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Microwave Mediated Synthesis of Nitrogen- and/or Oxygen-Containing Compounds


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MICROWAVE-MEDIATED SYNTHESIS OF NITROGENAND/OR OXYGENCONTAINING COMPOUNDS By CHUNMING CAI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006

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Copyright 2006 by Chunming Cai

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To my family (my father, Chen Cai; my mo ther, Shuiqin Zou; my brother, Chunhua Cai; my sisters, Jingbo Cai and Yinghui Cai; my wi fe, Yong Tao; and my son, Charles Yutao Cai)

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iv ACKNOWLEDGMENTS It has been very pleasant to pursue my PhD degree with the assistance of all the nice people who helped and supporte d me during the last 4 years. First, I give my deepest thanks to my supervisory committee chair (Alan R. Katritzky) for his support, guidance, and insp iration. I greatly appreciate the time and help given by my supervisory committee members (Lisa McElwee-White, Michael J. Scott, Daniel R. Talham, and Brij M. Moudgil). I greatly thank my wife (Yong Tao) and my son (Charles Yutao Cai) for making me a happy husband and father. I greatly thank my parents and my br other and sisters for their constant love and suppor t. I thank all my friends for making my life colorful. I thank everyone in Professor Alan R. Katritzkys group (especially Sandeep K. Singh, Kazuyuki Suzuki, and Sanjay K. Singh) for helping make my work and life easier.

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v TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES...........................................................................................................viii LIST OF FIGURES...........................................................................................................ix LIST OF SCHEMES............................................................................................................x ABSTRACT......................................................................................................................x ii CHAPTER 1 GENERAL INTRODUCTION....................................................................................1 2 BENZOTRIAZOLE AS AN ACID SCAVENGER IN THE SYNTHESIS OF N ACYLBENZOTRIAZOLES........................................................................................4 2.1 Introduction.............................................................................................................4 2.2 Results and Discussion...........................................................................................5 2.3 Conclusion..............................................................................................................7 2.4 Experimental Section..............................................................................................8 3 FACILE SYNTHESES OF OXAZOLINES AND THIAZOLINES USING N ACYLBENZOTRIAZOLES UNDER MICROWAVE IRRADIATION..................13 3.1 Introduction...........................................................................................................13 3.2 Results and Discussion.........................................................................................15 3.2.1 Preparation of N -Acylbenzotriazoles.........................................................15 3.2.2 Preparation of 2-Oxazolines.......................................................................15 3.2.3 Preparation of Thiazolines..........................................................................17 3.3 Conclusions...........................................................................................................19 3.4 Experimental Section............................................................................................19 3.4.1 General Procedure for Preparing 2-Oxazolines Using NAcylbenzotriazoles by Conventional Method..................................................20 3.4.2 General Procedure for Preparing 2-Oxazolines 3.3 or 2-Thiazolines 3.5 Using N-Acylbenzotriazoles 3.1 under Microwave Irradiation.......................20 3.4.3 Characterization of N -Acylbenzotrizazoles 3.1g,j......................................21 3.4.4 Characterization of Oxazolines 3.3aj.......................................................21 3.4.5 Characterization of Thiazolines 3.5af,h,i.................................................22

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vi 3.4.6 Characterization of Miscellane ous Heterocycles 3.6, 3.7, 3.8, 3.9, 3.10...24 4 PREPARATION OF SECONDARY AND TERTIARY AMIDES UNDER MICROWAVE IRRADIATION................................................................................26 4.1 Introduction...........................................................................................................26 4.2 Results and Discussion.........................................................................................26 4.3 Conclusion............................................................................................................28 4.4 Experimental Section............................................................................................28 4.4.1 General Procedure for the Preparation of Amides 4.1aAc.......................28 4.4.2 Characterizations of Amides 4.1................................................................29 4.3.3 Preparation of Amides 4.2..........................................................................36 4.4.4 Characterization of Amides 4.2..................................................................36 5 DIRECT SYNTHESIS OF ESTERS AND AMIDES FROM UNPROTECTED HYDROXY-AROMATIC AND ALIP HATIC CARBOXYLIC ACIDS................38 5.1 Abstract.................................................................................................................38 5.2 Introduction...........................................................................................................38 5.3 Results and Discussion.........................................................................................40 5.3.1 Preparation of Hydroxy Carboxamid es from Aliphatic Hydroxy Acids....40 5.3.2 Preparation of Hydroxyaromatic Amides from Hydroxyaromatic Acids..44 5.3.3 Preparation of Aliphatic -Hydroxycarboxylic Esters and Thiolesters from -Hydroxy Acids....................................................................................47 5.3.4 Preparation of Aromatic Esters from Substituted o -Hydroxy Aromatic Acids................................................................................................................51 5.4 Experimental Section............................................................................................53 5.4.1 General.......................................................................................................53 5.4.2 General Procedure for the Synthesis of Hydroxy Carboxamides 5.3 from Hydroxy Acids 5.1..................................................................................53 5.4.3 Characterization of Hydroxy Amides 5.3...................................................54 5.4.4 Synthesis of o -Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9.................58 5.4.5 Characterization of o -Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9......59 5.4.6 Synthesis of Amides of Substituted Salicylic and o -Hydroxy Naphthoic Acids (5.7, 5.10):.............................................................................................61 5.4.7 Characterization of Amides of Substituted Salicylic and o -Hydroxy Naphthoic Acids (5.7 and 5.10).......................................................................62 5.4.8 Synthesis of Hydroxy Aryl-/Alkyland Thioesters 5.11 from Hydroxy Acids................................................................................................................66 5.4.9 Characterization of Hydroxy Aryl-/ Alkyland Thioesters 5.11 from Hydroxy Acids.................................................................................................67 5.4.10 Synthesis of Esters of Substituted Salicylic 5.12 and o -Hydroxy Naphthoic Acids 5.13.......................................................................................68 5.4.11 Characterization of Esters of Substituted Salicylic 5.12 and o -Hydroxy Naphthoic Acids 5.13.......................................................................................69

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vii 6 SYNTHESIS OF IMIDOYLBENZOTRIAZOLES FROM SECONDARY AMIDES.....................................................................................................................74 6.1 Introduction...........................................................................................................74 6.2 Results and Discussions........................................................................................75 6.3. Conclusion...........................................................................................................77 6.4 Experimental Section............................................................................................78 6.4.1 General Procedure for the Preparat ion of Imidoylbenzotriazoles 6.1........78 6.4.2 Characterization of Im idoylbenzotriazoles 6.1...........................................78 7 EFFICIENT MICROWAVE ACCESS TO POLYSUBSTITUTED AMIDINES FROM IMIDOYLBENZOTRIAZOLES....................................................................89 7.1 Introduction...........................................................................................................89 7.2 Results and Discussion.........................................................................................91 7.3 Conclusion............................................................................................................94 7.4 Experimental Section............................................................................................95 7.4.1 General Procedure for the Preparation of Amidines 7.1:...........................95 7.4.2 Characterization of Amidines (7.1):...........................................................96 8 SYNTHESIS OF 1,5-DISUBSTITU TED TETRAZOLES UNDER MILD CONDITION VIA BENZOTRI AZOLE METHODOLOGY..................................105 8.1 Introduction.........................................................................................................105 8.2 Results and Discussion.......................................................................................107 8.3 Conclusion..........................................................................................................109 8.4 Experimental Section..........................................................................................109 8.4.1 General Procedure for the Preparat ion of 1,5-Disubstituted Tetrazoles...109 8.4.2 Characterization of 1,5-Dis ubstituted Tetrazoles 8.3...............................110 9 CONCLUSIONS......................................................................................................114 LIST OF REFERENCES.................................................................................................116 BIOGRAPHICAL SKETCH...........................................................................................132

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viii LIST OF TABLES Table page 2-1 Preparation of N -Acylbenzotriazoles from Acid Chlorides.......................................6 2-2 Preparation of N -Acylbenzotriazoles from Carboxylic Acidsa..................................7 3-1 Preparation of 2-S ubstituted 2-Oxazolines 3.3 using N -Acylbenzotriazoles...........17 3-2 Preparation of 2-Subs tituted Thiazolines using N -Acylbenzotriazoles 3.1af,h,i ...18 4-1 Microwave Preparation of Secondary Amides 4.1 Using N -Acylbenzotriazolesa...27 5-1 Synthesis of Hydroxy Carboxamides 5.3 from Aliphatic Hydroxy Acids 5.1a g .*............................................................................................................................. 43 5-2 The Synthesis of Substituted Salicylamides 5.7ah (a, X = H; b, X = 5-Br; c, X = 4-OH; d, X = 3-Me)..............................................................................................47 5-3 The Synthesis of Amides 5.10 ..................................................................................47 5-4 Synthesis of Hydroxy Esters 5.11ab and Thiolesters 5.11eg *.............................50 5-5 Synthesis of Esters 5.12 ...........................................................................................52 5-6 The Synthesis of Esters 5.13 ....................................................................................52 6-1 Preparation of Imidoylbenzotriazoles 6.1 ................................................................77 7-1 Preparation of Amidines 7.1 from Imidoylbenzotriazoles.......................................94 8-1 Literature Methods for th e Preparation of Tetrazoles............................................106 8-2 Preparation of Tetrazoles 8.3 .................................................................................108

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ix LIST OF FIGURES Figure page 1-1 Structure of benzotriazole and benzotriazolyl group.................................................1 3-1 More Heterocycles Prepared from N -Acylbenzotriazoles........................................19 4-1 Tertiary Amides Obtained from N-Acylbenzotriazoles under Microwave Irradiation.................................................................................................................28 5-1 Hydroxy Acids 5.1 ...................................................................................................42 5-2 Preparation of Hydroxy N -Acylbenzotriazoles........................................................46

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x LIST OF SCHEMES Scheme page 2-1 Synthesis of N -Acylbenzotriazoles (Literature Method)............................................5 2-2 Synthesis of Acid Chlorides and Alkyl Chlorides.....................................................5 2-3 Preparation of N -Acylbenzotriazoles from Acid Chlorides.......................................6 2-4 Preparation of N -Acylbenzotriazoles from Carboxylic Acids...................................7 3-1 Literature Preparation Methods for 2-Oxazolines....................................................14 3-2 Literature Preparation Methods for 2-Thiazolines...................................................14 3-3 Preliminary Experiments under Thermal Conditions...............................................15 3-4 Preparation of 2-Substit uted 2-Oxazolines using N -Acylbenzotriazoles.................17 3-5 Preparation of 2-Subs tituted Thiazolines using N -Acylbenzotriazoles....................18 4-1 Microwave Preparation of Secondary Amides 4.1 Using N -Acylbenzotriazoles....27 5-1 Synthesis of Hydroxy Carboxamides.......................................................................40 5-2 General Reactions to Deriva tives of Hydroxy Carboxylic Acid..............................42 5-3 Unsuccessful Synthesis of -Hydroxyacylbenzotriazole.........................................43 5-4 Literature Methods of Synthesis of the oHydroxynaphthyl Amides......................44 5-7 Preparation of Amides and Esters from Naphthoic Acids.......................................48 5-8 Synthesis of -Hydroxy Carboxylic Esters..............................................................48 5-9 Synthesis of Hydroxy Carboxylic Thiolesters..........................................................49 6-1 Literature Methods of Prepar ation of Imidoylbenzotriazoles..................................76 6-2 Preparation of Imidoylbenzotriazoles 6.1 ................................................................76 7-1 Literature Methods of Preparation of Amidines......................................................90

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xi 7-2 Mechanism of the Acid-catal yzed Formation of Amidines.....................................93 7-3 Preparation of Amidines 7.1 from Imidoylbenzotriazoles.......................................93 8-1 Preparation of Tetrazoles 8.3 .................................................................................108

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xii Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy MICROWAVE-MEDIATED SYNTHESIS OF NITROGENAND/OR OXYGENCONTAINING COMPOUNDS By Chunming Cai May, 2006 Chair: Alan R. Katritzky Major Department: Chemistry Benzotriazole is a widely used synthetic auxiliary to many synthetic applications. We developed convenient and efficient methods for preparing benzotriazole derivatives and used them to prepare a few kinds of nitrogenand/or oxygen -containing compounds. Microwave synthesizers are widely used by orga nic chemists because they give excellent and repeatable results. We examined preparation of N -acylbenzotriazoles from carboxylic acids or acid chlorides. These intermediates were used to synthesize oxazolin es and thiazolines, secondary and tertiary amides, hydroxyl carbox amides, and esters. We were able to complete high-yielding r eactions starting from N -acylbenzotriazoles in 10 min, using microwaves as the heating source. We prepared various imi doylbenzotriazoles via two nove l methods and examined the synthetic approaches to obtain polys ubstituted amidines and 1,5-disubstituted tetrazoles in high yields in brief reactions. To prepare polysubstituted amidines, we used a microwave synthesizer (CEM) to accelerat e the reactions. All the reactions were

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xiii completed within 10 min and high yields we re obtained. To prepare 1,5-disubstituted tetrazoles, we completed the reactions in ha lf an hour under room temperature to give high yields without using microwaves.

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1 CHAPTER 1 GENERAL INTRODUCTION Benzotriazole chemistry has been studied in Prof. Alan R. Katritzkys research group for many years, and its ap plications in synthetic chem istry have been previously addressed.1,2 Microwave synthesizers became popular recently because of their heating pattern (different from conventional heatin g) and because of their reproducibility and safety3. N H N N N N N N N N Benzotriazole Bt1 = Benzotriazol-1-yl Bt2 = Benzotriazol-2-yl Figure 1-1 Structure of benzotri azole and benzot riazolyl group Benzotriazole is an excellent synthetic auxi liary that can be readily introduced to a variety of substrates and can lead to a lot of transformations because it acts as a leaving group, electron-withdrawing group, and even an electron-donating group in different cases. Benzotriazole is a cheap, stable com pound that is soluble in common organic solvents such as ethanol, benzene, met hylene chloride, chloroform, THF and DMF. Benzotriazolyl group has excellent le aving ability when attached to -carbon atom adjacent to hetero-atoms such as N, O, and S. Unlike halogens, the C -linked benzotriazole group can rarely be replaced by nucleophiles if there is no hetero-atom at the -carbon atom. It is also a good leaving gr oup when attached to a carbonyl group to form N -acylbenzotriazoles or to an imidoyl group to form imidoylbenzotriazoles which are efficient N -acylating and N -imidoylating agents. The benzot riazole group can be used

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2 as an activating group for -hydrogen (adjacent CH). A wi dely realized good property of benzotriazole is that it can be easily re moved by basic solutions, such as sodium bicarbonate solution, after being replaced by othe r nucleophiles. If products are not stable towards base, but stable towards acid, hydroc hloric acid solution (4N) can be used. Another important aspect of the benzotriazo le group is that it is stable during various synthetic operations. It might be introduced at the beginning of a sequence and carried through several steps. This dissertation is a bout the preparation of N -acylbenzotriazoles and imidoylbenzotriazoles for formation of simple amides, C -hydroxy-carboxamides and esters, and oxazolines, thiazolines, amidines and tetrazoles. In chapter 2, the preparation of N -acylbenzotriazoles from carboxylic acids or acid chlorides is discussed. The mechanism of the reaction forming N -acylbenzotriazoles is also addressed. Chapter 3 describes the formation of he terocyclic rings i nvolving nucleophilic substitution of benzotriazol e group to give oxazolines a nd thiazolines. A microwave synthesizer was used to synthesize these compo unds to give high yields in brief reactions. In chapter 4, the preparation of seconda ry and tertiary amides under microwave irradiation is studied. N -Acybenzotriazoles are versatil e neutral acylating reagents. Previously, amides were prepared from N -acybenzotriazoles under room temperature in about 4-6 hours. With the help from microwav e synthesizer, the speed of the reactions is accelerated dramatically and amides can be prepared in 10 minutes in high yields. In chapter 5, C -hydroxy-carboxamides and esters are prepared from N acylbenzotriazoles withou t prior protection. A microwave synt hesizer is used to deal with

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3 some reactions which are difficult to comp lete under room temperature in neutral conditions. In chapter 6, the synthesis of imidoylbenz otriazoles from two di fferent routes is discussed. In one of the two routes described, microwave synthesizer is also used to give good results. In chapter 7, the application of imid oylbenzotriazoles in the synthesis of polysubstituted amidines is discussed. Three different conditions are used to obtain a variety of amidines in high yields. A micr owave synthesizer was used in all these preparations of amidines. In chapter 8, the application of imidoylb enzotriazoles is extended to prepare 1,5disubstituted tetrazoles. The reactions ar e fast enough under room temperature; thus microwave is not required in this case.

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4 CHAPTER 2 BENZOTRIAZOLE AS AN ACID SCAVENGER IN THE SYNTHESIS OF N ACYLBENZOTRIAZOLES 2.1 Introduction N -Acylbenzotriazoles4 have hitherto been reported as versatile reagents for N acylation,5-10 formylation,11 trifluoroacylation,12 O -acylation,13 C -acylation,14-18 S acylation9 and for the synthesis of polycyclic heteroaromatics.19 A one-pot reaction to obtain N -acylbenzotriazoles involving benzotri azole, thionyl chloride and carboxylic acids was published in 2003.20 Extensive work in Prof. Katr itzkys group was able to be carried out after that discovery because this mild reaction gives high yields on a regular basis. Many N -acylbenzotriazoles which were very di fficult or impossible to make in the past became readily available. However, the mechanism behind this reaction (Scheme 21) was not fully understood at the time th e discovery occurred. The intermediate was believed to be BtSOBt or BtSOCl, which ar e compounds that have never been isolated. There is no proof showing the formation of th ese intermediates. The formation of BtSOBt or BtSOCl should be accompanied by the form ation of hydrochloric acid which combines with benzotriazole to form the salt benzotri azole hydrochloride, which is insoluble in methylene chloride. But th e mixture of BtH and SOCl2 in methylene chloride is clear, showing no sign of the formation of benzotri azole hydrochloride salt. Meanwhile, there is always a large amount of benzotriazole left af ter the reaction is complete. In other words, more benzotriazole is used than necessary. However, the exact amount of benzotriazole needed for this reaction requires clarificat ion of the mechanism of the reaction.

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5 R OH O SOCl2 R Bt O + + 4BtH CH2Cl2 RT, 2 h (BtH = benzotriazole) Scheme 2-1 Synthesis of N -Acylbenzotriazoles (L iterature Method) The combination of benzotriazole and thionyl chloride (1:1 ratio) was initially used by Sachin et al. to prepare acid chlorides (Scheme 2-2).21 In that work, benzotriazole was believed to act as a weak base to neutraliz e the hydrochloride acid generated during the chlorination. The formation of the precipitat ed benzotriazole hydrochl oride salt drove the reaction to completion quickly. From the results in this work, acid chlorides could be easily supposed to be intermediates to N -acylbenzotriazoles in the reaction shown in Scheme 2-1. A study of reactions between aci d chlorides and benzotriazole supports this supposition. The correct amount of benzotriazole needed for the reaction is discussed in this dissertation. Benzotriazole is used in the reaction not only as the reactant but also the acid scavenger (pKa for proton gain: 1.2). R OH O SOCl2 R Cl O + + BtH CH2Cl2 RT, 10 min 11 examples Yield: 90-100% Scheme 2-2 Synthesis of Acid Chlorides and Alkyl Chlorides 2.2 Results and Discussion 2.2.1 Preparation of N -Acylbenzotriazoles (2.1b-d,f,h ,i,l-o) from Acid Chlorides N -Acylbenzotriazoles (Table 2-1) with aryl or heterocyclic groups were prepared in 92% yields from the corresponding acid ch lorides. Benzoyl chlo ride (1 equiv) was dissolved in methylene chloride, and benzotri azole (2 equiv) was added in one portion. The reaction mixture was stirred for 30 min under room temperature. The formation of white precipitated solid was observed immedi ately. After the comple tion of the reaction, the white precipitate was filtered out and the solid was washed with copious methylene

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6 chloride. Evaporating the solv ent of the combined solution gave crude product which was purified by crystallization from chlorofo rm/hexanes to give pure 1-benzoyl-1 H -1,2,3benzotriazole ( 2.1h ) in 96% yield. For substrates with two acid chloride functionalities, 4 equiv of benzotriazole was used to ensure the completion of the reaction. Similarly, 9 more N-acylbenzotriazoles were prepared in high yields. Compounds (entry 1, Table 2-1) were also prepared from carboxylic ac ids, so the full char acterization of these compounds will be only described once. Compounds (entry 8, Table 2-1, 2.1mo ) were fully characterized by 1H and 13C NMR spectroscopy and by comparison of melting points with literature values. O R Cl O R Bt + 2 BtH CH2Cl2 30 min 2.1b-d,f,h,i,l-o Scheme 2-3 Preparation of N -Acylbenzotriazoles from Acid Chlorides Table 2-1 Preparation of N -Acylbenzotriazoles from Acid Chlorides Entry R Product (Yield %)a Entry R Product (Yield %)a 1 2-thienyl 2.1c (95) 6 cyclohexyl 2.1l (96) 2 benzyl 2.1f (92) 7 hexyl 2.1b (95) 3 phenyl 2.1h (96) 8 p -phenyleneb2.1m (96) 4 p -tolyl 2.1d (95) 9 carbonicb 2.1n (91) 5 2-furyl 2.1i (92) 10 ethanedioylb 2.1o (97) aIsolated yield. bBenzotriazole (4 equiv) is used. 2.2.2 Preparation of N -Acylbenzotriazoles from Carboxylic Acids The addition of the reactions in Scheme 2-2 and 2-3 gives th e reaction shown in Scheme 2-4, where it clearly s howed that 3 equiv of benzot riazole should be the exact amount required for the conversion of acids to N -acylbenzotriazoles. This conclusion was further confirmed by the results shown in Table 2-2. The yields were always high; moreover, no washing and drying are needed during workup. The crude product is pure

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7 enough for further use. Recrysta llization of the crude product from chloroform gave pure N -acylbenzotriazoles. Compounds 2.1al were fully characterized by 1H and 13C NMR spectroscopy and by comparison of melti ng points with literature values. R1COBt + SOCl2 + 3 BtH 1-2 h, RT CH2Cl2 R1CO2H 2.1a l Scheme 2-4 Preparation of N -Acylbenzotriazoles from Carboxylic Acids Table 2-2 Preparation of N -Acylbenzotriazoles from Carboxylic Acidsa Entry R1 Product (Yield %)b Mp (oC) Lit. Mp (oC) 1 phenethyl 2.1a (89) 62 64 62 64 2 n -hexyl 2.1b (92) 48 50 50 52 3 2-thienyl 2.1c (93) 172 173 173 175 4 pnitrophenyl 2.1d (91) 191 192 5 2 furyl 2.1e (92) 170 171 6 benzyl 2.1f (89) 63 65 7 pmethoxyphenyl 2.1g (92) 109 113 8 phenyl 2.1h (96) 110 112 9 ptolyl 2.1i (95) 122 123 10 methyl 2.1j (96) 50 49 11 phenylethenyl 2.1k (96) 149 151 12 cyclohexyl 2.1l (85) 85 84 aBenzotriazole (3 equiv) is used. bIsolated yield. 2.3 Conclusion In this chapter, preparation of N -acylbenzotriazoles from carboxylic acids, thionyl chloride and benzotriazoles was optimized and an alternative pr eparative method to obtain N -acylbenzotriazoles from acid chlorides was also described. The mechanism of the preparation methods was also discussed and supported by the resu lts reported in this chapter. The formation of the insoluble benz otriazole hydrochloride sa lt was suggested to be the driving force for both of the two sets of reactions.

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8 2.4 Experimental Section Melting points are uncorrected. Reactions under microwave irradiation were conducted in heavy-walled Pyrex tubes sealed with aluminum crimp caps fitted with a silicon septum or in round bottomed flasks equipped with a reflux condenser. Microwave heating was carried out with a single mode cavity Disc over Microwave Synthesizer (CEM Corporation, NC, USA), producing continuous irradiation at 2450 MHz. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 (with TMS for 1H and chloroformd for 13C as the internal reference), unless specified otherwise. 2.4.1 General Procedure for the Preparation of N -Acylbenzotriazoles (2.1b-d,f,h,i,lo) from Acid Chlorides Benzotriazole (2 or 4 equiv depends on th e number of acid chloride functional groups in the starting material) was added in one por tion to acid chloride in methylene chloride. The reaction mixture was stirred for 30 min. Th e precipitated white solid was filtered off and the solvent was removed under reduced pr essure to obtain the crude product, which was purified by recrystallization fr om chloroform/hexanes to obtain N acylbenzotriazole. 2.4.2 General Procedure for the Preparation of N -Acylbenzotriazoles 2.1al from Carboxylic Acids Thionyl chloride (4.00 mL, 55 mmol, 1.1 equiv) and benzotriazole (18.45 g, 155 mmol, 3.1 equiv) in methylene chloride (100 mL) were added dropwise to the carboxylic acid (50 mmol, 1 equiv) in methylene chloride (100 mL). The reaction was monitored by TLC. The precipitated white solid was filtered off and the solvent was removed in vacuo to obtain the crude product, which wa s purified by recrystallization from chloroform/hexane to obtain Nacylbenzotriazoles (2.1a)

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9 2.4.3 Characterization of N -Acylbenzotriazoles 2.1 1-(3-Phenylpropanoyl)-1 H -1,2,3-benzotriazole (2.1a): colorless needles (from chloroform/hexanes); mp 62 oC (lit.5 mp 63 oC); yield, 89% (11.17 g); 1H NMR 3.21 (t, J = 7.7 Hz, 2H), 3.73 (t, J = 7.7 Hz, 2H), 7.17.23 (m, 1H), 7.25 7.30 (m, 4H), 7.44 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H); 13C NMR 30.0, 36.9, 114.2, 119.9, 125.9, 126.4, 128.3, 128.5, 130.2, 130.9, 139.7, 145.9, 171.4. 1-Heptanoyl-1 H -1,2,3-benzotriazole (2.1b): colorless needles (from chloroform/hexanes); mp 48 50 oC (lit.22 mp 50 52 oC); yield, 92% (10.63 g); 1H NMR 0.91 (t, J = 7.0 Hz, 3H), 1.29 1.52 (m, 6H), 1.86 1.96 (m, 2H), 3.39 3.44 (m, 2H), 7.49 (td, J = 7.3, 0.8 Hz, 1H), 7.64 (td, J = 7.3, 0.8 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H); 13C NMR 13.9, 22.4, 24.3, 28.7, 31.4, 35.4, 114.3, 120.0, 125.9, 130.2, 131.0, 146.1, 172.6. 1-(2-Thienylcarbonyl) 1 Hbenzotriazole (2.1c): colorless needles (from chloroform/hexanes); mp 172 oC (lit.20 mp 173 oC); yield 93% (10.65 g); 1H NMR 7.30 (dd, J = 5.0, 4.0 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.91 (dd, J = 5.0, 0.9 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.60 (dd, J = 4.0, 0.9 Hz, 1H); 13C NMR 114.8, 120.2, 126.2, 128.0, 130.4, 132.1, 133.3, 137.1, 138.4, 145.7, 159.1. 1-(4-Nitrobenzoyl)-1 H -1,2,3-benzotriazole (2.1d): white microcrystals (from chloroform/hexanes); mp 191 oC (lit.15 mp 192 oC); yield, 91% (12.19 g); 1H NMR 7.61 (t, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.29

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10 8.45 (m, 5H); 13C NMR 114.7, 120.5, 123.5, 126.9, 131.0, 132.0, 132.6, 136.9, 145.9, 150.5, 165.0. 1-(2-Furoyl)-1 H -1,2,3-benzotriazole (2.1e): colorless needles (from chloroform/hexanes); mp 170 oC (lit.5 mp 171 oC); yield, 92% (9.80 g); 1H NMR 6.74 (dd, J = 3.5, 1.3 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.70 (td, J = 7.7, 0.8 Hz, 1H), 7.88 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 8.41 (d, J = 8.2 Hz, 1H); 13C NMR 112.9, 114.7, 120.1, 124.7, 126.3, 130.4, 132.1, 144.5, 145.5, 148.9, 155.0. 1-(Phenylacetyl)-1 H -1,2,3-benzotriazole (2.1f): colorless needles (from chloroform/hexanes); mp 63 oC (lit.5 mp 65 oC); yield, 89% (10.55 g); 1H NMR 4.73 (s, 2H), 7.28 7.40 (m, 3H), 7.46 7.53 (m, 3H), 7.64 (td, J = 7.7, 0.8 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H); 13C NMR 41.9, 114.4, 120.1, 126.2, 127.6, 128.7, 129.8, 130.4, 131.1, 132.4, 146.2, 170.2. 1-(4-Methoxybenzoyl)-1 H -1,2,3-benzotriazole (2.1g): colorless prisms (from chloroform/hexanes); mp 109 oC (lit.22 mp 113 oC); yield, 92% (11.64 g); 3.93 (s, 3H ), 7.06 ( d, J = 8.9 Hz, 2H ), 7.51 ( t, J = 7.2 Hz, 1H ), 7.69 ( t, J = 7.1 Hz, 1H ), 8.16 ( d, J = 6.2 Hz, 1H ), 8.29 ( d, J = 8.9 Hz, 2H ), 8.37 ( d, J = 8.2 Hz, 1H ); 55.6, 103.3, 113.9, 114.8, 120.0, 126.1, 130.1, 134.4, 145.6, 164.2. 1-Benzoyl-1 H -1,2,3-benzotriazole (2.1h): white needles (from chloroform/hexanes); mp 110 oC (lit.20 mp 116 117 oC); yield, 96% (10.70 g); 1H NMR 7.67.52 (m, 3H), 7.70.72 (m, 2H), 8.23.15 (m, 3H), 8.38 (d, J = 8.3 Hz, 1H); 13C NMR 114.7, 120.1, 126.3, 128.4, 130.3, 131.4, 131.7, 132.3, 133.6, 145.7, 166.6.

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11 1-(4-Methylbenzoyl)-1 H -1,2,3-benzotriazole (2.1i): colorless prisms (from chloroform/hexanes); mp 121 oC (lit.15 mp 123 oC); yield, 95% (11.20 g); 1H NMR 2.47 (s, 3H), 7.37 (d, J = 8.1 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 8.13 (d, J = 8.1 Hz, 3H), 8.14 (d, J = 8.1 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H); 13C NMR 21.7, 114.7, 120.0, 126.1, 128.5, 129.1, 130.1, 131.8, 132.3, 144.7, 145.6, 166.4. 1-Acetyl-1 H -1,2,3-benzotriazole (2.1j): colorless needles (from chloroform/hexanes); mp 50 oC (lit.23 mp 49 oC); yield, 96% (7.73 g); 1H NMR 3.00 (s, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H); 13C NMR 23.1, 114.2, 120.0, 126.0, 130.2, 130.8, 146.1, 169.4. 1-[(2 E )-3-Phenylprop-2-enoyl]-1 H -1,2,3-benzotriazole (2.1k): colorless needles (from chloroform/hexanes); mp 149 oC (lit.20 mp 151 oC); yield, 96% (11.95 g); 1H NMR 7.48.51 (m, 3H), 7.54 (ddd, J = 7.7, 6.9, 1.0 Hz, 1H), 7.70 (ddd, J = 7.7, 6.9, 1.0 Hz, 1H), 7.76 7.79 (m, 2H), 8.13 (d, JAB = 16.0 Hz, A part of AB system, 1H), 8.17 (d, JAB = 16.0 Hz, B part of AB system, 1H), 8.18 (td, J = 6.5, 0.9 Hz, 1H), 8.43 (dt, J = 8.2, 1.0 Hz, 1H); 13C NMR 114.7, 116.0, 120.1, 126.1, 128.9, 129.0, 130.2, 131.4, 134.1, 146.3, 148.7, 163.8. 1-(Cyclohexylcarbonyl)-1 H -1,2,3-benzotriazole (2.1l): white microcrystals (from chloroform/hexanes); mp 85 oC (lit.22 mp 94 oC); yield, 85% (9.85 g); 1H NMR 1.27 1.40 (m, 1H), 1.44 1.56 (m, 2H), 1.65 1.82 (m, 3H), 1.88 1.90 (m, 2H), 2.13 2.17 (m, 2H), 3.87 3.95 (m, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H)); 13C NMR 25.3, 25.6, 29.1, 43.1, 114.4, 119.9, 125.8, 130.1, 131.1, 146.0, 175.4.

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12 1 H -1,2,3-Benzotriazol-1-yl[4-(1 H -1,2,3-benzotriazol-1ylcarbonyl)phenyl]methanone (2.1m): white microcrystals; mp 232 234 oC [lit.24 mp 238 242 oC]; 1H NMR (DMSOd6, 300 MHz) 7.60 (dd, J = 8.1, 6.9 Hz, 2H), 7.77 (dd, J = 8.2, 6.9 Hz, 2H), 8.21 (d, J = 8.2 Hz, 2H), 8.42 (s, 4H), 8.45 (d, J = 8.4 Hz, 2H); 13C NMR (DMSOd6, 75 MHz) 114.8, 120.4, 126.7, 130.8, 131.4, 132.1, 135.6, 145.9, 165.8. 1,1'-Carbonylbisbenzotriazole (2.1n): white microcrystals; mp 180 182 oC (lit.25 mp 182 184 oC); 1H NMR (DMSOd6, 300 MHz) 7.60 7.65 (m, 2H), 7.76 7.81 (m, 2H), 8.22 8.27 (m, 4H); 13C NMR (DMSOd6, 75 MHz) 113.5, 120.9, 126.8, 127.1, 130.9, 132.6, 145.8. 1,1'-(1,2-Dioxo-1,2-ethanediyl)bis-1H-benzotriazole (2.1o): white microcrystals; mp 162 163 oC (lit.26 mp 163 164 oC); 1H NMR 7.65 (t, J = 7.7 Hz, 2H), 7.83 (t, J = 7.7 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H), 8.39 (d, J = 8.2 Hz, 2H); 13C NMR 113.9, 120.9, 127.7, 130.3, 131.6, 146.3, 158.0.

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13 CHAPTER 3 FACILE SYNTHESES OF OXAZOLINES AND THIAZOLINES USING N ACYLBENZOTRIAZOLES UNDE R MICROWAVE IRRADIATION 3.1 Introduction Oxazolines and thiazolines ar e important heterocycles.27,28 2-Oxazolines are structural entities in natura lly occurring iron chelators,29,30 cytotoxic cyclic peptides,31 and in antimitotic32 and neuroprotective agents.33 Well known applications of 2oxazolines include their use as synthetic intermediates,34,35 protecting groups and as chiral auxiliaries. Thiazoline derivatives possess anti HIV-1,36 antimitotic,37 and bioluminescent activities,38 and have recently found applications as building blocks in pharmaceutical drug discovery.39 41 Reaction of carboxylic acids with amino alcoho ls is the most common method for the synthesis of oxazolines.42 47 Other carboxylate functionaliti es can be used in similar methods including imidate hydrochlorides,48 ortho esters,49 imino ether hydrochlorides,50 aldehydes51 or nitriles.52 54 Thiazolines have been prepar ed: (i) by the condensation of amino thiols with nitriles,36 esters,55 imino ethers56 or imino triflates;57 (ii) from N -acyl-2aminoethanols 43,58 or -hydroxy thioamides;59 61 or (iii) by multistep conversions from oxazolines.62 However, there are limitations associated with these literatu re methods: direct conversions of carboxylic acids into the corresponding 2-oxazolines proceed with elimination of water at high temperatures (160 220 oC), require long reaction times (12 18 h) and frequently give low yields.63

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14 R2 R1 O N R R2 R1 R OEt EtO EtO R H R OH O R R OEt NH.HCl R NH OEt O N HO NH2 Scheme 3-1 Literature Preparation Methods for 2-Oxazolines R2 N H2 SH R1 S N R R2 R1 R O OR' N R OTf R NR' R NH OEt Scheme 3-2 Literature Prepara tion Methods for 2-Thiazolines Use of nitriles requires a Lewis acid a nd proceeds at high temperatures with elimination of ammonia.52 Other methods utilize complex reagents45,60,64 or strongly acidic conditions.47 The problem of long reaction times in the synthesis of oxazolines has been solved to some extent using microwaves,42,50,54 but the reported procedures that involve domestic ovens suffer from low repr oducibility and lack ge neral applicability. N -Acylbenzotriazoles4 have hitherto been reported as versatile reagents for N acylation,5 formylation,11 trifluoroacylation,12 O -acylation,13 C -acylation,14,15 and for the synthesis of polycyclic heteroaromatics.19 We now apply N -acylbenzotriazoles in a mild and general procedure for the direct synt hesis of 2-substituted 2-oxazolines and 2-

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15 substituted 2-thiazolines under microwave irradiation using a single mode cavity synthesizer3 which assures reproducibility and safe ty. Microwave heating has emerged as a powerful technique to promote a variety of chemical reactions.3,65-69 Microwave reactions are also attractive in offering re duced pollution and low cost together with simplicity in processing and handling.70,71 3.2 Results and Discussion 3.2.1 Preparation of N -Acylbenzotriazoles. The starting N -acylbenzotriazoles 3.1a k with aryl or heterocyclic groups were prepared from the corresponding carboxylic ac ids following the procedure described in chapter 2. 3.2.2 Preparation of 2-Oxazolines. Microwave reactions were performed in sealed heavy-walled Pyrex tubes under controlled conditions in a safe and reproduc ible procedure. Single mode microwave irradiation was used at a fixed temperature, pressure and irradiation power during the reaction time by an automatic power control. NH2O H O N R N H O H O R O N reflux, CHCl 3 40-50% SM RT, 12 h + R = 4-tolyl RCOBt (1:1) SOCl2 other side products + + 70% 2 h, RT R Scheme 3-3 Preliminary Experiments under Thermal Conditions Optimization of the reaction conditions was carried out on the cyclocondensation of 1 H -1,2,3-benzotriazol-1-yl (4-tolyl)methanone ( 3.1a ) and 2-amino-2-methyl-1-propanol ( 3.2 ) in chloroform and different combinations of temperature, time, and irradiation

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16 power were studied in order to achieve th e maximum chemical yield at the lowest reaction temperature. Our initial microwav e experiment with the mixture containing 3.1a and 2-amino-2-methyl-1-propanol ( 3.2 ) at 80 oC and 50 W irradiation power for 10 min produced the desired oxazoline 3.3a along with the uncyclized intermediate, N -(2hydroxy-1,1-dimethylethyl)-4-methylbenzamide in a 2:1 ratio as determined by the 1H NMR spectrum of the crude product mixture. SOCl2 has been advantageously used for the cyclization of such intermediates.72 Accordingly, addition of SOCl2 to the above reaction mixture and subsequent irradiation for 2 min resulted in complete conversion of the uncyclized intermediate into 4,4dimethyl-2-(4-methylphenyl)oxazoline ( 3.3a ) without the formation of side products or any noticeable decomposition. Thus, a two-step one-pot procedure was developed for the s ynthesis of 2-substituted oxazolines from N acylbenzotriazoles under mild conditions using microw ave irradiation. By contrast, thermal reaction of 3.1a and the aminoalcohol 3.2 in refluxing chloroform for 30 min showed the presence of substantial amounts (40 50%) of starting materials and the formation of N -(2-hydroxy-1,1-dimethylethyl)-4-met hylbenzamide along with another side product. Stirring the reaction mixture at room temperature for 12 h resulted in a 1:1 ratio of the desired oxazoline 3.3a and the uncyclized intermed iate, which, on addition of SOCl2, cyclized in 2 h to give the oxazoline 3.3a in 70% yield (Scheme 3-3). Comparison of the above reaction conditions and result s obtained suggested the use of microwave irradiation as the energy source for the synthesis of 2-substituted 2-oxazolines from N acylbenzotriazoles. The above optimized microwave reaction cond itions were applied to the synthesis of a variety of 2-substituted 2-oxazolines 3.3a j (Table 3-1). These results illustrate the

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17 general applicability of this method for th e preparation of 2-substituted 2-oxazolines under mild conditions (80 oC) and short reaction times (12 min). Use of N acylbenzotriazoles also avoids some earli er observed complications in microwave reactions, such as dimerization or the excl usive formation of amides from carboxylic acids.50 R Bt O O H NH2 O N R + Microwavesa 3.1a j 3.2 3.3a j aMW, 80 W, 80 oC, 10 min, CHCl3, then SOCl2, MW, 2 min. Scheme 3-4 Preparation of 2-Substituted 2-Oxazolines 3.3a j using N Acylbenzotriazoles Table 3-1 Preparation of 2-Substituted 2-Oxazolines 3.3 using N -Acylbenzotriazoles Entry Reactants R Product (Yield %)a 1 3.1a + 3.2 4-CH3C6H4 3.3a (98) 2 3.1b + 3.2 4-CH3OC6H4 3.3b (95) 3 3.1c + 3.2 4-NO2C6H4 3.3c (90) 4 3.1d + 3.2 4-ClC6H4 3.3d (90) 5 3.1e + 3.2 2-ClC6H4 3.3e (98) 6 3.1f + 3.2 Phenyl 3.3f (86) 7 3.1g + 3.2 1-Naphthyl 3.3g (95) 8 3.1h + 3.2 2-Furyl 3.3h (95) 9 3.1i+3.2 2-Phenylethenyl 3.3i (84) 10 3.1j+3.2 1-(6-Methoxy-2naphthyl)ethyl 3.3j (91) aIsolated yield. 3.2.3 Preparation of Thiazolines The procedure developed for the synthesi s of oxazolines was successfully applied to the preparation of thiazolines. Thus, condensation of N -acylbenzotriazoles 3.1a f,h,i with 2-aminoethanethiol hydrochloride ( 3.4 ) in the presence of Et3N under microwave irradiation at 80 oC and 80 W irradiation power for 10 min, followed by the addition of

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18 SOCl2 and subsequent irradiation for 2 min, furnished the desired 2-substituted 2thiazolines 3.5a f,h,i in excellent yields (Table 3 2). Again, no formation of any side product was detected in the cr ude reaction mixtures as determined by TLC analysis and 1H NMR spectra. Our method also avoids multiste p preparation of starting materials or the requirement of special reagents.36, 45, 56, 58, 60, 61 N S R S H NH2.HCl + RCOBt 3.4 microwavesa 3.5a f,h,i 3.1a f,h,i aMW, 50 W, 80 oC, 10 min, Et3N, CHCl3, then SOCl2, MW, 2 min. Scheme 3-5 Preparation of 2Substituted Thiazolines using N -Acylbenzotriazoles 3.1a f,h,i Table 3-2 Preparation of 2-S ubstituted Thiazolines using N -Acylbenzotriazoles 3.1af,h,i Entry Reactants R Product (Yield %)a 1 3.1a + 3.4 4-CH3C6H4 3.5a (95) 2 3.1b + 3.4 4-CH3OC6H4 3.5b (97) 3 3.1c + 3.4 4-NO2C6H4 3.5c (94) 4 3.1d + 3.4 4-ClC6H4 3.5d (97) 5 3.1e + 3.4 2-ClC6H4 3.5e (91) 6 3.1f + 3.4 Phenyl 3.5f (85) 7 3.1h + 3.4 2-Furyl 3.5h (95) 8 3.1i+3.4 2-Phenylethenyl 3.5i (91) aIsolated yield. Further, we used this method to prepare the chiral oxazoline 3.6 by the reaction of (2S)-2-amino-3-phenyl-1-propanol and 1 H -1,2,3-benzotriazol-1-yl-phenylmethanone ( 3.1f ) in 82% yield. Bis-oxazoline 3.7 and -thiazoline 3.8 were prepared by the reactions of 1,1'-(1,4-phenyl enedicarbonyl)bis-1 H -benzotriazole ( 3.1k ) with 3.2 and 3.4 respectively, in 94 and 95% yields. This pro cedure also works well for the preparation of 5,6-dihydro-4 H -1,3-oxazines; reactions of 3.1c and 3.1d with 3-amino-1-propanol under

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19 the similar conditions furnished 5,6-dihydro-4 H -1,3-oxazines 3.9 and 3.10 in 84% and 96% yields, respectively. N O O N O N S N S N N O NO2 N O Cl 3.6 82% 3.7 95% 3.8 94% 3.9 84% 3.10 96% Figure 3-1 More Heterocycles Prepared from N -Acylbenzotriazoles 3.3 Conclusions In summary, we have introduced a genera l method for the direct preparation of a variety of 2-substituted oxazolines and -thi azolines in excellent yields from readily available N -acylbenzotriazoles, under mild conditi ons using microwaves in a safe and reproducible procedure. 3.4 Experimental Section Melting points are uncorrect ed. All of the reactions under microwave irradiation were conducted in heavy-walled Pyrex tubes seal ed with aluminum crimp caps fitted with a silicon septum. Microwave heating was carri ed out with a single mode cavity Discover Microwave Synthesizer (CEM Corporation, NC, USA), producing continuous irradiation at 2455 MHz. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 (with TMS for 1H and chloroformd for 13C as the internal reference).

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20 3.4.1 General Procedure for Preparing 2-Oxazolines Using N-Acylbenzotriazoles by Conventional Method A solution of 2-amino-2-methyl-1-propanol ( 3.2 ) (2 mmol) and 1H-1,2,3benzotriazol-1-yl(4-methylphenyl)methanone ( 3.1a ) (1 mmol) in CHCl3 (10 mL) was stirred at 25 oC for 12 h. SOCl2 (6 mmol) was added and the reaction mixture was stirred for 2 h. Aqueous work-up gave a residue th at was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2) to give 3.3a (70%). 3.4.2 General Procedure for Preparing 2-Oxazolines 3.3 or 2-Thiazolines 3.5 Using N-Acylbenzotriazoles 3.1 under Microwave Irradiation A dried heavy-walled Pyrex t ube containing a small stir bar was charged with 2amino-2-methyl-1-propanol ( 3.2 ) or 2-aminoethanethiol hydrochloride ( 3.4 ) (2 mmol), N acylbenzotriazole (1 mmol) and CHCl3 (0.5 mL) (reactions with 3.4 were carried out in presence of Et3N). The tube containing the reaction mi xture was sealed with an aluminum crimp cap fitted with a silicon septum and then it was exposed to microwave irradiation (50 W) for 10 min at a temperature of 80 oC. The build-up of pressure in the closed reaction vessel was carefully monitored and was found to be typically in the range 4 10 psi. After the irradiation, th e reaction tube was cooled with high-pressure air through an inbuilt system in the instrument un til the temperature had fallen below 30 oC ( ca 2 min). SOCl2 (6 mmol) was added and the reaction mi xture was again exposed to microwave irradiation (50 W) for 2 min at 80 oC. After cooling to room temperature, the reaction mixture was extracted with CHCl3. Aqueous work-up gave a re sidue that was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2) to give 2oxazolines 3.3a j or 2-thiazolines 3.5a i.

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21 3.4.3 Characterization of N -Acylbenzotrizazoles 3.1g,j 1 H -1,2,3-Benzotriazol-1-yl(1-naphthyl)methanone (3.1g): colorless needles (from benzene); mp 134 136 oC (Lit.5 mp 136 137 oC); yield, 88%. 1-[2-(6-Methoxy-2-naphthyl)propanoyl]-1 H -1,2,3-benzotriazole (3.1j):73 colorless needles (from chloroform); mp 163 165 oC; yield, 95%. 3.4.4 Characterization of Oxazolines 3.3aj 4,4-Dimethyl-2-(4-methylphenyl) -4,5-dihydro-1,3-oxazole (3.3a):74 colorless oil; yield, 98%; 1H NMR 7.82 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 4.08 (s, 2H), 2.38 (s, 3H), 1.37 (s, 6H); 13C NMR 162.1, 141.4, 128.9, 128.1, 125.2, 79.0, 67.4, 28.4, 21.5. 4,4-Dimethyl-2-(4-methoxyphenyl )-4,5-dihydro-1,3-oxazole (3.3b):75 colorless oil; yield, 95%; 1H NMR 7.88 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.08 (s, 2H), 3.84 (s, 3H), 1.37 (s, 6H); 13C NMR 161.9, 161.9, 129.9, 120.5, 113.6, 79.0, 67.4, 55.3, 28.4. 4,4-Dimethyl-2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole (3.3c):54 colorless oil; yield, 90%; 1H NMR 8.25 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 4.16 (s, 2H), 1.40 (s, 6H); 13C NMR 160.2, 149.3, 133.9, 129.2, 123.4, 79.5, 68.2, 28.3. 2-(4-Chlorophenyl)-4,4-dimethy l-4,5-dihydro-1,3-oxazole (3.3d):76 colorless oil; yield, 90%; 1H NMR 7.87 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 4.11 (s, 2H), 1.38 (s, 6H); 13C NMR 161.2, 137.3, 129.5, 128.5, 126.6, 79.2, 67.7, 28.4. 2-(2-Chlorophenyl)-4,4-dimethy l-4,5-dihydro-1,3-oxazole (3.3e):76 colorless oil; yield, 98%; 1H NMR 7.71 (dd, J = 5.6, 1.8 Hz, 1H), 7.44 7.28 (m, 3H), 4.13 (s, 2H), 1.41 (s, 6H); 13C NMR 160.9, 133.3, 131.3, 131.2, 130.4, 128.0, 126.4, 79.2, 68.0, 28.2.

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22 2-Phenyl-4,4-dimethyl-4,5dihydro-1,3-oxazole (3.3f):74 colorless oil; yield, 86%; 1H NMR 7.95 7.92 (m, 2H), 7.49 7.37 (m, 3H), 4.11 (s, 2H), 1.39 (s, 6H); 13C NMR 162.0, 131.1, 128.2, 128.2, 128.0, 79.1, 67.5, 28.4. 2-(1-Naphthyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (3.3g): colorless needles (from chloroform); mp 53 54oC (Lit.77 mp 56 57 oC); yield, 95%; 1H NMR 7.81 7.75 (m, 4H), 7.47 7.42 (m, 3H), 3.91 (s, 2H), 3.75 (s, 2H), 1.29 (s, 6H); 13C NMR 164.2, 133.5, 132.8, 132.4, 128.2, 127.6, 127.5, 126.9, 126.1, 125.7, 79.4, 67.1, 35.1, 28.3. 2-(2-Furyl)-4,5-dihydro-4,4dimethyl-1,3-oxazole (3.3h):54 colorless oil; yield, 95%; 1H NMR 7.52 (d, J = 1.0 Hz, 1H), 6.92 (d, J = 3.3 Hz, 1H), 6.47 (dd, J = 3.3, 1.6 Hz, 1H), 4.08 (s, 2H), 1.38 (s, 6H); 13C NMR 154.5, 145.0, 143.1, 114.0, 111.4, 79.1, 67.7, 28.3. 2-(2-Phenylethenyl)-4,5-dihydro-4,4-dimethyl-1,3-oxazole (3.3i):47 colorless oil; yield, 84%; 1H NMR 7.47 (dd, J = 8.0, 1.9 Hz, 2H), 7.38 7.31 (m, 4H), 6.60 (d, J = 16.2 Hz, 1H), 4.03 (s, 2H), 1.34 (s, 6H); 13C NMR 161.8, 139.6, 135.2, 129.3, 128.8, 127.3, 115.5, 78.8, 67.2, 28.3. 2-[1-(6-Methoxy-2-naphthalenyl)ethyl ]-4,5-dihydro-4,4-dimethyl-1,3-oxazole (3.3j): colorless needles (from chloroform); mp 101 102 oC (Lit.78 mp 103 105 oC); yield, 91%; 1H NMR 7.72 7.69 (m, 3H), 7.41 (dd, J = 6.8, 1.6 Hz, 1H), 7.15 7.11 (m, 2H), 3.91 3.80 (m, 6H), 1.60 (d, J = 7.1 Hz, 3H), 1.29 (s, 6H); 13C NMR 167.8, 157.6, 136.8, 133.6, 129.3, 129.0, 127.1, 126.0, 125.7, 118.8, 105.6, 79.1, 66.9, 55.3, 39.4, 28.4, 28.2, 19.4. 3.4.5 Characterization of Thiazolines 3.5af,h,i 2-(4-Methylphenyl)-4,5-dih ydro-1,3-thiazole (3.5a): brownish microcrystals (from diethyl ether); mp 40 42 oC (Lit.79 mp 41 oC); yield, 95%; 1H NMR 7.72 (d,

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23 J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 4.44 (t, J = 8.4 Hz, 2H), 3.40 (t, J = 8.4 Hz, 2H), 2.39 (s, 3H); 13C NMR 168.3, 141.4, 130.6, 129.1, 128.3, 65.1, 33.6, 21.4. 2-(4-Methoxyphenyl)-4,5-di hydro-1,3-thiazole (3.5b): colorless needles (from chloroform); mp 51 53 oC (Lit.79 mp 53 54 oC); yield, 97%; 1H NMR 7.78 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.42 (t, J = 8.2 Hz, 2H), 3.83 (s, 3H), 3.38 (t, J = 8.2 Hz, 2H); 13C NMR 167.6, 161.8, 129.9, 126.0, 113.7, 65.0, 55.3, 33.6. 2-(4-Nitrophenyl)-4,5-dihydro-1,3-thiazole (3.5c): colorless needles (from chloroform); mp 150 52 oC (Lit.79 mp 146 148 oC); yield, 94%; 1H NMR 8.27 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 4.53 (t, J = 8.5 Hz, 2H), 3.51 (t, J = 8.5 Hz, 2H); 13C NMR 166.6, 149.2, 138.7, 129.2, 123.7, 65.5, 34.2 2-(4-Chlorophenyl)-4,5-dih ydro-1,3-thiazole (3.5d): colorless needles (from chloroform); mp 50 52 oC (Lit.80 mp 53 55 oC); yield, 97%; 1H NMR 7.77 (dd, J = 6.9, 1.8 Hz, 2H), 7.38 (dd, J = 6.9, 1.8 Hz, 2H), 4.45 (t, J = 8.4 Hz, 2H), 3.43 (t, J = 8.4 Hz, 2H); 13C NMR 167.3, 137.1, 131.7, 129.6, 128.7, 65.2, 33.9. 2-(2-Chlorophenyl)-4,5-dih ydro-1,3-thiazole (3.5e):81 colorless oil; yield, 91%; 1H NMR 7.61 (dd, J = 5.1, 2.2 Hz, 1H), 7.44 (dd, J = 6.5, 1.5 Hz, 1H), 7.37 7.29 (m, 2H), 4.48 (t, J = 8.5 Hz, 2H), 3.47 (t, J = 8.5 Hz, 2H); 13C NMR 166.2, 133.0, 132.4, 130.9, 130.6, 130.4, 126.6, 65.1, 34.7. 2-Phenyl-4,5-dihydro-1,3-thiazole (3.5f):79 colorless oil; yield, 85%; 1H NMR 7.84 (d, J = 8.5 Hz, 2H), 7.47 7.41 (m, 3H), 4.47 (t, J = 8.4 Hz, 2H), 3.42 (t, J = 8.4 Hz, 2H); 13C NMR 168.5, 133.2, 131.1, 128.5, 128.3, 65.2, 33.6. 2-(2-Furyl)-4,5-dihydro-1,3-thiazole (3.5h):82 colorless oil; yield, 95%; 1H NMR 7.53 (d, J = 1.8 Hz, 1H), 6.90 (d, J = 3.4 Hz, 1H), 6.49 (dd, J = 3.4, 1.8 Hz, 1H), 4.43

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24 (t, J = 8.2 Hz, 2H), 3.40 (t, J = 8.2 Hz, 2H); 13C NMR 157.9, 147.9, 144.8, 113.7, 111.7, 64.8, 33.4. 2-[(1 E )2-Phenylethenyl]-4,5-dihy dro-1,3-thiazole (3.5i): colorless needles (from chloroform); mp 91 93 oC (Lit.83 mp 94 95 oC); yield, 91%; 1H NMR 7.50 (d, J = 7.7 Hz, 2H), 7.40 7.35 (m, 3H), 7.15 7.01 (m, 2H), 4.38 (t, J = 8.1 Hz, 2H), 3.35 (t, J = 8.1 Hz, 2H); 13C NMR 168.0, 141.3, 135.3, 129.4, 128.8, 127.5, 122.6, 64.6, 33.0. 3.4.6 Characterization of Miscellane ous Heterocycles 3.6, 3.7, 3.8, 3.9, 3.10 (4 S )-4-Benzyl-2-phenyl-4,5-dihydro-1,3-oxazole (3.6):84 prepared by the reaction of (2 S )-2-amino-3-phenyl-1-propanol and 3.1f according to the general procedure; colorless oil; yield, 82%; [ ]D 20 = 12o ( c = 1.53, CHCl3); 1H NMR 7.97 7.93 (m, 2H), 7.50 7.37 (m, 3H), 7.33 7.19 (m, 5H), 4.63 4.53 (m, 1H), 4.36 4.30 (m, 1H), 4.13 (dd, J = 8.5, 7.3 Hz, 1H), 3.23 (dd, J = 13.5, 5.0 Hz, 1H), 2.72 (dd, J = 13.5, 8.9 Hz, 1H), 13C NMR 163.9, 137.9, 131.3, 129.2, 128.6, 128.5, 128.1, 127.7, 126.4, 71.8, 67.8, 41.8. 2,2'-(1,4-Phenylene)bis[4,5-dihydr o-4,4-dimethyl-1,3-oxazole] (3.7):47 prepared by the reaction of 3.2 (2 equiv) and 3.1k (1 equiv) according to the general procedure; colorless oil; yield, 95%; 1H NMR 7.97 (s, 4H), 4.13 (s, 4H), 1.40 (s, 12H); 13C NMR 161.6, 130.5, 128.2, 79.2, 67.8, 28.4. 2,2'-(1,4-Phenylene)bis[4,5-di hydro-1,3-thiazole] (3.8):81 prepared by the reaction of 3.4 (2 equiv) and 3.1k (1 equiv) according to the general procedure; colorless needles (from chloroform); mp 106 108 oC; yield, 94%; 1H NMR 7.88 (s, 4H), 4.49 (t, J = 8.4 Hz, 4H), 3.45 (t, J = 8.5 Hz, 4H); 13C NMR 167.8, 135.5, 128.4, 65.3, 33.8. 2-(4-Nitrophenyl)-5,6-dihydro-4 H -1,3-oxazine (3.9): prepared by the reaction of 3-amino-1-propanol and 3.1c according to the general procedure; colorless needles (from

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25 chloroform); mp 143 144 oC (Lit.85 mp 145 146 oC); yield, 84%; 1H NMR 8.22 8.19 (m, 2H), 8.07 8.03 (m, 2H), 4.40 (t, J = 5.5 Hz, 2H), 3.65 (t, J = 5.8 Hz, 2H), 2.01 (qn, J = 5.8 Hz, 2H); 13C NMR 153.8, 148.9, 139.9, 127.8, 123.1, 65.4, 42.8, 21.7. 2-(4-Chlorophenyl)-5,6-dihydro-4 H -1,3-oxazine (3.10):86 prepared by the reaction of 3-amino-1-propanol and 1d according to the general procedure; colorless oil; yield, 96%; 1H NMR 7.84 7.80 (m, 2H), 7.35 7.30 (m, 2H), 4.35 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.8 Hz, 2H), 1.97 (qn, J = 5.8 Hz, 2H); 13C NMR 154.7, 136.3, 132.6, 128.3, 128.2, 65.2, 42.6, 21.8.

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26 CHAPTER 4 PREPARATION OF SECONDARY AND TERTIARY AMIDES UNDER MICROWAVE IRRADIATION 4.1 Introduction Secondary and tertiary amides are mostly prepared by the treatment of activated derivatives of acids, such as acid halides, acid anhydrides, or esters, with primary and secondary amines. Reactions of amines with acid halides are highly exothermic. Acid anhydrides, especially cyclic anhydrides, gi ve imides easily with primary amines. Acylations of primary and secondary amines by esters frequently require strongly basic catalysts and/or high pressure. N -Acylbenzotriazoles have been used to prepare primary, secondary and tertiary amides, but some of the reactions under conventional conditions require several hours (4-5 h) for completion.5 Meanwhile, there have been few successful attempts to obtain amides from unreactive N -acylbenzotriazoles (alkylacylbenzotriazoles) and amines (especially arylamines and bulky secondary amines). In this dissertation, microwave conditions have been used to produce the desired secondary and tertiary amides by the reactions of primary and s econdary amines with readily available N acylbenzotriazoles. 4.2 Results and Discussion We have now developed micr owave conditions that produ ced the desired secondary and tertiary amides by the reac tions of a variety of primary amines with readily available Nacylbenzotriazoles. Thus, amides 4.1a Ac, 4.2a b were obtained in 87% yields in 10 min under microwave irradiation (Table 41, Figure 4-1). Microwave reactions were

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27 performed in a 50 mL round-bottomed flask equipped with a reflux condenser for 4.1a Ac or a 10 mL sealed tube for 4.2a b Single-mode microwave irradiation was used at a fixed temperature, pressure and irradi ation power during the reaction time using an automatic power control. + O N H R2NH2 microwaves R1COBt R1 R2 4.1a Ac Scheme 4-1. Microwave Prepar ation of Secondary Amides 4.1a Ac Using N Acylbenzotriazoles Table 4-1. Microwave Prepara tion of Secondary Amides 4.1 Using N Acylbenzotriazolesa Entry R1 R2 Product (Yield %)bMp (oC) Lit. Mp (oC) 1 Cyclohexyl pTolyl 4.1a (96) 154 156 144.7 2 Phenyl 2 Pyridyl 4.1b (91) 77 78 82 3 Benzyl Benzyl 4.1c (90) 115 117 117 4 Benzyl pTolyl 4.1d (91) 133 135 5 Phenethyl pTolyl 4.1e (92) 127 129 6 pChlorophenyl pTolyl 4.1f (91) 206 213 7 pMethoxyphenyl Benzyl 4.1g (89) 128 128 8 pNitrophenyl Benzyl 4.1h (96) 136 141 9 2 Furyl pTolyl 4.1i (96) 108 109 10 nHexyl pTolyl 4.1j (93) 77 78 11 Phenyl 2 Furylmethyl 4.1k (90) 96 99 12 2 Furyl Cyclohexyl 4.1l (94) 106 110 13 pTolyl pTolyl 4.1m (91) 158 158 14 Phenethyl Benzyl 4.1n (93) 80 82 15 Phenyl pMethoxyphenyl 4.1o (88) 156 57 157 16 pNitrophenyl Phenyl 4.1p (95) 206 208 211 17 pTolyl n -Butyl 4.1q (92) 52 54 48 53 18 2-Thienyl pTolyl 4.1r (89) 103 105 104 19 2-Thienyl Benzyl 4.1s (92) 116 119 20 2-Thienyl 2 Furylmethyl 4.1t (92) 100 Novel 21 2-Indolyl Benzyl 4.1u (93) 218 220 22 Phenyl Benzyl 4.1v (92) 101 105 23 p -Phenylene Benzyl 4.1w (92) 262 264 24 p -Phenylene n -Butyl 4.1x (92) 230 233

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28 Table 4-1 Continued Entry R1 R2 Product (Yield %)bMp (oC) Lit. Mp (oC) 25 Methyl pTolyl 4.1y (93) 150 153 26 Ethylene Phenyl 4.1z (94) 250 254 27 Phenylethenyl pTolyl 4.1Aa (87) 156 159 28 Phenylethenyl Benzyl 4.1Ab (92) 107 107 29 pTolyl Methyl 4.1Ac (92) 143 143 aMW, 80 W, 80 oC, 10 min, CHCl3. bIsolated yield. N O O N O O 4.2a 95% 4.2b 96% Figure 4-1. Tertiary Amides Obtained fr om N-Acylbenzotriazoles under Microwave Irradiation 4.3 Conclusion In summary, various secondary and tertiary amides were prepared in high yields in 10 min under microwave irradiation. 4.4 Experimental Section 4.4.1 General Procedure for the Preparation of Amides 4.1aAc For amides 4.1a-v,y, the N acylbenzotriazole (10 mmol) and amine (10.5 mmol) in chloroform (10 mL) were exposed to microw ave irradiation (80 W) for 10 min at a temperature of 80 oC. The reaction mixture was diluted with chloroform (20 mL). Aqueous work up gave a residue that was purified by recrystallization (from chloroform or ethanol) or column chro matography to obtain amides 4.1a v,y. For amides 4.1w-x the N acylbenzotriazole (10 mmol) and amine ( 21.0 mmol) in chloroform (10 mL) were exposed to microwave irradiation (80 W) for 10 min at a temperature of 80 oC. The resulting white solid was filtered off and recrystalized from methanol to obtain amides

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29 4.1w-x For amide 4.1z, the N acylbenzotriazole (21 mmol) and amine (10 mmol) in chloroform (10 mL) were exposed to microw ave irradiation (80 W) for 10 min at a temperature of 80 oC. The resulting white solid was f iltered off and recrystalized from methanol to obtain amide 4.1z. For amides 4.1Aa-Ab, the N acylbenzotriazole (12 mmol) and amine (10 mmol) in chloroform (10 mL) were exposed to microwave irradiation (80 W) for 10 min at a temperature of 80 oC. The reaction mixture was diluted with chloroform (20 mL). Aqueous work up gave a residue that was purified by recrystallization (fro m methanol) or column chromatography to obtain amides 4.1Aa-Ab. 4.4.2 Characterizations of Amides 4.1 N -(4-Methylphenyl)cyclohexanecarboxamide (4.1a). 1-(Cyclohexylcarbonyl)1 H -1,2,3-benzotriazole (2.29 g, 10 mmol) and 4-methylaniline (1.12 g, 10.5 mmol) in chloroform (10 mL) were exposed to microw ave irradiation (80 W) for 10 min at a temperature of 80 oC. The reaction mixture was diluted with chloroform (20 mL). The reaction mixture was washed by concentrated sodium carbonate solution (20 mL, twice) and brine (20 mL). The organic layer was dr ied over magnesium sulfate. After filtration, CHCl3 was removed under reduced pressure to yield the crude product which was further purified by recrystallization from chloroform/h exanes to obtain colorless plates: mp 154 156 oC (lit.87 mp 144.7 oC); yield, 96% (2.08 g); 1H NMR 1.24 1.35 (m, 2H), 1.46 1.58 (m, 2H), 1.69 (m, 1H), 1.80 1.83 (m, 2H), 1.91 1.93 (m, 2H), 2.16 2.25 (m, 1H), 2.30 (s, 3H), 7.09 (d, J = 8.1 Hz, 2H), 7.35 (br s, 1H), 7.40 (d, J = 8.1 Hz, 3H); 13C NMR (1 signal is hidden) 20.7, 25.6, 29.6, 46.4, 119.9, 129.3, 133.6, 135.5, 174.3. NPyridin-2-ylbenzamide (4.1b): purified by recrystallization from methanol, white microcrystals; mp 77 oC (lit.88 mp 82 oC); yield, 91% (1.80 g); 1H NMR

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30 (DMSO -d6) 5.93 (br s, 1H), 6.42 6.48 (m, 2H), 7.33 7.38 (m, 1H), 7.50 (td, J = 7.4, 0.6 Hz, 2H), 7.62 (td, J = 7.1, 0.9 Hz, 1H), 7.89 (dd, J = 4.1, 0.8 Hz, 1H), 7.96 (dd, J = 7.5, 0.8 Hz, 2H); 13C NMR (DMSO -d6) 108.1, 111.8, 128.5, 129.3, 130.9, 132.8, 137.1, 147.4, 159.7, 167.5. NBenzyl-2-phenylacetamide (4.1c): purified by recrys tallization from chloroform/hexanes; white microcrystals; mp 115 oC (lit.89 mp 117 oC); yield, 90% (2.03 g); 1H NMR 3.56 (s, 2H), 4.36 (d, J = 5.9 Hz, 2H), 6.07 (br s, 1H), 7.15 7.34 (m, 10H); 13C NMR 43.4, 43.6, 127.2, 127.3, 127.4, 128.5, 128.9, 129.3, 134.8, 138.1, 170.9. N(4-Methylphenyl)-2-phenylacetamide (4.1d): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 133 oC (lit.90 mp 135 oC); yield, 91% (2.05 g); 1H NMR 2.27 (s, 3H), 3.68 (s, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.24 7.39 (m, 8H); 13C NMR 20.7, 44.5, 120.1, 127.4, 129.0, 129.3, 129.4, 134.0, 134.7, 135.1, 169.2. N(4-Methylphenyl)-3-phenylpropanamide (4.1e): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 127 oC (lit.91 mp 129 oC); yield, 92% (2.20 g); 1H NMR 2.28 (s, 3H), 2.58 (t, J = 7.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 7.07 (d, J = 8.1Hz, 2H), 7.18 7.36 (m, 8H); 13C NMR 20.8, 31.6, 39.3, 120.1, 126.3, 128.3, 128.6, 129.4, 133.9, 135.2, 140.7, 170.4. 4-ChloroN(4-methylphenyl)benzamide (4.1f): purified by recrystallizztion from methanol; yellow needles; mp 206 209 oC (lit.92 mp 213 215 oC); yield, 91% (2.24 g); 1H NMR (DMSO -d6) 2.27 (s, 3H), 7.15 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H),

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31 7.64 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.1 Hz, 2H), 10.24 (s, 1H); 13C NMR (DMSO -d6) 20.5, 120.5, 128.4, 129.0, 129.5, 132.8, 136.4, 164.2. 4-MethoxyN -phenylbenzamide (4.1g): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 128 130 oC (lit.93 mp 128 129 oC); yield, 89% (2.15 g); 1H NMR 3.82 (s, 3H), 4.60 (d, J = 4.5 Hz, 2H), 6.57 (br s, 1H), 6.89 (d, J = 7.4 Hz, 2H), 7.25 7.33 (m, 5H), 7.75 (d, J = 8.8 Hz, 2H); 13C NMR 44.0, 55.3, 113.7, 126.6, 127.4, 127.8, 128.7, 128.8, 138.4, 162.1, 167.0. NBenzyl-4-nitrobenzamide (4.1h): purified by recrystallization from chloroform/hexanes; pale yellow microcrystals; mp 136 137 oC (lit.93 mp 141 142 oC); yield, 96% (2.46 g); 1H NMR 4.64 (d, J = 5.6 Hz, 2H), 6.68 (s, 1H), 7.26 7.36 (m, 5H), 7.94 (d, J = 8.6 Hz, 2H), 8.26 (d, J = 8.6 Hz, 2H); 13C NMR 44.4, 123.8, 127.9, 127.9, 128.2, 128.9, 137.4, 139.9, 149.5, 165.3. N(4-Methylphenyl)-2-furamide (4.1i): purified by recrys tallization from chloroform/hexanes; yellow needles; mp 108 110 oC (lit.94 mp 109 110 oC), yield, 96% (1.93 g); 1H NMR 2.34 (s, 3H), 6.56 (dd, J = 3.4, 1.8 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 3.3 Hz, 1H), 7.50 (dd, J = 1.6, 0.7 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 8.03 (br s, 1H); 13C NMR 20.8, 112.4, 114.9, 119.9, 129.5, 134.0, 134.7, 144.0, 147.8, 156.0. N(4-Methylphenyl)heptanamide (4.1j): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 77 79 oC (lit.95 mp 78 79 oC); yield, 93% (2.04 g); 1H NMR 0.88 (t, J = 6.5 Hz, 3H), 1.31 1.37 (m, 6H), 1.65 1.72 (m, 2H), 2.30 (s, 3H), 2.31 2.35 (m, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.40 (br s,

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32 1H); 13C NMR 14.0, 20.8, 22.5, 25.6, 28.9, 31.5, 37.7, 120.0, 129.4, 133.7, 135.4, 171.5. N(2-Furylmethyl)benzamide (4.1k): purified by recrysta llization from chloroform/hexanes; yellow microcrystals; mp 96 98 oC (lit.96 mp 99 oC); yield, 90% (1.81 g); 1H NMR 4.61 (d, J = 5.5 Hz, 2H), 6.26 6.33 (m, 2H), 6.73 (br s, 1H), 7.35 7.42 (m, 3H), 7.46 7.50 (m, 1H), 7.79 (dd, J = 7.1, 1.5 Hz, 2H); 13C NMR 36.9, 107.6, 110.4, 127.0, 128.5, 131.5, 134.1, 142.2, 151.2, 167.2. NCyclohexyl-2-furamide (4.1l): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 106 107 oC (lit.94 mp 110 oC); yield, 94% (1.81 g); 1H NMR 1.18 1.31 (m, 3H), 1.35 1.47 (m, 2H), 1.62 1.78 (m, 3H), 1.97 2.01 (m, 2H), 3.89 3.96 (m, 1H), 6.21 (br s, 1H), 6.49 (dd, J = 3.6, 1.8 Hz, 1H), 7.09 (dd, J = 3.4, 0.8 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H); 13C NMR 24.8, 25.5, 33.1, 47.8, 112.0, 113.8, 143.5, 148.3, 157.4. 4-MethylN(4-methylphenyl)benzamide (4.1m): purified by recr ystallization from chloroform/hexanes; white plates; mp 158 160 oC (lit.92 mp 158 oC); yield, 91% (2.05 g); 1H NMR 2.31 (s, 3H), 2.38 (s, 3H), 7.12 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 8.03 (s, 1H); 13C NMR 20.8, 21.4, 120.3, 127.0, 129.2, 129.4, 132.1, 133.9, 135.4, 142.0, 165.7. NBenzyl-3-phenylpropanamide (4.1n): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 80 82 oC (lit.97 mp 82 oC); yield, 93% (2.22 g); 1H NMR 2.57 (d, J = 7.6 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 4.43 (d, J = 5.8 Hz, 2H), 5.99 (br s, 1H), 7.18 7.38 (m, 10H); 13C NMR 31.6, 38.3, 43.4, 126.2, 127.3, 127.6, 128.3, 128.5, 138.1, 140.7, 172.0.

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33 N(4-Methoxyphenyl)benzamide (4.1o): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 156 157 oC (lit.94 mp 157 158 oC); yield, 88% (2.0 g); 1H NMR 3.81 (s, 3H), 6.90 (d, J = 9.2 Hz, 2H), 7.44 7.56 (m, 5H), 7.84 7.87 (m, 3H); 13C NMR 55.5, 114.2, 122.1, 127.0, 128.7, 130.9, 131.7, 135.0, 156.6, 164.9. 4-NitroNphenylbenzamide (4.1p): purified by recrystalli zation from methanol; yellow needles; mp 206 208 oC (lit.98 mp 211 oC); yield; 95% (2.30 g); 1H NMR (DMSO -d6) 7.58 (t, J = 7.3 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 8.02 (dd, J = 7.0, 1.5 Hz, 2H), 8.11 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H), 10.8 (s, 1H); 13C NMR (DMSO d6) 119.8, 124.8, 128.0, 128.5, 132.2, 134.3, 142.4, 145.6, 166.3. NButyl-4-methylbenzamide (4.1q): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 52 54 oC (lit.99 mp 55 57 oC); yield, 92% (1.76 g); 1H NMR 0.93 (t, J = 7.3 Hz, 3H), 1.34 1.41 (m, 2H), 1.52 1.60 (m, 2H), 2.37 (s, 3H), 3.38 3.45 (m, 2H), 6.51 (br s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H); 13C NMR 13.7, 20.1, 21.3, 31.6, 39.6, 126.8, 129.0, 131.9, 141.5, 167.4. N(4-Methylphenyl)thiophene-2-carboxamide (4.1r): purified by recrystallization from chloroform/hex anes; white microcrystals; mp 103 105 oC (lit.94 mp 104 105 oC); yield, 89% (1.97 g); 1H NMR 2.34 (s, 3H), 7.12 (td, J = 4.4, 1.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 4.9, 1.2 Hz, 1H), 7.61 (dd, J = 3.7, 1.2 Hz, 1H), 7.64 (br s, 1H); 13C NMR 20.9, 120.3, 127.8, 128.3, 129.6, 130.6, 134.3, 135.0, 139.3, 159.9. NBenzylthiophene-2-carboxamide (4.1s): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 116 oC (lit.100 mp 119 oC); yield,

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34 92% (2.00 g); 1H NMR (DMSO -d6) 4.48 (d, J = 5.9 Hz, 2H), 7.16 (t, J = 4.0 Hz, 1H), 7.23.34 (m, 5H), 7.76 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 3.6 Hz, 1H), 9.08 (t, J = 5.8 Hz, 1H); 13C NMR (DMSO d6) 42.5, 126.8, 127.2, 127.9, 128.1, 128.3, 130.8, 139.5, 139.9, 161.1. N -(2-Furanylmethyl)-2-thiophenecarboxamide (4.1t): purified by recrystallization from chloroform/h exanes; yellow needles; mp 100 oC; yield, 92% (1.90 g); 1H NMR 4.62 (d, J = 5.5 Hz, 2H), 6.30.35 (m, 3H), 7.07 (td, J = 4.4, 1.1 Hz, 1H), 7.29 (s, 1H), 7.38 (d, J = 0.8 Hz, 1H), 7.48 (dd, J = 4.9, 1.0 Hz, 1H); 13C NMR 36.6, 107.4, 110.3, 127.5, 128.3, 130.1, 138.6, 141.9, 151.1, 161.9. Anal. Calcd for C10H9NO2S: C, 57.95; H, 4.38; N, 6.76. Found: C, 57.93; H, 4.28; N, 6.84. NBenzyl-1 H -indole-2-carboxamide (4.1u): purified by recrystallization from methanol; white microcrystals; mp 224 oC (lit.100 mp 230 oC); yield, 88% (2.20 g); 1H NMR (DMSOd6) 4.52 (d, J = 6.0 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 7.15.28 (m, 3H), 7.34.35 (m, 4H), 7.43 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 9.05 (t, J = 5.9 Hz, 1H), 11.62 (s, 1H); 13C NMR (DMSOd6) 42.1, 102.6, 112.3, 119.7, 121.5, 123.3, 126.8, 127.1, 127.2, 128.3, 131.6, 136.5, 139.6, 161.1. NBenzylbenzamide (4.1v): purified by recrysta llization from chloroform/hexanes; white microcrystals; mp 101 oC (lit.101 mp 105 oC ); yield, 92% (1.94 g); 1H NMR 4.63 (d, J = 5.8 Hz, 2H), 6.57 (br s, 1H), 7.25.51 (m, 8H), 7.79 (dd, J = 7.7, 1.4 Hz, 2H); 13C NMR 44.1, 126.9, 127.5, 127.9, 128.5, 128.7, 131.5, 134.3, 138.2, 167.3. N,N'Dibenzylterephthalamide (4.1w): purified by recrystallization from methanol; white microcrystals; mp 262 oC (lit.102 mp 264 oC); yield, 92% (3.16

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35 g); 1H NMR (DMSOd6) 0.91 (t, J = 7.3 Hz, 6H), 1.29.39 (m, 4H), 1.47.56 (m, 4H), 3.24.30 (m, 4H), 7.90 (s, 4H), 8.56 (s, 2H); 13C NMR (DMSOd6) 13.7, 19.7, 31.2, 127.1, 136.8, 165.4. N,N' -Dibutylterephthalamide (4.1x): purified by recrys tallization from methanol; white microcrystals; mp 230 oC (lit.103 mp 233 oC); yield, 96% (2.65 g); 1H NMR (DMSOd6) 0.91 (t, J = 7.3 Hz, 6H), 1.29.39 (m, 4H), 1.47.56 (m, 4H), 3.24.30 (m, 4H), 7.90 (s, 4H), 8.56 (s, 2H); 13C NMR (DMSOd6) 13.7, 19.7, 31.2, 39.2, 127.1, 136.8, 165.4. N -(4-Methylphenyl)acetamide (4.1y): purified by recrysta llization from chloroform/hexanes; pale ye llow microcrystals; mp 150 oC (lit.104 mp 153 oC); yield, 94 % (1.40 g); 1H NMR 2.14 (s, 3H), 2.30 (s, 3H), 7.10 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.57 (br s, 1H); 13C NMR 20.8, 24.4, 120.1, 129.4, 133.9, 135.3, 168.5. N,N' -Dibenzoylethylenediamine (4.1z): purified by recrystallization from methanol; white microcrystals; mp 250 oC (lit.105 mp 254 oC); yield, 94% (2.52 g); 1H NMR (DMSOd6) 3.45-3.46 (m, 4H), 7.44 7.55 (m, 6H), 7.85 (d, J = 7.0 Hz, 4H), 8.62 (s, 2H); 13C NMR (DMSOd6) 40.1, 127.2, 128.3, 131.1, 134.5, 166.6. N -(4-Methylphenyl)-3-phenyl-2-propenamide (4.1Aa): purified by recrystallization from methanol; white microcrystals; mp 156 oC (lit.106 mp 159 oC); yield, 87% (2.06 g); 1H NMR (DMSOd6) 2.27 (s, 3H), 6.84 (d, J = 15.7 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.41.48 (m, 4H), 7.56.61 (m, 3H), 7.62 (d, J = 15.6 Hz, 1H), 7.92 (br s, 1H); 13C NMR (DMSOd6) 20.5, 119.2, 122.4, 127.7, 129.0, 129.2, 129.7, 132.3, 134.8, 136.8, 139.9, 163.3.

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36 3-PhenylN -(phenylmethyl)-2-propenamide (4.1Ab): purified by column chromatography on basic alumina with ethyl acetate/hexanes (5:1) as eluent; white microcrystals (from chloroform/hexanes); mp 107 oC (lit.107 mp 107 oC); yield, 92% (2.18 g); 1H NMR 4.58 (d, J = 5.8 Hz, 2H), 5.95 (br s, 1H), 6.42 (d, J = 15.5 Hz, 1H), 7.29.37 (m, 8H), 7.48.51 (m, 2H), 7.68 (d, J = 15.5 Hz, 1H); 13C NMR 43.9, 120.3, 127.6, 127.8, 127.9, 128.8, 128.8, 129.7, 134.7, 138.1, 141.5, 165.7. N ,4-Dimethylbenzamide ( 4.1Ac ): purified by recrystallization in chloroform/hexanes; colorless needles; mp 143 oC (lit.108 mp 143 oC); yield, 92% (2.73 g); 1H NMR 2.38 (s, 3H), 2.98 (dd, J = 4.8, 0.7 Hz, 3H), 6.47 (br s, 1H), 7.20 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H); 13C NMR 21.3, 26.7, 126.8, 129.1, 131.7, 141.6, 168.2. 4.3.3 Preparation of Amides 4.2 In a sealed tube equipped with a magnetic stir bar was put N -acylbenzotriazole (1 mmol) and secondary amine (1.5 mmol). The reaction mixture was exposed to microwave irradiation (120 W) at 120 oC for 5 min. The reaction mixture was then dissolved in methylene chloride (20 mL). The solution was washed by concentrated sodium carbonate solution (15 mL x 2) and br ine (10 mL). After that the organic layer was dried over magnesium sulfate. Evapor ating the solvent yiel ded the crude product which was further purified by recrystallization in chloroform/hexanes to give pure amides 4.2a b 4.4.4 Characterization of Amides 4.2 4-(4-Methylbenzoyl)-morpholine (4.2a): purified by recrys tallization in chloroform/hexanes; white microcrystals; mp 71 oC (lit.109 mp 72 oC); yield, 95%

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37 (0.195 g); 1H NMR 2.38 (s, 3H), 3.55 (br s, 4H), 3.70 (br s, 4H), 7.21 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H); 13C NMR (one signal is hidden) 21.3, 66.9, 127.2, 129.1, 132.3, 140.0, 170.6. 4-(Benzylcarbonyl)-morpholine (4.2b): purified by recrystallization in chloroform/hexanes; mp 62 oC (lit.110 mp 62.5 oC); yield, 96% (0.197 g); 1H NMR 3.43.48 (m, 4H), 3.64 (s, 4H), 3.73 (m, 2H), 7.23.35 (m, 5H); 13C NMR 40.8, 42.0, 46.4, 66.4, 66.7, 126.8, 128.5, 128.7, 134.7, 169.5.

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38 CHAPTER 5 DIRECT SYNTHESIS OF ESTERS AND AMIDES FROM UNPROTECTED HYDROXY-AROMATIC AND ALIP HATIC CARBOXYLIC ACIDS 5.1 Abstract In a joint project together with postdoctoral researcher Sanjay K. Singh, a facile method for the activation of hydroxy substitu ted carboxylic acids us ing benzotriazole chemistry without prior protection of th e hydroxy substituents is presented. The N acylbenzotriazole intermediates 5.2ag 5.6ad 5.9ac have been used for high yielding synthesis of both aliphatic 5.3al and aromatic 5.7ah 5.10af hydroxy carboxamides. High yields of aromatic hydroxy esters 5.12ah 5.13ai were obtained using either neat alcohols in neutral microwave conditions or nucleophilic alkoxides and the intermediate N -(arylacyl)benzotriazoles. Moderate yields were obtained in case of aliphatic hydroxy esters 5.11ab and thiolesters 11eg from the intermediates 5.2ac. 5.2 Introduction The protection of an ancillary functiona l group while a transformation is being carried out at a different site in the molecule, followed by de-protection to regenerate the functionality, is frequently employed in orga nic synthesis. Various protecting groups are employed for a wide variety of functional groups.111, 112 Esters, thiolesters, and amides of hydr oxy carboxylic acids are important synthetic targets. Conventional methods for their pr eparation from the corresponding hydroxy acid requires initial protection of the hydroxyl group (as an ester, ketal or acetonide) conversion to the esters, thiolester or amide111, 112 and subsequent deprotection.

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39 Conventional activation of a carboxyl group using thionyl chlo ride or oxalyl chloride cannot be safely employed in the pr esence of a free hydroxy group. The use of diazocompounds is limited by their explosive ch aracter, lack of gene rality and toxicity.113 Several peptide coupling reagents (HBTU,114 BOP,115 PyBOP,116 DEPC,117 EDC/BtOH118,119) enable direct coupling of free hydroxy N -protected amino acids [HOR(NHP)-COOH HO-R(NHP)-CONHR ]. However strictly anhydrous conditions are required and activated acid intermediates fre quently cannot be stored, handled in moist air or even isolated. The carboxylic group of amino acid providing the NH for the coupling reaction frequently has to be esteri fied to make it sol uble in a non aqueous solvent. Aromatic amides and esters have been synthesized by in situ activation of hydroxy acids using carbodiimide (EDC, DCC)/BtOH,120 Mitsunobu121, 122 conditions (PPh3/DEAD) or CDI mediated coupling.123 EDC/BtOH/base has been employed in the direct syntheses of simple amides from hydroxy acids.124-126 Again the reaction requires strictly anhydrous conditions. A few reports directly transform -hydroxy acids into simple -hydroxy esters using boric acid,127 but require a large ex cess of the alcohol. N -Acylbenzotriazoles are versatile synthetic equivalents of acyl halides. They exist as stable solids at ambient conditions with moderate reactiv ity, which can be regulated. Appropriate N -acylbenzotriazoles affect formylation11 and trifluoroacylation.12 Regiospecific C -acylation of pyrrole and indoles15 and the synthesis of oxamides,26 1,3diketones,14 polycyclic heteroaromatics,19 Weinreb amides128 and N -protected dipeptides and tripeptides have been reported. In the case of peptides, protection of ancillary functional groups (hydroxy, thiol, imidazoleNH, indole-NH, amide and carboxylic acid)

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40 in the amino acid monomers were not required.7,10 Herein we utilize benzotriazole chemistry in direct synthesis of simple es ters, thiolesters and am ides from unprotected hydroxy -aliphatic and -aromatic acids. The use of this methodology provides an economically viable alternative to the various peptide coupling agents. 5.3 Results and Discussion 5.3.1 Preparation of Hydroxy Carboxamides from Aliphatic Hydroxy Acids Hydroxy amides are anti-convulsants129 ( -hydroxy amides), thrombin inhibitors130 and RARspecific retinoid agonists131 ( -hydroxy amides). They are intermediates for the synthesis of oxazolidinediones,132 oxindoles133 ( -hydroxy amides), -lactams134 ( hydroxy amides), antidepressant drugs, e. g. (R)-fluoxetine ( -hydroxy amides) and building blocks for the synthesis of various natural products.135 Common syntheses (Scheme 5-1) are a) from epoxy amides136 b) from keto amides,137 140 c) from a carbonyl and a nucleophile containing the amide,141, 142 d) from hydroxy acids.143 145 RN O OH R'' R' N O O R'' R' N O O R'' R' RH O N O R'' R' OHO OH+n=0,1,2,3 n=0,1,2,3 n=0 n=0,1,2,3 a b c d Scheme 5-1 Synthesis of Hydroxy Carboxamides Attempted one-pot conversions of -hydroxy acids to hydroxy carboxamides, via the bis-trimethylsilyl derivative followed by conversion to acid chloride and treatment with the appropriate amine, sometimes leads to the formation of -chloro amide143. Other

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41 direct syntheses of the hydroxy amides have been achieved when the ancillary alcohol is sterically hindered.130 N -Sulfinyl anilines have been used to synthesize -hydroxy N -aryl secondary amides from -hydroxy acids.143, 144 The syntheses of two -hydroxy amides ( N -arylamides) using N -(1-methanesulfonyl)benzotriazole have been reported from our laboratories,5 but there was no generalization of the methodology. The preparative method described in chapter 2 for the synthe sis of acyl benzotriazoles enabled us to successfully expand the method to incl ude a wide variety of substrates. The benzotriazole methodology was applie d for direct synthesis of known and novel hydroxy amides 5.3al from hydroxy acids 5.1ag (Fig. 5-1, Scheme 5-2 and Table 5-1). Attempts to isolate and purify the intermediate N -(hydroxyacyl)be nzotriazoles 5.2ag showed that most are unstable unlike non-functionalized N -acylbenzotriazoles. The N -acylbenzotriazole derivative 5.2c of () mandelic acid 5.1c was isolated in 25% yields by flash column chromatography. The 1H and 13C spectra supported the structure, depicting the amide carbon at 171.8, but the compound was not stable enough for elemental analysis. Formation of the N -acylbenzotriazoles 5.2ag conducted in THF or dichloromethane is completed in 2h and is ac companied by the formation of an insoluble solid. However, the crude N -(hydroxyacyl)benzotriazoles 5.2ag could be used directly. The supernatant containing N -(hydroxyacyl)benzotriazole wa s either syringed out or filtered to remove the accompanying solid a nd the filtrate used in further reactions. The crude intermediate N -(hydroxyacyl)benzotriazoles 5.2ag were treated with primary and secondary amines and the amides 5.3al obtained in varyi ng yields (Scheme 5-2 and Table 5-1). The -hydroxy acids 5.1ac gave high yields of secondary 5.3a 5.3c 5.3e and tertiary 5.3b 5.3d 5.3f amides.

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42 OH O X Y z OH O OH OH O OH OH O HO X Y 5.1a Z= Ph, Y = H, X = OH 5.1b Z= Y= CH3, X = OH 5.1d, Z = Cyclohexyl, Y = OH, X = Ph 5.1c, Mandelic acid 5.1e 5.1f X = Y = H, Lithocholic acid 5.1g X = Y = OH, Cholic acid Figure 5-1 Hydroxy Acids 5.1 AXR' O HO AOH O HO ABt O HO ANR'R'' O HO 5.1a-g 5.2a-g 5.11a-d X = O 5.11e-g, X= S 5.3a-l A = C1, C2, C3, Cn Scheme 5-2 General Reactions to De rivatives of Hydroxy Carboxylic Acid The use of aryl boronic acids145 for the synthesis of 5.3c has been reported for the case of -hydroxy acids (entry 3, Table 5.1). The synthesis of compounds 5.3e and 5.3f have been reported from thei r alkyl esters; the conditions employed involved either high temperatures (phenylethylamine reflux)132 or pressure146 (8 kbar) (see entries 5 and 6, Table 5-1). The benzotriazole method was ex tended for the syntheses of secondary amides 5.3j and 5.3k (entries 7 and 8; Table 5-1) of -hydroxy acid 5.1d. However, the synthesis of tertiary amines from -hydroxy acid presented difficu lties and mixtures were obtained. For -hydroxy acid 5.1e competitive intramolecular lactonization 5.4 was preferred over the formation of amide 5.3i (Scheme 5-3). Mono or poly hydroxyl bile

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43 acids like lithocholic acid 5.1f or cholic acid 5.1g that find application as gelating agents, presented no complications to this method. Us e of this simple benzotriazole route was comparable to that of a peptide coupling agent DEPC 117 (diethylphosphoryl cyanide) in case of 5.3l (entry 12, Table 5-1). The various amid es synthesized are depicted in the Table 5-1. Table 5-1. Synthesis of Hydroxy Carboxamides 5.3 from Aliphatic Hydroxy Acids 5.1a g .* Comp. Amine R Utilized R Prod Yield Mp 1 1a CH3(CH2)2CH2H 5.3a 72 46-47 2 1a CH3(CH2)6CH2CH35.3b 75 42-43 3 1b PhCH2H 5.3c 60 (96)a 84-85 4 1b -CH2CH2CH(Ph)CH2CH25.3d 61 103-104 5 1c PhCH2CH2H 5.3e 68 (83)b 100-101 6 1c -CH2(CH2)2CH25.3f 77 (96)c 94-95 7 1d PhCH2H 5.3g 75 139-140 8 1d CH2:CHCH2H 5.3h 62 97-98 9 1e -CH2(CH2)2CH25.3i 0d --10 1f CH3(CH2)3CH2H 5.3j 85 182-183 11 1f -CH2(CH2)2CH25.3k 93 167-168 12 1g PhCH2CH(COOCH3)H 5.3l 66 (70)e Gel aUsing 3,4,5-trifluorobenzeneboronic acid,145 bfrom the ethyl ester,132 cfrom the methyl ester,146 dlactone 5.4 formed, eusing (DEPC).117 *The experimental part in this table was carried out by Dr. Sanjay K. Singh. OH O OH HN N N SOCl2THF O O OH O N N N 5.1e+ +5.4 5.3i Scheme 5-3. Unsuccessful Synthesis of -Hydroxyacylbenzotriazole 5.3i

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44 5.3.2 Preparation of Hydroxyaromatic Am ides from Hydroxyaromatic Acids. Various amides of substituted salicyclic and naphthoic acids exhibit biological activity such as anthelmintic activity,147 anti plaque agents.148 The bis-naphthoic amides are used for the generation of chiral BINOL149,150 reagents and other hydroxy amides are important intermediates in synthetic organic chemistry. Common approaches towards the synthesi s of amides involve treatment of activated derivatives of acids, especially halides, acid a nhydrides, or esters, with the corresponding amine. Phenyl esters of salicyclic acid ha ve been effectively used,151 however their synthesis from salicyl ic acids requires harsh conditions.152 Yet another indirect method for the synthesis of ohydroxyaromatic amides would be via ortho aminocarbonylation of the alkali metal salts of phenols153,154 with isocyanates in high boiling solvents or under highly basic c onditions at very low temperatures.155,156 OH NRR' O OH NRR' O OH OH O O O NRR'a b c d Scheme 5-4. Literature Me thods of Synthesis of the oHydroxynaphthyl Amides The various methods of synthesis of the ohydroxynaphthyl amides (Scheme 5-4) are, a) from ortho amino carbonylation of naphthols;155 157 b) ortho hydroxylations of naphthyl amides;158,159 c) 42% yielding metal-mediat ed oxidative cyclization of appropriately substituted aryl keto amides;160 d) from o -hydroxynaphthoic acids using halogenating agents like PCl3,161 SOCl2 162 (used only in case of 2-hydroxy-3-naphthoic

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45 and 1-hydroxy-2-naphthoic acids) and diimides163 The indirect routes are harsh,157 low yielding160 or require very low temperatures.155 159 The limitations associated with these and other methods for the synthesis of amides have been discussed elsewhere.5 The salicyl amides 5.7ah were synthesized efficiently from the Nacylbenzotriazole derivatives 5.6ad of the corresponding salicylic acids 5.5ad (Scheme 5-5 and Table 5-2). Most of the intermediates 5.6ad could be isolated easily and were stable on silica gel at ambient cond itions. They were characterized by 1H and 13C NMR spectra and elemental analysis. A similar attempt with 2-hydroxy-1-naphthoic acid 5.8a (Scheme 5-6) gave a rather unstable N -acylbenzotriazole 5.9a that reacted with atmospheric water forming the acid 5.8a and with methanol giving the methyl ester 5.13a Pure 5.9a could, however, be isolated in a bout 25% yield by flash chromatography on silica gel and characterized spectrascopically and by elementa l analysis (the singlet for the free hydroxyl group was observed at 10.72 in 1H NMR and the carbonyl was observed at 167.3 in the 13C NMR spectra). Similarly, anal ytically pure samples of 5.9b and 5.9c were obtained by careful re crystallization from dichloromethane. These samples could be stored under refrigerated conditi ons without apparent decomposition. As for aliphatic acids, purification of the intermediate was not necessary. The supernatant containing the N -acylbenzotriazole could be used for further reactions. Various primary and secondary amines (3 equiv) were treated with the Nacylbenzotriazoles 5.6ad (Scheme 5-5) in the presence of triethyl amine (5 equiv) in THF (4 mL/mmol) (Method A) to give a series of known and novel secondary and tertiary amides 5.7ah (Table 5-2). The reactions were very rapid and the unprotected hydroxyl groups caused no complications. The pr oducts could be isolated in over 90%

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46 purity after the initial work up. Hardly surp risingly, a sterically demanding amine gave no yield (entry 9, Table 5-2) of the desired product while the other amines gave very high yields. These compounds gave satisfactory proton and carbon NMR data and also elemental analysis. The various amides synthesi zed from derivatives of salicylic acid are presented in Table 5-2. This me thodology could be extended to the o -hydroxynaphthoic acids 5.8ac Various secondary and tertiary amides 5.10af were synthesized (Scheme 5-6) in good yields. In case of synthesis of amides from poorly nucleophilic aromatic amines, microwave conditions (Method B) were required to obtain good yields (see entry 6 in Table 5-2; see en try 1 in Table 5-3). OH O OR OH OH O OH Bt O X X X OH O N R' R X 5.5a-d 5.6a-d 5.12a-h 5.7a-g Scheme 5-5. Preparation of Amides and Esters from Salicyclic Acids OH Bt O OH Bt O OH Bt O OH Bt O OH Bt O OH Bt O Br OH Bt O O H 5.6a 96% 5.6d 94% 5.6b 91% 5.6c 95% 5.9c 92% 5.9a 96% 5.9b 95% Figure 5-2. Preparation of Hydroxy N -Acylbenzotriazoles

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47 Table 5-2. The Synthesis of Substituted Salicylamides 5.7ah (a, X = H; b, X = 5-Br; c, X = 4-OH; d, X = 3-Me) Com R R Method Product Yield (%) Mp C 1 5a furfuryl H A 5.7a* 83 (97)a 109 110 2 5a -(CH2)5A 5.7b* 94 (69)a 142 143 3 5b n -pentyl H A 5.7c* 84 54 55 4 5b n -octyl CH3 A 5.7d* 82 92 93 5 5c n -pentyl H A 5.7e* 96 125 126 6 5c phenyl CH3 B 5.7f 93 150 152 7 5c -(CH2)2-O-(CH2)2B 5.7g 94 179 181 8 5d CH3(CH3)CH(CH2)2H A 5.7h* 93 Oil aReported yield using phenyl salicylate.164 *Compound was prepared by Sanjay K. Singh Table 5-3. The Synthesis of Amides 5.10 aUsing thionyl chloride.210 *Compound was prepared by Sanjay K. Singh 5.3.3 Preparation of Aliphatic -Hydroxycarboxylic Esters and Thiolesters from Hydroxy Acids -Hydroxy esters are important building bloc ks for synthesis of natural products. Common methods for their syntheses ar e a) from hydroxy Fischer carbenes,165 b) selective opening of the epoxy esters,166 c) via -chloroglycidic esters,167 d) oxidation of metal enolates,168 e) reduction of the a ppropriate keto esters,169,170 f) the glyoxalate-ene reaction171 and g) direct tran sformation of the -hydroxy acid127 as displayed in Scheme 5-7. However, there has been one re port for direct transformation of -hydroxy acid to simple -hydroxy esters using boric acid,127 but this requires reaction times of 18 h. Hydroxycarboxy thiolesters have received less attention although they are amenable to several functional group transformations172, 173 are bio-active in the areas of anti-tumor Comp. R R Method Product Yield (%) Mp C 1 5.8a Phenyl H B 5.10a 90 171-172 2 5.8a -(CH2)5A* 5.10b 93 242-243 3 5.8b PhCH2CH2H A* 5.10c 94 125-126 4 5.8b -(CH2)4A* 5.10d 97 93-94 5 5.8c CH2:CH-CH2H A* 5.10e 75 (85)a 121-122 6 5.8c -(CH2)2O(CH2)2A* 5.10f 73 216-217

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48 and glyoxalase I inhibitor174 and protect the unstable thio moiety while masking the undesired odor175 of the free thiol. OH COOH OH OH OH COBt CONR'R'' COO R 5.8a-c 5.9a-c 5.10a-f5.13a-i 5.8a : 2-hydroxy-1-naphthoic acid, 5.8b :1-hydroxy-2-naphthoic acid, 5.8c : 2-hydroxy-3naphthoic acid Scheme 5-7. Preparation of Amides and Esters from Naphthoic Acids COOEt H O R O O OR'' R''' R' OM X R H R OR'' O OH OH R OH O O R R' O R''' O OR'' Cr(CO)5R ONMe4 CO + + c R''OH + Cl2CHCOOPri + a b d e f g Scheme 5-8. Synthesis of -Hydroxy Carboxylic Esters Reported syntheses of -hydroxy thiolesters are a) th e Pinner reaction (average yield: 62%, 13 examples)176 b) from -chloro thioesters177 (average yield: 56%, 16 examples, restricted to 2aminothiols derivatives of -diaryl-chloro acids) c) ozonolysis of thiophene substitu ted Henry adduct (58%, 1 example)178 d) rearrangement of the glyoxal-thiol addu ct (average yield: 63% for 2 steps, 7 examples).179,180 e) from

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49 organo-aluminum reagents (90%, 1 example)181 f) via oxaborolidine mediated reduction of -phenyl thioenones followed by ozonolysis (average yield: 44%, 3 steps, 5 examples)182 and g) via pummerer reaction of 1,3-d ithiane-1,3-dioxide derivatives (70% yield, 3 steps, enantioselective).172 The processes displayed in the scheme (Scheme 5-7) suffer from drawbacks. Some ar e restricted to thiophenol esters (path c, f), some very specific (path b: R = Ar, R = Ar Path e : R = SC(CH3)3), some involve the use of toxic/harsh conditions (path a, c, f), while most are muti-step syntheses (paths a, c, d, f, g). Weinreb181 has reported only one exampl e of direct synthesis of -hydroxyt -butyl thiol ester from mandelic acid using organo-aluminum reagen t while the synthesis from -halo thiolester salts (not commercially available) is not ge neral as discussed elsewhere.177 SS O O SS OO ROP RR' HOCN O R''' R' SPh R' SPh OH R''' RR' HO NH.HX SR'' RR' HO O SR'' H HO OH O Ph RR' Cl SR'' O R O O H RCHO R O OH SR'' R OH SPh NO2H R''SH O2N SPh + R''SH + Anhydrous HX a e + d b c + f P = H P = THP g Scheme 5-9. Synthesis of Hydroxy Carboxylic Thiolesters Visibly from the two schemes (Schemes 5-8 and 5-9), synthesis of -hydroxy thiol esters does not analogously follow that of -hydroxy esters. It should be noted that modified reducing agents canno t be employed in case of hydroxy thiol esters due to labile

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50 nature of the CO-S bond. A mild, direct one-step procedure, de void of protection / deprotection operations, to synt hesize both the esters from a single starting material would be a useful tool in the syntheses of compound libraries. As in the case with the synthesis of hydroxy amides, dropwise addition through a syringe of the supernatant benzot riazolating mixture and the hydroxy acid 5.1af (Fig. 51) to a mixture of the sodium salt of th e alcohol or thiol (S cheme 5-2) at room temperature, ensured the forma tion of the hydroxy carboxylic ester 5.11ab or thiolester 5.11eg (Table 5-4). Two known esters and thre e novel thiol esters were synthesized using this method. Attempts to increase the yield of esters by treating the N -( hydroxyacyl)benzotriazoles 5.1a 5.1b using more nucleophilic aromatic phenoxides failed. Use of neutral microwave conditions c ould not rectify this. Attempts to increase the yield of thiolesters by refluxing the N -( -hydroxyacyl)benzotriazole 5.1ac with the sodium salt of thiol led to decom position. Conducting the reactions at 0 C also did not improve the yield. This method provides a mild protocol for the synthesis of both esters and thiolesters from one starting material, wh ich is a desirable property for the synthesis of library compounds. Table 5-4 Synthesis of Hydroxy Esters 5.11ab and Thiolesters 5.11eg Comp. R OH X Prod. Yield (%) Mp 1 5.1c MeOH O 5.11a 40 (99)a 56-57 2 5.1c EtOH O 5.11b 72 (93)b 35-36 3 5.1b PhOH O 5.11c Mix --4 5.1a p -Methoxyphenol O 5.11d Mix --5 5.1a hexanethiol S 5.11e 37 Oil 6 5.1c 4-methoxythiophenol S 5.11f 23 Oil 7 5.1b benzylthiol S 5.11g 24 69-70 aUsing boric acid.127 bUsing concentrated sulphuric acid.183 *Experimental part was carried by Sanjay K. Singh

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51 5.3.4 Preparation of Aromatic Esters from Substituted o -Hydroxy Aromatic Acids. Salicylihalamide,121 lasiodiplodin,122 and neocarzinostatin184 are biologically active salicylic and hydroxy naphthoic esters. Salicylic acids have been esterified using large excesses of the alchohol and/or strong acid,185 or bases.186 Stereo-specific Mitsunobu conditions122,187 have also been used in total sy ntheses. A tertiary amine and the appropriate activated halide188,189 esterify salicylic acids, but requires high temperatures. o -Hydroxynaphthoic esters are not common in the literature. The few reports which deal with their synthesis from the correspond ing acids, usually involve a) strongly acidic conditions190 for simple esters, b) use of toxic diazomethane,191 c) use of LiOH with DMS192 d) the use of carbodiimides193-196 that gives the urea side product or e) multi-step low yielding oxidative cycliz ation using Mn(III) and Ce(IV)160 to form the second aromatic ring. Zengin197 esterified 2-hydroxy-1-naphthoic acid in 90% yield using DCC in pyridine with a catalytic amount of p -toulenesufonic acid in the presence of excess methanol, but the study dealt with only one example. The methods described above and other methods for the esterification of o -hydroxyaromatic acids usually lack generality,192,198 involve sensitive reagents,199,200 are low yielding201 or lead to intersubstrate esterification.202 There is an obvious need for a general, efficient, gentle and high yielding process. N -Acylbenzotriazoles 5.6ad of various salicylic acids 5.5ad were synthesized using the SOCl2/BtH mixture Scheme 5.5. Esterifica tion was achieved by the dropwise addition of the supernatant to sodium methoxide in methanol over 30 min (Method A ) to give the methyl ester 5.12a and 5.13a in 94 and 85% yield respectively (Scheme 5-6). Alternatively, avoiding basic c onditions, the esters could be synthesized by heating the crude concentrated N -acylbenzotriazoles with 4 equiv of the appropriate neat alcohol

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52 for 10 min under microwave (method B). The este rs were obtained in good yields. Allyl alcohols (entry 4, Table 5-5 and entry 8, Ta ble 5-6) or the presence of a triple bond (entries 3 and 7, Table 5-6) caused no con cerns. Both primary and secondary alcohols were used. A series of mostly novel esters 5.12ag and 5.13ai were synthesized using the methods described above and the results are presented in Tables 5-5 and 5-6. This method provides an alternative mild high yielding method for the synthesis of o -hydroxy esters from o -hydroxyaryl carboxylic acids. Table 5-5 Synthesis of Esters 5.12 Compd. ROH Method Product Yield (%) Mp 1 5.5a Cyclopentanol B 5.12a 92 Oil 2 5.5a 1-Penten-3-ol B 5.12b 87 Oil 3 5.5b Ethanol B 5.12c 90 46-48 4 5.5b Cyclopentanol B 5.12d 91 45-47 5 5.5c n -Propanol B 5.12e 87 32-34 6 5.5c Cyclopentanol B 5.12f 91 Oil 7 5.5d CH3(CH2)8CH2OH B 5.12g 89 Oil Table 5-6 The Synthesis of Esters 5.13 Compd. ROH Method Product Yield (%) Mp 1 5.8a Cyclopentanol B 5.13a 94 Oil 2 5.8a 4-Pentyn-1-ol B 5.13b 87 Oil 3 5.8a Ethanol B 5.13c 95 (62)b 56-58 4 5.8b Ethanol B 5.13d 95 46-48 5 5.8b Cyclopentanol B 5.13e 94 61-63 6 5.8b 4-Pentyn-1-ol B 5.13f 91 65-67 7 5.8b 1-Penten-3-ol B 5.13g 91 Oil 8 5.8c n -Butanol B 5.13h 90 Oil aUsing p -TsOH.H2O/DCC/Py.197 bOxidative cyclization.160 In conclusion, we have developed an ec onomically viable alternative method for the activation of carboxylic ac ids in presence of free hydr oxy groups without their prior protection. The syntheses of amides in case of both aliphatic and aromatic hydroxy acids were high yielding. The hydroxy aromatic esters were synthesized in high yields both under basic and neutral conditions (microwave), while yields for the synthesis of esters

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53 and thiolesters from corresponding hydroxy acids were low. While in conventional direct synthesis, the activation of the hydroxy acid is performed in situ we have been able to separate the activati on step from the nucleophilic substi tution, thereby contributing to higher flexibility in reaction conditions and substrates. The major advantage of this methodology lies in the synthesis of aromatic am ides and esters where in the intermediate N -( o -hydroxyaryl)benzotriazoles ar e stable isolable solids that can be treated under neutral conditions with the appr opriate alcohol or amine. 5.4 Experimental Section 5.4.1 General Melting points were determined on a hot-s tage apparatus and are uncorrected. All NMR spectra were recorded in CDCl3 (unless specified as DMSOd6), with TMS as the internal standard for 1H (300 MHz) or the solvent as the internal standard for 13C (75 MHz). Microwave heating was carried out with a single mode cavity Discoverer Microwave Synthesizer (CEM Corporation, NC), producing continuous irradiation at 2455 MHz. THF was dried over sodium/benzophenone and used freshly distilled. Column chromatography was conducted on silica gel 200 425 meshes. The compounds 5.1a,203 5.1b,204 5.1d205 and 5.1e206 were synthesized from reported procedures. Compounds 5.1c, 5.1f, 5.1g and salicylic acid/ o -hydroxy naphthoic acid derivatives are available commercially. 5.4.2 General Procedure for the Synthe sis of Hydroxy Carboxamides 5.3 from Hydroxy Acids 5.1 To 6.3 mmols (750 mg) of benzotriazole in 12 mL of freshly dried THF or methylene chloride was added 2 mmol of SOCl2 (0.148 mL) under an atmosphere of argon. The mixture was allowed to stir at r oom temperature for 45 min before the rapid

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54 addition of the hydroxy acids ( 5.1af, 2 mmol) in 8 mL of fres hly dried THF / methylene chloride through a syringe while under inert atmosphere. The formation of a white solid was observed and the reaction mixture was stirred for 2 h at room temperature. The supernatant contains the N -(hydroxyacyl)benzotriazole. The stirring was stopped after 2 hours for the suspension to settle down for easy removal of the supernatant. In a separate round bottom flask the appropr iate amine (6 mmol) and triethyl amine (6 mmol) were taken in 2 mL of fres hly dried THF. The supernatant of the benzotriazolating mixture / hydroxy acid was ca refully syringed out and added dropwise to this mixture while stirring under an iner t atmosphere. The residual solid was washed with 5 mL of dry THF and the washings a dded to the amines. Af ter 30 min the reaction mixture was concentrated under vacuum to re move the solvent and triethyl amine. The brown residue was taken in ethe r (25 mL) and the organic laye r washed with 1N HCl (2 x 25 mL), saturated sodium carbonate (until be nzotriazole is not observed on TLC), brine, dried over magnesium sulphate and concentr ate under vacuum. The residue was refined by flash chromatography over silica gel to give the respective hydroxy amides ( 5.3al ). 5.4.3 Characterization of Hydroxy Amides 5.3 N -Butyl-2-hydroxy-3-phenylpropionamide (5.3a): white powder from ethyl acetate/hexanes; mp 46 C; yield, 72%; IR (neat) = 3334, 2936, 2863, 1624, 1468 cm-1; 1H NMR 7.35.23 (m, 5H), 6.42 (br s, 1H), 4.28 (dt, J = 8.4, 4.4 Hz, 1H), 3.28 3.19 (m, 2H + H, A part of AB system PhCH2), 2.90 (dd, J = 8.2, 6.9 Hz, 1H, B part of AB system), 2.56 (d, J = 4.7 Hz, 1H), 1.49.40 (m, 2H), 1.35.23 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR 172.3, 136.8, 129.5, 128.7, 127.0, 72.8, 41.0, 38.8, 31.5, 20.0,

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55 13.7. Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.92; H, 9.01; N, 6.34. 2-HydroxyN -methylN -octyl-3-phenylpropionamide (5.3b): white plates from ethyl acetate/hexanes; mixture of rota mers, mp 42 C; yield, 75%; IR (neat) = 3499, 2929, 2874, 1653, 1495 cm-1; 1H NMR 7.32.20 (m, 5H), 4.59.51 (m, 1H), 3.75 (d, J = 8.2 Hz, 0.5 H), 3.66 (d, J = 8.2 Hz, 0.5H), 3.49.11 (m, 2H), 2.96.77 (m, 3H), 2.94 (s, 1.5H, NCH3), 2.95.84 (m, 2H), 2.80 (s, 1.5 H, NCH3), 1.53.48 (m, 2H), 1.28.26 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR 173.5, 173.3, 137.0, 136.9, 129.3, 129.2, 128.4, 128.3, 126.7 (2C), 69.0 (2C), 49.8, 48.5, 42.3, 41.8, 34.3, 33.4, 31.7(2C), 22.6, 22.5, 29.3, 29.2, 29.1 (2), 28.0, 26.9, 26.8, 26.6, 14.0 (2C). Anal. Calcd for C18H29NO2: C, 74.18; H, 10.03; N, 4.81. Found: C, 74.49; H, 10.29; N, 4.72. N -Benzyl-2-hydroxy-3-methylbutyramide (5.3c):145 white amorphous powder from hexanes/ethyl acetate; mp 84 C; yield, 60%; IR (neat) = 3355, 2968, 2925, 1626, 1542, 1018 cm-1; 1H NMR 7.36.26 (m, 5H), 6.78 (br s, 1H), 4.50 (dd, J = 14.7, 8.7 Hz, 1H, A part of AB system), 4.45 (dd, J = 14.7, 8.7 Hz, 1H, B part of AB system), 4.03 (dd, J = 5.1, 3.2 Hz), 2.60 (br d, J = 5.2 Hz, 1H), 2.26.16 (m, 1H), 1.03 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H); 13C NMR 173.0, 138.0, 128.7, 127.8, 127.6, 76.4, 43.2, 31.9, 19.1, 15.4. Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.62; H, 8.44; N, 6.92. 1-(4-Benzylpiperidin-1-yl)-2-hyd roxy-3-methylbutan-1-one (5.3d): mixture of isomers, white amorphous powder from ethyl ace tate/hexanes; mp 103 C; yield, 61%; IR (neat) = 3417, 2962, 2870, 1634, 1494, 1022 cm-1; 1H NMR 7.32.26 (m, 2 H), 7.23.18 (m, 1H), 7.16.12 (m, 2H), 4.62.55 (m, 1H), 4.24.22 (m, 1H),

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56 3.74.67 (m, 2H), 3.00.88 (m, 1H), 2.64.49 (m, 3H), 1.84.69 (m, 4H), 1.23.13 (m, 2H), 1.09.03 (m, 3H), 0.82.75 (m, 3H); 13C NMR 172.2, 172.1, 139.7, 139.6, 129.0 (2C), 128.3 (2C), 126.1 (2C), 71.9, 71.8, 45.4, 45.0, 43.0, 42.9, 42.8 (2C), 38.2, 38.1, 32.5, 32.2, 31.9, 31.7, 31.6, 31.3, 19.8 (2C), 14.9, 14.7. Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C, 74.31; H, 9.47; N, 5.05. 2-HydroxyN -phenethyl-2-phenylacetamide (5.3e):132 white powder from ether; mp 100 C; yield, 68%; IR (neat) = 3378, 1655, 1602, 1061 cm-1; 1H NMR 7.39.19 (m, 8H), 7.03.00 (m, 2H). 6.06 (br s, 1H), 4.95 (d, J = 3.3 Hz, 1H), 3.70 (d, J = 3.4 Hz, 1H), 3.56 (sextet, J = 6.6 Hz, 1H), 3.45 (sextet, J = 6.6 Hz, 1H), 2.82 2.66 (m, 2H); 13C NMR 172.1, 139.4, 138.4, 128.8, 128.7, 128.6, 126.8, 126.5, 74.0, 40.7, 35.5. Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 74.91; H, 6.75; N, 5.55. 2-Hydroxy-2-phenyl-1-pyrrolidin-1-yl-ethanone (5.3f):207 white powder from ether; mp 94 C; yield, 77%; IR (neat) = 3384, 2971, 2877, 1634, 1066 cm-1; 1H NMR 7.39.30 (m, 5H), 5.04 (d, J = 6.0 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 3.66 3.35 (m, 3H), 2.89.81 (m, 1H), 1.93.68 (m, 4H); 13C NMR 170.6, 138.9, 128.9, 128.4, 127.7, 72.6, 46.5, 45.8, 25.9, 23.7. N -Benzyl-3-cyclohexyl-3-hydr oxy-2-phenylpropionamide (5.3g): white amorphous powder from ethyl acetate/hexanes; mp 139 C; yield, 75%; IR (neat) = 3287, 2925, 2851, 1640, 1545, 1030 cm-1; 1H NMR 7.37.23 (m, 8H), 7.14.11 (m 2H), 5.96 (br t, J = 6.2 Hz, 1H), 4.45 (dd, J = 15.0, 5.9 Hz, 1H, A part of AB system), 4.34 (dd, J = 15.0, 5.9 Hz, 1H, B part of AB system), 4.06 (br d, J = 4.4 Hz, 1H), 4.01 3.96 (m, 1H), 3.61 (d, J = 8.0 Hz, 1H), 1.71.98 (m, 11H); 13C NMR 174.1, 137.8,

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57 137.4, 129.0, 128.6, 128.4, 127.6, 127.4 (2C), 77.4, 55.2, 43.4, 39.8, 30.4, 26.3 (2C), 26.0, 25.8. Anal. Calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C, 78.28; H, 8.19; N, 4.22. N -Allyl-3-cyclohexyl-3-hydroxy2-phenylpropionamide (5.3h): white needles from hexanes/ethyl acetate, mp 97 C; yield, 62%; IR (neat) = 3301, 2926, 2852, 1640, 1544, 1033 cm-1; 1H NMR 7.39.27 (m, 5 H), 5.81.68 (m, 1H), 5.63 (br t, J = 5.3 Hz, 1H), 5.06 (dq, J = 8.0 Hz, 1.4 Hz, 1H), 5.01 (dq, J = 16.6, 1.6 Hz, 1H), 4.13 (br d, J = 4.0 Hz, 1H), 4.02.97 (m, 1H), 3.86. 82 (m, 2H), 3.59 (d, J = 8.2 Hz, 1H), 1.73.97 (m, 11 H); 13C NMR 174.1, 137.5, 133.7, 129.1, 128.5, 127.6, 116.2, 77.3, 55.1, 41.7, 39.8, 30.5, 26.4, 26.3, 26.0, 25.6. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.57; H, 8.91; N, 5.00. NLithocholyl -npentyl amide (5.3j): white needles from ether; mp 182 C; yield, 85%; IR (neat) = 3288, 2929, 2863, 1646, 1555, 1041 cm-1; 1H NMR 5.44 (br t, J = 6.5 Hz, 1H), 3.68.58 (m, 1H), 3.23 (q, J = 6.9 Hz, 2H), 2.28.18 (m, 1H), 2.10 0.84 (m, 43H), 0.64 (s, 3H); 13C NMR 173.5, 71.8, 56.5, 56.0, 42.7, 42.0, 40.4, 40.1, 39.5, 36.4, 35.8, 35.5, 35.3, 34.5, 33.7, 31.8, 30.5, 29.4, 29.0, 28.2, 27.2, 26.4, 24.2, 23.3, 22.3, 20.8, 18.4, 14.0, 12.0. Anal. Calcd for C29H51NO2: C, 78.14; H, 11.53; N, 3.14. Found: C, 77.85; H, 11.92; N, 3.07. N -Lithocholyl pyrro lidine amide (5.3k):208 white needles from ether; mp 167 168 C; yield, 93%; IR (neat) = 3406, 2934, 2863, 1626, 1446, 1041 cm-1; 1H NMR 3.62 (m, 1H), 3.46 (t, J = 6.87 Hz, 2H), 3.42 (t, J = 6.73 Hz, 2H), 2.36.1 (m, 2H), 1.97.92 (m, 37H), 0.64 (s, 3H); 13C NMR 172.2, 71.7, 56.4, 56.0, 46.5, 45.6, 42.7, 42.0, 40.4, 40.1, 36.4, 35.8, 35.5, 35.3, 34.5, 31.7, 30.9, 30.5, 28.2, 27.1, 26.4, 26.1, 24.4,

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58 24.2, 23.3, 20.8, 18.5, 12.0. Anal. Calcd for C28H47NO2: C, 78.27; H, 11.02; N, 3.26. Found: C, 77.90; H, 11.39; N, 3.28. N -Cholyl-D-phenylglycine methyl ester (5.3l):117 white amorphous solid from methanol/dichloromethane; yield, 66%; IR (neat) = 3420, 2953, 2866, 1746, 1654, 1522 cm-1; 1H NMR 7.36.31 (m, 5H), 6.91 (d, J = 7.3 Hz, 1H), 5.58 (d, J = 7.1 Hz, 1H), 3. 93 (br s, 1H), 3.80.64 (m, 2H), 3.70 (s, 3H), 3.80 (br s, 3H, OH), 3.40 (br s, 1H), 2.39.74 (m, 25 H), 0.95 (d, J = 5.5 Hz, 3 H), 0.86 (s, 3H), 0.62 (s, 3H); 13C NMR 173.3, 171.5, 136.5, 128.8, 128.3, 127.3, 73.0, 71.7, 68.4, 56.3, 53.4, 52.7, 46.5, 46.3, 41.5, 41.3, 39.3, 35.2, 34.6, 34.4, 32.7, 31.2, 30.1, 27.9, 27.5, 26.2, 23.2, 22.3, 17.3, 12.3. 5.4.4 Synthesis of o -Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9 According to the procedure described in Chapter 2, hydroxy N -acylbenzotriazoles ( 5.6ad, 5.9ac ) were prepared in high yields. Due to the poor solubility of 5.6c in methylene chloride, the solvent being used fo r this particular reaction was THF. To the substituted salicylic and o -hydroxy naphthoic acids ( 5.5c, 5.8ac 2 mmol) in 10 mL of freshly dried THF/methylene chloride was added 6.3 mmols (750 mg ) of benzotriazole and 2 mmol of SOCl2 (0.148 mL) in 20 mL of freshly dried THF/methylene chloride. The mixture was allowed to stir at room temper ature for 1 h. The formation of a white solid was observed. The solid was filtered out and washed with copious methylene chloride (or THF for 5.6c ). The crude product was obtained af ter removal of the solvent under reduced pressure. Further purification of the crude product by recr ystallization yielded pure N -acylbenzotriazoles ( 5.6ad, 5.9ac ) in 91 96% yield.

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59 5.4.5 Characterization of o -Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9 Benzotriazol-1-yl-(2-hydr oxyphenyl)methanone (5.6a): pale yellow needles from diethyl ether (96%); mp 115 C; IR (neat) = 3385 (br), 1648, 1479, 1449 cm1; 1H NMR 10.81 (s, 1H), 8.61 (dd, J = 8.3, 1.5 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.64.53 (m, 2H), 7.13 (d, J = 8.5 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H); 13C NMR 169.2, 163.6, 145.4, 137.1, 133.8, 132.4, 130.5, 126.5, 120.4, 119.6, 118.4, 114.9, 113.5. Anal. Calcd for C13H9N3O2: C, 65.27; H, 3.79; N, 17.56. Found: C, 65.51; H, 3.70; N, 17.51. Benzotriazol-1-yl-(5-bromo-2-h ydroxyphenyl)methanone (5.6b): yellow needles from diethyl ether ( 91%), mp 108 C; IR (neat) = 3122, 1651, 1483, 1451 cm-1; 1H NMR (DMSOd6) 10.67 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.84 (s, 1H), 7.86.81 (m, 1H), 7.69.63 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H); 13C NMR (DMSOd6) 165.3, 155.2, 145.5, 135.6, 132.1, 130.9, 130.8, 126.7, 123.0, 120.1, 118.6, 113.9, 109.6. Anal. Calcd for C13H8BrN3O2: C, 49.08; H, 2.53; N, 13.21. Found: C, 49.30; H, 2.35; N, 13.15. Benzotriazol-1-yl-(2,5-dihyd roxyphenyl)methanone (5.6c): yellow needles from diethyl ether (95%); mp 182 C (polymerizes); IR (KBr) = 3135, 1649, 1625 cm-1; 1H NMR (DMSOd6) 10.38 (s, 1H), 10.31 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 6.46.43 (m, 2H); 13C NMR (DMSOd6) 166.1, 163.3, 159.9, 145.3, 133.5, 131.3, 130.3, 126.2, 119.9, 113.8, 110.7, 107.4, 102.8. Anal. Calcd for C13H9N3O3: C, 61.18; H, 3.55; N, 16.46. Found: C, 61.09; H, 3.48; N, 16.32.

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60 Benzotriazole-1-yl-(3-methyl-2-hydroxyphenyl)methanone (5.6d): pale yellow needles from diethyl ether ( 94%); mp 124 C; IR (neat) = 3384 (br w), 1659, 1483, 1454 cm-1; 1H NMR 10.0 (br s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 6.96 (t, J = 7.7 Hz, 1H), 2.35 (s, 3H); 13C NMR 169.7, 162.0, 145.4, 138.0, 132.5, 131.4, 130.4, 127.3, 126.4, 120.3, 118.9, 114.9, 112.7, 15.9. Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.52; H, 4.27; N, 16.95. Benzotriazol-1-yl-(2-hydroxyna phthalen-1-yl)methanone (5.9a): white needles from diethyl ether; mp 1 38 C; yield, 96%; IR (neat) = 3384, 1718 cm-1; 1H NMR (DMSOd6) 10.72 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H); 13C NMR (DMSOd6) 167.3, 154.3, 145.8, 133.0, 131.5, 131.1, 130.8, 128.6, 128.1, 127.5, 126.9, 123.8, 122.7, 120.3, 118.3, 114.2, 113.9. Anal. Calcd for C17H11N3O2: C, 70.58; H, 3.83; N, 14.52. Found: C, 70.18; H, 3.81; N, 14.49. Benzotriazol-1-yl-(1-hydroxyna phthalen-2-yl)methanone (5.9b): yellow microcrystals from chloroform/hexanes, mp 150 C; yield, 95%; IR (neat) = 3444, 1632 cm-1; 1H NMR 12.58 (br s, 1H), 8.58 (d, J = 9.2 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.75 7.68 (m, 2H), 7.61.54 (m, 2H), 7.40 (d, J = 9.2 Hz, 1H) 13C NMR (DMSOd6) 169.8, 164.9, 145.3, 137.4, 132.5, 130.9, 130.4, 127.4, 126.7, 126.3, 126.1, 124.8, 124.4, 120.3, 118.9, 115.0, 106.7 Anal. Calcd for C17H11N3O2: C, 70.58; H, 3.83; N, 14.52. Found: C, 70.25; H, 3.68; N, 14.90.

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61 Benzotriazol-1-yl-(3-hydroxyna phthalen-2-yl)methanone (5.9c). Yellow microcrystals from dichloromethane; mp 157 C; yield, 92%; IR (neat) = 3198, 1659 cm-1; 1H NMR (DMSOd6) 10.52 (s, 1H), 8.34 (dt, J = 8.2, 1.0 Hz, 1H), 8.30 (dt, J = 8.2, 1.0 Hz, 1H), 8.30 (s, 1H), 7.94 (br d, J = 7.7 Hz, 1H), 7.86 (dt J = 8.2, 1.0 Hz, 1H), 7.84 (br d, J = 7.7 Hz, 1H), 7.68 (dt, J = 8.2, 1.0 Hz, 1H), 7.56 (dt, J = 8.2, 1.0 Hz), 7.40 (dt, J = 8.2, 1.0, 1H), 7. 34 (s, 1H) 13C NMR (DMSOd6) 166.9, 152.6, 145.6, 136.0, 131.1, 131.0, 130.8, 128.7, 128.4, 126.9, 126.8, 126.3, 124.2, 124.1, 120.3, 114.1, 110.0 Anal. Calcd for C17H11N3O2: C, 70.58; H, 3.83; N, 14.52. Found: C, 70.25 ; H, 3.69; N,14.86. 5.4.6 Synthesis of Amides of Substituted Salicylic and o -Hydroxy Naphthoic Acids (5.7, 5.10): Method A: In a 50 mL round bottomed flask, the appropr iate primary or secondary amine (3 mmol) and triethyl amine (3 mmol) in fres hly dried THF were stirred. The supernatant (as described in the synthesis of 5.6ad, 5.9ac ) was carefully syringed out and added rapidly to the mixture of amines under an inert atmosphere while being stirred. The stirring was continued for an additional 30 min. The reaction mixture was concentrated under vacuum to remove the solvent and exce ss triethyl amine. The crude residue was taken up in ether (25 mL) and washed with water (25 mL), 1N HCl (2 X 25 mL) and brine before being dried over magnesium sul phate. The concentrated organic layer was finally refined by column chromatography over silica gel to give the respective amides ( 5.7ae,h, 5.10bf ). Method B:

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62 The appropriate N acylbenzotriazole derivative 5.6f g 5.9a (1.2 mmol) and 1 equiv. of the appropriate amine were placed in a 10 mL microwave reaction tube equipped with a magnetic stir-bar. The reacti on mixture was then exposed to microwave irradiation (120 W) at 120 C for 10 min. The reaction mi xture was diluted with CHCl3 (10 mL) and the residue refined by column chromatography on silica gel to give the amides 5.7f,g and 5.10a 5.4.7 Characterization of Amides of Substituted Salicylic and o -Hydroxy Naphthoic Acids (5.7 and 5.10) N -(Furan-2-ylmethyl)-2-hydroxybenzamide (5.7a):209 white needles from diethyl ether; mp 109 C; yield, 83%; IR (neat) = 3364, 1645, 1592, 1546, 1496 cm-1; 1H NMR 12.20 (s, 1H), 7.42.34 (m, 3 H), 6.90 (dd, J = 8.24, 1.0 Hz, 1H), 6.84 (dt, J = 7.14, 1 Hz, 1H), 6.60 (br s, 1H), 6.35 (dd, J = 3.3, 1.8 Hz, 1H), 6.32 (d, J = 3.3 Hz, 1H), 4.63 (d, J = 5.94 Hz, 2H); 13C NMR 169.7, 161.6, 150.4, 142.6, 142.5, 134.4, 125.4, 118.7, 114.0, 110.6, 108.1, 36.5. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 65.97; H, 5.18; N, 6.49. (2-Hydroxyphenyl)pipe ridin-1-yl-methanone (5.7b):164 white needles from methanol; mp 142 C; yield, 94%; IR (neat) = 3153, 2939, 2856, 1591, 1475 cm-1; 1H NMR 9.67 (s, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 7.3 Hz, 1H), 3.65.61 (m, 4H), 1.70.62 (m, 6H); 13C NMR 170.6, 158.7, 132.2, 128.1, 118.4, 117.8, 117.5, 46.7, 26.0, 24.4. 5-Bromo-2-hydroxyN -pentylbenzamide (5.7c): pale yellow microcrystals from diethyl ether; mp 54 C; yield, 84%; IR (neat) = 3374, 2930, 2859, 1635, 1591, 1543, 1475 cm-1; 1H NMR 12.36 (s, 1H), 7.46.43 (m, 2H), 6.88 (d, J = 9.3 Hz, 1H),

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63 6.30 (br s, 1H), 3.43 (q, J = 6.3 Hz, 2H), 1.68.58 (m, 2H), 1.38.34 (m, 4H), 0.92 (t, J = 6.6 Hz, 3H); 13C NMR 68.7, 160.5, 136.7, 127.8, 120.5, 115.9, 110.1, 39.9, 29.1, 29.0, 22.3, 13.9. Anal. Calcd for C12H16BrNO2: C, 50.37; H, 5.64; N, 4.89. Found: C, 50.54; H, 5.57; N, 4.84. 5-Bromo-2-hydroxyN -methylN -octylbenzamide (5.7d): cream microcrystals from ethyl acetate; mp 92 C; yield, 82%; IR (neat) = 3125, 2927, 2855, 1612, 1490 cm-1; 1H NMR 9.74 (s, 1H), 7.40.37 (m, 2H), 6.87 (d, J = 9.5 Hz, 1H), 3.50.45 (m, 2H), 3.11 (s, 3H), 1.68.64 (m, 2H), 1.29 (br s, 10H). 0.88 (t, J = 6.2 Hz, 3H); 13C NMR 170.2, 157.7, 134.9, 130.5, 119.8, 119.6, 110.1, 31.7, 29.2, 29.1, 27.3, 26.6, 22.6, 14.1. Anal. Calcd for C16H24BrNO2: C, 56.15; H, 7.07; N, 4.09. Found: C, 56.46; H, 7.35; N, 4.10. 2,4-DihydroxyN -pentylbenzamide (5.7e): white microcrystals from ethyl acetate; mp 104 C; yield, 96%; IR (neat) = 3385, 1637 cm-1; 1H NMR (DMSOd6) 13.06 (s, 1H), 10.03 (s, 1H), 8.51 ( br t, J = 6.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 6.28 (dd, J = 8.8, 1.8 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 3.24 (q, J = 6.1 Hz, 2H), 1.54.50 (m, 2H), 1.29 (br s, 4H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (DMSOd6) 169.4, 162.7, 162.1, 128.8, 106.9, 106.6, 102.7, 39.5, 28.7, 21.9, 13.9. Anal. Calcd for C12H17NO3: C, 64.56; H, 7.67; N, 6.27. Found: C, 64.77; H, 7.89; N, 6.28. 2,4-DihydroxyN -methylN -phenylbenzamide (5.7f): white microcrystals from chloroform; mp 150 C; yield, 93%; IR (neat) = 3350, 1664, 1624, 1502 cm-1; 1H NMR 11.65 (s, 1H), 7.37.31 (m, 2H), 7.28.26 (m, 1H), 7.15.12 (m, 2H), 6.53 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 2.6 Hz, 1H), 5.88 (dd, J = 8.8, 2.6 Hz, 1H), 5.67 (br s, 1H), 3.46 (s, 3H) ; 13C NMR 171.7, 162.9, 160.0, 145.3, 132.3, 129.7, 127.1, 126.6,

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64 108.3, 106.3, 103.6, 39.5. Anal. Calcd for C14H13NO3: C, 69.13; H, 5.39; N, 5.76. Found: C, 68.77; H, 5.43; N, 5.77. 4-(Morpholin-4-ylcarbonyl)benzene-1,3-diol (5.7g): white microcrystals from chloroform; mp 179 C; yield, 94%; IR (neat) = 3378, 1620, 1578 cm-1; 1H NMR 9.60 (s, 1H), 8.19 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.30 (dd, J = 8.4, 2.3 Hz, 1H), 3.68.65 (m, 8H); 13C NMR 170.9, 160.0, 158.7, 129.9, 110.2, 107.4, 103.8, 66.7, 46.0. Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 58.83; H, 5.99; N, 6.19. 2-Hydroxy-3-methylN -(3-methylbutyl)benzamide (5.7h): colorless oil, yield, 93%; IR (neat) = 3384, 2962, 2926, 2875, 1633, 1609, 1588, 1541 cm-1; 1H NMR (DMSOd6) 12.65 (s, 1H), 7.25 (d, J = 6.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.73 (t, J = 7.7 Hz, 1H), 6.39 (br s, 1H), 3.42.21 (m 2H), 2.26 (s, 3H), 1.73.62 (m, 1H), 1.53.39 (m, 1H), 1.28.14 (m, 1H), 0.97.91 (m, 6H); 13C NMR (DMSOd6) 170.6, 159.9, 134.8, 127.7, 122.6, 117.8, 113.5, 45.2, 34.8, 27.0, 17.1, 15.8, 11.2. Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.77; H, 8.97; N, 6.63. 2-Hydroxy-N-phenyl-1-naphthamide (5.10a): white microcrystals from chloroform; mp 171 C; yield, 95%; IR (neat) = 3283 (br w), 1627, 1597, 1532, 1443 cm-1; 1H NMR s 8.19 (d, J = 8.5 Hz, 1H), 7.97 (br s, 1H), 7.85 (t, J = 8.2 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.1 Hz, 1H) 7.45.38 (m, 3H), 7.26 7.19 (m, 2H); 13C NMR 168.4, 159.8, 136.9, 134.4, 130.5, 129.7, 129.3, 128.8, 128.5, 125.3, 123.7, 122.3, 120.7, 119.4, 109.9. Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C, 77.17; H, 4.94; N, 5.31.

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65 (2-Hydroxynaphthalen-1-yl)pip eridin-1-yl-methanone (5.10b): white needles from methanol; mp 242 C; yield, 90%; IR (KBr) = 3175, 1606, 1514 cm-1; 1H NMR (DMSOd6) 9.93 (s, 1H), 7.83.77 (m, 2H), 7.51.41 (m, 2H), 7.33.28 (m, 1H), 7.19 (d, J = 8.9 Hz, 1H), 3.90 (br s, 1H), 3.56 (br s, 1H), 3.09 (s, 2H), 1.59 (s, 4H), 1.44 (br s, 1H), 1.24 (br s, 1H); 13C NMR (DMSOd6) 165.9, 150.7, 131.2, 129.6, 128.2, 127.7, 126.9, 123.6, 123.1, 118.2, 117.1, 47.0, 24.3. Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.34; H, 6.93; N, 5.15. 1-Hydroxynaphthalene-2-carboxylic acid N -phenethylamide (5.10c): pale yellow microcrystals from ethyl acetate; mp 125 C; yield, 94%; IR (neat) = 3417, 1615, 1594, 1542, 1501 cm-1; 1H NMR 13.84 (s, 1H), 8.42 (d, J = 7.1 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.59.49 (m, 2H), 7.36.11 (m, 7H), 6.34 (br s, 1H), 3.75 (q, J = 6.6 Hz, 2H), 2.96 (t, J = 6.8 Hz, 1H); 13C NMR 170.6, 160.6, 138.5, 136.2, 128.9, 128.8 (2C), 127.3, 126.8, 125.8, 125.6, 123.8, 120.6, 118.1, 106.6, 40.8, 35.6. Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C, 77.94; H, 5.94; N, 4.86. (1-Hydroxynaphthalen-2-yl)pyrro lidin-1-yl-methanone (5.10d): white microcrystals from ether; mp 93 C; yield, 97%; IR (neat) = 3445 (br w), 2972, 2877, 1584, 1438 cm-1; 1H NMR 12.87 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.58.47 (m, 3H), 7.24 (d, J = 8.6 Hz, 1H), 3.77.73 (m, 4H), 1.97.92 (m, 4H); 13C NMR 171.2, 159.4, 135.5, 128.5, 127.1, 125.5, 125.3, 123.9, 123.7, 116.9, 109.5, 48.9, 25.5. Anal. Calcd for C15H15NO2: C, 74.76; H, 6.27; N, 5.80. Found: C, 74.28; H, 6.30; N, 5.85. 3-Hydroxynaphthalene-2-carboxylic acid allylamide (5.10e):210 pale yellow microcrystals from ethyl acetate; mp 121 C; yield, 75%; IR (neat) = 3374, 1657,

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66 1584, 1509 cm-1; 1H NMR 11.72 (s, 1H), 7.97 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.47 (dt, J = 6.9, 1.1 Hz, 1H), 7.31.26 (m, 2H), 6.70 (br s, 1H), 6.03.09 (m, 1H), 5.33 (dq, J = 17.0, 1.2 Hz, 1H), 5.25 (dq, J = 10.2 Hz, 1.2 Hz, 1H), 4.14 (tt, J = 5.8, 1.5 Hz, 2H); 13C NMR 169.6, 156.6, 137.0, 133.3, 128.5, 128.4, 126.8, 126.7, 126.2, 123.9, 117.5, 116.8, 112.4, 42.2. Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.69; H, 5.86; N, 6.17. (3-Hydroxynaphthalen-2-yl)morp holin-4-yl-methanone (5.10f):162 white needles from ethyl acetate; mp 216 C; yield, 70%; IR (neat) = 3095, 2967, 2855, 1594, 1483 cm-1; 1H NMR 8.93 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.32 (s, 1H), 3.83 3.76 (m, 8H); 13C NMR 170.2, 154.1, 135.8, 128.7, 128.3, 128.1, 126.9, 126.4, 124.1, 119.7, 112.3, 66.9 (2C). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.70; H, 5.95; N, 5.44. 5.4.8 Synthesis of Hydroxy Aryl-/Alkyla nd Thioesters 5.11 from Hydroxy Acids The ( N -hydroxyacyl)benzotriazole wa s prepared as described in the synthesis of the hydroxy carboxamides. The appropriate alcohol/thiol (6 mmol) wa s treated with NaH (60% dispersion in oil) (6.2 mmol) in 12 mL of anhydrous THF and stirred for 30 min. The supernatant of the benzotriazolating mixture / hydroxy acid was carefully syringed out and added dropwise to the sodium salt of the alc hohol/thiol while under inert atmosphere. The residual solid was washed with 5 mL of dry THF and the washings added to the sodium salt of the alcohol. After 30 min the reaction was concentrated under vacuum. Water (20 mL) and ether (20 mL) were added to the re sidue. The layers were separated and the

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67 organic layer further washed with satura ted sodium carbonate solution (to remove benzotriazole), brine, dried over magnesium sulphate and concentrated. The residue was refined by flash chromatography over silica gel to give the hydroxy aryl-/alkyland thio esters. 5.4.9 Characterization of Hydroxy Aryl-/Al kyland Thioesters 5.11 from Hydroxy Acids Methyl (DL) mandelate (5.11a):211 white powder from hexanes; mp 56 C; yield, 40%; IR (neat) = 3468, 1735 cm-1; 1H NMR 7.43.32 (m, 5H), 5.18 (d, J = 5.6 Hz, 1H), 3.74 (s, 3H), 3.56 (d, J = 5.6 Hz, 1H); 13C NMR 174.1, 138.2, 128.6, 128.5, 126.5, 72.8, 53.0. Ethyl (DL)-mandelate (5.11b):212 microcrystals from hexanes; mp 35 C; yield, 72%; IR (neat) = 3469, 2983, 1735 cm-1; 1H NMR 7.44.28 (m, 5H), 5.15 ( d, J = 5.8 Hz, 1H), 4.31.10 (m, 2H), 3.61 (d, J = 5.9 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR 173.6, 138.4, 128.5, 128.3, 126.5, 72.8, 62.1, 13.9. 2-Hydroxy-3-phenylthiopropionic acid S-hexyl ester (5.11e): colorless oil; yield, 37%; IR (neat) = 3455, 2928, 2856, 1681 cm-1; 1H NMR 7.34-7.22 (m, 5H), 4.44 (ddd, J = 7.7, 6.5, 4.1 Hz, 1H), 3.17 (dd, J = 14.0, 4.1 Hz, 1H), 2.95 (dd, J = 14.0, 7.8 Hz, 1H), 2.9 (t, J = 7.3 Hz, 2H), 2.72 (d, J = 6.5 Hz, 1H), 1.62.52 (m, 2H), 1.41.21 (m, 6H), 0.89 (t, J = 6.7 Hz, 3H); 13C NMR 203.2, 136.0, 129.5, 128.5, 126.9, 78.1, 41.1, 31.2, 29.2, 28.4, 22.4, 14.0. Anal. Calcd for C15H22O2S: C, 67.63; H, 8.32. Found: C, 67.80; H, 8.60. Hydroxyphenylthioacetic acid S -(4-methoxyphenyl) ester (5.11f): colorless oil; yield, 23%; IR (neat) = 3462, 2940, 2837, 1698, 1592 cm-1; 1H NMR 7.48.36 (m,

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68 5H), 7.24 (AA'BB', JAB = 8.8 Hz, 2H), 6.90 (AA'BB', JAB = 8.8 Hz, 2H), 5.31 (d, J = 3.9 Hz, 1H), 3.79 (s, 3H), 3.73 (d, J = 4.5 Hz, 1H); 13C NMR 201.1, 160.7, 137.8, 136.1, 128.9, 128.8, 127.1, 117.0, 114.9, 79.8, 55.3. Anal. Calcd for C15H14O3S: C, 65.67; H, 5.14. Found: C, 65.42; H, 5.28. 2-Hydroxy-3-methyl-thiobutyric acid S -benzyl ester (5.11g): white needles from hexanes/ethyl acetate; mp 69 C; yield, 24%; IR (neat) = 3406, 2926, 2855, 1638 cm-1; 1H NMR 7.31.23 (m, 5H), 4.17.10 (m, 3H), 2.82 (d, J = 6.2 Hz, 1H), 2.21 2.11 (m, 1H), 1.05 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H); 13C NMR 203.0, 137.2, 128.8, 128.6, 127.3, 81.7, 32.9, 32.7, 19.1, 15.1. Anal. Calcd for C12H16O2S: C, 64.25; H, 7.19. Found: C, 64.47; H, 7.42. 5.4.10 Synthesis of Esters of Substituted Salicylic 5.12 and o -Hydroxy Naphthoic Acids 5.13 Method A: In a 50 ml round bottomed flask, the appropriate alcohol (3 mmol) was treated with NaH (60% dispersion in oil) (3.2 mmol) in 6 mL of anhydrous THF and stirred for half an hour. The supernatant containing the acyl benz otriazole derivative (as described in the synthesis of 5.6a-d, 5.9a-c ) was carefully syringed out and added drop-wise to the sodium salt of the alcohol under an inert at mosphere. After 30 min the reaction mixture was concentrated under vacuum. Water (20 mL) and ether (20 mL) were added to the concentrated residue. The layers were se parated and the organic layer dried over magnesium sulphate, concentrated unde r vacuum and refined by flash column chromatography to give the esters ( 5.12ab, 5.13a ). Method B (with variations):

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69 The N -acylbenzotriazole derivative 5.6ad, 5.9ac (1 mmol) and the appropriate alcohol (3 equiv) were placed in a 50 mL RBF equipped with a stir-bar. The flask was then exposed to microwave irradiation (120 W) at 120 C for 10 min. In the case of using ethanol and n -propanol as starting materials, th e reactions took place in a 10 mL microwave reaction tube sealed by aluminiu m cap, and the temperature for the reaction was set up to 100 oC. When the N -acylbenzotriazole being used is 5.6c complications will appear because more alcohol will conde nsate with the OH at 4-position to form another estereal functional group. In this case, the limiting agent was chosen to be 5.6c (1.2 equiv), and alcohol used is 1 equiv. Ot her conditions stayed the same. The reaction mixture was diluted with CH2Cl2 (10 mL) and the residue refined by column chromatography on silica gel with hexanes/ et hyl acetate (8/1) to give the respective ester 5.12ag, 5.13ah 5.4.11 Characterization of Esters of Substituted Salicylic 5.12 and o -Hydroxy Naphthoic Acids 5.13 Cyclopentyl salicylate (5.12a): colorless oil; yield, 92%; IR (neat) = 3145, 2965, 2874, 1672 cm-1; 1H NMR 10.93 (s, 1H), 7.80 (dd, J = 7.9, 1.5 Hz, 1H), 7.44 (td, J = 8.0, 1.7 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.86 (t, J = 7.3 Hz, 1H), 5.40.46 (m, 1H), 1.65.01 (m, 8H); 13C NMR 170.0, 161.6, 135.4, 129.8, 119.0, 117.5, 112.9, 32.7, 23.7. Anal. Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.86; H, 7.03. 1-Ethylprop-2-enyl salicylate (5.12b): colorless oil; yield, 87%; IR (neat) = 3186, 2972, 2880, 1675, 1614 cm-1; 1H NMR 10.86 (s, 1H), 7.89 (dd, J = 8.0, 1.7 Hz, 1H), 7.45 (td, J = 7.8, 1.6 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 5.83.94 (m, 1H), 5.34 (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.6 Hz, 1H), 1.75.86 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR 169.4, 161.7, 135.6, 135.5, 129.7, 119.0,

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70 117.5, 117.2, 112.6, 77.0, 27.2, 9.3. Anal. Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.87; H, 7.04. Ethyl 5-bromo-2-hydroxybenzoate (5.12c): colorless microcrystals; mp 46 C; yield, 90%; IR (neat) = 3143, 1681, 1608 cm-1; 1H NMR 10.80 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 8.9, 2.6 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR 169.1, 160.6, 138.3, 132.2, 119.5, 114.1, 110.7, 61.9, 14.1. Anal. Calcd for C12H14O3: C, 44.11; H, 3.70. Found: C, 44.29; H, 3.56. Cyclopentyl 5-bromo-2-hydroxybenzoate (5.12d): colorless needles from chloroform/hexanes; mp 45 C; yield, 91%; IR (neat) = 3412, 2966, 2873, 1674 cm1; 1H NMR 10.90 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 9.0, 2.4 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 5.45.41 (m, 1H), 2.04.68 (m, 8H); 13C NMR 168.9, 160.7, 138.2, 132.1, 119.5, 114.4, 110.6, 79.1, 32.7, 23.8. Anal. Calcd for C12H13BrO3: C, 50.55; H, 4.60. Found: C, 50.41; H, 4.52. Propyl 2,4-dihydroxybenzoate (5.12e): colorless microcrystals from hexanes/ethyl acetate; mp 32 C; yield, 87%; IR (neat) = 3384, 1666, 1623 cm-1; 1H NMR 11.17 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 6.62 (br s, 1H), 6.42 (d, J = 2.1 Hz, 1H), 6.39 (dd, J = 8.5, 2.1 Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 1.78 (sextet, J = 7.0 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR 170.2, 163.3, 162.2, 131.9, 108.0, 105.8, 103.0, 66.7, 21.9, 10.4. Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found: C, 61.30; H, 6.34. Cyclopentyl 2,4-dihydroxybenzoate (5.12f): colorless oil; yield, 91%; IR (neat) = 3372, 1660 cm-1; 1H NMR 11.25 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.09 (br s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 8.6, 2.3 Hz, 1H), 5.41.36 (m, 1H), 2.00.59

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71 (m, 8H); 13C NMR 170.0, 163.1, 162.2, 131.9, 108.0, 106.0, 102.9, 78.3, 32.7, 23.7. Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.58; H, 6.50. Decyl 2-hydroxy-3-methylbenzoate (5.12g): pale yellow oil; yi eld, 89%; IR (neat) = 3165, 2926, 2855, 1671 cm-1; 1H NMR 7.69 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 2.26 (s, 3H), 1.81.72 (m, 2H), 1.81.27 (m, 14H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR 170.7, 160.1, 136.3, 127.3, 126.5, 118.3, 111.8, 65.4, 31.9, 29.5, 29.3, 29.2, 28.5, 25.9, 22.6, 15.6, 14.1. Anal. Calcd for C18H28O3: C, 73.93; H, 9.65. Found: C, 73.65; H, 9.92. Cyclopentyl 2-hydroxy-1-naphthoate (5.13a): pale yellow oil; yield, 94%; IR (neat) = 3345 (br w), 2965, 2873, 1644 cm-1; 1H NMR 12.46 (s, 1H), 8.75 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.37.32 (m, 1H), 7.15 (d, J = 8.9 Hz, 1H), 5.65.59 (m, 1H), 2.09.69 (m, 8H); 13C NMR 172.2, 164.3, 136.6, 131.9, 129.1, 128.6, 128.3, 125.0, 123.5, 119.3, 105.0, 79.3, 32.8, 23.8. Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.88; H, 6.41. Pent-4-ynyl 2-hydroxy-1-naphthoate (5.13b): colorless oil; yiel d, 87%; IR (neat) = 3296, 1645 cm-1; 1H NMR 12.31 (s, 1H), 8.70 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.56.51 (m, 1H), 7.34 (td, J = 7.4, 0.9 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H), 4.61 (t, J = 6.4 Hz, 2H), 2.43 (td, J = 6.9, 2.5 Hz, 2H), 2.14 2.02 (m, 3H); 13C NMR 172.3, 164.4, 136.8, 131.7, 129.1, 128.5, 128.4, 125.1, 123.5, 119.2, 104.5, 82.5, 69.5, 64.3, 27.3, 15.4. Anal. Calcd for C16H14O3: C, 75.57; H, 5.55. Found: C, 75.32; H, 5.60. Ethyl 2-hydroxy-1-naphthoate (5.13c):160 colorless needles from chloroform/ hexanes; mp 56 58 C; yield, 95%; IR (neat) = 3358 (br w), 1644 cm-1; 1H NMR

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72 12.4 (s, 1H), 8.77 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (td, J = 6.1 Hz, 1H), 7.34 (td, J = 7.4, 0.9 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 4.55 (q, J = 4.2 Hz, 2H), 1.51 (t, J = 7.1 Hz, 3H); 13C NMR 172.3, 164.3, 136.7, 131.8, 129.0, 128.6, 128.3, 125.2, 123.5, 119.2, 104.6, 61.9, 14.3. Ethyl 1-hydroxy-2-naphthoate (5.13d):213 colorless needles from chloroform/hexanes; yield, 95%; mp 46 C; IR (neat) = 2990, 1656 cm-1; 1H NMR 12.1 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.73.68 (m, 2H), 7.54 (td, J = 8.1, 1.4 Hz, 1H), 7.46 (td, J = 7.0, 1.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 4.38 (q, J = 5.7 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR 171.0, 160.8, 137.0, 129.2, 127.3, 125.6, 124.7, 124.2, 123.7, 118.4, 105.7, 61.3, 14.1. Cyclopentyl 1-hydroxy-2-naphthoate (5.13e): white microcrystals from chloroform/hexanes; yield, 91%; mp 58 C; IR (neat) = 3385, 2964, 2866, 1655 cm1; 1H NMR 12.16 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.75.71 (m, 2H), 7.58 (td, J = 8.1, 1.2 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 5.50.45 (m, 1H), 2.05.65 (m, 8H); 13C NMR 170.8, 160.9, 137.1, 129.2, 127.4, 125.6, 124.8, 124.3, 123.8, 118.3, 106.1, 78.4, 32.8, 23.8. Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.80; H, 6.39. Pent-4-ynyl 1-hydroxy-2-naphthoate (5.13f): white powder from chloroform/ hexanes; yield, 91%; mp 65 C; IR (neat) = 3267, 2975, 2844, 1650 cm-1; 1H NMR 12.0 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.75.72 (m, 2H), 7.59 (td, J = 8.2, 1.4 Hz, 1H), 7.50 (td, J = 8.1, 1.1 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 4.49 (t, J = 6.3 Hz, 2H), 2.40 (td, J = 6.9, 2.6 Hz, 2H), 2.07.99 (m, 3H); 13C NMR 170.9, 161.0, 137.1,

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73 129.3, 127.4, 125.7, 124.7, 124.1, 123.8, 118.5, 105.5, 82.8, 69.3, 63.7, 27.5, 15.3. Anal. Calcd for C16H14O3: C, 75.57; H, 5.55. Found: C, 75.39; H, 5.56. 1-Ethylprop-2-enyl 1-hydroxy-2-naphthoate (5.13g): colorless oil; yield, 91%; IR (neat) = 3408, 2971, 2879, 1660, 1600 cm-1; 1H NMR 12.07 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.57 (td, J = 8.1, 1.2 Hz, 1H), 7.49 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 5.97.85 (m, 1H), 5.53.47 (m, 1H), 5.36 (d, J = 18.3 Hz, 1H), 5.25 (d, J = 6.2 Hz, 1H), 1.89.75 (m, 2H), 1.0 (t, J = 7.5 Hz, 3H); 13C NMR 170.4, 161.0, 137.1, 135.8, 129.3, 125.6, 127.4, 124.7, 124.2, 123.8, 118.4, 117.2, 105.8, 27.3, 9.4. Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.89; H, 6.44. Butyl 3-hydroxy-2-naphthoate (5.13h): yellow oil; yield, 90%; IR (neat) = 3226, 2961, 2873, 1681 cm-1; 1H NMR 10.55 (s, 1H), 8.42 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.45 (td, J = 8.1, 1.0 Hz, 1H), 7.30.25 (m, 2H), 4.38 (t, J = 6.6 Hz, 2H), 1.84.75 (m, 2H), 1.56.44 (m, 2H), 1.0 (t, J = 7.4 Hz, 3H); 13C NMR 169.9, 156.3, 137.7, 132.1, 129.1, 129.0, 126.9, 126.2, 123.8, 114.3, 111.5, 103.3, 65.5, 30.5, 19.2, 13.7. Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.64; H, 6.72 .

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74 CHAPTER 6 SYNTHESIS OF IMIDOYLBENZOTRIAZOLES FROM SECONDARY AMIDES 6.1 Introduction Imidoylbenzotriazoles are st able and useful substitu tes for imidoyl chlorides, 214 216 and have been reported as versatile reagents for the synthesis of enaminones217 and Nsubstituted enamino acid derivatives.218 Reported procedures (Scheme 6-1) for the preparat ion of imidoylbenzotriazoles include (i) the reaction of secondary amides with benzotriazole and POCl3 in the presence of triethylamine (8 examples, yield: 38 96%);214 (ii) reaction of oximes with 1 ( ptoluenesulfonyl)benzotriazole (12 examples, yield: 20 87%);219 (iii) reaction of sulfinyldibenzotriazole with second ary amides (10 examples, yield: 15 75%);215 (iv) the reaction of isonitriles with N(aminoalkyl)benzotriazole s in the presence of BF3.Et2O (11 examples, yield: 87 99%);220 (v) the reaction of Nacylbenzotriazoles with isocyanates (6 examples, yield: 71 99%);221 and (vi) the reaction of secondary amides with 1 chlorobenzotriazole in the pres ence of triphenylphosphine (9 examples, 40 90%).218 All these methods have lim itations, for example, tedious workup procedure which led to low yields and difficulties to scale-up (route i in Scheme 6-1) and limited availability of st arting materials (route ii and iv in Scheme 6-1). Furthermore, the preparation methods involving secondary amides (route I, iii and vi in Scheme 6-1) showed poor versat ility because acceptable yields cannot be obtained regularly from various starting materials or hars h conditions (high pressure

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75 and/or high temperature) were re quired. A general method for making imidoyobenzotriazoles is thus required. The combination of benzotriazole and thionyl chloride has been proved useful in the synthe sis of acid chlorides and N acylbenzotriazoles. Since it is widely reported that imidoyl chlorides can be prepared from various chlorinating agents, it is realistic to discover new preparation method based on literature work. Imidoyl ch lorides can be trea ted as chemical equivalents of acid chlorides. It should be possible to convert imidoyl chlorides into imidoylbenzotriazoles just like what has been done with ac id chlorides in Chapter 2. In this dissertation, both one-step and twostep reactions to convert amides to imidoylbenzotriazoles were studied. 6.2 Results and Discussions Prelimimary study showed that the react ion of secondary amides (1 equiv), SOCl2 (1 equiv) and benzotriazole (3 equiv) gave imidoylbenzotri azoles. However, two unwanted things occured during these reactions. On one hand, the reaction is normally slow and will not go to completion even after a couple of days; on the other hand, when R1 was aliphatic, side products formed easily and became the major products eventually to ruin th e reaction. For the reactions involving secondary amides that gave no side produc ts, a microwave synthesizer was used to accelerate the reactions. Also we used more SOCl2 and benzotriazole than required. We found that reactions of sec ondary amides (1 equiv), SOCl2 (2 equiv) and benzotriazole (4 equiv) at 80 oC, 80 W irradiation power for 10 min gives imidoylbenzotriazoles 6b e i l n r u w (with R1 = aryl group) in 78 95% yields (Table 6-3). To avoid forming si de products, imidoylbenzotriazoles 6a f h m s t

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76 (with R1 = aliphatic group) were prepared in 56 75% yields by the one-pot reaction (two steps) of amides (1 equiv), (COCl)2 (1 equiv) and benzot riazole (2 equiv) in presence of pyridine. Imidoyl chlorides were formed in th e first step, then converted into imidoylbenzotriazoles in the second st ep. No side products were observed in this case; however, the yields were not ve ry high because the ra tes of the reactions were low at room temperature. All compounds were fully characterized by 1H and 13C NMR spectroscopy and by either elemental analysis or comparison of melting point with literature data. The novel methods described in Scheme 6-2 have advantages over all the known methods because of their ability to give moderate to high yields (56 95%) starting from various readily available s econdary amides through brief reactions. R1 R2 N OH N R2 Bt R1 O N H R1 R2 O N H R1 R2 O N H R1 R2 (iii) (v) (vi) (ii) (i) (i) BtH, POCl3/Et3N; (ii) BtTs; (iii) Bt2SO; (iv) BtR1, BF3.Et2O ; (v) R1COBt; (vi) BtCl, PPh3 R2NCO (iv) R2NC Scheme 6-1 Literature Methods of Preparation of Imidoylbenzotriazoles O N H R1 BtH, SOCl2 6.1b e,i l,n r,u x R2 Method A 1) (COCl)2,Pyridine, 0 oC, 15min 2) 2 BtH, 4-6 h Method B R1 N Bt R2 R1 N Bt R2 R1 = alkyl R1 = aryl 6.1a,f h,m,s,t Scheme 6-2 Preparation of Imidoylbenzotriazoles 6.1a x

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77 Table 6-1 Preparation of Imidoylbenzotriazoles 6.1 Entry R1 R2 Product (Yield %)a Mp (oC) 1 Methyl Phenyl 6.1a (75) 106 2 Phenyl Phenyl 6.1b (88) 129 3 pTolyl pTolyl 6.1c (82) 138 4 2-Furyl pTolyl 6.1d (84) 120 5 Phenyl pMethoxyphenyl 6.1e (82) 100 6 Methyl pTolyl 6.1f (65) 113 7 Benzyl pTolyl 6.1g (62) 124 8 Benzyl Benzyl 6.1h (56) Oil 9 Phenyl Benzyl 6.1i (93) 108 10 pChlorophenyl pTolyl 6.1j (90) 118 11 pMethoxyphenyl Benzyl 6.1k (78) 115 12 Phenyl 2 Furylmethyl 6.1l (84) Oil 13 nHexyl pTolyl 6.1m (57) Oil 14 2 Furyl Cyclohexyl 6.1n (95) Oil 15 pNitrophenyl Benzyl 6.1o (86) 117 16 pNitrophenyl Phenyl 6.1p (88) 183 17 pTolyl nButyl 6.1q (84) Oil 18 2 Thienyl pTolyl 6.1r (91) 133 19 Phenethyl Benzyl 6.1s (57) 77 20 Phenethyl pTolyl 6.1t (64) 116 21 2 Thienyl Benzyl 6.1u (83) Oil 22 2 Thienyl 2 Furylmethyl 6.1v (81) Oil 23 Phenylethenyl pTolyl 6.1w (65) Oil 24 pTolyl Methyl 6.1x (84) 95 aIsolated yield. 6.3. Conclusion In summary, we have develope d the preparative methods for imidoylbenzotriazoles in mode rate to high yields starti ng from readily available secondary amides, benoztriazoles and chlorinating agents (SOCl2 or (COCl)2) under mild conditions.

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78 6.4 Experimental Section 6.4.1 General Procedure for the Preparat ion of Imidoylbenzotriazoles 6.1 Method A: For amides with R1=aliphatic group: to a solution of amide (5.0 mmol) in methylene chloride (20 mL), pyridine (0.45 mL, 5.5 mmol) followed by oxalyl chloride (0.48 mL, 5.5 mmol) in me thylene chloride (20 mL) was added dropwise at 0 oC. Gas evolution was observed during the proce ss. After the addition, the reaction was continued fo r 15 min, then benzotriazole (1.25 g, 10.5 mmol) was added in one portion to the reac tion flask. The ice bath was removed to allow the reaction to continue at room temperature and the reaction was monitored by TLC. The precipitated white solid wa s filtered off and sodium bicarbonate solution (saturated) was added to dilute the reaction mixture. Aqueous work-up gave a crude product which was purifie d by column chromatography on basic alumina using hexanes/EtOAc (8:1 to 5:1) as eluent. Method B: For amides with R1=aryl group: Thionyl chloride (0.77 mL, 10.5 mmol) and benzotriazole (2.44 g, 20.5 mmol) were dissolved in chloroform (10 mL) in a 50 mL round bottomed flask, and then amide (5 mmol) was added to the flask. The reaction mixture was exposed to microwave irradiation for 10 min at 80 oC and 80 W. The precipitated solid was filtered off and aqueous workup gave a crude product which was purified by either recrystallization from chloroform/hexanes or column chromatography on basic alumina using hexanes/EtOAc (8:1 to 5:1) as eluent. 6.4.2 Characterization of Imidoylbenzotriazoles 6.1 N[1-(1 H -1,2,3-Benzotriazol-1-yl)ethylidene]aniline (6.1a). To a solution of acetanilide (0.68 g, 5.0 mmol) in methylene chloride (20 mL), pyridine (0.45 mL,

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79 5.5 mmol) followed by oxalyl chloride (0.48 mL, 5.5 mmol) in methylene chloride (20 mL) was added dropwise at 0 oC. Gas evolution was observed during the process. After the addition, the react ion was continued for 15 min, then benzotriazole (1.25 g, 10.5 mmol) was adde d in one portion to the reaction flask. The ice bath was removed to allow the reac tion to continue at room temperature and the reaction was monitored by TLC. The pr ecipitated white solid was filtered off and sodium bicarbonate solution (saturat ed) was added to dilute the reaction mixture. Aqueous work-up gave a crude product which was purified by column chromatography on basic alumina using hexa nes/EtOAc (8:1) as eluent to give colorless needles (from chloroform/hexanes): mp 106 108 oC (lit.215 mp 108 oC); yield, 75% (0.89 g); 1H NMR 2.75 (s, 3H), 6.95 (d, J = 7.5 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.40 7.50 (m, 3H), 7.60 (t, J = 7.6 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H); 13C NMR 16.3, 115.7, 119.8, 120.2, 124.3, 125.4, 129.2, 129.2, 131.3, 146.6, 147.4, 154.0. 1-[Phenyl(phenylimino)methyl] 1 Hbenzotriazole (6.1b). Thionyl chloride (0.77 mL, 10.5 mmol) and be nzotriazole (2.44 g, 20.5 mm ol) were dissolved in chloroform (10 mL) in a 50 mL round bottomed flask, and then benzanilide (0.99 g, 5 mmol) was added to the flask. The r eaction mixture was e xposed to microwave irradiation for 10 min at 80 oC and 80 W. The precipitated solid was filtered off and aqueous workup gave a crude product which was purified by column chromatography on basic alumina using hexa nes/EtOAc (8:1) as eluent to give yellow needles (from chloroform/hexanes): mp 129 131 oC (lit.218 mp 132 oC); yield, 88% (1.31 g); 1H NMR 6.84 (d, J = 7.4 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H),

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80 7.23 (t, J = 7.8 Hz, 2H), 7.35 7.42 (m, 5H), 7.49 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H); 13C NMR 115.3, 119.9, 121.4, 124.1, 125.5, 128.1, 128.8, 129.2, 130.1, 130.2, 130.3, 132.0, 146.4, 146.9, 153.7. N[1 H1,2,3-Benzotriazol-1-yl(4-meth ylphenyl)methylidene]-4methylaniline (6.1c): purified by recrystallization from chloroform/hexanes; yellow needles; mp 138 140 oC; yield, 82% (1.34 g); 1H NMR 2.29 (s, 3H), 2.37 (s, 3H), 6.76 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.44 (d, J = 8.2 Hz, 1H); 13C NMR 20.9, 21.6, 115.3, 119.9, 121.5, 125.4, 127.5, 129.0, 129.1, 129.4, 130.2, 132.1, 133.7, 140.7, 144.5, 146.4, 153.5. Anal. Calcd for C21H18N4: C, 77.27; H, 5.57; N, 17.17. Found: C, 77.33; H, 5.59; N, 17.29. N[1 H1,2,3-Benzotriazol-1-yl(2-furyl)methylidene]-4-methylaniline (6.1d): purified by recrystallization from chloroform/hexanes; yellow microcrystals; mp 120 123 oC; yield, 84% (1.27 g); 1H NMR 2.38 (s, 3H), 6.72 6.74 (m, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.88 (s, 1H), 8.16 (d, J = 6.2 Hz, 1H), 8.18 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H); 13C NMR 21.7, 113.0, 114.7, 120.2, 124.8, 126.3, 127.2, 129.8, 130.5, 132.1, 140.7, 141.4, 144.5, 145.5, 148.9, 155.0. Anal. Calcd for C18H14N4O: C, 71.51; H, 4.68; N, 18.54. Found: C, 71.13; H, 4.49; N, 18.65. N[1 H -1,2,3-Benzotriazol-1-yl-(pheny l)methylidene]-4-methoxyaniline (6.1e): purified by recrystallization from ch loroform/hexanes; yellow plates; mp

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81 100 103 oC (lit.218 mp 104 oC); yield, 82% (1.34 g); 1H NMR 3.76 (s, 3H), 6.77 6.82 (m, 4H), 7.35 7.55 (m, 6H), 7.60 7.67(m, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H); 13C NMR 55.3, 114.1, 115.3, 119.9, 123.1, 125.4, 128.4, 129.1, 130.1, 130.3, 132.0, 139.8, 146.4, 153.1, 156.6. 1-[1-[(4-Methylphenyl)imino]ethyl] 1 Hbenzotriazole (6.1f): purified by column chromatography on basic alumina; white microcrystals (from chloroform/hexanes); mp 113 115 oC (lit.214 mp 115 oC); yield, 65% (0.81 g); 1H NMR 2.39 (s, 3H), 2.75 (s, 3H), 6.86 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.44 7.50 (m, 1H), 7.56 7.62 (m, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H); 13C NMR 16.1, 20.8, 115.7, 119.6, 120.2, 125.2, 129.1, 129.7, 131.3, 133.8, 144.7, 146.5, 153.9. N[1-(Benzotriazole-1-yl)-2-phenyle thylidene]-4-methylaniline (6.1g): purified by column chromatography on basi c alumina; pale yellow microcrystals (from chloroform/hexanes); mp 124 126 oC (lit.217 mp 123 oC); yield, 62% (1.01 g); 1H NMR 2.38 (s, 3H), 4.61 (s, 2H), 6.88 (d, J = 8.1 Hz, 2H), 7.14 7.22 (m, 7H), 7.45 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.1Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H); 13C NMR 21.0, 34.8, 115.7, 119.8, 120.2, 125.5, 126.8, 128.6, 128.8, 129.3, 129.9, 131.6, 134.1, 135.4, 144.5, 146.6, 154.7. N[(1 E )-1-(1 H -1,2,3-Benzotriazol-1-yl)-2-phenylethylidene]Nbenzylamine (6.1h):217 purified by column chromatography on basic alumina; colorless oil; yi eld, 56% (0.92 g); 1H NMR 4.76 (s, 2H), 4.95 (s, 2H), 7.16 7.46 (m, 11H), 7.51 (t, J = 7.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.51 (d, J = 8.4 Hz,

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82 1H); 13C NMR 33.9, 53.8, 115.7, 119.6, 125.1, 126.9, 127.0, 127.5, 128.4, 128.5, 128.8, 128.9, 131.5, 134.4, 139.2, 146.6, 155.4. N[1 H -1,2,3-Benzotriazol-1-yl (phenyl)methylene]Nbenzylamine (6.1i): purified by column chromatography on basic alumina; colorless needles (from chloroform/hexanes); mp 108 110 oC (lit.215 mp 108 oC); yield, 93% (1.45 g); 1H NMR 4.76 (s, 2H), 7.36 7.39 (m, 4H), 7.43 7.48 (m, 4H), 7.54 7.61 (m, 4H), 8.11 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H); 13C NMR 55.3, 115.4, 119.8, 125.2, 126.9, 127.5, 127.7, 128.5, 128.7, 129.0, 130.3, 130.5, 131.8, 139.5, 146.3, 155.7. N[1 H1,2,3-Benzotriazol-1-yl(4-chlorophenyl)methylene]N(4methylphenyl)amine (6.1j): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 118 120 oC; yield, 90% (1.56 g); 1H NMR 2.29 (s, 3H), 6.73 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 7.29 7.37 (m, 4H), 7.51 (t, J = 7.3 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H); 13C NMR 20.9, 115.3, 120.0, 121.4, 125.7, 128.6, 128.8, 129.3, 129.6, 131.6, 131.9, 134.1, 136.5, 143.9, 146.4, 152.3. Anal. Calcd for C20H15ClN4: C, 69.26; H, 4.37; N, 16.16. Found: C, 69.34; H, 4.25; N, 16.13. N[1 H -1,2,3-Benzotriazol-1-yl(4-methoxyphenyl)methylene]Nbenzylamine (6.1k): purified by column chromatography on basic alumina; white microcrystals (from chloroform/hexanes); mp 115 118 oC; yield, 78% (1.34 g); 1H NMR (mixture of two isomers) 3.80 (s, 0.7H), 3.88 (s, 3H), 4.56 (s, 0.5H), 4.82 (s, 2H), 6.86 (d, J = 8.9 Hz, 0.5H), 7.06 (d, J = 8.8 Hz, 2H), 7.23 7.47 (m, 10H), 7.56 (t, J = 7.6 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H); 13C

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83 NMR 55.3, 110.5, 114.0, 115.3, 119.7, 120.2, 122.4, 124.6, 125.1, 126.3, 126.9, 127.4, 127.7, 128.4, 128.5, 128.9, 130.1, 130.4, 131.9, 138.8, 139.7, 146.3, 155.5, 160.9. Anal. Calcd for C21H18N4O: C, 73.66; H, 5.31; N, 16.37. Found: C, 73.66; H, 5.32; N, 16.54. N[1-(1 H -1,2,3-benzotriazol-1-yl)heptylidene]N(2-furylmethyl)amine (6.1l): purified by column chromatography on ba sic alumina; colo rless oil; yield, 84% (1.27 g); 1H NMR 4.72 (s, 2H), 6.27 6.28 (m, 1H), 6.36 6.38 (m, 1H), 7.34 7.51 (m, 4H), 7.56 7.62 (m, 4H), 8.10 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H); 13C NMR 48.7, 106.7, 110.3, 110.6, 115.4, 119.8, 125.3, 128.6, 128.8, 129.1, 130.1, 130.4, 131.8, 142.0, 146.3, 152.6. Anal. Calcd for C18H14N4O: C, 71.51; H, 4.68; N, 18.54. Found: C, 71.15; H, 4.74; N, 18.55. N[1-(1 H -1,2,3-benzotriazol-1-yl)heptylidene]N(4-methylphenyl)amine (6.1m): purified by column chromatography on ba sic alumina; colorless oil; yield, 57% (0.91 g); 1H NMR 0.82 (t, J = 6.8 Hz, 3H), 1.16 1.36 (m, 6H), 1.71 1.81 (m, 2H), 2.38 (s, 3H), 3.10 3.15 (m, 2H), 6.83 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 8.2, 0.8 Hz, 1H), 7.56 (dd, J = 7.8, 0.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H); 13C NMR (1 signal is hidden) 13.9, 20.8, 22.3, 27.8, 29.1, 31.1, 115.7, 119.6, 119.8, 125.2, 129.0, 129.7, 131.4, 133.5, 144.8, 146.4, 157.6. Anal. Calcd for C20H24N4: C, 74.97; H, 7.57; N, 17.49. Found: C, 74.80; H, 7.67; N, 17.65. N[1 H -1,2,3-Benzotriazol-1-yl(2-furyl)methylene]Ncyclohexylamine (6.1n): purified by column chromatography on ba sic alumina; colorless oil; yield, 95% (1.40 g); 1H NMR 1.00 1.96 (m, 15H), 2.98 3.06 (m, 0.5H), 3.94 4.04 (m,

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84 1H), 6.18 (d, J = 3.4 Hz, 0.5 H), 6.40 6.42 (m, 0.5H), 6.60 6.62 (m, 1H), 6.88 (d, J = 3.6 Hz, 1H), 7.35 7.60 (m, 4H), 7.66 (d, J = 1.0 Hz, 1H), 8.09 (dd, J = 8.2, 0.6 Hz, 1H), 8.16 8.21 (m, 1.5H); 13C NMR 24.0, 24.1, 25.0, 25.4, 33.6, 34.2, 59.5, 60.0, 109.7, 111.1, 111.8, 114.1, 115.7, 116.7, 119.5, 120.0, 124.5, 124.8, 128.4, 128.6, 132.2, 132.9, 136.3, 141.5, 142.7, 144.5, 145.9, 146.0, 147.7. Anal. Calcd for C17H18N4O: C, 69.35; H, 6.18; N, 19.04. Found: C, 69.40; H, 6.30; N, 18.99. N[1 H1,2,3-Benzotriazol-1-yl(4-nitrophenyl)methylene]Nbenzylamine (6.1o): purified by column chromatography on basic alumina; pale yellow microcrystals (from chloroform/hexanes); mp 117 119 oC; yield, 86% (1.54 g); 1H NMR 4.73 (s, 2H), 7.30 8.57 (m, 13H); 13C NMR 55.2, 115.3, 119.9, 124.0, 125.7, 127.2, 127.3, 128.7, 129.5, 129.8, 131.5, 136.5, 138.7, 146.3, 148.7, 153.4. Anal. Calcd for C20H15N5O2: C, 67.21; H, 4.24; N, 19.60. Found: C, 67.32; H, 4.15; N, 19.37. N[1 H1,2,3-Benzotriazol-1-yl(4-nitrophenyl)methylene]Nphenylamine (6.1p): purified by recrystallization from chloroform/hexanes; pale yellow microcrystals; mp 183 185 oC; yield, 88% (1.50 g); 1H NMR 6.95 (d, J = 8.6 Hz, 2H), 7.38 7.57 (m, 6H), 7.68 (t, J = 7.4 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 8.17 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H); 13C NMR 115.2, 119.6, 120.3, 121.9, 124.9, 126.1, 128.6, 129.8, 130.1, 131.1, 131.9, 144.1, 146.5, 153.2, 155.1. Anal. Calcd for C19H13N5O2: C, 66.47; H, 3.82; N, 20.40. Found: C, 66.16; H, 3.70; N, 20.16. N[1 H1,2,3-Benzotriazol-1-yl(4-methylphenyl)methylene]Nbutylamine (6.1q): purified by column chromatography on ba sic alumina; colorless oil; yield,

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85 84% (1.23 g); 1H NMR (mixture of two isomers) 0.85 (t, J = 7.4 Hz, 0.7H), 0.94 (t, J = 7.4 Hz, 3H), 1.31 1.40 (m, 0.5H), 1.42 1.52 (m, 2H), 1.60 1.67 (m, 0.5H), 1.70 1.79 (m, 2H), 2.36 (s, 0.9H), 2.44 (s, 3H), 3.34 (t, J = 7.0 Hz, 0.5H), 3.57 (t, J = 6.9 Hz, 2H), 7.14 7.19 (m, 0.9H), 7.28 7.39 (m, 5H), 7.42 7.47 (m, 1.5H), 7.59 (td, J = 7.7, 0.7 Hz, 1H), 8.16 8.19 (m, 0.2H), 8.45 (d, J = 8.4 Hz, 1H); 13C NMR 13.7, 13.8, 20.4, 20.5, 21.4, 21.5, 32.7, 33.3, 51.2, 51.7, 109.2, 110.3, 115.2, 119.6, 120.0, 124.4, 125.0, 127.7, 128.0, 128.4, 128.5, 128.7, 129.2, 129.3, 131.2, 131.9, 140.2, 142.1, 144.7, 146.2, 146.6, 154.5. Anal. Calcd for C18H20N4: C, 73.93; H, 6.91; N, 19.17. Found: C, 74.17; H, 7.07; N, 19.38. N[1 H1,2,3-Benzotriazol-1-yl(thien 2-yl)methylene]N(4methylphenyl)amine (6.1r): purified by recrys tallization from chloroform/hexanes; yellow needles; mp 133 135 oC; yield, 91% (1.43 g); 1H NMR (mixture of two isomers) 2.12 (s, 1.8H), 2.35 (s, 3H), 6.58 (d, J = 8.1 Hz, 1.2H), 6.83 (d, J = 8.1 Hz, 3.3H), 7.00 7.16 (m, 5H), 7.29 7.33 (m, 2.2H), 7.46 7.53 (m, 2H), 7.57 7.62 (m, 1.7H), 8.03 8.06 (m, 0.6H), 8.16 (d, J = 8.2 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H); 13C NMR 20.8, 20.9, 110.5, 114.7, 119.9, 120.3, 121.0, 124.4, 125.4, 126.5, 128.0, 128.4, 129.1, 129.4, 129.8, 131.3, 131.9, 132.3, 132.6, 134.1, 134.6, 135.4, 139.5, 141.2, 143.2, 144.7, 144.9, 146.3, 146.7. Anal. Calcd for C18H14N4S: C, 67.90; H, 4.44; N, 17.60. Found: C, 67.65; H, 4.35; N, 17.73. N[1-(1 H -1,2,3-Benzotriazol-1-yl )-3-phenylpropylidene]Nbenzylamine (6.1s): purified by column chromatography on ba sic alumina; white needles (from chloroform/hexanes); mp 77 79 oC; yield, 57 % (0.97 g); 1H NMR (mixture of two isomers) 3.08 (t, J = 7.8 Hz, 2H), 3.23 (t, J = 7.6 Hz, 0.3H), 3.60 (t, J = 7.8 Hz,

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86 2H), 3.76 (t, J = 7.7 Hz, 0.3H), 4.62 (s, 2H), 7.19 7.38 (m, 11H), 7.40 7.49 (m, 1.3H), 7.51 7.54 (m, 1.3H), 7.63 (t, J = 7.3 Hz, 0.3H), 8.11 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 8.2 Hz, 0.3H), 8.45 (d, J = 8.4 Hz, 1H); 13C NMR 30.3, 32.9, 53.4, 115.7, 119.5, 125.1, 126.6, 126.9, 127.5, 128.4, 128.5, 128.6, 129.0, 131.4, 139.4, 140.0, 146.5, 156.7. Anal. Calcd for C22H20N4: C, 77.62; H, 5.93; N, 16.46. Found: C, 77.41; H, 5.97; N, 16.48. N[1-(1 H -1,2,3-Benzotriazol-1-yl )-3-phenylpropylidene]N(4methylphenyl)amine (6.1t): purified by column chromatography on basic alumina; white needles (from chloroform/hexanes); mp 116 118 oC; yield, 64 % (2.10 g); 1H NMR 2.37 (s, 3H), 3.09 (t, J = 8.4 Hz, 2H), 3.42 (t, J = 7.8 Hz, 2H), 6.64 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 6.0 Hz, 2H), 7.14 7.22 (m, 5H), 7.48 (t, J = 7.1 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.1 Hz, 1H); 13C NMR 20.8, 31.4, 33.8, 115.6, 119.6, 119.7, 125.4, 126.4, 128.4, 128.5, 129.2, 129.7, 131.4, 133.6, 140.0, 144.5, 146.5, 156.2. Anal. Calcd for C22H20N4: C, 77.62; H, 5.93; N, 16.46. Found: C, 77.36; H, 5.94; N, 16.35. N -[1 H -1,2,3-Benzotriazol-1-yl(2thienyl)methylidene](phe nyl)methanamine (6.1u): purified by column chromatography on basic alumina; yellow oil; yield, 83% (2.64 g); 1H NMR (mixture of two isomers) 4.52 (s, 1.8H), 4.95 (s, 2H), 6.73 (s, J = 3.7 Hz, 0.9H), 6.96 (t, J = 4.4 Hz, 0.9H), 7.19 7.59 (m, 18.3H), 7.66 (d, J = 5.1 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 7.7 Hz, 0.9H), 8.36 (d, J = 8.4 Hz, 1H); 13C NMR 55.1, 55.9, 110.3, 115.0, 119.8, 120.3, 124.7, 125.2, 126.9, 127.00, 127.04, 127.5, 127.6, 128.4, 128.6, 128.8, 129.0, 129.5, 131.0, 131.6, 131.7, 132.0, 132.7, 138.2,

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87 139.1, 139.3, 143.0, 144.8, 146.4, 149.0. Anal. Calcd for C18H14N4S: C, 67.90; H, 4.43; N, 17.60. Found: C, 67.97; H, 4.40; N, 17.51. N -[1 H -1,2,3-benzotriazol-1-yl(2 -thienyl)methylidene](2furyl)methanamine (6.1v): purified by column chromatography on basic alumina; orange oil; yield, 81% (2.50 g); 1H NMR (mixture of two isomers) 4.51 (s, 1.5 H), 4.91 (s, 2.2 H), 6.19 (d, J = 3.3 Hz, 0.8 H), 6.27 6.32 (m, 1.9 H), 6.38 6.39 (m, 1.9 H) 6.74 (d, J = 3.7 Hz, 0.7 H), 6.94 6.97 (m, 0.8 H), 7.18 7.26 (m, 1.9 H), 7.31 (d, J = 1.0 Hz, 0.8 H), 7.37 7.60 (m, 7.6 H), 7.68 (dd, J = 5.1, 0.8 Hz, 1.2 H), 7.77 (td, J = 5.4 Hz, 1.0 Hz, 0.8 H), 8.10 (d, J = 8.2 Hz, 1.1 H), 8.19 (d, J = 8.1 Hz, 0.7H), 8.33 (d, J = 8.2 Hz, 1H); 13C NMR 48.5, 49.3, 106.9, 107.3, 110.3, 110.4, 115.0, 119.8, 120.3, 124.8, 125.3, 126.9, 127.7, 128.2, 128.5, 128.8, 129.0, 129.8, 131.3, 131.9, 132.0, 132.7, 135.1, 142.0, 142.1, 143.9, 144.8, 146.3, 149.9, 151.2, 152.4. Anal. Calcd for C16H12N4OS: C, 62.32; H, 3.92; N, 18.17. Found: C, 61.96; H, 3.83; N, 17.78. N -[( E, 2 E )-1-(1 H -1,2,3-benzotriazol-1-yl)-3phenyl-2-propenylidene]-4methylaniline (6.1w): purified by column chromatography on basic alumina; yellow oil; yield, 65% (1.10 g); 1H NMR 2.41 (s, 3H), 6.99 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 16.6 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.34 0 (m, 5H), 7.40 (d, J = 16.3 Hz, 1H), 7.43 (m, 6H), 7.49 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H); 13C NMR 21.0, 105.3, 114.6, 115.2, 119.8, 120.9, 125.3, 127.8, 128.8, 129.0, 129.8, 130.1, 134.4, 135.1, 144.2, 144.7, 146.1, 151.1. Anal. Calcd for C22H18N4: C, 78.08; H, 5.36; N, 16.56. Found: C, 77.69; H, 5.42; N, 16.59.

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88 N -[1 H -1,2,3-Benzotriazol-1-yl(4 -methylphenyl)methylene]N methylamine (6.1x): purified by column chromat ography on basic alumina; pale yellow microcrystals, mp 95 oC; yield, 85% (1.06 g); (A mixture of two isomers (10/1)) Major one: 1H NMR 2.44 (s, 3H), 3.39 (s, 3H), 7.29 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H). 13C NMR 21.4, 38.8, 114.9, 119.6, 124.9, 127.2, 128.0, 128.5, 129.2, 131.7, 140.3, 146.2, 156.0. Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38. Found: C, 72.30; H, 5.61; N, 22.68.

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89 CHAPTER 7 EFFICIENT MICROWAVE ACCESS TO POLYSUBSTITUTED AMIDINES FROM IMIDOYLBENZOTRIAZOLES 7.1 Introduction The synthesis of amidines has received much attention due to their biological properties222-226 and applications in heterocyclic synthesis.227, 228 Literature methods include the preparation of (i) N -monosubstituted amidines by (a) addition of Grignard or organolithium reagents to carbodiimides or cyanoamides followed by hydrolysis and, in this approach a C C bond is formed;229 (b) heating hydrazones in the presence of NaNH2;105 (c) addition of the anions of urea and amines to nitriles;230 (d) addition of amines to nitriles in the presence of AlCl3;231-232 (ii) N N disubstituted amidines by reaction of sec ondary amines with imidic ester salts derived from nitriles in which one C-N bond is formed; (iii) N N -disubstituted amidines by reaction of two moles of an amine with ortho-esters, acetals or thioesters, in which both the C N bonds are formed and (iv) N N -disubstituted and N,N,N -trisubstituted amidines by imidoylation of amines with imidoyl chlorides ( 1 ) ,233-235 imidate fluoroborates ( 2 ) ,236 iminium triflates ( 3 ),237 or iminum sulfonates ( 4 )238 (Scheme 7-1). Imidoyl chlorides ( 1 ) are generally prepared in situ by treatment of the corresponding amides with phosgene, thi ophosgene, oxalyl chloride, phosphorus penta and trihalides, thionyl chloride, sulfuryl chloride, and halogens.239 Chlorides 1 are labile toward hydrolysis.

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90 (i) N -Monosubstituted amidines N N MgBr N N H H N H N Ar1 Ar2 N Ar2 N H2 Ar1 R NHNa NAr NAr R NH2 NHAr R NH R1NHCN 2R2MgBr R1 MgBr R2 H2O R1 R2 NaNH2 2RCN + ArNH2 + 2 Na RCN + R'NH2 AlCl3 a. b. c. d. H2O (ii) N N -Disubstituted amidines NH2 N H N N R1 R3 H R4 R1CN HCl R2OH R1 R2O + R3 R4 (iii) N N -Disubstituted amidines N N H R3 S OEt R1 OR2 OR2 OR2 R3NH2 R1 R3 R3NH2 R1 (iv) N N -Disubstituted and N N N -trisubstituted amidines O N N Cl N EtO H N TfO H N R2 N R1 R4 R3 R3N H R4 N N R NR' N O S O O Ar R2 R2 R1 R2 R1 + BF4 R2 R1 + OTf 1 2 3 R1 H R3NH2 R1 R3 H R2 4 Scheme 7-1 Literature Methods of Preparation of Amidines

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91 With amines at elevated temperatures side reactions have been reported if CH groups are present in the imidoyl chloride.240 Many amidines can be obtained in one step by heating the monosubstitut ed amide with amine and phosphorus pentachloride; in some cases, the imi doyl chloride has to be isolated.234 Iminium triflates and imidate fluoroborates requi re handling under inert atmosphere and cannot be isolated or purified.237 Imidoylbenzotriazoles are stable a nd useful substitutes for imidoyl chlorides,214, 215, 241 and have been reported as versatile reagents for the synthesis of enaminones217 and Nsubstituted enamino acid derivatives.218 We now apply imidoylbenzotriazoles under mi crowave irradiation in a m ild and general procedure for the direct synthesis of N N -disubstituted and N N N -trisubstituted amidines. Microwave heating has emerged as a power ful technique to promote a variety of chemical reactions,3,65 69,242 and the use of single mode cavity3 microwave synthesizer assures reproducibility, safet y, reduced pollution, and simplicity in processing and handling.71,243 7.2 Results and Discussion Prelimimary results showed that benzotriazol-1-yl group (Bt-) in imidoylbenzotriazoles was not as active as the Btin N -acylbenzotriazoles. Under room temperature, the mixture of im idoylbenzotriazole and morpholine in methylene chloride did not react at all ev en after a few days. Heating to reflux or using neat condition under microwave irradiation (120 oC, 120 W, 10 min) failed to accelerate the reaction. The reactions require d catalysts to accelerate. Under basic conditions (NaH, NaOMe, or t-BuOK), th e reaction gave complications possibly

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92 because the base can replace Btgro up; however, acid was found capable of catalyzing the reactions (mechanism is shown in Scheme 7-2). Microwave reactions of imidoylbenzotri azoles with amines were performed in sealed heavy-walled Pyrex tube s or 50 mL round-bottomed flask under controlled conditions in a safe and repr oducible procedure. Optimization of the microwave reaction conditions were carried out on the condensation of N[( E ) 1 (1 H1,2,3 benzotriazol 1 yl)ethylidene]aniline and morpho line in presence of acetic acid, for which different combinations of temperature, time and irradiation power were studied to achieve the optimum ch emical yield at the lowest reaction temperature. It was found th at microwave reaction of N[( E ) 1 (1 H1,2,3 benzotriazol 1 yl)ethylidene]aniline and morpholine at 120 oC and 120 W irradiation power for 10 min went to completion, however, the amidine 4 [( E ) 1 methyl 2 phenylethenyl]morpholine ( 7.1a ) was given as an acetic acid salt. Treatment of the acetic acid salt by sodi um hydroxide solution (4N) converted the salt partially into the free amidine 4 [( E ) 1 methyl 2 phenylethenyl]morpholine ( 7.1a ) (yield, 76%). In order to compare microwave heating with conventional heating, the same reaction was also carried out using a hot plat e to reflux. It was found that the entire starting material will not be consumed even after a fairly long period (6 h), and the crude NMR of the reaction mixture show ed the presence of amide (a side product of the decomposition of starting material). That further depicted the advantage of microwave reac tion with high speed and avoiding side products. The acylation of amines by acetic acid under high temperature gives water as a product, which competes with amines in replacing Btgroup in

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93 imidoylbenzotriazoles. To avoid complications we used either (i) a catalytic amount (20 % in moles) of Lewis acid (AlCl3) or (ii) the hydrochlorid e salts of amines at 80 oC and 80 W irradiation power for 10 min. Using the optimized microwave reaction conditions, we prepared a variet y of polysubstituted amidines 7.1a Aa in 76 94% yields (Table 7-1). These results illustrate the general applicability of this method for the preparation of amidin es under mild conditions (80 120 oC) and short reaction times (10 min). Imidoylbenzotriazole s are stable crystalline solids that can be purified and stored at room temperatur e; their use also av oids side reactions, toxic reagents and special handling procedures involved with imidoyl chlorides, iminium triflates and imidate fluoroborates.229 N N R1 R2 N N H+/AlCl3 N+ N R1 R2 N N H(AlCl3) N H R4 R3 N N R1 R2 N N H(AlCl3) N R3 R4 N N R1 R2 N N H+/AlCl3 R1 N R2 + H N R3 R4 -H+-H+N N R1 R2 R3R4 Scheme 7-2 Mechanism of the Acidcatalyzed Formation of Amidines N N R2 R3 R4 Bt R1 N R2 N R3 R4 R1 microwaves + 7.1a-Aa Scheme 7-3 Preparation of Amidines 7.1 from Imidoylbenzotriazoles

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94 Table 7-1 Preparation of Amidines 7.1 from Imidoylbenzotriazoles Entry R1 R2 R3 R4 Product (Yield %)a 1 Methyl Phenyl (CH2)2O(CH2)2 7.1a (76)b 2 Methyl Phenyl Ethyl Et 7.1b (88)b,c 3 Methyl Phenyl Benzyl H 7.1c (77) b,c 4 Methyl Phenyl pTolyl H 7.1d (89)b 5 Phenyl Phenyl Ethyl Et 7.1e (87)d 6 Phenyl Phenyl (CH2)2O(CH2)2 7.1f (90)d 7 Phenyl Phenyl pTolyl H 7.1g (91)e 8 4 MeOC6H4 Benzyl pTolyl H 7.1h (91)e 9 4 MeOC6H4 Benzyl (CH2)2O(CH2)2 7.1i (88)d 10 Benzyl pTolyl pTolyl H 7.1j (94)e 11 Benzyl pTolyl (CH2)2O(CH2)2 7.1k (88)d 12 2 Thienyl pTolyl pTolyl H 7.1l (88)e 13 2 Thienyl pTolyl (CH2)2O(CH2)2 7.1m (92)d 14 2 Furyl pTolyl pTolyl H 7.1n (90)e 15 2 Furyl pTolyl (CH2)2O(CH2)2 7.1o (89)d 16 4 O2NC6H4 Benzyl pTolyl H 7.1p (92)e 17 Methyl pTolyl pTolyl H 7.1q (91)e 18 Phenyl Benzyl pTolyl H 7.1r (87)e 19 2 Furyl Cyclohexyl pTolyl H 7.1s (85)e 20 Phenethyl pTolyl Phenyl Methyl 7.1t (91)d 21 4-ClC6H4 pTolyl Phenyl Methyl 7.1u (90)d 22 Methyl Phenyl n -Butyl H 7.1v (92)c 23 Phenyl Phenyl nButyl H 7.1w (91)d 24 Methyl Phenyl BnCHCO2Me H 7.1x (90)b,c 25 Methyl pTolyl (CH2)2O(CH2)2 7.1y (92)d 26 4 O2NC6H4 Phenyl Cyclohexyl H 7.1z (90)d 27 4 O2NC6H4 Phenyl pTolyl H 7.1Aa (91)c aIsolated yield. bHOAc, MW, 120 oC, 120 W, 10 min. cObtained as acetic acid salt. dAlCl3 (20% in moles), CHCl3, MW, 80 oC, 80 W, 10 min. eHCl salt of amine used, CHCl3, MW, 80 oC, 80 W, 10 min. fAmidines have been reported in literature in other forms other than acetic acid salts. 7.3 Conclusion In summary, we have developed a ne w general method for the synthesis of polysubstituted amidines from imidoylbenz otriazoles using microwaves under mild reaction conditions and short reaction times.

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95 7.4 Experimental Section 7.4.1 General Procedure for the Preparation of Amidines 7.1: Method A: Imidoylbenzotriazole (0.5 mmol), a primary or secondary amine (1 mmol), and acetic acid (1 mL) were pl aced in a 10 mL microwave reaction tube. The tube containing the reaction mixture wa s sealed with an aluminum crimp cap fitted with a silicon septum and then expos ed to microwave irradiation (120 W) for 10 min at 120 oC. The reaction mixture was dilu ted with chloroform (20 mL). Aqueous work-up gave a re sidue that was purified by column chromatography on basic alumina using methylene chloride/methanol (20:1 to 10:1). Method B: Imidoylbenzotriazole (0.5 mmol) was dissolved in chloroform (1 mL) in a 10 mL microwave reaction tube. Aluminum chloride (catalytic amount) was added to the tube followed by amine (1 mmol). The tube containing the reaction mixture was sealed with an al uminum crimp cap fitted with a silicon septum and then exposed to microwave irradiation (80 W) for 10 min at 80 oC. The reaction mixture was diluted with chloroform (20 mL). Aqueous work up gave a residue that was purified by recrystallization from chloroform or column chromatography on basic alumina using hexa nes/EtOAc (10:1 to 5:1) as eluent. Method C: Imidoylbenzotriazole (0.5 mm ol), amine hydrochloride (1.0 mmol) and chloroform (1 mL) were placed in a 10 mL microwave reaction tube. The tube containing the reaction mixture wa s sealed with an aluminum crimp cap fitted with a silicon septum and then expos ed to microwave irradiation (80 W) for 10 min at 80 oC. The reaction mixture was diluted with chloroform (20 mL) and the insoluble portion was filtered off. Aqueous work up gave a residue that was

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96 purified by recrystallization from chloroform or column chromatography on basic alumina using hexanes/EtOAc (10:1 to 5:1) as eluent. 7.4.2 Characterization of Amidines (7.1): N -[(1 E )-1-morpholin-4-ylethylidene]aniline (7.1a): purified by column chromatography on basic alumina; colorle ss needles (from chloroform/hexanes); mp 80 oC (lit.244 mp 82 oC); yield, 76% (0.080 g); 1H NMR 1.85 (s, 3H), 3.48 3.51 (m, 4H), 3.74 3.77 (m, 4H), 6.70 (dd, J = 7.3, 0.8 Hz, 2H), 6.96 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.6 Hz, 2H); 13C NMR 14.5, 45.2, 66.7, 121.7, 121.9, 128.8, 151.5, 156.9. (1 E ) -N,N -Diethyl -N'phenylethanimidamide acetate (7.1b): purified by column chromatography on basic alumina; colorless needles (from chloroform/hexanes); mp 102 oC; yield, 88% (0.110 g); 1H NMR 1.11 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), 2.08 (s, 3H), 2.14 (s, 3H), 3.26.41 (m, 4H), 7.06 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 3.8 Hz, 2H), 7.55 (d, J = 7.7 Hz, 1H), 8.71 (s, 1H); 13C NMR 12.9, 14.0, 21.3, 24.2, 39.9, 42.8, 119.9, 123.8, 128.6, 138.3, 169.0, 169.7. Anal. Calcd for C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found: C, 67.18; H, 8.89; N, 10.92. (1 E )N -BenzylN' -phenylethanimidamide acetate (7.1c): purified by column chromatography on basic alumina; colorless needles (from chloroform/hexanes); mp 88 oC; yield, 77% (0.110 g); 1H NMR 1.97 (s, 3H), 2.08 (s, 3H), 4.37 (d, J = 5.8 Hz, 2H), 6.47 (s, 1H), 7.06 (t, J = 7.3 Hz, 1H), 7.25 7.33 (m, 7 H), 7.52 (d, J = 8.0 Hz, 2H), 8.51 (br s, 1H); 13C NMR 23.0, 24.2, 43.5, 119.9, 123.9, 127.3, 127.6, 128.5, 28.7, 138.1, 138.2, 168.9, 170.2. Anal.

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97 Calcd for C17H20 N2O2: C, 71.79; H, 7.10; N, 9.85. Found: C, 71.50; H, 7.19; N, 9.85. (1 E )N -(4-Methylphenyl)N' -phenylethanimidamide (7.1d): purified by column chromatography on basic alumina; white microcrystals (from chloroform/hexanes); mp 87 oC (lit.245 mp 90 oC); yield, 89% (0.100 g); 1H NMR (DMSOd6) 1.88 (s, 3H), 2.24 (s, 3H ), 6.64.74 (m, 2H), 6.92 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.24 (t, J = 7.7 Hz, 2H), 7.65.76(m, 2H), 8.82 (br s, 1H); 13C NMR (DMSOd6) 17.7, 20.4, 119.0, 121.3, 128.6, 130.0, 153.0. N NDiethylN '-phenylbenzenecarboximidamide (7.1e).246 1[Phenyl(phenylimino)methyl] 1 Hbenzotriazole (0.149 g, 0.5 mmol) was dissolved in chloroform (1 mL) in a 10 mL micr owave reaction tube. Aluminum chloride (0.014 g, 0.1 mmol) was added to the tube followed by diethylamine (0.073 g, 1 mmol). The tube containing the reaction mi xture was sealed with an aluminum crimp cap fitted with a silicon septum and then exposed to microwave irradiation (80 W) for 10 min at 80 oC. The reaction mixture was diluted with chloroform (20 mL). Aqueous work up gave a residue that was pur ified by column chromatography on basic alumina using hexanes/EtOAc (8:1) as eluent to give a colorless oil: yield, 87% (0.110 g); 1H NMR 1.17 (br s, 6H), 3.35 (br s, 4H), 6.53 (d, J = 7.5 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.96 (t, J = 7.7 Hz, 2H), 7.07 7.10 (m, 2H), 7.18 7.23 (m, 3H); 13C NMR 13.4, 41.8, 120.7, 123.0, 127.9, 128.0, 128.6, 134.3, 151.7, 159.6. N -[(1 E )-Morpholin-4-yl(phenyl)methylene]aniline (7.1f ): purified by recrystallization from chloroform/h exanes; colorless needles; mp 85 87 oC (lit.244 mp 85 oC); yield, 90 % (0.120 g); 1H NMR 3.42 3.45 (m, 4H), 3.75 (m, 4H), 6.56

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98 (d, J = 7.4 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 7.00 (t, J = 8.0 Hz, 2H), 7.10 7.13 (m, 2H), 7.21 7.24 (m, 3H); 13C NMR 46.6, 66.8, 121.2, 122.6, 128.1, 128.7, 129.0, 133.0, 150.7, 160.6. N(4-Methylphenyl)N '-phenylbenzenecarboximidamide (7.1g): purified by recrystallization from chloroform/hex anes; pale yellow microcrystals; mp 130 132 oC (lit.247 mp 133 oC); yield, 91% (0.130 g); 1H NMR 2.26 (s, 3H), 6.40 7.62 (m, 14H); 13C NMR 20.8, 121.4, 122.0, 123.4, 128.3, 128.6, 129.2, 131.7, 135.1, 154.3. N '-Benzyl-4-methoxyN(4-methylphenyl)benzenecarboximidamide (7.1h). N[1 H -1,2,3-Benzotriazol-1-yl(4-methoxyphenyl)methylene]Nbenzylamine (0.171 g, 0.5 mmol), p -toluidine hydrochloride (0.144 g, 1.0 mmol) and chloroform (1 mL) were placed in a 10 mL microwave reaction tube. The tube containing the reaction mixture was sealed with an aluminum crimp cap fitted with a silicon septum and then exposed to micr owave irradiation (80 W) for 10 min at 80 oC. The reaction mixture was diluted with chloroform (20 mL) and the insoluble portion was filtered off. Aqueous work up gave a residue that was purified by recrystallization from chloroform/hexanes to give white microcrystals: mp 115 117 oC; yield, 91% (0.150 g); 1H NMR 2.21 (s, 3H), 3.74 (s, 3H), 4.67 (s, 2H), 6.58 (d, J = 7.4 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 7.0 Hz, 2H), 7.37 (t, J = 7.0 Hz, 2H), 7.44 (d, J = 7.1 Hz, 2H); 13C NMR (3 signals are hidden) 20.7, 46.2, 55.2, 113.5, 122.8, 127.3, 128.1, 128.6, 129.0, 130.0, 139.1, 148.3, 159.9. Anal. Calcd for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.67; H, 7.07; N, 8.24.

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99 N -[(1 Z )-(4-Methoxyphenyl)(morpholin-4-yl)methylene]-1phenylmethanamine (7.1i): purified by column chromatography on basic alumina; colorless oil; yield, 88% (0.140 g); 1H NMR 3.20 (s, 4H), 3.59 (t, J = 4.8 Hz, 4H), 3.74 (s, 3H), 4.21 (s, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.01.21 (m, 7H); 13C NMR 46.6, 54.3, 55.2, 66.8, 114.0, 125.6, 125.9, 127.0, 128.0, 129.2, 142.4, 169.7, 162.7. Anal. Calcd for C19H22 N2O2: C, 73.52; H, 7.14; N, 9.02. Found: C, 73.12; H, 7.13; N, 8.69. (1 Z )N N '-Bis(4-methylphenyl)-2-phenylethanimidamide (7.1j): purified by recrystallization from chloroform/hexanes; white microcrystals; mp 89 91 oC; yield, 94 % (0.150 g); 1H NMR 2.29 (s, 6H), 3.66 (s, 2H), 7.06 7.34 (m, 13H); 13C NMR (4 signals are hidden) 20.8, 37.7, 120.6, 127.1, 129.1, 129.4, 131.8. Anal. Calcd for C22H22N2: C, 84.04; H, 7.05; N, 8.91. Found: C, 84.38; H,7.32; N, 8.92. N(4-Methylphenyl)N[(1 E )-1-morpholin 4-yl-2-phenylethylidene]amine (7.1k): purified by recrystallization from chloroform/hexanes; colorless needles; mp 104 106 oC; yield, 88% (0.130 g); 1H NMR 2.25 (s, 3H), 3.42 3.45 (m, 4H), 3.56 3.59 (m, 4H), 3.70 (s, 2H), 6.65 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 7.14 7.23 (m, 3H), 7.27 7.32 (m, 2H); 13C NMR 20.7, 33.5, 45.2, 66.7, 121.5, 126.4, 127.7, 128.7, 129.4, 131.1, 136.3, 148.4, 157.1. Anal. Calcd for C19H22N2O: C, 77.51; H, 7.55; N, 9.52. Found: C, 77.21; H, 7.72; N, 9.69. N N '-bis(4-Methylphenyl)thiophene -2-carboximidamide (7.1l): purified by recrystallization from chloroform/hex anes; yellow microcrystals; mp 121 123 oC; yield, 88% (0.135 g); 1H NMR 2.28 (s, 6H), 6.32 (s, 1H), 6.78 7.29 (m, 11H); 13C

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100 NMR 20.8, 120.8, 121.4, 123.3, 126.7, 127.0, 128.0, 128.5, 129.3, 129.8, 130.1, 131.9, 132.9, 133.9, 134.8, 138.1, 139.0, 145.8, 147.2, 149.5. Anal. Calcd for C19H18N2S: C, 74.47; H, 5.93; N, 9.14. Found: C, 74.32; H, 5.99; N, 9.05. N(4-Methylphenyl)N[(1 E )-morpholin 4-yl(thien 2-yl)methylene]amine (7.1m): purified by recrystallization from chloroform/hexanes; pale yellow needles; mp 109 111 oC; yield, 92% (0.130 g); 1H NMR 2.20 (s, 3H), 3.42 (t, J = 4.8 Hz, 4H), 3.76 (t, J = 4.8 Hz, 4H), 6.52 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 3.4 Hz, 1H), 6.86 6.90 (m, 3H), 7.29 (d, J = 4.9 Hz, 1H); 13C NMR 20.7, 47.3, 66.7, 121.7, 126.8, 127.5, 128.9, 129.9, 131.0, 132.7, 148.1, 154.4. Anal. Calcd for C16H18N2OS: C, 67.10; H, 6.33; N, 9.78. Found: C, 67.24; H, 6.44; N, 9.79. N N '-Bis(4-methylphenyl)furan 2-carboximidamide (7.1n): purified by recrystallization from chloroform/hexanes; yellow needles; mp 120 122 oC; yield, 90% (0.130 g); 1H NMR 2.31 (s, 6H), 5.73 (s, 1H), 6.27 (s, 1H), 7.11 7.35 (m, 10H); 13C NMR (3 signals are hidden) 20.8, 111.8, 115.3, 120.2, 129.5, 131.9, 141.6. Anal. Calcd for C19H18N2O: C, 78.59; H, 6.29; N, 9.66. Found: C, 78.20; H, 6.29; N, 9.66. N[(1 E )-2-Furyl(morpholin 4-yl)methylene]N(4-methylphenyl)amine (7.1o): purified by recrystallization from chlo roform/hexanes; colorless needles; mp 94 96 oC; yield, 89% (0.120 g); 1H NMR 2.23 (s, 3H), 3.39 (t, J = 4.8 Hz, 4H), 3.78 (t, J = 4.8 Hz, 4H), 6.06 (d, J = 3.3 Hz, 1H), 6.25 6.27 (m, 1H), 6.51 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 1.2 Hz, 1H); 13C NMR 20.7, 46.8, 66.7, 110.8, 114.2, 121.3, 129.0, 131.1, 142.5, 144.3, 148.3, 151.3. Anal.

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101 Calcd for C16H18N2O2: C, 71.09; H, 6.73; N, 10.37. Found: C, 71.13; H, 6.92; N, 10.23. N '-BenzylN -(4-methylphenyl)-4-nitrobenzenecarboximidamide (7.1p): purified by recrystallization from chloro form/hexanes; yellow microcrystals; mp 121 oC; yield, 92% (0.160 g); 1H NMR (mixture of two isomers) 2.19 (s, 3H), 2.23 (s, 1.2H), 4.68 (s, 2H), 6.51 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.2 Hz, 0.8H), 6.87 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.1 Hz, 0.8H), 7.28.44 (m, 8.4H), 7.77 (d, J = 10.6 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 8.23 (d, J = 8.8 Hz, 0.8H); 13C NMR 20.7, 46.2, 115.2, 122.5, 123.4, 127.6, 128.1, 128.7, 129.2, 131.3, 138.4, 141.5, 147.7, 154.8. Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17. Found: C, 73.03; H, 5.57; N, 12.15. (1 E )N N '-Bis(4-methylphenyl)ethanimidamide (7.1q): purified by recrystallization from chloroform/hex anes; white microcrystals; mp 118 oC (lit.248 mp 119 oC); yield, 91 % (0.110 g); 1H NMR 1.96 (s, 3H), 2.30 (s, 6H), 7.04 7.11 (m, 8H); 13C NMR 20.8, 121.3, 129.5, 153.6. N '-BenzylN(4-methylphenyl)benzenecarboximidamide (7.1r): purified by recrystallization from chloroform/h exanes; white microcrystals; mp 114 116 oC (lit.249 127 127.5 oC); yield, 87% (0.130 g); 1H NMR 2.19 (s, 3H), 4.68 (s, 2H), 6.57 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 7.23 7.44 (m, 10H); 13C NMR (6 signals are hidden) 20.7, 46.1, 122.8, 127.4, 128.2, 128.5, 128.6, 128.9, 139.0. N -CyclohexylN '-(4-methylphenyl)furan-2-carboximidamide (7.1s): purified by column chromatography on basic alumina; colorless oil; yield, 85% (0.120 g); 1H NMR 1.23.75 (m, 8H), 2.16 (d, J = 8.6 Hz, 2H), 2.31 (s, 3H),

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102 3.97 (br s, 1H), 5.17 (br s, 1H), 5.60 (s, 1H), 6.20 (s, 1H), 6.68 (d, J = 7.7 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 7.27 (s, 1H); 13C NMR 20.8, 24.9, 25.9, 33.1, 48.8, 111.5, 114.3, 121.3, 129.6, 131.0, 141.2, 144.7, 145.0, 149.4. Anal. Calcd for C18H22 N2O: C, 76.56; H, 7.85; N, 9.92. Found: C, 76.41; H, 7.81; N, 9.56. N -MethylN' -(4-methylphenyl)N' ,3-diphenylpropanimidamide (7.1t): purified by recrystallization from chlorofo rm/hexanes; colorless microcrystals; mp 89 oC; yield, 91% (0.150 g); 1H NMR 2.31 (s, 3H), 2.40.51 (m, 4H), 3.36 (s, 3H), 6.56.58 (m, 2H), 6.70 (d, J = 8.2 Hz, 2H), 7.03.11 (m, 5H), 7.23.32 (m, 3H), 7.38.43 (m, 2H); 13C NMR 20.8, 30.5, 33.4, 39.8, 121.7, 125.9, 126.6, 127.8, 128.0, 128.1, 129.4, 130.9, 140.8, 146.2, 148.5, 159.5. Anal. Calcd for C23H24N2: C, 84.11; H, 7.36; N, 8.53. Found: C, 84.09; H, 7.51; N, 8.56. 4-ChloroN -methylN' -(4-methylphenyl)N phenylbenzenecarboximidamide (7.1u): purified by recrystallization from chloroform/hexanes; yellow needles; mp 123 oC, yield, 90% (0.150 g); 1H NMR 2.19 (s, 3H), 3.54 (s, 3H), 6.49 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.90 7.00 (m, 7H), 7.13 (t, J = 7.7 Hz, 2H); 13C NMR 20.7, 40.2, 122.3, 125.1, 126.9, 127.8, 128.8, 129.0, 130.6, 131.5, 132.1, 133.8, 146.0, 147.8, 158.1. Anal. Calcd for C21H19ClN2: C, 75.33; H, 5.72; N, 8.37. Found: C, 75.17; H, 5.80; N, 8.22. N -ButylN '-phenylethanimidamide acetate (7.1v). N[1-(1 H -1,2,3Benzotriazol-1-yl)ethylidene]aniline (0.118 g, 0.5 mmol), nbutylamine (0.073 g, 1 mmol), and acetic acid (1 mL) were placed in a 10 mL microwave reaction tube. The tube containing the reaction mixture wa s sealed with an aluminum crimp cap

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103 fitted with a silicon septum and then expos ed to microwave irradiation (120 W) for 10 min at 120 oC. The reaction mixture was dilu ted with chloroform (20 mL). Aqueous work-up gave a re sidue that was purified by column chromatography on basic alumina using methylene chlori de/methanol (20:1) to give pale yellow needles (from chloroform/hexanes): mp 88 90 oC, yield, 92% (0.115 g); 1H NMR 0.89 (t, J = 7.2 Hz, 3H), 1.25 1.37 (m, 2H), 1.44 1.51 (m, 2H), 1.96 (s, 3H), 2.15 (s, 3H), 3.20 (q, J = 6.8 Hz, 2H), 6.64 (br s, 1H) 7.06 (t, J = 7.3 Hz, 1H), 7.27 (t, J = 7.8 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H), 9.21 (br s, 1H); 13C NMR 13.5, 19.8, 22.9, 24.0, 31.3, 39.2, 120.0, 123.8, 128.5, 138.3, 169.3, 170.5. Anal. Calcd for C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found: C, 66.84; H, 8.86; N, 11.01. N -ButylN '-phenylbenzenecarboximidamide (7.1w): purified by recrystallization from chloroform/h exanes; white microcrystals; 95 97 oC, yield, 87% (0.110 g); 1H NMR 0.98 (t, J = 7.1 Hz, 3H), 1.43 1.50 (m, 2H), 1.61 1.70 (m, 2H), 6.63 (d, J = 7.4 Hz, 2H), 6.78 (t, J = 7.0 Hz, 1H), 7.03 (t, J = 7.3 Hz, 2H), 7.21 7.29 (m, 5H); 13C NMR 13.9, 20.3, 31.4, 41.6, 121.0, 123.1, 128.2, 128.5, 129.0, 135.5, 151.0, 157.5. Anal. Calcd for C17H20N2: C, 80.91; H, 7.99; N, 11.10. Found: C, 80.90; H, 7.98; N, 11.06. Methyl 3-phenyl-2-{[(1 E )N -phenylethanimidoyl]amino}propanoate acetate (7.1x): purified by recrystalli zation from chloroform/hexanes; colorless microcrystals; yield, 90% (0.160 g); mp 55 57 oC; 1H NMR 1.97 (s, 1H), 2.13 (s, 3H), 3.01 3.17 (m, 2H), 3.70 (s, 3H), 4.86 (q, J = 6.7 Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), 7.05 7.32 (m, 8H), 7.53 (d, J = 7.8 Hz, 2H), 8.47 (s, 1H); 13C NMR 22.9, 24.2, 37.6, 52.2, 119.9, 123.9, 127.0, 128.4, 128.7, 129.0, 135.7, 138.1, 169.0,

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104 170.0, 172.0. Anal. Calcd for C20H24N2O4: C, 67.40; H, 6.79; N, 7.86. Found: C, 67.14; H, 7.05; N, 8.40. N -(4-Methylphenyl)N -[(1 E )-1-morpholin-4-ylethy lidene]amine (7.1y): purified by recrystallization from chlorofo rm/hexanes; white microcrystals; yield, 92% (0.100 g); mp 67 68 oC; 1H NMR 1.84 (s, 3H), 2.29 (s, 3H), 3.47 (t, J = 4.9 Hz, 4H), 3.74 (t, J = 4.9 Hz, 4H), 6.60 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H); 13C NMR 14.4, 20.7, 45.2, 66.7, 121.6, 129.3, 130.9, 148.7, 157.1. Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C, 71.28; H, 8.78; N, 12.62. N -Cyclohexyl-4-nitroN' -phenylbenzenecarboximidamide (7.1z): purified by recrystallization from chloroform/hex anes; yellow microcrystals; mp 142 oC; 90% (0.145 g); 1H NMR 1H NMR 1.18 1.51 (m, 6H), 1.74 (m, 2H), 2.16 (d, J = 11.1 Hz, 2H), 3.99 (br s, 1H), 4.75 (d, J = 6.6 Hz, 2H), 6.65 (d, J = 8.9 Hz, 2H), 7.19 7.36 (m, 5H), 7.94 (d, J = 8.9 Hz, 2H); 13C NMR 24.7, 25.6, 32.8, 50.1, 122.9, 124.6, 128.3, 128.6, 129.8, 134.4, 141.4, 157.4, 158.5. Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found: C, 71.07; H, 6.96; N, 12.40. N -(4-Methylphenyl)-4-nitroN' -phenylbenzenecarboximidamide (7.1Aa): purified by recrystallization from chloro form/hexanes; yellow microcrystals; mp 127 oC (lit.250 mp 138 oC); 91% (0.150 g); 1H NMR 2.31 (s, 3H), 6.88 (br s, 2H), 7.11 (d, J = 7.7 Hz, 2H), 7.31 7.38 (m, 7H), 8.02 (d, J = 8.7 Hz, 2H); 13C NMR (3 signals are hidden) 20.8, 120.6, 122.1, 124.8, 128.5, 129.5, 130.3, 134.1, 142.2, 154.9.

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105 CHAPTER 8 SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES UNDER MILD CONDITION VIA BENZOTRIAZOLE METHODOLOGY 8.1 Introduction Compounds containing 1,5-dis ubstituted tetrazole moiety are very important in medicinal chemistry.251 264 For instance, this class of compounds have been studied for treatment of malaria, cancer and schistosomiasis,251 prodrug,252 protein kinase inhibitors,253 NAD(P)H oxidase inhibitors,254 modulators of chemokine receptor,255 amyloid inhibitors,256 glucokinase activators,257 hepatitis C virus (HCV) serine protease inhibitors,258 histamine H3 antagonists,259 calcitonin gene-related peptide receptor antagonists and antimigraine agents,260 hepatitis C serine protease inhibitors,261 Tachykinin antagonists,262 CB1 cannabinoid receptor,263 antifungal activity.264 They are also important in synthetic chemistry.265 274 A large number of methods are available for the preparations of 1,5-disubstituted tetrazoles (Table 8-1). The most common met hod of preparation involves the cyclization of substituted imidoyl azide (a product from imidoyl chloride and sodium azide, or hydrazoic acid, or trimethylsily l azide), however, the intermed iates, imidoyl chlorides, are not isolable and need ha ndle with care because they ar e labile towards hydrolysis. The drawbacks of each method of preparation of 1,5-disubs tituted tetrazoles are also shown in Table 1. For example, the reaction between imidoyl chlorides and sodium azide is slow in organic solvent because of the low solubility of sodium azide; hydrozoic acid is soluble in organic solvent, but it is very toxic, volatile (boiling point: 37 oC) and highly

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106 explosive. A two-phase system (organic solv ent and water) has been used in order to dissolve both imidoyl chlorides and sodium azide;275 however, imidoyl chlorides rapidly hydrolyse and the resulting reaction mixture of tetrazoles and amides requires tedious work-up involving hydrolysis of amides in refluxing 10% sulfuric acid.276 Thus a mild and efficient method is required for the pr eparation of 1,5-disubstituted tetrazoles. Imidoylbenzotriazoles are stable in wate r and useful subst itutes for imidoyl chlorides. A variety of imidoylbenzotriazoles ha ve been prepared previously [Chapter 6] in moderate to high yields (56 95%). In the present work, we report synthesis of 1,5disubstituted tetrazoles prepared from imi doylbenzotriazoles in high yields under mild conditions. Table 8-1. Literature Methods fo r the Preparation of Tetrazoles Reactants Drawbacks References Secondary amide, PCl5, HN3 Imidoyl chloride cannot be isolated or stored; hydrozoic acid is toxic, volatile and highly explosive. 277 281 Secondary amide, PCl5, NaN3 Slow in organic solv ent; gives amide back in water, which needs tedious work-up to get rid of. 282 286 5-Substituted tetrazole, alkylating agent 5-Substituted tetrazoles are not readily available; 1,5and 2,5isomers are obtained in a lot of cases. 264, 287 291 Secondary thioamide, TMSN3 Starting materials are not easily available 292 Alkyl azide and nitrile Long reaction time and high temperature may be required. 293 295 Vinylboronic acid 5-bromotetrazole Both starting materials are not readily available; long time and high temperature are needed. 296, 297 5-chlorotetrazole organic zinc agent Limited availability of starting materials. 298 Oxime, HN3 Oxime is not commonly used; hydrozoic acid is volatile and highly explosive. 299 TMSN3, ketone Yield is low and is omers could be obtained. 300, 301 Me3SnN3, RCN, RCl Me3SnN3 is not common. Strong basic condition (NaOH) is needed. 302

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107 Table 8-1 Continued Reactants Drawbacks References Amidrazones, N2O4 or HNO2 Low yield and harsh reaction condition; availability of starti ng material is limited 303, 304 NaN3, nitrilium ion The formation of nitrilium ion limits the versatility. 305 Ketone, NaN3 Amide is a side product in cases; isomers are usually obtained. 306 308 Amide, Tf2O, NaN3 Intermediate cannot be isolated; low yield. 309 8.2 Results and Discussion The replacement of benzotriazol-1-yl (Bt-) group by azide ion has not been reported before. To make sure it is possible to replace Btwith azide ion, N acylbenzotriazoles were utilized for pilot investigation because N -acylbenzotriazoles are more readily available than imidoylbenzot riazoles. The reacti on between 1-benzoyl-1 H 1,2,3-benzotriazole and sodium azide was carri ed out under different conditions in order to get an optimized condition. It was found that in any single solvent, such as chloroform, THF, acetonitrile, DMF, DMSO and water, the reaction gave poor conversion under room temperature even after a few days. A new TLC spot was observed in several cases showing that the substitution reaction occurre d, however, most starting material remained unreacted. Microwave conditions we re tried, but the result wa s unsatisfactory. It is not easy to find a solvent to dissolve both the N -acylbenzotriazole and sodium azide, so a two-solvent system has to be used. Methylene chloride-water (1:1) was chosen as the solvent, which enabled both starting materi als to dissolve. The reaction did not go any faster because the two starting materi als were in different phases. When tetrabutylammonium bromide (20% in moles) was added to the reaction mixture as a phase-transfer catalyst (PTC), the replacemen t of Btby azide ion completed within 2 h. However, reaction of 1-[1-[(4-methylphenyl)imino]ethyl] 1 Hbenzotriazole ( 8.2b ) and

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108 sodium azide for the preparation of 5-methyl-1-(4-methylphenyl)-1 H -tetrazole ( 8.3b ) was not that easy. Further study showed that there is no reaction between imidoylbenzotriazoles and sodium azide without acid catalyst (trifluoroacetic acid was used in the reaction). Finally, the reaction was found to complete in half an hour under room temperature in a two-phase solvent (CH2Cl2 and H2O) catalyzed by tetrabutylammonium bromide (TBAB) (20% in moles) and trifluoroacetic acid (TFA) (1 equiv.). After purification by column chromatography on basic alumina using ethyl acetate/hexanes (1/2), 5-methyl-1-(4-methylphenyl)-1 H -tetrazole ( 8.3b ) was obtained in 93% yield. This method of preparation of 1,5-disubstituted tetrazoles has been generalized by taking various substituent such as aliphatic, aromatic or heteroaromatic group in imidoylbenzotriazole. Thus, various 1,5-disubstituted tetrazoles have been prepared in high yields (90%, Table 8-1) All compounds were fully characterized by 1H and 13C NMR spectroscopy and by either elemental analysis or comparison of melting point with literature data. N NN N R2 R1 O R1 N H R2 N Bt R2 R1 8.1 8.2 8.3a o Scheme 8-1. Preparation of Tetrazoles 8.3 Table 8-2. Preparation of Tetrazoles 8.3 Entry R1 R2 Product (Yield %)a Mp (oC) Lit. Mp (oC) 1 methyl phenyl 8.3a (90) 95 97 97 98 2 methyl ptolyl 8.3b (93) 101 106 3 benzyl ptolyl 8.3c (94) 92 94 novel 4 phenethyl ptolyl 8.3d (92) Oil novel 5 phenyl phenyl 8.3e (90) 141 145 6 phenyl penzyl 8.3f (95) 88 90 7 ptolyl ptolyl 8.3g (92) 142 148

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109 Table 8-2 Continued Entry R1 R2 Product (Yield %)b Mp (oC) Lit. Mp (oC) 8 ptolyl methyl 8.3h (92) 113 115 9 p -methoxyphenyl benzyl 8.3i (94) 106 novelb 10 pchlorophenyl ptolyl 8.3j (90) 132 novel 11 pnitrophenyl phenyl 8.3k (91) 144 177 12 pnitrophenyl benzyl 8.3l (93) 131 novel 13 2-furyl ptolyl 8.3m (92) 118 novelb 14 2 furyl cyclohexyl 8.3n (94) oil novel 15 2-thienyl ptolyl 8.3o (92) 115 novelc aIsolated yield. bFound in literature or catal og with no characterization. 8.3 Conclusion Imidoylbenzotriazoles were used to prep are 1,5-disubstituted tetrazoles in high yields in half an hour under mild conditi ons. The advantage of imidoylbenzotriazoles over imidoyl chlorides in these reactions is that imidoylbenzot riazoles are stable in water and there were no side products (amides) observed, which makes the work up and purification easier. 8.4 Experimental Section 8.4.1 General Procedure for the Preparatio n of 1,5-Disubstituted Tetrazoles To a mixture of methylene chloride and water (10 mL/10mL) was added imidoylbenzotriazole ( 8.2ao ) (0.100 g), sodium azide (2 equiv), tetrabutylammonium bromide (0.2 equiv) and trifluoroacetic acid (1 equiv). The reaction mixture was stirred for half an hour under room temperature. Th e organic layer was separated and the water layer was washed methylene chloride (10 mL ). Purification of the combined organic layer by column chromatography on basic alum ina with ethyl acetate/hexanes (1/2) as eluent gave pure 1,5-disubstituted tetrazoles ( 8.3ao ).

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110 8.4.2 Characterization of 1,5-Di substituted Tetrazoles 8.3 5-Methyl-1-phenyl-1 H -tetrazole (8.3a): colorless needles; mp 95 oC (lit.310 mp 97 oC); yield, 90% (0.061 g); 1H NMR 2.63 (s, 3H), 7.46.49 (m, 2H), 7.59 7.63 (m, 3H); 13C NMR 9.8, 124.6, 130.0, 130.4, 133.9, 151.5. 5-Methyl-1-(4-methylphenyl)-1 H -tetrazole (8.3b): colorless needles; mp 101 103 oC (Lit.311 mp 106 oC); yield, 93% (0.065 g); 1H NMR 2.47 (s, 3H), 2.60 (s, 3H), 7.34 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H); 13C NMR 9.7, 21.2, 124.3, 130.4, 131.2, 140.6, 151.5. 5-Benzyl-1-(4-methylphenyl)-1 H -tetrazole (8.3c): white microcrystals; yield, 94% (0.072 g); 1H NMR 2.44 (s, 3H), 4.25 (s, 2H), 7.08.11 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.23.26 (m, 3H), 7.30 (d, J = 8.2 Hz, 2H); 13C NMR 21.2, 29.4, 124.9, 127.4, 128.4, 128.8, 130.2, 131.0, 134.2, 140.9, 153.8. Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38. Found: C, 71.97; H, 5.62; N, 23.02. 1-(4-Methylphenyl)-5-(2-phenylethyl)-1 H -tetrazole (8.3d): colorless oil; yield: 95% (0.073 g); 1H NMR 2.43 (s, 3H), 3.14 (s, 4H), 7.02.07 (m, 4H), 7.20.24 (m, 3H), 7.29 (d, J = 8.2 Hz, 2H); 13C NMR 21.2, 25.6, 33.4, 124.8, 126.6, 128.3, 128.6, 130.2, 130.9, 139.3, 140.7, 154.5. Anal. Calcd for C16H16N4: C, 72.70; H, 6.10; N, 21.20. Found: C, 73.04; H, 6.26; N, 21.11. 1,5-Diphenyl-1 H -tetrazole (8.3e): colorless needles; mp 141 oC (lit.297 mp: 145 oC); Yield: 90 % (0.067 g); 1H NMR 7.39.43 (m, 4H), 7.48.58 (m, 6H); 13C NMR 123.6, 125.3, 128.4, 128.9, 129.0, 129.9, 130.4, 131.3, 153.6. 1-Benzyl-5-phenyl-1 H -tetrazole (8.3f): white microcrystals; mp 88 90 oC (lit.312 mp 90 91 oC); yield, 95% (0.072 g); 1H NMR 5.62 (s, 2H), 7.14.17 (m, 2H), 7.32

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111 7.36 (m, 3H), 7.47.59 (m, 5H); 13C NMR 51.3, 123.6, 127.1, 128.7, 128.8, 129.1, 131.3, 133.8, 154.6. 1,5-Bis(4-methylphenyl)-1 H -tetrazole (8.3g): colorless needles; mp 142 oC (lit.313 mp 148 oC); yield, 92% (0.071 g); 1H NMR 2.38 (s, 3H), 2.45 (s, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H); 13C NMR 21.3, 21.5, 120.7, 125.1, 128.7, 129.6, 130.4, 132.1, 140.6, 141.6, 153.6. 1-Methyl-5-(4-methylphenyl)-1 H -tetrazole (8.3h): colorless needles; mp 113 115 oC (lit.314 mp 115 oC); yield, 92% (0.064 g); 1H NMR 2.46 (s, 3H), 4.17 (s, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H); 13C NMR 21.4, 35.0, 120.7, 128.4, 129.9, 141.7, 154.4. 1-Benzyl-5-(4-methoxyphenyl)-1 H -tetrazole (8.3i): colorless needles; mp 106 108 oC (Lit.296 no NMR data or melting point can be found in this paper); yield, 94% (0.072 g); 3.86 (s, 3H), 5.61 (s, 2H), 7.00 (d, J = 8.9 Hz, 2H), 7.15.18 (m, 2H), 7.34 7.38 (m, 3H), 7.54 (d, J = 8.8 Hz, 2H); 13C NMR 51.2, 55.4, 114.6, 115.6, 127.0, 128.6, 129.1, 130.3, 134.0, 154.5, 161.8. Anal. Calcd for C15H14N4O: C, 67.65; H, 5.32; N, 21.04. Found: C, 67.86; H, 5.32; N, 21.40. 5-(4-Chlorophenyl)-1-(4-methylphenyl)-1H-tetrazole (8.3j): colorless needles; mp: 132 oC; yield, 0.070 g (90 %); 1H NMR 2.47 (s, 3H), 7.26 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H); 13C NMR 21.3, 122.1, 125.1, 129.3, 130.1, 130.6, 131.8, 137.6, 141.1, 152.7. Anal. Calcd for C14H11 N4: C, 62.11; H, 4.10; N, 20.70. Found: C, 62.50; H, 4.04; N, 21.07. 5-(4-Nitrophenyl)-1-phenyl-1 H -tetrazole (8.3k): colorless needles; mp 144 oC (Lit. 313 mp 177 oC); yield, 91% (0.071 g); 1H NMR 7.46.61 (m, 5H), 7.65

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112 (d, J = 9.1 Hz, 2H), 8.40 (d, J = 9.1 Hz, 2H); 13C NMR 122.9, 125.3, 125.8, 129.0, 129.4, 131.9, 139.1, 148.3, 153.8. Anal. Calcd for C13H9N5O2: C, 58.43; H, 3.40; N, 26.22. Found: C, 58.36; H, 3.15; N, 26.62. 1-Benzyl-5-(4-nitrophenyl)-1 H -tetrazole (8.3l): colorless needles; mp 131 oC; yield: 93% (0.073 g); 1H NMR 5.68 (s, 2H), 7.14.16 (m, 2H), 7.37.39 (m, 3H), 7.79 (d, J = 8.9 Hz, 2H), 8.36 (d, J = 8.9 Hz, 2H); 13C NMR 51.8, 124.2, 127.0, 129.1, 129.4, 129.8, 130.0, 133.2, 149.4, 152.9. Anal. Calcd for C14H11N5O2: C, 59.78; H, 3.94; N, 24.90. Found: C, 60.11; H, 3.80; N, 25.27. 5-(2-Furyl)-1-(4-methylphenyl)-1 H -tetrazole (8.3m): colorless needles; novel (appeared in catalog, but no char acterization data could be found in literature); mp 118 120 oC; yield, 92% (0.069 g); 1H NMR 2.48 (s, 3H), 6.49.51 (m, 1H), 6.78 (td, J = 2.0, 0.5 Hz, 1H), 7.32.39 (m, 4H), 7.54 (s, 1H); 13C NMR 21.3, 112.0, 115.0, 125.5, 130.2, 131.6, 138.9, 141.2, 145.7, 146.6. Anal. Calcd for C12H14N4O: C, 63.71; H, 4.46; N, 24.76. Found: C, 63.96; H, 4.35; N, 25.11. 5-(2-Furyl)-1-cyclohexyl-1 H -tetrazole (8.3n): white microcrystals; mp 58 60 oC; 1H NMR 1.20 2.08 (m, 10 H), 4.70 4.80 (m, 1H), 6.58 (dd, J = 3.5, 1.9 Hz, 1H), 7.16 (dd, J = 3.6, 0.7 Hz, 1H), 7.63 (dd, J = 1.5, 0.7 Hz, 1H); 13C NMR 24.8, 25.2, 32.7, 59.0, 112.1, 114.5, 139.7, 145.2, 145.6. 1-(4-Methylphenyl)-5-thien-2-yl-1 H -tetrazole (8.3o): colorless needles; mp 115 117 oC; yield: 92% (0.070 g); novel (appears in catalog, but no characterization data could be found in literature); 1H NMR 2.51 (s, 3H), 7.04 (td, J = 4.4, 1.1 Hz, 1H), 7.27 (dd, J = 3.8, 1.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 5.1, 1.0 Hz, 1H); 13C NMR 21.4, 124.3, 128.0, 130.4, 130.5, 130.6, 131.4, 141.7,

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113 149.8. Anal. Calcd for C12H10N4S: C, 59.48; H, 4.16; N, 23.12. Found: C, 59.82; H, 4.07; N, 23.20.

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114 CHAPTER 9 CONCLUSIONS The objective of developing novel methods to target nitrogenand/or oxygencontaining compounds possessing synthetic utility, biological activity, and desirable physical properties was achieved. The succe ssful syntheses described herein employ convenient preparation of starting materials and mild conditions, and offer competitive and advantageous alternatives to ro utes reported in the literature. Chapters 2 and 6 discuss the easy access of two important classes of benzotriazole intermediates: N -acylbenzotriazoles and imidoylbenz otriazoles. Chapters 2, 7, and 8 highlight the versatility of synthetic met hodologies employing the benzotriazolyl group as a synthetic auxiliary to carry out organic functional group transformations. N -Acylbenzotriazoles were used to prepar ed heterocycles, such as oxazolines and thiazolines (Chapter 3), in hi gh yield under microwave irradiati ons in high yield in short times (10 min). The microwave syntheses of secondary and tertiary amides from N acylbenzotriazoles have advantages over conve ntional methods because high yields were generally obtained from brief reactions regard less the nature of the primary or secondary amines (reactive, unreactive or bulky) (Chapter 4). Furt her, the preparation of hydroxy carboxamide and hydroxyl esters without prior protection of the hydroxy group shows distinct advantages over conven tional methods (Chapter 5). Imidoylbenzotriazoles, synthetic equivalents of imidoyl chlorides, were synthesized via two novel routes (Chapter 6). The s ynthetic utilities of imidoylbenzotriazoles discussed herein again shows the adva ntages of benzot riazole methodology.

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115 Imidoylbenzotriazoles are easy to prepare, st able and easy to store and handle. Common advantages of benzotriazole-assisted synt heses over classical syntheses are access to novel compounds, simple purification procedur es, and avoidance of usin= unstable or hazardous reagents. The facile syntheses of a variety of nove l amidines (Chapter 7) and tetrazoles (Chapter 8) showed the advantag es imidoylbenzotriazoles had over imidoyl chlorides. Microwave reactions were employed in Chapter 2 and gave good results generally. The use of a microwave synthesi zer gives results quickly, avoids side reactions, accelerates reactions dramaticall y, and ensures reproducibility and safety. In this dissertation, the combination of using a microwave synthesizer and benzotriazole methodology proved to be time e fficient and cost effective and I believe that this technique will be utilized more and more in the future.

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132 BIOGRAPHICAL SKETCH Mr. Chunming Cai was born on Febrary 1, 1975. He earned a Bachelor of Science degree from Jilin University, P. R. China, in 1996. In 1999, he earned a Master of Science degree from Peking University, P. R. China. In Fall 2001, he began pursuing a Ph.D. in the Department of Chemistry at Un iversity of Florida, where he became a member of Dr. Alan R. Ka tritzkys research group.


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Permanent Link: http://ufdc.ufl.edu/UFE0013762/00001

Material Information

Title: Microwave Mediated Synthesis of Nitrogen- and/or Oxygen-Containing Compounds
Physical Description: Mixed Material
Copyright Date: 2008

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Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
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Permanent Link: http://ufdc.ufl.edu/UFE0013762/00001

Material Information

Title: Microwave Mediated Synthesis of Nitrogen- and/or Oxygen-Containing Compounds
Physical Description: Mixed Material
Copyright Date: 2008

Record Information

Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
System ID: UFE0013762:00001


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MICROWAVE-MEDIATED SYNTHESIS OF NITROGEN- AND/OR OXYGEN-
CONTAINING COMPOUNDS















By

CHUNMING CAI


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

UNIVERSITY OF FLORIDA


2006




























Copyright 2006

by

Chunming Cai

































To my family (my father, Chen Cai; my mother, Shuiqin Zou; my brother, Chunhua Cai;
my sisters, Jingbo Cai and Yinghui Cai; my wife, Yong Tao; and my son, Charles Yutao
Cai)















ACKNOWLEDGMENTS

It has been very pleasant to pursue my PhD degree with the assistance of all the

nice people who helped and supported me during the last 4 years.

First, I give my deepest thanks to my supervisory committee chair (Alan R.

Katritzky) for his support, guidance, and inspiration. I greatly appreciate the time and

help given by my supervisory committee members (Lisa McElwee-White, Michael J.

Scott, Daniel R. Talham, and Brij M. Moudgil).

I greatly thank my wife (Yong Tao) and my son (Charles Yutao Cai) for making

me a happy husband and father. I greatly thank my parents and my brother and sisters for

their constant love and support. I thank all my friends for making my life colorful.

I thank everyone in Professor Alan R. Katritzky's group (especially Sandeep K.

Singh, Kazuyuki Suzuki, and Sanjay K. Singh) for helping make my work and life easier.















TABLE OF CONTENTS

page

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

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

LIST OF FIGURES ......... ......................... ...... ........ ............ ix

LIST OF SCHEM ES ........... ... .......... ................................................. .x

ABSTRACT .............. ..................... .......... .............. xii

CHAPTER

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

2 BENZOTRIAZOLE AS AN ACID SCAVENGER IN THE SYNTHESIS OF N-
A CY LBEN ZO TRIAZOLES ........................................ ................................. 4

2.1 Introduction ............... .... ....................... .............. .......... 4
2.2 R results and D discussion ................. ..... .... ........ .................................. 5
2.3 Conclusion .............. ......... ....................... .......... .............. 7
2.4 E xperim ental Section ............................................ ....................................... 8

3 FACILE SYNTHESES OF OXAZOLINES AND THIAZOLINES USING N-
ACYLBENZOTRIAZOLES UNDER MICROWAVE IRRADIATION.................. 13

3.1 Introduction........................................................................ ....... ...... 13
3.2 R results and D iscu ssion .............. ....................................... ................... .... 15
3.2.1 Preparation of N-Acylbenzotriazoles .................................................15
3.2.2 Preparation of 2-Oxazolines. .................. ........ .................. ............... .15
3.2.3 Preparation of Thiazolines................................... .................................... 17
3 .3 C o n c lu sio n s ..................................................................................................... 1 9
3.4 E xperim mental Section ........................................... ............................... 19
3.4.1 General Procedure for Preparing 2-Oxazolines Using N-
Acylbenzotriazoles by Conventional M ethod...............................................20
3.4.2 General Procedure for Preparing 2-Oxazolines 3.3 or 2-Thiazolines 3.5
Using N-Acylbenzotriazoles 3.1 under Microwave Irradiation....................20
3.4.3 Characterization of N-Acylbenzotrizazoles 3.1g,j...................................21
3.4.4 Characterization of Oxazolines 3.3a-j ................................................. 21
3.4.5 Characterization of Thiazolines 3.5a-f,h,i .............................................22









3.4.6 Characterization of Miscellaneous Heterocycles 3.6, 3.7, 3.8, 3.9, 3.10 ...24

4 PREPARATION OF SECONDARY AND TERTIARY AMIDES UNDER
M ICR OW A VE IRRAD IA TION ...................................... .........................................26

4.1 Introduction........................................................................ ....... ...... 26
4 .2 R results and D iscu ssion ........................................ ...................... .....................26
4.3 Conclusion ....................................................................... ........ 28
4.4 Experim mental Section............................... ... ........................................... 28
4.4.1 General Procedure for the Preparation of Amides 4.1 a-Ac.....................28
4.4.2 Characterizations of Amides 4.1 ........................... ............... 29
4.3.3 Preparation of Am ides 4.2 ..................................................................... 36
4.4.4 Characterization of Amides 4.2....... ... ............. .................. .............. 36

5 DIRECT SYNTHESIS OF ESTERS AND AMIDES FROM UNPROTECTED
HYDROXY-AROMATIC AND -ALIPHATIC CARBOXYLIC ACIDS ................38

5 1 A b stract ........................................................ .......... ................. .. 3 8
5 .2 In tro du ctio n .................................................. ................ 3 8
5.3 R results and D discussion ...................... ..... .............................................. 40
5.3.1 Preparation of Hydroxy Carboxamides from Aliphatic Hydroxy Acids....40
5.3.2 Preparation of Hydroxyaromatic Amides from Hydroxyaromatic Acids. .44
5.3.3 Preparation of Aliphatic a-Hydroxycarboxylic Esters and Thiolesters
from a-H ydroxy A cids ....................................... ....... ... .....................47
5.3.4 Preparation of Aromatic Esters from Substituted o-Hydroxy Aromatic
A cids. .................................................................. 5 1
5 .4 E x p erim ental S section ............................................. ......................................... 53
5.4 .1 G general ........................................ ... ........ .. ...............53
5.4.2 General Procedure for the Synthesis of Hydroxy Carboxamides 5.3
from H ydroxy A cids 5.1 ............... ............................... .................... 53
5.4.3 Characterization of Hydroxy Amides 5.3.............................. ..............54
5.4.4 Synthesis of o-Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9 .................58
5.4.5 Characterization of o-Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9 ......59
5.4.6 Synthesis of Amides of Substituted Salicylic and o-Hydroxy Naphthoic
A cid s (5 .7, 5 .10): ................................................ ................... 6 1
5.4.7 Characterization of Amides of Substituted Salicylic and o-Hydroxy
N aphthoic A cids (5.7 and 5.10) ..................................................................... 62
5.4.8 Synthesis ofHydroxy Aryl-/Alkyl- and Thioesters 5.11 from Hydroxy
A cid s ................... ................... ................ .......... ..... ...................... 66
5.4.9 Characterization of Hydroxy Aryl-/Alkyl- and Thioesters 5.11 from
H ydroxy A cids ......... .. ....... .... ............... .... ... .. .... .............. 67
5.4.10 Synthesis of Esters of Substituted Salicylic 5.12 and o-Hydroxy
N aphthoic A cids 5.13 .................... ......... .... .. .......... .... ........... ... ............ 68
5.4.11 Characterization of Esters of Substituted Salicylic 5.12 and o-Hydroxy
N aphthoic A cids 5.13........................... .... .......... .................... ..............69









6 SYNTHESIS OF IMIDOYLBENZOTRIAZOLES FROM SECONDARY
A M ID E S ........................................................... ................ 7 4

6 .1 Introdu action ............... .................... ...................................... 74
6.2 R results and D iscussions............................................... ............................. 75
6.3. Conclusion ........................ .....................77
6.4 E xperim mental Section ..................... .... ............. ........................................ 78
6.4.1 General Procedure for the Preparation of Imidoylbenzotriazoles 6.1 ........78
6.4.2 Characterization of Imidoylbenzotriazoles 6.1............... ... ............ 78

7 EFFICIENT MICROWAVE ACCESS TO POLYSUBSTITUTED AMIDINES
FROM IMIDOYLBENZOTRIAZOLES.................................................................89

7.1 Introduction ........................... ............................ ............... 89
7 .2 R esu lts an d D iscu ssion ........................................ ...........................................9 1
7.3 C conclusion ................................................................................... ................. 94
7.4 E xperim mental Section ..................... .......... ... ........................................... 95
7.4.1 General Procedure for the Preparation of Amidines 7.1: ............ .........95
7.4.2 Characterization of Amidines (7.1): ............................................ .....96

8 SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES UNDER MILD
CONDITION VIA BENZOTRIAZOLE METHODOLOGY..............................105

8 .1 In tro d u ctio n .............................................. .. ............. ................ 10 5
8.2 Results and Discussion ........................... ................ ... ............... 107
8.3 Conclusion .................................. ........................... .... ......... 109
8.4 Experim ental Section........................ .. .... ............. ....................109
8.4.1 General Procedure for the Preparation of 1,5-Disubstituted Tetrazoles...109
8.4.2 Characterization of 1,5-Disubstituted Tetrazoles 8.3 ...........................110

9 CONCLUSIONS ................................................. ..... .................. 114

L IST O F R E FE R E N C E S ........................................................................ ................... 116

BIOGRAPHICAL SKETCH ............................................................. ............... 132
















LIST OF TABLES


Table page

2-1 Preparation of N-Acylbenzotriazoles from Acid Chlorides ..............................

2-2 Preparation of N-Acylbenzotriazoles from Carboxylic Acids"............. ...............7

3-1 Preparation of 2-Substituted 2-Oxazolines 3.3 using N-Acylbenzotriazoles...........17

3-2 Preparation of 2-Substituted Thiazolines using N-Acylbenzotriazoles 3.la-f,h,i...18

4-1 Microwave Preparation of Secondary Amides 4.1 Using N-Acylbenzotriazoles"...27

5-1 Synthesis of Hydroxy Carboxamides 5.3 from Aliphatic Hydroxy Acids 5.1a-
g ....................................................... 4 3

5-2 The Synthesis of Substituted Salicylamides 5.7a-h (a, X = H; b, X = 5-Br; c, X
= 4-OH ; d, X = 3-M e) .............................. ...... ....... .............. 47

5-3 The Synthesis of A m ides 5.10............................................................................... 47

5-4 Synthesis of Hydroxy Esters 5.11a-b and Thiolesters 5.11e-g*.............................50

5-5 Synthesis of E sters 5.12 ................................................................ 52

5-6 The Synthesis of E sters 5.13 ........................................................................ ... ...... 52

6-1 Preparation of Imidoylbenzotriazoles 6.1 .............. .............................. ..............77

7-1 Preparation of Amidines 7.1 from Imidoylbenzotriazoles............................94

8-1 Literature Methods for the Preparation of Tetrazoles ............. ......... .......106

8-2 Preparation of Tetrazoles 8.3 .....................................108


8-2 Preparation of Tetrazoles 8.3 ................................ 108
















LIST OF FIGURES

Figure page

1-1 Structure of benzotriazole and benzotriazolyl group .............................................1

3-1 More Heterocycles Prepared from N-Acylbenzotriazoles...................................19

4-1 Tertiary Amides Obtained from N-Acylbenzotriazoles under Microwave
Irradiation .............................................................................................................28

5-1 H ydroxy A cids 5.1 ...................... ...................... ................... .. ......42

5-2 Preparation of Hydroxy N-Acylbenzotriazoles ................. ............ ............... 46
















LIST OF SCHEMES


Schemege

2-1 Synthesis of N-Acylbenzotriazoles (Literature Method)............... .... ...........5

2-2 Synthesis of Acid Chlorides and Alkyl Chlorides ...................................................5

2-3 Preparation of N-Acylbenzotriazoles from Acid Chlorides .............. .................6

2-4 Preparation of N-Acylbenzotriazoles from Carboxylic Acids .............. ...............7

3-1 Literature Preparation Methods for 2-Oxazolines..............................................14

3-2 Literature Preparation Methods for 2-Thiazolines...................... .................14

3-3 Preliminary Experiments under Thermal Conditions.................... ...............15

3-4 Preparation of 2-Substituted 2-Oxazolines using N-Acylbenzotriazoles.................17

3-5 Preparation of 2-Substituted Thiazolines using N-Acylbenzotriazoles .................. 18

4-1 Microwave Preparation of Secondary Amides 4.1 Using N-Acylbenzotriazoles ....27

5-1 Synthesis of Hydroxy Carboxamides ............................................... ............... 40

5-2 General Reactions to Derivatives of Hydroxy Carboxylic Acid.............................42

5-3 Unsuccessful Synthesis of y-Hydroxyacylbenzotriazole .............. ...................43

5-4 Literature Methods of Synthesis of the o-Hydroxynaphthyl Amides .................44

5-7 Preparation of Amides and Esters from Naphthoic Acids .......................................48

5-8 Synthesis of oa-Hydroxy Carboxylic Esters................................... ........................48

5-9 Synthesis of Hydroxy Carboxylic Thiolesters.........................................................49

6-1 Literature Methods of Preparation of Imidoylbenzotriazoles .............................76

6-2 Preparation of Imidoylbenzotriazoles 6.1 ............................................................. 76

7-1 Literature Methods of Preparation of Amidines .................................................90











7-2 Mechanism of the Acid-catalyzed Formation of Amidines ...............................93

7-3 Preparation of Amidines 7.1 from Imidoylbenzotriazoles.................................93

8-1 Preparation of Tetrazoles 8.3 ................................ 108













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

MICROWAVE-MEDIATED SYNTHESIS OF NITROGEN- AND/OR OXYGEN-
CONTAINING COMPOUNDS

By

Chunming Cai

May, 2006

Chair: Alan R. Katritzky
Major Department: Chemistry

Benzotriazole is a widely used synthetic auxiliary to many synthetic applications.

We developed convenient and efficient methods for preparing benzotriazole derivatives

and used them to prepare a few kinds of nitrogen- and/or oxygen-containing compounds.

Microwave synthesizers are widely used by organic chemists because they give excellent

and repeatable results.

We examined preparation of N-acylbenzotriazoles from carboxylic acids or acid

chlorides. These intermediates were used to synthesize oxazolines and thiazolines,

secondary and tertiary amides, hydroxyl carboxamides, and esters. We were able to

complete high-yielding reactions starting from N-acylbenzotriazoles in 10 min, using

microwaves as the heating source.

We prepared various imidoylbenzotriazoles via two novel methods and examined

the synthetic approaches to obtain polysubstituted amidines and 1,5-disubstituted

tetrazoles in high yields in brief reactions. To prepare polysubstituted amidines, we used

a microwave synthesizer (CEM) to accelerate the reactions. All the reactions were









completed within 10 min and high yields were obtained. To prepare 1,5-disubstituted

tetrazoles, we completed the reactions in half an hour under room temperature to give

high yields without using microwaves.














CHAPTER 1
GENERAL INTRODUCTION

Benzotriazole chemistry has been studied in Prof Alan R. Katritzky's research

group for many years, and its applications in synthetic chemistry have been previously

addressed. 1,2 Microwave synthesizers became popular recently because of their heating

pattern (different from conventional heating) and because of their reproducibility and

safety3.


I N I N N-
N "N
H \
Benzotriazole Bt1 = Benzotriazol-1-yl Bt2 = Benzotriazol-2-yl

Figure 1-1 Structure of benzotriazole and benzotriazolyl group

Benzotriazole is an excellent synthetic auxiliary that can be readily introduced to a

variety of substrates and can lead to a lot of transformations because it acts as a leaving

group, electron-withdrawing group, and even an electron-donating group in different

cases. Benzotriazole is a cheap, stable compound that is soluble in common organic

solvents such as ethanol, benzene, methylene chloride, chloroform, THF and DMF.

Benzotriazolyl group has excellent leaving ability when attached to a-carbon atom

adjacent to hetero-atoms such as N, 0, and S. Unlike halogens, the C-linked

benzotriazole group can rarely be replaced by nucleophiles if there is no hetero-atom at

the a-carbon atom. It is also a good leaving group when attached to a carbonyl group to

form N-acylbenzotriazoles or to an imidoyl group to form imidoylbenzotriazoles which

are efficient N-acylating and N-imidoylating agents. The benzotriazole group can be used









as an activating group for a-hydrogen (adjacent CH). A widely realized good property of

benzotriazole is that it can be easily removed by basic solutions, such as sodium

bicarbonate solution, after being replaced by other nucleophiles. If products are not stable

towards base, but stable towards acid, hydrochloric acid solution (4N) can be used.

Another important aspect of the benzotriazole group is that it is stable during

various synthetic operations. It might be introduced at the beginning of a sequence and

carried through several steps.

This dissertation is about the preparation of N-acylbenzotriazoles and

imidoylbenzotriazoles for formation of simple amides, C-hydroxy-carboxamides and -

esters, and oxazolines, thiazolines, amidines and tetrazoles.

In chapter 2, the preparation ofN-acylbenzotriazoles from carboxylic acids or acid

chlorides is discussed. The mechanism of the reaction forming N-acylbenzotriazoles is

also addressed.

Chapter 3 describes the formation of heterocyclic rings involving nucleophilic

substitution of benzotriazole group to give oxazolines and thiazolines. A microwave

synthesizer was used to synthesize these compounds to give high yields in brief reactions.

In chapter 4, the preparation of secondary and tertiary amides under microwave

irradiation is studied. N-Acybenzotriazoles are versatile neutral acylating reagents.

Previously, amides were prepared from N-acybenzotriazoles under room temperature in

about 4-6 hours. With the help from microwave synthesizer, the speed of the reactions is

accelerated dramatically and amides can be prepared in 10 minutes in high yields.

In chapter 5, C-hydroxy-carboxamides and -esters are prepared from N-

acylbenzotriazoles without prior protection. A microwave synthesizer is used to deal with









some reactions which are difficult to complete under room temperature in neutral

conditions.

In chapter 6, the synthesis of imidoylbenzotriazoles from two different routes is

discussed. In one of the two routes described, microwave synthesizer is also used to give

good results.

In chapter 7, the application of imidoylbenzotriazoles in the synthesis of

polysubstituted amidines is discussed. Three different conditions are used to obtain a

variety of amidines in high yields. A microwave synthesizer was used in all these

preparations of amidines.

In chapter 8, the application of imidoylbenzotriazoles is extended to prepare 1,5-

disubstituted tetrazoles. The reactions are fast enough under room temperature; thus

microwave is not required in this case.














CHAPTER 2
BENZOTRIAZOLE AS AN ACID SCAVENGER IN THE SYNTHESIS OF N-
ACYLBENZOTRIAZOLES

2.1 Introduction

N-Acylbenzotriazoles4 have hitherto been reported as versatile reagents for N-

acylation,510 formylation,1l trifluoroacylation,12 O-acylation,13 C-acylation,14-18 S-

acylation9 and for the synthesis of polycyclic heteroaromatics.19 A one-pot reaction to

obtain N-acylbenzotriazoles involving benzotriazole, thionyl chloride and carboxylic

acids was published in 2003.20 Extensive work in Prof. Katritzky's group was able to be

carried out after that discovery because this mild reaction gives high yields on a regular

basis. Many N-acylbenzotriazoles which were very difficult or impossible to make in the

past became readily available. However, the mechanism behind this reaction (Scheme 2-

1) was not fully understood at the time the discovery occurred. The intermediate was

believed to be BtSOBt or BtSOC1, which are compounds that have never been isolated.

There is no proof showing the formation of these intermediates. The formation of BtSOBt

or BtSOCl should be accompanied by the formation of hydrochloric acid which combines

with benzotriazole to form the salt benzotriazole hydrochloride, which is insoluble in

methylene chloride. But the mixture of BtH and SOC12 in methylene chloride is clear,

showing no sign of the formation of benzotriazole hydrochloride salt. Meanwhile, there is

always a large amount of benzotriazole left after the reaction is complete. In other words,

more benzotriazole is used than necessary. However, the exact amount of benzotriazole

needed for this reaction requires clarification of the mechanism of the reaction.









O CH2Cl2 O
+ SOCl2 + 4BtH (BtH = benzotriazole)
R OH RT, 2 h R Bt

Scheme 2-1 Synthesis ofN-Acylbenzotriazoles (Literature Method)

The combination of benzotriazole and thionyl chloride (1:1 ratio) was initially used

by Sachin et al. to prepare acid chlorides (Scheme 2-2).21 In that work, benzotriazole was

believed to act as a weak base to neutralize the hydrochloride acid generated during the

chlorination. The formation of the precipitated benzotriazole hydrochloride salt drove the

reaction to completion quickly. From the results in this work, acid chlorides could be

easily supposed to be intermediates to N-acylbenzotriazoles in the reaction shown in

Scheme 2-1. A study of reactions between acid chlorides and benzotriazole supports this

supposition. The correct amount of benzotriazole needed for the reaction is discussed in

this dissertation. Benzotriazole is used in the reaction not only as the reactant but also the

acid scavenger (pKa for proton gain: 1.2).

O CH2Cl2 O
SO SOC1i + BtH ,- m 11 examples
R OH SOC2 RT, R C Yield: 90-100%

Scheme 2-2 Synthesis of Acid Chlorides and Alkyl Chlorides

2.2 Results and Discussion

2.2.1 Preparation of N-Acylbenzotriazoles (2.1b-d,f,h,i,l-o) from Acid Chlorides

N-Acylbenzotriazoles (Table 2-1) with aryl or heterocyclic groups were prepared

in 92-97% yields from the corresponding acid chlorides. Benzoyl chloride (1 equiv) was

dissolved in methylene chloride, and benzotriazole (2 equiv) was added in one portion.

The reaction mixture was stirred for 30 min under room temperature. The formation of

white precipitated solid was observed immediately. After the completion of the reaction,

the white precipitate was filtered out and the solid was washed with copious methylene









chloride. Evaporating the solvent of the combined solution gave crude product which was

purified by crystallization from chloroform/hexanes to give pure 1-benzoyl-1H-1,2,3-

benzotriazole (2.1h) in 96% yield. For substrates with two acid chloride functionalities, 4

equiv of benzotriazole was used to ensure the completion of the reaction. Similarly, 9

more N-acylbenzotriazoles were prepared in high yields. Compounds (entry 1-7, Table

2-1) were also prepared from carboxylic acids, so the full characterization of these

compounds will be only described once. Compounds (entry 8-10, Table 2-1, 2.1m-o)

were fully characterized by 1H and 13C NMR spectroscopy and by comparison of melting

points with literature values.

O CH2CI2 O
+ 2BtH >
R C + 2 BtH 30 min R Bt
2.1b-d,f,h,i,l-o

Scheme 2-3 Preparation of N-Acylbenzotriazoles from Acid Chlorides

Table 2-1 Preparation of N-Acylbenzotriazoles from Acid Chlorides
Entry R Product Entry R Product
(Yield %)" (Yield %)"
1 2-thienyl 2.1c (95) 6 cyclohexyl 2.11 (96)
2 benzyl 2.1f (92) 7 hexyl 2.1b (95)
3 phenyl 2.1h (96) 8 p-phenylene 2.1m (96)
4 p-tolyl 2.1d (95) 9 carbonic' 2.1n (91)
5 2-furyl 2.1i (92) 10 ethanedioylb 2.1o (97)
"Isolated yield. Benzotriazole (4 equiv) is used.

2.2.2 Preparation of N-Acylbenzotriazoles from Carboxylic Acids

The addition of the reactions in Scheme 2-2 and 2-3 gives the reaction shown in

Scheme 2-4, where it clearly showed that 3 equiv ofbenzotriazole should be the exact

amount required for the conversion of acids to N-acylbenzotriazoles. This conclusion was

further confirmed by the results shown in Table 2-2. The yields were always high;

moreover, no washing and drying are needed during workup. The crude product is pure










enough for further use. Recrystallization of the crude product from chloroform gave pure

N-acylbenzotriazoles. Compounds 2.1a-1 were fully characterized by 1H and 13C NMR

spectroscopy and by comparison of melting points with literature values.

1-2 h, RT
R1CO2H + SOCl2 + 3 BtH CH22 R1COBt
CH2CI2
2.1a-I

Scheme 2-4 Preparation of N-Acylbenzotriazoles from Carboxylic Acids

Table 2-2 Preparation of N-Acylbenzotriazoles from Carboxylic Acids'
Entry R1 Product Mp (oC) Lit. Mp
(Yield %)b (C)
1 phenethyl 2.1a (89) 62-64 62-64
2 n-hexyl 2.1b (92) 48-50 50-52
3 2-thienyl 2.1c (93) 172-173 173-175
4 p-nitrophenyl 2.1d (91) 191-193 192-193
5 2-furyl 2.1e (92) 170-172 171-173
6 benzyl 2.1f(89) 63-65 65-66
7 p-methoxyphenyl 2.1g (92) 109-111 113-114
8 phenyl 2.1h (96) 110-112 112
9 p1 -tolyl 2.1i (95) 122-124 123-124
10 methyl 2.1j (96) 50-52 49-51
11 phenylethenyl 2.1k (96) 149-150 151-152
12 cyclohexyl 2.11 (85) 85-88 84-96
"Benzotriazole (3 equiv) is used. 'Isolated yield.

2.3 Conclusion

In this chapter, preparation of N-acylbenzotriazoles from carboxylic acids, thionyl

chloride and benzotriazoles was optimized and an alternative preparative method to

obtain N-acylbenzotriazoles from acid chlorides was also described. The mechanism of

the preparation methods was also discussed and supported by the results reported in this

chapter. The formation of the insoluble benzotriazole hydrochloride salt was suggested to

be the driving force for both of the two sets of reactions.









2.4 Experimental Section

Melting points are uncorrected. Reactions under microwave irradiation were

conducted in heavy-walled Pyrex tubes sealed with aluminum crimp caps fitted with a

silicon septum or in round bottomed flasks equipped with a reflux condenser. Microwave

heating was carried out with a single mode cavity Discover Microwave Synthesizer

(CEM Corporation, NC, USA), producing continuous irradiation at 2450 MHz. H NMR

(300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDC13 (with TMS for 1H

and chloroform-d for 13C as the internal reference), unless specified otherwise.

2.4.1 General Procedure for the Preparation of N-Acylbenzotriazoles (2.1b-d,f,h,i,l-
o) from Acid Chlorides

Benzotriazole (2 or 4 equiv depends on the number of acid chloride functional groups

in the starting material) was added in one portion to acid chloride in methylene chloride.

The reaction mixture was stirred for 30 min. The precipitated white solid was filtered off

and the solvent was removed under reduced pressure to obtain the crude product, which

was purified by recrystallization from chloroform/hexanes to obtain N-acylbenzotriazole.

2.4.2 General Procedure for the Preparation of N-Acylbenzotriazoles 2.1a-l from
Carboxylic Acids

Thionyl chloride (4.00 mL, 55 mmol, 1.1 equiv) and benzotriazole (18.45 g, 155

mmol, 3.1 equiv) in methylene chloride (100 mL) were added dropwise to the carboxylic

acid (50 mmol, 1 equiv) in methylene chloride (100 mL). The reaction was monitored by

TLC. The precipitated white solid was filtered off and the solvent was removed in vacuo

to obtain the crude product, which was purified by recrystallization from

chloroform/hexane to obtain N-acylbenzotriazoles (2.1a-1)









2.4.3 Characterization of N-Acylbenzotriazoles 2.1

1-(3-Phenylpropanoyl)-1H-1,2,3-benzotriazole (2.1a): colorless needles (from

chloroform/hexanes); mp 62-64 C (lit.5 mp 63-64 C); yield, 89% (11.17 g); 1H NMR 6

3.21 (t, J= 7.7 Hz, 2H), 3.73 (t, J= 7.7 Hz, 2H), 7.17-7.23 (m, 1H), 7.25-7.30 (m, 4H),

7.44 (t, J= 7.6 Hz, 1H), 7.59 (t, J= 7.7 Hz, 1H), 8.06 (d, J= 8.4 Hz, 1H), 8.23 (d, J=

8.2 Hz, 1H); 13C NMR 6 30.0, 36.9, 114.2, 119.9, 125.9, 126.4, 128.3, 128.5, 130.2,

130.9, 139.7, 145.9, 171.4.

1-Heptanoyl-1H-1,2,3-benzotriazole (2.1b): colorless needles (from

chloroform/hexanes); mp 48-50 C (lit.22 mp 50-52 C); yield, 92% (10.63 g); 1H NMR 6

0.91 (t, J= 7.0 Hz, 3H), 1.29-1.52 (m, 6H), 1.86-1.96 (m, 2H), 3.39-3.44 (m, 2H), 7.49

(td, J= 7.3, 0.8 Hz, 1H), 7.64 (td, J= 7.3, 0.8 Hz, 1H), 8.11 (d, J= 8.2 Hz, 1H), 8.28 (d,

J -8.2 Hz, 1H); 13C NMR 6 13.9, 22.4, 24.3, 28.7, 31.4, 35.4, 114.3, 120.0, 125.9, 130.2,

131.0, 146.1, 172.6.

1-(2-Thienylcarbonyl)-1H-benzotriazole (2.1c): colorless needles (from

chloroform/hexanes); mp 172-173 C (lit.20 mp 173-175 C); yield 93% (10.65 g); 1H

NMR 6 7.30 (dd, J= 5.0, 4.0 Hz, 1H), 7.56 (t, J= 7.7 Hz, 1H), 7.71 (t, J= 7.6 Hz, 1H),

7.91 (dd, J= 5.0, 0.9 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.60

(dd, J= 4.0, 0.9 Hz, 1H); 3C NMR 114.8, 120.2, 126.2, 128.0, 130.4, 132.1, 133.3,

137.1, 138.4, 145.7, 159.1.

1-(4-Nitrobenzoyl)-lH-1,2,3-benzotriazole (2.1d): white microcrystals (from

chloroform/hexanes); mp 191-193 C (lit.15 mp 192-193 C); yield, 91% (12.19 g); 1H

NMR 6 7.61 (t, J= 7.6 Hz, 1H), 7.78 (t, J= 7.6 Hz, 1H), 8.21 (d, J= 8.2 Hz, 1H), 8.29


), 8.29-









8.45 (m, 5H); 13C NMR 6 114.7, 120.5, 123.5, 126.9, 131.0, 132.0, 132.6, 136.9, 145.9,

150.5, 165.0.

1-(2-Furoyl)-1H-1,2,3-benzotriazole (2.1e): colorless needles (from

chloroform/hexanes); mp 170-172 C (lit.5 mp 171-173 C); yield, 92% (9.80 g); 1H

NMR 6 6.74 (dd, J 3.5, 1.3 Hz, 1H), 7.55 (t, J= 7.7 Hz, 1H), 7.70 (td, J= 7.7, 0.8 Hz,

1H), 7.88 (s, 1H), 8.15 (d, J= 8.0 Hz, 1H), 8.17 (s, 1H), 8.41 (d, J= 8.2 Hz, 1H); 13C

NMR6 112.9, 114.7, 120.1, 124.7, 126.3, 130.4, 132.1, 144.5, 145.5, 148.9, 155.0.

1-(Phenylacetyl)-1H-1,2,3-benzotriazole (2.1f): colorless needles (from

chloroform/hexanes); mp 63-65 C (lit.5 mp 65-66 C); yield, 89% (10.55 g); H NMR 6

4.73 (s, 2H), 7.28-7.40 (m, 3H), 7.46-7.53 (m, 3H), 7.64 (td, J= 7.7, 0.8 Hz, 1H), 8.13

(d, J= 8.3 Hz, 1H), 8.27 (d, J= 8.2 Hz, 1H); 13C NMR 6 41.9, 114.4, 120.1, 126.2,

127.6, 128.7, 129.8, 130.4, 131.1, 132.4, 146.2, 170.2.

1-(4-Methoxybenzoyl)-1H-1,2,3-benzotriazole (2.1g): colorless prisms (from

chloroform/hexanes); mp 109-111 C (lit.22 mp 113-114 C); yield, 92% (11.64 g); 3.93

(s, 3H), 7.06 ( d, J 8.9 Hz, 2H), 7.51 (t,J 7.2 Hz, 1H), 7.69(t, J= 7.1 Hz, 1H),

8.16 (d, J = 6.2 Hz, 1H), 8.29 (d, J = 8.9 Hz, 2H), 8.37 ( d, J = 8.2 Hz, 1H); 55.6,

103.3, 113.9, 114.8, 120.0, 126.1, 130.1, 134.4, 145.6, 164.2.

1-Benzoyl-lH-1,2,3-benzotriazole (2.1h): white needles (from

chloroform/hexanes); mp 110-112 C (lit.20 mp 116-117 C); yield, 96% (10.70 g); 1H

NMR6 7.67-7.52 (m, 3H), 7.70-7.72 (m, 2H), 8.23-8.15 (m, 3H), 8.38 (d,J 8.3 Hz,

1H); 13C NMR 6 114.7, 120.1, 126.3, 128.4, 130.3, 131.4, 131.7, 132.3, 133.6, 145.7,

166.6.


.









1-(4-Methylbenzoyl)-lH-1,2,3-benzotriazole (2.1i): colorless prisms (from

chloroform/hexanes); mp 121-123 C (lit.15 mp 123-124 C); yield, 95% (11.20 g); 1H

NMR 6 2.47 (s, 3H), 7.37 (d, J = 8.1 Hz, 2H), 7.52 (t, J= 7.6 Hz, 1H), 7.67 (t, J= 7.6

Hz, 1H), 8.13 (d, J= 8.1 Hz, 3H), 8.14 (d, J= 8.1 Hz, 1H), 8.36 (d, J= 8.2 Hz, 1H); 13C

NMR 6 21.7, 114.7, 120.0, 126.1, 128.5, 129.1, 130.1, 131.8, 132.3, 144.7, 145.6, 166.4.

1-Acetyl-1H-1,2,3-benzotriazole (2.1j): colorless needles (from

chloroform/hexanes); mp 50-52 C (lit.23 mp 49-51 C); yield, 96% (7.73 g); H NMR 6

3.00 (s, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.63 (t, J= 7.6 Hz, 1H), 8.09 (d, J= 8.2 Hz, 1H),

8.25 (d, J= 8.2 Hz, 1H); 13C NMR 6 23.1, 114.2, 120.0, 126.0, 130.2, 130.8, 146.1,

169.4.

1-[(2E)-3-Phenylprop-2-enoyl]-1H-1,2,3-benzotriazole (2.1k): colorless needles

(from chloroform/hexanes); mp 149-150 C (lit.20 mp 151-152 oC); yield, 96% (11.95 g);

1HNMR 6 7.48-7.51 (m, 3H), 7.54 (ddd, J= 7.7, 6.9, 1.0 Hz, 1H), 7.70 (ddd, J= 7.7,

6.9, 1.0 Hz, 1H), 7.76-7.79 (m, 2H), 8.13 (d, JAB = 16.0 Hz, A part of AB system, 1H),

8.17 (d, JAB = 16.0 Hz, B part of AB system, 1H), 8.18 (td, J= 6.5, 0.9 Hz, 1H), 8.43 (dt,

J -8.2, 1.0 Hz, 1H); 13CNMR6 114.7, 116.0, 120.1, 126.1, 128.9, 129.0, 130.2, 131.4,

134.1, 146.3, 148.7, 163.8.

1-(Cyclohexylcarbonyl)-lH-1,2,3-benzotriazole (2.11): white microcrystals (from

chloroform/hexanes); mp 85-88 oC (lit.22 mp 94-96 oC); yield, 85% (9.85 g); 1H NMR 6

1.27-1.40 (m, 1H), 1.44-1.56 (m, 2H), 1.65-1.82 (m, 3H), 1.88-1.90 (m, 2H), 2.13-

2.17 (m, 2H), 3.87-3.95 (m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.63 (t, J= 7.7 Hz, 1H), 8.11

(d, J= 8.2 Hz, 1H), 8.28 (d, J= 8.2 Hz, 1H)); 13C NMR 6 25.3, 25.6, 29.1, 43.1, 114.4,

119.9, 125.8, 130.1, 131.1, 146.0, 175.4.


.4.









1H-1,2,3-Benzotriazol-l-yl[4-(1H-1,2,3-benzotriazol-1-

ylcarbonyl)phenyl]methanone (2.1m): white microcrystals; mp 232-234 oC [lit.24 mp

238-242 oC]; H NMR (DMSO-d6, 300 MHz) 6 7.60 (dd, J= 8.1, 6.9 Hz, 2H), 7.77 (dd,

J= 8.2, 6.9 Hz, 2H), 8.21 (d, J= 8.2 Hz, 2H), 8.42 (s, 4H), 8.45 (d, J= 8.4 Hz, 2H); 13C

NMR (DMSO-d6, 75 MHz)6 114.8, 120.4, 126.7, 130.8, 131.4, 132.1, 135.6, 145.9,

165.8.

1,1'-Carbonylbisbenzotriazole (2.1n): white microcrystals; mp 180-182 oC (lit.25

mp 182-184 oC); 1H NMR (DMSO-d6, 300 MHz) 6 7.60-7.65 (m, 2H), 7.76-7.81 (m,

2H), 8.22-8.27 (m, 4H); 13C NMR (DMSO-d6, 75 MHz) 6 113.5, 120.9, 126.8, 127.1,

130.9, 132.6, 145.8.

1,1'-(1,2-Dioxo-1,2-ethanediyl)bis-lH-benzotriazole (2.1o): white microcrystals;

mp 162-163 oC (lit.26 mp 163-164 oC); 1H NMR 6 7.65 (t, J= 7.7 Hz, 2H), 7.83 (t, J

7.7 Hz, 2H), 8.20 (d, J -8.4 Hz, 2H), 8.39 (d, J -8.2 Hz, 2H); 13C NMR 6 113.9, 120.9,

127.7, 130.3, 131.6, 146.3, 158.0.














CHAPTER 3
FACILE SYNTHESES OF OXAZOLINES AND THIAZOLINES USING N-
ACYLBENZOTRIAZOLES UNDER MICROWAVE IRRADIATION

3.1 Introduction

Oxazolines and thiazolines are important heterocycles.27'28 2-Oxazolines are

structural entities in naturally occurring iron chelators,29'30 cytotoxic cyclic peptides,31

and in antimitotic32 and neuroprotective agents.33 Well known applications of 2-

oxazolines include their use as synthetic intermediates,34'35 protecting groups and as chiral

auxiliaries. Thiazoline derivatives possess anti HIV-1,36 antimitotic,37 and bioluminescent

activities,38 and have recently found applications as building blocks in pharmaceutical

drug discovery.39-41

Reaction of carboxylic acids with amino alcohols is the most common method for

the synthesis of oxazolines.42-47 Other carboxylate functionalities can be used in similar

methods including imidate hydrochlorides,48 ortho esters,49 imino ether hydrochlorides,50

aldehydes51 or nitriles.52-54 Thiazolines have been prepared: (i) by the condensation of

amino thiols with nitriles,36 esters,55 imino ethers56 or imino triflates;57 (ii) from N-acyl-2-

aminoethanols 43,58 or /-hydroxy thioamides;59-61 or (iii) by multistep conversions from

oxazolines.62

However, there are limitations associated with these literature methods: direct

conversions of carboxylic acids into the corresponding 2-oxazolines proceed with

elimination of water at high temperatures (160-220 C), require long reaction times

(12-18 h) and frequently give low yields.63









o0 R R -NH R NH.HCI
R-_ N EtO+OEt RN H
R OH R H R-EtO OEt



R RR2

R1

RO-- R2
R N

Scheme 3-1 Literature Preparation Methods for 2-Oxazolines

0 R NH R NR'
R OR' R N OEt OTf




H2N SH
R1




Scheme 3-2 Literature Preparation Methods for 2-Thiazolines

Use of nitriles requires a Lewis acid and proceeds at high temperatures with

elimination of ammonia.52 Other methods utilize complex reagents45'60'64 or strongly

acidic conditions.47 The problem of long reaction times in the synthesis of oxazolines has

been solved to some extent using microwaves,42'50'54 but the reported procedures that

involve domestic ovens suffer from low reproducibility and lack general applicability.

N-Acylbenzotriazoles4 have hitherto been reported as versatile reagents for N-

acylation,5 formylation,11 trifluoroacylation,12 O-acylation,13 C-acylation,14,15 and for the

synthesis of polycyclic heteroaromatics.19 We now apply N-acylbenzotriazoles in a mild

and general procedure for the direct synthesis of 2-substituted 2-oxazolines and 2-









substituted 2-thiazolines under microwave irradiation using a single mode cavity

synthesizer3 which assures reproducibility and safety. Microwave heating has emerged as

a powerful technique to promote a variety of chemical reactions.3 65-69 Microwave

reactions are also attractive in offering reduced pollution and low cost together with

simplicity in processing and handling.70'71

3.2 Results and Discussion

3.2.1 Preparation of N-Acylbenzotriazoles.

The starting N-acylbenzotriazoles 3.1a-k with aryl or heterocyclic groups were

prepared from the corresponding carboxylic acids following the procedure described in

chapter 2.

3.2.2 Preparation of 2-Oxazolines.

Microwave reactions were performed in sealed heavy-walled Pyrex tubes under

controlled conditions in a safe and reproducible procedure. Single mode microwave

irradiation was used at a fixed temperature, pressure and irradiation power during the

reaction time by an automatic power control.


RO~ + \ reflux, CHCI 40-50% SM
RCOBt + +
R = 4-tolyl HO NH2 other side products


0H+ 0 SOC12
RT, 12h R N H R 2h,RT R N
(1:1) 70%


Scheme 3-3 Preliminary Experiments under Thermal Conditions

Optimization of the reaction conditions was carried out on the cyclocondensation of

lH-1,2,3-benzotriazol-1-yl(4-tolyl)methanone (3.1a) and 2-amino-2-methyl-l-propanol

(3.2) in chloroform and different combinations of temperature, time, and irradiation


1a) and 2-amino-2-methyl-l-propanol

(3.2) in chloroform and different combinations of temperature, time, and irradiation









power were studied in order to achieve the maximum chemical yield at the lowest

reaction temperature. Our initial microwave experiment with the mixture containing 3.1a

and 2-amino-2-methyl-l-propanol (3.2) at 80 C and 50 W irradiation power for 10 min

produced the desired oxazoline 3.3a along with the uncyclized intermediate, N-(2-

hydroxy-1,1-dimethylethyl)-4-methylbenzamide in a 2:1 ratio as determined by the 1H

NMR spectrum of the crude product mixture. SOC12 has been advantageously used for

the cyclization of such intermediates.72 Accordingly, addition of SOC12 to the above

reaction mixture and subsequent irradiation for 2 min resulted in complete conversion of

the uncyclized intermediate into 4,4-dimethyl-2-(4-methylphenyl)oxazoline (3.3a)

without the formation of side products or any noticeable decomposition. Thus, a two-step

one-pot procedure was developed for the synthesis of 2-substituted oxazolines from N-

acylbenzotriazoles under mild conditions using microwave irradiation. By contrast,

thermal reaction of 3.1a and the aminoalcohol 3.2 in refluxing chloroform for 30 min

showed the presence of substantial amounts (40-50%) of starting materials and the

formation of N-(2-hydroxy-1,1-dimethylethyl)-4-methylbenzamide along with another

side product. Stirring the reaction mixture at room temperature for 12 h resulted in a 1:1

ratio of the desired oxazoline 3.3a and the uncyclized intermediate, which, on addition of

SOC12, cyclized in 2 h to give the oxazoline 3.3a in 70% yield (Scheme 3-3). Comparison

of the above reaction conditions and results obtained suggested the use of microwave

irradiation as the energy source for the synthesis of 2-substituted 2-oxazolines from N-

acylbenzotriazoles.

The above optimized microwave reaction conditions were applied to the synthesis

of a variety of 2-substituted 2-oxazolines 3.3a-j (Table 3-1). These results illustrate the









general applicability of this method for the preparation of 2-substituted 2-oxazolines

under mild conditions (80 C) and short reaction times (12 min). Use of N-

acylbenzotriazoles also avoids some earlier observed complications in microwave

reactions, such as dimerization or the exclusive formation of amides from carboxylic

acids.5

O MicrowaveSa 0

R Bt HO NH2 R N

3.1a-j 3.2 3.3a-j
aMW, 80 W, 80 C, 10 min, CHCl3, then SOC12, MW, 2 min.

Scheme 3-4 Preparation of 2-Substituted 2-Oxazolines 3.3a-j using N-
Acylbenzotriazoles

Table 3-1 Preparation of 2-Substituted 2-Oxazolines 3.3 using N-Acylbenzotriazoles
Entry Reactants R Product
(Yield %)a
1 3.1a+3.2 4-CH3C6H4 3.3a (98)
2 3.1b+3.2 4-CH30C6H4 3.3b (95)
3 3.1c+3.2 4-NO2C6H4 3.3c (90)
4 3.1d+3.2 4-C1C6H4 3.3d (90)
5 3.1e+3.2 2-C1C6H4 3.3e (98)
6 3.1f+3.2 Phenyl 3.3f(86)
7 3.1g+3.2 1-Naphthyl 3.3g (95)
8 3.1h+3.2 2-Furyl 3.3h (95)
9 3.1i+3.2 2-Phenylethenyl 3.3i (84)
10 3.1j+3.2 1-(6-Methoxy-2- 3.3j (91)
naphthyl)ethyl
"Isolated yield.

3.2.3 Preparation of Thiazolines

The procedure developed for the synthesis of oxazolines was successfully applied

to the preparation of thiazolines. Thus, condensation of N-acylbenzotriazoles 3.1a-f,h,i

with 2-aminoethanethiol hydrochloride (3.4) in the presence of Et3N under microwave

irradiation at 80 C and 80 W irradiation power for 10 min, followed by the addition of











SOC12 and subsequent irradiation for 2 min, furnished the desired 2-substituted 2-

thiazolines 3.5a-f,h,i in excellent yields (Table 3-2). Again, no formation of any side

product was detected in the crude reaction mixtures as determined by TLC analysis and

1H NMR spectra. Our method also avoids multistep preparation of starting materials or

the requirement of special reagents.3645 56 58,60,61

R/, ~ microwaves S
HS NH2.HCI R N
3.la-f,h,i 3.4 3.5a-f,h,i

aMW, 50 W, 80 C, 10 min, Et3N, CHCl3, then SOC12, MW, 2 min.

Scheme 3-5 Preparation of 2-Substituted Thiazolines using N-Acylbenzotriazoles 3.1a-
f,h,i

Table 3-2 Preparation of 2-Substituted Thiazolines using N-Acylbenzotriazoles 3.1a-f,h,i
Entry Reactants R Product
(Yield %)"
1 3.1a+3.4 4-CH3C6H4 3.5a (95)
2 3.1b+3.4 4-CH30C6H4 3.5b (97)
3 3.1c+3.4 4-NO2C6H4 3.5c (94)
4 3.1d+3.4 4-C1C6H4 3.5d (97)
5 3.1e+3.4 2-C1C6H4 3.5e (91)
6 3.1f+3.4 Phenyl 3.5f (85)
7 3.1h+3.4 2-Furyl 3.5h (95)
8 3.1i+3.4 2-Phenylethenyl 3.5i (91)
"Isolated yield.


Further, we used this method to prepare the chiral oxazoline 3.6 by the reaction of

(2S)-2-amino-3-phenyl-l-propanol and 1H-1,2,3-benzotriazol-1-yl-phenylmethanone

(3.1f) in 82% yield. Bis-oxazoline 3.7 and -thiazoline 3.8 were prepared by the reactions

of 1,1'-(1,4-phenylenedicarbonyl)bis-1H-benzotriazole (3.1k) with 3.2 and 3.4,

respectively, in 94 and 95% yields. This procedure also works well for the preparation of

5,6-dihydro-4H-1,3-oxazines; reactions of 3.1c and 3.1d with 3-amino-1-propanol under









the similar conditions furnished 5,6-dihydro-4H-1,3-oxazines 3.9 and 3.10 in 84% and

96% yields, respectively.


0


3.6, 82% 3.7, 95%

N02

3.8, 94% 3.9, 84%


\ /N C
3.10, 96%

Figure 3-1 More Heterocycles Prepared from N-Acylbenzotriazoles



3.3 Conclusions

In summary, we have introduced a general method for the direct preparation of a

variety of 2-substituted oxazolines and -thiazolines in excellent yields from readily

available N-acylbenzotriazoles, under mild conditions using microwaves in a safe and

reproducible procedure.

3.4 Experimental Section

Melting points are uncorrected. All of the reactions under microwave irradiation

were conducted in heavy-walled Pyrex tubes sealed with aluminum crimp caps fitted with

a silicon septum. Microwave heating was carried out with a single mode cavity Discover

Microwave Synthesizer (CEM Corporation, NC, USA), producing continuous irradiation

at 2455 MHz. H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in

CDCl3 (with TMS for 1H and chloroform-d for 13C as the internal reference).









3.4.1 General Procedure for Preparing 2-Oxazolines Using N-Acylbenzotriazoles by
Conventional Method

A solution of 2-amino-2-methyl-1-propanol (3.2) (2 mmol) and 1H-1,2,3-

benzotriazol-l-yl(4-methylphenyl)methanone (3.1a) (1 mmol) in CHC13 (10 mL) was

stirred at 25 C for 12 h. SOC12 (6 mmol) was added and the reaction mixture was stirred

for 2 h. Aqueous work-up gave a residue that was purified by column chromatography on

silica gel using hexanes/ethyl acetate (3:2) to give 3.3a (70%).

3.4.2 General Procedure for Preparing 2-Oxazolines 3.3 or 2-Thiazolines 3.5 Using
N-Acylbenzotriazoles 3.1 under Microwave Irradiation

A dried heavy-walled Pyrex tube containing a small stir bar was charged with 2-

amino-2-methyl-1-propanol (3.2) or 2-aminoethanethiol hydrochloride (3.4) (2 mmol), N-

acylbenzotriazole (1 mmol) and CHC13 (0.5 mL) (reactions with 3.4 were carried out in

presence of Et3N). The tube containing the reaction mixture was sealed with an aluminum

crimp cap fitted with a silicon septum and then it was exposed to microwave irradiation

(50 W) for 10 min at a temperature of 80 C. The build-up of pressure in the closed

reaction vessel was carefully monitored and was found to be typically in the range 4-10

psi. After the irradiation, the reaction tube was cooled with high-pressure air through an

inbuilt system in the instrument until the temperature had fallen below 30 C (ca. 2 min).

SOC12 (6 mmol) was added and the reaction mixture was again exposed to microwave

irradiation (50 W) for 2 min at 80 C. After cooling to room temperature, the reaction

mixture was extracted with CHC13. Aqueous work-up gave a residue that was purified by

column chromatography on silica gel using hexanes/ethyl acetate (3:2) to give 2-

oxazolines 3.3a-j or 2-thiazolines 3.5a-i.









3.4.3 Characterization of N-Acylbenzotrizazoles 3.1g,j

1H-1,2,3-Benzotriazol-l-yl(1-naphthyl)methanone (3.1g): colorless needles

(from benzene); mp 134-136 C (Lit.5 mp 136-137 C); yield, 88%.

1-[2-(6-Methoxy-2-naphthyl)propanoyl]-1H-1,2,3-benzotriazole (3.1j):73

colorless needles (from chloroform); mp 163-165 C; yield, 95%.

3.4.4 Characterization of Oxazolines 3.3a-j

4,4-Dimethyl-2-(4-methylphenyl)-4,5-dihydro-l,3-oxazole (3.3a):74 colorless oil;

yield, 98%; 1H NMR 6 7.82 (d, J= 8.3 Hz, 2H), 7.19 (d, J= 8.3 Hz, 2H), 4.08 (s, 2H),

2.38 (s, 3H), 1.37 (s, 6H); 13C NMR 6 162.1, 141.4, 128.9, 128.1, 125.2, 79.0, 67.4, 28.4,

21.5.

4,4-Dimethyl-2-(4-methoxyphenyl)-4,5-dihydro-1,3-oxazole (3.3b):75 colorless

oil; yield, 95%; 1H NMR 6 7.88 (d, J= 8.9 Hz, 2H), 6.90 (d, J= 8.9 Hz, 2H), 4.08 (s,

2H), 3.84 (s, 3H), 1.37 (s, 6H); 13C NMR 6 161.9, 161.9, 129.9, 120.5, 113.6, 79.0, 67.4,

55.3, 28.4.

4,4-Dimethyl-2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole (3.3c):54 colorless oil;

yield, 90%; H NMR 6 8.25 (d, J= 8.4 Hz, 2H), 8.10 (d, J= 8.4 Hz, 2H), 4.16 (s, 2H),

1.40 (s, 6H); 13C NMR 6 160.2, 149.3, 133.9, 129.2, 123.4, 79.5, 68.2, 28.3.

2-(4-Chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (3.3d):76 colorless oil;

yield, 90%; 1H NMR 6 7.87 (d, J= 8.7 Hz, 2H), 7.37 (d, J= 8.7 Hz, 2H), 4.11 (s, 2H),

1.38 (s, 6H); 13C NMR 6 161.2, 137.3, 129.5, 128.5, 126.6, 79.2, 67.7, 28.4.

2-(2-Chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (3.3e):76 colorless oil;

yield, 98%; H NMR 6 7.71 (dd, J= 5.6, 1.8 Hz, 1H), 7.44-7.28 (m, 3H), 4.13 (s, 2H),

1.41 (s, 6H); 13C NMR 6 160.9, 133.3, 131.3, 131.2, 130.4, 128.0, 126.4, 79.2, 68.0, 28.2.












2-Phenyl-4,4-dimethyl-4,5-dihydro-1,3-oxazole (3.3f):74 colorless oil; yield,

86%; 1H NMR 6 7.95-7.92 (m, 2H), 7.49-7.37 (m, 3H), 4.11 (s, 2H), 1.39 (s, 6H); 13C

NMR 6 162.0, 131.1, 128.2, 128.2, 128.0, 79.1, 67.5, 28.4.

2-(1-Naphthyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (3.3g): colorless needles

(from chloroform); mp 53-540C (Lit.77 mp 56-57 oC); yield, 95%; H NMR 6 7.81-7.75

(m, 4H), 7.47-7.42 (m, 3H), 3.91 (s, 2H), 3.75 (s, 2H), 1.29 (s, 6H); 13C NMR 6 164.2,

133.5, 132.8, 132.4, 128.2, 127.6, 127.5, 126.9, 126.1, 125.7, 79.4, 67.1, 35.1, 28.3.

2-(2-Furyl)-4,5-dihydro-4,4-dimethyl-1,3-oxazole (3.3h):54 colorless oil; yield,

95%; 1H NMR 6 7.52 (d, J= 1.0 Hz, 1H), 6.92 (d, J= 3.3 Hz, 1H), 6.47 (dd, J= 3.3,

1.6 Hz, 1H), 4.08 (s, 2H), 1.38 (s, 6H); 13C NMR 6 154.5, 145.0, 143.1, 114.0, 111.4,

79.1, 67.7, 28.3.

2-(2-Phenylethenyl)-4,5-dihydro-4,4-dimethyl-1,3-oxazole (3.3i):47 colorless oil;

yield, 84%; 1H NMR 6 7.47 (dd, J= 8.0, 1.9 Hz, 2H), 7.38-7.31 (m, 4H), 6.60 (d, J=

16.2 Hz, 1H), 4.03 (s, 2H), 1.34 (s, 6H); 13C NMR 6 161.8, 139.6, 135.2, 129.3, 128.8,

127.3, 115.5, 78.8, 67.2, 28.3.

2-[1-(6-Methoxy-2-naphthalenyl)ethyl]-4,5-dihydro-4,4-dimethyl-1,3-oxazole

(3.3j): colorless needles (from chloroform); mp 101-102 oC (Lit.78 mp 103-105 oC);

yield, 91%; H NMR 6 7.72-7.69 (m, 3H), 7.41 (dd, J= 6.8, 1.6 Hz, 1H), 7.15-7.11 (m,

2H), 3.91-3.80 (m, 6H), 1.60 (d, J= 7.1 Hz, 3H), 1.29 (s, 6H); 13C NMR 6 167.8, 157.6,

136.8, 133.6, 129.3, 129.0, 127.1, 126.0, 125.7, 118.8, 105.6, 79.1, 66.9, 55.3, 39.4, 28.4,

28.2, 19.4.

3.4.5 Characterization of Thiazolines 3.5a-f,h,i

2-(4-Methylphenyl)-4,5-dihydro-1,3-thiazole (3.5a): brownish microcrystals

(from diethyl ether); mp 40-42 oC (Lit.79 mp 41-42 oC); yield, 95%; 1H NMR 6 7.72 (d,












J 8.1 Hz, 2H), 7.21 (d, J= 8.1 Hz, 2H), 4.44 (t,J 8.4 Hz, 2H), 3.40 (t, J= 8.4 Hz,

2H), 2.39 (s, 3H); 13C NMR 6 168.3, 141.4, 130.6, 129.1, 128.3, 65.1, 33.6, 21.4.

2-(4-Methoxyphenyl)-4,5-dihydro-1,3-thiazole (3.5b): colorless needles (from

chloroform); mp 51-53 oC (Lit.79 mp 53-54 oC); yield, 97%; H NMR 6 7.78 (d, J= 8.8

Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 4.42 (t, J= 8.2 Hz, 2H), 3.83 (s, 3H), 3.38 (t, J= 8.2

Hz, 2H); 13C NMR 6 167.6, 161.8, 129.9, 126.0, 113.7, 65.0, 55.3, 33.6.

2-(4-Nitrophenyl)-4,5-dihydro-1,3-thiazole (3.5c): colorless needles (from

chloroform); mp 150-152 oC (Lit.79 mp 146-148 oC); yield, 94%; H NMR 6 8.27 (d, J=

8.8 Hz, 2H), 8.00 (d, J= 8.8 Hz, 2H), 4.53 (t, J= 8.5 Hz, 2H), 3.51 (t, J= 8.5 Hz, 2H);

13C NMR 6 166.6, 149.2, 138.7, 129.2, 123.7, 65.5, 34.2

2-(4-Chlorophenyl)-4,5-dihydro-1,3-thiazole (3.5d): colorless needles (from

chloroform); mp 50-52 oC (Lit.80 mp 53-55 oC); yield, 97%; 1H NMR 6 7.77 (dd, J=

6.9, 1.8 Hz, 2H), 7.38 (dd, J 6.9, 1.8 Hz, 2H), 4.45 (t, J= 8.4 Hz, 2H), 3.43 (t, J= 8.4

Hz, 2H); 13C NMR 6 167.3, 137.1, 131.7, 129.6, 128.7, 65.2, 33.9.

2-(2-Chlorophenyl)-4,5-dihydro-1,3-thiazole (3.5e):81 colorless oil; yield, 91%;

H NMR 6 7.61 (dd, J= 5.1, 2.2 Hz, 1H), 7.44 (dd, J= 6.5, 1.5 Hz, 1H), 7.37-7.29 (m,

2H), 4.48 (t, J 8.5 Hz, 2H), 3.47 (t, J 8.5 Hz, 2H); 13C NMR 6 166.2, 133.0, 132.4,

130.9, 130.6, 130.4, 126.6, 65.1, 34.7.

2-Phenyl-4,5-dihydro-1,3-thiazole (3.5f):79 colorless oil; yield, 85%; 1H NMR 6

7.84 (d, J= 8.5 Hz, 2H), 7.47-7.41 (m, 3H), 4.47 (t, J= 8.4 Hz, 2H), 3.42 (t, J= 8.4 Hz,

2H); 13C NMR 6 168.5, 133.2, 131.1, 128.5, 128.3, 65.2, 33.6.

2-(2-Furyl)-4,5-dihydro-1,3-thiazole (3.5h):82 colorless oil; yield, 95%; 1H NMR

6 7.53 (d, J= 1.8 Hz, 1H), 6.90 (d, J= 3.4 Hz, 1H), 6.49 (dd, J= 3.4, 1.8 Hz, 1H), 4.43









(t,J 8.2 Hz, 2H), 3.40 (t,J 8.2 Hz, 2H); 13C NMR 6 157.9, 147.9, 144.8, 113.7,

111.7, 64.8, 33.4.

2-[(1E)2-Phenylethenyl]-4,5-dihydro-1,3-thiazole (3.5i): colorless needles (from

chloroform); mp 91-93 oC (Lit.83 mp 94-95 oC); yield, 91%; H NMR 6 7.50 (d, J= 7.7

Hz, 2H), 7.40-7.35 (m, 3H), 7.15-7.01 (m, 2H), 4.38 (t,J= 8.1 Hz, 2H), 3.35 (t,J= 8.1

Hz, 2H); 13C NMR 6 168.0, 141.3, 135.3, 129.4, 128.8, 127.5, 122.6, 64.6, 33.0.

3.4.6 Characterization of Miscellaneous Heterocycles 3.6, 3.7, 3.8, 3.9, 3.10

(4S)-4-Benzyl-2-phenyl-4,5-dihydro-1,3-oxazole (3.6):84 prepared by the reaction

of (2S)-2-amino-3-phenyl-1-propanol and 3.1f according to the general procedure;

colorless oil; yield, 82%; [a]D20 = -12 (c = 1.53, CHC13); 1H NMR 6 7.97-7.93 (m, 2H),

7.50-7.37 (m, 3H), 7.33 -7.19 (m, 5H), 4.63-4.53 (m, 1H), 4.36-4.30 (m, 1H), 4.13 (dd,

J = 8.5, 7.3 Hz, 1H), 3.23 (dd, J= 13.5, 5.0 Hz, 1H), 2.72 (dd, J= 13.5, 8.9 Hz, 1H), 13C

NMR 6 163.9, 137.9, 131.3, 129.2, 128.6, 128.5, 128.1, 127.7, 126.4, 71.8, 67.8, 41.8.

2,2'-(1,4-Phenylene)bis[4,5-dihydro-4,4-dimethyl-1,3-oxazole] (3.7):47 prepared

by the reaction of 3.2 (2 equiv) and 3.1k (1 equiv) according to the general procedure;

colorless oil; yield, 95%; 1H NMR 6 7.97 (s, 4H), 4.13 (s, 4H), 1.40 (s, 12H); 13C NMR 6

161.6, 130.5, 128.2, 79.2, 67.8, 28.4.

2,2'-(1,4-Phenylene)bis[4,5-dihydro-1,3-thiazole] (3.8):81 prepared by the

reaction of 3.4 (2 equiv) and 3.1k (1 equiv) according to the general procedure; colorless

needles (from chloroform); mp 106-108 oC; yield, 94%; 1H NMR 6 7.88 (s, 4H), 4.49 (t,

J 8.4 Hz, 4H), 3.45 (t, J 8.5 Hz, 4H); 13C NMR 6 167.8, 135.5, 128.4, 65.3, 33.8.

2-(4-Nitrophenyl)-5,6-dihydro-4H-1,3-oxazine (3.9): prepared by the reaction of

3-amino-1-propanol and 3.1c according to the general procedure; colorless needles (from









chloroform); mp 143-144 oC (Lit.8 mp 145-146 oC); yield, 84%; H NMR 6 8.22-8.19

(m, 2H), 8.07-8.03 (m, 2H), 4.40 (t, J= 5.5 Hz, 2H), 3.65 (t, J= 5.8 Hz, 2H), 2.01 (qn, J

S5.8 Hz, 2H); 13C NMR 153.8, 148.9, 139.9, 127.8, 123.1, 65.4, 42.8, 21.7.

2-(4-Chlorophenyl)-5,6-dihydro-4H-1,3-oxazine (3.10):86 prepared by the

reaction of 3-amino-1-propanol and ld according to the general procedure; colorless oil;

yield, 96%; 1H NMR 6 7.84-7.80 (m, 2H), 7.35-7.30 (m, 2H), 4.35 (t, J= 5.5 Hz, 2H),

3.59 (t, J= 5.8 Hz, 2H), 1.97 (qn, J= 5.8 Hz, 2H); 13C NMR 6 154.7, 136.3, 132.6, 128.3,

128.2, 65.2, 42.6, 21.8.














CHAPTER 4
PREPARATION OF SECONDARY AND TERTIARY AMIDES UNDER
MICROWAVE IRRADIATION

4.1 Introduction

Secondary and tertiary amides are mostly prepared by the treatment of activated

derivatives of acids, such as acid halides, acid anhydrides, or esters, with primary and

secondary amines. Reactions of amines with acid halides are highly exothermic. Acid

anhydrides, especially cyclic anhydrides, give imides easily with primary amines.

Acylations of primary and secondary amines by esters frequently require strongly basic

catalysts and/or high pressure. N-Acylbenzotriazoles have been used to prepare primary,

secondary and tertiary amides, but some of the reactions under conventional conditions

require several hours (4-5 h) for completion.5 Meanwhile, there have been few successful

attempts to obtain amides from unreactive N-acylbenzotriazoles (alkylacylbenzotriazoles)

and amines (especially arylamines and bulky secondary amines). In this dissertation,

microwave conditions have been used to produce the desired secondary and tertiary

amides by the reactions of primary and secondary amines with readily available N-

acylbenzotriazoles.

4.2 Results and Discussion

We have now developed microwave conditions that produced the desired secondary

and tertiary amides by the reactions of a variety of primary amines with readily available

N-acylbenzotriazoles. Thus, amides 4.1a-Ac, 4.2a-b were obtained in 87-96% yields in

10 min under microwave irradiation (Table 4-1, Figure 4-1). Microwave reactions were









performed in a 50 mL round-bottomed flask equipped with a reflux condenser for

4.1a-Ac or a 10 mL sealed tube for 4.2a-b. Single-mode microwave irradiation was used

at a fixed temperature, pressure and irradiation power during the reaction time using an

automatic power control.


microwaves
R1COBt + R2NH2 -


0

WR1A NR2
H
4.1 a-Ac


Scheme 4-1. Microwave Preparation of Secondary Amides 4.1a-Ac Using N-
Acylbenzotriazoles


Table 4-1. Microwave Preparation of Secondary Amides 4.1
Acvlbenzotriazolesa


Using N-


Entry R1 R2 Product Mp (oC) Lit. Mp
(Yield %)b (0C)
1 Cyclohexyl p-Tolyl 4.1a (96) 154-156 144.7-145
2 Phenyl 2-Pyridyl 4.1b (91) 77-78 82
3 Benzyl Benzyl 4.1c (90) 115-117 117-118
4 Benzyl p-Tolyl 4.1d (91) 133-135 135-137
5 Phenethyl p-Tolyl 4.1e (92) 127-129 129-130
6 p-Chlorophenyl p-Tolyl 4.1f (91) 206-209 213-215
7 p-Methoxyphenyl Benzyl 4.1g (89) 128-130 128-129
8 p-Nitrophenyl Benzyl 4.1h (96) 136-137 141-142
9 2-Furyl p-Tolyl 4.1i (96) 108-110 109-110
10 n-Hexyl p-Tolyl 4.1j (93) 77-79 78-79
11 Phenyl 2-Furylmethyl 4.1k (90) 96-98 99-100
12 2-Furyl Cyclohexyl 4.11(94) 106-107 110-111
13 p-Tolyl p-Tolyl 4.1m (91) 158-160 158-160
14 Phenethyl Benzyl 4.1n (93) 80-82 82-83
15 Phenyl p-Methoxyphenyl 4.1o (88) 156-157 157-158
16 p-Nitrophenyl Phenyl 4.1p (95) 206-208 211
17 p-Tolyl n-Butyl 4.1q (92) 52-54 48-53
18 2-Thienyl p-Tolyl 4.1r (89) 103-105 104-105
19 2-Thienyl Benzyl 4.1s (92) 116-118 119-120
20 2-Thienyl 2-Furylmethyl 4.1t (92) 100-102 Novel
21 2-Indolyl Benzyl 4.1u (93) 218-220 220
22 Phenyl Benzyl 4.1v (92) 101-103 105-106
23 p-Phenylene Benzyl 4.1w (92) 262-264 264-266
24 p-Phenylene n-Butyl 4.1x (92) 230-232 233-234









Table 4-1 Continued
Entry R1 R Product Mp (C) Lit. Mp
(Yield %)b (oC)
25 Methyl p-Tolyl 4.1y (93) 150-152 153
26 Ethylene Phenyl 4.1z (94) 250-252 254
27 Phenylethenyl p-Tolyl 4.1Aa(87) 156-158 159
28 Phenylethenyl Benzyl 4.1Ab(92) 107-109 107-110
29 p-Tolyl Methyl 4.1Ac(92) 143-145 143-144
aMW, 80 W, 80 oC, 10 min, CHC13. "Isolated yield.

0o 0
N- N NJ


4.2a, 95% 4.2b, 96%

Figure 4-1. Tertiary Amides Obtained from N-Acylbenzotriazoles under Microwave
Irradiation

4.3 Conclusion

In summary, various secondary and tertiary amides were prepared in high yields in

10 min under microwave irradiation.

4.4 Experimental Section

4.4.1 General Procedure for the Preparation of Amides 4.1a-Ac

For amides 4.1a-v,y, the N acylbenzotriazole (10 mmol) and amine (10.5 mmol) in

chloroform (10 mL) were exposed to microwave irradiation (80 W) for 10 min at a

temperature of 80 oC. The reaction mixture was diluted with chloroform (20 mL).

Aqueous work-up gave a residue that was purified by recrystallization (from chloroform

or ethanol) or column chromatography to obtain amides 4.1a-v,y. For amides 4.1w-x, the

N acylbenzotriazole (10 mmol) and amine (21.0 mmol) in chloroform (10 mL) were

exposed to microwave irradiation (80 W) for 10 min at a temperature of 80 oC. The

resulting white solid was filtered off and recrystalized from methanol to obtain amides









4.lw-x. For amide 4.1z, the N-acylbenzotriazole (21 mmol) and amine (10 mmol) in

chloroform (10 mL) were exposed to microwave irradiation (80 W) for 10 min at a

temperature of 80 TC. The resulting white solid was filtered off and recrystalized from

methanol to obtain amide 4.1z. For amides 4.1Aa-Ab, the N-acylbenzotriazole (12

mmol) and amine (10 mmol) in chloroform (10 mL) were exposed to microwave

irradiation (80 W) for 10 min at a temperature of 80 TC. The reaction mixture was diluted

with chloroform (20 mL). Aqueous work-up gave a residue that was purified by

recrystallization (from methanol) or column chromatography to obtain amides 4.1Aa-Ab.

4.4.2 Characterizations of Amides 4.1

N-(4-Methylphenyl)cyclohexanecarboxamide (4.1a). 1-(Cyclohexylcarbonyl)-

1H-1,2,3-benzotriazole (2.29 g, 10 mmol) and 4-methylaniline (1.12 g, 10.5 mmol) in

chloroform (10 mL) were exposed to microwave irradiation (80 W) for 10 min at a

temperature of 80 TC. The reaction mixture was diluted with chloroform (20 mL). The

reaction mixture was washed by concentrated sodium carbonate solution (20 mL, twice)

and brine (20 mL). The organic layer was dried over magnesium sulfate. After filtration,

CHCl3 was removed under reduced pressure to yield the crude product which was further

purified by recrystallization from chloroform/hexanes to obtain colorless plates: mp 154-

156 oC (lit.87 mp 144.7-145 oC); yield, 96% (2.08 g); 1H NMR 6 1.24-1.35 (m, 2H),

1.46-1.58 (m, 2H), 1.69 (m, 1H), 1.80-1.83 (m, 2H), 1.91-1.93 (m, 2H), 2.16-2.25 (m,

1H), 2.30 (s, 3H), 7.09 (d, J -8.1 Hz, 2H), 7.35 (br s, 1H), 7.40 (d, J = 8.1 Hz, 3H); 13C

NMR 6 (1 signal is hidden) 20.7, 25.6, 29.6, 46.4, 119.9, 129.3, 133.6, 135.5, 174.3.

N-Pyridin-2-ylbenzamide (4.1b): purified by recrystallization from methanol,

white microcrystals; mp 77-78 oC (lit.88 mp 82 oC); yield, 91% (1.80 g); 1H NMR









(DMSO-d6) 6 5.93 (br s, 1H), 6.42-6.48 (m, 2H), 7.33-7.38 (m, 1H), 7.50 (td, J= 7.4,

0.6 Hz, 2H), 7.62 (td, J= 7.1, 0.9 Hz, 1H), 7.89 (dd, J= 4.1, 0.8 Hz, 1H), 7.96 (dd, J

7.5, 0.8 Hz, 2H); 13C NMR (DMSO-d6) 6 108.1, 111.8, 128.5, 129.3, 130.9, 132.8, 137.1,

147.4, 159.7, 167.5.

N-Benzyl-2-phenylacetamide (4.1c): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 115-117 C (lit.89 mp 117-118 C); yield,

90% (2.03 g); 1HNMR 6 3.56 (s, 2H), 4.36 (d, J 5.9 Hz, 2H), 6.07 (br s, 1H), 7.15

7.34 (m, 10H); 13C NMR 6 43.4, 43.6, 127.2, 127.3, 127.4, 128.5, 128.9, 129.3, 134.8,

138.1, 170.9.

N-(4-Methylphenyl)-2-phenylacetamide (4.1d): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 133-135 C (lit.90 mp 135-137 C); yield,

91% (2.05 g); 1HNMR 6 2.27 (s, 3H), 3.68 (s, 2H), 7.06 (d, J= 8.1 Hz, 2H), 7.24-7.39

(m, 8H); 13C NMR 6 20.7, 44.5, 120.1, 127.4, 129.0, 129.3, 129.4, 134.0, 134.7, 135.1,

169.2.

N-(4-Methylphenyl)-3-phenylpropanamide (4.1e): purified by recrystallization

from chloroform/hexanes; white microcrystals; mp 127-129 oC (lit.91 mp 129-130 C);

yield, 92% (2.20 g); 1HNMR 6 2.28 (s, 3H), 2.58 (t, J= 7.8 Hz, 2H), 3.01 (t, J= 7.6 Hz,

2H), 7.07 (d, J= 8.1Hz, 2H), 7.18-7.36 (m, 8H); 13C NMR 6 20.8, 31.6, 39.3, 120.1,

126.3, 128.3, 128.6, 129.4, 133.9, 135.2, 140.7, 170.4.

4-Chloro-N-(4-methylphenyl)benzamide (4.1f): purified by recrystallizztion from

methanol; yellow needles; mp 206-209 oC (lit.92 mp 213-215 oC); yield, 91% (2.24 g);

1HNMR (DMSO-d6) 6 2.27 (s, 3H), 7.15 (d, J= 8.1 Hz, 2H), 7.59 (d, J= 8.2 Hz, 2H),


2H),









7.64 (d, J= 8.1 Hz, 2H), 7.97 (d, J= 8.1 Hz, 2H), 10.24 (s, 1H); 13C NMR (DMSO-d6) 6

20.5, 120.5, 128.4, 129.0, 129.5, 132.8, 136.4, 164.2.

4-Methoxy-N-phenylbenzamide (4.1g): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 128-130 oC (lit.93 mp 128-129 oC); yield,

89% (2.15 g); 1HNMR 6 3.82 (s, 3H), 4.60 (d, J= 4.5 Hz, 2H), 6.57 (br s, 1H), 6.89 (d, J

= 7.4 Hz, 2H), 7.25-7.33 (m, 5H), 7.75 (d, J= 8.8 Hz, 2H); 13C NMR 6 44.0, 55.3,

113.7, 126.6, 127.4, 127.8, 128.7, 128.8, 138.4, 162.1, 167.0.

N-Benzyl-4-nitrobenzamide (4.1h): purified by recrystallization from

chloroform/hexanes; pale yellow microcrystals; mp 136-137 oC (lit.93 mp 141-142 oC);

yield, 96% (2.46 g); 1H NMR 6 4.64 (d, J= 5.6 Hz, 2H), 6.68 (s, 1H), 7.26-7.36 (m, 5H),

7.94 (d, J -8.6 Hz, 2H), 8.26 (d, J -8.6 Hz, 2H); 13C NMR 6 44.4, 123.8, 127.9, 127.9,

128.2, 128.9, 137.4, 139.9, 149.5, 165.3.

N-(4-Methylphenyl)-2-furamide (4.1i): purified by recrystallization from

chloroform/hexanes; yellow needles; mp 108 110 oC (lit.94 mp 109-110 oC), yield, 96%

(1.93 g); 1H NMR6 2.34 (s, 3H), 6.56 (dd, J= 3.4, 1.8 Hz, 1H), 7.17 (d, J= 8.2 Hz,

2H), 7.20 (d, J= 3.3 Hz, 1H), 7.50 (dd, J= 1.6, 0.7 Hz, 1H), 7.54 (d, J= 8.4 Hz, 2H),

8.03 (br s, 1H); 13C NMR 6 20.8, 112.4, 114.9, 119.9, 129.5, 134.0, 134.7, 144.0, 147.8,

156.0.

N-(4-Methylphenyl)heptanamide (4.1j): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 77-79 oC (lit.95 mp 78-79 oC); yield, 93%

(2.04 g); 1HNMR 6 0.88 (t, J= 6.5 Hz, 3H), 1.31-1.37 (m, 6H), 1.65-1.72 (m, 2H), 2.30

(s, 3H), 2.31-2.35 (m, 2H), 7.09 (d, J= 8.2 Hz, 2H), 7.38 (d, J= 8.2 Hz, 2H), 7.40 (br s,


br s,









1H); 13C NMR 6 14.0, 20.8, 22.5, 25.6, 28.9, 31.5, 37.7, 120.0, 129.4, 133.7, 135.4,

171.5.

N-(2-Furylmethyl)benzamide (4.1k): purified by recrystallization from

chloroform/hexanes; yellow microcrystals; mp 96-98 oC (lit.96 mp 99-100 'C); yield,

90% (1.81 g); 1HNMR 6 4.61 (d, J = 5.5 Hz, 2H), 6.26-6.33 (m, 2H), 6.73 (br s, 1H),

7.35-7.42 (m, 3H), 7.46-7.50 (m, 1H), 7.79 (dd, J= 7.1, 1.5 Hz, 2H); 13C NMR 6 36.9,

107.6, 110.4, 127.0, 128.5, 131.5, 134.1, 142.2, 151.2, 167.2.

N-Cyclohexyl-2-furamide (4.11): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 106-107 oC (lit.94 mp 110-111 oC); yield,

94% (1.81 g); 1H NMR 6 1.18-1.31 (m, 3H), 1.35-1.47 (m, 2H), 1.62-1.78 (m, 3H),

1.97-2.01 (m, 2H), 3.89-3.96 (m, 1H), 6.21 (br s, 1H), 6.49 (dd, J= 3.6, 1.8 Hz, 1H),

7.09 (dd, J= 3.4, 0.8 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H); 13C NMR 6 24.8, 25.5, 33.1,

47.8, 112.0, 113.8, 143.5, 148.3, 157.4.

4-Methyl-N-(4-methylphenyl)benzamide (4.1m): purified by recrystallization

from chloroform/hexanes; white plates; mp 158-160 oC (lit.92 mp 158-160 oC); yield,

91% (2.05 g); 1H NMR 6 2.31 (s, 3H), 2.38 (s, 3H), 7.12 (d, J= 8.2 Hz, 2H), 7.21 (d, J

8.2 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 8.03 (s, 1H); 13C NMR 6

20.8, 21.4, 120.3, 127.0, 129.2, 129.4, 132.1, 133.9, 135.4, 142.0, 165.7.

N-Benzyl-3-phenylpropanamide (4.1n): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 80-82 oC (lit.97 mp 82-83 oC); yield, 93%

(2.22 g); 1H NMR 6 2.57 (d, J = 7.6 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 4.43 (d, J = 5.8

Hz, 2H), 5.99 (br s, 1H), 7.18-7.38 (m, 10H); 13C NMR 6 31.6, 38.3, 43.4, 126.2, 127.3,

127.6, 128.3, 128.5, 138.1, 140.7, 172.0.









N-(4-Methoxyphenyl)benzamide (4.1o): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 156-157 oC (lit.94 mp 157-158 oC); yield,

88% (2.0 g); 1HNMR 6 3.81 (s, 3H), 6.90 (d, J= 9.2 Hz, 2H), 7.44-7.56 (m, 5H), 7.84

7.87 (m, 3H); 13C NMR 6 55.5, 114.2, 122.1, 127.0, 128.7, 130.9, 131.7, 135.0, 156.6,

164.9.

4-Nitro-N-phenylbenzamide (4.1p): purified by recrystallization from methanol;

yellow needles; mp 206-208 oC (lit.98 mp 211 oC); yield; 95% (2.30 g); 1H NMR

(DMSO-d6) 6 7.58 (t, J= 7.3 Hz, 2H), 7.66 (t, J= 7.2 Hz, 1H), 8.02 (dd, J= 7.0, 1.5 Hz,

2H), 8.11 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H), 10.8 (s, 1H); 13C NMR (DMSO-

d6) 6 119.8, 124.8, 128.0, 128.5, 132.2, 134.3, 142.4, 145.6, 166.3.

N-Butyl-4-methylbenzamide (4.1q): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 52-54 oC (lit.99 mp 55-57 oC); yield, 92%

(1.76 g); 1HNMR 6 0.93 (t,J 7.3 Hz, 3H), 1.34-1.41 (m, 2H), 1.52-1.60 (m, 2H), 2.37

(s, 3H), 3.38-3.45 (m, 2H), 6.51 (br s, 1H), 7.19 (d, J= 8.1 Hz, 2H), 7.68 (d, J= 8.1 Hz,

2H); 13C NMR 6 13.7, 20.1, 21.3, 31.6, 39.6, 126.8, 129.0, 131.9, 141.5, 167.4.

N-(4-Methylphenyl)thiophene-2-carboxamide (4.1r): purified by

recrystallization from chloroform/hexanes; white microcrystals; mp 103-105 oC (lit.94 mp

104-105 oC); yield, 89% (1.97 g); 1H NMR 6 2.34 (s, 3H), 7.12 (td, J 4.4, 1.2 Hz, 1H),

7.17 (d,J 8.2 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 7.54 (dd, J= 4.9, 1.2 Hz, 1H), 7.61

(dd, J 3.7, 1.2 Hz, 1H), 7.64 (br s, 1H); 13C NMR 6 20.9, 120.3, 127.8, 128.3, 129.6,

130.6, 134.3, 135.0, 139.3, 159.9.

N-Benzylthiophene-2-carboxamide (4.1s): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 116-118 C (lit.100 mp 119-120 oC); yield,









92% (2.00 g); 1H NMR (DMSO-d6) 4.48 (d, J -5.9 Hz, 2H), 7.16 (t, J= 4.0 Hz, 1H),

7.23-7.34 (m, 5H), 7.76 (d, J= 4.9 Hz, 1H), 7.85 (d, J 3.6 Hz, 1H), 9.08 (t, J= 5.8 Hz,

1H); 13C NMR 6 (DMSO- d6) 42.5, 126.8, 127.2, 127.9, 128.1, 128.3, 130.8, 139.5,

139.9, 161.1.

N-(2-Furanylmethyl)-2-thiophenecarboxamide (4.1t): purified by

recrystallization from chloroform/hexanes; yellow needles; mp 100-102 C; yield, 92%

(1.90 g); 1HNMR 6 4.62 (d,J 5.5 Hz, 2H), 6.30-6.35 (m, 3H), 7.07 (td, J= 4.4, 1.1

Hz, 1H), 7.29 (s, 1H), 7.38 (d, J= 0.8 Hz, 1H), 7.48 (dd, J= 4.9, 1.0 Hz, 1H); 13C NMR

6 36.6, 107.4, 110.3, 127.5, 128.3, 130.1, 138.6, 141.9, 151.1, 161.9. Anal. Calcd for

CloH9NO2S: C, 57.95; H, 4.38; N, 6.76. Found: C, 57.93; H, 4.28; N, 6.84.

N-Benzyl-1H-indole-2-carboxamide (4.1u): purified by recrystallization from

methanol; white microcrystals; mp 224-226 oC (lit.100 mp 230 oC); yield, 88% (2.20 g);

1HNMR (DMSO-d6) 6 4.52 (d,J 6.0 Hz, 2H), 7.03 (t,J 7.4 Hz, 1H), 7.15-7.28 (m,

3H), 7.34-7.35 (m, 4H), 7.43 (d, J= 8.2 Hz, 1H), 7.61 (d, J= 8.0 Hz, 1H), 9.05 (t, J=

5.9 Hz, 1H), 11.62 (s, 1H); 13C NMR (DMSO- d6) 6 42.1, 102.6, 112.3, 119.7, 121.5,

123.3, 126.8, 127.1, 127.2, 128.3, 131.6, 136.5, 139.6, 161.1.

N-Benzylbenzamide (4.1v): purified by recrystallization from

chloroform/hexanes; white microcrystals; mp 101-103 oC (lit.101 mp 105-106 oC ); yield,

92% (1.94 g); 1HNMR 6 4.63 (d, J= 5.8 Hz, 2H), 6.57 (br s, 1H), 7.25-7.51 (m, 8H),

7.79 (dd, J= 7.7, 1.4Hz, 2H); 13C NMR 6 44.1, 126.9, 127.5, 127.9, 128.5, 128.7, 131.5,

134.3, 138.2, 167.3.

N,N'-Dibenzylterephthalamide (4.1w): purified by recrystallization from

methanol; white microcrystals; mp 262-264 oC (lit.102 mp 264-266 oC); yield, 92% (3.16









g); 1H NMR (DMSO-d6) 6 0.91 (t, J= 7.3 Hz, 6H), 1.29-1.39 (m, 4H), 1.47-1.56 (m,

4H), 3.24-3.30 (m, 4H), 7.90 (s, 4H), 8.56 (s, 2H); 13C NMR (DMSO- d) 6 13.7, 19.7,

31.2, 127.1, 136.8, 165.4.

N,N'-Dibutylterephthalamide (4.1x): purified by recrystallization from methanol;

white microcrystals; mp 230-232 C (lit.103 mp 233-234 C); yield, 96% (2.65 g); 1H

NMR (DMSO-d6) 6 0.91 (t, J= 7.3 Hz, 6H), 1.29-1.39 (m, 4H), 1.47-1.56 (m, 4H),

3.24-3.30 (m, 4H), 7.90 (s, 4H), 8.56 (s, 2H); 13C NMR (DMSO- d6)6 13.7, 19.7, 31.2,

39.2, 127.1, 136.8, 165.4.

N-(4-Methylphenyl)acetamide (4.1y): purified by recrystallization from

chloroform/hexanes; pale yellow microcrystals; mp 150-152 oC (lit.104 mp 153 oC); yield,

94 % (1.40 g); 1H NMR 6 2.14 (s, 3H), 2.30 (s, 3H), 7.10 (d, J= 8.1 Hz, 2H), 7.37 (d, J

S8.4 Hz, 2H), 7.57 (br s, 1H); 13C NMR 6 20.8, 24.4, 120.1, 129.4, 133.9, 135.3, 168.5.

N,N'-Dibenzoylethylenediamine (4.1z): purified by recrystallization from

methanol; white microcrystals; mp 250-252 oC (lit.105 mp 254 oC); yield, 94% (2.52 g);

1HNMR (DMSO-d6) 6 3.45-3.46 (m, 4H), 7.44 7.55 (m, 6H), 7.85 (d, J = 7.0 Hz, 4H),

8.62 (s, 2H); 13C NMR (DMSO-d6) 6 40.1, 127.2, 128.3, 131.1, 134.5, 166.6.

N-(4-Methylphenyl)-3-phenyl-2-propenamide (4.1Aa): purified by

recrystallization from methanol; white microcrystals; mp 156-158 oC (lit.106 mp 159 oC);

yield, 87% (2.06 g); 1HNMR (DMSO- d6) 6 2.27 (s, 3H), 6.84 (d, J= 15.7 Hz, 1H), 7.15

(d, J= 8.4 Hz, 2H), 7.41-7.48 (m, 4H), 7.56-7.61 (m, 3H), 7.62 (d, J= 15.6 Hz, 1H),

7.92 (br s, 1H); 13C NMR (DMSO-d) 6 20.5, 119.2, 122.4, 127.7, 129.0, 129.2, 129.7,

132.3, 134.8, 136.8, 139.9, 163.3.









3-Phenyl-N-(phenylmethyl)-2-propenamide (4.1Ab): purified by column

chromatography on basic alumina with ethyl acetate/hexanes (5:1) as eluent; white

microcrystals (from chloroform/hexanes); mp 107-109 TC (lit.107 mp 107-110 TC); yield,

92% (2.18 g); 1HNNMR 6 4.58 (d, J= 5.8 Hz, 2H), 5.95 (br s, 1H), 6.42 (d, J = 15.5 Hz,

1H), 7.29-7.37 (m, 8H), 7.48-7.51 (m, 2H), 7.68 (d, J= 15.5 Hz, 1H); 13C NMR 6 43.9,

120.3, 127.6, 127.8, 127.9, 128.8, 128.8, 129.7, 134.7, 138.1, 141.5, 165.7.

N,4-Dimethylbenzamide (4.1Ac): purified by recrystallization in

chloroform/hexanes; colorless needles; mp 143-145 TC (lit.10s mp 143-144 TC); yield,

92% (2.73 g); 1H NMR 6 2.38 (s, 3H), 2.98 (dd, J = 4.8, 0.7 Hz, 3H), 6.47 (br s, 1H),

7.20 (d, J= 8.9 Hz, 2H), 7.67 (d, J 8.9 Hz, 2H); 13C NMR 6 21.3, 26.7, 126.8, 129.1,

131.7, 141.6, 168.2.

4.3.3 Preparation of Amides 4.2

In a sealed tube equipped with a magnetic stir bar was put N-acylbenzotriazole (1

mmol) and secondary amine (1.5 mmol). The reaction mixture was exposed to

microwave irradiation (120 W) at 120 oC for 5 min. The reaction mixture was then

dissolved in methylene chloride (20 mL). The solution was washed by concentrated

sodium carbonate solution (15 mL x 2) and brine (10 mL). After that the organic layer

was dried over magnesium sulfate. Evaporating the solvent yielded the crude product

which was further purified by recrystallization in chloroform/hexanes to give pure amides

4.2a-b.

4.4.4 Characterization of Amides 4.2

4-(4-Methylbenzoyl)-morpholine (4.2a): purified by recrystallization in

chloroform/hexanes; white microcrystals; mp 71-73 TC (lit.109 mp 72-74 oC); yield, 95%






37


(0.195 g); H NMR 6 2.38 (s, 3H), 3.55 (br s, 4H), 3.70 (br s, 4H), 7.21 (d, J 8.0 Hz,

2H), 7.31 (d,J 8.1 Hz, 2H); 13C NMR (one signal is hidden) 6 21.3, 66.9, 127.2, 129.1,

132.3, 140.0, 170.6.

4-(Benzylcarbonyl)-morpholine (4.2b): purified by recrystallization in

chloroform/hexanes; mp 62-64 C (lit.110 mp 62.5-64 oC); yield, 96% (0.197 g); 1H NMR

6 3.43-3.48 (m, 4H), 3.64 (s, 4H), 3.73 (m, 2H), 7.23-7.35 (m, 5H); 13C NMR 6 40.8,

42.0, 46.4, 66.4, 66.7, 126.8, 128.5, 128.7, 134.7, 169.5.














CHAPTER 5
DIRECT SYNTHESIS OF ESTERS AND AMIDES FROM UNPROTECTED
HYDROXY-AROMATIC AND -ALIPHATIC CARBOXYLIC ACIDS

5.1 Abstract

In a joint project together with postdoctoral researcher Sanjay K. Singh, a facile

method for the activation of hydroxy substituted carboxylic acids using benzotriazole

chemistry without prior protection of the hydroxy substituents is presented. The N-

acylbenzotriazole intermediates 5.2a-g,5.6a-d,5.9a-c have been used for high yielding

synthesis of both aliphatic 5.3a-1 and aromatic 5.7a-h,5.10a-f hydroxy carboxamides.

High yields of aromatic hydroxy esters 5.12a-h,5.13a-i were obtained using either neat

alcohols in neutral microwave conditions or nucleophilic alkoxides and the intermediate

N-(arylacyl)benzotriazoles. Moderate yields were obtained in case of aliphatic hydroxy

esters 5.11a-b and thiolesters lle-g from the intermediates 5.2a-c.

5.2 Introduction

The protection of an ancillary functional group while a transformation is being

carried out at a different site in the molecule, followed by de-protection to regenerate the

functionality, is frequently employed in organic synthesis. Various protecting groups are

employed for a wide variety of functional groups.111, 112

Esters, thiolesters, and amides of hydroxy carboxylic acids are important synthetic

targets. Conventional methods for their preparation from the corresponding hydroxy acid

requires initial protection of the hydroxyl group (as an ester, ketal or acetonide)

conversion to the esters, thiolester or amide111' 112 and subsequent deprotection.









Conventional activation of a carboxyl group using thionyl chloride or oxalyl chloride

cannot be safely employed in the presence of a free hydroxy group. The use of

diazocompounds is limited by their explosive character, lack of generality and toxicity.113

Several peptide coupling reagents (HBTU,114 BOP,115 PyBOP,116 DEPC,117

EDC/BtOH118'119) enable direct coupling of free hydroxy N-protected amino acids [HO-

R(NHP)-COOH HO-R(NHP)-CONHR' ]. However strictly anhydrous conditions are

required and activated acid intermediates frequently cannot be stored, handled in moist

air or even isolated. The carboxylic group of amino acid providing the NH for the

coupling reaction frequently has to be esterified to make it soluble in a non aqueous

solvent.

Aromatic amides and esters have been synthesized by in situ activation of hydroxy

acids using carbodiimide (EDC, DCC)/BtOH,120 Mitsunobu121' 122 conditions

(PPh3/DEAD) or CDI mediated coupling.123 EDC/BtOH/base has been employed in the

direct syntheses of simple amides from hydroxy acids.124-126 Again the reaction requires

strictly anhydrous conditions. A few reports directly transform a-hydroxy acids into

simple a-hydroxy esters using boric acid,127 but require a large excess of the alcohol.

N-Acylbenzotriazoles are versatile synthetic equivalents of acyl halides. They exist

as stable solids at ambient conditions with moderate reactivity, which can be regulated.

Appropriate N-acylbenzotriazoles affect formylation11 and trifluoroacylation.12

Regiospecific C-acylation of pyrrole and indoles1 and the synthesis of oxamides,26 1,3-

diketones,14 polycyclic heteroaromatics,19 Weinreb amides128 and N-protected dipeptides

and tripeptides have been reported. In the case of peptides, protection of ancillary

functional groups (hydroxy, thiol, imidazole-NH, indole-NH, amide and carboxylic acid)










in the amino acid monomers were not required.7'10 Herein we utilize benzotriazole

chemistry in direct synthesis of simple esters, thiolesters and amides from unprotected

hydroxy -aliphatic and -aromatic acids. The use of this methodology provides an

economically viable alternative to the various peptide coupling agents.

5.3 Results and Discussion

5.3.1 Preparation of Hydroxy Carboxamides from Aliphatic Hydroxy Acids

Hydroxy amides are anti-convulsants129 (u-hydroxy amides), thrombin inhibitors130

and RAR-y specific retinoid agonists131 (c-hydroxy amides). They are intermediates for

the synthesis of oxazolidinediones,132 oxindoles133 (a-hydroxy amides), P-lactams134 (3-

hydroxy amides), antidepressant drugs, e. g. (R)-fluoxetine (P-hydroxy amides) and

building blocks for the synthesis of various natural products.135

Common syntheses (Scheme 5-1) are a) from epoxy amides136 b) from keto

amides,137-140 c) from a carbonyl and a nucleophile containing the amide,141, 142 d) from

hydroxy acids.143-145

0 0 0 0
NR' N'R'

n=O R" OH R" R
R.J N. R' n=0,1,2,3

OH 0 d0
H n=0,1,2,3 R + NR'
^ OH R HI
R"
n=0,1,2,3

Scheme 5-1 Synthesis of Hydroxy Carboxamides

Attempted one-pot conversions of a-hydroxy acids to hydroxy carboxamides, via

the bis-trimethylsilyl derivative followed by conversion to acid chloride and treatment

with the appropriate amine, sometimes leads to the formation of a-chloro amide143. Other


43. Other









direct syntheses of the hydroxy amides have been achieved when the ancillary alcohol is

sterically hindered. 130 N-Sulfinyl anilines have been used to synthesize a-hydroxy N-aryl

secondary amides from a-hydroxy acids.143, 144 The syntheses of two a-hydroxy amides

(N-arylamides) using N-(1-methanesulfonyl)benzotriazole have been reported from our

laboratories,5 but there was no generalization of the methodology. The preparative

method described in chapter 2 for the synthesis of acyl benzotriazoles enabled us to

successfully expand the method to include a wide variety of substrates.

The benzotriazole methodology was applied for direct synthesis of known and

novel hydroxy amides 5.3a-1 from hydroxy acids 5.1a-g (Fig. 5-1, Scheme 5-2 and Table

5-1). Attempts to isolate and purify the intermediate N-(hydroxyacyl)benzotriazoles

5.2a-g showed that most are unstable unlike non-functionalized N-acylbenzotriazoles.

The N-acylbenzotriazole derivative 5.2c of(+) mandelic acid 5.1c was isolated in 25%

yields by flash column chromatography. The 1H and 13C spectra supported the structure,

depicting the amide carbon at 6 171.8, but the compound was not stable enough for

elemental analysis. Formation of the N-acylbenzotriazoles 5.2a-g conducted in THF or

dichloromethane is completed in 2h and is accompanied by the formation of an insoluble

solid. However, the crude N-(hydroxyacyl)benzotriazoles 5.2a-g could be used directly.

The supernatant containing N-(hydroxyacyl)benzotriazole was either syringed out or

filtered to remove the accompanying solid and the filtrate used in further reactions.

The crude intermediate N-(hydroxyacyl)benzotriazoles 5.2a-g were treated with

primary and secondary amines and the amides 5.3a-1 obtained in varying yields (Scheme

5-2 and Table 5-1). The a-hydroxy acids 5.1a-c gave high yields of secondary 5.3a, 5.3c,

5.3e and tertiary 5.3b, 5.3d, 5.3f amides.










Y O OH OH
zOH O


5.1a, Z= PhY= H, X = OH 5., Mandelic acid 5.
5.1b, Z= Y= CH3, X = OH 5.1c, Mandelic acid 5.1e
5.1d, Z = Cyclohexyl, Y = OH, X = Ph
0

OH



H 5" = iX
5.1f, X = Y = H, Lithocholic acid
5.1g, X = Y = OH, Cholic acid

Figure 5-1 Hydroxy Acids 5.1

0
O
HO-A OH A = C, C2, 3, Cn
S5.1a-g

O O O
HOA, NR'R"-- HOA Bt HO'A XR'
5.3a-I 5.2a-g 5.11a-d, X = O
5.11e-g, X= S

Scheme 5-2 General Reactions to Derivatives of Hydroxy Carboxylic Acid

The use of aryl boronic acids145 for the synthesis of 5.3c has been reported for the

case of ca-hydroxy acids (entry 3, Table 5.1). The synthesis of compounds 5.3e and 5.3f

have been reported from their alkyl esters; the conditions employed involved either high

temperatures phenylethylaminee reflux)132 or pressure146 (8 kbar) (see entries 5 and 6,

Table 5-1). The benzotriazole method was extended for the syntheses of secondary

amides 5.3j and 5.3k (entries 7 and 8; Table 5-1) of P-hydroxy acid 5.1d. However, the

synthesis of tertiary amines from 3-hydroxy acid presented difficulties and mixtures were

obtained. For y-hydroxy acid 5.1e, competitive intramolecular lactonization 5.4 was

preferred over the formation of amide 5.3i (Scheme 5-3). Mono or poly hydroxyl bile










acids like lithocholic acid 5.1f or cholic acid 5.1g, that find application as gelating agents,

presented no complications to this method. Use of this simple benzotriazole route was

comparable to that of a peptide coupling agent DEPC 117 (diethylphosphoryl cyanide) in

case of 5.31 (entry 12, Table 5-1). The various amides synthesized are depicted in the

Table 5-1.

Table 5-1. Synthesis of Hydroxy Carboxamides 5.3 from Aliphatic Hydroxy Acids 5.1a-
g.*
Comp. Amine Utilized Prod. Yield Mp
R' R"
1 la CH3(CH2)2CH2- H 5.3a 72 46-47
2 la CH3(CH2)6CH2- CH3- 5.3b 75 42-43
3 Ib PhCH2- H 5.3c 60 (96)' 84-85
4 Ib -CH2CH2CH(Ph)CH2CH2- 5.3d 61 103-104
5 ic PhCH2CH2- H 5.3e 68 (83)" 100-101
6 ic -CH2(CH2)2CH2- 5.3f 77 (96)' 94-95
7 Id PhCH2- H 5.3g 75 139-140
8 ld CH2:CHCH2- H 5.3h 62 97-98
9 le -CH2(CH2)2CH2- 5.3i ---
10 If CH3(CH2)3CH2- H 5.3j 85 182-183
11 If -CH2(CH2)2CH2- 5.3k 93 167-168
12 1g PhCH2CH(COOCH3)- H 5.31 66 (70)e Gel
"Using 3,4,5-trifluorobenzeneboronic acid,'4 'from the ethyl ester,132 'from the
methyl ester,146 dlactone 5.4 formed, 'using (DEPC).117
The experimental part in this table was carried out by Dr. Sanjay K. Singh.

0
0

OH HN-N THF
OH N 5.4
O + + S O Cd 2 H.4
5.le OH
N- N


5.3i

Scheme 5-3. Unsuccessful Synthesis of Y -Hydroxyacylbenzotriazole 5.3i









5.3.2 Preparation of Hydroxyaromatic Amides from Hydroxyaromatic Acids.

Various amides of substituted salicyclic and naphthoic acids exhibit biological

activity such as anthelmintic activity,147 anti plaque agents.148 The bis-naphthoic amides

are used for the generation of chiral BINOL149,150 reagents and other hydroxy amides are

important intermediates in synthetic organic chemistry.

Common approaches towards the synthesis of amides involve treatment of

activated derivatives of acids, especially halides, acid anhydrides, or esters, with the

corresponding amine. Phenyl esters of salicyclic acid have been effectively used,151

however their synthesis from salicylic acids requires harsh conditions.152 Yet another

indirect method for the synthesis of o-hydroxyaromatic amides would be via ortho-

aminocarbonylation of the alkali metal salts of phenols153'154 with isocyanates in high

boiling solvents or under highly basic conditions at very low temperatures.155,156

O NRR'
OH

S a O NRR' b
OH


SOH
0O
O NRR'

Scheme 5-4. Literature Methods of Synthesis of the o-Hydroxynaphthyl Amides

The various methods of synthesis of the o-hydroxynaphthyl amides (Scheme 5-4)

are, a) from ortho amino carbonylation of naphthols;1557 b) ortho hydroxylations of

naphthyl amides;158'159 c) 42% yielding metal-mediated oxidative cyclization of

appropriately substituted aryl keto amides;160 d) from o-hydroxynaphthoic acids using

halogenating agents like PC13,161 SOC12162 (used only in case of 2-hydroxy-3-naphthoic


oic









and 1-hydroxy-2-naphthoic acids) and diimides163 The indirect routes are harsh,157 low

yielding160 or require very low temperatures.155-159 The limitations associated with these

and other methods for the synthesis of amides have been discussed elsewhere.5

The salicyl amides 5.7a-h were synthesized efficiently from the N-

acylbenzotriazole derivatives 5.6a-d of the corresponding salicylic acids 5.5a-d (Scheme

5-5 and Table 5-2). Most of the intermediates 5.6a-d could be isolated easily and were

stable on silica gel at ambient conditions. They were characterized by 1H and 13C NMR

spectra and elemental analysis. A similar attempt with 2-hydroxy-l-naphthoic acid 5.8a

(Scheme 5-6) gave a rather unstable N-acylbenzotriazole 5.9a that reacted with

atmospheric water forming the acid 5.8a, and with methanol giving the methyl ester

5.13a. Pure 5.9a could, however, be isolated in about 25% yield by flash chromatography

on silica gel and characterized spectrascopically and by elemental analysis (the singlet for

the free hydroxyl group was observed at 6 10.72 in 1H NMR and the carbonyl was

observed at 6 167.3 in the 13C NMR spectra). Similarly, analytically pure samples of 5.9b

and 5.9c were obtained by careful recrystallization from dichloromethane. These samples

could be stored under refrigerated conditions without apparent decomposition. As for

aliphatic acids, purification of the intermediate was not necessary. The supernatant

containing the N-acylbenzotriazole could be used for further reactions.

Various primary and secondary amines (3 equiv) were treated with the N-

acylbenzotriazoles 5.6a-d (Scheme 5-5) in the presence of triethyl amine (5 equiv) in

THF (4 mL/mmol) (Method A) to give a series of known and novel secondary and

tertiary amides 5.7a-h (Table 5-2). The reactions were very rapid and the unprotected

hydroxyl groups caused no complications. The products could be isolated in over 90%









purity after the initial work up. Hardly surprisingly, a sterically demanding amine gave

no yield (entry 9, Table 5-2) of the desired product while the other amines gave very high

yields. These compounds gave satisfactory proton and carbon NMR data and also

elemental analysis. The various amides synthesized from derivatives of salicylic acid are

presented in Table 5-2. This methodology could be extended to the o-hydroxynaphthoic

acids 5.8a-c. Various secondary and tertiary amides 5.10a-f were synthesized (Scheme

5-6) in good yields. In case of synthesis of amides from poorly nucleophilic aromatic

amines, microwave conditions (Method B) were required to obtain good yields (see entry

6 in Table 5-2; see entry 1 in Table 5-3).

OH O

S-IOH

X 5.5a-d


OH OHO OH O

S N'R R Bt OR
S R'
X: X
5.7a-g 5.6a-d 5.12a-h

Scheme 5-5. Preparation of Amides and Esters from Salicyclic Acids
O O
0 0








HOH OH
5 OH
5.9a, 96% 5.9b, 95% 5.9c, 92%


Figure 5-2. Preparation of Hydroxy N-Acylbenzotriazoles









Table 5-2. The Synthesis of Substituted Salicylamides 5.7a-h (a, X = H; b, X
Y = AWT. A Y = '2_1\/


= 5-Br; c,


IYI_ "-Vlli, U- I J- -VI.
Com R' R" Method Product Yield (%) MpC
1 5a furfuryl H A 5.7a* 83 (97)a 109-110
2 5a -(CH2)5- A 5.7b* 94 (69) 142-143
3 5b n-pentyl H A 5.7c 84 54-55
4 5b n-octyl CH3 A 5.7d* 82 92-93
5 5c n-pentyl H A 5.7e* 96 125-126
6 5c phenyl CH3 B 5.7f 93 150-152
7 5c -(CH2)2-O-(CH2)2- B 5.7g 94 179-181
8 5d CH3(CH3)CH(CH2)2- H A 5.7h* 93 Oil
61 4 *


Reported yield using phenyl salicylate.

Table 5-3. The Synthesis of Amides 5.10


Compound was prepared by Sanjay K. Singh


Comp. R' R" Method Product Yield MpC
(%)
1 5.8a Phenyl H B 5.10a 90 171-172
2 5.8a -(CH2)5- A* 5.10b 93 242-243
3 5.8b PhCH2CH2- H A 5.10c 94 125-126
4 5.8b -(CH2)4- A 5.10d 97 93-94
5 5.8c CH2:CH-CH2- H A 5.10e 75 (85)' 121-122
6 5.8c -(CH2)20(CH2)2- A* 5.10f 73 216-217
'Using thionyl chloride.210 Compound was prepared by Sanjay K. Singh

5.3.3 Preparation of Aliphatic a-Hydroxycarboxylic Esters and Thiolesters from a-
Hydroxy Acids

a-Hydroxy esters are important building blocks for synthesis of natural products.

Common methods for their syntheses are a) from hydroxy Fischer carbenes,165 b)

selective opening of the epoxy esters,166 c) via a-chloroglycidic esters,167 d) oxidation of

metal enolates,168 e) reduction of the appropriate keto esters,169'170 f) the glyoxalate-ene

reaction171 and g) direct transformation of the a-hydroxy acid127 as displayed in Scheme

5-7. However, there has been one report for direct transformation of a-hydroxy acid to

simple a-hydroxy esters using boric acid,127 but this requires reaction times of 18 h. a-

Hydroxycarboxy thiolesters have received less attention although they are amenable to

several functional group transformations172, 173 are bio-active in the areas of anti-tumor










and glyoxalase I inhibitor174 and protect the unstable thio moiety while masking the

undesired odor175 of the free thiol.


I ju-HCOOH
5.8a-c



OH OH )OH
h o CONR'R"-- COBt -C c OO

5.10a-f 5.9a-c 5.13a-i
5.8a: 2-hydroxy-1-naphthoic acid, 5.8b :1-hydroxy-2-naphthoic acid, 5.8c: 2-hydroxy-3-
naphthoic acid

Scheme 5-7. Preparation of Amides and Esters from Naphthoic Acids

OH
OH
ONMe4 R H
R"OH + CO + 0 0
R Cr(CO)5 R' 0
I T + R, + H "COOEt
OH
b 1, ,OR"
0 R e O
OR" 0 .OR"
R O/ d R O

R OM

R'+ X
H
C12CHCOOPr-i

Scheme 5-8. Synthesis of a-Hydroxy Carboxylic Esters

Reported syntheses of a-hydroxy thiolesters are a) the Pinner reaction (average

yield: 62%, 13 examples)176 b) from a-chloro thioesters177 (average yield: 56%, 16

examples, restricted to 2-aminothiols derivatives of a, a-diaryl-a-chloro acids) c)

ozonolysis of thiophene substituted Henry adduct (58%, 1 example)178 d) rearrangement

of the glyoxal-thiol adduct (average yield: 63% for 2 steps, 7 examples).179,180 e) from









organo-aluminum reagents (90%, 1 example)181 f) via oxaborolidine mediated reduction

of a-phenyl thioenones followed by ozonolysis (average yield: 44%, 3 steps, 5

examples)182 and g) via pummerer reaction of 1,3-dithiane-1,3-dioxide derivatives (70%

yield, 3 steps, enantioselective).172 The processes displayed in the scheme (Scheme 5-7)

suffer from drawbacks. Some are restricted to thiophenol esters (path c, f), some very

specific (path b: R = Ar, R'= Ar, Path e : R" = SC(CH3)3), some involve the use of

toxic/harsh conditions (path a, c, f), while most are muti-step syntheses (paths a, c, d, f,

g). Weinreb181 has reported only one example of direct synthesis of a-hydroxy-t-butyl

thiol ester from mandelic acid using organo-aluminum reagent while the synthesis from

a-halo thiolester salts (not commercially available) is not general as discussed

elsewhere. 177



Anhydrous HX S O OS S P HP

R"SH R OP OH 0
HO+ CN HO NH.HX a f R R R
R R R' R RS

R S b HO SRe" HO
R SR" R R Ph H 0

R-CHO OH 0 R H
+ RH SPh c R SR" + O
02N H NO2 OH R"-SH
SPh

Scheme 5-9. Synthesis of Hydroxy Carboxylic Thiolesters

Visibly from the two schemes (Schemes 5-8 and 5-9), synthesis of a-hydroxy thiol

esters does not analogously follow that of a-hydroxy esters. It should be noted that

modified reducing agents cannot be employed in case of hydroxy thiol esters due to labile


gents cannot be employed in case of hydroxy thiol esters due to labile









nature of the CO-S bond. A mild, direct one-step procedure, devoid of protection /

deprotection operations, to synthesize both the esters from a single starting material

would be a useful tool in the syntheses of compound libraries.

As in the case with the synthesis of hydroxy amides, dropwise addition through a

syringe of the supernatant benzotriazolating mixture and the hydroxy acid 5.1a-f, (Fig. 5-

1) to a mixture of the sodium salt of the alcohol or thiol (Scheme 5-2) at room

temperature, ensured the formation of the hydroxy carboxylic ester 5.11a-b or thiolester

5.11e-g (Table 5-4). Two known esters and three novel thiol esters were synthesized

using this method. Attempts to increase the yield of esters by treating the N-(a-

hydroxyacyl)benzotriazoles 5.1a, 5.1b using more nucleophilic aromatic phenoxides

failed. Use of neutral microwave conditions could not rectify this. Attempts to increase

the yield of thiolesters by refluxing the N-(c-hydroxyacyl)benzotriazole 5.1a-c with the

sodium salt of thiol led to decomposition. Conducting the reactions at 0 OC also did not

improve the yield. This method provides a mild protocol for the synthesis of both esters

and thiolesters from one starting material, which is a desirable property for the synthesis

of library compounds.

Table 5-4 Synthesis of Hydroxy Esters 5.11a-b and Thiolesters 5.11e-g*
Comp. R'OH X Prod. Yield (%) Mp
1 5.1c MeOH O 5.11a 40 (99)a 56-57
2 5.1c EtOH O 5.11b 72 (93) 35-36
3 5.1b PhOH O 5.11c Mix ---
4 5.1a p-Methoxyphenol O 5.11d Mix ---
5 5.1a hexanethiol S 5.11e 37 Oil
6 5.1c 4-methoxythiophenol S 5.11f 23 Oil
7 5.1b benzylthiol S 5.11g 24 69-70
"Using boric acid.127 Using concentrated sulphuric acid.
*Experimental part was carried by Sanjay K. Singh









5.3.4 Preparation of Aromatic Esters from Substituted o-Hydroxy Aromatic Acids.

Salicylihalamide,121 lasiodiplodin,122 and neocarzinostatin184 are biologically active

salicylic and hydroxy naphthoic esters. Salicylic acids have been esterified using large

excesses of the alcohol and/or strong acid,185 or bases.186 Stereo-specific Mitsunobu

conditions122'187 have also been used in total syntheses. A tertiary amine and the

appropriate activated halide188'189 esterify salicylic acids, but requires high temperatures.

o-Hydroxynaphthoic esters are not common in the literature. The few reports which

deal with their synthesis from the corresponding acids, usually involve a) strongly acidic

conditions190 for simple esters, b) use of toxic diazomethane,191 c) use of LiOH with

DMS192 d) the use of carbodiimides193-196 that gives the urea side product or e) multi-step

low yielding oxidative cyclization using Mn(III) and Ce(IV)160 to form the second

aromatic ring. Zengin197 esterified 2-hydroxy-1-naphthoic acid in 90% yield using DCC

in pyridine with a catalytic amount ofp-toulenesufonic acid in the presence of excess

methanol, but the study dealt with only one example. The methods described above and

other methods for the esterification of o-hydroxyaromatic acids usually lack

generality,192,198 involve sensitive reagents,199,200 are low yielding201 or lead to

intersubstrate esterification.202 There is an obvious need for a general, efficient, gentle

and high yielding process.

N-Acylbenzotriazoles 5.6a-d of various salicylic acids 5.5a-d were synthesized

using the SOC12/BtH mixture Scheme 5.5. Esterification was achieved by the dropwise

addition of the supernatant to sodium methoxide in methanol over 30 min (Method A) to

give the methyl ester 5.12a and 5.13a in 94 and 85% yield respectively (Scheme 5-6).

Alternatively, avoiding basic conditions, the esters could be synthesized by heating

the crude concentrated N-acylbenzotriazoles with 4 equiv of the appropriate neat alcohol









for 10 min under microwave (method B). The esters were obtained in good yields. Allyl

alcohols (entry 4, Table 5-5 and entry 8, Table 5-6) or the presence of a triple bond

(entries 3 and 7, Table 5-6) caused no concerns. Both primary and secondary alcohols

were used. A series of mostly novel esters 5.12a-g and 5.13a-i were synthesized using

the methods described above and the results are presented in Tables 5-5 and 5-6. This

method provides an alternative mild high yielding method for the synthesis of o-hydroxy

esters from o-hydroxyaryl carboxylic acids.

Table 5-5 Synthesis of Esters 5.12
Compd. ROH Method Product Yield (%) Mp
1 5.5a Cyclopentanol B 5.12a 92 Oil
2 5.5a 1-Penten-3-ol B 5.12b 87 Oil
3 5.5b Ethanol B 5.12c 90 46-48
4 5.5b Cyclopentanol B 5.12d 91 45-47
5 5.5c n-Propanol B 5.12e 87 32-34
6 5.5c Cyclopentanol B 5.12f 91 Oil
7 5.5d CH3(CH2)8CH20H B 5.12g 89 Oil

Table 5-6 The Synthesis of Esters 5.13
Compd. ROH Method Product Yield (%) Mp
1 5.8a Cyclopentanol B 5.13a 94 Oil
2 5.8a 4-Pentyn-l-ol B 5.13b 87 Oil
3 5.8a Ethanol B 5.13c 95 (62)b 56-58
4 5.8b Ethanol B 5.13d 95 46-48
5 5.8b Cyclopentanol B 5.13e 94 61-63
6 5.8b 4-Pentyn-l-ol B 5.13f 91 65-67
7 5.8b 1-Penten-3-ol B 5.13g 91 Oil
8 5.8c n-Butanol B 5.13h 90 Oil
"Using p-TsOH.H20/DCC/Py.197 bOxidative cyclization.160

In conclusion, we have developed an economically viable alternative method for

the activation of carboxylic acids in presence of free hydroxy groups without their prior

protection. The syntheses of amides in case of both aliphatic and aromatic hydroxy acids

were high yielding. The hydroxy aromatic esters were synthesized in high yields both

under basic and neutral conditions (microwave), while yields for the synthesis of esters









and thiolesters from corresponding hydroxy acids were low. While in conventional direct

synthesis, the activation of the hydroxy acid is performed in situ, we have been able to

separate the activation step from the nucleophilic substitution, thereby contributing to

higher flexibility in reaction conditions and substrates. The major advantage of this

methodology lies in the synthesis of aromatic amides and esters where in the intermediate

N-(o-hydroxyaryl)benzotriazoles are stable isolable solids that can be treated under

neutral conditions with the appropriate alcohol or amine.

5.4 Experimental Section

5.4.1 General

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

NMR spectra were recorded in CDC13 (unless specified as DMSO-d6), with TMS as the

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

MHz). Microwave heating was carried out with a single mode cavity Discoverer

Microwave Synthesizer (CEM Corporation, NC), producing continuous irradiation at

2455 MHz. THF was dried over sodium/benzophenone and used freshly distilled.

Column chromatography was conducted on silica gel 200-425 meshes. The compounds

5.1a,203 5.1b,204 5.1d205 and 5.1e206 were synthesized from reported procedures.

Compounds 5.1c, 5.1f, 5.1g and salicylic acid/o-hydroxy naphthoic acid derivatives are

available commercially.

5.4.2 General Procedure for the Synthesis of Hydroxy Carboxamides 5.3 from
Hydroxy Acids 5.1

To 6.3 mmols (750 mg) of benzotriazole in 12 mL of freshly dried THF or

methylene chloride was added 2 mmol of SOC12 (0.148 mL) under an atmosphere of

argon. The mixture was allowed to stir at room temperature for 45 min before the rapid









addition of the hydroxy acids (5.1a-f, 2 mmol) in 8 mL of freshly dried THF / methylene

chloride through a syringe while under inert atmosphere. The formation of a white solid

was observed and the reaction mixture was stirred for 2 h at room temperature. The

supernatant contains the N-(hydroxyacyl)benzotriazole. The stirring was stopped after 2

hours for the suspension to settle down for easy removal of the supernatant.

In a separate round bottom flask the appropriate amine (6 mmol) and triethyl amine

(6 mmol) were taken in 2 mL of freshly dried THF. The supernatant of the

benzotriazolating mixture / hydroxy acid was carefully syringed out and added dropwise

to this mixture while stirring under an inert atmosphere. The residual solid was washed

with 5 mL of dry THF and the washings added to the amines. After 30 min the reaction

mixture was concentrated under vacuum to remove the solvent and triethyl amine. The

brown residue was taken in ether (25 mL) and the organic layer washed with IN HC1 (2 x

25 mL), saturated sodium carbonate (until benzotriazole is not observed on TLC), brine,

dried over magnesium sulphate and concentrate under vacuum. The residue was refined

by flash chromatography over silica gel to give the respective hydroxy amides (5.3a-1).

5.4.3 Characterization of Hydroxy Amides 5.3

N-Butyl-2-hydroxy-3-phenylpropionamide (5.3a): white powder from ethyl

acetate/hexanes; mp 46-47 C; yield, 72%; IR (neat) v = 3334, 2936, 2863, 1624, 1468

cm1; 1H NMR 6 7.35-7.23 (m, 5H), 6.42 (br s, 1H), 4.28 (dt, J= 8.4, 4.4 Hz, 1H), 3.28-

3.19 (m, 2H + H, A part of AB system PhCH2), 2.90 (dd, J= 8.2, 6.9 Hz, 1H, B part of

AB system), 2.56 (d, J= 4.7 Hz, 1H), 1.49-1.40 (m, 2H), 1.35-1.23 (m, 2H), 0.91 (t, J=

7.3 Hz, 3H); 13C NMR 6 172.3, 136.8, 129.5, 128.7, 127.0, 72.8, 41.0, 38.8, 31.5, 20.0,










13.7. Anal. Calcd for C13H19N02: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.92; H, 9.01;

N, 6.34.

2-Hydroxy-N-methyl-N-octyl-3-phenylpropionamide (5.3b): white plates from

ethyl acetate/hexanes; mixture of rotamers, mp 42-43 C; yield, 75%; IR (neat) v = 3499,

2929, 2874, 1653, 1495 cm-1; 1H NMR 6 7.32-7.20 (m, 5H), 4.59-4.51 (m, 1H), 3.75 (d,

J 8.2 Hz, 0.5 H), 3.66 (d, J= 8.2 Hz, 0.5H), 3.49-3.11 (m, 2H), 2.96-2.77 (m, 3H),

2.94 (s, 1.5H, NCH3), 2.95-2.84 (m, 2H), 2.80 (s, 1.5 H, NCH3), 1.53-1.48 (m, 2H),

1.28-1.26 (m, 10H), 0.88 (t, J 6.6 Hz, 3H); 13C NMR 6 173.5, 173.3, 137.0, 136.9,

129.3, 129.2, 128.4, 128.3, 126.7 (2C), 69.0 (2C), 49.8, 48.5, 42.3, 41.8, 34.3, 33.4,

31.7(2C), 22.6, 22.5, 29.3, 29.2, 29.1 (2), 28.0, 26.9, 26.8, 26.6, 14.0 (2C). Anal. Calcd

for C18H29N02: C, 74.18; H, 10.03; N, 4.81. Found: C, 74.49; H, 10.29; N, 4.72.

N-Benzyl-2-hydroxy-3-methylbutyramide (5.3c):145 white amorphous powder

from hexanes/ethyl acetate; mp 84-85 C; yield, 60%; IR (neat) v = 3355, 2968, 2925,

1626, 1542, 1018 cm1; 1HNMR 6 7.36-7.26 (m, 5H), 6.78 (br s, 1H), 4.50 (dd, J=

14.7, 8.7 Hz, 1H, A part of AB system), 4.45 (dd, J= 14.7, 8.7 Hz, 1H, B part of AB

system), 4.03 (dd, J= 5.1, 3.2 Hz), 2.60 (br d, J= 5.2 Hz, 1H), 2.26-2.16 (m, 1H), 1.03

(d, J= 7.0 Hz, 3H), 0.87 (d, J= 6.7 Hz, 3H); 13C NMR 6 173.0, 138.0, 128.7, 127.8,

127.6, 76.4, 43.2, 31.9, 19.1, 15.4. Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N,

6.76. Found: C, 69.62; H, 8.44; N, 6.92.

1-(4-Benzylpiperidin-l-yl)-2-hydroxy-3-methylbutan-l-one (5.3d): mixture of

isomers, white amorphous powder from ethyl acetate/hexanes; mp 103-104 C; yield,

61%; IR (neat) v = 3417, 2962, 2870, 1634, 1494, 1022 cm-1; 1HNMR 6 7.32-7.26 (m,

2 H), 7.23-7.18 (m, 1H), 7.16-7.12 (m, 2H), 4.62-4.55 (m, 1H), 4.24-4.22 (m, 1H),










3.74-3.67 (m, 2H), 3.00-2.88 (m, 1H), 2.64-2.49 (m, 3H), 1.84-1.69 (m, 4H), 1.23-1.13

(m, 2H), 1.09-1.03 (m, 3H), 0.82-0.75 (m, 3H); 13C NMR 6 172.2, 172.1, 139.7, 139.6,

129.0 (2C), 128.3 (2C), 126.1 (2C), 71.9, 71.8, 45.4, 45.0, 43.0, 42.9, 42.8 (2C), 38.2,

38.1, 32.5, 32.2, 31.9, 31.7, 31.6, 31.3, 19.8 (2C), 14.9, 14.7. Anal. Calcd for C17H25N02:

C, 74.14; H, 9.15; N, 5.09. Found: C, 74.31; H, 9.47; N, 5.05.

2-Hydroxy-N-phenethyl-2-phenylacetamide (5.3e):132 white powder from ether;

mp 100-101 'C; yield, 68%; IR (neat) v = 3378, 1655, 1602, 1061 cmi1; 1H NMR

6 7.39-7.19 (m, 8H), 7.03-7.00 (m, 2H). 6.06 (br s, 1H), 4.95 (d, J= 3.3 Hz, 1H), 3.70

(d, J = 3.4 Hz, 1H), 3.56 (sextet, J = 6.6 Hz, 1H), 3.45 (sextet, J = 6.6 Hz, 1H), 2.82-

2.66 (m, 2H); 13C NMR 6 172.1, 139.4, 138.4, 128.8, 128.7, 128.6, 126.8, 126.5, 74.0,

40.7, 35.5. Anal. Calcd for C16H17N02: C, 75.27; H, 6.71; N, 5.49. Found: C, 74.91; H,

6.75; N, 5.55.

2-Hydroxy-2-phenyl-l-pyrrolidin-1-yl-ethanone (5.3f):207 white powder from

ether; mp 94-95 'C; yield, 77%; IR (neat) v = 3384, 2971, 2877, 1634, 1066 cm 1; 1H

NMR 6 7.39-7.30 (m, 5H), 5.04 (d, J = 6.0 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 3.66-

3.35 (m, 3H), 2.89-2.81 (m, 1H), 1.93-1.68 (m, 4H); 13C NMR 6 170.6, 138.9, 128.9,

128.4, 127.7, 72.6, 46.5, 45.8, 25.9, 23.7.

N-Benzyl-3-cyclohexyl-3-hydroxy-2-phenylpropionamide (5.3g): white

amorphous powder from ethyl acetate/hexanes; mp 139-140 'C; yield, 75%; IR (neat) v

= 3287, 2925, 2851, 1640, 1545, 1030 cm1; 1H NMR 6 7.37-7.23 (m, 8H), 7.14-7.11 (m

2H), 5.96 (br t, J= 6.2 Hz, 1H), 4.45 (dd, J= 15.0, 5.9 Hz, 1H, A part of AB system),

4.34 (dd, J= 15.0, 5.9 Hz, 1H, B part of AB system), 4.06 (br d, J= 4.4 Hz, 1H), 4.01-

3.96 (m, 1H), 3.61 (d, J= 8.0 Hz, 1H), 1.71-0.98 (m, 11H); 13C NMR 6 174.1, 137.8,









137.4, 129.0, 128.6, 128.4, 127.6, 127.4 (2C), 77.4, 55.2, 43.4, 39.8, 30.4, 26.3 (2C),

26.0, 25.8. Anal. Calcd for C22H27N02: C, 78.30; H, 8.06; N, 4.15. Found: C, 78.28; H,

8.19; N, 4.22.

N-Allyl-3-cyclohexyl-3-hydroxy-2-phenylpropionamide (5.3h): white needles

from hexanes/ethyl acetate, mp 97-98 C; yield, 62%; IR (neat) v = 3301, 2926, 2852,

1640, 1544, 1033 cm-1; 1HNMR 6 7.39-7.27 (m, 5 H), 5.81-5.68 (m, 1H), 5.63 (br t, J

5.3 Hz, 1H), 5.06 (dq, J 8.0 Hz, 1.4 Hz, 1H), 5.01 (dq, J 16.6, 1.6 Hz, 1H), 4.13 (br

d, J= 4.0 Hz, 1H), 4.02-3.97 (m, 1H), 3.86-3. 82 (m, 2H), 3.59 (d, J= 8.2 Hz, 1H),

1.73-0.97 (m, 11 H); 13C NMR 6 174.1, 137.5, 133.7, 129.1, 128.5, 127.6, 116.2, 77.3,

55.1, 41.7, 39.8, 30.5, 26.4, 26.3, 26.0, 25.6. Anal. Calcd for C18H25NO2: C, 75.22; H,

8.77; N, 4.87. Found: C, 75.57; H, 8.91; N, 5.00.

N-Lithocholyl-n-pentyl amide (5.3j): white needles from ether; mp 182-183 C;

yield, 85%; IR (neat) v = 3288, 2929, 2863, 1646, 1555, 1041 cm-1; 1H NMR 6 5.44 (brt,

J 6.5 Hz, 1H), 3.68-3.58 (m, 1H), 3.23 (q,J 6.9 Hz, 2H), 2.28-2.18 (m, 1H), 2.10-

0.84 (m, 43H), 0.64 (s, 3H); 13C NMR 6 173.5, 71.8, 56.5, 56.0, 42.7, 42.0, 40.4, 40.1,

39.5, 36.4, 35.8, 35.5, 35.3, 34.5, 33.7, 31.8, 30.5, 29.4, 29.0, 28.2, 27.2, 26.4, 24.2, 23.3,

22.3, 20.8, 18.4, 14.0, 12.0. Anal. Calcd for C29H51N02: C, 78.14; H, 11.53; N, 3.14.

Found: C, 77.85; H, 11.92; N, 3.07.

N-Lithocholyl pyrrolidine amide (5.3k):208 white needles from ether; mp 167-

168 C; yield, 93%; IR (neat) v = 3406, 2934, 2863, 1626, 1446, 1041 cm-1; H NMR

6 3.62 (m, 1H), 3.46 (t, J= 6.87 Hz, 2H), 3.42 (t, J= 6.73 Hz, 2H), 2.36-2.1 (m, 2H),

1.97-0.92 (m, 37H), 0.64 (s, 3H); 13C NMR 6 172.2, 71.7, 56.4, 56.0, 46.5, 45.6, 42.7,

42.0, 40.4, 40.1, 36.4, 35.8, 35.5, 35.3, 34.5, 31.7, 30.9, 30.5, 28.2, 27.1, 26.4, 26.1, 24.4,












24.2, 23.3, 20.8, 18.5, 12.0. Anal. Calcd for C28H47NO2: C, 78.27; H, 11.02; N, 3.26.

Found: C, 77.90; H, 11.39; N, 3.28.

N-Cholyl-D-phenylglycine methyl ester (5.31):117 white amorphous solid from

methanol/dichloromethane; yield, 66%; IR (neat) v = 3420, 2953, 2866, 1746, 1654,

1522 cm1; 1HNMR 6 7.36-7.31 (m, 5H), 6.91 (d,J 7.3 Hz, 1H), 5.58 (d, J= 7.1 Hz,

1H), 3. 93 (br s, 1H), 3.80-3.64 (m, 2H), 3.70 (s, 3H), 3.80 (br s, 3H, OH), 3.40 (br s,

1H), 2.39-0.74 (m, 25 H), 0.95 (d, J= 5.5 Hz, 3 H), 0.86 (s, 3H), 0.62 (s, 3H); 13C NMR

6 173.3, 171.5, 136.5, 128.8, 128.3, 127.3, 73.0, 71.7, 68.4, 56.3, 53.4, 52.7, 46.5, 46.3,

41.5, 41.3, 39.3, 35.2, 34.6, 34.4, 32.7, 31.2, 30.1, 27.9, 27.5, 26.2, 23.2, 22.3, 17.3, 12.3.

5.4.4 Synthesis of o-Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9

According to the procedure described in Chapter 2, hydroxy N-acylbenzotriazoles

(5.6a-d, 5.9a-c) were prepared in high yields. Due to the poor solubility of 5.6c in

methylene chloride, the solvent being used for this particular reaction was THF. To the

substituted salicylic and o-hydroxy naphthoic acids (5.5c, 5.8a-c 2 mmol) in 10 mL of

freshly dried THF/methylene chloride was added 6.3 mmols (750 mg) ofbenzotriazole

and 2 mmol of SOC12 (0.148 mL) in 20 mL of freshly dried THF/methylene chloride. The

mixture was allowed to stir at room temperature for 1 h. The formation of a white solid

was observed. The solid was filtered out and washed with copious methylene chloride (or

THF for 5.6c). The crude product was obtained after removal of the solvent under

reduced pressure. Further purification of the crude product by recrystallization yielded

pure N-acylbenzotriazoles (5.6a-d, 5.9a-c) in 91-96% yield.










5.4.5 Characterization of o-Hydroxy Aryl Acyl Benzotriazoles 5.6 and 5.9

Benzotriazol-l-yl-(2-hydroxyphenyl)methanone (5.6a): pale yellow needles

from diethyl ether (96%); mp 115-116 C; IR (neat) v = 3385 (br), 1648, 1479, 1449 cm

1; HNMR 6 10.81 (s, 1H), 8.61 (dd, J= 8.3, 1.5 Hz, 1H), 8.32 (d, J= 8.2 Hz, 1H),

8.18 (d, J= 8.1 Hz, 1H), 7.72 (t,J 7.3 Hz, 1H), 7.64-7.53 (m, 2H), 7.13 (d, J= 8.5 Hz,

1H), 7.06 (t, J= 7.3 Hz, 1H); 13C NMR 6 169.2, 163.6, 145.4, 137.1, 133.8, 132.4, 130.5,

126.5, 120.4, 119.6, 118.4, 114.9, 113.5. Anal. Calcd for C13H9N302: C, 65.27; H, 3.79;

N, 17.56. Found: C, 65.51; H, 3.70; N, 17.51.

Benzotriazol-l-yl-(5-bromo-2-hydroxyphenyl)methanone (5.6b): yellow

needles from diethyl ether (91%), mp 108-109 C; IR (neat) v = 3122, 1651, 1483, 1451

cm-1; 1H NMR (DMSO-d6) 6 10.67 (s, 1H), 8.31 (d, J= 8.2 Hz, 1H), 8.28 (d, J= 7.9

Hz, 1H), 7.84 (s, 1H), 7.86-7.81 (m, 1H), 7.69-7.63 (m, 2H), 7.00 (d, J= 8.8 Hz, 1H);

13C NMR (DMSO-d6) 6 165.3, 155.2, 145.5, 135.6, 132.1, 130.9, 130.8, 126.7, 123.0,

120.1, 118.6, 113.9, 109.6. Anal. Calcd for C13H8BrN302: C, 49.08; H, 2.53; N, 13.21.

Found: C, 49.30; H, 2.35; N, 13.15.

Benzotriazol-l-yl-(2,5-dihydroxyphenyl)methanone (5.6c): yellow needles from

diethyl ether (95%); mp 182 C (polymerizes); IR (KBr) v = 3135, 1649, 1625 cm-1; 1H

NMR (DMSO-d6) 6 10.38 (s, 1H), 10.31 (s, 1H), 8.27 (d, J= 8.2 Hz, 1H), 8.18 (d, J=

8.2 Hz, 1H), 7.78 (t, J 7.8 Hz, 1H), 7.61 (t, J 8.2 Hz, 1H), 7.58 (d, J 9.2 Hz, 1H),

6.46-6.43 (m, 2H); 13C NMR (DMSO-d6) 6 166.1, 163.3, 159.9, 145.3, 133.5, 131.3,

130.3, 126.2, 119.9, 113.8, 110.7, 107.4, 102.8. Anal. Calcd for C13H9N303: C, 61.18; H,

3.55; N, 16.46. Found: C, 61.09; H, 3.48; N, 16.32.









Benzotriazole-l-yl-(3-methyl-2-hydroxyphenyl)methanone (5.6d): pale yellow

needles from diethyl ether (94%); mp 124-126 C; IR (neat) v = 3384 (br w), 1659,

1483, 1454 cm-1; 1H NMR 6 10.0 (br s, 1H), 8.40 (d, J= 8.2 Hz, 1H), 8.31 (d, J= 8.4

Hz, 1H), 8.18 (d,J 8.2 Hz, 1H), 7.71 (t, J= 7.7 Hz, 1H), 7.56 (t, J= 7.7 Hz, 1H), 7.47

(d, J= 7.3 Hz, 1H), 6.96 (t, J= 7.7 Hz, 1H), 2.35 (s, 3H); 13C NMR 6 169.7, 162.0,

145.4, 138.0, 132.5, 131.4, 130.4, 127.3, 126.4, 120.3, 118.9, 114.9, 112.7, 15.9. Anal.

Calcd for C14H11N302: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.52; H, 4.27; N, 16.95.

Benzotriazol-l-yl-(2-hydroxynaphthalen-l-yl)methanone (5.9a): white needles

from diethyl ether; mp 138-140 C; yield, 96%; IR (neat) v = 3384, 1718 cm-1; H NMR

(DMSO-d6) 6 10.72 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.10 (d, J

= 8.9 Hz, 1H), 7.98 (d, J= 7.9 Hz, 1H), 7.89 (t, J= 7.7 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H),

7.65 (d, J= 7.5 Hz, 1H), 7.49 (t, J= 7.0 Hz, 1H), 7.41 (t, J= 7.8 Hz, 1H), 7.37 (d, J=

9.1 Hz, 1H); 13C NMR (DMSO-d6) 6 167.3, 154.3, 145.8, 133.0, 131.5, 131.1, 130.8,

128.6, 128.1, 127.5, 126.9, 123.8, 122.7, 120.3, 118.3, 114.2, 113.9. Anal. Calcd for

C17HllN302: C, 70.58; H, 3.83; N, 14.52. Found: C, 70.18; H, 3.81; N, 14.49.

Benzotriazol-l-yl-(1-hydroxynaphthalen-2-yl)methanone (5.9b): yellow

microcrystals from chloroform/hexanes, mp 150-151 C; yield, 95%; IR (neat) v = 3444,

1632 cm1; 1HNMR 6 12.58 (br s, 1H), 8.58 (d, J= 9.2 Hz, 1H), 8.53 (d, J= 8.4 Hz,

1H), 8.36 (d, J= 8.4 Hz, 1H), 8.20 (d, J= 8.2 Hz, 1H), 7.82 (d, J= 7.8 Hz, 1H), 7.75-

7.68 (m, 2H), 7.61-7.54 (m, 2H), 7.40 (d, J= 9.2 Hz, 1H); 13C NMR (DMSO-d6) 6

169.8, 164.9, 145.3, 137.4, 132.5, 130.9, 130.4, 127.4, 126.7, 126.3, 126.1, 124.8, 124.4,

120.3, 118.9, 115.0, 106.7. Anal. Calcd for C17HllN302: C, 70.58; H, 3.83; N, 14.52.

Found: C, 70.25; H, 3.68; N, 14.90.









Benzotriazol-l-yl-(3-hydroxynaphthalen-2-yl)methanone (5.9c). Yellow

microcrystals from dichloromethane; mp 157-158 C; yield, 92%; IR (neat) v = 3198,

1659 cm-1; 1H NMR (DMSO-d6) 6 10.52 (s, 1H), 8.34 (dt, J= 8.2, 1.0 Hz, 1H), 8.30 (dt,

J 8.2, 1.0 Hz, 1H), 8.30 (s, 1H), 7.94 (br d, J= 7.7 Hz, 1H), 7.86 (dt, J= 8.2, 1.0 Hz,

1H), 7.84 (br d, J 7.7 Hz, 1H), 7.68 (dt, J= 8.2, 1.0 Hz, 1H), 7.56 (dt, J= 8.2, 1.0

Hz), 7.40 (dt, J= 8.2, 1.0, 1H), 7. 34 (s, 1H); "3C NMR (DMSO-d6) 6 166.9, 152.6,

145.6, 136.0, 131.1, 131.0, 130.8, 128.7, 128.4, 126.9, 126.8, 126.3, 124.2, 124.1, 120.3,

114.1, 110.0. Anal. Calcd for C17H11N302: C, 70.58; H, 3.83; N, 14.52. Found: C, 70.25;

H, 3.69; N,14.86.

5.4.6 Synthesis of Amides of Substituted Salicylic and o-Hydroxy Naphthoic Acids
(5.7, 5.10):

Method A:

In a 50 mL round bottomed flask, the appropriate primary or secondary amine (3

mmol) and triethyl amine (3 mmol) in freshly dried THF were stirred. The supernatant

(as described in the synthesis of 5.6a-d, 5.9a-c) was carefully syringed out and added

rapidly to the mixture of amines under an inert atmosphere while being stirred. The

stirring was continued for an additional 30 min. The reaction mixture was concentrated

under vacuum to remove the solvent and excess triethyl amine. The crude residue was

taken up in ether (25 mL) and washed with water (25 mL), IN HC1 (2 X 25 mL) and

brine before being dried over magnesium sulphate. The concentrated organic layer was

finally refined by column chromatography over silica gel to give the respective amides

(5.7a-e,h, 5.10b-f).

Method B:









The appropriate N-acylbenzotriazole derivative 5.6f,g, 5.9a (1.2 mmol) and 1

equiv. of the appropriate amine were placed in a 10 mL microwave reaction tube

equipped with a magnetic stir-bar. The reaction mixture was then exposed to microwave

irradiation (120 W) at 120 OC for 10 min. The reaction mixture was diluted with CHC13

(10 mL) and the residue refined by column chromatography on silica gel to give the

amides 5.7f,g and 5.10a.

5.4.7 Characterization of Amides of Substituted Salicylic and o-Hydroxy Naphthoic
Acids (5.7 and 5.10)

N-(Furan-2-ylmethyl)-2-hydroxybenzamide (5.7a):209 white needles from diethyl

ether; mp 109-110 C; yield, 83%; IR (neat)v = 3364, 1645, 1592, 1546, 1496 cm-1; 1H

NMR 6 12.20 (s, 1H), 7.42-7.34 (m, 3 H), 6.90 (dd, J= 8.24, 1.0 Hz, 1H), 6.84 (dt, J=

7.14, 1 Hz, 1H), 6.60 (br s, 1H), 6.35 (dd, J= 3.3, 1.8 Hz, 1H), 6.32 (d, J= 3.3 Hz, 1H),

4.63 (d, J= 5.94 Hz, 2H); 13C NMR 6 169.7, 161.6, 150.4, 142.6, 142.5, 134.4, 125.4,

118.7, 114.0, 110.6, 108.1, 36.5. Anal. Calcd for C12HllN03: C, 66.35; H, 5.10; N, 6.45.

Found: C, 65.97; H, 5.18; N, 6.49.

(2-Hydroxyphenyl)piperidin-l-yl-methanone (5.7b):164 white needles from

methanol; mp 142-143 C; yield, 94%; IR (neat) v = 3153, 2939, 2856, 1591, 1475 cm1;

1H NMR 6 9.67 (s, 1H), 7.31 (t, J= 7.7 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H), 6.97 (d, J=

8.2 Hz, 1H), 6.82 (t, J= 7.3 Hz, 1H), 3.65-3.61 (m, 4H), 1.70-1.62 (m, 6H); 13C NMR

6 170.6, 158.7, 132.2, 128.1, 118.4, 117.8, 117.5, 46.7, 26.0, 24.4.

5-Bromo-2-hydroxy-N-pentylbenzamide (5.7c): pale yellow microcrystals from

diethyl ether; mp 54-55 C; yield, 84%; IR (neat) v = 3374, 2930, 2859, 1635, 1591,

1543, 1475 cm-1; 1HNMR 6 12.36 (s, 1H), 7.46-7.43 (m, 2H), 6.88 (d, J= 9.3 Hz, 1H),












6.30 (br s, 1H), 3.43 (q, J= 6.3 Hz, 2H), 1.68-1.58 (m, 2H), 1.38-1.34 (m, 4H), 0.92 (t,

J= 6.6 Hz, 3H); 13C NMR 6 68.7, 160.5, 136.7, 127.8, 120.5, 115.9, 110.1, 39.9, 29.1,

29.0, 22.3, 13.9. Anal. Calcd for C12H16BrNO2: C, 50.37; H, 5.64; N, 4.89. Found: C,

50.54; H, 5.57; N, 4.84.

5-Bromo-2-hydroxy-N-methyl-N-octylbenzamide (5.7d): cream microcrystals

from ethyl acetate; mp 92-93 'C; yield, 82%; IR (neat) v = 3125, 2927, 2855, 1612, 1490

cm 1; 1H NMR 6 9.74 (s, 1H), 7.40-7.37 (m, 2H), 6.87 (d, J= 9.5 Hz, 1H), 3.50-3.45

(m, 2H), 3.11 (s, 3H), 1.68-1.64 (m, 2H), 1.29 (br s, 10H). 0.88 (t, J= 6.2 Hz, 3H); 13C

NMR 6170.2, 157.7, 134.9, 130.5, 119.8, 119.6, 110.1, 31.7, 29.2, 29.1, 27.3, 26.6, 22.6,

14.1. Anal. Calcd for C16H24BrNO2: C, 56.15; H, 7.07; N, 4.09. Found: C, 56.46; H, 7.35;

N, 4.10.

2,4-Dihydroxy-N-pentylbenzamide (5.7e): white microcrystals from ethyl

acetate; mp 104-105 'C; yield, 96%; IR (neat) v = 3385, 1637 cm-1; H NMR (DMSO-

d6) 6 13.06 (s, 1H), 10.03 (s, 1H), 8.51 (br t, J= 6.2 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H),

6.28 (dd, J= 8.8, 1.8 Hz, 1H), 6.22 (d, J= 1.8 Hz, 1H), 3.24 (q, J= 6.1 Hz, 2H),

1.54-1.50 (m, 2H), 1.29 (br s, 4H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (DMSO-d6) 6

169.4, 162.7, 162.1, 128.8, 106.9, 106.6, 102.7, 39.5, 28.7, 21.9, 13.9. Anal. Calcd for

C12H17N03: C, 64.56; H, 7.67; N, 6.27. Found: C, 64.77; H, 7.89; N, 6.28.

2,4-Dihydroxy-N-methyl-N-phenylbenzamide (5.7f): white microcrystals from

chloroform; mp 150-152 'C; yield, 93%; IR (neat) v = 3350, 1664, 1624, 1502 cm-1; 1H

NMR 6 11.65 (s, 1H), 7.37-7.31 (m, 2H), 7.28-7.26 (m, 1H), 7.15-7.12 (m, 2H), 6.53 (d,

J = 8.8 Hz, 1H), 6.37 (d, J = 2.6 Hz, 1H), 5.88 (dd, J= 8.8, 2.6 Hz, 1H), 5.67 (br s,

1H), 3.46 (s, 3H); 13C NMR 6 171.7, 162.9, 160.0, 145.3, 132.3, 129.7, 127.1, 126.6,









108.3, 106.3, 103.6, 39.5. Anal. Calcd for C14H13N03: C, 69.13; H, 5.39; N, 5.76. Found:

C, 68.77; H, 5.43; N, 5.77.

4-(Morpholin-4-ylcarbonyl)benzene-1,3-diol (5.7g): white microcrystals from

chloroform; mp 179-181 'C; yield, 94%; IR (neat) v = 3378, 1620, 1578 cm 1; 1H NMR

6 9.60 (s, 1H), 8.19 (s, 1H), 7.05 (d, J= 8.4 Hz, 1H), 6.34 (d, J= 2.3 Hz, 1H), 6.30 (dd,

J= 8.4, 2.3 Hz, 1H), 3.68-3.65 (m, 8H); 13C NMR 6 170.9, 160.0, 158.7, 129.9, 110.2,

107.4, 103.8, 66.7, 46.0. Anal. Calcd for ClH13N04: C, 59.19; H, 5.87; N, 6.27. Found:

C, 58.83; H, 5.99; N, 6.19.

2-Hydroxy-3-methyl-N-(3-methylbutyl)benzamide (5.7h): colorless oil, yield,

93%; IR (neat) v = 3384, 2962, 2926, 2875, 1633, 1609, 1588, 1541 cm 1; 1H NMR

(DMSO-d6) 6 12.65 (s, 1H), 7.25 (d, J = 6.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.73 (t, J

= 7.7 Hz, 1H), 6.39 (br s, 1H), 3.42-3.21 (m, 2H), 2.26 (s, 3H), 1.73-1.62 (m, 1H),

1.53-1.39 (m, 1H), 1.28-1.14 (m, 1H), 0.97-0.91 (m, 6H); 13C NMR (DMSO-d6) 6

170.6, 159.9, 134.8, 127.7, 122.6, 117.8, 113.5, 45.2, 34.8, 27.0, 17.1, 15.8, 11.2. Anal.

Calcd for C13H19N02: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.77; H, 8.97; N, 6.63.

2-Hydroxy-N-phenyl-l-naphthamide (5.10a): white microcrystals from

chloroform; mp 171-172 'C; yield, 95%; IR (neat) v = 3283 (br w), 1627, 1597, 1532,

1443 cm-1; 1HNMR 6 11.1 (s, 1H), 8.19 (d, J= 8.5 Hz, 1H), 7.97 (br s, 1H), 7.85 (t, J=

8.2 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.1 Hz, 1H) 7.45-7.38 (m, 3H), 7.26-

7.19 (m, 2H); 13C NMR 6 168.4, 159.8, 136.9, 134.4, 130.5, 129.7, 129.3, 128.8, 128.5,

125.3, 123.7, 122.3, 120.7, 119.4, 109.9. Anal. Calcd for C17H13N02: C, 77.55; H, 4.98;

N, 5.32. Found: C, 77.17; H, 4.94; N, 5.31.









(2-Hydroxynaphthalen-1-yl)piperidin-1-yl-methanone (5.10b): white needles

from methanol; mp 242-243 'C; yield, 90%; IR (KBr) v = 3175, 1606, 1514 cm-1; 1H

NMR (DMSO-d6) 6 9.93 (s, 1H), 7.83-7.77 (m, 2H), 7.51-7.41 (m, 2H), 7.33-7.28 (m,

1H), 7.19 (d, J= 8.9 Hz, 1H), 3.90 (br s, 1H), 3.56 (br s, 1H), 3.09 (s, 2H), 1.59 (s, 4H),

1.44 (br s, 1H), 1.24 (br s, 1H); 13C NMR (DMSO-d6) 6 165.9, 150.7, 131.2, 129.6,

128.2, 127.7, 126.9, 123.6, 123.1, 118.2, 117.1, 47.0, 24.3. Anal. Calcd for C16H17N02:

C, 75.27; H, 6.71; N, 5.49. Found: C, 75.34; H, 6.93; N, 5.15.

1-Hydroxynaphthalene-2-carboxylic acid N-phenethylamide (5.10c): pale

yellow microcrystals from ethyl acetate; mp 125-126 'C; yield, 94%; IR (neat) v = 3417,

1615, 1594, 1542, 1501 cm 1; 1HNMR 6 13.84 (s, 1H), 8.42 (d, J= 7.1 Hz, 1H), 7.73 (d,

J= 7.9 Hz, 1H), 7.59-7.49 (m, 2H), 7.36-7.11 (m, 7H), 6.34 (br s, 1H), 3.75 (q, J= 6.6

Hz, 2H), 2.96 (t, J= 6.8 Hz, 1H); 13C NMR 6 170.6, 160.6, 138.5, 136.2, 128.9, 128.8

(2C), 127.3, 126.8, 125.8, 125.6, 123.8, 120.6, 118.1, 106.6, 40.8, 35.6. Anal. Calcd for

C19H17N02: C, 78.33; H, 5.88; N, 4.81. Found: C, 77.94; H, 5.94; N, 4.86.

(1-Hydroxynaphthalen-2-yl)pyrrolidin-1-yl-methanone (5.10d): white

microcrystals from ether; mp 93-94 'C; yield, 97%; IR (neat) v = 3445 (br w), 2972,

2877, 1584, 1438 cm 1; 1HNMR 6 12.87 (s, 1H), 8.40 (d, J= 8.1 Hz, 1H), 7.74 (d, J =

7.9 Hz, 1H), 7.58-7.47 (m, 3H), 7.24 (d, J= 8.6 Hz, 1H), 3.77-3.73 (m, 4H), 1.97-1.92

(m, 4H); 13C NMR 6 171.2, 159.4, 135.5, 128.5, 127.1, 125.5, 125.3, 123.9, 123.7, 116.9,

109.5, 48.9, 25.5. Anal. Calcd for C15H15N02: C, 74.76; H, 6.27; N, 5.80. Found: C,

74.28; H, 6.30; N, 5.85.

3-Hydroxynaphthalene-2-carboxylic acid allylamide (5.10e):210 pale yellow

microcrystals from ethyl acetate; mp 121-122 'C; yield, 75%; IR (neat) v = 3374, 1657,









1584, 1509 cm1; 1H NMR 6 11.72 (s, 1H), 7.97 (s, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.67

(d, J= 8.2 Hz, 1H), 7.47 (dt, J= 6.9, 1.1 Hz, 1H), 7.31-7.26 (m, 2H), 6.70 (br s, 1H),

6.03-5.09 (m, 1H), 5.33 (dq, J= 17.0, 1.2 Hz, 1H), 5.25 (dq, J= 10.2 Hz, 1.2 Hz, 1H),

4.14 (tt, J= 5.8, 1.5 Hz, 2H); 13C NMR 6 169.6, 156.6, 137.0, 133.3, 128.5, 128.4,

126.8, 126.7, 126.2, 123.9, 117.5, 116.8, 112.4, 42.2. Anal. Calcd for C14H13NO2: C,

73.99; H, 5.77; N, 6.16. Found: C, 73.69; H, 5.86; N, 6.17.

(3-Hydroxynaphthalen-2-yl)morpholin-4-yl-methanone (5.10f):162 white

needles from ethyl acetate; mp 216-217 'C; yield, 70%; IR (neat) v = 3095, 2967, 2855,

1594, 1483 cm-1; 1HNMR 6 8.93 (s, 1H), 7.74 (d, J= 7.8 Hz, 1H), 7.73 (s, 1H), 7.66 (d,

J = 8.2 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.32 (s, 1H), 3.83-

3.76 (m, 8H); 13C NMR 6 170.2, 154.1, 135.8, 128.7, 128.3, 128.1, 126.9, 126.4, 124.1,

119.7, 112.3, 66.9 (2C). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found:

C, 69.70; H, 5.95; N, 5.44.

5.4.8 Synthesis of Hydroxy Aryl-/Alkyl- and Thioesters 5.11 from Hydroxy Acids

The (N-hydroxyacyl)benzotriazole was prepared as described in the synthesis of the

hydroxy carboxamides.

The appropriate alcohol/thiol (6 mmol) was treated with NaH (60% dispersion in

oil) (6.2 mmol) in 12 mL of anhydrous THF and stirred for 30 min. The supernatant of

the benzotriazolating mixture / hydroxy acid was carefully syringed out and added

dropwise to the sodium salt of the alchohol/thiol while under inert atmosphere. The

residual solid was washed with 5 mL of dry THF and the washings added to the sodium

salt of the alcohol. After 30 min the reaction was concentrated under vacuum. Water (20

mL) and ether (20 mL) were added to the residue. The layers were separated and the









organic layer further washed with saturated sodium carbonate solution (to remove

benzotriazole), brine, dried over magnesium sulphate and concentrated. The residue was

refined by flash chromatography over silica gel to give the hydroxy aryl-/alkyl- and thio

esters.

5.4.9 Characterization of Hydroxy Aryl-/Alkyl- and Thioesters 5.11 from Hydroxy
Acids

Methyl (DL) mandelate (5.11a):211 white powder from hexanes; mp 56-57 C;

yield, 40%; IR (neat) v = 3468, 1735 cm1; 1H NMR 6 7.43-7.32 (m, 5H), 5.18 (d, J=

5.6 Hz, 1H), 3.74 (s, 3H), 3.56 (d, J 5.6 Hz, 1H); 13C NMR 6 174.1, 138.2, 128.6,

128.5, 126.5, 72.8, 53.0.

Ethyl (DL)-mandelate (5.11b):212 microcrystals from hexanes; mp 35-36 C;

yield, 72%; IR (neat) v = 3469, 2983, 1735 cm-1; H NMR 6 7.44-7.28 (m, 5H), 5.15 ( d,

J 5.8 Hz, 1H), 4.31-4.10 (m, 2H), 3.61 (d,J 5.9 Hz, 1H), 1.21 (t, J= 7.1 Hz, 3H);

13CNMR 6 173.6, 138.4, 128.5, 128.3, 126.5, 72.8, 62.1, 13.9.

2-Hydroxy-3-phenylthiopropionic acid S-hexyl ester (5.11e): colorless oil; yield,

37%; IR (neat) v = 3455, 2928, 2856, 1681 cm-1; H NMR 6 7.34-7.22 (m, 5H), 4.44

(ddd, J= 7.7, 6.5, 4.1 Hz, 1H), 3.17 (dd, J 14.0, 4.1 Hz, 1H), 2.95 (dd, J= 14.0,7.8

Hz, 1H), 2.9 (t, J= 7.3 Hz, 2H), 2.72 (d, J= 6.5 Hz, 1H), 1.62-1.52 (m, 2H), 1.4- 1.21

(m, 6H), 0.89 (t, J 6.7 Hz, 3H); 13C NMR 6 203.2, 136.0, 129.5, 128.5, 126.9, 78.1,

41.1, 31.2, 29.2, 28.4, 22.4, 14.0. Anal. Calcd for C15H2202S: C, 67.63; H, 8.32. Found:

C, 67.80; H, 8.60.

Hydroxyphenylthioacetic acid S-(4-methoxyphenyl) ester (5.11f): colorless oil;

yield, 23%; IR (neat) v = 3462, 2940, 2837, 1698, 1592 cm-1; 1H NMR 6 7.48-7.36 (m,











5H), 7.24 (AA'BB', JAB = 8.8 Hz, 2H), 6.90 (AA'BB', JAB = 8.8 Hz, 2H), 5.31 (d, J= 3.9

Hz, 1H), 3.79 (s, 3H), 3.73 (d, J= 4.5 Hz, 1H); 13C NMR 6 201.1, 160.7, 137.8, 136.1,

128.9, 128.8, 127.1, 117.0, 114.9, 79.8, 55.3. Anal. Calcd for C15H1403S: C, 65.67; H,

5.14. Found: C, 65.42; H, 5.28.

2-Hydroxy-3-methyl-thiobutyric acid S-benzyl ester (5.11g): white needles from

hexanes/ethyl acetate; mp 69-70 C; yield, 24%; IR (neat) v = 3406, 2926, 2855, 1638

cm 1; 1H NMR 6 7.31-7.23 (m, 5H), 4.17-4.10 (m, 3H), 2.82 (d, J= 6.2 Hz, 1H), 2.21-

2.11 (m, 1H), 1.05 (d, J= 6.9 Hz, 3H), 0.85 (d, J= 6.7 Hz, 3H); 13C NMR 6 203.0,

137.2, 128.8, 128.6, 127.3, 81.7, 32.9, 32.7, 19.1, 15.1. Anal. Calcd for C12H1602S: C,

64.25; H, 7.19. Found: C, 64.47; H, 7.42.

5.4.10 Synthesis of Esters of Substituted Salicylic 5.12 and o-Hydroxy Naphthoic
Acids 5.13

Method A:

In a 50 ml round bottomed flask, the appropriate alcohol (3 mmol) was treated with

NaH (60% dispersion in oil) (3.2 mmol) in 6 mL of anhydrous THF and stirred for half

an hour. The supernatant containing the acyl benzotriazole derivative (as described in the

synthesis of 5.6a-d, 5.9a-c) was carefully syringed out and added drop-wise to the

sodium salt of the alcohol under an inert atmosphere. After 30 min the reaction mixture

was concentrated under vacuum. Water (20 mL) and ether (20 mL) were added to the

concentrated residue. The layers were separated and the organic layer dried over

magnesium sulphate, concentrated under vacuum and refined by flash column

chromatography to give the esters (5.12a-b, 5.13a).

Method B (with variations):









The N-acylbenzotriazole derivative 5.6a-d, 5.9a-c (1 mmol) and the appropriate

alcohol (3 equiv) were placed in a 50 mL RBF equipped with a stir-bar. The flask was

then exposed to microwave irradiation (120 W) at 120 OC for 10 min. In the case of using

ethanol and n-propanol as starting materials, the reactions took place in a 10 mL

microwave reaction tube sealed by aluminium cap, and the temperature for the reaction

was set up to 100 C. When the N-acylbenzotriazole being used is 5.6c, complications

will appear because more alcohol will condensate with the -OH at 4-position to form

another estereal functional group. In this case, the limiting agent was chosen to be 5.6c

(1.2 equiv), and alcohol used is 1 equiv. Other conditions stayed the same. The reaction

mixture was diluted with CH2C2 (10 mL) and the residue refined by column

chromatography on silica gel with hexanes/ ethyl acetate (8/1) to give the respective ester

5.12a-g, 5.13a-h.

5.4.11 Characterization of Esters of Substituted Salicylic 5.12 and o-Hydroxy
Naphthoic Acids 5.13

Cyclopentyl salicylate (5.12a): colorless oil; yield, 92%; IR (neat) v = 3145, 2965,

2874, 1672 cm-1; 1HNMR 6 10.93 (s, 1H), 7.80 (dd, J= 7.9, 1.5 Hz, 1H), 7.44 (td, J=

8.0, 1.7 Hz, 1H), 6.97 (d, J= 8.3 Hz, 1H), 6.86 (t, J= 7.3 Hz, 1H), 5.40-5.46 (m, 1H),

1.65-2.01 (m, 8H); 13C NMR 6 170.0, 161.6, 135.4, 129.8, 119.0, 117.5, 112.9, 32.7,

23.7. Anal. Calcd for C12H1403: C, 69.89; H, 6.84. Found: C, 69.86; H, 7.03.

1-Ethylprop-2-enyl salicylate (5.12b): colorless oil; yield, 87%; IR (neat) v =

3186, 2972, 2880, 1675, 1614 cm-1; 1HNMR 6 10.86 (s, 1H), 7.89 (dd, J= 8.0, 1.7 Hz,

1H), 7.45 (td, J= 7.8, 1.6 Hz, 1H), 6.98 (d, J= 8.2 Hz, 1H), 6.88 (t, J= 7.6 Hz, 1H),

5.83-5.94 (m, 1H), 5.34 (d, J= 17.2 Hz, 1H), 5.24 (d, J= 10.6 Hz, 1H), 1.75-1.86 (m,

2H), 0.99 (t, J= 7.4 Hz, 3H); 13C NMR 6 169.4, 161.7, 135.6, 135.5, 129.7, 119.0,










117.5, 117.2, 112.6, 77.0, 27.2, 9.3. Anal. Calcd for C12H1403: C, 69.89; H, 6.84. Found:

C, 69.87; H, 7.04.

Ethyl 5-bromo-2-hydroxybenzoate (5.12c): colorless microcrystals; mp 46-48

C; yield, 90%; IR (neat) v = 3143, 1681, 1608 cm-1; 1HNMR 6 10.80 (s, 1H), 7.96 (d, J

= 2.5 Hz, 1H), 7.52 (dd, J 8.9, 2.6 Hz, 1H), 6.88 (d, J= 8.9 Hz, 1H), 4.42 (q, J= 7.1

Hz, 2H), 1.43 (t, J= 7.1 Hz, 3H); 13C NMR 6 169.1, 160.6, 138.3, 132.2, 119.5, 114.1,

110.7, 61.9, 14.1. Anal. Calcd for C12H1403: C, 44.11; H, 3.70. Found: C, 44.29; H, 3.56.

Cyclopentyl 5-bromo-2-hydroxybenzoate (5.12d): colorless needles from

chloroform/hexanes; mp 45-47 C; yield, 91%; IR (neat) v = 3412, 2966, 2873, 1674 cm

1; H NMR 6 10.90 (s, 1H), 7.88 (d, J= 2.6 Hz, 1H), 7.51 (dd, J= 9.0, 2.4 Hz, 1H),

6.88 (d, J= 9.0 Hz, 1H), 5.45-5.41 (m, 1H), 2.04-1.68 (m, 8H); 13C NMR 6 168.9,

160.7, 138.2, 132.1, 119.5, 114.4, 110.6, 79.1, 32.7, 23.8. Anal. Calcd for C12H13BrO3: C,

50.55; H, 4.60. Found: C, 50.41; H, 4.52.

Propyl 2,4-dihydroxybenzoate (5.12e): colorless microcrystals from

hexanes/ethyl acetate; mp 32-34 C; yield, 87%; IR (neat) v = 3384, 1666, 1623 cm-1; H

NMR 6 11.17 (s, 1H), 7.74 (d, J 8.5 Hz, 1H), 6.62 (br s, 1H), 6.42 (d, J= 2.1 Hz,

1H), 6.39 (dd, J= 8.5, 2.1 Hz, 1H), 4.27 (t, J= 6.6 Hz, 2H), 1.78 (sextet, J= 7.0 Hz,

2H), 1.02 (t, J= 7.4 Hz, 3H); 13C NMR 6 170.2, 163.3, 162.2, 131.9, 108.0, 105.8,

103.0, 66.7, 21.9, 10.4. Anal. Calcd for C10H1204: C, 61.22; H, 6.16. Found: C, 61.30; H,

6.34.

Cyclopentyl 2,4-dihydroxybenzoate (5.12f): colorless oil; yield, 91%; IR (neat) v

=3372, 1660 cm-1; H NMR 6 11.25 (s, 1H), 7.68 (d, J= 8.6 Hz, 1H), 7.09 (br s, 1H),

6.42 (d, J= 2.3 Hz, 1H), 6.39 (dd, J= 8.6, 2.3 Hz, 1H), 5.41-5.36 (m, 1H), 2.00-1.59










(m, 8H); 13C NMR 6 170.0, 163.1, 162.2, 131.9, 108.0, 106.0, 102.9, 78.3, 32.7, 23.7.

Anal. Calcd for C12H1404: C, 64.85; H, 6.35. Found: C, 64.58; H, 6.50.

Decyl 2-hydroxy-3-methylbenzoate (5.12g): pale yellow oil; yield, 89%; IR (neat)

v = 3165, 2926, 2855, 1671 cm 1; 1H NMR 6 7.69 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.3

Hz, 1H), 6.77 (t, J= 7.6 Hz, 1H), 4.32 (t, J= 6.6 Hz, 2H), 2.26 (s, 3H), 1.81-1.72 (m,

2H), 1.81-1.27 (m, 14H), 0.88 (t, J= 6.6 Hz, 3H); 13C NMR 6 170.7, 160.1, 136.3,

127.3, 126.5, 118.3, 111.8, 65.4, 31.9, 29.5, 29.3, 29.2, 28.5, 25.9, 22.6, 15.6, 14.1. Anal.

Calcd for C18H2803: C, 73.93; H, 9.65. Found: C, 73.65; H, 9.92.

Cyclopentyl 2-hydroxy-l-naphthoate (5.13a): pale yellow oil; yield, 94%; IR

(neat) v = 3345 (br w), 2965, 2873, 1644 cmi1; H NMR 6 12.46 (s, 1H), 8.75 (d, J= 8.9

Hz, 1H), 7.86 (d, J= 9.1 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.53 (t, J= 7.4 Hz, 1H),

7.37-7.32 (m, 1H), 7.15 (d, J= 8.9 Hz, 1H), 5.65-5.59 (m, 1H), 2.09-1.69 (m, 8H); 13C

NMR 6 172.2, 164.3, 136.6, 131.9, 129.1, 128.6, 128.3, 125.0, 123.5, 119.3, 105.0, 79.3,

32.8, 23.8. Anal. Calcd for C16H1603: C, 74.98; H, 6.29. Found: C, 74.88; H, 6.41.

Pent-4-ynyl 2-hydroxy-l-naphthoate (5.13b): colorless oil; yield, 87%; IR (neat)

v= 3296, 1645 cmi1; H NMR 6 12.31 (s, 1H), 8.70 (d, J= 8.7 Hz, 1H), 7.85 (d, J= 8.9

Hz, 1H), 7.71 (d, J= 7.1 Hz, 1H), 7.56-7.51 (m, 1H), 7.34 (td, J= 7.4, 0.9 Hz, 1H),

7.14 (d, J= 8.9 Hz, 1H), 4.61 (t, J= 6.4 Hz, 2H), 2.43 (td, J = 6.9, 2.5 Hz, 2H), 2.14-

2.02 (m, 3H); 13C NMR 6 172.3, 164.4, 136.8, 131.7, 129.1, 128.5, 128.4, 125.1, 123.5,

119.2, 104.5, 82.5, 69.5, 64.3, 27.3, 15.4. Anal. Calcd for C16H1403: C, 75.57; H, 5.55.

Found: C, 75.32; H, 5.60.

Ethyl 2-hydroxy-l-naphthoate (5.13c):160 colorless needles from chloroform/

hexanes; mp 56-58 'C; yield, 95%; IR (neat) v = 3358 (br w), 1644 cm 1; 1H NMR









6 12.4 (s, 1H), 8.77 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.0 Hz,

1H), 7.52 (td, J= 6.1 Hz, 1H), 7.34 (td, J= 7.4, 0.9 Hz, 1H), 7.14 (d, J= 9.1 Hz, 1H),

4.55 (q, J= 4.2 Hz, 2H), 1.51 (t, J= 7.1 Hz, 3H); 13C NMR 6 172.3, 164.3, 136.7,

131.8, 129.0, 128.6, 128.3, 125.2, 123.5, 119.2, 104.6, 61.9, 14.3.

Ethyl 1-hydroxy-2-naphthoate (5.13d):213 colorless needles from

chloroform/hexanes; yield, 95%; mp 46-48 'C; IR (neat) v = 2990, 1656 cm 1; H NMR

6 12.1 (s, 1H), 8.38 (d, J= 8.2 Hz, 1H), 7.73-7.68 (m, 2H), 7.54 (td, J= 8.1, 1.4 Hz,

1H), 7.46 (td, J = 7.0, 1.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 4.38 (q, J = 5.7 Hz, 2H),

1.39 (t, J= 7.1 Hz, 3H); 13C NMR 6 171.0, 160.8, 137.0, 129.2, 127.3, 125.6, 124.7,

124.2, 123.7, 118.4, 105.7, 61.3, 14.1.

Cyclopentyl 1-hydroxy-2-naphthoate (5.13e): white microcrystals from

chloroform/hexanes; yield, 91%; mp 58-60 'C; IR (neat) v = 3385, 2964, 2866, 1655 cm

1; H NMR 6 12.16 (s, 1H), 8.40 (d, J= 8.2 Hz, 1H), 7.75-7.71 (m, 2H), 7.58 (td, J=

8.1, 1.2 Hz, 1H), 7.50 (t, J= 8.2 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 5.50-5.45 (m, 1H),

2.05-1.65 (m, 8H); 13C NMR 6 170.8, 160.9, 137.1, 129.2, 127.4, 125.6, 124.8, 124.3,

123.8, 118.3, 106.1, 78.4, 32.8, 23.8. Anal. Calcd for C16H1603: C, 74.98; H, 6.29. Found:

C, 74.80; H, 6.39.

Pent-4-ynyl 1-hydroxy-2-naphthoate (5.13f): white powder from chloroform/

hexanes; yield, 91%; mp 65-67 'C; IR (neat) v = 3267, 2975, 2844, 1650 cm 1; 1H NMR

6 12.0 (s, 1H), 8.40 (d, J= 8.2 Hz, 1H), 7.75-7.72 (m, 2H), 7.59 (td, J= 8.2, 1.4 Hz,

1H), 7.50 (td, J= 8.1, 1.1 Hz, 1H), 7.25 (d, J= 8.8 Hz, 1H), 4.49 (t, J= 6.3 Hz, 2H),

2.40 (td, J= 6.9, 2.6 Hz, 2H), 2.07-1.99 (m, 3H); 13C NMR 6 170.9, 161.0, 137.1,









129.3, 127.4, 125.7, 124.7, 124.1, 123.8, 118.5, 105.5, 82.8, 69.3, 63.7, 27.5, 15.3. Anal.

Calcd for C16H1403: C, 75.57; H, 5.55. Found: C, 75.39; H, 5.56.

1-Ethylprop-2-enyl 1-hydroxy-2-naphthoate (5.13g): colorless oil; yield, 91%;

IR (neat) v = 3408, 2971, 2879, 1660, 1600 cm-1; H NMR 6 12.07 (s, 1H), 8.40 (d, J=

8.2 Hz, 1H), 7.81 (d,J 8.8 Hz, 1H), 7.74 (d, J= 8.1 Hz, 1H), 7.57 (td, J= 8.1, 1.2

Hz, 1H), 7.49 (td, J 7.6, 1.2 Hz, 1H), 7.26 (d, J= 8.9 Hz, 1H), 5.97-5.85 (m, 1H),

5.53-5.47 (m, 1H), 5.36 (d, J= 18.3 Hz, 1H), 5.25 (d, J= 6.2 Hz, 1H), 1.89-1.75 (m,

2H), 1.0 (t, J= 7.5 Hz, 3H); 13C NMR 6 170.4, 161.0, 137.1, 135.8, 129.3, 125.6, 127.4,

124.7, 124.2, 123.8, 118.4, 117.2, 105.8, 27.3, 9.4. Anal. Calcd for C16H1603: C, 74.98;

H, 6.29. Found: C, 74.89; H, 6.44.

Butyl 3-hydroxy-2-naphthoate (5.13h): yellow oil; yield, 90%; IR (neat) v =

3226, 2961, 2873, 1681 cm-1; 1HNMR 6 10.55 (s, 1H), 8.42 (s, 1H), 7.76 (d, J= 8.2

Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.45 (td, J= 8.1, 1.0 Hz, 1H), 7.30-7.25 (m, 2H),

4.38 (t, J= 6.6 Hz, 2H), 1.84-1.75 (m, 2H), 1.56-1.44 (m, 2H), 1.0 (t, J= 7.4 Hz, 3H);

13C NMR 6. 169.9, 156.3, 137.7, 132.1, 129.1, 129.0, 126.9, 126.2, 123.8, 114.3, 111.5,

103.3, 65.5, 30.5, 19.2, 13.7. Anal. Calcd for C15H1603: C, 73.75; H, 6.60. Found: C,

73.64; H, 6.72
















CHAPTER 6
SYNTHESIS OF IMIDOYLBENZOTRIAZOLES FROM SECONDARY
AMIDES

6.1 Introduction

Imidoylbenzotriazoles are stable and useful substitutes for imidoyl chlorides,

214-216 and have been reported as versatile reagents for the synthesis of

enaminones217 and N-substituted P-enamino acid derivatives.218 Reported

procedures (Scheme 6-1) for the preparation of imidoylbenzotriazoles include (i)

the reaction of secondary amides with benzotriazole and POC13 in the presence of

triethylamine (8 examples, yield: 38-96%);214 (ii) reaction of oximes with l-(p-

toluenesulfonyl)benzotriazole (12 examples, yield: 20-87%);219 (iii) reaction of

sulfinyldibenzotriazole with secondary amides (10 examples, yield: 15-75%);215

(iv) the reaction of isonitriles with N-(aminoalkyl)benzotriazoles in the presence of

BF3.Et20 (11 examples, yield: 87-99%);220 (v) the reaction of N-acylbenzotriazoles

with isocyanates (6 examples, yield: 71-99%);221 and (vi) the reaction of secondary

amides with 1-chlorobenzotriazole in the presence of triphenylphosphine (9

examples, 40-90%).218 All these methods have limitations, for example, tedious

workup procedure which led to low yields and difficulties to scale-up (route i in

Scheme 6-1) and limited availability of starting materials (route ii and iv in Scheme

6-1). Furthermore, the preparation methods involving secondary amides (route I, iii

and vi in Scheme 6-1) showed poor versatility because acceptable yields cannot be

obtained regularly from various starting materials or harsh conditions (high pressure










and/or high temperature) were required. A general method for making

imidoyobenzotriazoles is thus required. The combination of benzotriazole and

thionyl chloride has been proved useful in the synthesis of acid chlorides and N-

acylbenzotriazoles. Since it is widely reported that imidoyl chlorides can be

prepared from various chlorinating agents, it is realistic to discover new preparation

method based on literature work. Imidoyl chlorides can be treated as chemical

equivalents of acid chlorides. It should be possible to convert imidoyl chlorides into

imidoylbenzotriazoles just like what has been done with acid chlorides in Chapter 2.

In this dissertation, both one-step and two-step reactions to convert amides to

imidoylbenzotriazoles were studied.

6.2 Results and Discussions

Prelimimary study showed that the reaction of secondary amides (1 equiv),

SOC12 (1 equiv) and benzotriazole (3 equiv) gave imidoylbenzotriazoles. However,

two unwanted things occurred during these reactions. On one hand, the reaction is

normally slow and will not go to completion even after a couple of days; on the

other hand, when R1 was aliphatic, side products formed easily and became the

major products eventually to ruin the reaction. For the reactions involving

secondary amides that gave no side products, a microwave synthesizer was used to

accelerate the reactions. Also we used more SOC12 and benzotriazole than required.

We found that reactions of secondary amides (1 equiv), SOC12 (2 equiv) and

benzotriazole (4 equiv) at 80 oC, 80 W irradiation power for 10 min gives

imidoylbenzotriazoles 6b-e,i-l,n-r,u-w (with R1 = aryl group) in 78-95% yields

(Table 6-3). To avoid forming side products, imidoylbenzotriazoles 6a,f-h,m,s,t









(with R1 = aliphatic group) were prepared in 56-75% yields by the one-pot reaction

(two steps) of amides (1 equiv), (COC1)2 (1 equiv) and benzotriazole (2 equiv) in

presence of pyridine. Imidoyl chlorides were formed in the first step, then converted

into imidoylbenzotriazoles in the second step. No side products were observed in

this case; however, the yields were not very high because the rates of the reactions

were low at room temperature. All compounds were fully characterized by 1H and

13C NMR spectroscopy and by either elemental analysis or comparison of melting

point with literature data.

The novel methods described in Scheme 6-2 have advantages over all the

known methods because of their ability to give moderate to high yields (56-95%)

starting from various readily available secondary amides through brief reactions.


R2NC


,OH
N
R R (ii)

N/R2 (i)
R2
H


I M R2NCO

(vi) R2
H


(i) BtH, POC13/Et3N; (ii) BtTs; (iii) Bt2SO; (iv) BtR1, BF3.Et20 ; (v) R1COBt; (vi) BtCI, PPh3

Scheme 6-1 Literature Methods of Preparation of Imidoylbenzotriazoles

1) (COCI)2,Pyridine, 0 C,
,R2 15min /R2
N 2) 2 BtH, 4-6 hN R2 BtH, SOC2 N
SR1 N-R2 Method A
Bt R1 Method B H Bt R1
6.1a,f-h,m,s,t 6.1b-e,i-l,n-r,u-x
R1 = alkyl Ri = aryl


Scheme 6-2 Preparation of Imidoylbenzotriazoles 6.1a-x


ration of Imidoylbenzotriazoles 6.1a-x









Table 6-1 Preparation of Imidoylbenzotriazoles 6.1
Entry R R Product Mp (C)
(Yield %)"
1 Methyl Phenyl 6.1a (75) 106-108
2 Phenyl Phenyl 6.1b (88) 129-131
3 p-Tolyl p-Tolyl 6.1c (82) 138-140
4 2-Furyl p-Tolyl 6.1d (84) 120-123
5 Phenyl p-Methoxyphenyl 6.1e (82) 100-103
6 Methyl p-Tolyl 6.1f (65) 113-115
7 Benzyl p-Tolyl 6.1g (62) 124-126
8 Benzyl Benzyl 6.1h (56) Oil
9 Phenyl Benzyl 6.1i (93) 108-110
10 p-Chlorophenyl p-Tolyl 6.1j (90) 118-120
11 p-Methoxyphenyl Benzyl 6.1k (78) 115-118
12 Phenyl 2-Furylmethyl 6.11 (84) Oil
13 n-Hexyl p-Tolyl 6.1m (57) Oil
14 2-Furyl Cyclohexyl 6.1n (95) Oil
15 p-Nitrophenyl Benzyl 6.1o (86) 117-119
16 p-Nitrophenyl Phenyl 6.1p (88) 183-185
17 p-Tolyl n-Butyl 6.1q (84) Oil
18 2-Thienyl p-Tolyl 6.1r (91) 133-135
19 Phenethyl Benzyl 6.1s (57) 77-79
20 Phenethyl p-Tolyl 6.1t (64) 116-118
21 2-Thienyl Benzyl 6.1u (83) Oil
22 2-Thienyl 2-Furylmethyl 6.1v (81) Oil
23 Phenylethenyl p-Tolyl 6.1w (65) Oil
24 p-Tolyl Methyl 6.1x (84) 95-98
"Isolated yield.

6.3. Conclusion

In summary, we have developed the preparative methods for

imidoylbenzotriazoles in moderate to high yields starting from readily available

secondary amides, benoztriazoles and chlorinating agents (SOC12 or (COC1)2) under


mild conditions.









6.4 Experimental Section

6.4.1 General Procedure for the Preparation of Imidoylbenzotriazoles 6.1

Method A: For amides with R1=aliphatic group: to a solution of amide (5.0

mmol) in methylene chloride (20 mL), pyridine (0.45 mL, 5.5 mmol) followed by

oxalyl chloride (0.48 mL, 5.5 mmol) in methylene chloride (20 mL) was added

dropwise at 0 oC. Gas evolution was observed during the process. After the

addition, the reaction was continued for 15 min, then benzotriazole (1.25 g, 10.5

mmol) was added in one portion to the reaction flask. The ice bath was removed to

allow the reaction to continue at room temperature and the reaction was monitored

by TLC. The precipitated white solid was filtered off and sodium bicarbonate

solution (saturated) was added to dilute the reaction mixture. Aqueous work-up

gave a crude product which was purified by column chromatography on basic

alumina using hexanes/EtOAc (8:1 to 5:1) as eluent.

Method B: For amides with R1=aryl group: Thionyl chloride (0.77 mL, 10.5

mmol) and benzotriazole (2.44 g, 20.5 mmol) were dissolved in chloroform (10

mL) in a 50 mL round-bottomed flask, and then amide (5 mmol) was added to the

flask. The reaction mixture was exposed to microwave irradiation for 10 min at 80

TC and 80 W. The precipitated solid was filtered off and aqueous workup gave a

crude product which was purified by either recrystallization from

chloroform/hexanes or column chromatography on basic alumina using

hexanes/EtOAc (8:1 to 5:1) as eluent.

6.4.2 Characterization of Imidoylbenzotriazoles 6.1

N- [1-(1H-1,2,3-Benzotriazol-1-yl)ethylidene] aniline (6.1a). To a solution of

acetanilide (0.68 g, 5.0 mmol) in methylene chloride (20 mL), pyridine (0.45 mL,









5.5 mmol) followed by oxalyl chloride (0.48 mL, 5.5 mmol) in methylene chloride

(20 mL) was added dropwise at 0 oC. Gas evolution was observed during the

process. After the addition, the reaction was continued for 15 min, then

benzotriazole (1.25 g, 10.5 mmol) was added in one portion to the reaction flask.

The ice bath was removed to allow the reaction to continue at room temperature and

the reaction was monitored by TLC. The precipitated white solid was filtered off

and sodium bicarbonate solution (saturated) was added to dilute the reaction

mixture. Aqueous work-up gave a crude product which was purified by column

chromatography on basic alumina using hexanes/EtOAc (8:1) as eluent to give

colorless needles (from chloroform/hexanes): mp 106-108 oC (lit.215 mp 108 oC);

yield, 75% (0.89 g); H NMR 6 2.75 (s, 3H), 6.95 (d, J = 7.5 Hz, 2H), 7.19 (t, J=

7.3 Hz, 1H), 7.40-7.50 (m, 3H), 7.60 (t, J= 7.6 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H),

8.54 (d, J = 8.4 Hz, 1H); 13C NMR 6 16.3, 115.7, 119.8, 120.2, 124.3, 125.4, 129.2,

129.2, 131.3, 146.6, 147.4, 154.0.

1-[Phenyl(phenylimino)methyl]-1H-benzotriazole (6.1b). Thionyl chloride

(0.77 mL, 10.5 mmol) and benzotriazole (2.44 g, 20.5 mmol) were dissolved in

chloroform (10 mL) in a 50 mL round-bottomed flask, and then benzanilide (0.99

g, 5 mmol) was added to the flask. The reaction mixture was exposed to microwave

irradiation for 10 min at 80 oC and 80 W. The precipitated solid was filtered off and

aqueous workup gave a crude product which was purified by column

chromatography on basic alumina using hexanes/EtOAc (8:1) as eluent to give

yellow needles (from chloroform/hexanes): mp 129-131 oC (lit.218 mp 132-133 oC);

yield, 88% (1.31 g); 1H NMR 6 6.84 (d, J= 7.4 Hz, 2H), 7.02 (t, J= 7.4 Hz, 1H),









7.23 (t, J= 7.8 Hz, 2H), 7.35-7.42 (m, 5H), 7.49 (t, J= 7.6 Hz, 1H), 7.61 (t, J=

7.3 Hz, 1H), 8.15 (d, J 8.2 Hz, 1H), 8.48 (d, J= 8.4 Hz, 1H); 13CNMR 6 115.3,

119.9, 121.4, 124.1, 125.5, 128.1, 128.8, 129.2, 130.1, 130.2, 130.3, 132.0, 146.4,

146.9, 153.7.

N-[1H-1,2,3-Benzotriazol-1-yl(4-methylphenyl)methylidene]-4-

methylaniline (6.1c): purified by recrystallization from chloroform/hexanes;

yellow needles; mp 138-140 C; yield, 82% (1.34 g); 1H NMR 6 2.29 (s, 3H), 2.37

(s, 3H), 6.76 (d, J= 8.3 Hz, 2H), 7.04 (d, J= 8.1 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H),

7.25 (d, J -8.1 Hz, 2H), 7.49 (t, J -8.0 Hz, 1H), 7.61 (t, J= 7.7 Hz, 1H), 8.15 (d,

J -8.2 Hz, 1H), 8.44 (d, J= 8.2 Hz, 1H); 13C NMR 6 20.9, 21.6, 115.3, 119.9,

121.5, 125.4, 127.5, 129.0, 129.1, 129.4, 130.2, 132.1, 133.7, 140.7, 144.5, 146.4,

153.5. Anal. Calcd for C21H18N4: C, 77.27; H, 5.57; N, 17.17. Found: C, 77.33; H,

5.59; N, 17.29.

N-[1H-1,2,3-Benzotriazol-l-yl(2-furyl)methylidene]-4-methylaniline

(6.1d): purified by recrystallization from chloroform/hexanes; yellow

microcrystals; mp 120-123 C; yield, 84% (1.27 g); 1H NMR 6 2.38 (s, 3H), 6.72

6.74 (m, 1H), 7.21 (d, J= 8.2 Hz, 2H), 7.54 (t, J= 7.3 Hz, 1H), 7.70 (t, J= 7.7 Hz,

1H), 7.78 (d,J 8.3 Hz, 2H), 7.88 (s, 1H), 8.16 (d,J 6.2 Hz, 1H), 8.18 (s, 1H),

8.42 (d, J= 8.4 Hz, 1H); 13C NMR 6 21.7, 113.0, 114.7, 120.2, 124.8, 126.3, 127.2,

129.8, 130.5, 132.1, 140.7, 141.4, 144.5, 145.5, 148.9, 155.0. Anal. Calcd for

C18H14N40: C, 71.51; H, 4.68; N, 18.54. Found: C, 71.13; H, 4.49; N, 18.65.

N-[1H-1,2,3-Benzotriazol-1-yl-(phenyl)methylidene]-4-methoxyaniline

(6.1e): purified by recrystallization from chloroform/hexanes; yellow plates; mp









100-103 oC (lit.218 mp 104-105 oC); yield, 82% (1.34 g); 1H NMR 6 3.76 (s, 3H),

6.77-6.82 (m, 4H), 7.35-7.55 (m, 6H), 7.60-7.67(m, 1H), 8.15 (d, J = 8.2 Hz, 1H),

8.47 (d, J= 8.4 Hz, 1H); 13C NMR 6 55.3, 114.1, 115.3, 119.9, 123.1, 125.4, 128.4,

129.1, 130.1, 130.3, 132.0, 139.8, 146.4, 153.1, 156.6.

1- [1-[(4-Methylphenyl)imino] ethyl]-1H-benzotriazole (6.1f): purified by

column chromatography on basic alumina; white microcrystals (from

chloroform/hexanes); mp 113-115 oC (lit.214 mp 115 oC); yield, 65% (0.81 g); 1H

NMR 6 2.39 (s, 3H), 2.75 (s, 3H), 6.86 (d,J 8.1 Hz, 2H), 7.23 (d,J 8.1 Hz,

2H), 7.44-7.50 (m, 1H), 7.56-7.62 (m, 1H), 8.12 (d, J= 8.2 Hz, 1H), 8.54 (d, J=

8.4 Hz, 1H); 13C NMR 6 16.1, 20.8, 115.7, 119.6, 120.2, 125.2, 129.1, 129.7, 131.3,

133.8, 144.7, 146.5, 153.9.

N-[1-(Benzotriazole-l-yl)-2-phenylethylidene]-4-methylaniline (6.1g):

purified by column chromatography on basic alumina; pale yellow microcrystals

(from chloroform/hexanes); mp 124-126 oC (lit.217 mp 123-125 oC); yield, 62%

(1.01 g); HNMR 6 2.38 (s, 3H), 4.61 (s, 2H), 6.88 (d,J 8.1 Hz, 2H), 7.14-7.22

(m, 7H), 7.45 (t, J= 7.3 Hz, 1H), 7.58 (t, J= 7.1Hz, 1H), 8.09 (d, J= 8.2 Hz, 1H),

8.53 (d, J= 8.3 Hz, 1H); 13C NMR 6 21.0, 34.8, 115.7, 119.8, 120.2, 125.5, 126.8,

128.6, 128.8, 129.3, 129.9, 131.6, 134.1, 135.4, 144.5, 146.6, 154.7.

N-[(1E)-1-(1H-1,2,3-Benzotriazol-1-yl)-2-phenylethylidene]-N-

benzylamine (6.1h):217 purified by column chromatography on basic alumina;

colorless oil; yield, 56% (0.92 g); 1H NMR 6 4.76 (s, 2H), 4.95 (s, 2H), 7.16-7.46

(m, 11H), 7.51 (t,J 7.6 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.51 (d,J 8.4 Hz,












1H); 13C NMR 6 33.9, 53.8, 115.7, 119.6, 125.1, 126.9, 127.0, 127.5, 128.4, 128.5,

128.8, 128.9, 131.5, 134.4, 139.2, 146.6, 155.4.

N-[1H-1,2,3-Benzotriazol-l-yl(phenyl)methylene]-N-benzylamine (6.1i):

purified by column chromatography on basic alumina; colorless needles (from

chloroform/hexanes); mp 108 110 C (lit.215 mp 108 oC); yield, 93% (1.45 g); 1H

NMR 6 4.76 (s, 2H), 7.36-7.39 (m, 4H), 7.43-7.48 (m, 4H), 7.54-7.61 (m, 4H),

8.11 (d,J 8.2 Hz, 1H), 8.52 (d,J = 8.2 Hz, 1H); 13C NMR 6 55.3, 115.4, 119.8,

125.2, 126.9, 127.5, 127.7, 128.5, 128.7, 129.0, 130.3, 130.5, 131.8, 139.5, 146.3,

155.7.

N-[1H-1,2,3-Benzotriazol-1-yl(4-chlorophenyl)methylene]-N-(4-

methylphenyl)amine (6.1j): purified by recrystallization from chloroform/hexanes;

white microcrystals; mp 118-120 oC; yield, 90% (1.56 g); H NMR 6 2.29 (s, 3H),

6.73 (d, J= 8.1 Hz, 2H), 7.05 (d, J= 8.1 Hz, 2H), 7.29-7.37 (m, 4H), 7.51 (t, J

7.3 Hz, 1H), 7.63 (t, J= 7.7 Hz, 1H), 8.15 (d, J= 8.2 Hz, 1H), 8.48 (d, J= 8.4 Hz,

1H); 13C NMR6 20.9, 115.3, 120.0, 121.4, 125.7, 128.6, 128.8, 129.3, 129.6, 131.6,

131.9, 134.1, 136.5, 143.9, 146.4, 152.3. Anal. Calcd for C20H15C1N4: C, 69.26; H,

4.37; N, 16.16. Found: C, 69.34; H, 4.25; N, 16.13.

N-[1H-1,2,3-Benzotriazol--yl(4-methoxyphenyl)methylene]-N-

benzylamine (6.1k): purified by column chromatography on basic alumina; white

microcrystals (from chloroform/hexanes); mp 115-118 oC; yield, 78% (1.34 g); 1H

NMR (mixture of two isomers) 6 3.80 (s, 0.7H), 3.88 (s, 3H), 4.56 (s, 0.5H), 4.82

(s, 2H), 6.86 (d, J= 8.9 Hz, 0.5H), 7.06 (d, J= 8.8 Hz, 2H), 7.23 7.47 (m, 10H),

7.56 (t, J= 7.6 Hz, 1H), 8.10 (d, J -8.2 Hz, 1H), 8.47 (d, J= 8.4 Hz, 1H); 13C


; 13C









NMR 6 55.3, 110.5, 114.0, 115.3, 119.7, 120.2, 122.4, 124.6, 125.1, 126.3, 126.9,

127.4, 127.7, 128.4, 128.5, 128.9, 130.1, 130.4, 131.9, 138.8, 139.7, 146.3, 155.5,

160.9. Anal. Calcd for C21H18N40: C, 73.66; H, 5.31; N, 16.37. Found: C, 73.66; H,

5.32; N, 16.54.

N-[l-(1H-1,2,3-benzotriazol-1-yl)heptylidene]-N-(2-furylmethyl)amine

(6.11): purified by column chromatography on basic alumina; colorless oil; yield,

84% (1.27 g); 1H NMR 6 4.72 (s, 2H), 6.27-6.28 (m, 1H), 6.36-6.38 (m, 1H), 7.34-

7.51 (m, 4H), 7.56-7.62 (m, 4H), 8.10 (d, J= 8.2 Hz, 1H), 8.48 (d, J= 8.4 Hz, 1H);

13C NMR 6 48.7, 106.7, 110.3, 110.6, 115.4, 119.8, 125.3, 128.6, 128.8, 129.1,

130.1, 130.4, 131.8, 142.0, 146.3, 152.6. Anal. Calcd for C18H14N40: C, 71.51; H,

4.68; N, 18.54. Found: C, 71.15; H, 4.74; N, 18.55.

N-[l-(1H-1,2,3-benzotriazol-1-yl)heptylidene]-N-(4-methylphenyl)amine

(6.1m): purified by column chromatography on basic alumina; colorless oil; yield,

57% (0.91 g); 1H NMR 6 0.82 (t, J= 6.8 Hz, 3H), 1.16-1.36 (m, 6H), 1.71-1.81

(m, 2H), 2.38 (s, 3H), 3.10-3.15 (m, 2H), 6.83 (d, J= 8.1 Hz, 2H), 7.21 (d, J= 8.0

Hz, 2H), 7.45 (dd, J= 8.2, 0.8 Hz, 1H), 7.56 (dd, J= 7.8, 0.9 Hz, 1H), 8.11 (d, J=

8.2 Hz, 1H), 8.51 (d, J= 8.2 Hz, 1H); 13C NMR 6 (1 signal is hidden) 13.9, 20.8,

22.3, 27.8, 29.1, 31.1, 115.7, 119.6, 119.8, 125.2, 129.0, 129.7, 131.4, 133.5, 144.8,

146.4, 157.6. Anal. Calcd for C20H24N4: C, 74.97; H, 7.57; N, 17.49. Found: C,

74.80; H, 7.67; N, 17.65.

N-[1H-1,2,3-Benzotriazol-1-yl(2-furyl)methylenel-N-cyclohexylamine

(6.1n): purified by column chromatography on basic alumina; colorless oil; yield,

95% (1.40 g); 1H NMR 6 1.00-1.96 (m, 15H), 2.98-3.06 (m, 0.5H), 3.94-4.04 (m,









1H), 6.18 (d, J= 3.4 Hz, 0.5 H), 6.40-6.42 (m, 0.5H), 6.60-6.62 (m, 1H), 6.88 (d, J

=3.6 Hz, 1H), 7.35-7.60 (m, 4H), 7.66 (d, J= 1.0 Hz, 1H), 8.09 (dd, J= 8.2, 0.6

Hz, 1H), 8.16-8.21 (m, 1.5H); 13C NMR 6 24.0, 24.1, 25.0, 25.4, 33.6, 34.2, 59.5,

60.0, 109.7, 111.1, 111.8, 114.1, 115.7, 116.7, 119.5, 120.0, 124.5, 124.8, 128.4,

128.6, 132.2, 132.9, 136.3, 141.5, 142.7, 144.5, 145.9, 146.0, 147.7. Anal. Calcd for

C17H18N40: C, 69.35; H, 6.18; N, 19.04. Found: C, 69.40; H, 6.30; N, 18.99.

N-[1H-1,2,3-Benzotriazol-1-yl(4-nitrophenyl)methylene]-N-benzylamine

(6.1o): purified by column chromatography on basic alumina; pale yellow

microcrystals (from chloroform/hexanes); mp 117-119 C; yield, 86% (1.54 g); 1H

NMR 6 4.73 (s, 2H), 7.30-8.57 (m, 13H); 13C NMR 6 55.2, 115.3, 119.9, 124.0,

125.7, 127.2, 127.3, 128.7, 129.5, 129.8, 131.5, 136.5, 138.7, 146.3, 148.7, 153.4.

Anal. Calcd for C20H15N502: C, 67.21; H, 4.24; N, 19.60. Found: C, 67.32; H, 4.15;

N, 19.37.

N-[1H-1,2,3-Benzotriazol-1-yl(4-nitrophenyl)methylene]-N-phenylamine

(6.1p): purified by recrystallization from chloroform/hexanes; pale yellow

microcrystals; mp 183-185 C; yield, 88% (1.50 g); 1HNMR 6 6.95 (d, J= 8.6 Hz,

2H), 7.38-7.57 (m, 6H), 7.68 (t,J 7.4 Hz, 1H), 8.11 (d,J 8.5 Hz, 2H), 8.17 (d,

J -8.2 Hz, 1H), 8.43 (d,J 7.8 Hz, 1H); 13CNMR 115.2, 119.6, 120.3, 121.9,

124.9, 126.1, 128.6, 129.8, 130.1, 131.1, 131.9, 144.1, 146.5, 153.2, 155.1. Anal.

Calcd for C19H13N502: C, 66.47; H, 3.82; N, 20.40. Found: C, 66.16; H, 3.70; N,

20.16.

N-[1H-1,2,3-Benzotriazol--yl(4-methylphenylmethylene]-N-butylamine

(6.1q): purified by column chromatography on basic alumina; colorless oil; yield,


ld,









84% (1.23 g); 1H NMR (mixture of two isomers) 6 0.85 (t, J= 7.4 Hz, 0.7H), 0.94

(t, J= 7.4 Hz, 3H), 1.31-1.40 (m, 0.5H), 1.42-1.52 (m, 2H), 1.60-1.67 (m, 0.5H),

1.70-1.79 (m, 2H), 2.36 (s, 0.9H), 2.44 (s, 3H), 3.34 (t, J= 7.0 Hz, 0.5H), 3.57 (t, J

= 6.9 Hz, 2H), 7.14-7.19 (m, 0.9H), 7.28-7.39 (m, 5H), 7.42-7.47 (m, 1.5H), 7.59

(td, J= 7.7, 0.7 Hz, 1H), 8.16-8.19 (m, 0.2H), 8.45 (d, J 8.4 Hz, 1H); 13CNMR

13.7, 13.8, 20.4, 20.5, 21.4, 21.5, 32.7, 33.3, 51.2, 51.7, 109.2, 110.3, 115.2, 119.6,

120.0, 124.4, 125.0, 127.7, 128.0, 128.4, 128.5, 128.7, 129.2, 129.3, 131.2, 131.9,

140.2, 142.1, 144.7, 146.2, 146.6, 154.5. Anal. Calcd for C18H20N4: C, 73.93; H,

6.91; N, 19.17. Found: C, 74.17; H, 7.07; N, 19.38.

N-[1H-1,2,3-Benzotriazol- -yl(thien-2-yl)methylene]-N-(4-

methylphenyl)amine (6.1r): purified by recrystallization from

chloroform/hexanes; yellow needles; mp 133-135 C; yield, 91% (1.43 g); 1H NMR

6 (mixture of two isomers) 2.12 (s, 1.8H), 2.35 (s, 3H), 6.58 (d, J= 8.1 Hz, 1.2H),

6.83 (d, J= 8.1 Hz, 3.3H), 7.00-7.16 (m, 5H), 7.29-7.33 (m, 2.2H), 7.46-7.53 (m,

2H), 7.57-7.62 (m, 1.7H), 8.03-8.06 (m, 0.6H), 8.16 (d, J= 8.2 Hz, 1H), 8.32 (d, J

S8.2 Hz, 1H); 13C NMR 6 20.8, 20.9, 110.5, 114.7, 119.9, 120.3, 121.0, 124.4,

125.4, 126.5, 128.0, 128.4, 129.1, 129.4, 129.8, 131.3, 131.9, 132.3, 132.6, 134.1,

134.6, 135.4, 139.5, 141.2, 143.2, 144.7, 144.9, 146.3, 146.7. Anal. Calcd for

C18H14N4S: C, 67.90; H, 4.44; N, 17.60. Found: C, 67.65; H, 4.35; N, 17.73.

N-[l-(1H-1,2,3-Benzotriazol-l-yl)-3-phenylpropylidene]-N-benzylamine

(6.1s): purified by column chromatography on basic alumina; white needles (from

chloroform/hexanes); mp 77-79 C; yield, 57 % (0.97 g); 1H NMR 6 (mixture of

two isomers) 3.08 (t, J 7.8 Hz, 2H), 3.23 (t, J 7.6 Hz, 0.3H), 3.60 (t, J 7.8 Hz,


,









2H), 3.76 (t, J= 7.7 Hz, 0.3H), 4.62 (s, 2H), 7.19-7.38 (m, 11H), 7.40-7.49 (m,

1.3H), 7.51-7.54 (m, 1.3H), 7.63 (t, J= 7.3 Hz, 0.3H), 8.11 (d, J= 8.2 Hz, 1H),

8.29 (d, J 8.2 Hz, 0.3H), 8.45 (d, J = 8.4 Hz, 1H); 13C NMR 6 30.3, 32.9, 53.4,

115.7, 119.5, 125.1, 126.6, 126.9, 127.5, 128.4, 128.5, 128.6, 129.0, 131.4, 139.4,

140.0, 146.5, 156.7. Anal. Calcd for C22H20N4: C, 77.62; H, 5.93; N, 16.46. Found:

C, 77.41; H, 5.97; N, 16.48.

N-[l-(1H-1,2,3-Benzotriazol-1-yl)-3-phenylpropylidene]-N-(4-

methylphenyl)amine (6.1t): purified by column chromatography on basic alumina;

white needles (from chloroform/hexanes); mp 116-118 'C; yield, 64 % (2.10 g); 1H

NMR 6 2.37 (s, 3H), 3.09 (t, J = 8.4 Hz, 2H), 3.42 (t, J = 7.8 Hz, 2H), 6.64 (d, J =

7.8 Hz, 2H), 7.03 (d, J = 6.0 Hz, 2H), 7.14-7.22 (m, 5H), 7.48 (t, J= 7.1 Hz, 1H),

7.59 (t, J= 8.4 Hz, 1H), 8.14 (d, J -8.2 Hz, 1H), 8.48 (d, J= 8.1 Hz, 1H); 13C

NMR 6 20.8, 31.4, 33.8, 115.6, 119.6, 119.7, 125.4, 126.4, 128.4, 128.5, 129.2,

129.7, 131.4, 133.6, 140.0, 144.5, 146.5, 156.2. Anal. Calcd for C22H2oN4: C, 77.62;

H, 5.93; N, 16.46. Found: C, 77.36; H, 5.94; N, 16.35.

N-[1H-1,2,3-Benzotriazol-1-yl(2-

thienyl)methylidene](phenyl)methanamine (6.1u): purified by column

chromatography on basic alumina; yellow oil; yield, 83% (2.64 g); 1H NMR

(mixture of two isomers) 6 4.52 (s, 1.8H), 4.95 (s, 2H), 6.73 (s, J= 3.7 Hz, 0.9H),

6.96 (t, J= 4.4 Hz, 0.9H), 7.19-7.59 (m, 18.3H), 7.66 (d, J= 5.1 Hz, 1H), 8.11 (d,

J -8.2 Hz, 1H), 8.19 (d, J= 7.7 Hz, 0.9H), 8.36 (d, J= 8.4 Hz, 1H); 13C NMR 6

55.1, 55.9, 110.3, 115.0, 119.8, 120.3, 124.7, 125.2, 126.9, 127.00, 127.04, 127.5,

127.6, 128.4, 128.6, 128.8, 129.0, 129.5, 131.0, 131.6, 131.7, 132.0, 132.7, 138.2,









139.1, 139.3, 143.0, 144.8, 146.4, 149.0. Anal. Calcd for C18H14N4S: C, 67.90; H,

4.43; N, 17.60. Found: C, 67.97; H, 4.40; N, 17.51.

N-[1H-1,2,3-benzotriazol-1-yl(2-thienyl)methylidene](2-

furyl)methanamine (6.1v): purified by column chromatography on basic alumina;

orange oil; yield, 81% (2.50 g); 1H NMR (mixture of two isomers) 6 4.51 (s, 1.5 H),

4.91 (s, 2.2 H), 6.19 (d, J= 3.3 Hz, 0.8 H), 6.27-6.32 (m, 1.9 H), 6.38-6.39 (m, 1.9

H), 6.74 (d, J= 3.7 Hz, 0.7 H), 6.94-6.97 (m, 0.8 H), 7.18-7.26 (m, 1.9 H), 7.31

(d, J= 1.0 Hz, 0.8 H), 7.37-7.60 (m, 7.6 H), 7.68 (dd, J= 5.1, 0.8 Hz, 1.2 H), 7.77

(td, J= 5.4 Hz, 1.0 Hz, 0.8 H), 8.10 (d,J 8.2 Hz, 1.1 H), 8.19 (d, J= 8.1 Hz,

0.7H), 8.33 (d, J= 8.2 Hz, 1H); 13C NMR 6 48.5, 49.3, 106.9, 107.3, 110.3, 110.4,

115.0, 119.8, 120.3, 124.8, 125.3, 126.9, 127.7, 128.2, 128.5, 128.8, 129.0, 129.8,

131.3, 131.9, 132.0, 132.7, 135.1, 142.0, 142.1, 143.9, 144.8, 146.3, 149.9, 151.2,

152.4. Anal. Calcd for C16H12N40S: C, 62.32; H, 3.92; N, 18.17. Found: C, 61.96;

H, 3.83; N, 17.78.

N-[(E,2E)-1-(1H-1,2,3-benzotriazol-l-yl)-3-phenyl-2-propenylidene]-4-

methylaniline (6.1w): purified by column chromatography on basic alumina;

yellow oil; yield, 65% (1.10 g); 1H NMR 6 2.41 (s, 3H), 6.99 (d, J= 8.2 Hz, 2H),

7.09 (d, J= 16.6 Hz, 1H), 7.24 (d, J 8.1 Hz, 2H), 7.34-7.40 (m, 5H), 7.40 (d, J=

16.3 Hz, 1H), 7.43 (m, 6H), 7.49 (t, J= 7.6 Hz, 1H), 7.60 (t, J= 7.6 Hz, 1H), 8.16

(d,J 8.2 Hz, 1H), 8.29 (d,J 8.4 Hz, 1H); 13C NMR 6 21.0, 105.3, 114.6, 115.2,

119.8, 120.9, 125.3, 127.8, 128.8, 129.0, 129.8, 130.1, 134.4, 135.1, 144.2, 144.7,

146.1, 151.1. Anal. Calcd for C22H18N4: C, 78.08; H, 5.36; N, 16.56. Found: C,

77.69; H, 5.42; N, 16.59.


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