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Application of Synthetic Heterocyclic Chemistry

Permanent Link: http://ufdc.ufl.edu/UFE0021767/00001

Material Information

Title: Application of Synthetic Heterocyclic Chemistry
Physical Description: 1 online resource (141 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: acylation, acylbenzotriazole, amide, cyclization, heterocyclic, imidazolidinone, ionic, lactam, microwave, triphenylphosphoranylidene
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 1H-Benzotriazole is a versatile synthetic auxiliary, widely applied to many organic syntheses. In our continuous work on benzotriazole methodology, we have developed efficient methods for the preparation of heterocyclic compounds. The formation of N-protected peptidic alpha-triphenylphosphoranylidene esters by the C-acylation of P-ylide esters with N-protected peptidic (alpha-aminoacyl)benzotriazoles under microwave irradiation is described. The formation of distabilized triphenylphosphoranylidene moieties on pyrrolidine, pyrrolizine, and piperidine rings by the room temperature N-deprotection and cyclization of peptidic alpha-triphenylphosphoranylidene esters and nitriles is described. The formation of N-regioalkylated 4-substituted imidazoles by regioselective N-benzoylation and N-alkylation with quaternization, followed by debenzoylation and dequarternization is described. The formation of tetrasubstituted trans-imidazolidin-2-ones by treatment of imines with lithiated benzotriazole intermediates and subsequent treatment with Lewis acid and silylenol ethers to modify the 4- or 5-position is described.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: 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, 2008.
Local: Adviser: Katritzky, Alan R.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2008-11-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0021767:00001

Permanent Link: http://ufdc.ufl.edu/UFE0021767/00001

Material Information

Title: Application of Synthetic Heterocyclic Chemistry
Physical Description: 1 online resource (141 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: acylation, acylbenzotriazole, amide, cyclization, heterocyclic, imidazolidinone, ionic, lactam, microwave, triphenylphosphoranylidene
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 1H-Benzotriazole is a versatile synthetic auxiliary, widely applied to many organic syntheses. In our continuous work on benzotriazole methodology, we have developed efficient methods for the preparation of heterocyclic compounds. The formation of N-protected peptidic alpha-triphenylphosphoranylidene esters by the C-acylation of P-ylide esters with N-protected peptidic (alpha-aminoacyl)benzotriazoles under microwave irradiation is described. The formation of distabilized triphenylphosphoranylidene moieties on pyrrolidine, pyrrolizine, and piperidine rings by the room temperature N-deprotection and cyclization of peptidic alpha-triphenylphosphoranylidene esters and nitriles is described. The formation of N-regioalkylated 4-substituted imidazoles by regioselective N-benzoylation and N-alkylation with quaternization, followed by debenzoylation and dequarternization is described. The formation of tetrasubstituted trans-imidazolidin-2-ones by treatment of imines with lithiated benzotriazole intermediates and subsequent treatment with Lewis acid and silylenol ethers to modify the 4- or 5-position is described.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: 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, 2008.
Local: Adviser: Katritzky, Alan R.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2008-11-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0021767:00001


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1 APPLICATION OF SYNTHETI C HETEROCYCLIC CHEMISTRY By ADAM S. VINCEK A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2008

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2 2008 Adam S. Vincek

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3 To My Family Martina S. Vincek William C. & Martha M. Vincek Penny E. Vincek and Family Ilse Holzer and Family

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4 ACKNOWLEDGMENTS There is no doubt that the Game has its dangers. For that very reas on we love it; only the weak are sent out on paths without perils. From The Glass Bead Game, by Hermann Hesse I thank Alan R. Katritzky, my advisor for his knowledge, kindness, and strength. My special thanks go to my family. My very sp ecial thanks go to my wife, Martina. I thank Ben Smith, Lori Clar k, Eric F. V. Scriven, Zuoquan Wang, Joey Lott, Myong Sang Kim, Khalid Widyan, Danniebelle Haase, Me gumi Yoshioka, Novruz G. Akhmedov, Kazuyuki Suzuki, Dennis C. Hall, Dazhi Zhang, Janet Cu sido, Valerie RodriguezGarcia, Khanh Nguyen Bao Le, Ashraf A. A. Abdel-Fattah, Hongf ang Yang, Anamika Singh, Gala Vakulenko, Gwen McCann, Srinivasa Rao Tala, Kostyantyn Kiri chenko, Prabhu Mohapatra, Sasha Kulshyn, Niveen Khashab, Kapil and Rena Gyanda, and E lisabeth Sheppard my UF mentors and friends for their various support. I thank Kirk S. Scha nze, Ronald K. Castellano, Y. (Charles) Cao, and Anuj Chauhan, my excellent committee members, for their help and knowledge. I thank Rolf Krauss, Paul J. Kropp, Wayne and Cristie Brouillette, Julius B. Lucks, Tanja Wieber, Dorothe Alsentzer, Weixing (William) Li, Johann (Hans) Leban, Gabriel Garcia, Harald Schmitt, Sergei A. Belyakov, Peter J. Steel, Jan F. Mieses, Cathal Meere, and the Holzers my mentors and friends for their help and inspiration to obtain my goals.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........8 LIST OF FIGURES................................................................................................................ .........9 LIST OF SCHEMES................................................................................................................ ......10 ABSTRACT....................................................................................................................... ............19 CHAPTER 1 GENERAL INTRODUCTION..............................................................................................20 1.1 Opening Remarks.........................................................................................................20 1.2 General Discussion of Amides.....................................................................................20 1.2 General Overview of the Work....................................................................................23 1.4 Aim and Importance of the Work................................................................................38 2 MICROWAVE ASSISTED C-AC YLATION OF P-YLIDES..............................................41 2.1 Introduction..................................................................................................................41 2.2 Results and Discussion................................................................................................44 2.2.1 Protected (-Aminoacyl)benzotriazoles............................................................44 2.2.2 Chiral N-Protected Peptidic -Triphenylphosphoranylidene Esters.................45 2.2.3 Achiral N-Protected Peptidic -Triphenylphosphoranylidene Esters...............48 2.2.4 Peptidic -Triphenylphosphoranylid ene Diastereomers...................................49 2.3 Conclusions..................................................................................................................52 2.4 Experimental Section...................................................................................................52 2.4.1 Preparation of N-Protected (-Aminoacyl)benzotriazoles. 2.5ag, 2.8ac......53 2.4.2 Preparation of N-Pr otected Peptidic -Triphenylphosphoran ylidene Esters, Under Microwave Irradiation. 2.7ag, 2.9..................................................54 2.4.3 Preparation Under Conve ntional Heating. 2.7b,d.............................................54 2.4.4 Preparation of P-Ylide Salt. 2.13......................................................................56 2.4.5 Preparation of Peptidic Diastereomers. 2.14...............................................57 3 SYNTHESES OF 2,4-DIOXO-3-TR IPHENYLPHOSPHORANYLIDENE PYRROLIDINES AND OTHER DISTABILIZED TRIPHENYLPHOSPHORANYLIDENE SUBSTITUTED RINGS.....................................59 3.1 Introduction..................................................................................................................59 3.2 Results and Discussion................................................................................................67 3.2.1 Methylations and Salt Neutralization.................................................................71 3.2.2 Dibromopyrrolidin-2,4-dione.............................................................................73

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6 3.2.3 Dibromo-5-hydroxypyrrolidin-2,4-dione...........................................................74 3.2.4 Azido-3-bromopyrrol-2-one..............................................................................76 3.2.5 Benzotriazolpyrrol-2-one...................................................................................77 3.2.6 Protected (and -aminoacyl)benzotriazoles..................................................77 3.2.7 Protected-amino--oxo--triphenylphosphoranylidene and N-Cbzamino--oxo--triphenylphosphoranylidene Esters..........................................78 3.2.8 Dioxotriphenylphosphoranylidene Salts............................................................79 3.2.9 The DOT-Pyrrolidines, DOT-Pyrro lizines, and DOT Piperidine......................81 3.2.10 Protected-amino--oxo--triphenylphosphoranylidene and N-Cbzamino--oxo--triphenylphosphoranylidene Nitriles....................................83 3.2.11 Dihydropyrrol-3-one Bromide Salts and Tetrahydropyrrolizin-1-one Dibromide Salt...............................................................................................84 3.3 Conclusion...................................................................................................................86 3.4 Experimental Section...................................................................................................87 3.4.1 Preparation of Di bromide Salt 3.2a...................................................................87 3.4.2 Preparation of N-Methylat ed DOT-pyrrolidine 3.2b.........................................88 3.4.3 Preparation of Linear Free Amine 3.2c..............................................................88 3.4.4 Preparation of 3,3-Dibrom opyrrolidin-2,4-dione 3.3a.......................................89 3.4.5 Preparation of 3,3-Dibromo-5hydroxypyrrolidin-2,4-dione 3.3b....................89 3.4.6 Preparation of 4-Azido3-bromopyrrol-2-one 3.3c............................................89 3.4.7 Preparation of 4-Benzot riazolpyrrol-2-one 3.3d................................................90 3.4.8 Preparation of N-Acylbenzotriazoles 3.4a d, 3.13............................................90 3.4.9 Preparation of -Triphenylphosphoranylidene Esters 3.6a d...........................91 3.4.10 Preparation of DOT-salts 3.7ad...................................................................92 3.4.11 Preparation of DO T-pyrrolidines 3.8a c, DOT-pyrrolizines, and DOTpiperidines......................................................................................................93 3.4.12 Preparation of -Triphenylphosphoranyliden e Nitriles 3.10ad, 3.17..........94 3.4.13 Preparation of 2,4-Dihydr opyrrol-3-one Salts 3.11a c, Tetrahydropyrrolizin-1-one Salt 3.11d, and Nitrile Salt 3.18........................96 4 ENERGETIC IONIC LIQUIDS.............................................................................................97 4.1 Introduction..................................................................................................................97 4.2 Results and Discussion..............................................................................................100 4.3 Conclusion.................................................................................................................103 4.4 Experimental Section.................................................................................................103 4.4.1 Preparation of N-Alkylimid azoles (Method A) 4.6b,d, 4.7eg.......................104 4.4.2 Preparation of N-Alkylimidazo les (Method B) 4.6b,d,f,g, 4.7d......................104 4.4.3 Preparation of 1-Benzoyl-4-met hyland 1-Benzoyl-2,4-dimethylimidazoles 4.9a,b..............................................................................................105 4.4.4 Preparation of N-Alkylimidazoles (Method C) 4.6hk...................................105 5 SYNTHESIS OF CYCLIC KETONE DERIVATIZED TETRASUBSTITUTED trans IMIDAZOLIDIN-2-ONES...................................................................................................107 5.1 Introduction................................................................................................................107 5.2 Results and Discussion..............................................................................................110

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7 5.2.1 Imines...............................................................................................................111 5.2.2 The 1,1-Dipole Equivalents (Bt-Intermediates)...............................................112 5.2.3 Convergent Synthesis of Bt trans Imidazolidin-2-ones...................................113 5.2.4 Lewis Acid Mediated Synthesis of Cyclic Ketone Derivatized Tetrasubstituted trans-Imidazolidin-2-ones.....................................................115 5.3 Conclusion.................................................................................................................117 5.4 Experimental Section.................................................................................................117 5.4.1 Preparation of Imines.......................................................................................117 5.4.2 Preparation of Bt-Intermediates.......................................................................118 5.4.3 Preparation of Bt-Imidazolidin-2-ones............................................................119 5.4.4 Preparation of Cyclic Ketone Tetrasubstituted trans -Imidazolidin-2-ones.....121 6 GENERAL CONCLUSIONS...............................................................................................123 REFERENCES..................................................................................................................... .......127 BIOGRAPHICAL SKETCH.......................................................................................................141

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8 LIST OF TABLES Table page 2-1. Isolated Yields of N-Protected (-Aminoacyl)benzotriazoles 2.5ag 2.8ac ..................45 2-2. Isolated Yields of Chiral N-Protected Peptidic -Triphenylphosphoranylidene Esters 2.7ag .............................................................................................................................46 2-3. Attempted Optimization Reaction Conditions for 2.7b .....................................................47 3-1. Isolated Yields for Intermediates and Five-Membered Products 3.8ad, 3.11ad ...........68 3-2. The 13C-NMR Chemical Shifts, in ppm ( JPC in Hz) of Linear 3.2a,c and Cyclic 3.2b .............................................................................................................................. ..72 3-3. The 13C-NMR Chemical Shifts, in ppm ( JPC in Hz) of 3.6ad 3.14 ..............................79 3-4. The 13C-NMR Chemical Shifts, in ppm ( JPC in Hz) of 3.7ad 3.15 ..............................81 3-5. The 13C-NMR Chemical Shifts, in ppm ( JPC in Hz) of 3.8ad and 3.16 ........................82 3-6. The 13C-NMR Chemical Shifts, in ppm ( JPC in Hz) of 3.10ad 3.17 ............................84 3-7. The 13C-NMR Chemical Shifts, in ppm ( JPC in Hz) of 3.11ad and 3.18 .....................86 4-1. Isolated N-Alkylimidazoles 4.6ak .................................................................................101 4-2. Isolated N-Alkylimidazoles, with Energetic Groups, 4.7ak ..........................................101

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9 LIST OF FIGURES Figure page 1-1. Beta-Keto -Triphenylphosphoranylidene Esters and Nitriles (, and ).....................28 1-2. Structures of Pyrrolidin-2,4-dione with Enolization, 5-Amino-2,4-dihydropyrrol-3one, Piperidin-2,4-dione, Tetra hydropyrrolizin-1,3-dione, 3Aminotetrahydropyrrolizin-1one, and DOT-pyrrolidine..................................................29 1-3. Collaborative Effort: Modular Design of Heterocycles for EILs.....................................34 2-1. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 20 C................................50 2-2. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 60 C................................51 2-3. The 31P-NMR of the (DL)Diastereomer 2.15 at 20 C and 60 C.....................................51 3-1. Structures of Pyrrolidin-2,4-dione with Enolization, 5-Amino-2,4-dihydropyrrol-3one, Piperidin-2,4-dione, Tetra hydropyrrolizin-1,3-dione, 3Aminotetrahydropyrrolizin-1one, and DOT-pyrrolidine..................................................59 3-2. Major Canonical Forms of Peptidic syn--Keto -Triphenylphosphoranylidene antiEsters and Nitriles............................................................................................................ ..69 3-3. Crystal X-ray of 3.8c (Left), and Preliminary X-ray Crystal Structure of 3.11c with Two H2O molecules and Br (Right).................................................................................70 3-4. The X-ray Crystal Structure of 3.3b (Left), and Intermolecular Hydrogen Bonding (Right)........................................................................................................................ ........75 4-1. Collaborative Effort: Modular Design of Heterocycles for EILs.....................................98 5-1. Vicinal Diamino Tethered Ureas.....................................................................................107 5-2. Bioactive Imidazolidin-2-ones.........................................................................................108

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10 LIST OF SCHEMES Scheme page 1-1. Amide Resonance Forms...................................................................................................20 1-2. Acetamide Resonance Fo rms and Tautomers....................................................................21 1-3. Amide Isomers with Intermediate Barrier.........................................................................22 1-4. Bicyclic Penicillin Substructure.........................................................................................22 1-5. Benzotriazole Influence on Adjacent Carbon....................................................................23 1-6. Formation of N-Acylbenzotriazo le from Carboxylic Acids..............................................25 1-7. Retrosynthesis for N-Protected Peptidic -Triphenylphosphoranylidene Esters..............26 1-8. Applications of -Keto -Triphenylphosphoranylidene Esters.........................................26 1-9. Literature Methods for -Keto -Triphenylphosphoranylidene Esters.............................27 1-10. Early Reports of DOT-pyrroli dines and DOT-piperidine..................................................30 1-11. Delocalization of N-Methyl-DOT-pyrrolidine 3.2b Major Canonical Form 3.2b ..........31 1-12. Numbering of Substituted 4(or 5)-Monosubstitued Imidazoles........................................32 1-13. Regioselective N-Alkylation and Quater nization of Nitro-Substituted Imidazole............33 1-14. Regiospecfic N-Alkylation of 1-Alkylimidazoles 4.6hk .................................................34 1-15 Protected-N-(benzotriazol-1-ylmethyl ) Benzylamine, 1,1-Dipole Synthon......................36 1-16. Multiple Bond Formation in One Step for Imidazolidin-2-one.........................................37 1-17. Synthetic Overview of Protocols.......................................................................................38 2-1. Applications of -Keto -Triphenylphosphoranylidene Esters.........................................41 2-2. Literature Methods for -Keto -Triphenylphosphoranylidene Esters.............................42 2-3. Retrosynthesis for N-Protected Peptidic -Triphenylphosphoranylidene Esters..............43 2-4. Protected (-Aminoacyl)benzotriazoles 2.5ag 2.8ac from Protected Amino Acids...44 2-5. Rotameric Forms of 2.8b ...................................................................................................44

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11 2-6. Base Free C-Acylation for Ch iral N-Protected Peptidic Triphenylphosphoranylidene Esters 2.7ag ......................................................................46 2-7. Unsuccessful C-Acylations, and the Generation of Fmoc-Bt............................................48 2-8. Base Free C-Acylation for Achiral Esters 2.9.10 .........................................................49 2-9. Rotameric Forms of 2.10 ...................................................................................................49 2-10. Synthetic Route to (LL)and (DL)Diastereomers 2.14, 2.15 ...........................................50 3-1. General Methods for the Formation of Bonds aa, bb or cc to Construct 3.1 ......................60 3-2. Direct Intramolecular Wittig Alkena tion with Linear DOT Moieties...............................61 3-3. Indirect Intramolecular Wittig Alke nation with Linear DOT Moieties.............................63 3-4. Delocalization of N-Met hylated DOT-pyrrolidine 3.2b Major Canonical Form 3.2b ....63 3-5. Four Applications Using N-Methylated DOT-pyrrolidine................................................64 3-6. Speculative Applications: Oxidation and Reduction.........................................................65 3-7. Early Reports of DOT-pyrroli dines and DOT-piperidines................................................66 3-8. Synthetic Route to DOT-pyrrolidines 3.8ac DOT-pyrrolizines 3.8d 5-Amino-4triphenylphosphonio-2,4-dihydropyrrol-3-one Bromides 3.11ac and 3-Ammonio-2triphenylphosphoniotetrahydropy rrolizin-1-one Dibromide 3.11d ...................................68 3-9. Synthetic Route to DOT-piperidine 3.16 with Isolated Yields.........................................71 3-10. Methylation of 3.7c and 3.8c and Neutralization of 3.7c ...................................................72 3-11. Bromination of 3.2b with NBS, For 3.3a ..........................................................................73 3-12. Proposed Mechanism, From 3.2b to Int-1 to Int-2 to 3.3a ...............................................74 3-13. Bromination of 3.2b with TMSOEt and NBS, For 3.3a and 3.3b ....................................75 3-14. Proposed Mechanism, from 3.3a to 3.3b ...........................................................................76 3-15. Haloazidoalkenation of 3.2b with TMSN3 and NBS, For 3.3c ........................................77 3-16. Benzotriazolation of 3.2b with BtCl, For 3.3d .................................................................77 3-17. Acylbenzotriazolation of 3.12 with SOCl2 and BtH, Formed 3.13 ..................................78 3-18. Carbon-Acylation of 3.13 with 3.5 Formed 3.14 .............................................................78

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12 3-19. Rotameric Forms of Ester 3.6d and Nitrile 3.12d .............................................................79 3-20. Deprotection of 3.14 with HBr, For 3.15 ..........................................................................80 3-21. Method I and Method II, For 3.8c and 3.8d .......................................................................82 3-22. Carbon-Acylation of 3.13 with 3.9 For 3.17 ....................................................................83 3-23. Deprotection of 3.10c,d with HBr, For 3.11c,d ................................................................85 4-1. Regioselective N-Alkylation and Quater nization of Nitro-Substituted Imidazole............99 4-2. Targeted Regio-N-alkylated Imidazoles for Generation of Fused Salts..........................100 4-3. Method A and B for Preparation of 1-Alkylimidazoles...................................................100 4-4. Unsuccessful Regiospecific N-Alkylation.......................................................................102 4-5. Regiospecfic N-Alkylation of 1-Alkylimidazoles 4.6hk ...............................................103 5-1. Multiple Bond Formation in One Step for Imidazolidin-2-one.......................................109 5-2. The N -BocN -(benzotriazol-1-ylmethyl) Benzylamine, 1,1-Dipole Synthon in the Stereoselective Synthesis of 1,3,4,5-Tetras ubstituted trans-Im idazolidin-2-ones...........110 5-3. Synthetic Overview of Protocols.....................................................................................111 5-4. Imine Formation, From Aldehydes and Anilines............................................................111 5-5. Benzotriazole Intermediate Formation, Two Methods....................................................112 5-6. Convergent Syntheses, Using the Reported Literature Conditions.................................113 5-7. Optimized Convergent Conditions, Using Literature Reagents......................................114 5-8. Convergent Synthesis of N-Benzylated trans Bt-Imidazolidin-2-ones 5.4e,f .................114 5-9. Convergent Synthesis of N-Alkylated trans Bt-Imidazolidin-2-ones with 5.4g .............115 5-10. Lewis Acid Mediated Synthesis of Reported Cyclohexanone Analog 5.5a ....................115 5-11. Lewis Acid Mediated Synthesi s of Two Cyclohexanone Analogs 5.5b,c .......................116 5-12. Lewis Acid Mediated Synthesis of Two Cyclopentanone Analogs 5.5c,e ......................116

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13 LIST OF ABBREVIATIONS alpha locant [ ] specific rotation [expressed without units; the units, (deg.mL)/(g.dm) are understood] angstrom(s) ACN acetonitrile Aib aminoisobutyric acid Ala alanine anhyd anhydrous aq aqueous Asp aspartic acid beta locant Boc tert -butoxycarbonyl br broad (spectral) Brbromide anion Br+ bromonium cation BSA N O bis (trimethylsilyl)acetamide Bt benzotriazol-1-yl and benzotriazol-2-yl BtCl 1-chlorobenzotriazole BtCH2OH (benzotriazol-1-yl)methanol BtH 1 H -benzotriazole Bz benzoyl (not benzyl) Bzl benzyl C carbon C degrees Celsius

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14 calcd calculated Cbz benzyloxycarbonyl CDCl3 deuterated chloroform CDI carbonyl diimidazole CHC Center for Heterocyclic Chemistry chiroptical chiral-o ptical methods of palpati ng chirality by optical tools [polarimetry, optical rotatory disper sion (ORD), and circular dichroism (CD)] CGM Center for Green Manufacturing cm centimeter CNS central nervous system delta locant chemical shift in parts per million downfield from tetramethylsilane heat d doublet (spectral) D (10-point) dextrorotary (right) D (12-point) deuterium DCC N N -dicyclohexylcarbodiimide DCM dichloromethane DMAP 4-dimethylaminopyridine DMD 3,3-dimethyl dioxirane DMF dimethylformamide DMSO dimethyl sulfoxide DMSOd6 deuterated dimethyl sulfoxide DSC differential scanning calorimetry DOT di(oxo)triphenylphosphoranylidene

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15 EDCl 1-(3-dimethylaminopropyl)-3-e thylcarbodiimide hydrochloride EIL energetic ionic liquid eq equivalent(s) Et ethyl et al. and others Fmoc 9-fluorenylmethoxycarbonyl FVP flash vacuum pyrolysis gamma locant g gram(s) Gly glycine Glu glutamine h hour(s) H Hydrogen [H] reduction HBr hydrobromic acid HIV human immunodeficiency virus HRMS high-resolution mass spectrometry Hz hertz IL ionic liquid i iso (as in i -Pr; never i -propyl) ip ipso locant i -Pr isopropyl IR infrared J coupling constant (in NMR spectrometry) JCF coupling constant carbon-fluorine (in 13C-NMR spectrometry)

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16 JCP coupling constant carbon-phosphorus (in 13C-NMR spectrometry) L (10-point) levorotary (left) lit. literature (abbreviation used with period) micro -Wave microwave m multiplet (spectral); meter(s); milli m meta locant M+ parent molecular ion Me methyl MeI methyl iodide MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mmol millimole(s) MMP matrix metalloproteinase MMPP magnesium monoperphthalate mp melting point mol wt molecular weight m/z mass-to-charge ratio n normal (as in n -butyl, n -Bu) N nitrogen NaH sodium hydride NBS N -bromosuccinimide NMDA N -methyl-D-aspartate NMR nuclear magnetic resonance

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17 o ortho locant O oxygen [O] oxidation OEt ethoxy OMe methoxy Oxone potassium peroxymonosulfate p para locant P Phosphorus Pd(C) palladium on charcoal Pg protecting group Ph phenyl Phe phenylalanine ppm part(s) per million Pr propyl Pro proline PTSA paratoluene sulfonic acid P-ylide phosphorus ylide q quartet (spectral) R rectus (right) (naming groups around a central carbon) (opposite of S ) rb round bottom rt room temperature s singlet (spectral); second(s) S sinister (left) (naming groups around a central carbon) (opposite of R ) Sar sarcosine SARM selective androge n receptor modulators

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18 s -BuLi sec -butyllithium sec secondary (as in sec -butyl, sec -Bu) SiO2 silica gel SOCl2 thionyl chloride t triplet (spectral) t tertiary (as in t -Bu; but tert -butyl) TARS tetramic acid ring system TBDMS t -butyldimethylsilyl TEA triethylamine temp temperature tert tertiary Tf trifluoromethansulfonyl (triflyl) TFA trifluoroacetic acid TGA thermogravimetric analysis THF tetrahydrofuran TLC thin-layer chromatography TMS trimethylsilyl; tetramethylsilane Tr (triphenylmethane) trityl Trp tryptophan Ts para -toluensulfonyl (tosyl) UF University of Florida v:v volume:volume ratio Val valine VOC volatile organic compound W watt(s)

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19 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy APPLICATION OF SYNTHETI C HETEROCYCLIC CHEMISTRY By Adam S. Vincek May, 2008 Chair: Alan R. Katritzky Major: Chemistry Benzotriazole is a versatile synt hetic auxiliary, widely applied to many organic syntheses. In our continuous work on benzotriazole methodology, we have developed efficient methods for the preparation of heterocyclic compounds. The formation of N-protected peptidic triphenylphosphoranylidene esters by the C-acylation of P-ylide esters with N-protected peptidic (-aminoacyl)benzotriazoles under microwave irra diation is described. The formation of distabilized triphenylphosphora nylidene moieties on pyrrolidine, pyrrolizine, and piperidine rings by the room temperature N-deprot ection and cyclizat ion of peptidic triphenylphosphoranylidene esters and nitriles is described. The formation of N-regioalkylated 4-substituted imidazoles by regioselective N-benz oylation and N-alkylation with quaternization, followed by debenzoylation and dequarterniza tion is described. The formation of tetrasubstituted trans -imidazolidin-2-ones by treatment of im ines with lithiated benzotriazole intermediates and subsequent treat ment with Lewis acid and silylenol ethers to modify the 4or 5-position is described.

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20 CHAPTER 1 GENERAL INTRODUCTION 1.1 Opening Remarks The specific fields of heterocyclic, amino aci d, lactam, and ionic liquid chemistry can be viewed from the single perspective of organic ch emistry and are discussed in this work. Amide bonds are formed in key steps of every main ch apter and used for activ ation, protection, and cyclization. This general introduction commences with a brief discussion of amides and is followed by a brief overview to set the relevant chem istry topics in a broad context. In closing of this general introduction the aim and im portance of the work will be stated. 1.2 General Discussion of Amides Amides are one of the most fundamental func tional groups in chemis try and biology, and are surprisingly robust compared with structurally re lated derivatives [06N699]. The amide linkage gains stability from electron delocalization (Scheme 1-1) be tween the apolar and dipolar resonance forms, which differ in the locati on of the double bond [06N699]. The enhanced stability is maximized if the atoms around the carbon-nitrogen double bond in the dipolar form are coplanar in order to satisfy the geometri cal requirements of the carbon-nitrogen double bond [06N699]. O N R R R O N R R R ApolarDipolar Scheme 1-1. Amide Resonance Forms Amides are a good example of a conjugated allylic pi system with th e nitrogen lone pair joined by resonance, or a prot on shifting by tautomerization, with a carbonyl group [92MI6]. Conjugated, or delocalized, bonding exists in compounds containing one or more bonding

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21 orbitals not restricted to two atoms, but spread out over three or more [9 2MI34]. Each resonance form does not have a separate existence but is part of a hybrid whole [92MI6] and only electrons move. All resonance forms, or canonical forms [ 92MI34], are valid Lewis structure. The use of a double-headed, or resonance arrow ( ) between the forms reinforces the notion of electrons in the double bond spread, or delocalized, across the amide group, which behave as a hybrid representation of a single structur e. Acetamide (Scheme 1-2) is shown with the resonance forms and a tautomer denoted by the equilibrium arrow ( ). Resonance forms are not in equilibrium with each other, the atoms remain spatially in the same location, and the actual molecule is in a lower energy state than any of the resonance forms. O N Me H H O C+ N Me H H O N H2N H H O N Me H H Tautomers ResonanceForms Scheme 1-2. Acetamide Resonance Forms and Tautomers Scudder described tautomerization as the shif t of a hydrogen from a carbon adjacent to a carbon-heteroatom double bond to the heteroatom itself, and the reverse process, in an acidor base catalyzed equilibrium [92MI6]. Eliel de fined tautomers as read ily inter-convertible constitutional isomers, but, in contrast to conformational isomers and valence bond isomers, in tautomers there is a change of connectivity of a ligand [94MI23]. Eliel wrote about amide bonds with an intermediate barrier, the boxed structure in Scheme 1-3, while the amide isomer shown is generally implied to differ in conformation (by rotation about the CN bond) the E / Z nomenclature of double-bonded species is commonly applied, demonstrating a certain degree of

PAGE 22

22 ambivalence in these cases [94MI 23]! In this work we occasi onally refer to rotamers, as was previously describe in the lite rature [02JP1533], to describe these ambivalent cases which gave two distinct sets of NMR signals, caused by interconversi on between isomers through a bond rotation in rapidly equilibration. Me O N C6H2(NO2)3 Me +-Me O N C6H2(NO2)3 Me Me O N C6H2(NO2)3 Me Z -isomer Me O N C6H2(NO2)3 Me E -isomer amidebarrier21.0kcalmol-1Me O N C6H2(NO2)3 Me Scheme 1-3. Amide Isomers with Intermediate Barrier The geometry of bicyclic amides, or lactams, are highly twisted, which dramatically affects the stability and reactivity, and increases the basi city of the nitrogen, which often behaves more like an amine than a typical pl anar amide [06N731]. Typical acyclic amides are planar. However bicyclic lactams, such as the penicill in substructure (Scheme 1-4), cannot exist in a coplanar dipolar form which inhibits electron delocalization through reso nance and destabilizes the amide bond [06N731]. These intriguing qualities have lead to syntheses of bicyclic lactams to increase our understanding of this special type of bond the twisted amide [06N699]. N O N O ApolarDipolar Scheme 1-4. Bicyclic Penicillin Substructure

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23 1.2 General Overview of the Work Heterocyclic compounds are those which have a cy clic structure with tw o, or more, different kinds of atoms in the ring [97MI1]. Arnold We issberger, in 1953, wrote that the chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry [53MI1]. In the 1960s several research groups, in cluding that of Alan R. Katritz ky, began to fill in practical, theoretical, and physical gaps due to the molecular complexity of the heterocyclic field; it was then that Physical Methods in Heterocyclic Chemistry and Advances in Heterocyclic Chemistry began to appear [63PMH1, 63AHC1]. The work herein contains examples of the intrinsic difficulty of heterocyclic chemis try and how success requires understanding of substituent, electronic, and regiochemical effects, which may change drastically upon a seemingly minor modification. BtLeavingGroup N N N R X BtActivates-C toProtonLoss N N N H X BtElectronDonor N N N X Y Scheme 1-5. Benzotriazole Influence on Adjacent Carbon Hantzsch, in 1888, classified azoles as fi ve-membered polyheteroatomic ring systems containing at least one tertiary nitrogen [53M I1]. Relatively recently, the last 20 years, benzotriazole has received special attention in the Katritzky group as a versatile synthetic auxiliary which offers advantages such as low cost, high stability, low toxicity, and mild acidic strength (pKa = 8.2). The manipulation of benzotriazole as a highly versatile synthetic auxiliary,

PAGE 24

24 and its great importance as a tool for a variet y of synthetic reactions, has been periodically reviewed [98CRV409]. Benzotri azole as a substituent impart s both electron-donor and electronacceptor properties to the neighboring atom (S cheme 1-5). The ambivalent character of benzotriazole allows it to act as leaving group for nucleophilic di splacement reactions as well as an activating group, to facil itate proton abstraction at -C for the subseque nt introduction of electrophiles. The -Amino acids possess a limited but signifi cant number of functional groups, which facilitate synthetic operations for hetero cycles, protection, and deprotection, and are commercially available, usually in both enanti omerically pure forms for the synthesis of optically active compounds [02MI25]. Before th e mid-1960s, the enantiomer ic purity of a chiral molecule was usually assessed by using chiral-o ptical (chiroptical) methods [91CRV1441]. Chiroptical methods involve measur ing the optical rotation, or opt ical purity, of the sample using a polarimeter under defined conditions and provided that the measurement is carried out under rigorously controlled temperat ure, solvent, and concentration and at a given wavelength of the incident plane-polarized light along with appropriate calibra tions, then this value may be equated with enantiomeric puri ty [91CRV1441]. The two major problems w ith this method of analysis are the optical purity and enantiomeri c purity are not necessary equivalent and the literature is abound with many exam ples of incorrect optical rota tions for compounds considered to be enantiomerically pure [91CRV1441]. Sard ina and Rapoport wrote, in a large percentage of cases the question of the enan tiomeric purity of the compounds prepared was not addressed at all, while in a majority of articles the dete rmination was carried out by chiroptical methods, which, it must be stressed, are unreliable [96CRV1825] In this work, optical rotations of some

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25 molecules with a stereocenter are reported when previous literature repo rts already existed, but are unreliable for the reproduction of enantiomeric purity. R OH O (i)BtH,SOCl2 R Bt O N -Acylbenzotriazole (i)BtSO2Me Scheme 1-6. Formation of N-Acylbe nzotriazole from Carboxylic Acids Amide bond formation between amino acid compone nts is a main goal in the synthesis of many organic compounds of biological interest driving the discovery of peptide coupling reagents, which have essentially eliminated r acemization of the amino acid component and side reactions [02ARK134]. Two sta ndard methods (Scheme 1-6) used in the Katritzky group to prepare N -acylbenzotriazoles, a modern peptide coupling reagent, from carboxylic acids are by either, (i) in situ generation of thionyl bis(benzotriazole) [04S2645], or (ii) using N (methylsulfonyl)benzotriazole [ 02ARK134]. Acylbenzotriazoles have been reported by the Katritzky group as efficient neutral coupling r eagents for chiral N-acylation, regioselective Cacylation, and O-acylation of aldehydes [04S1806] and as suffic iently reactive to form amide bonds at ambient temperature, but stable enough to resist side reactions [04S2645]. Protected (-aminoacyl)benzotriazoles are efficient reagen ts for acylation of amino amides [02ARK134], amino sulfonamides [04ARK14], amino thiol es ters [04S1806], small peptides carrying side chains with alkyl groups [04S2645], small pe ptides with multi-func tional groups [05S397], and amino ketones [05JOC4993]. Protected N -acylbenzotriazoles, tame acid chloride equivalents, were used for C-acylation of phosphorus ylides (P -ylides) with microwave irradiation to form Nprotected peptidic -triphenylphosphoranylidene esters in Chapter 2 (Scheme 1-7) and in Chapter 3.

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26 O N R1Pg PPh3CO2Et + R3 O N Bt R1Pg R3 PPh3CO2Et H R2 R2 -Wave Scheme 1-7. Retrosynthesis for N-Protected Peptidic -Triphenylphosphoranylidene Esters Peptidic -triphenylphosphoranylidene esters and am ides have attracted considerable attention as important intermediate s for the preparation of peptidic -keto esters and of -keto amides [94JOC4364, 97JOC8972], compounds which ar e potential inhibitors of proteolytic enzymes [92JME451, 93JME2431] and leukotriene A4 hydrolases [93JME211]. The -Keto triphenylphosphoranylidene esters 2.1 have been used for the preparation (i) of alkynes 2.2 by flash vacuum pyrolysis (FVP) [85S764, 04T12231], (ii) ,-diketoesters 2.3 by oxidation ([O]) [94JOC4364, 97JOC8972], and (iii) -keto esters 2.4 by direct reduction ([H ]) (Scheme 1-8). PPh3CO2Et R O (i)FVP (ii)[O] (iii)[H] CO2Et R O CO2Et R O CO2Et R O 2.1 2.2 2.3 2.4 (iv)Deprotection NH O PPh3 O {Chapter3} 3.1 R=Cbz-NH-CH2 Scheme 1-8. Applications of -Keto -Triphenylphosphoranylidene Esters Previously reports determined -Keto -triphenylphosphoranylidene esters 2.1 are readily available by C-acylation of (car boxymethylene)triphenylphosphorane ( 2.6 ) with a proton sponge/acid scavenger such as N O -bis(trimethylsilyl)acetamid e (BSA) [90TL5205, 94JOC4364, 95JOC8231] and acyl chlorides [04T12231, 82JOC 4955], or cyclic anhydrides [82AJC2077, 85S764], or anhydrides with BSA [92TL6003] (S cheme 1-9). However, acyl chloride and

PAGE 27

27 anhydride methods are limited in their applicabil ity for chiral peptidic models due to high reactivity and byproducts causing potential probl ems with other functional groups. CarbonAcylation methods for chiral N-protected peptidic -triphenylphosphoranylidene esters have been reported, by activation of amino acids with carbonyl diimidazole (CDI) requiring 24 h reaction time [99JA1401], or with 1 -(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (EDCl) in the presence of 4dimethylaminopyridine (DMAP) requiring 16 h reaction time [93JOC4785, 94J OC4364, 97JOC8972]. Therefore, the development of an expedient, versatile method to C-acylate 2.6 with chiral amino acid derivatives for N-protected peptidic -triphenylphosphoranylidene esters is desirable. In Chap ter 2 we demonstrate the Cacylation of 2.6 with chiral, and achiral, N-protected (-aminoacyl)benzotriazoles, to prepare chiral, and achiral, N-protected peptidic -triphenylphosphoranylidene esters under microwave irradiation. PPh3CO2Et R O 2.1 PPh3HCO2Et R1O OH acidhalides withBSA or -Wave aminoacidsw/ EDCI,DMAP 16h orCDI,24h cyclic anyhydrides or anhydrides withBSA O Me N TMS TMS BSA= 2.6 Scheme 1-9. Literature Methods for -Keto -Triphenylphosphoranylidene Esters A single cavity microwave synthesizer provides an effective reproducible and safe technique for promoting a variety of reactions and shor tening reaction times while reducing pollution by

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28 using less solvent [02MI1, 03ARK68]. Micr owaves, a form of electromagnetic radiation between infrared (IR) and radio frequencies, us ed in a single cavity synthesizer accelerate reaction times and reduce the amount of solv ent required. The general mechanism behind microwave technology is that molecules with a permanent dipole become aligned with the electric field when irradiated with microwav es, oscillation of which changes the molecular alignment and increases the temperature. Oscill ation of the standing microwaves occurs at 4.9 x 109 times per second, causing the electromagnetically radiated molecules to become extremely agitated, as they align and realign themselves with the oscillating field, creates an intense internal heat that can escalate as quickly as 10 C per second [02JCO95]. In ternational convention dictates that most microwave ove ns operate at 12.2 cm (2450 MH z), so not to interfere with radar or other telecommunications devices. CO2Et PPh3 O N H R R CN PPh3 O N H R R Figure 1-1. Beta-Keto -Triphenylphosphoranylidene Esters and Nitriles (, and ) Novel distabilized triphenylphos phoranylidene tetramic acids, containing cyclic amide or lactam functionality, were obtained after room te mperature N-deprotection (iv, Scheme 1-8) and cyclization and exhibited high stability at the triphenylphospho ranylidene moiety. The work from Chapter 2 was extended in Chapter 3 to obtain not only Nprotected peptidic triphenylphosphoranylidene esters but also N-protected peptidic -triphenylphosphoranylidene nitriles (Figure 1-1). The versatile distabilized triphenyl phosphoranylidene moiety was readily formed on pyrrolidin-2,4-dione, 5-amino-2,4dihydropyrrol-3-one, piperidine-2,4-dione, tetrahydropyrrolizin-1,3-dione, a nd 3-aminotetrahydropyrrolizin-1 -one (Figure 1-2) with a

PAGE 29

29 distabilized triphenylphosphoranyl idene substituent. Four applications we re developed using 2,4-dioxo-3-triphenylphosphora nylidene pyrrolidine. O O NH O HO NH Pyrrolidin-2,4-dione DOTmoiety PPh3 O O NH DOT-pyrrolidine O N 5-Amino-2,4-dihydro pyrrol-3-one O O N NH O O Piperidin-2,4-dioneTetrahydro pyrrolizin-1,3-dione NH2 O N 3-Aminotetrahydro pyrrolizin-1-one NH2 4-Hydroxy-pyrrol-2-one 3.1 Figure 1-2. Structures of Pyrrolidin-2,4-dione with Eno lization, 5-Amino-2,4-dihydropyrrol3-one, Piperidin-2,4dione, Tetrahydropyrrolizin-1,3-dione, 3Aminotetrahydropyrrolizin-1 -one, and DOT-pyrrolidine The predominant species of pyrrolid in-2,4-dione exists in solution in the enolized form with a stable lactam bond [93AHC139, 03 MI109]. The discovery of the tetramic acid ring system 3.1 (Figure 1-2), a tautomer of pyrrolidin-2,4-dione in a number of natural products and pigments coincided with the discovery of their dive rse biological activitie s [93AHC139, 94MI97, 95CRV1981, 00JPP086628, 00MI195, 02MI25, 03MI 109]. Pyrrolidin-2,4-dione and 2,4dihyropyrrol-3-ones have been identified as N-methyl-D-aspartate (NMDA) receptor antagonists [99AP309, 05EJM391]. The 2,4-dioxo-3-triphe nylphosphoranylidene moiety, or DOT-moiety as shown on DOT-pyrrolidine (Figure 12), adds desirable physical prope rties such as crystallinity and stability to aldehydes [ 87LA649], strong bases [65JOC 1015], and high temperatures [01TL141]. The possible transformation th e 2,4-dioxo-3-triphenylphos phoranylidene (DOT)

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30 moiety provides when directly incorporated as part of a heterocyclic ring is unexplored and of considerable interest [01JCD639]. O NH Cbz R2CO2Et Ph3P Ph3P NH O O R1 (ii) (i) OH PPh3NH2O EtO2C R1 O +25C,2h+EtO2C R1 NH2 O 31% 26% 1)Pd(C),H22)FVP,600oC FVP,600oC Ph3P NH O O R2 EtO2C R2 HN Cbz F N O O N N N N PPh3 (iii) 60C DCM/AcOH F N O O O PPh3 obtainedonce notreproducible R1= O O F O TrO R2=H(21%) Me(58%) i -Pr(64%) N H O O O PPh3CO2Et +(iv) 60C DCM/AcOH 50% N H O O PPh3 NO2 O PPh3 CO2t -Bu (v) SnCl2 NH2 O PPh3 CO2t -Bu spontaneous [78MI7] [01TL141] [05MI385] [73JOC1047] [87S288] Scheme 1-10. Early Reports of DOT -pyrrolidines and DOT-piperidine Earlier reports of DOT-pyrroli dine substructure (Scheme 110) include (i) a byproduct during the preparation of showdomycin [78MI7], (ii) a flash vac uum pyrolysis method (FVP, 600 900 C, 102 Torr) which noted difficulties associat ed with N-deprotection by hydrogenolysis [01TL141], and (iii) a byproduc t without logical explanation of how it might be formed

PAGE 31

31 [05MI385]. Anomalous, spontan eous [87S288, 04SL353, 05SL 2763] cyclizations at rt, discovered by Aitken, were left unexplained in his publications [99 PS577, 01TL141, 03TCC41, 03MI289]. Earlier reports of the DOT-piperidin e substructure (Schem e 1-6) reported two articles of the same molecule as an (iv) unreactive novelty [73JOC1047] or an (v) unwanted dead-end [87S288]. Ph3P N+O O Ph3P N O O Me Ph3P+N O O Ph3P+N O O 3.2b Ph Ph Ph Ph 3.2b' Me Me Me Scheme 1-11. Delocalization of N-Methyl-DOT-pyrrolidine 3.2b, Major Canonical Form 3.2b The extra stabilization afforded by a second carbonyl on linear DOT sy stems [90TL5925] is also present in cyclic DOT systems. The DOT moiety resisted re fluxing alcoholic base [73JOC1047, 95T3279], high FVP temperatures [01TL141], and hydrobromic acid (HBr) [Section 3.2.8], to some extent due to the stable l actam bond and DOT functionality participating in delocalization (Scheme 1-11) [04SC4119]. Th e mechanism of the Wittig reaction is debated to occur either on the time scal e of a bond rotation or through an equilibrium process. Although the Wittig mechanism is intuitively underst ood as a -center mechanism [90JA3905], the inherent stability of the DOT moieti es requires further investigation. Although DOT-pyrrolidines are crysta lline, soluble in halogenate d and alcoholic solvents, and have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings [72JOC3458, 73JA7736] they have received little of the atten tion given to tetramic acids, presumably due to

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32 their lack of reactivity. In Chapter 3 we report the first convenient synthesis of DOTpyrrolidines, DOT-tetrahydropy rrolizine, DOT-piperidine, 5amino-4-triphenylphosphonio-2,4dihydropyrrol-3-one bromides, and 3-ammonio-2-triphenylph osphonio-tetrahydropyrrolizin-1one dibromide. Furthermore we develop four applications using N-methyl-DOT-pyrrolidine, 3.2b. N N H 1 2 3 4 5H R H N N 1 2 3 4 5H R H H Scheme 1-12. Numbering of Substituted 4(or 5)-Monosubstitued Imidazoles The regiospecific N-alkylation of substituted imidazoles, w ith an amide bond formed for a protecting group in Chapter 4, allowed the synthe sis of novel heterocyclic ionic liquids. Ionic liquids have been defined as salts with mel ting temperatures below 100 C, and composed of only cations and anions. Molten salts, sometimes considered th e ultimate non-volatile organic solvent, have several properties that compel their use as reaction media [02GC73]. The numbering around the imidazole ri ng is shown in Scheme 1-12. Numbering begins at the sp3 nitrogen and proceeds around the ring to assign th e smallest possible number to the tertiary nitrogen. Equilibration between regioisomers, in some cases when the R group in the 4or 5position is a substituent, requires the r eassignment of the regiochemistry. The synthetic efforts were not directed a priori to the preparation of energetic fluids, but rather to synthesizing new materials to enable the development of links between component functionality and physical propertie s. However, the approach br oadened and the strategy shifted from commercially available comp onents to newly synthesized an ions and cations. Alkylations of substituted imidazoles have been studied for almost a century [10JCS1814, 22JCS2616, 24JCS1431, 25JCS573, 60JCS1357, 63BSC2840, 66AF 23, 89AJC1281, 91SC427, 95CC9], and

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33 were used for medicinal chemistry applicati ons in the late sixties [67JME891, 68JME167, 03JME427, 03BMC2863]. Recently the CHC develope d regiospecific N-alkyl ation for a series of 1,3-dialkylimidazolium salts containing a stro ngly electron-withdrawing nitro group directly attached to the ring (Scheme 1-13) and othe r strategies for novel EILs [06NJC349]. N N Me O2N N H N O2N N N O2N Et N N Et Me O2N N N Me Me O2N X Et2SO4, NaOH(aq.) 45oC Me2SO4Et2SO44.2 X 4.1 4.7c 4.4 4.3 dioxane reflux Me2SO4,toluene MeOTf,toluene 20C,72h 20C,48h Scheme 1-13. Regioselective N-Alkylati on and Quaternization of N itro-Substituted Imidazole The regiospecific N-alkylati on strategy provided the more sterically hindered 1alkylimidazoles 4.6hk from the 4-substituted imidazoles 4.1e and 4.1f. The reaction sequence involved an initial benzoylati on followed by quaternization wi th alkyl triflates and base hydrolysis (Scheme 1-14) [02EJOC2633]. The 1-Benzoyl-4-methyl-imidazole 4.9a and 1benzoyl-2,4-dimethyl-imidazole 4.9b were prepared from benzoyl chloride with a twofold excess of the corresponding 4.1e,f in THF at rt [90S951]. Reaction of 4.9a,b with propyl and hexyl triflates in toluene at rt for 48 h gave the corresponding quaternary salts 4.10ad, which separated from the bulk solvent as oils and were used as intermediates. The salts 4.10ad

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34 hydrolyzed under biphasic aq sodi um hydroxide and diethyl ether conditions at rt to give 1alkylimidazoles 4.6hk. N N R2R3R1Bz TfO N H N R2R3 PhCOCl N N R2R3Bz R1OTf NaOH N N R2R3R1 4.6h-k 4.9a b water toluene 4.1e (R3=Me) f (R2,R3=Me) 4.10a,b (R1= n -Pr) c,d (R1= n -Hex) Scheme 1-14. Regiospecfic NAlkylation of 1-Alkylimidazoles 4.6hk Cation Anion New,functionalizedfusedsalt Cation Anion ModularDesign Thediversestructuralfuctionalities, appendeddirectlytotheheterocyclic ioncores,introducedthroughoutthe collaborationincluded: -alkylchainswithandwithout energeticgroups; -strainedringsystems; -oxygen-richfunctionalgroups (e.g.,OH,ether,epoxide); -energeticfunctionalities (e.g.,NO2,CN,N3,NH2); -unsaturatedfunctionalities. Metathesis -Byproduct Figure 1-3. Collaborative Effort: Modular Design of Heterocycles for EILs. The dual nature of ILs allows a unique tunable architectural platform with properties related to the structure of constituent ions [07MI1111]. The collaborative effort, between the Center for Heterocyclic Chemistry (CHC) in Gainesville, Florida together with The Center for Green Manufacturing (CGM) in Tuscaloosa, Alabama, has focused on the development of new energetic ionic liquids from the perspective of modular design in order to synthesize selected heterocycles for preparing fused salts (Figure 1-3). The propertie s of cation and/or anion within the ionic pair were independently modified, th en metathesis could generate new functional materials [05CC868, 06CEJ4630], whic h retain the core features of the IL state of matter. The final materials were monitored by DSC, TGA, and single crystal X-ra y crystallography, to

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35 examine how the modification to each component influenced decomposition temperature and melting point. Over the last several years, typical properties of ionic liquids (ILs) such as high ion content, liquidity over a wide temperature range, lo w viscosity, limited-volatility, and high ionic conductivity have proven to be important driv ers supporting numerous advances beyond the initial investigations of IL s as liquid electrolytes [06N JC349, 04FPE93, 04AJC113]. The properties of ILs have made it possible to repl ace damaging solvents which are used in huge amounts or are hard-to-contain, volatile organic compounds (VOCs) with recyclable, reusable, and easy to handle materials [99CRV2071, 01CC2399, 02JMC(A)419]. The rethinking, redesign, and implementation of ILs as designer solvents into many current chemical processes can deliver significant cost and environmen tal benefits [99CPP223], and lead to new technologies, e.g. the processi ng of cellulose [02JA 4974], biphasic chemi cal processes (e.g., BASF's BASIL) [06MI121], photovoltaics [96IC1168, 02CC2972], fuel cell electrolytes, [02MI185] polymer electrolyte s [04EA255], thermal fluids [05MI181], and lubricants [06MI347]. The synthesis of tetrasubstituted trans -imidazolidin-2-ones was e xplored in Chapter 5 and utilized a Boc-amide bond on N-subs tituted benzotriazoles. The N -Boc-(benzotriazol-1ylmethyl) benzylamine was demonstrated by th e Katritzky group (Scheme 1-15) [01JOC2858] to act as a 1,1-dipole equivalent in the stereose lective synthesis of 1,3,4,5-tetrasubstituted imidazolidin-2-ones. The transition states for the formation of 4,5-disubstitued 1,3-imidazolidin2-ones by the reaction of an -nitrogen carbanion with an imine was described by Kise et al. [96JOC428], and generally extended to the benz otriazole method. The formation of dipolestabilized carbanions adjacen t to nitrogen atoms [84CRV471, 96JOC428, 96JA3757] is further

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36 directed to lithiate chemos electively at a carbon adjacent to a benzotriazole residue [05AGE5867] and in the presence of an imine a highly trans vicinal diamine is formed. Urea forms spontaneously in most cases. The genera l benzotriazole protocol enables the introduction of a variety of substituents into the 4and 5-position of imidazolidin-2-ones with trans stereochemistry. N Boc Bt Ph N CH Boc Ph (i) s -BuLi N Bt Ph O O t-Bu Li N N O R2 H Bt H R3 Ph N Bt Ph O O t-Bu Li R3 N R2 N Bt Ph O O t-Bu Li N R3 +R3CH=NR2 R2 trans favored N Bt Ph O O t-Bu Li N R3 R2 H H Scheme 1-15 Protected-N-(benzotriazol-1-yl methyl) Benzylamine, 1,1-Dipole Synthon Nitrogen heterocycles containing a vicinal di amine moiety are considered biologically privileged active structures [ 06MI101, 07OL2035, 07JA762]. Like wise, nitrogen heterocycles containing the cyclic urea moiety incorporated as part of the core are found in a broad array of biologically active molecule s [94EP612741, 96MI301, 96JME3514, 02BBA02, 06OL2531] and provide increased structural rigidity as well as hydrogen bonding possibilities [95TL6647,

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37 98TL1477]. The presences of these two potentia lly bioactive properties encourages the exploration of vicinal diamino tethered ureas and unsaturated imidazol-2-ones, or saturated imidazolidin-2-ones in particul ar for medicinal screening. (iii)c,b,d(ii-a)c,d(ii-b)c,da b 5.1 c (i)a,bN N O R2 R1 R4 R5 H R3 N R2 R3 +N R1 Boc R5 Base R1=Ar,R5=Phor R1=(CH2)3=R5or R1=Alk,Bzl,R5=Bt R2=R3=Ar,HetAr d NCO R2 N R1 R4 R5 H R3 NaI R5 HN O R1 O H2N PPh3,CBr4Et3N,DCM R5 HN O R1 O H2N R1=SO2Ar,R5=Alk,Ar R3orR4=H,Alk,Ar, R6=Aror t -bu R1=Cbz,R5=Me R2=R4=H,R3=allyl R1=Cbz,R5=CO2H R2=R3=R4=H NaOCl Scheme 1-16. Multiple Bond Formation in One Step for Imidazolidin-2-one Vicinal diamine and urea formation in one si multaneous step to form imidazolidin-2-one (Scheme 1-16), was reported in the literature. The CC bond and urea formation, (i) bonds a and b were achieved by coupling of a lithiatied -nitrogen methylene to imines and intramolecular cyclization to the Boc-protecting group [96J A3757, 96JOC428, 01JOC 2858, 02EJOC301]. The urea and CN bond formation, (ii) bonds c and d were achieved by (ii-a) ring opening of N arylsulfonylaziridines with isocya nates in the presence iodide i ons [93T7787, 05TL479]; or (ii-b) dehydration of allyl carbamate with modified conditions (PPh3, CBr4, Et3N) provided allyl cyanate-to-isocyanate re arrangement with subseq uent intramolecular cy clization [06OL5737]. The urea and CN bond formation, (iii) bonds c b and d were achieved by Hoffman

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38 rearrangement [68BCJ2748, 89JME289]. Two st ep methods for imidazolidin-2-ones involve either formation of vicinal diamine [98 AGE2580, 05OL1641] or cyclic urea [95JME923, 96TL5309, 00AJC73, 03SL1635, 04OL2397, 04SL 489, 05T9281] and a cyclization step. 5.2 N N O R2 H Bt H R3 N R2 R3 +N Boc Bt NH2R2 +O R3 H2N [5.2.1][5.2.2] [5.2.3] [5.2.4] H H N N O R2 H H R3 O 5.3 5.4 5.5 R1 R1 R1 R1 Scheme 1-17. Synthetic Overview of Protocols In Chapter 5 we report the exte nsion of the previous work on Bt-intermediates to form novel tetra-substituted trans -imidazolidin-2-ones, with a synthe tic protocol (Scheme 1-17). The efficient protocol, section 5.2.1 for imines was based on the r eaction of aldehydes to anilines with the loss of a water molecule. The protocols; section 5.2.2 for Bt-intermediates, section 5.2.3 for the convergent production of trans -Bt-imidazolidin-2-ones; and section 5.2.4 for trans imidazolidin-2-ones cyclic ketones were based on the published literatur e method [01JOC2858]. 1.4 Aim and Importance of the Work My objective in doing this work was to investigate certain aspects of the chemistry of heterocyclic compounds in relati on to amino acids, lactams, and ionic liquids. A common theme that appeared throughout this wo rk was that of the amide bond. The serendipitous study and development of interesting synthetic organic ch emistry, including some green chemistry, will

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39 hopefully lead to novel molecules for the benefit of life, science, and society. My critical findings provide a solid framework for future investigations in these related areas. Peptidic -triphenylphosphoranylidene esters and am ides have attracted considerable attention as important intermediates for the preparation of peptidic -keto esters and of -keto amides, compounds which are potential inhibito rs of proteolytic enzymes and leukotriene A4 hydrolases. Therefore, the development of an e xpedient, versatile method to C-acylate P-ylides with chiral amino acid derivativ es for N-protected peptidic -triphenylphosphoranylidene esters is desirable. The N-Protected N -acylbenzotriazoles C-acylation of P-ylides with microwave irradiation adds to the robust list of N -acylbenzotriazoles applications. Although DOT-pyrrolidines are crysta lline, soluble in halogenate d and alcoholic solvents, and have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings they have received little of the attention given to tetram ic acids. The possible transformation the 2,4-dioxo3-triphenylphosphoranylidene (DOT) moiety provides when directly incorpor ated as part of a heterocyclic ring is unexplored and of consider able interest. Although the Wittig mechanism is intuitively understood as a center mechanism, the inherent stability of the DOT moieties requires further investigation. The properties of cation and/or an ion within the ionic pair were independently modified, then metathesis could generate new functional materials, which retain the core f eatures of the IL state of matter. The regiospecific N-alkylation strategy provided the more sterically hindered 1alkylimidazoles for the production of newly synthe sized anions and cations. Over the last several years, typical properties of ionic liquids (ILs) such as high ion c ontent, liquidity over a wide temperature range, low viscosity, limitedvolatility, and high ionic conductivity have

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40 proven to be important drivers supporting numerous advances beyond the initial investigations of ILs as liquid electrolytes. The synthesis of tetrasubstituted trans -imidazolidin-2-ones utilized a general benzotriazole protocol to enable the introduction of a variety of substituents into th e 4and 5-position of imidazolidin-2-ones with trans stereochemistry. The extension of the previous work allowed the formation of a vicinal diamine and urea in on e simultaneous step. The presences of two potentially bioactive properties encourages the e xploration of vicinal diam ino tethered ureas and unsaturated imidazol-2-ones, or saturated imidazolidin-2-ones in particular for medicinal screening.

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41 CHAPTER 2 MICROWAVE ASSISTED C-ACYLATION OF P-YLIDES 2.1 Introduction Peptidic -triphenylphosphoranylidene esters and am ides have attracted considerable attention as important intermediates for the preparation of peptidic -keto esters and of -keto amides [94JOC4364, 97JOC8972], compounds which are potential inhibito rs of proteolytic enzymes [92JME451, 93JME2431] and leukotriene A4 hydrolases [93JME211]. The -Keto triphenylphosphoranylidene esters 2.1 have been used for the preparation (i) of alkynes 2.2 by flash vacuum pyrolysis (FVP) [85S764, 04T12231], (ii) ,-diketoesters 2.3 by oxidation ([O]) [94JOC4364, 97JOC8972], and (iii) -keto esters 2.4 by direct reduction ([H ]) (Scheme 2-1). Further applications of distabil ized triphenylphosphoranylidenes ar e given in Chapter 3, section 3.1.0 PPh3CO2Et R O (i)FVP (ii)[O] (iii)[H] CO2Et R O CO2Et R O CO2Et R O 2.1 2.2 2.3 2.4 (iv)Deprotection NH O PPh3 O {Chapter3} 3.1 R=Cbz-NH-CH2 Scheme 2-1. Applications of -Keto -Triphenylphosphoranylidene Esters Beta-Keto -triphenylphosphoranylidene esters 2.1 are readily availa ble by C-acylation of (carboxymethylene)triphenylphosphorane ( 2.6 ) with a proton sponge/acid scavenger such as N O -bis(trimethylsilyl)acetamide (BSA) [90TL5205, 94JOC4364, 95JOC8231] and acyl chlorides [04T12231, 82JOC4955], or cyclic anh ydrides [82AJC2077, 85S764], or anhydrides with BSA [92TL6003] (Scheme 2-2). However, acyl chloride and anhydride methods are

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42 limited in their applicability for chiral peptid ic models due to high reactivity and byproducts causing potential problems with other functional groups. Car bon-acylation methods for chiral Nprotected peptidic -triphenylphosphoranylidene esters ha ve been reported by activation of amino acids with carbonyl diimidazole (CDI) re quiring 24 h reaction tim e [99JA1401], or with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydr ochloride (EDCl) in the presence of 4dimethylaminopyridine (DMAP) requiring 16 h reaction time [93JOC4785, 94JOC4364, 97JOC8972]. Therefore, the development of an expedient, versatile method to C-acylate 2.6 with chiral amino acid derivativ es for N-protected peptidic -triphenylphosphoranylidene esters is desirable. PPh3CO2Et R O 2.1 PPh3HCO2Et R1O OH acidhalides withBSA or -Wave aminoacidsw/ EDCI,DMAP 16h orCDI,24h cyclic anyhydrides or anhydrides withBSA O Me N TMS TMS BSA= 2.6 Scheme 2-2. Literature Methods for -Keto -Triphenylphosphoranylidene Esters Acylbenzotriazoles have been reported by the Katritzky group as efficient neutral coupling reagents for chiral N-acylati on, regioselective C-acylation, and O-acylation of aldehydes [04S1806] and as sufficiently reac tive to form amide bonds at ambi ent temperature, but stable enough to resist side reacti ons [04S2645]. Protected (-aminoacyl)benzotriazoles are efficient reagents for acylation of amino amides [02A RK134], amino sulfonamides [04ARK14], amino thiol esters [04S1806], small pep tides carrying side chains with alkyl groups [04S2645], small

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43 peptides with multi-functional groups [05S397], and amino ketones [05J OC4993]. We have now demonstrated the C-acylation of 2.6 with chiral, and ach iral, N-protected (aminoacyl)benzotriazoles 2.5ag and 2.8ac to prepare chiral, and achiral, N-protected peptidic -triphenylphosphoranylidene esters 2.7ag and 2.9.11 (Scheme 2-3) under microwave irradiation. O N R1Pg PPh3CO2Et + 2.5a-g,2.8a-c 2.6 2.7a-g 2.9-11 R3 O N Bt R1Pg R3 PPh3CO2Et H R2 R2 -Wave Scheme 2-3. Retrosynthesis for N-Protected Peptidic -Triphenylphosphoranylidene Esters A single cavity microwave synthe sizer provides an effective re producible and safe technique for promoting a variety of reactions and shor tening reaction times wh ile reducing pollution by using less solvent [02MI1, 03ARK68]. Micr owaves, a form of el ectromagnetic radiation between infrared (IR) and radio frequencies, us ed in a single cavity synthesizer accelerate reaction times and reduce the amount of solv ent required. The general mechanism behind microwave technology is that molecules with a permanent dipole become aligned with the electric field when irradiated with microwav es, oscillation of which changes the molecular alignment and increases the temperature. Oscilla tion of the standing microwaves occurs at 4.9 x 109 times per second, causing the electromagnetica lly radiated molecules to become extremely agitated, as they align and realign themselves with the oscillating field, creates an intense internal heat that can escalate as quick ly as 10 C per second [02JCO 95]. International convention dictates that most microwave ovens operate at 12.2 cm (2450 MHz), so not to interfere with radar or other telecommunications devices.

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44 2.2 Results and Discussion 2.2.1 Protected (-Aminoacyl)benzotriazoles The starting N-(Bocand Cbz--aminoacyl)benzotriazoles 2.5af (L-configuration), 2.5g (Dconfiguration), and 2.8ac (achiral) were prepared in 2998% yields (Table 2-1) from the corresponding N-protected amino acids following pr ocedures recently developed at the Center for Heterocyclic Chemistry (CHC) at the Univer sity of Florida (UF) (Scheme 2-4) [02ARK134, 04S2645, 05S397]. The two rotameric forms of 2.8b gave distinct and separate signals in the NMR spectra (Scheme 2-5). Novel 2.5e g and 2.8ac were supported by 1H-NMR, 13C-NMR, elemental analyses, and optical rotation. DCM O N R1Pg (i)SOCl2,BtH 2.5b-g 2.8a-c R3 O N Bt R1Cbz R3 OH R2 R2 Pg=BocorCbz (ii)BtSO2Me O N R1Boc R3 B t R2 2.5a Scheme 2-4. Protected (-Aminoacyl)benzotriazoles 2.5ag 2.8ac from Protected Amino Acids 2.8bZ-isomerE-isomer O N Bt Me O O Ph O N Bt Me O O Ph O N Bt Me O O Ph O N Bt Me O O Ph Scheme 2-5. Rotameric Forms of 2.8b

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45 Table 2-1. Isolated Yi elds of N-Protected (-Aminoacyl)benzotriazoles 2.5ag 2.8ac Product Amino Acid Pg R1 R2 R3 Yielda (%) Lit. Yield (%) 2.5a (L)Alanine (Ala) BocMe H H 29g 61b 2.5b (L)Ala CbzMe H H 85 95c 2.5c (L)Valine (Val) CbzCH(Me)2 H H 91e 91c 2.5d (L)Phenylalanine (Phe) CbzCH2Ph H H 98 88c 2.5e (L)Aspartic Acid (Asp) ( -OMe) CbzCH2CO2Me H H 86e,f 2.5f (L)Tryptophan (Trp) Cbz CH2-Indol3-yl H H 73 95d 2.5g (D)Ala CbzMe H H 85f 2.8a Glycine (Gly) CbzH H H 98f 2.8b Sarcosine (Sar) CbzH H Me84f 2.8c Aminoisobutyric Acid (Aib) CbzMe MeH 80f aIsolated yield. bLit. [02ARK134]. cLit. [04S2645]. dLit. [05S397]. eReaction by K. Suzuki. fNovel. gMethod (ii) Scheme 2-4. 2.2.2 Chiral N-Protected Peptidic -Triphenylphosphoranylidene Esters The chiral N-protected peptidic -triphenylphosphora nylidene esters 2.7ag (Scheme 2-6) were prepared in 6590% yields (Table 2-2) from chiral N-(Bocand Cbz-aminoacyl)benzotriazole 2.5af (L-configuration), 2.5g (D-configuration) and (carboxymethylene)triphenylphosphorane ( 2.6 ) in the microwave synthesizer, following the optimized procedure (Table 2-3). Microwave reactions were carried out in a standard 50 mL rb (round bottom) flask under controlled, safe, and reproducible conditions. The single cavity microwave synthesizer maintained a steady te mperature with a self-adjusting irradiation mechanism. Novel 2.7dg were supported by 1H-NMR, 13C-NMR, elemental analyses, and optical rotation.

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46 O N Bt H R1 ACN O N R1Pg PPh3CO2Et + -Wave(120W) 60oC,10min 2.6 Pg H 2.5a-g 2.7a-g PPh3 H CO2Et Scheme 2-6. Base Free C-Acylation for Ch iral N-Protected Peptidic Triphenylphosphoranylidene Esters 2.7ag Table 2-2. Isolated Yields of Chir al N-Protected Peptidic -Triphenylphosphoranylidene Esters 2.7ag Product Amino Acid Pg R1 Yielda (%) [ ]23 D Lit. Yield (%) Lit. [ ]23 D 2.7a (L)Ala Boc Me 65 +0.2 54c n/r 2.7b (L)Ala Cbz Me 88 (86)b +25.4 46d +20.3 2.7c (L)Val Cbz CH(Me)2 88 +28.0 88c,49d +28.7 2.7d (L)Phe Cbz CH2Ph 89e (79)b +0.6 2.7e (L)Asp(OMe) Cbz CH2CO2Me 90e,f +0.8 2.7f (L)Trp Cbz CH2-Indol3-yl 70e +40.0 2.7g (D)Ala Cbz Me 69e 17.5 aIsolated yield. bYields obtained in refluxing ACN. cLit. [95MI124] Boc-Protected Ncarboxyanydride with 2.6 at rt. dLit. [02JP(1)533] (EDCl, DMAP with N-CbzProtected amino acid at rt). eNovel. fReaction by K. Suzuki. gn/r = not reported. Carbon-acylation conditions were optimized using 2.6 with Cbz-(L)Ala-Bt ( 2.5b ) in three different solvents, dichloromethane (DCM), acet onitrile (ACN), and to luene (Table 2-3). Microwave assisted C-acylations performed in DCM, at 36 C for 30 min gave no detectable 2.7b Microwave assisted C-acylations performe d in toluene, at 110 C for 10 min formed 2.7b in 30% yield, along with a byproduct detected by 1H-NMR. Optimized microwave assisted Cacylation in ACN, at 60 C for 10 min gave pure 2.7b in 88% yield, after a simple workup by washing with saturated aq sodium carbonate. Carbon-Acylations of 2.6 with 2.5b and 2.5d in

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47 refluxing ACN, using an oil bath he at source, required 12 h to achieve 2.7b (86%) and 2.7d (79%), respectively. Although using an oil bath heat source generated satis factory yields, the use of the microwave assistance sign ificantly shortened the reaction time and reduced the amount of solvent required. The optimized microwave reaction conditi ons (60 C, 120 W, ACN, 10 min) were applied to the preparat ion of N-protected peptidic -triphenylphosphora nylidene esters 2.7a g (Scheme 2-5, Table 2-2). The microwave prot ocol afforded fast and clean C-acylation, and the use of N-protected (-aminoacyl)benzotriazoles 2.5a g avoided the need for base. Table 2-3. Attempted Optimization Reaction Conditions for 2.7b Solvent (1 mL) -Wave (W) T (C) t (h) Yield (%) DCM (70) 36 0.5 -a Toluene (200) 110 0.1 30b ACN (120) 60 0.1 88 ACNd (n/a) 82 12.0 86c aNo Reaction. bReaction provided undesired byproduct. cYields obtained in refluxi ng ACN heated by oil bath. d15 mL. Ester 2.7a was prepared in 54% yield using the corresponding ur ethane-protected Ncarboxyanhydride with 2.6 by Fehrentz et al. [95MI124] The urethane-protected Ncarboxyanhydrides are water sensi tive [90JA7415], and require se veral steps for preparation from N-carboxyanhydrides which exhibit poo r stability [87MI22]. Direct couplings of Cbz-AlaOH and Cbz-Val-OH with 2.6 were carried out in the presence of EDCl/DMAP, by Aitken et al., to produce 2.7b (46%) and 2.7 (49%), respectively [ 02JP(1)533]. The twelve -keto triphenylphosphoranylidene esters, by Aitken et al., were obtained in an average 47% yield. By our microwave assisted method, esters 2.7a c were obtained in an average 80% yield. The attempt to C-acylate 2.6 (Scheme 2-7) with Cbz-Glu-Bt [05S397] was unsuccessful. The attempt to C-acylate 2.6 with Fmoc-Ala-Bt resulted in cleav age of the Fmoc protecting group,

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48 which caused the formation of a complex mixture of products. Fmoc-Bt was isolated by column chromatography. The formation of Fmoc-Bt was explained, by the generation of the benzotriazole anion, which underwent addition-e limination to the carbonyl carbon of the Fmoc group. O N Bt F m oc Me ACN -Wave(120W) 60oC,10min H Bt O O +HN Bt O NH2 O Cbz ACN -Wave(120W) 60oC,10min + Fmoc-Bt decomposed reagents 2.6 2.6+complex mixture Scheme 2-7. Unsuccessful C-Acylations, and the Generation of Fmoc-Bt 2.2.3 Achiral N-Protected Peptidic -Triphenylphosphoranylidene Esters The achiral N-protected peptidic -triphenylphosphoranylidene esters 2.92.11 (Scheme 2-8) were prepared from achiral Cbz-N-(aminoacyl)benzotriazoles 2.8ac and 2.6 under the optimized microwave conditi ons (60 C, 120 W, ACN, 10 min). C-Acylation of 2.6 with CbzGly-Bt ( 2.8a ) or Cbz-Sar-Bt ( 2.8b ) gave 2.9 (80%) or 2.10 (89%), respectively. On the contrary, C-acylation of 2.6 with Cbz-Aib-Bt ( 2.8c ) gave 2.11 in 3% yield. Extension of the reaction time resulted in the decomposition of 2.8c Presumably the formation of 2.11 was inhibited by steric hindrance from the two methyl groups at the -position. The two rotameric forms of 2.10 gave distinct and separate signals in th e NMR spectra (Scheme 2-9). Novel 2.10 and 2.11 were supported by 1H-NMR, 13C-NMR, and elemental analyses.

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49 O N Bt Cbz R1 ACN O N R1Cbz PPh3CO2Et + -Wave(120W) 2.6 R2 R3 R2 R3 2.8a ,R1=R2=R3=H 2.8b ,R1=R2=H,R3=Me 2.8c ,R1=R2=Me,R3=H 2.9 R1=R2=R3=H(80%) 2.10 R1=R2=H,R3=Me(89%) 2.11 R1=R2=Me,R3=H(3%) 60oC,10min Scheme 2-8. Base Free C-Acylation for Achiral Esters 2.9.10 2.10 Z-isomer E-isomer O N PPh3CO2Et Me O O Ph O N Ph3PCO2Et Me O O Ph O N PPh3CO2Et Me O O Ph O N Ph3PCO2Et Me O O Ph Scheme 2-9. Rotameric Forms of 2.10 2.2.4 Peptidic -Triphenylphosphoranylidene Diastereomers The (LL)Diastereomer, 2.14 (61%) and (DL)Diastereomer, 2.15 (66%) were prepared, to test retention of the original ch irality during microwave irradi ation (Scheme 2-10). Novel 2.13 2.14 and 2.15 were characterized and supported by 1H-NMR, 13C-NMR, elemental analyses, and optical rotation. Coupling of (L)phenylalanine methyl ester with -bromoacetic acid in the presence of N,N dicyclohexylcarbodiimide (DCC) and DMAP gave 2.12 (95%) [03TA1935]. Preparation of 2.13 (81%) was achieved by reaction with triphenylphos phine in a solvent mixture (THF:diethyl ether = 1:3) [99JA1401]. (LL)Diastereomer 2.14 (61%) was obtained under microwave conditions

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50 (60 C, 120 W, ACN, 10 min) with 2.5b in the presence of equimolar triethylamine. Similarly, reaction of 2.13 with 2.5g gave (DL)diastereomer 2.15 (66%). O OMe NH Ph O PPh3 Br PPh3O OMe NH Ph O Br O OMe N H Ph O PPh3O H N Cbz Me BrCH2CO2H DCC,DMAP O OMe N H Ph O PPh3O H N Me Cbz O OMe H2N Ph 2.12 95% 2.13 81% 2.14 (i) 2.5b Et3N 61% 2.15 (i) 2.5g Et3N 66% THF,Et2O (i) -Wave(120W) 60oC,10min,ACN Scheme 2-10. Synthetic Route to (LL)and (DL)Diastereomers 2.14, 2.15 Figure 2-1. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 20 C

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51 Figure 2-2. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 60 C Figure 2-3. The 31P-NMR of the (DL)Diastereomer 2.15 at 20 C and 60 C The extent of preservation of original chirality was estimated as >95% by the 1H NMR spectra of the (LL)and (DL)diastereomers 2.14 and 2.15 respectively. While the Me group of enantiopure Ala (LL)diastereomer 2.14 gave a signal at 0.99 ppm, the Me group of the enantiopure Ala on the (DL)diastereomer 2.15 gave a signal at 0.86 ppm. Optical rotations of the (LL)diastereomer and (DL)diastereomer were .0 and +4.4 respectively. Additionally the 13CNMR spectra of the two diastereomers showed a broadening of some signals, and a complex

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52 series of signals in the aromatic region, es pecially between 131.5.2 ppm. The aromatic region 13C-NMR spectra of the (DL)diastereomer 2.15 at 20 C (Figure 2-1) and at 60 C (Figure 2-2), showed a sharpening of the signals at higher temperature and the complex multiplet separated into two sets of doublets. The 31P-NMR spectra of the (DL)diastereomer 2.15 (Figure 2-3) gave two broad singlets at rt, which at 60 C merged to form one sharp singlet. The different NMR chemical shifts and optical rotations in opposite di rections of the two diastereomers supported the preservation of chirality. 2.3 Conclusions The preparation of N-protected peptidic -triphenylphosphoranylid ene esters from N-(Bocor Cbz--aminoacyl)benzotriazoles was demonstrated under microwave irradiat ion without base. Retention of chirality was dem onstrated by the synthesis of (LL)and (DL)diastereomers and comparison of their optical rotation and NMR sp ectra. The C-acylation utilized versatile Nprotected (-aminoacyl)benzotriazoles avoiding the us e of base and microwave irradiation reduced reaction times and solvent. Furthermor e this procedure was f ound to be a convenient route to the tetramic acid ring system in Chapter 3. 2.4 Experimental Section Melting points were determined on a capillary point apparatus equi pped with a digital thermometer. NMR spectra were recorded in CDCl3 for 1H (300 MHz) and 13C (75 MHz) with tetramethylsilane (TMS) as the internal standard, unless otherwise specified. N-Bocand N-Cbzamino acids were purchased from Fluka and Acros, and used w ithout further purification. Acetonitrile was purchased from Al drich, and used without distil lation. Microwave heating was carried out with a si ngle cavity Discover Microwave Synthesizer (CEM Corporation, NC), producing continuous irra diation at 2455 MHz.

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53 2.4.1 Preparation of N-Protected (-Aminoacyl)benzotriazoles. 2.5ag, 2.8ac Compounds 2.5a (Boc protecting group) [02ARK134], 2.5bg (Cbz protecting group) [04S2645, 05S397], and 2.8ac were prepared by previous ly reported procedures. (3S)-4-(Benzotriazol-1-yl)-3-benzyloxycarbony lamino-1-methoxybutan -1,4-dione (Cbz(L)Asp(OMe)-Bt, 2.5e). (86% yield) Colorless needles (from chloroform / hexane) mp 72 74 C. [ ]23 D = 23.4 (c 1.75, CH2Cl2). 1H NMR 3.23 (dd, J = 16.6, 4.8 Hz, 1H), 3.38 (dd, J = 16.6, 4.8 Hz, 1H), 3.65 (s, 3H), 5.14 (s, 2H), 5.90 .97 (m, 1H), 6.11 (br s, 1H), 7.35 (br s, 5H), 7.51.56 (m, 1H), 7.65.71 (m, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H). 13C NMR 37.2, 51.7, 52.2, 67.4, 114.4, 120.3, 126.6, 128.1, 128.2, 128.5, 130.9, 131.2, 135.9, 145.9, 155.7, 169.2, 170.4. Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C, 59.76; H, 4.66; N, 14.58. (2R)-1-(Benzotriazol-1-yl)-2-benzyl oxycarbonylaminoprop-1-one (Cbz-(D)Ala-Bt, 2.5g). (85% yield) White microcry stals (from ethyl acetate / hexanes) mp 94 C. [ ]23 D = +80.2 (c 2.08, CH2Cl2). 1H NMR 1.69 (d, J = 7.0 Hz, 3H), 5.11 (d, J = 12.2 Hz, 1H), 5.17 (d, J = 12.2 Hz, 1H), 5.65 (d, J = 6.9 Hz, 1H), 5.81 (quintet, J = 7.1 Hz, 1H), 7.10.45 (m, 5H), 7.50.56 (m, 1H), 7.64.70 (m, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H). 13C NMR 18.9, 50.5, 67.1, 114.3, 120.3, 126.4, 128.1 (2C), 128.4, 130.6, 131.1, 136.0, 145.9, 155.6, 172.2. Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Fo und: C, 62.82; H, 4.97; N, 17.25. 1-(Benzotriazol-1-yl)-2-benzyloxycarbony laminoethan-1-one (Cbz-Gly-Bt, 2.8a). (98% yield) White microcrystals (from ch loroform / hexane) mp 106 C. 1H NMR 5.10 (d, J = 5.7 Hz, 1H), 5.20 (s, 2H), 5.55 (s, 1H), 7.35.39 (m, 5H), 7.51.56 (m, 1H), 7.66.71 (m, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H). 13C NMR 45.0, 67.7, 114.3, 120.6, 126.8, 128.4, 128.5, 128.8, 131.1, 136.2.146.2, 156.7, 168.6. Anal. Calcd for C16H14N4O3: C, 61.93; H, 4.55; N, 18.06. Found: C, 61.98; H, 4.57; N, 17.99. 1-(Benzotriazol-1-yl)-2-benzyloxycarbonyl(me thyl)aminoethan-1-one (Cbz-Sar-Bt, 2.8b). (Two rotameric forms) 84% yield. Colorless microcrystals (from ethyl acetate / hexane) mp 45 46 C. 1H NMR 3.17 (s, 3H), 5.12 (s, 1H), 5.15 (s, 1H ), 5.17 (s, 1H), 5.23 (s, 1H), 7.20.26 (m, 2H), 7.34.44, (m, 3H), 7.51.57 (m, 2H), 7.65.72 (m, 2H), 8.13.15 (m, 1H), 8.23 8.28 (m, 1H). 13C NMR 35.8, 36.3, 52.4, 52.8, 67.6, 67.8, 114.1, 120.3, 126.4, 126.5, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5, 130.7, 130.8, 131.0, 136.2, 136.4, 145.9, 156.1, 156.9, 167.8, 167.9. Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 62.82; H, 4.99; N, 17.30. 1-(Benzotriazol-1-yl)-2-benzyloxycarbonylamino -2-methylpropan-1-one (Cbz-Aib-Bt, 2.8c). (80% yield) Colorless needles (fro m chloroform / hexane) mp 98 C. 1H NMR 1.88 (s, 6H), 4.90 (s, 2H), 5.77 (br s, 1H), 7.11.20 (m, 5H), 7.47.53 (m, 1H ), 7.62.67 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H). 13C NMR 26.0, 58.9, 66.8, 115.0, 119.9, 126.0, 127.8, 128.0, 128.3, 130.5, 131.9, 135.9, 144.8, 155.3, 172.6. Anal. Calcd for C18H18N4O3: C, 63.89; H, 5.36; N, 16.56. F ound: C, 63.73; H, 5.22; N, 16.55.

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54 2.4.2 Preparation of N-Protected Peptidic -Triphenylphosphoranylidene Esters, Under Microwave Irradiation. 2.7ag, 2.9 Compounds 2.7ag, 2.9 were prepared in a dry 50 mL rb flask equipped with a condenser and a magnetic stir bar, charged w ith a solution of the corresponding 2.5ag, 2.8ac (1.1 mmol) and 2.6 (0.348 g, 1.0 mmol) in ACN (1 mL). Th e flask containing the reaction mixture was exposed to microwave irradiation (120 W) for 10 min at 60 C, and cooled with high-pressure air through an inbuilt system in the instrument until the temperature fell below 30 C. The reaction mixture was diluted with ethyl acetate and wash ed with a saturated aq sodium carbonate. The organic layer was collected and dried over anhydrous (anhyd) magnesium sulfate to give the crude product, which was purified by column chromatography (SiO2, hexane:ethyl acetate = 1:1). 2.4.3 Preparation Under Conven tional Heating. 2.7b,d Compounds 2.7b,d were prepared in a dry 50 mL rb flask equipped with a condenser and a magnetic stir bar, charged with a solution of the corresponding 2.5b,d (1.1 mmol) and 2.6 (0.348 g, 1.0 mmol) in ACN (15 mL). The reaction mixt ure was heated in an o il bath at 70 C for about 12 h until the starting materials were completely consumed (monitored by TLC, hexanes:ethyl acetate = 1:1). Af ter concentration under reduced pr essure, the residue was diluted with ethyl acetate and washed with saturated aq sodium car bonate. The organic layer was collected and dried over anhyd magnesium sulfate to give the crude produ ct, which was purified by column chromatography (SiO2, hexane:ethyl acetate = 1:1). (4S)-4-tert-Butoxycarbonylamino-1-ethoxy-2-tripheny lphosphoranylidenpentan-1,3-dione (Boc-(L)Ala P-Ester, 2.7a). (65% yield) Colorless microcryst als (from ethyl acetate / hexanes) mp 153 C (mp 153 C)lit.[95MI125]. [ ]23 D = +0.2 (c 1.67, CH2Cl2). 1H NMR 0.75 (t, J = 7.0 Hz, 3H), 1.38 (s, 9H), 1.43 (d, J = 6.3 Hz, 3H), 3.65.95 (m, 2H), 5.38.51 (m, 2H), 7.44.68 (m, 15H). 13C NMR 13.7, 20.1, 28.3, 51.9 (JCP = 8.0 Hz), 58.6, 68.9 (JCP = 110.5 Hz), 78.3, 126.1 (JCP = 93.3 Hz), 128.5 (JCP = 12.6 Hz), 131.7, 133.0 (JCP = 9.7 Hz), 155.2, 166.7 (JCP = 15.5 Hz), 195.5. (4S)-4-Benzyloxycarbonylamino-1 -ethoxy-2-triphenylphosphoranylidenpentan-1,3-dione (Cbz-(L)Ala P-Ester, 2.7b). (86% yield) Colorless microcrystals (from chloroform / hexane),

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55 mp 140 C, (mp 140 C)lit.[02JP(1)533]. [ ]23 D = +25.4 (c 1.58, CH2Cl2), ([ ]20D = +20.3 (c 1.0005, CH2Cl2)) lit. [02JP(1)533]. 1H NMR 0.75 (t, J = 7.0 Hz, 3H), 1.47 (d, J = 6.6 Hz, 3H), 3.69 3.82 (m, 2H), 5.06 (s, 2H), 5.49 (quintet, J = 7.1 Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 7.27.68 (m, 20H). 13C NMR 13.7, 20.4, 52.4 (JCP = 8.6 Hz), 58.6, 65.9, 68.8 (JCP = 111.1 Hz), 126.0 (JCP = 93.3 Hz), 127.6 (3C), 128.2, 128.5 (JCP = 12.6 Hz), 131.8 (JCP = 2.9 Hz), 133.0 (JCP = 9.7 Hz), 137.1, 155.4, 166.7 (JCP = 14.3 Hz), 194.7. Anal. Calcd for C33H32NO5P: C, 71.60; H, 5.83; N, 2.53. Found: C, 71.39; H, 5.78; N, 2.40. (4S)-4-Benzyloxycarbonylamino-1-ethoxy-5-me thyl-2-triphenylphosphoranylidenhexan1,3-dione (Cbz-(L)Val P-Ester, 2.7c). (88% yield) Colorless micr ocrystals (from ethyl acetate / hexanes) mp 88 C (mp 88 C)lit.[02JP(1)533]. [ ]23 D = +28.0 (c 1.66, CH2Cl2). 1H NMR 0.68 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H), 2.42.45 (m, 1H), 3.68.85 (m, 2H), 5.06 (s, 2H), 5.52.56 (m, 1H), 5.68 (d, J = 8.9 Hz, 1H), 7.39.20 (m, 5H), 7.51.40 (m, 10H), 7.80.63 (m, 5H). 13C NMR 13.8, 15.9, 20.7, 32.3, 58.6, 60.4 (JCP = 8.5 Hz), 66.0, 69.8 (JCP = 111.0 Hz), 126.0 (JCP = 93.9 Hz), 127.6 (3C), 128.2, 128.5 (JCP = 12.6 Hz), 131.8 (JCP = <2 Hz), 133.0 (JCP = 9.7 Hz), 137.1, 156.6, 166.8 (JCP = 14.2 Hz). (4S)-4-Benzyloxycarbonylamino-1-ethoxy-5-pheny l-2-triphenylphosphoranylidenpentan1,3-dione (Cbz-(L)Phe P-Ester, 2.7d). (79% yield) Colorless micr ocrystals (from ethyl acetate / hexanes) mp 51 C. [ ]23 D = +0.6 (c 1.66, CH2Cl2). 1H NMR 0.71 (t, J = 7.1 Hz, 3H), 2.83 (dd, J = 13.2, 7.7 Hz, 1H), 3.40 (dd, J = 13.2, 4.4 Hz, 1H), 3.70.85 (m, 2H), 4.95 (d, J = 12.8 Hz, 1H), 5.02 (d, J = 12.8 Hz, 1H), 5.58 (d, J = 8.9 Hz, 1H), 5.80.87 (m, 1H), 7.16.32 (m, 10H), 7.41.47 (m, 5H), 7.53.66 (m, 10H). 13C NMR 13.7, 39.8, 56.8 (JCP = 8.6 Hz), 58.7, 65.9, 70.1 (JCP = 108.8 Hz), 125.9 (JCP = 93.9 Hz) 126.0, 127.5, 127.9, 128.2, 128.5 (JCP = 12.6 Hz), 129.7, 131.7 (JCP = 2.9 Hz) 133.1 (JCP = 9.7 Hz), 137.1, 138.0, 155.7, 166.9 (JCP = 14.3 Hz), 193.5. Anal. Calcd for C39H36NO5P: C, 74.39; H, 5.76; N, 2.22. Found: C, 74.10; H, 5.83; N, 2.58. (4S)-4-Benzyloxycarbonylamino-1-ethoxy-6-me thoxy-2-triphenylphosphoranylidenhexan1,3,6-trione (Cbz-(L)Asp(OMe) P-Ester, 2.7e). (90% yield) Colorless microcrystals (from ethyl acetate / hexane s) mp 116 C. [ ]23 D = +0.8 (c 1.91, CH2Cl2). 1H NMR 0.72 (t, J = 6.9 Hz, 3H), 2.82 (dd, J = 14.3, 6.7 Hz, 1H), 3.09 (dd, J = 14.3, 3.4 Hz, 1H), 3.56 (s, 3H), 3.69 3.85 (m, 2H), 5.06 (s, 2H), 5.76.81 (m, 1H), 5.91 (d, J = 8.1 Hz, 1H), 7.22.72 (m, 20H). 13C NMR 13.6, 38.6, 51.5, 53.6 (JCP = 9.2 Hz), 58.8, 66.1, 69.3 (JCP = 109.4 Hz), 125.6 (JCP = 93.9 Hz), 127.5, 127.6, 128.2, 128.5 (JCP = 12.6 Hz), 131.8 (JCP = 2.9 Hz), 133.1 (JCP = 9.7 Hz), 136.9, 155.6, 166.7 (JCP = 14.3 Hz), 171.5, 191.8. Anal. Calcd for C35H34NO7P: C, 68.73; H, 5.60; N, 2.29. Found: C, 68.66; H, 5.65; N, 2.22. (4S)-4-Benzyloxycarbonylamino -1-ethoxy-5-(i ndol-3-yl)-2triphenylphosphoranylidenpentan-1,3,-dione (Cbz-(L)Trp P-Ester, 2.7f). (71% yield) White microcrystals (from chloroform / hexanes) mp 88 C. [ ]23 D = +40.0 (c 1.67, CH2Cl2). 1H NMR 0.72 (t, J = 7.0 Hz, 3H), 3.26 (dd, J = 14.7, 6.9 Hz, 1H), 3.51 (dd, J = 14.7, 4.5 Hz, 1H), 3.68.83 (m, 2H), 4.97 (s, 2H), 5.70.80 (m, 1H), 5.80.91 (m, 1H), 6.91 (s, 1H), 7.00.40 (m, 15H), 7.40.60 (m, 9H), 7.71 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H). 13C NMR 13.7, 28.8, 56.5 (JCP = 8.6 Hz), 58.8, 68.3 (JCP = 96.3 Hz), 110.9, 111.5, 119.0, 121.3, 122.9, 125.9 (JCP = 93.3 Hz), 127.6, 127.9, 128.2, 128.5 (JCP = 12.6 Hz), 131.6, 132.0, 132.1, 133.0 (JCP = 9.7 Hz), 135.9,

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56 137.0, 155.8, 166.9 (JCP = 13.7 Hz), 193.9. Anal. Calcd for C41H37N2O5P: C, 73.64; H, 5.58; N, 4.19. Found: C, 73.07; H, 5.58; N, 4.16. HRMS m/z Calcd for C41H37N2O5P 669.2513 [M+H]+, Found 669.2523. (4R)-4-Benzyloxycarbonylamino-1 -ethoxy-2-triphenylphosphoranylidenpentan-1,3,-dione (Cbz-(D)Ala P-Ester, 2.7g). (69% yield) Colorless microcry stals (from ethyl acetate / hexane) mp 135 C. [ ]23 D = 17.5 (c 2.08, CH2Cl2). 1H NMR 0.75 (t, J = 7.1 Hz, 3H), 1.48 (d, J = 7.1 Hz, 3H), 3.66.88 (m, 2H), 5.06 (s, 2H), 5.50 (quintet, J = 6.7 Hz, 1H), 5.86 (d, J = 7.7 Hz, 1H), 7.26.68 (m, 20H). 13C NMR 13.7, 20.3, 52.4 (JCP = 8.6 Hz), 58.6, 65.8, 68.8 (JCP = 110.5 Hz), 125.8 (JCP = 93.9 Hz), 127.5, 127.6, 128.2, 128.5 (JCP = 12.6 Hz), 131.7, 131.8 (JCP = 2.9 Hz), 132.9 (JCP = 9.7 Hz), 137.0, 155.4, 166.7 (JCP = 14.3 Hz), 194.8. Anal. Calcd for C33H32NO5P: C, 71.60; H, 5.83; N, 2.53. F ound: C, 71.20; H, 5.89; N, 2.56. 4-Benzyloxycarbonylamino-1-ethoxy-2-tripheny lphosphoranylidenbutan-1,3,-dione (CbzGly P-Ester, 2.9). (80% yield) White microcrystals (from ethyl acetate / hexanes) mp 134 136 C, (mp 134 C)lit.[95MI124]. 1H NMR 0.75 (t, J = 7.0 Hz, 3H), 3.70.82 (m, 2H), 4.60 (d, J = 4.0 Hz, 2H), 5.06 (s, 2H), 5.85 (s, 1H), 7.22.70 (m, 20H). 13C NMR 13.8, 49.3 (JCP = 8.6 Hz), 58.6, 66.1, 68.9 (JCP = 112.8 Hz) 125.7 (JCP = 93.3 Hz), 127.6, 127.7, 128.6 (JCP = 12.6 Hz), 131.9 (JCP = 2.9 Hz), 133.1 (JCP = 9.7 Hz), 136.9, 156.1, 167.3 (JCP = 14.3 Hz), 190.3. Anal. Calcd for C32H30NO5P: C, 71.23; H, 5.60; N, 2.60. F ound: C, 71.11; H, 5.79; N, 2.63. 4-Benzyloxycarbonyl(methyl)amino-1-ethoxy -2-triphenylphosphoranylidenbutan-1,3,dione (Cbz-Sar P-Ester, 2.10). (Two rotameric forms) (89% yield) White microcrystals (from ethyl acetate / hexa nes) mp 133 C. 1H NMR 0.64 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 6.9 Hz, 3H), 2.83 (s, 3H), 2.85 (s, 3H), 3.74 (quintet, J = 7.1 Hz, 2H), 4.69 (s, 2H), 5.04 (s, 1H), 5.06 (s, 1H), 7.25.70 (m, 20H). 13C NMR 13.5, 13.7, 35.5, 36.1, 57.1 (JCP = 8.6 Hz), 57.5 (JCP = 8.0 Hz), 58.2, 66.3, 66.6, 68.6 (JCP = 109.9 Hz), 68.9 (JCP = 111.7 Hz), 125.9 (JCP = 93.3 Hz), 126.0 (JCP = 93.3 Hz), 126.9, 127.2, 127.4, 127.5, 128.1, 128.1, 128.3 (JCP = 12.6 Hz), 128.3 (JCP = 12.6 Hz), 131.5, 131.5, 131.6, 131.8, 131.9, 132.9, 133.0, 133.1, 137.0, 137.3, 156.6, 156.7, 167.5 167.7, 167.9, 191.1 (JCP = 3.4 Hz), 191.6 (JCP = 3.4 Hz). HRMS m/z Calcd for C33H32NO5P 554.2091 [M+H]+, Found 554.2106. 4-Benzyloxycarbonylamino-1-ethoxy-4-methyl -2-triphenylphosphoranylidenpentan-1,3,dione (Cbz-Aib P-Ester, 2.11). (3% yield) White microcrystal s (from ethyl acetate / hexanes) mp 80 C. 1H NMR 0.56 (t, J = 7.1 Hz, 3H), 1.63 (s, 6H), 3.58 (q, J = 7.1 Hz, 2H), 5.14 (br s, 2H), 6.79 (s, 1H), 7.25.68 (m, 20H). 13C NMR 13.5, 25.0, 58.7, 60.1, 60.2, 65.6, 68.9 (JCP = 109.4 Hz), 127.0 (JCP = 93.9 Hz), 127.4, 127.5, 128.3, 128.5 (JCP = 12.0 Hz), 131.4 (JCP = 2.9 Hz), 132.9 (JCP = 9.7 Hz), 137.4, 155.8, 167.2 (JCP = 13.2 Hz), 198.2. HRMS m/z Calcd for C34H34NO5P 568.2247 [M+H]+, Found 568.2269. 2.4.4 Preparation of P-Ylide Salt. 2.13 Compound 2.13 was prepared from (L)phenylalanine methyl ester hydrochloride (35.0 g, 162.3 mmol) dissolved in H2O (75 mL) and neutralized with sa turated aq sodium carbonate. The

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57 alkaline solution was extracted with DCM (100 mL, 4x), dried over anhyd magnesium sulfate, and filtered. -Bromoacetic acid (24.8 g, 178.5 mmol), DCC (36.8 g, 178.5 mmol), and DMAP (1.0 g, 8.1 mmol) were added to (L)phenylalanine methyl ester (29. 1 g, 162.3 mmol) in DCM, at 0 C and stirred for 3 h. The white precipitate was removed by filtration. The filtrate was collected and concentrated under re duced pressure, to give the cr ude product, which was purified by column chromatography (SiO2, hexane:ethyl acetate). N-(2-Bromoacetyl)-(L)Phe-OMe 2.12 (10.0 g, 33.3 mmol) was dissolved in a 1:3 ratio mixture of THF:diethyl ether (160 mL) and triphenylphosphine (8.7 g, 33.3 mm ol) at rt and stirred for 3 days The white precipitated P-ylide salt 2.13 was collected by filtration and wa shed with ethyl acetate [99JA1401]. (2S)-1-methoxy-3-phenyl-2-(2-triphenylphospho nioethan-1-on-1-yl)aminoprop-1-one bromide (2.13). (81% yield) White microcrystals (from DCM / hexanes) mp 155 C. [ ]23 D = 9.7 (c 2.08, CH2Cl2). DMSO-d6 1H NMR 2.83 (dd, J = 13.9, 8.8 Hz, 1H), 2.97 (dd, J = 13.9, 5.5 Hz, 1H), 3.56 (s, 3H), 4.38.43 (m, 1H), 5.02.09 (m, 2H), 7.13.35 (m, 5H), 7.50 7.91 (m, 15H), 9.07 (d, J = 7.6 Hz, 1H). DMSO-d6 13C NMR 30.6 (JCP = 57.3 Hz), 36.5, 52.0, 54.3, 118.6 (JCP = 88.2 Hz), 126.7, 128.3, 129.1, 129.9 (JCP = 13.2 Hz), 133.7 (JCP = 10.3 Hz), 134.8, 136.5, 163.0 (JCP = 4.6 Hz), 170.9. Anal. Calcd for C30H29BrNO3P: C, 64.06; H, 5.20; N, 2.49. Found: C, 63.76; H, 5.18; N, 2.41. 2.4.5 Preparation of Peptid ic Diastereomers. 2.14 Compounds 2.14 were prepared in a dry 50 mL rb flask equipped with a condenser and a magnetic stir bar, charged with a solution of the P-ylide salt 2.13 (1.12 g, 2.0 mmol), triethylamine (0.24 g, 2.4 mmol), and 2.5b (0.84 g, 2.6 mmol), or 2.5g, in ACN (1 mL). The flask containing the reaction mixt ure was exposed to microwave irradiation (120 W) for 10 min at a temperature of 60 C, and cooled with hi gh-pressure air through an inbuilt system in the instrument until the temperature fell below 30 C. The reaction mixture was diluted with ethyl acetate and washed with saturated aq sodium car bonate. The organic layer was collected, dried over anhyd magnesium sulfate, filtered, and concentrated under reduced pressure, to give the

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58 crude products. Final pu rification was performed by column chromatography (SiO2, hexane:ethyl acetate = 1:1). (4S)-4-Benzyloxycarbonylamino-1-[(2S)-(1-methoxy-3-phenylprop an-1-on-2-yl)amino]-2triphenylphosphoranylidenpentan-1,3,-dione ((LL)Diastereomer, 2.14). (61% yield) White microcrystals (from DCM / hexanes) mp 65 C. [ ]23 D = 20.0 (c 2.08, CH2Cl2). 1H NMR 0.99 (d, J = 4.8 Hz, 3H), 1.87 (s, 1H), 2.99 (dd, J = 13.5, 8.5 Hz, 1H), 3.12 (dd, J = 13.5, 5.2 Hz, 1H), 3.61 (s, 3H), 4.65.72 (m, 1H) 4.95.06 (m, 2H), 5.66 (br s, 1H), 7.23.70 (m, 26H). 13C NMR 20.4, 38.1, 50.5, 51.7, 53.6, 65.9, 72.2 (JCP = 116.8 Hz), 126.1 (d, JCP = 93.3 Hz,), 126.3, 127.5, 127.6, 128.0, 128.1, 128.2, 128.3, 128.5 (JCP = 12.6 Hz), 129.2, 131.5, 131.7, 131.9, 132.9 (JCP = 9.7 Hz), 136.6, 137.0, 155.1, 168.5, 172.6, 191.2. Anal. Calcd for C41H39N2O6P: C, 71.71; H, 5.72; N, 4.08. Found: C, 71.85; H, 5.81; N, 3.75. (4R)-4-Benzyloxycarbonylamino-1-[(2S)-(1-methoxy-3-phenylprop an-1-on-2-yl)amino]-2triphenylphosphoranylidenpentan-1,3,-dione ((DL)Diastereomer, 2.15). (66% yield) White microcrystals (from DCM / hexanes) mp 46 C. [ ]23 D = +4.4 (c 2.08, CH2Cl2). 1H NMR 0.86 (d, J = 6.7 Hz, 3H), 1.90 (s, 1H), 2.98 (dd, J = 13.6, 7.9 Hz, 1H), 3.11 (dd, J = 13.6, 5.4 Hz, 1H), 3.61 (s, 3H), 4.67.74 (m, 1H) 5.03 (br s, 2H), 5.60 (br s, 1H), 7.15.70 (m, 26H). 13C NMR 20.3, 38.1, 50.6, 51.8 (JCP = 4.6 Hz), 53.7, 66.1, 72.8 (JCP = 119.7 Hz), 126.5 (JCP = 93.9 Hz,), 126.5, 127.7, 127.8, 128.3, 128.4, 128.5, 128.7 (JCP = 12.6 Hz), 129.2, 131.7, 131.9, 131.9, 132.0, 132.1, 133.2 (JCP = 9.7 Hz), 136.7, 137.1, 155.3, 169.2, 172.8, 191.5. [13C NMR (CDCl3, 60 oC, aromatic region, Figure 2-2) 127.0 (JCP = 93.7 Hz,), 126.5, 127.8,128.3, 128.4, 128.5 (JCP = 12.1 Hz), 128.7 (JCP = 12.6 Hz), 129.3, 131.8 (JCP = 3.3 Hz), 131.9 (JCP = 3.0 Hz), 132.2 (JCP = 9.8 Hz), 133.4 (JCP = 9.8 Hz), 136.7, 137.1.]. Anal. Calcd for C41H39N2O6P: C, 71.71; H, 5.72; N, 4.08. Found: C, 71.34; H, 5.89; N, 3.51.

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59 CHAPTER 3 SYNTHESES OF 2,4-DIOXO-3-TRIPHENYLPHOSPHORANYLIDENE PYRROLIDINES AND OTHER DISTABILIZED TRIPHENYLPHOSPHORANYLIDENE SUBSTITUTED RINGS 3.1 Introduction The predominant species of pyrrolid in-2,4-dione exists in solution in the enolized form with a stable lactam bond [93AHC139, 03 MI109]. The discovery of the tetramic acid ring system 3.1 (Figure 3-1), a tautomer of pyrrolidin-2,4-dione in a number of natural products and pigments coincided with the discovery of their dive rse biological activities [93AHC139, 94MI97, 95CRV1981, 00JPP086628, 00MI195, 02MI25, 03MI 109]. Pyrrolidin-2,4-dione and 2,4dihyropyrrol-3-ones have been identified as N-methyl-D-aspartate (NMDA) receptor antagonists [99AP309, 05EJM391]. O O NH O HO NH Pyrrolidin-2,4-dione DOTmoiety PPh3 O O NH DOT-pyrrolidine O N 5-Amino-2,4-dihydro pyrrol-3-one O O N NH O O Piperidin-2,4-dioneTetrahydro pyrrolizin-1,3-dione NH2 O N 3-Aminotetrahydro pyrrolizin-1-one NH2 4-Hydroxy-pyrrol-2-one3.1 Figure 3-1. Structures of Pyrrolidin-2,4-dione with Eno lization, 5-Amino-2,4-dihydropyrrol3-one, Piperidin-2,4-dione, Te trahydropyrrolizin-1,3-dione, 3Aminotetrahydropyrrolizin-1 -one, and DOT-pyrrolidine

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60 We investigate pyrrolidin-2,4dione, 5-amino-2,4-dihydropyrrol3-one, piperidine-2,4-dione, tetrahydropyrrolizin-1,3-dione, a nd 3-aminotetrahydropyrrolizin-1 -one (Figure 3-1) with a distabilized triphenylphosphoranylid ene substituent. The 2,4-dioxo-3triphenylphosphoranylidene moiety, or DOT-moiet y as shown on DOT-pyrro lidine (Figure 3-1), adds desirable physical properties such as crys tallinity and stability to aldehydes [87LA649], strong bases [65JOC1015], and hi gh temperatures [01TL141]. Th e possible transformation the 2,4-dioxo-3-triphenylphosphoranyliden e (DOT) moiety provides when directly inco rporated as part of a heterocyclic ring is unexplored and of considerable interest [01JCD639]. N O CO2H Me NHR1 PPh3(PS) N O R3R4O2C R1 O O OMe CO2R R3NHR1 (vi)a(v)a(vii)bO N R2'N O O R1Me (viii)bO O O O HO R3Me Me NHR1 N O O R1R3R2 (iv)aO N Y R2'R1R3 (ix)b(iii)aMe O O NHR1O Me R3 (i)a(ii)aR4O CO2R Br R3 O N CO2R R3R2R1(BzlorPG) H a bbase R1=Ts coupling agents base R1=PG3.1 R1NH2 c (x)cMeOH O O N R1 O R2 R4 R=alkyl PG=protectinggroup PS=Polystyrene Y=CO2R,CN CH2Br NHBzl O O (xi)cbase R2'=COR4,CO2R,Ar Scheme 3-1. General Methods for the Formation of Bonds aa, bb or cc to Construct 3.1

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61 R3 R1 R2 O R4 PPh3 R1=R2=OMe R3=OCO2Ph R4=CO2Bzl R5=H (i) O R1 R2 O R4 O Ph (ii)200-220oC O O Ar 59% toluene,28h 50-60% sealedtube,15h N O O Bzl O PPh3 CO2Et N O Bzl O EtO2C (iv)FVP 67% 500oC,102Torr R1=R2=R5= H R3=COAr R4=CO2Et R2 R1 (iii)180-200oC R3 R4 13-31% neat,0.5h R5 -Ph3PCCO N H O R4 R5 CF3 R5 R1=R2=H R3=NHCOCF3R4=CO2Et R5=H,Cl,orBr R5 R5 R2 R1 R2 R1 Scheme 3-2. Direct Intramolecular Wittig Alkenation with Linear DOT Moieties Reported syntheses of tetramic acids (S cheme 3-1) are by the formation of bond a, b or c in 3.1 Bond a is made by cyclization of (i) -amino--keto esters [98AP389, 98CPB587, 99H1427]; (ii) -bromoesters [84TL1871, 86TL5285]; (iii) -amino cyclic-enol esters [87H2611]; (iv) 5-(2-amino1-hydroxyethyliden)-2,2-dime thyl-1,3-dioxan-4,6-diones (Meldrums acid esters) [95MI124, 04M629]; (v ) aminomethyl pyrone esters [89TL3217]; or (vi) aminomethyl isoxazole carboxylic acids [99SL873, 99JP(1)765]. Bond b in 3.1 is formed by (vii) intramolecular Wittig olef ination [88TL2063, 06S3902], of -triphenylphosphoranylidene amides with immobilized ylid e [04OBC3524, 05T2301]; (viii) intramolecular Dieckmann type cyclization of succinimides [ 78JA4237, 87JOC469, 87TL4385] a nd (ix) other intramolecular

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62 Dieckmann cyclizations [50JA1236, 54JCS 850, 88JOC1356, 94H1839, 97AGE2454]. Bond c in 3.1 is closed by (x) alcoholysis of spiro--lactams [83HCA362]; a nd (xi) intramolecular nucleophilic cyclization of -bromo -keto carboxamides [00CPB563]. Examples found in the literature indicated to perform direct intramolecular Wittig alkenation using a linear DOT moiety (Scheme 3-2) therma l energy was required, which caused problems in some cases. Two successful cases used DOT in close proximity to (i) carbonate [81CC474] or (ii) ketone [84TL4389]. The similar case (iii ) of DOT with urethane was unsuccessful in yielding desired quinolone deri vatives [94JHC1083], and the mechanism, proposed by Murphy et al., involved the loss of kete nylidintriphenylphosphoran e and ethanol to give an iminoketene intermediate, which formed fluoro acetyl anthranilate. The cases of (iv) DOT with succinimides, using flash vacuum pyrolysis (F VP), required extensive efforts to isolate the products in pure form, which Aitken et al. reported as largely unsuccessful [95JP(1)475]. Examples found in the literature indicated to perform indirect intramolecular Wittig alkenation using a linear DOT moiety (Scheme 3-3), equilib ration or activation bypassed some of the problems. Equilibration of DOT with an acid functionality [97CJC1322, 99JP(1)3049], attached by an alkyl chain, fo rm (i) enol-lactones or (ii) ha lo-enol-lactones rapidly in the presence of a halogenating reagen t [95JP(1)953]. The coupling of [86S41], or (iii) -carbonyl acids with N-phenyliminoketenylidentriphenylphosphorane formed a DOT (iv) which eliminated urethane upon heating in the pr esence of ethanol. The deprot ected P-ylide underwent internal Wittig alkenation to form a cyclic olefin [97S 107]. The mechanism of the Wittig reaction is debated to occur either on the time scale of a bond rotation or through an equilibrium process. Although the Wittig mechanism is intuitively unde rstood as a -center mechanism [90JA3905], the inherent stability of the DOT moieties requires further investigation.

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63 O Ph3P toluene/EtOH 15h,67% (iv) HN O Ph H N O Ph EtO Me Me R1 O O Me Me R1 O CO2H R1 Me Me R1=OTBDMS (iii)80oC C-C +PPh3 N Ph toluene 5h O EtO2C PPh3 CbzHN CO2H Bzl CbzHN Bzl O O EtO2C (i) THF,6h 73% (ii)0-rt,Br2TEA,DCM 1h,E:Z54:46% Br O CbzHN Bzl O O EtO2C Ph3P + + CbzHN Bzl O O EtO2C H Scheme 3-3. Indirect Intramolecular Wittig Alkenation with Linear DOT Moieties Ph3P N+O O Ph3P N O O Me Ph3P+N O O Ph3P+N O O 3.2bPh Ph Ph Ph 3.2b'Me Me Me Scheme 3-4. Delocalization of N-Methylated DOT-pyrrolidine 3.2b Major Canonical Form 3.2b The extra stabilization afforded by a second carbonyl on linear DOT sy stems [90TL5925] is also present in cyclic DOT systems. The DOT moiety resisted re fluxing alcoholic base [73JOC1047, 95T3279], high FVP temperatures [01TL141], and hydrobromic acid (HBr) [Section 3.2.8 ], to some extent due to the stable l actam bond and DOT functionality participating

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64 in delocalization (Scheme 34) [04SC4119]. The NMR of 3.2b remained unchanged, after treatment in a sealed tube w ith 4-nitrobenzaldehyde at 130 C for three days, confirming its stability. Ph3P N O O 3.3b 3.3c Me Br N O O Me 3.2b N O Me Br (ii)NBS(1.4eq) (iii)NBS(1.4eq) (iv)BtCl(1.1eq) N O Me Bt H 3.3d Ph Ph Ph Ph N3 Br DCM,5min 88% DCM,5min 84% DCM,5min 92% OH 3.3a Br N O O Me Ph Br (i)NBS(~1.1eq) THF,5min 79% RCO2H(1.1eq) TMSOEt(1.4eq) TMSN3(1.4eq) 3.3a+ Scheme 3-5. Four Applications Using NMethylated DOT-pyrrolidine Although DOT-pyrrolidines are crysta lline, soluble in halogenate d and alcoholic solvents, and have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings [72JOC3458, 73JA7736] they have received little of the atte ntion given to tetramic acids. Furthermore as illustrated in Scheme 3-5 treatment of the N-methylated DOT-pyrrolidine 3.2b with: (i) slight excess N-bromosuccinimide (NBS, ~1.1 eq) [99MOL219] in the presence of a carboxylic acid (1.1 eq), formed 3,3-dibromopyrrolidine-2,4-dione 3.3a ; (ii) excess NBS (1.4 eq), in the presence of ethoxytrimethylsilane (EtOTMS, 1.4 eq), gave 3.3a and 3,3-dibromo-5-hydroxypyrrolidine2,4-dione 3.3b ; (iii) NBS and azidotrimethylsilane (TMSN3) formed haloazidoalkene 3.3c [01T6203]; (iv) 1-chlorobe nzotriazole (BtCl) [98JOC401] gave benzotriazole s ubstituted pyrrol-

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65 2-one 3.3d The versatile stable 2, 4-dioxo-3-triphenylphos phoranylidene rings can be readily formed and easily transformed. [O] [H] N O O Me N O O Me O Ph Ph N OO Me Ph Ph OH (ii) (i) (iii) N O O Me Ph Ph (iv) (v) (i)oxidation;(ii)PhCH2N2;(iii)reduction;(iv)PhCHO;(v)1)H2O2/base2)Et3OBF4 Ph3P N O O Me 3.2b Ph Scheme 3-6. Speculative Applications: Oxidation and Reduction Oxidation and reduction applicatio ns are suggested in the litera ture for the transformation of linear DOT systems and are generally extended to cyclic N-methylated DOT-pyrrolidine in Scheme 3-6. (i) Oxidation of triphenylphosphoranylidene on 3.2b with O2, O3, potassium peroxymonosulfate (Oxone), sodium periodate, magnesium monoperphthalate (MMPP), or 3,3dimethyl dioxirane (DMD) may form ,-diketo-amide [03T6771, 04JCO181, 07OL949], (ii) which with phenyldiazomethane may ring expand to form aza-grevellin analogs [00AP211, 03JHC61]; (iii) redu ction of triphenylphosphoranylidene on 3.2b with aluminum-amalgam may form pyrrolidin-2,4-dione [82JOC4963, 86SC299 ], (iv) which with aldehydes may form arylidene tetramic acids, (v) which with oxida tion and triethyloxonium tetrafluoroborate may ring expand for another route to aza-grevellin an alogs [00AP221]. Earlier reports of DOT-pyrroli dine substructure (Scheme 37) include (i) a byproduct during the preparation of showdomycin [78MI7], (ii) a flash vac uum pyrolysis method (FVP, 600 900 C, 102 Torr) which noted difficulties associat ed with N-deprotection by hydrogenolysis [01TL141], and (iii) a byproduc t without logical explanation of how it might be formed

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66 [05MI385]. Anomalous, spontan eous [87S288, 04SL353, 05SL 2763] cyclizations at rt, discovered by Aitken, were left unexplained in his publications [99 PS577, 01TL141, 03TCC41, 03MI289]. Earlier reports of the DOT-piperidin e substructure (Schem e 3-7) reported two articles of the same molecule as an (iv) unreactive novelty [73JOC1047] or an (v) unwanted dead-end [87S288]. O NH Cbz R2CO2Et Ph3P Ph3P NH O O R1 (ii) (i) OH PPh3NH2O EtO2C R1 O +25C,2h+EtO2C R1 NH2 O 31% 26% 1)Pd(C),H22)FVP,600oC FVP,600oC Ph3P NH O O R2 EtO2C R2 HN Cbz F N O O N N N N PPh3 (iii) 60C DCM/AcOH F N O O O PPh3 obtainedonce notreproducible R1= O O F O TrO R2=H(21%) Me(58%) i -Pr(64%) N H O O O PPh3CO2Et +(iv) 60C DCM/AcOH 50% N H O O PPh3 NO2 O PPh3 CO2t -Bu (v) SnCl2 NH2 O PPh3 CO2t -Bu spontaneous [78MI7] [01TL141] [05MI385] [73JOC1047] [87S288] Scheme 3-7. Early Reports of DOT -pyrrolidines and DOT-piperidines

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67 Previously in Chapter 2, we reported C-acy lation of (carboxymethyl ene)triphenylphosphorane ( 3.5 ) with N-protected peptidic (-aminoacyl)benzotriazoles ( 3.4ad ) in the absence of base under microwave irradiation for the generation of related stereospecific N-protected peptidic triphenylphosphoranylidene esters 3.6ad [05ARK116]. Hydrogenolysis of N-Cbz--amino-oxo--triphenylphosphoranylidene ester 3.6b was attempted and gave DOT-pyrrolidine 3.8b (45%) by crystallization, instead of the expect ed linear free amine. We now report the first convenient synthesis of DOT-pyrrolidines 3.8ac DOT-tetrahydropyrrolizine 3.8d DOTpiperidine 3.16 5-amino-4-triphenylphosphonio-2, 4-dihydropyrrol-3-one bromides 3.11ac and 3-ammonio-2-triphenylp hosphoniotetrahydropyrrolizin-1-one dibromide 3.11d 3.2 Results and Discussion The synthetic route for five-membered system s (Scheme 3-8) involved: C-Acylation of (carboxymethylene)triphenylphosphorane ( 3.5 ) or (triphenylphosphoranylidene)acetonitrile ( 3.9 ) with N-Cbz-(-aminoacyl)benzotriazoles 3.4ad under (ii) microwave irradiation gave the corresponding N-Cbz--amino--oxo--triphenylphosphoranylidene esters 3.6ad (66%), or N-Cbz--amino--oxo--triphenylphosphorany lidene nitriles 3.10ad (64%). The Ndeprotection of 3.6ad with (iii) HBr formed DOT-salts 3.7ad (21%) cyclized with (iv) strong base into DOT-pyrrolidines 3.8ac (97%) and DOT-pyrrolizine 3.8d (88%). Methylation of 3.7c with (vi) methyl iodide (MeI) and sodium hydride (NaH ) gave the linear Ntrimethylated salt 3.2a (95%). Methylation of 3.8c (vi) afforded DOT-pyrrolidine 3.2b (92%). Alternatively simultaneous hydroge nolysis and cyclization of 3.7ad with (v) palladium on charcoal (Pd(C)) gave DOT-pyrrolidines 3.8 ac (45%) and DOT-pyrrolizine 3.8 d (45%). Comparable treatment of nitriles 3.10ad with (iii) hydrobromic acid caused simultaneous Ndeprotection and cyclization to afford 5-am ino-4-triphenylphosphoni o-2,4-dihydropyrrol-3-one

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68 bromides 3.11ac (70-72%), and 3-ammoni o-2-triphenylphosphoniotet rahydropyrrolizin-1-one dibromide 3.11d (66%). Isolated yields for the interm ediates and five-membered products are shown in Table 3-1, with indication of the R1 and R2 substituents. 3.6a-d 3.10a-d 3.5 3.8a-d 3.9 3.7a-d 3.11a-c O N Cbz R1CO2Et Ph3P R2 O+NH2R1CO2Et Ph3P+R2 O R N Cbz R1R2 O N Cbz R1CN Ph3P Ph3P+N O NH2R1 Ph3P N O O R1R2 (ii) (iii) (iv) 2Br-3.8c 3.2b (vi) (v) Br-(ii) (iii) 3.8'a-d R2 3.7c 3.2a (vi) CN Ph3P CO2Et Ph3P 66-95% 64-85% 21-99% 66-71% 95% 92% 88-99% 45-60% (i)SOCl2,BtH,DCM,1h (ii) -Wave,ACN,60C,10min; MethodI (iii)33%HBrinAcOH,5h;(iv)EtOH,aqbase,5h; MethodII (v)5%Pd(C),H2,EtOH,48h; (vi)MeI,NaH,DCM:THF,16h R1andR2aredefinedinTable3-1 (i) R=Bt 3.4a-d R=OH 3.11d Ph3P+N O NH3 + Br-BrScheme 3-8. Synthetic R oute to DOT-pyrrolidines 3.8ac DOT-pyrrolizines 3.8d 5-Amino-4triphenylphosphonio-2,4-dihydr opyrrol-3-one Bromides 3.11ac and 3-Ammonio-2triphenylphosphoniotetrahydropy rrolizin-1-one Dibromide 3.11d Table 3-1. Isolated Yields for Inte rmediates and Five-Membered Products 3.8ad, 3.11ad Entry R1 R2 N-Cbz Amino Acid 3.6 3.7 3.8 3.8 3.10 3.11 a H H Glycine 91 21a,b 97 60 85 71e b Me H (L)Alanine 86 99 99 45 79 70e c CH2Ph H (L)Phenylalanine 83 91 99 45 79 72e d R1(CH2)3R2 (L)Proline 66 90c 88d 45d 64 66d,f 3.8 yield from Method II. aIsolated as +NH3 monobromide. bHygroscopic. cIsolated as +PPh3 monobromide. dBicyclic. eR2 as lone pair electrons, doubl e bond as shown at N1C5. fR2 as in table, +NH3/+PPh3 dibromide, double bond at C4C5 (not at N1C5).

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69 Dominant conformations with respect to the P-atom of syn--keto triphenylphosphoranylidene anti-ester [01AXC180, 07PS151] and of syn--keto triphenylphosphoranylidene nitril e [07AXC65] in linear systems have been determined by Castaeda et al., who concluded that it is no t reasonable to draw phosphonium ylides bearing two adjacent stabilizing groups with a classical ylidic double bond [07PS151]. These data generally extend to peptidic -triphenylphosphoranylidene esters and nitriles support the view that the major canonical forms are as shown in Figure 3-2. Planarity allows optimal electron delocalization [03PS1973] and favorable interactions betwee n cationoid phosphorus and acyl oxygen, with no indication of slow conformati onal rotation around linear ylidic centers. Ph3 +P NH2 -O O R OEt H Ph3 +P NH2 -O R H N peptidyl syn -keto, triphenylphosphoranylidene, nitrile peptidyl syn -keto, triphenylphosphoranylidene, anti -ester Figure 3-2. Major Canoni cal Forms of Peptidic syn--Keto -Triphenylphosphoranylidene anti-Esters and Nitriles In contrast to their linear starting materials the syn--keto -triphenylphosphoranylidene synamide of DOT ring systems cannot exhibit c onformational rotation. The structure of 3.8c was unambiguously confirmed by X-ray crystallograp hy which showed the OCC(P)CO atoms to lie in approximately the same plane, to w ithin 0.003(3) (Figure 3-3). The P=C bond length of 1.732(2) and the attached C-C bond lengths (1.422(3) a nd 1.450(2) ) and the C=O bond lengths (1.230(2) and 1. 253(2) ) are all very similar to those in the only two other DOTpyrrolidines to have been crys tallographically characterized [ 78MI7, 05MI385]. As is common with amides, the molecules pack in pairs abou t a crystallographic center of inversion with N-

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70 HO=C hydrogen bonds. In addition a prelimin ary X-ray crystallogr aphic study on a highly twinned crystal was able to confirm the structure of (2RS)-5-amino-2-benzyl-4triphenylphosphonio-2,4-dihydropy rrol-3-one bromide hydrate ( 3.11c ). Both 3.8c and 3.11c are racemic suggesting racemization was caused by the HBr treatment. Figure 3-3. Crystal X-ray of 3.8c (Left), and Preliminary X-ray Crystal Structure of 3.11c with Two H2O molecules and Br (Right) The synthetic route to DOT-piper idine involved: Activation of N-Cbz--alanine with (i) thionyl chloride and BtH gave N-Cbz-(-aminoacyl)benzotriazole ( 3.13 ). Carbon-Acylation of 3.5 or 3.9 with 3.13 under (ii) microwave irradia tion gave the corresponding N-Cbz--amino-oxo--triphenylphosphoranylidene ester 3.14 (77%), or nitrile 3.17 (63%). Hydrobromic acid (iii) caused N-deprotection of 3.14 and 3.17 formed DOT-salt 3.15 (92%) and the bromide salt of -ammonio--oxo--triphenylphosphoranylidene nitrile 3.18 (35%), respectively. Aqueous base with reflux (iv) cyclized 3.15 into DOT-piperidine 3.16 (65%). The literature FVP method on 3.14 drove a thermal extrusion of triphenylphosph ine oxide to form the alkyne byproduct (Scheme 3-9) [01TL141]. The linear 3.18 failed to cyclize under acidic conditions possibly due

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71 to the extra degrees of freedom associated wi th this salt. The isolated yields for the intermediates and one DOT-piperidin e are shown in Scheme 3-9. 3.14 3.17 3.5 3.16 3.9 3.15 3.18 OHNCbz CO2Et Ph3P ONH3 +CO2Et Ph3P+ O R HNCbz Ph3P NH O O (ii) (iii) (iv) 2Br-BrOHN Cbz CN Ph3P 63% 77% 64% 92% ONH3 +CN Ph3P 35% 90% (ii) (iii) (i) 3.13 R=Bt 3.12 R=OH (i)SOCl2,BtH,DCM,1h (ii)ACN, -Wave,60C,10min;(iii)33%HBrinAcOH,5h;(iv)aqbase,reflux15h 3.16 + 2)FVP,600oC 34% NH2CO2Et 1)Pd(C),H216% 01TL141 Scheme 3-9. Synthetic Route to DOT-piperidine 3.16 with Isolated Yields 3.2.1 Methylations and Salt Neutralization Treatment of 3.7c and 3.8c with methyl iodide gave the N-trimethylated salt 3.2a (95%) and the N-methylated DOT-pyrrolidine 3.2b (92%). Linear 3.7c was optically inactive. Treatment of 3.7c with Et3N in DCM cleanly gave the linear free amine 3.2c (Scheme 3-10). A solvent mixture (THF:DCM = 1:1) was re quired to unite the base with 3.7c or 3.8c The structures of novel 3.2a,b were supported by 1H-NMR, 13C-NMR (Table 3-2), and elemental analysis. The 13C-NMR chemical shifts and JPC coupling values of the -C, -keto, -C=P, and ester/amide/nitrile/imine carbon sign als were recorded throughout th e course of reactions (Table 3-2Table 3-7). The P-(ipso)Ph, P-(ortho)Ph, P-(meta)Ph, and P-(para)Ph carbon signals remained essentially invariant but were incl uded in the tables for completeness. The 13C-NMR chemical shifts and JPC values are insensitive to changes in solvent and temp [03PS2505] but reflect local electron densities [ 90HAC151]. The magnitude of the JPC value is affected by the

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72 distance between carbon and phosphorus and more s ubtly by local electron density as in the common case of P-(ortho)Ph and P-(meta)Ph JPC values, which are also influenced by charge distribution around the ring. Similarl y, electron density effects on the -keto and ester JPC values were affected by adjacent atoms and y lidic delocalization in distabilized triphenylphosphoranylidene systems. 3.7c O+NH3CO2Et Ph3P+ Ph3P NH O O 2Br-92% 3.8c 3.2a 95% Ph O+NMe3CO2Et Ph3P+ Ph Ph Ph3P N O O Me Ph 3.2b 2Br-(i) (i) (ii) 99% (i)MeI,NaH DCM:THF,16h (ii)EtOH,aqbase,5h (iii)NEt3,DCM,1h (iii) 99% O NH2CO2Et Ph3P Ph 3.2c Scheme 3-10. Methylation of 3.7c and 3.8c and Neutralization of 3.7c Table 3-2. The 13C-NMR Chemical Shifts, in ppm (JPC in Hz) of Linear 3.2a,c and Cyclic 3.2b Entry -C -Keto -C=P Ester/ Amide P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph 3.2a 71.0 (8.6) 184.4 (6.3) 75.9 (104.2) 166.8 (10.9)a 123.1 (93.3) 132.2 (10.3) 128.2 (13.2) 131.9 (2.9) 3.2b 67.6 (13.2) 193.9 (6.9) 64.1 (123.1) 173.8 (16.6)b 122.7 (92.8) 133.8 (10.9) 128.6 (12.6) 132.6 (2.9) 3.2c 57.2 (7.4) 198.0 (2.9) 69.3 (108.2) 167.2 (14.3)a 126.4 (93.3) 132.9 (9.7) 128.5 (12.6) 131.6 (2.9) aEster.; bAmide. The 13C-NMR data (Table 3-2) of linear 3.2a,c and cyclic 3.2b are juxtaposed for general comparison between uncyclized and cyclized forms. The -C signal of 3.2b shifted upfield and the JPC value increased relative to 3.2a The -keto carbon signal of 3.2b shifted downfield, due to the decreased shielding and JPC values were similar. Both -keto carbonyls are predicted to

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73 exist in the dominant syn conformation with respect to the P-atom. The -C=P carbon signal of 3.2b was shifted upfield, due to increased shielding, and the JPC value increased. The amide carbon signal is shifted downfield fr om the ester carbon signal and the JPC value increased. Conformational differences between the syn-amide carbonyl and anti-ester carbonyl are, in part, responsible. 3.2.2 Dibromopyrrolidin-2,4-dione The 3,3-dibromopyrro lidin-2,4-dione 3.3a (79%) was prepared from 3.2b (Scheme 3-11). 4Chlorobenzoic acid and 3.2b were heated under reflux together in THF for 1 h and no reaction was detected by TLC. Upon addition of NBS the reaction was completed after 5 min of stirring at rt. This is the first highly versatil e [06SL194] 3,3-dibrom o-pyrrolidine-2,4-dione 3.3a reported with a racemic stereocenter [85AP311, 05CC5106] and obtained without Lewis acid [02JOC7429]. The structure of novel 3.3a was supported by 1H-NMR, 13C-NMR, and elemental analysis. + Cl O OH THF Ph3P N O O Me Ph 3.2b N O O Me Ph Br Br 3.3a NBS rt,5min NoReaction reflux Scheme 3-11. Bromination of 3.2b with NBS, For 3.3a The proposed mechanism (Scheme 3-12) was initiated by the ra dical formation of bromine (Br2) from NBS, shown mechanistically [94MI2 55] and considered a source of bromonium cation (Br+). The major canonical form 3.2b is brominated to form intermediate-1 ( Int-1 ), as was postulated for a linear system in the lite rature [97S673]. Activ ation of a nucleophile, carboxylic acid, generates HBr whic h returns more bromine to the system. Nucleophilic addition

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74 on Int-1 eliminates triphenylphosphine oxide in a center mechanism [90JA3905] and subsequent bromination of the olefin forms Intermediate-2 ( Int-2 ). Activation of a second nucleophile, carboxylic acid, generates HBr and th e nucleophile adds to release an anhydride byproduct and form 3.3a Ph3P N O O Me Ph N O O Me Ph Br Br 3.3a NBS Ph3P+N-O O Me Ph Succinimide HBr Br2 +PPh3N-O O Me Ph Int-I Br+ -OPPh33.2b' Br N Nuc O Me Ph Br+ Int-2 -(RCO)2O Br-NucH= RCO2H Nuc-= RCOOInSolution 1)Nuc-2)Br2NucScheme 3-12. Proposed Mechanism, From 3.2b to Int-1 to Int-2 to 3.3a 3.2.3 Dibromo-5-hydroxypyrrolidin-2,4-dione The 3,3-dibromo-5-hydroxypyrrolidin-2,4-dione 3.3b (88%) was prepared from 3.2b (Scheme 3-13). Ethoxytrimethylsilane (T MSOEt) and NBS were combined in DCM for 2 min and added to 3.2b dissolved separately in DCM. The reaction was complete af ter 5 min stirring at rt. The crude material was added directly to a silica gel column A mixture of 3.3a and 3.3b (1:1) eluted together and was detected by 1Hand 13C-NMR signals after purification. White, sheetlike crystals formed in the CDCl3 NMR solution overnight and were confirmed as (5RS)-5-benzyl3,3-dibromo-5-hydroxy-1-met hylpyrrolidin-2,4-dione ( 3.3b ) by X-ray crystal analysis (Figure 34, by P. Steel). In this case the molecule s pack in chains with the hydroxy hydrogen atom H-

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75 bonded to the carbonyl of an adjacent molecule and th e crystals were racemic. This is the first 3,3-dibromo-5-hydroxypyrrolidi ne-2,4-dione ever reporte d and the structure of 3.3b was supported by 1H-NMR, 13C-NMR, elemental analysis, and an X-ray crystal structure. Ph3P N O O Me Ph 3.2b N O O Me Ph Br Br 3.3a NBS(1.4eq.) rt,5min TMSOEt(1.4eq.) N O O Me Ph Br Br 3.3b OH + Scheme 3-13. Bromination of 3.2b with TMSOEt and NBS, For 3.3a and 3.3b Figure 3-4. The X-ray Crystal Structure of 3.3b (Left), and Intermolecular Hydrogen Bonding (Right) The proposed mechanism (Scheme 3-14) from 3.3a consisted of acid-catalyzed bromination [00MI786], displacement, and loss of ethylene gas. In this case, 3.3a formation occurred presumably in a mechan ism similar to the final step, i nvolving the loss of ethylene gas [87H617]. Bromination of the enol olefin 3.3a forms Intermediate-3 ( Int-3 ). Activation of a nucleophile, TMSOEt, forms TMSBr and ethoxy ani on. Ethoxy addition di splaces the Br-atom

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76 and regenerates the carbonyl to form Intermediate-4 ( Int-4 ). Protonation and subsequent deprotonation of OEt with in situ HBr releases ethylene gas to form 3.3b N O O Me Ph Br B r 3.3a N HO O Me Ph Br B r N O O Me Ph Br Br OH 3.3b TMSBr Br-TMSOEt -OEt -HBr -CH2CH2 Br2N HO O Me Ph Br Br Br+ Int-3 3.3a' -TMSBr N O O Me Ph Br Br O+ H2C H Br-H Int-4 Scheme 3-14. Proposed Mechanism, from 3.3a to 3.3b 3.2.4 Azido-3-bromopyrrol-2-one The 4-azido-3-bromopyrrol-2-one 3.3c (84%) was prepared from 3.2b (Scheme 3-15). Azidotrimethylsilane (TMSN3) and NBS were combined in DCM for 2 min and added to 3.2b separately dissolved in DCM. The reaction was complete after 5 min stirring at rt. The crude material was added directly to a silica gel column without workup. The pure material decomposed spontaneously to an unidentifia ble brown tar, when left under high vacuum overnight. Azido-3-bromo-pyrro l-2-one was obtained, where previously reported in the literature chloro derivatives were used to make -lactams [78JA2245 79ACC125, 88CRV297], and bromo derivatives were trapped with tri phenylphosphine to make a Staudinger reagent [80ZC54]. The structure of novel 3.3c was supported by 1H-NMR, 13C-NMR, and HRMS.

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77 84% Ph3P N O O Me Ph 3.2b N N3O Me Ph 3.3c Br NBS,TMSN3DCM,rt N O Me Ph Br wasalsodetectedinHRMS N [M+H]+=279.028 Scheme 3-15. Haloazidoalkenation of 3.2b with TMSN3 and NBS, For 3.3c 3.2.5 Benzotriazolpyrrol-2-one The benzotriazolpyrrol-2-one 3.3d (92%) was prepared from 3.2b (Scheme 3-16). 1Chlorobenzotriazole (BtCl) and 3.2b were combined and dissolved in a minimum amount of DCM (<1.0 mL). The reaction was complete after 5 min stirring at rt. The crude material was added directly to a silica gel column and the purified material was s hown to contain a 1:1 mixture of benzotriazole isomers, by 1Hand 13C-NMR. This is the first 4-benzotriazol-1-ylpyrrol-2-one reported. The structure of novel 3.3d was supported by 1H-NMR and 13C-NMR. 84% Ph3P N O O Me Ph 3.2b N N O Me Ph 3.3d N N O Me Ph 1:1 BtCl DCM N Bt O Me Ph onlythereducedproduct wasdetectedinHRMS [M+H]+= 303.1240+N N N N Scheme 3-16. Benzotriazolation of 3.2b with BtCl, For 3.3d 3.2.6 Protected (and -aminoacyl)benzotriazoles The starting N-Cbz-(-aminoacyl)benzotriazoles 3.4a d (90%), and N-Cbz-(aminoacyl)benzotriazole 3.13 (90%) (Scheme 3-17) were prep ared from the corresponding NCbz amino acids following recently developed procedures [Chapter 22.4.1 04S2645, 04S1806, 05ARK116, 06S411]. The proline derived N-Cbz-(-aminoacyl)benzotriazole ( 3.4d ) was seen

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78 by NMR as two sets of distinct signals due to rotamers. We confir med the structure of 3.4d previously reported by the Katrit zky group, with improved resolution of rotamer signals. The structure of novel 3.13 was supported by 1H-NMR, 13C-NMR, and elemental analysis. 90% 3.12 OH O HN Cbz Bt O HN Cbz (i) 3.13 (i)SOCl2,BtH,DCM,rt,1h Scheme 3-17. Acylbenzotriazolation of 3.12 with SOCl2 and BtH, Formed 3.13 3.2.7 Protected--amino--oxo--triphenylphosphoranylidene and N-Cbz--amino--oxo--triphenylphosphoranylidene Esters The N-Cbz--amino--oxo--triphenylphosphoranylidene esters 3.6a d (66%), and NCbz--amino--oxo--triphenylphosphora nylidene esters 3.14 (77%) (Scheme 3-18) were prepared from the corresponding 3.4ad 3.13 and (carboxymethylene) triphenylphosphorane ( 3.5 ), following a recently developed procedure [Cha pter 2, 05ARK116]. Microwave reactions were carried out in a standard 50 mL rb flas k under controlled and reproducible open vessel conditions. The single mode micr owave irradiation was used at a fixed temp and irradiation power, which maintained the temp, automatically. The structure of novel 3.14 was supported by 1H-NMR, 13C-NMR (Table 3-3), and elemental analysis. 77% 3.14 O HN Cbz Ph3P CO2Et 3.13 Bt O HN Cbz + Ph3P CO2Et 3.5 (i) (i)ACN, -Wave 60C,10min Scheme 3-18. Carbon-Acylation of 3.13 with 3.5 Formed 3.14 The 13C-NMR -C and -C=P carbon signals of 3.6ad (Table 3-3) appear ed in the ranges 49.3.7 ppm (6.3.6 Hz) and 68.6.1 ppm (108. 8.8 Hz), respectively. The ylidic delocalized -keto and ester carbon si gnals appeared in the ranges 190.3.3 ppm (2.9.0 Hz) and 166.7.3 ppm (14.3.5 Hz), respectively. The -alanine derived 3.14 signals were

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79 mostly inline with those of the other derivatives 3.6ad The -C carbon signal was shifted upfield due to increased shielding. The tw o rotameric forms of proline derived ester 3.6d (Scheme 3-19) and nitrile 3.12d gave distinct and sepa rate signals in the 13C-NMR. Ph3P R N O O O Ph Ph3P R N+O -O O Ph R=CO2EtorCNZ-isomer E-isomer Ph3P R N O O O Ph Ph3P R N O O O Ph Scheme 3-19. Rotameric Forms of Ester 3.6d and Nitrile 3.12d Table 3-3. The 13C-NMR Chemical Shifts, in ppm (JPC in Hz) of 3.6ad 3.14 3.2.8 Dioxotriphenylphosphoranylidene Salts Salts of -amino--oxo--triphenylphosphoranylidene esters 3.7a d (21%), and -amino--oxo--triphenylphosphoranylidene esters 3.15 (92%) (Scheme 3-20) were obtained for Method I and were prepared from the corresponding 3.6ad 3.14 by hydrogenolysis of the N-Cbz group on 3.6ad 3.14 using 33% HBr in acetic aci d [00T9763]. Two atom sites Nand Pwere Entry -C -Keto -C=P Ester P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph 3.6ab 49.3 (8.6) 190.3 (<4.0)a 68.9 (112.8) 167.3 (14.3) 125.7 (93.3) 133.1 (9.7) 128.6 (12.6) 131.9 (2.9) 3.6bb 52.4 (8.6) 194.7 (<4.0)a 68.8 (111.1) 166.7 (14.3) 126.0 (93.3) 133.0 (9.7) 128.5 (12.6) 131.8 (2.9) 3.6cb 56.8 (8.6) 193.5 (<4.0)a 70.1 (108.8) 166.9 (14.3) 125.9 (93.9) 133.1 (9.7) 128.5 (12.6) 131.7 (2.9) 3.6dc 62.2 (7.4) 194.8 (2.9) 68.6 (109.9) 167.3 (15.5) 125.9 (93.9) 132.6 (9.7) 128.1 (12.6) 131.2 (2.9) 3.6dd 62.7 (6.3) 195.3 (2.9) 69.0 (111.1) 167.1 (14.3) 126.1 (93.3) 133.0 (9.7) 128.2 (12.0) 131.3 (2.3) 3.14 39.6 (6.9) 195.5 (3.4) 71.2 (110.5) 167.5 (14.3) 125.9 (93.3) 132.6 (9.7) 128.2 (12.6) 131.3 (2.3) aSmall couplings not clearly resolved we re estimated as less than 4.0 Hz. bLit. [05ARK116]. cRotamer I. dRotamer II.

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80 available for salt generation. Detecti on of a broad signal around 9 ppm in the 1H-NMR spectra indicated P-salt formation. Th e salt mixtures were isolated by column chromatography (SiO2). Extension of the stirring time in the 33% HBr so lution for up to 5 h resulted in formation of dibromide salts, which were easily isolated as white powders by filtration from diethyl ether in most cases. The highly hygros copic dibromide salt resulted in a low yield of achiral monobromide ammonium salt 3.7a (21%) due to loss during isol ation. Melting points were generally not sharp with initial melts to amorphous solids typically in the range between 100 200 C, followed by a session of bubbling and recrys tallization, which then melted again above 200 C probably due to the thermal cyclization involving th e loss of ethanol. The structures of novel 3.7ad and 3.15 were supported by 1H-NMR, 13C-NMR (Table 3-4), and elemental analysis. 92% 3.14 O HN Cbz Ph3P CO2Et 3.15 O +NH3 Ph3P+ CO2Et 2Br-(i) (i)33%HBrinAcOH,5h Scheme 3-20. Deprotection of 3.14 with HBr, For 3.15 The 13C-NMR -C and -CP+ carbon signals of 3.7ad (Table 3-4) appeared in the ranges 45.4.6 ppm (8.0.7 Hz) and 68.1.6 pp m (108.2.1 Hz), respectively. The -keto and ester carbons appeared in th e ranges 185.3.5 ppm (4.6. 7 Hz) and 166.2.7 ppm (12.0 13.2 Hz), respectively. The 13C-NMR signals of the -alanine derived 3.15 were mostly inline with the other derivatives 3.7ad Cleavage of the Cbz group for the proline derived 3.7d resulted in 1Hand 13C-NMR spectra free of rotameric signals.

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81 Table 3-4. The 13C-NMR Chemical Shifts, in ppm (JPC in Hz) of 3.7ad 3.15 3.2.9 The DOT-Pyrrolidines, DOT-Pyrrolizines, and DOT Piperidine The DOT-pyrrolidines 3.8ac and DOT-pyrrolizine 3.8d were prepare by Method I (20%) from the corresponding 3.7ad and by Method II (45%) from the corresponding 3.6ad (Scheme 3-21). The DOT-piperidine 3.16 (Scheme 3-9) was prepared by Method I from 3.15 (60%). The starting salts 3.7ad 3.15 were dissolved in ethanol and then aq base was added, which resulted in precipitation of a white solid. Extraction gave 3.8ac (97%) and 3.8d (88%) to complete Method I. The achiral 3.15 was heated under reflux in aq base to afford DOT-piperidine 3.16 (65%). Hydrogenolysis of 3.6ad with Pd(C) in ethanol required 48 h and by crystallization gave 3.8 bd (45%) for Method II. Pyrrolidiz-1,3-dione 3.8d should be inhibited to delocalize the amide electrons thr ough resonance due to the highly strained, or twisted, dipolar bicyclic lactam [06N699]. To furnish achiral 3.8 a (60%) heating under reflux in ethanol was required. We provide supporting characterization for the structures of compounds 3.8a,b,d and 3.16 which were previously repo rted without characteriza tion. The structure of novel 3.8c was supported by 1H-NMR, 13C-NMR (Table 3-5), elemen tal analysis and X-ray. Entry -C -Keto -CP+ Ester P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph 3.7ac 45.4 (8.0) 185.3 (5.7) 69.5 (111.1)c 166.7 (13.2) 124.1 (93.3) 132.9 (10.3) 128.6 (12.6) 132.1 (2.3) 3.7bbf 51.1 (8.6) 190.5 (4.6) 68.1 (109.4) 166.2 (12.6) 124.9 (92.8) 132.8 (9.7) 129.0 (12.6) 132.3 (2.9) 3.7cbef 55.9 (8.6) 189.0 (4.6) 69.1 (108.2) 166.4 (12.0) 124.8 (92.8) 133.0 (9.7) 129.0 (12.6) 132.3 (<4.0)a 3.7dd 63.6 (9.7) 187.7 (5.2) 69.6 (109.9) 166.2 (12.6) 124.2 (93.9) 133.0 (9.7) 128.9 (12.6) 132.5 (2.9) 3.15bf 37.1 (7.4) 192.4 (4.0) 69.7 (109.4) 166.8 (13.2) 125.7 (92.8) 132.8 (9.7) 128.9 (12.6) 132.1 (<4.0)a aSmall couplings not clearly resolved were estimated as less than 4.0 Hz. b(NH3)+/(PPh3)+ Dibromide. c(NH3)+ Monobromide, -C=P. d(PPh3)+ Monobromide. epH = 5.0 in water. fNMR done in DMSO-d6

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82 92% 3.8c O NH Ph3P 3.7c O +NH3 Ph3P+ CO2Et 2BrO (i)MethodI(i)HBr,5h (ii)EtOH,aqbase,5h Ph Ph O NH Ph3P CO2Et Ph Cbz 3.6c 45% (ii)MethodII(iii)H2,Pd(C),EtOH,48h (iii) 99% 92% 3.8d 3.7d O NH Ph3P+ CO2Et (i) O N Ph3P CO2Et Cbz 3.6d 45% (ii) (iii) 90% O N Ph3P O BrO N Ph3P O HighlyTwisted Scheme 3-21. Method I and Method II, For 3.8c and 3.8d Table 3-5. The 13C-NMR Chemical Shifts, in ppm (JPC in Hz) of 3.8ad and 3.16 Entry -C -Keto -C=P Amide P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph 3.8aa 52.4 (13.2) 194.8 (8.6) 64.2 (122.6) 177.4 (17.4) 122.8 (93.3) 134.0 (10.9) 128.7 (12.6) 132.9 (2.9) 3.8ba 58.0 (13.7) 197.7 (7.4) 62.8 (122.5) 176.2 (16.6) 122.9 (92.8) 133.9 (10.9) 128.7 (12.6) 132.8 (2.3) 3.8c 63.5 (13.2) 195.5 (7.4) 64.0 (122.0) 175.9 (16.0) 122.7 (93.3) 133.9 (10.9) 128.7 (13.2) 132.8 (2.9) 3.8da 69.1 (13.2) 197.6 (8.0) 65.2 (117.4) 179.7 (16.0) 122.6 (92.8) 133.8 (10.9) 128.7 (13.2) 132.8 (2.9) 3.16a 37.1 (9.2) 191.9 (4.6) 70.0 (115.1) 171.1 (10.9) 125.0 (92.8) 133.3 (10.3) 128.2 (12.6) 131.7 (2.9) apreviously reported without characterization [01TL141]. The 13C-NMR -C and -C=P+ carbon signals of 3.8ad (Table 3-5) appeared in the ranges 52.4.1 ppm (13.2.7 Hz) and 62.8.2 ppm (117.4.6 Hz), respectively. The -keto and amide carbon signals appeared in the ra nges of 194.8.7 ppm (7.4.6 Hz) and 175.9 179.7 ppm (16.0.4 Hz), respect ively. The piperidine 3.16 13C-NMR signals differed from the pyrrolidine derivatives 3.8ad due to conformational and electronic effects. The -C and -keto carbon signals, 37.1 ppm (9.2 Hz) and 191. 9 ppm (4.6 Hz), shifted upfield and JPC couplings

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83 were larger. The -C=P carbon signal 70.0 ppm (115. 1 Hz) shifted downfield and JPC coupling was smaller. The amide carbon signal, 171. 1 ppm (10.9 Hz), shifted upfield and JPC coupling was smaller, probably due to the extra degrees of freedom allowing a less rigid syn-syn conformation. 3.2.10 Protected--amino--oxo--triphenylphosphoranylidene and N-Cbz--amino--oxo--triphenylphosphoranylidene Nitriles The N-Cbz--amino--oxo--triphenylphosphoranylidene nitriles 3.10ad (64%), and NCbz--amino--oxo--triphenylphosphora nylidene nitriles 3.17 (63%) (Scheme 3-22) were prepared from the corresponding 3.4ad 3.13 and (triphenylphosphoran ylidene)acetonitrile ( 3.9 ). The reaction conditions were the same as described in section 3.2.7 Compounds 3.5b,c have been reported without elemental analys is for the preparation of peptidic -ketoesters and ketoamides [00T9763, 03T6771]. Compound 3.13 has been reported as an intermediate without characterization and used as an interesting precursor to -amino--keto esters [94JOC4364, 98TL6889], or to synthesize en antioselective 3-h ydroxypyrrolidin-2-ones [99TL1069]. We report 1H-NMR, 13C-NMR, and elemental analysis to support the structure of 3.17 The structures of novel 3.10a,b,d were supported by 1H-NMR, 13C-NMR (Table 3-6), and elemental analysis. 63% 3.17 O HN Cbz Ph3P CN 3.13 Bt O HN Cbz + Ph3P CN 3.9 (i) (i) -Wave, ACN,60C,10min Scheme 3-22. Carbon-Acylation of 3.13 with 3.9 For 3.17 The 13C-NMR -C and -C=P carbon signals of 3.10ad (Error! Not a valid bookmark selfreference. ) appeared in the ranges 47.5.4 ppm (9.0.9 Hz) and 46.2.9 ppm (126.0 127.7 Hz), respectively. The -C=P carbon signal was upfield and JPC coupling was larger for

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84 the nitrile derivatives than fo r the ester derivatives. The -keto and nitrile carbon signals appeared in the ranges 189.9.9 ppm (3 .5.0 Hz) and 120.6.5 ppm (14.7.4 Hz), respectively. The nitrile carbon signal was upfield and JPC coupling was larger than for the ester derivatives. The 13C-NMR signals of the -alanine derived nitrile 3.17 were similar to those of the other nitrile derivatives 3.10ad The two rotameric forms of proline derived N-Cbz-(aminoacyl)-triphenylphos phoranylidene nitrile ( 3.10d ), gave distinct signals (Scheme 3-19). Table 3-6. The 13C-NMR Chemical Shifts, in ppm (JPC in Hz) of 3.10ad 3.17 Entry -C -Keto -C=P Nitrile P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph 3.10a 47.5 (10.9) 189.9 (<4.0)a 46.4 (127.7) 120.6 (14.9) 122.3 (93.3) 133.5 (10.3) 129.2 (13.2) 133.3 (3.4) 3.10bb 52.2 (9.0) 194.3 (3.6) 46.5 (127.5) 120.7 (14.9) 122.3 (93.3) 133.2 (10.3) 129.0 (12.6) 131.7 (4.0) 3.10cc 57.2 (9.0) 192.9 (<4.0)a 47.9 (126.0) 121.0 (16.0) 122.4 (93.9) 133.5 (10.3) 129.1 (12.6) 133.2 (3.4) 3.10dd 61.8 (9.1) 194.7 (3.5) 46.2 (126.3) 121.5 (15.4) 122.6 (93.4) 133.2 (10.5) 128.8 (12.6) 132.9 (2.8) 3.10de 62.4 (9.1) 194.9 (3.5) 46.3 (127.0) 121.3 (14.7) 122.9 (93.4) 133.4 (10.5) 128.9 (12.6) 132.8 (2.8) 3.17f 38.6 (9.2) 194.9 (<4.0)a 49.0 (126.0) 121.8 (16.6) 122.6 (93.9) 133.3 (10.3) 129.0 (13.2) 133.1 (2.9) aSmall couplings not clearly resolved were estimated as less than 4.0 Hz. bLit. [03T6771]. cLit. [00T9763]. dRotamer I. eRotamer II. fLit. [99TL1069]. 3.2.11 Dihydropyrrol-3-one Bromide Salts and Tetrahydropyrrolizin-1-one Dibromide Salt The 5-amino-4-tripheny lphosphonio-2,4-dihydropy rrol-3-one bromides 3.11ac (70%) and 3-ammonio-2-triphe nylphosphoniotetrahydropyrro lizin-1-one dibromide 3.11d (66%) were prepare from the corresponding 3.10ad (Scheme 3-23). Simultaneous N-deprotection and cyclization of 3.10a d occurred upon trea tment with 33% HBr in acetic acid gave 3.11a d Wasserman et al. have reported a byproduct in a similar reaction where the imino functionality was exocyclic to the ring (Sch eme 3-23) [97TL953, 03T6771]. The 1H-NMR signals and splitting patterns of compounds 3.11ac indicated phosphonium salts [82AJC2277] had formed

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85 and the imino functionality was endocyclic. The 1H-NMR signals and splitting patterns of compounds 3.11d indicated dibromide salt was formed w ith the olefin shifted away from the more strained bicyclic pyrrolizinium salt. The same method applied to N-Cbz--amino--oxo-triphenylphosphoranylidene nitrile 3.17 (Scheme 3-9) gave the linear 3.18 (35%). The structures of novel 3.11ad and 3.18 were supported by 1H-NMR, 13C-NMR (Table 3-7), and elemental analysis. 71% 3.11c O N Ph3P+ O NH Ph3P CN NH2 (i) Br-Cbz 3.10c (i)33%HBrinAcOH,5h Ph Ph 66% 3.11d O N Ph3P+ O N Ph3P CN +NH3 (i) Br-Cbz 3.10d BrO H NCbz Et CN Ph3P Ph3P NH O NH Et Pd(C),H2EtOAc O NH2Et CN Ph3P O H NCbz Et CN Ph3P isolatedratio1:1:2 [97TL953,03T6771] startingmaterial mp253-255oC mp238-240oC mp70-80oC O N Ph3P+ NH2 Br-BrHighlyTwisted Scheme 3-23. Deprotection of 3.10c,d with HBr, For 3.11c,d The 13C-NMR -C and -C=P carbon signals of the 3.11ad (Table 3-7) appeared in the ranges 52.2.0 ppm (10.3 Hz) and 63.1.9 ppm (119.1.8 Hz), respectively. The -keto and imino carbon signals appeared in the ranges 194.5.7 ppm (5.7.3 Hz) and 168.8.9 ppm (15.5.2 Hz), respectively. The 13C-NMR signals of the linear -alanine derived 3.18

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86 differed from those of the pyrrol-3-one series 3.11ad Cleavage of the Cbz group for the proline derived salt 3.11d resulted in 1Hand 13C-NMR spectra free of rotameric signals. Table 3-7. The 13C-NMR Chemical Shifts, in ppm (JPC in Hz) of 3.11ad and 3.18 Entry -C -Keto -C-P+ Imino/ Nitrile P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph 3.11a 52.2 (10.3) 194.5 (6.3) 64.8 (125.4) 170.3 (17.2) 119.7 (93.3) 133.6 (10.9) 130.1 (13.2) 134.6 (2.9) 3.11b 58.5 (10.3) 197.7 (5.7) 63.1 (124.3) 168.8 (17.2) 120.1 (93.3) 133.6 (10.9) 130.1 (13.1) 134.6 (2.9) 3.11c 63.3 (10.3) 195.3 (6.3) 64.0 (127.8) 169.3 (16.6) 119.7 (92.8) 133.7 (10.9) 130.0 (12.6) 134.5 (2.9) 3.11da 70.0 (10.3) 196.2 (5.7) 65.9 (119.1) 170.9 (15.5) 119.4 (92.8) 133.5 (10.9) 130.0 (13.1) 134.6 (2.9) 3.18b 33.4 (8.0) 195.0 (4.0) 50.4 (124.3)f 120.8c (16.0) 121.8 (93.3) 133.4 (10.3) 129.3 (13.2) 133.5 (2.3) aIsolated as +NH3/+PPh3 dibromide, double bond at C4-C5. bLinear. cImino. eNitrile. f -C=P. 3.3 Conclusion This is the first convenient method to 2,4dioxo-3-triphenylphosphora nylidene pyrrolidines, 1,3-dioxo-2-triphenylphosphoranylidene tetrahydropy rrolizine, 2, 4-dioxo-3triphenylphosphoranylidene pipe ridine, 5-amino-4-triphenylp hosphonio-2,4-dihydropyrrol-3-one bromides, and 3-ammonio-2-triphenylphosphoniot etrahydropyrrolizin-1-one dibromide. The developed Method I was versatile, inexpensive, reproduc ible, and high yielding. Racemization was caused by HBr, however the nove l linear salts could be cleanly N-methylated or neutralized without cyclization, or cycliz ed for distabilized triphenylphos phoranylidene substituted rings. Crystalline DOT-pyrrolidines, are stable to aldehydes [87L A649], strong bases [65JOC1015], and high temperatures [01TL141], and repr esent versatile intermediates. The 13C-NMR chemical shifts and JPC values provide valuable information for the analysis of distabilized triphenylphosphoranylidene systems, JPC couplings increased with less partial positive character and decreased with more partial positive character on the respective carbons.

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87 We have developed four novel applications for DOT-pyrrolidines. The first highly versatile [06SL194] 3,3-dibromopyrrolidine -2,4-dione [85AP311, 05CC5106] with a racemic stereocenter, was obtained without Lewis acid [02JOC7429]. The first 3,3-dibr omo-5-hydroxypyrrolidine2,4-dione, was obtained and unambiguously iden tified by X-ray crystallography. 4-Azido-3bromopyrrol-2-one was obtained, where previously reported chloro derivatives were used to make -lactams [78JA2245 79ACC125, 88CRV297], and br omo derivatives were trapped with triphenylphosphine to make a Staudinger reagen t [80ZC54]. The first 4-benzotriazolpyrrol-2one was obtained. In conclusi on the versatile stable 2,4-diox o-3-triphenylphosphoranylidene can be practically formed on rings and easily transformed into novel molecules. 3.4 Experimental Section Melting points were determined on a capillary point apparatus equi pped with a digital thermometer. NMR spectra were recorded in CDCl3, unless otherwise stated in DMSO-d6, with TMS for 1H (300 MHz) and 13C (75 MHz) as the internal reference. The N-Cbz-amino acids were purchased from Fluka and we re used without furt her purification. Ac etonitrile was freshly distilled from calcium hydride. Microwave heat ing was carried out with a single mode cavity Discover Microwave Synthesizer (CEM Corporation, NC), produci ng continuous irradiation at 2455 MHz. 3.4.1 Preparation of Dibromide Salt 3.2a To a solution of 3.7c (1.0 g, 1.52 mmol) dissolved in a solvent mixture (THF:DCM = v:v = 1:1, 40 mL), NaH 60% on mineral oil (0.610 g, 15.2 mmol) was added and stirred for 1 h. Methyl iodide (1.0 mL, 15.2 mmol) was added dropwis e to the reaction mixture with stirring at rt. The reaction mixture was stirred for a further 16 h. The solvent mixture was evacuated and the residue was extracted with DCM. The crude pr oduct was filtered and subjected to column chromatography (SiO2, DCM:methanol = 98:2) to give 3.2a

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88 (4RS)-4-Trimethylammonio-1-eth oxy-5-phenyl-2-triphenylpho sphoniopentan-1,3-dione Dibromide (3.2a). (1.01 g, 95%) White needles (from DCM / diethyl ether) mp 189191 C. 1H NMR 0.38 (t, J = 7.0 Hz, 3H), 2.43 (s, 1H), 3.04. 08 (m, 1H), 3.23.51 (m, 12H), 6.02 (dd, J = 11.2, 3.5 Hz, 1H), 7.08.11 (m, 2H), 7.25.32 (m, 9H), 7.36.52 (m, 7H), 7.48.54 (m, 3H). 13C NMR 12.6, 32.6, 52.2, 58.8, 71.0 (JCP = 8.6 Hz), 75.9 (JCP = 104.2 Hz), 123.1 (JCP = 93.3 Hz), 126.7, 128.1, 128.2 (JCP = 13.2 Hz), 128.8, 131.9 (JCP = 2.9 Hz), 132.2 (JCP = 10.3 Hz), 133.3, 166.8 (JCP = 10.9 Hz), 184.4 (JCP = 6.3 Hz). Anal. Calcd. for C34H38Br2NO3P: C, 58.38; H, 5.48; N, 2.00. F ound: C, 58.22; H, 5.78; N, 1.98. 3.4.2 Preparation of N-Meth ylated DOT-pyrrolidine 3.2b To a solution of 3.8c (1.0 g, 2.2 mmol) dissolved in a so lvent mixture (THF:D CM = v:v = 1:1, 40 mL), NaH 60% on mineral oil (0.890 g, 22.2 mmol) was added. Methyl iodide (1.4 mL, 22.2 mmol) was added dropwise to the reaction mixture a nd stirred at rt for 16 h. The solvent mixture was evacuated and the residue was extracted with DCM. The crude product was filtered and subjected to column chromatography (SiO2, DCM:methanol = 98:2) to give 3.2b (5RS)-5-Benzyl-1-methyl-3-triphenylphospho ranylidenpyrrolidin-2,4-dione (3.2b). (0.95g 92%) White plates (from ethyl acetate) mp 180 C. 1H NMR 2.94 (s, 3H), 3.13 (d, J = 4.1 Hz, 2H), 3.93 (t, J = 4.3 Hz, 1H), 7.17.25 (m, 5H), 7.36.46 (m, 12H), 7.54.60 (m, 3H). 13C NMR 27.7, 35.0, 64.1 (JCP = 123.1 Hz), 67.6 (JCP = 13.2 Hz), 122.7 (JCP = 92.8 Hz), 126.0, 127.8, 128.6 (JCP = 12.6 Hz), 130.1, 132.6 (JCP = 2.9 Hz), 133.8 (JCP = 10.9 Hz), 136.7, 173.8 (JCP = 16.6 Hz), 193.9 (JCP = 6.9 Hz). Anal. Calcd. for C30H26NO2P: C, 77.74; H, 5.65; N, 2.95. Found: C, 77.45; H, 5.70; N, 2.96. 3.4.3 Preparation of Linear Free Amine 3.2c To a solution of 3.8c (0.66 g, 1.0 mmol) dissolved in DC M (10 mL), triethylamine (3.0 eq) was added and stirred for 1 h. The solvent mi xture was washed with saturated aq sodium chloride. The organic layer was dried with an hyd magnesium sulfate, filtered, and removed under vacuum to give 3.2c (4RS)-4-Amino-1-ethoxy-5-phenyl-2-(triphenylpho sphoranyliden)pentan-1,3-dione (3.2c). (0.45 g, quantitative) Clear oil, 1H NMR 0.63 (t, J = 7.0 Hz, 3H) 1.53 (br s, 2H), 2.50 (dd, J = 12.6, 9.1 Hz, 1H), 3.31 (dd, J = 12.6, 4.9 Hz, 1H), 3.62.78 (m, 2H), 4.90.95 (m, 1H), 7.14 7.31 (m, 5H), 7.40.65 (m, 15H). 13C NMR 13.6, 42.4, 57.2 (JCP = 7.4 Hz), 58.4, 69.3 (JCP = 108.2 Hz), 125.8, 126.4 (JCP = 93.3 Hz), 128.1, 128.5 (JCP = 12.6 Hz), 129.6, 131.6 (JCP = 2.9 Hz), 132.9 (JCP = 9.7 Hz), 139.8, 167.2 (JCP = 14.3 Hz), 198.0 (JCP = 2.9 Hz). Anal. Calcd. for C30H26NO2P: C, 75.14; H, 6.10; N, 2.83. F ound: C, 74.37; H, 6.06; N, 2.97.

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89 3.4.4 Preparation of 3,3-Dibr omopyrrolidin-2,4-dione 3.3a The 4-Chlorobenzoic acid (0.05 g, 0.32 mmol) and 3.2b (0.13 g, 0.28 mmol) were refluxed in THF (25 mL) for 1 h, no reaction was detected by TLC. Upon the addi tion of NBS (~0.09 g, 0.32 mmol) the reaction was completed after 5 mi n of stirring at rt. The organic phase was washed with saturated aq sodium chloride solution. The crude product was subjected to column chromatography (SiO2, hexane:ethyl acetate = 4:1), to give 3.3a (5RS)-5-Benzyl-3,3-dibromo-1-methyl pyrrolidin-2,4-dione (3.3a). (0.08 g, 79%) Yellowish oil. 1H NMR 3.05 (s, 3H), 3.23 (d, J = 4.9 Hz, 2H), 4.51 (t, J = 4.9 Hz, 1H), 7.07.11 (m, 2H), 7.22.33 (m, 3H). 13C NMR 29.4, 35.5, 44.7, 66.6, 127.7, 129.9, 129.6, 133.7, 164.8, 194.4. Anal. Calcd. for C12H11Br2NO2: C, 39.92; H, 3.07; N, 3.88. F ound: C, 40.45; H, 3.22; N, 3.40. 3.4.5 Preparation of 3,3-Dibromo5-hydroxypyrrolidin-2,4-dione 3.3b Ethoxytrimethylsilane (0.057 g, 0.5 mmol) and NBS (0.081 g, 0.5 mmol) were combined in DCM (1 mL) for 2 min and added to 3.2b (0.15 g, 0.3 mmol) separately dissolved in DCM (1 mL). The reaction was complete after 5 min stir ring at rt. The crude pr oduct was subjected to column chromatography (SiO2, hexane:ethyl acetate = 4:1) and allowed a mixture (1:1) of 3.3a (0.05 g, 44%) and 3.3b (0.05 g, 44%) to be obtained in 88% yield, without workup. (5RS)-5-Benzyl-3,3-dibromo-5hydroxy-1-methylpyrrolidin-2,4-dione (3.3b). (0.05 g, 44%) White sheets (from ch loroform) mp = 134136 C. 1H NMR 3.13 (s, 3H), 3.21 (d, J = 8.4 Hz, 1H), 3.32 (d, J = 14.0 Hz, 1H), 4.66 (br s, 1H), 7.05.09 (m, 2H), 7.24.28 (m, 3H). 13C NMR 25.9, 41.1, 42.6, 90.8, 128.1, 129.0, 130.4, 131.8, 165.1, 194.3. Anal. Calcd. for C12H11Br2NO3: C, 38.23; H, 2.94; N, 3.72. Found: C, 37. 48; H, 2.82; N, 3.50. Crystal data: C12H11Br2NO3, MW 377.04, monoclinic, space group P21/n, a = 6.8928(5), b = 28.975(2), c = 7.0527(5) = 110.311(2) o, V = 1320.99(16) 3, F(000) = 736, Z = 4, T = -170 oC, colorless plate, 0.53 x 0.26 x 0.14 mm, (MoK ) = 6.135 mm-1, Dcalcd = 1.896 g.cm-3, 2 max 53o, wR(F2) = 0.0754 (all 2540 data), R = 0.0268 (2274 data with I > 2 I). 3.4.6 Preparation of 4-Azido-3-bromopyrrol-2-one 3.3c The N-Bromosuccinimide (0.135 g, 0.76 mmol) a nd TMS-azide (0.1 mL, 0.76 mmol) were combined in DCM (5 mL) and added to 3.2b (0.25 g, 0.54 mmol) dissolv ed in DCM (1 mL).

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90 The reaction was stirred at rt for 5 min. The crude product was subjected to column chromatography (SiO2, hexane:ethyl acetate = 4:1) without workup, to give 3.3c (5RS)-4-Azido-5-benzyl-3-bromo-1-methylpyrrol-2-one (3.3c). (0.14 g, 84%) Clear oil. 1H NMR 2.93 (dd, J = 14.7, 4.9 Hz, 1H), 2.95 (s, 3H), 3.16 (dd, J = 14.7, 4.2 Hz, 1H), 4.08 (t, J = 4.9 Hz, 1H), 7.07.11 (m, 2H), 7.23.31 (m, 3H). 13C NMR 28.7, 35.8, 63.3, 103.1, 127.4, 128.6, 129.0, 134.0, 149.3, 165.8. C12H11BrN4O HRMS m/z Calcd 307.0194, 309.0174 [M+H]+, Found 307.0190, 309.0119. 3.4.7 Preparation of 4-Benz otriazolpyrrol-2-one 3.3d The 1-Chlorobenzotriazole (0.7 g, 0.48 mmol) and 3.2b (0.2 g, 0.43 mmol) were dissolved together in DCM (1 mL). The reaction was s tirred at rt for 5 min. The crude product was subjected to column chromatography (SiO2, hexane:ethyl acetate = 9: 1) without workup to give 3.3d (5RS)-4-(Benzotriazol-1(2)-yl)-5-benzyl-1-methylpyrrol-2-one (3.3d). (0.12 g, 92%) Yellow microcrystals (from diethyl ether) mp = 124126 C. 1H NMR (Bt1:Bt2 = 1:1) 2.90 (dd, J = 14.0, 4.9 Hz, 2H), 3.13.30 (m, 7H), 3.37.50 (m, 2H), 5.21 (t, J = 4.2 Hz, 1H), 5.34 (t, J = 4.2 Hz, 1H), 6.47 (s, 1H), 6.49 (s, 1H), 6.65.68 (m, 2H), 6.99.02 (m, 2H), 7.11.14 (m, 4H), 7.31 (d, J = 8.4 Hz, 1H), 7.40.57 (m, 5H), 7.87.98 (m, 3H), 8.16 (d, J = 7.7 Hz, 1H). 13C NMR 28.8, 29.0, 35.1, 35.8, 62.0, 62.7, 112.5, 115.0, 116.4, 117.6, 118.6, 120.5, 125.3, 125.7, 127.3, 127.4, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 131.6, 133.0, 133.5, 143.8, 144.7, 145.2, 145.9, 164.6, 164.7. Anal. Calcd. for C18H16N4O: C, 71.01; H, 5.30; N, 18.41. Found: C, 68.39; H, 4.90; N, 18.53. Reduced product C18H14N4O HRMS m/z Calcd 303.0120, 325.1060 [M+H]+, [M+Na]+ Found 303.1233, 325.1054. 3.4.8 Preparation of N-Acylbenzotriazoles 3.4ad, 3.13 Compounds 3.4ad and 3.13 were prepared from the corresponding N-Cbz amino acids (25 mmol) and BtH (3.0 eq) in the presence of thionyl chloride (1.01 eq), following recently developed procedures [Chapter 22.4.1 05ARK116, 04S2645, 04S1806, 06S411]. (2S)-1-Benzyloxycarbonyl(benzotri azol-1-carbonyl)pyrrolidine (3.4d). (Two rotameric forms) (6.3g, 72%) Clear oil. [ ]23 D = .6 (c 1.83, DMF)lit.[06S411]. 1H NMR 1.99.14 (m, 2H), 2.15.26 (m, 1H), 2.54.68 (m, 1H), 3. 64.88 (m, 2H), 4.95.11 (m, 1H), 5.12.24 (m, 1H), 5.83.88 (m, 1H), 6.97.06 (m, 2H), 7.30.42 (m, 3H), 7.50.56 (m, 1H), 7.65 7.70 (m, 1H), 8.11.16 (m, 1H), 8.19.31 (m, 1H). 13C NMR 23.7, 24.5, 30.7, 31.6, 46.9, 47.3, 59.2, 60.0, 67.3, 114.3, 114.5, 120.2, 126.4, 127.5, 127.9, 128.1, 128.5, 130.5, 130.6, 145.9,

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91 154.0, 154.9, 171.1, 171.6. Anal. Calcd. for C19H18N4O3: C, 65.13; H, 5.18; N, 15.99. Found: C, 64.98; H, 5.24; N, 15.77. 3-(Benzotriazol-1-yl)-1-(benzyloxy)c arbonylamino-propan-3-one (3.13). (7.3 g, 90%) White needles (from diethyl ether) mp 111112 C. 1H NMR 3.66.69 (m, 2H), 3.74.80 (m, 2H), 5.09 (s, 2H), 5.47 (br s, 1H), 7.28.36 (m, 5H ), 7.48.53 (m, 1H), 7.62.67 (m, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H). 13C NMR 35.9, 36.1, 66.8, 114.2, 120.2, 126.3, 128.1, 128.5, 130.5, 130.8, 136.2, 146.1, 156.2, 171.2. Anal. Calcd. for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 63.19; H, 4.86; N, 17.41. 3.4.9 Preparation of -Triphenylphosphoranylidene Esters 3.6ad Compounds 3.6ad and 3.14 were prepared from the corresponding 3.4ad and 3.13 (1.1 mmol) and 3.5 (0.348 g, 1.0 mmol) in ACN (1 mL) in a dry 50 mL rb flask with a magnetic stir bar was equipped with a condenser. The flask containing the reaction mi xture was exposed to microwave irradiation (120 W) for 10 min at a temp of 60 C, and cooled with high-pressure air through an inbuilt system in the instrument un til the temp fell below 30 C. The reaction mixture was diluted with ethyl acetate and washed with a satura ted aq sodium carbonate solution. The organic layer was collected, dr ied over anhyd magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product wa s purified by column chromatography (SiO2, hexane:ethyl acetate = 3:1) to give 3.6ad (2S)-1-Benzyloxycarbonyl-2-(ethoxycarbonyltri phenylphosphoranylidenacetyl)pyrrolidine (3.6d). (Two rotameric forms) (0.38 g, 66%) White microcrystals (from chloroform / hexane) mp 129130 C. [ ]23 D = .4 (c 1.50, CH2Cl2) ([ ]20 D = .0 (c 1.03, CH2Cl2)lit.[02JP(1)533]. 1H NMR 0.66 (t, J = 7.1 Hz, 3H), 1.75 (br s, 2H), 1.98.16 (m, 1H), 2.30.50 (m, 1H), 3.35 3.56 (m, 2H), 3.62.84 (m, 2H) 4.89.27 (m, 2H), 5.64.76 (m, 1H), 7.20.74 (m, 20H). 13C NMR 13.4, 22.7, 23.5, 30.5, 31.5, 46.6, 47.1, 58.0, 58.1, 62.2 (JCP = 7.4 Hz), 62.7 (JCP = 6.3), 65.7, 65.9, 68.7 (JCP = 109.9 Hz), 69.0 (JCP = 111.1 Hz), 125.9 (JCP = 93.9 Hz), 126.1 (JCP = 93.3 Hz), 126.3, 126.9, 127.2, 127.3, 127.9, 128.1 (JCP = 12.6 Hz), 128.2 (JCP = 12.0 Hz), 131.2 (JCP = 2.9 Hz), 131.3 (JCP = 2.3 Hz), 131.6, 131.8, 132.6 (JCP = 9.7 Hz), 133.0 (JCP = 9.7 Hz), 137.1, 137.2, 154.2 (JCP = 4.0 Hz), 167.1 (JCP = 15.5 Hz), 167.3 (JCP = 14.3 Hz), 194.9 (JCP = 2.9 Hz), 195.4 (JCP = 2.9 Hz). Anal. Calcd. for C35H34NO5P: C, 72.53; H, 5.91; N, 2.42. Found: C, 72.19; H, 5.90; N, 2.76. 5-(Benzyloxy)carbonylamino-1-ethoxy-2-triphe nylphosphoranylidenpentan-1,3-one (3.14). (0.43 g, 77%) Yellowish needles (from diethyl ether) mp 88 C. 1H NMR 0.64 (t, J = 7.0 Hz, 3H), 3.15 (t, J = 5.5 Hz, 2H), 3.40.50 (m, 2H), 3.71 (q, J = 7.0 Hz, 2H), 5.06 (s, 2H), 5.57

PAGE 92

92 (t, J = 5.1Hz, 1H), 7.23.52 (m, 15H), 7.59.70 (m, 5H). 13C NMR 13.3, 37.2, 39.6 (JCP =6.3 Hz), 58.1, 65.7, 71.2 (JCP =110.5 Hz), 125.9 (JCP = 93.3 Hz), 127.5, 128.0, 128.2 (JCP = 12.6 Hz), 131.3 (JCP = 2.3 Hz), 131.7, 132.6 (JCP = 9.7 Hz), 136.6, 155.9, 167.5 (JCP = 14.3 Hz) 195.5 (JCP = 3.4 Hz). Anal. Calcd. for C33H32NO5P: C, 71.60; H, 5.83; N, 2.53. Found: C, 71.57; H, 5.97; N, 2.45. 3.4.10 Preparation of DOT-salts 3.7ad Compounds 3.7ad and 3.15 were prepared from the corresponding 3.6ad and 3.14 3.6c (2.0 mmol) was stirred for 5 h in 33% HBr in acetic acid (10 mL). The reaction mixture was diluted with diethyl ether ( 150 mL) and stirred for 12 h. The white precipitated salt 3.7c was filtered from the solution and used without further purification. 4-Ammonio-1-ethoxy-2-triphe nylphosphoranylidenbutan-1,3-dione Bromide (3.7a). Hygroscopic (0.20 g, 21%) White plates (from DCM / ethyl acetate) mp 101103 C. 1H NMR 0.67 (t, J = 7.0 Hz, 3H), 3.72 (q, J = 7.0 Hz, 2H), 4.18 (br s, 2H ), 6.83 (br s, 3H), 7.47.69 (m, 15H). 13C NMR 13.4, 45.4 (JCP = 8.0 Hz), 49.8, 58.7, 69.5 (JCP = 111.1 Hz), 124.1 (JCP = 93.3 Hz), 128.6 (JCP = 12.6 Hz), 132.1 (JCP = 2.3 Hz), 132.9 (JCP = 10.3 Hz), 166.7 (JCP = 13.2 Hz), 185.3 (JCP = 5.7 Hz). Anal. Calcd. for C24H25BrNO3P: C, 59.27; H, 5.18; N, 2.88. Found: C, 58.64; H, 5.29; N, 2.52 (4RS)-4-Ammonio-1-ethoxy-2-triphenylphosphoni opentan-1,3-dione Dibromide (3.7b). ( 1.15 g, 99%) White microcrystals (from DC M / ethyl acetate) mp 147 C. DMSO-d6 1H NMR 0.48 (t, J = 7.0 Hz, 3H), 1.45 (d, J = 6.3 Hz, 3H), 3.50.64 (m, 2H), 4.89 (t, J = 6.3 Hz, 1H), 7.59.69 (m, 15H), 7.80 (br s, 3H), 8.51 (br s, 1H). DMSO-d6 13C NMR 13.3, 17.4, 51.1 (JCP = 8.6 Hz), 58.2, 68.1 (JCP = 109.4 Hz), 124.9 (JCP = 92.8 Hz), 129.0 (JCP = 12.6 Hz), 132.3 (JCP = 2.9 Hz), 132.8 (JCP = 9.7 Hz), 166.2 (JCP = 12.6 Hz), 190.5 (JCP = 4.6 Hz). Anal. Calcd. for C25H28Br2NO3P: C, 51.66; H, 4.86; N, 2.41. F ound: C, 51.32; H, 4.88; N, 2.35. (4RS)-4-Ammonio-1-ethoxy-5-phenyl-2-triphenyl phosphoniopentan-1,3-dione Dibromide (3.7c). (1.20 g, 91%) White microcryst als (from DCM / ethyl acetate) mp 145147 C. DMSO-d6 1H NMR 0.46 (t, J = 7.1 Hz, 3H), 2.80 (dd, J = 14.0, 9.2 Hz, 1H), 3.38 (dd, J = 14.0, 4.3 Hz, 1H), 3.50.66 (m, 2H), 5.18 (br s, 1H ), 5.68 (br s, 3H), 7.25.45 (m, 5H), 7.56.77 (m, 15H). DMSO-d6 13C NMR 13.3, 37.4, 58.9 (JCP = 8.6 Hz), 58.3, 69.1 (JCP = 108.2 Hz), 124.8 (JCP = 92.8 Hz), 126.9, 128.5, 129.0 (JCP = 12.6 Hz), 129.6, 132.3, 133.0 (JCP = 9.7 Hz), 136.0, 166.4 (JCP = 12.0 Hz), 188.9 (JCP = 4.6 Hz). Anal. Calcd. for C31H32Br2NO3P: C, 56.64; H, 4.91; N, 2.13. Found: C, 57.09; H, 4.93; N, 2.22. (2RS)-2-(Ethoxycarbonyltriphenylphosphonioacetyl)pyrrolidine Bromide (3.7d). (0.95 g, 90%) White microcrystals (from DCM / ethyl acetate) mp 81 C. 1H NMR 0.69 (t, J = 7.3 Hz, 3H), 1.61.80 (m, 1H), 2.02.20 (m, 2H), 2.65.84 (m, 1H), 3.16 (br s, 1H), 3.40.60 (m, 1H), 3.73.85 (m, 3H), 5.38 (br s, 1H ), 7.42.71 (m, 15H), 10.70 (br s, 1H). 13C NMR 13.6, 24.5, 31.8, 46.5, 59.2, 63.6 (JCP = 9.7 Hz), 69.6 (JCP = 109.9 Hz), 124.2 (JCP = 93.9 Hz),

PAGE 93

93 128.9 (JCP = 12.6 Hz), 132.5 (JCP = 2.9 Hz), 133.0 (JCP = 9.7 Hz), 166.2 (JCP = 12.6 Hz), 187.7 (JCP = 5.2 Hz). Anal. Calcd. for C27H29BrNO3P: C, 61.61; H,5.55; N, 2.66. Found: C, 61.28; H, 5.45; N, 3.34. (5-Ammonio-1-ethoxy-2-triphenylphosphoni opentan-1,3-dione) Dibromide (3.15). (1.08 g, 92%) White plates (from DCM / diethyl ether) mp 126128 C. DMSO-d6 1H NMR 0.50 (t, J = 7.0 Hz, 3H), 2.80.95 (m, 2H), 3.22 (t, J = 6.3 Hz, 2H), 3.56 (q, J = 7.0 Hz, 2H), 7.55.80 (m, 18H), 9.50 (br s, 1H). DMSO-d6 13C NMR 13.4, 35.3, 37.1 (JCP = 7.4 Hz), 55.1, 57.9, 69.7 (JCP = 109.4 Hz), 125.7 (JCP = 92.8 Hz), 128.9 (JCP = 12.6 Hz), 132.1, 132.8 (JCP = 9.7 Hz), 166.8 (JCP = 13.2 Hz), 192.4 (JCP = 4.0 Hz). Anal. Calcd. for C25H28Br2NO3P: C, 51.66; H, 4.86; N, 2.41; Found: C, 51.35; H, 4.88; N, 2.14. 3.4.11 Preparation of DOT-pyrrolidines 3.8ac, DOT-pyrrolizines, and DOT-piperidines Method I: Compounds 3.8ad were prepared from the corresponding 3.7ad Salt 3.7ad (1.0 mmol) was dissolved in ethanol (1.0 mL) an d added to aq sodium hydroxide (10.0 mL, 7.5 M), which precipitated a white solid almost imme diately. Extraction wa s performed with DCM after 5 h. Compound 3.16 was prepared from 3.15 (1.0 mmol), following the same procedure with an added reflux in aq sodium hydroxide (7.5 M) for 15 h. Method II: Compounds 3.8 ad were prepared from the corresponding 3.6ad A round bottom flask charged with 3.6ad (2.0 mmol) and 5% Pd(C) (2 eq) were stirred vigorously in ethanol, under a hydrogen atmosphere for 48 h. The reaction mixture was filtered through celite and diluted with ethyl acetate to crystallize 3.8 ad 3-Triphenylphosphoranylidenpy rrolidin-2,4-dione (3.8a). (0.35 g, 97%) (Method I 20%) ( 3.8 a Method II 0.43 g, 60%) (21%)lit.[01TL141] White needles (from DCM / ethyl acetate) mp 222224 C. 1H NMR 3.79 (s, 2H), 5.40 (br s, 1H), 7.47.56 (m, 6H), 7.58.74 (m, 9H). 13C NMR 52.4 (JCP = 13.2 Hz), 64.2 (JCP = 122.6 Hz), 122.8 (JCP = 93.3 Hz), 128.7 (JCP = 12.6), 132.9 (JCP = 2.9 Hz), 134.0 (JCP = 10.9 Hz), 177.4 (JCP = 17.4 Hz), 194.8 (JCP = 8.6 Hz). Anal. Calcd. for C22H18NO2P: C, 73.53; H, 5.05; N, 3.90. F ound: C, 73.28; H, 4.98; N, 3.88. (5RS)-5-Methyl-3-triphenylphosphorany lidenpyrrolidin-2,4-dione (3.8b). (0.37 g, 99%) (Method I 98%) ( 3.8 b Method II 0.34 g, 45%) (58%)lit.[01TL141] White needles (from DCM / ethyl acetate) mp 210211 C. 1H NMR 1.34 (d, J = 6.7 Hz, 3H), 3.87 (q, J = 6.7 Hz, 1H), 5.30 (s, 1H), 7.40.80 (m, 15H). 13C NMR 18.5, 58.0 (JCP = 13.7 Hz), 62.8 (JCP = 122.5 Hz), 122.9 (JCP = 92.8 Hz), 128.7 (JCP = 12.6 Hz), 132.8 (JCP = 2.3 Hz), 133.9 (JCP = 10.9 Hz), 176.2 (JCP = 16.6 Hz), 197.7 (JCP = 7.4 Hz). Anal. Calcd. for C23H20NO2P: C, 73.98; H, 5.40; N, 3.75.

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94 Found: C, 73.72; H, 5.38; N, 3.46. HRMS m/z Calcd for C23H20NO2P 373.1226 [M+H]+, Found 373.1215. (5RS)-5-Benzyl-3-triphenylphosphoranylid enpyrrolidin-2,4-dione (3.8c). (0.45 g, 99%) (Method I = 89%) ( 3.8 c Method II 0.40 g, 45%) White plates (f rom DCM / ethyl acetate) mp 238242 C. 1H NMR 2.82 (dd, J = 13.7, 8.1 Hz, 1H), 3.18 (dd, J = 13.2, 3.4 Hz, 1H), 4.05 4.08 (m, 1H), 5.17 (s, 1H), 7.20.30 (m, 5H), 7.44.63 (m, 15H). 13C NMR 38.7, 63.5 (JCP = 13.2 Hz), 64.0 (JCP = 122.0 Hz), 122.7 (JCP = 93.3 Hz), 126.3, 128.2, 128.7 (JCP = 13.2 Hz), 129.6, 132.8 (JCP = 2.9 Hz), 133.9 (JCP = 10.9 Hz), 137.8, 175.9 (JCP = 16.0 Hz), 195.5 (JCP = 7.4 Hz). Anal. Calcd. for C29H24NO2P: C, 77.49; H, 5.38; N, 3.12. F ound: C, 77.22; H, 5.45; N, 2.76. HRMS m/z Calcd for C29H24NO2P 450.1617 [M+H]+, Found 450.1628. Crystal data: C29H24NO2P, MW 449.460, monoclinic, space group P21/n, a = 10.7276(2), b = 14.2746(3), c = 14.8455(4) = 90.353(1) o, V = 2273.28(9) 3, F(000) = 944, Z = 4, T = -180 oC, colorless block, 0.44 x 0.22 x 0.12 mm, (MoK ) = 0.148 mm-1, Dcalcd = 1.313 g.cm-3, 2 max 50o, wR(F2) = 0.0997 (all 4022 data), R = 0.0402 (3788 data with I > 2 I). (2RS)-2-(Triphenylphosphoranyliden)tetrah ydropyrrolizin-1,3-dione (3.8d). (0.35 g, 88%) (Method I 79%) ( 22 d Method II 0.36 g, 45%) (60%)lit.[01TL141] White needles (from DCM / ethyl acetate) mp 211213 C. 1H NMR 1.60.73 (m, 1H), 1.88.18 (m, 3H), 3.04.12 (m, 1H), 3.70 (dt, J = 11.2, 7.5 Hz, 1H) 3.99 (app t, J = 7.7 Hz, 1H), 7.40.70 (m, 15H). 13C NMR 27.0, 28.2, 44.6, 65.2 (JCP = 117.4 Hz), 69.1 (JCP = 13.2 Hz), 122.6 (JCP = 92.8 Hz), 128.7 (JCP = 13.2 Hz), 132.8 (JCP = 2.9 Hz), 133.8 (JCP = 10.9 Hz), 179.7 (JCP = 16.0 Hz), 197.6 (JCP = 8.0 Hz). Anal. Calcd. for C25H22NO2P: C, 75.18; H, 5.55; N, 3.51. Fo und: C, 74.96; H, 5.62; N, 3.47. 3-Triphenylphosphoranylidenpi peridin-2,4-dione (3.16). (0.29 g, 65%) (Method I 60%) (34%)lit.[01TL141] White microcrystals (from DCM / ethyl acetate) mp 241 C. 1H NMR 2.42 (t, J = 6.3 Hz, 2H), 3.37 (dt, J = 6.3, 2.8 Hz, 2H), 5.65 (br s, 1H), 7.39.53 (m, 9H), 7.64 7.71 (m, 6H). 13C NMR 37.1 (JCP = 9.2 Hz), 37.9, 70.0 (JCP = 115.1 Hz), 125.0 (JCP = 92.8 Hz), 128.2 (JCP = 12.6 Hz), 131.7 (JCP = 2.9 Hz), 133.3 (JCP = 10.3 Hz), 171.1 (JCP = 10.9 Hz), 191.9 (JCP = 4.6 Hz). Anal. Calcd. for C23H20NO2P: C, 73.98; H, 5.40; N, 3.75. Found: C, 74.03; H, 5.55; N, 3.58. 3.4.12 Preparation of -Triphenylphosphoranyliden e Nitriles 3.10ad, 3.17 Compounds 3.10ad and 3.17 were prepared from the corresponding 3.4ad and 3.13 (1.1 mmol) and 3.9 (1.0 mmol), following the procedure developed for -triphenylphosphoranylidene esters in section 3.4.9 4-Benzyloxycarbonylamino-3-oxo-2-tripheny lphosphoranylidenbutane nitrile (3.10a). (0.42 g, 85%) White microcrystals (from diethyl ether / hexanes) mp 171173 C. 1H NMR 4.41 (d, J = 4.3 Hz, 2H), 5.09 (s, 2H), 5.59 (br s, 1H), 7.26.40 (m, 5H), 7.42.72 (m, 15H). 13C NMR 46.4 (JCP = 127.7 Hz), 47.5 (JCP = 10.9 Hz), 66.4, 120.6 (JCP = 14.9 Hz), 122.3 (JCP = 93.3 Hz), 127.8, 128.3, 129.2 (JCP = 13.2 Hz), 133.3 (JCP = 3.4 Hz), 133.5 (JCP = 10.3 Hz), 136.6, 156.0,

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95 189.9. Anal. Calcd. for C30H25N2O3P: C, 73.16; H, 5.12; N, 5.69. Found: C, 72.80; H, 5.08; N, 5.59. (4S)-Benzyloxycarbonylamino-3-oxo-2-triphenyl phosphoranylidenpentane nitrile (3.10b). (0.40 g, 79%) White microcrystals (f rom diethyl ether / hexanes) mp 7375 C. [ ]23 D = +21.5 (c 1.00, CH2Cl2) ([ ]20 D = +18.96 (c 1.00, CHCl3)) lit. [03T6771]. 1H NMR 1.53 (d, J = 6.7 Hz, 3H), 4.92.02 (m, 1H), 5.08 (s, 2H), 5.75 (d, J = 6.9 Hz, 1H), 7.22.36 (m, 5H), 7.40.72 (m, 15H). 13C NMR 19.4, 46.5 (JCP = 127.5 Hz), 52.2, 66.0, 120.7 (JCP = 14.9 Hz), 122.3 (JCP = 93.3 Hz), 127.6, 128.2, 129.0 (JCP = 12.6 Hz), 131.7 (JCP = 4.0 Hz), 131.8, 133.2 (JCP = 10.3 Hz), 136.5, 155.2, 194.3. Anal. Calcd. for C31H27N2O3P: C, 73.51; H, 5.37; N, 5.53. Found: C, 73.13; H, 5.38; N, 5.36. (4S)-Benzyloxycarbonylamino-3-oxo-5-phenyl-2 -triphenylphosphoranylidenpentane nitrile (3.10c). (0.44 g, 79%) (78%)lit.[00T9763] White microcrystals (from DCM / diethyl ether) mp 101103 C. [ ]23 D = +7.6 (c 1.10, CH2Cl2). 1H NMR 3.08 (dd, J = 13.9, 7.0 Hz, 1H), 3.34 (dd, J = 13.9, 4.9 Hz 1H), 5.06 (s, 2H), 5.20 (q, J = 7.0 Hz, 1H), 5.58 (d, J = 7.7 Hz, 1H), 7.17.23 (m, 5H), 7.25.33 (m, 5H), 7.48.57 (m, 10H) 7.60.66 (m, 5H). 13C NMR 38.7, 47.9 (JCP = 126.0 Hz), 57.2 (JCP = 9.0 Hz), 66.3, 121.0 (JCP = 16.0 Hz), 122.4 (JCP = 93.9 Hz), 126.4, 127.8. 128.1, 128.3, 129.1 (JCP = 12.6 Hz), 129.7, 133.2 (JCP = 3.4 Hz), 133.5 (JCP = 10.3 Hz), 136.8, 155.5, 192.9. Anal. Calcd. for C37H31N2O3P: C, 76.27; H, 5.36; N, 4.81. Found: C, 76.52; H, 5.38; N, 2.94. (2S)-1-Benzyloxycarbonyl-(cyanotriphenylphospho ranylidenacetyl)pyrrolidine (3.10d). (Two rotameric forms) (0.34 g, 64%) White mi crocrystals (from DCM / diethyl ether) mp 141143 C. [ ]23 D = .7 (c 1.20, CH2Cl2). 1H NMR 1.79.12 (m, 3H), 2.29.47 (m, 1H), 3.44.58 (m, 2H), 4.99.27 (m, 3H), 7.21.70 (m, 20H). 13C NMR 23.6, 24.4, 30.4, 31.6, 46.2 (JCP = 126.3 Hz), 46.3 (JCP = 127.0 Hz), 46.8, 47.4, 61.8 (JCP = 9.1 Hz), 62.4 (JCP = 9.1 Hz), 66.4, 121.3 (JCP = 14.7 Hz), 121.5 (JCP = 15.4 Hz), 122.6 (JCP = 93.4 Hz), 122.9 (JCP = 93.4 Hz), 126.9, 127.2, 127.4, 127.4, 128.1, 128.2, 128.4, 128.8 (JCP = 12.6 Hz), 128.9 (JCP = 12.6 Hz), 131.8, 131.9, 132.8 (JCP = 2.8 Hz). 132.9 (JCP = 2.8 Hz), 133.2 (JCP = 10.5 Hz), 133.4 (JCP = 10.5 Hz), 136.9, 137.0, 154.2, 154.4, 194.7 (JCP = 3.5 Hz), 194.9 (JCP = 3.5 Hz). HRMS m/z Calcd for C33H29N2O3P 533.1989 [M+H]+, Found 533.1995. 5-Benzyloxycarbonylamino-3-oxo-2-triphenyl phosphoranylidenpentane nitrile (3.17). (0.32 g, 63%) White microcrystals (from diethyl ether / hexanes) mp 156158 C. 1H NMR 2.95 (t, J = 5.9 Hz, 2H), 3.45.50 (m, 2H), 5.08 (s, 2H ), 5.41 (br s, 1H), 7.24.38 (m, 5H), 7.44.64 (m, 15H). 13C NMR 36.9, 38.6 (JCP = 9.2 Hz), 49.0 (JCP = 126.0 Hz), 66.1, 121.8 (JCP = 16.6 Hz), 122.6 (JCP = 93.9 Hz), 127.7, 127.8, 128.2, 129.0 (JCP = 13.2 Hz), 133.1 (JCP = 2.9 Hz), 133.3 (JCP = 10.3 Hz), 136.6, 156.0, 195.0. Anal. Calcd. for C31H27N2O3P: C, 73.51; H, 5.37; N, 5.53. Found: C, 73.50; H, 5.37; N, 5.50.

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96 3.4.13 Preparation of 2,4-Dihydropyrrol-3-one Salts 3.11ac, Tetrahydropyrrolizin-1-one Salt 3.11d, and Nitrile Salt 3.18 Compounds 3.11ad and 3.18 were prepared from the corresponding 3.10ad and 3.17 (1.0 mmol), following the procedure developed in section 3.4.10 5-Amino-4-triphenylphosphonio-2,4-di hydropyrrol-3-one Bromide (3.11a). (0.31 g, 71%) White plates (from DCM / di ethyl ether) mp 255 C. 1H NMR 3.99 (s, 2H), 7.64.71 (m, 12H), 7.74.81 (m, 3H), 8.72 (br s, 1H). 13C NMR 52.2 (JCP = 10.3 Hz), 64.8 (JCP = 125.4 Hz), 119.7 (JCP = 93.3 Hz), 130.1 (JCP = 13.2 Hz), 133.6 (JCP = 10.9 Hz), 134.6 (JCP = 2.9 Hz), 170.3 (JCP = 17.2 Hz), 194.5 (JCP = 6.3 Hz). Anal. Calcd. for C22H20BrN2OP: C, 60.15; H, 4.59; N, 6.38; Found: C, 60.11; H, 4.94; N, 5.59. (2RS)-5-Amino-2-methyl-4-triphenylphosphonio2,4-dihydropyrrol-3-one Bromide (3.11b). (0.26 g, 70%) White plates (from DCM / diethyl ether) mp 260262 C. 1H NMR 1.45 (d, J = 7.0 Hz, 3H), 1.72 (br s, 2H), 4.03 (q, J = 7.0 Hz, 1H), 7.63.69 (m, 12H), 7.75.81 (m, 3H), 8.76 (br s, 1H). 13C NMR 17.3, 58.5 (JCP = 10.3 Hz), 63.1 (JCP = 124.3 Hz), 120.1 (JCP = 93.3 Hz), 130.1 (JCP = 13.1 Hz), 133.6 (JCP = 10.9 Hz), 134.6 (JCP = 2.9 Hz), 168.8 (JCP = 17.2 Hz), 197.7 (JCP = 5.7 Hz). Anal. Calcd. for C23H22BrN2OP: C, 60.94; H, 4.89; N, 6.18; Found: C, 60.58; H, 4.78; N, 5.96. (2RS)-5-Amino-2-benzyl-4-triphenylphosphonio2,4-dihydropyrrol-3-one Bromide (3.11c). (0.38 g, 72%) White plates (from DCM / diethyl ether) mp 253255 C. 1H NMR 1.69 (s, 2H), 3.11 (dd, J = 14.0, 4.9 Hz, 1H), 3,21 (dd, J = 14.0, 3.5 Hz, 1H), 4.28 (t, J = 4.2 Hz, 1H), 7.32 7.42 (m, 11H), 7.54.59 (m, 6H), 7.71.76 (m, 3H), 9.06 (br d, JHP = 2.1 Hz, 1H). 13C NMR 36.6, 63.3 (JCP = 10.3 Hz), 64.0 (JCP = 127.8 Hz), 119.7 (JCP = 92.8 Hz), 126.8, 128.4, 130.0 (JCP = 12.6 Hz), 130.6, 133.7 (JCP = 10.9 Hz), 134.5 (JCP = 2.9 Hz), 134.9, 169.3 (JCP = 16.6 Hz), 195.3 (JCP = 6.3 Hz). Anal. Calcd. for C29H26BrN2OP + H2O: C, 63.63; H, 5.16; N, 5.12. Found: C, 63.21; H, 4.77; N, 4.94. (4RS)-3-Ammonio-2-triphenylphosphonio-tetrahyd ropyrrolizin-1-one Dibromide (3.11d). (0.37 g, 66%) White plates (from DCM / diethyl ether) mp 238240 C. 1H NMR 1.48.59 (m, 1H), 1.93.25 (m, 3H), 3.57.70 (m, 1H), 3.81.88 (m, 1H), 4.02.08 (m, 1H), 7.54 7.64 (m, 11H), 7.69.79 (m, 4H). 13C NMR 26.7, 27.8, 49.1, 65.9 (JCP = 119.1 Hz), 70.0 (JCP = 10.3 Hz), 119.4 (JCP = 92.8 Hz), 130.0 (JCP = 13.1 Hz), 133.5 (JCP = 10.9 Hz), 134.6 (JCP = 2.9Hz), 170.9 (JCP = 15.5 Hz), 196.2 (JCP = 5.7 Hz). Anal. Calcd. for C25H25Br2N2OP: C, 53.59; H, 4.50; N, 5.00. Found: C, 53.99; H, 4.39; N, 4.52. 1-Ammonio-3-oxo-4-triphenylphosphora nylidenpentan-5-nitrile Bromide ( 3.18). ( 0.16 g, 35%) White microcrystals (from diethyl ether / hexanes) mp 238 C. 1H NMR 3.17.24 (m, 4H), 7.42 (br s, 3H ), 7.51.68 (m, 15H). 13C NMR 33.4 (JCP = 8.0 Hz), 37.0, 50.4 (JCP = 124.3 Hz), 120.8 (JCP = 16.0 Hz), 121.8 (JCP = 93.3 Hz), 129.3 (JCP = 13.2 Hz), 133.4 (JCP = 10.3 Hz), 133.5 (JCP = 2.3 Hz), 195.0 (JCP = 4.0 Hz). Anal. Calcd. for C23H24BrN2O2P: C, 58.61; H, 5.13; N, 5.94. Found: C, 58.63; H, 5.15; N, 5.39.

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97 CHAPTER 4 ENERGETIC IONIC LIQUIDS 4.1 Introduction Over the last several years, typical properties of ionic liquids (ILs) such as high ion content, liquidity over a wide temperature range, lo w viscosity, limited-volatility, and high ionic conductivity have proven to be important driv ers supporting numerous advances beyond the initial investigations of IL s as liquid electrolytes [06N JC349, 04FPE93, 04AJC113]. The properties of ILs have made it possible to repl ace damaging solvents which are used in huge amounts or are hard-to-contain, volatile organic compounds (VOCs) with recyclable, reusable, and easy to handle materials [99CRV2071, 01CC2399, 02JMC(A)419]. The rethinking, redesign, and implementation of ILs as designer solvents into many current chemical processes can deliver significant cost and environmen tal benefits [99CPP223], and lead to new technologies, e.g. the processi ng of cellulose [02JA 4974], biphasic chemical processes (e.g., BASF's BASIL) [06MI121], photovoltaics [96IC1168, 02CC2972], fuel cell electrolytes, [02MI185] polymer electrolyte s [04EA255], thermal fluids [05MI181], and lubricants [06MI347]. Safety and environmental issues have limited the ability to safely store and handle high performance energetic material s [01GC75, 04C409]. The excl usion of hydrazines, metals, halides, perchlorates, and other hazardous and potentially toxic compounds from the processing and final energetic material has benefits on reac tivity, cost, and handli ng [02GC407]. The liquid state, negligible vapor pressure, and high de nsity of ILs should bypass some problems with current energetic materials and allow for safer transportation, handling, and processing from early production to end-use. Separated compone nts could be less hazardous than an active energetic ionic liquid (EIL) fused in the last step of synthesis. Moreover energetic ILs have good

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98 thermal stabilities at elev ated temperatures and most have re asonable impact values [03PEP174]. Thus, endowing energetic materials with IL behavior rather than merely th e liquid state is highly desirable [05US0269001]. Cation Anion New,functionalizedfusedsalt CationAnion ModularDesign Thediversestructuralfuctionalities, appendeddirectlytotheheterocyclic ioncores,introducedthroughoutthe collaborationincluded: -alkylchainswithandwithout energeticgroups; -strainedringsystems; -oxygen-richfunctionalgroups (e.g.,OH,ether,epoxide); -energeticfunctionalities (e.g.,NO2,CN,N3,NH2); -unsaturatedfunctionalities. Metathesis -Byproduct Figure 4-1. Collaborative Effort: Modular Design of Heterocycles for EILs. The dual nature of ILs allows a unique tunable architectural platform with properties related to the structure of constituent ions [07MI1111]. The collaborative effort, between the Center for Heterocyclic Chemistry (CHC) in Gainesville, Florida together with The Center for Green Manufacturing (CGM) in Tuscaloosa, Alabama, has focused on the development of new energetic ionic liquids from the perspective of modular design in order to synthesize selected heterocycles for preparing fused salts (Figure 4-1). The propertie s of cation and/or anion within the ionic pair were independently modified, th en metathesis could generate new functional materials [05CC868, 06CEJ4630], whic h retain the core features of the IL state of matter. The final materials were monitored by DSC, TGA, and single crystal X-ra y crystallography, to examine how the modification to each component influenced decomposition temperature and melting point. The synthetic efforts were not directed a priori to the preparation of energetic fluids, but rather to synthesizing new materials to enable the development of links between component

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99 functionality and physical propertie s. However, the approach br oadened and the strategy shifted from commercially available comp onents to newly synthesized an ions and cations. The CHC at UF, prepared a series of 1,3-dialkylimidazolium salts containing strongly electron-withdrawing nitro and nitrile groups directly attached to th e ring (Scheme 4-1). Alkylations of substituted imidazoles have been studied for almost a century [10JCS1814, 22JCS2616, 24JCS1431, 25JCS573, 60JCS1357, 63BSC2840, 66AF23, 89AJC 1281, 91SC427, 95CC9], and were used for medicinal chemistry applications in th e late sixties [67JME891, 68JME167, 03JME427, 03BMC2863]. Recently the CHC deve loped regiospecific N-alkylation to generate strategies for novel EILs [06NJC349]. N N Me O2N N H N O2N N N O2N Et N N Et Me O2N N N Me Me O2N X Et2SO4, NaOH(aq.) 45oC Me2SO4Et2SO44.2 X 4.1 4.7c a b 4.4 4.3 dioxane reflux Reactionconditions: a)Me2SO4,toluene, 20C,48h; b)MeOTf,toluene, 20C,72h; Scheme 4-1. Regioselective N-Alkylation and Quater nization of Nitro-Substituted Imidazole To further augment the strategic toolbox of regi oalkylation of imidazole and further explore the role of functional groups on imidazolium cation of the ionic liquid system, the CHC prepared another series of 1-alkylimidazole s, containing nitro gr oups or alkyl substitu ents (Scheme 4-2). The CGM made on site, picrat e and nitrate EIL and measur ed melting and decomposition temperatures to evaluate how different functi onality and substitution patterns on a cation ring affected the physical properties of the resulting salts.

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100 4.6a-k 4.7a-k (w/energeticgroup) N N R1 R2 R3 R4 R1=Alkyl R2=H,Me,NO2R3=H,NO2,CN R4=H,Me,NO2,CN N+N R1 R2 R3 R4 H N+N R1 R2 R3 R4 H NO2 O2N NO2 -O N+ -O O OPicricAcid NitricAcid [ 4.6a-k ][ Picr. ] [ 4.7a-k ][ NO3] Reg i ospec i f i c N-alkylating Strategies Developed bytheCHC Fuseds a l t sex a m i ned b y t heCGM [ 4.6a-k ][ NO3] [ 4.7a-k ][ Picr. ] Scheme 4-2. Targeted Regio-N-alkylated Imidazoles for Generation of Fused Salts 4.2 Results and Discussion Series of N-alkylated imidazole s (i) without energetic groups 4.6ak (Table 4-1) and (ii) with energetic groups 4.7ak (Table 4-2) were used as starting ma terials for the generation of picrate and nitrate salts. Unavailable N-alkylimidazoles were prepared using Methods A, B, or C. 1Alkyl imidazoles 4.6b,d 4.7eg were prepared in 14% yields by the alkylation of the corresponding imidazoles 4.1af with corresponding alky l bromides in ACN in the presence of potassium carbonate under reflux (Scheme 4-3, Method A) [93SC2611, 03BMC2863]. N N H R2R3 R1BrN N R1R2R3 4.1a (R2=R3=R4=H) b (R2=Me,R3=NO2,R4=H) c (R2=R4=H,R3=NO2) d (R2=Me,R3=R4=H) e (R2=R4=H,R3=Me) f (R2=R3=Me,R4=H) 2 4.6b,d,f,g MethodAorB N N R2R3 4.6'h-k R1 R4 R4 R4 4.7d-g + RegiomericMixture MethodA :K2CO3,Bu4NBr,acetonitrile,reflux; MethodB :KOBut,DMF,rt. 4.6 seeTable4-1 4.7 seeTable4.2 Scheme 4-3. Method A and B for Preparation of 1-Alkylimidazoles

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101 Table 4-1. Isolated N-Alkylimidazoles 4.6ak Method Imidazole R1 R2 R3 R4 A B C 4.6aa Me H H H 4.6b Pr H H H 14b 82b 4.6ca n-Bu H H H 4.6d n-C6H13 H H H 44b 72b 4.6ea Me Me H H 4.6f n-Bu Me H H 87b 4.6g n-C5H11 Me H H 92b 4.6h Pr H H Me -c 70 4.6i n-C6H13 H H Me -c 89 4.6j Pr Me H Me -c 94 4.6k n-C6H13 Me H Me -c 79 aCommercial Source, bIsolated Yield by D. Zhang, cMixture of Regioisomers by S. Singh Table 4-2. Isolated N-Alkylimidazoles, with Energetic Groups, 4.7ak Method Imidazole R1 R2 R3 R4 A B C 4.7aa Me NO2 H H 4.7ba Et NO2 H H 4.7ca Et H NO2 H 4.7d i-Pr H NO2 H 78b 4.7e n-C6H13 H NO2 H 62b 4.7f n-Bu Me NO2 H 84b 4.7g n-C5H11 Me NO2 H 65b 4.7ha Me Me H NO2 4.7ia Me NO2 NO2 H 4.7ja Me H NO2 NO2 4.7ka Me H CN CN aLit. [06NJC349] bIsolated Yield by Dhazi Zhang. The alkylation of unsubstituted imidazoles by Method A gave unsatisfactory 14% yields. The lower yields for imidazole derived 4.6ad were probably caused by th e low boiling points of propyl and i-Pr bromides and the conditions were switched to potassium tert-butoxide in DMF at rt (Scheme 4-3, Method B). Products 4.6b,d were obtained in yields of 72%. Also, Method B was successfully employed for the preparation of 1-alkylimidazoles 4.6f,g (Table 4-1) and 4.7d (Table 4-2) in yields of 78%. Howe ver reactions of alkyl bromides with 4-

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102 methylimidazole ( 4.1e) and 2,4-dimethylimidazole ( 4.1f ) in DMF in the presence of potassium tert-butoxide gave inseparable regiomeric mixtures of N-alkylated products 4.6 hk Regiospecific N-alkylation of 4-methylimidazo le with a urea protection was unsuccessful (Scheme 4-4). The known reaction of 4.1e with phenyl isocyanate readily gives 4-methyl-1(phenylcarbamoyl)imidazole ( 4.8a ) [83JHC1103]. Treatment of 4.8a with alkybromide at rt gave no reaction, and at elevated temperatures dissociation of 4.8a to starting materials occurred [83JHC1103] to give a regiomeric mixture of N-alkylated products. N N Me N H O Ph R1Br rt Noreaction 40-80oCN N Me R1 N N Me R1 +N H N Me -PhNCO R1Br 4.1e RegiomericMixture 4.8a Scheme 4-4. Unsuccessful Re giospecific N-Alkylation The regiospecific N-alkylation of 4.1e and 4.1f to 1-alkylimidazoles 4.6hk was performed successfully using Method C. The reaction sequence involved an initial benzoylation followed by quaternization with alkyl triflates and base hydrolysis (Scheme 4-5, Method C) [02EJOC2633]. The 1-Be nzoyl-4-methyl-imidazole 4.9a (96%) and 1-benzoyl-2,4-dimethylimidazole 4.9b (70%) were prepared from benzoyl ch loride with a twof old excess of the corresponding 4.1e,f in THF at rt [90S951]. n-Propyl, i-Pr, and n-hexyl triflates were prepared in quantitative yields from the co rresponding alcohols with trifl uoromethane sulfonic anhydride and pyridine in DCM and used dire ctly after filtration and a short aq workup [75CB2947, 85JOC1872, 84S1039, 85S759, 96TL667]. Reaction of 4.9a,b with propyl and hexyl triflates in toluene at rt for 48 h gave the corresponding quaternary salts 4.10ad which separated from the

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103 bulk solvent as oils and were used as intermediates. The salts 4.10ad hydrolyzed under biphasic aq sodium hydroxide and diethyl ether conditions at rt to give 1-alkylimidazoles 4.6hk (70%). Quaternization reaction was not observed on treatment of 4.9a,b with i-Pr triflate under the same reaction conditions a nd the corresponding starting imidazoles 4.1e,f were recovered after base treatment. Concerted de hydration of isopropanol upon N-alkylation of 4methylimidazole has been reported [ 95CC9], which likely occurred with i-Pr triflate. Structures of the compounds 4.6b,d,fk 4.7dg and 4.9a,b were supported by their 1H-NMR, 13C-NMR, and elemental analysis or by reference to the literature. N N R2R3R1Bz TfO N H N R2R3 PhCOCl N N R2R3Bz R1OTf NaOH N N R2R3R1 4.6h-k 4.9a b water toluene 4.1e (R3=Me) f (R2,R3=Me) R1OH (a) (a)=Tf2O,Pyridine DCM,rt,15min 4.10a,b (R1= n -Pr) c,d (R1= n -Hex) Scheme 4-5. Regiospecfic NAlkylation of 1-Alkylimidazoles 4.6hk 4.3 Conclusion Alkylation of 4-alkyl and 2,4dialkylimidazole with alkyl br omides provides a regiomeric mixture of 1,4-disubstituted and 1,5-disubstituted imidazole. Prot ection of the N1 with benzoyl allows regioselective N-alkylation of the 3-position, with triflate quaternization. Debenzoylation and dequaternization with aq base afforded the mo re sterically hindered 1alkylated imidazoles. Substituted heterocycles continue to be a powerful tool in the search for energetic IL compounds. 4.4 Experimental Section Melting points were determined on a capillary point apparatus equi pped with a digital thermometer. NMR spectra were obtained in CDCl3 with TMS as the internal standard for 1H (300 MHz) and 13C (75 MHz). Chemicals were employed as supplied.

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104 4.4.1 Preparation of N-Alkylimidaz oles (Method A) 4.6b,d, 4.7eg Appropriate imidazole 4.1ac (10 mmol) and alkyl bromide 2 (12 mmol) were mixed with potassium carbonate (3.32 g, 24 mmol), and tetrabutylammonium bromide (0.032 g, 0.1 mmol) in ACN (50 mL). The reaction mixture was stirre d vigorously and heated under reflux for 2 h. After cooling to rt, the precipitate was filtered off and washed with ACN. The filtrate was evaporated, and the crude products were purifie d by column chromatography using ethyl acetate and hexane. 4.4.2 Preparation of N-Alkylimidazol es (Method B) 4.6b,d,f,g, 4.7d Appropriate imidazole 4.1af (50 mmol) was dissolved in DMF (10 mL). Potassium tertbutoxide (6.7 g, 60 mmol) was added at 0 C followed by the addition of appropriate alkyl bromide 2 (72 mmol). The reaction mixture was stirred at rt overnight. Water (20 mL) was added to the mixture. The solution was extracted with ethyl acetate (3 40 mL). The extract was washed with brine and dried over anhyd magn esium sulfate. The solvent was evaporated under reduced pressure (bath 60 C, to remove DMF) and the residue was purified with column chromatography using ethyl acet ate and hexane to give the desired N-alkylimidazoles. 1-Propylimidazole (4.6b)lit.[73AJC2435]. (Method A = 14%) (Method B = 60%) Oil. 1H NMR 7.45 (s, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 3.89 (t, J = 7.1 Hz, 2H), 1.851.73 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR 136.8, 129.0, 118.5, 48.3, 24.1, 10.8. 1-Hexylimidazole (4.6d)lit.[02JHC287]. (Method A = 44%) (Method B = 72%) Oil. Anal. Calcd for C9H16N2: C, 71.01; H, 10.59; N, 18.40. Found: C, 69.96; H, 10.98; N, 18.39. 1-Butyl-2-methyl imidazole (4.6f)lit.[02JHC287]. (Method B = 87%) Oil. Anal. Calcd for C8H14N2: C, 69.52; H, 10.21; N, 20.27. Found: C, 68.91; H, 10.62; N, 20.02. 1-Pentyl-2-methylimidazole (4.6g)lit.[02JHC287]. (Method B = 92%) Oil. Anal. Calcd for C9H16N2: C, 71.01; H, 10.59; N, 18.40. Found: C, 70.25; H, 11.09; N, 17.96. 1-Isopropyl-4-nitro imidazole (4.7d). (Method A = 78%) Plates (from ethyl acetate / hexane) mp 5053 C. 1H NMR 7.91 (d, J = 1.3 Hz, 1 H), 7.58 (d, J = 1.1 Hz, 1H), 4.564.47 (m, 1H), 1.59 (d, J = 6.7 Hz, 6H). 13C NMR 147.9, 134.3, 117.3, 50.9, 23.3. Anal. Calcd for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08. Found: C, 46.85; H, 5.82; N, 27.11.

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105 1-Hexyl-4-nitroimidazole (4.7e). (Method A = 62%) Microcrystals (from ethyl acetate / hexane) mp 3941 C. 1H NMR 7.79 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 1.3 Hz, 1H), 4.04 (t, J = 7.1 Hz, 2H), 1.901.80 (m, 2H), 1.361.28 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR 147.9, 135.9, 119.1, 48.3, 30.9, 30.5, 25.8, 22.2, 13.7. Anal. Calcd for C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C, 55.13; H, 7.93; N, 21.10. 1-Butyl-2-methyl-4-nitroimidazole (4.7f). (Method A = 84%) Microcrystals (from ethyl acetate / hexane) mp 5860 C. 1H NMR 7.71 (s, 1H), 3.94 (t, J = 7.3 Hz, 2H), 2.44 (s, 3H), 1.841.74 (m, 2H), 1.461.33 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR 146.2, 144.5, 119.5, 46.9, 32.1, 19.5, 13.4, 13.0. Anal. Calcd for C8H13N3O2: C, 52.45; H, 7.15; N, 22.94. Found: C, 52.80; H, 7.33; N, 22.87. 1-Pentyl-2-methyl-4-nitr oimidazole (4.7g). (Method A = 65%) Microcrystals (from ethyl acetate / hexane) mp 3537 C. 1H NMR 7.70 (s, 1H), 3.92 (t, J = 7.4 Hz, 2H), 2.44 (s, 3H), 1.851.75 (m, 2H), 1.401.32 (m, 4H), 0.93 (t, J = 6.7 Hz, 3H). 13C NMR 146.3, 144.5, 119.5, 47.2, 29.9, 28.4, 22.1, 13.7, 13.1. Anal. Calcd for C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C, 55.13; H, 7.90; N, 21.22. 4.4.3 Preparation of 1-Benzoyl-4-methyla nd 1-Benzoyl-2,4-dimethyl-imidazoles 4.9a,b The appropriate imidazole 4.1e,f (8.21 g, 100.0 mmol), was di ssolved in DCM (50 ml) and cooled to 0 C, with stirring. Benzoyl chlori de (5.8 mL, 50.0 mmol) wa s added dropwise over 5 min and the reaction mixture warmed to rt over 1 h. The precipitate was filtered and the filtrate was concentrated on the rotovap under reduced pressure. The solid residue was recrystallized from hexanes to yield the 1-benzoylated imidazoles 4.9a,b (4-Methyl-imidazol-1-yl)phenylmethanone (4.9a)lit.[13CB1913]. (64% yield) White needles (from hexanes) mp 6970 C. 1H NMR 2.22 (s, 3H), 6.80 (s, 1H), 7. 35-7.45 (m, 3H), 8.00-8.05 (m, 3H). 13C NMR 9.9, 116.1, 127.8, 128.9, 129.8, 130.9, 132.4, 135.4, 173.1. Anal. Calcd for C11H10N2O1: C, 70.95; H, 5.41; N, 15.04. F ound: C, 71.26; H, 5.68; N, 14.67. (2,4-Dimethyl-imidazol-1-yl)phenylmethanone (4.9b). (96% yield) Yellow needles (from hexanes) mp 4748 C. 1H NMR 2.17 (d, J = 1.0 Hz, 3H), 2.68 (s, 3H), 6.76 (d, J = 1.0 Hz, 1H), 7.50-7.57 (m, 2H), 7.62-7.69 (m, 1H), 7.74-7.77 (m, 2H). 13C NMR 10.6, 12.1, 115.6, 127.8, 129.0, 129.7, 130.3, 137.6, 143.2, 173.9. Anal. Calcd for C12H12N2O1: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.80; H, 6.05; N, 13.41. 4.4.4 Preparation of N-Alkylimid azoles (Method C) 4.6hk Under a nitrogen atmosphere, th e appropriate alkyl triflate (10.0 mmol) was added with a syringe to the appropriate l-benzoylimidazole 4.9a,b (10.0 mmol) dissolved in toluene (100 mL).

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106 After 48 h of stirring, 1-benzoyl -3-alkylimidazolium triflate 4.10ad (solid quaternary salt for 4.10a and dense liquid for 4.10bd ) was separated from the reaction mixture. The crude quaternary salts were added to aq sodium hydrox ide (20 mL, 7.5 M) and diethyl ether (20 mL) and the mixture was stirred for 1 h. The layers were separated and the aq layer was further extracted with DCM (2 x 30 mL). Organic laye rs were dried over anhyd magnesium sulfate, filtered, and dried under reduced pressure. The crude material was purified by column chromatography on silica gel with DCM a nd methanol to yield regiospecific 1-N-alkylimidazoles 4.6hk 5-Methyl-1-propylimidazole (4.6h)lit.[95CC9]. (70% yield) Clear oil. 1H NMR 0.87 (t, J = 7.6 Hz, 3H), 1.61-1.73 (m, 2H), 2.13 (s, 3H), 3.73 (t, J = 7.1 Hz, 2H), 6.69 (s, 1H), 7.33 (s, 1H). 13C NMR 7.4, 9.3, 22.4, 44.4, 124.9, 125.2, 135.1. Anal. Calcd for C7H12N2: C, 67.70; H, 9.74; N, 22.56. Found: C, 66.23; H, 10.17; N, 21.91. 1-Hexyl-5-methylim idazole (4.6i). (89% yield) Brown oil. 1H NMR 0.88 (t, J = 6.6 Hz, 3H), 1.22-1.38 (m, 6H), 1.63-1.76 (m 2H), 2.18 (s, 3H), 3.80 (t, J = 7.3, 2H), 6.73 (s, 1H), 7.37 (s, 1H). 13C NMR 8.7, 13.4, 21.9, 25.7, 30.2, 30.7, 44.1, 126.1, 126.4, 136.1. Anal. Calcd for C10H18N2: C, 72.24; H, 10.91; N, 16.85. F ound: C, 71.89; H, 11.42; N, 16.41. 2,5-Dimethyl-1-propylimidazole (4.6j)lit.[69NKZ704]. (94% yield) Blue oil. 1H NMR 0.94 (t, J = 7.4 Hz, 3H), 1.60-1.73 (m, 2H), 2.16 (s, 3H), 2.35 (s, 3H), 3.71 (t, J = 7.6 Hz, 2H), 6.61 (s, 1H). 13C NMR 7.7, 9.1, 11.2, 21.7, 43.1, 121.4, 125.3, 141.8. Anal. Calcd for C8H14N2: C, 69.52; H, 10.21; N, 20.27. Found: C, 69.10; H, 10.64; N, 19.65. 1-Hexyl-2,5-dimethylimid azole hydrate(4.6k). (79% yield) Green oil. 1H NMR 0.90 (t, J = 6.6 Hz, 3H), 1.25-1.38 (m, 6H), 1.59-1.66 (m 2H), 2.18 (s, 3H), 2.38 (s, 3H), 3.75 (t, J = 7.7 Hz, 2H), 4.09 (br s, 2H), 6.61 (s, 1H). 13C NMR 8.8, 12.2, 13.0, 21.6, 25.5, 29.4, 30.5, 42.7, 122.4, 126.1, 142.8. Anal. Calcd for C11H22N2: C, 66.62; H, 11.18; N, 14.13. Found: C, 67.77; H, 10.84; N, 14.21.

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107 CHAPTER 5 SYNTHESIS OF CYCLIC KETONE DERIVATIZED TETRASUBSTITUTED TRANSIMIDAZOLIDIN-2-ONES 5.1 Introduction Nitrogen heterocycles containi ng a vicinal diamine moiety are considered biologically privileged active structures [ 06MI101, 07OL2035, 07JA762]. Like wise, nitrogen heterocycles containing the cyclic urea moiety incorporated as part of the core are found in a broad array of biologically active molecules [94EP612741, 96MI301, 96JME3514, 02BBA02, 06OL2531] and provide increased structural rigidity as well as hydrogen bonding possibilities [95TL6647, 98TL1477]. The presences of these two potentia lly bioactive properties encourages the exploration of vicinal diamino tethered ureas and unsaturated imidazol-2-ones, or saturated imidazolidin-2-ones (Figure 5-1), in pa rticular for medicinal screening. N N O R2 R1 R3 Imidazol-2-one R4 N N O R2 R1 R4 R5 R6 R3 Imidazolidin-2-one Figure 5-1. Vicinal Di amino Tethered Ureas Planar imidazol-2-ones, exhibit a diverse por tfolio of biological activities [66JME858, 95MI115, 98LS297, 99BMC749, 99JME2706, 00TL6387, 00WOP0078750, 02BMC653, 04SL2167, 05SL1322]. Our main focus on imidazo lidin-2-one, w ith a potential for complex diastereomers, provides an opportuni ty to study the stereospecific synthesis of a heterocyclic scaffold of high interest in medicinal chemistry. Imidazolidin-2-one is a key functional unit in molecules (Figure 5-2) for (i) selective a ndrogen receptor modulators (SARMs) [07JME3015], (ii) cholinergic agonists [ 91JME2314], (iii) central nervous system (CNS) depressants [66JME852], (iv) selective agonism of 3 adrenergic receptors [99B MC755], (v) HIV-1 protease

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108 inhibitors [04BMC5685], (vi) ma trix metalloproteinase (MMP) inhibitors [01B MC1211], (vii) farnesyl transferase inhibitors [98USP5780492], and (viii) biotin, a natural occurring molecule of biological and commercial importance for more th an fifty years [07S1159]. The development of a general and efficient method, which enables the introduction of a variety of substituents into the 4and 5-position of imidazolidin-2-ones ster eospecifically and in good yields, would be highly desirable for the genera tion of combinatorial libraries [99JCC195, 02TL4571, 03OL511]. N N O Ph Ph OH N S O O MeO (v)HIV-1proteaseinhibitor DuPontMerck;WO9709150 (vii)Farnesyltransferaseinhibitor; Merck&Co.;WO9736892 N N O Cl N N CN N N O OH H Et Me Cl NC N N O Me S NH O O HN N HO (i)SARM(modulator) (iv) 3AdrenergicReceptorAgonist N N Me (ii)CholinergicAgonist (iii)CNSDeppresant N N O N N O Me Cl NMe2 NH N O NH (vi)MMP-13inhibitor O F O OH NH HN S O H H CO2H (viii)D-(+)-Biotin Figure 5-2. Bioactive Imidazolidin-2-ones

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109 Vicinal diamine and urea formation in one si multaneous step to form imidazolidin-2-one (Scheme 5-1), was reported in the literature The CC bond and urea formation, (i) bonds a and b, were achieved by coupling of a lithiatied -nitrogen methylene to imines and intramolecular cyclization to the Boc-protecting group [96J A3757, 96JOC428, 01JOC2858, 02EJOC301]. The urea and CN bond formation, (ii) bonds c and d, were achieved by (ii-a) ring opening of Narylsulfonylaziridines with isocya nates in the presence iodide i ons [93T7787, 05TL479]; or (ii-b) dehydration of allyl carbamate with modified conditions (PPh3, CBr4, Et3N) provided allyl cyanate-to-isocyanate re arrangement with subseq uent intramolecular cy clization [06OL5737]. The urea and CN bond formation, (iii) bonds c, b, and d, were achieved by Hoffman rearrangement [68BCJ2748, 89JME289]. Two st ep methods for imidazolidin-2-ones involve either formation of vicinal diamine [98 AGE2580, 05OL1641] or cyclic urea [95JME923, 96TL5309, 00AJC73, 03SL1635, 04OL2397, 04SL 489, 05T9281] and a cyclization step. (iii)c,b,d(ii-a)c,d(ii-b)c,da b5.1 c(i)a,bN N O R2 R1 R4 R5 H R3 N R2 R3 +N R1 Boc R5 Base R1=Ar,R5=Phor R1=(CH2)3=R5or R1=Alk,Bzl,R5=Bt R2=R3=Ar,HetAr dNCO R2 N R1 R4 R5 H R3 NaI R5 HN O R1 O H2N PPh3,CBr4Et3N,DCM R5 HN O R1 O H2N R1=SO2Ar,R5=Alk,Ar R3orR4=H,Alk,Ar, R6=Arort-bu R1=Cbz,R5=Me R2=R4=H,R3=allyl R1=Cbz,R5=CO2H R2=R3=R4=H NaOCl Scheme 5-1. Multiple Bond Formation in One Step for Imidazolidin-2-one The N-Boc-N-(benzotriazol-1-ylmethyl) benzylamin e was demonstrated by the Katritzky group (Scheme 5-2) [01JOC2858], to act as a 1, 1-dipole equivalent in the stereoselective

PAGE 110

110 synthesis of 1,3,4,5-tetrasubstituted trans-imidazolidin-2-ones. The transition states for the formation of 4,5-disubstittued 1,3imidazolidin-2-ones by the reaction of -nitrogen carbanion with imines were described by Kise et al [96JOC428], and generally extended to our benzotriazole method. The formation of dipole-st abilized carbanions adja cent to nitrogen atoms [84CRV471, 96JOC428, 96JA 3757] is further directed chemoselectively to lithiate at the carbon adjacent to the benzotriazole re sidue [05AGE5867] and in the pr esence of an imine a highly trans vicinal diamine is formed. Urea form ation is spontaneous in most cases. N Boc Bt Ph N CH Boc Ph (i)s-BuLi N Bt Ph O O t-Bu Li N N O R2 H Bt H R3 Ph N Bt Ph O O t-Bu Li R3 N R2 N Bt Ph O O t-Bu Li N R3 Trans-Favored+R3CH=NR2 R2 Scheme 5-2. The N-Boc-N-(benzotriazol-1-ylmethyl) Benzyl amine, 1,1-Dipole Synthon in the Stereoselective Synthesis of 1,3,4,5-Tetrasubstitute d trans-Imidazolidin-2-ones 5.2 Results and Discussion We now report the extension of the previous work on Bt-intermediates to form novel tetrasubstituted trans-imidazolidin-2-ones, with a synthetic protocol (Scheme 5-3). The efficient protocol, section 5.2.1 for imines was based on the reaction of aldehydes to anilines with the loss of a water molecule. The protocols; section 5.2.2 for Bt-intermediates, section 5.2.3 for the convergent production of trans-Bt-imidazolidin-2-ones; and section 5.2.4 for trans-imidazolidin2-ones cyclic ketones were based on th e published literature method [01JOC2858].

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111 5.2 N N O R2 H Bt H R3 N R2 R3 +N Boc Bt NH2R2 +O R3 H2N [5.2.1][5.2.2] [5.2.3] [5.2.4] H H N N O R2 H H R3 O 5.3 5.4 5.5 R1 R1 R1 R1 Scheme 5-3. Synthetic Overview of Protocols 5.2.1 Imines An efficient method for the preparation of imines was required for the convergent synthesis. The known method gave imines from the reaction of amines with aldehydes with simultaneous condensation of a water molecule [89MI769]. Quantitative yields were obtained from the reactions of aldehydes with aniline (Scheme 5-4), or 4-substituted anilines using a Dean-Stark apparatus to affect the azeotropic removal of water. The structures of the known imines 5.2a [05T11148], 5.2b [06OL3175], 5.2c [72JA9113], and 5.2d [05JOC5665] were supported by 1HNMR, 13C-NMR, and elemental analysis. Toluene reflux 5.2a R1=Cl,R2=H 5.2b R1=Me,R2=H 5.2c R1=Me,R2=F 5.2d R1=H,R2=OMe CHO R1 N R1 R2 H2N R2 +Dean-Stark Scheme 5-4. Imine Formation, From Aldehydes and Anilines

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112 5.2.2 The 1,1-Dipole Equival ents (Bt-Intermediates) Two efficient protocols we re used (Scheme 5-5) for the preparation of Bt-intermediates. The two-step procedure involved th e protection of an amine fo llowed by a coupling causing the condensation of a water molecule Furfurylamine was protected with Boc-anhydride to afford NBoc-furfurylamine. The N-Boc-furfurylamine was treated with paraformaldehyde, 1Hbenzotriazole, and catalytic p-toluene sulfonic acid ( PTSA) to affect the azeo tropic remove water, collected with a DeanStark apparatus. The novel benzotriazol-1-ylmet hyl furan-2-ylmethyl tert-butyl carbamate 5.3a (72%) was obtaine d and supported by 1H-NMR, 13C-NMR, and elemental analysis. H2N N Boc Bt PTSA O O 5.3a 1)(Boc)2O,Et3N 2)BtH,(CH2O)nDean-Stark 72% R1H2N R1N Boc Bt 5.3b R1=Bzl,70% 5.3c R1=Prn,71% PTSA 1)(Boc)2O,Et3N 2)BtCH2OH Dean-Stark Scheme 5-5. Benzotriazole Intermediate Formation, Two Methods Residual paraformaldehyde was tedious to rem ove from the desired product, even with column chromatography, and (ben zotriazol-1-yl)methanol (BtCH2OH) in place of 1Hbenzotriazole and paraformaldehyde avoided th is drawback. Benzylamine and propylamine were protected with Boc-anhydride to afford N-Boc-benzylamine and N-Boc-propylamine, respectively. The N-Boc-protected amines were reacted with BtCH2OH and catalytic PTSA to affect the azeotropic remove water, collect ed with a DeanStark apparatus. The known

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113 benzotriazol-1-yl methyl benzyl tert-butyl carbamate 5.3b (70%) was obtained without the need for purification. Similarly the novel benzotriazol-1ylmethyl propyl tert-butyl carbamate 5.3c (71%) was obtained and was supported by 1H-NMR, 13C-NMR, and elemental analysis. 5.2.3 Convergent Synthesis of Bt trans-Imidazolidin-2-ones Reproduction of the literature procedure gave undesired products. Treatment of 5.3b with (i) s-BuLi in THF at C for 0.5 h, followed by the addition of imine 5.2a as electrophile, disappointingly resulte d in the isolation of a nonpolar diastereomeric oil 5.4a and recovery of starting material by column chromatography (Sch eme 5-6). Returning to the original imine 5.2d from the literature, with the literature conditions (ii), resulted again in a non-polar oil. The column purification results were quantified as recovered starting material (50%), non-polar diastereomeric oil 5.4b (39%), and uncyclized vicinal diamine 5.4c ( 11% ) Uncyclized vicinal diamine 5.4c was detected probabl y due to quenching at 78 C. Novel 5.4a and 5.4b [72BSC3426] were supported by 1H-NMR, 13C-NMR, and elemental analysis. Compound 5.4c was confirmed by elemental analysis. 5.3b inTHF s-BuLi,1.0eq Quenchedat -78oC 4hat-78oC 1portion 0.5hthen 5.2a 5.2a ,1.0eq inTHF 2) 1) PhNH unreacted 5.3b byTLC. 5.4a ,31%+ Cl NH Ph MeO 5.4b ,39% recovered 5.3b ,50% NH Ph N Bt MeO Ph 5.4c ,Uncyclized,11%+ +Boc 5.3b inTHF s-BuLi,1.0eq Quenchedat -78oC 4hat-78oC 1portion 0.5hthen 5.2d 5.2d ,1.0eq inTHF 2) 1) (i) (ii) Scheme 5-6. Convergent Syntheses, Us ing the Reported Literature Conditions

PAGE 114

114 Optimization of the reaction conditions (Scheme 5-7) by addition of s-BuLi in three portions, each potion added after 1 h, and an additional 3 h at 78 C, lithiated 5.3b The imine 5.2d was added to the lithiated 5.3b and overnight the reaction warmed to rt. Column purification gave the Bt trans-imidazolidin-2-one 5.4d (28%), reproduced from the literature. The known structure of 5.4d was supported by 1H-NMR and 13C-NMR. N Ph N O Bt MeO Ph -78-21oC 5.4d Trans28% 3portions/2h +3hthen 5.2d 5.3b inTHF s-BuLi,1.1eq 5.2d ,1.1eq inTHF 2) 1) Overnight Scheme 5-7. Optimized Convergent C onditions, Using Literature Reagents NN O Bt Ph Ph Me 5.4e Trans24% N N O Bt Ph Me F 5.4f Trans23%-78-21oC 5.3b 5.2b 2) 1) Optimized Conditions s-BuLi-78-21oC 5.3b 5.2c 2) 1) Optimized Conditions s-BuLi Scheme 5-8. Convergent Synthe sis of N-Benzylated trans-Bt-Imidazolidin-2-ones 5.4e,f Although low yields were occurr ing, the yields were sufficient to make three novel Bt transimidazolidin-2-one examples. Two N-benzyl derivatives and one N-propyl derivative were successfully converted to novel trans-Bt-imidazolidin-2-ones by this method (Scheme 5-8). The optimized convergent conditions were used for the lithiation of 5.3b followed by addition of

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115 5.2b, or 5.2c to give 5.4e (24%), or 5.4f (23%), respectively. Similarly the optimized convergent conditions were used for the lithiation of 5.3c followed by addition of 5.2b, to give 5.4g (24%) (Scheme 5-9). The novel 5.4eg were supported by 1H-NMR, 13C-NMR, and elemental analysis. Ph N N O Bt 5.4g Me Trans24%-78-21oC 5.3c 5.2b 2) 1) Optimized Conditions s-BuLi Scheme 5-9. Convergent Synt hesis of N-Alkylated trans-Bt-Imidazolidin-2-ones with 5.4g 5.2.4 Lewis Acid Mediated Synthesi s of Cyclic Ketone Derivatized Tetrasubstituted transImidazolidin-2-ones The reproduction of the final li terature step (Scheme 5-10) gave the desired cyclohexanone tetrasubstituted trans-imidazolidin-2-one 5.5a The Bt trans-imidazolidin-2-one 5.4d was treated with Lewis acid and cyclohexenyl oxytrimethylsilane to smoothly produce 5.5a (70%). The reproduction of the literature protocol established a viable method to further develop a general method, which enables the introduction of a variety of substituents into the 4and 5position of imidazolidin-2-ones stereospecifically. O Me3Si 5.5a N Ph N O Bzl MeO O BF3Et2O 70% 5.4d+ Scheme 5-10. Lewis Acid Mediated Sy nthesis of Reported Cyclohexanone Analog 5.5a The Lewis acid method was extended to generate two novel cyclohexanone transimidazolidin-2-ones (Scheme 5-11). The trans-Bt-imidazolidin-2-ones 5.4f and 5.4g were treated with Lewis acid and cyclohe xenyloxytrimethylsilane to give 5.5b (57%) and 5.5c (70%),

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116 respectively. The two novel cyclohexanone trans-imidazolidin-2-ones were sent to SanofiAventis for their general use. O Me3Si BF3Et2O NN O Bzl Ph Me O 5.5b 70% 5.4g NN O Bzl Me F O 5.5c 57% 5.4f + O Me3Si BF3Et2O + Scheme 5-11. Lewis Acid Mediated Sy nthesis of Two Cyclohexanone Analogs 5.5b,c The Lewis acid method was extended to generate two novel cyclopentanone transimidazolidin-2-ones (Scheme 5-12). The Bt trans-imidazolidin-2-ones 5.4f and 5.4g were treated with Lewis acid and cyclope ntenyloxytrimethylsilane to give 5.5d (86%) and 5.5e (47%), respectively. The two novel cyclopentanone trans-imidazolidin-2-ones were sent to SanofiAventis for their general use. 86% 5.4e N N O Ph Ph Me O 5.5d 47% 5.4c N N O Ph Me F O 5.5e BF3Et2O O Me3Si + + O Me3Si BF3Et2O Scheme 5-12. Lewis Acid Mediated Sy nthesis of Two Cyclopentanone Analogs 5.5c,e

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117 5.3 Conclusion The general protocol enabled th e introduction of a variety of s ubstituents into the 4and 5position of imidazolidin-2-ones stereospecifically The low yielding convergent step using sBuLi, was a set back for the efficiency this met hod. General versatility and applicability to a robust combinatorial library was hampered and requires additional optimization of the convergent step. Three novel Bt trans-imidazolidin-2-ones were is olated and characterized. Two of the novel Bt trans-imidazoidin-2-ones were used to successful synthesize four novel cyclic ketone derivatized tetrasubstituted trans-imidazolidin-2-ones. 5.4 Experimental Section Melting points were determined on a capillary point apparatus equi pped with a digital thermometer. The NMR spect ra were obtained in CDCl3 with TMS as the internal standard for 1H (300 MHz) or the solvent as the internal standard for 13C (75 MHz). Tetrahydrofuran was freshly distilled from benzophe none and sodium metal prior to use. Dichloromethane was freshly distilled from sodium metal prior to use. Chemicals were employed as supplied. 5.4.1 Preparation of Imines Imines 5.2ad were prepared from their corresponding aniline and aldehyde. Anilines (25 mmol) and aldehydes (25 mmol) were mixed together in toluene ( 125mL) and heated to reflux. The azeotropic removal of water was performed using a Dean-Stark apparatus. Toluene was removed under vacuum. The crude was dissolved in hexane, filtered, and concentrated to obtain the pure imines. N-(4-Chlorobenzyliden e)aniline (5.2a). (99% yield) White microc rystals (from ethyl acetate / hexanes) mp 61 C (mp 60 C)lit.[05T11148]. 1H NMR 7.17 (br s, 3H), 7.30.45 (m, 4H), 7.77 (d, J = 7.0 Hz, 2H), 8.33 (s, 1H). 13C NMR 120.8, 126.1, 128.9, 129.1, 129.9, 134.6, 137.2, 151.5, 158.7. Anal. Calcd. for C13H10ClN: C, 72.40; H, 4.67; N, 6.49. Found: C, 72.13; H, 4.55; N, 6.39.

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118 N-(4-Methylbenzylidene)-aniline (5.2b). (92% yield) Yellow needles (from hexanes) mp 42 43 C (mp 42 C)lit.[06OL3175]. 1H NMR 2.34 (s, 3H), 7.07.20 (m, 5H), 7.27.32 (m, 2H), 7.71 (d, J = 7.7 Hz, 2H), 8.33 (s, 1H). 13C NMR 21.6, 120.8, 125.7, 128.8, 129.1, 129.5, 133.6, 141.8, 152.2, 160.4. Anal. Calcd. for C14H13N: C, 86.11; H, 6.71; N, 7.17. Found: C, 86.69; H, 6.82; N, 7.04. N-(4-Fluorophenyl)-(4-methylb enzylidene)-amine (5.2c). (98% yield) Or ange needles (from hexanes) mp 67 C (mp 67 C)lit.[72JA9113]. 1H NMR 2.40 (s, 3H), 7.04 (t, J = 8.4 Hz, 2H), 7.14.18 (m, 2H), 7.25 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 8.36 (s, 1H). 13C NMR 21.6, 115.8 (d, JCF = 22.3 Hz), 122.2 (d, JCF = 8.0 Hz), 128.7, 129.5, 133.4, 141.9, 148.1, 160.1, 161.0 (d, JCF = 244.5 Hz). Anal. Calcd. for C14H12FN: C, 78.85; H, 5.67; N, 6.57. Found: C, 78.68; H, 5.85; N, 6.30. N-Benzylidene-4-methoxybenzenamine (5.2d). (99% yield) White plates (from hexanes) mp 68 C (mp 68 C)lit.[05JOC5665]. 1H NMR 3.75 (s, 3H), 6.88 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.39.40 (m, 3H), 7.83.84 (m, 2H), 8.41 (s, 1H). 13C NMR 55.3, 114.2, 112.1, 128.5, 128.6, 130.9, 136.2, 144.6, 158.2, 158.3. Anal. Calcd. for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.24; H, 6.23; N, 6.55. 5.4.2 Preparation of Bt-Intermediates The Boc-protection: Triethylamine (150 mmol) was a dded to a solution of amine (150 mmol) in DCM (400 mL) at 0 C. The Boc-anhydr ide (150 mmol) was dissolved in a separate portion of DCM (150 mL) and added to the reac tion mixture using an addition funnel over 20 min. The solution was keep at 0 C for 1 h and warmed overnight. If necessary column chromatography purification (SiO2, hexane = 100%) could be executed, to yield the pure intermediates The Bt-intermediates using pa raformaldehyde (Method 1): The tert-Butylfuran-2ylmethylcarbamate (25.46 g, 129.1 mmol), 1H-benzotriazole (15.38 g, 129.1 mmol), paraformaldehyde (3.87 g, 129.1 mmol), and p-toluenesulfonic acid m onohydrate (0.61 g, 3.2 mmol) were mixed together in toluene (750 mL). The reaction mixture wa s heated under reflux, equipped with a Dean-Stark apparatus for 5h. Column chromatography (SiO2, hexane:DCM = 1:1) was performed to yield benzot riazol-1-ylmethyl furan-2-ylmethyl tert-butyl carbamate (30.6 g, 93.2 mmol) 72% yield.

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119 The Bt-intermediates using BtCH2OH (Method 2): The crude N-Boc amines (100 mmol), and BtCH2OH (100 mmol) were mixed together in tolu ene (500 mL) and heated to 115 C, or fully dissolved, and removed from the heat source. At this point, p-toluenesulfonic acid monohydrate (~480 mg), was quickly added. Direct ly afterwards the formation of water was seen in the reaction flask and azeotropic remova l of water was performe d with a Dean-Stark apparatus over 3h. The crude material was heated in diethyl ether and filtered. The solvent was evacuated to yield pure Bt-intermediates. Benzotriazol-1-ylmethyl furan-2-ylmethyl tert-butyl carbamate (5.3a). (Amide Tautomers) (Method 1, 72% yield) White prisms (from DCM), mp 80 C. 1H NMR 1.50.61 (m, 9H), 4.40.50 (m, 2H), 6.10.16 (m, 2H), 6.21 (s, 1H ), 6.27 (s, 1H), 7.29 (s, 1H), 7.34.40 (m, 1H), 7.46.51 (m, 1H), 7.90 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H). 13C NMR 28.1, 42.1, 57.6, 81.6, 108.4, 110.2, 110.9, 119.6, 124.2, 127.7, 132.4, 142.3, 146.2, 150.3, 154.8. Anal. Calcd. for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06. Fo und: C, 62.47; H, 6.20; N, 16.96. Benzotriazol-1-ylmethyl benzyl tert-butyl carbamate (5.3b). (Amide Tautomers) (Method 2, 70% yield) White plates (from hexanes) mp 126 C (mp 126 C)lit.[01JOC2858]. Benzotriazol-1-ylmethyl propyl tert-butyl carbamate (5.3c). (Amide Tautomers) (Method 2, 71% yield) White needles (fro m diethyl ether) mp 98 C. 1H NMR 0.82 (t, J = 7.0 Hz, 3H), 1.35.60 (m, 11H), 3.21 (t, J = 7.0 Hz, 2H), 6.13 (s, 2H), 7.35.40 (m, 1H), 7.46.51 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H). 13C NMR 11.0, 21.3, 28.1, 47.6, 58.5, 80.9, 111.1, 119.5, 124.1, 127.6, 132.3, 146.2, 155.4. Anal. Calcd. for C15H22N4O2: C, 62.05; H, 7.64; N, 19.30. Found: C, 61.87; H, 7.81; N, 19.54. 5.4.3 Preparation of Bt-Imidazolidin-2-ones Compound 3.3b (2.0 g, 5.9 mmol) was dissolved in THF (40 mL), in a dry schlenk flask under nitrogen and cooled to 78 C. s-Butyllithium (1.4 M, 4. 8 mL) was added slowly in 1.6 mL in 3 portions over 3 h. Lithiation, at 78 C, was allowed for a further 3 h. A solution of imine (6.6 mmol) in THF (10mL) was slowly adde d. The reaction was le ft to warm overnight and stirred at rt. Quenched w ith saturated aq ammonium chlori de, and extracted with 2 portions of ethyl acetate. The combined organic laye rs were washed using brine, dried over anhyd

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120 sodium sulfate. Column ch romatography purification (SiO2, hexane:ethyl acetate = 9:1) afforded the desired products [1-(4-Chlorophenyl)-2-methyl butyl]phenylamine (5.4a). (Mixture of Diastereomers) (31% yield) Brown oil. 1H NMR 0.74-0.85 (m, 6H), 1.02.17 (m, 1H), 1.34.50 (m, 1H), 1.60 1.70 (m, 1H), 3.95 (br s, 1H), 4.07 (d, J = 5.6 Hz, 0.61H), 4.17 (d, J = 4.9 Hz, 0.39H), 6.35 (d, J = 7.7 Hz, 2H), 6.52 (t, J = 7.0 Hz, 1H), 6.93.99 (m, 2H), 7.09.16 (m, 4H). 13C NMR 11.7, 11.9, 14.2, 15.9, 25.2, 26.7, 41.4, 41.7, 60.9, 61.9, 113.1, 117.2, 128.3, 128.4, 128.6, 129.0, 132.2, 132.3, 140.8, 141.5, 147.3. Anal. Calcd. for C17H20ClN: C, 74.57; H, 7.36; N, 5.12. Found: C, 74.77; H, 7.51; N, 5.11. N-(4-Methoxyphenyl)-1-phenyl-2methyl-1-aminobutane (5.4b)lit.[72BSC3426]. (Mixture of Diastereomers) (39% yield) Brown oil. 1H NMR 0.73.84 (m, 6H), 1.00.17 (m, 1H), 1.34 1.50 (m, 1H), 1.62.68 (m, 1H), 3.52 (s, 3H), 3.65 (br s, 1H), 4.01 (d, J = 5.6 Hz, 0.43H), 4.11 (d, J = 4.9 Hz, 0.57H), 6.32 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 9.1 Hz, 2H), 7.02.10 (m, 1H), 7.12.17 (m, 4H). 13C NMR 11.7, 11.9, 14.3, 15.9, 25.3, 26.7, 41.4, 41.8, 55.5, 62.2, 63.3, 114.1, 114.2, 114.6, 126.4, 126.6, 126.9, 127.3, 127.9, 128.1, 141.9, 142.4, 143.1, 151.5. Anal. Calcd. for C18H23NO: C, 80.25; H, 8.61; N, 5.20. F ound: C, 79.95; H, 8.93; N, 5.00. 2-Phenyl-2-(4-methoxyphenylamino)-1-b enzotriazol-1-yl-ethyl benzyl tert-butyl carbamate (5.4c). (11% yield) Clear oil. Anal. Calcd. for C33H35N5O3: C, 72.11; H, 6.42; N, 12.74. Found: C, 72.11; H, 6.53; N, 12.62. (4S,5S)-4-(Benzotriazol-1-yl)-3-benzyl-1-(4-met hoxyphenyl)-5-phenylimidazolidin-2-one (5.4d). (28% yield) White needles (from hexanes) mp 155 C (mp 155 C)lit.[01JOC2858]. 1H NMR 3.70 (s, 3H), 3.84 (d, J = 15.4 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H), 5.31 (d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 9.1 Hz, 2H), 7.07.19 (m, 7H), 7.24-7.33 (m, 3H), 7.34.42 (m, 5H), 8.07 (d, J = 8.4 Hz, 1H). 13C NMR 45.4, 55.3, 64.5, 75.4, 109.6, 114.2, 120.4, 122.4, 124.6, 125.9, 127.7, 128.1, 128.5, 129.0, 129.4, 130.5, 130.7, 134.9, 137.5, 146.8, 156.2, 156.4. Anal. Calcd. for C29H25N5O2: C, 73.25; H, 5.30; N, 14.73. Found: C, 73.12; H, 5.53; N, 14.88. (4S,5S)-4-(Benzotriazol-1-yl)-3-benzyl-1-phenyl-5-p-tolylimidazolidin-2-one (5.4e). (24% yield) White microcrystals (f rom hexanes), mp 72 C. 1H NMR 2.30 (s, 3H), 3.84 (d, J = 15.5 Hz, 1H), 4.85 (d, J = 15.4 Hz, 1H), 5.32 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 2.1 Hz, 1H), 7.02 7.15 (m, 9H), 7.25.42 (m, 6H), 7.55 (d, J = 7.7 Hz, 2H), 8.05.08 (m, 1H). 13C NMR 21.1, 45.4, 63.7, 75.7, 109.6, 119.7, 120.5, 123.9, 124.6, 125.7, 127.8. 128.2, 128.5, 129.1, 130.2, 134.6, 135.1, 137.9, 139.0, 146.9, 155.9, 157.7. Anal. Calcd. for C29H25N5O: C, 75.79; H, 5.48; N, 15.24. Found: C, 74.62; H, 5.90; N, 14.22. (4S,5S)-4-(Benzotriazol-1-yl)-3-benzyl-1-(4-fluorophenyl)-5-p-tolylimidazolidin-2-one (5.4f). (23% yield) White microcrystal s (from hexanes), mp 72 C. 1H NMR 2.31 (s, 3H), 3.83 (d, J = 15.4 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H), 5.27 (d, J = 2.8 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 6.96 (t, J = 9.1 Hz, 2H), 7.03.17 (m, 9H ), 7.29.50 (m, 5H), 8.08 (d, J = 7.7 Hz, 1H). 13C NMR 21.1, 45.4, 64.1, 75.4, 109.4, 115.8 (d, JCF = 22.3 Hz), 120.6, 121.8 (d, JCF = 8.0 Hz),

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121 124.6, 125.7, 127.9, 128.2, 128.5, 130.2, 134.3, 134.9, 139.2, 146.9, 156.0, 159.2 (d, JCF = 243.9 Hz). Anal. Calcd. for C29H24FN5O: C, 72.94; H, 5.07; N, 14.67. Found: C, 72.62; H, 5.19; N, 14.38. (4S,5S)-4-(Benzotriazol-1-yl)-1-phenyl-3-propyl-5-p-tolylimidazolidin-2-one (5.4g). (24% yield) White microcrystals (f rom hexanes), mp 115 C. 1H NMR 0.81 (t, J = 7.0 Hz, 3H), 1.34.50 (m, 2H), 2.34 (s, 3H), 2.65. 74 (m, 1H), 3.52.62 (m, 1H), 5.30 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 7.02 (t, J = 7.0 Hz, 1H), 7.15.27 (m, 6H ), 7.38.46 (m, 3H), 7.54 (d, J = 7.7 Hz, 2H), 8.12 ( d, J = 7.7 Hz, 1H). 13C NMR 10.9, 20.6, 21.1, 42.7, 63.6, 76.4, 109.7, 119.2, 120.6, 123.6, 124.7, 125.5, 128.8, 129.0, 130.3, 130.5, 134.7, 137.9, 139.0, 147.1, 156.1. Anal. Calcd. for C25H25N5O: C, 72.97; H, 6.12; N, 17.02. F ound: C, 72.37; H, 6.71; N, 16.37. 5.4.4 Preparation of Cyclic Ketone Tetrasubstituted trans-Imidazolidin-2-ones A solution of Bt trans-imidazolidin-2-one (0.5 mmol) in DCM (10 mL) was prepared under nitrogen and cooled to 78 C. Lewis acid (BF3Et2O, 2.5 mmol) was added and the solution was stirred for 30 min. Cyclohexenyl oxytrimethylsilane (2.5 mmol) wa s added and stirred overnight. A precipitate appeared in the final reaction mixt ure. Quenched with saturated aq ammonium chloride and extracted with two portions of ethyl acetate. Combined organic layers were washed with brine, dried over anhyd sodi um sulfate. Column chroma tography Si-Gel (hexane:ethyl acetate = 9:1) eluted the desired products. (4S,5S)-1-Benzyl-3-(4-methoxyphenyl)-5-(2-oxocyc lohexyl)-4-phenylimidazolidin-2-one hydrate (5.5a)lit.[01JOC2858]. (70% yield) Clear oil. 1H NMR 1.21.60 (m, 2H), 1.83.97 (m, 2H), 2.02.14 (m, 2H), 2.30.35 (m, 1H), 2. 52.56 (m, 1H), 3.66 (s, 3H), 3.92 (t, J = 2.8 Hz, 1H), 4.26 (d, J = 14.7 Hz, 1H), 4.61 (d, J = 3.5 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 6.73 (d, J = 9.1 Hz, 2H), 7.18.35 (m, 2H). 13C NMR 24.7, 26.4, 27.5, 42.0, 47.5, 54.3, 55.2, 60.2, 63.7, 113.9, 121.8, 126.0, 127.2, 127.9, 128.2, 128.7, 128.8, 132.6, 137.7, 140.8, 155.5, 158.4, 210.2. Anal. Calcd. for C29H32N2O4: C, 73.70; H, 6.82; N, 5.93. Fou nd: C, 72.81; H, 6.44; N, 5.93. (4S,5S)-1-Benzyl-5-(2-oxocyclohexyl)-3-phenyl-4-p-tolylimidazolidin-2-one (5.5b). (Conformational Isomers) (57% yield) White microcrystals (from hexanes), mp 78 C. 1H NMR 1.36.63 (m, 4H), 1.87.38 (m, 7H), 2.42.57 (m, 1H), 3.84.92 (m, 1H), 4.21.27 (m, 1H), 4.63.73 (m, 2H), 6.92.34 (m, 12H), 7.41.47 (m, 2H). 13C NMR 21.1, 24.8, 26.6, 27.7, 42.1, 47.7, 54.8, 60.3, 63.2, 118.2, 119.2, 122.2, 122.7, 125.8, 125.9, 127.3, 128.0, 128.3, 128.5, 128.6, 128.7, 128.8, 128.4, 129.6, 137.6, 137.7, 139.6, 158.1, 210.4. Anal. Calcd. for C29H30N2O2: C, 79.42; H, 6.89; N, 6.39. Fou nd: C, 79.13; H, 6.98; N, 6.53. (4S,5S)-1-Benzyl-3-(4-fluorophenyl)-5-(2-oxocyclohexyl)-4-p-tolylimidazolidin-2-one (5.5c). (Conformational Isomers) (70% yield) White microcrystals (from hexanes), mp 84 C. 1H NMR 1.38.67 (m, 4H), 1.90.40 (m, 7H), 2.40. 60 (m, 1H), 3.94 (br s, 1H), 4.33 (d, J =

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122 15.4 Hz, 1H), 4.65 (d, J = 3.5 Hz, 1H), 4.70 (d, J = 15.4 Hz, 1H), 6.92 (t, J = 8.4 Hz, 2H), 7.06 (br s, 3H), 7.26.44 (m, 8H). 13C NMR 20.9, 24.7, 26.5, 27.6, 42.0, 47.5, 54.0, 60.5, 63.2, 115.2 (d, JCF = 22.3 Hz), 121.4 (d, JCF = 8.0 Hz), 125.9, 128.2, 128.7, 129.6, 137.5 (d, JCF = 3.4 Hz), 137.8, 158.2, 158.5 (d, JCF = 242.2 Hz), 210.1. Anal. Calcd. for C29H29FN2O2: C, 76.29; H, 6.40; N, 6.14. Found: C, 76.08; H, 6.68; N, 6.22. (4S,5S)-1-Benzyl-5-(2-oxocyclopentyl)-3-phenyl-4-p-tolylimidazolidin-2-one (5.5d). (86% yield) White microcrystals (f rom hexanes), mp 78 C. 1H NMR 1.64.36 (m, 10H), 3.85 (br s, 1H), 4.17 (d, J = 14.7 Hz, 1H), 4.56 (d, 15.4 Hz, 1H ), 4.76 (br s, 1H), 6.96.09 (m, 5H), 7.15.30 (m, 7H), 7.42 (d, J = 7.7 Hz, 2H). 13C NMR 20.2, 21.1, 23.6, 38.2, 47.7, 53.1, 60.9, 63.2, 119.6, 123.0, 125.8, 127.4, 128.3, 128.5, 128.6, 129.7, 136.9, 137.1, 138.0, 139.2, 158.3, 218.0. Anal. Calcd. for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found: C, 78.90; H, 6.94; N, 6.77. (4S,5S)-1-Benzyl-3-(4-fluorophenyl)-5-(2-oxocyclopentyl)-4-p-tolylimidazolidin-2-one (5.5e). (47% yield) White microcrystal s (from hexanes), mp 72 C. 1H NMR 1.60.34 (m, 10H), 3.87 (t, J = 4.2 Hz, 1H), 4.18 (d, J = 15.4 Hz, 1H), 4.53 (d, J = 15.4 Hz, 1H), 4.70 (d, J = 4.2 Hz, 1H), 6.89 (t, J = 9.1 Hz, 2H), 6.99.08 (m, 4H), 7. 20.24 (m, 5H), 7.32.37 (m, 2H). 13C NMR 20.2, 21.0, 23.5, 38.1, 47.8, 52.7, 60.9, 63.4, 115.3 (d, JCF = 22.3 Hz), 121.6 (d, JCF = 8.0 Hz), 125.9, 127.4, 128.3, 128.5, 129.7, 135.1 (d, JCF = 2.9 Hz), 136.5, 137.0, 138.2, 158.4, 158.7 (d, JCF = 242.8 Hz), 217.8. Anal. Calcd. for C28H27FN2O2: C, 75.99; H, 6.15; N, 6.33. Found: C, 75.71; H, 6.41; N, 6.56.

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123 CHAPTER 6 GENERAL CONCLUSIONS My objective in doing this work was to investigate certain aspects of the chemistry of heterocyclic compounds in relati on to amino acids, lactams, and ionic liquids. A common theme that appeared throughout this wo rk was that of the amide bond. The serendipitous study and development of interesting synthetic organic ch emistry, including some green chemistry, will hopefully lead to novel molecules for the benefit of life, science, and society. My critical findings provide a solid framework for future investigations in these related areas. Peptidic -triphenylphosphoranylidene esters and am ides have attracted considerable attention as important intermediates for the preparation of peptidic -keto esters and of -keto amides, compounds which are potential inhibito rs of proteolytic enzymes and leukotriene A4 hydrolases. Therefore, the development of an e xpedient, versatile method to C-acylate P-ylides with chiral amino acid derivativ es for N-protected peptidic -triphenylphosphoranylidene esters is desirable. The N-Protected N-acylbenzotriazoles C-acylation of P-ylides with microwave irradiation adds to the robust list of N-acylbenzotriazoles applications. In Chapter 2, the preparati on of N-protected peptidic -triphenylphosphoranylidene esters from N-(Bocor Cbz--aminoacyl)benzotriazoles was de monstrated under microwave irradiation without base. Rete ntion of chirality was demons trated by the synthesis of (LL)and (DL)diastereomers and comparison of their optical rotation and NMR spectra. The C-acylation utilized versatile N-protected (-aminoacyl)benzotriazoles avoi ding the use of base and microwave irradiation reduced reaction times a nd solvent. Furthermore this procedure was found to be a convenient route to the te tramic acid ring system in Chapter 3. Although DOT-pyrrolidines are crysta lline, soluble in halogenate d and alcoholic solvents, and have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings they have

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124 received little of the attention given to tetram ic acids. The possible tr ansformation the 2,4-dioxo3-triphenylphosphoranylidene (DOT) moiety provides when directly incorpor ated as part of a heterocyclic ring is unexplored and of consider able interest. Although the Wittig mechanism is intuitively understood as a center mechanism, the inherent stability of the DOT moieties requires further investigation. In Chapter 3, the first convenient met hod to 2,4-dioxo-3-trip henylphosphoranylidene pyrrolidines, 1,3-dioxo-2-tri phenylphosphoranylidene tetrahyd ropyrrolizine, 2,4-dioxo-3triphenylphosphoranylidene pipe ridine, 5-amino-4-triphenylp hosphonio-2,4-dihydropyrrol-3-one bromides, and 3-ammonio-2-triphenylphosphoni otetrahydropyrrolizin1-one dibromide was described. The developed Method I was versatile, inexpensive, re producible, and hi gh yielding. Racemization was caused by HBr, how ever the novel linear salts c ould be cleanly N-methylated or neutralized without cycliza tion, or cyclized for distabil ized triphenylphosphoranylidene substituted rings. Crystalline DOT-pyrrolidines, are stable to aldehydes, strong bases, and high temperatures, and represent versatile intermediates. The 13C-NMR chemical shifts and JPC values provide valuable informa tion for the analysis of distab ilized triphenylphosphoranylidene systems, JPC couplings increased with less partial positive character and decreased with more partial positive character on the respective carbons. Furthermore in Chapter 3, we developed four novel applications for DOT -pyrrolidines. The first highly versatile 3,3-dibromopyrrolidine-2,4dione with a racemic stereocenter, was obtained without Lewis acid. The first 3,3-dibromo5-hydroxypyrrolidine-2,4-dione, was obtained and unambiguously identified by X-ra y crystallography. 4-Azido-3bromopyrrol-2-one was obtained, where previously reported chloro derivatives were used to make -lactams, and bromo derivatives were trapped with triphenylphosphine to make a Staudinger reagent. The first 4-

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125 benzotriazolpyrrol-2-one was obtained. In conclusion the versatil e stable 2,4-dioxo-3triphenylphosphoranylidene can be practically formed on rings and easily transformed into novel molecules. The properties of cation and/or an ion within the ionic pair were independently modified, then metathesis could generate new functional materials, which retain the core f eatures of the IL state of matter. The regiospecific N-alkylation strategy provided the more sterically hindered 1alkylimidazoles for the production of newly synthe sized anions and cations. Over the last several years, typical properties of ionic liquids (ILs) such as high ion c ontent, liquidity over a wide temperature range, low viscosity, limitedvolatility, and high i onic conductivity have proven to be important drivers supporting numerous advances beyond the initial investigations of ILs as liquid electrolytes. In Chapter 4, N-alkylation of 4-alkyl and 2,4-dialkylimidazole with alkyl bromides provided a regiomeric mixture of 1,4-disubstituted and 1,5disubstituted imidazole. Protection of the N1 with benzoyl allows regi oselective N-alkylation of the 3-positi on, with triflate quaternization. Debenzoylation and dequarterniza tion with aq base afforded th e more sterically hindered 1alkylated imidazoles. Substituted heterocycles con tinue to be a powerful tool in the search for energetic IL compounds. The synthesis of tetrasubstituted trans-imidazolidin-2-ones utilized a general benzotriazole protocol to enable the introduction of a variety of substituents into th e 4and 5-position of imidazolidin-2-ones with trans stereochemistry. The extension of the previous work allowed the formation of a vicinal diamine and urea in on e simultaneous step. The presences of two potentially bioactive properties encourages the e xploration of vicinal diam ino tethered ureas and

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126 unsaturated imidazol-2-ones, or saturated imidazolidin-2-ones in particular for medicinal screening. In Chapter 5, the general protocol enabled the in troduction of a variety of substituents into the 4and 5-position of imidazolidin -2-ones stereospecifi cally. The low yielding convergent step using s-BuLi, was a set back for the efficiency this method. General versatility and applicability to a robust combinatorial library was hampered and requires additional optimization of the convergent step. Three novel Bt trans-imidazolidin-2-ones were is olated and characterized. Two of the novel Bt trans-imidazoidin-2-ones were used to successful synthesize four novel cyclic ketone derivatized tetrasubstituted trans-imidazolidin-2-ones.

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127 REFERENCES The reference citation system empl oyed throughout this dissertati on is that from Advances in Heterocyclic Chemistry (vol. 92) Academic Pre ss, 2006 (Ed. A. R. Katritzky). Each time a reference is cited a number-letter code is designated to the corre sponding reference with the first two, or four if before 1910, nu mbers indicating the year followed by the letter code of the journal and the page number in the end. Additional notes to this reference system are as follows: (i) Each reference code is followed by the conventional literatu re citation in the Advances Heterocyclic Chemistry style. (ii) Less commonly used Books and journals are coded as MI for miscellaneous. (iii) The list of the reference is arrange accordi ng to the designated c ode in the order of (a) year; (b) journal in alphabe tical order; (c) page number. (iv) The ACS Style Guide was frequently used as a general reference [86MI1]. (v) The chapter(s) containing the referen ce is superscripted after the period. 10JCS1814 F. L. Pyman, J. Chem. Soc., Trans. 97 1814 (1910).1,4 13CB1913 O. Gerngross, Chem. Ber. 46 1913 (1913).4 22JCS2616 F. L. Pyman, J. Chem. Soc., Trans. 121 2616 (1922).1,4 24JCS1431 C. E. Hazeldine, F. L. Pyman, and J. Winchester, J. Chem. Soc. 125 1431 (1924).1,4 25JCS573 W. G. Forsyth and F. L. Pyman, J. Chem. Soc., Trans. 127 573 (1925).1,4 50JA1236 J. A. King and F. H. McMillan, J. Am. Chem. Soc. 72 1236 (1950).3 53MI1 K. Hofmann, Imidazole and Its Derivatives Interscience Publishers Inc., New York., p. 3. (1953).1 54JCS850 R. N. Lacey, J. Chem. Soc. 850 (1954).3

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141 BIOGRAPHICAL SKETCH Adam Spencer Vincek was born in 1975, in Topeka, KansasUSA. Adam spent a majority of his formative years in Pennsylva niaUSA. He studied in Su rreyEngland from 1991 to 1992. He began his undergraduate education at the Univ ersity of North Carolina at Chapel Hill as continuing studies student in 1995. During his undergraduate studi es he received two summer internships where he develope d practical skills in organic synthesis, in 1998 at UABBirmingham, Alabama, and in 2000 at a pharmaceutic al company in Baltimore, Maryland. He was awarded a B.Sc. chemistry degree in 2000. Then, he worked professionally in Munich, Germany, from 2001 to 2003 conducting organic synthe sis with a biotech company, and was first introduced to hydroxybenzotriazole in order to ma ke biotin hydroxamic acid. He was accepted into the Ph.D. program at the University of Florida in Ga inesville in January 2004.