.20 (t, J = 6.2 Hz, 2H), 1.89 1.74 (m, 4H), 1.65 1.56 (m, 2H), 1.52 1.43 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H) ; 13C NMR 173.0, 171.5, 145.2, 131.8, 127.3, 123.7, 119.1, 118.5, 111.8, 43.8, 30.3, 27.8, 27.5, 21.8, 20.7, 20.0, 13.4. Anal. Calcd for C17H22N4S: C, 64.93; H, 7.05; N, 17.82. Found: C, 65.14; H, 7.29; N, 18.17. ( Z )-1-(1 H -1,2,3-benzotriazol-1-yl)-3-(butylam ino)-2-pentene-1-thione (5.5e) Light yellow microcrystals (78%), mp 58 60 C; 1H NMR 13.30 (br s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.56 7.51 (m, 1H), 7.43 7.37 (m, 1H), 7.16 (s, 1H), 3.57 3.51 (m, 2H), 2.55 (q, J = 7.6 Hz, 2H), 1.82 1.75 (m, 2H), 1.66 1.54 (m, 2H), 1.31 (t, J = 7.6 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR 178.4, 173.4, 147.0, 132.6, 128.3, 124.6, 119.7, 115.6, 104.8, 43.6, 31.4, 27.3, 20.2, 13.6, 12.1. Anal. Calcd for C15H20N4S: C, 62.47; H, 6.99; N, 19.43. Found: C, 62.66; H, 7.09; N, 19.78. 1 H -1,2,3-Benzotriazol-1-yl [2-(benzylamino )-1-cyclohexen-1-yl]methanethione (5.5f). Red yellow microcrystals (95%), mp 89 91 C; 1H NMR 15.24 (br s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.52 7.27 (m, 7H), 4.73 (d, J = 5.8 Hz, 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.21 (t, J = 6.4 Hz, 2H), 1.76 1.68 (m, 2H), 1.50 1.42 (m, 2H); 13C NMR 175.2, 171.9, 145.4, 134.7, 132.2, 129.2, 128.3, 127.8, 127.5, 124.2, 119.4, 118.9, 112.2, 47.8, 28.2, 27.9, 22.0, 20.9. Anal. Calcd for C20H20N4S: C, 68.93; H, 5.78; N, 16.08. Found: C, 68.71; H, 5.90; N, 16.35.

PAGE 78

65 General procedure for the preparation of -enamino thioamides 5.6 from benzotriazolyl -enaminothiones 5.5. Benzotriazolyl -enaminothione 5.5 (0.3 mmol) was dissolved in a secondary amine (2 mL). The reaction mixture was exposed to microwave irradiation (80 Watts, 80 C) for 0.5 h. The solvent was removed under vaccuum. The residue was dissolved in CH2Cl2 (10 mL) and washed with 5% aqueous Na2CO3 (310 mL), followed by brine (10 mL ). The organic layer was dried over anhydrous Na2SO4. After removing the solvent under vacuum, the residue was purified by flash chromatography (hexanes/ethyl acet ate, 5/1) on a silica gel to give the pure product 5.6 ( Z )-3-(Butylamino)-1-morpholino-3-phenyl-2-propene-1-thione (5.6a). Light yellow oil (91%); 1H NMR 11.97 (br s, 1H), 7.43 7.41 (m, 3H), 7.34 7.33 (m, 2H), 5.14 (s, 1H), 3.95 (br s, 4H), 3.71 (t, J = 5.1 Hz, 4H), 3.15 3.08 (m, 2H), 1.55 1.48 (m, 2H), 1.41 1.34 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR 187.0, 164.2, 138.0, 128.9, 128.4, 127.5, 93.3, 66.6, 47.8, 44.7, 32.6, 20.0, 13.6. Anal. Calcd for C17H24N2OS: C, 67.07; H, 7.95; N, 9.20. Found: C, 66.80; H, 7.97; N, 9.08. ( Z )-3-(Butylamino)-3-phenyl-1-piperidino-2-propene-1-thione (5.6b). Light yellow oil (95%); 1H NMR 11.79 (br s, 1H), 7.42 7.33 (m, 5H), 5.15 (s, 1H), 3.92 (br s, 4H), 3.11 3.05 (m, 2H), 1.69 1.47 (m, 8H), 1.40 1.33 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR 185,7, 163.2, 138.3, 128.6, 128.2, 127.6, 93.4, 59.1, 44.5, 32.6, 25.8, 24.6, 20.0, 13.6. Anal. Calcd for C18H26N2S: C, 71.47; H, 8.66; N, 9.26. Found: C, 71.54; H, 8.87; N, 9.33. ( Z )-3(Butylamino)-1-morpholino-3(4-p yridinyl)-2-propene -1-thione (5.6c). Light yellow oil (92%); 1H NMR 11.85 (br s, 1H), 8.69 (d, J = 6.1 Hz, 2H), 7.26 (d, J =

PAGE 79

66 6.4 Hz, 2H), 5.07 (s, 1H), 3.96 (br s, 4H), 3.74 3.71 (m, 4H), 3.10 3.04 (m, 2H), 1.56 1.48 (m, 2H), 1.41 1.34 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR 187.7, 160.8, 150.1, 145.6, 122.3, 93.0, 66.5, 47.9, 44.8, 32.6, 20.0, 13.6. Anal. Calcd for C16H23N3OS: C, 62.92; H, 7.59; N, 13.76. Found: C, 62.25; H, 7.89; N, 12.96. General procedure for the preparation of -enamino thioesters 5.7 from benzotriazolyl -enaminothiones 5.5. Benzotriazolyl -enaminothione 5.5 (0.3 mmol) was dissolved in 2N alcoholic sodium hydroxi de solution (2 mL). The reaction mixture was exposed to microwave irradiation ( 80 Watts, 80 C) for 0.5 h. The solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL) and washed with 5% aqueous Na2CO3 (310 mL), followed by brine (10 mL). The organic layer was dried over anhydrous Na2SO4. After removing the solvent under vacuum, the residue was purified by flash chromatography (hexanes/ethyl acetate, 5/1) on a silica gel to give the pure product 5.7 O -Methyl ( Z )-3-(butylamino)-3-phenyl2-propenethioate (5.7a). Light yellow oil (95%); 1H NMR 11.44 (br s, 1H), 7.43 7.41 (m, 3H), 7.36 7.31 (m, 2H), 5.49 (s, 1H), 3.97 (s, 3H), 3.21 (q, J = 6.2 Hz, 2H), 1.60 1.53 (m, 2H), 1.44 1.34 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR 202.2, 166.0, 136.4, 129.4, 128.4, 127.4, 100.0, 55.1, 44.8, 32.5, 19.9, 13.6. Anal. Calcd for C14H19NOS: C, 67.43; H, 7.68; N, 5.62; Found: C, 67.41; H, 7.59; N, 6.93. O -Propyl ( Z )-3-(butylamino)-3-phenyl-2-propenethioate (5.7b). Light yellow oil (94%); 1H NMR 11.46 (br s, 1H), 7.43 7.41 (m, 3H), 7.36 7.32 (m, 2H), 5.49 (s, 1H), 4.35 (t, J = 6.7 Hz, 2H), 3.23 3.16 (m, 2H), 1.78 1.71 (m, 2H), 1.60 1.50 (m, 2H), 1.44 1.32 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR 201.9,

PAGE 80

67 136.5, 129.3, 128.6, 128.4, 127.4, 100.3, 69.6, 44.8, 32.5, 22.0, 19.9, 13.6, 10.5. Anal. Calcd for C16H23NOS: C, 69.27; H, 8.36; N, 5.05. Found: C, 69.47; H, 8.51; N, 4.89. O -Methyl ( Z )-3-(butylamino)-3(4-pyridin yl)-2-propenethioate (5.7c). Yellow oil (74%); 1H NMR 11.29 (br s, 1H), 8.73 8.70 (m, 2H), 7.27 7.26 (m, 2H), 5.40 (s, 1H), 3.98 (s, 3H), 3.18 3.12 (m, 2H), 1.64 1.50 (m, 2H), 1.42 1.32 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR 162.4, 150.5, 150.2, 144.2, 122.1, 99.7, 55.4, 44.9, 32.5, 19.9, 13.6. Anal. Calcd for C13H18N2OS: C, 62.37; H, 7.25; N, 11.19. Found: C, 62.07; H, 7.70; N, 11.50. General procedure for the preparation of -enamino dithioesters 5.8 from benzotriazolyl -enaminothiones 5.5. Benzotriazolyl -enaminothione 5.5 (0.3 mmol) and potassium hydroxide (0.2 g) was dissolved in thiol (2 mL ). The reaction mixture was exposed to microwave irradiation (80 Watts, 80 C) for 0.5 h. Solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL) and washed with 5% aqueous Na2CO3 (310 mL), followed by brine (10 mL ). The organic layer was dried over anhydrous Na2SO4. After removing the solvent under vacuum, the residue was purified by flash chromatography (hexanes/ethyl acet ate, 5/1) on a silica gel to give the pure product 5.8 Hexyl ( Z )-3-(butylamino)-3-phenyl-2propenedithioate (5.8a). Light yellow oil (85%); 1H NMR 12.85 (br s, 1H), 7.45 7.43 (m, 3H), 7.37 7.33 (m, 2H), 6.11 (s, 1H), 3.26 3.16 (m, 4H), 1.72 1.51 (m, 4H), 1.44 1.25 (m, 8H), 0.91 0.85 (m, 6H); 13C NMR 203.4, 163.6, 135.6, 129.6, 128.6, 127.4, 109.6, 44.9, 33.0, 32.3, 31.4, 28.8, 28.7, 22.5, 19.9, 14.0, 13.5. Anal. Calcd for C19H29NS2: C, 68.00; H, 8.71; N, 4.17. Found: C, 67.71; H, 9.03; N, 4.14.

PAGE 81

68 Phenyl ( Z )-3-(butylamino)-3-phenyl-2-propenedithioate (5.8b). Yellow microcrystals (87%), mp 76 78 C; 1H NMR 13.16 (br s, 1H), 7.54 7.50 (m, 2H), 7.41 7.38 (m, 6H), 7.26 7.22 (m, 2H), 5.88 (s, 1H), 3.27 3.21 (m, 2H), 1.60 1.50 (m, 2H), 1.41 1.33 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR 201.7, 165.0, 135.6, 135.2, 132.2, 129.9, 129.5, 129.2, 128.6, 127.3, 108.6, 45.2, 32.1, 19.9, 13.5. Anal. Calcd for C19H21NS2: C, 69.68; H, 6.46; N, 4.28. Found: C, 69.78; H, 6.54; N, 4.04. Phenyl ( Z )-3-(butylamino)-3(4-pyridin yl)-2-propenedithioate (5.8c). Red yellow oil (92%); 1H NMR 13.04 (br s, 1H), 8.70 8.68 (m, 2H), 7.52 7.47 (m, 2H), 7.42 7.40 (m, 3H), 7.19 7.17 (m, 2H), 5.79 (s, 1H), 3.21 3.14 (m, 2H), 1.59 1.49 (m, 2H), 1.43 1.33 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR 204.8, 161.3, 150.3, 142.8, 135.6, 131.7, 129.8, 129.2, 121.6, 107.3, 45.1, 32.1, 19.8, 13.4. Anal. Calcd for C18H20N2S2: C, 65.81; H, 6.14; N, 8.53. Found: C, 66.11; H, 6.30; N, 8.02. General procedure for the preparation of -enaminothiones 5.10a–c and thioamides 5.11a from 1-thioacylbenzotriazoles 5.9a–c. (6-Nitrobenzotriazol-1yl)methanethione (1.0 mmol) and ZnBr2 (2.0 mmol) were dissolved in THF (20 mL) and stirred at room temperature for 1 h. The appr opriate ketimine (1.0 mmol) in THF (10 mL) was added dropwise into this mixture duri ng 5 min and allowed to stir at room temperature for 3 d. The completion of the reaction was monitored by TLC. The reaction was quenched with 5% aqueous KOH (20 mL ) and the product was extracted with CH2Cl2 (315 mL). The extract was washed w ith brine (215 mL), dried over anhydrous MgSO4 and concentrated to give the crude product, which was purified by flash chromatography (chloroform) on silica gel to give the pure product 5.10a–c or 5.11a

PAGE 82

69 ( Z )-3-(Butylamino)-1-(4-chlorophenyl)-3 -phenyl-2-propene-1-thione (5.10a). Red oil (91%); 1H NMR 14.49 (br s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.51–7.46 (m, 3H), 7.42–7.38 (m, 2H), 7.29–7.26 (d, J = 9.2 Hz, 2H), 6.54 (s, 1H), 3.37 (q, J = 6.7 Hz, 2H), 1.70–1.61 (m, 2H), 1.48–1.39 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR 199.7, 167.8, 146.9, 135.4, 135.2, 130.1, 128.8, 128.2, 128.0, 127.3, 113.0, 45.3, 2.1, 20.1, 13.6. Anal. Calcd for C19H20ClNS: C, 69.18; H, 6.11; N, 4.25. Found: C, 68.82; H, 6.41; N, 3.89. ( Z )-3-(Butylamino)-1-(2-thie nyl)-3-phenyl-2-propene-1-thione (5.10b). Red oil (76%); 1H NMR 14.04 (br s, 1H), 7.50–7.40 (m, 7H), 6.65 (s, 1H), 3.33 (q, J = 6.4 Hz, 2H), 1.67–1.47(m, 2H), 1.46–1.39 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR 189.6, 167.3, 154.4, 135.6, 130.9, 129.9, 128.8, 127.8, 127.3, 124.6, 109.9, 45.3, 32.1, 20.0, 13.5. Anal. Calcd for C17H19NS2: C, 67.73; H, 6.35; N, 4.65. Found: C, 68.09; H, 6.48; N, 4.25. ( Z )-3-(Butylamino)-1-(2-furyl)-3-phe nyl-2-propene-1-thione (5.10c). Red oil (45%); 1H NMR 4.16 (br s, 1H), 7.42–7.40 (m, 3H), 7.34–7.31 (m, 3H), 7.12 (d, J = 3.7Hz, 1H), 6.72 (s, 1H), 6.36 (dd, J = 3.4, 1.5Hz, 1H), 3.27 (q, J = 6.4Hz, 2H), 1.58– 1.51 (m, 2H), 1.39–1.31 (m, 2H), 0.82 (t, J = 7.3Hz, 3H); 13C NMR 183.0, 167.8, 158.9, 143.6, 135.6, 129.9, 128.7, 127.3, 113.9, 112.7, 109.0, 45.3, 32.1, 20.0, 13.5. Anal. Calcd for C17H19NOS: C, 71.54; H, 6.71; N, 4.91. Found: C, 71.58; H, 7.02; N, 4.53. 4-ChloroN -phenyl-thiobenzamide (5.11a). Light yellow microcrystals (35%), mp 153 155 C (lit. mp 157 158 C [90CCCC307]); 1H NMR (DMSOd6) 11.83 (br s, 1H), 7.87 7.80 (m, 4H), 7.54 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H); 13C NMR (DMSOd6) 195.9, 141.2, 139.9, 135.5, 129.3, 128.5, 128.0, 126.4, 124.2.

PAGE 83

70 CHAPTER 6 THE GENERATION AND REACTIVITY OF POLYANION DERIVED FROM 1,1DIBENZOTRIAZOLYLETHANE 6.1 Introduction Reactions of diand polyanions with electrophiles are important in synthetic organic chemistry. Such reactions frequently involve only the most nucleophilic center of the polyanion; however, reactions of dianions as dinucleophil es with electrophiles have also been studied widely [97JOC41 48, 99SL135, 99CC2439, 02ARK(x)80, 03EJOC771]. Previously Katritzky’s group [95H131] and Knight’s group [96TL5615, 98SL1141, 00JCSP(1)2343, 00JCSP(1)3752, 01JCSP(1) 1771] reported that certain N -substituted benzotriazoles can be dilithia ted by deprotonation both at the -position of the N substituent and at the 7-positi on of the benzotriazole ring. Most recently, the reactions of dianion from 1-vinylbenzotriazole 6.1 and electrophiles were inve stigated by Katritzky’s group (Scheme 6-1) [03JOC5713]. Lith iation of 1-vinylbenzotriazole 6.1 with n -BuLi (2 eq.) generated dianion 6.2 which upon subsequent reacti on with 1,2and 1,4-diketones affords 6.4 and 6.3 which are representatives of the 5,6-dihydro-4 H -[1,2,3]triazolo[4,5,1ij ]quinoline and 5,6,7,8-tetrahydro-4 H -[1,2,3]triazolo[4,5,1kl ][1]benzazocine ring systems, respectively. Reactions of dianion 6.2 with isocyanates give 6.5 which contains the 4,5,6,7-tetrahydro [1,2,3]triazolo[4,5,1jk ][1,4]benzodiazepine ring system. These achievements demonstrated that double lith iation of 1-vinylbenz otriazole followed by reaction with bis-electroph iles and isocyanates open up new routes to diverse heterocyclic ring systems.

PAGE 84

71 N N NCH2 N H N O N N N O Ar Ar n B u L iA r N C ON N N CH2Li Li ( C H3C O C H2)2( P h C O )2N N N CH2CH3OH H3C OH N N N CH2Ph Ph OH OH 6.3 6.4 6.5 6.1 6.2 Scheme 6-1. The Generation of Dianion 6.2 from 1-Vinylbenzotriazole 6.1 and its Reactivity toward Diverse Electrophiles. Following the successful formation of th ree novel heterocyclic ring systems 6.3 6.4 and 6.5 from dianion 6.2 the generation of polyanion 6.7 from dibenzotriazolylmethane 6.6 and its reactivity toward diffe rent electrophiles was also investigated by Dr. Sergey Bobrov in th e Katritzky research group (Scheme 6-2) [05T3305]. Dr. Sergey Bobrov found that compound 6.6 was treated with excess of n -BuLi (4.1 eq.) in THF at –78 C for a period of 12 h to give polyanion 6.7 which was treated with 4 molar equivalents of methyl iodide at the same temperature for 1 h to furnish products 6.8 and 6.9 (Scheme 6-2). The reaction of 6.7 with p -tolyl isocyanate (4 eq.) gave the corresponding amide 6.10 in 40% yield. Treatment of polyanion 6.7 with 4methylbenzonitrile (4 eq.) gave only enamine 6.11 in 70% yield as a result of single addition – tautomerization [87JCSP(1)781, 95JHC323, 95JOC246]. Reaction of 6.7 with dibenzoylmethane gave only th e product of single addition 6.12 in 80% yield probably due to the high acidity of the methylene prot ons of the diketone. Unlike the reaction of

PAGE 85

72 6.7 with methyl iodide, treatment with benzyl bromide produced a single product 6.13 ; no products involving the reaction of the 7position of the benzotriazole rings in 6.7 were observed. Attempts to trap polyanion 6.7 with diand tri-electrophiles, such as benzotrichloride, diethyl oxalate, diphenylethanedione hexachloroethane and 1,2diiodoethane gave complex mixtures of products. N N N N N N N N N N N N Li Li Li N N N Bt Me Me Me N N N N N N Me Me Me N HN NH NH O O O p -Tol p -Tol p -Tol N N N N N Bt Bt p -Tol H2N Bt Bt Bzl Bzl Bt Bt Ph O OH Ph -78 oC, THF n -BuLi (4eq.) MeI (4.1eq) 6.6 6.7 6.10 (40%) 6.12 (80%) 6.13 (50%) 6.11 (70%) 6.9 (30%) 6.8 (30%) +p M e C6H4N C O ( 4 e q )BzlBr (4 eq.) p -MeC6H4CN (4 eq.)B z2C H2 ( 1 e q ) Scheme 6-2. The Generation of Polyanion 6.7 from Dibenzotriazolylmethane 6.6 and its Reactivity toward Different Electrophiles. Parallel to Dr. Sergey Bobrov’ s work (the investigation of the versatile reactivity of polyanion 6.7 toward different electrophiles), the continuing efforts to develop new routes to heterocycles led to the generation of polyanion 6.15 from 1,1-

PAGE 86

73 dibenzotriazolylethane 6.14 and the subsequent investiga tion of the reactivity of polyanion 6.15 toward a variety of mono-, diand tr ielectrophiles, is described here. 6.2 Results and Discussion As mentioned above, the previous resear ch results indicated that the most nucleophilic center of polyanion 6.7 was the position to the N -substituent. However, after the anion formation at the -carbon is trapped by the first molar equivalent of electrophile, the second proton at that positi on can then undergo proton-lithium exchange with lithium at 7-position to regenerate an anion at the -position. In order to block the proton lithium exchange between -position of N -substituent and 7-pos ition of polyanion 6.7 1,1-dibenzotriazolylethane 6.14, which has a methyl group at the -carbon instead of an active proton, was used in a model st udy in which the generation of polyanion 6.15 was investigated. Upon reaction with various electrophiles, polyanion 6.15 afforded the corresponding products 6.9 and 6.16–6.18 of addition or substitution. In one case, heterocyclization took place to give product 6.19 (Scheme 6-3). To determine the extent of lithiation, compound 6.14 was treated with excess of n BuLi (4 eq.) in THF at –78 C for a period of 12 h to generate its polyanion, which was then trapped with methyl iodide (4 eq.) at the same temperature. This resulted in the formation of a single compound 6.9 in 65% yield. Assuming th at lithiation initially produced the dianion 6.15 compound 6.14 was treated with 2 molar equivalents of n BuLi in THF at –78 C for a period of 12 h and then reac ted with 2 molar equivalents of methyl iodide to afford 6.9 in 90% yield. The electron-dono r inductive effect of the methyl group in 6.14 may decrease the acidity of the C-7 protons in the benzotriazolyl groups and thus preclude lithiation of the second benzotriazolyl group in 6.15 Having

PAGE 87

74 established efficient conditions for the generation of dianion 6.15 its reactivity toward a range of electrophiles was also tested (Scheme 6-3). N N N N N N Me N N N Bt Me Me Me N N N Bt Me Li Li N N N Bt Me Br N N N Bt Me OH OH O N N N Bt Et Et Me Bt Bt Et Me Bt Bt Me I P h C H B r2-78 oC, THF n -BuLi (2 eq.) 6.14 6.15 6.9 (90%) 6.20 (77%) 6.19 (85%)M e I ( 2 e q )( C O2E t )2 ( 1 e q )( 1 eq )+ 6.17 (33%) 6.18 (29%) EtI (2 eq.) (2 eq.) 6.16 41% Scheme 6-3. The Generation of Dianion 6.15 and its Reactivity toward a Range of Electrophiles. Reaction of 6.15 with 3-iodopropene (2 eq.) gave 6.16 as the only product isolated, by addition at the -carbon adjacent to the benzotriazole group in 41% yield. The reaction of iodoethane (2 eq.) with 6.15 produced a mixture of products (i) 6.17 from addition at the -carbon and the 7-position of the benzotriazole ring, and (ii) 6.18 from addition at -carbon; compounds 6.17 and 6.18 were isolated in 33% and 29% yields respectively. Significantly, the fo rmation of triazoloquinolinone 6.19 in 85% yield was achieved by the reaction of dianion 6.15 with diethyl oxalate. The electron-withdrawing property of benzotriazolyl group and -carbonyl group favored the formation of -

PAGE 88

75 carbonyl geminal diol structure during aque ous work-up. The attempted reaction of 6.15 with benzylidene bromide gave lithium – brom ine exchange resulting in the formation of the 7-bromo derivative 6.20 in 77% yield. As a result of these reactions, functio nalization both at the 7-position of the benzotriazole ring and the -carbon of N -substituent can be achieved. Attempted trapping of dianion 6.15 with diethyl malonate and diethyl phenylmalonate failed, probably due to the high acidity of the methylene protons in these 1,3-dielectrophiles. Only lithiumhydrogen exchange was observed together with the recovery of corresponding starting materials. The treatment of 6.15 with diethyl 2,2-diethylm alonate gave a complex mixture of products, probably due to the -carbon’s steric hindrance (Scheme 6-4). N N N N N N Me N N N Bt Me Li Li -78 oC, THF n -BuLi (2 eq.) 6.14 6.15C H2( C O2E t )2 ( 1 e q ) recovery of starting materials PhCH(CO2Et)2 recovery of starting materials(C2H5)2C (C O2E t )2 complex mixture of products(1 eq )(1 eq.) Scheme 6-4. Attempted Trapping of Dianion 6.15 with 1,3-Dielectrophiles. The structure of the products was confirmed by 1H, and 13C NMR data (see Experimental section). Signi ficantly, the recently reported 1H and 13C NMR data for

PAGE 89

76 related compounds were supported by X-ray analysis [87JCSP(1)781, 95JHC323, 95JOC246]. The analysis of the 1H NMR data for 6.9 and 6.17 – 19 shows the absence of signals for the protons at the -carbon of N -substituents and for 6.9 6.17 and 6.19 the absence of a signal for the pr oton assigned to the 7-position of the benzotriazole ring. The 13C NMR of 6.9 6.17 and 6.19 – 20 show twelve signals of the carbon atoms corresponding to two unsymmetrical benzotriazolyl groups and for 6.9 6.17 and 6.19 – 20 the lack of a signal around 110 ppm, typical of the 7-unsubstit uted benzotriazole ring of starting compounds 6.14 In contrast, the 13C NMR of compounds 6.16 and 6.18 show only six carbon resonance signals atoms charact eristic of two symmetrical benzotriazolyl groups. The 1H NMR spectra 6.20 show that the protons of the methyl group and the proton at the -carbon of the N -substituents resonate as doublets and quartets respectively. 6.3 Conclusion In summary, the generation of polya nion from benzotriazole derivative, 1,1dibenzotriazolylethane, 6.14 and the reactivity of the resulting polyanion 6.15 with a range of electrophiles were investigated. Th e present research extended the scope of previous reports [95H131, 96TL5615, 03JOC 5713]. In one case, when polyanion 6.15 reacted with dielectrophile diet hyl oxalate, the heterocyclizat ion took place to give novel triazoloquinolinone 6.19 in high yield. 6.4 Experimental Section General. Melting points were determined by a capillary melting point apparatus equipped with a digital thermometer and Br istoline hot-stage microscope and were uncorrected. NMR spectra were recorded in CDCl3, acetoned6 or DMSOd6 with TMS as

PAGE 90

77 the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C (75 MHz). Microanalyses were performed on an EA–1108 elemental analyzer. THF was dried over sodium / benzophenone and used fr eshly distilled. Column chromatography was conducted on silica gel 200 425 meshes. 1,1-Dibenzotriazolylethane 6.14 was prepared according to published procedures [87JCSP(1)811] as white micr ocrystals (32%), mp 141-142 C (lit. mp 141-142 C [87JCSP(1)811]). Procedure for preparation of dianion (6.15) solution. A stirred solution of 1,1dibenzotriazolylethane 6.14 (1 g, 3.79 mmol) in THF (50 mL) was cooled to –78 C, and a solution of n -BuLi (4.9 mL, 7.58 mmol, 1.6 M in he xanes) was added dropwise. The reaction mixture was stirred at this temper ature for 12 h and then treated with an appropriate electrophile at the same temperature. Procedure for the preparation of (6.9) from dianion (6.15). A solution of methyl iodide (1.07g, 7.58 mmol) in TH F (15 mL) was added dropwise to a stirred solution of dianion 6.15 (3.79 mmol) at –78 C. The reaction mixture was st irred at this temperature for 1 h and then water was added and the pr oduct was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The re sidue was purified by column chromatography on silica gel (hexanes/ethyl acetate, 6/1) to give 6.9 as microcrystals (90%). 1-[1-(1 H -1,2,3-Benzotriazol-1-yl )-1-methylethy l]-7-methyl-1 H -1,2,3benzotriazole (6.9). Off-white microcrystals (90%), mp 146 147 C; 1H NMR 8.07 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.30 7.20 (m, 2H), 7.17 7.00 (m, 2H), 6.24 (d, J = 8.3 Hz, 1H), 2.68 (s, 6H), 1.61 (s, 3H); 13C NMR 148.2, 146.9, 131.9, 131.5, 130.9,

PAGE 91

78 128.2, 124.7, 124.4, 121.2, 120.2, 118.3, 110.2, 79.8, 30.0, 20.0. Anal. Calcd for C16H16N6: C, 65.74; H, 5.52; N, 28.75. Found: C, 65.45; H, 5.56; N, 29.17. General procedure for the preparation of compounds 6.16–20. A solution of corresponding electrophile (8.00 mmol) in THF (15 mL) was added dropwise to a stirred solution of dianion 6.15 (3.79 mmol) at –78 C. The reaction mixture was stirred at this temperature for 1 h and then water was adde d and the product was ex tracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resi due was purified by column chromatography on silica gel (hexanes/ethyl acetate, 6/1) to give 6.16–20 1-[1-(1 H -1,2,3-Benzotriazol-1-yl)-1-methyl-3-butenyl]-1 H -1,2,3-benzotriazole (6.16). White microcrystals (41%), mp 91 92 C; 1H NMR 8.04 8.07 (m, 2H), 7.14 7.29 (m, 4H), 6.68 6.71 (m, 2H), 5.49 5.58 (m, 1H), 5.06 5.12 (m, 2H), 4.02 (d, J = 7 Hz, 2H), 2.68 (s, 3H); 13C NMR 146.7, 131.2, 129.1, 128.1, 124.4, 121.7, 120.2, 110.0, 80.6, 42.9, 24.9. Anal. Calcd for C17H16N6: C, 67.09; H, 5.30; N, 27.61. Found: C, 67.15; H, 5.29; N, 27.61. 1-[1-(1 H -1,2,3-Benzotriazol-1-yl )-1-methylethy l]-7-ethyl-1 H -1,2,3benzotriazole (6.17). White microcrystals (33%), mp 93 95 C; 1H NMR 8.04 8.07 (m, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.24 7.34 (m, 2H), 7.10 7.18 (m, 2H), 6.30 (d, J = 8.5 Hz, 1H), 3.30 3.41 (m, 1H), 3.13 3.26 (m, 1H), 2.62 (s, 3H), 2.05 (q, J = 7.0 Hz, 2H), 0.78 (t, J = 7.0 Hz, 3H), 0.56 (t, J = 7.0 Hz, 3H); 13C NMR 148.1, 146.8, 131.8, 131.4, 128.6, 128.1, 127.8, 124.8, 124.4, 120.2, 118.0, 110.3, 83.0, 34.0, 26.5, 24.5, 14.8, 7.9. Anal. Calcd for C18H20N6: C, 67.48; H, 6.29; N, 26.23. F ound: C, 67.64; H, 6.35; N, 26.33.

PAGE 92

79 1-[1-(1 H -1,2,3-Benzotriazol-1-yl)-1-methylpropyl]-1 H -1,2,3-benzotriazole (6.18). White microcrystals (29%), mp 93 94 C; 1H NMR 8.03 8.07 (m, 2H), 7.12 7.28 (m, 4H), 6.63 6.66 (m, 2H), 3.32 (q, J = 7.4 Hz, 2H), 2.67 (s, 3H), 0.91 (t, J = 7.6 Hz, 3H); 13C NMR 146.9, 131.4, 128.1, 124.5, 120.3, 110.2, 82.2, 31.8, 24.3, 7.7. Anal. Calcd for C16H16N6: C, 65.74; H, 5.52; N, 28.75. F ound: C, 66.11; H, 5.58; N, 28.65. 4-(1 H -1,2,3-Benzotriazol-1-yl)-5,5-dih ydroxy-4-methyl-4,5-dihydro-6 H [1,2,3]triazolo[4,5,1-ij]quinolin-6-one (6.19). White plates (78%), mp 182 186 C; 1H NMR (DMSOd6) 8.50 (d, J = 8.2 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.75 7.70 (m, 1H), 7.68 7.62 (m, 1H), 7.48 7.42 (m, 1H), 3.03 (s, 3H); 13C NMR (DMSOd6) 186.9, 145.2, 143.9, 134.2, 132.1, 128.6, 125.8, 125.5, 125.3, 124.5, 119.6, 117.1, 113.0, 95.1, 83.7, 16.5. Anal. Calcd for C16H12N6O3: C, 57.14; H, 3.60; N, 24.99. Found: C, 56.90; H, 3.94; N, 26.03. 1-[1-(1 H -1,2,3-Benzotriazol-1 -yl)ethyl]-7-bromo-1 H -1,2,3-benzotriazole (6.20). Off-white microcrystals (77%), mp 165 166 C; 1H NMR 8.72 (q, J = 6.9 Hz, 1H), 8.06 8.01 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.70 7.63 (m, 1H), 7.48 7.40 (m, 1H), 7.38 7.31 (m, 1H), 7.28 7.20 (m, 1H), 2.67 (d, J = 6.9 Hz, 3H); 13C NMR 147.2, 146.6, 132.8, 131.1, 130.7, 128.0, 125.7, 124.3, 120.1, 119.6, 110.8, 102.2, 67.8, 20.3. Anal. Calcd for C14H11BrN6: C, 49.00; H, 3.23; N, 24.49. Found: C, 49.00; H, 3.15; N, 24.32.

PAGE 93

80 CHAPTER 7 CONCLUSION Various novel approaches to targets were achieved via benzotriazole auxiliary. The successful syntheses described herein em ploy convenient preparations of starting materials, and relatively mild conditions. They provide synthetically useful yields, and offer competitive and advantageous alternatives to routes reported in the literature. Chapter 2 and Chapter 5 discuss novel a pproaches to two types of thioacyl derivatives: thioureas and -enamino thioic acid derivativ es. An alternative to the classical thiourea preparations via O/S exchange was developed by treating (benzotriazol1-yl)carboximidamides with hydrogen sulfide (Chapter 2). In Chapter 5, novel benzotriazole intermidates, benzotriazolyl -enaminothiones, were prepared and employed in the syntheses of novel -enamino thioic acid derivatives. Important advantages of the benzotriazo le-assisted thioacylations desc ribed herein include avoiding the use of unstable or hazardous reagents. Further, the relatively mild conditions employed tolerate a variety of functional groups. The yiel ds obtained are comparable. In Chapter 3, novel and advantageous methods for the syntheses of -cyano sulfones and -sulfonyl sulfones have been devel oped using 1-sulfonylbenzotriazoles. These approaches broaden the range of available sulfone derivatives, which are compounds of major synthetic, biological, and medicinal importance. Advantages of these procedures include the following: i) the use of sulfonyl chlorides and of foulsmelling sulfides is avoided; ii) 1-sulf onylbenzotriazoles are neutral and odorless

PAGE 94

81 crystalline compounds, easily accessi ble, and stable to storage over months and iii) the C sulfonylated products are genera lly obtained in synthetically useful yields. These results represent the first example of the successful use of sulfonamides as C -sulfonylating reagents and suggest that few limitations are to be expected for sulf onylation of nitriles and sulfones using benzotriazole methodology. In Chapter 4, 1-acylbenzotriazoles are used as acylating agents to prepare -ketoamino esters, which can be easily reduced to -amino acids. Compared to classic acylating agents, such as acy l halides, esters, and anhydrid es, our 1-acylbenzotriazoles show advantages due to i) their neutral char acter (they can be used to substrates with acid-sensitive group); ii) their appropriate reactivity between highly reactive acyl halides, which has less selectivity and is less difficu lt to handle, and less reactive esters and anhydrides; and iii) their good stability to air and moisture. When chiral substrates are employed, the chiral center is retained. 1-Acylbenzotriazoles have shown great potential in the amino acid and peptide chemistry. Chapter 6 describes the generation of pol yanions from 1,1-dibenzotriazolylethane and the reactivity of the resu lting polyanion was investigated with a range of electrophiles. The efforts led to an approach to a novel ring system, triazoloquinolinone, which may have potential applic ations in the synthesis of bi oactive heterocycles and drug design.

PAGE 95

82 LIST OF REFERENCES1 [30JA3647] Evans, T. W.; Dehn, W. M. J. Am. Chem. Soc. 1930 52 3647. [34JA1408] Douglass, I. B.; Dains, F. B. J. Am. Chem. Soc. 1934 56 1408. [39JA3386] Pomerantz, A.; Connor, R. J. Am. Chem. Soc. 1939 61 3386. [51JA906] Bernstein, J.; Yale, H. L.; Losee, K.; Holsing, M.; Martins, J.; Lott, W. A. J. Am. Chem. Soc. 1951 73 906. [51OS19] Kurzer, F. Org. Synth. 1951 31 19. [55CR181] Schroeder, D. C. Chem. Rev. 1955 55 181. [55OS609] Cressman, H. W. J. Org. Synth. 1955 CV3 609. 1 The reference citation system employed throughout this dissertation is that from Comprehensive Heterocyclic Chemistry II (Vol. 1); Pergamon Press : New York 1996 (Eds. Katritzky, A. R.; Rees, C. W. and Scriven, E.). Each time a reference is cited, a number-letter code is designated to the corresponding reference with the first two (or four if the reference is before 1910) num bers indicating the year followed by the letter code of the journal and the page number in the end. Additional notes to this reference system are as follows: 1. Each reference code is followed by the conv entional literature citation in the ACS style. 2. Journals which are published in more than one part include in the abbreviation cited the appropriate part. 3. Less commonly used books and journals are still abbreviated as using initials of the journal name. 4. Patents are assigned appropriate three letter codes an d are listed at the end in alphabetic order. 5. The list of the reference is arranged according to th e designated code in the order of (a) year; (b) journal in alphabetical order; (c) part number or volume number if it is included in the code; (d) page number. 6. Project number is used to code the unpublished results.

PAGE 96

83 [55OS617] Moore, M. L.; Crossley, F. S. Org. Synth. 1955 CV3 617. [55OS735] Frank, R. L.; Smith, P. V. Org. Synth. 1955 CV3 735. [56AC545] Mameli, E.; D'Angeli, F.; Richter, K. F. Ann. Chim. (Rome) 1956 46 545 (CA: 1956 51 76964). [56JCS659] Baxter, J. N.; Cymerman-C raig, J.; Moyle, M.; White, R. A. J. Chem. Soc. 1956 659. [56JOC483] Erickson, J. G. J. Org. Chem. 1956 21 483. [56OS56] Cymerman-Craig, J.; Moyle, M.; White, R. A. Org. Synth. 1956 36 56. [60JOC770] Tišler, M.; Vrbaški, Ž. J. Org. Chem. 1960 25 770. [63OS180] Kurzer, F. Org. Synth. 1963 CV4 180. [65JHC486] Orth, R. E.; Soedigdo, S. J. Heterocycl. Chem. 1965 486. [67JA4760] Hermes, M. E.; Marsh, F. D. J. Am. Chem. Soc 1967 89 4760. [69JOC3085] Parker, W. L.; Woodward, R. B. J. Org. Chem. 1969 34 3085. [69RC299] Chimiak, A. Rocz. Chim. 1969 43 299. [70CB2775] Bohme, H.; Fuchs, G. Chem. Ber. 1970 103 2775. [71P3155] Kjr, A.; Schuster, A. Phytochem. 1971 10, 3155. [72JMC1024] Loev, B.; Bender, P. E.; Bowman, H.; Helt, A.; McLean, R.; Jen, T. J. Med. Chem. 1972 15 1024. [73JOC2675] West, C. T.; Donnelly, S. J.; Kooistra, D. A.; Doyle, M. P. J. Org. Chem. 1973 38 2675. [73OS801] Neville, R. G.; McGee, J. J. Org. Synth. 1973 CV5 801. [73RC2199] Bierowska-charytonowicz, D.; Konieczny, M. Rocz. Chem. 1973 47 2199. [74LAC1315] Stetter, H.; Steinbeck, K. Liebigs Ann. Chem. 1974 1315. [75JCSP(1)897] Campbell, R. V. M.; Crombie, L.; Findley, D. A. R.; King, R. W.; Pattenden, G.; Whiting, D. A. J. Chem. Soc., Perkin Trans 1 1975 897.

PAGE 97

84 [75S260] Ooms, P. H. J.; Scheer en, J. W.; Nivard, R. J. F. Synthesis 1975 260. [77CPB29] Tseng, C. C.; Terashinma, S.; Yamada, S. Chem. Pharm. Bull. 1977 25 29. [77HCA2747] Buchschacher P.; Cassal, J. M.; Furst, A.; Meier, W. Helv. Chim. Acta. 1977 2747. [77S690] Ono, N.; Tamura, R.; Tanikaga, R.; Kaji, A. Synthesis 1977 690. [77TL4037] Shibasaki, M.; Ikegami, S. Tetrahedron Lett 1977 18 4037. [78JA5221] Tamaru, Y.; Harada, T.; Iwamoton, H.; Yoshida, Z.-i. J. Am. Chem. Soc. 1978 100 5221. [78JOC337] Larsen, C.; St eliou, K.; Harrp, D. N. J. Org. Chem. 1978 337. [79CB1956] Hussein, A. Q.; Jochims, J. C. Chem. Ber. 1979 112 1956. [79JA1316] Tamaru, Y.; Harada, T.; Yoshida, Z.-i. J. Am. Chem. Soc. 1979 101 1316. [79JOC2805] Curphey, T. J. J. Org. Chem. 1979 44 2805. [79S942] Walter, W.; Proll, T. Synthesis 1979 942. [80S453] Meslin, J. C.; Reliquet, A.; Reliquet, F.; Quiniou, H. Synthesis 1980 453. [80S565] Messinger, P.; Kusuma, K. Synthesis 1980 565. [80T3047] Shabana, R.; Rassmussen, J. B.; Olesen, S.O.; Lawesson, S.-O. Tetrahedron 1980 36 3047. [81TL3175] Adiwidjaja, G.; Proll, T.; Walter, W. Tetrahedron Lett. 1981 22 3175. [81TL3409] Tamaru, Y.; Kagotani, M.; Yoshida, Z.-i. Tetrahedron Lett. 1981 22 3409. [82JA5221] Cambell, P.; Nashed, N. T. J. Am. Chem. Soc. 1982 104 5221. [82T2857] Vedejs, E.; Krafft, G. A. Tetrahedron 1982 38 2857. [83JA4396] Smith, J. K.; Bergbreiter, D. E.; Newcomb, M. J. Am. Chem. Soc. 1983 4396.

PAGE 98

85 [83JMC1158] Hargrave, K. D.; Hess, F. K.; Oliver, J. T. J. Med. Chem. 1983 26 1158. [83S605] Ramadas, S. R.; Srinivasan, P. S.; Ramachandran, J.; Sastry, V. V. S. K. Synthesis 1983 605. [84JA726] Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc 1984 106 7260. [84JOC1125] Sepiol, J. J.; Sepi ol, J. A.; Soulen, R. L. J. Org. Chem. 1984 49 1125. [84JOC997] Patil, D. G.; Chedekel, M. R. J. Org. Chem. 1984 49 997. [84S1045] Perez, M. A.; Soto, J L.; Guzman, F.; Diaz, A. Synthesis 1984 1045. [85H1225] Coen, S.; Ragonnet, B.; Vi eillescazes, C.; Roggero, J. Heterocycles 1985 23 1225. [85JOC2806] Ono, N.; Yanai, T.; Hamamoto, I.; Kamimura, A.; Kaji, A. J. Org. Chem. 1985 50 2807. [85T5061] Cava, M. P.; Levinson, M. I. Tetrahedron 1985 41 5087. [86JA2358] Hendrickson, J. B.; Boudreaux, G. J.; Palumbo, P. S. J. Am. Chem. Soc. 1986 108 2358. [86JA2780] Kato, Y.; Fusetani, N.; Mats unaga, S.; Hashimoto, K.; Fujita, S.; Furuya, T. J. Am. Chem. Soc. 1986 108 2780. [86JOC1882] Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. J. Org. Chem. 1986 51 1882. [86S1041] Winckelmann, I.; Larsen, E. H. Synthesis 1986 1041. [87JCSP(1)781] Katritzky, A. R.; Rachwal, S.; Caster, K. C.; Manhi, F.; K. W. Law, K. W.; Rubio, O. J. Chem. Soc., Perkin Trans. 1 1987, 781. [87JCSP(1)811] Katritzky, A.R.; Kuzmierkie wicz, W.; Rachwal, B.; Rachwal, S.; Thomson, J. J. Chem. Soc., Perkin Trans. 1 1987 811. [87JOC1703] Matsuyama, H.; Miyazawa, Y.; Takei, Y.; Kobayashi, M. J. Org. Chem. 1987 52 1703. [87S56] Bram, G.; Loupy, A.; Roux-Schmitt, M. C.; Sansoulet, J.; Strzalko, T.; Seyden-Penne, J. Synthesis 1987 56.

PAGE 99

86 [87S452] Wrobel, J. T.; Hejchman, E. Synthesis 1987 452. [88CL29] Vuddhakul, V.; Jacobsen, N. W.; Rose, S. E.; Ioannoni, B.; Seow, W. K.; Thong, Y. H. Cancer Lett. 1988 42 29. [88JCSP(1)1739] Barluenga, J.; Gonzalez, F. J.; Gotor, V.; Fustero, S. J. Chem. Soc. Perkin. Trans. 1 1988 1739. [88JMC1719] Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem. 1983 26 1158. [88LAC983] Elghandour, A. H. H.; Ramiz, M. M. M.; Ghozlan, S. A. S.; Elmoghayar, M. R. H. Liebigs Ann. Chem. 1988 983. [88MI] Patai, S.; Rappoport, Z.; Stirli ng, C. J. M., Eds. The Chemistry of Sulphones and Sulphoxide; Wiley: Chichester, UK, 1988 [88S456] Rasmussen, C. R.; Villani, F. J., Jr.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Powell, E. T.; Molinari, A. J. Synthesis 1988 456. [89JA779] (55) Ranasinghe, M. G.; Fuchs, P. L. J. Am. Chem. Soc. 1989 111 779. [90JMC2323] Bock, M. G.; Dipardo, R. M.; Williams, P. D.; Pettibone, D. J.; Clineschmidt, B. V.; Ball, R. G.; Veber, D. F.; Freidinger, R. M. J. Med. Chem. 1990 33 2323. [90JOC955] Padwa, A.; Bulllock, H. W.; Dyszlewski, A. D. J. Org. Chem. 1990 55 955. [90SC2291] Huang, X.; Pi, J-H. Synth. Comm. 1990 20 2291. [90T6715] Tan, W.; Bourdieu, C.; Foucaud, A. Tetrahedron 1990 46 6715. [91RRC573] Katritzky, A. R.; Brzezinski, J. Z.; Lam, J. N. Rev. Roum. Chim. 1991 36 573. [91S1205] Hanack, M.; Bailer, G.; Hackenberg, J.; Subramanian, l. R. Synthesis 1991 1205. [91T2683] Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron 1991 47 2683.

PAGE 100

87 [91TL5983] Hamada, Y.; Yoshihisa, T.; Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 1991 32 5983. [92JMC2562] Patt, W. C.; Hamilton, H. W. ; Taylor, M. D.; Ryan, M. J.; Taylor, D. G. Jr.; Connolly, C. J. C.; Doherty, A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B. L.; Painchaud, C. A.; Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C. J. J. Med. Chem. 1992 35 2562. [92MC369] Meijs, G. F.; Rizzardo, E.; Le, T. P. T.; Chen, Y. Macromol. Chem. 1992 193 369. [92S1104] Marini, A. E.; Roumestant, M. L.; Viallefont, P.; Razafindramboa, D.; Bonato, M.; Follet, M. Synthesis 1992 1104. [92S1185] Metzner, P. Synthesis 1992 1185. [92S552] Sakamoto, T.; Kondo, Y.; Suginom e, T.; Ohba, S.; Yamanaka, H. Synthesis 1992 552. [92T7817] Katritzky, A. R.; Shobana, N. Pe rnak, J.; Afridi, A. S.; Fan, W.-Q. Tetrahedron 1992 48 7817. [93JOC1702] Kascheres, A.; Kasc heres, C.; Braga, A.C.H. J. Org. Chem. 1993 58 1702. [93MI] Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford, UK, 1993 [94AA31] Katritzky, A. R.; Yang, Z.; Cundy, D. J. Aldrichim. Acta 1994 27 31. [94BMCL1601] Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994 4 1601. [94H345] Katritzky, A. R.; Gupta, V.; Garet, C.; Stevens, C. V.; Gordeev, M. Heterocycles 1994 38 345. [94JOC1257] Hoeg-Jensen, T.; Olsen, C. E.; Holm, A. J. Org. Chem. 1994 59 1257. [94JOC1518] Benedetti, F.; Berti, F.; Fabrissin, S.; Gianferrara, T. J. Org. Chem. 1994 59 1518. [94JOC2014] Jacobs, H. K.; Gopalan, A. S. J. Org. Chem. 1994 59 2014. [94JOC6287] Petit, G. R.; Singh, S. B.; Harald, D. L.; Lloyd-Williams, P.; Kaantoci, D.; Burkett, D. D.; Barcokzy, J.; Hogan, F.; Wardlaw, T. R. D. J. Org. Chem. 1994 59 6287.

PAGE 101

88 [94JOC7219] Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M. L.; Smith, C. D. J. Org. Chem. 1994 59 7219. [94S445] Katritzky, A. R.; Lan, X.; Fan, W. -Q.; Synthesis 1994 445. [94S898] Braibante, M. E. F.; Braibant e, H. S.; Missio, L.; Andricopulo, A. Synthesis 1994 898. [94SC215] Katritzky, A. R.; Zh ang, G.; Wu, J. Synth. Comm. 1994 24, 205. [94TL6017] Ku, Y. Y.; Patel, R. R.; Roden, B. A.; Sawick, D. P. Tetrahedron Lett. 1994 35 6017. [95COFGT569] Barluenga, J, Rubio, E.; Tomas, M. In Comprehensive Organic Functional Group Transformations; Vo l. 6; Eds. Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W. Pergamon Press: Oxford, UK, 1995 569. [95H131] Katritzky, A. R.; Ignatchenko, A. V.; Lang, H. Heterocycles 1995 41 131. [95JHC323] Katritzky, A. R.; Verin, V. J. Heterocycl. Chem. 1995 32 323. [95JMC4929] Bell, F. W.; Cantrell, A. S.; Hoberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordon, C. L.; Kinnick, M. D.' Lind, P.; Morin, J. P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H.; Zhou, X.-X. J. Med. Chem. 1995 3 8, 4929. [95JOC246] Katritzky, A. R.; Yang, B.; Jiang, J. J. Org. Chem. 1995 60 246. [95JOC3074] Cativiela, C.; Serra no, J. L.; Zurbano, M. M. J. Org. Chem. 1995 60 3074. [95SC4063] Zhao, H.; Biehl, E. R. Synth. Comm. 1995 25 4063. [95SL645] Zhang, C.; Lu, X. Synlett. 1995 646. [95T12337] Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G. Tetrahedron 1995 51 12337. [96BMC1493] Wilde, T. G.; Billheimer, J. T.; Germain, S. J.; Hausner, E. A.; Meunier, P. C.; Munzer, D. A.; St oltenborg, J. K.; Gillies, P. J.; Burcham, D. L.; Huang, S. M.; Klackiewick, J. D.; Ko, S. S.; Wexler, R.R. Bioorg. Med. Chem. 1996 4 1493. [96BMCL111] Feldman, P. L.; Chi, S. Bioorg. Med. Chem. Lett. 1996 6 111.

PAGE 102

89 [96BMCL1409] Bailey, N.; Dean, A. W.; J udd, D. B.; Middlemiss, D.; Storer, R.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996 6 1409. [96HCA1203] Jefford, C. W.; McNu lty, J.; Lu, Z.-H.; Wang, J. B. Helv. Chim. Acta 1996 79 1203. [96JHC1243] Missio, L. J.; Braibante, H. S.; Braibante, M. E. F. J. Heterocyclic Chem. 1996 33 1243. [96LA881] Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H liebigs Ann. 1996 881. [96MI] Cremlyn, R. J. An Introduc tion to Organosulfur Chemistry; John Wiley & Sons: New York, 1996 [96SL1067] Franzone, G.; Carle, S.; Dorizon, P.; Ollivier, J.; Salaun, J. Synlett 1996 1067. [96SL1117] Sosnicki, J. G.; Liebscher, J. Synlett. 1996 1117. [96TL3165] Seki, M.; Matsumoto, K. Tetrahedron Lett. 1996 37 3165. [96TL5615] Li, S. K. Y.; Knight, D. W.; Little, P. B. Tetrahedron Lett. 1996 37 5615. [97CL1023] Orita, A.; Yoshioka, N.; Oteru, J. Chem. Lett. 1997 1023. [97CL1025] Orita, A.; Watanabe, A.; Oteru, J. Chem. Lett. 1997 1025. [97JCS(P1)695] Yoshimatsu, M.; Kawahigashi, M.; Honda, E.; Kataoka, T. J. Chem. Soc., Perkin Trans 1 1997 695. [97JCSCC12101] Giovannini, R.; Petrini, M. J. Chem. Soc. Chem. Comm. 1997 19 12101. [97JOC4148] Katritzky, A. R.: Fali, C. N.; Li, J. J. Org. Chem. 1997 62 4148. [97JOC4562] Kurose, N.; Takahashi, T.; Koizumi, T. J. Org. Chem. 1997 62 4562. [97S573] Jahn, U.; Andersch, J.; Schroth, W. Synthesis 1997 573. [97T12867] Smreina, M.; Majer, P.; Majerova, E.; Guerassina, T. A.; Eissenstat, M. A. Tetrahedron 1997 53 12867. [97T2931] Palacios, F.; Aparicio, D.; Garcia, J. Tetrahedron 1997 53 1173.

PAGE 103

90 [97T307] Phillips, A. D.; Wa rren, E. S.; Whitham, G. H. Tetrahedron 1997 53 307. [97TL163] Hanessian, S. and Schaum, R. Tetrahedron Lett. 1997 38 163. [97TL5503] Denis, J. N.; Tchertchia n, S.; Tomassini, A.; Vallee, Y. Tetrahedron Lett. 1997 38 5503. [98AA35] Katritzky, A. R.; Rogovoy, B. V. Aldrichim. Acta 1998 27, 35. [98ACIE1402] Stadlwieser, J.; Ellmer er-Muller, E. P.; Tako, A.; Maslouh, N.; Bannwarth, W. Angew. Chem. Int. Ed. 1998 37 1402. [98BMCL2203] Albert, R.; Knecht, H.; Ande rsen, E.; Hungerford, V.' Schreier, M. H.; Papagerogiou, C. Bioorg. Med. Chem. Lett. 1998 8 2203. [98CR409] Katritzky, A. R.; lan, X.; Yang, J.; Denisko, O.V. Chem. Rev. 1998 409. [98HCA983] Hitermann, T.; Gademann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998 81 983. [98JA8569] Hanessian, S.; Luo, X. ; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998 120 8569. [98JOC196] Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org. Chem. 1998 63 196. [98JOC3067] Yamamoto, Y.; Shim, J.-G. J. Org. Chem. 1998 63 3067. [98JOC9608] Giambastiani, G.; Poli, G. J. Org. Chem. 1998 63 9608. [98S153] Katritzky, A. R.; Levell, J. R.; Pleynet, D. P. M. Synthesis 1998 153. [98S460] Rasmussen, C. R.; Villani, F. J., Jr.; Reynolds, B. E.; Plampin, J. N.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Howse, R. M., Jr.; Molinari, A. J. Synthesis 1998, 460. [98SL1141] Knight, D. W.; Little, P. B. Synlett 1998 1141. [98T15063] Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V. Tetrahedron 1998 54 15063. [98TL2663] Kearney, P. C.; Fernandez, M.; Flygare, J. A. Tetrahedron Lett. 1998 39 2663.

PAGE 104

91 [99CC1001] Saito, T.; Takekawa, K.; Takahashi, T. Chem. Comm. 1999 1001. [99CC2439] Peter, L.; Manfred, D. Chem. Comm. 1999 2439. [99JCSP(1)11363] Boga, C.; Forlani, L.; Silv estroni, C.; Corradi, A. B.; Sgarabotto, P. J. Chem. Soc., Perkin Trans. 1 1999 1363. [99JHC777] Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocyclic Chem. 1999 36 777. [99JOC7579] Dexter, C. S.; Jackson, R. F. W. J. Org. Chem. 1999 64 7579. [99OL1351] Fu, M.; Fernandez, M. ; Smith, M. L.; Flygare, J. A. Org. Lett 1999 1 1351. [99S1169] Bondavalli, F.; Bruno, O.; Presti E. L.; Menozzi, G.; Mosti, L. Synthesis 1999 7, 1169. [99SL135] Peter, L.; Manfred, D.; Dietmar, S. Synlett. 1999 135. [99TL9309] Catasus, M.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron Lett. 1999 40 9309. [00B387] Levesque, G.; Arsene, P.; Fanneau-Bellenger, V.; Pham, T. Biomacromolecules, 2000 1 387. [00JCC378] Gopalsamy, A.; Yang, H. J. Comb. Chem. 2000 2 378. [00JCSP(1)2343] Knight, D. W.; Little, P. B. J. Chem. Soc., Perkin Trans. 1 2000 2343. [00JCSP(1)3752] Knight, D. W.; Little, P. B. J. Chem. Soc., Perkin Trans. 1 2000 3752. [00JMC2362] Linney, I. D.; Buck, I. M. ; Harper, E. A.; Barret Kalindjian, S.; Pether, M. J.; Shankley, N. P.; Watt, G. F.; Wright, P. T. J. Med. Chem. 2000 43 2362. [00JOC1298] Seki, M.; Shimizu, T.; Matsumoto, K. J. Org. Chem. 2000 65 1298. [00JOC3679] Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000 65 3679. [00JOC8080] Katritzky, A. R.; Rogovoy, B. V.; Chassaing C.; Vvedensky V. J. Org. Chem. 2000 65 8080.

PAGE 105

92 [00JOC8210] Katritzky, A. R.; He, H-Y.; Suzuki, K. J. Org. Chem. 2000 65 8210. [00JOC8210] Katritzky, A. R. ; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000 65 8210. [00M243] MAyadunne, R. T.; Rizzardo, E.; Chiefari, J.; Krstina, J.; Moad, G.; Postma, A.; Thang, S. H. Macromolecules 2001 33 243. [00T3909] Al-Badri, H.; Collignon, N.; Maddalino, J.; Masson, S. Tetrahedron 2000 56 3909. [00T8263] Suzuki, M; Doi, H.; Kat o, K.; Bjorkman, M.; Longstrom, B.; Watanabe, Y.; Noyori, R. Tetrahedron 2000 56 8263. [00TL2797] Goldstein, A. S.; Gelb, M. H. Tetrahedron Lett. 2000 41 1797. [01ARK(iii)33] Flp, F.; Ma rtinek, T.; Bernth, G. Arkivoc 2001 iii 33. [01ARK(v)119] Majcen Le Marechal, A.; Le Grel, P.; Robert, A.; Biškup, J.; Ferk, V.; Toplak, R. Arkivoc 2001 v 119. [01CC1710] Cox, R. J.; Hadfiel d, A. T.; Mayo-Martin, M. B. Chem. Comm. 2001 1710. [01JCSP(1)1771] Knight, D. W.; Little, P. B. J. Chem. Soc., Perkin Trans. 1 2001 1771. [01JOC7051] Tomioka, K.; Shioya, Y.; Nagaoka, Y.; Yamada, K. J. Org. Chem. 2001 66 7051. [01M7849] Barner-Howollik, C.; Quinn, J. F.; Nquyen, T. L. U.; Heuts, J. P. A.; Davis, T. P. Macromolecules 2001 34 7849. [01MFC947] Bogdanowicz-Szwed, K.; Budzowski, A. Monatshefte Fur Chemie 2001 132 947. [01S897] Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.; Kovalenko, K.; Steel, P. J.; Markov, V. I.; Forood, B. Synthesis 2001 897. [01SC2089] Zhao, Z.; Ding, Y.; Zhao, G. Synth. Comm. 2001 31 2089. [01T8705] Sosnicki, J. G.; Jagodzinski, T. S.; Hansen, P. E. Tetrahedron 2001 57, 8705. [01TL4433] Yang, R.-Y.; Kaplan, A. P. Tetrahedron Lett. 2001 42 4433.

PAGE 106

93 [01TL6333] Koketsu, M.; Fukuta, Y.; Ishihara, H. Tetrahedron Lett. 2001 42 6333. [02ARK(i)7] Fathalla, W.; Pazdera, P. Arkivoc 2002 i 7. [02ARK(x)72] Bouchekara, M.; Djaf ri, A.; Vanthuyne, N.; Roussel, C. Arkivoc 2002 x 72. [02ARK(x)80] Brun, E-M.; Gil, S.; Parra, M. Arkivoc 2002 x 80. [02ARK(viii)134] Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.; Akhmedov, N. G. Arkivoc 2002 viii 134. [02BMC1809] Katritzky, A. R.; Rogovoy, B. V.; Kirichenko, N.; Vvedensky, V. Bioorg. Med. Chem. Lett. 2002 12 1809. [02EJOC3909] Manimala, J. C.; Anslyn, E. V. Eur. J. Org. Chem. 2002 3909. [02JCC285] Katritzky, A. R.; Vvedensky, V.; Rogovoy, B. V.; Kovalenko, K.; Torres, E.; Forood, B. J. Comb. Chem. 2002 4 285. [02JCC290] Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.; Kovalenko, K.; Forood, B. J. Comb. Chem. 2002 4 290. [02JOC5197] Fernandez-Rivas, C.; Me ndez, M.; Nieto-Oberhuber, C.; Echavarren, A. M. J. Org. Chem. 2002 67 5197. [02JOC922] Kitagawa, O.; Yamada, Y.; Fujiwara, H.; Taguchi, T. J. Org. Chem. 2002 67 922. [02M8271] Faviere, A.; Charreyre, M.; Chaumont, P.; Pichot, C. Macromolecules 2002 35 8271. [02T7991] Liu, M.; Sibi, M. P. Tetrahedron 2002 58 7991. [03APK(viii)8] Katritzky, A. R.; Kirichenko, N.; Rogovoy, B. V. Arkivoc 2003 viii 8. [03ARK(iv)93] Eynde, J. J. V.; Watt, O. Arkivoc 2003 iv 93. [03CC536] Jiang, B.; Zhang, F.; Xiong, W. Chem. Comm. 2003 536. [03CEJ4586] Katritzky, A. R.; Rogovoy, B. V. Chem. Eur. J. 2003 9 4586. [03EJOC1064] Adam, W.; Gogonas, E.; Hadjiarapoglou, L. P. Eur. J. Org. Chem. 2003 1064.

PAGE 107

94 [03EJOC771] Barluenga, J.; Faans, F. J.; Sanz, R.; Ignacio, J .M. Eur. J. Org. Chem. 2003 771. [03JA15114] Liao, S.; Collum, D.B. J. Am. Chem. Soc. 2003 125 15114. [03JMC3] Acemoglu, L.; Williams, J. M. J. J. Mol. Catalysis A: Chem. 2003 196 3. [03JOC1443] Katritzky, A. R.; A bdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003 68 1443. [03JOC4932] Katritzky, A. R.; A bdel-Fattah, A. A. A.; Wang, M. J. Org. Chem 2003 68 4932. [03JOC5713] Katritzky, A. R.; Bobrov, S.; Kirichenko, K.; Ji, Y.; Steel, P. J. J. Org. Chem. 2003 68 5713. [03JOC5720] Katritzky, A. R.; Suzuki, K.; Sandeep K. Singh, J. Org. Chem. 2003 68 5720. [03JOC8003] You, J.; Verkade, J. G. J. Org. Chem. 2003 68 8003. [03TL3551] Eggelkraut-Gottanka, R.; Kl ose, A.; Beck-sickinger, A. G.; Beyermann, M. Tetrahedron Lett. 2003 44 3551. [03TL8229] Haldar, P.; Ray, J. K. Tetrahedron Lett. 2003 44 8229. [04AGIE2402] Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Angew. Chem. Int. Ed. 2004 43 2402. [04ARK(xii)14] Katritzky, A. R.; Hoffmann, S.; Suzuki, K. Arkivoc 2004 xii 14. [04CCA175] Katritzky, A. R.; Suzuki, K.; Singh, S. K. Croat. Chem. Acta 2004 175. [04JOC1849] Katritzky, A. R.; Rodrig uez-Garcia, V.; Nair, S. K. J. Org. Chem. 2004, 69 1849. [04JOC6617] Katritzky, A. R.; Wang, Z.; Wang, M.; Wilkerson, C. R.; Hall, C. D.; Akhmedov, N. G. J. Org. Chem. 2004 69 6617. [04S1799] Katritzky, A. R.; Kiriche nko, N.; Rogovoy, B. V.; Kister, J.; Tao, H. Synthesis 2004 1799. [04S1806] Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004 1806.

PAGE 108

95 [04S2645] Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004 2645. [05JOC4993] Katritzky, A. R. ; Jiang, R.; Suzuki, K. J. Org. Chem. 2005 70 4993. [05JOC7866] Katritzky, A. R.; Witek, R. M.; Rodriguez-Garcia, V.; Mohapatra, P. P.; Rogers, J. W.; Cusido, J. Abdel-Fattah, A. A. A.; Steel, P. J. J. Org. Chem. 2005 70 7866. [05JOC9191] Katritzky, A. R.; Abdel-Fa ttah, A. A. A.; Vakulenko, A. V.; Tao, H. J. Org. Chem. 2005 70 9191. [05S297] Katritzky, A. R.; Angrish, P., Hr, D., Suzuki, K. Synthesis 2005 297. [05T2555] Katritzky, A. R.; Manju, K. ; Singh, K. S.; Meher, N. K. Tetrahedron 2005 61 2555. [05T3305] Katritzky, A. R.; Bobrov, S.; Tao, H.; Kirichenko, K. Tetrahedron 2005 61 3305. [1475] Katritzky, A. R.; Tao, H.; Jia ng, R., Suzuki, K.; Kirichenko, K. Unpublished Results. [51USP2520715] Fetterly, L. C. U. S. Pat. 2520715, 1951 [72USP3700664] Girgis, M. M. US Patent. 1972 3,700,664 (CA: 1972 76 24933). [86JP61134389] Hirai, K.; Sugimoto, H.; Mizushima, T. Jpn. Kokai Tokkyo Koho 1986 JP 61134389 A2. [88USP4780127] Michaely, W. J.; Krattz, G. W. U. S. Pat. 4,780,127, 1988 ; Chem. Abstr. : 1989 111 P 129017a. [93USP5260489] Robsein, R. L.; Straw, J. J.; Fahey, D. R. U. S. Pat. 5,260,489, 1993 ; Chem. Abstr. : 1994 120 P 165200z. [03USP6525042] Kobayashi, S.; Komoriya, S. ; Ito, M.; Nagata, T.; Mochizuki, A.; Haginoya, N.; Nagahara, T.; Horino, H. US Pat. 6,525,042 B1, 2003

PAGE 109

96 BIOGRAPHICAL SKETCH Hui Tao was born in June 19th, 1975 in Shijiazhuang, Hebei, China. She received her Bachelor of Science in applied chemis try in August 1997 from Tianjin University. In 1998, she was admitted to the Chemistry Department of East China University of Sicence&Techology, China, majoring in organometallic chemistry under the supervision of Professor Xiaochun Tao, and rece ived her Master of Science in June 2001. After working as a research assistan t in the R&D Department of Shanghai Goodway Industrial Co. Ltd. for a year, she commenced her Ph.D. study under the supervision of Professor Alan R. Kkatri tzky at the Chemistry Department of the University of Florida in 2002.


Permanent Link: http://ufdc.ufl.edu/UFE0015000/00001

Material Information

Title: Synthetic Application in Thioacylation, Acylation, and Sulfonylation
Physical Description: Mixed Material
Copyright Date: 2008

Record Information

Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
System ID: UFE0015000:00001

Permanent Link: http://ufdc.ufl.edu/UFE0015000/00001

Material Information

Title: Synthetic Application in Thioacylation, Acylation, and Sulfonylation
Physical Description: Mixed Material
Copyright Date: 2008

Record Information

Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
System ID: UFE0015000:00001


This item has the following downloads:


Full Text












SYNTHETIC APPLICATION IN THIOACYLATION, ACYLATION AND
SULFONYLATION
















By

HUI TAO














A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY


UNIVERSITY OF FLORIDA


2006


































Copyright 2006

By

Hui Tao


































Dedicated to my family, my father Banghe Tao, my mother Pingfen Li and my twin sister
Yong Tao















ACKNOWLEDGMENTS

It is a great pleasure to acknowledge the support and assistance I have received

from people around me. I would not have achieved my Ph.D. without their guidance,

support and encouragement.

My deepest gratitude goes to my supervisor, Professor Alan R. Katritzky, whose

supervision, guidance and support are essential in my chemistry journey. I greatly thank

my committee members, Dr. William R. Dolbier, Dr. Lisa McElwee-White, Dr. Daniel R.

Talham and Dr. Kenneth Sloan, for their time and help. Particularly, I thank Dr. Dolbier

for excellent teaching in physical organic chemistry and the organic bull session he holds

every semester, which brought my understanding of organic chemistry to a new level,

and Dr. Kenneth Sloan, who opened the door of medicinal chemistry for me and led me

to a new world where I can fully apply the knowledge and skills I learned and challenge

my potential in a different way.

I also want to express my deepest appreciation to my colleagues in the Katritzky

group for their collaboration and friendship. My special thanks are given to Dr.

Chunming Cai, Dr. Kostyantyn Kirichenko and Dr. Sanjay Singh for their constant help

and encouragement, carefully checking my thesis and shaping my approaches to research.
















TABLE OF CONTENTS



A C K N O W L E D G M E N T S ................................................................................................. iv

LIST OF TABLES ...... .... .... ........ .... .... ...... ..................... .. .... vii

LIST OF FIGURES ......... ...... ..................................... .. ............... viii

LIST O F SCH EM E S................... ...................... .................. .. .. ............ .. ............ ix

ABSTRACT ........ .............. ............. .. ...... .......... .......... xii

CHAPTER

1 G EN ER A L IN TR O D U C TIO N ......................................................... .....................1

2 SYNTHESIS OF N-MONO AND N,N-DISUBSTITUTED THIOUREAS FROM
(BENZOTRIAZOL- 1-YL)CARBOXIMIDAMIDES .............. ......... ........... ....7

2.1 Introduction..................................................... ................... .. ....... ...... 7
2.2 R results and D discussion ........................................................... ............... 11
2.3 Conclusion ...................................................................... ......... 14
2 .4 E x p erim ental S section ............................................. ......................................... 15

3 EFFICIENT C-SULFONYLATION OF NITRILES AND SULFONES WITH 1-
SULFONYLBENZOTRIAZOLES ................................ .................................. 20

3.1 Introduction ............... ......... ................. ...... .............. ......... 20
3.2 R results and D discussion .................................................................................. 21
3.2.1 Preparation of Sulfonylbenzotriazoles 3.1 .............................................. 21
3.2.2 Synthesis of a-Cyano Sulfones ............. .......................... ................... 22
3.2.3 Synthesis of a-Sulfonyl Sulfones......... ...................................... 25
3.3 Conclusion ................................. .........................................26
3 .4 E x p erim ental S section ......................................... .............................................2 7

4 NOVEL SYNTHESES OF y-AMINO ACID DERIVATIVES UTILIZING N-
PROTECTED AMINOACYLBENZOTRIAZOLES FROM GLUTAMIC ACID ...35

4.1 Introduction........................................................................ ....... ...... 35
4 .2 R results and D iscu ssion ........................................ ...........................................39









4.2.1 Preparation of 1-(N-Tfa-a-Aminoacyl)benzotriazoles 4.10 ...................39
4.2.2 Syntheses of y-Keto-y-amino Esters 4.11 ................................................40
4.2.3 Preparation of 6-Aryl-y-amino Esters 4.12 and 6-Aryl-y-amino Acids
4.13 by Reduction of y-Keto-y-amino Esters 4.11.........................................41
4.2.4 Configuration Study of 6-Aryl-y-amino Acids 4.13.............................. 42
4.3 C conclusion ............. .................................................................... ....... ......... 43
4 .4 E x p erim ental S section ......................................... .............................................44

5 MICROWAVE MEDIATED SYNTHESIS OF P-ENAMINO THIOIC ACID
DERIVATIVES FROM DIBENZOTRIAZOLYLMETHANETHIONE .................. 50

5.1 Introduction........................................................................ ....... ...... 50
5.2 R results and D iscu ssion ........................................... ........................................ 52
5.3 Conclusion ..................................................................... ......... 60
5 .4 E x p erim ental S section ......................................... .............................................6 1

6 THE GENERATION AND REACTIVITY OF POLYANION DERIVED FROM
1,1-DIBENZOTRIAZOLYLETHANE ................................................. ...............70

6.1 Introduction ........... .. ................ ...............70
6 .2 R results and D iscu ssion ........................................ ...........................................73
6.3 Conclusion ................ ........ .................. 76
6 .4 E x p erim ental S section ......................................... .............................................76

7 C O N C L U SIO N ......... ......................................................................... ........ .. ..... .. 80

LIST OF REFEREN CES ........ ......................................................... ............... 82

B IO G R A PH IC A L SK E TCH ..................................................................... ..................96
















LIST OF TABLES


Table page

2-1 Preparation of N-Mono- and N,N-Disubstituted Thioureas 2.3a-e from 1-
Benzotriazole-1-carbothioam ide 2.2. ..................................................................... 10

2-2 Preparation of Mono- and N,N-Disubstituted Thioureas 2.3a-d,f-j .................. 13

3-1 Synthesis of 1-Sulfonylbenzotriazoles 3. la-i from Corresponding Alkyl or Aryl
Sulfonyl Chlorides 3.2 or Organolithium Reagents 3.3........................................22

3-2 Preparation of a-Cyano Sulfones 3.5a-i via C-Sulfonylation ofNitriles 3.4a-f
with Sulfonylbenzotriazoles 3.1a-f ........................................................................24

3-3 Preparation of a-Sulfonyl Sulfones 3.7a-g via C-Sulfonylation of Sulfones
3.6a-d with Sulfonylbenzotriazoles 3.1a,b,d,e,g.................................................26

4-1 Syntheses of y-Keto-y-Amino Esters 4.11....................... .................. ........... 41

4-2 Preparation of 6-Aryl-y-amino Esters 4.12e,f. .................................... ............... 41

4-3 Preperation of 6-Aryl-y-amino Acids 4.13 .................................................... 42

4-4 The Comparison of Chiral HPLC Results of 4.13b (L) with Corresponding DL-
M fixtures 4.13g. .......................................................................43

5-1 The Synthesis ofBenzotriazolyl 3-Enaminothiones 5.5. ......................................54

5-2 Microwave-mediated Synthesis of P-Enamino Thioic Acid Derivatives 5.6-5.8....55

5-3 C-Thioacylation of Ketimines 5.2a with Thioacylbenzotriazoles 5.9a-c. ...............57
















LIST OF FIGURES


Figure page

1-1 Benzotriazole Interm ediate 1.1 ............................................................................ 2

1-2 New Types of Benzotriazole Intermediates 1.2-1.6. ...............................................3

2-1 The Tautomarization of N-Aryl(benzotriazol-l1-yl)carboximidamides 2.4a,d,j.......14

3-1 Sulfonyl Group, a Termporary Transformer of Chemical Reactivity....................20

4-1 Known Biologically Active Compounds Containing Fragments of y-Amino
A cids D derivatives. .................................. ....... .. ...... ...... ........ .. 36

5-1 The Structure of ZnBr2-Thioacylbenzotriazole Complex 5.12 ............. ...............59















LIST OF SCHEMES


Scheme page

1-1 Classical Prototype of Benzotriazole-mediated ca-Hetero-alkylations.......................2

1-2 The Synthesis of Mono- and N,N-Disubstituted Thioureas from (Benzotriazol-1-
yl)carboxim idam ides 1.2. .................... .. .......................... ........ .......... ...... .

1-3 N-Sulfonylbenzotriazoles as Advantageous Reagents for C-Sulfonylation ..............4

1-4 Novel Syntheses of Chiral y-Amino Acid Derivatives Utilizing N-(Protected
aminoacyl)benzotriazoles from L-Glutamic Acid................... ...................

1-5 The Synthesis of P-Enaminothiones 1.8 from Thioacylbenzotriazoles 1.5. ............5

1-6 The Synthesis of Benzotriazolyl P-Enaminothiones 1.6.......................................5

1-7 The Synthesis of P-Enamino Thioic Acid Derivatives..................... ...............6

2-1 W ell-known Routes to Substituted Thioureas................................. .....................9

2-2 Attempted Synthesis of 1-Benzotriazole-l-Carbothioamide 2.2 from 1-
Cyanobenzotriazole 2.1 via Benzotriazole-1-carboxylic Acid Amide...................10

2-3 N-Mono- and N,N-Disubstituted Thioureas 2.3a-e from 1-Cyanobenzotriazole
2.1 via 1-Benzotriazole-1-carbothioamide 2.2. ................................... .................10

2-4 Preparation of (Benzotriazol-l-yl)carboximidamides 2.4a-d,f-j ...........................12

2-5 Previous Study on Nucleophilic Displacement of Benzotriazole in
(Benzotriazol-1-yl)carboximidamides 2.4. ............. ................................................13

2-6 The Proposed Mechanism for the Reaction of (Benzotriazol-1-
yl)carboximidamides with Hydrogen Sulfide. ................................. ............... 14

3-1 1-Sulfonylbenzotriazoles 3.1 as Activating Reagents in N-Acylation of
Benzotriazole and Benzotriazolylalkylation of Aromatic Compounds .................21

3-2 1-Sulfonylbenzotriazoles 3.1 as Effective Reagents for N-Sulfonylation of
Amines and O-Sulfonylation of Phenols................................. ............. ........... 21

3-3 Preparation of 1-Sulfonylbenzotriazoles 3.1a-i ...... .... ....................................... 22









3-4 Known Approaches to a-Cyano Sulfones.............. ................................................23

3-5 A Novel Approach to a-Cyano Sulfones 3.5a-i. .............................................. 24

3-6 A N ovel Approach to a-Sulfonyl Sulfones ...................................... .....................26

4-1 Literature Methods of Synthesis of y-Amino Acids from a-Amino Acids..............37

4-2 y-Amino Acids from Glutamic Acid ......................................................................38

4-3 Novel Syntheses of p-amino Acid Derivatives, y-Aryl-P-amino Acids 4.6.............39

4-4 Preparation of N-(Tfa-a-aminoacyl)benzotriazoles, Tfa-Glu(OMe)-Bt 4.10 ...........39

4-5 Chiral N-Protected (a-Aminoacyl)benzotriazoles as Acylating Reagents in
Friedel-Craft A cylation. ................................................ ............................... 40

4-6 Syntheses of y-Keto-y-amino Esters 4.11................... ........ .. ... ............ 40

4-7 Preparation of 6-Aryl-y-amino Esters 4.12e,f by the Reduction of y-Keto-y-
am ino E sters 4.1 le,f. ............................... ................ .. .. .... .. ........ .... 4 1

4-8 Preparation of 6-Aryl-y-amino Acids 4.13a,b by the Reduction of y-Keto-y-
am ino Esters 4. 1 a,b ..................................... .............. .. ........ .. 42

4-9 Synthesis of Compounds 4.13g (DL)............................... ..................... 43

5-1 Novel Approach to Dibenzotriazolylmethanethione 5.1............... ................... 52

5-2 Known Reactions of Benzotriazole and Related Derivatives with Thiphosgene.....53

5-3 The Reactivity of Dibenzotriazolylmethanethione 5.1 toward Ketimines,
Aldimines and Enamines ............................ ......... .. ..... ............... 54

5-4 Novel Approach to P-Enamino Thioic Acid Derivatives 5.6-5.8............................55

5-5 Plausible Mechanism for the Reaction ofBenzotriazolyl P-Enaminothiones 5.5
w ith N ucleophiles ................................................ .. .... .... .. ........ .... 56

5-6 Published Benzotriazole-Mediated Thioacylation. .............................................57

5-7 Novel Approach to P-Enaminothiones 5.10.................................. ............... 57

5-8 Attempts to Obtain P-Enaminothiones 5.10 from Diverse Ketimines ...................58

5-9 Ketimine with High Reactivity Reacts Through the Enamino Form with the
C om plex 5.12. ........................................................................60









5-10 Ketimine with Low Reactivity Reacts through Imino Form with the Complex
5 .12 ............................................................................. . 6 0

6-1 The Generation of Dianion 6.2 from 1-Vinylbenzotriazole 6.1 and its Reactivity
tow ard Diverse Electrophiles. ............................................................................71

6-2 The Generation of Polyanion 6.7 from Dibenzotriazolylmethane 6.6 and its
Reactivity toward Different Electrophiles.........................................................72

6-3 The Generation of Dianion 6.15 and its Reactivity toward a Range of
E le ctro p h ile s ...................................... ............ ................ ................ 7 4

6-4 Attempted Trapping of Dianion 6.15 with 1,3-Dielectrophiles. ............................75















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

SYNTHETIC APPLICATIONS IN THIOACYLATION, ACYLATION AND
SULFONYLATION
By

Hui Tao

August, 2006

Chair: Alan R. Katritzky
Major Department: Chemistry

Novel synthetic applications of benzotriazole methodology in thioacylation,

acylation and sulfonylation have been developed to synthesize a wide range of

biologically and synthetically useful compounds.

Chapter 2 describes the reaction of (benzotriazol-1-yl)carboximidamides with

hydrogen sulfide, which provide N-mono and N,N-disubstituted thioureas under mild

conditions in 21-99% yields.

1-Sulfonylbenzotriazoles, as advantageous sulfonylating reagents, have been

applied in N-sulfonylation and O-sulfonylation. In a logical sequel, C-sulfonylation with

1-sulfonylbenzotriazoles was investigated, which is discussed in Chapter 3. The

subsequent investigation led to novel syntheses of a-cyano sulfones and a-sulfonyl

sulfones, which are not easy to synthesize by known methods (i.e., via classic

sulfonylation of nitriles and sulfones) in synthetic useful yields.









Recently, katritzky group has extensively studied 1-acylbenzotriazoles as powerful

neutral acylating reagents. In a further extension of this methodology, a novel approach

to y-amino acid derivatives utilizing N-protected aminoacylbenzotriazoles was achieved

and described in Chapter 4. Friedel-Crafts reactions of readily available N-protected a-

aminoacylbenzotriazoles with hetero- and benzenoid- aromatics give a-amino ketones

which can be reduced by either triethyl silane or sodium borohydride to form

corresponding y-amino acid derivatives. The preservation of chirality throughout this

process was confirmed by chiral HPLC results.

In Chapter 5, the synthesis of air and moisture stable benzotriazole derivatives,

benzotriazolyl P-enaminothiones, from dibenzotriazolylmethanethione is discussed.

Subsequent investigation of their synthetic utilities led to a simple and efficient approach

to p-enamino thioic acid derivatives, including thioamides, thioesters and dithioesters via

microwave mediated nucleophlic substitution of the benzotriazolyl moiety in

benzotriazolyl P-enaminothiones in 74-99% yields. C-Thioacylation with 1-

thioacylbenzotriazoles has also been studied in this chapter.

At the end, continuing efforts to develop new routes to heterocycles led to the

generation of polyanion from 1,1-dibenzotriazolylethane and the subsequent investigation

of the reactivity of polyanions toward a variety of mono-, di- and trielectrophiles was

described in Chapter 6. In one case, when the generated polyanion reacted with

dielectrophile diethyl oxalate, the heterocyclization took place to give a novel

triazoloquinolinone in high yield.














CHAPTER 1
GENERAL INTRODUCTION

Benzotriazole has found wide application as an efficient synthetic auxiliary in

organic chemistry. Its derivatives are employed in the photographic, dye and

pharmaceutical industries. Diverse applications of benzotriazole as a synthetic auxiliary

are due to its unique properties, which allow benzotriazole to (i) be easily introduced at

the beginning of a synthetic sequence; (ii) activate attached functionality; (iii) be easily

substituted with various nucleophiles; (iv) be recycled at the end of a reaction sequence

by simple washing with a weak aqueous basic solution, such as sodium carbonate or

bicarbonate (benzotriazole is an acid of appreciable strength with pKa 8.2). The

benzotriazole ring system is stable under diverse reaction conditions, and the presence of

both pyrrole and pyridine-like nitrogen atoms as well as the aromatic system endows

benzotriazole with either electron donor or electron acceptor properties, depending on the

nature of the attached substituent, and the reaction conditions. The above special

chemical dichotomy gives benzotriazole unique chemical characteristics: the ability to act

as a nucleofuge and the ability to activate the a-CH toward proton loss are close to those

of cyano and phenylsulfonyl groups, and better than both phenyl and vinyl groups.

The applications of benzotriazole methodology as a versatile synthetic tool and

chemical properties of benzotriazole derivatives have been periodically reviewed

[91T2683, 94S445, 94AA31, 98CR409, 98AA35, 03CEJ4586, 05T2555]. Readily

available benzotriazole intermediates of type 1.1 (Fig. 1-1) can react with a variety of

nucleophiles providing access to products of substitution of the benzotriazolyl moiety.









Extensive exploration of the utility of benzotriazole derivatives 1.1 resulted in

development of highly important processes of amino-alkylation (X = NR2), amido-

alkylation (X = NHCOR), thioamido-alkylation (X = NHCSR), sulfonamide-alkylation

(X = NHSO2R), alkoxy-alkylation (X = OR), alkylthio-alkylation (X = SR) and silyl-

alkylation (X = SiR3) (Schemel-1). Typical nucleophiles utilized in these reactions

[91T2683, 94S445, 94AA31, 98CR409, 98AA35, 03CEJ4586, 05T2555] include

Grignard, organozinc, organolithium, organosamarium and tin reagents, enolates, silyl

enol ethers, allyl trimethyl silane, active methylenes, amines, thiols, alcohols, phosphates,

and metal hydrides.

X

R1 Bt
1.1
Bt = benzotriazol-1-yl
X = NR2, NHCOR, NHCSR, NHSO2R, OR, SR, SiR3
R1 = alkyl, aryl
Figure 1-1. Benzotriazole Intermediate 1.1.

X X
R Bt + Nu- iAR, u + Bt-
R Bt R Nu
1.1
X = NR2, NHCOR, NHCSR, NHSO2R, OR, SR, SiR3

Scheme 1-1. Classical Prototype of Benzotriazole-mediated c-Hetero-alkylations.

Further effort to develop new benzotriazole intermediates and investigate their

synthetic applications is of great importance. In the present thesis, new types of

benzotriazole intermediates, including (benzotriazol-l-yl)carboximidamides 1.2, 1-

sulfonylbenzotriazoles 1.3, 1-acylbenzotriazoles 1.4, 1-thioacylbenzotriazoles 1.5, and

benzotriazolyl 3-enaminothiones 1.6, have been developed and utilized for the synthesis









of various synthetically useful compounds (Fig. 1-2). Novel and useful aspects of these

benzotriazole intermediates are investigated.

NH O S
Bt R Bt-S-R -R Bt HN-R1
0 Bt R Bt R 2 R3
R'
1.2 1.3 1.4 1.5 1.6

R = alkyl, aryl, heteroaryl, O2N",
R'= H, alkyl, aryl, Bt' = 0N N
R1 = Bu, R2 = H, alkyl, R3 = alkyl, aryl N
Figure 1-2. New Types of Benzotriazole Intermediates 1.2-1.6.

The results of studies on transformations of (benzotriazol-l-yl)carboximidamides

1.2 to N-mono- and N,N-disubstituted thioureas are discussed in Chapter 2.

(Benzotriazol-1-yl)carboximidamides 1.2 reacted with hydrogen sulfide in THF giving

the corresponding mono- and N,N-disubstituted thioureas in moderate to high yields

under mild conditions (Scheme 1-2). The possible mechanism and potential synthetic

advantages are discussed.

NH HS ST

Bt N.R THF R'N NH2
R R
1.2

Scheme 1-2. The Synthesis of Mono- and N,N-Disubstituted Thioureas from
(Benzotriazol-1-yl)carboximidamides 1.2.

In Chapter 3, a novel approach to a-functionalized sulfones is discussed. Reactions

of readily available N-(alkyl-, aryl-, and heteroarylsulfonyl)benzotriazoles 1.3 with

anions, generated from nitriles or sulfones, produce a-cyanoalkyl sulfones and a-

sulfonylalkyl sulfones respectively, in moderate to high yields (Scheme 1-3).










In Chapter 4, novel syntheses of chiral y-amino acid derivatives, utilizing N-

protected aminoacylbenzotriazoles, prepared from L-glutamic acid is discussed. The

preservation of chirality throughout this process is confirmed by chiral HPLC tests

(Scheme 1-4).


R1 R1

0S 2R n-BuLi )
R2 R2


CN R2 MCN
+ R2_ n-BuLi R2
R1 THF RO2S R1


Scheme 1-3. N-Sulfonylbenzotriazoles as Advantageous Reagents for C-Sulfonylation.


0 OMe


TFANO 0
H
Bt

TFA-Glu(OMe)-Bt
1.4


0 OMe


TiCI4
TFA. O
Aromatics N
H Ar
Ar

46-88%


Et3SiH
CF3COOH






NaBH4
DMF/H20


0 OMe


TFA 'N
Ar



0 OH



TFAN
Ar


Scheme 1-4. Novel Syntheses of Chiral y-Amino Acid Derivatives Utilizing N-Protected
aminoacylbenzotriazoles from L-Glutamic Acid.

In Chapter 5, the syntheses and synthetic applications of two benzotriazole

derivatives, 1-thioacylbenzotriazoles 1.5 and benzotriazolyl P-enaminothiones 1.6, are

discussed.

The reactivity of thioacylbenzotriazoles 1.5 toward various nucleophiles is

investigated and it is found that the reactive ketimines 1.7 reacted with









thioacylbenzotriazoles 1.5 smoothly to give P-enaminothiones 1.8 in moderate to good

yields (Scheme 1-5).

Inspired by the results obtained in the synthesis of P-enaminothiones 1.8, this

methodology is extended to the synthesis of novel benzotriazole intermediates,

benzotriazolyl P-enaminothiones 1.6, from dibenzotriazolylmethanethione 1.9 and

ketimines 1.7 (Scheme 1-6).

NR3 S 4 RNH S

R+ 02N N ZnBr2 R1 R4

R2 +A: N THF, r.t. R2
1.7 1.5 1.8
R1 = Ph, R2 = H
R3 = Bu

Scheme 1-5. The Synthesis of P-Enaminothiones 1.8 from Thioacylbenzotriazoles 1.5.



R3 THF RNH S
NR THF
SBt R1 r.t. 6h R1 Bt
Bt R2 R2
1.9 1.7 1.6

Scheme 1-6. The Synthesis of Benzotriazolyl P-Enaminothiones 1.6.

Further investigations support benzotriazolyl P-enaminothiones 1.6 as effective

synthetic precursors to p-enamino thioic acid derivatives 1.10, including thioamides,

thioesters (thiocarboxylic-O-esters) and dithioesters (thiocarboxylic-S-esters) (Scheme 1-

7).

R3 R3
RNH S base R'NH S
R1 Bt microwave irradiation R1 XR4
R2 R2
X = O,S, NR4
1.6 1.10






6


Scheme 1-7. The Synthesis of P-Enamino Thioic Acid Derivatives.

As mentioned previously, besides acting as a leaving group, a benzotriazolyl group

also activates the deprotonation of ca-H. Futhermore, treatment of some benzotriazole

derivatives by excess base leads to deprotonation of the benzotriazolyl group at the 7-

position giving a polyanion. The reactivity of polyanions, generated from 1,1-

dibenzotriazolylethane, toward electrophiles, including reactions with a variety of mono-,

di-, and trielectrophiles, is discussed in Chapter 6.














CHAPTER 2
SYNTHESIS OF N-MONO AND N,N-DISUBSTITUTED THIOUREAS FROM
(BENZOTRIAZOL-1-YL)CARBOXIMIDAMIDES

2.1 Introduction

Thiourea-containing compounds are important because of their numerous chemical

and pharmaceutical applications. For example, thiourea derivatives are efficient

guanylating agents both in solution [86JOC1882, 98S460] and on solid support

[98T15063, 98TL2663, 02EJOC3909]. Thermal decomposition of N-arylthioureas gives

aryl isothiocyanates [56JCS659, 560S56]. Oxidation of arylthioureas with lead

tetraacetate [510S19] or iodic acid [30JA3647] affords arylcyanamides. Thioureas are

also widely used as building blocks to construct libraries of small heterocyclic ring

systems that have potential utility in pharmaceutical applications and related areas. Solid-

phase Biginelli pyrimidine synthesis [03ARK(iv)93] and synthesis of imidazolone

derivatives [990L1351] using resin-bound thioureas were recently reported. Thioureas

also condense with a-halocarbonyl compounds to afford 2-amino-1,3-thiazoles

[96CL1409, 98JOC196, 98ACIE1402, 99JCSP(1)11363, 01ARK(v)119, 02ARK(x)72],

which are potential drug candidates for the treatment of allergies [83JMC 1158],

hypertension [92JMC2562], inflammation [88JMC1719], bacterial infections

[94BMCL1601], and HIV [95JMC4929]. Benzothiazoles can be prepared from

arylthioureas in the presence of bromine [84JOC997]. The utility of thioureas to prepare

1,3-thiazines [97S573], 1,3-diazines [86S1041], 1,3-quinazolines [00JCC378] and 1,2,4-

triazin-5-ones [01TL4433] was also described recently. In particular, 1,2,4-triazin-5-ones









have exhibited anticancer [88CL29], antiulcer [86JP61134389] and anti-inflammatory

[73RC2199] activities. Commercially, thioureas are used in industries as diverse as dye

products, photographic films, elastomers, plastics and textiles. Some thiourea derivatives

are insecticides, preservatives, rodenticides and pharmaceuticals [55CR181].

Furthermore, the ability of thioureas to form crystalline complexes with branched

hydrocarbons and cycloaliphatic structures has led to their use in the characterization and

separation of mixtures of organic compounds [51USP2520715].

Synthetic approaches to thioureas have been investigated extensively [55CR181,

95COFGT569]. Well-known routes to substituted thioureas (Scheme 2-1) involve

reactions of(i) anilines with sodium [72JMC1024] or ammonium thiocyanate [630S180]

in the presence of strong acids (TFA or concentrated HC1); (ii) aroyl isothiocyanates with

amines followed by basic hydrolysis [34JA1408, 550S735, 88S456]; most recently,

mono and N,N-disubstituted thioureas were also prepared on solid support using Fmoc-

isothiocyanate followed by subsequent deprotection [990L1351]; (iii) silicon

tetraisothiocyanate with primary or secondary amines [730S801]; (iv) unsubstituted

thioureas with primary alkyl amines at 170-180 C [56JOC483]; (v) isothiocyanates with

ammonia or amines [550S617, 01ARK(iii)33, 02ARK(i)7]; (vi) primary amines with

carbon disulfide in the presence of mercury acetate and aqueous ammonia [51JACS906];

(vii) disubstituted cyanamides with hydrogen chloride and LiA1HSH [01TL6333] or

hydrogen sulfide and ammonia [550S609].

Although these synthetic approaches have proven to be of great utility for specific

classes of the title compounds, method (i) was limited to monosubstituted thioureas;

methods (ii), (iii), (v) and (vii) require aroyl isothiocyanates, silicon tetraisothiocyanate,









isothiocyanates and disubstituted cyanamides respectively; methods (iv) and (vi) need

either harsh reaction conditions (170-180 oC) or the presence of mercury salt while

method (vi) was also limited to the preparation of monosubstituted thioureas.

S
Si(NCS)4 .
PhCONCS H2N NH2
1. R1R2NH
(ii) (iii) 2 H (IV)
1. R1R2NH R3=H R1 NH2
2. OH- R2, R3 = H
R3 = PhCO

R1 =Aryl (i) 1, R3 (V)
R1NH2 MSCN N R3NCS
M =Na, NH4 2 H R1R2NH
R2, R3 = H

(vii) c (i)
SLiAIHSH or2
1 / H2S/NH3 Hg(OAc)2
SNH3
N N R3=H R2, R3=H R1NH2
R2


Scheme 2-1. Well-known Routes to Substituted Thioureas.

Inspired by the wide applications of thiourea, new approaches to the synthesis of

thioureas were attempted. The synthesis of mono and N,N-disubstituted thioureas from

(benzotriazol-l-yl)carboximidamides is addressed in this chapter.

Recently, a new and efficient reagent, benzotriazole-1-carboxylic acid amide, for

the preparation of mono and N,N-disubstituted ureas (Scheme 2-2) [03ARK(viii)8] was

developed.

Attempts to prepare 1-benzotriazole-l-carbothioamide from the previously

described benzotriazole-1-carboxylic acid amide [03ARK(viii)8] with Lawesson's

reagent gave only benzotriazole (Scheme 2-2). Reactions of benzotriazole or 1-










trimethylsilyl benzotriazole with sodium thiocyanate, sodium hydrogen sulfide or

trimethylsilyl isothiocyanate failed under various conditions. Finally, the desired 1-

benzotriazole-1-carbothioamide 2.2 was prepared by Nataliya Kirichenko in 84% yield

from 1-cyanobenzotriazole 2.1 in DME under hydrogen sulfide gas flow (Scheme 2-3).

30% H202 O
(n-C4H9)4N+HSO4 R1R2NH II
Bt IN NH2
CH2C2, r.t. Bt NH2 THF NH
R2
2.1
Lawesson's reagent



S

Bt ,"NH2
2.2

Scheme 2-2. Attempted Synthesis of 1-Benzotriazole-1-Carbothioamide 2.2 from 1-
Cyanobenzotriazole 2.1 via Benzotriazole-1-carboxylic Acid Amide.

Nataliya Kirichenko in the Katritzky research group found that 1-benzotriazole-1-

carbothioamide 2.2 was unreactive toward amines in THF at 20 C and only reacted

sluggishly under reflux. Treatment of 2.2 with amines in refluxing toluene gave the

corresponding thioureas 2.3a-e in moderate yields (39-71%) (Scheme 2-3, Table 2-1)

[04S1799].

S
H2S S R1R2NH
Bt =N DME, r. t. Bt NH2 toluene N NH2
reflux R2

2.1 2.2 2.3a-e

Scheme 2-3. Mono- and N,N-Disubstituted Thioureas 2.3a-e from 1-Cyanobenzotriazole
2.1 via 1-Benzotriazole-l-carbothioamide 2.2.









Table 2-1. Preparation of Mono- and N,N-Disubstituted Thioureas 2.3a-e from 1-
Benzotriazole-1-carbothioamide 2.2.
Entry Prodcut R1R2 Yield(%)
1 2.3a 4-CH30-C6H4 H 54
2 2.3b Benzyl Benzyl 67
3 2.3c pyrrolidinyl 54
4 2.3d Phenyl H 71
5 2.3e PhNH H 39

2.2 Results and Discussion

The moderate yields of thioureas 2.3a-e (Table 2.1), under relatively harsh reaction

conditions make it necessary to find an alternative approach via (benzotriazol-1-

yl)carboximidamides 2.4. (Benzotriazol-l-yl)carboximidamides 2.4a-d,f-j (Scheme 2-4)

were prepared from di(benzotriazolyl)methanimine 2.5, available as mixture of isomers

2.5' and 2.5" (Scheme 2-4), and primary or secondary amines in 56-82% yield

[00JOC8080]. The displacement of the first benzotriazole moiety was affected by the

addition of an amine of choice to a solution of isomers 2.5' and 2.5" in THF. Compounds

2.4a-d,f-j were obtained exclusively as pure Bt1 isomers, probably due to the

preferential displacement of the Bt2 group in the 2.5" isomer. Furthermore, compared to

the previous approach via 1-cyanobenzotriazole 2.1, di(benzotriazolyl)methanimine 2.5 is

more air and moisture stable, more crystalline-like (1-cyanobenzotriazole 2.1,

amorphous, mp 73-75 C [67JA4760]; di(benzotriazolyl)methanimine 2.5, white

microneedles, mp 162-163 C [00JOC8080]), and is prepared under mild conditions (no

NaH required). These chemical and physical properties make

di(benzotriazolyl)methanimine 2.5 a better starting material for the synthesis of thioureas.

Nucleophilic displacement of benzotriazole in (benzotriazol-1-

yl)carboximidamides 2.4a-d,f-j by a variety of amines with the formation of tri- and

tetrasubstituted guanidines has been reported previously [00JOC8080]. Previous reports









[91RRC573, 00JOC8080] also indicate that mono-substituted (benzotriazol-1-

yl)carboximidamides 2.4a,d,h,i,j are stable compounds which are resistant to

displacement of benzotriazole by amines [00JOC8080] and to elimination in highly basic

conditions (Scheme 2-5) [91RRC573].

BrN NH NH
2 BtH -Bt BtBt + Btl Bt2

2.5' 2.5"


S
R1 THF NH H2STHF NNH
2.5'& 2.5" mixture + HN2 H 2 H R1 R
H2% r. t. Bt N R2 THF N NH2
SI R R2
R1

2.4a-d,f-j 2.3a-d, f-j


Bt = Bt1N B t2 = r --



Scheme 2-4. Preparation of (Benzotriazol-1-yl)carboximidamides 2.4a-d,f-j.

Continuing the efforts in benzotriazole methodology, the reactivity of

(benzotriazol- -yl)carboximidamides 2.4 toward substitution of benzotriazolyl group

with hydrogen sulfide has investigated. (Benzotriazol-1-yl)carboximidamides 2.4b,c,f-i

reacted with hydrogen sulfide smoothly in THF at 20 C and gave the desired mono and

N,N-disubstituted thioureas 2.3b,c,f-i (method A). However, N-aryl(benzotriazol-1-

yl)carboximidamides 2.4a,d,j, did not react with hydrogen sulfide at room temperature.

In refluxing THF, rapid desorption of hydrogen sulfide from the reaction mixture

apparently occurred resulting in no reaction. Heating the reaction mixture in a sealed tube

at 90 C in THF saturated with hydrogen sulfide, results in successful conversion of N-









aryl substituted compounds 2.4a,d,j into the desired thioureas 2.3a,d,j in 21-78%

isolated yields (method B) (Scheme 2-4, Table 2-2).


NH
jAN.R2 R3
Bt N + HN
R1 R4

2.4
R1 = alkyl, aryl

R2 = alkyl R2 = H
PhCI, heat KOH/MeOH


NH
R2 = alkyl R3 NHR2
THF, reflux 4 1




R2 = H
TH, ru no reaction
THF, reflux


R1
N-CN
R2

Scheme 2-5. Previous Study on Nucleophilic Displacement of Benzotriazole in
(Benzotriazol-1-yl)carboximidamides 2.4.

Table 2-2. Preparation of Mono- and N,N-Disubstituted Thioureas 2.3 a-d,f-j.
Entry Prodcut R R Method" Yield(%)
1 2.3a 4-CH30-C6H4 H B 59
2 2.3b Benzyl Benzyl A 86
3 2.3c pyrrolidinyl A 85
4 2.3d Phenyl H B 78
5 2.3f (CH2)20(CH2)2 A 99
6 2.3g Ethyl Ethyl A 92
7 2.3h Benzyl H A 76
8 2.3i n-Butyl H A 94
9 2.3j 4-C1-C6H4 H B 21
a: Method A: THF, rt; Method B: THF, sealed tube, 90 C.

These reaction results suggest a plausible mechanism of substitution, which

involves initial formation of the cationic carbodiimide 2.4', followed by the nucleophilic

addition of hydrogen sulfide and tautomarization to afford 2.3 as final product (Scheme

2-6). This mechanism was also supported by previous research results (Scheme 2-5)

[91RRC573, 00JOC8080].










NH NH SH NH S
O nR 2 THF C R1 + R1,A
Bt N' Bt- A R1 'N SH2 RN NH2
R R1 R22 T2 R2
2.4 -2.3

Scheme 2-6. The Proposed Mechanism for the Reaction of (Benzotriazol-1-
yl)carboximidamides with Hydrogen Sulfide.

As depicted in Scheme 2-6, the formation of the cationic carbodiimide 2.4' would

be facilitated by aliphatic chains on the quarternary nitrogen. These cationic

carbodiimides readily react with hydrogen sulfide followed by tautomerization to give the

desired thioureas, in a total effect of benzotriazole substitution. However, in the presence

of an aromatic substitutent on the nitrogen, structural tautomers play an important role.

Compounds 2.4a,d,j prefer to exist in the more conjugated tautomeric form 2.4"a,d,j

(Figure 2-1). This fact is supported by the NMR spectra of aryl substituted (benzotriazol-

1-yl)carboximidamides 2.4a,d,j, where a 2-proton broad signal, corresponding to NH2 in

the range of 5.76-5.80 ppm is observed. The formation of cationic carbodiimide requires

higher energy.

NH NH2

R1
R1 = aryl
2.4a,d,j aryl 2.4"a,d,j
Figure 2-1. The Tautomerization of N-Aryl(benzotriazol-l1-yl)carboximidamides 2.4a,d,j.

2.3 Conclusion

In summary, di(benzotriazolyl)methanimine 2.5 [00JOC8080] readily reacts with

primary and secondary amines to give (benzotriazol-l-yl)carboximidamides 2.4a-d,f-j,

which are easily converted into mono and N,N-disubstituted thioureas 2.3a-d,f-j with

hydrogen sulfide under mild reaction conditions. The present procedure is advantageous

in comparison to literature methods by avoiding the use of strong acids [630S180,









72JMC1024], strong bases [34JA1408, 550S735, 88S456], difficult to handle reagents

(such as silicon tetraisothiocyanate [730S801] or LiA1HSH [01TL6333]), high reaction

temperatures [56JOC483] and environmentally hazardous heavy metal salts [51JA906].

Furthermore, since the preparation of (benzotriazol-l-yl)carboximidamides

[02JCC285, 02JCC290] on solid support has been described, the development of this

protocol could be valuable in combinatorial synthesis.

2.4 Experimental Section

General. All reactions were carried out under nitrogen atmosphere. THF and DME

were freshly distilled over sodium / benzophenone; toluene was distilled over sodium

before use. Other materials were used as supplied. Melting points were determined by

using a capillary melting point apparatus equipped with a digital thermometer and

Bristoline hot-stage microscope and were uncorrected. 1H NMR (300 MHz) and 13C

NMR (75 MHz) spectra were recorded on a Varian Gemini 300 spectrometer in CDC13

(with TMS for 1H and CDC13 for 13C as the internal reference), unless otherwise stated.

The elemental analyses were performed on a Carlo Erba EA-1108 instrument. Column

chromatography was conducted on silica gel 200-425 mesh.

Di(benzotriazolyl)methanimine 2.5 was prepared according to published procedure

[00JOC8080] as off-white microcrystals (62%), mp 162-163 C, (lit. mp 162-163 C

[00JOC8080]).

Compounds 2.4a-d,f-j were prepared according to the published

procedures[00JOC8080, 01S897]: benzotriazol-1-yl(tetrahydro- 1H-pyrrol-1-

yl)methanimine (2.4c), yellow oil [00JOC8080] (70%); N'-phenyl benzotriazole-1-

carboximidamide (2.4d), white prisms from methanol (56%), mp 123-124 C (lit. mp









123-124 C [00JOC8080]); benzotriazol-l-yl(tetrahydro-4H-1,4-oxazin-4-

yl)methanimine (2.4f), light yellow oil [00JOC8080] (65%); N,N-diethyl-1H-

benzotriazole-1-carboximidamide (2.4g), yellow oil [01S897] (60%); N-

(benzyl)benzotriazole-1-carboximidamide (2.4h), colorless needles (82%), mp 97-98 C

(lit. mp 97-98 C [00JOC8080]).

N'-(4-Methoxyphenyl)-1H-1,2,3-benzotriazole-l-carboximidamide (2.4a). Light

yellow microcrystals (87%); mp 140-141 C; 1H NMR 6 3.82 (s, 3H), 5.80 (br s, 2H),

6.93-6.97 (m, 2H), 7.04-7.07 (m, 2H), 7.43-7.49 (m, 1H), 7.57-7.62 (m, 1H), 8.10 (d, J

= 8.1 Hz, 1H), 8.54 (d, J= 8.4 Hz, 1H); 13C NMR 6 55.5, 115.0, 115.4, 119.7, 122.8,

125.2, 129.3, 131.2, 139.5, 144.4, 146.7, 156.2. Anal. Calcd for C14H13N50: C, 62.91; H,

4.90; N, 26.20. Found: C, 63.14; H, 4.75; N, 26.56.

N,N-Dibenzyl-1H-1,2,3-benzotriazole-l-carboximidamide (2.4b). Colorless oil

(55%); H NMR 6 4.49 (s, 4H), 7.25-7.36 (m, 11H), 7.40-7.50 (m, 1H), 7.53-7.59 (m,

1H), 7.69 (d, J= 8.2 Hz, 1H), 8.10 (d, J= 8.4 Hz, 1H); 13C NMR 6 51.7, 111.0, 120.3,

124.9, 127.7, 127.9, 128.7, 129.2, 132.1, 136.2, 145.7, 152.0. Anal. Calcd for C21H19N5:

C, 73.88; H, 5.61; N, 20.51. Found: C, 74.16; H, 5.77; N, 20.97.

N-Butyl-1H-1,2,3-benzotriazole-l-carboximidamide (2.4i). Off-white

microcrystals (92%), mp 56-58 C; 1H NMR (DMSO-d6) 6 0.98 (t, J= 7.1 Hz, 3H),

1.50-1.52 (m, 2H), 1.66-1.70 (m, 2H), 3.33 (t, J= 6.8 Hz, 2H), 7.06 (br s, 2H), 7.53 (t, J

= 7.3 Hz, 1H), 7.67 (d, J= 7.3 Hz, 1H), 8.16 (d, J= 8.2 Hz, 1H), 8.45 (d, J= 8.2 Hz, 1H);

13C NMR (DMSO-d6) 6 13.9,20.3, 33.0,46.3, 115.2, 119.2, 124.9, 128.7, 131.0, 144.8,

145.8. Anal. Calcd for CljH15N5: C, 60.81; H, 6.96; N, 32.23. Found: C, 61.25; H, 7.13;

N, 32.49.









N'-(4-Chlorophenyl-1H-1,2,3-benzotriazole-l-carboximidamide (2.4j). Off-

white microcrystals (45%), mp 146-148 C; 1H NMR 6 5.76 (br s, 2H), 7.05 (d, J= 8.4

Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.49 (t, J= 8.1 Hz, 1H), 7.62 (t, J= 8.1 Hz, 1H), 8.12

(d, J= 8.1 Hz, 1H), 8.51 (d, J= 8.1 Hz, 1H); 13C NMR 6 115.3, 119.8, 123.2, 125.3,

129.1, 129.5, 129.7, 131.2, 144.2, 145.2, 146.7. Anal. Calcd for C13H1oC1N5: C, 57.47; H,

3.71; N, 25.78. Found: C, 57.93; H, 3.64; N, 25.56.

General Procedure for the Preparation of Compounds 2.3a-d,f-j from 2.4a-

d,f-j. Hydrogen sulfide was bubbled into THF (40 mL) for 2 minutes under dry

conditions. The (benzotriazol-l-yl)carboximidamide 2.4 (2.0 mmol) was added and the

reaction mixture was stirred at room temperature for 1 h (for 2.3b-c,f-i) under a flow of

hydrogen sulfide. Completion of the reaction was monitored by TLC.

For compounds 2.3a,d,j the reaction was very slow at room temperature. After

bubbling hydrogen sulfide into the reaction mixture for 1 h at room temperature, the

hydrogen sulfide flow was stopped and the reaction mixture was allowed to react at 90 C

for 4 h in a sealed tube. The solvent was removed under reduced pressure and the residue

was dissolved in dichloromethane and washed with 10 % aqueous Na2CO3. The organic

layer was separated, dried over anhydrous MgSO4 and concentrated under reduced

pressure. For thioureas 2.3b,c,g no further purification was required; 2.3d,f,h-j were

purified by gradient column chromatography on silica gel with ethyl acetate/hexanes

from 1/6 to 1/1.

Compound 2.3a precipitated from the reaction mixture, was filtered and washed

with hexanes.









p-Methoxyphenylthiourea (2.3a). Off-white microcrystals (59%), mp 209-210 C

(lit. mp 210-210 C [60JOC770]); 1H NMR (DMSO-d) 6 3.74 (s, 3H), 6.90 (d, J= 8.8

Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H), 7.24-7.62 (m, 2H, NH2), 9.48 (s, 1H, NH); 13C NMR

(DMSO-d6) 6 55.2, 114.0, 125.6, 131.7, 156.6, 181.1.

N,N-Dibenzylthiourea (2.3b). White microcrystals (86%), mp 137-138 C (lit. mp

138-139 C [79CB1956]); 1H NMR 6 4.92 (br s, 4H), 5.84 (br s, 2H), 7.26-7.39 (m,

10H); 13C NMR 6 54.6, 126.9, 127.9, 129.0, 135.2, 183.8.

1-Thiocarbamoylpyrrolidine (2.3c). Off-white microcrystals (54%), mp 194-

196 C (lit. mp 193-197 C [56AC545]); 1H NMR (DMSO-d6) 8 1.80-1.92 (m, 4H),

3.27-3.38 (m, 2H), 3.54-3.60 (m, 2H), 7.09 (br s, 2H); 3C NMR (DMSO-d6) 6 24.6,

25.9, 47.5, 51.4, 178.3.

Phenylthiourea (2.3d). White microcrystals (71%), mp 153-154 C (lit. mp 154-

154 C [60JOC770]); 1H NMR (acetone-64) 6 6.90-7.10 (m, 4H), 7.20 (t, J= 7.2 Hz,

1H), 7.35-7.46 (m, 4H), 9.16 (br s, 1H); 13C NMR (acetone-6) 6 124.8, 126.3, 130.0,

139.7, 183.3.

4-Thiocarbamoylmorpholine (2.3f). White microcrystals (99%), mp 159-161 C

(lit. mp 160-161 C [72USP3700664]); 1H NMR (DMSO-d6) 6 3.55-3.58 (m, 4H), 3.70-

3.73 (m, 4H), 7.50 (br s, 2H); 13C NMR (DMSO-d6) 6 47.9, 66.0, 182.7.

1,1-Diethylthiourea (2.3g). Light-yellow microcrystals (92%), mp 82-84 "C (lit.

mp 98-101 C [01TL6333]); H NMR 6 1.18 (t, J= 7.1 Hz, 6H), 3.58 (br s, 4H), 5.91 (br

s, 2H); 13C NMR 6 12.3, 46.0, 180.3.

Benzylthiourea (2.3h). Colorless microcrystals (76%), mp 154-155 C (lit. mp

155-1560C [88LAC983]); H NMR (DMSO-d6) 6 4.66 (s, 2H), 6.60 (s, 1H), 7.11 (br s,









1H), 7.28-7.39 (m, 5H), 8.03 (br s, 1H); 13C NMR (DMSO-d6) 6 47.5, 127.0, 127.4,

128.4, 139.3, 183.5.

Butylthiourea (2.3i). White microcrystals (94%), mp 67-69 C (lit. mp 71-72 C

[71P3155]); 1HNMR 6 0.94 (t, J= 7.3 Hz, 3H), 1.36-1.43 (m, 2H), 1.55-1.65 (m, 2H),

3.20 (br s, 2H), 5.88 (br s, 2H), 6.39 (br s, 1H); 13C NMR 6 13.5, 19.9, 30.5, 44.2, 44.9,

180.4, 182.8 (mixture of rotamers).

(4-Chlorophenyl)thiourea (2.3j). Off-white microcrystals (21%), mp 178-179 C

(lit. mp 180-181 C [00JMC2362]); H NMR (DMSO-d6) 6 7.37-7.51 (m, 6H), 9.78 (s,

1H); 13C NMR (DMSO-d6) 6 124.6, 128.1, 128.5, 138.2, 181.2.















CHAPTER 3
EFFICIENT C-SULFONYLATION OF NITRILES AND SULFONES WITH 1-
SULFONYLBENZOTRIAZOLES

3.1 Introduction

Sulfones are one of the fundamental classes of intermediates in organic synthesis

[88MI, 93MI, 97CL1023] and have wide applicability in fields as diverse as

agrochemicals [88USP4780127], pharmaceuticals [90JOC955, 03USP6525042] and

polymers [93USP5260489]. Sulfones have been described as "chemical chameleons" and

therefore have sustained the interest of chemists all over the world. The sulfonyl group

has the ability to serve as a temporary transformer of chemical reactivity [84JA7260], it

can function as an electrophile via the sulfur atom or as a leaving group (Figure 3-1)

[94TL6017]. This, coupled with its powerful stabilizing properties for the adjacent

carbanions in carbon-carbon bond forming reactions [94JOC2014, 97CL1025,

97JCSCC1210, 97T307], gives sufficient driving force to the intramolecular nucleophilic

substitution in the formation of cyclopropanes [69JOC3085, 75JCSP(1)897].

R1 R1
I I
RO2S-C-H = G C 0
R2 R2
Figure 3-1. Sulfonyl Group, a Termporary Transformer of Chemical Reactivity.

1-Sulfonylbenzotriazoles have been previously used in the preparation ofN-

acylbenzotriazoles [00JOC8210]. They also act as an activating moiety of aldehydes in

the benzotriazolylalkylation of aromatic compounds (Scheme 3-1) [94H345].











Ar1 ArlCHO PhSO2Bt RCO2H, Et3N
K11 RCOBt
Ar2 Bt Ar2H 3.1a THF, r.t.
Scheme 3-1. 1-Sulfonylbenzotriazoles 3.1 as Activating Reagents in N-Acylation of
Benzotriazole and Benzotriazolylalkylation of Aromatic Compounds.

1-Sulfonylbenzotriazoles have also been used as effective N-sulfonylation agents of

amines and O-sulfonylation agents of phenols to give the corresponding sulfonamides

and sulfonates, respectively (Scheme 3-2) [94SC205, 04JOC1849].

THF
R1SO2Bt + NHR2R3 R1SO2NR2R3
r.t.
3.1
= aryl, alkyl, heteroaryl 15 examples (yield: 51-99%)
R1 = aryl, alkyl, heteroaryl

THF
R1SO2Bt + ArOH -- R1SO3Ar
r.t.
3.1
R1 = aryl, alkyl 10 examples (yield: 51-99%)
Scheme 3-2. 1-Sulfonylbenzotriazoles 3.1 as Effective Reagents for N-Sulfonylation of
Amines and O-Sulfonylation of Phenols.

Using this approach, C-sulfonylation with 1-sulfonylbenzotriazoles was

investigated. Novel syntheses of a-cyano sulfones and a-sulfonyl sulfones, which are not

easily available by known methods i.e. via classic sulfonylation of nitriles and sulfones,

are developed in this chapter.

3.2 Results and Discussion

3.2.1 Preparation of Sulfonylbenzotriazoles 3.1

Sulfonylbenzotriazoles 3.1 were prepared according to the literature procedures

[92T7817]. The reaction of alkyl or aryl sulfonyl chlorides with benzotriazole in the

presence of pyridine afforded the corresponding alkyl- and arylsulfonylbenzotriazoles

3.1a-e, while the reaction of organolithium reagents with sulfur dioxide at -78 C gave









lithium sulfinates that reacted with N-chlorobenzotriazole in the presence of triethylamine

to give heteroarylsulfonylbenzotriazoles 3.1f-i (Scheme 3-3, Table 3-1) [04JOC1849].

i) S02
BtH, C5H5N ii) BtCI, NEt3
RSO2CI BtSO2R RLi
R = alkyl or aryl R = heteroaryl
3.2 3.1a-g 3.3
method A method B

Scheme 3-3. Preparation of 1-Sulfonylbenzotriazoles 3.1a-i.

Table 3-1. Synthesis of 1-Sulfonylbenzotriazoles 3.1a-i from Corresponding Alkyl or
Aryl Sulfonyl Chlorides 3.2 or Organolithium Reagents 3.3.
Prodcut R Method Yield(%)
3.1a Methyl A 97
3.1b 4-Tolyl A 78
3.1c Phenyl A 81
3.1d Butyl A 81
3.1e 4-NO2C6H4 A 87
3.1f 2-Thienyl B 82
3.1g 2-Pyridinyl B 71
3.1h 3-Pyridinyl B 52
3.1i Benzofur-2-yl B 81

3.2.2 Synthesis of a-Cyano Sulfones

a-Cyano sulfones are important precursors in synthetic chemistry [77S690,

80S565, 92S552, 94JOC1518, 95SL645, 96SL1067, 97JOC4562]. They are utilized in

the preparation of numerous compounds, including pyridones [99S1169], 4-

aminopyrimidines [84S1045], 5,6-dihydro-4H-pyrans [75S260], tetrahydrofurans,

[98JOC3067] tetrasubstituted cylcobutanes [75S260], and cyclopropanes [85JOC2806,

03CC536]. In addition, they are also valuable building blocks for constructing

biologically active compounds such as P-amido sulfones [39JA3386] and L-indospicines

[96BMCL111].

Published synthetic routes to a-cyano sulfones include (Scheme 3-4): (i) oxidation

of the corresponding sulfides [87S453]; (ii) alkylation ofbenzenesulfinate salts with a-









halo nitriles either under the conditions of anionic activation [77S690, 84JOC1125] or

heat in two-phase system (solid-liquid) in the presence of phase-transfer catalyst [87S56]

or alkylation of phenyl sulfonyl chloride with a-halo acetonitriles in the presence of

sodium diethylphosphorotellurite [90SC2291]; (iii) Cp2TiCl2-catalyzed addition of

Reformatsky reagents to geminal cyanosulfonylalkenes [01SC2089] and (iv)

sulfonylation of nitriles with phenyl tosylate [95SC4063]. Although these synthetic

approaches are of great utility for specific classes of the title compounds, there are

drawbacks. Method (i) suffers from foul smelling starting material while approaches (ii)

and (iii) require a-halo nitriles and geminal cyanosulfonylalkenes which are not usually

readily available. They are also limited by their functional tolerance. The method (iv) was

reported for the tosylation of arylacetonitriles only.

CN

R R1
(i) Oxidation

RSO2CI or RSO2Na O RSO3Ph
+ o(ii) RS CN R = p-tolyl CN
CN O (iv)
CN R1 R1
Hal-(1
R1 ( = R=CR R4
R = aryl, R1 = H ii R12 = R3
RSO2 CN
S+ R4ZnX
R3 R2

Scheme 3-4. Known Approaches to a-Cyano Sulfones.

With the objective to develop a general and efficient route to a-cyano sulfones, the

reactions of nitriles 3.4 with 1-sulfonylbenzotriazoles 3.1 were investigated. It was found

that 1-sulfonylbenzotriazoles 3.1 reacted with nitriles 3.4 smoothly in the presence of









either n-BuLi or t-BuOK to afford the desired a-cyano sulfones in good to high yields

(Scheme 3-5, Table 3-2).

2 CN 1) Base R2 CN
R1 2) BtSO2R RO2S R1

3.4a-f A) n-BuLi, THF, -78 C 3.5a-i
B) t-BuOK, DMSO, r.t.
Scheme 3-5. A Novel Approach to a-Cyano Sulfones 3.5a-i.

Table 3-2. Preparation of a-Cyano Sulfones 3.5a-i via C-Sulfonylation of Nitriles 3.4a-f
with Sulfonylbenzotriazoles 3.1a-f.
Product R R1 R2 Method Yield (%)
3.5a Phenyl Phenyl H A 76
3.5b Phenyl H H A 50
3.5c 2-Thienyl 2,4-Cl2C6H3 H A 90
3.5d 2-Pyridinyl n-Hexyl H A 54
3.5e 3-Pyridinyl Phenyl Methyl A 73
3.5f Methyl 4-BrC6H4 H B 82
3.5g* Methyl 2,4-Cl2C6H3 H B 87
3.5h* 4-Tolyl 4-BrC6H4 H A 93
3.5i* 4-Tolyl 2,4-Cl2C6H3 H B 97
*: compounds 3.5f,g,h,i were prepared by Dr. AshrafA. A. Abdel-Fattah, which were not
included in experimental part. Spectroscopic and analytical data of these compounds are
available in the corresponding published paper [05JOC9191].

Initially, 4-bromophenyl acetonitrile 3.4f was successively treated with 1.2 molar

equivalents n-butyllithium and 1-(4-tolyl)sulfonyl benzotriazole 3.1b at -78 C in THF.

The reaction mixture was allowed to stir at room temperature overnight. Aqueous workup

gave 4-bromophenyl(toluene-4-sulfonyl)acetonitrile 3.5h in 43% yield along with about

50% of the starting material nitrile 3.4a. The yield of 3.5h was improved to 93% by using

two-fold excess of n-butyllithium. To simplify the procedure, the reaction of nitrile 3.4f

with 3.1b was examined in the presence of of t-BuOK in DMSO (2 eq.) at room

temperature. This reaction proceeded smoothly and provided a-cyano sulfone 3.5h in

88% yield. The use of a two-fold excess of either n-BuLi in THF at -78 C or t-BuOK in









DMSO at room temperature proved effective for the sulfonylation of nitriles. The

reactions of 1-sulfonylbenzotriazoles 3.1a-f with nitriles 3.4a-f were performed under

these optimized conditions. In all cases, the reaction proceeded smoothly to give the

corresponding a-cyano sulfones 3.5a-i (Scheme 3-5 and Table 3-1). Success with a wide

range of 1-sulfonylbenzotriazoles and nitriles demonstrates the general applicability of

this procedure. It can be used for alkylsulfonylbenzotriazoles for preparation of a-

cyanoalkyl sulfones 3.5f,g in 82% and 87% yields, respectively.

Arylsulfonylbenzotriazoles were also used to convert acetonitrile itself or a-

arylacetonitriles into the corresponding sulfonylated products 3.5a,b,h,i in 50-97%

yields. Heterocyclic sulfonylating reagents, 1-(2-thienyl, 2-pyridinyl-, or 3-

pyridinyl)sulfonylbenzotriazoles 3.1d-f, reacted with a variety of nitriles to give the

desired products 3.5c-e in 54-90% yields.

The structures of compounds 3.5a-i were supported by NMR spectral data and

elemental analyses. The 1H NMR and 13C NMR spectra of a-cyano sulfones 3.5a-i

showed characteristic signals in the regions 4.10-5.85 ppm and 45.7-62.5 ppm which

were assigned to the proton and carbon alpha to the cyano group.

3.2.3 Synthesis of a-Sulfonyl Sulfones

a-Sulfonyl methyl sulfones are valuable intermediates in the synthesis of

carbocycles [02JOC922, 02JOC5197, 04AGIE2402], and heterocycles [97JCS(P1)695].

They are also reactive substrates in Ramberg-Backlund olefinations [86JA2358,

87JOC1703], Knoevenagel condensation [91S1205] and metal-catalyzed cross-coupling

reactions [98JOC9608, 03EJOC1064]. In addition, some a-sulfonyl sulfones are useful

for the synthesis of a-aryl propanoic acids, ibuprofen analogs [03JMC3].









In spite of these applications, approaches to their syntheses are scarce: the well-

known route to a-sulfonyl sulfones involves the oxidation of the corresponding disulfides

[00T8263] or a-sulfonyl sulfides [89JA779]. The lack of available methods prompts us to

study the generality of the benzotriazole-mediated C-sulfonylation methodology. A high

yielding and general method to a diverse range of target molecules is herein reported.

Treatment of sulfones 3.6 with 2 molar equivalents of n-BuLi at -78 C followed

by the addition of 1-sulfonyl]benzotriazole 3.1 gave the corresponding a-sulfonyl

sulfones in moderate to excellent yields (Scheme 3-6 and Table 3-3).

R3 1) n-BuLi, THF RO2S-R3

SO2R4 2) BtSO2R SO2R4
3.1a,b,d,e,g
3.6a-d 3.7a-g

Scheme 3-6. A Novel Approach to a-Sulfonyl Sulfones.

Table 3-3 Preparation of a-Sulfonyl Sulfones 3.7a-g via C-Sulfonylation of Sulfones
3.6a-d with Sulfonylbenzotriazoles 3.1a,b,d,e,g.
Product R R R4 Yield (%)
3.7a Phenyl Methyl Ethyl 91
3.7b 2-Pyridinyl Methyl Ethyl 87
3.7c Benzofur-2-yl (-CH2-)3 67
3.7d 2-Thienyl Ethyl Ethyl 71
3.7e* 4-Tolyl Phenyl Phenyl 96
3.7f* 4-Tolyl H Phenyl 87
3.7g* 4-Tolyl (-CH2-)3 78
*: compounds 3.7e,f,g were prepared by Dr. AshrafA. A. Abdel-Fattah, which were
not included in experimental part. Spectroscopic and analytical data of these compounds
are available in the corresponding published paper [05JOC9191].


3.3 Conclusion

A high yielding and convenient method for the syntheses of two classes of C-

sulfonylated products has been developed by the treatment of 1-sulfonylbenzotriazoles

with appropriate nitriles and sulfones. In general, the use of 1-sulfonylbenzotriazoles as









C-sulfonylating agents compared with sulfonyl halides is advantageous because of their

neutral character, easy accessibility and high stability. In addition, the approach offers a

general protocol for the preparation of a variety of a-cyano sulfones and a-sulfonyl

sulfones where the corresponding sulfonyl halides or sulfides are not readily available.

The present procedure, combining readily available reagents, simple manipulations and

high yields, should be valuable for obtaining the targeted sulfone derivatives. The present

work provides additional evidence for the good leaving ability of a benzotriazole group.

3.4 Experimental Section

General. Melting points were determined by a capillary melting point apparatus

equipped with a digital thermometer and Bristoline hot-stage microscope and were

uncorrected. NMR spectra were recorded in CDC13 or DMSO-d6 with tetramethylsilanes

as internal standard for 1H (300 MHz) or as the internal standard for 13C (75 MHz). The

elemental analyses were performed on a Carlo Erba EA-1108 instrument.. Anhydrous

THF was freshly distilled over sodium/benzophenone before use. Column

chromatography was conducted on silica gel 200-245 mesh.

General procedure for the preparation of sulfonylbenzotriazoles 3.1.

Method A: The mixture of benzotriazole (20 mmol), alkyl or aryl sulphonyl

chloride (20 mmol) and pyridine (28 mmol) in methylene chloride (50 mL) was stirred at

room temperature for 10 h. After quenching the reaction by adding water (50 mL), the

product was extracted with ethyl acetate (3 x30 mL). The combined organic layer was

dried over anhydrous MgSO4. After evaporation of solvent under reduced pressure, the

residue was recrystallized from ethyl acetate to give pure products 3.1a-e.









Method B: A solution of heteroaryl compound (35 mmol) in anhydrous THF (120

mL) was cooled to -78 C under nitrogen and then treated dropwise with n-BuLi (21.8

mL of 1.55 M in hexanes, 35 mmol) to afford a clear solution, which was stirred at this

temperature for 15 minutes, and then at room temperature for 1 h. Sulfur dioxide was

bubbled into the reaction mixture at -78 C and stirred at this temperature for 15 minutes,

and then at room temperature for 1 h. N-Chlorobenzotriazole (5.4 g, 35 mmol) was added

in one portion at room temperature. The mixture was stirred for 2 h. Triethylamine (5.3

mL, 40 mmol) was added followed by stirring at room temperature for 10 h. Water (300

mL) was added to the reaction mixture, and the product was extracted with ethyl acetate

(3 x300 mL). The combined organic layers were washed with water and brine and dried

over anhydrous MgSO4. After evaporation of solvent under reduced pressure, the residue

was recrystallized from ethyl acetate to give pure products 3.1f-i.

1-(Methylsulfonyl)-1H-1,2,3-benzotriazole (3.1a). Colorless microcrystals (97%),

mp 109-111 C (Lit. mp 110-112 C [00JOC8210]); 1HNMR 6 8.15 (d, J= 8.4 Hz, 1H),

8.01 (d, J= 8.4 Hz, 1H), 7.69 (t, J= 7.5 Hz, 1H), 7.54 (t, J= 7.5 Hz, 1H), 3.52 (s, 3H).

13CNMR 6 145.2, 131.6, 130.5, 126.0, 120.6, 111.9, 42.8.

1-(4-Methylbenzenesulfonyl)-1H-1,2,3-benzotriazole (3.1b). Colorless

microcrystals (78%), mp 126-129 C (Lit. mp 128-129 C [92T7817]); H NMR 6 8.13-

8.06 (m, 2H), 8.01 (d, J= 8.4 Hz, 1H), 7.66 (dt, J= 7.8, 0.8 Hz, 1 H), 7.47 (dt, J= 7.8,

0.8 Hz, 1H), 7.32 (d, J= 8.4 Hz, 2H), 2.39 (s, 3H). 13CNMR 6 146.8, 145.5, 134.0, 131.6,

130.3, 130.2, 128.0, 125.8, 120.6, 112.1, 21.8.

1-(Benzensulfonyl)-1H-1,2,3-benzotriazole (3.1c). Colorless microcrystals (81%),

mp 124-125 C (Lit. mp 123-126 C [92T7817]); 1H NMR 6 8.07-8.14 (m, 4H), 7.64-









7.70 (m, 2H), 7.46-7.57 (m, 3H). 13CNMR 6 145.4, 139.4, 137.0, 135.2, 130.3, 129.7,

127.9, 125.9, 120.6, 112.0.

1-(Butane-l-sulfonyl)-1H-1,2,3-benzotriazole (3.1d). Yellow microcrystals

(78%), mp 32-34 C (Lit. yellow oil [04JOC1849]); 1HNMR 6 8.17 (d, J= 8.3 Hz, 1H),

8.02 (d, J= 8.3 Hz, 1H), 7.67 (t, J= 7.2 Hz, 1H), 7.56-7.51 (m, 1H), 3.65-3.6-0 (m, 2H),

1.77-1.69 (m, 2H), 1.45-1.37 (m, 2H), 0.88 (t, J= 7.3 Hz, 3H). 13CNMR 6 145.1, 132.2,

130.4, 125.9, 120.6, 111.9, 55.4, 24.7, 21.1, 13.2.

1-(4-Nitrobenzenesulfonyl)-1H-1,2,3-benzotriazole (3.1e). Yellow microcrystals

(87%), mp 172-174 oC; 1H NMR 6 8.40-8.32 (m, 4H), 8.11 (d, J= 8.3 Hz, 2H), 7.75-7.70

(m, 1H), 7.57-7.51 (m, 1H). 13CNMR 6 151.3, 145.4, 142.2, 131.4, 130.9, 129.4, 126.4,

124.9, 120.9, 111.7. Anal. Calcd. For C12HsN404S: C, 47.37; H, 2.65; N, 18.41. Found:

C, 47.65; H, 2.53; N, 18.34.

1-(2-Thienylsulfonyl)-lH-1,2,3-benzotriazole (3.1f). Purple microcrystals (82%),

mp 143-144 C (Lit. mp 143-144 C [04JOC1849]); H NMR 6 8.12-8.11 (m, 1H), 8.09-

8.08 (m, 1H), 7.96 (dd, J= 3.8, 1.4 Hz, 1H), 7.75 (dd, J= 5.0, 1.4 Hz, 1H), 7.72-7.67 (m,

1H), 7.54-7.49 (m, 1H), 7.14-7.11 (m, 1H). 13CNMR 6 145.4, 138.5, 136.2, 135.8, 131.3,

130.4, 128.2, 126.0, 120.6, 112.0.

1-(2-Pyridinylsulfonyl)-lH-1,2,3-benzotriazole (3.1g). Light red microcrystals

(71%), mp 132-133 oC (Lit. mp 133-135 oC [04JOC1849]); H NMR 6 8.59 (d, J= 4.7

Hz, 1H), 8.36 (d, J= 7.8 Hz, 1H), 8.23 (d, J= 8.4 Hz, 1H), 8.10 (d, J= 8.4 Hz, 1H), 8.02

(td, J= 7.9, 1.8Hz, 1H), 7.73-7.67 (m, 1H) 7.59-7.49 (m, 2H). 13CNMR 6 154.6, 150.7,

145.3, 138.7, 132.6, 130.4, 128.7, 125.9, 123.3, 120.3, 112.6.









1-(3-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.1h). Colorless microcrystals

(52%), mp 128-129 C (Lit. mp 129 C [04JOC 1849]); 1H NMR 6 9.30 (d, J= 2.0 Hz,

1H), 8.87 (d, J=3.8Hz, 1H), 8.42 (d, J= 8.2 Hz, 1H), 8.14-8.10 (m, 2H), 7.71 (t, J= 5.5

Hz, 1H), 7.55-7.50 (m, 1H). 13CNMR 6 155.5, 148.4, 145.4, 135.7, 134.0, 131.5, 130.8,

126.3, 124.1, 120.8, 111.8.

1-(Benzofuran-2-ylsulfonyl)-1H-1,2,3-benzotriazole (3.1i). Colorless

microcrystals (81%), mp 147-148 C; H NMR 6 8.16 (d, J= 8.4 Hz, 1H), 8.12 (d, J=

8.4 Hz, 1H), 7.86 (s, 1H), 7.75-7.70 (m, 2H), 7.56-7.46 (m, 3H), 7.38-7.32 (m, 1H).

13CNMR 6 156.5, 145.5, 131.6, 130.7, 129.4, 126.2, 125.2, 124.9, 123.6, 120.7, 116.9,

112.7, 112.2. Anal. Calcd. For C14H9N303S: C, 56.18; H, 3.03; N, 14.04. Found: C, 56.4;

H, 2.83; N, 14.12.

General procedure for the preparation of a-cyano sulfones 3.5a-f.

Method A: A solution of the nitrile 3.4 (2 mmol) in anhydrous THF (15 mL) was

cooled to -78 C under nitrogen and then treated dropwise with n-BuLi (2.6 mL of 1.55

M in hexanes 4 mmol) to afford a clear solution, which was stirred at this temperature for

1 h. A solution of 1-sulfonylbenzotriazole 3.1 in anhydrous THF (5-10 ml) was added

dropwise to the stirred mixture. The reaction mixture was allowed to warm to room

temperature while stirring overnight. After quenching the reaction by addition of

saturated aqueous NH4C1, the product was extracted with ethyl acetate. The organic

extract was washed with 10 % aqueous Na2CO3 and brine, and dried over anhydrous

MgSO4. After evaporation of solvent under reduced pressure, the residue was purified by

flash chromatography (hexanes/ethyl acetate, 5/1) to afford the desired product 3.5.









Method B: A mixture of nitrile 3.4 (2 mmol) and t-BuOK (0.45 g, 4 mmol) in

DMSO (10 mL) was stirred below 10 C for 10 minutes. After addition of 1-

sulfonylbenzotriazole 3.3 (2 mmol) in DMSO (5 mL), the mixture was allowed to warm

to room temperature and stirred for 8 h. The mixture was poured into water (40 mL),

acidified with NH4Cl and then extracted with ethyl acetate (3 x30 mL). The extracts were

washed with water, dried over anhydrous Na2SO4 and the solvent removed under reduced

pressure. The residue was purified by flash chromatography (hexanes/ethyl acetate, 5/1)

on silica gel to give the pure product 3.5.

Benzenesulfonyl-phenyl-acetonitrile (3.5a). Colorless crystals (76%), mp

148-150 C (Lit. mp 147.0-148 C [03JOC8003]); 1H NMR 6 7.73-7.70 (m, 3H),

7.55-7.26 (m, 7H), 5.14 (s, 1H). 13CNMR 6 135.2, 134.3, 130.5, 130.1, 129.7, 129.2,

129.0, 125.3, 113.4, 63.1. Anal. Calcd. For C14HllN02S: N, 5.44. Found: N, 5.71.

Benzenesulfonyl acetonitrile (3.5b). Colorless crystals (50%), mp 87-88 C (lit.

mp 88 C [70CB2775]); H NMR 6 8.06-8.02 (m, 2H), 7.82-7.77 (m, 1H), 7.69-7.64

(m, 2H), 4.10 (s, 2H). 13CNMR 6 136.6, 135.4, 129.8, 128.8, 110.4, 45.7. Anal. Calcd.

For CsH7NO2S: C, 53.03; H, 3.89; N, 7.73. Found: C, 53.09; H, 3.81; N, 7.62.

2,4-Dichlorophenyl(thiophene-2-sulfonyl)acetonitrile (3.5c). Pale yellow plates

(90%), mp 142-144 C; H NMR 6 7.91 (d, J= 4.9 Hz, 1H), 7.73 (d, J= 3.8 Hz, 1H),

7.48 (d, J= 8.5 Hz, 1H), 7.46 (d, J= 1.9 Hz, 1H), 7.36 (dd, J= 8.4, 1.9 Hz, 1H), 7.25

(dd, J= 4.9, 3.3 Hz, 1H), 5.85 (s, 1H). "3C NMR 6 137.9, 137.8, 137.5, 135.9, 134.6,

131.8, 130.1, 128.6, 128.1, 122.7, 112.8, 59.4. Anal. Calcd. For C12H7C12NO2S: C, 43.38;

H, 2.12; N, 4.22. Found: C, 43.43; H, 2.01; N, 4.07.









2-Methyl-2-(2-pyridinylsulfonyl)hexanenitrile (3.5d). Red oil (54%); 1H NMR 6

8.82- 8.80 (m, 1H), 8.19 (d, J= 7.8 Hz, 1H), 8.06 (td, J= 7.8, 1.6 HZ, 1H), 7.67(dd, J=

7.7, 4.8 Hz, 1H), 4.64 (dd, J= 10.2, 5.0 Hz, 1H), 2.25-2.13 (m, 2H), 1.76-1.50 (m, 2H),

1.45-1.21 (m, 6H), 0.90 (t, J= 6.6 Hz, 3H). 13C NMR 6 154.5, 150.5, 138.6, 128.5,

123.6, 113.4, 63.1, 31.0, 28.2, 26.4, 25.0, 22.2, 13.8. Anal. Calcd. For C13H18N202S: C,

58.62; H, 6.81; N, 10.52. Found: C, 59.39; H, 7.13; N, 10.48.

2-Phenyl-2-(3-pyridinylsulfonyl)propanenitrile (3.5e). Colorless microcrystals

(73%), mp 121-122 oC; 1H NMR 6 8.85 (dd, J= 4.9, 1.7 Hz, 1H), 8.57 (d, J= 2.2Hz,

1H), 7.95 (d, J= 8.0 Hz, 1H), 7.46-7.37 (m, 6H), 2.28 (s, 3H). 13C NMR 6 155.1, 150.8,

138.3, 130.6, 130.1, 129.5, 129.0, 128.1, 123.4, 116.8, 67.2, 19.2. Anal. Calcd. For

C14H12N202S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.77; H, 4.44; N, 10.05.

4-Bromophenyl methanesulfonyl acetonitrile (3.5f). Colorless plates (82%), mp

111-113 oC; 1H NMR 6 7.64 (d, J= 7.6 Hz, 2H), 7.43 (d, J= 7.7 Hz, 2H), 5.07 (s, 1H),

3.07 (s, 3H). 13C NMR 6 132.8, 131.1, 125.7, 123.4, 113.0, 60.5, 38.1. Anal. Calcd. For

C9HsBrNO2S: C, 39.43; H, 2.94; N, 5.11. Found: C, 39.60; H, 2.84; N, 5.00.

General procedure for the preparation of a-sulfonyl sulfones 3.7a-d. A solution

of the sulfone 3.6 (2 mmol) in anhydrous THF (15 mL) was cooled to -78 oC under

nitrogen and thereafter treated dropwise with n-BuLi (2.6 mL of 1.55 M in hexane, 4

mmol) to afford a clear solution, which was stirred at this temperature for lh. Then

sulfonylbenzotriazole 3.1 (dissolved in 5-10 mL anhydrous THF) was added dropwise.

The reaction mixture was allowed to warm to room temperature while stirring overnight.

After the reaction was quenched by addition of saturated aqueous NH4C1, the reaction

mixture was extracted with ethyl acetate. The organic extracts were combined, washed









with 10% aqueous Na2CO3 and brine, and dried over anhydrous MgSO4. After

cencetration under vacuum, the residue was purified by flash chromatography

(hexanes/ethyl acetate, 5/1) to afford the desired product 3.7.

(1-Ethanesulfonyl-ethanesulfonyl)benzene (3.7a). Colorless crystals (91%), mp

96-97 C (Lit. mp 93-94 C [74LAC1315]); 1H NMR 6 7.97 (d, J= 7.4 Hz, 2H),

7.76-7.71 (m, 1H), 7.63-7.58 (m, 2H), 4.38 (q, J= 7.4 Hz, 1H), 3.67-3.47 (m, 2H), 1.69

(d, J= 7.3 Hz, 3H), 1.49 (t, J= 7.4 Hz, 3H). 13C NMR 6 135.7, 134.9, 130.1, 129.1, 76.0,

48.2, 9.5, 6.2. Anal. Calcd. For C10H1404S2: C, 45.78; H, 5.38. Found: C, 45.73; H, 5.37.

2-(1-Ethanesulfonyl-ethanesulfonyl)-pyridine (3.7b). Red microcrystals (87%),

mp 118-120 C; 1H NMR 6 8.77 (br d, J= 4.5 Hz, 1H), 8.14 (d, J= 7.8 Hz, 1H), 8.04-

7.99 (m, 1H), 7.64-7.60 (m, 1H), 5.14 (q, J= 7.6 Hz, 1H), 3.60-3.33 (m, 2H), 1.86 (d, J

= 7.5 Hz, 3H), 1.45 (t, J= 7.6 Hz, 3H). 13C NMR 6 155.8, 150.2, 138.3, 128.0, 123.4,

72.4, 46.7, 8.8, 5.5. Anal. Calcd. For C9H13NO4S2: C, 41.05; H, 4.98; N, 5.32. Found: C,

41.20; H, 4.94; N, 5.17.

2-(1-Benzofuran-2-ylsulfonyl)tetrahydrothiophene-1,1-dione (3.7c). Colorless

crystals (67%), mp 147-148 OC; 1H NMR 6 7.97 (s, 1H), 7.91 (d, J= 7.9 Hz, 1H), 7.82

(d, J= 8.1 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 5.42 (t, J= 8.5 Hz,

1H), 3.42-3.35 (m, 1H), 3.28-3.18 (m, 1H), 2.54-2.46 (m, 2H), 2.25-2.17 (m, 1H),

2.07-1.99 (m, 1H). 13CNMR 6 155.8, 148.3, 129.1, 125.6, 124.0, 117.1, 112.6, 76.7,

52.4, 25.3, 19.0. Anal. Calcd. For C12H1205S2: C, 47.99; H, 4.03. Found: C, 47.58; H,

4.15.

Ethyl 1-(2-thienylsulfonyl)ethyl sulfone (3.7d). Yellow oil (71%); 1H NMR 6

7.87 (dd, J= 4.9, 1.2 Hz, 1H), 7.83 (dd, J= 3.8, 1.2 Hz, 1H), 7.22 (dd, J= 4 .8, 4.0 Hz,






34


1H), 4.50 (q, J= 7.3 Hz, 1H), 3.62-3.46 (m, 2H), 1.75 (d, J= 7.3 Hz, 3H), 1.47 (t, J= 7.4

Hz, 3H). 13C NMR 6 137.4, 136.4, 135.5, 128.0, 76.1, 48.3, 9.5, 6.0. Anal. Calcd. For

C8H1204S3: C, 35.80; H, 4.51. Found: C, 35.95; H, 4.37.














CHAPTER 4
NOVEL SYNTHESES OF y-AMINO ACID DERIVATIVES UTILIZING N-
PROTECTED AMINOACYLBENZOTRIAZOLES FROM GLUTAMIC ACID

4.1 Introduction

Non-natural y-amino acids have gained considerable attention due to their

important roles in design and synthesis of bioactive molecules as well as in the study of

biomimetic polymers that contain both secondary and tertiary structural analogous to

those of natural proteins. Typically, y-amino acids play an important part in the structure

of natural products with antitumor activity such as hapalosin [94JOC7219, 99SL1118,

99TL9309], dolastatin [94JOC6287], caliculins [86JA2780, 91T15983], and of various

enzyme inhibitor GABA-analogues (Figure 4-1) [97TL5503]. In addition, they are

attractive starting materials for the formation of peptides with helical secondary

structures [98HCA983, 98JA8569].

Given this significance of y-amino acids, the development of efficient methods for

the synthesis of enantiomerically pure y-amino acids is important. Four methods for the

synthesis of y-amino acids from natural a-amino acids have been reported (Scheme 4-1).

(i) Double Arndt-Eistert homologation [69RC299, 77HCA2747]. However, the Amdt-

Eistert homologation protocol is not suitable for large scale synthesis due to the high cost

of the silver catalyst and difficult handling of the hazardous reagent CH2N2 [02T7991].

Although Longobarbo's modification provided a method to avoid using the silver catalyst

and CH2N2, the procedure took four steps [95T12337]. (ii) Wittig reaction of

Ph3P=CHCO2Et with aldehydes available from natural a-amino acids followed by









reduction, which is limited to y-alkyl y-amino acid derivatives [97TL163]. (iii) Reaction

of diethyl potassiomalonate with N-tosylaziridines generated in situ from N, O-ditosyl

protected a-amino alcohols derived from a-amino acids [77CPB29]. However, removal

of N-tosyl group requires harsh reaction conditions (reflux in 47% aqueous HBr), which

may be incompatible with sensitive functionalities [77CPB29]. Smreina etal. reported

the synthesis of y-substituted y-amino acid via N-Boc-5-substituted pyrrolidinones

(Scheme 4-1, route iv), but the decarboxylative ring closure requires high temperature (77

to 110 C) [97T12867].


,, OH O R3
00 N




HO OH



OMe










Calyculins
Figure 4-1. Known Biologically Active Compounds Containing Fragments of y-Amino

Acid Derivatives.
H 0 eMeO N
O NH



D olastatin HO O H










R 1)SOCl2 R O R 0 R
(i) PGN yOH 2) CH2N2 ,PGN OH 1) SOCl2 PG.'NN cat. Ag PG, OH
H N v JrO
H 3)H20/Ag2 H 2) CH2N2 H H

0 1) DIBALH, then O
(ii) R OMe PhP=CHC 2R2 BaseR R OR2 R1 = Bn, iPr, Me, iBu
SG 2) Pd/C, H2 MeOH OR2 E+/THF NH E
NH-PG H-PG NH E
PG
Ph Ph
(iii) h TsCI Ph K2CO3 Ph-'S7 1) diethyl potassiomalonate Ph 0
H2N H2N Pyridine HN OTs N 2) 47% HBr, reflux, 17 hr OH
O OH Ts Ts NH2

RR R
(iv) LJOH a RI b R 1 BocN( d OH
B(i HN O BocHN BocHNR 0 BO e BocHN OH
00 0 0
a) Meldrum's acid, DCC, DMAP; b) NaBH4, AcOH; c) Toluene, reflux; d) NaOH, acetone/water.

Scheme 4-1. Literature Methods of Synthesis of y-Amino Acids from a-Amino Acids.

Other reported syntheses of optically pure y-amino acids from glutamic acid are

(Scheme 4-2): (i) the nucleophilic substitution of iodo derivatives of glutamic acid with

organocuprates [92S1104] and (ii) coupling of organozinc reagent of glutamic acid with

aryl iodides in the presence of Pd [99JOC7579]. However, a major limitation of using

organometallic reagents is the incompatibility with many functionalities [92S1104,

97T12867, 99JOC7579].


The Katritzky research group has investigated 1-acylbenzotriazoles as efficient

acylating agents for N-acylation [98S153, 00JOC8210, 02ARK(viii)134, 02BMC1809,

04ARK(xii)14, 04S2645], C-acylation [00JOC3679, 03JOC1443, 03JOC4932,

03JOC5720, 04CCA175, 04JOC6617], O-acylation [96LA881, 99JHC777, 04JOC6617]

and S-acylation reactions [04S1806]. In particular, 1-acylbenzotriazoles, which are

advantageously stable toward moisture and storable for a long period of time, are

efficient for the C-acylation of electron rich heterocycles, such as indole, pyrrole

[03JOC5720], furan, and thiophene [04CCA175] in the presence of Lewis acids, such as










A1C13. Recently, the preparation of N-TFA- and Fmoc-a-amino ketones by C-acylation of

pyrroles and indoles with chiral N-protected a-aminoacylbenzotriazoles

[02ARK(viii)134, 04S2645, 05S297] was successfully achieved in the presence of AlC13

with preservation of chirality, as demonstrated by configurational analysis [05JOC4993].

Subsequently, Dr. Rong Jiang and Dr. Kostyantyn Kiricheko in Katritzky's group

developed a novel synthesis of y-aryl-P-amino acids 4.6, from L-aspartic acid via (N-

protected) aminoacylbenzotriazoles 4.5 (Scheme 4-3) [1475].

O O 0 0
I1 i) CICO2Et HR1 i) TsCI/Py I
i) HO^SOR i)aH HO1 OR 1- IOR1
ii) NaBH4 ii) Nal
PGNH PG-NH PG-NH
SR2Cu/THF
0
0 i) Hydrolysis R2 OR
R -OH ii) Deprotection NH
NH2 PGN



ii) HO)OR1 NHS, DCC -OOR NaBH4 HO' OR

PG H GNH PGNH
12, PPh3, imidazole

o 0
Ar ]OH i) Zn, Pd2(dba)3, Ar-1, (o-Tol)3P IOR1
Ar -OH I^^^ OR1
NH ii) Hydrolysis NH
NH2 ii) Deprotection PG


Scheme 4-2. y-Amino Acids from Glutamic Acid.

Here, a novel and practical method for the synthesis with preservation (>99%) of

the chirality of y-amino acid derivatives, 6-aryl-y-amino esters 4.12 and acids 4.13 by the

Friedel-Crafts acylation of aromatics with chiral N-protected (a-aminoacyl)benzotriazoles










4.10, readily available from L-glutamic acid, followed by the reduction of formed y-keto-

y-amino esters 4.11 is presented.

0 0 0 0
SOH SOCH + OMe CF3COOEt -OOMe Me
S-_ TFA BtH, OSOC Me
H2N MeOH CI3N Et3N, MeOH 0 CH2CI2 N
OH 80% OH 87H 91% H Bt
4.1 4.2 4.3
TFA-Asp(OMe)-Bt (4.4)
0 0 TFA = CF3CO

TiCI4 OMe reduction OX
-TFA'N O "TFA'N X= H or Me
Aromatics H A H A
Ar Ar
4.5 (45-89%) 4.6

Scheme 4-3. Novel Syntheses of p-amino Acid Derivatives, y-Aryl-P-amino Acids 4.6.
4.2 Results and Discussion

4.2.1 Preparation of 1-(N-Tfa-a-Aminoacyl)benzotriazoles 4.10

L-Glutamic acid 4.7 reacted with methanol and thionyl chloride to form the 6-mono

methyl amino ester 4.8 in 80% yield (Scheme 4-4) [01CC1710]. Amino ester 4.8 was

protected with N-trifluoroacetyl (TFA) group using ethyl trifluoroacetate in the presence

of Et3N (2 eq.) in methanol to generate N-TFA-glutamic monoester 4.9. [72JOC2805] On

treatment with a mixture of thionyl chloride (4 eq.) and benzotriazole (4 eq.), N-Tfa-

glutamic ester 4.9 gave the corresponding acylbenzotriazole TFA-Glu(OMe)-Bt 4.10 in

93% yield (overall yield: 66%).

O OH 0 OMe 0 OMe 0 OMe

SOCl2 + CF3COOEt TEBtH,
o ____+0 BtH, SOC12
H2N 0 MeOH Cl H3N Et3N, MeOH TFA'N CHCI, TFAN
OH 80% OH 89% OH 93% H Bt
4.7 4.8 4.9
TFA-Glu(OMe)-Bt (4.10)

Scheme 4-4. Preparation of N-(TFA-a-aminoacyl)benzotriazoles, TFA-Glu(OMe)-Bt
4.10.









4.2.2 Syntheses ofy-Keto-y-amino Esters 4.11

Previously, the synthesis of a-amino ketones by Friedel-Craft acylation of N-

heterocycles utilizing chiral N-protected a-aminoacylbenzotriazoles in presence of AlC13

had been achieved by Katritzky's research group (Scheme 4-5) [05JOC4993].

R "R Nc

PG' OH BtH, SOCI2 PG N Bt N-Heterocycles PG.N Het
H H AIC13 H
H O 0
PG = TFA, Fmoc;
R = H, phenyl, indol-3-yl, CH2SMe

Scheme 4-5. Chiral N-Protected a-Aminoacylbenzotriazoles as Acylating Reagents in
Friedel-Craft Acylation.

Unfortunately, efforts to extend this method to the preparation of y-keto-y-amino

esters 4.11 by acylation of aromatics with TFA-Glu(OMe)-Bt 4.10 under the same

reaction conditions failed. The starting material 4.10 was decomposed in one hour, and

no desired product formed. The results from Lewis acids screening led to TiC14 as a

promising catalyst (starting materials were recovered when BF3 or ZnBr2 was used). The

reaction of Tfa-Glu(OMe)-Bt 4.10 with aromatics (1.1 eq.) in the presence of TiC14 (1.5

eq.) at room temperature for 1 h gave the corresponding y-keto-y-amino esters 4.11a-f in

46-88% yield (Scheme 4-6, Table 4-1).


O OMe 0 OMe

Aromatics
TFA'N 0 TiCl4 TFAN 0
H t Ar

Tfa-Glu(OMe)-Bt 4.10 4.11a-f

Scheme 4-6. Syntheses of y-Keto-y-amino Esters 4.11.









Table 4-1. Syntheses of y-Keto-y-Amino Esters 4.11.
Entry Aromatics y-Keto-y-amino esters 4.11 (%)
1 Indole 4.11a (80)
2 N-Methylindole 4.11b (88)
3* N-Methylpyrrole 4.11c (69)
4* Pyrrole 4.11d (50)
5 1,3-(MeO)2C6H4 4.11e (48)
6 1,3,5-(MeO)3C6H3 4.11f (46)
*: compounds 4.11c,d were prepared by Dr. RongJiang, which were not included in
experimental part. Spectroscopic and analytical data of these compounds are available in
Dr. Rong Jiang's Ph. D. dissertation.


4.2.3 Preparation of 8-Aryl-y-amino Esters 4.12 and 6-Aryl-y-amino Acids 4.13 by
Reduction of y-Keto-y-amino Esters 4.11.

The reduction of y-keto-y-amino esters 4.11e,f by triethylsilane in trifluoroacetic

acid at room temperature gave the corresponding 6-aryl-y-amino esters 4.12e,f in 84%

and 88% yield respectively (Scheme 4-7, Table 4-2) [73JOC2675].


0 OMe


TFAN 0O
HAr


Et3SiH
CF3COOH


4.11e,f


0 OMe


TFA, N
H Ar

4.12e,f


Scheme 4-7. Preparation of 6-Aryl-y-amino Esters 4.12e,f by the Reduction of y-Keto-y-
amino Esters 4.11 e,f.

Table 4-2. Preparation of 6-Aryl-y-amino Esters 4.12e,f.
Entry Aromatics 6-Aryl-y-amino esters 4.12 (%)
1 1,3-(MeO)2C6H4 4.12e (84)
2 1,3,5-(MeO)3C6H3 4.12f (88)

However, the attempts to reduce y-keto-y-amino esters 4.11a,b with triethyl silane

in trifluoroacetic acid were unsuccessful. Unlike their phenyl analogs, 4.11e,f, carbonyl

group in 4.11a,b could not be reduced to methylene under these conditions. On the other









hand, when y-keto-y-amino esters 4.11a,b were treated with 4 molar equivalents sodium

borohydride in DMF/H20 (v/v = 5/1) mixture for two hours, the corresponding 6-aryl-y-

amino acids 4.13a,b were isolated in 87% and 73% yield, respectively (Scheme 4-8,

Table 4-3) [03TL8229].


0 OMe 0 OH

NaBH4
TFA'N O DMF/HO2 TFA'N
H r H Ar

4.11a,b 4.13a,b

Scheme 4-8. Preparation of 6-Aryl-y-amino Acids 4.13a,b by the Reduction of y-Keto-y-
amino Esters 4.1 la,b.

Table 4-3. Preparation of 6-Aryl-y-amino Acids 4.13.
Entry Aromatics 6-Aryl-y-amino acids 4.13 (%)
1 Indole 4.13a (87)
2 N-Methylindole 4.13b (73)

4.2.4 Configuration Study of 8-Aryl-y-amino Acids 4.13.

Since the key feature of biologically active amino acid derivatives is associated

with the absolute configuration of the a-carbon to the amino group, total control of

chirality represents a major goal in the synthesis of amino acid derivatives. To evaluate

the chiral integrity of these reactions, (DL)-5-(1-methyl-1H-indole-3-yl)-4-[(2,2,2-

trifluoroacetyl)amino]pentanoic acid 4.13g was prepared starting from DL-glutamic acid,

following the procedure for 4.13b (Scheme 4-9). The chiral resolution of 4.13g (DL) by

chiral HPLC [CHIROBIOTIC T column; eluted with 60/40 (v/v) 0.1% TEAA

(triethylamine acetate) methanol solution/water; flow rate 0.4 mL/min at room

temperature; UV detection at 210 nm] gave two distinct signals with equal intensity at

13.22 min and 13.68 min, while 4.13b (L) gave only one signal at 13.7 min under same










conditions that demonstrated the complete chiral preservation (>99%) of synthesis of 6-

aryl-y-amino acid derivitaives 4.12 and 4.13 (Table 4-4).


0 OH


TFA.
0OOMe 0 OMe O


TFA'N N-methyl indole TFA DMF/H0 N
T N '8N DMF/H20 H
H Bt H 71%
Bt N
N /
DL-TFA-Glu(OMe)-Bt (4.10g) 4.11g (DL) 4.13g (D

Scheme 4-9. Synthesis of Compounds 4.13g (DL).

Table 4-4. The Comparison of Chiral HPLC Results of 4.13b (L) with Corresponding
DL-Mixtures 4.13g.
Entry Compound Retention Time (min)
L D
1 4.13b (L) 13.7 a
2 4.13g (DL) 13.7 13.2


L)


ano peak detected.

The complete preservation of chirality of this process is due to the mild reaction

condition and the avoidance of the formation of hydrogen chloride, which is a typical

side product of classic Friedel-Crafts acylation.

4.3 Conclusion

A novel and efficient approach to y-amino acids from glutamic acid through their

corresponding benzotriazole intermediates has been developed. Complete preservation of

chirality of this process was supported by chiral HPLC results. Compared with other

published methods, the present benzotriazole methodology advantageously uses mild

reaction conditions (no strong acid or base needed) at low reaction temperatures (room

temperature). In addition, the easy accessibility and high stability of the corresponding

benzotriazole intermediates offer an alternative route for the preparations of a variety









aromatic and heteroaromatic analogs of y-amino acids. The present procedures,

combining readily available reagents, simple manipulations and synthetic useful yields,

should be valuable for obtaining certain y-amino acid derivatives with specific synthetic

requirements and biological activity concerns.

4.4 Experimental Section

General. Melting points were determined by using a capillary melting point

apparatus equipped with a digital thermometer and Bristoline hot-stage microscope and

were uncorrected. NMR spectra were recorded in CDC13 or DMSO-d6 with

tetramethylsilane as the internal standard for 1H (300 MHz) or solvent as the internal

standard for 13C (75 MHz). Elemental analyses were performed on a Carlo Erba-1106

instrument. HPLC analyses were performed on Beckman system gold programmable

solvent module 126 using Chirobiotic T column (4.6x250 mm), detection at 210 nm, flow

rate of 0.4 mL/min and 0.1% TEAA [triethylamine acetate: it is a mixture of

triethylamine and glacial acetic acid (1/1; v/v)] methanol solution/water as an eluting

solvent. Amino acids purchased from Acros and DL-glutamic acid from TCI, were used

without further purification. THF was distilled over sodium/benzophenone prior to use.

All of the reactions were carried out under N2. Column chromatography was conducted

on silica gel 200-425 mesh.

Procedure for the preparation of N-Tfa-(aminoacyl)benzotriazoles 4.10. To a

solution ofbenzotriazole (0.95 g, 8 mmol) in CH2C2, SOC12 (0.24 g, 2 mmol) was added,

and the reaction mixture was refluxed for 30 min. Then, the reaction mixture was cooled

to 0 oC, and Tfa-Glu(OMe)-OH (0.516 g, 2 mmol) in CH2C2 (10 mL) was added

dropwise. The reaction mixture was stirred at 23 C for 2 h, and then it was washed with









10% aqueous Na2CO3 until BtH was completely removed. The oganic layer was dried

over anhydrous MgSO4. After removing the solvent, the white residue was recrystallized

from CHC13/hexanes to give the desired product Tfa-Glu(OMe)-Bt (4.10) in 93% yield.

Methyl (4S)-5-(1H-1,2,3-benzotriazol-1-yl)-5-oxo-4-[(2,2,2-

trifluoroacetyl)amino] pentanoate (4.10). Colorless needles (93%), mp 90-92 C;

[a]23D = 49.04 o (c 6.67, CHC13); 1H NMR 6 8.27-8.16 (m, 3H), 7.75-7.70 (m, 1H),

7.60-7.55 (m, 1H), 6.03-5.98 (m, 1H), 3.71 (s, 3H), 2.65-2.43 (m, 4H); 13C NMR 6

173.9, 168.8, 157.4 (q, J= 38.9 Hz), 146.0, 131.2, 130.9, 126.9, 120.5, 115.6 (q,J=

287.4 Hz), 114.2, 53.4, 52.4, 30.1, 26.4. Anal. Calcd for C14H13F3N404: C, 46.93; H,

3.66; N, 15.64. Found: C, 46.95; H, 3.64; N, 14.91.

General procedure for the preparation of y-keto-y-amino esters 4.11. To a

solution of Tfa-Glu(OMe)-Bt (4.10) (0.34 g, 1 mmol) and aromatics (1.1 mmol) in

anhydrous CH2C2 (10 mL) was added TiC14 (1.5 mL, 1.5 mmol) at 0 oC. The mixture

was stirred at room temperature for 1 h and purified by flash chromatography (dry

loading method, hexanes/ethyl acetate, 3/1).

Methyl (4S)-5-(1H-indol-3-yl)-5-oxo-4- [(2,2,2-

trifluoroacetyl)amino]pentanoate (4.11a). Colorless microcrystals (80%), mp 132-133

oC; [c]23D = + 4.50 0 (c 2.00, CHC13); 1H NMR 6 1.92-1.97 (m, 1H), 2.42-2.54 (m, 3H),

3.72 (s, 3H), 5.49-5.55 (m, 1H), 7.31-7.36 (m, 2H), 7.43-7.46 (m, 1H), 7.76 (d, J= 7.5

Hz, 1H), 8.32-8.35 (m, 2H), 9.26 (br s, 1H); 13C NMR 6 190.5, 173.7, 157.6 (q, J= 37.6

Hz), 136.4, 133.5, 125.5, 124.4, 123.4, 122.1, 115.8 (q, J= 285.8 Hz), 114.2, 111.8, 54.1,

52.0, 30.2, 29.4. Anal. Calcd for C16H15F3N204: C, 53.94; H, 4.24; N, 7.86; Found: C,

54.22; H, 4.27; N, 7.69.









Methyl (4S)-5-(1-methyl- 1H-indol-3-yl)-5-oxo-4- [(2,2,2-trifluoroacetyl)amino]

pentanoate (4.11b). Colorless needles (88%), mp 137-139 C; [a]23D = + 15.30 o (c 2.00,

CHC13); 1H NMR 6 8.32-8.35 (m, 1H), 8.21 (s, 1H), 7.89 (d, J= 7.5 Hz, 1H), 7.33-7.36

(m, 3H), 5.45-5.51 (m, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 2.40-2.55 (m, 3H), 1.93-2.01 (m,

1H); 13C NMR 6 190.2, 173.6, 157.5 (q, J= 37.1 Hz), 137.8, 137.6, 126.6, 124.2, 123.5,

122.5, 116.0 (q, J= 286.3 Hz), 112.9, 110.2, 54.3, 52.1, 34.0, 30.3, 29.6. Anal. Calcd for

C17H17F3N204: C, 55.14; H, 4.63; N, 7.56. Found: C, 55.04; H, 4.61; N, 7.44.

Methyl (4S)-5-(2,4-dimethoxyphenyl)-5-oxo-4-[(2,2,2-trifluoroacetyl)amino]

pentanoate (4.11e). White microcrystals (48%), mp 136-137 oC; [a]23D = + 7.29 o (c

1.40, CHC13); 1HNMR 6 7.94 (d, J= 8.9 Hz, 1H), 7.66 (d, J= 7.0 Hz, 1H), 6.59 (dd, J=

8.8, 2.2 Hz, 1H), 6.48 (d, J= 2.2 Hz, 1H), 5.71-5.67 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H),

3.64 (s, 3H), 2.43-2.25 (m, 3H), 1.96-1.86 (m, 1H); 13C NMR 6 194.5, 173.0, 166.1,

161.2, 156.9 (q, J= 37.8 Hz), 134.1, 116.4, 115.8 (q, J= 287.4 Hz), 106.3, 98.3, 57.5,

55.8, 55.7, 51.8, 29.8, 27.2. Anal. Calcd for C16H18F3NO6: C, 50.93; H, 4.81; N, 3.71.

Found: C, 50.97; H, 4.77; N, 3.70.

Methyl (4S)-5-(2,4,6-trimethoxyphenyl)-5-oxo-4-[(2,2,2-trifluoroacetyl)amino]

pentanoate (4.11f). White microcrystals (46%), mp 99-100 oC; [a]23D = + 5.02 o (c

16.01, CHC13); 1H NMR 6 7.55 (d, J= 7.5 Hz, 1H), 6.13 (s, 2H), 5.36-5.30 (m, 1H), 3.84

(s, 3H), 3.80 (s, 6H), 3.64 (s, 3H), 2.37- 2.27 (m, 3H), 2.03 1.90 (m, 1H). 13C NMR 6

198.4, 173.0, 163.7, 159.3, 156.7 (q, J= 37.0 Hz), 115.6 (q, J= 285.7Hz), 108.1, 90.5,

58.5, 55.7 (2C), 55.3, 51.5, 29.2, 26.1. Anal. Calcd for C17H20F3NO7: C, 50.13; H, 3.44;

N, 4.95. Found: C, 50.13; H, 3.40; N, 4.93.









General procedure for the preparation of of 8-aryl-y-amino esters 4.12. To y-

keto-y-amino esters 4.11e,f (Immol) in trifluoroacetic acid (0.45 mL) was added triethyl

silane (0.4 mL, 2.5 mmol). After stirring at room temperature for 4 h, water was added

and the mixture was extracted with ether. The ether layer was dried over anhydrous

MgSO4. Solvent was then removed under reduced pressure. The residue was purified by

flash chromatography (hexanes/ethyl acetate, 6/1).

Methyl (4S)-5-(2,4-dimethoxyphenyl)- 4-[(2,2,2-

trifluoroacetyl)amino]pentanoate (4.12e). White microcrystals(84%), mp 85-86 C;

[a]23D = 8.33 o (c 1.92, CHC13); 1H NMR 6 7.06-7.00 (m, 2H), 6.46-6.43 (m, 2H),

4.16-4.04 (m, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.67 (s, 3H), 2.83-2.80 (m, 2H), 2.51-2.31

(m, 2H), 2.01-1.77 (m, 2H); 13C NMR (CDC13) 6 173.7, 160.1, 157.9, 157.0 (q, J= 36.4

Hz), 131.7, 117.3, 115.9 (q, J= 288.3 Hz), 104.6, 98.6, 55.4, 55.2, 51.8, 51.7, 33.8, 30.6,

29.1. Anal. Calcd for C16H20F3NOs: C, 52.89; H, 5.55; N, 3.85; Found: C, 53.78; H, 5.71;

N, 3.72.

Methyl (4S)-5-(2,4,6-trimethoxyphenyl)- 4-[(2,2,2-

trifluoroacetyl)amino]pentanoate (4.12f).White microcrystals (88%), mp 88-89 C;

[a]23D = + 3.12 o (c 3.08, CHC13); 1HNMR 6 7.15 (d, J= 7.0 Hz, 1H), 6.13 (s, 2H), 4.04-

3.98 (m, 1H), 3.81 (s, 3H), 3.80 (s, 6H), 3.68 (s, 3H), 2.87 (dd, J= 3.9, 13.9 Hz, 1H),

2.76 (dd, J= 9.5, 13.9 Hz, 1H), 2.55-2.35 (m, 2H), 2.04- 1.84 (m, 2H); 13C NMR

(CDCl3)6 160.2, 158.6, 157.1 (q, J= 36.5 Hz), 174.0, 115.9 (q, J= 286.9 Hz), 105.5,

90.4, 55.5 (2C), 55.3, 51.7, 51.6, 30.6, 29.5, 26.4. Anal. Calcd for C16H20F3NOs: C,

51.91; H, 5.64; N, 3.56. Found: C, 51.72; H, 5.61; N, 3.44.









General procedure for the preparation of 8-aryl-y-amino acids 4.13. NaBH4

(0.05 g, 1.3 mmol) was added to y-keto-y-amino esters 4.11a,b (0.33 mmol) in DMF/H20

(5 mL/1 mL). The mixture was stirred at room temperature for 2 h and quenched with 15

mL water. Then the reaction mixture was acidified with IN HC1 aqueous solution to PH

= 4, followed by extraction with EtOAc (4x30 mL). The organic layers were combined

and washed with water (30 mL) and dried over anhydrous Na2SO4. After removing

solvent, the product was purified by recrystallization from CHC13/hexane.

(4S)-5-(1H-Indol-3-yl)-4-[(2,2,2-trifluoroacetyl)amino]pentanoic acid (4.13a).

White microcrystals (87%), mp 127-130C; [c]23D = + 14.48 o (c 0.67, CHC13); 1H NMR

(DMSO-d6) 6 12.10 (br s, 1H), 10.85 (s, 1H), 9.27 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 7.7

Hz, 1H), 7.33 (d,J= 8.0 Hz, 1H), 7.12-6.96 (m, 3H), 4.14-3.98 (m, 1H), 2.91 (d,J= 7.0

Hz, 2H), 2.31-2.16 (m, 2H), 1.92-1.73 (m, 2H); 13C NMR (DMSO-d6)6 174.1, 156.1 (q,

J= 36.0 Hz), 136.2, 127.4, 123.3, 121.0, 118.4, 118.3, 116.0 (q, J= 288.6 Hz), 111.4,

110.5, 50.5, 30.5, 29.8, 28.5. Anal. Calcd for C15H15F3N203: C, 54.88; H, 4.61; N, 5.83.

Found: C, 54.64; H, 4.71; N, 8.35.

(4S)-5-(1-Methyl- 1H-indol-3-yl)-4-[2,2,2-trifluoroacetyl)amino]pentanoic acid

(4.13b). Light brown microcrystals (73%), mp 185-186 oC; [a]23D = + 12..24 o (c 0.67,

CHC13); 1H NMR (DMSO-d6) 6 12.09 (br s, 1H), 9.27 (d, J= 8.5 Hz, 1H), 7.56 (d, J=

7.7 Hz, 1H), 7.37 (d, J= 8.1 Hz, 1H), 7.16-7.09 (m, 2H), 7.02 (t, J= 7.6 Hz, 1H), 4.04-

3.99 (m, 1H), 3.72 (s, 3H), 2.89 (d, J= 6.9Hz, 2H), 2.25-2.18 (m, 2H), 1.85-1.75 (m,

2H); 13C NMR (DMSO) 174.0, 156.1 (q, J= 36.1 Hz), 136.6, 127.8, 127.7, 121.1,

118.5, 118.4, 116.0 (q, J= 288.6 Hz), 109.8, 109.6, 50.6, 32.3, 30.5, 29.7, 28.3. Anal.

Calcd for C16H17F3N203: C, 56.04; H, 5.01. Found: C, 56.01; H, 5.22.









5-(1-Methyl-1H-indol-3-yl)-4-[2,2,2-trifluoroacetyl)amino]pentanoic acid

(4.13g). Light brown microcrystals (71%), mp 148-150 oC; H NMR (DMSO) 6 12.10 (br

s, 1H), 9.28 (d, J= 8.5 Hz, 1H), 7.56 (d, J= 7.8 Hz, 1H), 7.37 (d, J= 8.1 Hz, 1H), 7.16-

7.10 (m, 2H), 7.02 (t, J= 7.4 Hz, 1H), 4.10-3.94 (m, 1H), 3.73 (s, 3H), 2.90-2.88 (m,

2H), 2.25-2.17 (m, 2H), 1.87-1.72 (m, 2H); 13C NMR (DMSO) 6 174.0, 156.1 (q, J=

36.1 Hz), 136.6, 127.8, 127.7, 121.1, 118.5, 118.4, 116.0 (q, J= 288.6 Hz), 109.8, 109.6,

50.6, 32.3, 30.5, 29.7, 28.3. Anal. Calcd for C16H17F3N203: C, 56.04; H, 5.01. Found: C,

55.93; H, 5.03.














CHAPTER 5
MICROWAVE MEDIATED SYNTHESIS OF P-ENAMINO THIOIC ACID
DERIVATIVES FROM DIBENZOTRIAZOLYLMETHANETHIONE

5.1 Introduction

Organosulfur compounds are of considerable interest both for their rich and varied

chemistry, and for their diverse biological properties [77TL4037, 82T2857, 96BMC1493,

96MI]. Among them, P-enamino thioic acid derivatives are important building blocks for

the construction of a variety of heterocyclic compounds including pyrazoles

[96JHC1243], 4-aminoquinolines [97T2931], dihydrothiopyrans [00T3909, 01MFC947],

thiazolines [85H1225], thazolin-4-ones [85H1225], 1,3-thiazolin-4-ones [85H1225], 6H-

1,3-thiazines [80S453], as well as precursors for liquid crystals [95JOC3074] and P-keto

thioic acid derivatives [88JCSP(I)1739]. They have been reported as good 1-thia-1,3-

dienes [81TL3175, 93JOC1702,01M947] and Michael acceptors [01T8705]. a,P-

Unsaturated carbodithioic esters generally show good reactivity as heterodienes in

thermally or Lewis acid induced cycloadditions with various dienophiles [99CC 1001].

ua,P-Unsaturated thioamides form C-C bonds in reaction with C-nucleophiles such as

alkyllithiums, alkylmagnesiums [78JA5221, 81TL3409], lithium enolates [79JA1316]

and nitromethane in the presence of base [96SL 1117]. Characteristic reactivities of the

thiocarbonyl group are also Known: thiophilic addition of nucleophiles, cycloaddition

reaction with dienes, easy thio-Claisen rearrangement and high reactivity with 1,3-dipoles

[92S1185]. Apart from their wide use as intermediates in organic synthesis, thioamides

have also attracted attention in the field of peptide chemistry [00B387, 00TL2797,









03TL3551]. These modified peptides have often retained biological activity, sometimes

associated with significant selectivity between different cellular receptors [94JOC1257].

Partial resistance toward proteases has been observed [82JA5221]. Thioamide

substitution in a peptide has been used as a tool to determine the possible involvement of

an individual peptides bond in receptor interaction (structure-activity relationships)

[90JMC2323]. Furthermore, dithioesters have attracted the attention of polymer chemists

for their ability to control radical polymerization: indeed the RAFT (Reversible Addition

Fragmentation Chain Transfer) radical polymerization of such monomers as N-

acryloylmorpholine, styrene and methacrylates is based on the use of dithioesters as

transfer agents [00M243, 01M7849, 02M8271]. Recently, the influence of thionoesters as

effective chain transfer agents in the polymerization of styrene, methyl acrylate, and

related olefins was reported [92MC369].

Despite the importance and interest in this class of derivatives, existing methods for

the preparation of P-enamino thioic acid derivatives are limited to: i) the reaction of 3-

enaminones with phosphorus pentasulfide or other O/S exchange reagents, such as

Lawesson's reagents [79S942, 80T3047, 85T5061]; ii) the cycloaddition of unactivated

2-aza-1,3-dienes with isothiocyanates followed by the reduction of the 1,2-

dihydropyrimidin-4(3H)-thiones with LiAlH4 to provide P-enamino thioamides

[88JCSP(1)1739]; iii) the reaction of P-enaminones with aryl isothiocyanates at 90 C

[94S898, 98BMCL2203]; and iv) cyclopentanones and 2-substituted cyclopentanones

with carbon disulphide and ammonia at 0 OC [83S605]. The first method is plagued by

the foul smell of the starting material, while other methods are limited to specific

substrates.









The need for an efficient and general approach to P-enamino thioic derivatives

stimulates considerable interest. A novel and efficient procedure of the synthesis of P-

enamino thioic acid derivatives from dibenzotriazolylmethanethione is discussed herein.

5.2 Results and Discussion

Unlike the reported reaction of thiophosgene with benzotriazole (2 eq.) in dioxane

giving 1-(benzothiazol-2-yl)benzotriazole (Scheme 5-2) [65JHC486], the straightforward

reaction of thiophosgene with four equivalents of benzotriazole in methylene chloride at

0 C gave dibenzotriazolylmethanethione 5.1 in 87% yield (Scheme 5-1).

S CH2C12 Bt
4BtH + A 0Oc =S 87%
CI1CI 00C Bt

5.1

Scheme 5-1. Novel Approach to Dibenzotriazolylmethanethione 5.1.

The use of two-fold excess of benzotriazole advantageously avoids the use of either

1-trimethylsilylbenzotriazole [78JOC337] or sodium salt of benzotriazole (no yield of 5.1

is reported) (Scheme 5-2) [65JHC486], required in the previously available methods.

Excess benzotriazole and low reaction temperature appear to be essential for successful

preparation of 5.1.

Dibenzotriazolylmethanethione 5.1 reacted with equimolar ketimines 5.2a-f in

THF at 20 C to give benzotriazolyl P-enaminothiones 5.5a-f (78-97%). The treatment

of 5.2 with two equivalents of ketimine 5.2a-f, aiming to substitute both benzotriazolyl

groups in 5.1, however resulted in exclusive formation of benzotriazolyl P-

enaminothiones 5.5a-f. Unfortunately, under the same reaction conditions, treatment of

5.1 with aldimines 5.3 and 1-cyclohexenylpyrrolidine 5.4 caused the decomposition of

dibenzotriazolylmethanethione 5.1 (Scheme 5-3).














i) 2BtH +


ii)


iii)


S

Cl 'Cl


S N
dioxane
1-(-be t i e i50%
250C-reflux N
e i ,N

1 -(2-benzothiazolyl)benzotriazole


H (NH4)2SO4
BtH + N (NH4) BtSiMe3 93
Me3Si 'SiMe3 reflux, 18h

S S
BtSiMe3 + 1,1,2-trichloroethane ,
C CBtSiMe3i Bt Bt
r.t. 5.1

S benzene S
2 BtNa + 2--..
2 BtNa i C reflux-r.t. Bt Bt
5.1


90%


Scheme 5-2. Known Reactions of Benzotriazole and Related Derivatives with
Thiophosgene.

Structures of compounds 5.5a-f were supported by 1H and 13C NMR spectra, and

elemental analyses (see Experimental Section). In the 1H NMR spectra of benzotriazolyl

P-enaminothiones 5.5a-f, the broad singlet signal in the range 13.21-15.24 ppm and the

singlet signal at 7.16-7.21 ppm (for compounds 5.5a,b,e) corresponding to NH and CH

of the enamine fragment, respectively, confirmed the exclusive formation of the in Z-

enamine form resulting from N .-H- S. chelation. Further effort to prove the Z-enamine

form by X-ray crystallography will be done in the near future.


3%









R3
RNH S
R2 THF N

S 5.2 r.t. 6h R1 Bt 5.5
N IR R2
H
Bt R2_ NR3 5.3
=S decomposition
Bt THF 5.3a: R2 = vinyl, R3 = Ph
5.1 5.3b: R2 = Et, R3 = Bn
THF
NH decomposition
5.4 r.t. 10 mins

Scheme 5-3. The Reactivity of Dibenzotriazolylmethanethione 5.1 toward Ketimines,
Aldimines and Enamines.

Table 5-1. The Synthesis of Benzotriazolyl -Enaminothiones 5.5.
5.5 R R2 R3 Yield (%)
5.5a Phenyl H Butyl 97
5.5b 4-Pyridinyl H Butyl 94
5.5c Phenyl Methyl Butyl 83
5.5d -(CH2)4- Butyl 78
5.5e Ethyl H Butyl 78
5.5f -(CH2)4- Benzyl 95

Treatment of compound 5.5a,b under microwave irradiation at 80 OC with

secondary amines gave p-enamino thioamides 5.6a-c (92-95%). Similar treatments of

5.5a,b with alcohols or thiols in the presence of sodium or potassium hydroxide afforded

thioesters 5.7a-c (74-99%) and dithioesters 5.8a-c (85-92%), respectively (Scheme 5-4,

Table 5-2).

Similarly to compounds 5.5, 1H NMR spectra of products 5.6-5.8 showed the

presence of the broad singlet signal in the range 11.44-13.16 ppm corresponding to NH

proton and suggesting exclusive Z-enaminothione configuration of the products (Scheme

5-4).















o3
R1 NH S

R1 )Y Bt
R2
5.5a,b


secondary amine
Microwave irradiation


ROH, NaC
Microwave irra


RSH, KOI
Microwave irra



Scheme 5-4. Novel Approach to

Table 5-2. Microwave-mediated
5.8.


5.6

RNH S
H Ri OR
idiation 2
R
5.7



R1 SR
diation
R2
5.8

P-Enamino Thioic Acid Derivatives 5.6-5.8.

Synthesis of P-Enamino Thioic Acid Derivatives 5.6-


Entry R1 R2 R3 R4 R5 R Product Yield(%)
1 Phenyl H Butyl C2H40C2H4- 5.6a 93
2 Phenyl H Butyl -(CH2)5- 5.6b 95
3 4-Pyridinyl H Butyl C2H40C2H4- 5.6c 92
4 Phenyl H Butyl Methyl 5.7a 99
5 Phenyl H Butyl Propyl 5.7b 98
6 4-Pyridinyl H Butyl Methyl 5.7c 74
7 Phenyl H Butyl n-Hexyl 5.8a 85
8 Phenyl H Butyl Phenyl 5.8b 87
9 4-Pyridinyl H Butyl Phenyl 5.8c 92

However, under the same conditions, treatment of benzotriazolyl P-enaminothiones

5.5c-e with alcohols, thiols or amines resulted in the recovery of 5.5c-e. The attempted

reaction of 5.5c-e with sodium methoxide in methanol under microwave irradiation as

well as stirring at room temperature for 48 h gave the same results. The reaction results,

suggest that the nucleophilic substitution undergoes addition-elimination mechanism,

which is shown in Scheme 5-5.









When R1 group is aryl or heteroaryl group (compounds 5.5a,b), which behaves as

electron withdrawing group, the electrophilicity of thioacyl group increases, making the

benzotriazolyl P-enaminothione reactive toward secondary amines, alcohols and thiols.

However, when R1 group is alkyl group (compounds 5.5d,e), which behaves as electron

donating group, the electrophilicity of thioacyl group decreases, resulting in no reaction

observed under same reaction conditions. Compound 5.5c also appears to be unreactive

toward secondary amines, alcohols and thiols, probably due to the steric hindrance.

Further efforts to activate less reactive benzotriazolyl P-enaminothiones by Lewis acid

will be attempted in the future.

R"NH S, R3NH S R3NH S
R1 Bt R. R1 N + Bt-
R2 Nu R2 R2
5.5 5.6-5.8
Nu = secondary amines, alcohols & thiols

Scheme 5-5. Plausible Mechanism for the Reaction of Benzotriazolyl P-Enaminothiones
5.5 with Nucleophiles.

The reaction of benzotriazolyl P-enaminothione 5.5a with hydrazine under

microwave irradiation at 80 C failed and resulted in a complex set of polar products.

Treatment of 5.5a with nitromethane or acetonitrile at 80 OC under microwave irradiation

in the presence of sodium hydroxide gave no reaction.

Meanwhile, the reactivity of 1-thioacylbenzotriazoles 5.9 toward ketimines 5.2

were investigated, which led to a novel approach to P-enaminothiones 5.10.

The Katritzky research group has developed efficient thioacylating agents, 1-

thioacylbenzotriazoles, for N-, 0-, and S-thioacylation (Scheme 5-6) [05JOC7866]. In









particular, 1-thioacylbenzotriazoles are advantageously stable toward moisture and

storable for a long period of time.

As a logical sequel, the C-thioacylation potential of 1-thioacylbenzotriazoles was

studied. After careful screening of a series of nucleophiles, including Grignard,

organozinc, organolithium reagents, enolates, silyl enol ethers, allyl trimethyl silane, and

active methylenes, enamines and aldimines, only ketimines stood out as effective

nucleophiles to be thioacylated by 1-thioacylbenzotriazoles.


R1R2NH


S

N R
R2


S

Btj- R


R = alkyl, aryl, heteroaryl
R1 = alkyl
R2 = alkyl, H
R3 = aryl


5.9 S
SRXH R3X R

X = S

Scheme 5-6. Published Benzotriazole-Mediated Thioacylation.

1-Thioacylbenzotriazoles 5.9a-c reacted with ketimine 5.2a in the presence of

ZnBr2 in THF at room temperature for 3 days, to give the desired P-enaminothiones

5.10a-c in moderate to good yield (Scheme 5-7, Table 5-3).

Scheme 5-7. Novel Approach to P-Enaminothiones 5.10

NR3 S 4 3
R1+ 02N N ZnBr2 R1 4
RN R1 R4
R2 N THF, r.t. R2
5.2 5.9a-c 5.10a-c

Table 5-3. C-Thioacylation of Ketimines 5.2a with Thioacylbenzotriazoles 5.9a-c.
Product R1 R2 RR4 Yield (%
5.10a Phenyl H Butyl 4-C1C6H4 91
5.10b Phenyl H Butyl 2-thienyl 76
5.10c Phenyl H Butyl 2-furyl 45









To broaden the scope of this methodology, the reactivity of 1-

thioacylbenzotriazoles 5.9a with ketimines 5.2f-g was examined. Unfortunately, all the

attempts failed to give P-enaminothiones corresponding to 5.10a-c and resulted in either

a low yield of thioamide 5.11a (3 5%) or complex mixtures of products (Scheme 5-8).

We have observed that the order of addition has remarkable influence on the

chemical yield of compound 5.10a-c. Thus, the best results were obtained when a THF

solution of thioacylbenzotriazole 5.9 was allowed to react firstly with ZnBr2, followed by

slow addition of the appropriate ketimine 5.2. By contrast, reactions carried out by initial

addition of the Lewis acid to a THF solution of ketimine 5.2 were less efficient and

resulted in a marked decrease in the yield.

Ph,
Ph S R4 S

+ 02NN ZnBr2 Ph-Np R
N THE, r.t. H

5.2g 5.9a 5.11a

Ph S
N 02N N ZnBr2
R + -N THF r complex mixture
R' I[ N' THF, r.t.
R2
5.9a
5.2f: R1, R2 = -(CH2)4-
5.2h: R1= Et, R2 = H

Scheme 5-8. Attempts to Obtain P-Enaminothiones 5.10 from Diverse Ketimines.

We presume that the initial formation of the complex 5.12 can take place in two

different ways: either via a benzotriazolium intermediate 5.12a or through the

coordination of the zinc atom with the carbonyl sulfur 5.12b in a similar way as in the

case of carbonyl compounds (Figure 5-1).









S e
R4 Br2Zn ,
02 N NR4
C N 02N N
ZnBr2 II N

5.12a 5.12b
Figure 5-1. The Structure of ZnBr2-Thioacylbenzotriazole Complex 5.12.

In both cases the electrophilicity of the thioacyl carbon increases, permitting the

thioacylbenzotriazole to become reactive toward ketimines. Depending on their nature,

ketimines 5.2 react with the complex 5.12 through the enamino forms (Scheme 5-9) or

imino forms (Scheme 5-10) in an addition-elimination process, involving the formation

of a new carbon-carbon bond in 5.13 (Scheme 5-9) or carbon-nitrogen bond in 5.14

(Scheme 5-10), followed by the elimination of benzotriazole. As result, the reaction

proceeds by either of these two competitive mechanisms or by both of them with low

regioselectivity. With more reactive ketimine 5.2a [03JA15114], enamino pathway is

predominant. The reaction pathway involves nucleophilic addition of enamine tautomer

5.2' to thioacyl group, followed by elimination of benzotriazole from intermediate 5.13 to

give ompounds 5.10 in the more stable enamino tautomeric form 5.10" (Scheme 5-9). In

contrast, the less reactive to ketimine 5.2g [03JA15114], imino pathway is predominant.

Compounds 5.11a was isolated as the major product, possibly via reaction sequence

depicted in Scheme 5-10. When the ketimine's reactivity is moderate, such as ketimines

5.2f,h [03JA15114], the reaction proceeds by both pathways to provide complex mixtures

of products.










R3 R3
R3N R"NH R3 G
R R, complex 5.12 R R 4
R 2 R 2 addition R1 N
R2 R R2 N
5.2 5.2' / N
02N' -
5.13
R R3 R3 1
R"N S NH S
elimination R1 R1
--- R1 -4 R1R4
R2 R2

5.10' 5.10"

Scheme 5-9. Ketimine with High Reactivity Reacts Through the Enamino Form with the
Complex 5.12.

S
3 R3-N ~ R4
N complex 5.12 H20
R addition NN 2 basic work-up
R2
NO2
5.2


H
R3N RN H
N R4 + R\O +
5.11 NN2 R

Scheme 5-10. Ketimine with Low Reactivity Reacts through Imino Form with the
Complex 5.12.

5.3 Conclusion

In conclusion, novel approach to the P-enamino thioic acid derivatives has been

developed. The described procedure appears to be an efficient and simple route to 3-

enamino thioic acid derivatives. We also investigated the reaction of 1-

thioacylbenzotriazoles with ketimines, and provided a plausible explanation for related

results.









5.4 Experimental Section

General. Melting points were determined by a capillary melting point apparatus

equipped with a digital thermometer and Bristoline hot-stage microscope and were

uncorrected. NMR spectra were recorded in CDC13 or DMSO-d6 with tetramethylsilane

as the internal standard for H (300 MHz) or solvent as the internal standard for 13C (75

MHz). The elemental analyses were performed on a Carlo Erba EA-1108 instrument.

Anhydrous THF was used freshly distilled over sodium/benzophenone. Column

chromatography was conducted on silica gel 200-245 mesh.

Ketimines 5.2 were prepared according to the published procedures [83JA4396,

90T6715]: butyl (1-phenylethylidene)amine (5.2a), colorless oil [83JA4396] (91%); butyl

(1-pyridin-4-yl-ethylidene)amine (5.2b), colorless oil [83JA4396 ] (78%); butyl (1-

phenylpropylidene)amine (5.2c), colorless oil [83JA4396] (88%); butyl

cyclohexylideneamine (5.2d), colorless oil [90T6715] (83%); butyl (butylidene)amine

(5.2e), colorless oil [90T6715] (88%); benzyl cyclohexylidene-amine (5.2f), colorless oil

[90T6715] (85%); benzyl (butylidene)amine (5.2h), colorless oil [90T6715] (78%).

Aldimines 5.3 were prepared according to the published procedures: [90T6715,

01JOC7051] N-[(E)-3-butenylidene]aniline (5.3a), colorless oil [90T6715] (73%); benzyl

propylideneamine (5.3b), colorless oil [01JOC7051] (84%).

1-Thioacylbenzotriazoles 5.9a-c were prepared according to the published

procedures: [05JOC7866] (6-nitrobenzotriazol-1-yl) (2-thienyl)methanethione (5.9b),

gray green microcrystals (40%), mp 132-134 C (lit. mp 133-134 C [05JOC7866]); (6-

nitrobenzotriazol-1-yl) (2-furyl)methanethione (5.9c), red orange microcrystals (80%),

mp 162-163 C (lit. mp 161-162 C [05JOC7866]).









(6-Nitrobenzotriazol-l-yl)-4-chlorophenylmethanethione (5.9a). Pink

microcrystals (93%), mp 161-163 C; 1HNMR 6 9.49 (d, J= 1.9 Hz, 1H), 8.47 (dd, J=

8.9, 2.1 Hz, 1H), 8.34 (d, J= 8.9 Hz, 1H), 7.76 (d, J= 8.6 Hz, 2H), 7.47 (d, J= 8.6 Hz,

2H); 13C NMR 199.4, 149.1, 140.2, 132.9, 132.1, 128.7, 121.9, 121.4, 112.2. Anal.

Calcd for C13H7C1N402S: C, 48.99; H, 2.21; N, 17.58. Found: C, 49.11; H, 2.19; N,

16.22.

Procedure for the preparation of dibenzotriaolylmethanethione 5.1.

Thiophogene (10 mmol.) was added dropwise to a solution ofbenzotriazole (40 mmol) in

CH2C12 (50 mL) at 0 C. The reaction mixture was stirred at the same temperature for 3 h.

After filtration, the residue was washed with CH2C12 (3x30 mL). The combined filtrate

was washed with 5% aqueous Na2CO3 (3 x50 mL). After removing solvent under

vacuum, the residue was recrystallized from CH2C12 to give pure product di-(1H-1,2,3-

benzotriaol-1-yl)methanethione in 87% yield as yellow microcrystals.

Di(1H-1,2,3-benzotriazol-l-yl)methanethione (5.1). Yellow microcrystals (87%),

mp 171-171 C (lit. mp 170-172 C [78JOC337]); H NMR 6 8.27 (d, J= 8.2 Hz, 2H),

8.21 (d, J= 8.2 Hz, 2H), 7.76-7.71 (m, 2H), 7.62-7.57 (m, 2H); 13C NMR 6 169.6,

146.8, 133.1, 130.6, 126.9, 121.0, 113.9.

General procedure for the preparation of benzotriazolyl P-enaminothiones 5.5

from dibenzotriaolylmethanethione 5.1. To a solution of

dibenzotriazolylmethanethione (1 mmol) in THF (50 mL), the appropriate ketimine (1

mmol) was added at room temperature. The reaction mixture was stirred at the same

temperature for 6 h, and then concentrated under vacuum. The residue was dissolved in

ethyl acetate (50 mL), and was washed with 5% aqueous Na2CO3 (3 x30 mL), followed









by brine (30 mL). The organic layer was dried over anhydrous Na2SO4. After removing

the solvent under vacuum, the residue was either recrystallized from CH2Cl2/hexanes or

was purified by flash chromatography (hexanes/ethyl acetate, 5/1) on silica gel to give the

pure product 5.5.

(Z)-l-(1H-1,2,3-Benzotriazol-l-yl)-3-(butylamino)-3-phenyl-2-propene-1-

thione (5.5a). Yellow microcrystals (95%), mp 94-96 C; H NMR 6 13.36 (br s, 1H),

8.82 (d, J= 8.5 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 7.58-7.38 (m, 7H), 7.21 (s, 1H),

3.45-3.40 (m, 2H), 1.73-1.64 (m, 2H), 1.53-1.41 (m, 2H), 0.93 (t, J= 7.3 Hz, 3H); 13C

NMR 6 179.3, 169.4, 147.0, 135.1, 132.5, 130.3, 128.8, 128.5, 127.3, 124.7, 119.8,

115.7, 106.5, 45.7, 32.1, 19.9, 13.5. Anal. Calcd for C19H20N4S: C, 67.83; H, 5.99; N,

16.65. Found: C, 67.80; H, 6.04; N, 16.74.

(Z)-1- (1H-1,2,3-Benzotriazol-l-yl)-3-(butylamino)-3-(4-pyridinyl)-2-propene-

1-thione (5.5b). Yellow microcrystals (94%), mp 100-102 OC; 1H NMR 6 13.21 (br s,

1H), 8.85-8.80 (m, 3H), 8.07 (d, J= 8.3 Hz, 1H), 7.61-7.55 (m, 1H), 7.46-7.38 (m, 3H),

7.19 (s, 1H), 3.40-3.34 (m, 2H), 1.73-1.64 (m, 2H), 1.54-1.42 (m, 2H), 0.95 (t, J= 7.3

Hz, 3H); 13C NMR 6 181.5, 165.8, 150.6, 147.0, 142.8, 132.5, 129.0, 125.0, 121.7, 120.0,

115.7, 104.8, 45.6, 32.1, 19.9, 13.5. Anal. Calcd for C18H19N5S: C, 64.07; H, 5.68; N,

20.75. Found: C, 64.33; H, 5.69; N, 20.72.

(Z)-1-(1H-1,2,3-Benzotriazol-1-yl)-3-(butylamino)-2-methyl-3-phenyl-2-

propene-1-thione (5.5c). Red yellow oil (83%); H NMR 6 15.22 (br s, 1H), 8.04 (d, J=

8.5 Hz, 1H), 7.87 (d, J= 8.5 Hz, 1H), 7.56-7.39 (m, 4H), 7.37-7.27 (m, 3H), 3.28-3.22

(m, 2H), 1.71-1.60 (m, 2H), 1.51-1.35 (m, 5H), 0.90 (t, J= 7.0 Hz, 3H); 13C NMR 6

175.0, 172.6, 145.3, 133.2, 132.0, 129.5, 129.0, 127.4, 125.9, 123.7, 119.1, 115.5, 112.1,









46.2, 31.4, 19.7, 19.2, 13.2. Anal. Calcd for C20H22N4S: C, 68.54; H, 6.33; N, 15.99.

Found: C, 68.68; H, 6.40; N, 15.62.

1H-1,2,3-Benzotriazol-l-yl [2-(butylamino)-l-cylohexen-l-yl]methanethione

(5.5d). Thick red oil (78%); 1H NMR 6 14.95 (br s, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.78 (d,

J= 8.2 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 7.39 -7.34 (m, 1H), 3.57-3.50 (m, 2H), 2.67 (t,

J= 6.7 Hz, 2H), 2.20 (t, J= 6.2 Hz, 2H), 1.89-1.74 (m, 4H), 1.65-1.56 (m, 2H),

1.52-1.43 (m, 2H), 1.02 (t, J= 7.3 Hz, 3H) ; 13CNMR6 173.0, 171.5, 145.2, 131.8,

127.3, 123.7, 119.1, 118.5, 111.8, 43.8, 30.3, 27.8, 27.5, 21.8, 20.7, 20.0, 13.4. Anal.

Calcd for C17H22N4S: C, 64.93; H, 7.05; N, 17.82. Found: C, 65.14; H, 7.29; N, 18.17.

(Z)-l-(1H-1,2,3-benzotriazol-1-yl)-3-(butylamino)-2-pentene-l-thione (5.5e).

Light yellow microcrystals (78%), mp 58-60 C; H NMR 6 13.30 (br s, 1H), 8.77 (d, J=

8.2 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 7.56-7.51 (m, 1H), 7.43-7.37 (m, 1H), 7.16 (s,

1H), 3.57-3.51 (m, 2H), 2.55 (q, J= 7.6 Hz, 2H), 1.82-1.75 (m, 2H), 1.66-1.54 (m, 2H),

1.31 (t, J= 7.6 Hz, 3H), 1.02 (t, J= 7.3 Hz, 3H); 13C NMR 6 178.4, 173.4, 147.0, 132.6,

128.3, 124.6, 119.7, 115.6, 104.8, 43.6, 31.4, 27.3, 20.2, 13.6, 12.1. Anal. Calcd for

C15H20N4S: C, 62.47; H, 6.99; N, 19.43. Found: C, 62.66; H, 7.09; N, 19.78.

1H-1,2,3-Benzotriazol-l-yl [2-(benzylamino)-l-cyclohexen-l-yl]methanethione

(5.5f). Red yellow microcrystals (95%), mp 89- 91 C; 1H NMR 6 15.24 (br s, 1H), 8.07

(d, J= 8.2 Hz, 1H), 7.78 (d, J= 8.6 Hz, 1H), 7.52-7.27 (m, 7H), 4.73 (d, J= 5.8 Hz, 2H),

2.67 (t, J= 6.7 Hz, 2H), 2.21 (t, J= 6.4 Hz, 2H), 1.76-1.68 (m, 2H), 1.50-1.42 (m, 2H);

13C NMR 6 175.2, 171.9, 145.4, 134.7, 132.2, 129.2, 128.3, 127.8, 127.5, 124.2, 119.4,

118.9, 112.2, 47.8, 28.2, 27.9, 22.0, 20.9. Anal. Calcd for C20H20N4S: C, 68.93; H, 5.78;

N, 16.08. Found: C, 68.71; H, 5.90; N, 16.35.









General procedure for the preparation of p-enamino thioamides 5.6 from

benzotriazolyl p-enaminothiones 5.5. Benzotriazolyl P-enaminothione 5.5 (0.3 mmol)

was dissolved in a secondary amine (2 mL). The reaction mixture was exposed to

microwave irradiation (80 Watts, 80 oC) for 0.5 h. The solvent was removed under

vaccuum. The residue was dissolved in CH2C2 (10 mL) and washed with 5% aqueous

Na2CO3 (3 x10 mL), followed by brine (10 mL). The organic layer was dried over

anhydrous Na2SO4. After removing the solvent under vacuum, the residue was purified

by flash chromatography (hexanes/ethyl acetate, 5/1) on a silica gel to give the pure

product 5.6.

(Z)-3-(Butylamino)-l-morpholino-3-phenyl-2-propene-l-thione (5.6a). Light

yellow oil (91%); 1H NMR 6 11.97 (br s, 1H), 7.43-7.41 (m, 3H), 7.34-7.33 (m, 2H),

5.14 (s, 1H), 3.95 (br s, 4H), 3.71 (t, J= 5.1 Hz, 4H), 3.15-3.08 (m, 2H), 1.55-1.48 (m,

2H), 1.41-1.34 (m, 2H), 0.86 (t, J= 7.4 Hz, 3H); 13C NMR 6 187.0, 164.2, 138.0, 128.9,

128.4, 127.5, 93.3, 66.6, 47.8, 44.7, 32.6, 20.0, 13.6. Anal. Calcd for C17H24N20S: C,

67.07; H, 7.95; N, 9.20. Found: C, 66.80; H, 7.97; N, 9.08.

(Z)-3-(Butylamino)-3-phenyl-l-piperidino-2-propene-l-thione (5.6b). Light

yellow oil (95%); 1H NMR 6 11.79 (br s, 1H), 7.42-7.33 (m, 5H), 5.15 (s, 1H), 3.92 (br

s, 4H), 3.11-3.05 (m, 2H), 1.69-1.47 (m, 8H), 1.40-1.33 (m, 2H), 0.85 (t, J= 7.3 Hz,

3H); 13C NMR 6 185,7, 163.2, 138.3, 128.6, 128.2, 127.6, 93.4, 59.1, 44.5, 32.6, 25.8,

24.6, 20.0, 13.6. Anal. Calcd for C18H26N2S: C, 71.47; H, 8.66; N, 9.26. Found: C, 71.54;

H, 8.87; N, 9.33.

(Z)-3- (Butylamino)-l-morpholino-3- (4-pyridinyl)-2-propene-l-thione (5.6c).

Light yellow oil (92%); 1H NMR 6 11.85 (br s, 1H), 8.69 (d, J= 6.1 Hz, 2H), 7.26 (d, J=









6.4 Hz, 2H), 5.07 (s, 1H), 3.96 (br s, 4H), 3.74-3.71 (m, 4H), 3.10-3.04 (m, 2H),

1.56-1.48 (m, 2H), 1.41-1.34 (m, 2H), 0.88 (t, J= 7.3 Hz, 3H); 13C NMR 6 187.7, 160.8,

150.1, 145.6, 122.3, 93.0, 66.5, 47.9, 44.8, 32.6, 20.0, 13.6. Anal. Calcd for C16H23N30S:

C, 62.92; H, 7.59; N, 13.76. Found: C, 62.25; H, 7.89; N, 12.96.

General procedure for the preparation of p-enamino thioesters 5.7 from

benzotriazolyl P-enaminothiones 5.5. Benzotriazolyl P-enaminothione 5.5 (0.3 mmol)

was dissolved in 2N alcoholic sodium hydroxide solution (2 mL). The reaction mixture

was exposed to microwave irradiation (80 Watts, 80 oC) for 0.5 h. The solvent was

removed under vacuum. The residue was dissolved in CH2C2 (10 mL) and washed with

5% aqueous Na2CO3 (3 x 10 mL), followed by brine (10 mL). The organic layer was dried

over anhydrous Na2SO4. After removing the solvent under vacuum, the residue was

purified by flash chromatography (hexanes/ethyl acetate, 5/1) on a silica gel to give the

pure product 5.7.

O-Methyl (Z)-3-(butylamino)-3-phenyl-2-propenethioate (5.7a). Light yellow

oil (95%); H NMR 6 11.44 (br s, 1H), 7.43-7.41 (m, 3H), 7.36-7.31 (m, 2H), 5.49 (s,

1H), 3.97 (s, 3H), 3.21 (q, J= 6.2 Hz, 2H), 1.60-1.53 (m, 2H), 1.44-1.34 (m, 2H), 0.87

(t, J= 7.3 Hz, 3H); 13C NMR 6 202.2, 166.0, 136.4, 129.4, 128.4, 127.4, 100.0, 55.1,

44.8, 32.5, 19.9, 13.6. Anal. Calcd for C14H19NOS: C, 67.43; H, 7.68; N, 5.62; Found: C,

67.41; H, 7.59; N, 6.93.

O-Propyl (Z)-3-(butylamino)-3-phenyl-2-propenethioate (5.7b). Light yellow oil

(94%); 1H NMR 6 11.46 (br s, 1H), 7.43-7.41 (m, 3H), 7.36-7.32 (m, 2H), 5.49 (s, 1H),

4.35 (t, J= 6.7 Hz, 2H), 3.23-3.16 (m, 2H), 1.78-1.71 (m, 2H), 1.60-1.50 (m, 2H),

1.44-1.32 (m, 2H), 0.98 (t, J= 7.4 Hz, 3H), 0.87 (t, J= 7.4 Hz, 3H); 13C NMR 6 201.9,









136.5, 129.3, 128.6, 128.4, 127.4, 100.3, 69.6, 44.8, 32.5, 22.0, 19.9, 13.6, 10.5. Anal.

Calcd for C16H23NOS: C, 69.27; H, 8.36; N, 5.05. Found: C, 69.47; H, 8.51; N, 4.89.

O-Methyl (Z)-3-(butylamino)-3- (4-pyridinyl)-2-propenethioate (5.7c). Yellow

oil (74%); 1H NMR 6 11.29 (br s, 1H), 8.73-8.70 (m, 2H), 7.27-7.26 (m, 2H), 5.40 (s,

1H), 3.98 (s, 3H), 3.18-3.12 (m, 2H), 1.64-1.50 (m, 2H), 1.42-1.32 (m, 2H), 0.89 (t, J=

7.3 Hz, 3H); 13C NMR 6 162.4, 150.5, 150.2, 144.2, 122.1, 99.7, 55.4, 44.9, 32.5, 19.9,

13.6. Anal. Calcd for C13H18N20S: C, 62.37; H, 7.25; N, 11.19. Found: C, 62.07; H, 7.70;

N, 11.50.

General procedure for the preparation of p-enamino dithioesters 5.8 from

benzotriazolyl P-enaminothiones 5.5. Benzotriazolyl P-enaminothione 5.5 (0.3 mmol)

and potassium hydroxide (0.2 g) was dissolved in thiol (2 mL). The reaction mixture was

exposed to microwave irradiation (80 Watts, 80 oC) for 0.5 h. Solvent was removed under

vacuum. The residue was dissolved in CH2C2 (10 mL) and washed with 5% aqueous

Na2CO3 (3 x10 mL), followed by brine (10 mL). The organic layer was dried over

anhydrous Na2SO4. After removing the solvent under vacuum, the residue was purified

by flash chromatography (hexanes/ethyl acetate, 5/1) on a silica gel to give the pure

product 5.8.

Hexyl (Z)-3-(butylamino)-3-phenyl-2-propenedithioate (5.8a). Light yellow oil

(85%); H NMR 6 12.85 (br s, 1H), 7.45-7.43 (m, 3H), 7.37-7.33 (m, 2H), 6.11 (s, 1H),

3.26-3.16 (m, 4H), 1.72-1.51 (m, 4H), 1.44-1.25 (m, 8H), 0.91-0.85 (m, 6H); 13C NMR

6 203.4, 163.6, 135.6, 129.6, 128.6, 127.4, 109.6, 44.9, 33.0, 32.3, 31.4, 28.8, 28.7, 22.5,

19.9, 14.0, 13.5. Anal. Calcd for C19H29NS2: C, 68.00; H, 8.71; N, 4.17. Found: C, 67.71;

H, 9.03; N, 4.14.









Phenyl (Z)-3-(butylamino)-3-phenyl-2-propenedithioate (5.8b). Yellow

microcrystals (87%), mp 76-78 C; 1HNMR 6 13.16 (br s, 1H), 7.54-7.50 (m, 2H),

7.41-7.38 (m, 6H), 7.26-7.22 (m, 2H), 5.88 (s, 1H), 3.27-3.21 (m, 2H), 1.60-1.50 (m,

2H), 1.41-1.33 (m, 2H), 0.85 (t, J= 7.3 Hz, 3H); 13C NMR 6 201.7, 165.0, 135.6, 135.2,

132.2, 129.9, 129.5, 129.2, 128.6, 127.3, 108.6, 45.2, 32.1, 19.9, 13.5. Anal. Calcd for

C19H21NS2: C, 69.68; H, 6.46; N, 4.28. Found: C, 69.78; H, 6.54; N, 4.04.

Phenyl (Z)-3-(butylamino)-3- (4-pyridinyl)-2-propenedithioate (5.8c). Red

yellow oil (92%); 1H NMR 6 13.04 (br s, 1H), 8.70-8.68 (m, 2H), 7.52-7.47 (m, 2H),

7.42-7.40 (m, 3H), 7.19-7.17 (m, 2H), 5.79 (s, 1H), 3.21-3.14 (m, 2H), 1.59-1.49 (m,

2H), 1.43-1.33 (m, 2H), 0.86 (t, J= 7.3 Hz, 3H); 13C NMR 6 204.8, 161.3, 150.3, 142.8,

135.6, 131.7, 129.8, 129.2, 121.6, 107.3, 45.1, 32.1, 19.8, 13.4. Anal. Calcd for

C18H20N2S2: C, 65.81; H, 6.14; N, 8.53. Found: C, 66.11; H, 6.30; N, 8.02.

General procedure for the preparation of j-enaminothiones 5.10a-c and

thioamides 5.11a from 1-thioacylbenzotriazoles 5.9a-c. (6-Nitrobenzotriazol-1-

yl)methanethione (1.0 mmol) and ZnBr2 (2.0 mmol) were dissolved in THF (20 mL) and

stirred at room temperature for 1 h. The appropriate ketimine (1.0 mmol) in THF (10 mL)

was added dropwise into this mixture during 5 min and allowed to stir at room

temperature for 3 d. The completion of the reaction was monitored by TLC. The reaction

was quenched with 5% aqueous KOH (20 mL) and the product was extracted with

CH2C12 (3x15 mL). The extract was washed with brine (2x15 mL), dried over anhydrous

MgSO4 and concentrated to give the crude product, which was purified by flash

chromatography (chloroform) on silica gel to give the pure product 5.10a-c or 5.11a.









(Z)-3-(Butylamino)-l-(4-chlorophenyl)-3-phenyl-2-propene-l-thione (5.10a).

Red oil (91%); 1HNMR 6 14.49 (br s, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.51-7.46 (m, 3H),

7.42-7.38 (m, 2H), 7.29-7.26 (d, J= 9.2 Hz, 2H), 6.54 (s, 1H), 3.37 (q, J= 6.7 Hz, 2H),

1.70-1.61 (m, 2H), 1.48-1.39 (m, 2H), 0.91 (t, J= 7.3 Hz, 3H); 13C NMR 6 199.7, 167.8,

146.9, 135.4, 135.2, 130.1, 128.8, 128.2, 128.0, 127.3, 113.0, 45.3, 2.1, 20.1, 13.6. Anal.

Calcd for C19H20ClNS: C, 69.18; H, 6.11; N, 4.25. Found: C, 68.82; H, 6.41; N, 3.89.

(Z)-3-(Butylamino)-l-(2-thienyl)-3-phenyl-2-propene-l-thione (5.10b). Red oil

(76%); 1H NMR 6 14.04 (br s, 1H), 7.50-7.40 (m, 7H), 6.65 (s, 1H), 3.33 (q, J= 6.4 Hz,

2H), 1.67-1.47(m, 2H), 1.46-1.39 (m, 2H), 0.89 (t, J= 7.3 Hz, 3H); 13C NMR 6 189.6,

167.3, 154.4, 135.6, 130.9, 129.9, 128.8, 127.8, 127.3, 124.6, 109.9, 45.3, 32.1, 20.0,

13.5. Anal. Calcd for C17H19NS2: C, 67.73; H, 6.35; N, 4.65. Found: C, 68.09; H, 6.48; N,

4.25.

(Z)-3-(Butylamino)-l-(2-furyl)-3-phenyl-2-propene-l-thione (5.10c). Red oil

(45%); H NMR 6 4.16 (br s, 1H), 7.42-7.40 (m, 3H), 7.34-7.31 (m, 3H), 7.12 (d, J=

3.7Hz, 1H), 6.72 (s, 1H), 6.36 (dd, J= 3.4, 1.5Hz, 1H), 3.27 (q, J= 6.4Hz, 2H), 1.58-

1.51 (m, 2H), 1.39-1.31 (m, 2H), 0.82 (t, J= 7.3Hz, 3H); 3C NMR 6 183.0, 167.8,

158.9, 143.6, 135.6, 129.9, 128.7, 127.3, 113.9, 112.7, 109.0, 45.3, 32.1, 20.0, 13.5. Anal.

Calcd for C17H19NOS: C, 71.54; H, 6.71; N, 4.91. Found: C, 71.58; H, 7.02; N, 4.53.

4-Chloro-N-phenyl-thiobenzamide (5.11a). Light yellow microcrystals (35%),

mp 153-155 C (lit. mp 157-158 C [90CCCC307]); 1H NMR (DMSO-d6) 6 11.83 (br s,

1H), 7.87-7.80 (m, 4H), 7.54 (d, J= 8.1 Hz, 2H), 7.45 (t, J= 7.7 Hz, 2H), 7.28 (t, J= 7.3

Hz, 1H); 13C NMR (DMSO-d6) 6 195.9, 141.2, 139.9, 135.5, 129.3, 128.5, 128.0, 126.4,

124.2.














CHAPTER 6
THE GENERATION AND REACTIVITY OF POLYANION DERIVED FROM 1,1-
DIBENZOTRIAZOLYLETHANE

6.1 Introduction

Reactions of di- and polyanions with electrophiles are important in synthetic

organic chemistry. Such reactions frequently involve only the most nucleophilic center of

the polyanion; however, reactions of dianions as dinucleophiles with electrophiles have

also been studied widely [97JOC4148, 99SL135, 99CC2439, 02ARK(x)80, 03EJOC771].

Previously Katritzky's group [95H131] and Knight's group [96TL5615, 98SL1141,

00JCSP(1)2343, 00JCSP(1)3752, 01JCSP(1)1771] reported that certain N-substituted

benzotriazoles can be dilithiated by deprotonation both at the a-position of the N-

substituent and at the 7-position of the benzotriazole ring. Most recently, the reactions of

dianion from 1-vinylbenzotriazole 6.1 and electrophiles were investigated by Katritzky's

group (Scheme 6-1) [03JOC5713]. Lithiation of 1-vinylbenzotriazole 6.1 with n-BuLi (2

eq.) generated dianion 6.2, which upon subsequent reaction with 1,2- and 1,4-diketones

affords 6.4 and 6.3, which are representatives of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-

ij]quinoline and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-k] [1]benzazocine ring

systems, respectively. Reactions of dianion 6.2 with isocyanates give 6.5, which contains

the 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk] [1,4]benzodiazepine ring system. These

achievements demonstrated that double lithiation of 1-vinylbenzotriazole followed by

reaction with bis-electrophiles and isocyanates open up new routes to diverse

heterocyclic ring systems.











N
N- NI-N CH2





CHH, 66.4
N \ / %0 N H3



&N NP ,
0&?k "'OH


6.5 OH OH
6.4


Scheme 6-1. The Generation of Dianion 6.2 from 1-Vinylbenzotriazole 6.1 and its
Reactivity toward Diverse Electrophiles.

Following the successful formation of three novel heterocyclic ring systems 6.3,

6.4 and 6.5 from dianion 6.2, the generation of polyanion 6.7 from

dibenzotriazolylmethane 6.6 and its reactivity toward different electrophiles was also

investigated by Dr. Sergey Bobrov in the Katritzky research group (Scheme 6-2)

[05T3305].

Dr. Sergey Bobrov found that compound 6.6 was treated with excess of n-BuLi

(4.1 eq.) in THF at -78 OC for a period of 12 h to give polyanion 6.7, which was treated

with 4 molar equivalents of methyl iodide at the same temperature for 1 h to furnish

products 6.8 and 6.9 (Scheme 6-2). The reaction of 6.7 withp-tolyl isocyanate (4 eq.)

gave the corresponding amide 6.10 in 40% yield. Treatment of polyanion 6.7 with 4-

methylbenzonitrile (4 eq.) gave only enamine 6.11 in 70% yield as a result of single

addition tautomerization [87JCSP(1)781, 95JHC323, 95JOC246]. Reaction of 6.7 with

dibenzoylmethane gave only the product of single addition 6.12 in 80% yield probably

due to the high acidity of the methylene protons of the diketone. Unlike the reaction of









6.7 with methyl iodide, treatment with benzyl bromide produced a single product 6.13; no

products involving the reaction of the 7-position of the benzotriazole rings in 6.7 were

observed. Attempts to trap polyanion 6.7 with di- and tri-electrophiles, such as

benzotrichloride, diethyl oxalate, diphenylethanedione, hexachloroethane and 1,2-

diiodoethane gave complex mixtures of products.

N p-Tol N ,





6.8 (30%) 6.9 (30%) p-Tol 6.10(40%)

Mel(4.1 eq) ^%
rN N
-N








N ;N p-Tol Bt

N \ p-MeC+6H4CN
S -BuLi (4eq. Li q.) H2N Bt
M e -- -M e / (11e7=C o 'p-ToI









N N -78 C, THF NLi

6.( 6. ) 6.11(70%)
L6.7 iCC



BzlBr (4 eq.) Ph

Bzl Bt Bt 0
Bzl^ PhB
Bt OH
6.13 (50%) 6.12 (80%)

Scheme 6-2. The Generation of Polyanion 6.7 from Dibenzotriazolylmethane 6.6 and its
Reactivity toward Different Electrophiles.

Parallel to Dr. Sergey Bobrov's work (the investigation of the versatile reactivity of

polyanion 6.7 toward different electrophiles), the continuing efforts to develop new

routes to heterocycles led to the generation of polyanion 6.15 from 1,1-









dibenzotriazolylethane 6.14 and the subsequent investigation of the reactivity of

polyanion 6.15 toward a variety of mono-, di- and trielectrophiles, is described here.

6.2 Results and Discussion

As mentioned above, the previous research results indicated that the most

nucleophilic center of polyanion 6.7 was the position a to the N-substituent. However,

after the anion formation at the a-carbon is trapped by the first molar equivalent of

electrophile, the second proton at that position can then undergo proton-lithium exchange

with lithium at 7-position to regenerate an anion at the a-position. In order to block the

proton lithium exchange between a-position of N-substituent and 7-position of polyanion

6.7, 1,1-dibenzotriazolylethane 6.14, which has a methyl group at the a-carbon instead of

an active proton, was used in a model study in which the generation of polyanion 6.15

was investigated. Upon reaction with various electrophiles, polyanion 6.15 afforded the

corresponding products 6.9 and 6.16-6.18 of addition or substitution. In one case,

heterocyclization took place to give product 6.19 (Scheme 6-3).

To determine the extent of lithiation, compound 6.14 was treated with excess of n-

BuLi (4 eq.) in THF at -78 C for a period of 12 h to generate its polyanion, which was

then trapped with methyl iodide (4 eq.) at the same temperature. This resulted in the

formation of a single compound 6.9 in 65% yield. Assuming that lithiation initially

produced the dianion 6.15, compound 6.14 was treated with 2 molar equivalents of n-

BuLi in THF at -78 C for a period of 12 h and then reacted with 2 molar equivalents of

methyl iodide to afford 6.9 in 90% yield. The electron-donor inductive effect of the a-

methyl group in 6.14 may decrease the acidity of the C-7 protons in the benzotriazolyl

groups and thus preclude lithiation of the second benzotriazolyl group in 6.15. Having









established efficient conditions for the generation of dianion 6.15, its reactivity toward a

range of electrophiles was also tested (Scheme 6-3).


N
% Bt -
MeMe N- MeB
Me/ Me Bt
Bt I 6.1641%
6.9 (90%) q.
(2 eq.)


I n-BuLi (2 eq.) t N EtI (2 eq.E

N-N Bt





Br Bt Me Bt
1-OH
N O
SN 6.20 (77%) 6.19(85%)



Scheme 6-3. The Generation of Dianion 6.15 and its Reactivity toward a Range of
Electrophiles.

Reaction of 6.15 with 3-iodopropene (2 eq.) gave 6.16 as the only product isolated,

by addition at the a-carbon adjacent to the benzotriazole group in 41% yield. The

reaction of iodoethane (2 eq.) with 6.15 produced a mixture of products (i) 6.17 from

addition at the a-carbon and the 7-position of the benzotriazole ring, and (ii) 6.18 from

addition at a-carbon; compounds 6.17 and 6.18 were isolated in 33% and 29% yields

respectively. Significantly, the formation of triazoloquinolinone 6.19 in 85% yield was

achieved by the reaction of dianion 6.15 with diethyl oxalate. The electron-withdrawing

property of benzotriazolyl group and a-carbonyl group favored the formation of a-









carbonyl geminal diol structure during aqueous work-up. The attempted reaction of 6.15

with benzylidene bromide gave lithium bromine exchange resulting in the formation of

the 7-bromo derivative 6.20 in 77% yield.

As a result of these reactions, functionalization both at the 7-position of the

benzotriazole ring and the a-carbon of N-substituent can be achieved. Attempted trapping

of dianion 6.15 with diethyl malonate and diethyl phenylmalonate failed, probably due to

the high acidity of the methylene protons in these 1,3-dielectrophiles. Only lithium-

hydrogen exchange was observed together with the recovery of corresponding starting

materials. The treatment of 6.15 with diethyl 2,2-diethylmalonate gave a complex

mixture of products, probably due to the a-carbon's steric hindrance (Scheme 6-4).

0 recovery of
starting materials



4-/

\ N N
I n-BuLi (2 eq.) I N'e PhCH(CO2Et)2 recovery of
IN. -78 -C, TF N Me (1 eq.) starting materials
N / -78 oC, THF r i Li (1 eq.)
N Me L Bt
6.14 6.15
re



complex mixture
of products

Scheme 6-4. Attempted Trapping of Dianion 6.15 with 1,3-Dielectrophiles.

The structure of the products was confirmed by 1H, and 13C NMR data (see

Experimental section). Significantly, the recently reported 1H and 13C NMR data for









related compounds were supported by X-ray analysis [87JCSP(1)781, 95JHC323,

95JOC246]. The analysis of the 1H NMR data for 6.9 and 6.17-19 shows the absence of

signals for the protons at the a-carbon ofN-substituents and for 6.9, 6.17 and 6.19 the

absence of a signal for the proton assigned to the 7-position of the benzotriazole ring. The

1C NMR of 6.9, 6.17 and 6.19-20 show twelve signals of the carbon atoms

corresponding to two unsymmetrical benzotriazolyl groups and for 6.9, 6.17 and 6.19-20

the lack of a signal around 110 ppm, typical of the 7-unsubstituted benzotriazole ring of

starting compounds 6.14. In contrast, the 13C NMR of compounds 6.16 and 6.18 show

only six carbon resonance signals atoms characteristic of two symmetrical benzotriazolyl

groups. The 1H NMR spectra 6.20 show that the protons of the methyl group and the

proton at the a-carbon of the N-substituents resonate as doublets and quartets

respectively.

6.3 Conclusion

In summary, the generation of polyanion from benzotriazole derivative, 1,1-

dibenzotriazolylethane, 6.14 and the reactivity of the resulting polyanion 6.15 with a

range of electrophiles were investigated. The present research extended the scope of

previous reports [95H131, 96TL5615, 03JOC5713]. In one case, when polyanion 6.15

reacted with dielectrophile diethyl oxalate, the heterocyclization took place to give novel

triazoloquinolinone 6.19 in high yield.

6.4 Experimental Section

General. Melting points were determined by a capillary melting point apparatus

equipped with a digital thermometer and Bristoline hot-stage microscope and were

uncorrected. NMR spectra were recorded in CDC13, acetone-d6 or DMSO-d6 with TMS as









the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C (75

MHz). Microanalyses were performed on an EA-1108 elemental analyzer. THF was

dried over sodium / benzophenone and used freshly distilled. Column chromatography

was conducted on silica gel 200- 425 meshes.

1,1-Dibenzotriazolylethane 6.14 was prepared according to published procedures

[87JCSP(1)811] as white microcrystals (32%), mp 141-142 C (lit. mp 141-142 C

[87JCSP(1)811]).

Procedure for preparation of dianion (6.15) solution. A stirred solution of 1,1-

dibenzotriazolylethane 6.14 (1 g, 3.79 mmol) in THF (50 mL) was cooled to -78 C, and

a solution of n-BuLi (4.9 mL, 7.58 mmol, 1.6 M in hexanes) was added dropwise. The

reaction mixture was stirred at this temperature for 12 h and then treated with an

appropriate electrophile at the same temperature.

Procedure for the preparation of (6.9) from dianion (6.15). A solution of methyl

iodide (1.07g, 7.58 mmol) in THF (15 mL) was added dropwise to a stirred solution of

dianion 6.15 (3.79 mmol) at -78 C. The reaction mixture was stirred at this temperature

for 1 h and then water was added and the product was extracted with diethyl ether. The

extract was washed with water, dried over anhydrous magnesium sulfate and evaporated

under reduced pressure. The residue was purified by column chromatography on silica

gel (hexanes/ethyl acetate, 6/1) to give 6.9 as microcrystals (90%).

1-[1-(1H-1,2,3-Benzotriazol-l-yl)-l-methylethyl]-7-methyl-lH-1,2,3-

benzotriazole (6.9). Off-white microcrystals (90%), mp 146-147 C; 1H NMR 6 8.07 (d,

J= 8.3 Hz, 1H), 8.00 (d, J= 8.3 Hz, 1H), 7.30-7.20 (m, 2H), 7.17-7.00 (m, 2H), 6.24 (d,

J= 8.3 Hz, 1H), 2.68 (s, 6H), 1.61 (s, 3H); 13CNMR 6 148.2, 146.9, 131.9, 131.5, 130.9,









128.2, 124.7, 124.4, 121.2, 120.2, 118.3, 110.2, 79.8, 30.0, 20.0. Anal. Calcd for

C16H16N6: C, 65.74; H, 5.52; N, 28.75. Found: C, 65.45; H, 5.56; N, 29.17.

General procedure for the preparation of compounds 6.16-20. A solution of

corresponding electrophile (8.00 mmol) in THF (15 mL) was added dropwise to a stirred

solution of dianion 6.15 (3.79 mmol) at -78 C. The reaction mixture was stirred at this

temperature for 1 h and then water was added and the product was extracted with diethyl

ether. The extract was washed with water, dried over anhydrous magnesium sulfate and

evaporated under reduced pressure. The residue was purified by column chromatography

on silica gel (hexanes/ethyl acetate, 6/1) to give 6.16-20.

1-[l-(1H-1,2,3-Benzotriazol-l-yl)-l-methyl-3-butenyl]-lH-1,2,3-benzotriazole

(6.16). White microcrystals (41%), mp 91-92 C; 1H NMR 6 8.04-8.07 (m, 2H),

7.14-7.29 (m, 4H), 6.68-6.71 (m, 2H), 5.49-5.58 (m, 1H), 5.06-5.12 (m, 2H), 4.02 (d, J

= 7 Hz, 2H), 2.68 (s, 3H); 13C NMR 6 146.7, 131.2, 129.1, 128.1, 124.4, 121.7, 120.2,

110.0, 80.6, 42.9, 24.9. Anal. Calcd for C17H16N6: C, 67.09; H, 5.30; N, 27.61. Found: C,

67.15; H, 5.29; N, 27.61.

1-[l-(1H-1,2,3-Benzotriazol-l-yl)-l-methylethyl]-7-ethyl-lH-1,2,3-

benzotriazole (6.17). White microcrystals (33%), mp 93-95 OC; 1H NMR 6 8.04-8.07

(m, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.24-7.34 (m, 2H), 7.10-7.18 (m, 2H), 6.30 (d, J= 8.5

Hz, 1H), 3.30-3.41 (m, 1H), 3.13-3.26 (m, 1H), 2.62 (s, 3H), 2.05 (q, J= 7.0 Hz, 2H),

0.78 (t, J= 7.0 Hz, 3H), 0.56 (t, J= 7.0 Hz, 3H); 13C NMR 6 148.1, 146.8, 131.8, 131.4,,

128.6, 128.1, 127.8, 124.8, 124.4, 120.2, 118.0, 110.3, 83.0, 34.0, 26.5, 24.5, 14.8, 7.9.

Anal. Calcd for C18H20N6: C, 67.48; H, 6.29; N, 26.23. Found: C, 67.64; H, 6.35; N,

26.33.









1-[1-(1H-1,2,3-Benzotriazol-l-yl)-l-methylpropyl]-lH-1,2,3-benzotriazole

(6.18). White microcrystals (29%), mp 93-94 C; 1H NMR 6 8.03-8.07 (m, 2H),

7.12-7.28 (m, 4H), 6.63-6.66 (m, 2H), 3.32 (q, J= 7.4 Hz, 2H), 2.67 (s, 3H), 0.91 (t, J=

7.6 Hz, 3H); 13C NMR 6 146.9, 131.4, 128.1, 124.5, 120.3, 110.2, 82.2, 31.8, 24.3, 7.7.

Anal. Calcd for C16H16N6: C, 65.74; H, 5.52; N, 28.75. Found: C, 66.11; H, 5.58; N,

28.65.

4-(1H-1,2,3-Benzotriazol-1-yl)-5,5-dihydroxy-4-methyl-4,5-dihydro-6H-

[1,2,3]triazolo[4,5,1-ij]quinolin-6-one (6.19). White plates (78%), mp 182-186 C; 1H

NMR (DMSO-d6) 6 8.50 (d, J= 8.2 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J= 7.1 Hz, 1H), 8.16

(d, J= 8.5 Hz, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.80 (s, 1H), 7.75-7.70 (m, 1H), 7.68-7.62

(m, 1H), 7.48-7.42 (m, 1H), 3.03 (s, 3H); 13C NMR (DMSO-d6) 6 186.9, 145.2, 143.9,

134.2, 132.1, 128.6, 125.8, 125.5, 125.3, 124.5, 119.6, 117.1, 113.0, 95.1, 83.7, 16.5.

Anal. Calcd for C16H12N603: C, 57.14; H, 3.60; N, 24.99. Found: C, 56.90; H, 3.94; N,

26.03.

1-[l-(1H-1,2,3-Benzotriazol-1-yl)ethyl]-7-bromo-lH-1,2,3-benzotriazole (6.20).

Off-white microcrystals (77%), mp 165-166 OC; H NMR 6 8.72 (q, J= 6.9 Hz, 1H),

8.06-8.01 (m, 2H), 7.82 (d, J= 8.4 Hz, 1H), 7.70-7.63 (m, 1H), 7.48-7.40 (m, 1H),

7.38-7.31 (m, 1H), 7.28-7.20 (m, 1H), 2.67 (d, J= 6.9 Hz, 3H); 13C NMR 6 147.2,

146.6, 132.8, 131.1, 130.7, 128.0, 125.7, 124.3, 120.1, 119.6, 110.8, 102.2, 67.8, 20.3.

Anal. Calcd for C14H,,BrN6: C, 49.00; H, 3.23; N, 24.49. Found: C, 49.00; H, 3.15; N,

24.32.














CHAPTER 7
CONCLUSION

Various novel approaches to targets were achieved via benzotriazole auxiliary. The

successful syntheses described herein employ convenient preparations of starting

materials, and relatively mild conditions. They provide synthetically useful yields, and

offer competitive and advantageous alternatives to routes reported in the literature.

Chapter 2 and Chapter 5 discuss novel approaches to two types of thioacyl

derivatives: thioureas and P-enamino thioic acid derivatives. An alternative to the

classical thiourea preparations via O/S exchange was developed by treating (benzotriazol-

1-yl)carboximidamides with hydrogen sulfide (Chapter 2). In Chapter 5, novel

benzotriazole intermidates, benzotriazolyl P-enaminothiones, were prepared and

employed in the syntheses of novel P-enamino thioic acid derivatives. Important

advantages of the benzotriazole-assisted thioacylations described herein include avoiding

the use of unstable or hazardous reagents. Further, the relatively mild conditions

employed tolerate a variety of functional groups. The yields obtained are comparable.

In Chapter 3, novel and advantageous methods for the syntheses of a-cyano

sulfones and a-sulfonyl sulfones have been developed using 1-sulfonylbenzotriazoles.

These approaches broaden the range of available sulfone derivatives, which are

compounds of major synthetic, biological, and medicinal importance. Advantages of

these procedures include the following: i) the use of sulfonyl chlorides and of foul-

smelling sulfides is avoided; ii) 1-sulfonylbenzotriazoles are neutral and odorless









crystalline compounds, easily accessible, and stable to storage over months and iii) the C-

sulfonylated products are generally obtained in synthetically useful yields. These results

represent the first example of the successful use of sulfonamides as C-sulfonylating

reagents and suggest that few limitations are to be expected for sulfonylation of nitriles

and sulfones using benzotriazole methodology.

In Chapter 4, 1-acylbenzotriazoles are used as acylating agents to prepare y-keto-y-

amino esters, which can be easily reduced to -y-amino acids. Compared to classic

acylating agents, such as acyl halides, esters, and anhydrides, our 1-acylbenzotriazoles

show advantages due to i) their neutral character (they can be used to substrates with

acid-sensitive group); ii) their appropriate reactivity between highly reactive acyl halides,

which has less selectivity and is less difficult to handle, and less reactive esters and

anhydrides; and iii) their good stability to air and moisture. When chiral substrates are

employed, the chiral center is retained. 1-Acylbenzotriazoles have shown great potential

in the amino acid and peptide chemistry.

Chapter 6 describes the generation of polyanions from 1,1-dibenzotriazolylethane

and the reactivity of the resulting polyanion was investigated with a range of

electrophiles. The efforts led to an approach to a novel ring system, triazoloquinolinone,

which may have potential applications in the synthesis of bioactive heterocycles and drug

design.



















[30JA3647]

[34JA1408]

[39JA3386]

[51JA906]


[510S19]

[55CR181]

[550S609]


LIST OF REFERENCES1

Evans, T. W.; Dehn, W. M. J. Am. Chem. Soc. 1930, 52, 3647.

Douglass, I. B.; Dains, F. B. J. Am. Chem. Soc. 1934, 56, 1408.

Pomerantz, A.; Connor, R. J. Am. Chem. Soc. 1939, 61, 3386.

Bernstein, J.; Yale, H. L.; Losee, K.; Holsing, M.; Martins, J.;
Lott, W. A. J. Am. Chem. Soc. 1951, 73, 906.

Kurzer, F. Org. Synth. 1951, 31, 19.

Schroeder, D. C. Chem. Rev. 1955, 55, 181.

Cressman, H. W. J. Org. Synth. 1955, CV3, 609.


1 The reference citation system employed throughout this dissertation is that from Comprehensive
Heterocyclic Chemistry II (Vol. 1); Pergamon Press: New York 1996 (Eds. Katritzky, A. R.; Rees, C. W.
and Scriven, E.).

Each time a reference is cited, a number-letter code is designated to the corresponding reference with the
first two (or four if the reference is before 1910) numbers indicating the year followed by the letter code of
the journal and the page number in the end.

Additional notes to this reference system are as follows:

1. Each reference code is followed by the conventional literature citation in the ACS style.

2. Journals which are published in more than one part include in the abbreviation cited the
appropriate part.

3. Less commonly used books and journals are still abbreviated as using initials of the journal name.

4. Patents are assigned appropriate three letter codes and are listed at the end in alphabetic order.

5. The list of the reference is arranged according to the designated code in the order of (a) year; (b)
journal in alphabetical order; (c) part number or volume number if it is included in the code; (d)
page number.

6. Project number is used to code the unpublished results.









[550S617]

[550S735]

[56AC545]


[56JCS659]


[56JOC483]

[560S56]


[60JOC770]

[630S180]

[65JHC486]

[67JA4760]

[69JOC3085]

[69RC299]

[70CB2775]

[71P3155]

[72JMC1024]


[73JOC2675]


[730S801]

[73RC2199]


[74LAC1315]

[75JCSP(1)897]


Moore, M. L.; Crossley, F. S. Org. Synth. 1955, CV3, 617.

Frank, R. L.; Smith, P. V. Org. Synth. 1955, CV3, 735.

Mameli, E.; D'Angeli, F.; Richter, K. F. Ann. Chim. (Rome) 1956,
46, 545 (CA: 1956, 51, 76964).

Baxter, J. N.; Cymerman-Craig, J.; Moyle, M.; White, R. A. J
Chem. Soc. 1956, 659.

Erickson, J. G. J. Org. Chem. 1956, 21, 483.

Cymerman-Craig, J.; Moyle, M.; White, R. A. Org. Synth. 1956,
36, 56.

Tigler, M.; VrbaSki, Z. J. Org. Chem. 1960, 25, 770.

Kurzer, F. Org. Synth. 1963, CV4, 180.

Orth, R. E.; Soedigdo, S. J. Heterocycl. Chem. 1965, 486.

Hermes, M. E.; Marsh, F. D. J. Am. Chem. Soc. 1967, 89, 4760.

Parker, W. L.; Woodward, R. B. J. Org. Chem. 1969, 34, 3085.

Chimiak, A. Rocz. Chim. 1969, 43, 299.

Bohme, H.; Fuchs, G. Chem. Ber. 1970, 103, 2775.

Kjaer, A.; Schuster, A. Phytochem. 1971, 10, 3155.

Loev, B.; Bender, P. E.; Bowman, H.; Helt, A.; McLean, R.; Jen,
T. J. Med. Chem. 1972, 15, 1024.

West, C. T.; Donnelly, S. J.; Kooistra, D. A.; Doyle, M. P. J. Org.
Chem. 1973, 38, 2675.

Neville, R. G.; McGee, J. J. Org. Synth. 1973, CV5, 801.

Bierowska-charytonowicz, D.; Konieczny, M. Rocz. Chem. 1973,
47, 2199.

Stetter, H.; Steinbeck, K. Liebigs Ann. Chem. 1974, 1315.

Campbell, R. V. M.; Crombie, L.; Findley, D. A. R.; King, R. W.;
Pattenden, G.; Whiting, D. A. J. Chem. Soc., Perkin Trans 1 1975,
897.









[75S260]


[77CPB29]


[77HCA2747]


[77S690]

[77TL4037]

[78JA5221]


[78JOC337]

[79CB1956]

[79JA1316]


[79JOC2805]

[79S942]

[80S453]


[80S565]

[80T3047]


[81TL3175]


[81TL3409]


[82JA5221]

[82T2857]

[83JA4396]


Ooms, P. H. J.; Scheeren, J. W.; Nivard, R. J. F. Syithe,/i 1975,
260.

Tseng, C. C.; Terashinma, S.; Yamada, S. Chem. Pharm. Bull.
1977, 25, 29.

Buchschacher, P.; Cassal, J. M.; Furst, A.; Meier, W. Helv. Chim.
Acta. 1977, 2747.

Ono, N.; Tamura, R.; Tanikaga, R.; Kaji, A. Synthesis 1977, 690.

Shibasaki, M.; Ikegami, S. Tetrahedron Lett. 1977, 18, 4037.

Tamaru, Y.; Harada, T.; Iwamoton, H.; Yoshida, Z.-i. J. Am.
Chem. Soc. 1978, 100, 5221.

Larsen, C.; Steliou, K.; Harrp, D. N. J. Org. Chem. 1978, 337.

Hussein, A. Q.; Jochims, J. C. Chem. Ber. 1979, 112, 1956.

Tamaru, Y.; Harada, T.; Yoshida, Z.-i. J. Am. Chem. Soc. 1979,
101, 1316.

Curphey, T. J. J. Org. Chem. 1979, 44, 2805.

Walter, W.; Proll, T. Synuthei 1979, 942.

Meslin, J. C.; Reliquet, A.; Reliquet, F.; Quiniou, H. Synuthe\i
1980, 453.

Messinger, P.; Kusuma, K. Synthesis 1980, 565.

Shabana, R.; Rassmussen, J. B.; Olesen, S.O.; Lawesson, S.-O.
Tetrahedron 1980, 36, 3047.

Adiwidjaja, G.; Proll, T.; Walter, W. Tetrahedron Lett. 1981, 22,
3175.

Tamaru, Y.; Kagotani, M.; Yoshida, Z.-i. Tetrahedron Lett. 1981,
22, 3409.

Cambell, P.; Nashed, N. T. J. Am. Chem. Soc. 1982, 104, 5221.

Vedejs, E.; Krafft, G. A. Tetrahedron 1982, 38, 2857.

Smith, J. K.; Bergbreiter, D. E.; Newcomb, M. J. Am. Chem. Soc.
1983, 4396.









[83JMC1158]


[83S605]


[84JA726]

[84JOC1125]


[84JOC997]

[84S1045]


[85H1225]


[85JOC2806]


[85T5061]

[86JA2358]


[86JA2780]


[86JOC1882]


[86S1041]

[87JCSP(1)781]


[87JCSP(1)811]


[87JOC1703]


[87S56]


Hargrave, K. D.; Hess, F. K.; Oliver, J. T. J. Med. Chem. 1983, 26,
1158.

Ramadas, S. R.; Srinivasan, P. S.; Ramachandran, J.; Sastry, V. V.
S. K. Synithe/i 1983, 605.

Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc. 1984, 106, 7260.

Sepiol, J. J.; Sepiol, J. A.; Soulen, R. L. J. Org. Chem. 1984, 49,
1125.

Patil, D. G.; Chedekel, M. R. J. Org. Chem. 1984, 49, 997.

Perez, M. A.; Soto, J L.; Guzman, F.; Diaz, A. Synthesis 1984,
1045.

Coen, S.; Ragonnet, B.; Vieillescazes, C.; Roggero, J.
Heterocycles 1985, 23, 1225.

Ono, N.; Yanai, T.; Hamamoto, I.; Kamimura, A.; Kaji, A. J. Org.
Chem. 1985, 50, 2807.

Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5087.

Hendrickson, J. B.; Boudreaux, G. J.; Palumbo, P. S. J. Am. Chem.
Soc. 1986, 108, 2358.

Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.;
Furuya, T. J. Am. Chem. Soc. 1986, 108, 2780.

Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. J.
Org. Chem. 1986, 51, 1882.

Winckelmann, I.; Larsen, E. H. S)ytheli 1986, 1041.

Katritzky, A. R.; Rachwal, S.; Caster, K. C.; Manhi, F.; K. W.
Law, K. W.; Rubio, O. J. Chem. Soc., Perkin Trans. 1 1987, 781.

Katritzky, A.R.; Kuzmierkiewicz, W.; Rachwal, B.; Rachwal, S.;
Thomson, J. J. Chem. Soc., Perkin Trans. 1 1987, 811.

Matsuyama, H.; Miyazawa, Y.; Takei, Y.; Kobayashi, M. J. Org.
Chem. 1987, 52, 1703.

Bram, G.; Loupy, A.; Roux-Schmitt, M. C.; Sansoulet, J.;
Strzalko, T.; Seyden-Penne, J. Synthesis 1987, 56.









[87S452]

[88CL29]


[88JCSP(1)1739]


[88JMC1719]



[88LAC983]


[88MI]


[88S456]




[89JA779]


[90JMC2323]



[90JOC955]


[90SC2291]

[90T6715]

[91RRC573]


[91S1205]


[91T2683]


Wrobel, J. T.; Hejchman, E. S)yithe,/i 1987, 452.

Vuddhakul, V.; Jacobsen, N. W.; Rose, S. E.; loannoni, B.; Seow,
W. K.; Thong, Y. H. Cancer Lett. 1988, 42, 29.

Barluenga, J.; Gonzalez, F. J.; Gotor, V.; Fustero, S. J. Chem. Soc.
Perkin. Trans. 1 1988, 1739.

Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.;
Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.; Carter,
G. W. J. Med. Chem. 1983, 26, 1158.

Elghandour, A. H. H.; Ramiz, M. M. M.; Ghozlan, S. A. S.;
Elmoghayar, M. R. H. Liebigs Ann. Chem. 1988, 983.

Patai, S.; Rappoport, Z.; Stirling, C. J. M., Eds. The Chemistry of
Sulphones and Sulphoxide; Wiley: Chichester, UK, 1988.

Rasmussen, C. R.; Villani, F. J., Jr.; Weaner, L. E.; Reynolds, B.
E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.;
Costanzo, M. J.; Powell, E. T.; Molinari, A. J. Synthesis 1988,
456.

(55) Ranasinghe, M. G.; Fuchs, P. L. J. Am. Chem. Soc. 1989,
111, 779.

Bock, M. G.; Dipardo, R. M.; Williams, P. D.; Pettibone, D. J.;
Clineschmidt, B. V.; Ball, R. G.; Veber, D. F.; Freidinger, R. M. J.
Med. Chem. 1990, 33, 2323.

Padwa, A.; Bulllock, H. W.; Dyszlewski, A. D. J. Org. Chem.
1990, 55, 955.

Huang, X.; Pi, J-H. Synth. Comm. 1990, 20, 2291.

Tan, W.; Bourdieu, C.; Foucaud, A. Tetrahedron 1990, 46, 6715.

Katritzky, A. R.; Brzezinski, J. Z.; Lam, J. N. Rev. Roum. Chim.
1991, 36, 573.

Hanack, M.; Bailer, G.; Hackenberg, J.; Subramanian, 1. R.
S)'nlhei\ 1991, 1205.

Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron 1991,
47, 2683.









[91TL5983]


[92JMC2562]





[92MC369]


[92S1104]


[92S1185]

[92S552]


[92T7817]


[93JOC1702]


[93MI]


[94AA31]


[94BMCL1601]

[94H345]


[94JOC1257]


[94JOC1518]


[94JOC2014]

[94JOC6287]


87


Hamada, Y.; Yoshihisa, T.; Yokokawa, F.; Shioiri, T. Tetrahedron
Lett. 1991, 32, 5983.

Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.; Taylor,
D. G. Jr.; Connolly, C. J. C.; Doherty, A. M.; Klutchko, S. R.;
Sircar, I.; Steinbaugh, B. A.; Batley, B. L.; Painchaud, C. A.;
Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C. J. J. Med.
Chem. 1992, 35, 2562.

Meijs, G. F.; Rizzardo, E.; Le, T. P. T.; Chen, Y. Macromol.
Chem. 1992, 193, 369.

Marini, A. E.; Roumestant, M. L.; Viallefont, P.; Razafindramboa,
D.; Bonato, M.; Follet, M. S)yithe,/i 1992, 1104.

Metzner, P. Synthesis 1992, 1185.

Sakamoto, T.; Kondo, Y.; Suginome, T.; Ohba, S.; Yamanaka, H.
Synth'lll i 1992, 552.

Katritzky, A. R.; Shobana, N. Pernak, J.; Afridi, A. S.; Fan, W.-Q.
Tetrahedron 1992, 48, 7817.

Kascheres, A.; Kascheres, C.; Braga, A.C.H. J. Org. Chem. 1993,
58, 1702.

Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press:
Oxford, UK, 1993.

Katritzky, A. R.; Yang, Z.; Cundy, D. J. Aldrichim. Acta 1994, 27,
31.

Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601.

Katritzky, A. R.; Gupta, V.; Garet, C.; Stevens, C. V.; Gordeev,
M. Heterocycles 1994, 38, 345.

Hoeg-Jensen, T.; Olsen, C. E.; Holm, A. J. Org. Chem. 1994, 59,
1257.

Benedetti, F.; Berti, F.; Fabrissin, S.; Gianferrara, T. J. Org.
Chem. 1994, 59, 1518.

Jacobs, H. K.; Gopalan, A. S. J. Org. Chem. 1994, 59, 2014.

Petit, G. R.; Singh, S. B.; Harald, D. L.; Lloyd-Williams, P.;
Kaantoci, D.; Burkett, D. D.; Barcokzy, J.; Hogan, F.; Wardlaw,
T. R. D. J. Org. Chem. 1994, 59, 6287.