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Benzotriazole-Mediated Synthesis of N-Acylbenzotriazoles and 2H-Azirines

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Benzotriazole-Mediated Synthesis of N-Acylbenzotriazoles and 2H-Azirines
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WILKERSON, CHAVON RENEE ( Author, Primary )
Copyright Date:
2008

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Anions ( jstor )
Carbon ( jstor )
Carboxylic acids ( jstor )
Chlorides ( jstor )
Esters ( jstor )
Molecules ( jstor )
Nitrogen ( jstor )
Oximes ( jstor )
Reagents ( jstor )
Tetrahedrons ( jstor )

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University of Florida
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University of Florida
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Copyright Chavon Renee Wilkerson. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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6/1/2004
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53315919 ( OCLC )

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BENZOTRIAZOLE-MEDIATED SYNTHESIS OF N -ACYLBENZOTRIAZOLES AND 2 H -AZIRINES By CHAVON RENEE WILKERSON A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTERS OF SCIENCE UNIVERSITY OF FLORIDA 2003

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Copyright 2003 by Chavon R. Wilkerson

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This document is dedicated to Larry Jr., Lauren, Lyndsey, and Johnny Jr..

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iv ACKNOWLEDGMENTS I thank my parents, Lana and Larry Wilkerson for their love and continuous support of my career. I thank my sister for her friendship and words of encouragement. I thank all my friends and family for their support. I thank Professor Alan Katritzky for the opportunity to learn, study, and practice chemistry under his advisement.

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v TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES.............................................................................................................vi LIST OF FIGURES..........................................................................................................vii ABSTRACT....................................................................................................................... ..x CHAPTER 1 GENERAL INTRODUCTION....................................................................................1 1.1 Importance of Heterocyclic Chemistry.................................................................1 1.2 Benzotriazole-Mediated Appro ach to Heterocyclic Synthesis.............................3 2 SYNTHESIS OF N-ACYLBENZOTRIAZOLES.....................................................10 2.1 Introduction...........................................................................................................10 2.2 Synthetic Utility Of N -Acylbenzotriazoles...........................................................12 2.3 Results and Discussion.........................................................................................23 2.4 Experimental Methods..........................................................................................26 3 SYNTHESIS OF 2 H -AZIRINES...............................................................................29 3.1 Introduction...........................................................................................................29 3.2 Synthetic Strategies for 2 h -Azirines.....................................................................31 3.3 Benzotriazole Mediated Approach to 2 h -Azirines...............................................37 3.4 Results and Discussion.........................................................................................39 3.3 Conclusion............................................................................................................45 3.4 Experimental Methods..........................................................................................46 4 CONCLUSIONS........................................................................................................50 LIST OF REFERENCES...................................................................................................51 BIOGRAPHICAL SKETCH.............................................................................................60

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vi LIST OF TABLES Table page 1.1 Preparation of N -Alkylbenzotriazoles, RBt...............................................................7 2.1 Synthesis of N -acylbenzotriazoles...........................................................................25 3.1 2 Hazirines 3.28 and their derivatives 3.35, 336, and 3.37 ......................................45

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vii LIST OF FIGURES Figure page 1.1 Heterocycles in living systems...................................................................................1 1.2 Parent benzotriazole molecule....................................................................................3 1.3 Comparison of benzotriaz ole as a leaving group to cyano and phenylsulfonyl.........4 1.4 Benzotriazole is activated to -C-H proton loss........................................................5 1.5 Benzotriazole has electron donor a nd electron acceptor abilities..............................5 1.6 Benzotriazole exists as two isomers of similar stability............................................6 1.7 Reaction of benzotriazole and acid chlorides without base.......................................7 1.8 Conversion of carboxylate anions into N-acylbenzotriazoles mediated by Nsulfonylbenzotriazole.................................................................................................8 1.9 Removal of benzotriazolyl group...............................................................................9 2.1 Resonance hybridization of tertiary amides.............................................................11 2.2 N -acylimidazoles as acylation reagents....................................................................11 2.3 Utility of N -acylbenzotriazoles................................................................................12 2.4 Ring synthesis of substitute d 3,4-dihydro-2-pyrones from N acylbenzotriazoles..13 2.5 Polycyclic heteroaromatics from N -acylbenzotriazoles...........................................13 2.6 Formation of butyrolactones from N -acylbenzotriazoles.........................................14 2.7 Simple conversion of N -acylbenzotriazo les to amides.............................................15 2.8 General synthesis of unsymme trical tetrasubstituted ureas......................................16 2.9 General synthesis of unsymmetr ical tetrasubstituted oxamides...............................16 2.10 Trifluoroacetylated Nacylbenzotriazole as a novel protecting group.....................17

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viii 2.11 Compounds with the Bt-C-O functionality..............................................................18 2.12 Synthesis of 1-(benzotri azol-1-yl)alkyl esters by N -acylbenzotriazoles..................18 2.13 Common reactions of carbonyl com pounds containing an alpha proton.................19 2.14 C-acylation of ketimines by N -acylbenzotriazoles for the synthesis of enaminones...............................................................................................................20 2.15 Conversion of sulfones into -keto sulfones by N -acylbenzotriazoles....................21 2.16 Synthesis of 1,3-diaralyacetones from N -(arylacetyl)benzotriazoles.......................22 2.17 Conversion of arenesulfinate ani ons into aryl benzyl sulfoxides.............................22 2.18 Formation of N -acylbenzotriazoles..........................................................................24 2.19 Formation of N -acylbenzotriazole............................................................................25 3.1 Structure of azirines.................................................................................................29 3.2 Synthetic routes to 2 H -azirines................................................................................31 3.3 Example of 2 H -azirine formation by a nitrile and carbene......................................32 3.4 Thermal or photochemical rear rangement of isoxazoles to 2 H -azirines..................33 3.5 Ring-contraction of oxazaphospholes to 2 H -azirines..............................................33 3.6 Base-catalyzed elimination of aziridines..................................................................33 3.7 Oxidation of aziridines to 2 H -azirines.....................................................................34 3.8 Synthesis of 2 H -azirines by thermolysi s of vinyl azides.........................................34 3.9 Photolysis of vinyl azides.........................................................................................35 3.10 Pathways to azirine s via vinyl azides.......................................................................36 3.11 Neber rearrangement of oximes to produce 2 H -azirines..........................................36 3.12 Example of modified Neber reaction.......................................................................37 3.13 Synthesis of ketoxime tosylates...............................................................................38 3.14 Synthetic approach to 2 H -azirines...........................................................................38 3.15 Synthesis of N -acylmethylbenzotriazoles................................................................40 3.16 Acylation of benzotriazole.......................................................................................41

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ix 3.17 Synthesis of benzotriazole-substituted oximes........................................................42 3.18 Synthesis of benzotriazole-substituted 2 H -azirines...................................................43 3.19 Substitution of benzotriazole in 2 H -azirines............................................................46

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x Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science BENZOTRIAZOLE-MEDIATED SYNTHESIS OF N -ACYLBENZOTRIAZOLES AND 2 H -AZIRINES By Chavon Renee Wilkerson August 2003 Chair: Alan R. Katritzky Major Department: Chemistry Benzotriazole, a well-known synthetic aux iliary was used in the synthesis of diverse N -acylbenzotriazoles and 2 H -azirines. N -Acylbenzotriazoles are efficient acylating reagents as well as intermediate s in the synthesis of various important compounds. The synthesis of five N -acylbenzotriazoles was accomplished. Azirines, the smallest nitrogen-containing heterocyclic molecules, were synthesized via a Neber rearrangement of a benzotriazole-substituted oxime p -toluenesulfonate. The first example of nucleophilic attack with Grignard reagents on the azirine ring system was obtained, thus providing novel 2 H -azirines.

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1 CHAPTER 1 GENERAL INTRODUCTION 1.1 Importance of Heterocyclic Chemistry A heterocycle is any organic cyclic compound with a ring containing one or more carbons and at least one other element, namely O, S, N. About half of the known organic compounds contain at least one heterocyclic component, thus heterocyclic compounds are very widely distributed in nature. Their functions are often of fundamental importance to living systems as they play a vital role in the metabolism of all living cells. For example, the nucleic acid bases, which are derivatives of the pyrimidine 1.1 and purine 1.2 ring (Figure 1.1) systems are crucial to the mechanism of replication. Essential diet ingredients such as thiamin (vitamin B1), riboflavin (vitamin B2), pyridoxyl (vitamin B6), and ascorbic acid (vitamin C) are heterocyclic compounds. Two of the essential amino acids, tryptophan and histidine are heterocyclic. The structural complexity of heterocycles provides an almost limitless series of compounds with a wide range of physical, chemical, and biological properties. The successful application to many problems makes for continued interest in their chemistry. Figure 1.1 Heterocycles in living systems Perhaps the most widely studied application of heterocycles is the preparation of biologically active and medicinally important molecules. The successful treatment of N N N N NH N 1.1 1.2

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2 various ailments ranging from malaria to cancer to heart disease is often triggered by the presence of various heterocyclic compounds in extracts derived from plants, animals, and insects. Heterocyclic derivatives such as morphine alkaloids, -lactam antibiotics, and benzodiazepines are just a few familiar examples from various pharmaceuticals featuring a heterocyclic component[91AG(E)1278]. The ability of mankind to synthetically prepare medicinally important molecules during the past century has allowed for a continued decrease in the mortality rate from numerous diseases. However, many diseases, viruses, and infections continue to prosper among mankind and escape suitable and long-lasting treatments or cures. Teams of scientists trained in areas like medicinal chemistry, pharmacology, molecular biology, biochemistry, enzymology and others work tirelessly to find suitable treatments and cures. Modern drug discovery focuses on synthesis of specific biomolecular targets, which invariably contain a heterocyclic component. A key challenge in the synthesis of such targets continues to be the development of new pathways and improvement of existing pathways to biologically important molecules. Efforts by many researchers throughout the world have added tremendously to the knowledge base of heterocyclic chemistry and have allowed for the development of pharmaceutical, agricultural, and industrially important products. Katritzky and co-workers have studied the design of new synthetic reactions, especially practical, high-yield methods for the synthesis of complex organic molecules for nearly fifty years[91T2683][98CR409]. Th e development of superior synthetic methods and preparation of useful compounds within the Katritzky group is based on the

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3 use of a well-known synthetic auxiliary, benzotriazole, to be discussed in the following section. 1.2 Benzotriazole-Mediated Approach to Heterocyclic Synthesis Any chemical entity providing support, or serving as an aid in organic synthesis can be viewed as a synthetic auxiliary . A useful synthetic auxiliary should display several characteristics. It should be readily introduced at the beginning of the sequence, remain stable during various synthetic operations, and, if possible, exert an activating influence on other parts of the molecule. In addition, it must be easy to remove at the end of the synthetic sequence. Perhaps few other synthetic auxiliaries have consistently contributed to the development of mild and efficient reaction pathways in organic synthesis when compared with benzotriazole 1.3 . Figure 1.2 Parent benzotriazole molecule Major efforts to explore novel and useful aspects of benzotriazole chemistry began in 1987 when Katritzky and co-workers carried out systematic studies of the properties and reactions of N -substituents in heterocyclic compounds [87JCS(P1)781][87JCS(P1)791][87JCS(P1)799]. Since that time, benzotriazole has proven to be a highly valuable synthetic auxiliary. Five key attributes contribute to the success of benzotriazole as a desirable synthetic auxiliary: Introduction and removal from organic compounds easily. Ability to convey multiple activating influences on molecules to which it is attached. N N N H 1.3

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4 Intrinsically unreactive and stable. Desirable physical and biological properties. Ready availability. Additionally, when compared with other well-known activating groups, benzotriazole displays quite a few advantages. The leaving ability of benzotriazole is comparable to cyano and sulfonyl[95S1315]. These are good leaving groups only when activated in one of two alternative ways: i) by an electron donor substituent attached to the same sp3-hybridized carbon atom, ii) by an electron acceptor as when the group is attached to an sp2-(or sp) hybridized carbon atom which also carries an attached double bond to oxygen or nitrogen. The halogens and tosylate behave as leaving groups in each case i), ii), and iii) when attached to an unactivated sp3(or sp2) hybridized carbon. Especially in case (i), halogens and tosylates are often so reactive as to be difficult to isolate. For this reason benzotriazole (Bt) may be compared with a tame halogen substituent because of its leaving abilities and offers a clear advantage since it forms a stable, non-volatile anion in solution compared with the unstable halogen and tosylate and the toxic cyano group. (Figure 1.3) N N N C H X R X N S O O X -cyano is volatile, poisonous -poor leaving group -lachrymator -not recoverable -Bt is stable -non-volatile -reusable Figure 1.3 Comparison of benzotriazole as a leaving group to cyano and phenylsulfonyl. Heteroatom-assisted deprotonation of an -hydrogen is well known[86JOC86]. For example, the Nalkyl protons to a nitrogen incorporated in a five-membered heteroaromatic ring such as Nalkylpyrazole are activated[69CR693]. A benzotriazolyl

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5 moiety similarly provides activation to allow for deprotonation of an C-H. Detachment of a proton in the 1position of benzotriazole most likely occurs due to the presence of two electron-attracting, pyridine–like nitrogen atoms which increase the acidity of said proton (Figure 1.4). This type of activation to proton loss is an extremely important attribute of benzotriazole as it allows for subsequent reactions with electrophiles to form a variety of interesting compounds[93JHC1261][93T7445][95JOC6]. N N N H R X X= O, N, S electron attracting pyridine-like Natoms acidic proton Figure 1.4 Benzotriazole is activated to -C-H proton loss. Furthermore, benzotriazole possesses both electron-donor and electron-acceptor properties and, because of this, compounds with an heteroatom (typically N, O, and S) 1.4 attached to a benzotriazole nitrogen can ionize in two ways. Ionization may form the benzotriazole anion and an immonium, oxonium, or thionium cation 1.5 , or result in the loss of the heteroatom substituent to give 1.6 . (Figure 1.5) N N N H R X N N N H R X N N N H R + X=NR2, OR, SR typically for typically for X= halogen, OH electron donor and acceptor properties 1.4 1.6 1.5 + XFigure 1.5 Benzotriazole has electron donor and electron acceptor abilities.

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6 NSubstituted benzotriazoles exist as two isomers: 1and 2-substituted. They typically exist in equilibrium (Figure 1.6), with 1.3b of the same order of stability as 1.3a , and often show the same reactivity. For simplification, the isomers will be notated Bt1= benzotriazol-1-yl (3a) , Bt2= benzotriazol-2-yl ( 3b) , and Bt= benzotriazol-1-yl and benzotriazol-2-yl throughout this presentation. N N N R N N N R 1.3a 1.3b Figure 1.6 Benzotriazole exists as two isomers of similar stability. Benzotriazole (Bt) groups are easily inserted into a molecule by a variety of substitution, addition, and three component condensation reactions. Examples of some of these methods are described below. 1. Displacement from alkyl halides: RX + BtR-Bt + XA valuable method involves reaction of benzotriazole with alkyl halides, use of DMF as the solvent and NaOH as the base resulting in high yields (Table 1.1) [91RTC369]. Alkylation of benzotriazole with alkyl halides can also be achieved either in basic media in the presence of a phase-transfer catalyst or in the absence of base by conventional and microwave heating . Various other methods utilizing displacement from alkyl halides also exist [93TL2673] [96JHC 607] [96JHC203]. In general, reaction of benzotriazole with primary alkyl halides leads to a mixture of N -1 and N -2 isomers, and sometimes observation of the quaternization product. 2. Displacement from Acyl Halides: RCOX + BtRCOBt + XA direct method from benzotriazole and an acid chloride at 80-100 C without solvent allows for the preparation of 1-acylbenzotriazoles in good yields (Figure 1.7). N -

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7 Acylbenzotriazoles have also been prepared from reactions of acid chlorides with i) 1-(trimethylsilyl)-benzotriazole[80JOM 141], (ii)1-(tributylstannyl)benzotriazole [77JOM185], or (iii) 1-(hydroxymethyl)b enzotriazole [54JA285][57JOC1022]. Table 1.1 Preparation of N -Alkylbenzotriazoles, RBt RX R Yield (%) MeI Me 95 i-PrI i-Pr 80 n-Bu n-Bu 86 Et(Me)CHBr Et(Me)CH 65 PhCH2Br PhCH2 99 Ph3CCl Ph3C 100 EtOOCCH2Cl EtOOCCH2 95 PhCOCH2Br PhCOCH2 98 BtH + RCOCl RCOBt1 1.7a: R=Me, 70% 1.7b: R=Et, 90% 1.7c : R= n -Bu, 79% 1.7d : R=Ph, 90% heat Figure 1.7 Reaction of benzotriazole and acid chlorides without base. Reaction of 1-(methylsulfonyl)benzotriazole with carboxylic acid anions leads to the formation of 1-acylbenzotriazoles (Figure 1.8), an activated form of an acid[00JOC8210]. The 1-acylbenzotriazoles are more stable than the corresponding acid chlorides and offer a mild, highly efficient way of introducing benzotriazole. The reaction is believed to involve attack of the acid anion on the sulfonyl group to give a mixed anhydride. The benzotriazole anion then attacks the carbonyl group of the anhydride to form the acylbenzotriazole.

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8 Bt1SO2Me Bt1COR R O O SO2Me + RCOO-Bt BtFigure 1.8 Conversion of carboxylate anions into N-acylbenzotriazoles mediated by Nsulfonylbenzotriazole. 3. Displacement of OH in Alcohols: ROH + BtRBt This method is particularly valuable for the preparation of those N alkylbenzotriazoles which cannot conveniently be synthesized from the corresponding alkyl halides either because they are not readily available or are unstable [93JPO567]. 4. Displacement of Alkoxy Group in Acetals, Ketals . : R2C(OR2) + BtR2C(OR)Bt Benzotriazole can displace one of the alkoxy groups in acetals or ketals to give 1( -alkoxyalkyl) benzotriazoles[89JOC6022][ 91S279]. Generally, only one alkoxy group of acetals and ketals can be substituted by the Bt group, even when an excess of Bt is used. However, the presence of a carbonyl group promotes this reaction[87JCS(P1)791]. It is evident from the above illustrations that benzotriazole is a reagent capable of being introduced into a variety of organic molecules by many mild and effective procedures. Moreover, the benzotriazole residue can be removed from molecules just as easily depending on its environment. The four major ways in which a benzotriazolyl group is removed from a molecule of type 1.8 are depicted in Figure 1.9. The first three modes all depend on dissociation to Btand a cation 1.8a . This dissociation is assisted by a suitable heteroatom X, and also by proton or Lewis acid catalysis which helps the departure of the benzotriazolyl group. Analogous vinylogous activation to benzotriazole

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9 loss is also possible. For a comprehensive review of reactions involving the removal of benzotriazole groups please see Chemical Reviews , 1998 , 98 , 409. N N N R X Y H N N N R X Y H R Y Nu X H R X Y HY O R + Nu-H+ 1. removal by substitution 2. removal by elimination 1.8 H2O 3. removal by hydrolysis 4. removal by ring scission 1.8a Figure 1.9 Removal of benzotriazolyl group. The key to the reactivity of benzotriazole is the influence it has on molecules to which it is attached. The presence of a Bt residue allows it to act as a leaving group, proton activator, an ambident anion dir ecting group, cation stabilizer, and as both a radical and anion precursor[98T2647][99JOC3335] . Furthermore, the benzotriazole ring system is itself intrinsically unreactive, stable, and exhibits desirable physical and innocuous biological properties. The parent benzotriazole 1.3 is a moderate acid (pKa = 8.2), a non-volatile, crystalline, odorless, and non-toxic reagent. At a cost of just $44 for 500 g (Aldrich), benzotriazole is certainly a us er-friendly, mild reagent that has been used extensively in organic synthesis, particularly to provide access to heterocycles. Our extensive use of benzotriazole-substituted molecules as versatile synthetic auxiliaries led us to synthesize some useful Nacylbenzotriazoles (see Chapter 2). We also developed a novel approach to substituted 2 H -azirines via a benzotriazole-mediated Neber reaction (Chapter 3).

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10 CHAPTER 2 SYNTHESIS OF N-ACYLBENZOTRIAZOLES 2.1 Introduction Compounds containing carbonyl groups are plentiful in nature. Many play a vital role in in biological processes. Hormones, vitamins, amino acids, drugs, and flavorings are just a few carbonyl-containing compounds that affect us daily. Polarization of the carbonyl group (C=O) with partial negative charge on oxygen and partial positive charge at carbon renders the carbon atom of a carbonyl group susceptible to nucleophilic attack. For this reason, carbonyl-containing compounds are used extensively as building blocks toward complex organic structures. Carboxylic acids are widely available carbonyl containing compounds due to their stability and low reactivity. The unreactive nature of carboxylic acids especially toward nucleophilic acyl substitution exists (i) because the hydroxyl group is a poor leaving group, and (ii) because in basic media the oxygen anion is an even worse leaving group. Chemists need a useful way to activate carboxylic acids in order to take advantage of the reactivity of the polarized carbonyl group. Acyl halides and acid anhydrides are commonly used as activated carboxylic acid derivatives. However, they are highly reactive and often must be prepared just prior to reaction with a nucleophile. Additionally, many acid halides are unstable, difficult to prepare, and/or liquids with unpleasant odors. Thus the availability of suitably substituted and activated carboxylic acid derivatives is important. Acylazoles are versatile activated derivatives of carboxylic acids, especially useful for acylations (introduction of RCOor ArCOinto a molecule) when the acid chloride could produce

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11 undesired complications[84CHEC(5)451]. Reactive heterocyclic amides or “azolides” implies amides whose amide nitrogen is a member of an aromatic five-membered ring containing at least two nitrogen atoms, i.e. “azoles” [62AG(E)351]. N -Acylazoles contain an electron pair on the ring nitrogen that is part of the aromatic sextet, hence unlike other tertiary amides there is little contribution from resonance structures of type 2.1 (Figure 2.1) to the resonance hybrid. Consequently the positive nature of the carbonyl carbon is undiminished. R O N R R O N R R R R O N R R + + 2.1 1 2 1 2 1 2 Figure 2.1 Resonance hybridization of tertiary amides. NAcylimidazoles and N -acylbenzimidazoles have been well developed and reviewed as powerful acylation reagents[79LA1756][80BCJ1638][98MI1]. They have been widely involved in reactions that result in the acylation of diverse nucleophiles to produce aldehydes, ketones, carboxylic acids, carboxylic esters, amides, hydrazides and anhydrides (Figure 2.2). N N COR R'OH R'NH2 H2O R'SH R'CO2H H2NNHR' LiAlH4 R'MgBr RCONHR' + ImH RCO2R' + ImH RCO2H + ImH ImH + RCOR' RCHO + ImH RCONHNHR' + ImH RCO2COR' + ImH RCOSR' + ImH ImH=imidazole Figure 2.2 N -acylimidazoles as acylation reagents

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12 2.2 Synthetic Utility Of N -Acylbenzotriazoles Use of N -acylbenzotriazoles as valuable synthetic intermediates has been welldocumented[1895JA449][72BCJ515][76EJB25 ][79JPS(A)277][83S327]. Katritzky and co-workers have demonstrated, especially during the past decade, the great synthetic utility associated with such compounds. A comprehensive review of their utility is beyond the scope of this thesis. However, in an effort to convince the reader of how important N -acylbenzotriazoles are, a short summary is presented. N -Acylbenzotriazoles have found applications in the preparation of various classes of compounds. They are most used in organic synthesis as reagents for preparation of heterocycles (Route A, see section 2.2.1), N -acylation (Route B), O-acylation (Route C), C-acylation (Route D), and preparation of valuable intermediates (Route E, see section 2.2.6) (Figure 2.3). R O N R O O R Bt R O O R R O Bt E A D C B R1R2 1 1 1 R2 NHR1R2 R1CH2COR2 R1CHO heterocycles intermediates Figure 2.3 Utility of N -acylbenzotriazoles. 2.2.1 Preparation of Heterocycles Katritzky and co-workers demonstrated that hetero-olefinic and hetero-aromatic heterocycles could be obtained from various N -acylbenzotriazoles. Lithiated 1alkylcarbonylbenzotriazoles undergo 1,4-addition to ,-unsaturated aromatic ketones

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13 (chalcones) to afford previously unknow n 3-alkyl-4,6-diaryl-3,4-dihydropyran-2-ones 2.5 and 2.6 predominantly (or exclusively) as 3,4trans -isomers, in good yields[02JOC3104] (Figure 2.4). Dihydropyrones are useful in the development of therapies for the treatment of viral infections, and diseases, including AIDS [98TA2197] [99TA3659] [99BMC2217] [00JMC843]. N N N R O O OLi COBt O O O O 1) LDA, THF -78 2) 2.2a : R1=Et 2.2b : R1= n -C6H132.2c : R1= i -Pr 1 -LiBt + 2.4 2.3 2.5 2.6 1 R2 R3 R3 R2 R1 R2 R1 R3 R3 R2 R1 Figure 2.4 Ring synthesis of subs tituted 3,4-dihydro-2-pyrones from N acylbenzotriazoles. Aryl isocyanates have been widely used for preparation of various heterocyclic compounds[65JOC3247][78JOC3231][99JOC925]. C ondensations of aryl isocyanates 2.7 with alkanoyl-, acetyl-, aroyl-, heterocyclic and cinnamoylbenzotriazoles led to a diverse group of polycyclic heteroaromatic compounds[00JOC8069], namely quinolines, pyrimidino[5,4,c ]quinolines, benz[ b ]-1,8-naphthyridines, phenanthridines, and indolo[2,3,b ]quinolines (Figure 2.5). N N N O R N O R N NHAr NHAr R1=CH3 =CH2CH3 =1,3,3-trimethylbutyl =acetoacetyl =phenyl =thiophenyl =cinnamoyl 1 + 2 R2=H =CH3 =OCH3 sealed tube 24h 2.7 polycyclic heteroaromatics e.g . quinolines (Ar= p -CH3C6H4) Figure 2.5 Polycyclic heteroaromatics from N -acylbenzotriazoles

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14 Schick and co-workers reported formation of diand trisubstituted butyrolactones 2.9 by intramolecular cyclization of the organolithium intermediates 2.8 , prepared by 1,2addition of lithium enolates of N -acylbenzotriazoles 2.2 to carbonyl compounds[96LA881][02JOC3104] (Figure 2.6). This reaction was demonstrated for nonbranched aliphatic (R1=Et, n -C6H13) and arylalkyl (R1=PhCH2) acylbenzotriazoles, while aliphatic ketones and alkyl or (arylalkyl)aldehydes were used as carbonyl components. N N N O O O Bt O Li O O 1) LDA or n -BuLi/HMDS 2) 2.2a : R1=Et 2.2b : R1= n -C6H13 2.2c : R1= i -Pr -LiBt 2.8 2.9 Figure 2.6 Formation of butyrolactones from Nacylbenzotriazoles R1 R2 R3 R2 R3 R1 R1 R2 R3 Figure 2.6 Formation of butyrolactones from N -acylbenzotriazoles 2.2.2 NAcylbenzotriazoles as N -Acylating Reagents The amide linkage underlies the properties of a vast array of organic molecules, polymers, and materials. It contributes to the unique properties of amino acids, peptides, lactams, nucleosides, and alkaloids to name but a few. Common routes to primary, secondary, and tertiary amides mostly involve the treatment of activated derivatives of acids, especially acyl halides, acid anhydrides, or esters with ammonia or primary and secondary amines [89MI1]. Limitations are associated with these methods. Acylations of ammonia, primary and secondary amines by esters frequently require strongly basic catalysts and/or high pressure, while reactions of ammonia or amines with acyl halides

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15 are highly exothermic. Reactions with acid anhydrides easily form imides with ammonia and primary amines. Use of N -acylbenzotriazoles as the acylation reagent for Nacylation offers a clear advantage over such methods. Treatment of N -acylbenzotriazoles with ammonia, primary, and secondary amines provides a simple, mild, and general procedure for the preparation of primary 2.10, secondary 2.11, and tertiary amides 2.12, respectively [00JOC8210] (Figure2.7). RCOBt1 NH4OH R1NH2 R2R3NH RCONH2 RCONHR1 RCONR2R3 2.12 2.11 2.10 Figure 2.7 Simple conversion of N -acylbenzotriazoles to amides Preparation of unsymmetrical tetrasubstituted ureas have been the subject of much attention and synthetic effort due to their applications which include uses as antioxidants in gasoline, as additives in detergents to prevent carbon deposits, as plant growth regulators, pesticides, herbicides, HIV-1 protease inhibitors, and other medicinal preparations [85RCR249] [91AAC2209] [93JMC288]. Diverse unsymmetrical tetrasubstituted ureas 2.14 were prepared by successive treatment of 1,1Â’carbonylbisbenzotriazole 2.13 with secondary amines under mild conditions[97JOC4155] (Figure 2.8), further illustrating Nacylbenzotriazoles as efficient Nacylating reagents.

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16 N N N N N N O N N N O N R R N O N R R R R 2.13 R1R2NH 1 2 + BtH R3R4NH 1 2 4 3 + BtH 2.14 Figure 2.8 General synthesis of unsymmetrical tetrasubsituted ureas Figure 2.8 General synthesis of unsymmetrical tetrasubstituted ureas Reaction of 1,1Â’-(1,2-dioxoethane-1,2-diyl)bis-1 H -benzotriazole 2.15 with secondary amines provides tetrasubstituted unsymmetrical oxamides 2.16 [98S153] (Figure 2.9) which have potential application in the synthesis of -diketones[93TL571], vicinal diamines[92SC1081], as ligands in organometallic complexes[91TMC92], chelating agents [94CA9431], polymer additives[95CA314553], HIV-1 protease inhibitors[96TL1153], Tumor Necrosis F actor inhibitors[94CA30551], and aldose reductase inhibitors[92CA131072]. Bt O O Bt N O O Bt R R N O O N R R R R 2.15 R1R2NH 2 1 R3R4NH 1 2 2.16 3 4 Figure 2.9 General synthesis of unsymmetrical tetrasubstituted oxamides NAcylation is an efficient method to protect amines. Simple amide derivatives are usually of no value as protecting groups because the conditions required to remove them are harsh. The trifluoroacetamide group is exceptionally labile to basic hydrolysis and therefore useful in the protection of prim ary and secondary amines[56CB647]. It is readily cleaved by potassium carbonate in aqueous methanol under conditions that preserve simple methyl esters[88JOC 3108][89JOC2498]. Conventional reagents for

PAGE 27

17 trifluoroacetylation all have drawbacks or limitations. For example, trifluoroacetyl triflate is extremely reactive[79JOC313][87JOC4156], N (trifluoroacetoxy)succinimide is unstable and has to be stored as a benzene solution in a freezer[88JOC3108], and N (trifluoroacetyl)imidazole is highly moisture sensitive [60AG35]. Katritzky et al. recently introduced a novel and facile trifluoroacetylating reagent for amines and alcohols. Reaction of trifluoroacetic anydrid e with benzotriazole in dry THF provides in almost quantitative yield (trifluoroacetyl) benzotriazole 2.17 [97JOC726] (Figure 2.10). In a molecule with both primary amino and secondary amino groups, trifluoroacetylation only occurred at the primary amino group. The 2-amino-2-phenylethanol molecule, contains both an amino and a hydroxyl group and is selectively trifluoroacetylated at the amino group. Thus, (trifluoroacetyl)benzotri azole is a convenient trifluoroacetylation reagent due to its selectivity, facile preparation, easy handling, and stability. N N N H N N N O CF3 + (CF3CO)2O THF room temperature + TFA 2.17 Figure 2.10 Trifluoroacetylated Nacylbenzotriazole as a novel protecting group 2.2.3 O-Acylation Compounds containing the Bt-C-O functionality are versatile intermediates in organic synthesis [98CR409]. Among such be nzotriazole derivatives, 1-(benzotriazol-1yl) alkyl ethers 2.18 (Figure 2.11) have been widely used in the preparation of various heterocycles[95JOC7612][95JOC7625], -functionalized ketones [95JOC7619] [97JOC706], amides[88JOC5854], and ethers[ 89JOC6022] to name but a few. The corresponding 1-(benzotriazol-1-yl) alkyl esters 2.19 should offer similar synthetic opportunities. Initial routes to molecules of type 2.19 involved intermediates of low-

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18 stability and extreme sensitivity to moisture[91S69]. Thus a more general and useful synthesis of the 1-(benzotriazol-1-yl) alkyl esters was obtained by use of Nacylbenzotriazoles. N N N O R R' N N N R O R' O R=H, alkyl, aryl R'=Aryl, alkyl 2.18 2.19 Figure 2.11 Compounds with the Bt-C-O functionality Katritzky and co-workers found that 1-(benzotriazol-1-yl) alkyl esters 2.19 can be obtained from the direct reaction of the corresponding N -acylbenzotriazole derivatives 2.20 and an aldehyde in excellent yields. The best results are obtained when the reaction is carried out in acetonitrile at a 0.3 M concentration in the presence of a catalytic amount of base (Figure 2.12). The method is tolerant to base sensitive moieties such as halosubstituents, nitrile, or esters and is able to provide products unobtainable from previously published methods. Thus N -acylbenzotriazoles are efficient O-acylating reagents in their additions to aldehydes to give esters of type 2.19. N N N R O N N N R O O R' MeCN K2CO3 (cat) R'CHO 2.20 2.19 Figure 2.12 Synthesis of 1-(benzotriazol-1-yl)alkyl esters by N -acylbenzotriazoles 2.2.4 C-Acylation Carbon acylations are synthetically important and have been widely reviewed since they provide a valuable entry to car bon-carbon bonds[73JOC514] [79MI1] [89OPP179].

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19 Monocarbonyl compounds such as ketones and aldehydes and various carboxylic acid derivatives, which contain alpha protons are converted to resonance-stabilized anions 2.21, generally known as enolate anions , in the presence of base. Metal enolates of carbonyl compounds undergo reactions with a variety of heteroand carbon-atom electrophiles. Such reactions rank alongside addition reactions of carbanionic species to carbonyl groups as the most important methods of carbon-carbon bond formation for synthesis of complex systems. Metal enolates normally react with carbon electrophiles at the alpha position to form products of type 2.22 (Figure 2.13). However, the C and O modes of reaction may compete. Reactions with certain highly reactive electrophiles may result in enol derivatives of type 2.23 as the exclusive product[73JOC514]. Versatile synthetic intermediates may be obtained by reactions involving enolate anions and i) alkyl halides and related reagents (alkylation reactions) [79MI1], ii) acylating reagents (Claisen and related reactions)[54OR59], iii) carbonyl groups of aldehydes and ketones (Aldol and related 1,2-additions)[68OR1], iv) , -unsaturated carbonyl compounds (Michael and related 1,4-additions) [79MI1]. H O R O R H H O R H H O R E O H E R H acidic alpha proton base electrophile or 2.21 2.23 2.22H H Figure 2.13 Common reactions of carbonyl compounds containing an alpha proton

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20 Carbon acylation of simple ketone enolates for the synthesis of 1,3-diketones and 1,3-ketoesters has been investigated using a wide variety of acylating reagents including formates and oxalates[79MI1], acid chlorides[77TL1187], N -acylimidazoles[82LA1891], methyl methoxymagnesium carbonate[59JA2598], and acyl cyanides[83TL5425][98TL2249]. The C-acylati on potential of 1-acylbenzotriazoles in the regioselective preparation of -diketones has been examined by Katritzky et al. [00JOC3679]. Reactions of alkyl and aryl N -acylbenzotriazoles with saturated cyclic ketones, unsaturated cyclic ketones, and aliphatic ketones in the presence of lithium diisopropylamide (LDA) and tetrahydrofuran (THF) at -78°C resulted in C-acylated products in excellent yields. The C-acylation of other intermediates was explored with N -acylbenzotriazoles. Enaminones 2.26 were obtained by acylation of metalated ketimines 2.25a-c (1eq.) with LDA (2eq.) in THF at 0°C, using N -acylbenzotriazoles 2.24a-f (1eq.) as acylating agents [00S2029] (Figure 2.14). Enaminones are important synthetic intermediates for the synthesis of carbazolequinone alkaloids [98JCS(P1)4115], tricyclic benzo[ a ]quinolizines[98JOC4936], pyrroles[ 98TL8263], benzodiazepines[99H803], isoxazoles[93H1617], and quinolines [93H2805]. Bt O R N R R N O R R H R + 1 2 3 2 1 3 2.24a-f 2.25a-c 2.26 R1 a Ph b t -Bu c p-MeOC6H4d p-MeC6H4e ClCH2f styryl R2 R3 a i -Pr n -Bu b Ph t -Bu c c -Pr c -hexyl Bt = benzotriazolyl Figure 2.14 C-acylation of ketimines by N -acylbenzotriazoles for the synthesis of enaminones

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21 N -Acylbenzotriazoles have also recently been used in a convenient preparation of aliphatic, aromatic, and heteroaromatic keto sulfones 2.27[03JOC1443](Figure 2.15). Keto sulfones possess wide-spread synthetic applications as intermediates in the synthesis of, among others, disubstitute d acetylenes[84JA3670], olefins[95T9873], allenes[95TL7925], vinyl sulfones[ 98TA2311], and polyfunctionalized 4 H pyrans[97JOC6575]. Reductive elimination of the sulfonyl group provides a nice entry to ketones[85JOC3846][98T9791][00SC2564]. Some keto sulfones exhibit fungicidal activity[99JST113] while others are precursors for optically active -hydroxy sulfones [01TA513] [99TA1369]. R' S O R'' O N N N O R S O O R'' O R R' + n -BuLi, THF 2.27 -78 degrees Figure 2.15 Conversion of sulfones into -keto sulfones by N -acylbenzotriazoles 2.2.5 Preparation of Other Intermediates In addition to serving as excellent acylating reagents, Nacylbenzotriazoles are key synthons for generating valuable intermediates. Wang and Zhang presented a facile synthesis of 1,2-diketones by a samarium diiodide-promoted coupling of two N acylbenzotriazole molecules [02TL5431]. Un like acyl chlorides and keto cyanides, the preparation of which is tedious [55OS112], re quires high temperature or the use of toxic cyanides, N -acylbenzotriazoles are stable crystalline solids, readily available from carboxylic acids and N -(1-methanesulfonyl) benzotriazole. Thus use of the benzotriazolyl auxiliary allows for mild reaction conditions as well as easily accessible starting materials for the preparation of 1,2-diketones.

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22 Elimination of benzotriazole from N(arylacetyl)benzotriazoles under basic conditions allows for the formation of arylketene intermediates which can subsequently be used to provide other important intermediates. N(Arylacetyl)benzotriazoles 2.28 on treatment with sodium hydride in THF followed by hydrolysis with water gives the symmetrical ketones 2.30 in good yields[96HAC365](Figure 2.16). The ketones 2.30 are most likely formed by the intermediate ketenes dimerizing to 2.29, followed by addition of water and loss of carbon dioxide[47JA2444]. N N N H N N N O R R R R O O R O H R H O R H R H R1R2CHCOCl Et3N 2 1 NaH THF R2=H 2 1 1 2.27 2.28 H20 -CO2 1 1 2.29 1 Figure 2.16 Synthesis of 1,3-diaralyacetones from N -(arylacetyl)benzotriazoles Reactions of N -(arylacetyl)benzotriazoles with sodium sulfinates provide a novel method for generating aryl benzyl sulfoxides 2.33 in high yields (70-90%). The reaction mechanism involves arylketene intermediates 2.32 formed in the basic elimination of benzotriazole from the N(arylacetyl)benzotriazoles[96SL701](Figure 2.17). N N N O Ar Ar Ar S O ONa Ar S O Ar weak base heating 2.31 2.32 2.33 Figure 2.16 Conversion of arenesulfinate anions into aryl benzyl sulfoxides =C=O Figure 2.17 Conversion of arenesulfinate anions into aryl benzyl sulfoxides

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23 It is clear that Nacylbenzotriazoles are versatile synthetic intermediates used as C-, O-, and Nacylating agents as well as precursors to heterocycles and other valuable synthetic targets. This chapter explores the synthesis of some aliphatic, aromatic, and heteroaromatic N -acylbenzotriazoles. 2.3 Results and Discussion Several synthetic methods for Nacylbenzotriazoles are available. Previous preparations of acylbenzotriazoles have utilized acid chlorides by reaction with i) 1(trimethylsilyl) benzotriazole [80JOM141] , ii) 1-(tributylstannyl) benzotriazole [77JOM185], or iii) 1-(hydroxymethyl) benzotriazole[54JA285] which loses formaldehyde. Katritzky et al. found that Nacylbenzotriazoles could be obtained in good yields directly from benzotriazole and acid chloride without using any solvent [92T7817]. For example, 1-benzoyl-, 1-acetyl-, 1-propa noyl-, and 1-pentanoyl-benzotriazole were prepared in 70-90% yields by an equimolar mixture of benzotriazole and the respective acid chloride at 80-100°C. An even better method utilizing the acid chloride involves dissolving benzotriazole in dichloromethane at zero degrees followed by dropwise addition of triethylamine and subsequent addition of the acid chloride. This procedure allows the use of many different acid chlorides[99JHC777]. Compounds 2.34a (Table 2.1) and 2.34b were both prepared in 98% yield by this improved method. Compound 2.34a was serendipitously discovered during earlier work in the Katritzky group. It was found to be a side product formed from reaction of di(benzotriazol-1-yl)-1-methoxy methane with trimethylacetyl chloride in lithium diisopropamide at -78°C. After its discovery a more practical procedure was found which involved treatment of trimethylacetyl chloride and benzotriazole with sodium hydrogen carbonate in tetrahydrofuran for fi ve hours. This method provided yields

PAGE 34

24 around 70%. We found that 1-(1H-1,2,3-benz otriazol-1-yl)-2,2-dimethyl-1-propanone 2.34a was more easily obtained in almost quantitative yield by reaction of benzotriazole with the corresponding acid chloride and triethylamine according to a previously reported procedure [99JHC777]. Similarly we found that previously unknown 4-fluorobenzoyl-1benzotriazole 2.34b could be obtained in high yields by treatment of the 4-fluorobenzoyl chloride with benzotriazole and triethylamine followed by an acid-base work up procedure. Presumably benzotriazole is deprotonated by triethylamine to form a reactive species 2.35 which then reacts as a nucleophile towards the acyl halide to form the expected product 2.34(Fig. 2.18). N N N H N N N N R O Cl N N N O Cl R N N N O R .. + a R= t-Bu b R=4-fluorophenyl 2.34 Figure 2.18 Formation of N -acylbenzotriazoles 1-(Methanesulfonyl)benzotriazole 2.35 is a useful reagent for the conversion of carboxylic acids into their corresponding 1-acylbenzotriazoles 2.34 and for the many carboxylic acids of which the corresponding acid chlorides are unstable or difficult to obtain such as the pyridinecarboxylic acids[92T7817]. This procedure involves heating under reflux an equimolar mixture of the carboxylic acid and 1-(methanesulfonyl)

PAGE 35

25 benzotriazole in tetrahydrofuran and in the presence of an equimolar amount of triethylamine. Based on spectral data, 2-acylbenzotriazoles are not observed. The mechanism for the formation of acylbenzotriazoles 2.34c-e from 1-methanesulfonyl benzotriazoles and carboxylic acid is illustrated in Figure 2.19: the carboxylate (formed in the presence of triethylamine) attack s the sulfur atom of 1-(methanesulfonyl) benzotriazole followed by the departure of benzotriazole to give the intermediate 2.36. Then the addition of benzotriazole anion to the carbonyl carbon and elimination of methanesulfonate gives the final product 2.34. R O O SO2Me N N N O R R O O H N R O O N N N S O O CH3 S O O CH3 O R Bt2.36 +Bt 2.34 .. + 2.35 o -Bt Bt------Figure 2.19 Formation of N -acylbenzotriazole Table 2.1 Synthesis of N -acylbenzotriazoles ______________________________________________________________ 2.34 R Yield (%) ______________________________________________________________ a t -Bu 98 b 4-flurophenyl 98 c 2-furanyl 83 d 1-napthyl 98 e 4-pyridyl 84

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26 In summary, we have shown that versatile N -acylbenzotriazoles can be prepared under mild conditions in high yields for a variety of synthetic purposes. 2.4 Experimental Methods General Methods Melting points were determined using a Thomas Hoover capillary Melting Point Apparatus and are uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a Varian Gemini-300 spectrometer using deuteriochloroform as solvent with tetramethylsilane (0 ppm) as the internal reference for 1H nmr and the central line of deuteriochloroform (77 ppm) as the reference for 13C nmr. Tetrahydrofuran was distilled under nitrogen immediately prior to use from sodium benzophenone ketyl. All reagents were purchased from Aldrich and us ed without further purification. General Procedure for the Preparation of N -Acylbenzotriazoles 2.34a-b To a solution of benzotriazole (11.9 g, 0.1 mole) in anhydrous dichloromethane (200ml) at 0°C under nitrogen was added dropwise triethylamine (17 ml, 0.12 mole), followed by addition of the corresponding acid chloride (0.11 mole). The resulting mixture was stirred at room temperature fo r one-two hours. The reaction was quenched at this temperature with hydrochloric acid (2 N , 100 ml), and the organic phase was separated and then washed with hydrochloric acid (2 N , 2 x 50 ml) and water (50 ml) successively. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a white powdery solid which was purified by recrystallization. 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2-dimethyl-1-propanone (2.34a) This compound was obtained as white needles (98%), m.p. 64.0-66.0°C ([99JHC777] mp 68-70°C, 71%); 1H nmr (CDCl3): 1.65 (s, 9H), 7.47 (m, 1H), 7.61 (m,

PAGE 37

27 1H), 8.10 (m, 1H), 8.32 (d, J = 8.3, 1H); 13C nmr (CDCl3): 27.6, 42.5, 115.0, 119.8, 125.9, 130.2, 132.2, 144.8, 159.6, 177.3 1-(1 H -1,2,3-Benzotriazol-1-yl)(4-fluorophenyl)methanone (2.34b) This compound was obtained as a white solid (98%), m.p. 108.0-110.0°C; 1H nmr (CDCl3): 8.33 (m, 3H), 8.20 (d, J = 8.20 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.3 Hz, 2H); 13C nmr (CDCl3): 114.7, 115.6 (d, J = 22.4 Hz), 120.2, 126.3, 127.5, 130.4, 132.3, 134.5 (d, J = 9.1 Hz), 145.6, 164.3, 165.3, 167.7 Preparation of N -(1-Methanesulfonyl)benzotriaozole (2.35) To an ice-cold solution of benzotriazole (11.9 g, 0.10 mol) and triethylamine (15.2 g, 0.15 mol) in dry toluene (120 mL) was added dropwise methylsulfonyl chloride (9.3 mL, 0.12 mol) in toluene (50 mL). The mixture was stirred overnight (15-20 hours) at room temperature. Ethyl acetate (150 mL) and water (100 mL) were added. The organic layer was separated, successively washed with water and brine, and dried over anhydrous magnesium sulfate. Removal of solvents in vacuo gave a solid, which was recrystallized from benzene or toluene to afford N -(1-methanesulfonyl)benzotriaozole (18 g, 89%) as colorless needles: mp 109-111°C. General Procedure for the Preparation of N -Acylbenzotriazoles 2.34c-e A mixture of aromatic or aliphatic acid (10.0 mmol) and 1(methylsulfonyl)benzotriazole (1.97 g, 10.0 mmol) and triethylamine (2.0 mL, 14.0 mmol) were refluxed in THF (50 ml) overnight (15-20 hours). The solvent was evaporated and the residue was dissolved in chloroform (100 mL). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to give a

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28 crude product, which was recrystallized from an appropriate solvent to give pure N (arylcarbonyl)benzotriazole 2.34c-e. 1 H -1,2,3-Benzotriazol-1-yl(2-furanyl)methanone (2.34c) yield 83%; off-white powder (recrystallized from 4:1 hexane/et hyl acetate); mp 164.0-166.0° C ([00JOC8210] mp 171-173°, 92%); 1H nmr (CDCl3): 8.40 (d, J = 8.4 Hz, 1H), 8.14 (m, 2H), 7.88 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 6.72 (dd, J = 6.7 H, 6.7 Hz, 1H); 13C nmr (CDCl3): 113.0, 114.6, 120.1, 124.7, 126.3, 130.4, 132.1, 144.5, 145.5, 148.9, 154.9 1 H -(1,2,3)-Benzotriazoly-1-yl)(1-naphthyl)methanone (2.34d) yield 98%; lightbrown solid (recrystallized from benzene); mp 134.0-136.0° C ([00JOC8210] mp 136137° C, 88%); 1H nmr (CDCl3): 8.48 (d, J = 8.5 Hz, 1H), 8.10 (m, 3H), 7.93 (m, 2H), 7.73 (t, J = 7.75 Hz, 1H), 7.55 (m, 4H); 13C nmr (CDCl3): 114.6, 120.3, 124.3, 124.7, 126.4, 126.7, 127.9, 128.7, 129.3, 130.1, 130.5, 130.9, 132.0, 132.9, 133.6, 146.2, 167.6 1H-(1,2,3)-Benzotriazol-1-yl)(4-pyridyl)m ethanone (2.34e) yield 84%; off-white solid (recrystallized from chloroform and hexanes); mp 144.0-146.0° C ([00JOC8210] mp 149-151° C, 84%); 1H nmr (CDCl3): 8.91 (m, 2H), 8.37 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.02 (m, 2H), 7.72 (m , 1H), 7.57 (m, 1H); 13C nmr (CDCl3): 114.7, 120.5, 124.4, 126.9, 130.9, 131.8, 138.6, 145.8, 150.4, 165.3

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29 CHAPTER 3 SYNTHESIS OF 2 H -AZIRINES 3.1 Introduction Azirines have attracted considerable attention in recent years. Interest in these three-membered nitrogen containing heterocycles arises from the general influence of ring strain upon chemical reactivity and the potential of their derivatives to act as precursors to more elaborate molecules. Two isomeric azirines exist, namely 3.1 and 3.2 (Figure 3.1) designated by Chemical Abstract and The Ring Index as 1 H -azirine and 2 H azirine, respectively. Alternate names such as 2-azirine for 1 Hazirine and 1-azirine for 2 H -azirine have been suggested in the literature. The structure, biological applications, and the synthetic chemistry of these heterocycles have been explored since the mid-1960s and a number of general reviews on azirine s have appeared [83M1] [84CHEC47] [91AG(E)238][02OPP219]. N N H 1 Hazirine (2-azirine) 3.1 2 H -azirine (1-azirine) 3.2 Figure 3.1 Structure of azirines The 1 H -azirine system represents a cyclic conjugated system with 4electrons and according to HuckelÂ’s rule would not be predicted to be stabilized by electron delocalization. Simple molecular orbital (MO) calculations on the parent 1 H -azirine systems shows DE 0.00 (N = C + 1.5; C-N = C-C)[68JA2875]. The

PAGE 40

30 corresponding uncyclized enamine has DE 0.30, suggesting that cyclic conjugation results in destabilization. Thus the 1 H -azirine system has been classified as antiaromatic [67JA4383][68AG(E)565] and only a limited amount of work has been completed on the system. Consequently most work on azirines has been directed to the chemistry of 2 H azirines. Similarly, this presentation is focused on the synthesis and reactions of 2 H azirines. Throughout this presentation, the 2 H -azirine ring system will be referred to as such, as 1-azirine, or simply as “the azirine”. Due to their high reactivity, 2 Hazirines have been explored extensively for various synthetic purposes[84CHEC47][83MI1]. The dimensions of 2 Hazirines have been determined by single crystal X-ray [91AG(E)238] [92HCA1866] [97EJC1757] [00K303]. Most accounts report a consid erable C-N bond lengthening and C-C bond shortening when compared to normal open chain congeners and are consistent with estimated bond lengths from theoretical calculations [87JPC6484][93JA11074] [98JCU912]. The strain energy associated w ith these heterocycles is mainly due to deformation of normal bond angle between the atoms of the ring and has been estimated at about 48 kcal/mol[91AG(E)238]. Compared with an oxirane or thiirane which have strain energies estimated at 27kcal/mol and 34 kcal/mol respectively, it is clear that 2 Hazirines are reactive heterocycles capable of releasing a considerable amount of energy to drive chemical processes. The N -lone pair of electrons on the azirine makes it an electron rich “pyridinelike nitrogen” capable of reactions with electrophiles. The combination of high ring strain, a reactive -bond resulting from polarization of the C=N bond, and the lone pair

PAGE 41

31 on the nitrogen atom allow for reactions where the azirine can act as a nucleophile, electrophile, dienophile or dipolarophile in cycloaddition reactions. Current synthetic strategies available for the construction of the three-membered 2 H -azirine ring include: (i) intermolecular cycloaddition reactions between nitriles and carbenes or nitrenes and acetylenes, (ii) ring-contraction of isoxazoles, and oxazaphospholes, (iii) elimination and oxidation reactions on aziridines, (iv) intramolecular reactions of N -functionalized imines and vinyl azides (Figure 3.2). All these methods are discussed in the next section, and representative examples to illustrate each procedure are mentioned. N N LG N3 Y O N N NX Y = C, P : N : + + : iv. i. i. iv. ii. iii. Figure 3.2 Synthetic routes to 2 H -azirines 3.2 Synthetic Strategies for 2 h -Azirines Although a few examples are known[97EJC1757], reactions of type (i) (Figure 3.2) are not widely used as they lack generality and typically proceed with low yields unsuitable for preparative applications. An example of such a reaction is the [1+2] cycloaddition reaction between a phosphanylcarbene 3.3 and benzonitrile 3.4 which affords the corresponding phosphorus-substituted 2 H -azirine 3.5 in good yield (Figure

PAGE 42

32 3.3)[95AG(E)1246]. However, in spite of its simplicity, no more examples of this approach have been reported. PhN PR2 SiMe3 N PR2 SiMe3 Ph : + 3.3 3.4 3.5 (85%) Figure 3.3 Example of 2 H -azirine formation by a nitrile and carbene Rearrangement or ring contraction of five-membered rings such as isoxazoles, triazoles, and oxazaphospholes provides an important entry to azirines (Figure 3.2, route(ii)). Ring-contraction of isoxazoles, and oxazaphospholes has been reported in numerous studies[66JA1844][67JA6911][70T453]. Thermal or photochemical treatment of isoxazoles 3.6 produces ring contraction to acyl-2 H -azirines 3.7, which sometimes rearrange to form other heterocycles like oxazoles 3.8 [90JOC4011][90LA403](Figure 3.4). These transformations have proved to be reversible at high temperature or with a change in the irradiation wavelength. Although the thermal rearrangement of isoxazoles has produced several azirines with good yields[88TL6067], this synthesis is of limited preparative value due to the high temperatures usually needed. Ring contraction from isoxazoles to azirines can also be promoted by iron(II) catalysts. Thus, 5-alkoxy-and 5aminoisoxazoles isomerize to 2 H -azirines-2-carboxylic esters and to 2 H -azirine-2carboxamides, respectively, in nearly quantitative yield by reaction with FeCl2 [97T10911]. Thermally induced extrusion of phosphane oxide from 1,3,5and 1,2,-5oxazaphosphole heterocycles also leads to 2 H -azirines by ring contraction [67TL917][79JOC3861][86AG99][86AG(E)85]. Electron-withdrawing substituents at

PAGE 43

33 C4 in 1,2,5-oxazaphospholes 3.9 (Figure 3.5) favor formation of the corresponding keteneimine rather than 2 H -azirine 3.10 which is produced in low yields. O N R R N O R R O N R R 254 nm or heat 254 nm 2 2 2 1 1 1 3.6 3.7 3.8 Figure 3.4 Thermal or photochemical rearrangement of isoxazoles to 2 H -azirines O N PPh3R R R O N R R R Ph3P N R R R heat 1 2 3 + 1 3 2 -Ph3PO 1 2 3 3.9 3.10 Figure 3.5 Ring-contraction of oxazaphospholes to 2 H -azirines Rearrangement or modification of threemembered rings, namely aziridines also provides an entry to 1-azirines. NSubstituted aziridines 3.11 such as N -chloro [88T4447], N -sulfonyl, N -sulfinyl, and N -acyl derivatives are prone to elimination when treated with base to give 2 H -azirines 3.12 (Figure 3.6). Pyrolysis, light-induced [93CB2337], and fluoride-induced eliminati ons of aziridines to azirines are known. NX R H R R N R R R base X= Cl, OSO2Ph, SO p -Tol, COPh R= H, alkyl, aryl 3.12 3 1 2 3.11 1 2 3 Figure 3.6 Base-catalyzed elimination of aziridines

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34 A variation to the elimination reactions is the oxidation of aziridine derivatives. Zwanenburg et al. found they could obtain chiral azirine carboxylate esters 3.14 with the Swern reagent (DMSO/(COCl)2/Et3N)[95TL4665]. Oxidation of either the trans-3.13 or the cis -3.15 isomers afforded 2 H -azirine carboxylate 3.14 where the integrity of the stereogenic center at C-2 is retained (Figure 3.7). N H H CO2R R H N R H CO2R N H H CO2R H R 1. DMSO/(COCl)2 2. Et3N 72-86% 1. DMSO/(COCl)2 2. Et3N 54-70% 2 2 1 1 1 trans 3.13 3.14 cis 3.15 Figure 3.7 Oxidation of aziridines to 2 H -azirines The thermal and/or photochemical treatment of vinyl azides can be used for the construction of 2 H -azirines[84MI1](route (iv), Figure 3.2). Smolinsky et al. reported the first general synthesis of 1-azirines[61JA4483] by the vapor phase thermolysis of vinyl azides 3.16 (Figure 3.8). They reported moderate yields (50-60%) of 2 H -azirines along with small amounts (5%) of keteneimines, presumably generated by migration of the -R group of the azide onto the nitrogen atom through a Curtius type rearrangement. R H H N3 N H H R RN H H heat + R = Ph = o -CH3, C6H4 = n -C4H9 3.16 Figure 3.8 Synthesis of 2 H -azirines by thermolysis of vinyl azides The formation of 2 H -azirines by thermolysis depends largely on the structure of the vinyl azide[86JOC3176]. Vinyl azides substitu ted at the 1-position with aryl, alkoxy,

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35 amine, or carboethoxy groups give stab le azirines, while hydrogen or carbonyl substituted afford nitriles or other heterocycles instead of the azirine ring. In some cases, it is difficult to isolate the 2 H -azirines after heating the vinyl azides because of the thermal instability of the heterocycle. However, the photochemical reaction at low temperature can in some instances lead to a more efficient synthesis of azirines. Harvey and Ratts reported the first synthesis of 1-azirines through photolysis. They obtained azirines 3.19 through photolysis of -azidocrotonates 3.18 which were prepared by the addition of sodium azide in THF/H20 to the allenic ester 3.17 [66JOC3907](Figure 3.9). They subsequently reported the prepar ation of a number of 1-azirines[68JA2686]. H CO2Et H R C H3 N3R CO2Et N C H3 R CO2Et NaN3 3.17 3.18 3.19 light Figure 3.9 Photolysis of vinyl azides The most widely accepted mechanism for photolysis and thermolysis involves the concerted cyclization-elimination of N2 assisted by the -bond [86JOC3176] [97JA10291] (route b, Figure 3.10). Formation of a transient vinylnitrene intermediate (route a, Figure 3.10) by loss of molecular nitrogen from the thermally or photolytically excited vinyl azide is also a possible mechanism[70MI1]. If the 1-azirine is formed from singlet nitrene, then the conversion is a symmetry-allowed conrotatory electron cyclization[69AG(E)797]. A third possible mechanism, involving the formation of a triazole intermediate, which then loses N2, has also been considered (route c, Figure 3.10).

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36 N3 N N N N N NN N a b -N2 -N2 electrocyclic closure c -N2 : : .. : + Figure 3.9 Pathways to azirines via vinyl azides Figure 3.10 Pathways to azirines via vinyl azides Intramolecular reactions of N-functionalized imines (route (iv), Figure 3.2) constitute an important strategy in the synthesis of 2H-azirines. Neber and coworkers described the first rearrangement of a ketoxime intermediate to an azirine. They found that in the presence of tosyl chloride and pyridine, the oxime 3.20 is converted via 3.21 into aziridines 3.22, and 1-azirines 3.23 could then be prepared by treating 3.22 with sodium carbonate [32LA281] [35LA283] (Figure3.11). R N R OTs N N R R H N H R R NO2O2N N R OH R 1 2 1 2 + R1 = R2 = CH3, Ph 3.20 3.21 3.22 3.23 2 1 1 2 Figure 3.11 Neber rearrangement of oximes to produce 2H-azirines Modifications of their method described in Figure 3.11 have been developed in recent years. Perhaps the most widely used modification involves the reaction of

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37 quaternary hydrazonium salts with sodium isoproproxide in isopropanol. For example, Parcell and then later Nair reported the synthesis of 2,2,-dimethyl-3-phenyl-2H-azirine 3.25 by treatment of isobutyrophenone N,N,N-trimethylhydrazonium iodide 3.24 with base[63CI(L)1396][68JOC2121](Figure 3.12). N N(CH3)3 CH3 CH3 Ph N CH3 CH3 Ph + INaOCH(CH3)2 i -PrOH 3.24 3.25 Figure 3.12 Example of modified Neber reaction Many others have also used this modified Neber reaction towards the synthesis of substituted 2H-azirines[65JOC579][68BCJ1440][78JOC2029]. Sato et al. reported the modified Neber reaction is affected by the type of hydrogen that is available on the carbon atom[68BCJ1440]. The reaction generally proceeds in high yields if the hydrogen is tertiary. This is probably related to the fact that the mechanism of the Neber rearrangement involves the formation of a species resembling a vinylnitrene which undergoes subsequent cyclization[63JOC2271]. Th e transition state leading to the azirine ring would be expected to be lower in energy when the double bond is tetrasubstituted. 3.3 Benzotriazole Mediated Approach to 2h-Azirines Although the modified Neber reaction is widely used, the traditional approach starting with ketoxime tosylates like 3.21 is still a favorable and mild way to make 2Hazirines. Zwaneburg and co-workers utilized the traditional Neber reaction in an asymmetric synthesis of 2H-azirine carboxylic esters[96JA8491]. They found that -keto esters 3.26 are readily converted into the ketoxime tosylates 3.27 in a two-step procedure in fair yields followed by treatment of 3.27 with triethylamine in dichloromethane to give

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38 the desired azirines (Figure 3.13). This method is limited because the intermediate ketoximes must be tosylated immediately after their preparation, as otherwise the competing formation of isoxazol ones takes place[70BSF2685][86JOC4037]. R O O OR' R N O OR' OTs 1) NH2OH.HCl, NaOH 2) pTolSO2Cl, pyridine,CH2Cl2 3.26 3.27 Figure 3.13 Synthesis of ketoxime tosylates The presence of electron-withdrawing groups at the -position to N-functionalized imines seems to be a necessary functional group to facilitate formation of the azirine. With this in mind, we decided to pursue the synthesis of 2H-azirines using the traditional Neber approach with benzotriazole as a synthetic auxiliary. We have now developed a mild and reproducible approach to substituted 2H-azirines utilizing benzotriazole methodology. The presence of benzotriazole in this synthesis allows for deprotonation of the methylene protons under mild reaction conditions. Furthermore, the presence of benzotriazole as an electron-withdrawing group instead of an ester (as in 3.27) or other base sensitive group allows for a wider variety of reaction conditions. We envisioned a Neber-type reaction whereby 3.29 (Figure 3.14) served as the key intermediate in the synthesis of the azirine ring. The presence of benzotriazole and an aryl group makes the methylene protons doubly activated to proton loss. N Bt R R N Bt OTs R N Bt OH R O Bt 3.29 R=aryl 3.30 3.31 3.28 Figure 3.14 Synthetic approach to 2H-azirines

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39 3.4 Results and Discussion A post-doctoral researcher in the Katritzky group, Dr. Mingyi Wang, first began to study how the azirine ring could be obtained from an intermediate of type 3.29. The key starting material, substituted or unsubstituted -(benzotriazol-1-yl) acetophenone 3.31 was easily obtained by either method described below. 1-(Trimethylsilylmethyl) azoles have been prepared by various methods and utilized for a range of synthetic transformations[86JOC3897][86H240][ 87JCS(P1)769][87JOC844][80JOM141]. Multigram quantities of 1-(trimethylsilylmethyl) benzotriazole 3.32 (Figure 3.15) are readily prepared by stirring the sodium salt of benzotriazole and chloromethyltrimethylsilane in dimethylformamide at room temperature for approximately 24 hours. Some of the corresponding 2-(trimethylsilylmethyl) benzotriazole is also formed, but it is an oil and stays in solution. Katritzky et al. found that desilylation of 3.32 can be effected by treatment with acyl halides to afford ketones of type 3.31 in yields of about 70% or greater[ 90HAC21]. Thus, this silicon-containing N-substituent allows for successful introduction of acyl groups at the -position to the benzotriazole ring.

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40 N N N Na Cl Si N N N Si N N N O R + DMF 3.32 THF reflux 3.31 RCOCl R=H R=Cl R=CH3 Figure 3.15 Synthesis of N-acylmethylbenzotriazoles In the absence of any added base in refluxing toluene or benzene, benzotriazole replaces the halogen atom of an -halogenated ketone or a carboxylic ester to give the corresponding N-1-substituted benzotriazole 3.31 as the only isomer[94S597]. The regiospecific or regioselective alkylation reacti ons of benzotriazole in the absence of base can be explained as follows. In dilute solutions, benzotriazole exists completely in the 1H-tautomeric form[51JA4360]. Furthermore, in nonpolar solvents like benzene and toluene, benzotriazole is largely associated into dimers and higher conglomerates [42JCS420][55JPC1044]. Thus, a model of dimer 3.33 (Figure 3.16) bonded by intermolecular hydrogen-bonding can be constructed. It is believed that when a carbonyl group is present in a suitable position in the halide, formation of hydrogen-bonding between the dimer 3.33 and the substrate, as indicated by 3.34, along with the high nucleophilicity of the 1-N position enhances the selectivity for formation of only the N-1substituted benzotriazole derivative. Thus a mixture of -chloroacetophenone and

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41 benzotriazole can be refluxed under nitrogen gas in toluene or benzene for 24 hours to provide compounds of type 3.31. For our purposes, use of (1-trimethylsilylmethyl) benzotriazole was the preferred method while -chloroketones were used only in the absence of the silicon-containing intermediate. N N N H N N N H N N N H N N N H O R X ----3.33 ----3.34 Figure 3.16 Acylation of benzotriazole The precursor 3.30, easily obtained from reaction of 3.31 with hydroxylamine hydrochloride in ethanol and 10 % sodium hydroxide, provided oximes as single isomers in good yields (Figure 3.17). Compound 3.30a was previously prepared in the Katritzky group while I and a fellow graduate student, Ms. Hongfang Yang, prepared 3.30b for the first time. Additionally, I prepared the previously unknown compound 3.30c. With the crystalline benzotriazole-substituted oximes in hand, Dr. Wang first attempted to prepare oxime tosylates of type 3.29 for further reaction with a suitable base to obtain the azirine. All efforts to obtain this compound with a reproducible procedure and satisfactory yields failed. Synthesis of the azirine ring was then attempted by preparation of 3.29 in situ from the benzotriazole-substituted oxime.

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42 Bt O R N Bt O H R 3.31a-c NH2OH.HCl 10%NaOH EtOH reflux R=H R=Cl R=CH3 a, b, c, 3.30a-c Figure 3.17 Synthesis of benzotriazole-substituted oximes We developed a reproducible, one-pot pr ocedure which provided benzotriazolesubstituted 2Hazirines in good yields (Figure 3.18). Crystalline oximes 3.30a-c were dissolved in a 4:1 mixture of chloroform and anhydrous diethyl ether at 0°C followed by 10 equivalents of a 10% aqueous KOH solution and a catalytic amount of tetra-nbutylammonium hydrogen sulfate (as a phase tran sfer catalyst). The mixture was stirred for about 30 minutes to one hour followed by dropwise addition of a tosyl chloride solution in ether. While maintaining the reaction temperature at 0°C-5 °C for 5-6 hours, the color of the reaction changed from clear to light-yellow to dark red/burgundy. Upon observation by thin-layer chromatography that all starting oxime 3.30a-c was consumed, the reaction was quenched. The concentration and amount of aqueous KOH and the reaction time significantly affected product yields. Optimal conditions were found to be 10 equivalents of 10% KOH and 5-6 hours of r eaction time at 0°C thus to avoid isolation of oxime tosylates 3.32a-c.

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43 N Bt O H R N Bt TsO R N Bt R 3.30a-c 1) 10 eq. 10%KOH, diethyl ether, chloroform (tetra-n-butylammonium sulfate) 2) tosyl chloride, diethyl ether 0 deg. Celsius, 5-6h 3.32a-c 3.28a-c Figure 3.18 Synthesis of benzotriazole-substituted 2H-azirines The benzotriazole-substituted 2H-azirines 3.28a-c (Table 3.1) were isolated after column chromatography in yields of 60, 58, and 66%. Carbon-13 NMR spectra of 3.28ac displayed the expected signals characteristic of benzotriazolyl at ca. 146 and 110 ppm, and of the sp3 carbon (C-2) and the sp2 carbon (C-3) of the 2H-azirine ring at ca. 42 and 164, respectively. With the desired azirines in hand, we proceeded to test the reactivity of the compounds, especially toward nucleophilic attack. Displacements of benzotriazole by nucleophiles have been reviewed[94S445]. Most documented reactions of 2Hazirines with nucleophiles involve nucleophilic a ddition to the imine bond [84CHEC47] [99JCS(P1)1305][00SL1843] to produce aziridines instead of retaining the structure of the azirine. Additionally, no previous nucleophilic replacement of a 3-substituent of 2Hazirines with a C-nucleophile has been reported. Reported successful halide

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44 displacements of 2-halo-2H-azirines with nucleophiles have all involved an additional electron-withdrawing group, e.g. carboxyl ate, at the 2-position[00TL7217]. We studied the reactivity of 2-(benzotriazol-1-yl)-2H-azirines using organometallic reagents, phthalimide anion, and sodium benzenethiol as nucleophiles. Treatment of 2(benzotriazol-1-yl)-2H-azirine 3.28a-c with benzylmagnesium chloride or 4methylbenzylmagnesium chloride in the presence of zinc chloride gave the desired products 3.35a-f in moderate to good yields (Figure 3.19, Table 3.1). Except for 3.35a-f, no other products were observed in each case. Compared with 2H-azirines 3.28a-c, the 13C NMR spectra of 3.35a-f revealed the disappearance of benzotriazole moiety signals, and the appearance of signals characteristic of benzyl at ca. 33.233.6. The spectral data of 3.35a are also consistent with that reported[00EJO257]. In the presence of zinc chloride, unfortunately, reactions of 3.28a-c with other Grignard reagents, both aryl (e.g. phenyl, p-chlorophenyl, p-tolyl) and alkyl (e.g. phenylethyl, pentyl) failed. In some cases, the reactions did not proceed, but allowed the recovery of the starting 2-(benzotriazol-1-yl)-2H-azirines. In other cases, the disappearance of the starting 2-(benzotriazol-1-yl)-2H-azirines resulted in a complicated mixture. Following a literature procedure[02JOC66], treatment of 2-(benzotriazol-1-yl)-2Hazirines 3.28a-c with potassium phthalimide and sodium benzenethiol at room temperature in DMF led to the synthesis of novel 2H-azirine derivatives 3.35a-c and 3.36a in good yields (Figure 3.19, Table 3.1).

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45 Table 3.1 2H-azirines 3.28 and their derivatives 3.35, 336, and 3.37 Entry R R' Yield (%) Mp (oC) 13C NMR 3.28a Ph / 60 99-100 42.6 (C-2) 164.6 (C-3) 3.28b 4-ClC6H4 / 58 158-160 42.4 (C-2) 163.8 (C-3) 3.28c 4-MeC6H4 / 66 101-102 42.6 (C-2) 164.1 (C-3) 3.35a Ph C6H5CH2 66 Oil 40.1 (C-2) 171.6 (C-3) 3.35b Ph 4-MeC6H4CH2 53 Oil 39.7 (C-2) 171.3 (C-3) 3.35c 4-ClC6H4 C6H5CH2 44 Oil 40.0 (C-2) 170.9 (C-3) 3.35d 4-ClC6H4 4-MeC6H4CH2 66 93-95 39.6 (C-2) 171.0 (C-3) 3.35e 4-MeC6H4 C6H5CH2 71 oil 40.2 (C-2) 171.1 (C-3) 3.35f 4-MeC6H4 4-MeC6H4CH2 50 oil 39.9 (C-2) 171.3 (C-3) 3.36a Ph Phthalimido 71 139-140 35.6 (C-2) 165.3 (C-3) 3.36b 4-ClC6H4 Phthalimido 57 182.5184.5 35.7 (C-2) 164.7 (C-3) 3.36c 4-MeC6H4 Phthalimido 79 145-146 35.5 (C-2) 164.8(C-3) 3.37a Ph PhS 60 oil 37.6 (C-2) 166.4 (C-3) 3.3 Conclusion We have developed a methodology for the synthesis of 2-(benzotriazol-1-yl)-2Hazirines under mild conditions, and have disclosed the first example of nucleophilic substitution reactions of 2H-azirines with organometallic reagents. Novel 2H-azirine derivatives were thus obtained.

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46 N R Bt N R S N R R' N R N O O 3.28a-c 3.35a-f 3.36a-c C6H4CH2MgBr or CH3C6H4CH2MgBr Potassium phthalimide DMF 3.37a NaSPh DMF Figure 3.19 Substitution of benzotriazole in 2H-azirines 3.4 Experimental Methods Melting points were determined on a MEL-TEMP capillary melting point apparatus equipped with a Fluke 51 digital thermometer. NMR spectra were taken in CDCl3 (unless stated otherwise) with tetramethylsilane as the internal standard for 1H (300 MHz) or a solvent as the internal standard for 13C (75MHz). All anhydrous solvents were distilled from sodium under nitrogen immediately prior to use. All reactions with air-sensitive compounds were carried out under an argon or nitrogen atmosphere. General Procedure for the Oximes 3.30a-c To a solution of hydroxylamine hydrochloride (30 mmol) in water (50 mL), was added a solution of benzotriazolylmethylketones 3.31a-c (15 mmol) in ethanol (50 mL) followed by dropwise addition of 10% NaOH ( 30 mmol) solution at room temperature. After addition, the yellow or off-white colored mixture was stirred under reflux overnight. Upon cooling to room temperature, white crystals of the product formed and were collected by filtration with no further purification necessary.

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47 2-(1H-1,2,3-Benzotriazol-1-yl)-1-(4-chlorophenyl)-1-ethanoneoxime (3.30b) White needles (91%), mp 226227 °C; 1H NMR (DMSO-d6) 12.33 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 7.8, 7.0 Hz, 1H), 7.437.37 (m, 3H), 6.10 (s, 2H); 13C NMR (DMSO-d6) 149.9, 144.8, 134.0, 132.8, 128.4, 128.0, 127.4, 124.0, 119.1, 110.4, 41.0. Anal. Calcd for C15H14N4O: C, 67.65; H, 5.31; N, 21.04. Found: C, 67.43; H, 5.47; N, 21.02. 2-(1H-1,2,3-Benzotriazol-1-yl)-1-(4-methylphenyl)-1-ethanoneoxime (3.30c) White microcrystals (92%), mp 185188 oC; 1H NMR (DMSO-d6) 12.11 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.627.53 (m, 3H), 7.37 (dd, J = 8.0, 7.3 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.07 (s, 2H), 2.24 (s, 3H); 13C NMR (DMSO-d6) 150.6, 144.9, 138.8, 132.8, 131.1, 128.9, 127.4, 126.2, 124.0, 119.1, 110.4, 41.0, 20.7. Anal. Calcd for C14H11ClN4O: C, 58.65; H, 3.87; N, 19.54. Found: C, 58.47; H, 3.92; N, 19.49. General procedure for 2-(benzotriazol-1-yl)-2H-azirines 3.28b-c. To a solution of oxime (20 mmol) in a mixture of ethyl ether (150 mL) and chloroform (50 mL), was added dropwise aqueous KOH (11.2 g KOH dissolved in 50 mL of water) at 0 oC. After the addition of the base solution, the mixture was stirred vigorously at this temperature for 30 min, and then a catalytic amount of Bu4NHSO4 was added. A solution of p-toluenesulfonyl chloride (TsCl) in Et2O (50 mL) was added dropwise at 0 oC. After this addition, the final mixture was stirred at 05 oC for 6h until the solid reactants disappeared. The reaction mixture was transferred into a separatory funnel and extracted with ethyl ether. The co mbined organic layer was washed with water

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48 and dried over MgSO4. The residue on removal of solvents was purified by column (hexane-ethyl acetate) to give the desired products 3.28a-c. 1-[3-(4-Chlorophenyl)-2H-aziren-2-yl]-1H-1,2,3-benzotriazole (3.28b) Yellow prism (58%), mp 158160 °C; 1H NMR 8.10 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.39 (dd, J = 8.0, 7.3 Hz, 1H), 5.17 (s, 1H); 13C NMR 163.8, 146.2, 140.9, 132.9, 131.7, 130.0, 127.9, 124.3, 121.6, 120.2, 109.7, 42.4. Anal. Calcd for C14H9ClN4: C, 62.58; H, 3.38; N, 20.85. Found: C, 62.81; H, 3.34; N, 20.84. 1-[3-(4-Methylphenyl)-2H-aziren-2-yl]-1H-1,2,3-benzotriazole (3.28c) Yellow microcrystals (66%), mp 101102 °C; 1H NMR 8.078.02 (m, 3H), 7.69 (d, J = 8.2 Hz, 1H), 7.507.44 (m, 3H), 7.37 (dd, J = 7.8, 7.4 Hz, 1H), 5.18 (s, 1H), 2.5 (s, 3H). 13C NMR 164.1, 146.1, 145.6, 132.8, 130.6, 130.2, 127.7, 124.2, 120.3, 120.1, 109.9, 42.6, 22.0. Anal. Calcd for C15H12N4: C, 72.56; H, 4.87; N, 22.57. Found: C, 72.63; H, 4.96; N, 24.46. General procedure for 2H-azirine 3.35a-d. Under N2, activated Mg powder (2 mmol) was added into a dried two-necked flask equipped with a condenser and magnetic stirrer. Then 5 mL of Et2O was added. With the starting of the stirrer, 34 drops of a solution of the bromide (2 mmol) in 5 mL of Et2O was added by syringe, and several minutes later, the remaining bromide solution was added dropwise. The mixture was heated and refluxed slowly for 1h. Upon cooling to –18 oC (ice-salt bath), ZnCl2 solution (1.0 M, 2.0 mL) was added, and 3040 minutes later, a solution of starting material (0.5 mmol) in 5 mL of toluene was added at this temperature. After these additions, the final mixture was stirred at –18 oC to room temperature

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49 overnight (around 24 h). TLC showed almost no starting material. The reaction was quenched with water, and the reaction mixture was diluted with Et2O, washed with water, and dried over MgSO4. The residue on removal of solvents was purified by column (hexane-ethyl acetate) to give the desired products 3.35a-f. 2-Benzyl-3-phenyl-2H-azirine (3.35a) Oil (70%);14 1H NMR 7.777.75 (m, 2H), 7.557.47 (m, 3H), 7.317.21 (m, 5H), 3.06 (dd, J =14.6, 5.1, 1H), 2.76 (dd, J = 14.6, 5.1 Hz, 1H), 2.51 (t, J = 5.1 Hz, 1H); 13C NMR 171.6, 139.3, 132.8, 129.3, 129.0, 128.9, 128.5, 126.3, 125.5, 40.1, 33.2. 2-(4-Methylbenzyl)-3-phenyl-2H-azirine (3.35b) Oil (70%); 1H NMR 7.867.83 (m, 2H), 7.657.55 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 3.08 (dd, J = 14.6 4.9 Hz, 1H), 2.77 (dd, J = 14.6, 5.3 Hz, 1H), 2.55 (t, J = 5.1 Hz, 1H), 2.40 (s, 3H); 13C NMR 171.7, 136.2, 135.8, 132.8, 129.4, 129.2, 129.0, 128.8, 125.6, 39.7, 33.4, 21.0. Anal. Calcd for C16 H15N: C, 86.84; H, 6.83; N, 6.33. Found: C, 86.53; H, 7.24; N, 6.20. 2-[3-(4-Chlorophenyl)-2H-aziren-2-yl]-1H-isoindole-1,3(2H)-dione (3.36b) Yellow needles (57%), mp 182.5184.5 °C; 1H NMR 8.03 (d, J = 8.4 Hz, 2H), 7.857.81 (m, 2H), 7.757.72 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.27 (s, 1H). 13C NMR 167.9, 164.7, 139.9, 134.4, 131.8, 131.5, 129.5, 123.5, 123.3, 35.7. HRMS (FAB) Calcd for C16H9N2O2 [M+]: 296.0353. Found: 296.0351.

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50 CHAPTER 4 CONCLUSIONS An exploration of the synthetic utility of benzotriazole was undertaken. Benzotriazole is readily introduced into molecules, influences reactivity and selectivity in many reactions, and is easily removed from molecules. Our extensive use of benzotriazole-substituted molecules as versatile synthetic auxiliaries led us to synthesize some useful N-acylbenzotriazoles and novel 2H-azirines. Diverse N-acylbenzotriazoles were prepared using different procedures. The presence of benzotriazole does not limit, but in fact expands the variety of reaction conditions available for the synthesis of important organic intermediates. NAcylbenzotriazoles are valuable intermediates in the synthesis of heterocycles, other intermediates, N-, C-, and O-acylated products. A general, reproducible method for the synthesis of benzotriazole-substituted 2Hazirines has been developed starting from N-acylmethylbenzotriazoles. Nucleophilic displacement of benzotriazole by diverse nucleophiles, namely carbon, nitrogen and sulfur was achieved.

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51 LIST OF REFERENCES The reference citation system employed throughout this thesis 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 and letter code appear in brackets, for example [03ABC000]. The first two digits de note the year of the twentieth century, the letter code is an abbreviation for the journal or book cited and the last digits represent the page number. Additional notes to this reference system are as follows: (ii) References are listed consecutively by year, alphabetically by the journal code and then by page number. (iii) Each reference code is followed by the conventional literature citation complete with the name of the authors. (iv) Journals which are published in more th an one part, or more than one volume per year, include in the abbreviation cited the appropriate part or volume number. (v) Books and journals which are less commonly used are called “MI” for miscellaneous. [1895JA449] Mixter, W.G. J. Am. Chem. Soc. 1895, 17, 449 [32LA281] Neber, P.W.; Burgard, A. Liebigs Ann. Chem. 1932, 493, 281

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52 [35LA283] Neber, P.W.; Huh, G. Liebigs Ann. Chem. 1935, 515, 283 [47JA2444] Sauer, J.C. J. Am. Chem. Soc. 1947, 69, 2444 [54JA285] Gaylord, N. J. Am. Chem. Soc. 1954, 76, 285. [54OR59] Houser, C.R.; Swamer, F.W.; Adams, J.T. Org. React. 1954, 8, 59 [55OS112] Oakwood, T.S.; Weisberger, C.A. Org. Synth. 1955, 3, 112 [56CB647] Weygand, F.; Geiger, R.Chem. Ber. 1956, 89, 647 [57JOC1022] Gaylord, N.; Naughton J.M. J. Org. Chem. 1957, 22, 1022. [59JA2598] Stiles, M. J. Am. Chem. Soc. 1959, 81, 2598 [61JA4483] Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 4483 [62AG(E)351] Staab, H.A. Angew. Chem. Int. Ed. Eng. 1962, 1, 351 [63CI(L)1396] Parcell, R. F. Chem. Ind. (London) 1963, 1396 [63JOC2271] House, H.O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 2271 [65JOC579] Morrow, D.F.; Butler, M.E.; Huang, E.C.Y. J. Org.Chem. 1965, 30, 579 [65JOC3247] Sheehan, J.C.; Daves, G.D., Jr. J. Org. Chem. 1965, 30, 3247 [66JA1844] Ullman, E.F.; Singh, B. J. Am. Chem. Soc. 1972, 94, 1199 [66JOC3907] Harvey, G.R.; Ratts, K.W. J. Org. Chem. 1966, 31, 3907 [67JA4383] Breslow, R., Brown, J., and Gajewski, J.J. 1967, J. Am.Chem. Soc., 89, 4383 [67JA6911] Singh, B.; Ullman, E.F.; J. Am. Chem. Soc. 1967, 89, 6911 [68AG(E)565] Breslow, R. Angew. Chem. Int. Ed. Engl. 1968, 7, 565 [68BCJ1440] Sato, S. Bull. Chem. Soc. Jpn. 1968, 41, 1440 [68JA2686] Hassner, A.; Fowler, F.W. J. Org. Chem. 1968 , 33, 2686 [68JA2875] Fowler, F.W., Hassner, A. J. Am. Chem. Soc. 1968 90, 2875 [68JOC2121] Nair, V. J. Org. Chem. 1968, 33, 2121 [69CR693] Mallan, J.M.; Bebb, R. L. Chem. Rev. 1969, 69, 693.

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53 [70BSF2685] Jacquier, R.; Petrus, C.; Petrus, F.; Verducci, J. Bull. Soc. Chim. Fr. 1970 , 7, 2685 [70T453] Nishiwaki, T.; Kitimura, T.; Nakano, A. Tetrahedron 1970, 26, 453 [72BCJ515] Tsujimoto, K.; Ohashi, M.; Yonezawa, T. Bull. Chem. Soc. Jpn. 1972, 45, 515 [73JOC514] House, H.O.; Auerbach, R.A.; Gall, M.; Peet, N.P. J. Org. Chem. 1973, 38, 514 [76EJB25] Reboud-Ravaux, M.; Ghelis, C. Eur. J. Biochem. 1976, 65, 25 [77JOM185] Gassend, R.; Maire, J.C.; Pommier, C. J. Organometallic Chem. 1977 , 137, 185 [78JOC2029] Padwa, A.; Carlsen, P.H.J. J. Org. Chem. 1978, 43, 2029 [78JOC3231] Ohtsukay, Y. J. Org. Chem. 1978, 43, 3231 [79JOC313] Forbus, T.R., Jr.; Martin, J.C. J. Org. Chem. 1987, 52, 4156 [79JOC3861] Hassner, A.; Alexanian, V. J. Org. Chem. 1979, 44, 3861 [79JPS(A)277] Ferruti, P.; Tanzi, M.C.; Vaccaroni, F.J. J. Polym. Sci., Polym. Chem. Ed. 1979, 17, 277 [79LA1756] Walter, W.; Radke, M.; Liebigs Ann. Chem. 1979, 11, 1872 [79MI1] Caine, D. In Carbon-Carbon Bond Formation; Augustine, R.L., Ed.; Marcel Dekker: New York, 1979, p. 250 [80BCJ1638] Keumi, T.; Saga, H.; Kitajima, H.; Bull. Chem. Soc. Jpn. 1980, 53, 1638 [80JOM141] Gasparani, J.P.; Gassend, R. J. Organometallic Chem. 1980, 188, 141 [82LA1891] Sucrow, W.; Brockmann, R.; Liebigs Ann. Chem. 1982, 1891 [83MI1] Nair, V. In Heterocyclic Compounds; Hassner, A.; Ed.; John Wiley and Sons: New York, 1983; Vol.42, Part 1, p.215-332 [83S327] Butula, I.; Zorc, B.; Ljubic, M.; Karlovic, G. Synthesis, 1983, 327 [83TL5425] Mander, L.N.; Sethi, S.P. Tetrahedron Lett. 1998, 39, 5425

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54 [84CHEC47] Padwa, A.; Woolhouse, A.D. In Comprehensive Heterocyclic Chemistry; Katritzky, A.R.; Rees, C.W., Eds.; Pergamon Press: Oxford, 1984; Vol.7, p.47-93 [85JOC3846] Kurth, M.J.; OÂ’Brien, M.J.; J. Org. Chem. 1985, 50, 3846 [85RCR249] Vishnyakova, T.P.; Golubeva, I.A.; Slebova, E.V. Russ. Chem. Rev. (Engl. Transl.) 1985, 54, 249 [86H240] Tsuge, O.; Matsuda, K.; Kanemasa, S. Heterocycles, 1986, 24, 240 [86JOC3176] Hassner, A.; Wiegand, N.H.; Gottlieb, H.E. J. Org. Chem. 1986, 51, 3176 [86JOC3897] Shimizu, S.; Ogata, M. J. Org. Chem. 1986, 51, 3897 [86JOC4037] Katritzky, A.R.; Barczynski, P.; Ostercamp, D.L.; Yousuf, T.I. J. Org. Chem. 1986, 51, 4037 [86JOU86] Borovikova, G.S.; Levchenko, E.S.; Kaniskaya, E.T. J. Org. Chem. USSR Engl. Trans. 1986, 22, 86 [87JCS(P1)769] Katritzky, A.R.; Vazquez de Miguel, L.M.; Aurrecoechea, J.M. J. Chem. Soc. Perkin Trans. 1 1987, 769 [87JCS(P1)781] Katritzky, A.R. J. Chem. Soc. Perkin. Trans. 1 1987, 781. [87JCS(P1)791] Katritzky, A.R. J. Chem. Soc. Perkin. Trans. 1 1987, 791. [87JCS(P1)799] Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Chem. Soc. Perkin. Trans. 1 1987, 799 [87JOC844] Katritzky, A.R.; Kuzmierkiewicz, W.; Aurrecoechea, J.M. J. Org. Chem. 1987, 52, 844 [87JPC6484] Mo, O., de Pay, J.L.G., Yanez, M., J. Phys. Chem., 1987, 91, 6484 [88JOC3108] Bergeron, R.J.; McManis, J.S. J. Org. Chem. 1997, 62, 726 [88JOC5854] Katritzky, A.R.; Drewniak, M.; Lue, P. J. Org. Chem. 1989, 54, 5854 [88T4447] Guillemin, J.C.; Dennis, J.-M.; Lasne, M.-C.; Ripoll, J.-L. Tetrahedron 1988, 44, 4447 [88TL6067] Lipshutz, B.H.; Reuter, D.C. Tetrahedron Lett 1988, 29, 6067 [89JOC6022] Katritzky, A.R.; Rachwal, S.; Rachwal, B. J. Org. Chem. 1989, 54, 6022.

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55 [89MI1] Vogel, A. Practical Organic Chemistry: Langman Scientific & Technical and Wiley: New York, 1989; p. 708 [89OPP179] Black, T.H. Org. Prep. Proced. Int. 1989, 21, 179 [90HAC21] Katritzky, A.R.; Lam, J.N. Heteroatom Chemistry, 1990, 21 [90JOC4011] Sauers, R.R.; Hadel, L.M. J. Org. Chem. 1990, 55, 4011 [90LA403] Himbert, G.; Kuhn, H.; Barz, M. Liebigs Ann. Chem. 1990, 403 [91AAC2209] Kempf, D.J.; Marsh, K.C.; Paul, D.A. J. Antimicrob. Agent. Chemother. 1991, 35, 2209 [91AG(E)238] Heimgartner, H., Angew. Chem. Int. Ed. Engl., 30, 238 (1991) [91AG(E)1278] Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278. [91RTC369] Katritzky, A.R.; Kuzmierkiewicz, W.; Greenhill, J.V. Recl. Trav. Chim. Pays-Bas 1991, 369 [91S69] Katritzky, A.R.; Rachwal, S.; Rachwal, B. Synthesis, 1991, 69 [91S279] Katritzky, A.R.; Bayyuk, S.I.; Rachwal, S. Synthesis 1991, 279 [91T2683] Katritzky, A.R.; Rachwal, S.; Hitchings, G.J. Tetrahedron 1991, 47, 2683. [91TMC92] Quaeyhaegens, F.J.; Desseyn, H.O. Transition Met. Chem. 1991, 16, 92 [92CA131072] Britain, D.R.; Brown, S.P.; Cooper, A.L. Chem. Abstr. , 1992, 117, 131072 [92HCA1866] Villalgordo, J.M., Heimgartner, H. Helv. Chim. Acta, 1992, 75, 1866 [92SC1081] Nutaitis, C.F. Synth. Commun. 1992, 22, 1081 [92T7817] Katritzky, A.R.; Shobana, N. et al. Tetrahedron 1992, 48, 7817 [93CB2337] Maier, G.; Schmidt, C. Chem Ber, 1993, 126, 2337 [93H1617] Maeba, I.;Ito, Y.; Wakimura, M.;Ito, C. Heterocycles 1993, 36, 1617 [93JA11074] Alcami, M.; Mo, O.; Yanez, M. J. Am. Chem. Soc. 1993, 115, 11074

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56 [93JHC1261] Katritzky , A.R.; Szajda, M.; Lam, J.N. J. Heterocyl. Chem. 1993, 30, 1261 [93JMC288] Getman, D.P.; Decrescenzo, G.A.; Heintz, R.M.; et al. J. Med. Chem. 1993, 36, 288 [93JPO567] Katritzky, A.R.; Zhang, G.-F.; Fan, W.-Q.; Wu, J.; Pernak, J. J. Phys. Org. Chem. 1993 , 567. [93T7445] Katrtitzky, A.R.; Lang, H.; Lan, X. Tetrahedron 1993, 49, 7445. [93TL571] Mueller-Westerhoff, U.T.; Zhou, M. Tetrahedron Lett. 1993, 34, 571 [93TL2673] Molina, A.; Vaquero, J.J.; Garcia, J.L.; Alvarez, J. Tetrahedron Lett. 1993, 34, 2673 [94CA9431] Speranza, G.P.; Champion, D.H.; Plishka, M.J. Chem. Abstr. 1994 , 121, 9431 [94CA30551] Christensen, S.B. Chem. Abstr. 1994, 120, 30551 [94S445] Katritzky, A.R.; Lan, X; Fan, W.-Q. Synthesis 1994, 445 [95AG(E)1246] Alcaraz, G., Wecker, U., B aceiredo, A., Dahan, F., Bertrand, G. Angew. Chem. Int. Ed. Engl. 1995, 34, 1246 [95CA314553] Macleay, R.E.; Kmiec, J.P.; Stein, D.L. Chem. Abstr, 1995, 122, 314553 [95JOC6] Katritzky, A.R.; Jiang, J. J. Org. Chem. 1995, 60, 6. [95JOC7612] Katritzky, A.R.; Lang, H. J. Org. Chem. 1995, 60, 7612 [95JOC7619] Katritzky, A.R.; Lang, H.; Wang, Z. J. Org. Chem. 1995, 60, 7619 [95JOC7625] Katritzky, A.R.; Zhang, G.; Jiang, J.; J. Org. Chem. 1995, 60, 7625 [95S1315] Katritzky, A.R.; Wu, H.; Xie, L. Synthesis 1995, 1315. [95TL4665] Gentilucci, L.; Zwanenburg, B.; Grijzen, Y.; Thijs, L. Tetrahedron Lett. 1995, 36, 4665 [96HAC365] Katritzky, A.R.; Soleiman, M.; Yang, B. Heteroatom Chemistry 1996, 7, 365 [96JA8491] Zwanenburg, B.; Verstappen, M.M.H,; Ariaans, G.J.A. J. Am. Chem. Soc. 1996, 118, 8491

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57 [96JHC203] Schulze, K.; Ernst, S. J. Heterocycl. Chem. 1996, 33, 203. [96JHC607] Katritzky, A.R.; Yang, B. J. Heterocyl. Chem. 1996, 33, 607. [96LA881] Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H. Liebigs Ann. Chem. 1996, 881 [96SL701] Katritzky, A.R.; Yang, B.; Qian, Y. Synlett 1996, 701 [96TL1153] Jadhav, P.K.; Man, H.-W. Tetrahedron Lett. 1996, 37, 1153 [97EJC1757] Piquet, V., Baceiredo, A., Go rnitzka, H., Dahan, F., Bertrand, G. J. Eur. Chem., 1997, 3, 1757 [97JA10291] Suarez, P.; Sordo, T.L. J. Am. Chem. Soc. 1997, 119, 10291 [97JOC706] Katritzky, A.R.; Feng, O.; Lang, H. J. Org. Chem. 1997, 62, 706 [97JOC4155] Katritzky, A.R.; Pleynet, D.P.M.; Yang, B.; J. Org. Chem. 1997, 62, 4155 [97JOC6575] Marco, J.L. J. Org. Chem. 1997, 62, 6575 [97T10911] Aurricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A.M. Tetrahedron 1997, 53, 10911 [98CR409] Katritzky, A.R.; Lan, X.; Yang, J.Z.; Denisko, O.V. Chem. Rev. 1998, 98, 409 [98JCS(P1)4115] Murphy, W.S.; Bertrand, M. J. Chem. Soc. Perkin Trans. 1 1998, 4115 [98JCU912] Calvo-Cosada, S., Quirante, J.J., Suarez, D., Sordo, T.L. J. Comput. Chem., 1998, 19, 912 [98JOC4936] Kirschbaum, S.; Waldman, H. J. Org. Chem. 1998, 63, 4936 [98MI1] Staab, H.A.; Bauer, H.; Schneider, K.M. In Azolides in Organic Synthesis and Biochemistry; Wiley-VCH: Germany, 1998; p.129 [98S153] Katritzky, A.R.; Levell, J.R.; Pleynet, D.P.M. Synthesis 1998, 153 [98T9791] Sengupta, S.; Sarma, D.S.; Mondal, S. Tetrahedron 1998, 54, 9791 [98TA2197] Soriente, A.; De Rosa, M.; Dovinola, P. Tetrahedron: Asymmetry, 10, 1999, 2197 [98TA2311] Sengupta, S.; Sarma, D.S.; Mondal, S. Tetrahedron: Asymmetry, 1995, 51, 9873

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58 [98TL2249] Tang, Q.; Sen. S.E. Tetrahedron Lett. 1998, 39, 2249 [98TL8263] Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263 [99BMC2217] Prasad, J.V.N.; Markoski, L.J.; Boyer, F.E. Bio & Med. Chem. Lett. 1999, 9, 2217 [99H803] Nishimura, N.; Koyano, Y.; Sugiura, M.; Maeba, I. Heterocycles 1999, 51, 803 [99JHC777] Katritzky, A.R.; Pastor, A.; Voronkov, M.V. J. Heterocycl. Chem. 1999, 36, 777 [99JOC925] Shi, C.; Zhang, Q.; Wang, K.K. J. Org. Chem. 2000, 65, 8069 [99JCS(P1)1305] Alves, M.J.; Gilchrist, T.L.; Sousa, J.H. J. Chem. Soc., Perkin Trans. 1 1977, 877 [99JST113] Wolf, W.M.; J. Mol. Struct. 1999, 474, 113 [99TA1369] Bentus, P.; Phansavath, P.; Ratovelomanana-Vidal, V. et al. Tetrahedron: Asymmetry 1999, 10, 1369 [99TA3659] De Rosa, M.; DellÂ’Aglio, R.; Soriente, A. Tetrahedron: Asymmetry 1999, 10, 3659 [00JMC843] Boyer, F.E.; Prasad, J.V.N.; Domagala, J.M. J. Med. Chem. 2000, 43, 843 [00JOC3679] Katritzky, A.R.; Pastor, A. J. Org. Chem. 2000, 65, 3679 [00JOC8069] Katritzky, A.R.; Huang, T.B.; Voronkov, M.V. J. Org. Chem. 2000, 65, 8069 [00JOC8210] Katritzky, A.R.; He, H.Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210 [00K303] Peters, K., Peters, E.-M., Hergenrother, T., Quast, H., Kristallografiya, 2000, 215, 303 [00S2029] Katritzky, A.R.; Fang, Y.; Donkor, A.; Xu, J. Synthesis 2000, 2029 [00SC2564] Guo, H.; Zhang, Y. Synth. Commun. 2000, 30, 2564 [01TA513] Gotor, V.; Rebolledo, F.; Liz, R. Tetrahedron: Asymmetry 2001, 12, 513

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59 [02JOC3104] Katritzky, A.R.; Denisko, O.V. J. Org. Chem. 2002, 67, 3104 [02OPP219] Palacios, F.; Ochoa de Retana, A.M.; de Marigorta, E. M.; de los Santos, J.M. Org. Prep. Proc. Int. 2002, 34, 219 [02TL5431] Wang, X.; Zhang, Y. Tetrahedron Lett. 2002, 43, 5431 [03JOC1443] Katritzky, A.R.; Abdel-Fattah, A.A.A.; Wang, M. J. Org. Chem. 2003, 68, 1443

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60 BIOGRAPHICAL SKETCH Chavon R. Wilkerson was born and raised in the suburbs of Detroit, Michigan, by her loving and supportive parents. They encouraged her to pursue a college career in her field of choice---chemistry. As an undergraduate student at North Carolina Agricultural & Technical State University, Chavon immersed herself in her studies. She was awarded a prestigious National Institutes of Health scholarship which exposed her to many opportunities available in biomedical research. Her participation in the scholarship program and her continued interest in chemical research led her to pursue a graduate education at the University of Florida. Af ter obtaining the Master of Science degree from the University of Florida, Chavon plans to continue her career in scientific research.