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Studies in Heterocyclic Synthesis

Permanent Link: http://ufdc.ufl.edu/UFE0042398/00001

Material Information

Title: Studies in Heterocyclic Synthesis
Physical Description: 1 online resource (166 p.)
Language: english
Creator: Huang, Longchuan
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: benzotriazole, heterocyclic, n, synthesis
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: STUDIES IN HETEROCYCLIC SYNTHESIS By 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-?-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-hydroxy- amidoximes and hydrazidines, which are important classes of nitrogen-rich heterocycle precursors.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Longchuan Huang.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Katritzky, Alan R.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042398:00001

Permanent Link: http://ufdc.ufl.edu/UFE0042398/00001

Material Information

Title: Studies in Heterocyclic Synthesis
Physical Description: 1 online resource (166 p.)
Language: english
Creator: Huang, Longchuan
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: benzotriazole, heterocyclic, n, synthesis
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: STUDIES IN HETEROCYCLIC SYNTHESIS By 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-?-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-hydroxy- amidoximes and hydrazidines, which are important classes of nitrogen-rich heterocycle precursors.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Longchuan Huang.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Katritzky, Alan R.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042398:00001


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1 S TUDIES IN HETEROCYCLIC SYNTHESI S By 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 UNIVERSIT Y OF FLORIDA 2010

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2 2010 Longchuan Huang

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

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4 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 impress ive. 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 s uggestions 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 commit tee. 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 pr oject described in Appendix I would like to thank all of the present and past members o f the Katritzky research group. I have made some great friends and enjoyed their company during the past four years Their friendship and support ha ve made this period of my life more pleasant and memorable.

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5 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 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 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

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6 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 Intr oduction ................................ ................................ ................................ ....... 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 Oth er 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 Procedu re for the Preparation of 1,3,4 Oxadiazole .................... 77 4 OVERVIEW OF N HYDROXYAMIDOXIMES, N AMINOAMIDOXIMES AND HYDRAZIDINES ................................ ................................ ................................ ..... 81 4.1 Intro duction ................................ ................................ ................................ ....... 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 me thods for di O alkyl derivatives of N hydroxyamidoximes ................................ ................................ ............ 88 4.3.2 N Aminoamidoximes and Their Derivatives ................................ ............. 89 4.3.2.1 From oxime c hlorides or amidoximes ................................ ............. 89

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7 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 a nd 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 w ith 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 R eaction 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 R eduction of hydrazidines ................................ .......................... 108 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 inorg anic 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 tu berculosis agents ................................ .......................... 115 4.5.3.3 As environmentally friendly dyes ................................ .................. 115 4.6 Conclusions ................................ ................................ ................................ .... 116 5 SUMMARY OF ACHIEVEMENTS ................................ ................................ ........ 117

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8 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 Propel lant 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 Effe ct ................................ ................................ .............. 126 A 3 Conclusions ................................ ................................ ................................ .... 135 A 4 Experimental Section ................................ ................................ ..................... 136 LIST OF REFERENCES ................................ ................................ ............................. 142 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 166

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9 LIST OF TABLES Table page 2 1 Naphthoquinone a mino acid/ester conjugates ................................ ................... 44 2 2 Naphthoquinone aminoacylbenzotriazoles ................................ ......................... 45 2 3 Synthes is 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 st rain 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 loadi ng (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

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10 LIST OF FIGURES Figure page 1 1 Isomerization of Benzotriazoles ................................ ................................ .......... 21 1 2 1 H 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 Doxoru bicin molecules intercalating DNA ................................ ........................... 37 2 3 Naturally occurring quinones ................................ ................................ .............. 39 2 4 Classes of quinones participating in biological red ox 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 Hydrazidin es 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

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11 A 1 Common rocket propellant binders ................................ ................................ ... 118 A 2 Dogbone mold cont aining 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

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12 LIST OF SCHEMES Scheme page 1 1 Alkylation of 1 H 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 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 protected aminoacl)steroids and O 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 conjugate s 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

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13 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 diacylh ydrazines ... 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

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14 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 trip henylformazan ................................ ................................ ........... 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 o f N hydroxyamidoxime with benzophenone ................................ ....... 97 4 27 Preparation of 3,5 disustitued 1 H [1,2,4]triazoles ................................ ............... 98 4 28 Synthesis of 3 benzyl 5 ( p tolyl) 4 H 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 d ibenzylidene 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

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15 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 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

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16 LIST OF ABBREVIATION S Ac a cetyl (CH 3 C=O) Al aluminum Al a a lanine Ar a ryl Boc t b utyloxycarbonyl Bn b enzyl br broad (spectral) brs broad singlet (spectral) Bt b enzotriazoyl BtH 1 H b enzotriazole BTNO b enzotriazole N ) Bz b enzoyl C carbon Cu copper o C degree Celcius Calcd calculated CAN c erium IV ammonium nitrate Cbz c arbobenzyloxy (BnOC=O) CDCl 3 d euterated chloroform CH 3 CN a cetonitr ile d doublet (spectral) DCC d icyclohexyl c arbodiimide

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17 DCM m ethylene chloride DMAP 4 d imethylami nopyridine (base catalyst) DMSO d imethyl s ulfoxide (solvent) DMSO d 6 d eut erated dimethyl sulfoxide DMF d imethylformamide (solvent) E e ntgegen (opposite, trans ) EDC 1 e thyl 3 (3 dimethylaminopropyl) carbodiimide equiv equivalent(s) et al. and others E tOAc e thyl a cetate Fe iron g gram(s) Glu g lutamic acid Glu O Me g lutamic methylester Gly g lycine h hour H hydrogen HBT 1 h ydroxybenzotriazole HOBT N h ydroxybenzotriazole HBTU O b enzotriazolye tetramethyluronium hexafluoro phosphate HCl h ydrochloric acid HDPE high density polyethylene

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18 HMDS h examethyldisila zide HRMS high resolution mass spectrometry HTPB hydroxy terminator polybutadiene Hz hertz i Pr isopropyl J c oupling co nstant (NMR) LDA lithium aluminium hydride LDPE low density polyethylene Leu l eucine lit literature Lle i soleucine Lys l ysine m multiplet (spectral); metre(s); milli MeCN a cetonitrile MgSO 4 m agnesium sulfate m. p. melting point Ms m ethanesulfonyl (m esyl, CH 3 SO 2 ) m / z mass to charge ratio N ni trogen NaCl s odium chloride NMR n uclear m agnetic r esonance O oxygen PBAN polybutadiene acrylic acid acrylonitrile

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19 Phe phenylalanine PMMA polymethylmethacrylate PU polyurethane RT r oom t emperature s singlet (spectral) S s ulfur SOCl 2 t hionyl chloride t triplet (spectral) t tertiary TBAF t etrabutyl ammonium floride TEA t riethylamine (Et 3 N) THF t etrahydrofuran ( solvent ) TMS t etramethylsilane, also t rimethylsilyl Tryp t ryptophan Ts t osyl (p CH 3 C 6 H 4 SO 2 ) UV ultra violet Val v aline wt% weight percent Z z usammen (together, cis )

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20 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 By Longchuan Huang December 2010 Chair: Alan R. Katritzky Major: Chemistry 1 H Benzotriazole and its derivatives are versatile synthetic auxiliar ies My research studies have further investigated the application of N acylbenzotriazole s in th e synthesis of heterocyclic compounds. In C hapter 2, an efficient N acylbenzotriazole mediated preparation of naphthoquinones dipeptides from naphthoquinone amino acid conjugates as potential cytotoxic agents is reported. In C hapter 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, reactivi ty and utility of N amino and N hydroxy amidoximes and hydrazidines, which are important classes of nitroge n rich heterocycle precu r sors

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21 CHAPTER 1 INTRODUCTION TO BENZ OTRIAZOLE CHEMISTRY 1.1 Benzotriazole 1.1.1 Structure and Isomerization Benzotriazol e ( 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 agen t in photographic development. [2009JAE269, 2009JMPT1729, 2009ME367] Benzotriazole derivatives are employed in pharmaceuticals such as antifungal, antiba cterial, anthelmintic drugs, and polymerization catalysts. [ 2003CEJ4586, 2010CR1564] Figure 1 1 Isomerization of Benzotriazole s 1 H Benzotriazole exists in solution as an equilibrium mixture of 1 benzotriazole ( 1.1 ) and 2 benzotriazole ( 1.2 ) (Figure 1 1) [1975JCS ( PT 1 ) 1181] Such isomerization is general for disubstituted N (aminomethyl)benzotriazoles, such as N (aminoalkyl) ( 1.3 )

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22 [1987JCS ( PT 1) 2673 1989H1121, 1990JOC5683], N (alkoxyalkyl) [ 1992JOC4932 ], N (alkylthioalkyl) ( 1.5 ) [ 1991HCA1936 ], and N (diarylmethyl) benzotriazoles [ 1990JCS ( PT 2) 2059 ], but not for simple N a lkylbenzotriazoles. 1 H 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 anot her aspect of a good auxiliary, BtH can act as a weak base (pKa = 1.6) or a weak acid (pKa = 8.3) [ 19 48JCS2240 1991T2683], which facilitate s the easy removal of benzotriazole from the reaction mixture by washing with base or acid. Moreover, 1 H benzotriazo le is an inexpensive, stable compound that is soluble in common organic solvents such as ethanol, benzene, chloroform, and DMF. Figure 1 2 1 H Benzotriazole functions as an excellent synthetic auxiliary Alkylation of 1 H 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) t o 50:50 (R = C 6 H 11 CH 2 ) (Scheme 1 1 ). [1994LAC1]

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23 Scheme 1 1 Alkylation of 1 H benzotriazole 1.1.2 Synthesis of Benzotriazole s Benzotriazole is produced by reaction of o phenylenediamine ( 1.12 ) with sodium nitrite and aceti c acid. The conversion proceeds via diazotization of one of the amin o groups (Scheme 1 2 ). [2001HYDX350 1981US P 4299965 ] Scheme 1 2 Synthesis of benzotriazole Reduction of compound ( 1.13 ) gave 4,6 dinitro N 1 phenylbenzen e 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 nit rated with nitric or mixed acid, and its derivatives ha ve 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

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24 1.2 Activation Abil ity of the Benzotria zole Ring Benzotriazole derivatives are important synthetic auxiliaries that offer versatile applications in organic chemistry including a vast array of synthetic transformations. [ 19 98CR409, 20 03CEJ4586] Benzotriazole methodology has been applied to alky lation [ 19 94CSR363], acylation [ 20 03JOC4932, 20 03JOC5720, 20 05S1656], imine acylation [ 20 00S2029], and imidoylation [ 1997TL6771, 1999OL977, 2002JOC4667 2003CEJ4586 ]. It has also been utilized in Mannich reactions [ 19 94JHC917], Michael reactions [ 20 01BCSJ2 133] and Grignard reactions [ 20 07S3141]. 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 meticulous ly by our group since 1980s especially with reference to the synthesis of heterocyclic molecules. A benzotriazole group commonly activates the carbo n atom to which it is attached; hence, benzotriazole intermediates are widely used to introduce a variety o f functional groups into molecules. F ive major applications of benzotriazole group in organic t ransformations are illustrated below: 1.2.1 As a P roton A ctivator or an Anion S tabilizer Many synthetic applications of benzotriazole derivatives are based on t he ability of the benzotriazolyl substituent to stabilize an adjacent carbanion. [ 1998CR409, 2003CEJ4586, 20 06S3231 ] n BuLi or LDA can convert 1 ( n alkyl)benzotriazoles ( 1. 1 6) to anions ( 1.1 7) (R 1 = H or alkyl), consecutively treating with alkyl halides w ill give 1 alkylbenzotriazoles ( 1.1 8) bearing secondary alkyl groups. Carbonyl electrophiles can be used to trap the Bt stabilized anion ( 1.1 7 ) to form ( 1. 20 ) Reaction of ( 1.17 ) with CO 2 or ethyl benzoate

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25 gives carboxylic acid ( 1.19 ) and ketone ( 1.21 ) re spectively (Scheme 1 4 ) [1991CB1819] Scheme 1 4 Reaction s of benzotriazolyl stabilized carbanion s with electrophiles 1.2.2 As a Leaving G roup The leaving group ability of benzotriazole is comparable to cyano and sulfo nyl groups [ 19 95S1315]. The acid chlorides and acyl tosylate s are often so reactive as to be hard to isolate. Compar ed with the more reactive halogen, tosyl ate and the toxic cyano group s be zotriazole (Bt) behaves as a tame halogen substituent and has the a dvantage of forming a stable, non volatile anion in solution. benzotriazole amines and ethers are stable compounds that are much easier to work

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26 with than the corresponding toxic chloro derivatives. The displacement of benzotriazole group can be easily achieved by nucleophilic attack [ 19 94CSR363], or by different nucleophilic atoms such as C, S, N, O, or even by Grignard reagents (Scheme 1 5 ). [ 1991T2683, 19 96JOC1624 ] Scheme 1 5 Reaction with Grignard reagen t 1.2.3 As an Ambient Anion Directing G roup In an all ylic system ( 1.25 ) the benzotriazolyl moiety a cts as an anion directing group Hence, the alpha posit i on 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 R adical S tabilizer or a Radical Precu r sor The benzotriazolyl moiety can act as a radical precursor ( 1.30 ) (Scheme 1 7). The generation of the aminoxyl radical benzotriazole N oxyl ) (i.e., BTNO) ( 1.29 a ) from 1 hydroxybenzotriazole (HBT) ( 1.28 a ) by monoe lectronic oxidation with cerium IV 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 ).

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27 Scheme 1 7 Benzotriazole acts as an radical stabilizer or precursor 1.2.5 As an A nion P recursor Benzotriazole moieties can act as a c arbanion ( 1.32 ) precursor via reductive elimination (Scheme 1 8 ). [ 19 97JOC4148 19 96LA C 745, 19 92JCS ( PT 1) 1111] The c arbanion can react further with other electrophiles such as ketones/aldehydes to form alcohols ( 1.33 ). Sch eme 1 8 Reductive elimination of benzotriazole 1.3 N A cylb enzotriazoles in Heterocyclic S ynthesi s 1.3.1 Preparation of N A cylbenzotriazoles N A cyl benzotriazoles are stable crystalline compounds that can be easily prepared and handled in the lab. The clas sical preparation of acylazoles wa s 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 ca rboxylic 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 )

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28 eagent; in the presence of Et 3 N, c arboxylic 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, 20 00J OC8210] A wide range of N acylbenzotriazoles ha ve been prepared in our group via the methods mentioned above including alkyl a nd aryl carboxylic acids, many heterocyclic carboxylic acids, unsaturated carboxylic acids, and carboxylic acids with vari ous oth er functionalities. [ 1992T7817, 2000JOC8210 2003S2795] Scheme 1 9 Methods for preparation of N acylbenzotriazoles 1.3.2 N A cylbenzotriazoles for N S C and O A cylation 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 t o prepare [1998AA35 1999T8263] Several r ecent demonstrations of 1 ac yl 1 H benzotriazoles as versatile synthetic auxiliaries in our group include:

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29 1.3. 2. 1 S elective synthesi s 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 slight ly different reaction conditions (Scheme 1 10 ). [ 20 09JOC7165] Scheme 1 10 Selective synthesis of S acyl and N acylcysteines 1.3 .2 .2 Selective synthesis of S acyl glutathiones and N acyl glutathiones 1 A cyl 1 H benzotriazol es ( 1.40 ) were used in the selective syntheses of S acyl glutathiones ( 1.42 ) and N acyl glutathiones ( 1.43 ) [2010SL 1337] The transformation is facile and has general applications for S acylation and N acylation of biologically important larger peptides and glycopeptides (Scheme 1 1 1 ) Scheme 1 11 Selective synthesis of S acyl glutathiones and N acylglutathiones

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30 1.3 2. 3 Synthesis of N Cbz aminoacyl)methylenepyridines and quinolines Aminoacyl conjugates of nitro gen heterocycles ( 1.46 ) were synthesized as chiral potential novel p harmacophores from 2 m ethyl and 4 methylpyridine and 2 methylquinoline ( 1.45 ) by reacting with benzotriazole activated (Cbz) p r otected amino acids ( 1.44 ) (Scheme 1 1 2 ). [2010JOC3938] Scheme 1 12 Synthesis of N Cbz aminoacyl)methylenepyridines and quinolines 1.3 2. 4 Synthesis of S acyl isotripeptides Cysteine and C terminal cysteine peptides ( 1.47 ) are selectively S acylated by N (Pg aminoacyl)benzotriazoles ( 1.34 ) to give N Pg S acyl isotripeptide s ( 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] Schem e 1 13 Preparation of S acyl isotripeptides

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31 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 int ermediates, and usually require complex procedures, harsh reaction conditions and/or give low yields. By comparison, the new method s for preparing a zo dye labeled amino acids ( 1.52 ) and amines ( 1.53 ) were developed by react ion of N (4 arylazobenzoyl) 1 H be nzotriazole ( 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 label ed amino acids and amines 1.3. 2. 6 Synthesis of chiral O protected aminoacyl)steroids Chiral O protected aminoacyl)steroids ( 1.56 ) and O 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 aminoacyl) benzotriazoles ( 1.54 ) and Z dipeptidoylbenzotriazole ( 1.57 ). (Scheme 1 15) [2006Steroids660]

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32 Scheme 1 15 Microwave assisted synthesis of chiral O protected aminoac y l)steroids and O protected dipeptidoyl)steroids 1.3 2. 7 Synthesis of pyridin 2 ylmethyl ketones Katritzky el. al. reported that 2 or 4 p icoline ( 1.62 ) was lithiated by LDA and then treated with acy lbenzotriazoles ( 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. [2005A RKIVO C329, 2010CR1564] Scheme 1 16 Synthesis of pyridin 2 ylmethyl ketones mediated via N acylbenzotriazoles

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33 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 [ 19 98CR409] One of the example s is 1 (benzotriazol 1 yl) alkyl ethers ( 1 65 ) ( Figure 1 3 ) which have been widely used for the preparation of various heterocycles [ 19 95JOC7612 19 95JOC7625] fu nctionalized ketones [ 19 95JOC7619, 19 97JOC706], amides [ 19 88JOC5854], and ethers [ 19 89JOC6022] Another example is 1 (benzotriazol 1 yl) alkyl esters ( 1 66 ) which should offer similar synthetic functions The initial route for the prepar ation of ( 1.6 6 ) was reported from forming unstable intermediates with high sensitivity to moisture [ 19 91S69] 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 aldeh ydes ( 1.68 ) (Scheme 1 1 7 ) [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 B t mediated C acylation Carbon acylations provide an entry to carbon carbon bonds [ 19 73JOC514] 1 A cylbenzotriazoles mediated C acylation was dem onstrated in the regioselective synthesis of diketones. [2000JOC3679] Reactions of alkyl and aryl N

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34 acylbenzot riazoles with saturated cyclic ketones, unsaturated cyclic ketones, and aliphatic ketones in the presence of lithium diisopropylamide (LDA) and tetrahydrofuran (THF) at 78C resulted in C acylated products in excellent yields. Enaminones ( 1.71 ) were obtai ned 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 S cope for N A cylben zotriazole A pplications in Heterocyclic S ynthesi s N A cyl benzotriazoles are versatile synthetic auxiliaries used as C O S and N acylating agents as well as precursors to many valuable heterocycles P art of my research efforts has been focused o n the ex pansion of the scope of N acylbenzotriazole s as activated reagent s toward heterocyclic synthesi s specifically, naphthoquinone di peptides and 1,3 4 oxa diazoles. In C hapter 2, an N acylbenzotriazole mediated preparation of naphthoquinones dipeptides from na phthoquinone amino acid conjugates as potential cytotoxic agents is described also some investigation of benzoquinone amino acid conjugates are documented. In C hapter 3, 1,3,4 oxadiazoles were prepared from functionalized N acylbenz otriazoles and acyl h ydrazides.

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35 CHAPTER 2 EFFICIENT SYNTHESES OF NAPHTHOQUINONE DI PEPTIDES 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 p arasites [20 07BMCL2340] Some quinonic derivatives are used as medicines for treating bacterial and fungal diseases, and others exhibit potent antimalarial capacities. [20 02AA71] Many naturally occurring quinones are antitumor agents, and those approved fo r 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 (mitox antrone ( 2.7 ), streptonigrin ( 2.8 )) (Figure 2 1) [20 05MRMC449, 20 08OBC637 20 07MRMC481] Menadione ( 2.1 ) has been used e xperimentally as a chemotherapeutic agent for cancer. The combination of vitamin C and Menadione ( 2.1 ) has antitumor activities and a bility 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 als o 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 s hown in Figure 2 2. [1990B 2538] Reproduced in part with permission from Synthesis, 2010 12, 2011 Copyright 2010 Wiley

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36 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 dam age DNA via initiating radical reactions with DNA strand breaks. Also, i t can disrupt DNA function by alkylating or crosslinking DNA during all phases of the cell cycle. [1998L139] Figure 2 1 Important d rugs containing quinone moities

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37 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 ha s been used in the treatment of several typ es of cancer. [1979JMC1024] Streptonigrin ( 2.8 ) is an aminoquinone isolated from the bacterium Streptomyces flocculus It can act as a reverse tr anscriptase inhibitor and cause free radical mediated cellular damag e. 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

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38 The cell cytoto xicity 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 fun ction and nucle ic 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 relea sing 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 [19 98LPS421] somatostatin [19 90JSBMB1083] bombesin [19 83P683] vasoactive i ntestinal peptide [1990P1205] and growt h factors, including epidermal and insulin like [19 95 J A N YAS 402] have been detected in the cancers of prostate, breast pancreas, ovary, lung, colon and in brain tumors [19 87CL223] 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 a ntibi otics and quinones derivatives which exhibited a wide range of specific binding affinities towards LH RH receptors. Preliminary finding proved that quino n yl amino acids incorporated into a biological active peptide showed cytotoxic and anticancer act ivity [19 98LPS421], which aroused our interest in synthesis of different quinones amino amino side chain of a D lysine residue possess cytotoxic activity against human breast a nd prostate cancer cell lines. [19 92PNAS972, 19 96LPS263]

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39 2.1.2 Interaction of Q uinones and A mino A cids in N ature 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 ant h raquinones ( 2.12 ) [2006AA173 ] (Figure 2 3). Quinones are involved in mechanisms of elect ron and hydrogen transfer [2005BMCL5324, 20 07EJOC1244] Figure 2 3 Naturally occurring quinones 2.1 3 Ap plication of Quinone Amino Acid C onjugates Quinones and amino acids [ 2003AAPP 34 ] constitute two ubiquitous classes of naturally occurring compounds with diverse important properties and applications. Naph thoquinones ( 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. [2007E OTP649, 2005BMCL5324] Figure 2 4 Classes of quinones participating in biological redox processes

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40 The efficiency of the quinonic compounds in inhibiting cancer cells growth is believed to stem from their ability to assoc iate 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. [2002AA 71] In the living cells quinones can undergo non enzymatic or enzymatic one electron reduction to give toxic semiquinone anion radical s After additional redox reactions semiquinone anion radicals form superoxide anion radicals and hydroxyl radical which p roduces 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. [2 005BMCL5324] 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 2001AA1 35 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 pharmacologica l activities [2002CSR324 2003ACIE3996] 2. 1 4 Literature Preparative M ethods for Quinone A mino Acid C onjugates Considerable efforts have been devoted to the synthesis of quinone amino acid conjugates utilizing diverse ro u t e s including (Figure 2 5): (i) tr ansamination, to give

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41 quino ne amino acid conjugates linked via a vinylic spacer ( 2.16 ) (Scheme 2 1); [20 01AA381] (ii) quinone amino acid hybrids ( 2.17 ) synthesized via c ross enyne metathesis and Diels Alder reactions (Scheme 2 2); [2007EJOC1244] (iii) N q uinonyl amino acids ( 2.18 ) obtained from chlor o substituted quinones (Scheme 2 3); [2002AA71] ( i v) 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 Quin onyl amino acids obtained with chloro substituted quinones

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42 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 tempera ture in 24 48 h, which initially yielded hydroquinone conjugates ( 2.21a b ) which were not isolated [1996LPS263] O xidation by excess of 1,4 naphthoquinone in the reaction mixture yielded the desired naphthoquinone dipeptide conjugates ( 2.22a b ) in 63% and 48% yi eld (Scheme 2 5 ). [1996LPS263] Scheme 2 5 Preparation of naphthoquinone dipeptide s 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 st udy their spectral properties. Herein, an efficient N acylbenzotriazole mediated preparation of naphthoquinones dipeptides was developed from naphthoquinone amino acid conjugates with 76 89% yie lds in aqueous media at 20 C. In addition, to demonstrate the efficient formation of quinone

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43 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 amino acids via N addition (Scheme 2 9 ), then further activat ed with benzotriazole group, which were used for the next step peptide synthesis. However, the preparation of acyl benzotriazole s from S substitued quino ne amino acid conjugates proved difficult but only one example was obtained after many attempts (Scheme 2 10 ). 2.2 Results an d Discussion 2.2 .1 Reaction of Naphthoquinone A mino Acid C onjugates 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 Et 3 N The reaction mixture was subjected to column chromatography to first yield nap hthoquinone amino acid triethyl ammonium salt, which upon washing with aqueous hydrochloric acid solution yi elded 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

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44 Table 2 1 Naphthoquinone amino acid/ester conjugates Entry Amino acid ( 2.24 ) Target Compounds ( 2.25 ) Yield (%) Mp (C) 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 64 137 139 a 4 L Tryptophan ( 2.24d ) 2.25d 58 208 211 b 5 L Proline OMe ( 2.24e ) 2.25e 90 151 153 6 D Val OMe ( 2.24f ) 2.25f 76 255 256 7 alanine ( 2.24g ) 2.25g 80 205 207 a Lit. m. p. 139 142 C [2000AA469]; b lit. m. p. 210 213 C [1996S1468] Activation of the terminal carboxylic acid of naphthoquinone amino acid conjugates ( 2.25a d ) was achieved by reaction with same equivalent of benzot riazole ( 2.26 ) and dicyclohexylcarbodimide (DCC) to yield naphthoquinone amino acyl benzotriazole s ( 2.27a d ). The reaction was initially attempted with BtH/SOCl 2 /THF/ RT, 2 5h or BtSO 2 Me/THF/ Et 3 N/reflux, 8 12h, but a complex mixture was obtained. Fina lly N acyl benzotriazole derivative s w ere obtained in DCM at room temperature in 4h using DCC as the coupling agent. (Scheme 2 7 Table 2 2). Scheme 2 7 Sy nthesis of naphthoquinone aminoacyl benzotriazole conjugates

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45 T ab le 2 2. Naphthoquinone amino acylbenzotriazole s Entry Naphthoquinone Amino Acid Conjugates ( 2.5 ) Target compounds ( 2.27 ) Yield (%) Mp (C) 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 Acylbenzotria zole ( 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 excell ent yields (76 89%). (Scheme 2 8 Table 2 3) Scheme 2 8 Preparation of naphthoquinone dipeptide conjugates

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46 Table 2 3. Synthesis of Naphthoquinone dipeptides (continued on the next page ) Entry Naphthoquinone amino N acylb enzo t riazol e conjugate Amino acid ( 2.24 ) Target compound ( 2.28 ) yield (%) Mp (C) 1 2.27a L Alanine ( 2.24c ) 2.28a 89 166 168 2 2.27a L Valine ( 2.24e ) 2.28b 81 175 177 3 2.27a L Tryptophan ( 2.24d ) 2.28c 81 215 217 4 2.27b L Tryptophan ( 2.24d ) 2.28d 81 223 225 5 2.27b L Alanine ( 2.24c ) 2.28e 89 172 174 6 2.27b L Glutamic acid methyl ester ( 2.24f ) 2.28f 81 153 155

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47 Table 2 3. Continued Entry Naphthoquinone amino N acylbenzotriazol e conjugate Amino acid ( 2.24 ) Target compound ( 2.28 ) yield (%) Mp (C) 7 2.27c L Tryptophan ( 2.24d ) 2.28g 82 243 245 8 2.27d L Leucine ( 2.24b ) 2.28h 79 114 120 9 2.27d L Glutamic acid methyl ester ( 2.24f ) 2.28i 76 104 111 10 2.27d L Phenylalanine ( 2.24a ) 2.28j 81 121 123 1 1 2.27b L Phenylalanine ( 2.24a ) 2.28k 78 161 164 2. 2 .2 Reaction of T hio substi tuted Benzoquinone with Amino A cids 2 (C yclohexylsulfanyl) p benzoquinone ( 2.29 ) was prepared from cyclohexyl mercaptan ( 2.20 ) by react ion wi th two equivalen ts of p benzoquinone ( 2.10 ) at room temperature for 2 hours. Compound ( 2.29 ) was used as the starting material for the

PAGE 48

48 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 amino acids ( 2.30a b ) in a cetonitrile at 20 C (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 benzoquinon e amino acid conjugates Table 2 4. Thiol substituted benzoquinone amino acid congjugates Amino acid ( 2.30 ) Product ( 2.31 ) Yield (%) Mp (C) D Alanine ( 2.30 a ) ( 2.31 a ) 63 139 141 DL Alanine ( 2.30 a + 2.30a ) ( 2.31 a + 2.31 a ) 63 140 141 L Phenylalanine ( 2.30 b ) ( 2.31 b ) 71 127 129

PAGE 49

49 2.2 .3 Preparation of Benzotriazole Activated Benzoquinone Amino Acid C onjugates 2 (4 Cyclohexylsulfanyl 3,6 dioxocyclohexa 1 ,4 dienylamino)propionic acid ( 2.31 a + 2.31 a ) on treatment with 1 H benzotriazole and thionyl chloride in DCM gave the corresponding stable crystalline racemic acylbenzotriazole ( 2.32 a + 2.32 a ) in 65 % yield (Scheme 2 10 ). S che me 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 methodol ogy 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 thi o substituted benzoquinone N amino acylbenzotriazoles was challenging, due to the many side products formed during the reaction. Only one example ( 2.32 a + 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 in CDCl 3 or DMSO d 6 with TMS for 1 H (300 MHz) and 13 C (75 MHz) as internal reference. Free amino acids were p urchased from Fluka (Buchs, Switzerland) and

PAGE 50

50 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) w ere dissolved in a mixture of EtOH H 2 O (50 : 5 mL). Triethyl amine (20 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 12 h. The result ing solut ion was evaporated under reduced pressure, and the residue was subjected to column chromatography, elutin g with EtOAc/Hexane (2:8) first to remov e the nonpolar impurities, and then with 100% EtOAc to yield a solid, which was characterized as the triethylam ine 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 ami no acid/ester conjugate. ( S ) 2 ((1,4 dioxo 1,4 dihydronaphthalen 2 yl)amino) 3 phenylpropanoic acid (2.25a) Black microcrystals ; y ield: 72%; m. p. 200 203 o C. (lit. m. p. 200 202 o C ); [2002AA71] 1 H NMR (DMSO d 6 ) : 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 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H); 13 C NMR (DMSO d 6 ) : 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.

PAGE 51

51 ( S ) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 2 yl)amino) 4 methylpentanoic acid (2.25b) Black crystal s ; y ield: 79%; m. p. 115 117 o C; 1 H NMR (DMSO d 6 ) : 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 Hz, 1H); 13 C NMR (DMSO d 6 ) : 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 C 16 H 18 NO 4 : [M+H] + 288.1320, found 288.1233. ( S) 2 (1,4 Dioxo 1,4 dihydronaphthalen 2 ylami no)propanoic acid (2.25c) Red crystal s ; y ield: 64%; m. p. 137 139 o C. ( lit. m. p. 139 142 C ); [ 2000 AA 439 ] 1 H NMR (DMSO d 6 ) : 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); 13 C NMR (DMSO d 6 ) : 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 D ioxo 1,4 dihydronaphthalen 2 yl)amino) 3 (1H indol 3 yl)propanoic acid (2.25d)

PAGE 52

52 Orange brown crystal s ; y ield: 58%; m. p. 208 211 o C. (l it m. p. 210 213 C ); [ 1996S1468] 1 H NMR (DMSO d 6 ) : 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), 7.92 8.00 (m, 2H), 10.90 (s, 1H); 13 C NMR (DMSO d 6 ) : 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 ) M ethyl 1 (1,4 dioxo 1,4 dihydronaphthalen 2 yl)pyrrolidine 2 carboxylate (2.25e) Black crystal s ; y ield: 90%; m. p. 151 153 o C (l it m. p. 149 150 C ); [1977BCSJ2170] 1 H NMR (DMSO d 6 ) : 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 = 7.5 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H); 13 C NMR (DMSO d 6 ) : 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 ) M ethyl 2 ((1,4 dioxo 1,4 dihydronaphthalen 2 yl)amino) 3 methylbutanoate (2.25f) Black crystal s ; yield: 76%; m. p. 255 256 o C (lit. m. p. 256 257 o C ); [1977BCSJ2170] 1 H NMR (CDCl 3 ) : 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),

PAGE 53

53 7.60 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 8.01 8.05 (m, 2H); 13 C NMR (CDCl 3 ) : 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 D ioxo 1,4 dihydronaphthalen 2 yl)amino)propanoic acid (2.25g ) B rown crystal s ; y ield: 80%; m. p. 205 207 o C (l it. m. p. 206 207 C ); [ 2002AA71] 1 H NMR (DMSO d 6 ) : 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); 13 C NMR (DMSO d 6) : 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) i n anhydrous DCM (30 mL), benzotriazole (0.60 g, 5 mmol) and N,N' dicyclohexylcarbodi i mide (DCC) (0.95 g, 5 mmol) w ere added. The reaction mixture was stirred at room temperature for 4 h, then filtered through celite at least twice. The organic layer was co ncentrated under vacuo and the residue was recrystallized from EtOAc/Hexane to yield 2.27a and 2.27d as pure product s 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 n ext coupling reaction.

PAGE 54

54 ( S ) 2 ((1 (1 H B enzo[d][1,2,3]triazol 1 yl) 1 oxo 3 phenylpropan 2 yl)amino)naphthalene 1,4 dione (2.27a) Black crystal s ; y ield: 86%; m. p. 115 117 o C; 1 H NMR (CDCl 3 ) : 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 = 7.5 Hz, 2H); 13 C NMR (CDCl 3 ) : 38.9, 56.6, 103.0, 114.4, 120.8, 126.4, 126.6, 12 7.1, 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 C 25 H 18 N 4 O 3 : C, 71.08; H, 4.29; N, 13.26. Found: C, 70.80; H, 5.04; N, 13.49. 2 (((2 S ) 1 (1 H B enzo[d][1,2,3]triazol 1 yl) 3 (2,7a d ihydro 1H indol 3 yl) 1 oxopropan 2 yl)amino)naphthalene 1,4 dione (2.27d) Yellow microcrystals ; y ield: 83%; m. p. 114.0 115.0 o C; 1 H NMR (CDCl 3 ) : 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 (t, J = 6.9 Hz, 2H), 8.26 (br s, 1H); 13 C NMR (CDCl 3 ) : 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 C 27 H 20 N 5 O 3 [M+H] + 462.1488, found 462.1556.

PAGE 55

55 General method for preparation of Naphthoquinone dipeptides (2.28a j) A solution of L amino acid (1 mmol) ( 2.24a f ) and Et 3 N (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 4 N 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 r esulting solution. The precipitated solid was filtered and dried under vacuum to yield naphthoquinone dipeptides ( 2.28a j ). ( S ) 2 (( S ) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 3 phenylpropanamido) propanoic acid (2.28a) Orange crystal s ; y ield = 89%; m. p. 166 168 C; 1 H NMR (CD 3 COCD 3 d 6 ) : 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), 7.1 9 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); 13 C NMR (CDCl 3 ) : 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 C 22 H 21 N 2 O 5 : [M +H] + 393.1445, found 393.1601.

PAGE 56

56 (S) 2 ((S) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 3 phenylpropanamido) 3 methylbutanoic acid (2.28b) Red cry s tal s ; y ield: 81%; m. p. 175 177 o C; 1 H NMR (CD 3 COCD 3 d 6 ) : 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); 13 C NMR (CD 3 COCD 3 d 6 ) : 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 C 24 H 25 N 2 O 5 : [M+H] + 421.1758, found 421.1778. ( S ) 2 (( S ) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 3 phenylpropanamido) 3 (1H indol 2 yl)propanoic acid (2.28c) Red crystal s ; y ield: 81%; m. p. 215 217 o C; 1 H NMR (DMSO d 6 ) : 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 H z, 1H), 7.97 (d, J = 7.5 Hz, 1H), 8.65 (d, J = 8.1 Hz, 1H), 10.87 (s, 1H); 13 C NMR (DMSO d 6 ) : 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,

PAGE 57

57 132 .3, 132.6, 134.8, 136.0, 136.9, 147.2, 169.6, 172.8, 180.9, 181.6; HRMS calcd for C 30 H 26 N 3 O 5 : [M+H] + 508.1867, found 508.1886. ( S ) 2 (( S ) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 4 methylpentanamido) 3 (1H indol 2 yl)propanoic acid (2.28d) Red crystal s ; y ield: 81%; m. p. 223 225 o C; 1 H NMR (DMSO d 6 ) : 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 (d d, J = 7.8 & 1.2 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 10.81 (s, 1H); 13 C NMR (DMSO d 6 ) : 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 C 27 H 27 N 3 O 5 : 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 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 4 methylpentanamido) propanoic acid (2.28e) Orange crystal s ; y ield: 89%; m. p. 172 174 o C; 1 H NMR (DMSO d 6 ) : 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

PAGE 58

58 (t, J = 7.5 Hz, 1H), 7.9 3 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 6.9 Hz, 1H); 13 C NMR (DMSO d 6 ) : 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 C 19 H 23 N 2 O 5 : [M+H] + 359.1601, fou nd 359.1596. ( S ) 2 (( S ) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 4 methylpentanamido) 5 methoxy 5 oxopentanoic acid (2.28f) Red crystal s ; y ield: 81%; m. p. 153 155 o C; 1 H NMR (DMSO d 6 ) : 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 = 7.2 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H); 13 C NMR (DMSO d 6 ) : 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 C 22 H 27 N 2 O 7 : [M+H] + 431.1813 found 431.1816. ( S ) 2 (( S ) 2 ((1,4 d ioxo 1,4 dihydronaphthalen 3 yl)amino)propanamido) 3 (1H indol 3 yl)propanoic acid (2.28g)

PAGE 59

59 Red crystal s ; y ield: 82%; m. p. 243 245 o C; 1 H NMR (DMSO d 6 ) : 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 (d, J = 8.1Hz, 1H), 10.85 (s, 1H); 13 C NMR (DMSO d 6 ) : 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 C 24 H 21 N 3 O 5 : 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 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 3 (1H indol 3 yl)propanamido) 4 methylpenta noic acid (2.28h) Orange crystal s ; y ield: 79%; m. p. 114 120 C; 1 H NMR (DMSO d 6 ) : 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 = 7.8 Hz, 1H), 10.89 (s, 1H); 13 C NMR (DMSO d 6 ) : 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,

PAGE 60

60 132.3, 132.7, 134.8, 136.1, 147.3, 170.2, 173.7, 181.0, 181.5; Anal. Calcd for C 27 H 27 N 3 O 5 : 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 (1 H indol 3 yl)propanamido) 5 methoxy 5 oxopentanoic acid (2.28i) Yellow crystal s ; y ield: 76%; m. p. 104 111 C; 1 H NMR (DMSO d 6 ) : 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, 1H), 10.88 (s, 1H); 13 C NMR (DMSO d 6 ) : 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 C 27 H 25 N 3 O 7 : 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 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 3 (1H indol 3 yl)propanamido) 3 phenylpropanoic acid (2.28j) Yellow crystal s ; y ield: 81%; m. p. 121 123 C; 1 H NMR (DMSO d 6 ) : 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)

PAGE 61

61 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, 1H), 7.90 7.94 (m, 2H), 8.70 (d, J = 7.2 Hz, 1H), 10.88 (s, 1H); 13 C NMR (DMSO d 6 ) : 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 C 30 H 25 N 3 O 5 : C, 70.99; H, 4.96; N, 8.28. Found: C, 71,26; H, 5.29; N, 7.85. HRMS calcd for C 30 H 26 N 3 O 5 : [M+H] + 508.1867, found 508.1886. ( S ) 2 (( S ) 2 ((1,4 D ioxo 1,4 dihydronaphthalen 3 yl)amino) 4 methylpentanamido) 3 phenylpropanoic acid (2.28k) Red cry s tal s ; y ield: 78%; m. p. 161 164 C ; 1 H NMR (DMSO d 6 ) : 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); 13 C NMR (DMSO d 6 ) : 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 C 25 H 27 N 2 O 5 : [M+H] + 435.1914; found 435.1934. General procedure for preparation of 2 (cyclohexylthio)cyclohexa 2,5 diene 1,4 dione (2.29) Cyclohexyl mer captan (4.9 mL, 40 mmol) in MeOH (5 mL) was added

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62 dropwise to a suspension of 1,4 benzoquinone (8.67 g, 81 mmol) in MeOH (50 mL), and the mixture was stirred at 20 o C for 2 h. Water (100 mL) was added, and the resulting precipitate was collected by filtrat ion. The orange crystals were recrystallized from CH 2 Cl 2 /MeOH to give the pure form of ( 2.29 ). 2 (Cyclohexylthio)cyclohexa 2,5 diene 1,4 dione (2.29) Brown crystal s ; y ield: 80%; m. p. 104 106 o C ( l it. m. p. 102 106 o C ) ; [ 1991JOC5808 ] 1 H NMR (CDCl 3 ) : 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, 2.1 Hz, 1H), 6.81 (d, J = 10.2 Hz, 1H); 13 C NMR (CDCl 3 ) : 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 benzoquinon e amino acid conjugates (2.31a b ) To a solution of 2 (cyclohexylsulfanyl) p benzoquinone ( 2.29 ) (0.22 g, 1 mmol) in (MeCN:H 2 O 6: 3mL) at RT, a solut ion 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 stirr ed for 3 h at RT. Acetonitrile was removed under reduced pressure, and the residue was purified by flash chromatog raphy on silica gel eluting with chlorof orm/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 4 N aqueous HCl

PAGE 63

63 ( R ) 2 ((4 (C yclohexy lthio) 3,6 dioxocyclohexa 1,4 dien 1 yl)amino)propanoic acid (2.31a ) Red microcrystals; y ield: 63%; m. p. 139 141 o C ; 1H NMR (CDCl 3 ) : 1.21 2.12 (m, 13H), 3.0 3.28 (m, 1H), 3.93 (t, J = 6.3 Hz, 1H), 5.42 (s, 1 H), 6.22 (s 1H), 6.72 (bs, 1H); 13C NMR (CDCl3) : 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 C 15 H 19 NO 4 S (309.39): C, 58.23; H, 6.19; N, 4.53. Found: C, 58.34; H, 6.33; 4.33. 2 ((4 (C yclohexylthio) 3,6 dioxocyclohexa 1,4 dien 1 yl)amino)propanoic acid (2.31a+2.31a ') Deep br own microcrystals; y ield: 63%; m. p 140 141 o C ; 1 H NMR (CDCl 3 ) 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), 6.52 (d, J = 6.9 Hz, 1H), 8.55 (bs, 1H). 13 C NMR (CDCl 3 ) : 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 C 15 H 19 NO 4 S (309.39): C, 58.23 ; H, 6.19; N, 4.53. Found: C, 58.34; H, 6.33; 4.3 3. ( S ) 2 ((4 (cyclohexylthio) 3,6 dioxocyclohexa 1,4 dien 1 yl)amin o) 3 phenylpropanoic acid (2.31b )

PAGE 64

64 Red crystals ; yield: 71%; m. p. 127 129 o C; 1 H NMR (DMSO d 6 ) : 1.00 1.58 (m, 6 H), 1.58 1.70 (m, 1H), 1.70 1.80 (m, 2 H) 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, 1H); 13 C NMR (DMSO d 6 ) : 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 C 21 H 27 NO 6 S (421.52): C, 5 9.84; H, 6.46; N, 3.32. Found: C, 60.33; H, 5.85; 3.16. General procedure for preparation of benzot riazole activated t hiosubstituted benzoquinone amino acid conjug ates (2.32a +2.32 a '). Benzotriazol (0.17 g, 1.4 mmol) and thionyl chloride 0.05 g (0.39 mmol) were dissolved in DCM (10 mL) at 25 o C and stirred for 10 min. 2 (4 C yclohexylsulfanyl 3,6 dioxo cy clohexa 1,4 dienylamino) propionic acid ( 2.31 a + 2.31 a ) (0.15 g, 0.35 mmol) was added to the solution The reaction mixture was stirred at 15 o C for 5 h then at RT overnight. The reaction mixture was filt er d and dichloromethane was evaporated under redu ced pressure to give the crude residue, which was subjected to column chromatography with dichloromethane to yield a stable crystalline racemic acylbenzotriazole ( 2.32 a + 2.32 a ), which was re crystallized 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 (2.32 a +2.32 a ')

PAGE 65

65 Red crystals; y ield: 65%; m. p. 172 174 o C. 1 H NMR (DMSO d 6 ) : 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 (d, J = 6.9 Hz); 13 C NMR (DMSO d 6 ) : 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 C 21 H 24 N 4 O 4 S H 2 O (428.51): C, 58.86; H, 5.65; N, 13.07; found: C, 59.38; H, 5.18; N, 13.10.

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66 CHAPTER 3 1,3,4 OXADIAZOLES FROM FUCTIONAL IZED N ACYLBENZOTRIAZOLES A ND ACYLHYDRAZIDES 3.1 Introduction 3.1.1 Oxadiazoles Oxadiazoles are heterocyclic aromatic compounds consisting of fused 5 membered ring s containing two carbons, two nitrogen atoms and one oxygen atom The four possible oxadiazol es (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 o xadiazole moiety is an important structural class in medicinal chemistry due to its widespread use a s a pharmacophore. [ 2006JOC9548, 2006T10223, 2006TL105, 2006TL4827, 2006TL6497, 2007EJMC235, 2007EJMC893, 2007EJMC934 ] O xadiazoles of type ( 3.1 ), amino oxadiazoles of type ( 3.2 ) [2006JOC9548], and oxadiazolinethiones of type ( 3.3 ) [1988IJC(B)542] w er e reported with demonstrated b acteri cidal and/or fungicidal activities. The tin derivative ( 3.4 ) is a useful fungicide and the t hione derivative ( 3.5 ) shows antimicrobial activities Diaryloxadiazoles ( 3.6 ) possesses certain anti inflammatory, sedative an d analgesic properties. [1984FES414] Amino oxadiazoles ( 3.7 ) show a nalgesic activity and amino oxi dazoles ( 3.8 ) exhibit both anti inflammatory and antiproteolytic properties. [1989JPS999] Anticonvulsant and nervous system depressant activity was reported f or amino oxadiazoles ( 3.9 ), where R

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67 is quinazolin 3 yl group. [1991PHA290] Amino oxadiazoles ( 3.10 ) show local anesthetic activity. [1983JIC575] O xadiazolinone ( 3.11 ) is an orally active antiallergic agent, for example in the treatment of asthma or allergi es and is claimed to be more potent than sodium cromoglycate. [1984JMC121] O xadiazolinones ( 3.12 and 3.13 ( 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 aromati c 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

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68 aromatic diamines and oxadiazole dialdehydes. [ 1990JPS(A)3647 ] The activating effect of the oxadiazole ring in 4 fluorophenyl and 4 nitro phenyl 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 lumines cent 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. [1990JHC168 5] 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 ) [ 1984G PO3245202] and 1,4 bis (5 phenyl 1,3,4 oxadiazol 2 yl)naphthalene [ 1983 GPO3126464 ] 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 el ectroluminescent devices. [1991CL285] 1,3,4 Oxadiazoles were recently tested for their possible use in organic light emi tting diodes (OLED). [ 2007 USP085073 2007DP641, 2007DP753 ]

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69 Figure 3 4 1,3,4 Oxdiazoles with interes ting optical properties 3.1.5 Other Miscellaneous Applications Fu n ctionalized 1,3,4 o xadiazoles are also i mportant starting materials for a variety of cycloaddition reactions [2007JFC740] especially for the synthesi s of furans and natural products [2002JO C7361]. Key cycloaddition cascade reactions of 1,3,4 oxadiaozle moieties were applied in the total synt hesis of Vindoline and related a lkaloids (Scheme 3 1). [2006JACS10596] Scheme 3 1. Cycloaddition reactions of 1,3,4 ox adiazole s in total synthesis of natural product

PAGE 70

70 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 w ith alkanes (Figure 3 5). 4,4' C arbonylbis (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 f or 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 agent s including chlorosulfonic acid [1983MI406 01] or phenyl dichlorop hosphite [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

PAGE 71

71 The cyanohydrazones ( 3.27 ), on heating in dimethyl sulfoxide, cyc lized 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 ). [1985T 5 187] Scheme 3 3 Preparation of 2,5 disubstituted 1,3,4 oxadi azoles from hydrazones Treating allyl esters ( 3.31 ) with DIPEA forms oxadiazolinones ( 3.33 ), probably via Claisen rearrangement of an initially formed oxadiazolinone ( 3.32 ) intermedia te (Scheme 3 4 ). [1988JOC38 ] Scheme 3 4 P reparation of 1,3,4 oxadiazol inones Important routes to monosubstituted oxadiazoles ( 3.34a ), amino oxidazoles ( 3.34b ), oxadiazolinones ( 3.35a ), and oxadiazolinethiones ( 3.35b ) involve reaction of hydrazides R 1 CONHNH 2 with triethyl orthoformate, cyanogen bromide, phosgene, or carbon di s ulfide (or CSCl 2 ) respectively. Reaction of hydrazide ( 3.36 ) with triethylorthoformate, or with CS 2 /KOH, allowed the synthesis of oxadiazole ( 3.37) (Scheme 3 5) [1982M C 793]

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72 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 thiosemi carbazide ( 3.39 ), which is readily prepared by acylation of a given hydrazide ( 3.38 ) with the approp riate isothiocyanate (Scheme 3 6 ). [2006JOC9548] Scheme 3 6 Preparation of 2 amino 1,3,4 oxadiazoles 1,3,4 Oxadiazoles a re most commonly prepared by the coupling of acylhydrazides with carboxylic acids followed by a dehydration step. [2006JOC9548, 2006SC3287, 2006TL105, 2006TL4827, 2006TL6497, 2006T10223, 2007TL1549 2007SC1201]

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73 Rajapakse reported a mild and efficient one p ot 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 pyrid ine ( 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 o f carboxylic acids [2005SL1656 ] and have been applied to (i) N acylation, (ii) O acylation, [2006S4135] (iii) C acylations, [2006TL3767] [2005JOC4993] [2005JOC77 92, 2005ARKIVO C329 ] 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,

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74 [2007JOC5802] (xiii) heteroaro matics [2000JOC8069] and (xiv) het erocycles. [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 CBr 4 (1 mmol) and Ph 3 P (1 mmol) at R T for 12 h gave 2 phenyl 5 (( E ) styryl) 1,3,4 oxadiazole ( 3.46a ) in 84% yiel d (23% yield in [2006TL4827]). The 1 H NMR spectra of ( 3.46a ) showed the disappearance of the Bt signals in the aromatic region, indicating the loss of the benzotriazolyl group duri ng the reaction. The 13 C 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 benzot riazolyl 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 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

PAGE 75

75 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 yl methanone ( 3.45e ) with benzoic acid hydrazi de 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 ), 1 H benzotriazol 1 yl(1 hydroxy 2 naphthalenyl) methanone ( 3.45g ) and 1 H 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 ( 3.46 f ), 2 (5 phenyl 1,3,4 oxadiazol 2 yl) naphthalen 1 ol ( 3.46 g ) and novel 4 bromo 2 (5 phenyl 1,3,4 oxadiazol 2 yl) phenol ( 3.46 h ) in 86%, 66% and 89% yield s respectively (Table 3 1). Scheme 3 8 1,3,4 Oxadiazoles from N ac ylbenzotriazoles 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.

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76 Table 3 1 Reaction of N acylbenzotriazoles with benzoic acid hydrazide Entry Product Product Structure Yield a ( % ) 1 3.46a 84 b 2 3.46b 82 3 3.46c 79 4 3.46d 73 5 3.46e 76 6 3.46f 86 7 3.46g 66 8 3.46h 89 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 uncor rected. 1 H (300 MHz, with TMS as the internal standard) and 13 C NMR (75 MHz) NMR spectra

PAGE 77

77 were recorded in CDCl 3 Elemental analysis was carried out in an Eager 200 CHN analyzer. 3.4.1 General Procedur e for the Preparation of 1,3,4 O xadiazole 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 CBr 4 (332 mg, 1 mmol) and Ph 3 P (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 oxadiazole s ( 3.46a h ) in 66 89% yield. 2 Phenyl 5 (( E ) styryl) 1,3,4 oxadiazole (3.46a) White microcrystals; y ield : 104 mg (84%); m. p. 125 127 o C (lit. m. p. 128 130 o C [2006TL4827]); 1 H NMR (300 MHz, CDCl 3 ) : 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); 13 C NMR (75 MHz, CDCl 3 ) : 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 thioph en 2 yl vinyl) 1,3,4 oxadia zole (3.46b) Yellow microcrystals; y ield : 104 mg (82%); m. p. 110 114 o C; 1 H NMR (300 MHz, CDCl 3 ) : 8.13 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 16.2 Hz, 1H),

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78 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, 3.7 Hz 1H), 6.91 (d, J = 16.1 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 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 C 14 H 10 N 2 OS: 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; y ield : 94 mg (79%); m. p. 115 117 o C ( lit. m. p. 118 119 o C [1995CHC208]); 1 H NMR (300 MHz, CDCl 3 ) : 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, J = 3.3 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 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 C 14 H 10 N 2 O 2 : 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; y ield : 94 mg (73%); m. p. 129 130 o C; 1 H NMR (300 MHz, CDCl 3 ) : 8.13 8.10 (m, 2H), 7.68 7.65 (m, 2H), 7.60 7.40 (m, 6H); 13 C NMR (75 MHz, CDCl 3 ) : 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 C 16 H 10 N 2 O: C, 78.03; H, 4.09; N, 11.38. Found: C, 77.75; H, 4.07; N, 11.28.

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79 2 (5 Phenyl 1,3,4 oxadiazol 2 yl)naphthalen 2 ol (3.46e) White microcrystals; y ield : 219 mg (76%); m. p. 196 198 o C; 1 H NMR (300 MHz, CDCl 3 ) : 11.13 (bs, 1H), 8.4 8 (d, J = 7.7 Hz, 1H), 8.18 8.16 (m, 2H), 7.84 7.80 (m, 2H), 7.63 7.56 (m, 5H), 7.47 (d, J = 8.6 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 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 C 18 H 12 N 2 O 2 : 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; y ield : 125 mg (86%); m. p. 255 25 6 o C; 1 H NMR (300 MHz, CDCl 3 ) : 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, CDCl 3 ) : 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 C 15 H 13 ClN 2 O 2 : 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)

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80 Pale green microcrystals; y ield : 190 mg (66%); m. p. 196 198 o C; 1 H NMR (300 MHz, CDCl 3 ) : 11.13 (bs, 1H), 8.48 (d, J = 7.7 Hz, 1H), 8.18 8.16 (m, 2H), 7.84 7.80 (m, 2H), 7.63 7.56 (m, 5H), 7.47 (d, J = 8.6 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 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 C 18 H 12 N 2 O 2 : 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; y ield : 282 mg (89%); m. p. 146 148 o C; 1 H NMR (300 MHz, CDCl 3 ) : 10.15 (bs, 1H), 8.08 (d, J = 6.6 Hz, 2H), 7.87 (d, J = 2.2 Hz, 1H), 7.57 7.44 (m, 4H), 6.98 (d, J = 8.9 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) : 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 C 14 H 9 BrN 2 O 2 : C, 53.02; H, 2.86; N, 8.83. Found: C, 52.69; H, 2.79; N, 8.54.

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81 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 NH 2 Y = OH or NH 2 an d R is a linear side chain, carbocycle residue or heterocyc le residue (Figure 4 1). Compound ( 4. 2 4. 3 and 4. 4 ) can all be considered as amidines in which one of the hydrogen atom s 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. R eviews published on the synthetic and biological application s of amidrazones and amidoximes [1962CR 155, 1970CR15 1, 1989CHC717, 2008CPD1001] do not cover N hydroxyamidoximes, N aminoamidoximes and hydrazidines and their preparative methods, synthetic utilit y and biological applications The fol lowing attempts to re ddress 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 buildi ng blocks for t he construction of heterocycles; [1955HCA1560] from the limited number of N h ydroxyamidoximes 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 subst ituted derivatives ( 4. 7 4. 8 )

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82 Figure 4 1. Structure s of N hydroxyamidoximes, N aminoamidoxime s and hydrazidine s 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, 196 6JOC157, 2000TJC1 2004S2877]

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83 Hydrazidines form a class of chemical compounds with the general formula RC(NHNH 2 ) =NNH 2 ( 4.4 ) (Figure 4 4), and are derived from carboxylic acids by replacing OH with NHNH 2 (or N substituted analogues) and =O with =NNH 2 ( 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 group s 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., t here are 24 examples of imidazole ( III ), benzimidazole ( IV ) and triazole ( V ) analogues, and 33 examples of type ( I ) and substituted hydrazidines ( II ) but these hete ocycles 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 de rivatives 4.2 Structure and Configuration 4.2.1 N Hydroxyamidoxime s N Hydroxyamidoximes ( 4.2 ) are sometimes named as N,N' dihydroxyimidamides or oxyamidoximes. [1962CR155] S ystematic studies reported with respect to configurations or conformations of the m any classes of N hydroxyamidoximes are so far limited to N hydroxybenzamidoxime ( 4.2a ). Clement et. al. studied and compared

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84 chemical shifts and coupling constants J ( 15 N, 1 H) of several amidoximes with N hydroxyamidoxime ( 4.2a ) via 15 N NMR. As observed b y the 15 N 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 15 N si gnals 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 an d found that the Z configuration ( 4.2 Z ) is favored energetically over configuration ( 4.2 E ), 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.

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85 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 paper s depict them as structure ( 4.3a ) rather than ( 4.3b ). Again, b ased 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 kn owledge, 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). Fi gure 4 7. Configuration of hydrazidines

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86 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 hydrox ylamine 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 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. [1914Ber294 1] 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

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87 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] Sche me 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 hydroxyam idoxime 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 N 2 hydroxyamidinyl N 1 oximes ( 4.12a d ), namely N hydroxyamidoxime in 45 68% yield (Scheme 4 5). [1975CB 2764]

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88 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 hydrox ymethylamidoxime 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 methylhydro xylamine ( 4.17 ) under pressure gave two products ( 4.18 ) and ( 4.19 ), a di O methylsubstituted p sulfamido N hydroxybenzamidoxime (Scheme 4 7). [1962CR155]

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89 Scheme 4 7. Synthesis of di O methy lsubstituted 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=NH 2 ) 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 Amin o N nitrophenyl benzamidoxime (4.23 ) was prepared by Katritzky et. al. by the reaction of 1 H 1,2,3 benzotriazol 1 ylme thanone 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

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90 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 ) (S che me 4 2 4 ), 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 deriv atives

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91 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 tempe ratures below hydrazidine ( 4.4 ) was isolated, while at elevated temperatures (40 50 ) other cyclic by products were produced (Scheme 4 13). [1931MC106, 1976T1031] Scheme 4 13. Synthesis of aliphatic hydrazidines The use of monos ubstituted hydrazines ( 4.32 ) reduce s the number of by products, and react s 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 substitut ed formazans ( 4.33 ) are obtained when excess hydrazine ( 4.32 ) is employed (Scheme 4 14). [1884Ber182, 1954JCS3319, 1955JPSJ726, 1956JCS2853, 1955CRV355]

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92 Scheme 4 14. Synthesis of substituted formazans 4.3.3.2 From amidoxi mes 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 o C give s 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 ) w ith hydrazine ( 4.32a ) at low temperature. The t riazole ( 4.40 ) was formed as a by product in this hydrazinolysis when the temperature was above 40 o C (Scheme 4 17) [1967JCS(C)742]

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93 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 me dication 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 t he reaction of hydrazonyl bromid e ( 4.45a f ) and hydrazine hydrate in alcohol formed hydrazidines ( 4.46a f ). The React ion 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]

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94 Scheme 4 19. Synthesis of hydrazidines from hydrazonyl bromide 4.3.3.6 From triazines Grundmann discovered that s t riazine ( 4.50 ) react ed 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 a nd 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]

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95 Scheme 4 21. Conversion of N hydroxybenamidoxime into benzamidoxime 4.4.1.2 Oxidation of N hydroxyamidoximes Armand and Minvielle also found that f ormic hydroxyamidoxime ( 4.55 ), which is amphoteric, can be oxidized by KIO 4 to potassium salt of nitrosol ic 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, ga ve the azo derivative ( 4.57 ) which disproportionated to benzamidoxime ( 4.34 ) a nd the deep blue potassium salt of benzonitrosolic acid ( 4.58 ). [2007COC959]

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96 Scheme 4 23. Synthesis of 3 ,5 diphenyl 1,2,4 oxadiazole Sheremet ev et. al. oxidized nitrosolic acid salts ( 4.58a b ), derivatives of of N hydroxyamidoxime to nitrolic acid ( 4.62a b ) with dinitrogen tetraoxide (N 2 O 4 ) 3,4 Diphenylfuroxan ( 4.60 ) was prepared by treating phenylnitrosolic acid silver ammoniate salt ( 4.58c) with two equivalents of N 2 O 4 (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 prec ursors to the preparation of 4 hydroxyoxadiazolines ( 4.64 ) (Scheme 4 25). [1978RRC203]

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97 Scheme 4 25. Synthesis of 4 hydroxyoxadiazolines 4.4.1.4 Reaction with ketones Desherces et. al. also found that ( Z ) N hydroxybenzamid oxime ( 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 sydn onyl 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 ) ga ve 5 alkyl 3 (3 arylsydnon 4 yl) 1H [1,2,4]triazoles ( 4.69a c ) (Scheme 4 27). [2004S2877]

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98 Scheme 4 27. Preparation of 3,5 disustitued 1 H [1,2,4]triazoles 4.4.2.2 Cyclization in basic media to hydroxytriazoles Another N am inoamidoxime 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) 4 H 1,2,4 triazol 4 ol ( 4.70 ) (Scheme 4 28). [1986JSCT9] Schem e 4 28. Synthesis of 3 benzyl 5 ( p tolyl) 4 H 1,2,4 triazol 4 ol Ikizler et. al. discovered that N aminoamidoxime derivative ( 4.30 ) (Schem e 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 (Sc heme 4 29). [1992MC257]

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99 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 us ed 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 h ydrazidine 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. a l 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

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100 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 Reac tion with anhydrides Neunhoeffer et. al. reported that h ydrazidines can react with anhydrides to pr oduce 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 derivative s ( 4.89 ), ( 4.90 ) and ( 4.91 ). The r eaction 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(4 H ) one hydrochloride ( 4.83 ). [1975CB3509] Other heterocycles ( 4.93, 4.94 and 4.95 ) were

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101 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

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102 4.4.3.3 Reaction with diketones Hydrazidines have been studied for the generation of different fused and nonfused six membered heterocyclic sys tems 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 hydrazidin e ( 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 ins tead. Similarly, ( 4.4a ) on react ion 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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103 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(4 H ) 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 keto esters ( 4.115a c ) (Scheme 4 34). [1992LAC115]

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104 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 tr iazine ( 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 di hydro 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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105 heteroaromatic system s such as 3,4 dihy droxy 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 dime thylester ( 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 Et 3 N, 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 dime thyl 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]

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106 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 f orm. (Scheme 4 38). [1977BCSJ953]

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107 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 methylis othiocarbonohydrazide hydroiodid e ( 4.132 ) to form dihydrotetrazines ( 4.134 ) which can be oxidized to (meth ylthio)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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108 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 derivativ e ( 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 R eduction of hyd razidines 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. Re duction of formazans

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109 Regitz and Eistert used p henylhydrazine to reduce formazan ( 4.139b ) to amidrazone ( 4.140b ) at 50 100 o C (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 m ethods 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 oxid ized back to the formazan ( 4.139c ) on exposure to air. Lithium aluminum hydride (LAH) has no effect on triphenylformazan ( 4.139c ) in ether tetrahydrofuran (Et 2 O THF) at room temperature (RT) but cleaves it on boiling for several hours, giving the correspon ding amidrazone ( 4.140c ). [1952CB470] 4.4.3.12 halo ketones Beyer et. al. bromo ketones ( 4.145 ) with N,N' diaminoguandine / aminohydrazidine ( 4.146 ) gave the condensation product ( 4.147 ) (Scheme 4 42). [1968CB29] S cheme 4 42. Reaction of halo ketones with hydrazidine amine

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110 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 h ydrazidines. 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 th e 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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111 4.5 Applications 4.5.1 N Aminoamidoximes 4.5.1.1 As a prodrug model Clement and Reeh reported that drugs containing amidine function s 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 fu nctions, 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 bioa vailability 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 synt hesis 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 NH 3 or by oxidation with KIO 4 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 nitrodicyanomet hanide, [(O 2 N)C(CN) 2 ] are predicted as potential propellants similar to

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112 nitrite and nitrate salts respectively based on theoretical calculations. [1999IC2709] Brand et. al. developed a two step synthesis of DNM salts (DNM = dinitrosomethanide) from for mamidinium nitrate. Treating a methanolic solution of ( 4.156 ) and hydroxylammonium nitrate ( 4.157 ) (2 equiv) with a methanolic solution of KO t Bu (2 equiv) resulted in the formation of the labile intermediate dihydroxyformamidinium nitrate ( 4.158 ) (Sch eme 4 46). The reaction of ( 4.158 with MO t Bu (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 derivative s 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 ) show ed a strong stabilization of Fe(I I) 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 ethylnitro solic 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 aldeh yde s

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113 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 ). (Sch eme 4 47 & 4 48). [2005TJC107, 2006TJC563] vic Diox imes 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 exc hange chromatography, analytical chemistry, catalysis, pigments and dyes. [1974CCR1] vic Dioximes complexes are model coordination compounds for studying the structure of vitamin B 12 and coenzyme B 13 which have important roles in biology. [2003JMS647] Scheme 4 47. Synthesis of novel vic dioxime derivatives of hydrazones

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114 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 amino benzamidoxime and studied its spectroscopic / electrochemical properties. [2006IJC1126] Figure 4 10. N Aminobenzamidxoime cobalt(II) perchlo rate 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 o f 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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115 adsorbents bearing hydrazidine (POLYORGS 35) groups have been studied with respect to heavy and noble methods. It wa s 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 preconcentr ation 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 h ydrazidine der ivative ( 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 bi nd to metal s such as Cu, Fe, Ni, Co, and they have important applications in t he textile industry. [2000EPA10, 2007DP8 1995TCC13 1989EPA315046A2] C opper complexes of some hydrazidine derivatives, e.g. bis(o hydroxyphenyl) C phenylformazan ( 4.169 ) a re suitable agents for the dyeing of protein fibers in neutral or slightly acid media, and t hey have fairly s trong affinity to wool [1959ICBS532] Freeman et. al. synthesized some Fe complexed hydrazidine derivatives ( 4.170 4.171 ) as environmentally frie ndly dyes (Figure 4 11). They can substitute metals such as Cr and Co without adversely affecting technical and mutagenic properties, again offering applications in th e textile industry. [1995TCC13, 2007DP8]

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116 Figure 4 11. E nvironmental 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 a s 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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117 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 interm ediates, 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. 1 H Benzotriazole and its derivatives are known and used as impo rtant synthetic auxiliaries in heterocyclic synthesis. Many important aspects of 1 H benzotriazole chemistry have been explored over the last 30 years. My graduate studies aimed to further apply the benzotriazole methodology to synthesize different heterocy clic compounds with important applications. To summarize, Chapter 1 provides an overview of 1 H benzotriazole methodology and some recent applications of 1 H benzotriazole and its derivatives in heterocyclic synthesis. In Chapter 2, an efficient N acylbenzot riazole 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 a cylbenzotriazole methodology. Chapter 4 provides a systematic review of the structure, synthesis, reactivity and utility of N hydroxy and N amino amidoximes and hydrazidines, which are important classes of nitrogen rich building blocks. Apart from the ab ove mentioned work I participated in and completed the synthesis and studies of the mechanical property of highly filled crosslinked poly triazoles which is described in Appendix A

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118 APPENDIX A HIGHLY FILLED CROSSL INKED 1,2,3 TRIAZOLE POLYMERS AS NOVEL R OCKET 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 oxidi zers. [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 pol ymeric 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 polybu tadiene (HTPB) (Figure A 1). Recently, 1,2,3 triazole polymers prepared via 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 propel lant binders. [2008JPS(A)PC238, 2001HPP313 1992EPA481838 ] Figure A 1. Common rocket propellant binders Reproduced in part with permission from Jounal of Applied Polymer Sciences 2010 117, 121 127. Copyright 2010 John Wiley and Sons.

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119 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 polymeriz ation 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 physi cal 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 No vel 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 cyc loaddition 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 lo w temperature curing and heat resistant poly triazole resins as adv anced composites. [2007PAT556, 2007JAPS1038, 2007JMS ( PA ) PAC175] Our group has developed

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120 strategies for low temperature synthesis of oligo triazoles as binder ingredients. [2006ARKIVOC43] Tr iazole 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 me et the requirements of the specification of rocket propellant binders, the monomers are required to polymerize at low temperatures (room temperature to 60 o 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 prefer entially 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 a ddition 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 polyme rs. 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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121 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 inves tigate the relationship between crosslinker concentration and mechanical properties of unfilled and filled triazole polymers in terms of elongation strain (% elongation at break) and Another aim of the project was to inv estigate 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 modu lus, 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 f illers [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 fille r that improves mechanical, electrical and thermal properties of polythiourethane modified epoxy adhesives

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122 [2008POC133], low density polyethylene (LDPE) [2007JAPS2436] and high density polyethylene (HDPE) composites [2006JAPS2161], natural rubber (NR) comp osites [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 si ze 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 po lymer matrices. [2004JAPS2144, 1999JAPS1133, 2004P7579] Ozkar et. al. systematically studied the effec t 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 tria zole 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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123 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 whi le using aluminum (10 14 micron ) as the main filler, has a diminishing effect on the modulus and strain of the crosslinked triazole polymers. T riazole 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 ox idizer, 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 (espec ially 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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124 desired mechanical properti es 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 re quired 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 di azide ( 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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125 (>200g each) follow in g 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 mi xing 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 elasti modulu s) 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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126 Figure A 2. Dogbone mold containing filled and unfilled triazole polymers Fi gure 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. Re ena 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 continuat ion 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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127 dipropi olate ( 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 crossl inked 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: t he 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 s amples 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 specific ally 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 po lymers are summarized in Table A 1. [ 2010JAPS121 ] Table A 1. Strain and modulus of unfilled and filled crosslinked triazole polymers Entry Crosslinker concentration (mol %) Filler wt% (Al : 10 14 micron) Strain (%) Modulu s (MP a) 1 6 0 683 0.044 2 6 43 441 0.267 3 8 0 338 0.174 4 8 43 171 0.898

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128 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 sy stematically increased (Scheme A 1) from 34.18 to 74.14 weigh t 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 o C 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 stra in values of these two sets of filled gumstock samples with the increase in filler loading. T able A 2. Effect of filler loading (Al: 10 14 micron) on strain and modulus of crosslinked triazole polymers Entry Crosslinker concentration (mol %) Filler Wt % (Al : 10 14 micron) Strain (%) Modulus (MP a) 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 cros slinked triazole polymers Entry Crosslinker concentration (mol %) Filler Wt % (Al : < 75 micron) Strain (%) Modulus (MP a) 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

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129 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 th e modulus increased from 0.64 MPa to 13.68 MP a as the aluminum with particle size 10 14 micron is loaded from 34.2 to 74.2 w t. 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 t o 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 p ropylene 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 MP a) 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]

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130 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 crossli nked triazole polymers. (Table A 1 & A 2, Figure A 5). The strain of the filled crosslinked triazole polymers decrease s 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 res pectively). 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.

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131 Figure A 5. Effect of filler loading on strain of crosslinked triazole polymers The studies were ext ended 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 si ze 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.

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132 Table A 4. Effect of fil ler loading (NaCl: 45 50 micron ) on strain and mo dulus of mechanical properties of crosslinked triazole polymers Entry Crosslinker concentration (mol %) Filler Wt% (NaCl: 45 50 micron ) Strain (%) Modulus (MP a) 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 fill er loading (NaCl: 83 105 micron ) on strain and modulus of crosslinked triazole polymers Entry Crosslinker concentration (mol %) Filler Wt% (NaCl: 83 105 micron ) Strain (%) Modulus (MP a) 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 o f 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 tot al filler content. The mixture of fillers was systematically incre ased separately (Scheme A 4) from 34.2 to 74.2 weight percent (Table A 2 & A 3) resulting in three separate s ets of gumstock samples (Table A 4, A 5, A 6, A 7 & A 8), which were cured and me chanically tested in the usual manner.

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133 Table A 6. Effect of mixed filler loading (mixture of two different particle sized Aluminum) on strain and modulus of crosslinked triazole polymers Entry Crosslinker concentration (mol %) Filler Wt % (Al : < 75 mi cron + Al: 10 14 micron )(1:1) Strain (%) Modulus (MP a) 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 s train and modulus of crosslinked triazole polymers Entry Crosslinker concentration (mol %) Filler Wt % (Al : 10 14 micron + NaCl: 45 50 micron)(1:1) Strain (%) Modulus (MP a) 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 Entry Crosslinker concentration (mol %) Filler Wt % (Al : 10 14 micron + NaCl: 83 105 micron)(1:1) Strain ( %) Modulus (MP a) 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 properti es 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

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134 general, the use o f Al (particle size < 75 micron ) and N a Cl (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. Figure A 6. Effect of mixed filler loading on modulus of crosslinked triazole polymers

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135 Figure A 7. Effect of mixed filler loading on strain of cro sslinked 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 polym ers 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 dipropiolat e 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

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136 of the crosslinker and filler, the triazole polymers with desired mechanical properties could be obtained. The mech anical 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. Overal l, 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 streng th 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 CDCl 3 or DMSO d 6 with TMS for 1 H (300 MHz) an d 13 C (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 tetr afunctional 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 syst ematically dried by azeotropic distillation and lyophilization. The uni axial test specimen was a standard micro tensile dogbone 8). [ 1992JPCE ] The dogbone mold containing filled and unfilled triaz o le polymers is shown in Figure A 2. Strain

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137 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 d ata 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 poly ethylene 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 r esidue was dissolved in CHCl 3 (150 mL) washed with saturated NaHCO 3 (70 mL), water (50 mL) and brine (50 mL). The chloroform layer was dried over anhydrous MgSO 4 filtered and the solvent was evaporated to give tetraethyleneglycoldipropiolate (13.94 g, 91% ) as yellow oil.

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138 Tetraethyleneglycoldiprop iolate (A 1) Yellow oil; yield: 13.94 g (91%); 1 H NMR (CDCl 3 ) : 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 (CDCl 3 ) : 65.2, 68.5, 70.6, 70.6, 74.5, 75.2, 152.6; Anal. Calcd for C 14 H 18 O 7 : C, 56.37; H, 6.08; Found: C, 56.07; H, 6.22. Preparation of 1 azido 2 {2 [2 (2 azid oethoxy)ethoxy]ethoxy}ethane (A 2). A mixture of tetraethylene glycol dimesylate (14.4 g, 41.43 mmol) and NaN 3 (10.77 g, 165.72 mmol) in 100 mL CH 3 CN /H 2 O (9:1) was refluxed at 80 o 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 azi doethoxy)ethoxy]ethoxy}ethane(A 2). Colorless oil; yield: 7.88 g (78%); 1 H NMR (CDCl 3 ) : 3.70 3.67 (m, 12H), 3.40 (t, J = 4.8Hz, 4H); 13 C NMR (CDCl 3 ) : 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. H 2 SO 4 (0.5 ml) in benzene (75 ml) was h eated under reflux using a Dean Stark apparatus for 12.5 h. The reaction mixture was cooled in ice and neutralized with solid Na 2 CO 3 filtered, washed with ether and the filtrate was evaporated to obtain a solid. The solid was dissolved in CH 2 Cl 2 (100 ml) washed with saturated NaHCO 3 (50 ml), water (50 ml) and brine (25 ml). The dichloromethane layer was dried over anhydrous MgSO 4 filtered and the solvent was evaporated to give pentaerythritol tetrapropiolate as a white powder.

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139 3 (Propioloyloxy) 2,2 bis[(p ropioloyloxy)methyl]propyl propiolate (A 3). White microcrystals; yield 6.5 g (51 %); 1 H NMR (CDCl 3 ) : 2.98 (s, 4H), 4.31 (s, 8H); 13 C NMR (CDCl 3 ) : 41.7, 63.3, 73.6, 76.4, 151.8; Anal. Calcd for C 17 H 12 O 8 : C, 59.31; H, 3.51; Found: C, 59.05; H, 3.57. Pro cedure for the p reparation 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 diss olve 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 (i ncluding 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 stoichiometri c ratios 1:1 The mixture was c ast 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 o C for 7 2 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 homogeneou s 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 o C for 1h. The mixture was then stirred again and cured at 55 o C for an additional 71 h.

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140 Procedure for the pr eparation 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. Unfilled Triazole Pol ymer ( P 1). Light yellow rubbery polymer; 1 H NMR (CDCl 3 ) : 3.56 3.67 (m, ( O C H 2 C H 2 O )), 3.81 3.95 (m, ( COO C H 2 C H 2 O) & ( triazole CH 2 CH 2 O )), 4.48 4.51 (m, ( C H 2 triazole )), 4.60 4.63 (m, (triazole COO C H 2 )), 8.34 (s, ( triazole H) ); 13 C NMR (CD Cl 3 ) : 50.4, 64.1, 68.9, 70.3, 70.4, 70.5, 77.2, 130.0, 139.7, 160.8. Anal. Calcd for C 26 H 42 N 6 O 12 : 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 o n 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 stoichio metric 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 min utes and then cured in an oven at 55 o C for 72 h. The dogbone samples were carefully removed from the mold. After the cooling, they were

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141 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

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147 Abstr., 101 173 038 (1984) [1985CB3481] B. Clement and T. Kampchen, Chem. Ber 118 3481 (1985). [1985LAC78] H. Neunhoeffer, G. Khler and H. J. Degen, Liebigs Ann Chem. 78 (19 85). [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) [1986J SCT 9] 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 5 42 (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).

PAGE 148

148 [1989CHC 717] K. N. Zelenin, O. V. Solod and V. A. Khrustalev, Chem. Heterocycl. Comp. 25 717 (1989). [1989EP A 315046A2] 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). [1990B 2538] 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). [1990JHC16 85] A. B. Theocharis and N. E. Alexandrou, J. Heterocycl. Chem. 27 1685 (1990).

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149 [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. Nakamu ra, 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. Simmond s 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 a nd 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).

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150 [1991RC T181] 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). [1992AJC51 3] 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/ASM E/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. Rachw al, 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). [1992LA C115] H. Neunhoeffer, U. Karafiat, G. Khler and B. Sowa, Liebigs Ann Chem 115 (1992).

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151 [1992M C257] 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. Het erocycl. 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). [1995JANYAS 402] 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).

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152 [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, Sy nthesis 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 an d J. Li, J. Org. Chem ., 61 1624 (1996). [1996LA C 745] 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 a nd J. Li, J. Org. Chem. 62 4148 (1997). [1997JP36] J. Louwers, J. Pyrotechnics 6 36 (1997). [1997TL6771] S. Fustero, B. Pina and A. Simn Fuentes, Tetrahedron Lett. 38 6771 (1997). [1998AA35] A. R. Katritzky and S. A. Belyakov, Aldrichimica Acta 31 35

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153 (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. Rah imipour, 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 an d 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). [19 99OL977] M. Garcia de la Torre, A. Navarro, C. Ramrez de Arellano and A. Simn, 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).

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154 [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. Che m. 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). [2000S20 29] 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,

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155 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). [20 02JOC4667] S. Fustero, B. Pina, E. Salavert, A. Navarro, M. C. Ramrez de Arellano and A. Simn Fuentes, J. Org. Chem. 67 4667 (2002). [2002JOC7361] S. E. Wolkenbe rg 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). [2003CE J4586] 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).

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156 [2003JOC5720] A. R. Katritzky, K. Suzuki, S. K. Singh and H. Y. He, J. Org. C hem ., 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. Katritz ky, 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).

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157 [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. M ed. 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. C hem ., 70 7792 (2005). [2005JOC9521] P. Brandi, C. Galli and P. Gentili, J. Org. Chem ., 70 9521

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158 (2005). [2005MRMC449] C. Asche, Mini Rev. Med. Chem ., 5 449 (2005). [ 2005SL 1656] A. R. Katritzky, K. Suzuki and Z. Wang, Synlett 1656 (2005). [2005S397] A. R. Katritzky, P. Angrish, D. Hr 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, A RKIVOC 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. Elliot t, J. Velcicky,Y. Choi and D L. Boger J A m. C he m. S oc., 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. Khel ashvili, and P. P.

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159 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). [2006JOC954 8] 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 (2 006). [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).

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166 BIOGRAPHICAL SKETCH Longch uan 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 undergraduat e 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 Manag ement, 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 hospitali ty industry. She started applying for graduate schools in the USA, while meanwhile work ing as a part time English teacher at Xicheng Fo reign 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 A fter some preparation, she traveled to the USA in January 2005, and started her studies and research special izing in bioorganic chemistry in She completed her MS in Chemist ry from FIT in December 2006, then she joined Chemistry, University of Florida, pu rsuring her Doctoral research studies in the synthesis of heterocyclic compounds. In Janua ry 2011, she looks forward to joining the group of Prof essor Amos B. Smith III at University of Pennsylvania as a postdoctor al research associate