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STUDIES IN HETEROCYCLIC SYNTHESIS

LONGCHUAN HUANG

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

2010

To my parents Fayun Huang and Miaorong Zhu, to my brother Jiajia Huang, and to my dear friends for their unconditional love and support

ACKNOWLEDGMENTS

I would like to express my gratitude to my advisor, Professor Alan R. Katritzky, for his consistant support and guidance, which were essential for me to complete my studies. His overall knowledge of science, not just chemistry, and his strong devotions to science and education is extremely impressive. His mentorship has guided me through many challenges as a graduate student, and I will always remain appreciative and thankful for the opportunity working with him. I would especially like to thank Dr. C.

Dennis Hall for his constructive and helpful suggestions for my research and for his kindness and patience with reading and correcting my writing over and over again. Also,

I want to thank Dr. John Reynolds, Dr. Ion Ghiviriga, Dr. Weihong Tan and Dr. Fazil

Najafi for their time as members of my committee. Their knowledge, advice, and support have been a valuable and cherished resource during my graduate career.

This work would not have been possible without the hard work of my coworkers with whom I have interacted: Dr. Rajeev Sakhuja for his expertise in both chemistry and as a group leader; Dr. Prahbu Mohapatra for the teamwork on the synthesis of 1,3,4- oxadiazoles in Chapter 3. My thanks must go to Dr. Yuming Song, Ms. Reena Gyanda and Ms. Ling Wang who all have contributed to the triazole-polymer project described in

Appendix. I would like to thank all of the present and past members of the Katritzky research group. I have made some great friends and enjoyed their company during the past four years. Their friendship and support have made this period of my life more pleasant and memorable.

TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ...... 4

TABLE OF CONTENTS ...... 5

LIST OF TABLES ...... 9

LIST OF FIGURES ...... 10

LIST OF SCHEMES ...... 12

LIST OF ABBREVIATIONS ...... 16

ABSTRACT ...... 20

CHAPTER

1 INTRODUCTION TO BENZOTRIAZOLE CHEMISTRY ...... 21

1.1 Benzotriazole ...... 21 1.1.1 Structure and Isomerization ...... 21 1.1.2 Synthesis of Benzotriazoles ...... 23 1.2 Activation Ability of the Benzotriazole Ring ...... 24 1.2.1 As a Proton Activator or an Anion Stabilizer ...... 24 1.2.2 As a Leaving Group ...... 25 1.2.3 As an Ambient Anion-Directing Group ...... 26 1.2.4 As a Radical Stabilizer or a Radical Precursor ...... 26 1.2.5 As an Anion Precursor ...... 27 1.3 N-Acylbenzotriazoles in Heterocyclic Synthesis ...... 27 1.3.1 Preparation of N-Acylbenzotriazoles ...... 27 1.3.2 N-Acylbenzotriazoles for N-, S- , C- and O- Acylation ...... 28 1.3.2.1 Selective synthesis of S-acyl and N-acylcysteines ...... 29 1.3.2.2 Selective synthesis of S-acylglutathiones and N- acylglutathiones ...... 29 1.3.2.3 Synthesis of N-Cbz-protected (α-aminoacyl)methylenepyridines and -quinolines ...... 30 1.3.2.4 Synthesis of S-acylisotripeptides ...... 30 1.3.2.5 Synthesis of azo-dye labeled amino acids and amines ...... 31 1.3.2.6 Synthesis of chiral O-(α-protected-aminoacyl)steroids ...... 31 1.3.2.7 Synthesis of pyridin-2-ylmethyl ketones ...... 32 1.3.2.8 Synthesis of 1-(benzotriazol-1-yl)alkyl- ethers and esters ...... 33 1.3.2.9 Bt-mediated C-acylation ...... 33 1.3.3 Expansion of the Scope for N-Acylbenzotriazole Applications in Heterocyclic Synthesis ...... 34

2 EFFICIENT SYNTHESES OF NAPHTHOQUINONE DIPEPTIDES ...... 35

2.1 Introduction ...... 35 2.1.1 Background ...... 35 2.1.2 Interaction of Quinones and Amino Acids in Nature ...... 39 2.1.3 Application of Quinone-Amino Acid Conjugates ...... 39 2.1.4 Literature Preparative Methods for Quinone-Amino Acid Conjugates ..... 40 2.2 Results and Discussion ...... 43 2.2.1 Reaction of Naphthoquinone-Amino Acid Conjugates ...... 43 2.2.2 Reaction of Thio-substituted Benzoquinone with Amino Acids ...... 47 2.2.3 Preparation of Benzotriazole Activated Benzoquinone-Amino Acid Conjugates ...... 49 2.3 Conclusion ...... 49 2.4 Experimental Section ...... 49

3 1,3,4-OXADIAZOLES FROM FUCTIONALIZED N-ACYLBENZOTRIAZOLES AND ACYLHYDRAZIDES ...... 66

3.1 Introduction ...... 66 3.1.1 Oxadiazoles ...... 66 3.1.2 Biologically Active 1,3,4-Oxadiazoles ...... 66 3.1.3 Polymeric 1,3,4-Oxadiazoles ...... 67 3.1.4 Luminescent Compounds, Dyes and Photosensitive Materials ...... 68 3.1.5 Other Miscellaneous Applications ...... 69 3.1.6 Literature Preparative Methods for 1,3,4-Oxadiazoles ...... 70 3.2 Results and Discussion ...... 74 3.3 Conclusion ...... 75 3.4 Experimental Section ...... 76 3.4.1 General Procedure for the Preparation of 1,3,4-Oxadiazole ...... 77

4 OVERVIEW OF N-HYDROXYAMIDOXIMES, N-AMINOAMIDOXIMES AND HYDRAZIDINES ...... 81

4.1 Introduction ...... 81 4.2 Structure and Configuration ...... 83 4.2.1 N-Hydroxyamidoximes ...... 83 4.2.2 N-Aminoamidoxime ...... 85 4.2.3 Hydrazidines ...... 85 4.3 Preparative Methods ...... 86 4.3.1 N-Hydroxyamidoximes and Their Derivatives ...... 86 4.3.1.1 From oximidoyl chlorides and hydroxyamines ...... 86 4.3.1.2 From amidoximes and hydroxyamine ...... 87 4.3.1.3 From nitrile oxides and hydroxyamines ...... 87 4.3.1.4 Miscellaneous preparative methods for di-O-alkyl derivatives of N-hydroxyamidoximes ...... 88 4.3.2 N-Aminoamidoximes and Their Derivatives ...... 89 4.3.2.1 From oxime chlorides or amidoximes ...... 89

4.3.2.2 From oximebenzotriazoles and hydrazines ...... 89 4.3.2.3 From N-hydroxyimidates and hydrazides ...... 90 4.3.2.4 From oxyimidoylchlorides and hydrazines ...... 90 4.3.2.5 From hydrazide imidate and hydroxyamine ...... 91 4.3.3 Hydrazidines ...... 91 4.3.3.1 From imidate salts and hydrazines...... 91 4.3.3.2 From amidoximes and hydrazines ...... 92 4.3.3.3 From amidrazones and hydrazines ...... 92 4.3.3.4 From diethoxy-N,N-dimethylethanamine and hydrazides ...... 93 4.3.3.5 From hydrazonyl bromides and hydrazines ...... 93 4.3.3.6 From triazines ...... 94 4.4 Chemistry and Reactions ...... 94 4.4.1 N-Hydroxyamidoximes ...... 94 4.4.1.1 Reduction of N-hydroxyamidoximes ...... 94 4.4.1.2 Oxidation of N-hydroxyamidoximes...... 95 4.4.1.3 Reaction with aldehydes ...... 96 4.4.1.4 Reaction with ketones ...... 97 4.4.2 N-Aminoamidoximes ...... 97 4.4.2.1 Reaction with aldehydes ...... 97 4.4.2.2 Cyclization in basic media to hydroxytriazoles ...... 98 4.4.3 Hydrazidines ...... 99 4.4.3.1 Reaction with aldehydes ...... 99 4.4.3.2 Reaction with anhydrides ...... 100 4.4.3.3 Reaction with diketones ...... 102 4.3.3.4 Reaction with alpha-keto- acids or esters ...... 103 4.4.3.5 Reaction with acylnitriles ...... 104 4.4.3.6 Reaction with cyclopentadiene derivatives ...... 104 4.4.3.7 Reaction with diketoesters ...... 105 4.4.3.8 Reaction with formic acid ...... 106 4.3.3.9 Reaction with thioesters ...... 107 4.3.3.10 Reaction with hydrazine ...... 108 4.4.3.11 Reduction of hydrazidines ...... 108 4.4.3.12 Condensation with α-halo ketones ...... 109 4.4.3.13 Miscellaneous reactions ...... 110 4.5 Applications ...... 111 4.5.1 N-Aminoamidoximes ...... 111 4.5.1.1 As a prodrug model ...... 111 4.5.1.2 Applications in inorganic chemistry ...... 111 4.5.2 N-Aminoamidoximes ...... 112 4.5.2.1 As metal ligands for important coordination compounds ...... 112 4.5.3 Hydrazidines ...... 114 4.5.3.1 As new fibrous adsorbents ...... 114 4.5.3.2 As anti-tuberculosis agents ...... 115 4.5.3.3 As environmentally friendly dyes ...... 115 4.6 Conclusions ...... 116

5 SUMMARY OF ACHIEVEMENTS ...... 117 7

APPENDIX

A HIGHLY FILLED CROSSLINKED 1,2,3-TRIAZOLE POLYMERS AS NOVEL ROCKET PROPELLANT BINDERS ...... 118

A-1 Introduction ...... 118 A-1-1 Rocket Propellant Binders ...... 118 A-1-2 Triazole Polymers as Novel Rocket Propellant Binders ...... 119 A-2 Results and Discussion ...... 124 A-2-1 Selection of Model Polymer System ...... 124 A-2-2 Preparation of Monomers ...... 124 A-2-3 Preparation of Dogbone Samples ...... 125 A-2-4 Filler Loading Effect ...... 126 A-3 Conclusions ...... 135 A-4 Experimental Section ...... 136

LIST OF REFERENCES ...... 142

BIOGRAPHICAL SKETCH ...... 166

LIST OF TABLES

Table page

2-1 Naphthoquinone-amino acid/ester conjugates ...... 44

2-2 Naphthoquinone-aminoacylbenzotriazoles ...... 45

2-3 Synthesis of Naphthoquinone-dipeptides ...... 46

2-4 Thiol-substituted benzoquinone-amino acid congjugates ...... 48

3-1 Reaction of N-acylbenzotriazoles with benzoic acid hydrazide ...... 76

A-1 Strain and modulus of unfilled and filled crosslinked triazole polymers ...... 127

A-2 Effect of filler loading (Al: 10-14 micron) on strain and modulus of crosslinked triazole polymers ...... 128

A-3 Effect of filler loading (Al: < 75 micron) on strain and modulus of crosslinked triazole polymers ...... 128

A-4 Effect of filler loading (NaCl: 45-50 micron) on strain and modulus of mechanical properties of crosslinked triazole polymers ...... 132

A-5 Effect of filler loading (NaCl: 83-105 micron) on strain and modulus of crosslinked triazole polymers ...... 132

A-6 Effect of mixed filler loading (mixture of two different particle sized Aluminum) on strain and modulus of crosslinked triazole polymers ...... 133

A-7 Effect of mixed filler loading (mixture of Aluminum and NaCl) on strain and modulus of crosslinked triazole polymers ...... 133

A-8 Effect of mixed filler loading (mixture of Aluminum and NaCl) on strain and modulus of crosslinked triazole polymers ...... 133

LIST OF FIGURES

Figure page

1-1 Isomerization of Benzotriazoles ...... 21

1-2 1H-Benzotriazole functions as an excellent synthetic auxiliary ...... 22

1-3 Compounds with the Bt-C-O functionality ...... 33

2-1 Important drugs containing quinone moities ...... 36

2-2 Doxorubicin molecules intercalating DNA ...... 37

2-3 Naturally occurring quinones ...... 39

2-4 Classes of quinones participating in biological redox processes ...... 39

3-1 Four types of oxadiazoles ...... 66

3-2 Biologically important oxadiazoles ...... 67

3-3 Polymers containing 1,3,4-oxadiazoles ...... 68

3-4 1,3,4-Oxdiazoles with interesting optical properties ...... 69

3-5 Other applications of 1,3,4-oxidazoles ...... 70

4-1 Structure of N-hydroxyamidoximes, N-aminoamidoxime & hydrazidine ...... 82

4-2 N-Hydroxyamidoximes and their derivatives in the literature ...... 82

4-3 Known N-aminoamidoximes and their derivatives ...... 82

4-4 Hydrazidines and their derivatives ...... 83

4-5 Tautomerization, conformation and configuration of N-hydroxyamidoxime ...... 85

4-6 Configuration of N-aminoamidoximes ...... 85

4-7 Configuration of hydrazidines ...... 85

4-8 N-Hydroxybenzamidoxime derivatives ...... 87

4-9 Acetohydroximic oxime and ethylnitrosolic acid ...... 112

4-10 N-Aminobenzamidxoime cobalt(II) perchlorate complex ...... 114

4-11 Environmental friendly dye ligands ...... 116

A-1 Common rocket propellant binders ...... 118

A-2 Dogbone mold containing filled and unfilled triazole polymers ...... 126

A-3. nstron universal tensile testing machine ...... 126

A-4 Effect of filler loading on modulus of crosslinked triazole polymers ...... 130

A-5 Effect of filler loading on strain of crosslinked triazole polymers ...... 131

A-6 Effect of mixed filler loading on modulus of crosslinked triazole polymers ...... 134

A-7 Effect of mixed filler loading on strain of crosslinked triazole polymers ...... 135

A-8 Dimensions of dogbone mold and dogbone sample ...... 137

LIST OF SCHEMES

Scheme page

1-1 Alkylation of 1H-benzotriazole ...... 23

1-2 Synthesis of benzotriazole ...... 23

1-3 Synthesis of 5,7-dinitro-1-phenylbenzotriazole ...... 23

1-4 Reactions of benzotriazolyl-stabilized carbanions with electrophiles ...... 25

1-5 Reaction with Grignard reagent ...... 26

1-6 Benzotriazole acts as an anion-directing group ...... 26

1-7 Benzotriazole acts as an radical stabilizer or precursor ...... 27

1-8 Reductive elimination of benzotriazole ...... 27

1-9 Methods for preparation of N-acylbenzotriazoles ...... 28

1-10 Selective synthesis of S-acyl and N-acylcysteines ...... 29

1-11 Selective synthesis of S-acylglutathiones and N-acylglutathiones ...... 29

1-12 Synthesis of N-Cbz-protected (α-aminoacyl)methylenepyridines and - quinolines ...... 30

1-13 Preparation of S-acylisotripeptides ...... 30

1-14 Synthesis of azo-dye labeled amino acids and amines ...... 31

1-15 Microwave assisted synthesis of chiral O-(α-protected-aminoacl)steroids and O-(α-protected-dipeptidoyl)steroids ...... 32

1-16 Synthesis of pyridin-2-ylmethyl ketones mediated via N-acylbenzotriazoles ...... 32

1-17 Synthesis of 1-(benzotriazol-1-yl)alkyl esters by N-acylbenzotriazoles ...... 33

1-18 Enaminones via C-acylation of ketimines with N-acylbenzotriazoles ...... 34

2-1 Quinone-amino acid conjugates linked via a vinylic spacer ...... 41

2-2 Synthesis of quinone-amino acid hybrids via Cross-Enyne Metathesis and Diels-Alder reactions ...... 41

2-3 N-Quinonyl amino acids obtained with chloro-substituted quinones ...... 41

2-4 Synthesis of N-quinonyl amino acids by addition to S-substituted benzoquinone ...... 42

2-5 Preparation of naphthoquinone-dipeptides ...... 42

2-6 Synthesis of naphthoquinone-amino acid/ester conjugates ...... 43

2-7 Synthesis of naphthoquinone-aminoacylbenzotriazole conjugates...... 44

2-8 Preparation of naphthoquinone dipeptide conjugates ...... 45

2-9 Synthesis of thiol-substituted benzoquinone-amino acid conjugates ...... 48

2-10 Synthesis of benzoquinone-amino acid benzotriazole derivative ...... 49

3-1 Cycloaddition reactions of 1,3,4-oxadiazoles in total synthesis of natural product ...... 69

3-2 Preparation of 2,5-disubstituted 1,3,4-oxadiazoles from 1,2-diacylhydrazines ... 70

3-3 Preparation of 2,5-disubstituted 1,3,4-oxadiazoles from hydrazones ...... 71

3-4 Preparation of 1,3,4-oxadiazolinones ...... 71

3-5 1,3,4-Oxadiazole ring synthesis from acyclic precursors ...... 72

3-6 Preparation of 2-amino-1,3,4-oxadiazoles ...... 72

3-7 One-pot syntheses of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles ...... 73

3-8 1,3,4-Oxadiazoles from N-acylbenzotriazoles ...... 75

4-1 Preparation of N-hydroxybenzamidoxime ...... 86

4-2 Preparation of N-hydroxypyridylamidoximes ...... 86

4-3 Preparation of 2,6-dichloro-N-hydroxybenzaldoxime hydrochloride salt ...... 87

4-4 Preparation of formic hydroxyamidoxime hydrochloride salt ...... 87

4-5 Synthesis of N-hydroxyamidoximes from nitrile oxides ...... 88

4-6 Preparation of di-O-benzyl derivative of N-hydroxymethylamidoxime ...... 88

4-7 Synthesis of di-O-methylsubstituted p-sulfamido-N-hydroxybenzamidoximes ... 89

4-8 General route to N-aminoamidoximes ...... 89

4-9 Synthesis of N-amino-N´-nitrophenyl benzamidoxime ...... 89

4-10 Preparation of N-(ethoxycarbonyl)amide benzamidoxime ...... 90

4-11 Preparation of 3-(3-arylsydnon-4-yl)triazole derivatives ...... 90

4-12 Preparation of hydroxamic acid ethoxycarbonylhydrazides ...... 91

4-13 Synthesis of aliphatic hydrazidines ...... 91

4-14 Synthesis of substituted formazans ...... 92

4-15 Synthesis of triphenylformazan ...... 92

4-16 Synthesis of hydrazidine hydrochlorides ...... 92

4-17 Synthesis of diaminoguanidine / amino-hydrazidine ...... 93

4-18 Synthesis of hydrazidine derivatives ...... 93

4-19 Synthesis of hydrazidines from hydrazonyl bromide ...... 94

4-20 From triazine to hydrazidines...... 94

4-21 Conversion of N-hydroxybenamidoxime into benzamidoxime ...... 95

4-22 Conversion of formic hydroxyamidoxime to its nitrosolic acid ...... 95

4-23 Synthesis of 3 ,5-diphenyl-1,2,4-oxadiazole ...... 96

4-24 Reaction of nitrosolic acid salts with dinitrogen tetraoxide ...... 96

4-25 Synthesis of 4-hydroxyoxadiazolines ...... 97

4-26 Reaction of N-hydroxyamidoxime with benzophenone ...... 97

4-27 Preparation of 3,5-disustitued 1H-[1,2,4]triazoles ...... 98

4-28 Synthesis of 3-benzyl-5-(p-tolyl)-4H-1,2,4-triazol-4-ol ...... 98

4-29 Synthesis of 3-phenyl-4-hydroxy-4,5-dihydro-1,2,4-triazol-5-one ...... 99

4-30 Synthesis of dibenzylidene hydrazidine 4-amino-1,2,4-triazole hydrochloride .... 99

4-31 Reaction of hydrazidines with aldehydes ...... 100

4-32 Synthesis of pyrrolo[1,2-b][1,2,4,5]tetrazines ...... 101

4-33 Reaction with diketones ...... 103

4-34 Syntheses of triazinones ...... 104

4-35 Reaction of hydrazidines with acylnitriles ...... 104

4-36 Synthesis of 4-aminocyclopenta[e]-1,2,4-triazines ...... 105

4-37 Reaction of hydrazidines with diketoesters ...... 106

4-38 Reaction hydrazidines with formic acid ...... 107

4-39 Synthesis of unsymmetrically substituted 1,2,4,5-tetrazines ...... 107

4-40 Synthesis of 3-methyl-6-pyridyl-1,2,4,5-tetrazine ...... 108

4-41 Reduction of formazans ...... 108

4-42 Reaction of α-halo ketones with hydrazidine amine ...... 109

4-43 Hydrazidine radical ...... 110

4-44 Reaction of hydrazine hydrazidine with acetylacetone ...... 110

4-45 In vitro biotransformation of N-hydroxybenzamidoxime ...... 111

4-46 Synthesis of dinitrosomethanide (DNM) salt ...... 112

4-47 Synthesis of novel vic-dioxime derivatives of hydrazones ...... 113

4-48 Synthesis of vic-dioxime derivatives and their metal complexes ...... 114

A-1 Triazole polymer model system ...... 124

A-2 Preparation of monomers ...... 125

A-3 General route to crosslinked 1,2,3-triazole polymers with fillers ...... 141

LIST OF ABBREVIATIONS

Ac acetyl (CH3C=O)

Al aluminum

Ala alanine

Ar aryl

Boc t-butyloxycarbonyl

Bn benzyl br broad (spectral) brs broad singlet (spectral)

Bt benzotriazoyl

BtH 1H-benzotriazole

BTNO benzotriazole-N-aminoxyl radical (>N−O•)

Bz benzoyl

C carbon

Cu copper oC degree Celcius

Calcd calculated

CAN ceriumIV ammonium nitrate

Cbz carbobenzyloxy (BnOC=O)

CDCl3 deuterated chloroform

CH3CN acetonitrile d doublet (spectral)

DCC dicyclohexyl carbodiimide

DCM methylene chloride

DMAP 4-dimethylaminopyridine (base catalyst)

DMSO dimethyl sulfoxide (solvent)

DMSO-d6 deuterated dimethyl sulfoxide

DMF dimethylformamide (solvent)

E entgegen (opposite, trans)

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv equivalent(s) et al. and others

EtOAc ethyl acetate

Fe iron g gram(s)

Glu glutamic acid

Glu-OMe glutamic methylester

Gly glycine h hour

H hydrogen

HBT 1-hydroxybenzotriazole

HOBT N-hydroxybenzotriazole

HBTU O-benzotriazolye-N,N,N’,N’-tetramethyluroniumhexafluoro-

phosphate

HCl hydrochloric acid

HDPE high density polyethylene

HMDS hexamethyldisilazide

HRMS high resolution mass spectrometry

HTPB hydroxy-terminator polybutadiene

Hz hertz i-Pr isopropyl

J coupling constant (NMR)

LDA lithium aluminium hydride

LDPE low density polyethylene

Leu leucine lit literature

Lle isoleucine

Lys lysine m multiplet (spectral); metre(s); milli

MeCN acetonitrile

MgSO4 magnesium sulfate m. p. melting point

Ms methanesulfonyl (mesyl, CH3SO2) m/z mass-to-charge ratio

N nitrogen

NaCl sodium chloride

NMR nuclear magnetic resonance

O oxygen

PBAN polybutadiene acrylic acid acrylonitrile

Phe phenylalanine

PMMA polymethylmethacrylate

PU polyurethane

RT room temperature s singlet (spectral)

S sulfur

SOCl2 thionyl chloride t triplet (spectral) t tertiary

TBAF tetrabutylammonium floride

TEA triethylamine (Et3N)

THF tetrahydrofuran (solvent)

TMS tetramethylsilane, also trimethylsilyl

Tryp tryptophan

Ts tosyl (p-CH3C6H4SO2)

UV ultra violet

Val valine wt% weight percent

Z zusammen (together, cis)

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

STUDIES IN HETEROCYCLIC SYNTHESIS

Longchuan Huang

December 2010

Chair: Alan R. Katritzky Major: Chemistry

1H-Benzotriazole and its derivatives are versatile synthetic auxiliaries. My research studies have further investigated the application of N-acylbenzotriazoles in the synthesis of heterocyclic compounds. In Chapter 2, an efficient N-acylbenzotriazole mediated preparation of naphthoquinones-dipeptides from naphthoquinone-α-amino acid conjugates as potential cytotoxic agents is reported. In Chapter 3, a convenient preparation of 1,3,4-oxadiazoles from functionalized N-acylbenzotriazoles and acyl hydrazides is described. Chapter 4 presents a review of the synthesis, reactivity and utility of N-amino- and N-hydroxyamidoximes and hydrazidines, which are important classes of nitrogen-rich heterocycle precursors.

CHAPTER 1 INTRODUCTION TO BENZOTRIAZOLE CHEMISTRY

1.1 Benzotriazole

1.1.1 Structure and Isomerization

Benzotriazole (1.1) is classified as a 1,2,3-triazole, i.e. a cyclic compound featuring two fused rings containing the linkage -N=N-NH- or =N-NH-N=. Benzotriazole is used as corrosion inhibitor, e.g. for silver protection in dishwashing detergents and an anti-fog agent in photographic development. [2009JAE269, 2009JMPT1729, 2009ME367]

Benzotriazole derivatives are employed in pharmaceuticals such as antifungal, antibacterial, anthelmintic drugs, and polymerization catalysts. [2003CEJ4586,

2010CR1564]

Figure 1-1. Isomerization of Benzotriazoles

1H-Benzotriazole exists in solution as an equilibrium mixture of 1-benzotriazole

(1.1) and 2-benzotriazole (1.2) (Figure 1-1). [1975JCS(PT1)1181] Such isomerization is general for disubstituted N-(aminomethyl)benzotriazoles, such as N-(aminoalkyl)- (1.3)

[1987JCS(PT1)2673, 1989H1121, 1990JOC5683], N-(alkoxyalkyl)- [1992JOC4932], N-

(alkylthioalkyl)- (1.5) [1991HCA1936], and N-(diarylmethyl)-benzotriazoles

[1990JCS(PT2)2059], but not for simple N-alkylbenzotriazoles.

1H-Benzotriazole is an excellent synthetic auxiliary. [1991T2683, 1998CR409,

2003CEJ4586] As summarized in Section 1.1.2, it can act as a leaving group, an electron-withdrawing group and an electron-donating group (Figure 1-2). As another aspect of a good auxiliary, BtH can act as a weak base (pKa = 1.6) or a weak acid (pKa

= 8.3) [1948JCS2240, 1991T2683], which facilitates the easy removal of benzotriazole from the reaction mixture by washing with base or acid. Moreover, 1H-benzotriazole is an inexpensive, stable compound that is soluble in common organic solvents such as ethanol, benzene, chloroform, and DMF.

Figure 1-2. 1H-Benzotriazole functions as an excellent synthetic auxiliary

Alkylation of 1H-benzotriazole (1.1) with alkyl halides or sulfates in the presence of a base yield mixtures of 1-alkylbenzotriazoles (1.10) and 2-alkylbenzotriazoles (1.11).

The ratio of product depends on the bulkiness of the alkyl group and varies from 78:22

(R = Et) to 50:50 (R = C6H11CH2) (Scheme 1-1). [1994LAC1]

Scheme 1-1. Alkylation of 1H-benzotriazole

1.1.2 Synthesis of Benzotriazoles

Benzotriazole is produced by reaction of o-phenylenediamine (1.12) with sodium nitrite and acetic acid. The conversion proceeds via diazotization of one of the amino groups (Scheme 1-2). [2001HYDX350, 1981USP4299965]

Scheme 1-2. Synthesis of benzotriazole

Reduction of compound (1.13) gave 4,6-dinitro-N1-phenylbenzene-1,2-diamine

(1.14), which were further subjected to the reaction with acetic acid and sodium nitrite to yield 5,7-dinitro-1-phenyl-benzotriazole (1.15). Dinitrobenzotriazole (1.15) may be further nitrated with nitric or mixed acid, and its derivatives have been examined as potential energetic materials with particular reference to their densities (Scheme 1-3).

[1992AJC513]

Scheme 1-3. Synthesis of 5,7-dinitro-1-phenylbenzotriazole

1.2 Activation Ability of the Benzotriazole Ring

Benzotriazole derivatives are important synthetic auxiliaries that offer versatile applications in organic chemistry including a vast array of synthetic transformations.

[1998CR409, 2003CEJ4586] Benzotriazole methodology has been applied to alkylation

[1994CSR363], acylation [2003JOC4932, 2003JOC5720, 2005S1656], imine acylation

[2000S2029], and imidoylation [1997TL6771, 1999OL977, 2002JOC4667,

2003CEJ4586]. It has also been utilized in Mannich reactions [1994JHC917], Michael reactions [2001BCSJ2133] and Grignard reactions [2007S3141].

Many heterocycles are biologically active compounds; therefore, heterocyclic scaffolds are of major interest to chemists. The application of benzotriazole derivatives in organic synthesis has been studied meticulously by our group since 1980s, especially with reference to the synthesis of heterocyclic molecules. A benzotriazole group commonly activates the carbon atom to which it is attached; hence, benzotriazole intermediates are widely used to introduce a variety of functional groups into molecules.

Five major applications of benzotriazole group in organic transformations are illustrated below:

1.2.1 As a Proton Activator or an Anion Stabilizer

Many synthetic applications of benzotriazole derivatives are based on the ability of the benzotriazolyl substituent to stabilize an adjacent carbanion. [1998CR409,

2003CEJ4586, 2006S3231]

n-BuLi or LDA can convert 1-(n-alkyl)benzotriazoles (1.16) to anions (1.17) (R1 =

H or alkyl), consecutively treating with alkyl halides will give 1-alkylbenzotriazoles (1.18) bearing secondary alkyl groups. Carbonyl electrophiles can be used to trap the Bt- stabilized anion (1.17) to form (1.20). Reaction of (1.17) with CO2, or ethyl benzoate

gives carboxylic acid (1.19) and ketone (1.21) respectively (Scheme 1-4).

[1991CB1819]

Scheme 1-4. Reactions of benzotriazolyl-stabilized carbanions with electrophiles

1.2.2 As a Leaving Group

The leaving group ability of benzotriazole is comparable to cyano and sulfonyl groups [1995S1315]. The acid chlorides and acyltosylates are often so reactive as to be hard to isolate. Compared with the more reactive halogen, tosylate and the toxic cyano groups, bezotriazole (Bt) behaves as a tame halogen substituent and has the advantage of forming a stable, non-volatile anion in solution. For example, α- benzotriazole amines and ethers are stable compounds that are much easier to work

with than the corresponding toxic chloro derivatives. The displacement of benzotriazole group can be easily achieved by nucleophilic attack [1994CSR363], or by different nucleophilic atoms such as C, S, N, O, or even by Grignard reagents (Scheme 1-5).

[1991T2683, 1996JOC1624]

Scheme 1-5. Reaction with Grignard reagent

1.2.3 As an Ambient Anion-Directing Group

In an allylic system (1.25), the benzotriazolyl moiety acts as an anion-directing group. Hence, the alpha position to Bt group is favored for attack of various electrophiles (Scheme 1-6). [1990HC21, 1992LAC843]

Scheme 1-6. Benzotriazole acts as an anion-directing group

1.2.4 As a Radical Stabilizer or a Radical Precursor

The benzotriazolyl moiety can act as a radical precursor (1.30) (Scheme 1-7). The generation of the aminoxyl radical benzotriazole-N-oxyl (>N−O•) (i.e., BTNO) (1.29a) from 1-hydroxybenzotriazole (HBT) (1.28a) by monoelectronic oxidation with ceriumIV ammonium nitrate (i.e., CAN) in MeCN solution is shown in Scheme 1-7. [2004CC2356,

2005JOC9521] BTNO radical (1.29a) can be trapped and used to initiate other radical reactions via generating a different radical such as (1.30a).

Scheme 1-7. Benzotriazole acts as an radical stabilizer or precursor

1.2.5 As an Anion Precursor

Benzotriazole moieties can act as a carbanion (1.32) precursor via reductive elimination (Scheme 1-8). [1997JOC4148, 1996LAC745, 1992JCS(PT1)1111] The carbanion can react further with other electrophiles such as ketones/aldehydes to form alcohols (1.33).

Scheme 1-8. Reductive elimination of benzotriazole

1.3 N-Acylbenzotriazoles in Heterocyclic Synthesis

1.3.1 Preparation of N-Acylbenzotriazoles

N-Acylbenzotriazoles are stable crystalline compounds that can be easily prepared and handled in the lab. The classical preparation of acylazoles was from the corresponding acid chlorides (Scheme 1-9). N-Acylbenzotriazoles can now be prepared directly from carboxylic acids (1.35), obviating the necessity of isolating acid chlorides.

The second method is reaction of carboxylic acids with thionyl chloride in the presence of excess benzotriazole, providing N-acylbenzotriazoles (1.35) in high yields (Scheme

1-9). [2003S2795] The third method uses a sulfonylbenzotriazole (1.36) as a “counter

attack” reagent; in the presence of Et3N, carboxylic acids (1.35) are directly converted into the acylbenzotriazoles (1.34) through intermediate formation of the mixed carboxylic sulfonic anhydride and benzotriazole anion, which are then acylated by the mixed anhydride. [1992T7817, 2000JOC8210]

A wide range of N-acylbenzotriazoles have been prepared in our group via the methods mentioned above, including alkyl and aryl carboxylic acids, many heterocyclic carboxylic acids, unsaturated carboxylic acids, and carboxylic acids with various other functionalities. [1992T7817, 2000JOC8210, 2003S2795]

Scheme 1-9. Methods for preparation of N-acylbenzotriazoles

1.3.2 N-Acylbenzotriazoles for N-, S- , C- and O- Acylation

N-Acylbenzotriazoles are advantageous for N-, O-, C-, and S-acylation,

[2000JOC8210, 2003JOC5720, 2005SL1656, 2005S397, 2006S411, 2006S3231,

2008OBC2400] especially where the corresponding acid chlorides are unstable or difficult to prepare [1998AA35, 1999T8263]. Several recent demonstrations of 1-acyl-

1H-benzotriazoles as versatile synthetic auxiliaries in our group include:

1.3.2.1 Selective synthesis of S-acyl and N-acylcysteines

Cysteine (1.37) can be exclusively S- or N- acylated to (1.38) or (1.39) with N- acylbenzotriazoles (1.34) under slightly different reaction conditions (Scheme 1-10).

[2009JOC7165]

Scheme 1-10. Selective synthesis of S-acyl and N-acylcysteines

1.3.2.2 Selective synthesis of S-acylglutathiones and N-acylglutathiones

1-Acyl-1H-benzotriazoles (1.40) were used in the selective syntheses of S- acylglutathiones (1.42) and N-acylglutathiones (1.43). [2010SL1337] The transformation is facile and has general applications for S-acylation and N-acylation of biologically important larger peptides and glycopeptides (Scheme 1-11).

Scheme 1-11. Selective synthesis of S-acylglutathiones and N-acylglutathiones

1.3.2.3 Synthesis of N-Cbz-protected (α-aminoacyl)methylenepyridines and - quinolines

Aminoacyl-conjugates of nitrogen heterocycles (1.46) were synthesized as chiral potential novel pharmacophores from 2-methyl- and 4-methylpyridine and 2- methylquinoline (1.45) by reacting with benzotriazole-activated (Cbz)-protected amino acids (1.44) (Scheme 1-12). [2010JOC3938]

Scheme 1-12. Synthesis of N-Cbz-protected (α-aminoacyl)methylenepyridines and - quinolines

1.3.2.4 Synthesis of S-acylisotripeptides

Cysteine and C-terminal cysteine peptides (1.47) are selectively S-acylated by N-

(Pg-α-aminoacyl)benzotriazoles (1.34) to give N-Pg-S-acylisotripeptides (1.48) (Scheme

1-13), which can undergo chemical ligation after deprotection to give the corresponding native tetra-peptides via migration of the cysteine S-acyl groups to the N-terminal amino acids. [2010OBC2316]

Scheme 1-13. Preparation of S-acylisotripeptides

1.3.2.5 Synthesis of azo-dye labeled amino acids and amines

Traditional methods to link azo-dye carboxylic acids to bio-moieties have used coupling reagents such as DCC, EDCI, HOBT, HBTU, or via acyl chloride intermediates, and usually require complex procedures, harsh reaction conditions and/or give low yields. By comparison, the new methods for preparing azo-dye labeled amino acids (1.52) and amines (1.53) were developed by reaction of N-(4- arylazobenzoyl)-1H-benzotriazole (1.49) with amino acids (1.50) or amines (1.51) under mild reaction conditions to give high yields with no racemization of chiral compounds

(Scheme 1-14). [2008OBC2400]

Scheme 1-14. Synthesis of azo-dye labeled amino acids and amines

1.3.2.6 Synthesis of chiral O-(α-protected-aminoacyl)steroids

Chiral O-(α-protected-aminoacyl)steroids (1.56) and O-(α-protected- dipeptidoyl)steroids (1.59, 1.61) were prepared under microwave irradiation from naturally occurring steroidal alcohols (1.55, 1.58, 1.60) with complete retention of chirality mediated by N-(Z-α-aminoacyl)-benzotriazoles (1.54) and Z- dipeptidoylbenzotriazole (1.57). (Scheme 1-15) [2006Steroids660]

Scheme 1-15. Microwave assisted synthesis of chiral O-(α-protected-aminoacyl)steroids and O-(α-protected-dipeptidoyl)steroids

1.3.2.7 Synthesis of pyridin-2-ylmethyl ketones

Katritzky el. al. reported that 2- or 4-picoline (1.62) was lithiated by LDA and then treated with acylbenzotriazoles (1.63) to afford pyridin-2-ylmethyl ketones (1.64) in good yields (60-84%) (Scheme 1-16). In comparison with previous methods, this approach utilizing N-acylbenzotriazole simplifies the procedure and provides generally better yields. [2005ARKIVOC329, 2010CR1564]

Scheme 1-16. Synthesis of pyridin-2-ylmethyl ketones mediated via N- acylbenzotriazoles

1.3.2.8 Synthesis of 1-(benzotriazol-1-yl)alkyl- ethers and esters

Benzotriazole derivatives containing the Bt-C-O functionality are versatile intermediates in organic synthesis. [1998CR409] One of the examples is 1-

(benzotriazol-1-yl) alkyl ethers (1.65) (Figure 1-3) which have been widely used for the preparation of various heterocycles [1995JOC7612, 1995JOC7625], α-functionalized ketones [1995JOC7619, 1997JOC706], amides [1988JOC5854], and ethers

[1989JOC6022]. Another example is 1-(benzotriazol-1-yl) alkyl esters (1.66) which should offer similar synthetic functions. The initial route for the preparation of (1.66) was reported from forming unstable intermediates with high sensitivity to moisture.

[1991S69] A more general and useful synthesis of the 1-(benzotriazol-1-yl) alkyl esters

(1.66) was achieved by the use of N-acylbenzotriazoles (1.67) reacting with aldehydes

(1.68) (Scheme 1-17). [1999JHC777]

Figure 1-3. Compounds with the Bt-C-O functionality

Scheme 1-17. Synthesis of 1-(benzotriazol-1-yl) alkyl esters by N-acylbenzotriazoles

1.3.2.9 Bt-mediated C-acylation

Carbon acylations provide an entry to carbon-carbon bonds. [1973JOC514] 1-

Acylbenzotriazoles-mediated C-acylation was demonstrated in the regioselective synthesis of β-diketones. [2000JOC3679] Reactions of alkyl and aryl N-

acylbenzotriazoles with saturated cyclic ketones, unsaturated cyclic ketones, and aliphatic ketones in the presence of lithium diisopropylamide (LDA) and tetrahydrofuran

(THF) at -78°C resulted in C-acylated products in excellent yields. Enaminones (1.71) were obtained by C-acylation of ketimines (1.70) with N-acylbenzotriazoles (1.69)

(Scheme 1-18). [2000S2029]

Scheme 1-18. Enaminones via C-acylation of ketimines with N-acylbenzotriazoles

1.3.3 Expansion of the Scope for N-Acylbenzotriazole Applications in Heterocyclic Synthesis

N-Acylbenzotriazoles are versatile synthetic auxiliaries used as C-, O-, S- and N- acylating agents as well as precursors to many valuable heterocycles. Part of my research efforts has been focused on the expansion of the scope of N- acylbenzotriazoles as activated reagents toward heterocyclic synthesis, specifically, naphthoquinone-dipeptides and 1,3,4-oxadiazoles. In Chapter 2, an N-acylbenzotriazole mediated preparation of naphthoquinones-dipeptides from naphthoquinone-α-amino acid conjugates as potential cytotoxic agents is described, also some investigation of benzoquinone amino acid conjugates are documented. In Chapter 3, 1,3,4-oxadiazoles were prepared from functionalized N-acylbenzotriazoles and acylhydrazides.

CHAPTER 2 EFFICIENT SYNTHESES OF NAPHTHOQUINONE DIPEPTIDES

2.1 Introduction

2.1.1 Background

Quinones play vital roles in the biochemistry of living cells including respiration, photosynthesis and cellular defense against bacteria, fungi and parasites.

[2007BMCL2340] Some quinonic derivatives are used as medicines for treating bacterial and fungal diseases, and others exhibit potent antimalarial capacities.

[2002AA71] Many naturally occurring quinones are antitumor agents, and those approved for clinical use include: menadione (2-methyl-1,4-naphthoquinone) (2.1), anthracycline-glycosides (daunorubicin (2.2), doxorubicin (2.3)), benzoquinone derivatives (mitomycin C (2.4), carbazilquinone (2.5), diaziquone (2.6)), and more complex quinones (mitoxantrone (2.7), streptonigrin (2.8)) (Figure 2-1) [2005MRMC449,

2008OBC637, 2007MRMC481].

Menadione (2.1) has been used experimentally as a chemotherapeutic agent for cancer. The combination of vitamin C and Menadione (2.1) has antitumor activities and ability to prevent and treat breast and prostate cancer. [2001JN158S] Daunorubicin

(2.2) is a chemotherapeutic natural product of the anthracycline family. It has been used for treatment of some cancers, and also specific types of leukaemia. Doxorubicin (2.3) is another anthrocycline-type of drug used in cancer chemotherapy. All anthracyclines have anticancer abilities by intercalating DNA and. inhibiting DNA replication in cancer cells. The cartoon diagram of two doxorubicin molecules intercalating DNA is shown in

Figure 2-2. [1990B2538]

Mitomycin C (2.4) is a type of anti-tumor antibiotic that binds covalently to DNA.

[2008OBC637] Mitomycin-C (2.4) and Carbazilquinone (2.5) both contain quinonyl, aziridinyl and carbamoyloxy groups, and both have significant effects on plasmacytoma

X5563 in C3H/He mice. [2007MRMC481] Diaziquone (2.6) is a synthetic quinonic derivative with potential antineoplastic activities. It can damage DNA via initiating radical reactions with DNA strand breaks. Also, it can disrupt DNA function by alkylating or crosslinking DNA during all phases of the cell cycle. [1998L139]

Figure 2-1. Important drugs containing quinone moities

Mitoxantrone (2.7) is a type II topoisomerase inhibitor which can disrupt DNA synthesis and repair in both healthy cells and cancer cells by intercalation with DNA. It has been used in the treatment of several types of cancer. [1979JMC1024]

Streptonigrin (2.8) is an aminoquinone isolated from the bacterium Streptomyces flocculus. It can act as a reverse transcriptase inhibitor and cause free radical-mediated cellular damage. It can also complex with DNA and topoisomerase II, resulting in DNA cleavage and inhibition of DNA replication and RNA synthesis. [1977BBRC387]

(wwwPDB – Worldwide Protein Data Bank) Figure 2-2. Doxorubicin molecules intercalating DNA

The cell cytotoxicity of quinonic drugs is due to (i) their ability to undergo a reversible one electron reduction followed by formation of semiquinone radicals and (ii) their ability to associate and intercalate with DNA duplexes, thus impairing appropriate template function and nucleic acid synthesis. [2000AA439]

Varieties of human tumors are hormone-dependent and contain corresponding hormone receptors. Receptors for peptide hormones such as luteinizing hormone- releasing hormone (LH-RH, also known as Gonadotropin-releasing hormone (GnRH) and luliberin which is a tropic peptide hormone responsible for the release of Follicle- stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary

[1998LPS421], somatostatin [1990JSBMB1083], bombesin [1983P683], vasoactive intestinal peptide [1990P1205] and growth factors, including epidermal and insulin-like

[1995JANYAS402], have been detected in the cancers of prostate, breast pancreas, ovary, lung, colon and in brain tumors [1987CL223]. In view of abundancy of tumors having LH-RH receptors, related target chemotherapy has gained considerable attention over the years. Thus, different analogs of LH-RH, agonists and antagonists, were conjugated to cytotoxic compounds such as alkylated nitrogen mustard, anticancer antibiotics and quinones derivatives, which exhibited a wide range of specific binding affinities towards LH-RH receptors. Preliminary finding proved that quinonyl-amino acids incorporated into a biological active peptide showed cytotoxic and anticancer activity

[1998LPS421], which aroused our interest in synthesis of different quinones-amino acids dipeptides. Several peptides with quinone moieties attached through the ε-amino side chain of a D-lysine residue possess cytotoxic activity against human breast and prostate cancer cell lines. [1992PNAS972, 1996LPS263]

2.1.2 Interaction of Quinones and Amino Acids in Nature

Quinones and amino acids both exist in living systems, but usually in separate organs. Naturally occurring quinones include naphthoquinone (2.9) [2005BMCL5324], p-benzoquinone (2.10) [2006AA173], o-benzoquinone (2.11) [2007EJOC1244] and anthraquinones (2.12) [2006AA173] (Figure 2-3). Quinones are involved in mechanisms of electron and hydrogen transfer. [2005BMCL5324, 2007EJOC1244]

Figure 2-3. Naturally occurring quinones

2.1.3 Application of Quinone-Amino Acid Conjugates

Quinones and amino acids [2003AAPP34] constitute two ubiquitous classes of naturally occurring compounds with diverse important properties and applications.

Naphthoquinones (2.13), ubiquinone (2.14) and plastoquinones (2.15) examplify many classes of quinones that can participate in the electron-transporting chains during diverse biological redox processes, involving cellular respiration and photosynthesis.

[2007EOTP649, 2005BMCL5324]

Figure 2-4. Classes of quinones participating in biological redox processes

The efficiency of the quinonic compounds in inhibiting cancer cells growth is believed to stem from their ability to associate and intercalate with DNA duplexes and their participation in key cellular redox mechanisms with consequent generation of highly reactive oxygen species (ROS), which in turn modify and degrade nucleic acids and proteins within the cancer cells. [2002AA71] In the living cells quinones can undergo non-enzymatic or enzymatic one-electron reduction to give toxic semiquinone anion radicals. After additional redox reactions semiquinone anion radicals form superoxide anion radicals and hydroxyl radical which produces high cytotoxicity. Cell cytotoxicity is expressed by various mechanisms including redox cycling, arylation, intercalation, induction of DNA strand breaks, generation of site-specific free radicals and interference with mitochondrial respiration. [2005BMCL5324] Many biological peptides and proteins exert their activity following binding to specific cellular receptors and have therefore been used extensively as vectors for drug targeting.

Quinone-amino acid conjugates [1996S1468, 2000AA439, 2001AA135,

2001AA381, 2001T407, 2002AA71, 2005BMCL5324, 2007EJOC1244] have significant potential for drug applications, and thus cytotoxic quinone-peptide conjugates

[1996LPS263, 1998LPS421] are attractive synthetic targets. Quinone-amino acid conjugates are made up of two components and thus offer almost unlimited potential structural variations, for the reason that the combination of the features of two or more biologically active natural moieties in a single molecule may result in more pronounced pharmacological activities. [2002CSR324, 2003ACIE3996]

2.1.4 Literature Preparative Methods for Quinone-Amino Acid Conjugates

Considerable efforts have been devoted to the synthesis of quinone-amino acid conjugates utilizing diverse routes including (Figure 2-5): (i) transamination, to give 40

quinone-amino acid conjugates linked via a vinylic spacer (2.16) (Scheme 2-1);

[2001AA381] (ii) quinone-amino acid hybrids (2.17) synthesized via cross-enyne metathesis and Diels-Alder reactions (Scheme 2-2); [2007EJOC1244] (iii) N-quinonyl amino acids (2.18) obtained from chloro-substituted quinones (Scheme 2-3);

[2002AA71] (iv) S-substituted benzoquinones (2.19) synthesized by the reaction of amino acids with S-substituted benzoquinone (Scheme 2-4). [2001AA135]

Scheme 2-1. Quinone-amino acid conjugates linked via a vinylic spacer

Scheme 2-2. Synthesis of quinone-amino acid hybrids via Cross-Enyne Metathesis and Diels-Alder reactions

Scheme 2-3. N-Quinonyl amino acids obtained with chloro-substituted quinones

Scheme 2-4. Synthesis of N-quinonyl amino acids by addition to S-substituted benzoquinone

Two naphthoquinone-dipeptides namely N-(1,4-naphthoquinonyl)-glycyl-glycine

(2.22a) and N-(2-chloro-1,4-naphthoquinonyl)-glycyl-glycine (2.22b) was synthesized by the reaction of glycyl-glycine and 1,4-naphthoquinone (or 2,3-dichloro-1,4- naphthoquinone) (2.13a-b) in aqueous ethanol at room temperature in 24-48 h, which initially yielded hydroquinone conjugates (2.21a-b) which were not isolated.

[1996LPS263] Oxidation by excess of 1,4-naphthoquinone in the reaction mixture yielded the desired naphthoquinone-dipeptide conjugates (2.22a-b) in 63% and 48% yield (Scheme 2-5). [1996LPS263]

Scheme 2-5. Preparation of naphthoquinone-dipeptides

In view of the potential clinical significance of cytotoxic quinone-bearing peptides, it became important to increase the arsenal of related natural naphthoquinonoyl-amino acids, synthesize them in good yield and study their spectral properties. Herein, an efficient N-acylbenzotriazole mediated preparation of naphthoquinones-dipeptides was developed from naphthoquinone-α-amino acid conjugates with 76-89% yields in aqueous media at 20 °C. In addition, to demonstrate the efficient formation of quinone-

α-amino acid conjugates derived from S-substituted benzoquinone, the thiol group is considered to contribute redox properties to the target conjugates and potentially increase biological activities. For this purpose S-substituted p-benzoquinones were first reacted with natural α-amino acids via N- addition (Scheme 2-9), then further activated with benzotriazole group, which were used for the next step peptide synthesis.

However, the preparation of acylbenzotriazoles from S-substitued quinone-amino acid conjugates proved difficult, but only one example was obtained after many attempts

(Scheme 2-10).

2.2 Results and Discussion

2.2.1 Reaction of Naphthoquinone-Amino Acid Conjugates

Naphthoquinone-amino acid conjugates (2.25a-g) were synthesized from 2- naphthalene-1,4-dione (2.23) and amino acid or amino ester (2.24a-g) by modifying a literature procedure [1996LPS263] in aqueous EtOH at room temperature for 10-12 h in presence of Et3N. The reaction mixture was subjected to column chromatography to first yield naphthoquinone-amino acid triethylammonium salt, which upon washing with aqueous hydrochloric acid solution yielded the expected naphthoquinone-amino acid conjugates (2.25a-g) in 58-90% yield (Scheme 2-6, Table 2-1). [2010S2011]

Scheme 2-6. Synthesis of naphthoquinone-amino acid/ester conjugates

Table 2-1. Naphthoquinone-amino acid/ester conjugates Entry Amino acid Target Compounds Yield Mp (ºC) (2.24) (2.25) (%) 1 L-Phenylalanine (2.24a) 2.25a 72 200-203 2 L-Leucine (2.24b) 2.25b 79 115-117 3 L-Alanine (2.24c) 2.25c 64 137-139a 4 L-Tryptophan (2.24d) 2.25d 58 208-211b 5 L-Proline OMe (2.24e) 2.25e 90 151-153 6 D-Val-OMe (2.24f) 2.25f 76 255-256 7 β-alanine (2.24g) 2.25g 80 205-207 aLit. m. p. 139-142 ºC [2000AA469]; b lit. m. p. 210-213 ºC [1996S1468]

Activation of the terminal carboxylic acid of naphthoquinone-amino acid conjugates (2.25a-d) was achieved by reaction with same equivalent of benzotriazole

(2.26) and N, N’-dicyclohexylcarbodimide (DCC) to yield naphthoquinone aminoacylbenzotriazoles (2.27a-d). The reaction was initially attempted with BtH/SOCl2/THF/

RT, 2-5h or BtSO2Me/THF/Et3N/reflux, 8-12h, but a complex mixture was obtained.

Finally, N-acylbenzotriazole derivatives were obtained in DCM at room temperature in

4h using DCC as the coupling agent. (Scheme 2-7, Table 2-2).

Scheme 2-7. Synthesis of naphthoquinone-aminoacylbenzotriazole conjugates

Table 2-2. Naphthoquinone-aminoacylbenzotriazoles Naphthoquinone Amino Target Yield Mp Entry Acid Conjugates compounds (%) (ºC) (2.5) (2.27) 1 2.25a 2.27a 86 115-117 2 2.25b 2.27b n/a n/a 3 2.25c 2.27c n/a n/a 4 2.25d 2.27d 83 114-115

N-Acylbenzotriazole (2.27a-d) derivatives were coupled with various natural amino acids (2.24a-f) in aqueous acetonitrile-triethylamine at 20 °C in 4 hours to give naphthoquinone dipeptides (2.28a-k) in good to excellent yields (76-89%). (Scheme 2-

8, Table 2-3)

Scheme 2-8. Preparation of naphthoquinone dipeptide conjugates

Table 2-3. Synthesis of Naphthoquinone-dipeptides (continued on the next page) Naphthoquinone - amino N- Amino acid Target compound yield Mp Entry acylbenzotriazol (2.24) (2.28) (%) (ºC) e conjugate

L-Alanine 1 2.27a 89 166-168 (2.24c)

2.28a

L-Valine 2 2.27a 81 175-177 (2.24e)

2.28b

L-Tryptophan 3 2.27a 81 215-217 (2.24d)

2.28c

L-Tryptophan 4 2.27b 81 223-225 (2.24d)

2.28d

5 2.27b L-Alanine (2.24c) 89 172-174

2.28e

L-Glutamic acid 6 2.27b methyl ester 81 153-155 (2.24f)

2.28f

Table 2-3. Continued Naphthoquinone - amino N- Amino acid Target compound yield Mp Entry acylbenzotriazol (2.24) (2.28) (%) (ºC) e conjugate

L-Tryptophan 7 2.27c 82 243-245 (2.24d)

2.28g

L-Leucine 8 2.27d 79 114-120 (2.24b)

2.28h

L-Glutamic acid 9 2.27d methyl ester 76 104-111 (2.24f)

2.28i

L-Phenylalanine 10 2.27d 81 121-123 (2.24a)

2.28j

L-Phenylalanine 11 2.27b 78 161-164 (2.24a)

2.28k

2.2.2 Reaction of Thio-substituted Benzoquinone with Amino Acids

2-(Cyclohexylsulfanyl)-p-benzoquinone (2.29) was prepared from cyclohexyl mercaptan (2.20) by reaction with two equivalents of p-benzoquinone (2.10) at room temperature for 2 hours. Compound (2.29) was used as the starting material for the

investigation of the Michael addition reaction of thiol-substituted benzoquinone with amino acids (2.30a-b).

The reaction of 2-(cyclohexylsulfanyl)-p-benzoquinone (2.29) with L- and DL α- amino acids (2.30a-b) in acetonitrile at 20 ºC (Scheme 2-9, Table 2-4) for 3 hours yielded 2-(cyclohexylsulfanyl)-p-benzoquinone-5-amino acid conjugates (2.31a-b).

Scheme 2-9. Synthesis of thiol-substituted benzoquinone-amino acid conjugates

Table 2-4. Thiol-substituted benzoquinone-amino acid congjugates Amino acid Product Yield Mp (2.30) (2.31) (%) (ºC)

D-Alanine 63 139-141 (2.30a)

(2.31a)

DL-Alanine 63 140-141 (2.30a+2.30a')

(2.31a+2.31a')

L-Phenylalanine 71 127-129 (2.30b)

(2.31b)

2.2.3 Preparation of Benzotriazole Activated Benzoquinone-Amino Acid Conjugates

2-(4-Cyclohexylsulfanyl-3,6-dioxocyclohexa-1,4-dienylamino)propionic acid

(2.31a+2.31a’) on treatment with 1H-benzotriazole and thionyl chloride in DCM gave the corresponding stable, crystalline racemic acylbenzotriazole (2.32a+2.32a’) in 65 % yield

(Scheme 2-10).

Scheme 2-10. Synthesis of benzoquinone-amino acid benzotriazole derivative

2.3 Conclusion

Naphthoquinones-dipeptides (2.28a-j) were synthesized as potential cytotoxic agents from naphthoquinone-amino acid conjugates (2.25a-d) by N-acylbenzotriazole methodology in aqueous medium at 20 °C in 76-89% yield. Three examples of thiol- subsituted benzoquinone-amino acids (2.31a-b) were prepared in moderate yields, but the preparation of thio-substituted benzoquinone-N-aminoacylbenzotriazoles was challenging, due to the many side products formed during the reaction. Only one example (2.32a+2.32a’) was obtained after many attempts. Disubstituted benzoquinones resist further substitution in the presence of N- or S- nucleophiles.

2.4 Experimental Section

General methods. Melting points were determined on a capillary point apparatus equipped with a digital thermometer and are uncorrected. NMR spectra were recorded

1 13 in CDCl3 or DMSO-d6 with TMS for H (300 MHz) and C (75 MHz) as internal reference. Free amino acids were purchased from Fluka (Buchs, Switzerland) and

Acros (Suwanee, GA, USA) and used without further purification. Elemental analyses were performed on a Carlo Erba-1106 instrument.

General method for preparation of naphthoquinone-amino acid conjugates

(2.25a-g). 2-Naphthalene-1,4-dione (20 mmol) and amino acid/ester (10 mmol) were dissolved in a mixture of EtOH-H2O (50 : 5 mL). Triethylamine (20 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 12 h. The resulting solution was evaporated under reduced pressure, and the residue was subjected to column chromatography, eluting with EtOAc/Hexane (2:8) first to remove the nonpolar impurities, and then with 100% EtOAc to yield a solid, which was characterized as the triethylamine salt of the expected product. The salt was dissolved in EtOAc (50 mL), and washed with 3N HCl solution (3 x 50 mL). The organic layer was dried over sodium sulfate anhydrous, filtered and evaporated under vacuum to yield the required naphthoquinone-amino acid/ester conjugate.

(S)-2-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)-3-phenylpropanoic acid (2.25a)

Black microcrystals; yield: 72%; m. p. 200-203 oC. (lit. m. p. 200-202 oC);

1 [2002AA71] H NMR (DMSO-d6) : 3.22 (t, J = 7.5 Hz, 2H), 4.54-4.48 (m, 1H), 5.74 (s,

1H), 7.26-7.01 (m, 6H), 7.74 (t, J = 7.5 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.91 (d, J = 7.5

13 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H); C NMR (DMSO-d6) : 35.9, 55.7, 101.2, 125.6,

126.2, 126.8, 128.4, 129.4, 130.3, 132.6, 132.9, 135.2, 137.0, 147.6, 172.0, 181.4,

182.0.

(S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-2-yl)amino)-4-methylpentanoic acid (2.25b)

o 1 Black crystals; yield: 79%; m. p. 115–117 C; H NMR (DMSO-d6) : 0.87 (d, J =

6.0 Hz, 3H). 0.92 (d, J = 6.3 Hz, 3H), 1.71-1.65 (m, 2H), 1.88-1.96 (m, J = 8.4 Hz, 1H),

4.11-4.07 (m, 1H), 5.68 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.74 (td, J = 7.5 & 1.5 Hz, 1H),

7.83 (td, J = 7.5 & 1.5 Hz, 1H), 7.94 (dd, J = 7.5 & 1.2 Hz, 1H), 8.00 (dd, J = 7.5 & 1.2

13 Hz, 1H); C NMR (DMSO-d6) : 21.6, 22.7, 24.6, 53.4, 100.7, 125.4, 126.0, 130.3,

+ 132.5, 132.8, 134.9, 148.1, 172.9, 181.3, 181.7; HRMS calcd for C16H18NO4: [M+H]

288.1320, found 288.1233.

(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)propanoic acid (2.25c)

Red crystals; yield: 64%; m. p. 137–139 oC. (lit. m. p. 139–142 ºC); [2000AA439]

1 H NMR (DMSO-d6) : 1.31 (d, J = 2.7 Hz, 3H), 3.60-3.80 (m, 1H), 5.58 (s, 1H), 7.43 (d,

J = 6.0 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.92-7.99 (m, 2H); 13C

NMR (DMSO-d6) : 17.1, 51.5, 99.1, 125.3, 125.8, 130.2, 132.0, 133.3, 134.8, 146.5,

173.6, 181.0, 181.6.

(S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-2-yl)amino)-3-(1H-indol-3- yl)propanoic acid (2.25d)

Orange brown crystals; yield: 58%; m. p. 208–211 oC. (lit. m. p. 210–213 ºC);

1 [1996S1468] H NMR (DMSO-d6) : 3.36-3.38 (m, 2H), 4.45-4.52 (m, 1H), 5.74 (s, 1H),

6.91-6.97 (m, 2H), 7.05 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.1,

0.6 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H),

13 7.92-8.00 (m, 2H), 10.90 (s, 1H); C NMR (DMSO-d6) : 26.1, 55.2, 100.9, 108.8,

111.4, 118.1, 118.4, 120.9, 124.0, 125.3, 125.9, 127.2, 130.0, 132.3, 134.9, 136.0,

147.2, 172.1, 181.1, 181.7.

(S)-Methyl 1-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)pyrrolidine-2-carboxylate (2.25e)

Black crystals; yield: 90%; m. p. 151–153 oC (lit. m. p. 149–150 ºC);

1 [1977BCSJ2170] H NMR (DMSO-d6) : 1.83-2.13 (m, 3H), 2.21-2.34 (m, 1H), 3.38-

3.47 (m, 2H), 3.69 (s, 3H), 4.98 (bs, 1H), 5.77 (s, 1H), 7.71 (t, J = 7.5Hz, 1H), 7.83 (t, J

13 = 7.5 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H); C NMR (DMSO-d6) : 21.8, 31.0, 50.9, 52.1,

62.4, 105.1, 124.8, 126.3, 131.2, 132.2, 132.3, 134.5, 148.4, 172.6, 181.3, 182.6.

(R)-Methyl 2-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)-3- methylbutanoate (2.25f)

Black crystals; yield: 76%; m. p. 255–256 oC (lit. m. p. 256–257 oC);

1 [1977BCSJ2170] H NMR (CDCl3) : 0.98 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H),

2.23-2.30 (m, 1), 3.76(s, 3H), 3.84-3.89 (m, 1H), 5.66 (s, 1H), 6.29 (d, J = 8.7 Hz, 1H),

13 7.60 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 8.01-8.05 (m, 2H); C NMR (CDCl3) :

18.6, 19.0, 31.3, 52.6, 60.6, 102.0, 126.3, 126.5, 130.5, 132.3, 133.4, 134.9, 147.3,

171.1, 181.5, 183.3.

3-((1,4-Dioxo-1,4-dihydronaphthalen-2-yl)amino)propanoic acid (2.25g)

Brown crystals; yield: 80%; m. p. 205–207 oC (lit. m. p. 206–207 ºC); [2002AA71]

1 H NMR (DMSO-d6) : 2.60 (t, J = 6.9 Hz, 2H), 3.38-3.42 (m, 2H), 5.72 (s, 1H), 7.50 (t, J

= 6.0 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.93-7.99 (m, 2H); 13C

NMR (DMSO-d6) : 32.3, 38.0, 99.8, 125.5, 126.1, 130.5, 132.4, 133.2, 135.1, 148.5,

172.9, 181.6.

General method for preparation of naphthoquinone-amino acyl benzotriazole conjugates (2.27a-d). To a solution of naphthoquinone-amino acid conjugate (2.25a-d)

(5 mmol) in anhydrous DCM (30 mL), benzotriazole (0.60 g, 5 mmol) and N,N'- dicyclohexylcarbodiimide (DCC) (0.95 g, 5 mmol) were added. The reaction mixture was stirred at room temperature for 4 h, then filtered through celite at least twice. The organic layer was concentrated under vacuo and the residue was recrystallized from

EtOAc/Hexane to yield 2.27a and 2.27d as pure products. Compounds 2.27b-c were not isolated in pure form, but used as crude (NMR shows trace amount of DBU coexisting with the product) for the next coupling reaction.

(S)-2-((1-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-oxo-3-phenylpropan-2- yl)amino)naphthalene-1,4-dione (2.27a)

o 1 Black crystals; yield: 86%; m. p. 115–117 C; H NMR (CDCl3) : 3.37 (dd, J = 7.5

& 13.8 Hz, 1H), 3.60 (dd, J = 4.8 & 13.8 Hz, 1H), 5.76 (s, 1H), 5.56-5.82 (m, 1H), 6.55

(d, J = 7.8 Hz, NH), 7.33 (m, 5H), 7.72-7.54 (m, 4H), 8.04 (t, J = 6.0 Hz, 2H), 8.20 (t, J =

13 7.5 Hz, 2H); C NMR (CDCl3) : 38.9, 56.6, 103.0, 114.4, 120.8, 126.4, 126.6, 127.1,

127.9, 129.1, 129.3, 130.5, 131.0, 131.3, 132.5, 133.2, 134.8, 134.9, 146.3, 146.6,

169.6, 181.3, 183.3; Anal. Calcd for C25H18N4O3: C, 71.08; H, 4.29; N, 13.26. Found: C,

70.80; H, 5.04; N, 13.49.

2-(((2S)-1-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(2,7a-dihydro-1H-indol-3-yl)-1- oxopropan-2-yl)amino)naphthalene-1,4-dione (2.27d)

o 1 Yellow microcrystals; yield: 83%; m. p. 114.0 – 115.0 C; H NMR (CDCl3) : 3.60

(dd, J = 7.6, 15.0 Hz, 1H), 3.80 (dd, J = 4.8, 14.7 Hz, 1H), 5.72 (s, 1H), 5.92 (q, J = 4.8

Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 7.10-7.17 (m, 2H), 7.29 (d, J =

8.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.54 -7.72 (m, 5H), 8.02 (d, J = 7.8 Hz, 1H), 8.18

13 (t, J = 6.9 Hz, 2H), 8.26 (br s, 1H); C NMR (CDCl3) : 29.3, 56.1, 103.0, 111.7, 114.6,

118.5, 120.3, 120.8, 122.9, 123.7, 126.5, 126.7, 127.1, 131.4, 132.6, 135.0, 147.0,

+ 170.1; HRMS calcd for C27H20N5O3 [M+H] 462.1488, found 462.1556.

General method for preparation of Naphthoquinone-dipeptides (2.28a-j). A solution of L-amino acid (1 mmol) (2.24a-f) and Et3N (1.2 mmol) in water (4 mL) was added to a solution of N-acyl benzotriazole derivative (1 mmol) (2.25a-d) in MeCN (50 mL). The reaction mixture was stirred at room temperature for 3-4 h, and then quenched with 4 N aqueous HCl (2 mL). The reaction mixture was concentrated, diluted with

EtOAc (100 mL), and washed with 4N aqueous HCl (30 mL x 3), and brine (30 mL x 2).

The organic layer was concentrated, and cold hexane (30 mL) was added to the resulting solution. The precipitated solid was filtered and dried under vacuum to yield naphthoquinone-dipeptides (2.28a-j).

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-3- phenylpropanamido) propanoic acid (2.28a)

1 Orange crystals; yield = 89%; m. p. 166–168 ºC; H NMR (CD3COCD3-d6) : 1.40

(d, J = 7.2 Hz, 3H), 3.21 (dd, J = 14.1 Hz & 7.5 Hz, 1H), 3.37 (dd, J = 13.8 Hz & 4.8 Hz,

1H), 4.45-4.52 (m, 2H), 5.66 (s, 1H), 6.45 (s, 1H), 7.14 (d, J = 6.3 Hz, 1H), 7.19-7.36 (m,

5H), 7.72 (t, J = 7.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 8.01 (t, J = 6.0 Hz, 2H); 13C NMR

(CDCl3) : 18.3, 21.9, 22.8, 24.4, 48.8, 54.5, 100.7, 125.4, 126.0, 130.3, 132.4, 132.8,

+ 134.9, 147.8, 169.9, 181.2, 181.8; HRMS calcd for C22H21N2O5: [M+H] 393.1445, found

393.1601.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-3- phenylpropanamido)-3-methylbutanoic acid (2.28b)

o 1 Red crystals; yield: 81%; m. p. 175–177 C; H NMR (CD3COCD3-d6) : 0.97 (t, J

= 5.4 Hz, 6H), 2.27-2.16 (m, 1H), 3.23 (dd, J = 13.8 & 7.8 Hz, 1H), 3.36 (dd, J = 13.8 &

5.1 Hz, 1H), 4.60-4.47 (m, 2H), 5.72 (s, 1H), 6.68 (d, J = 7.2 Hz, 1H), 7.34-7.16 (m, 5H),

7.81-7.65 (m, 2H), 7.83 (t, J = 13.9 Hz, 1H), 8.02 (t, J = 7.5 Hz, 2H); 13C NMR

(CD3COCD3-d6) : 18.2, 19.5, 31.6, 38.6, 57.77, 57.84, 58.1, 102.6, 126.5, 126.6, 126.8,

127.7, 129.3, 129.5, 130.3, 131.5, 133.1, 134.2, 135.5, 137.7, 147.9, 170.9, 172.8,

+ 182.2, 182.7; HRMS calcd for C24H25N2O5: [M+H] 421.1758, found 421.1778.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-3- phenylpropanamido)-3-(1H-indol-2-yl)propanoic acid (2.28c)

o 1 Red crystals; yield: 81%; m. p. 215–217 C; H NMR (DMSO-d6) : 3.14-3.06 (m,

3H), 3.23 (dd, J = 5.4 & 5.1 Hz, 1H), 4.38-4.31 (m, 1H), 4.59-4.52 (m, 1H), 5.57 (s, 1H),

6.93 (t, J = 7.2 Hz, 1H), 7.04-7.00 (m, 2H), 7.24-7.14 (m, 5H), 7.32 (d, J = 7.8 Hz, 1H),

7.53 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.91 (d, J = 7.2

Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 8.65 (d, J = 8.1 Hz, 1H), 10.87 (s, 1H); 13C NMR

(DMSO-d6) : 27.1, 37.1, 53.0, 56.6, 100.9, 109.5, 111.3,116.4, 118.1, 118.3, 120.8,

123.6, 124.5, 125.3, 125.7, 125.9, 126.0, 126.4, 127.1, 128.1, 128.5, 129.1, 130.0,

132.3, 132.6, 134.8, 136.0, 136.9, 147.2, 169.6, 172.8, 180.9, 181.6; HRMS calcd for

+ C30H26N3O5: [M+H] 508.1867, found 508.1886.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-4- methylpentanamido)-3-(1H-indol-2-yl)propanoic acid (2.28d)

o 1 Red crystals; yield: 81%; m. p. 223–225 C; H NMR (DMSO-d6) : 0.82 (d, J = 6.3

Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 1.61-1.52 (m, 2H), 1.75-1.64 (m, 1H), 3.06 (dd, J =

14.4 & 5.4 Hz, 1H), 3.19 (dd, J = 14.4 & 5.4 Hz, 1H), 4.08-4.01 (m, 1H), 4.54-4.51 (m,

1H), 5.73 (s, 1H), 7.03-6.90 (m, 3H), 7.14 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H),

7.51 (td, J = 7.5 & 1.5 Hz,1H), 7.74 (td, J = 7.5 & 1.5 Hz, 1H), 7.84 (td, J = 7.5 &1.2 Hz,

1H), 7.95 (dd, J = 8.1 & 1.2 Hz, 1H), 8.00 (dd, J = 7.8 & 1.2 Hz, 1H), 8.47 (d, J = 8.1 Hz,

13 1H), 10.81 (s, 1H); C NMR (DMSO-d6) : 22.0, 22.7, 24.3, 53.0, 54.4, 100.8, 109.6,

111.4, 118.1, 118.3, 120.8, 123.6, 125.4, 126.0, 127.2, 130.3, 132.4, 132.8, 134.9,

136.1, 147.6, 170.7, 172.9, 181.2, 181.8; Anal. Calcd for C27H27N3O5: C, 68.48; H, 5.75;

N, 8.87. Found: C, 68.58; H, 5.51; N, 8.45.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-4- methylpentanamido) propanoic acid (2.28e)

o 1 Orange crystals; yield: 89%; m. p. 172–174 C; H NMR (DMSO-d6) : 0.85 & 0.92

(dd, J = 6.3 Hz, 6H), 1.23 (d, J = 7.2 Hz, 3H), 1.69-1.55 (m, 2H), 1.80-1.69 (m, 1H),

4.12-4.05 (m, 2H), 5.73 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.83

(t, J = 7.5 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 6.9 Hz,

13 1H); C NMR (DMSO-d6) : 18.3, 21.9, 22.8, 24.4, 48.8, 54.5, 100.7, 125.4, 126.0,

130.3, 132.4, 132.8, 134.9, 147.8, 169.9, 181.2, 181.8; HRMS calcd for C19H23N2O5:

[M+H]+ 359.1601, found 359.1596.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-4- methylpentanamido)-5-methoxy-5-oxopentanoic acid (2.28f)

o 1 Red crystals; yield: 81%; m. p. 153–155 C; H NMR (DMSO-d6) : 0.86 (d, J = 6.3

Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H), 1.71-1.58 (m, 2H), 1.85-1.76 (m, 2H), 2.03-2.00 (m,

1H), 2.35-2.29 (m, 1H), 3.51 (s, 3H), 4.16-4.00 (m, 2H), 5.75 (s, 1H), 7.12 (d, J = 8.7 Hz,

1H), 7.73 (t, J = 7.5 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.99 (d, J

13 = 7.2 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H); C NMR (DMSO-d6) : 13.9, 21.9, 22.1, 22.8,

24.4, 26.9, 29.7, 31.0, 51.2, 52.0, 54.5, 100.9, 125.4, 126.0, 130.3, 132.4, 132.8, 134.9,

+ 147.7, 170.4, 172.9, 181.3, 181.7; HRMS calcd for C22H27N2O7: [M+H] 431.1813 found

431.1816.

(S)-2-((S)-2-((1,4-dioxo-1,4-dihydronaphthalen-3-yl)amino)propanamido)-3- (1H-indol-3-yl)propanoic acid (2.28g)

o 1 Red crystals; yield: 82%; m. p. 243–245 C; H NMR (DMSO-d6) : 1.36 (d, J = 6.6

Hz, 3H), 3.08 (dd, J = 14.7 & 5.1 Hz, 1H), 3.22 (dd, J = 14.7 & 5.1 Hz, 1H), 4.12 (t, J =

7.2 Hz, 1H), 4.57-4.50 (m, 1H), 5.60 (s, 1H), 7.08-6.93 (m, 3H), 7.16 (d, J = 2.1Hz,

1H), 7.31 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H),7.75 (td, J = 7.5 & 1.2 Hz, 1H),

7.85 (td, J = 7.5 & 1.2 Hz, 1H), 7.95 (d, J = 6.6 Hz, 1H), 8.00 ( d, J = 6.9 Hz, 1H), 8.50

13 (d, J = 8.1Hz, 1H), 10.85 (s, 1H); C NMR (DMSO-d6) : 17.6, 27.0, 50.8, 52.9, 100.7,

109.5, 111.3, 118.0, 118.3, 120.8, 123.5, 125.3, 125.9, 127.1, 130.2, 132.3, 132.8,

134.8, 136.0, 147.0, 171.0, 172.8, 181.1, 181.6; Anal. Calcd for C24H21N3O5: C, 66.81;

H, 4.91; N, 9.74. Found: C, 66.57; H, 4.79; N, 9.50.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-3-(1H-indol-3- yl)propanamido)-4-methylpentanoic acid (2.28h)

1 Orange crystals; yield: 79%; m. p. 114–120 ºC; H NMR (DMSO-d6) : 0.81 (d, J =

6.0 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H), 1.22-1.25 (m, 1H), 1.54-1.77 (m, 2H), 3.27-3.30

(m, 2H), 4.28-4.38 (m, 2H), 5.59 (s, 1H), 6.90-6.99 (m, 2H), 7.05 (t, J = 7.8 Hz, 1H),

7.27 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H),

7.80 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 8.61 (d, J =

13 7.8 Hz, 1H), 10.89 (s, 1H); C NMR (DMSO-d6) : 21.0, 22.8, 24.3, 27.4, 33.3, 38.6,

50.2, 56.1, 100.9, 109.0, 111.3, 118.2, 118.3, 120.9, 124.2, 125.3, 125.8, 127.2, 130.1,

132.3, 132.7, 134.8, 136.1, 147.3, 170.2, 173.7, 181.0, 181.5; Anal. Calcd for

C27H27N3O5: C, 68.48; H, 5.75; N, 8.87. Found: C, 68.20; H, 5.90; N, 8.47.

(S)-2-((S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-(1H-indol-3- yl)propanamido)-5-methoxy-5-oxopentanoic acid (2.28i)

1 Yellow crystals; yield: 76%; m. p. 104–111 ºC; H NMR (DMSO-d6) : 1.85-1.92

(m, 1H), 1.98-2.15 (m, 1H), 2.37 (t, J = 7.2 Hz, 2H), 3.29-3.38 (m, 2H), 3.56 (s, 3H),

4.26-4.40 (m, 2H), 5.61 (s, 1H), 6.96 (t, J = 7.2 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 7.25 (s,

1H), 7.31 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.81 (t, J

= 7.2 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 8.59 (d, J = 7.8 Hz,

13 1H), 10.88 (s, 1H); C NMR (DMSO-d6) : 26.2, 27.3, 29.6, 51.1, 51.2, 56.1, 100.8,

109.0, 111.3, 118.1, 118.3, 120.9, 124.1, 125.3, 125.8, 127.2, 130.1, 132.3, 132.7,

134.8, 136.1, 147.3, 170.3, 172.5, 181.3, 181.5; Anal. Calcd for C27H25N3O7: C, 64.41;

H, 5.00; N, 8.35. Found: C, 64.09; H, 5.05; N, 7.98.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-3-(1H-indol-3- yl)propanamido) -3-phenylpropanoic acid (2.28j)

1 Yellow crystals; yield: 81%; m. p. 121–123 ºC; H NMR (DMSO-d6) : 2.94-3.00

(m, 1H), 3.05-3.18 (m, 1H), 3.20-3.28 (m, 2H), 4.20-4.35 (m, 1H), 4.51-4.55 (m, 1H),

5.61 (s, 1H), 6.90-7.01 (m, 2H), 7.07 (t, J = 6.9 Hz, 1H), 7.12-7.25 (m, 6H), 7.33 (d, J

= 7.8 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 6.3 Hz, 1H), 7.80 (t, J = 7.5 Hz,

13 1H), 7.90-7.94 (m, 2H), 8.70 (d, J = 7.2 Hz, 1H), 10.88 (s, 1H); C NMR (DMSO-d6) :

27.9, 37.3, 54.0, 56.7, 101.4, 109.7, 111.9, 118.7, 118.8, 121.5, 124.6, 125.8, 126.4,

126.9, 127.7, 128.6, 129.6, 130.6, 132.8, 133.2, 135.4, 136.6, 137.8, 147.8, 170.7,

173.0, 181.5, 182.1; Anal. Calcd for C30H25N3O5: C, 70.99; H, 4.96; N, 8.28. Found: C,

+ 71,26; H, 5.29; N, 7.85. HRMS calcd for C30H26N3O5: [M+H] 508.1867, found

508.1886.

(S)-2-((S)-2-((1,4-Dioxo-1,4-dihydronaphthalen-3-yl)amino)-4- methylpentanamido)-3-phenylpropanoic acid (2.28k)

1 Red crystals; yield: 78%; m. p. 161–164 ºC; H NMR (DMSO-d6) : 0.83 (d, J = 3.0

Hz, 3H), 0.90 (d, J = 3.0 Hz, 3H), 1.47-1.62 (m, 2H), 1.78-1.70 (m, 1H), 2.89 (dd, J =

6.3 & 13.8 Hz, 1H), 3.08 (dd, J = 4.5 & 13.8 Hz, 1H), 3.98-4.05 (m, 1H), 4.44-4.50 (m,

1H), 5.74 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.11-7.06 (m, 1H), 7.20-7.15 (m, 4H), 7.75 (t,

J = 7.5 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.95-8.02 (m, 2H), 8.51 (d, J = 8.1 Hz, 1H); 13C

NMR (DMSO-d6) : 21.7, 22.4, 24.1, 36.4, 53.1, 54.1, 100.7, 125.1, 125.7, 126.0, 127.8,

128.9, 130.0, 132.2, 132.5, 134.7, 137.0, 147.2, 170.4, 172.2, 180.9, 181.5; HRMS

+ calcd for C25H27N2O5: [M+H] 435.1914; found 435.1934.

General procedure for preparation of 2-(cyclohexylthio)cyclohexa-2,5-diene-

1,4-dione (2.29). Cyclohexyl mercaptan (4.9 mL, 40 mmol) in MeOH (5 mL) was added

dropwise to a suspension of 1,4-benzoquinone (8.67 g, 81 mmol) in MeOH (50 mL), and the mixture was stirred at 20 oC for 2 h. Water (100 mL) was added, and the resulting precipitate was collected by filtration. The orange crystals were recrystallized from

CH2Cl2/MeOH to give the pure form of (2.29).

2-(Cyclohexylthio)cyclohexa-2,5-diene-1,4-dione (2.29)

Brown crystals; yield: 80%; m. p. 104–106 oC (lit. m. p. 102–106 oC);

1 [1991JOC5808] H NMR (CDCl3) : 1.28-1.59 (m, 5H), 1.61-1.72 (m, 1H), 1.75-1.90 (m,

2H), 1.97-2.14 (m, 2H), 2.98-3.20 (m, 1H), 6.42 (d, J = 1.8 Hz, 1H), 6.71 (dd, J = 6.0,

13 2.1 Hz, 1H), 6.81 (d, J = 10.2 Hz, 1H); C NMR (CDCl3) : 25.5, 25.6, 31.9, 42.5, 124.8,

136.2, 137.3, 152.0, 169.9, 184.1.

General procedure for peparation of thiol-substituted benzoquinone-amino acid conjugates (2.31a-b). To a solution of 2-(cyclohexylsulfanyl)-p-benzoquinone

(2.29) (0.22 g, 1 mmol) in (MeCN:H2O 6: 3mL) at RT, a solution of amino acid (2.30a-b)

(0.5 mmol) and triethylamine (0.1 mL, 0.7 mmol) in water (5 mL) was added slowly. The reaction mixture was stirred for 3 h at RT. Acetonitrile was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with chloroform/methanol (20:1) to give the triethylamine salt of the thiol-substituted benzoquinone-amino acid conjugates, which can be converted to free acid form via neutralizating with 4N aqueous HCl.

(R)-2-((4-(Cyclohexylthio)-3,6-dioxocyclohexa-1,4-dien-1-yl)amino)propanoic acid (2.31a)

o Red microcrystals; yield: 63%; m. p. 139–141 C; 1H NMR (CDCl3) δ: 1.21-2.12

(m, 13H), 3.0-3.28 (m, 1H), 3.93 (t, J = 6.3 Hz, 1H), 5.42 (s, 1H), 6.22 (s, 1H), 6.72 (bs,

1H); 13C NMR (CDCl3) δ: 8.1, 16.9, 25.1, 25.2, 31.5, 42.1, 44.9, 50.6, 96.8, 119.6,

143.1, 145.8, 157.6, 178.5, 180.9. Anal. Calcd for C15H19NO4S (309.39): C, 58.23; H,

6.19; N, 4.53. Found: C, 58.34; H, 6.33; 4.33.

2-((4-(Cyclohexylthio)-3,6-dioxocyclohexa-1,4-dien-1-yl)amino)propanoic acid (2.31a+2.31a')

o 1 Deep brown microcrystals; yield: 63%; m. p. 140–141 C; H NMR (CDCl3) δ: 1.21-

2.22 (m, 13H), 3.01-3.15 (m, 1H), 3.99 (t, J = 7.2 Hz, 1H), 5.44 (s, 1H), 6.25 (s, 1H),

13 6.52 (d, J = 6.9 Hz, 1H), 8.55 (bs, 1H). C NMR (CDCl3) δ: 16.8, 25.1, 25.2, 31.5, 42.1,

49.9, 97.3, 119.7, 145.7, 157.4, 172.8, 178.4, 181.1. Anal. Calcd. for C15H19NO4S

(309.39): C, 58.23; H, 6.19; N, 4.53. Found: C, 58.34; H, 6.33; 4.33.

(S)-2-((4-(cyclohexylthio)-3,6-dioxocyclohexa-1,4-dien-1-yl)amino)-3- phenylpropanoic acid (2.31b)

o 1 Red crystals; yield: 71%; m. p. 127–129 C; H NMR (DMSO-d6) : 1.00-1.58 (m,

6H), 1.58-1.70 (m, 1H), 1.70-1.80 (m, 2H), 1.80-2.15 (m, 2H), 2.95-3.10 (m, 1H), 3.15

(dd, J = 14.15 Hz, 5.22 Hz, 1H), 3.32 (dd, J = 14.15 Hz, 5.22 Hz, 1H), 4.15-4.35 (m,

1H), 5.54 (s, 1H), 6.24 (s, 1H), 6.29 (d, J = 7.69 Hz, 1H), 7.00 -7.50 (m, 5H), 8.80 (bs,

13 1H); C NMR (DMSO-d6) δ: 25.5, 25.6, 31.8, 37.1, 42.8, 55.9, 98.2, 120.1, 127.6,

128.9, 129.1, 134.7, 146.6, 158.1, 173.3, 178.2, 182.4. Anal. Calcd for C21H27NO6S

(421.52): C, 59.84; H, 6.46; N, 3.32. Found: C, 60.33; H, 5.85; 3.16.

General procedure for preparation of benzotriazole activated thiosubstituted benzoquinone-amino acid conjugates (2.32a+2.32a'). Benzotriazol (0.17 g, 1.4 mmol) and thionyl chloride 0.05 g (0.39 mmol) were dissolved in DCM (10 mL) at 25oC and stirred for 10 min. 2-(4-Cyclohexylsulfanyl-3,6-dioxo-cyclohexa-1,4-dienylamino)- propionic acid (2.31a+2.31a') (0.15 g, 0.35 mmol) was added to the solution. The reaction mixture was stirred at – 15 oC for 5 h, then at RT overnight. The reaction mixture was filterd and dichloromethane was evaporated under reduced pressure to give the crude residue, which was subjected to column chromatography with dichloromethane to yield a stable, crystalline racemic acylbenzotriazole (2.32a+2.32a'), which was recrystallized from DCM/Hexane before the elemental analysis.

2-((1-(1H-benzo[d][1,2,3]triazol-1-yl)-1-oxopropan-2-yl)amino)-5- (cyclohexylthio)cyclohexa -2,5-diene-1,4-dione (2.32a+2.32a')

o 1 Red crystals; yield: 65%; m. p. 172–174 C. H NMR (DMSO-d6) δ: 1.20-2.30 (m,

15H), 3.00-3.20 (m, 1H), 5.46 (s, 1H), 4.40-5.70 (m, 1H), 6.31 (s, 1H), 6.50 (d, J = 7.7

Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 8.19 (d, J = 6.9 Hz, 1H), 8.26

13 (d, J = 6.9 Hz); C NMR (DMSO-d6) δ: 18.5, 25.5, 25.6, 42.7, 51.0, 99.0, 114.2, 120.2,

120.6, 126.9, 130.9, 131.1, 145.8, 146.1, 157.8, 170.4, 178.7, 181.8; Anal. Calcd for

. C21H24N4O4S H2O (428.51): C, 58.86; H, 5.65; N, 13.07; found: C, 59.38; H, 5.18; N,

13.10.

CHAPTER 3 1,3,4-OXADIAZOLES FROM FUCTIONALIZED N-ACYLBENZOTRIAZOLES AND ACYLHYDRAZIDES

3.1 Introduction

3.1.1 Oxadiazoles

Oxadiazoles are heterocyclic aromatic compounds consisting of fused 5- membered rings containing two carbons, two nitrogen atoms and one oxygen atom. The four possible oxadiazoles (A-D) are shown in Figure 3-1.

Figure 3-1. Four types of oxadiazoles

3.1.2 Biologically Active 1,3,4-Oxadiazoles

The 1,3,4-oxadiazole moiety is an important structural class in medicinal chemistry due to its widespread use as a pharmacophore. [2006JOC9548, 2006T10223,

2006TL105, 2006TL4827, 2006TL6497, 2007EJMC235, 2007EJMC893,

2007EJMC934]

Oxadiazoles of type (3.1), amino-oxadiazoles of type (3.2) [2006JOC9548], and oxadiazolinethiones of type (3.3) [1988IJC(B)542] were reported with demonstrated bactericidal and/or fungicidal activities. The tin derivative (3.4) is a useful fungicide, and the thione derivative (3.5) shows antimicrobial activities. Diaryloxadiazoles (3.6) possesses certain anti-inflammatory, sedative and analgesic properties. [1984FES414]

Amino-oxadiazoles (3.7) show analgesic activity and amino-oxidazoles (3.8) exhibit both anti-inflammatory and antiproteolytic properties. [1989JPS999] Anticonvulsant and nervous system depressant activity was reported for amino-oxadiazoles (3.9), where R

is quinazolin-3-yl group. [1991PHA290] Amino-oxadiazoles (3.10) show local anesthetic activity. [1983JIC575] Oxadiazolinone (3.11) is an orally active antiallergic agent, for example in the treatment of asthma or allergies, and is claimed to be more potent than sodium cromoglycate. [1984JMC121] Oxadiazolinones (3.12 and 3.13) and “oxadiazon”

(3.14) are herbicides, while oxadiazolinones (3.15 and 3.16) and oxadiazole (3.17) have insecticidal activity (Figure 3-2).

Figure 3-2. Biologically important oxadiazoles

3.1.3 Polymeric 1,3,4-Oxadiazoles

Heat resistant polyazomethines (3.18) are used as insulators, and are obtained from 2,5-di-(3-aminophenyl)-1,3,4-oxadiazole by reaction with aromatic dialdehydes

Ar(CHO)2. They can be converted to semiconductors by doping with iodine.

[1992JPS(A)1369] Polyazomethines having an alternative structure were prepared from

aromatic diamines and oxadiazole-dialdehydes. [1990JPS(A)3647] The activating effect of the oxadiazole ring in 4-fluorophenyl- and 4-nitrophenyl-1,3,4-oxadiazoles allows nucleophilic displacement of these subsitutents. Thus 2,5-diaryloxadiazoles react with biphenols to give high molecular weight polyethers (3.19) (Figure 3-3). [1992MM2021]

Figure 3-3. Polymers containing 1,3,4-oxadiazoles

3.1.4 Luminescent Compounds, Dyes and Photosensitive Materials

There are various applications of 1,3,4-oxadiazoles containing three or more conjugated rings as luminescent compounds, because oxadiazoles have strong absorptions in the UV and strong fluorescence activity. Bis-oxadiazoles (3.20) adsorb at

267 – 299 nm, which indicates less than full conjugation, and show strong fluorescence at 420nm in ethanol. [1990JHC1685] 2,5-Disubstituted-1,3,4-oxadiazoles often fluorensce, which makes them potentially useful as laser dyes, optical brighteners and scintillators. For example, oxadiazole (3.21a) [1984GPO3245202] and 1,4-bis-(5- phenyl-1,3,4-oxadiazol-2-yl)naphthalene [1983GPO3126464] are fluorescent whiteners on polyester fiber. Applications of oxadiazole (3.21b) (Figure 3-4) include use as a laser dye, a blue-emitting phosphor, a wide range of applications as scintillator, and as an electron-transport layer in thin-film electroluminescent devices. [1991CL285] 1,3,4-

Oxadiazoles were recently tested for their possible use in organic light-emitting diodes

(OLED). [2007USP085073, 2007DP641, 2007DP753].

Figure 3-4. 1,3,4-Oxdiazoles with interesting optical properties

3.1.5 Other Miscellaneous Applications

Functionalized 1,3,4-oxadiazoles are also important starting materials for a variety of cycloaddition reactions [2007JFC740], especially for the synthesis of furans and natural products [2002JOC7361]. Key cycloaddition cascade reactions of 1,3,4- oxadiaozle moieties were applied in the total synthesis of Vindoline and related alkaloids (Scheme 3-1). [2006JACS10596]

Scheme 3-1. Cycloaddition reactions of 1,3,4-oxadiazoles in total synthesis of natural product

2,5-Dipicryl-1,3,4-oxadiazole (3.22) is used as an explosive initiator

[1988USP43262] and 2,5-dimethyl-1,3,4-oxadiazole (3.23) has been used to extract aromatic hydrocarbons from mixtures with alkanes (Figure 3-5). 4,4'-Carbonylbis-(2- phenyl-5-oxo-1,3,4-oxadiazole) (3.24) is used as a blowing agent for foaming thermoplastic compositions (e.g. polycarbonate). [1985USP4500653]

Figure 3-5. Other applications of 1,3,4-oxidazoles

3.1.6 Literature Preparative Methods for 1,3,4-Oxadiazoles

2,5-Disubsituted 1,3,4-oxadiazoles (3.30) are formed in the reaction of 1,2- diacylhydrazines (3.25) with strong dehydrating agents, including chlorosulfonic acid

[1983MI406-01] or phenyl dichlorophosphite [1982RRC935] in DMF (Scheme 3-2). A nonaqueous, nonacidic route to oxadiazoles (3.30) involves treatment of hydrazine

(3.25) with hexamethyldisilazide (HMDS) and tetrabutylammonium fluoride (TBAF), the last step presumably being fluoride-catalyzed cyclization of intermediate bis-silyl ether

(3.26). [1986SC1665]

Scheme 3-2. Preparation of 2,5-disubstituted 1,3,4-oxadiazoles from 1,2- diacylhydrazines

The cyanohydrazones (3.27), on heating in dimethyl sulfoxide, cyclized with loss of

HCN to give unsymmetrical 2,5-disubsituted oxadiazoles (3.30). [1984S146]

Benzophenone acylhydrazones (3.28) cyclized on reaction with acid chlorides RCOCl to oxadiazoles (3.29). [1985T5187]

Scheme 3-3. Preparation of 2,5-disubstituted 1,3,4-oxadiazoles from hydrazones

Treating allyl esters (3.31) with DIPEA forms oxadiazolinones (3.33), probably via

Claisen rearrangement of an initially formed oxadiazolinone (3.32) intermediate

(Scheme 3-4). [1988JOC38]

Scheme 3-4. Preparation of 1,3,4-oxadiazolinones

Important routes to monosubstituted oxadiazoles (3.34a), amino-oxidazoles

(3.34b), oxadiazolinones (3.35a), and oxadiazolinethiones (3.35b) involve reaction of

1 hydrazides R CONHNH2 with triethylorthoformate, cyanogen bromide, phosgene, or carbon disulfide (or CSCl2) respectively. Reaction of hydrazide (3.36) with triethylorthoformate, or with CS2/KOH, allowed the synthesis of oxadiazole (3.37)

(Scheme 3-5). [1982MC793]

Scheme 3-5. 1,3,4-Oxadiazole ring synthesis from acyclic precursors

Dolman et. al. reported the synthesis of 2-amino-1,3,4-oxadiazoles (3.40) via

TsCl/Py-mediated cyclization of a thiosemicarbazide (3.39), which is readily prepared by acylation of a given hydrazide (3.38) with the appropriate isothiocyanate (Scheme 3-6).

[2006JOC9548]

Scheme 3-6. Preparation of 2-amino-1,3,4-oxadiazoles

1,3,4-Oxadiazoles are most commonly prepared by the coupling of acylhydrazides with carboxylic acids followed by a dehydration step. [2006JOC9548, 2006SC3287,

2006TL105, 2006TL4827, 2006TL6497, 2006T10223, 2007TL1549, 2007SC1201]

Rajapakse reported a mild and efficient one pot synthesis of 2,5-disubstituted 1,3,4- oxadiazoles (3.41) in good yield (Scheme 3-7), from the cyclization-oxidation reaction of acylhydrazones. Also, the synthesis was achieved by condensation of acyl hydrazides and aromatic aldehydes in the presence of ceric ammonium nitrate in dichloromethane.

However, the conjugation of the carboxylic acid partner with -functionality such as a styryl group gave a very low yield of 1,3,4-oxadiazoles. Moreover, incorporation of nucleophilic functionality such as a pyridine (3.42) or phenol (3.43) moiety on the acid partner was not feasible and the corresponding 1,3,4-oxadiazoles could not be obtained. [2006TL4827]

Scheme 3-7. One-pot syntheses of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles

N-Acylbenzotriazoles are easily prepared from activated derivatives of carboxylic acids [2005SL1656] and have been applied to (i) N-acylation, (ii) O-acylation,

[2006S4135] (iii) C-acylations, [2006TL3767] [2005JOC4993] [2005JOC7792,

2005ARKIVOC329] syntheses of (iv) peptides, [2006S411, 2006MI37, 2006MI42,

2006MI326, 2007JOC407, 2007JOC4268, 2007BC994] (v) esters, [2006JOC3364] (vi) benzodioxin-4-ones, [2007ARKIVOC6] (viii) ketones, [2006JOC9861] (xi) acyl azides,

[2007JOC5802] (xiii) heteroaromatics [2000JOC8069] and (xiv) heterocycles.

[2004JOC9313] Compared with acid chlorides, N-acybenzotriazoles in general showed better functional group tolerance, ease of reaction conditions for many types of coupling reactions, especially for constructing N-C bonds. A series of N-acybenzotriazoles

(3.45a-h) were reacted with phenylhydrazide (3.44) toward the syntheses of 2.5- disubsituted-1,3,4-oxadiazoles (3.46a-h) (Scheme 3-6). The results are discussed in the next section. [2008ARKIVOC62]

3.2 Results and Discussion

Reaction of (E)-1-benzotriazol-1-yl-3-phenylpropenone (3.45a) (0.5 mmol) with benzoic acid hydrazide (3.44) (0.5 mmol) and sodium hydride (1 mmol) in dichloromethane at RT for 12 h followed by treatment with CBr4 (1 mmol) and Ph3P (1 mmol) at RT for 12 h gave 2-phenyl-5-((E)-styryl)-1,3,4-oxadiazole (3.46a) in 84% yield

(23% yield in [2006TL4827]). The 1H NMR spectra of (3.46a) showed the disappearance of the Bt signals in the aromatic region, indicating the loss of the benzotriazolyl group during the reaction. The 13C NMR spectra of (3.46a) showed two signals at 164.5 and 164.2 ppm corresponding to the two C=N functions of the product and the disappearance of the signal at 168.8 ppm belonging to the carbonyl group at the  position of the benzotriazolyl group in the starting material. Thus, a series of reactions of benzoic acid hydrazide with a range of N-acylbenzotriazoles (3.45a-h) were explored to test the generality of this method. The results are shown in Table 3-1.

Reaction of heteroaryl-α,β-unsaturated acylbenzotriazoles such as (E)-1- benzotriazol-1-yl-3-thiophen-2-ylpropenone (3.45b) and (E)-1-benzotriazol-1-yl-3-furan-

2-ylpropenone (2c) with benzoic acid hydrazide furnished novel 2-phenyl-5-((E)-2-

thiophen-2-yl-vinyl)-1,3,4-oxadiazole (3.46b) and 2-((E)-2-furan-2-yl-vinyl)-5-phenyl-

1,3,4-oxadiazole (3.46c) in 82% and 79% yield respectively. Similarly, reaction of 1- benzotriazol-1-yl-3-phenylpropynone (3.45d) and benzotriazol-1-yl-naphthalen-2-ylmethanone (3.45e) with benzoic acid hydrazide produced novel 2-phenyl-5- phenylethynyl-1,3,4-oxadiazole (3.46d) and 2-(5-phenyl-1,3,4-oxadiazol-2-yl)- naphthalen-1-ol (3.46e) in 73% and 76% yield respectively (Table 3-1).

Further reaction of hydroxyaryl acylbenzotriazoles including benzotriazol-1-yl-(2- hydroxy-3-methyl-phenyl)-methanone (3.45f), 1H-benzotriazol-1-yl(1-hydroxy-2- naphthalenyl)-methanone (3.45g) and 1H-benzotriazol-1-yl(1-hydroxy-4-bromo-2- phenyl)methanone (3.45h) gave 2-methyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)-phenol hydrochloride (3.46f), 2-(5-phenyl-1,3,4-oxadiazol-2-yl)-naphthalen-1-ol (3.46g) and novel 4-bromo-2-(5-phenyl-1,3,4-oxadiazol-2-yl)-phenol (3.46h) in 86%, 66% and 89% yields respectively (Table 3-1).

Scheme 3-8. 1,3,4-Oxadiazoles from N-acylbenzotriazoles

3.3 Conclusion

A convenient route has been developed from N-acylbenzotriazoles and acyl hydrazides for the one pot synthesis of 1,3,4-oxadiazoles incorporating a -functionality or a nucleophilic group in the side chain, most of which are not easily accessible by previous methods.

Table 3-1. Reaction of N-acylbenzotriazoles with benzoic acid hydrazide Entry Product Product Structure Yielda (%)

Ph O b 1 3.46a Ph 84 N N

2 3.46b S O 82 Ph N N

3 3.46c O O 79 Ph N N Ph

4 3.46d O 73 Ph N N OH

5 3.46e O 76 Ph N N Me OH 6 3.46f 86 O Ph N N OH N N Ph 7 3.46g O 66

OH N N Ph O 8 3.46h 89

Br a Isolated yields after column purification and determined from a single experiment. b 23% [2006TL4827]

3.4 Experimental Section

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

(300 MHz, with TMS as the internal standard) and 13C NMR (75 MHz) NMR spectra

were recorded in CDCl3. Elemental analysis was carried out in an Eager 200 CHN analyzer.

3.4.1 General Procedure for the Preparation of 1,3,4-Oxadiazole

To a solution of N-acylbenzotriazole (3.45a-h) (0.5 mmol) and benzoic acid hydrazide (3.44) (68 mg, 0.5 mmol) in dichloromethane (5 mL) at RT was added sodium hydride (60% in mineral oil, 40 mg, 1 mmol). The coupling was allowed to proceed at

RT for 12 h, then CBr4 (332 mg, 1 mmol) and Ph3P (262 mg, 1 mmol) were added in one portion. The dehydration step was allowed to proceed at RT for 12 h and the reaction was poured onto a silica gel column for purification (silica gel, 10-15% EtOAc/hexanes) to afford 1,3,4-oxadiazoles (3.46a-h) in 66-89% yield.

2-Phenyl-5-((E)-styryl)-1,3,4-oxadiazole (3.46a)

Ph O Ph N N

White microcrystals; yield: 104 mg (84%); m. p. 125–127 oC (lit. m. p. 128–130 oC

1 [2006TL4827]); H NMR (300 MHz, CDCl3) : 8.14–8.12 (m, 2H), 7.64 (d, J = 16.9 Hz,

1H), 7.58–7.54 (m, 5H), 7.44–7.42 (m, 3H), 7.12 (d, J = 16.5 Hz, 1H); 13C NMR (75

MHz, CDCl3) : 164.5, 164.2, 139.1, 135.0, 132.0, 130.2, 129.3, 129.2, 127.7, 127.2,

124.0, 110.2.

2-Phenyl-5-((E)-2-thiophen-2-yl-vinyl)-1,3,4-oxadiazole (3.46b)

S O Ph N N

Yellow microcrystals; yield: 104 mg (82%); m. p. 110–114 oC; 1H NMR (300 MHz,

CDCl3) : 8.13 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 16.2 Hz, 1H),

7.55–7.53 (m, 3H), 7.41 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.10 (dd, J =5.1,

13 3.7 Hz , 1H), 6.91 (d, J = 16.1 Hz, 1H); C NMR (75 MHz, CDCl3) : 164.2, 164.2,

140.3, 132.0, 131.8, 130.0, 129.3, 128.4, 128.2, 127.2, 124.1, 109.1. Anal. Calcd for

C14H10N2OS: C, 66.12; H, 3.96; N, 11.02. Found: C, 66.01; H, 3.85; N, 10.95.

2-((E)-2-Furan-2-yl-vinyl)-5-phenyl-1,3,4-oxadiazole (3.46c)

White microcrystals; yield: 94 mg (79%); m. p. 115–117 oC (lit. m. p. 118–119 oC

1 [1995CHC208]); H NMR (300 MHz, CDCl3) : 8.11 (d, J = 1.8Hz, 1H), 8.08 (d, J = 2.6

Hz, 1H), 7.54–7.47 (m, 4H), 7.39 (d, J = 16.2 Hz, 1H), 6.97 (d, J = 16.2 Hz, 1H), 6.62 (d,

13 J = 3.3 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H); C NMR (75 MHz, CDCl3) : 164.4,

164.1, 155.2, 144.7, 131.9, 129.2, 127.1, 125.7, 124.0, 113.9, 112.5, 107.8. Anal. Calcd for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.36; H, 4.25; N, 11.81.

2-Phenyl-5-phenylethynyl-1,3,4-oxadiazole (3.46d)

White microcrystals; yield: 94 mg (73%); m. p. 129–130 oC; 1H NMR (300 MHz,

13 CDCl3) : 8.13–8.10 (m, 2H), 7.68–7.65 (m, 2H), 7.60–7.40 (m, 6H); C NMR (75 MHz,

CDCl3) : 165.1, 151.0, 132.6, 132.4, 130.9, 129.4, 128.9, 127.4, 123.6, 120.0, 97.4,

73.3. Anal. Calcd for C16H10N2O: C, 78.03; H, 4.09; N, 11.38. Found: C, 77.75; H, 4.07;

N, 11.28.

2-(5-Phenyl-1,3,4-oxadiazol-2-yl)naphthalen-2-ol (3.46e)

White microcrystals; yield: 219 mg (76%); m. p. 196–198 oC; 1H NMR (300 MHz,

CDCl3) : 11.13 (bs, 1H), 8.48 (d, J = 7.7 Hz, 1H), 8.18–8.16 (m, 2H), 7.84–7.80 (m,

13 2H), 7.63–7.56 (m, 5H), 7.47 (d, J = 8.6 Hz, 1H); C NMR (75 MHz, CDCl3) : 165.1,

163.2, 156.2, 136.2, 132.2, 129.4, 129.3, 129.1, 127.8, 127.2, 127.1, 126.4, 124.9,

123.9, 123.6, 121.8, 120.1, 101.4. Anal. Calcd for C18H12N2O2: C, 74.99; H, 4.20; N,

9.72. Found: C, 74.72; H, 4.00; N, 9.89.

2-Methyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)phenol hydrochloride (3.46f)

White microcrystals; yield: 125 mg (86%); m. p. 255–256 oC; 1H NMR (300 MHz,

CDCl3) : 10.91 (bs, 1H), 10.66 (bs, 1H), 7.97 (d, J = 7.0 Hz, 2H), 7.84 (d, J = 7.7 Hz,

1H), 7.66–7.55 (m, 4H), 7.42 (d, J = 7.1 Hz, 1H), 6.89 (t, J = 7.7 Hz, 1H), 2.22 (s, 3H);

13 C NMR (75 MHz, CDCl3) : 169.8, 165.7, 159.2, 135.1, 132.1, 132.0, 128.5, 127.4,

126.1, 124.5, 118.1, 111.9, 15.4. Anal. Calcd for C15H13ClN2O2: C, 62.40; H, 4.54; N,

9.70. Found: C, 63.86; H, 5.02; N, 9.89.

2-(5-Phenyl-1,3,4-oxadiazol-2-yl)naphthalen-1-ol (3.46g)

Pale green microcrystals; yield: 190 mg (66%); m. p. 196–198 oC; 1H NMR (300

MHz, CDCl3) : 11.13 (bs, 1H), 8.48 (d, J = 7.7 Hz, 1H), 8.18-8.16 (m, 2H), 7.84-7.80

13 (m, 2H), 7.63-7.56 (m, 5H), 7.47 (d, J = 8.6 Hz, 1H); C NMR (75 MHz, CDCl3) :

165.1, 163.2, 156.2, 136.2, 132.2, 129.4, 129.3, 129.1, 127.8, 127.2, 127.1, 126.4,

124.9, 123.9, 123.6, 121.8, 120.1, 101.4. Anal. Calcd for C18H12N2O2: C, 74.99; H, 4.20;

N, 9.72. Found: C, 74.72; H, 4.00; N, 9.89.

4-Bromo-2-(5-phenyl-1,3,4-oxadiazol-2-yl)phenol (3.46h)

Off-white microcrystals; yield: 282 mg (89%); m. p. 146–148 oC; 1H NMR (300

MHz, CDCl3) : 10.15 (bs, 1H), 8.08 (d, J = 6.6 Hz, 2H), 7.87 (d, J = 2.2 Hz, 1H), 7.57-

13 7.44 (m, 4H), 6.98 (d, J = 8.9 Hz, 1H); C NMR (75 MHz, CDCl3) : 163.6, 163.1, 156.7,

136.4, 132.5, 129.3, 128.7, 127.2, 123.0, 119.6, 111.7, 109.7. Anal. Calcd for

C14H9BrN2O2: C, 53.02; H, 2.86; N, 8.83. Found: C, 52.69; H, 2.79; N, 8.54.

CHAPTER 4 OVERVIEW OF N-HYDROXYAMIDOXIMES, N-AMINOAMIDOXIMES AND HYDRAZIDINES

4.1 Introduction

N-Hydroxyamidoximes (4.2), N-aminoamidoximes (4.3) and hydrazidines (4.4) all belong to the class of compounds with the general formula RC=NX(NHY) derived from the generic structure (4.1), where X = OH or NH2, Y = OH or NH2 and R is a linear side chain, carbocycle residue or heterocycle residue (Figure 4-1). Compound (4.2, 4.3 and

4.4) can all be considered as amidines in which one of the hydrogen atoms of the imido group is replaced by a hydroxy or amino radical, and the amine group is replaced by a hydroxylamine or hydrazine group. Their structures are thus similar to those of amidoximes and amidrazones, but they possess very different synthetic utility and pharmacological applications. Reviews published on the synthetic and biological applications of amidrazones and amidoximes [1962CR155, 1970CR151, 1989CHC717,

2008CPD1001] do not cover N-hydroxyamidoximes, N-aminoamidoximes and hydrazidines and their preparative methods, synthetic utility and biological applications.

The following attempts to reddress the situation in a general and comprehensive review of the structure, synthesis and applications of these three classes of compounds.

N-Hydroxyamidoximes are derivatives of amidoximes and amidines and used as intermediate building blocks for the construction of heterocycles; [1955HCA1560] from the limited number of N-hydroxyamidoximes documented in the literature, representative (4.2a-f, 4.5, 4.6) are shown in Figure 4-2 and together with two examples of their still rarer O-substituted derivatives (4.7, 4.8)

Figure 4-1. Structures of N-hydroxyamidoximes, N-aminoamidoximes and hydrazidines

Figure 4-2. N-Hydroxyamidoximes and their derivatives in the literature

N-Aminoamidoximes (4.3) incorporate hydroxylamine and hydrazine moieties

(Figure 4-3); representatives of the few examples are shown in Figure 4-3.

Figure 4-3. Known N-aminoamidoximes and their derivatives [2006JOC9051, 1966JOC157, 2000TJC1, 2004S2877]

Hydrazidines form a class of chemical compounds with the general formula

RC(NHNH2) =NNH2 (4.4) (Figure 4-4), and are derived from carboxylic acids by replacing – OH with – NHNH2 (or N-substituted analogues) and =O with =NNH2 (or N- substituted analogues). Hydrazidines are alternatively denoted as hydrazide- hydrazones, dihydroxyformazans and N-aminoamidrazones. We located a total of 57 structures have been reported for diverse R groups in the acyclic (I) and (II) types

(Figure 4-4). Many more examples are known of hydrazidine moieties as part of a heterocycle: e. g., there are 24 examples of imidazole (III), benzimidazole (IV) and triazole (V) analogues, and 33 examples of type (I) and substituted hydrazidines (II), but these heteocycles are outside of the scope of the present review. The preparative methods, chemistry and applications of acyclic hydrazidines and their derivatives are summarized in this review.

Figure 4-4. Hydrazidines and their derivatives

4.2 Structure and Configuration

4.2.1 N-Hydroxyamidoximes

N-Hydroxyamidoximes (4.2) are sometimes named as N,N'-dihydroxyimidamides or oxyamidoximes. [1962CR155] Systematic studies reported with respect to configurations or conformations of the many classes of N-hydroxyamidoximes are so far limited to N-hydroxybenzamidoxime (4.2a). Clement et. al. studied and compared

chemical shifts and coupling constants J ( 15N, 1H) of several amidoximes with N- hydroxyamidoxime (4.2a) via 15N NMR. As observed by the 15N NMR, benzamidoxime

(4.24) exists only in the form of an oxime with no other tautomer detected, but N- hydroxybenzamidoxime (4.2) exists in two tautomeric forms in which a rapid equilibrium exists between (4.2a) and (4.2b) (Figure 4-2). Two 15N signals were detected: an oxime type nitrogen and a hydroxylamine type nitrogen. No NH coupling was observed due to the rapid tautomerization. [1985CB3481, 2007JMC6730] Barassin et. al. studied the configuration and conformation of N-hydroxybenzamidoxime and found that the Z- configuration (4.2Z) is favored energetically over configuration (4.2E), and conformation

(4.2c) is the predominant form due to the stabilization by hydrogen bonding (Figure 4-

5). [1969BSCF3409] This is in agreement with the calculation results by Chem3D MM2.

The minimized total energy (-3.0061 kcal/mol) for structure (4.2Z) is much lower than that of structure (4.2E), which is 5.6273 kcal/mol.

Figure 4-5. Tautomerization, conformation and configuration of N-hydroxyamidoxime

4.2.2 N-Aminoamidoxime

In 1910, Wieland first synthesized N-aminobenzamidoxime (4.3a, 4.3b) from benzohydroxamyl chloride and hydrazine hydrate, and named them as hydrazide oximes. [1910Ber4199] To the best of our knowledge, there are no studies in the literature related to the configuration or conformation of any N-aminoamidoximes, but most papers depict them as structure (4.3a) rather than (4.3b). Again, based on the energy minimizing calculations via Chem3D MM2, structure (4.3a) has lower total energy (-2.7554 kcal/mol) than that of structure (4.3b) (-0.5433 kcal/mol) (Figure 4-6).

Figure 4-6. Configuration of N-aminoamidoximes

4.2.3 Hydrazidines

To the best of our knowledge, there is literature data on the structure and configuration of hydrazidines. Chem3D MM2 energy minimizing calculations, however found that structure (4.4b) is considerably less stable than (4.4a) (Figure 4-7).

Figure 4-7. Configuration of hydrazidines

4.3 Preparative Methods

4.3.1 N-Hydroxyamidoximes and Their Derivatives

4.3.1.1 From oximidoyl chlorides and hydroxyamines

N-Hydroxybenzamidoxime (4.2a) is commonly prepared from oxyimidoyl chlorides

(4.6) and hydroxylamine via the route shown in Scheme 4-1. [1980JOC3916,

1914Ber2938, 1898Ber2126] The reaction of hydroxylamine with benzaldehyde gave benzaldoxime as the intermediate; further reaction with N-chlorosuccinimide (NCS) in

DMF gave α-chlorobenzaldoxime (4.6a), and subsequent reaction with hydroxylamine gave N-hydroxybenzamidoxime (4.2a) (Scheme 4-1). Ley and Ulrich synthesized compound (4.2d) and (4.2e) (Figure 4-8) in the same manner. [1914Ber2941]

Scheme 4-1. Preparation of N-hydroxybenzamidoxime

Huether et. al. prepared N-hydroxypyridylamidoxime (4.2b, 4.2c) from the corresponding pyridyl-oxyimidoylchlorides (4.6b, 4.6c) by reaction with excess hydroxylamine in methanol (Scheme 4-2). [1963JCED624]

Scheme 4-2. Preparation of N-hydroxypyridylamidoximes

Figure 4-8. N-Hydroxybenzamidoxime derivatives

Johannes et. al. synthesized alpha-hydroxylamine-2,6-dichloro-N- hydroxybenzaldoxime hydrochloride (4.2f) from the corresponding benzaldoxime chloride derivative (4.6f) (Scheme 4-3). [1966US3234255A]

Scheme 4-3. Preparation of 2,6-dichloro-N-hydroxybenzaldoxime hydrochloride salt

4.3.1.2 From amidoximes and hydroxyamine

Armand and Minvielle prepared formic N-hydroxyamidoxime hydrochloride (4.9) from formic amidoxime (4.8) and hydroxylamine hydrochloride (4.7) (Scheme 4-4).

[1965CR2512]

Scheme 4-4. Preparation of formic hydroxyamidoxime hydrochloride salt

4.3.1.3 From nitrile oxides and hydroxyamines

In a different approach, Aurich et. al. reacted nitrile oxide (4.11) with N-substituted hydroxylamine (4.10) to afford N-substituted hydroxyamidoxime (4.12). Nitrile oxides

(4.11a-c) react with hydroxylamines (4.10a-b) to give N2-hydroxyamidinyl N1-oximes

(4.12a-d), namely N-hydroxyamidoxime in 45-68% yield (Scheme 4-5). [1975CB2764]

Scheme 4-5. Synthesis of N-hydroxyamidoximes from nitrile oxides

4.3.1.4 Miscellaneous preparative methods for di-O-alkyl derivatives of N- hydroxyamidoximes

Benzotriazole methodology has been used to prepare N–hydroxymethylamidoxime derivatives. Katritzky and his coworkers prepared compound (4.15), a di-O-benzyl derivative of N-hydroxymethylamidoxime by the reaction of 1H-1,2,3-benzotriazol-1- ylmethanone oxime (4.13) with benzyloxyhydroxylamine (4.14) under microwave radiation (Scheme 4-6). [2006JOC9051]

Scheme 4-6. Preparation of di-O-benzyl derivative of N-hydroxymethylamidoxime

Treatment of an alcoholic solution of p-sulfamidobenzimidate hydrochloride salt

(4.16) with O-methylhydroxylamine (4.17) under pressure gave two products (4.18) and

(4.19), a di-O-methylsubstituted p-sulfamido-N-hydroxybenzamidoxime (Scheme 4-7).

[1962CR155]

Scheme 4-7. Synthesis of di-O-methylsubstituted p-sulfamido-N- hydroxybenzamidoximes

4.3.2 N-Aminoamidoximes and Their Derivatives

4.3.2.1 From oxime chlorides or amidoximes

Previous preparations of aminoamidoximes include the reactants of oxime chlorides (4.6, X=Cl) or simple amidoximes (4.6, X=NH2) with hydrazines (4.20) to give aminoamidoximes (4.21) in 21-30% yield (Scheme 4-8). [1980CRS304, 1981PJC1253]

Scheme 4-8. General route to N-aminoamidoximes

4.3.2.2 From oximebenzotriazoles and hydrazines

N-Amino-N´-nitrophenyl benzamidoxime (4.23) was prepared by Katritzky et. al. by the reaction of 1H-1,2,3-benzotriazol-1-ylmethanone oxime (4.7) with hydrazine

(4.22) under microwave radiation in 71% yield and isolated as a viscous oil (Scheme 4-

9). [2006JOC9051]

Scheme 4-9. Synthesis of N-amino-N´-nitrophenyl benzamidoxime

4.3.2.3 From N-hydroxyimidates and hydrazides

Bel Hadj and Baccar prepared N-(Ethoxycarbonyl)amide-N- hydroxybenzamidoximes (4.26) by the reaction of hydrazide (4.25) with ethyl N- hydroxybenzimidate (4.24) in 98% yield (Scheme 4-10). [1986JSCT9]

Scheme 4-10. Preparation of N-(ethoxycarbonyl)amide benzamidoxime

4.3.2.4 From oxyimidoylchlorides and hydrazines

The reaction of 1,2,3-oxadiazolium carbohydrazimic chloride (4.27) with hydrazine gave N-aminoamidoxime derivative (4.28) (Scheme 4-11). [2004S2877] Hydrazino(3- arylsydnon-4-yl)methanone oximes (4.28) are good precursors for the synthesis of triazolyl sydnones (4.69a-f) (Scheme 4-24), some of which have important pharmacological activities, such as antimicrobial, anti-inflammatory, analgesic and antipyretic properties. [2004S2877]

Scheme 4-11. Preparation of 3-(3-arylsydnon-4-yl)triazole derivatives

4.3.2.5 From hydrazide imidate and hydroxyamine

Ikizler et. al. prepared a series of hydroxamic acid ethoxycarbonylhydrazides

(4.30) by reaction of hydrazide imidate (4.29) with hydroxylamine (Scheme 4-12).

[1992MC257]

Scheme 4-12. Preparation of hydroxamic acid ethoxycarbonylhydrazides

4.3.3 Hydrazidines

4.3.3.1 From imidate salts and hydrazines

When excess hydrazine (4.32a) was added to aliphatic imidate salt (4.31) (R = alkyl) under anhydrous conditions at temperatures below 0 ˚C, hydrazidine (4.4) was isolated, while at elevated temperatures (40-50 ˚C) other cyclic by-products were produced (Scheme 4-13). [1931MC106, 1976T1031]

Scheme 4-13. Synthesis of aliphatic hydrazidines

The use of monosubstituted hydrazines (4.32) reduces the number of by-products, and reacts smoothly with imidate salts (4.31) in alcohol at room temperature. The main products are N-substituted amidrazones when equimolar quantities of the reactants are used, but substituted formazans (4.33) are obtained when excess hydrazine (4.32) is employed (Scheme 4-14). [1884Ber182, 1954JCS3319, 1955JPSJ726, 1956JCS2853,

1955CRV355]

Scheme 4-14. Synthesis of substituted formazans

4.3.3.2 From amidoximes and hydrazines

In the only reaction located between an amidoxime (4.34) and phenylhydrazine

(4.32b), Bamberger used excess phenylhydrazine and isolated the product as triphenylformazan (4.35) (Scheme 4-15). [1894Ber160]

Scheme 4-15. Synthesis of triphenylformazan

4.3.3.3 From amidrazones and hydrazines

The reaction of the amidrazone hydrochlorides (4.36a-d) with anhydrous hydrazine (4.32a) at 40 oC gives hydrazidine hydrochlorides (4.37a-d) in 40-98% yields.

(Scheme 4-16). [1972LAC16, 1975LAC1120]

Scheme 4-16. Synthesis of hydrazidine hydrochlorides

Kurzer and Douraghi-Zadeh obtained phenylaminohydrazidine (4.39) similarly via the reaction of isothiosemicarbazide / amidrazone (4.38) with hydrazine (4.32a) at low temperature. The triazole (4.40) was formed as a by-product in this hydrazinolysis when the temperature was above 40 oC (Scheme 4-17). [1967JCS(C)742]

Scheme 4-17. Synthesis of diaminoguanidine / amino-hydrazidine

4.3.3.4 From diethoxy-N,N-dimethylethanamine and hydrazides

Glushkov et. al. prepared hydrazidine derivative (4.44) from 1,1-diethoxy-N,N- dimethylethanamineacetyle (4.42) and isonicotinylhydrazide (INH) (4.41), known as

Isoniazid, a medication in the prevention and treatment of antituberculosis. [2004KFZ16]

The first step forms the amidine derivative (4.43), which was derivatized further to the hydrazidine hydrochloride salt derivative (4.44) via the reaction with another equivalent of (4.41) in refluxing acid-ethanol solution (Scheme 4-18).

Scheme 4-18. Synthesis of hydrazidine derivatives

4.3.3.5 From hydrazonyl bromides and hydrazines

Takahashi et. al. reported that the reaction of hydrazonyl bromide (4.45a-f) and hydrazine hydrate in alcohol formed hydrazidines (4.46a-f). The Reaction of hydrazonyl bromide (4.45a-g) with benzoylhydrazines (4.47a-d) at room temperature can yield benzoylbenzohydrazide hydrazones (4.48a-g), which can further cyclize to N- aminotriazoles (4.49a-g) upon heating in acetic acid (Scheme 4-19). [1977BCSJ953]

Scheme 4-19. Synthesis of hydrazidines from hydrazonyl bromide

4.3.3.6 From triazines

Grundmann discovered that s-triazine (4.50) reacted with dimethylhydrazine (4.51) or hydrazine (4.53) to give hydrazidine (4.52) or amidrazone (4.54) depending on the hydrazines used (Scheme 4-20). [1963ACIEE309]

Scheme 4-20. From triazine to hydrazidines

4.4 Chemistry and Reactions

4.4.1 N-Hydroxyamidoximes

4.4.1.1 Reduction of N-hydroxyamidoximes

Ley and Ulrich showed that N-hydroxybenzamidoxime (4.2a) may be reduced by sulfur dioxide to benzamidoxime (4.34) (Scheme 4-21). [1914Ber2941]

Scheme 4-21. Conversion of N-hydroxybenamidoxime into benzamidoxime

4.4.1.2 Oxidation of N-hydroxyamidoximes

Armand and Minvielle also found that formic hydroxyamidoxime (4.55), which is amphoteric, can be oxidized by KIO4 to potassium salt of nitrosolic acid (4.56) (Scheme

4-22). [1965CR2512]

Scheme 4-22. Conversion of formic hydroxyamidoxime to its nitrosolic acid

Armand and Minvielle reported the periodate oxidation of N- hydroxybenzamidoxime (4.2a) to benzonitrosolate salt characterized as the potassium salt (4.58), which is a precursor for the synthesis of 3,5-diphenyl-1,2,4-oxadiazole (4.61)

(Scheme 4-23). [1965CR2512] Quadrelli and Caramella discovered that N- hydroxybenzamidoxime (4.2a), on treatment with alkali, gave the azo-derivative (4.57) which disproportionated to benzamidoxime (4.34) and the deep blue potassium salt of benzonitrosolic acid (4.58). [2007COC959]

Scheme 4-23. Synthesis of 3 ,5-diphenyl-1,2,4-oxadiazole

Sheremetev et. al. oxidized nitrosolic acid salts (4.58a-b), derivatives of of N- hydroxyamidoxime to nitrolic acid (4.62a-b) with dinitrogen tetraoxide (N2O4). 3,4-

Diphenylfuroxan (4.60) was prepared by treating phenylnitrosolic acid silver ammoniate salt (4.58c) with two equivalents of N2O4 (Scheme 4-24). [2009RCB487]

Scheme 4-24. Reaction of nitrosolic acid salts with dinitrogen tetraoxide

4.4.1.3 Reaction with aldehydes

Desherces et. al. used N-hydroxyamidoximes (4.2) as precursors to the preparation of 4-hydroxyoxadiazolines (4.64) (Scheme 4-25). [1978RRC203]

Scheme 4-25. Synthesis of 4-hydroxyoxadiazolines

4.4.1.4 Reaction with ketones

Desherces et. al. also found that (Z)-N-hydroxybenzamidoxime (4.2a) reacted with benzophenone (4.65) to give hydroxamic acid (4.66) and benzophenone oxime (4.67)

(Scheme 4-26). [1978RRC203]

Scheme 4-26. Reaction of N-hydroxyamidoxime with benzophenone

4.4.2 N-Aminoamidoximes

4.4.2.1 Reaction with aldehydes

N-Aminoamidoxime (4.28), prepared as a precursor as shown in Scheme 4-11, reacts with aromatic aldehydes (4.68) in acetonitrile in the presence of a suitable quantity of concentrated sulfuric acid to afford the desired 3-sydnonyl triazoles (4.69a-f) in 40-63%, as depicted in Scheme 4-27. [2004S2877] The reactions of hydrazino(3- phenylsydnon-4-yl)methanone oxime (4.28a) with aliphatic aldehydes including hexanal

(4.68a), heptanal (4.68b) and cyclohexanecarboxaldehyde (4.68c) gave 5-alkyl-3-(3- arylsydnon-4-yl)-1H-[1,2,4]triazoles (4.69a-c) (Scheme 4-27). [2004S2877]

Scheme 4-27. Preparation of 3,5-disustitued 1H-[1,2,4]triazoles

4.4.2.2 Cyclization in basic media to hydroxytriazoles

Another N-aminoamidoxime derivative, N-(benzyloxycarbonyl)amide-4- methylbenzamidoxime (4.26a) was used as a precursor (Scheme 4-10) in the synthesis of 3-benzyl-5-(p-tolyl)-4H-1,2,4-triazol-4-ol (4.70) (Scheme 4-28). [1986JSCT9]

Scheme 4-28. Synthesis of 3-benzyl-5-(p-tolyl)-4H-1,2,4-triazol-4-ol

Ikizler et. al. discovered that N-aminoamidoxime derivative (4.30) (Scheme 4-12) cyclizes in basic media to form 3-substituted 4-hydroxy-4,5-dihydro-1,2,4-triazol-5-one

(4.61) in 73% yield (Scheme 4-29). [1992MC257]

Scheme 4-29. Synthesis of 3-phenyl-4-hydroxy-4,5-dihydro-1,2,4-triazol-5-one

4.4.3 Hydrazidines

4.4.3.1 Reaction with aldehydes

Hydrazidines (4.4a-d) can react with benzaldehyde (4.68c) or can be used as important synthetic auxiliaries for the synthesis of 4-amino-1,2,4-triazole hydrochlorides

(4.74a-e) by the reaction with triethoxyformate (4.72) (Scheme 4-30) [1975LAC1120]

Scheme 4-30. Synthesis of dibenzylidene hydrazidine 4-amino-1,2,4-triazole hydrochloride

Neunhoeffer et. al. reported that the reaction of aromatic hydrazidines (4.4a) with benzaldehyde (4.68c) gave noncyclic structure (4.77) in 79% yield as the product

(Scheme 4-31). [1992LAC115] Takahashi et. al. found that the oxidation of N- benzylidene-N-(2-bromo-4-nitrophenyl)benzohydazidine (4.78a) formed from the reaction of (4.75a) with aldehyde (4.76), with mercuric oxide (HgO) in refluxing ethanol gave 4-amino-1,2,4-triazole (4.79), and 3-Alkyl and aryl-5-aryl-4-arylamino-1,2,4-

triazoles (4.79a-e) were prepared from N-aryl-N-arylmethylenehydrazidines (4.78a-e) in

28-75% yield in this manner. [1977BCSJ953]

Scheme 4-31. Reaction of hydrazidines with aldehydes

4.4.3.2 Reaction with anhydrides

Neunhoeffer et. al. reported that hydrazidines can react with anhydrides to produce tetrazines (Scheme 4-32). [1979CB1981] The reaction of acetohydrazidine

(4.4a) with phthalaldehydic acid (4.87) can yield 3-methyl-1,10b-dihydro-1,2,4,5- tetrazino[3, 2-a]isoindol-6(4H)-one) (4.88), which can be further converted to 3-methyl-

1,2,4,5-tetra-amino[3, 2-a]isoindol-6(4H)-one (4.92) upon mild oxidation. Compound

(4.92) can also be obtained by the reaction of (4.4a) with phthalic acid derivatives

(4.89), (4.90) and (4.91). The reaction of (4.4a) and nitrophthalic anhydride (4.80) yielded two isomeric nitro-1,2,4,5-tetrazino [3, 2-a]- isoindol-6(4H)-ones (4.81a, 4.81b).

The reaction of acetohydrazidine (4.4a) with dichloromalealdehydic acid (4.82) gave

7,8-dichloro-3-methyl-1,8-dihydropyrrolo [1, 2-b]-1,2,4,5-tetrazine-6(4H)-one hydrochloride (4.83). [1975CB3509] Other heterocycles (4.93, 4.94 and 4.95) were

100

prepared by the reaction of benzylhydrazidine (4.4b) with anhydrides (4.81, 4.82)

(Scheme 4-32). [1992LAC115]

Scheme 4-32. Synthesis of pyrrolo[1,2-b][1,2,4,5]tetrazines

101

4.4.3.3 Reaction with diketones

Hydrazidines have been studied for the generation of different fused and nonfused six-membered heterocyclic systems such as tetraphenylpyrazine (4.98) and 1,2,4- triazines (4.101) (Scheme 4-33). The reaction of (4.4a) with benzoin (4.96) forms the monocondensation product (4.97) first, then 2,3,5,6-tetraphenylpyrazine (4.98) upon heating. The reaction of hydrazidine (4.4a) with benzil (4.99) gives preferentially 4- amino-1,2,4-triazines (4.93). [1989LAC105] The reaction of (4.4a) with 4,4-dimethyl-1,2- cyclopentandione (4.102) failed to produce cyclopentatriazine (4.104), but octaaza[14]- annulen (4.103) was formed instead. Similarly, (4.4a) on reaction with diketone (4.105) gave 14-membered structure octaazo-cyclotetradecin (4.106). (Scheme 4-33)

[1989LAC105] Neunhoeffer et. al. obtained three compounds (4.107, 4.108, 4.109) by reaction of benzylhydrazidine (4.4a) with isophorone (4.102) (Scheme 4-33).

[1992LAC115]

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Scheme 4-33. Reaction with diketones

4.3.3.4 Reaction with alpha-keto- acids or esters

Draber et. al. reacted benzylhydrazidine (4.4c) with alpha-ketocarboxylic acid

(4.110) and obtained 4-amino-6-benzyl-3-methyl-1,2,4-triazine-5-one (4.111) in 56% isolated yield (Scheme 4-34). [1976LAC2206] Hydrazidines (4.4) react with phenylglyoxyl-methylester (4.112) to yield 4-amino-3-methyl-6-phenyl-1,2,4-triazin-

5(4H)-one (4.114) via the monocondensation intermediate (4.113) (Scheme 4-34).

[1985LAC78] Neunhoeffer et. al. prepared many 6-membered heterocycles (4.116a-i) by reaction of aromatic hydrazidines (4.4a-c) with α-ketoesters (4.115a-c) (Scheme 4-

34). [1992LAC115] 103

Scheme 4-34. Syntheses of triazinones

4.4.3.5 Reaction with acylnitriles

The reaction of hydrazidines (4.4a-b) with benzoyl cyanide (4.117) give 4-amino-5- imino-1,2,4-triazine (4.118), which is readily converted to triazinones (4.114) (Scheme

4-35). [1985LAC78]

Scheme 4-35. Reaction of hydrazidines with acylnitriles

4.4.3.6 Reaction with cyclopentadiene derivatives

Acetohydrazidine (4.4a) reacts with 2,3-dihydroxycyclo-pentadiene-1,4- dicarboxylate-dimethylester (4.117a-b) to give 4-amino-4,6-dihydro-3-methyl-1H- cyclopenta[e]1,2,4-triazin-5,7-dicarboxylester (4.118a-b). The reactions of (4.4a) with a

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heteroaromatic systems such as 3,4-dihydroxy-2,5-furan dicarboxylate-dimethylester

(4.119a) or 3,4-dihydroxy-2,5-thiophenedicarboxylate-dimethylester (4.119b) gives

1,2,4-triazine (4.120a) and (4.120b). Likewise, 2,3- dihydroxy-5,5-dimethyl-1,3- cyclopentadiene-1,4-dicarboxylate-dimethylester (4.119c) reacts with (4.4a) to form

(4.120c) as the major product (Scheme 4-36). [1989LAC105]

Scheme 4-36. Synthesis of 4-aminocyclopenta[e]-1,2,4-triazines

4.4.3.7 Reaction with diketoesters

The reaction of (4.4a) with dimethylester (4.121) yields diketone-triazine (4.122) but in only 7% isolated yield. The reaction of (4.4a) with thioxamidyl methyl ester (4.123) with triethylamine as base gives monocondensation product first, which cyclizes to

(4.124) upon heating. When (4.4a) is reacted with dimethyl acetylenedicarboxylate

(4.125) in MeOH in the presence of Et3N, crystalline pyrazolinone (4.126) was isolated in 37% yield (Scheme 4-37). [1985LAC78]

The reaction of N-(2-bromo-4-nitrophenyl)benzohydrazidine (4.127a) with dimethyl acetylenedicarboxylate (4.125) in tetrahydrofuran (THF) under reflux gives an orange product, identified as 2,3,4,5-tetrahydro-1,2,4,5-tetrazine (4.128a). Other tetrahydro- tetrazine derivatives (4.128a-e) can be prepared in a similar manner by heating the mixture under reflux in THF (Scheme 4-37). [1977BCSJ953] 105

Scheme 4-37. Reaction of hydrazidines with diketoesters

4.4.3.8 Reaction with formic acid

3-Alkyl and arylamino-1,2,4-triazoles (4.131a and 4.131e) were first obtained upon heating (4.127a, 4.127e) in formic acid. The reaction presumably proceeds via formylated hydrazidine (4.130) to (4.131). However, this method produces many by- products, and only (4.131f) and (4.131g) were reported as being isolated in pure form.

(Scheme 4-38). [1977BCSJ953]

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Scheme 4-38. Reaction of hydrazidines with formic acid

4.3.3.9 Reaction with thioesters

S-Methylisothiocarbonohydrazide salt is used as a bis-aminoguanidine equivalent in the synthesis of 6-aryl-3-aminotetrazines from dithio-p-benzoate esters (Scheme 4-

39). [1979JHC881] For example, dithio-p-benzoate esters (4.133) react with S- methylisothiocarbonohydrazide hydroiodide (4.132) to form dihydrotetrazines (4.134) which can be oxidized to (methylthio)tetrazines (4.135). The methylthio group serves to deactivate the internal latent guanidine nitrogens for cyclization [1975JCS(PT1)1787] and also to provide a handle for the subsequent amination to form 6-aryl-3- aminotetrazines (4.136). [1977JHC587]

Scheme 4-39. Synthesis of unsymmetrically substituted 1,2,4,5-tetrazines

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4.3.3.10 Reaction with hydrazine

Glushkov et. al. synthesized 3-methyl-6-pyridyl-1,2,4,5-tetrazine (4.138) by the reaction of hydrazidine derivative (4.137) with hydrazine hydrate in methanolic media at room temperature (Scheme 4-40). [2004KFZ16]

Scheme 4-40. Synthesis of 3-methyl-6-pyridyl-1,2,4,5-tetrazine

4.4.3.11 Reduction of hydrazidines

Bamberger et. al. discovered that ammonium sulfide in cold alcoholic solutions reduced hydrazidines (4.139a) to amidrazones (4.140a) with amines (4.141a) as by- products (Scheme 4-41). [1925LAC260]

Scheme 4-41. Reduction of formazans

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Regitz and Eistert used phenylhydrazine to reduce formazan (4.139b) to amidrazone (4.140b) at 50-100 oC (Scheme 4-41). [1963ibid3121] Hauser et. al. used stannous chloride as a reducing agent to convert formazan (4.139) to its parent acid

(4.142a) and amines (4.141a-c), but the reaction did not give an amidrazone (Scheme

4-41). [1951CB651]

Jerchel et. al. studied the stepwise hydrogenation of tetrazolium salt (4.143) to formazans (4.139c). [1950LAC185, 1957ibid191] Three successful methods of reduction were reported: (i) hydrogenation using 5% palladium on barium sulfate, (ii)

Raney nickel in methanol, and (iii) sodium dithionite. The reduction process is shown in

Scheme 4-41. Hydrazidine (4.144) is only stable in solution and is oxidized back to the formazan (4.139c) on exposure to air. Lithium aluminum hydride (LAH) has no effect on triphenylformazan (4.139c) in ether-tetrahydrofuran (Et2O-THF) at room temperature

(RT) but cleaves it on boiling for several hours, giving the corresponding amidrazone

(4.140c). [1952CB470]

4.4.3.12 Condensation with α-halo ketones

Beyer et. al. reported that the reaction of α-bromo ketones (4.145) with N,N'- diaminoguandine / aminohydrazidine (4.146) gave the condensation product (4.147)

(Scheme 4-42). [1968CB29]

Scheme 4-42. Reaction of α-halo ketones with hydrazidine amine

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4.4.3.13 Miscellaneous reactions

Hydrazidine (4.148) may be readily oxidized to the blue-green free radical (4.149), which is related to, but less stable than the cyclic verdazyl free radicals (4.150)

(Scheme 4-43). [1964ACIEE232, 1966MC517, 1968ACIEE489]

Scheme 4-43. Hydrazidine radical

Butler et. al. reported that the reaction of a hydrazidine derivative – polyhydrazine triaminoguanidines with diketones gave hydrazidines. For example, on treatment of triaminoguanidine nitrate (4.151) with acetylacetone (4.152), a complex reaction occurred giving rise to products (4.153, 4.154 and 4.155), the proportions of which varied with the conditions of the reaction. In the presence of sufficient (4.152), the dipyrazolylmethylenehydrazono-derivative (4.155) is the main product, whereas at a molar ratio of 1:2 for triaminoguanidine and acetylacetone, di-pyrazolylketone hydrazone (4.154) is isolated in highest yield (Scheme 4-44). [1970JCS(C)2510]

Scheme 4-44. Reaction of hydrazine hydrazidine with acetylacetone

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4.5 Applications

4.5.1 N-Aminoamidoximes

4.5.1.1 As a prodrug model

Clement and Reeh reported that drugs containing amidine functions could be efficiently absorbed by the gastrointestinal tract after oral administration.

[2009USP0270440A1] N-Hydroxybenzamidoxime derivatives (4.2c) represent a new class of prodrug to improve the oral bioavailability of medications containing amidine functions, because they have lower basicity but higher lipophilicity than amidine derivatives, and can be quickly absorbed, then reduced rapidly to benzamidoxime (4.24) via N-reductases in vitro after oral administration (Scheme 4-45). [2007JMC6730] The bioavailability of N-hydroxyamidoxime exceeds that of benzamidine after the oral application. [2007JMC2730]

Scheme 4-45. In vitro biotransformation of N-hydroxybenzamidoxime

4.5.1.2 Applications in inorganic chemistry

The synthesis of alkali and silver nitrosolates (M[RC(NO)2], M = Metal, R = organic substituent) was first described about a century ago. [1905Ber1445] Wieland and Hess obtained nitrosolates from unstable N-hydroxyamidoximes by disproportion in NH3 or by oxidation with KIO4 in basic solution. [1906Ber65, 1907LAC65, 1909Ber4175] For R =

H, these procedures lead to the formation of potassium dinitrosomethanide when KOH

- is used. [1909Ber4175] Recently, salts of nitrosodicyanomethanide [(ON)C(CN)2] and

- nitrodicyanomethanide, [(O2N)C(CN) 2] are predicted as potential propellants similar to

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nitrite and nitrate salts respectively based on theoretical calculations. [1999IC2709] .

Brand et. al. developed a two-step synthesis of DNM salts (DNM = dinitrosomethanide) from formamidinium nitrate. Treating a methanolic solution of (4.156) and hydroxylammonium nitrate (4.157) (2 equiv) with a methanolic solution of KOtBu (2 equiv) resulted in the formation of the labile intermediate N,N’-dihydroxyformamidinium nitrate (4.158) (Scheme 4-46). The reaction of (4.158 with MOtBu (2 equiv) in the presence of oxygen yields the deep blue DNM salt (4.159). [2005JACS1360]

Scheme 4-46. Synthesis of dinitrosomethanide (DNM) salt

N-Hydroxyamidoxime derivatives are efficient ligands for transition metals in redox systems. [1971JCPPCB601] A study of the reactions between the two redox systems Fe(II)/Fe(III) and acetohydroximic oxime (4.160a) and ethylnitrosolic acid

(4.160b) showed a strong stabilization of Fe(II) by ethylnitrosolate (Figure 4-9). The systems Fe(II) – (4.160a), Fe(III) – (4.160a), Fe(III) – (4.160b) are unstable and evolve towards Fe(II) – (4.160b). [1972JCPPCB689]

Figure 4-9. Acetohydroximic oxime and ethylnitrosolic acid

4.5.2 N-Aminoamidoximes

4.5.2.1 As metal ligands for important coordination compounds

Sarikavakli et. al. prepared N-aminoamidoxime (4.162) from the hydrazimic chloride precursor (4.161), which may be further derivatized via reaction with aldehydes

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or ketones (4.165) to (4.163) and (4.166), both of which can complex with transition metal ions (Ni, Cu, Co), to form novel vic-dioxime derivatives of hydrazone metal complexes (4.164 and 4.167). (Scheme 4-47 & 4-48). [2005TJC107, 2006TJC563] vic-

Dioximes can also form stable metal complexes of transition, inner-transition or actinide metal ions, and the ligands or their metal complexes have played a significant role in stereochemistry, isomerism, magnetism, spectroscopy, cation exchange and ligand exchange chromatography, analytical chemistry, catalysis, pigments and dyes.

[1974CCR1] vic-Dioximes complexes are model coordination compounds for studying the structure of vitamin B12 and coenzyme B13, which have important roles in biology.

[2003JMS647]

Scheme 4-47. Synthesis of novel vic-dioxime derivatives of hydrazones

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Scheme 4-48. Synthesis of vic-dioxime derivatives and their metal complexes

Chandrama et. al. synthesized a new thioether ligated octahedral low-spin cobalt(II) complex (4.168) (Figure 4-10) from N-aminobenzamidoxime and studied its spectroscopic / electrochemical properties. [2006IJC1126]

Figure 4-10. N-Aminobenzamidxoime cobalt(II) perchlorate complex

4.5.3 Hydrazidines

4.5.3.1 As new fibrous adsorbents

Fibrous complexing adsorbents offer vital advantages over granular adsorbents and have been utilized for trace element preconcentration in chemical analysis.

[1989ZNK675] The properties of complexing fibrous adsorbent POLYORGS 33, which was prepared by treating a freshly formed poly(acrylonitrile) fiber with a mixture of hydroxylamine and hydrazine hydrate, and the properties of novel filled fibrous

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adsorbents bearing hydrazidine (POLYORGS 35) groups have been studied with respect to heavy and noble methods. It was shown that new adsorbents can be used for the dynamic preconcentration of metals and radionuclides from aqueous solution and these adsorbents can also be used for the preconcentration of heavy, noble, and rare metals and radionuclides from aqueous salt solutions. [2000JAC549]

4.5.3.2 As anti-tuberculosis agents

Some hydrazidine analogues of isonicotinylhydrazine demonstrate in-vitro anti- tuberculosis activity, with hydrazidine derivative (4.87) possessing the best in-vitro activity against the tuberculosis pathogen. [2004KFZ16]

4.5.3.3 As environmentally friendly dyes

Dozens of patents and journals describe various hydrazidine- or formazan- derived compounds as dye ligands that bind to metals such as Cu, Fe, Ni, Co, and they have important applications in the textile industry. [2000EPA10, 2007DP8, 1995TCC13,

1989EPA315046A2]

Copper complexes of some hydrazidine derivatives, e.g. N, N’-bis(o- hydroxyphenyl)-C-phenylformazan (4.169) are suitable agents for the dyeing of protein fibers in neutral or slightly acid media, and they have fairly strong affinity to wool.

[1959ICBS532] Freeman et. al. synthesized some Fe-complexed hydrazidine derivatives (4.170, 4.171) as environmentally friendly dyes (Figure 4-11). They can substitute metals such as Cr and Co without adversely affecting technical and mutagenic properties, again offering applications in the textile industry. [1995TCC13,

2007DP8]

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Figure 4-11. Environmental friendly dye ligands

4.6 Conclusions

In summary, N-hydroxyamidoximes, N-aminoamidoximes and hydrazidines are classes of amidine derivatives with versatile synthetic utilities and pharmacological applications. They have been used extensively as starting materials for the preparation of nitrogen-rich heterocycles. Typically they cyclize with various electrophiles such as aldehydes, ketones carboxylates and acids and they have important applications in drugs, dyes and polymers.

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CHAPTER 5 SUMMARY OF ACHIEVEMENTS

Heterocyclic chemistry is an intriguing aspect of organic chemistry. It is a subject with major studies focused on cyclic organic compounds made up of carbon, oxygen, nitrogen and sulphur atoms. Many natural products, pharmaceutical intermediates, drugs, textile dyes and polymers are heterocyclic molecules. Heterocyclic chemistry is important to mankind and society for its immense applications that touch all of our daily lives. 1H-Benzotriazole and its derivatives are known and used as important synthetic auxiliaries in heterocyclic synthesis. Many important aspects of 1H-benzotriazole chemistry have been explored over the last 30 years. My graduate studies aimed to further apply the benzotriazole methodology to synthesize different heterocyclic compounds with important applications. To summarize, Chapter 1 provides an overview of 1H-benzotriazole methodology and some recent applications of 1H-benzotriazole and its derivatives in heterocyclic synthesis. In Chapter 2, an efficient N-acylbenzotriazole mediated synthesis of naphthoquinone-dipeptide conjugates is reported. Chapter 3 presents a straightforward approach to the synthesis of 1,3,4-oxadiazoles from functionalized N-acylbenzotriazoles and acylhydrazides, which is an extension of the N- acylbenzotriazole methodology. Chapter 4 provides a systematic review of the structure, synthesis, reactivity and utility of N-hydroxy and N-aminoamidoximes and hydrazidines, which are important classes of nitrogen-rich building blocks.

Apart from the above mentioned work, I participated in and completed the synthesis and studies of the mechanical property of highly-filled crosslinked polytriazoles, which is described in Appendix A.

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APPENDIX A HIGHLY FILLED CROSSLINKED 1,2,3-TRIAZOLE POLYMERS AS NOVEL ROCKET PROPELLANT BINDERS

A-1 Introduction

A-1-1 Rocket Propellant Binders

Rockets propellants are materials that give spacecraft a forward push via producing large volumes of hot gas upon burning. Commonly, rocket propellants consist of fuels and the oxidizers. [1997JP36, 1999JEM1, 2007PEP213] The fuel is generally aluminum; the oxidizer is often finely ground ammonium perchlorate powder, which constitutes 60% - 90% of the mass of the propellant. The other important ingredient for rocket propellant is a polymeric binder which binds fuel, oxidizer and other additives together. The most commonly used binders are polyurethane (PU), polybutadiene acrylic acid acrylonitrile (PBAN), and hydroxy-terminator polybutadiene (HTPB) (Figure

A-1). Recently, 1,2,3-triazole-polymers prepared via “Click Chemistry” [2001ACIE2004,

2007MRC15, 2007ACIE1018] were reported as novel binders for high-energy explosive and propellant materials, with advantages in terms of lower tensile stress and modulus comparable to the polyurethanes used extensively as rocket propellant binders.

[2008JPS(A)PC238, 2001HPP313, 1992EPA481838]

Figure A-1. Common rocket propellant binders

The mechanical properties of solid rocket propellants and binders are important for the functioning of rocket motors. [2003JTAC921] Polyurethanes were found to have good physical properties, and aluminum powder could be incorporated for higher specific impulse. However, polyurethanes are so viscous that the amount of oxidizers and other solid additives that could be incorporated is limited. Polyurethane can undergo side reactions during and after polymerization that degrade the mechanical properties of the resulting propellant, e.g., loss of elasticity. Polyurethane propellants tend to possess low tensile stress and modulus. [2000USP6103029] Polybutadiene- based propellants such as PBAN and (HTPB) have physical properties superior to those of polyurethanes. However, PBAN propellant is difficult to process and requires an elevated curing temperature, and HTPB uses isocyanates for curing, which are very toxic for the environment.

A-1-2 Triazole Polymers as Novel Rocket Propellant Binders

1,2,3-Triazole polymers (Figure A-1) are novel macromolecules that have received growing interest in the area of polymer chemistry and material science. [2007ACIE1018]

Typically, they are synthesized by Huisgen 1,3-dipolar cycloaddition of azides with terminal alkynes, which has been utilized for the synthesis of functionalized monomers

[2008JPS(A)PC2897], polymers [2008JPS(A)PC2316], chromophores [2005CC2029], conjugated polymers [2005CC4333], glyco-polymers [2005EJOC3182] and macrocyclic polymers [2006JACS4238]. Reed et. al. synthesized crosslinked triazoles as energetic binders with improved mechanical properties and stability. [1992EPA481838]

[2001HPP313] Huang et. al. synthesized and characterized several series of novel low- temperature curing and heat-resistant poly-triazole resins as advanced composites.

[2007PAT556, 2007JAPS1038, 2007JMS(PA)PAC175] Our group has developed 119

strategies for low-temperature synthesis of oligo-triazoles as binder ingredients.

[2006ARKIVOC43] Triazole-cured polymers were prepared with various alkynes and azides without any solvent or copper catalysts under mild conditions near room temperature. [1996JAPS2347] However, the mechanical properties of those triazole polymers were not quantified. To meet the requirements of the specification of rocket propellant binders, the monomers are required to polymerize at low temperatures (room

o temperature to 60 C) with no or little side reactions. The polymerization process should proceed in the absence of any solvent or heavy metal catalysts. In addition, the polymerization should be capable of being scaled up easily. Polymerization through triazole linkages proceeds readily and the components of the triazole cure (ethynyl groups and azido groups) react preferentially with each other [2005EJOC3182], which largely avoids the possibility of side reactions.

Since crosslinkers provide less mobility and increase the stiffness of the polymer, the addition of crosslinkers can modify polymer mechanical properties such as tensile strength, modulus and elasticity by limiting the mobility of individual polymer chains. It is known that the mechanical properties of triazole polymers are significantly influenced by their molecular structures such as the chain length between the triazole groups.

[1996JAPS2347] Crosslinker effects on mechanical properties of conventional rubbers have been studied for many years and are well understood. [2001JAPS710] However, such studies have not been systematically performed on triazole polymers. Hence, we are interested in investigating the crosslinker effect on the mechanical properties of formed triazole polymers. Triazole polymer formation is a good model to understand the relationship between crosslinking and polymer mechanical properties, because

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acetylene and azide groups should react with each other at 1:1 molar ratio, no small molecules are produced, the reaction should not be influenced by residual moisture, and side reactions should not occur. Thus, syntheses were carried out to investigate the relationship between crosslinker concentration and mechanical properties of unfilled and filled triazole polymers in terms of elongation strain (% elongation at break) and elastic modulus (Young’s modulus).

Another aim of the project was to investigate the filler effects (types, sizes) on the mechanical properties of the crosslinker triazole polymers in order to maximize the amount of fillers in the polymeric binders based on military requirements. The binder for propellants should possess a low reactivity to the filler ingredients and to the oxygen in the air over long period storage at ambient temperature. In addition, the binder must be able to tolerate a high loading of particulate solid ingredients. All else being equal, the more solids one can blend into a given binder, the higher the performance of the energetic formulation. The inclusion of particulate fillers in polymeric materials is an established industrial practice which is performed in order to enhance polymer properties such as modulus, fracture resistance and toughness while reducing the overall component cost. [1977JMS1605] The effects of using different weight percentages of fillers such as carbon black, silica, aluminum oxide, zirconium oxide

[1998JAPS1057], metal or metal clad fillers [2003USP113531], carbon nanotubes

[2006MCP132], glass-ceramic [2004B949] and sodium sulfate [1991RCT181] on the thermal and mechanical properties of elastomers have been reported in detail by several groups. Aluminum powder is a commonly used filler that improves mechanical, electrical and thermal properties of polythiourethane-modified epoxy adhesives

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[2008POC133], low density polyethylene (LDPE) [2007JAPS2436] and high density polyethylene (HDPE) composites [2006JAPS2161], natural rubber (NR) composites

[2007PPTE667], polymethylmethacrylate (PMMA) [2001JP5267] and ethylene- propylene-diene terpolymer (EPDM) composites [2007PPTE1201].

The mechanical properties of a composite material depend strongly on particle- matrix interface adhesion, particle size and particle loading. [2008CBE933] Landon et al studied the importance of adhesion between filler and the matrix phase in explaining the mechanical behavior of the composite. [1977JMS1605] The dependence of filler particle size on mechanical properties has also been studied with Chalk-filled PP models

[1993CM509]. Bhattarcharya et. al. examined the effect of particle size ratios of the polymer to metal particles on the mechanical properties of PVC-Cu composites.

[1978JMS2109] Significant improvements in the mechanical properties were achieved by incorporating a few weight percent of inorganic exfoliated clay minerals consisting of layered silicate into polymer matrices. [2004JAPS2144, 1999JAPS1133, 2004P7579]

Ozkar et. al. systematically studied the effect of the use of additional fillers apart from the main filler, in improving the thermal, rheological and tensile properties of polyurethane elastomers. [1998JAPS1057] However, no such studies on the use of mixed fillers on the mechanical properties of triazole polymers have been conducted to date.

Therefore, experiments were designed to study the effect of filler loading on the mechanical properties of crosslinked triazole polymers obtained by the selected model polymerization reaction of E300 dipropiolate (A-1), diazide (A-2) and tetraacetylene- functionalized crosslinker (A-3). Aluminum (10-14 micron) was used as the main filler

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during the formulations; the effect of using secondary fillers such as aluminum (<75 micron), NaCl (45-50 and 83-105 micron) was monitored with the increase in the total filler loading. The modulus of the aluminum-filled crosslinked triazole polymers increases with increase of the filler content while using either of the two particle sizes of aluminum powder. The use of Al (particle size < 75 micron) and NaCl (particle size 45-

50 micron and 83-105 micron) as secondary or additional fillers while using aluminum

(10-14 micron) as the main filler, has a diminishing effect on the modulus and strain of the crosslinked triazole polymers. Triazole polymers described here have the ability to wet and adhere large quantities of inorganic salts and thus the mechanical properties of the composite remain comparable to typical polyurethane elastomeric matrices, regardless of the chemistry of the oxidizer, which imparts them with important and necessary binder characteristics for energetic composites. My research carried out extensive studies on the use of two different particle sized aluminum fillers and mixtures of different particle sized aluminum and sodium chloride fillers, on the mechanical properties of crosslinked triazole polymers. These experiments are intended to evaluate the degree to which the triazole-cured binder candidates can tolerate increases in the loadings of various solids (especially that of sodium chloride, the model for inorganic oxidizing salts in general) and still maintain good stress and a reasonable strain capability.

In summary, my research efforts were a continuation of the work of developing a novel robust binder cure system, with improved mechanical property comparable to that of the urethane cure and with minimum possible incompatibility with new high-energy ingredients. The optimum parameters were investigated for the triazole polymer with

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desired mechanical properties by 1,3-dipolar cycloadditions between bis- or polyacetylenes and polyazides in terms of crosslinker concentration, filler types, sizes and concentrations.

A-2 Results and Discussion

A-2-1 Selection of Model Polymer System

Based on the criteria required by standard rocket propellants such as the appreciable modulus and elasticity, nature and availability of the starting monomers, time of reaction, temperature conditions and ease of scaling up, different diazides, diacetylenes and crosslinkers were screened and thirteen different polymers were synthesized and compared by our group members (Dr. Yuming Song, Ms. Reena

Gyanda and Dr. Rajeev Sakhuja). [2009JPS(A)PC3748] Accordingly, the reaction of

E300 dipropiolate (A-1), tetraethylene glycol-derived diazide (A-2), and tetrapropiolate crosslinker (A-3) was selected as a model binder system to study the relationship between the effects of crosslinker and filler on the mechanical properties of triazole polymers.

Scheme A-1. Triazole polymer model system

A-2-2 Preparation of Monomers

For each series of studies, I prepared three monomers E300 dipropiolate (A-1), tetraethylene glycol diazide (A-2) and tetrapropiolate crosslinker (A-3) in large quantities

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(>200g each) following literature methods (Scheme A-2). [2006ARKIVOC43,

2008JPS(A)PC238, 2009JPS(A)PC3748, 2010JAPS121]

Scheme A-2. Preparation of monomers

A-2-3 Preparation of Dogbone Samples

Each dogbone sample was prepared by thoroughly mixing the three reactants (A-

1, A-2 and A-3) manually in an aluminum pan (~ 1 h per sample), then transferring the uniform mixture to the dogbone molds before the curing process. The mechanical properties - strain (percentage elongation at break) and elastic modulus (Young’s modulus) for dogbone samples (Figure A-2) of filled and unfilled triazole polymers were measured at a strain rate of 50 mm/min by Instron universal tensile testing machine located at Department of Material Science, University of Florida. (Figure A-3)

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Figure A-2. Dogbone mold containing filled and unfilled triazole polymers

Figure A-3. Instron universal tensile testing machine

A-2-4 Filler Loading Effect

The earlier studies conducted by our group members (Dr. Yongming Song, Ms.

Reena Gyanda, Dr. Rajeev Sakhuja) [2010JAPS2612] found that with the use of

43wt% aluminum filler in a crosslinked triazole polymerization process, the polymer had good processability and a better modulus compared to unfilled triazole polymers. In continuation of the development a robust polymeric triazole system with improved mechanical properties, I studied the effect of increase in the filler type and content on the mechanical properties of the crosslinked triazole polymers obtained by mixing E300

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dipropiolate (A-1), tetrafunctionalized crosslinker (A-3) and diazide (A-2) obtained from

E300 ethylene glycol in stoichiometric ratios.

To select an optimum percentage of the crosslinker that could be used and set constant for the synthesis of the filled crosslinked triazole polymers throughout our present studies, some preliminary experiments based on earlier experience for the preparation of crosslinked triazole polymers was needed. We used 4 mol% of the crosslinker with freshly prepared monomers: the polymers were obtained by the reaction of E300 dipropiolate (A-1) and diazide (A-2) and 4 mol% crosslinker (A-3), keeping end group stoichiometry 1:1 and samples cured both with and without 43 wt% aluminum filler (10-14 micron particle size). Upon curing these samples were tacky and soft and testing via Instron Machine was difficult. However, these results were different from those obtained in our earlier studies. This could be explained by the fact that use of a different batch of starting monomer, more specifically E300 dipropiolate, as E300 polyol itself is not a single compound. Thus, further triazole polymerization reactions were carried using 6 and 8 mol% of the crosslinker with and without 43 wt% of the aluminum (10-14 micron). The mechanical properties of the cured, crosslinked triazole polymers are summarized in Table A-1. [2010JAPS121]

Table A-1. Strain and modulus of unfilled and filled crosslinked triazole polymers Crosslinker Filler wt% Modulus Entry Strain (%) concentration (mol %) (Al : 10-14 micron) (MPa) 1 6 0 683 0.044 2 6 43 441 0.267 3 8 0 338 0.174 4 8 43 171 0.898

127

The physical nature of the polymers and the modulus and strain values suggested that the use of 8 mol% crosslinker would be better in a study of the effect of different filler loadings on the mechanical properties of the resulting triazole polymers.

The content of the aluminum filler with particle size 10-14 micron and <75 micron was systematically increased (Scheme A-1) from 34.18 to 74.14 weight percent (Table

A-2 and Table A-3) resulting in two separate sets of gumstock samples, which were cured in standard dogbone molds at 55 oC for 72 h. The cured polymers were tested using Instron tensile testing machine.

Figures A-4 and Figure A-5 show the variation of the modulus and strain values of these two sets of filled gumstock samples with the increase in filler loading.

Table A-2. Effect of filler loading (Al: 10-14 micron) on strain and modulus of crosslinked triazole polymers Crosslinker Filler Wt % Modulus Entry Strain (%) concentration (mol %) (Al : 10-14 micron) (MPa) 1 8 34.2 205.4 0.64 2 8 43.0 171.0 0.90 3 8 58.1 97.5 2.33 4 8 67.5 48.3 5.06 5 8 71.7 29.6 11.31 6 8 74.2 18.7 13.68

Table A-3. Effect of filler loading (Al: < 75 micron) on strain and modulus of crosslinked triazole polymers Crosslinker Filler Wt % Modulus Entry Strain (%) concentration (mol %) (Al : < 75 micron) (MPa) 1 8 34.2 108.1 0.88 2 8 43.0 93.7 1.68 3 8 58.1 41.0 4.70 4 8 67.5 33.1 9.72 5 8 71.7 10.7 25.39 6 8 74.2 9.2 32.07

128

In general, it may be concluded that the modulus of the aluminum-filled crosslinked triazole polymers increases with increase of the filler content using either of the two particle sized aluminum powders. The value of the modulus increased from 0.64

MPa to 13.68 MPa as the aluminum with particle size 10-14 micron is loaded from 34.2 to 74.2 wt. percent of the binder. The 74.2 value is the maximum percentage of the filler resulting in polymers which are processable. Beyond this point the binder does not completely wet all the filler particles resulting in a highly viscous, non uniform material difficult to cast into molds before curing. The same result was inferred from the mechanical data generated by using <75 micron aluminum powder. The addition of rigid particles to a polymeric matrix improves the modulus since the rigidity of the inorganic fillers is generally higher than that of organic polymers. [2008CBE933] Anuar and coworkers observed similar trends with the use of aluminum on natural rubber (NR) and ethylene-propylene-diene-terpolymer (EPDM) composites. [2007PPTE1201]

However, there is an increase in the value of the modulus while shifting from 10-14 micron to <75 micron particle size for the same filler content (for example 0.64 to 0.88

MPa; 0.90 to 1.68 MPa). For lower weight percentages of filler, the modulus is almost independent of particle size, but the difference in modulus values increases with increase of the filler loading. [2008CBE933]

129

Al (10-14 microns) Al (< 75 microns)

15 Modulus (Mpa)

0 0 10 20 30 40 50 60 70 80 Filler content (Wt%)

Figure A-4. Effect of filler loading on modulus of crosslinked triazole polymers

Similar observations were inferred from the strain data obtained by the mechanical testing of two sets of filled crosslinked triazole polymers. (Table A-1 & A-2, Figure A-5).

The strain of the filled crosslinked triazole polymers decreases with the increase in the filler content as expected. However, the strain values are reduced by almost half by switching from 10-14 micron to < 75 micron aluminum powder (for example 205.5 to

108.8; 18.7 to 9.2 for 34.2 and 74.2 wt% of the filler used respectively). Given that the modulus values of both filled systems are similar, it is likely that the strain differences are mainly due to the larger filler particles providing more nucleation sites for failure.

Perhaps the effect of the smaller particles is to better resist dewetting by the binder until a concentration of solids is reached of which the binder is unable to fully cover either particle size.

130

Al (10-14 microns) Al (< 75 microns)

250

200

150

Strain (%) 100

0 0 10 20 30 40 50 60 70 80 Filler content (Wt%)

Figure A-5. Effect of filler loading on strain of crosslinked triazole polymers

The studies were extended by using two different particle sizes of NaCl powder as fillers. Tables A-4 and A-5 show the variation of the modulus and strain of the filled crosslinked triazole polymers with NaCl as the main filler with the increase in the content and particle size of NaCl (Scheme A-3). The samples prepared were somewhat sticky and non-uniform, and the mechanical testing was therefore difficult. However, the trend for the modulus and the strain with increase in the filler content was similar to that obtained with aluminum, but the values of the modulus were quite low. Thus it made sense to study the effect of NaCl as secondary/additional filler while retaining aluminum as the main filler.

131

Table A-4. Effect of filler loading (NaCl: 45-50 micron) on strain and modulus of mechanical properties of crosslinked triazole polymers Crosslinker Filler Wt% (NaCl: Modulus Entry Strain (%) concentration (mol %) 45-50 micron) (MPa) 1 8 34.2 237.6 0.38 2 8 43.0 208.9 0.44 3 8 58.0 60.4 1.49 4 8 67.5 41.3 1.65

Table A-5. Effect of filler loading (NaCl: 83-105 micron) on strain and modulus of crosslinked triazole polymers Crosslinker Filler Wt% (NaCl: Modulus Entry Strain (%) concentration (mol %) 83-105 micron) (MPa) 1 8 34.2 180.3 0.27 2 8 43.0 128.8 0.33 3 8 58.0 95.8 1.09 4 8 67.5 56.0 1.48

It appears that the addition of NaCl increases strain capability but this comes at the expense of lower modulus values, which in turn may be due to poorer adhesion between the binder and filler.

Further, the effect on the use of the additional or secondary fillers such as NaCl with particle size 45-50 micron and 83-105 micron and aluminum with particle size < 75 micron along with aluminum with particle size 10-14 micron as the main filler was studied with the increase in the total filler content. The mixture of fillers was systematically increased separately (Scheme A-4) from 34.2 to 74.2 weight percent

(Table A-2 & A-3) resulting in three separate sets of gumstock samples (Table A-4, A-5,

A-6, A-7 & A-8), which were cured and mechanically tested in the usual manner.

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Table A-6. Effect of mixed filler loading (mixture of two different particle sized Aluminum) on strain and modulus of crosslinked triazole polymers Filler Wt % Crosslinker (Al : < 75 micron + Modulus Entry Strain (%) concentration (mol %) Al: 10-14 (MPa) micron)(1:1) 1 8 34.2 100.8 0.78 2 8 43.0 91.2 1.47 3 8 58.0 63.6 3.51 4 8 67.5 36.2 4.70 5 8 71.7 21.3 7.21 6 8 74.2 19.4 9.37

Table A-7. Effect of mixed filler loading (mixture of Aluminum and NaCl) on strain and modulus of crosslinked triazole polymers Filler Wt % (Al : 10- Crosslinker Modulus Entry 14 micron + NaCl: Strain (%) concentration (mol %) (MPa) 45-50 micron)(1:1) 1 8 34.2 79.8 0.73 2 8 43.0 57.7 0.91 3 8 58.0 40.9 1.90 4 8 67.5 34.8 3.52 5 8 71.7 26.7 4.68

Table A-8. Effect of mixed filler loading (mixture of Aluminum and NaCl) on strain and modulus of crosslinked triazole polymers Filler Wt % (Al : 10- Crosslinker Modulus Entry 14 micron + NaCl: Strain (%) concentration (mol %) (MPa) 83-105 micron)(1:1) 1 8 34.2 68.6 0.71 2 8 43.0 55.4 0.95 3 8 58.0 44.9 1.32 4 8 67.5 35.7 3.59 5 8 71.7 24.8 4.45

Figures A-6 and A-7 compare the results on the use of additional fillers with the main filler in the ratio 1:1 on the mechanical properties of crosslinked triazole polymers.

These data include equal weights of mixed fillers of two different particle sized aluminum powders and aluminum with two different particle sized NaCl powder. In

133

general, the use of Al (particle size < 75 micron) and NaCl (particle size 45-50 micron and 83-105 micron) as secondary or additional fillers while using aluminum (10-14 micron) as the main filler, has a diminishing effect on the modulus and strain of the crosslinked triazole polymers. Perhaps the effect of the larger aluminum particles in reducing strain capability is overriding the effect of the smaller aluminum.

(Al : 10-14 microns + Al: <75 microns)(1:1) (Al : 10-14 microns + NaCl: 45-50 microns)(1:1) (Al : 10-14 microns + NaCl: 83-105 microns)(1:1)

6 5

4 Modulus (Mpa) 3

0 0 10 20 30 40 50 60 70 80 Filler content (Wt%)

Figure A-6. Effect of mixed filler loading on modulus of crosslinked triazole polymers

134

(Al : 10-14 microns + Al: <75 microns)(1:1) (Al : 10-14 microns + NaCl: 45-50 microns)(1:1) (Al : 10-14 microns + NaCl: 83-105 microns)(1:1)

120

100

60 Strain (%) 40

0 0 10 20 30 40 50 60 70 80 Filler content (Wt%)

Figure A-7. Effect of mixed filler loading on strain of crosslinked triazole polymers

Also, 74.14 weight % was not achievable while using mixed fillers of aluminum and

NaCl due to non uniformity and brittleness of the resultant triazole polymers. On comparing the strain and the modulus values of the triazole polymers obtained by using mixtures of aluminum and two different particle sized NaCl fillers, very little difference in the values was observed. These data suggest that the mixed systems show lower stain values.

A-3 Conclusions

The reaction of E300 dipropiolate with tetraethylene glycol diazide was selected to study the effects of crosslinker concentration and filler (type and size) on the mechanical properties of resulting triazole polymers. We found that the modulus of the polymers increases while the strain decreases with increasing crosslinker concentration and filler loading. By selecting an appropriate crosslinker and tuning the concentration

135

of the crosslinker and filler, the triazole polymers with desired mechanical properties could be obtained. The mechanical properties of these triazole polymers are superior to the typical polyurethane elastomeric matrices for rocket propellant binders, and some highly filled crosslinked triazole polymers possess properties of potential rocket propellant binders. Overall, the study suggests, as expected, that the aluminum fillers give rise to better mechanical properties than inorganic materials (sodium chloride).

The data suggest that the smaller metal particles act to produce enhanced mechanical properties whereas the mixed metal/inorganic filler simply produce samples of intermediate mechanical properties over the compositions tested. Triazole polymers described have the ability to wet and adhere large quantities of inorganic salts and thus maintain the tensile strength of the composite, regardless of the chemistry of the oxidizer, thus imparting important binder characteristic for energetic composites.

A-4 Experimental Section

General methods. NMR spectra were recorded in CDCl3 or DMSO-d6 with TMS for 1H (300 MHz) and 13C (75 MHz) as internal reference. Elemental analyses were performed on a Carlo Erba-1106 instrument. Commercially obtained reagents were used without further purification. E300 dipropiolate (A-1), diazide (A-2) derived from ethylene glycol and the tetrafunctional crosslinker 3-(propioloyloxy)-2,2- bis[(propioloylxy)methyl]propylpropiolate (A-3) were prepared following reported procedures. [2008JPS(A)PC238] In view of the stringent stoichiometry requirements for step polymerization, the monomers were systematically dried by azeotropic distillation and lyophilization. The uni-axial test specimen was a standard micro-tensile dogbone with dimensions of 0.88’’× 0.19’’× 0.13’’ inches (Figure A-8). [1992JPCE] The dogbone mold containing filled and unfilled triazole polymers is shown in Figure A-2. Strain 136

(percentage elongation at break) and elastic modulus (Young’s modulus) were measured by an Instron universal tensile testing machine (model number 4301) with a strain rate of 50 mm/min. Aluminum (10-14 micron and < 75 micron) was purchased from Aldrich. Anhydrous sodium chloride was ground and passed through a series of sieves of different pore sizes to obtain NaCl in 45-50 micron and 83-105 micron mono- disperse particle sizes. Each data entry in the Tables (Table A-1 – Table A-8) is an average of at least three measurements.

Figure A-8. Dimensions of dogbone mold and dogbone sample

Preparation of tetraethyleneglycoldipropiolate (A-1). A solution of E300 polyethylene glycol (10 g, 51.5 mmol), propiolic acid (7.9 g, 113.0 mmol) and p- toluenesulfonic acid (0.5 g, 2.63 mmol) in toluene (100 mL) was heated under reflux using a Dean Stark apparatus for 48 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in CHCl3 (150 mL) washed with saturated NaHCO3 (70 mL), water (50 mL) and brine (50 mL). The chloroform layer was dried over anhydrous MgSO4, filtered and the solvent was evaporated to give tetraethyleneglycoldipropiolate (13.94 g, 91%) as yellow oil.

137

Tetraethyleneglycoldipropiolate (A-1). Yellow oil; yield: 13.94 g (91%); 1H NMR

(CDCl3) : 2.93 (s, 2H), 3.67 (s, 8H), 3.75 (t, J = 4.8 Hz, 4H), 4.35 (t, J = 4.8 Hz, 4H);

13 C NMR (CDCl3) : 65.2, 68.5, 70.6, 70.6, 74.5, 75.2, 152.6; Anal. Calcd for C14H18O7:

C, 56.37; H, 6.08; Found: C, 56.07; H, 6.22.

Preparation of 1-azido-2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethane (A-2). A mixture of tetraethylene glycol dimesylate (14.4 g, 41.43 mmol) and NaN3 (10.77 g,

o 165.72 mmol) in 100 mL CH3CN /H2O (9:1) was refluxed at 80 C for 24 h. The mixture was filtered, the filtrate diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and solvent was removed under vacuum to obtain pure 1-azido-2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethane (7.88 g,

78%) as a light yellow oil.

1-Azido-2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethane(A-2). Colorless oil; yield:

1 13 7.88 g (78%); H NMR (CDCl3) : 3.70-3.67 (m, 12H), 3.40 (t, J = 4.8Hz, 4H); C NMR

(CDCl3) : 70.5, 69.8, 50.5.

Preparation of 3-(propioloyloxy)-2,2-bis[(propioloyloxy)methyl]propyl propiolate (tetrapropiolate) (A-3). A solution of pentaerythritol (5 g, 36.72 mmol), propiolic acid (14.91 g, 213 mmol) and conc. H2SO4 (0.5 ml) in benzene (75 ml) was heated under reflux using a Dean Stark apparatus for 12.5 h. The reaction mixture was cooled in ice and neutralized with solid Na2CO3, filtered, washed with ether and the filtrate was evaporated to obtain a solid. The solid was dissolved in CH2Cl2 (100 ml) washed with saturated NaHCO3 (50 ml), water (50 ml) and brine (25 ml). The dichloromethane layer was dried over anhydrous MgSO4, filtered and the solvent was evaporated to give pentaerythritol tetrapropiolate as a white powder.

138

3-(Propioloyloxy)-2,2-bis[(propioloyloxy)methyl]propyl propiolate (A-3).

1 White microcrystals; yield 6.5 g (51 %); H NMR (CDCl3) : 2.98 (s, 4H), 4.31 (s, 8H);

13 C NMR (CDCl3) : 41.7, 63.3, 73.6, 76.4, 151.8; Anal. Calcd for C17H12O8: C, 59.31; H,

3.51; Found: C, 59.05; H, 3.57.

Procedure for the preparation of dogbone samples for mechanical studies.

In an aluminum pan, E300 diacetylene (A-1) was weighed and different concentrations of crosslinker (A-3) were added and stirred until the crosslinker dissolved. The time required to dissolve crosslinker varied from 5-20 min with the increase in the concentration of the crosslinker. This was followed by the addition of diazide (A-2), which on stirring gave a homogeneous mixture (Scheme A-3). The reactions were carried out a scale of 2 g (including the three reactants for each dogbone sample) in aluminium pans by taking 100mol% of diazide (A-2) and calculating the concentrations of diacetylene (A-1) and the crosslinker (A-3) as shown in Scheme A-3, keeping the overall end group stoichiometric ratios 1:1. The mixture was cast into dogbone molds

(Figure A-14), and the dogbone molds were degassed under vacuum at room temperature for 15 minutes and left at room temperature for 3-4 h. The curing was then carried out in a vacuum oven at 55 oC for 72 h. The dogbone samples were carefully removed from the mold. After the cooling, they were tested using a Universal Tensile

Test Machine with a 200 lb load cell and 50 mm/min test speed. For the filled systems, aluminum powder was added to the homogeneous mixture of diacetylene (A-1), diazide

(A-2) and crosslinker (A-3), then mixed uniformly and degassed followed by curing in a vacuum oven at 55 oC for 1h. The mixture was then stirred again and cured at 55 oC for an additional 71 h.

139

Procedure for the preparation of linear triazole polymer P-1. The monomers diacetylene (A-1) and diazides (A-2) were mixed manually in 1:1 equivalent in an aluminum pan until a homogenous mixture was obtained. The pan was cured in a vacuum oven for 72 h.

1 Unfilled Triazole Polymer (P-1). Light yellow rubbery polymer; H NMR (CDCl3)

: 3.56-3.67 (m, (-O-CH2-CH2-O-)), 3.81-3.95 (m, (-COO-CH2-CH2-O) & (-triazole-CH2-

CH2-O-)), 4.48-4.51 (m, (-CH2-triazole-)), 4.60-4.63 (m, -(triazole-COO-CH2-)), 8.34 (s,

13 (-triazole-H)); C NMR (CDCl3) : 50.4, 64.1, 68.9, 70.3, 70.4, 70.5, 77.2, 130.0, 139.7,

160.8. Anal. Calcd for C26H42N6O12: C, 49.52; H, 6.71; N, 13.33 Found: C, 49.38; H,

6.72; N, 13.00.

General procedure for preparation of crosslinked triazole polymers. E300

Dipropiolate (A-1) and crosslinker (A-3) were weighed into an aluminum pan, and stirred until homogeneous. The time for dissolving the crosslinker varied from 15 to 30 minutes. Diazide (A-2) was added with stirring to give a homogeneous mixture. The reactions were carried on a total scale of 2 g (comprising the three reactants for each dogbone sample) in aluminum pans by taking 100mol% of (A-2) and calculating the concentrations of (A-1) and the crosslinker (A-3) as shown in Scheme A-3, keeping the overall end group stoichiometric ratios 1:1. (Scheme A-3) The filler (or mixture of fillers) was then added to the homogeneous mixture and mixed uniformly by hand for about 45 minutes. The mixtures were cast into a dogbone molds, degassed under vacuum at room temperature for 15 minutes and then cured in an oven at 55 oC for 72 h. The dogbone samples were carefully removed from the mold. After the cooling, they were

140

tested at ambient temperature using a Universal Tensile Test Machine with a 22 lb load cell and 50 mm/min test speed.

Scheme A-3. General route to crosslinked 1,2,3-triazole polymers with fillers

141

LIST OF REFERENCES

[1884Ber182] A. Pinner, Ber., 17, 182 (1884).

[1894Ber160] E. Bamberger, Ber., 27, 160 (1894).

[1898Ber2126] H. Ley, Ber., 31, 2126 (1898).

[1905Ber1445] H. Wieland, Ber., 38, 1445 (1905).

[1906Ber65] H. Wieland, Ber., 39, 1480 (1906).

[1907LAC65] H. Wieland, Liebigs Ann. Chem., 353, 65 (1907).

[1909Ber4175] H. Wieland and H. Hess, Ber., 42, 4175 (1909).

[1910Ber4199] H. Wieland, Ber., 42, 4199 (1910).

[1914Ber2941] H. Ley and M. Ulrich, Ber., 47, 2941 (1914).

[1914Ber2938] H. Ley and M. Ulrich, Ber., 47, 2938 (1914).

[1925LAC260] E. Bamberger, R. Padova, and E. Ormerod, Liebigs Ann.

Chem., 446, 260 (1925).

[1931MC106] W. Oberhummer, Monatsh. Chem., 57, 106 (1931).

[1948JCS2240] A. Albert, R. Goldacre and J. L. Philips, J. Chem. Soc., 2240

(1948).

[1950LAC185] D. Jerchel and R. Kuhn, Liebigs Ann. Chem., 568, 185

(1950).

[1951CB651] I. Hauser, D. Jerchel and R. Kuhn, Chem. Ber., 84,

651(1951).

[1952CB470] W. Reid and F. Muller, Chem. Ber., 85, 470 (1952).

[1954JCS3319] M. R. Atkinson and J. B. Polya, J. Chem. Soc., 3319 (1954).

[1955CRV355] A. W. Nineham, Chem. Rev., 55, 355 (1955).

142

[1955HCA1473] A. Marxer, Helv. Chim. Acta., 38, 1473 (1955).

[1955HCA1560] P. Schmidt and J. Druey, Helv. Chim. Acta., 188, 1560

(1955).

[1955JPSJ726] N. Kunimine and K. Itano, J. Pharm. Soc. Jap., 74, 726

(1954); Chem. Abstr., 49, 11, 627 (1955).

[1956JCS2853] F. P. Doyle, W. Ferrier, D., Holland, M. D. Mehta, and J. H. C.

Nayler, J. Chem. Soc., 2853 (1956).

[1957ibid191] D. Jerchel and W. Wotichy, ibid., 605, 191 (1957).

[1959ICBS532] H. Ziegler, Ind. Chim. Belge. Suppl., 2, 532 (1959).

[1962CR155] F. Eloy and R. Lenaers, Chem. Rev., 62, 155 (1962).

[1963ACIEE309] C. Grundmann, Angew. Chem. Intern. Ed. Engl., 2, 309

(1963).

[1963ibid3121] M. Regitz and B. Eistert, ibid., 96, 3121 (1963).

[1963JCED624] C. Huether, J.M. Cretsos, J.M. Shackelford, J. Chem. Engin.

Data, 8, 624 (1963).

[1964ACIEE232] R. Kuhn, F. A. Neugebauer, and H. Trischmann, Angew.

Chem. Intern. Ed. Ennl., 3, 232 (1964).

[1965CR2512] J. Armand and R. M. Minvielle, Compt. Rend., 260, 2512

(1965).

[1965JOC931] F. H. Case, J. Org. Chem., 931 (1965).

[1966JOC157] C. Grundmann and H. –D. Frommeld, J. Org. Chem., 31, 157

(1966).

[1966MC517] R. Kuhn and G. Fischer-Schwarz, Monatsh. Chem., 97, 517

143

(1966).

[1966US3234255A] T. H. Johannes, A. H. Paulus and P. R. Herbert, U. S. Pat.,

3,234,255 A (1966).

[1967JCS(C)742] F. Kurzer and K. Douraghi-Zadeh, J. Chem. Soc., C, 742

(1967).

[1968ACIEE489] O. Westphal, Angew. Chem. Intern. Ed. Engl., 7, 489 (1968).

[1968CB29] T. Pyl, L. Seidl, and H. Beyer, Chem. Ber., 101, 29 (1968).

[1969BSCF3409] J, Barassin, J. Armand and H. Lumbroso, Bull. Soc. Chem.

Fr., 10, 3409 (1969).

[1970CR151] D. G. Neilson, R. Roger, J. W. M. Heatlie and L. R.

Newlands, Chem. Rev., 70, 151 (1970).

[1970JCS(C)2510] R. N. Butler, F. L. Scott and R. D. Scott, J. Chem. Soc. C,

2510 (1970).

[1971JCPPCB601] F. Valentini, P. Gouzerh and P. Souchay, J. Chim. Physique

Physico-Chim. Biologique, 68, 601 (1971).

[1972JCPPCB689] F. Valentini, P. Gouzerh and P. Souchay, J. Chim. Physique

Physico-Chim. Biologique, 69, 689 (1972).

[1972LAC16] H. Neunhoeffer and F. Weischedel, Leibigs Ann. Chem., 749,

16 (1972).

[1973JOC514] H. O. House, R. A. Auerbach, M. Gall and N. P. Peet, J. Org.

Chem., 514 (1973).

[1974CCR1] A. Chakravorty, Coord. Chem. Rev., 13, 1 (1974).

[1975CB3509] H. Neunhoeffer and H. –J. Degen, Chem. Ber., 108, 3509

144

(1975).

[1975CB2764] H. G. Aurich and K. Stork, Chem. Ber., 108, 2764 (1975).

[1975LAC1120] H. Neunhoeffer, H. –J. Degen and J. J. Kohler, Leibigs Ann.

Chem., 1120 (1975).

[1975JCS(PT1)1787] Esmail, R.; Kurzer, F. J. Chem. Soc., Perkin Trans. 1, 1787

(1975).

[1975JCS(PT1)1181] J. R. L. Smith and J. S. Sadd, J. Chem. Soc., Perkin Trans. 1,

1181 (1975).

[1976LAC2206] W. Draber, H. Timmler, K. Dickore and W. Donner, Liebigs

Ann. Chem., 2206 (1976).

[1976T1031] K.M. Doyle and F. Kurzer, Tetrahedron, 32, 1031 (1976).

[1977BBRC387] J. R. White, Biochem. Biophys. Res. Comm., 77, 387 (1977).

[1977BCSJ953] M. Takahashi, H. Tan, K. Fukushima and H. Yamazaki, Bull.

Chem. Soc. Jpn., 50, 953 (1977).

[1977JHC587] A. Mangia, F. Bortesi and U. Amendola, J. Heterocycl.

Chem., 14, 587 (1977).

[1977JMS1605] G. Landon, G. Lewis and G. F. Boden, J. Mater. Sci., 12,

1605 (1977).

[1978JMS2109] S. K. Bhattacharyya, S. Basu and S. K. De, J. Mater. Sci., 13,

2109 (1978).

[1978RRC203] S. Desherces, J. Barrans and J. L. Roubaty, Revue

Roumaine Chim., 23, 203 (1978).

[1979CB1981] H. -J. Degen, S. Haller, K. Heeg and H. Neunhoeffer, Chem.

145

Ber., 112, 1981 (1979).

[1979JHC881] L. Werbel, J. MaNamara, N. Colbry and J. Johnson, J.

Heterocycl. Chem., 16, 881 (1979).

[1979JMC1024] K. C. Murdock, R. G. Child, P. F. Fabio, R. D. Angier, R. E.

Wallace, F. E. Durr and R. V. Citarella, J. Med. Chem., 22,

1024 (1979).

[1980CRS304] J. Armand and P. Bassinet, J. Chem. Res. Synop., 304

(1980).

[1980JOC3916] K.-C. Liu, B. R. Shelton and R. K. Howe, J. Org. Chem., 45,

3916 (1980).

[1981PJC1253] E. Zygmunt, R. Dorota, R. Bany and P. Jelenski, Polish J.

Chem., 55, 1253 (1981).

[1981USP4299965] M. S. Chan and W. E. Hunter, U. S. Pat., 4,299,965 (1981).

[1982MC793] B. Kuebel, Monatsh. Chem., 113, 793 (1982).

[1983GPO3126464] E. Schinzel, T. Martini, W. Spatzier and H.Probst, Ger. Pat.

Offen. 3,126,464 (1983); Chem. Abstr., 98, 199850 (1983).

[1983P683] T. W. Moody, V. Bertness and D. N. Carney, Peptides, 4, 683

(1983).

[1984FES414] G. Mazzone, F. Bonina, G. Puglisi, A. M. Panico and R. R.

Arrigo, Farmaco Ed. Sci., 39, 414 (1984).

[1984JMC121] J. H. Musser, J. Med. Chem., 21, 1807 (1984).

[1984S146] F. Pochat, Synthesis, 146 (1984).

[1984GPO3245202] U. Eckstein, Ger. Pat. Offen., 3,245,202 (1984); Chem.

146

Abstr., 101, 173038 (1984).

[1985CB3481] B. Clement and T. Kampchen, Chem. Ber., 118, 3481 (1985).

[1985LAC78] H. Neunhoeffer, G. Köhler and H. –J. Degen, Liebigs Ann.

Chem., 78 (1985).

[1985T5187] L. Somogyi, Tetrahedron, 41, 5187 (1985).

[1985USP4500653] M. Schmidt, M. W. Witman, G. E. Reinert and I. C. Lim, U. S.

Pat., 4,500,653 (1985); Chem. Abstr., 102, 166761 (1985).

[1986JSCT9] A. A. Bel Hadj and B. Baccar, J. Soc. Chim. Tunisie, 2, 9

(1986).

[1986SC1665] B. Rigo, P. Cauliez, D. Fasseur and D. Couturier, Syn.

Commun., 16, 1665 (1986).

[1987CL223] M. N., Pollak, J. F. Perdue, R. G. Margolese, K. Baer and M.

Richard, Cancer Lett., 38, 223 (1987).

[1987JCS(PT1)2673] A. R. Katritzky, K. Yannakopoulou, W. Kuzmierkiewicz, J. M.

Aurrecoechea, G. J. Palenik, A. E. Koziol, M. Szczesniak and

R. Skarjune, J. Chem. Soc., Perkin Trans. 1, 2673 (1987).

[1988IJC(B)542] V. A. Adhikari and V. V. Badiger, Indian J. Chem., Sect. B,

27, 542 (1988).

[1988JOC38] K. H. Pilgram, R. D. Skiles and D. A. Kleier, J. Org. Chem.,

53, 38 (1988).

[1988JOC5854] A. R. Katritzky, M. Drewniak and P. Lue, J. Org. Chem., 54,

5854 (1989).

[1988USP43262] M. F. Sitzmann, U. S. Pat., 43,262 (1988).

147

[1989CHC717] K. N. Zelenin, O. V. Solod and V. A. Khrustalev, Chem.

Heterocycl. Comp., 25, 717 (1989).

[1989EPA315046A2] K. Pandl and M. Patsch, Eur. Pat. Appl., EP 315,046 A2, 7

(1989).

[1989H1121] A. R. Katritzky and K. Yannakopoulou, Heterocycl., 28, 1121

(1989).

[1989JOC6022] A. R. Katritzky, S. Rachwal and B. Rachwal, J. Org. Chem.,

54, 6022 (1989).

[1989JPS999] K. Raman, S. S. Parmar and S. K. Salzman, J. Pharm. Sci.,

78, 999 (1989).

[1989LAC105] H. Neunhoeffer, W. Diehl and U. Karafiat, Liebigs Ann.

Chem., 105 (1985).

[1989PNASU6318] S. Bajusz, T. Janaky, V. J. Csernus, L. Bokser, M. Fekete, G.

Srkalovic, T. W. Redding and A. V. Schally, Proc. Natl. Acad.

Sci. USA, 86, 6318 (1989).

[1989ZNK675] I.Y. Andreeva, E.K. Bocharova, E.A. Danilova, Zh. Anal.

Khim, 44, 675 (1989).

[1990B2538] C. A. Frederick, L. D. Williams, G. Ughetto, G. A. van der

Marel, B. J. H. Van, A. Rich and A. H. Wang, Biochemistry,

29, 2538 (1990).

[1990HC21] A. R. Katritzky and J. N. Lam, Heteroat. Chem., 1, 21 (1990).

[1990JHC1685] A. B. Theocharis and N. E. Alexandrou, J. Heterocycl. Chem.,

27, 1685 (1990).

148

[1990JOC5683] A. R. Katritzky, K. Yannakopoulou, E. Anders, J. Stevens and

M. Szafran, J. Org. Chem., 55, 5683 (1990).

[1990JPS(A)3647] Y. Saegusa, K. Sekiba and S. Nakamura, J. Polym. Sci.,

Polym. Chem., Part A, 28, 3647 (1990).

[1990P1205] M. Lee, R. T. Jensen, G. Bepler, L. Y. Korman and T. W.

Moody, Peptides, 11, 1205 (1990).

[1990JSBMB1083] A. Manni, A. E. Boucher, L. M. Demers, H. A. Harvey, A.

Lipton, M. A. Simmonds and M. Bartholomew, J. Steroid

Biochem. Mol. Biol., 37, 1083 (1990).

[1990JCS(PT2)2059] A. R. Katritzky, S. Perumal and W.-Q. Fan, J. Chem. Soc.

Perkin Trans. 2, 2059 (1990).

[1991CB1819] A. R. Katritzky, X. Lan and J. N. Lam, Chem. Ber., 123, 1819

(1991).

[1991CL285] Y. Saitoh, M. Matsuoka, Y. Nakao and T. Kitao, Chem. Lett.,

285 (1991).

[1991HCA1936] A. R. Katritzky, W. Kuzmierkiewicz and S. Perumal, Helv.

Chim. Acta, 74, 1936 (1991).

[1991IJI393] M. L. Bourguet-Kondraki, A. Longeon, E. Morel and M.

Guyot, Int. J. Immunopharmacol., 13, 393 (1991).

[1991JOC5808] H. Grennberg, A. Gogoll and J.-E, Backvall, J. Org. Chem.,

56, 5808 (1991).

[1991PHA290] N. Ergenc, S. Buyuktimkin, G. Capan, G. Baktir and S.

Rollas, Pharmazi, 46, 290 (1991).

149

[1991RCT181] R. D., Vargo and F. N. Kelley, Rubber Chem. Technol., 64,

181 (1991).

[1991S69] A. R. Katritzky, S. Rachwal and B. Rachwal, Synthesis, 69

(1991).

[1991T2683] A. R. Katritzky, S. Rachwal and G. J. Hitchings, Tetrahedron,

47, 2683 (1991).

[1992AJC513] J. L. Flippen-Anderson, R. D. Gilardi, A. M. Pitt and W. S.

Wilson, Australian J. Chem., 45, 513 (1992).

[1992EPA481838] M. Andre, J. P. Mazer and B. Nouguez, Eur. Pat. Appl.,

481,838 (1992).

[1992JPCE] D. Riser, J. Hunter and R. Rast, AIAA/SAE/ASME/ASEE 28th

Joint Propulsion Conference and Exhibit, Nashville, TN, July

6 (1992).

[1992JCS(PT1)1111] A. R. Katritzky, M. F. Gordeev, J. V. Greenhill and P. J. Steel,

J. Chem. Soc. Perkin Trans. 1, 1111 (1992).

[1992JOC4932] A. R. Katritzky, S. Rachwal, B. Rachwal and P. J. Steel, J.

Org. Chem., 57, 4932 (1992).

[1992JPS(A)1369] Y. Saegusa, T. Koshikawa and S. Nakamura, J. Polym. Sci.,

Polym. Chem., Part A, 30, 1369 (1992).

[1992LAC843] A. R. Katritzky, J. Li and N. Malhotra, Liebigs Ann. Chem.,

843 (1992).

[1992LAC115] H. Neunhoeffer, U. Karafiat, G. Köhler and B. Sowa, Liebigs

Ann. Chem., 115 (1992).

150

[1992MC257] A. A. Ikizler and K. Sancak, Monatsh. Chem., 123, 257

(1992).

[1992MM2021] J. L. Hendrick and R. Twieg, Marcromolecules, 25, 2021

(1992).

[1992PNAS972] T. Janaky, A. Juhasz, S. Bajusz, V. Csernus, G. Srkalovic, L.

Bokser, S. Milovanovic, T. W. Redding, Z. Rekasi, A. Nagy

and A. V. Schally, Proc. Natl. Acad. Sci., 89, 972 (1992).

[1992T7817] A. R. Katritzky, N. Shobana, J. Pernak, A. S. Afridi and W.-Q.

Fan, Tetrahedron, 48, 7817 (1992).

[1993CM509] J. M. Adams, Clay Mineral, 28, 509 (1993).

[1994CSR363] A. R. Katritzky and X. Lan, Chem. Soc. Rev., 363 (1994).

[1994JHC917] A. R. Katritzky, B. Galuszka, S. Rachwal and M. Black, J.

Heterocycl. Chem., 31, 917 (1994).

[1994LAC1] A. R. Katritzky, J. Wu, W. Kuzmierkiewicz and S. Rachwal,

Liebigs Ann. Chem., 1 (1994).

[1995CHC208] R. A. Karakhanov, V. I. Kelarev, V. N. Koshelev, G. V.

Morozova, A. Dibi, Chem. Heterocycl. Compounds, 31, 208

(1995).

[1995JANYAS402] D. LeRoith, H. Werner, S. Neuenschwander, T. Kalebic and

L. Helman, J. Ann. New York Acad. Sci., 766, 402 (1995).

[1995JOC7612] A. R. Katritzky and H. Lang, J. Org. Chem., 60, 7612 (1995).

[1995JOC7619] A. R. Katritzky, H. Lang, Z. Wang, Z. Zhang and H. Song, J.

Org. Chem., 60, 7619 (1995).

151

[1995JOC7625] A. R. Katritzky, G. Zhang and J. Jiang, J. Org. Chem., 60,

7625 (1995).

[1995S1315] A. R. Katritzky, H. Wu, L. Xie, S. Rachwal, B. Rachwal, J.

Jiang, G. Zhang and H. Lang, Synthesis, 1315 (1995).

[1995TCC13] H. S. Freeman, J. Sokolowska-Gajda and A. Reife, Text.

Chem. Color, 27, 13 (1995).

[1996JAPS2347] S. B. Haska, E. Bayramli, F. Pekel and S. Ozkar, J. Appl.

Polym. Sci., 64, 2347 (1996).

[1996JOC1624] A. R. Katritzky and J. Li, J. Org. Chem., 61, 1624 (1996).

[1996LAC745] A. R. Katritzky, A. Jesorka, J. Wang, B. Yang, J. Wu and P.

J. Steel, Liebigs Ann. Chem., 745 (1996).

[1996LPS263] S. Rahimipour, L. Weiner, M. Fridkin, P. B. Shrestha-Dawadi,

S. Bittner, Lett. Pept. Sci., 3, 263 (1996).

[1996S1468] P. B. Shreshta-Dawadi, S. Bittner, M. Fridkin and S.

Rahimipour, Synthesis, 12, 1468 (1996).

[1997JOC706] A. R. Katritzky, O. Feng and H. Lang, J. Org. Chem., 62, 706

(1997).

[1997JOC4148] A. R. Katritzky, C. N. Fali and J. Li, J. Org. Chem., 62, 4148

(1997).

[1997JP36] J. Louwers, J. Pyrotechnics, 6, 36 (1997).

[1997TL6771] S. Fustero, B. Pina and A. Simón-Fuentes, Tetrahedron Lett.,

38, 6771 (1997).

[1998AA35] A. R. Katritzky and S. A. Belyakov, Aldrichimica Acta, 31, 35

152

(1998).

[1998CR409] A. R. Katritzky, X. Lan, J. Z. Yang and O. V. Denisco, Chem.

Rev., 98, 409 (1998).

[1998L139] E. J. Lee, S. L. George, P. C. Amrein, P. A. Paciucci, S. L.

Allen and C. A. Schiffer, Leukemia, 12, 139 (1998).

[1998LPS421] S. Rahimipour, L. Weiner, P. B. Shrestha-Dawadi, S. Bittner,

Y. Koch and M. Fridkin, Lett. Pept. Sci., 5, 421 (1998).

[1998JAPS1057] S. Benli, U. Yilmazer, F. Pekel and S. Ozkar, J. Appl. Polym.

Sci., 68, 1057 (1998).

[1999IC2709] N. Arulsamy, D. S. Bohle and B. Doletski, Inorg. Chem., 38,

2709 (1999).

[1999JAPS1133] L. Liu, Z. Qi and X. Zhu, J. Appl. Polym. Sci., 71, 1133

(1999).

[1999JEM1] D. M. Hanson-Parr and T. P. Parr, J. of Energ. Mater., 17, 1

(1999).

[1999JHC777] A. R. Katritzky, A. Pastor and M. V. Voronkov, J. Heterocycl.

Chem., 36, 777 (1999).

[1999OL977] M. Garcia de la Torre, A. Navarro, C. Ramírez de Arellano

and A. Simón, Org. Lett., 1, 977 (1999).

[1999T8263] A. R. Katritzky, J. Li and L. Xie, Tetrahedron, 55, 8263

(1999).

[2000AA439] S. Bittner, E. Gorohovsky, E. Lozinsky and A. I. Shames,

Amino Acids, 19, 439 (2000).

153

[2000EPA10] R. Pedemonte and W. Russ, Eur. Pat. Appl., 10 (2000).

[2000JAC549] G. V. Myasoedova, V. A. Nikashina, N. P. Molochnikova and

L. V. Lileeva, J. Anal. Chem., 55, 6, 549 (2000).

[2000JOC3679] A. R. Katritzky and A. Pastor, J. Org. Chem., 65, 3679

(2000).

[2000JOC8210] A. R. Katritzky, H. Y. He and K. Suzuki, J. Org. Chem., 65,

8210 (2000).

[2000USP6103029] R. Reed, U.S. Pat., 6,103,029 (2000).

[2000S2029] A. R. Katritzky, Y. Fang, A. Donkor and J. Xu, Synthesis,

2029 (2000).

[2001AA381] M.; Alnabari and S. Bittner, Amino Acids, 20, 381 (2001).

[2001AA135] S. Gorohovsky and S. Bittner, Amino Acids, 20, 135 (2001).

[2001ACIE2004] H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.

Int. Ed., 40, 2004 (2001).

[2001BCSJ2133] S. H. Mashraqui, S. Kumar and C. D. Mudaliar, Bull. Chem.

Soc. Jpn., 74, 2133 (2001).

[2001HPP313] C. M. Thompson and P. M. Hergenrother, High Perform

Polym., 13, 313 (2001).

[2001HYDX350] B. Du and H. Han, Henan Yike Daxue Xuebao, 36, 350

(2001).

[2001JAPS710] R. Fan, Y. Zhang, C. Huang, Y. Zhang, Y. Fan and K. Sun, J.

Appl. Polym. Sci., 81, 710 (2001).

[2001JN158S] J. M. Jamison, J. Gilloteaux, H. S. Taper and J. L. Summers,

154

J. Nutr., 131, 158S (2001).

[2001JP5267] S. N. Goyanes, J. D. Marconi, P. G. Konig, G. H. Rubiolo, C.

L. Matteo and A. Marzocca, J. Polymer, 42, 5267 (2001).

[2001RCT 915] A. R. Katritzky, H. H. Odens, M. V. Voronkov, C. J. Rostek

and O. W. Maender, Rubber Chem. Technol. 74, 915 (2001).

[2001T407] G. R.; Sridhar, V. S. Murty, S. H. Lee, I. A. Blair and T. M.

Penning, Tetrahedron, 57, 407 (2001).

[2002AA71] S. Bittner, S. Gorohovsky, O. Paz-Tal and J. Y. Becker,

Amino Acids, 22, 71 (2002).

[2002CSR324] G. Mehta and V. Singh, Chem. Soc. Rev., 31, 324 (2002).

[2002JOC4667] S. Fustero, B. Pina, E. Salavert, A. Navarro, M. C. Ramírez

de Arellano and A. Simón Fuentes, J. Org. Chem., 67, 4667

(2002).

[2002JOC7361] S. E. Wolkenberg and D. L. Boger, J. Org. Chem., 67, 7361

(2002).

[2003AAPP34] G. C. Barrett and J. S. Davies, Amino Acids, Peptides and

Proteins, 34 (2003).

[2003ACIE3996] L. F. Tietze, H. P. Bell and S. Chandrasekhar, Angew. Chem.

Int. Ed., 42, 3996 (2003).

[2003CEJ4586] A. R. Katritzky and B. V. Rogovoy, Chem. Eur. J., 9, 4586

(2003).

[2003JOC4932] A. R. Katritzky, S. Rachwal, B. Rachwal and P. J. Steel, J.

Org. Chem., 57, 4932 (2003).

155

[2003JOC5720] A. R. Katritzky, K. Suzuki, S. K. Singh and H. Y. He, J. Org.

Chem., 68, 5720 (2003).

[2003JMS647] T. Ozpozan, D. Kucukusta and Z. Buyukumumcu, J. Mol.

Struct., 661-662, 647 (2003).

[2003JTAC921] G. Herder, F. P. Weterings and W. P. C. de Klerk, J. Therm.

Analy. Calorim., 72, 921 (2003).

[2003S2795] A. R. Katritzky, Y. Zhang and S. K. Singh, Synthesis, 2795

(2003).

[2003USP113531] K. Hajmrle, B. W. Callen and J. K. Mah, U. S. Pat., 113,531

(2003).

[2004B949] J. A. Juhasz, S. M. Best, R. Brooks, M. Kawashita, N. Miyata,

T. Kokubo, T. Nakamura and W. Bonfield, Biomaterials, 25,

949 (2004).

[2004CC2356] C. Galli, P. Gentili, O. Lanzalunga, M. Lucarini and G. F.,

Pedulli, Chem. Commun., 2356 (2004).

[2004COC1720] M. Aguilar-Martinez, N. A. Macias-Ruvalcaba, J. A. Bautista-

Martinez, M. Gomez, F. J. Gonzalez and I. Gonzalez, Curr.

Org. Chem., 8, 1721 (2004).

[2004JAPS2144] M. H. Kim, C. I. Park, W. M. Choi, J. W. Lee, J. G. Lim, O. O.

Park and J. M. Kim, J. Appl. Polym. Sci., 92, 2144 (2004).

[2004KFZ16] R. G. Glushkov, G. A. Modnikova, A. I. L'vov, L. Yu. Krylova,

T. V. Pushkina, T. A. Gus'kova and N. P. Solov'eva, Khim.-

Farm. Zh., 38, 16 (2004).

156

[2004P7579] Y. H. Zhang, J. T. Wu, S. Y. Fu, S. Y. Yang, Y. Li, L. Fan, R.

Li, L. F. Li and Q. Yan, Polymer, 45, 7579 (2004).

[2004S2877] M.-H. Shih, M.-Y. Yeh, M.-J. Lee and Y.-S. Su, Synthesis, 17,

2877 (2004).

[2005ARKIVOC329] A. R. Katritzky, A. A. Abdel-Fattah and R. G. Akhmedova,

ARKIVOC, vi, 329 (2005).

[2005BMCL5324] V. K. Tandon, D. B. Yadav, R. V. Singh, A. K. Chaturvedi and

P. K. Shukla, Bioorg. Med. Chem. Lett., 15, 5324 (2005).

[2005CC2029] M. Parent, O. Mongin, K. Kamada, C. Katan and M.

Blanchard-Desce, Chem. Commun., 2029 (2005).

[2005CC4333] D. J. V. C. Van Steenis, O. R. P. David, G. P. F. Van

Strijdonck, J. H. Van Maarseveen and J. N. H. Reek, Chem.

Commun., 4333 (2005).

[2005EJOC3182] J. A. F. Joosten, N. T. H. Tholen, F. A. Ei Maate, A. J.

Brouwer, G. W. Van Esse, D. T. S. Rijkers, R. M. J. Liskamp

and R. J. Pieters, Eur. J. Org. Chem., 3182 (2005).

[2005JACS1360] H. Brand, P. Mayer, K. Polborn, A. Schulz and J. J. Weigand,

J. Am. Chem. Soc., 127, 1360 (2005).

[2005JOC4993] A. R. Katritzky, R. Jiang and K. Suzuki, J. Org. Chem., 70,

4993 (2005).

[2005JOC7792] A. R. Katritzky, N. K. Meher and S. K. Singh, J. Org. Chem.,

70, 7792 (2005).

[2005JOC9521] P. Brandi, C. Galli and P. Gentili, J. Org. Chem., 70, 9521

157

(2005).

[2005MRMC449] C. Asche, Mini-Rev. Med. Chem., 5, 449 (2005).

[2005SL1656] A. R. Katritzky, K. Suzuki and Z. Wang, Synlett, 1656 (2005).

[2005S397] A. R. Katritzky, P. Angrish, D. Hür and K. Suzuki, Synthesis,

397 (2005).

[2005TJC107] N. Sarikavakli, I. Nursabah and G. Irez, Turk. J. Chem., 29,

107 (2005).

[2006AA173] J. A. McCourt and R. G. Duggleby, Amino Acids, 31, 173

(2006).

[2006ARKIVOC43] A. R. Katritzky, S. K. Singh, N. K. Meher, J. Doskocz, K.

Suzuki, R. Jiang, G. L. Sommen, D. A. Ciaramitaro and P. J.

Steel, ARKIVOC, 5, 43 (2006).

[2006IJC1126] B. Chandrama, C. Santanu and M. Soma, Indian Journal of

Chemistry, Section A: Inorganic, Bio-inorganic, Physical,

Theoretical & Analytical Chemistry, 45A, 1126 (2006).

[2006JACS4238] B. A. Laurent and S. M. Grayson, J. Am. Chem. Soc., 128,

4238 (2006).

[2006JACS10596] H. Ishikawa, G. I. Elliott, J. Velcicky,Y. Choi and D. L. Boger,

J. Am. Chem. Soc., 128, 10596 (2006).

[2006JAPS2161] I. H. Tavman, J. Appl. Polym. Sci., 62, 2161 (1996).

[2006JOC3364] A. R. Katritzky, S. K. Singh, C. Cai and S. Bobrov, J. Org.

Chem., 71, 3364 (2006).

[2006JOC9861] A. R. Katritzky, K. N. B. Le, L. Khelashvili, and P. P.

158

Mohapatra, J. Org. Chem., 71, 9861 (2006).

[2006JOC9051] A. R. Katritzky, N. M. Khashab, N. Kirchenko and A. Singh, J.

Org. Chem., 71, 9051 (2006).

[2006JOC9548] Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J.

Org. Chem., 71, 9548 (2006).

[2006MCP132] G. D. Liang and S. C. Tjong, Mater. Chem. Phys., 100, 132

(2006).

[2006S411] A. R. Katritzky, P. Angrish and K. Suzuki, Synthesis, 3, 411

(2006).

[2006S3231] A. R. Katritzky, S. R. Tala and S. K. Singh, Synthesis, 3231

(2006).

[2006S4135] A. R. Katritzky and P. Angrish, Synthesis, 4135 (2006).

[2006SC3287] Z. Li, Y. Xing, X. Ma, S. Xiao and Z. Lu, Synth. Commun., 36,

3287 (2006).

[2006Steroids660] A. R. Katritzky and P. Angrish, Steroids, 71, 660 (2006).

[2006T10223] S. Cesarini, N. Colombo, M. Pulici, E. R. Felder and W. K.-D.

Brill, Tetrahedron, 62, 10223 (2006).

[2006TJC563] I. Babahan, H. Anil and N. Sarikavakli, Turk. J. Chem., 30(5),

563 (2006).

[2006TL105] Y. Wang, D. R. Sauer and S.W. Djuric, Tetrahedron Lett., 47,

105 (2006).

[2006TL3767] X. Zou, X. Wang, C. Cheng, L. Kong and H. Mao,

Tetrahedron Lett., 47, 3767 (2006).

159

[2006TL4827] H. A. Rajapakse, H. Zhu, M. B. Young and B. T. Mott,

Tetrahedron Lett., 47, 4827 (2006).

[2006TL6497] C. O. Kangani, D. E. Kelley and B. W. Day, Tetrahedron Lett.,

47, 6497 (2006).

[2007ACIE1018] J.-F. Lutz, Angew. Chem. Int. Ed., 46, 1018 (2007).

[2007BC994] A. R. Katritzky, P. Angrish and T. Narindoshvili, Bioconjugate

Chem., 18, 994 (2007).

[2007BMCL2340] C. Valente, R. Moreira, R. C. Guedes, J. Iley, M. Jaffarc and

K. Douglasc, Bioorg. Med. Chem. Lett., 15, 2340 (2007).

[2007USP085073] H. Inoue, M. Egawa and S. Seo, U. S. Pat., 085073; Chem.

Abstr., 146, 402092 (2007).

[2007COC959] P. Quadrelli and P. Caramella, Curr. Org. Chem., 11, 959

(2007).

[2007DP8] M. Szymczyk, A. El-Shafei and H. S. Freeman, Dyes and

Pigments, 72, 8 (2007).

[2007DP753] E. Wolarz, E. Chrzumnicka, T. Fischer and J. Stumpe, Dyes

Pigments, 75, 753 (2007).

[2007DP641] Y. Qian, Z. Lu, C. Lu, Z. Chen and Y. Cui, Dyes Pigments,

75, 641 (2007).

[2007EJOC1244] S. Kotha, K. Mandal, S. Banerjee and S. M. Mobin, Eur. J.

Org. Chem., 1244 (2007).

[2007EOTP649] F. J. Alcain, and J. M. Villalba, Expert Opin. Ther. Pat. 17,

649 (2007).

160

[2007EJMC235] A. A. Kadi, N. R. El-Brollosy, O. A. Al-Deeb, E. E. Habib, T.

M. Ibrahim and A. A. El-Emam, Eur. J. Med. Chem., 42, 235

(2007).

[2007EJMC893] S. G. Kuecuekguezel, I. Kuecuekguezel, E. Tatar, S. Rollas,

F. Sahin, M. Guelluece, E. De Clercq and L. Kabasakal, Eur.

J. Med. Chem., 42, 893 (2007).

[2007EJMC934] A. I. Hashem, A. S. A. Youssef, K. A. Kandeel and W. S.

Abou-Elmagd, Eur. J. Med. Chem., 42, 934 (2007).

[2007JAPS1038] L. Wan, Y. Luo, L. Xue, J. Tian, Y. Hu, H. Qi, X. Shen, F.

Huang, L. Du and X. Chen, J. Appl. Polym. Sci., 104, 1038

(2007).

[2007JAPS2436] M. D. Dasture and D. S. Kelkar, J. Appl. Polym. Sci., 106,

2436 (2007).

[2007JOC407] A. R. Katritzky, H. Tao, R. Jiang, K. Suzuki and K.

Kirichenko, J. Org. Chem , 72, 407 (2007).

[2007JOC4268] A. R. Katritzky, P. P. Mohapatra, D. Fedoseyenko, M.

Duncton and P. J. Steel, J. Org. Chem., 72, 4268 (2007).

[2007JOC5802] A. R. Katritzky, K. Widyan and K. Kirichenko, J. Org. Chem.,

72, 5802 (2007).

[2007JFC740] N. V. Vasil'ev, D. V. Romanov, A. A. Bazhenov, K. A.

Lyssenko and G. V. Zatonsky, J. Fluorine Chem., 128, 740

(2007).

[2007JMC6730] C. Reeh, J. Wundt and B. Clement, J. Med. Chem., 50, 6730

161

(2007).

[2007JMS(PA)PAC175] L. Wan, J. Tian, J. Huang, Y. Hu, F. Huang and L. Du, J. M.

Sci., Part A: Pure and Appl. Chem., 44, 175 (2007).

[2007MRC15] W. H. Binder and R. Sachsenhofer, Macromol. Rapid.

Comm., 28, 15 (2007).

[2007MRMC481] L. Garuti, M. Roberti and D. Pizzirani, Mini-Rev. Med. Chem.,

7, 481(2007).

[2007PAT556] J. Tian, L. Wan, J. Huang, Y. Hu, F. Huang and L. Du, Polym.

Adv. Tech., 18, 556 (2007).

[2007PEP213] V. Weiser, N. Eisenreich, A. Koleczko and E. Roth,

Propellants, Explosives, Pyrotechnics, 32(2), 213 (2007).

[2007PPTE667] J. Anuar, M. Mariatti and H. Ismail, Polym.-Plast. Tech. Eng.,

46, 667 (2007).

[2007PPTE1201] J. Anuar, M. Mariatti and H. Ismail, Polym.-Plast. Tech. Eng.,

46, 1201 (2007).

[2007S3141] A. R. Katritzky, K. N. B. Le and P. P. Mohapatra, Synthesis,

3141 (2007).

[2007SC1201] M. Dabiri, P. Salehi, M. Baghbanzadeh, M. A. Zolfigol and M.

Bahramnejad, Synth. Comm., 37, 1201 (2007).

[2007TL1549] A. Souldozi and A. Ramazani, Tetrahedron Lett., 48, 1549

(2007).

[2008ARKIVOC62] A. R. Katritzky, P. P. Mohapatra and L. Huang, ARKIVOC, ix,

62 (2008).

162

[2008CPD1001] K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas, E.

A. Varella and D. Nicolaides, Curr. Pharm. Design, 14,

1001(2008).

[2008CBE933] S. Y. Fu, X. Q. Feng, B. Lauke and Y. Mai, Compos. B: Eng.,

39, 933 (2008).

[2008JPS(A)PC238] A. R. Katritzky, N. K. Meher, S. Hanci, R. Gyanda, S. R. Tala,

S. Mathai, R. S. Duran, S. Bernard, F. Sabri, S. K. Singh, J.

Doskocz and D. A. Ciaramitaro, J. Polym. Sci. Part A: Polym.

Chem., 46, 238 (2008).

[2008JPS(A)PC2316] A. Nagal, Y. Kamel, X. Wang, M. Omura, A. Sudo, H.

Nishida, E. Kawamoto and T. Endo, J. Polym. Sci. Part A:

Polym. Chem., 46, 2316 (2008).

[2008JPS(A)PC2897] K. Takizawa, H. Nulwala, R. J. Thibault, P. Lowenhielm, K.

Yoshinaga, K. Wooley and C. J. Hawker, J. Polym. Sci. Part

A: Polym. Chem., 46, 2897 (2008).

[2008OBC637] M. A. Colucci, G. D. Couch and C. Moody, J. Org. Biomol.

Chem., 6, 637 (2008).

[2008OBC2400] A. R. Katritzky, Q.-Y. Chen and S. R. Tala, Org. Biomol.

Chem., 6, 2400 (2008).

[2008POC133] K. Strzelec and P. Pospiech, Prog. Org. Coat., 63, 133

(2008).

[2009JAE269] D. Gopi, K. M. Govindaraju, V. Collins Arun Prakash, V.

Manivannan and L. Kavitha, J. Appl. Electrochem., 39, 269

163

(2009).

[2009JMPT1729] H. Lee, B. Park and H. Jeong, J. Mater. Process Tech., 209,

1729 (2009).

[2009JOC7165] A. R. Katritzky, S. Tala, N. Abo-Dya, K. Gyanda, B. El-Gendy,

Z. Abdel-Samii and P. Steel, J. Org. Chem, 74, 7165 (2009).

[2009JPS(A)PC3748] A. R. Katritzky, Y. Song, R. Sakhuja, R. Gyanda, N. K.

Meher, L. Wang, R. S. Duran, D. A. Ciaramitaro and C. D.

Bedford, J. Poly. Sci., Part A: Poly. Chem., 47, 3748 (2009).

[2009ME367] S. Pandija, D. Roy and S. V. Babu, Microelec. Eng., 86, 367

(2009).

[2009RCB487] A. B. Sheremetev, N. S. Aleksandrova, T. R. Tukhbatshin, S.

V. Penzin and P. A. Belyakov, Russ.Chem. Bull. Int. Ed., 58,

487 (2009).

[2009USP0270440A1] B. Clement and C. Reeh, U. S. Pat., 0,270,440 A1 (2009).

[2010CR1564] A. R. Katritzky and S. Rachwal, Chem. Rev., 110, 1564

(2010).

[2010JAPS121] A. R. Katritzky, R. Sakhuja, L. Huang, R. Gyanda, L. Wang,

D. C. Jackson, D. A. Ciaramitaro, C. D. Bedford and R. S.

Duran, J. Appl. Poly. Sci., 117, 121 (2010).

[2010JAPS2612] L. Wang, R. Gyanda, R. Sakhuja, N. K. Meher, S. Hanci, K.

Gyanda, S. Mathai, F. Sabri, D. A. Ciaramitaro, C. D.

Bedford, A. R. Katritzky and R. S. Duran, J. Appl. Poly. Sci.,

117, 2612 (2010).

164

[2010JOC3938] A. R. Katritzky, K. Bajaj, M. Charpentier and E. G. Zadeh, J.

Org. Chem., 75, 3938 (2010)

[2010OBC2316] A. R. Katritzky, S. R. Tala and N. Abo-Dya, Org. Biomed.

Chem., 8, 2316 (2010).

[2010S2011] A. R. Katritzky, L. Huang, R. Sakhuja, Synthesis, 12, 2011

(2010).

[2010SL1337] A. R. Katritzky, N. Abo-Dya, S. R. Tala, E. G. Zadeh, K. Bajaj

and S. A. El-Feky, Synlett, 9, 1337 (2010).

165

BIOGRAPHICAL SKETCH

Longchuan Huang was born in October 1981, in Yuantan, Anhui province, China.

She was the first of daughter of Fayuan Huang and Miaorong Zhu. From 1986 to 1997, she attended Yuantan Primary school and later Yuantan High School. Afterward, she did her undergraduate studies at Beijing Institute of Petrochemical Technology (BIPT) where she received a Bachelor of Science in Polymer Chemistry. Upon graduation in

July 2001, she attended Hongkong Polytechnic University, Hangzhou campus majoring in Hotel and Tourism Management, and graduated with a Master of Science degree in

July 2003. She worked briefly in Crown Plaza (Beijing) shortly where she realized her interest is not in the hospitality industry. She started applying for graduate schools in the

USA, while meanwhile working as a part-time English teacher at Xicheng Foreign

Language School of Beijing. In 2004, she received an admission offer from Florida

Institute of Technology (FIT) (Melbourne, FL) with full teaching assistantship for a

Master’s degree in Chemistry. After some preparation, she traveled to the USA in

January 2005, and started her studies and research specializing in bioorganic chemistry in Dr. Nasri Nesnas’s laborotary, where she synthesized a type of goldfish pheromone.

She completed her MS in Chemistry from FIT in December 2006, then she joined

Professor Alan R. Katritzky’s research group at the Florida Center for Heterocyclic

Chemistry, University of Florida, pursuring her Doctoral research studies in the synthesis of heterocyclic compounds. In January 2011, she looks forward to joining the group of Professor Amos B. Smith III at University of Pennsylvania as a postdoctoral research associate.

166