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Novel Guanylating and Imidoylating Reagents

HIDE
 Title Page
 Dedication
 Acknowledgement
 Table of Contents
 List of Tables
 List of Schemes
 Abstract
 Introduction
 Benzotriazolyl-mediated 1,2-shifts...
 The preparation of N, N', N"-trisubstituted...
 Preparations of substituted thiosemicarbazides...
 Synthesis of mono- and symmetrical...
 Microwave assisted preparations...
 C-imidoylation of esters, sulfones,...
 References
 Biographical sketch
 

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NOVEL GUANYLATING AND IMIDOYLATING REAGENTS By NIVEEN M. KHASHAB A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006

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Copyright 2006 by Niveen M. Khashab

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I dedicate this work to my grandmother Sa mia Al-Halabi, my mother Wafaa Elias and my father Mohammad Ali Khashab. This is al so for my sisters Nermeen Iskandarani and Nadine Iskandarani, my brothers Mohammad Iskandarani and Yehya Yasine, and finally my great husband Hussam Khatib. I never would have achieved any of this without their love, support, and words of wisdom.

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iv ACKNOWLEDGMENTS I am greatly indebted to many people in the preparation of this manuscript. First, I am fortunate to have had th e opportunity of working for Pr of. Alan R. Katritzky, whose drive and dedication compel those around him to strive for higher goals. I thank my committee members (Dr. Liza McElwee-White Dr. Kenneth Wagener, Dr. Kenneth Sloan, and Dr. David Powell) for their helpful suggestions and instru ctions. I would like to thank all members in Dr. Katritzkys gr oup, my colleagues, and my dear friends: Dr. Rachel Witeck, Dr. Anamika Singh, Megumi Yoshioka, Danniebelle Haase, Robert Johnson, and Andrew Hartman. Very special thanks go to Dr. Makhloof Haddadin, Dr. Moussa Nazer, Dr. Jim Deyrup, Dr. Steven Benner, Lori Clark, Elizabeth Cox, Dr. Sergey Bobrov, Gwen McCann, and all my fellow chemistry Gators at the University of Florida.

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v TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES...........................................................................................................viii LIST OF SCHEMES............................................................................................................x ABSTRACT.....................................................................................................................xiii CHAPTER 1 GENERAL INTRODUCTION....................................................................................1 2 BENZOTRIAZOLYL-MEDIATED 1,2-SHIFTS OF ELECTRON-RICH HETEROCYCLES.......................................................................................................4 2.1 Introduction.............................................................................................................4 2.2 Results and Discussion...........................................................................................5 2.3 Conclusion..............................................................................................................8 2.4 Experimental Section..............................................................................................9 3 THE PREPARATION OF N N N TRISUBSTITUTED GUANIDINES.............22 3.1 Introduction...........................................................................................................22 3.2 Results and Discussion.........................................................................................25 3.3 Conclusion............................................................................................................29 3.4 Experimental Section............................................................................................29 3.4.1 General Procedure for the Preparation of Compounds 3.10ag .................30 3.4.2 General Procedure for the Preparation of Compounds 3.11af .................31 3.4.3 General Procedure for the Preparation of Compounds 3.12ah ................33 3.4.4 General Procedure for the Preparation of Compounds 3.13al .................35 3.4.5 General Procedure for the Preparation of Compounds 3.15ae .................39 3.4.6 General Procedure for the Preparation of Compounds 3.16ae .................40 3.4.7 General Procedure for the Preparation of Compounds 3.17af .................42 3.4.8 General Procedure for the Preparation of Compounds 3.18ah ................44 4 PREPARATIONS OF SUBSTITUTED THIOSEMICARBAZIDES AND N HYDROXYTHIOUREAS..........................................................................................47

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vi 4.1 Introduction...........................................................................................................47 4.2 Results and Discussion.........................................................................................49 4.3 Conclusion............................................................................................................51 4.4 Experimental Section............................................................................................52 5 SYNTHESIS OF MONOAND SYMMETRICAL DIN -HYDROXYAND N AMINOGUANIDINES............................................................................................56 5.1 Introduction...........................................................................................................56 5.2 Results and Discussion.........................................................................................62 5.2.1 Preparation of Unsymmetrical N -Hydroxyguanidines 5.13aj ..................63 5.2.2 Preparation of Unsymmetrical N -Aminoguanidines 5.14ah ....................64 5.2.3 Preparation of Symmetrical Dihydroxyguanidine 5.16 and Diaminoguanidine 5.17 ....................................................................................66 5.3 Conclusion............................................................................................................67 5.4 Experimental Section............................................................................................67 5.4.1 General Procedure for the Preparation of Compounds 5.13aj .................68 5.4.2 General Procedure for the Preparation of Compounds 5.14ah ................70 5.4.3 Preparation of N,N -Diisopropyl-5-phenyl-1-(2-pyridinyl)-1H-1,2,4triazol-3-amine 5.15 .........................................................................................72 5.4.4 General Procedure for the Preparation of Compounds 5.16 and 5.17 ........73 5.4.5 Preparation of N -Hydroxy-1 H -1,2,3-benzotriazole-1-carboximidamide 5.18 ...................................................................................................................74 5.4.6 General Procedure for the Preparation of Compound 5.19 ........................74 6 MICROWAVE ASSISTED PREPARAT IONS OF AMIDRAZONES AND AMIDOXIMES..........................................................................................................75 6.1 Introduction to Amidrazones................................................................................75 6.2 Introduction to Amidoximes.................................................................................77 6.3 Results and Discussion.........................................................................................80 6.4 Aminoamidoximes and Diamidoximes................................................................84 6.5 Conclusion............................................................................................................85 6.6 Experimental Section............................................................................................85 6.6.1 General Procedure for the Preparation of Amidrazones 1ah ...................85 6.6.2 General Procedure for the Preparation of Amidoximes 6.2ah .................86 6.6.3 General Procedure for the Preparation of 6.4ad .......................................88 6.6.4 General Procedure for the Preparation of 6.6 and 6.7 ................................89 7 C-IMIDOYLATION OF ESTERS, SULF ONES, SULFOXIDES, AMIDES AND NITRO COMPOUNDS..............................................................................................91 7.1 Introduction...........................................................................................................91 7.2 C-Imidoylation of Esters.......................................................................................92 7.3 C-Imidoylation of Sulfones..................................................................................94 7.4 C-Imidoylation of Sulfoxide.................................................................................96 7.5 C-Imidoylation of Amides....................................................................................97

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vii 7.6 C-Imidoylation of Nitro Compounds....................................................................99 7.7 Experimental Section..........................................................................................100 7.7.1 General Procedure for the Preparation of -Enaminoesters 7.2ad .........100 7.7.2 General Procedure for the Preparation of -Iminosulfones 7.4ac ..........102 7.7.3 General Procedure for the Preparation of -Iminosulfoxides 7.6ac .......102 7.7.4 General Procedure for the Preparation of -Iminoamides 7.7ad ...........103 7.7.5 General Procedure for the Preparation of -Nitroimines 7.9ac ..............104 LIST OF REFERENCES.................................................................................................106 BIOGRAPHICAL SKETCH...........................................................................................120

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viii LIST OF TABLES Table page 2.1 Preparation of intermediates 2.3 and ketones 2.4 .......................................................7 2.2 Preparation of intermediates 2.3 and ketones 2.4 .......................................................8 3.1 Preparation of guanylating reagents 3.11a-f and 3.13a-l .........................................27 3.2 Preparation of symmetrical and cyclic trisubstituted guanidines 3.15ae and 3.16ae .....................................................................................................................28 3.3 Preparation of substituted unsymmetrical guanidines 3.17af and 3.18ah ...........30 4.1 Preparation of substituted and unsubstituted thiosemicarbazides*..........................50 4.2 Preparation of substituted and unsubstituted N -hydroxythioureas *........................51 5.1 Preparation of unsymmetrical N -hydroxyguanidines 5.13aj .................................64 5.2 Synthesis of N -aminoguanidines 5.14ah ................................................................66 5.3 Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17 ........................66 6.1 The eight class I amidrazones existing as 6.1A .......................................................78 6.2 Five sub-classes of amidoximes 6.2A ......................................................................81 6.3 Four sub-classes of amidoximes 6.2B ......................................................................82 6.4 Preparation of amidrazones 6.1ah from 6.3bd,f* ................................................83 6.5 Preparation of 1,2,4-triazoles 6.4ad from 6.3a,b,d ................................................83 6.6 Preparation of amidoximes 6.2ah *........................................................................84 7.1 Preparations of -enaminoesters 7.2ad ..................................................................94 7.2 Preparations of -iminosulfones 7.4ac* .................................................................96 7.3 Preparations of -iminosulfoxides 7.6ac* ..............................................................97

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ix 7.4 Preparations of -iminoamides 7.7ad* ..................................................................98 7.5 Preparations of -nitroimines 7.9ac .....................................................................100

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x LIST OF SCHEMES Scheme page 1.1 Properties of a benzotriazole group............................................................................1 1.2 Halogen analogues of a benzotriazole group to an amino or ether functionality....2 2.1 Mechanism of zinc bromide promot ed oxirane ring-closure-ring opening rearrangement.............................................................................................................4 2.2 Preparation of intermediates 2.3a-m and ketones 2.4a-i, k-m ...................................6 3.1 Common methods for the pr eparation of guanidines 3.3 .........................................23 3.2 Benzotriazole-based guanylating reagents...............................................................24 3.3 Preparation of guanidine s utilizing benzotriazole-b ased guanylating reagents.......25 3.4 Preparation of novel guanylating reagents 3.11a-f and 3.13a-l ...............................26 3.5 Attempts to prepare 3.11 and 3.13 with R= benzyl..................................................27 3.6 Preparation of symmetrical and cyclic trisubstituted guanidines.............................28 3.7 Preparation of substituted unsymmetrical guanidines..............................................29 4.1 Common methods of prepara tion of thiosemicarbazides.........................................48 4.2 Common methods of preparation of N -hydroxythioureas........................................48 4.3 Synthesis of di and trisubstituted thioureas 4.2 ........................................................49 4.4 Synthesis of thiosemicarbazides 4.5 and N-hydroxythioureas 4.6 ...........................49 5.1 Tautomerism of guanidines......................................................................................57 5.2 Literature syntheses of N -hydroxyguanidines 5.2 ....................................................59 5.3 Literature syntheses of substituted aminoguanidines 5.4 .........................................60 5.4 Tautomerism of hydroxyguanidi nes and aminoguanidines.....................................61

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xi 5.5 Synthesis of benzotriazole intermediates 5.8 and 5.10 ............................................62 5.6 Synthesis of benzotriazole intermediates 5.11a,b and substituted guanidines 5.12 ...........................................................................................................................63 5.7 Preparation of unsymmetrical N -hydroxyguanidines 5.13aj .................................64 5.8 Synthesis of N -aminoguanidines 5.14ah ................................................................65 5.9 Synthesis of trisubstituted 1,2,4-triazole 15 .............................................................65 5.10 Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17........................66 5.11 Synthesis of N -hydroxyN -aminoguanidine 5.19 ...................................................67 6.1 Preparative routes to amidrazones............................................................................76 6.2 Tautomeric forms of amidrazones............................................................................76 6.3 Tautomeric forms of amidoximes............................................................................77 6.4 Preparative routes to amidoximes of type 6.2A.......................................................79 6.5 Preparative routes to amidoximes of type 6.2B .......................................................79 6.6 Reactions of imidoylbenzotriazoles with hydrazines and hydroxylamines.............82 6.7 Preparative routes to aminoamidoximes..................................................................84 6.8 Preparation of aminoamidoxime 6.6 and diamidoxime 6.7 .....................................85 7.1 Preparation of imidoylbenzotriazoles 7.1ai ...........................................................92 7.2 Published methods to C-imidoylation products.......................................................93 7.3 Preparations of -enaminoesters 7.2ad ..................................................................94 7.4 Imidoylation of sulfones by fluorinated imidoyl chlorides......................................95 7.5 Preparations of -iminosulfones 7.4ac ...................................................................95 7.6 Literature methods for C-imidoylation of sulfoxides...............................................96 7.7 Preparations of -iminosulfoxides 7.6ac ................................................................97 7.8 Preparations of -iminoamides 7.7ad ....................................................................98

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xii 7.9 Reported C-imidoylation produc t of a nitro compound...........................................99 7.10 ` Preparations of -nitroimines 7.9ac ....................................................................100

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xiii Abstract of Dissertation Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy NOVEL GUANYLATING AND IMIDOYLATING REAGENTS By Niveen M. Khashab December 2006 Chair: Alan R. Katritzky Major Department: Chemistry The theme of this work is development of novel methodologies for the preparation of a variety of synthetic targets. Chap ter 1 provides a gene ral overview of the methodologies employed in the preparation of the target compounds and includes an overview of cognate work carried out in these fields. Chapter 2 describes the regi oselective 1,2-shift of an el ectron rich heterocyclic group in the presence of competitive alkyl and aryl groups. We have investigated benzotriazole-mediated one carbon insertions in heteroaryl ketones and reported the successful synthesis of homol ogated ketones via 1,2-shift of the diverse heterocyclic groups or phenyl group. In chapter 3, we have extended benzotri azole-based guanylation to include two new reagent classes ( bis -benzotriazol-1-yl-methylene)amines and benzotriazole-1carboxamidines, which allow for the facile preparation of N,N,N -tisubstituted guanidines.

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xiv Applications of the thioacylating reagent (RNHCSBt) in the preparation of thiosemicarbazides and hydroxythioureas are de scribed in Chapter 4. A new route for the preparation of thiosemicarbazides and N -hydroxythioureas of different substitution patterns has been established. This methodol ogy provides easy access to this class of compounds with excellent yields without any obvious limitations. A continuation to the work described in chapter 3 is presented in chapter 5, comprising our reports of the synthe sis of monoand symmetrical diN -hydroxyand N aminoguanidines. N -Hydroxyguanidines were prepared in high yield by the reaction of guanylating reagents with hydroxylamine hydroc hloride in refluxing toluene for 4-12hrs in the presence of triethylamine. Similarly, Naminoguanidines were prepared by the reaction of guanylating r eagents with hydrazines. In Chapter 6, microwave assisted synt hesis of amidrazones and amidoximes is carried out utilizing imidoylbenz otriazoles. We presented a s imple, efficient, and broadly applicable synthetic methodology for the prepar ation of these two cl asses of compounds under microwave conditions via the nucleophi lic attack on imidoylbenzotriazoles by hydrazines or hydroxylamines. The last chapter of this dissertation (Chapt er 7) describes the i nvestigation of the Cimidoylation of esters, sulfones, sulfoxides, amides and nitro compounds.Access to these compounds is provided by deprotonation of the corresponding parent using a base followed by reactions with C-imidoylbenzotri azoles under mild conditions. The presented synthetic methadology affords imidoylation of the desired material through a C-C bond formation in good yields under mild conditions.

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1 CHAPTER 1 GENERAL INTRODUCTION 1 H -Benzotriazole is an excellent synthetic auxiliary [98CR409] which acts as a leaving group, an electron-withdrawing group, and even as an el ectron-donating group (Scheme 1.1). As another aspect of a good a uxiliary, benzotriazole is readily removed from the reaction mixture by simply washing with base due to the acidity (p K a 8.2) of 1 H -benzotriazole. Moreover, 1 H -benzotriazole is an inexpensive, stable compound that is soluble in common organic solvents such as ethanol, benzene, chloroform, and DMF. N N N R X Leaving group N N N H X Activating CH to proton loss N N N X Electron donor Y 1.1 1.21.3 Scheme 1.1 Properties of a benzotriazole group Benzotriazole is comparable in many ways to a halogen substituent because of its leaving abilities, but it should be compared to a tame halogen substituent. Compounds with a benzotriazole group to an amino or ether functionality 1.2 (X= NR2, OR) are stable, nonvolatile, easily prepared, and versatile, while their halogen analogues 1.4 and 1.6 (Scheme 1.2) are often physiologically dange rous and too reactive to be conveniently used as reagents. In the course of investigations on the us e of benzotriazole derivatives in organic synthesis, it has been found that the be nzotriazolyl moiety is both a good anion-

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2 stabilizing group and a good leaving group. Th ese properties, coupled with the ready availability of benzotriazole derivatives, suggested its pote ntial to provide general and efficient carbon-insert ion methods. In Chapter 2, be nzotriazole-mediated one-carbon insertions in heteroaryl ket ones to synthesize a novel series of homologated ketones via a 1,2 shift rearrangement are described. N Cl R1 R2 R2N H R1 R2 R2 O R1 Cl R2 1.4 1.5 1.6 Scheme 1.2 Halogen analogues of a benzotriazole group to an amino or ether functionality In Chapter 3, two novel guanylating reagents were prepared following benzotriazole methodology. Using these reag ents, a series of symmetrical and unsymmetrical trisubstitued guanidine s was prepared in 67-99% yield. Thiocarbamoylbenzotriazoles, novel reagen ts developed by our group as stable isothiocyanate equivalents, were reacted by earlier members of our group with different amines to give diand tris ubstituted thioureas [04JOC2976]. Now in Chapter 4, the utility of thiocarbamoyl-benzotriazo le was expanded by reacti ng it with hydrazines and N hydroxylamines of various substitution pa tterns to give thiosemicarbazides and N hydroxythioureas, respectivel y, in 73-91% yield. In Chapter 5, the utility of novel guanylating reagents ( bis -benzotriazol-1-ylmethylene)amines and benzotriazole-1-car boxamidines was expanded to include the preparation of monoand symmetrical diN -hydroxyand N -aminoguanidines in 22-91% yield.

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3 Microwave-assisted synthesis of amidr azones and amidoximes is described in Chapter 6. Imidoylbenzotriazoles were reacted with vari ous hydazines and hydroxylamines under microwave radiation and mild conditions to give the desired amidrazones and amidoximes, respectively, in 65-85% yield. In Chapter 7, preparation of C-imidoylated esters, sulfones, sulfoxides, amides, and nitro compounds is described. The procedur e includes deprotonation of the desired group using a base followed by reaction with Cimidoylbenzotriazoles under mild conditions. This synthetic methodology affords imidoylati on of the desired material through a C-C bond formation.

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4 CHAPTER 2 BENZOTRIAZOLYL-MEDIATED 1,2-SHIFTS OF ELECTRON-RICH HETEROCYCLES 2.1 Introduction In preceding work [95JA12015, 95TL841, 96JOC7564, 96JOC7571], an efficient benzotriazole-mediated insertion of single ca rbon atoms, carrying O-, S-, N-linked, aryl and heteroaryl substituents, into com pounds adjacant to a carbonyl group to give alkoxyalkyl-, -(alkylthio)alkyl-, -(carbazol-9-yl)alkyl-, -aryland -heteroarylsubstituted ketones has recently been de scribed. One possible mechanism of these rearrangements involves zinc bromide-prom oted oxirane ring-closure-ring-opening followed by the migration of the group that ca n best stabilize an electron deficiency (Scheme 2.1). X Bt R R1R2O Bt X R R1R2 -O ZnBr21) n -BuLi 2) O X R R1R2X R1R R2O Scheme 2.1 Mechanism of zinc bromide pr omoted oxirane ring-closure-ring opening rearrangement Application of a similar procedure for th e regioselective 1,2-shift of an electronrich heterocyclic group in th e presence of competitive al kyl or aryl groups is of considerable utility. Such selective shifts we re relatively unexplored ; known pinacol-type rearrangements provide few examples of the selective migration of 2-furyl [87JCS(P1)225, 92CL81, 93JOC5944], 2thienyl [87JCS(P1)225, 99EJOC497,

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5 02TL6937, 03S141], their benzoanalogues [02TL6937, 03S141], or 2and 3-indolyl groups [02TL6937, 03S141]. To explore the ability of elec tron-rich heterocycles to migrate in the presence of the alkyl and aryl groups, we have now inve stigated benzotriazole-mediated one carbon insertions in heteroaryl ketones 2.2am (Schemes 2.1 and 2.2) and herein report the successful synthesis of homologated ketones 2.4ai,km via 1,2-shift of the diverse heterocyclic groups or phenyl group shown in Table 2.1. 2.2 Results and Discussion Treatment of compound 2.1 with n -BuLi (1 equiv.) at C under a nitrogen atmosphere in THF for 1 h, followed by a reaction with the co rresponding ketones 2.2a m (1 equiv.) at C for 1 h, gave intermediates 2.3am in 40% yields (Scheme 2.1, Table 2.1). The intermediates 2.3am were isolated as 1:1 mixtures of two diastereoisomers which were generally us ed for the next step without separation. However, in certain cases the pure diastereomeric forms of 2.3am were isolated by recrystallization of the corres ponding crude products from acetonediethyl ether; also chromatography provided enriched samples of each diastereomer. The structures of compounds 2.3am were supported by their 1H NMR and 13C NMR spectra (see experimental section). All rearrangements were accomplished in the presence of a threefold molar excess of anhydrous zinc bromide. For intermediates 2.3a and 2.3b the 1,2-shift of the 2-, and 3-thienyl groups was effected by refluxing in 1,2-dichloroethane for 20 h to give ketones 2.4a and 2.4b in 61% yields (Scheme 2.1, Table 2.1). However, the same reaction conditions applied for the re arrangement of furyl analog 2.3d were ineffective for the

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6 selective transformation to the homologous ketone 2.4d However, selective 1,2migration of the 2-furyl group was effected by the reaction of the anion of compound 2.3d in THF at 130 C (sealed tube) to give ketone 2.4d in 20% yield (Scheme 2.2). Heating of compound 2.3d in 1,1,2,2-tetrachloroethane at 140 C for 1h was found to be efficient for the 1,2-migration of the 2-furyl group to give ketone 2.4d in 40% yield (Scheme 2.2, Table 2.1). Attempted 1,2-sh ift of 1-methylindol-3-yl group in 2.3c under various conditions led to comple x mixtures from which ketone 2.4c was isolated in 7% yield, apparently due to concur rent processes of dehydration or benzotriazole elimination [04JOC303] (Scheme 2.2, Table 2.1). SMe N N N OH R1R -78 oC, THF MeS N N N SMe R1R O R O R1ZnBr22.3a-m i) n -BuLi ii) 2.12.4a-i,k-m 2.2a-m SMe Me R O SMe N N N OLi Me R ZnBr2THF 2.3c,d -78 oC, THF i) n -BuLi 2.4c,d sealed tube Scheme 2.2 Preparation of intermediates 2.3a-m and ketones 2.4a-i, k-m Initial attempts to rearrange the lithium alcoholates of 2.3e,f failed. The rearrangements of adducts 2.3ei,km were achieved optimally in 1,1,2,2-tetrachloroethane at 85 C or 140 C to give ketones 2.4ei,km in 23% yields (Scheme 2.2, Table 2.1 and 2.2). Unfortunately, attempts to induce 1,2-shift of the 1-methylindol-3-yl group in 2.3j under various conditions led to complex mixtures.

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7 Table 2.1 Preparation of intermediates 2.3 and ketones 2.4 2.2 2.3 2.4 R R1 yield,a yield, % / solvent / temp. / time S Me 82 60 / ClCH2CH2Cl / 85 C / 20h S Me 85 64 / ClCH2CH2Cl / 85 C / 20h N Me Me 82 7 / THF / 100 C / 15h sealed tube O Me 72 40 / Cl2CHCHCl2 / 140 C / 1h O Me 75 40 / Cl2CHCHCl2 / 140 C / 1h S Me 94 40 / Cl2CHCHCl2 / 140 C / 1h S Me 40 71 / Cl2CHCHCl2 / 140 C / 10 min a) Yields of mixtures of diastereomers. Significantly, the heteroaromatic group of adducts 2.3ag adjacent to the hydroxylated carbon was found in all cases to sh ift more rapidly than the methyl group. This resulted in the formation of ketones 2.4ag According to the 1H NMR analysis, in compounds 2.4ag the protons of the methyl group and the proton of the methine group each resonate as singlets and no spin-spin coupling between of CH3 and CH was observed. This precludes migration of the methyl group. For the intermediates 2.3h,i,km migration of the phenyl group occurred rather than the corresponding heteroarom atic groups to give ketones 2.4h,i,km .The analysis of the 1H NMR data for ketones 2.4ag and 2.4h,i,km showed the lowfield shift of

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8 signals of the methine proton for 2.4h,i,km (4.55.80 ppm) around 1 ppm in comparison with signals of the methine proton for 2.4ag (5.57.80 ppm). Moreover, for ketone 2.4k the irradiation of the methine pr oton at 5.59 ppm resulted in clear NOE effect on the ortho -phenyl protons at 7.97.95 ppm. The structures of compounds 2.4h,i,km were supported by their 1H NMR and 13C NMR spectra. Table 2.2 Preparation of intermediates 2.3 and ketones 2.4 2.2 2.3 2.4 R R1 yield, %a yield, % / solvent / temp. / time h Ph S 75 40 / Cl2CHCHCl2 / 140 C / 1h i Ph O 40 23 / Cl2CHCHCl2 / 85 C / 12h j Ph N Me 72 Complex mixture k Ph O 70 46 / Cl2CHCHCl2 / 140 C / 1h l Ph S 98 40 / Cl2CHCHCl2 / 140 C / 1h m Ph S 50 58 / Cl2CHCHCl2 / 140 C / 30 min a) Yields of mixtures of diastereomers. 2.3 Conclusion In order to extend the synt hetic utility of benzotri azolyl-mediated one carbon insertion, the migrat ory aptitude of -electron-rich heterocycles of adducts 2.3am in the presence of alkyl and aryl groups has b een investigated. Rearrangements of the intermediates 2.3ag accompanied by 1,2-shift of heteroaromatic groups gave one carbon

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9 homologated ketones 2.4ag ; thus these rearrangements should find utility in the synthesis of ketones bearing asymmetric centers adjacent to heterocycles. In contrast, for the rearrangement of intermediates 2.3h,i,km migration of the phenyl group occurred preferentially instead of the corresponding he teroaromatic groups to give the one carbon homologated ketones 2.4h,i,km 2.4 Experimental Section General Melting points were determined on a hot-stage apparatus and are uncorrected. NMR spectra were recorded in CDCl3, acetoned6 or DMSOd6 with TMS as the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C (75 MHz). THF was dried over sodiumbenzophenone and used freshly distilled. Column chromatography was conducted on silica gel 200 425 meshes. 1-(Methylthio)-1-methyl1 H -benzotriazole 2.1 was prepared according to pr eviously reported procedure [98JOC2110]. 2.4.1 General procedure for the pr eparation of intermediates 2.3am A solution of 2.1 (5.58 mmol) in THF (50 mL) under nitrogen was cooled to -78 C, and a solution of n -BuLi (5.58 mmol, 1.58 M in hexane, 3.57 mL) was added dropwise. The reaction mixture was stirred at the same temperature for 1 h and a solution of an appropriate ketone (5.58 mmol ) in THF (15 mL) was added. The mixture was stirred for an additional 1 h at C. Then aqueous solution of ammonium chloride was added (30 mL) and the reaction mixture was extracted with diethyl ether. The ex tract was dried over anhydrous magnesium sulfate and evaporated under reduced pressu re. The residue was purified by column chromatography on silica gel to give 2.3am as equal mixtures of two

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10 diastereoisomers. In certain cases the isol ation of the diastereomeric pure forms was succeeded by a single recrystallization from acetonediethyl ether mixture (1:1). 1-(1H-1,2,3-Benzotriazol-1-yl)-1-(methylthio )-2-(2-thienyl)-2-propanol (2.3a) (one diastereoisomer): microcrystals from acetone-diethyl ether (41%); mp 138 139 C; 1H NMR (CDCl3): 7.95 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.45 7.40 (m, 1H), 7.35 7.29 (m, 1H), 7.00 (dd, J = 4.7, 1.4 Hz, 1H), 6.76 6.68 (m, 2H), 6.03 (s, 1H), 4.09 (s, 1H), 2.02 (s, 3H), 1.92 (s, 3H); 13C NMR (CDCl3): 148.3, 145.6, 132.8, 127.3, 126.7, 124.8, 124.1, 123.9, 119.7, 111.9, 77.4, 75.7, 29.0, 14.7. (Mixture of two diastereoisomers) : colorless oil (82%); 1H NMR (CDCl3): 8.06 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.47.30 (m, 4H), 7.28.25 (m, 1H), 7.01 (dd, J = 4.6, 1.6 Hz, 1H), 6.97.95 (m, 2H), 6.73 .68 (m, 2H), 6.07 (s, 1H), 6.02 (s, 1H), 3.88 (s, 1H), 3.29 (s, 1H), 2.02 (s, 3H), 1.94 (s, 3H), 1.84 (s, 3H), 1.57 (s, 1H), (double set of signals); 13C NMR (CDCl3): 148.8, 148.3, 146.2, 145.6, 132.8, 132.5, 127.3, 127.2, 127.1, 126.7, 124.9, 124.8, 124.2, 124.1, 123.9, 123.8, 119.7, 119.7, 112.9, 112.1, 77.3, 77.3, 77.1, 75.8, 29.0, 28.8, 14.9, 14.7, (double set of signals). Anal. Calcd for C14H15N3OS2: C, 55.06; H, 4.95; N, 13.76. Found: C, 55.25; H, 5.14; N, 13.85. 1-(1 H -1,2,3-Benzotriazol-1-yl)-1-(methylthio )-2-(3-thienyl)-2-propanol (2.3b) (mixture of two diastereoisomers): microcrystals from diet hyl ether (88 %), mp 118 122 C; 1H NMR (CDCl3): 8.03 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.45 7.35 (m, 3H), 7.33 7.26 (m, 3H), 7.10 (dd, J = 4.7, 1.7 Hz, 1H), 7.05 (dd, J = 5.0, 3.0 Hz, 1H), 6.91 (dd, J = 3.0, 1.4 Hz, 1H), 6.83 (dd, J = 5.1, 1.4 Hz, 1H), 6.07 (s, 1H), 6.04 (s, 1H), 3.74 (s, 1H), 3.30 (s, 1H), 1.93 (s, 3H), 1.91 (s, 3H), 1.78 (s, 3H), 1.50 (s, 3H), (double set of signals); 13C NMR (CDCl3):

PAGE 25

11 146.3, 145.7, 145.6, 145.3, 132.6, 132.5, 127.3, 127.1, 126.3, 126.0, 125.3, 124.9, 124.2, 124.0, 121.6, 121.2, 119.8, 119.7, 112.8, 112.1, 76.9, 75.7, 28.2, 28.0, 14.7, 14.6, (double set of signals). Anal. Calcd for C14H15N3OS2: C, 55.06; H, 4.95; N, 13.76. Found: C, 55.35; H, 5.03; N, 13.80. 1-(1 H -1,2,3-Benzotriazol-1-yl)-2-(1-methyl-1 H -indol-3-yl)-1-(methylthio)-2propanol (2.3c) (one diastereoisomer): microcrystals from acetonediethyl ether (41 %), mp 186 187 C; 1H NMR (CDCl3): 8.07 8.04 (m, 1H), 7.90 7.86 (m, 2H), 7.43 7.24 (m, 4H), 7.21 7.16 (m, 1H), 7.07 (s, 1H), 6.42 (s, 1H), 3.74 (s, 3H), 3.11 (s, 1H), 1.75 (s, 3H), 1.58 (s, 3H); 13C NMR (CDCl3): 146.3, 137.6, 132.8, 127.1, 126.8, 124.9, 124.1, 121.8, 120.1, 119.8, 119.6, 118.3, 112.8, 109.8, 76.7, 75.7, 32.8, 27.5, 14.7. (Mixture of two diastereoisomers): colorless oil (82 %); 1H NMR (CDCl3): 8.06.03 (m, 1H), 7.92.86 (m, 3H), 7.78.74 (m, 1H), 7.56.53 (m, 1H), 7.42.32 (m, 3H), 7.31.23 (m, 4H), 7.22.15 (m, 3H), 7.10.04 (m, 2H), 6.78 (s, 1H), 6.40 (s, 1H), 6.35 (s, 1H), 3.72 (s, 3H), 3.64 (s, 1H), 3.53 (s, 3H), 3.13 (s 1H), 2.05 (s, 3H), 1.86 (s, 3H), 1.74 (s, 3H), 1.56 (3H), (double set of signals); 13C NMR (CDCl3): 146.3, 145.5, 137.6, 137.3, 133.2, 132.8, 127.1, 127.0, 126.8, 126.7, 124.9, 124.7, 124.1, 123.8, 121.8, 121.6, 120.1, 119.9, 119.8, 119.6, 119.6, 119.3, 118.3, 118.0, 112.8, 111.6, 109.8, 109.6, 76.7, 75.7, 74.3, 32.8, 32.6, 27.5, 27.5, 14.7 (double set of signals). Anal. Calcd for C19H20N4OS: C, 64.75; H, 5.72; N, 15.90. Found: C, 64.94; H, 5.84; N, 15.70. 1-(1 H -1,2,3-Benzotriazol-1-yl)-2-(2-furyl)-1-(m ethylthio)-2-propanol (2.3d) (first diastereoisomer): microcrystals from acetonediethyl ether (37%), mp 127 128 C; 1H NMR (CDCl3): 7.98 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.45 7.39 (m, 1H), 7.35 7.29 (m, 1H), 7.13 (dd, J = 1.8, 0.8 Hz, 1H), 6.13 (s, 1H), 6.08 (dd, J = 3.4, 1.8 Hz,

PAGE 26

12 1H), 6.03 (dd, J = 3.4, 0.8 Hz, 1H), 3.96 (s, 1H), 1.96 (s, 3H), 1.87 (s, 3H); 13C NMR (CDCl3): 155.5, 145.6, 141.9, 132.8, 127.3, 124.1, 119.8, 111.4, 110.4, 106.7, 75.3, 73.7, 25.2, 14.7. Anal. Calcd for C14H15N3O2S: C, 58.11; H, 5.23; N, 14.52. Found: C, 58.25; H, 5.42; N, 14.63. (Second diastereoisomer): colorless oil (35 %); 1H NMR (CDCl3): 8.06 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.49.33 (m, 3H), 6.40 6.36 (m, 2H), 6.25 (s, 1H), 3.37 (s, 1H), 1.84 (s, 3H), 1.46 (s, 3H); 13C NMR (CDCl3): 155.9, 146.1, 141.9, 132.3, 127.1, 124.1, 119.4, 113.3, 110.5, 106.5, 75.4, 74.9, 25.7, 14.5. 2-(1-Benzofuran-2-yl)-1-(1 H -1,2,3-benzotriazol-1-yl)-1 -(methylthio)-2-propanol (2.3e) (mixture of two diastereoisomers): microcrystals from diethyl ether (75 %), mp 141 142 C; 1H NMR (CDCl3): 8.07 8.02 (m, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.57 7.54 (m, 1H), 7.49 7.20 (m, 9H), 7.16 7.05 (m, 2H), 6.85 (s, 1H), 6.46 (s, 1H), 6.41 (s, 1H), 6.27 (s, 1H), 4.41 (s 1H), 3.89 (s, 1H), 1.98 (s, 3H), 1.96 (s, 3H), 1.84 (s, 3H), 1.46 (s, 3H), (double set of signals); 13C NMR (DMSOd6): 160.4, 160.0, 154.2, 154.1, 146.0, 145.5, 132.4, 132.2, 127.9, 127.5, 126.9, 126.6, 124.1, 124.1, 124.0, 123.8, 122.9, 122.7, 121.1, 121.0, 119.1, 118.9, 114.3, 114.3, 111.2, 110.9, 103.3, 102.9, 74.6, 74.5, 74.4, 25.6, 25.4, 14.0, 13.9, (double set of signals). Anal. Calcd for C18H17N3O2S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.68; H, 5.04; N, 12.36. 2-(1-Benzothiophen-2-yl)-1-(1 H -1,2,3-benzotriazol-1-yl)-1-(methylthio)-2propanol (2.3f) (mixture of two diastereoisomers): microcrystals from diethyl ether acetone (94 %), mp 139 140 C; 1H NMR (CDCl3): 8.06 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.83 7.70 (m, 3H), 7.62 7.59 (m, 1H), 7.52 7.49 (m, 1H), 7.47 7.14 (m, 9H), 7.02 (s, 1H), 6.17 (s, 1H), 6.11 (s, 1H), 4.37 (s,

PAGE 27

13 1H), 3.64 (s, 1H), 2.05 (s, 3H), 1.94 (s, 3H), 1.82 (s, 3H), 1.5 (s, 3H), (double set of signals); 13C NMR (CDCl3): 149.4, 149.1, 146.3, 145.4, 139.6, 139.3, 139.2, 139.0, 132.9, 132.5, 127.5, 127.4, 124.4, 124.4, 124.3, 124.2, 124.2, 124.2, 123.6, 123.5, 122.3, 122.0, 120.7, 120.6, 119.8, 119.8, 113.0, 111.6, 77.7, 77.7, 76.7, 74.6, 29.1, 28.8, 14.9, 14.7, (double set of signals). Anal. Calcd for C18H17N3OS2: C, 60.82; H, 4.82; N, 11.82. Found: C, 60.77; H, 4.74; N, 11.77. 2-(1-Benzothiophen-3-yl)-1-(1 H -1,2,3-benzotriazol-1-yl)-1-(methylthio)-2propanol (2.3g) (first diastereoisomer): microcrystals from diethyl etheracetone (20%); mp 159 160 C; 1H NMR (CDCl3): 8.15 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.41 7.36 (m, 1H), 7.33 7.24 (m, 3H) 7.21 (s, 1H), 6.47 (s, 1H), 4.01 (s, 1H), 2.12 (s, 3H), 1.89 (s, 3H); 13C NMR (CDCl3): 145.4, 141.3, 138.6, 135.7, 132.9, 127.3, 124.0, 124.0, 123.2, 123.1, 119.9, 111.0, 78.1, 73.1, 26.8, 14.7. Anal. Calcd for C18H17N3OS2: C, 60.82; H, 4.82; N, 11.82. Found: C, 60.92; H, 4.78; N, 11.65. (Second diastereoisomer): colorless oil (20%); 8.23 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.41.33 (m, 2H), 7.30.25 (m, 2H), 7.23 (s, 1H ), 6.49 (s, 1H), 5.41 (s, 1H), 2.09 (s, 3H), 1.80 (s, 3H); 13C NMR (CDCl3): 145.5, 140.7, 139.2, 136.0, 132.5, 126.6, 123.6, 123.6, 123.6, 122.6, 119.1, 112.7, 77.1, 74.5, 26.5, 14.3. 2-(1 H -1,2,3-Benzotriazol-1-yl)-2-(methylthio )-1-phenyl-1-(2-thienyl)-1-ethanol (2.3h) (mixture of two diastereoisomers): microcrystals from diet hyl ether (75%); mp 182 183 C; 1H NMR (CDCl3): 8.03 (d, J = 8.2 Hz, 1H), 7.93.83 (m, 3H), 7.79.76 (m, 2H), 7.54.26 (m, 11H), 7.05.95 (m, 5H), 6.73 (dd, J = 3.7, 1.1 Hz, 1H), 6.67 (s, 1H), 6.62 (dd, J = 5.1, 3.7 Hz, 1H), 6.56 (s, 1H), 4.92 (s 1H), 4.57 (s, 1H), 1.95 (s, 3H),

PAGE 28

14 1.82 (s, 3H), (double set of signals); 13C NMR (DMSOd6): 149.9, 149.1, 145.7, 145.4, 144.0, 143.2, 132.7, 132.1, 128.0, 127.4, 127.2, 127.0, 126.7, 126.6, 126.2, 125.8, 125.4, 125.3, 124.7, 124.4, 123.8, 123.8, 119.5, 118.9, 118.8, 114.9, 114.4, 111.6, 80.3, 80.2, 75.8, 75.5, 14.1, 14.0, (double set of signals). Anal. Calcd for C19H17N3OS2: C, 62.10; H, 4.66; N, 11.43. Found: C, 62.35; H, 4.30; N, 11.33. 2-(1 H -1,2,3-Benzotriazol-1-yl)-1-(2-furyl) -2-(methylthio)-1-p henyl-1-ethanol (2.3i) (mixture of two diasterisomers): microcrystals from diethyl etheracetone (40%); mp 170 172 C; 1H NMR (CDCl3): 8.01 (d, J = 8.4 Hz, 1H), 7.95 7.88 (m, 2H), 7.83 7.76 (m, 3H), 7.50 7.28 (m, 10H), 7.03 6.99 (m, 4H), 6.74 (s, 1H), 6.63 (d, J = 3.3, Hz 1H), 6.56 (s, 1H), 6.46 (dd, J = 3.3, 1.8 Hz, 1H), 6.14 (d, J = 3.3 Hz, 1H), 6.01 (dd, J = 3.3, 1.9 Hz, 1H), 4.70 (s, 1H), 4.32 (s, 1H), 1.92 (s, 3H), 1.81 (s, 3H), (double sets of signals); 13C NMR (CDCl3): 155.0, 155.0, 145.7, 145.4, 142.2, 142.1, 140.5, 140.4, 133.1, 132.7, 128.4, 128.2, 128.0, 127.8, 127.6, 127.4, 125.6, 124.7, 124.3, 124.0, 120.0, 119.8, 111.9, 111.1, 110.9, 110.4, 107.5, 107.4, 79.7, 79.1, 73.1, 72.6, 14.7 (double sets of signals ). Anal. Calcd for C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96. Found: C, 65.05; H, 4.85; N, 12.01. 2-(1 H -1,2,3-Benzotriazol-1-yl)-1-(1-methyl-1 H -indol-3-yl)-2-(methylthio)-1phenyl-1-ethanol (2.3j) (one diastereoisomer): microcrystals from diethyl ether (36%); mp 119 20 C; 1H NMR (CDCl3): 7.79 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.67 7.64 (m, 2H), 7.41 7.25 (m, 7H), 7.15 7.04 (m, 2H), 6.88 6.82 (m, 1H), 6.69 (s, 1H), 3.64 (s, 3H), 3.58 (s, 1H), 1.72 (s, 3H); 13C NMR (CDCl3): 146.1, 143.0, 137.0, 133.0, 128.0, 127.6, 127.2, 127.0, 126.4, 125.7, 124.1, 121.9, 120.7, 119.7, 119.4, 117.1, 112.9, 109.3, 80.0, 75.3, 32.8, 14.7. (Mixture of two diastereoisomers): colorless oil

PAGE 29

15 (72%); 1H NMR (DMSOd6 CDCl3): 8.35 (d, J = 8.4 Hz, 1H), 7.96.84 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.70.67 (m, 3H), 7.48.10 (m, 15H), 7.03.98 (m, 1H), 6.93 6.85 (m, 5H), 6.77.73 (m, 2H), 5.81 (s, 1H), 5. 54 (s, 1H), 3.86 (s, 3H), 3.62 (s, 3H), 1.84 (s, 3H), 1.70 (s, 3H), (double set of signals); 13C NMR (DMSOd6 CDCl3): 145.6, 145.5, 143.2, 142.7, 136.6, 136.3, 132.5, 131.8, 127.2, 126.9, 126.6, 126.6, 126.4, 126.1, 125.9, 125.9, 125.7, 125.4, 125.1, 123.3, 123.1, 121.1, 121.0, 120.9, 120.7, 118.6, 118.5, 118.3, 118.3, 117.1, 117.0, 114.2, 113.5, 108.7, 108.4, 78.7, 78.6, 76.0, 75.1, 32.4, 32.2, 14.0, 13.7, (double set of signals). Anal. Calcd for C24H22N4OS: C, 69.54; H, 5.35; N, 13.52. Found: C, 69.83; H, 5.49; N, 13.94. 1-(1-Benzofuran-2-yl)-2-(1 H -1,2,3-benzotriazol-1-yl)-2 -(methylthio)-1-phenyl-1ethanol (2.3k) (mixture of two diastereoisomers): microcrystals from diethyl ether (70%); mp 88 90 C; 1H NMR (CDCl3): 7.97 7.88 (m, 5H), 7.82 (d, J = 8.4 Hz, 1H), 7.61 7.59 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.51 7.36 (m, 7H), 7.34 7.27 (m, 5H), 7.17 (d, J = 8.1 Hz, 1H), 7.11 7.08 (m, 1H), 7.05 6.98 (m, 5H), 6.88 (s, 1H), 6.71 (s, 1H), 6.64 (s, 1H), 5.10 (s, 1H), 4.68 (s, 1H), 1.95 (s, 3H), 1.85 (s, 3H), (double set of signals); 13C NMR (CDCl3): 157.7, 157.6, 154.8, 154.4, 145.6, 145.2, 140.2, 140.1, 133.2, 132.9, 128.5, 128.4, 128.1, 128.1, 128.0, 127.8, 127.6, 127.5, 125.6, 124.7, 124.5, 124.4, 124.2, 124.2, 123.2, 122.8, 121.5, 121.3, 120.1, 119.9, 111.5, 111.3, 110.8, 110.7, 104.3, 104.1, 80.0, 79.3, 72.2, 71.8, 14.8, 14.8, (double set of signals). Anal. Calcd for C23H19N3O2S: C, 68.81; H, 4.77; N, 10.47. Found: C, 68.74; H, 4.79; N, 10.51. 1-(1-Benzothiophen-2-yl)-2-(1 H -1,2,3-benzotriazol-1-yl) -2-(methylthio)-1-phenyl1-ethanol (2.3l) (mixture of two diastereoisomers): microcrystals from diethyl ether (98%); mp 165 166 C; 1H NMR (CDCl3): 8.01 7.90 (m, 3H), 7.84 7.75 (m, 5H),

PAGE 30

16 7.55 7.29 (m, 15H), 7.19 7.13 (m, 2H), 7.09 (s, 1H), 7.05 6.97 (m, 2H), 6.77 (s, 1H), 6.65 (s, 1H), 5.31 (s, 1H), 4.83 (s, 1H), 1.97 (s, 3H), 1.84 (s, 3H), (double set of signals); 13C NMR (CDCl3): 149.1, 148.7, 145.5, 145.4, 141.9, 141.7, 139.6, 139.3, 139.3, 139.0, 133.3, 132.7, 128.45 128.2, 128.0, 128.0, 127.8, 127.7, 125.5, 124.7, 124.6, 124.5, 124.5, 124.3, 124.2, 124.1, 123.9, 123.6, 122.2, 122.0, 121.8, 120.8, 120.2, 120.0, 111.5, 111.0, 81.5, 81.2, 74.0, 72.8, 14.9, 14.8, (double set of signals). Anal. Calcd for C23H19N3OS2: C, 66.16; H, 4.59; N, 10.06. Found: C, 66.05; H, 4.51; N, 10.10. 2-(1H-1,2,3-Benzotriazol-1-yl)-2-(methylth io)-1-phenyl-1-(3-thienyl)-1-ethanol (2.3m) (mixture of two diastereoisomers): microcrystals from diethyl etherhexane (50%); mp 189-190C; 1H NMR (DMSOd6): 8.40 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.89.83 (m, 4H), 7.53.45 (m, 3H), 7.43.29 (m, 4H), 7.23.15 (m, 3H), 7.11.06 (m, 3H), 7.00.94 (m, 3H), 6.84.78 (m, 3H), 3.38 (s, 1H), 1.80 (s, 3H), 1.72 (s, 3H), (double set of signals); 13C NMR (DMSOd6): 146.4, 145.9, 145.6, 145.6, 144.3, 143.5, 132.6, 132.2, 127.9, 127.5, 127.3, 127.1, 126.7, 126.5, 126.4, 126.4, 126.0, 125.5, 125.3, 125.3, 123.8, 123.7, 122.0, 121.4, 118.8, 118.7, 115.0, 114.9, 80.3, 80.3, 75.6, 75.1, 13.9, 13.9, (double set of signals). Anal. Calcd for C19H17N3OS2: C, 62.10; H, 4.66; N, 11.43. Found: C, 61.77; H, 4.87; N, 11.23. 2.4.2 General procedure for the preparation of ketones 2.4a and 2.4b To a solution of 2.3a or 2.3b (mixtures of two diastereoisomers) (0.3 g, 0.98 mmol) in 1,1,2,2-tetrachloroethane (15 mL) under nitr ogen, a solution of zinc bromide (2.95 mmol, 1M in tetrahydrofuran, 2.95 mL) was a dded and the reaction mixture was heated at 140 C for 20 h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chro matography on silica gel to give 2.4a and 2.4b

PAGE 31

17 ( )-1-(Methylthio)-1-(2-thi enyl)acetone (2.4a): colorless oil (60%); 1H NMR (CDCl3): 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.09 7.07 (m, 1H), 6.99 (dd, J = 5.1, 3.6 Hz, 1H), 4.78 (s, 1H), 2.32 (s, 3H), 2.04 (s, 3H); 13C NMR (CDCl3): 201.1, 137.7, 127.0, 126.8, 126.1, 54.6, 26.6, 14.0. The spectral data of this compound are identical to that reported in the lite rature [82CPB3579]. ( )-1-(Methylthio)-1-(3-thi enyl)acetone (2.4b): colorless oil (64%); 1H NMR (CDCl3): 7.36 7.31 (m, 2H), 7.08 7.06 (m, 1H), 4.58 (s, 1H), 2.25 (s, 3H), 2.00 (s, 3H); 13C NMR (CDCl3): 202.3, 135.3, 127.3, 126.2, 123.6, 55.4, 26.6, 14.0. Anal. Calcd for C8H10OS2: C, 51.58; H, 5.41; Found: C, 51.83; H, 5.48. 2.4.3 Preparation of ( )-1-(1-Methyl-1H-indol-3-yl )-1-methylthio-propan-2-one 2.4c The solution of 2.3c (mixture of two diastereoisomers) (0.4 g, 1.14 mmol) in THF (15 mL) was cooled to C, and the solution of n -BuLi (1.14 mmol, 1.58 M in hexane, 0.73 mL) was added dropwise. The reaction mixt ure was stirred at the same temperature for 1 h and a solution of zinc bromide (3.40 mmol, 1M in tetrahydrofuran, 3.40 mL) under nitrogen was added. The reaction mixture was heated in a sealed tube at 100 C for 15 h, and after cooling a solvent was evaporat ed under reduced pressu re. The residue was purified by column chromatography on silica gel to give 2.4c as brown oil (7%); 1H NMR (CDCl3): 7.64.61 (m, 1H), 7.34.23 (m, 3H), 7.17.12 (m, 1H), 4.82 (s, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.01 (s, 3H); 13C NMR (CDCl3): 203.1, 146.2, 137.0, 128.4, 126.8, 122.2, 119.6, 119.0, 109.5, 52.0, 32.9, 13.9. Anal. Calcd for C13H15NOS: C, 66.92; H, 6.48; N, 6.00; Found: C, 66.99; H, 6.51; N, 6.03.

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18 2.4.4 Preparation of ( )-1-(2-Furyl)-1-(methylthio)acetone 2.4d Method A: The solution of 2.3d (mixture of two diastereoisomers) (0.4 g, 1.38 mmol) in THF (15 mL) under ni trogen was cooled to C, and the solution of n -BuLi (1.38 mmol, 1.58 M in hexane, 0.9 mL) was a dded dropwise. The reaction mixture was stirred at the same temperature for 1 h and a solution of zinc bromide (6.50 mmol, 1M in tetrahydrofuran, 6.5 mL) was added. The reaction mixture was heated in sealed tube at 130 C for 80 h and after cooling poured into the 1N aqueous hydrochloric acid. Then reaction mixture was extracted with diethyl ether. The ether solution was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was purified by column chro matography on silica gel to give 2.4d as colorless oil (21%); 1H NMR (CDCl3): 7.41 (d, J = 1.1 Hz, 1H), 6.45 (d, J = 3.1 Hz, 1H), 6.38.36 (m, 1H), 4.55 (s, 1H), 2. 29 (s, 3H), 2.03 (s, 3H). 13C NMR (CDCl3): 200.1, 148.0, 142.7, 110.6, 109.5, 52.6, 26.8, 13.7. Method B: To a solution of 2.3d (mixture of two diastereoisomers) (0.69 mmol) in 1,1,2,2-tetrachloroethane (15 mL) under nitrogen, a solution of zinc bromide (2.1 mmol, 1M in tetrahydrofuran) wa s added and the reaction mixture was heated at 140 C for 1h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel to give 2.3d (40%). The spectral data of this compound are identical to that reporte d in the literature [82CPB3579]. 2.4.5 General procedure for the preparation of ketones 2.4ei,km To a solution of 2.3ei,km (mixtures of two diastereoisomers) (0.57 mmol) in 1,1,2,2-tetrachloroethane (15 mL) under nitrogen, a solution of zinc bromide (1.71 mmol, 1M in tetrahydrofuran) wa s added and the reaction mixture was heated at 140 C for the

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19 period from 10 min to 1h (see Table1). The reaction mixture was concentrated under reduced pressure and the resi due purified by column chroma tography on silica gel to give 2.4ei,km ( )-1-(1-Benzofuran2-yl)-1-(methylthio)acetone (2.4e): colorless oil (40%); 1H NMR (CDCl3): 7.57 7.54 (m,1H), 7.46 (d, J = 8.2 Hz, 1H), 7.31 7.19 (m, 2H), 6.87 (s,1H), 4.66 (s, 1H), 2.35 (s, 3H), 2.07 (s, 3H); 13C NMR (CDCl3): 199.6, 154.8, 150.7, 128.0, 124.5, 123.0, 121.0, 111.2, 106.4, 52.6, 27.1, 13.8. Anal. Calcd for C12H12O2S: C, 65.43; H, 5.49; Found: C, 65.73; H, 5.50; ( )-1-(1-Benzothiophen-2-yl)-1-( methylthio)acetone (2.4f): colorless oil (40%); 1H NMR (CDCl3): 7.80 7.77 (m, 1H), 1.74 7.70 (m, 1H), 7.35 7.30 (m, 3H), 4.81 (s, 1H), 2.36 (s, 3H), 2.07 (s, 3H); 13C NMR (CDCl3): 200.8, 139.9, 139.2, 138.9, 124.5, 124.4, 124.0, 123.5, 122.2, 55.3, 27.0, 14.1. Anal. Calcd for C12H12OS2: C, 60.98; H, 5.12; Found: C, 60.75; H, 5.09; ( )-1-(1-Benzothiophen-3-yl)-1-( methylthio)acetone (2.4g): yellow oil (71%); 1H NMR (CDCl3): 7.88 7.85 (m, 1H), 7.79 7.76 (m, 1H), 7.66 (s, 1H), 7.40 7.37 (m, 1H), 4.81 (s, 1H), 2.22 (s, 3H), 2.04 (s, 3H); 13C NMR (CDCl3): 202.0, 140.2, 137.4, 128.9, 125.6, 124.8, 124.4, 122.9, 121.7, 53.9, 26.4, 14.1. Anal. Calcd for C12H12OS2: C, 60.98; H, 5.12; Found: C, 60.80; H, 5.09; ( )-2-(Methylthio)-2-phenyl-1-(2thienyl)-1-ethanone (2.4h): colorless oil (40%); 1H NMR (CDCl3): 7.98 7.95 (m, 2H), 7.52 7.48 (m, 1H), 7.42 7.37 (m, 2H), 7.24 7.22 (m, 1H), 7.09 7.08 (m, 1H), 6.93 6.89 (m, 1H), 5.71 (d, J = 1.1 Hz, 1H), 1.99 (d, J = 1.6 Hz, 3H); 13C NMR (CDCl3): 192.5, 138.3, 135.2, 133.4, 128.8, 128.7, 127.3,

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20 126.5, 126.4, 47.9, 13.6. Anal. Calcd for C13H12OS2: C, 62.87; H, 4.87; Found: C, 62.94; H, 5.06. ( )-1-(2-Furyl)-2 -(methylthio)-2-phenyl-1-ethanone (2.4i): yellow oil (23%); 1H NMR (CDCl3): 8.02.99 (m, 2H), 7.60.55 (m, 1H), 7.49.42 (m, 3H), 6.59.57 (m, 1H), 6.38.36 (m, 1H), 5.57 (s, 1H), 2.05 (s, 3H); 13C NMR (CDCl3): 191.2, 148.3, 142.6, 135.3, 133.4, 128.7, 110.7, 110.0, 46.1, 13.2. Anal. Calcd for C13H12O2S: C, 67.22; H, 5.21; Found: C, 67.10; H, 5.39. ( )-1-(1-Benzofuran-2-yl )-2-(methylthio)-2 -phenyl-1-ethanone (2.4k): yellow oil (46%); 1H NMR (CDCl3): 7.97 7.95 (m, 2H), 7.49 7.45 (m, 2H), 7.40 7.35 (m, 3H), 7.22 7.10 (m, 2H), 6.92 (s, 1H), 5.5 9 (s, 1H), 2.00 (s, 3H); 13C NMR (CDCl3): 190.8, 154.8, 151.1, 135.1, 133.5, 128.7, 128.7, 128.2, 124.4, 122.9, 121.1, 111.2, 107.0, 46.1, 13.3. Anal. Calcd for C17H14O2S: C, 72.31; H, 5.00; Found: C, 72.27; H, 5.30. ( )-1-(1-Benzothiophen-2-yl)-2-(methy lthio)-2-phenyl-1-ethanone (2.4l): yellow microcrystals from diethyl etherhexane to give (40%); mp 71-72C; 1H NMR (CDCl3): 8.06 (d, J = 7.3 Hz, 2H), 7.80 7.77 (m, 1H), 7.72 7.69 (m, 1H), 7.59 7.54 (m, 1H), 7.49 7.45 (m, 2H), 7.40 (s, 1H), 7.34 7.26 (m, 2H), 5.80 (s, 1H), 2.11 (s, 3H); 13C NMR (CDCl3): 192.4, 140.2, 139.6, 139.2, 135.2, 133.5, 128.8, 128.7, 124.4, 124.3, 124.3, 123.6, 122.2, 48.7, 13.7. Anal. Calcd for C17H14OS2: C, 68.42; H, 4.73; Found: C, 68.17; H, 4.72. ( )-2-(Methylthio)-2-phenyl-1-(3thienyl)-1-ethanone (2.4m): colorless oil (71%); 1H NMR 8.00 (d, J = 8.2 Hz, 2H), 7.57 7.52 (m, 1H), 7.47 7.42 (m, 3H), 7.32 7.30 (m, 1H), 7.18 (d, J = 5.1 Hz, 1H), 5.57 (s, 1H), 2.01 (s, 3H); 13C NMR 193.7, 135.8,

PAGE 35

21 135.7, 133.2, 128.7, 128.6, 127.9, 126.0, 124.0, 48.8, 13.6. Anal. Calcd for C13H12OS2: C, 62.87; H, 4.87; Found: C, 62.79; H, 4.87.

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22 CHAPTER 3 THE PREPARATION OF N N N TRISUBSTITUTED GUANIDINES 3.1 Introduction A wide variety of structurally diverse mo lecules that incorporate guanidine units have been isolated from most living microor ganisms, as well as from higher plants [99NPR339, 00CSR57]. Guanidines are the core features of many therapeutically active compounds [96B16174, 96JMC4527, 98JMC 787, 98JMC3298, 99BR78, 00JOC2399, 00TL1849]. Guanidine alkaloids exhibit antiv iral, antifungal and an titumor activities [99NPR339]. Thus, procedures fo r the preparation of guanidine s are of great interest in medicinal chemistry, and much effort has been directed on developi ng efficient syntheses of these compounds. The basicity of guanidines complicates their synthesis. For this reason, many syntheses utilize intermediate s with easily removable pr otective groups. Most common methods for the preparation of guanidines 3.3 involve the attack of an amine 3.1 on various active guanidinylating reagents 3.2aj (Scheme 3.1): a) ureas 3.2a were reacted with phosgene and treated with Vils meier salts formed from amines 3.1 [82JCS(P1)2085]; b) triflylguanidines 3.2b [98JOC3804]; (c) guanylpyrazoles 3.2c have been used as guanidinylating reagents [93TL3389] Primary amines react smoothly and efficiently with these reagents whereas sterically more demanding secondary or electronically-deactivated aromatic amines cause various difficulties.

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23 ArHN S NHAr R N PPh3 BocHN NHBoc S BocHN NBoc SMe H2N NHBoc S H2N NR1SMe HgCl2 TEA, DMF, 60oC NMe Cl I N NH N N R2R1 HN R N N Cl O Cl NH2R H2N NR1SO3H R1HN NH SMe R1HN NR1N N R1HN NTf NHR1 R1HN O NHR1 3.2a-j + a R1 = Alkyl Et2O, 0oC b R1 = Boc, Cbz DCM, 20oC c R1 = Boc, Cbz THF, 20oC d R1 = Ph, Pr MeCN, 20oC e R1 = Mtr, Pmc Hg(ClO4)2 TEA f g h EDCl, TEA, DCM, 20oC i R1 = Ar t -BuOH, heat j R = Ar, 3.4 R1= Ar, Alk; R2 = H THF, reflux 3.13.33.5 3.2a 3.2b 3.2c 3.2d 3.2e 3.2f 3.2g 3.2h 3.2i 3.2j Scheme 3.1 Common methods for th e preparation of guanidines 3.3 Several common methods for th e preparation of guanidines 3.3 involve the treatment of amines with el ectrophilic species generated from thioureas (Scheme 3.1): d) Maryanoff reacted amines with sulfonic acids derived from N -alkyl substituted thioureas 3.2d [86JOC1882]; e) Cody used aryl sulf onate-protected S-methylisothioureas 3.2e [96TL8711] in the presence of mercury sa lts; (f) Cammidge and others used bis -Bocisothioureas 3.2f with mercuric chloride [ 93SC1443, 93TL7677, 97TL5291, 00SC2933]; g) Lipton developed methodology using Mukaiyamas reagent to form a carbodiimide from bis -Boc-thiourea 3.2g which was subsequently trea ted with amines [97JOC1540]; h) Poss used Boc-protected thioureas 3.2h to react with amines in the presence of the

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24 water-soluble carbodiimide, EDCI, under mild conditions [92TL5933]; i) Rasmussen explored a method of guanidinylation, which wa s initiated by attack of aryl amines on Smethylisothiourea 3.2i in refluxing t -butanol [88S456, 88S460]; j) Wu and coworkers used imidazole-1-carboxamidines 3.2j as guanylating reagents [02JOC7553]; and k) Molina reacted 1,3-diarylthioureas 3.5 with iminophosphoranes 3.4 to form trisubstituted guanidines 3.3 (Scheme 3.1) [83SC67]. Several benzotriazole-based guanylating r eagents have recently been introduced: benzotriazole-1-carboxamidinium tosylate 3.6 [95SC1173], benzotriazolylcarboximidoyl chlorides 3.7 [01JOC2854] and di(benzo triazolyl)carboximidamide 3.8a and 3.8b [00JOC8080] (Scheme 3.2). H2N NH2 +Bt Bt NH Bt Bt NR Cl Bt=Benzotriazole R = Ar, Alk Bt NCOR Bt TsO 3.63.73.8a 3.8b Scheme 3.2 Benzotriazole-based guanylating reagents Reagents 3.6.8 all guanylate primary and secondary amines under mild conditions in high yields (Scheme 3.2). Be nzotriazole-1-carboxamidinium tosylate 3.6 afforded guanidines under mild conditions, in moderate to good yields. Benzotriazolylcarboximidoyl chlorides 3.7 allow the preparation of unsymmetrical guanidines and are considered advantageous because 3.7 are stable, odorless, and convenient to handle. Di(ben zotriazolyl)carboximidamides 3.8a were applied to the synthesis of triand tetra-substituted guanidines and are insensitive to electronic and steric effects allowing the use of a wide variety of amines. Di(benzotriazolyl)carboximidamides 3.8b are efficient for the preparation of

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25 acylguanidines and also provide three atom synthons for the preparation of 5-amino1,2,8-triazoles and 4(6)-amino-1,3,5triazine-2-ones [04JOC309]. H2NNH2NH2 + TsO-Bt1Bt1NH 3.8 N N NN N NBt1,2Cl NR 3.6 3.7 5586% i) R1R2NH ii) R3R4NH i) R1R2NH ii) R3R4NH 42-90% 48-85% i) R1R2NH = Bt Scheme 3.3 Preparation of guani dines utilizing benzotriazole -based guanylating reagents Benzotriazole-based guanylation was now extended to include two new reagent classes, ( bis -benzotriazol-1-yl-methylene)amines 3.11 and benzotriazole-1carboxamidines 3.13 which allow for the facile preparation of N, N N -trisubstituted guanidines (Schemes 3.4, 3.6 and 3.7). 3.2 Results and Discussion The approach now presented utilizes ( bis -benzotriazol-1-yl-methylene)amines 3.11 and benzotriazole-1-carboxamidines 3.13 Substituted guanidines 3.15ae and 3.16ae are derived from 3.11 (Scheme 3.6, Table 3.2). Reagents 3.13 are used to produce 3.17af and 3.18ah all provided by reactions with vari ous amines (Scheme 3.7, Table 3.3). Bis -benzotriazol-1-yl-methylene amines 3.11af were prepared by reaction of bis benzotriazol-1-yl-methanethione 3.9 and triphenylphosphine imides 3.10 in toluene at 70 C for 3 hours followed by purification by column chromatography (Scheme 3.4, Table 3.1). The synthesis of benzotriazole-1-carboxamidines 3.13 was achieved from bis benzotriazol-1-yl-methanethione 3.9 and aromatic amines in dichloromethane at 20 C to

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26 yield compounds 3.12 that were further reacted with triphenylphosphine imides 3.10 to give benzotriazole-1-carboxamidines 3.13al (Scheme 3.4, Table 3.1). A simple one-step procedure for the preparation of compounds 3.12 in nearly quantitative yields has recently been developed in our group [04JOC2976]. Bis -benzotriazol-1-yl-methylene amines 3.11af and benzotriazole-1-carboxamidines 3.13al are stable, crystalline substances that have been stored at room temperature for 3 weeks with no apparent loss of activity. Bt Bt S Bt R Bt N Bt S R1NH R Bt N R1NH RNPPh3 RNPPh3 3.9 3.10 3.12 3.11a-f 3.13a-l 3.10 3.12a R1 = Bn, 98 % 3.12b R1 = i -Pr, 95 % 3.12c R1 = Ph, 90 % 3.12d R1 = n -Bu, 98 % 3.10a R = Ph 3.10b R = p -Tol 3.10c R = C6H4CNm 3.10d R = C6H4CO2Et 3.10e R = C6H4Clp 3.10f R = COPh 3.10g R = C6H2(Me)3-2,4,6 3.12e R1 = (CH2)2Ph, 93 % 3.12f R1 = (CH2)5CH, 95 % 3.12g R1 = CH2CH(CH3)CH2CH3, 98 % 3.12h R1 = 2-furylmethyl, 91 % R1NH2 Scheme 3.4 Preparation of novel guanylating reagents 3.11a-f and 3.13a-l A variety of triphenylphosphine imides 3.10 were synthesized from the corresponding organic azides and triphe nylphosphine [66CJC2793] (Scheme 3.4). In addition, our efforts to prepare 3.11 and 3.13 when R is benzyl also failed to give corresponding substituted thioureas 3.12a and 3.14 respectively (Scheme 3.5). To investigate the scope and lim itations of our new reagents, 3.11 and 3.13 were reacted with a series of st ructurally different amines Syntheses of symmetrical guanidines 3.15ae from 3.11 and primary amines (aliphatic and aromatic amines) were

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27 Bt Bt S N H N H S Bn N PPh3Bn N PPh3Bn 3.9 Toluene 70oC, 4h Toluene reflux, 1h 3.12a 3.12b 3.14 Scheme 3.5 Attempts to prepare 3.11 and 3.13 with R= benzyl Table 3.1 Preparation of guanylating reagents 3.11a-f and 3.13a-l Product 3.11 R Yield (%) Reactants 3.12+3.10 R1 R Product 3.13 Yield (%) 3.11a Ph 65 3.12a+3.10a Bn Ph 3.13a 91 3.11b p -Tol 73 3.12a+3.10b Bn p -Tol 3.13b 96 3.11c C6H4CNm 78 3.12b+3.10b i -Pr p -Tol 3.13c 92 3.11d C6H4CO2Et 53 3.12b+3.10e i -Pr C6H4Clp 3.13d 67 3.11e C6H4Clp 63 3.12c+3.10g Ph Mesityl 3.13e 80 3.11f COPh 86 3.12d+3.10d n -Bu C6H4CO2Et 3.13f 53 3.12d+3.10g n -Bu Mesityl 3.13g 84 3.12e+3.10c Phenethyl C6H4CNm 3.13h 95 3.12f+3.10e Cyclohexyl C6H4Clp 3.13i 40 3.12g+3.10b 2-Methylbutyl p -Tol 3.13j 82 3.12h+3.10e 2-Furylmethyl C6H4Clp 3.13k 93 3.12d+3.10e n -Bu C6H4Clp 3.13l 87 accomplished in high yields on heating under reflux in toluene for 1h (Scheme 3.6, Table 3.2). However, we failed to pr epare symmetrical guanidines 3.15 from secondary amines possibly due to carbodiimide fo rmation [81T233] (Scheme 3.6). Further results from the i nvestigation of reagents 3.11 and 3.13 are shown in Tables 3.2 and 3.3. Reagents 3.11 were successfully employed in the guanylation of diamines to

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28 Bt Bt N R Bt NH N R R1 NH NH N R R1R1 R1NH2HN HN N R NH2NH2BtH RNCR1N 3.11 Toluene, reflux 1h Toluene, reflux 1h 3.16a-e 3.15a-e R1NH2 Scheme 3.6 Preparation of symmetrical and cyclic trisubstituted guanidines give cyclic trisubstituted guanidines 3.16ae in nearly quantitative yields (Scheme 3.6, Table 3.2). Table 3.2 Preparation of symmetrical and cyclic trisubstituted guanidines 3.15ae and 3.16ae 3.11 R R1 Product Yield (%) 3.11 Diamine R Product Yield (%) 3.11a Ph Cy 3.15a 79 3.11b NH2(CH2)3NH2 p -Tol 3.16a 95 3.11b p -Tol n -Bu 3.15b 83 3.11b NH2(CH2)2NH2 p -Tol 3.16b 95 3.11c C6H4CNm i -Pr 3.15c 87 3.11a (NH2CH2)2C(CH3)2 C6H4Clp 3.16c 96 3.11d C6H4CO2Et 1Phenyl ethyl 3.15d 91 3.11a NH2(CH2)3NHCH3 Ph 3.16d 89 3.11e C6H4Clp Bn 3.15e 85 3.11f NH2(CH2)3NH2 COPh 3.16e 77 Initially, the reactions of 3.13 with secondary amines were typically carried out in refluxing toluene for 1h and were found to re act rather sluggishly. Extension of reflux time to 12h was efficient to affect transf ormation to the unsymmetrical guanidines 3.17a f (Scheme 3.7, Table 3.3). The benzotriazole group in 3.13 was displaced with the primary alkylamines in refluxing toluen e to form unsymmetrical guanidines 3.18ah in high yields (Scheme 3.6, Table 3.3). The be nzotriazole formed as a byproduct was removed by washing with saturated aqueous sodium carbonate.

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29 R1HN Bt N R R1HN N N R R3R2 R1HN HN N R R2 R2NH2R3NHR23.13 Toluene, reflux 12h Toluene, reflux 1h 3.17a-f 3.18a-h Scheme 3.7 Preparation of subs tituted unsymmetrical guanidines 3.3 Conclusion In summary, new routes for the guanylation of a series of structurally different amines have been described. The preparation of new reagents 3.11 and 3.13 are facile and less demanding than some known guanylation r eagents. We believe that our new reagents will find widespread use in the synt hesis of guanidine-containing compounds. 3.4 Experimental Section General Melting points were determined on a hot-stage apparatus and are uncorrected. NMR spectra were recorded in CDCl3, or DMSOd6 with TMS as the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75 MHz). Column chromatography was conducted on silica gel (200 425 mesh) or on basic alumina (60 mesh). Bis -benzotriazol-1-yl-methanethione 3.3 was prepared according to previously reported procedure; Mp 171-172 C, yield 98%, (Lit. Mp 170-171 C, yield 90%) [78JOC337].

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30 Table 3.3 Preparation of substi tuted unsymmetrical guanidines 3.17af and 3.18ah 3.13 R R1 R2 R3 Product Yield (%) 3.13a Ph Bn i -Pr i -Pr 3.17a 67 3.13b p -Tol Bn -(CH2)2O(CH2)23.17b 90 3.13f -C6H4CO2Et n -Bu n -Pr n -Pr 3.17c 96 3.13i -C6H4Clp Cyclohexyl -(CH3)CH(CH2)3CH(CH3)3.17d 93 3.13h -C6H4CNm Phenethyl -(CH2)43.17e 91 3.13g Mesityl n -Bu Et Et 3.17f 93 3.13a Ph Bn n -Bu __ 3.18a 99 3.13b p -Tol Bn Pentyl __ 3.18b 93 3.13c p -Tol i -Pr 1-Phenylethyl __ 3.18c 71 3.13d -C6H4Clp i -Pr Bn __ 3.18d 89 3.13g Mesityl n -Bu i -Pr __ 3.18e 83 3.13e Mesityl Ph i -Pr __ 3.18f 96 3.13j p -Tol 2-Methylbutyl Bn __ 3.18g 85 3.13k -C6H4Clp 2-Furylmethyl n -Bu __ 3.18h 91 3.4.1 General Procedure for the Preparation of Compounds 3.10ag Compounds 3.10a g were prepared by adding trip henylphosphine to an ethereal solution of the corresponding azide. After th e solution was heated under reflux for two h, the solvent was removed under re duced pressure and the resi due was crystallized from absolute ethanol. (Phenylimino)(triphenyl)phosphorane ( 3.10a ): White microcrystals from ethanol (100%), Mp 134-135 C (Lit. Mp 133-134 C) [66CJC2793]. [(4-Methylphenyl)imino]( triphenyl)phosphorane ( 3.10b ): Yellow microcrystals from ethanol (99%), Mp 136-137 C (Lit. Mp 136-137 C) [66CJC2793].

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31 3-[(Triphenyl5-phosphanylidene)amino]benzonitrile ( 3.10c ): White microcrystals from ethanol (96%), Mp 159-160 C (Lit. Mp 157-158 C) [66CJC2793]. Ethyl 4-[(triphenyl5-phosphanylidene)amino]benzoate ( 3.10d ): White microcrystals from ethanol (85%), Mp 136-137 C (Lit. Mp 136C) [66CJC2793]. [(4-Chlorophenyl)imino]( triphenyl)phosphorane ( 3.10e ): White microcrystals from ethanol (71%), Mp 161-162 C (Lit. Mp 160-161 C) [66CJC2793]. N -(Triphenyl5-phosphanylidene)benzamide ( 3.10f ): White microcrystals from ethanol (98%), Mp 194-195 C (Lit. Mp 195-196 C) [84TL4651]. (Mesitylimino)(triphenyl)phosphorane ( 3.10g ): White microcrystals from ethanol (77%), Mp 146-147 C (Lit. Mp 146-146.5 C) [83ZOK1763]. 3.4.2 General Procedure for the Preparation of Compounds 3.11af To a stirred solution of 3.9 (0.007 mol) in toluene (12 mL), the appropriate ( 3.10a f ) (0.007 mol) was added at room temperature and the resulting mixt ure was heated at 60 C for 4 h. Completion of the reaction wa s monitored by TLC. Upon completion, the reaction mixture was concentrated under re duced pressure and residue purified by gradient column chromatography (ethyl acetate/hexanes) on s ilica gel to give 3.11af. N -[Di(1 H -1,2,3-benzotriazol-1-yl)methylene]-4-methylaniline (3.11a): White microcrystals from ethyl acetate / hexanes (76%), Mp 155 156 C; 1H-NMR (CDCl3): 8.4 (d, J = 8.4, 1H), 8.21 (d, J = 8.1, 1H), 8.13 8.12 (m, 1H), 7.75 (t, J = 7.4, 1H), 7.60 (t, J = 7.7, 1H), 7.41 7.38 (m, 2H), 7.20 7.03 (m, 4H), 6.8 (d, J = 8.2, 2H); 13C-NMR (CDCl3): 143.4, 130.2, 129.3, 129.2, 126.4, 126.3, 125.0, 121.2, 120.6, 114.3, 110.1. Anal. Calc. for C19H13N7: C 67.25, H 3.86, N 28.89; Found: C 67.49, H 4.01, N 28.50.

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32 N -[Di(1 H -1,2,3-benzotriazol-1-yl)methylene]-4-methylaniline (3.11b): White microcrystals from ethyl acetate / hexanes (73%), Mp 165 166 C; 1H-NMR (CDCl3): 8.41 (d, J = 8.2, 1H), 8.18 (d, J = 8.2, 1H), 8.14 8.11 (m, 1H), 7.75 7.70 (m 1H), 7.59 7.54 (m, 1H), 7.41 7.38 (m, 2H), 7.13 7.10 (m, 1H), 6.96 (d, J = 9.0, 2H), 6.73 (d, J = 9.0, 2H); 13C-NMR (CDCl3): 146.6, 144.8, 140.7, 136.3, 133.9, 132.4, 131.8, 130.1, 129.8, 129.3, 126.2, 125.0, 121.3, 120.5, 114.2, 110.1, 20.9. Anal. Calc. for C20H15N7: C 67.98, H 4.28, N 27.74; Found: C 67.81, H, 4.22, N 27.43. 3-{[Di(1 H -1,2,3-benzotriazol-1-yl)met hylene]amino}benzonitrile (3.11c): Yellow microcrystals from ethyl acetate / hexanes (79%), Mp 205 206 C; 1H-NMR (CDCl3): 8.38 (d, J = 8.1, 1H), 8.22 (d, J = 8.1, 1H), 8.14 (d, J = 7.6, 1H), 7.81 7.76 (m, 1H), 7.63.59 (m, 1H), 7.51 7.45 (m, 2H), 7.37 (d, J = 7.7, 1H), 7.30 7.24 (m, 2H), 7.10 (d, J = 7.6, 1H), 6.99 (d, J = 8.1, 1H); 13C-NMR (CDCl3): 146.8, 144.8, 144.6, 132.5, 131.5, 130.6, 130.2, 129.9, 129.4, 126.7, 125.5, 125.2, 124.9, 120.8, 117.8, 114.2, 113.4, 109.9. Anal. Calc. for C20H12N8: C 65.17, H 3.32, N 30.11; Found: C 64.71, H 3.20, N 29.83. Ethyl 4-{[di(1 H -1,2,3-benzotriazol-1-yl)m ethylene]amino}benzoate (3.11d): Yellow microcrystals from ethyl acetate / hexanes (53%), Mp 197 198 C; 1H-NMR (CDCl3): 8.46 8.36 (m, 1H), 8.26 8.08 (m, 2H), 7.88 (d, J = 8.5, 2H), 7.81 7.71 (m, 1H), 7.62 (br s, 2H), 7.43 (br s, 1H), 7.12 ( br s, 1H), 6.92 (d, J = 8.5, 2H), 4.31 (q, J = 7.1, 2H), 1.35 (t, J = 7.1, 3H); 13C-NMR (CDCl3): 165.7, 147.6, 135.4, 130.8, 130.4, 127.9, 126.6, 125.3, 120.9, 120.7, 114.2, 110.0, 61.0, 14.22. Anal. Calc. for C22H17N7O2: C 64.23, H 4.16, N 23.83; Found: C 64.12, H 4.11, N 23.88. N -(4-Chlorophenyl)N -[di(1 H -1,2,3-benzotriazol-1-yl)methylene]amine (3.11e): White microcrystals from ethyl acetate / hexanes (58%), Mp 167 168 C; 1H-NMR

PAGE 47

33 (CDCl3): 8.39 (d, J = 8.1, 1H), 8.20 (d, J = 8.2, 1H), 8.16 8.13 (m, 1H), 7.78 7.73 (m, 1H), 7.62 7.57 (m, 1H), 7.45 7.42 (m, 2H), 7.16 7.09 (m, 3H), 6.79 (d, J = 8.7, 2H); 13C-NMR (CDCl3): 146.7, 144.8, 142.0, 135.0, 131.8, 130.3, 129.6, 129.4, 126.5, 125.2, 122.6, 120.7, 114.2, 110.0. Anal. Calc. for C19H12ClN7: C 61.05, H 3.24, N 26.23; Found: C 60.95, H 3.11, N 26.02. N -[Di(1 H -1,2,3-benzotriazol-1-yl )methylene]benzamide (3.11f): [04JOC309] White needles from ethyl acetate / hexanes (86%), Mp 108 109 C; 1H-NMR (CDCl3): 8.40 (d, J = 8.2, 1H), 8.23 8.16 (m, 4H), 7.74 7.68 (m, 3H), 7.61 7.56 (m, 4H); 13CNMR (CDCl3): 166.7, 145.7, 133.6, 132.3, 131.7, 131.4, 130.4, 128.4, 126.3, 120.2, 114.8, 109.6. 3.4.3 General Procedure for the Preparation of Compounds 3.12ah 1-Thiocarbamoylbenzotriazoles 3.12ah were synthesized by the reaction of compound 3.3 (2 mmol) and the appropriate prim ary amine (2 mmol) in methylene chloride at room temperature for 18 h according to reported procedure [04JOC2976]. Melting points and spectral data were used to characterize known 3.12a,f,h and were found to be identical to reported values: 3.12a Mp 108-109 C (Lit. Mp 108-109 C) [83ZOK1763]; 3.12f Mp 72 C (Lit. Mp 72-73 C) [83ZOK1763]; 3.12h Mp 117 C (Lit. Mp 117-119 C) [83ZOK1763]. N -Isopropyl-1 H -1,2,3-benzotriazole-1 -carbothioamide ( 3.12b ): White powder (95%); Mp 107.7 C; 1H-NMR (CDCl3): 8.84 (d, J = 8.5, 2H), 8.00 (d, J = 8.2, 1H), 7.57.52 (m, 1H), 7.41.36 (m, 1H), 4.67 (septet, J = 7.0, 1H), 1.36 (d, J = 6.4, 6H); 13C-NMR (CDCl3): 173.1, 147.0, 132.4, 130.1, 125.5, 120.1, 116.1, 47.0, 21.5. Anal. Calc. for C10H12N4S: C 54.52, H 5.49, N 25.43; Found: C 54.55, H 5.49, N 25.27.

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34 N -Phenyl-1 H -1,2,3-benzotriazole-1 -carbothioamide ( 3.12c ): White powder (90%); Mp 98.5 C; 1H-NMR (CDCl3): 10.74 (s, 1H), 8.94 (d, J = 8.5, 1H), 8.13 (d, J = 8.4, 1H), 7.77 (d, J = 8.0, 2H), 7.70.65 (m,1H), 7.54.46 (m, 2H), 7.38.32 (m, 1H), 7.29 7.20 (m, 1H); 13C-NMR (CDCl3): 179.7, 137.1, 129.5, 129.4, 127.2, 126.9, 125.6, 125.1. Anal. Calc. for C13H10N4S: C 63.40, H 3.96, N 18.33; Found: C 63.85, H 4.33, N 18.54. N -Butyl-1 H -1,2,3-benzotriazole-1-carbothioamide ( 3.12d ): White powder (98%); Mp 92.3 C; 1H-NMR (CDCl3): 9.10 (br s, 1H), 8.92 (d, J = 8.5, 1H), 8.09 (d, J = 8.2, 1H), 7.64 (t, J = 7.7, 1H), 7.47 (t, J = 7.87, 1H), 3.85 (dd, J = 12.8, 7.0, 2H), 1.83.75 (m, 2H), 1.54.47 (m, 2H), 1.01 (t, J = 7.3, 3H); 13C-NMR (CDCl3): 174.1, 147.0, 132.4, 130.2, 125.6, 120.2, 116.0, 44.8, 30.1, 20.2, 13.7. Anal. Calc. for C11H14N4S: C 56.38, H 6.02, N 23.81; Found: C 56.74, H 6.40, N 23.47. N -Phenethyl-1 H -1,2,3-benzotriazole-1 -carbothioamide ( 3.12e ): White powder (93%); Mp 110.2 C; 1H-NMR (CDCl3): 9.18 (s, 1H), 8.91 (d, J = 8.5, 1H), 8.07 (d, J = 8.2, 1H), 7.65.60 (m, 1H), 7.48.43 (m, 1H), 7.36.22 (m, 5H), 4.10 (t, J = 7.1, 2H), 3.11 (t, J = 7.1, 2H); 13C-NMR (CDCl3): 174.4, 147.0, 137.8, 132.3, 130.2, 128.8, 128.6, 126.9, 125.6, 120.2, 116.0, 46.1, 34.0. Anal. Calc. for C15H14N4S: C 63.80, H 5.00, N 19.84; Found: C 63.92, H 4.98, N 19.59. N -(2-Methylbutyl)-1 H -1,2,3-benzotriazole-1-carbothioamide ( 3.12g ): White powder (98%); Mp 96 C; 1H-NMR (CDCl3): 9.06 (s, 1H), 8.91 (d, J = 8.5, 1H), 8.10 (d, J = 8.2, 1H), 7.64 (t, J = 7.5, 1H), 7.47 (t, J = 7.4, 1H), 1.97.93 (m, 1H), 1.38.26 (m, 2H), 1.06 (d, J = 6.7, 3H), 1.01.99 (m, 3H), 0.96.86 (m, 2H); 13C-NMR (CDCl3):174.3, 146.9, 132.2, 130.1, 125.5, 120.0, 115.9, 50.6, 33.8, 27.1, 17.3, 11.1. Anal. Calc. for C12H16N4S: C 58.04, H 6.49, N 22.56; Found: C 57.92, H 6.45, N 22.37.

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35 3.4.4 General Procedure for the Preparation of Compounds 3.13al To a stirred solution of 3.12ah (0.01 mol) in toluene (12 mL), the corresponding triphenylphosphene (see Table 1) 3.10 (0.01 mol) was added at room temperature and the resulting mixture was heated at 110 C for 1 h. Completion of the reaction was monitored by TLC. Upon completion, the reaction mixture wa s concentrated under reduced pressure and residue purified by gradient column chromatography (et hylacetate/hexan es) on silica gel to give 3.13al N -BenzylN -phenyl-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13a): White microcrystals from ethyl acetate / hexanes (91%), Mp 129 130 C; 1H-NMR (CDCl3): 8.14 (br s, 1H), 8.06 (d, J = 8.2, 1H), 7.51 7.46 (m, 1H), 7.42 7.37 (m, 1H), 7.32 7.22 (m, 7H), 7.03 6.94 (m, 3H), 6.53 (br s, 1H), 4.31 (s, 2H); 13C-NMR (CDCl3): 146.5, 141.0, 137.4, 131.6, 129.0, 128.9, 128.7, 127.8, 127.5, 125.0, 122.9, 121.6, 119.8, 114.5, 47.8. Anal. Calc. for C20H17N5: C 73.37, H 5.23, N 21.39; Found: C 73.78, H 5.25, N 21.27. N -BenzylN -(4-methylphenyl)-1 H -1,2,3-benzotriazole-1 -carboximidamide ( 3.13b ): Yellow oil (96%); 1H-NMR (CDCl3): 8.06 (d, J = 8.1, 1H), 7.51 7.46 (m, 1H), 7.42 7.37 (m, 1H), 7.33 7.24 (m, 6H), 7.05 (d, J = 7.1, 2H), 6.86 (d, J = 7.1, 2H), 6.45 (br s, 1H), 4.31 (s, 2H), 2.30 (s, 3H); 13C-NMR (CDCl3): 143.9, 137.5, 134.6, 132.3, 131.7, 129.5, 129.2, 129.0, 128.7, 127.7, 127.5, 125.0, 121.4, 119.7, 115.3, 47.9, 20.8. Anal. Calc. for C21H19N5: C 73.88, H 5.61, N 19.90; Found: C 73.83, H 5.96, N 19.85. N -IsopropylN -(4-methylphenyl)-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13c): Yellow oil (92%); 1H-NMR (CDCl3): 7.97 (d, J = 8.2, 1H), 7.67 7.60 (m, 1H), 7.45 7.28 (m, 2H), 7.00 (d, J = 7.0, 2H), 6.82 (d, J = 7.0, 2H), 5.82 (br s 1H), 3.61 (br s,

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36 1H), 2.22 (s, 3H), 1.08 (d, J = 6.2, 6H); 13C-NMR (CDCl3): 144.3, 132.3, 132.1, 131.7, 129.5, 128.8, 128.5, 128.4, 124.8, 121.1, 119.6, 44.5, 23.0, 20.8. Anal. Calc. for C17H19N5: C 69.60, H 6.53, N 23.87; Found: C 69.40, H 6.38, N 23.62. N -(4-Chlorophenyl)N -isopropyl-1H-1,2,3-benzotri azole-1-carboximidamide (3.13d): Yellow oil (67%); 1H-NMR (CDCl3): 8.06 (d, J = 8.2, 2H), 7.51 7.46 (m, 1H), 7.42 7.37 (m, 1H), 7.20 (d, J = 8.2, 2H), 6.90 (d, J = 8.0, 2H), 6.02 (br s, 1H), 3.69 (br s, 1H), 1.19 (d, J = 6.3, 6H); 13C-NMR (CDCl3): 146.3, 145.6, 141.3, 131.5, 129.0, 128.9, 127.8, 125.0, 122.6, 119.8, 114.1, 44.6, 22.8. Anal. Calc. for C16H16ClN5: C 61.24, H 5.14, N 22.32; Found: C 61.43, H 5.11, N 21.95. N -MesitylN -phenyl-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13e): Yellow microcrystals from ethyl acetate / hexanes (80%), Mp 140 141 C; 1H-NMR (CDCl3): 8.42 8.40 (m, 1H), 8.10 (d, J = 8.4, 1H), 7.87 (br s, 1H), 7.59 7.54 (m, 1H), 7.48 7.43 (m, 1H), 7.02 6.85 (m, 3H), 6.76 6.70 (m, 2H), 6.66 (s, 1H), 6.59 (s, 1H), 2.23 (s, 3H), 2.15 (s, 6H); 13C-NMR (CDCl3): 135.0, 132.3, 132.2, 131.5, 129.2, 128.7, 128.5, 128.4, 128.2, 127.7, 125.1, 123.1, 122.3, 120.5, 119.8, 20.6, 18.4 (2C). Anal. Calc. for C22H21N5: C 74.34, H 5.95, N 19.70; Found: C 74.15, H 6.03, N 19.44. Ethyl 4-{[1 H -1,2,3-benzotriazol-1-yl(butylami no)methylidene]amino}benzoate (3.13f): Yellow oil (53%); 1H-NMR (CDCl3): 8.00 (d, J = 8.2, 1H), 7.96 (d, J = 8.2, 1H), 7.87 (d, J = 8.4, 2H), 7.42 7.37 (m, 1H), 7.33 7.28 (m, 1H), 6.91 (d, J = 8.2, 2H), 6.40 6.30 (m, 1H), 4.25 (q, J = 7.1, 2H), 3.00 (q, J = 6.3, 2H), 1.44 (quintet, J = 7.3, 2H), 1.29 (t, J = 7.1, 3H), 1.23 (sextet, J = 7.5, 2H), 0.77 (t, J = 7.3, 3H); 13C-NMR (CDCl3): 166.4, 151.5, 146.3, 141.3, 131.4, 130.4, 129.1, 125.0, 124.4, 121.3, 119.7, 114.2, 60.6,

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37 43.4, 31.5, 19.6, 14.2, 13.5. Anal. Calc. for C20H23N5O2: C 65.73, H 6.34, N 19.16; Found: C 65.63, H 6.77, N 18.90. N -ButylN -mesityl-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13g): Yellow oil (84%); 1H-NMR (CDCl3): 8.40 (d, J = 8.3, 1H), 8.02 (d, J = 8.2, 1H), 7.48 7.43 (m, 1H), 7.38 7.33 (m, 1H), 6.78 (s, 2H), 6.28 (br s, 1H), 2.78 (q, J = 6.7, 2H), 2.20 (s, 3H), 2.11 (s, 6H), 1.34 (quintet, J = 7.1, 2H), 1.16 (sextet, J = 7.1, 2H), 0.73 (t, J = 7.3, 3H); 13CNMR (CDCl3): 146.7, 141.8, 139.5, 131.9, 131.7, 128.9, 128.2, 128.1, 124.9, 119.6, 115.5, 42.2, 32.1, 20.7, 19.7, 18.6 (2C), 13.4. Anal. Calc. for C20H25N5: C 71.61, H 7.51, N 20.53; Found: C 71.90, H 7.80, N 20.19. N -(3-Cyanophenyl)N -phenethyl-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13h): Yellow oil (95%); 1H-NMR (CDCl3): 8.02 (d, J = 8.2, 1H), 7.91 (br s, 1H), 7.50 7.45 (m, 1H), 7.41 7.36 (m, 1H), 7.32 7.24 (m, 5H), 7.21 7.20 (m, 1H), 7.12 7.10 (m, 3H), 6.47 (br s, 1H), 3.45 3.43 (m, 2H), 2.87 (t, J = 7.0, 2H); 13C-NMR (CDCl3): 147.7, 146.1, 141.8, 137.5, 131.2, 129.6, 129.1, 128.6, 128.6, 126.7, 126.1, 126.0, 125.0, 124.8, 119.8, 118.6, 113.6, 112.6, 44.6, 35.6. Anal. Calc. for C22H18N6: C 71.61, H 5.35, N 23.04; Found: C 71.22, H 5.07, N 23.12. N -(4-Chlorophenyl)N -cyclohexyl-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13i): Yellow oil (40%); 1H-NMR (CDCl3): 8.06 (d, J = 8.2, 2H), 7.52 7.47 (m, 1H), 7.42 7.37 (m, 1H), 7.22 (d, J = 8.2, 2H), 6.90 (d, J = 8.0, 2H), 6.09 (br s, 1H), 3.30 (br s, 1H), 1.94 1.92 (m, 2H), 1.74 1.66 (m, 2H), 1.52 (br s, 1H), 1.32 1.09 (m, 5H) ; 13CNMR (CDCl3): 146.4, 145.7, 141.2, 131.6, 129.0, 128.9, 127.8, 125.0, 122.6, 119.8, 114.2, 51.3, 33.0, 25.3, 24.4. Anal. Calc. for C19H20ClN5: C 63.13, H 5.70, N 18.79; Found: C 62.70, H 5.65, N 18.91.

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38 N -(2-Methylbutyl)N' -(4-methylphenyl)-1H-1,2,3-benzotriazole-1carboximidamide (3.13j): Yellow oil (82%); 1H-NMR (CDCl3): 8.06 (d, J = 8.2, 1H), 7.51.46 (m, 1H), 7.42.37 (m, 1H), 7.07 (d, J = 7.1, 2H), 6.89 (br s, 2H), 6.22 (br s, 1H), 3.08.90 (m, 2H), 2.30 (s, 3H), 1.62.45 (m, 1H), 1.36.30 (m, 1H), 1.17.08 (m, 1H), 0.88 (d, J = 6.7, 3H), 0.81 (t, J = 7.4, 3H) ; 13C-NMR (CDCl3): 144.2, 141.6, 132.0, 131.7, 129.4, 128.9, 126.1, 124.9, 121.3, 119.6, 117.9, 49.2, 35.1, 26.7, 20.8, 17.0, 11.0. Anal. Calc. for C19H23N5: C 71.00, H 7.21, N 21.79; Found: C 71.15, H 7.45, N 21.65. N' -(4-Chlorophenyl)N -(2-furylmethyl)-1 H1,2,3-benzotriazole-1 -carboximidamide (3.13k): Yellow oil (93%); 1H-NMR (CDCl3): 8.00 (d, J = 8.2, 2H), 7.50.40 (m, 1H), 7.35.30 (m, 1H), 7.27 (d, J = 1.0, 1H), 7.14 (d, J = 8.2, 2H), 6.81 (d, J = 8.0, 2H), 6.45 (s, 1H), 6.23.21 (m, 1H), 6.11 (s, 1H), 4.26 (s, 2H); 13C-NMR (CDCl3): 150.1, 145.0, 142.6, 141.2, 131.5, 129.2, 129.0, 128.7, 128.2, 125.1, 122.8, 120.0, 119.9, 110.4, 108.0, 40.8 Anal. Calc. for C18H14ClN5O: C 61.45, H 4.01, N 18.91; Found: C 61.10, H 3.89, N 18.50. N -ButylN' -(4-chlorophenyl)-1 H -1,2,3-benzotriazole-1-carboximidamide (3.13l): Yellow oil (87%); 1H-NMR (CDCl3): 7.98 (d, J = 8.2, 1H), 7.44.39 (m, 1H), 7.34.25 (m, 1H), 7.13 (d, J = 8.3, 2H), 6.82 (d, J = 8.1, 2H), 6.17 (s, 1H), 3.03 (br s, 2H), 1.51 1.41 (m, 2H), 1.28.18 (m, 2H), 0.79 (t, J = 7.3, 3H); 13C-NMR (CDCl3): 146.4, 145.6, 141.7, 131.5, 129.1, 128.8, 128.8, 127.7, 125.0, 122.8, 119.8, 43.5, 31.7, 19.7, 13.6. Anal. Calc. for C17H18ClN5: C 62.29, H 5.53, N 21.36; Found: C 62.69, H 5.59, N 20.98.

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39 3.4.5 General Procedure for the Preparation of Compounds 3.15ae To a solution of 3.11a e (see Table 3.2) (0.85 mmol) in toluene (10 mL), the amine of choice (2.5 mmol) was added with stirri ng. The reaction mixture was heated to reflux and kept at that temperature until the full conve rsion of starting mate rials (1-2 hrs). Upon completion, the solvent was evaporated under reduced pressure; crude product was dissolved in methylene chloride, washed twi ce with saturated aqueous sodium carbonate, dried over magnesium sulfate, and filtere d. The solvent was removed under reduced pressure. Desired guanidines were isolated by flash column chromatography on basic alumina (first ethyl acetate to remove impuritie s and methanol to elute guanidine) to give 3.15a e. N,N -DicyclohexylN -phenylguanidine (3.15a): [67JOC2511] Yellow oil (79%); 1H-NMR (CDCl3): 7.24 7.19 (m, 2H), 7.03 6.98 (m, 3H), 3.16 3.09 (m, 2H), 1.91 (s, 2H), 1.83 1.80 (m, 4H), 1.61 (br s, 4H), 1.48 (br s, 2H), 1.23 1.15 (m, 5H), 1.11 1.05 (m, 5H); 13C-NMR (CDCl3): 179.6, 153.6, 129.4, 124.2, 122.6, 52.2, 33.2, 25.0, 24.8, 24.7. N N -DibutylN -(4-methylphenyl)guanidine (3.15b): Yellow oil (83%); 1H-NMR (CDCl3): 7.08 (d, J = 8.2, 2H), 6.95 (d, J = 8.2, 2H), 3.04 (t, J = 7.0, 4H), 2.30 (s, 3H), 1.95 (s, 2H), 1.51 (quintet, J = 7.4, 4H), 1.26 (sextet, J = 7.4, 4H), 0.84 (t, J = 7.3, 6H); 13C-NMR (CDCl3): 179.2, 155.9, 134.5, 129.9, 122.1, 43.2, 31.3, 20.8, 19.8, 13.5. Anal. Calc. for C16H27N3: C 73.52, H 10.41, N 16.07; Found: C 73.28, H 10.39, N 16.38. N -(3-Cyanophenyl)N N -diisopropylguanidine (3.15c): Yellow oil (87%); 1HNMR (DMSOd6): 8.81 (s, 1H), 7.94 (s, 1H), 7.57 (dd, J = 8.3, 1.0, 1H), 7.42 (t, J = 8.0, 1H), 7.31 (d, J = 7.6, 1H), 6.33 (d, J = 7.4, 1H), 3.76 ( septet J = 6.7, 2H), 1.1 (d, J = 6.7,

PAGE 54

40 12H); 13C-NMR (DMSOd6): 154.3, 141.5, 130.0, 124.3, 122.1, 119.9, 119.0, 111.4, 41.0, 22.8. Anal. Calc. for C14H20N4: C 73.74, H 8.25, N 22.93; Found: C 73.89, H 8.30, N 23.54. Ethyl 4-({bis[(1-phenylethyl)ami no]methylene}amino)benzoate (3.15d): Yellow oil (91%); 1H-NMR (CDCl3): 7.86 7.83 (m, 3H), 7.34 7.21 (m, 3H), 7.19 7.15 (m, 3H), 6.96 6.93 (m, 4H), 6.80 (d, J = 8.2, 1H), 4.78 (q, J = 6.4, 1H), 4.52 (q, J = 6.2, 1H), 4.30 4.22 (m, 4H), 1.40 (d, J = 6.7, 2H), 1.33 1.27 (m, 7H); 13C-NMR (CDCl3): 166.3, 147.1, 143.4, 143.3, 131.0, 129.0, 128.8, 127.8, 127.5, 125.9, 125.6, 124.6, 122.3, 120.7, 60.7, 52.2, 23.6, 23.1, 14.3. Anal. Calc. for C26H29N3O2: C 70.75, H 7.03, N 9.41; Found: C 70.27, H 6.80, N 8.95. N,N -DibenzylN -(4-chlorophenyl)guanidine (3.15e): Yellow oil (85%); 1H-NMR (CDCl3): 7.24 7.22 (m, 6H), 7.2 (d, J = 8.6, 2H), 7.08 7.05 (m, 4H), 6.81 (d, J = 8.6, 2H), 4.18 (s, 4H), 1.80 (s, 2H); 13C-NMR (CDCl3): 179.8, 154.6, 137.1, 129.4, 129.1, 128.8, 127.7, 127.0, 123.7, 46.5; Anal. Calc. for C21H20ClN3: C 68.09, H 5.76, N 10.21; Found: C 68.41, H 5.94, N 10.50. 3.4.6 General Procedure for the Preparation of Compounds 3.16ae To a solution of appropriate 3.11 (see Table 3.2) (0.70 mmol) in toluene (10 mL), the diamine of choice (0.7 mmol) was adde d with stirring. The reaction mixture was heated to reflux and kept at that temperatur e until the full conversion of starting materials (1-2 hrs). Upon completion, the solvent was evaporated under reduced pressure; crude product was dissolved in methylene chloride washed twice with saturated aqueous sodium carbonate, dried over magnesium sulfat e, and filtered. The solvent was removed under reduced pressure. Desired guanidi nes were isolated by flash column

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41 chromatography on basic alumina (first ethyl acetate to remove impurities and methanol to elute guanidine) to give 3.16a e (Tetrahydropyrimidin-2-ylidene)p -tolylamine (3.16a): Colorless oil (95%); 1HNMR (CDCl3): 7.2 (d, J = 8.2, 2H), 7.07 (d, J = 8.2, 2H), 3.37 3.33 (m, 4H), 2.32 (s, 3H), 11.98 (s, 2H), 198.93 (m, 2H); 13C-NMR (CDCl3): 152.7, 136.5, 132.7, 130.5, 125.2, 38.4, 24.2, 20.9, 20.2. Anal. Calc. for C11H15N3: C 69.81, H 7.99, N 22.20; Found: C 70.01, H 8.25, N 22.27. Imidazolidin-2-ylidenep -tolylamine (3.16b): [74JHC257] Yellow oil (95%); 1HNMR (CDCl3): 7.13 (d, J = 8.2, 2H), 7.06 (d, J = 8.2, 2H), 3.66 (s, 4H), 2.31 (s, 3H), 1.94 (s, 2H); 13C-NMR (CDCl3): 159.6, 136.0, 134.1, 130.2, 123.1, 42.9, 20.8. 4-ChloroN -[5,5-dimethyltetrahydro-2(1 H )-pyrimidinylidene]aniline (3.16c): Yellow oil (96%); 1H-NMR (CDCl3): 7.26 (d, J = 8.6, 2H), 7.08 (d, J = 8.6, 2H), 2.97 (s, 4H), 1.91 (s, 2H), 1.02 (s, 6H); 13C-NMR (CDCl3): 152.0, 134.1, 132.2, 130.1, 126.3, 50.1, 27.2, 24.1. Anal. Calc. for C12H16ClN3: C 60.63, H 6.78, N, 17.68; Found: C 60.78, H 6.55, N 17.77. N -[1-Methyltetrahydro-2 (1 H )-pyrimidinylidene]N -phenylamine (3.16d): Yellow oil (89%); 1H-NMR (CDCl3): 7.31 7.26 (m, 2H), 7.08 7.03 (m, 1H), 7.00 (d, J = 7.8, 2H), 3.42 3.33 (m, 4H), 2.75 (s, 3H), 2.11 2.03 (m, 2H), 1.99 (s, 1H); 13C-NMR (CDCl3): 154.4, 139.9, 129.4, 123.7, 121.1, 48.5, 39.6, 38.5, 21.8. Anal. Calc. for C11H15N3: C 69.81, H 7.99, N 22.20; Found: C 69.98, H 7.75, N 22.57. N -Tetrahydro-2(1 H )-pyrimidinylidenebenzamide (3.16e): [67CB2569] White microcrystals from ethyl acetate / hexanes (77%), Mp 132 133 C; 1H-NMR (CDCl3):

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42 7.80 (d, J = 7.1, 2H), 7.41 7.32 (m, 5H), 3.41.49 (m, 4H), 1.78 1.62 (m, 2H); 13CNMR (CDCl3): 183.3, 168.2, 134.2, 131.5, 128.5, 127.0, 36.2, 29.8. 3.4.7 General Procedure for the Preparation of Compounds 3.17af To a stirred solution of 3.13a k (see Table 3.3) (1.6 mmol) in toluene (10 mL) was added the secondary amine of choice (1.6 mmol) at room temperature. The reaction mixture was heated to reflux and allowed to react at this temperature overnight. Completion of the reaction was monitored by TLC. Upon completion, the solvent was evaporated and the obtained residue was disso lved in methylene chloride. The solution was washed twice with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the solvent was evaporated unde r reduced pressure. The desired guanidines 3.17af were obtained after purifi cation by flash column chromatography on basic alumina (first ethyl acetate to re move impurities and methanol to elute guanidine). N -BenzylN,N -diisopropylN -phenylguanidine (3.17a): Yellow oil (67%); 1HNMR (CDCl3): 7.22 7.08 (m, 8H), 6.89 6.85 (m, 2H), 4.07 (s, 2H), 3.77 (septet, J = 6.8, 2H), 1.89 (s, 2H), 1.12 (d, J = 6.9, 12H); 13C-NMR (CDCl3): 151.3, 150.0, 139.1, 129.3, 128.7, 127.4, 127.3, 123.5, 121.6, 46.0, 41.6, 31.8, 19.9. Anal. Calc. for C20H27N3: N 13.58; Found: N 13.73. N -BenzylN -(4-methylphenyl)-4-morpholinecarboximidamide (3.17b): Yellow oil (93%); 1H-NMR (CDCl3): 7.26 7.16 (m, 3H), 7.13 7.10 (m, 2H), 6.91 (d, J = 8.1, 2H), 6.76 (br s, 1H), 6.52 (d, J = 8.1, 2H), 4.11 (s, 2H), 3.67 3.64 (m, 4H), 3.19 3.16 (m, 4H), 2.17 (s, 3H); 13C-NMR (CDCl3): 156.0, 151.2, 146.5, 138.8, 131.2, 129.8, 129.7, 128.6, 127.4, 127.3, 122.0, 66.7, 66.4, 49.3, 48.3, 46.9, 20.6, 0.9. Anal. Calc. for C19H23N3O: C 73.76, H 7.49; N 13.58; Found: C 73.36, H 7.76, N 13.26.

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43 Ethyl 4-{[(butylamino)(dipropyl amino)methylene]amino}benzoate (3.17c): Yellow oil (96%); 1H-NMR (CDCl3): 7.83 (d, J = 8.5, 2H), 6.76 (d, J = 8.5, 2H), 4.26 (q, J = 7.1, 2H), 3.08 (t, J = 7.4, 4H), 2.89 (t, J = 7.0, 2H), 1.55.48 (m, 4H), 1.40.28 (m, 5H), 1.22.17 (m, 2H), 0.82 (t, J = 7.3, 6H), 0.79 (t, J = 7.2, 3H); 13C-NMR (CDCl3): 166.9, 156.1, 130.9, 130.8, 129.7, 121.0, 60.4, 50.8, 44.5, 32.1, 21.4, 19.9, 14.4, 13.7, 11.4, 1.0. Anal. Calc. for C20H33N3O2.HCl: C 62.96, H 9.33, N 10.14; Found: C 63.24, H 9.75, N 9.91 N '-(4-Chlorophenyl)N -cyclohexyl-2,6-dimethyltetrahydro-1(2H)pyridinecarboximidamide (3.17d): Yellow oil (93%); 1H-NMR (DMSOd6) 7.41 (d, J = 8.9, 2H), 7.24 (d, J = 8.9, 2H), 6.30 (d, J = 7.8, 1H), 3.51.45 (m, 1H), 3.02.97 (m, 2H), 1.80.64 (m, 7H), 1.55.42 (m, 2H), 1.33.10 (m, 3H); 13C-NMR (DMSOd6) 154.3, 139.7, 128.4, 124.1, 118.8, 52.2, 47.49, 32.9, 30.1, 25.2, 24.3, 22.4, 19.4. Anal. Calc. for C20H30ClN3.HCl: N 10.93; Found: N 11.13. N -(3-Cyanophenyl)N -phenethyl-1-pyrroli dinecarboximidamide (3.17e): Yellow oil (91%); 1H-NMR (CDCl3): 7.32 7.21 (m, 4H), 7.2 (d, J = 6.9, 2H), 7.1 (d, J = 7.6, 1H), 7.03 7.00 (m, 2H), 4.95 (br s, 1H), 3.39 3.31 (m, 2H), 3.16 3.11 (m, 4H), 2.82 2.78 (m, 2H), 1.83 1.79 (m, 4H); 13C-NMR (CDCl3): 153.0, 138.5, 132.0, 129.5, 128.7, 128.6, 126.6, 126.5, 124.6, 123.2, 119.5, 112.3, 48.0, 44.7, 36.0, 25.3. Anal. Calc. for C20H22N4: C 75.44, H 6.96, N 17.59; Found: C 75.62, H 7.19, N 17.28. N -ButylN,N -diethylN -mesitylguanidine (3.17f): Yellow oil (93%); 1H-NMR (CDCl3): 6.73 (s, 2H), 3.19 (q, J = 7.0, 4H), 2.83 (t, J = 7.0, 2H), 2.15 2.12 (m, 5H), 1.97 (s, 6H), 1.09 (t, J = 7.0, 6H), 1.26.17 (m, 2H), 0.75 (t, J = 7.0, 3H); 13C-NMR (CDCl3):

PAGE 58

44 154.9, 130.6, 129.6, 129.0, 128.6, 44.5, 42.6, 32.9, 20.7, 19.8, 18.3, 13.7, 12.8. Anal. Calc. for C18H31N3: C 74.69, H 10.79, N, 14.32; Found: C 74.68, H 10.91, N 13.88. 3.4.8 General Procedure for the Preparation of Compounds 3.18ah To a solution of appropriate 3.13 (see Table 3.3) (2.2 mmol) in toluene (10 mL), the amine (see Table 3.3 and Scheme 3.7), (2.2 mmol) was added with stirring. The reaction mixture was heated to reflux and kept at that temperature about 1h, until the full conversion of starting materials (TLC c ontrol). Upon completion, the solvent was evaporated under reduced pressu re; crude product was dissolv ed in methylene chloride, washed twice with saturate d aqueous sodium carbonate, dr ied over magnesium sulfate, and filtered. The solvent was removed under re duced pressure. Desired guanidines were isolated by flash column chromatography on basi c alumina (first ethyl acetate to remove impurities and methanol to elute guanidine) to give 3.18a h N -BenzylN -butylN -phenylguanidine (3.18a): Yellow oil (99%); 1H-NMR (CDCl3): 7.27 7.26 (m, 4H), 7.21 7.16 (m, 3H), 6.89 6.83 (m, 3H), 4.30 (s, 2H), 3.86 (br s, 1H), 3.03 ( t J = 7.0, 2H), 1.34 (quintet, J = 7.2, 2H), 1.16 (sextet, J = 7.2, 2H), 0.79 (t, J = 7.3, 3H); 13C-NMR (CDCl3): 151.3, 150.0, 139.1, 129.3, 128.7, 127.4, 127.3, 123.6, 121.6, 46.03, 41.6, 31.8, 19.9, 13.7. Anal. Calc. for C18H23N3: C 76.43, H 8.95, N 14.93; Found: C 75.84, H 8.50, N 14.76. N -BenzylN -pentylN -(4-methylphenyl)guanidi ne (two tautomers) (3.18b): Yellow oil (93%); 1H-NMR (CDCl3): 7.26 7.17 (m, 5H), 7.00 (d, J = 8.0, 2H), 6.81 (d, J = 8.2, 2H), 4.29 (s, 2H), 2.90 (t, J = 6.9, 2H), 2.29 (s, 3H ), 1.96 (s, 3H) 1.44 1.34 (m, 2H), 1.26 1.10 (m, 3H), 1.05 0.87 (m, 1H), 0.84 0.74 (m, 4H); 13C-NMR (CDCl3): 179.3, 155.6, 155.4, 137.5, 133.7, 133.7, 129.7, 128.5, 128.5, 127.4, 127.0, 127.0, 122.1,

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45 48.8, 46.1, 43.1, 34.6, 28.8, 28.5, 26.5, 24.4, 22.0, 20.6, 16.7, 13.7, 10.8. Anal. Calc. for C20H27N3: C 77.63, H 8.79, N 13.58; Found: C 77.58, H 8.43, N 13.61 N -IsopropylN -(4-methylphenyl)N -(1-phenylethyl)guanidine (3.18c): Yellow oil (71%); 1H-NMR (CDCl3): 7.38 7.21 (m, 5H), 7.09 7.06 (m, 2H), 6.79 (d, J = 7.8, 2H), 4.62 4.60 (m, 1H), 3.76 (br s, 1H), 2.30 (s, 3H), 1.39 1.37 (m, 3H), 1.08 (d, J = 6.3, 3H), 0.90 (d, J = 6.3, 3H); 13C-NMR (CDCl3): 151.3, 144.5, 129.9, 128.8, 128.6, 127.4, 125.7, 125.6, 123.2,51.8, 43.0, 23.8, 23.3, 22.8, 20.8. Anal. Calc. for C19H25N3: C 77.85, H 8.61, N 13.54; Found: C 77.63, H 8.44, N 13.10. N -BenzylN -(4-chlorophenyl)N -isopropylguanidine (3.18d): yellow oil (89%); 1H NMR (CDCl3): 7.22-7.10 (m, 7H), 6.86 (d, J = 8.6 Hz, 2H), 4.18 (s, 2H), 3.47-3.43 (m, 1H), 1.89 (s, 2H), 0.95 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3): 155.0, 136.9, 129.9, 129.5, 128.9, 128.0, 127.2, 125.1, 123.4, 46.7, 45.3, 22.6. Anal. Calcd for C17H20ClN3: C, 67.65; H, 7.35; N, 13.92. Found: C, 67.77; H, 6.69; N, 13.06. N -ButylN -isopropylN -mesitylguanidine (3.18e): yellow oil (83%); 1H NMR (CDCl3): 6.85 (s, 2H), 3.56 (br s, 1H), 2.98 (br s, 2H), 2.25 (s, 3H), 2.19 (s, 6H), 1.90 (s, 2H), 1.46-1.36 (m, 2H), 1.34-1.20 (m, 2H),1.19-1.04 (m, 5H), 0.9-0.83 (m, 4H); 13C NMR (CDCl3): 155.1, 136.2, 134.4, 129.3, 128.8, 44.8, 42.8, 31.4, 24.5, 23.0, 20.8, 19.8, 18.1, 13.5. Anal. Calcd for C17H29N3: C, 74.13; H, 10.61; N, 15.26. Found: C, 74.31; H, 9.50; N, 10.27. N -IsopropylN -mesitylN -phenylguanidine (3.18f): Yellow oil (96%); 1H-NMR (CDCl3): 7.27 7.19 (m, 3H), 7.06 6.99 (m, 3H), 6.81 (s, 1H), 3.74 (br s, 1H), 2.19 (s, 3H), 2.16 (s, 6H), 1.93 (s, 1H), 1.00 (d, J = 6.6, 6H); 13C-NMR (CDCl3): 151.1, 138.9,

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46 129.5, 129.3, 128.8, 124,7, 123.9, 123.4, 114.9, 43.7, 23.0, 20.8, 18.1. Anal. Calc. for C19H25N3: C 77.85, H 8.61, N 13.54; Found: C 77.70, H 8.46, N 13.09 N -BenzylN' -(2-methylbutyl)N'' -(4-methylphenyl)guanidine (3.18g): Yellow oil (85%); 1H-NMR (CDCl3): 7.36.25 (m, 5H), 7.06 (d, J = 8.1, 2H), 6.91 (d, J = 8.1, 2H), 4.30 ( s 2H), 2.85(dd, J =13.0, 6.0, 1H), 2.71 (dd, J = 13.0, 7.1, 1H), 2.28 (s, 3H), 1.99 (s, 2H), 1.52.40 (m, 1H), 1.23.18 (m, 1H), 1.03.96 (m, 1H), 0.74 (d, J = 7.4, 3H), 0.73 (d, J = 7.4, 3H); 13C-NMR (CDCl3): 156.3, 137.0, 134.8, 130.0, 129.0, 128.0, 127.1, 124.9, 122.5, 49.4, 46.7, 34.8, 26.6, 20.8, 16.9, 11.0. Anal. Calc. for C20H27N3 HCl: N 12.15; Found: N 11.78. N -ButylN'' -(4-chlorophenyl)N' -(2-furylmethyl)guanidine (3.18h): Yellow oil (91%); 1H-NMR (CDCl3): 7.38.37 (m, 1H), 7.23 (d, J = 8.5, 2H), 6.89 (d, J = 8.5, 2H), 6.34.33 (m, 1H), 6.28.27 (m, 1H), 4.42 (s, 2H), 3.15 (t, J = 7.1, 2H), 1.52.44 (m, 2H), 1.34.26 (m, 2H), 0.85 (t, J = 7.3, 3H); 13C-NMR (CDCl3): 152.5, 151.2, 142.4, 129.5, 129.4, 124.7, 124.0, 110.5, 107.8, 42.3, 39.4, 31.5, 19.9, 13.7. Anal. Calc. for C16H20ClN3O HCl: C 56.15, H 6.18, N 12.28; Found: C 56.28, H 6.20, N 12.36

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47 CHAPTER 4 PREPARATIONS OF SUBSTITUTED THIOSEMICARBAZIDES AND N HYDROXYTHIOUREAS 4.1 Introduction Thiosemicarbazides are valuable buildi ng blocks for the synthesis of fivemembered heterocycles [00APPMC347, 04JCC7 46], and thiosemicarbazide derivatives are biologically active, e.g. 1,3,4-thiadiazoles, as antibacterial [61J OC88] and antifungal [00APPMC347] agents, and 1,3,4-thiadiazolium2-amidines as anticonvulsant [88JMC7], antimicrobial [02EJMC979], and antitumor agents [97AD88]. Published preparations of thiosemicarbazides 4.1 (Scheme 4.1) include (i) reactions of isothiocyanates [01ARK7, 01A RK12, 01ARK94, 01ARK129, 03ARK178] with hydrazines, this method is most frequently used [74JMC1025, 79OCSST139, 86S559, 93T4439, 03BMCL2625] but isothiocyanates are difficult to handle and store; (ii) reduction of thiosemicarbazones by sodium bor ohydride is used for the preparation of 4.1 with various substitution patterns except for tetrasubstitution [83JCS2297]; (iii) reaction of hydrazines with reactive thiocarbamic acid derivatives although the yields are greatly affected by side reactions [68ActaChemScan.1, 79ZOK171, 04 BMCL2571]; (iv) reaction of cyanohydrazines with hydrogen sulfide yields both mono and disubstituted thiosemicarbazides 4.1 [54JOC749]; or (v) reac tion of 1,2,4-triazolyl or bis(imidazolyl)methanethiones with a mmonia and hydrazines to give diand trisubstituted thiosemicarbazides 4.1 [67ActaChemScan.2061, 84PS91].

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48 N R5R4NH R3 XN R1S R2 N R5R4N R3CN H2S S N R1N N R4R5R3R2 NaBH4N NNH S R5R4R3R1 N R5R4NH R3 X S X N R5R4N H R3 N R1C S 4.1+ R2= HX= Cl, OAlk, SAlk, NH2(C=S)S, (ROOC)S + + X= imidazole, 1,2,4triazole( i )(iii)( i v )(v) R2=H (ii) +NH3 Scheme 4.1 Common methods of prep aration of thiosemicarbazides N -Hydroxythioureas are toxic to Lactobacillus arabinosus Leuconostoc dextranicum and Streptococcus Faecalis [70JMC377], and some derivatives, e.g. S methylN -hydroxyisothiourea, inhibit nitrous oxide synthase (NOS) [99JMC1842]. Methods for preparation of N -hydroxythioureas 4.2 (Scheme 4.2) include: (i) reactions of isothiocyanates with hydroxylamine to give 4.2 in 23-66% yields [69ActaChemScan.324, 70JMC377, 76JMC336, 99 JMC1842, 00JOC2399] and (ii) the reduction of unstable N N dihydroxythioureas [70LA171]. NCS R1H2N O R2R1N H N O R2S R1, R3 = Alk, Ar R2 = H, Alk, Ar + R1NN OH S OHR3R2=H R3R3=H (i) (ii) 4.2 Scheme 4.2 Common methods of preparation of N -hydroxythioureas Recently, we reported the efficient synthe sis of diand trisubstituted thioureas 4.7 utilizing 1-(alkyl-or-arylthiocarbamoyl)benzotriazoles 4.4 (Scheme 4.3) [04JOC2976].

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49 We have now expanded this methodology to in clude the synthesis of thiosemicarbazides 4.5ak and N -hydroxythioureas 4.6aj S Bt Bt NH2R S N H Bt R NH R1R2S N H N R R1R24.3 4.4 4.7 Scheme 4.3 Synthesis of di and trisubstituted thioureas 4.2 4.2 Results and Discussion Bis(benzotriazolyl)methanethione 4.3 a thiophosgene equivalent, is easily prepared from 1-trimethylsilylbenzotri azole and thiophosgene in qua ntitative yield [78JOC337]. Treatment of 4.3 with various primary amines in met hylene chloride at room temperature followed by a 5% Na2CO3 wash and recrystallizati on afforded 1-(alkyl-orarylthiocarbamoyl)benzotriazoles 4.4ai in 90-98% yields (Scheme 4.4) [04JOC2976]. N S NHR1R2R3R2R3N N R4HN S NHR1R5N H O R6N S NHR1R6O R54.4a-i 4.5a-k 4.6a-j N S N N N N N R1NH24.3 N N 4.4a R1 = Bn, 98 % 4.4b R1 = i -Pr, 95 % 4.4c R1 = Ph, 90 % 4.4d R1 = n -Bu, 98 % 4.4e R1 = (CH2)2Ph, 93 % R44.4f R1 = (CH2)5CH, 95 % 4.4g R1 = C(CH3)Bn, 97 % 4.4h R1 = 2-Furfuryl, 93 % 4.4i R1 = Allyl, 95 % N Scheme 4.4 Synthesis of thiosemicarbazides 4.5 and N-hydroxythioureas 4.6 Substituted thiosemicarbazides 4.5ak were prepared via a single step reaction of 1-(alkyl-or-arylthiocarbamoyl)benzotriazoles 4.4ai with the appropr iate hydrazine

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50 (Scheme 4.4, Table 4.1). S tirring 1 equivalent of 4.4 in methylene chloride at room temperature with 1.1 equivalents of the hydr azine and 2 equivalents of triethylamine followed by a 5% Na2CO3 wash afforded 4.5 in excellent yields (T able 4.1). The reaction reached completion after 3 hours as monito red by TLC. Substituted thiosemicarbazides 4.5ak were purified using column chromatogra phy (EtOAc/Hex) and fully characterized using NMR (1H, 13C) and elemental analysis Melting points for known 4.5ad,fk were found to be identical to reported values (see the Experimental Section). Novel 4.5e was characterized by 1H, 13C NMR spectra and elemental analysis (see the Experimental Section). Our method for the preparation of thiosemicarbazides is compatible with various substitution patterns of hydrazines as no apparent limitations were observed. Table 4.1 Preparation of substituted and unsubstituted thiosemicarbazides* R1 R2 R3 R4 Product Yield% Cy Ph H H 4.5a 88 nBu Ph H H 4.5b 85 EthylBn H H H 4.5c 85 Cy H H H 4.5d 91 Furyl Me Me H 4.5e 83 nBu Me Me H 4.5f 85 (DL)methylbenzyl Me Me H 4.5g 73 Propylpyrrolidine H H H 4.5h 74 i -Pr Me H Me 4.5i 78 Bn Me H Me 4.5j 97 Bn H H H 4.5k 97 Compounds 4.5h-k were prepared by my colleague Anna Gromova N -Hydroxythioureas 4.6aj were prepared from th e reaction of 1-(alkyl-orarylthiocarbamoyl)benzotriazoles 4.4aj in methylene chloride at room temperature with 1.5 equivalents of the corres ponding hydroxylamine and 3 equivalents of triethylamine (Scheme 4.4, Table 4.2). Starting materials di sappeared completely after 5-12 hours as monitored by TLC. Formation of a white prec ipitate (triethylamine salt) marked the

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51 completion of the reaction. The precipitate was filtered and the filtrate washed with 5% Na2CO3. The organic layer was extracted with me thylene chloride (3 times), evaporated under vacuum, and chromatographed (EtOAc/Hex) to give N -hydroxythioureas 4.6aj in excellent yields (Table 4.2). N -hydroxythioureas 4.6aj were fully characterized using NMR (1H, 13C) and elemental analysis. Melting points for known 4.6a,c,i were found to be identical to reported values. Novel 4.6b,dh,j were characterized by 1H, 13C NMR spectra and elemental analyses. Table 4.2 Preparation of substi tuted and unsubstituted N -hydroxythioureas R1 R5 R6 Product Yield% Bn H H 4.6a 90 nBu H H 4.6b 77 Cy H H 4.6c 83 Furyl H H 4.6d 81 i -Pr Me H 4.6e 68 nBu Me H 4.6f 87 Propylpyrrolidine Cy H 4.6g 72 i -Pr H Me 4.6h 81 Ph H Bn 4.6i 87 (DL)-methylbenzyl H Me 4.6j 83 Compounds 4.6b,d,e,g-j were prepared by my colleague Anna Gromova 4.3 Conclusion A new route for the preparati on of thiosemicarbazides and N -hydroxythioureas of different substitution patterns has been established. This methodology provides easy access to this class of compounds in excellent yields without any obvious limitations. The procedure is efficient with relatively short r eaction times and most importantly avoids the use of unstable isothiocyanate s as the classical starting ma terials for preparation of thiosemicarbazides and N -hydroxythioureas.

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52 4.4 Experimental Section General Melting points were determined on a hot-stage apparatus and are uncorrected. NMR spectra were recorded in CDCl3, or DMSOd6 with TMS as the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75 MHz). Column chromatography was conducted on silica gel (200 425 mesh) Bis benzotriazol-1-yl-methanethione 3 was prepared according to previously reported procedure; Mp 171-172 C, yield 98%, (Lit. Mp 170-171 C, yield 90%) [78JOC337]. 4.4.1 General procedure for the preparation of compounds 4.4ai 1-Thiocarbamoylbenzotriazoles 4.4ai were synthesized by the reaction of compound 4.3 (2 mmol) and the appropriate prim ary amine (2 mmol) in methylene chloride at room temperature for 2 h according to reported procedure [04JOC2976]. Melting points and spectral data were used to characterize known 4.4a f,h-i and were found to be identical to reported values: 4.4a Mp 108-109 C (Lit. Mp 108-109 C) [04JOC2976]; 4.4b Mp 107-108 C (Lit. Mp 107.7C) [05HCA1664]; 4.4c Mp 98-99 C (Lit. Mp 98.5C) [05HCA1664]; 4.4d Mp 92-93 C (Lit. Mp 92.3C) [05HCA1664]; 4.4e Mp 110.5 C (Lit. Mp 110.2C) [05HCA1664]; 4.4f Mp 72 C (Lit. Mp 72-73 C) [04JOC2976]; 4.4h Mp 117 C (Lit. Mp 117-119 C) [83ZOK1763]; 4.4i Mp 56.4 C (Lit. Mp 56-57 C ) [04JOC2976]. Known 4.4g was isolated as a yellow oil [04JOC2976]; spectral data and elemental analysis were used for characterization. 4.4.2 General Procedure for the Preparation of Compounds 4.5ak To a stirred solution of (1.15 mmol) 4.4ai in 12ml of dichloromethane, was added (1.27mmol) of the corresponding hydrazine hydrate followed by (2.5 mmol) of triethylamine. The mixture was stirred for 3 hours at room temperature, then 10 ml of Na2CO3 5% were added to remove excess benzot riazole. The solution was extracted with

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53 dichloromethane and the organic layer was dried over magnesium sulfate. Evaporating the solvent under reduced pr essure followed by column chromatography (EtOAc/Hex gradient) afforded pure 4.5ak in 73-97% yield. N -Cyclohexyl-2-phenyl-1hydrazinecarbothioamide (4.5a). Recrystallized from EtOAc/Hex to give pink crystals (88%), mp 165 165 C (lit. [ 70LA158 ] 163 163 C); 1H NMR 7.32 7.26 (m, 2H), 7.19 (s, 1H), 7.12 7.10 (m, 1H), 7.00 (t, J = 7,4 Hz, 1H), 6.84 (d, J = 7.7 Hz, 2H), 5.71 (s, 1H), 4.27 4.24 (m, 1H), 2.06 2.03 (m, 2H), 1.72 1.61 (m, 3H), 1.42 1.34 (m, 2H), 1.23 1.11 (m, 3H); 13C NMR 146.1, 134.8, 129.6, 122.4, 113.5, 53.0, 32.7, 25.4, 24.8. N -Butyl-2-phenyl-1-hydrazinecarbothioamide (4.5b). [68ACS1] oil (85%); 1H NMR 7.48 (s, 1H), 7.30 7.23 (m, 3H), 6.98 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 7.7 Hz, 2H), 5.89 (s, 1H), 6.63 (q, J = 7.1 Hz), 1.59 1.54 (m, 2H), 1.37 1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR 146.1, 129.5, 129.3, 122.3, 113.5, 44.1, 31.1, 19.9, 13.7. N -Phenethyl-1-hydrazinecarbothioamide (4.5c). Recrystallized from EtOAc/Hex to give white prisms (85%), mp 115 C (lit. [ 68ACS1 ] 113 C); 1H NMR 8.13 (s, 1H), 7.49 (s, 1H), 7.33 7.27 (m, 2H), 7.24 7.22 (m, 3H), 3.89 3.83 (m, 2H), 3.77 (s, 2H), 2.94 2.89 (m, 2H) ; 13C NMR (DMSO) 158.7, 128.7, 128.4, 128.3, 126.1, 36.2, 34.9. N -Cyclohexyl-1-hydrazinecarbothioamide (4.5d). Recrystallized from EtOAc/Hex to give white crystals (91%), mp 142 142 C (lit. [66JCS950 ] 143 143 C); 1H NMR 7.34 (brs, 1H), 7.19 (brs, 1H), 4.26 4.20 (m, 1H), 3.71 (s, 2H), 2.08 2.03 (m, 2H), 1.77 1.71 (m, 2H), 1.66 1.60 (m, 2H), 1.46 1.36 (m, 2H), 1.30 1.18 (m, 2H); 13C NMR 152.4, 52.6, 32.9, 25.5, 24.8.

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54 N (2-Furylmethyl)-2,2-dimet hyl-1-hydrazinecarbothioamide (4.5e) Recrystallized from EtOAc/Hex to give colorless rods (83%), mp 106 C; 1H NMR 7.57 (brs, 1H), 7.39 (s, 1H), 7.02 (br-s, 1H), 6.36 6.34 (m, 1H), 6.31 6.30 (m, 1H), 4.84 (d, J = 5.5 Hz, 2H), 2.54 (s, 6H); 13C NMR 150.7, 142.2, 138.0, 110.4, 107.8, 47.0, 40.8. Anal. Calcd for C8H13N3OS: C, 48.22; H, 6.58; N, 21.09. Fo und: C, 48.55; H, 6.77; N, 21.34. N -Butyl-2,2-dimethyl-1hydrazinecarbothioamide (4.5f) [68ACS1] oil (85%); 1H NMR 7.23 (brs, 1H), 6.25 (brs, 1H), 3.67 3.60 (m, 2H), 2.53 (s, 6H), 1.66 1.57 (m, 2H), 1.43 1.35 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR 158.0, 47.2, 43.8, 31.3, 20.1, 13.8. 2,2-DimethylN -(1-phenylethyl)-1-hydrazinecarbothioamide (4.5g). Recrystallized from EtOAc/Hex to give white crystals (50%), mp 105 107 C (lit. [68ACS1 ] 105 C); 1H NMR 7.6 (br-s, 1H), 7.36 7.35 (m, 4H), 7.30 7.26 (m, 1H), 6.59 (br-s, 1H), 5.69 5.64 (m, 1H), 2.53 (d, J = 13.0 Hz, 6H), 1.60 (d, J = 7.0 Hz, 3H); 13C NMR 142.8, 135.5, 128.6, 127.3, 126.2, 52.6, 47.3, 47.1, 21.6. 4.4.3 General procedure for the preparation of compounds 4.6aj To a stirred solution of (2.0 mmol) 4.4ai in 15ml of dichloromethane, was added (3.0 mmol) of the corresponding hydroxylamine hydrochloride followed by (9.0 mmol) of triethylamine. The mixture was stirred for 5 hours at room temper ature. Completion of the reaction is marked by the formation of a white precipitate (triethylamine salt). The precipitate is filtered, then 10 ml of Na2CO3 5% were added to remove excess benzotriazle. The solution was extracted with dichloromethane and the organic layer was dried over magnesium sulfate. Evaporating the solvent under reduced pressure followed by column chromatography (EtOAc/Hex gradient) afforded pure 4.5ak in 7290% yield.

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55 N -BenzylN -hydroxythiourea (4.6a). Recrystallized from EtOAc/hexane to give white powder (90%), mp 156 C (lit. [ 70JMC377 ] 155 157 C); 1H NMR 7.26 7.22 (m, 3H), 7.19 7.15 (m, 2H), 6.05 (brs, 1H), 4.56 (s, 2H), 1.54 (br-s, 1H) ; 13C NMR 153.7, 136.5, 128.9, 128.0, 127.5, 48.6. N -CyclohexylN -hydroxythiourea (4.6c) Recrystallized from EtOAc/Hex to give brown powder (83%), mp 116 C (lit. [ 70JMC377 ] 116 118 C); 1H NMR 6.01 (brs, 1H), 4.53 (br-s, 1H), 3.49 3.45 (m, 1H), 2.00 1.92 (m, 2H), 1.74 1.60 (m, 3H), 142 1.06 (m, 5H); 13C NMR 158.2, 49.4, 33.6, 25.5, 24.8. N ButylN -hydroxyNmethylthiourea (4.6f) oil (87%); 1H NMR 7.90 (brs, 1H), 6.99 (brs, 1H), 3.61 (s, 3H), 3.55 (q, J = 7.1 Hz, 2H), 1.62 1.54 (m, 2H), 1.42 1.35 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR 157.3, 44.9, 42.0, 31.3, 20.0, 13.8. Anal. Calcd for C6H14N2OS: C, 44.42; H, 8.70; N, 17.27. Fo und: C, 45.75; H, 9.17; N, 17.52.

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56 CHAPTER 5 SYNTHESIS OF MONOAND SYMMETRICAL DIN -HYDROXYAND N AMINOGUANIDINES 5.1 Introduction Guanidines possess a wide range of inte resting and important biochemical and pharmaceutical properties. Guanidines are st rongly basic and are fully protonated under physiological conditions which is crucial fo r specific ligand-receptor interactions. Identification of guanidine metabolites has pr ovided leads for drugs for the treatment of metabolic disorders, cancer, cardiovascul ar diseases, and diabetes [05ARK49]. Guanidino-containing drugs such as MIBG and MGBG were shown several decades ago to have antitumor properties and have been s ubjected to intense preclinical and clinical evaluation [01BP1183]. The guanidine unit combines pi donor a nd acceptor nitrogens in an interesting manner. The symmetrical cation Y (scheme 5.1) looses prefer entially the most acidic proton, ie from the least basic nitrogen atom, so that if R is electron withdrawing either mesomerically (eg R=CO, NO2, ect) or inductively (eg NR2 or OR), the neutral species exists as X and not as the rival tautomer Z [95MRC383]. This gene ralization has been supported by crystal structures of cyanogua nidine, nitroguanidine, acylguanidines, and heterocyclic guanidines [ 95MRC383, 04OL3933]. Quantummechanical calculations on methyland ethylguanidines suggest small energy difference between X and Z when R is an alkyl group [05JCTC986].

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57 NNH2NH2R H NNH2NH2R H NNH NH2R H+H+X Y Z Scheme 5.1 Tautomerism of guanidines Syntheses of guanidines fre quently utilizes thioureas of ten with initial activation, but in many cases the active intermediates ar e not described, charac terized, isolated or even defined [05ARK49]. Isothioureas, particularly, S -methylisothioureas, are also well developed guanylating agents due to their eas y preparation and availability. Guanidines have also been successfully prepared from N -arylsulfonyl S -methylisothioureas [96TL8711]. Other guanylating reagents in clude carbodiimides [03S714], cyanoamides [98JMC3298], pyrazole-1-carboximidam ide [92JOC2497], triflyl guanidines [98JOC3804], and benzotriazole and im idazole-containing reagents [95JSC1173, 00JOC8080, 01OL3859, 02J OC7553, 05HCA1664]. Recently, we reported a facile and effi cient method for the preparation of N, N, N -trisubstituted guanidines by interaction of st ructurally different amines with the new guanylating reagents (bis-benzotriazol-1yl-methylene)amines and benzotriazole-1carboxamidines [05HCA1664]. We have now expanded this methodology to include N hydroxyand N -aminoguanidines. Functionalized guanidines [02ARK24, 05ARK49] are important structural elements in a variety of na tural products [93BCF193] and show interesting biological properties [02BB439]. In particular, N -hydroxyguanidines are elec tron donor [98NO270] substrates for heme-containing enzyme s such as nitric oxide synthases [02JMC944, 03JMC2271] (NOS) and peroxidase s [03EJB47]. Interest in N -hydroxyguanidines has grown since it was demonstrated that N -arylN -hydroxyguanidines are reducing

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58 substrates for dopamine -hydroxylase [04BBRC1081] and that N -hydroxy-L-arginine (NOHA) is a key intermediate in the biosynthe sis of nitric oxide (NO) from L-arginine [98CC1191, 03ABB65, 04FRBM1105]. N -Hydroxyguanidines can act as antihypertensive agents [ 73JMC151] and scavengers of peroxynitrate (PN) [98FRBM914], which is generated from the reac tion of NO with superoxide anions; (PN) is generally considered to be more t oxic than NO or superoxide [01MAD47]. Aminoguanidines display both dopamine -oxidase inhibition, and antihypertensive properties [64JOC395]. Some s ubstituted aminoguanidines inhi bit nitric oxide synthase (NOS) [97JPET265] and 2-ethylaminoguanidine displays high selectivity for iNOS compared with nNOS and eNOS isoform vari ations [97JPET265]. Di and trisubstituted aminoguanidines inhibit the formation of advanced non-enzymatic glycosylation of proteins [93CA73676, 97CA131465] and arylam inoguanidines are a novel class of 5HT2aA receptor antagonists with enhanced activity [96LS1259]. Common methods for th e preparation of N -hydroxyguanidines 5.2 involve the reaction of electrophilic nitrogen rich species 5.1af with hydroxylamine or its derivatives (Scheme 5.2). A popular approach to N -hydroxyguanidines 5.2 starts from primary amines through intermediate fo rmation of the corresponding cyanamides 5.1a (Scheme 5.2) [73JMC151, 01JMC 3199, 02BMCL1507, 02BMC3049, 02JMC944]. However, only mono-substituted N -hydroxyguanidines of type 5.20 can be prepared by this method. Substituted thioureas 5.1b react with hydroxylamine or O benzylhydroxylamine in the pr esence of mercury (II) salt s to form disubstituted N hydroxyguanidines 5.2 [74CA37274, 94JCS(P1)769, 02B13868]. Cyclic 1,3-ethyleneand 1,3-trimethylene-2-hydroxyguanidines 5.2 were synthesized by nucleophilic

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59 displacement of a thiomethyl group from 5.1c [70TL1879]. Zinner et al [72CB1709] reported the synthesis of tri and tetra substituted 5.2 starting from the carbodiimides 5.1d, but this method suffers from long reaction times (3-5 days) and limited applicability. Acyclic trisubstituted and tetrasubstituted N -hydroxyguanidines have been prepared in moderate yields by use of chloroformamidinium chlorides 5.1e generated from the corresponding ureas or thioureas [76JOC3253]. A limited number of N hydroxyguanidines 5.2 were synthesized by treatm ent of the corresponding aminoiminomethansulfonic acids 5.1f with hydroxylamine hydrochloride and triethylamine [90SC217]. NCNR1R1 N SMe N H NH2OH NH2OH NH2O O N Cl N R1R4R3R2 Cl NN N HO NH2OR NH2OH HN N SO3R2Ph R1 NH2OH N H S N H R2R1 NCN R1R2 N NH2N R1R2HO R1 = Alk, Ar R2= H, Alk, Ar 5.2 5.1a 5.1e 5.1d 5.1f R1 = i -C3H7, o -C6H11R1 = H, R2 = Ph R1 = Et, R2 = H R1 = Ar, Alk; R2 = R3 = Alk; R4 = Alk, H 5.1c n = 0,1 ( )nR = H, Bn R1 = R2 = Alk; 5.1b 5.20 Scheme 5.2 Literature syntheses of N -hydroxyguanidines 5.2 Syntheses of substituted aminoguanidines 5.4 include reactions of hydrazine or its derivatives with: i) Vilsmeier salt 5.3a [90T3897]; ii) cyanamides 5.3b [38CRV213, 70BAPS375]; iii) diphenylcarbodiimide 5.3c [53CR145]; iv) 1,3-disubstituted thioureas 5.3d in the presence of PbO [1900BDCG1058, 00F331]; v) 1,2,3-trimethylisothiourea

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60 5.3e [51JA1858] or S-alkyl thiourea salts [62LA651]. The synthesis of substituted aminoguanidines 5.4 was also reported from S -ethylthiosemicarbazidium salt 5.3f [70JHC689] or N -aminocarbonimidic dichloride 5.3g [72JOC2005, 90T3897] by the reaction with amines (routes vi and vii) (Scheme 5.3). All these methods were utilized for specific classes of aminoguanidines. But a pparently, no general method is available for this class of compounds. Cl Me2N Cl NMe2 ONH H2NNHR N Cl NHR Cl Me Cl Cl NH H2N SEt NH3Br NCN R1R2 NN N RHN N2H4 N2H4N2H4N N H R1R1MeS N2H4CN NPh Ph N H S N H R1R2 5.4 5.3b 5.3e 5.3d 5.3f 5.3a 5.3g R 1 = Me R 1 = Ar, Alk R 2= H, Ar, Alk 5.3c R = R1 = Ar, heteroaryl R2 = Ar; R = H iiiii iv v vi vii i R = Het Scheme 5.3 Literature syntheses of substituted aminoguanidines 5.4 Tautomerism of hydroxyguanidines has recently been studied when these substrates are connected to nitrogen oxide synthase (NOS) in connectio n with the activity of each conformation [99B3704, 04JA10267, 05JPC23706]. Most research groups prefer to depict N -hydroxyguanidines as structure A (Equ. 5.1, Scheme 5.4), but others use structure C ; the common cation B is mesomeric [99B3704]. Sp ectral methods [99B3704] suggest that N -hydroxyL -arginine exists in a tautomer of type A (Eq.5.1, Scheme 5.4).

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61 Aminoguanidines could exis t in either structure D or E (Equ 5.2, Scheme 5.4). Little is known on N -hydroxyN -aminoguanidines which are 20-30 times more active than the hydroxyguanidines as inhibitors of ribonucleotide reductase from rat Novikoff tumors [83JMC1326]. 15N NMR studies on N -hydroxyN -aminoguanidines support expected structure for the conjugate acid of N -hydroxyN -aminoguanidine G (Equ 5.3, Scheme 5.4) [83JMC1326], and that the depr otonated free base exists as structure F (Equ 5.3, Scheme 5.4) [83JMC1326]. NNH2NH2HO NNH2NH2HO H NNH H2N HO H+AB C H+H NN NH2HO H H H Eq. 5.1 NNH2NH2H2N H NNH NH2H2N DE Eq. 5.2 Eq. 5.3 NNH NH2HO H NN NH2HO H NN NH2HO H+H+F G NH2 H NH2 NH2 H Scheme 5.4 Tautomerism of hydrox yguanidines and aminoguanidines In this chapter we describe a general approach for the conversion of hydroxylamine or hydrazine derivatives into the corresponding N -hydroxyor N -aminoguanidines utilizing benzotriazole containing reagents.

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62 5.2 Results and Discussion Recently, we have utilized bis -benzotriazol-1-yl-methanethione 5.5 [05HCA1664] and di(benzotriazol-1-yl)methanimine 5.6 [00JOC8080] in the synthesis of substituted guanidines. Reaction of bis -benzotriazol-1-yl -methanethione 5.5 with triphenylphosphine ylides 5.7 gave symmetrical guanylation reagents 5.8 in 73-76% yield [05HCA1664] (Scheme 5.5). A simple one step procedure for the preparation of 5.9 from bis benzotriazol-1-yl-methanethione 5.5 in nearly quantitative yi elds has recently been developed in our group [04JOC2976]. Refluxing 5.9 with triphenylphosphine ylides 5.7 afforded a new class of guanylation reagents 5.10 in 40-96% yields [05HCA1664] (Scheme 5.5). Bt S Bt Bt S N RNPPh3 Bt N N R 5.9 5.10 5.7 CH2Cl2, 25oC 5.5 5.10a: R= p -Tol, R1=Bn, R2=H, 96% 5.10b: R= p -Tol, R1= i -Pr, R2=H, 92% 5.10c: R=C6H4Clp ,R1= i -Pr,R2=H, 67% 5.10d: R=C6H4Clp ,R1=Cy,R2=H, 40% 5.10e: R=mesityl, R1= n -Bu, R2=H, 84% 5.10f : R=C6H4CO2Et, R1= n -Bu, R2=H, 53% 5.10g: R=COPh, R1=Et, R2=Et, 87% 5.10h: R=COPh, R1, R2= (CH2)2O(CH2)2, 91% 5.10i: R=COPh, R1= i -Pr, R2= i -Pr, 83% 5.9a R1= Bn, R2=H, 98 % 5.9b R1 = i -Pr, R2=H, 95 % 5.9c R1 =(CH2)5CH, R2=H, 95 % 5.9d R1 = n -Bu, R2=H, 98 % 5.9e R1 = Et, R2=Et, 81 % 5.9f R1,R2= (CH2)2O(CH2)2,97 % RNPPh3 Bt N Bt 5.8 R 5.7 NH R1 R2R1 R2 R1 R2 5.8a: R=C6H4CO2Et 73% 5.8b: R=Ph, 76% Scheme 5.5 Synthesis of benzotriazole intermediates 5.8 and 5.10 Alternatively, stirring di(ben zotriazol-1-yl)methanimine 5.6 at room temperature in THF with the appropriate amin e gave guanylating reagents 5.11 in 75-91% yield (Scheme 5.6) [00JOC 8080]. Reaction of 5.11 with primary and secondary amines in refluxing THF afforded substituted guanidines 5.12 (Scheme 5.6). In a continuation of this approach we have now utilized 5.6 and 5.8 in the synthesis of symmetrical

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63 dihydroxyguanidines 5.16 and diaminoguanidines 5.17 Benzotriazole intermediates 5.10 and 5.11a,b were used in the synthesis of monoN -hydroxyguanidines 5.13aj and N aminoguanidines 5.14ah Bt NH Bt NH R1R2 Bt NH N R1R2 NH R3R4 N NH N R3R4R1R2 5.11 THF, rt 5.6 5.11a R1 = Bn, R2= H, 91 % 5.11b R1 = n -Bu, R2= H, 75 % THF, reflux 5.12 Scheme 5.6 Synthesis of benzotriazole intermediates 5.11a,b and substituted guanidines 5.12 5.2.1 Preparation of Unsymmetrical N -Hydroxyguanidines 5.13aj N -Hydroxyguanidines 5.13aj were prepared in high yields by the reaction of 5.10ai, and 5.11a,b with hydroxylamine hydrochloride in refluxing toluene for 4-12hr in the presence of triethyl amine (Schem e 5.7). The completion of the reaction was monitored by TLC. The white triethylamine hydrochloride salt was filtered from the reaction mixture. Concentrati on of the reaction mixture followed by a flash basic alumina column afforded 5.13aj in 22-87% yield (Scheme 5.7, Table 5.1). Ethyl acetate was used as an eluant to wash out the impu rities followed by methanol to obtain the N hydroxyguanidines as colorless oils. The highl y basic nature of guanidines (pka= 12) causes difficulties in the isol ation and characterization of these compounds. Structures 5.13aj were supported by elemental analysis, 1H and 13C NMR spectra. 1H NMR spectra no longer showed distinctive signals in the range of 7.0.2 ppm corresponding to the benzotriazole group. The NH protons were di fficult to detect in the spectra of 5.13c,e,f,h mainly due their fast exchange rate between the guanidine 3 nitrogen atoms. The

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64 dominant tautomeric structure has the doubl e bond involving the hydroxylamine nitrogen ( 5.13a-h Scheme 5.7). However, N -substituted hydroxylamines obviously form structures 5.13i,j (Scheme 5.7). 5.10 ,5.11 Et3N, Toluene, reflux N N R N R3NHOR4x HCl 5.13 i,j R3 R2 R1 O R4 Et3N, Toluene, reflux NH2OR4x HCl NH N R N R2 R1 O R4 5.13 a-5.13 h Scheme 5.7 Preparation of unsymmetrical N -hydroxyguanidines 5.13aj Table 5.1 Preparation of unsymmetrical N -hydroxyguanidines 5.13aj Reactant R R1 R2 R3 R4 Product Yield, % 5.10a p -Tol Bn H H H 5.13a 80 5.10b p -Tol i -Pr H H H 5.13b 72 5.10d C6H4Clp Cy H H H 5.13c 56 5.10e Mesityl n -Bu H H H 5.13d 87 5.10g COPh Et Et H H 5.13e 71 5.10h COPh (CH2)2O(CH2)2 H H 5.13f 74 5.10b p -Tol i -Pr H H Bn 5.13g 41 5.11a H Bn H H Me 5.13h 67 5.10a p -Tol Bn H Me H 5.13i 53 5.11b H n -Bu H Me Me 5.13j 22 5.2.2 Preparation of Unsymmetrical N -Aminoguanidines 5.14ah Reagents 5.10ai, and 5.11a were successfully employe d in the synthesis of N aminoguanidines 5.14ah Refluxing 5.10 or 5.11 with 1.1 equivalents of the hydrazine in toluene for 3 hrs in the presence of 2 equivalents of triethylamine afforded 5.14ah in excellent yields (Scheme 5.8, Table 5.2). Th e completion of the reaction was monitored by TLC. The benzotriazole generated as a side product was easily removed by flash chromatography on basic alumina with ethyl acet ate as an eluant. Pr oducts were isolated as oils using methanol as eluant. Novel 5.14ah were characterized by elemental analysis, 1H and 13C NMR spectra. Compound 5.14c was not stable at room temperature

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65 and decomposed after 2 hrs. Similar to Nhydroxyguanidines, the NH protons were not visible in the 1H spectra of 5.14a,d,e,h probably because they are interchanging rapidly producing different ta utomeric forms of 5.14 The dominant tautomeric structure has the double bond involving the hydrazine nitrogen (R7=H) ( 5.14a-g Scheme 5.8). However, if R7 is different from H, then structure 5.14h obviously forms (Scheme 5.8). 5.10,5.11 Et3N, Toluene, reflux N N R N R5R6NNR7H 5.14 h R2 R1 N R5 R6 R7 Et3N, Toluene, reflux R5R6NNH2NH N R N 5.14a-g R2 R1 N R5 R6 Scheme 5.8 Synthesis of N -aminoguanidines 5.14ah On the other hand, reacting 5.10i with 2-hydrazinopyridine afforded a cyclic product 5.15 via a simple intramolecular conden sation with the loss of one water molecule. Compound 5.15 was isolated as fluorescent white micocrystals in 93% yield (Scheme 5.9). A single example of a 1,3,5 s ubstituted 1,2,4-triazole was reported in literature [75BSCF1649]. Guanidynal hydroiodi de was reacted with acetic acid and methyl iodide to give 3-methyl-5-amino-1,2,4triazole in moderate yield [75BSCF1649]. N N N N N O NN H NH2 Et3N N N N N N Toluene, reflux + 5.10i 5.15 93% Scheme 5.9 Synthesis of trisubstituted 1,2,4-triazole 15

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66 Table 5.2 Synthesis of N -aminoguanidines 5.14ah Reactant R R1 R2 R5 R6 R7 Product Yield, % 5.10b p -Tol iPr H H H H 5.14a 84 5.11b H nBu H C6H4OMep H H 5.14b 91 5.10c C6H4Clp iPr H SO2Ph H H 5.14c 76 5.10a p -Tol Bn H Me Me H 5.14d 82 5.10f C6H4CO2Et n -Bu H Me Me H 5.14e 84 5.10h COPh (CH2)2O(CH2)2 Me Me H 5.14f 71 5.11b H nBu H Me Ph H 5.14g 85 5.10c C6H4Clp iPr H Me H Me 5.14h 30 5.2.3 Preparation of Symmetrical Dihydroxyguanidine 5.16 and Diaminoguanidine 5.17 Syntheses of novel dihydroxyguanidine 5.16 and diaminoguanidine 5.17 was accomplished in high yields from the reaction of 5.6 and 5.8a with 3 equivalents of hydroxylamines hydrochloride or hydrazines in the presence of 3 equivalents of triethylamine in refluxing toluene for 30 min (Scheme 5.10, Table 5.3). Reaction time for the preparation of N -hydroxy and N -aminoguanidines is signifi cantly shorter than that for the preparation of guanidines due to enhancement of nuc leophilicity by the alpha effect [78RCR631]. NH N H R N H N H N R5R5 R5NHNH2NH2OR4x HCl NH N H R N O O R4R4 5.17 Et3N, Toluene, reflux Et3N, Toluene, reflux 5.16 5.6 5.8a Scheme 5.10 Syntheses of dihydroxygua nidine 5.16 and di aminoguanidine 5.17 Table 5.3. Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17 Reactant R R4 R5 Product Yield% 5.8a C6H4CO2Et H 5.16 91 5.6 H C6H4OMep 5.17 61

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67 A novel guanylating reagent 5.18 was prepared from the reaction of 1 equiv. di(benzotriazol-1-yl)methanimine 5.6 with 1.2 equiv. of hydroxylamine in THF. The mixture was refluxed for 1h then washed with 10% sodium carbonate. Extracting the organic layer afforded 5.18 in 89% yield. Microwave reaction of 5.18 with hydrazine afforded compounds N -hydroxyN -aminoguanidine 5.19 in 61% yield (Scheme 5.11). The structure of novel 5.19 was verified by 1H and 13C NMR spectra, and high resolution mass spectroscopy. Schiff bases of N -hydroxyN -aminoguanidines are often used as anticancer, antibacterial, and antiviral agents [85JMC1103, 94E JMC781], and recently electron acceptors for xant hine oxidase [04JMC3105]. R5NHNH2NH2N N HO 5.19 microwave 5.18 N N NH2N H N HO N R5 R5 = p -TolSO2, 61% yield Scheme 5.11 Synthesis of N -hydroxyN -aminoguanidine 5.19 5.3 Conclusion An efficient and simple route to monoand symmetrical diN -hydroxyand N aminoguanidines has been developed usi ng benzotriazole guanylating reagents. The procedure uses no aggressive reagents, occurs under mild reaction c onditions, and allows ease of isolation of the products. 5.4 Experimental Section Melting points were determined on a hot -stage apparatus an d are uncorrected. NMR spectra were recorded in CDCl3, or DMSOd6 with TMS as the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75 MHz). Column

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68 chromatography was conducted on silica gel (200 425 mesh) or on basic alumina (60 325 mesh). 5.4.1 General Procedure for the Preparation of Compounds 5.13aj To a solution of 5.10a,b,d,e,g,h or 5.11a,b (see Schemes 5.3 and 5.4) (1.70 mmol) in toluene (13 mL), was added (2.55 mmol) of the hydroxylamine of choice followed by (2.55 mmol, 0.4 mL) of triethylamine. The r eaction mixture was heated under reflux until full conversion of starting materials (4-12h). Upon completion, the solvent was evaporated under reduced pressure. The cr ude product was dissolved in methylene chloride, washed twice with saturated aque ous sodium carbonate, dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The desired N hydroxyguanidines were isolated by flash column chromatography on basic alumina (first ethyl acetate to remove impurities and methanol to elute guanidine) to give 5.13aj. N -BenzylN -hydroxyN -(4-methylphenyl)guanidine (5.13a). oil (80%); 1H NMR 7.31 7.21 (m, 5H), 7.13 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.68 (br s, 1H), 5.35 (br s, 1H), 4.37 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H), 1.67 (br s, 1H); 13C NMR 156.2, 155.6, 139.0, 135.6, 129.8, 128.6, 127.4, 127.3, 122.0, 44.2, 20.8. Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.18; H, 6.46; N, 16.84. N -IsopropylN -hydroxyN -methylN -(4-methylphenyl)guanidine (5.13b). oil (72%); 1H NMR 7.08 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.68 (br s, 1H), 4.87 (d, J = 8.1 Hz, 1H), 3.94 3.87 (m, 1H), 2.22 (s, 3H), 1.68 (br s, 1H), 1.06 (d, J = 6.3 Hz, 6H); 13C NMR 155.6, 136.1, 129.7, 128.7, 121.4, 42.0, 23.2, 20.8. Anal. Calcd for C11H17N3O: C, 69.54; H, 10.21; N, 20.27. Found: C, 69.86; H, 10.22; N, 20.14.

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69 N -(4-Chlorophenyl)N -cyclohexylN -hydroxyguanidine (5.13c). oil (56%); 1H NMR 7.38 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 3.66 3.65 (m, 3H), 2.00 1.96 (m, 2H), 1.79 1.70 (m, 2H), 1.62 1.50 (m, 2H), 1.43 1.26 (m, 5H); 13C NMR 129.1, 128.9, 120.8, 116.2, 33.9, 33.6, 32.2, 25.5, 24.8, 24.3. Anal. Calcd for C13H18ClN3O: C, 58.31; H, 6.78. Found: C, 58.26; H, 6.47. N -ButylN -hydroxyN -mesitylguanidine (5.13d) oil (87%); 1H NMR 6.86 (s, 2H), 5.67 (br s, 1H), 4.20 (br s, 1H), 4.19 (br s, 1H), 3.10 (q, J = 6.7 Hz, 2H), 2.22 (s, 3H), 2.17 (s, 6H), 1.36 1.28 (m, 2H), 1.25 1.15 (m, 2H), 0.80 (t, J = 7.1 Hz, 3H); 13C NMR 157.1, 137.7, 137.1, 131.2, 129.4, 39.9, 32.5, 20.9, 19.9, 18.1, 13.8. Anal. Calcd for C14H23N3O: C, 66.43; H, 9.30; N, 11.55. Found: C, 66.22; H, 9.25; N, 11.29. N -BenzoylN N -diethylN -hydroxyguanidine (5.13e). oil (71%); 1H NMR 7.77 7.56 (m, 5H), 3.15 (q, J = 7.4 Hz, 2H), 3.04 (q, J = 7.4 Hz, 2H), 1.48 (t, J = 7.3 Hz, 3H), 1.42 (t, J = 7.4 Hz, 3H); 13C NMR 168.2, 143.5, 134.2, 131.5, 128.5, 127.0, 36.2, 29.8. Anal. Calcd for C12H17N3O2: C, 61.26; H, 7.28. Found: C, 61.28; H, 7.55. N -[( E )-(Hydroxyamino)(morpholino)methylidene]benzamide (5.13f). oil (74%); 1H NMR 8.12 8.09 (m, 2H), 7.61 7.54 (m, 3H), 3.88 3.84 (m, 4H), 3.58 3.55 (m, 4H), 1.73 (br s, 1H); 13C NMR 159.9, 146.0, 132.5, 129.3, 128.9, 127.9, 66.2, 46.3. Anal. Calcd for C12H15N3O3: C, 57.42; H, 6.07; N, 18.86. Found: C, 57.12; H, 6.08; N, 18.53. N -(Benzyloxy)N -isopropylN -(4-methylphenyl)guanidine (5.13g). Oil (41%); 1H NMR 7.31 7.26 (m, 5H), 6.96 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 4.83 (s, 2H), 3.45 (br s, 1H), 2.19 (s, 3H), 0.98 (d, J = 6.3 Hz, 6H); 13C NMR 152.4, 138.0, 129.7, 128.5, 128.4, 128.3, 128.1, 127.9, 127.6, 75.4, 23.1, 43.5, 20.6. Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80. Found: C, 72.60; H, 7.66.

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70 N -BenzylN -methoxyguanidinehydrochloride (5.13h) oil (67%); 1H NMR 7.27 7.18 (m, 5H), 5.17 (br s, 2H), 3.60 (s, 2H), 2.08 (s, 3H); 13C NMR 147.61, 128.9, 128.7, 127.6, 126.2, 48.2, 30.9. Anal. Calcd for C9H14ClN3O: C, 50.12; H, 6.54; N, 10.48. Found: C, 50.02; H, 6.94; N, 10.21. N -BenzylN -hydroxyN -methylN (4-methylphenyl)guanidine (5.13i). oil (53%); 1H NMR 7.68 (br s, 1H), 7.33 7.26 (m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.3 Hz, 2H), 6.18 (brs, 1H), 4.87 (d, J = 5.4 Hz, 2H), 2.33 (s, 3H), 1.61 (br s, 3H); 13C NMR 137.8, 137.3, 132.9, 130.9, 128.8, 127.7, 127.6, 125.6, 49.5, 21.0. Anal. Calcd for C16H19N3O: C, 71.35; H, 7.08; N, 13.60. Found: C, 71.20; H, 7.90; N, 13.55. N -ButylN -methoxyN -methylguanidine (5.13j). oil (22%); 1H NMR 6.92 (br s, 2H), 3.62 (s, 3H), 3.25 (t, J = 7.1 Hz, 2H), 3.20 (s, 3H), 1.60 1.52 (m, 2H), 1.36 1.29 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR 152.6, 31.6, 31.2, 29.7, 22.6, 19.9, 14.1. HRMS (EI) Calcd for C7H17N3O (M+1): 160.1444. Found: 160.1445. 5.4.2 General Procedure for the Preparation of Compounds 5.14ah To a solution of 5.10ac,f,h or 5.11b (see Schemes 3 and 4) (0.68 mmol) in toluene (10 mL), was added (0.75 mmol) of the hydrazine of choice followed by (1.36 mmol, 0.25 mL) of triethylamine. Th e reaction mixture was heated under reflux until full conversion of starting material s (3h). Upon completion, the solvent was evaporated under reduced pressure. The crude product was dissolv ed in methylene chloride, washed twice with saturated aqueous sodium carbonate, drie d over magnesium sulfate, and filtered. The solvent was removed under re duced pressure. The desired N -aminoguanidines were isolated by flash column chromatography on basi c alumina (first ethyl acetate to remove impurities and methanol to elute guanidine) to give 5.14ah.

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71 N -IsopropylN -(4-methylphenyl)-1-hydrazinecarboximidamide (5.14a). oil (84%); 1H NMR 7.78 (s, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 4.02 3.91 (m, 1H), 2.37 (s, 3H), 2.10 (s, 2H), 1.17 (d, J = 6.3 Hz, 6H); 13C NMR 153.4, 139.7, 139.5, 130.9, 125.0, 45.6, 29.7, 23.1. Anal. Calcd for C11H18N4: C, 64.05; H, 8.79; N, 27.16. Found: C, 63.98; H, 8.42; N, 27.01. N -Butyl-2-(4-methoxyphenyl)-1-hydrazinecarboximidamide (5.14b). oil (91%); 1H NMR 7.73 (d, J = 9.1 Hz, 2H), 6.97 (d, J = 9.1 Hz, 2H), 3.88 3.81 (m, 5H), 2.17 (s, 1H), 1.57 (s, 3H), 1.32 1.26 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR 145.0, 129.3, 124.2, 114.0, 113.7, 55.4, 54.9, 30.7, 21.8, 14.0. Anal. Calcd for C12H20N4O: C, 60.99; H, 8.53; N, 23.71. Found: C, 61.39; H, 7.22; N, 23.64. N -Benzyl-2,2-dimethylN -(4-methylphenyl)-1-hydrazinecarboximidamide (5.14d). oil (82%); 1H NMR 7.34 7.26 (m, 5H), 7.07 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H), 4.33 (s, 2H), 2.80 (s, 6H), 2.26 (s, 3H); 13C NMR 157.6, 138.2, 129.9, 128.7, 127.5, 127.3, 124.3, 121.8, 115.4, 49.8, 48.7, 39.4. Anal. Calcd for C17H22N4: C, 72.31; H, 7.85; N, 19.84. Found: C, 72.05; H, 7.89; N, 19.48 Ethyl-4-{[(butylamino)(2,2-dimethyl hydrazino)methylene]amino}benzoate (5.14e) oil (84%); 1H NMR 7.85 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.60 (br s, 1H), 4.26 (q, J = 7.0 Hz, 2H), 3.25 3.20 (m, 2H), 2.37 (s, 6H), 1.57 1.45 (m, 2H), 1.35 1.28 (m, 5H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR 166.8, 154.5, 150.1, 131.5, 130.9, 122.9, 60.4, 47.9, 40.6, 31.8, 20.2, 14.4, 13.9. Anal. Calcd for C16H26N4O2: C, 62.72; H, 8.55; N, 16.28. Found: C, 62.90; H, 8.65; N, 16.00. N -[(2,2-Dimethylhydrazino)(mor pholino)methylene]benzamide (5.14f ). oil (84%); 1H NMR 8.1-8.06 (m, 2H), 7.37 7.31 (m, 3H), 4.72 (s, 1H), 3.86 3.83 (m, 4H), 3.72 3.68

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72 (m, 4H), 2.50 (s, 6H); 13C NMR 176.3, 161.0, 138.4, 131.1, 129.0, 127.8, 66.9, 48.0, 47,6. Anal. Calcd for C14H20N4O2: C, 61.25; H, 7.29; N, 19.17. Found: C, 61.59; H, 7.57; N, 19.20. N -Butyl-2-methyl-2-phenyl-1-hydrazinecarboximidamide (5.14g). oil (85%); 1H NMR 7.29 7.24 (m, 2H), 7.02 6.99 (m, 2H), 6.84-6.78 (m, 2H), 4.34 (br s, 1H), 3.73 (br s, 2H), 3.10 (s, 3H), 3.03 (t, J = 7.0 Hz, 2H), 1.59 1.51 (m, 2H), 1.41 1.34 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR 152.5, 128.8, 118.5, 116.7, 113.4, 45.6, 44.4, 31.5, 19.3, 13.4 .HRMS calcd for C12H20N4 (M+1): 221.1761. Found: 221.1756. N -(4-Chlorophenyl)-N-isopropyl-1,2-dimethyl -1-hydrazinecarboximidamide hydrate (5.14h ) oil (30%); 1H NMR 8.16 (br s, 1H), 7.20 (br s, 2H), 7.04 (br s, 2H), 4.55 4.46 (m, 1H), 1.94 (s, 3H), 1.81 (s, 3H), 1.22 ( d, J = 6.6 Hz, 6H); 13C NMR 148.7, 129.5, 129.0, 124.5, 116.2, 46.3, 29.7, 25.1, 22.5. Anal. Calcd for C12H19ClN4: C, 51.57; H, 8.52; N, 16.99. Found: C, 51.40; H, 8.42; N, 16.81. 5.4.3 Preparation of N,N -Diisopropyl-5-phenyl-1-(2-pyrid inyl)-1H-1,2,4-triazol-3-amine 5.15 To a solution of (0.15g, 0.43 mmol) N -[1H-1,2,3-benzotriazol-1-yl (diisopropylamino)methylidene]benzamid e in 15 ml toluene, was added (0.14g, 1.3mmol) of 2-hydrazinopyridine. The mixt ure was stirred for 5 minutes and then brought to reflux. After 2h, the reaction was st opped and the solven t evaporated under vacuum. The crude product was washed with 10 % Na2CO3 and then extracted with dichloromethane (3 x 20 ml). Evaporating the organic fraction followed by flash column chromatography on basic alumina afforded 5.15 (0.13, 93%). N N -Diisopropyl-5-phenyl-1-(2-pyridinyl)-1 H -1,2,4-triazol-3-amine (5.15) Recrystallized from EtOAc-Hexanes to give white crystals (93%), mp 104 105 C; 1H NMR 8.30 (br

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73 d, J=4.8 Hz, 1H), 7.72 (t d, J=8.1 Hz, 2.0 Hz, 1H), 7.55 7.50 (m, 3H), 7.36 7.29 (m, 3H), 7.15 (dd, J=7.5, 4.8 Hz, 1H), 4.17 (septet, J = 6.7 Hz, 2H), 1.37 (d, J = 6.9 Hz, 12H); 13C NMR 163.1, 152.7, 151.3, 148.1, 138.2, 129.7, 129.2, 129.1, 127.9, 122.1, 118.2, 46.4, 20.7. Anal. Calcd for C19H23N5: C, 71.00; H, 7.21; N, 21.79. Found: C, 71.32; H, 7.56; N, 21.98. 5.4.4 General Procedure for the Preparation of Compounds 5.16 and 5.17 To a solution of 5.8a or 5.6 (see Schemes 5.3 and 5.4) (0.6 mmol) in toluene (10 mL), was added (1.8 mmol) of the hydroxyl amine or hydrazine of choice followed by (1.8 mmol, 0.3 mL) of triethylamine. The r eaction mixture was heated under reflux until full conversion of starting materials ( 30-45min). Upon completion, the solvent was evaporated under reduced pressure. The cr ude product was dissolved in methylene chloride, washed twice with saturated aque ous sodium carbonate, dried over magnesium sulfate, and filtered. The solvent was rem oved under reduced pressure. The desired products were isolated by flash column ch romatography on basic alumina (first ethyl acetate to remove impurities and meth anol to elute guanidine) to give 5.16 and 5.17. Ethyl-4-{[(hydroxyamino)(hydroxyimino)methyl]amino}benzoate (5.16). oil (90%); 1H NMR 7.79 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.99 (br s, 2H), 1.59 (br s, 1H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR 166.7, 150.7, 131.5, 123.0, 120.0, 113.7, 60.3, 14.4. HRMS calcd for C10H13 N3 O4, (M+1): 240.2275. Found: 240.2280. N -2-bis(4-methoxyphenyl)-1hydrazinecarboximidohydrazide (5.17). oil (61%); 1H NMR 7.66 (d, J = 8.9 Hz, 4H), 6.90 (d, J = 8.9 Hz, 4H), 3.81 (s, 4H), 1.50 (s, 6H); 13C NMR

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74 140.0, 130.6, 129.3, 128.2, 113.8, 29.7. Anal. Calcd for C15H19N5O2: C, 59.79; H, 6.36; N, 13.24. Found: C, 59.80; H, 6.46; N, 12.65. 5.4.5 Preparation of N -Hydroxy-1 H -1,2,3-benzotriazole-1-carboximidamide 5.18 To a solution of (2.0 g, 7.6 mmol) di(1 H -1,2,3-benzotriazol-1-yl)methaneamine in THF (30 mL), was added (0.72 g, 15.2 mmol ) of hydroxylamine hydrochloride followed by of triethylamine (2.0 mL). The mixture was re fluxed for 1 hour and then left to cool at room temperature. The reaction mixture was washed with 10% Na2CO3, and extracted with methylene chloride (3 x 20ml). Th e organic layer was dried over anhydrous magnesium sulfate. Evaporat ing the solvent under reduced pressure afforded pure 18 (1.2g, 89%) 5.4.6 General Procedure for the Preparation of Compound 5.19 To (0.56 mmol) N '-hydroxy-1 H -1,2,3-benzotriazole-1-carboximidamide 5.18 was added (0.56 mmol) of the hydrazine of choice. The mixture was microwaved neat for 5 min. (T :115 C, P: 120 W). The reaction was then st opped, and the mixture washed with 10% Na2CO3 and extracted with dichloromethane (3 x 20ml). Evaporating the organic fraction followed by flash column chromatography on basic alumina afforded 5.19. N -hydroxy-2-[(4-methylphenyl)sulf onyl]-1-hydrazinecarboximidamide (5.19). oil (61%); 1H NMR 7.38 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 2.32 (s, 3H), 1.55 (s, 1H); 13C NMR 137.4, 133.9, 129.8, 129.7, 128.5, 21.0. HRMS (EI) calcd for C8H12N4O3S (M+ Na): 267.2598. Found: 267.2593.

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75 CHAPTER 6 MICROWAVE ASSISTED PREPARAT IONS OF AMIDRAZONES AND AMIDOXIMES 6.1 Introduction to Amidrazones Amidrazones 6.1 display fungistatic, bacterio static, antimycotic activity [01EJMC75], and also function as herbicid es [63CA11276] and lipoxyg enase-1 inhibitors [01BBA88]. Amidrazones are used to prepare 1,2,4-triazines [55HCA1560]. Reactions of nitriles with hydrazines [Scheme 6.1, (i)] is frequently used for the preparation of amidrazones [56JA 2253, 61JOC3783, 63CA11276, 70CRV151] but the outcome depends on the nature of the nitril e [56JA2253] and further reaction can give dihydrotetrazines and subsequently tetraz ines [70CRV151]. Alternative methods (Scheme 6.1) for the synthesis of amidrazone s avoid the use of n itriles by reaction of hydrazine with (ii) imidates or their salts (X=O, S; R2= Alk) [68JOC1679, 92ACS671], (iii) imidoyl halides [70CRV151, 79JCS1961] (iv) amides and thioamides in the presence of POCl3 [50JA2783, 55HCA1560, 58JOC1931], (v) dihydroxythiazoledioxides [62JOC3240], or (vi) ketenimines (R, R1= Ar) [65JOC3718]. Further routes to amidrazones include (vii) reaction of am ines with hydrazonoyl halides (X= Cl, Br) [46JA588, 58TL209, 02T5317]; (vii i) reduction of nitraz ones by ammonium sulfide [58CA11919] or (ix) reduction of formazans (R, R1= Ar) [70CRV151]. Two possible tautomers 6.1A and 6.1B exist for amidrazones (Scheme 6.2). If N2 is substituted then amidrazones 6.1 are fixed in form 6.1B otherwise, spectral data [73JOC1344] suggest that amidrazones exist exclusively in form 6.1A (Scheme 6.2).

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76 R N N H NR1NR2 R N NO2H NR1 (viii) (ix)R X N R2R1 R N Cl R1 RCCNR1 O2S O N R R1 N1N N R N X H NR1 R N X R1R2 RCN (i) (ii) (iii) (iv) (v) (vi) (vii)Reagents:a (i-vi) reactions with hydrazine, (vii) reaction with amine R, R1, R2 = alkyl or aryl 6.1A (X= O, S) 2 3 N1N N 6.1B2 3 Scheme 6.1 Preparative routes to amidrazones N1N N fixed in form 6.1A R 2 3N1N N fixed in form 6.1B2 3R R N1N N H 2 3 6.1A N1N N 2 3H 6.1B Scheme 6.2 Tautomeric forms of amidrazones Thus, amidrazones are of two major types: class I which do not carry a substituent on N2 and exist predominantly in structure 6.1A (Scheme 6.2); class II which are substituted on N2 and exist necessarily as 6.1B (Scheme 6.2). Class I compounds can in turn be divided into eight subclasses (A-H ) as shown in Table 6.1 (two mono, three di, three tri, one tetra substituted). Almost all of these sub-classes c ould potentially be made by one or more of the existing methods; how ever, literature sub-structural searches showed no known examples of compounds of cla ss G. The present work provides an easy access to novel class G in addition to classes A, B, D, E. As to cl ass II, a single example

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77 was reported for the preparation of such co mpounds as a hydroiodide salt in 75% yield [84LAC283]. 6.2 Introduction to Amidoximes Amidoximes 6.2 are biologically active as anti tumor agents [78Cancer Res.1291], antimalerial agents [72JMC1194], and nitr ic oxide synthases (NOS) substrates [98APMC375, 98B17179]. Amidoximes are prodrugs for amidines [96JMC3139, 02DMR565], and intermediates for the preparati on of heterocycles such as oxadiazoles [03JOC7316]. Tautomerism in simple amidoximes had been the subject of some debate, although most authors accept the structure of potentially tautomeric amidoximes to be the amino oxime form ( 6.2A ) not the amino hydroxylamine structure ( 6.2B ) (Scheme 6.3). N1N O fixed in form 6.2A R 2N1N O fixed in form 6.2B2R R N1N O H 2 6.2A N1N O 2H 6.2B Scheme 6.3 Tautomeric forms of amidoximes Thus, similar to amidrazones, amidoximes 6.2 can be divided into two classes: class I which do not carry a substituent on N2 exist predominantly as structure 6.2A (Scheme 6.3); class II which are substituted on N2 exist necessarily as 6.2B (Scheme 6.3). Common methods (Scheme 6.4) for the prep aration of class I amidoximes include reactions of hydroxylamines with (i) nitriles [62CRV155, 69JCS861, 76AJC357, 03H2287, 04JMC3642], (ii) thioamides [1886CB1668, 1891CB3658, 62CRV155] for the preparation of aromatic amidoximes, (i ii) imidates [1884CB184, 80JOC4198], or (iv) amidines and their salts (4952% yield) [1884CB184, 02PJC1137].

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78 Table 6.1 The eight class I amidrazones existing as 6.1A N1N N 6.1A 2 3 Mono-Nsubstituted Di-N-substituted Tri-N-substituted Tetra-Nsubstituted Sub-class A B C D E F G H Method N1 N3 N1N1 N3N3 N1N3 N1N1N3 N1N3N3 N1N1N3N3 i N R N R N N N N ii R R N R P N P N iii R R N P R N P N iv P R N P R R P R v N P N R N N N N vi R P N P P N P N vii N R N P R P P P viii N R N P N N N N ix N R N P N N N N x N P N N R P N N This work R P N P R N R N R: Reported; P: Possible but no ex ample reported; N: Not possible Alternative routes in clude (v) reaction of amines w ith hydroximic acid chlorides and oximinoethers [62CRV155, 80JOC4198, 82JCS907, 85JOC3348, 03CC1870, 04TL861]; (vi) reduction of oxyamidoximes [62CRV155]; (vii) platinum catalyzed reduction of nitrosolic and nitrolic acids [62CRV155, 1906B er1480], (viii) aldol condensations of formamidoxime with aroma tic aldehydes [62CRV155]; or (ix) oxazole ring cleavage [88JHC931, 95H619] A single procedure for th e preparation of class II amidrazones includes the reaction of imidoyl halides [03ARK96] with arylnitrenium ion (Scheme 6.4) [83CB1822]. Moreover, O -substituted amidoximes ar e prepared directly by the reaction of amidoximes with methy liodide or dimethylsulfate to give O -

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79 methylamidoxime (22% yield) [80JOC4144, 89BSCB203], or ace tylene to yield O vinylamidoximes (80 % yield) [01S2427-33]. O N N R R1 RCN R O H H N NH2OH R N NO2OH R S N R2R1 R N NHOH OH R NH OR1 R N LG OR1 R NH NH2.HCl Reagents:a (i-iv) reactions with hydroxyamine or RONH2, (v) reaction with amine, R, R1, R2 = alkyl or aryl, (vi) reduction with SO2, (vii) Platinum catalyzed reduction, (viii) aldol condensation, (ix) photorearrangement of oxazole ring+ (viii) (ix) N N O (i) (ii) (iii) (iv) (v) (vi) (vii)6.2A 1 2 Scheme 6.4 Preparative routes to amidoximes of type 6.2A Amidoximes 6.2A can be divided into five sub-cl asses (two mono, two di, one tri) substituted as shown in Table 6.2. As to amidoximes 6.2B, four sub-classes (one mono, two di, one tri) can also exist as shown in Table 6.3. The ten reported methods for the preparation of 6.2A and 6.2B (Schemes 6.4 and 6.5) generally target specific sub-classes of amidoximes (Tables 6.2 and 6.3). We now report routes to many classes including class I' where no examples have been reported to date. N RCl R1 R, R1 = aryl N N HO R 6.2B Ph 1 2N O Ph O + R1 (x) Scheme 6.5 Preparative routes to amidoximes of type 6.2B

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80 6.3 Results and Discussion Imidoylbenzotriazoles 6.3 have become important as stable alternatives to the corresponding imidoyl chlorides [ 95H231, 01JOC1043, 04JOC5108]. Recently, we reported a novel procedure for the preparati on of amidines using imidoylbenzotriazoles [06JOC3375-35]. We have now expanded the ut ility of imidoylbenzotriazoles to include the preparation of amidrazones 6.1ah and amidoximes 6.2ah. Imidoylbenzotriazoles 6.3ah (Scheme 6.6) were prepared in good yields (50-91%) from the reaction of secondary amide (1 equiv), oxalyl chloride (1 equiv) and benzotriazole (2 equiv) in the presence of pyridine [06JOC3375-35]. The crude products were chromatographed, after washing w ith sodium carbonate, on basic alumina (EtOAc/Hex) to give pure imidoylbenzotriazoles 6.3ah (Scheme 6.6). Known 6.3a e,g,h and novel 6.3f were fully characterized by 1H and 13C NMR spectroscopy, and in the case of 6.3f by elemental analysis. Most imidoylbe nzotriazoles are easy to handle and can be stored indefinitely ; however, we noted slow d ecomposition of 1-[phenyl(2pyridinylimino)methyl]-1 H -benzotriazole 6.3g after 3 days. Attempts to prepare amidrazones 6.1ah in solution phase initially met with significant difficulties: incomplete reaction at moderate conditions and decomposition on extensive heating. We theref ore turned to solvent-free solid supported synthesis. Reagents immobilized on porous solid mate rials have several advantages over the conventional solution phase reactions becau se of the good dispersion of active sites leading to improved reactivity and milder reac tion conditions; indeed solvent-free use of supported reagents in combination with mi crowave irradiation ga ve reduced reaction time, and easier work-up procedure and enhan ced selectivity and re activity [01TL5347]. Thus, stirring 1 equivalent of imidoylbenzotriazoles 6.3bd,f with 1.5 equivalents of the

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81 corresponding hydrazine in the presence of a 7 fold excess of sodium sulfate for 5 min under microwave irradiation afforded amidrazones 6.1ah in 66-85% yields (Scheme 6.6 and Table 6.4). Table 6.2 Five sub-classes of amidoximes 6.2A N N O 6.2A 1 2 Mono Di Tri Sub-class A B C D E Method N1 O N1N1 N1O N1N1O i N P N N N ii R R N P N iii N P N N N iv N N N R N v R P N R N vi N P N N N vii N P N N N viii N P N N N ix N N N R N This work R P N R N R: Reported; P: Possible but not reported; N: Not possible The progress of the reaction was mon itored by TLC. Upon completion of the reaction, water was added to remove sodium sulfate. The organic layer was extracted with dichloromethane then purified usi ng column chromatography to give novel 6.1ah as colorless oils. Structures of novel 6.1ah were supported by NMR spectroscopy, high resolution mass spectroscopy, and el emental analysis. Amidrazones 6.1ah exhibit tautomerism, thus, it is hard to assign th e NH protons, especially since they were not always visible.

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82 Table 6.3 Four sub-classes of amidoximes 6.2B N N O 6.2B 2 1 Mono Di Tri Sub-class F G H I Method N2 N2O N1N2 N1N2O x N N R N This work P P R R R: Reported; P: Possible but not reported; N: Not possible N N R R1 N N HN R R1 N R R1 6.3a-h N H N R2 6.2a-h N O R5 R4 6.1a-h N N N R R3 R1 6.4a-d H NNH2 R5O N H R4 N H NH2 6.3a R=Bn, R1= p -Tol, 61% 6.3b R=Me, R1= p -Tol, 67% 6.3c R=Ph, R1= i -Bu, 60% 6.3d R= p -Tol, R1=4-MeOC6H4, 70% 6.3e R=Ph, R1=Ph, 90% 6.3f R=Me, R1= i -Bu, 50% 6.3g R=Ph, R1= 2Pyridyl, 86% 6.3h R=2-Furyl, R1= p -Tol, 91% O R3 R2 CH3COOHFor identity of R, R1, and R2, see Tables 6.4, 6.5, and 6.6 Scheme 6.6 Reactions of imidoylbenzotriazoles with hydrazines and hydroxylamines Reacting imidoylbenzotriazole 6.3a,b,d with hydrazines (R3CONHNH2) in the presence of catalytic amounts of acetic acid under microwave conditions afforded cyclic 1,2,4-triazoles 6.4ad [03ARK62,03ARK65, 03ARK98, 05JOC6362] (Scheme 6.6 and Table 6.5) via a simple intramolecular condens ation followed by the loss of one molecule of water. Upon completion of the reaction (5-10 min), the sample was diluted with dichloromethane then purified using flash column chromatography to give 6.4ad in 77-

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83 100% yields. Novel 6.4ad were isolated as white microcrystals and characterized by 1H and 13C NMR spectroscopy and elemental analysis. Table 6.4 Preparation of amidrazones 6.1ah from 6.3bd,f* Imidoyl benzotriazole 6.3 R R1 R2 Conditions (t, oC, Power, W, time, min) Product Yield, % 6.3b Me p -Tol H 95, 105, 10 6.1a 85 6.3b Me p -Tol Ph 90, 120, 15 6.1b 70 6.3c Ph i -Bu PhCO 120, 130, 15 6.1c 72 6.3d p -Tol 4-MeOC6H4 Ph 80, 80, 10 6.1d 82 6.3f Me i -Bu 4-NO2OC6H4 110, 120, 20 6.1e 68 6.3b Me p -Tol PhCO 120, 125, 12 6.1f 66 6.3c Ph i -Bu 4-ClC6H4CO 160, 160, 12 6.1g 87 6.3f Me i -Bu COCH3 105, 115, 9 6.1h 80 Compounds 6.1c,e-h were prepared by my co lleague Dr. Anamika Singh Table 6.5 Preparation of 1,2,4-triazoles 6.4ad from 6.3a,b,d Imidoyl benzotriazole 6.3 R R1 R3 Conditions (t, oC, Power, W, time, min) Product Yield, % 6.3a Bn p -Tol Me 80, 120, 10 6.4a 77 6.3b Me p -Tol p -Tol 80, 120, 5 6.4b 94 6.3d p -Tol 4-MeOC6H4 p -Tol 80, 120, 5 6.4c 100 6.3d p -Tol 4-MeOC6H4 Ph 80, 120, 10 6.4d 88 Amidoximes 6.2ah were prepared in 65-81% yi elds from the reaction of imidoylbenzotriazoles 6.3af,h with the corresponding hydr oxylamines (Scheme 6.6 and Table 6.6). Using microwave, r eaction of imidoylbenzotriazole 6.3af,h with hydroxylamines reached completion after 5 to 15 minutes. The reaction mixture was then dissolved in DCM and washed with 10% solution of Na2CO3. The combined organic layers were dried over anhydrous MgSO4 and concentrated unde r reduced pressure. The residue obtained was purified by gradient column chromat ography (EtAc/Hex) to obtain pure amidoximes 6.2ah Structures of novel 6.2ah were supported by elemental analysis and 1H and 13C NMR spectra. The 1H spectra no longer showed distinctive

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84 signals in the range of 7.0.2 ppm corres ponding to the benzotriazole group. Some NH protons were not visible due to fast exchange. Table 6.6 Preparation of amidoximes 6.2ah Imidoyl bezotriazole 6.3 R R1 R4 R5 Conditions (t, oC, Power, W, time, min) Product Yield, % 6.3a Bn p -Tol H H 100, 120, 5 6.2a 65 6.3b Me p -Tol H Bn 100, 120, 10 6.2b 79 6.3c Ph i -Bu H Me 100, 120, 5 6.2c 68 6.3c Ph i -Bu Me H 60, 120, 5 6.2d 81 6.3d p -Tol 4-MeOC6H4 H H 100, 120, 5 6.2e 78 6.3e Ph Ph H Me 80, 120, 5 6.2f 80 6.3f Me i -Bu H Bn 80, 120, 15 6.2g 68 6.3h 2-Furyl p -Tol Me H 60, 100, 10 6.2h 73 Compounds 6.2a-d were prepared by my co lleague Natalia Kirichinko 6.4 Aminoamidoximes and Diamidoximes Aminoamidoximes 6.6 are compounds with both hydroxylamine and hydrazine moieties. Previous preparations of such compounds include reacting oxime chlorides [80JCS304] or simple amidoximes [66 CRSAS592] with hydrazines to give aminoamidoximes in 21% yields (Scheme 6.7). Diamidoximes 6.7 are compounds with two hydroxylamine moieties and to the best of our knowledge, they are not known in the literature (Scheme 6.8). N X CH3 OH H NNH2 N N H CH3 OH N R R X= Cl, NH2R= H, Ph Scheme 6.7 Preparative routes to aminoamidoximes Aminoamidoxime 6.6 and diamidoxime 6.7 were prepared starting from 1 H -1,2,3benzotriazol-1-yl-methanone oxime 6.5 (Scheme 6.8) Reagent 6.5 was prepared from the

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85 appropriate oxime (1 equiv.), 1-chloro-1 H -benzotriazole (1 equiv.), and potassium tertbutoxide (1.1equiv.) in diethylether at -30 C. The reaction was stirred at room temperature for 5h before it was quenc hed with water and extracted with dichloromethane. Evaporation of the organic layer afforded oxime 6.5 in 90% yield. Using microwave, reagent 6.5 was reacted with the appropriate hydrazine or hydroxylamine under mild conditions (refer to experimental section) to give 6.6 or 6.7 respectively (Scheme 6.8). Novel 6.6 and 6.7 were isolated as viscous oils and were characterized by elemental analysis and 1H and 13C NMR spectra. N N R OH N N 6.5 H NNH2 N N H R OH N R6 R6 H2NO R7 N N H R O O R7 R7 6.6 R=Ph, R6=SO2p-Tol, Yield= 70% 6.6 6.7 R=Me, R7=Bn, Yield= 64% 6.7 Scheme 6.8 Preparation of aminoamidoxime 6.6 and diamidoxime 6.7 6.5 Conclusion A simple, efficient, and broadly ap plicable synthetic methodology for the preparation of amidrazones and amidoxime s under microwave conditions has been developed via the nucleoph ilic attack on imidoylbenz otriazoles by hydrazines or hydroxylamines. The easy accessibility of imi doylbenzotriazoles from the corresponding amide and the simple workup gives the approaches substantial utility. 6.6 Experimental Section 6.6.1 General Procedure for the Preparation of Amidrazones 1ah An intimate mixture of 6.3 (0.36 mmol), hydrazine (0.43 mmol) and sodium sulfate (anhydrous, 0.3 g) was stirred in a sealed tube (10 mL) under mi crowave irradiation (conditions vary in each case). After comple tion of the reaction as indicated by TLC, the

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86 reaction mixture was washed with DCM (10 mL ) then filtered off and washed with 5% solution of Na2CO3 (2x15 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressu re. The residue obt ained was either recrystallized from EtOAc/he x (unless indicated otherwis e) or purified by column chromatography on silica gel with EtOAc/Hex to give pure 6.1ah N (4-Methylphenyl)ethanehydrazonamide (6.1a). Viscous oil (85%); 1H NMR 6.97 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 4.8 (br s, 1H), 2.42 (s, 3H), 2.23 (s, 3H). ; 13C NMR 142.6, 129.7, 125.5, 124.1, 117.5, 115.2, 20.4, 10.0. Anal. Calcd for C9H13N3: C, 66.23; H, 8.03; N, 25.74. Found: C, 66.47; H, 8.21; N, 25.70. N -(4-Methylphenyl)N -phenylethanimidohydrazide (6.1b) Colorless oil (70%); 1H NMR 7.29 7.04 (m, 10H), 2.31 (s, 3H), 2.04 (s, 3H), 1.95 (br s, 2H); 13C NMR 153.3, 130.4, 129.5, 128.9, 128.2, 127.1, 125.2, 122.5, 121.0, 29.7, 25.2. Anal. Calcd for C15H17N3: C, 75.28; H, 7.16; N, 17.56. Found: C, 75.44; H, 7.01; N, 17.01. N -(4-Methoxyphenyl)-4-methylN -phenylbenzenecarbohydrazonamide 1/2hydrate (6.1d). Yellow oil (82%); 1H NMR 7.57 (d, J = 8.0 Hz, 2H), 7.21 7.26 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.84 (t, J = 7.2 Hz, 1H), 6.75 6.78 (m, 2H), 6.63 6.68 (m, 2H), 5.60 (br s, 1H), 3.73 (s, 3H), 2.34 (s, 3H); 13C NMR 154.3, 145.5, 139.8, 138.9, 134.6, 132.0, 129.1, 126.7, 119.8, 118.3, 115.1, 114.6, 113.3, 55.5, 21.3. Anal. Calcd for C42H42N6O2.0.5H2O: C, 74.09; H, 6.51; N, 12.34. Found: C, 74.45; H, 6.78; N, 12.03. 6.6.2 General Procedure for the Preparation of Amidoximes 6.2ah A mixture of the appropriate 6.3 (0.35 mmol) (see Sche me 6.6 and Table 6.6), hydroxylamine hydrochloride (0.4 mmol) and Et3N (0.4 mmol) was stirred in a sealed

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87 tube (10 mL) under microwave irradiation (c onditions vary in each case). The mixture was dissolved in DCM and washed with 10% solution of Na2CO3 (2x15 mL). The combined organic layers we re dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue obtained was purified by gradient column chromatography with EtOAc/Hex or recrystallized from EtOAc /hexanes (unless specified otherwise) to give pure 6.2ah. N -HydroxyN -(4-methoxyphenyl)-4-methylbenzenecarboximidamide (6.2e). Recrystallized from EtOAc/Hex to give off-white microcrystals (78%), mp 57 58 C; 1H NMR 2.32 (s, 3H), 3.71 (s, 3H ), 6.66 (s, 4H), 7.07 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H); 13C NMR 21.3, 55.3, 113.9, 123.8, 128.2, 128.4, 129.0, 133.0, 139.4, 152.6, 155.6. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.00; H, 6.43; N, 10.82. N -MethoxyN -phenylbenzenecarboximidamide (6.2f). Yellow oil (80%); 1H NMR 3.97 (s, 3H), 6.64 (d, J = 7.6 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 2H), 7.18 (br s, 1H), 7.23 7.33 (m, 3H), 7.41 7.44 (m, 2H); 13C NMR 61.6, 121.0, 122.5, 128.3, 128.4, 128.7, 129.5, 131.0, 139.7, 151.0. Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 74.27; H, 6.31; N, 12.35. N -(Benzyloxy)N -isobutylethanimidamide (6.2g). Yellow oil (68%); 1H NMR 0.89 (d, J = 6.6 Hz, 6H), 1.16 1.69 (m, 1H), 1.83 (s, 3H), 2.87 (t, J = 6.6 Hz, 2H), 4.95 (s, 2H), 5.26 (br s, 1H), 7.24 7.39 (m, 5H); 13C NMR 15.0, 19.9, 29.7, 50.1, 74.9, 127.5, 128.0, 128.2, 138.3, 153.0. Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found: C, 71.20; H, 9.17; N, 13.28.

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88 N -HydroxyN -methylN -(4-methylphenyl)-2-furancarboximidamide (6.2h). Grey oil (73%); 1H NMR 7.55 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 8.1 Hz, 2H), 6.48 (s, 2H), 3.63 (s, 3H), 2.24 (s, 3H); 13C NMR 144.5, 139.8, 138.4, 135.8, 133.3, 129.4, 120.7, 115.0, 111.5, 44.3, 20.6. Anal. Calcd for C26H30N4O5: C, 65.26; H, 6.32; N, 11.71. Found: C, 64.94; H, 6.00; N, 12.41. 6.6.3 General Procedure for the Preparation of 6.4ad A mixture of the appropriate 6.3 (0.5 mmol) and the corresponding hydrazine (0.51 mmol) in the presence of catalytic amount of CH3COOH (1-2 drops) was stirred in sealed tube (10 mL) under microwave irradiation (c onditions vary in each case). The mixture was dissolved in DCM and washed with 10% solution of Na2CO3 (2x15 mL). The combined organic layers we re dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue obtained was r ecrystallized from the appropriate solvent (designated below) to give pure 6.4ad as white microcrystals. 3-Benzyl-5-methyl-4-(4-methylphenyl)-4 H -1,2,4-triazole (6.4a) Recrystallized from CHCl3/MeOH to give white microcrystals (77%), mp 60 61 C; 1H NMR 2.21 (s, 3H), 2.42 (s, 3H), 3.97 (s, 2H), 6.81 (d, J = 8.2 Hz, 2H), 6.93 6.97 (m, 2H), 7.14 7.16 (m, 3H), 7.21 (d, J = 8.2 Hz, 2H); 13C NMR 10.9, 21.1, 31.4, 126.5, 126.7, 128.2, 128.4, 130.2, 131.0, 135.7, 139.8, 151.9, 153.6. Anal. Calcd for C17H17N3: C, 77.54; H, 6.51; N, 15.96. Found: C, 77.09; H, 6.56; N, 15.94. 3-Methyl-4,5-bis(4-methylphenyl)-4 H -1,2,4-triazole (6.4b) Recrystallized from CHCl3/MeOH to give white microcrystals (94%), mp 142 144 C; 1H NMR 2.30 (s, 3H), 2.32 (s, 3H), 2.43 (s, 3H), 7.06 (d, J = 8.0 Hz, 4H), 7.27 7.32 (m, 4H); 13C NMR 11.3, 21.1, 21.2, 124.1, 126.8, 127.9, 129.0, 130.5, 132.3, 139.3, 139.6, 152.5, 153.9.

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89 Anal. Calcd for C17H17N3: C, 77.54; H, 7.27; N, 15.96. F ound: C, 77.63; H, 6.73; N, 15.88. 4-(4-Methoxyphenyl)-3,5-b is(4-methylphenyl)-4 H -1,2,4-triazole (6.4c). Recrystallized from toluene to give white microcrystals (100%), mp 220 221 C; 1H NMR 2.33 (s, 6H), 3.85 (s, 3H), 6.90 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.0 Hz, 4H), 7.32 (d, J = 8.0 Hz, 4H); 13C NMR 21.3, 55.5, 114.9, 124.2, 127.9, 128.6, 128.9, 129.1, 139.5, 154.9, 159.9. Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.66; H, 6.03; N, 11.63. 4-(4-Methoxyphenyl)-3-(4-me thylphenyl)-5-phenyl-4 H -1,2,4-triazole (6.4d). Recrystallized from CHCl3/Hex to give white microcrystals (88%), mp 211 213 C; 1H NMR 2.33 (s, 3H), 3.84 (s, 3H), 6.91 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.29 7.35 (m, 5H), 7.43 7.45 (m, 2H); 13C NMR 21.3, 55.5, 115.0, 124.2, 127.2, 127.9, 128.3, 128.6, 128.7, 128.9, 129.1, 129.4, 139.6, 154.8, 155.0, 160.0.. Anal. Calcd for C22H19N3O: C, 77.40; H, 5.61; N, 12.31. Found: C, 76.82; H, 5.62; N, 12.27. 6.6.4 General Procedure for the Preparation of 6.6 and 6.7 An intimate mixture of oxime 6.5 (0.42 mmol), the appropriate hydrazine or hydroxylamine (1.05 mmol) and sodium sulfate (anhydrous, 0.1 g) was stirred in sealed tube (10 mL) under microwave irradiation (115W) at approx. 110C (indications) for 10 min. After completion of the reaction, as indicated by TLC, the reaction mixture was dissolved in DCM (10 mL) and then washed with 5% solution of Na2CO3 (2 X 15 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under

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90 reduced pressure. The residue obtained was washed with benzene to give the corresponding products as viscous oils. N -HydroxyN -[(4-methylphenyl)sulfonyl]benzenecarbohyrazonamide (6.6). Oil (70%); 1H NMR 7.69 7.58 (m, 2H), 7.51 7.45 (m, 3H), 7.38 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 2.32 (s, 3H).; 13C NMR 167.0, 144.7, 136.4, 132.1, 131.2, 130.2, 129.7, 127.5, 126.3, 124.6, 119.8, 112.0. Anal. Calcd for C13H12N4O3: C, 57.35; H, 4.44; N, 29.58. Found: C, 57.58; H, 4.53; N, 29.18. N N -Bis(benzyloxy)ethanimidamide (6.7). Oil (64%); 1H NMR 7.91 (br s, 1H), 7.30-7.35 (m, 10H), 4.94 (s, 2H), 4.74 (s, 2H), 1.92 (s, 3H); 13C NMR 154.6, 137.6, 135.6, 129.0, 128.5, 128.3, 128.1, 127.8, 78.6, 75.7, 14.1. Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.08; H, 6.75; N, 10.69

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91 CHAPTER 7 C-IMIDOYLATION OF ESTERS, SULF ONES, SULFOXIDES, AMIDES AND NITRO COMPOUNDS 7.1 Introduction C-Acylations of activated CH groups ar e familiar for many classes of compounds including alkanecarboxylic esters [42J ACS2271, 47JACS119], alkyl sulfones [03JOC1443] and sulfoxides [03JOC5766], a nd aliphatic nitro compounds [59JACS4882, 91S629]. By contrast there are only limited inves tigations of analogous C-imidoylations reactions which are useful for the prepar ation of natural products such as apoerythroidine [65JACS1397] (+/-)-lupinine [87H2335], and many biologically active compounds including terpenes [92EP0503634], for the preparation of drug, food and perfume, 2,2 -biimidazoles [06T731], for th e preparation of metal complexes, receptors, and spramolecular architectures, and useful synthetic precursors such as selenoimidates [00JOC5022]. Moreover, radical mediated gr oup-transfer imidoylation has been widely implied for synthetic and theoretical st udies of organometallic compounds [00TL7517, 01JACS3697]. We reasoned that Nimidoylbenzotriazoles could enable efficient C-imidoylation by analogy to the many applications of Nacylbenzotriazoles [01ARK41, 03ARK131] in C-acylation [03JOC1443, 03JOC5723, 04JOC 6617, 05SL1656]. We now disclose a simple procedure for imidoylation at carbon of esters, sulfones, sulfoxides, amides, and

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92 nitro compounds via their de protonation in the presence of a strong base followed by nucleophilic substitution of the benzotriazolyl group in imidoylbenzotriazoles 7.1ai Imidoylbenzotriazoles 7.1 have become important as stable alternatives to the corresponding imidoylchlorides. Some of the ma jor synthetic strategies utilized for the preparation of imidoylbenzotriazoles 7.1 include reaction of secondary amides with: benzotriazole and POCl3 in the presence of triethylamine [90CB1545]; triphenylphosphine and 1-chlorobe nzotriazole [04JOC5108]; or 1,1sulfinyldibenzotriazole [ 95H231]. Imidoylbenzotriazoles 1ai were prepared in good yields (50-90%) from the reacti on of secondary amide (1 equiv), oxalyl chloride (1 equiv) and benzotriazole (2 equiv) in the presen ce of pyridine [06JOC3375] (Scheme 7.1). The crude product was chromatographed, after washing with sodium carbonate, on basic alumina (EtOAc/Hex) to give pure imidoylbenzotriazoles 7.1ai R3HN R4O N N HN (COCl)2R3N N R4N N + 7.1 7.1a R3= Me, R4= p -Tol 67% 7.1b R3= Me, R4= iBu 50% 7.1c R3= Bn, R4= pTol 61% 7.1d R3= Ph, R4= iBu 60% 7.1e R3= p -Tol R4=4-OMeC6H4 70% 7.1f R3= Ph, R4=Ph 90% 7.1g R3= furyl, R4= pTol 70% 7.1h R3= thiophene, R4=Me 80% 7.1i R3= Me, R4=CH2(CO(CH)3) 82% Scheme 7.1 Preparation of imidoylbenzotriazoles 7.1ai 7.2 C-Imidoylation of Esters -Enaminoesters 7.2ad were prepared in 77% yiel d from the reaction of the corresponding ester enolate with imidoylbenzotriazoles 7.1 ( Scheme 7.3, Table 7.1 ).

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93 Published C-imidoylations products of esters 7.2 (Scheme 7.2) include (i) efficient reactions of ester enolates w ith fluorinated imidoyl chloride s which appears to be limited to flourinated imidoyl chlorides [97 TL6771, 99OL977, 02JOC4667]; (ii) reaction of malonic esters with alkyl caboximidates, alkyl carboximidothioates, or carboximidic chlorides [83S195], (iii) a single reaction of isocyanides with cyanoester sulfides [85JOC771]; or (iv) condensation of ethyl cy anoacetate with bis(imidoyl)chloride (single example) [00JOC729]. Alternatively, compound 7.2 can be prepared by amination of ketoesters [04JOC6276]. NC O O Et Cl NPh NPh Cl Cl N R1R O O R3R2 R3O O NH R R1R2 O O R2R1NC R3 RNC RNCR3 O O CH3CH3O O H N R1R R1N X R OO H3CCH3OO (i) (iv) (iii)R1=fluorinated alkyl or aryl+ (ii) LDA + R1= SR4+ + + 7.2 R1C(CN)CO2Me R1= Ar, Alk Scheme 7.2 Published methods to C-imidoylation products Imidoylbenzotriazoles 7.1a,b were reacted with enolates generated from corresponding esters 7.3ad by treatment with potassium tert -butoxide at room temperature (Scheme 7.3). Initia l attempts included reacting 1 equiv. of the ester enolate with 1 equiv. of imidoylbenzotriazole 7.1 in the presence of 1.1 equivalence of potassium tert -butoxide. However, the reaction took 36 hrs to reach completion and in some cases, traces of imidoylbenzotriazole s could still be detected. Tr eatment of 2 equiv. of ester 7.3 with 2.5 equiv. of potassium tert -butoxide in THF at room temperature followed by 1 equiv. of imidoylbenzotriazoles 7.1 afforded -enaminoesters 7.2ad in excellent yields

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94 (Table 7.1). The reaction time was tremendous ly reduced to 1 hrs. The reaction was quenched by the addition of water. Extraction of the organic layer using dichloromethane followed by flash colomn chromatography on silica gel afforded pure -enaminoesters 7.2ad in 77-88% yield (Table 7.1). Elemental an alysis and NMR spectral data support the structural assignments of novel 7.2ad The 1H-NMR spectra of -enaminoesters 7.2ad reveal a characteristic broad signa l in the region 11.25.40 ppm which is assigned to N-H proton. T hus, the structures of 7.2ad have a double bond between the ester and the imidoyl carbons (Scheme 7.3). R1O O R2 i) t-BuOK O O R2R1NH R3R4 7.3a-d 7.2a-d ii) 7.1a,b Scheme 7.3 Preparations of -enaminoesters 7.2ad Table 7.1 Preparations of -enaminoesters 7.2ad 7.3 R1 R2 R3 R4 Product Yield% 7.3a Ph Me Me p -Tol 7.2a 88 7.3b Napthyl Me Me p -Tol 7.2b 85 7.3c H i -Pr Me p -Tol 7.2c 82 7.3d H Me Me i -Bu 7.2d 77 7.3 C-Imidoylation of Sulfones -Iminosulfones 7.4ac were prepared in 75 % yi eld from the reaction of imidoylbenzotriazoles 7.1a,f with sulfones 7.5a,b (Scheme 7.5, Table 7.2). Previously, imidoylation of sulfones by imidoyl chloride s succeeded in the case of fluorinated imidoyl chlorides with arylmethyl sulfones (Scheme 7.4) [98JOC6210, 03OL2707]. Other methods describe the C-imidoylation of sulfones 7.4 on the basis of analytical and spectral data, no actual products were reporte d to be isolated [87JOC1417, 89JOC2862]. Other than forming a CC between im idoyl chlorides and sulfones, compound 7.4 can be

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95 prepared from the reaction of linear -ketosulfones with simple amines [03ARK210]. However, linear -ketoalkyl sulfones are not stable under various reaction conditions, thus, dramatically effecti ng the yields [03ARK210]. R N Cl R2S R3 O O R1 + LDA, THF, -78 C S R3 O O N R R1 R= florinated alkyl or aryl R2= Me 7.4 Scheme 7.4 Imidoylation of sulfones by fluorinated imidoyl chlorides Treatment of sulfones 7.5a,b (2 equiv) with potassium tert -butoxide (2.5 equiv) in THF followed by (1 equiv) imidoylbenzotriazoles 7.1a,f afforded -iminosulfones 7.4ac (Scheme 7.5). The progress of the reaction was monitored by TLC. Upon completion of the reaction, water was added and the organi c layer was separated than chromatographed to give pure -iminosulfones 7.4ac 20% yield (Table 7.2). Novel -Iminosulfones 7.4ac were characterized by NMR spectra and elemental analysis. In the 1H-NMR, a signal in the region 4.30.16 is assigned to th e proton attached to the carbon between the sulfone and the imidoyl groups. R1S O R2 i) t-BuOK S O R2R1N R3R4 7.5a,b7.4a-c O O ii) 7.1a,f Scheme 7.5 Preparations of -iminosulfones 7.4ac

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96 Table 7.2. Preparations of -iminosulfones 7.4ac* R1 R2 R3 R4 Product Yield% Ph Ph Me pTol 7.4a 97 Ph Ph Furyl pTol 7.4b 55 Ph Ph Ph i -Bu 7.4c 20 Compounds 7.4b,c were prepared by my colleague Dr. Anamika Singh 7.4 C-Imidoylation of Sulfoxide -Iminosulfoxides 7.6ac were prepared in 48% yi eld from the reaction of imidoylbenzotriazoles 7.1ce with dimethylsulfoxide (Scheme 7.7, Table 7.3). Reported methods for imidoylation products of sulfoxides 7.3 involve (i) reaction of fluorinated imidoyl chlorides with methylsulfinyl carbani on, however, yields were greatly influenced by the nature of the methylsulfinyl ca rbanion [97TL4891, 98JOC6210, 02T3217]; or (ii) reaction of unstable nitriles with methylsulfinyl carbanion (R1=H) (Scheme 7.6) [78TL147]. Me S O R2 RCN R N S O R2R1 Me S O R2 R N Cl R1 (i) (ii) + + LDA LDA 7.6 Scheme 7.6 Literature methods for C-imidoylation of sulfoxides To a stirred solution of sulfoxide (2 equiv.) in THF, t -BuOK (2 equiv.) was added at room temp. and the reaction mixture was stirred for 15 min. Imidoylbenzotriazole (1 equiv.) was added slowly and the mixture wa s allowed to react for 1.5 h at room temp. (TLC control). The reaction mixture was hydrolyzed with water and extracted with chloroform. The aqueous phase was acidified to pH 6-7 by addition of hydrochloric acid and extracted with chloroform, combined organic layer was dried over anhydrous

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97 magnesium sulfate, filtered and evaporated under vacuum. The re sidue was purified by flash column chromatography on silica to afford pure -Iminosulfoxides 7.6ac (Scheme 7.7, Table 7.3) For compound 7.6a only one tautomeric struct ure was isolated in 78% yield. The N-H proton could be seen at 7.2 ppm. However in the case of 7.6c a mixture of both the imine and the enamine tautomeric structures was isol ated. The N-H proton appeared at 7.6 ppm. S O i) t-BuOK S O R2NH R3R4 7.6a-c ii) 7.1c-e R2 R1 R1 Scheme 7.7 Preparations of -iminosulfoxides 7.6ac Table 7.3 Preparations of -iminosulfoxides 7.6ac* R1 R2 R3 R4 Product Yield% Ph Ph Ph Ph 7.6a 78 H Me Me pTol 7.6b 48 H Me p -Tol 4-OMeC6H4 7.6c 71 Compound 7.6b was prepared by my colleague Dr. Anamika Singh 7.5 C-Imidoylation of Amides -Iminoamides 7.7ad were prepared in 35% yield from the reaction of imidoylbenzotriazoles 7.1ad with amides 7.8ac (Scheme 7.8, Table 7.4). CImidoylation of amides is a relatively unexplored area as no example of C-C bond formation for the preparation of -Iminoamides was reported. A single example on the preparation of -iminoamides, relatively similar compounds, from the reaction of imidoyl chlorides with carbamoylsilane under pallad ium(0) catalysis wa s recently reported [05JOC5344].

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98 To amide 7.8ac (1 equiv.) in THF at -78 C was added (1.1 equiv.) nBuLi dropwise over a period of 15 min. The mixture was warmed to -20 C, stirred for 1 h at this temperature, and recooled to -78 C. A solution of imidoylbenzotriazole (1 equiv.) in THF was added to the mixture over a period of 15 min. The reaction mixture was stirred for 2 h at -78 C, then warmed to room temperature overnight. The mixture was quenched with saturated NH4Cl then extracted with dichlorome thane. The organic layer was dried on magnesium sulfate, concentrated, and ch romatographed on silica gel to give pure iminoamides 7.7ad (Scheme 7.8, Table 7.4). NMR data proves that we got the imine tautomeric structure of compounds 7.7ad There was no evidence of the N-H proton, instead a singlet assigned to the proton on the carbon was seen around 3.6ppm. The two Et groups of 7.7a,c showed different signals in H-NMR proving that these compounds are rotamers. The structures of novel 7.7ad were further verified using elemental analysis. R1O N R2 i) nBuLi O N R2R1N R3R4 7.8a-c 7.7a-d ii) 7.1a-d R2 R2 Scheme 7.8 Preparations of -iminoamides 7.7ad Table 7.4 Preparations of -iminoamides 7.7ad* R1 R2 R3 R4 Product Yield% Ph Et Me p -Tol 7.7a 51 Me Me Me iBu 7.7b 48 Ph Et Bn p -Tol 7.7c 75 Me Ph Ph i -Bu 7.7d 35 Compounds 7.7b,d were prepared by my colleague Dr. Anamika Singh

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99 7.6 C-Imidoylation of Nitro Compounds -Nitroimines 7.9ac were prepared in 34% yi eld from the reaction of imidoylbenzotriazoles 7.1ac with nitroethane (Scheme 7.10, Table 7.5).A single example of C-imidoylation product of nitro compounds 7.9 was prepared from the reaction of ethyl nitroacetate with imidoyl chlorides [83UKZ65] (Scheme 7.9). So far, no general procedure for C-imidoylation of nitro compounds has been established. Furthermore, it was hypothesized that 7.9 can be prepared from the rearrangement of N nitroenamine according to infrared a nd NMR spectra evidence [79JOC4116]. EtO O NO2 N Cl Ph SPh Ph N Ph SPh Ph NO2O OEt + 7.9 Scheme 7.9 Reported C-imidoylation pr oduct of a nitro compound To nitroethane (2 equiv.) was added ( 2.5 equiv.) t-BuOK at room temperature followed by imidoylbenzotriazole (1 equiv.) in DMSO.The mixture was heated and stirred at 50 C for 5 hours. Progress of the r eaction was monitored by TLC. Upon completion of the reaction, HCl or acetic acid were used to render the reaction mixture acidic (PH= 6). The organic layer was then extracted with dichloromethane. The combined extracts were dried over anhydr ous magnesium sulfate. The solvent was removed under reduced pressure and the re maining residue was purified by gradient colomn chromatography on silica gel to give pure -nitroimines 7.9ac (Scheme 7.10, Table 7.5). Compounds 7.9ac were isolated as the enamin e tautomeric structure as it was evident from the proton spectra where the N-H peak was detected at 7.2.7 ppm.

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100 There was no evidence for any other tautomeric structure. Elemental analysis was also used to further verify the structures of novel 7.9ac. NO2 i) t-BuOK NO2NH R3R4 7.9a-c ii) 7.1a-c Scheme 7.10 Preparations of -nitroimines 7.9ac Table 7.5 Preparations of -nitroimines 7.9ac R3 R4 Product Yield% Me pTol 7.9a 60 pTol 4-OMeC6H4 7.9b 34 Bn pTol 7.9c 50 7.7 Experimental Section General. Melting points were determined on a hot-stage apparatus and are uncorrected. NMR spectra were recorded in CDCl3, or DMSOd6 with TMS as the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75 MHz). Column chromatography was conducted on silica gel (200 425 mesh) or on basic alumina (60 mesh). Microwave heating was carried out with a single-mode cavity Discover Microwave Synthesizer (CEM Corporation, NC). 7.7.1 General Procedure for the Preparation of -Enaminoesters 7.2ad To a stirred solution of the corres ponding ester (1.2mmol) and potassium tert butoxide (1.5 mmol) in THF ( 20 ml) was added (0.6 mmol) of 1. The mixture was stirred at room temperature for 1 hours. Progress of the reaction was monitored by TLC. After the reaction was complete, water (20 ml) wa s added to the reaction mixture which was then extracted with dichloromethane (3x30 ml ). The combined extracts were dried over anhydrous magnesium sulfate. The solvent wa s removed under reduced pressure and the

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101 remaining residue was purified by gradient column chromatography on silica gel (ethyl acetate/hexenes) to give pure -enaminoesters 7.2ad Methyl-3-[(4-methylphenyl)imino]-2-phenylbutanoate (7.2a). white solid (88%), mp 94 95 C; 1H NMR 11.21 (br s, 1H), 7.27 7.10 (m, 5H), 7.05 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 3.53 (s, 3H), 2.24 (s, 3H), 1.67 (s, 3H); 13C NMR 170.4, 158.1, 138.3, 136.8, 134.8, 132.0, 129.6, 127.9, 126.2, 125.1, 50.8, 41.1, 20.8, 18.4. Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.62; H, 6.94; N, 4.81. Methyl-(Z)-2-(1-naphthyl)-3-(4-toluidino)-2-butenoate (7.2b). Recrystallized from EtOAc-Hexanes to give white solid (85%), mp 111 112 C; 1H NMR 11.25 (br s, 1H), 7.85 7.82 (m, 1H), 7.78 7.75 (m, 1H), 7.72 7.69 (m, 1H), 7.41 7.35 (m, 3H), 7.28 7.25 (m, 1H), 7.05 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 3.42 (s, 3H), 2.24 (s, 3H), 1.53 (s, 3H) ; 13C NMR 170.8, 158.8, 136.8, 135.8, 134.9, 133.8, 133.8, 129.6, 129.6, 128.3, 127.2, 125.8, 125.6, 125.5, 125.1, 95.9, 50.8, 50.8, 20.8, 18.0. Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C, 79.53; H, 6.50; N, 4.35. Isopropyl (Z)-3(4-toluidino)-2-butenoate (7.2c) oil (82%); 1H NMR 11.32 (br s, 1H), 7.08 (d, J = 8.1, 2H), 6.65 (d, J = 8.1 Hz, 2H), 5.18 (septet, J = 6.2 Hz,1H), 2.30 (s, 3H), 1.78 (s, 3H), 1.30 (d, J = 6.2 Hz, 6H); 13C NMR 160.4, 144.3, 131.8, 129.5, 120.9, 115.7, 67.4, 58.8, 37.9, 22.6, 20.8 Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.57; H, 8.08; N, 6.08. Methyl (Z)-3(isobutylamino)-2-butenoate (7.2d) oil (78%); 1H NMR 11.40 (br s, 1H), 4.42 (s, 1H), 3.00 (t, J = 6.3 Hz, 2H), 1.92 (s, 3H), 1.71 1.64 (m, 1H), 1.18 (s, 3H), 0.84 (d, J = 6.7 Hz, 6H); 13C NMR 170.0, 155.9, 47.0, 31.9, 29.7, 28.4, 23.4, 20.1.

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102 7.7.2 General Procedure for the Preparation of -Iminosulfones 7.4ac To a stirred solution of the correspondi ng sulfone (1.2mmol) and potassium tertbutoxide (1.5 mmol) in THF ( 20 ml) was added (0.6 mmol) of 7.1. The mixture was stirred at room temperature for 1 h. Progr ess of the reaction was monitored by TLC. After the reaction was complete, water (20 ml ) was added to the reaction mixture which was then extracted with dichloromethane ( 3x30 ml). The combined extracts were dried over anhydrous magnesium sulfate. The solven t was removed under reduced pressure and the remaining residue was purified by grad ient column chromatography on silica gel (ethyl acetate/hexenes) to give pure -iminosulfones 7.4ac 4-MethylN -[1-methyl-2-phenyl-2-(phenylsulfonyl)ethylidene]aniline (7.4a) oil (97%); 1H NMR 7.50 (d, J = 7.8 Hz, 2H), 7.36 7.19 (m, 8H), 6.89 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 8.1 Hz, 2H), 5.16 (s, 1H), 2.31 (s, 3H), 2.16 (s, 3H); 13C NMR 156.4, 144.8, 135.4, 134.0, 132.6, 130.3, 129.8, 129.7, 128.7, 128.5, 127.0, 124.3, 115.2, 53.5, 41.9, 34.6. Anal. Calcd for C22H21NO2S: C, 72.70; H, 5.82; N, 3.85. Found: C, 72.25; H, 5.87; N, 3.89. 7.7.3 General Procedure for the Preparation of -Iminosulfoxides 7.6ac To a stirred solution of the correspondi ng sulfoxide (0.7 mmol) and THF (10 mL), t -BuOK (0.7 mmol) was added at room temp a nd the reaction mixture was stirred for 15 min. A solution of 7.1 (0.35 mmol) in THF (2 mL) was added slowly by syringe, and the mixture was allowed to react for 1.5 h at r oom temperature (TLC control). The reaction mixture was hydrolyzed with water (10-15 mL) and extracted with chloroform. The aqueous phase was acidified at pH 6-7 by a ddition of hydrochloric acid and extracted with chloroform. Combined organic laye rs were dried over anhydrous magnesium

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103 sulfate, filtered and evaporated under vac uum. The residue was purified by flash column chromatography on silica using hexanes/Et OAc(9/1) as an eluent to give pure iminosulfoxides 7.6ac N -[ (E)-1,2-diphenyl-2(phenyl sulfinyl)ethylidene]aniline (7.6a) oil (78%); 1H NMR 7.84 (d, J = 7.3 Hz, 5H), 7.65 (d, J = 8.2 Hz, 4H), 7.55 7.44 (m, 5H), 7.37 (t, J = 7.8 Hz, 4H), 7.16 (t, J = 7.4 Hz, 3H); 13C NMR 165.7, 148.8, 137.9, 135.0, 133.7, 132.6, 131.8, 130.8, 129.1, 128.8, 128.7, 128.6, 127.0, 124.6, 120.2, 62.8. Anal. Calcd for C26H21NOS: C, 78.95; H, 5.35; N, 3.54. Found: C, 79.24; H, 5.62; N, 3.88. N -(4-Methoxyphenyl)-N-[(Z)-1-(4-met hylphenyl)-2-(methylsulfinyl)-1ethenyl]amine (7.6c). Recrystallized from EtOAc/hexane to give white crystals (71%), mp 137 139 C; 1H NMR (mixture of tautomers) 7.74 (d. J = 8.1 Hz, 2H), 7.58 (brs, 1H), 7.51 (d. J = 8.7 Hz, 2H), 7.25 (d. J = 9.0 Hz, 2H), 7.15 (d. J = 8.1 Hz, 2H), 6.97 (d. J = 8.1 Hz, 2H), 6.90 (d. J = 9.0 Hz, 2H), 6.69 (d. J = 9.0 Hz, 2H), 6.57 (d. J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H)., 1.61 (s, 6H), 1.41 (s, 1H), 1.27 (s, 1H).; 13C NMR (mixture of tautomers) 157.7, 156.5, 142.2, 139.1, 132.0, 131.1, 129.5, 129.4, 128.5, 126.9, 122.3, 122.0, 114.2, 114.0, 55.5, 55.4, 28.3, 21.5, 21.3.. Anal. Calcd for C17H19NO2S: C, 67.74; H, 6.35; N, 4.65. Found: C, 67.22; H, 6.69; N, 4.58. 7.7.4 General Procedure for the Preparation of -Iminoamides 7.7ad To (0.8 mmol) of the correspondi ng amide in 15 ml THF at -78 C was added (0.88 mmol) n BuLi dropwise over a period of 15 minu tes. The mixture was warmed to -20 C, stirred for 1 h at this temperat ure, and then recooled to -78 C. A solution of 7.1 (0.8 mmol) in 10 ml THF was added to the mi xture over a period of 15 min. The reaction mixture was stirred for 2 h at -78 C, then warmed to room temperature overnight. The

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104 mixture was quenched with 20ml saturated NH4Cl and then extracted with (3x50ml) dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under vacuum, and chromatograp hed on silica gel (EtOAc/ Hex gradient) to give pure -iminoamides 7.7ad N,N -Diethyl-3-[ (4-methylphenyl)imino] -2-phenylbutanamidehydrochloride (7.7a). oil (51%); 1H NMR 7.31 (d, J = 8.4 Hz, 2H), 7.23 7.13 (m, 5H), 6.97 (d, J = 8.2 Hz, 2H), 3.61 (s, 1H), 3.30 (q, J = 7.1 Hz, 2H), 3.22 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H), 1.98 (s, 3H), 1.06 0.98 (m, 6H) ; 13C NMR 170.2, 168.8, 135.7, 135.2, 133.3, 129.1, 128.5, 126.6, 120.0, 119.7, 42.3, 40.6, 40.1, 24.0, 20.6, 14.0, 12.8. Anal. Calcd for C42H53ClN4O2: C, 74.04; H, 7.84; N, 8.22. Found: C, 73.82; H, 8.08; N, 8.46. N,N -Diethyl-3-[ (4-methylphenyl)imino]2,4-diphenylbutanamide hydrochloride (7.7c). oil (75%); 1H NMR 7.80 (br s, 1H), 7.34 7.22 (m, 12H), 7.05 (d, J = 8.2 Hz, 1H), 3.71 (s, 2H), 3.67 (s, 1H), 3.40 (q, J = 7.1 Hz, 2H), 3.30 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.15 1.07 (m, 6H) ; 13C NMR 170.2, 169.2, 135.3, 134.7, 133.7, 129.8, 129.3, 129.2, 128.9, 128.5, 127.4, 127.2, 126.6, 119.9, 44.4, 42.3, 40.8, 40.1, 20.7, 14.1, 12.8. Anal. Calcd for C27H31N2OCl: C, 74.55; H, 6.95; N, 6.44. Found: C, 74.49; H, 7.47; N, 5.80. 7.7.5 General Procedure for the Preparation of -Nitroimines 7.9ac To (1.2 mmol) of the corresponding nitro compound was added (1.5 mmol) potassium tert-butoxide at room te mperature followed by (0.6 mmol) of 7.1 in DMSO (10 ml). The mixture was heated and stirred at 50 C for 5 h. Progress of the reaction was monitored by TLC. Upon the completion of the reaction, HCl or acetic acid was used to render the reaction mixture acidic. The or ganic layer was then extracted with

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105 dichloromethane (3x30 ml). The combined extracts were dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining residue was purified by grad ient colomn chromatogr aphy on silica gel (ethyl acetate/hexenes) to give pure -nitroimines 7.9ac 4-MethylN -[ (Z)-1-methyl-2-nitropropylidene]aniline (7.9a) oil (60%); 1H NMR 7.71 (br s,1H), 7.30 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 2.32 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H); 13C NMR 168.6, 135.4, 133.7, 129.3, 120.0, 70.4, 24.3, 20.8, 16.3. Anal. Calcd for C22H30N4O5: C, 61.38; H, 7.02; N, 13.01. Found: C, 61.96; H, 7.28; N, 11.32. N -(4-Methoxyphenyl)-N-[(Z)-1-(4-methyl phenyl)-2-nitro-1-propenyl]amine (7.9b). oil (34%); 1H NMR 7.54 (br s,1H), 7.14 (d. J = 8.1 Hz, 2H), 7.06 (d. J = 8.1 Hz, 2H), 6.72-6.62 (m, 4H), 3.71 (s, 3H), 2.35 (s, 3H), 1.98 (s, 3H); 13C NMR 157.4, 139.9, 131.1, 130.4, 129.8, 129.5, 129.2, 128.6, 125.6, 114.0, 55.3, 21.7, 16.2. Anal. Calcd for C34H36N4O7.1/2H2O: C, 66.43; H, 6.23; N, 9.11. Found: C, 66.84; H, 6.45; N, 9.69. N -[(Z)-1-Benzyl-2-nitro-1-propenyl]-N-(4-methylphenyl)amine (7.9c). oil (50%); 1H NMR 7.37-7.26 (m, 7H), 7.07 (d, J = 8.4 Hz, 2H), 3.73 (s, 2H), 2.28 (s, 3H), 1.25 (s, 3H); 13C NMR 168.9, 135.0, 134.5, 134.0, 129.7, 129.5, 129.3, 129.1, 127.5, 119.9, 44.7, 29.7, 20.8. Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C, 71.98; H, 6.62; N, 9.85.

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120 BIOGRAPHICAL SKETCH Niveen Khashab was born on July 13, 1981, in Beirut, Lebanon. She worked under the supervision of professor Makhloof Haddadin at the Ameri can University of Beirut, where she received her Bachelor of Science in June 2002. She joined the University of Florida Center of Heterocyclic Compounds supe rvised by Professor Alan R. Katritzky in December 2002, and started her Ph.D program in the Chemistry Department of the University of Florida in January 2003.


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Table of Contents
    Title Page
        Page i
        Page ii
    Dedication
        Page iii
    Acknowledgement
        Page iv
    Table of Contents
        Page v
        Page vi
        Page vii
    List of Tables
        Page viii
        Page ix
    List of Schemes
        Page x
        Page xi
        Page xii
    Abstract
        Page xiii
        Page xiv
    Introduction
        Page 1
        Page 2
        Page 3
    Benzotriazolyl-mediated 1,2-shifts of electron-rich heterocycles
        Page 4
        Page 5
        Page 6
        Page 7
        Page 8
        Page 9
        Page 10
        Page 11
        Page 12
        Page 13
        Page 14
        Page 15
        Page 16
        Page 17
        Page 18
        Page 19
        Page 20
        Page 21
    The preparation of N, N', N"-trisubstituted guanidines
        Page 22
        Page 23
        Page 24
        Page 25
        Page 26
        Page 27
        Page 28
        Page 29
        Page 30
        Page 31
        Page 32
        Page 33
        Page 34
        Page 35
        Page 36
        Page 37
        Page 38
        Page 39
        Page 40
        Page 41
        Page 42
        Page 43
        Page 44
        Page 45
        Page 46
    Preparations of substituted thiosemicarbazides and N-hydroxythioureas
        Page 47
        Page 48
        Page 49
        Page 50
        Page 51
        Page 52
        Page 53
        Page 54
        Page 55
    Synthesis of mono- and symmetrical di- N-hydroxy - and N-amino-guanidines
        Page 56
        Page 57
        Page 58
        Page 59
        Page 60
        Page 61
        Page 62
        Page 63
        Page 64
        Page 65
        Page 66
        Page 67
        Page 68
        Page 69
        Page 70
        Page 71
        Page 72
        Page 73
        Page 74
    Microwave assisted preparations of amidrazones and amidoximes
        Page 75
        Page 76
        Page 77
        Page 78
        Page 79
        Page 80
        Page 81
        Page 82
        Page 83
        Page 84
        Page 85
        Page 86
        Page 87
        Page 88
        Page 89
        Page 90
    C-imidoylation of esters, sulfones, sulfoxides, amides and nitro compounds
        Page 91
        Page 92
        Page 93
        Page 94
        Page 95
        Page 96
        Page 97
        Page 98
        Page 99
        Page 100
        Page 101
        Page 102
        Page 103
        Page 104
        Page 105
    References
        Page 106
        Page 107
        Page 108
        Page 109
        Page 110
        Page 111
        Page 112
        Page 113
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        Page 118
        Page 119
    Biographical sketch
        Page 120
Full Text












NOVEL GUANYLATING AND IMIDOYLATING REAGENTS


By

NIVEEN M. KHASHAB


















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

UNIVERSITY OF FLORIDA


2006


































Copyright 2006

by

Niveen M. Khashab
































I dedicate this work to my grandmother Samia Al-Halabi, my mother Wafaa Elias and
my father Mohammad Ali Khashab. This is also for my sisters Nermeen Iskandarani and
Nadine Iskandarani, my brothers Mohammad Iskandarani and Yehya Yasine, and finally
my great husband Hussam Khatib. I never would have achieved any of this without their
love, support, and words of wisdom.















ACKNOWLEDGMENTS

I am greatly indebted to many people in the preparation of this manuscript. First, I

am fortunate to have had the opportunity of working for Prof. Alan R. Katritzky, whose

drive and dedication compel those around him to strive for higher goals. I thank my

committee members (Dr. Liza McElwee-White, Dr. Kenneth Wagener, Dr. Kenneth

Sloan, and Dr. David Powell) for their helpful suggestions and instructions. I would like

to thank all members in Dr. Katritzky's group, my colleagues, and my dear friends: Dr.

Rachel Witeck, Dr. Anamika Singh, Megumi Yoshioka, Danniebelle Haase, Robert

Johnson, and Andrew Hartman.

Very special thanks go to Dr. Makhloof Haddadin, Dr. Moussa Nazer, Dr. Jim

Deyrup, Dr. Steven Benner, Lori Clark, Elizabeth Cox, Dr. Sergey Bobrov, Gwen

McCann, and all my fellow chemistry Gators at the University of Florida.
















TABLE OF CONTENTS



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

LIST OF TABLES .. ................... ............ ......... .............. viii

L IST O F SC H E M E S ............................................................................ ............. ............... x

ABSTRACT ............................................ ............. ................. xiii

CHAPTER

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

2 BENZOTRIAZOLYL-MEDIATED 1,2-SHIFTS OF ELECTRON-RICH
H E TE R O C Y C L E S ............................................................... ................. ...... ..4

2 .1 In tro d u ctio n ...................................................................................................... .. 4
2.2 R results and D discussion ................................................................... ............... 5
2 .3 C o n clu sio n ..................................................................................................... 8
2 .4 E xperim ental Section ...................................................................... ...............9...

3 THE PREPARATION OF N, N', N" TRISUBSTITUTED GUANIDINES .............22

3 .1 In tro d u ctio n ........................................................................................................... 2 2
3.2 R results and D iscu ssion ......................................... ........................ ................ 25
3 .3 C o n c lu sio n ............................................................................................................ 2 9
3.4 E xperim ental Section .................2.... .9...... ..... ......................................... 29
3.4.1 General Procedure for the Preparation of Compounds 3.10a-g.............. 30
3.4.2 General Procedure for the Preparation of Compounds 3.11a-f ............31
3.4.3 General Procedure for the Preparation of Compounds 3.12a-h ............33
3.4.4 General Procedure for the Preparation of Compounds 3.13a-1 .................35
3.4.5 General Procedure for the Preparation of Compounds 3.15a-e.............39
3.4.6 General Procedure for the Preparation of Compounds 3.16a-e.............40
3.4.7 General Procedure for the Preparation of Compounds 3.17a-f ............42
3.4.8 General Procedure for the Preparation of Compounds 3.18a-h ............44

4 PREPARATIONS OF SUBSTITUTED THIOSEMICARBAZIDES AND N-
H Y D R O X Y TH IO U R E A S ..........................................................................................47









4 .1 In tro d u ctio n ...........................................................................................................4 7
4 .2 R results and D iscu ssion ......................................... ........................ ................ 49
4 .3 C o n c lu sio n ............................................................................................................5 1
4 .4 E xperim ental Section ........................................... ......................... ............... 52

5 SYNTHESIS OF MONO- AND SYMMETRICAL DI- N-HYDROXY- AND N-
A M IN O G U A N ID IN E S ....................................................................... ................ 56

5 .1 In tro d u ctio n ........................................................................................................... 5 6
5.2 R results and D iscu ssion .................................................................... ................ 62
5.2.1 Preparation of Unsymmetrical N-Hydroxyguanidines 5.13a-j............... 63
5.2.2 Preparation of Unsymmetrical N-Aminoguanidines 5.14a-h.................64
5.2.3 Preparation of Symmetrical Dihydroxyguanidine 5.16 and
D iam inoguanidine 5.17 ...................................... ...................... ................ 66
5 .3 C o n clu sio n ............................................................................................................ 6 7
5 .4 E x p erim ental S section ................................ ................. ......................................... 67
5.4.1 General Procedure for the Preparation of Compounds 5.13a-j ..............68
5.4.2 General Procedure for the Preparation of Compounds 5.14a-h .............70
5.4.3 Preparation of N,N-Diisopropyl-5-phenyl-l-(2-pyridinyl)-lH-1,2,4-
triazol-3-am ine 5.15 .................................................................. .. .... ............ 72
5.4.4 General Procedure for the Preparation of Compounds 5.16 and 5.17........73
5.4.5 Preparation of N'-Hydroxy-lH-1,2,3-benzotriazole-l-carboximidamide
5 .1 8 ............................................................................. .. ............................. 7 4
5.4.6 General Procedure for the Preparation of Compound 5.19 .....................74

6 MICROWAVE ASSISTED PREPARATIONS OF AMIDRAZONES AND
A M ID O X IM E S ................................................... ............................................... 75

6.1 Introduction to A m idrazones ........................................................... ................ 75
6.2 Introduction to A m idoxim es............................................................ ................ 77
6.3 R results and D iscu ssion ......................................... ........................ ............... 80
6.4 Am inoam idoxim es and D iam idoxim es ........................................... ................ 84
6 .5 C o n c lu sio n ............................................................................................................ 8 5
6 .6 E xperim ental Section .................................................................... ... ............... 85
6.6.1 General Procedure for the Preparation of Amidrazones la-h ...................85
6.6.2 General Procedure for the Preparation of Amidoximes 6.2a-h .................86
6.6.3 General Procedure for the Preparation of 6.4a-d ..................................... 88
6.6.4 General Procedure for the Preparation of 6.6 and 6.7 ................................89

7 C-IMIDOYLATION OF ESTERS, SULFONES, SULFOXIDES, AMIDES AND
N ITR O C O M PO U N D S ..................................................................... ................ 91

7 .1 In tro d u ctio n ........................................................................................................... 9 1
7.2 C -Im idoylation of E sters........................................ ....................... ................ 92
7.3 C -Im idoylation of Sulfones ............................................................. ................ 94
7.4 C -Im idoylation of Sulfoxide............................................................ ................ 96
7.5 C -Im idoylation of A m ides ...................................... ...................... ................ 97









7.6 C-Imidoylation of Nitro Compounds..................................................... 99
7.7 E xperim ental Section .............................................................. ..... ................ 100
7.7.1 General Procedure for the Preparation of P-Enaminoesters 7.2a-d.........100
7.7.2 General Procedure for the Preparation of 0-Iminosulfones 7.4a-c..........102
7.7.3 General Procedure for the Preparation of 0-Iminosulfoxides 7.6a-c.......102
7.7.4 General Procedure for the Preparation of P-Iminoamides 7.7a-d .........103
7.7.5 General Procedure for the Preparation of a-Nitroimines 7.9a-c............104

LIST O F R EFEREN CE S .. .................................................................... ............... 106

BIOGRAPH ICAL SKETCH ................. ............................................................... 120















LIST OF TABLES


Table page

2.1 Preparation of interim ediates 2.3 and ketones 2.4.................................. ...............7...

2.2 Preparation of interim ediates 2.3 and ketones 2.4.................................. ...............8...

3.1 Preparation of guanylating reagents 3.11a-f and 3.13a-1....................................27

3.2 Preparation of symmetrical and cyclic trisubstituted guanidines 3.15a-e and
3 .1 6 a e .................................................................................................................. ... 2 8

3.3 Preparation of substituted unsymmetrical guanidines 3.17a-f and 3.18a-h ...........30

4.1 Preparation of substituted and unsubstituted thiosemicarbazides* .......................50

4.2 Preparation of substituted and unsubstituted N-hydroxythioureas *......................51

5.1 Preparation of unsymmetrical N-hydroxyguanidines 5.13a-j ...............................64

5.2 Synthesis ofN-am inoguanidines 5.14a-h ............... .............. ..................... 66

5.3 Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17.....................66

6.1 The eight class I am idrazones existing as 6.1A .................................. ................ 78

6.2 Five sub-classes of am idoxim es 6.2A ................................................. ................ 81

6.3 Four sub-classes of am idoxim es 6.2B ....................... .................... .....................82

6.4 Preparation of amidrazones 6.1a-h from 6.3b-d,f* ..................... ..................... 83

6.5 Preparation of 1,2,4-triazoles 6.4a-d from 6.3a,b,d ..................... ..................... 83

6.6 Preparation of am idoxim es 6.2a-h* ......................... ........................... ............. 84

7.1 Preparations of P-enam inoesters 7.2a-d ............................................. ................ 94

7.2 Preparations of 0-im inosulfones 7.4a-c*............................................ ................ 96

7.3 Preparations of 0-im inosulfoxides 7.6a-c*......................................... ................ 97









7.4 Preparations of 0-im inoam ides 7.7a-d* ............................................. ................ 98

7.5 Preparations of a-nitroimines 7.9a-c ....... ... ........................ 100
















LIST OF SCHEMES


Scheme page

1.1 Properties of a benzotriazole group....................................................... ...............1...

1.2 Halogen analogues of a benzotriazole group a to an amino or ether functionality....2

2.1 Mechanism of zinc bromide promoted oxirane ring-closure-ring opening
rearran g em en t ..................................................................................................... 4

2.2 Preparation of intermediates 2.3a-m and ketones 2.4a-i, k-m ............... ............... 6

3.1 Common methods for the preparation of guanidines 3.3 .............. ..................... 23

3.2 Benzotriazole-based guanylating reagents .................................... ..................... 24

3.3 Preparation of guanidines utilizing benzotriazole-based guanylating reagents .......25

3.4 Preparation of novel guanylating reagents 3.11a-f and 3.13a-1 ..............................26

3.5 Attempts to prepare 3.11 and 3.13 with R= benzyl ....................... ..................... 27

3.6 Preparation of symmetrical and cyclic trisubstituted guanidines..........................28

3.7 Preparation of substituted unsymmetrical guanidines.........................................29

4.1 Common methods of preparation of thiosemicarbazides....................................48

4.2 Common methods of preparation of N-hydroxythioureas...................................48

4.3 Synthesis of di and trisubstituted thioureas 4.2................................... ................ 49

4.4 Synthesis of thiosemicarbazides 4.5 and N-hydroxythioureas 4.6........................49

5.1 T autom erism of guanidines ....................................... ....................... ................ 57

5.2 Literature syntheses of N-hydroxyguanidines 5.2 ......................... ..................... 59

5.3 Literature syntheses of substituted aminoguanidines 5.4 ..................................... 60

5.4 Tautomerism of hydroxyguanidines and aminoguanidines ................................61









5.5 Synthesis of benzotriazole intermediates 5.8 and 5.10. ......................................62

5.6 Synthesis of benzotriazole intermediates 5.11a,b and substituted guanidines
5 .1 2 ....................................................................................................... . ....... .. 6 3

5.7 Preparation of unsymmetrical N-hydroxyguanidines 5.13a-j ...............................64

5.8 Synthesis of N-aminoguanidines 5.14a-h ............... .............. ..................... 65

5.9 Synthesis of trisubstituted 1,2,4-triazole 15 ........................................ ................ 65

5.10 Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17.....................66

5.11 Synthesis of N-hydroxy-N'-aminoguanidine 5.19 .............................................67

6.1 Preparative routes to am idrazones....................................................... ................ 76

6.2 Tautom eric form s of am idrazones....................................................... ................ 76

6.3 Tautom eric form s of am idoxim es ....................................................... ................ 77

6.4 Preparative routes to amidoximes of type 6.2A..................................................79

6.5 Preparative routes to amidoximes of type 6.2B ..................................................79

6.6 Reactions of imidoylbenzotriazoles with hydrazines and hydroxylamines .............82

6.7 Preparative routes to am inoam idoxim es ............................................. ................ 84

6.8 Preparation of aminoamidoxime 6.6 and diamidoxime 6.7 .................................... 85

7.1 Preparation of imidoylbenzotriazoles 7.1a-i ......................................................92

7.2 Published methods to C-imidoylation products ..................................................93

7.3 Preparations of 3-enam inoesters 7.2a-d ............................................. ................ 94

7.4 Imidoylation of sulfones by fluorinated imidoyl chlorides.................................95

7.5 Preparations of 0-im inosulfones 7.4a-c.............................................. ................ 95

7.6 Literature methods for C-imidoylation of sulfoxides.........................................96

7.7 Preparations of 0-im inosulfoxides 7.6a-c........................................... ................ 97

7.8 Preparations of 0-im inoam ides 7.7a-d ............................................... ................ 98









7.9 Reported C-imidoylation product of a nitro compound ................ ..................... 99

7.10 'Preparations of a-nitroimines 7.9a-c............... .........................1... 00















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

NOVEL GUANYLATING AND IMIDOYLATING REAGENTS

By

Niveen M. Khashab

December 2006

Chair: Alan R. Katritzky
Major Department: Chemistry

The theme of this work is development of novel methodologies for the preparation

of a variety of synthetic targets. Chapter 1 provides a general overview of the

methodologies employed in the preparation of the target compounds and includes an

overview of cognate work carried out in these fields.

Chapter 2 describes the regioselective 1,2-shift of an electron rich heterocyclic

group in the presence of competitive alkyl and aryl groups. We have investigated

benzotriazole-mediated one carbon insertions in heteroaryl ketones and reported the

successful synthesis of homologated ketones via 1,2-shift of the diverse heterocyclic

groups or phenyl group.

In chapter 3, we have extended benzotriazole-based guanylation to include two new

reagent classes (bis-benzotriazol-1-yl-methylene)amines and benzotriazole-1-

carboxamidines, which allow for the facile preparation of N,N',N"-tisubstituted

guanidines.









Applications of the thioacylating reagent (RNHCSBt) in the preparation of

thiosemicarbazides and hydroxythioureas are described in Chapter 4. A new route for the

preparation of thiosemicarbazides and N-hydroxythioureas of different substitution

patterns has been established. This methodology provides easy access to this class of

compounds with excellent yields without any obvious limitations.

A continuation to the work described in chapter 3 is presented in chapter 5,

comprising our reports of the synthesis of mono- and symmetrical di- N-hydroxy- and N-

aminoguanidines. N-Hydroxyguanidines were prepared in high yield by the reaction of

guanylating reagents with hydroxylamine hydrochloride in refluxing toluene for 4-12hrs

in the presence of triethylamine. Similarly, N-aminoguanidines were prepared by the

reaction of guanylating reagents with hydrazines.

In Chapter 6, microwave assisted synthesis of amidrazones and amidoximes is

carried out utilizing imidoylbenzotriazoles. We presented a simple, efficient, and broadly

applicable synthetic methodology for the preparation of these two classes of compounds

under microwave conditions via the nucleophilic attack on imidoylbenzotriazoles by

hydrazines or hydroxylamines.

The last chapter of this dissertation (Chapter 7) describes the investigation of the C-

imidoylation of esters, sulfones, sulfoxides, amides and nitro compounds.Access to these

compounds is provided by deprotonation of the corresponding parent using a base

followed by reactions with C-imidoylbenzotriazoles under mild conditions. The presented

synthetic methadology affords imidoylation of the desired material through a C-C bond

formation in good yields under mild conditions.














CHAPTER 1
GENERAL INTRODUCTION

1H-Benzotriazole is an excellent synthetic auxiliary [98CR409] which acts as a

leaving group, an electron-withdrawing group, and even as an electron-donating group

(Scheme 1.1). As another aspect of a good auxiliary, benzotriazole is readily removed

from the reaction mixture by simply washing with base due to the acidity (pKa 8.2) of

1H-benzotriazole. Moreover, 1H-benzotriazole is an inexpensive, stable compound that is

soluble in common organic solvents such as ethanol, benzene, chloroform, and DMF.

N N I N NN
"NN "N



R ) X H X
1.1 1.2 1.3
Leaving group Activating CH Electron donor
to proton loss

Scheme 1.1 Properties of a benzotriazole group

Benzotriazole is comparable in many ways to a halogen substituent because of its

leaving abilities, but it should be compared to a tame halogen substituent. Compounds

with a benzotriazole group a to an amino or ether functionality 1.2 (X= NR2, OR) are

stable, nonvolatile, easily prepared, and versatile, while their halogen analogues 1.4 and

1.6 (Scheme 1.2) are often physiologically dangerous and too reactive to be conveniently

used as reagents.

In the course of investigations on the use of benzotriazole derivatives in organic

synthesis, it has been found that the benzotriazolyl moiety is both a good anion-









stabilizing group and a good leaving group. These properties, coupled with the ready

availability of benzotriazole derivatives, suggested its potential to provide general and

efficient carbon-insertion methods. In Chapter 2, benzotriazole-mediated one-carbon

insertions in heteroaryl ketones to synthesize a novel series of homologated ketones via a

1,2 shift rearrangement are described.

R2 ci R2 H R2'O

R2 R1 R2 R1 R1 CI
1.4 1.5 1.6

Scheme 1.2 Halogen analogues of a benzotriazole group a to an amino or ether
functionality

In Chapter 3, two novel guanylating reagents were prepared following

benzotriazole methodology. Using these reagents, a series of symmetrical and

unsymmetrical trisubstitued guanidines was prepared in 67-99% yield.

Thiocarbamoylbenzotriazoles, novel reagents developed by our group as stable

isothiocyanate equivalents, were reacted by earlier members of our group with different

amines to give di- and trisubstituted thioureas [04JOC2976]. Now in Chapter 4, the utility

of thiocarbamoyl-benzotriazole was expanded by reacting it with hydrazines and N-

hydroxylamines of various substitution patterns to give thiosemicarbazides and N-

hydroxythioureas, respectively, in 73-91% yield.

In Chapter 5, the utility of novel guanylating reagents (bis-benzotriazol-1-yl-

methylene)amines and benzotriazole-1-carboxamidines was expanded to include the

preparation of mono- and symmetrical di- N-hydroxy- and N-aminoguanidines in 22-91%

yield.









Microwave-assisted synthesis of amidrazones and amidoximes is described in

Chapter 6. Imidoylbenzotriazoles were reacted with various hydazines and

hydroxylamines under microwave radiation and mild conditions to give the desired

amidrazones and amidoximes, respectively, in 65-85% yield.

In Chapter 7, preparation of C-imidoylated esters, sulfones, sulfoxides, amides, and

nitro compounds is described. The procedure includes deprotonation of the desired group

using a base followed by reaction with C-imidoylbenzotriazoles under mild conditions.

This synthetic methodology affords imidoylation of the desired material through a C-C

bond formation.














CHAPTER 2
BENZOTRIAZOLYL-MEDIATED 1,2-SHIFTS OF ELECTRON-RICH
HETEROCYCLES

2.1 Introduction

In preceding work [95JA12015, 95TL841, 96JOC7564, 96JOC7571], an efficient

benzotriazole-mediated insertion of single carbon atoms, carrying 0-, S-, N-linked, aryl

and heteroaryl substituents, into compounds adjacent to a carbonyl group to give a-

alkoxyalkyl-, a-(alkylthio)alkyl-, a-(carbazol-9-yl)alkyl-, a-aryl- and a-heteroaryl-

substituted ketones has recently been described. One possible mechanism of these

rearrangements involves zinc bromide-promoted oxirane ring-closure-ring-opening

followed by the migration of the group that can best stabilize an electron deficiency

(Scheme 2.1).


X 1) n-BuLi 0-B R ZnBr2 X1 __ ,
BRR ZnBr2- X R-" X
Bt R2) RI Bt R R R2 R R

R2

Scheme 2.1 Mechanism of zinc bromide promoted oxirane ring-closure-ring opening
rearrangement

Application of a similar procedure for the regioselective 1,2-shift of an electron-

rich heterocyclic group in the presence of competitive alkyl or aryl groups is of

considerable utility. Such selective shifts were relatively unexplored; known pinacol-type

rearrangements provide few examples of the selective migration of 2-furyl

[87JCS(P1)225, 92CL81, 93JOC5944], 2-thienyl [87JCS(P1)225, 99EJOC497,









02TL6937, 03S141], their benzoanalogues [02TL6937, 03S141], or 2- and 3-indolyl

groups [02TL6937, 03S141].

To explore the ability of electron-rich heterocycles to migrate in the presence of the

alkyl and aryl groups, we have now investigated benzotriazole-mediated one carbon

insertions in heteroaryl ketones 2.2a-m (Schemes 2.1 and 2.2) and herein report the

successful synthesis of homologated ketones 2.4a-i,k-m via 1,2-shift of the diverse

heterocyclic groups or phenyl group shown in Table 2.1.

2.2 Results and Discussion

Treatment of compound 2.1 with n-BuLi (1 equiv.) at -78 C under a nitrogen

atmosphere in THF for 1 h, followed by a reaction with the corresponding ketones 2.2a-

m (1 equiv.) at -78 C for 1 h, gave intermediates 2.3a-m in 40-98% yields (Scheme

2.1, Table 2.1). The intermediates 2.3a-m were isolated as 1:1 mixtures of two

diastereoisomers which were generally used for the next step without separation.

However, in certain cases the pure diastereomeric forms of 2.3a-m were isolated by

recrystallization of the corresponding crude products from acetone-diethyl ether; also

chromatography provided enriched samples of each diastereomer. The structures of

compounds 2.3a-m were supported by their 1H NMR and 13C NMR spectra (see

experimental section).

All rearrangements were accomplished in the presence of a threefold molar excess

of anhydrous zinc bromide. For intermediates 2.3a and 2.3b, the 1,2-shift of the 2-, and

3-thienyl groups was effected by refluxing in 1,2-dichloroethane for 20 h to give ketones

2.4a and 2.4b in 61-64% yields (Scheme 2.1, Table 2.1). However, the same reaction

conditions applied for the rearrangement of furyl analog 2.3d were ineffective for the









selective transformation to the homologous ketone 2.4d. However, selective 1,2-

migration of the 2-furyl group was effected by the reaction of the anion of compound

2.3d in THF at 130 C (sealed tube) to give ketone 2.4d in 20% yield (Scheme 2.2).

Heating of compound 2.3d in 1,1,2,2-tetrachloroethane at 140 C for Ih was found

to be efficient for the 1,2-migration of the 2-furyl group to give ketone 2.4d in 40% yield

(Scheme 2.2, Table 2.1). Attempted 1,2-shift of 1-methylindol-3-yl group in 2.3c under

various conditions led to complex mixtures from which ketone 2.4c was isolated in 7%

yield, apparently due to concurrent processes of dehydration or benzotriazole elimination

[04JOC303] (Scheme 2.2, Table 2.1).

MeS i) n-BuLi
\ i i) O rn
i 2.2a-m / R SMe

N\I R R1 N N SMe ZnBr2
N 78 OC, THF N OH R
2.1 R" 2.3a-m 2.4a-i,k-m


i) n-BuLi \ ZnBr2 R SMe
2.3c,d l N SMe- TH
-78 OC, THF N -- THF
N RI OLi sealed tube
R Mei 2.4c,d
Me

Scheme 2.2 Preparation of intermediates 2.3a-m and ketones 2.4a-i, k-m

Initial attempts to rearrange the lithium alcoholates of 2.3e,f failed. The rearrangements

of adducts 2.3e-i,k-m were achieved optimally in 1,1,2,2-tetrachloroethane at 85 oC or 140 C

to give ketones 2.4e-i,k-m in 23-71% yields (Scheme 2.2, Table 2.1 and 2.2). Unfortunately,

attempts to induce 1,2-shift of the 1-methylindol-3-yl group in 2.3j under various conditions

led to complex mixtures.









Table 2.1 Preparation of intermediates 2.3 and ketones 2.4.
2.2 2.3 2.4
R R1 yield,a yield, % / solvent / temp. / time

/ Me 82 60 / ClCH2CH2Cl / 850C / 20h
S

/S \Me 85 64 / CCH2CH2Cl / 85C/20h

Me
N Me 82 7 / THF / 100C / 15h
Sealed tube


Me 72 40 / Cl2CHCHCl2 / 1400C / lh


I / Me 75 40 / Cl2CHCHCl2/ 1400C / lh


I / Me 94 40 / Cl2CHCHCl2 / 140C / lh


Me 40 71 / Cl2CHCHCl2 / 1400C / 10
mm
a) Yields of mixtures of diastereomers.

Significantly, the heteroaromatic group of adducts 2.3a-g adjacent to the

hydroxylated carbon was found in all cases to shift more rapidly than the methyl group.

This resulted in the formation of ketones 2.4a-g. According to the 1H NMR analysis, in

compounds 2.4a-g the protons of the methyl group and the proton of the methine group

each resonate as singlets and no spin-spin coupling between of CH3 and CH was

observed. This precludes migration of the methyl group.

For the intermediates 2.3h,i,k-m, migration of the phenyl group occurred rather

than the corresponding heteroaromatic groups to give ketones 2.4h,i,k-m.The analysis of

the 1H NMR data for ketones 2.4a-g and 2.4h,i,k-m showed the low-field shift of









signals of the methine proton for 2.4h,i,k-m (4.55-4.80 ppm) around 1 ppm in

comparison with signals of the methine proton for 2.4a-g (5.57-5.80 ppm). Moreover,

for ketone 2.4k the irradiation of the methine proton at 5.59 ppm resulted in clear NOE

effect on the ortho-phenyl protons at 7.97-7.95 ppm. The structures of compounds

2.4h,i,k-m were supported by their 1H NMR and 13C NMR spectra.

Table 2.2 Preparation of intermediates 2.3 and ketones 2.4
2.2 2.3 2.4
R R1 yield, %a yield, % / solvent / temp. / time

h Ph / 75 40 / Cl2CHCHCl2 / 1400C / lh



0
i Ph 40 23 / Cl2CHCHCl2 / 85C / 12h

Me
j Ph / 72 Complex mixture



k Ph /70 46 / Cl2CHCHCl2/ 1400C / lh


1 Ph /98 40 / Cl2CHCHCl2 / 1400C / lh


m Ph / 50 58 / Cl2CHCHCl2/1400C / 30 min
S
a) Yields of mixtures of diastereomers.

2.3 Conclusion

In order to extend the synthetic utility of benzotriazolyl-mediated one carbon

insertion, the migratory aptitude of 7t-electron-rich heterocycles of adducts 2.3a-m in the

presence of alkyl and aryl groups has been investigated. Rearrangements of the

intermediates 2.3a-g accompanied by 1,2-shift of heteroaromatic groups gave one carbon









homologated ketones 2.4a-g; thus these rearrangements should find utility in the

synthesis of ketones bearing asymmetric centers adjacent to heterocycles. In contrast, for

the rearrangement of intermediates 2.3h,i,k-m migration of the phenyl group occurred

preferentially instead of the corresponding heteroaromatic groups to give the one carbon

homologated ketones 2.4h,i,k-m.

2.4 Experimental Section

General. Melting points were determined on a hot-stage apparatus and are

uncorrected. NMR spectra were recorded in CDC13, acetone-d6 or DMSO-d6 with TMS as

the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C (75

MHz). THF was dried over sodiumbenzophenone and used freshly distilled. Column

chromatography was conducted on silica gel 200-425 meshes. 1-(Methylthio)-1-methyl-

1H-benzotriazole 2.1 was prepared according to previously reported procedure

[98JOC2110].

2.4.1 General procedure for the preparation of intermediates 2.3a-m

A solution of 2.1 (5.58 mmol) in THF (50 mL) under nitrogen was cooled to -780C,

and a solution of n-BuLi (5.58 mmol, 1.58 M in hexane, 3.57 mL) was added dropwise.

The reaction mixture was stirred at the same temperature for 1 h and a solution of an

appropriate ketone (5.58 mmol) in THF (15 mL) was added. The mixture was stirred for

an additional 1 h at -78 C. Then aqueous solution of ammonium chloride was added (30

mL) and the reaction mixture was extracted with diethyl ether. The extract was dried over

anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was

purified by column chromatography on silica gel to give 2.3a-m as equal mixtures of two









diastereoisomers. In certain cases the isolation of the diastereomeric pure forms was

succeeded by a single recrystallization from acetone-diethyl ether mixture (1:1).

1-(1H-1,2,3-Benzotriazol-1-yl)-l-(methylthio)-2-(2-thienyl)-2-propanol (2.3a) (one

diastereoisomer): microcrystals from acetone-diethyl ether (41%); mp 138-139 OC; 1H

NMR (CDCl3): 6 7.95 (d, J= 8.2 Hz, 1H), 7.73 (d, J= 8.3 Hz, 1H), 7.45-7.40 (m, 1H),

7.35-7.29 (m, 1H), 7.00 (dd, J= 4.7, 1.4 Hz, 1H), 6.76-6.68 (m, 2H), 6.03 (s, 1H), 4.09

(s, 1H), 2.02 (s, 3H), 1.92 (s, 3H); 13C NMR (CDCl3): 6 148.3, 145.6, 132.8, 127.3,

126.7, 124.8, 124.1, 123.9, 119.7, 111.9, 77.4, 75.7, 29.0, 14.7. (Mixture of two

diastereoisomers): colorless oil (82%); 1H NMR (CDCl3): 6 8.06 (d, J= 8.1 Hz, 1H), 7.97

(d, J= 8.2 Hz, 1H), 7.85 (d, J= 8.2 Hz, 1H), 7.47-7.30 (m, 4H), 7.28-7.25 (m, 1H), 7.01

(dd, J= 4.6, 1.6 Hz, 1H), 6.97-6.95 (m, 2H), 6.73-6.68 (m, 2H), 6.07 (s, 1H), 6.02 (s,

1H), 3.88 (s, 1H), 3.29 (s, 1H), 2.02 (s, 3H), 1.94 (s, 3H), 1.84 (s, 3H), 1.57 (s, 1H),

(double set of signals); 13C NMR (CDCl3): 6 148.8, 148.3, 146.2, 145.6, 132.8, 132.5,

127.3, 127.2, 127.1, 126.7, 124.9, 124.8, 124.2, 124.1, 123.9, 123.8, 119.7, 119.7, 112.9,

112.1, 77.3, 77.3, 77.1, 75.8, 29.0, 28.8, 14.9, 14.7, (double set of signals). Anal. Calcd

for C14H15N30S2: C, 55.06; H, 4.95; N, 13.76. Found: C, 55.25; H, 5.14; N, 13.85.

1-(1H-1,2,3-Benzotriazol-1-yl)-1-(methylthio)-2-(3-thienyl)-2-propanol (2.3b)

(mixture of two diastereoisomers): microcrystals from diethyl ether (88 %), mp 118-122

OC; 1H NMR (CDCl3): 6 8.03 (d, J= 8.2 Hz, 1H), 7.93 (d, J= 8.2 Hz, 1H), 7.83 (d, J=

8.1 Hz, 1H), 7.70 (d, J= 8.2 Hz, 1H), 7.45-7.35 (m, 3H), 7.33-7.26 (m, 3H), 7.10 (dd, J

= 4.7, 1.7 Hz, 1H), 7.05 (dd, J= 5.0, 3.0 Hz, 1H), 6.91 (dd, J= 3.0, 1.4 Hz, 1H), 6.83 (dd,

J= 5.1, 1.4 Hz, 1H), 6.07 (s, 1H), 6.04 (s, 1H), 3.74 (s, 1H), 3.30 (s, 1H), 1.93 (s, 3H),

1.91 (s, 3H), 1.78 (s, 3H), 1.50 (s, 3H), (double set of signals); 13C NMR (CDC13): 6









146.3, 145.7, 145.6, 145.3, 132.6, 132.5, 127.3, 127.1, 126.3, 126.0, 125.3, 124.9, 124.2,

124.0, 121.6, 121.2, 119.8, 119.7, 112.8, 112.1, 76.9, 75.7, 28.2, 28.0, 14.7, 14.6, (double

set of signals). Anal. Calcd for C14H15N3OS2: C, 55.06; H, 4.95; N, 13.76. Found: C,

55.35; H, 5.03; N, 13.80.

1-(1H-1,2,3-Benzotriazol-1-yl)-2-(1-methyl-1H-indol-3-yl)- -(methylthio)-2-

propanol (2.3c) (one diastereoisomer): microcrystals from acetone-diethyl ether (41%),

mp 186-187 C; 1HNMR (CDCl3): 6 8.07-8.04 (m, 1H), 7.90-7.86 (m, 2H), 7.43-7.24

(m, 4H), 7.21-7.16 (m, 1H), 7.07 (s, 1H), 6.42 (s, 1H), 3.74 (s, 3H), 3.11 (s, 1H), 1.75 (s,

3H), 1.58 (s, 3H); 13C NMR (CDCl3): 6 146.3, 137.6, 132.8, 127.1, 126.8, 124.9, 124.1,

121.8, 120.1, 119.8, 119.6, 118.3, 112.8, 109.8, 76.7, 75.7, 32.8, 27.5, 14.7. (Mixture of

two diastereoisomers): colorless oil (82 %); 1H NMR (CDCl3): 6 8.06-8.03 (m, 1H),

7.92-7.86 (m, 3H), 7.78-7.74 (m, 1H), 7.56-7.53 (m, 1H), 7.42-7.32 (m, 3H), 7.31-7.23

(m, 4H), 7.22-7.15 (m, 3H), 7.10-7.04 (m, 2H), 6.78 (s, 1H), 6.40 (s, 1H), 6.35 (s, 1H),

3.72 (s, 3H), 3.64 (s, 1H), 3.53 (s, 3H), 3.13 (s, 1H), 2.05 (s, 3H), 1.86 (s, 3H), 1.74 (s,

3H), 1.56 (3H), (double set of signals); 13C NMR (CDCl3): 6 146.3, 145.5, 137.6, 137.3,

133.2, 132.8, 127.1, 127.0, 126.8, 126.7, 124.9, 124.7, 124.1, 123.8, 121.8, 121.6, 120.1,

119.9, 119.8, 119.6, 119.6, 119.3, 118.3, 118.0, 112.8, 111.6, 109.8, 109.6, 76.7, 75.7,

74.3, 32.8, 32.6, 27.5, 27.5, 14.7 (double set of signals). Anal. Calcd for C19H20N40S: C,

64.75; H, 5.72; N, 15.90. Found: C, 64.94; H, 5.84; N, 15.70.

1-(1H-1,2,3-Benzotriazol-1-yl)-2-(2-furvl)-l-(methylthio)-2-propanol (2.3d) (first

diastereoisomer): microcrystals from acetone-diethyl ether (37%), mp 127-128 OC; 1H

NMR (CDCl3): 6 7.98 (d, J= 8.2 Hz, 1H), 7.62 (d, J= 8.2 Hz, 1H), 7.45-7.39 (m, 1H),

7.35-7.29 (m, 1H), 7.13 (dd, J= 1.8, 0.8 Hz, 1H), 6.13 (s, 1H), 6.08 (dd, J= 3.4, 1.8 Hz,









1H), 6.03 (dd, J= 3.4, 0.8 Hz, 1H), 3.96 (s, 1H), 1.96 (s, 3H), 1.87 (s, 3H); 13C NMR

(CDC13): 6 155.5, 145.6, 141.9, 132.8, 127.3, 124.1, 119.8, 111.4, 110.4, 106.7, 75.3,

73.7, 25.2, 14.7. Anal. Calcd for C14H15N302S: C, 58.11; H, 5.23; N, 14.52. Found: C,

58.25; H, 5.42; N, 14.63. (Second diastereoisomer): colorless oil (35 %); 1H NMR

(CDCl3): 6 8.06 (d, J= 8.2 Hz, 1H), 7.91 (d, J= 8.3 Hz, 1H), 7.49-7.33 (m, 3H), 6.40-

6.36 (m, 2H), 6.25 (s, 1H), 3.37 (s, 1H), 1.84 (s, 3H), 1.46 (s, 3H); 13C NMR (CDCl3): 6

155.9, 146.1, 141.9, 132.3, 127.1, 124.1, 119.4, 113.3, 110.5, 106.5, 75.4, 74.9, 25.7,

14.5.

2-(1-Benzofuran-2-yl)-1-(1H-1,2,3-benzotriazol-1-yl)-1-(methylthio)-2-propanol

(2.3e) (mixture of two diastereoisomers): microcrystals from diethyl ether (75 %), mp

141-142 C; 1HNMR (CDCl3): 6 8.07-8.02 (m, 2H), 7.90 (d, J= 8.3 Hz, 1H), 7.70 (d, J

= 8.3 Hz, 1H), 7.57-7.54 (m, 1H), 7.49-7.20 (m, 9H), 7.16-7.05 (m, 2H), 6.85 (s, 1H),

6.46 (s, 1H), 6.41 (s, 1H), 6.27 (s, 1H), 4.41 (s, 1H), 3.89 (s, 1H), 1.98 (s, 3H), 1.96 (s,

3H), 1.84 (s, 3H), 1.46 (s, 3H), (double set of signals); 13C NMR (DMSO-d6): 6 160.4,

160.0, 154.2, 154.1, 146.0, 145.5, 132.4, 132.2, 127.9, 127.5, 126.9, 126.6, 124.1, 124.1,

124.0, 123.8, 122.9, 122.7, 121.1, 121.0, 119.1, 118.9, 114.3, 114.3, 111.2, 110.9, 103.3,

102.9, 74.6, 74.5, 74.4, 25.6, 25.4, 14.0, 13.9, (double set of signals). Anal. Calcd for

C18H17N302S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.68; H, 5.04; N, 12.36.

2-(1-Benzothiophen-2-vl)-1-(1H-1,2,3-benzotriazol-1-yl)-1-(methylthio)-2-

propanol (2.3f) (mixture of two diastereoisomers): microcrystals from diethyl ether-

acetone (94 %), mp 139-140 C; 1HNMR (CDCl3): 6 8.06 (d, J= 8.4 Hz, 1H), 8.00 (d, J

= 8.3 Hz, 1H), 7.91 (d, J= 8.3 Hz, 1H), 7.83-7.70 (m, 3H), 7.62-7.59 (m, 1H),

7.52-7.49 (m, 1H), 7.47-7.14 (m, 9H), 7.02 (s, 1H), 6.17 (s, 1H), 6.11 (s, 1H), 4.37 (s,









1H), 3.64 (s, 1H), 2.05 (s, 3H), 1.94 (s, 3H), 1.82 (s, 3H), 1.5 (s, 3H), (double set of

signals); 13C NMR (CDCl3): 6 149.4, 149.1, 146.3, 145.4, 139.6, 139.3, 139.2, 139.0,

132.9, 132.5, 127.5, 127.4, 124.4, 124.4, 124.3, 124.2, 124.2, 124.2, 123.6, 123.5, 122.3,

122.0, 120.7, 120.6, 119.8, 119.8, 113.0, 111.6, 77.7, 77.7, 76.7, 74.6, 29.1, 28.8, 14.9,

14.7, (double set of signals). Anal. Calcd for C18H17N30S2: C, 60.82; H, 4.82; N, 11.82.

Found: C, 60.77; H, 4.74; N, 11.77.

2-(1-Benzothiophen-3-yl)-1-(1H-1,2,3-benzotriazol-1-yl)-1-(methylthio)-2-

propanol (2.3g) (first diastereoisomer): microcrystals from diethyl ether-acetone (20%);

mp 159-160 C; 1HNMR (CDC13): 6 8.15 (d, J= 8.1 Hz, 1H), 7.90 (d, J= 8.1 Hz, 1H),

7.72 (d, J= 8.1 Hz, 1H), 7.57 (d, J= 8.1 Hz, 1H), 7.41-7.36 (m, 1H), 7.33-7.24 (m, 3H)

7.21 (s, 1H), 6.47 (s, 1H), 4.01 (s, 1H), 2.12 (s, 3H), 1.89 (s, 3H); 13C NMR (CDCl3): 6

145.4, 141.3, 138.6, 135.7, 132.9, 127.3, 124.0, 124.0, 123.2, 123.1, 119.9, 111.0, 78.1,

73.1, 26.8, 14.7. Anal. Calcd for C18H17N30S2: C, 60.82; H, 4.82; N, 11.82. Found: C,

60.92; H, 4.78; N, 11.65. (Second diastereoisomer): colorless oil (20%); 6 8.23 (d, J= 8.0

Hz, 1H), 7.95 (d, J= 8.3 Hz, 1H), 7.88 (d, J= 8.2 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H),

7.41-7.33 (m, 2H), 7.30-7.25 (m, 2H), 7.23 (s, 1H), 6.49 (s, 1H), 5.41 (s, 1H), 2.09 (s,

3H), 1.80 (s, 3H); 13C NMR (CDCl3): 6 145.5, 140.7, 139.2, 136.0, 132.5, 126.6, 123.6,

123.6, 123.6, 122.6, 119.1, 112.7, 77.1, 74.5, 26.5, 14.3.

2-(1H-1,2,3-Benzotriazol-l-vl)-2-(methylthio)- -phenyl-l-(2-thienyl)-l-ethanol

(2.3h) (mixture of two diastereoisomers): microcrystals from diethyl ether (75%); mp

182-183 C; 1HNMR (CDCl3): 6 8.03 (d, J= 8.2 Hz, 1H), 7.93-7.83 (m, 3H), 7.79-7.76

(m, 2H), 7.54-7.26 (m, 11H), 7.05-6.95 (m, 5H), 6.73 (dd, J= 3.7, 1.1 Hz, 1H), 6.67 (s,

1H), 6.62 (dd, J= 5.1, 3.7 Hz, 1H), 6.56 (s, 1H), 4.92 (s, 1H), 4.57 (s, 1H), 1.95 (s, 3H),









1.82 (s, 3H), (double set of signals); 13C NMR (DMSO-d6): 6 149.9, 149.1, 145.7, 145.4,

144.0, 143.2, 132.7, 132.1, 128.0, 127.4, 127.2, 127.0, 126.7, 126.6, 126.2, 125.8, 125.4,

125.3, 124.7, 124.4, 123.8, 123.8, 119.5, 118.9, 118.8, 114.9, 114.4, 111.6, 80.3, 80.2,

75.8, 75.5, 14.1, 14.0, (double set of signals). Anal. Calcd for C19H17N30S2: C, 62.10; H,

4.66; N, 11.43. Found: C, 62.35; H, 4.30; N, 11.33.

2-(1H-1,2,3-Benzotriazol-l-vl)-l-(2-furyl)-2-(methylthio)- -phenyl- -ethanol

(2.3i) (mixture of two diasterisomers): microcrystals from diethyl ether-acetone (40%);

mp 170-172 C; 1H NMR (CDCl3): 6 8.01 (d, J= 8.4 Hz, 1H), 7.95-7.88 (m, 2H),

7.83-7.76 (m, 3H), 7.50-7.28 (m, 10H), 7.03-6.99 (m, 4H), 6.74 (s, 1H), 6.63 (d, J=

3.3, Hz 1H), 6.56 (s, 1H), 6.46 (dd, J= 3.3, 1.8 Hz, 1H), 6.14 (d, J= 3.3 Hz, 1H), 6.01

(dd, J= 3.3, 1.9 Hz, 1H), 4.70 (s, 1H), 4.32 (s, 1H), 1.92 (s, 3H), 1.81 (s, 3H), (double

sets of signals); 13C NMR (CDCl3): 6 155.0, 155.0, 145.7, 145.4, 142.2, 142.1, 140.5,

140.4, 133.1, 132.7, 128.4, 128.2, 128.0, 127.8, 127.6, 127.4, 125.6, 124.7, 124.3, 124.0,

120.0, 119.8, 111.9, 111.1, 110.9, 110.4, 107.5, 107.4, 79.7, 79.1, 73.1, 72.6, 14.7

(double sets of signals). Anal. Calcd for C19H17N302S: C, 64.94; H, 4.88; N, 11.96.

Found: C, 65.05; H, 4.85; N, 12.01.

2-(1H-1,2,3-Benzotriazol-1-yl)-l-(1-methyl-1H-indol-3-yl)-2-(methylthio)-l-

phenyl-1-ethanol (2.3j) (one diastereoisomer): microcrystals from diethyl ether (36%);

mp 119-120 C; 1H NMR (CDC13): 6 7.79 (d, J= 7.8 Hz, 1H), 7.82 (d, J= 8.1 Hz, 1H),

7.67-7.64 (m, 2H), 7.41-7.25 (m, 7H), 7.15-7.04 (m, 2H), 6.88-6.82 (m, 1H), 6.69 (s,

1H), 3.64 (s, 3H), 3.58 (s, 1H), 1.72 (s, 3H); 13C NMR (CDCl3): 6 146.1, 143.0, 137.0,

133.0, 128.0, 127.6, 127.2, 127.0, 126.4, 125.7, 124.1, 121.9, 120.7, 119.7, 119.4, 117.1,

112.9, 109.3, 80.0, 75.3, 32.8, 14.7. (Mixture of two diastereoisomers): colorless oil









(72%); H NMR (DMSO-d6-CDCl3): 6 8.35 (d, J= 8.4 Hz, 1H), 7.96-7.84 (m, 2H), 7.83

(d, J= 8.2 Hz, 1H), 7.70-7.67 (m, 3H), 7.48-7.10 (m, 15H), 7.03-6.98 (m, 1H), 6.93-

6.85 (m, 5H), 6.77-6.73 (m, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.86 (s, 3H), 3.62 (s, 3H),

1.84 (s, 3H), 1.70 (s, 3H), (double set of signals); 13C NMR (DMSO-d6 -CDCl3): 6 145.6,

145.5, 143.2, 142.7, 136.6, 136.3, 132.5, 131.8, 127.2, 126.9, 126.6, 126.6, 126.4, 126.1,

125.9, 125.9, 125.7, 125.4, 125.1, 123.3, 123.1, 121.1, 121.0, 120.9, 120.7, 118.6, 118.5,

118.3, 118.3, 117.1, 117.0, 114.2, 113.5, 108.7, 108.4, 78.7, 78.6, 76.0, 75.1, 32.4, 32.2,

14.0, 13.7, (double set of signals). Anal. Calcd for C24H22N40S: C, 69.54; H, 5.35; N,

13.52. Found: C, 69.83; H, 5.49; N, 13.94.

1 -(1-Benzofuran-2-yl)-2-( 1H-1,2,3 -benzotriazol-1 -vl)-2-(methylthio)-1 -phenyl-1 -

ethanol (2.3k) (mixture of two diastereoisomers): microcrystals from diethyl ether (70%);

mp 88-90 C; 1HNMR (CDCl3): 6 7.97-7.88 (m, 5H), 7.82 (d, J= 8.4 Hz, 1H),

7.61-7.59 (m, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.51-7.36 (m, 7H), 7.34-7.27 (m, 5H), 7.17

(d,J= 8.1 Hz, 1H), 7.11-7.08 (m, 1H), 7.05-6.98 (m, 5H), 6.88 (s, 1H), 6.71 (s, 1H),

6.64 (s, 1H), 5.10 (s, 1H), 4.68 (s, 1H), 1.95 (s, 3H), 1.85 (s, 3H), (double set of signals);

13C NMR (CDC13): 6 157.7, 157.6, 154.8, 154.4, 145.6, 145.2, 140.2, 140.1, 133.2, 132.9,

128.5, 128.4, 128.1, 128.1, 128.0, 127.8, 127.6, 127.5, 125.6, 124.7, 124.5, 124.4, 124.2,

124.2, 123.2, 122.8, 121.5, 121.3, 120.1, 119.9, 111.5, 111.3, 110.8, 110.7, 104.3, 104.1,

80.0, 79.3, 72.2, 71.8, 14.8, 14.8, (double set of signals). Anal. Calcd for C23H19N302S:

C, 68.81; H, 4.77; N, 10.47. Found: C, 68.74; H, 4.79; N, 10.51.

1 -(1 -Benzothiophen-2-vl)-2-(1H-1,2,3-benzotriazol-1 -vl)-2-(methylthio)-1 -phenyl-

1-ethanol (2.31) (mixture of two diastereoisomers): microcrystals from diethyl ether

(98%); mp 165-166 C; H NMR (CDC13): 6 8.01-7.90 (m, 3H), 7.84-7.75 (m, 5H),









7.55-7.29 (m, 15H), 7.19-7.13 (m, 2H), 7.09 (s, 1H), 7.05-6.97 (m, 2H), 6.77 (s, 1H),

6.65 (s, 1H), 5.31 (s, 1H), 4.83 (s, 1H), 1.97 (s, 3H), 1.84 (s, 3H), (double set of signals);

13C NMR (CDCl3): 6 149.1, 148.7, 145.5, 145.4, 141.9, 141.7, 139.6, 139.3, 139.3, 139.0,

133.3, 132.7, 128.45 128.2, 128.0, 128.0, 127.8, 127.7, 125.5, 124.7, 124.6, 124.5, 124.5,

124.3, 124.2, 124.1, 123.9, 123.6, 122.2, 122.0, 121.8, 120.8, 120.2, 120.0, 111.5, 111.0,

81.5, 81.2, 74.0, 72.8, 14.9, 14.8, (double set of signals). Anal. Calcd for C23H19N30S2:

C, 66.16; H, 4.59; N, 10.06. Found: C, 66.05; H, 4.51; N, 10.10.

2-(1H-1,2,3-Benzotriazol-l-yl)-2-(methylthio)- -phenyl-l-(3-thienyl)-l-ethanol

(2.3m) (mixture of two diastereoisomers): microcrystals from diethyl ether-hexane

(50%); mp 189-1900C; 1HNMR (DMSO-d6): 6 8.40 (d, J= 8.3 Hz, 1H), 8.34 (d, J= 8.5

Hz, 1H), 7.95 (d, J= 8.2 Hz, 1H), 7.89-7.83 (m, 4H), 7.53-7.45 (m, 3H), 7.43-7.29 (m,

4H), 7.23-7.15 (m, 3H), 7.11-7.06 (m, 3H), 7.00-6.94 (m, 3H), 6.84-6.78 (m, 3H), 3.38

(s, 1H), 1.80 (s, 3H), 1.72 (s, 3H), (double set of signals); 13C NMR (DMSO-d6): 6 146.4,

145.9, 145.6, 145.6, 144.3, 143.5, 132.6, 132.2, 127.9, 127.5, 127.3, 127.1, 126.7, 126.5,

126.4, 126.4, 126.0, 125.5, 125.3, 125.3, 123.8, 123.7, 122.0, 121.4, 118.8, 118.7, 115.0,

114.9, 80.3, 80.3, 75.6, 75.1, 13.9, 13.9, (double set of signals). Anal. Calcd for

C19H17N30S2: C, 62.10; H, 4.66; N, 11.43. Found: C, 61.77; H, 4.87; N, 11.23.

2.4.2 General procedure for the preparation of ketones 2.4a and 2.4b

To a solution of 2.3a or 2.3b (mixtures of two diastereoisomers) (0.3 g, 0.98 mmol)

in 1,1,2,2-tetrachloroethane (15 mL) under nitrogen, a solution of zinc bromide (2.95

mmol, IM in tetrahydrofuran, 2.95 mL) was added and the reaction mixture was heated

at 140 C for 20 h. The reaction mixture was concentrated under reduced pressure and the

residue purified by column chromatography on silica gel to give 2.4a and 2.4b.









(+)-1-(Methylthio)-1-(2-thienyl)acetone (2.4a): colorless oil (60%); 1H NMR

(CDCl3): 6 7.29 (dd, J= 5.1, 1.2 Hz, 1H), 7.09-7.07 (m, 1H), 6.99 (dd, J= 5.1, 3.6 Hz,

1H), 4.78 (s, 1H), 2.32 (s, 3H), 2.04 (s, 3H); 13C NMR (CDCl3): 6 201.1, 137.7, 127.0,

126.8, 126.1, 54.6, 26.6, 14.0. The spectral data of this compound are identical to that

reported in the literature [82CPB3579].

(+)- 1 -(Methylthio)- 1 -(3 -thienyl)acetone (2.4b): colorless oil (64%); 1H NMR

(CDCl3): 6 7.36-7.31 (m, 2H), 7.08-7.06 (m, 1H), 4.58 (s, 1H), 2.25 (s, 3H), 2.00 (s,

3H); 13C NMR (CDCl3): 6 202.3, 135.3, 127.3, 126.2, 123.6, 55.4, 26.6, 14.0. Anal.

Calcd for C8HioOS2: C, 51.58; H, 5.41; Found: C, 51.83; H, 5.48.

2.4.3 Preparation of ()-l-(1-Methyl-iH-indol-3-yl)-l-methylthio-propan-2-one 2.4c

The solution of 2.3c (mixture of two diastereoisomers) (0.4 g, 1.14 mmol) in THF

(15 mL) was cooled to -78 C, and the solution of n-BuLi (1.14 mmol, 1.58 M in hexane,

0.73 mL) was added dropwise. The reaction mixture was stirred at the same temperature

for 1 h and a solution of zinc bromide (3.40 mmol, IM in tetrahydrofuran, 3.40 mL)

under nitrogen was added. The reaction mixture was heated in a sealed tube at 100 C for

15 h, and after cooling a solvent was evaporated under reduced pressure. The residue was

purified by column chromatography on silica gel to give 2.4c as brown oil (7%); 1H

NMR (CDCl3): 6 7.64-7.61 (m, 1H), 7.34-7.23 (m, 3H), 7.17-7.12 (m, 1H), 4.82 (s, 1H),

3.79 (s, 3H), 2.27 (s, 3H), 2.01 (s, 3H); 13C NMR (CDCl3): 6 203.1, 146.2, 137.0, 128.4,

126.8, 122.2, 119.6, 119.0, 109.5, 52.0, 32.9, 13.9. Anal. Calcd for C13H15NOS: C, 66.92;

H, 6.48; N, 6.00; Found: C, 66.99; H, 6.51; N, 6.03.









2.4.4 Preparation of (+)- 1-(2-Furyl)- 1-(methylthio)acetone 2.4d

Method A: The solution of 2.3d (mixture of two diastereoisomers) (0.4 g, 1.38

mmol) in THF (15 mL) under nitrogen was cooled to -78 C, and the solution of n-BuLi

(1.38 mmol, 1.58 M in hexane, 0.9 mL) was added dropwise. The reaction mixture was

stirred at the same temperature for 1 h and a solution of zinc bromide (6.50 mmol, IM in

tetrahydrofuran, 6.5 mL) was added. The reaction mixture was heated in sealed tube at

130 C for 80 h and after cooling poured into the IN aqueous hydrochloric acid. Then

reaction mixture was extracted with diethyl ether. The ether solution was washed with

water, dried over potassium carbonate and evaporated under reduced pressure. The

residue was purified by column chromatography on silica gel to give 2.4d as colorless oil

(21%); H NMR (CDC13): 6 7.41 (d,J= 1.1 Hz, 1H), 6.45 (d, J= 3.1 Hz, 1H), 6.38-6.36

(m, 1H), 4.55 (s, 1H), 2.29 (s, 3H), 2.03 (s, 3H). 13C NMR (CDCl3): 6 200.1, 148.0,

142.7, 110.6, 109.5, 52.6, 26.8, 13.7.

Method B: To a solution of 2.3d (mixture of two diastereoisomers) (0.69 mmol) in

1,1,2,2-tetrachloroethane (15 mL) under nitrogen, a solution of zinc bromide (2.1 mmol,

IM in tetrahydrofuran) was added and the reaction mixture was heated at 140 C for Ih.

The reaction mixture was concentrated under reduced pressure and the residue purified

by column chromatography on silica gel to give 2.3d (40%). The spectral data of this

compound are identical to that reported in the literature [82CPB3579].

2.4.5 General procedure for the preparation of ketones 2.4e-i,k-m

To a solution of 2.3e-i,k-m (mixtures of two diastereoisomers) (0.57 mmol) in

1,1,2,2-tetrachloroethane (15 mL) under nitrogen, a solution of zinc bromide (1.71 mmol,

IM in tetrahydrofuran) was added and the reaction mixture was heated at 140 C for the









period from 10 min to lh (see Tablel). The reaction mixture was concentrated under

reduced pressure and the residue purified by column chromatography on silica gel to give

2.4e-i,k-m.

(+)-1 -(1-B enzofuran-2-yl)-1 -(methylthio)acetone (2.4e): colorless oil (40%); 1H

NMR (CDCl3): 6 7.57-7.54 (m,1H), 7.46 (d, J= 8.2 Hz, 1H), 7.31-7.19 (m, 2H), 6.87

(s,1H), 4.66 (s, 1H), 2.35 (s, 3H), 2.07 (s, 3H); 13C NMR (CDCl3): 6 199.6, 154.8, 150.7,

128.0, 124.5, 123.0, 121.0, 111.2, 106.4, 52.6, 27.1, 13.8. Anal. Calcd for C12H1202S: C,

65.43; H, 5.49; Found: C, 65.73; H, 5.50;

(+)-1 -(1-Benzothiophen-2-yl)-1 -(methylthio)acetone (2.4f): colorless oil (40%); 1H

NMR (CDCl3): 6 7.80-7.77 (m, 1H), 1.74-7.70 (m, 1H), 7.35-7.30 (m, 3H), 4.81 (s, 1H),

2.36 (s, 3H), 2.07 (s, 3H); 13C NMR (CDC13): 6 200.8, 139.9, 139.2, 138.9, 124.5, 124.4,

124.0, 123.5, 122.2, 55.3, 27.0, 14.1. Anal. Calcd for C12H120S2: C, 60.98; H, 5.12;

Found: C, 60.75; H, 5.09;

(+)-1 -(1-Benzothiophen-3-yl)-1 -(methylthio)acetone (2.4g): yellow oil (71%); 1H

NMR (CDCl3): 6 7.88-7.85 (m, 1H), 7.79-7.76 (m, 1H), 7.66 (s, 1H), 7.40-7.37 (m,

1H), 4.81 (s, 1H), 2.22 (s, 3H), 2.04 (s, 3H); 13C NMR (CDCl3): 6 202.0, 140.2, 137.4,

128.9, 125.6, 124.8, 124.4, 122.9, 121.7, 53.9, 26.4, 14.1. Anal. Calcd for C12H120S2: C,

60.98; H, 5.12; Found: C, 60.80; H, 5.09;

(+)-2-(Methylthio)-2-phenyl-1-(2-thienyl)-1-ethanone (2.4h): colorless oil (40%);

1HNMR (CDCl3): 6 7.98-7.95 (m, 2H), 7.52-7.48 (m, 1H), 7.42-7.37 (m, 2H),

7.24-7.22 (m, 1H), 7.09-7.08 (m, 1H), 6.93-6.89 (m, 1H), 5.71 (d, J= 1.1 Hz, 1H), 1.99

(d, J= 1.6 Hz, 3H); 13C NMR (CDC13): 6 192.5, 138.3, 135.2, 133.4, 128.8, 128.7, 127.3,









126.5, 126.4, 47.9, 13.6. Anal. Calcd for C13H120S2: C, 62.87; H, 4.87; Found: C, 62.94;

H, 5.06.

(+)-1 -(2-Furyl)-2-(methylthio)-2-phenyl-1 -ethanone (2.4i): yellow oil (23%); 1H

NMR (CDCl3): 6 8.02-7.99 (m, 2H), 7.60-7.55 (m, 1H), 7.49-7.42 (m, 3H), 6.59-6.57

(m, 1H), 6.38-6.36 (m, 1H), 5.57 (s, 1H), 2.05 (s, 3H); 13C NMR (CDC13): 6 191.2,

148.3, 142.6, 135.3, 133.4, 128.7, 110.7, 110.0, 46.1, 13.2. Anal. Calcd for C13H1202S: C,

67.22; H, 5.21; Found: C, 67.10; H, 5.39.

(+)-1 -(1-Benzofuran-2-yvl)-2-(methylthio)-2-phenyl-1 -ethanone (2.4k): yellow oil

(46%); H NMR (CDCl3): 6 7.97-7.95 (m, 2H), 7.49-7.45 (m, 2H), 7.40-7.35 (m, 3H),

7.22-7.10 (m, 2H), 6.92 (s, 1H), 5.59 (s, 1H), 2.00 (s, 3H); 13C NMR (CDCl3): 6 190.8,

154.8, 151.1, 135.1, 133.5, 128.7, 128.7, 128.2, 124.4, 122.9, 121.1, 111.2, 107.0, 46.1,

13.3. Anal. Calcd for C17H1402S: C, 72.31; H, 5.00; Found: C, 72.27; H, 5.30.

(+)-l-(1-Benzothiophen-2-yl)-2-(methylthio)-2-phenyl-l-ethanone (2.41): yellow

microcrystals from diethyl ether- hexane to give (40%); mp 71-720C; 1H NMR (CDCl3):

6 8.06 (d, J= 7.3 Hz, 2H), 7.80-7.77 (m, 1H), 7.72-7.69 (m, 1H), 7.59-7.54 (m, 1H),

7.49-7.45 (m, 2H), 7.40 (s, 1H), 7.34-7.26 (m, 2H), 5.80 (s, 1H), 2.11 (s, 3H); 13C NMR

(CDCl3): 6 192.4, 140.2, 139.6, 139.2, 135.2, 133.5, 128.8, 128.7, 124.4, 124.3, 124.3,

123.6, 122.2, 48.7, 13.7. Anal. Calcd for C17H140S2: C, 68.42; H, 4.73; Found: C, 68.17;

H, 4.72.

(+)-2-(Methylthio)-2-phenyl-1-(3-thienyl)-1-ethanone (2.4m): colorless oil (71%);

H NMR 6 8.00 (d, J= 8.2 Hz, 2H), 7.57-7.52 (m, 1H), 7.47-7.42 (m, 3H), 7.32-7.30

(m, 1H), 7.18 (d, J= 5.1 Hz, 1H), 5.57 (s, 1H), 2.01 (s, 3H); 13C NMR 6 193.7, 135.8,






21


135.7, 133.2, 128.7, 128.6, 127.9, 126.0, 124.0, 48.8, 13.6. Anal. Calcd for C13H120S2: C,

62.87; H, 4.87; Found: C, 62.79; H, 4.87.














CHAPTER 3
THE PREPARATION OF N, N', N" TRISUBSTITUTED GUANIDINES

3.1 Introduction

A wide variety of structurally diverse molecules that incorporate guanidine units

have been isolated from most living microorganisms, as well as from higher plants

[99NPR339, OOCSR57]. Guanidines are the core features of many therapeutically active

compounds [96B16174, 96JMC4527, 98JMC787, 98JMC3298, 99BR78, 00JOC2399,

00TL1849]. Guanidine alkaloids exhibit antiviral, antifungal and antitumor activities

[99NPR339]. Thus, procedures for the preparation of guanidines are of great interest in

medicinal chemistry, and much effort has been directed on developing efficient syntheses

of these compounds.

The basicity of guanidines complicates their synthesis. For this reason, many

syntheses utilize intermediates with easily removable protective groups. Most common

methods for the preparation of guanidines 3.3 involve the attack of an amine 3.1 on

various active guanidinylating reagents 3.2a-j (Scheme 3.1): a) ureas 3.2a were reacted

with phosgene and treated with Vilsmeier salts formed from amines 3.1

[82JCS(P1)2085]; b) triflylguanidines 3.2b [98JOC3804]; (c) guanylpyrazoles 3.2c have

been used as guanidinylating reagents [93TL3389]. Primary amines react smoothly and

efficiently with these reagents whereas sterically more demanding secondary or

electronically-deactivated aromatic amines cause various difficulties.









R s
3.2a-j HN N N=PPh3 ArHN NHAr
R-NH2 ArHN NHAr
3.1 ,N 3.3 R = Ar, 3.4 3.5


0 0 i NBoc HgCI2 TEA,
S R1 = Alkyl f DMF 600
SR1HN NHR CI CI Et2O, 00C BocHN SMe

3.2a 3.2f ci
NTf R1 = Boc, Cbz NHBoc -
b R1HN NHR1 DCM, 200g BocHN.S C /- -Me
I
3.2b 3.2g
NR1 R1 = Boc, Cbz NHBoc EDCI, TEA,
c R1HN N-N THF, 200C h H2N DCM, 200C

3.2c 3.2h
NR1 R1 = Ph, Pr NR1 R1 =Ar
d H2N SO3H MeCN, 200C H2N SMe t-BuOH, heat
3.2d 3.2i
NH R1 = Mtr, Pmc NH R1= Ar, Alk;
e R1HN SMe Hg(CI04)2, TEA J R N N R2=H
R2 v&N THF, reflux
3.2e
3.2j

Scheme 3.1 Common methods for the preparation of guanidines 3.3

Several common methods for the preparation of guanidines 3.3 involve the

treatment of amines with electrophilic species generated from thioureas (Scheme 3.1): d)

Maryanoff reacted amines with sulfonic acids derived from N-alkyl substituted thioureas

3.2d [86JOC1882]; e) Cody used aryl sulfonate-protected S-methylisothioureas 3.2e

[96TL8711] in the presence of mercury salts; (f) Cammidge and others used bis-Boc-

isothioureas 3.2f with mercuric chloride [93SC1443, 93TL7677, 97TL5291, 00SC2933];

g) Lipton developed methodology using Mukaiyama's reagent to form a carbodiimide

from bis-Boc-thiourea 3.2g, which was subsequently treated with amines [97JOC1540];

h) Poss used Boc-protected thioureas 3.2h to react with amines in the presence of the









water-soluble carbodiimide, EDCI, under mild conditions [92TL5933]; i) Rasmussen

explored a method of guanidinylation, which was initiated by attack of aryl amines on S-

methylisothiourea 3.2i in refluxing t-butanol [88S456, 88S460]; j) Wu and coworkers

used imidazole-1-carboxamidines 3.2j as guanylating reagents [02JOC7553]; and k)

Molina reacted 1,3-diarylthioureas 3.5 with iminophosphoranes 3.4 to form trisubstituted

guanidines 3.3 (Scheme 3.1) [83SC67].

Several benzotriazole-based guanylating reagents have recently been introduced:

benzotriazole-1-carboxamidinium tosylate 3.6 [95SC 1173], benzotriazolylcarboximidoyl

chlorides 3.7 [01JOC2854] and di(benzotriazolyl)carboximidamide 3.8a and 3.8b

[00JOC8080] (Scheme 3.2).

NH2+ NR NH NCOR
H2N Bt Bt CI Bt Bt Bt "Bt
3.6 3.7 3.8a 3.8b
R = Ar, Alk
Bt = Benzotriazole

Scheme 3.2 Benzotriazole-based guanylating reagents

Reagents 3.6-3.8 all guanylate primary and secondary amines under mild

conditions in high yields (Scheme 3.2). Benzotriazole-1-carboxamidinium tosylate 3.6

afforded guanidines under mild conditions, in moderate to good yields.

Benzotriazolylcarboximidoyl chlorides 3.7 allow the preparation of unsymmetrical

guanidines and are considered advantageous because 3.7 are stable, odorless, and

convenient to handle. Di(benzotriazolyl)carboximidamides 3.8a were applied to the

synthesis of tri- and tetra-substituted guanidines and are insensitive to electronic and

steric effects allowing the use of a wide variety of amines.

Di(benzotriazolyl)carboximidamides 3.8b are efficient for the preparation of









acylguanidines and also provide three atom synthons for the preparation of 5-amino-

1,2,8-triazoles and 4(6)-amino-1,3,5-triazine-2-ones [04JOC309].

NH2+ TsO-
H2N NH2 N
3.6 "N = Bt
-N
i) R1R2NH 55- 86%


NR i) R1R2NH vi) R1R2NH NH

Bt,2 C ii) R3R4NH N N ii) R3R4NH Bt4Bt
3.7 42-90% 48-85% 3.8
3.7 N 3.8


Scheme 3.3 Preparation of guanidines utilizing benzotriazole-based guanylating reagents

Benzotriazole-based guanylation was now extended to include two new reagent

classes, (bis-benzotriazol-1-yl-methylene)amines 3.11 and benzotriazole-1-

carboxamidines 3.13, which allow for the facile preparation of N, N', N"-trisubstituted

guanidines (Schemes 3.4, 3.6 and 3.7).

3.2 Results and Discussion

The approach now presented utilizes (bis-benzotriazol-1-yl-methylene)amines 3.11

and benzotriazole-1-carboxamidines 3.13. Substituted guanidines 3.15a-e and 3.16a-e

are derived from 3.11(Scheme 3.6, Table 3.2). Reagents 3.13 are used to produce 3.17a-f

and 3.18a-h, all provided by reactions with various amines (Scheme 3.7, Table 3.3).

Bis-benzotriazol-1-yl-methylene amines 3.11a-f were prepared by reaction of bis-

benzotriazol-1-yl-methanethione 3.9 and triphenylphosphine imides 3.10 in toluene at 70

oC for 3 hours followed by purification by column chromatography (Scheme 3.4, Table

3.1). The synthesis of benzotriazole-1-carboxamidines 3.13 was achieved from bis-

benzotriazol-1-yl-methanethione 3.9 and aromatic amines in dichloromethane at 200C to









yield compounds 3.12 that were further reacted with triphenylphosphine imides 3.10 to

give benzotriazole-1-carboxamidines 3.13a-1 (Scheme 3.4, Table 3.1). A simple one-step

procedure for the preparation of compounds 3.12 in nearly quantitative yields has

recently been developed in our group [04JOC2976]. Bis-benzotriazol-1-yl-methylene

amines 3.11a-f and benzotriazole-1-carboxamidines 3.13a-1 are stable, crystalline

substances that have been stored at room temperature for 3 weeks with no apparent loss

of activity.

Bt R-N=PPh3 3.10 Bt R 3.10a R = Ph
=S N 3.1 Ob R=p-Tol
Bt Bt 3.10 Oc R = C6H4CN-m
3.9 3.11a-f 3.10d R = C6H4CO2Et
3.10 Oe R = C6H4CI-p
R1 NH2 3.1 Of R = COPh
3.10g R = C6H2(Me)3-2,4,6
Bt R-N=PPh3 3.10 Bt R

R-NH R1-NH
3.12 3.13a-I
3.12a R1 = Bn, 98 % 3.12e R1 = (CH2)2Ph, 93 %
3.12b R1 = i-Pr, 95 % 3.12f R1 = (CH2)5CH, 95 %
3.12c R1 = Ph, 90 % 3.12g R1 = CH2CH(CH3)CH2CH3, 98 %
3.12d R1 = n-Bu, 98 % 3.12h R1 = 2-furylmethyl, 91 %


Scheme 3.4 Preparation of novel guanylating reagents 3.11a-f and 3.13a-1

A variety of triphenylphosphine imides 3.10 were synthesized from the

corresponding organic azides and triphenylphosphine [66CJC2793] (Scheme 3.4). In

addition, our efforts to prepare 3.11 and 3.13 when R is benzyl also failed to give

corresponding substituted thioureas 3.12a and 3.14 respectively (Scheme 3.5).

To investigate the scope and limitations of our new reagents, 3.11 and 3.13 were

reacted with a series of structurally different amines. Syntheses of symmetrical

guanidines 3.15a-e from 3.11 and primary amines aliphaticc and aromatic amines) were









Bt Bn.N,,PPh3
= S ---- 3 1 2 a
Bt Toluene
3.9 700C, 4h


Bn ..NPPh3 S
3.12b Bn
Toluene N N
reflux, 1 h H H 3.14
3.14

Scheme 3.5 Attempts to prepare 3.11 and 3.13 with R= benzyl

Table 3.1 Preparation of guanylating reagents 3.11a-f and 3.13a-1
Product R Yield Reactants R1 R Product Yield
3.11 (%) 3.12+3.10 3.13 (%)
3.11a Ph 65 3.12a+3.10a Bn Ph 3.13a 91
3.11b p-Tol 73 3.12a+3.10b Bn p-Tol 3.13b 96
3.11c C6H4CN-m 78 3.12b+3.10b i-Pr p-Tol 3.13c 92
3.11d C6H4CO2Et 53 3.12b+3.10e i-Pr C6H4Cl-p 3.13d 67

3.11e C6H4Cl-p 63 3.12c+3.10g Ph Mesityl 3.13e 80

3.11f COPh 86 3.12d+3.10d n-Bu C6H4CO2 3.13f 53
Et
3.12d+3.10g n-Bu Mesityl 3.13g 84

3.12e+3.10c Phenethyl C6H4CN- 3.13h 95
m
3.12f+3.10e Cyclohexyl C6H4Cl-p 3.13i 40

3.12g+3.10b 2-Methylbutyl p-Tol 3.13j 82

3.12h+3.10e 2-Furylmethyl C6H4Cl-p 3.13k 93

3.12d+3.10e n-Bu C6H4Cl-p 3.131 87


accomplished in high yields on heating under reflux in toluene for lh (Scheme 3.6, Table

3.2). However, we failed to prepare symmetrical guanidines 3.15 from secondary amines

possibly due to carbodiimide formation [81T233] (Scheme 3.6).

Further results from the investigation of reagents 3.11 and 3.13 are shown in Tables

3.2 and 3.3. Reagents 3.11 were successfully employed in the guanylation of diamines to









Bt R1NH2 R1-NH BtH N=C=N

-Bt R Toluene, N _
Bt reflux 1h Bt R
3.11

Toluene, ," NH2
reflux 1 h R1NH2
,. NH2

HN R1-NH

'. HN R 3.16a-e R1-NH R 3.15a-e

Scheme 3.6 Preparation of symmetrical and cyclic trisubstituted guanidines

give cyclic trisubstituted guanidines 3.16a-e in nearly quantitative yields (Scheme 3.6,

Table 3.2).

Table 3.2 Preparation of symmetrical and cyclic trisubstituted guanidines 3.15a-e and
3.16a-e
3.11 R R1 Product Yield 3.11 Diamine R Product Yield
(%0) (%)
3.11a Ph Cy 3.15a 79 3.11b NH2(CH2)3NH2 p-Tol 3.16a 95
3.11b p-Tol n-Bu 3.15b 83 3.11b NH2(CH1 1 i- p-Tol 3.16b 95
3.11c C6H4CN- i-Pr 3.15c 87 3.11a (NH2CH2)2C(CH3)2 C6H4 3.16c 96
m Cl-p
3.11d C6H4CO2 1- 3.15d 91 3.11a NH2(CH2)3NHCH3 Ph 3.16d 89
Et Phenyl
ethyl
3.11e C6H4Cl-p Bn 3.15e 85 3.11f NH2(CH2)3NH2 COPh 3.16e 77



Initially, the reactions of 3.13 with secondary amines were typically carried out in

refluxing toluene for lh and were found to react rather sluggishly. Extension of reflux

time to 12h was efficient to affect transformation to the unsymmetrical guanidines 3.17a-

f (Scheme 3.7, Table 3.3). The benzotriazole group in 3.13 was displaced with the

primary alkylamines in refluxing toluene to form unsymmetrical guanidines 3.18a-h in

high yields (Scheme 3.6, Table 3.3). The benzotriazole formed as a byproduct was

removed by washing with saturated aqueous sodium carbonate.









R3
Bt R3NHR2 R2-N
)=N
R1HN R Toluene,
reflux 12h R1HN R
3.13 3.17a-f
Toluene,
reflux 1h R2NH2


R2
HN
--N
R1HN R 3.18a-h

Scheme 3.7 Preparation of substituted unsymmetrical guanidines

3.3 Conclusion

In summary, new routes for the guanylation of a series of structurally different

amines have been described. The preparation of new reagents 3.11 and 3.13 are facile and

less demanding than some known guanylation reagents. We believe that our new reagents

will find widespread use in the synthesis of guanidine-containing compounds.

3.4 Experimental Section

General. Melting points were determined on a hot-stage apparatus and are

uncorrected. NMR spectra were recorded in CDC13, or DMSO-d6 with TMS as the

internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75

MHz). Column chromatography was conducted on silica gel (200-425 mesh) or on basic

alumina (60-325 mesh). Bis-benzotriazol-1-yl-methanethione 3.3 was prepared according

to previously reported procedure; Mp 171-172 C, yield 98%, (Lit. Mp 170-171 C, yield

90%) [78JOC337].











Table 3.3 Preparation of substituted unsymmetrical guanidines 3.17a-f and 3.18a-h
3.13 R R R2 R3 Product Yield
(%)
3.13a Ph Bn i-Pr i-Pr 3.17a 67
3.13b p-Tol Bn -(CH2)20(CH2)2- 3.17b 90
3.13f -C6H4CO2Et n-Bu n-Pr n-Pr 3.17c 96

3.13i -C6H4Cl-p Cyclohexyl -(CH3)CH(CH2)3CH(CH3)- 3.17d 93
3.13h -C6H4CN-m Phenethyl -(CH2)4- 3.17e 91

3.13g Mesityl n-Bu Et Et 3.17f 93

3.13a Ph Bn n-Bu 3.18a 99

3.13b p-Tol Bn Pentyl 3.18b 93

3.13c p-Tol i-Pr 1-Phenylethyl 3.18c 71

3.13d -C6H4Cl-p i-Pr Bn 3.18d 89

3.13g Mesityl n-Bu i-Pr 3.18e 83

3.13e Mesityl Ph i-Pr 3.18f 96

3.13j p-Tol 2-Methylbutyl Bn 3.18g 85

3.13k -C6H4Cl-p 2-Furylmethyl n-Bu 3.18h 91


3.4.1 General Procedure for the Preparation of Compounds 3.10a-g

Compounds 3.10a-g were prepared by adding triphenylphosphine to an ethereal

solution of the corresponding azide. After the solution was heated under reflux for two h,

the solvent was removed under reduced pressure and the residue was crystallized from

absolute ethanol.

(Phenylimino)(triphenyl)phosphorane (3.10a): White microcrystals from ethanol

(100%), Mp 134-135 C (Lit. Mp 133-134 C) [66CJC2793].

[(4-Methylphenyl)imino](triphenyl)phosphorane (3.10b): Yellow microcrystals

from ethanol (99%), Mp 136-137 C (Lit. Mp 136-137 C) [66CJC2793].









3-[(Triphenyl-X5-phosphanylidene)aminolbenzonitrile (3.10c): White microcrystals

from ethanol (96%), Mp 159-160 C (Lit. Mp 157-158 C) [66CJC2793].

Ethyl 4-[(triphenvl-X5-phosphanvlidene)aminolbenzoate (3.10d): White

microcrystals from ethanol (85%), Mp 136-137 C (Lit. Mp 1360C) [66CJC2793].

[(4-Chlorophenyl)imino](triphenyl)phosphorane (3.10e): White microcrystals from

ethanol (71%), Mp 161-162 C (Lit. Mp 160-161 C) [66CJC2793].

N-(Triphenyl-X5-phosphanylidene)benzamide (3.10f): White microcrystals from

ethanol (98%), Mp 194-195 C (Lit. Mp 195-196 C) [84TL4651].

(Mesitvylimino)(triphenyl)phosphorane (3.10g): White microcrystals from ethanol

(77%), Mp 146-147 C (Lit. Mp 146-146.5 C) [83ZOK1763].

3.4.2 General Procedure for the Preparation of Compounds 3.11a-f

To a stirred solution of 3.9 (0.007 mol) in toluene (12 mL), the appropriate (3.10a-

f) (0.007 mol) was added at room temperature and the resulting mixture was heated at 60

C for 4 h. Completion of the reaction was monitored by TLC. Upon completion, the

reaction mixture was concentrated under reduced pressure and residue purified by

gradient column chromatography (ethylacetate/hexanes) on silica gel to give 3.11a-f.

N-[Di(1H- 1,2,3-benzotriazol- 1-yl)methylene]-4-methylaniline (3.1 la): White

microcrystals from ethyl acetate / hexanes (76%), Mp 155-156 OC; 1H-NMR (CDCl3):

8.4 (d, J= 8.4, 1H), 8.21 (d, J= 8.1, 1H), 8.13-8.12 (m, 1H), 7.75 (t, J= 7.4, 1H), 7.60

(t, J= 7.7, 1H), 7.41-7.38 (m, 2H), 7.20-7.03 (m, 4H), 6.8 (d, J= 8.2, 2H); 13C-NMR

(CDCl3): 143.4, 130.2, 129.3, 129.2, 126.4, 126.3, 125.0, 121.2, 120.6, 114.3, 110.1.

Anal. Calc. for C19H13N7: C 67.25, H 3.86, N 28.89; Found: C 67.49, H 4.01, N 28.50.









N-[Di(lH- 1,2,3-benzotriazol- 1-yl)methylene]-4-methylaniline (3.1 b): White

microcrystals from ethyl acetate / hexanes (73%), Mp 165-166 OC; 1H-NMR (CDC13):

8.41 (d,J= 8.2, 1H), 8.18 (d,J= 8.2, 1H), 8.14-8.11 (m, 1H), 7.75-7.70 (m 1H),

7.59-7.54 (m, 1H), 7.41-7.38 (m, 2H), 7.13-7.10 (m, 1H), 6.96 (d, J= 9.0, 2H), 6.73 (d,

J= 9.0, 2H); 13C-NMR (CDCl3): 146.6, 144.8, 140.7, 136.3, 133.9, 132.4, 131.8, 130.1,

129.8, 129.3, 126.2, 125.0, 121.3, 120.5, 114.2, 110.1, 20.9. Anal. Calc. for C20H15N7: C

67.98, H 4.28, N 27.74; Found: C 67.81, H, 4.22, N 27.43.

3- { [Di(1H-1,2,3-benzotriazol-l-yl)methylene]amino}benzonitrile (3.11c): Yellow

microcrystals from ethyl acetate / hexanes (79%), Mp 205-206 OC; 1H-NMR (CDCl3):

8.38 (d, J= 8.1, 1H), 8.22 (d, J= 8.1, 1H), 8.14 (d, J= 7.6, 1H), 7.81-7.76 (m, 1H),

7.63-7.59 (m, 1H), 7.51-7.45 (m, 2H), 7.37 (d, J= 7.7, 1H), 7.30-7.24 (m, 2H), 7.10 (d,

J= 7.6, 1H), 6.99 (d, J= 8.1, 1H); 13C-NMR (CDCl3): 146.8, 144.8, 144.6, 132.5, 131.5,

130.6, 130.2, 129.9, 129.4, 126.7, 125.5, 125.2, 124.9, 120.8, 117.8, 114.2, 113.4, 109.9.

Anal. Calc. for C20H12N8: C 65.17, H 3.32, N 30.11; Found: C 64.71, H 3.20, N 29.83.

Ethyl 4-{ [di(1H-1,2,3-benzotriazol- -yl)methylene]amino}benzoate (3.11d):

Yellow microcrystals from ethyl acetate / hexanes (53%), Mp 197-198 OC; 1H-NMR

(CDCl3): 8.46-8.36 (m, 1H), 8.26-8.08 (m, 2H), 7.88 (d, J= 8.5, 2H), 7.81-7.71 (m,

1H), 7.62 (br s, 2H), 7.43 (br s, 1H), 7.12 (br s, 1H), 6.92 (d, J= 8.5, 2H), 4.31 (q, J=

7.1, 2H), 1.35 (t,J= 7.1, 3H); 13C-NMR (CDCl3): 165.7, 147.6, 135.4, 130.8, 130.4,

127.9, 126.6, 125.3, 120.9, 120.7, 114.2, 110.0, 61.0, 14.22. Anal. Calc. for C22H17N702:

C 64.23, H 4.16, N 23.83; Found: C 64.12, H 4.11, N 23.88.

N-(4-Chlorophenyl)-N-[di(1H-1,2,3-benzotriazol-1-yl)methylene]amine (3.11e):

White microcrystals from ethyl acetate / hexanes (58%), Mp 167-168 OC; 1H-NMR









(CDCl3): 8.39 (d, J= 8.1, 1H), 8.20 (d, J= 8.2, 1H), 8.16-8.13 (m, 1H), 7.78-7.73 (m,

1H), 7.62-7.57 (m, 1H), 7.45-7.42 (m, 2H), 7.16-7.09 (m, 3H), 6.79 (d, J= 8.7, 2H);

13C-NMR (CDC13): 146.7, 144.8, 142.0, 135.0, 131.8, 130.3, 129.6, 129.4, 126.5, 125.2,

122.6, 120.7, 114.2, 110.0. Anal. Calc. for C19H12CIN7: C 61.05, H 3.24, N 26.23; Found:

C 60.95, H 3.11, N 26.02.

N-[Di(1H-1,2,3-benzotriazol-1 -yl)methylene]benzamide (3.1 If): [04JOC309]

White needles from ethyl acetate / hexanes (86%), Mp 108-109 OC; 1H-NMR (CDCl3):

8.40 (d, J= 8.2, 1H), 8.23-8.16 (m, 4H), 7.74-7.68 (m, 3H), 7.61-7.56 (m, 4H); 13C-

NMR (CDCl3): 166.7, 145.7, 133.6, 132.3, 131.7, 131.4, 130.4, 128.4, 126.3, 120.2,

114.8, 109.6.

3.4.3 General Procedure for the Preparation of Compounds 3.12a-h

1-Thiocarbamoylbenzotriazoles 3.12a-h were synthesized by the reaction of

compound 3.3 (2 mmol) and the appropriate primary amine (2 mmol) in methylene

chloride at room temperature for 18 h according to reported procedure [04JOC2976].

Melting points and spectral data were used to characterize known 3.12a,f,h and were

found to be identical to reported values: 3.12a Mp 108-109 OC (Lit. Mp 108-109 OC)

[83ZOK1763]; 3.12fMp 72 OC (Lit. Mp 72-73 OC) [83ZOK1763]; 3.12h Mp 117 OC (Lit.

Mp 117-119 OC) [83ZOK1763].

N-Isopropyl- 1H-1,2,3-benzotriazole-1-carbothioamide (3.12b): White powder

(95%); Mp 107.7 OC; 1H-NMR (CDCl3): 8.84 (d, J= 8.5, 2H), 8.00 (d, J= 8.2, 1H),

7.57-7.52 (m, 1H), 7.41-7.36 (m, 1H), 4.67 (septet, J= 7.0, 1H), 1.36 (d, J= 6.4, 6H);
13C-NMR (CDC13): 173.1, 147.0, 132.4, 130.1, 125.5, 120.1, 116.1, 47.0, 21.5. Anal.

Calc. for CloH12N4S: C 54.52, H 5.49, N 25.43; Found: C 54.55, H 5.49, N 25.27.









N-Phenvl- 1H-1,2,3-benzotriazole-1-carbothioamide (3.12c): White powder (90%);

Mp 98.5 C; 1H-NMR (CDC13): 10.74 (s, 1H), 8.94 (d, J= 8.5, 1H), 8.13 (d, J= 8.4, 1H),

7.77 (d, J= 8.0, 2H), 7.70-7.65 (m,1H), 7.54-7.46 (m, 2H), 7.38-7.32 (m, 1H), 7.29-

7.20 (m, 1H); 13C-NMR (CDC13): 179.7, 137.1, 129.5, 129.4, 127.2, 126.9, 125.6, 125.1.

Anal. Calc. for C13Ho1N4S: C 63.40, H 3.96, N 18.33; Found: C 63.85, H 4.33, N 18.54.

N-Butvyl-1H-1,2,3-benzotriazole-1-carbothioamide (3.12d): White powder (98%);

Mp 92.3 C; 1H-NMR (CDCl3): 9.10 (br s, 1H), 8.92 (d, J= 8.5, 1H), 8.09 (d, J= 8.2,

1H), 7.64 (t, J= 7.7, 1H), 7.47 (t, J= 7.87, 1H), 3.85 (dd, J= 12.8, 7.0, 2H), 1.83-1.75

(m, 2H), 1.54-1.47 (m, 2H), 1.01 (t, J= 7.3, 3H); 13C-NMR (CDCl3): 174.1, 147.0,

132.4, 130.2, 125.6, 120.2, 116.0, 44.8, 30.1, 20.2, 13.7. Anal. Calc. for CliH14N4S: C

56.38, H 6.02, N 23.81; Found: C 56.74, H 6.40, N 23.47.

N-Phenethyl-lH-1,2,3-benzotriazole-l-carbothioamide (3.12e): White powder

(93%); Mp 110.2 C; 1H-NMR (CDCl3): 9.18 (s, 1H), 8.91 (d, J= 8.5, 1H), 8.07 (d, J=

8.2, 1H), 7.65-7.60 (m, 1H), 7.48-7.43 (m, 1H), 7.36-7.22 (m, 5H), 4.10 (t, J= 7.1, 2H),

3.11 (t,J= 7.1, 2H); 13C-NMR (CDCl3): 174.4, 147.0, 137.8, 132.3, 130.2, 128.8, 128.6,

126.9, 125.6, 120.2, 116.0, 46.1, 34.0. Anal. Calc. for C15H14N4S: C 63.80, H 5.00, N

19.84; Found: C 63.92, H 4.98, N 19.59.

N-(2-Methylbutyl)- 1H-1,2,3-benzotriazole-1 -carbothioamide (3.12g): White

powder (98%); Mp 96 C; 1H-NMR (CDCl3): 9.06 (s, 1H), 8.91 (d, J= 8.5, 1H), 8.10 (d,

J= 8.2, 1H), 7.64 (t, J= 7.5, 1H), 7.47 (t, J= 7.4, 1H), 1.97-1.93 (m, 1H), 1.38-1.26 (m,

2H), 1.06 (d, J= 6.7, 3H), 1.01-0.99 (m, 3H), 0.96-0.86 (m, 2H); 13C-NMR

(CDCl3):174.3, 146.9, 132.2, 130.1, 125.5, 120.0, 115.9, 50.6, 33.8, 27.1, 17.3, 11.1.

Anal. Calc. for C12H16N4S: C 58.04, H 6.49, N 22.56; Found: C 57.92, H 6.45, N 22.37.









3.4.4 General Procedure for the Preparation of Compounds 3.13a-1

To a stirred solution of 3.12a-h (0.01 mol) in toluene (12 mL), the corresponding

triphenylphosphene (see Table 1) 3.10 (0.01 mol) was added at room temperature and the

resulting mixture was heated at 110 C for 1 h. Completion of the reaction was monitored

by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure

and residue purified by gradient column chromatography (ethylacetate/hexanes) on silica

gel to give 3.13a-1.

N-Benzyl-N'-phenyl-lH-1,2,3-benzotriazole-1-carboximidamide (3.13a): White

microcrystals from ethyl acetate / hexanes (91%), Mp 129-130 oC; 1H-NMR (CDCl3):

8.14 (br s, 1H), 8.06 (d, J= 8.2, 1H), 7.51-7.46 (m, 1H), 7.42-7.37 (m, 1H), 7.32-7.22

(m, 7H), 7.03-6.94 (m, 3H), 6.53 (br s, 1H), 4.31 (s, 2H); 13C-NMR (CDCl3): 146.5,

141.0, 137.4, 131.6, 129.0, 128.9, 128.7, 127.8, 127.5, 125.0, 122.9, 121.6, 119.8, 114.5,

47.8. Anal. Calc. for C20H17N5: C 73.37, H 5.23, N 21.39; Found: C 73.78, H 5.25, N

21.27.

N-Benzyl-N'-(4-methylphenyl)- 1H-1,2,3-benzotriazole-1-carboximidamide

(3.13b): Yellow oil (96%); 1H-NMR (CDCl3): 8.06 (d, J= 8.1, 1H), 7.51-7.46 (m, 1H),

7.42-7.37 (m, 1H), 7.33-7.24 (m, 6H), 7.05 (d, J= 7.1, 2H), 6.86 (d, J= 7.1, 2H), 6.45

(br s, 1H), 4.31 (s, 2H), 2.30 (s, 3H); 13C-NMR (CDCl3): 143.9, 137.5, 134.6, 132.3,

131.7, 129.5, 129.2, 129.0, 128.7, 127.7, 127.5, 125.0, 121.4, 119.7, 115.3, 47.9, 20.8.

Anal. Calc. for C21H19N5: C 73.88, H 5.61, N 19.90; Found: C 73.83, H 5.96, N 19.85.

N-Isopropyl-N'-(4-methylphenyl)- lH-1,2,3-benzotriazole-l-carboximidamide

(3.13c): Yellow oil (92%); 1H-NMR (CDCl3): 7.97 (d, J= 8.2, 1H), 7.67-7.60 (m, 1H),

7.45-7.28 (m, 2H), 7.00 (d, J= 7.0, 2H), 6.82 (d, J= 7.0, 2H), 5.82 (br s 1H), 3.61 (br s,









1H), 2.22 (s, 3H), 1.08 (d,J= 6.2, 6H); 13C-NMR (CDC13): 144.3, 132.3, 132.1, 131.7,

129.5, 128.8, 128.5, 128.4, 124.8, 121.1, 119.6, 44.5, 23.0, 20.8. Anal. Calc. for

C17H19N5: C 69.60, H 6.53, N 23.87; Found: C 69.40, H 6.38, N 23.62.

N'-(4-Chlorophenyl)-N-isopropyl-lH-1,2,3-benzotriazole-l-carboximidamide

(3.13d): Yellow oil (67%); 1H-NMR (CDCl3): 8.06 (d, J= 8.2, 2H), 7.51-7.46 (m, 1H),

7.42-7.37 (m, 1H), 7.20 (d, J= 8.2, 2H), 6.90 (d, J= 8.0, 2H), 6.02 (br s, 1H), 3.69 (br s,

1H), 1.19 (d, J= 6.3, 6H); 13C-NMR (CDCl3): 146.3, 145.6, 141.3, 131.5, 129.0, 128.9,

127.8, 125.0, 122.6, 119.8, 114.1, 44.6, 22.8. Anal. Calc. for C16H16CIN5: C 61.24, H

5.14, N 22.32; Found: C 61.43, H 5.11, N 21.95.

N'-Mesitvyl-N-phenyl- 1H-1,2,3-benzotriazole-1-carboximidamide (3.13e): Yellow

microcrystals from ethyl acetate / hexanes (80%), Mp 140-141 OC; 1H-NMR (CDCl3):

8.42-8.40 (m, 1H), 8.10 (d, J= 8.4, 1H), 7.87 (br s, 1H), 7.59-7.54 (m, 1H), 7.48-7.43

(m, 1H), 7.02-6.85 (m, 3H), 6.76-6.70 (m, 2H), 6.66 (s, 1H), 6.59 (s, 1H), 2.23 (s, 3H),

2.15 (s, 6H); 13C-NMR (CDCl3): 135.0, 132.3, 132.2, 131.5, 129.2, 128.7, 128.5, 128.4,

128.2, 127.7, 125.1, 123.1, 122.3, 120.5, 119.8, 20.6, 18.4 (2C). Anal. Calc. for

C22H21N5: C 74.34, H 5.95, N 19.70; Found: C 74.15, H 6.03, N 19.44.

Ethyl 4- { 1H- 1,2,3-benzotriazol- 1-yl(butvylamino)methylidene]amino }benzoate

(3.13f): Yellow oil (53%); 1H-NMR (CDCl3): 8.00 (d, J= 8.2, 1H), 7.96 (d, J= 8.2, 1H),

7.87 (d, J= 8.4, 2H), 7.42-7.37 (m, 1H), 7.33-7.28 (m, 1H), 6.91 (d, J= 8.2, 2H),

6.40-6.30 (m, 1H), 4.25 (q, J= 7.1, 2H), 3.00 (q, J= 6.3, 2H), 1.44 (quintet, J= 7.3, 2H),

1.29 (t, J= 7.1, 3H), 1.23 (sextet, J= 7.5, 2H), 0.77 (t, J= 7.3, 3H); 13C-NMR (CDCl3):

166.4, 151.5, 146.3, 141.3, 131.4, 130.4, 129.1, 125.0, 124.4, 121.3, 119.7, 114.2, 60.6,









43.4, 31.5, 19.6, 14.2, 13.5. Anal. Calc. for C20H23NO502: C 65.73, H 6.34, N 19.16;

Found: C 65.63, H 6.77, N 18.90.

N-Butvyl-N'-mesitvyl-1H-1,2,3-benzotriazole-1-carboximidamide (3.13g): Yellow oil

(84%); 1H-NMR (CDCl3): 8.40 (d, J= 8.3, 1H), 8.02 (d, J= 8.2, 1H), 7.48-7.43 (m, 1H),

7.38-7.33 (m, 1H), 6.78 (s, 2H), 6.28 (br s, 1H), 2.78 (q, J= 6.7, 2H), 2.20 (s, 3H), 2.11

(s, 6H), 1.34 (quintet, J= 7.1, 2H), 1.16 (sextet, J= 7.1, 2H), 0.73 (t, J= 7.3, 3H); 13C-

NMR (CDCl3): 146.7, 141.8, 139.5, 131.9, 131.7, 128.9, 128.2, 128.1, 124.9, 119.6,

115.5, 42.2, 32.1, 20.7, 19.7, 18.6 (2C), 13.4. Anal. Calc. for C20H25N5: C 71.61, H 7.51,

N 20.53; Found: C 71.90, H 7.80, N 20.19.

N'-(3-Cyanophenyl)-N-phenethyl-lH-1,2,3-benzotriazole-1-carboximidamide

(3.13h): Yellow oil (95%); 'H-NMR (CDCl3): 8.02 (d, J= 8.2, 1H), 7.91 (br s, 1H),

7.50-7.45 (m, 1H), 7.41-7.36 (m, 1H), 7.32-7.24 (m, 5H), 7.21-7.20 (m, 1H), 7.12-7.10

(m, 3H), 6.47 (br s, 1H), 3.45-3.43 (m, 2H), 2.87 (t, J= 7.0, 2H); 13C-NMR (CDCl3):

147.7, 146.1, 141.8, 137.5, 131.2, 129.6, 129.1, 128.6, 128.6, 126.7, 126.1, 126.0, 125.0,

124.8, 119.8, 118.6, 113.6, 112.6, 44.6, 35.6. Anal. Calc. for C22H18N6: C 71.61, H 5.35,

N 23.04; Found: C 71.22, H 5.07, N 23.12.

N'-(4-Chlorophenyl)-N-cyclohexyl-lH-1,2,3-benzotriazole-l-carboximidamide

(3.13i): Yellow oil (40%); 1H-NMR (CDCl3): 8.06 (d, J= 8.2, 2H), 7.52-7.47 (m, 1H),

7.42-7.37 (m, 1H), 7.22 (d, J= 8.2, 2H), 6.90 (d, J= 8.0, 2H), 6.09 (br s, 1H), 3.30 (br s,

1H), 1.94-1.92 (m, 2H), 1.74-1.66 (m, 2H), 1.52 (br s, 1H), 1.32-1.09 (m, 5H); 13C-

NMR (CDCl3): 146.4, 145.7, 141.2, 131.6, 129.0, 128.9, 127.8, 125.0, 122.6, 119.8,

114.2, 51.3, 33.0, 25.3, 24.4. Anal. Calc. for C19H20CIN5: C 63.13, H 5.70, N 18.79;

Found: C 62.70, H 5.65, N 18.91.









N-(2-Methylbutvl)-N'-(4-methylphenyl)- H-1,2,3-benzotriazole-1-

carboximidamide (3.13j): Yellow oil (82%); 1H-NMR (CDC13): 8.06 (d, J= 8.2, 1H),

7.51-7.46 (m, 1H), 7.42-7.37 (m, 1H), 7.07 (d, J= 7.1, 2H), 6.89 (br s, 2H), 6.22 (br s,

1H), 3.08-2.90 (m, 2H), 2.30 (s, 3H), 1.62-1.45 (m, 1H), 1.36-1.30 (m, 1H), 1.17-1.08

(m, 1H), 0.88 (d, J= 6.7, 3H), 0.81 (t, J= 7.4, 3H); 13C-NMR (CDCl3): 144.2, 141.6,

132.0, 131.7, 129.4, 128.9, 126.1, 124.9, 121.3, 119.6, 117.9, 49.2, 35.1, 26.7, 20.8, 17.0,

11.0. Anal. Calc. for C19H23N5: C 71.00, H 7.21, N 21.79; Found: C 71.15, H 7.45, N

21.65.

N'-(4-Chlorophenyl)-N-(2-furylmethyl)-lH-1,2,3-benzotriazole-l-carboximidamide

(3.13k): Yellow oil (93%); 1H-NMR (CDCl3): 8.00 (d, J= 8.2, 2H), 7.50-7.40 (m, 1H),

7.35-7.30 (m, 1H), 7.27 (d, J= 1.0, 1H), 7.14 (d, J= 8.2, 2H), 6.81 (d, J= 8.0, 2H), 6.45

(s, 1H), 6.23-6.21 (m, 1H), 6.11 (s, 1H), 4.26 (s, 2H); 13C-NMR (CDCl3): 150.1, 145.0,

142.6, 141.2, 131.5, 129.2, 129.0, 128.7, 128.2, 125.1, 122.8, 120.0, 119.9, 110.4, 108.0,

40.8 Anal. Calc. for C18H14CIN50: C 61.45, H 4.01, N 18.91; Found: C 61.10, H 3.89, N

18.50.

N-Butvyl-N'-(4-chlorophenyvl)- 1H-1,2,3-benzotriazole-1-carboximidamide (3.131):

Yellow oil (87%); 1H-NMR (CDCl3): 7.98 (d, J= 8.2, 1H), 7.44-7.39 (m, 1H), 7.34-7.25

(m, 1H), 7.13 (d, J= 8.3, 2H), 6.82 (d, J= 8.1, 2H), 6.17 (s, 1H), 3.03 (br s, 2H), 1.51-

1.41 (m, 2H), 1.28-1.18 (m, 2H), 0.79 (t, J= 7.3, 3H); 13C-NMR (CDCl3): 146.4, 145.6,

141.7, 131.5, 129.1, 128.8, 128.8, 127.7, 125.0, 122.8, 119.8, 43.5, 31.7, 19.7, 13.6. Anal.

Calc. for C17H18CIN5: C 62.29, H 5.53, N 21.36; Found: C 62.69, H 5.59, N 20.98.









3.4.5 General Procedure for the Preparation of Compounds 3.15a-e

To a solution of 3.11a-e (see Table 3.2) (0.85 mmol) in toluene (10 mL), the amine

of choice (2.5 mmol) was added with stirring. The reaction mixture was heated to reflux

and kept at that temperature until the full conversion of starting materials (1-2 hrs). Upon

completion, the solvent was evaporated under reduced pressure; crude product was

dissolved in methylene chloride, washed twice with saturated aqueous sodium carbonate,

dried over magnesium sulfate, and filtered. The solvent was removed under reduced

pressure. Desired guanidines were isolated by flash column chromatography on basic

alumina (first ethyl acetate to remove impurities and methanol to elute guanidine) to give

3.15a-e.

N,N'-Dicyclohexyl-N"-phenylguanidine (3.15a): [67JOC2511] Yellow oil (79%);

H-NMR (CDCl3): 7.24-7.19 (m, 2H), 7.03-6.98 (m, 3H), 3.16-3.09 (m, 2H), 1.91 (s,

2H), 1.83-1.80 (m, 4H), 1.61 (br s, 4H), 1.48 (br s, 2H), 1.23-1.15 (m, 5H), 1.11-1.05

(m, 5H); 13C-NMR (CDCl3): 179.6, 153.6, 129.4, 124.2, 122.6, 52.2, 33.2, 25.0, 24.8,

24.7.

N,N'-Dibutvl-N"-(4-methylphenyl)guanidine (3.15b): Yellow oil (83%); 1H-NMR

(CDCl3): 7.08 (d, J= 8.2, 2H), 6.95 (d, J= 8.2, 2H), 3.04 (t, J= 7.0, 4H), 2.30 (s, 3H),

1.95 (s, 2H), 1.51 (quintet, J= 7.4, 4H), 1.26 (sextet, J= 7.4, 4H), 0.84 (t, J= 7.3, 6H);
13C-NMR (CDC13): 179.2, 155.9, 134.5, 129.9, 122.1, 43.2, 31.3, 20.8, 19.8, 13.5. Anal.

Calc. for C16H27N3: C 73.52, H 10.41, N 16.07; Found: C 73.28, H 10.39, N 16.38.

N"-(3-Cyanophenyvl)-N,N'-diisopropylguanidine (3.15c): Yellow oil (87%); 1H-

NMR (DMSO-d6): 8.81 (s, 1H), 7.94 (s, 1H), 7.57 (dd, J= 8.3, 1.0, 1H), 7.42 (t, J= 8.0,

1H), 7.31 (d, J= 7.6, 1H), 6.33 (d, J= 7.4, 1H), 3.76 (septet, J= 6.7, 2H), 1.1 (d, J= 6.7,









12H); 13C-NMR (DMSO-d6): 154.3, 141.5, 130.0, 124.3, 122.1, 119.9, 119.0, 111.4,

41.0, 22.8. Anal. Calc. for C14H20N4: C 73.74, H 8.25, N 22.93; Found: C 73.89, H 8.30,

N 23.54.

Ethyl 4-({bis[(1-phenylethyl)amino]methylene}amino)benzoate (3.15d): Yellow

oil (91%); 1H-NMR (CDCl3): 7.86-7.83 (m, 3H), 7.34-7.21 (m, 3H), 7.19-7.15 (m, 3H),

6.96-6.93 (m, 4H), 6.80 (d, J= 8.2, 1H), 4.78 (q, J= 6.4, 1H), 4.52 (q, J= 6.2, 1H),

4.30-4.22 (m, 4H), 1.40 (d, J= 6.7, 2H), 1.33-1.27 (m, 7H); 13C-NMR (CDCl3): 166.3,

147.1, 143.4, 143.3, 131.0, 129.0, 128.8, 127.8, 127.5, 125.9, 125.6, 124.6, 122.3, 120.7,

60.7, 52.2, 23.6, 23.1, 14.3. Anal. Calc. for C26H29N302: C 70.75, H 7.03, N 9.41; Found:

C 70.27, H 6.80, N 8.95.

N,N'-Dibenzyvl-N"-(4-chlorophenyl)guanidine (3.15e): Yellow oil (85%); 1H-NMR

(CDCl3): 7.24-7.22 (m, 6H), 7.2 (d, J= 8.6, 2H), 7.08-7.05 (m, 4H), 6.81 (d, J= 8.6,

2H), 4.18 (s, 4H), 1.80 (s, 2H); 13C-NMR (CDCl3): 179.8, 154.6, 137.1, 129.4, 129.1,

128.8, 127.7, 127.0, 123.7, 46.5; Anal. Calc. for C21H20CIN3: C 68.09, H 5.76, N 10.21;

Found: C 68.41, H 5.94, N 10.50.

3.4.6 General Procedure for the Preparation of Compounds 3.16a-e

To a solution of appropriate 3.11 (see Table 3.2) (0.70 mmol) in toluene (10 mL),

the diamine of choice (0.7 mmol) was added with stirring. The reaction mixture was

heated to reflux and kept at that temperature until the full conversion of starting materials

(1-2 hrs). Upon completion, the solvent was evaporated under reduced pressure; crude

product was dissolved in methylene chloride, washed twice with saturated aqueous

sodium carbonate, dried over magnesium sulfate, and filtered. The solvent was removed

under reduced pressure. Desired guanidines were isolated by flash column









chromatography on basic alumina (first ethyl acetate to remove impurities and methanol

to elute guanidine) to give 3.16a-e.

(Tetrahydropyrimidin-2-ylidene)-p-tolylamine (3.16a): Colorless oil (95%); 1H-

NMR (CDCl3): 7.2 (d, J= 8.2, 2H), 7.07 (d, J= 8.2, 2H), 3.37-3.33 (m, 4H), 2.32 (s,

3H), 11.98 (s, 2H), 198-1.93 (m, 2H); 13C-NMR (CDCl3): 152.7, 136.5, 132.7, 130.5,

125.2, 38.4, 24.2, 20.9, 20.2. Anal. Calc. for CjlH15N3: C 69.81, H 7.99, N 22.20; Found:

C 70.01, H 8.25, N 22.27.

Imidazolidin-2-ylidene-p-tolylamine (3.16b): [74JHC257] Yellow oil (95%); 1H-

NMR (CDCl3): 7.13 (d, J= 8.2, 2H), 7.06 (d, J= 8.2, 2H), 3.66 (s, 4H), 2.31 (s, 3H), 1.94

(s, 2H); 13C-NMR (CDCl3): 159.6, 136.0, 134.1, 130.2, 123.1, 42.9, 20.8.

4-Chloro-N-[5,5-dimethyltetrahydro-2(1H)-pyrimidinylidene]aniline (3.16c):

Yellow oil (96%); 1H-NMR (CDCl3): 7.26 (d, J= 8.6, 2H), 7.08 (d, J= 8.6, 2H), 2.97 (s,

4H), 1.91 (s, 2H), 1.02 (s, 6H); 13C-NMR (CDCl3): 152.0, 134.1, 132.2, 130.1, 126.3,

50.1, 27.2, 24.1. Anal. Calc. for C12H16CIN3: C 60.63, H 6.78, N, 17.68; Found: C 60.78,

H 6.55, N 17.77.

N-[1-Methyltetrahydro-2 (1H)-pyrimidinylidene]-N-phenylamine (3.16d): Yellow

oil (89%); 1H-NMR (CDCl3): 7.31-7.26 (m, 2H), 7.08-7.03 (m, 1H), 7.00 (d, J= 7.8,

2H), 3.42-3.33 (m, 4H), 2.75 (s, 3H), 2.11-2.03 (m, 2H), 1.99 (s, 1H); 13C-NMR

(CDCl3): 154.4, 139.9, 129.4, 123.7, 121.1, 48.5, 39.6, 38.5, 21.8. Anal. Calc. for

ClnH15N3: C 69.81, H 7.99, N 22.20; Found: C 69.98, H 7.75, N 22.57.

N-Tetrahydro-2(1H)-pyrimidinylidenebenzamide (3.16e): [67CB2569] White

microcrystals from ethyl acetate / hexanes (77%), Mp 132-133 OC; 1H-NMR (CDC13):









7.80 (d, J= 7.1, 2H), 7.41-7.32 (m, 5H), 3.41-3.49 (m, 4H), 1.78-1.62 (m, 2H); 13C-

NMR (CDCl3): 183.3, 168.2, 134.2, 131.5, 128.5, 127.0, 36.2, 29.8.

3.4.7 General Procedure for the Preparation of Compounds 3.17a-f

To a stirred solution of 3.13a-k (see Table 3.3) (1.6 mmol) in toluene (10 mL) was

added the secondary amine of choice (1.6 mmol) at room temperature. The reaction

mixture was heated to reflux and allowed to react at this temperature overnight.

Completion of the reaction was monitored by TLC. Upon completion, the solvent was

evaporated and the obtained residue was dissolved in methylene chloride. The solution

was washed twice with saturated aqueous sodium carbonate and dried over magnesium

sulfate, and the solvent was evaporated under reduced pressure. The desired guanidines

3.17af were obtained after purification by flash column chromatography on basic alumina

(first ethyl acetate to remove impurities and methanol to elute guanidine).

N'-Benzyl-N,N-diisopropyl-N"-phenylguanidine (3.17a): Yellow oil (67%); 1H-

NMR (CDCl3): 7.22-7.08 (m, 8H), 6.89-6.85 (m, 2H), 4.07 (s, 2H), 3.77 (septet, J= 6.8,

2H), 1.89 (s, 2H), 1.12 (d, J= 6.9, 12H); 13C-NMR (CDCl3): 151.3, 150.0, 139.1, 129.3,

128.7, 127.4, 127.3, 123.5, 121.6, 46.0, 41.6, 31.8, 19.9. Anal. Calc. for C20H27N3: N

13.58; Found: N 13.73.

N-Benzyl-N'-(4-methylphenyl)-4-morpholinecarboximidamide (3.17b): Yellow oil

(93%); 1H-NMR (CDCl3): 7.26-7.16 (m, 3H), 7.13-7.10 (m, 2H), 6.91 (d, J= 8.1, 2H),

6.76 (br s, 1H), 6.52 (d, J= 8.1, 2H), 4.11 (s, 2H), 3.67-3.64 (m, 4H), 3.19-3.16 (m, 4H),

2.17 (s, 3H); 13C-NMR (CDCl3): 156.0, 151.2, 146.5, 138.8, 131.2, 129.8, 129.7, 128.6,

127.4, 127.3, 122.0, 66.7, 66.4, 49.3, 48.3, 46.9, 20.6, 0.9. Anal. Calc. for C19H23N30: C

73.76, H 7.49; N 13.58; Found: C 73.36, H 7.76, N 13.26.









Ethyl 4-{ [(butvlamino)(dipropylamino)methylene]amino}benzoate (3.17c): Yellow

oil (96%); 1H-NMR (CDCl3): 7.83 (d, J= 8.5, 2H), 6.76 (d, J= 8.5, 2H), 4.26 (q, J= 7.1,

2H), 3.08 (t, J= 7.4, 4H), 2.89 (t, J= 7.0, 2H), 1.55-1.48 (m, 4H), 1.40-1.28 (m, 5H),

1.22-1.17 (m, 2H), 0.82 (t, J= 7.3, 6H), 0.79 (t, J= 7.2, 3H); 13C-NMR (CDCl3): 166.9,

156.1, 130.9, 130.8, 129.7, 121.0, 60.4, 50.8, 44.5, 32.1, 21.4, 19.9, 14.4, 13.7, 11.4, 1.0.

Anal. Calc. for C20H33N302.HCl: C 62.96, H 9.33, N 10.14; Found: C 63.24, H 9.75, N

9.91

NV-(4-Chlorophenvl)-N-cyclohexvl-2,6-dimethyltetrahydro-1 (2H)-

pyridinecarboximidamide (3.17d): Yellow oil (93%); 1H-NMR (DMSO-d6) 7.41 (d, J=

8.9, 2H), 7.24 (d, J= 8.9, 2H), 6.30 (d, J= 7.8, 1H), 3.51-3.45 (m, 1H), 3.02-2.97 (m,

2H), 1.80-1.64 (m, 7H), 1.55-1.42 (m, 2H), 1.33-1.10 (m, 3H); 13C-NMR (DMSO-d6)

154.3, 139.7, 128.4, 124.1, 118.8, 52.2, 47.49, 32.9, 30.1, 25.2, 24.3, 22.4, 19.4. Anal.

Calc. for C20H30CIN3.HCl: N 10.93; Found: N 11.13.

N'-(3-Cyanophenyl)-N-phenethyl-l-pyrrolidinecarboximidamide (3.17e): Yellow

oil (91%); 1H-NMR (CDC13): 7.32-7.21 (m, 4H), 7.2 (d, J= 6.9, 2H), 7.1 (d, J= 7.6,

1H), 7.03-7.00 (m, 2H), 4.95 (br s, 1H), 3.39-3.31 (m, 2H), 3.16-3.11 (m, 4H),

2.82-2.78 (m, 2H), 1.83-1.79 (m, 4H); 13C-NMR (CDCl3): 153.0, 138.5, 132.0, 129.5,

128.7, 128.6, 126.6, 126.5, 124.6, 123.2, 119.5, 112.3, 48.0, 44.7, 36.0, 25.3. Anal. Calc.

for C20H22N4: C 75.44, H 6.96, N 17.59; Found: C 75.62, H 7.19, N 17.28.

N'-Butyl-N,N-diethyl-N"-mesitylguanidine (3.17f): Yellow oil (93%); 1H-NMR

(CDCl3): 6.73 (s, 2H), 3.19 (q, J= 7.0, 4H), 2.83 (t, J= 7.0, 2H), 2.15-2.12 (m, 5H), 1.97

(s, 6H), 1.09 (t, J= 7.0, 6H), 1.26-1.17 (m, 2H), 0.75 (t, J= 7.0, 3H); 13C-NMR (CDC13):









154.9, 130.6, 129.6, 129.0, 128.6, 44.5, 42.6, 32.9, 20.7, 19.8, 18.3, 13.7, 12.8. Anal.

Calc. for C18H31N3: C 74.69, H 10.79, N, 14.32; Found: C 74.68, H 10.91, N 13.88.

3.4.8 General Procedure for the Preparation of Compounds 3.18a-h

To a solution of appropriate 3.13 (see Table 3.3) (2.2 mmol) in toluene (10 mL),

the amine (see Table 3.3 and Scheme 3.7), (2.2 mmol) was added with stirring. The

reaction mixture was heated to reflux and kept at that temperature about lh, until the full

conversion of starting materials (TLC control). Upon completion, the solvent was

evaporated under reduced pressure; crude product was dissolved in methylene chloride,

washed twice with saturated aqueous sodium carbonate, dried over magnesium sulfate,

and filtered. The solvent was removed under reduced pressure. Desired guanidines were

isolated by flash column chromatography on basic alumina (first ethyl acetate to remove

impurities and methanol to elute guanidine) to give 3.18a-h.

N-Benzyvl-N'-butvl-N"-phenylguanidine (3.18a): Yellow oil (99%); 1H-NMR

(CDCl3): 7.27-7.26 (m, 4H), 7.21-7.16 (m, 3H), 6.89-6.83 (m, 3H), 4.30 (s, 2H), 3.86

(br s, 1H), 3.03 (t, J= 7.0, 2H), 1.34 (quintet, J= 7.2, 2H), 1.16 (sextet, J= 7.2, 2H), 0.79

(t, J= 7.3, 3H); 13C-NMR (CDCl3): 151.3, 150.0, 139.1, 129.3, 128.7, 127.4, 127.3,

123.6, 121.6, 46.03, 41.6, 31.8, 19.9, 13.7. Anal. Calc. for C18H23N3: C 76.43, H 8.95, N

14.93; Found: C 75.84, H 8.50, N 14.76.

N-Benzyl-N'-pentyl-N"-(4-methylphenyl)guanidine (two tautomers) (3.18b):

Yellow oil (93%); 1H-NMR (CDCl3): 7.26-7.17 (m, 5H), 7.00 (d, J= 8.0, 2H), 6.81 (d, J

= 8.2, 2H), 4.29 (s, 2H), 2.90 (t, J= 6.9, 2H), 2.29 (s, 3H), 1.96 (s, 3H) 1.44-1.34 (m,

2H), 1.26-1.10 (m, 3H), 1.05-0.87 (m, 1H), 0.84-0.74 (m, 4H); 13C-NMR (CDCl3):

179.3, 155.6, 155.4, 137.5, 133.7, 133.7, 129.7, 128.5, 128.5, 127.4, 127.0, 127.0, 122.1,









48.8, 46.1, 43.1, 34.6, 28.8, 28.5, 26.5, 24.4, 22.0, 20.6, 16.7, 13.7, 10.8. Anal. Calc. for

C20H27N3: C 77.63, H 8.79, N 13.58; Found: C 77.58, H 8.43, N 13.61

N-Isopropyl-N"-(4-methylphenyl)-N'-(1-phenylethyl)guanidine (3.18c): Yellow oil

(71%); 1H-NMR (CDCl3): 7.38-7.21 (m, 5H), 7.09-7.06 (m, 2H), 6.79 (d, J= 7.8, 2H),

4.62-4.60 (m, 1H), 3.76 (br s, 1H), 2.30 (s, 3H), 1.39-1.37 (m, 3H), 1.08 (d, J= 6.3, 3H),

0.90 (d, J= 6.3, 3H); 13C-NMR (CDCl3): 151.3, 144.5, 129.9, 128.8, 128.6, 127.4, 125.7,

125.6, 123.2,51.8, 43.0, 23.8, 23.3, 22.8, 20.8. Anal. Calc. for C19H25N3: C 77.85, H 8.61,

N 13.54; Found: C 77.63, H 8.44, N 13.10.

N-Benzyl-N"-(4-chlorophenyl)-N'-isopropylguanidine (3.18d): yellow oil (89%);

1HNMR (CDCl3): 7.22-7.10 (m, 7H), 6.86 (d, J= 8.6 Hz, 2H), 4.18 (s, 2H), 3.47-3.43

(m, 1H), 1.89 (s, 2H), 0.95 (d, J= 6.3 Hz, 6H); 13C NMR (CDCl3): 155.0, 136.9, 129.9,

129.5, 128.9, 128.0, 127.2, 125.1, 123.4, 46.7, 45.3, 22.6. Anal. Calcd for C17H20CIN3: C,

67.65; H, 7.35; N, 13.92. Found: C, 67.77; H, 6.69; N, 13.06.

N-Butvyl-N'-isopropyl-N"-mesitvylguanidine (3.18e): yellow oil (83%); 1H NMR

(CDCl3): 6.85 (s, 2H), 3.56 (br s, 1H), 2.98 (br s, 2H), 2.25 (s, 3H), 2.19 (s, 6H), 1.90 (s,

2H), 1.46-1.36 (m, 2H), 1.34-1.20 (m, 2H),1.19-1.04 (m, 5H), 0.9-0.83 (m, 4H); 13C

NMR (CDCl3): 155.1, 136.2, 134.4, 129.3, 128.8, 44.8, 42.8, 31.4, 24.5, 23.0, 20.8, 19.8,

18.1, 13.5. Anal. Calcd for C17H29N3: C, 74.13; H, 10.61; N, 15.26. Found: C, 74.31; H,

9.50; N, 10.27.

N-Isopropyl-N"-mesitvl-N'-phenvlguanidine (3.18f): Yellow oil (96%); 1H-NMR

(CDCl3): 7.27-7.19 (m, 3H), 7.06-6.99 (m, 3H), 6.81 (s, 1H), 3.74 (br s, 1H), 2.19 (s,

3H), 2.16 (s, 6H), 1.93 (s, 1H), 1.00 (d, J= 6.6, 6H); 13C-NMR (CDC13): 151.1, 138.9,









129.5, 129.3, 128.8, 124,7, 123.9, 123.4, 114.9, 43.7, 23.0, 20.8, 18.1. Anal. Calc. for

C19H25N3: C 77.85, H 8.61, N 13.54; Found: C 77.70, H 8.46, N 13.09

N-Benzyl-N'-(2-methylbutyl)-N"-(4-methylphenyl)guanidine (3.18g): Yellow oil

(85%); 1H-NMR (CDCl3): 7.36-7.25 (m, 5H), 7.06 (d, J= 8.1, 2H), 6.91 (d, J= 8.1, 2H),

4.30 (s, 2H), 2.85(dd, J=13.0, 6.0, 1H), 2.71 (dd, J= 13.0, 7.1, 1H), 2.28 (s, 3H), 1.99 (s,

2H), 1.52-1.40 (m, 1H), 1.23-1.18 (m, 1H), 1.03-0.96 (m, 1H), 0.74 (d, J= 7.4, 3H),

0.73 (d, J= 7.4, 3H); 13C-NMR (CDCl3): 156.3, 137.0, 134.8, 130.0, 129.0, 128.0, 127.1,

124.9, 122.5, 49.4, 46.7, 34.8, 26.6, 20.8, 16.9, 11.0. Anal. Calc. for C20H27N3 HCI: N

12.15; Found: N 11.78.

N-Butvl-N"-(4-chlorophenyl)-N'-(2-furylmethyl)guanidine (3.18h): Yellow oil

(91%); 1H-NMR (CDCl3): 7.38-7.37 (m, 1H), 7.23 (d, J= 8.5, 2H), 6.89 (d, J= 8.5,

2H), 6.34-6.33 (m, 1H), 6.28-6.27 (m, 1H), 4.42 (s, 2H), 3.15 (t, J= 7.1, 2H), 1.52-1.44

(m, 2H), 1.34-1.26 (m, 2H), 0.85 (t, J= 7.3, 3H); 13C-NMR (CDCl3): 152.5, 151.2,

142.4, 129.5, 129.4, 124.7, 124.0, 110.5, 107.8, 42.3, 39.4, 31.5, 19.9, 13.7. Anal. Calc.

for C16H20CIN30 HCI: C 56.15, H 6.18, N 12.28; Found: C 56.28, H 6.20, N 12.36














CHAPTER 4
PREPARATIONS OF SUBSTITUTED THIOSEMICARBAZIDES AND N-
HYDROXYTHIOUREAS

4.1 Introduction

Thiosemicarbazides are valuable building blocks for the synthesis of five-

membered heterocycles [00APPMC347, 04JCC746], and thiosemicarbazide derivatives

are biologically active, e.g. 1,3,4-thiadiazoles, as antibacterial [61JOC88] and antifungal

[OOAPPMC347] agents, and 1,3,4-thiadiazolium-2-amidines as anticonvulsant [88JMC7],

antimicrobial [02EJMC979], and antitumor agents [97AD88].

Published preparations of thiosemicarbazides 4.1 (Scheme 4.1) include (i) reactions

of isothiocyanates [01ARK7, 01ARK12, 01ARK94, 01ARK129, 03ARK178] with

hydrazines, this method is most frequently used [74JMC1025, 790CSST139, 86S559,

93T4439, 03BMCL2625] but isothiocyanates are difficult to handle and store; (ii)

reduction of thiosemicarbazones by sodium borohydride is used for the preparation of 4.1

with various substitution patterns except for tetrasubstitution [83JCS2297]; (iii) reaction

of hydrazines with reactive thiocarbamic acid derivatives although the yields are greatly

affected by side reactions [68ActaChemScan.1, 79ZOK171, 04BMCL2571]; (iv) reaction

of cyanohydrazines with hydrogen sulfide yields both mono and disubstituted

thiosemicarbazides 4.1 [54JOC749]; or (v) reaction of 1,2,4-triazolyl or

bis(imidazolyl)methanethiones with ammonia and hydrazines to give di- and

trisubstituted thiosemicarbazides 4.1 [67ActaChemScan.2061, 84PS91].










S R5 R3
X X + N-NH + NH3
X= imidazole, R4
R1 5 1,2,4- triazole (V) R3
NC--S NR3 R5, NCN
R4 H H HR4

R5 SN R5 S R5 R3
R N NH (ii) NaBH4 R4.NN R1 (iii) X N + N-NH
R4 3 R1 R2=H R2 R2
4.1 X= CI, OAlk, SAK NH2(C=S)S, (ROOC)S






Scheme 4.1 Common methods of preparation of thiosemicarbazides

N-Hydroxythioureas are toxic to Lactobacillus arabinosus, Leuconostoc

dextranicum and Streptococcus Faecalis [70JMC377], and some derivatives, e.g. S-

methyl-N-hydroxyisothiourea, inhibit nitrous oxide synthase (NOS) [99JMC1842].

Methods for preparation of N-hydroxythioureas 4.2 (Scheme 4.2) include: (i)

reactions of isothiocyanates with hydroxylamine to give 4.2 in 23-66% yields

[69ActaChemScan.324, 70JMC377, 76JMC336, 99JMC1842, 00JOC2399] and (ii) the

reduction of unstable NV, N'- dihydroxythioureas [70LA171].

s s
R1-N=C=S + H2N 'R2 ) R N AN'O R2 R N N H
R3=H H R3 R=H OH R3
4.2
R1, R3 = AIk, Ar
R2 = H, Alk, Ar

Scheme 4.2 Common methods of preparation of N-hydroxythioureas

Recently, we reported the efficient synthesis of di- and trisubstituted thioureas 4.7

utilizing 1-(alkyl-or-arylthiocarbamoyl)benzotriazoles 4.4 (Scheme 4.3) [04JOC2976].









We have now expanded this methodology to include the synthesis of thiosemicarbazides

4.5a-k and N-hydroxythioureas 4.6a-j.

R\
S S NH S

Bt Bt R-NH2- Bt N'R _R2/ -- RN N RN
H R2 H
4.3 4.4 4.7

Scheme 4.3 Synthesis of di and trisubstituted thioureas 4.2

4.2 Results and Discussion

Bis(benzotriazolyl)methanethione 4.3, a thiophosgene equivalent, is easily prepared

from 1-trimethylsilylbenzotriazole and thiophosgene in quantitative yield [78JOC337].

Treatment of 4.3 with various primary amines in methylene chloride at room temperature

followed by a 5% Na2CO3 wash and recrystallization afforded 1-(alkyl-or-

arylthiocarbamoyl)benzotriazoles 4.4a-i in 90-98% yields (Scheme 4.4) [04JOC2976].

R2
\N-N NHR1
R- R3 4
4.5a-k
S 1



N N R 6 0 N NHR1
N4.3N 4 R60 NHR

4.4a R1 = Bn, 98 % 4.4f R1 = (CH2)5CH, 95 % R5 4.6a-j
4.4b R1 = i-Pr, 95 % 4.4g R1 = C(CH3)Bn, 97 %
4.4c R1 = Ph, 90 % 4.4h R1 = 2-Furfuryl, 93 %
4.4d R1 = n-Bu, 98 % 4.4i R1 = Allyl, 95 %
4.4e R1 = (CH2)2Ph, 93 %

Scheme 4.4 Synthesis of thiosemicarbazides 4.5 and N-hydroxythioureas 4.6

Substituted thiosemicarbazides 4.5a-k were prepared via a single step reaction of

1-(alkyl-or-arylthiocarbamoyl)benzotriazoles 4.4a-i with the appropriate hydrazine









(Scheme 4.4, Table 4.1). Stirring 1 equivalent of 4.4 in methylene chloride at room

temperature with 1.1 equivalents of the hydrazine and 2 equivalents of triethylamine

followed by a 5% Na2CO3 wash afforded 4.5 in excellent yields (Table 4.1). The reaction

reached completion after 3 hours as monitored by TLC. Substituted thiosemicarbazides

4.5a-k were purified using column chromatography (EtOAc/Hex) and fully characterized

using NMR (1H, 13C) and elemental analysis. Melting points for known 4.5a-d,f-k were

found to be identical to reported values (see the Experimental Section). Novel 4.5e was

characterized by 1H, 13C NMR spectra and elemental analysis (see the Experimental

Section). Our method for the preparation of thiosemicarbazides is compatible with

various substitution patterns of hydrazines as no apparent limitations were observed.

Table 4.1 Preparation of substituted and unsubstituted thiosemicarbazides*
R1 R2 R3 R4 Product Yield%

Cy Ph H H 4.5a 88
n-Bu Ph H H 4.5b 85
EthylBn H H H 4.5c 85
Cy H H H 4.5d 91
Furyl Me Me H 4.5e 83
n-Bu Me Me H 4.5f 85
(DL)- methylbenzyl Me Me H 4.5g 73
Propylpyrrolidine H H H 4.5h 74
i-Pr Me H Me 4.5i 78
Bn Me H Me 4.5j 97
Bn H H H 4.5k 97
Compounds 4.5h-k were prepared by my colleague Anna Gromova

N-Hydroxythioureas 4.6a-j were prepared from the reaction of 1-(alkyl-or-

arylthiocarbamoyl)benzotriazoles 4.4a-j in methylene chloride at room temperature with

1.5 equivalents of the corresponding hydroxylamine and 3 equivalents of triethylamine

(Scheme 4.4, Table 4.2). Starting materials disappeared completely after 5-12 hours as

monitored by TLC. Formation of a white precipitate (triethylamine salt) marked the









completion of the reaction. The precipitate was filtered and the filtrate washed with 5%

Na2CO3. The organic layer was extracted with methylene chloride (3 times), evaporated

under vacuum, and chromatographed (EtOAc/Hex) to give N-hydroxythioureas 4.6a-j in

excellent yields (Table 4.2). N-hydroxythioureas 4.6a-j were fully characterized using

NMR (1H, 13C) and elemental analysis. Melting points for known 4.6a,c,i were found to

be identical to reported values. Novel 4.6b,d-h,j were characterized by 1H, 13C NMR

spectra and elemental analyses.

Table 4.2 Preparation of substituted and unsubstituted N-hydroxythioureas *
RI R5 R6 Product Yield%

Bn H H 4.6a 90
n-Bu H H 4.6b 77
Cy H H 4.6c 83
Furyl H H 4.6d 81
i-Pr Me H 4.6e 68
n-Bu Me H 4.6f 87
Propylpyrrolidine Cy H 4.6g 72
i-Pr H Me 4.6h 81
Ph H Bn 4.6i 87
(DL)-methylbenzyl H Me 4.6,j 83
Compounds 4.6b,d,e,g-j were prepared by my colleague Anna Gromova

4.3 Conclusion

A new route for the preparation of thiosemicarbazides and N-hydroxythioureas of

different substitution patterns has been established. This methodology provides easy

access to this class of compounds in excellent yields without any obvious limitations. The

procedure is efficient with relatively short reaction times and most importantly avoids the

use of unstable isothiocyanates as the classical starting materials for preparation of

thiosemicarbazides and N-hydroxythioureas.









4.4 Experimental Section

General. Melting points were determined on a hot-stage apparatus and are

uncorrected. NMR spectra were recorded in CDC13, or DMSO-d6 with TMS as the

internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75

MHz). Column chromatography was conducted on silica gel (200-425 mesh) Bis-

benzotriazol-1-yl-methanethione 3 was prepared according to previously reported

procedure; Mp 171-172 C, yield 98%, (Lit. Mp 170-171 C, yield 90%) [78JOC337].

4.4.1 General procedure for the preparation of compounds 4.4a-i

1-Thiocarbamoylbenzotriazoles 4.4a-i were synthesized by the reaction of

compound 4.3 (2 mmol) and the appropriate primary amine (2 mmol) in methylene

chloride at room temperature for 2 h according to reported procedure [04JOC2976].

Melting points and spectral data were used to characterize known 4.4a-f,h-i and were

found to be identical to reported values: 4.4a Mp 108-109 C (Lit. Mp 108-109 C)

[04JOC2976]; 4.4b Mp 107-108 C (Lit. Mp 107.70C) [05HCA1664]; 4.4c Mp 98-99 C

(Lit. Mp 98.50C) [05HCA1664]; 4.4d Mp 92-93 C (Lit. Mp 92.30C) [05HCA1664]; 4.4e

Mp 110.5 C (Lit. Mp 110.2C) [05HCA1664]; 4.4fMp 72 C (Lit. Mp 72-73 C)

[04JOC2976]; 4.4h Mp 117 C (Lit. Mp 117-119 C) [83ZOK1763]; 4.4i Mp 56.4 C

(Lit. Mp 56-57 C) [04JOC2976]. Known 4.4g was isolated as a yellow oil [04JOC2976];

spectral data and elemental analysis were used for characterization.

4.4.2 General Procedure for the Preparation of Compounds 4.5a-k

To a stirred solution of (1.15 mmol) 4.4a-i in 12ml of dichloromethane, was added

(1.27mmol) of the corresponding hydrazine hydrate followed by (2.5 mmol) of

triethylamine. The mixture was stirred for 3 hours at room temperature, then 10 ml of

Na2CO3 5% were added to remove excess benzotriazole. The solution was extracted with









dichloromethane and the organic layer was dried over magnesium sulfate. Evaporating

the solvent under reduced pressure followed by column chromatography (EtOAc/Hex

gradient) afforded pure 4.5a-k in 73-97% yield.

N-Cyclohexyl-2-phenyl-1-hydrazinecarbothioamide (4.5a). Recrystallized from

EtOAc/Hex to give pink crystals (88%), mp 165-165 C (lit. [ 70LA158 ] 163-163 C);

1H NMR 6 7.32-7.26 (m, 2H), 7.19 (s, 1H), 7.12-7.10 (m, 1H), 7.00 (t, J= 7,4 Hz, 1H),

6.84 (d, J= 7.7 Hz, 2H), 5.71 (s, 1H), 4.27- 4.24 (m, 1H), 2.06-2.03 (m, 2H), 1.72-1.61

(m, 3H), 1.42-1.34 (m, 2H), 1.23-1.11 (m, 3H); 13C NMR 6 146.1, 134.8, 129.6, 122.4,

113.5, 53.0, 32.7, 25.4, 24.8.

N-Butyl-2-phenyl-1 -hydrazinecarbothioamide (4.5b). [68ACS1] oil (85%); 1H

NMR 6 7.48 (s, 1H), 7.30-7.23 (m, 3H), 6.98 (t, J= 7.3 Hz, 1H), 6.84 (d, J= 7.7 Hz,

2H), 5.89 (s, 1H), 6.63 (q, J= 7.1 Hz), 1.59-1.54 (m, 2H), 1.37-1.29 (m, 2H), 0.91 (t, J=

7.3 Hz, 3H); 13C NMR 6 146.1, 129.5, 129.3, 122.3, 113.5, 44.1, 31.1, 19.9, 13.7.

N-Phenethyl-1-hydrazinecarbothioamide (4.5c). Recrystallized from EtOAc/Hex to

give white prisms (85%), mp 115 C (lit. [ 68ACS1 ] 113 C); 1H NMR 6 8.13 (s, 1H),

7.49 (s, 1H), 7.33-7.27 (m, 2H), 7.24-7.22 (m, 3H), 3.89-3.83 (m, 2H), 3.77 (s, 2H),

2.94-2.89 (m, 2H); 13C NMR (DMSO) 6 158.7, 128.7, 128.4, 128.3, 126.1, 36.2, 34.9.

N-Cyclohexyl-1-hydrazinecarbothioamide (4.5d). Recrystallized from EtOAc/Hex

to give white crystals (91%), mp 142-142 C (lit. [66JCS950 ] 143-143 C); 1H NMR 6

7.34 (brs, 1H), 7.19 (brs, 1H), 4.26-4.20 (m, 1H), 3.71 (s, 2H), 2.08-2.03 (m, 2H),

1.77-1.71 (m, 2H), 1.66-1.60 (m, 2H), 1.46-1.36 (m, 2H), 1.30-1.18 (m, 2H); "C NMR

6 152.4, 52.6, 32.9, 25.5, 24.8.









N- (2-Furvlmethyl)-2,2-dimethyl-1-hydrazinecarbothioamide (4.5e). Recrystallized

from EtOAc/Hex to give colorless rods (83%), mp 106 C; H NMR 6 7.57 (brs, 1H),

7.39 (s, 1H), 7.02 (br-s, 1H), 6.36-6.34 (m, 1H), 6.31-6.30 (m, 1H), 4.84 (d, J= 5.5 Hz,

2H), 2.54 (s, 6H); 13C NMR 6 150.7, 142.2, 138.0, 110.4, 107.8, 47.0, 40.8. Anal. Calcd

for C8H13N30S: C, 48.22; H, 6.58; N, 21.09. Found: C, 48.55; H, 6.77; N, 21.34.

N-Butvl-2,2-dimethyl- 1-hydrazinecarbothioamide (4.5f). [68ACS1] oil (85%); 1H

NMR 6 7.23 (brs, 1H), 6.25 (brs, 1H), 3.67-3.60 (m, 2H), 2.53 (s, 6H), 1.66-1.57 (m,

2H), 1.43-1.35 (m, 2H), 0.96 (t, J= 7.3 Hz, 3H); 13C NMR 6 158.0, 47.2, 43.8, 31.3,

20.1, 13.8.

2,2-Dimethyl-N-(1-phenylethyl)- -hydrazinecarbothioamide (4.5g). Recrystallized

from EtOAc/Hex to give white crystals (50%), mp 105-107 C (lit. [68ACS1 ] 105 C);

1HNMR 6 7.6 (br-s, 1H), 7.36-7.35 (m, 4H), 7.30-7.26 (m, 1H), 6.59 (br-s, 1H),

5.69-5.64 (m, 1H), 2.53 (d, J= 13.0 Hz, 6H), 1.60 (d, J= 7.0 Hz, 3H); 13C NMR 6 142.8,

135.5, 128.6, 127.3, 126.2, 52.6, 47.3, 47.1, 21.6.

4.4.3 General procedure for the preparation of compounds 4.6a-j

To a stirred solution of (2.0 mmol) 4.4a-i in 15ml of dichloromethane, was added

(3.0 mmol) of the corresponding hydroxylamine hydrochloride followed by (9.0 mmol)

of triethylamine. The mixture was stirred for 5 hours at room temperature. Completion of

the reaction is marked by the formation of a white precipitate (triethylamine salt). The

precipitate is filtered, then 10 ml of Na2CO3 5% were added to remove excess

benzotriazle. The solution was extracted with dichloromethane and the organic layer was

dried over magnesium sulfate. Evaporating the solvent under reduced pressure followed

by column chromatography (EtOAc/Hex gradient) afforded pure 4.5a-k in 7290% yield.









N-Benzyl-N-hydroxythiourea (4.6a). Recrystallized from EtOAc/hexane to give

white powder (90%), mp 156 C (lit. [ 70JMC377 ] 155-157 C); 1HNMR 6 7.26-7.22

(m, 3H), 7.19-7.15 (m, 2H), 6.05 (brs, 1H), 4.56 (s, 2H), 1.54 (br-s, 1H); 13C NMR 6

153.7, 136.5, 128.9, 128.0, 127.5, 48.6.

N-Cyclohexyl-N-hydroxythiourea (4.6c). Recrystallized from EtOAc/Hex to give

brown powder (83%), mp 116 C (lit. [ 70JMC377 ] 116-118 C); H NMR 6 6.01 (brs,

1H), 4.53 (br-s, 1H), 3.49-3.45 (m, 1H), 2.00-1.92 (m, 2H), 1.74-1.60 (m, 3H), 142-

1.06 (m, 5H); 13C NMR 6 158.2, 49.4, 33.6, 25.5, 24.8.

N'-Butvl-N-hydroxy-N-methylthiourea (4.6f). oil (87%); 1H NMR 6 7.90 (brs, 1H),

6.99 (brs, 1H), 3.61 (s, 3H), 3.55 (q, J= 7.1 Hz, 2H), 1.62-1.54 (m, 2H), 1.42-1.35 (m,

2H), 0.95 (t, J= 7.4 Hz, 3H); 13C NMR 6 157.3, 44.9, 42.0, 31.3, 20.0, 13.8. Anal. Calcd

for C6H14N20S: C, 44.42; H, 8.70; N, 17.27. Found: C, 45.75; H, 9.17; N, 17.52.














CHAPTER 5
SYNTHESIS OF MONO- AND SYMMETRICAL DI- N-HYDROXY- AND N-
AMINO- GUANIDINES

5.1 Introduction

Guanidines possess a wide range of interesting and important biochemical and

pharmaceutical properties. Guanidines are strongly basic and are fully protonated under

physiological conditions which is crucial for specific ligand-receptor interactions.

Identification of guanidine metabolites has provided leads for drugs for the treatment of

metabolic disorders, cancer, cardiovascular diseases, and diabetes [05ARK49].

Guanidino-containing drugs such as MIBG and MGBG were shown several decades ago

to have antitumor properties and have been subjected to intense preclinical and clinical

evaluation [01BP1183].

The guanidine unit combines pi donor and acceptor nitrogens in an interesting

manner. The symmetrical cation Y (scheme 5.1) looses preferentially the most acidic

proton, ie from the least basic nitrogen atom, so that if R is electron withdrawing either

mesomerically (eg R=CO, NO2, ect) or inductively (eg NR2 or OR), the neutral species

exists as X and not as the rival tautomer Z [95MRC383]. This generalization has been

supported by crystal structures of cyanoguanidine, nitroguanidine, acylguanidines, and

heterocyclic guanidines [95MRC383, 040L3933]. Quantum-mechanical calculations on

methyl- and ethyl- guanidines suggest small energy difference between X and Z when R

is an alkyl group [05JCTC986].









H H
R.N NH2 R, .N NH2 H+ RN NH
NH2 NH2 NH2
X Y Z

Scheme 5.1 Tautomerism of guanidines

Syntheses of guanidines frequently utilizes thioureas often with initial activation,

but in many cases the active intermediates are not described, characterized, isolated or

even defined [05ARK49]. Isothioureas, particularly, S-methylisothioureas, are also well

developed guanylating agents due to their easy preparation and availability. Guanidines

have also been successfully prepared from N-arylsulfonyl S-methylisothioureas

[96TL8711]. Other guanylating reagents include carbodiimides [03S714], cyanoamides

[98JMC3298], pyrazole-1-carboximidamide [92JOC2497], triflyl guanidines

[98JOC3804], and benzotriazole and imidazole-containing reagents [95JSC1173,

00JOC8080, 010L3859, 02JOC7553, 05HCA1664].

Recently, we reported a facile and efficient method for the preparation of N, N',

N "-trisubstituted guanidines by interaction of structurally different amines with the new

guanylating reagents (bis-benzotriazol-1-yl-methylene)amines and benzotriazole-1-

carboxamidines [05HCA1664]. We have now expanded this methodology to include N-

hydroxy- and N-aminoguanidines.

Functionalized guanidines [02ARK24, 05ARK49] are important structural

elements in a variety of natural products [93BCF 193] and show interesting biological

properties [02BB439]. In particular, N-hydroxyguanidines are electron donor [98NO270]

substrates for heme-containing enzymes such as nitric oxide synthases [02JMC944,

03JMC2271] (NOS) and peroxidases [03EJB47]. Interest in N-hydroxyguanidines has

grown since it was demonstrated that N-aryl-N'-hydroxyguanidines are reducing









substrates for dopamine P-hydroxylase [04BBRC1081] and that N'-hydroxy-L-arginine

(NOHA) is a key intermediate in the biosynthesis of nitric oxide (NO) from L-arginine

[98CC1191, 03ABB65, 04FRBM1105]. N-Hydroxyguanidines can act as

antihypertensive agents [73JMC151] and scavengers of peroxynitrate (PN)

[98FRBM914], which is generated from the reaction of NO with superoxide anions; (PN)

is generally considered to be more toxic than NO or superoxide [01MAD47].

Aminoguanidines display both dopamine P-oxidase inhibition, and antihypertensive

properties [64JOC395]. Some substituted aminoguanidines inhibit nitric oxide synthase

(NOS) [97JPET265] and 2-ethylaminoguanidine displays high selectivity for iNOS

compared with nNOS and eNOS isoform variations [97JPET265]. Di- and trisubstituted

aminoguanidines inhibit the formation of advanced non-enzymatic glycosylation of

proteins [93CA73676, 97CA131465] and arylaminoguanidines are a novel class of 5-

HT2aA receptor antagonists with enhanced activity [96LS1259].

Common methods for the preparation of N-hydroxyguanidines 5.2 involve the

reaction of electrophilic nitrogen rich species 5.1a-f with hydroxylamine or its

derivatives (Scheme 5.2). A popular approach to N-hydroxyguanidines 5.2 starts from

primary amines through intermediate formation of the corresponding cyanamides 5.1a

(Scheme 5.2) [73JMC151, 01JMC3199, 02BMCL1507, 02BMC3049, 02JMC944].

However, only mono-substituted N-hydroxyguanidines of type 5.20 can be prepared by

this method. Substituted thioureas 5.1b react with hydroxylamine or 0-

benzylhydroxylamine in the presence of mercury (II) salts to form disubstituted N-

hydroxyguanidines 5.2 [74CA37274, 94JCS(P 1)769, 02B 13868]. Cyclic 1,3-ethylene-

and 1,3-trimethylene-2-hydroxyguanidines 5.2 were synthesized by nucleophilic









displacement of a thiomethyl group from 5.1c [70TL1879]. Zinner et al [72CB1709]

reported the synthesis of tri and tetra substituted 5.2 starting from the carbodiimides 5.1d,

but this method suffers from long reaction times (3-5 days) and limited applicability.

Acyclic trisubstituted and tetrasubstituted N-hydroxyguanidines have been prepared in

moderate yields by use of chloroformamidinium chlorides 5.1e generated from the

corresponding ureas or thioureas [76JOC3253]. A limited number of N-

hydroxyguanidines 5.2 were synthesized by treatment of the corresponding

aminoiminomethansulfonic acids 5.1f with hydroxylamine hydrochloride and

triethylamine [90SC217].


S
RN N NR2
H H
5.1b NH20R
R = H, Bn 5.1
R1 = R2 = Alk; "

R1, NH2OH
N-CN HO-N N

R1 = Alk, Ar 5.1a N .
R2= H, Alk, Ar
-HO- NH2O
HO,

RIN NH2 PhN S03
R2 5.201 R1/ H-R2 5.1f

R1 = H, R2 = P
R1 = Et, R2 = I-


SMe
N N-H
NH2OH n 5.1c n = 0,1



R1-N=C=N-R1
NH20H R1 = i-C3H7,
s o-06H11
5.2 5.1d
o0
\ 0 NH2

CI
R-K /R4

R2 R3 Cie
5.1e R1 = Ar, Alk;
h R2 = R3 = Alk;
I RR4 = Alk, H


Scheme 5.2 Literature syntheses of N-hydroxyguanidines 5.2

Syntheses of substituted aminoguanidines 5.4 include reactions of hydrazine or its

derivatives with: i) Vilsmeier salt 5.3a [90T3897]; ii) cyanamides 5.3b [38CRV213,

70BAPS375]; iii) diphenylcarbodiimide 5.3c [53CR145]; iv) 1,3-disubstituted thioureas

5.3d in the presence of PbO [1900BDCG1058, 00F331]; v) 1,2,3-trimethylisothiourea










5.3e [51JA1858] or S-alkyl thiourea salts [62LA651]. The synthesis of substituted

aminoguanidines 5.4 was also reported from S-ethylthiosemicarbazidium salt 5.3f

[70JHC689] or N-aminocarbonimidic dichloride 5.3g [72JOC2005, 90T3897] by the

reaction with amines (routes vi and vii) (Scheme 5.3). All these methods were utilized for

specific classes of aminoguanidines. But apparently, no general method is available for

this class of compounds.


R1
NC-N(
R2
R 1 = Ar, Alk 5.3b
R 2= H, Ar, Alk ii ~


K


H2NNHR


NMe2 i
5.3a
0 NH
Cl \I\ vii
N-NHR
5.3g Me

R = -CI H
Cl


N rI I1 V

SE

2N


Ph-N=C=N-Ph

NH4 5.3c


2H S
N2H4 RIN... LN R2

H H
5.4 5.3d
HR1 4= Ar, heter
v2 R2 = Ar; R = I

ji MeS
-t RN NR1

NH3Br 5.3e R1 = Me

5.3f


roaryl
H-


Scheme 5.3 Literature syntheses of substituted aminoguanidines 5.4

Tautomerism of hydroxyguanidines has recently been studied when these substrates

are connected to nitrogen oxide synthase (NOS) in connection with the activity of each

conformation [99B3704, 04JA10267, 05JPC23706]. Most research groups prefer to

depict N-hydroxyguanidines as structure A (Equ. 5.1, Scheme 5.4), but others use

structure C; the common cation B is mesomeric [99B3704]. Spectral methods [99B3704]

suggest that N-hydroxy-L-arginine exists in a tautomer of type A (Eq.5.1, Scheme 5.4).


SCI

Me2N

R = Het










Aminoguanidines could exist in either structure D or E (Equ 5.2, Scheme 5.4).

Little is known on N-hydroxy-N-aminoguanidines which are 20-30 times more active

than the hydroxyguanidines as inhibitors of ribonucleotide reductase from rat Novikoff

tumors [83JMC1326]. 15N NMR studies on N-hydroxy-N-aminoguanidines support

expected structure for the conjugate acid of N-hydroxy-N-aminoguanidine G (Equ 5.3,

Scheme 5.4) [83JMC1326], and that the deprotonated free base exists as structure F (Equ

5.3, Scheme 5.4) [83JMC1326].


Eq. 5.1
H H H
I I H
HON NH2 H+ N. NH2 -- HON N-H H ON NH
HO HO'_ HO' HO- Y
NH2 NH2 NH2 H2N
A B C

Eq. 5.2
H
H2N N NH2 H2N N NH
NH2 NH2
D E

Eq. 5.3

NH2 H NH2
I N H H N HH
HO NH ,N -N-H H N N
NH2 NH2 NH2

F G H


Scheme 5.4 Tautomerism of hydroxyguanidines and aminoguanidines

In this chapter we describe a general approach for the conversion of hydroxylamine

or hydrazine derivatives into the corresponding N-hydroxy- or N-aminoguanidines

utilizing benzotriazole containing reagents.










5.2 Results and Discussion

Recently, we have utilized bis-benzotriazol-1-yl-methanethione 5.5 [05HCA1664]

and di(benzotriazol-1-yl)methanimine 5.6 [00JOC8080] in the synthesis of substituted

guanidines. Reaction of bis-benzotriazol-1-yl-methanethione 5.5 with triphenylphosphine

ylides 5.7 gave symmetrical guanylation reagents 5.8 in 73-76% yield [05HCA1664]

(Scheme 5.5). A simple one step procedure for the preparation of 5.9 from bis-

benzotriazol-1-yl-methanethione 5.5 in nearly quantitative yields has recently been

developed in our group [04JOC2976]. Refluxing 5.9 with triphenylphosphine ylides 5.7

afforded a new class of guanylation reagents 5.10 in 40-96% yields [05HCA1664]

(Scheme 5.5).


S R1 S
I R1 NH R R-N
Bt Bt R2 Bt NR
5.5 CH2C12, 250C 5.9 R2
5.9a R1= Bn, R2=H, 98 %
R-N=PPh3 5.9b R1 = i-Pr, R2=H, 95 %
5.9c R1 =(CH2)5CH, R2=H, 95 %
6.7 5.9d R1 = n-Bu, R2=H, 98 %
NR 5.9e R1 = Et, R2=Et, 81 %
t 5.9f R1,R2= (CH2)20(CH2)2,97 %
Bt 5.8 Bt

5.8a: R=C6H4CO2Et, 73%
5.8b: R=Ph, 76%


NR
=PPh3 ){1 ,R1
>.7 Bt N
5.10
5.10a: R=p-Tol, Ri=Bn, R2=H, 96%
5.10b: R=p-Tol, R1=i-Pr, R2=H, 92%
5.10c: R=C6H4CI-p,R1=i-Pr,R2=H, 67%
5.10d: R=C6H4CI-p,R1=Cy,R2=H, 40%
5.10e: R=mesityl, Rl=n-Bu, R2=H, 84%
5.10f: R=C6H4CO2Et, R1=n-Bu, R2=H, 53%
5.10g:R=COPh, Ri=Et, R2=Et, 87%
5.10h:R=COPh, R1, R2= (CH2)20(CH2)2, 91%
5.10i: R=COPh, R1=i-Pr, R2=i-Pr, 83%


Scheme 5.5 Synthesis of benzotriazole intermediates 5.8 and 5.10.

Alternatively, stirring di(benzotriazol-1-yl)methanimine 5.6 at room temperature in

THF with the appropriate amine gave guanylating reagents 5.11 in 75-91% yield

(Scheme 5.6) [00JOC8080]. Reaction of 5.11 with primary and secondary amines in

refluxing TIHF afforded substituted guanidines 5.12 (Scheme 5.6). In a continuation of

this approach we have now utilized 5.6 and 5.8 in the synthesis of symmetrical









dihydroxyguanidines 5.16 and diaminoguanidines 5.17. Benzotriazole intermediates 5.10

and 5.11a,b were used in the synthesis of mono-N-hydroxyguanidines 5.13a-j and N-

aminoguanidines 5.14a-h.



NH 1 R2 NH R,4 NH
BtABt -NH'- Bt N R_"NH. R.N N'R
THF, rt R2 THF, reflux R4 R2
5.6 5.11 5.12
5.11a R1 = Bn, R2= H, 91 %
5.11b R1 = n-Bu, R2= H, 75 %

Scheme 5.6 Synthesis of benzotriazole intermediates 5.11a,b and substituted guanidines
5.12.

5.2.1 Preparation of Unsymmetrical N-Hydroxyguanidines 5.13a-j

N-Hydroxyguanidines 5.13a-j were prepared in high yields by the reaction of

5.10a-i, and 5.11a,b with hydroxylamine hydrochloride in refluxing toluene for 4-12hr in

the presence of triethyl amine (Scheme 5.7). The completion of the reaction was

monitored by TLC. The white triethylamine hydrochloride salt was filtered from the

reaction mixture. Concentration of the reaction mixture followed by a flash basic alumina

column afforded 5.13a-j in 22-87% yield (Scheme 5.7, Table 5.1). Ethyl acetate was

used as an eluant to wash out the impurities followed by methanol to obtain the N-

hydroxyguanidines as colorless oils. The highly basic nature of guanidines (pka= 12)

causes difficulties in the isolation and characterization of these compounds. Structures

5.13a-j were supported by elemental analysis, 1H and 13C NMR spectra. 1H NMR spectra

no longer showed distinctive signals in the range of 7.0-8.2 ppm corresponding to the

benzotriazole group. The NH protons were difficult to detect in the spectra of 5.13c,e,f,h

mainly due their fast exchange rate between the guanidine 3 nitrogen atoms. The









dominant tautomeric structure has the double bond involving the hydroxylamine nitrogen

(5.13a-h, Scheme 5.7). However, N-substituted hydroxylamines obviously form

structures 5.13i,j (Scheme 5.7).

R R
NH N
R4 O.N AN R1 NH2OR4x HCI 5.10,5.11 R 3NHOR4x HCI R4O.N NR1
N2 Et3N, Toluene, Et3N, Toluene, N3 N
reflux reflux R R
5.13 a-5.13 h 5.13 i,j

Scheme 5.7 Preparation of unsymmetrical N-hydroxyguanidines 5.13a-j

Table 5.1 Preparation of unsymmetrical N-hydroxyguanidines 5.13a-j
Reactant R R1 R2 R3 R4 Product Yield,
%
5.10a p-Tol Bn H H H 5.13a 80
5.10b p-Tol i-Pr H H H 5.13b 72
5.10d C6H4Cl-p Cy H H H 5.13c 56
5.10e Mesityl n-Bu H H H 5.13d 87
5.10g COPh Et Et H H 5.13e 71
5.10h COPh (CH2)20(CH2)2 H H 5.13f 74
5.10b p-Tol i-Pr H H Bn 5.13g 41
5.11a H Bn H H Me 5.13h 67
5.10a p-Tol Bn H Me H 5.13i 53
5.11b H n-Bu H Me Me 5.13j 22

5.2.2 Preparation of Unsymmetrical N-Aminoguanidines 5.14a-h

Reagents 5.10a-i, and 5.11a were successfully employed in the synthesis of N-

aminoguanidines 5.14a-h. Refluxing 5.10 or 5.11 with 1.1 equivalents of the hydrazine

in toluene for 3 hrs in the presence of 2 equivalents of triethylamine afforded 5.14a-h in

excellent yields (Scheme 5.8, Table 5.2). The completion of the reaction was monitored

by TLC. The benzotriazole generated as a side product was easily removed by flash

chromatography on basic alumina with ethyl acetate as an eluant. Products were isolated

as oils using methanol as eluant. Novel 5.14a-h were characterized by elemental

analysis, 1H and 13C NMR spectra. Compound 5.14c was not stable at room temperature









and decomposed after 2 hrs. Similar to N-hydroxyguanidines, the NH protons were not

visible in the 1H spectra of 5.14a,d,e,h probably because they are interchanging rapidly

producing different tautomeric forms of 5.14. The dominant tautomeric structure has the

double bond involving the hydrazine nitrogen (R =H) (5.14a-g, Scheme 5.8). However, if

R7 is different from H, then structure 5.14h obviously forms (Scheme 5.8).

R R
R5 NH R5 N
RNN/NR1 R5R6NNH2 5.10,5.11 R5R6NNR7H R6.NN, ,R1
R2 Et3N, Toluene, Et3N, Toluene, R7 R2
reflux reflux
5.14a-g 5.14 h

Scheme 5.8 Synthesis of N-aminoguanidines 5.14a-h

On the other hand, reacting 5.10i with 2-hydrazinopyridine afforded a cyclic

product 5.15 via a simple intramolecular condensation with the loss of one water

molecule. Compound 5.15 was isolated as fluorescent white micocrystals in 93% yield

(Scheme 5.9). A single example of a 1,3,5 substituted 1,2,4-triazole was reported in

literature [75BSCF 1649]. Guanidynal hydroiodide was reacted with acetic acid and

methyl iodide to give 3-methyl-5-amino-1,2,4-triazole in moderate yield [75BSCF1649].





0 N
Et3N N'
NNN + N NH2 Toluene, reflux
NN H N. \

5.10i 5.15 93%


Scheme 5.9 Synthesis of trisubstituted 1,2,4-triazole 15









Table 5.2 Synthesis of N-aminoguanidines 5.14a-h
Reactant R R1 R2 R5 R6 R7 Product Yield, %

5.10b p-Tol i-Pr H H H H 5.14a 84
5.11b H n-Bu H C6H4OMe-p H H 5.14b 91
5.10c C6H4Cl-p i-Pr H SO2Ph H H 5.14c 76
5.10a p-Tol Bn H Me Me H 5.14d 82
5.10f C6H4CO2Et n-Bu H Me Me H 5.14e 84
5.10h COPh (CH2)20(CH2)2 Me Me H 5.14f 71
5.11b H n-Bu H Me Ph H 5.14g 85
5.10c C6H4Cl-p i-Pr H Me H Me 5.14h 30

5.2.3 Preparation of Symmetrical Dihydroxyguanidine 5.16 and Diaminoguanidine 5.17

Syntheses of novel dihydroxyguanidine 5.16 and diaminoguanidine 5.17 was

accomplished in high yields from the reaction of 5.6 and 5.8a with 3 equivalents of

hydroxylamines hydrochloride or hydrazines in the presence of 3 equivalents of

triethylamine in refluxing toluene for 30-45 min (Scheme 5.10, Table 5.3). Reaction time

for the preparation of N-hydroxy and N-aminoguanidines is significantly shorter than that

for the preparation of guanidines due to enhancement of nucleophilicity by the alpha

effect [78RCR631].

R
NH R
R4..0 ,NOR4 NH2OR4x HCI 5.6 R5NHNH2 NH
H Et3N, Toluene, 5.8a Et3N, Toluene, R5'SN N'NR5
reflux reflux H
5.16 5.17

Scheme 5.10 Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17

Table 5.3. Syntheses of dihydroxyguanidine 5.16 and diaminoguanidine 5.17
Reactant R R4 R5 Product Yield%

5.8a C6H4CO2Et H 5.16 91

5.6 H C6H4OMe-p 5.17 61









A novel guanylating reagent 5.18 was prepared from the reaction of 1 equiv.

di(benzotriazol-1-yl)methanimine 5.6 with 1.2 equiv. of hydroxylamine in THF. The

mixture was refluxed for Ih then washed with 10% sodium carbonate. Extracting the

organic layer afforded 5.18 in 89% yield. Microwave reaction of 5.18 with hydrazine

afforded compounds N-hydroxy-N'-aminoguanidine 5.19 in 61% yield (Scheme 5.11).

The structure of novel 5.19 was verified by 1H and 13C NMR spectra, and high resolution

mass spectroscopy. Schiff bases of N-hydroxy-N'-aminoguanidines are often used as

anticancer, antibacterial, and antiviral agents [85JMC1103, 94EJMC781], and recently

electron acceptors for xanthine oxidase [04JMC3105].

NH2 R NHNH2 NH2
HO,. N- -N R 2 HOKN NNR
\ microwaveN N R
N'N H
5.18 5.19
R5 = p-TolSO2, 61% yield

Scheme 5.11 Synthesis of N-hydroxy-N'-aminoguanidine 5.19

5.3 Conclusion

An efficient and simple route to mono- and symmetrical di- N-hydroxy- and N-

amino- guanidines has been developed using benzotriazole guanylating reagents. The

procedure uses no aggressive reagents, occurs under mild reaction conditions, and allows

ease of isolation of the products.

5.4 Experimental Section

Melting points were determined on a hot-stage apparatus and are uncorrected.

NMR spectra were recorded in CDC13, or DMSO-d6 with TMS as the internal standard

for 1H (300 MHz) or a solvent as the internal standard for 13C NMR (75 MHz). Column









chromatography was conducted on silica gel (200-425 mesh) or on basic alumina (60-

325 mesh).

5.4.1 General Procedure for the Preparation of Compounds 5.13a-j

To a solution of 5.10a,b,d,e,g,h or 5.11a,b (see Schemes 5.3 and 5.4) (1.70 mmol)

in toluene (13 mL), was added (2.55 mmol) of the hydroxylamine of choice followed by

(2.55 mmol, 0.4 mL) of triethylamine. The reaction mixture was heated under reflux until

full conversion of starting materials (4-12h). Upon completion, the solvent was

evaporated under reduced pressure. The crude product was dissolved in methylene

chloride, washed twice with saturated aqueous sodium carbonate, dried over magnesium

sulfate, and filtered. The solvent was removed under reduced pressure. The desired N-

hydroxyguanidines were isolated by flash column chromatography on basic alumina (first

ethyl acetate to remove impurities and methanol to elute guanidine) to give 5.13a-j.

N-Benzyl-N-hydroxy-N '-(4-methylphenyl)guanidine (5.13a). oil (80%); 1H NMR 6

7.31-7.21 (m, 5H), 7.13 (d, J= 8.4 Hz, 2H), 7.06 (d, J= 8.4 Hz, 2H), 6.68 (br s, 1H),

5.35 (br s, 1H), 4.37 (d, J= 5.8 Hz, 2H), 2.28 (s, 3H), 1.67 (br s, 1H); 13C NMR 6 156.2,

155.6, 139.0, 135.6, 129.8, 128.6, 127.4, 127.3, 122.0, 44.2, 20.8. Anal. Calcd for

C15H17N30: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.18; H, 6.46; N, 16.84.

N -Isopropyl-N-hydroxy-N-methyl-N '-(4-methylphenyl)guanidine (5.13b). oil (72%); 1H

NMR 6 7.08 (d, J= 8.0 Hz, 2H), 7.01 (d, J= 8.0 Hz, 2H), 6.68 (br s, 1H), 4.87 (d, J= 8.1

Hz, 1H), 3.94-3.87 (m, 1H), 2.22 (s, 3H), 1.68 (br s, 1H), 1.06 (d, J= 6.3 Hz, 6H); 13C

NMR 6 155.6, 136.1, 129.7, 128.7, 121.4, 42.0, 23.2, 20.8. Anal. Calcd for C11H17N30:

C, 69.54; H, 10.21; N, 20.27. Found: C, 69.86; H, 10.22; N, 20.14.









N-(4-Chlorophenyl)-N'-cyclohexyl-N"-hydroxyguanidine (5.13c). oil (56%); 1H NMR 6

7.38 (d, J= 8.6 Hz, 2H), 7.16 (d, J= 8.6 Hz, 2H), 3.66-3.65 (m, 3H), 2.00-1.96 (m, 2H),

1.79-1.70 (m, 2H), 1.62-1.50 (m, 2H), 1.43-1.26 (m, 5H); 13C NMR 6 129.1, 128.9,

120.8, 116.2, 33.9, 33.6, 32.2, 25.5, 24.8, 24.3. Anal. Calcd for C13H18CIN30: C, 58.31;

H, 6.78. Found: C, 58.26; H, 6.47.

N-Butvl-N-hydroxy-N"-mesitvylguanidine (5.13d). oil (87%); 1H NMR 6 6.86 (s, 2H),

5.67 (br s, 1H), 4.20 (br s, 1H), 4.19 (br s, 1H), 3.10 (q, J= 6.7 Hz, 2H), 2.22 (s, 3H),

2.17 (s, 6H), 1.36-1.28 (m, 2H), 1.25-1.15 (m, 2H), 0.80 (t, J= 7.1 Hz, 3H); 13C NMR 6

157.1, 137.7, 137.1, 131.2, 129.4, 39.9, 32.5, 20.9, 19.9, 18.1, 13.8. Anal. Calcd for

C14H23N30: C, 66.43; H, 9.30; N, 11.55. Found: C, 66.22; H, 9.25; N, 11.29.

N"-Benzoyl-NN-diethyl-N'-hydroxyguanidine (5.13e). oil (71%); 1H NMR 6 7.77-7.56

(m, 5H), 3.15 (q, J= 7.4 Hz, 2H), 3.04 (q, J= 7.4 Hz, 2H), 1.48 (t, J= 7.3 Hz, 3H), 1.42

(t, J= 7.4 Hz, 3H); 13C NMR 6 168.2, 143.5, 134.2, 131.5, 128.5, 127.0, 36.2, 29.8. Anal.

Calcd for C12H,7N302: C, 61.26; H, 7.28. Found: C, 61.28; H, 7.55.

N-[(E)-(Hydroxyamino)(morpholino)methylidene]benzamide (5.13f). oil (74%); 1H

NMR 6 8.12-8.09 (m, 2H), 7.61-7.54 (m, 3H), 3.88-3.84 (m, 4H), 3.58-3.55 (m, 4H),

1.73 (br s, 1H); 13C NMR 6 159.9, 146.0, 132.5, 129.3, 128.9, 127.9, 66.2, 46.3. Anal.

Calcd for C12H15N303: C, 57.42; H, 6.07; N, 18.86. Found: C, 57.12; H, 6.08; N, 18.53.

I" -(Benzyloxy)-N-i sopropyl-N'-(4-methylphenyl)guanidine (5.13g). Oil (41%); 1H

NMR 6 7.31-7.26 (m, 5H), 6.96 (d, J= 8.3 Hz, 2H), 6.82 (d, J= 8.3 Hz, 2H), 4.83 (s,

2H), 3.45 (br s, 1H), 2.19 (s, 3H), 0.98 (d, J= 6.3 Hz, 6H); 13C NMR 6 152.4, 138.0,

129.7, 128.5, 128.4, 128.3, 128.1, 127.9, 127.6, 75.4, 23.1, 43.5, 20.6. Anal. Calcd for

C18H23N30: C, 72.70; H, 7.80. Found: C, 72.60; H, 7.66.









N-Benzyl-N-methoxyguanidinehydrochloride (5.13h). oil (67%); 1H NMR 6 7.27-7.18

(m, 5H), 5.17 (br s, 2H), 3.60 (s, 2H), 2.08 (s, 3H); 13C NMR 6 147.61, 128.9, 128.7,

127.6, 126.2, 48.2, 30.9. Anal. Calcd for C9H14CIN30: C, 50.12; H, 6.54; N, 10.48.

Found: C, 50.02; H, 6.94; N, 10.21.

N'-Benzyl-N-hydroxy-N-methyl-N"- (4-methylphenyl)guanidine (5.13i). oil (53%); 1H

NMR 6 7.68 (br s, 1H), 7.33-7.26 (m, 5H), 7.20 (d, J= 8.1 Hz, 2H), 7.09 (d, J= 7.3 Hz,

2H), 6.18 (brs, 1H), 4.87 (d, J= 5.4 Hz, 2H), 2.33 (s, 3H), 1.61 (br s, 3H); 13C NMR 6

137.8, 137.3, 132.9, 130.9, 128.8, 127.7, 127.6, 125.6, 49.5, 21.0. Anal. Calcd for

C16H19N30: C, 71.35; H, 7.08; N, 13.60. Found: C, 71.20; H, 7.90; N, 13.55.

N'-Butyl-N-methoxy-N-methylguanidine (5.13j). oil (22%); 1H NMR 6 6.92 (br s, 2H),

3.62 (s, 3H), 3.25 (t, J= 7.1 Hz, 2H), 3.20 (s, 3H), 1.60-1.52 (m, 2H), 1.36-1.29 (m,

2H), 0.88 (t, J= 7.3 Hz, 3H); 13C NMR 6 152.6, 31.6, 31.2, 29.7, 22.6, 19.9, 14.1. HRMS

(EI) Calcd for C7H17N30 (M+I): 160.1444. Found: 160.1445.

5.4.2 General Procedure for the Preparation of Compounds 5.14a-h

To a solution of 5.10a-c,f,h or 5.11b (see Schemes 3 and 4) (0.68 mmol) in toluene

(10 mL), was added (0.75 mmol) of the hydrazine of choice followed by (1.36 mmol,

0.25 mL) of triethylamine. The reaction mixture was heated under reflux until full

conversion of starting materials (3h). Upon completion, the solvent was evaporated under

reduced pressure. The crude product was dissolved in methylene chloride, washed twice

with saturated aqueous sodium carbonate, dried over magnesium sulfate, and filtered. The

solvent was removed under reduced pressure. The desired N-aminoguanidines were

isolated by flash column chromatography on basic alumina (first ethyl acetate to remove

impurities and methanol to elute guanidine) to give 5.14a-h.









N-Isopropyl-N'-(4-methylphenyl)-l-hydrazinecarboximidamide (5.14a). oil (84%); 1H

NMR 6 7.78 (s, 1H), 7.27 (d, J= 8.1 Hz, 2H), 7.14 (d, J= 8.1 Hz, 2H), 4.02-3.91 (m,

1H), 2.37 (s, 3H), 2.10 (s, 2H), 1.17 (d, J= 6.3 Hz, 6H); 13C NMR 6 153.4, 139.7, 139.5,

130.9, 125.0, 45.6, 29.7, 23.1. Anal. Calcd for ClH18N4: C, 64.05; H, 8.79; N, 27.16.

Found: C, 63.98; H, 8.42; N, 27.01.

N-Butvyl-2-(4-methoxyphenyl)- 1-hydrazinecarboximidamide (5.14b). oil (91%); 1H NMR

6 7.73 (d, J= 9.1 Hz, 2H), 6.97 (d, J= 9.1 Hz, 2H), 3.88-3.81 (m, 5H), 2.17 (s, 1H), 1.57

(s, 3H), 1.32-1.26 (m, 4H), 0.88 (t, J= 7.1 Hz, 3H); 13C NMR 6 145.0, 129.3, 124.2,

114.0, 113.7, 55.4, 54.9, 30.7, 21.8, 14.0. Anal. Calcd for C12H20N40: C, 60.99; H, 8.53;

N, 23.71. Found: C, 61.39; H, 7.22; N, 23.64.

N-Benzyl-2,2-dimethyl-N'-(4-methylphenyl)-l-hydrazinecarboximidamide (5.14d). oil

(82%); H NMR 6 7.34-7.26 (m, 5H), 7.07 (d, J= 8.1 Hz, 2H), 6.72 (d, J= 8.1 Hz, 2H),

4.33 (s, 2H), 2.80 (s, 6H), 2.26 (s, 3H); 13C NMR 6 157.6, 138.2, 129.9, 128.7, 127.5,

127.3, 124.3, 121.8, 115.4, 49.8, 48.7, 39.4. Anal. Calcd for C17H22N4: C, 72.31; H, 7.85;

N, 19.84. Found: C, 72.05; H, 7.89; N, 19.48.

Ethyl-4-{ [(butvlamino)(2,2-dimethylhydrazino)methylene]amino}benzoate (5.14e). oil

(84%); H NMR 6 7.85 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 8.4 Hz, 2H), 5.60 (br s, 1H), 4.26

(q, J= 7.0 Hz, 2H), 3.25-3.20 (m, 2H), 2.37 (s, 6H), 1.57-1.45 (m, 2H), 1.35-1.28 (m,

5H), 0.89 (t, J= 7.4 Hz, 3H); 13C NMR 6 166.8, 154.5, 150.1, 131.5, 130.9, 122.9, 60.4,

47.9, 40.6, 31.8, 20.2, 14.4, 13.9. Anal. Calcd for C16H26N402: C, 62.72; H, 8.55; N,

16.28. Found: C, 62.90; H, 8.65; N, 16.00.

N-[(2,2-Dimethylhydrazino)(morpholino)methylene]benzamide (5.140. oil (84%); 1H

NMRR6 8.1-8.06 (m, 2H), 7.37-7.31 (m, 3H), 4.72 (s, 1H), 3.86-3.83 (m, 4H), 3.72-3.68









(m, 4H), 2.50 (s, 6H); "3C NMR 6 176.3, 161.0, 138.4, 131.1, 129.0, 127.8, 66.9, 48.0,

47,6. Anal. Calcd for C14H20N402: C, 61.25; H, 7.29; N, 19.17. Found: C, 61.59; H, 7.57;

N, 19.20.

N-Butvyl-2-methyl-2-phenyl- -hydrazinecarboximidamide (5.14g). oil (85%); 1H NMR 6

7.29-7.24 (m, 2H), 7.02-6.99 (m, 2H), 6.84-6.78 (m, 2H), 4.34 (br s, 1H), 3.73 (br s,

2H), 3.10 (s, 3H), 3.03 (t, J= 7.0 Hz, 2H), 1.59-1.51 (m, 2H), 1.41-1.34 (m, 2H), 0.93 (t,

J= 7.3 Hz, 3H); 13C NMR 6 152.5, 128.8, 118.5, 116.7, 113.4, 45.6, 44.4, 31.5, 19.3,

13.4 .HRMS calcd for C12H20N4 (M+1): 221.1761. Found: 221.1756.

AN'-(4-Chlorophenyl)-N-isopropyl-1,2-dimethyl-1-hydrazinecarboximidamide hydrate

(5.14h) oil (30%); 1H NMR 6 8.16 (br s, 1H), 7.20 (br s, 2H), 7.04 (br s, 2H), 4.55-4.46

(m, 1H), 1.94 (s, 3H), 1.81 (s, 3H), 1.22 ( d, J= 6.6 Hz, 6H); 13C NMR 6 148.7, 129.5,

129.0, 124.5, 116.2, 46.3, 29.7, 25.1, 22.5. Anal. Calcd for C12H19CIN4: C, 51.57; H,

8.52; N, 16.99. Found: C, 51.40; H, 8.42; N, 16.81.

5.4.3 Preparation of N,N-Diisopropyl-5-phenyl-l-(2-pyridinyl)-lH-1,2,4-triazol-3-amine
5.15

To a solution of (0.15g, 0.43 mmol) N-[1H-1,2,3-benzotriazol-1-yl

(diisopropylamino)methylidene]benzamide in 15 ml toluene, was added (0.14g,

1.3mmol) of 2-hydrazinopyridine. The mixture was stirred for 5 minutes and then

brought to reflux. After 2h, the reaction was stopped and the solvent evaporated under

vacuum. The crude product was washed with 10 % Na2CO3 and then extracted with

dichloromethane (3 x 20 ml). Evaporating the organic fraction followed by flash column

chromatography on basic alumina afforded 5.15 (0.13, 93%).

N,N-Diisopropyl-5-phenyl-1-(2-pyridinyl)- 1H-1,2,4-triazol-3-amine(5.15) Recrystallized

from EtOAc-Hexanes to give white crystals (93%), mp 104-105 OC; 1H NMR 6 8.30 (br









d, J=4.8 Hz, 1H), 7.72 (t d, J=8.1 Hz, 2.0 Hz, 1H), 7.55-7.50 (m, 3H), 7.36-7.29 (m,

3H), 7.15 (dd, J=7.5, 4.8 Hz, 1H), 4.17 (septet, J = 6.7 Hz, 2H), 1.37 (d, J= 6.9 Hz, 12H);

13CNMR6 163.1, 152.7, 151.3, 148.1, 138.2, 129.7, 129.2, 129.1, 127.9, 122.1, 118.2,

46.4, 20.7. Anal. Calcd for C19H23N5: C, 71.00; H, 7.21; N, 21.79. Found: C, 71.32; H,

7.56; N, 21.98.

5.4.4 General Procedure for the Preparation of Compounds 5.16 and 5.17

To a solution of 5.8a or 5.6 (see Schemes 5.3 and 5.4) (0.6 mmol) in toluene (10

mL), was added (1.8 mmol) of the hydroxylamine or hydrazine of choice followed by

(1.8 mmol, 0.3 mL) of triethylamine. The reaction mixture was heated under reflux until

full conversion of starting materials (30-45min). Upon completion, the solvent was

evaporated under reduced pressure. The crude product was dissolved in methylene

chloride, washed twice with saturated aqueous sodium carbonate, dried over magnesium

sulfate, and filtered. The solvent was removed under reduced pressure. The desired

products were isolated by flash column chromatography on basic alumina (first ethyl

acetate to remove impurities and methanol to elute guanidine) to give 5.16 and 5.17.

Ethyl-4- [(hvdroxvamino)(hvdroxvimino)methyl]amino benzoate (5.16). oil (90%); 1H

NMR 6 7.79 (d, J= 8.5 Hz, 2H), 6.57 (d, J= 8.5 Hz, 2H), 4.24 (q, J= 7.1 Hz, 2H), 3.99

(br s, 2H), 1.59 (br s, 1H), 1.29 (t, J= 7.1 Hz, 3H); 13C NMR 6 166.7, 150.7, 131.5,

123.0, 120.0, 113.7, 60.3, 14.4. HRMS calcd for C10H13 N3 04, (M+1): 240.2275. Found:

240.2280.

N-2-bis(4-methoxyphenvl)- 1-hydrazinecarboximidohydrazide (5.17). oil (61%); 1H NMR

6 7.66 (d, J= 8.9 Hz, 4H), 6.90 (d, J= 8.9 Hz, 4H), 3.81 (s, 4H), 1.50 (s, 6H); 13C NMR









6 140.0, 130.6, 129.3, 128.2, 113.8, 29.7. Anal. Calcd for C15H19N502: C, 59.79; H, 6.36;

N, 13.24. Found: C, 59.80; H, 6.46; N, 12.65.

5.4.5 Preparation of N'-Hydroxy- 1H-1,2,3-benzotriazole-1-carboximidamide 5.18

To a solution of (2.0 g, 7.6 mmol) di(1H-1,2,3-benzotriazol-1-yl)methaneamine in

THF (30 mL), was added (0.72 g, 15.2 mmol) of hydroxylamine hydrochloride followed

by of triethylamine (2.0 mL). The mixture was refluxed for 1 hour and then left to cool at

room temperature. The reaction mixture was washed with 10% Na2CO3, and extracted

with methylene chloride (3 x 20ml). The organic layer was dried over anhydrous

magnesium sulfate. Evaporating the solvent under reduced pressure afforded pure 18

(1.2g, 89%)

5.4.6 General Procedure for the Preparation of Compound 5.19

To (0.56 mmol) N-hydroxy- 1H-1,2,3-benzotriazole-1-carboximidamide 5.18 was added

(0.56 mmol) of the hydrazine of choice. The mixture was microwaved neat for 5 min. (T

:115 C, P: 120 W). The reaction was then stopped, and the mixture washed with 10%

Na2CO3 and extracted with dichloromethane (3 x 20ml). Evaporating the organic fraction

followed by flash column chromatography on basic alumina afforded 5.19.

N'-hydroxy-2-[(4-methylphenyl)sulfonyvl]-l-hydrazinecarboximidamide (5.19). oil

(61%); 1H NMR 6 7.38 (d, J 8.1 Hz, 2H), 7.10 (d, J= 7.8 Hz, 2H), 2.32 (s, 3H), 1.55

(s, 1H); 13C NMR 6 137.4, 133.9, 129.8, 129.7, 128.5, 21.0. HRMS (EI) calcd for

CsH12N403S (M+ Na): 267.2598. Found: 267.2593.














CHAPTER 6
MICROWAVE ASSISTED PREPARATIONS OF AMIDRAZONES AND
AMIDOXIMES

6.1 Introduction to Amidrazones

Amidrazones 6.1 display fungistatic, bacteriostatic, antimycotic activity

[01EJMC75], and also function as herbicides [63CA11276] and lipoxygenase-1 inhibitors

[01BBA88]. Amidrazones are used to prepare 1,2,4-triazines [55HCA1560].

Reactions of nitriles with hydrazines [Scheme 6.1, (i)] is frequently used for the

preparation of amidrazones [56JA2253, 61JOC3783, 63CA11276, 70CRV151] but the

outcome depends on the nature of the nitrile [56JA2253] and further reaction can give

dihydrotetrazines and subsequently tetrazines [70CRV151]. Alternative methods

(Scheme 6.1) for the synthesis of amidrazones avoid the use of nitriles by reaction of

hydrazine with (ii) imidates or their salts (X=0, S; R2= Alk) [68JOC1679, 92ACS671],

(iii) imidoyl halides [70CRV151, 79JCS 1961] (iv) amides and thioamides in the presence

of POC13 [50JA2783, 55HCA1560, 58JOC 1931], (v) dihydroxythiazoledioxides

[62JOC3240], or (vi) ketenimines (R, R1= Ar) [65JOC3718]. Further routes to

amidrazones include (vii) reaction of amines with hydrazonoyl halides (X= Cl, Br)

[46JA588, 58TL209, 02T5317]; (viii) reduction of nitrazones by ammonium sulfide

[58CA11919] or (ix) reduction of formazans (R, R1= Ar) [70CRV15 1]. Two possible

tautomers 6.1A and 6.1B exist for amidrazones (Scheme 6.2). IfN2 is substituted then

amidrazones 6.1 are fixed in form 6.1B otherwise, spectral data [73JOC1344] suggest

that amidrazones exist exclusively in form 6.1A (Scheme 6.2).










R1 ,R1
N N X
R-CEN R XR R CI R. NR
(i) (ii) (iii) (iv) R1 (X= S)



H x N1 ,
SN R1 N ON2,1 0 Ri
RA=N-R2 6.IA (v)
N (ix)
S6.1B H
N-R1 H-R
N N' R-C=C=N-R1
R NO2 R1 X
(viii) (vii) (vi)

Reagents:a (i-vi) reactions with hydrazine, (vii) reaction with amine
R, R1, R2 = alkyl or aryl

Scheme 6.1 Preparative routes to amidrazones


R-N1-R /N1-H 1 1
23N 3 I N1
N N> __< N2/ VYN'
6.1A H 6.1B R
fixed in form fixed in form
6.1A 6.1B

Scheme 6.2 Tautomeric forms of amidrazones

Thus, amidrazones are of two major types: class I which do not carry a substituent

on N2 and exist predominantly in structure 6.1A (Scheme 6.2); class II which are

substituted on N2 and exist necessarily as 6.1B (Scheme 6.2). Class I compounds can in

turn be divided into eight subclasses (A-H) as shown in Table 6.1 (two mono, three di,

three tri, one tetra substituted). Almost all of these sub-classes could potentially be made

by one or more of the existing methods; however, literature sub-structural searches

showed no known examples of compounds of class G. The present work provides an easy

access to novel class G in addition to classes A, B, D, E. As to class II, a single example









was reported for the preparation of such compounds as a hydroiodide salt in 75% yield

[84LAC283].

6.2 Introduction to Amidoximes

Amidoximes 6.2 are biologically active as antitumor agents [78Cancer Res.1291],

antimalerial agents [72JMC1194], and nitric oxide synthases (NOS) substrates

[98APMC375, 98B 17179]. Amidoximes are prodrugs for amidines [96JMC3139,

02DMR565], and intermediates for the preparation of heterocycles such as oxadiazoles

[03JOC7316]. Tautomerism in simple amidoximes had been the subject of some debate,

although most authors accept the structure of potentially tautomeric amidoximes to be the
"amino oxime" form (6.2A) not the "amino hydroxylamine" structure (6.2B) (Scheme

6.3).


R-N1-R N1-H N N


6.2A H 6.2B R
fixed in form fixed in form
6.2A 6.2B

Scheme 6.3 Tautomeric forms of amidoximes

Thus, similar to amidrazones, amidoximes 6.2 can be divided into two classes:

class I which do not carry a substituent on N2 exist predominantly as structure 6.2A

(Scheme 6.3); class II which are substituted on N2 exist necessarily as 6.2B (Scheme 6.3).

Common methods (Scheme 6.4) for the preparation of class I amidoximes include

reactions of hydroxylamines with (i) nitriles [62CRV155, 69JCS861, 76AJC357,

03H2287, 04JMC3642], (ii) thioamides [1886CB1668, 1891CB3658, 62CRV155] for the

preparation of aromatic amidoximes, (iii) imidates [1884CB184, 80JOC4198], or (iv)

amidines and their salts (49-52% yield) [1884CB184, 02PJC 1137].









Table 6.1 The eight class I amidrazones existing as 6.1A




6.1A


Mono-N- Tri-N-substituted Tetra-N-
Di-N-substituted
substituted substituted
Sub-class A B C D E F G H
Method N1 N3 N1N' N3N3 NIN3 NININ3 NIN3N3 NININ3N3
i N R N R N N N N
ii R R N R P N P N
iii R R N P R N P N
iv P R N P R R P R
v N P N R N N N N
vi R P N P P N P N
vii N R N P R P P P
viii N R N P N N N N
ix N R N P N N N N
x N P N N R P N N
This R P N P R N R N
work
R: Reported; P: Possible but no example reported; N: Not possible

Alternative routes include (v) reaction of amines with hydroximic acid chlorides

and oximinoethers [62CRV155, 80JOC4198, 82JCS907, 85JOC3348, 03CC1870,

04TL861]; (vi) reduction of oxyamidoximes [62CRV155]; (vii) platinum catalyzed

reduction of nitrosolic and nitrolic acids [62CRV155, 1906Ber1480], (viii) aldol

condensations of formamidoxime with aromatic aldehydes [62CRV155]; or (ix) oxazole

ring cleavage [88JHC931, 95H619]. A single procedure for the preparation of class II

amidrazones includes the reaction of imidoyl halides [03ARK96] with arylnitrenium ion

(Scheme 6.4) [83CB1822]. Moreover, O-substituted amidoximes are prepared directly by

the reaction of amidoximes with methyliodide or dimethylsulfate to give O-









methylamidoxime (22% yield) [80JOC4144, 89BSCB203], or acetylene to yield 0-

vinylamidoximes (80 % yield) [01S2427-33].

S
RJ 2 NH NH
R-C=N R N'
R R OR R NH2.HCI
(i) (ii) (iii) (iv)





R' (ix) N R LG
6.2A (v)



0 N' NOH N-OH
R Hv+H ii NH2 R NO2 R NHOH
(viii) (vii) (vi)

Reagents:a (i-iv) reactions with hydroxyamine or RONH2, (v) reaction with amine,
R, R1, R2 = alkyl or aryl, (vi) reduction with SO2, (vii) Platinum catalyzed reduction, (viii) aldol
condensation, (ix) photorearrangement of oxazole ring

Scheme 6.4 Preparative routes to amidoximes of type 6.2A

Amidoximes 6.2A can be divided into five sub-classes (two mono, two di, one tri)

substituted as shown in Table 6.2. As to amidoximes 6.2B, four sub-classes (one mono,

two di, one tri) can also exist as shown in Table 6.3. The ten reported methods for the

preparation of 6.2A and 6.2B (Schemes 6.4 and 6.5) generally target specific sub-classes

of amidoximes (Tables 6.2 and 6.3). We now report routes to many classes including

class I' where no examples have been reported to date.

R1R1 1
NR1 O N
R_____+___1 HO0, 2j),
R CIl + 0=N-Ph "N R
(x) Ph
6.2B
R, R1 = aryl


Scheme 6.5 Preparative routes to amidoximes of type 6.2B









6.3 Results and Discussion

Imidoylbenzotriazoles 6.3 have become important as stable alternatives to the

corresponding imidoyl chlorides [95H231, 01JOC1043, 04JOC5108]. Recently, we

reported a novel procedure for the preparation of amidines using imidoylbenzotriazoles

[06JOC3375-35]. We have now expanded the utility of imidoylbenzotriazoles to include

the preparation of amidrazones 6.1a-h and amidoximes 6.2a-h.

Imidoylbenzotriazoles 6.3a-h (Scheme 6.6) were prepared in good yields (50-91%)

from the reaction of secondary amide (1 equiv), oxalyl chloride (1 equiv) and

benzotriazole (2 equiv) in the presence of pyridine [06JOC3375-35]. The crude products

were chromatographed, after washing with sodium carbonate, on basic alumina

(EtOAc/Hex) to give pure imidoylbenzotriazoles 6.3a-h (Scheme 6.6). Known 6.3a-

e,g,h and novel 6.3f were fully characterized by 1H and 13C NMR spectroscopy, and in

the case of 6.3f by elemental analysis. Most imidoylbenzotriazoles are easy to handle and

can be stored indefinitely; however, we noted slow decomposition of 1-[phenyl(2-

pyridinylimino)methyl]-1H-benzotriazole 6.3g after 3 days.

Attempts to prepare amidrazones 6.1a-h in solution phase initially met with

significant difficulties: incomplete reaction at moderate conditions and decomposition on

extensive heating. We therefore turned to solvent-free solid supported synthesis.

Reagents immobilized on porous solid materials have several advantages over the

conventional solution phase reactions because of the good dispersion of active sites

leading to improved reactivity and milder reaction conditions; indeed solvent-free use of

supported reagents in combination with microwave irradiation gave reduced reaction

time, and easier work-up procedure and enhanced selectivity and reactivity [01TL5347].

Thus, stirring 1 equivalent of imidoylbenzotriazoles 6.3b-d,f with 1.5 equivalents of the









corresponding hydrazine in the presence of a 7 fold excess of sodium sulfate for 5-20

min under microwave irradiation afforded amidrazones 6.1a-h in 66-85% yields

(Scheme 6.6 and Table 6.4).

Table 6.2 Five sub-classes of amidoximes 6.2A




6.2A

Mono Di Tri
Sub-class A' B' C' D' E'
Method N O NN1 N1NO N NNO
i N P N N N
ii R R N P N
iii N P N N N
iv N N N R N
v R P N R N
vi N P N N N
vii N P N N N
viii N P N N N
ix N N N R N
This work R P N R N
R: Reported; P: Possible but not reported; N: Not possible

The progress of the reaction was monitored by TLC. Upon completion of the

reaction, water was added to remove sodium sulfate. The organic layer was extracted

with dichloromethane then purified using column chromatography to give novel 6.1a-h

as colorless oils. Structures of novel 6.1a-h were supported by NMR spectroscopy, high

resolution mass spectroscopy, and elemental analysis. Amidrazones 6.1a-h exhibit

tautomerism, thus, it is hard to assign the NH protons, especially since they were not

always visible.










Table 6.3 Four sub-classes of amidoximes 6.2B
1/
N
|O'N /
I 6.2B

Mono Di Tri
Sub-class F' G' H' I'
Method N2 N2O N1N2 N1 NO
x N N R N
This work P P R R
R: Reported; P: Possible but not reported; N: Not possible


R H R1
H HN' R2-N-NH2 N'

R2.-NN R / N N1,R

6.1a-h NN 6.3a-h



R5.O' N R4
H


NR1

R5'O' NJ R


0I R1
R3 N-NH2 R N
H N />R3
CH3COOH '-N
6.4a-d

6.3a R=Bn, Rl=p-Tol, 61%
6.3b R=Me, Rl=p-Tol, 67%
6.3c R=Ph, Ri=i-Bu, 60%
6.3d R=p-Tol, R1=4-MeOC6H4, 70%
6.3e R=Ph, Ri=Ph, 90%
6.3f R=Me, R1=i-Bu, 50%
6.3g R=Ph, R1=2-Pyridyl, 86%
6.3h R=2-Furyl, Rl=p-Tol, 91%


6.2a-h
For identity of R, R1, and R2, see Tables 6.4, 6.5, and 6.6



Scheme 6.6 Reactions of imidoylbenzotriazoles with hydrazines and hydroxylamines

Reacting imidoylbenzotriazole 6.3a,b,d with hydrazines (R3CONHNH2) in the

presence of catalytic amounts of acetic acid under microwave conditions afforded cyclic

1,2,4-triazoles 6.4a-d [03ARK62,03ARK65, 03ARK98, 05JOC6362] (Scheme 6.6 and

Table 6.5) via a simple intramolecular condensation followed by the loss of one molecule

of water. Upon completion of the reaction (5-10 min), the sample was diluted with

dichloromethane then purified using flash column chromatography to give 6.4a-d in 77-









100% yields. Novel 6.4a-d were isolated as white microcrystals and characterized by 1H

and 13C NMR spectroscopy and elemental analysis.

Table 6.4 Preparation of amidrazones 6.1a-h from 6.3b-d,f*
Imidoyl Conditions (t, Product Yield
benzotriazole R R R C, Power, W, Yield,
6.3 time, min)
6.3b Me p-Tol H 95, 105, 10 6.1a 85
6.3b Me p-Tol Ph 90, 120, 15 6.1b 70
6.3c Ph i-Bu PhCO 120, 130, 15 6.1c 72
6.3d p-Tol 4-MeOC6H4 Ph 80, 80, 10 6.1d 82
6.3f Me i-Bu 4-NO20C6H4 110, 120, 20 6.1e 68
6.3b Me p-Tol PhCO 120, 125, 12 6.1f 66
6.3c Ph i-Bu 4-ClC6H4CO 160, 160, 12 6.1g 87
6.3f Me i-Bu COCH3 105, 115,9 6.1h 80
Compounds 6.1c,e-h were prepared by my colleague Dr. Anamika Singh

Table 6.5 Preparation of 1,2,4-triazoles 6.4a-d from 6.3a,b,d
Imidoyl Conditions (t, Product
benzotriazole R R R3 C, Power, W, Yield,
6.3 time, min)
6.3a Bn p-Tol Me 80, 120, 10 6.4a 77
6.3b Me p-Tol p-Tol 80, 120, 5 6.4b 94
6.3d p-Tol 4-MeOC6H4 p-Tol 80, 120, 5 6.4c 100
6.3d p-Tol 4-MeOC6H4 Ph 80, 120, 10 6.4d 88

Amidoximes 6.2a-h were prepared in 65-81% yields from the reaction of

imidoylbenzotriazoles 6.3a-f,h with the corresponding hydroxylamines (Scheme 6.6 and

Table 6.6). Using microwave, reaction of imidoylbenzotriazole 6.3a-f,h with

hydroxylamines reached completion after 5 to 15 minutes. The reaction mixture was then

dissolved in DCM and washed with 10% solution of Na2CO3. The combined organic

layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The

residue obtained was purified by gradient column chromatography (EtAc/Hex) to obtain

pure amidoximes 6.2a-h. Structures of novel 6.2a-h were supported by elemental

analysis and 1H and 13C NMR spectra. The 1H spectra no longer showed distinctive









signals in the range of 7.0-8.2 ppm corresponding to the benzotriazole group. Some NH

protons were not visible due to fast exchange.

Table 6.6 Preparation of amidoximes 6.2a-h*


Imidoyl Conditions
bezotriazole R1 4 R5 (t, C, Product Yield,
6.3 Power, W, %
time, min)
6.3a Bn p-Tol H H 100, 120, 5 6.2a 65
6.3b Me p-Tol H Bn 100, 120, 10 6.2b 79
6.3c Ph i-Bu H Me 100, 120, 5 6.2c 68
6.3c Ph i-Bu Me H 60, 120, 5 6.2d 81
6.3d p-Tol 4-MeOC6H4 H H 100, 120, 5 6.2e 78
6.3e Ph Ph H Me 80, 120, 5 6.2f 80
6.3f Me i-Bu H Bn 80, 120, 15 6.2g 68
6.3h 2-Furyl p-Tol Me H 60, 100, 10 6.2h 73
Compounds 6.2a-d were prepared by my colleague Natalia Kirichinko

6.4 Aminoamidoximes and Diamidoximes

Aminoamidoximes 6.6 are compounds with both hydroxylamine and hydrazine

moieties. Previous preparations of such compounds include reacting oxime chlorides

[80JCS304] or simple amidoximes [66CRSAS592] with hydrazines to give

aminoamidoximes in 21-30% yields (Scheme 6.7). Diamidoximes 6.7 are compounds

with two hydroxylamine moieties and to the best of our knowledge, they are not known

in the literature (Scheme 6.8).


,NOH N.,OH
N H N
., R-N-NH2 N H3
X CH3 R N CH3
H
X= CI, NH2
R= H, Ph

Scheme 6.7 Preparative routes to aminoamidoximes

Aminoamidoxime 6.6 and diamidoxime 6.7 were prepared starting from 1H-1,2,3-

benzotriazol-1-yl-methanone oxime 6.5 (Scheme 6.8). Reagent 6.5 was prepared from the









appropriate oxime (1 equiv.), 1-chloro-1H-benzotriazole (1 equiv.), and potassium tert-

butoxide (1. lequiv.) in diethylether at -30C. The reaction was stirred at room

temperature for 5h before it was quenched with water and extracted with

dichloromethane. Evaporation of the organic layer afforded oxime 6.5 in 90% yield.

Using microwave, reagent 6.5 was reacted with the appropriate hydrazine or

hydroxylamine under mild conditions (refer to experimental section) to give 6.6 or 6.7

respectively (Scheme 6.8). Novel 6.6 and 6.7 were isolated as viscous oils and were

characterized by elemental analysis and 1H and 13C NMR spectra.

N'OH N OH NNO-R7
R6'.N R R6-N-NH2 N 'R 2 R7O N R
H N:N H
6.6 6.5 6.7
6.6 R=Ph, R6=SO2p-Tol, Yield= 70% 6.7 R=Me, R7 =Bn, Yield= 64%


Scheme 6.8 Preparation of aminoamidoxime 6.6 and diamidoxime 6.7

6.5 Conclusion

A simple, efficient, and broadly applicable synthetic methodology for the

preparation of amidrazones and amidoximes under microwave conditions has been

developed via the nucleophilic attack on imidoylbenzotriazoles by hydrazines or

hydroxylamines. The easy accessibility of imidoylbenzotriazoles from the corresponding

amide and the simple workup gives the approaches substantial utility.

6.6 Experimental Section

6.6.1 General Procedure for the Preparation of Amidrazones la-h

An intimate mixture of 6.3 (0.36 mmol), hydrazine (0.43 mmol) and sodium sulfate

(anhydrous, 0.3 g) was stirred in a sealed tube (10 mL) under microwave irradiation

(conditions vary in each case). After completion of the reaction as indicated by TLC, the









reaction mixture was washed with DCM (10 mL) then filtered off and washed with 5%

solution of Na2CO3 (2x15 mL). The combined organic layers were dried over anhydrous

MgSO4 and concentrated under reduced pressure. The residue obtained was either

recrystallized from EtOAc/hex (unless indicated otherwise) or purified by column

chromatography on silica gel with EtOAc/Hex to give pure 6.1a-h

N- (4-Methylphenyl)ethanehydrazonamide (6.1a). Viscous oil (85%); 1H NMR 6

6.97 (d, J= 8.4 Hz, 2H), 6.62 (d, J= 8.4 Hz, 2H), 4.8 (br s, 1H), 2.42 (s, 3H), 2.23 (s,

3H). ; 13CNMR6 142.6, 129.7, 125.5, 124.1, 117.5, 115.2, 20.4, 10.0. Anal. Calcd for

C9H13N3: C, 66.23; H, 8.03; N, 25.74. Found: C, 66.47; H, 8.21; N, 25.70.

NA -(4-Methylphenvl)-N'-phenylethanimidohydrazide (6.1b). Colorless oil (70%); 1H

NMR 6 7.29-7.04 (m, 10H), 2.31 (s, 3H), 2.04 (s, 3H), 1.95 (br s, 2H); 13C NMR 6

153.3, 130.4, 129.5, 128.9, 128.2, 127.1, 125.2, 122.5, 121.0, 29.7, 25.2. Anal. Calcd for

C15H17N3: C, 75.28; H, 7.16; N, 17.56. Found: C, 75.44; H, 7.01; N, 17.01.

N-(4-Methoxyphenyl)-4-methyl-N'-phenvlbenzenecarbohydrazonamide 1/2hydrate

(6.1d). Yellow oil (82%); 1H NMR 6 7.57 (d, J= 8.0 Hz, 2H), 7.21-7.26 (m, 3H), 7.13

(d, J= 8.0 Hz, 2H), 7.07 (d, J= 8.0 Hz, 2H), 6.84 (t, J= 7.2 Hz, 1H), 6.75-6.78 (m, 2H),

6.63-6.68 (m, 2H), 5.60 (br s, 1H), 3.73 (s, 3H), 2.34 (s, 3H); 13C NMR 6 154.3, 145.5,

139.8, 138.9, 134.6, 132.0, 129.1, 126.7, 119.8, 118.3, 115.1, 114.6, 113.3, 55.5, 21.3.

Anal. Calcd for C42H42N602.0.5H20: C, 74.09; H, 6.51; N, 12.34. Found: C, 74.45; H,

6.78; N, 12.03.

6.6.2 General Procedure for the Preparation of Amidoximes 6.2a-h

A mixture of the appropriate 6.3 (0.35 mmol) (see Scheme 6.6 and Table 6.6),

hydroxylamine hydrochloride (0.4 mmol) and Et3N (0.4 mmol) was stirred in a sealed