Novel Strategies in the Chemistry of N-Amino Heterocycles

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Novel Strategies in the Chemistry of N-Amino Heterocycles
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english
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Jishkariani, Davit
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University of Florida
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Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Katritzky, Alan R
Committee Members:
Mcelwee-White, Lisa A
Aponick, Aaron Steven
Ghiviriga, Ion
James, Margaret O

Subjects

Subjects / Keywords:
acylation -- benzotriazole -- betaines -- carbenes -- copper -- cycloadditions -- heterocycles -- nhc -- peptides -- spirodithiohydantoins -- ylids -- zwitterions
Chemistry -- Dissertations, Academic -- UF
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theses   ( marcgt )
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Abstract:
The theme of this work is to develop novel methodologies for the synthesis of various organic compounds. Chapter 1 provides a general introduction to the subsequent chapters and the methods used throughout the thesis. Chapter 2 describes the utility of N-acylbenzotriazoles for the synthesis of ibuprofen and naproxen prodrugs. Chapters 3, 4, and 5 examine the chemistry of N-amino heterocycles. Chapter 3 describes the synthesis of 1-aminobenzimidazoles and their transformations towards zwitterionic betaines and spirocyclic dithiohydantoins mediated by N-heterocyclic carbenes (NHC). The reversible thermal equilibrium of these spirocyclic dithiohydantoins is presented in Chapter 4, where the equilibrium is studied by various analytical methods. Chapter 5 focuses on the regioselective synthesis of pyrazolo5,1-c-1,2,4-triazoles. Synthesis of pyrazolo5,1-c-1,2,4-triazoles was achieved via one-pot Cu (I) catalyzed reactions between 1,2,4-triazolium N-imides and terminal alkynes. The scope of alkyne substrates together with the effect of variations in the 1-alkyl substituent and the nature of the leaving group was examined. Conclusions, summary of the achievements and final remarks are presented in Chapter 6.
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In the series University of Florida Digital Collections.
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Includes vita.
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by Davit Jishkariani.
Thesis:
Thesis (Ph.D.)--University of Florida, 2012.
Local:
Adviser: Katritzky, Alan R.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-08-31

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1 NOVEL STRATEGIES IN THE CHEMISTRY OF N AMINO HETEROCYCLES By DAVIT JISHKARIANI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOC TOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2012

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2 2012 Davit Jishkariani

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3 To my m o ther Liana Kukhalashvili, my sister Tamuna Jishkariani and to the memory of my f ather Murman Jishkariani

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4 ACKNOWLEDGMENTS I would like to thank God for all the blessings he brings into my life. I would like to express my deepest gratitude to my advisor, Professor Alan R. Katritzky, for his excellent guidance, support and patience I am grateful to my scientific committee members (Professor Lisa McElwee White, P rof essor Aaron Aponick, Dr. Ion Ghiviriga, and Professor Margaret O. James) for their help and assistance. I am thankful to Dr. C. Dennis Hall for all his help and support during these years. I am also grateful to all members of p who have contributed to this work: Dr. Tamari Narindoshvili, Dr. Rajeev Sakhuja, Dr. Alexander Oliferenko, Mr. Zuoquan Wang and two undergraduates Blake Tomlin and David Leino as well as to the Department of Chemistry professors at University of Florida Also I would like to express my gratitude to Professor Bezhan Chankvetadze, Professor Guram Supatashvili and Professor Shota Sidamonidze for their help, teaching and encouragement during my at Iv. Javakhishvili Tbilisi state Univer sity. I would like to thank all my friends : Mirna El Khatib, Dr. Siva Panda, Dr. Ilker Avan, Dr. Bogdan Draghici, Khanh Ha and Dr. Maia Tsikolia for the support they gave me during th ese years. Special thanks go to Mirna for the help and encouragement she gave me during th ese years and all the enjoyable time we ha d together. Finally, I would like to express my gratitude to my family, my mother and my sister for their love, prayers, support and constant encouragement

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF SCHEMES ................................ ................................ ................................ ........ 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 10 ABSTRACT ................................ ................................ ................................ ................... 15 CHAPTER 1 GENERAL INTRODUCTION ................................ ................................ .................. 17 2 CONVENIENT SYNTHESIS OF AMINOACYL, DIPEPTIDOYL AND ESTER DERIVATIVES OF IBUPROFEN AND NAPROXEN ................................ ............... 21 2.1 Introduction ................................ ................................ ................................ ....... 21 2.2 Results and Discussion ................................ ................................ ..................... 22 2.2.1 Preparation of Benzotriazole Activated Ibuprofen (2.3+2.3') an d Naproxen 2.4 ................................ ................................ ................................ 23 2.2.2 Preparation of DL Ibuprofen and L Naproxen Amino Acid Conjugates ... 23 2.2.3 Preparation of Ibuprofen and N aproxen Stigmasteryl and Estronyl Ester Prodrugs ................................ ................................ .............................. 26 2.2.4 Preparation of Ibuprofen and Naproxen Prodrugs with Protected Sugars ................................ ................................ ................................ ........... 27 2.3 Experimental Section ................................ ................................ ........................ 28 2.3.1 General Methods ................................ ................................ ..................... 28 2.3.2 General Procedure for the Preparation of Benzotriazole Activated Ib uprofen and Naproxen (2.3+2.3'), 2.4 ................................ ........................ 28 2.3.3 General Procedure for the Preparation of Ibuprofen and Naproxen Amino Acids ( 2. 6a+ 2. 6a ) ( 2. 6f+ 2. 6f ), 2. 7a 2. 7g, ( 2. 7c+ 2. 7c ) ( 2. 7g+ 2. 7g ) and Di peptides 2. 8 2. 10 ................................ ................................ ............... 30 3 CARBENE MEDIATED TRANSFORMATIONS OF 1 (BENZYLIDENEAMINO)BENZIMIDAZOLES ................................ .......................... 40 3.1 Introduction ................................ ................................ ................................ ....... 40 3.2 Results and Discussion ................................ ................................ ..................... 41 3.3 Experimental Section ................................ ................................ ........................ 47 3.3.1 General Me thod for the Preparation of Imines 3.4a f ............................... 48

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6 3.3.2 General Method for Preparation of N (3 Butylbenzimidazol 3 ium 1 yl) 1 arylmethanimine Iodides 3. 6a f ................................ ............................. 49 3.3.3 General Method for the Preparation of NHC CS 2 Betaines 3. 9a c, 3. 10 ................................ ................................ ................................ ............... 52 3.3.4 General Method for Preparation of Spirocyclic Derivatives 3. 13a b ........ 53 3.3.5 General Method for Preparation of NHC RC(O) NCS Betaines 3. 15a c, 3. 16 ................................ ................................ ................................ ............... 54 3.3.6 General Method for Amination ................................ ................................ 56 4 REVERSIBLE DISSOCIATION OF SPIRODITHIOHYDANTOINS ......................... 59 4.1 Introduction ................................ ................................ ................................ ....... 59 4.2 Results a nd Discussion ................................ ................................ ..................... 60 4.2.1 NMR Study of the Formation of Zwitterionic Betaines From Spirodithiohydantoins ................................ ................................ .................... 60 4.2.2 NMR Study of the Formation of Parent Dithiohydantoin .......................... 64 4.2.3 In situ Formation and Trapping of NHC ................................ ................... 65 4.3. Experimental Section ................................ ................................ ....................... 67 4.3.1 General Methods ................................ ................................ ..................... 67 4.3.2 General Procedure for the Preparation of Spirodithiohydantoins 3.13a,b ................................ ................................ ................................ .......... 67 4.3.3 General Procedure for the Preparation of Benzimidazolium salts 3.6a,b ................................ ................................ ................................ ............ 67 4.3.4 General Procedure for the Preparation of Benzimidazole thiones 4.4a b From Spir odithiohydantoins 3.13a,b ................................ ........................... 67 4.3.5 General Procedure for the Preparation of Benzimidazole thiones 4.4a,b From Benzimidazolium Salts 3.6a,b ................................ ................... 68 5 CU (I) CATALYZED NOVEL, REGIOSELECTIVE SYNTHESIS OF PYRAZOLO[5,1 C] 1,2,4 TRIAZOLES ................................ ................................ ... 69 5.1 Introduction ................................ ................................ ................................ ....... 69 5.2 R esults and Discussion ................................ ................................ ..................... 70 5.3 Experimental Section ................................ ................................ ........................ 80 5.3.1 General Methods ................................ ................................ ..................... 80 5.3.2 General Procedure for the Preparation of 1,2,4 Triazolium Salts 5.2a c ................................ ................................ ................................ .................... 81 5.3.3. General Procedure for the Preparation of 1,2,4 Triazolium N Imides 5.3a d ................................ ................................ ................................ ............ 81 5.4.4. General Method for the Preparation of Pyrazolo[5,1 c ][1,2,4]triazoles 5.7a g ................................ ................................ ................................ ............ 84 6 CONCLUSIONS AND SUMMARY OF ACHIEVEMENTS ................................ ....... 88 LIST OF REFERENCES ................................ ................................ ............................... 90 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 99

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7 LIST OF TABLES Table page 2 1 Synthesis of DL ibuprofen amino acid conjugates (2.6a+2.6a ') (2.6f+2.6f') ..... 24 2 2 Synthesis of L naproxen amino acid conjugates ................................ ................ 25 3 1 Synthesis of 1 (benzylidineamino)benzimidazole 3.4a f and 1 (benzylidineamino)benzimidazolium iodides 3.6a f ................................ ............ 42 3 2 Synthesis of NHCCS 2 beta ines 3.9a c, 3.10 ................................ ..................... 43 3 3 Synthesis of spirodithiohydantoins 3.13a b ................................ ........................ 44 3 4 Synthesis of zwitterionic NHC RNCS betaines 3.15a c, 3.16 ............................. 46 3 5 Amination of 1 aminobenzimidazole 3. 2 and imines 3. 4a f ................................ 47 5 1 Synthesis of 1,2,4 triazoliun N imides ................................ ................................ 71 5 2 Optimization of reaction conditions ................................ ................................ ..... 72 5 3 Synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles ................................ ........................ 73 5 4 Reactions of 1,2,4 triazolium N imide 5.3a with electron deficient dipolarophiles 5.6f j ................................ ................................ ............................ 77

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8 LIST OF FIGURES Figure page 3 1 X ray structure of 3. 9a. ................................ ................................ ....................... 43 3 2 X ray structure of 3. 13a. ................................ ................................ ..................... 45 3 3 X ray structure of 3. 16. ................................ ................................ ....................... 46 4 1 Structural motifs of hydantoin, thiohydantoin and dithiohydantoin. ..................... 59 4 2 Selected examples of biologically active hydantoins and dithiohydantoins. ....... 59 4 3 Spirodithiohydantoin scaffold. ................................ ................................ ............. 60 4 4 Variation of [4.1a]:[3.13a] ratios with temperature and time. .............................. 61 4 5 NMR study of [4.1a]:[3.13a] ratios with temperature and time. ........................... 62 4 6 Expanded aliphatic region of NMR study of [4.1a]:[3.13a] ratios with temper ature and time. ................................ ................................ ........................ 63 4 7 Direct insertion probe (DIP EI) mass spectrometry analysis of reaction mixture. ................................ ................................ ................................ ............... 64 4 8 Formation of par ent 3.13a with and without presence of excess isopropyl isothiocyanate. ................................ ................................ ................................ .... 65

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9 LIST OF SCHEMES Scheme page 1 1 Synthesis of ibuprofe n and naproxen prodrugs. ................................ ................. 18 1 2 Synthesis of NHC zwitterionic betaines and spirocyclic derivatives. ................... 19 1 3 R eversible dissocia tion reaction of spirodithiohydantoins. ................................ .. 19 1 4 Synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles. ................................ ....................... 20 2 1 Synthesis of benzotriazole activated ibuprofen (2.3+2.3') and naproxen 2.4. ..... 23 2 2 Synthesis of ibuprofen and naproxen dipeptides. ................................ ............... 26 2 3 Preparation of ibuprofen and naproxen stigmasteryl and estronyl ester derivatives. ................................ ................................ ................................ ......... 27 2 4 Preparation of ibuprofen and naproxen prodrugs with protected sugars. ........... 28 3 1 Synthesis of ( 1,3 dimethylbenzimidazol 3 ium 2 carbothioyl) isopropylazanide 3. 12. ................................ ................................ ........................ 44 4 1 Dissociation of the spirodithiohydantoins 3.13a. ................................ ................. 61 4 2 Reversible formation of zwitterionic betains 4.1a b and free NHCs 4.3a b ......... 65 4 3 Synthesis of novel 4.4a b from spirodithiohydantoins. ................................ ........ 66 4 4 Synthesis of novel 4.4a,b from 1 (benzylidineamino)benzimidazolium iodides 3.6a,b. ................................ ................................ ................................ ................ 66 5 1 Literature synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles. ................................ ....... 70 5 2 Proposed mechanism for the Cu (I) catalyzed regioselective synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles 5.7a g ................................ ................................ 76 5 3 Proposed mechanism for the reactions of 1,2,4 triazolium N imide 5.3a with propiolates 5.6f h. ................................ ................................ ............................... 78 5 4 Energy diagram for the formation of 5.8a. ................................ .......................... 80

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10 LIST OF ABBREVIATION S Alpha locant D Specific rotation Ac 2 O Acetic anhydride Ala Alanine AgOTf Silver triflate Ar Aryl Beta locant Bn Benzyl Boc t Butoxycarbonyl br Broad Bt Benzotriazol 1 yl Bu Butyl C Car bon Degree Celcius Calcd Calculated Cbz Carbobenzyloxy CDCl 3 Deuterated chloroform Cl Chlorine CS 2 Carbon disulfide Cu 2 Br 2 C o pper (I) Bromide CuOAc C o pper acetate Cys Cysteine Chemical shift in parts per million downfield from tetramethylsilane d Days; Douplet (spectra)

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11 D Dextrorotatory (right) DCC N N' Dicyclohexylcarbodiimide DCM Dichloromethane DMF Dimethylformamide DMSO Dimethylsulfoxide D 2 O Deuterium oxide EDC 1 Ethyl 3 (3 dimethylaminopro pyl) c arbodiimide (stands as an abbreviation for EDAC and EDCI as well) eq u iv Equivalent ESI Electrospray ionization Et Ethyl et al. And others Et 3 N Triethylamine EtOAc Ethyl acetate EtOH Ethanol g Gram(s) Gly Glycine h Hour H Hydrogen HCl Hydrochloric acid HOBt 1 Hydroxybenzotriazole HPLC High performance liquid chromatography HRMS High resolution mass spectrometry Hz Hertz J Coupling constant L Levorotatory (left)

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12 Leu Leucine Lit Literature m Multiplet M Molar Me Methyl MeCN Acetonitrile MeOH Methanol Met Methionine min Minute(s) MgSO 4 Magnesium sulfate mL Milliliter M ol Mole(s) mp Melting point MW Microwave m/z Mass to charge ratio N Nitrogen NaH Sodium hydride Na 2 CO 3 S odium carbonate NaOH Sodium hydroxide NHC N heterocyclic carbene NMR Nuclear magnetic resonance Ns Nosyl o Ortho locant O Oxygen OEt Ethoxy

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13 OH Hydroxyl group OMe M ethoxy p Para locant Ph Phenyl Phe Phenylalanine ppm Part pe r million Pro Proline Py Pyridine q Quartet R Rectus (right) ref. Reference rt Room temperature s Singlet S Si n ister (left) S Sulfur Ser Serine SOCl 2 Thionyl chloride t Triplet t Tertiary TEA T riethanolamine TFA Triflu oroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilane Trp Tryptophan

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14 Ts Tosyl Val Valine W Watt(s)

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15 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Pa rtial Fulfillment of the Requirements for the Degree of Doctor of Philosophy NOVEL STRATEGIES IN THE CHEMISTRY OF N AMINO HETEROCYCLES By Davit Jishkariani August 2012 Chair: Alan R. Katritzky Major: Chemistry The theme of this work is to develop n ove l methodologies for the synthesis of various organic compounds Chapter 1 provides a general introduction to the subsequent chapters and the methods used throughout the thesis. Chapter 2 describes the utility of N acylbenzotriazoles for the synthesis of ib uprofen and naproxen prodrugs. Chapters 3, 4, and 5 examine the chemistry of N amino heterocycles. Chapter 3 describes the synthesis of 1 aminobenzimidazoles and their transformations towards zwitterionic betaines and spirocyclic dithiohydantoins mediated by N heterocyclic carbenes (NHC). The reversible thermal equilibrium of these spirocyclic dithiohydantoins is presented in Chapter 4, where the equilibrium is studied by various analytical methods. Chapter 5 focuses on the regioselective synthesis of p yra zolo[5,1 c] 1,2,4 triazoles. Synthesis of pyrazolo[5,1 c] 1,2,4 triazoles w as achieved via one pot Cu (I) catalyzed reactions between 1,2,4 triazolium N imides and terminal alkynes T he scope of alkyne substrates together with the effect of variations in t he 1 alkyl substituent and the nature of the leaving group w as examined.

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16 Conclusions, summary of the achievements and final remarks are presented in Chapter 6

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17 CHAPTER 1 GENERAL INTRODUCTION Heterocyclic chemistry is o ne of the most important fields in organic chemistry Heterocycles are cyclic compounds containing at least two different atoms. They differ in the size number and type of rings and in the number and nature of the heteroatoms. Heterocyclic chemistry and heterocyclic compounds have had eno rmous influence to humankind and society. 1 4 Among all heterocycles, heteroaromatic compounds are of special importan ce due to their diverse biological activity This thesis describes the synthesis and utility of various different nitrogen containing heteroaromatic compounds. Chapter 2 describes the utility of N acylbenzotriazoles in the synthesis of ibuprofen and naproxen prodrugs. Benzotriazole is an extremely valuable synthetic auxiliary 5 8 and has been studied as: i) a leaving group, ii) a proton activator, iii) a cation stabilizer, iv) a radical precursor, v) an a nion precursor vi) a ligand for metal catalysis and vii) intermediates in the synthesis of biologically active heterocycles. 9 13 It is inexpensive and stable an d is soluble in many organic solvents such as ethanol, benzene, THF, chloroform, and DMF as well as in partial ly aqueous media. It can act as a weak base (pKa= 1.6) or weak acid (pKa = 8.3) and can therefore be removed under acidic or basic conditions. N A cylbenzotriazoles can be prepared directly from carboxylic acids using a one step procedure and are advantageous for different acylation reactions, 14 15 especially when the corresponding acid halides are difficult to prepare, unstable, toxic or give low yields. In Chapter 2 I report the use of N acylbenzotriazoles as intermediates, for the synthesis of ibu profen and naproxen prodrugs (Scheme 1 1). 16

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18 Scheme 1 1. Synthesis of ibuprofen and naproxen prodrugs Chapter s 3, 4 and 5 de scribe the synthetic utility of N amino heterocycles. N A mino heterocycles are heterocyclic compounds where a free am i no group is directly located on a heteroatom. Chapter 3 present s the synthesis and utility of NHCs generated from N amino benz imidazole s. This chapter describes the synthetic routes towards the preparation of zwitterionic betaines and spirocyclic systems mediated by NHC. N H eterocyclic carbenes (NHC) are the most studied members among nucleophilic carbenes and are generally known as excelle nt ligands for metal based catalysis. 17 19 However, there is great interest in their use as organocatalysts 17 20 21 due to their environmentally friendly nature and low cost. NHCs are well known organocataysts for benzo in condensations, 20 22 Stetter 23 24 and Staudinger reactions, 25 oxidative amidation, 26 annulation of enals, 27 ring opening

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19 polymerizat ions, 28 29 transesterifications 18 30 and other transformations. 17 Moreover, their donating ability and nucleophilic character offers opportunities for the construction of numerous heterocycles 31 36 and novel molecula r frameworks. 37 38 In C hapter 3, I present the NHC mediated transformations of 1 (benzylideneamino)benzimidazoles. S uch reactions were used to afford zwitterionic betaines and spirocyclic derivatives of NHC (Scheme 1 2). 39 Scheme 1 2. Synthesis of NHC zwitterionic betaines an d spirocyclic d erivatives. Spiro dithiohydantoins derived from NHC have interesting thermal properties. They undergo thermal reversible dissociation reactions (Scheme 1 3). The thermal behavior and detailed study of such reactions is presented in Chapter 4. Scheme 1 3. R eversible dissociation reaction of spirodithiohydantoins.

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20 Chapter 5 describes the regioselective synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles. Such systems are interesting due to their diverse applications as azo dyes, 40 41 inkjets and color filters, 42 photographic materials, 43 44 electrophotographic toners, 45 antibacterial agents with reduced human toxicity 46 and antitumor agents. 47 Synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles w as achieved via one pot Cu (I) catalyzed reactions between 1,2,4 triazolium N imides and terminal alkynes (Scheme 1 4). Scheme 1 4. Synthesis of py razolo[5,1 c ] 1,2,4 triazoles Chapter 6 presents a summary of the achievements together with final remarks.

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21 CHAPTER 2 CONVENIENT SYNTHESIS OF AMINOACYL, DIPEPT IDOYL AND ESTER DERIVATIVES OF IBUPR OFEN AND NAPROXEN 2.1 Introduction DL Ibuprofen ( 2.1+2.1 ) and L naproxen 2.2 (Scheme 2 1) are among the most commonly prescribed non steroidal anti inflammatory drugs (NSAIDs) for the management of inflammation and pain. 48 49 They block the enzymes (COX1 and COX2) that produce prostaglandins and as a consequence, reduce inflammation, pain and fever. Ibuprofen also inhibits smooth muscle cell mitogenesis, 50 acts as a central analgesic 51 and inhibits fungal activity. 52 However, these drugs are associated with significant adverse side effects especially upper gastrointestinal (GI) ulcer complications 53 57 with considerable economic consequences. 58 59 In a clinical trial cardiovascular risk compared to a placebo. 60 Ways to minimize side effects include: (i) more rational use of NSAIDs, 61 (ii) use of cotherapy to prevent NSAID associated toxicity in selected patients, 62 and (iii) the synthesis of new and better NSAID candidates. Masking th e carboxylic group of NSAIDs significantly reduces topical irritant action. 63 Thus, the utilization of prodrugs which temporarily mask the acidic groups of NSAIDs s hould reduce or suppress the irritation due to direct contact, and increase uptake. 64 65 Well known nonst eroidal anti inflammatory drugs, including indomethacin, diclofenac, 66 ibuprofen and naproxen 67 70 have been modified by linking them to natural amino acids. Tests for the elimination of undesired side effects produced a new series of nonsteroidal antiinflamatory drugs Reproduced with permission from Chemical biology & Drug Design 2009 73 618 626. Copyright 2009 John Wiley & Sons, Inc.

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22 (NSAIDs) in which ibuprofen was linked to furoxan and fura zan moieties to produce derivatives with comparable anti inflammatory activity but less acute gastrotoxicity than ibuprofen. Literature methods for the synthesis of ibuprofen amino acids, 68 71 72 have coupled ibuprofen with (i) amino acid esters utilizing carbodiimide based coupling reagents includi ng: DCC/HOBt/TEA (triethanolamine), 71 EDC/DMAP in DMF 72 or (ii) with amino acids by the DCC or mixed anhydride methods, achieving 48 88 % yields. 68 Ibuprofen and naproxen chloroanhydrides were used for the coupling with amino acid esters. 69 70 Conventio nal methods for the synthesis of ibuprofen dipeptides, after two coupling reactions with amino acid esters used coupling reagent EDC with DMAP in DMF; 72 utilizat ion of amino acid esters need s an additional deprotection step. During the last decade, N acylbenzotriazoles have been studied extensively for the N acylation of amines and amides, 14 73 for C acylation 15 74 75 and for O acylation. 76 77 In this work, I s tudied N acylbenzotriazole mediated syntheses of ibuprofen and naproxen amino acids, dipeptides, sugars and steroid bioconjugates which compared to classical methods offer simple preparative and workup procedures take less time to complete, use inexpensi ve reagents and give high yields. 2. 2 Results a nd Discussion Our two step synthetic route consists of: (i) conversion of DL ibuprofen ( 2.1 + 2.1' ) and L naproxen 2.2 into their active benzotriazolides ( 2.3 + 2.3' ) and 2.4 respectively (Scheme 2 1) and (ii) t he coupling of ( 2.3 + 2.3' ) and 2.4 with the N terminus of free amino acids and dipeptides, or the acylation of free OH groups of protected sugars and diverse steroids to provide potential anti inflammatory drug candidates.

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23 2.2.1 Preparation of B enzotriazole A ctivated I buprofen (2.3+2.3') and N aproxen 2.4 DL Ibuprofen ( 2.1 + 2.1' ) and L naproxen 2.2 were treated with 1 H benzotriazole and thionyl chloride in CH 2 Cl 2 at 20 C to give the corresponding acylbenzotriazoles ( 2.3 + 2.3' ) (95%) and 2.4 (92%) as stable cr ystalline compounds (Scheme 2 1). Scheme 2 1. Synthesis of benzotriazole activated ibuprofen ( 2.3+2.3' ) and naproxen 2.4 2.2.2 Preparation of DL I buprofen and L N aproxen A mino A cid C onjugates DL Ibuprofen benzotriazoli de ( 2.3 + 2.3' ) was then coupled with diverse L amino acids 2.5a f at room temperature in aqueous acetonitrile in the presence of Et 3 N during 3 12 h to give the diastereomeric mixtures ( 2. 6a + 2. 6a ) ( 2. 6f + 2. 6f ) (Table 2 1).

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24 Table 2 1. Synthesis of DL i buprofen amino acid conjugates ( 2.6a + 2.6a ) ( 2.6f + 2.6f' ) Amino acid Product Yield (%) Mp (C) 23 D L Ala OH 2.5a DL Ibuprofen L Ala OH ( 2.6a + 2.6a ) 94 107.0 109.0 15.26 L Val OH 2. 5b DL Ibuprofen L Val OH ( 2. 6b + 2 6b ) 86 140.0 141.0 31.02 L Phe OH 2. 5c DL Ibuprofen L Phe OH ( 2. 6c + 2. 6c ) 72 115.0 116.0 +27.29 L Ser OH 2. 5d DL Ibuprofen L Ser OH ( 2. 6d + 2. 6d ) 88 167.0 169.0 +6.79 L Leu OH 2. 5e DL Ibuprofen L Leu OH ( 2. 6e + 2. 6e ) 95 62.0 64.0 19.82 L Trp OH 2. 5f DL Ibuprofen L Trp OH ( 2. 6f + 2. 6f ) 90 166.0 168.0 +10.35 L Naproxen benzotriazole 2. 4 was similarly coupled with free L amino acids 2. 5a g and racemates ( 2. 5c + 1. 5c' ), ( 2. 5g + 2. 5g' CH 3 CN/H 2 O/Et 3 N to give enantiopure products 2. 7a g and diastereomeric mixtures ( 2. 7c + 2. 7c' ), ( 2. 7g + 2. 7g' ) in yields of 70 84%. The enantiopurity of 2. 7a g was supported by chiral HPLC; each enantiomer of 2. 7a g showed a singl e retention time peak, whereas the diastereomeric mixtures ( 2. 7c + 2. 7c' ), ( 2. 7g + 2. 7g' ) each displayed two peaks. (Table 2 2).

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25 Table 2 2. Synthesis of L naproxen amino acid conjugates Amino acid Product Yield (%) Mp (C) [ D 24 t R (min) L Ala OH 2. 5a L Naproxen L Ala OH 2.7a 84 150.0 152.0 13.00 18.2 L Val OH 2. 5b L Naproxen L Val OH 2. 7 b 83 154.0 156.0 28.82 7.1 L Phe OH 2. 5c L Naproxen L Phe OH 2.7 c 74 120.0 43.86 18 0 DL Phe OH ( 2. 5c + 2. 5c ) L Naproxen DL Ph e OH ( 2. 7c + 2. 7c ) 76 141.0 142.0 38.00 7. 2 18. 2 L Ser OH 2. 5d L Naproxen L Ser OH 2.7d 80 193.0 195.0 11.47 8.3 L Leu OH 2. 5e L Naproxen L Leu OH 2.7 e 82 136.0 33.7 7.1 L Trp OH 2. 5f L Naproxen L Trp OH 2. 7f 70 115.0 116.0 27.26 7. 1 L Met OH 2. 5g L Naproxen L Met OH 2. 7 g 79 143.0 144.0 32.08 5. 4 DL Met OH ( 2. 5g + 2. 5g ) L Naproxen DL Met OH ( 2. 7g + 2. 7g ) 78 132.0 133.0 29.04 5.3 11.0 The free dipeptides Gly L Ala OH, Gly Gly OH were coupled with ( 2 3 + 2 3 ) and Gly L Ala OH with 2 4 to give ibuprofen and naproxen dipeptides ( 2 8 + 2 8 ), ( 2 9 + 2 9 ) and 2 10 in 75 89 % yield s (Scheme 2 2 ) by a procedure similar to that used for the amino acid conjugates 2 6 2 7

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26 Scheme 2 2 Synthesis of ibuprofen and naproxen dipeptides 2 .2.3 Preparation of I buprofen and N aproxen S tigmasteryl and E stronyl E ster P rodrugs Benzotriazole activated L naproxen 2 .4 w as coupled to stigmasterol 2 .11 and phenolic steroid estrone 2 .13 in CH 2 Cl 2 at room temperature in the presence of DMAP (0.5 equiv.) to give L naproxen O stigmasterol 2 .12 in 81% yield and and L naproxen O estrone 2 .15 in 92 % yield (Scheme 2 3 ). Under the same conditions, DL ibuprofen O estrone ( 2 .14 + 2 .14 ) was obtained in 71 % yield from ( 2 .3 + 2 .3 ) (Scheme 2 3 ). The proposed structures were characterized by 1 H and 13 C NMR spectroscopy and elemental analysis

PAGE 27

27 Scheme 2 3 Preparation of ibuprofen and naproxen stigmasteryl and estronyl ester derivatives 2 .2.4 Preparation of I buprofen and N aproxen P rodrugs with P rotected S ugars Ibuprofen and naproxen bound to a protected sugar ( 2 .16 + 2 .16 ), 2 .17 (Scheme 2 4 ) were prepared by coupling of ibuprofen and naproxen benzotriazolide with the 6 OH of 1,2:3,4 di O isoprop y lidene D galactopyranose, in CH 2 Cl 2 and in the presence of 1 equiv of DMAP at 20 C for 24 hour. After an acid workup and silica gel column chromatography using EtOAc/hexanes (1:4) as eluent, ( 2 .16 + 2 .16 ) and 1.17 were isolated in 61 68 % yields.

PAGE 28

28 Scheme 2 4 Preparation of ibuprofen and naproxen prodrugs with protected sugars 2 .3 E xperimental S ection 2.3.1 General Methods M elting points were determined on a capillary point apparatus equipped with a digital thermometer. NMR spectra were recorded in CDCl 3 or DMSO d 6 with TMS for 1 H (300 MHz) and 13 C (75 MHz) as internal reference. Ibuprofen, naproxen and free amino acids were purchased from Fluka (Buchs, Switzerland) and Acros (Suwanee, GA, USA) and u sed without further purification. Elemental analyses were performed on a Carlo Erba 1106 instrument. Optical rotations were measured using the sodium D line. HPLC analyses were performed on a Shimadzu SPD 20A LC equipment using a (S, S) Whelk 01 chiral col umn (4.6 250 mm), detection at 254 nm, flow rate of 1.0 mL/min and n Hexane/2 propanol = 8/2 as eluting solvent. 2.3.2 General P rocedure for the P reparation of B enzotriazole A ctivated I buprofen and N aproxen ( 2.3 + 2.3' ) 2.4 Thionyl chloride (2.64 mmol) w as added to a solution of 1 H benzotriazole (1.03 g, 8.7 mmol) in dry CH 2 Cl 2 (60 ml) at room temperature and the reaction was stirred for 20 min. Ibuprofen ( 2.1 + 2.1' ) (2.2 mmol) or naproxen 2.2 (2.2 mmol) were added and the mixture were stirred for 4 h at r oom temperature. The white precipitate formed was filtered off, and the filtrate was concentrated under reduced pressure. Each residue was

PAGE 29

29 diluted with EtOAc (50 mL) and each solution was washed with 4N HCl (315 mL ) and dried over MgSO 4 filtered and r emo val of the solvent under reduced pressure gave the products ( 2.3 + 2.3' ) and 2.4 which were recrystallized from hexanes to give 0.68 g (95%) ( 2.3 + 2.3' ), and 0.66 g (92%) 2.4 as pure products. 1 (1H Benzo[d][1,2,3]triazol 1 yl) 2 (4 isobutylphenyl)propan 1 on e ( 2.3 + 2.3' ) White microcrystals (95%) mp 75.0 1 H NMR (300 MHz, CDCl 3 ) 0.86 (d, J = 6.4 Hz, 6H), 1.75 (d, J = 6.9 Hz, 3H), 1.78 1.90 (m, 1H), 2.41 (d, J = 7.2 Hz, 2H), 5.41 (q, J = 7.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.4 7.5 (m, 3H), 7.61 (t, J = 8.1 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 18.8, 22.6, 30.3, 44.6, 45.2, 114.7, 120.3, 126.3, 128.0, 129.8, 130.5, 131.5, 136.6, 141.3, 146.4, 173.8; Elemental Analysis: calcd for C 19 H 21 N 3 O: C, 74.24 ; H, 6.89; N, 13.67. Found: C, 74.29; H, 6.94; N, 13.83. (S) 1 (1H Benzo[d][1,2,3]triazol 1 yl) 2 (6 methoxynaphthalen 2 yl)propan 1 one ( 2.4 ). Microcrystals (92%) mp 182.0 183.0 D 24 = + 251.91 (c = 1.9, DMF) ; 1 H NMR (300 MHz, CDCl 3 ) : 1.83 (d, J = 7.0 Hz, 3H), 3.89 (s, 3H), 5.55 (q, J = 7.0 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 8.9; 2.5 Hz, 1H), 7.43 7.50 (m, 1H), 7.59 7.66 (m, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 1.1 Hz, 1H), 8.07 (d, J = 10.1 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 18.6, 44.7, 55.3, 105.5, 114.5, 119.1, 120.1, 126.1, 126.4, 126.9, 127.4, 128.9, 129.3, 130.3, 131.3, 133.8, 134.3, 146.2, 157.8, 173.5; Elemental Analysis: calcd for C 20 H 17 N 3 O 2 : C, 72.49; H, 5.17; N, 12.68. Found: C, 72.14; H, 5.28; N, 12.69.

PAGE 30

30 2.3.3 Gene ral P rocedure for the P reparation of I buprofen and N aproxen A mino A cids ( 2. 6a + 2. 6a ) ( 2. 6f + 2. 6f ) 2. 7a 2. 7g, ( 2. 7c + 2. 7c ) ( 2. 7g + 2. 7g ) and D ipeptides 2. 8 2. 10 The appropriate benzotriazolide ( 2. 3 + 2. 3 ), 2.4 (0.65 mmol) was added to a solution of (0.65 m mol) of different amino acids or dipeptides in MeCN/H 2 O (10ml/5ml) mixture, in the presence of Et 3 N (1,8 mmol). Each reaction mixture was stirred at room temperature for 6 24 hour. Aqueous 4N HCl (1 m L ) was then added and MeCN removed under reduced pressur e. Residue was dissolved in EtOAc (40 mL), washed with 4N HCl (315 mL) and dried over MgSO 4 After evaporation of solvent, each residue was crystallized from EtOAc hexanes to give the corresponding pure product. (2S) 2 (2 (4 Isobutylphenyl)propanamido)pro panoic acid ( 2. 6a + 2. 6a ). 68 Microcrystals (94%) mp 107.0 109.0 ] D 24 = 15.26 (c = 1,8, DMF); 1 H NMR (300 MHz, CDCl 3 ) : 0.89 (d, J = 6.6 Hz, 6H), 1.31 1.39 (m, 3H), 1.48 1.54 (m, 3H), 1.85 (sept, J = 6.7 Hz, 1H), 2.45 (d, J = 7.2 Hz, 2 H), 3.55 3.64 (m, 1H), 4.45 4.56 (m, 1H), 5.92 6.03 (m, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 8.11 (br s, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 18.0, 18.1, 18.5, 22.5, 30.3, 45.2, 46.5, 46.6, 48.5, 127.5, 127.6, 129.9, 137.7, 138.0, 141.1, 141.1, 175.4, 175.4, 176.5, 176.5; Elemental Analysis: calcd for C 16 H 23 NO 3 : C, 69.29; H, 8.36; N, 5.05. Found: C, 68.99; H, 8.75; N, 5.12. (2S) 2 (2 (4 Isobutylphenyl)propanamido) 3 methylbutanoic acid ( 2. 6b + 2. 6b ). 68 Microcrystals (86%) mp 140.0 ] D 24 = 31.02 (c = 1.4, DMF); 1 H NMR (300 MHz, CDCl 3 ) : 0.69 0.96 (m, 12 H), 1.55 (d, J = 7.3 Hz, 3H), 1.85 (hept, J = 6.8 Hz, 1H), 2.11 2.22 (m, 1H), 2.46 (d, J = 7.1 Hz, 2H), 3.66 (q, J = 7.3 Hz, 1H), 4.44 4.53 (m, 1H), 5.85 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0, 2H), 9.39 (br s, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 17.5, 18.2, 19.1, 22.5, 30.4, 31.0, 45.2, 46.8, 57.2,

PAGE 31

31 127.6, 129.9, 137.7, 141.2, 175.7; Elemental Analysis: calcd for C 18 H 27 NO 3 : C, 70.79; H, 8. 91; N, 4.59. Found: C, 70.50; H, 9.20; N, 4.57. (2S) 2 (2 (4 Isobutylphenyl)propanamido) 3 phenylpropanoic acid ( 2. 6c + 2. 6c ) 67 Microcrystals (72%) mp 115.0 116. 0 ] D 24 = +27.29 (c = 1.3, DMF); 1 H NMR (300 MHz, CDCl 3 ) : 0.97 1.10 (m, 6 H), 1.47 1.58 (m, 3H), 1.85 1.98 (m, 1H), 2.49 2.56 (m, 2H), 3.02 3.24 (m, 2H), 3.53 3.66 (m, 1H), 4.84 (q, J = 6.7 Hz, 0.5 H), 4.92 (q, J = 6.7 Hz, 0.5 H), 5.94 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.1 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H), 7.11 7.32 (m, 7H), 8.66 (br s, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 18.1, 18.2, 22.6, 30.3, 30.4, 37.2, 37.3, 45.2, 46.6, 46.7, 53.1, 53.4, 127.2, 127.3, 127.5, 127.6, 127.6, 128.7, 128.8, 1 29.4, 129.5, 129.6, 129.9, 135.5, 135.7, 137.3, 138.0, 141.1, 141.1, 174.9, 175.2, 175.2, 175.5; Elemental Analysis: calcd for C 22 H 27 NO 3 : C, 74.76; H, 7.70; N, 3.96. Found: C, 74.37; H, 7.77; N, 3.90. (2S) 3 Hydroxy 2 (2 (4 isobutylphenyl)propanamido)propa noic acid ( 2. 6d + 2. 6d ) Microcrystals (88%) mp 167.0 ] D 24 = +6.79 (c = 1.4, DMF) ; 1 H NMR (300 MHz, CDCl 3 ) : 0.70 0.97 (m, 6H), 1.40 1.46 (m, 3H), 1.73 1.85 (m, 1H), 2.33 2.45 (m, 2H), 3.54 3.95 (m, 3H), 4.44 4.49 (m, 1H), 6.33 (br s, 2 H) 6.84 (dd, J = 24.9, 7.0 Hz, 1H), 7.03 (d, J = 7.8Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) : 18.6, 18.7, 22.6, 30.3, 45.2, 46.3, 54.9, 62,6, 62.7, 127.4, 127.5, 129.7, 137.8, 138.1, 141.0, 141.1, 172.9, 173.3, 176.4, 176.5; Elemental Analysis: calcd for [C 16 H 23 NO 4 ]0.5 H 2 O: C, 63.56; H, 8.00; N, 4.63. Found: C, 63.66; H, 7.94; N, 4.56. (2S) 2 (2 (4 Isobutylphenyl)propanamido) 4 methylpentanoic acid ( 2. 6e + 2. ). 68 Microcrystals (95%) mp 62.0 ] D 24 = 19.82 (c = 1.7, DMF); 1 H NMR (300 MHz, CDCl 3 ) : 0.81 0.95 (m, 12H), 1.38 1.76 (m, 6H), 1.81 1.98 (m, 1H), 2.49 (d, J =

PAGE 32

32 7.1 Hz, 2H), 3.59 3.7 2 (m, 1H), 4.54 4.63 (m, 1H), 5.85 5.94 (m, 1H), 7.12 7.19 (m, 2H), 7.20 7.27 (m, 2H), 8.28 (s, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 18.2, 18.3, 21.9, 22.0, 22.5, 22.9, 24.9, 25.0, 30.4, 41.0, 41.0, 45.2, 46.6, 46.7, 51.1, 51.2, 127.5, 127.6, 129.8, 129 .9, 137.7, 138.3, 141.1, 141.1, 175.3, 175.6, 176.9, 177.0; Elemental Analysis: calcd for C 19 H 29 NO 3 : C, 71.44; H, 9.15; N, 4.38. Found: C, 71.40; H, 9.30; N, 4.20. (2S) 3 (1H Indol 3 yl) 2 (2 (4 isobutylphenyl)propanamido)propanoic acid ( 2. 6f + 2. 6f ) Micr ocrystals (90%) mp 166.0 168.0 ] D 24 = +10.35 (c = 1.7, DMF); 1 H NMR, (300 MHz, DMSO d 6 ) : 0.84 (d, J = 6.6 Hz, 6H), 1.19 (d, J = 7.0 Hz, 1.5H), 1.29 (d, J = 7.1 Hz, 1.5H), 1.73 1.84 (m, 1H), 2.39 (d, J = 7.0 Hz, 2H), 2.95 3.23 (m, 2H), 3.61 3 .71 (m, 1H), 4.42 4.53 (m, 1H), 6.92 7.13 (m, 6H), 7.17 (d, J =8.1 Hz, 1H), 7.32 (t, J =10.0 Hz, 1H), 7.45 (d, J = 7.8 Hz, 0.5 H), 7.55 (d, J = 7.7 Hz, 0.5H), 8.15 (d, J = 7.7 Hz, 0.5 H), 8.20 (d, J = 7.8 Hz, 0.5 H), 10.77 (s, 0.5H), 10.85 (s, 0.5 H); 13 C NMR (75 MHz, DMSO d 6 ) : 18.1, 18.7, 22.2, 27.0, 27.2, 29.6, 44.0, 44.2, 44.3, 52.9, 109.6, 109.9, 111.3, 111.3, 118.3, 120.8, 120.9, 123.5, 123.6, 127.0, 127.1, 127.1, 127.3, 128.6, 136.0, 136.1, 139.0, 139.1, 139.2, 173.3, 173.4, 173.5; Elemental Analysis: calcd for C 24 H 28 N 2 O 3 : C, 73.44; H, 7.19; N, 7.14. Found: C, 73.27; H, 7.54; N, 7.14. (S) 2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamido)propanoic acid ( 2. 7a ). 78 Microcrystals (84%) mp 150.0 152.0 153.0; [ ] D 24 = 13.00 (c = 2.0, MeOH); 1 H NMR (300 MHz, CDCl 3 ) : 1.34 (d, J = 7.1Hz, 3H), 1.59 (d, J = 7.1 Hz, 3H), 3.74 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.52 (quint, J = 7.3Hz, 1H), 5.99 (d, J = 6.8 Hz, 1H), 6.74 (br s, 1H), 7.1 0 7.18 (m, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.65 7.74 (m,

PAGE 33

33 3H); 13 C NMR (75 MHz, CDCl 3 ) : 17.9, 18.6, 47.0, 48.6, 55.5, 105.9, 119.4, 126.4, 126.5, 127.9, 129.2, 129.5, 134.0, 135.7, 158.0, 175.2, 176.3. (S) 2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamid o) 3 methylbutanoic acid ( 2. 7b ) 79 Microcrystals (83%) mp 154.0 156.0 ] D 24 = 28.82 (c = 2.0, DMF); 1 H NMR (300 MHz, DMSO d 6 ) : 0.90 (d, J = 6.6 Hz, 6H ), 1.41 (d, J = 7.0 Hz, 3H), 2.02 2.11 (m, 1H), 3.86 (s, 3H), 3.96 ( q, J = 7.0 Hz, 1H), 4.11 4.21 (m, 1H), 7.13 (dd, J = 8.0, 1.9 Hz, 1H), 7.27 (s, 1H), 7.48 (d, J = 8.5, 1H), 7.71 7.82 (m, 3H), 8.20 (d, J = 8.4 Hz, 1H); 13 C NMR (75 MHz, DMSO d 6 ) : 18.1, 19.0, 19.2, 30.1, 44.2, 55.1, 57.1, 105.6, 118.5, 125.3, 126.4, 126.7, 128.4, 129.1, 133.1, 137.2, 157.0, 173.1, 173.8; Elemental Analysis: calcd for [C 19 H 23 NO 4 ]H 2 O: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.75; H, 7.00; N, 3.88. (S) 2 ((S) 2 (6 Me thoxynaphthalen 2 yl)propanamido) 3 phenylpropanoic acid ( 2. 7c ) 79 Microcrystals (74%) mp 120.0 ] D 24 = 43.86 (c = 1.4, DMF); 1 H NMR (300 MHz, DMSO d 6 ) : 1.26 (d, J = 7.0 Hz, 3H), 2.88 (dd, J = 13.4, 9.7 Hz, 1H), 3.07 (dd, J = 13.8, 4.8 Hz, 1H), 3.76 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H), 4.39 4.47 (m, 1H), 7.10 7.27 (m, 7H), 7.39 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.74 (t, J = 9.0 Hz, 2H), 8.33 (d, J = 8.1 Hz, 1H); 13 C NMR (75 MHz, DMSO d 6 ) : 18.5, 36.6, 44.4, 53.2, 55.0, 105.5, 118.4, 125.3, 126.2, 126.3, 126.5, 128.0, 128.2, 129.0, 129.1, 133.0, 136.9, 137.6, 156.9, 172.8, 173.2; Elemental Analysis: calcd for C 23 H 23 NO 4 : C, 73.19; H, 6.14; N, 3.71. Found: C, 72.94; H, 6.25; N, 3.66. 2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamido) 3 phenylpropanoic acid ( 2. 7c + 2. ) Microcrystals (79%) mp 141.0 142.0 ] D 24 = 38.00 (c = 1.5, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) : 1.54 (d, J = 7.0 Hz, 1.5H), 1.58 (d, J = 7.3 Hz, 1.5H), 2.91

PAGE 34

34 3.13 (m, 2H), 3.69 (dt, J = 21.6, 7.0 Hz, 1H), 3.93 (s, 1.5 H), 3.95 (s, 1.5H), 4.80 (dq, J = 28.1, 6.4 Hz, 1H), 5.82 (d, J = 7.0 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6 .81 6.88 (m, 2H), 6.96 7.22 (m, 4H), 7.27 (d, J = 6.3 Hz, 1H), 7.56 (s, 1H), 7.64 7.72 (m, 2H); 13 C NMR (75 MHz, CDCl 3 ) : 18.0, 18.1, 37.0, 37.1, 46.9, 46.9, 53.0, 53.3, 55.5, 105.7, 119.3, 126.1, 126.4, 126.4, 126.5, 127.1, 127.2, 127.8, 127.8, 128 .5, 128.7, 129.1, 129.1, 129.2, 129.2, 129.5, 129.5, 134.0, 134.0, 135.1, 135.4, 135.9, 158.0, 174.7, 174.9, 175.0, 175.4; Elemental Analysis: calcd for C 23 H 23 NO 4 : C, 73.19; H, 6.14; N, 3.71. Found: C, 73.20; H, 6.29; N, 3.72. (S) 3 Hydroxy 2 ((S) 2 (6 met hoxynaphthalen 2 yl)propanamido)propanoic acid ( 2. 7d ) Microcrystals (80%) mp 193.0 195.0 ] D 24 = 11.4 (c = 1.3, DMF) ; 1 H NMR (300 MHz, DMSO d 6 ) : 1.40 (d, J = 6.8 Hz, 3H), 3.61 3.74 (m, 2H), 3.86 (s, 3H), 3.89 3.95 (m, 1H), 4.27 4.33 (m,1H), 7.13 (dd, J = 8.2; 1.8 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.72 7.79 (m, 3 H), 8.14 (d, J = 8.0, 1H); 13 C NMR (75 MHz, DMSO d 6 ) : 18.8, 44.4, 54.7, 55.2, 61.5, 105.7, 118.6, 125.5, 126.5, 126.8, 128.4, 129.2, 133.2, 137.3, 157.0, 172.0, 173.6; Elemental Analysis: calcd for [C 17 H 19 NO 5 ]0.5 H 2 O: C, 62.57; H, 6.18; N, 4.29. Found: C, 62.49; H, 5.96; N, 4.21. (S) 2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamido) 4 methylpentanoic acid ( 2. 7e ). 79 Microcrystals (82%) mp 136.0 Lit m.p. 135.0 137.0; [ ] D 24 = 33.7 (c = 1.4, DMF) ; 1 H NMR (300 MHz, DMSO d 6 ) : 0.87 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 1.40 (d, J = 6.6 Hz, 3H), 1.48 1.58 (m, 2H), 1.60 1.69 (m, 1H), 3.78 3.88 (m, 4H), 4.20 4.29 (m, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.70 7.79 (m, 3H), 8.29 (d, J = 5.8 Hz, 1H); 13 C NMR (75 MHz, DMSO d 6 ) : 18.7,

PAGE 35

35 21.2, 22.7, 24.3, 44.4, 50.1, 55.0, 105.5, 118.4, 125.2, 126.3, 126.6, 128.2, 129.0, 133.0, 137.0, 156.8, 173.3, 174. 0. (S) 3 (1H Indol 3 yl) 2 ((S) 2 (6 methoxynaphthalen 2 yl)propanamido)propanoic acid ( 2. 7f ) 79 Microcrystals (70%) mp 115.0 116.0 ] D 24 = 27.26 (c = 1.2, DMF) ; 1 H NMR (300 MHz, DMSO d 6 ) : 1.29 (d, J = 7.0 Hz, 3H), 3.05 (dd, J = 14.5, 8.4 Hz, 1H), 3.21 (dd, J = 14.5, 4.7 Hz, 1H), 3.78 3.88 (m, 4H), 4.47 4.56 (m, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.11 7.16 (m, 2H), 7.26 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.68 7.77 (m, 3H), 8.31 (d, J = 7.8 Hz, 1H), 10.87 (s, 1H); 13 C NMR (100 MHz, DMSO d 6 ) : 18.6, 27.1, 44.4, 52.9, 55.0, 105.5, 109.9, 111.3, 118.2, 118.2, 118.4, 120.8, 123. 5, 125.3, 126.3, 126.5, 127.2, 128.2, 129.0, 133.0, 136.0, 137.1, 156.9, 173.2, 173.2; Elemental Analysis: calcd for [C 25 H 24 N 2 O 4 ]1/3 H 2 O: C, 71.07; H, 5.88; N, 6.63. Found: C, 71.38; H, 6.32; N, 6.30. (S) 2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamido) 4 (methylthio)butanoic acid ( 2. 7g ) Microcrystals (79%) mp 143.0 144.0 ] D 24 = 32.08 (c = 1.8, DMF) ; 1 H NMR (300 MHz, DMSO d 6 ) : 1.41 (d, J = 6.9, 3H), 1.83 2.01 (m, 2H), 2.03 (s, 3H), 2.47 2.51 (m, 2H), 3.81 3.87 (m, 4H), 4.29 4.39 (m, 1H), 7.14 (d, J = 9.4 Hz, 1H) 7.28 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.72 7.79 (m, 3H), 8.34 (d, J = 7.7 Hz, 1H); 13 C NMR (75 MHz, DMSO d 6 ) : 14.6, 18.8, 29.7, 30.8, 44.6, 51.0, 55.1, 105.7, 118.5, 125.4, 126.5, 126.6, 128.4, 129.1, 133.1, 137.1, 157.0, 173.3, 173.6; Elemental Analysis: calcd for C 19 H 23 NO 4 S: C, 63.14; H, 6.4 1; N, 3.88. Found: C, 63.50; H, 6.56; N, 3.79. 2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamido) 4 (methylthio)butanoic acid ( 2. 7g + 2. ). Microcrystals (78%) mp 132.0 133.0 ] D 24 = 29.04 (c = 1.4, DMF);

PAGE 36

36 1 H NMR (300 MHz, CDCl 3 ) : 1.61 (d, J = 7.3 Hz, 3H), 1.82 (s, 0.8H), 1.91 (s, 2.2 H), 1.84 1.98 (m, 1H), 2.04 2.14 (m, 1H), 2.29 (t, J = 7.2 Hz, 0.6 H), 2.41 (t, J = 7.2 Hz, 1.4H), 3.78 (q, J = 8.2 Hz, 1H), 3.91 (s, 3H), 4.59 4.69 (m, 1H), 6.27 6.34 (m, 1H), 7.10 7.17 (m, 2H), 7.36 (dd, J = 8.3, 1.3 Hz, 1H), 7.66 7.73 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) : 15.5, 18.5, 30.2, 30.6, 47.0, 52.3, 55.5, 103.6, 105.9, 119.4, 126.5, 126.5, 127.9, 129.2, 129.5, 134.1, 135.6, 158.0, 174.9, 175.7; Elemental Analysis: calcd for C 19 H 23 NO 4 S: C, 63.14; H, 6.41; N, 3.88. Found: C, 63.28; H, 6.38; N, 3.81. (2S) 2 (2 (2 (4 Isobutylphenyl)propanamido)acetamido)propanoic acid ( 2. 8 + 2. ). Microcrystals (89%) mp 135.0 ] D 24 = 11.27 (c = 1.6, DMF) ; 1 H NMR (300 MHz, DMSO d 6 ) : 0.85 (d, J = 6.2 Hz, 6H), 1.23 (d, J = 8.1 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H), 1.74 1. 85 (m, 1H), 2.39 (d, J = 6.9 Hz, 2H), 3.57 3.81 (m, 4H), 4.15 4.23 (m, 1H), 7.06 (d, J = 7.4 Hz, 2H), 7.22 (d, J = 7.4 Hz, 2H), 8.00 8.15 (m, 2H); 13 C NMR (75 MHz, DMSO d 6 ) : 17.2, 18.4, 18.5, 22.1, 29.5, 41.6, 44.1, 44.3, 47.3, 127.0, 127.0, 128.6, 139.1, 139.3, 168.4, 173.6, 173.9; Elemental Analysis: calcd for [C 18 H 26 N 2 O 4 ]1/2 H 2 O: C, 62.95; H, 7.92; N, 8.16. Found: C, 62.93; H, 7.89; N, 8.47. 2 (2 (2 (4 Isobutylphenyl)propanamido)acetamido)acetic acid ( 2. 9 + 2. ). Microcrystals (75%), mp 135.0 137.0 1 H NMR (300 MHz, DMSO d 6 ) : 0.85 (d, J = 6.6 Hz, 6H), 1.31(d, J = 6.9 Hz, 3H), 1.73 1.85 (m, 1H), 2.39 (d, J = 7.0 Hz, 2H), 3.58 3.83 (m, 5H), 7.06 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H), 8.11 8.22 (m, 2H); 13 C NMR (75 MHz, DMSO d 6 ) : 18.5, 22.1, 29.5, 40.5, 41.7, 44.2, 44.3, 127.0, 128.6, 139.1, 139.3, 169.1, 171.1, 173.7; Elemental Analysis: calcd for C 17 H 24 N 2 O 4 : C, 63.73; H, 7.55; N, 8.74. Found: C, 63.63; H, 7.91; N, 8.98.

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37 (S) 2 (2 ((S) 2 (6 Methoxynaphthalen 2 yl)propanamido)a cetamido)propanoic acid ( 2. 10 ) Microcrystals (75%), mp 147.0 148.0 ] D 24 = + 21.46 (c = 1.4, DMF) ; 1 H NMR (300 MHz, DMSO d 6 ) : 1.23 (d, J = 7.2 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 3.69 3.75 (m, 2H), 3.81 3.88 (m, 4H), 4.14 4.23 (m, 1H), 7.10 7.17 (m, 1H), 7.27 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.71 7.80 (m, 3H), 8.12 (d, J = 7.1 Hz, 1H), 8.08 8.24 (m, 2H); 13 C NMR (75 MHz, DMSO d 6 ) : 17.2, 18.4, 41.6, 44.6, 47.3, 55.0, 105.5, 118.5, 125.3, 126.5, 128.3, 129.0, 133.0, 137.1, 156.9, 168. 4, 173.6, 173.9; Elemental Analysis: calcd for C 19 H 22 N 2 O 5 : C, 63.67; H, 6.19; N, 7.82. Found: C, 63.44; H, 6.25; N, 7.67. (S) ((3S,8S,9S,10R,13R,14S,17R) 17 ((2R,5S,E) 5 Ethyl 6 methylhept 3 en 2 yl) 10,13 dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17 tetra decahydro 1H cyclopenta[a]phenanthren 3 yl) 2 (6 methoxynaphthalen 2 yl)propanoate ( 2. 12 ). Microcrystals (81%), mp 143.0 ] D 24 = 14.5 (c = 1.0 CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) : 0.68 (s, 3H), 0.77 0.88 (m, 9H), 0.97 (s, 3H) 0.99 1.05 (m, 5H), 1.12 1.27 (m, 6H), 1.39 1.60 (m, 13H), 1.63 1.76 (m, 2H), 1.80 2.07 (m, 5H), 2.16 2.33 (m, 2H), 3. 81 (q, J = 7.1 Hz, 1H), 3.91 (s, 3H), 4.56 4.68 (m, 1H), 5.00 (dd, J = 15.1, 8.2 Hz, 1H), 5.15 (dd, J = 15.1, 8.5 Hz, 1H), 5.28 5.38 (m, 1H), 7.10 7.17 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.65 7.74 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) : 12.2, 12.4, 1 8.8, 19.1, 19.4, 21.1, 21.2, 21.4, 24.5, 25.6, 27.8, 29.1, 31.9, 32.0, 36.7, 37.1, 37.9, 39.7, 40.7, 42.3, 45.8, 50.1, 51.4, 55.4, 56.0, 56.9, 74.4, 105.7, 119.0, 122.7, 126.0, 126.4, 127.2, 129.1, 129.4, 129.4, 133.7, 136.1, 138.5, 139.7, 157.7, 174.3; El emental Analysis: calcd for C 43 H 62 O 3 : C, 82.38; H, 9.97; N, 0. Found: C, 82.46; H, 10.22; N, 0.06.

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38 (8R,9S,13S,14S) 13 Methyl 17 oxo 7,8,9,11,12,13,14,15,16,17 decahydro 6H cyclopenta[a] phenanthren 3 yl 2 (4 isobutylphenyl)propanoate ( 2. 14 + 2. 14 ) Oil (71 %); [ ] D 24 = +92.72 (c = 0.6, DMF); 1 H NMR (300 MHz, DMSO d 6 ) 0.83 0.88 (m, 8H), 1.33 1.59 (m, 8H), 1.75 2.09 (m, 5H), 2.18 2.28 (m, 1H), 2.44 (d, J = 7.4 Hz, 2H), 2.78 2.84 (m, 2H), 3.34 (s, 3H), 4.01 (q, J = 7.1 Hz, 1H), 6.67 6.78 (m, 2H), 7.16 (d, J = 7.6 Hz, 2H), 7.25 7.31 (m, 3H); 13 C NMR (75 MHz, DMSO d 6 ) : 13.4, 18.4, 21.0, 22.1, 25.2, 25.7, 28.7, 29.5, 31.2, 35.3, 37.3, 43.4, 44.1, 44.1, 47.2, 49.4, 118.5, 121.1, 126.2, 127.0, 129.2, 137.1, 137.4, 137.7, 139.9, 148.2, 172. 9, 219.5; Elemental Analysis: calcd for C 31 H 38 O 3 : C, 81.18; H, 8.35; N, 0. Found: C, 80.96; H, 8.71; N, 0.08. (S) ((8R,9S,13S,14S) 13 Methyl 17 oxo 7,8,9,11,12,13,14,15,16,17 decahydro 6H cyclopenta[a]phenanthren 3 yl) 2 (6 methoxynaphthalen 2 yl)propanoa te ( 2. 15 ) Microcrystals (92%); mp 160.0 ] D 24 = +31.5 (c = 1.6, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) : 1.01 (s, 3H), 1.48 1.74 (m, 5H), 1.81 (d, J = 7.1 Hz, 3H), 2.02 2.68 (m, 7H), 2.94 3.024 (m, 2H), 4.05 (s, 3H), 4.21 (q, J = 7.0 Hz, 1H), 6.82 6.85 (m, 1H), 6.88 (dd, J = 8.3, 2.4 Hz, 1H), 7.27 (s, 1H), 7.28 7.38 (m, 2H), 7.39 (s, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 7.83 7.92 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) : 13.8, 18.6, 21.5, 25.7, 26.3, 29.3, 31.5, 35.8, 37.9, 44.1, 45.5, 47.9, 50.3, 55.3, 105.5, 118.5, 119 .0, 121.3, 126.1, 126.1, 126.3, 127.3, 128.9, 129.3, 133.7, 135.2, 137.2, 137.9, 148.6, 157.7, 173.4, 220.9; Elemental Analysis: calcd for C 32 H 34 O 4 : C, 79.64; H, 7.10; N, 0; Found: C, 79.33; H, 7.18; N, 0.06. ((3aR,5R,5aS,8aS,8bR) 2,2,7,7 tetramethyltetrah ydro 3aH bis[1,3]dioxolo[4,5 b:4',5' d]pyran 5 yl)methyl 2 (4 isobutylphenyl)propanoate ( 2. 16 + 2. 16 ) 80 Oil (68 %); [ ] D 24 = 33.11 (c = 0.7, DMF) ; 1 H NMR (300 MHz, CDCl 3 ) : 0.88(d, J = 6.6 Hz, 6H ),

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39 1.27 1.34 (m, 6H), 1.39 1.52 (m, 8H), 1.59 (s, 1H), 1.75 1.91 (m, 1H), 2.43 (d, J = 7.1 Hz, 2H), 3.74 (q, J = 7.1 Hz, 1H), 3.91 3.98 (m, 1H), 4.01 4.21 (m, 2H), 4.2 6 4.34 (m, 2H), 4.51 4.58 (m, 1H), 5.51 (d, J = 4.9 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.5 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) : 18.5, 18.8, 22.5, 24.5, 25.1, 26.0, 26.0, 30.3, 45.0, 45.2, 63.4, 63.8, 65.8, 66.2, 70.6, 70.7, 71.0, 71.1, 96.4 96.4, 108.9, 108.9, 109.7, 109.7, 127.4, 129.4, 129.4, 137.7, 140.5, 140.6, 174.8; Elemental Analysis: calcd for; C 26 H 32 O 8 : C, 66.94; H, 8.09; N, 0. Found: C, 67.14; H, 8.47; N, 0.04. (S) ((3aR,5R,5aS,8aS,8bR) 2,2,7,7 tetramethyltetrahydro 3aH bis[1,3]di oxolo[4,5 b:4',5' d]pyran 5 yl)methyl 2 (6 methoxynaphthalen 2 yl) propanoate ( 2. 17 ). 80 Oil (61 %); [ ] D 24 = 13.125 (c = 0.6, DMF); 1 H NMR (300 MHz, CDCl 3 ) : 1.25 (s, 3H), 1.30 (s, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H), 3.91 (s, 3H), 3.92 4.04 (m, 3H), 4.16 4.27 (m, 1H), 4.27 4.35 (m, 2H), 4.50 (dd, J = 7.8, 1.7 Hz, 1H), 5.51 (d, J = 4.9 Hz, 1H), 7.10 7.15 (m, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.68 7.73 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) : 18.7, 24.4, 25.1, 26.0, 45.5, 55.4, 63.5, 65.8, 70.5, 70.7, 70.9, 96.4, 105.6, 108.8, 109.6, 119.0, 126.1, 126.4, 127.2, 129.0, 129.5, 133.8, 1 35.6, 157.7, 174.7; Elemental Analysis: calcd for C 26 H 32 O 8 : C, 66.09; H, 6.83; N, 0. Found: C, 66.40; H, 7.25; N, 0.16.

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40 CHAPTER 3 CARBENE MEDIATED TRA NSFORMATIONS OF 1 (BENZYLIDENEAMINO) BENZIMIDAZOLES 3.1 I ntroduction Carbenes derived from nitrogen hete rocycles (NHC) are well known organocataysts for benzoin condensations, 20 22 Stetter 23 24 and Staudinger reactions, 25 oxidative amidation, 26 annulation of enals, 27 ring opening polymerizations, 28 29 transesterifications 18 30 and other transformations. 17 Moreover, they are excellent ligands for transition metals. 81 83 donating ability and nucleophilic character of NHC offers opportunities for the construction of numerous heterocycles 31 36 and novel molecular frameworks. 37 38 An important property of NHCs is the ability to react with CO 2 84 86 CS 2 87 89 and isothiocyanates 87 89 to form imidazol 2 ylidene, 1,3 thiazol 2 ylidene, 32 90 1,2,4 triazol 3 ylidene 32 91 92 and isothiazol 3 ylidene adducts. A wide range of stable benzimidazolium or imidazol(in)ium CS 2 adducts have been studied as latent catalysts, 93 novel ionic liquids, 85 87 94 as catalysts in the cyanosilylation of aldehydes, 95 as intermediates for sulfur heterocycles, 96 as ligands for gold complexes, as surface units for gold nanoparticles 96 and as promising antifungal and antibacterial agents. 89 97 NHC zwitterionic betaine adducts with isothiocyanates (NHCRNCS) are powerful intermediates for the synthesis of a variety of heterocycles. 98 99 Cheng and coworkers utilized 2 thiocarbamoyl benzimidazolium, imidazolium and triazolium zwitterionic inner salts in [3+2] cycloaddition reactions, resulting in spiro heterocycles. 98 99 Reproduced with permission from The Journal of Organic Chemistry 2011 76 4082 4087. Copyright 201 1 American Chemical Society

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41 Most literature NHC examples are based on imidazole and benzimidaz ole nuclei bearing various alkyl or aryl groups on nitrogen. An early report by Balch described a template synthesis of an N aminosubstituted N heterocyclic carbene. 100 Lassaletta described the synthesis and application of a class of N heterocyclic carbenes based on bis( N N dialkylamino)im idazolin 2 ylidines. 101 102 No literature reports were found about NHC CS 2 or NHC RNCS betaines or spirocycli c derivatives of N (arylmethyleneimino)benzimidazoles. Consequently, I have studied the synthesis and NHC mediated transformations of 1 (benzylideneamino)benzimidazoles. 3.2 R esults and D iscussion 1 Aminobenzimidazole 3.2 was synthesized from benzimidazol e 3.1 and hydroxylamine O sulfonic acid in 75% yield following a literature procedure. 103 N (Arylmethyleneimino)benzimidazoles 3.4a f were synthesized in 69 94% y ield by the reaction of 1 aminobenzimidazole 3.2 with aldehydes 3.3a f in ethanol in the presence of a catalytic quantity of sulfuric acid 104 (Table 3 1). Quaternization of N (arylmethyleneimino)benzimidazoles 3.4a f with butyl iodide 3.5 gave the corresponding 3 butyl N (arylmethyleneimino)benzimidazoliu m iodides 3.6a f in quantitative yields. (Table 3 1)

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42 Table 3 1. Synthesis of 1 (benzylidineamino)benzimidazole 3.4a f and 1 (benzylidineamino)benzimidazolium iodides 3.6a f Entry Ar Products 3.4a f Products 3.6a f Yield (%) Mp (C) Yield (%) Mp (C) a 4 CH 3 O C 6 H 4 92 93 95 100 154 155 b C 6 H 5 94 125 100 171 172 c 4 Br 2 thiophenyl 69 174 175 100 175 176 d 4 CH 3 C 6 H 4 82 74 75 100 167 169 e 4 NO 2 C 6 H 4 79 225 226 100 217 219 f 4 Et 2 N C 6 H 4 91 118 100 151 152 1,3 Dimethylbenzimidazolium iodide 3. 7 was synthesized from benzimidazole following a literature procedure. 105 The singlet carbene generated in situ at the C 2 position of 1,3 dimethylbenzimidazolium iodide 3. 7 by treatment with sodium hydride, on reaction with carbon disulfide 3. 8 gave 1,3 dimethy lbenzimidazol 3 ium 2 carbodithioate 3. 10 in 85% yield (Table 3 2) Deprotonation of N (3 butylbenzimidazol 3 ium 1 yl) 1 (aryl)methanimine iodides 3. 6a c using sodium hydride, followed by reaction with carbon disulfide 3. 8 at room temperature formed the c orresponding NHCCS 2 betaines 3. 9a c in 68 76% yield (Table 3 2). Isolation of the NHCCS 2 betaine adducts was achieved by crystallization in all cases.

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43 Table 3 2. Synthesis of NHCCS 2 betaines 3.9a c 3.10 Reactant Product R R 1 Yield (%) Mp (C) 3. 6a 3. 9a N=CH (4 CH 3 O C 6 H 4 ) nBu 70 160 161 3. 6b 3. 9b N=CH C 6 H 5 nBu 76 171 172 3. 6c 3. 9c N=CH (4 Br 2 thiophenyl) nBu 68 170 173 3. 7 3. 10 CH 3 CH 3 85 235 236 The structure of a representative example, 3. 9a w as confirmed by single crystal X ray diffraction (Figure 3 1) Figure 3 1. X r ay structure of 3. 9a

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44 Interestingly, under similar experimental conditions, 1,3 dimethylbenzimidazolium iodide 3. 7 on reacti on with excess of isopropyl isothiocyanate 3. 11 in the presence of sodium hydride/THF at room temperature gave (1,3 dimethylbenzimidazol 3 ium 2 carbothioyl) isopropylazanide 3. 12 in 86% yield (Scheme 3 1) Scheme 3 1 S ynthesis of ( 1,3 dimethylbenzimidazol 3 ium 2 carbothioyl) isopropylazanide 3. 12 However, the reaction of N (3 butylbenzimidazol 3 ium 1 yl) 1 (aryl)methanimine iodides 3. 6a b with excess of isopropyl isothiocyanate 3. 11 in the presence of NaH/THF at room temperature led to the formation of red crystalline compounds 3. 13a b in 74 77% yield. (Table 3 3) The 1 H and 13 C NMR spectra were complex and did not correspond to the formation of the carbodithioate product. In fact, the spectroscopic data revealed two isopropyl groups and the structure of representative example 3. 13a was further confirmed by single cr ystal X ray diffraction studies (Figure 3 2) Table 3 3. Synthesis of spirodithiohydantoins 3.13a b Reactant Product A r Yield (%) Mp (C) 3. 6a 3. 13a 4 CH 3 O C 6 H 4 77 141 142 3. 6b 3. 13b C 6 H 5 74 116 119

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45 The X ray crystallographic data proved the formation of 1 butyl 1',3' diisopropyl 3 [( E ) (aryl)methyleneamino]spiro[benzimidazole 2,5' imidazolidine] 2',4' dithiones 3. 13 a b resulting from the addition of a second molecule of isopropyl isothiocyanate to the NHC RNCS betaine adduct. With an imine function in the side chain, I was unable to isolate NHCRNCS betaine adducts, because the corresponding adducts reacted further with heteroallene even when the reagents were present in stoichiometric (1:1) or sub stoichiometric quantities. However, in the case of 1,3 dimethylbenzimidazolium iodide 3. 7 the reaction stopped at the NHCRNCS betaine step and no spirocyclic product was observed even in presence of excess isopropyl isothiocyanate or at elevated temperatures. Figure 3 2. X ray structure of 3. 13a Zwitterionic NHC RNCS betaine intermediates were is olated only when a strongly deactivated isothiocyanate (benzoyl isothiocyanate) was used. Thus the reaction of benzimidazolium salts 3. 6a c 3. 7 with equivalent amounts of benzoyl isothiocyanate

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46 3. 14 in the presence of NaH/THF led to benzoyl benzimidazoliu m 2 carbonothioyl)amides 3. 15a c 3. 16 in 74 85% yield (Table 3 4). Table 3 4. Synthesis of zwitterionic NHC RNCS betaines 3.15a c 3.16 Reactant Product R R 1 Yield (%) Mp (C) 3. 6a 3. 15a N=CH (4 CH 3 O C 6 H 4 ) nBu 83 1 26 128 3. 6b 3. 15b N=CH C 6 H 5 nBu 77 125 127 3. 6c 3. 15c N=CH (4 Br 2 thiophenyl) nBu 74 151 154 3. 7 3. 16 CH 3 CH 3 85 207 210 The structure of representative example 3. 16 was confirmed by single cr ystal X ray diffraction studies (Figure 3 3) Figure 3 3. X ray structure of 3. 16 In order to explore this area further, amination of 1 aminobenzimidazole 3. 2 and its derivatives 3. 4a f was studied. Amination of aminobenzimidazole 3. 2 was carried out using 2,4 dinitrophenyl hydroxylamine 3. 17 to afford 1,3 diaminobenzimidazole 3. 18

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47 Amination of 3 [( E ) (aryl)methyleneamino] benzimidazol 1 ium 1 amine; 2,4 dinitrophenolate salts, 3. 19a f however, gave only 3.19a 3.19d and 3.19f 106 Thus only imines with electron donating substituents in the side chain, gave observa ble yields of aminated products (Table 3 5) Table 3 5. Amination o f 1 aminobenzimidazole 3. 2 and imines 3. 4a f Reactant Product R Yield (%) Mp (C) 3. 2 3. 18 NH 2 80 166 168 3. 4a 3. 19a N=CH (4 CH 3 O C 6 H 4 ) 42 146 148 3. 4b 3. 19b N=CH C 6 H 5 0 3. 4c 3. 19c N=CH (4 Br 2 thiophenyl) 0 3. 4d 3. 19d N=CH (4 CH 3 C 6 H 4 ) 40 132 134 3. 4e 3. 19e N=CH (4 NO 2 C 6 H 4 ) 0 3. 4f 3. 19f N=CH (4 Et 3 N C 6 H 4 ) 60 180 3.3 E xperimental S ection Melting points were determined on a capillary point apparatus equipped with a digital thermometer and are uncorre cted. NMR spectra were recorded in CDCl 3 or DMSO d 6 with TMS for 1 H (300 MHz) and 13 C (75 MHz) as an internal reference. Aminating agent 3. 17 was prepared via a two step literature procedure. 107 Elemental analysis was performed on a Carlo Erba 1106 instr ument.

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48 3.3.1 General M ethod for the P reparation of I mines 3.4a f 1 Aminobenzimidazole and corresponding aldehyde (1.05 eq) were dissolved in absolute ethanol and stirred in the presence of a catalytic amount sulfuric acid. After 5 h the solvent was removed under reduced pressure and the imines were obtained by recrystallization from EtOAc/hexanes. N (Benzimidazol 1 yl) 1 (4 methoxyphenyl)methanimine ( 3. 4a ). White microcrystals (92%), mp 93 .0 95.0 C; 1 H NMR (CDCl 3 ): 8.69 (s, 1H), 8.32 (s, 1H), 7.85 7. 78 (m, 3H), 7.75 7.70 (m, 1H), 7.39 7.28 (m, 2H), 7.02 6.97 (m, 2H), 3.87 (s, 3H,); 13 C NMR (CDCl 3 ): 162.5, 152.2, 142.5, 136.5, 131.9, 129.9, 125.6, 123.9, 123.0, 120.7, 114.5, 110.8, 55.5; Anal. Calcd. For C 15 H 13 N 3 O: C, 71.70; H, 5.21; N, 16.72. Found: C, 71.87; H, 5.28; N, 16.78. N (Benzimidazol 1 yl) 1 phenyl methanimine ( 3. 4b ). White microcrystals (94%), mp 125.0 C (lit. 108 mp 125 .0 126 .0 C); 1 H NMR (CDCl 3 ): 8.76 (d, J = 2.7 Hz, 1H), 8.37 (s, 1H), 7.91 7.86 (m, 2H), 7.84 7.80 (m, 1H), 7.78 7.73 (m, 1H), 7.52 7.47 (m, 3H), 7.41 7.29 (m, 2H); 13 C NMR (CDCl 3 ): 151.7, 142.5, 136.6, 132.9, 131.8, 131.6, 129.0, 128.1, 124.1, 123.1, 120.7, 110.8; Anal. Calcd. For C 14 H 11 N 3 : C, 76.00; H, 5.01; N, 18.99. Found: C, 75.82; H, 4.99; N, 19.07. N (Benzimidazol 1 yl) 1 (4 bromo 2 thienyl)methanimine ( 3. 4c ). Colourless crystals (79%), mp 174.0 175.0 C; 1 H NMR (DMSO d 6 ): 9.36 (s, 1H), 8.90 (s, 1H), 7.99 (s, 1H ), 7.78 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H); 13 C NMR (DMSO d 6 ): 146.4, 141.6, 138.9, 137.4, 134.4, 131.4, 128.1, 123.8, 122.8, 119.9, 110.6, 109.6; Anal. Calcd. For C 12 H 8 BrN 3 S: C 47.07; H, 2.63; N, 13.72. Found: C, 47.12; H, 2.59; N, 13.60.

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49 N (Benzimidazol 1 yl) 1 (p tolyl)methanimine ( 3. 4d ). White microcrystals (82%), mp 74 .0 75.0 C; 1 H NMR (CDCl 3 ): 8.71 (s, 1H), 8.38 (s, 1H), 7.83 7.72 (m, 4H), 7.39 7.25 (m, 4H), 2.42 (s, 3H); 13 C NMR (CDCl 3 ): 152.4, 142.4, 142.3, 136.6, 131.9, 130.3, 129.8, 128.2, 124.1, 123.2, 120.7, 110.9, 21.7; Anal. Calcd. For C 15 H 13 N 3 : C, 76.57; H, 5.57; N, 17.86. Found: C, 76.67; H, 5.61; N, 17.99. N (Benzimidazol 1 yl) 1 (4 nitrophenyl)methan imine ( 3. 4e ) Yellow microcrystals (79%) mp 225 .0 226 .0 C (lit. 109 mp 223 .0 C); 1 H NMR (DMSO d 6 ): 9.36 (s, 1H), 9.03 (s, 1H), 8.40 (d, J = 7.8 Hz, 2H), 8.20 (d, J = 7.7 Hz, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H); 13 C NMR (DM SO d 6 ): 150.1, 148.5, 141.7, 139.2, 137.1, 131.8, 128.8, 124.1, 123.0, 120.0, 110.8; Anal. Calcd. For C 14 H 10 N 4 O 2 : C, 63.15; H, 3.79; N, 21.04. Found: C, 63.03; H, 3.70; N, 20.79. 4 [(E) Benzimidazol 1 yliminomethyl] N,N diethylaniline ( 3. 4f ). Green crys tals (91%), mp 118.0 C, (lit. 110 mp not available); 1 H NMR (DMSO d 6 ): 8.96 (s, 1H), 8.89 (s, 1H), 7.77 7.70 (m 4H), 7.35 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.6 Hz 1H), 6.78 (d, J = 9.0 Hz, 2H), 3.42 (q, J = 7.0 Hz, 4H), 1.13 (t, J = 6.9 Hz, 6H); 13 C NMR (DMSO d 6 ): 154.6, 149.9, 141.5, 136.5, 132.0, 130.0, 123.2, 122.1, 119.7, 119.1, 111.0, 110.5, 43.7, 12.3; Anal. Calcd. For C 18 H 20 N 4 : C, 73.94; H, 6.89; N, 19.16. Found: C, 73.56; H, 7.00; N, 18.99. 3.3.2 Genera l M ethod for P reparation of N (3 Butylbenzimidazol 3 ium 1 yl) 1 arylmethanimine I odides 3. 6a f 1 Iodobutane (3 equivalents) and the corresponding imines 3. 4a f were heated with stirring at 100C in a round bottom flask for 5 h without solvent. Excess 1

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50 i odobutane was removed under reduced pressure at 50C to give the corresponding 3 butyl N (arylmethyleneimino)benzimidazolium iodides 3. 6a f in quantitative yields. N (3 Butylbenzimidazol 3 ium 1 yl) 1 (4 methoxyphenyl)methanimine iodide ( 3. 6a ). White cryst als (100%), mp 154.0 155.0 C; 1 H NMR (DMSO d 6 ): 10.57 (s, 1H), 9.38 (s, 1H), 8.23 8.20 (m, 1H), 8.13 8.09 (m, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.80 7.74 (m, 2H), 7.20 (d, J = 8.8 Hz, 2H), 4.59 (t, J = 7.3 Hz, 2H), 3.90 (s, 3H), 2.03 (quintet, J = 7.4 Hz, 2H), 1.45 (sextet, J = 7.3 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 163.3, 162.1, 135.7, 131.3, 130.0, 129.4, 127.2, 126.9, 123.6, 114.9, 113.8, 113.1, 55.7, 47.1, 30.4, 19.1, 13.4; Anal. Calcd. For C 19 H 22 IN 3 O: C, 52.42; H, 5.09; N, 9.65. Found: C, 52.33; H, 5.15; N, 9.51. N (3 Butylbenzimidazol 3 ium 1 yl) 1 phenylmethanimine iodide ( 3. 6b ). White crystals (100%), mp 171.0 172.0 C; 1 H NMR (DMSO d 6 ): 10.58 (s, 1H), 9.44 (s, 1H), 8.25 8.15 (m, 2H), 8.08 (d, J = 6.9 Hz, 2H), 7.82 7.76 (m, 2H), 7.74 7.64 (m, 3H), 4.59 (t, J = 7.2 Hz, 2H), 2.02 (quintet, J = 7.5 Hz, 2H), 1.45 (sextet, J = 7.5 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13 C NMR (DMSO d 6 ): 162.6, 136.0, 133.3, 131.2, 130.0, 129.4, 129.3, 129.1, 127.3, 127.0, 113.9, 113.1, 47.1, 30.4, 19.1, 13.4; Anal. Calcd. For C 18 H 20 IN 3 : C, 53.35; H, 4.97; N, 10.37. Found: C, 53.06; H, 4.95; N, 10.18. 1 (4 Bromo 2 thienyl) N (3 butylbenzimidazol 3 ium 1 yl)methanimine iodide ( 3. 6c ). Brown crystals (100%), mp 175.0 176.0 C; 1 H NMR (DMS O d 6 ): 10.54 (s, 1H), 9.59 (s, 1H), 8.25 8.21 (m, 2H), 8.11 8.07 (m, 1H), 7.98 (s, 1H), 7.80 7.75 (m, 2H), 4.59 (t, J = 7.2 Hz, 2H), 2.01 (quintet, J = 7.2 Hz, 2H), 1.44 (sextet, J = 7.5 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13 C NMR (DMSO d 6 ): 155.5, 137.7 136.5, 136.4, 131.4,

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51 130.0, 129.0, 127.4, 127.0, 113.9, 113.0, 110.4, 47.1, 30.3, 19.0, 13.4; Anal. Calcd. For C 16 H 17 IBrN 3 S: C, 39.20; H, 3.50; N, 8.57. Found: C, 39.08; H, 3.60; N, 8.17. N (3 Butylbenzimidazol 3 ium 1 yl) 1 (p tolyl)methanimine iodide ( 3. 6d ). White crystals (100%), mp 167.0 169.0 C; 1 H NMR (DMSO d 6 ): 10.55 (s, 1H), 9.38 (s, 1H), 8.23 8.19 (m, 1H), 8.17 8.12 (m, 1H), 7.97 (t, J = 8.1 Hz, 2H), 7.79 7.74 (m, 2H), 7.47 (d, J = 7.8 Hz, 2H), 4.59 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.08 1.98 (m, 2H), 1.50 1.40 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (DMSO d 6 ): 162.5, 143.9, 135.9, 130.0, 129.4, 129.2, 128.5, 127.3, 127.0, 113.9, 113.1, 47.1, 30.4, 21.4, 19.1, 13.4; Anal. Calcd. For C 19 H 22 IN 3 : C, 54.42; H, 5.29; N, 10.02. Found: C, 54.43; H, 5.31; N, 9.90. N (3 butylbenzimidazol 3 ium 1 yl) 1 ( 4 nitrophenyl)methanimine iodide ( 3. 6e ). Brown crystals (100%), mp 217.0 219.0 C; 1 H NMR (DMSO d 6 ): 10.57 (s, 1H), 9.55 (s, 1H), 8.47 (d, J = 8.4 Hz, 2H), 8.32 (d, J = 8.7 Hz, 2H), 8.28 8.20 (m, 2H), 7.83 7.77 (m, 2H), 4.60 (t, J = 7.2 Hz, 2H), 2.01 (quintet, J = 7.4 Hz, 2H), 1.44 (sextet, J = 7.8 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 160.0, 149.8, 137.0, 136.5, 130.3, 130.1, 129.4, 127.6, 127.3, 124.4, 114.0, 113.3, 47.2, 30.4, 19.1, 13.4; Anal. Calcd. For C 18 H 19 IN 4 O 2 : C, 48.01; H, 4.25; N, 12.44. Found: C, 47.73; H, 4.14; N, 12.18, 4 [(E) (3 Butylbenzimidazol 3 ium 1 yl)iminomethyl] N,N diethylaniline iodide ( 3. 6f ). Yellow microcrystals (100%), mp 151.0 152.0 C; 1 H NMR (DMSO d 6 ): 10.35 (s, 1H), 9.03 (s, 1H), 8.18 8.14 (m, 1H ), 8.07 8.03 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.74 7.71 (m, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.53 (t, J = 7.2 Hz, 2H), 3.47 (q, J = 6.8 Hz, 4H), 1.97 (quintet J = 7.5 Hz, 2H), 1.41 (sextet, J = 7.5 Hz, 2H), 1.15 (t, J = 7.0 Hz, 6H), 0.95 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 163.0, 151.3, 135.5, 131.6, 130.1,

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52 129.5, 126.9, 126.9, 116.9, 113.7, 113.1, 111.3, 46.8, 44.0, 30.6, 19.1, 13.4, 12.4; Anal. Calcd. For C 22 H 29 IN 4 : C, 55.47; H, 6.14; N, 11.76. Found: C, 55.11; H, 6.13; N, 11.57. 1,3 Dimethylbenzimidazol 3 ium iodide ( 3. 7 ) White needles (94%), mp 193.0 C (lit. 105 mp 190 .0 191 .0 C); 1 H NMR (DMSO d 6 ): 9.76 (s, 1H), 8.12 7.98 (m, 2H), 7.76 7.65 (m, 2H), 4.12 (s, 6H); 13 C NMR (DMSO d 6 ): 142.8, 131.4, 126.2, 113.2, 33.5. 3.3.3 General M ethod for the P reparation of NHC CS 2 B etaines 3. 9a c, 3. 10 Sodium hydride (1.2 equivalents ) was added to a mixture of carbon disulfide (2 equivalents) and 1,3 dimethylbenzimidazolium iodide 3. 7 or N (3 butylbenzimidazol 3 ium 1 yl) 1 (aryl)methanimine iodides 3. 6a c in dry THF and stirred for 5 h (12 h in the case of 3. 7 ) at room temperature u nder argon. The solution was filtered, the filtrate concentrated under reduced pressure and the residue was recrystallized from EtOH to obtain the corresponding NHC CS 2 betaines 3. 9a c 3. 10 1 Butyl 3 [(E) (4 methoxyphenyl)methyleneamino] benzimidazol 1 i um 2 carbodithioate ( 3. 9a ). Red crystals (70%), mp 160.0 161.0 C; 1 H NMR (DMSO d 6 ): 9.25 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.93 7.87 (m, 3H), 7.73 7.61 (m, 2H), 7.14 (d, J = 8.7 Hz, 2H), 4.44 (t, J = 7.7 Hz, 2H), 3.87 (s, 3H), 1.91 (quintet, J = 7.5 Hz, 2H), 1.38 (sextet, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13 C NMR (DMSO d 6 ): 222.6, 168.2, 163.5, 146.6, 131.4, 128.1, 127.3, 126.6, 123.6, 114.7, 113.5, 112.8, 55.7, 44.7, 30.4, 19.3, 13.4. 1 [(E) Benzylideneamino] 3 butyl benzimidazol 3 iu m 2 carbodithioate ( 3. 9b ). Red crystals (76%), mp 171.0 172.0 C; 1 H NMR (DMSO d 6 ): 9.38 (s, 1H), 8.09 8.05 (m, 1H), 8.00 7.92 (m, 3H), 7.74 7.65 (m, 3H), 7.64 7.56 (m, 2H), 4.45 (t, J = 7.7 Hz, 2H), 1.92 (quintet, J = 7.2 Hz, 2H), 1.39 (sextet J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H);

PAGE 53

53 13 C NMR (DMSO d 6 ): 222.5, 168.2, 146.6, 133.5, 131.3, 129.2, 129.1, 128.2, 127.2, 126.7, 113.5, 113.0, 44.7, 40.3, 30.4, 19.3, 13.4; Anal. Calcd. For C 19 H 19 N 3 S 2 : C, 64.56; H, 5.42; N, 11.89. Found: C, 64.34; H 5.47; N, 11.85. 1 [(E) (4 Bromo 2 thienyl)methyleneamino] 3 butyl benzimidazol 3 ium 2 carbodithioate ( 3. 9c ). Red crystals (68%), mp 170.0 173.0 C; 1 H NMR (DMSO d 6 ): 9.47 (s, 1H), 8.16 (s, 1H), 8.10 8.03 (m, 1H), 7.98 7.93 (m, 1H), 7.90 (s, 1H), 7.75 7.65 (m, 2H), 4.46 4.38 (m, 2H), 1.95 1.85 (m 2H), 1.45 1.32 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 221.9, 160.7, 146.6, 138.4, 136.3, 131.4, 128.2, 127.0, 126.8, 113.6, 112.9, 110.2, 44.8, 30.3, 19.3, 13.4; Anal. Calcd. For C 17 H 16 BrN 3 S 3 : C, 46.57; H, 3.68; N, 9.58. Found: C, 46.26; H, 3.53; N, 9.30. 1,3 Dimethylbenzimidazol 3 ium 2 carbodithioate ( 3. 10 ). Red crystals (85%), mp 235.0 236.0 C (lit. 97 mp 237 .0 238 .0 C); 1 H NMR (DMSO d 6 ): 7.92 (dd, J = 6.0, 3.0 Hz, 2H), 7.64 (dd, J = 6.0, 3.0 Hz, 2H), 3.88 (s, 6H); 13 C NMR (DMSO d 6 ): 223.8, 151.5, 129.9, 126.0, 112.9, 31.0; Anal. Calcd. For C 10 H 10 N 2 S 2 : C, 54.02; H, 4.53; N, 12.60. Found: C, 53.87; H, 4.44; N, 12.39. (1,3 Dimethylbenzimidazol 3 ium 2 carbothioyl) isopropyl azanide ( 3. 12 ). Colourless crystals (86%), mp 140.0 141.0 C; 1 H NMR (DMSO d 6 ): 8.14 (dd, J = 6.3, 3.0 Hz, 2H), 7.74 (dd, J = 6.3, 3.0 Hz, 2H), 3.99 (s, 6H), 1.37 (d, J = 6.6 Hz, 6H); 13 C NMR (DMSO d 6 ): 173.9, 145.1, 130.5, 127.3, 113.7, 47.8, 32.2, 20.2; Anal. Calcd. For C 13 H 17 N 3 S.H 2 O: C, 58.84; H, 7.22; N, 15.83. Found: C, 58.97 ; H, 7.40; N, 15.86. 3.3.4 General M ethod for P reparation of S pirocyclic D erivatives 3. 13a b Sodium hydride (1.2 equivalents) was added to a mixture of isopropyl isothiocyanate (2.2 equivalents) and the corresponding N (3 butylbenzimidazol 3 ium 1 yl) 1 (a ryl)methanimine iodides 3. 6a b in dry THF and stirred for 5h at room

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54 temperature under argon. The solution was filtered, the filtrate concentrated under reduced pressure and the residue was recrystallized from EtOAc to obtain pure spirocyclic derivatives 3 13a b as red crystals. 1 Butyl 1',3' diisopropyl 3 [(E) (4 methoxyphenyl) methyleneamino]spiro[benzimidazole 2,5' imidazolidine] 2',4' dithione ( 3. 13a ). Red crystals (77%), mp 141.0 142.0C; 1 H NMR (DMSO d 6 ): 7.84 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7. 26 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.83 (t, J = 7.5 Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 5.68 (br s, 1H), 4.13 4.03 (m, 1H), 3.77 (s, 3H), 3.19 2.96 (m, 2H), 1.65 1.52 (m, 8H), 1.38 1.29 (m, 5H), 1.23 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 160.3, 139.6, 136.6, 132.2, 127.4, 121.4, 118.2, 114.3, 107.8, 104.8, 103.9, 99.4, 55.2, 42.8, 29.6, 19.8, 19.0, 17.9, 13.5; Anal. Calcd. For C 27 H 35 N 5 OS 2 : C, 63.62; H, 6.92; N, 13.74. Found: C, 63.80; H, 7.21; N, 13.76. 1 [(E) Benzylideneamino] 3 butyl 1 ',3' diisopropyl spiro[benzimidazole 2,5' imidazolidine] 2',4' dithione ( 3. 13b ) Red crystals (74%), mp 116.0 119.0 C; 1 H NMR (DMSO d 6 ): 7.85 (s, 1H), 7.61 7.55 (m, 2H), 7.42 7.30 (m, 4H), 6.86 (t, J = 7.7 Hz, 1H), 6.74 (t, J = 7.7 Hz, 1H), 6.67 ( d, J = 7.6 Hz, 1H), 5.68 (br s, 1H), 4.16 4.05 (m, 1H), 3.20 2.97 (m, 2H), 1.64 1.48 (m, 8H), 1.38 1.29 (m, 5H), 1.23 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (DMSO d 6 ): 139.0, 136.6, 134.8, 131.9, 129.2, 128.7, 125.8, 121.8, 118.2, 108.3, 105.0, 103.6, 42.8, 29.5, 19.8, 19.0, 17.9, 13.6; Anal. Calcd. For C 26 H 33 N 5 S 2 : C, 65.10; H, 6.93; N, 14.60. Found: C, 65.10; H, 7.06; N, 14.58. 3.3.5 General M ethod for P reparation of NHC RC(O) NCS B etaines 3. 15a c, 3. 16 Sodium hydride (1.2 equival ents) was added to a mixture of benzoylisothiocyanate and the corresponding close up N (3 butylbenzimidazol 3 ium 1 yl) 1 (aryl)methanimine

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55 iodides 3. 6a c in 1/1 molar ratio in dry THF and stirred for 5 h (12 h in the case of 3. 7 ) at room temperature unde r argon. The solution was filtered, the filtrate concentrated under reduced pressure and the residue was purified by flash chromatography using EtOAc/hexanes to obtain betaine adducts 3. 15a c 3. 16 Benzoyl [1 butyl 3 [(E) (4 methoxyphenyl)methyleneamino]b enzimidazol 1 ium 2 carbothioyl]azanide ( 3. 15a ). Yellow microcrystals (83%), mp 126.0 128.0C; 1 H NMR (DMSO d 6 ): 9.35 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.03 7.94 (m, 5H), 7.75 7.65 (m, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 4.63 (t, J = 7.2 Hz, 2H), 3.89 (s, 3H), 2.02 1.92 (m, 2H), 1.47 1.36 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 179.1, 169.8, 168.2, 163.6, 145.1, 133.7, 132.3, 131.6, 129.2, 128.9, 128.3, 127.5, 126.8, 123.8, 114.8, 113.6, 113.2, 55.7, 45.2, 30.6, 19.4, 13.5; Anal. Calcd. For C 27 H 26 N 4 O 2 S: C, 68.91; H, 5.57; N, 11.91. Found: C, 68. 63; H, 5.63; N, 11.73. Benzoyl [1 [(E) benzylideneamino] 3 butyl benzimidazol 3 ium 2 carbothioyl]azanide ( 3. 15b ) Yellow crystals. (77%), mp 125.0 127.0 C; 1 H NMR (DMSO d 6 ): 9.48 (s, 1H), 8.18 8.08 (m, 2H), 8.04 7.94 (m, 4H), 7.78 7.69 (m, 3H), 7.63 (t, J = 7.4 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 4.64 (t, J = 7.3 Hz, 2H), 2.05 1.93 (m, 2H), 1.43 (sextet, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13 C NMR (DMSO d 6 ): 179.0, 169.8, 168.1, 145.3, 133.7, 133.5, 132.3, 131 .3, 129.3, 129.1, 128.9, 128.2, 127.2, 126.9, 126.9, 113.6, 113.2, 45.2, 30.5, 19.3, 13.4; Anal. Calcd. For C 26 H 24 N 4 OS: C, 70.88; H, 5.49; N, 12.72. Found: C, 70.57; H, 5.60; N, 12.51. Benzoyl [1 [(E) (4 bromo 2 thienyl)methyleneamino] 3 butyl benzimidazo l 3 ium 2 carbothioyl]azanide ( 3. 15c ). Yellow crystals (74%), mp 151.0 154.0 C; 1 H NMR

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56 (DMSO d 6 ): 9.55 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 7.3 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.87 (s, 1H), 7.75 7.66 (m, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 4.61 (t, J = 7.2 Hz, 2H), 1.99 1.90 (m, 2H), 1.46 1.34 (m, 2H ), 0.89 (t, J = 7.4 Hz, 3H); 13 C NMR (DMSO d 6 ): 179.1, 170.1, 161.0, 145.6, 138.7, 136.5, 133.8, 132.5, 131.8, 129.4, 129.0, 128.6, 128.4, 127.1, 127.1, 113.8, 113.3, 110.4, 45.4, 30.5, 19.4, 13.5; Anal. Calcd. For C 24 H 21 BrN 4 OS 2 : C, 54.86; H, 4.03; N, 10 .66. Found: C, 55.19; H, 4.09; N, 10.42. Benzoyl (1,3 dimethylbenzimidazol 3 ium 2 carbothioyl)azanide ( 3. 16 ) Yellow crystals (85%), mp 207.0 210.0 C; 1 H NMR (DMSO d 6 ): 8.02 7.94 (m, 4H), 7.69 7.64 (m, 2H), 7.59 (d, J = 6.7 Hz, 1H), 7.55 7.48 (m, 2H), 4.02 (s, 6H); 13 C NMR (DMSO d 6 ): 178.7, 172.0, 150.0, 134.2, 132.4, 130.4, 129.2, 128.5, 126.2, 113.1, 31.7; 3.3.6 General M ethod for A mination To a solution of 1 amino benzimidazole 2 or its imine derivatives 4a f in dichloromethane/ethanol (5:1), O (2, 4 dinitrophenyl) hydroxylamine ( 1.5 equiv ) was added with stirring over a period of 2 3 min. The mixture was heated under reflux for 5 h After cooling and standing for 30 min, the solid was filtered off, washed twice with ethyl acetate (20 mL) and d ried under vacuum to obtain the corresponding 2,4 dinitrophenolate salts. Benzimidazol 3 ium 1,3 diamine; 2,4 dinitrophenolate ( 3. 18 ) Brown microcrystals (80%), mp 166.0 168.0 C; 1 H NMR (DMSO d 6 ): 9.88 (s, 1H), 8.60 (d, J = 3.0 Hz, 1H), 7.93 7.87 (m, 2H), 7.80 (dd, J = 9.8, 3.2 Hz, 1H), 7.75 7.67 (m, 2H), 6.91 (s, 4H), 6.34 (d, J = 9.9 Hz, 1H); 13 C NMR (DMSO d 6 ): 169.7, 142.4, 136.1, 131.0, 127.8,

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57 127.5, 126.5, 126.1, 124.8, 112.9; Anal. Cal cd. For C 13 H 12 N 6 O 5 : C, 46.99; H, 3.64; N, 25.29. Found: C, 46.96; H, 3.49; N, 25.14. 3 [(E) (4 Methoxyphenyl)methyleneamino]benzimidazol 1 ium 1 amine; 2,4 dinitrophenolate ( 3. 19a ). Yellow microcrystals (42%), mp 146.0 148.0 C; 1 H NMR (DMSO d 6 ): 10.40 (s, 1H), 9.23 (s, 1H), 8.58 (d, J = 3.9 Hz, 1H), 8.13 8.09 (m, 1H), 8.01 7.95 (m, 3H), 7.80 7.72 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.13 (s, 2H), 6.30 (d, J = 9.8 Hz, 1H); 13 C NMR (DMSO d 6 ): 170.3, 165.1, 163.4, 162.5, 136.0, 131.3, 131.1, 128.5, 127.4, 126.9, 126.5, 125.0, 123.7, 114.9, 113.3, 112.9, 109.2, 55.7; Anal. Calcd. For C 21 H 18 N 6 O 6 : C, 56.00; H, 4.03; N, 18.66. Found: C, 55.86; H, 3.86; N, 18.58. 3 [(E) P Tolylmethyleneamino]benzimidazol 1 ium 1 amine; 2,4 dinitrophenolate ( 3. 19d ). Brown microcrystals (40%), mp 132.0 134.0 C; 1 H NMR (DMSO d 6 ): 10.45 (s, 1H), 9.28 (s, 1H), 8.58 (d, J = 3.3 Hz, 1H), 8.14 8.11 (m, 1H), 8.01 7.97 (m, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.80 7.72 (m, 3H), 7.45 (d, J = 7.9 Hz, 2H), 7.16 (s, 2H), 6.32 (d, J = 9.8 Hz, 1H), 2.43 (s, 3H); 13 C NMR (DMSO d 6 ): 169.9, 16 2.5, 143.9, 136.0, 135.9, 131.0, 129.9, 129.1, 128.6, 128.5, 127.7, 127.5, 127.4, 126.9, 126.3, 124.8, 113.2, 112.9, 21.3; Anal. Calcd. For C 21 H 18 N 6 O 5 : C, 58.06; H, 4.18; N, 19.35. Found: C, 57.64; H, 4.05; N, 19.38. 3 [(E) [4 (Diethylamino)phenyl]methylen eamino]benzimidazol 1 ium 1 amine; 2,4 dinitrophenolate ( 3. 19f ). Brown microcrystals (60%), mp 180.0 C; 1 H NMR (DMSO d 6 ): 10.38 (s, 1H), 9.01 (s, 1H), 8.63 (d, J = 2.7 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.88 (dd, J = 9.6, 3.0 Hz, 1H), 7.80 7.68 (m, 4H), 7.09 (br s, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 9.6 Hz, 1H), 3.46 (q, J = 6.6 Hz, 4H), 1.16 (t, J = 6.8 Hz, 6H); 13 C NMR (DMSO d 6 ): 168.6, 162.8, 151.2, 136.0, 135.7, 131.5, 131.1, 129.0,

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58 128.5, 127.7, 127.0, 126.7, 125.5, 124.5, 117.0, 113.1, 112.8, 111.1, 43.9, 12.3; Anal. Calcd. For C 24 H 25 N 7 O 5 : C, 58.65; H, 5.13; N, 19.95. Found: C, 58 .32; H, 5.26; N, 19.88.

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59 CHAPTER 4 REVERSIBLE DISSOCIAT ION OF SPIRODITHIOHY DANTOINS 4.1 Introduction Hydantoins, thiohydantoins and dithiohydantoins are 5 membered heterocycles of great importance due to their interesting biological activities. Their deri vatives have medical applications such as antiepileptic drugs, 111 112 anti HIV 1, 113 114 anticonvulsant, 115 116 antitumor 117 119 and antileishmaniasis agents. 120 Such systems have also been shown to be important building blocks for the synthesis of biologically active complex molecules. 121 S tructural motifs of these heterocycles are shown on Figure 4 1. Figure 4 1. Structural motifs of hydantoin, thiohydantoin and dithiohydantoin Hydantoin libraries created and evaluated to determine structure activity relationships, 122 emphasize the crucial importance of substitution at position 5 for pharmacological activity 122 123 Cycloalkane spiro 5 hydantoins and thiohydantoins have been tested as aldosoreductase inhibitors. 124 Selected examples of biologically active compounds of this type are presented i n Fig ure 4 2. Figure 4 2. Selected examples of biologically active hydantoin s and dithiohydantoin s

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60 Among num erous reactions available for the formation of 5 membered heterocycles, 1,3 dipolar cycloadditions are extremely important due to their effectiveness and selectively. 4 125 126 Although, reports of such molecules are increasing, there are less than 1 0 report s on spirodithiohydantoin derivatives 39 87 127 133 of the type shown i n Figure 4 3 Figure 4 3. Spirodithiohydantoin scaffold I n C hapter 3, the synthesis of novel spi rodithiohydantoins 3.13a,b from N aminobenzimidazole is described 39 Further study has demonstrated, that these spirocyclic systems undergo a thermal dissociation, a phenomenon not previously reported. Herein, I report the NMR and mass spectrometric analysis of the dissociation reaction of 3.13a,b 4.2 Results and Discussion 4.2.1 NMR S tudy of the F ormation of Z witterionic B etaines F rom S pirodithiohydantoins Reversible dissociation of t he spirodithiohydantoins 3.13a b occurs above 50 C (Scheme 4 1 ) This phenomenon has been studied by 1 H NMR at various temperatures and time intervals at concentrations of (15mg/m L in DMSO d 6 ) ( Scheme 4 2, Figure 4 4 ). At 50 C and above 3.13a gave the zwitterionic betaine 4. 1 a and the concentration of 4. 1 a increased with time at any given temperature. Figure 4 4 summarizes changes in the ratio [ 4. 1 a ]:[ 3.13a ] as the temperature was gradually increased from 25 C to 80 C over 300 minutes.

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61 Scheme 4 1 D issociation of the spirodithiohydantoins 3.13a Time (min) Figure 4 4 Variation of [ 4. 1 a ]:[ 3.13a ] ratios with temperature and time. This phenomenon was studied by 1 H and 13 C NMR and by direct insertion probe (DIP EI) mass spectr ometric analysis. Formation of zwitterionic betaine 4. 1 a and isopropyl isothiocyanate 4. 2 was detected by a number of changes in the NMR spectra. The singlet at 9.3 ppm, doublet at 7.8 ppm ( J = 8.8 Hz), multiplet at 7.7 7.6 ppm, doublet at 7.1 ppm ( J = 8 .8 Hz), multiplet at 4.5 4.4 ppm, singlet at 3.9 ppm, multiplet Temperature C

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62 at 2.0 1.9 ppm, doublet at 1.0 ppm ( J = 6.5 Hz) and triplet at 0.9 ( J = 7.3 Hz) were assigned and used for qualitative and quantitative determination of the equilibrium ratio of [ 4. 1 a ]:[ 3. 13a ] Formation of free isopropyl isothiocyanate 4. 2 was suggested by the appearance of a multiplet at 4.1 4.0 ppm and a doublet at 1.3 ppm (J = 6.4 Hz) as shown in Figure 4 5 and Figure 4 6 Figure 4 5 NMR study of [ 4. 1 a ]:[ 3.13a ] ratios with tempera ture and time

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63 Figure 4 6 Expanded aliphatic region of NMR study of [ 4. 1 a ]:[ 3.13a ] ratios with temperature and time The formation of isopropyl isothiocyanate 4. 2 was confirmed by 13 C NMR of the heated sample and direct insertion probe (DIP EI) mass s pectrometry. D irect insertion probe (DIP EI) mass spectrometry data revealed a molecular ion M = 101 (100%) together with M+1 = 102 (58%) and M+2 (8%) (Figure 4 7) These data are consistent with the formation of isopropyl isothiocyanate 4. 2 and betaine 4. 1 a

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64 Figure 4 7. D irect insertion probe (DIP EI) mass spectrometry analysis of reaction mixture 4.2.2 NMR S tudy of the F ormation of P arent D ithiohydantoin In order to study the equilibrium further the reverse reaction, that is the formation of the spirocyclic system 4.1 a was monitored. Once the ratio of [ 4. 1 a ]:[ 3.13a ] reached 0.5, the sample was divided in two, allowed to cool room temperature, and excess (10 fold) isopropyl isothiocyanate added to one sample. Immediate 1 H NMR analysis proved the ratio [ 4. 1 a ]:[ 3.13a ] = 0.5 was not changed in either sample. There was however, a significant increase in the rate of the reversible reaction 4. 1 a 3.13a in the presence of excess isopropyl isothiocyanate since in the presence of excess isopropyl isothio cyanate reversal was complete in 33 h, whereas reversal without excess isopropyl isothiocyanate took 7 days (Fig ure 4 8 ).

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65 Figure 4 8 Formation of parent 3.13a with and without presence of excess isopropyl isothiocyanate 4.2.3 In situ F ormation and T r apping of NHC H eating of spirodithiohydantoin 3.13a and its analogue 3.13b at 80 C and above resulted in the formation of an equivalent of isopropyl isothiocyanate 4. 2 and the corresponding N heterocyclic carbenes 4. 3 a and 4. 3 b (Scheme 4 2 ). Scheme 4 2 Reversible formation of zwitterionic betains 4.1 a b and free NHCs 4. 3 a b The f ormation of the N heterocyclic carbene (NHC) species was confirmed by trapping it with elemental sulfur. Wh en 3 .1 3a and 3.13b were heated with excess

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66 elemental sulfur at 80 C for 5h novel compounds 4. 4 a and 4. 4 b were formed and characterized by 1 H 13 C NMR a nd elemental analysis (Scheme 4 3 ) Scheme 4 3 Synthesis of novel 4. 4 a b from spirodithiohydantoins The spectral data of 4. 4 a and 4. 4 b were found to be identical to those obtained by th e reaction of sulfur with in situ generated carbenes from benzimidazolium salts 3.6a and 3.6b (Scheme 4 4 ). Scheme 4 4 Synthesis of novel 4. 4 a b from 1 (benzylidineamino)benzimidazolium iodides 3.6a b F ormation of NHC s 4.3a,b from spirodithiohydantoins 3.13a,b is a novel phenomenon and may be used to generate NHCs in latent catalysis. Previous reports of the us e of NHC adducts as latent catalysts generally involve a transition metal, 86 134 carbon dioxide, 84 135 carbonyl sulfide or isothiocyanate. 93 Use of zwitterionic adducts

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67 c a n however be limited due to their 1,3 dipolar nature st ability and temperature needed for such transformations. 93 136 W hereas spirocyclic compounds are inert at room temperature and can be used to generate NHC as latent catalys ts T emperature needed for this process is 80 C, significantly lower than similar NHC isothiocyanate adducts reported in the literature (12 0 C). 92 4.3. Experimental Section 4.3.1 General M ethods Melting points were determined on a capillary point apparatus equipped with a digital the r mometer. NMR spectra were recorded in CDCl 3 or DMSO d 6 with TMS for 1 H (300 MHz) and 13 C (75 MHz) as internal reference. Elemental analyses were performed on a Carlo Erba 1106 i n strument. All solvents were freshly distilled before use and all reactions carried under nitrogen atmosphere. 4.3. 2 General P rocedure for the P reparation of S pirodithiohydantoins 3.13a b Spirodithiohydantoins 3.1a b were prepared according to the procedure described in Chapter 3. 4.3. 3 General P rocedure for the P reparation of B enzimidazolium salts 3.6a b Benzimidazolium salts 3.6a b we re prepared according to the procedure described in Chapter 3. 4.3.4 General P rocedure for the P reparation of B enz i midazole thiones 4. 4 a b F rom S pirodithiohydantoins 3.13a b Spirodithiohydantoin 3.13a b and elemental sulfur (10 equiv) were mixed and heate d at 80 C for 5h without solvent After 5 h, reaction mixture was purified by flash chromatography using EtOAc/Hexanes to get pure benzimidazole thione 4. 4 a b

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68 4.3.5 General P rocedure for the P reparation of B enzimidazole thiones 4. 4 a b F rom Benzimidazoli um S alts 3.6a b Sodium hydride (0.031 g, 1.3 mmol) was added to a mixture of corresponding benzimidazolium iodide 3.6a b (0.405 g, 1.0 mmol) and elemental sulfur (0. 128 g, 4.0 mmol) in dry THF (30 mL) and stirred for 5 h at room temperature under argon at mosphere. After 5 hours the solution was filtered, filtrate was concentrated under reduced pressure and purified by flash chromatography using EtOAc/Hexanes to get pure benzimidazole thione 4. 4 a b (E) 1 butyl 3 ((4 methoxybenzylidene)amino) 1H benzo[d]im idazole 2(3H) thione ( 4.4a ) Colorless oil (90%), 1 H NMR (CDCl 3 ): 10.07 (s, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.50 7.46 (m, 1H), 7.27 7.18 (m, 3H), 6.99 (d, J = 8.7 Hz, 2H), 4.35 (t J = 7.5 Hz, 2H), 1.89 1.79 (m, 2H), 1.53 1.41 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H) ; 13 C NMR (CDCl 3 ): 163.6, 162.4, 161.1, 131.5, 130.1, 129.8, 125.6, 123.2, 122.8, 114.1, 109.9, 108. 5, 55.4, 44.1, 29.9, 20.2, 13.8; Anal. Calcd. For C 1 9 H 21 N 3 OS: C, 67.23 ; H, 6. 24 ; N, 1 2.38 Found: C, 67.26 ; H, 6.38 ; N, 1 2.33 (E) 1 (benz ylideneamino) 3 butyl 1H benzo[d]imidazole 2(3H) thione ( 4.4b ) Colorless oil (88%), 1 H NMR (CDCl 3 ): 10.36 (s, 1H), 7.97 7.94 (m, 2H), 7.54 7.45 (m, 4H), 7.29 7.18 (m, 3H), 4.35 (t, J = 7.5 Hz, 2H), 1.89 1.79 (m, 2 H), 1.51 1.41 (m, 2H), 1.00 ( t, J = 7.2 Hz, 3H). 13 C NMR (CDCl 3 ): 163.8, 160.3, 133.3, 131.7, 130.0, 128.8, 128.5, 123.5, 123.0, 110.2, 108.7, 44.0, 29.8, 20.2, 13.9. Anal. Calcd. For C 1 8 H 19 N 3 S: C, 69.87 ; H, 6.19 ; N, 13.58 Found: C, 69.98 ; H, 6.42 ; N, 13.43

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69 CHAPTER 5 CU (I) CATAL YZED NOVEL, REGIOSEL ECTIVE SYNTHESIS OF PYRAZOLO[5,1 C] 1,2,4 TRIAZOLES 5.1 Introduction P yrazoloazines and pyrazoloazoles with bridgehead nitrogen have aroused interest in their synthesis due to their diverse applications The pyrazolo[5,1 c ] 1,2,4 triaz ole s have unique properties and have been studied as azo dyes, 40 41 inkjets and color filters, 42 photographic materials, 43 44 electrophotographic toners, 45 a ntibacterial agents with reduced human toxicity 46 and antitumor agents. 47 The synthetic methods for the preparation of pyrazolo[5,1 c ] 1,2,4 triazole systems fall into three groups: (i) starting from substituted pyrazolo derivatives such as 3 amino, 137 138 3 hydrazino, 40 139 144 3 hydroxy 138 or 3 diazonium salts, 145 146 (ii) cyclic condensations of 4 amino 5 thioxo 1,2,4 triazoles, 147 3,4 diamino 1,2,4 triazoles, 148 149 3 methylthio 1,2,4 triazolium salts 150 or 4 amino 1,2,4 triazolium salts 151 and (iii) ring contraction of [1,2,4]triazolo[3,4 b ][1,3,4]thiadiazines 152 153 (Scheme 5 1). Interest in the chemistry of heterocyclic compounds derived from 4 amino 1,2,4 triazole resulted in a novel, efficient process for the regioselective preparation of pyrazolo[5,1 c ] 1,2,4 tri azole derivatives Herein, I report a one pot, Cu (I) catalyzed synthesis of the pyrazolo[5,1 c ] 1,2,4 triazole moiety, starting from 1,2,4 triazolium N imides and terminal alkynes. I have examined the scope of alkyne substrates the effect of variations i n the 1 alkyl substituent and the nature of the leaving group on the course of the reactions. 154 Reproduced with permission from The Journal of Organic Chemi stry 201 2 ASAP, DOI: 10.1021/jo300611a Copyright 201 2 American Chemical Society

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70 Scheme 5 1 Literature synthesis of pyrazolo[5,1 c ] 1,2,4 triazole s 5.2 R esults and D iscussion 1,2,4 Triazolium N imides 5 3a d and 5 5a b were prepared in 83 94% yield via a two step procedure. Sulfonimids 5 3a d were prepared by rea ction of 4 amino 1,2,4 triazolium salts 5.2a c with the corresponding arylsulfonyl chlorides. 155 156 In the case of N nitroimides 5 5a b we first generated 1,2,4 triazolium N nitroimide 5.4 by nitration 157 followed by reaction with the corresponding alkyl halides 158 (Table 5 1).

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71 Table 5 1. Synthesis of 1,2,4 triazoliun N imides Entry Product 5.2a c Product 5.3a d Product 5.5a,b R X Yield (%) R Ar Yield (%) R Yield (%) a Bn Br >99 Bn 4 Me C 6 H 4 94 Bn 57 b Me I >99 Me 4 Me C 6 H 4 83 Me 93 c n Bu Br >99 n Bu 4 Me C 6 H 4 88 d n Bu 4 NO 2 C 6 H 4 91 Substrate 5 3a underwent a one pot, Cu (I) catalyzed reaction with phenylacetylene 5 6a under basic conditions to give 5 7a We then investigated the effects of various parameters to optimize the conditions and study the regiochemical outcome of the react ion (Table 5 2). The reaction of (1 benzyl 1 H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide 5 3a with phenylacetylene 5 6a in the presence of 5 mol% Cu 2 Br 2 and pyridine (3 equiv) at room temperature gave 1 benzyl 6 phenyl 1 H pyrazolo[5,1 c ][1,2,4]triazole 5 7a as a single regioisomer in 62% yield. In the absence of catalyst or base there was either no conversion or a reduced yield. An increase of catalyst loading had a deleterious effect (Table 5 2).

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72 Table 5 2. Optimization of reaction conditions Entry Solvent t C /time Catalyst Base 5. 7a 5. 7a' 1 CH 2 Cl 2 25 C/24h 0 0 2 CH 2 Cl 2 40 C/24h 0 0 3 THF 60 C/24h Et 3 N 0 0 4 CH 2 Cl 2 25 C/24h 5% Cu 2 Br 2 Pyridine 62 0 5 CH 2 Cl 2 25 C/24h 5% Cu 2 Br 2 30 0 6 CH 2 Cl 2 25 C/24h 20% C u 2 Br 2 Pyridine 20 0 7 CH 2 Cl 2 25 C/24h 5% Cu 2 Br 2 Et 3 N 45 0 8 CH 2 Cl 2 25 C/24h 1% Cu 2 Br 2 Pyridine 25 0 9 CH 2 Cl 2 25 C/24h 10% CuOAc Pyridine <5 0 10 CH 2 Cl 2 25 C/24h 10% AgOTf Pyridine <15 0 11 CH 2 Cl 2 40 C/24h 5% Cu 2 Br 2 Pyridine 26 0 12 THF 60 C/24h 5% Cu 2 Br 2 Pyridine <15 0 Using the optimized conditions, we examined the scope of this transformation (Table 5 3). 1,2,4 Triazol 1 ium amides 5 3a d 5 5a b were reacted with terminal or disubstituted alkynes 5 6a d While terminal alkynes 5 6a b gave d esired products 5 7a f in 62 78% yields, attempts to use disubstituted aromatic alkynes 5 6c d resulted in recovery of starting materials.

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73 Table 5 3. Synthesis of pyrazolo[5,1 c ] 1,2,4 triazoles Entry Substrate 5.3 Subst rate 5.6 Product 5.7 Yield (%) 1 5 3a 5 6a 5 7a 62 2 5 3a 5 6b 5 7b 65 3 5 5a 5 6a 5 7a 72 4 5 5a 5 6b 5 7b 69 5 5 3b 5 6a 5 7c 54 6 5 3b 5 6b 5 7d 57

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74 Table 5 3. C ontinued Entry Substrate 5.3 Substrate 5.6 Product 5.7 Yield (%) 7 5 5b 5 6a 5 7c 62 8 5 5b 5 6b 5 7d 73 9 5 3c 5 6a 5 7e 75 10 5 3c 5 6b 5 7f 71 11 5 3d 5 6a 5 7e 78 12 5. 3d 5. 6b 5. 7f 70

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75 Table 5 3. Continued Entry Substrate 5.3 Substrate 5.6 Product 5.7 Yield (%) 13 5.3c 5.6c 5.7g 68 14 5. 3d 5.6c 5.7g 77 1 5 5 3a 5 6 d 5 7 h 0 1 6 5 3a 5 6 e 5 7 i 0 Based on these results, copper (I) mediated formation of intermediate C followed by a double bond migration and elimination of NO 2 or the arylsulfonyl moiety is proposed to give pyrazolo[5,1 c ] 1,2, 4 triazoles 5.7a g (Scheme 5 2 ).

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76 Scheme 5 2. Proposed mechanism for the Cu (I) catalyzed regioselective synthesis of pyrazolo[5,1 c ] 1,2, 4 triazoles 5.7a g Attempts to synthesize the pyrazolo 1,2,4 triazole moiety by a Cu (I) catalysed one pot reaction using methyl propiolate 5 6 f resulted in the regioselective formation of a compound which contained the N tosyl moiety. Based on 1 H an d 13 C NMR and HRMS spectral data, it was identified as 5 8a (Table 5 4 ). Similarly, the reaction with DMAD 5 6 g and ethyl but 2 ynoate 5 6 h furnished compounds 5 8b c in 98 99% yields. No catalyst was needed for these reactions, but ethyl acrylate 5 6 i and fumaronitrile 5 6 j failed to react as dipolarophiles (Table 5 4 ). This outcome is probably the result of extended conjugation between the nitrogen lone pair and ester moiety in intermediate I (Scheme 5 3 ) which clearly would be absent in the analogous int ermediates from 5 6 i and 5 6 j

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77 Table 5 4. Reactions of 1,2,4 triazolium N imide 5.3 a with electron deficient dipolarophiles 5.6f j Entry Substrate 5.3a Substrate 5.6 f j Product 5.8a f Yield (%) 1 5 3a 5 6 f 5 8a >99 2 5 3a 5 6 g 5 8b >99 3 5 3a 5 6 h 5 8c 98 4 5. 3a 5 6 i 5 8d 0 5 5 3a 5 6 j 5 8e 0 I pr opose that, a [3+2] dipolar cycloaddition of 5 3a with 5 6 f h is followed by a ring opening rearrangement to regenerate the aromatic 1,2,4 triazole unit 159 161 t hus producing 5 8a c (Scheme 5 3 ).

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78 Scheme 5 3. Proposed mechanism for the reactions of 1,2,4 triazolium N imide 5.3 a with propiolates 5.6f h To rationalize the different regiochemistry dependent on the acetylene reactant used (phenylacetylene or methyl propiolate) and gain further insight into this process, Dr. Alexander Oliferenko employed theory and computations. 154 Table 5 3 and Table 5 4 demonstrate that phenylacetylene adds to 5 3a d and 5 5a b to fashion, considering the 1,2,4 triazole ring and the phenyl ring as the heads in 5 3a and 5 6a respectively. Unlike phenylacetylene, methyl propiolate 5 6 f to to 5 3a These two terminal acetylenes differ mainly in the nature of the substituent, which are phenyl and carb o methoxy, respectively. Methoxycarbonyl is the stronger electron withdrawing group, as measured by a larger residual negative charge remaining on the acetylenic moiety. Molecular structures of the substrate 5 3a and the reactants 5 6a and 5 6 f were optimized using Firefly/GAMESS quantum chemical software. Geometry optimization and SCF en ergy calculations were performed at the HF/6 31G* level of theory. Mulliken population analysis (atomic charges) and dipole moments were calculated at the same level of theory. Atomic charge distributions, starting from the terminal hydrogen atom, are as f ollows: 0.297 (H), 0.548 (C1), 0.165 (C2) and 0.314 (H), 0.474 (C1), 0.158 (C2) for the acetylenic units of 5 6a and 5 6 f

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79 respectively. Summing up the charges gives residual negative charges on the acetylenic units as 0.086 and 0.002 for 5 6a and 5 6 f respectively. The gamma aromatic system of the carb o methoxy group withdraws a significant amount of electron density from the acetylenic unit thus making 5 6 f a better dipolarophile. Dipole moment orientation can be another factor of regioselectivity: di pole moments of the substrate 5 3a and dipolarophile 5 6a interact beneficially only if 5 3a and 5 6a to 5 6 f the dipole moment direction is different, whi ch affords more beneficial orientations with the 1,3 dipole. Assuming the intermediate I as shown in Scheme 5 4, relative energies of the two reaction pathways can be calculate d : one leading to the isolated regioisomer 5. 8a and the other leading to the hy pothetical cyclic structure 5 .8a' The energy outcome of pathway I 5 .8a can be evaluated directly by making a comparison of the total energies of the intermediate I and the final product 5 8a because I and 5 8a have the same number of nuclei and electro ns. These pathways are displayed in Scheme 5 4 It is seen that the total energy of product 5 8a lies 59.00 kcal/mol below the intermediate I As for the hypothetical pathway I 5 8a' it can only be estimated as an isodesmic reaction involving two disjoint ed products: cyclic structure 5 8a' and toluenesulfinic acid. The reaction enthalpy of this isodesmic reaction was calculated to be 35.6 kcal/mol, which means that pathway I 5 8a' is 23.4 kcal/mol less favorable than pathway I 5 8a Another factor that ca n contribute to the higher stability of 5 8a is an intramolecular hydrogen bond found between the ring nitrogen and the hydrogen atom of the NH Ts moiety in the optimized structure of 5 8a (Scheme 5 4 ). The quantum

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80 chemical calculations and theoretical rea soning illustrate the preference for formation of the ring opened product 5 8a and also explain the different regiochemistry of phenylacetylenes 5 6a c and propiolates 5 6 f h Scheme 5 4. Energy diagram for the formation of 5.8a 5.3 E xperimental S ection 5.3.1 General M ethods Melting points were determined on a capillary point apparatus equipped with a digital the r mometer. NMR spectra were recorded in CDCl 3 or DMSO d 6 with TMS for 1 H (300 MHz) and 13 C (75 MHz) as internal reference. Elemental analyses were performed on a Carlo Erba 1106 i n strument.

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81 5.3.2 General P rocedure for the P reparation of 1,2,4 T riazolium S alts 5.2a c A mixture of 4 H 1,2,4 triazol 4 amine 5.1 (5.0 mmol) and alkyl halide (5.0 mmol, 15.0 mmol in case of methyl iodide) in acetonitrile was stirred under reflux for 5 h (rt. for 72 h in case of methyl iodide). The solvent and excess alkyl halide were removed under reduced pressure to give the corresponding 1,2,4 triazolium salts 5. 2a c For analytical purity each residue was recrystallized from MeOH. 4 Amino 1 benzyl 1H 1,2,4 triazol 4 ium bromide ( 5 .2a ). White crystals (>99%), mp 141.0 142.0 C (lit. 151 mp 141.0 143.0 C ); 1 H NMR (DMSO d 6 ): 10.57 (s, 1H), 9.25 (s, 1H), 7.48 7.40 (m, 5H), 7.07 (br s, 2H), 5.67 (s, 2H) ; 13 C NMR (DMSO d 6 ): 145.4, 142.6, 133.3, 128.7, 128.6, 54.6. 4 Amino 1 methyl 4H 1,2,4 triazol 1 ium iodide ( 5 .2b ) Yellow crystals (>99%), mp 101.0 C (lit. 162 mp 101.0 C); 1 H NMR (DMSO d 6 ): 10 .16 (s, 1H), 9.18 (s, 1H), 6.95 (br s, 2H), 4.07 (s, 3H); 13 C NMR (DMSO d 6 ): 144.9, 142.8, 39.0. 4 Amino 1 butyl 1H 1,2,4 triazol 4 ium bromide ( 5 .2c ). Low melting solid (>99%), mp 46.0 C (lit. 163 mp 47.5 49.0 C); 1 H NMR (CDCl 3 ): 10.78 (s, 1H), 8.99 (s, 1H), 6.76 (br s, 2H), 4.48 (t, J = 7.2 Hz, 2H), 2.05 1.89 (m, 2H), 1.52 1.35 (m, 2H), 0.96 (t, J = 6.9 Hz, 3H); 13 C NMR (CDCl 3 ): 144.8, 142.6, 52.8, 30.7, 19.4, 13.5. 5.3.3. General P rocedure for the P reparation of 1,2,4 T riazolium N I mides 5. 3a d Arylsulfonyl chloride (10.0 mmol) was added portionwise to a solution of corresponding 1,2,4 triazolium salt 5 .2a c (5.0 mmol) in pyridine (5 mL) and stirred for 1 h at room temperature. After 1 h, EtOAc (70 mL) was added to the r eaction mixture, washed with 10 % NaOH solution (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give corresponding

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82 1,2,4 triazolium N imide 5. 3a d For analytical purity, each residue was rec rystallized from MeOH. (1 Benzyl 1H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide ( 5 .3a ) White crystals (85%), mp 170.0 C (lit. 155 mp 171.0 173.0 C); 1 H NMR (DMSO d 6 ): 9.9 0 (s, 1H), 8.73 (s, 1H), 7.45 7.35 (m, 5H), 7.29 7.19 (m, 4H), 5.47 (s, 2H), 2.33 (s, 3H); 13 C NMR (DMSO d 6 ): 173.7, 145.6, 142.0, 140.5, 133.8, 129.1, 128.8, 128.6, 128.1, 126.3, 54.5, 20.8. (1 Methyl 1H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide ( 5 .3b ). White crystals (83%), mp 203.0 C; 1 H NMR (CDCl 3 ): 9.72 (s, 1H), 8.64 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 3.93 (s, 3H), 2.33 (s, 3H) ; 13 C NMR (CDCl 3 ): 144.9, 142.1, 140.4, 140.1, 129.0, 126.3, 38.5, 20.8; Anal. Calcd. For C 1 0 H 12 N 4 O 2 S: C, 47.61; H, 4.79; N, 22.21. Found: C, 47.82; H, 4.83; N, 22.27. (1 Butyl 1H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide ( 5 .3c ) White crystals (88%), mp 178.0 180.0 C; 1 H NMR (CDCl 3 ): 10.00 (s, 1H), 7.85 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.20 ( d, J = 8.1 Hz, 2H), 4.35 (t, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.96 1.85 (m, 2H), 1.36 1.25 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H) ; 13 C NMR (CDCl 3 ): 144.1, 142.5, 141.8, 138.9, 129.4, 127.0, 52.5, 30.8, 21.4, 19.3, 13.3; Anal. Calcd. For C 13 H 18 N 4 O 2 S: C, 53.0 4; H, 6.16; N, 19.03. Found: C, 53.21; H, 6.61; N, 19.16. (1 Butyl 1H 1,2,4 triazol 4 ium 4 yl)((4 nitrophenyl)sulfonyl)amide ( 5 .3d ). White crystals (91%), mp 198.0 200.0 C; 1 H NMR (DMSO d 6 ): 9.81 (s, 1H), 8.79 (s, 1H), 8.29 (d, J = 9.0 Hz, 2H), 7.78 (d, J = 9.3 Hz, 2H), 4.23 (t, J = 6.9 Hz, 2H), 1.80 1.71 (m, 2H), 1.23 1.10 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO d 6 ): 148.6, 148.5, 145.2, 141.9, 127.7, 124.1, 51.2, 29.9, 18.5, 13.0; Anal. Calcd. For C 12 H 15 N 5 O 4 S: C, 44.30; H, 4.65; N, 21 .53. Found: C, 44.55; H, 4.98; N, 21.64.

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83 N (4H 1,2,4 Triazol 4 yl)nitramide ( 5 .4 ). Concentrated nitric acid (70%, 50 mL) was added dropwise to a cooled (0 C) solution of 4 amino 1,2,4 triazole (20.0 mmol) in sulfuric acid (90%, 50 mL). The resulting solu tion was stirred for 30 min and gradually warmed to room temperature. The mixture was stirred for an additional 1 h and poured into ice water (200 mL). The precipitate was collected by filtration, washed with cold water, dried and recrystallized from MeOH to afford N (4 H 1,2,4 triazol 4 yl)nitramide 5 4 as colorless needles (63%), mp 175.0 C (lit. 157 mp 175.0 176.0 C); 1 H NMR (DMSO d 6 ): 9.66 (s, 2H); 13 C NMR (DMSO d 6 ): 142.8; Anal. Calcd. For C 2 H 3 N 5 O 2 : C, 18.61; H, 2.34; N, 54.26. Found: C, 18.80; H, 2.22; N, 54.09. (1 Benzyl 4H 1,2,4 triazol 1 ium 4 yl)(nitro)amide ( 5 .5a ). The mixture of sodium hydroxide (5.0 mmol) and N (4 H 1,2,4 tr iazol 4 yl)nitramide 5 4 in water (10 mL) was stirred at room temperature for 1 h and evaporated to dryness under reduced pressure. The resulting white powder was dissolved in acetonitrile (10 mL). Benzyl bromide (5.0 mmol) was added in one portion and the resulting mixture heated under reflux for 12 h. After cooling to room temperature, excess solvent was removed under reduced pressure. The remaining solid was dissolved in EtOAc (50 mL), washed with water (3 x 20 mL), dried over anhydrous sodium sulfate an d concentrated under reduced pressure to afford corresponding N nitroimide 5 5a as w hite crystals (57%), mp 165.0 C (lit. 164 mp 164 .0 C); 1 H NMR (DMSO d 6 ): 10.41 (s, 1H), 9.28 (s, 1H), 7.44 7.40 (m, 5H), 5.60 (s, 2H) ; 13 C NMR (DMSO d 6 ): 144.3, 141.5, 133.5, 128.9, 128.9, 128.7, 55.0 (1 Methyl 1H 1,2,4 triazol 4 ium 4 yl)(nitro)amide ( 5 .5b ). A mixture of sodium hydroxide (2 mmol) and N (4 H 1,2,4 triazol 4 yl)nitramide 5 4 in water (10 mL) was stirred at room temperature for 1h and evaporated to dryness under reduced pressure.

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84 The resulting white powder was dissolved in DMF (5 mL). Methyl iodide (5.0 mmol) was added in one portion and the mixture stirred at room temperature for 12 h. The precipitate was removed by filtration and the filtrate diluted with Et 2 O (100 mL). The resulting precipitate collected by filtration was dried and recrystallized from EtOH to give the corresponding N nitroimide 5 5b as w hite crystals (93%), mp 169.0 C (lit. 165 mp 169.0 170.0 C); 1 H NMR (DMSO d 6 ): 10.17 (s, 1H), 9.24 (s, 1H), 4.06 (s, 3H); 13 C NMR (DMSO d 6 ): 143.7, 141.6, 38.7. 5.4.4. General M ethod for the P reparation of P yrazolo[5,1 c ][1,2,4]triazoles 5. 7a g Copper (I) bromide (0.025 mmol) was added to a mixture of 1,2,4 triazolium N imide 5.3a d 5.5a,b (0.5 mmol), arylacetylene 5.6a c (0.5 mmol) and pyridine (1.5 mmol) in dichloromethane (2 mL) and the resulting mixture stirred for 24 h. Solvent was removed under reduced pressure and the residue purified by column chromatography (EtOAc/Hexanes) to afford the corresponding pyrazolo[5,1 c ][1,2,4]triazoles 5 7a g 1 Benzyl 6 phenyl 1H pyrazolo[5,1 c][1,2,4]triazole ( 5 .7a ). White crystals (62%), mp 113.0 C; 1 H NMR (CDCl 3 ): 8.25(s, 1H), 7.79(d, J = 6.9Hz, 2H), 7.41 7.29(m, 8H), 5.70(s, 1H), 5.29(s, 2H) ; 13 C NMR (CDCl 3 ): 160.1, 147.2, 134.5, 133.7, 129.0, 128.6, 128.5, 128.2, 128.0, 126.2, 75.1, 54.5; Anal. Calcd. For C 17 H 14 N 4 : C, 74.43; H, 5.14; N, 20.42. Found: C, 74.31; H, 5.09; N, 20.44. 1 Benzyl 6 (4 methoxyphenyl) 1H pyrazolo[5,1 c][1,2,4]triazole ( 5 .7b ). White crystals (65%), mp 110.0 C; 1 H NMR (CDCl 3 ): 8.23 (s 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.38 7.31 (m, 5H), 6.92 (d, J = 9.0 Hz, 2H), 5.62 (s, 1H), 5.27 (s, 2H), 3.83 (s, 3H) ; 13 C NMR (CDCl 3 ): 159.9, 134.5, 129.9, 129.2, 128.9, 128.5, 128.1, 127.9, 127.4, 126.2, 114.0, 74.6, 55.3, 54.4; HRMS m/z for C 18 H 17 N 4 O [M + H] + calcd. 305.1397, found 305.1403.

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85 1 Methyl 6 phenyl 1H pyrazolo[5,1 c][1,2,4]triazole ( 5 .7c ). Colorless crystals (62%), mp 140.0 C; 1 H NMR (CDCl 3 ): 8.22 (s, 1H), 7.88 7.83 (m, 2H), 7.46 7.36 (m, 3H), 6.00 (s, 1H), 3.88 (s, 3H) ; 13 C NMR (C DCl 3 ): 160.1, 133.7, 128.7, 128.6, 127.6, 126.2 ; HRMS m/z for C 11 H 10 N 4 [M + H] + calcd. 199.0978, found 199.0986. 6 (4 Methoxyphenyl) 1 methyl 1H pyrazolo[5,1 c][1,2,4]triazole ( 5 .7d ). White crystals (73%), mp 152.0 153.0 C; 1 H NMR (CDCl 3 ): 8.22 (s, 1H), 7.78 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 5.91 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H); 13 C NMR (CDCl 3 ): 160.1, 160.0, 148.0, 127.6, 127.4, 126.4, 114.1, 73.7, 55.3, 36.7; HRMS m/z for C 12 H 12 N 4 O [M + H] + calcd. 229. 1084, found 229.1092. 1 But yl 6 phenyl 1H pyrazolo[5,1 c][1,2,4]triazole ( 5 .7e ). Yellow solid (78%), mp 35.0 40.0 C; 1 H NMR (CDCl 3 ): 8.21, (s, 1H), 7.88 7.84 (m, 2H), 7.46 7.38 (m, 2H), 7.38 7.32 (m, 1H), 5.99 (s, 2H), 4.12 (t, J = 7.2 Hz, 2H), 1.95 1.84 (m, 2H), 1.46 1.33 (m, 2H), 0.97 (t, J = 6.9 Hz, 3H) ; 13 C NMR (CDCl 3 ): 160.0, 147.3, 133.9, 128.7, 128.5, 127.4, 126.1, 74.3, 50.2, 30.7, 19.8, 13.6; HRMS m/z for C 14 H 17 N 4 [M + H] + calcd. 241.1448, found 241.1447. 1 Butyl 6 (4 methoxyphenyl) 1H pyrazolo[5,1 c][1,2,4] triazole ( 5 .7f ). Yellow solid (71%), mp 60 C; 1 H NMR (CDCl 3 ): 8.19 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 5.91 (s, 1H), 4.10 (t, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.93 1.83 (m, 2H), 1.44 1.32 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H) ; 13 C NMR (CDCl 3 ): 159.9, 147.3, 129.6, 127.3, 126.5, 124.2, 114.0, 73.8, 55.3, 50.1, 30.7, 19.8, 13.6; HRMS m/z for C 15 H 19 N 4 O [M + H] + calcd. 271.1553, found 271.1551. 1 Butyl 6 (p tolyl) 1H pyrazolo[5,1 c][1,2,4]triazole ( 7g ). Yellow solid (77%), mp 54.0 55.0 C; 1 H NMR (CDCl 3 ): 8.20 (s, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.4

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86 Hz, 2H), 5.96 (s, 1H), 4.12 (t, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.95 1.85 (m, 2H), 1.46 1.33 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13 C NMR (CDCl 3 ): 160.1, 147.3, 138.4 131.0, 129.4, 127.4, 126.0, 50.2, 30.7, 21.3, 19.8, 13.6 ; HRMS m/z for C 15 H 19 N 4 [M + H] + calcd. 255.1604, found 255.1607. (E) Methyl2 (1 benzyl 1H 1,2,4 triazol 5 yl) 3 (4 methylphenylsulfonamido)acrylate ( 5 .8a ). Methyl propiolate 5 6f (2.0 mmol) was add ed dropwise to a solution of (1 benzyl 1H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide 5 3a (2.0 mmol) in DCM (5 mL) and stirred for 24 h at room temperature. After 24 h, the reaction mixture was concentrated under reduced pressure to afford pure ( E ) methyl 2 (1 benzyl 1 H 1,2,4 triazol 5 yl) 3 (4 methylphenylsulfonamido)acrylate 5 8a as c olorless microcrystals (>99%), mp 100.0 100.2 C; 1 H NMR (DMSO d 6 ): 8.32 (s, 1H), 8.08 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.23 7.15 (m, 3H), 7.05 ( d, J = 6.0 Hz, 2H), 5.09 (s, 2H), 3.54 (s, 3H), 2.38 (s, 3H); 13 C NMR (DMSO d 6 ): 165.1, 148.3, 148.1, 147.8, 143.2, 137.9, 134.9, 129.7, 128.1, 127.6, 126.2, 92.1, 52.2, 51.4, 20.9 ; HRMS m/z for C 20 H 21 N 4 O 4 S [M + H] + calcd. 413.1278, found 413.1274. Dimet hyl2 (1 benzyl 1H 1,2,4 triazol 5 yl) 3 (4 methylphenylsulfonamido)maleate ( 5 .8b ). Dimethyl but 2 ynedioate 5 6g (2.0 mmol) was added dropwise to a solution of (1 benzyl 1 H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide 5 3a (2.0 mmol) in DCM (5 mL) at 78 C and s tirred for 30 min. After 30 min, t he reaction was allowed to warm to room temperature and was left for an additional 12 h. T he reaction mixture was concentrated under reduced pressure to afford pure dimethyl2 (1 benzyl 1 H 1,2,4 triazol 5 yl) 3 (4 methylphe nylsulfonamido)maleate 5 8b as a white solid (>99%), mp 45.0 47.0 C; 1 H NMR (DMSO d 6 ): 8.90 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.32 7.25 (m, 5H), 7.07

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87 7.03 (m, 2H), 4.99 (s, 1H), 3.77 (s, 3H), 3.40 (s, 3H), 2.34 (s, 3H) ; 13 C NMR (DMSO d 6 ): 165.4 163.9, 159.3, 149.7, 144.1, 141.5, 140.9, 133.7, 129.0, 128.5, 128.1, 128.0, 125.9, 81.8, 52.7, 52.1, 50.8, 20.8 ; Anal. Calcd. For C 22 H 22 N 4 O 6 S: C, 56.16; H, 4.71; N, 11.91. Found: C, 56.01; H, 4.87; N, 11.41. (E) Ethyl 2 (1 benzyl 1H 1,2,4 triazol 5 yl) 3 (4 methylphenylsulfonamido)but 2 enoate ( 5 .8c ). Ethyl but 2 ynoate 5 6h (2.0 mmol) was added dropwise to a solution of (1 benzyl 1 H 1,2,4 triazol 4 ium 4 yl)(tosyl)amide 5 3a (2.0 mmol) in DCM (5 mL) at room temperature over a period of 10 min. The resul ting mixture was stirred under reflux for an additional 12 h. T he reaction was then allowed to cool to room temperature, concentrated under reduced pressure and the residue purified by flash chromatography (EtOAc/Hexanes) to afford pure ( E ) ethyl 2 (1 benz yl 1 H 1,2,4 triazol 5 yl) 3 (4 methylphenylsulfonamido)but 2 enoate as white microcrystals (98%), mp 128.0 130.0 C; 1 H NMR (CDCl 3 ): 12.14 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.34 (d. J = 8.4 Hz, 2H), 7.28 7.23 (m, 3H), 7.16 7.11 (m, 2H), 5.15 5.03 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.59 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H) ; 13 C NMR (CDCl 3 ): 167.4, 157 .3, 151.0, 149.6, 144.9, 136.9, 134.7, 130.1, 128.7, 128.3, 127.9, 127.4, 95.2, 61.3, 52.8, 21.6, 16.7, 13.9 ; Anal. Calcd. For C 22 H 24 N 4 O 4 S: C, 59.98; H, 5.49; N, 12.72. Found: C, 60.24; H, 5.74; N, 12.54.

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88 CHAPTER 6 CONCLUSIONS AND SUMM ARY OF ACHIEVEMENTS Chapter 1 introduces the main themes throughout this thesis and inclure N acylbenzotriazole, 1 aminobenzimidazole, NHC, spirodithiohydantoin and 4 amino 1,2,4 triazole in organic synthsis Chapter 2 of this thesis presents a convenient route for the synth esis of ibuprofen and naproxen prodrugs. B enzotriazole activated ibuprofen and naproxen are shelf stable, crystalline compounds and useful intermediates in acylation reactions. This methodology was shown to be general avoids long reaction times and harsh conditions and affords good yield. In Chapter s 3,4 and 5 the novel synthetic utilit y of N amino heterocycles is described C hapter 3 presents the synthesis and NHC mediated transformations of 1 (benzylideneamino)benzimidazoles afford ing an efficient synth esis of novel NHC zwitterionic betaines. It was found that the reaction of such NHC with isopropyl isothiocyanate gives spirodithiohydantoins. T he novel reversible equilibrium of such spirodithiohydantoins is described in C hapter 4 It was found that spi rodithiohydantoins undergo thermal equilibrium to give the corresponding zwitterionic betaines, which upon further heating generate free N heterocyclic carbenes. The equilibrium was studied by NMR and direct insertion probe m ass s pectromet ry a nalysis. Form ation of free NHC was confirmed by a reaction with elemental sulfur. In Chapter 5, a mild, efficient and regioselective one pot Cu (I) mediated synthesis of pyrazolo 1,2,4 triazoles is de scribed This transformation affords the products at room temperatur e under basic conditions. The different regioselectivity of

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89 phenylacetylenes and propiolates again highlights the influence of substitution and electron density distribution in the dipolarophile. Electrostatic reasons cause phenylacetylenes to advantageous ly add to 1,2,4 triazolium N imides to afford pyrazolo[5,1 c ] 1,2,4 triazole bicyclic systems. The different reactivity of methyl propiolates (ring opening) is explained by utilizing the formalism of model isodesmic reactions.

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99 BIOGRAPHICAL SKETCH Davit Jishkariani was born in Khoni, Georgia. He received his b with honors in July 2005 and m isi State University. During his m aster s degree he worked under the supervision of During his study at Iv. Javakhishvili State University, Davit was awarded with two 3 rd one 1 st and one 2 nd nternational conference th International Symposium on th International Symposium on Capillary Electroseparation expert criminalist at Ministry of Internal Affairs of Georgia. Davit received an invitation to join the Un iversity Of Florida Center Of Heterocyclic Compounds supervised by Professor Alan R. Katritzky where he started in 2008. In 2009, Davit joined graduate program and started his Ph.D. in the Department of Chemistry at the University of Florida working under the supervision of Professor Alan R. Katritzky. His research was focused on the synthesis of ibuprofen and naproxen prodrugs and the novel synthetic utilities of N re cognized with the Procter & Gamble Award for Research Excellence (2011), W. M. Jones Award for Research Originality and Creativity (2011) and Best poster award at FloHet 13 conference (2012).