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Benzotriazole-Mediated Synthesis of Alpha-Amino Acid Conjugates and Peptidomemtics

Permanent Link: http://ufdc.ufl.edu/UFE0044751/00001

Material Information

Title: Benzotriazole-Mediated Synthesis of Alpha-Amino Acid Conjugates and Peptidomemtics
Physical Description: 1 online resource (61 p.)
Language: english
Creator: Ghazvini Zadeh, Ebrahim H
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2012

Subjects

Subjects / Keywords: aminoacids -- aminoacylamidrazones -- benzotriazole -- peptidomemtics -- triazines -- triazoles
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 1H-Benzotriazole was employed for the introduction of 1H-1,2,4-triazole or 1,2,4-triazine to the peptide backbone as a versatile biomimetic approach towards developing  a variety of proteolytically stable chiral a-aminoacyl-1H-1,2,4-triazoles and a-aminoacyl-1,2,4-triazines. The method used was assessed at both the protecting groups level as well as the side chains level, concluding that the conditions used are reproducible, compatible with different protecting groups, and responsive to microwave irradiation as indicated by the enhanced reaction rates and shorter reaction times. A different study highlighted the use of 1H-benzotriazole as an effective synthetic auxiliary to prepare N-Cbz-a-amino acylpicolines and quinaldines as scaffolds for the construction of biologically active heterocyclic a-amino acids. The chiral integrity of the target heterocyclic a-amino acids was retained following this method as indicated by HPLC analysis.  This result represents the first simple preparative and purification procedure to prepare such amino acyl conjugates with a complete retention of configuration as opposed to the literature procedures when other auxiliaries were employed. This thesis describes the synthesis and spectroscopic studies of chiral a-aminoacyl-1H-1,2,4-triazoles and a-aminoacyl-1,2,4-triazines as well as chiral amino acyl conjugates of picolines and quinalidine.
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 Ebrahim H Ghazvini Zadeh.
Thesis: Thesis (M.S.)--University of Florida, 2012.
Local: Adviser: Katritzky, Alan R.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2012
System ID: UFE0044751:00001

Permanent Link: http://ufdc.ufl.edu/UFE0044751/00001

Material Information

Title: Benzotriazole-Mediated Synthesis of Alpha-Amino Acid Conjugates and Peptidomemtics
Physical Description: 1 online resource (61 p.)
Language: english
Creator: Ghazvini Zadeh, Ebrahim H
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2012

Subjects

Subjects / Keywords: aminoacids -- aminoacylamidrazones -- benzotriazole -- peptidomemtics -- triazines -- triazoles
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 1H-Benzotriazole was employed for the introduction of 1H-1,2,4-triazole or 1,2,4-triazine to the peptide backbone as a versatile biomimetic approach towards developing  a variety of proteolytically stable chiral a-aminoacyl-1H-1,2,4-triazoles and a-aminoacyl-1,2,4-triazines. The method used was assessed at both the protecting groups level as well as the side chains level, concluding that the conditions used are reproducible, compatible with different protecting groups, and responsive to microwave irradiation as indicated by the enhanced reaction rates and shorter reaction times. A different study highlighted the use of 1H-benzotriazole as an effective synthetic auxiliary to prepare N-Cbz-a-amino acylpicolines and quinaldines as scaffolds for the construction of biologically active heterocyclic a-amino acids. The chiral integrity of the target heterocyclic a-amino acids was retained following this method as indicated by HPLC analysis.  This result represents the first simple preparative and purification procedure to prepare such amino acyl conjugates with a complete retention of configuration as opposed to the literature procedures when other auxiliaries were employed. This thesis describes the synthesis and spectroscopic studies of chiral a-aminoacyl-1H-1,2,4-triazoles and a-aminoacyl-1,2,4-triazines as well as chiral amino acyl conjugates of picolines and quinalidine.
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 Ebrahim H Ghazvini Zadeh.
Thesis: Thesis (M.S.)--University of Florida, 2012.
Local: Adviser: Katritzky, Alan R.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2012
System ID: UFE0044751:00001


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1 BENZOTRIAZOLE MEDIATED SYNTHESIS OF ALPHA AMINO ACID CONJUGATES AND PEPTIDOMEMTICS By EBRAHIM GHAZVINI ZADEH A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FO R THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2012

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2 2012 Ebrahim Ghazvini Zadeh

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3 To my beloved family

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4 ACKNOWLEDGMENTS It is an honor to thank the people behind the success of this thesis. I would like to thank my advis e r Prof. Alan Katritzky for this great opportunity to have worked under his supervision. My sincere gratitude goes to my previous adviser Prof. Makhlouf Haddadin for his encouragement, sound advice and good teachings. I wish to thank my committee members, Dr. Kh alil Abboud and Dr. Ronald Castellano for their valuable advice. Many thanks go to Dr. Bahaa El Dien M. El Gendy and Dr. Nader E. Abo Dya with whom I wor k ed and co auth o red two publications. I would also like to thank my dearest friend Ms. Raghida Bou Zer dan for her continuous support and valuable discussions. My thanks also go to my pa rtners Ms. Ania Sotuyo and Alex Pop. Thanks to all of the Katritzky group members, especially for Dr. Dennis Hall for his proofreading and editorial advice.

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5 TABLE OF CONTEN TS P age ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF SCHEMES ................................ ................................ ................................ ........ 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 10 ABSTRACT ................................ ................................ ................................ ................... 14 CHAPTER 1 GENERAL INTRODUCTION ................................ ................................ .................. 16 2 AMINO ACID DERIVED 1 H 1,2,4 TRIAZOLES and 1,2,4 TRIAZINEs ................................ ................................ .............................. 17 2. 1. Amino Acid Derived 1 H 1,2,4 Triazoles: Synthesis and Characterization ... 17 2. 1. 1. Therapeutic peptides: benefits and limitations ................................ ...... 17 2.2 Results and Discussion ................................ ................................ ..................... 19 2.2.1 Synthesis of aminoacylamidrazones 2.12 ................................ ............... 19 2.2.2 1 H NMR spectros copic study of E / Z isomers of aminoacylamidrazones 2.12 ................................ ................................ ................................ ............... 19 2.2.3 Preparation of N (Cbz, Fmoc, Boc or Acetyl) 3 aminoacyl) 1 H 1,2,4 triazoles 2.13 ................................ ................................ ....................... 20 ................................ ................................ ......... 23 2.3 Synthesis of novel N Cbz amino acid derived 1,2,4 triazines ................. 23 2.3 Conclusion ................................ ................................ ................................ ........ 25 2.4 Experimental ................................ ................................ ................................ ..... 26 2.4.1 General methods ................................ ................................ ..................... 26 2.4.2 General procedure for the synthesis of aminoacylamidrazones 2.12 ...... 26 2.4.3 Ge neral procedure for the synthesis of aminoacyl 1 H 1,2,4 triazoles 2.13a p, and 2.13f': ................................ ................................ ....................... 33 2.4.4 General procedure for the synthesis of amino acylhydrazides 2.20a g, 2.20a', 2.20f': ................................ ................................ ................................ 40 2.4.5 General procedure for the synthesis of 3,6 disubstituted 1,2,4 triazines 2.22: ................................ ................................ ................................ 43 2.4.6 General procedure for the synthesis of 3,5 ,6 trisubstituted 1,2,4 triazines 2.24: ................................ ................................ ................................ 45

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6 3 BENZOTRIAZOLE MEDIATED SYNTHESIS AND TAUTOMERIC STUDY OF CHIRAL HETEROCYCLIC AMINO ACIDS ................................ .......................... 47 3.1 Heterocyclic Amino Acids ................................ ................................ .............. 47 3.2 Results and Discussion ................................ ................................ ..................... 49 3.2.1 Preparation of N (Cbz aminoacyl)benzotriazoles 3.11a e and ................................ ................................ ................................ .......... 49 3.2.2 Synthesis of 2 and 4 ( N Cbz aminoacyl)methylpyridines 3.13a d and 3.13e,f, and 2 ( N Cbz aminoacyl)methylquinoline 3.13g k and ................................ ................................ ................................ ............ 50 ................................ .......... 52 3.3 Conclusion ................................ ................................ ................................ ........ 52 3.4 Experimental ................................ ................................ ................................ ..... 53 3.4.1 General methods ................................ ................................ ..................... 53 3.4.2 General procedure for the synthesis of N (Cbz aminoacyl)benzotriazoles 3.11a ................................ ............... 53 3.4.3 General procedure for the synthesis of 3.13. ................................ ........... 55 LIST OF REFERENCES ................................ ................................ ............................... 57 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 61

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7 LIST OF TABLES Table P age 2 1 Preparation of amino acylami drazone 2.12 ................................ ....................... 20 2 2 Synthesis of N pg 1 H 1,2,4 triazole derivatives 2.13a p ................................ .... 22 2 3 Synthesis of N Pg amino acylhydrazides 2.20 ................................ ................... 24 2 4 Synthesis of N Cbz amino acid derived 1,2,4 triazines 2.22 ........................... 25 3 1 Synthesis of N (Cbz aminoacyl)benzotriazoles 3.11a e and ......... 50 3 2 Synthesis of 3.13 ................................ ................................ ................................ 51

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8 LIST OF FIGURES Figure P age 2 1 Exampl es of biologically active amino acid derived 1,2,4 triazoles. ................... 18 2 2 VT NMR for 2.12f E / Z isomers ................................ ................................ ........... 21 2 3 HPLC of 2.12f and 2.12f using Chiralcel OD column (hexanes : i PrOH, 2:3) .... 23 2 4 Naturally occurring 1,2,4 triazines antibiotics ................................ ..................... 24 3 1 LY2497282 3.5 DPP IV inhibitor ................................ ................................ ........ 48

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9 LIST OF SCHEMES Scheme page 2 1 Synthetic route for the preparation of 2.9 as devised by Luthman ...................... 18 2 2 Synthesis of 3,5,6 trisubstituted 1,2,4 triazines 2.24a,b and ................... 25 3 1 Synthesis of ketone intermediate 3.8 ................................ ................................ .. 48

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10 LIST OF ABBREVIATION S Alpha locant D Specific rotation Ala Alanine Boc t Butoxycarbonyl br Broad (spectral) Bt Benzotriazol 1 yl C Carbon Degree Celcius Cal Calories Calcd Calculated Cbz Carboxybenzyl CDCl 3 Deuterated chloroform CNS Central nervou s system Cys Cysteine Chemical shift in parts per million downfield from TMS Gibbs free energy d Doublet D Dextrorotatory (right) DCC N,N' Dicyclohexylcarbodiimide DCM Dichloromethane DIPEA N N Diisopropylethylamine DMF Dimethylformami de DMSO Dimethylsulfoxide

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11 E Entgegen e e Enantiomeric excess et al And others Et 3 N Triethylamine EtOAc Ethyl acetate Fmoc 9 Fluorenylmethoxycarbonyl g Gram(s) GHS R Ghrelin receptor Gly Glycine h Hour H Hydrogen HDAC Histone deacetylase H PLC High performance liquid chromatography HRMS High resolution mass spectrometry Hz Hertz i iso (as in i Pr) Ile Isoleucine i Pr Isopropyl J Coupling constant (in NMR spectroscopy) K Kilo L Levorotatory (left) Leu Leucine Lit Literatu re Lys lysine m Multiplet (spectral)

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12 M Molar Me Methyl MeCN Acetonitrile MeOH Methanol Min Minute(s) MgSO 4 Magnesium sulfate mmol Millimole(s) mol Mole(s) mp. Melting point MW Microwave m/z Mass to charge ratio N Nitrogen Na 2 CO 3 Sodium carbonate NMR Nuclear magnetic resonance O Oxygen OH Hydroxyl group OMe Methoxy Pg Protecting group Phe Phenylalanine ppm Parts per million q Quartet R Rectus (right) ref. Reference RNA Ribonucleic acid rt Room temperature

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13 s Singlet S Sinister (left) SOCl 2 Thionyl chloride t Triplet TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilane Trp Tryptophan Val Valine VT Variable temperature W Watt(s) Z Carboxybenzyl s ame as Cbz Z Zusammen

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14 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science BENZOTRIAZOLE MEDIATED SYNTHESIS OF ALPHA AMINO ACID CONJUGATES AND PEPTIDOMEMTICS By Ebrahim H. Ghazvini Zadeh August 2012 Chair: Alan R. Katritzky Major: Chemistry 1 H Benzotriazole was employed for the introduction of 1 H 1,2,4 triazole or 1,2,4 triazine to the peptide backbone as a versatile biomimetic approach towards developing aminoacyl 1 H 1,2,4 triazoles and aminoacyl 1,2,4 triazines. The method used was assessed at both the protecting groups level as well as the side chain s level, concluding that the conditions used are reproduci ble, compatible with different protecting groups, and responsive to microwave irradiation as indicated by the enhanced reaction rates and shorter reaction times. A different study highlighted the use of 1 H benzotriazole as a n effective synthetic auxiliary to prepare N Cbz amino a cyl picolines and quinaldines as scaffolds for the amino acids. The chiral integrity of the amino acids was retained following this method as indicated by HPLC analysis. This result represents the first simple preparative and purification procedure to prepare such amino acyl conjugates with a complete retention of configuration as opposed to the literature procedures whe n other auxiliaries were employed.

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15 This thesis describes the synthes is and spectroscopic studies of aminoacyl 1 H 1,2,4 triazoles aminoacyl 1,2,4 triazines as well as chiral amino acyl conjugates of picolines and quinalidine.

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16 CHAPTER 1 GENERAL INTRODUCTION Benzotriazole intermediates provide access to various organic transformations and le d to the introduction of a plethora of functional group s into organic molecules. A glance at the contents page as well as the 193 references associated with the 2010 Chemical Reviews paper by Katritzky bear witness to th e synthetic utilities of benzotriazo le [2010CR 1564 ] One of these functions is to employ benzotriazole as an activating reagent for coupling N protected amino acids to various nucleophiles leading to the C N O and S acylation of amino acids Such modifications can be exploited to prepare peptidomimetics and small amino acid based therapeutics. Inspired by the various chemical modifications that ben zotriazole furnishes, as well the advantages of the stable, crystalline and versatile benzotriazole intermediates, we devised a simple protocol for preparing aminoacyl 1 H 1,2,4 triazoles C hapter 2 of this thesis discusses the advantages of the me thod developed for preparing aminoacyl 1 H 1,2,4 triazoles and introduce s a novel class of heterocyclic amino ac ids through modification at the amino acid C terminal. Chapter 3 again highlights the advantage of using benzotriazole as an activati ng reagent. N (Cbz aminoacyl)benzotriazoles were coupled to picolines and quinalidine to afford the corresponding conjugates in moderate to good yields. The essence of this simple procedure lies in preparing these conjugates with complete retention of c onfiguration as opposed to literature methods. A summary of the achievements follows each chapter.

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17 CHAPTER 2 VERSATILE SYNTHESIS OF AMINO ACID DERIVED 1 H 1,2,4 TRIAZOLES AND 1,2,4 TRIAZINE S 1 2. 1. Amino A cid D erived 1 H 1,2,4 Triazoles : Synthesis and C haracterization 2. 1. 1. Therapeutic p eptides: b enefits and l imitations Peptides are the means to a healthier future They show a marked affinity and specificity towards biological ly significant processes [ 20 01P2329 20 05EBR88 ] Nevertheless, their introdu ction to the drug industry has met obstacles due to their low oral bioavailability and tendency to be quickly degraded [ 20 05CEN17] In order to address these limitations, a plethora of chemical transformations have been developed to enhance the peptide bio logical activity and slow down biodegradation [ 20 06AAPSJE76, 20 01P2329, 20 06MB499] These chemical changes may consist of peptide sequence c yclization [ 20 06MB499], amino acid residue s ubstitution N or C terminal ends blocking [ 20 02NRDD847], and/or amide bond modification between two amino acids [ 20 10DDT40]. These modifications have led to the de sign and synthesis of numerous am ide bond isosteres or mimics. Thus L tryptophan derived 1,2,4 triazoles 2.1 have been developed as ghrelin receptor (GHS R1a) li gands, and function as potent partial agonists and antagonists for the GHS 1a receptor. [ 20 07JMC1939] Further example s of amino acid derived 1,2,4 triazoles devised as a potential therapeutics include: 1,2,4 triazoles originating from lysine 2.2 which are reported as histone d eacetylase (HDAC) inhibitors [ 20 09BMCL1866] dipeptido 1 ,2,4 triazole derivatives 2. 3 which exhibit high 1 Med. Chem. Commun., 2012 3 52 Reproduced in part by permission of the Royal Society of Chemistry.

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18 levels of CNS activity and Ribavarin 2.4 which act s as an i nhibitor of RNA virus infection (Figure 2 1) [ 20 08CDM827 ] Figure 2 1. Examples of biologically active amino acid derived 1,2,4 triazole s. The most important p rotocol employed to access such 1,2,4 triazoles is the one devised by Luthman [ 95JOC3112 ] but the methodology suffers from re latively harsh conditions (180 200 C), limited versatility and moderate to low yields (Scheme 2 1). Scheme 2 1. Synthetic route for the preparation of 2.9 as devised by Luthman This chapter introduce s an efficient microw ave assisted t hree step protocol for the synthesis of a variety of chiral N (Cbz, Fmoc, Boc or Acetyl ) 3 aminoacyl) 1 H 1,2,4

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19 triazoles 2.1 3 in good yields In addition, I describe the preparation of 1,2,4 triazine s 2. 22 and 2.24 as a new class of potent ial amino acid derived therapeutic agents 2.2 Results and Discussion 2.2.1 Synthesis of a minoacylamidrazones 2.1 2 Upon examining the route described by Luthman to prepare 1,2,4 triazole 2.9 it was envisag ed that a relatively more stable intermediate migh t be used instead of 2.6 Additionally, the use of an acid or a base to catalyze the cyclization of 2.8 would replace the relatively harsh conditions employed to prepare 2.9 Thus 1 H benzo triazole was used to synthesize N protected amino acylbenzotriazole s 2.10 which are known to be stable crystalline and eas ily prepare d [2009SL2392] Amidrazone 2.11 was coupled with 2.10 in acetonitrile at room temperature to afford the corresponding aminoacylamidrazones 2.1 2 ( Table 2 1 ). Although the reaction proceeds without the use of a base, an equimolar amount of DIPEA enhances the rate of coupling reaction as evidenced by the rapid formation of a white precipitate 2.2.2 1 H NMR s pectroscopic s tudy of E / Z i somers of a minoacylamidrazones 2.1 2 The 1 H NMR and 13 C spec tra of acylamidrazones 2.1 2 ( in DMSO d 6 ) show two sets of chemical shifts (Figure 2 2). This is consistent with t he existence of E / Z isomer s 2.1 2 f ( E ) and 2.1 2 f ( Z ) varying in ratio over the range of 1:1 t o 1: 3 In order to estimate the free energy of rotati on about the N(sp 2 ) N (sp 2 ), a variable temperature 1 H NMR experiment was performed, and the G at 90 C, the coalescence temperature was calculated using the following equation: c = 19.14 T c [10.32 + log ( T c / k c where k c 2 + 6 J AB 2 ) 1/2 and T c = temperature at coalescence in K.

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2 0 Table 2 1. Preparation of amino acylamidrazone 2.12 Entry Amidrazone 2.12 R 1 Pg Yield ( % ) 1 a CH(CH 3 ) 2 Cbz 73 2 b CH 2 C 6 H 5 Cbz 72 3 c H Cbz 85 4 d CH(CH 3 )CH 2 CH 3 Cbz 75 5 e methylen e 3 indole Cbz 69 6 f CH 3 Cbz 80 7 f' 2 CH 3 ( D L ) Cbz 74 8 g CH(CH 3 ) 2 Fmoc 79 9 h H Fmoc 75 10 i CH 2 CH(CH 3 ) 2 Fmoc 71 11 j CH 2 O t Bu Fmoc 77 12 k CH 2 Ph Fmoc 76 13 l methylene 3 indole Fmoc 72 14 m H Boc 91 15 n CH 3 Boc 71 2.2.3 Preparation of N (Cb z, Fmoc, Boc or Acetyl ) 3 aminoacyl) 1 H 1,2,4 triazoles 2.1 3 Cyclization of 2.1 2 into 1 H 1,2,4 triazole 2.13 was examined following literature procedures. [ 2005ARK 208 2007M103 ] Low yields (< 1 0%) of 2.13 were obtained when 2.12 was kept at temperatur es 10 C above the melting point for 10 20 min The use of strong inorganic acids such as conc. H 2 SO 4 afforded only the deprotected 1 H 1,2,4 triazole in trace amounts (< 3%) probably due to problem during the work up However, 2 Compound numbers written with primes indicate a 1:1 racemic mixture, e.g. 2.12f

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21 heating under reflux in ac etic acid for 1 h cyclized 2.12 a l into 1 H 1,2,4 triazole 2.13 a l (Table 2 2 ). These conditions were shown to achieve cyclization in scalable quantities Microwave irradiation (35 W at 1 4 0 C) of 2.12 in acetic acid (0.3 g/1 mL) accelerated the cyclization rate, thus achieving comparable yields to reactions involving convention al heating. Figure 2 2. VT NMR for 2.12f E / Z isomers

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22 Cyclization of 2.12m n in acetic acid led to a mixture of products, perhaps due to partial de protection of the Boc protecting group To circumvent such a problem, 2. 12m,n were heated in EtOH at 85 C with a catalytic amount of AcOH to afford the N Boc protected 1 H 1,2,4 t riazol e 2.13m,n When subjected to microwave irradiation of 100W at 180 C 2 .12m,n afforded N acetyl 1 H 1,2,4 t riazol e derivatives 2.13o,p in 89 90% yields over two steps. Table 2 2. Synthesis of N pg 1 H 1,2,4 t riazol e derivatives 2.13a p Entry 1 H 1,2,4 triazole 2.13 R 1 Pg Yield ( % ) 1 a CH(CH 3 ) 2 Cbz 90 a 2 b CH 2 C 6 H 5 Cbz 89 a 3 c H Cbz 80 b 4 d CH(CH 3 )CH 2 CH 3 Cbz 84 a 5 e methylene 3 indole Cbz 90 b 6 f CH 3 Cbz 75 b 7 f' CH 3 ( D,L ) Cbz 90 a 8 g CH(CH 3 ) 2 Fmoc 90 a 9 h H Fmoc 89 a 10 i CH 2 CH(CH 3 ) 2 Fmoc 80 b 11 j CH 2 O t Bu Fmoc 84 a 12 k CH 2 Ph Fmoc 90 b 13 l methylene 3 indole Fmoc 75 b 14 m H Boc 79 c 15 n CH 3 Boc 83 c 16 o H Ac 90 d 17 p CH 3 Ac 89 d a HOAc, (1 h), b microwave irradiation (50 W), 130 C (5 min), c HOAc (2%) in ethanol, (2 h), d microwave irradiation in HOAc (100 W), 180 C (10 min).

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23 2 .2.4 HPLC of 2.1 3 f and 2.13 HPLC of 2.1 3 f using Chiralcel OD column (hexanes : i PrOH, 2:3) show ed a single peak with retention time of 1 0 59 min whereas the racemic mixture 2.1 3 show ed two peaks with retention times of 1 0 .6 6 and 12. 49 min (Figure 2 3) t h us confirm s the enantiomeric purity of 2.1 3 f T his result can be extrapolated to the remaining triazole derivatives 2.1 3 Figure 2 3. HPLC of 2.1 3 f and 2.1 3 using Chiralcel OD column (hexanes : i PrOH, 2:3) 2.3 Synthesis of n ovel N Cbz amino a ci d derived 1,2,4 t riazines Naturally occurring 1,2,4 t riazine antibiotics such as fervenulin (planomy cin) 2.14 toxoflavin 2.15 reumycin 2.16 pseudoiodinine 2.17 nostocine A 2.18 and fluviols A 2.19 prompt ed us t o develop 1,2,4 t riazines amino acids as potential therapeutic agents ( Figure 2 4) [2008JOC5442, 2010JOC6009 ]

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24 Figure 2 4. Naturally occurring 1,2,4 t riazine antibiotics N Cbz (Aminoacyl)hydrazides 2.20a c and prepared by treating 2 .10 wit h N 2 H 4 H 2 O (Table 2 3), were converted into 3 (aminoacyl) conjugates of 1,2,4 triazines by a modified Saraswathi method. [ 19777T1043 2005HCA1491 ] Thus 2,4' dibromoacetophenone 2.21 was condensed with 2. 20 in EtOH/AcOH in the presence of KOAc to afford 1,2 ,4 triazines 2.22c,d and in 28 43% yields Microwave irradiation (50 W, 95 C) shortened the reaction time from 18 h to 2h and afforded 2.22a,b in 61% and 40%, respectively (Table 2 4) Table 2 3. Synthesis of N Pg amino acylhydrazides 2.20 Entry 2.10 Pg R 1 2.20 m.p. (C) Yield % 1 a Cbz CH(CH 3 ) 2 ( L ) a 163.0 165.0 86 2 o Cbz CH(CH 3 ) 2 ( D L ) a 126.0 128.0 90 3 b Cbz CH 2 C 6 H 5 b 153.0 155.0 94 4 c Cbz H c 93.0 95.0 70 5 d Cbz CH(CH 3 )CH 2 CH 3 d 159.0 161.0 8 7 6 e Cbz methylene 3 indole e 163.0 165.0 90 7 f Cbz CH 3 ( L ) f 111.0 113.0 78 8 f' Cbz CH 3 ( D L ) f 116.0 118.0 80 9 i Fmoc CH 2 CH(CH 3 ) 2 g 165.0 167.0 75

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25 Table 2 4. Synthesis of N Cbz amino acid derived 1,2,4 triazine s 2.22 Entry 2.20 R 1 2.2 2 m.p. (C) Yield (%) 1 a CH(CH 3 ) 2 a 96.0 98.0 61 a 2 b CH 2 C 6 H 5 b 141.0 143.0 40 a 3 c H c 132.0 134.0 43 b 4 f CH 3 d 139.0 140.0 28 b 5 f' CH 3 ( D L ) d' 57.0 59.0 30 b a KOAc, HOAc, microwave (50 W, 95 C, 1 h). b KOAc, HOAc, EtOH, 85 C, 7 h. Z hao and his co workers reported the synthesis of trisubstituted 1,2,4 triazines using arylhydrazide and 1,2 diones in the presence of excess NH 4 OAc. [ 2003TL1123 ] This method afforded N Cbz amino acyl derived 3,5,6 trisubstituted 1,2,4 triazines 2.2 4 a,b and 2.2 4 in 61 68% yields when 2.20 and 1,2 acenaphthenedione 2.23 were heated under microwave irradiation in the presence of 2 equiv. of NH 4 OAc. Scheme 2 2 Synthesis of 3,5,6 trisubstituted 1,2,4 triazines 2.2 4 a,b and 2. 2 4 2.3 C onclusion In conclusion, a wide variety of N pg amino acid derived 1,2,4 triazoles w ere prepared following a general and scalable synthetic protocol that afford s the desired triazoles with complete retention o f configuration T he synthesis was re producible and compatible with different protecting groups and the use of m icrowave irradiation enhance d the reaction rates and shorten ed the reaction times. The synthesis of 1,2,4 triazine conjugates is unknown, although the approach employed have been used for other various derivatives. We predict interesting biological activities for such amino acid

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26 derived 1,2,4 triazines due to the reactive triazine core that is present in n aturally occurring antibiotics 2.4 E xperimental 2.4.1 General m ethods Meltin g points were determined on a capillary point apparatus equipped with a digital thermometer and are uncorrected. The 1 H and 13 C NMR spectra for starting materials were recorded on a Varian Gemini or Mercury 300 instrument, operating at 300 MHz for 1 H and 75 MHz for 13 C with TMS as an internal reference. 2.4.2 General p rocedure for the s ynthesis of a minoacylamidrazones 2.12 Method A: A solution of N protected amino acylbenzotriazole 2.10 a n, 2.10 f' (1.0 mmol), 2 pyridylamidrazone 2.11 (1.0 mmol) and diisop ropylethylamine (1.0 mmol) in acetonitrile (10 mL) was stirred at room temperature for 5 h. The precipitate was collected on a Buchner funnel and was washed with diethylether (20 mL), water (30 mL) and methanol (5 mL). The solid was dried in vacuo to affor d the desired aminoacylamidrazones 2.12 as a white solid. Method B: A solution of 2.10 a n, 2.10 f' (1.0 mmol) and 2.11 (1.0 mmol) was heated to reflux in acetonitrile (5 mL) for 1 h. The mixture was worked up as in method A. ( S ) Benzyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 3 methyl 1 oxobutan 2 yl)carbamate ( 2.12 a) White microcrystals (73%); mp 203.0 205.0 C. Two rotamers (2:1): 1 H NMR (DMSO d 6 300 MHz) Two rotamers: 10.08 (s, 0.3H), 9.95 (s, 0.7H), 8.60 8.56 (m, 1H), 8.08 (t, J = 8.4 Hz, 1H), 7.93 7.80 (m, 1H), 7.49 7.43 (m, 2H), 7.41 7.23 (m, 5H), 6.74 (s, 1H), 6.68 (s, 1H), 5.05 4.99 (m, 2H), 3.94 .85 (m, 1H), 2.30 2.15 (m, 0.3H), 2.05 1.90 (m, J = 6.9 Hz, 0.7H), 1.00 0.87 (m, 6H). 13 C NMR (DMSO d 6 75 MHz) 172.4, 167.1, 156.2, 150.5, 148. 1, 146.3, 142.5, 137.1, 137.0,

PAGE 27

27 136.8, 128.3, 127.8, 127.7, 124.6, 124.5, 120.6, 119.2, 65.4, 65.3, 59.6, 56.0, 30.3, 29.5, 19.6, 19.3, 19.1, 18.7. Anal. Calcd. for C 19 H 23 N 5 O 3 (369.43): C, 61.77; H, 6.28; N, 18.96. Found: C, 61.88; H, 6.51; N, 18.60. ( S ) Be nzyl(1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 1 oxo 3 phenylpropan 2 yl) carbamate ( 2.12 b) White microcrystals (72%); mp 168.0 170.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz) Two rotamers: 10.10 (s, 0.5H), 10.02 (s, 0.5H), 8.59 (d, J = 4.8 Hz, 1H), 8.10 (dd, J = 8.1, 3.6 Hz, 1H), 7.94 7.85 (m, 1H), 7.70 (d, J = 8.4 Hz, 0.5H), 7.53 (d, J = 9.0 Hz, 0.5H), 7.50 7.45 (m, 1H), 7.38 7.12 (m, 9H), 6.73 6.65 (m, 2H), 5.38 5.15 (m, 0. 5H), 5.00 4.90 (m, 2H), 4.38 (sextet, J = 4.5 Hz, 0.5H), 3.14 2.95 (m, 1H), 2.91 2.70 (m, 1H). 13 C NMR (DMSO d 6 75 MHz) 172.4, 166.4, 156.0, 150.8, 148.2, 148.1, 146.4, 143.0, 138.6, 137.2, 136.9, 129.1, 129.3, 128.3, 128.3, 128.1, 127.6, 127.5, 127.4, 126.3, 125.0, 120.6, 65.2, 65.1, 55.0, 52.5, 38.0, 37.0. Anal. Calcd. for C 23 H 23 N 5 O 3 (417.47): C, 66.17; H, 5.55; N, 16.78. Found: C, 66.08; H, 5.55; N, 16.87. Benzyl (2 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 2 oxoethyl)carbamate ( 2.12 c) White micro crystals (83%); mp 153.0 155.0 C. Two rotamers (2:1): 1 H NMR (DMSO d 6 300 MHz) 10.11 (s, 0.7H), 9.89 (br s, 0.3H), 8.57 (t, J = 5.1 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.86 (q, J = 7.8 Hz, 1H), 7.54 7.25 (m, 7H), 6.70 6.60 (m, 2H), 5.07 5.03 (m, 2H), 4.16 (d, J = 6.0 Hz, 1.3H), 3.74 (d, J = 6.0 Hz, 0.7H). 13 C NMR (DMSO d 6 75 MHz) 170.0, 164.4, 156.6, 150.3, 148.0, 142.8, 137.2, 136.8, 128.3, 127.7, 124.5, 120.5, 120.2, 65.3, 42.2, 41.9. Anal. Calcd. for C 16 H 17 N 5 O 3 (327.35): C, 58.71; H, 5.23; N, 21.39. Found: C, 58.63; H, 5.27; N, 21.42.

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28 Benzyl ((2 S ,3 S ) 1 (2 (amino(pyridin 2 yl)m ethylene)hydrazinyl) 3 methyl 1 oxo pentan 2 yl)carbamate ( 2.12 d) White microcrystals (71%); mp 223.0 224.0 C. Two rotamers (2:1): 1 H NMR (DMSO d 6 300 MHz) 10.07 (br s, 0.4H), 9.96 (br s, 0.6H), 8.59 (d, J = 3.3 Hz, 1H), 8.08 (t, J = 8.1 Hz, 1H), 7.89 (q, J = 7.5 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.47 7.44 (m, 1H), 7.39 7.20 (m, 5H), 6.75 (br s, 1H), 6.67 (br s, 1H), 5.05 5.00 (m, 2H), 3.96 (t, J = 9.0 Hz, 1H), 1.98 1.88 (m, 0.33H), 1.82 1.70 (m, 0.67H), 1.60 1.40 (m, 1H), 1.28 1.10 (m, 1H), 0.95 0.78 (m, 6H). 13 C NMR (DMSO d 6 75 MHz) 172.3, 167.2, 156.1, 150.5, 148.0, 146.3, 142.4, 137.1, 136.8, 128.3, 127.6, 124.6, 124.4, 120.6, 119.9, 65.4, 58.3, 55.0, 36.1, 24.6, 23.9, 15.8, 15.4, 11.3, 10.7. Anal. Calcd. for C 20 H 25 N 5 O 3 (383.45): C, 62.65; H, 6.57; N, 18.26. Found: C, 62.96; H, 6. 71; N, 18.32. ( S ) Benzyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 3 (1 H indol 3 yl) 1 oxopropan 2 yl)carbamate ( 2.12 e) White microcrystals (69%); mp 171.0 173.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz) 10.82 (d, J = 3.9 Hz, 1H), 10.07 (b r s, 1H), 8.60 (t, J = 4.5 Hz, 1H), 8.09 (t, J = 9.9 Hz, 1H), 7.92 7.78 (m, 1H), 7.2 7.40 (m, 3H), 7.40 7.26 (m, 5H), 7.20 (d, J = 2.1 Hz, 1H), 7.09 6.97 (m, 2H), 6.85 (t, J = 7.5 Hz, 1H), 6.74 (br s, 2H), 5.30 (td, J = 9.6, 4.2 Hz, 0.5H), 5.03 4.86 (m, 2H ), 4.49 4.40 (m, 0.5H), 3.24 3.09 (m, 1H), 3.05 2.91 (m, 1H). 13 C NMR (DMSO d 6 75 MHz) 173.0, 167.6, 155.9, 150.5, 148.2, 148.1, 146.7, 143.3, 137.2, 136.8, 136.1, 128.3, 128.3, 127.6, 127.5, 127.3, 123.9, 120.9, 120.8, 120.6, 118.4, 118.2, 118.1, 111.3, 110.5, 110.1, 65.3, 65.1, 52.0, 46.2, 26.3. Anal. Calcd. for C 25 H 26 N 6 O 3 (456.51): C, 6 5.78; H, 5.30; N, 18.41. Found: C, 65.57; H, 5.24; N, 18.44.

PAGE 29

29 ( S ) Benzyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 1 oxopropan 2 yl)carbamate ( 2.12 f) White microcrystals (80%); mp 141.0 143.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz) 10.02 (br s, 0.5H), 9.96 (br s, 0.5H), 8.60 8.56 (m, 1H), 8.08 (t, J = 7.5 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H), 7.58 7.42 (m, 2H), 7.40 7.20 (m, 5H), 6.80 6.65 (m, 2H), 5.03 (s, 2H), 5.10 4.90 (m, 0.5H), 4.18 (quin, J = 7.2 Hz, 0.5H), 1.32 (d, J = 7.2 Hz, 1.5H), 1 .27 (d, J = 7.2 Hz, 1.5H). 13 C NMR (DMSO d 6 75 MHz) 168.2, 155.7, 150.4, 148.0, 142.6, 136.9, 128.3, 127.7, 124.6, 124.4, 120.5, 120.0, 65.4, 65.2, 49.2, 47.1, 18.5, 17.0. Anal. Calcd. for C 17 H 19 N 5 O 3 (341.37): C, 59.81; H, 5.61; N, 20.52. Found: C, 59.67; H, 5.66; N, 20.55. Benzyl (1 (2 (amino(pyridin 2 y l)methylene)hydrazinyl) 1 oxopropan 2 yl)carbamate ( 2.12 f') White microcrystals (79%); mp 178.0 179.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz) 10.02 (s, 0.5H) 9.97 (s, 0.5H), 8.57 (s, 1H), 8.08 (t, J = 8.1 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7. 54 (d, J = 6.9 Hz, 0.5H), 7.50 7.21 (m, 6.5H), 6.70 (d, J = 12.6 Hz, 2H), 5.03 (s, 2H), 4.99 (quint, J = 6.9 Hz, 0.5H), 4.18 (quint, J = 6.9 Hz, 0.5H), 1.33 (d, J = 7.2 Hz, 1.5H), 1.28 (d, J = 7.2 Hz, 1.5). 13 C NMR (DMSO d 6 75 MHz) 173.4, 168.3, 155.7, 155.7, 150.5, 150.4, 148.1, 146.4, 142.6, 137.2, 137.1, 136.9, 136.8, 128.3, 127.7, 124.6, 124.5, 120.5, 120.0, 65.4, 65.2, 49.2, 47.1, 18.4, 17.0. Anal. Calcd. for C 17 H 19 N 5 O 3 (341.37): C, 59.81; H, 5.61; N, 20.52. Found: C, 60.16; H, 5.70; N, 20.55. ( S ) ( 9 H Fluoren 9 yl)methyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 1 oxo 3 (trityloxy)propan 2 yl)carbamate ( 2.12 g). White microcrystals (79%); mp 224.0 226.0 C. Two rotamers (3:2): 1 H NMR (DMSO d 6 300 MHz) 10.08 (s, 0.4H), 9.95 (s, 0.6H), 8.58 8.55 (m, 1H), 8.08 (t, J = 9.9 Hz, 1H), 7.90 7.84 (m, 3H), 7.76 (t, J =

PAGE 30

30 6.0 Hz, 2H), 7.62 (d, J = 8.7 Hz, 0.6H) 7.48 7.38 (m, 3H), 7.34 7.29 (m, 2.4H), 6.73 6.67 (m, 2H), 5.03 (dd, J = 8.4, 5.7 Hz, 0.4H), 4.29 4.22 ( m, 3H), 3.91 (t, J = 8.7 Hz, 0.6H), 2.23 (sextet, J = 6.9 Hz, 0.4H), 2.00 (sextet, J = 6.9 Hz, 0.6H), 1.00 0.85 (m, 6H). 13 C NMR (DMSO d 6 75 MHz) 172.4, 167.0, 156.4, 150.5, 148.0, 146.2, 143.9, 143.7, 140.6, 136.8, 128.9, 127.6, 127.2, 127.0, 125.4, 12 4.6, 121.3, 120.5, 120.0, 65.7, 59.6, 46.7, 30.2, 19.3, 18.8. Anal. Calcd. for C 26 H 27 N 5 O 3 (457.54): C, 68.25; H, 5.95; N, 15.31. Found: C, 68.53; H, 6.06; N, 15.23. (9 H Fluoren 9 yl)methyl (2 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 2 oxoethyl) carbam ate ( 2.12 h) White microcrystals (75%); mp 195.0 197.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz) 10.12 (s, 0.7H), 9.89 (s, 0.3H), 8.57 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.91 7.77 (m, 3H), 7.75 (d, J = 5.4 Hz, 2H), 7.70 7.57 (m, 0.5H), 7.44 7.23 (m, 5.5H), 6.70 6.62 (m, 2H), 4.30 4.16 (m, 5H), 3.76 3.74 (m, 0.7H), 3.65 3.55 (m, 0.3H). 13 C NMR (DMSO d 6 75 MHz) 170.7, 165.2, 157.3, 151.0, 148.7, 144.6, 143.4, 141.4, 137.5, 128.3, 127.8, 126.0, 125.1, 120.8, 66.3, 47.4, 42.5. Anal. Calcd. for C 23 H 21 N 5 O 3 (415.46): C, 66.49; H, 5.09; N, 16.86. Found: C, 66.54; H, 5.16; N, 16.62. ( S ) (9 H Fluoren 9 yl)me thyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 4 methyl 1 oxopentan 2 yl)carbamate ( 2.12 i) White microcrystals (71%); mp 179.0 181.0C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz): 10.01 (s, 1H), 8.58 (s, 1H), 8.11 (t, J = 7.5 Hz, 1H), 8.00 7.60 (m, 6H), 7.58 7.20 (m, 5H), 6.79 (br s, 1H), 6.72 (br s, 1H), 5.22 5.07 (m, 0.5H), 4.27 (s, 3H), 3.70 3.40 (m, 0.5H), 1.88 1.40 (m, 3H), 1.08 0.75 (m, 6H). 13 C NMR (DMSO d 6 75 MHz) 173.6, 168.1, 156.1, 150.6, 148.1, 146.4, 143.9, 143.8, 142.7, 140.7, 1 36.8, 129.0, 127.6, 127.0, 125.4, 124.5, 120.7,

PAGE 31

31 120.6, 120.9, 120.1, 119.8, 66.4, 65.6, 52.0, 49.0, 46.7, 41.0, 24.5, 24.3, 23.4, 23.0, 21.7, 21.3. Anal. Calcd. for C 23 H 21 N 5 O 3 (471.56): C, 68.77; H, 6.20; N, 14.85. Found: C, 68.53; H, 6.32; N, 14.69. ( S ) ( 9 H F luoren 9 yl)methyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 3 (tertbutoxy) 1 oxopropan 2 yl)carbamate ( 2.12 j) White microcrystals (77%); mp 186.0 188.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz): 10.11 (br s, 0.4H), 9.95 (br s, 0.6H), 8.58 (t, J = 4.8 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.95 7.80 (m, 3H), 7.75 (d, J = 7.5 Hz, 2H), 7.57 7.30 (m, 6H), 6.74 (br s, 1H), 6.68 (br s, 1H), 4.38 4.16 (m, 3H), 3.72 3.42 (m, 3H), 1.09 (d, J = 9.6 Hz, 9H). 1 3 C NMR (DMSO d 6 75 MHz): 148.7, 143.3, 140.1, 138.1, 137.5, 129.6, 128.0, 122.1, 120.7, 110.4, 28.0. Anal. Calcd. for C 28 H 31 N 5 O 4 (501.59): C, 67.05; H, 6.23; N, 13.96. Found: C, 67.46; H, 6.35; N, 13.98. ( S ) (9 H Fluoren 9 yl)methyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 1 oxo 3 phenylpropan 2 yl)carbamate ( 2.12 k) White microcrystals (76%); mp 207.0 209.0 C. Two rotamers (1:1): 1H NMR (DMSO d 6 300 MHz) 10.11 (s, 0.5H), 10.0 (s, 0.5H), 8.59 (d, J = 3.9 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.92 7.82 (m, 3H), 7.70 7.65 (m, 2H), 7.53 7.17 (m, 11H), 6.80 6.65 (m, 2H), 5.30 5.17 (m, 0.5H), 4.39 (sextet, J = 4.5 Hz, 0.5H), 4.25 4.10 (m, 3H), 3.14 2.80 (m, 2H). 13C NMR (DMSO d 6 75 MHz) 172.3, 167.2, 155.8, 150.5, 148.1, 148.1, 146.7, 143.8, 143.7, 1 43.0, 140.6, 138.6, 138.0, 136.8, 129.3, 129.1, 128.1, 128.1, 127.6, 127.0, 126.3, 125.3, 124.7, 124.5, 120.6, 120.1, 65.7, 65.6, 55.3, 53.2, 46.5, 37.8, 36.5. Anal. Calcd. For C 30 H 27 N 5 O 3 (505.58): C, 71.27; H, 5.38; N, 13.85. Found: C, 71.09; H, 5.34; N, 13.77.

PAGE 32

32 ( S Z ) (9 H Fluoren 9 yl)methyl (1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 3 (1 H indol 3 yl) 1 oxopropan 2 yl)carbamate ( 2.12 l) White microcrystals (67%); mp 158.0 160.0 C. Two rotamers (1:1): 1 H NMR (DMSO d 6 300 MHz) 10.85 (br s, 1H), 10.09 (s, 1H), 8.60 (t, J = 4.2 Hz, 1H), 8.13 8.05 (m 1H), 7.89 7.87 (m, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.76 7.59 (m, 3H), 7.50 7.23 (m, 7H), 7.10 6.98 (m, 2H), 6.84 (t, J = 7.5 Hz, 1H), 6.80 6.70 (m, 2H), 5.50 5.25 (m, 0.5H), 4.50 4. 40 (m, 0.5H), 4.35 3.93 (m, 3H), 3.30 2.94 (m, 2H). 13 C NMR (DMSO d 6 75 MHz) 173.1, 167.7, 155.9, 150.5, 150.5, 148.1, 148.1, 146.7, 143.8, 143.8, 143.3, 140.7, 136.8, 136.7, 136.1, 127.6, 127.3, 127.1, 125.4, 124.6, 124.6, 123.9, 120.9, 120.8, 120.6, 12 0.3, 120.1, 118.6, 118.4, 118.2, 118.1, 111.3, 110.6, 110.2, 65.7, 65.6, 64.9, 54.5, 52.1, 46.6, 28.0, 26.9, 15.2. Anal. Calcd. for C 32 H 28 N 6 O 3 (544.62): C, 70.57; H, 5.18; N, 15.43. Found: C, 70.20; H, 5.29; N, 15.71. t Butyl(2 (2 (amino(pyridin 2 yl)methy lene)hydrazinyl) 2 oxoethyl)carbamate ( 2.12 m) White microcrystals (91%); mp 159.0 161.0 C. Two rotamers (2:1): 1 H NMR (DMSO d 6 300 MHz) 10.05 (s, 0.7H), 9.83 (br s, 0.3H), 8.57 (t, J = 4.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.90 7.82 (m, 1H), 7.48 7.42 (m, 1H), 6.98 (t, J = 5.4 Hz, 0.3H), 6.75 (t, J = 5.4 Hz, 0.7H), 6.67 6.63(m, 2H), 4.09 (d, J = 6.0 Hz, 1.3H), 3.64 (d, J = 6.0 Hz, 0.7H) 1.40 (s, 9H). 13 C NMR (DMSO d 6 75 MHz) 170.2, 165.0, 155.8, 150.4, 150.3, 147.9, 146.4, 142.6, 136.8, 124.6, 124.4, 120.4, 120.1, 77.7, 42.3, 41.4, 28.1. Anal. Calcd. for C 13 H 19 N 5 O 3 (293.33): C, 53.23; H, 6.53; N, 23.88. Found: C, 53.42; H, 6.51; N, 2 3.97. ( S ) t Butyl(1 (2 (amino(pyridin 2 yl)methylene)hydrazinyl) 1 oxopropan 2 yl)carbamate ( 2.12 n) White microcrystals (71%); mp 208.0 210.0 C. Two rotamers

PAGE 33

33 (1:1): 1 H NMR (DMSO d 6 300 MHz) 9.95 (s, 0.54H), 9.81 (s, 0.46H), 8.57 (t, J = 4.5 Hz, 1H), 8 .10 (t, J = 8.7 Hz, 1H), 7.89 7.82 (m, 1H), 7.48 7.42 (m, 1H), 6.85 (t, J = 4.8 Hz, 0.44H), 6.77 (t, J = 4.8 Hz, 0.56H), 6.66 (s, 0.86H), 6.62 (s,1.14H), 3.23 (sextet, J = 6.6 Hz, 2H), 2.77 (t, J = 6.9 Hz, 1H), 2.36 (t, J = 6.9 Hz, 1H), 1.46 1.31 (m, 9H). 13 C NMR (DMSO d 6 75 MHz) 172.9, 166.7, 156.1, 151.3, 151.2, 148.7, 148.6, 146.6, 142.9, 137.5, 137.4, 125.2, 125.0, 121.1, 120.9, 78.3, 37.5, 36.4, 33.5, 28.9. Anal. Calcd. for C 14 H 21 N 5 O 3 (307.36): C, 54.71; H, 6.89; N, 22.79. Found: C, 54.67; H, 6.95; N, 22.66. 2.4.3 General p r ocedure for the s ynthesis of a minoacyl 1 H 1,2,4 triazoles 2.13 a p, and 2.13 f': Method A: A solution of acylamidrazone 2.12 (2.0 mmol) in glacial acetic acid (1.00 mL) was heated under reflux for 1 h. The solution was poured over cold brine (20 mL) and the precipitate was filtered and washed with water. The resulting white solid was suspended in methanol (5 mL) and was filtered and dried in vacuo to afford the desired product as white microcrystals. In cases where a precipitate was not formed upon pouring th e reaction mixture over cold brine, the mixture was extracted using DCM (20 mL 3), and the organic layer was evaporated to afford 2.13 For the synthesis of 2.13 m,n HOAc (0.2 mL) was added to a solution of 2.12 m,n (1.0 mmol) in ethanol (10 mL) which was heated under reflux for 2 h. The solvent was evaporated under reduced pressure and the resulting solid was suspended in saturated Na 2 CO 3 /Ether (1:1, 20 mL). The suspension was stirred vigorously for 10 min, and the solid was filter ed and dried to afford t he desired product. F or the synthesis of 2.13 o,p (1.0 mmol) in HOAc (1 mL) was subjected to microwave irradiation of 100 W for 30 min at 180 C. The solution was evaporated under reduced pressure, and the resulting solid was stirred in diethyl

PAGE 34

34 ether for 2 0 min at rt. The precipitate was filtered and dried in vacuo to afford 2.13 o,p as a white solid. Method B: A solution of 2.12 (2.0 mmol) in glacial acetic acid (1.00 mL) was irradiated (50 W, + cooling) at 130 C for 5 min. The mixture was worked up as in A. ( S ) Benzyl (2 methyl 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)propyl)carbamate ( 2.13 a) White microcrystals (87%); mp 127.0 129.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.51 (br s, 1H), 8.70 (s, 1H), 8.04 (d, J = 7.5 Hz, 1H), 8.00 7.87 (m, 1H), 7.65 7.45 (m, 2H), 7.40 7.20 (m, 5H), 5.04 (s, 1H), 5.04 (s, 1H), 4.55 (t, J = 8.1 Hz, 1H), 2.25 2.15 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz) 164.2, 156.1, 149.5, 146.0, 137.5, 137.0, 128.3, 127.7, 124.9, 127.6, 121.2, 6 5.3, 55.0, 31.6, 19.4, 18.6. Anal. Calcd. For C 19 H 21 N 5 O 2 (351.41): C, 64.94; H, 6.02; N, 19.93. Found: C, 65.16; H, 6.13; N, 19.66. ( S ) Benzyl (2 phenyl 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)ethyl)carbamate ( 2.13 b) White microcrystals (82%); mp 134.0 136.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.56 (br s, 1H), 8.70 (br s, 1H), 8.06 (t, J = 7.5 Hz, 1H), 8.10 7.94 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 5.7 Hz, 1H), 7.38 7.14 (m, 9H), 5.10 4.90 (m, 3H), 3.29 3.03 (m, 2H). 13 C NMR (DMSO d 6 75 MHz) 164.7, 155.7, 154.0, 149.5, 146.3, 13 8.4, 137.8, 137.2, 129.2, 128.2, 128.1, 127.6, 127.4, 126.2, 125.0, 121.2, 65.1, 51.2. Anal. Calcd. for C 23 H 21 N 5 O 2 (399.46): C, 69.16; H, 5.30; N, 17.53. Found: C, 69.49; H, 5.26; N, 17.44. Benzyl (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)methylcarbamate ( 2. 13 c) : White microcrystals (90%); mp 191.0 193.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.57 (br s, 1H), 8.69 (d, J = 4.2 Hz, 1H), 8.08 (m, 2H), 7.83 (t, J = 6.0 Hz, 1H), 7.51 (t, J = 5.7 Hz,

PAGE 35

35 1H), 7.42 7.25 (m, 5H), 5.07 (s, 2H), 4.33 (d, J = 5.7 Hz, 2H). 13 C NMR (DMSO d 6 75 MHz) 161.9, 156.3, 154.1, 149.5, 146.2, 137.8, 137.2, 128.3, 1 27.7, 125.0, 121.2, 65.4, 38.4. Anal. Calcd. for C 16 H 15 N 5 O 2 (309.33): C, 62.13; H, 4.89; N, 22.64. Found: C, 62.12; H, 4.84; N, 22.81. Benzyl ((1 S ,2 S ) 2 methyl 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)butyl)carbamate ( 2.13 d) White microcrystals (81%); mp 109.0 111.0 C. 1 H NMR (CDCl3, 300 MHz) 11.90 10.95 (br, 1H), 8.69 (d, J = 4.5 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.35 7.26 (m, 5H), 6.54 (d, J = 9.3 Hz, 1H), 5.19 5.00 (m, 3H), 2.10 1.95 (m, 1H), 1.65 152 (m, 1H), 1.22 1.10 (m, 1H), 0.94 0.85 (m, 6H). 13 C NMR (CDCl3, 75 MHz) 174.2, 162.6, 156.4, 155.9, 149.2, 146.7, 137.8, 136.4, 128.4, 128.0, 124.8, 122.2, 66.9, 53.9, 39.4, 25.0, 15.4, 11.4. Anal. Calcd. for C 20 H 23 N 5 O 2 (365.43): C, 65.73; H, 6.34; N, 19.16. Found: C, 65.74; H, 6.38; N, 19.14. ( S ) Benzyl (2 (1 H indo l 3 yl) 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)ethyl)carbamate ( 2.13 e) White microcrystals (72%); mp 88.0 90.0 C. 1 H NMR (DMSO d 6 300 MHz) 13.42 (br s, 1H), 8.45 (s, 2H), 8.03 (d, J = 7.8 Hz,1H), 7.61 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.28 6.78 (m, 9H), 6.58 (s, 1H), 6.36 (d, J = 7.2 Hz 1H), 5.50 5.30 (m, 1H), 5.03 (d, J = 12.0 Hz, 1H), 4.94 (d, J = 12.0 Hz, 1H), 3.50 3.20 (m, 2H). 13 C NMR (CDCl 3 75 MHz) 162.5, 156.4, 156.3, 149.4, 147.1, 137.5, 136.5, 136.0, 128.5, 128.1, 127.8, 1 24.7, 123.5, 122.1, 121.7, 119.3, 118.6, 111.2, 110.2, 66.9, 50.3, 30.8. Anal. Calcd. for C 25 H 22 N 6 O 2 2 O (438.49): C, 67.55; H, 5.14; N, 18.91. Found: C, 67.81; H, 5.08; N, 18.38. ( S ) Benzyl 1 (3 (pyridin 2 yl) 1 H 1,2,4 triazol 5 yl)ethylcarbamate ( 2.13 f) White microcrystals (86%); mp 156.0 158.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.53

PAGE 36

36 (br s, 1H), 8.68 (d, J = 4.2 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 7.5 Hz, 1H), 7.82 (br s, 1H), 7.49 (t, J = 5.7 Hz, 1H), 7.42 7.22 (m, 5H), 5.04 (s, 2H), 4.85 (qu in, J = 7.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz) 155.6, 149.5, 137.6, 137.1, 128.3, 127.7, 124.6, 121.2, 65.3, 44.8, 20.1. Anal. Calcd. for C 17 H 17 N 5 O 2 (323.36): C, 63.15; H, 5.30; N, 21.66. Found: C, 63.10; H, 5.32; N, 21.82. Benz yl (1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)ethyl)carbamate ( 2.13 f') White microcrystals (85%); mp 160.0 162.0 C. 1 H NMR (DMSO d 6 300 MHz) 8.65 (d, J = 4.5 Hz, 1H), 8.10 8.00 (m, 2H), 7.91 (t, J = 6.9 Hz, 1H), 7.50 7.20 (m, 7H), 5.15 4.98 (m, 2H), 4 .87 (quint, J = 7.5 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz) 156.9, 149.5, 147.2, 143.9, 142.6, 139.4, 137.4, 137.4, 135.4, 133.2, 129.5, 128.9, 127.7, 127.3, 124.5, 124.3, 123.9, 122.2, 121.4, 121.2, 121.2, 120.7, 120.0, 109.8, 47.2, 46.0, 24.3, 22.7, 22.2, 21.8. Anal. Calcd. for C 17 H 17 N 5 O 2 (323.36): C, 63.15; H, 5.30; N, 21.66. Found: C, 63.50; H, 5.28; N, 21.84. ( S ) (9 H Fluoren 9 yl)methyl (2 methyl 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)propyl)carbamate ( 2.13 g) White microcrys tals (90%); mp 169.0 171.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.23 (br s, 1H), 8.69 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.87 (d, J = 7.7 Hz, 3H), 7.75 (t, J = 8.7 Hz, 2H), 7.49 (t, J = 5.7 Hz, 1H), 7.45 7.35 (m, 2H), 7.33 7.25 (m, 2H), 4.54 (t, J = 8.1 Hz, 1H), 4.33 4.15 (m, 3H ), 2.23 (sextet, J = 7.2 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz) 156.9, 146.5, 147.2, 143.9, 124.6, 139.4, 137.4, 137.4, 125.4, 133.2, 129.5, 128.9, 127.7, 124.5, 124.3, 123.9, 122.2, 121.4, 121.2, 121.2, 120 .7, 120.0, 109.8, 47.2, 46.0, 24.3, 22.7, 22.2, 21.8. Anal. Calcd. for C 26 H 25 N 5 O 2 (439.52): C, 71.05; H, 5.73; N, 15.93. Found: C, 70.73; H, 5.70; N, 15.64.

PAGE 37

37 (9 H Fluoren 9 yl)methyl (3 (pyridin 2 yl) 1 H 1,2,4 triazol 5 yl)methylcarbamate ( 2.13 h) White micr ocrystals (89%); mp 203.0 205.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.56 (br s, 1H), 8.69 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.00 7.91 (m, 2H), 7.88 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 5.7 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 4.44 4.19 (m, 5H). 13 C NMR (DMSO d 6 75 MHz) 161.9, 156.3, 154.1, 149.5, 146.2, 143.9, 140.7, 137.8, 127.6, 127.1, 125.3, 125.0, 121.2, 120.1, 65.7, 46.7, 38.4. Anal. Calcd. For C 23 H 19 N 5 O 2 (397.44): C, 69.51; H, 4.82; N, 17.62. Found: C, 69.20; H, 4.65; N, 17.62. ( S ) (9 H Fluoren 9 yl)meth yl (3 methyl 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)butyl)carbamate ( 2.13 i) White microcrystals (80%); mp 109.0 111.0 C. 1 H NMR (DMSO d 6 300 MHz) 9.97 (br s, 1H), 8.58 (br s, 1H), 8.07 (t, J = 7.8 Hz, 1H), 7.88 7.25 (m, 9H), 6.76 (s, 1H), 6.69 (s, 1H), 5.18 5.00 (m, 1H), 4.38 4.10 (m, 3H), 1.82 1.40 (m, 3H), 1.00 0.80 (m, 6H). 13 C NMR (DMSO d 6 75 MHz) 155.8, 149.5, 143.9, 140.7, 127.6, 127.0, 125.3, 121.2, 120.1, 65.5, 46.7, 24.2, 22.8, 21.7. Anal. Calcd. for C 27 H 27 N 5 O2 (439.52): C, 71.50; H, 6.0 0; N, 15.44. Found: C, 71.13; H, 6.23; N, 15.32. ( R ) (9 H Fluoren 9 yl)methyl (2 (tert butoxy) 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)ethyl)carbamate ( 2.13 j) White microcrystals (84%); mp 108.0 111.0 C. 1 H NMR (DMSO d 6 300 MHz) 8.72 (s, 1H), 8.19 (d J = 7.5 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 2H, 7.41 7.22 (m, 6H), 6.27 (d, J = 6.6 Hz, 1H), 5.30 5.20 (m, 1H), 4.49 (d, J = 6.6 Hz, 2H), 4.23 (t, J = 6.6 Hz, 1H), 3.98 3.88 (m, 1H), 3.83 3.77 (m, 1H), 1.13 ( s, 9H) 13 C NMR (DMSO d 6 75 MHz) 156.4, 147.3, 144.0, 141.4, 137.4, 127.8, 127.2, 125.3, 124.8, 121.8, 120.1, 73.9, 67.3, 63.4,

PAGE 38

38 50.3, 47.4, 27.6. Anal. Calcd. for C 28 H 29 N 5 O 3 (483.58): C, 69.55; H, 6.04; N, 14.48. Found: C, 69.38; H, 6.26; N, 14.02. ( S ) (9 H Fluoren 9 yl)methyl (2 phenyl 1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)ethyl)carbamate ( 2.13 k) White microcrystals (90%); mp 178.0 180.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.55 (br s, 1H), 8.72 (s, 1H), 8.08 (d, J = 7.2 Hz, 1H), 8.00 (t, J = 7.8 Hz, 1.5H), 7.88 (d, J = 7.5 Hz, 2H), 7.6 7 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 5.1 Hz, 1H), 7.43 7.17 (m, 9.5H), 7.32 7.15 (m, 7H), 5.05 4.90 (m, 1H), 4.30 4.10 (m, 3H), 3.39 3.05 (m, 2H). 13 C NMR (DMSO d 6 75 MHz) 155.6, 149.5, 143.8, 140.6, 137.6, 129.2, 128.1, 127.6, 127.0, 126.2, 125.3, 121.2, 120.0, 65.6, 46.6. Anal. Calcd. For C 30 H 25 N 5 O 2 (487.57): C, 73.90; H, 5.28; N, 14.36. Found: C, 73.58; H, 5.28; N, 14.15. ( S ) (9 H Fluoren 9 yl)methyl(2 (1 H indol 3 yl) 1 (3 (pyridin 2 yl) 1 H 1,2,4 triazol 5 yl)ethyl)carbamate hydrate ( 2.13 l) White microc rystals (81%); mp 133.0 135.0 C. 1 H NMR (DMSO d 6 300 MHz): 10.83 (s, 1H), 8.69 (d, J = 4.5 Hz, 1H), 8.09 (d, J = 4.8 Hz, 1H), 8.04 7.92 (m, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.5 Hz, 1H), 7.46 7.22 (m, 5H), 7.10 (d, J = 2.1 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.96 (t, J = 7.5 Hz 1H), 5.03 (q, J = 8.4 Hz, 1H), 4.25 4.04 (m, 3H), 3.40 (dd, J = 14.7, 6.3 Hz, 1H), 3.24 (dd, J = 14.7 Hz, 6.3 Hz, 1H). 13 C NMR (CDCl 3 75 MHz) 162.5, 156.6, 156.3, 149.3, 147.0, 144.0, 143.8, 141.3, 137.7, 136.0, 127.7, 127.1, 125.2, 124.8, 123.5, 122. 1, 121.9, 120.0, 119.5, 118.6, 11.3, 110.3, 67.1, 50.3, 47.2, 30.7. Anal. Calcd. for C 32 H 26 N 6 O 2 .H 2 O (544.62): C, 70.57; H, 5.18; N, 15.43. Found: C, 70.20; H, 5.29; N, 15.71. t Butyl ((5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)methyl)carbamate ( 2.13 m) White microcrystals (79%); mp 194.0 196.0 C. 1 H NMR (DMSO d 6 300 MHz): 14.31

PAGE 39

39 (br s, 1H), 8.67 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 8.00 (t, J = 7.8 Hz, 1H), 7.48 (t, J = 6.0 Hz, 1H), 7.34 (t, J = 5.7 Hz, 1H), 4.24 (d, J = 5.7 Hz, 2H), 1.39 (s, 9H). 13 C NMR (DMSO d 6 75 MHz) 170.2, 165.0, 155.8, 150.5, 150.3, 148 .0, 147.9, 146.7, 142.6, 136.8, 124.6, 124.4, 120.4, 120.1, 78.0, 77.8, 42.4, 41.5, 28.2. Anal. Calcd. for C 13 H 17 N 5 O 2 (275.31): C, 56.72; H, 6.22; N, 25.44. Found: C, 56.59; H, 6.33; N, 24.27. ( S ) t Butyl (1 (5 (pyridin 2 yl) 1 H 1,2,4 triazol 3 yl)ethyl)ca rbamate ( 2.13 n) White microcrystals. (83%), mp 162.0. 164.0 C. 1 H NMR (DMSO d 6 300 MHz) 8.74 (d, J = 3.9 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.86 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 6.9 Hz, 1H), 5.60 (d, J = 7.5 Hz, 1H), 5.09 (br s, 1H), 1.62 (d, J = 6.9 Hz, 3H), 1.45 (s, 9H). 13 C NMR (DMSO d 6 75 MHz) 155.5, 149.6, 137.6, 124.8, 122.0, 44.9 28.5, 21.4. HRMS Calcd. for C 13 H 17 N 5 O 2 [M+H] + : 290.1612. Found [M+H] + : 290.1604 N ((3 (Pyridin 2 yl) 1 H 1,2,4 triazol 5 yl)methyl)acetamide (2.13 o). White solid (91%); mp 178.0 180.0 C. 1 H NMR (DMSO d 6 300 MHz) 14.65 14.20 (m, 1H), 8.66 (s, 1H), 8.43 (br s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.47 (s, 1H), 4.38 (s, 2H), 1.88 (s, 3H). 13 C NMR (DMSO d 6 75 MHz) 169.2, 161.7, 154.2, 149.5, 146.0, 137.8, 125.0, 121.2, 36.5, 22.6. Anal. Calcd. for C 10 H 11 N 5 O (217.23): C, 51.06; H, 4.71; N, 29.77. Found: C, 51.01; H, 4.62; N, 29.50. ( S ) N (1 (3 (Pyridin 2 yl) 1 H 1,2,4 triazol 5 yl)ethyl)acetamide ( 2.13 p). White solid (90%); mp 195.0 196.0 C. 1 H NMR (DMSO d 6 300 MHz) 8.67 (dd, J = 3.9, 0.9 Hz, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.94 (t, J = 7.5 Hz, 1H), 7.47 (d, 6.3 Hz, 1H), 5.08 (quint, J = 7.2 Hz, 1H), 1.86 (s, 3H), 1.44 (d, J = 7.2 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz) 168.6, 149.5, 137.5, 127.6, 121.2, 42.4, 22.6, 20.2. Anal. Calcd. for C 11 H 13 N 5 O (231.26): C, 57.06; H, 5. 67; N, 30.28. Found: C, 57.06; H, 5.67; N, 30.25.

PAGE 40

40 2.4.4 General p rocedure for the s ynthesis of a mino acyl hydrazide s 2.20 a g, 2.20 a', 2.20 f': Hydrazine hydrate (1.0 mmol) was added to a solution of N protected amino acylbenzotriazole 2.10 (1.0 mmol) in THF (10 mL). The solution was stirred for 15 min at room temperature. The solvent was removed under reduced pressure and the resulting crude mixture was dissolved in ethyl acetate and washed with water (20 mL x 2). The organic layer was dried over anhydrous so dium sulfate and was dried under reduced pressure. The resulting solid was suspended in ether and the insoluble solid was collected on a Buchner funnel to afford the desired product as white microcrystals. ( S ) Benzyl (1 hydrazinyl 3 methyl 1 oxobutan 2 yl) carbamate ( 2.20 a) White microcrystals (86%); mp 163.0 165.0 C (Lit. mp 178.0 C)25. 1 H NMR (CDCl 3 300 MHz) 7 7.79 (br s, 1H), 7.34 7.26 (m, 5H), 5.56 (d, J = 9.0 Hz, 1H), 5.15 5.05 (m, 2H), 3.94 (dd, J = 9.0, 7.2 Hz, 1H), 2.13 2.04 (m, 1H), 0.95 0.92 (m, 6H). 13 C NMR (CDCl 3 75 MHz) 172.2, 156.1, 136.1, 128.7, 128.4, 128.2, 64.3, 59.5, 31.0, 19.3, 18.2. Ana l. Calcd. for C 13 H 19 N 3 O 3 (265.31): C, 58.85; H, 7.22; N, 15.84. Found: C, 59.00; H, 7.47; N, 15.64. Benzyl (1 hydrazinyl 3 methyl 1 oxobutan 2 yl)carbamate (1:1) ( 2.20 a'). White microcrystals (78%); mp 126.0 128.0 C. 1 H NMR (CDCl 3 300 MHz) 8.40 8.20 (b r s, 1H), 7.40 7.26 (m, 5H), 5.84 (d, J = 9.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.04 (d, J = 12.3 Hz, 1H), 4.15 3.85 (m, 3H), 2.05 (sextet, J = 6.0 Hz, 1H), 0.91 (d, J = 6.6 Hz, 6H). 13 C NMR (CDCl 3 75 MHz) 172.3, 156.7, 136.2, 128.6, 128.3, 128.1, 67. 2, 59.4, 31.0, 19.3, 18.2. Anal. Calcd. for C 13 H 19 N 3 O 3 (265.31): C, 58.85; H, 7.22; N, 15.84. Found: C, 58.61; H, 6.97; N, 16.01.

PAGE 41

41 ( S ) Benzyl (1 hydrazinyl 1 oxo 3 phenylpropan 2 yl)carbamate ( 2.20 b) White microcrystals (94%); mp 153.0 155.0 C (Lit. mp 16 4.0 165.0 C). 1 H NMR (DMSO d 6 300 MHz) 9.27 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.36 7.10 (m, 10H), 4.94 (s, 2H), 4.30 4.18 (m, 3H), 2.97 2.75 (m, 2H). 13 C NMR (DMSO d 6 75 MHz) 170.8, 155.7, 138.1, 137.0, 129.2, 128.3, 128.1, 127.7, 127.5, 126.3, 65.2, 55.0, 37.8. Anal. Calcd. for C 10 H 13 N 3 O 3 (313.36): C, 65.16; H, 6.11; N, 13.41. Found: C, 64.88; H, 6.12; N, 13.32. Benzyl (2 hydrazinyl 2 oxoethyl)carbamate ( 2.20 c) White microcrystals (86%); mp 163.0 165.0 C (Lit. mp 115.0 C). 1 H NMR (DMSO d 6 300 MHz) 9.07 (s, 1H), 7.45 (t, J = 6.3 Hz, 1H), 7.37 7.28 (m, 5H), 5.02 (s, 2H), 4.20 (s, 2H), 3.58 (d, J = 6.3 Hz, 2H). 13 C NMR (DMSO d 6 75 MHz) 168.5, 156.4, 137.0, 128.3, 127.7, 65.5, 42.3. Anal. Calcd. For C 10 H 13 N 3 O 3 (313.36): C, 53.81; H, 5.87; N, 18.82. Found: C, 53.52; H, 5.77; N, 18.68. ( S ) Benzyl (1 hydrazinyl 4 methyl 1 oxopentan 2 yl)carbamate ( 2.20 d) White microcrystals (87%); mp 159.0 161.0 C. 1 H NMR (CDCl 3 300 MHz) 7.85 (br s, 1H), 7.40 7.26 (m, 5H), 5 8 (d, J = 8.7 Hz, 1H), 5.14 5.03 (m, 2H), 3.99 (dd, J = 9.0, 7.2 Hz, 1H), 1. 82 1.78 (m, 1H), 1.60 1.45 (m, 1H), 1.16 1.06 (m, 1H), 0.92 0.85 (m, 6H). 13 C NMR (CDCl 3 75 MHz) 172.2, 156.5, 136.2, 128.7, 128.4, 128.2, 67.3, 58.6, 37.2, 24.9, 15.6, 11.3. Anal. Calcd. for C 14 H 21 N 3 O 3 (279.34): C, 60.20; H, 7.58; N, 15.04. Found: C, 6 0.37; H, 7.90; N, 14.89. ( S ) Benzyl (1 hydrazinyl 3 (1 H indol 3 yl) 1 oxopropan 2 yl)carbamate ( 2.20 e) White microcrystals (90%); mp 163.0 165.0 C. 1 H NMR (DMSO d 6 300 MHz) 10.81 (br s, 1H), 9.26 (br s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 7.24 (m, 6H), 7.14 (d, J = 1.5 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 5.00

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42 4.89 (m, 2H), 4.25 4.21 (m, 3H), 3.04 (dd, J = 14.4, 5.1 Hz, 1H), 2.91 (dd, J = 14.6, 9.5 Hz, 2H). 13 C NMR (DMSO d 6 75 MHz) 171.1, 155.7, 137. 0, 136.0, 128.3, 127.7, 127.5, 127.2, 123.8, 120.8, 118.5, 118.2, 111.3, 110.1, 65.2, 54.2, 28.1. Anal. Calcd. for C 19 H 20 N 4 O 3 (352.40): C, 64.76; H, 5.72; N, 15.90. Found: C, 64.94; H, 5.89; N, 15.95. ( S ) Benzyl (1 hydrazinyl 1 oxopropan 2 yl)carbamate ( 2. 20 f). White microcrystals (78%); mp 111.0 113.0 C (Lit. mp 138.5 C). 1 H NMR (DMSO d 6 300 MHz) 7.79 (br s, 1H), 7.40 7.20 (m, 5H), 5.43 (d, J = 7.2 Hz, 1H), 5.15 5.04 (m, 2H), 4.30 4.15 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz) 173.1, 156.1, 136.1, 128.7, 128.4, 128.3, 67.4, 49.4, 18.5. Anal. Calcd. for C 14 H 21 N 3 O 3 (237.26): C, 55.69; H, 6.37; N, 17.71. Found: C, 56.01; H, 6.38; N, 17.90. ( R and S ) Benzyl (1 hydrazinyl 1 oxopropan 2 yl)carbamate (1:1) ( 2.20 f). White microcrystals (75%); mp 116.0 11 8.0 C (Lit. mp 119.0 120.0 C) 1 H NMR (DMSO d 6 300 MHz) 9.08 (s, 1H), 7.44 7.30 (m, 6H), 5.00 (s, 2H), 4.19 (s, 2H), 4.00 (quint, J = 7.5 Hz, 1H), 1.18 (d, J = 7.2 Hz, 3H). 13 C NMR (DMSO d 6 75 MHz): 171.8, 155.5, 137.0, 128.3, 127.7, 65.3, 48.8, 18.4. Anal. Calcd. for C 14 H 21 N 3 O 3 (237.26): C, 55.69; H, 6.37; N, 17.71. Found: C, 55.83; H, 6.51; N, 17.65. ( S ) (9 H Fluoren 9 yl)methyl (1 hydrazinyl 4 methyl 1 oxopentan 2 yl)carbamate ( 2.20 g). White microcrystals (75%); mp 165.0 167.0 C. 1 H NMR (DMSO d 6 300 MHz) 9.13 (br s, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 7.5 Hz, 2H) 7.50 7.27 (m, 5H), 4.28 4.15 (m, 5H), 4.03 3.95 (m, 1H), 1.57 1.30 (m, 3H), 1.00 0.75 (m, 6H). 13 C NMR (DMSO d 6 75 MHz): 171.5, 155.8, 143.9, 143.8, 140.7, 127.6, 127.0, 125.3, 120.1, 65.5, 51.7, 46.7, 41.0, 24.2, 22.9, 21.6. Anal. Calcd. for C 21 H 25 N 3 O 3 (367.45): C, 68.64; H, 6.86; N, 11.44. Found: C, 68.94; H, 7.10; N, 11.62.

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43 2.4.5 General p rocedure for the s ynthesis of 3,6 d isubstituted 1,2,4 triazine s 2.22 : Method A: N Cbz aminoacylhydrazide 2.20 (2.0 mmol) was heated in a mixture of ethanol (2.00 m L) and glacial AcOH (0.50 mL) at 60 C, until a c B romo ketone 2.21 (1.0 mmol) was then added to the solution which was irradiated by microwave (50 W, 95 C) for 1 h. K OAc (2.0 mmol) was added to the brownish solution which was irr adiated under the same conditions for 1h. The solvent was removed under reduced pressure and the crude solid was dissolved in DCM (20 mL), and was washed with brine (2 20 mL), sat. Na 2 CO 3 (3 20 mL) and water (20 mL). The elution was dried over anhydrou s Na 2 SO 4 and was evaporated under reduced pressure. The resulting solid was purified using column chromatography (hexanes: ethyl acetate, 3:1) to afford the title product 2.22 Method B: N Cbz aminoacylhydrazide 2.20 (2.0 mmol) was heated in a mixture of e thanol (3.00 mL) and glacial AcOH (1.00 mL) at 60 C, until a clear solution resulted. NaOAc (1.1 mmol) and 2.21 (1.0 mmol) were added, and the mixture was heated under reflux for 7 h. The solution was poured onto ice/H2O and neutralized with NaHCO 3 The s olution was extracted with DCM (3 x 20 mL), the organic layer dried over anhydrous Na 2 SO 4 and the solvent evaporated under reduced pressure. The resulting crude solid was purified using column chromatography (hexanes: ethyl acetate, 3:1) to afford the titl e product 2.22 ( S ) Benzyl (1 (6 (4 bromophenyl) 1,2,4 triazin 3 yl)ethyl)carbamate (2.22 a) Yellow microcrystals (61%); mp 96.0 98.0 C. 1 H NMR (DMSO d 6 300 MHz) 9.43 (s, 1H), 8.18 (d, J = 7.5 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H) 7.44 7.26 (m, 5H), 5.05 (d, J = 12.3 Hz, 1H), 4.99 (d, J = 12.6 Hz, 1H), 4.76 (t, J = 7.5 Hz, 1H), 2.35 2.18 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.3 Hz, 3H). 13 C NMR

PAGE 44

44 (DMSO d 6 75 MHz): 167.6, 156.3, 154.5, 147.7, 137.0, 132.3, 132.2, 128.9, 128.3, 127.8, 127.7, 124.8, 65.4, 61.6, 31.8, 19.4, 18.7. Anal. Calcd. for C 21 H 21 BrN 4 O 2 (441.33): C, 57.15; H, 4.80; N, 12.70. Found: C, 57.44; H, 4.76; N, 12.15. ( S ) Benzyl (1 (6 (4 bromophenyl) 1,2,4 triazin 3 yl) 2 phenylethyl)carbamate hydrate ( 2.22 b) Yellow microcrystals (40%); mp 141.0 143.0 C. 1 H NMR (CDCl 3 300 MHz) 8.90 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.40 7.14 (m, 8H), 7.01 (br s, 2H), 5.96 (br, 1H), 5.88 (d, J = 8.1 Hz, 1H), 5.65 5.50 (m, 1H), 5.12 (d, J = 12.3 H z, 1H), 5.06 (d, J = 12.6 Hz, 1H), 3.42 (dd, J = 13.7, 5.9 Hz, 1H), 3.30 (dd, J = 13.7, 6.8 Hz, 1H). 13 C NMR (CDCl 3 75 MHz): 166.9, 155.9, 155.2, 146.2, 136.2, 136.1, 132.9, 131.9, 128.7, 128.5, 128.3, 127.1, 126.3, 67.2, 56.5, 41.5. Anal. Calcd. for C 2 5 H 21 BrN 4 O 2 .H 2 O (507.39): C, 59.18; H, 4.57; N, 11.04. Found: C, 59.34; H, 4.03; N, 11.01. Benzyl (6 (4 bromophenyl) 1,2,4 triazin 3 yl)methylcarbamate ( 2.22 c) White microcrystals (43%); mp 132.0 134.0 C. 1 H NMR (CDCl 3 300 MHz) 8.95 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.50 7.26 (m, 5H), 5.96 (br, 1H), 5.17 (s, 2H), 4.89 (d, J = 5.7 Hz, 2H). 13 C NMR (CDCl 3 75 MHz) 164.4, 156.7, 155.5, 146.6, 136.5, 132.9, 131.9, 128.7, 128.4, 128.3, 126.2, 67.3, 45.4. Anal. Calcd. for C 18 H 15 Br N 4 O 2 (399.25): C, 54.15; H, 3.79; N, 14.03. Found: C, 54.23; H, 3.69; N, 13.96. ( S ) Benzyl (1 (6 (4 bromophenyl) 1,2,4 triazin 3 yl)ethyl)carbamate ( 2.22 d) Yellow microcrystals (28%); mp 139.0 140.0 C. 1 H NMR (CDCl 3 300 MHz) 8.94 (s, 1H), 7.96 (dt, J = 8.7, 2.1 Hz, 2H), 7.70 (dt, J = 8.7, 2.1 Hz, 2H), 7.45 7.25 (m, 5H), 5.99 (d, J = 4.8 Hz, 1H), 5.33 (quint, J = 7.2 Hz, 1H), 5.16 (d, J = 12.3 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 1.65 (d, J = 7.5 Hz, 3H). 13 C NMR (CDCl 3 75 MHz) 168.2, 155.4, 155.3,

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45 14 6.6, 136.5, 132.8, 132.0, 128.6, 128.4, 128.2, 126.1, 67.0, 51.7, 21.9. Anal. Calcd. for C 19 H 17 BrN 4 O 2 (413.28): C, 52.22; H, 4.15; N, 13.56. Found: C, 55.20; H, 4.06; N, 13.16. Benzyl (1 (6 (4 bromophenyl) 1,2,4 triazin 3 yl)ethyl)carbamate ( 2.22 d) Yello w microcrystals (30%); mp 57.0 59.0 C. 1 H NMR (CDCl 3 300 MHz) 8.95 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.40 7.26 (m, 5H), 5.94 (d, J = 7.5 Hz, 1H), 5.33 (quint, J = 7.2 Hz, 1H), 5.13 (dd, J = 19.8, 12.3 Hz, 2H), 1.65 (d, J = 6. 9 Hz, 3H). 13 C NMR (CDCl 3 75 MHz) 168.2, 155.3, 146.6, 136.5, 132.8, 132.0, 128.6, 128.4, 128.3, 126.1, 67.1, 51.7, 22.0. Anal. Calcd. for C 19 H 17 BrN 4 O 2 (413.28): C, 55.22; H, 4.15; N, 13.56. Found: C, 55.30; H, 4.03; N, 13.40. 2.4.6 General p rocedure fo r the s ynthesis of 3,5,6 t risubstituted 1,2,4 triazine s 2.24 : A solution of N Cbz aminoacylhydrazide 2.20 (1.0 mmol), acenaphthenequinone 2.23 (1.0 mmol), and ammonium acetate (2.0 mmol) was subjected to microwave irradiation of 100 W at 180 C for 10 min. The resulting black solution was poured onto ice/water and the aqueous solution was washed with DCM (20 mL 3). The organic layer was dried over Na 2 SO 4 (anhyd.) and was evaporated under reduced pressure. The resulting crude solid was purified using colum n chromatography (hexanes: ethyl acetate; 3:1) to afford the desired product. ( S ) Benzyl (1 (acenaphtho[1,2 e ][1,2,4]triazin 9 yl) 2 methylpropyl)carbamate ( 2.24 a) Orange microcrystals (68%); mp 108.0 110.0 C. 1 H NMR (CDCl 3 300 MHz) 8.43 (d, J = 6.9 H z, 1H), 8.39 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.83 (dt, J = 8.1, 1.2 Hz, 2H), 7.42 7.26 (m, 5H), 6.17 (d, J = 9.3 Hz, 1H), 5.25 (dd, J = 9.0, 5.4 Hz, 1H), 5.17 (s, 2H), 1.05 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H).13C NMR (CDCl 3 75 MHz) 165.4, 157.4, 156.6, 155.7, 136.7, 134.3, 132.6,

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46 130.5, 130.0, 129.6, 128.9, 128.7, 128.3, 125.5, 123.9, 67.1, 61.1, 34.2, 19.8, 17.7. Anal. Calcd. for C 25 H 22 N 4 O 2 (410.48): C, 73.15; H, 5.40; N, 13.65. Found: C, 73.46; H, 5.38 ; N, 13.52. Benzyl (1 (acenaphtho[1,2 e ][1,2,4]triazin 9 yl) 2 methylpropyl)carbamate ( 2.24 a') Orange oil (64%). 1 H NMR (CDCl 3 300 MHz) 8.45 (d, J = 7.2 Hz, 1H), 8.41 (d, J = 6.9 Hz, 1H), 8.21(d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.84 (t, J = 7.5 Hz, H), 7.42 7.26 (m, 5H), 6.16 (d, J = 9.3 Hz, 1H), 5.25 (dd, J = 9.3, 5.7 Hz, 1H), 5.17 (s, 2H), 2.44 (sextet, J = 6.6 Hz, 1H), 1.05 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H). 13 C NMR (CDCl 3 75 MHz) 165.4, 157.4, 156.5, 155.7, 136.7, 134.3, 13 2.5, 130.4, 130.0, 129.6, 129.1, 128.9, 128.6, 128.3, 125.5, 123.9, 67.0, 61.1, 34.2, 19.7, 17.7. Anal. Calcd. for C 25 H 22 N 4 O 2 (410.48): C, 73.15; H, 5.40; N, 13.65. Found: C, 73.32; H, 5.44; N, 13.52. (S) Benzyl (1 (acenaphtho[1,2 e ][1,2,4]triazin 9 yl) 2 phenylethyl)carbamate ( 2.24 b) Orange microcrystals (61%); mp 112.0 114.0 C. 1 H NMR (CDCl 3 300 MHz) 88.49 (d, J = 4.2 Hz, 1H), 8.42 (d, J = 6.9 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.87 (t, J = 7.2 Hz, 2H), 7.42 7.00 (m, 10 H), 6.14 (d, J = 8.4 Hz, 1H), 5.67 (q, J = 7.5 Hz, 1H), 5.19 5.08 (m, 2H), 3.50 (dd, J = 13.9, 5.9 Hz, 1H), 3.38 (dd, J = 13.7, 6.8 Hz, 1H). 13 C NMR (CDCl 3 75 MHz) 165.1, 157.5, 156.0, 155.8, 136.5, 134.4, 132.7, 130.5, 130.0, 129.7, 128.7, 129.5, 129.2, 12 9.1, 129.0, 128.6, 128.5, 128.2, 126.8, 125.7, 124.1, 109.8, 66.9, 57.0, 41.7. Anal. Calcd. for C 29 H 22 N 4 O 2 (458.52): C, 75.97; H, 4.84; N, 12.22. Found: C, 75.57; H, 4.78; N, 12.12.

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47 CHAPTER 3 BENZOTRIAZOLE MEDIATED SYNTHESIS AND TAUTOMERIC STUDY OF CHIRAL HETEROCYCLIC AMINO AC IDS 1 3.1 H eterocyclic A mino A cids It is well known that amino acids can serve as fundamental scaffolds to a broad array of heterocyclic compounds that exhibit in teresting biological activit ies [ 2008EJOC5583 2007ACIE7930 2001J CSPT2404 ] One prominent example include s t he incorporation o f metal binding motifs into the peptide chain that ha s been employed as fluorescent probes for in vivo and in vitro imaging of peptide dynamics. [ 2004JACS8598 ] In addition, heterocyclic substitute amino acids such as pyridines posses several pharmacological activities. [ 1994T1539 ] For instance, lathyrine 3.1 mimosine 3. 2 and azatyrosine 3. 3 show antibiotic, antitumor, and cell arrest activities (Figure 3 1) [ 1994T1539 2001B14862 1992CR1628 1999ECR148 1996JOC813 ] Furthermore, 2 aminopicoline containing cysteine 3.4 was designed as potent inhibito r of the human nitric oxide synthase ( NOS ) isozymes [ 2006BMC3536 ] Figure 3 amino acids of know n pharmacological effects Readily accessible pyridine and quinoline substituted amino acid s which have emerged to mimic inhibitors of t he HI V l protease have inspire d chemists to develop thera p eutics for the treatment of diseases such as osteoporosis, [ 2001JCS2404 ] diabetes [ 2008OPRD218 ] and ovarian cancer. [1992BJC1044] However, t he limited 1 Reproduced in part with permission from The Journal of Organic Chemistry 2010 75 3938 3940 Copyright 2010 American Chemical Society

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48 availability of natural amino acids for therapeutic studies h as stimulated the development of synthetic methods to approach such amino acids in hi gh enantio purity. [ 1995JOC2640 1991JACS9276 2011EJOC730 ] A potent example is the synthesis of DPP IV inhibitor LY2497282 3. 5 for the treatment of t ype 2 diabetes which was developed by Yu and co workers (Figure 3 1) [ 2008OPRD218 ] Figure 3 1. LY2497282 3.5 DPP IV inhibitor Scheme 3 1. Synthesis of ketone intermediate 3.8 A key step in the synthesis of LY2497282 3.5 was to achieve the chirally retained ketone 3.8 through coupling nico tinamide 3. 6 and Weinreb amide 3. 7 (Scheme 3 1) E pimerization was observed even though a variety of reaction conditions was employed to obtain the ketone intermediate 3.8 Whereas the maximum enantiomeric excess (ee) achieved for intermediate 3.8 was 80% lower ee was obtained upon scaling up the reaction The authors hypothesized that epimerization of intermediate 3.8 may be

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49 facilitated by the hydrogen bonding that may take place between the pyridine nitrogen and enol keto oxygen. T he authors employed a d ifferent strategy that afforded 3.5 in 10 step synthesis with overall yields of 39% because of difficulties encountered in resolving the diasteriomers obtained at later stages of the synthesis Several groups have reported the synthesis of chiral N protect ed amino ketones via coupling of Weinreb amides and nucleophiles. Yet the aforementioned example necessitated the search for an alternative coupling method for the synthesis of pharmacological heterocyclic amino acids. [ 1994BMCL1385, 1993TL5217, 1996TL 3165 ] Although a number of commercially available coupli ng reagents have been utilized as substrates to be C acylated by carbonyl activated N protected amino acids, [002JCC470] their use has been limited to readily active nucleophiles, e.g. d. The present work employ s benzotriazole activated N protected amino acids as substitute s for their corresponding Weinreb amides to prepare chirally pure N protected amino ketones 3.2 Results and Discussion 3.2.1 Preparation of N (Cbz aminoacyl)ben zotriazoles 3.11a N ( P aminoacyl)benzotriazoles are efficient ly versatile intermediates for N O C and S acylation by a plethora of biologically relevant compounds. [ 2000JOC8210, 2003JOC5720, 2005SL1656, 2005S397, 2006S411, 20 06S3231, 2008OBC2400] N ( Cbz aminoacyl)benzotriazoles 3.1 1 a e and 3.1 1 were prepared by treating commercially available N Cbz amino acids 3.9a e and 3.9( with 1 H benzo[ d ][1,2,3]triazole and thionyl chloride in dry THF at 20C for 2 3 hours (Tabl e 3 1)

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50 Table 3 1. Synthesis of N (Cbz aminoacyl)benzotriazoles 3.11a e and Entry Reactant 3.9 Product 3.11 Yield (%) Mp. ( C) [ ] 25 D 1 Z L Ala OH 3.9 a Z L Ala Bt 3.11 a 83 90 114 11 6 8.0 2 Z DL Ala OH 3.9 ( Z DL Ala Bt 3.11 70 111 11 3 0 3 Z L Val OH 3.9 b Z L Val Bt 3.11 b 72 86 106 108 30.5 4 Z L Ile OH 3.9 c Z L Ile Bt 3.11 c 64 71 77 79 3.9 5 Z L Trp OH 3.9 d Z L Trp Bt 3.11 d 65 75 104 106 + 25.3 6 Z L Lys(Z) OH 3.9 e Z L Lys(Z) Bt 1 3.11 e 50 74 83 + 24.5 1 Prepared by Mr. Mael Charpentier 3.2.2 Synthesis of 2 and 4 ( N Cbz aminoacyl)methylpyridines 3 .13 a d and 3.13e f and 2 ( N Cbz aminoacyl)methyl quinoline 3.1 3g 2 ( N C bz A minoacyl)methylpyridines 3.13 a d were prepared in 33 53% yield by reacting the lithium salt of 2 picoline 3.12 a with 3. 11 a d in THF at 78 C under dry conditions (Table 3 2 Entry 1 4 ) According to the work of Yu, the deprotonation of the exchangeable amide proton was faster than the nucleophilic atta ck of the dianion 3.7 at the W einr e b amide 3.6 (Scheme 3 1) Therefore, 3.6 was treated with i PrMgCl/THF prior to coupling with dianion 3.7 As a result we treated 2 picoline 3.12 a with 2.5 equiv of n BuLi for 1 h at 20 C The excess base was used to ensure that the acid/base reaction would only involve the amidic hydrogen when 3.11a d are added to the reaction mixture. 1 H NMR spectral analysis of in CDCl 3 indicated th at 3.13a d exist in keto / enol tautomeric forms. Such 3 (2 pyridyl)ketones are known i n the literature [ 2005ARK329 ]

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51 and tend to shift to the more dipolar keto form with increasing solvent polarity. The ratio s of 3.13a d isomers are summarized in Table 3 2. Table 3 2. Synthesis of 3.13 Entry 3.11 Het CH 2 Li 3 .1 2 3.13 Keto (%) Yield (%) [ ] 25 D 1 Z L Ala Bt 3.11 a 2 Picoline 3.12 a a 1 71 50 +7.6 2 Z L Val Bt 3.11 b 2 Picoline 3.12 a b 1 59 50 +2.0 3 Z L Ile Bt 3.11 c 2 Picoline 3.12 a c 1 59 53 + 1 1.0 4 Z L Trp Bt 3.11 d 2 Picoline 3.12 a d 1 67 33 + 26 .0 5 Z L Ala Bt 3.11 a 4 Picoline 3.12b e 100 44 5.0 6 Z L Val Bt 3.11 b 4 Picoline 3.12b f 100 46 +19 .0 7 Z L Ala Bt 3.11 a Quinaldine 3.12c g 2 0 48 25.5 8 Z DL Ala Bt 3.11 Quinaldine 3.12c 0 32 0 9 Z L Val Bt 3.11 b Quinaldine 3.12c h 2 0 53 79.8 10 Z L Ile Bt 3.11 c Quinaldine 3.12c i 2 0 52 70.3 11 Z L Trp Bt 3.11 d Quinaldine 3.12c j 2 0 49 +6.6 12 Z L Lys(Z) Bt 3.11 e Quinaldine 3.12c k 2 0 52 39.3 1 Prepared by Dr. Kiran Bajaj. 2 Prepared by Mr. Mael Charpentier 4 ( N Cbz aminoacyl)methylpyridines 3.1 3e f were prepared in moderate yields (44 46%) using the same conditions employed previously Although the resulting amino ketones 3.13e,f posses acidic methylene protons, the position of the endocyclic nitrogen of picoline does not affix 3.13e,f in the enol ic form as depicted in the corresponding 1 H NMR spectra ( methylene proton s of the keto appear as a singlet at 3.80, in CDCl 3 ).

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52 N Cbz aminoacyl q uinaldine 3.13g k were prepared following the same previous conditions. 1 H NMR spectra of 3.13g k (in CDCl 3 at ambient temperatures) interestingly showed only the enol tautomer We speculated that the lone pair of the endocyclic nitrogen of q uinaldine stabilizes the enol tautomers of 3.13g k via H bonding. Such H bonding is further pronounced in the quinaldine derivatives as compared to 2 picolines 3.13a d 3.2.2 HPLC s tudies on 3.13g and r acemate 3.13 Although the conditions employed to synthesize 3.13 afforded the desired targets in moderate yields (32 53%), it was important to determine the efficacy of thi s method in preparing chirally retained N heterocyclic amino acid conjugates. Hence, ketone 3.13g and a racemic mixture of D and L isomers 3.13g w ere analyzed by normal phase hexane/2 propanol chromatography on a Chiralcel OD H column with ( + ) ESI MS The chromatogram of 3.13g show ed a single peak with retention time of 34. 4 min and [M+H] + of 349.15 and whereas the racemic mixture 3 .1 3 show ed two peaks of 349.15 and with retention times of 34.4 and 61.4 min t h us confirm s the enantiomeric purity of 2 .1 3g 3.3 C onclusion This chapter present s a convenient one step synthesis of chirally retained aminoacyl conjugates of p icolines and qu in aldines. Such systems are known to exhibit a broad range of biological activities, yet their syntheses presented a challenge, particularly with regard to the chiral integrity. Although speculations regarding the loss of chirality ha ve been linked with the H bonding observed by such enolizable ketones, HPLC MS studies showed that these compounds, particular ly the quinol ine deriv atives that exist predominantly as the enol tautomer are enantiomerically pure In addition,

PAGE 53

53 these results shed light on the reaction conditions and workup methods used in the literature to prepare nitrogen containing aminoketones, and present 1 H benzotriazole as a reliable and suitable auxiliary for amino acids coupling reactions. 3.4 E xperimental 3.4.1 General m ethods Melting points were determined on a capillary point apparatus equipped with a digital thermometer and are uncorrected. The 1 H a nd 13 C NMR spectra for starting materials were recorded on a Varian Gemini or Mercury 300 instrument, operating at 300 MHz for 1 H and 75 MHz for 13 C with TMS as an internal reference. All reactions were carried out under an atmosphere of nitro gen unless o therwise specified. Anhydrous THF was obtained by distillation immediately prior to use, from sodium/benzophenone ketyl. Column chromatography was carried out on silica gel S733 3.4.2 General p rocedu re for the s ynthesis of N (Cbz aminoacyl)be nzotriazoles 3.11a e and 3.11 N (Cbz aminoacyl)benzotriazoles 3.11a e and 3.1 are prepared following our well established procedure [ 2009ARK47 ]. A solution of 1 H benzo[ d ][1,2,3]triazole (4.0 mmol) and SOCl 2 in dry THF was stirred at rt for 20 min. N Cbz amino acid (1.0 mmol) was then added to the solution. After stirring for 3 h, the precipitate ( S ) B enzyl (1 (1H benzo[ d ][1,2,3]triazol 1 yl) 1 oxopropan 2 yl)carbamate ( 3.11a ) : White microcrystals ( 7 2 86 %) ; mp 106.0 108.0 C 1 H NMR (300 MHz, CDCl 3 ) 8.26 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.67 (td, J = 8.1, 0.8 Hz, 1H), 7.5 5 7.5 0 (m, 1H), 7. 42 7. 33 (m, 4H), 7.14 (br s, 1H), 5.78 5.84 (m, 1H), 5.69 (d, J = 7.6 Hz, 1H), 5.17 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 12.2 Hz, 1H), 1.69 (d, J = 7.0 Hz, 3H). 13 C

PAGE 54

54 NMR (75 MHz, CDCl 3 ) 172.2, 155.6, 146.0, 136.0, 131.1, 130.7, 128.5, 128.2, 128.1, 126.5, 120.3, 114.3, 67.2, 50.5, 19.0. Anal. Calcd for C 17 H 16 N 4 O 3 : C, 62.95; H, 4.97; N, 17.27. Found: C 63.21; H, 4.88; N, 17.40. Benzyl N [2 (1 H 1,2,3 Benzotriazol 1 yl) 1 methyl 2 oxoethyl]carbamate (3.11 White microcrystals (70 90 %); mp 111.0 112.0 C. 1 H NMR (300 MHz, CDCl 3 ) 8.27 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7. 70 7. 62 (m, 1H ), 7.5 5 7. 48 (m, 1H ), 7.36 (s, 4 H), 7.14 (br s, 1 H), 5. 85 5. 77 (m, 1H ), 5.69 (d, J = 7.6 Hz, 1H ), 5.17 (d, J = 12.2 Hz, 1H ), 5.11 (d, J = 12.2 Hz, 1H ), 1.69 (d, J = 7.0 Hz, 3H ). 13 C NMR (75 MHz, CDCl 3 ) 170.8 155.7 146 135.9 134.9 130.9 130.8 129.2 1 28.7 128.5 128.1 127.4 126.6 120.4 114.3 67.2 55.6 38.8 Anal. Calcd for C 17 H 16 N 4 O 3 : C, 62.95; H, 4.97; N, 17.27. Found: C, 63.24; H, 4.96; N, 17.26. Benzyl N [(1 S ) 1 (1 H 1,2,3 b enzotriazol 1 ylcarbonyl) 2 methylpropyl] c arbamate (3.11b) White mic rocrystals ( 83 90 %); mp 106.0 108.0 C. 1 H NMR (300 MHz, CDCl 3 ) 8.2 8 (d, J = 8.2 Hz, 1H), 8.1 2 (d, J = 8.3 Hz, 1H ), 7.6 9 7.6 3 (m, 1H ), 7.5 5 7.5 0 (m, 1 H), 7.3 6 (br s, 4 H ), 7.15 (br s, 1H ), 5.77 (dd, J = 9.0, 4.5 Hz, 1H ), 5.68 (d, J = 9.0 Hz, 1H ), 5.1 5 (d, J = 12.4 Hz, 1H ), 5.13 (d, J = 12.4 Hz, 1H ), 2.55 2. 4 4 (m, 1H) 1.13 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H ) 13 C NMR (75 MHz, CDCl 3 ) 170.8, 156.2, 146, 136, 131, 130.6, 128.5, 128.1, 126.4, 120.3, 114.3, 67.3, 59.4, 31.6, 19.6, 16.9 Anal. Ca lcd for C 19 H 20 N 4 O 3 : C, 64.76; H, 5.72; N, 15.90. Found: C, 64.82; H, 5.77; N, 15.80. Benzyl ((2 S ,3 S ) 1 (1 H benzo[ d ][1,2,3]triazol 1 yl) 3 methyl 1 oxopentan 2 yl)carbamate (3.11c) White microcrystals (64 71%); mp 64.0 66.0 C. 1 H NMR (300 MHz, CDCl 3 ) 8.2 8 ( d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.5 Hz,

PAGE 55

55 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.36 (br s, 5H), 5.80 5.71 (m, 1H), 5.60 5.54 (m, 1H), 2.32 2.18 (m, 1H), 1.28 1.15 (m, 2H), 1.08 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) 171.7, 156.2, 146.1, 136.1, 131.1, 120.7, 128.5, 128.2, 126.5, 120.4, 114.4, 67.3, 59.3, 38.3, 24.2, 16.0, 11.3. Anal. Calcd for C 20 H 2 2 N 4 O 3 : C, 6 5 5 6; H, 6.05 ; N, 15. 29 Found: C, 65.87 ; H, 6.09 ; N, 14.89 ( S ) B enzyl (1 (1 H benzo[ d ][1,2, 3]triazol 1 yl) 3 (1 H indol 3 yl) 1 oxopropan 2 yl)carbamate ( 3.11d) Pale yellow microcrystals (65 75%); mp 100.0 102.0 C. 1 H NMR (300 MHz, CDCl 3 ) 8.22 (br s, 1H ) 8.16 (d, J = 8.2 Hz, 1 H), 8.12 (d, J = 8.2 Hz, 1 H), 7. 63 7. 58 (m, 1 H), 7.52 7.47 (m, 1H ), 7.40 (d, J = 7. 8 Hz, 1H), 7.29 (m, 5 H), 7. 13 7. 08 (m, 1H), 6.98 6.90 (m, 3 H), 6.13 (dd, J = 12.5, 7.0 Hz, 1H), 5.70 (d, J = 7.5 Hz, 1 H), 5.06 (s, 2H), 3.61 (dd, J = 14.7, 7.1 Hz, 1 H), 3.43 (dd, J = 14.7, 7.1 Hz, 1 H). 13 C NMR (75 MHz, CDCl 3 ) 171.1, 1 55.9 145.9 136.1 135.9 131 .0, 130.7 128.5 128.4 128.1 127.1 126.4 123.1 122.2 120.2 119.7 118.3 114.3 111.2 109 .0, 67.2 55.1 3.4. 3 General p rocedure for the s ynthesis of 3.13 n BuLi (2.5 mmol ,1.6 M in hexane) was added dropwise to a solu tion of 3.12 (1 .0 mmol ) in dry THF ( 1 0 .0 mL) at 78 C, followed by the addition of HMPA (6 .0 mmol ) The mixture was stirred for 1 h, afterwhich a solution of 3.11 (1.0 mmol) in dry THF (5.0 mL) was added dropwise to mixture, and the temperature was adjus ted to 20 C. After 3 h, the reaction was quenched by a saturated solution of NH 4 Cl. The volatile material were evaporated under reduced pressure, and the resulting solution was diluted with ethyl acetate (25 mL), and the organic layer was washed saturated NaCl, and was dried over Na 2 SO 4 The solvent was evaporated and the crude solid was purified by column chromatography to afford the 3.13

PAGE 56

56 ( S ) Benzyl (3 oxo 4 (pyridin 4 yl) butan 3 yl) carbamate (13e). Yellow microcrystal (44%); mp 95.0 98.0 C 1 H NMR (30 0 MHz, CDCl 3 ) 8.52 (br s, 2H), 7.33 (br s, 5H), 7.14 7.08 (m, 2H), 5.70 (d, J = 5.7 Hz, 1H), 5.09 (br s, 2H), 4.46 (t, J = 7.1 Hz, 1H), 3.80 (s, 2H), 1.38 (d, J = 6.9 Hz, 3H); 13 CNMR(75 MHz, CDCl 3 ) 204.9, 155.7, 149.8, 142.1, 136.0, 128.5, 128.2, 128.0 124.7, 67.0, 55.5, 44.9, 17.2; HRMS Calcd for C 17 H 19 N 2 O 3 [M + H] + 299.1390, found 299.1389. ( S ) Benzyl (4 methyl 2 oxo 1 (pyridin 4 yl)pentan 3 yl) carbamate (13 f ). Y ellow microcrystal (46%); mp 70.0 72.0 C. 1 H NMR (300 MHz, CDCl 3 ) 8.56 (d, J = 4.2 H z, 2H), 7.42 7.28 (m, 5H), 7.12 (d, J = 4.2 Hz, 2H), 5.37 (d, J = 8.1 Hz, 1H), 5.15 5.02 (m, 2H), 4.47 4.42 (m, 1H), 3.87 3.75 (m, 2H), 2.29 2.23 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) 205.1, 156.7, 150.0, 14 2.2, 136.2, 128.7, 128.4, 128.2, 125.0, 67.3, 64.9, 46.6, 29.9, 20.0,17.0. Anal. Calcd for C 19 H 22 N 2 O 3 : C, 69.92; H, 6.79; N, 8.58. Found C, 69.96; H, 7.05; N, 8.91. ( Z S ) Benzyl (3 hydroxy 4 (quinolin 2 yl)but 3 en 2 yl)carbamate (3.13 ) Yellow (32%); o il. 1 H NMR (300 MHz, CDCl 3 ) 14.70 (br s, 1H), 7.60 (d, J = 9.3 Hz, 1H), 7.53 7.48 (m, 2H), 7.37 7.26 (m, 7H), 7.24 7.21 (m, 1H), 6.70 (d, J = 9.3 Hz 1H ), 5.75 (m, 1H), 5.37 (s, 1H), 5.12 5.10 (m, 2H), 4.14 (m, 1H), 1.41 (d, J = 6.9 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) 192.8, 155.9, 153.6, 137.0, 136.7, 131.2, 128.6, 128.1, 127.8, 123.9, 122.9, 122.0, 117.3, 89.1, 66.7, 53.7, 20.6. HRMS Calcd for C 21 H 21 N 2 O 3 [M+H] + 349.1547. Found, 349.1563.

PAGE 57

57 LIST OF REFERENCES The reference citation system applied throughout the thesis is adopted from Katritzky). By means of this system references are cited in the text by giving two or three letter code to every journal. This code is preceded by the year (using all four digits) and followed by the beginning page number Additional notes to this reference system are as follows: (i) Each reference code is followed by the conventional literature citation as depicted in the Advances in Heterocyclic Chemistry instruction for authors (iii) The list of references is arranged according to the designated code in the order of (a) year, (b) journal in alphabetical order, (c) v olume or part number, and (d) page number. 19777T1043 T. Saraswathi, and V. Srinivasan, Tetrahedron 33 1043 (1977). 1982JMC1466 K. Hirai, T. Fujishita, T. Ishiba, H. Sugimoto, S. Matsutani, Y. Tsukinoki and K. Hirose, J. Med. Chem. 25 1466 (1982). 1991JACS9276 R. Williams, and M. Im, J. Am. Chem. Soc. 113 9276 (1991). 1992BJC1044 E. Boven, H. Hendriks, C. Erkelens, and H. Pinedo, Br. J. Cancer 66 1044 (1992). 1992CR1628 M. Izawa, S. Takayama, N. Shindo Okada, S. Doi, M. Kimura, M. Katsuki,2 a nd S. Nishimura, Cancer Res., 52 ,1628 (1992). 1993TL5217 A. Bohnstedt, J. Prasad, and D. Rich, Tetrahedron Lett. 34 5217(1993). 1994BMCL1385 S. Kaldor, M. Hammond, B. Dressman, J. Fritz, T. Crowell, and R. Hermann, Bioorg. Med. Chem. Lett. 4 1385 (1 994) 1994T1539 R. Duthaler, Tetrahedron 50 1539 (1994). 1995JOC2640 B. Ye, and T. Burke, J. Org. Chem. 60 2640 (1995).

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58 1995JOC3112 S. Borg, G. Estenne Bouhtou, K. Luthman, I. Csregh, W. Hemelink, and U. Hacksell, J. Org. Chem. 60 3112 (1995). 1 996JOC813 A. Myers and J. Gleason J. Org. Chem. 61 813 (1996). 1996TL3165 M. Seki, and K. Matsumoto, Tetrahedron Lett. 37 3165 (1996). 1999ECR148 T. Krude, Exp. Cell Res. 247 148 (1999). 2000JOC8210 A. R. Katritzky, H. Y. He and K. Suzuki, J. Or g. Chem. 65 8210 (2000). 2001B14862 E. Watkins, and R. Phillips, Biochemistry 40 14862 (2001). 2001JCS2404 L. Anastasia, M. Anastasia, and P. Allevi, P. J. Chem. Soc. Perkin Trans. 1 19 2404 (2001). 2001P2329 K. Witt, T. Gillespie, J. Huber, R. E gleton, and T. Davis, Peptides 22 2329 (2001). 2002JCC470 S. Raillard, W. Chen, E. Sullivan, W. Bajjalieh, A. Bhandari, and T. Baer, J. Comb. Chem. 4 470 (2002). 2002NRDD847 V. Hruby Nat. Rev. Drug Discov., 1 847 (2002) 2003JOC5720 A. R. Katritzky, K. Suzuki, S. K. Singh and H. Y. He, J. Org. Chem ., 68 5720 (2003). 2003TL1123 Z. Zhao, W. Leister, K. Strauss, D. Wisnoski and C. Lindsley, Tetrahedron Lett., 44 1123 (2003). 2004JACS8598 K. Stephenson, S. Banerjee, T. Besanger, O. Sogbein, M. Levad ala, N. McFarlane, J. Lemon, D. Boreham, K. Maresca, J. Brennan, J. Babich, J. Zubieta, and John Valliant, J. Am. Chem. Soc. 126 8598 (2004). 2005ARK208 V. Nuriev, N. Zyk, and S. Vatsadze, ARKIVOC, iv 208 (2005). 2005CEN17 V. Marx, Chem. Eng. News 83 17 (2005). 2005EBR88 C. Pichereau, and C. Allary, Eur. Biopharm. Rev. winter issue, 88 (2005). 2005HCA1491 M. Ernd, M. Heuschmann, M. and H. Zipse, Helv. Chim. Acta. 88 1491 (2005). 2005S397 A. R. Katritzky, P. Angrish, D. Hr and K. Suzuki, Synth esis, 397 (2005). 2005SL1656 A. R. Katritzky, K. Suzuki and Z. Wang, Synlett 1656 (2005).

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59 2006AAPSJE76 K. Witt, and T. Davis, AAPS J. 8 E76 (2006). 2006BMC3536 R. Ijuin, N. Umezawa, and T. Higuchi, Bioorg. Med. Chem. 14 3563 (2006). 2006MB499 G. Hummel U. Reineke and U. Reimer Mol. Biosyst. 2 499 (2006). 2006S3231 A. R. Katritzky, S. R. Tala and S. K. Singh, Synthesis 3231 (2006). 2006S411 A. R. Katritzky, P. Angrish and K. Suzuki, Synthesis 3 411 (2006). 2007ACIE7930 R. Hughes and C. Moody, Angew. Chem. Int. Ed. 46 7930 (2007). 2007JMC1939 L. Demange, D. Boeglin, A. Moulin, D. Mousseaux, J. Ryan, G. Berge, D. Gagne, A. Heitz, D. Perrissoud, V. Locatelli, A. Torsello, J. C. Galleyrand, J. A. Fehrentz and J. Martinez, J. Med. Chem., 5 0 1939 (2007). 2007M103 O. Pintilie, L. Profire, V. Sunel, M. Popa, and A. Pui, Molecules, 12 103 (2007). 2008CDM827 R. Mandrioli, L. Mercolini, and M. Raggi, Curr. Drug Metab ., 9 827 (2008). 2008EJOC5583 S. Hirner, D. Kirchner, and P. Somfai, Eur. J Org. Chem. 33 5583 (2008). 2008JOC5442 A. Katritzky, B. E. El Gendy, E. Todadze, and A. Abdel Fattah, J. Org. Chem 73 5442 (2008). 2008OBC2400 A. R. Katritzky, Q. Y. Chen and S. R. Tala, Org. Biomol. Chem ., 6 2400 (2008). 2008OPRD218 H. Yu, R. R ichey, J. Stout, M. LaPack, R. Gu, V. Khau, S. Frank, J. Ott, R.Miller, M.Carr, and T. Zhang, Org. Process Res. Dev. 12 218 (2008). 2009BMCL1866 S. Manku, M. Allan, N. Nguyen, A. Ajamian, J. Rodrigue, E. Therrien, J. Wang, T. Guo, J. Rahil, A. J. Petsch ner, A. Nicolescu, S. Lefebvre, Z. Li, M. Fournel, J. M. Besterman, R. Deziel and A. Wahhab, Bioorg. Med. Chem. Lett., 19 1866 (2009). 2009S2392 A. Katritzky, P. Angrish, and E. Todadze, Synlett, 15 2392 (2009). 2010CR1564 A. R. Katritzky and S. Rachw al Chem. Rev. 110, 1564 (2010) 2010DDT40 P. Vlieghe, V. Lisowski, J. Martinez, and M. Khrestchatisk Drug Discov. Today 15 40 (2010).

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60 2010JOC6009 A. Katritzky, C. El Nachef, K. Bajaj, J. Kubik, J. and D. Haase, J. Org. Chem. 75 6009 (2010). 2011EJOC 730 A. El Dahshan, S. Nazir, Ahsanullah, F.Ansari, and J. Rademann, Eur. J. Org. Chem. 730 (2011).

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61 BIOGRAPHICAL SKETCH Ebrahim Ghazvini Zadeh was born in Beirut during what is known as the Forth Phase of the Lebanese Sectarian Civil War. He was raised a mong his five sisters. After being awarded with the Lebanese Baccalaureate in Life Science s from Ren Mawaad Public School, he joined the Lebanese University. Upon his graduation with a t eaching d iploma in G eneral C hemistry, he joined the chemistry graduat e program at the American University of Beirut in 2007 and worked under the supervision of Professor Makhlouf J. Haddadin. In 2009, he graduated with a m aster of s cience in Chemistry, and traveled to the United States of America where he worked as an adj unct research scholar at the L abs of Katritzky G roup. In fall 2010, he joined the graduate program offered by the C hemistry D epartment at the University of Florida and worked under the supervision of Professor Alan R. Katritzky He received his M.S. degre e in C hemistry from the University of Florida in the s ummer of 2012.