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Efficient Methodology for the Synthesis of 2,4-Benzodiazepin-1-ones, Sulfonylbenzotriazoles, Sulfonamides, Ethylene Sul...


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EFFICIENT METHODOLOGY FOR THE SY NTHESIS OF 2,4-BENZODIAZEPIN-1ONES, SULFONYLBENZOTRIAZOLES, SULFONAMIDES, ETHYLENE SULFONAMIDES, THIOCARBAMA TES, DITHIOCARBAMATES AND THIOAMIDES By VALERIE RODRIGUEZ-GARCIA 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 2004

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I owe my achievements to my family, my mother Iris Garc ia, my father Francisco V. Rodriguez, my brothers Emmanuel and Rasi k, my cousins Sonia, Mia Alexandra and Roberto Mateo. I have been ra ised in their deepest love, a nd it continues today also. This I do for them.

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ACKNOWLEDGMENTS I want to mention first that I believe nothing happens without a purpose. My life these past years has been guided to make much sense, for all the things I have seen I never thought I would, all the places I have visited and all the caring beings that have been included in the story of my life. I definitely owe so much to graduate school and to those who made it possible. Forever my respect and gratitude go to my supervisor, Professor Alan R. Katritzky, and to my supervisory committee members, Dr. William R. Dolbier, Dr. Eric Enholm, Dr. Steven A. Benner and Dr. Dinesh O. Shah. I immensely thank Dr. Jeffrey L. Krause; the date of my final defense would not have been possible if he had not agreed to assist. I thank Dr. Dennis Hall for correcting my thesis, and thanks go to Dr. Suman Majumder and to Dr. Sanjay Singh for their help always in English and content corrections. I thank all Katritzky members for their friendship and encouragement. I want to give special thanks to Eladio Rivera and Wigberto Hernandez for their help during my undergraduate studies and for their friendship through distance. I thank my husband Igor V. Schweigert and my other loves in the Chemistry Department, Rachel Witek, Hongfang Yang and Chaya Pooput, for their support and their genuine interest in my well being. iii

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TABLE OF CONTENTS page ACKNOWLEDGMENTS..................................................................................................iii LIST OF TABLES............................................................................................................vii LIST OF FIGURES.........................................................................................................viiii LIST OF SCHEMES........................................................................................................ixx ABSTRACT.......................................................................................................................x i CHAPTER 1 GENERAL INTRODUCTION...................................................................................1 2 ONE POT SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES USING BENZOTRIAZOLE METHODOLOGY....................................................................5 2.1 Introduction..........................................................................................................5 2.2 Results and Discussion.........................................................................................8 2.3 Conclusion..........................................................................................................12 2.4 Experimental Section.........................................................................................12 2.4.1 General Procedure for the Preparation of N, N-bis(Benzotriazolylmethyl)alkyl amines 2.9a-d...................................12 2.4.2 General Procedure for the Preparation of N-Alkyl-arylbenzamides 2.11a-d.................................................................................................13 2.4.3 General Procedure for the Preparation of 2,4-Benzodiazepin-1-ones 2.13a-h.................................................................................................15 3 A GENERAL AND EFFICIENT SYNTHESIS OF SULFONYLBENZOTRIAZOLES FROM N-CHLOROBENZOTRIAZOLE AND SULFINIC ACID SALTS...............................................................................19 3.1 Introduction........................................................................................................19 3.2 Results and Discussion.......................................................................................24 3.2.1 Preparation of Benzotriazole Reagents 3.27..........................................24 3.2.2 Synthesis of Sulfonamides 3.29-3.37 using Reagents 3.27...................28 3.3 Conclusion..........................................................................................................29 3.4 Experimental Section.........................................................................................31 iv

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3.4.1 General Procedure for the Preparation of Sulfonylbenzotriazoles 3.27aj.................................................................................................31 3.4.2 General Procedure for the Preparation of Sulfonamides 3.293.37......34 4 1-[2-BENZOTRIAZOL-1-YL)ETHYL]SULFONYLBENZOTRIAZOLE: A VERSATILE SYNTHON FOR THE PREPARATION OF ETHYLENESULFONAMIDES AND ALKYLSULFONATE ESTERS................38 4.1 Introduction........................................................................................................38 4.2 Results and Discussion.....................................................................................433 4.2.1 Preparation of Sulfonamides 4.7a-g and Sulfonate ester 4.7h............444 4.2.2 Preparation of Ethylenesulfonamides 4.8a, f.......................................455 4.3 Conclusion..........................................................................................................46 4.4 Experimental Procedure.....................................................................................46 4.4.1 Procedure for the Synthesis of Novel Intermediate 4.5.......................466 4.4.2 General Procedure for the Preparation of Sulfonamides 4.7a-g............47 4.4.3 Procedure for the Preparation of Sulfonate ester 4.7h...........................49 4.4.4 General Procedure for the Synthesis of Ethylenesulfonamides 4.8a, f.50 5 VERSATILE SYNTHESIS OF THIOCARBAMOYLBENZOTRIAZOLES, THIOAMIDES, THIOCARBAMATES AND DITHIOCARBAMATES FROM BIS(BENZOTRIAZOLYL)METHANETHIONE...................................................52 5.1 Introduction........................................................................................................52 5.2 Results and Discussion.......................................................................................55 5.2.1 Preparation of 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5.............55 5.2.2 Preparation of Thioamides 5.9a-j..........................................................57 5.2.3 Preparation of Thiocarbamates (5.10) and Dithiocarbamates (5.11) from Thiocarbamoylbenzotriazoles 5.5...............................................59 5.3 Conclusion..........................................................................................................62 5.4 Experimental Section.........................................................................................63 5.4.1 General Procedure for the Preparation of 1-Alkyland 1-Aryl-thiocarbamoylbenzotriazoles 5.5a-k....................................................63 5.4.2 General Procedure for the Preparation of Mono-substituted Thioamides 5.9a-f................................................................................67 5.4.3 General Procedure for the Preparation of Di-substituted Thioamides 5.9g-j....................................................................................................69 5.4.4 General Procedure for the Preparation of Di-substituted Thiocarbamates 5.10a-b.....................................................................70 5.4.5 General Procedure for the Preparation of Di-substituted Dithiocarbamates 5.11a.......................................................................71 5.4.6 General Procedure for the Preparation of Mono-substituted Dithiocarbamates 5.11b-d....................................................................72 v

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6 CONCLUSION.........................................................................................................74 REFERENCES...................................................................................................................75 BIOGRAPHICAL SKETCH..............................................................................................83 vi

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LIST OF TABLES Table page 2-1 Synthesis of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d .............................8 2-2 Yield of benzamides prepared ....................................................................................9 2-3 Yields of 2, 4-Benzodiazepine-1-ones prepared ......................................................11 3-1 Alkyl/arylsulfonylbenzotriazoles 3.27 .....................................................................28 3-2 Sulfonamides 3.29-3.37 prepared using reagents 3.27 .............................................30 4-1 Sulfonamides 4.7a-g and sulfonate ester 4.7h prepared ..........................................45 5-1 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 prepared ........................................56 5-2 Preparation of mono-substituted thioamides from thiocarbamoylbenzotriazoles ....58 5-3 Preparation of di-substituted thioamides from thiocarbamoylbenzotriazoles ..........59 5-4 Preparation of thiocarbamates 5.10 ..........................................................................61 5-5 Preparation of dithiocarbamates 5.11 ......................................................................62 vii

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LIST OF FIGURES Figure page 2-1 Biologically active benzodiazepines ..........................................................................6 2-2 1H NMR spectrum of 2.13b .....................................................................................18 3-1 Prontosil 3.1 and the active metabolite sulfanilamide 3.2 ........................................19 3-2 Various clinically used sulfonamide drugs ..............................................................20 1H NMR spectrum of 1-(2-thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h) 3-3 ..........27 4-1 Intermediate 4.1 used in the preparation of ethylenesulfonamides ..........................43 5-1 Organometallic reagents used ..................................................................................57 5-2 Alcohols and thiols used ..........................................................................................60 viii

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LIST OF SCHEMES Scheme page 1-1 Some isomers of N-substituted benzotriazoles ..........................................................2 2-1 Literature methods to synthesize 2,4-benzodiazepines ..............................................7 2-2 Retrosynthetic analysis ...............................................................................................7 2-3 Preparation of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d ..........................8 2-4 Preparation of benzamides .........................................................................................9 2-5 Synthesis of 2, 4-Benzodiazepine-1-ones ................................................................11 3-1 Example of the preparation of sulfonamides ............................................................21 3-2 Various methods for the synthesis of sulfonamides .................................................22 3-3 Synthesis of benzenesulfonamides and aryl benznesulfonates from 1-phenylsulfonylbenzotriazole .................................................................................23 3-4 Synthesis of p-tolylsulfonylbenzotriazole using our method ...................................25 3-5 Proposed mechanism for the formation of sulfonylbenzotriazoles ..........................25 3-6 Preparation of 1-alkyl/arylsulfonylbenzotriazoles 3.27 ...........................................28 3-7 Preparation of sulfonamides .....................................................................................29 4-1 Transformations of ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters .........................................................................................................................39 4-2 Desulfonation Reactions ..........................................................................................40 4-3 Synthetic protocols toward ethylenesulfonate esters, vinyl sulfones and ethylenesulfonamides ...............................................................................................42 4-4 Synthesis of 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5 ......................43 4-5 Attempt to prepare 4.2 ..............................................................................................44 ix

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4-6 Preparation of sulfonamides and sulfonate ester 4.7 ................................................45 4-7 Synthesis of ethylenesulfonamides ..........................................................................46 5-1 Preparation of bis(benzotriazolyl)methanethione 5.3 ..............................................52 5-2 Use of bis(benzotriazolyl)methanethione 5.3 in the preparation of thioureas 5.7 ...53 5-3 Synthetic utility of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 .........................55 5-4 Preparation of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 .................................56 5-5 Preparation of thioamides 5.9 ...................................................................................58 5-6 Synthesis of thiocarbamates 5.10 and dithiocarbamates 5.11 ..................................61 x

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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy EFFICIENT METHODOLOGY FOR THE SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES, SULFONYLBENZOTRIAZOLES, SULFONAMIDES, ETHYLENE SULFONAMIDES, THIOCARBAMATES, DITHIOCARBAMATES AND THIOAMIDES By Valerie Rodriguez-Garcia August 2004 Chair: Alan R. Katritzky Major Department: Chemistry Benzotriazole, as a synthetic auxiliary, provided an efficient methodology for the preparation of various pharmaceutically and industrially important compounds. Benzodiazepines display potent pharmacological activity. Published synthetic routes to 2,4-benzodiazepines-1-ones are scarce. N, N-Bis(benzotriazolylmethyl)-alkylamines are excellent nitrogen centered 1, 3-dication synthons, which taken in one-pot reactions with ortholithiated benzamides in the presence of zinc bromide provided novel 2,4-benzodiazepin-1-ones in moderate to good yields. The details are shown in Chapter 2. Sulfonylbenzotriazoles are very stable and efficient sulfonylating agents. In Chapter 3 N-(alkane-, areneand heteroarene-sulfonyl)benzotriazoles were prepared in one-pot, in yields of 41% by reaction of N-chlorobenzotriazole with various sulfinic acid salts (produced from organometallic reagents with SO 2 ). Reactions of xi

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sulfonylbenzotriazoles with primary and secondary amines at 20 o C afforded sulfonamides in 64% yield. Sulfonamides are used as antibacterial and anti microbial drugs. In Chapter 4 other alkyl sulfonamides, some ethylene sulfonamides and an alkylsulfonate ester were also prepared in good yields utilizing the stable solid 1-{[2-(1H-1,2,3-benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole. 1-{[2-(1H-1,2,3-Benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole is a potential replacement for 2-chloroethylsulfonyl-1-chloride, which is commonly used in these type of reactions. Thioamides, thiocarbamates and dithiocarbamates are also industrially important. Reactions of thiocarbamoylbenzotriazoles with carbon, oxygen, and sulfur nucleophiles afforded the corresponding thioamides, thiocarbamates, and dithiocarbamates in 36-99% yields. Some thiocarbamoylbenzotriazoles, prepared in yields of 76-100%, act as efficient isothiocyanate analogues (Chapter 5). xii

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CHAPTER 1 GENERAL INTRODUCTION Benzodiazepines, sulfonamides, thiocarbamates dithiocarbamates and thioamides display potent pharmacological activity. Some benzodiazepines are naturally occurring antitumor antibiotics [99JOC290] and others are industrially important anti-psychotic drugs [02JMC5136]. Sulfonamides include bactericidal and anti-infective drugs [90MI_255]. Examples of thiocarbamates are good insecticides [90JAE293], herbicides [75MI_675] and nematocides [89MI_158]. Some dithiocarbamates are fungicides and others are used as additives in the rubber industry. Various thioamides exhibit antileprosy [85MI_587], anthelmintic [01MI_1000], immunosuppressive [98MI_2203] and antituberculotic [02IF71] activity. Also, thiocarbamates, dithiocarbamates and thioamides are precursors of interesting molecular functionalities. In the field of synthesis, new pathways to efficiently produce scientifically attractive compounds are constantly being sought. It is important industrially to find synthetic approaches that can produce as many derivatives as possible, in good quantities and with easy purification methods. For more than 20 years our group has been exploiting the versatility of benzotriazole [98CRV409], towards new and better methodologies for the synthesis of organic compounds. Benzotriazole is an effective synthetic auxiliary. It is easily introduced at the beginning of a synthetic sequence and easy to remove at the end of a synthetic sequence. Benzotriazole intermediates are stable under many synthetic conditions. In addition to being a good leaving group, when activated by an electron donor group, benzotriazole also selectively activates the part of 1

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2 the molecule to which it is attached without affecting the chemical properties of other functionalities in the molecule. Benzotriazole, as a byproduct of a reaction, is easily removed in the workup by a mild base wash. Some N-substituted benzotriazoles exist as 1and 2-substituted isomers (Scheme 1). This happens when a benzotriazole anion can dissociate from a molecule and reattach itself at a different position. The isomers often exist in equilibrium and show the same reactivity and stability, so it is not necessary to separate them for subsequent reactions. NNN X R NNN R X NNN H R X+ 1-substituted Bt 2-substituted Bt 1.3 tendency for X=NR2, OR, SR 1.2 1.4 Scheme 1-1. Some isomers of N-substituted benzotriazoles Many properties of N-substituted benzotriazoles are comparable to those of the halogen analogues, but with the advantage of extra stability, easier preparation, versatility and non-toxicity. Other than the easy preparation of the benzotriazole derivatives studied here, the efficient and selective elimination of benzotriazole from the molecules upon reaction with nucleophilic carbons, amines, alcohols and mercaptans justifies the importance of the methodology presented here. Many reactions utilizing substituted benzotriazoles as reagents are more convenient than commonly used methods. Particularly N, N-bis(benzotriazolylmethyl)alkyl amines are very interesting reagents.

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3 They act as bis-electrophiles, liberating benzotriazole in the presence of acids or strong nucleophiles, allowing for one pot procedures. This is the advantage that makes them good synthons for the preparation of 2,4-benzodiazepin-1-ones (Chapter 2). Sulfonylbenzotriazoles are efficient sulfonating reagents, much more stable than the commonly used sulfonyl halides. Many of them are solids, easy to handle and store. The benzotriazole in sulfonylbenzotriazoles can be substituted by amines or alcohols to give sulfonamides and sulfonate esters under mild conditions and without the need for a base. Utilizing N-chlorobenzotriazole and sulfinic acid salts these sulfonylbenzotriazoles are readily prepared (Chapters 3). The synthesis of ethylenesulfonamides also takes advantage of the stability that benzotriazole induces in a molecule, and the selectivity when attempting substitution and elimination of benzotriazole. The ethylenesulfonamide generating derivative, 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole, contains two benzotriazole moieties that can be eliminated to afford a variety of ethylenesulfonamides. Due to its characteristics, the first nucleophilic attack by an amine displaces the benzotriazole attached to the sulfur atom, the second one leaving by elimination upon reaction with a strong base (Chapter 4). Thioamides, thiocarbamates and dithiocarbamates are now synthesized from thiocarbamoylbenzotriazoles for the first time (Chapter 5). Many thiocarbamoylbenzotriazoles act as effective isothiocyanate equivalents, which are building blocks in many synthetic operations such as in the formation of heterocycles [03JOC8693]. Bisbenzotriazolylmethanethione, a benzotriazole derivative of thiophosgene, is the precursor to thiocarbamoylbenzotriazoles. This derivative exhibits great stability and tremendous selectivity towards nucleophilic substitution.

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4 In summary, efficient approaches for the preparation of 2,4-benzodiazepin-1-ones, N-(alkyland aryl-sulfony)lbenzotriazoles, sulfonamides, ethylenesulfonamides, thiocarbamates, thioamides and dithiocarbamates were discovered utilizing benzotriazole methodology. N-(Alkyland aryl-sulfonyl)benzotriazoles were synthesized from scratch for the first time, and applied to the preparation of novel sulfonamides. The procedures herein take advantage of the benzotriazole anion as a selective but good leaving group, which can be displaced by carbon nucleophiles, amines, mercaptans and alcohols.

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CHAPTER 2 ONE POT SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES USING BENZOTRIAZOLE METHODOLOGY 2.1 Introduction Benzodiazepines are a class of compounds that have selective activity against a diverse array of biological targets. Their basic structure comprises a benzene ring fused to a seven-membered ring heterocycle, which contains two nitrogen atoms within the ring (Figure 2-1). The names of the benzodiazepines are derived from the location of the nitrogen atoms within the heterocycle ring. 2,3-Benzodiazepines have been evaluated for their anticonvulsant, anti epileptic and anti seizure properties [99JMC4414; 00JMC4834]. 1,4-Benzodiazepines are the most commonly studied because their derivatives display a wide variety of properties, and they have the ability to mimic natural ligands [88JMC2235]. For example, pyrrolo-1,4-benzodiazepin-5-ones occur as antitumor agents (2.1), gene regulators, and DNA probes [99JOC290] whereas 1,4-benzodiazepin-2,5-diones are anticonvulsants [89JHC1807] and potent inhibitors of platelet aggregation [94JA5077]. Drugs currently in use in the treatment of anxiety, panic, schizophrenia, and sleep disorders contain the 1,4-benzodiazepine core (Valium (2.2) and Xanax (2.3)) and 1,5-benzodiazepines are being investigated for their central nervous system depressant properties [02JMC5136; 00JMC3596]. Additionally, many benzodiazepine alkaloids found in nature, such as Circumdatin F (2.4) and Circumdatin C (2.5), are isolated from the fungus Aspergillus ochraceus [01JOC2784]. 5

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6 O NHMe H NN O R N N O Cl Me N Cl NNN Me N O OH N H MeO Antibiotic DC-81 2.1 Valium Xanax 2.2 2.3 F: R = HC: R = OH 2.4 2.5 Circumdatin Figure 2-1. Biologically active benzodiazepines Much of the literature to date has focused on the development of structure-activity relationship (SAR) studies and synthetic (library) strategies for 1,4-benzodiazepines [99OL1835; 97JOC1240; 98JOC8021], 1,5-benzodiazepines [00JMC3596; 00OL3555; 00JCB513], and 2,3-benzodiazepines [99JMC4414; 00JMC4834]. Very little has been reported on the synthesis of 2,4-benzodiazepines. Bocelli et al. [99TL2623] synthesized a 2,4-benzodiazepin-1,3-dione derivative by the palladium-catalyzed intramolecular cyclization of 1-butyl-1(o-iodobenzyl)-3-phenylurea (Scheme 2-1, reaction a) and Mohrle and Lessel reported the synthesis of 2,4-benzodiazepin-1-one by electrolysis of 2-[(dimethylamino)methyl]benzamide (Scheme 2-1, reaction b) [91AP367]. These previous methods produce low yields of the desired 2,4-benzodiazepine and the method described in reaction (b) utilizes toxic mercury.

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7 I N N H Bu Ph O N N O Bu O Ph N Bu O N NH2 O NH NO N O CO, Pd(0) 80oC + (a) (b) Hg(II)-EDTA + Scheme 2-1. Literature methods to synthesize 2,4-benzodiazepines We envisioned that a facile synthetic route to 2,4-benzodiazepin-1-ones would be achieved by the connection of benzamides to bis electrophilic alkyl/aryl amines (Scheme 2-2). This requires connection of the ortho position and the nitrogen atom of the benzamide to a nitrogen centered 1,3-dicarbocation to form the seven membered ring. N N O R R NH O R N X X R 11 Scheme 2-2. Retrosynthetic analysis N, N-Bis(benzotriazolylmethyl)alkylamines 2.9 (Scheme 2-3) have been used previously for the synthesis of julolidines [96JOC3117], 1,3-oxazolidines [98TL6835] and 3-arylpyrrolidines [98H2535]. Bis(benzotriazolylmethyl)amines 2.9 are nitrogen centered 1, 3-dication synthons, as exemplified by the synthesis of substituted piperidines [99JOC3328].

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8 N-Alkylbenzamides afford dianions upon treatment with 2 equivalents of a strong base. Coordination of the base to either heteroatom, N or O, in the amide moiety, directs the deprotonation of the ortho position in the phenyl ring. This synthetic strategy is well known in directed ortho metalation chemistry [90CRV879]. N-Alkyland N-aryl-benzamides 2.11a-d were prepared (Scheme 2-4), and were then used in the directed ortho metalation process to generate ortholithiated benzamides. Below we report the use of benzotriazole methodology combined with an ortho metalation procedure to produce 2,4-benzodiazepin-1-ones in one pot. 2.2 Results and Discussion N, N-Bis(benzotriazolylmethyl)alkyl amines 2.9a-d were easily prepared by the reaction of primary amines, benzotriazole and formaldehyde following published procedures [87JCS(P1)799; 90CJC446] (Scheme 2-3, Table 2-1 ). NHNN H H O NNN NNN N R NH2R1 (2eqs) + + (2eqs)1 MeOH/H2O p-TsOH 2.9a-d 2.6 2.7 2.8 Scheme 2-3. Preparation of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d Table 2-1. Synthesis of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d R 1 2.9 Yield (%) a C4H9 60 b Phenethyl 92 c Cyclohexyl 70 d C2H5 69

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9 Compounds 2.9a-d were characterized by 1 H and 13 C NMR spectra. For the four compounds the 1 H NMR showed the characteristic singlet peak due to Bt-CH 2 -N at 5.6-6.0 ppm and integrating for four protons. In the 13 C NMR the Bt-CH 2 -N carbons were found at 63.0-64.0 ppm. Compounds 2.9a and b showed various degrees of isomerization to the 2-benzotriazole systems. In these instances, where 1-substituted benzotriazole and 2-substituted benzotriazole were present together, all the peaks in the spectra appeared as a double set of signals. Reactions of benzoyl chloride with the respective amines provided benzamides 2.11a-d. These were also identified by 1 H and 13 C NMR spectra. For example, the 1 H NMR of 2.11 b displayed the expected signal characteristic of a tert-butyl group at 1.42 ppm as a singlet with an integral of nine protons. The signals for the phenyl ring were also visible as five protons at 7.38-7.73 ppm. The N-H peak was found as a singlet at 5.99 ppm. The carbonyl peak (C=O) was visible in the 13 C NMR at 167.0 ppm. Cl O NH O R NH2RNEt3CH2Cl22.102.11 Scheme 2-4. Preparation of benzamides Table 2-2. Yield of benzamides prepared 2.11 R Yield (%) a CH3 71 t Bu b 80 c C6H5 63 p-ClC6H6 d 42

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10 N-Methylbenzamide 2.11a was treated with butyllithium at o C in tetrahydrofuran, then stirred for 1 h at room temperature and reacted with bisbenzotriazolyl derivative 2.9a (Scheme 2-5). After workup, only the starting materials were recovered. Tetramethylene diamine (TMEDA) was then used to help in the formation of the dimetalated benzamide. TMEDA was added to 2.11a in THF, followed by butyllithium at o C and reagent 2.9a. The starting materials were recovered once more. However, when ZnBr 2 was added to the reaction mixture the reaction took place as desired. After addition of 2.9a, the reaction mixture was stirred overnight at room temperature. Aqueous workup and isolation yielded the benzodiazepin-1-one 2.13a in 22% yield but the yield of 2.13a was improved to 64% by conducting the reaction at 10 o C. The ZnBr 2 acts in this reaction as a Lewis acid, by activating the benzotriazole and thus facilitating C-N bond scission, a common feature of benzotriazole chemistry [99JOC3328]. Bis(benzotriazolylmethylalkyl)amines prepared from other primary amines reacted similarly under the modified conditions giving the corresponding 2,4 benzodiazepin-1-ones 2.13b-h in good to moderate yields. The results are summarized in Table 2-3. The 1 H and 13 C NMR spectra of 2.13a-h were in accordance with the proposed structures. 1 H NMR and 13 C NMR showed no evidence for the presence of benzotriazole. Two distinct singlets in the region between 3.5-5.8 ppm appeared in the 1 H NMR for compounds 2.13 a, cd. Each singlet integrated for two protons and both were assigned to the two new bonds formed with -CH 2 -NR-CH 2 -. Compound 2.13b is a very interesting example, where instead of two singlets the 1 H NMR spectra displayed only a singlet at 3.77 ppm integrating for four hydrogens (Figure 2-2). This denotes that the

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11 protons in -CH 2 -NR-CH 2 -, after the new bonds formed in 2.13b, are accidentally equivalent. CH3-C4H9C6H5R NH O R N OLi R Li N N O R R N Bt Bt R 11 C4H9C6H5(CH2)2C2H5cyclohexyl NNN -ClC6H4R 1 2.11 a b c d 2.11a-d 2.12 1. ZnBr2 BuLi/-10o C THF 2. 2.9a-d t2.9 a b c d 2.13a-h Bt = p Scheme 2-5. Synthesis of 2, 4-Benzodiazepine-1-ones Table 2-3. Yields of 2, 4-Benzodiazepine-1-ones prepared Entry R R 1 Yield(%) 2.13a CH 3 C 4 H 9 64 2.13b t Bu C 4 H 9 82 2.13c C 6 H 5 Phenethyl 53 2.13d pCl-C 6 H 4 C 4 H 9 57 2.13e C 6 H 5 C 4 H 9 47 2.13f t Bu Phenethyl 36 2.13g C 6 H 5 cyclohexyl 74 2.13h CH 3 cyclohexyl 57

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12 2.3 Conclusion We have demonstrated the capability of benzotriazole reagents 2.9 as dication sources. Utilizing simple chemistry we have carried out a one-pot synthesis of 2,4-benzodiazepin-1-ones starting from easily affordable starting materials. 2.4 Experimental Section Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution. Column chromatography was performed on silica gel (300-400 mesh). Elemental analyses were performed on a Carlo Erba-1106 instrument. THF was distilled from sodium-benzophenone ketal prior to use. All the reactions were performed under a nitrogen atmosphere and in oven dried glassware. 2.4.1 General Procedure for the Preparation of N, N-bis(Benzotriazolylmethyl)alkyl amines 2.9a-d The respective primary amine (20 mmol) and benzotriazole (40 mmol) were dissolved in methanol/water (4:1). Formaldehyde was added (40 mmol) and a catalytic amount of para-toluenesulfonic acid. The mixture was stirred for 18 h. The precipitate was filtered and washed with hexanes. N-bis(Benzotriazolyl-1-methyl)butylamine (2.9a): Filtered, washed with hexanes and obtained as colorless crystals (60%), mp 85-87 C (Lit. mp 111-114 o C, [90JCS(P1)541]). 1 H NMR 0.80 (t, J = 7.1 Hz, 3H), 1.22 (q, J = 7.3 Hz, 2H), 1.58 (t, J = 7.7 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 5.63 (s, 4H), 7.42 (t, J = 7.6 Hz, 2H), 7.54 (t, J = 8.1 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.2 Hz, 2H). 13 C NMR 13.69, 20.0, 29.6, 50.3, 64.4, 109.9, 120.1, 124.4, 127.9, 133.3, 146.1.

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13 N-bis(Benzotriazolyl-1-methyl)phenethylamine (2.9b): Filtered, washed with hexanes and obtained as white crystals (92%), mp 117-118C (Lit. mp 122-124 o C, [87JCS(P1)799]). 1 H NMR 2.632.67 (m, 2H), 2.973.03 (m, 2H), 5.94 (s, 4H), 6.97 (s, 2H), 7.12 (m, 3H), 7.427.47 (m, 2H), 7.547.59 (m, 2H), 7.95 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H). 13 C NMR 34.1, 52.3, 64.5, 109.9, 120.1, 124.3, 126.5, 128.0, 128.5, 128.6, 133.2, 138.7, 146.1. N-bis(Benzotriazolyl-1-methyl)cyclohexylamine (2.9c): Filtered, washed with hexanes and obtained as white crystals (70%), mp 119.0.0C, (Lit. mp 118-119 o C, [87JCS(P1)799]). 1 H NMR 8.09 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.347.52 (m, 4H), 5.71 (s, 4H), 3.06 (m, 1H), 1.451.82 (m, 6H), 0.091.04 (m, 4H). 13 C NMR in DMSO 25.1, 25.5, 30.2, 59.1, 63.3, 111.1, 119.2, 124.1, 127.4, 132.6, 145.4. N-bis(Benzotriazolyl-1-methyl)ethylamine (2.9d): Recrystallized in ethanol, filtered and washed with hexanes. Obtained as white crystals (69%), mp 79-81C (Lit. mp 82-84 o C, [87JCS(P1)799]). 1 H NMR 1.26 (t, J = 7.2 Hz, 3H), 2.98 (q, J = 7.2 Hz, 2H), 5.68 (s, 4H), 7.46 (t, J = 7.8 Hz, 2H), 7.58 (t, J = 7.8 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.1Hz, 2H). 13 C NMR 13.0, 45.0, 63.9, 109.9, 120.1, 124.3, 128.0, 133.3, 146.1. 2.4.2 General Procedure for the Preparation of N-Alkyl-arylbenzamides 2.11a-d The respective amine (28 mmol) was dissolved in CH 2 Cl 2 (50 mL). Triethyl amine (28 mmol) was added and the mixture stirred under an ice bath. Benzoyl chloride (28 mmol) was added dropwise and the mixture stirred for 2 h at room temperature. The

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14 solvent was evaporated and ethyl acetate added. The organic layer was washed with water (x2), dried over sodium sulfate, filtered and concentrated. N-Methylbenzamide (2.11a): Recrystallized in ethyl acetate and obtained as white crystals (71%), mp 78C (Lit. mp 79 o C, [87H1313]). 1 H NMR 2.97 (d, J = 4.8 Hz, 3H), 6.56 (s, 1H), 7.377.50 (m, 3H), 7.78 (d, J = 7.5 Hz, 2H). 13 C NMR 26.8, 126.8, 128.5, 131.3, 134.5, 168.3. N-t-Butylbenzamide (2.11b): Recrystallized in ethyl acetate and obtained as white crystals (80%), mp 133-134C (Lit. mp 135-137 o C, [87S487]). 1 H NMR 1.42 (s, 9H), 5.99 (s, 1H), 7.387.49 (m, 3H), 7.72 (d, J = 7.2 Hz, 2H). 13 C NMR 28.9, 51.6, 126.7, 128.5, 131.1, 135.9, 167.0. N-Phenylbenzamide (2.11c): Recrystallized in ethyl acetate and obtained as colorless crystals (63%), mp 155-158C (Lit. mp 163 o C, [01SC1803]). 1 H NMR 7.117.16 (m, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.547.63 (m, 3H), 7.817.83 (m, 2H), 7.988.01 (m, 2H), 10.3 (s, 1H). 13 C NMR 120.3, 124.5, 127.1, 128.7, 129.0, 131.7, 134.9, 138.0, 165.8. N-(p-Chlorophenyl)benzamide (2.11d): Obtained as white crystals (42%), mp 189C (Lit. mp 190-191 o C, [83S791]). 1 H NMR 7.337.36 (m, 2H), 7.467.62 (m, 5H), 7.80 (s, 1H), 7.857.88 (m, 2H). 13 C NMR 122.0, 127.4, 127.8, 128.6, 128.7, 131.9, 134.9, 138.3. N-Cyclohexylbenzamide (2.11e): Obtained as white crystals (81%), mp 146-147C (Lit. mp 151-152 o C, [88H323]). 1 H NMR 1.171.48 (m, 6H), 1.631.77 (m, 3H), 1.992.03 (m, 2H), 3.963.98 (m, 1H), 6.10 (s, 1H), 7.387.50 (m, 3H), 7.747.77 (m, 2H). 13 C NMR 25.0, 25.6, 33.2, 48.7, 126.9, 128.5, 131.2, 135.1, 166.7.

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15 2.4.3 General Procedure for the Preparation of 2,4-Benzodiazepin-1-ones 2.13a-h The N-substituted benzamide (3mmol) was dissolved in THF (30 ml). n-BuLi (6.6 mmol) was added dropwise at o C. The mixture was gradually warmed to 0 o C and stirred for 30 min. After being cooled to o C, ZnBr 2 (7 mmol) was added to the mixture followed by the addition of the N,N-bis(benzotriazolyl)amine (3 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with 2 M NaOH, washed with brine and extracted with ethyl acetate. Column chromatography (Al 2 O 3 from 10/1 to 6/1 hexanes/EtOAc) afforded the analytically pure benzodiazepines. 2-Methyl-4-Butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13a): Yellow oil (64%). 1 H NMR 7.777.74 (m, 1H), 7.447.40 (m, 2H), 7.267.24 (m, 1H), 4.09 (s, 2H), 3.64 (s, 2H), 3.27 (s, 3H), 2.71 (t, J = 7.3Hz, 2H), 1.621.56 (m, 2H), 1.441.37 (m, 2H), 0.97 (t, J = 7.4Hz, 3H). 13 C NMR 171.1, 136.5, 134.4, 131.1, 129.0, 128.5, 128.2, 68.1, 55.2(2), 36.3, 30.1, 20.4, 13.9. HRMS (FAB): Calcd For C 14 H 20 N 2 O (M+H) 233.1654, Found 233.1629. 2-(tert-Butyl)-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13b): Isolated as colorless oil (82%). 1 H NMR 7.76 (dd, J = 6.7, 2.2 Hz, 1H), 7.437.37 (m, 2H), 7.10 (dd, J = 6.5, 1.9 Hz, 1H), 3.78 (s, 4H), 2.31 (t, J = 7.0 Hz, 2H), 1.59 (s, 9H), 1.511.46 (m, 2H), 1.401.35 (m, 2H), 0.93 (t, J = 7.2Hz, 3H). 13 C NMR 172.1, 138.3, 131.5, 130.8, 128.8, 128.2, 128.0, 63.2, 57.1, 53.6, 51.8, 30.1, 28.7, 20.5, 14.0. Anal. Calcd. For C 17 H 26 N 2 O C, 74.41; H, 9.55; N, 10.21. Found: C, 74.35; H, 10.06; N, 10.40. 2-Phenyl-4-phenyethyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13c): Isolated as yellow oil (53%). 1 HNMR 7.85 (dd, J = 6.9, 1.6Hz, 1H), 7.507.40

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16 (m, 6H), 7.397.17 (m, 5H), 6.98 (d, J = 6.7Hz, 2H), 4.56 (s, 2H), 3.92 (s, 2H), 2.842.79 (m, 2H), 2.742.69 (m, 2H). 13 C NMR 170.7, 143.2, 139.4, 136.3, 134.0, 131.6, 129.3, 129.1, 129.1, 128.6, 128.4, 126.7, 126.2, 126.1, 68.1, 56.6, 55.3, 34.6. Anal. Calcd. For C 23 H 22 N 2 O C, 80.67; H, 6.48; N, 8.18. Found: C, 80.53; H, 6.46; N, 8.19. 2-(4-Chlorophenyl)-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13d): Isolated as colorless oil (57%). 1 H NMR 7.527.39 (m, 6H), 7.337.26 (m, 2H), 4.65 (s, 2H), 4.00 (s, 2H), 2.55 (t, J = 7.3Hz, 2H), 1.401.24 (m, 4H), 0.83 (t, J =7.3Hz, 3H). 13 C NMR 171.0, 136.0, 135.6, 130.9, 129.6, 128.6, 128.4, 127.5, 126.7, 126.3, 125.3, 66.0, 53.0, 52.3, 29.7, 20.3, 13.9. Anal. Calcd. For C 19 H 21 ClN 2 O C, 69.4; H, 6.74; N, 8.52. Found: C, 69.3; H, 6.57; N, 8.52. 2-Phenyl-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13e): Isolated as yellow oil (47%). 1 H NMR 7.84 (dd, J = 6.9, 1.9Hz, 1H), 7.527.39 (m, 6H), 7.337.26 (m, 2H), 4.50 (s, 2H), 3.86 (s, 2H), 2.57 (t, J = 7.3Hz, 2H), 1.431.38 (m, 2H), 1.291.22 (m, 2H), 0.83 (t, J = 7.3Hz, 3H). 13 C NMR 170.8, 143.3, 136.4, 134.2, 131.6, 129.3, 129.1, 129.0, 128.5, 126.6, 126.2, 68.6, 55.2, 54.7, 29.8, 20.3, 13.8. Anal. Calcd. For C 19 H 22 N 2 O C, 77.52; H, 7.53; N, 9.52. Found: C, 76.57; H, 8.64; N, 9.43. 2-(tert-Butyl)-4-phenylethyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13f): Isolated as yellow oil (36%) 1 H NMR 7.787.75 (m, 1H), 7.417.37 (m, 2H), 7.317.25 (m, 2H), 7.227.18 (m, 3H), 7.117.08 (m, 1H), 3.84 (s, 2H), 3.82 (s, 2H), 2.82 (t, J = 7.0Hz, 2H), 2.58 (t, J = 7.0Hz, 2H), 1.56 (s, 3H). 13 C NMR 172.1, 139.9, 138.2, 131.3, 130.9, 128.7, 128.6, 128.4, 128.2, 128.1, 126.2, 63.1, 57.1, 54.0, 53.7, 34.8,

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17 28.6. Anal. Calcd. For C 21 H 26 N 2 O C, 78.22; H, 8.13; N, 8.69. Found: C, 78.09; H, 8.19; N, 8.72. 2-Phenyl-4-cyclohexyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13g): Isolated as colorless crystals (EtOAc/Hexane), 74%, mp 102-103 o C. 1 H NMR 7.987.81 (m, 1H), 7.587.25 (m, 8H), 4.62 (s, 2H), 3.96 (s, 2H), 2.552.40 (m, 1H), 1.901.45 (m, 6H), 1.201.05 (m, 4H). 13 C NMR 170.8, 142.6, 136.3, 134.9, 131.7, 129.3, 129.2, 129.0, 128.4, 126.6, 126.3, 64.8, 60.5, 52.8, 31.1, 25.8, 25.0. Anal. Calcd. For C 21 H 24 N 2 O C, 78.71; H, 7.55; N, 8.74. Found: C, 76.01; H, 7.55; N, 7.96. 2-Methyl-4-cyclohexyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13h): Isolated as colorless liquid (57%) 1 H NMR 7.777.75(m, 1H), 7.467.39 (m, 2H), 7.257.37 (m, 1H), 4.21 (s, 2H), 3.75 (s, 2H), 3.24 (s, 3H), 2.652.55 (m, 1H), 2.172.07 (m, 2H), 1.901.78 (m, 2H), 1.381.21 (m, 6H). 13 C NMR 171.2, 136.4, 135.0, 131.3, 129.2, 128.4, 128.2, 64.4, 60.7, 52.4, 35.6, 31.3, 25.9, 25.3. Anal. Calcd. For C 16 H 22 N 2 O C, 74.38; H, 8.58; N, 10.84. Found: C, 72.21; H, 9.75; N, 10.35.

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18 N N O Figure 2-2. 1 H NMR spectrum of 2.13b

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CHAPTER 3 A GENERAL AND EFFICIENT SYNTHESIS OF SULFONYLBENZOTRIAZOLES FROM N-CHLOROBENZOTRIAZOLE AND SULFINIC ACID SALTS 3.1 Introduction The sulfonyl group plays a very important role as key constituent of a number of biologically active molecules. Sulfonyl compounds are of interest to the synthetic chemist due to their bioactive nature and chemical applications. Sulfonamides occupy a unique position in the drug industry. Also known as sulfa drugs, sulfonamides have a history that dates back 70 years, during which their action as antiinfective drugs and their effective bactericidal properties in vivo in small animals was discovered [90MI_255]. The first clinically used sulfonamide was named prontosil 3.1 (Figure 3-1), a red azo dye that showed protective action against streptococci in mice. Prontosil was active in vivo, but ineffective in vitro, which led to the conclusion that prontosil itself was not the active drug. When metabolized in the body prontosil produces sulfanilamide 3.2, the real active agent [90MI_255], it interferes with p-aminobenzoic acid utilization by bacteria. This discovery started rapid progress in the investigation and production of new sulfonamides. NH2 N N SO2NH2 NH2 NH2 SO2NH2 3.1 3.2 Figure 3-1. Prontosil 3.1 and the active metabolite sulfanilamide 3.2 19

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20 At present, over 30 drugs containing the sulfonamide moiety are used clinically, as therapeutic agents and for the treatment of bacterial and viral infections. Examples of well-known drugs are sulfamethoxazole 3.3, sulfisoxazole 3.4, sulfasalazine 3.5, and Celebrex 3.6 (Figure 3-2). Sulfonamides are also diuretics, anticonvulsants and hypoglycemic agents as well as protease inhibitors [98JA10994]. Arylsulfonyl substituents have been used as effective protecting groups for oxygen and nitrogen functionalities [92JOC4775]. Sulfonamides introduced into azo dyes improve the properties of these dyes by giving extra light stability, greater water solubility and a better fixation to fibre [90MI_255]. N S NH2 N Me F F F O O NH2 S NH O O ON Me N S NH O O N N OH O OH NH2 S NH O O NO Me Me 3.3 Antibacterial and antiprotozoal3.5 Antiinflammatory3.6 For the treatment of arthritisand osteoarthritis3.4 Urinary tract antibacterial Figure 3-2. Various clinically used sulfonamide drugs Sulfonamides are commonly prepared by the reaction of ammonia, a primary amine 3.8 or a secondary amine with a sulfonyl chloride 3.7 in the presence of a base 3.9 [79COC345] (Scheme 3-1). However, this approach is limited by the availability of the sulfonyl halide, some of which can be difficult to prepare, store and handle. Also, side

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21 reactions are possible due to the presence of the base, even with relatively stable substrates if harsh conditions are applied. The formation of a disulfonamide 3.11 is a common side reaction when primary amines or ammonia are utilized [79COC345] (Scheme 3-1). Me S Cl O O Me S NH O O NO2 NH2 NO2 Me S N O O S O O Me NO2 CaCO3 + 3.7 3.8 3.9 3.10 3.11 Scheme 3-1. Example of the preparation of sulfonamides Because of their importance and their relative difficulty in preparation numerous synthetic methods have been developed with the purpose of solving problems of sulfonamide synthesis (Scheme 3-2). Thus, sulfonamides can be prepared (i) by reaction of sulfinic acid salts with hydroxylamine-O-sulfonic acid [86S1031]; (ii) by reduction of arylsulfonyl azides [97SL1253; 98SC1721]; (iii) from aromatic and aliphatic sulfinic acid salts using bis(2,2,2-trichloroethyl) azodicarboxylate as an electrophilic nitrogen source [02TL4537]; (iv) from alkyl or aryl halides by means of sodium 3-methoxy-3-oxopropane-1-sulfinate as a sulfinate transfer reagent [02TL8479]; (v) by the radical addition of organo halides to pentafluorophenyl ethylenesulfonate [02OL2549] followed by substitution of the pentafluorophenyl moiety by amines and (vi) by the sulfamoylation of aromatics using sulfamoyl chloride [02SL1928]. Alkyl/aryl sulfonyl imidazoles,

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22 prepared from sulfonyl halides and 1H-imidazole or 1-trimethylsilyl imidazole, have also been used as sulfonyl transfer reagents in the preparation of sulfonamides ((vii) in Scheme3-2) [92JOC4775]. However, the imidazole ring requires activation as its 3-methylimidazolium triflate to act as a leaving group in its reactions with Nand O-nucleophiles. RSOON32 [H]RSO2MRSO2MR=ArSROONNNNOOOOCCl3Cl3CSOONR1RR2(vii)TfO(vi)R=ArArHRXIn(OTf)3(v)ClSOONR1R2OSNaOCO2MeSOOOFFFFFRIHNR1R2R=Ar R1=R2=HR=Ar, R1=R2=HR = alkylR =alkyl/arylR1=R2=HR1=R2=H++(i)(ii)(iii)+(iv)+HNR1R2R=alkylR1=R2=alkyl/arylR1=R2=alkyl++H2NOSO3HH2NOSO3H Scheme 3-2. Various methods for the synthesis of sulfonamides Although these additional synthetic methodologies help to overcome some of the problems, they are mostly utilized for specific classes of substrates. A straightforward and general method towards accessing sulfonamides is highly desirable, where a sulfonating reagent would react under mild conditions in the absence of a strong base or competing nucleophile.

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23 Previously, our group reported the preparation of 1-phenylsulfonylbenzotriazole 3.12 and its utility in the synthesis of benzenesulfonamides and aryl benzenesulfonates [94SC205]. 1-Phenylsulfonylbenzotriazole 3.12 is a convenient benzenesulfonylating reagent which reacts with primary 3.14 and secondary amines 3.15 and with alcohols 3.13 under mild conditions (usually stirring in THF at rt) to give the corresponding sulfonamides 3.17, 3.18 and sulfonates 3.16 [94SC205] (Scheme 3-3) in yields of 51-99%. S O O NNN Ph S O O NH PhR S O O N PhR R S O O O PhAr NHR R NH2R OHAr 113.123.143.153.133.163.173.18 Scheme 3-3. Synthesis of benzenesulfonamides and aryl benzenesulfonates from 1-phenylsulfonylbenzotriazole The sulfonylbenzotriazole motif was shown to be a good substitute for the highly reactive, frequently labile and often difficult to access sulfonyl halide unit. Other than its use as a benzenesulfonating agent, 3.12 and its analogues have also been widely used in the preparation of i) N-acylbenzotriazoles (well-known synthetic equivalents to acyl halides [00JOC8210; 92T7817]; ii) N-imidoylbenzotriazoles [99OL577], and iii) for the benzotriazolylalkylation of aromatic compounds [94H345]. However, the preparation of aryl/alkylsulfonylbenzotriazoles involved the corresponding sulfonyl halides by reactions with either 1H-benzotriazole or 1

PAGE 36

24 trimethylsilylbenzotriazoles [94SC205]. This limits their application in the synthesis of sulfonamides. We believe that a general method to prepare sulfonylbenzotriazoles avoiding the sulfonyl halides and starting from easily available materials would be useful. We have developed such an approach starting from aryl/alkyl lithiums or Grignard reagents by reacting successively with SO 2 and N-chlorobenzotriazole. We demonstrate here that the aryl/alkylsulfonylbenzotriazoles prepared in this way react easily with amines to give sulfonamides in excellent yields. 3.2 Results and Discussion 3.2.1 Preparation of Benzotriazole Reagents 3.27 Pinnic and co-workers reported the reactions of organometallic reagents with sulfur dioxide to give sulfinic acid salts [79JOC160]. Furukawa reported the oxidation of sulfinic acids with chloramines to produce a 50:50 mixture of sulfonamide and sulfonyl chloride [83CPB1374]. Utilizing this information together with existing benzotriazole methodology we have envisioned the synthesis of sulfonylbenzotriazoles as follows. Sulfur dioxide is condensed in THF at C and an organometallic reagent is added, which forms a sulfinic acid salt. At room temperature, addition of N-chlorobenzotriazole to the intermediate sulfinic acid salt gives the corresponding sulfonylbenzotriazole. For example, the reaction of p-tolylmagnesium bromide 3.19 and sulfur dioxide 3.20 followed by treating the intermediate sulfinic acid salt 3.21 with N-chlorobenzotriazole 3.22 proceeded smoothly at 20 o C to give the p-tolylsulfonylbenzotriazole 3.27d in 68% yield (Scheme 3-4). This was confirmed by 1 H and 13 C NMR, as the spectra of the product were in accordance with those previously reported [94SC205].

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25 SO2 SOMgBr O Me THFSO O N NN Me Me MgBr N NN Cl + -78-25 oC 3.27d 3.19 3.20 3.21 3.22 Scheme 3-4. Synthesis of p-tolylsulfonylbenzotriazole using our method Use of one equivalent of triethylamine with the N-chlorobenzotriazole 3.22 gave a significant improvement: p-tolylsulfonylbenzotriazole 3.27d was isolated in 93% yield under this modified condition. N-Chlorobenzotriazole has been described previously as a good oxidizing agent, liberating the chloro atom acts as an electrophile together with the benzotriazole anion [69JCS(C)1474; 69JCS(CC)365; 69JCS(C)1478]. The mechanism of this reaction involves the formation of a sulfinic acid salt 3.24 followed by attack of the sulfur atom of this salt on the chloro atom in N-chlorobenzotriazole 3.22. Then, the benzotriazole anion 3.26 may attack the intermediate sulfonyl chloride 3.25 formed in situ (Scheme 3-5). The effect of triethylamine may be to coordinate with the magnesium cation. Other organomagnesium reagents also afforded the corresponding sulfonylbenzotriazoles 3.27 in good to excellent yields, as shown in Table 3-1. RS O O M RS O O Cl NNN M RS O O N NN NNN Cl ++ 3.24 3.25 3.26 3.27 3.22 NEt3 Scheme 3-5. Proposed mechanism for the formation of sulfonylbenzotriazoles Aryl organolithiums can also be used in the preparation of arylsulfonylbenzotriazoles. Thus, thiophene was lithiated at C2 and the lithium reagent

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26 was allowed to react with SO 2 and N-chorobenzotriazole under the conditions described above. Thiophene-2-sulfonylbenzotriazole was isolated in 82% yield (Table 3-1, entry 3.27h). The 1 H NMR spectrum of 3.27h reveals signals of the four protons of 1-substituted benzotriazole as two doublets of triplets at 8.11 ppm (H9) and 8.08 ppm (H6), and two doublets of doublets of doublets (ddd) at 7.70 (H7) and at 7.51 ppm (H8). The three protons of 2-substituted thienyl are presented as three doublets of doublets at 7.96 ppm (H4), 7.76 ppm (H2) and 7.13 ppm (H3) respectively (Figure 3-3). We have used a variety of alkyland arylorganometallic reagents to check the general applicability and functional group tolerance of this method. The respective N-sulfonylbenzotriazoles were isolated mostly in good yields (41-93%, Table 3-1). The yields are largely dependent on the difficulty of formation of the organometallic reagents. In the case of 1-methylindole, the reaction provided a mixture of many products. Only after extensive column chromatography purification were two products isolated and identified. The expected 2-sulfonylated product 3.27i was isolated in 20% yield along with 11% of 2-benzotriazolyl-1-methylindole, which might have formed by the addition of 2-lithio-1-methylindole to N-chlorobenzotriazole. Attempts to react prop-2-ene sulfinic acid salt, formed from the reaction of allylmagnesium bromide and SO 2 with N-chlorobenzotriazole to prepare allylsulfonylbenzotriazole gave only unidentifiable by-products and benzotriazole. Prop-2-ene sulfinic acids are known to be very unstable and to undergo acid catalyzed decomposition to SO 2 and the olefin [78JA4634]. Similar unsatisfactory results were also obtained with acetylenic Grignard reagents.

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27 NNN S O O S 23456789 10 Figure 3-3. 1 H NMR spectrum of 1-(2-thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h)

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28 RM OS O RS O O M NNN Cl RS O O NNN ++3.203.28THF, -78oC3.243.273.22 Scheme 3-6. Preparation of 1-alkyl/arylsulfonylbenzotriazoles 3.27 Table 3-1. Alkyl/arylsulfonylbenzotriazoles 3.27 3.27 R M Yield(%) Mp( o C) a n-Butyl Li 65 Oil b Cyclohexyl MgCl 71 117119 c Isobutyl MgBr 75 Oil d p-CH 3 C 6 H 5 MgBr 93 133134 a e 2-Pyridyl Li 71 132135 f 3-Pyridyl Li 41 128129 g 2-Furyl Li 83 107109 h 2-Thienyl Li 82 143144 i 1-Methyl-2-indolyl Li 20 131132 j 1-Methylimidazolyl Li 80 147150 a Ref. [01H1703] gives mp 134-135: all other compounds are novel. 3.2.2 Synthesis of Sulfonamides 3.29-3.37 using Reagents 3.27 The benzotriazolylsulfonamides 3.27a-j reacted as expected with diverse amines to generate novel sulfonamides (Scheme 3-7). Based on our previous experience [94SC205], we tried the reaction in THF at rt in the absence of a base. Thus, when 3.27a was treated with cyclohexylamine, the corresponding sulfonamide 3.29 was obtained in 89% yield (Table 3-2). Sulfonylbenzotriazoles 3.27c and 3.27h also reacted under the

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29 same conditions with N-methylbenzylamine and piperidine yielding the resultant sulfonamides in 72% and 85% yields, respectively. However, for reagents 3.27f, 3.27g, 3.27j, and 3.27i the smooth displacement of benzotriazole took place with aliphatic amines (Table 3-2) in DMF at 80C but not in refluxing THF or acetonitrile. With this method it was possible to obtain various sulfonamides in quantitative yields. RS O O NNN RS O O NR R NHR R RR12121 = H or alkyl2 = alkyl3.273.29-3.37 Scheme 3-7. Preparation of sulfonamides 3.3 Conclusion N-Chlorobenzotriazole is a useful reagent for converting sulfinate salts to sulfonylbenzotriazoles, which offer access to a wide variety of sulfonamides where the corresponding sulfonyl halide is not readily available. In addition, the approach obviates the formation of disulfonimides that can arise during the ammonolysis of sulfonyl halides [79COC345]. The particular usefulness of the method lies in the ease with which benzotriazole group can be replaced by N-nucleophiles. The easy accessibility of sulfinic acid salts from SO 2 and organometallics and the preparative ease of N-chlorobenzotriazole should afford the approach substantial utility.

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30 Table 3-2. Sulfonamides 3.29-3.37 prepared using reagents 3.27. Reagent 3.27 Amine Condition Sulfonamide Yield (%) S Bt O O Cyclohexylamine THF/rt/ 18 h S O O NH 3.29 89 S Bt O O N-Methylbenzyl-amine THF/rt/ 15 h S O O N Ph 3.30 72 S Bt O O S Piperidine THF/rt/ 42 h S N O O S 3.31 85 S Bt O O O 2-Aminopentane DMF/80 o C /24 h S NH O O O 3.32 99 SBt O O N Piperidine DMF/80 o C /48 h SN O O N 3.33 99 S Bt NN O O Morpholine DMF/80 o C /24 h S N NN O O O 3.34 91 SBt O O Piperidine THF/rt/ 20 h SN O O 3.35 99 S Bt NN O O 1, 5Dimethyl-hexylamine DMF/80 o C /24 h S NH NN O O 3.36 64 S Bt O O S Phenethylamine DMF/80 o C /48 h S NH O O S 3.37 80

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31 3.4 Experimental Section Melting points were determined on a hot-stage apparatus and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution unless stated. Column chromatography was performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone ketyl prior to use. All the reactions were performed under a nitrogen atmosphere and in oven dried glasswares. Commercially available Grignard reagents were used for the preparation of sulfinic acid salts. Organolithium reagents were prepared following literature methods [79OR; 82OR]. All sufinic acid salts were prepared from organo magnesium or lithium reagents and commercially available sulfur dioxide following the method described by Pinnick and co-workers [79JOC160]. 3.4.1 General Procedure for the Preparation of Sulfonylbenzotriazoles 3.27aj Sulfur dioxide was bubbled into THF (20 mL) at o C in excess (for about 10 min). The organometallic reagent (7 mmol) was added to the previous solution at o C. The mixture was stirred at that temperature for 15 min, then at room temperature for 1 h. N-Chlorobenzotriazole (1.07 g, 7 mmol) was then added in one portion and the mixture was stirred for 2 h at rt. Triethylamine (0.92 mL, 7 mmol) was added followed by stirring at rt for 10 h. Water (ca 100 mL) was added and the mixture was extracted with ethyl acetate (3 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave an oil, which was further purified either by re-crystallization or column chromatography. 1-(Butane-l-sulfonyl)-1H-1,2,3-benzotriazole (3.27a): Purified by column chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as a brown oil (65%).

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32 1 H NMR 0.88 (t, J = 7.4 Hz, 3H), 1.351.48 (m, 2H), 1.691.79 (m, 2H), 3.62 (t, J = 8.0 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H). 13 C NMR 13.1, 20.9, 24.6, 55.3, 111.8, 120.4, 125.8, 130.3, 132.1, 145.0. Anal. Calcd For C 10 H 13 N 3 O 2 S: C, 50.19; H, 5.48; N, 17.56. Found: C, 50.41; H, 5.39; N, 17.89. 1-(Cyclohexylsulfonyl)-1H-1,2,3-benzotriazole (3.27b): Purified by column chromatography with hexanes/EtOAc = 2:1 as eluent and obtained as colorless prisms (71%), mp 117119 o C. 1 H NMR 1.101.30 (m, 3H), 1.501.70 (m, 3H), 1.851.90 (m, 2H), 2.022.06 (m, 2H), 3.513.62 (m, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H). 13 C NMR 24.6, 24.7, 25.8, 65.2, 112.1, 120.5, 125.8, 130.3, 132.6, 145.0. Anal. Calcd For C 12 H 15 N 3 O 2 S: C, 54.32; H, 5.70; N, 15.84. Found: C, 54.47; H, 5.68; N, 15.71. 1-(Isobutylsulfonyl)-1H-1,2,3-benzotriazole (3.27c): Purified by column chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as brown oil (75%). 1 H NMR 1.09 (d, J = 6.9 Hz, 6H), 2.30 (sep, J= 6.6 Hz, 1H), 3.51 (d, J = 6.6 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H). 13 C NMR 22.1, 24.6, 63.2, 111.9, 120.5, 125.9, 130.4, 132.0, 145.1. Anal. Calcd For C 10 H 13 N 3 O 2 S: C, 50.19; H, 5.48; N, 17.56. Found: C, 50.08; H, 5.23; N, 17.55. 1-[(4-Methylphenyl)sulfonyl]-1H-1,2,3-benzotriazole (3.27d): Colorless needles (from EtOAc, 93%), mp 126129 o C (Lit. mp 128129 o C) [01H1703]. 1 H NMR 2.39 (s, 3H), 7.32 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 8.10 (t, J = 9.6 Hz, 2H). 13 C NMR 21.7, 112.0, 120.5, 125.8, 128.0, 130.2, 130.3, 131.5, 134.0, 145.4, 146.7.

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33 1-(2-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.27e): Purple needles (from EtOAc, 71%), mp 132135 o C. 1 H NMR 7.487.59 (m, 2H), 7.677.73 (m, 1H), 8.02 (dt, J = 7.8, 1.8 Hz, 1H), 8.088.12 (m, 1H), 8.218.25 (m, 1H), 8.36 (dt, J = 8.1, 0.9 Hz, 1H), 8.59 (ddd, J = 4.8, 1.5, 0.6 Hz, 1H). 13 C NMR 112.7, 120.4, 123.4, 126.0, 128.6, 130.4, 132.7, 138.7, 145.4, 150.7, 154.7. Anal. Calcd For C 11 H 8 N 4 O 2 S: C, 50.76; H, 3.10; N, 21.53. Found: C, 50.81; H, 3.05; N, 21.51. 1-(3-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.27f): Cream needles (from EtOAc, 41%), mp 128129 o C. 1 H NMR 7.497.56 (m, 2H), 7.647.74 (m, 1H), 8.108.15 (m, 2H), 8.42 (ddd, J = 8.1, 2.4, 1.8 Hz, 1H), 8.87 (dd, J = 4.8, 1.8 Hz, 1H), 9.309.31 (m, 1H). 13 C NMR 111.9, 120.8, 124.1, 126.3, 130.8, 131.5, 134.1, 135.7, 145.5, 148.4, 155.5. Anal. Calcd For C 11 H 8 N 4 O 2 S: C, 50.76; H, 3.10; N, 21.52. Found: C, 50.60; H, 3.01; N, 21.13. 1-(2-Furylsulfonyl)-1H-1,2,3-benzotriazole (3.27g): Amber needles (from EtOAc, 83%), mp 107109 o C. 1 H NMR 6.60 (dd, J = 3.6, 1.8 Hz, 1H), 7.517.56 (m, 2H), 7.607.61 (m, 1H), 7.71 (dt, J = 8.1, 0.9 Hz, 1H), 8.11 (t, J = 8.6 Hz, 2H). 13 C NMR 112.0, 112.3, 120.6, 121.1, 126.1, 130.5, 131.5, 144.9, 145.4, 149.1. Anal. Calcd For C 10 H 7 N 3 O 3 S: C, 48.19; H, 2.83; N, 16.86. Found: C, 47.82; H, 2.57; N, 16.52. 1-(2-Thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h): Needles (from EtOAc, 82%), mp 143144 o C. 1 H NMR 7.13 (dd, J = 5.1, 3.9 Hz, 1H), 7.487.54 (m, 1H), 7.667.72 (m, 1H), 7.76 (dd, J = 5.1, 1.2 Hz, 1H), 7.96 (dd, J = 3.6, 1.2 Hz, 1H), 8.088.09 (m, 1H), 8.108.12 (m, 1H). 13 C NMR 112.0, 120.6, 126.0, 128.2, 130.4, 131.2, 135.8, 136.3, 136.4, 145.4. Anal. Calcd For C 10 H 7 N 3 O 2 S 2 : C, 45.27; H, 2.66; N, 15.84. Found: C, 45.36; H, 2.34; N, 15.71.

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34 1-[(1-Methyl-1H-indol-2-yl)sulfonyl]-1H-1,2,3-benzotriazole (3.27i): Purified by column chromatography with hexanes/EtOAc = 6:1 as eluent and obtained as colorless prisms (20%), mp 150152 o C. 1 H NMR 4.08 (s, 3H), 7.19 (t, J = 6.9 Hz, 1H), 7.33-7.51 (m, 3H), 7.607.69 (m, 3H), 8.068.11 (m, 2H). 13 C NMR 31.7, 110.7, 112.0, 113.6, 120.7, 121.9, 123.2, 124.6, 126.0, 127.3, 129.5, 130.3, 131.2, 140.2, 145.6. Anal. Calcd For C 15 H 12 N 4 O 2 S: C, 57.68; H, 3.87; N, 17.94. Found: C, 57.54; H, 3.76; N, 17.82. 1-[(1-Methyl-1H-imidazol-2-yl)sulfonyl]-1H-1,2,3-benzotriazole (3.27j): Purified by column chromatography with hexanes/EtOAc = 3:7 as eluent and obtained as colorless prisms (80%), mp 147150 o C. 1 H NMR 4.18 (s, 3H), 7.13 (d, J = 3.6 Hz, 2H), 7.51(t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H). 13 C NMR 36.1, 112.5, 120.4, 126.2, 127.9, 130.6, 130.7, 131.6, 138.5, 145.3. Anal. Calcd For C 10 H 9 N 5 O 2 S: C, 45.62; H, 3.45; N, 26.60. Found: C, 45.64; H, 3.35; N, 26.49. 3.4.2 General Procedure for the Preparation of Sulfonamides 3.293.37 The respective sulfonylbenzotriazole 3.27 (1 equiv.) was heated at the established temperature in the chosen solvent with the appropriate primary or secondary amine (1 equiv.) for the established time (See Table 3-2). Water (ca 100 mL) was added and the mixture was extracted with ethyl acetate (3 100 mL). The combined organic layers were washed with water, 1M HCl, brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave an oil, which was further purified either by re-crystallization or column chromatography over silica gel (200400 Mesh). N-Cyclohexyl-1-butanesulfonamide (3.29): Purified by column chromatography with CHCl 3 as eluent and obtained as colorless prisms (89%), mp 64-65 o C (Lit. mp

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35 71.8 o C) [42CB42]. 1 H NMR 0.95 (t, J = 7.2 Hz, 3H), 1.14.49 (m, 7H), 1.56.84 (m, 5H), 1.95.99 (m, 2H), 3.01 (t, J = 8.0 Hz, 2H), 3.20-3.33 (m, 1H), 4.31 (d, J = 6.6 Hz, 1H). 13 C NMR 13.6, 21.5, 24.8, 25.1, 25.8, 34.7, 52.7, 53.9. Anal. Calcd For C 10 H 21 NO 2 S: C, 54.76; H, 9.65; N, 6.39. Found: C, 54.77; H, 9.67; N, 6.34. N-Benzyl-N,2-dimethyl-1-propanesulfonamide (3.30): Purified by column chromatography with hexanes/Et 2 O = 6:1 as eluent and obtained as colorless needles (72%), mp 32-34 o C. 1 H NMR 1.13 (d, J = 6.6 Hz, 6H), 2.32 (sep, J = 6.6 Hz, 1 H), 2.76 (s, 3H), 2.83 (d, J = 6.6 Hz, 2H), 4.32 (s, 2H), 7.31.36 (m, 5H). 13 C NMR 22.7, 24.5, 34.1, 53.7, 57.4, 127.9, 128.3, 128.7, 135.9. Anal. Calcd For C 12 H 19 NO 2 S: C, 59.72; H, 7.93; N, 5.80. Found: C, 59.88; H, 8.10; N, 5.92. 1-(2-Thienylsulfonyl)piperidine (3.31): Purified by column chromatography with CHCl 3 as eluent and obtained as colorless prisms (85%), mp 76 o C (Lit. mp 65 o C) [95CB1195]. 1 H NMR 1.41.49 (m, 2H), 1.64.72 (m, 4H), 3.04 (t, J = 5.6 Hz, 4H), 7.14 (dd, J = 4.8, 3.6 Hz, 1H), 7.52 (dd, J = 3.6, 1.2 Hz, 1H), 7.61 (dd, J = 4.8, 1.2 Hz, 1H). 13 C NMR 23.4, 25.0, 47.0, 127.5, 131.7, 132.1, 136.7. Anal. Calcd For C 9 H 13 NO 2 S 2 : C, 46.73; H, 5.66; N, 6.05. Found: C, 46.98; H, 5.64; N, 6.15. N-(1-Methylbutyl)-2-furansulfonamide (3.32): Purified by column chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as cream prisms (100%), mp 57 o C. 1 H NMR 0.82.87 (m, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.21.38 (m, 4H), 3.33-3.45 (m, 1H), 4.45 (d, J = 7.8 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 7.03 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H). 13 C NMR 13.6, 18.6, 21.9, 39.5, 50.2, 103.4, 111.2, 116.0, 145.7. Anal. Calcd For C 9 H 15 NO 3 S: C, 49.75; H, 6.96; N, 6.45. Found: C, 49.95; H, 6.97; N, 6.37.

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36 1-(3-Pyridinylsulfonyl)piperidine (3.33): Purified by column chromatography with hexanes/EtOAc/CHCl 3 = 4:1:5 as eluent and obtained as white prisms (100%), mp 88 o C (Lit. mp 94 o C) [83S822]. 1 H NMR 1.43.49 (m, 2H), 1.63.71 (m, 4H), 3.05 (t, J = 5.6 Hz, 4H), 7.49 (dd, J = 2.7, 5.1 Hz, 1H), 8.05 (dt, J = 8.1, 1.8 Hz, 1H), 8.82 (dd, J = 4.8, 1.5 Hz, 1H), 8.99 (d, J = 2.1 Hz, 1H). 13 C NMR 23.4, 25.1, 46.8, 123.6, 133.3, 135.2, 148.4, 153.2. Anal. Calcd For C 10 H 14 N 2 O 2 S: C, 53.08; H, 6.24; N, 12.38. Found: C, 53.10; H, 6.32; N, 11.96. 4-[(1-Methyl-1H-imidazol-2-yl)sulfonyl]morpholine (3.34): Colorless oil (91%). 1 H NMR 3.40 (t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.8 Hz, 4H), 3.85 (s, 3H), 6.91 (s, 1H), 7.01 (s, 1H). 13 C NMR 34.7, 46.5, 66.2, 124.6, 128.4, 141.9. Anal. Calcd For C 8 H 13 N 3 O 3 S: C, 41.55; H, 5.67; N, 18.17. Found: C, 41.45; H, 6.04; N, 15.99. 1-[(4-Methylphenyl)sulfonyl]piperidine (3.35): White prisms (from EtOAc, 100%), mp 93 o C (Lit. mp 96 o C) [81JOC5077]. 1 H NMR 1.36.45 (m, 2H), 1.601.67 (m, 4H), 2.43 (s, 3H), 2.97 (t, J = 5.7 Hz, 4H), 7.32 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H). 13 C NMR 21.5, 23.4, 25.1, 46.9, 127.6, 129.5, 133.2, 143.2. Anal. Calcd For C 12 H 17 NO 2 S: C, 60.22; H, 7.16; N, 5.85. Found: C, 60.01; H, 7.27; N, 5.95. N-(1,5-Dimethylhexyl)-1-methyl-1H-imidazole-2-sulfonamide (3.36): Purified by column chromatography with hexanes/EtOAc = 3:1 as eluent and obtained as white prisms (64%), mp 82 o C. 1 H NMR 0.84 (d, J = 6.6 Hz, 6H), 1.06.35 (m, 7H), 1.38.55 (m, 3H), 3.46-3.55 (m, 1H), 3.94 (s, 3H), 5.25 (s, 1H), 6.96 (s, 1H), 7.09 (s, 1H). 13 C NMR 21.4, 22.5, 23.3, 27.8, 35.1, 37.7, 38.5, 51.1, 124.6, 128.1, 143.4. Anal. Calcd For C 12 H 23 N 3 O 2 S: C, 52.72; H, 8.48; N, 15.37. Found: C, 52.54; H, 8.07; N, 15.84.

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37 N-Phenethyl-2-thiophenesulfonamide (3.37): Purified by column chromatography with hexanes/EtOAc = 3:1 as eluent and obtained as yellow oil (80%). 1 H NMR 2.81 (t, J = 6.9 Hz, 2H), 3.32 (q, J = 6.6 Hz, 2H), 4.54 (br s, 1H), 7.06.13 (m, 3H), 7.20.32 (m, 3H), 7.56.59 (m, 2H). 13 C NMR 35.6, 44.4, 126.9, 127.4, 128.7, 128.8, 131.8, 132.1, 137.5, 140.9. Anal. Calcd For C 12 H 13 NO 2 S 2 : C, 53.91; H, 4.90; N, 5.24. Found: C, 54.21; H, 4.89; N, 5.59.

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CHAPTER 4 1-[2-BENZOTRIAZOL-1-YL)ETHYL]SULFONYLBENZOTRIAZOLE: A VERSATILE SYNTHON FOR THE PREPARATION OF ETHYLENESULFONAMIDES AND ALKYLSULFONATE ESTERS 4.1 Introduction In the previous chapter we mentioned that many compounds containing the sulfonyl group are interesting from the medicinal and industrial point of view. Ethylenesulfonamides and sulfonate esters are a significant subset of the extensive family of compounds containing the sulfone (SO 2 ) moiety. Most importantly, the addition of vinyl functionality to sulfones enriches the chemistry of these compounds by providing an opening to further transformations. Transformations such as i) epoxidation [87TL1101], ii) aziridination [83S816], iii) Diels-Alder cycloaddition [80JA853], and iv) nitrone cycloaddition [87H101] can be carried out with the vinyl functional group of the ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters (Scheme 4-1). Modifications to the ethylene functionality increase the synthetic range of sulfur containing compounds. Additionally, new carbon-carbon and carbon-hydrogen bonds can be generated concurrently with loss of the sulfone moiety [90T6951]. Examples of desulfonation reactions include reductive and alkylative desulfonations, base eliminations and methods using tin (Scheme 4-2) [90T6951]. Vinyl sulfones, ethylenesulfonamides, and ethylenesulfonate esters are also known to be excellent Michael acceptors [90T6951; 91JOC3549] {Scheme 4-1, (v)}. Peptide Michael acceptors are inhibitors of some protease enzymes [84JMC711; 86JMC104], which regulate physiological functions by processing peptides and proteins. 38

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39 SO3Et OSO3Bu4N NRSO2X SO2X SO2X Br Br R NH2, DMSO SO2Ph SO2N(Et)2 ON R R N(Et)2SO2 N+ H R O R SO2N(PMB)2 SO2Ph R CO2Me R SO2N(PMB)2 CO2Me1) t-BuOOH, Triton B, THF2) Bu4NHSO4, CH2Cl2-H2O(i) Epoxidation(ii) AziridinationBr2X = NHR, OR(iii) Diels-Alder cycloaddition(iv) Nitrone cycloaddition+(v) Michael addition++250 0C, 110 h1122 K2CO311 Scheme 4-1. Transformations of ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters

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40 R R R R PhO2S SO2Me PhBu Ph Bu3B SO2Ph OAc R R R R' SO2Ph R R' SO2Ph SnBu3 R R' Bu3SnLi 2 mol % Ni(acac)22 eq. n-BuMgCl(i) Reductivewith transition metal catalysts(iii) Base-Elimination(iii) Tin method(ii) Alkylative tBuOK mixture of isomers Scheme 4-2. Desulfonation Reactions Vinyl sulfones and ethylenesulfonamides are believed to bind irreversibly to cysteine proteases, enzymes implicated in a number of diseases such as osteoporosis, arthritis, Alzheimers disease, cancer metastasis, and programmed cell death [95JMC3193] thus inhibiting their action [99JMC3789]. Certain vinyl sulfones have

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41 proven effective against Trypanosoma cruzi, a protozoa agent of Chagas disease [98JEM725], and as antimalarial agents [96AAC1600]. Sulfonamides have been used for almost a century as antibiotics, as antimigrain agents, and as drugs in the treatment of diseases caused by diverse pathogenic microorganisms, such as the hemolytic streptococci, by inhibiting their cell division. Not surprisingly, the development of new methodology to synthesize vinyl sulfones, ethylenesulfonamides and ethylenesulfonate esters attracts great attention. Known approaches to ethylenesulfonate esters and ethylenesulfonamides are: i) the Horner-Wadsworth-Emmons reaction of -phosphorylmethanesulfonate with an aldehyde or ketone [98JA10994]; ii) elimination of a -halo or -aceto-substituted sulfone in the presence of a base [91JOC3549]; iii) addition of a sulfone carbanion to a carbonyl compound followed by elimination; iv) the Peterson reaction [90T6951]; v) amidation or esterification reactions of sulfonyl chlorides [98JA10994] or sulfonates [02OL2549], with the desired amines (Scheme 4-3). Recently, Caddick [02OL2549] and co-workers reported the preparation of a variety of sulfonamides using the novel pentafluorophenyl vinyl sulfonate 4.1 as an intermediate (Figure 4-1). It is interesting to see that the intermediate 4.1 is stable. This intermediate is a potential replacement for the sulfonyl chloride unit, because on exposure to nucleophiles it does not liberate hydrochloric acid. However, alkylations to the olefin were performed before amidation to avoid possible side reactions of the nucleophile with the vinyl double bond. Also, the alkylations were performed only by radical reactions and not by carbon-carbon nucleophilic attack. It is probable that there is no selectivity in

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42 SO2Cl R BocNH H O CH2CH2Ph PO SO3Et EtOEtOBuLi, THF BocN CH2CH2Ph SO3Et H SO2Cl Cl ClCH2CH2Cl-H2O OH SO3Ph PhS SO2Ph R O SPh SO2Ph Ac2ONEt3, DMAP R PhS SO2Ph OO O OO SO2Ph SO2Ph Me3Si BuLi, DMER NH2R OH R SO2NHR SO3R R DBU(i)(ii)(iii)(iv)(v) 25 % NaOH, 0OC + 1) BuLi 2) RCHO1112222 Scheme 4-3. Synthetic protocols toward ethylenesulfonate esters, vinyl sulfones and ethylenesulfonamides the reactivity of the vinyl bond vs. the ester site if both are present and a nucleophile is used. We therefore thought of preparing a similar intermediate 4.2 and by taking advantage of the characteristics of benzotriazole, as stabilizer and as activator of certain

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43 functional groups, we would solve the limitations of previously published procedures. The program would include a study on target 4.2 and a study of its reactivity. Thus, this chapter describes an approach to sulfonate esters and ethylenesulfonamides utilizing a synthetic equivalent formed with benzotriazole. O F F F F F S O O NNN S O O 4.1 4.2 Figure 4-1. Intermediate 4.1 used in the preparation of ethylenesulfonamides 4.2 Results and Discussion Our approach employs a novel intermediate 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5 easily obtained from the reaction of 2-chloroethanesulfonyl chloride 4.3 and benzotriazole 4.4 in 88% yield (Scheme 4-4). Intermediate 4.5 is a solid, compared to the starting material and many other sulfonyl chlorides, which are often liquids. It liberates benzotriazole instead of hydrochloric acid and it is stable to air and at room temperature. Cl S Cl O O NHNN N S N O NN NN O CH2Cl2NEt3 + 0 oC-rt 4.3 4.4 4.5 (88%) Scheme 4-4. Synthesis of 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5 The preparation of benzotriazolyl reagent 4.2 from 4.5 failed. Elimination of the benzotriazole attached to the ethyl chain was attempted using potassium tert-butoxide and triethyl amine. The reaction did not generate 4.2 or allow recovery of the starting

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44 material (Scheme 4-5). Attempts to perform an intramolecular Michael addition using hydrazine or hydroxylamine also failed. N S N O NN NN O S N O NN O 4.5 4.2 KOBut or NEt3 Scheme 4-5. Attempt to prepare 4.2 Our attention then shifted to intermediate 4.5. We noticed that upon exposure to nucleophiles the reactive site is only at sulfur. The ethyl chain is not attacked by nucleophiles because it is protected by the presence of benzotriazole. Thus 4.5 resembles a sulfonyl chloride with a masked double bond. Nucleophilic attack occurs without the need of a base, which shows that the reactions proceed via direct displacement of benzotriazole by the nucleophile. Nitrogen and oxygen nucleophiles can be employed in these reactions. Herein, we describe the facile preparation of alkylsulfonamides, sulfonate esters and ethylenesulfonamides utilizing the novel intermediate 4.5. 4.2.1 Preparation of Sulfonamides 4.7a-g and Sulfonate ester 4.7h Displacement of the benzotriazole attached to the sulfonyl moiety was achieved by the reaction of 4.5 in THF or CH 2 Cl 2 at room temperature with oxygen and nitrogen nucleophiles. No base was necessary for the reactions to occur with nitrogen nucleophiles. Only the desired products and benzotriazole were observed in the reaction mixtures, and most of the products were purified by a mild basic wash. As expected, the corresponding sulfonate ester and sulfonamides were formed in good to excellent yields as shown in Scheme 4-6 and Table 4-1. The 1 H and 13 C NMR of the new products

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45 showed the absence of the benzotriazole group and the introduction of the nucleophile used. N S N O NN NN O NuN S O NN O Nu THF/rt 4.5 4.7a-h Scheme 4-6. Preparation of sulfonamides and sulfonate ester 4.7 Table 4-1. Sulfonamides 4.7a-g and sulfonate ester 4.7h prepared NH2 ONa Nu NH NH NH2 O NH2 Nu NH2 MeONH2 abcd%yield997177e74fgh%yield68998452 4.7 4.7 4.2.2 Preparation of Ethylenesulfonamides 4.8a, f Base catalyzed elimination of benzotriazole from sulfonamides 4.7a and f was carried out to afford the ethylenesulfonamides 4.8a, f (Scheme 4-7). The starting material had first to be dissolved by heating in THF, then treated with potassium tert-butoxide at 0C. Mild water workup afforded the corresponding ethylenesulfonamides 4.8a and 4.8f in excellent yields.

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46 NN N S O O NH S O O NH NN N S O O NH S O O NH 4.7a4.8atBuOKTHF, 0oC, 10min93% yield4.7f4.8ftBuOKTHF, 0oC, 10min94% yield Scheme 4-7. Synthesis of ethylenesulfonamides 4.3 Conclusion The use of intermediate 4.5 makes this new approach simple and versatile to afford high yields of a variety of products under mild conditions and with easy purification. We have described the facile preparation of alkyl sulfonamides, sulfonate esters and ethylene sulfonamides utilizing novel intermediate 4.5. 4.4 Experimental Procedure Melting points were determined on a hot-stage apparatus and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution unless stated. Column chromatography was performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone ketyl prior to use. 4.4.1 Procedure for the Synthesis of Novel Intermediate 4.5 A solution of benzotriazole (3 g, 24.54 mmol) and triethylamine (4.5 mL, 30.68 mmol) in dichloromethane was cooled to 0C. 2-Chloroethylsulfonyl chloride (1.29 mL, 12.27 mmol) was added dropwise and the mixture left stirring overnight. The solvent was removed under vacuo and the residue was dissolved in ethyl acetate. The mixture in

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47 ethyl acetate was washed with water (x3) and brine. It was dried, filtered, concentrated, and recrystallized from ethyl acetate to afford 3.56 g (88%) of 1-{[2-(1H-1,2,3-benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole. 1-{[2-(1H-1,2,3-Benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole (4.5): White flakes (88%), mp 98.1.8C. 1 H NMR 4.93 (t, J = 6.3 Hz, 2H), 5.26 (t, J = 6.3 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.55 (dd, J = 8.4, 15.6 Hz, 2H), 7.68 (J = 7.2 Hz, 1H), 7.80.94 (m, 3H), 8.18 (d, J = 8.1 Hz, 1H). 13 C NMR 41.4, 54.0, 108.8, 111.6, 117.8, 120.12, 120.3, 120.7, 124.4, 126.0, 126.2, 126.9, 128.1, 130.7. Anal. Calcd. For C 14 H 20 N 4 O 2 S: C, 51.21; H, 3.68; N, 25.59. Found: C, 51.52; H, 3.61; N, 25.69 4.4.2 General Procedure for the Preparation of Sulfonamides 4.7a-g A solution of the respective amine (3.03 mmol) and 1-{[2-(1H-1,2,3-benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole (1.0 g, 3.03 mmol) in THF was stirred at room temperature 24 h. The solvent was evaporated and ethyl acetate added. After washing with water and 1M NaOH (x1) the solution was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave an oil, which was further purified by re-crystallization or column chromatography over silica gel (200-400 Mesh). 2-(1H-1,2,3-Benzotriazol-1-yl)-N-benzyl-1-ethanesulfonamide (4.7a): Colorless prisms (99%), mp 151.8.9C. 1 H NMR 3.63 (t, J = 6.6 Hz, 2H), 4.12 (d, J = 6.0 Hz, 2H), 4.58 (s, 1H), 5.04 (t, J = 6.6 Hz, 2H), 7.14.16 (m, 2H), 7.26.28 (m, 3H), 7.40 (m, 1H), 7.52 (m, 2H), 8.10 (m, 1H). 13 C NMR in DMSO 40.3, 42.2, 45.9, 50.6, 110.7, 119.1, 124.0, 127.3, 127.6, 128.4, 128.4, 132.1, 145. 2-(1H-1,2,3-Benzotriazol-1-yl)-N-(4-methoxybenzyl)-1-ethanesulfonamide (4.7b): Purified by column chromatography with hexanes/ ethyl acetate/ chloroform =

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48 1:2:7 as eluent and obtained as colorless prisms (71%), mp 115.0C. 1 H NMR 3.58 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 4.08 (d, J = 5.7 Hz, 2H), 4.80 (s, 1H), 5.00 (t, J = 6.6 Hz, 2H), 6.77 (d, J =8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 7.38.42 (m, 1H), 7.48.52 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H). 13 C NMR 42.5, 46.7, 51.8, 55.3, 109.1, 114.2, 120.2, 124.4, 128.0, 128.2, 129.4, 132.9, 145.8, 159.5. 1-[2-(Piperidine-1-sulfonyl)-ethyl]-1H-benzotriazole (4.7c): Colorless prisms (77%), mp 130.0.8C. 1 H NMR 1.50.63 (m, 6H), 3.16.18 (m, 4H), 3.69 (t, J = 7.1 Hz, 2H), 5.10 (t, J = 7.2 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H). 13 C NMR 23.4, 25.3, 42.1, 46.3, 48.2, 109.2, 120.1, 124.3, 127.9, 133.0, 145.8. 1-[2-(1-Pyrrolidinylsulfonyl)ethyl]-1H-1,2,3-benzotriazole (4.7d): Colorless prisms (74%), mp 127.0C. 1 H NMR 1.76 (m, 4H), 3.18 (t, J = 6.8 Hz, 4H), 3.72 (t, J = 6.9 Hz, 2H), 5.07 (t, J = 6.9 Hz, 2H), 7.41 (t, J = 7.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.62.65 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H). 13 C NMR 25.6, 42.2, 47.5, 48.5, 109.2, 120.0, 124.2, 127.8, 133.0, 145.7. Anal. Calcd. For C 12 H 16 N 4 O 2 S: C, 51.41; H, 5.75; N, 19.98. Found: C, 51.78; H, 5.79; N, 19.93. 2-(1H-1,2,3-Benzotriazol-1-yl)-N-(2-furylmethyl)-1-ethanesulfonamide (4.7e): Colorless prisms (68%), mp 125.6.0C. 1 H NMR 3.59 (t, J = 6.8 Hz, 2H), 4.25 (d, J = 4.2 Hz, 2H), 5.02 (t, J = 6.9 Hz, 3H), 6.22-6.25 (m, 2H), 7.20 (s, 1H), 7.39.43 (m, 1H), 7.54 (d, J = 3.6 Hz, 2H), 8.07 (d, J = 6.9 Hz, 1H). 13 C NMR 39.8, 42.4, 52.0, 100.3, 108.9, 109.0, 110.5, 120.3, 121.9, 124.3, 128.0, 143.0, 149.4. Anal. Calcd. For C 13 H 14 N 4 O 3 S: C, 50.97; H, 4.61; N, 18.29. Found: C, 50.90; H, 4.47; N, 18.04.

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49 2-(1H-1,2,3-Benzotriazol-1-yl)-N-cyclohexyl-1-ethanesulfonamide (4.7f): Colorless prisms (99%), mp 110.4C. 1 H NMR 1.04.13 (m, 3H), 1.18.28 (m, 2H), 1.51.67 (m, 3H), 1.76.81 (m, 2H), 3.10.25 (m, 1H), 3.73 (t, J = 6.9 Hz, 2H), 4.454.55 (m, 1H), 5.09 (t, J = 6.9 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H). 13 C NMR 24.7, 25.0, 34.2, 42.7, 52.8, 53.1, 109.2, 120.2, 124.4, 128.0, 133.1, 145.9. Anal. Calcd. For C 14 H 20 N 4 O 2 S: C, 54.52; H, 6.54; N, 18.17. Found: C, 54.55; H, 6.56; N, 17.84. 2-(1H-1,2,3-Benzotriazol-1-yl)-N-(1,5-dimethylhexyl)-1-ethanesulfonamide (4.7g): Purified by column chromatography with hexanes/ ethyl acetate/ chloroform = 1:2:7 as eluent and obtained as colorless prisms (84%), mp 72.2.7C. 1 H NMR 0.84 (d, J = 6.6 Hz, 6H), 1.06.16 (m, 5H), 1.18.40 (m, 4H), 1.43.50 (m, 1H), 3.40 (t, J = 7.5 Hz, 1H), 3.72 (t, J = 6.9 Hz, 2H), 4.39 (d, J = 8.4 Hz, 1H), 5.10 (t, J = 6.9 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H). 13 C NMR 21.9, 22.4, 22.5, 23.4, 27.7, 37.8, 38.5, 42.6, 50.6, 52.7, 109.1, 120.2, 124.3, 128.0, 133.0, 145.8. Anal. Calcd. For C 16 H 26 N 4 O 2 S: C, 56.78; H, 7.74; N, 16.55. Found: C, 57.03; H, 8.00; N, 16.51. 4.4.3 Procedure for the Preparation of Sulfonate ester 4.7h Beta-hydroxynaphthalene (0.48 g, 3.33 mmol) and NaOH (0.18 g, 4.55 mmol) were dissolved in anhydrous methylene chloride (40 mL). This mixture was added to a solution of 1-{[2-(1H-1,2,3-benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole (1.0 g, 3.03 mmol) at 0C and stirred overnight. Concentration under reduced pressure gave an oil, which was further purified by column chromatography over silica gel (200-400 Mesh) using hexanes/ethyl acetate = 70:30 as eluent.

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50 2-Naphthyl-2-(1H-1,2,3-benzotriazol-1-yl)-1-ethanesulfonate (4.7h): Pink crystals (52%), mp 92.2.0C. 1 H NMR 4.04 (t, J = 6.8 Hz, 2H), 5.23 (t, J = 6.9 Hz, 2H), 7.17 (dd, J = 2.4, 9 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.46.57 (m, 4H), 7.63 (d, J = 8.4 Hz, 1H), 7.76.83 (m, 3H), 8.08 (d, J = 8.4 Hz, 1H). 13 C NMR 42.1, 49.5, 103.3, 109.1, 119.2, 120.2, 120.3, 124.4, 126.7, 127.2, 127.7, 127.9, 128.1, 132.0, 133.1, 133.4, 145.7, 146.0. 4.4.4 General Procedure for the Synthesis of Ethylenesulfonamides 4.8a, f The respective sulfonamide (0.36 g, 1.13 mmol) was dissolved in 15 mL of anhydrous THF at 0C. Potassium tert-butoxide (0.38 g, 3.41 mmol) was added and the reaction mixture stirred under nitrogen atmosphere for 10 to 30 min. Water was added, the product was extracted with ethylacetate, washed with water, brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave an oil, which was further purified by re-crystallization or column chromatography over silica gel (200-400 Mesh). Ethenesulfonic acid benzylamide (4.8a): Purified by column chromatography with hexanes/ethyl acetate = 72: 28 as eluent and obtained as yellow oil (93%). 1 H NMR 4.22 (d, J = 6 Hz, 2H), 4.65 (s, 1H), 5.93 (d, J = 9.9 Hz, 1H), 6.26 (d, J = 16.8 Hz, 1H), 6.48 (dd, J = 9.6, 16.5 Hz, 1H), 7.30.35 (m, 5H). 13 C NMR 47.0, 126.8, 127.9, 128.1, 128.8, 136.0, 136.4. Anal. Calcd. For C 9 H 11 NO 2 S: C, 54.78; H, 5.63; N, 7.10. Found: C, 54.72; H, 5.73; N, 7.53. Ethenesulfonic acid cyclohexylamide (4.8f): Yellow needles (94%), mp 50C. 1 H NMR 1.14.40 (m, 5H), 1.54.59 (m, 1H), 1.69.73 (m, 2H), 1.92.96 (m, 2H), 3.14-3.20 (m, 1H), 4.52-4.56 (m, 1H), 5.89 (d, J = 9.9 Hz, 1H), 6.24 (d, J = 16.5 Hz, 1H),

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51 6.55 (dd, J = 9.9, 16.5 Hz, 1H). 13 C NMR 24.7, 25.1, 34.2, 52.6, 125.5, 137.2. Anal. Calcd. For C 8 H 15 NO 2 S: C, 50.77; H, 7.99; N, 7.40. Found: C, 50.41; H, 8.13; N, 7.40.

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CHAPTER 5 VERSATILE SYNTHESIS OF THIOCARBAMOYLBENZOTRIAZOLES, THIOAMIDES, THIOCARBAMATES AND DITHIOCARBAMATES FROM BIS(BENZOTRIAZOLYL)METHANETHIONE 5.1 Introduction Recently bis(benzotriazolyl)methanethione 5.3 was recognized as an excellent thiocarbonyl transfer agent [04JOC2976]. Although 5.3 was first prepared by Keating and Skell [76MI_573] 30 years ago, the yield was never reported. Two years later, Larsen and coworkers prepared 5.3 in 90% yield from the silylated heterocycle and thiophosgene; bis(benzotriazolyl)methanethione 5.3 was reacted with aniline to obtain a symmetrical thiourea [78JOC337] and further used in Diels-Alder reactions [80JOC3713]. N N S NN NN NNN Si Me Me Me Cl Cl S 5.3 5.1 5.2 + 2 eq. Scheme 5-1. Preparation of bis(benzotriazolyl)methanethione 5.3 Our group has previously reported the application of 5.3 in the facile preparation of diand tri-substituted thioureas [04JOC2976]. Bis(benzotriazolyl)methanethione 5.3 was reacted with one equivalent of the respective amine and only the desired products,1-alkyland 1aryl-thiocarbamoylbenzotriazoles 5.5, were obtained (Scheme 5-2) in yields of 91-99%. 1-Alkyl/arylthiocarbamoylbenzotriazoles 5.5 from primary amines were further reacted with nitrogen nucleophiles thus displacing the second benzotriazole of 5.3 to afford symmetrical and unsymmetrical diand tri-substituted thioureas 5.7 (Scheme 52

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53 5-2) in good to excellent yields [04JOC2976]. Di-substituted thiocarbamoylbenzotriazoles 5.5 (R 1 R 2 H) did not yield thioureas. Apparently, these reactions proceeded by the in situ formation of isothiocyanate intermediates. It was this recent work that prompted further exploration of the uses of bis(benzotriazolyl)methanethione 5.3 and its derivative 5.5, since no examples of reactions with other than nitrogen nucleophiles have been reported. N N S NN NN NHR R N N S NN R R N N S R RH R NHR R 5.312 5.412 + R1 = alkyl, arylR2 = H, alkyl, aryl R1 = alkyl, arylR2 = HR3 = alkyl, arylR4 = H, alkyl, aryl 5.513443 5.6 5.7 Scheme 5-2. Use of bis(benzotriazolyl)methanethione 5.3 in the preparation of thioureas 5.7 1-Alkyl/arylthiocarbamoylbenzotriazoles 5.5 in which R 2 is H act as stable isothiocyanate equivalents. Isothiocyanates are versatile precursors for inter-alia thioureas [01JCB90], thioamides [71JIC791], ketene aminals [04JOC188], thiazoles [04JOC202; 03JOC8693], 3-thio-1,2,4-triazoles and 2-thioimidazoles [02JCB315], thiopyranes [02JA28] pyrimidine nucleoside analogues [03JOC8583], thiopyrroles and thiophenes [01JOC2850], benzothieno-quinolines [00JOC8669], diaminoquinazolines

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54 [01OL585], dihydro and tetrahydroquinazolines [03JCB775] and thiourazoles [02JCB491]. A moderate number of isothiocyanates are commercially available; many are tedious to prepare and are susceptible to decomposition. The reaction of bis(benzotriazolyl)methanethione 5.3 with amines to afford alkyl/arylthiocarbamoyl-benzotriazoles 5.5 is a convenient route to prepare an isothiocyanate synthon. Subsequently, 1-alkyl/arylthiocarbamoylbenzotriazoles 5.5 can be treated with oxygen, sulfur and carbon nucleophiles to afford O,N-alkyl/arylthiocarbamates, S,N-alkyl/aryldithiocarbamates and thioamides respectively, thus giving rise to molecular diversity. Thiocarbamates, dithiocarbamates and thioamides are precursors of interesting molecular functionalities. Thiocarbamates include good insecticides [90JAE293], herbicides [75MI_675] and nematocides [89MI_158]. Recently, dimethylthiocarbamate (DMTC) has also been employed as an alcohol protecting group [03OL4755]. Some dithiocarbamates are fungicides and others are used as additives in the rubber industry. Various thioamides exhibit antileprosy [85JL587], anthelmintic [01PMS1000], immunosuppressive [98BMCL2203] and antituberculotic [02IF71] activity. We expect that bis(benzotriazolyl)methanethione 5.3 will be a precursor for the easy access to the above classes of compounds. In this work, we describe the preparation of various novel and known 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 and their application in the synthesis of thioamides 5.9, thiocarbamates 5.10 and dithiocarbamates 5.11 (Scheme 5-3).

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55 S Bt Bt NHR R N S R R Bt N NN N S R R R N S R R RO N S R R RS 5.3125.55.4125.95.11125.101212Bt = only whenR1, R2 = H Scheme 5-3. Synthetic utility of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 5.2 Results and Discussion 5.2.1 Preparation of 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 Bis(benzotriazolyl)methanethione 5.3, prepared from literature procedure [78JOC337] in 87% yield, was treated with one equivalent of the primary or secondary amine (in DCM at room temperature) to afford the respective thiocarbamoylbenzotriazoles 5.5a-k in yields of 60-98% (Scheme 5-4, Table 5-1). Their purification is fairly simple; several requiring only a mild base wash to remove benzotriazole by-product from the reaction mixture. Many are crystalline solids, enabling their storage and handling to be very convenient. These thiocarbamoylbenzotriazoles 5.5a-k proved to be stable at ambient conditions for weeks. In the following work it will be shown that many of them are good isothiocyanate

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56 analogues useful in the preparation of various thioamides, thiocarbamates and dithiocarbamates. N N S NN NN NHR R N N S NN R R 5.312 5.5 5.412 + Scheme 5-4. Preparation of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 Table 5-1. 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 prepared R1R2HHHMePhCH2CH2-HHHMePh-HCH2CO2CH3t-Bu% Yieldn-Bu-cyclohexylfurfuryl(R)-methylbenzyl-(CH2)5-2,3-dihydroindolyl5.5abcdefghij85769294878976601,5-dimethylhexyl8784Mp (oC)86.0 87.0118.9 -120.0aoila112.3 113.361.3-63.0oilaoil128.0 -130.0a123.0 124.0137.7 138.1a Previously prepared in [04JOC2976].k76129.0-130.0

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57 5.2.2 Preparation of Thioamides 5.9a-j Diand mono-substituted thiocarbamoylbenzotriazoles 5.5 were reacted with organolithium or Grignard reagents 5.6a-h presented in Figure 1-1 (Scheme 5-5). For example, when benzotriazole-1-carbothioic acid (furan-2-ylmethyl)-amide 5.5b was reacted with pentyl magnesium bromide 5.6h, hexanethioic acid (furan-2-ylmethyl)-amide 5.9b was obtained in 99% yield (Scheme 5-5, Table 5-2). The reaction was carried out in tetrahydrofuran using 2.5 equivalents of the Grignard reagent and only required 10% Na 2 CO 3 wash for purification. Di-substituted thiocarbamoylbenzotriazoles reacted in a similar way, requiring only the addition of 1.5 equivalents of the organometallic reagent. The higher yielding thioamides were obtained from commercially available reagents (5.6a, c, d, f and h). All other organometallic reagents were prepared following literature procedures [82MI; 79MI]. Table 5-2 and Table 5-3 show the diand mono-substituted thioamides 5.9 isolated after purification in yields of 36-99%. Li MgBr MgBr O S Li MgBr MgBr N Li O Li 5.6a 5.6b 5.6c 5.6d 5.6e 5.6f 5.6g 5.6h Figure 5-1. Organometallic reagents used

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58 N N S NN R R RM R N S R R 5.512THF5.9a-j12rt5.6a-h Scheme 5-5. Preparation of thioamides 5.9 Table 5-2: Preparation of mono-substituted thioamides from thiocarbamoylbenzotriazoles Reagent 5.5 R-M Thioamide 5.9 Yield (%) Bt NH S a 5.6f NH S a 87 Bt NH S O b 5.6h NH S O b 99 Bt NH S e 5.6e NH S O c 47 Bt NH S f 5.6f NH S d 56 NH S PhBt c 5.6c NH S Ph O e 85 Bt NH S a 5.6g NH S N f 35

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59 Table 5-3. Preparation of di-substituted thioamides from thiocarbamoylbenzotriazoles Reagent 5.5 R-M Thioamide 5.9 Yield (%) Bt N S g 5.6d N S g 99 Bt N S i 5.6a N S h 55 Bt N S i 5.6b N S S i 53 Bt N S Ph j 5.6d N S Ph j 75 We have demonstrated that thiocarbamoylbenzotriazoles 5.5 act as isothiocyanate analogues in the formation of thioamides 5.9 from the reaction of organometallic reagents. We now apply 5.5 in further reactions with other nucleophiles. In a previous paper, our group has already shown that thiocarbamoylbenzotriazoles react with nitrogen nucleophiles [04JOC2976], thus we illustrate here reactions of thiocarbamoylbenzotriazoles 5.5 with oxygen and sulfur nucleophiles. 5.2.3 Preparation of Thiocarbamates (5.10) and Dithiocarbamates (5.11) from Thiocarbamoylbenzotriazoles 5.5 When thiocarbamoylbenzotriazole 5.5h was reacted with the sodium salts of 5.7a and 5.8a, the corresponding thiocarbamate 5.10a and dithiocarbamate 5.11a were isolated in yields of 59% and 99% respectively (Scheme 5-6, Tables 5-4 and 5-5).

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60 OH SH OMe SH SH 5.7a 5.8a 5.8b 5.8d Figure 5-2. Alcohols and thiols used The reactions were performed in methylene chloride at room temperature. The salts were first prepared by stirring the desired alcohol or thiol with twelve equivalents of NaH in methylene chloride at room temperature for 30 minutes. The salt solution was then carefully added to the solution of the thiocarbamoylbenzotriazole. Purification of 5.11a was achieved by column chromatography, while 5.10a was purified with mild base wash. These novel compounds were characterized by 1 H and 13 C NMR and both passed elemental analysis. Other dithiocarbamates 5.11b-d and di-substituted thiocarbamate 5.10b were also prepared in good to excellent yields. Thus, when thiocarbamoylbenzotriazoles from primary amines were treated with thiols 5.8 in the presence of only one equivalent of triethylamine the respective dithiocarbamates 5.11b-d were obtained in yields of 60-92%. Thiocarbamoylbenzotriazoles 5.5a,b and d readily reacted with sulfur compounds while no products were obtained using oxygen nucleophiles. When reactions of 5.5a,b and d with alcohols 5.7 were attempted, the reactions did not produce the expected thiocarbamates 5.10, the starting materials were recovered in these cases. However, when thiocarbamoylbenzotriazoles 5.5a,b and d were treated with the alcohols 5.7 as their salt or in the presence of excess triethylamine, formation of the isothiocyanates was observed and the starting materials could no longer be recovered. We believe that the sodium salts or the use of excess triethylamine is too strong to

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61 deprotonate the thiocarbamoylbenzotriazoles into isothiocyanates while the use of one equivalent of triethylamine is not sufficiently basic to deprotonate the alcohols 5.7. N N S NN R R XR X N S R R R 5.512CH2Cl25.10-5.1112base+HX= O, S Scheme 5-6. Synthesis of thiocarbamates 5.10 and dithiocarbamates 5.11 Table 5-4. Preparation of thiocarbamates 5.10 Reagent 5.5 5.7 salt Thiocarbamates 5.10 Yield (%) Bt N S h ONa O N S a 59 Bt N S CH3 j ONa O N S CH3 b 60

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62 Table 5-5. Preparation of dithiocarbamates 5.11 Reagent 5.5 5.8 Dithiocarbamates 5.11 Yield (%) Bt N S h SNa OMe S N S MeO a 99 Bt NH S O b OMeSH NH S O S MeO b 83 Bt NH S a SH S NH S c 92 Bt NH S d SH S NH S d 77 5.3 Conclusion Many 1-alkyl/arylthiocarbamoylbenzotriazoles 5.5 are synthetically equivalent to isothiocyanates (only when R 2 =H) with the additional advantage that many of them are stable solids that do not decompose when stored at ambient conditions for weeks. Reactions with alkylor aryl-thiocarbamoylbenzotriazoles 5.5 do not require harsh conditions or complicated purification methods. In this work, we have revealed the versatility of compounds 5.5 in reactions with carbon, oxygen and sulfur nucleophiles to afford good yields of the respective thioamides, thiocarbamates and dithiocarbamates.

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63 Alkyl/Arylthiocarbamoylbenzotriazoles 5.5 were easily obtained and in high yields from bis(benzotriazolyl)methanethione 5.3, a stable solid that behaves as a thiophosgene equivalent without the inconveniences that originate from working with thiophosgene itself. 5.4 Experimental Section Melting points were determined on a hot-stage apparatus and are uncorrected. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution unless stated. Column chromatography was performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone ketyl prior to use. Commercially available Grignards and organolithium reagents were used for the preparation of thioamides. Organolithium reagents were prepared following literature methods [79OR; 82OR]. The organometallic reactions were performed under a nitrogen atmosphere and in oven dried glassware. 5.4.1 General Procedure for the Preparation of 1-Alkyland 1-Arylthiocarbamoylbenzotriazoles 5.5a-k Bisbenzotriazol-1-yl methanethione 5.3 [78JOC337] (0.90 g, 3.21 mmol) was dissolved in 20 mL methylene chloride at room temperature. The appropriate primary or secondary amine (3.21 mmol) was added dropwise and the mixture was stirred for 18 h. The solvent was removed under vacuum and ethyl acetate was added. The organic solution was washed with 5% aqueous sodium carbonate (40 ml x 5), water, brine, dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave the pure product or a mixture, which was further purified either by re-crystallization or column chromatography.

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64 Benzotriazole-1-carbothioic acid cyclohexylamide (5.5a): Colorless cubes (from EtOAc/Hexanes), (85%) mp 128.0130.0C (Lit. mp 72-73 o C) [04JOC2976]. 1 H NMR 1.211.58 (m, 5H), 1.651.90 (m, 3H), 2.132.30 (m, 2H), 4.394.54 (m, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.90-9.10 (m, 2H). 13 C NMR 24.6, 25.3, 31.6, 53.6, 116.1, 120.1, 125.5, 130.1, 132.4, 147.0, 173.0. Anal. Calcd. For C 13 H 16 N 4 S: C, 59.97; H, 6.19; N, 21.52. Found: C, 60.07; H, 6.32; N, 21.60. Benzotriazole-1-carbothioic acid (furan-2-ylmethyl)amide (5.5b): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as brown needles (94%), mp 118.9120.0C (Lit. mp 117-119 o C) [04JOC2976]. 1 H NMR 5.04 (d, J = 5.1 Hz, 2H), 6.38-6.46 (m, 2H), 7.447.52 (m, 2H), 7.627.70 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.91 (d, J = 8.4 Hz, 1H), 9.30 (s, 1H). 13 C NMR 41.8, 103.4, 109.4, 110.7, 116.0, 120.4, 125.8, 130.5, 143.0, 147.1, 148.5, 174.3. Anal. Calcd. For C 12 H 10 N 4 OS: C, 55.80; H, 3.90; N, 21.69. Found: C, 56.10; H, 3.86; N, 21.70. Benzotriazole-1-carbothioic acid ((R)-1-phenylethyl)amide (5.5c): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow oil (87%) [04JOC2976]. 1 H NMR 1.741.76 (m, 3H), 5.785.81 (m, 1H), 7.217.65 (m, 7H), 8.008.13 (m, 1H), 8.828.98 (m, 1H), 9.229.41 (m, 1H). 13 C NMR 21.0, 54.0, 116.0, 120.1, 125.6, 126.4, 127.9, 128.8, 130.2, 132.3, 141.0, 147.0, 173.3. Anal. Calcd. For C 15 H 14 N 4 S: C, 63.80; H, 5.00; N, 19.84. Found: C, 63.63; H, 4.95; N, 19.82. Benzotriazole-1-carbothioic acid phenethyl-amide (5.5d): White needles (from EtOAc/Hexanes), (89%), mp 112.3113.3C. 1 H NMR 3.12 (t, J = 6.9 Hz, 2H), 4.074.14 (m, 2H), 7.227.39 (m, 5H), 7.437.51 (m, 1H), 7.607.68 (m, 1H), 8.058.11 (m, 1H), 8.888.96 (m, 1H), 9.14 (s, 1H). 13 C NMR 34.1, 46.1, 116.0, 120.2, 125.7,

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65 127.0, 128.7, 128.9, 130.3, 132.4, 137.8, 147.0, 174.4. Anal. Calcd. For C 15 H 14 N 4 S: C, 63.80; H, 5.00; N, 19.84. Found: C, 63.81; H, 4.90; N, 19.70. Benzotriazole-1-carbothioic acid tert-butyl amide(5.5e): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow needles (60%), mp 61.363.0C. 1 H NMR 1.71 (s, 9H), 7.45 (t, J = 7.8 Hz, 1H), 7.59-7.64 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.91 (d, J = 8.7 Hz, 1H), 9.05 (s, 1H). 13 C NMR 27.9, 55.5, 103.3, 116.4, 120.1, 125.4, 130.0, 132.2, 147.1, 172.6. Anal. Calcd. For C 11 H 14 N 4 S: C, 56.38; H, 6.02; N, 23.91. Found: C, 56.31; H, 5.93; N, 24.10. Benzotriazole-1-carbothioic acid (1,5-dimethylhexyl)amide (5.5f): Purified by column chromatography with hexanes/EtOAc = 94:6 as eluent and obtained as yellow oil (87%), [04JOC2976]. 1 H NMR 0.87 (d, J = 6.3 Hz, 6H), 1.221.85 (m, 10H), 4.604.75 (m, 1H), 7.427.51 (m, 1H) 7.587.68 (m, 1H), 8.048.12 (m, 1H), 8.898.98 (m, 2H). 13 C NMR 19.5, 22.5, 23.7, 27.8, 36.1, 38.6, 51.0, 116.1, 120.1, 125.5, 130.1, 132.4, 147.0, 173.3. Anal. Calcd. For C 15 H 22 N 4 S: C, 62.03; H, 7.64; N, 19.29. Found: C, 62.47; H, 7.84; N, 19.70. Benzotriazole-1-carbothioic acid N-butyl-N-methylamide (5.5g): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow oil (76%). 1 H NMR 0.76 (t, J = 7.4 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H), 1.10 1.18 (m, 2H), 1.431.55 (m, 2H), 1.641.76 (m, 2H), 1.821.93 (m, 2H), 3.23 (s, 3H), 3.493.59 (m, 5H), 4.09 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.58 (t, J = 7.7 Hz, 2H), 7.998.10 (m, 4H). 13 C NMR 13.2, 13.6, 19.4, 19.8, 27.4, 30.0, 41.4, 42.0, 55.6, 55.7, 113.2, 113.6, 119.5, 124.8, 128.6, 128.7, 132.9, 133.1, 145.6, 174.8, 175.3. Anal. Calcd. For C 12 H 16 N 4 S: C, 58.04; H, 6.49; N, 22.56. Found: C, 57.81; H, 6.41; N, 22.85.

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66 1H-1,2,3-benzotriazol-1-yl(2,3-dihydro-1H-indol-1-yl)methanethione (5.5h): Purified by column chromatography with hexanes/EtOAc = 91:9 as eluent and obtained as yellow flakes (84%), mp 123.0124.0C. 1 H NMR in DMSO 3.16 (s, 1H), 3.26 (t, J = 7.7 Hz, 2H), 4.53 (t, J = 7.5 Hz, 2H), 7.02 (s, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.537.58 (m, 1H), 7.687.73 (m, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.198.22 (m, 1H). 13 C NMR in DMSO 26.6, 56.7, 112.7, 115.9, 119.5, 125.2, 125.7, 126.0, 126.6, 129.2, 131.4, 135.5, 140.9, 145.1, 168.8. Anal. Calcd. For C 15 H 12 N 4 S: C, 64.26; H, 4.31; N, 19.98. Found: C, 64.26; H, 4.21; N, 20.15. Benzotriazol-1-yl-piperidin-1-yl-methanethione (5.5i): Yellow prisms (from EtOAc/Hexanes), (76%), mp 86.087.0C. 1 H NMR 1.712.03 (m, 6H), 3.60 (s, 2H), 4.33 (s, 2H), 7.417.47 (m, 1H), 7.577.62 (m, 2H), 8.07 (d, J = 9 Hz, 2H). 13 C NMR 24.0, 25.4, 26.8, 52.7, 53.4, 113.7, 119.8, 125.0, 128.8, 133.3, 146.0, 174.1. Anal. Calcd. For C 12 H 14 N 4 S: C, 58.51; H, 5.73; N, 22.74. Found: C, 58.88; H, 5.73; N, 22.95. Benzotriazole-1-carbothioic acid methyl-phenyl-amide (5.5j): Colorless plates (from EtOAc/Hexanes), (92%), mp 137.7138.1C. 1 H NMR 3.96 (s, 3H), 7.017.10 (m, 2H), 7.157.26 (m, 3H), 7.367.42 (m, 1H), 7.567.61 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H). 13 C NMR 46.0, 113.0, 119.8, 124.6, 124.8, 127.7, 128.8, 129.4, 133.0, 145.4, 145.5, 175.7. Anal. Calcd. For C 14 H 12 N 4 S: C, 62.66; H, 4.51; N, 20.88. Found: C, 63.00; H, 4.49; N, 20.97. [(Benzotriazole-1-carbothioyl)-amino]-acetic acid methyl ester (5.5k): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as cream color flakes (76%), mp 129.0130.0C. 1 H NMR 3.87 (s, 3H), 4.62 (d, J = 3.6 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.86 (d, J

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67 = 8.7 Hz, 1H), 9.53 (s, 1H). 13 C NMR 46.2, 52.8, 115.8, 120.4, 125.8, 130.5, 132.3, 147.0, 168.5, 174.7. 5.4.2 General Procedure for the Preparation of Mono-substituted Thioamides 5.9a-f The desired thiocarbamoylbenzotriazole 5.5 (0.495 mmol) was dissolved in 10 mL dry THF under nitrogen atmosphere. The desired Grignard or organolithium reagent (1.24 mmol) was added dropwise at room temperature and the reaction mixture was stirred for 16 h. Water was added and was extracted with ethyl acetate (20 mL x3). The organic layers were combined, washed with water, washed with 10% sodium carbonate solution (35 mL x 5), washed with brine, dried over sodium sulfate, and filtered. Concentration under reduced pressure gave the pure product or a mixture, which was further purified either by re-crystallization or column chromatography. N-Cyclohexylbenzenecarbothioamide (5.9a): Purified by column chromatography with hexanes/EtOAc = 91:9 as eluent and obtained as yellow microcrystals (87%), mp 84.486.2C, (Lit. mp 91.0-92.0 o C) [49JOC962]. 1 H NMR 1.19.60 (m, 5H), 1.62.85 (m, 3H), 2.17.25 (m, 2H), 4.48.61 (m, 1H), 7.33.49 (m, 4H), 7.68.74 (m, 2H). 13 C NMR 24.6, 25.5, 31.6, 54.8, 126.5, 128.5, 130.9, 142.4, 197.7. Anal. Calcd. For C 13 H 17 NS: C, 71.18; H, 7.81; N, 6.39. Found: C, 70.96; H, 7.94; N, 6.48. N-(2-Furylmethyl)hexanethioamide (5.9b): Brown oil (99%). 1 H NMR 0.89 (t, J = 7.2 Hz, 3H), 1.25.40 (m, 4H), 1.72.83 (m, 2H), 2.66 (t, J = 7.8 Hz, 2H), 4.82 (d, J = 4.8 Hz, 2H), 6.33.37 (m, 2H), 7.39.45 (m, 2H). 13 C NMR 13.9, 22.3, 29.0, 31.0, 42.9, 47.0, 108.9, 110.6, 142.6, 149.1, 205.8. Anal. Calcd. For C 11 H 17 NOS: C, 62.52; H, 8.11; N, 6.63. Found: C, 62.86; H, 8.43; N, 6.63.

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68 N-(tert-Butyl)-2-furancarbothioamide (5.9c): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as brown oil (47%), (Lit. mp 45.0-46.0 o C) [89BSB327]. 1 H NMR 1.65 (s, 9H), 6.44.46 (m, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.39.40 (m, 1H), 7.82 (s, 1H). 13 C NMR 28.0, 55.5, 113.1, 116.8, 143.0, 153.2, 181.3. Anal. Calcd. For C 9 H 13 NOS: C, 59.82; H, 7.15; N, 7.64. Found: C, 59.22; H, 7.29; N, 7.93. N-(1,5-Dimethylhexyl)-thiobenzamide (5.9d): Purified by column chromatography with hexanes/EtOAc = 92:8 as eluent and obtained as yellow oil (56%). 1 H NMR 0.88 (d, J = 6.6 Hz, 6H), 1.21.70 (m, 10H), 4.72.77 (m, 1H), 7.34.47 (m, 4H), 7.67.70 (m, 2H). 13 C NMR 19.4, 22.5, 23.7, 27.8, 36.2, 38.7, 52.0, 126.5, 128.4, 130.8, 142.4, 198.0. Anal. Calcd. For C 15 H 23 NS: C, 72.23; H, 9.29; N, 5.62. Found: C, 72.00; H, 9.50; N, 5.90. 4-Methoxy-N-((R)-1-phenyl-ethyl)thiobenzamide (5.9e): Purified by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow needles (85%), mp 89.091.0C, [77CB730]. 1 H NMR 1.68 (d, J = 6.6 Hz, 3H), 3.81 (s, 3H), 5.885.94 (m, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.257.42 (m, 5H), 7.627.74 (m, 3H). 13 C NMR 20.2, 55.0, 55.4, 113.5, 126.5, 127.7, 128.4, 128.8, 134.2, 141.5, 162.1, 196.8. Anal. Calcd. For C 16 H 17 NOS: C, 70.81; H, 6.31; N, 5.16. Found: C, 70.78; H, 6.27; N, 5.11. N-Cyclohexyl-2-pyridinecarbothioamide (5.9f): Purified by column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as yellow oil (35%). 1 H NMR 1.251.90 (m, 8H), 2.132.29 (m, 2H), 4.524.68 (m, 1H), 7.46 (t, J = 5.7 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 8.53 (d, J = 4.5 Hz, 1H), 8.76 (d, J = 8.1 Hz, 1H), 10.13

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69 (s, 1H). 13 C NMR 24.6, 25.6, 31.4, 53.8, 124.9, 125.8, 137.1, 146.8, 151.2, 188.8. Anal. Calcd. For C 12 H 16 N 2 S: C, 65.41; H, 7.32; N, 12.71. Found: C, 65.79; H, 7.58; N, 12.57. 5.4.3 General Procedure for the Preparation of Di-substituted Thioamides 5.9g-j The desired thiocarbamoylbenzotriazole 5.5 (0.495 mmol) was dissolved in 10 mL dry THF under nitrogen atmosphere. The desired Grignard or organolithium reagent (0.743 mmol) was added dropwise at room temperature and the reaction mixture was stirred for 16 h. Water was added and was extracted with ethyl acetate (20 mL x3). The organic layers were combined, washed with water, washed with 10% sodium carbonate solution (35 mL x 5), washed with brine, dried over sodium sulfate, and filtered. Concentration under reduced pressure gave the pure product or a mixture, which was further purified either by re-crystallization or column chromatography. N-Butyl-N-methyl-3-butenethioamide (5.9g): Purified by column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as brown oil (98%). 1 H NMR 0.931.02 (m, 6H), 1.301.43 (m, 4H), 1.601.75 (m, 4H), 3.25 (s, 3H), 3.43 (s, 3H), 3.533.67 (m, 6H), 3.99 (t, J = 7.8 Hz, 2H), 5.115.22 (m, 4H), 5.906.80 (m, 2H). 13 C NMR 13.6, 13.7, 19.8, 19.9, 27.6, 30.1, 39.5, 42.4, 47.8, 48.8, 54.2, 55.7, 116.8, 117.0, 132.7, 133.5, 199.9. Anal. Calcd. For C 9 H 17 NS: C, 63.10; H, 10.00; N, 8.18. Found: C, 62.89; H, 10.30; N, 8.40. 1-Piperidino-1-pentanethione (5.9h): Purified by column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as yellow oil (55%) [65BSF3623]. 1 H NMR 0.94 (t, J = 7.4 Hz, 3H), 1.391.74 (m, 10H), 3.30 (t, J = 7.5 Hz, 2H), 3.90 (s, 2H), 4.29 (s, 2H). 13 C NMR 13.7, 22.1, 24.3, 26.0, 30.7, 37.0, 52.5, 196.1.

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70 Piperidino(2-thienyl)methanethione (5.9i): Purified by column chromatography with hexanes/EtOAc = 91:9 as eluent and obtained as yellow microcrystals (53%), mp 84.686.0C, (Lit. mp 89 o C) [65CB829]. 1 H NMR in DMSO 1.67 (s, 6H), 3.83 (s, 2H), 4.21 (s, 2H), 7.04 (t, J = 4.2 Hz, 1H), 7.14 (d, J= 3.9 Hz, 1H), 7.68 (d, J = 5.1 Hz, 1H). 13 C NMR in DMSO 23.8, 25.8, 26.8, 51.9, 52.9, 125.6, 126.8, 129.7, 145.0, 188.7. Anal. Calcd. For C 10 H 13 NS 2 : C, 56.83; H, 6.20; N, 6.63. Found: C, 56.96; H, 6.27; N, 6.55. N-Methyl-N-phenyl-3-butenethioamide (5.9j): Purified by column chromatography with hexanes/EtOAc = 85:15 as eluent and obtained as brown oil (78%). 1 H NMR 3.30 (d, J = 6.6 Hz, 2H), 3.74 (s, 3H), 4.824.89 (m, 2H), 5.03 (d, J = 9.9 Hz, 1H), 5.896.02 (m, 1H), 7.177.20 (m, 2H), 7.387.50 (m, 3H). 13 C NMR 45.8, 48.5, 116.9, 125.7, 128.6, 129.8, 134.3, 145.3, 202.7. Anal. Calcd. For C 11 H 13 NS: C, 69.06; H, 6.85; N, 7.32. Found: C, 69.18; H, 7.14; N, 7.53. 5.4.4 General Procedure for the Preparation of Di-substituted Thiocarbamates 5.10a-b The desired thiocarbamoylbenzotriazole 5.5 (0.36 mmol) was dissolved in 7 mL methylene chloride. In another flask, the desired alcohol (0.36 mmol) and NaH (0.17 g, 4.32 mmol) were stirred for 10 min in 7 mL methylene chloride. The sodium salt solution was added to the thiocarbamoylbenzotriazole solution and the mixture was stirred for 18 h. The solvent was removed under vacuum; water was added and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with water, 10% sodium carbonate solution (2 x 30 mL), dried over sodium sulfate, and filtered. Concentration under reduced pressure gave the pure product or a mixture, which was further purified either by re-crystallization or column chromatography.

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71 O-Benzhydryl1-indolinecarbothioate (5.10a): Colorless prisms (from EtOAc/Hexanes), (59%), mp 150.5153.7C. 1 H NMR 3.12 (t, J = 8.4 Hz, 2H), 4.40 (t, J = 8.4 Hz, 2H), 6.997.42 (m, 12H), 7.767.87 (m, 2H). 13 C NMR 26.6, 54.2, 83.9, 117.7, 124.3, 125.5, 127.6, 127.7, 128.0, 128.5, 133.6, 139.6, 141.3, 184.0. Anal. Calcd. For C 22 H 19 NOS: C, 76.49; H, 5.54; N, 4.05. Found: C, 76.62; H, 5.55; N, 4.04. O-Benzhydryl N-methyl-N-phenylcarbamothioate (5.10b): Colorless plates (from acetone), (60%), mp 102.2103.2C. 1 H NMR 3.62 (s, 3H), 7.097.49 (m, 16H). 13 C NMR 44.0, 83.3, 126.1, 126.8, 127.6, 128.3, 129.2, 130.0, 140.3, 143.5, 187.3. Anal. Calcd. For C 21 H 19 NOS: C, 75.64; H, 5.74; N, 4.20. Found: C, 75.65; H, 5.91; N, 4.17. 5.4.5 General Procedure for the Preparation of Di-substituted Dithiocarbamate 5.11a The desired thiocarbamoylbenzotriazole 5.5 (0.32 mmol) was dissolved in 7 mL methylene chloride. In another flask, the desired mercapto reagent (0.36 mmol) and NaH (0.02 g, 0.49 mmol) were stirred for 10 min in 7 mL methylene chloride. The sodium salt solution was added to the thiocarbamoylbenzotriazole solution and the mixture was stirred for 18 h. The solvent was removed under vacuum; water was added and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with water, 10% sodium carbonate solution (2 x 30 mL), dried over sodium sulfate, and filtered. Concentration under reduced pressure gave the pure product or a mixture, which was further purified either by re-crystallization or column chromatography. 3-Methoxyphenyl-1-indolinecarbodithioate (5.11a): Purified by column chromatography with hexanes/EtOAc = 92:8 as eluent and obtained as orange powder (99%), mp 103.6105.0C. 1 H NMR in DMSO at 70 C 3.23 (t, J = 8.1 Hz, 2H), 3.79

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72 (s, 3H), 4.56 (t, J = 7.5 Hz, 2H), 7.047.43 (m, 5), 7.347.43 (m, 2H), 8.93 (d, J = 8.1 Hz, 1H). 13 C NMR in DMSO at 70 C 26.7, 54.8, 55.1, 115.8, 117.7, 121.7, 125.0, 125.1, 126.0, 128.5, 129.6, 131.0, 135.0, 143.2, 159.3, 190.5. Anal. Calcd. For C 16 H 15 NOS 2 : C, 63.75; H, 5.02; N, 4.65. Found: C, 63.38; H, 5.03; N, 4.28. 5.4.6 General Procedure for the preparation of Mono-substituted Dithiocarbamates 5.11b-d The desired mono-substituted thiocarbamoylbenzotriazole 5.5 (0.36 mmol) was dissolved in 7 mL methylene chloride. The desired mercapto reagent (0.36 mmol) was added dropwise followed by exactly one equivalent of triethyl amine (0.36 mmol). The reaction mixture was stirred for 16 h. The solvent was removed under vacuum; water was added and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with water, dried over sodium sulfate, and filtered. Concentration under reduced pressure gave a mixture that was further purified either by re-crystallization or column chromatography. 3-Methoxyphenyl N-(2-furylmethyl)carbamodithioate (5.11b): Purified by column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as colorless prisms (83%), mp 73.274.7C. 1 H NMR 3.81 (s, 3H), 4.82 (d, J = 4.8 Hz, 2H), 6.22 (s, 1H), 6.30 (s, 1H), 6.947.16 (m, 4H), 7.267.30 (m, 1H), 7.40 (t, J = 7.8 Hz, 1H). 13 C NMR 43.02, 55.5, 108.6, 110.5, 117.6, 119.7, 127.3, 129.3, 131.3, 142.6, 148.8, 160.6, 195.0. Anal. Calcd. For C 13 H 13 NO 2 S 2 : C, 55.89; H, 4.69; N, 5.01. Found: C, 55.90; H, 4.71; N, 5.01. Benzyl N-cyclohexylcarbamodithioate (5.11c): Purified by column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as colorless crystals (92%), mp 70.271.0C, (Lit. mp 6667 o C) [69ABC1367]. 1 H NMR in DMSO

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73 1.051.35 (m, 5H), 1.551.62 (m, 1H), 1.671.76 (m, 2H), 1.841.95 (m, 2H), 4.25 (s, 1H), 4.49 (s, 2H), 7.207.42 (m, 5H), 9.86 (d, J = 7.2 Hz, 1H). 13 C NMR in DMSO 24.7, 25.1, 31.0, 38.0, 56.0, 127.1, 128.5, 129.0, 137.5, 194.1. Anal. Calcd. For C 14 H 19 NS 2 : C, 63.35; H, 7.21; N, 5.28. Found: C, 63.42; H, 7.38; N, 5.22. Phenyl N-phenethylcarbamodithioate (5.11d): Purified by column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as colorless crystals (60%), (Lit. mp 7374 o C) [63AP310]. 1 H NMR 2.82 (t, J = 6.6 Hz, 2H), 3.87 (q, J= 6.3 Hz, 2H), 6.55 (s, 1H), 6.946.97 (m, 2H), 7.207.22 (m, 3H), 7.377.39 (m, 4H), 7.427.50 (m, 1H). 13 C NMR 33.6, 46.9, 126.6, 128.0, 128.4, 128.8, 130.3, 131.0, 135.4, 137.5, 194.8. Anal. Calcd. For C 15 H 15 NS 2 : C, 65.89; H, 5.53; N, 5.12. Found: C, 65.38; H, 5.50; N, 6.01.

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CHAPTER 6 CONCLUSION Benzotriazole proved to be a good synthetic auxiliary for the preparation of biologically important compounds. In chapter 2 the synthesis of 2,4-benzodiazepin-1-ones (2.13) was achieved utilizing simple chemistry. We have showed that N, N-bis(benzotriazolylmethyl)alkyl amines (2.9) are a good di-cation source. An efficient methodology for sulfonylation was introduced in chapter 3. Both sulfonamides and sulfonylbenzotriazoles were synthesized in good yields. Sulfonamides were prepared from novel sulfonylbenzotriazoles (3.27), which are excellent sulfonyl chloride analogues. Using a simple procedure, alkyl sulfonamides, ethylene sulfonamides and a sulfonate ester were synthesized through 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole (4.5) intermediate (Chapter 4). The benzotriazole intermediate (4.5) is convenient to use, avoiding the difficulty in handling and the excessive reactivity of the commonly used 2-chloroethanesulfonyl chloride. A new procedure was developed for the preparation of thioamides, thiocarbamates and dithiocarbamates that does not require rigorous reaction conditions (Chapter 4). This procedure utilizes bis(benzotriazolyl)methanethione (5.3), where both of the benzotriazole molecules are displaced by different nucleophiles. Bis(benzotriazolyl)methanethione (5.3) showed to be an excellent thiocarbonyl transfer agent. 74

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REFERENCES The reference citation system employed throughout this dissertation is that from Comprehensive Heterocyclic Chemistry II (Vol.1) Pergamon Press, 1996 (Eds. Katritzky, A. R.; Rees, C. W. and Scriven, E.). Each time a reference is cited, a number-letter code is designated to the corresponding reference with the first two (or four if the reference is before 1910s) number indicating the year followed by the letter code of the journal and the page number in the end. Additional notes to this reference system are as follows: (i) Each reference code is followed by the conventional literature citation in the ACS style. (ii) Journals which are published in more than one part, or more than one volume per year, include in the abbreviation cited the appropriate part or volume number. (iii) Less commonly used books and journals are coded as MI for miscellaneous. (iv) The list of the reference is arranged according to the designated code in the order of (a) year; (b) journal in alphabetical order; (c) part number or volume number if it is included in the code; (d) page number. (v) Using project number to code the unpublished results. 75

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76 [42CB42] Asinger; F.; Ebeneder; F.; Boeck, E. Chem. Ber. 1942, 42. [49JOC962] Alliger, G.; Smith, G. E.P.; Carr, E. L.; Stevens, H. P. J. Org. Chem. 1949, 14, 962. [63AP310] Rieche, A.; Hilgetag, G.; Martin, D.; Kreyzi, I. Arch. Pharm. 1963, 296, 310. [65BSF3623] Reynaud, P.; Moreau, R.C.; Samama, J.P. Bull. Soc. Chim. Fr. 1965, 3623. [65CB829] Meyer, R.; Scheithauer, S. Chem. Ber. 1965, 829. [69ABC1367] Wakamori, S.; Yoshida, Y; Ishii, Y. Agric. Biol. Chem. 1969, 1367. [69JCS(C)1474] Rees, C. W.; Storr, R. C. J. Chem. Soc. (C) 1969, 1474. [69JCS(C)1478] Rees, C. W.; Storr, R. C. J. Chem. Soc. (C) 1969, 1478. [69JCS(CC)365] Iles, D. H.; Ledwith, A. J. Chem. Soc. (CC) 1969, 365. [71JIC791] Ginwala, K. K.; Trivedi, J. P. J. Indian Chem. Soc. 1971, 48, 791. [75MI_675] Casida, J. E.; Kimmel, E. C.; Lay, M.; Ohkawa, H.; Rodebush, J. E.; Gray, R. A.; Tseng, C. K.; Tilles, H. Environmental Quality and Safety Supplement 1975, 3, 675. [76MI_573] Keating, J. T.; Skell, P. S. Carbonium Ions 1976, 2, 573. [78JA4634] Masilamani, D.; Rogic, M. M. J. Am. Chem. Soc. 1978, 100, 4634. [78JOC337] Larsen, C.; Steliou, K.; Harpp, D. N. J. Org. Chem. 1978, 43, 337. [79COC345] Andersen, K. K. In Comprehensive Organic Chemistry; Jones, D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3, p 345. [79JOC160] Pinnick, H. W.; Reynold, M. A. J. Org. Chem. 1979, 44, 160. [79OR] Gschwend, H. W.; Rodriguez, H. R. In Organic Reactions; John Wiley & Sons, Inc.: New York, 1979; Vol. 26, Ch 1. [80JA853] Collins, C. J.; Hombach, H.-P.; Maxwell, B.; Woody, M. C.; Benjamin, B. M. J. Am. Chem. Soc. 1980, 102, 853. [80JOC3713] Larsen, C.; Harpp, D. N. J. Org. Chem. 1980, 45, 3713.

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77 [81JOC5077] Scully, F. E.; Bowdring, K. J. Org. Chem. 1981, 46, 5077. [82OR] Biellmann, J. F.; Ducep, J. B. Organic Reactions; John Wiley & Sons, Inc.: New York, 1982; Vol. 27, Ch 1. [83CPB1374] Nishikawa, M.; Inaba, Y.; Furukawa, M. Chem. Pharm. Bull. 1983, 31, 1374. [83S791] Singh, H.; Aggarwal, S. K.; Malhotra, N. Synthesis 1983, 791. [83S816] Aumaitre, G.; Chanet-Ray, J.; Durand, J.; Vessiere, R. Synthesis 1983, 10, 816. [83S822] Breant, P.; Marsais, F.; Queguiner, G. Synthesis 1983, 822. [84JMC711] Hanzlik, R. P.; Thompson, S. A. J. Med. Chem. 1984, 27, 711; [85MI_587] Shepard, C. C.; Jenner, P. J.; Ellard, G. A.; Lancaster, R. D. International Journal of Leprosy and Other Mycobacterial Diseases 1985, 53, 587. [86JMC104] Thompson, S. A.; Andrews, P. R.; Hanzlik, R. P. J. Med. Chem. 1986, 29, 104. [86S1031] Graham, S. L.; Scholz, T. H. Synthesis 1986, 12, 1031. [87H101] Chanet-Ray, J.; Vessiere, R.; Zeroual, A. Heterocycles 1987, 26, 101. [87H1313] Kato, H.; Tani, K.; Kuiumisawa, H.; Tamura, Y. Heterocycles 1987, 1313. [87JCS(P1)799] Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Chem. Soc., Perkin Trans. I 1987, 799. [87S487] Koziara, A.; Osowska-Pacewika, K.; Zawadzki, S.; Zwierzak, A. Synthesis 1987, 487. [87TL1101] Carretero J. C.; Ghosez, L. Tetrahedron Lett. 1987, 28, 1101. [88H323] Iwataka, C.; Watanabe, M.; Okamoto, S.; Fujimoto, M.; Sakae, M. Heterocycles 1988, 323. [88JMC2235] Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen,

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78 T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235. [89BSB327] Jagodzinski, T. D.; Dziembowska, T. M.; Szczodrowska, B. Bull. Soc. Chim. Belg. 1989, 327. [89JHC1807] Cho, N. S.; Song, K. Y.; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807. [89MI_158] Koschansky, J.; Feldmesser, J. Journal of Nematology 1989, 21, 158. [90CJC446] Katritzky, A. R.; Rachwal, S.; Wu, J. Can. J. Chem. 1990, 68, 446. [90CRV879] Snieckus, V. Chem. Rev. 1990, 90, 879. [90JAE293] Kochansky, J.; Cohen, C. F. J. of Agricultural Entomology 1990, 7, 293. [90JCS(P1)541] Katritzky, A. R.; Pitarski, B.; Urogdi, L. J. Chem. Soc., Perkin Trans. 1 1990, 541. [90MI_255] Hansch, C.; Sammes, P. G.; Taylor, J. B. In Comprehensive Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol. 2, Chapter 7.1, p 255. [90T6951] Simpkins, N. S. Tetrahedron, 1990, 46, 6951. [91AP367] Mohrle, H.; Lessel, J. Arch. Pharm. 1991, 324, 367. [91JOC3549] Morris, J.; Wishka, D. G.; J. Org. Chem. 1991, 56, 3549. [92JOC4775] O Connell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57, 4775. [92T7817] Katritzky, A. R.; Shobana, N.; Pernak, J.; Afridi, A. S.; Fan, W-Q. Tetrahedron 1992, 48, 7817. [94H345] Katritzky, A. R.; Gupta, V.; Garot, C.; Stevens, C. V.; Gordeev, M. F. Heterocycles 1994, 38, 345. [94JA5077] McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb II, R. R.; Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077. [94SC205] Katritzky, A. R.; Zhang, G.; Wu, J. Synth. Commun. 1994, 24, 205.

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79 [95CB1195] Lube, A.; Neumann, W. P.; Niestroj, M. Chem. Ber. 1995, 1195. [95JMC3193] Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. J. Med. Chem. 1995, 38, 3193. [95MI_1021] Gilmore, J.; Gallagher, P. T. In Comprehensive Organic Functional Group Transformations, 1 st ed.; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Elsevier Science Ltd.: New York, 1995; Vol. 5, p 1021. [96AAC1600] Rosenthal, P. J.; Olson, J. E.; Lee, G. K.; Palmer, J. T.; Klaus, J. L.; Rasnick, D. Antimicrob. Agents Chemother. 1996, 1600. [96JOC3117] Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem. 1996, 61, 3117. [97JOC1240] Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997, 62, 1240. [97SL1253] Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J. S. Synlett 1997, 1253. [98MI_2203] Alber, R.; Knecht, H.; Andersen, E.; Hungerford, V.; Schreier, M. H.; Papageorgiou, C. Bioorg. Med. Chem. Lett. 1998, 8, 2203. [98CRV409] Katritzky, A.R.; Lan, X.; Yang, J.; Denisko, O. V. Chem. Rev. 1998, 98, 409. [98H2535] Katritzky, A. R.; Feng, Y.; Qi, M.; Feng, D. Heterocycles 1998, 48, 2535. [98JA10994] Roush, W. R.; Gwaltney II, S. L.; Cheng, J.; Scheidt, K. A.; McKeorrow, J. H.; Hansell, E. J. Am. Chem. Soc. 1998, 120, 10994. [98JEM725] Engel, J. C.; Doyle, P. S.; Hsieh, I.; McKerrow, J. H. J. Exp. Med. 1998, 188, 725. [98JOC8021] Hulme, C.; Peng, J.; Tang, S. -Y.; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. [98SC1721] Iyer, S.; Sattar, A. K. Synth. Commun. 1998, 28, 1721. [98TL6835] Katritzky, A. R.; Feng, D.; Qi, M. Tetrahedron Lett. 1998, 39, 6835.

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80 [99JMC3789] Owa, T.; Yoshino, H.; Okauchi, T.; Yoshimatsu, K.; Ozawa, Y.; Sugi, N. H.; Nagasu, T.; Koyanagi, N.; Kitoh, K. J. Med. Chem. 1999, 42, 3789. [99JMC4414] Grasso, S.; De Sarro, G.; De Sarro, A.; Micale, N.; Zappala, M.; Puia, G.; Baraldi, M.; De Micheli, C. J. Med. Chem. 1999, 42, 4414. [99JOC290] Damayanthi, Y.; Reddy, B. S. P.; Lown, J. W. J. Org. Chem. 1999, 64, 290. [99JOC2914] Juaristi, E.; Leon-Romo, J. L.; Ramirez-Quiros, Y. J. Org. Chem. 1999, 64, 2914. [99JOC3328] Katritzky, A. R.; Luo, Z.; Cui, X.-L. J. Org. Chem. 1999, 64, 3328. [99OL577] Katritzky, A. R.; Monteux, D. A.; Tymoshenko, D. O. Org. Lett. 1999, 1, 577. [99OL1835] Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org. Lett. 1999, 1, 1835. [99TL2623] Bocelli, G.; Catellani, M.; Cugini, F.; Ferraccioli, R. Tetrahedron Lett. 1999, 40, 2623. [00JCB513] Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513. [00JMC3596] Ursini, A.; Capelli, A. M.; Carr, R. A. E.; Cassara, P.; Corsi, M.; Curcuruto, O.; Curotto, G.; Cin, M. D.; Davalli, S.; Donati, D.; Feriani, A.; Finch, H.; Finizia, G.; Gaviraghi, G.; Marien, M,; Pentassuglia, G.; Polinelli, S.; Ratti, E.; Reggiani, A.; Tarzia, G.; Tedesco, G.; Tranquillini, M. E.; Trist, D. G.; Van Amsterdam, F. T. M. J. Med. Chem. 2000, 43, 3596. [00JMC4834] Zappala, M.; Gitto, R.; Bevacqua, F.; Quartarone, S.; Chimirri, A.; Rizzo, M.; De Sarro, G.; De Sarro, A. J. Med. Chem. 2000, 43, 4834. [00JOC8210] Katritzky, A. R.; He, H-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210. [00JOC8669] Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. J. Org. Chem. 2000, 65, 8669.

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81 [00OL3555] Chuang, T. -H.; Sharpless, K. B. Org. Lett. 2000, 2, 3555. [01H1703] Katritzky, A. R.; Kurz, T.; Zhang, S.; Voronkov, M.; Steel, P. J. Heterocylcles 2001, 55, 1703. [01JCB90] Pirrung, M. C.; Pansare, S. V. J. Comb. Chem. 2001, 3, 90. [01JOC2784] Witt, A.; Bergman, J. J. Org. Chem. 2001, 66, 2784. [01JOC2850] Katritzky, A. R.; Wang, X.; Denisenko, A. J. Org. Chem. 2001, 66, 2850. [01MI_1000] Jeschke, P.; Harder, A.; Etzel, W.; Gau, W.; Thielking, G.; Bonse, G.; Linuma, K. Pest Management Sci. 2001, 57, 1000. [01OL585] Wilson, L. J. Org. Lett. 2001, 3, 585. [01SC1803] Ghiaci, M.; Bakhtiari, K. Synth. Commun. 2001, 1803. [02IF71] Krinkova, J.; Dolezal, M.; Hartl, J.; Buchta, V.; Pour, M. Il Farmaco 2002, 57, 71. [02JA28] Yamamoto, Y.; Takagishi, H.; Itoh, K. J. Am. Chem. Soc. 2002, 124, 28. [02JCB315] Theoclitou, M.-E.; Delaet, N. G.; Robinson, L. A. J. Comb. Chem. 2002, 4, 315. [02JCB491] Phoon, C. W.; Sim, M. M. J. Comb. Chem. 2002, 4, 491. [02JMC5136] Liegeois, J. F.; Eyrolles, L.; Ellenbroek, B. A.; Lejeune, C.; Carato, P.; Bruhwyler, J.; Geczy, J.; Damas, J.; Delarge, J. J. Med. Chem. 2002, 45, 5136. [02OL2549] Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd, D. B. Org. Lett. 2002, 4, 2549. [02SL1928] Frost, C. G.; Hartely, J. P.; Griffin, D. Synlett 2002, 1928. [02TL4537] Chan, W. Y.; Berthelette, C. Tetrahedron Lett. 2002, 43, 4537. [02TL8479] Baskin, J. M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479. [03JCB775] Ivachtchenko, A. V.; Kovalenko, S. M.; Drushlyak, O. G. J. Comb. Chem. 2003, 5, 775.

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82 [03JOC8583] Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin, J. C.; Deniaud, D. J. Org. Chem. 2003, 68, 8583. [03JOC8693] Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org. Chem. 2003, 68, 8693. [03OL4755] Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.; Falck, J. R. Org. Lett. 2003, 5, 4755. [04JOC188] Shi, J.; Zhang, J.; Grazier, N.; Stein, P. D.; Atwal, K. S.; Traeger, S. C.; Callahan, S. P.; Malley, M. F.; Galella, M. A.; Gougoutas, J. Z. J. Org. Chem. 2004, 69, 188. [04JOC202] Isac-Garcia, J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.; Santoyo-Gonzales, F. J. Org. Chem. 2004, 69, 202. [04JOC2976] Katritzky, A. R.; Ledoux, S.; Witek, R. M.; Nair, S. K. J. Org. Chem. 2004, 69, 2976.

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BIOGRAPHICAL SKETCH Valerie Rodriguez Garcia was born in January 7, 1977, in Rio Piedras, Puerto Rico. While doing her undergraduate studies in chemistry in the University of Puerto Rico, Recinto de Rio Piedras, she worked for one year in organic synthesis under the supervision of Dr. Jorge Colon and Dr. Osvaldo Cox. She obtained her Bachelor of Science in chemistry in May 2000 and started the PhD program in the Chemistry Department of the University of Florida in August 2000 with Dr. Alan R. Katritzky. She married in June 2003 to Igor Schweigert, who is doing his PhD in chemistry under the supervision of Dr. Rodney Bartlett. 83


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Title: Efficient Methodology for the Synthesis of 2,4-Benzodiazepin-1-ones, Sulfonylbenzotriazoles, Sulfonamides, Ethylene Sulfonamides, Thiocarbamates, Dithiocarbamates and Thioamides
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EFFICIENT METHODOLOGY FOR THE SYNTHESIS OF 2,4-BENZODIAZEPIN-1-
ONES, SULFONYLBENZOTRIAZOLES, SULFONAMIDES, ETHYLENE
SULFONAMIDES, THIOCARBAMATES, DITHIOCARBAMATES AND
THIOAMIDES














By

VALERIE RODRIGUEZ-GARCIA


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


2004




























I owe my achievements to my family, my mother Iris Garcia, my father Francisco V.
Rodriguez, my brothers Emmanuel and Rasik, my cousins Sonia, Mia Alexandra and
Roberto Mateo. I have been raised in their deepest love, and it continues today also.
This I do for them.















ACKNOWLEDGMENTS

I want to mention first that I believe nothing happens without a purpose. My life

these past years has been guided to make much sense, for all the things I have seen I

never thought I would, all the places I have visited and all the caring beings that have

been included in the story of my life. I definitely owe so much to graduate school and to

those who made it possible.

Forever my respect and gratitude go to my supervisor, Professor Alan R. Katritzky,

and to my supervisory committee members, Dr. William R. Dolbier, Dr. Eric Enholm,

Dr. Steven A. Benner and Dr. Dinesh 0. Shah. I immensely thank Dr. Jeffrey L. Krause;

the date of my final defense would not have been possible if he had not agreed to assist.

I thank Dr. Dennis Hall for correcting my thesis, and thanks go to Dr. Suman

Majumder and to Dr. Sanjay Singh for their help always in English and content

corrections. I thank all Katritzky members for their friendship and encouragement.

I want to give special thanks to Eladio Rivera and Wigberto Hernandez for their

help during my undergraduate studies and for their friendship through distance.

I thank my husband Igor V. Schweigert and my other loves in the Chemistry

Department, Rachel Witek, Hongfang Yang and Chaya Pooput, for their support and their

genuine interest in my well being.















TABLE OF CONTENTS



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

LIST OF TABLES ............................... ............ .................................... vii

L IST O F F IG U R E S ................................................... .............................................. viiii

LIST OF SCHEMES ............................... ........... ............................ ixx

A B S T R A C T ...................................................................................................... ............ x i

CHAPTER

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

2 ONE POT SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES USING
BENZOTRIAZOLE METHODOLOGY..............................................................5...

2 .1 In tro d u ctio n ................................................................................................... .. 5
2 .2 R results and D iscu ssion ......................................... ........................ ............... 8
2 .3 C o n clu sio n .......................................................................................................... 12
2 .4 E xperim ental Section .................................................................... ............... 12
2.4.1 General Procedure for the Preparation of N, N-
bis(Benzotriazolylmethyl)alkyl amines 2.9a-d ..............................12
2.4.2 General Procedure for the Preparation of N-Alkyl-arylbenzamides
2.11a-d ............... ... ............ .. ............... .. ........................... 13
2.4.3 General Procedure for the Preparation of 2,4-Benzodiazepin- -ones
2.13a-h ................ ........ .............. ............... 15

3 A GENERAL AND EFFICIENT SYNTHESIS OF
SULFONYLBENZOTRIAZOLES FROM N-CHLOROBENZOTRIAZOLE
A N D SU LFIN IC A C ID SA L T S ...............................................................................19

3 .1 In tro d u ctio n ........................................................................................................ 19
3.2 R results and D iscu ssion .................................................................. ................ 24
3.2.1 Preparation of Benzotriazole Reagents 3.27.....................................24
3.2.2 Synthesis of Sulfonamides 3.29-3.37 using Reagents 3.27................28
3 .3 C o n clu sio n .......................................................................................................... 2 9
3.4 E xperim ental Section ......................................... ........................ .................. 3 1









3.4.1 General Procedure for the Preparation of Sulfonylbenzotriazoles
3 .2 7 a- j .......................... ................. .. ............. ........................... .. 3 1
3.4.2 General Procedure for the Preparation of Sulfonamides 3.29-3.37 ......34

4 1-[2-BENZOTRIAZOL-1-YL)ETHYL]SULFONYLBENZOTRIAZOLE: A
VERSATILE SYNTHON FOR THE PREPARATION OF
ETHYLENESULFONAMIDES AND ALKYLSULFONATE ESTERS ................ 38

4 .1 In tro d u ctio n ........................................................................................................ 3 8
4 .2 R results and D iscu ssion .................. ....... .. .............. .............. .......................... 433
4.2.1 Preparation of Sulfonamides 4.7a-g and Sulfonate ester 4.7h ..........444
4.2.2 Preparation of Ethylenesulfonamides 4.8a, f.................................455
4 .3 C o n clu sio n .......................................................................................................... 4 6
4 .4 E xperim ental P procedure .................................................................................... 46
4.4.1 Procedure for the Synthesis of Novel Intermediate 4.5.....................466
4.4.2 General Procedure for the Preparation of Sulfonamides 4.7a-g............47
4.4.3 Procedure for the Preparation of Sulfonate ester 4.7h ...........................49
4.4.4 General Procedure for the Synthesis of Ethylenesulfonamides 4.8a, f .50

5 VERSATILE SYNTHESIS OF THIOCARBAMOYLBENZOTRIAZOLES,
THIOAMIDES, THIOCARBAMATES AND DITHIOCARBAMATES FROM
BIS(BENZOTRIAZOLYL)METHANETHIONE ........................ ..................... 52

5 .1 In tro d u ctio n ........................................................................................................ 5 2
5.2 R results and D iscu ssion ........................................................... ... .................. 55
5.2.1 Preparation of 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5.............55
5.2.2 Preparation of Thioam ides 5.9a-j ..................................... ................ 57
5.2.3 Preparation of Thiocarbamates (5.10) and Dithiocarbamates (5.11)
from Thiocarbamoylbenzotriazoles 5.5 .......................... ................ 59
5 .3 C o n clu sio n .......................................................................................................... 6 2
5.4 E xperim ental Section ........................................................... ......................... 63
5.4.1 General Procedure for the Preparation of 1-Alkyl- and 1-Aryl-
thiocarbam oylbenzotriazoles 5.5a-k.................................................. 63
5.4.2 General Procedure for the Preparation of Mono-substituted
Thioam ides 5.9a-f ............... ...... .. .... ... .. ........................ ........ 67
5.4.3 General Procedure for the Preparation of Di-substituted Thioamides
5 .9 g -j ................. ........... ........ ..... .............. ............... 6 9
5.4.4 General Procedure for the Preparation of Di-substituted
T hiocarbam ates 5.10a-b ................................................... ............... 70
5.4.5 General Procedure for the Preparation of Di-substituted
D ithiocarbam ates 5.11a ................................................................ 71
5.4.6 General Procedure for the Preparation of Mono-substituted
D ithiocarbam ates 5.11b-d..................................................... 72









6 C O N C L U SIO N ................. .. ................ .................... ......................................... 74

REFERENCES ............................................ ...... 75

B IO G R A PH IC A L SK E TC H .. ...................................................................... ................ 83















LIST OF TABLES


Table page

2-1 Synthesis of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d ..........................8...

2-2 Y ield ofbenzam ides prepared ......................................................... ..................... 9

2-3 Yields of 2, 4-Benzodiazepine-1-ones prepared .................................................11

3-1 A lkyl/arylsulfonylbenzotriazoles 3.27 ................................................ ................ 28

3-2 Sulfonamides 3.29-3.37 prepared using reagents 3.27........................................30

4-1 Sulfonamides 4.7a-g and sulfonate ester 4.7h prepared ............... ..................... 45

5-1 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 prepared ...................................56

5-2 Preparation of mono-substituted thioamides from thiocarbamoylbenzotriazoles ....58

5-3 Preparation of di-substituted thioamides from thiocarbamoylbenzotriazoles..........59

5-4 Preparation of thiocarbam ates 5.10..................................................... ................ 61

5-5 Preparation of dithiocarbam ates 5.11 ................................................. ................ 62
















LIST OF FIGURES


Figure page

2-1 B iologically active benzodiazepines ..................................................... ...............6...

2-2 1H N M R spectrum of 2.13b ..................................................................................... 18

3-1 Prontosil 3.1 and the active metabolite sulfanilamide 3.2 ..................................... 19

3-2 Various clinically used sulfonamide drugs .........................................................20

3-3 1HNMR spectrum of 1-(2-thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h)..........27

4-1 Intermediate 4.1 used in the preparation of ethylenesulfonamides.......................43

5-1 O rganom etallic reagents used ............................................................. ................ 57

5-2 A lcohols and thiols u sed ......................................... ......................... ................ 60
















LIST OF SCHEMES


Scheme page

1-1 Some isom ers of N-substituted benzotriazoles .............. .....................................2...

2-1 Literature methods to synthesize 2,4-benzodiazepines........................................7...

2-2 R etrosynthetic analysis. ...................................................................... ...............7...

2-3 Preparation of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d .......................8...

2-4 P reparation of benzam ides .............................................................. ..................... 9

2-5 Synthesis of 2, 4-Benzodiazepine-1-ones ........................................... ................ 11

3-1 Example of the preparation of sulfonamides....................................... ................ 21

3-2 Various methods for the synthesis of sulfonamides............................................22

3-3 Synthesis of benzenesulfonamides and aryl benznesulfonates from
1-phenylsulfonylbenzotriazole ......................................................... 23

3-4 Synthesis ofp-tolylsulfonylbenzotriazole using our method...............................25

3-5 Proposed mechanism for the formation of sulfonylbenzotriazoles.......................25

3-6 Preparation of 1-alkyl/arylsulfonylbenzotriazoles 3.27 ......................................28

3-7 Preparation of sulfonam ides....................................... ...................... ................ 29

4-1 Transformations of ethylenesulfonamides, vinyl sulfones and ethylenesulfonate
e sters ...................................................................................................... ....... .. 3 9

4-2 D esulfonation R actions ......................................... ......................... ................ 40

4-3 Synthetic protocols toward ethylenesulfonate esters, vinyl sulfones and
ethylenesulfonam ides ............. .. ............... .............................................. 42

4-4 Synthesis of 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5 ...................43

4-5 A ttem pt to prepare 4.2 ...................................................................... ................ 44









4-6 Preparation of sulfonamides and sulfonate ester 4.7...........................................45

4-7 Synthesis of ethylenesulfonamides ................................................... 46

5-1 Preparation of bis(benzotriazolyl)methanethione 5.3 ........................................52

5-2 Use of bis(benzotriazolyl)methanethione 5.3 in the preparation of thioureas 5.7 ...53

5-3 Synthetic utility of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 ......................55

5-4 Preparation of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5...............................56

5-5 Preparation of thioam ides 5.9.............................................................. ................ 58

5-6 Synthesis of thiocarbamates 5.10 and dithiocarbamates 5.11................................61














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

EFFICIENT METHODOLOGY FOR THE SYNTHESIS OF 2,4-BENZODIAZEPIN-1-
ONES, SULFONYLBENZOTRIAZOLES, SULFONAMIDES, ETHYLENE
SULFONAMIDES, THIOCARBAMATES, DITHIOCARBAMATES AND
THIOAMIDES


By

Valerie Rodriguez-Garcia

August 2004

Chair: Alan R. Katritzky
Major Department: Chemistry

Benzotriazole, as a synthetic auxiliary, provided an efficient methodology for the

preparation of various pharmaceutically and industrially important compounds.

Benzodiazepines display potent pharmacological activity. Published synthetic

routes to 2,4-benzodiazepines-l-ones are scarce. N, N-Bis(benzotriazolylmethyl)-

alkylamines are excellent nitrogen centered 1, 3-dication synthons, which taken in one-

pot reactions with ortholithiated benzamides in the presence of zinc bromide provided

novel 2,4-benzodiazepin-1-ones in moderate to good yields. The details are shown in

Chapter 2.

Sulfonylbenzotriazoles are very stable and efficient sulfonylating agents. In

Chapter 3 N-(alkane-, arene- and heteroarene-sulfonyl)benzotriazoles were prepared in

one-pot, in yields of 41-93% by reaction of N-chlorobenzotriazole with various sulfinic

acid salts (produced from organometallic reagents with SO2). Reactions of









sulfonylbenzotriazoles with primary and secondary amines at 20-80C afforded

sulfonamides in 64-100% yield. Sulfonamides are used as antibacterial and anti

microbial drugs.

In Chapter 4 other alkyl sulfonamides, some ethylene sulfonamides and an

alkylsulfonate ester were also prepared in good yields utilizing the stable solid 1-{ [2-(1H-

1,2,3-benzotriazol-1-yl)ethyl]sulfonyl }-1H-1,2,3-benzotriazole. 1- { [2-(1H-1,2,3-

Benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole is a potential replacement for

2-chloroethylsulfonyl-1-chloride, which is commonly used in these type of reactions.

Thioamides, thiocarbamates and dithiocarbamates are also industrially important.

Reactions of thiocarbamoylbenzotriazoles with carbon, oxygen, and sulfur nucleophiles

afforded the corresponding thioamides, thiocarbamates, and dithiocarbamates in 36-99%

yields. Some thiocarbamoylbenzotriazoles, prepared in yields of 76-100%, act as

efficient isothiocyanate analogues (Chapter 5).














CHAPTER 1
GENERAL INTRODUCTION

Benzodiazepines, sulfonamides, thiocarbamates dithiocarbamates and thioamides

display potent pharmacological activity. Some benzodiazepines are naturally occurring

antitumor antibiotics [99JOC290] and others are industrially important anti-psychotic

drugs [02JMC5136]. Sulfonamides include bactericidal and anti-infective drugs

[90MI_255]. Examples of thiocarbamates are good insecticides [90JAE293], herbicides

[75MI_675] and nematocides [89MI_158]. Some dithiocarbamates are fungicides and

others are used as additives in the rubber industry. Various thioamides exhibit

antileprosy [85MI_587], anthelmintic [01MI_1000], immunosuppressive [98MI_2203]

and antituberculotic [02IF71] activity. Also, thiocarbamates, dithiocarbamates and

thioamides are precursors of interesting molecular functionalities.

In the field of synthesis, new pathways to efficiently produce scientifically

attractive compounds are constantly being sought. It is important industrially to find

synthetic approaches that can produce as many derivatives as possible, in good quantities

and with easy purification methods. For more than 20 years our group has been

exploiting the versatility of benzotriazole [98CRV409], towards new and better

methodologies for the synthesis of organic compounds. Benzotriazole is an effective

synthetic auxiliary. It is easily introduced at the beginning of a synthetic sequence and

easy to remove at the end of a synthetic sequence. Benzotriazole intermediates are stable

under many synthetic conditions. In addition to being a good leaving group, when

activated by an electron donor group, benzotriazole also selectively activates the part of









the molecule to which it is attached without affecting the chemical properties of other

functionalities in the molecule. Benzotriazole, as a byproduct of a reaction, is easily

removed in the workup by a mild base wash.

Some N-substituted benzotriazoles exist as 1- and 2-substituted isomers (Scheme

1-1). This happens when a benzotriazole anion can dissociate from a molecule and

reattach itself at a different position. The isomers often exist in equilibrium and show the

same reactivity and stability, so it is not necessary to separate them for subsequent

reactions.

NN
N N N
:N N R


R x H =x+
R R
1.2 1.4
1 -substituted Bt 1.3 2-substituted Bt
tendency for
X=NR2, OR, SR

Scheme 1-1. Some isomers of N-substituted benzotriazoles

Many properties of N-substituted benzotriazoles are comparable to those of the

halogen analogues, but with the advantage of extra stability, easier preparation, versatility

and non-toxicity. Other than the easy preparation of the benzotriazole derivatives studied

here, the efficient and selective elimination of benzotriazole from the molecules upon

reaction with nucleophilic carbons, amines, alcohols and mercaptans justifies the

importance of the methodology presented here. Many reactions utilizing substituted

benzotriazoles as reagents are more convenient than commonly used methods.

Particularly N, N-bis(benzotriazolylmethyl)alkyl amines are very interesting reagents.









They act as bis-electrophiles, liberating benzotriazole in the presence of acids or strong

nucleophiles, allowing for one pot procedures. This is the advantage that makes them

good synthons for the preparation of 2,4-benzodiazepin-1-ones (Chapter 2).

Sulfonylbenzotriazoles are efficient sulfonating reagents, much more stable than

the commonly used sulfonyl halides. Many of them are solids, easy to handle and store.

The benzotriazole in sulfonylbenzotriazoles can be substituted by amines or alcohols to

give sulfonamides and sulfonate esters under mild conditions and without the need for a

base. Utilizing N-chlorobenzotriazole and sulfinic acid salts these sulfonylbenzotriazoles

are readily prepared (Chapters 3). The synthesis of ethylenesulfonamides also takes

advantage of the stability that benzotriazole induces in a molecule, and the selectivity

when attempting substitution and elimination of benzotriazole. The ethylenesulfonamide

generating derivative, 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole, contains two

benzotriazole moieties that can be eliminated to afford a variety of ethylenesulfonamides.

Due to its characteristics, the first nucleophilic attack by an amine displaces the

benzotriazole attached to the sulfur atom, the second one leaving by elimination upon

reaction with a strong base (Chapter 4).

Thioamides, thiocarbamates and dithiocarbamates are now synthesized from

thiocarbamoylbenzotriazoles for the first time (Chapter 5). Many

thiocarbamoylbenzotriazoles act as effective isothiocyanate equivalents, which are

building blocks in many synthetic operations such as in the formation of heterocycles

[03JOC8693]. Bisbenzotriazolylmethanethione, a benzotriazole derivative of

thiophosgene, is the precursor to thiocarbamoylbenzotriazoles. This derivative exhibits

great stability and tremendous selectivity towards nucleophilic substitution.






4


In summary, efficient approaches for the preparation of 2,4-benzodiazepin-1-ones,

N-(alkyl- and aryl-sulfony)lbenzotriazoles, sulfonamides, ethylenesulfonamides,

thiocarbamates, thioamides and dithiocarbamates were discovered utilizing benzotriazole

methodology. N-(Alkyl- and aryl-sulfonyl)benzotriazoles were synthesized from scratch

for the first time, and applied to the preparation of novel sulfonamides. The procedures

herein take advantage of the benzotriazole anion as a selective but good leaving group,

which can be displaced by carbon nucleophiles, amines, mercaptans and alcohols.














CHAPTER 2
ONE POT SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES USING
BENZOTRIAZOLE METHODOLOGY

2.1 Introduction

Benzodiazepines are a class of compounds that have selective activity against a

diverse array of biological targets. Their basic structure comprises a benzene ring fused

to a seven-membered ring heterocycle, which contains two nitrogen atoms within the ring

(Figure 2-1). The names of the benzodiazepines are derived from the location of the

nitrogen atoms within the heterocycle ring.

2,3-Benzodiazepines have been evaluated for their anticonvulsant, anti epileptic

and anti seizure properties [99JMC4414; 00JMC4834]. 1,4-Benzodiazepines are the

most commonly studied because their derivatives display a wide variety of properties,

and they have the ability to mimic natural ligands [88JMC2235]. For example, pyrrolo-

1,4-benzodiazepin-5-ones occur as antitumor agents (2.1), gene regulators, and DNA

probes [99JOC290] whereas 1,4-benzodiazepin-2,5-diones are anticonvulsants

[89JHC1807] and potent inhibitors of platelet aggregation [94JA5077]. Drugs currently

in use in the treatment of anxiety, panic, schizophrenia, and sleep disorders contain the

1,4-benzodiazepine core (Valium (2.2) and Xanax (2.3)) and 1,5-benzodiazepines are

being investigated for their central nervous system depressant properties [02JMC5136;

OOJMC3596]. Additionally, many benzodiazepine alkaloids found in nature, such as

Circumdatin F (2.4) and Circumdatin C (2.5), are isolated from the fungus Aspergillus

ochraceus [01JOC2784].









Me Me N
0 N /N
MeO N I
CNl
HON H CI N CI N

Antibiotic DC-81
2.1 Valium Xanax

2.2 2.3
0
H
R N
I Me
N N H Circumdatin
N 2.4 F: R = H
0 2.5 C: R = OH



Figure 2-1. Biologically active benzodiazepines

Much of the literature to date has focused on the development of structure-activity

relationship (SAR) studies and synthetic (library) strategies for 1,4-benzodiazepines

[990L1835; 97JOC1240; 98JOC8021], 1,5-benzodiazepines [00JMC3596; 00OL3555;

OOJCB513], and 2,3-benzodiazepines [99JMC4414; 00JMC4834]. Very little has been

reported on the synthesis of 2,4-benzodiazepines. Bocelli et al. [99TL2623] synthesized

a 2,4-benzodiazepin-1,3-dione derivative by the palladium-catalyzed intramolecular

cyclization of 1-butyl-1(o-iodobenzyl)-3-phenylurea (Scheme 2-1, reaction a) and Mohrle

and Lessel reported the synthesis of 2,4-benzodiazepin-1-one by electrolysis of 2-

[(dimethylamino)methyl]benzamide (Scheme 2-1, reaction b) [91AP367]. These

previous methods produce low yields of the desired 2,4-benzodiazepine and the method

described in reaction (b) utilizes toxic mercury.









(a)Bu H CO, Pd(O) N
N(a) N O + N-Bu
Y Ph 800C N
0 Bu


0 0 0

( NH2 Hg(II)-EDTA N + N-
(b) N- ~ N
\

Scheme 2-1. Literature methods to synthesize 2,4-benzodiazepines

We envisioned that a facile synthetic route to 2,4-benzodiazepin-1-ones would be

achieved by the connection of benzamides to bis electrophilic alkyl/aryl amines (Scheme

2-2). This requires connection of the ortho position and the nitrogen atom of the

benzamide to a nitrogen centered 1,3-dicarbocation to form the seven membered ring.

O0


"">z H
N\R O
N
x j

R

Scheme 2-2. Retrosynthetic analysis

N, N-Bis(benzotriazolylmethyl)alkylamines 2.9 (Scheme 2-3) have been used

previously for the synthesis ofjulolidines [96JOC3117], 1,3-oxazolidines [98TL6835]

and 3-arylpyrrolidines [98H2535]. Bis(benzotriazolylmethyl)amines 2.9 are nitrogen

centered 1, 3-dication synthons, as exemplified by the synthesis of substituted piperidines

[99JOC3328].









N-Alkylbenzamides afford dianions upon treatment with 2 equivalents of a strong

base. Coordination of the base to either heteroatom, N or 0, in the amide moiety, directs

the deprotonation of the ortho position in the phenyl ring. This synthetic strategy is well

known in directed ortho metalation chemistry [90CRV879]. N-Alkyl- and N-aryl-

benzamides 2.11a-d were prepared (Scheme 2-4), and were then used in the directed

ortho metalation process to generate ortholithiated benzamides.

Below we report the use of benzotriazole methodology combined with an ortho

metalation procedure to produce 2,4-benzodiazepin-1-ones in one pot.

2.2 Results and Discussion

N, N-Bis(benzotriazolylmethyl)alkyl amines 2.9a-d were easily prepared by the

reaction of primary amines, benzotriazole and formaldehyde following published

procedures [87JCS(P1)799; 90CJC446] (Scheme 2-3, Table 2-1 ).


1 \ P-TsOH
NH2R + (2eqs) /N + (2eqs) H -" NT-\ --N"
N H H MeOH/H20 \ _/ N -
N=N I1 NN
2.6 2.7 2.8 R
2.9a-d

Scheme 2-3. Preparation of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d

Table 2-1. Synthesis of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d

2.9 R1 Yield (%)


a C4H9 60

b Phenethyl 92

c Cyclohexyl 70

d C2H5 69









Compounds 2.9a-d were characterized by 1H and 13C NMR spectra. For the four

compounds the 1H NMR showed the characteristic singlet peak due to Bt-CH2-N at 5.6-

6.0 ppm and integrating for four protons. In the 13C NMR the Bt-CH2-N carbons were

found at 63.0-64.0 ppm. Compounds 2.9a and b showed various degrees of

isomerization to the 2-benzotriazole systems. In these instances, where 1-substituted

benzotriazole and 2-substituted benzotriazole were present together, all the peaks in the

spectra appeared as a double set of signals.

Reactions of benzoyl chloride with the respective amines provided benzamides

2.11a-d. These were also identified by 1H and 13C NMR spectra. For example, the 1H

NMR of 2.11 b displayed the expected signal characteristic of a tert-butyl group at 1.42

ppm as a singlet with an integral of nine protons. The signals for the phenyl ring were

also visible as five protons at 7.38-7.73 ppm. The N-H peak was found as a singlet at

5.99 ppm. The carbonyl peak (C=O) was visible in the 13C NMR at 167.0 ppm.

0 0
SNH2R R
NEt3 H
CH2CI2
2.10 2.11

Scheme 2-4. Preparation of benzamides

Table 2-2. Yield of benzamides prepared
2.11 R Yield (%)


a CH3 71

b tBu 80

c C6H5 63

d p-CIC6H6 42









N-Methylbenzamide 2.11a was treated with butyllithium at -780C in

tetrahydrofuran, then stirred for 1 h at room temperature and reacted with

bisbenzotriazolyl derivative 2.9a (Scheme 2-5). After workup, only the starting materials

were recovered. Tetramethylene diamine (TMEDA) was then used to help in the

formation of the dimetalated benzamide. TMEDA was added to 2.11a in THF, followed

by butyllithium at -780C and reagent 2.9a. The starting materials were recovered once

more. However, when ZnBr2 was added to the reaction mixture the reaction took place

as desired. After addition of 2.9a, the reaction mixture was stirred overnight at room

temperature. Aqueous workup and isolation yielded the benzodiazepin-1-one 2.13a in

22% yield but the yield of 2.13a was improved to 64% by conducting the reaction at

- 10C. The ZnBr2 acts in this reaction as a Lewis acid, by activating the benzotriazole

and thus facilitating C-N bond scission, a common feature of benzotriazole chemistry

[99JOC3328].

Bis(benzotriazolylmethylalkyl)amines prepared from other primary amines reacted

similarly under the modified conditions giving the corresponding 2,4 benzodiazepin-1-

ones 2.13b-h in good to moderate yields. The results are summarized in Table 2-3.

The 1H and 13C NMR spectra of 2.13a-h were in accordance with the proposed

structures. 1H NMR and 13C NMR showed no evidence for the presence of benzotriazole.

Two distinct singlets in the region between 3.5-5.8 ppm appeared in the 1H NMR for

compounds 2.13 a, c- d. Each singlet integrated for two protons and both were assigned

to the two new bonds formed with -CH2-NR-CH2-. Compound 2.13b is a very

interesting example, where instead of two singlets the 1H NMR spectra displayed only a

singlet at 3.77 ppm integrating for four hydrogens (Figure 2-2). This denotes that the








protons in -CH2-NR-CH2-, after the new bonds formed in 2.13b, are accidentally

equivalent.


0 OLi R
SJNR BuLi/-100C N N R 1. ZnBr2 N )
H THF K Li R N, 1
SJ 2. BtN NvBt R

2.11a-d 2.12 2.9a-d 2.13a-h

2.11 R N r.- N 2.9 R1
a CH3 Bt = N 'N
N aN 04H9
b t-C4H9 b C6H5(CH2)2
C p6H5 c cyclohexyl
d p-CIC6H4 d C2H5


Scheme 2-5. Synthesis of 2, 4-Benzodiazepine-1-ones

Table 2-3. Yields of 2, 4-Benzodiazepine-1-ones prepared
Entry R R1 Yield(%)

2.13a CH3 C4H9 64

2.13b 'Bu C4H9 82

2.13c C6H5 Phenethyl 53

2.13d pCl-C6H4 C4H9 57

2.13e C6H5 C4H9 47

2.13f 'Bu Phenethyl 36

2.13g C6H5 cyclohexyl 74

2.13h CH3 cyclohexyl 57









2.3 Conclusion

We have demonstrated the capability of benzotriazole reagents 2.9 as dication

sources. Utilizing simple chemistry we have carried out a one-pot synthesis of 2,4-

benzodiazepin-1-ones starting from easily affordable starting materials.

2.4 Experimental Section

Melting points were determined using a Bristoline hot-stage microscope and are

uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300

MHz NMR spectrometer in chloroform-d solution. Column chromatography was

performed on silica gel (300-400 mesh). Elemental analyses were performed on a Carlo

Erba-1106 instrument. THF was distilled from sodium-benzophenone ketal prior to use.

All the reactions were performed under a nitrogen atmosphere and in oven dried

glassware.

2.4.1 General Procedure for the Preparation of N, N-bis(Benzotriazolylmethyl)alkyl
amines 2.9a-d

The respective primary amine (20 mmol) and benzotriazole (40 mmol) were

dissolved in methanol/water (4:1). Formaldehyde was added (40 mmol) and a catalytic

amount of para-toluenesulfonic acid. The mixture was stirred for 18 h. The precipitate

was filtered and washed with hexanes.

N-bis(Benzotriazolyl-l-methyl)butylamine (2.9a): Filtered, washed with

hexanes and obtained as colorless crystals (60%), mp 85-87 C (Lit. mp 111-114C,

[90JCS(P1)541]). 1H NMR 6 0.80 (t, J= 7.1 Hz, 3H), 1.22 (q, J= 7.3 Hz, 2H), 1.58 (t, J

= 7.7 Hz, 2H), 2.85 (t, J= 6.9 Hz, 2H), 5.63 (s, 4H), 7.42 (t, J= 7.6 Hz, 2H), 7.54 (t, J=

8.1 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H), 8.10 (d, J= 8.2 Hz, 2H). 13C NMR 6 13.69, 20.0,

29.6, 50.3, 64.4, 109.9, 120.1, 124.4, 127.9, 133.3, 146.1.









N-bis(Benzotriazolyl-l-methyl)phenethylamine (2.9b): Filtered, washed with

hexanes and obtained as white crystals (92%), mp 117-1180C (Lit. mp 122-124C,

[87JCS(P1)799]). 1HNMR 6 2.63-2.67 (m, 2H), 2.97-3.03 (m, 2H), 5.94 (s, 4H), 6.97

(s, 2H), 7.12 (m, 3H), 7.42-7.47 (m, 2H), 7.54-7.59 (m, 2H), 7.95 (d, J= 8.4 Hz, 2H),

8.09 (d, J= 8.4 Hz, 2H). 13C NMR 6 34.1, 52.3, 64.5, 109.9, 120.1, 124.3, 126.5, 128.0,

128.5, 128.6, 133.2, 138.7, 146.1.

N-bis(Benzotriazolyl-l-methyl)cyclohexylamine (2.9c): Filtered, washed with

hexanes and obtained as white crystals (70%), mp 119.0-120.00C, (Lit. mp 118-1190C,

[87JCS(P1)799]). 'HNMR6 8.09 (d,J= 8.1 Hz, 2H), 7.63 (d,J= 8.4 Hz, 2H),

7.34-7.52 (m, 4H), 5.71 (s, 4H), 3.06 (m, 1H), 1.45-1.82 (m, 6H), 0.09-1.04 (m, 4H).

13C NMR in DMSO 8 25.1, 25.5, 30.2, 59.1, 63.3, 111.1, 119.2, 124.1, 127.4, 132.6,

145.4.

N-bis(Benzotriazolyl-l-methyl)ethylamine (2.9d): Recrystallized in ethanol,

filtered and washed with hexanes. Obtained as white crystals (69%), mp 79-810C (Lit.

mp 82-84C, [87JCS(P1)799]). 'HNMR6 1.26 (t, J= 7.2 Hz, 3H), 2.98 (q, J= 7.2 Hz,

2H), 5.68 (s, 4H), 7.46 (t, J= 7.8 Hz, 2H), 7.58 (t, J= 7.8 Hz, 2H), 7.75 (d, J= 8.1 Hz,

2H), 8.15 (d,J= 8.1Hz, 2H). 13CNMR 6 13.0, 45.0, 63.9, 109.9, 120.1, 124.3, 128.0,

133.3, 146.1.

2.4.2 General Procedure for the Preparation of N-Alkyl-arylbenzamides 2.11a-d

The respective amine (28 mmol) was dissolved in CH2C2 (50 mL). Triethyl

amine (28 mmol) was added and the mixture stirred under an ice bath. Benzoyl chloride

(28 mmol) was added dropwise and the mixture stirred for 2 h at room temperature. The









solvent was evaporated and ethyl acetate added. The organic layer was washed with

water (x2), dried over sodium sulfate, filtered and concentrated.

N-Methylbenzamide (2.11a): Recrystallized in ethyl acetate and obtained as

white crystals (71%), mp 780C (Lit. mp 790C, [87H1313]). 1HNMR 6 2.97 (d, J= 4.8

Hz, 3H), 6.56 (s, 1H), 7.37-7.50 (m, 3H), 7.78 (d, J= 7.5 Hz, 2H). 13C NMR 6 26.8,

126.8, 128.5, 131.3, 134.5, 168.3.

N-t-Butylbenzamide (2.11b): Recrystallized in ethyl acetate and obtained as

white crystals (80%), mp 133-1340C (Lit. mp 135-137C, [87S487]). H NMR 6 1.42 (s,

9H), 5.99 (s, 1H), 7.38-7.49 (m, 3H), 7.72 (d, J= 7.2 Hz, 2H). 13C NMR 6 28.9, 51.6,

126.7, 128.5, 131.1, 135.9, 167.0.

N-Phenylbenzamide (2.11c): Recrystallized in ethyl acetate and obtained as

colorless crystals (63%), mp 155-1580C (Lit. mp 163C, [01SC1803]). 1HNMR6

7.11-7.16 (m, 1H), 7.39 (t, J= 7.8 Hz, 2H), 7.54-7.63 (m, 3H), 7.81-7.83 (m, 2H),

7.98-8.01 (m, 2H), 10.3 (s, 1H). 13C NMR 6 120.3, 124.5, 127.1, 128.7, 129.0, 131.7,

134.9, 138.0, 165.8.

N-(p-Chlorophenyl)benzamide (2.11d): Obtained as white crystals (42%), mp

1890C (Lit. mp 190-191C, [83S791]). 1HNMR 6 7.33-7.36 (m, 2H), 7.46-7.62 (m,

5H), 7.80 (s, 1H), 7.85-7.88 (m, 2H). "~C NMR 6 122.0, 127.4, 127.8, 128.6, 128.7,

131.9, 134.9, 138.3.

N-Cyclohexylbenzamide (2.11e): Obtained as white crystals (81%), mp 146-

1470C (Lit. mp 151-152C, [88H323]). H NMR 6 1.17-1.48 (m, 6H), 1.63-1.77 (m,

3H), 1.99-2.03 (m, 2H), 3.96-3.98 (m, 1H), 6.10 (s, 1H), 7.38-7.50 (m, 3H), 7.74-7.77

(m, 2H). 13C NMR 6 25.0, 25.6, 33.2, 48.7, 126.9, 128.5, 131.2, 135.1, 166.7.









2.4.3 General Procedure for the Preparation of 2,4-Benzodiazepin- -ones 2.13a-h

The N-substituted benzamide (3mmol) was dissolved in THF (30 ml). n-BuLi

(6.6 mmol) was added dropwise at -10C. The mixture was gradually warmed to 0C

and stirred for 30 min. After being cooled to -10C, ZnBr2 (7 mmol) was added to the

mixture followed by the addition of the N,N-bis(benzotriazolyl)amine (3 mmol). The

resulting mixture was allowed to warm to room temperature and stirred for 24 h. The

reaction was quenched with 2 M NaOH, washed with brine and extracted with ethyl

acetate. Column chromatography (A1203, from 10/1 to 6/1 hexanes/EtOAc) afforded the

analytically pure benzodiazepines.

2-Methyl-4-Butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13a):

Yellow oil (64%). 1H NMR 6 7.77-7.74 (m, 1H), 7.44-7.40 (m, 2H), 7.26-7.24 (m, 1H),

4.09 (s, 2H), 3.64 (s, 2H), 3.27 (s, 3H), 2.71 (t, J= 7.3Hz, 2H), 1.62-1.56 (m, 2H),

1.44-1.37 (m, 2H), 0.97 (t, J= 7.4Hz, 3H). 13C NMR 6 171.1, 136.5, 134.4, 131.1,

129.0, 128.5, 128.2, 68.1, 55.2(2), 36.3, 30.1, 20.4, 13.9. HRMS (FAB): Calcd For

C14H20N20 (M+H) 233.1654, Found 233.1629.

2-(tert-Butyl)-4-butyl-2,3,4,5-tetrahydro- 1H-2,4-benzodiazepin- 1-one (2.13b):

Isolated as colorless oil (82%). 1H NMR 6 7.76 (dd, J= 6.7, 2.2 Hz, 1H), 7.43-7.37 (m,

2H), 7.10 (dd, J= 6.5, 1.9 Hz, 1H), 3.78 (s, 4H), 2.31 (t, J= 7.0 Hz, 2H), 1.59 (s, 9H),

1.51-1.46 (m, 2H), 1.40-1.35 (m, 2H), 0.93 (t, J= 7.2Hz, 3H). 13C NMR 6 172.1, 138.3,

131.5, 130.8, 128.8, 128.2, 128.0, 63.2, 57.1, 53.6, 51.8, 30.1, 28.7, 20.5, 14.0. Anal.

Calcd. For C17H26N20 C, 74.41; H, 9.55; N, 10.21. Found: C, 74.35; H, 10.06; N, 10.40.

2-Phenyl-4-phenyethyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one

(2.13c): Isolated as yellow oil (53%). 1HNMR 6 7.85 (dd, J= 6.9, 1.6Hz, 1H), 7.50-7.40









(m, 6H), 7.39-7.17 (m, 5H), 6.98 (d, J= 6.7Hz, 2H), 4.56 (s, 2H), 3.92 (s, 2H),

2.84-2.79 (m, 2H), 2.74-2.69 (m, 2H). 13C NMR 6 170.7, 143.2, 139.4, 136.3, 134.0,

131.6, 129.3, 129.1, 129.1, 128.6, 128.4, 126.7, 126.2, 126.1, 68.1, 56.6, 55.3, 34.6.

Anal. Calcd. For C23H22N20 C, 80.67; H, 6.48; N, 8.18. Found: C, 80.53; H, 6.46; N,

8.19.

2-(4-Chlorophenyl)-4-butyl-2,3,4,5-tetrahydro- 1H-2,4-benzodiazepin- 1-one

(2.13d): Isolated as colorless oil (57%). H NMR 6 7.52-7.39 (m, 6H), 7.33-7.26 (m,

2H), 4.65 (s, 2H), 4.00 (s, 2H), 2.55 (t, J= 7.3Hz, 2H), 1.40-1.24 (m, 4H), 0.83 (t, J

=7.3Hz, 3H). 13C NMR 6 171.0, 136.0, 135.6, 130.9, 129.6, 128.6, 128.4, 127.5, 126.7,

126.3, 125.3, 66.0, 53.0, 52.3, 29.7, 20.3, 13.9. Anal. Calcd. For C19H21CIN20 C, 69.4;

H, 6.74; N, 8.52. Found: C, 69.3; H, 6.57; N, 8.52.

2-Phenyl-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13e):

Isolated as yellow oil (47%). 1H NMR 6 7.84 (dd, J= 6.9, 1.9Hz, 1H), 7.52-7.39 (m,

6H), 7.33-7.26 (m, 2H), 4.50 (s, 2H), 3.86 (s, 2H), 2.57 (t, J= 7.3Hz, 2H), 1.43-1.38 (m,

2H), 1.29-1.22 (m, 2H), 0.83 (t, J= 7.3Hz, 3H). 13C NMR 6 170.8, 143.3, 136.4, 134.2,

131.6, 129.3, 129.1, 129.0, 128.5, 126.6, 126.2, 68.6, 55.2, 54.7, 29.8, 20.3, 13.8. Anal.

Calcd. For C19H22N20 C, 77.52; H, 7.53; N, 9.52. Found: C, 76.57; H, 8.64; N, 9.43.

2-(tert-Butyl)-4-phenylethyl-2,3,4,5-tetrahydro- 1 H-2,4-benzodiazepin- 1-one

(2.13f): Isolated as yellow oil (36%) 1HNMR 6 7.78-7.75 (m, 1H), 7.41-7.37 (m, 2H),

7.31-7.25 (m, 2H), 7.22-7.18 (m, 3H), 7.11-7.08 (m, 1H), 3.84 (s, 2H), 3.82 (s, 2H),

2.82 (t, J= 7.0Hz, 2H), 2.58 (t, J= 7.0Hz, 2H), 1.56 (s, 3H). 13C NMR 6 172.1, 139.9,

138.2, 131.3, 130.9, 128.7, 128.6, 128.4, 128.2, 128.1, 126.2, 63.1, 57.1, 54.0, 53.7, 34.8,









28.6. Anal. Calcd. For C21H26N20 C, 78.22; H, 8.13; N, 8.69. Found: C, 78.09; H, 8.19;

N, 8.72.

2-Phenyl-4-cyclohexyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one

(2.13g): Isolated as colorless crystals (EtOAc/Hexane), 74%, mp 102-103C. H NMR 6

7.98-7.81 (m, 1H), 7.58-7.25 (m, 8H), 4.62 (s, 2H), 3.96 (s, 2H), 2.55-2.40 (m, 1H),

1.90-1.45 (m, 6H), 1.20-1.05 (m, 4H). 13CNMR6 170.8, 142.6, 136.3, 134.9, 131.7,

129.3, 129.2, 129.0, 128.4, 126.6, 126.3, 64.8, 60.5, 52.8, 31.1, 25.8, 25.0. Anal. Calcd.

For C21H24N20 C, 78.71; H, 7.55; N, 8.74. Found: C, 76.01; H, 7.55; N, 7.96.

2-Methyl-4-cyclohexyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one

(2.13h): Isolated as colorless liquid (57%) 1H NMR 6 7.77-7.75(m, 1H), 7.46-7.39 (m,

2H), 7.25-7.37 (m, 1H), 4.21 (s, 2H), 3.75 (s, 2H), 3.24 (s, 3H), 2.65-2.55 (m, 1H),

2.17-2.07 (m, 2H), 1.90-1.78 (m, 2H), 1.38-1.21 (m, 6H). 3C NMR 6 171.2, 136.4,

135.0, 131.3, 129.2, 128.4, 128.2, 64.4, 60.7, 52.4, 35.6, 31.3, 25.9, 25.3. Anal. Calcd.

For C16H22N20 C, 74.38; H, 8.58; N, 10.84. Found: C, 72.21; H, 9.75; N, 10.35.







18



I.













-
















N N





















Figure 2-2. H NMR spectrum of 2.13b













CHAPTER 3
A GENERAL AND EFFICIENT SYNTHESIS OF SULFONYLBENZOTRIAZOLES
FROM N-CHLOROBENZOTRIAZOLE AND SULFINIC ACID SALTS

3.1 Introduction

The sulfonyl group plays a very important role as key constituent of a number of

biologically active molecules. Sulfonyl compounds are of interest to the synthetic

chemist due to their bioactive nature and chemical applications. Sulfonamides occupy a

unique position in the drug industry. Also known as sulfa drugs, sulfonamides have a

history that dates back 70 years, during which their action as antiinfective drugs and their

effective bactericidal properties in vivo in small animals was discovered [90MI_255].

The first clinically used sulfonamide was named prontosil 3.1 (Figure 3-1), a red

azo dye that showed protective action against streptococci in mice. Prontosil was active

in vivo, but ineffective in vitro, which led to the conclusion that prontosil itself was not

the active drug. When metabolized in the body prontosil produces sulfanilamide 3.2, the

real active agent [90MI_255], it interferes with p-aminobenzoic acid utilization by

bacteria. This discovery started rapid progress in the investigation and production of new

sulfonamides.


NH2
NH2 2 2 SO2NH

N\ N N 22


3.1 3.2

Figure 3-1. Prontosil 3.1 and the active metabolite sulfanilamide 3.2









At present, over 30 drugs containing the sulfonamide moiety are used clinically, as

therapeutic agents and for the treatment of bacterial and viral infections. Examples of

well-known drugs are sulfamethoxazole 3.3, sulfisoxazole 3.4, sulfasalazine 3.5, and

Celebrex 3.6 (Figure 3-2). Sulfonamides are also diuretics, anticonvulsants and

hypoglycemic agents as well as protease inhibitors [98JA10994]. Arylsulfonyl

substituents have been used as effective protecting groups for oxygen and nitrogen

functionalities [92JOC4775]. Sulfonamides introduced into azo dyes improve the

properties of these dyes by giving extra light stability, greater water solubility and a

better fixation to fibre [90MI_255].

Me Me
Oo Me

'N' N\Y I 01 N"\\
SNH2
S0NH 2 H 0 NH2
3.3 3.4
Antibacterial and antiprotozoal Urinary tract antibacterial


-SN 0 \

N NH H2N \\ F-
0.N N y

3.5 OH Me
For the treatment of arthritis
Antiinflammatory O OH and osteoarthritis

Figure 3-2. Various clinically used sulfonamide drugs

Sulfonamides are commonly prepared by the reaction of ammonia, a primary amine

3.8 or a secondary amine with a sulfonyl chloride 3.7 in the presence of a base 3.9

[79COC345] (Scheme 3-1). However, this approach is limited by the availability of the

sulfonyl halide, some of which can be difficult to prepare, store and handle. Also, side









reactions are possible due to the presence of the base, even with relatively stable

substrates if harsh conditions are applied. The formation of a disulfonamide 3.11 is a

common side reaction when primary amines or ammonia are utilized [79COC345]

(Scheme 3-1).



S C1IO 3.9 NS

Me H2NMe 3.10
3.7 3.8
0 0
-- II II


Me \N Me

3.11
N02

Scheme 3-1. Example of the preparation of sulfonamides

Because of their importance and their relative difficulty in preparation numerous

synthetic methods have been developed with the purpose of solving problems of

sulfonamide synthesis (Scheme 3-2). Thus, sulfonamides can be prepared (i) by reaction

of sulfinic acid salts with hydroxylamine-O-sulfonic acid [86S103 1]; (ii) by reduction of

arylsulfonyl azides [97SL1253; 98SC1721]; (iii) from aromatic and aliphatic sulfinic acid

salts using bis(2,2,2-trichloroethyl) azodicarboxylate as an electrophilic nitrogen source

[02TL4537]; (iv) from alkyl or aryl halides by means of sodium 3-methoxy-3-

oxopropane-1-sulfinate as a sulfinate transfer reagent [02TL8479]; (v) by the radical

addition of organo halides to pentafluorophenyl ethylenesulfonate [020L2549] followed

by substitution of the pentafluorophenyl moiety by amines and (vi) by the sulfamoylation

of aromatics using sulfamoyl chloride [02SL1928]. Alkyl/aryl sulfonyl imidazoles,










prepared from sulfonyl halides and 1H-imidazole or 1-trimethylsilyl imidazole, have also

been used as sulfonyl transfer reagents in the preparation of sulfonamides ((vii) in

Scheme3-2) [92JOC4775]. However, the imidazole ring requires activation as its 3-

methylimidazolium triflate to act as a leaving group in its reactions with N- and 0-

nucleophiles.


0
11
R-S-N3
I I
0
2 [H]


O


R-SO2M + O= Cl3C


CC13

4- (iii)


R=Ar
R1= R2 =H
H2NOSO3H + R-SO2M --
(i)

HNR 1R2/
R=Ar (vii)

0 (0
R N N
0 _j TfO


O R2 R
R-S-N F
I1 1
O R




R=Ar
(vi) Rl=R2=alky

In(OTf)3

O R1
ArH + CI-S-N
S'R2


=alkyl/aryl
Rl=R2= H
(iv)


0

+ NaO-S"C02Me
H2NOSO3H


R=alkyl
(v) R R2=alkyl/aryl

F O-

F F


R2
+ RI + HN
'R1


Scheme 3-2. Various methods for the synthesis of sulfonamides

Although these additional synthetic methodologies help to overcome some of the

problems, they are mostly utilized for specific classes of substrates. A straightforward

and general method towards accessing sulfonamides is highly desirable, where a

sulfonating reagent would react under mild conditions in the absence of a strong base or

competing nucleophile.









Previously, our group reported the preparation of 1-phenylsulfonylbenzotriazole

3.12 and its utility in the synthesis of benzenesulfonamides and aryl benzenesulfonates

[94SC205]. 1-Phenylsulfonylbenzotriazole 3.12 is a convenient benzenesulfonylating

reagent which reacts with primary 3.14 and secondary amines 3.15 and with alcohols

3.13 under mild conditions (usually stirring in THF at rt) to give the corresponding

sulfonamides 3.17, 3.18 and sulfonates 3.16 [94SC205] (Scheme 3-3) in yields of

51-99%.

HO-Ar 3.13 1
S Ph-S OAr 3.16
0
0
II
Ph-S N R 0
SN N H2N 3.14 3.17

O N PhR H .17
/ HNXR
I o
R 3.15 II
3.12 Ph-S \\N/R 3.18

R

Scheme 3-3. Synthesis of benzenesulfonamides and aryl benzenesulfonates from
1-phenylsulfonylbenzotriazole

The sulfonylbenzotriazole motif was shown to be a good substitute for the highly

reactive, frequently labile and often difficult to access sulfonyl halide unit. Other than its

use as a benzenesulfonating agent, 3.12 and its analogues have also been widely used in

the preparation of i) N-acylbenzotriazoles (well-known synthetic equivalents to acyl

halides [00JOC8210; 92T7817]; ii) N-imidoylbenzotriazoles [990L577], and iii) for the

benzotriazolylalkylation of aromatic compounds [94H345].

However, the preparation of aryl/alkylsulfonylbenzotriazoles involved the

corresponding sulfonyl halides by reactions with either 1H-benzotriazole or 1-









trimethylsilylbenzotriazoles [94SC205]. This limits their application in the synthesis of

sulfonamides. We believe that a general method to prepare sulfonylbenzotriazoles

avoiding the sulfonyl halides and starting from easily available materials would be useful.

We have developed such an approach starting from aryl/alkyl lithiums or Grignard

reagents by reacting successively with SO2 and N-chlorobenzotriazole. We demonstrate

here that the aryl/alkylsulfonylbenzotriazoles prepared in this way react easily with

amines to give sulfonamides in excellent yields.

3.2 Results and Discussion

3.2.1 Preparation of Benzotriazole Reagents 3.27

Pinnic and co-workers reported the reactions of organometallic reagents with sulfur

dioxide to give sulfinic acid salts [79JOC160]. Furukawa reported the oxidation of

sulfinic acids with chloramines to produce a 50:50 mixture of sulfonamide and sulfonyl

chloride [83CPB1374]. Utilizing this information together with existing benzotriazole

methodology we have envisioned the synthesis of sulfonylbenzotriazoles as follows.

Sulfur dioxide is condensed in THF at -780C and an organometallic reagent is

added, which forms a sulfinic acid salt. At room temperature, addition of N-

chlorobenzotriazole to the intermediate sulfinic acid salt gives the corresponding

sulfonylbenzotriazole. For example, the reaction ofp-tolylmagnesium bromide 3.19 and

sulfur dioxide 3.20 followed by treating the intermediate sulfinic acid salt 3.21 with N-

chlorobenzotriazole 3.22 proceeded smoothly at 20C to give the p-

tolylsulfonylbenzotriazole 3.27d in 68% yield (Scheme 3-4). This was confirmed by 1H

and 13C NMR, as the spectra of the product were in accordance with those previously

reported [94SC205].













MgBr THF
Me + S 78-25
Me a -78-25 C


3.22
Cl
,N

N MeS-N
-0 0


3.19 3.20 3.21 3.27d
Scheme 3-4. Synthesis ofp-tolylsulfonylbenzotriazole using our method

Use of one equivalent of triethylamine with the N-chlorobenzotriazole 3.22 gave a

significant improvement: p-tolylsulfonylbenzotriazole 3.27d was isolated in 93% yield

under this modified condition.

N-Chlorobenzotriazole has been described previously as a good oxidizing agent,

liberating the chloro atom acts as an electrophile together with the benzotriazole anion

[69JCS(C)1474; 69JCS(CC)365; 69JCS(C)1478]. The mechanism of this reaction

involves the formation of a sulfinic acid salt 3.24 followed by attack of the sulfur atom of

this salt on the chloro atom in N-chlorobenzotriazole 3.22. Then, the benzotriazole anion

3.26 may attack the intermediate sulfonyl chloride 3.25 formed in situ (Scheme 3-5). The

effect of triethylamine may be to coordinate with the magnesium cation. Other

organomagnesium reagents also afforded the corresponding sulfonylbenzotriazoles 3.27

in good to excellent yields, as shown in Table 3-1.


M,) N- 0 0 Nz

SNEt3 N R N


3.24 3.22 3.25 3.26 3.27
Scheme 3-5. Proposed mechanism for the formation of sulfonylbenzotriazoles

Aryl organolithiums can also be used in the preparation of

arylsulfonylbenzotriazoles. Thus, thiophene was lithiated at C2 and the lithium reagent









was allowed to react with SO2 and N-chorobenzotriazole under the conditions described

above. Thiophene-2-sulfonylbenzotriazole was isolated in 82% yield (Table 3-1, entry

3.27h). The 1H NMR spectrum of 3.27h reveals signals of the four protons of 1-

substituted benzotriazole as two doublets of triplets at 8.11 ppm (H9) and 8.08 ppm (H6),

and two doublets of doublets of doublets (ddd) at 7.70 (H7) and at 7.51 ppm (H8). The

three protons of 2-substituted thienyl are presented as three doublets of doublets at 7.96

ppm (H4), 7.76 ppm (H2) and 7.13 ppm (H3) respectively (Figure 3-3).

We have used a variety of alkyl- and aryl- organometallic reagents to check the

general applicability and functional group tolerance of this method. The respective N-

sulfonylbenzotriazoles were isolated mostly in good yields (41-93%, Table 3-1). The

yields are largely dependent on the difficulty of formation of the organometallic reagents.

In the case of 1-methylindole, the reaction provided a mixture of many products. Only

after extensive column chromatography purification were two products isolated and

identified. The expected 2-sulfonylated product 3.27i was isolated in 20% yield along

with 11% of 2-benzotriazolyl-1-methylindole, which might have formed by the addition

of 2-lithio-1-methylindole to N-chlorobenzotriazole.

Attempts to react prop-2-ene sulfinic acid salt, formed from the reaction of

allylmagnesium bromide and SO2, with N-chlorobenzotriazole to prepare

allylsulfonylbenzotriazole gave only unidentifiable by-products and benzotriazole. Prop-

2-ene sulfinic acids are known to be very unstable and to undergo acid catalyzed

decomposition to SO2 and the olefin [78JA4634]. Similar unsatisfactory results were

also obtained with acetylenic Grignard reagents.






















T* Z'a




"*4


0'T













96


8 7



OTS'l TS'

SS' L-
ga











_s.


oi" l I a

























Figure 3-3. 1 NMR spectrum of 1-(2-thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h)









0

or JO + RM R S\NN
THF, -780C R

3.20 3.28 3.24 3.22 3.27

Scheme 3-6. Preparation of 1-alkyl/arylsulfonylbenzotriazoles 3.27

Table 3-1. Alkyl/arylsulfonylbenzotriazoles 3.27
3.27 R M Yield(%) Mp(C)

a n-Butyl Li 65 Oil

b Cyclohexyl MgCl 71 117-119

c Isobutyl MgBr 75 Oil

d p-CH3C6H5 MgBr 93 133-134a

e 2-Pyridyl Li 71 132-135

f 3-Pyridyl Li 41 128-129

g 2-Furyl Li 83 107-109

h 2-Thienyl Li 82 143-144

i 1-Methyl-2-indolyl Li 20 131-132

j 1-Methylimidazolyl Li 80 147-150

a Ref. [01H1703] gives mp 134-135: all other compounds are novel.

3.2.2 Synthesis of Sulfonamides 3.29-3.37 using Reagents 3.27

The benzotriazolylsulfonamides 3.27a-j reacted as expected with diverse amines to

generate novel sulfonamides (Scheme 3-7). Based on our previous experience

[94SC205], we tried the reaction in THF at rt in the absence of a base. Thus, when 3.27a

was treated with cyclohexylamine, the corresponding sulfonamide 3.29 was obtained in

89% yield (Table 3-2). Sulfonylbenzotriazoles 3.27c and 3.27h also reacted under the









same conditions with N-methylbenzylamine and piperidine yielding the resultant

sulfonamides in 72% and 85% yields, respectively. However, for reagents 3.27f, 3.27g,

3.27j, and 3.27i the smooth displacement of benzotriazole took place with aliphatic

amines (Table 3-2) in DMF at 800C but not in refluxing THF or acetonitrile. With this

method it was possible to obtain various sulfonamides in quantitative yields.

O
11 1 2
R \ N R, 'N R 0
R N N H I R I\-\ N R
1 H R\N
R = H or alkyl I 2
S R2= alkyl R

3.27 3.29-3.37

Scheme 3-7. Preparation of sulfonamides

3.3 Conclusion

N-Chlorobenzotriazole is a useful reagent for converting sulfinate salts to

sulfonylbenzotriazoles, which offer access to a wide variety of sulfonamides where the

corresponding sulfonyl halide is not readily available. In addition, the approach obviates

the formation of disulfonimides that can arise during the ammonolysis of sulfonyl halides

[79COC345]. The particular usefulness of the method lies in the ease with which

benzotriazole group can be replaced by N-nucleophiles. The easy accessibility of sulfinic

acid salts from SO2 and organometallics and the preparative ease of N-

chlorobenzotriazole should afford the approach substantial utility.










Table 3-2. Sulfonamides 3.29-3.37 prepared using reagents 3.27.
Reagent 3.27 Amine Condition Sulfonamide Yield (%)


0
- .\! Bt


0
\ ,8Bt
II

o

,\s Bt







0 Bt



N^ 0


\- ,Bt




/N S Bt
O

0\\ Bt
/ 11
1 1



o


Cyclohexylamine




N-Methylbenzyl-
amine


Piperidine


2-Aminopentane


Piperidine


Morpholine


Piperidine


1, 5- Dimethyl-
hexylamine


Phenethylamine


THF/rt/ o 12\
N
18h H
3.29


THF/rt/
15 h


THF/rt/
42 h


DMF/80 C
/24 h


DMF/80C
/48 h


DMF/80C
/24 h


THF/rt/
20 h


DMF/80C
/24 h


DMF/80C
/48 h


0 \



3.30



II

3.31

n HN
0
3.32




N 0
3.33


/ N I


3.34



-2 0
3.35
0 H


3.36

o, H


3.37









3.4 Experimental Section

Melting points were determined on a hot-stage apparatus and are uncorrected. 1H

(300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 MHz NMR

spectrometer in chloroform-d solution unless stated. Column chromatography was

performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone

ketyl prior to use. All the reactions were performed under a nitrogen atmosphere and in

oven dried glasswares. Commercially available Grignard reagents were used for the

preparation of sulfinic acid salts. Organolithium reagents were prepared following

literature methods [790R; 820R]. All sufinic acid salts were prepared from organo

magnesium or lithium reagents and commercially available sulfur dioxide following the

method described by Pinnick and co-workers [79JOC 160].

3.4.1 General Procedure for the Preparation of Sulfonylbenzotriazoles 3.27a-j

Sulfur dioxide was bubbled into THF (20 mL) at -78C in excess (for about 10

min). The organometallic reagent (7 mmol) was added to the previous solution at -78C.

The mixture was stirred at that temperature for 15 min, then at room temperature for 1 h.

N-Chlorobenzotriazole (1.07 g, 7 mmol) was then added in one portion and the mixture

was stirred for 2 h at rt. Triethylamine (0.92 mL, 7 mmol) was added followed by

stirring at rt for 10 h. Water (ca 100 mL) was added and the mixture was extracted with

ethyl acetate (3 x 100 mL). The combined organic layers were washed with water, brine,

dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure

gave an oil, which was further purified either by re-crystallization or column

chromatography.

1-(Butane-l-sulfonyl)-lH-1,2,3-benzotriazole (3.27a): Purified by column

chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as a brown oil (65%).









1H NMR 6 0.88 (t, J= 7.4 Hz, 3H), 1.35-1.48 (m, 2H), 1.69-1.79 (m, 2H), 3.62 (t, J=

8.0 Hz, 2H), 7.54 (t, J= 8.1 Hz, 1H), 7.68 (t, J= 7.2 Hz, 1H), 8.02 (d, J= 8.4 Hz, 1H),

8.17 (d, J= 8.4 Hz, 1H). 13C NMR 6 13.1, 20.9, 24.6, 55.3, 111.8, 120.4, 125.8, 130.3,

132.1, 145.0. Anal. Calcd For C0lH13N302S: C, 50.19; H, 5.48; N, 17.56. Found: C,

50.41; H, 5.39; N, 17.89.

1-(Cyclohexylsulfonyl)-lH-1,2,3-benzotriazole (3.27b): Purified by column

chromatography with hexanes/EtOAc = 2:1 as eluent and obtained as colorless prisms

(71%), mp 117-1190C. H NMR 6 1.10-1.30 (m, 3H), 1.50-1.70 (m, 3H), 1.85-1.90 (m,

2H), 2.02-2.06 (m, 2H), 3.51-3.62 (m, 1H), 7.52 (t, J= 7.2 Hz, 1H), 7.66 (t, J= 7.2 Hz,

1H), 8.01 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 8.1 Hz, 1H). 13C NMR 6 24.6, 24.7, 25.8, 65.2,

112.1, 120.5, 125.8, 130.3, 132.6, 145.0. Anal. Calcd For C12H15N302S: C, 54.32; H,

5.70; N, 15.84. Found: C, 54.47; H, 5.68; N, 15.71.

1-(Isobutylsulfonyl)-lH-1,2,3-benzotriazole (3.27c): Purified by column

chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as brown oil (75%).1H

NMR 6 1.09 (d, J= 6.9 Hz, 6H), 2.30 (sep, J= 6.6 Hz, 1H), 3.51 (d, J= 6.6 Hz, 2H), 7.53

(t, J= 7.2 Hz, 1H), 7.68 (t, J= 7.2 Hz, 1H), 8.03 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 8.4 Hz,

1H). 13C NMR 6 22.1, 24.6, 63.2, 111.9, 120.5, 125.9, 130.4, 132.0, 145.1. Anal. Calcd

For C10H13N302S: C, 50.19; H, 5.48; N, 17.56. Found: C, 50.08; H, 5.23; N, 17.55.

1-[(4-Methylphenyl)sulfonyl]-1H-1,2,3-benzotriazole (3.27d): Colorless

needles (from EtOAc, 93%), mp 126-1290C (Lit. mp 128-1290C) [01H1703]. 1H NMR

6 2.39 (s, 3H), 7.32 (d, J= 8.1 Hz, 2H), 7.48 (t, J= 7.7 Hz, 1H), 7.66 (t, J= 7.8 Hz, 1H),

8.00 (d, J= 8.1 Hz, 2H), 8.10 (t, J= 9.6 Hz, 2H). 13C NMR 6 21.7, 112.0, 120.5, 125.8,

128.0, 130.2, 130.3, 131.5, 134.0, 145.4, 146.7.









1-(2-Pyridinylsulfonyl)-lH-1,2,3-benzotriazole (3.27e): Purple needles (from

EtOAc, 71%), mp 132-1350C. 1H NMR 6 7.48-7.59 (m, 2H), 7.67-7.73 (m, 1H), 8.02

(dt, J= 7.8, 1.8 Hz, 1H), 8.08-8.12 (m, 1H), 8.21-8.25 (m, 1H), 8.36 (dt, J= 8.1, 0.9

Hz, 1H), 8.59 (ddd, J = 4.8, 1.5, 0.6 Hz, 1H). 13C NMR 6 112.7, 120.4, 123.4, 126.0,

128.6, 130.4, 132.7, 138.7, 145.4, 150.7, 154.7. Anal. Calcd For ClHs8N402S: C, 50.76;

H, 3.10; N, 21.53. Found: C, 50.81; H, 3.05; N, 21.51.

1-(3-Pyridinylsulfonyl)-lH-1,2,3-benzotriazole (3.27f): Cream needles (from

EtOAc, 41%), mp 128-1290C. 1H NMR 6 7.49-7.56 (m, 2H), 7.64-7.74 (m, 1H),

8.10-8.15 (m, 2H), 8.42 (ddd, J= 8.1, 2.4, 1.8 Hz, 1H), 8.87 (dd, J= 4.8, 1.8 Hz, 1H),

9.30-9.31 (m, 1H). 13C NMR 111.9, 120.8, 124.1, 126.3, 130.8, 131.5, 134.1, 135.7,

145.5, 148.4, 155.5. Anal. Calcd For CjlH8N402S: C, 50.76; H, 3.10; N, 21.52. Found: C,

50.60; H, 3.01; N, 21.13.

1-(2-Furylsulfonyl)-lH-1,2,3-benzotriazole (3.27g): Amber needles (from

EtOAc, 83%), mp 107-1090C. 1H NMR 6 6.60 (dd, J= 3.6, 1.8 Hz, 1H), 7.51-7.56 (m,

2H), 7.60-7.61 (m, 1H), 7.71 (dt, J= 8.1, 0.9 Hz, 1H), 8.11 (t, J= 8.6 Hz, 2H). 13C NMR

6 112.0, 112.3, 120.6, 121.1, 126.1, 130.5, 131.5, 144.9, 145.4, 149.1. Anal. Calcd For

CloH7N303S: C, 48.19; H, 2.83; N, 16.86. Found: C, 47.82; H, 2.57; N, 16.52.

1-(2-Thienylsulfonyl)-lH-1,2,3-benzotriazole (3.27h): Needles (from EtOAc,

82%), mp 143-1440C. 1H NMR 6 7.13 (dd, J = 5.1, 3.9 Hz, 1H), 7.48-7.54 (m, 1H),

7.66-7.72 (m, 1H), 7.76 (dd, J = 5.1, 1.2 Hz, 1H), 7.96 (dd, J = 3.6, 1.2 Hz, 1H),

8.08-8.09 (m, 1H), 8.10-8.12 (m, 1H). 13C NMR 6 112.0, 120.6, 126.0, 128.2, 130.4,

131.2, 135.8, 136.3, 136.4, 145.4. Anal. Calcd For C10H7N302S2: C, 45.27; H, 2.66; N,

15.84. Found: C, 45.36; H, 2.34; N, 15.71.









1-[(1-Methyl-1H-indol-2-yl)sulfonyl]-lH-1,2,3-benzotriazole (3.27i): Purified

by column chromatography with hexanes/EtOAc = 6:1 as eluent and obtained as colorless

prisms (20%), mp 150-1520C. 1H NMR 6 4.08 (s, 3H), 7.19 (t, J= 6.9 Hz, 1H), 7.33-

7.51 (m, 3H), 7.60-7.69 (m, 3H), 8.06-8.11 (m, 2H).13C NMR 6 31.7, 110.7, 112.0,

113.6, 120.7, 121.9, 123.2, 124.6, 126.0, 127.3, 129.5, 130.3, 131.2, 140.2, 145.6. Anal.

Calcd For C15H12N402S: C, 57.68; H, 3.87; N, 17.94. Found: C, 57.54; H, 3.76; N, 17.82.

1-[(1-Methyl-1H-imidazol-2-yl)sulfonyl]- 1H-1,2,3-benzotriazole (3.27j):

Purified by column chromatography with hexanes/EtOAc = 3:7 as eluent and obtained as

colorless prisms (80%), mp 147-1500C. 1H NMR 6 4.18 (s, 3H), 7.13 (d, J= 3.6 Hz, 2H),

7.5 1(t, J= 7.5 Hz, 1H), 7.69 (t, J= 7.2 Hz, 1H), 8.09 (d, J= 8.1 Hz, 1H), 8.19 (d, J= 8.4

Hz, 1H). 13C NMR 6 36.1, 112.5, 120.4, 126.2, 127.9, 130.6, 130.7, 131.6, 138.5, 145.3.

Anal. Calcd For C10H9N502S: C, 45.62; H, 3.45; N, 26.60. Found: C, 45.64; H, 3.35; N,

26.49.

3.4.2 General Procedure for the Preparation of Sulfonamides 3.29-3.37

The respective sulfonylbenzotriazole 3.27 (1 equiv.) was heated at the established

temperature in the chosen solvent with the appropriate primary or secondary amine

(1 equiv.) for the established time (See Table 3-2). Water (ca 100 mL) was added and the

mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers

were washed with water, IM HC1, brine, dried over anhydrous sodium sulfate and

filtered. Concentration under reduced pressure gave an oil, which was further purified

either by re-crystallization or column chromatography over silica gel (200-400 Mesh).

N-Cyclohexyl-1-butanesulfonamide (3.29): Purified by column chromatography

with CHCl3 as eluent and obtained as colorless prisms (89%), mp 64-650C (Lit. mp









71.8C) [42CB42]. 1HNMR6 0.95 (t, J= 7.2 Hz, 3H), 1.14-1.49 (m, 7H), 1.56-1.84

(m, 5H), 1.95-1.99 (m, 2H), 3.01 (t, J= 8.0 Hz, 2H), 3.20-3.33 (m, 1H), 4.31 (d, J= 6.6

Hz, 1H). 13C NMR 6 13.6, 21.5, 24.8, 25.1, 25.8, 34.7, 52.7, 53.9. Anal. Calcd For

C10H21N02S: C, 54.76; H, 9.65; N, 6.39. Found: C, 54.77; H, 9.67; N, 6.34.

N-Benzyl-N,2-dimethyl-1-propanesulfonamide (3.30): Purified by column

chromatography with hexanes/Et20 = 6:1 as eluent and obtained as colorless needles

(72%), mp 32-34C. H NMR 6 1.13 (d, J= 6.6 Hz, 6H), 2.32 (sep, J= 6.6 Hz, 1 H),

2.76 (s, 3H), 2.83 (d, J= 6.6 Hz, 2H), 4.32 (s, 2H), 7.31-7.36 (m, 5H).13C NMR 6 22.7,

24.5, 34.1, 53.7, 57.4, 127.9, 128.3, 128.7, 135.9. Anal. Calcd For C12H19N02S: C, 59.72;

H, 7.93; N, 5.80. Found: C, 59.88; H, 8.10; N, 5.92.

1-(2-Thienylsulfonyl)piperidine (3.31): Purified by column chromatography with

CHCl3 as eluent and obtained as colorless prisms (85%), mp 76-77C (Lit. mp 65C)

[95CB1195]. H NMR 6 1.41-1.49 (m, 2H), 1.64-1.72 (m, 4H), 3.04 (t, J= 5.6 Hz, 4H),

7.14 (dd, J= 4.8, 3.6 Hz, 1H), 7.52 (dd, J= 3.6, 1.2 Hz, 1H), 7.61 (dd, J= 4.8, 1.2 Hz,

1H). 13C NMR 6 23.4, 25.0, 47.0, 127.5, 131.7, 132.1, 136.7. Anal. Calcd For

C9H13NO2S2: C, 46.73; H, 5.66; N, 6.05. Found: C, 46.98; H, 5.64; N, 6.15.

N-(1-Methylbutyl)-2-furansulfonamide (3.32): Purified by column

chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as cream prisms

(100%), mp 57-58C. 1H NMR 6 0.82-0.87 (m, 3H), 1.08 (d, J= 6.6 Hz, 3H), 1.21-1.38

(m, 4H), 3.33-3.45 (m, 1H), 4.45 (d, J= 7.8 Hz, 1H), 6.50 (dd, J= 3.3, 1.8 Hz, 1H), 7.03

(d, J= 3.3 Hz, 1H), 7.55 (d, J= 1.8 Hz, 1H). 13C NMR 6 13.6, 18.6, 21.9, 39.5, 50.2,

103.4, 111.2, 116.0, 145.7. Anal. Calcd For C9H15NO3S: C, 49.75; H, 6.96; N, 6.45.

Found: C, 49.95; H, 6.97; N, 6.37.









1-(3-Pyridinylsulfonyl)piperidine (3.33): Purified by column chromatography

with hexanes/EtOAc/CHCl3 = 4:1:5 as eluent and obtained as white prisms (100%), mp

88-890C (Lit. mp 940C) [83S822]. 1HNMR 6 1.43-1.49 (m, 2H), 1.63-1.71 (m, 4H),

3.05 (t, J= 5.6 Hz, 4H), 7.49 (dd, J= 2.7, 5.1 Hz, 1H), 8.05 (dt, J= 8.1, 1.8 Hz, 1H), 8.82

(dd, J= 4.8, 1.5 Hz, 1H), 8.99 (d, J= 2.1 Hz, 1H). 13C NMR 6 23.4, 25.1, 46.8, 123.6,

133.3, 135.2, 148.4, 153.2. Anal. Calcd For C10H14N202S: C, 53.08; H, 6.24; N, 12.38.

Found: C, 53.10; H, 6.32; N, 11.96.

4-[(1-Methyl-1H-imidazol-2-yl)sulfonyl]morpholine (3.34): Colorless oil (91%).

H NMR 6 3.40 (t, J= 4.8 Hz, 4H), 3.72 (t, J= 4.8 Hz, 4H), 3.85 (s, 3H), 6.91 (s, 1H),

7.01 (s, 1H). 13C NMR 6 34.7, 46.5, 66.2, 124.6, 128.4, 141.9. Anal. Calcd For

CsH13N303S: C, 41.55; H, 5.67; N, 18.17. Found: C, 41.45; H, 6.04; N, 15.99.

1-[(4-Methylphenyl)sulfonyl]piperidine (3.35): White prisms (from EtOAc,

100%), mp 930C (Lit. mp 96-980C) [81JOC5077]. 1HNMR 6 1.36-1.45 (m, 2H), 1.60-

1.67 (m, 4H), 2.43 (s, 3H), 2.97 (t, J= 5.7 Hz, 4H), 7.32 (d, J= 8.1 Hz, 2H), 7.64 (d, J=

8.1 Hz, 2H). 13C NMR 6 21.5, 23.4, 25.1, 46.9, 127.6, 129.5, 133.2, 143.2. Anal. Calcd

For C12H17N02S: C, 60.22; H, 7.16; N, 5.85. Found: C, 60.01; H, 7.27; N, 5.95.

N-(1,5-Dimethylhexyl)-1-methyl-1H-imidazole-2-sulfonamide (3.36): Purified

by column chromatography with hexanes/EtOAc = 3:1 as eluent and obtained as white

prisms (64%), mp 82-840C. H NMR 6 0.84 (d, J= 6.6 Hz, 6H), 1.06-1.35 (m, 7H),

1.38-1.55 (m, 3H), 3.46-3.55 (m, 1H), 3.94 (s, 3H), 5.25 (s, 1H), 6.96 (s, 1H), 7.09 (s,

1H). 13C NMR 6 21.4, 22.5, 23.3, 27.8, 35.1, 37.7, 38.5, 51.1, 124.6, 128.1, 143.4. Anal.

Calcd For C12H23N302S: C, 52.72; H, 8.48; N, 15.37. Found: C, 52.54; H, 8.07; N, 15.84.






37


N-Phenethyl-2-thiophenesulfonamide (3.37): Purified by column

chromatography with hexanes/EtOAc = 3:1 as eluent and obtained as yellow oil (80%).

1HNMR 6 2.81 (t, J= 6.9 Hz, 2H), 3.32 (q, J= 6.6 Hz, 2H), 4.54 (br s, 1H), 7.06-7.13

(m, 3H), 7.20-7.32 (m, 3H), 7.56-7.59 (m, 2H). 13C NMR 6 35.6, 44.4, 126.9, 127.4,

128.7, 128.8, 131.8, 132.1, 137.5, 140.9. Anal. Calcd For C12H13NO2S2: C, 53.91; H,

4.90; N, 5.24. Found: C, 54.21; H, 4.89; N, 5.59.














CHAPTER 4
1-[2-BENZOTRIAZOL-1 -YL)ETHYL] SULFONYLBENZOTRIAZOLE: A
VERSATILE SYNTHON FOR THE PREPARATION OF
ETHYLENESULFONAMIDES AND ALKYLSULFONATE ESTERS

4.1 Introduction

In the previous chapter we mentioned that many compounds containing the

sulfonyl group are interesting from the medicinal and industrial point of view.

Ethylenesulfonamides and sulfonate esters are a significant subset of the extensive family

of compounds containing the sulfone (SO2) moiety. Most importantly, the addition of

vinyl functionality to sulfones enriches the chemistry of these compounds by providing

an opening to further transformations. Transformations such as i) epoxidation

[87TL1101], ii) aziridination [83S816], iii) Diels-Alder cycloaddition [80JA853], and iv)

nitrone cycloaddition [87H101] can be carried out with the vinyl functional group of the

ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters (Scheme 4-1).

Modifications to the ethylene functionality increase the synthetic range of sulfur

containing compounds. Additionally, new carbon-carbon and carbon-hydrogen bonds

can be generated concurrently with loss of the sulfone moiety [90T6951]. Examples of

desulfonation reactions include reductive and alkylative desulfonations, base eliminations

and methods using tin (Scheme 4-2) [90T6951].

Vinyl sulfones, ethylenesulfonamides, and ethylenesulfonate esters are also known

to be excellent Michael acceptors [90T6951; 91JOC3549] { Scheme 4-1, (v)}. Peptide

Michael acceptors are inhibitors of some protease enzymes [84JMC711; 86JMC 104],

which regulate physiological functions by processing peptides and proteins.









(i) Epoxidation


-"SO3Et


1) t-BuOOH,
Triton B, THF

2) Bu4NHSO4,
CH2CI2-H20


0

-SO3Bu4N


(/i) Aziridination
Br
S02X Br2 gr S02X


1
R NH2, DMSO
-------*


X= NHR, OR


(iii) Diels-Alder cycloaddition


'-"SO2Ph


0


250 C, 110 h


K-"S02N(E%)


R1
+ H ZN
R2


R2 N


N(Et)2SO2


(v) Michael addition


-"SO2N(PMB)2 +


K2C03


.SO2N(PMB)2


Scheme 4-1. Transformations of ethylenesulfonamides, vinyl sulfones and
ethylenesulfonate esters


NR1

-SO2X


(iv) Nitrone cycloaddition


-SO2Ph









(I) Reductive- with transition metal catalysts

PhO2S 2 mol % Ni(acac)2


R 2 eq. n-BuMgCI


(ii) Alkylative


SO2Me
.Ph


Bu3B


(iii) Base-Elimination


R tBuOK
30


"s~ R


SO2Ph
Bu3SnLi R-Y SnBu3 3 R'

R' mixture of isomers


Scheme 4-2. Desulfonation Reactions

Vinyl sulfones and ethylenesulfonamides are believed to bind irreversibly to

cysteine proteases, enzymes implicated in a number of diseases such as osteoporosis,

arthritis, Alzheimer's disease, cancer metastasis, and programmed cell death

[95JMC3193] thus inhibiting their action [99JMC3789]. Certain vinyl sulfones have


R
R


Bu ^Ph


OAc


(iii) Tin method


SO2Ph


R'









proven effective against Trypanosoma cruzi, a protozoa agent of Chaga's disease

[98JEM725], and as antimalarial agents [96AAC1600]. Sulfonamides have been used for

almost a century as antibiotics, as antimigrain agents, and as drugs in the treatment of

diseases caused by diverse pathogenic microorganisms, such as the hemolytic

streptococci, by inhibiting their cell division. Not surprisingly, the development of new

methodology to synthesize vinyl sulfones, ethylenesulfonamides and ethylenesulfonate

esters attracts great attention.

Known approaches to ethylenesulfonate esters and ethylenesulfonamides are: i) the

Horner-Wadsworth-Emmons reaction of a-phosphorylmethanesulfonate with an

aldehyde or ketone [98JA10994]; ii) elimination of a fl-halo or f/-aceto-substituted

sulfone in the presence of a base [91JOC3549]; iii) addition of a sulfone carbanion to a

carbonyl compound followed by elimination; iv) the Peterson reaction [90T6951]; v)

amidation or esterification reactions of sulfonyl chlorides [98JA10994] or sulfonates

[020L2549], with the desired amines (Scheme 4-3).

Recently, Caddick [020L2549] and co-workers reported the preparation of a variety of

sulfonamides using the novel pentafluorophenyl vinyl sulfonate 4.1 as an intermediate

(Figure 4-1). It is interesting to see that the intermediate 4.1 is stable. This intermediate

is a potential replacement for the sulfonyl chloride unit, because on exposure to

nucleophiles it does not liberate hydrochloric acid. However, alkylations to the olefin

were performed before amidation to avoid possible side reactions of the nucleophile with

the vinyl double bond. Also, the alkylations were performed only by radical reactions

and not by carbon-carbon nucleophilic attack. It is probable that there is no selectivity in









CH2CH2Ph

(I) BocNH H
0


0
EtO
EtOPI SO3Et
EtO B 3

BuLi, THF


CH2CH2Ph

BocN SO3Et
H


01i) 200 +OH 25 % NaOH, 0C
() SO2cI + CICH2CH2CI-H20


SO) 2Ph 1) BuLi

PhS 2) RCHO


Ac20

NEt3, DMAP


R \-SO2Ph

PhS


(iv)
0j --I


Me3Si -SO2Ph

BuLi, DME


/ O SO2Ph
0 /


R2NH2 R- SO2NHR2
1 DBU
(v) R,' SO2C
R OH R- SO3R 2


Scheme 4-3. Synthetic protocols toward ethylenesulfonate esters, vinyl sulfones and
ethylenesulfonamides

the reactivity of the vinyl bond vs. the ester site if both are present and a nucleophile is

used.

We therefore thought of preparing a similar intermediate 4.2 and by taking

advantage of the characteristics of benzotriazole, as stabilizer and as activator of certain


#SO3Ph









functional groups, we would solve the limitations of previously published procedures.

The program would include a study on target 4.2 and a study of its reactivity. Thus, this

chapter describes an approach to sulfonate esters and ethylenesulfonamides utilizing a

synthetic equivalent formed with benzotriazole.

F
F F 0

F 1N

F 0 N 0N
4.1 4.2

Figure 4-1. Intermediate 4.1 used in the preparation of ethylenesulfonamides

4.2 Results and Discussion

Our approach employs a novel intermediate 1-[2-benzotriazol-1-

yl)ethyl]sulfonylbenzotriazole 4.5 easily obtained from the reaction of 2-

chloroethanesulfonyl chloride 4.3 and benzotriazole 4.4 in 88% yield (Scheme 4-4).

Intermediate 4.5 is a solid, compared to the starting material and many other sulfonyl

chlorides, which are often liquids. It liberates benzotriazole instead of hydrochloric acid

and it is stable to air and at room temperature.

0 01t
l + NC NEtl 3

0 o CHCIo
0 OC-rt
4.3 4.4 4.5 (88%)

Scheme 4-4. Synthesis of 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5

The preparation of benzotriazolyl reagent 4.2 from 4.5 failed. Elimination of the

benzotriazole attached to the ethyl chain was attempted using potassium tert-butoxide and

triethyl amine. The reaction did not generate 4.2 or allow recovery of the starting









material (Scheme 4-5). Attempts to perform an intramolecular Michael addition using

hydrazine or hydroxylamine also failed.


/ N -N KOBut /
i 0N 0' / I I N
N=N NN /or N/N
4.5 NEt3 4.2

Scheme 4-5. Attempt to prepare 4.2

Our attention then shifted to intermediate 4.5. We noticed that upon exposure to

nucleophiles the reactive site is only at sulfur. The ethyl chain is not attacked by

nucleophiles because it is protected by the presence of benzotriazole. Thus 4.5 resembles

a sulfonyl chloride with a masked double bond. Nucleophilic attack occurs without the

need of a base, which shows that the reactions proceed via direct displacement of

benzotriazole by the nucleophile. Nitrogen and oxygen nucleophiles can be employed in

these reactions. Herein, we describe the facile preparation of alkylsulfonamides,

sulfonate esters and ethylenesulfonamides utilizing the novel intermediate 4.5.

4.2.1 Preparation of Sulfonamides 4.7a-g and Sulfonate ester 4.7h

Displacement of the benzotriazole attached to the sulfonyl moiety was achieved

by the reaction of 4.5 in THF or CH2C2 at room temperature with oxygen and nitrogen

nucleophiles. No base was necessary for the reactions to occur with nitrogen

nucleophiles. Only the desired products and benzotriazole were observed in the reaction

mixtures, and most of the products were purified by a mild basic wash. As expected, the

corresponding sulfonate ester and sulfonamides were formed in good to excellent yields

as shown in Scheme 4-6 and Table 4-1. The 1H and 13C NMR of the new products









showed the absence of the benzotriazole group and the introduction of the nucleophile

used.


0


N::N NzzN


Nu

T H F/rt


4.5

Scheme 4-6. Preparation of sulfonamides and sulfonate ester 4.7

Table 4-1. Sulfonamides 4.7a-g and sulfonate ester 4.7h prepared


4.7


%yield


4.7


4.7a-h


%yield


~r NH2



MeO NH

ONH

CNH


0r NH2

ONH2


-<-4 N H2

ONa


4.2.2 Preparation of Ethylenesulfonamides 4.8a, f

Base catalyzed elimination of benzotriazole from sulfonamides 4.7a and f was

carried out to afford the ethylenesulfonamides 4.8a, f (Scheme 4-7). The starting

material had first to be dissolved by heating in THF, then treated with potassium tert-

butoxide at 0C. Mild water workup afforded the corresponding ethylenesulfonamides

4.8a and 4.8f in excellent yields.










II H II H
^ N S. 0N tBuOK N -
1N 0 THF, 0C, 10min 0
4.7a 4.8a
93% yield


11 H 11 H
N -N tBuOK SN
N-N 4.7f THF, 0C, 10min 4.8f
4.7f 4.8f
94% yield

Scheme 4-7. Synthesis of ethylenesulfonamides

4.3 Conclusion

The use of intermediate 4.5 makes this new approach simple and versatile to afford

high yields of a variety of products under mild conditions and with easy purification. We

have described the facile preparation of alkyl sulfonamides, sulfonate esters and ethylene

sulfonamides utilizing novel intermediate 4.5.

4.4 Experimental Procedure

Melting points were determined on a hot-stage apparatus and are uncorrected. 1H

(300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 MHz NMR

spectrometer in chloroform-d solution unless stated. Column chromatography was

performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone

ketyl prior to use.

4.4.1 Procedure for the Synthesis of Novel Intermediate 4.5

A solution of benzotriazole (3 g, 24.54 mmol) and triethylamine (4.5 mL, 30.68

mmol) in dichloromethane was cooled to 0C. 2-Chloroethylsulfonyl chloride (1.29 mL,

12.27 mmol) was added dropwise and the mixture left stirring overnight. The solvent

was removed under vacuo and the residue was dissolved in ethyl acetate. The mixture in









ethyl acetate was washed with water (x3) and brine. It was dried, filtered, concentrated,

and recrystallized from ethyl acetate to afford 3.56 g (88%) of 1- { [2-(1H-1,2,3-

benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole.

1-{[2-(1H-1,2,3-Benzotriazol-1-yl)ethyl]sulfonyl}-lH-1,2,3-benzotriazole (4.5):

White flakes (88%), mp 98.1-98.80C. H NMR 6 4.93 (t, J= 6.3 Hz, 2H), 5.26 (t, J= 6.3

Hz, 2H), 7.38 (t, J= 7.8 Hz, 1H), 7.55 (dd, J= 8.4, 15.6 Hz, 2H), 7.68 (J= 7.2 Hz, 1H),

7.80-7.94 (m, 3H), 8.18 (d,J= 8.1 Hz, 1H). 13C NMR 6 41.4, 54.0, 108.8, 111.6, 117.8,

120.12, 120.3, 120.7, 124.4, 126.0, 126.2, 126.9, 128.1, 130.7. Anal. Calcd. For

C14H20N402S: C, 51.21; H, 3.68; N, 25.59. Found: C, 51.52; H, 3.61; N, 25.69

4.4.2 General Procedure for the Preparation of Sulfonamides 4.7a-g

A solution of the respective amine (3.03 mmol) and 1-{[2-(1H-1,2,3-benzotriazol-

1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole (1.0 g, 3.03 mmol) in THF was stirred at

room temperature 24 h. The solvent was evaporated and ethyl acetate added. After

washing with water and IM NaOH (xl) the solution was dried over anhydrous sodium

sulfate and filtered. Concentration under reduced pressure gave an oil, which was further

purified by re-crystallization or column chromatography over silica gel (200-400 Mesh).

2-(1H-1,2,3-Benzotriazol-1-yl)-N-benzyl-l-ethanesulfonamide (4.7a): Colorless

prisms (99%), mp 151.8-152.90C. 1HNMR 6 3.63 (t, J= 6.6 Hz, 2H), 4.12 (d, J= 6.0

Hz, 2H), 4.58 (s, 1H), 5.04 (t, J= 6.6 Hz, 2H), 7.14-7.16 (m, 2H), 7.26-7.28 (m, 3H),

7.40 (m, 1H), 7.52 (m, 2H), 8.10 (m, 1H). 13C NMR in DMSO 6 40.3, 42.2, 45.9, 50.6,

110.7, 119.1, 124.0, 127.3, 127.6, 128.4, 128.4, 132.1, 145.

2-(1H-1,2,3-Benzotriazol-1-yl)-N-(4-methoxybenzyl)-l-ethanesulfonamide

(4.7b): Purified by column chromatography with hexanes/ ethyl acetate/ chloroform =









1:2:7 as eluent and obtained as colorless prisms (71%), mp 115.00C. 1H NMR 6 3.58 (t,

J= 6.8 Hz, 2H), 3.75 (s, 3H), 4.08 (d, J= 5.7 Hz, 2H), 4.80 (s, 1H), 5.00 (t, J= 6.6 Hz,

2H), 6.77 (d, J=8.7 Hz, 2H), 7.08 (d, J= 8.7 Hz, 2H), 7.38-7.42 (m, 1H), 7.48-7.52 (m,

2H), 8.06 (d, J= 8.4 Hz, 1H). 13C NMR 6 42.5, 46.7, 51.8, 55.3, 109.1, 114.2, 120.2,

124.4, 128.0, 128.2, 129.4, 132.9, 145.8, 159.5.

1-[2-(Piperidine-l-sulfonyl)-ethyl]-lH-benzotriazole (4.7c): Colorless prisms

(77%), mp 130.0-130.80C. 1HNMR 6 1.50-1.63 (m, 6H), 3.16-3.18 (m, 4H), 3.69 (t, J

= 7.1 Hz, 2H), 5.10 (t, J= 7.2 Hz, 2H), 7.46 (t, J= 7.5 Hz, 1H), 7.60 (t, J= 7.4 Hz, 1H),

7.67 (d, J= 8.4 Hz, 1H), 8.13 (d, J= 8.4 Hz, 1H). 13C NMR 6 23.4, 25.3, 42.1, 46.3,

48.2, 109.2, 120.1, 124.3, 127.9, 133.0, 145.8.

1-[2-(1-Pyrrolidinylsulfonyl)ethyl]-lH-1,2,3-benzotriazole (4.7d): Colorless

prisms (74%), mp 127.0C. 1HNMR 6 1.76 (m, 4H), 3.18 (t, J= 6.8 Hz, 4H), 3.72 (t, J

= 6.9 Hz, 2H), 5.07 (t, J= 6.9 Hz, 2H), 7.41 (t, J= 7.7 Hz, 1H), 7.55 (t, J= 7.5 Hz, 1H),

7.62-7.65 (m, 1H), 8.07 (d, J= 8.4 Hz, 1H). 13C NMR 6 25.6, 42.2, 47.5, 48.5, 109.2,

120.0, 124.2, 127.8, 133.0, 145.7. Anal. Calcd. For C12H16N402S: C, 51.41; H, 5.75; N,

19.98. Found: C, 51.78; H, 5.79; N, 19.93.

2-(1H-1,2,3-Benzotriazol- 1-yl)-N-(2-furylmethyl)- 1-ethanesulfonamide (4.7e):

Colorless prisms (68%), mp 125.6-126.0C. 1H NMR 6 3.59 (t, J= 6.8 Hz, 2H), 4.25 (d,

J= 4.2 Hz, 2H), 5.02 (t, J= 6.9 Hz, 3H), 6.22-6.25 (m, 2H), 7.20 (s, 1H), 7.39-7.43 (m,

1H), 7.54 (d, J= 3.6 Hz, 2H), 8.07 (d, J= 6.9 Hz, 1H). 13C NMR 6 39.8, 42.4, 52.0,

100.3, 108.9, 109.0, 110.5, 120.3, 121.9, 124.3, 128.0, 143.0, 149.4. Anal. Calcd. For

C13H14N403S: C, 50.97; H, 4.61; N, 18.29. Found: C, 50.90; H, 4.47; N, 18.04.









2-(1H-1,2,3-Benzotriazol-1-yl)-N-cyclohexyl-1-ethanesulfonamide (4.7f):

Colorless prisms (99%), mp 110.40C. H NMR 6 1.04-1.13 (m, 3H), 1.18-1.28 (m, 2H),

1.51-1.67 (m, 3H), 1.76-1.81 (m, 2H), 3.10-3.25 (m, 1H), 3.73 (t, J= 6.9 Hz, 2H), 4.45-

4.55 (m, 1H), 5.09 (t, J= 6.9 Hz, 2H), 7.41 (t, J= 7.5 Hz, 1H), 7.55 (t, J= 7.5 Hz, 1H),

7.63 (d, J= 8.4 Hz, 1H), 8.07 (d, J= 8.4 Hz, 1H). 13C NMR 6 24.7, 25.0, 34.2, 42.7,

52.8, 53.1, 109.2, 120.2, 124.4, 128.0, 133.1, 145.9. Anal. Calcd. For C14H20N402S: C,

54.52; H, 6.54; N, 18.17. Found: C, 54.55; H, 6.56; N, 17.84.

2-(1H-1,2,3-Benzotriazol-1-yl)-N-(1,5-dimethylhexyl)-l-ethanesulfonamide

(4.7g): Purified by column chromatography with hexanes/ ethyl acetate/ chloroform =

1:2:7 as eluent and obtained as colorless prisms (84%), mp 72.2-74.70C. 1H NMR 6 0.84

(d, J= 6.6 Hz, 6H), 1.06-1.16 (m, 5H), 1.18-1.40 (m, 4H), 1.43-1.50 (m, 1H), 3.40 (t, J

= 7.5 Hz, 1H), 3.72 (t, J= 6.9 Hz, 2H), 4.39 (d, J= 8.4 Hz, 1H), 5.10 (t, J= 6.9 Hz, 2H),

7.41 (t, J= 7.2 Hz, 1H), 7.55 (t, J= 7.8 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 8.08 (d, J= 8.4

Hz, 1H). 13C NMR 6 21.9, 22.4, 22.5, 23.4, 27.7, 37.8, 38.5, 42.6, 50.6, 52.7, 109.1,

120.2, 124.3, 128.0, 133.0, 145.8. Anal. Calcd. For C16H26N402S: C, 56.78; H, 7.74; N,

16.55. Found: C, 57.03; H, 8.00; N, 16.51.

4.4.3 Procedure for the Preparation of Sulfonate ester 4.7h

Beta-hydroxynaphthalene (0.48 g, 3.33 mmol) and NaOH (0.18 g, 4.55 mmol) were

dissolved in anhydrous methylene chloride (40 mL). This mixture was added to a

solution of 1-{[2-(1H-1,2,3-benzotriazol-1-yl)ethyl]sulfonyl}-lH-1,2,3-benzotriazole

(1.0 g, 3.03 mmol) at 0C and stirred overnight. Concentration under reduced pressure

gave an oil, which was further purified by column chromatography over silica gel (200-

400 Mesh) using hexanes/ethyl acetate = 70:30 as eluent.









2-Naphthyl-2-(1H-1,2,3-benzotriazol-1-yl)-l-ethanesulfonate (4.7h): Pink

crystals (52%), mp 92.2-94.00C. 1H NMR 6 4.04 (t, J= 6.8 Hz, 2H), 5.23 (t, J= 6.9 Hz,

2H), 7.17 (dd, J= 2.4, 9 Hz, 1H), 7.40 (t, J= 7.7 Hz, 1H), 7.46-7.57 (m, 4H), 7.63 (d, J=

8.4 Hz, 1H), 7.76-7.83 (m, 3H), 8.08 (d, J= 8.4 Hz, 1H). 13C NMR 6 42.1, 49.5, 103.3,

109.1, 119.2, 120.2, 120.3, 124.4, 126.7, 127.2, 127.7, 127.9, 128.1, 132.0, 133.1, 133.4,

145.7, 146.0.

4.4.4 General Procedure for the Synthesis of Ethylenesulfonamides 4.8a, f

The respective sulfonamide (0.36 g, 1.13 mmol) was dissolved in 15 mL of

anhydrous THF at 0C. Potassium tert-butoxide (0.38 g, 3.41 mmol) was added and the

reaction mixture stirred under nitrogen atmosphere for 10 to 30 min. Water was added,

the product was extracted with ethylacetate, washed with water, brine, dried over

anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave an oil,

which was further purified by re-crystallization or column chromatography over silica gel

(200-400 Mesh).

Ethenesulfonic acid benzylamide (4.8a): Purified by column chromatography

with hexanes/ethyl acetate = 72: 28 as eluent and obtained as yellow oil (93%). 1H NMR

6 4.22 (d, J= 6 Hz, 2H), 4.65 (s, 1H), 5.93 (d, J= 9.9 Hz, 1H), 6.26 (d, J= 16.8 Hz, 1H),

6.48 (dd, J= 9.6, 16.5 Hz, 1H), 7.30-7.35 (m, 5H). 13C NMR 6 47.0, 126.8, 127.9,

128.1, 128.8, 136.0, 136.4. Anal. Calcd. For C9HjjN02S: C, 54.78; H, 5.63; N, 7.10.

Found: C, 54.72; H, 5.73; N, 7.53.

Ethenesulfonic acid cyclohexylamide (4.8f): Yellow needles (94%), mp 50-510C.

1HNMR 6 1.14-1.40 (m, 5H), 1.54-1.59 (m, 1H), 1.69-1.73 (m, 2H), 1.92-1.96 (m, 2H),

3.14-3.20 (m, 1H), 4.52-4.56 (m, 1H), 5.89 (d, J= 9.9 Hz, 1H), 6.24 (d, J= 16.5 Hz, 1H),






51


6.55 (dd, J= 9.9, 16.5 Hz, 1H). 13C NMR 6 24.7, 25.1, 34.2, 52.6, 125.5, 137.2. Anal.

Calcd. For C8H15NO2S: C, 50.77; H, 7.99; N, 7.40. Found: C, 50.41; H, 8.13; N, 7.40.















CHAPTER 5
VERSATILE SYNTHESIS OF THIOCARBAMOYLBENZOTRIAZOLES,
THIOAMIDES, THIOCARBAMATES AND DITHIOCARBAMATES FROM
BIS(BENZOTRIAZOLYL)METHANETHIONE

5.1 Introduction

Recently bis(benzotriazolyl)methanethione 5.3 was recognized as an excellent

thiocarbonyl transfer agent [04JOC2976]. Although 5.3 was first prepared by Keating

and Skell [76MI_573] 30 years ago, the yield was never reported. Two years later,

Larsen and coworkers prepared 5.3 in 90% yield from the silylated heterocycle and

thiophosgene; bis(benzotriazolyl)methanethione 5.3 was reacted with aniline to obtain a

symmetrical thiourea [78JOC337] and further used in Diels-Alder reactions

[80JOC3713].

Me \ |
N S N N N
SN' Me + 1 N I
2eq. I Me CI CI :sNN
N'N
5.1 5.2 5.3

Scheme 5-1. Preparation of bis(benzotriazolyl)methanethione 5.3

Our group has previously reported the application of 5.3 in the facile preparation of

di- and tri-substituted thioureas [04JOC2976]. Bis(benzotriazolyl)methanethione 5.3 was

reacted with one equivalent of the respective amine and only the desired products, 1-

alkyl- and 1-aryl-thiocarbamoylbenzotriazoles 5.5, were obtained (Scheme 5-2) in yields

of 91-99%. 1-Alkyl/arylthiocarbamoylbenzotriazoles 5.5 from primary amines were

further reacted with nitrogen nucleophiles thus displacing the second benzotriazole of 5.3

to afford symmetrical and unsymmetrical di- and tri-substituted thioureas 5.7 (Scheme










5-2) in good to excellent yields [04JOC2976]. Di-substituted

thiocarbamoylbenzotriazoles 5.5 (R1, R2 H) did not yield thioureas. Apparently, these

reactions proceeded by the in situ formation of isothiocyanate intermediates. It was this

recent work that prompted further exploration of the uses of

bis(benzotriazolyl)methanethione 5.3 and its derivative 5.5, since no examples of

reactions with other than nitrogen nucleophiles have been reported.





N NN N 2 R
/NN + H 2N R1
\ H R1 = alkyl, aryl



R1 = alkyl, aryl 3 4
R2= H R R
R3 = alkyl, aryl N
R4= H, alkyl, aryl H 5.6

S
3 R
RN N"
14 I
R H
5.7

Scheme 5-2. Use of bis(benzotriazolyl)methanethione 5.3 in the preparation of thioureas
5.7

1-Alkyl/arylthiocarbamoylbenzotriazoles 5.5 in which R2 is H act as stable

isothiocyanate equivalents. Isothiocyanates are versatile precursors for inter-alia

thioureas [01JCB90], thioamides [71JIC791], ketene aminals [04JOC188], thiazoles

[04JOC202; 03JOC8693], 3-thio-1,2,4-triazoles and 2-thioimidazoles [02JCB315],

thiopyranes [02JA28] pyrimidine nucleoside analogues [03JOC8583], thiopyrroles and

thiophenes [01JOC2850], benzothieno-quinolines [00JOC8669], diaminoquinazolines









[010L585], dihydro and tetrahydroquinazolines [03JCB775] and thiourazoles

[02JCB491].

A moderate number of isothiocyanates are commercially available; many are

tedious to prepare and are susceptible to decomposition. The reaction of

bis(benzotriazolyl)methanethione 5.3 with amines to afford alkyl/arylthiocarbamoyl-

benzotriazoles 5.5 is a convenient route to prepare an isothiocyanate synthon.

Subsequently, 1-alkyl/arylthiocarbamoylbenzotriazoles 5.5 can be treated with oxygen,

sulfur and carbon nucleophiles to afford O,N-alkyl/arylthiocarbamates, S,N-

alkyl/aryldithiocarbamates and thioamides respectively, thus giving rise to molecular

diversity.

Thiocarbamates, dithiocarbamates and thioamides are precursors of interesting

molecular functionalities. Thiocarbamates include good insecticides [90JAE293],

herbicides [75MI_675] and nematocides [89MI_158]. Recently, dimethylthiocarbamate

(DMTC) has also been employed as an alcohol protecting group [030L4755]. Some

dithiocarbamates are fungicides and others are used as additives in the rubber industry.

Various thioamides exhibit antileprosy [85JL587], anthelmintic [01PMS1000],

immunosuppressive [98BMCL2203] and antituberculotic [02IF71] activity. We expect

that bis(benzotriazolyl)methanethione 5.3 will be a precursor for the easy access to the

above classes of compounds.

In this work, we describe the preparation of various novel and known 1-

(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 and their application in the synthesis of

thioamides 5.9, thiocarbamates 5.10 and dithiocarbamates 5.11 (Scheme 5-3).









S

R N
12
R
5.9
2 1 S
S R2NNR S NR1
B 5.4 N ,. R1 RO N
Bt Bt Bt N only when 5.1 2
I 2 R1, R2 H 5.10 R
5.3 5.5 R
S

Bt =N RS N12
^N 5.11




Scheme 5-3. Synthetic utility of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5



5.2 Results and Discussion

5.2.1 Preparation of 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5

Bis(benzotriazolyl)methanethione 5.3, prepared from literature procedure

[78JOC337] in 87% yield, was treated with one equivalent of the primary or secondary

amine (in DCM at room temperature) to afford the respective

thiocarbamoylbenzotriazoles 5.5a-k in yields of 60-98% (Scheme 5-4, Table 5-1). Their

purification is fairly simple; several requiring only a mild base wash to remove

benzotriazole by-product from the reaction mixture. Many are crystalline solids,

enabling their storage and handling to be very convenient. These

thiocarbamoylbenzotriazoles 5.5a-k proved to be stable at ambient conditions for weeks.

In the following work it will be shown that many of them are good isothiocyanate











analogues useful in the preparation of various thioamides, thiocarbamates and

dithiocarbamates.



N N N RN R N NR
N-N + H N \-N R2

5.3 5.4 5.5


Scheme 5-4. Preparation of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5

Table 5-1. 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 prepared


R 1R2

cyclohexyl H

furfuryl H

(R)-methylbenzyl H

PhCH2CH2_- H

t-Bu H

1,5-dimethylhexyl H

n-Bu- Me

2,3-dihydroindolyl

-(CH2)5-


Ph-


CH2CO2CH3


% Yield

85

94

87

89

60

87

76

84

76

92

76


Mp (C)

128.0 -130.0a

118.9 -120.0a

oila


112.3 113.3

61.3-63.0

oila

oil

123.0- 124.0

86.0 87.0

137.7 138.1

129.0-130.0


aPreviously prepared in [04JOC2976].









5.2.2 Preparation of Thioamides 5.9a-j

Di- and mono-substituted thiocarbamoylbenzotriazoles 5.5 were reacted with

organolithium or Grignard reagents 5.6a-h presented in Figure 1-1 (Scheme 5-5). For

example, when benzotriazole-1-carbothioic acid (furan-2-ylmethyl)-amide 5.5b was

reacted with pentyl magnesium bromide 5.6h, hexanethioic acid (furan-2-ylmethyl)-

amide 5.9b was obtained in 99% yield (Scheme 5-5, Table 5-2). The reaction was carried

out in tetrahydrofuran using 2.5 equivalents of the Grignard reagent and only required

10% Na2CO3 wash for purification. Di-substituted thiocarbamoylbenzotriazoles reacted

in a similar way, requiring only the addition of 1.5 equivalents of the organometallic

reagent. The higher yielding thioamides were obtained from commercially available

reagents (5.6a, c, d, f and h). All other organometallic reagents were prepared following

literature procedures [82MI; 79MI]. Table 5-2 and Table 5-3 show the di- and mono-

substituted thioamides 5.9 isolated after purification in yields of 36-99%.

Si Li MgBr

5.6a 5.6b 5.6c
,. MgBr 0 Li MgBr
5.6d
5.6e
MgBr 5.6f

N Li ^ MgBr
5.6g 5.6h

Figure 5-1. Organometallic reagents used










S

1 12,
N-N R


5.5 5.6a-h 5.9a-j

Scheme 5-5. Preparation of thioamides 5.9

Table 5-2: Preparation of mono-substituted thioamides from thiocarbamoylbenzotriazoles
Reagent 5.5 R-M Thioamide 5.9 Yield (%)



Bt N5.6f H 87
H
a
a


S

Bt N
H I1/

b


Bt
H
e


BtI N Ph
H
f
S

Bt N Ph
H




BtN'a
H
a


5.6h


5.6e




5.6f


5.6c


5.6g


S

H U

b



N
H

C
S

N N
H

d
S

"" N Ph
10 H

e


N SN


f


THF
rt


S

R N
12
R









Table 5-3. Preparation of di-substituted thioamides from thiocarbamoylbenzotriazoles
Reagent 5.5 R-M Thioamide 5.9 Yield (%)
s s
Bt"J" N 5.6d N 99
I I
g g





i h
s s
Bt' NQ 5.6b Q N0 53

i

s s
Bt N 'Ph 5.6d NN'Ph 75

J J


We have demonstrated that thiocarbamoylbenzotriazoles 5.5 act as isothiocyanate

analogues in the formation of thioamides 5.9 from the reaction of organometallic

reagents. We now apply 5.5 in further reactions with other nucleophiles. In a previous

paper, our group has already shown that thiocarbamoylbenzotriazoles react with nitrogen

nucleophiles [04JOC2976], thus we illustrate here reactions of

thiocarbamoylbenzotriazoles 5.5 with oxygen and sulfur nucleophiles.

5.2.3 Preparation of Thiocarbamates (5.10) and Dithiocarbamates (5.11) from
Thiocarbamoylbenzotriazoles 5.5

When thiocarbamoylbenzotriazole 5.5h was reacted with the sodium salts of 5.7a

and 5.8a, the corresponding thiocarbamate 5.10a and dithiocarbamate 5.11a were isolated

in yields of 59% and 99% respectively (Scheme 5-6, Tables 5-4 and 5-5).











,/ OH SH SH SH


OMe

5.7a 5.8a 5.8b 5.8d

Figure 5-2. Alcohols and thiols used

The reactions were performed in methylene chloride at room temperature. The

salts were first prepared by stirring the desired alcohol or thiol with twelve equivalents of

NaH in methylene chloride at room temperature for 30 minutes. The salt solution was

then carefully added to the solution of the thiocarbamoylbenzotriazole. Purification of

5.11a was achieved by column chromatography, while 5.10a was purified with mild base

wash. These novel compounds were characterized by 1H and 13C NMR and both passed

elemental analysis.

Other dithiocarbamates 5.11b-d and di-substituted thiocarbamate 5.10b were also

prepared in good to excellent yields. Thus, when thiocarbamoylbenzotriazoles from

primary amines were treated with thiols 5.8 in the presence of only one equivalent of

triethylamine the respective dithiocarbamates 5.11b-d were obtained in yields of 60-92%.

Thiocarbamoylbenzotriazoles 5.5a,b and d readily reacted with sulfur compounds while

no products were obtained using oxygen nucleophiles.

When reactions of 5.5a,b and d with alcohols 5.7 were attempted, the reactions

did not produce the expected thiocarbamates 5.10, the starting materials were recovered

in these cases. However, when thiocarbamoylbenzotriazoles 5.5a,b and d were treated

with the alcohols 5.7 as their salt or in the presence of excess triethylamine, formation of

the isothiocyanates was observed and the starting materials could no longer be recovered.

We believe that the sodium salts or the use of excess triethylamine is too strong to









deprotonate the thiocarbamoylbenzotriazoles into isothiocyanates while the use of one

equivalent of triethylamine is not sufficiently basic to deprotonate the alcohols 5.7.

S S
N R1 RX1N.eR1
N N HX CH2CI2 X N
N-N R base R
5.5 X= 0, S 5.10-5.11

Scheme 5-6. Synthesis of thiocarbamates 5.10 and dithiocarbamates 5.11

Table 5-4. Preparation of thiocarbamates 5.10
Reagent 5.5 5.7 salt Thiocarbamates 5.10 Yield (%)

S ONa
Bt< N S9 Iu59
h
a


Bt NWO ONa S
6CH3 |0 N0 C J 60
SCH3









Table 5-5. Preparation of dithiocarbamates 5.11

Reagent 5.5 5.8 Dithiocarbamates 5.11 Yield (%)


Bt N 99SNa N

h MeO
a

S s
Bt N 0Me S HJN 08
B H [ S N" /U 83
b SH MeO 8
b

Bt N SH S' N' 92
H H
a
c



Bt N O SH S N 77
H H
d d


5.3 Conclusion

Many 1-alkyl/arylthiocarbamoylbenzotriazoles 5.5 are synthetically equivalent to

isothiocyanates (only when R2=H) with the additional advantage that many of them are

stable solids that do not decompose when stored at ambient conditions for weeks.

Reactions with alkyl- or aryl-thiocarbamoylbenzotriazoles 5.5 do not require harsh

conditions or complicated purification methods. In this work, we have revealed the

versatility of compounds 5.5 in reactions with carbon, oxygen and sulfur nucleophiles to

afford good yields of the respective thioamides, thiocarbamates and dithiocarbamates.









Alkyl/Arylthiocarbamoylbenzotriazoles 5.5 were easily obtained and in high yields

from bis(benzotriazolyl)methanethione 5.3, a stable solid that behaves as a thiophosgene

equivalent without the inconveniences that originate from working with thiophosgene

itself.

5.4 Experimental Section

Melting points were determined on a hot-stage apparatus and are uncorrected. 1H

(300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 MHz NMR

spectrometer in chloroform-d solution unless stated. Column chromatography was

performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone

ketyl prior to use. Commercially available Grignards and organolithium reagents were

used for the preparation of thioamides. Organolithium reagents were prepared following

literature methods [790R; 820R]. The organometallic reactions were performed under a

nitrogen atmosphere and in oven dried glassware.

5.4.1 General Procedure for the Preparation of 1-Alkyl- and 1-Aryl-
thiocarbamoylbenzotriazoles 5.5a-k

Bisbenzotriazol-1-yl methanethione 5.3 [78JOC337] (0.90 g, 3.21 mmol) was

dissolved in 20 mL methylene chloride at room temperature. The appropriate primary or

secondary amine (3.21 mmol) was added dropwise and the mixture was stirred for 18 h.

The solvent was removed under vacuum and ethyl acetate was added. The organic

solution was washed with 5% aqueous sodium carbonate (40 ml x 5), water, brine, dried

over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave

the pure product or a mixture, which was further purified either by re-crystallization or

column chromatography.









Benzotriazole-1-carbothioic acid cyclohexylamide (5.5a): Colorless cubes (from

EtOAc/Hexanes), (85%) mp 128.0-130.00C (Lit. mp 72-730C) [04JOC2976]. H NMR

6 1.21-1.58 (m, 5H), 1.65-1.90 (m, 3H), 2.13-2.30 (m, 2H), 4.39-4.54 (m, 1H), 7.47 (t,

J= 7.7 Hz, 1H), 7.63 (t, J= 7.7 Hz, 1H), 8.09 (d, J= 8.4 Hz, 1H), 8.90-9.10 (m, 2H). 13C

NMR 6 24.6, 25.3, 31.6, 53.6, 116.1, 120.1, 125.5, 130.1, 132.4, 147.0, 173.0. Anal.

Calcd. For C13H16N4S: C, 59.97; H, 6.19; N, 21.52. Found: C, 60.07; H, 6.32; N, 21.60.

Benzotriazole-1-carbothioic acid (furan-2-ylmethyl)amide (5.5b): Purified by

column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as brown

needles (94%), mp 118.9-120.00C (Lit. mp 117-1190C) [04JOC2976]. H NMR 6 5.04

(d, J= 5.1 Hz, 2H), 6.38-6.46 (m, 2H), 7.44-7.52 (m, 2H), 7.62-7.70 (m, 1H), 8.10 (d, J

= 8.1 Hz, 1H), 8.91 (d, J= 8.4 Hz, 1H), 9.30 (s, 1H). 13C NMR 6 41.8, 103.4, 109.4,

110.7, 116.0, 120.4, 125.8, 130.5, 143.0, 147.1, 148.5, 174.3. Anal. Calcd. For

C12HioN40S: C, 55.80; H, 3.90; N, 21.69. Found: C, 56.10; H, 3.86; N, 21.70.

Benzotriazole-1-carbothioic acid ((R)-1-phenylethyl)amide (5.5c): Purified by

column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow oil

(87%) [04JOC2976]. 1HNMR6 1.74-1.76 (m, 3H), 5.78-5.81 (m, 1H), 7.21-7.65 (m,

7H), 8.00-8.13 (m, 1H), 8.82-8.98 (m, 1H), 9.22-9.41 (m, 1H). 13C NMR 6 21.0, 54.0,

116.0, 120.1, 125.6, 126.4, 127.9, 128.8, 130.2, 132.3, 141.0, 147.0, 173.3. Anal. Calcd.

For C15H14N4S: C, 63.80; H, 5.00; N, 19.84. Found: C, 63.63; H, 4.95; N, 19.82.

Benzotriazole-1-carbothioic acid phenethyl-amide (5.5d): White needles (from

EtOAc/Hexanes), (89%), mp 112.3-113.30C. H NMR6 3.12 (t, J= 6.9 Hz, 2H),

4.07-4.14 (m, 2H), 7.22-7.39 (m, 5H), 7.43-7.51 (m, 1H), 7.60-7.68 (m, 1H), 8.05-8.11

(m, 1H), 8.88-8.96 (m, 1H), 9.14 (s, 1H). 13C NMR 6 34.1, 46.1, 116.0, 120.2, 125.7,









127.0, 128.7, 128.9, 130.3, 132.4, 137.8, 147.0, 174.4. Anal. Calcd. For C15H14N4S: C,

63.80; H, 5.00; N, 19.84. Found: C, 63.81; H, 4.90; N, 19.70.

Benzotriazole-1-carbothioic acid tert-butyl amide(5.5e): Purified by column

chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow needles

(60%), mp 61.3-63.0C. 1HNMR 6 1.71 (s, 9H), 7.45 (t, J= 7.8 Hz, 1H), 7.59-7.64 (m,

1H), 8.07 (d, J = 8.4 Hz, 1H), 8.91 (d, J = 8.7 Hz, 1H), 9.05 (s, 1H). 13C NMR 6 27.9,

55.5, 103.3, 116.4, 120.1, 125.4, 130.0, 132.2, 147.1, 172.6. Anal. Calcd. For

CllH14N4S: C, 56.38; H, 6.02; N, 23.91. Found: C, 56.31; H, 5.93; N, 24.10.

Benzotriazole-1-carbothioic acid (1,5-dimethylhexyl)amide (5.5f): Purified by

column chromatography with hexanes/EtOAc = 94:6 as eluent and obtained as yellow oil

(87%), [04JOC2976]. 1HNMR 6 0.87 (d, J= 6.3 Hz, 6H), 1.22-1.85 (m, 10H),

4.60-4.75 (m, 1H), 7.42-7.51 (m, 1H) 7.58-7.68 (m, 1H), 8.04-8.12 (m, 1H), 8.89-8.98

(m, 2H). 13CNMRv6 19.5, 22.5, 23.7, 27.8, 36.1, 38.6, 51.0, 116.1, 120.1, 125.5, 130.1,

132.4, 147.0, 173.3. Anal. Calcd. For C15H22N4S: C, 62.03; H, 7.64; N, 19.29. Found: C,

62.47; H, 7.84; N, 19.70.

Benzotriazole-1-carbothioic acid N-butyl-N-methylamide (5.5g): Purified by

column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow oil

(76%). H NMR 6 0.76 (t, J= 7.4 Hz, 3H), 1.02 (t, J= 7.5 Hz, 3H), 1.10- 1.18 (m, 2H),

1.43-1.55 (m, 2H), 1.64-1.76 (m, 2H), 1.82-1.93 (m, 2H), 3.23 (s, 3H), 3.49-3.59 (m,

5H), 4.09 (t, J= 7.7 Hz, 2H), 7.42 (t, J= 7.7 Hz, 2H), 7.58 (t, J= 7.7 Hz, 2H), 7.99-8.10

(m, 4H). 13C NMR 6 13.2, 13.6, 19.4, 19.8, 27.4, 30.0, 41.4, 42.0, 55.6, 55.7, 113.2,

113.6, 119.5, 124.8, 128.6, 128.7, 132.9, 133.1, 145.6, 174.8, 175.3. Anal. Calcd. For

C12H16N4S: C, 58.04; H, 6.49; N, 22.56. Found: C, 57.81; H, 6.41; N, 22.85.









1H-1,2,3-benzotriazol-1-yl(2,3-dihydro-lH-indol-1-yl)methanethione (5.5h):

Purified by column chromatography with hexanes/EtOAc = 91:9 as eluent and obtained

as yellow flakes (84%), mp 123.0-124.00C. H NMR in DMSO 6 3.16 (s, 1H), 3.26 (t, J

= 7.7 Hz, 2H), 4.53 (t, J= 7.5 Hz, 2H), 7.02 (s, 1H), 7.14 (t, J= 7.4 Hz, 1H), 7.41 (d, J=

7.5 Hz, 1H), 7.53-7.58 (m, 1H), 7.68-7.73 (m, 1H), 7.99 (d, J= 8.4 Hz, 1H), 8.19-8.22

(m, 1H). 13C NMR in DMSO 8 26.6, 56.7, 112.7, 115.9, 119.5, 125.2, 125.7, 126.0,

126.6, 129.2, 131.4, 135.5, 140.9, 145.1, 168.8. Anal. Calcd. For C15H12N4S: C, 64.26;

H, 4.31; N, 19.98. Found: C, 64.26; H, 4.21; N, 20.15.

Benzotriazol-1-yl-piperidin-1-yl-methanethione (5.5i): Yellow prisms (from

EtOAc/Hexanes), (76%), mp 86.0-87.0C. 1H NMR 6 1.71-2.03 (m, 6H), 3.60 (s, 2H),

4.33 (s, 2H), 7.41-7.47 (m, 1H), 7.57-7.62 (m, 2H), 8.07 (d, J= 9 Hz, 2H). 13C NMR 6

24.0, 25.4, 26.8, 52.7, 53.4, 113.7, 119.8, 125.0, 128.8, 133.3, 146.0, 174.1. Anal. Calcd.

For C12H14N4S: C, 58.51; H, 5.73; N, 22.74. Found: C, 58.88; H, 5.73; N, 22.95.

Benzotriazole-1-carbothioic acid methyl-phenyl-amide (5.5j): Colorless plates

(from EtOAc/Hexanes), (92%), mp 137.7-138.10C. H NMR6 3.96 (s, 3H), 7.01-7.10

(m, 2H), 7.15-7.26 (m, 3H), 7.36-7.42 (m, 1H), 7.56-7.61 (m, 1H), 7.94 (d, J= 8.4 Hz,

1H), 8.13 (d, J= 8.4 Hz, 1H). 13C NMR 6 46.0, 113.0, 119.8, 124.6, 124.8, 127.7, 128.8,

129.4, 133.0, 145.4, 145.5, 175.7. Anal. Calcd. For C14H12N4S: C, 62.66; H, 4.51; N,

20.88. Found: C, 63.00; H, 4.49; N, 20.97.

[(Benzotriazole-1-carbothioyl)-amino]-acetic acid methyl ester (5.5k): Purified

by column chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as cream

color flakes (76%), mp 129.0-130.0C. 1HNMR 6 3.87 (s, 3H), 4.62 (d, J= 3.6 Hz,

2H), 7.50 (t, J= 7.5 Hz, 1H), 7.68 (t, J= 7.5 Hz, 1H), 8.12 (d, J= 8.1 Hz, 1H), 8.86 (d, J









= 8.7 Hz, 1H), 9.53 (s, 1H). 1C NMR 6 46.2, 52.8, 115.8, 120.4, 125.8, 130.5, 132.3,

147.0, 168.5, 174.7.

5.4.2 General Procedure for the Preparation of Mono-substituted Thioamides 5.9a-f

The desired thiocarbamoylbenzotriazole 5.5 (0.495 mmol) was dissolved in 10 mL

dry THF under nitrogen atmosphere. The desired Grignard or organolithium reagent

(1.24 mmol) was added dropwise at room temperature and the reaction mixture was

stirred for 16 h. Water was added and was extracted with ethyl acetate (20 mL x3). The

organic layers were combined, washed with water, washed with 10% sodium carbonate

solution (35 mL x 5), washed with brine, dried over sodium sulfate, and filtered.

Concentration under reduced pressure gave the pure product or a mixture, which was

further purified either by re-crystallization or column chromatography.

N-Cyclohexylbenzenecarbothioamide (5.9a): Purified by column

chromatography with hexanes/EtOAc = 91:9 as eluent and obtained as yellow

microcrystals (87%), mp 84.4-86.20C, (Lit. mp 91.0-92.0C) [49JOC962]. 1H NMR 6

1.19-1.60 (m, 5H), 1.62-1.85 (m, 3H), 2.17-2.25 (m, 2H), 4.48-4.61 (m, 1H), 7.33-7.49

(m, 4H), 7.68-7.74 (m, 2H). 13C NMR 6 24.6, 25.5, 31.6, 54.8, 126.5, 128.5, 130.9,

142.4, 197.7. Anal. Calcd. For C13H17NS: C, 71.18; H, 7.81; N, 6.39. Found: C, 70.96;

H, 7.94; N, 6.48.

N-(2-Furylmethyl)hexanethioamide (5.9b): Brown oil (99%). 1H NMR 6 0.89

(t, J= 7.2 Hz, 3H), 1.25-1.40 (m, 4H), 1.72-1.83 (m, 2H), 2.66 (t, J= 7.8 Hz, 2H), 4.82

(d, J= 4.8 Hz, 2H), 6.33-6.37 (m, 2H), 7.39-7.45 (m, 2H). 13C NMR 6 13.9, 22.3, 29.0,

31.0, 42.9, 47.0, 108.9, 110.6, 142.6, 149.1, 205.8. Anal. Calcd. For C11H17NOS: C,

62.52; H, 8.11; N, 6.63. Found: C, 62.86; H, 8.43; N, 6.63.









N-(tert-Butyl)-2-furancarbothioamide (5.9c): Purified by column

chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as brown oil (47%),

(Lit. mp 45.0-46.0C) [89BSB327]. 'H NMR 6 1.65 (s, 9H), 6.44-6.46 (m, 1H), 7.33 (d,

J= 3.6 Hz, 1H), 7.39-7.40 (m, 1H), 7.82 (s, 1H). 13C NMR6 28.0, 55.5, 113.1, 116.8,

143.0, 153.2, 181.3. Anal. Calcd. For C9H13NOS: C, 59.82; H, 7.15; N, 7.64. Found: C,

59.22; H, 7.29; N, 7.93.

N-(1,5-Dimethylhexyl)-thiobenzamide (5.9d): Purified by column

chromatography with hexanes/EtOAc = 92:8 as eluent and obtained as yellow oil (56%).

H NMR 6 0.88 (d, J= 6.6 Hz, 6H), 1.21-1.70 (m, 10H), 4.72-4.77 (m, 1H), 7.34-7.47

(m, 4H), 7.67-7.70 (m, 2H). 13C NMR 6 19.4, 22.5, 23.7, 27.8, 36.2, 38.7, 52.0, 126.5,

128.4, 130.8, 142.4, 198.0. Anal. Calcd. For C15H23NS: C, 72.23; H, 9.29; N, 5.62.

Found: C, 72.00; H, 9.50; N, 5.90.

4-Methoxy-N-((R)-1-phenyl-ethyl)thiobenzamide (5.9e): Purified by column

chromatography with hexanes/EtOAc = 9:1 as eluent and obtained as yellow needles

(85%), mp 89.0-91.0C, [77CB730]. 1H NMR 6 1.68 (d, J= 6.6 Hz, 3H), 3.81 (s, 3H),

5.88-5.94 (m, 1H), 6.84 (d, J= 8.7 Hz, 2H), 7.25-7.42 (m, 5H), 7.62-7.74 (m, 3H). 13C

NMRR6 20.2, 55.0, 55.4, 113.5, 126.5, 127.7, 128.4, 128.8, 134.2, 141.5, 162.1, 196.8.

Anal. Calcd. For C16H17NOS: C, 70.81; H, 6.31; N, 5.16. Found: C, 70.78; H, 6.27; N,

5.11.

N-Cyclohexyl-2-pyridinecarbothioamide (5.9f): Purified by column

chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as yellow oil (35%).

1HNMR 6 1.25-1.90 (m, 8H), 2.13-2.29 (m, 2H), 4.52-4.68 (m, 1H), 7.46 (t, J= 5.7

Hz, 1H), 7.87 (t, J= 7.8 Hz, 1H), 8.53 (d, J= 4.5 Hz, 1H), 8.76 (d, J= 8.1 Hz, 1H), 10.13









(s, 1H). 13C NMR 6 24.6, 25.6, 31.4, 53.8, 124.9, 125.8, 137.1, 146.8, 151.2, 188.8.

Anal. Calcd. For C12H16N2S: C, 65.41; H, 7.32; N, 12.71. Found: C, 65.79; H, 7.58; N,

12.57.

5.4.3 General Procedure for the Preparation of Di-substituted Thioamides 5.9g-j

The desired thiocarbamoylbenzotriazole 5.5 (0.495 mmol) was dissolved in 10 mL

dry THF under nitrogen atmosphere. The desired Grignard or organolithium reagent

(0.743 mmol) was added dropwise at room temperature and the reaction mixture was

stirred for 16 h. Water was added and was extracted with ethyl acetate (20 mL x3). The

organic layers were combined, washed with water, washed with 10% sodium carbonate

solution (35 mL x 5), washed with brine, dried over sodium sulfate, and filtered.

Concentration under reduced pressure gave the pure product or a mixture, which was

further purified either by re-crystallization or column chromatography.

N-Butyl-N-methyl-3-butenethioamide (5.9g): Purified by column

chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as brown oil (98%).

1HNMR 6 0.93-1.02 (m, 6H), 1.30-1.43 (m, 4H), 1.60-1.75 (m, 4H), 3.25 (s, 3H), 3.43

(s, 3H), 3.53-3.67 (m, 6H), 3.99 (t, J= 7.8 Hz, 2H), 5.11-5.22 (m, 4H), 5.90-6.80 (m,

2H). 13C NMR 6 13.6, 13.7, 19.8, 19.9, 27.6, 30.1, 39.5, 42.4, 47.8, 48.8, 54.2, 55.7,

116.8, 117.0, 132.7, 133.5, 199.9. Anal. Calcd. For C9H17NS: C, 63.10; H, 10.00; N,

8.18. Found: C, 62.89; H, 10.30; N, 8.40.

1-Piperidino-1-pentanethione (5.9h): Purified by column chromatography with

hexanes/EtOAc = 95:5 as eluent and obtained as yellow oil (55%) [65BSF3623]. 1H

NMR 6 0.94 (t, J= 7.4 Hz, 3H), 1.39-1.74 (m, 10H), 3.30 (t, J= 7.5 Hz, 2H), 3.90 (s,

2H), 4.29 (s, 2H). 13C NMR 6 13.7, 22.1, 24.3, 26.0, 30.7, 37.0, 52.5, 196.1.









Piperidino(2-thienyl)methanethione (5.9i): Purified by column chromatography

with hexanes/EtOAc = 91:9 as eluent and obtained as yellow microcrystals (53%), mp

84.6-86.00C, (Lit. mp 890C) [65CB829]. H NMR in DMSO 6 1.67 (s, 6H), 3.83 (s,

2H), 4.21 (s, 2H), 7.04 (t, J= 4.2 Hz, 1H), 7.14 (d, J= 3.9 Hz, 1H), 7.68 (d, J= 5.1 Hz,

1H). 13C NMR in DMSO 6 23.8, 25.8, 26.8, 51.9, 52.9, 125.6, 126.8, 129.7, 145.0,

188.7. Anal. Calcd. For C10H13NS2: C, 56.83; H, 6.20; N, 6.63. Found: C, 56.96; H,

6.27; N, 6.55.

N-Methyl-N-phenyl-3-butenethioamide (5.9j): Purified by column

chromatography with hexanes/EtOAc = 85:15 as eluent and obtained as brown oil (78%).

1H NMR 6 3.30 (d, J= 6.6 Hz, 2H), 3.74 (s, 3H), 4.82-4.89 (m, 2H), 5.03 (d, J= 9.9 Hz,

1H), 5.89-6.02 (m, 1H), 7.17-7.20 (m, 2H), 7.38-7.50 (m, 3H). 13C NMR 6 45.8, 48.5,

116.9, 125.7, 128.6, 129.8, 134.3, 145.3, 202.7. Anal. Calcd. For CjlH13NS: C, 69.06; H,

6.85; N, 7.32. Found: C, 69.18; H, 7.14; N, 7.53.

5.4.4 General Procedure for the Preparation of Di-substituted Thiocarbamates 5.10a-b

The desired thiocarbamoylbenzotriazole 5.5 (0.36 mmol) was dissolved in 7 mL

methylene chloride. In another flask, the desired alcohol (0.36 mmol) and NaH (0.17 g,

4.32 mmol) were stirred for 10 min in 7 mL methylene chloride. The sodium salt

solution was added to the thiocarbamoylbenzotriazole solution and the mixture was

stirred for 18 h. The solvent was removed under vacuum; water was added and extracted

with ethyl acetate (2 x 25 mL). The organic layer was washed with water, 10% sodium

carbonate solution (2 x 30 mL), dried over sodium sulfate, and filtered. Concentration

under reduced pressure gave the pure product or a mixture, which was further purified

either by re-crystallization or column chromatography.









O-Benzhydryl- 1-indolinecarbothioate (5.10a): Colorless prisms (from

EtOAc/Hexanes), (59%), mp 150.5-153.70C. H NMR 6 3.12 (t,J= 8.4 Hz, 2H), 4.40

(t, J= 8.4 Hz, 2H), 6.99-7.42 (m, 12H), 7.76-7.87 (m, 2H). 13C NMR 6 26.6, 54.2, 83.9,

117.7, 124.3, 125.5, 127.6, 127.7, 128.0, 128.5, 133.6, 139.6, 141.3, 184.0. Anal. Calcd.

For C22H19NOS: C, 76.49; H, 5.54; N, 4.05. Found: C, 76.62; H, 5.55; N, 4.04.

O-Benzhydryl N-methyl-N-phenylcarbamothioate (5.10b): Colorless plates

(from acetone), (60%), mp 102.2-103.20C. 1H NMR 6 3.62 (s, 3H), 7.09-7.49 (m,

16H). 13C NMR 6 44.0, 83.3, 126.1, 126.8, 127.6, 128.3, 129.2, 130.0, 140.3, 143.5,

187.3. Anal. Calcd. For C21H19NOS: C, 75.64; H, 5.74; N, 4.20. Found: C, 75.65; H,

5.91; N, 4.17.

5.4.5 General Procedure for the Preparation of Di-substituted Dithiocarbamate 5.11a

The desired thiocarbamoylbenzotriazole 5.5 (0.32 mmol) was dissolved in 7 mL

methylene chloride. In another flask, the desired mercapto reagent (0.36 mmol) and NaH

(0.02 g, 0.49 mmol) were stirred for 10 min in 7 mL methylene chloride. The sodium salt

solution was added to the thiocarbamoylbenzotriazole solution and the mixture was

stirred for 18 h. The solvent was removed under vacuum; water was added and extracted

with ethyl acetate (2 x 25 mL). The organic layer was washed with water, 10% sodium

carbonate solution (2 x 30 mL), dried over sodium sulfate, and filtered. Concentration

under reduced pressure gave the pure product or a mixture, which was further purified

either by re-crystallization or column chromatography.

3-Methoxyphenyl-l-indolinecarbodithioate (5.11a): Purified by column

chromatography with hexanes/EtOAc = 92:8 as eluent and obtained as orange powder

(99%), mp 103.6-105.0C. H NMR in DMSO at 70 oC 6 3.23 (t, J= 8.1 Hz, 2H), 3.79









(s, 3H), 4.56 (t, J= 7.5 Hz, 2H), 7.04-7.43 (m, 5), 7.34-7.43 (m, 2H), 8.93 (d, J= 8.1

Hz, 1H). 13C NMR in DMSO at 70 0C 6 26.7, 54.8, 55.1, 115.8, 117.7, 121.7, 125.0,

125.1, 126.0, 128.5, 129.6, 131.0, 135.0, 143.2, 159.3, 190.5. Anal. Calcd. For

C16H15NOS2: C, 63.75; H, 5.02; N, 4.65. Found: C, 63.38; H, 5.03; N, 4.28.

5.4.6 General Procedure for the preparation of Mono-substituted Dithiocarbamates
5.11b-d

The desired mono-substituted thiocarbamoylbenzotriazole 5.5 (0.36 mmol) was

dissolved in 7 mL methylene chloride. The desired mercapto reagent (0.36 mmol) was

added dropwise followed by exactly one equivalent of triethyl amine (0.36 mmol). The

reaction mixture was stirred for 16 h. The solvent was removed under vacuum; water

was added and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed

with water, dried over sodium sulfate, and filtered. Concentration under reduced pressure

gave a mixture that was further purified either by re-crystallization or column

chromatography.

3-Methoxyphenyl N-(2-furylmethyl)carbamodithioate (5.11b): Purified by

column chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as colorless

prisms (83%), mp 73.2-74.70C. 1HNMR 3.81 (s, 3H), 4.82 (d, J= 4.8 Hz, 2H), 6.22 (s,

1H), 6.30 (s, 1H), 6.94-7.16 (m, 4H), 7.26-7.30 (m, 1H), 7.40 (t, J= 7.8 Hz, 1H). 13C

NMR 43.02, 55.5, 108.6, 110.5, 117.6, 119.7, 127.3, 129.3, 131.3, 142.6, 148.8, 160.6,

195.0. Anal. Calcd. For C13H13NO2S2: C, 55.89; H, 4.69; N, 5.01. Found: C, 55.90; H,

4.71; N, 5.01.

Benzyl N-cyclohexylcarbamodithioate (5.11c): Purified by column

chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as colorless crystals

(92%), mp 70.2-71.0C, (Lit. mp 66-67C) [69ABC1367]. H NMR in DMSO 6









1.05-1.35 (m, 5H), 1.55-1.62 (m, 1H), 1.67-1.76 (m, 2H), 1.84-1.95 (m, 2H), 4.25 (s,

1H), 4.49 (s, 2H), 7.20-7.42 (m, 5H), 9.86 (d, J= 7.2 Hz, 1H). 13C NMR in DMSO 6

24.7, 25.1, 31.0, 38.0, 56.0, 127.1, 128.5, 129.0, 137.5, 194.1. Anal. Calcd. For

C14H19NS2: C, 63.35; H, 7.21; N, 5.28. Found: C, 63.42; H, 7.38; N, 5.22.

Phenyl N-phenethylcarbamodithioate (5.11d): Purified by column

chromatography with hexanes/EtOAc = 95:5 as eluent and obtained as colorless crystals

(60%), (Lit. mp 73-740C) [63AP310]. H NMR 6 2.82 (t, J= 6.6 Hz, 2H), 3.87 (q, J=

6.3 Hz, 2H), 6.55 (s, 1H), 6.94-6.97 (m, 2H), 7.20-7.22 (m, 3H), 7.37-7.39 (m, 4H),

7.42-7.50 (m, 1H). 13C NMR 6 33.6, 46.9, 126.6, 128.0, 128.4, 128.8, 130.3, 131.0,

135.4, 137.5, 194.8. Anal. Calcd. For C15H15NS2: C, 65.89; H, 5.53; N, 5.12. Found: C,

65.38: H. 5.50: N. 6.01.














CHAPTER 6
CONCLUSION

Benzotriazole proved to be a good synthetic auxiliary for the preparation of

biologically important compounds. In chapter 2 the synthesis of 2,4-benzodiazepin-1-

ones (2.13) was achieved utilizing simple chemistry. We have showed that N, N-

bis(benzotriazolylmethyl)alkyl amines (2.9) are a good di-cation source.

An efficient methodology for sulfonylation was introduced in chapter 3. Both

sulfonamides and sulfonylbenzotriazoles were synthesized in good yields. Sulfonamides

were prepared from novel sulfonylbenzotriazoles (3.27), which are excellent sulfonyl

chloride analogues.

Using a simple procedure, alkyl sulfonamides, ethylene sulfonamides and a

sulfonate ester were synthesized through 1-[2-benzotriazol-1-

yl)ethyl]sulfonylbenzotriazole (4.5) intermediate (Chapter 4). The benzotriazole

intermediate (4.5) is convenient to use, avoiding the difficulty in handling and the

excessive reactivity of the commonly used 2-chloroethanesulfonyl chloride.

A new procedure was developed for the preparation of thioamides, thiocarbamates

and dithiocarbamates that does not require rigorous reaction conditions (Chapter 4). This

procedure utilizes bis(benzotriazolyl)methanethione (5.3), where both of the

benzotriazole molecules are displaced by different nucleophiles.

Bis(benzotriazolyl)methanethione (5.3) showed to be an excellent thiocarbonyl transfer

agent.















REFERENCES


The reference citation system employed throughout this dissertation is that from

Comprehensive Heterocyclic Chemistry II (Vol.1) Pergamon Press, 1996 (Eds. Katritzky,

A. R.; Rees, C. W. and Scriven, E.).

Each time a reference is cited, a number-letter code is designated to the

corresponding reference with the first two (or four if the reference is before 1910's)

number indicating the year followed by the letter code of the journal and the page number

in the end.

Additional notes to this reference system are as follows:

(i) Each reference code is followed by the conventional literature citation in the
ACS style.
(ii) Journals which are published in more than one part, or more than one volume
per year, include in the abbreviation cited the appropriate part or volume
number.
(iii) Less commonly used books and journals are coded as "MI" for miscellaneous.
(iv) The list of the reference is arranged according to the designated code in the
order of (a) year; (b) journal in alphabetical order; (c) part number or volume
number if it is included in the code; (d) page number.
(v) Using project number to code the unpublished results.









[42CB42]

[49JOC962]


[63AP310]


[65BSF3623]


[65CB829]

[69ABC1367]


[69JCS(C)1474]

[69JCS(C)1478]

[69JCS(CC)365]

[71JIC791]

[75MI_675]



[76MI_573]

[78JA4634]

[78JOC337]

[79COC345]


[79JOC160]

[790R]


[80JA853]


[80JOC3713]


Asinger; F.; Ebeneder; F.; Boeck, E. Chem. Ber. 1942, 42.

Alliger, G.; Smith, G. E.P.; Carr, E. L.; Stevens, H. P. J. Org.
Chem. 1949, 14, 962.

Rieche, A.; Hilgetag, G.; Martin, D.; Kreyzi, I. Arch. Pharm. 1963,
296, 310.

Reynaud, P.; Moreau, R.C.; Samama, J.P. Bull. Soc. Chim. Fr.
1965, 3623.

Meyer, R.; Scheithauer, S. Chem. Ber. 1965, 829.

Wakamori, S.; Yoshida, Y; Ishii, Y. Agric. Biol. Chem. 1969,
1367.

Rees, C. W.; Storr, R. C. J. Chem. Soc. (C) 1969, 1474.

Rees, C. W.; Storr, R. C. J. Chem. Soc. (C) 1969, 1478.

Iles, D. H.; Ledwith, A. J. Chem. Soc. (CC) 1969, 365.

Ginwala, K. K.; Trivedi, J. P. J. Indian Chem. Soc. 1971, 48, 791.

Casida, J. E.; Kimmel, E. C.; Lay, M.; Ohkawa, H.; Rodebush, J.
E.; Gray, R. A.; Tseng, C. K.; Tilles, H. Environmental Quality
and Safety Supplement 1975, 3, 675.

Keating, J. T.; Skell, P. S. Carbonium Ions 1976, 2, 573.

Masilamani, D.; Rogic, M. M. J. Am. Chem. Soc. 1978, 100, 4634.

Larsen, C.; Steliou, K.; Harpp, D. N. J. Org. Chem. 1978, 43, 337.

Andersen, K. K. In Comprehensive Organic Chemistry; Jones, D.
N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3, p 345.

Pinnick, H. W.; Reynold, M. A. J. Org. Chem. 1979, 44, 160.

Gschwend, H. W.; Rodriguez, H. R. In Organic Reactions; John
Wiley & Sons, Inc.: New York, 1979; Vol. 26, Ch 1.

Collins, C. J.; Hombach, H.-P.; Maxwell, B.; Woody, M. C.;
Benjamin, B. M. J. Am. Chem. Soc. 1980, 102, 853.

Larsen, C.; Harpp, D. N. J. Org. Chem. 1980, 45, 3713.










[81JOC5077]

[820R]


[83CPB1374]


[83S791]

[83S816]


[83S822]

[84JMC711]

[85MI_587]



[86JMC104]


[86S1031]

[87H101]


[87H1313]


[87JCS(P1)799]


[87S487]


[87TL1101]

[88H323]

[88JMC2235]


Scully, F. E.; Bowdring, K. J. Org. Chem. 1981, 46, 5077.

Biellmann, J. -F.; Ducep, J. -B. Organic Reactions; John Wiley
& Sons, Inc.: New York, 1982; Vol. 27, Ch 1.

Nishikawa, M.; Inaba, Y.; Furukawa, M. Chem. Pharm. Bull.
1983, 31, 1374.

Singh, H.; Aggarwal, S. K.; Malhotra, N. Syi)hei, 1983, 791.

Aumaitre, G.; Chanet-Ray, J.; Durand, J.; Vessiere, R. Syi)ihei,
1983, 10, 816.

Breant, P.; Marsais, F.; Queguiner, G. Synthesis 1983, 822.

Hanzlik, R. P.; Thompson, S. A. J. Med. Chem. 1984, 27, 711;

Shepard, C. C.; Jenner, P. J.; Ellard, G. A.; Lancaster, R. D.
International Journal of Leprosy and Other Mycobacterial
Diseases 1985, 53, 587.

Thompson, S. A.; Andrews, P. R.; Hanzlik, R. P. J. Med. Chem.
1986, 29, 104.

Graham, S. L.; Scholz, T. H. Sy)uhi, 1986, 12, 1031.

Chanet-Ray, J.; Vessiere, R.; Zeroual, A. Heterocycles 1987, 26,
101.

Kato, H.; Tani, K.; Kuiumisawa, H.; Tamura, Y. Heterocycles
1987, 1313.

Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Chem. Soc., Perkin
Trans. 1 1987, 799.

Koziara, A.; Osowska-Pacewika, K.; Zawadzki, S.; Zwierzak, A.
Syi)1heii 1987, 487.

Carretero J. C.; Ghosez, L. Tetrahedron Lett. 1987, 28, 1101.

Iwataka, C.; Watanabe, M.; Okamoto, S.; Fujimoto, M.; Sakae, M.
Heterocycles 1988, 323.
Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen,












[89BSB327]


[89JHC1807]


[89MI_158]


[90CJC446]

[90CRV879]

[90JAE293]


[90JCS(P1)541]


[90MI_255]



[90T6951]

[91AP367]

[91JOC3549]

[92JOC4775]

[92T7817]


[94H345]


[94JA5077]


[94SC205]


T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J.
Med. Chem. 1988, 31, 2235.

Jagodzinski, T. D.; Dziembowska, T. M.; Szczodrowska, B. Bull.
Soc. Chim. Belg. 1989, 327.

Cho, N. S.; Song, K. Y.; Parkanyi, C. J. Heterocycl. Chem. 1989,
26, 1807.

Koschansky, J.; Feldmesser, J. Journal of Nematology 1989, 21,
158.

Katritzky, A. R.; Rachwal, S.; Wu, J. Can. J. Chem. 1990, 68, 446.

Snieckus, V. Chem. Rev. 1990, 90, 879.

Kochansky, J.; Cohen, C. F. J. ofAgricultural Entomology 1990, 7,
293.

Katritzky, A. R.; Pitarski, B.; Urogdi, L. J. Chem. Soc., Perkin
Trans. 1 1990, 541.

Hansch, C.; Sammes, P. G.; Taylor, J. B. In Comprehensive
Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol. 2,
Chapter 7.1, p 255.

Simpkins, N. S. Tetrahedron, 1990, 46, 6951.

Mohrle, H.; Lessel, J. Arch. Pharm. 1991, 324, 367.

Morris, J.; Wishka, D. G.; J. Org. Chem. 1991, 56, 3549.

0' Connell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57, 4775.

Katritzky, A. R.; Shobana, N.; Pernak, J.; Afridi, A. S.; Fan, W-Q.
Tetrahedron 1992, 48, 7817.

Katritzky, A. R.; Gupta, V.; Garot, C.; Stevens, C. V.; Gordeev, M.
F. Heterocycles 1994, 38, 345.

McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.;
Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.;
Thorsett, E. D.; Tischler, M.; Webb II, R. R.; Venuti, M. C. J. Am.
Chem. Soc. 1994, 116, 5077.

Katritzky, A. R.; Zhang, G.; Wu, J. Synth. Commun. 1994, 24, 205.










[95CB1195]

[95JMC3193]


[95MI_1021]




[96AAC1600]


[96JOC3117]


[97JOC1240]


[97SL1253]


[98MI_2203]


[98CRV409]


[98H2535]


[98JA10994]



[98JEM725]


[98JOC8021]


[98SC1721]

[98TL6835]


Lube, A.; Neumann, W. P.; Niestroj, M. Chem. Ber. 1995, 1195.

Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. J. Med. Chem.
1995, 38, 3193.

Gilmore, J.; Gallagher, P. T. In Comprehensive Organic
Functional Group Transformations, 1st ed.; Katritzky, A. R., Meth-
Cohn, 0., Rees, C. W., Eds.; Elsevier Science Ltd.: New York,
1995; Vol. 5, p 1021.

Rosenthal, P. J.; Olson, J. E.; Lee, G. K.; Palmer, J. T.; Klaus, J.
L.; Rasnick, D. Antimicrob. Agents Chemother. 1996, 1600.

Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem. 1996,
61, 3117.

Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J.
Org. Chem. 1997, 62, 1240.

Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J. S. Synlett 1997,
1253.

Alber, R.; Knecht, H.; Andersen, E.; Hungerford, V.; Schreier, M.
H.; Papageorgiou, C. Bioorg. Med. Chem. Lett. 1998, 8, 2203.

Katritzky, A.R.; Lan, X.; Yang, J.; Denisko, 0. V. Chem. Rev.
1998, 98, 409.

Katritzky, A. R.; Feng, Y.; Qi, M.; Feng, D. Heterocycles 1998,
48, 2535.

Roush, W. R.; Gwaltney II, S. L.; Cheng, J.; Scheidt, K. A.;
McKeorrow, J. H.; Hansell, E. J. Am. Chem. Soc. 1998, 120,
10994.

Engel, J. C.; Doyle, P. S.; Hsieh, I.; McKerrow, J. H. J. Exp. Med.
1998, 188, 725.

Hulme, C.; Peng, J.; Tang, S. -Y.; Burns, C. J.; Morize, I.;
Labaudiniere, R. J. Org. Chem. 1998, 63, 8021.

Iyer, S.; Sattar, A. K. Synth. Commun. 1998, 28, 1721.

Katritzky, A. R.; Feng, D.; Qi, M. Tetrahedron Lett. 1998, 39,
6835.










[99JMC3789]



[99JMC4414]



[99JOC290]


[99JOC2914]


[99JOC3328]


[990L577]


[990L1835]

[99TL2623]


[OOJCB513]


[OOJMC3596]







[00JMC4834]



[00JOC8210]


[00JOC8669]


Owa, T.; Yoshino, H.; Okauchi, T.; Yoshimatsu, K.; Ozawa, Y.;
Sugi, N. H.; Nagasu, T.; Koyanagi, N.; Kitoh, K. J. Med. Chem.
1999, 42, 3789.

Grasso, S.; De Sarro, G.; De Sarro, A.; Micale, N.; Zappala, M.;
Puia, G.; Baraldi, M.; De Micheli, C. J. Med. Chem. 1999, 42,
4414.

Damayanthi, Y.; Reddy, B. S. P.; Lown, J. W. J. Org. Chem. 1999,
64, 290.

Juaristi, E.; Leon-Romo, J. L.; Ramirez-Quiros, Y. J. Org. Chem.
1999, 64, 2914.

Katritzky, A. R.; Luo, Z.; Cui, X.-L. J. Org. Chem. 1999, 64,
3328.

Katritzky, A. R.; Monteux, D. A.; Tymoshenko, D. 0. Org. Lett.
1999, 1, 577.

Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org. Lett. 1999, 1, 1835.

Bocelli, G.; Catellani, M.; Cugini, F.; Ferraccioli, R. Tetrahedron
Lett. 1999, 40, 2623.

Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513.

Ursini, A.; Capelli, A. M.; Carr, R. A. E.; Cassara, P.; Corsi, M.;
Curcuruto, 0.; Curotto, G.; Cin, M. D.; Davalli, S.; Donati, D.;
Feriani, A.; Finch, H.; Finizia, G.; Gaviraghi, G.; Marien, M,;
Pentassuglia, G.; Polinelli, S.; Ratti, E.; Reggiani, A.; Tarzia, G.;
Tedesco, G.; Tranquillini, M. E.; Trist, D. G.; Van Amsterdam, F.
T. M. J. Med. Chem. 2000, 43, 3596.

Zappala, M.; Gitto, R.; Bevacqua, F.; Quartarone, S.; Chimirri, A.;
Rizzo, M.; De Sarro, G.; De Sarro, A. J. Med. Chem. 2000, 43,
4834.

Katritzky, A. R.; He, H-Y.; Suzuki, K. J. Org. Chem. 2000, 65,
8210.

Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Zanardi, G. J. Org. Chem. 2000, 65, 8669.









[00OL3555]

[01H1703]


[01JCB90]

[01JOC2784]

[01JOC2850]


[01MI_1000]


[01OL585]

[01SC1803]

[02IF71]


[02JA28]


[02JCB315]


[02JCB491]

[02JMC5136]



[020L2549]


[02SL1928]

[02TL4537]

[02TL8479]

[03JCB775]


Chuang, T. -H.; Sharpless, K. B. Org. Lett. 2000, 2, 3555.

Katritzky, A. R.; Kurz, T.; Zhang, S.; Voronkov, M.; Steel, P. J.
Heterocylcles 2001, 55, 1703.

Pirrung, M. C.; Pansare, S. V. J. Comb. Chem. 2001, 3, 90.

Witt, A.; Bergman, J. J. Org. Chem. 2001, 66, 2784.

Katritzky, A. R.; Wang, X.; Denisenko, A. J. Org. Chem. 2001, 66,
2850.

Jeschke, P.; Harder, A.; Etzel, W.; Gau, W.; Thielking, G.; Bonse,
G.; Linuma, K. Pest Management Sci. 2001, 57, 1000.

Wilson, L. J. Org. Lett. 2001, 3, 585.

Ghiaci, M.; Bakhtiari, K. Synth. Commun. 2001, 1803.

Krinkova, J.; Dolezal, M.; Hartl, J.; Buchta, V.; Pour, M. II
Farmaco 2002, 57, 71.

Yamamoto, Y.; Takagishi, H.; Itoh, K. J. Am. Chem. Soc. 2002,
124, 28.

Theoclitou, M.-E.; Delaet, N. G.; Robinson, L. A. J. Comb. Chem.
2002, 4, 315.

Phoon, C. W.; Sim, M. M. J. Comb. Chem. 2002, 4, 491.

Liegeois, J. F.; Eyrolles, L.; Ellenbroek, B. A.; Lejeune, C.;
Carato, P.; Bruhwyler, J.; Geczy, J.; Damas, J.; Delarge, J. J. Med.
Chem. 2002, 45, 5136.

Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd, D.
B. Org. Lett. 2002, 4, 2549.

Frost, C. G.; Hartely, J. P.; Griffin, D. Synlett 2002, 1928.

Chan, W. Y.; Berthelette, C. Tetrahedron Lett. 2002, 43, 4537.

Baskin, J. M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479.

Ivachtchenko, A. V.; Kovalenko, S. M.; Drushlyak, 0. G. J. Comb.
Chem. 2003, 5, 775.









[03JOC8583]


[03JOC8693]

[030L4755]


[04JOC188]



[04JOC202]


[04JOC2976]


Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin, J. C.;
Deniaud, D. J. Org. Chem. 2003, 68, 8583.

Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org. Chem. 2003, 68, 8693.

Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.; Falck, J. R.
Org. Lett. 2003, 5, 4755.

Shi, J.; Zhang, J.; Grazier, N.; Stein, P. D.; Atwal, K. S.; Traeger,
S. C.; Callahan, S. P.; Malley, M. F.; Galella, M. A.; Gougoutas, J.
Z. J. Org. Chem. 2004, 69, 188.

Isac-Garcia, J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.;
Santoyo-Gonzales, F. J. Org. Chem. 2004, 69, 202.

Katritzky, A. R.; Ledoux, S.; Witek, R. M.; Nair, S. K. J. Org.
Chem. 2004, 69, 2976.















BIOGRAPHICAL SKETCH

Valerie Rodriguez Garcia was born in January 7, 1977, in Rio Piedras, Puerto Rico.

While doing her undergraduate studies in chemistry in the University of Puerto Rico,

Recinto de Rio Piedras, she worked for one year in organic synthesis under the

supervision of Dr. Jorge Colon and Dr. Osvaldo Cox. She obtained her Bachelor of

Science in chemistry in May 2000 and started the PhD program in the Chemistry

Department of the University of Florida in August 2000 with Dr. Alan R. Katritzky.

She married in June 2003 to Igor Schweigert, who is doing his PhD in chemistry

under the supervision of Dr. Rodney Bartlett.