BENZOTRIAZOLE MEDIATED HETEROALKYLATION
AND ARYLALKYLATION IN ORGANIC SYNTHESIS
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
To my daughter, Stephanie, with love
I am deeply indebted to my supervisor, Professor Alan R. Katritzky, for his
invaluable guidance, encouragement and trust over the years. It has been a rewarding
experience and a pleasure to work with him.
I would like to express my sincere gratitude to Dr.
William Dolbier, Dr. Eric
Enholm, Dr. Richard Yost and Dr. Dinesh Shah, for their help, suggestions and time
as my supervisory committee members.
I would like to give my special thanks to Dr.
Wei-Qiang Fan and Dr. Darren
Cundy for their help and cooperation during these years.
The people in the Katritzky Group are like a big family and have always been
very supportive. Thanks also go to them for their help and friendship.
I am deeply grateful to my parents and my parents-in-law, for their love and
support, for taking very good care of my little baby.
Last but not the least, I am greatly indebted to my husband, Jianqing, for his
constant understanding, encouragement and support, for everything he has done for
TABLE OF CONTENTS
AMIDOALKYLATION OF AMINES AND THIOLS
SYNTHESIS OF a-AMINO ISONITRILES AND
-ALKYLTHIO ISONTRILES .............................. ..........
Introduction ............. .............................................. ......
Results and Discussion .................................... .... ........
Experimental ............. ........... ............... ..... .. ....... ..... .....
THIOALKYLATION OF REACTIVE AROMATIC
COMPOUNDS WITH a-(BENZOTRIAZOL-1-YL)BENZYL
PHENYL SULFIDE ............... ....... .... ..... ...................... ......
3.1 Introduction ....................... ....... .......................... ........
3.2 Results and Discussion ....................................................
3.3 Experim mental .............. ................... .............................
HETEROARYLALKYLATION OF ELECTRON-RICH HETERO-
AROMATIC COMPOUNDS: CONVENIENT NOVEL SYNTHESIS
OF 1, 1 BIS (HETEROARYL)ALKANES ..................... .... ...........
Introduction ....... .................. ................... ..... .............
Results and Discussion ... .......................... .................
Experimental ...... .... ............ ...... ............ ............ .... ......
INDOLYLALKLATION. PART I: A
OF 3-SUBSTITUTED INDOLES
Introduction ............................ .......................... ........
INDOLYLALKYLATION. PART II: A GENERAL
AND FACILE SYNTHESIS OF HETEROCYCLO[B]-
FUSED CARBAZOLES ............................................................
Results and Discussion ......................................................
Experimental ........................ ....................................... ...
................ ...ec. ......... mce. .... a. a. -. emeem
* .............. W.............. .. ..eec
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
BENZOTRIAZOLE MEDIATED HETEROALKYLATION
AND ARYLALKYLATION IN ORGANIC SYNTHESIS
Chairman: Alan R. Katritzky, FRS
Major Department: Chemistry
a-(Benzotriazol-1-yl)alkyl groups are incorporated into amides, sulfides and
amidoalkylation, thioalkylation and heteroarylalkylation with the displacement of the
benzotriazolyl group by various nucleophiles to furnish a
dehydrations of N-(a-aminoalkyl)formamides and N-[a-(alkylthio)alkyl]formamides,
compounds to afford a variety of thioalkylated products.
a-(Benzotriazol-l-yl)alkyl groups are incorporated into thiophene,
indole systems via the reaction of N-[(a-benzotriazol-1-yl)alkyl]carbamates,
with 2-methylthiophene, 2-methylfuran and 1-methylindole, respectively.
Following a similar protocol, a variety of 3-substituted indoles are prepared
3-methylindole with N-[(a-benzotriazol-l-yl)alkyl]carbamates or via the reactions of
lithiated 1-methyl-3-[(benzotriazol- 1-yl)methyl]indole with electrophiles.
with t-butyllithium and the resulting carbanion reacts with thiophenecarboxaldehydes,
methyl iodide, the corresponding methyl ether intermediate products are obtained in
excellent yields. Intramolecular indolylalkylation of these intermediates is effected by
Work in our laboratory has demonstrated benzotriazole as a useful synthetic
One of the
aldehyde and a compound containing an active hydrogen atom to form a variety of
the other is that its anion is a good leaving group
which can be displaced by various types of nucleophiles in its derivatives of type
compounds to be readily accessible.
BENZOTRIAZOLE MEDIATED HETEROALKYLATION
displacement of benzotriazole by nucleophile
benzotriazole. Conceptually similar, benzotri
is called heteroalkylation mediated by
\azole mediated arylalkylation indicates
the displacement of type Bt-C-Ar 1.3 and 1.5 by nucleophiles. In these processes, the
dissociation of the C-Bt bond is assisted by the lone electron pair on the heteroatom X
to form reactive intermediates, cations 1.2, 1.4 and 1.6 [87JCS(P1)2673, 89H1121],
which subsequently react with nucleophiles to fulfil the transformations.
BENZOTRIAZOLE MEDIATED ARYLALKYLATION
or ortho position
Since benzotriazolyl derivatives are usually more stable and/or more readily
to be a highly
and in many
cases even a
The objective of this project is to investigate the applications of benzotriazole
mediated heteroalkylation and arylalkylation in the synthesis of a variety of useful
describes the synthesis of a-amino isocyanides and a-alkylthio isocyanides via the
followed by the dehydration of formed intermediate products. Chapter III discusses
the thioalkylation of reactive aromatic compounds with a-(benzotriazol-l-yl)benzyl
mediated heteroarylalkylation in
the synthesis of
alkanes and 3-substituted indoles.
The work in Chapter VI extends the benzotriazole
carbazoles and indolo[b]carbazoles.
AMIDOALKYLATION OF AMINES AND THIOLS WITH
SYNTHESIS OF a-AMINO ISONITRILES AND a-ALKYLTHIO ISONITRILES
The chemistry of isonitriles in general is well documented [71MI1], but far
less work has been reported on functionalized, specifically a-substituted isonitriles
2.1. Bohme and Fuchs reported the three-step synthesis of (isocyanomethyl)phenyl
sulfone (2.1, Y
= PhSO2, R
= H) and of N-(isocyanomethyl)phthalimide starting from
(alkylthio)methyl isocyanides (2.1,
= RS) [70CB2775].
= (EtO)2P(O), R =
H) was prepared from the reaction of triethyl
isocyanomethyl substituted phosphorus compounds have also been reported [74LA44,
N-(isocyanomethyl)-N-nitropropylamine (2.1, Y
= O2NNPr, R
= H) which rearranged
to its corresponding nitrile form [81AP459]. 1-Isocyanomethylazoles RCH2NC (R =
benzotriazolyl) were synthe-
sized by the reaction of RH with HCONHCH2N+Me3I- followed by dehydration of
a-(arylthio)methyl isonitriles (2.1,
= ArS, R
= H) [88TL1435] and
alkenyl isonitriles [85RTC177] have also been reported.
Our own group recently disclosed the synthesis of a-(benzo-
1-(1-formylaminoalkyl)benzotriazoles (2.3) which were prepared by the condensation
benzotriazole, an aldehyde and formamide [90JCS(P1)1847].
unsymmetrical formamidines. In
we now report for the first time the
Results and Discussion
1-[a-(Formylamino)benzyl]benzotriazole (2.3a) and 1-[1-(formylamino)-
-2-methylpropyl]benzotriazole (2.3b) were prepared from
and the appropriate aldehyde as previously described [90JCS(P1)1847].
RCHO / H2NCHO
R'SH / EtOH / Na
(R = Ph)
K2C03 / MeOH
POCL / CH2CI2
2.5, 2.7 R R'
a i- Pr Ph
b Ph 3 -MeC6H4
c Ph i Pr
.POC13 / CH2C12
gave N- (a-morpholinobenzyl)formamide
- 2.5e in good yields.
The byproduct sodium or potassium
- 2.5c) with POC13 in the presence of i-Pr2NH
- 2.7c in
compounds 2.3a and 2.3b involve electrophilic attack by the carbocation of type 1.2
The dehydration of formamide derivatives with POC13 in the presence of an
amine and other dehydrating reagents, such as tosyl chloride [65CA 1441],
chloride and base [72JOC187] or triphenylphosphine in CC14 [71AG143] are well
= RS) are the key to the synthesis of the
usually been synthesized by the condensation of formamide with formaldehyde and
secondary amines, but the condensation is, in general, not applicable to either other
formamidomethyl alkyl sulfides (2.2,
= H), the precursors for (alkylthio)-
= RS, R
The novel aspect of
work is that using
1-(1-formylaminoalkyl)benzotriazoles now provides a convenient
route to the preparation of both a-(formamidoalkyl)dialkylamines and a-(formamido-
alkyl)alkyl sulfides in good yield. This method works particularly well with aromatic
and aliphatic aldehydes under mild conditions.
formamides (2.5a-2.5c) were characterized by elemental analyses and by their 1H and
13C NMR spectra. In the 1H NMR spectra of 2.4 and 2.5, the NH protons appear as
doublets at 8.64 to 9.1
ppm with coupling constants ranging from 9.3
10.0 Hz, and
the formyl CH protons at 8.28-7.78 ppm with small coupling constants (0.9 Hz). In
the 13C NMR spectra, formyl carbonyl carbons appear at 160.0
carbons at 68.9
161.2 ppm and CH
- 52.9 ppm. All of the a-substituted isocyanides are new compounds.
The isocyanide structure is confirmed by the strong IR abortion band at 2250 cm-1
for the compound 2.6 and 2120 cm"1 for compounds 2.7, and by the 13C signals of
the isocyanato carbons at 159.7
- 160.4 ppm.
The structures of the isonitrile 2.6 is
resolution mass spectra.
1H (300 MHZ) NMR and 1"C (75 MHz) NMR spectra were recorded on
'7- 2<- -A -- A '-
previously described [90JCS(P1)1847].
2.3.1 N-(a-Morpholinobenzyl)formamide (2.4)
A mixture of 1-(1-formylamidobenzyl)benzotriazole (2.3) (1.89 g, 7.5 mmol),
morpholine (0.86 g, 10 mmol) and potassium carbonate (2.25 g) in methanol (20 ml)
was stirred at 200C overnight.
The solvent was evaporated, the residue dissolved in
ethyl acetate (100 ml),
washed with aqueous sodium hydroxide (3 x 20 ml,
water (2 x 10 ml) and dried (MgSO4).
Evaporation of the solvent gave a white solid
which was recrystallized from ethyl acetate/hexane (3/1) to give 2.4 as white needles
(1 g, 62
= 8.74 (d, 1H, J
= 9.3 Hz, NH),
8.28 (d, 1H, J
= 0.9 Hz, CHO), 7.47-7.30 (m,
5H, ArH), 5.71-5.68 (d, 1H,
= 9.6 Hz,
CH), 3.57 (t,
= 4.2 Hz), 2.38 (t,
138.6, 128.3, 128.
127.6, 127.2, 68.9 (CH), 66.2 (CH20),
for C12H16N202 (220.3): calc.
found C 65.20
2.3.2 N-(1-Phenylthio-2-methylpropyl)formamide (2.5a)
A solution of thiophenol (3.3 g, 30 mmol) and sodium (0.7
g, 30 mmol) in
was removed under reduced pressure and the residue dissolved in ethyl acetate (100
ml), washed with aqueous NaOH (3 x 20 ml, 10%) and water (2 x 10 ml) and dried
Evaporation of the solvent and recrystallization from ethyl acetate/hexane
(3/1) gave 2.5a as white needles (2.32 g, 74%),
= 10.0 Hz, NH),
= 0.9 Hz, CHO),
.4 Hz, CH),
1.00 (m, 6H,
Analysis for C11H15NOS (209.2):
found C 62.99
N-[a-(3-Methylphenylthio)benzyll form amide
, mp 132-1330C.
= 9.05 (d,
1H, J = 9.6 Hz,
7.78 (s, 1H,
CHO), 7.36-6.86 (m,
ArH), 6.32 (d,
= 9.6 Hz, 1H),
for C15Hs1NOS (
N 5.44; found C 69.57
N-[(a-IsoDropylthio)benzvllformamide (2.5c): Needles
= 9.15 (d, 1H,
= 9.6 Hz, NH),
= 9.6 Hz, CH),
(d, 3H, J
= 6.6 Hz, CH3); 1.19 (d,
= 6.6 Hz, CH3)
126.6, 52.9, 34.6,
Analysis for C1iH1sNOS
(209.2): calc. C 63.1
N 6.69; found C 63.34
2 x CH3);
2.3.3 a-Morpholinobenzyl isocyanide (2.6)
Typical Procedure for the Preparation of
2.6, 2.7a, 2.7b, 2.7c
Diisopropylamine (0.303 g, 3 mmol) was added to N-(a-morpholinobenzyl)-
formamide (2.4) (0.
g, 1 mmol) in CH2C12 (40 ml).
Phosphorous oxychloride (0.20
g, 1.3 mmol) in CH2C12 was added dropwise at 0C with stirring.
The solution was
stirred for 4h at 0C and aqueous sodium carbonate (8 ml, 20%) was added slowly.
After stirring at 200C for
, CH2C12 (20 ml) and water (20 ml) were added.
organic layer was washed with water (3 x 15 ml),
dried (MgSO4) and evaporated. The
crude product was purified by column chromatography (silica,
CH2C12) to give a
yellowish solid (0.19 g, 96%),
2 x CH2N)
, 129.0, 128.8, 127.9, 115.1,
, 49.9; IR
= 2250.0 (-NC). Analysis for C12H14N20 (202.2): calc.
found C 71.00
1 -Phenylthio-2-methylpropyl isocyanide (2.7a):
This compound was prepared
as an oil
from 2.5a by the same procedure as 2.6.
1H-NMR (CDC13): 8
1.13 (d, 3H,
1.11 (d, 3H,
1 Hz, CH3)
= 2120 (-NC).
Cl1H13NS, calc. 191.0752
160.4, 139.1, 135.4, 133.9, 131.8,
a-(Isopropylthio)benzyl isocyanide (2.7c):
This compound was prepared as an
oil (74%) from 2.5c by the same procedure as 2.6.
1H, CH), 3.27 (m, 1H, CH),
1.43 (d, 3H, J
= 6.6 Hz, CH3),
191.0772; found 191.0770.
THIOALKYLATION OF REACTIVE AROMATIC COMPOUNDS
WITH a-(BENZOTRIAZOL-1-YL)BENZYL PHENYL SULFIDE
hydrogen atom in OH, SH, NH or CH compounds by a group CRR"NHCOR' is well
the synthesis of
However, the analogous concept of "thioalkylation", i.e.
the replacement of H in XH
by the group CRR"SR' is less familiar, but has previously been accomplished in a
RR"CSR'Y where Y is a leaving group:
phenyl sulfides (3.1)
ich participates in
electrophilic substitution of aromatic compounds to give the thioalkylation products
3.2 (Scheme 3.1). However, application of this method appears to be limited to cases
where at least one of the alkyl groups in RR"C is strongly electron-withdrawing, i.e.
corresponding sulfides with N-chlorosuccinimide [77MI51].
Lewis Acid / ArH
= OR: Treatment of trimethylstyrylsilanes with 1-ethoxy-1-(phenylthio)-
ethane (3.3) or 2-ethoxy-l,3-dithiolane (3.4) in the presence of Lewis acids gives allyl
sulfides 3.5 and 3.6, respectively (Scheme 3.2) [83BCJ1569], but the yields were low
The reaction of enol silyl ethers with 2-ethoxy-1,3-dithiolane (3.4) in the
only for some
methoxyethyl phenyl sulfide (3.8) does not generate the corresponding carbocation
[87BCJ3823, 87JOC5489], and no thioalkylation was observed.
mercaptal and ethyl orthotrithioformate (3.9) react with copper(II) chelates 3.13 of
1,3-dicarbonyl compounds, or with anisole in the presence of cupric chloride, to give
requirement for copper(II) salts for this thioalkylation has restricted its use. Moreover,
the case of anisole, the alkylthio group is often replaced by another anisole residue,
three products [69JA4315].
The sulfo-selenoacetals 3.10 are cleaved by butyllithium in THF
(-78 C) to give a-sulfo-carbanions,
which add to a variety of carbonyl compounds
Carbanions from deprotonation of a-(phenylthio)alkaneboronic esters 3.11 can
be acylated with methyl esters to form a-(phenylthio)ketones [78JA1325].
phenylthioalkylboronic esters themselves have to be made
dimethyl sulfoxide can be used for the (methylthio)methylation of phenols but gives
low yields (3
a-(benzotriazol-l-yl)alkyl phenyl sulfides, a new useful thioalkylation reagent,
various electron-rich aromatic compounds.
3.2 Results and Discussion
a- (benzotriazol-1 -yl)benzyl
The thioalkylation reactions were carried out in dry ether at reflux in
a-(benzotriazolyl)alkyl phenyl sulfides 3.18a and
active aromatic compounds
moderate to good yields.
These reactions and results are listed in Scheme 3.4 and
The active aromatic compounds used include anisole, dimethoxybenzene
nn A n, ni-i, nw. rn nfhti, ol anac' nhanalc nnA\C lI nnnbttrtc* or T~.,ana n.r*4ohn1 .k04..
nn~ m n)~ nvr m nnl\~l\ nlonno
N,N-dimethylaniline no sulfur containing product was isolated but a product similar to
replaced by N,N-dimethylaniline. Similar reactions have been reported [69JA4315].
PhSH / RCHO
benzene / p-TsOH
ArH / ZnBr
- MeC6H4 64
3.19 R Ar 3.19 R Ar
a Ph 4-MeOC6H4 f Ph 4-HOC6H4
b Ph 4-MeOCioH6 g Ph 2-Me-4-HOC6H3
c Ph 1-MeOC1oH6 h Ph 4-HOCloH6
d Ph 2-MeOC1oH6 i 4-MeC6H4 3,4-(MeO)2C6H3
e Ph 3,4-(MeO)2C6H3
'., A WV I L IU '-- 'l I tI *S*
w lL I
benzotriazolyl group with ZnClz greatly enhances its leaving ability, thus facilitating
For monosubstituted benzenes (anisole and phenol) the thioalkylation occurred
at the para-position as clearly shown by the typical signals for the para disubstituted
benzene in the 1H NMR spectra of the thioalkylation products (3.19a and 3.19f). The
thioalkylation of 2-substituted naphthalenes occurred at the 1-position as we compared
1-methoxynaphthalene reacted to give mainly the 4-substituted
isomers were separated by column chromatography and assigned by their 1H NMR
spectra. For the 4-substituted product 3.19b, the doublet of C4 proton at 7.60 ppm
[88MI1] disappeared and the doublet of C2 proton at 6.50 remained. By contrast, the
C4 proton was seen and C2 proton was replaced in the
1H NMR of the compound
The structures were characterized
by their elemental analyses or high
resolution mass spectra (Table 3.2) and by their 1H and 13C NMR spectral data. The
1H and 13C NMR chemical shifts and their assignments are listed in the experimental
section. In the 1H NMR spectra, typical singlets were observed at 5.38-6.72 ppm for
- 6.72 ppm), while those of other thioalkylation products occurred at higher field
- ~1 2-- -.an-.
(themselves easily available from benzotriazole, an aldehyde and thiophenol) to form
the thioalkylation products. Although the yields are moderate, the products are easily
thioalkylation reagents is advantageous in that our method gives similar yields under
reagents in being more easily prepared and/or more stable.
Melting points were determined on a hot stage apparatus and are uncorrected.
(300 MHz) NMR and
13C (75 MHz) NMR spectra were recorded on a
obtained from a Finnigan Mat 95. Column chromatography was performed with MCB
silica gel (230-400 mesh).
3.3.1 a-(Benzotriazol-1-yl)benzyl phenyl sulfide (3.18a)
A mixture of benzotriazole (3.6 g, 30 mmol), thiophenol (3.3 g, 30 mmol) and
benzaldehyde (3,2 g, 30 mmol) was refluxed in benzene (200 mL) in the presence of
p-toluenesulfonic acid (0.5 g) under a Dean-Stark head. After the collection of water
and thiol. Diethyl ether (300 ml) was added to the mixture and the organic
separated, washed with water, dried (MgSO4) and the solvent removed to give an oily
was recrystallized from Et20,
[91HCA1931] mp. 80
[(benzotriazol-1 -vl)(4-methylphenvl)1 methyl
, mp. 97-980C; 1H NMR(CDC13) 8 8.05 (d, J
= 8.0 Hz, 1H),
7.95 (d, J
= 8.0 Hz,
1H), 7.57 (m, 3H), 7.40 (t, J= 7
7.35-7.10 (m, 8H),
.29 (3H, CH3); 13C
132.1, 130.6, 129.4, 129.1, 128.9, 128.4,
127.7, 127.6, 127
124.3, 119.4, 111.3, 66.9, 20.7 (CH3). Analysis for C2oH17N3S (331.4): calc. C 72.48
found C 72.14
3.3.2 1 -(4-Methoxyphenyl)-1 -phenyl-1-phenylthiomethane (3.19a); Typical procedure
Anisole (0.54 g,
mmol) in dry ether (20 mL) was added to a solution of
a-(benzotriazol-l-yl)benzyl phenyl sulfide (3.18a, 1.59 g,
5 mmol) and zinc bromide
(1.4 g, 5 mmol) in dry ether (50 mL). The mixture was refluxed under argon for 10 hr,
cooled, filtered and the solvent removed under reduced pressure. The oily residue was
ether-petroleum ether to give colorless prisms.
IH NMR 8 7.40 (d,
7.35-7.13 (m, 10H), 6.80 (d, J =
3.72 (s, 3H)
13C NMR 8
, 141.2, 136.6, 133.0, 130.3,
129.4, 128.6, 12
Other thioalkylation products were prepared similarly
aromatics and compounds 3.18a or 3.18b.
1- (A-MPthnrv- 1 -nnnhthvll- 1 -nhpnvl- 1 -fnhp.nvlthinimp.th an.(3_1 9h
2H), 7.30 (m, 1H), 7.29-7.04 (m, 9H),
6.73 (d, J
= 8.1 Hz, 1H), 6.24 (s, 1H, CH),
13C NMR 8
, 132.4, 129
, 126.8, 126.6, 126.9, 124.9, 124.0, 123.3, 122.7, 103
1H NMR 8
3H), 6.77 (d, J
= 8.7 Hz, 1H), 7.88 (d, J
= 8.1 Hz, 1H),
= 7.8 Hz, 1H), 7.45-7
6.72 (s, 1H, CH), 6.59 (d, J
= 8.1 Hz, 1H),
13C NMR 8
,126.0, 124.8, 124.0, 122
1-(2-Methoxxy-1-naphthyl)- 1-phenyl-1-phenylthiomethane (3.19d):
1H NMR 8
3H), 7.39-7.26 (m, 5H), 7.24-7.06 (m, 8H),
NMR 8 157.6, 139.6, 134.4, 132.4,
5.42 (s, 1H), 3.79 (s,
.4, 126.6, 126.2, 123.4, 118
4-[Phenvl(phenvlthio)methyll- 1,2-dimethoxybenzene (3.19e):
1H NMR 8 7.31
= 7.8 Hz
,2H), 7.20-7.00 (m, 8H),
6.80 (d, J
= 8.4 Hz, 1H),
3.68 (s, 3H)
; 13C NMR
110.8, 56.9, 56.8,
4- rPhenyl(phenylthio)methyllphenol (3.19f):
1H NMR 8 7.40 (d, J
= 8.6 Hz
7.30-7.10 (m, 9H),
6.82 (d, J
4 Hz, 1H),
.37 (br, 1H, OH);
13C NMR 8 154.6
, 127.1, 126.5, 120.7
1H NMR 8 7.40-7.36
7.10 (m, 8H),
6.63 (m, 2H),
.65 (s, 1H, CH),
.30 (br, 1H, OH),
13 NMR 8
1 1() 01
4-fPhenyl(phenylthio)methyll -1 -naphthol
8.05 (d, 1H), 7.54 (d, 1H),
7.35-7.02 (m, 9H),
6.62 (d, 1H), 6.
23 (s, 1H,
5.94 (br, 1H, OH); 13C NMR
, 137.0, 132.1,
, 127.9, 127.1,
,124.9, 123.4, 122.
NMR 8 7.20 (d, J
=7.6 Hz, 2H),
7.13 (d, J
=7.8 Hz, 2H),
7.05-6.95 (m, 5H), 6.86 (s,
6.80 (d, J
6.61 (d, J
= 8.4 Hz,
1H, CH), 3.66 (s, 6H,
2 x OCH3),
16 (s, 3H, CH3)
, 147.9, 137.9,
, 136.3, 133
,120.4, 111.4, 110.8, 56.6,
, 55.6, 20.9 (CH3).
Table 3.1 Thioalkylation of Active Aromatic Compounds
.2 Microanalyses / HRMS data of Thioalkylated Products 3.19a-i
Analysis / HRM
HETEROARYLALKYLATION OF HETEROAROMATIC COMPOUNDS:
CONVENIENT NOVEL SYNTHESES OF 1,1-BIS(HETEROARYL)ALKANES
For example, difuryl-
and dithienyl- alkanes are flavor agents in coffee
chemistry as they are readily oxidized to the corresponding cyanine dyes
1,1-bis(heterocyclyl)alkanes are important
intermediates in total syntheses of porphyrins [78MI1]. The action of dichloromethyl
polycyclic heteroaromatic systems [73JCS(P 1)1099].
Several synthetic routes to bis-heteroarylmethanes 4.1 are known, but none is
symmetrical bis(heterocyclyl)methanes. Di-2-furylmethane has been prepared by the
However, most of these methods are limited to the preparation of
compounds in which an unsubstituted methylene group links the two heteroaromatic
pyrroles with free a-positions are susceptible to electrophilic attack by aldehydes or
[63AHC1]. However, this type of condensation generally requires a strong inorganic
catalyst, such as
75% H2S04 [51JA1377] or hydrochloric acid [56CJC1147].
[51JA1270] and degradation [72ACS1018] of the heterocyclic rings of substrates and
Unsymmetrical bis(heterocyclyl)methanes are far less explored, in fact some
heterocyclic ring systems, are not known.
to a limited number of
compounds of this class.
Perhaps the most
- -- .- ~ ~-L-- .L1.
cv-. a: -~
diheteroarylmethanes in 32-76%
yield [910PP403], however,
use of this reduction
method has been confined to the methylene derivatives (4.1, R = H). Moreover, the
N-methylindole in the presence of Lewis acids to give diarylacetic esters [92SL745],
but the starting materials are not easily available and
this method is not
Condensation of an a-acetoxymethylpyrrole with an appropriately substituted pyrrole
unsymmetrical dipyrrolylmethanes. However, the isolation of the product from tarry
reaction by products is tedious. Symmetrical pyrrolylmethanes are often formed as
75CC570], and the method is useful only for the fully substituted dipyrrolylmethanes
in order to avoid polymerization. Unsymmetrical difurylmethanes are obtained from
but this method is not general.
furan, thiophene, and pyrrole with furfuryl alcohol in
the presence of the strongly
2-furylhetarylmethanes [89KGS746], however,
the yields are low and
in this chapter
preparation of both symmetrical and unsymmetrical bis-heterocyclic alkanes via the
4.2 Results and Discussion
4.2.1 Condensation of Benzotriazole, Aldehydes and Carbamates
Mannich condensation of benzotriazole, an aldehyde, and a carbamate is
Thus the benzotriazole derivatives 4.2a,
4.2c and 4.2d were prepared by the
literature procedures in 84%, 78%, 74% and 69
yields respectively (see
(Scheme 4.1 ). The 1H and 13C NMR spectra of these benzotriazolylalkyl carbamates
and 4.3) indicated that they were all benzotriazol-1-yl isomers, furthermore
N-( 1-amidoalkyl)benzotriazoles [90JOC2206].
TsOH / Benzene
4.2.2 Preparation of Symmetrical Bis-heteroarvlalkanes
reacted smoothly with an excess amount of 2-methylthiophene or
benzotriazole and methoxycarbamoyl acted as leaving groups and each was replaced
occurred at the free a-positions of furan and thiophene as shown by the
spectra of the products.
N- (a-benzotriazol- 1-ylbenzyl)carbamate
a,a-di(5-methylfur-2-yl)toluene 4.4b in 65%
2-methylfuran in CH2Cl2
with zinc bromide as the ca
treatment with an excess of
italyst. However, the methyl
carbamate is a better reagent in light of the yield and the ease of product purification.
The five symmetrical 1,1-bis(heterocyclyl)methanes (4.3a-c, 4.4a-b) were all
previously unknown and were characterized by elemental analyses or high resolution
mass spectrometry and by 1H and 13C NMR spectra (Table 4.5 and 4.6).
4.2.3 Preparation of Unsymmetrical Bis-heteroarylalkanes
It is clear that the
departure of either benzotriazole or the alkoxyamido group with the assistance of the
remaining carbamate or benzotriazolyl group (via the iminium ion).
then attacks the electron-rich heterocycle ring to give a monosubstituted intermediate.
This process is repeated if
excess of the heterocycle is present in the solution to
intermediate should be formed. If it could be isolated, it should react further with a
different heterocyclic molecule, and provide a useful synthetic route to unsymmetrical
when methyl N-(a-benzotriazol-l-ylalkyl)carbamate 4.2a was treated
(thiophen-2-yl)-2-methylpropyl]carbamate 4.6, and the bis(thiophen-2-yl)alkane 4.3a
2-Methyl-5-[ 1-(benzotriazol-1 -yl)-2-methylpropyl]thiophene
; separated either by
or by recrystallization from
unsymmetrical bis-heteroaryl alkanes 4.7 and 4.8 in 92% and
yields (Table 4.7),
Jll_... ~ ~. l_~.lt_~ ~1.~..1_ _C I r Pr"
methoxycarbamoyl group is also a suitable leaving group and can also be substituted
2-methylfuran under the same conditions gave the expected product 4.7 in 95%
and with 2-methylpyrrole afforded the compound 4.8 in 65% yield (Scheme 4.5).
yl)-2-methylpropyl]carbamate 4.10 and
Treatment of the mixture of compounds 4.9 and 4.10 with 1-methylpyrrole in CH2C12
in the presence of zinc chloride at room temperature gave
The carbamate 4.2a reacted with
1-methylindole in a
ratio in CH2C12
[(a-benzotriazol- 1-yl)alkyl]indole 4.12
3-(a-thiophen-2-yl)alkylindole (4.14) respectively in excellent yields (Scheme 4.7).
0C to r.t.
reacting 4.2a with successive molar equivalents of 1- methylindole and 2-methylfuran
as illustrated in Scheme 4.8.
The proposed structures of the new unsymmetrical bis-heteroaryl alkanes 4.5,
4.7, 4.8, 4.11-4.14 were confirmed by NMR spectroscopy, elemental analyses or high
resolution mass spectrometry.
features of the NMR spectra of the benzotriazolyl substituted intermediates 4.5 and
4.12 indicated that they were the benzotriazol-1-yl regioisomers. For those products
containing either the 2-methylthiophene or 2-methylfuran moieties the two doublets (J
4.13 and 4.14 was indicative of substitution of the 3-position. Detailed assignments of
the NMR spectra are listed in Table 4.8, 4.9 and in the experimental section.
We believe that the reaction of a-benzotriazolylalkyl substituted heterocycles
with thiophene, furan or indole involved electrophilic attack by the carbocation of
1.4 which was stabilized by the heteroatom as illustrated in the introduction.
ionization of these benzotriazole derivatives.
reactions with a variety of heteroaromatics has provided a new and significantly more
convenient route to the corresponding bis-heteroarylalkanes. In addition to affording
good to excellent yields,
this novel methodology also incorporates the advantage of
simple removal of the benzotriazole auxiliary from the product mixture by extraction
with dilute base.
Melting points were determined
with a Kofler hot stage apparatus without
13C NMR spectra were taken at 300 and 75 MHz, respectively.
Tetramethylsilane was used as the internal standard for the 1H NMR spectra, and the
central line of CDC13 (5
= 77.0) or DMSO-d6 (5
= 39.5) was referenced in 13C NMR
4.3.1 N-(a-Benzotriazolvlalkyl)carbamates 4.2a, 4.2b, 4.2c and 4.2d
4.3.2 General Procedure for the Preparation of Symmetrical 1,1-Bis(heteroaryl)-
alkanes 4.3a, 4.3b, 4.3c, 4.4a and 4.4b
mmol) and zinc chloride (20 mmol) in dry methylene chloride (50
mmol) was stirred at room temperature overnight and poured into ice-water (50 ml).
The water layer was extracted with chloroform (2 x 20 ml).
layer was washed with NaOH solution (30 ml,
MgSO4 (10 mg).
The combined organic
and water (30 ml) and dried over
The solvent was evaporated and the residue was purified by column
chromatography (silica gel, CH2C12) to give the pure product (Table 4.4).
4.3.3 2-Methyl-5- 1l-(benzotriazol- 1-yl)-2-methylpropyllthiophene (4.5)
N-[ 1 -(benzotriazol- 1 -yl)-2-methylpropyl]-
56%). mp. 90-91C.
IH NMR (CDC13) 6 7.94 (d, J
= 8.3 Hz, 1H),
7.50 (d, J
= 8.3 Hz,
7.34 (t, J
= 8.1 Hz, 1H), 7
= 8.2 Hz, 1H), 6.85 (d, J
= 3.4 Hz, 1H), 6.45 (d,
= 3.4 Hz, 1H), 5.50 (d, J
1.01 (d, J
= 10.4 Hz
6.6 Hz, 3H, CH3),
.96 (m, 1H, CHMe2),
z, 3H, CH3)
2.28 (s, 3H,
13C NMR 8
, 132.4, 126.9, 126.6, 124.4, 123.6, 119.9,
, 66.1 (CH), 33.7
20.6, 20.5, 19.9.
Anal.Calcd for C15H17N3S: C,
6.31; N, 15.48.
chromatograpy (silica gel, CH2C12), it gave 4.3a (10%) and a mixture of 4.5 and 4.6
(59% and 16% respectively based on the 'H NMR).
4.4.4 1-Methyl-3-[1-(Benzotriazol-1 -vl)-2-methvlpropyl]indole (4.12)
1-Methylindole (10 mmol) was added to a mixture of
4.2a (10 mmol) and
ZnCl2 (15 mmole) in dry CH2C12 (40 ml) at 0C. The solution was stirred at 0C for
2h then allowed to warm to room temperature and stirring continued overnight. After
work-up as above, the product was purified by column chromatography (silica gel,
CH2C12). (yield 70%). mp.147-1480C,
1H NMR (CDC13) 8 8.00 (d, J
.2 Hz, 1H),
7.69 (d, J
= 8.0 Hz, 1H), 7.55 (d, J
= 8.4 Hz, 1H), 7.38-
(m, 3H), 7.18 (t, J = 6.7
7.08 (t, J
= 7.9 Hz
5.80 (d, J = 10.2 Hz, 1H, CH), 3.72 (s, 3H, CH3),
3.23 (m, 1H, CHMe2), 1.12 (d, J
= 6.6 Hz, 3H, CH3), 0.85 (d, J
6.6 Hz, 3H, CH3)
13C NMR 8
, 111.9, 109.9, 109.3, 62.9,
20.9, 20.1. Anal.Calcd for C19H20N4: C,
C, 75.03; H,
4.4.5 1-(5-Methylfur-2-yl)-1-(5-methylthiophen-2-yl)-2-meth ylpropane (4.7); Typical
procedure for Unsymmetrical 1,1-Bis(heteroaryl)alkanes 4.7, 4.8, 4.11, 4.13 and
To a solution of either compound 4.5 (2.6g, 10mmol) or a mixture of 4.5 + 4.6
(10mmol) in dry methylene chloride was added 2-methylfuran (0.82g, 10mmol) and
zinc chloride (1.4g, 10mmol).
The mixture was stirred at room temperature overnight
and worked-up as for the symmetrical derivatives. Similarly, 4.8 was prepared from
1-methylpyrrole and either 4.5 or the mixture of
4.5 + 4.6
compound 4.14 from 2-methylthiophene and 4.12 (Table 4.7).
4.4.6 One-pot Preparation of 1-(5-Methylfur-2-yl)-1-(1-methylindol-3-vyl)-2-methyl-
A mixture of 4.2a (10 mmol), 1-methylindole (10 mmol) and zinc chloride (10
2-Methylfuran (10 mmol) and zinc chloride (10 mmol) were added and the solution
stirred at the same temperature for an additional lOh.
The work-up procedure was as
Preparation of N-(1-benzotriazolylalkyl)carbamates
compd R R' mp(C) yield(%) molecular found (required)
formula C H N
4.2a iPr Me 118-120 84 C12HI6N402 58.05 6.53 22.44
(58.05) (6.50) (22.57)
4.2b Ph Me 123-124 78 C15H14N402 63.87 5.03 19.90
(63.82) (5.00) (19.85)
4.2c H Me 155-156 74 C9H1oN402 52.38 4.86 27.45
(52.42) (4.89) (27.17)
69.59 4.73 16.27
4.2d Ph Ph 162-164 69 C2oH6N402 69.59
(69.76) (4.68) (16.27)
1H NMR Data of N-(1-Benzotriazolylalkyl)carbamates 4.2
6.15(t, J=9.0, 1H),
(d, J=9,0) (t, J=
.4) (d, J
(d, J=6.6, 3H)
a Overlapped with Ph-H
Ca rr -) en
Uv 'a _'a
N '-00 N1
-~~o Go, 00 CMtf
'a en; 'a';Inc
'- ON( In ''vn0 I
I In tA v
o~ ON n en I
-4 en 001 C M
SU 4-4 -
Cuv- In ~.Otf
od C) '-4 -4
C() -l *
ON -4 -I -4
en U -
o~ cl 'ci" ON
N Nu N
Preparation of Symmestry 1,1-Bis(heteroaryl)alkanes 4.3, 4.4
HR MS / Analysis
Cpd Heteroaryl R mp Molecular found required Yield
(C) Formula C H C H (%)
4.3a 5-methyl- i-Pr 45 -46 C14H18S2 67.07 7.26 67.15 7.25 90
4.3b 5-methyl- Ph oil C17H16S2 284.0717 284.0694 94
4.3c 5-methyl- H oil C11H12S2 208.0380 208.0380 86
4.4a 5-methyl- i-Pr oil C14H1802 218.1304 218.1307 88
4.4b 5-methyl- Ph oil C17H1602 252.1167 252.1150 90
phenyl N-(1-benzotrazol-l-yl) carbamates 4.2d
1H NMR Data of Symmetrical 1,1-Bis(heteroaryl)alkanes 4.3, 4.4
Cpd heteroaryl 5-methyl CH R
4.3a 6.56(d,J=3.3Hz,2H), 2.38 3.89(d,J=9.0Hz) 2.17(m,1H,CHMe2),
4.3b 6.56(d,J=3.4Hz,2H), 2.39 5.66(s) 7.29(d,J=4.2Hz,2H)
4.3c 6.62(d,J=3.4Hz,2H), 2.40 4.16(s,2H,CH2)
4.4a 5.96(s,2H), 2.24 3.68(d,J=8.0Hz) 2.29(m,lH,CHMe2),
4.4b 5.80(s,2H), 2.02 5.28(s) 7.20-7.08(m,5H,Ph)
"C NMR Data of Symmetrical 1,1-Bis(heteroaryl)alkanes 4.3, 4.4
Cpd heteroaryl 5-methyl CH R
4.3a 145.5,137.7, 15.2 50.5 35.4(CH),21.3(CH3)
4.3b 145.1,138.9, 15.4 47.8 143.6,128.3,128.2,126.8
4.3c 141.1,138.4, 15.3 30.5 -
4.4a 153.2,150.2, 13.6 46.3 31.2(CH),20.7(CH3)
4.4b 152.7,151.2, 13.7 45.1 139.8,128.3,128.2,126.8
Preparation of Unsymmestrical 1,1-Bis(Heteroaryl)alkanes
HR -MS / Analysis
4.5 + 4.6
4.9 + 4.10
H NMR Data of Unsymmetrical l,l-Bis(Heteroaryl)alkanes
4.7-8, 4.11, 4.13-14
Cpd Het1 Het2 CH iPr
a 'IIm -U NrOT-I
13C NMR Data of Unsymmetrical 1,1-Bis(Heteroaryl)alkanes
Cpd Het1 Het2 CH iPr
INDOLYLALKYLATION. PART I:
VERSATILE SYNTHESIS OF 3-SUBSTITUTED INDOLES
important substances [91JMC 140,
89JMC890]. Accordingly, the
synthetic elaboration of the indole side chain at the 3-position has been employed as a
key step in the synthesis of related alkaloids.
extending functionalized carbon chains at C-3. However, both of these methods are
limited to the preparation of compounds
n which an unsubstituted methylene group
links the indole ring and the nucleophile.
N-heteroaromatics pyridinee and quinoline) followed by electrophile quenching is an
laboratory has succeeded in introducing functionality to the 2-alkyl side chain with
carbon dioxide [86JA6808], but few other methods are known for the metallation of
an alkyl group on C-2 [90JCS(P1)179].
We are aware of only two reports dealing with
both methods are confined
amide in liquid
ammonia [62BSF290] and (ii) sodium hydride [74KGS1502] gave a cyano stabilized
carbanion which was subsequently quenched by electrophiles.
Work in our laboratory has demonstrated that benzotriazole can sufficiently
to its electron-withdrawing
heterocycles in the synthesis of 1,1-bis-(heteroaryl)alkanes (also
see Katritzky et al
Of these derivatives the utility of 3-(benzotriazolylalkyl)indoles has
now been further extended to provide new routes to a wide range of 3-substituted
Results and Discussion
Our previous work has shown that
5.1a was readily available from the corresponding methyl N-(benzotriazol-l-ylalkyl)-
1-methylindole (see Chapter
Compound 5.1b was prepared in
yield by the same procedure (Scheme
1 and Table
1). However, this method
was limited to the preparation of compounds in which R was an alkyl group.
In order to explore the generality of this methodology, attention was turned to
functionalize the side chain at the 3-position.
We were unable to access 5.2 by the
nn.- .min,,r I, A oln.r4.aA nkr,, FCr C 1, lo qn n C lh nr1,cilm!hlxv hptr-aiie it i; rnnr rtiffkillt tn
compound 5.2 was prepared
benzotriazole and 1-methvlindole in 40% vield As we expected denrntnnntinn nf 5.2
chlorotrimethylsilane gave the corresponding alkylated and silylated products 5.1c
and 5.1d in yields of 95% and 93%, respectively (Scheme 5.1 and Table 5.1). Using
corresponding alcohol 5.1e and amide 5.1f in excellent yields (Scheme 5.1 and Table
spectrometry and by 1H and 13C NMR spectroscopy (Tables
5.3 and 5.4).
chemical shift of the methine carbon of 5.id was upfield of those of the alkylated
derivatives 5.1a-c and 5.1le-f, due to the shielding effect of silicon.
The presence of
the chiral center of 5.1e rendered the two phenyl groups non-equivalent as illustrated
by its 13C NMR spectrum, similar to the two methyl groups in 5.1la.
1 -methyl-3-(benzotriazol-1 -ylalkyl)indoles
can be displaced by a variety of nucleophiles. As exemplified by the reactions of 5.1a,
Compounds 5.3c (74%) and 5.3d (53%) were obtained by heating 5.la with
N,N-dimethylaniline or N-methylaniline respectively at
1500C. Noteworthy was the
fact that, in each case, the substitution occurred exclusively at the para-position of the
aniline moiety as shown by the AB pattern in the iH NMR spectra of the products.
- CN 5.4
singlet at ca 6.9 ppm for the 2-proton of the indole ring. An analogous result was
observed in the displacement of trimethylamine from 3-indolylmethylammonium salt
by cyanide ion [72CHE179].
3-Vinylindoles are important intermediates
for the synthesis of
and are readily
available from 3-(benzotriazol-l-ylalkyl)indoles.
la was heated at
1500C for two days, the product isolated displayed no benzotriazole resonances in the
NMR spectra. Furthermore,
the presence of a vinylic proton signal illustrated that
.2 and Table 5.5).
Its formation is likely to occur by El elimination via the
carbocation of type 1.4.
(Trimethylsilylmethyl)arenes have been recognized as versatile intermediates
example of the synthesis of (trimethylsilylmethyl)indoles.
While Ishibashi et al have
yields are low (highest 34%) [93SC2381]).
We now report a readily accessible and
1-benzotriazol-l-yl)methyl]indole (5.1d) with an excess of methylmagnesium iodide
in toluene at 80C for 5 h gave (1-trimethylsilylalkyl)indole (5.6) in excellent yield
5.3 and Table 5.5).
It is worthwhile to mention
that our attempts to replace the benzotriazolyl
group from 5.1e and 5. f were unsuccessful. Upon treatment with thiophenolate 5.1e
reverted back to its starting materials, 5.2 and benzophenone,
while the reaction of
On the other hand, treatment of 5.1f either with thiophenolate in refluxing ethanol or
with 2-methylfuran under Lewis acid conditions always led to the total recovery of
the starting materials. This result indicated that compound 5.1f is not reactive towards
nucleophilic substitution due to the existence of the electron-withdrawing group, the
amide group, which is in agreement with the carbocation mechanism discussed above.
Following a similar protocol,
a-indol-3-yl ketones, 5.7 and 5.8, were readily prepared in good yields
in one-pot by the subsequent addition of ZnBr2 to the reaction mixture of lithiated
cyclohexanone (Scheme 5.4, Table 5.5).
These results might be explained in terms of the formation of the carbocations
5.7b and 5.8b with the assistance of ZnBr2, and their subsequent rearrangements. In
n-BuLi / THF
1. n-BuLi / THF
The structures of indole derivatives 5.3a-d, 5.4, 5.5, 5.6, 5.7
and 5.8 were
confirmed by the 'H and 13C NMR data and by CHN microanalyses or high resolution
mass spectrometry. For 5.3a-d, the chiral center induced magnetic non-equivalence of
the two methyl groups in the adjacent iso-propyl group, as indicated by their 'H NMR
and / or 1C NMR spectra. Detailed assignments of the NMR data are given in Tables
5.6 and 5.7.
were determined with a
Kofler hot stage apparatus without
'H and 13C NMR spectra were recorded at 300 and 75 MHz, respectively.
Tetramethylsilane was used as the internal standard for the 'H NMR spectra, and the
central line of CDCl3 (6 =
77.0) or DMSO-d6 (6 =
) was referenced in the '"C
5.3.1 1-Methyvl-3-(benzotriazol-1-vlalkyl)indoles 5.1a and 5.1b
They were prepared by the literature procedure [Chapter IV and 93JOC4376].
5.3.2 General Procedure for the Preparation of 1-Methvl-3-(benzotriazol-1-ylalkyl)-
n-butyllithium (2.5 M in hexanes
.0 mmol) at
The solution was
78"C for 1 h, and a solution of the corresponding electrophile (5.0 mmol)
* r..- in 1' t .
* *s t. U l 't *~ -*~ .n n nn au)n n a nfl e~vg -nr a r.a km .t *I~ ao -U nl~o -
30 ml). The organic layer was then washed with H20 and dried (MgSO4). The solvent
chromatography (silica gel,
CH2C12) to give pure product.
5.3.3 1-Methvl-3-(benzotriazol-l-vlmethyl)indole 5.2
benzotriazole (6.7 g,
45 mmol) in toluene (150 ml) was refluxed for 40 h. After the
solvent was evaporated, the residue was purified by column chromatography (silica
gel, CH2C12) to give the pure product (40%),
.3.4 1-Methyl-3-(1-phenvlthio-2-methvlpropyl)indole 5.3a
To a solution of thiophenol (0.55
g, 5 mmol) and sodium metal (0.12 g, 5
mmol) in n-butanol (50 ml) 5.1a (0.91 g, 3 mmol) was added and the mixture refluxed
for 50 h. n-Butanol was removed under reduced pressure and the residue dissolved in
CH2C12 (30 ml), washed with water (2
x 10 ml) and dried (MgSO4).
The solvent was
: 1) to give the pure product (73%).
1-Methyl-3-( -ethyl-2-methvlropyvl)indole 5.3b
To a solution of 5.la (0.91 g, 3 mmol) in toluene (50 ml) was added a solution
with Et20 (3
x 30 ml).
layer was dried over MgSO4 and the solvent
The residue was purified by column chromatography (silica gel, hexanes)
to give a colorless oil (47%).
5.3.6 1-Methvl-3-[1-(4-N,N-dimethvlamino)phenvl-2-methyll proDvlindole 5.3c
To a small vial 5.la (0.4 g,
1.3 mmol) and N,N-dimethylaniline (0.24 g, 2
mmol) were added.
The mixture was heated in an oil bath at 1500C for
2 days and
then separated by column chromatography (silica gel, hexanes : ethyl acetate = 1 :1)
to give the pure product (74%).
5.3.7 1-Methvl-3-fl-(4-N-methvlamino)phenvl-2-methv lpropylindole 5.3d
To a small
vial 5.la (0.25
mmol) and N-methylaniline (0.13
mmol) were added.
The mixture was heated in an oil bath at 150C for
then separated by column chromatography (silica gel,
ethyl acetate = 3
to give the pure product (53%).
5.3.8 1-Methyl-2-cvano-3-(2-methylpropvl)indole 5.4
To a solution of 5.1a (0.6 g,
mmol) in DMF (40 ml) was added sodium
4 mmol). The mixture was stirred at 1300C for 50 h. Ethyl acetate (60
ml) was added and the mixture washed with water (4
x 40 ml).
The organic layer was
chromatography (silica gel, CH2Cl2
hexanes = 1 :1 ) to yield the pure product (60%)
as a colorless oil.
5.3.9 1-Methvl-3-(2-methvlpropen- 1-vl)indole 5.5
A solution of 5.1a (0.91 g, 3 mmol) in DMF (20 ml) was heated at 1500C for
days. Ethyl acetate (30 ml) was added and the mixture washed with water (3
x 30 ml).
layer was dried
(MgSO4) and the solvent removed.
The residue was
separated by column chromatography (silica gel, CH2C12
: 1) to afford
the pure product (50%) as a colorless oil.
5.3.10 1-Methyl-3-( 1-trimethylsilvlethyl)indole 5.6
To a solution of 5.1d (1.0 g, 3 mmol) in toluene (50 ml) was added a solution
of methylmagnesium iodide (8 mmol) in Et20O (10 ml).
The mixture was heated at
hours. The reaction mixture was then poured into saturated aqueous NH4C1
(40 ml), and the aqueous layer extracted with Et20 (3 x 30 ml). The organic layer was
dried over MgSO4.
The solvent was evaporated and the residue purified by column
chromatography (silica gel, hexanes) to give a white solid (90%).
5.3.11 f1-Methvl-3-(4-chlorobenzoyl)methyllindole 5.7 and [1-methyl-3-(2-oxocarbo-
heptvl)lindole 5.8; General procedure
THF (10 ml) was added.
The reaction mixture was stirred at this temperature for
further 2 h and a solution of ZnBr2 (0.95g,
4.2 mmol) in THF (10 ml) was added. The
to r.t. overnight and
aqueous work-up, the crude product was purified by column (silica gel, hexanes
: 1) to yield the pure product.
Table 5.1 Preparation of Adducts 5.1a-f and 5.2
Compd Yield Method mp
5.la d 70 b 147-148
5.lb 58 b 131-132
5.1c 95 c oil
5.1d 93 c 176-177
5.1e 91 c 214-215
5.1f 90 c 233-234
5.2 40 a 153-154
aCondensation of 3-methylindole with BtCH2OH.
b Condensation of 3-methylindole with N-(benzotriazol- l-yl)-
c Lithiation / eletrophile-quenching of 5.2
d Previously obtained and characterized (Chapter IV)
o\N 0d eno
Vd V t 'n V
'C ci 0 en 0
zcC; cd i ad
-C -r 'C
4) ~ \ VO V V it t)V
vN en cicc
~f'oc oorci c;
Vt t V
C ~~ c UZ Z
Z rJurZ Z Z
ci Vt 0' Vt3:31
U U UU U
o -d -1 -b -) -
C)r ()( r
00 9 en 6 &
ci (1 '-a
vrII Ca '-I- II c
CM e Nn *
enI II N
+- o II- 14
clm 00 tii '- -4I
en Nn N
r--N, -. In
O 4J *J/?
>1 N m -4S1-
E 'a'1 Ca '~ e
t-:~~I U II3 m3
in~I cI N-c~
ci -r-" Bj t
U' S.. U.m\do
C.) -N 'a uN en *,,,
-' 5- en'. QON;=dF
-I II 3,N 4 c
001 -c.l F'II ci d
en oE rr
o ~ I _
N ~-b I
0I a' 1
Z Ci -ci 3 5
-A -. U' ci5'
-4i '- 'S-- Ca O \\
C- en NI 00 CM 00
U' '0r ccaar
a ~ re 5
en en eni en e;vi
N o o n o
vi t~cc; en ent
N N\ -l -Q 0
'1CJ 0~ C( N
eND % 0
& NZ h~
en 0% cM y O
y;~.4 CMl CM 'C N N
(%4 c -i -I -1
tfl N enC tl-
o~\ ci enC -
CI 'C cih
-V UJ N1 -
en N\ c d r 5
*-- ci4 -
-S Inoo rLo o~ d
t n n 4 en 0 0 0 0 '
ON Njvi In; 'C In 0% Nj N
INDOLYLALKYLATION. PART II: A GENERAL AND FACILE
SYNTHESIS OF HETEROCYCLO[B]-FUSED CARBAZOLES
Heterocyclo[b]-fused carbazole systems
great importance as they
present in many natural products [88MI3, 85MI1]. Moreover, many heterocycle-fused
such as pyridocarbazoles
very interesting biological activities [88MI3, 86MI1673, 85MI1].
JOC1509], they usually used either
confined to indolocarbazole systems.
There are no general methods available in the
carbazole and furo[b]carbazole systems remain unknown previously.
inaccessibility is a possible explanation.
for the construction
heterocyclo[b]-fused carbazoles: indolo[b]carbazole, thieno[b]carbazole, and furo[b]-
1 -methyl-3-[(benzotriazol- -yl)-
versatility of benzotriazolylalkyl substituted heterocycles in the synthesis of 1,1-bis-
[(benzotriazol-1-yl)methyl]indole (5.2) has been especially extended to the synthesis
of a wide range of 3-substituted indoles as described in Chapter V
. Compound 5.2 has
now been further developed to provide an efficient route to various heterocyclo[b]-
6.2 Results and Discussion
The requisite 1-methyl-3-[(benzotriazol-l-yl)methyl]indole (5.2) was prepared
in 40% yield from 1-methyl indole as described in Chapter V.
One of the key steps to heterocyclo[b]-fused carbazoles 6.7 is the generation
directly from indoles has been well documented [53JA375, 73JOC3324, 89H745], the
at the side chain
to the electron
benzotriazolyl group as demonstrated by our previous observations (see Chapter V).
Regioselective bromination of 5.2 was readily accomplished
obtained in 81% yield. That this bromination is regioselective in the desired sense was
indicated by the disappearance of the 1H singlet (2-proton of indole) at ca 7.0 ppm in
the 'H NMR spectrum of 6.1.
Mel / HMPA
detectable side chain
tert-butyllithium (-780C, THF) resulted in the immediate formation of a deep brown
color due to the anion 6.2. After 5 min this solution was treated with thiophene-3-
carboxaldehyde and indole-3-carboxaldehyde respectively, followed by the protection
of the oxygen anion formed with methyl iodide and HMPA to give the intermediate
products 6.4a-e in excellent yields (Table 6.1). The structures of 6.4a-e are confirmed
by elemental analyses and NMR spectra data. In these compounds, the chiral center
induces magnetic non-equivalence of the two protons of the methylene group adjacent
to the benzotriazole and indole rings, as indicated by the two doublets at ca 6.0 ppm
As discussed in previous chapters,
various types of benzotriazole derivatives
reversibly ionize to yield the benzotriazolyl anion and the corresponding carbocations
presumably exist in equilibrium with ion pairs 6.5 under certain reaction conditions
which should react intramolecularly to furnish the cyclized products.
compounds 6.4 were very unstable in the presence of Lewis acid such
as zinc bromide even at low temperature (-100C) and immediately led to oligomers.
This result however is not very surprising as the existence of the Lewis acid greatly
After the unsuccessful attempts to cyclize under Lewis acid conditions,
examined high temperature methodology as a means with which to effect the desired
ionization and ring closure and we found that it was very successful.
the solution of compounds 6.4a-d respectively in
1,2,4-trichlorobenzene (ca 2160C)
carbazole (6.7c) and 5-methylfuro[2,3-b]carbazole (6.7d) in good yields (Table 6.2).
Compound 6.4e is less stable and more reactive than 6.4a-d and its cyclization was
envisioned to proceed via intramolecular cyclization to form intermediates 6.6,
undergo aromatization in situ by losing a molecule of methanol to afford the desired
products 6.7. Fused carbazoles 6.7a-d are new and thieno[3,2-b]carbazole,
unknown tetracyclic condensed systems.
Their structures (see Scheme 6.3) are fully
supported by elemental analyses and NMR spectra data (see experimental section).
1H singlets (4,10-protons) in
the region of 7.4-8
ppm in the
5,11-Dimethylindolo[3,2-b]carbazole (6.7e) is known previously [76LA1090] and its
structure is also confirmed by CHN analysis and NMR spectra data (see experimental
indicative of the symmetrical structure of the indolo[3,2-b]carbazole 6.7e.
It is worthwhile to mention that our attempted cyclization from compound 6.3,
protection of the oxygen anion as shown in Scheme 6.1, was unsuccessful and no pure
compound 6.7a was isolated although trace of the product was detected by 1H NMR
The existence of the labile hydroxy group might be responsible for the
In conclusion, a general,
facile route to heterocyclo[b]-fused carbazoles has
been developed, simply starting from 1-methylindole. One obvious attractive feature
of this synthetic approach is that by appropriate choice of the heteroaryl aldehydes a
of heterocyclo[b]-fused carbazoles can
- a- .- a a r rr ~
r 5a "N 4a N
6 5| 4
5a N 4a
6 5| 4
S.; a-sN- 4a v 3a C
6 5I 4 3
s 4a'N a ( "a 6hb N
4 i5 6 7
was distilled under nitrogen immediately
from sodium / benzophenone. All reactions with air-sensitive compounds were carried
out in argon atmospheres.
Column chromatography was conducted
with silica gel
prepared according to previous procedure (see Chapter V).
6.3.1 1 -Methvl-2-bromo-3-r(benzotriazol-1 -vl)methvllindole(6.1):
methylene chloride (100 ml)
mmol, 1.3 g) in methylene chloride (30 ml) at 0C. After addition was
finished, the reaction mixture was further stirred at 0C
for 45 mm. Cold sodium
bicarbonate solution (5%,
70 ml) was added.
The organic layer was further washed
with sodium bicarbonate solution (5%,
70 ml), then water. After drying over MgSO4,
the solvent was evaporated. The crude product was purified by washing with hot ethyl
acetate (20 ml) to give the pure compound in 80% yield. mp 145-146 C; 1H NMR 8
3.71 (s, 3H,
CH3), 5.96 (s, 2H, CH2), 7.04-7.07 (m,
1H, In), 7.15-7.27 (m, 3H, Bt and
In, overlapped), 7.30-7.35 (m, 1H,
= 8.0 Hz, 1H, In), 7.63 (d, J
(d, J = 8.0 Hz, Bt);
1"C NMR 8 31.5 (CH4),
44.3 (CH2), 107.9 (In),
109.4 (Bt), 110.0 (In),
115.0 (In), 118.5 (In), 119.7 (In), 120.6 (Bt), 122.5 (In), 123.6
.3.2 1-Methyl-2- r(1-hydroxy- 1-thien-3-yl)methvll-3-r(benzotriazol- 1-yl)methyll-
To a solution of
(3.5 mmol, 1
g) in THF (40 ml) was added tert-BuLi (4.2
.5 ml, 1.7 M in
petane) at -780C under argon.
mm, thiophene-3-carboxaldehyde (4.2 mmol,
0.47 g) in THF (8 ml) was added dropwise. The reaction mixture was stirred at -780C
2 h and quenched with water.
The organic layer was washed with water and dried
: ethyl acetate
: 1) to afford pure product (91
H NMR 8 3.34 (s,
5.32 (d, J
= 4.7 Hz, 1H,
.63 (d, J
70 (d, J
= 4.7 Hz, 1H, OH), 6.87-7.08 (m,
, Bt, In, and thiophene),
7.29 (d, J
.2 Hz, 1H,
7.42 (d, J
= 7.9 Hz, 1H, In),
7.60 (d, J
13C NMR 8 30.5 (NCH3),
42.3 (CH2), 64.8 (CH),
105.9 (In), 109.3 (In),
123.7 (Bt), 126.0 (2C,
Anal. Calcd for C
6.3.3 General Procedure for the Preparation of Intermediate Products 6.4a-e:
To the solution of 1-methyl-2-bromo-3-[(benzotriazol-l-yl)methyl]indole (6.1)
(3.5 mmol, 1
THF (40 ml) was added tert-BuLi (4.2 mmol,
5 ml, 1.7 M in
-,norq a._. Arx rt .. r IA fl -l !--I,..11 I
Methyl iodide (1.7 ml) and HMPA (30 ml) were then added. The mixture was allowed
to warm to room temperature and stirred overnight.
After aqueous work-up,
product was subjected to column chromatography (hexanes
: ethyl acetate
give pure compound.
indole 6.4a: 1H NMR 8 3.18 (s,
3.54 (s, 3H, OCH3),
6.05 (d, J
6.14 (d, J
Hz, 1H, CHBt),
6.69 (d, J
= 5.0 Hz,
1H, thiophene), 6.90 (d, J
= 4.3 Hz,
, Bt, In, and
= 7.7 Hz, In, 1H),
Bt, 1 H)
42.6 (CH2), 56.5 (OCH3),
(Bt), 118.3 (In),
119.7 (In), 120.3 (Bt), 121.5 (thiophene),
123.6 (Bt), 125.9
indole 6.4b: 1H NMR 8 3.61 (s,
.91 (d, J
1H, furan), 6.03 (s,
6.04 (d, J
5.4 Hz, 1H, CHBt),
6.11 (d, J
= 15.4 Hz,
7.06 (d, J
7.18-7.29 (m, 6H,
Bt, In, and furan),
7.36-7.39 (m, 1H, Bt),
7.76 (d, J
1H, Bt); 13C NMR 8
42.5 (CH2), 56.3 (OCH3), 70.8 (CH),
107.7 (In), 108.9 (furan),
139.5 (furan), 143.2
IUA ,A 1 tn *r%, C. f4 n TrrlTr % r-
I' nr rl t
1 1A tt
1H, thiophene), 6.76 (m,
7H), 7.74 (d, J
= 7.6 Hz, 1H,
In), 7.93-7.96 (m, 1H, Bt);
13C NMR 8 30.9 (NCH3),
(In), 109.4 (In), 109.9 (Bt), 118.4 (In),
120.3 (Bt), 122.6 (In),
123.5 (Bt), 124.4 (thiophene), 1
135.5 (In), 137.3 (In), 143.1 (thiophene),
'H NMR 6 3.26 (s,
3.75 (s, 3H, OCH3),
2H, CHBt and thiophene, overlapped), 6.14 (d, J
.5 Hz, 1H,
21-6.23 (m, 1H, thiophene),
7H, Bt, In,
7.67 (d, J
= 7.9 Hz, 1
= 6.9 and
"13C NMR 8 30.9
[1-methoxvy- 1-(1-methylindol-3-vl)1methyl}-3- (benzotriazol-
1H NMR 8 3.23 (s,
.99 (d, J
6.14 (d, J
7.43 (d, J
= 8.1 Hz, 1H,
Bt), 7.72 (d, J
= 7.7 Hz, 1H,
Hz, 1H, Bt)
13C NMR 8 31.0 (NCH3), 3
42.9 (CH2), 56.5 (OCH3),
119.7 (In), 120.3 (Bt),
126.5 (In, 2C),
127.5 (Bt), 132.6 (Bt), 136.7 (In),
137.3 (In, 2C), 146.0 (Bt).
1,2,4-trichlorobenzene (40 ml) (for 6.4a-d) or in
6.4e) was refluxed under argon for 48 h. The solvi
dichlorobenzene (40 ml) (for
ent was evaporated and the residue
was subjected to column chromatography (hexanes
: methylene chloride
give pure product.
H NMR 8 3.80 (s, 3H, CH3), 7.18-7.23
= 7.7 Hz, 1H, 8-H),
8.08 (d, J
C NMR 8 28
, 112.4, 117.8, 119.3,
,130.4, 137.4, 139.1,
5-Methvlfuror3,2-blcarbazole 6.7b: 1H NMR 8 3.79 (s,
7.86 (d, J
7.21 (t, J
= 7.7 Hz, 1H,
= 7.7 Hz, 1H,
7.47 (t, J
= 7.7 Hz, 1H, 7-H), 7.69 (d,
Hz, 1H, 2-H), 8.10 (d, J
, 9-H), 8.15 (s,
1H, 10-H); I
C NMR 8 29.
, 121.4, 1
5-Methvlthienof2,3-b1carbazole 6.7c: 'H NMR 8 3.79 (s,
7.43 (d, J
= 5.5 Hz, 1H,
2-H), 7.49 (t, J
= 7.5 Hz, 1H, 7-H), 7.76 (s, 1H,
= 7.5 Hz,
"13C NMR 8 29
'H NMR 8 3.8
, 3H, CH3),
6.88 (d, J
= 8.0 Hz, 2H, H-4,10),
= 7.8 Hz, 2H, H-1,7)
"3C NMR 8 29.4 (2CH3), 98.6
122.9 (C-6a, C12a),
ci 'n c: 'n; 0
z a; Ini v;vi
ci i I vi
Ur ~ I 5 6
Cd c: -4 N
U ON ON ON '
U &- 6 ad 6
'-4 V N V N
C.)~tf c 0I
r 00 N M
N CM cM CM CM
00 t6 Z fl O
0. -- 4 -
-E I I I I
en ci ci en
I Ij Id Id Id
'n 'n oR 0
V1 Cz V~ C
Cl CM Crl Cl
U~r vi n
I -n en C- V
C)r 00j Cl 00- C'f
r'A '.6 oRoo
Ua N nCN0
N 00 NO 0 00
C)o U) 0 ( 0
-- zc z\ z
ON Cl 00 Nr c
I Ii \l ON \
wide spectrum of useful organic compounds, a-functionalized isonitriles,
l,l-bis(heteroaryl)alkanes, 3-substituted indoles and heterocyclo[b]-fused carbazoles,
have been synthesized via benzotriazole mediated heteroalkylation and arylalkylation
prepared and the benzotriazolyl group can be displaced subsequently by a wide range
of nucleophiles proves this methodology to be general and facile.
The reference system used here is that from the book series "Comprehensive
designated a number-letter coding of which the first two numbers denote tens and
units of the year of publication, the next one to three letters denote the journal, and the
final numbers denote the page.
This code appears in the text each time a reference is
Some commonly used additional notes are given below:
The list of reference is arranged in order of (a) year, (b) journal in alphabetical
order of journal code, (c) part letter or number if relevant, (d) volume number
if relevant, (e) page number.
In the reference list the code is followed by the complete literature citation in
the conventional manner.
For journals which are published in separate parts, the part letter of number is
volumn numbers are not included in the code numbers unless more
than one volume was published in the year in question, in which case the
volume number is included in parentheses immediately after the journal code
Patents are assigned appropriate three letter codes.
Frequently cited books are assigned codes, but the whole code is now prefixed
by the letter "B-"
Less common journals and books are given the code "MI" for miscellaneous.
Where journals have changed names, the same code is used throughout.
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