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Carbonylation of Amino Amides and Amines to Ureas and Formamides

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Title:
Carbonylation of Amino Amides and Amines to Ureas and Formamides
Creator:
Johns, Jennifer Ilene
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[Gainesville, Fla.]
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Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
MCELWEE-WHITE,LISA ANN
Committee Co-Chair:
VEIGE,ADAM S
Committee Members:
APONICK,AARON
MILLER,STEPHEN ALBERT
PERCIVAL,SUSAN S
Graduation Date:
12/13/2013

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Subjects / Keywords:
Amides ( jstor )
Amines ( jstor )
Amino acids ( jstor )
ATMs ( jstor )
Carbamates ( jstor )
Catalysts ( jstor )
Chromatography ( jstor )
Formamides ( jstor )
Hydantoins ( jstor )
Solvents ( jstor )
Chemistry -- Dissertations, Academic -- UF
carbonylation -- dihydrouracil -- formamide -- hydantoin
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bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Chemistry thesis, Ph.D.

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Abstract:
W(CO)6-catalyzed oxidative carbonylation ofamines to ureas provides an alternative to stoichiometric reaction of amineswith phosgene or its derivatives such as 1,1-carbonyldiimidazole (CDI). Due tothe successful synthesis of a range of cyclic targets employing W(CO)6 as catalyst, CO as the carbonyl source, and I2 as oxidant, alpha- and beta-amino amides were explored as carbonylation substrates to afford hydantoins and dihydrouracils. Hydantoins were synthesized in moderate to good yields with substitution at the amide and C-5 position. Carbonylation of beta-amino amides proved to be sensitive to substitution at the beta-alkyl position, as the beta-alkyl and aryl substituted substrates resulted in acyclic urea formation, whereas a-alkyl substitution or no substitution resulted in carbonylation to the dihydrouracil.The catalytic method was also expanded to the synthesis of unsymmetrical diarylureas that were previously inaccessible from carbonylation of aniline substrates. Reaction scope was successfully extended to new classes ofbiologically active molecules with hydantoins, dihydrouracils, and diarylureas. Base-mediatedcarbonylation of amines to formamides provides a metal-free alternative synthesis which does not involve high temperatures or stoichiometric amounts of formic acid. The optimized reaction conditions for the synthesis of formamides from benzyl amines were 35 atm CO and 3 equivalents of K2CO3in methanol solvent for 7 h at room temperature. A reaction time of 24 hensured the reaction completed for less reactive substrates. Carbonylation toformamides had reasonably broad substrate scope including primary, cyclicsecondary, and substituted benzylamines. Electron rich benzylamines proved tobe the most reactive and gave the best yields ( en )
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In the series University of Florida Digital Collections.
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Includes vita.
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Includes bibliographical references.
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This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: MCELWEE-WHITE,LISA ANN.
Local:
Co-adviser: VEIGE,ADAM S.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-12-31
Statement of Responsibility:
by Jennifer Ilene Johns.

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Embargo Date:
12/31/2015
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LD1780 2013 ( lcc )

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1 CARBONYLATION OF AMI NO AMIDES A ND AMIN ES TO UREAS AND FORMAMIDES By JENNIFER ILENE JOHNS A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILL MENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2013

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2 2013 Jennifer Ilene Johns

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3 In all things Christ preeminent.

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4 ACKNOWLEDGMENTS I would like to thank my adviso r Professor McElwee White for her guidance support, and for undoubtedly shaping the way in which I go about chemistry in the way she let me wrestle through obstacles and focused me when I needed it. I would also like to thank the rest of my committee for their time, stimulating discussion, and support. I must also acknowledge my fellow McElwee White group member s who were a constant source of solidarity and camaraderie. I will always be happy to have been a been helped by wonderful undergrads, Caroline Hoyt and Brian Vincent who brought enthusiasm to lab and shared my passion for Gator sports. To Sarah Goforth who shared my passion for singing, pumpkin flavored anything, and LOST in addition to chemistry an d Ciera Gerack who broadened my movie tastes, was always willing to go on a Du date, and is st ill a source of loyal friendship both were with me from the beginning to end, despite the need to phone in their support now. I am also indebted to Philip Shelton and Seth Dumbris who took me in both as a chemist and a friend from the guidance, I know that I am a better chemist, and also have gained a lifelong friendship. To my other chemistry friends, I must thank them for keeping me sane. Randi Price was always there to bounce ideas off, whether it was chemistry or source of distraction. And I am so blessed to have had Abby Shelton as a friend as she managed me through my f irst major graduate school hurdle while navigating her last. I am also forever thankful for her ability to stop me from burning things down when my brain became too full of chemistry to remember how to cook.

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5 I would be remiss if I did not thank my family, my parents Bob and Pam Johns who have been supportive and encouraging over the years. They instilled a desire for learning and figuring out the unknown that has been crucial to my success as a chemist. They also both have endured many a late night phone c all that bemoaned chemistry and ones where chemistry simply was talked at them. Their prayers, I am certain have made as much a difference in my graduate school success as any bit chemistry knowledge I have gained. Also I would like to thank my siblings J ustin and Christy fellow scientists in their own right with whom both my relationship s have grown in getting to share our UF experiences. And to Christy who, here at the very end, has endured my insanity, clutter, and constant need to have sports on. She has helped me even through her own craziness, and I cannot wait to stand beside her in a ceremony far more exciting than getting a PhD.

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6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURES ................................ ................................ ................................ ........ 10 LIST OF ABBREVIATIONS ................................ ................................ ........................... 13 ABSTRACT ................................ ................................ ................................ ................... 14 CHAPTER 1 TRANSITION METAL CATALYZED OXIDATIVE CARBONYLATION ................... 16 Background ................................ ................................ ................................ ............. 16 Palladium Catalysts ................................ ................................ .......................... 17 Nickel Catalysts ................................ ................................ ................................ 19 Cobalt Catalysts ................................ ................................ ............................... 20 Carbonylation of Amines Using Tungsten Cat alysts ................................ ............... 21 Carbonylation of Primary Amines to Acyclic Ureas ................................ .......... 23 Carbonylation of Primary and Secondary Diamines to Cyclic Ureas ................ 24 Conclusion ................................ ................................ ................................ .............. 33 2 CATALYTIC OXIDATIVE CARBONYLATION OF AMINO AMIDES TO FORM HYDANTOINS AND DIHYDROURACILS ................................ ............................... 34 Background ................................ ................................ ................................ ............. 34 Classic and Recent Methods to Synthesize Hydantoins ................................ ......... 34 Synthesis of Hy Amino Amides .............. 39 Hydantoin Conclusions ................................ ................................ ........................... 42 Classic Ways to Synthesize Dihydrouracils ................................ ............................ 43 Synthesis of 5,6 Dihydrouracils by Catalytic Oxidative Carbonylation .................... 46 Results and Discussion ................................ ................................ ........................... 49 Benzouracils ................................ ................................ ................................ ........... 54 Dihydrouracil and Benzouracil Conclusions ................................ ............................ 57 3 OXIDATIVE CARBONYLATION OF ARYL AMINES TO UNSYMMETRICAL DIARYL UREAS ................................ ................................ ................................ ..... 58 Background ................................ ................................ ................................ ............. 58 Carbonylation to Unsymmetical Ureas ................................ ................................ .... 62 Conclusions ................................ ................................ ................................ ............ 66 4 BASE MEDIATED CARBON YLATION OF AMINES TO FORMAMIDES ............... 68

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7 Background ................................ ................................ ................................ ............. 68 Transition Metal Free Carbonylation of Amines to Ureas ................................ ....... 72 Transition Metal Free Carbonylation of Amines to Formamides ............................. 73 Conclusions ................................ ................................ ................................ ............ 82 5 EXPERIMENTAL SECTION ................................ ................................ ................... 83 Synthesis of and Amino Amides for Oxidative Carbonylation .......................... 83 General Procedures ................................ ................................ ......................... 83 General Procedure A for the Synthesis of Amino Amid es 7 10 ..................... 83 ( S ) 2 Amino N methyl 3 phenylpropionamide (7) ................................ ...... 83 ( S ) 2 Amino N ethyl 3 phenylpropionamide (8) ................................ ......... 84 ( S ) 2 Amino N isopropyl 3 phenylpropionamide (9) ................................ .. 84 ( S ) 2 Amino N benzyl 3 phenylpropionamide (10) ................................ .... 84 General Procedure B for Carbonylation of Amino Amide (7) ......................... 85 (S) 5 Benzyl 3 methylimidazolidine 2,4 dione (7a) ................................ .... 85 (S) 5 Benzyl 3 ethylimidazolidine 2,4 dione (8a) ................................ ....... 85 (S) 5 Benzyl 3 benzylimidazolidine 2,4 dione (9a) ................................ .... 86 Preparation of A mino Amide (11) by MAC ................................ .................... 86 Deprotection of amino amide 11 to afford 12 ................................ ................ 87 (S) 3 Benzyl 5 (hydroxymethyl)imidazolidine 2,4 dione (12a) ................... 87 3 (( tert butoxycarbonyl)amino) 3 phenylpropanoic acid (13) ..................... 88 General Procedure C for N Boc Protection of Amino Acid s to Form 15 ........ 89 3 (( tert butoxycarbonyl)amino) 4 phenylbutanoic acid (16) ....................... 90 3 (( tert butoxycarbonyl)amino) 4 methylpentanoic ac id (17) ...................... 90 3 (( tert butoxycarbonyl)amino) 2 methylpropanoic acid (18) ..................... 91 General Procedure D for Mixed Anhydride Coupling of Amino Acid 8 to Form 19 ................................ ................................ ................................ ......... 91 3 (( tert butoxycarbonyl)amino) N benzyl butanamide (20) ........................ 92 3 (( tert butoxycarbonyl)amino) N benzyl 4 phenyl butanamide (21) ......... 93 3 (( tert butoxycarbonyl)amino) N benzyl 4 phenyl butanamide (22) ......... 93 3 (( tert butoxycarbonyl)amino) N benzyl 4 methyl pentanamide (23) ....... 93 3 ((tert butoxycarbonyl)amino) N benzyl 2 methyl propanamide (24) ....... 94 General Deptrotection Reaction E to afford 3 amino N benzyl butanamide (25) ................................ ................................ ................................ ................ 94 3 amino N benzyl butanamide (26) ................................ ........................... 95 3 amino N benzyl 3 phenyl propanami de (27) ................................ .......... 96 3 amino N benzyl 4 phenyl butanamide (28) ................................ ............. 96 3 amino N benzyl 4 methyl pentanamide (29) ................................ ........... 97 3 amino N benzyl 2 methyl propanamide (30) ................................ ........... 97 Amino Amides 25 30 to Form 25a 30a ................................ ................................ ................................ ......... 98 Urea (26a) ................................ ................................ ................................ .. 99 Urea (27a) ................................ ................................ ................................ .. 99 Urea (28a) ................................ ................................ ................................ 100 Urea (30a) ................................ ................................ ................................ 100 General MAC pro amino amide (31) ................. 101

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8 3 (( tert butoxycarbonyl)amino) N methyl butanamide (32) ...................... 102 Synthesis of Unsym metic Ureas ................................ ................................ ........... 103 General Procedure A for the Catalytic Carbonylation of p Substituted Aryl Amines ................................ ................................ ................................ ........ 103 N,N' diphenylurea (41a) ................................ ................................ ................. 103 1 (4 Cyanophenyl) 3 (4 nitrophenyl)urea (42hi). ................................ ............ 103 Ethyl 4 (3 (4 nitrophenyl)ureido)benzoate (42hj). ................................ ........... 104 1 (4 Chlorophenyl) 3 (4 methoxyphenyl)urea (42be). ................................ .... 104 1 (4 Chloro 3 (trifluoromethyl)phenyl) 3 (4 methoxyphenyl)urea (42pe). ....... 105 1 (4 Chlorophenyl) 3 (4 phenoxyphenyl)urea (42bf). ................................ ..... 105 1 (4 C hloro 3 ( t rifluoromethyl) p henyl) 3 (4 p henoxyphenyl) u rea (42pf). ........ 106 1 Methyl 1,3 D iphenylurea (42aq). ................................ ................................ 106 1 M ethyl 3 (4 p henoxyphenyl) 1 p henylurea (42fq). ................................ ...... 106 3 (4 C hloro 3 ( t rifluoromethyl) p henyl) 1 m ethyl 1 p henylurea (42pq). ........... 107 1 (4 Chlorophenyl) 3 (4 methoxyphenyl)urea (42be, authentic sample). ....... 107 1 (4 Chlorophenyl) 3 (4 p henoxyphenyl) u rea (42bf, authentic sample). ........ 108 General Procedure for Carbonylation of Amines to Formamides .......................... 108 Procedure A ................................ ................................ ................................ ... 108 Procedure B ................................ ................................ ................................ ... 109 Procedure C ................................ ................................ ................................ ... 110 Procedure D ................................ ................................ ................................ ... 111 Formamide Products ................................ ................................ ............................. 111 N (4 Nitrobenzyl)formamide (67). ................................ ................................ ... 111 N (4 Methylthio)formamide (47). ................................ ................................ .... 112 N (4 Methylbenzyl)formamide (49). ................................ ................................ 112 N (4 Vinylbenzyl)for mamide (51). ................................ ................................ ... 112 N (4 Fluorobenzyl)formamide (55). ................................ ................................ 113 N (4 Iodobenzyl)formamide (57). ................................ ................................ ... 113 N (4 Bromobenzyl)formamide (59). ................................ ................................ 113 N (4 Chlorobenzyl)formamide (61). ................................ ................................ 114 Methyl 4 (formamidomethyl) benzoate (63). ................................ .................... 114 N (4 Formamidomethyl)benzoic acid (65). ................................ ..................... 115 N (4 Nitrobenzyl)formamide (67). ................................ ................................ ... 115 N (4 (Trifluromethyl)benzyl)formamide (69). ................................ .................. 115 N (4 Cyanobenzyl)formamide (71). ................................ ................................ 116 N Formy lpyrrolidine (82). ................................ ................................ ................ 116 N Formylmorpholine (82). ................................ ................................ ............... 116 N Formylpiperazine (86). ................................ ................................ ................ 117 N Propylformamide (72). ................................ ................................ ................ 117 N Isopropylformamide (74). ................................ ................................ ............ 117 N Isobutylformamide (76). ................................ ................................ .............. 117 N Tertbutylformamide (78). ................................ ................................ ............ 118 N Cyclohexylformamide (80). ................................ ................................ ......... 118 LIST OF REFERENCES ................................ ................................ ............................. 119 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 128

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9 LIST OF TABLES Table page 1 1 Oxidative carbonylation of prim ary amines to ureas under optimized conditions ................................ ................................ ................................ ........... 24 1 2 Tungsten catalyzed oxidative carbonylation of substituted primary diamines .... 27 1 3 Tungsten catalyzed catalytic carbonylation of substituted benzylamines to ureas ................................ ................................ ................................ .................. 29 1 4 Tungsten catalyzed oxidative carbonylation of aminoalcohols to ureas and carbamates. ................................ ................................ ................................ ........ 31 2 1 Optimization of carbonylation conditions for 25 to form 25a ............................... 50 2 2 Yields of 26a 29a ................................ ................................ ................................ 52 2 3 Yields of 31 36 from MAC and deprotection reactions ................................ ....... 53 3 1 Oxidative carbonylation of various aryl amines to symmetrical N, N` diarylureas using the W(CO) 6 / I 2 catalyst system. ................................ .............. 61 3 2 Carbonylation of anilines to unsymmetrical ureas. ................................ ............. 62 3 3 Synthesis of trisubstituted aryl ureas. ................................ ................................ 66 4 1 Optimization of carbonylation of 43 to 45 without NaIO 4 ................................ .... 78 4 2 Functional group compatibility ................................ ................................ ............ 79 4 3 Carbonylation of secondary amines to formamides. ................................ ........... 81 4 4 Carbonylation of primary amines to formamides. ................................ ............... 82

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10 LIST OF FIGURES Figure page 1 1 Oxidative carbonylation of alkylamines using PdI 2 and KI. ................................ 17 1 2 Mechanism for the Pd catalyzed conversion of primary amines to ureas. .......... 18 1 3 Pd catalyzed carbonylation of phenols, thiophenols, and anilines. ..................... 19 1 4 Nickel catalyzed rea ction of amines to ureas and oxamides. ............................. 19 1 5 bis(salicylidene)ethylenediamineocobalt(II). ................................ ............... 20 1 6 Cobalt catalyzed reaction of aryl amines to ureas with TBD promoter. .............. 21 1 7 Catalytic cycle for carbonylation of amines by tungsten dimer 1 ....................... 22 1 8 W(CO) 6 catalyzed reaction or primary and secondary amines to cyclic ureas. ... 25 1 9 Carbonylation of gem dialkyl diamines. ................................ .............................. 26 1 10 Subs tituent study of the W(CO) 6 /I 2 catalyzed carbonylation of benzylamines. ... 28 1 11 Carbonylation of diamines with protected alcohols to form DMP 323 and DMP 450 core structure. ................................ ................................ ..................... 32 1 12 Synthesis of biotin methyl ester using the W(CO) 6 /I 2 catalyst. ............................ 32 2 1 Hydantoin ring numbering system. ................................ ................................ ..... 34 2 2 Synthetic approaches to hydantoins. ................................ ................................ .. 35 2 3 Four component, one pot synthesis of hydantoin. ................................ .............. 36 2 4 Synthesis of hydantoins and thiohydantoins. ................................ ...................... 36 2 5 Solvent free synthesis of hydantoins. ................................ ................................ 37 2 6 Proposed mechanism for DBP mediated synthesis of hydantoins. .................... 37 2 7 Solid state and microwave synthesis of hydantoins. ................................ ........... 38 2 8 ................................ ................................ ............... 39 2 9 Retrosynthetic analysis of hydantoins. ................................ ............................... 40 2 10 Synthesis of amino amides from amino ester hydrochlorides. ............................ 40

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11 2 11 Synthesis of hydantoins 7a 10a amino amides 7 10 .............................. 40 2 12 amino acid to hydantoin. ................................ ..... 41 2 13 Synthesis of hydantoin 12a ................................ ................................ ................ 42 2 14 5,6 Dihydrouracil. ................................ ................................ ............................... 43 2 15 Synthesi s of 5,6 dihydrouracils using unsaturated carboxylic acids. ............ 44 2 16 Solid Phase Organic Chemistry synthesis of 5,6 dihydrouracils. ........................ 44 2 17 L selectride re duction of uracils to form 5,6 dihydrouracils. ................................ 45 2 18 Retrosynthetic analysis of 5, 6 amino acid. ........................ 46 2 19 N Boc protection in acetonitrile. ................................ ................................ .......... 47 2 20 N amino acids in t BuOH and NaOH. ................................ ... 48 2 21 amino amides 19 24 ................................ .................. 48 2 22 Deprotection of N Boc amino amides to afford 25 30 ................................ ........ 49 2 23 General carbonylation reaction of amino amide 25 ................................ ........... 49 2 24 Carbonylation of substrates 26 29 to form 26a 29a using optimized conditions from 29a ................................ ................................ ........................... 52 2 25 Amino N methyl amide synthesis and carbonylation, R= H, Me, Ph. .................. 53 2 26 W(CO) 6 catalyzed carbonylation of 30 ................................ .............................. 54 2 27 Synthesis of 38a and 37a ................................ ................................ .................. 55 2 28 Synthesis of anthranilamide derivatives. ................................ ............................ 5 6 2 29 Attempted carbonylation of 39 ................................ ................................ ........... 56 3 1 General scheme of unsymmetrical urea synthesis. ................................ ............ 58 3 2 (a) Unsymmetrical urea synthesis from thrifluoroethyl carbamate. (b) One pot unsymmetrical urea synthesis ................................ ................................ ........... 59 3 3 Oxidative carbonylation of various p substituted aryl amines to symmetric N, N diarylureas ................................ ................................ ................................ ..... 60 3 4 Carbonylation of ani lines to unsymmetrical ureas. ................................ ............. 62

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12 3 5 Structure of sorafenib. ................................ ................................ ........................ 64 3 6 Synthesis of unsymmetrical ureas with CDI. ................................ ...................... 65 3 7 Attempted Carbonylation of N Methylaniline. ................................ ...................... 65 4 1 Formylation with formic acid and CDMT. ................................ ............................ 69 4 2 Formylation of amines by methyl formate and catalyst. ................................ ...... 69 4 3 N formylation of amines with formic acid and sulfated tungstate catalyst. .......... 70 4 4 Ru catalyzed reaction of dialkyl amine to formamide in methanol. ..................... 72 4 5 Oxidative carbonylation of 43 forming 44 and 45 ................................ ............... 73 4 6 Optimized conditions for urea synthesis using NaIO 4 and NaI. .......................... 73 4 7 Possible outcomes for incorporation of 13 C from labeled methanol. ................... 74 4 8 Incorporation of deuterium from deuterated methanol. ................................ ....... 75 4 9 Proposed mechanism for the base mediated pathway to formamides. .............. 76

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13 LIST OF ABBREVIATIONS atm Atmospheres CDI Carbonyldiimidazole DBU 1,8 Diazabicyclo[5.4.0]undec 7 ene DCC Dicyclohexylcarbodiimide DCE Dichloroethane DCM Dichloromethane DMAP 4 (Dimethylamino)pyridine DMDTC Dimethyldithiocarbamate DMF Di methylformamide DMSO Dimethylsulfoxide MAC Mixed Anhydride Coupling MW Microwave irradiation NHC N Heterocyclic carbene NMM N Methylmorpholine ppm Parts per million Pyr Pyridine SEM [ 2 (Trimethylsilyl)ethoxy]methyl TBD 1,5,7 Triazabicyclo[4.4.0]dec 5 ene TEMPO (2,2,6,6 Tetramethyl piperidin 1 yl)oxyl TLC Thin layer chromatography

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14 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 Ph ilosophy CARBONYLATION OF AMI NO AMIDES AND AMINES TO UREAS AND FORMAMIDES By Jennifer Ilene Johns December 2013 Chair: Lisa McElwee White Major: Chemistry W(CO) 6 catalyzed oxidative carbonylation of amines to ureas provides an alternative to stoichiome tric reaction of amines with phosgen e or its derivatives such as 1, 1 carbonyldiimidazole (CDI). Due to the successful synthesis of a range of cyclic targets employing W(CO) 6 as catalyst, CO as the carbonyl source, and I 2 amino amides w ere explored as carbonylation substrates to afford hydantoins and dihydrouracils. Hydantoins were synthesized in moderate to good yields with substitution at the amide and C amino amides proved to be sensitive to substitution alkyl and aryl substituted alkyl substitution or no substitution resulted in carbonylation to the dihydrouracil. The catalytic method was also expanded to the synth esis of unsymmetrical diaryl ureas that were previously inaccessible from carbonylation of aniline substrates. Reaction scope was successfully extended to new classes of biologically active molecules with hydantoins, dihydrouracils, and diaryl ureas. Base mediated carbonylation of amines to formamides provides a metal free alternative synthesis which does not involve high temperatures or stoichiometric

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15 amounts of formic acid. The optimized reaction conditions for the synthesis of formamides from benzyl ami nes were 35 atm CO and 3 equivalents of K 2 CO 3 in methanol solvent for 7 h at room temperature. A reaction time of 24 h ensured the reaction completed for less reactive substrates. Carbonylation to formamides had reasonably broad substrate scope including p rimary, cyclic secondary, and substituted benzylamines. Electron rich be n zylamines proved to be the most reactive and gave the best yields.

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16 CHAPTER 1 TRANSITION METAL CATALYZED OXIDATIVE CARBONYLATION Background Carbonylation is an important synthetic t echnique for the incorporation of carbon monoxide into an organic substrate. The use of transition metal catalysts to carbonylate heteroatom substrates is an attractive synthetic route from an atom economy standpoint which facilitates green chemistry techn iques 1 3 Products of transition metal catalyzed carbonylation reactions include ureas, 4 6 carbamates, 2 7 10 urethanes, 11 12 oxamides, 13 16 formamides, 17 21 benzoimidazoles, 22 and oxa zolidinones 23 from a wide range of rep orted catalysts such as Mn 6 24 Fe, 25 Co, 23 26 29 Ni, 16 30 Ru, 18 31 32 Rh, 33 34 Pd, 35 39 W, 4 40 47 Pt, 48 Ir, 48 and Au. 49 50 These reactio ns typically involve moderate to high pressure of CO, resulting in efforts to explore more mild conditions. Specifically the synthesis of ureas ha s garnered interest due to the presence of the moity in pharmaceuticals 51 54 agrochemicals, resin precursors, dyes 55 and additives of petrochemicals and polymers. 56 Traditionally, ureas have been synthesized from isocyanates phosgene, and phosgene derivatives. 57 However, substantial drawbacks are associated with both isocyanates and phosgene due to their toxicity. Ph osgene, while cost effective and efficient for the synthesis of ureas, is a highly toxic corrosive gas that requires specialized techniques to minimize damage to equipment and keep personnel safe. 58 While phosgene deriva tives such as 1,1 carbodimidazole (CDI), triphosgene, and dimethyl dithiocarbamate (DMDTC) are much safer for use, they are limited to a laboratory scale due to their cost and increased waste stream associated with 2 equivalents of their leaving groups. Is ocyanates which also suffer from the disadvantage of toxicity, are often synthesized from phosgene.

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17 Palladium Catalysts Palladium is the most commonly utilitzed transition metal for oxidative carbonylation reactions. Instances of homogeneous catalysis, 59 61 catalysis in ionic liquids, 62 63 and electrocatalytic carbonylation 64 have been reported in the literature. Oxidative c arbonylation using Pd complexes is typically attributed to reduction of Pd(II) to a Pd(0) species which can be reoxidized in the presence of an external oxidant. The first reports of Pd catalyzed oxidative carbonylation of alkylamin es using CO were documented by Fukuoka 48 and Chaudhari. 65 Using a heterogeneous Pd/C system with iodide salts as p romoter and O 2 as an oxidant, alkylamines were carbonylated to urea and carbamates in good yields. Gabriele more recently reported similar findings using a homogeneous PdI 2 catalyst This reaction was optimized to afford high yields of ureas and cyclic car bamates 66 with turnover numbers of over 4900 (Figure 1 1) 67 Figure 1 1. Oxidative carb onylation of alkylamines using PdI 2 and KI. A study by Shimizu and Yamamoto examined the reoxidation of the Pd(0) species in the catalytic cycle of carbonylation of am ines to ureas and oxamides. 13 Mechanistic studies on the palladium catalyzed reaction of amines to ureas suggest that a carbamoyl palladium c omplex is a crucia l intermediate. When O 2 or DCB was used as the oxidant, reductive elimi nation of two carbamoyls afforded oxamides When I 2 was used as the oxidant, amines were carbonylated to their corresponding urea. Two possible mechanism s for urea synthesis were propos ed. The first mechanism involves the carbamoyl intermediate which undergoes reductive eliminat ion with an amido ligand to afford the urea. The second possibility had literature precedent in a proposal by

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18 Gabriele. In this mechanism, an alkyl isocyanate is formed from the N monoalkylcarbamoyl species which can then be attacked by a primary or secondary amine to afford a symmetric or unsymmetic urea (Figure 1 2 ). When diamine substrates are carbonylated to cyclic ureas, it is suggested that the carbamoyl comp lex experiences intramolecular nucleophilic displacement to produce the urea. Figure 1 2 Mechanism for the Pd catalyzed conversion of primary amines to ureas. Troisi has reported the use of Pd(OAc) 2 catalyst to carbonyl ate to benzo fused five and six membered heterocycles (Figure 1 3 ) 68 The reaction was run at high temperatures of 100 110 C and modest pressure of 27 a tm CO along with Et 3 N and PPh 3 in THF. Ortho substituted phenols, thiop h enols, and anilines afforded five membered rings in moderate to excellent yields. Lowest yields were observed with o p h enylenediamines even at increased reaction times. Synthesis of si x membered rings was achieved in only poor to moderate yields, presumably due to the decreased nucleophilicity of the anionic sulfamidic NH group responsible for nucleophilic attack.

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19 Figure 1 3 Pd catalyzed carbonylation of p h enols, thiop h enols, and an ilines. Nickel Catalyst s Nickel is another transition metal that has the ability to form carbamoyl complexes and therefore is considered for carbonylation chemistry. 30 Oxamides were originally reported as the product of nickel catalyzed carbonylation of amines. However, Gian dialkylureas from aliphatic primary amines with Ni(II) complexes. 16 At temperatures above 50 C decomposition and side reactions become competitive with carbonylation. However, at lower temperatures the necessary reductive elimination to the oxamide did not occur. Sele ctivity of the reaction was observed to be dependent on the amount of water present. Anhydrous conditions yielded oxamides, whereas ureas were obtained in the presence of water (Figure 1 4 ). It was postulated that water in the system coordinated to the Ni catalyst and allowed for only one carbamoyl to coordinate to the metal. 16 This intermediate was susceptible to nucleophilic attack by the amine to give the urea. Without water, two carbamoyls could form and reductively eliminate to afford the oxamide. Figure 1 4 Nic kel catalyzed reaction of amines to ureas and oxamides.

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20 Cobalt Catalysts Ureas have been effectively synthesized from primary aryl and aliphatic amines as well as secondary aliphatic amines by Co(salen) (figure 1 5) catalyst. 69 70 Aryl amines with electron withdrawing groups experienced lower conversions and yields than those with electron donating sub stituents. 28 Cyc amino a lcohols in high yields. 23 Catalyst recovery was enhanced by covalently bonding Co(salen) to a silica gel matrix via sol gel process. When anilines were carbonylated in methanol only a 60% yield was achieved, but catalyst could be re cycled up to 5 times with little loss in activity. 71 Figure 1 bis(salicylidene)ethylenediamineocobalt(II) A recent improvement on Co(salen) catalyzed reaction of amines to carbamates was reported by Saliu through the use of cyclic nitrogen containing organobases as promoters (Figure 1 6 ) 29 Amines were reacted in methanol with a mixture of CO/O 2 and heterocyclic base promoter. Selectivity for carbamates was observed in methanol at a temperature of 100 C. At lower temp erature (60 C) conversion dropped for all tested substrates, and the corresponding urea became the major product. Use of toluene as solvent gave only ureas as products. With 4 fluoroaninile as the optimization substrate, all heterocyclic base promoters in creased the yield of the urea from the yield without promoter DMAP performed the best, but the TBD promoted reaction had a nearly identical yield while also being a less toxic, more environmentally friendly base than DMAP. Yiel ds for carbamates and ureas increased (>80%) upon addition of TBD for

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21 primary aryl, primary aliphatic, and secondary aliphatic amines when subjected to carbonylation conditions. Figure 1 6 Cobalt catalyzed reaction of aryl amines to ureas with TBD promoter. Carbonylation of A mines U sing T ungsten Catalysts While transition metal catalyzed carbonylation reactions are quite common as previously discussed, reactions involving group 6 metals are still rare. The McElwee White group initially reported the carbonylation of amines when the iodo bridged dimer of [(CO) 2 W(NPh)I 2 ] ( 1 ) was reacted in stoichiometric amounts of amine to produc e monomer 2 that was t hen oxidized when exposed to ambient air (Figure 1 7) 72 This reaction utilized the CO ligand present in the metal complex to carbonylate primary and secondary amines to ureas and formamides respectively. A catalytic version was easily achieved by providing a source of CO to regenerate the meta l complex after ca rbonylation and release of the product from the complex To devise a catalytic variant of the initial reaction, dimer 1 was used as a precatalyst to convert amines to ureas 72 Reaction with two equivalents of the amine gave the monomer with the coordin ated amine while an additional two equivalents resulted in a second amine replacing an iodide ligand to afford the cationic tungsten complex 3 (Figure 1 7 ) The carbonyl ligand in 3 is susceptible to nucleophilic attack by excess amine in solution to obtai n the carbamoyl species 4 after proton abstraction Indication for this step is seen by an IR stretching frequency of 2066 cm 1 in 3 which is high enough for nucleophilic attack on the carbonyl Evidence of a carbamoyl was

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22 observed for both n butylamine a nd piperidine by FT IR which is consistent with a variety of catalytic carbonylation systems such as palladium cata lyzed reactions 3 13 Precedent for tungsten carbamoyls w as documented by Angelici in the carbonylation of methylamine with 5 C 5 H 5 )W(CO) 4 ]PF 6 The carbamoyl species was formed after two equivalents of amine reacted with the cationic species [( 5 C 5 H 5 )W(CO) 4 ] + to give the carbamoyl complex ( 5 C 5 H 5 )W(CO) 3 (CONHCH 3 ). 74 Figure 1 7. Catalytic cycle for carbonylation of amines by tungsten dimer 1 The following step in the catalytic cycles is assumed to be oxidation due to the disappearan ce of carbamoyl 4 upon exposure to air. Oxidation should make the carbamoyl proton more acidic for deprotonation by amine in solution, allowing for the

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23 formation of an isocyanate intermediate 5 though no spectroscopic evidence was seen Attack on either t he coordinated or the free isocyanate by amine affords the urea along with the catalyst with an empty coordination site 6 This site can be filled with carbon monoxide to regenerate 3 and complete the catalytic cycle. Carbonylation of Primary Amines to Acy clic Ureas Based on these observations, it was theorized that different tungsten iodide species would be suitable to catalyze carbonylation of amines. Control reactions with bromide and chloride tungsten carbonyl complexes showed no activity and confirmed that iodide was crucial to the reaction. The examination of W(CO) 6 as a catalyst was chosen for its low cost, commercial availability, and stability in air which contributed to its ease of use over other catalysts. Initial reactions were assessed using W( CO) 6 100 equivalents of n butylamine, 50 equivalents of iodine, and 100 equivalents of K 2 CO 3 in a 125 mL Parr high pressure autoclave pressurized to 100 atm with CO. Di n butylurea was synthesized in 80% yield which corresponded to a turnover number of 39 for the W(CO) 6 The reactions conditions were then optimized using n propylamine. Once the ideal catalyst loading of 2 mol% was found other parameters were examined. Chlorinated solvents such as CHCl 3 and CH 2 Cl 2 worked the best with solvents such as ace tonitrile and THF having diminished yields probably due to coordination with the catalyst. The optimal conditions were 1.5 equivalents of K 2 CO 3 0.5 equivalents of I 2 80 atm CO, at 90 C. Control reactions with Mo(CO) 6 and Cr(CO) 6 confirmed that tungsten w as the best catalyst despite being a third row transition metal. The inclusion of a base was crucial to prevent the formation of amine hydro iodide salts that would deplete the starting material, making it unavailable for carbonylation. Primary alkyl and ar yl amines

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24 were subjected to t hese conditions and achieve d good to excellent yields for the alkyl amines (Table 1 1) 42 A niline could not be carbonylated under the given conditions presuma bly due to its decreased nucleophilicity. Table 1 1. Oxidative carbonylation of primary amines to ureas under optimized conditions Amine Product %Yield in CH 2 Cl 2 90 84 53 55 72 0 Carbonylation of P rimary a nd S econdary D iamines to C yclic U reas Common methods for the conversion of diamines into cyclic ureas ar e based on nucleophilic attack on the carbonyl in phosgene or phosgene derivatives in stoichiometric amounts. In terms of transition metal catalysts, pa rticularly with CO, the research is limited. The m anganese carbonyl catalyst, Mn 2 (CO) 10 was tested in the carbonylation of diamines H 2 N(CH 2 ) n NH 2 and only achieved successful formation of the cyclic urea when n = 3 Even then, the six membered ring only g ave a 6% yield. 75 Another metal car bonyl catalyst, Ni(CO) 4 catalyzed the synthesis of 2 imidazolidinon e in 10% yield as the minor side product. 76 Additional techniques involving direct carbonylation of secondary amines to cyclic u reas are uncommon, with deprotonation of

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25 the urea followed by N alkylation being more prevalent. Due to these limitations the catalytic carbonylation of diamines to cyclic ureas using W(CO) 6 as the catalyst, I 2 as the oxidant, and CO as the carbonyl source was investigated Both primary and diamines were used as starting material and were found to yield the corresponding N N disubstituted cyclic ureas (Figure 1 8) Figure 1 8 W(CO) 6 catalyzed reaction or primary and secondary amines to cyclic ureas. Primary diamines were su ccessfully carbonylated to the corresponding five six and seven membered rings in moderate to good yields. 40 Only trace amounts of the eight membered ring were detected which is consistent with the fact that t here are no literature reports for the synthesis of the urea from 1,5 pentanediamine. Highest yields were observed for the six membered ring at 51%. Additionally, a chiral 2 imidizolidinone derivative was synthesized from (+) (1R,2R) 1,2 diphenyl 1,2 ethan ediamine in 46% yield. Secondar y diamines RNHCH 2 CH 2 NHR (F igure 1 8 ) were carbonylated in yields very similar to their primary counterparts when R = Me, Et and Bn. However when R = i Pr the reaction was suppressed and the yield dropped to 10%, revealing tha t sterics can inhibit the reaction in the instance of bulky groups Reactions were conducted at room temperature and increasing the temperature resulted in negli gi ble change in the overall yield of the di substituted ureas. In all substrates submitted to th e reaction conditions, o ligo merization was competitive with cyclization ; therefore high dilution was used to limit these side products a technique which is also used in conjunction with phosgene based methods. 77

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26 Steric effects on carbonylation of diamines was further explored by examining the effect of substitution on the linker carbons ( Figure 1 9 ) These types of gem dialkyl diamines can take advantage of the Thorpe Ingold effect t o push the terminal amines closer to one another and provid e better orientation for cyclization. 78 The additional alkyl groups also i ncrease the solubility of the substrate s in dichloromethane therefore promoting higher yields. For six membered rings substituted with dimethyl and diphenyl groups, yields dramatically increased to 80% and 70% respectively (table 1 2) The g em dibenzyl substituted gave a compa rable yield to that of the unsubstitu t ed 1,3 propanediamine. A s drastic of an effect was not seen with five membered rings, due probably to the increased steric bulk around the amine that has been shown to lower yields in alkyl amines. Most interestingly, the eight membered ring which was only observed in trace amounts when unsubstituted along the linker was synthesiz ed in 38% yield with ethyl, buty l substitution at the C 3 position Figure 1 9. Carbonylation of gem dialky l diamines. In contrast to the similar yields previously achieved with secondary diamines, the introduction of steric bulk along the linker resulted in much lower yields in the range of 10 30%. The gem dialkyl secondary diamines were seen to show preferenc e to the synthesis of tetrahydropyrimidine derivatives under reaction conditions when groups larger than methyl were present on the amine position. Control experiments revealed that the side reaction proceeded without the presence of W(CO) 6 and CO.

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27 Table 1 2 Tungsten catalyzed oxidative carbonylation of substituted primary diamines Amine Product % Yield 52 80 70 48 50 33 38

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28 The success in synthesizing cyclic ureas suggested that W(CO) 6 /I 2 could be a possible attractive alternative for synthesizing more complex targets. However, before these could be explored, functional group compatibility of the catalyst needed to be probed as it is often an issue with transition metals This was accomplished using para substituted benzyl amines to eliminate any intramolecular interaction betwe en the additional moiety and the reactive amine. The study showed the reaction to be tolerant of a broad range of function al groups including halides, esters, nitriles, thioesters, and alkenes 42 Of particular interest, the catalyst was tolerant of an unprotected alcohol, forming the urea with no carbamate or carbonate side products. This is in contrast to phosgene derivatives which typically s how a mixture of products w hen reacted with amines that also contain unprotected alcohols. While using the initial set of optimized conditions with DCM as the chosen solvent, yields for ureas were low to moderate at best. However, switching to a biphasic solvent system of DCM/H 2 O helped solubilize all of the components of the reaction, catalyst, starting material, base, and amine salts (Figure 1 10 ) Under t hese phase transfer conditions, h ydroiodide salts of the starting material in the aqueous phase could be deprotonated by the base (K 2 CO 3 ) and return ed to the organic phase to be carbonylated as the free amine This allowed for drastic increase s in yield ra nging from 30 to 50% with most substrates affording good yields of their corresponding urea (Table 1 3 ) Figure 1 10 Substituent study of the W(CO) 6 /I 2 catalyzed carbonylation of benzylamines.

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29 Table 1 3. Tungsten c ata lyzed catalytic carbonylation of substituted benzylamines to u reas Amine %Yield a,b CH 2 Cl 2 %Yield a,c CH 2 Cl 2 /H 2 O Amine %Yield a CH 2 Cl 2 %Yield b CH 2 Cl 2 /H 2 O 63 73 36 55 35 77 0 37 30 77 41 69 39 70 45 76 47 70 37 68 24 81 28 14 5 58 17 20 0 0 a Reacti on conditions: amine (7.1 mmol), W(CO) 6 (0.14 mmol), I 2 (3.5 mmol), K 2 CO 3 (10.7 mmol), CH 2 Cl 2 b The solvent was CH 2 Cl 2 (21 mL) plus H 2 O (3 mL). Other conditions are as in footnote b. In order to better understand the lim itations of the W(CO) 6 /I 2 catalyzed method, amino alcohol substrates were tested for their reactivity and selectivity of products. 44 While initial functional group scope with benzyl amines revealed an exclusive preference for the urea, th is was not observed when the possibility of intramolecular carbonylation to the carbamate was an available reaction pathway. Reactions were examined for urea, carbonate, cyclic carbamate, and acyclic carbamate products from 1,2 1,3 1,4 and 1,5 amino alcohols. To aid in purification and workup, the base for

PAGE 30

30 the reaction was switched to pyridine. Carbonylation of 5 aminopentanol afforded no acyclic carbamate, only 2% yield of the 8 membered ring carbamate, and 64% yield for the urea, with CDI and DMDTC having comparable selectivity. For 4 amino methylbutan 1 ol, all three methods showed selectivity for the urea with no carbamate despite attempts to take advantage of ring closure by a methyl group on the linker. Various 1 ,3 amino alcohols were tested wit h alkyl and aryl substitution at all three positions of the carbon chain. The W(CO) 6 /I 2 catalyzed reaction performed the best when benzyl branching was on the same carbon as the amine. Urea was afforded in 95% yield with only trace amounts of cyclic carbam ate (Figure 1 4) In contrast the CDI reaction produced the carbamate as the major product in 60% yield. While DMDTC gave preference to the urea it only achieved a 30% yield. When branching was moved t oward the hydroxyl using 1 phenyl 3 aminopropanol sel ectivity decreased for W(CO) 6 /I 2 with a urea to carbamate ratio of 5:1.This result was still better than the CDI based reaction ratio of urea to carbamate or 3:2. DMDTC preferentially afforded the carbamate. The gem dimethyl amino a l cohol was used as a sub strate that would promote ring closure Surprisingly W(CO) 6 and CDI reactions resulted in more urea and DMDTC gave both products in approximately equal yields. Synthesis of the 5 membered rings from 1,2 amino alcohols gave the highest carbamate yields for the W(CO) 6 /I 2 catalyzed reaction but only 10 14%. DMDTC performed best yielding only trace amounts of the carbamate but urea yields were comparable to the W(CO) 6 catalyzed reaction.

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31 Table 1 4. Tungsten catalyzed oxidative carbonylation of aminoalcohols to ureas and carbamates. Substrate Reagent Urea (%) Cyclic Carbamate (%) W(CO) 6 /CO 64 2 CDI 80 Trace DMDTC 45 0 W(CO) 6 /CO 93 0 CDI 70 Trace DMDTC 93 0 W(CO) 6 /CO 95 Trace CDI 36 60 DMDTC 30 8 W(CO) 6 /CO 72 14 CDI 49 30 DMDTC 34 47 W(CO) 6 /CO 60 5 CDI 55 28 DMDTC 32 29 W(CO) 6 /CO 78 10 CDI 18 22 DMDTC 72 Trace W(CO) 6 /CO 79 14 CDI 30 52 DMDTC 73 Trace Once the broad functional group tolerance was established, synthetic targets were chosen i n light of the ability of W(CO) 6 /I 2 to catalyze amines to urea through oxidative carbonylation. Core structures of DMP 323 and DMP 450, two HIV protease inhibitors, contain the urea moiety that could be installed used the W(CO) 6 /I 2 catalyzed

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32 reaction (Figu re 1 11) 43 Current techniques involve the use of phosgene or phosgene derivatives to install the carbonyl in these sub strates. When W(CO) 6 /I 2 reaction is compared with that of CDI yields are similar, with both methods showing a variation dependent on the identity of the protecting group present on the diol. While W(CO) 6 /I 2 catalyzed reaction had previously show n tolerance to unprotected alcohols, yields were much higher when protecting groups were utilized. Figure 1 11 Carbonylation of diamines with protected alcohols to form DMP 323 and DMP 450 core structure Another bi o logical target containing th e cyclic urea moiety is biotin. Initial attempts under a variety of conditions to synthesize biotin from the ammonium salt were unsuccessful possibly due to insolubility of the starting mater ial since carboxylic acids were already observed to compatible with this catalyst Further support was seen when attempts to carbonylate 6 aminocaproic acid only resulted in trace amounts of the urea with 90% of the starting material recovered. However, sw itching to the methyl ester of 6 aminocaproic acid improved solubility and the corresponding urea was synthesized in 70% yield. When the methyl ester derivative of biotin was targeted, the desired urea was afforded in 84% yield (Figure 1 12 ) 79 F igure 1 12 Synthesis of biotin methyl ester using the W(CO) 6 /I 2 catalyst

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33 Conclusion Transition metal carbonylation of amines offers efficient methods to synthesize ureas and many other important targets through the use of CO as the carbonyl source. This alternative to synthes e s involving stoichiometric amounts of toxic or costly reagents such as phosgene and its derivatives provides a much greener and safer option. Transition metal catalysts of Pd, Ni, Co, and W have been successfully used in catalytic o xidative carbonylation. Tungsten catalyzed reactions have been very effective in synthesizing ureas from amines, showing good functional group tolerance as well as being effective in the synthesis of more complex targets containing the urea moiety.

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34 CHAPTE R 2 CATALYTIC OXIDATIVE CARBONYLATION OF A MINO AMIDES TO FORM HYDANTOINS AND DIHYDROURACILS Background Cyclic ureas, including derivatives of the five membered ring hydantoin are important moieties for a variety of biologically active molecules. Hydantoin s compose the core structure of molecules with properties ranging from anticonvulsant, 80 antidepressant, 81 82 antiviral, 81 82 antibacterial, 81 her b icidal, 83 and platelet inhibitory activity. 84 Substitution often occurs at the C 5 position in these biologically active species. Figure 2 1. Hydantoin ring numbering sy stem Classic and Recent Method s to Synthesize Hydantoins There are many diverse synthetic methods used in the preparation of hydantoins involving both solution and solid state chemistry methods. Different strategies vary with respect to where substitution is a llowed on the ring and install the carbonyl through the use of ureas, cyanates, phosgene, or phosgene derivatives. 83 The most common protocols utilized in the formation of hydantoins are the Bucherer Bergs synthesis and the Reed synthesis. The B u cherer Bergs synthesis reacts a ketone or aldehyde with an inorganic cyanide and ammonium carbonate to give the desired hydantoin (Figure 2 2a) In t he Reed type reaction amino acids are combined with isocyanates or isothiocyanates to afford hydantoins and thiohydantoins respectively (Figure 2 2b) Both methods suffer from lack of solubility of substrates and

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35 difficult reaction conditions, while additionally only allowing hydrogen substitution at N 3. In a similar fashion amino acids react with alkyl and aryl isothiocyanates to result in thiohydantoins but this method allows for substitution at N 3 (Figure 2 2c). A simple method developed by Blitz for hydantoin preparation is from ureas and carbonyl compounds (Figure 2 2d). Amino amides can be carbonylated using phosgene to install the second carbonyl moiety, C 2 (Figure 2 2e) halo amides can also be reacted with isothiocyanates to give substitution at N 1 and N 2 (Figure 2 2f) Figure 2 2. Synthetic approaches to hydantoins.

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36 Whereas most approaches to synthesizing hydantoins focus on combining two components to install a carbonyl moiety multi component reactions can also be employed. A four component reaction of a primary amine, arylsulfonyl isocyanate and alkyl propiolate or dialkyl acetylene dicarboxylate can be conducted as a o ne pot reaction with triphenyl phosphine in DCM at room temperature to afford stabiliz ed hydantoin derivatives (Figure 2 3) 85 Figure 2 3 Four component, o ne pot synthesis of hydantoin Hydanto in synthesis continues to be an expanding field with recent innovations with respect to aqueous solution and solvent free conditions The relatively simple reaction of urea, glyoxal derivatives, and P 4 O 10 resulted in hydantoins in moderate yields (Figure 2 4) Th is reaction worked best (10% increase in yield) when P 4 O 10 was added to aqueous aldehyde followed by urea instead of a one pot mixture. Mild aqueous and room temperature conditions made fo r a green reaction that can be expanded to that of thiohydant oins through use of thiourea starting material, giving higher yields than their hydantoin c ounterparts. However synthesis was limited with respect to substitution at either nitrogen by use of N methylurea, leading to a mixture of products with decreased se lectivity for substitution at the N 3 position, and therefore overall diminished yields 86 Figure 2 4. Synthesis of hydantoins and thi ohydantoins

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37 The development of a solvent free reaction by Kaushik provides an efficient synthesis of hydantoins substituted at N 1 and C 5. Methyl N cyano N alkyl or arylaminoacetate was reacted with dibutyl phosphate at 100 C to synthesize hydantoins in good yields of 80 92% (Figure 2 5) 87 A wide scope of alk yl (primary, secondary, and tertiary) and aryl (electron withdrawing and electron donating substituents ) were tolerated at the N 1 position. The proposed mechanism suggests that the nucleophili c attack on the cyanamide by the hydroxyl group of dib utyl phos phate results in an unstable intermediate that reacts with a second phosphate. This interm ediate can rearrange to a terminal urea that then acts as a nucleophile in intramolecular attack to form the hydantoin (Figure 2 6) Figure 2 5. Solvent free synthesis of hydantoins Figure 2 6. Proposed mechanism for DBP mediated synthesis of hydantoi ns In addition to solution methods, solid state synthesis of hydantoins is carried out typically by formation of a terminal urea through reaction with isocyanate followed by

PAGE 38

38 cleavage from the solid support through acid cycloelimination or the more mild technique of base promoted cycloelimination (Figure 2 7) Autocleavage and thermal cycloelimination are also observed for removal from the solid support. Polystyrene Wang resin was first used by DeWitt in 1993 but 2 poly s tyry l sulfonyl ethanol and high loading radiation grafted polymers have since been utilized. 83 A recent development in solid state synthesis of hydantoins is that of its use in combination with microwave technology to increase the overall efficiency of the reaction. 88 The solid state support system limits side reactions from occurring, resulti ng in high purity and yields, while use of microwave radiation shortens the overall reaction time. This synthesis utilized an N protected amino acid tethered to a solid resin support along with a linker that is deprotected without microwave assistance thro ugh conventional deprotection techniques dependent on the protecting group (Boc or Fmoc). The unprotected amine was then converted to a terminal urea by reaction with an is ocyanate in THF with microwave irradiation for 10 min utes. Cyclization to hydantoi n and release from the solid support is promoted by irradiation for 15 minutes along with triethylamine in a THF/DMF mixture (Figure 2 7 ) Under the optimized conditions synthesis was achieved in 25 minutes compared to 22 hours by comparable conventional app roaches Figure 2 7 Solid state and microwave synthesis of hydantoin s

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39 Synthesis of Hydantoins by Oxidative Carbonylation o Amino Amides The use of W(CO) 6 /I 2 as catalyst and oxidant and high pressure carbon White group. 45 The prerequisite diphenyl substituted amino amide was synthesized from the amino acid through diphenylglycine was Boc protected using Boc anhydride in acetonitrile. Serendipitously, conversion to the amide with SOCl 2 and saturated NH 3 in THF resulted in deprotection as well. Carbonylation conditions of the amino amide were opt imized to 7 mol % catalyst loading, and DBU as a strong base in DCM at 35 C for 24 h (Figure 2 8 ) Decomposition to benzophenone was competitive with the reaction even with the use of anhydrous solvents. Dichloromethane was chosen as the ideal solvent due to increased solubility of the starting material and the minimized formation of oligomers Figu re 2 8 Synthetic route to Due the success of the W(CO) 6 /I 2 system in carbonylating diamines to cyclic ureas, the s ynthesis of hydantoin s, which contain a cyclic urea moiety was the next amino amide, carbonylation was postulated to occur between the amine and amide nitrogens to give the hydantoin (Figure 2 9 ) Optim ization and scope of this reaction was extensively studied by

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40 examining reaction time, temperature, pressure, base identity, solvent identity, and substitution at the amino, amide, and C 5 positions. 45 Figure 2 9 Retro synthetic analysis o f hydantoins Amino amides were synthesized from the corresponding amino acid methyl ester hydrochloride salt with the appropriate amine in anhydrous methanol. 89 The amino N methyl, ethyl, benzyl, and isopropyl amides were al l synthesized by this technique ( Figure 2 10 ). Amino amide 7 was used for optimization of carbonylation reaction conditions, to which the other amino amides were then subjected. The carbonylation to 7 a and 10 a was achieved in good yields, 8 a in moder ate y ield and 9 a in poor yield (Figure 2 11) Figure 2 10 Synthesis of amino amides from amino ester hydrochlorides Figure 2 1 1 Synthesis of hydantoins 7 a 10 a amino amides 7 10 The bulkier amino amides 9 and 10 were produced in lower yield s resulting in a change of the technique to afford the amino amides. More synthetic steps are necessary as protection of the amino acid is required for use of the mixed anhydride

PAGE 41

41 coupling (MAC) re action. 90 Although this alteration resulted in a longer synthesis in terms of steps, the benzyl and isopropyl substituted substrates were achieved in higher yields along wi th shorter overall reaction times. The three steps included protection of the amino acid, mixed anhydride coupling to form the protected amino amide, and deprotection of the amino amide (Figure 2 1 2 ) These steps served as a template for the later synthe sis of the six membered ring dihydrouracil. Figure 2 1 2 amino acid to hydantoin Because the W(CO) 6 /I 2 method had previously exhibited tolerance of an unprotected hydroxyl group, the effect o amino amides was tested. A literature pr ocedure was modified for the mixed anhydride coupling reaction. 90 The protected amino acid was reacted with N methyl morpholine, isobutyl chloroformate, and benzylamine stepwise in THF at 78 C. After allowing to warm to room temperature, the reaction was stirred for 3 h and amino amide 11 was afforded in moderate yield. Subsequent deprotect ion was comple ted in high yield through use of hydrogen with Pd/C. Pure amino amide 12 was subjected to optimized carbonylation conditions for hydantoins ( Figure 2 1 3 ). As wit h formation of ureas, the unpro tected hydroxyl group was unreactive during car bonylation and no side reactions to form the carbamate occurred. The hydroxyl substituted hydantoin 12 a was synthesized in 50% yield.

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42 Figure 2 1 3 Synthesis of hydantoin 12 a Hydantoin Conclusions Hydantoins were synthe sized in moderate to good yields (50% 73%) by catalytic carbonylation using W(CO) 6 /I 2 Even though the amide nitrogen posse s s es lower nucleophilicity than the amine, the acyclic urea was not formed possibly because of the favorable kinetics in the formati on of the five membered ring. Due to the higher p K a of the amide proton, a stronger base such as 1,8 d iazabicyclo[5.4.0]undec 7 ene ( DBU ) or 1,4 diazabicyclo[2.2.2]octane ( DABCO ), is necessary to obtain optimum yield of the hydantoin. Solvent identity is also crucial to maintaining the proper concentration for formation of product. Unlike the synthesis of phenytoin, use of DCM as solvent produced low yields with DCE proving t o be the ideal solvent. Additionally a longer reaction time of 36 h did not res ult in the same amount of decomposition and gave higher yields. Substitution of the N amide position by a benzyl group produced the best yield with yields from the N methyl derivative slightly lower 75% and 73% respectively. The method is tolerant of a wide range of alkyl and aryl substituents at the C 5 position, including disubstituted subs trates. In contrast, the amino nitrogen showed little tolerance for substitution with diminished yields obtained when secondary amines were utilized.

PAGE 43

43 However the suc cessful carbonylation of such secondary amine substrate s negates the possibility of an isocyanate as the exclusive mechanistic pathway. Classic Ways to Synthesize Dihydrouracils Dihydrouracils ( Figure 2 1 4 ) are important targets for organic synthesis due t o their biological activity. 91 Dihydrouracils can be used for diverse applications including being important core structures for a variety of molecules with b iological functions. Functionality at the C 5 position has led to HIV 1 integrase and viral replication inhibitors. 92 Additionally, uracil is the core structure for certain fungicides and herbicides. 93 5,6 Dihyd ro 5 fluorouracil is being investigated as a prodrug form of 5 fluorouracil, a widely prescribed drug for the treatment of breast and colorectal cancer. 94 Figure 2 1 4 5,6 Dihydrouracil De spite research conducted on the variety of biological properties of dihydrouracils, their synthesis has not been extensively investigated. Only a few solution methods have been developed, and of those methods the simple reduction of the uracil is most fre quently employed despite limitations. 91 amino acids with ureas provides N substituted dihydrouracils ( Figure 2 1 5 ). 95 96 This reaction is carried out in ethylene glycol with yields typically not higher than 45%. To improve upon this synthesis, a te chnique was developed that employed the use of a stainless steel tube which allowed the reaction to be conducted on a small scale (0.05 0 .1 mol ) at 195 C for 1 2 h. Depending on substitution yields could reach as high as 80%. However, o ne limitation of t his method due to the use of condensation with urea or N,N dimethyl

PAGE 44

44 urea is the need to use matched substituents on both nitrogen positions to avoid regiochemical scrambling in the products Figure 2 1 5 Synthesis of 5,6 d ihydrouracils using unsaturated carboxylic acids. More recently, a solid phase organic chemistry method which takes advantage of ureido esters has been employed for the synthesis of dihydrouracils ( Figure 2 1 6 ). 93 The solid phase organic chemistry strategy operates through synthesis of N amines. 93 aminoesters. 97 aminoester was subsequently treated with isocyanates yielding ureido ester for tandem cyclization cleavage of ureido ester This afford ed the desired N substituted dihydrouracil in poor to moderate yields (13% 76%). The nitrogen substituents do not have to be identical, but aryl groups do appear to decrease the yield compared to alkyl substituents Figure 2 1 6 Solid Phase Organic Chemistry synthesis of 5,6 dihydrouracils

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45 While the hydrogenation of uracils to afford 5,6 dihydrouracils can be carried out by several procedures, drawbacks to the methods do exist. The use of hydrogen with Rh 4 are all conventional techniques. 98 Low yield is the main problem with these methodologies, but epimerization at C 5 and even removal of the N 1 alkyl group also re main challenges of the synthesis. 99 More recently, a synthesis has been develo ped that uses ammonium formate as a hydrogen source in me thanol. This technique does not epimerize C 5, but still only achieves moderate yields of 39 50% 100 A milder technique for the reduction of uracils was developed with lithium tri sec butylborohydride (L selectride) in THF. The reaction procedes through a carbanion intermediate which can yield the 5,6 dihydrouracil when reacted with water ( Figure 2 1 7 ) 91 or the C 5 alkyl substituted dihydrouracil when reacted with alkyl iodide. 94 A diverse range of alkyl groups at the C 6 position are tolerated by this system, includi ng propargyl, methyl, and benzyl. The main disadvantage of this system is that both nitrogens must be protected because of the incompatibility of the N H bonds with L selectride. Additionally, the nitrogen must be substituted with aryl or methyl groups o f the same identity, providing some limitation for the system despite its improved yields compared to previous reductions of uracils Figure 2 17 L selectride reduction of uracils to form 5,6 dihydrouracils.

PAGE 46

46 Synthesis of 5,6 dihydrofluorouracil is desired due to its potential as a prodrug form of 5 fluorouracil. 94 As with the problems seen in the hydrogenation of uracil to 5,6 dihydrour a cil, the use of hydrogen with Pd/C (10 mol%) to reduc e 5 fluorouracil resulted in both the desired product 5,6 dihydrofluorouracil and formation of undesired dihydrouracil by hydrogenolysis of the C F bond. However a change to the more mild technique of reduction by L selectride in THF was successful in the presence of the fluoro subst itu ent in 44 70% yield depending on the protecting group. When the fluorine was added after reduction of the protected uracil instead of prior, desired product was obtained in 83% yield. Synthesis of 5,6 Dihydrouracils by Cata lytic Oxidative Carbonylation Due to the success of the W(CO) 6 /I 2 amino amides to give 5,6 dihydrouracils was the next development of the research. While the formation of the six membered ring is not as kinetically favorable as the five membered, the ability of this system to form the six membered cyclic urea from the 1,3 diaminopropane is an indicator that this is amino amide substrate used for carbonylat ion to the dihydrouracil was synthesiz ed through a general three step sequence: protection of a amino acid, mixed anhydride coupling to form the protected amino amide, and deprotection ( Figure 2 1 8 ). Due to the fact that substitution at the C 4 position is difficult once the di hydrouracil is formed, alkyl and aryl subst itution beta to the carbonyl was explored from the outset of the synthesis. Figure 2 1 8 Retro synthetic analysis of 5, 6 amino acid

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47 to the carbonyl was synthesized to explore the effect of the substituents on cyclization. Because previous work in the synthesis of hydantoins showed increased yield and ea sier purification with the benzyl group on the N amide position, benzamides were initially studied alanine was the only amino acid that was commercially available as an N amino acids required in itial protection. Both Boc and Cbz protecting groups were utilized in the course of the synthesis. Two different protocols were used for Boc protection. The initial synthesis employed acetonitrile and tetrabutylammonium hydroxide with Boc 2 O ( Figure 2 1 9 ). A variety of methods were used to try to increase the yield including increased time, temperature, and equivalents of Boc 2 O. H owever, the reaction conditions were optimized with a three day reaction time while starting the reaction at reflux. When lo wer yields for the protection of benzylic substituted substrate 9 were obtained (54%), a new protocol 101 was sought for efficient Boc protection ( Figure 2 2 0 ). Th e reaction of Boc 2 O in t butanol and sodium hydroxide proved to be much faster, being completed in methyl substituted. The reactio n was also superior as it used fewer equivalents of Boc 2 O and gav e higher yields. All substituted amino acids were protected using this new method, with the exception of DL phenylalanine. Figure 2 1 9 N Boc protection in acetonitrile

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48 Figure 2 20 N B amino acids in t BuOH and NaOH Following N protection of the amino acid, conversion to the protected amino amide s ( 19 24 ) was carried out through the previously employed MAC procedure. Despite the reaction being modified from a literatu re procedure which employed Cbz protected substrates, 90 it was found that the Cbz protected phenyl substituted amino acid provided less than a 10% yield due to poor solubili ty of the starting material. As the Boc protected substrates did not show this problem, they were used for the remainder of the synthes e s. With the methyl substituted amino acid, all substrates gave moderate to high yields ( Figure 2 21 ) A longer reaction time may be necessary for 24 as this was the case for the Boc protection of this substrate. Figure 2 21 amino amides 1 9 24 Deprotection with 4.0 M HCl in dioxane to afford t he amino amide ( Figure 2 22 ) proved to be more challenging as drastically different reaction times were needed to bring the reaction to completion. Additionally, because the reaction was run closed with a septum due to the production of HCl gas, constant monitoring of the reaction by TLC

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49 was conducted only after visible solid had precipitated out of solutio n. Reaction times of 5 min to 2 h were utilized with long reaction time s resulting in decomposition of the material into an intractable yellow oil. Figure 2 22 Deprotection of N Boc amino amides to afford 25 30 Results and Discussion amino amide 25 was selected for optimization of the carbonylation reactions because of its lack of steric bulk that c ould hinder the reaction. In keeping with modeling the system after the hydantoin synthesis, the previously optimized conditions of 1.1 equiv of DBU, 35 C, and 24 h with dichloromethane (DCM) as solvent were tested. However, under these conditions no 5 ,6 d i hydrouracil was formed. The temperature was then increased to 60 C, but again no product was obtained. A new set of optimized conditions was then pursued by examining base concentration, base identity, solvent identity, temperature, and time ( Figur e 2 23 Table 2 1 ) Figure 2 23 General carbonylation reaction of amino amide 25

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50 Table 2 1 Optimization of carbonylation conditions for 25 to form 25a Entry Time (h) Temperature (C) Base (Equiv.) Solvent %Yield 25 a 1 24 35 DBU (1.1) DCM 0 2 24 60 DBU (1.1) DCM 0 3 24 35 DBU (1.1) DCE b 48 4 24 30 DBU (2.5) DCE 27 5 24 30 DBU (4.0) DCE 8 6 24 30 Pyridine (1.1) DCE 13 7 8 30 DBU (1.1) DCE 5 8 12 30 DBU (1.1) DCE 45 9 36 30 DBU (1.1) DCE 7 10 24 45 DBU (1.1) DCE 88 11 24 60 DBU (1.1) DCE 13 a All reactions used 7 mol% W(CO) 6 0.69 equiv alents of I 2 and 20 mL solvent b 1,2 dichloroethane During the optimization of the carbonylation, the molar amounts of 25 W(CO) 6 I 2 and the solvent volume were held constant f or the optimization experiments as previous work with this system has optimized the catalyst loading and I 2 molar amount. Solvent volume is limited by the design of the autoclave system used to perform the carbonylations. The best set of conditions was e n try 10 with 45 C, 24 h, and 1.1 equivalents of DBU with 1,2 dichloroethane (DCE) as solvent. Similar to the hydantoin synthesis, solvent identity played an important role in achieving carbonylation. By only switching the solvent from DCM to DCE, a 45% y ield was achieved compared to a 0% yield. Better solubility of the reactants in DCE may be an important reason for this difference. Base amino amides have similar p K a values for the more b asic amide proton. As seen by e ntry 6, the change to the less basic pyridine resulted in diminished yield of the dihydrouracil The r emaining experiments used DBU with the strong base being essential to achieve high reaction yields. Reaction time s longer than 24 h resulted in decomposition ( Table

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51 2 1, entry 9). A higher temperature than that utilized in the hydantoin system was necessary, but an increase to 60 C proved to be too vigorous and resulted in decomposition. The formation of 5,6 dihydrouracil was confirmed in all optimization reactions through 1 H and 13 C NMR as well as IR spectroscopy The IR spectra revealed a new CO stretch ing fr equency at 1726 cm 1 which is consistent with the literature reported range of CO stretches for 5,6 dihydrouracils. 31 Purity of isolated yields was also confirmed through 1 H and 13 C NMR Using the optimized conditions from 25 the alkyl and aryl substitu ted amino amides were subjected to carbonylation. Whereas the unsubstituted 5,6 dihydrouracil was made in high yield under these conditions substituted am ino amides resulted in formation of the only acy c lic urea through intermolecular carbonylation ( Figure 2 2 4 ) T he acy c lic ureas could be identified by their CO stretch ing frequencies at approximately 1640 cm 1 This roughly 80 cm 1 difference from the dihydrouracils is a clear indication that the acyclic urea was formed instead of the dihydrouracil. High resolution mass spectrometry also confirmed the acyclic urea in reaction mixtures from carbonylation of the met hyl substituted substrate An increase of the amount of solvent to 100 mL was tested to see if a high dilution reaction could promote intramolecular carbonylation to the dihydrouracil over intermolecular carbony lation to the acyclic urea While a peak fo r the di hydrouracil could be seen in the mass spectrum along with the acyclic urea, it was not formed in any appreciable yield.

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52 Figure 2 2 4 Carbonylation of substrates 26 29 to form 26a 2 9a using optimized conditions from 2 9a Table 2 2 Yields of 2 6 a 2 9 a Amino Amide R Group % Yield of Acyclic Urea 2 6 a CH 3 86 2 7 a Ph 7 2 8 a CH 2 Ph 29 2 9 a i Pr 0 While the lower nucleophilicity of the amide nitrogen is a probable contributor to the formation of the acyclic urea, steri cs also seems to be involved. The highest yield for the acyclic urea was afforded from the methyl substituted amino amide 2 6 in 86%. The yields decreased along with increasing steric bulk, with the bulkiest substrate tested, the isopropyl compound 29 res ulting in complete decomposition of starting material. The less bulky phenyl substituted amino amide 2 7 was able to form the urea but only in very low yield. Sterics, however, must not be playing the only role in the resulting urea yield, as the benzyl s ubstituted amino amide 2 8 has a significantly diminished yield compared to methyl substituted 26 (29% v. 86%). When using A values to approximate steric bulk, it is seen that the benzyl group has a lower value of 1.68 kcal/mol compared to f 1.74 kcal/mol. If steric bulk is the critical aspect of this system, one

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53 would expect the yields for these two amino amides to be much more similar than their results indicate. A much more complicated relationship between sterics and electronics is pre sent in this reaction than can be clearly elucidated by examining properties of the alkyl and aryl substituents. A mino N methyl amides were explored as possible carbonylation substrates due to the good yield s of the hydantoin s with similar amide substituti on. Amino amides were synthesized with methyl, phenyl, and no substitution at the position. Mixed anhydride coupling was conducted for a longer reaction time of three days to produce good yields (81% 95%), D eprotection afforded the HCl salt s of the amino amide s after recrystallization in good also in good yield (80% 82%) However, car bonylation conditions resulted in only decomposition and the formation of DBU salts. Other strong heterocyclic bases and solvents were explored with no success (Figure 2 25 ) Figure 2 25 Amino N methyl amide synthesis an d carbonylation, R= H, Me, Ph. Table 2 3. Yields of 31 36 from MAC and deprotection reactions R Compound Yield (%) Compound Yield (%) H 31 82 34 82 Me 32 81 35 81 Ph 33 95 36 80 It is of note that the hydantoin system was very tolerant of steric bulk position, the only carbon available for substitution. In the synthesis of phen y toin, two phenyl groups were tolerated at this position. While the formation of a five membered ring is more kinetically favorable than a six membered ring, it was pos tulated that amino amide could result in

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54 formation of the substituted dihydrouracil. The methyl amino amide 30 was subjected to the optimized carbonylation conditions ( Figure 2 26 ). The IR shows a new carbonyl peak at 1697 cm 1 instead of the ~1640 cm 1 indicative of the acyclic urea. Additionally, HR MS shows peaks for the dihydrouracil ([M+H] + = 219.1119 and [M+Na] + = 241.0944) and not for the acyclic urea. Due to only isolating 30 a in <10% yiel d and the problematic nature of carbonylating amino amides to dihydrouracils, further attempts to optimize this yield were abandoned. Figure 2 26 W(CO) 6 catalyzed carbonylation of 30 Benzouracils Anthranil amide 37 was e xplored as a possible substrate for carbonylat ion to benzouracil. Due to decreased nucleophilicity of the aniline nitrogen compared t o the amine nitrogen in the amino amides which would limit acyclic urea formation in conjunction with the locked conforma tion resulting from t he benzene backbone it was hypothesized that the substrate might be more suitable for intramolecular carbonylation. Initial attempts to carbonylate using the optimized dihydrouracil conditions resulted in only decomposition. Previous attempts to carbonylate similar diamine substrate s 38 under bi phasic conditions with K 2 CO 3 w ere limitedly successful. However the substrate scope was later expanded to anilines by changing the reaction conditions. This allowed for the cyclization product 38a to be synthesized in 41% yield T he synthesis of N N disubst ituted ureas from anilines will be di scussed later in further detail. From this, a combination of conditions w as devised that allowed for synthesis of 25 a By changing

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55 the base identity from D BU to DMAP while retaining DCE as solvent cyclization was promoted to benzouracil 37a (Figure 2 27 ) Many temperatures and reaction times were explored, however crude yields never surpassed 40% and complete purification could not be achieved due to the ov erall lack of product solubility Figure 2 27. Synthesis of 38a and 37a As purification proved to be the main difficulty in isolating pure benzouracil, derivatives with aryl substitution at the N amide position were exp lored to aid in the overall solubili ty of the molecule. Benzyl and 4 methoxybenzyl groups were utilized with no additional substitution at the amine position to limit the additional steric bulk of the substrate These compounds were synthesized using the s ame protection, MAC, deprotection scheme as previous amino amides. A ll compounds were puri fied through recrystallizations, which w as achieved with some difficulty due to the hygroscopic nature of the substrates that interfered with recrystallization. Iodin ation of the benzene backbone by electrophi lic aromatic substitution was competitive with carbonylation and

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56 TLC showed mostly unreacted starting material The benzouracil derivative product that was synthesized was iodinated and isolated by flash chromatog raphy in only 4% yield. Figure 2 28. Synthesis of anthranilamide derivatives In order to probe the tolerance of secondary amines while also increasing solubility of t he substrate 2 methylaminobe n zamide 39 was subjected to carbonylation conditions Because 39 is commercially available no additional synthesis was employed. Carbonylation a ttempts resulted in isolation of amine salts, unconsumed starting material, and iodinated starting material at the C 5 position Increa se of reaction time and temperature had no effect. Figure 2 2 9. Attempted carbonylation of 39 While benzouracil was synthesized by using a combination of conditions similar to those optimized for dihydrouracils and anil ines, purification was problematic due to the lack of solubility in any solvents. With a well established wide range of synthetic routes available that furnish this product in excellent yields, further attempts to optimize the reaction were not conducted.

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57 Dihydrouracil and Benzouracil Conclusions Carbonylation of amino amides was only limitedly successful. Dihydrouracil 25a was synthesized in good yields; h owever any substitution by alkyl or aryl groups at the position resulted in synthesis of the acyclic urea instead of the dihydrouracil. Additionally, steric bulk resulted in competitive decomposition and overall diminished yields. m ethyl substitution, and use of amino N methylamide afforded only DBU salts. Benzouracil, while synthesized in moderate crude yields, was unable to be adequately puri fied.

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58 CHAPTER 3 OXIDATIVE CARBONYLATION OF ARYL AMINES TO UNSYMMETRICAL DIARYL UREAS Back ground N,N disubstituted unsymmetrical ureas have numerous applications in areas such as pharmaceuticals pesticides, herbicides, and dyes. Most synthetic methods for unsymmetrical ureas involve the same general scheme (Figure 3 1). 102 A primary amine is reacted with a carbonyl source (phosgene, 103 104 phosgene derivatives, 105 108 carbonyl benzotriazole, 107 carbamates, 109 112 and chloroformates 113 ) which either then forms the isocyanate when subjected to a base or reacts directly with another amine to give the desired urea. Isocyanates c an also be easily reacted with a primary or secondary amine to afford the unsymmetrical urea. However, phosgene poses handling issues due to its toxicity, while its derivatives produce undesirable byproduct s 58 I n light of these problems developing a less hazardous synthetic route for ureas ha s attracted considerable interest over the years. 114 118 Figure 3 1. General scheme of unsymmetrical urea synthesis Transition metal catalysts have been shown as an alternative route to the synthesis of ureas from amines. 4 Reaction conditions typically involve amines, an oxidant, and CO or CO 2 as the carbonyl source. C atalyst s, including complexes of Pd 10 61 Se 119 120 Co 26 and Ru 121 have been employed for the oxidative carbonylation of amines to unsymmetical ureas

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59 A more recen t technique to synthesize asymmetric ureas is the use of trifluoroethyl chloroformate to form a trifluoroethyl carbamate that can react with amines to give ureas. 113 chloroformate can be reacted with a variety of primary amines to afford the trifluoroethy l carbamate with no formation of the symmetric urea. The carbamate can then be reacted with primary or secondary amines to afford un symmetric al ureas in 75 86% yield. Trifluoroethyl chloroformate was synthesized initially from bis(trichloromethyl)carbonate (BTC) and trifluoroethanol resulting in overall three step synthesis that did not use any isocyanate. This reaction was modified to be one pot through the use of an isocyanate and trifluoroethanol reacting to form the carbamate intermediate to which the a mine is added in situ (Figure 3 2). Figure 3 2. (a) Unsymmetrical urea synthesis from thrifluoroethyl carbamate. (b) One pot unsymmetrical urea synthesis. Initial attempts to carbonylate anilines using W(CO) 6 /I 2 were unsuc cessful presumably due to decreased nucleophilicity of the substrate. 42 The success of carbonylation of the amino amides provided a greater understanding of this synthetic method and led to a reexamination of anilines as possible carbonylation substrates. Initially, carbonylation reaction conditi ons for the conversion of aniline to N,N' diphenylurea were screened. Variables such as temperature, solvent, CO pressure and

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60 equivalents of base were examined, and base identity proved to be crucial in synthesizing the desired ureas. The heterocyclic bas es DBU and pyridine effected carbonylation to diphenyl urea in trace amounts. DMAP was the ideal base, resulting in carbonylation to ureas in excellent yield after conditions were optimized by examining base identity, solvent identity, catalyst loading, am ount of I 2 CO pressure, reaction time, and reaction temperature. Optimal conditions for the carbonylation reaction were determined to be 40 C, 80 atm CO, 1 equiv of I 2 2 equiv of DMAP, and CH 2 Cl 2 as solvent (Figure 3 3). Figure 3 3. O xidative c arbonylation of v arious p substituted aryl amines to s ymmetric N, N d iarylureas The effect of halogen substituents was evaluated first. The yield of urea 41b from 4 chloroaniline ( 40b ) was good (66%). Bromo ( 40c ) and iodo subs tituted ( 40d ) anilines afforded their respective N N disubstituted ureas in nearly identical yields (Table 3 1, entries 3 4). In contrast to the halogenated anilines, substitution with the electron donating methoxy group ( 40e ) resulted in a significant d ecrease in the yield of urea (38%, Table3 1, entry 5). However, other donating groups gave good yields (Table 3 2, entry 6 and 7). The phenoxyaniline 40f and the thioether 40g produced their ureas in 82% and 72% yields, respectively. The electron poor p nitroaniline 40h was successfully carbonylated to its urea in 84% yield. This trend of higher yields with electron withdrawing substituents is followed by ethyl aminobenzoate ( 40j ) (83%). An exception is 4 aminobenzonitrile ( 40i ), which affords just 48% of the urea (Table 3 1, entry 9), despite its electron withdrawing cyano substituent. However, the ability of the

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61 nitrile moiety to serve as ligand for the catalyst may be affecting the yield. In prior studies on p substituted benzyl amines under the or iginal reaction conditions amines with coordinating substituents such as carboxylates gave poor yields. Table 3 1. Oxidative c arbonylation of various aryl a mines to symmetrical N, N` diarylureas u sing the W(CO) 6 / I 2 catalyst system 47 E ntry Amine Urea Yield a,b (%) 1 40a R = H 41a R = H 8 5 2 40b R = p Cl 41b R = p Cl 66 3 40c R = p I 41c R = p I 68 4 40d R = p Br 41d R= p Br 64 5 40e R = p OMe 41e R = p OMe 38 6 40f R = p NO 2 41f R = p NO 2 84 7 40g R = p CN 41g R = p CN 48 8 40h R = p COOEt 41h R = p COOEt 83 9 40i 41i 10 10 40j 41j 0 11 40k R = p CH 2 OH 41k R = p CH 2 OH 0 12 40l R = p COOH 41l R = p COOH 0 a Reaction Conditions: 5.0 mmol of aryl aniline, 3 mol % W(CO) 6 5 .0 mmol I 2 10.0 mmol DMAP, in 40mL CH 2 Cl 2 40 C, 80 atm CO, 8h. b Iso lated yield based on aryl amine.

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62 Carbonylation to Unsymmetical Ureas Catalyzed carbonylation of aryl amines with various functional groups to symmetrical ureas suggested the possibility that unsymmetrical ureas might also be synt hesized with the same reaction conditions (Table 3 2). Figure 3 4. Carbonylation of anilines to unsymmetrical ureas Table 3 2. Carbonylation of anilines to unsymmetrical ureas Entry Amines Ratio Ureas (% Yield) a,b 1 p NO 2 40h p CN 40i 1:1 42hi (58) 41h (0) 41i (0) 2 p NO 2 40h p COOEt 40j 1:1 42hj (46) 41h (0) 41j (34) 3 p Cl 40b p OMe 40e 1:1 42be (12) 41b (1 9) 41e (24) 4 40b 40e 1:2 42be (0) 41b (0) 41e (36) 5 40b 40e 2:1 42be (43) 41b (11) 41e (0) 6 40b 40e 5:1 42be (11) 41b (14) 41e (0) 7 p Cl, m CF 3 40p 40e 2:1 42pe (12) 41p ( trace ) 41e (24) 8 p Cl 40b p OPh 40f 2:1 42bf (41)c 41b (4) c 41f (23) c 9 p Cl, m CF 3 40p p OPh 40f 5:1 42pf (45) 41p (0) 41f (10) [ a ] Isolated yield based on aryl amine, values are + 5%. [ b ] The reactions were carried out with aryl amine s (1 .0 mmol + 1 .0 mmol), W(CO) 6 (0.06 mmol), I 2 (2 .0 mmol), DMAP (4 mmol), CH 2 Cl 2 (40 mL), 40 C, 8 0 atm C O, 20 h. [c] NMR yield.

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63 To explore the feasibility of aryl amines with electron withdrawing groups producing unsymmetrical ureas, com pounds 40h ( p NO 2 ), and 40i ( p CN) were subjected to the same reaction conditions. This reaction provided the desired unsymmetrical urea 42hi as the major product in 58% yield (Table 3 2, entry 1), without formation of the symmetrical ureas 41h and 41i in the product mixture. When 40h was paired with 40j ( p CO 2 Et), the unsymmetrical urea 42hj was only slightly favored over symmetrical urea 41j (Table 3 2, entry 2). The equimolar pair of aryl amines 40b (R 1 = Cl) and 40e (R 2 = OCH 3 ) featured an electron wi thdrawing and an electron donating substituent. The desired unsymmetrical urea 42be was obtained in low yield (12%, Table 3 2, entry 1). The symmetrical products, 1,3 bis(4 chlorophenyl)urea 41b and 1,3 bis(4 methoxyphenyl) urea 41e were the major produ cts in the mixture and were obtained in yields of 19% and 24%, respectively. Although the yield of unsymmetrical urea 42be was low, the yields of symmetrical ureas from electron rich aryl amines are also relatively low and it is possible that 40e is just m oderately unreactive. However, the presence of the unsymmetrical urea suggests that manipulation of the reaction conditions could tip the product mixture in its favor. When the ratio was 1:2 in favor of 40e however, the symmetric urea 41e was formed exc lusively in 36% yield (Table 3, entry 4). Using more of the p chloroaniline 40b (2:1, Table 3 2, entry 5) resulted in 43% yield of the unsymmet rical urea 42be and 11% of 41b (Table 3 2, entry 5). A large excess of 40b resulted in the formation of its res pective symmetric urea 41b and a low yield of the unsymmetrical urea (Table 3 2, entry 6). Compound 42be was of interest because it represents a substructure of the anticancer drug sorafenib. When the less electron rich 4 phenoxyaniline ( 40f ) was used i n place of methoxy compound 40e in a

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64 reaction with p chloroaniline ( 40b ) the unsymmetrical urea 42bf was obtained as the major product (41%, Table 3 2, entry 8). Symmetrical urea 41f was obtained in 23% yield, while 41b was present in small quantities (4% yield). Figure 3 5. Structure of sorafenib. Since the electron poor aniline 40h had given the highest yields of unsymmetrical ureas ( 42hi and 42hj ), we investigated adding the CF 3 group that is present in the diaryl a mine moiety of sorafenib (Figure 3 5). Coupling of 4 chloro 3 (trifluoromethyl)aniline ( 40p ) with anisidine ( 40e ) using a 2:1 ratio of 40p to 40e produced a mixture of products (Table 3 2, entry 7). The symmetric urea 41e was the major product (24% yield ) while the unsymmetrical urea 42pe was produced in low yield (12%). Only trace amounts of symmetric urea 41p were detected. Although aryl amines with one electron withdrawing substituent give good yields of ureas, it is possible that the increased elect ron deficiency of the parent aniline 41p renders it insufficiently nucleophilic for facile urea formation. Urea 42pf is a better model for sorafenib and was obtained in 45% yield from a 5:1 ratio of 40p to 40f without competitive formation of 41p (Table 3 2, entry 9). For unsymmetrical urea synthesis using aniline 41p an excess of 41p is required to shift the product mixtures toward the unsymmetrical product. Authentic samples of 42be and 42bf were synthesized using CDI. Initial attempts to create an u nsymmetrical urea intermediate that could then be reacted with a second aniline to produce the desired product were unsuccessful. All attempts afforded the

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65 symmetric urea while aniline starting material still remained. However, when the two aniline species were combined in a one pot reaction with CDI in THF and the more electron withdrawing species of 4 chloroaniline in slight excess, the unsymmetrical urea was obtained in good yield. Figure 3 6. Synthesis of unsymmetrical ureas with CDI To probe whether the reaction proceeds through an isocyanate intermediate, the secondary amine N methylaniline ( 40q ), which cannot form an isocyanate, was subjected to carbonylation conditions.[28] After 20 hours under 80 atm of CO at 40 C, urea 41q was not observed in the product mixture. Most of the starting material was recovered along with trace quantities of p iodo ( N methyl)aniline ( 40r ), a result of the electrophilic aromatic substitution of N methylaniline with elemental iodine (F igure 3 7). The lack of urea in the product mixture is consistent with the intermediacy of an isocyanate in the reaction pathway Figure 3 7. Attempted Carbonylation of N Methylaniline. Furthermore, when N methylaniline ( 40q ) and aniline ( 40a ) were combined under optimized conditions, the major product was unsymmetrical urea 42aq (31% yield,

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66 Table 3 3, entry 1) when excess 40q was used. Diphenylurea ( 41a ) was detected in only trace amounts. Some aniline was also recover ed due to incomplete conversion. Although the yield was modest, formation of the unsymmetrical urea is consistent with formation of an isocyanate from the primary aryl amine followed by attack of the more nucleophilic secondary aryl amine. When N methyla niline is coupled with 4 phenoxyaniline ( 40f ), there is competitive formation of the symmetrical urea 41f because of the increased nucleophilicity of 40f given by the phenoxy substituent (Table 3 3, entry 2). In contrast, coupling of an electron deficient aryl amine ( 40p ) with 40q provides the unsymmetrical urea 42pq as the only product in 25% yield (Table 3 3, entry 3). Table 3 3. Synthesis of trisubstituted aryl ureas. Entry Amines Rati o Ureas (% Yield) a,b 1 40a 40q 1:5 42aq (31) 41a (trace) 2 40f 40q 1:3 42fq (19) c 41f (30) c 3 40p 40q 1:3 42pq (25) 41p (0) a Isolated yield based on aryl amine. b The reactions were carried out with aryl amine s (1 .0 mmol each, unless otherwise noted), W(CO) 6 (0.06 mmol), I 2 (2 .0 mmol), DMAP (4 mmol), CH 2 Cl 2 (40 mL), 80 C, 80 atm CO, 20 h. c NMR yield. Conclusion s In conclusion, we ha ve demonstrated the catalyti c carbonylation of aniline to N,N' diphenylurea using the W(CO) 6 /I 2 catalyst After o ptimizing the conditions for the

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67 carbonylation of aniline various p substituted aryl amines were also oxidatively carbonyla ted to symmetrical and unsymmetrical diaryl ur eas. Coupling of N methylaniline with aryl amines produced results consistent with intermediacy of an isocyanate in the mechanism. T he se results demonstrate the moderately broad tolerance of functionality during the oxidative carbonylation reaction and pr ovide an alternative to the reaction of amines with phosgene and phosgene derivatives

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68 CHAPTER 4 BASE MEDIATED CARBON YLATION OF AMINES TO FORMAMIDES Background Formamides have a wide range of applications. They are known to be important precursors in the synthesis of many biologically active molecules such as fungicides, 122 123 herbicides, cancer chemotherapeut ic agents, 124 and other pharmaceuticals 122 125 126 Formamides also serve as intermediates in the synthesis of isocyanates, formamidine s and nitrile s. 127 Their application is also observed in the allylation 128 and hydrosilation 129 of carbonyl compounds. Conventional synthesis of formamides is conducted using formic acid, formamide, chloral, a variety of formates, or potassium cy anide/dimethyl malonate. 127 Transition metal catalysts are used in conjunction with some of these techniques and can also serve as Lewis aci d s. 130 Howeve r, some disadvantages of these techniques include the need for specialized glassware, harsh conditions, or removal of transition metal catalyst. The use of f ormic acid, while being a common and inexpensive technique for formylation often requires high re action temperatures. However r ecently anilines have been successfully formylated at 80 C in moderate to good yields by using a slight excess of formic acid with no catalyst. 131 This solvent free reaction is simple and efficient Formylation of amino acid esters and amines can be achi eved using formic acid and 2 ch loro 4,6 dimethoxy [1,3,5 ]triazine (CDMT) as a coupling agent. 132 A temperature of only 35 C degrees was necessary to facilitate the reactions that lasted 4 13 hours depending on the subs trate. Reaction times could be reduced to mere

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69 minutes when u tilizing microwave irradiation. Simple workup with aqueous HCl, water, aqueous NaHCO 3 and brine washes afforded pure product after evaporation of DCM. Figure 4 1. Formylation with formic acid and CDMT. Improvement s towards using methyl formate as a formylating agent w ere investigated by Deutsch. 133 Bicyclic heterocy c l es were explored as possibl e catalysts and 1,5,7 triazabicyclo[4.4.0]dec 5 en e (TBD) was found to give the best performance The formyl group was transferred to TBD by methyl formate to produce an intermediate that was more reactive with amines. A wide scope of amines could be formylated by this reaction in high yields. Figure 4 2 Formylation of amines by methyl formate and catalyst. Transition metals can also be used to catalyze f ormylating reactions. Known catalysts include Lewis acids of Zn, 134 Fe, 130 Al, 130 Ni 130 and Hf; 135 Au and Ag surfaces; 136 138 and complexes of W, 42 139 Ir, 140 Ru, 18 20 21 141 143 Co, 144 and Cu. 144 145 While s ome of these catalysts allow for the formylation of amines with CO or CO 2 as the carbonyl source, most require stoichiometric amounts of traditional formylating agents such as formic acid or formates High pressure CO and CO 2 reactions typically show selectivity for ureas over formamides. Akamanchi reported sulfated tungstate as an effective formylation catalyst in the reaction of formic acid with an amine under solvent free conditions at 70 C and reaction

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70 times of 10 45 minut es 139 Similar to acid catalyzed reactions the sulfated tungst ate activates formic acid followed by nucleophilic attack by the amine to afford the desired formamide. Aryl, primary, a nd secondary amines were all successfully formylated in excellent yields (85 99%) with simple pur ification. The sulfated tungstate ca talyst could be recycled four times without significant loss in activity. Figure 4 3 N formylation of amines with formic acid and sulfated tungstate catalyst. Jenner has reported the use of ruthenium catalysts to carbonylate primary and secondary amines with CO. 18 Several catalysts including complexes of Co and Rh were tested befo re it was determined that ruthenium tricholoride trihydrate (RuCl 3 3H 2 O) achieved the highest reactivity and formamide selectivity. Co catalysts gave low overall con version. Rh had good activity but lacked selectivity for the formamide. High reaction tem peratures (200 C) and pressures (445 atm CO) were necessary to give desired products in excellent yields. Primary amines were carbonylated to the hydrogen was present therefore anilines and t butyl amine were unreactive. This cou ld be an indic ator of an amidine intermediate or possibly the result of steric bulk (t butylamine) or decreased nucleophilicity ( aniline ). Carbonylation of secondary amines also went through a transalkylation side reaction to give a tria l kylamine and a pri mary amine that was then formylated, resulting in a mixture of products. A combination of cobalt and ruthenium increased selectivity of the reaction for formamides.

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71 Cyclic amines were also successfully carbonylated to formamides using RuCl 3 3H 2 O with CO Reactivity could be achieved with l ower temperature (180 C) and pressure (100 atm) than with the acyclic secondary amines. Interestingly, use of p iperazine with its two amine sites for carbonylation afford ed the monoformylated, diformylated, or a mixtur e of the two products depending on reaction conditions. High pressure of 440 bar and methanol as solvent gave monoformylated product while dioxane at lower pressure (115 bar) generated diformylated product Some degree of polymerization was also observed. IN order to address the problems associated with the RuCl 3 2 O catalyzed reaction for acyclic secondary amines and the unreactive primary amines, solvent effects were investigated by Jenner. 17 It was hoped that the side reactions, which included t ransalkylation and carbonylation to the urea could be suppressed by new reaction conditions. After testing a broad range of solvents, no correlation was observed between formamide selectivity and solvent dielectric constant. Aprotic solvents did lower the conversion due to the dilution effect Depending on amine identity, w ater gave varied results of e ither increasing selectivity to the urea or inhibiting the overall rate of carbonylation Alcohols had the best selectivity for formamides, and methanol performed the best with a mixed Ru/Co catalyst system. I ncreasing the pressure to 750 atm from 445 atm, while running the reaction at 180 C, allowed for complete suppression of urea formation (Figure 4 4 ). It was observed that at least equal volumes of methanol and amine were needed for optimized yields implying that methanol is being used in the reaction stoichiometrically. Jenner proposed that methanol was being carbonylated to methyl formate which would react with the amine to afford the

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72 formamide and regenerate the methanol. Conversion of other alcohols to their formates would also explain how other al cohols experienced similar selectivity compared to different solvents. Dialkyl amines, anilines, and tert butylamine were all carbonylated to their formamides under these new conditions, despite the aryl amines still displaying some decreased reactivity an d undesired transalkylation side products. Figure 4 4 Ru catalyzed reaction of dialkyl amine to formamide in methanol. Transition Metal Free Carbonylation of Amines to Ureas While there are numerous transition meta l cat alyzed carbonylation reactions, many of which have been previously discussed, there are drawbacks to these methods. Many are expensive and there is the possibility of contamination by the metal catalyst. Transition meta l free catalysts such as sulfur and selenium can be used in carbonylation, however, they produce the toxic byproducts of H 2 S and SeH 2 respectively. The McElwee White group while in the process of examining different oxidants for their W(CO) 6 catalyzed reaction of amines to ureas observed that the reaction proceeded in the presence of the oxidant sodium metaperiodate and iodide salt promoter without any tungsten catalyst. 146 When a biphasic solvent system of DCM/H 2 O was used, h igh yields were observed for ureas synthesized from unhindered alkyl amin es and substituted benzylamines. Initially formamide was observed as a side product in the reaction when DCM was used as the solvent (Figure 4 5 ) Use of NaI

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73 instead of I 2 r esulted in optimization toward the urea. DMAP also proved to be the ideal base even under biphasic solvent conditions (Figure 4 6 ) Figure 4 5 Oxidative carbonylation of 4 3 formi ng 4 4 and 4 5 Figure 4 6 Optimized conditions for urea synthesis using NaIO 4 and NaI Transition Metal Free Carbonylation of Amines to Formamides In light of the success of the transition metal free reaction for carbonyl ation to ureas, the reactions conditions were change d to optimize for the formamide product instead of the urea. It was found that solvent identity was the crucial condition as switching to methanol resulted in exclusive formation of the formamide. This is conditions resulted in synthesis of the formamide. 17 Conditions for the reaction after methanol was chosen as the solvent were then optimized with a focus on base identity. The best set of conditions used 4 equivalents of K 2 CO 3 and 1 equivalent NaIO 4 in methanol at 2 5 C for 24 h. Early optimization also revealed that the iodide salt promoter necessary for carbonylation to ureas with NaIO 4 was not needed for synthesis of formamides 147 After optimization, functional group tolerance was examined. Of the formamides that were easily isolated yields were

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74 moderate to good. Cyclic secondary amines were also carbonylated to formamides in low to good yields. Focus was then given to the reaction mechanism The first concern was that incorporation of methanol and not carbon monoxide was the source of the carbonyl in the product. The first indication that this was not the case was that 4 5 was syn thesized in 55% when ethanol was used as a solvent. If the alcohol w ere being incorporated, an amide instead of the formamide would be expected. However this is far from conclusive as a different solvent could easily lead to a different mechanism Therefo re, a series of isotopic labeling studies were conducted to probe the source of the carbonyl and the formyl hydrogen. When 50% of the methanol was 13 C labeled, only natural abundance was observed by mass spec trometry confirming that the carbonyl source i s CO and not the solvent (Figure 4 7 ) Labeling studies were also used to confirm if the formyl proton was incorporated by H abstraction from the hydroxyl group or the methyl group. Figure 4 7 Possible outcomes for inco rporation of 13 C from labeled methanol.

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75 Isotopic labeling studies of the formylation reaction showed that the carbonyl source was carbon monoxide, not methanol, and that the formyl hydrogen source was the methanol hydroxyl proton. The carbonylation reactio n was run in CD 3 OH as another method to confirm the source of the formyl hydrogen Carbonyl stretches in the IR and integration of the formyl proton peak in 1 H NMR were identical to that run in non deuterated methanol. However when CH 3 OD was used as solve formamide shifted to 1624 cm 1 from 1642 cm 1 indicative of deuterium incorporation at the formyl proton. This was also confirmed by a diminished integration of the formamide proton in the 1 H NMR to 0.1 H from the expected 1.0 H if no d euterium had been incorporated (Figure 4 8 ) Figure 4 8 Incorporati on of deuterium from deuterated methanol. Taking into consideration the isotopic labeling studies, probable mechanisms were explored. Ini tially, a radi cal mechanism was considered, as NaIO 4 is known to form radical species 148 However use of the radical trap TEMPO resulted in no isolated adducts or diminished yield that would be expected if a radical intermediate was present. A second mechanism was then considered involving a methyl formate intermediate. There is l iterature precedent for the carbonylation to formamides from amines in alcohol solvents in the work of Bitsi and Jenner. 17 The ruthenium catalyzed

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76 reaction was postulated to go through a methyl formate intermediate. However with no metal catalyst present in the NaIO 4 mediated reaction to formamides an alternative mechanism for the formation of a methyl formate intermediate were necessary. Jogunola 149 reported that methyl format e can be synthesized from potassium methoxide and methanol at high pressures of CO. The CO would combine with the potassium methoxide followed by proton abstraction from methanol to regenerate the methoxide. A similar mechanism would be consistent with the isotopic labeling stud ies conducted on the reaction of 4 3 with CO, NaIO 4 and K 2 CO 3 in MeOH A proposed pathway is s hown in Figure 4 9 Figure 4 9 Proposed mechanism for the base mediated pathway to formamides. With li terature precedent observed for the formation of methyl formate from methanol, potassium methoxide, and high pressures of carbon monoxide, it was

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77 theorized that the oxidant could be unnecessary in the reaction. A control reaction with no sodium metaperioda te yielded the desired formamide 4 5 in the same yield as the reaction run with the oxidant This allowed for its removal from the reaction conditions To confirm that no Fe (CO ) 5 that could possibly be in the CO tank utilized was catalyzing the reaction, an aluminum tank was purchased. A r eaction was run using CO from the aluminum tank proceeded normally, leading to the conclusion that the reaction is base mediated. Conditions were then reoptimized for the reaction without the presence of sodium metaperiodat e. The 4 methoxybenzylamine substrate again was chose n for the optimization reactions which examined reaction time, pressure of carbon monoxide, and amount of potassium carbonate in the absence of NaIO 4 Reaction time and pressure showed the most dependen ce of the variables (Table 4 1) Times less than seven hours resulted in unreacted starting material. Complete reaction was observed with 25 atmospheres of CO for the 24 hour reaction ( Table 4 1, entry 12) but higher pressure was necess ary at the shorter reaction times ( Table 4 1, entries 3, 8, and 11) As evidenced by multiple set s of conditions with yields in the 78 81% range, there is a delicate balance between reaction conditions and optimum yield The two be st sets of conditions were entries 11 and 12 with the former using a shorter reaction time of 7 h with 3 equiv base and 35 atm of CO and the lat t er using the longer reaction time of 24 h to allow for less base (2 equiv alents ) and CO (25 atm). Additionally it was observed that when reactions were run on stir plates that stirred at lower r ates yields similarly decreased. This is consistent methyl formate concentration. This increase was seen due to the increased mass

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78 transfer area of carbon monoxide bubbles in solution which allowed for increased gas absorption. Subsequent reactions were all run on identical stir plates set to 500 rpm to ensure consistent stirring Table 4 1 Optimization of carbonylation of 43 t o 45 without NaIO 4 Entry Time (h) Pressure CO (atm) K 2 CO 3 (equiv) Yield (%) 1 2 45 4 49 2 4 45 4 63 3 7 45 4 78 4 8 45 4 81 5 24 45 4 81 6 8 45 1.1 72 7 8 45 2 76 8 8 45 3 81 9 7 15 3 44 10 7 25 3 60 11 7 35 3 78 12 24 25 2 79 13 24 35 2 80 14 24 45 2 84 Conditions: 60 mL MeOH, 25 C, and 500 rpm stirring Functional group tolerance was examined with substitution at the para position of benzylamine. The methoxy substituent proved to give the best yield with complete reaction within 7 h, howe ver this was not observed with most other substrates. To ensure reaction completion and allow for better comparison of functional group e ffects, the carbonylation reaction was run for 24 hours. This increase in reaction time resulted in much higher yields for most substrates, particularly the halogenated benzylamines with increases of up to 45%. After optimizing the reaction with 43 the effect of halogen substituen ts was evaluated. The yields of formamides 61 (84%) and 55 (78%) from 4 chlorobenzylamine an d 4 fluorobenz ylamine respectively were good. Yields decreased going down the periodic table to 4 bromobenzylamine 58 (68%) and 4 iodobenzylamine 56 (61%) This

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79 is the opposite t rend observed by carbonylation of halogenated benzylamines to ureas using NaIO 4 and K 2 CO 3 146 Table 4 2: Functional g roup c ompatibility Entry Amine Product Yield a (%) 7 h 150 Yield (%) 24 h 1 b 78 79 2 63 3 b 61 80 4 c 71 79 5 b 49 71 6 b 67 78 7 c 33 d 61 d 8 b 48 68 9 b 47 84 10 c 27 d 55 d a Isolated yield per equiv of amine. b Conditions: 4 mmol amine, 12 mmol K 2 CO 3 35 atm CO, 60 mL CH 3 OH, 7 h, 25 C. c Conditions: 2 mmol amine, 6 mmol K 2 CO 3 35 atm CO, 30 mL CH 3 OH, 25 C. d One extra equiv of base was added because the amine was an HCl salt.

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80 Table 4 2. Continued Entry Amine Product Yield a (%) 7 h Yield a (%) 24 h 1 1 b 25 41 1 2 7 d 35 d 1 3 c 23 36 1 4 b 17 d 35 a Isolated yield per equiv of amine. b Conditions: 4 mmol amine, 12 mmol K 2 CO 3 35 atm CO, 60 mL CH 3 OH, 7 h, 25 C. c Conditions: 2 mmol amine, 6 mmol K 2 CO 3 35 atm CO, 30 mL CH 3 OH, 25 C. d One extra equiv of base was added because the amine was an HCl salt. Benzylamines substituted with electron withdrawing groups in the para position had substantially lower yields but most also had unreacted starting material present after 24 h Reaction of the electron poor amines 4 nitrobenzylamine 66 4 cya nobenzylamine 70 and 4 trifluorobenzylamine 68 resulted in the lowest yields (Table 4 2 entries 13, 14, and 15) and all had substantial decomposition p roducts competitive with carbonylation. Electron rich benzylamines consistently gave good, near ident ical yields (entries 1, 3, and 4) Only the thioether 46 afforded formamide 47 in moderate yield (63%) The 4 methylbenzylamine and vinylbenzylamine produced formamides 49 and 51 in 80% and 79% yields, respectively. Under the 7 h reaction conditions, f ormam ide 51 was also synthesized in the good yield of 71%, despite other substrates needing a longer

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81 reaction time No oligomerization was observed for 50 another indicator that a radical mechanism is unlikely The scope of the reaction was extended to include cyclic secondary amines. Piperidine 74 was carbonylated to the formamide in good y ield (78%) with other substrates having yields ranging from 39 66%. Six membered rings performed better than the five membered ring pyr r olidine Carbonylation of morpholine 76 resulted in selectivity for formylation at the amine position, while only one of the two amine moieties of piperazine was converted to formamide 79 Acyclic secondary amines were unreactive under current conditions. Table 4 3 Carbon ylation of secondar y amines to formamides. Entry a Amine Product Yield b (%) 1 39 2 78 3 66 4 55 d Conditions: 4 mmol amine, 12 mmol K 2 CO 3 35 atm CO, 7 h, 25 C. b Isolated yield based on equiv of amine. Primary alkyl amines were examined using a 24 h re action time to ensure complete reactivity. Less sterically hindered substrates typically gave the highest yields (Table 4 entry 3), with the bulkiest substrate, t butylamine 88 only showing trace amounts of the formamide. This is consistent with nucleo philic attack on methyl formate as a step in the mechanism. Workup might also play a role in isolated yields, as substrates that are more soluble in organic solvents afforded higher yields of the

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82 formamide ( Table 4 4, entry 3 and 5). Ex tens ion of the react ion to amino acids, amino amides, and anilines ha s thus far been unsuccessful. Table 4 4 Carbonylation of primary amines to formamides. Entry Amine Product Yield a (%) 1 b 40 2 b 37 3 b 76 4 c 61 5 b Trace 6 c 71 a Isolated yield based on equiv of amine. b Conditions: 1 mmol amine, 4 mmol K 2 CO 3 25 atm CO, 15 mL CH 3 OH, 24 h, 25 C. c Conditions: 2 mmol amin e, 4 mmol K 2 CO 3 25 atm CO, 15 mL CH 3 OH, 24 h, 25 C. Conclusions Carbonylation of amines to formamides by high pressure CO with K 2 CO 3 in methanol gave reasonably broad substrate scope including primary, secondary, and substituted benzylamines. Yields wer e good to moderate and sensitive to changes in reaction time, pressure of CO, and stirring rate. Amines with e lectron withdrawing substituents had decomposition pathways competitive with carbonylation. A base mediated mechanistic pathway is proposed for th is reaction in the absence of oxidant.

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83 CHAPTER 5 EXPERIMENTAL SECTION Synthesis of and Amino Amides for Oxidative Carbonylation General Procedures All experiments, unless otherwise noted, were carried out under an inert argon atmosphere with oven dri ed glassware. Commercially available substrates were used without further purification. The tetrahydrofuran solvent was dried over 3A sieves. All column chromatography was conducted with 270 400 mesh silica. All 1 H and 13 C NMR spectra were obtained on a Varian Gemini 300 MHz, VXR 300 MHz, or Mercury 300 MHz spectrometer. Infrared spectra were recorded on a Perkin Elmer 1600 FT IR. High resolution mass spectrometry was performed by the University of Florida analytical service General Procedure A for t he Synthesis of Amino Amides 7 10 The amino acid methyl ester hy drochloride (4.0 mmol) and the alkylamine (40 mmol) were dissolved in anhydrous methanol (20 mL) and stirred at room temperature for 3 days, in accordance with literature protocol. 89 The reaction mixture was concentrated, and the residue was purified by column chromatography using 4:96 amino amides 7 10 Product identification was made from literature comparison. 14,15 ( S ) 2 Am ino N methyl 3 phenylpropionamide (7) 1 H NMR (CDCl 3 2 ), 2.67 (dd, 1H, CH 2 CHCO), 2.84 (d, 3H, NHCH 3 ), 3.48 (d, 2H, PhCH 2 ), 7.22 7.30 (m, 5H, C 6 H 5 ).

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84 ( S ) 2 Amino N ethyl 3 phenylpropionamide (8) 1 H NMR (CDCl 3 2 ), 2.65 (t, 3H, NHCH 2 CH 3 ), 2.71 (dd, 1H, CH 2 CHCO), 3.31 (m, 2H, NCH 2 CH 3 ), 3.64 (d, 2H, PhCH 2 CH), 7.25 7.34 (m, 5H, C 6 H 5 ). ( S ) 2 Amino N isopropyl 3 phenylpropionamide (9) 1 H NMR (CDCl 3 .52 (broad s, 2H, NH 2 ), 2.43 (d, 6H, NHCH(CH 3 ) 2 ), 2.59 (dd, 1H, CH 2 CHCO), 3.17 (m, 1H, NCH(CH 3 ) 2 ), 3.46 (d, 2H, PhCH 2 CH), 7.21 7.30 (m, 5H, C 6 H 5 ). ( S ) 2 Amino N benzyl 3 phenylpropionamide (10) 1 H NMR (CDCl 3 s, 2H, NH 2 ), 2.72 (dd, 1H, CH 2 CHCO), 3.37 (d, 2H, PhCH 2 CH), 3.51 (d, 2H, NHCH 2 Ph), 7.25 7.38 (m, 10H, aromatics).

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85 General Procedure B for Carbonylation of Amino Amide (7) To a 300 mL glass lined Parr high pressure vesse l containing 35 mL of 1,2 amino amide 7 (400 mg, 2.20 mmol), W(CO) 6 (56 mg, 0.16 mmol), I 2 (396 mg, 1.56 mmol), and DBU (1.36 mL, 8.96 mmol). The vessel was then charged with 80 atm CO and heated to 60 C for 36 hours with cons tant stirring. After cooling, the pressure was released and 15 mL water was added. The organics were then separated and washed successively with Na 2 SO 3 and 0.1 M HCl. The aqueous layer was then extracted with EtOAc (20 mL x 4). The combined organic lay ers were then dried over MgSO 4 filtered and concentrated. The resulting residue was purified via flash column chromatography using DCM/EtOAc (80:20) to afford hydantoin 7a The same procedure was applied to prepare hydantoins 7a 9a,6a The products wer e identified by comparison to literature data. 14,29,30 (S) 5 Benzyl 3 methylimidazolidine 2,4 dione (7a) 1 H NMR (CDCl 3 2 C H ), 3.0 (s, 3H, NCH 3 ), 3.32 (dd, 1H, PhCH 2 ), 4.25 (dd, 1H, PhCH 2 ), 5.19 (broad s, 1H, NH), 7.21 7.40 (m, 5H, C 6 H 5 ); 1 3 C NMR (CDCl 3 CO 1772, 1709 cm 1 (S) 5 Benzyl 3 ethylimidazolidine 2,4 dione (8a) Hydantoin 8a was synthesized through the same carbonylation procedure as 7a 1 H NMR (CDCl 3 2 C H 3 ), 2.82 (dd, 1H, C H 2 CH 3 ), 3.24 (dd, 1H, C H 2 CH 3 ), 3.43 3.60 (m, 2H, C H 2 Ph), 4.21 (dd, 1H, CH 2 C H CO), 7.19 7.39 (m, 5H,

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86 C 6 H 5 ); 13 C NMR (CDCl 3 CO 1770, 1714 cm 1 (S) 5 Benzyl 3 benzylimidazolidine 2,4 dione (9a) Hydantoin 9a was synthesized through the same carbonylation procedure as 7a 1 H NMR (CDCl 3 H 2 Ph), 3.24 (dd, 1H, C H 2 Ph), 4.22 (s, 2H, C H 2 Ph), 4.60 (t, 1H, CH 2 C H CO), 5.38 (broad s, 1H, N H ), 7.23 7.42 (m, 10H, C 6 H 5 ); 13 C NMR (CDCl 3 CO 1775, 1716 cm 1 Preparation o f Amino Amide (11) by MAC A two step procedure, as described in the literature, 90 was followed starting with commercially available Cbz serine. A 25 mL solution of dry TH F containing carbobenzyloxy DL serine (2.00 g, 8.40 mmol) was cooled to 78 C and then 4 methylmorpholine (1.29 g, 10.5 mmol) was added and stirred for 5 minutes. Isobutyl chloroformate (1.46 g, 10.5 mmol) was then added and the reaction mixture was stri rred for 15 minutes after which benzylamine (1.08 g, 10.5 mmol) was added. The reaction was then stirred for 15 minutes at 78 C, before allowing to warm to room temperature where it continued to stir for one hour. The reaction mixture was filtered and the filtrate

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87 evaporated by reduced pressure. The concentrated residue was suspended in ether (75 mL) and filtered again. The crude product was purified by column chromatography with 5% MeOH/DCM eluent. A 1.95 g amount of product 11 was isolated, a 74% y ield. Deprotection of amino amide 11 to afford 12 The hydrogenation of the Cbz protecting group was then accomplished. A flask containing 1.71 g (5.44 mmol) amount of the purified benzamide 11 (vide supra) was combined with 0.286 g of Pd/C (10% w/w) and slurried in 50 mL anhydrous MeOH. The reaction was stirred under an atmosphere of H 2 for 3 hours after which the mixture was filtered through a 2 cm pad of Celite. The filtrate was condensed by reduced pressure. The cr ude residue was purified by column chromatography using 7.5% MeOH/DCM as eluent affording 0.951 g of 12 in a yield of 90%. The product was identified by comparison to literature values. 90 1 H 2 ), 3.23 (t, 1H, CH 2 C H CO), 3.41 (m, 2H, C H 2 OH), 4.25 (d, 2H, NHC H 2 Ph), 4.76 (broad s, 1H, O H ), 7.18 7.31(m, 5H, C 6 H 5 ), 8.36 (broad s, 1H, N H ). (S) 3 Benzyl 5 (hydroxymethyl)imidazolidi ne 2,4 dione (12a) Hydantoin 12a was synthesized through the same carbonylation procedure as 7a 1 H 2 Ph), 3.53 (dd, 1H, C H 2 Ph), 4.26 (t, 1H,

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88 CH 2 C H CO), 4.48 (d, 2H, C H 2 OH), 4.77 (broad s, 1H, O H ), 7.21 7.30, (m, 5H, C 6 H 5 ). I R CO 1765, 1708 cm 1 3 ( ( tert butoxycarbonyl)amino) 3 phenylpropanoic acid (13) In a 100 mL round bottom flask, 10 mmol (1.625 g) of DL phenylalanine was refluxed in 80 mL of acetonitrile. The minimum amount of TMAH 2 5% w/w H 2 O was added to solubilized the amino acid. To the reaction flask, 30 mmol (6.51 g) of Boc 2 O was added and mixture over the course of 3 days with 10 mmol being added each day. After refluxing for 24 hours the reaction was stirred at room temperatu re for the remaining 48 hours. The solvent was removed under reduced pressure and solids were partitioned between 40 mL water and 40 mL dichloromethane. The dichloromethane layer was discarded and the aqueous layer was acidified to pH 4 with 1 M hydrochlo ric acid followed by three extractions of 20 mL 3:1 chloroform:ethanol. The organics were combined and the volatiles were removed under reduced pressure until only solid remained. The pink solid was purified by column chromatography, using DCM as eluent with a gradient shift to 1% MeOH/DCM after 400 mL. Isolated 1.90 g, 71.6% yield. 1 H NMR (CDCl 3 H 3 ) 3 ), 2.84 (broad s, 2H, C H 2 ), 5.09 (broad s, 1H, C H Ph), 5.54 (broad s, 1H, N H Boc), 7.25 7.36 (m, 5H, C 6 H 5 ), 9.90 (broad s, 1H, COO H ). 13 C NMR (CDCl 3 HRMS [M+ Na] + calcd 288.1206, found 288.1193.

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89 General Procedure C for N Boc Protection of Amino Acids to Form 15 amino acid was slurried in 10 mL tert butanol and 10 mL 1.0 N NaOH was then cooled to 0 C in accordance with literature procedure. Boc 2 O (11 mmol, 2.40 g) was added in one portion, stirred at 0 C for 10 minutes, then allowed to warm to room temperature. The pH of the reaction mixture was adjusted continuously to pH 9 10 by adding 4.0 N NaOH. After the reaction stirred for a total of 3 hours, tert butanol was removed by reduced pressure until the mixture was concentrated to approximately 15 mL. The remaining aqueous layer was covered with 20 mL EtOAc and cooled to 0 C where it was then acidified to pH 1 2 using 5.0 N HCl. The organics were separated and the aqueous layer extracted with EtOAc 3 x 25 mL. The organics were combined and dried with MgSO 4 filtered The volatiles were then removed by reduced pressure. The resulting clear oil was placed under vacuum for 12 hours to give a white solid. The solid was purified by column chromatography starting with 3/97 MeOH/DCM and gradient shifting to 5/95 MeOH/DCM after 500 mL, resulting in 1. 862 g of amino acid 15 Yield 92 %. Product identification was made by comparison to literature data. 27 1 H NMR (CDCl 3 3H, C H 3 ), 1.40 (s, 9H, C(C H 3 ) 3 ), 2.42 (d, 2H, C H 2 ), 3.96 (m, 1H, C H CH 3 ), 5.2 (broad s, 1H, BocN H ). 13 C NMR (CDCl 3 55.7, 170.9.

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90 3 ( ( tert butoxycarbonyl)amino) 4 phenylbutanoic acid (16) Protected amino acid 16 was afforded through the same general procedure as 15 using 5.58 mmol of alanine (1.000 g) and 6.14 mmol of Boc 2 O ( 1.54 g). The reaction was monitored by TLC and stirred for 24 hrs. The white solid was purified by column chromatography starting with DCM and gradient shifting to 2% MeOH/DCM, resulting in 1. 245 g of amino acid 16 Yield 79 %. 1 H NMR (CDCl 3 9H, C(C H 3 ) 3 ), 2.53 (d, 2H, CHC H 2 COOH), 2.86 (m, 1H, NHC H CH 2 ), 4.18 (d, 2H, PhC H 2 ), 7.20 7.32 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 129.5, 138.3, 155.2, 170.9. 3 (( tert butoxycarbon yl)amino) 4 methylpentanoic acid (17) The p rotected amino acid 17 was afforded through the same general procedure as 15 using 7.62 mmol of DL leucine (1.000 g) and 8.39 mmol of Boc 2 O (g). The white solid was purified by column chromatography starting wit h DCM and gradient shifting to 1.5% MeOH/DCM after 5 5 0 mL, resulting in 1. 431 g of amino acid 17 Yield 81 %. 1 H NMR (CDCl 3 H 3 ) 2 ), 1.44 (s, 9H, C(C H 3 ) 3 ), 1.86 (m, 1H, C H (CH 3 ) 2 ), 2.55 (d, 2H, CH 2 COOH), 3.76 (m, 1H, CHNHC H CH 2 ). 13 C NMR (CDCl 3 28.6, 31.9, 37.4, 63.1, 155.9, 177.3.

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91 3 (( tert butoxycarbonyl)amino) 2 methyl p rop an oic acid (18) The protected amino acid 18 was afforded through the same general procedure as 15 using 9.70 mmol of ( ) 3 amino iso butanoic acid (1.000 g) and a total of 21.34 mmol of Boc 2 O (4.68 g). The first portion of 10.67 mmol Boc 2 O was added initially to the reaction and the second 10.67 mmol portion was added after 4 hours when TLC showed starting material was still present. The reaction continued to stir for an additional 2 hours for a total of 6 hours reaction time. The white solid was purified by column chromatography starting with 3/97 MeOH/DCM and gradient shifting to 5 /95 MeOH/DCM after 500 mL, resulting in 1. 8 98 g of amino acid 18 Yield 96 %. Product identification was made by comparison to literature data. 1 H NMR (CDCl 3 CHC H 3 ), 1.38 (s, 9H, C C(CH 3 ) 3 ), 2.61 (m, 1H, CH 2 C H CH 3 ), 3.21 (m, 2H, NHC H 2 CH), 5.73 (broad s, 1H, NH), 7.18 7.31(m, 5H, C 6 H 5 ), 8.36 (broad s, 1H, O H ). 13 C (CDCl 3 /CD 3 OD) 14.51, 28.20, 39.77, 42.72, 79.48, 156.20, 178.93. General Procedure D for Mixed Anhydride Coupling of Amino Acid 8 to Form 19 Into a 100 mL round bottom flask 5.29 mmol of N Boc alanine (1.00 g) was dissolved in 20 mL THF and 6.6 mmol N methylmorpholine (0.66 g) was added The flask was cooled to 78 C and stirred for 5 minutes before addition of 6.61 mmol isobutylchloroformate (0.88 g) After 10 minutes of stirring, 6. 61 mmol benzylamine (0.71 mL) was added and stirred for 1 5 minutes before allowing the flask to warm to room temperature. The reaction was then stirred for one and a half hours after which the mixture was condensed under reduced pressure and the solid was stirred in

PAGE 92

92 hexanes for 30 minutes The suspension was filtered using vacuum filtration. T he filtrate was concentrated by reduced pressure then re suspended in hexanes and filtered again. The white solids were combined and purified by column chromatograp hy 95/5 (DCM:MeOH). Isolated 1.37 g, 93% yield of 1 9 1 H NMR (CDCl 3 C(C H 3 ) 3 ), 2.45 (t, 2H, C H 2 CONHBn) 3.42 (t, 2H, C H 2 NHBoc), 5.21 (broad s, 1H, N H ), 6.15 (broad s, 1H, N H ), 7.24 7.33 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 ) 20.5, 31.3, 36.1, 44. 1, 63.7, 126.7, 127.1, 128.2, 137.4, 155.4, 173.9. HRMS [M+Na] + calcd 301.1523, found 301.1515. 3 ( ( tert butoxycarbonyl)amino) N benzyl butanamide (20) The procedure followed was the same as described in general procedure D to afford compound 20 THF was not removed from the reaction mixture by reduced pressure due to the large amount of solids. The s olids were combined and purified by column c hromatography in 3/97 MeOH/DCM Isolated 2.103 g, 82% yield. 1 H NMR (CDCl 3 H 3 ), 2.42 (t, 2H, CHC H 2 CO), 3.97 (sextet, 1H, NHBocC H ), 4.42 (d, 2H, NHC H 2 Ph), 5.21 (broad s, 1H, N H ), 6.25 (broad s, 1H, N H ), 7.26 7.34 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 138.1, 1 55.4, 170.6. HRMS [2M+Na] + calcd 607.3466, found 607.3454.

PAGE 93

93 3 ( ( tert butoxycarbonyl)amino) N benzyl 4 phenyl butanamide (21) The procedure followed was the same as described in general procedure D to afford compound 21 T he s olids were combined and purified by column c hromatography in 3/97 MeOH/DCM The product was isolated in 90% yield (0.740 g). 1 H NMR (CDCl 3 /CD 3 1.33 (s, 9H, C(C H 3 ) 3 ) 2.64 (d, 2H, CHC H 2 CO), 4. 26 (d, 2H, NHC H 2 Ph), 4. 9 1 (t, 1H,PhC H CH 2 ), 7. 09 7. 29 (m, 10H, aromatics). 3 (( tert butoxycarbonyl)amino) N benzyl 4 phenyl butanamide (22) The procedure followed was the same as described in general procedure D to afford compound 22 The s olids were combined and purified by column chromatography in 1.5% MeOH/DCM The product was isolated in 79% yield (1.175 g). 1 H NMR (CDCl 3 H 3 ) 3 ), 2.46 (d, 2H, CHC H 2 CO), 4.12 (m, 1H, C H NHBoc), 4.40 (d, 2H, NHC H 2 Ph), 4.47 (d, 2H, PhC H 2 CH), 5.42 (broad s, 1H, N H), 5.94 (broad s, 1H, N H), 7.15 7.34 (m, 10H, aromatics). 13 C NMR (CDCl 3 33.7, 43.8, 49.8, 59.6, 126.7, 127.7, 128.0, 128.7, 129.0, 129.5, 138.2 138.6, 155.7, 170.9. 3 ( ( tert butoxycarbonyl)amino) N benzyl 4 methyl pentanamide (23) The procedure followed was the same as described in general procedure D to afford compound 23 The s olids were combined and purified by column

PAGE 94

94 c hromatography in 1% MeOH/DCM and gradient shifting to 5% MeOH/DCM after 900 mL The product was isolated in 80% yield (1.520 g). 1 H NMR (CDCl 3 CH(C H 3 ) 2 ), 1.39 (s, 9H, C(C H 3 ) 3 ), 1.83 (m, 1H, C H (CH 3 ) 2 ), 2.46 (d, 2H, NHCHC H 2 ), 3.67 (m, 1H, NHC H CH 2 ), 4.41 (d, 2H, NHC H 2 Ph), 5.07 (broad s, 1H, NH), 6.47 (broad s, 1H, NH). 13 C NMR (CDCl 3 .4, 127.7, 128.6, 138.2, 163.4, 166.7. 3 ((tert butoxycarbonyl)amino) N benzyl 2 methyl propanamide ( 24 ) The procedure followed was the same as described in general procedure D to afford compound 24 The s olids were combin ed and purified by column chromatography in 3/97 MeOH/DCM The product was isolated in 52% yield (1.310 g). 1 H NMR (CDCl 3 ) 1 3 (d, 3H, CHC H 3 ), 1.39 (s, 9H, C(C H 3 ) 3 ), 2. 55 ( m 1 H, CH 3 C H C H 2 ), 3. 22 ( m 2 H, NHBocC H 2 ), 4. 39 ( m 2H, NHC H 2 Ph), 5.1 0 (broad s, 1H, N H ), 6. 19 (broad s, 1H, N H ), 7.2 1 7.34 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 15.45, 28.31, 41.03, 43.36, 43.65, 79.24, 127.39, 127.51, 128.63, 138.17, 156.18, 174.87. HRMS [M+H] + calcd 293.1860 found 293.1857 General Dep trotection Reaction E to afford 3 amino N benzyl butanamide (25) Compound 25 (4.91 mmol, 1.36 g), was placed in a round bottom flask and dissolved in 10 mL DCM. Then 24.6 mmol (6.13 mL) of 4.0 M HCl in dioxane was

PAGE 95

95 added and stirred for 18 hours. After th e reaction time was complete the excess HCl was removed by sparging with N 2 The resulting solid was purified via column chromatography using 5% MeOH in DCM and gradient shifting by 2.5% MeOH increa ses per 400 mL eluent used a final percentage of 15% MeO H/DCM was achieved. The remaining impurities were removed by dual solvent recystalization in ethanol and hexanes. The solids were obtained through vacuum filtration. The product was i solated in 95% yield ( 0.832 g ). 1 H NMR (CDCl 3 /CD 3 CH 2 C H 2 CO), 3.04 (t, 2H, NH 2 C H 2 CH 2 ), 4.22 (s, 2H, NHC H 2 Ph) 7.08 7.20 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 [M+H] + calcd 179.1179, found 179.1175. 3 amino N benzyl b utanamide (26) The procedure followed was the same as d escribed in general procedure E to afford compound 26 No DCM was used to dissolve the starting material as the protected amino amide completely dissolved in HCl/dioxane. The reaction ran for 20 minut es before the product precipitated. The resulting solid was purified via column chromatography using 5% MeOH in DCM and gradient shifting by 2.5% MeOH increases per 400 mL eluent until a final percentage of 15% MeOH/DCM was achieved. Compound 26 was isolat ed in 96% yield. 1 H NMR (CDCl 3 /CD 3 CHC H 3 ), 2.50 (d, 2H, CHC H 2 CO), 3.51 (m, 1H, CH 3 C H CH 2 ), 4.25 (s, 2H, NHC H 2 Ph), 7.13 7.20 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 127.4, 128.3, 137.5, 164.7.

PAGE 96

96 3 amino N benzyl 3 phenyl propanamide ( 2 7) The procedure followed was the same as described in general procedure E to afford compound 27 The reaction ran for 4 hours before the product precipitated. The resulting solid was purified v ia column chromatography 5% MeOH in DCM for 500 mL and gradient shifting by 2.5% MeOH increases per 400 mL eluent used until a final percentage of 1 0 % MeOH/DCM was achieved. Compound 27 was isolated in 85% yield. 1 H NMR (CDCl 3 /CD 3 H 2 CO), 4.10 (d, 2H, NHC H 2 Ph), 4.81 (t, 1H,PhC H CH 2 ), 7.15 7.35 (m, 10H, aromatics). 13 C NMR (CDCl 3 /CD 3 44.2, 48.4, 127.1, 127.6, 127.9, 128.2, 128.7, 129.1, 135.4, 137.2, 171.9. 3 amino N b enzyl 4 phenyl butanamide ( 28 ) The procedure followed was the same as described in the general procedure E to afford compound 28 The solid was purified through column chromatography with 500 mL 5/95 MeOH/DCM followed by 10/90 MeOH/DCM. Compound 28 was is olated in 90% yield. 1 H NMR (CDCl 3 /CD 3 O H 2 CO), 2.99 (dd, 1H, PhC H 2 CH), 3.29 (dd, 1H, PhC H 2 CH), 3.88 (m, 1H, PhCH 2 C H CH 2 ), 7.10 7.525 (m, 10H, aromatics). 13 C NMR (CDCl 3 /CD 3 128.6, 128.9, 129.5, 135.9, 137.7, 174.9. HRMS [M+ H] + calcd 269.1648, found 269.1639.

PAGE 97

97 3 amino N benzyl 4 methyl pentanamide (29) The procedure followed was the same as described in general proc edure E to afford compound 29 No DCM was used to dissolve the starting materi al as the protected amino amide completely dissolved in HCl/dioxane. The reaction ran for 15 minutes before the product precipitated. The resulting solid was purified via column chromatography using 3 % MeOH in DCM and gradient shifting by 2.5% MeOH increas es per 4 00 mL eluent used until a final percentage of 1 0 % MeOH/DCM was achieved. Compound 29 was isolated in 90% yield. 1 H NMR (CDCl 3 /CD 3 6H, CH(C H 3 ) 2 ), 1.87 (m, 1H, C H (CH 3 ) 2 ), 2.48 (d, 2H, CHC H 2 CO), 3.17 (m, 1H, NH 2 C H CH 2 ), 4.23 (d, 2H, NHC H 2 Ph), 7.10 7.17 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 HRMS [M+H] + calcd 221.1648, found 221.1656. 3 amino N benzyl 2 methyl p rop anamide (30) The procedure followed was the same as d escribed in general procedure E to afford compound 30 No DCM was used to dissolve the starting material as the protected amino amide completely dissolved in HCl/dioxane. The reaction ran for 2.5 hours before the product precipi tated. The resulting solid was purified two times via column chromatography using 5% MeOH in DCM and gradient shifting by 2.5% MeOH

PAGE 98

98 i ncreases per 400 mL eluent until a final percentage of 1 0 % MeOH/DCM was achieved. The product was isolated in 89% yield (0. 758 g). 1 H NMR (CDCl 3 /CD 3 2 (d, 3H, CHC H 3 ), 2. 93 ( m 2H, CHC H 2 NH 2 ), 3.12 (m, 1H, CH 3 C H CH 2 ), 4. 36 ( dd 2H, NHC H 2 Ph), 7. 24 7. 36 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 5.85, 37.36, 41.94, 43.11, 127.13, 127.31, 128.36, 137.58, 173.99. HRMS [M+H] + ca lcd 193 .1 335 found 193.1347 Amino Amides 25 30 to Form 25 a 30 a To a 300 mL glass lined Parr high pressure vessel containing 20 mL of 1,2 amino amide 25 (99 mg, 0.55 mmol), W(CO) 6 (14 mg, 0.04 mmol), I 2 (98 mg, 0.39 mmol), and DBU (0. 092 mL 0.61 mmol). The interstitial space between the glass liner and the high pressure vessel was filled with 18 mL of DCE to ensure that system is saturated at higher t emperatures. The vessel was then charged with 80 atm CO and heated to 45 C for 24 hours with constant stirring. After cooling, the pressure was released and the organics were then washed immediately with Na 2 SO 3 and separated. The aqueous layer was then extracted with 3:1 CHCl 3 /EtOH solution (3 x 20 mL). The combined organic layers were then dried with MgSO 4 filtered, and concentrated under reduced pressure The resulting residue was then purified via flash column chromatography using a gradient shift of DCM to 3/97 MeOH/DCM to afford 3 benzyl dihydropyrimidine 2,4(1 H ) dione 25 a in 88% isolated yeild 1 H NMR (CDCl 3 /CD 3 2 C H 2 CONCH 2 Ph), 3.53 (q, 2H, NHC H 2 CH 2 ), 4.39 (d, 2H, NC H 2 Ph), 7.19 7.34 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 OD)

PAGE 99

99 CO 1726, 1678 cm 1 The product was identified by comparison to literature values. 31 Urea (26a) The procedure followed was the same as described in general procedure F as to afford compound 2 0a The product was purified via flash column chromatography using DCM as elue nt and gradient shifted to 1/99 MeOH/DCM after 700 mL to afford the acyclic urea 26a in 86% isolated yield 1 H 3 ), 2.31 (d, 2H, CHC H 2 CO), 3.92 (m, 1H, CH 3 C H CH 2 ), 4.25 (d, 2H, NCH 2 Ph), 7.21 7.29 (m, 5H, C 6 H 5 ), 8.33 (s, 1H, NH). 13 CO 1651, 16 87 cm 1 Urea (27a) The procedure followed was the same as described in general procedure F to afford compound 27 a After the sodium sulfite wash, 15 mL water and 5 mL methanol was added to help reduce formation of solid d uring extractions. The product was purified via flash column chromatography using 3/97 MeOH/DCM as eluent to afford the acyclic urea 27a in 7% isolated yield 1 H 2 CO), 4.21 (t, 1H, PhC H CH 2 ), 5.10 (d, 2H, NC H 2 Ph), 7.13 7.28 (m, 10H, C 6 H 5 ). 13 C NMR (DMSO)

PAGE 100

100 CO 1665, 1698 cm 1 Urea (28 a ) The procedure followed was the same as described in general procedure F to afford compound 28 a in 29% isolated yield 1 H NMR (CDCl 3 /CD 3 CHC H 2 CO), 2.81 (d, 2H, PhC H 2 CH), 4.14 (quintet, 1H, PhCH 2 C H CH 2 ), 4.36 (d, 2H, NC H 2 Ph), 7.12 7.34 (m, 10H, aromatics), 7.71 (broad s, 1H, N H ). 13 C NMR (CDCl 3 /CD 3 CO 1637, 1684 cm 1 HRMS [M+H] + calcd 563.301 7, found 563.3013. Urea (30a) The procedure followed was the same as described in general procedure F as to afford compound 3 0a The product was purified via flash column chromatography using DCM as eluent and gradient shi fted to 1/99 MeOH/DCM after 700 mL to afford the acyclic urea 30a 13 16.1 42.7 45.36 62.3, 127.4, 127.9, 129.0 1 40.15 1 67.6 .2, 17 4 4 CO 1 638, 1655 16 9 7 cm 1 HRMS [M+H] + calcd 219.1128, [M+H] + found 219.1119, [M+Na] + calcd 241.0947 [M+Na] + found 241.0944.

PAGE 101

101 amino amide (31) In a 100 mL round bottom flask, 5.29 mmol (1.000 g) of 3 tert butoxycarbonyl amino propanoic acid was dissolved in 10 mL THF and cooled to 78 C. Under N 2 6.61 mmol (6.72 mL) NMM was added and reaction stirred for 5 minutes before 6.61 mmol (0.86 mL) of isobutylchloroformate was added. After stirring for 10 minutes, 11.64 mmol (5.82 mL) of methylamine in THF was added and the reaction was monitored for venting of excess methylamine gas ove r the following 30 minutes. A final 5.82 mmol (2.91 mL) of CH 3 NH 2 /THF was added for a total of 17.46 mmol. The reaction was stirred for an additional 30 minutes before being allowed to warm to room temperature and stir for 3 days. Then reaction mixture wa s condensed under reduced pressure and the resulting solids were washed with hexanes. The filtrate was concentrated by reduced pressure then stirred in hexanes and filtered again. The solids were combined and purified by column chromatography with 3/97 M eOH /DCM gradient shifted to 10/90 MeOH/DCM as eluent. The product was isolated in 82% yield (880 mg). The product was confirmed by comparison to literature values. 33 1 H NMR (CDCl 3 42 (s, 9H, C(CH 3 ) 3 ), 2. 39 ( t 2 H, CH 2 C H 2CO ), 2.80 (d, 3H, N HC H 3 ), 3. 40 ( q 1 H, NHC H 2 C H 2 ), 5. 20 (broad s, 1H, NH), 5.87 (broad s, 1H, NH ) 13 C NMR (CDCl 3 ) 26.20, 28.34, 36.20, 36.61, 79.32, 157.49, 171.95.

PAGE 102

102 3 (( tert butoxycarbonyl)amino) N methyl butanamide (32) The protected amino amide 32 was afforded through the same general procedure as 31 .The washed solids in hexane were filtered using a fine frit. The filtrate was concentrated under reduced pressure, re suspend ed in hexanes and filtered a total of six times. The solids were purified by column chromatography with 5/95 MeOH/DCM as eluent. The product was isolated in 82% yield (1.517 g). The product was confirmed by comparison to literature values. 33 1 H NMR (CDCl 3 21 (d, 3H, CHC H 3 ), 1. 42 (s, 9H, C(CH 3 ) 3 ), 2. 38 (m, 2 H, C H C H 2 CO ), 2.78 (d, 3H, N HC H 3 ), 3. 95 ( m 1 H, NHC H C H 3 ), 5. 26 (broad s, 1H, NH), 6.14 (broad s, 1H, NH ) 13 C NMR (CDCl 3 ) 20.70, 26.13, 42.80, 44.15, 79.31, 155.54, 171.46. The protected amino amide 33 was afforded through the same general procedure as 31 The washed solids in hexane were filtered using a fine frit. The filtrate was concentrated under reduced pressure, re suspended in hexanes and filtered for a to tal of six times. The solids were purified by column chromatography with 5/95 MeOH/DCM as eluent. The product was isolated in 82% yield (1.517 g). The product was confirmed by comparison to literature values. 33 1 H NMR (CDCl 3 21 (d, 3H, CHC H 3 ), 1. 42 (s, 9H, C(CH 3 ) 3 ), 2. 38 (m, 2 H, C H C H 2 CO ), 2.78 (d, 3H, N HC H 3 ), 3. 95 ( m

PAGE 103

103 1 H, NHC H C H 3 ), 5. 26 (broad s, 1H, NH), 6.14 (broad s, 1H, NH ) 13 C NMR (CDCl 3 20.70, 26.13, 42.80, 44.15, 79.31, 155.54, 171.46. Synthesis of Unsymmeti c Ureas General P rocedure A for the C atalytic C arbonylati on of p Substituted Aryl Amines N,N' diphenylurea (41 a ) Aniline (0.46 g, 5.0 mmol) was added to a glass lined 3 0 0 mL Parr high pressure vessel with W(CO) 6 (0.053 g, 0.15 mmol, I 2 (1.27 g, 5.00 mmol ) DMAP (1.22 g, 10.0 mmol ) in CH 2 Cl 2 ( 40m L) The vessel was charged with 80 atm CO and the reaction was left to stir for 8 h under 40 C. After that the autoclave was cooled, the excess CO gas was released, and the reaction mixture was filtered and washed with saturated Na 2 SO 3 T he resulting solution was then dried with MgSO 4 filtered, and the excess solvent removed by evaporation. T he crude residue was purified by flash chromatograph y on silica gel using mixture s of e thyl a cetate and CH 2 Cl 2 as eluent to recover 41 a in 85 % yield (0.45 g) The product was identified by comparison with literature data. 151 IR (neat) CO 1635 cm 1 1 H NMR (300 MHz, DMSO d 6 ) 8.60 (s, 2H NH ) 7.40 (d, J = 8.47 Hz, 2 H Ar ) 7.22 (t, J = 7.59 Hz, 2 H Ar ) 6.84 6.97 (m, 1 H Ar ) ppm 13 C NMR (75 MHz, DMSO d 6 ) 153.1, 140.3, 129.4, 122.4, 118.8 ppm 1 (4 Cyanophenyl) 3 (4 nitrophenyl)urea (42hi). Pro cedure A afford ed urea 42 hi from p n itroaniline 40 h (0. 138 g, 1 .00 mmol) and 4 a minobenzonitrile 40 i (0.118g, 1 .00 mmol) in 5 8 % yield (0.150 g). The product was identified by comparison with literature data. 152 IR (neat) CO 1644 cm 1 1 H NMR (300MHz, CDCl 3 ) 7.90 (d, J = 9.1 Hz, 2H) 7.32 (d, J = 3.6 Hz, 4H) 7.22 (s, 4H) ppm HRMS calcd fo r C 14 H 10 N 4 O 3 [M + H] + 283.0826, found [M + H] + 283.0755.

PAGE 104

104 Ethyl 4 (3 (4 nitrophenyl)ureido)benzoate (42hj). Procedure A afforded urea 42 hj from p nitroaniline 40 h (0.138 g, 1.00 mmol) and benzocaine 40 j (0.165 g, 1.0 cm 1. 1H NMR (300MHz, DMSO 2H), 7.92 (d, J = 7.3 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.3 Hz, 2H), 4.29 (q, J = 6.8 Hz, 2H), 1.31 (t J = 6.4 Hz, 3H) ppm. 13 C NMR (75MHz, DMSO 152.4, 146.6, 144.3, 142.0, 138.3, 131.0, 125.8, 124.1, 118.4, 61.0, 14.9 ppm. HRMS calcd for C 16 H 15 N 3 O 5 [M + H] + 330.1084, found [M + H] + 330.1079. 1 (4 Chlo rophenyl) 3 (4 methoxyphenyl)urea (42be). P ro cedure A afford ed urea 42 be 153 from 4 c hlor o aniline 40 b ( 0.255 g, 2.00 mmol) and p a nisidine 1e (0.123 g, 1 .00 mmol) in 43 % yield (0.118 g). IR (neat) CO 1633 cm 1 1 H NMR (300 MHz, DMSO d 6 ) 8.66 (s, 1H) 8.44 (s, 1H) 7.41 (d, J = 8.91 Hz, 4H) 7.16 7.34 (m, 4H) 6.81 (d, J = 8.91 Hz, 2H) 3.66 (s, 3 H) ppm. 13 C NMR (75MHz, DMSO d 6 55.15 ppm HRMS calcd C 14 H 13 ClN 2 O 2 [M + H] + 277.0738, found [M + H] + 277.0742.

PAGE 105

105 1 (4 Chloro 3 (trifluoromethyl)phenyl) 3 (4 methoxyphenyl)urea (42pe). Procedure A produced urea 42 pe from p anisidine 40 e (0.123 g, 1.00 mmol) and 4 chloro 3 (trifluoromethyl) aniline 40 p (0.391 g, 2.00 mmol) in 12% yield (0.042 g). IR (neat) CO 16 27 cm 1 1 H NMR (300MHz, DMSO d 6 1H), 7.64 7.48 (m, 2H), 7.31 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 3.67 (s, 3H) ppm 13 C NMR (75 MHz, DMSO d 6 11 4.6, 55.8, 23.4 ppm HRMS calcd C 1 5 H 1 2 Cl F 3 N 2 O 2 [M + H] + 345 .0 612 found [M + H] + 345 .0 608. 1 (4 Chlorophenyl) 3 (4 phenoxyphenyl)urea (42bf). Procedure A afforded 42 bf from 4 phenoxyaniline 40 f (0.185 g, 0.999 mmol) a nd 4 chloroaniline 40 b CO 1633 cm 1 1 H NMR (300MHz, DMSO d 6 ) 8.79 (s, 1H), 8.71 (s, 1H), 7.51 7.45 (m, 4H), 7.40 7.27 (m, 4H), 7.14 7.03 (m, 1H), 7.01 6.91 (m, 4H) ppm 13 C NMR (75 MHz, DMSO d 6 ) 158 .2, 153.1, 151.4, 139.4, 136.1, 130.5, 125.9, 123.4, 120.7, 120.4, 120.3, 118.3 ppm HRMS calcd for C 19 H 15 ClN 2 O 2 [M + Na ] + 361.0706 found [M + Na ] + 306.0706.

PAGE 106

106 1 (4 C hloro 3 ( t rifluoromethyl) p heny l) 3 (4 p henoxypheny l) u rea (42pf ) Procedure A afforded 42pf from 4 chloro 3 (trifluoromethyl) aniline 40 p (0.978 g, 5.00 mmol) and 4 phenoxyaniline 40 f (0.185 g, 1.00 mmol) in 45% yield (0.183 g). IR (neat) CO 1649 cm 1 1 H NMR (300MHz, DMSO d 6 ) H), 8.09 (d, J = 2.1 Hz, 1H), 7.71 7.53 (m, 2 H), 7.46 (d, J = 9.1 Hz, 2 H), 7.34 (t, J = 7.9 Hz, 2 H), 7.14 7.03 (m, 1H), 7.01 6.88 (m, 3 H) ppm 13 C NMR ( 75 MHz, DMSO d 6 ) 158.2, 153. 2, 151.8, 140.1, 135.8, 132.6, 130.6, 123.5, 121.2, 120.4, 118.4 ppm HRMS calcd for C 2 0 H 14 ClF 3 N 2 O 2 [M + H ] + found [M + Na ] + 407.0774 1 Methyl 1,3 D iphenylurea (42aq ) Procedure A afforded 42 aq 154 from aniline 40 a (0.093 g, 1.00 mmol) and N methylaniline 40 q (0.536 g, 5.00 mmol) in 31% yield (0.070 g). IR (nea t) CO 1662 cm 1 1 H NMR (300MHz, CDCl 3 ) 7.16 (m, 9H), 7.04 6.94 (m, 1H), 6.25 (br. s., 1H), 3.34 (s, 3 H) ppm 13 C NMR (75 MHz, CDCl 3 127.61, 123.0 119.4, 37.4 ppm 1 M ethyl 3 (4 p henoxyphenyl) 1 p henylurea ( 42 fq). Procedure A afforded urea 42 fq from 4 phenoxyaniline 40 f (0.093 g, 0.500 mmol) and N methylaniline 40 q (0.161 g, 1.50 mmol) in 19% yield (0.030 g). IR (neat) CO 1645 cm 1 1 H NMR (300 MHz, DMSO d 6 ) = 8.20 (s, 1H), 7.54 7.29 (m, 9H), 7.28

PAGE 107

107 7.19 (m, 1H), 7.13 7.03 (m, 3H), 3.36 (s, 3H). 13 C NMR (75 MHz, DMSO d 6 ) 155.5, 151.5, 144.7, 136.7, 136.4, 129.8, 126.9, 126.3, 122.3, 120.6, 120.4, 119.8, 118.2, 38.2 ppm HRMS calcd for C 2 0 H 18 N 2 O 2 [M + Na ] + 341.1260 found [M + Na ] + 341.1269. 3 (4 C hloro 3 ( t rifluoromethyl) p henyl) 1 m ethyl 1 p henylurea (42pq). Procedure A afforded urea 42 pq from 4 chloro 3 (trifluoromethyl)aniline 40 p (0.196 g, 1.00 mmol) and N methyl aniline 40 q (0.321 g, 3.00 mmol) in 25% yield (0.0812 g). IR (neat) CO 1661 cm 1 1 H NMR (300 MHz, CDCl 3 ) 7.62 7.15 (m, 8H), 6.33 (br. s., 1H), 3.35 (d, J = 1.8 Hz, 3H) ppm 13 C NMR (75 MHz, CDCl 3 ) 154.1, 142.4, 137.9, 131.9, 130.8, 128.6, 127.7, 123.3, 118.4, 109.9, 37.6 ppm HRMS calcd for C 15 H 12 ClF 3 N 2 O [M + N a ] + 351.0482 found [M + Na ] + 351.0491. 1 (4 C hlorophenyl) 3 (4 m ethoxyphenyl) u rea ( 42 be, authentic sample). In a 50 mL round bottom flask, 1,1' carbonyldiimidazole (0.700 g, 4.31 mmol) was slurried in 6 mL dry tetrah ydrofuran (THF), followed by dropwise addition of 4 chloroaniline (0.500 g, 3.93 mmol) and p anisidine (0.459 g, 3.72 mmol) dissolved in 10 mL dry THF. The reaction was stirred for 36 hours under argon. A white solid precipitate was collected by vacuum f iltration and washed with cold ethyl acetate. The yellow filtrate was washed with water (3 x 15 mL). Hexanes were slowly added to the

PAGE 108

108 organic layer resulting in a white precipitate of 3be that was collected by vacuum filtration. Yield: 0.965 mg, 89%. 1 (4 C hlorophenyl) 3 (4 p henoxyphenyl) u rea (42bf, authentic sample). In a 50 mL round bottom flask, 4.31 mmol (0.700 g) 1,1' carbonyldiimidazole was slurried in 6 mL dry THF, followed by dropwise addition of 3.93 mmol (0.50 0 g) of 4 chloroaniline and 3.93 mmol (0.530 g) of 4 phenoxyaniline dissolved in 10 mL dry THF. The reaction was stirred at room temperature for 3 days under argon. Solvent was removed under reduced pressure and the solid was partitioned between 15 mL wate r and 15 mL ethyl acetate. The organic layer was washed with water (3x 15 mL) and the resulting solid was vacuum filtered and then recrystallized in ethanol. Yield: 0.984 g of white solid, 74%. General Procedure for Ca rbonylation of Amines to Formamides Procedure A N (4 Methoxybenzyl)formamide ( 4 5 ). To a 300 mL glass liner for a Parr high pressure vessel were added methanol (60 mL), NaI (0.600 g, 4.00 mmol), NaIO 4 (1.37

PAGE 109

109 g, 6.40 mmol), potassium carbonate (2.21 g 16.0 mmol) and amine 4 3 (0.631 g, 4.06 mmol). The liner was placed in the vessel and methanol was added to the space between the liner and vessel. The vessel was then closed, charged to 45 atm with carbon monoxide, heated to 90 C and stirred for 24 h. At the completion of the reaction the solution was placed in a separatory funnel. Saturated sodium sulfite was added to the solution and mixed thoroughly. Water was added to dissolve the solid salt present and the mixture was extracted with DCM (3 x 25 mL). The organic layers were combined and the solvent was removed via rotary evaporation leaving an off white solid residue. The solid was purified via column chromatography using silica gel and ethyl acetate/hexanes as the el uent (50:50 ethyl acetate: hexanes shifted to pure ethyl acetate) to provide 4 5 as a white solid (0.604 g, 80% yield). The compound was identified by comparison with literature data. 155 1 H NMR (DMSO d 6 8.10 (s, 1 H), 7.19 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 4.23 (d, J = 6.0 Hz, 2 H), 3.73 (s, 3 H); 13 C NMR (DMSO d 6 IR (solid) 1641 cm 1 ; HRMS (ESI): Calcd for C 9 H 11 NO 2 [M+Na] + 188.0682, found 188.0690. Procedure B N (Benzyl)formamide To a 300 mL glass liner for a Parr high pressure vessel were added methanol (60 mL), potassium carbonate (1.66 g, 1 2.0 mmol), and amine 52 (0.429 g, 4.00 mmol). The liner was placed in the vessel. The vessel was then closed, charged to 35 atm with carbon monoxide, and stirred for 24 h. At the completion of the

PAGE 110

110 reaction the solution was placed in a separatory funnel. Water was added to dissolve any soli d base and to achieve separation between methanol and DCM. The mixture was extracted with DCM (3 x 25 mL). The organic layers were combined and the solvent was removed via rotary evaporation leaving an off white solid residue. The solid was purified via column chromatography using silica gel and ethyl acetate/hexanes as the eluent (50:50 ethyl acetate: hexanes shifted to pure ethyl acetate) to provide 5 3 as a white solid (0.268 g, 49% yield). The compound was identified by comparison with literature dat a. 156 1 H NMR (DMSO d 6 7.13 (m, 5 H), 4.30 (d, J = 6.1 Hz, 2 H); IR (solid) 1638 cm 1 Procedure C N Formylpiperidine ( 84 ) To a 300 mL glass liner for a Parr high pressure vessel were added methanol (60 mL), potassium carbonate (1 .66 g, 12.0 mmol) and amine 83 (0.325 g, 3.82 mmol). The liner was placed in the vessel. The vessel was then closed, charged to 35 atm with carbon monoxide, and stirred for 7 h. At the completion of the reaction the solution was placed in a separatory funnel. Water was added to dissolve any solid base and to achieve separation between methanol and chloroform. The mixture was extracted with chloroform (3 x 25 mL). The organi c layers were combined and the solvent was removed via rotary evaporation leaving a slightly yellow oil residue. The oil was purified via column chromatography using silica gel and CHCl 3 /CH 3 OH as the eluent (CHCl 3 shifted to 100:5 CHCl 3 /CH 3 OH) to provide 84 as a

PAGE 111

111 colorless oil (0.335 g, 78% yield). The compound was identified by comparison with literature data. 157 Procedure D N Butylformamide ( 74 ) To a 25 mL glass vial for a multi chamber Parr high pressure vess el were added methanol (15 mL), potassium carbonat e (0.553 g, 4.00 mmol) and amine 73 (0.0788 g, 1.08 mmol). The liner was placed in the vessel. The vessel was then closed, charged to 25 atm with carbon monoxide, and stirred for 24 h. At the completion of the reaction the solution was acidified with 3.0 M HCl to approximately pH 2 and placed in a separatory funnel. Water was added to achieve separation between methanol and DCM. The mixture was extracted with DCM (3 x 10 mL). The organic layers were co mbined and the solvent was removed via rotary evaporation to afford 74 as a colorless oil (0.0828 g, 77% yield). The compound was identified by comparison with literature data. 158 Forma mide Products N (4 Nitrobenzyl)formamide ( 67 ). Procedure A was used with the HCl salt of amine 6 6 (0.755 g, 4.01 mmol). The procedure was altered to include an additional purification via column chromatography using silica gel and 7:3 ethyl acetate: DCM. The product was afforded in a 7 % yield and was identified by comparison to literature data. 159

PAGE 112

112 N (4 Methylthio )formamide ( 47 ). Procedure B was used with amine 46 ( 0.400 mL 2.87 mmol). The product was afforded in a 7 % yield and was identified by comparison to literature data. 160 N (4 Methylbenzyl)formamide ( 49 ). Procedure B was used with amine 4 8 (0.483 g, 3.99 mmo l) and afforded the product in 80 % yield. 1 H NMR (DMSO d 6 7 .02 (m, 4 H), 4.25 (d, J = 6.0 Hz, 2 H), 2.27 (s, 3 H); 13 C NMR (DMSO d 6 135.9, 128.8, 127.3, 40.5, 20.7; IR (solid) 1650 cm 1 ; HRMS (ESI): Calcd for C 9 H 12 NO [M+H] + 150.0913, found 150.0915; Anal. Calcd for C 9 H 11 NO: C, 72.46; H, 7.43; N, 9.39; found: C, 72.64; H, 7.62; N, 9.31. N (4 Vinylbenzyl)formamide ( 51 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (0.829 g, 6.00 mmol), and amine 50 (0.263 g, 1.97 mmol) to afford the product i n a 7 9 % yield. 1 H NMR (DMSO d 6 J = 7.9 Hz, 2 H), 6.71 (dd, J = 10.8, 17.7 Hz, 1 H), 5.80 (d, J = 17.7 Hz, 1 H), 5.23 (d, J = 10.8 Hz, 1 H), 4.29 (d, J = 5.8 Hz, 2 H); 13 C NMR (DMSO d 6 13 5.5, 127.2, 125.8, 113.7, 40.2; IR (solid) 1651 cm 1 ; HRMS (ESI): Calcd for C 10 H 12 NO

PAGE 113

113 [M+H] + 162.0913, found 162.0913; Anal. Calcd for C 10 H 11 NO: C, 74.51; H, 6.88; N, 8.69; found: C, 74.40; H, 7.31; N, 8.35. N (4 Fluorobenz yl)formamide ( 55 ). Procedure B was used with amine 5 4 (0.501 g, 4.00 mmol) and afforded the product in a 78 % yield. The solid was identified by comparison with literature data. 161 N (4 Iodobenzyl)formamide ( 5 7 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (1.11 g, 8.03 mmol) and the HCl salt of amine 5 6 (0.538 g, 1.82 mmol) to afford the product in a 61 % yield. 1 H NMR (DMSO d 6 J = 8.3 Hz, 2 H), 7.07 (d, J = 8.2 Hz, 2 H), 4.24 (d, J = 6.3 Hz, 2 H); 13 C NMR (CDCl 3 137.2, 129.6, 93.1, 41.6; IR (solid) 1648 cm 1 ; HRMS (APCI): Calcd for C 8 H 9 INO [M+H] + 261.9723, found 261.9723; Anal. Calcd for C 8 H 8 INO: C, 36.81; H, 3.09; N, 5.37; found: C, 37.06; H, 3.03; N, 5.13. N (4 Bromobenzyl)formamide ( 5 9 ). Procedure B was used with amine 5 8 (0.753 g, 4.05 mmol) and afforded the product in a 6 8% yield. 1 H NMR (DMSO d 6 J

PAGE 114

114 = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 4.27 (d, J = 6.0 Hz, 2 H); 13 C NMR (DMSO d 6 ): 1 ; HRMS (APCI): Calcd for C 8 H 9 BrNO [M+H] + 213.9862, found 213.9867; Anal. Calcd for C 8 H 8 BrNO: C, 44.89, H, 3.77; N, 6.54; found: C, 44.87 ; H, 3.77; N, 6.54. N (4 Chlorobenzyl)formamide ( 61 ). Procedure B was used with amine 60 (0.566 g, 3.99 mmol) and afforded the product in a 84 % yield. The solid was identified by comparison with literature data. 161 Met hyl 4 (formamidomethyl)benzoate ( 63 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (1.11 g, 8.03 mmol) and the HCl salt of amine 62 (0.396 g, 1.96 mmol) to afford the product in a 55 % yield. 1 H NMR (DMSO d 6 J = 7.7 Hz, 2 H), 7.40 (d, J = 7.7 Hz, 2 H), 4.38 (d, J = 6.0 Hz, 2 H), 3.84 (s, 3 H); 13 C NMR (DMSO d 6 cm 1 ; HRMS (ESI): C alcd for C 10 H 12 NO 3 [M+H] + 194.0812, found 194.0809; Anal. Calcd for C 10 H 11 NO 3 : C, 62.17; H, 5.74; N, 7.25; found: C, 62.39; H, 5.71; N, 6.96

PAGE 115

115 N (4 Formamidomethyl)benzoic acid ( 65 ). Procedure B was used with amine 6 4 (0.603 g, 3.99 mol). The procedure w as altered in the following way: before extraction the pH was adjusted to 1 with 3.0 M HCl, after which no further purification was necessary. The product was obtained in a 41 % yield. 1 H NMR (DMSO d 6 J = 7.7 Hz, 2 H), 7.37 (d, J = 7.7 Hz, 2 H), 4.37 (d, J = 6.0 Hz, 2 H); 13 C NMR (DMSO d 6 ): 1 ; HRMS (ESI): Cal cd for C 9 H 10 NO 3 [M H] 178.0510, found 178.0514; Anal. Calcd for C 9 H 9 NO 3 : C, 60.33; H, 5.06; N, 7.82; found: C, 60.28; H, 5.41; N, 7.00. N (4 Nitrobenzyl)formamide ( 6 7 ). Procedure B was used with the HCl salt of amine 6 6 ( 0.755 g, 4.01 mmol). The procedure was altered to include an additional purification via column chromatography using silica gel and 7:3 ethyl acetate: DCM The product was afforded in 35 % yield and was identified by comparison to literature data. 159 N (4 (Trifluromethyl)benzyl)formamide ( 6 9 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (0.829 g, 6.00 mmo l) and amine 6 8 (0.351 g, 2.01 mmo l) and afforded the product in 36 % yield. The solid was identified by comparison with literature data. 161

PAGE 116

116 N (4 Cyanobenzyl)form amide ( 71 ). Procedure B was altered to use the HCl salt of amine 70 (0.674 g, 4.00 mmol) and potassium carbonate (2.21 g, 16.0 mmol) The product was afforded in 35 % yield. 1 H NMR (DMSO d 6 J = 7.9 Hz, 2 H), 7.45 (d, J = 7.9 Hz, 2 H), 4.38 (d, J = 6.0 Hz, 2 H); 13 C NMR (DMSO d 6 128.0, 118.8, 109.6, 40.5; IR (solid) 2229, 1651 cm 1 ; HRMS (ESI): Calcd for C 9 H 9 N 2 O [M+H] + 161 .0705, found 161.0709; Anal. Calcd for C 9 H 8 N 2 O: C, 67.49; H, 5.03; N, 17.49; found: C,67.50; H, 4.81; N, 17.11. N Formylpyrrolidine ( 82 ). Procedure C was used with amine 81 (0.285 g, 4.01 mmo l) and afforded the product in 39% yield. The oil was identified by comparison with literature data. 157 N Formylmorpholine ( 8 2 ). Procedure C was used with amine 8 1 (0.350 g, 4.02 mmo l) and afforded the product in 66% yield. The oil was identi fied by comparison to literature data. 162

PAGE 117

117 N Formyl piperazine ( 8 6 ). Procedure C was used with amine 8 5 (0.350 g, 4.02 mmo l) and afforded the product in 55 % yield. The oil was identified by comparison to lite ]] rature data. 162 N Propylformamide ( 72 ). Procedure D was used with amine 71 (0.0543 g, 0.919 mmo l) and afforded the product in 40% yield. The oil was identified by comparison to literature data. 163 N Isopropylformamide ( 74 ). Procedure D was used with amine 7 3 (0.0564 g, 0.954 mmo l) and afforded the product in 37% yield. The oil was identified by comparison to literature data. 163 N Isobutylformamide ( 76 ). Procedure D was used with amine 75 (0.1470 g, 2.01 mmol) and afforded the p roduct in 61% yield. The oil was identified by comparison to literature data. 164

PAGE 118

118 N Tertbutylformamide ( 78 ). Procedure D was used with amine 77 (0.0793 g, 1.08 mmol). Trace amo unts of product were identified spectroscopically by comparison to literature data. 156 N Cyclohexylformamide ( 80 ). Procedure D was used with amine 79 (0.1974 g, 1.99 mmol) and afforded the product in a 71% yield. The oil was identified by comparison to literature data. 165

PAGE 119

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128 BIOGRAPHICAL SKETCH Jennifer Johns was born in Chapel Hill, North Carolina, in 1985 to Bob and Pam Johns. She received her B.S. in chemistry from Covenant College in 2007, and worked in the chemistry department under Dr. Larry Mehne. While working for the American renewed and she enrolled in graduate school at the University of Florida. Under the guidance of Professor McElwee White, Jennifer has worked to complete the McElwee she has presented numerous presentations receiving an ACS DOC travel award for the 238 th ACS National Meeting and Exposition. Jennifer will graduate in Decem ber 2013 with PhD in Chemistry