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Benzotriazole-Mediated Syntheses of Heterocyclic Compounds and Acylations Utilizing N-Acylbenzotriazoles

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PAGE 1

BENZOTRIAZOLE-MEDIATED SYNTHESES OF HETEROCYCLIC COMPOUNDS AND ACYLATIONS UTILIZING N-ACYLBENZOTRIAZOLES By KAZUYUKI SUZUKI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2004

PAGE 2

Copyright 2004 by Kazuyuki Suzuki

PAGE 3

This document is dedicated to my family, my father Toshio Suzuki, my mother Mitsue Suzuki, .my sister Hiroko Inamura, and my brother Shin-ichi Suzuki.

PAGE 4

iv ACKNOWLEDGMENTS Things that I have heard, thi ngs that I have seen, things that I have thought are my valuable experience. Things that I have suffe red are my treasures. They will guide me to a certain conclusion. Here, I sincerely give my acknowledgments to those who helped me pursue my Ph.D. My deepest gratitude goes to my superv isor, Professor Alan R. Katritzky, and I greatly thank my committee me mbers, Dr. William R. Dolbier, Dr. Ion Ghiviriga, Dr. Vaneica Young, and Dr. Hartmut Derendorf. I cannot thank my wife, Yoko Suzuki, enough for her support and patience. I give special thanks to my parents for supporting and letting me do whatever I believe is right. Finally, I thank my friends who always inspire me.

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v TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES.............................................................................................................ix LIST OF SCHEMES............................................................................................................x ABSTRACT......................................................................................................................x ii CHAPTER 1 GENERAL INTRODUCTION....................................................................................1 2 CONVENIENT SYNTHESIS OF UN SYMMETRICAL IMIDAZOLIDINES..........4 2.1 Introduction.............................................................................................................4 2.2 Results and Discussion...........................................................................................6 2.2.1 Preparation of 1-Substituted-3-benzotriazolylmethylimidazolidines 2.9a c .................................................................................................................6 2.2.2 Nucleophilic Substitutions of 2.9a c with NaBH4, Grignard Reagents, Sodium Cyanide, Benzenethi ol and Triethyl Phosphite. (cf. Scheme 2-2).......7 2.2.3 Syntheses of Optically Active Imidazolidines. (cf. Scheme 2-3).................8 2.2.4 Modification of the 2-Position of the Imidazolidine Ring.........................10 2.2.5 Preparation of 1-Methyl-3-substituted-2,3-dihydro-1 H -benzimidazoles 2.28, 2.29..........................................................................................................11 2.3 Conclusion............................................................................................................13 2.4 Experimental Section............................................................................................13 2.4.1 General Procedure for the Preparation of 1-Substituted-3(benzotriazolylmethyl) Imidazolidines 2.9a c ................................................13 2.4.2 Procedure for Reduction of 2.9a with NaBH4............................................15 2.4.4 General Procedure for the Nucleophilic Substitutions of 2.9a c with Grignard Reagents...........................................................................................15 2.4.5 General Procedure for the Reaction of 2.9a c with NaCN........................18 2.4.6 Procedure for the Nucleophilic Substitution of 2.9a with Benzenethiol....................................................................................................20 2.4.7 Procedure for the Nucleophilic Substitution of 2.9a with Triethyl Phosphite..........................................................................................................20

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vi 2.4.8 General Procedure for the Preparation of Chiral Diamines 2.18a c from N -Boc--amino Acids 2.15a c ...............................................................21 2.4.9 General Procedure for the Preparation of Optically Active Imidazolidines 2.20a d 2.21 2.22 .................................................................22 2.4.10 Procedure for the Preparati on of the Bt Intermediate 2.24 and its Substitution with NaCN...................................................................................26 2.4.11 Procedure for the Preparation of 1-Substituted-3-methyl-2,3-dihydro1 H -benzimidazoles 2.28 2.29 .........................................................................27 2.4.12 Procedure for the Preparation of 2-(2-Anilinoanilino)acetonitrile (2.31)................................................................................................................29 3 NOVEL SYNTHESES OF HEXAH YDROIMIDAZO[1,5-B]ISOQUINOLINES AND TETRAHYDROIMIDAZO[1,5B ]ISOQUINOLIN-1(5 H )-ONES VIA IMINIUM CATION CYCLIZATIONS.....................................................................30 3.1 Introduction...........................................................................................................30 3.2 Results and Discussion.........................................................................................31 3.2.1 Preparation of Chiral Diamines 3.11a c from N -Boc-Phe-OH ( 3.7 ).........31 3.2.2 Syntheses of 1,2,3,5,10,10a-Hexahydroimidazo[1,5b ]isoquinolines 3.1a c ...............................................................................................................32 3.2.3 Syntheses of 2,3,10,10a-Tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )ones 3.15a c (c.f. Scheme 3-3)......................................................................33 3.2.4 Syntheses of Chiral 3-Subs tituted-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.18a c (c.f. Scheme 3-4).....................................34 3.2.5 Attempts to Synthesize 1,2a,3,4a,5,9b-Hexahydrobenzo[ g ]imidazo [2,1,5cd ]indolizin-4(2 H )-one ( 3.23 )...............................................................37 3.3 Conclusion............................................................................................................38 3.4 Experimental Section............................................................................................38 3.4.1 General Procedure for the Preparation of Chiral -Amino-amides 3.10a c and Diamines 3.11a c from N -Boc-Phe-OH ( 3.7 )............................39 3.4.2 General Procedure for the Preparat ion of Benzotriazolyl intermediates 3.12a c .............................................................................................................39 3.4.3 General Procedure for the Preparation of 1,2,3,5,10,10aHexahydroimidazo[1,5b ]isoquinolines 3.1a c ...............................................40 3.4.4 General Procedure for the Preparati on of Benzotriazolyl Intermediates 3.13 and 3.14a c ..............................................................................................42 3.4.5 General Procedure for the Preparation of 2,3,10,10aTetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.15a c ............................44 3.4.6 General Procedure for the Preparat ion of 2,3,5-Trisubstituted-tetrahydro4 H -imidazol-4-ones 3.16a c ...........................................................................45 3.4.7 General Procedure for the Preparation of Bt intermediates 3.17a c and 3.17 a .........................................................................................................46 3.4.8 General Procedure for the Lewis Acid Promoted Cyclization of 3.17a c and 3.17 a .........................................................................................................48 3.4.9 Procedure for the Preparation of Bt intermediate 3.22 ...............................50

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vii 4 N -ACYLBENZOTRIAZOLES: NEUTRAL ACYLATING REAGENTS FOR THE PREPARATION OF PRIMARY, SECONDARY AND TERTIARY AMIDES.....................................................................................................................52 4.1 Introduction...........................................................................................................52 4.2 Results and Discussion.........................................................................................53 4.2.1 Preparation of N -Acylbenzotriazoles 4.2a-q ..............................................53 4.2.2 Preparation of Primary Amides 4.3a-n from N -Acylbenzotriazoles 4.2 with Ammonia...........................................................................................55 4.2.3 Preparation of Secondary Amides 4.4a-j from N -Acylbenzotriazoles 4.2 with Primary Amines.......................................................................................56 4.2.4 Preparation of Tertiary Amides 5a-k from N -Acylbenzotriazoles 4.2 with Secondary Amines...................................................................................57 4.2.5 Preparation of –Hydroxyamides using BtSO2CH3..................................58 4.2.6 Preparation of 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2,3,3,4,4,4heptafluorobutan-1-one ( 4.8 ) and its Perfluoroacyla tion with Primary and Secondary Amines...........................................................................................59 4.3 Conclusion............................................................................................................61 4.4 Experimental Section............................................................................................61 4.4.1 Modified procedure for the Preparation of N -(1methanesulfonyl)benzotriazole ( 4.1 )...............................................................61 4.4.2 General procedure for the Preparation of N -Acylbenzotriazoles 4.2 .........62 4.4.3 General procedure for the Reaction of N -Acylbenzotriazoles 4.2 with Aqueous ammonia...........................................................................................65 4.4.4 General procedure for the Reaction of N -Acylbenzotriazoles 4.2 with Primary amines................................................................................................65 4.4.5 General procedure for the Reaction of N -Acylbenzotriazoles 4.2 with Secondary amines............................................................................................67 4.4.6 General procedure for the Preparation of -Hydroxyamides.....................68 4.4.7 Preparation of 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2,3,3,4,4,4heptafluorobutan-1-one ( 4.8 )...........................................................................69 4.4.8 General Procedure for the Reaction 4.8 with Primary and Secondary amines..............................................................................................................69 5 HIGHLY DIASTEREOSELECTIVE PE PTIDE CHAIN EXTENSIONS OF UNPROTECTED AMINO ACIDS WITH N -(Z-AMINOACYL) BENZOTRIAZOLES.................................................................................................71 5.1 Introduction...........................................................................................................71 5.2 Results and Discussion.........................................................................................73 5.2.1 Preparation of N -(Z-Aminoacyl)benzotriazoles from N -Cbz-Amino acids 5.1a d .....................................................................................................73 5.2.2 Preparation of N -Z-Dipeptides...................................................................75 5.2.3 Preparation of N -Acylbenzotriazoles derived from N -Z-Dipeptides..........76 5.2.4 Preparation of N -Z-Tripeptides..................................................................77 5.2.5 Preparation of N -Z-Tetrapeptides...............................................................78

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viii 5.3 Conclusion............................................................................................................78 5.4 Experimental Section............................................................................................79 5.4.1 General procedure for the Preparation of 5.1a d and 5.3a b ....................79 5.4.2 General procedure for the Preparation of 5.2a i 5.4a f 5.4a' and 5.5a b ..............................................................................................................82 5.4.3 Preparation of Boc-Protected dipeptide from Boc-Phe-Bt.........................91 6 REGIOSELECTIVE C -ACYLATION OF PYRROLES, INDOLES, 2METHYLFURAN AND THIOPHENE USING N -ACYLBENZOTRIAZOLES.....92 6.1 Introduction...........................................................................................................92 6.2 Results and Discussion.........................................................................................93 6.2.1 Preparation of N -Acylbenzotriazoles.........................................................93 6.2.2 Preparation of 2-Acylpyrroles....................................................................94 6.2.3 Preparation of 3-Acylpyrroles....................................................................96 6.2.4 Preparation of 3-Acylindoles......................................................................97 6.2.5 Synthesis of 2-Acyl-5-methylfurans...........................................................99 6.2.6 Synthesis of 2-Acylthiophenes.................................................................100 6.3 Conclusion..........................................................................................................100 6.4 Experimental Section..........................................................................................101 6.4.1 General Procedure for the Preparation of N -Acylbenzotriazoles 6.1a g ............................................................................................................101 6.4.2 General Procedure for C -Acylation of Pyrroles ( 6.2 6.4 6.6 ) or Indoles ( 6.9 6.11 ) Using N -Acylbenzotriazoles 6.1a g ...............................102 6.4.3 General Procedure for C-Acylation of 2-methylfuran and thiophene Using N-Acylbenzotriazoles 6.1a, c, e, h, i, j. ...............................................112 LIST OF REFERENCES.................................................................................................115 BIOGRAPHICAL SKETCH...........................................................................................127

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ix LIST OF TABLES Table page 2-1 Preparation of 1,3-disubstituted imidazolidines 2.11a l ...........................................7 4-1 Preparation of N -acylbenzotriazoles 4.2a-q .............................................................55 4-2 Preparation of primary amides 4.3a-n ......................................................................56 4-3 Preparation of secondary amides 4.4a-j ...................................................................57 4-4 Preparation of tertiary amides 4.5a-k .......................................................................58 5-1 Conversion of N -Z-amino acids into N -(Z-aminoacyl)benzotriazoles.................74 5-2 Preparation of N -Z-dipeptides from N -(Z-aminoacyl)benzotriazoles and unprotected amino acids...........................................................................................76 5-3 Conversion of N -Cbz-dipeptides into N -(Z-dipeptidoyl)benzotriazoles..................77 5-4 Preparation of N -Cbz-tripeptides.............................................................................78 5-5 Preparation of N -Z-tetrapeptides from dipeptidoylbenzotriazoles and an unprotected dipeptide...............................................................................................78 6-1 Preparation of 2-acylated pyrrole ( 6.2 ) and 1-methylpyrrole ( 6.4 )..........................96 6-2 Preparation of 3acylated TIPS-pyrrole ( 6.6 )...........................................................97 6-3 Preparation of 3-acylated indole ( 6.9 ) and 1-methylindole ( 6.11 )...........................98 6-4 Preparation of 2-acy lated 2-methylfuran..................................................................99 6-5 Preparation of 2-acylated thiophene.......................................................................100

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x LIST OF SCHEMES Scheme page 1-1 Isomers of the N-substituted benzotriazoles..............................................................1 1-2 The formation of imnium cation and benzotriazole anion.........................................2 1-3 Conversion of carboxylic acid into N -acylbenzotriazole...........................................3 2-1 Previously reported methods for imidazolidines........................................................5 2-2 Nucleophilic substation to unsymmetrical imidazolidines.........................................6 2-3 Preparation of optical ly active imidazolidines...........................................................9 2-4 Modification of the 2-positi on of the imidazolidine ring.........................................11 2-5 Preparation of benzimidazoles.................................................................................12 3-1 Intramolecular cycliza tions utilizing Lewis acidactivated benzotriazole...............31 3-2 Synthesis of 2-substituted hexahydroimidazo[1,5b ]isoquinolines.........................32 3-3 Synthesis of tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones...............................34 3-4 Syntheses of chiral 3-substituted tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )ones........................................................................................................................... 36 3-5 Isomerization of chiral 3substituted tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )ones........................................................................................................................... 36 3-6 Attempts to synthesize 1,2a,3,4a,5,9b-hexahydrobenzo[ g ]imidazo[2,1,5cd ]indolizin-4(2 H )-one.............................................................................................37 4-1 Preparation of N -acylbenzotriazoles and amides.....................................................55 4-2 Reaction of BtSO2CH3 with 2-hydroxy-2-phenylacetic acid...................................59 4-3 Synthesis of perfluoroalkylated amides...................................................................60 5-1 Coupling reactions with N-(Z-aminoacyl)benzotriazoles........................................73

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xi 5-2 1H NMR spectra of compound 5.2f (left) and racemized 5.2f (right) in CDCl3 (CH3 signal in L -Ala)....................................................................................75 6-1 2-Acylation of pyrrole ( 6.2 ) and 1-methylpyrrole ( 6.4 ) using N -Acylbenzotriazoles 6.1a g ...................................................................................95 6-2 3-Acylation of TIPS-pyrrole ( 6.6 ) using N -acylbenzotriazoles 6.1a g ...................97 6-3 3-Acylation of indole ( 6.9 ) and 1-methylindole ( 6.11 ) using N -Acylbenzotriazoles 6.1a g ...................................................................................98 6-4 C-Acylation of 2-methylfuran..................................................................................99 6-5 C-Acylation of Thiophene......................................................................................100

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xii Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy BENZOTRIAZOLE-MEDIATED SYNTHESES OF HETEROCYCLIC COMPOUNDS AND ACYLATIONS UTILIZING N-ACYLBENZOTRIAZOLES By Kazuyuki Suzuki December 2004 Chair: Alan R. Katritzky Major Department: Chemistry 1 H -Benzotriazole is a versatile synthetic a uxiliary, and has widely been applied to many organic syntheses. In our continuous work on the methodology, we have developed convenient and efficient methods for pr eparation of heterocyclic compounds. In chapter 2, formation of imidazolidin e rings by the Mannich reaction involving 1 H -benzotriazole as a neucleophile is described, and followed by nucleophilic substitution of the benzotriazole group utilizing Grignard reag ents to give unsymmetrical imidazolidines. In chapter 3, the study of the imidazolidines was further expanded to preparation of multi-cyclic compounds hexahydroimidazo[1,5b ]isoquinolines and tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones. These heterocycles are synthesized via iminium cation cyclizations in the presence of AlCl3.

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xiii In chapter 4, N -acylbenzotriazole is introduced as neutral acylating reagents for the preparation of primary, secondary, and tertiary amides. Reaction of N -acylbenzotriazoles with various amines under mild conditions is discussed. In chapter 5, syntheses of di-, tri-, and tetra-peptides is demonstrated utilizing N -(Zaminoacyl)benzotriazoles with unprotect ed amino acids in aqueous solution. N -(ZAminoacyl)benzotriazoles are prepared from N -Z-amino acids and an intemediate obtained by reaction of 1 H -benzotriazole and thionyl chloride. In chapter 6, N -acylbenzotriazoles are applied to C -acylation under Friedel-Crafts conditions using heterocyclic compounds such as pyrrole, N -methylpyrrole, indole, N methylindole, 2-methylfuran, and thiophene This method provides heteroaromatic ketones, and is especially useful wh en the acid chlorides corresponding to N acylbenzotriazoles are not readily available.

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1 CHAPTER 1 GENERAL INTRODUCTION The benzotriazole chemistry has been st udied intensively in our group, and its various utilities have been reported. [98CR409] 1 H -Benzotriazole is an excellent synthetic auxiliary and acts as a leaving group, electron-withdrawing group, and even an electron-donating group (Scheme 1-1). As another aspect of a good auxili ary, the benzotriazole group is readily removed from the reaction mixture by simply washing with base due to the acidity (p K a 8.2) of 1 H benzotriazole. Moreover, 1 H -benzotriazole is an inexpens ive, stable compound that is soluble in common organic solvents such as ethanol, benzene, chloroform, and DMF. N N N R X Leaving group N N N H X Activating CH to proton loss N N N X Electron donor Y 1.1 1.21.3 Scheme 1-1. Isomers of the N-substituted benzotriazoles As a good synthetic auxiliary, there should be several characte ristics including the advantages mentioned above. It has been s hown to be an excelle nt leaving group when attached to -carbon atom adjacent to hetero-atoms such as N, O, and S. Unlike halogens, the benzotriazole gr oup rarely leaves if there is no hetero-atom at the -carbon atom. It is also a good leaving group wh en attached to a carbonyl group to form N acylbenzotriazoles, which are efficient N-acy lating reagents. The benzotriazole group can

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2 be used as an activating group for -hydrogen (adjacent CH). Furthermore, the benzotriazole group is easily removed by wash ing with a basic aqueous solution such as sodium carbonate and sodium hydroxide soluti on when products are stable in the basic solutions. If products are not stable towards base, but stable to an acid wash, 2-4N hydrochloric acid solution can be used. Anothe r important aspect of the benzotriazole group is that it is stable duri ng various synthetic operations. It must be introduced at the beginning of the sequence and may be carried through several reactions. This dissertation includes r eactions of Bt-C-N type compounds for the nucleophilic substitution, and reactions of N -acylbenzotriazoles for formation of simple amides, peptide coupling and Friedel-Crafts type reaction. N-Substituted benzotirazole derivatives (Bt-C-N) have shown electr on-acceptor properties, which lead to the formation of imnium cation and be nzotriazole anion (Scheme 1-2). In chapter 2, formation of imidazolidin e rings by the Mannich reaction involving 1 H -benzotriazole as a nucleophile is desc ribed, and followed by nucleophilic substitution of benzotriazole group to give unsy mmetrical imidazolidines. Symmetrical, unsymmetrical, and optically active imidazolid ines were synthesized by the method using Grignard reagents, triethyl phosphite and sodium cyanide. N R'' R'Bt N N N N R'' R' N N N + Bt = 1.4 1.5 Scheme 1-2. The formation of imni um cation and benzotriazole anion

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3 In Chapter 3, the study of the imidazolidin es was extended to the preparation of multi-cyclic compounds hexahydroimidazo[1,5b ]isoquinolines and tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones. These heterocycles are synthesized via iminium cation cyclizations in the presence of AlCl3. N -Acybenzotriazoles are versatil e neutral acylating reagents. N -Acylation is discussed in Chapter 4 for the preparation of primary, secondar y and tertiary amides. N-Protected (aminoacyl)benzotriazoles are N -acylbenzotriazoles derived from Nprotected amino acids, and they are utilized for peptide coupling using unprotected amino acids in aqueous solution (Chapter 5). 1.6 R O OH R O Bt N-Acylbenzotriazole O OH 1.7 N-Protected (aminoacyl)benzotriazole NH R Pg Pg = protecting group O Bt NH R Pg Scheme 1-3. Conversion of carboxylic acid into N-acylbenzotriazole N -Acylbenzotriazoles can be applied to a Fr iedel-Crafts reaction. In the presence of a Lewis acid, the reaction was carried out to gi ve various ketones with heterocycles such as pyrrole, indole, furan and thiophene (C hepter 6). This method is especially advantageous when the corresponding acid chlorides are not r eadily available.

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4 CHAPTER 2 CONVENIENT SYNTHESIS OF UN SYMMETRICAL IMIDAZOLIDINES 2.1 Introduction Imidazolidines have attracted attention due to their important role as building blocks in the synthesis of biological ly active compounds. [ 96JMC3483] [96EJP273] [98B13893] [00CPB729] [93PR 913] [94EJP223] [70JMC121 2] [70JMC1215] Early symmetrical imidazolidines prepared by condensation of N N-diaryl-1,2-ethanediamines with formaldehyde were reported by Bi schoff et al. [1898CB3248] in 1898 and by Scholtz et al. [1901CB1504] in 1901. Since thei r work, preparation of other symmetrical imidazolidines including 1,3-diary limidazolidines [59LAC120] and 1,3dialkylimidazolidines from N N-dialkyl-1,2-ethanediamines [49JOC952] was demonstrated using the same methodology. Ot her methods were also reported: i) the reduction of symmetrical cyclic ureas with LiAlH4, [86JOC2228] ii) reactions of 1,3,6,8tetraazatricyclo[4.4.1.13,8]dodecane with p -substituted phenols, [93SC2919] and iii) the Mannich reaction of 1,2-ethanediamine, be nzotriazole and formaldehyde followed by nucleophilic substitutions with the Grignard reagents. [90JCS(P1)541] On the other hand, few synt heses of unsymmetrical N,N-disubstituted imidazolidines have been reporte d. Kliegel et al. demonstrated in 1977 that preparation of 1-phenyl-3-alkylimidazolidines by reactions of formaldehyde with N -alkylN-phenyl1,2-ethanediamines previously pr epared by the condensation of -aminosulfonic acids and primary amines. [77LAC956] Lambert s ynthesized unsymmetrical imidazolidines

PAGE 18

5 from diethyl oxalate with primary amines in three-steps involving LiAlH4 reduction of the corresponding oxamides to unsymmetrical N,N-disubstituted-1,2-ethanediamines and condensation with formaldehyde. [86S657] Per illo et al. [00JHC57] recently prepared 1benzyl-3-arylimidazolidines from formaldehyde and N -benzylN-aryl-1,2ethanediamines, produced by BH3 reduction of the corresponding N -benzoylN-aryl-1,2ethanediamines. [98SC1625] R1 and R2 (alkyl or aryl) groups ar e generally introduced when N,N-disubstituted1,2-ethanediamines are prepared in the protocols mentioned above. However, the methods limit the efficiency and the productiv ity for preparation of a wide variety of imidazolidines. N-Substituted benzotriazoles ha ve been reported as useful synthetic precursors due to the easy replacement of th e benzotriazole group as a leaving group via nucleophilic substitution, elimination, re duction, cyclization, etc.[98CR409] We now report a simple and efficient way to prep are novel unsymmetrical imidazolidines, and optically active imidazolidines in good to ex cellent yields and extend this methodology to the preparation of 2,3-dihydro-1 H -benzimidazoles using benzotriazole as a synthetic auxiliary. N N Bt Bt RMgX N N Ar1YPh HH HCHO BH3N N R1R2HCHO EtOOEt O O HCHO N N R1R2HH N N Ph R2HH 2.2 (R1 = R2) 2.1 2.3 2.4 Bt = benzotriazolyl 4 steps 2.5 2.6 Y = CH22.7 Y = C=O Scheme 2-1. Previously repor ted methods for imidazolidines

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6 2.2 Results and Discussion 2.2.1 Preparation of 1-Substituted-3-benzotriazolylmethylimidazolidines 2.9a c Mannich condensation of N -substituted-1,2-ethanediamines 2.8a c with 1 equivalent of benzotriazole a nd 2 equivalents of formaldehyde (37% aqueous solution) in MeOH/H2O at room temperature gave 1-s ubstituted-3-benzotriazolylmethylimidazolidines 2.9a c in 96%, 85% and 92% yields respectively (Scheme 2-2). Compound 2.9a was initially obtained solely as the Bt1 isomer, but in CDCl3 it gradually changes to a mixture of Bt1 and Bt2 isomers in ca. 5.6:1 ratio after 3 days. Compounds 2.9b c were obtained as mixtures of Bt1 and Bt2 isomers, each in ca. 5:1 ratio. Based on our previous results, which showed li ttle difference in the reactivity of Bt1 and Bt2 isomers, [91T2683] [01JOC148] 2.9b c were used directly as mi xtures for the subsequent reactions. In the 13C NMR spectrum of 2.9a the signal of 145.8 ppm is believed to contain two carbons, since it changes to two signals ( 145.0 and 146.0 ppm, respectively) in DMSOd6. Benzotriazolyl intermediates 2.9a c were used as crude products for the subsequent reactions. N N Ph Me N PhN P OEt O OEt N N R1Bt N N R1HH H N PhN SPh N N CN R1N N R1R22.9a R1 = Ph 2.9b R1 = Et 2.9c R1 = PhCH22.8a R1 = Ph 2.8b R1 = Et 2.8c R1 = PhCH22.11a l 2.13 iv iii 2.14 BtH, 2 HCHO 2.10 i 2.12a R1 = Ph 2.12b R1 = Et 2.12c R1 = PhCH2iiv i) NaBH4 (R1 = Ph); ii) R2MgX; iii) NaCN; iv) PhSH/NaH (R1 = Ph); v) P(OEt)3/ZnBr2 (R1 = Ph) Scheme 2-2. Nucleophilic substitution to unsymmetrical imidazolidines

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7 Table 2-1. Preparation of 1,3-Disubstituted Imidazolidines 2.11a l 2.11 R1 R2 a Yield (%) Methodb a Ph n -Bu 80 A; 1.4 eq of GRc b Ph CH2CH2Ph 96 A; 1.2 eq of GR c Ph CH2Ph 96 A; 2.0 eq of GR d Ph C6H4OMep 81 A; 1.2 eq of GR e Ph C CPh 80 A; 1.2 eq of GR f Ph CH=CH2 75 A; 1.2 eq of GR g Et CH2Ph 75 B; 2.0 eq of GR h Et C6H4Mep 71 B; 2.0 eq of GR i PhCH2 CH2C6H5 79 B; 2.0 eq of GR j PhCH2 CH=CH2 63 B; 2.0 eq of GR k PhCH2 C CPh 65 B; 1.2 eq of GR l PhCH2 n -C5H11 80 B; 1.6 eq of GR aR2MgBr was used except for 2.11c g when PhCH2MgCl was used.; bMethod A: in THF (10 mL), rt, 0.5 h, then reflux 1 h; Method B: in toluene (10 mL), rt, 0.5 h, then 1 h at 50 C.; cGR = Grignard reagent. 2.2.2 Nucleophilic Substitutions of 2.9a c with NaBH 4 Grignard Reagents, Sodium Cyanide, Benzenethiol and Triethyl Phosphite. (cf. Scheme 2-2) Treatment of 2.9a with 2 equivalents of sodi um borohydride in refluxing THF replaced the Bt group with hydrogen to give 1-phenyl-3-methylimidazolidine ( 2.10 ) in 96% yield. The methylene protons between two nitrogen atoms in 2.10 appeared at 3.97 ppm as a singlet. We previously reported that the benzotriazo lyl group attached to a nitrogen is easily replaced by nucleophiles. [89JCS(P1)225] [00JOC4364] [00JOC 3683] Nucleophilic substitutions of 2.9a c with alkyl-, vinyl-, aryla nd phenylethynyl-magnesium bromide and, for the preparation of 2.11c g benzyl magnesium chloride, in dry THF or toluene furnished novel unsymmetrical 1,3-disubstituted imidazolidines 2.11a l in 63 96% yields. The isolated yields and reaction conditions for 2.11 are summarized in Table 1. Compounds 2.11g l were easily decomposed on silica gel, so they were isolated by neutral aluminum oxide column chromatography. The structures of 2.11a l were

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8 supported by their 1H, 13C NMR spectra and microanalyses or HRMS results. The methylene groups between the two nitrogens in 2.11a f appeared at around 4.0 ppm as singlets. The benzotriazolyl group in 2.9a c can be substituted by cyano anion to give 2-(3substituted-1-imidazolidinyl)acetonitriles 2.12a c in 77 97% yields. Reaction of 2.9a with benzenethiol in the presence of sodium hydride produced 1-phenyl-3-(phenylthiomethyl)imidazolidine ( 2.13 ) in 66% yield. The benzotriazolyl group in 2.9a was replaced in the presence of ZnBr2 by a P-nucleophile (triethyl phosphite) to afford diethyl (3-phenyl-1-imidazolidinyl)methylphosphonate ( 2.14 ) in 70% yield. The Lewis acid ZnBr2 facilitates loss of the benzotriazolyl ani on to form an iminium cation, which is then attacked by the P-nucleophile. [00JOC3683] Th us, various useful functionalities were introduced to the imidazolidine ring system via nucleophilic substitution of the benzotriazolyl group. 2.2.3 Syntheses of Optically Active Imidazolidines. (cf. Scheme 2-3) We further investigated the preparation of optically active imidazolidines starting from commercially available N -Boc--amino acids 2.15a c Based on our recent paper,[01JCS(P1)1767] -amino amides 2.17a c were easily obtained in two steps from the optically active N -Boc--amino acids 2.15a c (R3 = Me, i -Bu, or PhCH2) and 4methylphenylamine. Crombie and Hooper reduced 2-aminoN -phenylpropanamide with LiAlH4 to 2-aminopropylaniline without reportin g a detailed procedure.[55JCS3010] We found that refluxing of 2.17b (R3 = i -Bu) with 3 equiv of LiAlH4 in dry THF for 1 day gave a 1:1 mixture of 2.17b and 2.18b When 6 equiv of LiAlH4 in dry THF for 2 days was used, reduction of 2.17a c afforded chiral diamines 2.18a c in more than 90%

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9 yields. Intermediates 2.16a c 2.17a c and 2.18a c were all used as crude products without further purification for subsequent reactions. Reaction of diamines 2.18a c with benzotriazole and formaldehyde generated benzotriazol-1-yl intermediates 2.19a c in 85%, 93% and 93% yields, respectively. Nucleophilic substitution of 2.19a c by Grignard reagents, trie thyl phosphite or sodium cyanide gave optically active imidazolidines 2.20a d 2.21 or 2.22 in 66 99% yields. The structures of 2.20 22 are supported by their 1H, 13C NMR spectra and microanalyses. The two diastereotopic methylene hydrogens at the 5-position a ppear at different chemical shifts due to the chirality at postion-4. For 2.20a 2.21 irradiation of the annular CH3 caused a positive NOE effect for one of th e methylene hydrogens at 5-position; thus this hydrogen at a higher fi eld is assigned to be the anti -hydrogen Ha. We did not attempt to assign Ha and Hb for 2.20b d 2.22 because of their overlap with other protons, but we believe that their anti -Ha would be upfield by analogy to what was observed for 2.20a and 2.21 BocNOH O R3H H2NNHC6H4Me-pR3LiAlH4H BocNNHC6H4Me-pO R3H2NNHC6H4Me-pO R3p-MeC6H4NH2i ii, iii 2.15a-c 2.16a-c2.17a-c 2.18a-c N N R3Bt1C6H4Me-pBtH, 2 HCHO 2.19a-c Scheme 2-3. Preparation of optically active imidazolidines

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10 Scheme 2-3 contd. N N R3Bt1C6H4Me-pNaCN P(OEt)3ZnBr2N N R3R4C6H4Me-pHaHbN N PhH2C NC C6H4Me-pHaHbMe N N P C6H4Me-pEtO O EtO HaHb i) ClCOOBu-i, N-methylmorpholine; ii) HCl/Et2O (2 M); iii) aq. NaOH 2.19a-c R4MgBr 2.20 R3 R4 a Me allyl b i-Bu CH=CH2 c i-Bu C6H4Me-p d CH2Ph C CPh 2.21 R3 = Me R3 = PhCH22.225 2.2.4 Modification of the 2-Position of the Imidazolidine Ring. Following a previously reported procedur e, [90JOC1772] 4-nitrophenyl group was introduced onto the imidazolidine ring at the 2-position by the reaction of N -ethyl-1,2ethanediamine with 4-nitrobenzaldehyde us ing azeotropic distillation. To avoid the formation of chain tautomers due to possibl e ring-chain tautomerism, [90JOC1772] we did not attempt to use N -phenyl-1,2-ethanediamine ( 2.8a ) as the starting material. Compound 2.23 exists only in its cyclic form since no spectral evidence for the open tautomer was observed. Reaction of 2.23 with 1 equiv of benzotriazole and formaldehyde gave the Bt intermediate 2.24 which was treated with sodium cy anide to afford 2-[3-ethyl-2-(4nitrophenyl)-1-imidazolidinyl]acetonitrile ( 2.25 ) in 92% yield (Scheme 2-4).

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11 N N Et HH H N N Et H C6H4NO2-pNaCN N N Et C6H4NO2-pR i) p-O2NC6H4CHO; ii) BtH, HCHO ii 2.8b2.23 2.24 R = Bt 2.25 R = CN i Scheme 2-4. Modification of the 2-position of the imidazolidine ring 2.2.5 Preparation of 1-Methyl-3-substituted-2,3-dihydro-1 H -benzimidazoles 2.28, 2.29. 2,3-Dihydro-1 H -benzimidazoles are usually prepared by condensation of the corresponding N N-disubstituted-1,2-benzenediamine s with formaldehyde.[21JCS1537] [88JCS(P1)1939] We reported the formati on of 1,3-bis(benzotriazolylmethyl)-2,3dihydro-1 H -benzimidazole by treatment of 1,2-benzenediamines with 1 H -benzotriazole and formaldehyde.[90CJC446] We found that condensation of N -methyl-1,2benzenediamine ( 2.26a ) with benzotriazole and 2 equi v of formaldehyde produced Bt intermediate 2.27 in 85% yield (Scheme 2-5). Compound 2.27 was obtained as a mixture of Bt1 and Bt2 isomers in ca. 5.9:1 ratio, which was used directly for the subsequent reactions. Reaction of 2.27 with vinyl magnesium bromide was found to give unidentifiable products probably opening the five-membered ring. The weaker nucleophile, vinyl zinc bromide (prepared from vinyl magnesium brom ide and zinc chloride ), gave 1-allyl-3methyl-2,3-dihydro-1 H -benzimidazole ( 2.28 ) in 83% yield. Compound 2.28 is extremely sensitive to silica gel or neutral Al2O3; it was finally purified by flash column chromatography on basic Al2O3. It also easily decomposes in CDCl3 with disappearance of the NCH2N methylene group, so NMR analys is was performed in DMSOd6. Treatment of 2.27 with 2 equiv of NaCN produced 94% yield of 2-(3-methyl-2,3-

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12 dihydro-1 H -benzimidazol-1-yl)acetonitrile ( 2.29 ), which was also purified by flash column chromatography on basic Al2O3. Compounds 2.28 and 2.29 are both labile to air, so are used in situ for other transformations, since their crude NMR spectra and GC analyses show more than 90% purity. In th e absence of mechanistic studies, a possible reason for instability is that compounds 2.28 and 2.29 are readily oxidized. Condensation of 2.26b (R = Ph) with benzotriazol e and formaldehyde (1 or 2 equiv) only generated th e acyclic intermediate 2.30 possibly due to the increased steric hindrance caused by the PhNHAr fragment. The Bt group in 2.30 was further substituted by cyanide anion to give 2-(2 -anilinoanilino)acetonitrile ( 2.31 ) in 77% yield. BtH HCHO N N R H H H N N Me Bt CH2=CHZnBr BtH HCHO N N Me NaCN N N Ph H H Bt N N Me CN NaCN N N Ph H H CN 2.26a R = Me 2.26b R = Ph 2.27 2.282.29 R = Me 2.30 2.31 R = Ph Scheme 2-5. Preparation of benzimidazoles

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13 2.3 Conclusion In summary, an efficient method has b een developed for the preparation of unsymmetrical imidazoli dines and 2,3-dihydro-1 H -benzimidazoles via Mannich reactions of diamines with benzotriazole and form aldehyde, followed by nucleophilic substitution of the benzotriazolyl group with other functionalities. Compared to the previous methods (multi-step and low yields) for the preparation of unsymmetrical imidazolidines, [86S657] [77LAC956] [00JHC57] our method needs only two steps, utilizes easily available starting materials, and generall y affords the desired products in good to excellent yields. 2.4 Experimental Section THF or toluene was distilled from sodium-benzophenone prior to use. Melting points are uncorrected. 1H, 13C NMR spectra were recorded (300 MHz and 75 MHz respectively) in CDCl3 (with TMS for 1H and chloroformd for 13C as the internal reference), unless otherwise stated. Elementa l analyses were performed on a Carlo Erba1106 instrument. Optical rotation values were measured with the use of the sodium D line. Column chromatography was performed on silica gel (200 425 mesh), neutral alumina (60 325 mesh) or basic alumina (60 325 mesh). All of the reactions were carried out under N2. 2.4.1 General Procedure for the Preparation of 1-Substituted-3-(b enzotriazolylmethyl) Imidazolidines 2.9a c A mixture of a N -substituted-1,2-ethanediamine 2.8a c (3.0 mmol), BtH (0.36 g, 3.0 mmol), and formaldehyde (37% a queous solution, 0.49 g, 6 mmol) in CH3OH/H2O (10 mL/5 mL) was stirred for 4 h at 20 C. For 2.9a the precipitate formed was filtered and washed with cool Et2O. For 2.9b c the mixture was extracted with EtOAc, the

PAGE 27

14 organic fraction was washed with 1 M NaOH, brine and dried over anhyd Na2SO4. Removal of solvents in vacuo gave 2.9b c as oil. Bt intermediates 2.9a c were used as crude products for the subsequent reactions. 1-(1 H -1,2,3-Benzotriazolylmethyl)3-phenylimidazolidine (2.9a): white microcrystals (from CHCl3/hexanes); yield, 96%; mp 123 124 C; 1H NMR 3.20 (t, J = 6.1 Hz, 2H), 3.35 (t, J = 6.1 Hz, 2H), 4.24 (s, 2H), 5.62 (s, 2H, Bt1CH2), 6.43 (d, J = 7.9 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H); 13C NMR 45.9, 49.6, 64.4, 67.0 (Bt1CH2), 109.6, 111.6, 116.8, 119.9, 124.1, 127.7, 129.1, 133.4, 145.8, 145.8. Anal. Calcd for C16H17N5: C, 68.79; H, 6.13; N, 25.07. Found: C, 68.96; H, 6.18; N, 25.13. 1-Benzotriazolylmethyl-3-e thylimidazo lidine (2.9b): colorless oil; obtained as a mixture of Bt1 and Bt2 isomers in 5:1 ratio (only 1H and 13C NMR data for the Bt1 isomer are presented); yield, 90%; 1H NMR (Bt1) 1.06 (t, J = 7.1 Hz, 3H), 2.48 (q, J = 7.1 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 3.64 (s, 2H), 5.57 (s, 2H), 7.34 7.39 (m, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H); 13C NMR (Bt1) 13.8, 48.4, 48.9, 52.1, 65.4, 73.1, 109.8, 119.8, 123.9, 127.5, 133.5, 145.9. Anal. Calcd for C12H17N5: N, 30.28. Found: N, 30.20. 1-Benzotriazolylmethyl-3-b enzylimidazolidine (2.9c): yellowish oil; obtained as a mixture of Bt1 and Bt2 isomers in 5:1 ratio (only 1H and 13C NMR data for the Bt1 isomer are presented); yield, 92%; 1H NMR (Bt1) 2.70 (t, J = 7.1 Hz, 2H), 3.12 (t, J = 7.1 Hz, 2H), 3.56 (s, 2H), 3.61 (s, 2H), 5.54 (s, 2H), 7.18 7.36 (m, 7H), 7.59 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H); 13C NMR (Bt1) 48.8, 52.2, 58.4, 65.5, 73.2, 109.7,

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15 118.2, 119.8, 123.8, 127.0, 127.4, 128.1, 133.4, 138.4, 145.9. Anal. Calcd for C17H19N5: H, 6.53; N, 23.87. Found: H, 6.24; N, 23.70. 2.4.2 Procedure for Reduction of 2.9a with NaBH 4 A mixture of 2.9a (0.28 g, 1 mmol) and NaBH4 (0.076 g, 2 mmol) was refluxed in dry THF (10 mL) overnight. After removal of the solvent in vacuo, the residue was diluted with EtOAc. The organic extracts were washed with 1 M NaOH, brine, and dried over anhyd MgSO4. Evaporation of the solvent in vacuo gave 1-methyl-3phenylimidazolidine ( 2.10 ). 1-Methyl-3-phenylimidazolidine (2.10): colorless flakes (from Et2O); yield, 96%; mp 33 34 C (mp lit[77LAC956] 32 34 C); 1H NMR 2.48 (s, 3H), 2.96 (t, J = 6.3 Hz, 2H), 3.42 (t, J = 6.3 Hz, 2H), 3.97 (s, 2H), 6.53 (d, J = 7.8 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 7.23 (t, J = 7.3 Hz, 2H); 13C NMR 40.8, 46.3, 54.8, 71.8, 111.4, 116.1, 129.2, 146.4. 2.4.4 General Procedure for the Nucleophilic Substitutions of 2.9a c with Grignard Reagents. To a solution of 1-substituted-3-(benzotriazolylmethyl)imidazolidine 2.9a c (1.0 mmol) in dry THF or toluene (10 mL) at 0 C, an appropriate Gr ignard reagent was added dropwise. The amount of the Grigna rd reagent and the subsequent reaction conditions are collected in Ta ble 1. After being cooled, th e mixture was quenched with water and extracted with Et2O. The combined extracts were washed with 1 M NaOH, brine, and dried over anhyd MgSO4. After removal of solvents in vacuo, the residue was purified by column chromatography (silica gel) with hexanes/EtOAc as an eluent to give 1,3-disubstituted-imidazolidine 2.11a f Compounds 2.11g l were purified by neutral Al2O3 column chromatography.

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16 1-Pentyl-3-phenylim idazolidine (2.11a): colorless oil; yield, 80%; 1H NMR 0.91 (t, J = 6.3 Hz, 3H), 1.34 1.40 (m, 4H), 1.53 1.58 (m, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 6.3 Hz, 2H), 3.40 (t, J = 6.3 Hz, 2H), 3.98 (s, 2H), 6.48 (d, J = 8.2 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.7 Hz, 2H); 13C NMR 14.0, 22.6, 28.5, 29.6, 46.1, 52.9, 54.7, 70.3, 111.3, 116.0, 129.1, 146.4. Anal. Calcd for C14H22N2: C, 77.01; H, 10.16; N, 12.83. Found: C, 77.30; H, 10.49; N, 13.14. 1-Phenyl-3-(3-phenylpropyl)imidazolidine (2.11b): yellow oil; yield, 96%; 1H NMR 1.85 1.93 (m, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H), 3.39 (t, J = 6.2 Hz, 2H), 3.98 (s, 2H), 6.48 (d, J = 7.7 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 7.18 7.31 (m, 7H); 13C NMR 30.3, 33.5, 46.1, 52.8, 53.9, 70.3, 111.4, 116.1, 125.8, 128.3, 128.4, 129.1, 141.9, 146.4. Anal. Calcd for C18H22N2: C, 81.16; H, 8.32; N, 10.52. Found: C, 81.39; H, 8.61; N, 10.50. 1-Phenethyl-3-phenylimidazolidine (2.11c): white microcrystals (from EtOH); yield, 96%; mp 77 78 C; 1H NMR 2.83 2.90 (m, 4H), 3.03 (t, J = 6.2 Hz, 2H), 3.42 (t, J = 6.2 Hz, 2H), 4.06 (s, 2H), 6.45 6.51 (m, 2H), 6.67 6.73 (m, 1H), 7.19 7.33 (m, 7H); 13C NMR 35.5, 46.2, 53.0, 56.4, 70.4, 111.4, 116.3, 126.2, 128.5, 128.6, 129.2, 139.8, 146.4. Anal. Calcd for C17H20N2: C, 80.91; H, 7.99; N, 11.10. Found: C, 80.76; H, 8.05; N, 11.15. 1-(4-Methoxybenzyl)-3-phe nylimidazolidine (2.11d): white needles (from CH3OH); yield, 81%; mp 80 81 C; 1H NMR 3.01 (t, J = 6.2 Hz, 2H), 3.43 (t, J = 6.2 Hz, 2H), 3.70 (s, 2H), 3.81 (s 3H), 3.99 (s, 2H), 6.46 (d, J = 8.2 Hz, 2H), 6.70 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.21 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H); 13C NMR 46.1, 52.6, 55.3, 58.1, 69.9, 111.4, 113.8, 116.1, 129.1, 129.9, 130.3, 146.4,

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17 158.8. Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C, 75.85; H, 8.00; N, 10.60. HRMS Calcd for C17H20N2O 268.1576 (M), found 268.1574. 1-Phenyl-3-phenylethyn-2-ylimidazolidine (2.11e): orange prisms; yield, 80%; mp 68 69 C; 1H NMR 3.18 (t, J = 6.2 Hz, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.76 (s, 2H), 4.20 (s, 2H), 6.52 (d, J = 7.9 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 7.21 7.41 (m, 5H), 7.41 7.44 (m, 2H); 13C NMR 42.6, 46.2, 51.4, 68.8, 84.2, 85.1, 111.5, 116.3, 122.7, 128.2, 129.2, 131.7, 146.3. Anal. Calcd for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.68; H, 7.18; N, 10.78. 1-Allyl-3-phenylimidazolidine (2.11f): yellow oil; yield, 75%; 1H NMR 2.99 (t, J = 6.2 Hz, 2H), 3.21 3.24 (m, 2H), 3.39 (t, J = 6.2 Hz, 2H), 4.00 (s, 2H), 5.14 5.29 (m, 2H), 5.89 5.98 (m, 1H), 6.47 6.50 (m, 2H), 6.66 6.71 (m, 1H), 7.19 7.24 (m, 2H); 13C NMR 45.9, 52.5, 57.4, 69.9, 111.4, 116.1, 117.5, 129.1, 135.2, 146.4. Anal. Calcd for C12H16N2: C, 76.56; H, 8.57; N, 14.88. Found: C, 76.25; H, 8.63; N, 15.07. 1-Ethyl-3-phenethylimidazolidine (2.11g): colorless oil; yield, 75%; 1H NMR 1.10 (t, J = 7.5 Hz, 3H), 2.56 (q, J = 7.4 Hz, 2H), 2.78 2.86 (m, 8H). 3.46 (s, 2H), 7.19 7.31 (m, 5H); 13C NMR 14.1, 35.8, 49.3, 52.2, 52.5, 57.4, 76.4, 126.0, 128.3, 128.6, 140.1. Anal. Calcd for C13H20N2: C, 76.42; H, 9.87. Found: C, 76.53; H, 9.77. 1-Ethyl-3-(4-methylbenzyl)imidazolidine (2.11h): yellowish oil; yield, 71%; 1H NMR 1.08 (t, J = 7.3 Hz, 3H), 2.33 (s, 4H), 2.50 2.57 (m, 2H), 2.81 (s, 3H), 3.39 (s, 2H), 3.67 (s, 2H), 7.12 (d, J = 7.7 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H); 13C NMR 14.0, 21.0, 49.1, 52.2, 52.3, 59.3, 76.3, 128.4, 128.9, 136.2, 136.5. Anal. Calcd for C13H20N2: C, 76.42; H, 9.87. Found: C, 76.65; H, 10.34. HRMS Calcd for C13H21N2 205.1704 (M+1), found 205.1693.

PAGE 31

18 1-Benzyl-3-phenethylimidazolidine (2.11i): colorless oil; yield, 79%; 1H NMR 2.76 (br s, 4H), 2.84 (br s, 4H), 3.44 (s, 2H), 3.70 (s, 2H), 7.19 7.33 (m, 10H); 13C NMR 35.8, 52.3, 52.5, 57.1, 59.5, 76.5, 126.0, 126.9, 128.2, 128.3, 128.4, 128.5, 139.2, 140.1. Anal. Calcd for C18H22N2: C, 81.16; H, 8.32; N, 10.52. F ound: C, 81.21; H, 8.63; N, 10.31. 1-Allyl-3-benzylimidazolidine (2.11j): colorless oil; yield, 63%; 1H NMR 2.83 (s, 4H), 3.17 (d, J = 6.2 Hz, 2H), 3.41 (s, 2H), 3.71 (s, 2H), 5.08 (d, J = 10.1 Hz, 1H), 5.18 (dd, J = 17.1, 2.4 Hz, 1H), 5.84 5.93 (m, 1H), 7.24 7.37 (m, 5H); 13C NMR 52.1, 52.4, 58.2, 59.4, 76.2, 116.8, 126.9, 128.2, 128.5, 135.9, 139.2. Anal. Calcd for C13H18N2: C, 77.18; H, 8.97; N, 13.85. Found: C, 76.85; H, 9.29; N, 13.65. 1-Benzyl-3-(3-phenyl-2-propynyl)imidazolidine (2.11k): brown oil; yield, 65%; 1H NMR 2.87 (t, J = 6.2 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H), 3.58 (s 2H), 3.64 (s, 2H), 3.74 (s, 2H), 7.24 7.43 (m, 10H); 13C NMR 43.1, 50.8, 52.6, 59.3, 75.0, 84.2, 85.3, 123.0, 126.9, 128.0, 128.1, 128.2, 128.4, 131.6, 139.1. Anal. Calcd for C19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C, 82.25; H, 7.64; N, 9.99. 1-Benzyl-3-hexylimidazolidine (2.11l): yellow oil; yield, 80%; 1H NMR 0.88 (t, J = 6.7 Hz, 3H), 1.28 (br s, 6H), 1.45 (br s, 2H), 2.47 (t, J = 7.5 Hz, 2H), 2.81 (s, 4H), 3.39 (s, 2H), 3.70 (s, 2H), 7.23 7.36 (m, 5H); 13C NMR 14.0, 22.5, 27.1, 29.0, 31.7, 52.3, 52.5, 55.5, 59.6, 76.6, 126.8, 128.1, 128.4, 139.2. Anal. Calcd for C19H20N2: N, 11.37. Found: N, 11.44. HRMS Calcd for C16H27N2 247.2174 (M+1), found 247.2171. 2.4.5 General Procedure for the Reaction of 2.9a c with NaCN. A mixture of 2.9a c (1.0 mmol) and NaCN (0.050 g, 1.0 mmol) in DMSO (5 mL) was stirred at 25 C for 20 h. The mixture was poured into 20 mL water. For 2.12a the

PAGE 32

19 precipitate formed was filtered to give white powder, which was recrystallized from EtOH. For 2.12b c the mixture was extracted with CH2Cl2, and the organic extracts were washed with 1 M NaOH, water, brine, and dried over anhyd MgSO4. After removal of the solvent in vacuo, the residue was purif ied by column chromatography to give 2.12b c 2-(3-Phenyl-1-imidazolidin yl)acetonitrile (2.12a): white microcrystals (from EtOH); yield, 77%; mp 65 66 C; 1H NMR 3.15 (t, J = 6.2 Hz, 2H), 3.49 (t, J = 6.2 Hz, 2H), 3.74 (s, 2H), 4.15 (s, 2H), 6.51 (d, J = 8.1 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 7.25 (t, J = 7.9 Hz, 2H); 13C NMR 40.6, 46.2, 51.3, 68.6, 111.7, 114.9, 117.0, 129.3, 145.9. Anal. Calcd for C11H13N3: C, 70.56; H, 7.00; N, 22.44. F ound: C, 70.31; H, 7.14; N, 22.45. 2-(3-Ethyl-1-imidazolidin yl)acetonitrile (2.12b): separated by flash basic Al2O3 column chromatography with CH2Cl2 as an eluent; colorl ess oil; yield, 90%; 1H NMR 1.11 (t, J = 7.2 Hz, 3H), 2.56 (q, J = 7.2 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H), 3.51 (s, 2H), 3.65 (s, 2H); 13C NMR 13.9, 41.2, 48.6, 50.5, 52.0, 74.5, 115.6. HRMS Calcd for C7H13N3 139.1109 (M), found 139.1105. 2-(3-Benzyl-1-imidazolidin yl)acetonitrile (2.12c): separated by flash silica gel column chromatography with hexanes/EtOAc (7:3) as an eluent; colorless oil; yield, 97%; 1H NMR 2.85 2.89 (m, 2H), 2.95 3.00 (m, 2H), 3.47 (s, 2H ), 3.59 (s, 2H), 3.70 (s, 2H), 7.24 7.36 (m, 5H); 13C NMR 41.2, 50.5, 52.2, 58.6, 74.4, 115.6, 127.0, 128.2, 128.3, 138.5. Anal. Calcd for C12H15N3: C, 71.61; H, 7.51; N, 20.88. Found: C, 71.26; H, 7.41; N, 21.11.

PAGE 33

20 2.4.6 Procedure for the Nucleophilic Substitution of 2.9a with Benzenethiol. To a solution of benzenethiol (0.13 g, 1.2 mmol) in dry THF (10 mL), NaH (60% in mineral oil, 0.05 g, 1.3 mmol) was added, and the mixture was stirred at 20 C for 10 min. One drop of methanol was adde d to quench excess NaH and then 2.9a (0.28 g, 1.0 mmol) was added. The mixture was refluxe d for 38 h. After removal of THF under reduced pressure, the residue was extracted with Et2O. The organic extracts were washed with 2 M NaOH, brine and dried over anhyd MgSO4. The desired compound was purified by column chromatography with hexa nes/EtOAc (4:1) as an eluent. 1-Phenyl-3-(phenylthiomethyl)imidazolidine (2.13): white flakes (from CH3OH); yield, 66%; mp 64 65 C; 1H NMR 3.12 (t, J = 6.2 Hz, 2H), 3.99 (t, J = 6.3 Hz, 2H), 4.14 (s, 2H), 4.55 (s, 2H), 6.43 6.46 (m, 2H), 6.70 (t, J = 7.3 Hz, 1H), 7.18 7.30 (m, 5H), 7.45 7.48 (m, 2H); 13C NMR 46.3, 49.6, 60.2, 67.1, 111.6, 116.4, 126.6, 129.0, 129.2, 130.9, 137.1, 146.2. Anal. Calcd for C16H18N2S: C, 71.07; H, 6.71; N, 10.36. Found: C, 71.09; H, 6.88; N, 10.30. 2.4.7 Procedure for the Nucleophilic Substitution of 2.9a with Triethyl Phosphite. To a solution of 2.9a (0.28 g, 1.0 mmol) in dry CH2Cl2 (20 mL) at 0 C, ZnBr2 (0.22 g, 1.0 mmol) and triethyl phosphite ( 0.34 mL, 2.0 mmol) were added sequentially. The reaction mixture was stirred at 0 C for 2 h and at room temperature overnight. After extraction with CH2Cl2, the combined organic layers were washed with 1 M NaOH, brine and dried over anhyd MgSO4. After removal of the solvent in vacuo, the desired product was purified by column chromatography with hexanes/EtOAc (4:1) as an eluent. Diethyl (3-Phenyl-1-imidazolidinyl)methylphosphonate (2.14): yellowish oil; yield, 70%; 1H NMR 1.36 (t, J = 7.0 Hz, 6H), 3.02 (d, J = 12.5 Hz, 2H), 3.17 (t, J = 6.3

PAGE 34

21 Hz, 2H), 3.41 (t, J = 6.1 Hz, 2H), 4.05 4.23 (m, 6H), 6.50 (d, J = 8.2 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 7.23 (t, J = 7.7 Hz, 2H); 13C NMR 16.5 (d, J = 5.3 Hz), 45.8, 50.2 (d, J = 167.3 Hz), 54.7 (d, J = 10.6 Hz), 62.3 (d, J = 6.4 Hz), 71.5 (d, J = 12.7 Hz), 111.5, 116.4, 129.2, 146.2. Anal. Calcd for C14H23N2O3P: C, 56.37; H, 7.77; N, 9.39. Found: C, 56.39; H, 7.89; N, 9.59. 2.4.8 General Procedure for the Preparation of Chiral Diamines 2.18a c from N -Boc-amino Acids 2.15a c -Amino amides 17a c were obtained according to our recent paper. [01JCS(P1)1767] Therefore, we did not obtain these elemental analyses. A mixture of 2.17a c (3 mmol) and LiAlH4 (powder, 0.68 g, 18 mmol) in dry THF (30 mL) was refluxed for 2 days. The mixtur e was slowly quenched with water under icebath. The precipitate formed was filtered off and washed with CH2Cl2. The combined filtration was washed with 1M Na OH, brine and dried over anhydrous K2CO3. Removal of solvents afforded diamine 2.18a c which was directly used for the subsequent reaction. GC analyses sh ow that the purity of 2.18a c is more than 90%. (2 S )N1-(4-Methylphenyl)-1,2-propanediamine (2.18a): yellowish oil; yield, 96%; 1H NMR 1.20 (d, J = 7.1 Hz, 3H), 1.20 1.80 (br s, 2H), 2.31 (s, 3H), 2.90 (dd, J = 12.1, 8.0 Hz, 1H), 3.14 3.22 (m, 2H), 3.80 4.25 (br s, 1H), 6.62 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H); 13C NMR 20.1, 21.8, 45.9, 52.3, 112.8, 126.1, 129.5, 146.0. (2 S )-4-MethylN1-(4-methylphenyl)-1,2-pentanediamine (2.18b): colorless oil; yield, 93%; 1H NMR 0.91 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.28 (t, J = 6.7 Hz, 2H), 1.20 1.40 (br s, 2H), 1.70 1.81 (m, 1H), 2.24 (s, 3H), 2.79 (dd, J = 11.8, 8.7 Hz, 1H), 3.00 3.08 (m, 1H), 3.13 3.20 (m, 1H), 3.80 4.10 (br s, 1H), 6.56 (d, J = 8.1

PAGE 35

22 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H); 13C NMR 20.3, 22.1, 23.5, 24.7, 45.7, 48.4, 51.3, 113.1, 126.5, 129.7, 146.3. (2 S )N1-(4-Methylphenyl)-3-phenyl-1,2-propanediamine (2.18c): yellowish oil; yield, 94%; 1H NMR 1.02 1.40 (br s, 2H), 2.23 (s, 3H), 2.56 (dd, J = 13.3, 8.4 Hz, 1H), 2.78 2.94 (m, 2H), 3.18 3.27 (m, 2H), 3.90 4.05 (br s, 1H), 6.53 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 7.18 7.32 (m, 5H); 13C NMR 20.3, 42.7, 50.3, 52.1, 113.0, 126.3, 126.5, 128.4, 129.1, 129.6, 138.7, 146.1. 2.4.9 General Procedure for the Preparation of Optically Active Imidazolidines 2.20a d 2.21 2.22 To a solution of a diamine 2.18a c (3.0 mmol), BtH (0.36 g, 3.0 mmol) in CH3OH/H2O (10 mL/5 mL), formaldehyde (37% aqueous solution, 0.49 g, 6 mmol) was added, and the reaction mixture was stirred for 4 h at 20 C. The precipitate formed was filtered and washed with cool Et2O to give 2.19a c After dried under reduced pressure at 30 oC for 24 h, the products were crystallized out from appropriate solvents described below. To a solution of 2.19a c (1.0 mmol) in dry THF (15 mL), an appropriate Grignard reagent (1.2 mmol) in THF was added dropwis e. The reaction mixt ure was stirred at room temperature for 30 min and then refluxe d for 1 h. The same work-up as used for the preparation of 2.11 gave 2.20a d which was purified by flash column chromatography (silica gel). The same procedure as used for the preparation of 2.14 and 2.12b afforded 2.21 and 2.22 respectively.

PAGE 36

23 1-{[(5 S )-5-Methyl-3-(4-methylphenyl)tetrahydro-1 H -imidazol-1-yl]methyl}1 H -1,2,3-benzotriazole (2.19a): colorless microcrystals (from EtOH); yield, 85%; mp 129 130 C; [ ]25 D = 16.2 ( c 1.71, CHCl3); 1H NMR 1.41 (d, J = 6.1 Hz, 3H), 2.21 (s, 3H), 3.02 (t, J = 8.1 Hz, 1H), 3.25 3.31 (m, 1H), 3.45 (t, J = 7.3 Hz, 1H), 4.13, 4.38 (AB, J = 4.1 Hz, 2H), 5.64 (d, J = 3.5 Hz, 2H), 6.34 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13C NMR 16.9, 20.2, 54.1, 54.6, 61.8, 68.1, 109.5, 111.7, 120.0, 124.0, 126.0, 127.7, 129.7, 133.6, 143.9, 145.9. Anal. Calcd for C18H21N5: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.24; H, 7.11; N, 22.95. 1-{[(5 S )-5-Isobutyl-3-(4-methylphenyl)tetrahydro-1 H -imidazol-1-yl]methyl}1 H -1,2,3-benzotriazole (2.19b): colorless microcrystals (f rom hexanes/EtOAc); yield, 93%; mp 103 104 C; [ ]25 D = +4.8 ( c 1.62, CHCl3); 1H NMR 0.92 (d, J = 6.3 Hz, 3H), 0.93 (d, J = 6.3 Hz, 3H), 1.37 1.46 (m, 1H), 1.61 1.72 (m, 1H), 1.76 1.84 (m, 1H), 2.22 (s, 3H), 2.99 (t, J = 7.5 Hz, 1H), 3.29 3.33 (m, 1H), 3.49 (t, J = 7.5 Hz, 1H), 4.19, 4.31 (AB, J = 4.8 Hz, 2H), 5.61 (d, J = 2.8 Hz, 2H), 6.37 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13C NMR 20.3, 22.3, 23.5, 25.7, 41.9, 52.5, 58.1, 63.5, 67.9, 109.7, 112.0, 120.0, 124.0, 126.1, 127.6, 129.7, 133.5, 144.0, 146.0. Anal. Calcd for C21H27N5: C, 72.17; H, 7.79; N, 20.04. Found: C, 72.39; H, 7.82; N, 20.23. 1-{[(5 S )-5-Benzyl-3-(4-methylphenyl)tetrahydro-1 H -imidazol-1-yl]methyl}1 H -1,2,3-benzotriazole (2.19c): white microcrystals (f rom EtOH); yield, 93%; mp 94 95 C; [ ]25 D = +1.8 ( c 1.70, CHCl3); 1H NMR 2.21 (s, 3H), 2.74 (dd, J = 13.2, 8.3 Hz, 1H), 3.08 (t, J = 7.6 Hz, 1H), 3.22 3.31 (m, 2H), 3.58 3.63 (m, 1H), 4.24, 4.39 (AB,

PAGE 37

24 J = 5.0 Hz, 2H), 5.56, 5.67 (AB, J = 13.7 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 7.22 7.40 (m, 6H), 7.45 7.49 (m, 2H), 8.05 (d, J = 8.2 Hz, 1H); 13C NMR 20.3, 39.2, 52.2, 61.2, 63.7, 68.2, 109.7, 112.3, 120.0, 124.0, 126.4, 126.6, 127.7, 128.6, 129.0, 129.6, 133.5, 138.1, 144.0, 145.9. Anal. Calcd for C24H25N5: C, 75.17; H, 6.57; N, 18.26. Found: C, 74.95; H, 6.77; N, 18.29. (4 S )-3-(3-Butenyl)-4-methyl-1-(4-methylphenyl)tetrahydro-1 H -imidazole (2.20a): yellowish oil; yield, 94%; [ ]25 D = +111 ( c 2.17, CHCl3); 1H NMR 1.20 (d, J = 6.0 Hz, 3H), 2.24 (s, 3H), 2.30 2.37 (m, 3H), 2.82 2.94 (m, 2H), 3.02 (t, J = 8.2 Hz, 1H, Ha), 3.44 (t, J = 7.4 Hz, 1H, Hb), 3.68, 4.43 (AB, J = 4.1 Hz, 2H), 5.04 (d, J = 10.2 Hz, 1H), 5.11 (d, J = 17.0 Hz, 1H), 5.79 5.92 (m, 1H), 6.40 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H); 13C NMR 16.8, 20.2, 33.2, 51.8, 53.9, 58.7, 70.8, 111.3, 115.8, 125.1, 129.6, 136.3, 144.3. Anal. Calcd for C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C, 78.05; H, 9.63; N, 11.99. (4 S )-3-Allyl-4-isobutyl-1-(4-methylphenyl)tetrahydro-1 H -imidazole (2.20b): yellowish oil; yield, 78%; [ ]25 D = +28.7 ( c 1.67, CHCl3); 1H NMR 0.93 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.30 1.40 (m, 1H), 1.53 1.69 (m, 2H), 2.24 (s, 3H), 2.91 3.05 (m, 3H), 3.47 3.54 (m, 2H), 3.73, 4.31 (AB, J = 5.1 Hz, 2H), 5.15 (d, J = 10.2 Hz, 1H), 5.25 (d, J = 17.0 Hz, 1H), 5.87 6.00 (m, 1H), 6.41 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H); 13C NMR 20.3, 22.3, 23.7, 25.8, 41.9, 52.5, 56.1, 61.4, 70.3, 111.6, 117.4, 125.3, 129.6, 135.6, 144.5. Anal. Calcd for C17H26N2: C, 79.02; H, 10.14; N, 10.84. Found: C, 78.79; H, 9.84; N, 10.70. (4 S )-4-Isobutyl-3-(4-methylbenzyl)-1-(4-methylphenyl)tetrahydro-1 H imidazole (2.20c): yellowish oil; yield, 85%; [ ]25 D = +74.9 ( c 2.50, CHCl3); 1H NMR

PAGE 38

25 0.94 (d, J = 5.9 Hz, 6H), 1.41 1.46 (m, 1H), 1.63 1.76 (m, 2H), 2.22 (s, 3H), 2.34 (s, 3H), 2.99 3.09 (m, 1H), 3.06 (q, J = 7.6 Hz, 1H), 3.37, 4.02 (AB, J = 13.0 Hz, 2H), 3.55 (dd, J = 7.4, 6.6 Hz, 1H), 3.68, 4.15 (AB, J = 5.1 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H); 13C NMR 20.3, 21.1, 22.4, 23.7, 25.9, 42.0, 52.6, 57.0, 61.6, 70.4, 111.6, 125.2, 128.6, 129.0, 129.6, 135.8, 136.7, 144.5. Anal. Calcd for C22H30N2: C, 81.94; H, 9.38; N, 8.69. Found: C, 81.66; H, 9.58; N, 8.72. (4 S )-4-Benzyl-1-(4-methylphenyl)-3-(3 -phenyl-2-propynyl)tetrahydro-1 H imidazole (2.20d): pale brown prism; yield, 66%; mp 91 92 C; [ ]25 D = +6.8 ( c 1.51, CHCl3); 1H NMR 2.23 (s, 3H), 2.68 (dd, J = 13.3, 9.2 Hz, 1H), 3.13 3.20 (m, 2H), 3.30 3.35 (m, 1H), 3.47 3.52 (m, 1H), 3.83 (d, J = 17.7 Hz, 2H), 4.17, 4.45 (AB, J = 4.2 Hz, 2H), 6.40 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 7.21 7.33 (m, 8H), 7.41 7.43 (m, 2H); 13C NMR 20.3, 38.6, 40.4, 52.4, 62.0, 69.8, 83.8, 85.4, 111.7, 122.0, 125.5, 126.4, 128.2, 128.3, 128.5, 129.0, 129.6, 131.7, 138.5, 144.3. Anal. Calcd for C26H26N2: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.16; H, 7.16; N, 7.99. Diethyl [(5 S )-5-methyl-3-(4-methylphenyl)tetrahydro-1 H -imidazol-1yl]methylphosphonate (2.21): yellowish oil; yield, 90%; [ ]25 D = +50.6 ( c 1.58, CHCl3); 1H NMR 1.22 (d, J = 5.4 Hz, 3H), 1.35 (t, J = 7.0 Hz, 6H), 2.24 (s, 3H), 2.77 (dd, J = 15.1, 6.6 Hz, 1H, Ha), 2.98 3.02 (m, 2H), 3.20 (dd, J = 17.7, 15.1 Hz, 1H, Hb), 3.46 3.47 (m, 1H), 3.87, 4.65 (AB, J = 4.7 Hz, 2H), 4.12 4.22 (m, 4H), 6.42 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H); 13C NMR 16.4 (d, J = 5.7 Hz), 16.5 (d, J = 5.7 Hz), 16.7, 20.2, 47.8 (d, J = 167.2 Hz), 53.4, 60.1 (d, J = 17.8 Hz), 61.9 (d, J = 6.3 Hz), 62.5 (d, J = 6.3

PAGE 39

26 Hz), 71.9 (d, J = 2.3 Hz), 111.5, 125.4, 129.6, 144.2. Anal. Calcd for C16H27N2O3P: C, 58.88; H, 8.34; N, 8.58. Found: C, 58.58; H, 8.33; N, 8.60. 2-[(5 S )-5-Benzyl-3-(4-methylphenyl)tetrahydro-1 H -imidazol-1-yl]acetonitrile (2.22): yellowish flakes (from EtOH); yield, 99%; mp 76 77 C; [ ]25 D = +40.4 ( c 1.98, CHCl3); 1H NMR 2.23 (s, 3H), 2.71 (dd, J = 13.0, 7.1 Hz, 1H), 2.98 (dd, J = 13.3, 5.1 Hz, 1H), 3.14 (br s, 1H), 3.36 3.41 (m, 2H), 3.63 (s, 2H), 4.05, 4.37 (AB, J = 4.0 Hz, 2H), 6.38 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 7.21 7.35 (m, 5H); 13C NMR 20.2, 38.6, 38.9, 52.3, 62.1, 69.9, 111.9, 114.8, 126.2, 126.7, 128.6, 128.8, 129.6, 137.5, 143.7. Anal. Calcd for C19H21N3: C, 78.31; H, 7.26; N, 14.42. Found: C, 78.45; H, 7.45; N, 14.11. 2.4.10 Procedure for the Preparati on of the Bt Intermediate 2.24 and its Substitution with NaCN. A mixture of 1-ethyl-2-(4nitrophenyl)imidazolidine ( 2.23 0.66 g, 3.0 mmol), BtH (0.36 g, 3.0 mmol), formaldehyde (37% aq solution; 0.25 g, 3.0 mmol) in CH3OH/H2O (10/4 mL) was stirred at room temperature fo r 24 h. The precipitate formed was filtered and recrystallized from EtOH to give 2.24 A mixture of 2.24 (0.35 g, 1.0 mmol) and NaCN (0.10 g, 2.0 mmol) was stirred in DMSO (3 mL) at 25 C for 24 hours. The mixture was diluted with CH2Cl2, washed with water and dried over anhyd MgSO4. After removal of the solv ent in vacuo, the residue was purified by flash basic Al2O3 column chromatography with hexanes/EtOAc (6:4) as an eluent to afford 2.25 1-{[3-Ethyl-2-(4-nitrophenyl)-1-imidazolidinyl]methyl}-1 H -1,2,3-benzotriazole (2.24): pale yellow microcrystals ( from EtOH); yield, 85%; mp 121 122 C; 1H NMR 0.92 (t, J = 7.2 Hz, 3H), 2.06 2.13 (m, 1H), 2.29 2.42 (m, 2H), 3.10 3.17 (m, 1H),

PAGE 40

27 3.33 3.40 (m, 1H), 3.51 (q, J = 7.4 Hz, 1H), 4.11 (s, 1H), 5.29, 5.45 (AB, J = 14.0 Hz, 2H), 7.34 7.39 (m, 2H), 7.48 (t, J = 7.1 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 7.4 Hz, 1H), 8.21 (d, J = 8.7 Hz, 2H); 13C NMR 13.4, 46.4, 48.1, 50.6, 62.2, 83.4, 109.4, 119.9, 123.4, 124.0, 127.6, 130.2, 133.6, 145.6, 147.4, 148.3. Anal. Calcd for C18H20N6O2: C, 61.35; H, 5.72; N, 23.85. Found: C, 61.29; H, 5.83; N, 23.90. 2-[3-Ethyl-2-(4-nitrophenyl)-1-imi dazolidinyl]acetonitrile (2.25): Brown oil; yield, 92%; 1H NMR 1.00 (t, J = 7.2 Hz, 3H), 2.22 2.34 (m, 1H), 2.42 2.54 (m, 1H), 2.62 2.71 (m, 1H), 2.99 3.06 (m, 1H), 3.24 (d, J = 17.6 Hz, 1H), 3.39 3.54 (m, 2H), 3.57 (d, J = 17.7 Hz, 1H), 3.92 (s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 8.23 (d, J = 8.6 Hz, 2H); 13C NMR 13.4, 39.0, 46.5, 49.5, 50.2, 85.4, 115.0, 123.7, 129.9, 146.4, 148.6. Anal. Calcd for C13H16N4O2: C, 59.99; H, 6.20; N, 21.52. Found: C, 59.93; H, 6.17; N, 21.80. 2.4.11 Procedure for the Preparation of 1-Substituted-3-methyl-2,3-dihydro-1 H benzimidazoles 2.28 2.29 A mixture of N -(2-aminophenyl)N -methylamine ( 2.26a 0.37 g, 3.0 mmol), BtH (0.36 g, 3.0 mmol), formaldehyde (37% aq solution; 0.49 g, 6 mmol) in CH3OH/H2O (10 mL/4 mL) was stirred at room temperature overnight. Then an additional 10 mL water was added and the mixture was stirred for 1 h. The precipitate formed was filtered and washed with cool ethanol to give 27 To a solution of vinyl magnesium brom ide (2.0 M in THF; 0.7 mL, 1.4 mmol) at 0 C, ZnCl2 (0.5 M in Et2O; 3.0 mL, 1.5 mmol) and a solution of 2.27 (0.26 g, 1.0 mmol) in dry THF (10 mL) was added subsequently. The reaction mixture was stirred for 20 min at room temperature, and then refluxed for 2 h. After cooling, the mixture was quenched with water, and extracted with CH2Cl2. The organic extracts were washed with 1M NaOH, water, brine, and dried over anhydrous K2CO3. Evaporation of the solvent in

PAGE 41

28 reduced pressure gave the crude product 2.28 which was purified by flash column chromatography on basic Al2O3 with hexanes/ethyl acetate (8:2). The same procedure as used for the preparation of 2.25 afforded 2.29 1-Benzotriazolylmethyl -3-methyl-2,3-dihydro-1 H -benzimidazole (2.27): obtained as a mixture of Bt1 and Bt2 isomers in ca. 6:1 ratio (only 1H, 13C NMR data for the Bt1 isomer are presented); wh ite microcrystals (from CH3OH); yield, 85%; mp 122 124 C; 1H NMR (Bt1) 2.66 (s, 3H), 4.61 (s, 2H), 5.96 (s, 2H), 6.38 6.41 (m, 1H), 6.67 6.77 (m, 2H), 6.81 6.83 (m, 1H), 7.34 7.39 (m, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H); 13C NMR (Bt1) 34.0, 60.2, 76.0, 106.6, 106.7, 109.7, 118.8, 119.9, 120.8, 124.1, 127.8, 132.7, 138.6, 142.9, 146.1. Anal. Calcd for C15H15N5: C, 67.90; H, 5.70; N, 26.40. Found: C, 67.72; H, 5.46; N, 26.40. 1-Allyl-3-methyl-2,3-dihydro-1 H -benzimidazole (2.28): Rf = 0.70 [eluent: hexanes/CH2Cl2 = 7:3; Al2O3 TLC plate (Aldrich, Cat No. Z23421-4)]; extremely labile to air; yellowish oil; yield, 83%; 1H NMR (DMSO-d6) 2.64 (s, 3H), 2.79 (d, J = 6.1 Hz, 2H), 4.29 (s, 2H), 5.19 (d, J = 12.1, 2.1 Hz, 1H), 5.30 (dd, J = 17.2, 2.0 Hz, 1H), 5.84 5.94 (m, 1H), 6.38 6.45 (m, 2H), 6.50 6.55 (m, 2H); 13C NMR (DMSO-d6) 34.0, 50.4, 77.5, 105.8, 106.2, 117.5, 118.5, 118.7, 134.1, 141.9, 143.2; GC-MS (EI): 174 (M+). 2-(3-Methyl-2,3-dihydro-1 H -benzimidazol-1-yl)acetonitrile (2.29): Rf = 0.70 [eluent: hexanes/CH2Cl2 = 7:3; Al2O3 TLC plate (Aldrich, Cat No. Z23421-4)]; separated by flash basic Al2O3 column chromatography with CH2Cl2 as an eluent; extremely labile to air; brown oil; yield, 94%; 1H NMR (DMSO-d6) 2.72 (s, 3H), 4.38 (s, 2H), 4.46 (s, 2H), 6.55 (d, J = 7.2 Hz, 1H), 6.65 6.78 (m, 3H); 13C NMR (DMSO-d6) 34.0, 35.4,

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29 76.7, 106.7, 115.9, 118.7, 120.8, 139.4, 143.3; GC-MS (EI): 173 (M+). Anal. Calcd for C10H11N3: H, 6.40; N, 24.26. Found: H, 6.54; N, 24.16. 2.4.12 Procedure for the Preparation of 2-(2-Anilinoanilino) acetonitrile (2.31). The same procedure as used for the preparation of 2.24 and 2.25 gave compounds 2.30 and 2.31 respectively. N -(1 H -1,2,3-Benzotriazol-1-ylmethyl)N-phenyl-1,2-benzenediamine (2.30): white microcrystals; yield, 92%; mp 146 147 C; 1H NMR 5.18 (s, 1H), 5.51 (t, J = 6.8 Hz, 1H), 6.07 (d, J = 7.0 Hz, 2H), 6.85 (d, J = 7.9 Hz, 2H), 6.78 6.85 (m, 2H), 7.05 7.16 (m, 5H), 7.31 7.42 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H); 13C NMR 57.9, 109.9, 112.8, 115.2, 119.6, 120.0, 120.1, 124.0, 126.1, 126.8, 127.4, 128.8, 129.3, 132.3, 141.2, 145.6, 146.4. Anal. Calcd for C19H17N5: C, 72.36; H, 5.43; N, 22.21. Found: C, 72.47; H, 5.79; N, 22.27. 2-(2-Anilinoanilino)acetonitrile (2.31): separated by basic Al2O3 flash column chromatography; yellow plates (from ethanol/hexanes); yield, 77%; mp 102 103 C; 1H NMR 4.08 (d, J = 7.0 Hz, 2H), 4.55 (t, J = 6.7 Hz, 1H), 5.13 (s, 1H), 6.68 (d, J = 7.8 Hz, 2H), 6.81 6.90 (m, 3H), 7.15 7.25 (m, 4H); 13C NMR 32.4, 111.9, 115.2, 116.8, 119.8, 120.2, 125.7, 126.5, 129.3, 129.4, 141.2, 145.3. Anal. Calcd for C14H13N3: C, 75.31; H, 5.87; N, 18.82. Found: C, 75.60; H, 5.65; N, 18.89.

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30 CHAPTER 3 NOVEL SYNTHESES OF HEXAHYDROI MIDAZO[1,5-b]ISOQUINOLINES AND TETRAHYDROIMIDAZO[1,5b ]ISOQUINOLIN-1(5 H )-ONES VIA IMINIUM CATION CYCLIZATIONS 3.1 Introduction Following our recent syntheses of optically active imidazolidines 3.6 from N -Boc--amino-acids, [02JOC3109] we have now developed routes to novel tricyclic 1,2,3,5,10,10a-hexahydroimidazo[1,5b ]isoquinolines 3.1 and 2,3,10,10atetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.2 The nearest known analogs of 3.1 and 3.2 are 10,10a-dihydroimidazo[1,5b ]isoquinoline-1,3(2 H ,5 H )-diones 3.3 which are of interest as inhibitors of inflamma tion, [77CA155653q] [78JPS718] apoprotein B-100 biosynthesis, [99CA52421k] and matrix-degrading metallo proteinase. [99CA184961s] The parent compound 3.3 (R1 = R2 = R3 = H) was obtained by cyclization of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid with KOCN. [77CA155653q] [78JPS718] Significant synthetic acti vity to prepare derivatives of 3 has involved (i) N alkylation of 3.3 (R1 = R2 = R3 = H) with N -(2-chloroethyl)piper idine; [77CA155653q] [78JPS718] (ii) Mann ich condensation of 3.3 (R1 = R2 = R3 = H) with formaldehyde and secondary amines;[90CCC540] (iii) modification of 3.3 (R1 = H, alkyl or Ph, R2 = R3 = H) via bromination and nucleophilic subs titution. [99CA524 21k] [91JCS(P1)119] Additional analogs of 3.3 have been made by (iv) solid phase supported intramolecular cyclization of N -Z--amino-amides. [96TL937] Optically active imidazolidines 3.6 were synthesized by Mannich condensations of chiral diamines 3.4 with benzotriazole and form aldehyde, followed by nucleophilic

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31 substitutions of the benzotriazolyl group in 3.5 [02JOC3109] Previous syntheses of 1,4dihydro-3(2 H )-isoquinolinones, [93JHC381] tetrahydro[1,3]oxazolo[3,4b ]isoquinolin-3ones [99TA255] and tetrahydr oisoquinolines [01TA2427] by intramolecular cyclizations utilizing Lewis acid-activated benzotriazole as a leaving group, s uggested a route to 3.1 by iminium cation Lewis acid promoted cyclizations of intermediates 3.5 (Scheme 3-1). Success of the methodology led to its ex tension to prepare 2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.2 N N H HH R Ph N NR BtH 2 HCHO N N O R1R2N N R Bt Ph X N N R R3R2 H+N N O R1O N N R Nu Ph * 3.1 3.2 3.3 Nu_3.43.53.6 L.A.+3.1 BtH = benzotriazole Bt Scheme 3-1. Intramolecular cyclizations u tilizing Lewis acid-activated benzotriazole 3.2 Results and Discussion 3.2.1 Preparation of Chiral Diamines 3.11a c from N -Boc-Phe-OH ( 3.7 ). N -Boc--amino-amides 3.9a c were readily obtained from optically active N -BocPhe-OH ( 3.7 ) and primary amines 3.8a c (R = p -CH3C6H4, c -C6H11 or PhCH2) using the mixed anhydride method. [01JCS(P1)1767] [0 0TL37] We previously used excess

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32 HCl/EtOAc to remove the Boc pr otecting group (usually needs 12 24 h until the disappearance of 3.9 ). [02JOC3109] [01JCS(P1)1767] We now find that 8 equiv of CF3COOH in dry CH2Cl2 efficiently removes N -Boc in 2 5 h giving the -amino-amides 3.10a c in 88% yields. Treatment of 3.10a c with 6 equiv of LiAlH4 in refluxing THF for 2 days afforded chiral diamines 3.11a c in 90% yields. Intermediates 3.9a c 3.10a c and 3.11a c were all used as crude produc ts for the subsequent reactions. BocNOH O Ph BocNNHR O Ph N N Bt1R Ph N NR H H H2NNHR Ph H2NNHR O Ph + RNH2i ii, iii i) ClCOOBui N -methylmorpholine; ii) CF3COOH; iii) aq. NaOH iv) LiAlH4; v) BtH, 2 HCHO (aq.); vi) AlCl33.7 3.9a c 3.11a c iv 3.12a c 3.8a c 3.1a c v vi 3.10a c a R = p -MeC6H4; b R = c -C6H11; c R = PhCH2 Scheme 3-2. Synthesis of 2-substituted hexahydroimidazo[1,5b ]isoquinolines 3.2.2 Syntheses of 1,2,3,5,10,10a-Hexahydroimidazo[1,5b ]isoquinolines 3.1a c Mannich condensation of chiral diamines 3.11a c with 1 equiv of benzotriazole and 2 equiv of formaldehyde (37% aqueous solution) in an aqueous solution at 25 C gave benzotriazolyl intermediates 3.12a c in 93%, 96% and 90% yields, respectively. Compounds 3.12a c were obtained solely as benzotriazol-1-yl isomers; 3.12b was obtained as a mixture of Bt1 and Bt2 isomers in ca. 26:1 ratio.

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33 Treatment of crude 3.12a c with 3 equiv of AlCl3 in refluxing CH2Cl2 afforded 2substituted-1,2,3,5,10,10a-hexahydroimidazo[1,5b ]isoquinolines 3.1a c (Scheme 3-2). The structures of 3.1a c are supported by their 1H, 13C NMR spectra and microanalyses. Lewis acid AlCl3 facilitates loss of the benzotriazol yl anion to form an iminium cation, which then undergoes intramolecu lar cyclization to afford 3.1a c 3.2.3 Syntheses of 2,3,10,10a-Tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.15a c (c.f. Scheme 3-3) The reaction of -amino-amide 3.10a with benzotriazole and formaldehyde in aqueous solution at 25 C did not produce the desired cyclized compound 3.14a ; instead acyclic 3.13 was obtained in 92% yield, due to the lower nucleophilic activity of amide nitrogen. Therefore, stronger conditions using azeotropic distillation with paraformaldehyde was applied and Bt intermediates 3.14a c were prepared in 92%, 91% and 94% yields, respectively. Attempts to purify 3.14a c by column chromatography failed due to their significant decompos ition on silica gel. Therefore, compounds 3.14a c were used directly for the subsequent cyclizations. The treatment of 3.14a c with 3 equiv of AlCl3 in refluxing CH2Cl2 gave 2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.15a c in 82%, 83% and 78% yields, respectively. The structures of 3.15a c are supported by the their 1H, 13C NMR spectra and microanalyses. The two methylene protons at the 5-position in 3.15a c appear at 3.7 4.0 ppm as a typical AB system with JAB = 14 Hz. We attempted direct treatment of -amino-amide 3.10a with excess paraformaldehyde in the presence of AlCl3, but could not isolate any desired tricyclic 3.15a This result highlighted the necessity of using the benzotriazole.

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34 H2NNHR O Ph N N Bt1R Ph O AlCl3H NNHC6H4Mep O Ph N NR O 3.15a c 3.10a c BtH aq. HCHO 3.13 Bt1CH2 BtH (CH2O)n a R = p -MeC6H4; b R = c -C6H11; c R = PhCH23.14a c3R = C6H4Mep (CH2O)n, AlCl3 5 Scheme 3-3. Synthesis of tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.2.4 Syntheses of Chiral 3-Subs tituted-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin1(5 H )-ones 3.18a c (c.f. Scheme 3-4) We further investigated the modifi cation of 2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.15 at 3-position. In agreement w ith the previous reactions of -amino-amides and aldehydes, [ 85T611] [75JHC995] we obtained 3.16b c exclusively as the trans -isomers; however, trans 3.16a was isolated in 38% yield together with the corresponding cis 3.16 a in 31% isolated yield. The absolute configurations of trans 3.16a c and cis 3.16 a were determined by NOE experiments. For example, a strong positive NOE effect between H(2) (5.81 pp m, s) and H(5) (4.00 ppm, t) in 16 a confirms its cis -configuration. For trans 16a c no positive NOE effect was observed between H(2) and H(5); however, small but distin ct NOE effects between H(2) and PhC H2 at the 5-position proved their trans -configurations. Reaction of 3.16a c with benzotriazole and aqueous formaldehyde readily gave Bt intermediates 3.17a c which were directly treated with AlCl3 to furnish enantiopure trans -3-substituted-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.18a c

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35 The same route from cis 3.16 a led to enantiopure cis 3.18 a The 1H NMR spectra show that NC H N (5.68 ppm, d) in trans 3.18a appears at a lower field than NC H N (5.32 ppm, d) in cis 3.18 a The positive NOE effect of H(3) and H(10a) in 3.18 a also confirms its cis -configuration. We attempted reactions of 3.16a c with paraformaldehyde and AlCl3 in the absence of benzotriazole. The crude NMR spect ra of the products showed a mixture of trans 3.18a c and cis 3.18 a c in a ratio ranging from 4:1 to 5:1. It is impossible to separate trans 3.18a c and cis 3.18 a c by column chromatography due to their very close Rf values on alumina or silica gel TLC plate. This result indicates the possible Lewis acid promoted ring opening and cl osing of the five-membered ring in 3.16a c We further treated trans 3.16a with AlCl3 only, and did observe the formation of cis 3.16 a in 1:4 ratio. We have suggested two recemization proce sses; 1) the nitrogen at position-1 may coordinate with AlCl3 to form intermediate A which undergoes ring opening to generate an iminium cation intermediate B The lone electron pair of the nitrogen in B attacks the iminium cation from above (I) or below (II) the plane, leading to trans 3.16a and cis 3.16 a respectively (Scheme 3-5, left). 2) The oxygen may coordinate with AlCl3 to form intermediate C The -hydrogen would leave to form the enolate intermediate D which lead to the racemizati on for the formation of 3.16 a (Scheme 3-5, right).

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36 N N H R Ph O Ph H2H5BtH HCHO PhCHO N N R Ph O Ph H Bt AlCl3H2NNHR O Ph N NR O H Ph 3.16a ca3.17a c 3.18a ca For trans 16a the cis -1 6'a was isolated in 31% yield.b This route resulted in a mixture of trans 18a c and cis 18'a c in a ratio range from 4:1 to 5:1.33.10a c a R = p -MeC6H4; b R = c -C6H11; c R = PhCH2(CH2O)nAlCl3 b 10a Scheme 3-4. Syntheses of chiral 3-substituted tetrahydroimidazo[1,5b ]isoquinolin1(5 H )-ones N N H Ar Ph O Ph H AlCl3N N Ar Ph O Ph H H H D N N Ar Ph O Ph H H H AlCl3AlCl3C Ph O Ph H N N H Ar II I B N N+Ar Ph O Cl3Al H Ph H N N H Ar Ph O H Ph II I AlCl3AlCl3N+N Ar Ph O Ph H Cl3Al H A Ph O Ph H N N H Ar3.16a 3.16'a. ._ _a Ar = p -MeC6H4; Reflux of only trans 16a resulted in a mixtu r e o f trans 16a and c i s 16'a inca.4:1 r atio.13.16a 3.16''a1+ AlCl3 Scheme 3-5. Isomerization of chiral 3-substituted tetrahydroimidazo[1,5b ]isoquinolin1(5 H )-ones

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37 3.2.5 Attempts to Synthesize 1,2a,3,4a,5,9b-Hexahydrobenzo[ g ]imidazo[2,1,5cd ]indolizin-4(2 H )-one ( 3.23 ). We recently reported reacti on of succindialdehyde ( 3.19 ) with benzotriazole and N phenylethylenediamine leading to 1-phe nyl-5-(benzotriazol-1-yl)hexahydro-1 H pyrrolo[1,2a ]imidazole 3.20 The benzotriazolyl group at the 5-position in 3.20 is readily removed by nucleophilic substituti ons with Grignard reagents allylsilanes, silyl enol ethers, or triethyl phosphite to furnis h novel 1-phenyl-5-substituted-hexahydro-1 H pyrrolo[1,2a ]imidazoles 3.21 [Nu = alkyl, aryl, allyl and P(O)(OEt)2] (Scheme 3-6). [00JOC3683] Since chiral diamines 3.11a c were readily obtaine d in high yields, our initial idea intended to use chiral diamine 3.11a instead of N -phenylethylenediamine, in order to control the two new chiral centers at 5and 7a-positions. Subsequent treatment of Bt intermediates 3.22 was supposed to undergo intram olecular cyclizations at the tethered phenyl group to give 3.23 CHO CHONPh H2N HN N H5H7aH3Bt C6H4Mep Ph BtH N NPh Bt1AlCl3N N H7aH C6H4Mep N NPh Nu 3.19 3.20 3.21 Nu3.22 (de > 99%) NOE 11a BtH 3.23 Scheme 3-6. Attempts to synthesize 1,2a,3,4a,5,9b-hexahydrobenzo[ g ]imidazo[2,1,5cd ]indolizin-4(2 H )-one

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38 Reaction of chiral diamine 3.11a with succindialdehyde ( 3.19 obtained by treatment of 2,5-dimethoxytetrahydrofuran w ith 0.1 M HCl) and benzotriazole in CH2Cl2 at room temperature for 24 h read ily afforded Bt intermediate 3.22 as a single enantiomer in 81% yield (Scheme 3-6). The stereochemistry of 3.22 was determined by NOE NMR experiments. 1H NMR spectra of 3.22 show that H(3), H(7a) a nd H(5) appear at 3.7 ppm (multiplet), 5.1 ppm (doublet-doublet) and 6.0 pp m (triplet), respectively. A significant positive NOE effect was observed between H(3) and H(5), and no NOE effect was observed between H(7a) with either H(3) or H(5). Thus, NOE analysis demonstrates that H(3) and H(5) in 3.22 are in a cis -orientation whereas H(3) and H(7a) are in trans orientation. Treatment of 3.22 with 2 equiv of AlCl3 did not afford the desired 3.23 but gave a decomposed mixture possibly due to the labile NCHN moiety in the presence of a Lewis acid. 3.3 Conclusion In summary, starting from easily available N -Boc--amino-acids, we have developed an efficient method for the preparation of novel enantiopure 1,2,3,5,10,10ahexahydroimidazo[1,5b ]isoquinolines 3.1a c 2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.15a c and 3.18a c via Lewis acid promoted iminium cation intramolecular cyclizations. 3.4 Experimental Section Column chromatography was performed on silica gel (200 425 mesh). All of reactions were carried out under nitrogen.

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39 3.4.1 General Procedure for the Preparation of Chiral -Amino-amides 3.10a c and Diamines 3.11a c from N -Boc-Phe-OH ( 3.7 ). -Amino-amides 3.10a c and diamines 3.11a c were prepared from N -Boc-PheOH ( 3.7 ) and primary amines 3.8a c according to our recent paper. [02JOC3109] [01JCS(P1)1767] [02TA933] 3.4.2 General Procedure for the Preparat ion of Benzotriazolyl intermediates 3.12a c A mixture of a diamine 3.11a c (3.0 mmol), BtH (0.36 g, 3.0 mmol) and formaldehyde (37% aqueous solution, 0.49 g, 6 mmol) in CH3OH/H2O (10 mL/5 mL) was stirred at 25 C for 4 h. The precipitate formed was filtered and washed with cool Et2O to give 3.12a c which was used directly for the subsequent reactions. For microanalyses and optical activity, crude 3.12a c was recrystallized from appropriate solvents. 1-{[(5 S )-5-Benzyl-3-(4-methylphenyl)tetrahydro-1 H -imidazol-1-yl]methyl}1 H -1,2,3-benzotriazole (3.12a): white microcrystals (f rom EtOH); yield, 93%; mp 94 95 C; [ ]25 D = +1.8 ( c 1.70, CHCl3); 1H NMR 2.21 (s, 3H), 2.74 (dd, J = 13.2, 8.3 Hz, 1H), 3.08 (t, J = 7.6 Hz, 1H), 3.22 3.31 (m, 2H), 3.58 3.63 (m, 1H), 4.24, 4.39 (AB, J = 5.0 Hz, 2H), 5.56, 5.67 (AB, J = 13.7 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 7.22 7.40 (m, 6H), 7.48 (d, J = 3.6 Hz, 2H), 8.05 (d, J = 8.2 Hz, 1H); 13C NMR 20.3, 39.2, 52.2, 61.2, 63.7, 68.2, 109.7, 112.3, 120.0, 124.0, 126.4, 126.6, 127.7, 128.6, 129.0, 129.7, 133.5, 138.1, 144.0, 146.0. Anal. Calcd for C24H25N5: C, 75.17; H, 6.57; N, 18.26. Found: C, 74.95; H, 6.77; N, 18.29. 1-{[(5 S )-5-Benzyl-3-cyclohexyltetrahydro-1 H -imidazol-1-yl]methyl} benzotriazole (3.12b): obtained as a mixture of Bt1 and Bt2 isomers in 26:1 ratio, and

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40 NMR data are reported for the major Bt1 isomer; white needles (f rom EtOH); yield, 90%; mp 94 95 C; [ ]25 D = +30.5 ( c 1.64, CHCl3); 1H NMR 1.02 1.14 (m, 5H), 1.53 1.67 (m, 5H), 1.90 (br s, 1H), 2.41 (dd, J = 8.8, 6.8 Hz, 1H), 2.65 2.77 (m, 2H), 2.99 (dd, J = 13.4, 6.1 Hz, 1H), 3.43 3.48 (m, 1H), 3.70 (s, 2H), 5.31, 5.49 (AB, J = 13.5 Hz, 2H), 7.20 7.48 (m, 8H), 8.04 (d, J = 8.2 Hz, 1H); 13C NMR 24.4, 24.6, 25.8, 31.6, 31.7, 41.1, 56.3, 61.4, 61.5, 65.1, 72.3, 109.8, 119.8, 123.8, 126.3, 127.3, 128.4, 129.1, 133.4, 138.8, 145.8. Anal. Calcd for C23H29N5: C, 73.57; H, 7.78; N, 18.65. Found: C, 73.94; H, 8.17; N, 18.77. 1-{[(5 S )-3,5-Dibenzyltetrahydro-1 H -imidazol-1-yl]methyl}-1 H -1,2,3benzotriazole (3.12c) : white microcrystals (from EtOH); yield, 96%; mp 81 82 C; [ ]25 D = +40.8 ( c 1.87, CHCl3); 1H NMR 2.34 (dd, J = 9.4, 6.5 Hz, 1H), 2.67 2.81 (m, 2H), 2.92 (dd, J = 13.2, 6.6 Hz, 1H), 3.42, 3.52 (AB, J = 13.2 Hz, 2H), 3.52 3.60 (m, 1H), 3.62, 3.70 (AB, J = 6.3 Hz, 2H), 5.38, 5.43 (AB, J = 13.6 Hz, 2H), 7.12 7.45 (m, 13H), 8.05 (d, J = 8.1 Hz, 1H); 13C NMR 41.3, 57.8, 58.6, 61.8, 65.5, 73.9, 109.8, 119.8, 123.8, 126.3, 127.0, 127.3, 128.2, 128.3, 128.4, 129.2, 133.4, 138.3, 138.8, 145.9. Anal. Calcd for C24H25N5: C, 75.17; H, 6.57; N, 18.26. F ound: C, 75.03; H, 6.32; N, 18.30. 3.4.3 General Procedure for the Prepar ation of 1,2,3,5,10,10a-Hexahydroimidazo[1,5b ]isoquinolines 3.1a c A mixture of 3.12a c (1.0 mmol) and anhyd AlCl3 (0.40 g, 3.0 mmol) was stirred in dry CH2Cl2 (20 mL) refluxing for 12 h. After cooling, the reaction mixture was added CH2Cl2 (30 mL) and the organic layer was wash ed with 2 M NaOH, brine and dried over anhydrous K2CO3. After removal of the solvent in reduced pressure, the crude product

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41 was purified by column chromatography with hexa nes/EtOAc (3:1 to 1:1) as an eluent to give 3.1a c (10a S )-2-(4-Methylphenyl)-1,2,3,5,10,10a-hexahydroimidazo[1,5b ]isoquinoline (3.1a): colorless microcrystals (from hexanes/CHCl3); yield, 76%; mp 189 190 C; [ ]25 D = 50.3 ( c 1.68, CHCl3); 1H NMR 2.26 (s, 3H), 2.91 3.06 (m, 3H), 3.24 (t, J = 8.2 Hz, 1H), 3.62 3.70 (m, 2H), 3.84 (d, J = 3.6 Hz, 1H), 4.18 (d, J = 14.4 Hz, 1H), 4.60 (d, J = 3.6 Hz, 1H), 6.45 (d, J = 8.5 Hz, 2H), 7.05 7.19 (m, 6H); 13C NMR 20.3, 33.2, 52.8, 53.0, 59.2, 71.1, 111.3, 125.3, 126.0, 126.5, 126.8, 129.1, 129.7, 133.5, 134.0, 144.3. Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60. Found: C, 81.61; H, 7.88; N, 10.71. (10a S )-2-Cyclohexyl-1,2,3,5,10,10a-hexahydroimidazo[1,5b ]isoquinoline (3.1b): colorless prism (from hexanes/CHCl3); yield, 77%; mp 101 102 C; [ ]25 D = 35.5 ( c 1.66, CHCl3); 1H NMR 1.24 (br s, 5H), 1.56 1.62 (m, 1H), 1.74 (br s, 2H), 1.88 (br s, 2H), 2.31 (br s, 1H), 2.63 (t, J = 8.4 Hz, 1H), 2.76 2.93 (m, 3H), 3.17 (dd, J = 8.4, 5.5 Hz, 1H), 3.43 (d, J = 4.6 Hz, 1H), 3.56, 4.02 (AB, J = 14.3 Hz, 2H), 4.03 (d, J = 4.6 Hz, 1H), 7.04 7.26 (m, 4H); 13C NMR 24.7, 24.8, 26.0, 31.6, 32.2, 33.5, 52.9, 56.0, 58.8, 62.2, 74.1, 125.7, 126.2, 126.7, 129.0, 134.4, 134.8. Anal. Calcd for C17H24N2: C, 79.64; H, 9.44; N, 10.93. Found: C, 79.94; H, 9.69; N, 10.87. (10a S )-2-Benzyl-1,2,3,5,10,10a-hexahydroimidazo[1,5b ]isoquinoline (3.1c): white needles (from hexane s/EtOH); yield, 85%; mp 73 74 C; [ ]25 D = 30.3 ( c 1.77, CHCl3); 1H NMR 2.64 (t, J = 8.7 Hz, 1H), 2.77 2.95 (m, 3H), 3.21 (dd, J = 8.7, 5.7 Hz, 1H), 3.43, 3.93 (AB, J = 5.4 Hz, 2H), 3.55, 3.99 (AB, J = 14.2 Hz, 2H), 3.84 (s, 2H), 7.04 7.16 (m, 4H), 7.23 7.39 (m, 5H); 13C NMR 33.5, 52.6, 59.0, 59.1, 60.6, 76.5,

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42 125.9, 126.4, 126.7, 127.0, 128.3, 128.5, 128.9, 134.4, 134.7, 139.4. Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60. Found: C, 81.52; H, 7.37; N, 10.65. 3.4.4 General Procedure for the Preparat ion of Benzotriazolyl Intermediates 3.13 and 3.14a c Using the same procedure as for the preparation of 3.12a c reaction of 3.10a with benzotriazole and aqueous formal dehyde (1 or 2 equiv) led to 3.13 (2 S )-2-[(1 H -1,2,3-Benzotriazol-1-ylmethyl)amino]N -(4-methylphenyl)-3phenylpropanamide (3.13): white microcrystals (from CH3OH); yield, 92%; mp 136 137 C; [ ]25 D = 74.5 ( c 1.76, CHCl3); 1H NMR 2.32 (s, 3H), 2.70 (br s, 1H), 2.79 (dd, J = 13.8, 8.7 Hz, 1H), 3.01 (dd, J = 14.1, 4.8 Hz, 1H), 3.61 (dd, J = 8.4, 4.5 Hz, 1H), 5.41 5.53 (m, 2H), 6.87 6.89 (m, 2H), 7.08 7.14 (m, 5H), 7.33 7.40 (m, 4H), 7.44 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 8.67 (s, 1H); 13CNMR 20.8, 39.0, 60.9, 61.3, 108.8, 119.7, 120.1, 124.1, 127.0, 127.8, 128.6, 128.7, 129.4, 132.5, 134.1, 134.6, 135.9, 146.0, 170.2. Anal. Calcd for C23H23N5O: C, 71.67; H, 6.01; N, 18.17. Found: C, 71.60; H, 6.25; N, 18.29. A mixture of 3.10a c (2.0 mmol), BtH (0.48 g, 4.0 mm ol) and paraformaldehyde (0.18 g, 6.0 mmol) with p -TsOHH2O (0.08 g, 0.4 mmol) was sti rred in refluxing benzene (25 mL) using a Dean-Stark apparatus for 2 h. After cooling, benzene was evaporated and toluene (25 mL) was added, and then the mi xture was refluxed for another 1 h. The mixture was washed with 2 M NaOH. The a queous phase was extracted with EtOAc and the combined organic phase was washed w ith water, brine, and dried over anhyd K2CO3. Removal of solvent under re duced pressure gave crude 3.14a c which were used directly for the subsequent reac tions. Attempt to purify 3.14a c failed due to their significant decomposition on silica gel.

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43 (5 S )-1-(Benzotriazolylmethyl)-5-benzyl-3-(4-methylphenyl)tetrahydro-4 H imidazol-4-one (3.14a): obtained as a mixture of Bt1 and Bt2 isomers in 3:1 ratio, and NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 92%; 1H NMR 2.29 (s, 3H), 3.09 (dd, J = 14.2, 7.4 Hz, 1H), 3.35 (dd, J = 14.2, 3.9 Hz, 1H), 3.91 (dd, J = 7.3, 3.8 Hz, 1H), 4.63, 4.85 (AB, J = 5.6 Hz, 2H), 5.41 (s, 2H), 7.06 7.46 (m, 12H), 8.04 (d, J = 8.2 Hz, 1H). (5 S )-1-(Benzotriazolylmethyl)-5-benzyl-3-cyclohexyltetrahydro-4 H -imidazol4-one (3.14b): obtained as a mixture of Bt1 and Bt2 isomers in 4:1 ratio, and NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 91%; 1H NMR 0.90 1.40 (m, 6H), 1.50 1.80 (m, 4H), 2.95 (dd, J = 13.9, 7.4 Hz, 1H), 3.24 (dd, J = 13.8, 3.4 Hz, 1H), 3.70 3.81 (m, 2H), 4.21, 4.43 (AB, J = 5.6 Hz, 2H), 5.31 (d, J = 4.8 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.27 7.45 (m, 7H), 8.04 (d, J = 8.1 Hz, 1H). (5 S )-1-(Benzotriazolylmethyl)-3,5-dibenzyltetrahydro-4 H -imidazol-4-one (3.14c): obtained as a mixture of Bt1 and Bt2 isomers in 5:1 ratio, and NMR data are reported for the major Bt1 isomer; pale brown oil; yield, 94%; 1H NMR 3.04 (dd, J = 14.0, 6.8 Hz, 1H), 3.29 (dd, J = 14.0, 3.7 Hz, 1H), 3.87 3.90 (m, 1H), 4.09, 4.57 (AB, J = 10.7 Hz, 2H), 4.11 4.13 (m, 1H), 4.32 (d, J = 5.2 Hz, 1H), 5.35 (s, 2H), 6.91 6.93 (m, 2H), 7.11 7.45 (m, 11H), 8.05 (d, J = 8.1 Hz, 1H); 13C NMR 37.4, 44.9, 62.9, 63.3, 65.1, 109.1, 120.0, 124.2, 126.8, 127.5, 127.7, 127.9, 128.5, 128.7, 130.0, 133.4, 134.9, 137.3, 145.7, 170.6.

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44 3.4.5 General Procedure for the Preparation of 2,3,10,10a-Tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-ones 3.15a c Treatment of crude 3.14a c with 3 equiv of AlCl3 afforded 3.15a c using the same procedure as for the preparation of 3.1a c The isolated yields of 3.15a c were based on -amino-amides 3.10a c (10aS)-2-(4-Methylphenyl)-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin1(5 H )-one (3.15a): colorless needles; yield, 82%; mp 185 186 C; [ ]25 D = 62.7 ( c 1.66, CHCl3); 1H NMR 2.32 (s, 3H), 3.04 3.21 (m, 2H), 3.38 3.43 (m, 1H), 3.83, 4.05 (AB, J = 14.0 Hz, 2H), 4.48 (dd, J = 4.8, 1.6 Hz, 1H), 4.76 (d, J = 5.0 Hz, 1H), 7.10 7.21 (m, 6H), 7.44 (d, J = 8.5 Hz, 2H); 13C NMR 20.8, 29.9, 52.3, 61.4, 69.6, 119.2, 126.2, 126.6, 126.9, 129.4, 129.5, 133.3, 133.7, 134.5, 135.0, 170.9. Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.48; H, 6.54; N, 10.10. (10a S )-2-Cyclohexyl-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )one (3.15b): colorless microcrystal s; yield, 83%; mp 72 73 C; [ ]25 D = 89.8 ( c 1.75, CHCl3); 1H NMR 1.03 1.16 (m, 1H), 1.23 1.42 (m, 4H), 1.66 1.82 (m, 5H), 2.98 (AB dd, J = 15.6, 9.6 Hz, 1H), 3.10 (AB dd, J = 15.6, 4.8 Hz, 1H), 3.28 (dd, J = 9.2, 4.8 Hz, 1H), 3.78, 3.96 (AB, J = 14.1 Hz, 2H), 3.90 3.95 (m, 1H), 4.04 (dd, J = 4.8, 2.1 Hz, 1H), 4.36 (d, J = 4.8 Hz, 1H), 7.08 7.10 (m, 1H), 7.17 7.20 (m, 3H); 13C NMR 25.2, 25.2, 25.4, 29.8, 30.2, 30.6, 49.9, 52.3, 60.9, 65.1, 126.1, 126.5, 126.8, 129.3, 133.6, 133.9, 171.3; HRMS m/z calcd for C17H22N2O 270.1732 (M), found 270.1738. Anal. Calcd for C17H22N2O: C, 75.52; N, 10.36. Found: C, 75.18; N, 10.32. (10a S )-2-Benzyl-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-one (3.15c): colorless prism; yield, 78%; mp 50 51 C; [ ]25 D = 64.8 ( c 1.66, CHCl3); 1H

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45 NMR 3.10 (d, J = 6.6 Hz, 2H), 3.49 (t, J = 6.9 Hz, 1H), 3.77, 3.84 (AB, J = 14.5 Hz, 2H), 4.05 (dd, J = 5.2, 1.8 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 4.29, 4.65 (AB, J = 15.3 Hz, 2H), 7.02 7.15 (m, 3H), 7.16 7.27 (m, 6H); 13C NMR 30.0, 44.8, 52.4, 60.4, 68.4, 126.3, 126.6, 127.0, 127.5, 127.6, 128.7, 129.2, 133.8, 134.4, 135.6, 172.3. Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.50; H, 6.83; N, 10.09. 3.4.6 General Procedure for the Preparat ion of 2,3,5-Trisubstituted-tetrahydro-4 H imidazol-4-ones 3.16a c A mixture of -amino-amide 3.10a c (2.0 mmol), benzaldehyde (0.27 g, 2 mmol) and p -TsOH (0.4 mmol) in CH3OH (15 mL) with anhydrous Na2SO4 (3.0 g) was stirred refluxing for 12 hours. After evaporation of CH3OH under reduced pressure, the reaction mixture was diluted with EtOAc. The organic phase was washed with 2 M NaOH, water, brine, and dried over anhyd K2CO3. After removal of solvent in vacuo, the residue was purified by column chromatography with hexa nes/EtOAc (6:4) as an eluent to give trans 3.16a and cis 3.16 a and trans 3.16b c (2 R ,5 S )-5-Benzyl-3-(4-methylphenyl)-2-phenyltetrahydro-4 H -imidazol-4-one (3.16a): yellowish microcrystals; yield, 38%; mp 106 107 C; [ ]25 D = 52.5 ( c 1.86, CHCl3); 1H NMR 1.70 (br s, 1H), 2.24 (s, 3H), 3.09 3.21(m, 2H), 4.13 (t, J = 5.5 Hz, 1H), 5.55 (s, 1H), 7.03, 7.11 (AB, J = 8.5 Hz, 4H), 7.22 7.32 (m, 10H); 13C NMR 20.8, 38.0, 60.2, 77.1, 122.0, 126.4, 126.8, 128.5, 128.8, 128.9, 129.4, 129.8, 134.2, 135.1, 137.3, 139.4, 173.7. Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found: C, 80.39; H, 6.51; N, 7.94. (2 S ,5 S )-5-Benzyl-3-(4-methylphenyl)-2-phenyltetrahydro-4 H -imidazol-4-one (3.16 a): yellowish microcrystals; yield, 31%; mp 97 98 C; [ ]25 D = 29.8 ( c 1.58,

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46 CHCl3); 1H NMR 1.88 (br s, 1H), 2.20 (s, 3H), 3.17 (dd, J = 14.1, 4.8 Hz, 1H), 3.40 (dd, J = 14.1, 5.4 Hz, 1H), 4.00 (t, J = 4.6 Hz, 1H), 5.81 (s, 1H), 6.81 (d, J = 7.0 Hz, 2H), 6.98 7.33 (m, 12H); 13C NMR 20.9, 36.6, 60.9, 77.2, 122.8, 127.0, 127.1, 128.8, 128.9, 129.1, 129.3, 129.9, 134.0, 135.3, 136.4, 138.5, 174.0. Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found: C, 80.40; H, 6.30; N, 8.28. (2 R ,5 S )-5-Benzyl-3-cyclohexyl-2-phenyltetrahydro-4 H -imidazol-4-one (3.16b): colorless microcrystal s; yield, 69%; mp 92 93 C; [ ]25 D = 32.2 ( c 1.81, CHCl3); 1H NMR 0.87 0.99 (m, 2H), 1.07 1.28 (m, 2H), 1.43 1.61 (m, 5H), 1.65 1.70 (m, 1H), 1.99 (br s, 1H), 2.90 (dd, J = 13.5, 7.5 Hz, 1H), 3.13 (dd, J = 13.6, 3.9 Hz, 1H), 3.53 3.64 (m, 1H), 4.07 4.11 (m, 1H), 5.16 (s, 1H), 7.20 7.34 (m, 10H); 13C NMR 25.1, 25.6, 25.7, 29.9, 30.9, 38.7, 52.8, 59.7, 75.0, 126.4, 126.5, 128.3, 128.8, 129.0, 129.7, 137.8, 141.9, 173.6. Anal. Calcd for C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.55; H, 7.99; N, 8.29. (2 R ,5 S )-3,5-Dibenzyl-2-phenyltetrahydro-4 H -imidazol-4-one (3.16c): colorless needles (from hexanes/EtOAc); yield, 74%; mp 128 129 C; [ ]25 D = 19.7 ( c 1.73, CHCl3); 1H NMR 2.15 (br s, 1H), 3.04 (AB dd, J = 13.8, 6.9 Hz, 1H), 3.16 (AB dd, J = 13.8, 4.2 Hz, 1H), 3.46, 5.02 (AB, J = 14.9 Hz, 2H), 4.17 (br s, 1H), 4.96 (s, 1H), 6.85 6.87 (m, 2H), 7.14 7.36 (m, 13H); 13C NMR 38.1, 43.9, 59.8, 74.8, 126.7, 126.8, 127.5, 128.0, 128.5, 128.6, 129.1, 129.2, 129.8, 135.5, 137.2, 139.3, 173.6. Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found: C, 80.31; H, 6.63; N, 8.13. 3.4.7 General Procedure for the Preparation of Bt intermediates 3.17a c and 3.17 a A mixture of 3.16a c or 3.16 a (1.0 mmol), benzotriazole (0.14 g, 1.2mmol) and formaldehyde (37% aq. solution, 0.12 g, 1.5 mmol) was stirred in CH3OH (15 mL) at 25

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47 C overnight. After evaporation of CH3OH, EtOAc was added to the mixture. The organic phase was washed with 1 M NaOH aqueous solution, brine, water, and dried over anhyd K2CO3. Removal of solvent in vacuo gave essentially pure 3.17a and 3.17 a which were purified by recrystallization for an alytical purposes. Attempts to purify 3.17b c (both obtained as sticky oil) by column chroma tography (silica gel) failed, thus they were used directly for the subseque nt reaction as crude products. (2 R ,5 S )-1-(1 H -1,2,3-Benzotriazol-1-ylmethyl)-5 -benzyl-3-(4-methylphenyl)-2phenyltetrahydro-4 H -imidazol-4-one (3.17a): white needles (from EtOH); yield, 89%; mp 153 154 C; [ ]25 D = 20.4 ( c 1.80, CHCl3); 1H NMR 2.19 (s, 3H), 3.30 3.43 (m, 2H), 4.46 (br s, 1H), 5.34, 5.65 (AB, J = 13.8 Hz, 2H), 5.45 (d, J = 2.1 Hz, 1H, NC H N), 6.84 6.97 (m, 5H), 7.08 7.32 (m, 12H), 7.98 8.01 (m, 1H); 13C NMR 20.8, 36.3, 60.2, 63.2, 80.1, 109.7, 119.7, 123.6, 123.9, 126.8, 127.2, 128.0, 128.5, 128.8, 129.4, 129.6, 129.8, 132.3, 132.9, 135.9, 136.0, 136.7, 145.9, 170.6. Anal. Calcd for C30H27N5O: C, 76.09; H, 5.75; N, 14.79. Found: C, 75.74; H, 6.01; N, 14.69. (2 S ,5 S )-1-(Benzotriazolylmethyl)-5-benzyl-3-(4-methylphenyl)-2phenyltetrahydro-4 H -imidazol-4-one (3.17 a): obtained as a mixture of Bt1 and Bt2 isomers in 17:1 ratio, and NMR data are reported for the major Bt1 isomer; white prism (from EtOH); yield, 85%; mp 197 198 C; [ ]25 D = 185 ( c 1.56, CHCl3); 1H NMR 2.16 (s, 3H), 3.38 (AB dd, J = 14.0, 4.4 Hz, 1H), 3.47 (AB dd, J = 14.0, 4.4 Hz, 1H), 4.08 (br s, 1H), 5.34, 5.46 (AB, J = 14.8 Hz, 2H), 5.82 (s, 1H, NC H N), 6.84 (d, J = 8.2 Hz, 2H), 6.88 6.96 (m, 4H), 7.13 7.36 (m, 4H), 7.40 7.50 (m, 7H), 8.11 (d, J = 8.1 Hz, 1H); 13C NMR 20.9, 36.9, 58.9, 61.6, 77.8, 108.8, 120.2, 124.2, 124.5, 126.8, 128.0, 128.4,

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48 128.5, 128.9, 129.3, 129.4, 130.5, 132.5, 134.0, 136.3, 136.7, 137.1, 145.6, 169.5. Anal. Calcd for C30H27N5O: C, 76.09; H, 5.75; N, 14.79. Found: C, 75.84; H, 5.96; N, 14.54. (2 R ,5 S )-1-(Benzotriazolylmethyl)-5-benzyl -3-cyclohexyl-2-phenyltetrahydro4 H -imidazol-4-one (3.17b): obtained as a mixture of Bt1 and Bt2 isomers in 10:1 ratio, and NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 94%; 1H NMR 0.85 1.07 (m, 2H), 1.12 1.26 (m, 2H), 1.40 1.72 (m, 6H), 3.20 3.30 (m, 2H), 3.40 3.60 (m, 1H), 4.40 (s, 1H), 5.15 (s, 1H), 5.24, 5.41 (AB, J = 13.6 Hz, 2H), 7.09 7.45 (m, 12H), 7.55 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H). (2 R ,5 S )-1-(Benzotriazolylmethyl)-5-benz yl-3-benzyl-2-phenyltetrahydro-4 H imidazol-4-one (3.17c): obtained as a mixture of Bt1 and Bt2 isomers in 7:1 ratio, and NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 95%; 1H NMR 3.21 3.35 (m, 2H), 4.60 (d, J = 3.3 Hz, 1H), 5.01 5.07 (m, 2H), 5.05 (d, J = 2.1 Hz, 1H), 5.30, 5.55 (AB, J = 14.2 Hz, 2H), 6.58 (d, J = 7.0 Hz, 2H), 6.90 7.38 (m, 16H), 7.95 (d, J = 8.1 Hz, 1H). 3.4.8 General Procedure for the Lewis Acid Promoted Cyclization of 3.17a c and 3.17 a Using the same procedure as for the preparation of 3.1a c treatment of 3.17a c and 3.17 a with 3 equiv of AlCl3 afforded 3.18a c and 3.18 a After work-up, all of the products were obtained as essentially NMR pur e solids, which were recrystallized from EtOH for analytical purposes. (3 R ,10a S )-2-(4-Methylphenyl)-3-pheny l-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-one (3.18a): colorless needles (from EtOH); yield, 91%; mp 189 190 C; [ ]25 D = 79.2 ( c 1.83, CHCl3); 1H NMR 2.22 (s, 3H), 3.14 (d, J = 6.9 Hz, 2H), 3.62, 3.81 (AB, J = 14.7 Hz, 2H), 4.02 (td, J = 7.0, 1.4 Hz, 1H), 5.68 (d, J = 1.4 Hz,

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49 1H, NC H N), 7.00 7.08 (m, 3H), 7.15 7.28 (m, 5H), 7.32 7.39 (m, 5H); 13C NMR 20.8, 30.0, 49.6, 58.3, 81.9, 122.4, 124.2, 126.3, 126.6, 127.0, 127.3, 128.8, 129.1, 129.4, 133.9, 134.0, 134.5, 135.3, 136.7, 172.3. Anal. Calcd for C24H22N2O: C, 81.32; H, 6.26; N, 7.90. Found: C, 81.07; H, 6.53; N, 7.97. (3 S ,10a S )-2-(4-Methylphenyl)-3-pheny l-2,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-one (3.18 a): colorless needles (from EtOH); yield, 91%; mp 212.5 213 C; [ ]25 D = 83.9 ( c 1.59, CHCl3); 1H NMR 2.22 (s, 3H), 3.22 3.35 (m, 2H), 3.44 (ddd, J = 10.8, 4.2, 2.2 Hz, 1H), 3.79 (s, 2H), 5.32 (d, J = 2.1 Hz, 1H, NC H N), 6.97 7.11 (m, 5H), 7.11 7.33 (m, 6H), 7.40 7.43 (m, 2H); 13C NMR 20.9, 30.8, 50.6, 60.8, 82.7, 124.2, 126.1, 126.6, 126.8, 128.4, 128.9, 129.3, 129.4, 129.8, 133.3, 133.4, 133.7, 135.6, 136.1, 171.4. Anal. Calcd for C24H22N2O: C, 81.32; H, 6.26; N, 7.90. Found: C, 81.07; H, 6.61; N, 8.04. (3 R ,10a S )-2-Cyclohexyl-3-phenyl-2 ,3,10,10a-tetrahydroimidazo[1,5b ]isoquinolin-1(5 H )-one (3.18b): white microcrystals (from EtOH); yield, 78%; mp 150 151 C; [ ]25 D = 66.6 ( c 1.79, CHCl3); 1H NMR 0.84 1.00 (m, 2H), 1.11 1.26 (m, 2H), 1.40 1.72 (m, 6H), 2.80 3.12 (m, 2H), 3.47, 3.64 (AB, J = 14.5 Hz, 2H), 3.60 3.70 (m, 1H), 3.86 3.91 (m, 1H), 5.19 (s, 1H, NC H N), 7.02 (d, J = 6.4 Hz, 1H), 7.12 7.41 (m, 8H); 13C NMR 25.1, 25.6, 25.7. 30.1, 30.3. 31.1, 49.6, 52.4, 58.1, 79.4, 126.1, 126.5, 126.9, 127.4, 128.7, 129.0, 131.7, 134.1, 134.7, 138.8, 172.7; HRMS m/z calcd for C23H26N2O 346.2045 (M), found 346.2042. Anal. Calcd for C23H26N2O: N, 8.09. Found: N, 8.05. (3 R ,10a S )-2-Benzyl-3-phenyl-2,3,10,10a -tetrahydroimidazo[1,5b ]isoquinolin1(5 H )-one (3.18c): white needles; yield, 78%; mp 108 109 C; [ ]25 D = +65.1 ( c 1.23,

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50 CHCl3); 1H NMR 3.05 (dd, J = 15.2, 6.7 Hz, 1H), 3.22 (dd, J = 15.2, 4.8 Hz, 1H), 3.29, 4.99 (AB, J = 15.2 Hz, 2H), 3.58, 3.81 (AB, J = 15.2 Hz, 2H), 4.24 (br t, J = 4.7 Hz, 1H), 4.66 (d, J = 2.3 Hz, 1H, NC H N), 6.53 (d, J = 7.0 Hz, 2H), 7.02 7.39 (m, 12H); 13C NMR 29.9, 43.4, 50.1, 59.2, 80.5, 126.5, 127.1, 127.2, 127.3, 127.5, 128.4, 128.5, 128.6, 128.8, 129.2, 134.6, 134.9, 135.6, 138.1, 172.9. Anal. Calcd for C24H22N2O: C, 81.32; H, 6.26; N, 7.90. Found: C, 81.16; H, 6.38; N, 7.87. 3.4.9 Procedure for the preparation of Bt intermediate 3.22 A mixture of 2,5-dimethoxytetrahydrofur an (0.66 g, 5.1 mmol) and HCl aqueous solution (0.1 M, 20 mL) was heated to 100 C for 45 mins, then cooled to room temperature. CH2Cl2 (40 mL), benzotriazole (0.61 g, 5.1 mmol) and diamine 3.11a (1.20 g, 5 mmol) were added successively and st irred at room temperature for 24 h. The reaction mixture was washed with 1 M NaOH and the aqueous phase was extracted with CH2Cl2. The combined organic phase was wa shed with brine and dried over anhyd Na2SO4. After removal of the solvent in vac uo, the residue was pur ified by column chromatography with hexanes/EtOAc (3:1) as an eluent to give 3.22 However, subsequent treatment of 3.22 with AlCl3 did not afford the desired tetracyclic compound 3.23 (3 S ,5 R ,7a S )-5-Benzotriazolyl-3-benzyl-1-(4-methylphenyl)hexahydro-1 H pyrrolo[1,2a ]imidazole (3.22): obtained as a mixture of Bt1 and Bt2 isomers in 4.5:1 ratio, and NMR data are reported for the major Bt1 isomer; colorless needles (from CHCl3/Et2O); mp 145 146 C; [ ]25 D = 4.2 ( c 1.37, CHCl3); 1H NMR 2.06 2.17 (m, 1H), 2.29 (s, 3H), 2.45 2.64 (m, 5H), 3.18 (dd, J = 9.2, 4.0 Hz, 1H), 3.70 3.80 [m, 1H, H(3)], 3.85 (dd, J = 9.2, 6.5 Hz, 1H), 5.10 (dd, J = 5.3, 4.0 Hz, 1H, NC H N), 6.02 (t, J =

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51 7.0 Hz, 1H, BtC H N), 6.58 (d, J = 8.3 Hz, 2H), 6.79 6.82 (m, 2H), 6.92 6.98 (m, 3H), 7.10 (d, J = 8.1 Hz, 2H), 7.32 7.36 (m, 2H), 7.61 7.64 (m, 1H), 8.00 8.03 (m, 1H); 13C NMR 20.2, 30.6, 30.9, 41.0, 52.8, 63.7, 79.2, 81.6, 111.5, 113.5, 119.6, 123.6, 125.9, 126.7, 126.8, 127.8, 128.4, 129.7, 131.2, 137.8, 143.9, 146.6. Anal. Calcd for C26H27N5: C, 76.25; H, 6.65; N, 17.10. Found: C, 76.05; H, 6.88; N, 17.03.

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52 CHAPTER 4 N -ACYLBENZOTRIAZOLES: NEUTRAL ACYLATING REAGENTS FOR THE PREPARATION OF PRIMARY, SECONDARY AND TERTIARY AMIDES 4.1 Introduction Common routes to primary, secondary and tertiary amides mostly involve the treatment of activated derivatives of acids, es pecially acyl halides, acid anhydrides or esters, with ammonia, primary and seconda ry amines. [89Prac.Org.Chem.] However, limitations are associated with these methods. Reactions of ammonia or amines with acyl halides are highly exothermic. Acid anhydrides especially cyclic anhydrides, easily form imides with ammonia and primary amines. Acylations of ammonia, primary and secondary amines by esters frequently re quire strongly basic cat alysts and/or high pressure. Reactions of carboxylic acids themselves with ammonia or amines are seldom of preparative value. [92Adv.Org.Chem] Othe r preparations of primary amides include the activation of carboxylic acids using 1-hydroxybenz otriazole (HOBt) and N,N’ dicyclohexylcarbodiimide (DCC) [89S37] or the treatment of carboxylic acids with ammonium chloride, tertiary amine and coupling agents typically used in peptide synthesis. [99TL2501] With these last tw o methods, difficulties can arise from the insolubility of starting materials and pr oducts or by competitive hydrolysis of the activated carboxyl group. As recently documented by Staab, Bauer and Schneider, [98Azolides] acyl-azolides in general, and N -acylimidazoles in particular, are efficient acylating reagents. They have been widely reacted with amm onia or primary amines to give the corresponding primary

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53 [80JOC3640] [79JOC4536] [79JMC1340] [ 88JHC555] [95JACS7379] or secondary amides. [88JOC685] [94T11113] [92T10233] [95SC3701] [90T5665] [89JHC901] [68TL3185] The classical azolide method nor mally involves two steps (which can, however, be combined in one-pot): i) re action of the free carboxylic acid at 20 C with (usually) 1,1’-carbonyldiimidazole (CDI) in a 1:1 molar ratio to fo rm the carboxylic acid imidazole via elimination of CO2 and imidazole; ii) after CO2 evolution has ceased, addition of an equimolar amount of amine. T hus, two molar equivalents of the imidazole moieties are used. Furthermore, relatively few reports have been reported for reactions of N -acylimidazoles with secondary amines. N -Acylbenzotriazoles have been used as acylating agents in our group specifically for formylation, [95S503] trifluoroacyla tion [97JOC726] and to provide oxamides [98S153]; and by others in isolated applications. [98J CR(M)701] [96NN1459] [97Janti100] We now report a simple, mild a nd general procedure for the preparation of primary, secondary and tertiary amides. Ca rboxylic acids are conve rted in a one-pot reaction into N -acylbenzotriazoles and subsequently treated with ammonia, primary, or secondary amines. This methodology should be particularly applicable to solid-phase syntheses. 4.2 Results and Discussion 4.2.1 Preparation of N -Acylbenzotriazoles 4.2a-q 1-(Trimethylsilyl)benzotriazole, readily available from benzotriazole and N N bis(trimethylsilyl)amine, [80JOM141] was previously reacted with methanesulfonyl chloride to generate N -(1-methanesulfonyl )benzotriazole ( 4.1 ) in 60% yield. [92T7817] We now find that compound 4.1 is produced in 89% yiel d by direct treatment of benzotriazole with methanesulfonyl chlo ride in the presence of pyridine.

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54 N -Acylbenzotriazoles 4.2a-m with R as aryl groups were readily prepared in 72% 92% yields by the previous ly reported reaction of N -(1-methanesulfonyl) benzotriazole ( 4.1 ) with arene carboxylic acids (Sch eme 4-1). [92T7817] We previously synthesized N -(alkanecarbonyl)or N -(arylacetyl)-benzotriazoles 4.2 (R = alkyl, arylmethyl) by the reaction of benzotriazole with alkanecarb onyl chlorides [92T7817] or arylacetyl chlorides [96HAC365] in the presence of triethylamine. The reported yields of 4.2o 4.2p and 4.2q are 80%, 80% and 79%, respec tively. [92T7817] [96HAC365] We now find that N -(alkanecarbonyl)b enzotriazoles 4.2o 4.2p and 4.2q can be obtained in 84%, 89% and 83% yield, respectively, from the corresponding ali phatic carboxylic acids and BtSO2CH3 in the presence of triethylamine (Scheme 4-1). The mechanism for the formation of N -acylbenzotriazoles 4.2 involves attack of the carboxylate (formed in the presence of triethylamine) on the sulfur atom of 4.1 followed by the departure of benzotriazole anion to give the intermediate RCOOSO2CH3. Then, addition of the benzotriazole anion to the carbonyl carbon and elimination of alkanesulfonate affords the final products 4.2 The N -Acylbenzotriazoles 4.2a q are listed in Table 4-1. The diverse carboxylic acids used include aromatic, hetero aromatic and aliphatic Novel structures 4.2b f and 4.2l n were supported by 1H, 13C NMR spectra and microanalysis.

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55 RCOOSO2CH3Bt Et3N+H NH4OH Bt1SO2CH3 ( 4.1 ) Et3N RCONH2RCOOH N N N R = aryl or alkyl RCOBt14.2a-q R1NH2RCONHR1R2R3NH RCONR2R34.3a-n 4.4a-j4.5a-k Bt1 = +_ Scheme 4-1. Preparation of N -acylbenzotriazoles and amides Table 4-1. Preparation of N -acylbenzotriazoles 4.2a-q 4.2 R Yield (%) mp ( C) mplit. ( C) a C6H5 89 112-113 112-11311 b 2-CH3OC6H4 72 96-97 a c 3-ClC6H4 74 120-121 a d 4-Et2NC6H4 85 86-87 a e 4-O2N C6H4 83 193-194 a f 4-ClC6H4 74 138-139 a g 4-CH3C6H4 91 123-124 123-12411 h 2-furanyl 92 171-173 172-17411 i 2-pyridyl 91 98-100 97-10011 j 3-pyridyl 88 87-89 86-8911 k 4-pyridyl 84 149-151 148-15011 l 1-naphthyl 88 136-137 a m 2-pyrazinyl 76 146-147 a n PhCH2CH2 84 63-64 a o PhCH2 84 65-66 66-6712 p Ph2CH 89 88-89 106-10712 q n -C4H9 83 42-44 42-4411 aNovel compound 4.2.2 Preparation of Primary Amides 4.3a-n from N -Acylbenzotriazoles 4.2 with Ammonia. Direct treatment of N -acylbenzotriazoles 4.2a-e and 4.2h-q with excess ammonium hydroxide (30% aqueous solu tion) in EtOH/THF (1:1) at room temperature for 2 4 h gave crude products, which were recrystallized from benzene to afford pure primary amides 4.3a-n (Scheme 4-1). The yields and me lting points including the literature

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56 melting points, for the primary amides 4.3a-n are summarized in Table 4-2; mps and spectra of the products are in accord with literature da ta. The benzotriazole by-product (BtH, p Ka = 8.2 [98CR409]) formed in these reacti ons dissolved in the excess aqueous ammonia solution. Table 4-2. Preparation of primary amides 4.3a-n 4.3 R Yield (%) mp ( C) mpa ( C) a C6H5 100 128-130 130 b 2-CH3OC6H4 100 128-129 129 c 3-ClC6H4 87 134-135 134 d 4-NO2C6H4 100 199-200 201 e 2-furanyl 100 142-143 142-143 f 1-naphthyl 100 201-202 202 g 2-pyridyl 100 107-108 107-109 h 3-pyridyl 100 128-130 129-130 i 4-pyridyl 100 155-156 155-156 j 2-pyrazinyl 100 188-189 189-191 k PhCH2 100 158-159 157-158 l PhCH2CH2 85 104-105 105 m Ph2CH 90 168-169 167-168 n n -C4H9 72 104-105 106 aCadogan J. I. G. et al, Dictionary of Organic Compounds; Sixth edition, Chapman & Hall, London, UK.; 4.3a, B-0-00069; 4.3b, M-0-00635; 4.3c, C0-00557; 4.3d, N-0-00821; 4.3e, F-0-01325; 4.3f, N-0-00046; 4.3g, P-003885; 4.3h, P-0-03881; 4.3i, P0-03887; 4.3j, P-0-03652; 4.3k, P-0-01232; 4.3l, P-0-02416; 4.3m, D-0-11687; 4.3n, P-0-00666. 4.2.3 Preparation of Secondary Amides 4.4a-j from N -Acylbenzotriazoles 4.2 with Primary Amines. Treatment of N -acylbenzotriazoles 4.2 with one equiv. of primary amines in THF at room temperature for 4 h furnished the corresponding secondary amides 4.4a j in 70% 100% yields (Scheme 4-1 and Ta ble 4-3). After dilution of the concentrated residue in ethyl acetate, the by-product, 1 H -benzotriazole, was easily washed away by a 2 M NaOH aqueous solution, and simple removal of EtOAc in vacuo gave secondary amides 4.4a j which were recrystallized from appropria te solvents to afford pure products. The

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57 primary amines used include aryl amines (phenyl, 4-nitrophenyl) and alkylamines ( n butyl, cyclo -hexyl, sec -butyl and tert -butyl). Table 4-3. Preparation of secondary amides 4.4a-j 4.4 R R1 Yield (%) mp ( C) mplit. ( C) a 4-ClC6H4 EtCH(CH3) 95 82-83 a b 4-ClC6H4 C6H5 75 195-197 195-196[97SC361] c 4-Et2NC6H4 n -C4H9 92 73-74 b d C6H5 t -C4H9 75 133-134 134-135[73SC185] e 2-furanyl n -C4H9 94 40-41 40-41[40JACS1960] f 1-naphthyl n -C4H9 92 92-93 b g 2-pyridyl 4-CH3OC6H4 83 86-87 b h 4-pyridyl EtCH(CH3) 100 50-52 b i 2-pyrazinyl (CH3)3C 100 87-88 b j Ph2CH C6H5 70 117-118 117-118[62JOC3315] aIR spectrum data of 4.4a were given in ref. [63SpecActs509]; bNovel compound. 4.2.4 Preparation of Tertiary Amides 5a k from N -Acylbenzotriazoles 4.2 with Secondary Amines. When 1 H -1,2,3-benzotriazol-1-yl(4-chlorophe nyl)methanone was reacted with tetrahydro-1 H -pyrrole at room temperature in EtOH, the crude 1H NMR spectrum showed that the isolated product was a mixture of (4-chlor ophenyl)(tetrahydro-1 H pyrrol-1-yl)methanone and ethyl 4-chlorobenzoate with a ratio of 9:1. The use of THF avoided the formation of esters by-products. Treatment of N -acylbenzotriazoles 4.2 with one equiv. of secondary amines in THF at room temperature produced th e corresponding te rtiary amides 4.5a and 4.5d k in good to excellent yields (Scheme 4-1 a nd Table 4-4). However, when using N -ethylN -(1methylethyl)amine or N N -bis(1-methylethyl)amine as a secondary amine, no desired N ethyl-4-methylN -(1-methylethyl) or 4-methylN N -bis(1-methylethyl)benzamide ( 4.5b or 4.5c ) was isolated, probably due to the h eavily hindered nitrogen. Reaction of less hindered N N -diethylamine with 1 H -1,2,3-benzotriazol-1-yl(4-methylphenyl)methanone

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58 ( 4.2g ) produced N N -diethyl-4-methylbenzamide ( 4.5a ) in moderate yield (44%). A moderate yield (51%) was also obtained for N N -diethylfuran-2-amine ( 4.5g ) from N N diethylamine. These results show that the cyclic aliphatic amines, e.g., tetrahydro-1 H pyrrole, produce the secondary amides in much better yields than the acyclic aliphatic amines, e.g., N N -diethylamine. Table 4-4. Preparation of tertiary amides 4.5a-k 4.5 R R2 R3 Yield (%) mp ( C) mplit.( C) a 4-CH3C6H4 C2H5 C2H5 44 oil oil a b 4-CH3C6H4 i -Pr C2H5 0 c 4-CH3C6H4 i -Pr i -Pr 0 d 4-O2NC6H4 -(CH2)496 73-74 b e C6H5 -(CH2)4100 oil oil[86AG(Int)565] f 2-CH3OC6H4 -(CH2)498 oil b g 2-furanyl C2H5 C2H5 51 oil oil[71CC733] h 1-naphthyl -(CH2)494 51-52 b i 4-pyridinyl -(CH2)4100 oil b j PhCH2 -(CH2)499 oil oil[89TL2771] k Ph2CH -(CH2)568 114-116 b aCadogan J. I. G. et al, Dictionary of Organic Compounds, Sixth edition, Chapman & Hall, London, UK. 4.5a, M-01138; bNovel compound. 4.2.5 Preparation of –Hydroxyamides using BtSO 2 CH 3 Development of synthetic methods for -hydroxyamides has attracted considerable interest, since they include valuable therapeu tic agents and also possess synthetic utility. General routes to -hydroxyamides include: i) the reduction of -keto-amides with sodium borohydride, [82CC1282] [85JCS(P 1)769] [90CC1321] with other metal borohydrides, such as LiBEt3H, KBEt3H and Zn(BH4)2 [87CL2021] or with magnesiumor titanium-based reagents; [90 BCS(Jpn)1894] ii) the hydrogenation of -keto-amides in the presence of palladium on charcoal [84BCS(Jpn)3203] or neutral rhodium (I) complexes [84CL1603] [86CL737] [88TL3675]; iii) the oxidation of acyclic, tetrasubstituted amide-enolates by oxaziridine s with yields of around 50%. [87JOC5288]

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59 Methods i) and ii) need -keto-amides prepared, e.g., from -ketoacids [85JCS(P1)769] or -keto-acyl chlorides. [90CC1321] The only previous direct conversion of hydroxycarboxylic acids to -hydroxyamides is their reaction with N -sulfinylamines (RNSO). [86TL1921] After reaction of BtSO2CH3 with 2-hydroxy-2-phenylacetic acid ( 4.6 ) in the presence of triethyl amine, we failed to isolate the corresponding -hydroxyN acylbenzotriazoles probably due to their instability. However, when one equiv. of aniline or 4-methylaniline was added into the mixture obtained by refluxing 4.6 BtSO2CH3 and Et3N in dry THF for about 20 min, -hydroxyamides 4.7a and 4.7b were obtained in 68% and 72% yields, respectively (Scheme 4-2). Products 4.7a and 4.7b were not formed in the absence of BtSO2CH3. When n -butylamine or pyrrolidine was used as the amine reactant, no desired products we re obtained. The role of BtSO2CH3 is the same as with other reactions. C OH H COOH C OH H CONHR i) BtSO2CH3 Et3N ii) RNH2DL4.64.7a R = C6H54.7b R = 4-CH3C6H4 Scheme 4-2. Reaction of BtSO2CH3 with 2-hydroxy-2-phenylacetic acid 4.2.6 Preparation of 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2,3,3,4 ,4,4-heptafluorobutan-1-one ( 4.8 ) and its Perfluoroacylation with Primary and Secondary Amines. In 1997, we reported (trifluoroacetyl)benzotriazole as a convenient trifluoroacetylating agent for amines a nd alcohols. [97JOC726 ] (Trifluoroacetyl)benzotriazole was prepared by the reaction of benzotriazole w ith trifluoroacetic anhydride [(CF3CO)2O] and, thus, trifluoroacetic acid was formed as a byproduct. The

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60 analogous preparation of perfluor oacylbenzotriazoles, e.g., 1-(1 H -1,2,3-benzotriazol-1yl)-2,2,3,3,4,4,4-heptaflu orobutan-1-one ( 4.8 ) from n -(C3F7CO)2O, means that half of the carbon-fluorine moiety is not utilized. No reaction occurred between BtSO2CH3 and n -C3F7COOH in the presence of Et3N. However, reaction of 1-(trimethylsilyl) benzotriazole (BtTMS) with one equiv. of 2,2,3,3,4,4,4-heptafluorobutanoyl chloride ( n -C3F7COCl) gave 4.8 in 86% yield (NMR yield) as the sole Bt1 isomer, together with byproduct Bt H, due to the easy hydrolysis of BtTMS. The 1H NMR spectrum of the mixture shows the molar ratio of 4.8 to BtH is about 6:1. Attempts to obtain the pure 4.8 by washing with aqueous sodium hydroxide solution to remove BtH failed b ecause of rapid hydrolysis of 4.8 Compound 4.8 cannot be separated from BtH by column, as they have almost identical Rf values. Nevertheless, the presence of BtH should not affect the perfluoroacylation of amines with n -C3F7COBt ( 4.8 ), which will also generate benzotriazole as a byproduct. Therefore, the mixture of 4.8 and BtH was used for the subsequent reactio ns without separation, and indeed treatment of primary and secondary amines with 4.8 readily produced the perfluoroalkylated amides 4.9a d in good yields (Scheme 4-3). BtTMS n -C3F7COCl 4.8 R1R2NH n -C3F7CONR1R24.9 R1 R2a 4-CH3C6H4 H b PhCH(CH3) H c -(CH2)4d -(CH2)2O(CH2)2n -C3F7COBt1 Scheme 4-3. Synthesis of perfluoroalkylated amides

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61 4.3 Conclusion In summary, a simple and efficient method for the preparation of primary, secondary and tertiary amides has been developed by the treatment of N acylbenzotriazoles with a mmonia, primary and secondary amines, respectively. Advantages of this procedure include: 1) Th e neutral reaction condi tions are useful for ammoniation and amination of compounds possessing acidor base-sensitive substituents; 2) the use of acyl chlorides is avoided; 3) most N -acylbenzotriazoles can be recrystallized and are stable to storage ove r months; 4) work-up is very simple; 5) primary, secondary and tertiary amides are ge nerally obtained in good to excellent yields; 6) the method can be extended to -hydroxyamides and perfluoroalkylated amides. 4.4 Experimental Section 1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 NMR spectrometer in CDCl3 (with TMS for 1H and CDCl3 for 13C as the internal reference). 19F NMR spectra were recorded on a 300 NMR spectrometer at 282 MHz in CDCl3 with CFCl3 as an internal reference. 4.4.1 Modified procedure for the Preparation of N -(1-Methanesulfonyl )benzotriazole ( 4.1 ). To an ice-cold solution of benzotri azole (11.9 g, 0.10 mol) and pyridine (12.0 g, 0.16 mol) in dry toluene (120 mL), was added dropwise methylsulfonyl chloride (9.3 mL, 0.12 mol) in toluene (30 mL). The mixtur e was then stirred overnight at room temperature. AcOEt (150 mL) and H2O (100 mL) were added. The organic layer was separated and successively washed with wa ter, brine and dried over anhydrous MgSO4. Removal of solvents in vacuo gave a solid, which was recr ystallized from benzene to

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62 afford N -(1-methanesulfonyl)benzotriazole ( 4.1 ) (17.5 g, 89 %) as colorless needles [mp 110 112 C (mp [92TL7817] [72AJC1341] 110 112 C)]. 4.4.2 General procedure for the Preparation of N -Acylbenzotriazoles 4.2 A mixture of aromatic or aliphatic acid (10.0 mmol) and 1-(methylsulfonyl)benzotriazole 4.1 (1.97 g, 10.0 mmol), triethylamine ( 2.0 mL, 14.0 mmol) were heated in refluxing THF (50 mL) overnight. The solven t was evaporated and the residue was dissolved in chloroform (100 mL). The organi c layer was washed with water, dried over anhydrous MgSO4 and evaporated to give a crude pr oduct, which was recrystallized from an appropriate solvent to give pure N -(arylcarbonyl)or N -(alkanecarbonyl)benzotriazole 4.2a-q 1 H -1,2,3-Benzotriazol-1-yl(2-me thoxyphenyl)methanone (4.2b): yield, 72%; Colorless flake (recrystallized from ethanol); mp 96 97 C; 1H NMR 8.38 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.63 7.50 (m, 3H), 7.14 7.05 (m, 2H), 3.77 (s, 3H); 13C NMR 166.9 (C=O), 157.8, 146.0, 133.5, 131.4, 130.2, 130.1, 126.1, 122.6, 120.4, 120.0, 114.4, 111.7, 55.7 (CH3). Anal. Calcd for C14H11N3O2: C, 66.38; H, 4.38; N, 16.60. Found: C, 66.53; H, 4.41; N, 16.66. 1 H -1,2,3-Benzotriazol-1-yl(3-chlorophenyl)methanone (4.2c): yield, 74%; Colorless needles (recrystallized from chloroform/hexane); mp 120 121 C; 1H NMR 8.38 (d, J = 8.4 Hz, 1H), 8.20 8.11 (m, 3H), 7.75 7.65 (m, 2H), 7.60 7.53 (m, 2H); 13C NMR 165.3 (C=O), 145.7, 134.6, 133.6, 133.1, 132.1, 131.5, 130.6, 129.8, 129.7, 126.6, 120.3, 114.7. Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.75; H, 3.01; N, 16.38.

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63 1 H -1,2,3-Benzotriazol-1-yl[4-(dieth ylamino)phenyl]methanone (4.2d): yield, 85%; Yellow needles (recrystallized from ethanol/hexane); mp 86 87 C; 1H NMR 8.34 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 9.3 Hz, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 9.0 Hz, 2H), 3.47 (q, J = 7.1 Hz, 4H), 1.24 (t, J = 7.0 Hz, 6H); 13C NMR 165.2 (C=O), 151.9, 145.5, 134.8, 132.9, 129.6, 125.6, 119.8, 116.3, 114.8, 110.3, 44.6 (CH2), 12.5 (CH3). Anal. Calcd for C17H18N4O: C, 69.37; H, 6.16; N, 19.03. Found: C, 69.50; H, 6.37; N, 19.16. 1 H -1,2,3-Benzotriazol-1-yl(4-nitrophenyl)methanone (4.2e): yield, 83%; Yellow needles (recrystallized from chloroform/hexane); mp 193 194 C; 1H NMR 8.45 8.30 (m, 5H), 8.20 (d, J = 8.4 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H); 13C NMR 165.0 (C=O), 145.9, 136.9, 132.6, 132.0, 131.0, 127.0, 123.7, 123.5, 120.5, 114.8. Anal. Calcd for C13H8N4O3: C, 58.20; H, 3.01; N, 20.90. Found: C, 58.21; H, 2.89; N, 20.95. 1 H -1,2,3-Benzotriazol-1-yl(4-chlorophenyl)methanone (4.2f): yield, 74%; Colorless needles (recrystallized from chloroform/hexane); mp 138 139 C; 1H NMR 8.38 (d, J = 8.1 Hz, 1H), 8.22 8.16 (m, 3H), 7.72 (t, J = 7.5 Hz, 1H), 7.58 7.54 (m, 3H); 13C NMR 165.6 (C=O), 145.7, 140.4, 133.2, 132.2, 130.6, 129.7, 128.8, 126.5, 120.3, 114.8. Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.51; H, 3.02; N, 16.43. 1 H -1,2,3-Benzotriazol-1-yl(1-naphthyl)methanone (4.2l): yield, 88%; Colorless needles (recrystallized from benzene); mp 136.5 137.5 C; 1H NMR 8.50 (d, J = 8.4 Hz, 1H), 8.20 8.11 (m, 3H), 7.99 7.94 (m, 2H), 7.76 (t, J = 7.5 Hz, 1H), 7.65 7.56 (m, 4H); 13C NMR 167.6 (C=O), 146.2, 133.6, 133.0, 132.0, 131.0, 130.5, 130.2, 129.3,

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64 128.7, 127.9, 126.7, 126.5, 124.7, 124.3, 120.3, 114.7. Anal. Calcd for C17H11N3O: C, 74.71; H, 4.06; N, 15.38. Found: C, 74.57; H, 4.14; N, 15.38. 1 H -1,2,3-Benzotriazol-1-yl(2-pyrazinyl)methanone (4.2m): yield, 76%; Pale red needles (recrystallized from chloroform/hexane); mp 146 147 C; 1H NMR 9.35 (s, 1H), 8.89 8.87 (m, 2H), 8.41 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H); 13C NMR 163.7 (C=O), 147.5, 146.7, 145.8, 144.4, 131.7, 130.9, 126.9, 120.5, 114.5. Anal. Calcd for C11H7N5O: C, 58.67; H, 3.13; N, 31.10. Found: C, 58.72; H, 3.11; N, 31.27. 1-(1 H -1,2,3-Benzotriazol-1-yl)-3phenyl-1-propanone (4.2n): yield, 84%; Colorless needles (recrystallized from chloroform/hexane); mp 63 64 C; 1H NMR 8.18 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.28 7.26 (m, 3H), 7.20 7.17(m, 2H), 3.70 (t, J = 7.6 Hz, 2H), 3.18 (t, J = 7.6 Hz, 2H); 13C NMR 171.3 (C=O), 145.8, 139.6, 130.7, 130.0, 128.4, 128.2, 126.2, 125.8, 119.8, 114.0, 36.8, 29.8. Anal. Calcd for C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found: C, 71.48; H, 5.35; N, 16.77. 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2-d iphenyl-1-ethanone (4.2p): yield, 89%; Colorless needles; mp 88 89 C (mp[96HAC365] 106 107 C); 1H NMR 8.32 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 7.3, 7.3 Hz, 1H), 7.50 7.35 (m, 5H), 7.32 7.25 (m, 6H), 6.82 (s, 1H); 13C NMR 171.2 (C=O), 146.3, 137.4, 131.2, 130.4, 128.9, 128.8, 127.7, 126.3, 120.2, 114.5, 55.8 (CH).

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65 4.4.3 General procedure for the Reaction of N -Acylbenzotriazoles 4.2 with Aqueous ammonia. The N -acylbenzotriazole 4.2 (2.5 mmol) was stirred w ith ammonium hydroxide (30% aqueous solution, 5 mL, 43 mmol) in EtOH (5 mL) and THF (5 mL) at room temperature for 2-4 h. After evaporation of so lvents in vacuo, the residue was added 2 M NaOH (20 mL) and extracted with EtOAc. The co mbined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent gave a solid, which was recrystallized from benzene to afford the pure primary amide 4.3a-n The isolated yields, melting points and the reported melting points of 4.3a-n are summarized in Table 4-2. 4.4.4 General procedure for the Reaction of N -Acylbenzotriazoles 4.2 with Primary amines. The N -acylbenzotriazole 4.2 (1 mmol) was stirred with the appropriate primary amine (1 mmol) in THF (10 mL) at room te mperature for 4 h. After evaporation of solvents in vacuo the residue was added to 2 M NaOH (20 mL) and the product was extracted with EtOAc. The combined organi c layers were dried over anhydrous MgSO4. Evaporation of the solvent gave a secondary amide 4.4a-j which was recrystallized from appropriate solvents. N -Butyl-4-(diethylamino)benzamide (4.4c): yield, 92%; Yellow crystals (recrystallized from benzene/hexane); 1H NMR 7.63 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 5.93 (br s, 1H), 3.46 3.54 (m, 6H), 1.62 1.53 (m, 2H), 1.43 1.36 (m, 2H), 1.18 (t, J = 7.0 Hz, 6H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR 167.3(C=O), 149.7, 128.5, 120.5, 110.3, 44.3, 39.5, 31.9, 20.1, 13.7, 12.4. HRMS Calcd for C15H25N2O: 249.1967 (M+1), found: 249.1974.

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66 N -Butyl-1-naphthamide (4.4f): yield, 92%; Colorless needles (recrystallized from benzene); 1H NMR 8.23 8.20 (m, 1H), 7.84 7.78 (m, 2H), 7.49 7.45 (m, 3H), 7.36 7.31 (m, 1H), 6.28 (br s, 1H), 3.37 (t, J = 6.1 Hz, 2H), 1.58 1.51 (m, 2H), 1.39 1.32 (m, 2H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR 169.5 (C=O), 134.7, 133.5, 130.2, 130.0, 128.1, 126.8, 126.2, 125.3, 124.6, 124.5, 39.6, 31.5, 20.0, 13.7. Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.24; H, 7.68; N, 6.11. N -(4-Methoxyphenyl)-2-pyr idinecarboxamide (4.4g): yield, 83%; Colorless needles (recrystallized from benzene/hexane); 1 H NMR 9.95 (s, 1H), 8.59 (d, J = 4.5 Hz, 1H), 8.29 (d, J = 7.5 Hz, 1H), 7.91 7.85 (m, 1H), 7.73 7.69 (m, 2H), 7.48 7.43 (m, 1H), 6.94 6.90 (m, 2H), 3.80 (s, 3H); 13C NMR 161.7 (C=O), 156.3, 149.7, 147.9, 137.6, 130.8, 126.2, 122.2, 121.2, 114.1, 55.4. Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.56; H, 5.38; N, 12.36. N -(1-Methylpropyl)pyridine-4-carboxamide (4.4h): yield, 100%; Colorless needles (recrystallized from benzene/hexane); 1H NMR 8.73 (dd, J = 4.4, 1.6 Hz, 2H), 7.61 (dd, J = 4.4, 1.6 Hz, 2H), 6.16 (br s, 1H), 4.18 4.08 (m, 1H), 1.64 1.55 (m, 2H), 1.24 (d, J = 6.6 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR 165.0 (C=O), 150.0, 142.1, 121.0, 47.4, 29.3, 20.1, 10.4. HRMS Calcd for C10H15N2O: 179.1184 (M+1), found: 179.1184. N -( tert -Butyl)-2-pyrazinecarboxamide (4.4i): yield, 100%; Colorless flakes (recrystallized from benzene); 1H NMR 9.39 (d, J = 1.3 Hz, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 1.5, 1.5 Hz, 1H), 7.75 (br s, 1H), 1.50 (s, 9H); 13C NMR 161.9 (C=O), 146.8, 145.1 143.9, 142.1, 51.2, 28.6. Anal. Calcd for C9H13N3O: C, 60.32; H, 7.31; N, 23.45. Found: C, 60.16; H, 7.63; N, 23.28.

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67 4.4.5 General procedure for the Reaction of N -Acylbenzotriazoles 4.2 with Secondary amines. The same procedure as used in the preparation of the secondary amides 4.4 afforded pure tertiary amides 4.5a-k (4-Nitrophenyl)(tetrahydro-1H-p yrrol-1-yl)methanone (4.5d): yield, 96%; light yellow solid; 1H NMR 8.17 (dd, J = 8.4, 2.0 Hz, 2H), 7.62 (dd, J = 8.4, 2.0 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 3.30 (t, J = 6.0 Hz, 2H), 1.99 1.74 (m, 4H); 13C NMR 167.0 (C=O), 148.0, 142.9, 127.9, 123.3, 49.1, 46.1, 26.1, 24.1. Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C, 59.85; H, 5.54; N, 12.69. (2-Methoxyphenyl)(tetrahydro-1 H -pyrrol-1-yl)methanone (4.5f): yield, 98%; Yellow oil; 1H NMR 7.36 7.25 (m, 2H), 7.00 6.90 (m, 2H), 3.82 (s, 3H), 3.65 (t, J = 6.3 Hz, 2H), 3.22 (t, J = 6.3 Hz, 2H), 1.97 1.83 (m, 4H); 13C NMR 167.7 (C=O), 155.0, 130.2, 127.5, 127.3, 120.6, 110.9, 55.4, 47.5, 45.3, 25.6, 24.4. HRMS Calcd for C12H16NO2: 206.1181 (M+1), found: 206.1178. 1-Naphthyl(tetrahydro-1 H -pyrrol-1-yl)methanone (4.5h): yield, 94%; Colorless needles (recrystallized from benzene/hexane); 1H NMR 7.88 7.84 (m, 3H), 7.53 7.43 (m, 4H), 3.79 (t, J = 6.9 Hz, 2H), 3.11 (t, J = 6.9 Hz, 2H), 2.01 1.94 (m, 2H), 1.83 1.78 (m, 2H); 13C NMR 169.1 (C=O), 135.6, 133.4, 129.0, 128.9, 128.2, 126.8, 126.1, 125.0, 124.7, 123.5, 48.4, 45.5, 25.9, 24.5. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.86; H, 6.84; N, 6.14. 4-Pyridinyl(tetrahydro-1 H -pyrrol-1-yl)methanone (4.5i): yield, 100%; Yellow oil; 1H NMR 8.73 8.71 (m, 2H), 7.43 7.40 (m, 2H), 3.68 (t, J = 6.9 Hz, 2H), 3.40 (t, J

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68 = 6.9 Hz, 2H), 2.05 1.88 (m, 4H); 13C NMR 167.1 (C=O), 150.0, 144.5, 121.2, 49.2, 46.3, 26.2, 24.2. HRMS Calcd for C10H13N2O: 177.1028 (M+1), found: 177.1017. 2,2-Diphenyl-1-piperidino-1-ethanone (4.5k): yield, 68%; Colorless needles (recrystallized from benzene); 1H NMR 7.32 7.20 (m, 10H), 5.22 (s, 1H), 3.64 3.61 (m, 2H), 3.41 3.37 (m, 2H), 1.55 1.53 (m, 4H), 1.30 1.20 (m, 2H); 13C NMR 169.9 (C=O), 139.7, 129.0, 128.4, 126.8, 54.7, 49.0, 43.2, 26.0, 25.5, 24.4. Anal. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.69; H, 7.76; N, 5.02. 4.4.6 General procedure for the preparation of -hydroxyamides. A mixture of BtSO2CH3 (0.49 g, 2.5 mmol), 2-hydroxy-2-phenylacetic acid (0.38 g, 2.5 mmol) and Et3N (0.35 g, 3.5 mmol) was heated unde r reflux in dry THF for about 20 min, then an appropriate amine (2.5 mmol) was added and the mixture was refluxed for 18 h. After being concentrated, EtOAc (50 mL) was added and the organic phase was washed with 2 M NaOH, dried over anhyd MgSO4. Removal of the solvent gave a solid, which was recrystallized from CHCl3 to furnish -hydroxyamide 4.7a b 2-HydroxyN ,2-diphenylacetamide (4.7a): yield, 68%; Colorless flakes; mp 143 144 C (mp[86TL1921] 150 151 C); 1H NMR 9.08 (br s, 1H), 7.59 7.51 (m, 2H), 7.49 7.40 (m, 2H), 7.40 7.20 (m, 5H), 7.07 (t, J = 7.4 Hz, 1H), 6.07 (br s, 1H), 5.13 (s, 1H); 13C NMR 170.5 (C=O), 139.7, 137.2, 128.4, 127.9, 127.6, 126.3, 123.7, 119.2, 73.8. Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.72; H, 5.91; N, 6.14. 2-HydroxyN -(4-methylphenyl)-2-phenylacetamide (4.7b): yield, 72%; Colorless flakes; mp 169 170 C (mp[86TL1921] 170 172 C); 1H NMR 9.02 (br s, 1H), 7.53 7.45 (m, 4H), 7.37 7.24 (m, 1H), 7.33 (d, J = 7.5 Hz, 2H), 7.09 (d, J = 8.3 Hz,

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69 2H), 6.11 (d, J = 4.4 Hz, 1H), 5.14 (d, J = 4.2 Hz, 1H), 2.29 (s, 3H); 13C NMR 170.2 (C=O), 139.9, 134.7, 133.1, 128.8, 127.8, 127.5, 126.3, 119.1, 73.7, 20.3. Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.43; H, 6.63; N, 5.77. 4.4.7 Preparation of 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2,3,3,4 ,4,4-heptafluorobutan-1-one ( 4.8 ). To a solution of BtTMS (1.9 g, 10 mmol) in dry THF (20 mL) under argon, was added dropwise n -C3F7COCl (2.3 g, 10 mmol). The mixtur e was stirred at rt for 3 h. Then, removal of the solvent afforded C3F7COBt ( 4.8 ), together with byproduct BtH. The 1H NMR spectrum of the mixture shows that the molar ratio of th ese two compounds is 6:1. 1-(1 H -1,2,3-Benzotriazol-1-yl)-2,2,3,3,4,4,4-he ptafluorobutan-1-one (4.8): white powder (a mixture with benzotriazole w ith ratio as 6:1); Yield determined by 1H NMR, 86%; 1H NMR 8.28 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H); 19F NMR -80.7 (t, J = 9.3 Hz, 3F, CF3), -112.5 -112.7 (m, 2F, -CF2CO-), -124.8 (s, 2F, -CF2-). 4.4.8 General Procedure for the Reaction 4.8 with Primary and Secondary amines. The mixture of 4.8 and BtH (212 mg, 0.63 mmol of 4.8 ) and an appropriate amine (0.63 mmol) was stirred at rt for 6 h. After being concentrated, the mixture was washed with 2 M NaOH and extracted with EtOAc (20 mL 2). The organic phase was dried over anhyd MgSO4. Removal of the solvent in vacuo afforded perfluoroalkylated amide 4.9a-d The isolated yields of 4.9a-d were based on n -C3F7COBt. 2,2,3,3,4,4,4-HeptafluoroN -(4-methylphenyl)butanamide (4.9a): [96PCJ690] yield, 90%; Colorless needles; mp 99 100 C; 1H NMR 10.03 (br s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H); 19F NMR -81.0 (t, J = 8.2 Hz, 3F,

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70 CF3), -120.2 -120.3 (m, 2F, -CF2CO-), -127.3 (s, 2F, -CF2-). Anal. Calcd for C11H8NF7O: C, 43.58; H, 2.66; N, 4.62. Found: C, 43.25; H, 2.86; N, 4.82. 2,2,3,3,4,4,4-HeptafluoroN -(1-phenylethyl)butanamide (4.9b): yield, 87%; Colorless needles; mp 91 92 C (mp[72JPS1235] 89 90 C); 1H NMR 7.41 7.30 (m, 5H), 6.65 (br s, 1H), 5.19 (q, J = 7.2 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H); 19F NMR -81.1 (t, J = 8.2 Hz, 3F, CF3), -121.2 -121.3 (m, 2F, -CF2CO-), -127.5 (s, 2F, -CF2-). Anal. Calcd for C12H10NF7O: C, 45.44; H, 3.18; N, 4.42. Found: C, 45.65; H, 3.56; N, 4.32. 2,2,3,3,4,4,4-Heptafluoro-1-tetrahydro-1 H -pyrrol-1-ylbutan-1-one (4.9c): colorless oil, bp[55JACS6662] 65 C/2 mmHg; Yield, 88%; 1H NMR 3.71 3.67 (m, 2H), 3.66 3.59 (m, 2H), 2.06 1.99 (m, 2H), 1.97 1.88 (m, 2H); 19F NMR -80.7 (t, J = 9.3 Hz, 3F, CF3), -116.0 -116.1 (m, 2F, -CF2CO-), -126.6 (s, 2F, -CF2-). 2,2,3,3,4,4,4-Heptafluoro-1-tetrahydro-4 H -1,4-oxazin-4-ylbutan-1-one (4.9d): colorless oil, bp[98CJC549] 90 C/10 mmHg; Yield, 85%; 1H NMR 3.80 3.65 (m, 8H); 19F NMR -80.3 (t, J = 9.3 Hz, 3F, CF3), -112.3 -112.4 (m, 2F, -CF2CO-), -126.3 (s, 2F, -CF2-).

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71 CHAPTER 5 HIGHLY DIASTEREOSELECTIVE PE PTIDE CHAIN EXTENSIONS OF UNPROTECTED AMINO ACIDS WITH N -(Z-AMINOACYL)BENZOTRIAZOLES 5.1 Introduction The many coupling reagents [79Peptide] [ 01SPP] developed for the formation of amide bonds in the synthesis of biologi cally active peptides and their analogs [95CR2115] [97CR 2243] [98CR763] include: (i) carbodiimides in combination with additives such as 1-hydroxybenzotriazole (HOBt), [02T7851] [03OL2793] 1-hydroxy-7azabenzotriazole (HOAt) and analogs [01OL2793] or N -hydroxysuccinimide (HOSu); [64JACS1839] (ii) phosphonium [75TL1219] [90TL205] and uronium salts [84S572] [01S1811] of HOBt or HOAt; (iii) N -acylazoles such as 1,1'-carbonylbis(1 H -imidazole) (CDI); [00HCA2607] (iv) mi xed anhydrides; [51JACS5553] or (v) carboxylic acid fluorides. [90JACS9651] [91JOC2611] A commonly encountered problem in peptid e synthesis is epim erization of the amino acid component during activation of the carboxylic acid group. Many of the coupling reagents require prior protection a nd subsequent deprotec tion of various amino acid functional groups. [91CSP] Coupling reactions with such reagents are frequently moisture sensitive. Furthermore, isolati on and purification processes often involve column chromatography due to the formation of by-products from the coupling reagents. The literature reveals that the reactions of N-protected C-activated amino acids with unprotected amino acids have been le ss explored than thei r reactions with Cprotected amino acids. In 1980 Hegarty et al reported peptide coupling of unprotected

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72 amino acids with imidoyl halides RC(:NNR '2)X (derivatives of acid hydrazides) as condensation reagents ; they observed 1.0 21.0% of racemization at pH 7.2 9.3. [80JACS4537] N -Hydroxysuccinimide esters of am ino acids couple with unprotected amino acids in dioxane in the presence of sodium hydroxide. [ 87S236] Recent one-pot, two-step preparations of diand tripeptides coupled unprotected amino acids in aqueous acetonitrile with p -nitrophenyl esters of N-protected amino acids in 15 98% yields, with high retention of ch irality. [02TL7717] N -Acylbenzotriazoles are efficient neutral c oupling reagents for: (i) preparation of primary, secondary, and tertia ry amides; [00JOC8210] (ii) C -acylation of pyrroles and indoles, [03JOC5720] 2-methylfuran and th iophene; [04CCA175] ( iii) acylation of primary and secondary al kyl cyanides. [03JOC4932] N -Acylbenzotriazoles are sufficiently r eactive to form amide bonds at ambient temperature, but stable enough to resist side reactions. We previously prepared aminoamides from 1-( -Boc-aminoacyl)benzotriazoles and amines in 82 99% yields with no detectable racemization. [02A RK(viii)134] Advantageously, N -acylbenzotriazoles are usually crystalline and can be stored at room temperature for long periods. We report herein the preparation of N-terminal protected peptides by reactions of N acylbenzotriazoles with unprotec ted amino acids in aqueous/org anic solvents in a broadly applicable, simple and efficient coupling method (Scheme 5-1).

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73 O HN NH R1Z HO O R2O HN NH R1Z HN O R2O HN O HO O Bt NH R1Z O HN NH R1Z Bt O R2O OH NH R1Z O HN NH R1Z HN O R2O HO R35.1a-d5.2a-i 5.4a-f, 5.4a' 5.3a-b i) 5.5a-b ii) iv) iii) v) vi) R1 = CH3, CH(CH3)2, CH2Ph R2 = H, CH3, CH(CH3)2, CH2Ph, CH2OH, CH2(indol-3-yl) R3 = H, CH3, CH2CH(CH3)2, CH2OH, CH2(indol-3-yl) R4 = CH2CH(CH3)2Z = benzyloxycarbonyl Bt = benzotriazol-1-yl Scheme 5-1. Coupling reactions with N -(Z-aminoacyl)benzotriazoles i) SOCl2, BtH at 25 oC, ii) Unprotected amino acid, Et3N in CH3CN/H2O. iii) SOCl2, BtH at 0 oC, iv) Gly-Leu-OH or Gly-Gly-OH, Et3N in CH3CN/H2O, v) Unprotected amino acid, Et3N in CH3CN/H2O. vi) Gly-Leu-OH, Et3N in CH3CN/H2O. 5.2 Results and Discussion 5.2.1 Preparation of N -(Z-Aminoacyl)benzotriazoles from N -Z-Amino acids 5.1a d The Z group is a favorite protecting group due to (i) its stability towards both acidic and basic conditions, (ii) easy purification of solid Z-protected amino acids and peptides, and (iii) its ready cleavage by hydrogenation. [01SPP] [02TL7717] Th e Boc group is also a popular protecting group, [ 64JACS1839] [97S1499] but is not preferred under strongly acidic conditions. Chiral 1-( -Boc-aminoacyl)benzotriazoles were prev iously prepared by the reaction of BtSO2Me with Boc-protected amino acids in refluxing THF in the presence of Et3N with

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74 no detectable racemization. [02ARK(v iii)134] Although Z-Ala-OH and Z-Phe-OH produced the corresponding N -acylbenzotriazole derivatives with 15 50% of racemization under these conditions, our recen tly developed mild alternative procedure for the preparation of N -acylbenzotriazoles prov ed beneficial. [03S2795] Under this protocol, the N -Z-amino acid was reacted with four e quivalents of benzotriazole and one equivalent of SOCl2 in CH2Cl2 at room temperature for 2 h to give N -(Zaminoacyl)benzotriazoles 5.1a d in 85 95% yields; compounds 1a c were obtained with minimal racemization (Table 5-1). Table 5-1. Conversion of N -Z-amino acids into ( N -Z-aminoacyl) benzotriazoles compound yield (%) mp (oC) [ ]D 25 Z-Ala-Bt ( 5.1a ) 95 114 115 0.8 Z-Val-Bt ( 5.1b ) 91 73 74 32.5 Z-Phe-Bt ( 5.1c ) 88 151 152 +18.6 ZDL -Ala-Bt ( 5.1d ) 94 112 113 -To test the optical purity of N -(Z-aminoacyl)benzotriazoles 5.1a c prepared by the above procedure with commercially availabl e, enantiomerically pure unprotected amino acids, [03S2795] we performed 1H NMR analysis of the crude dipeptides 5.2 Thus, ZDL -AlaL -Phe-OH prepared by coupling ZDL -Ala-Bt ( 5.1d ) with L -Phe-OH showed two separate doublets for the methyl prot ons at 1.25 and 1.20 ppm corresponding to the LL and DL -diastereomers, respectively. In comparison, ZL -AlaL -Phe-OH ( 5.2a ) prepared by the coupling of ZL -Ala-Bt ( 5.1a ) with L -Phe-OH showed a single doublet in the 1H NMR spectrum at 1.25 ppm. Similarly, partially racemized ZL -Phe-Bt with L -Ala formed two diastereomers (ZDL -PheL -Ala-OH) with signals at 1.32 and 1.23 ppm in the 1H NMR spectrum while ZL -PheL -Ala-OH ( 5.2f ) prepared from ZL -Phe-Bt ( 5.1c ) and L -Ala-OH showed a single doublet for the methyl group at 1.32 ppm (see Fig. 5-1).

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75 Compounds 5.1a d are novel compounds which were fully characterized by 1H and 13C NMR spectroscopy and elemental analysis. Fig.5-2 1H NMR spectra of compound 5.2f (left) and racemized 5.2f (right) in CDCl3 (CH3 signal in L -Ala) 5.2.2 Preparation of N -Z-Dipeptides. Coupling reactions of 5.1a d were carried out with diverse unprotected amino acids in partially aqueous solution (CH3CN/H2O) in the presence of Et3N for 10 to 40 min. After washing with 6 N HCl, the resulting peptides 5.2a i were obtained in 85 98% yields (Table 5-2). The crude products were estimated to be >95% pure and the absence of epimerization was established by 1H NMR experiments. Thus, ZL -Phe-Bt ( 5.1c ) was reacted with racemic DL -Ala-OH. While enantiopure ZL -PheL -Ala-OH ( 5.2f ) showed the methyl group on the alanine fragment at 1.32 ppm as a doublet, the methyl groups in NH N O O OH C H 3 H Z H (RS, S) NH N O O OH C H 3 H Z H (S, S)

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76 diastereomers ZL -PheD -Ala-OH and ZL -PheL -Ala-OH resonated at 1.23 and 1.32 ppm, respectively. Furthermore, the dipeptides were analyzed by HP LC (detection at 254 nm, flow rate 1.0 mL/min, and solvents 50/50 MeOH/H2O contained 0.1% TFA); while ZL -PheDL -Ala-OH gave two peaks at 15.1 and 19.8 min, ZL -PheL -Ala-OH ( 5.2f ) showed a only single peak at 15.1 min. This result confirmed minimal epimerization in the reaction. Table 5-2. Preparation of N -Z-dipeptides from ( N -Z-aminoacyl)benzotriazoles and unprotected amino acids. RCOBt reactant amino acid Product yield (%) Ref.. 5.1a Phe Z-Ala-Phe-OH ( 5.2a ) 90 [02OL4005] 5.1a Ser Z-Ala-Ser-OH ( 5.2b ) 85 [84JCS(P1)2439] 5.1a Try Z-Ala-Trp-OH ( 5.2c ) 97 [84JCS(P1)2439] 5.1b Phe Z-Val-Phe-OH ( 5.2d) 98 [83LAC1712] 5.1b Try Z-Val-Try-OH ( 5.2e ) 96 [96BP1051] 5.1c Ala Z-Phe-Ala-OH ( 5.2f ) 98 [68JCS(C)1208] 5.1c Val Z-Phe-Val-OH ( 5.2g ) 95 [82TL3831] 5.1c Phe Z-Phe-Phe-OH ( 5.2h ) 98 [67LAC227] 5.1c Ser Z-Phe-Ser-OH ( 5.2i ) 96 [02TL7717] 5.2.3 Preparation of N -Acylbenzotriazoles derived from N -Z-Dipeptides. Z-Phe-Ala-Bt ( 5.3a ) and Z-Ala-Phe-Bt ( 5.3b ) were prepared from N -Z-protected dipeptides by reaction with benzotriazole and SOCl2 at 0 oC for 2 h. This reaction proceeded at 0 oC without visible racemization (i.e. 5.0% as indicated by 1H NMR of the crude products), and gave 5.3a and 5.3b in 85% and 95% yields, respectively (Table 5-3). However, at 25 oC, 5 15% racemization was observed: the methyl group in ZL PheDL -Ala-Bt showed peaks at 1.58 ppm ( LL ) and 1.47 ppm ( LD ). Compound 5.3a and 5.3b are novel compounds and we re fully characterized by 1H and 13C NMR spectroscopy and elemental analysis.

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77 Table 5-3. Conversion of N -Z-dipeptides into N -(Z-dipeptidoyl)benzotriazoles. Compound yield (%) mp (oC) [ ]D 25 Z-Phe-Ala-Bt ( 5.3a ) 85 180 181 57.1 Z-Ala-Phe-Bt ( 5.3b ) 90 148 149 8.7 5.2.4 Preparation of N -Z-Tripeptides. Tripeptides 5.4a f were prepared according to two di fferent protocols: (i) reactions of N -acylbenzotriazole derivatives of N -Z-protected amino acids 5.1a 5.1b and 5.1c with free dipeptides, GlyL -Leu-OH and Gly-Gly-OH, and (ii) reactions of N acylbenzotriazole derivatives of N -Z-protected dipeptides 5.3a and 5.3b with free amino acids (see Scheme 5-1 and Table 5-3). The reaction conditions were similar to those described above for the preparation of the dipeptides 5.2a i but longer reaction times (around 30 to 120 min) were required. Afte r work-up as described above for the preparation of the dipeptides 5.2a i the enantiopure tripeptides 5.4a f were obtained in 85 98% yields (Table 5-4). In order to check the enantiopurity, a racemic mixture of ZL -Ala-GlyL -Leu-OH ( 5.4a ) and ZD -Ala-GlyL -Leu-OH ( 5.4a' ) was prepared from racemic compound 5.1d with GlyL -Leu-OH for comparison with the enantiopure tripeptide 5.4a The 1H NMR of the mixture ( 5.4a 5.4a' ) showed broadened peaks for protons of two methyl groups in the iso -butyl group and complicated multiplets for three NH protons (7.55, 7.91 and 8.17 ppm) while 5.4a gave two sharp doublets for the two methyl groups and two doublets and a broa d singlet for the NH protons. In the 13C NMR spectrum, the 5.4a 5.4a' mixture of diastereomers gave separate signals at 50.0 (from ZL -Ala-GlyL -Leu-OH, 5.4a ) and 50.2 ppm (from ZD -Ala-GlyL -Leu-OH, 5.4a' ), but many other signals from 5.4a and 5.4a' overlapped. Moreover, HPLC was utilized to confirm the negligible racemization; 5.4a showed a single peak at 11.7 min when a mixture of 5.4a and 5.4b showed two peaks at 11.7 and 14.1 min (detection at 230 and

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78 254 nm, flow rate 1.0 mL/min, and solvents 50/50 MeOH/H2O containing 0.1% TFA). Tripeptides 5.4b 5.4e and 5.4f are novel compounds, and were characterized by 1H and 13C NMR spectroscopy, elemental anal ysis, and optical rotation. Table 5-4. Preparation of N -Z-tripeptides (i) from N -(Z-aminoacyl)benzotriazoles and unprotected dipeptides (with 5.1a c ) (ii) from N -(Zdipeptidoyl)benzotriazoles and unprotected amino acids (with 5.3a and 5.3b ). RCOBt reactant amino acid or dipeptide Product yield (%) Ref. 5.1a Gly-Leu Z-Ala-Gly-Leu-OH ( 5.4a ) 93 -5.1d Gly-Leu ZDL -Ala-Gly-Leu-OH ( 5.4a+5.4a' ) 94 -5.1b Gly-Leu Z-Val-Gly-Leu-OH ( 5.4b ) 85 [79CB2145] 5.1c Gly-Gyl Z-Phe-Gly-Gly-OH ( 5.4c ) 98 [91SL35] 5.3a Ala Z-Phe-Ala-Ala-OH ( 5.4d ) 92 -5.3a Ser Z-Phe-Ala-Ser-OH ( 5.4e ) 94 -5.3b Try Z-Ala-Phe-Try-OH ( 5.4f ) 95 -5.2.5 Preparation of N -Z-Tetrapeptides. Reactions of 5.3a and 5.3b with GlyL -Leu-OH for 2 4 h gave tetrapeptides 5.5a and 5.5b in 86% and 85% yields, respectively (Table 5-5). These novel compounds were characterized by 1H and 13C NMR spectroscopy, elemental anal ysis, and optical rotation. Table 5-5. Preparation of N -Z-tetrapeptides from N -(Z-dipeptidoyl)benzo triazoles and an unprotected dipeptide. RCOBt reactant dipeptide Product yield (%) 5.3a Gly-Leu Z-Phe-Ala-Gly-Leu-OH ( 5.5a ) 86 5.3b Gly-Leu Z-Ala-Phe-Gly-Leu-OH ( 5.5b ) 85 5.3 Conclusion In summary, N -acylbenzotriazoles derived from N-protected amino acids or peptides have been introduced as new c oupling reagents. The peptide coupling reaction utilizing the N -acylbenzotriazole derivatives and unprotected amino acids proceeds with minimal epimerization in partially aqueous solution under mild conditions.

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79 5.4 Experimental Section Melting points were determined on a capi llary point apparatus equipped with a digital thermometer. NMR spectra were recorded in CDCl3 or DMSOd6 with TMS for 1H (300 MHz) and 13C (75 MHz) as the internal refere nce unless specified otherwise. The HPLC was performed with Chirobiotic T column 4.6 250 mm, detection at 254 nm, flow rate 1.0 mL/min, and solvents (MeOH/H2O contained 0.1% TFA). THF was distilled from sodium metal in the presen ce of benzophenone under nitrogen atmosphere immediately prior to use. Am ino acids and peptides are L -configuration unless specified otherwise. 5.4.1 General procedure for the Preparation of 5.1a d and 5.3a b For preparation of 5.1a d and 5.3a b thionyl chloride (5 mmol) was added to a solution of 1H-benzotriazole (20 mmol) in dry THF (15 mL) at 25 oC, and the reaction mixture was stirred for 20 min. To the r eaction mixture, N-protected amino acid (5 mmol) dissolved in dry THF (5 mL) was a dded dropwise, and stirred for 1 hour at 25 oC. For compounds 5.3a and 5.3b the reaction mixture was cooled to 0 oC, and N -Zdipeptide (5 mmol) dissolved in dry THF (5 mL) was added dropwise, and stirred at 0 oC for 2 hours. The reaction mixture was con centrated under reduced pressure, and the residue was purified by column chromatography (EtOAc:Hexanes = 1:1 for 5.1a d CHCl3:Hexanes = 1:1 for 5.3a and 5.3b ) to give the desired product. Further purification was performed by recrys tallization from CHCl3/hexanes for the purpose of elemental analysis. Crude 5.1a d can be purified by washing with 5% Na2CO3 solution to remove BtH, instead of column chromatography.

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80 Benzyl N -[(1 S )-2-(1 H -1,2,3-benzotriazol-1-yl)-1-me thyl-2-oxoethyl]carbam-ate (Z-Ala-Bt, 5.1a): Colorless fine needles (95%), mp 114 115 oC: [ ]25 D = 0.8o ( c 1.8, CHCl3); 1H NMR (CDCl3) 1.69 (d, J = 7.0 Hz, 3H, CH 3), 5.11 (d, J = 12.2 Hz, 1H, O OCH 2Ph), 5.17 (d, J = 12.2 Hz, 1H, OCH 2Ph), 5.69 (d, J = 7.6 Hz, 1H, NH ), 5.78 5.84 (m, 1H, NCH CO), 7.14 (br s, 1H, ArH ), 7.36 7.42 (m, 4H), 7.50 7.55 (m, 1H, ArH in Bt), 7.67 (td, J = 8.1, 0.8 Hz, 1H, ArH in Bt), 8.13 (d, J = 8.2 Hz, 1H, ArH in Bt), 8.26 (d, J = 8.1 Hz, 1H, ArH in Bt). 13C NMR (CDCl3) 19.0, 50.5, 67.2, 114.3, 120.3, 126.5, 128.1, 128.2, 128.5, 130.7, 131.1, 136.0, 146.0, 155.6, 172.2. Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 63.21; H, 4.88; N, 17.40. Benzyl N -[(1 S )-1-(1 H -1,2,3-benzotriazol-1-ylcarbo-nyl)-2-methylpropyl]carbamate (Z-Val-Bt, 5.1b): Colorless needles (91%), mp 73 74 oC: [ ]25 D = 32.5o ( c 2.0, CHCl3); 1H NMR (CDCl3) 0.97 (d, J = 6.8 Hz, 3H, CHCH 3), 1.13 (d, J = 6.8 Hz, 3H, CHCH 3), 2.48 2.54 (m, 1H, CHCH (CH3)2), 5.13 (d, J = 12.4 Hz, 1H, OCH 2Ph), 5.16 (d, J = 12.4 Hz, 1H, OCH 2Ph), 5.68 (d, J = 9.0 Hz, 1H, NH ), 5.77 (dd, J = 9.0, 4.5 Hz, 1H, NCH CO), 7.15 (br s, 1H, ArH ), 7.36 (br s, 4H, ArH ), 7.50 7.55 (m, 1H, ArH in Bt), 7.64 7.69 (m, 1H, ArH in Bt), 8.13 (d, J = 8.3 Hz, 1H, ArH in Bt), 8.27 (d, J = 8.2 Hz, 1H, ArH in Bt). 13C NMR (CDCl3) 16.9, 19.6, 31.6, 59.4, 67.3, 114.3, 120.3, 126.4, 128.1, 128.5, 130.6, 131.0, 136.0, 146.0, 156.2, 171.5. Anal. Calcd for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C, 64.82; H, 5.77; N, 15.80. Benzyl N -[(1 S )-2-(1 H -1,2,3-benzotriazol-1-yl)-1-ben zyl-2-oxoethyl]carbamate (Z-Phe-Bt, 5.1c): Colorless plates (89%), mp 151 152 oC: [ ]25 D = +18.6o ( c 2.0, CHCl3); 1H NMR (CDCl3) 3.23 (dd, J = 13.9, 7.7 Hz, 1H, CHCH 2Ph), 3.49 (dd, J = 13.9, 4.9 Hz, 1H, CHCH 2Ph), 5.09 (s, 2H, OCH 2Ph), 5.51 (d, J = 8.2 Hz, 1H, NH ),

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81 6.05 6.10 (m, 1H, NCH CO), 7.12 7.14 (m, 2H), 7.23 7.33 (m, 8H), 7.53 7.58 (m, 1H, ArH in Bt), 7.66 7.72 (m, 1H, ArH in Bt), 8.16 (d, J = 8.1 Hz, 1H, ArH in Bt), 8.24 (d, J = 8.1 Hz, 1H, ArH in Bt). 13C NMR (CDCl3) 38.8, 55.6, 67.2, 114.3, 120.4, 126.6, 127.4, 128.1, 128.5, 128.7, 129.2, 130.8, 134.9, 146.0, 155.7, 170.8. Anal. Calcd for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99. Found: C, 69.19; H, 5.11; N, 14.05. Benzyl N -[2-(1 H -1,2,3-benzotriazol-1-yl)-1-met hyl-2-oxoethyl]carbamate (ZDL -Ala-Bt, 5.1d): Colorless crystals (94%), mp 112 113 oC; 1H NMR (CDCl3) 1.69 (d, J = 7.0 Hz, 3H, CH 3), 5.11 (d, J = 12.2 Hz, 1H, OCH 2Ph), 5.17 (d, J = 12.2 Hz, 1H, OCH 2Ph), 5.69 (d, J = 7.6 Hz, 1H, NH ), 5.78 5.84 (m, 1H, NCH CO), 7.14 (br s, 1H), 7.36 (s, 4H), 7.50 7.55 (m, 1H, ArH in Bt), 7.64 7.70 (m, 1H, ArH in Bt), 8.13 (d, J = 8.2 Hz, 1H, ArH in Bt), 8.26 (d, J = 8.1 Hz, 1H, ArH in Bt). 13C NMR (CDCl3) 38.8, 55.6, 67.2, 114.3, 120.4, 126.6, 127.4, 128.1, 128.5, 128.7, 129.2, 130.8, 130.9, 134.9, 135.9, 146.0, 155.7, 170.8. Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 63.24; H, 4.96; N, 17.26. Benzyl N -((1 S )-2-{[(1 S )-2-(1 H -1,2,3-benzotriazol-1-yl )-1-methyl-2-oxoethyl] amino}-1-benzyl-2-oxoethyl) ca rbamate (Z-Phe-Ala-Bt, 5.3a): Colorless needles (85%), mp 180 181 oC: [ ]25 D = 57.1o ( c 0.83, CHCl3); 1H NMR (DMSOd6) 1.61 (d, J = 7.1 Hz, 3H, CHCH 3), 2.70 2.78 (m, 1H, CHCH 2Ph), 3.07 (dd, J = 13.6, 3.0 Hz, 1H, CHCH 2Ph), 4.34 4.41 (m, 1H, NCH CO), 4.93 (s, 2H, OCH 2Ph), 5.63 (apparent q, J 6.5 Hz, 1H, NCH CO), 7.21 7.35 (m, 10H), 7.55 (d, J = 8.8 Hz, 1H, NH ), 7.65 (t, J = 7.6 Hz, 1H, ArH in Bt), 7.82 (t, J = 7.7 Hz, 1H, ArH in Bt), 8.25 (d, J = 8.3 Hz, 1H, ArH in Bt), 8.31 (d, J = 8.4 Hz, 1H, ArH in Bt), 9.02 (d, J = 5.5 Hz, 1H, NH ). 13C NMR (DMSOd6) 16.6, 37.3, 48.6, 55.6, 65.1, 113.9, 120.1, 126.2, 126.6, 127.4, 127.6, 127.9, 128.2,

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82 129.1, 130.6, 131.0, 136.9, 137.9, 145.3, 155.8, 171.7, 172.0. Anal. Calcd for C26H25N5O4: C, 66.23; H, 5.34; N, 14.85. Found: C, 65.80; H, 5.48; N, 14.52. Benzyl N -((1 S )-2-{[(1 S )-2-(1 H -1,2,3-benzotriazol-1-yl)-1-benzyl-2-oxoethyl] amino}-1-methyl-2-oxoethyl) ca rbamate (Z-Ala-Phe-Bt, 5.3b): Colorless microcrystals (90%), mp 148 149 oC: [ ]25 D = 8.7o ( c 2.0, CHCl3); 1H NMR (CDCl3) 1.34 (d, J = 7.0 Hz, 3H, CHCH 3), 3.22 (dd, J = 14.0, 7.8 Hz, 1H, CHCH 2Ph), 3.47 (dd, J = 14.0, 4.8 Hz, 1H, CHCH 2Ph), 4.30 4.33 (m, 1H, NCH CO), 5.07 (d, J = 12.2 Hz, 1H, OCH 2Ph), 5.13 (d, J = 12.2 Hz, 1H, OCH 2Ph), 5.34 (d, J = 6.2 Hz, 1H, NH ), 6.20 6.23 (m, 1H, NCH CO), 7.04 7.35 (m, 11H), 7.51 7.57 (m, 1H, ArH in Bt), 7.65 7.70 (m, 1H, ArH in Bt), 8.15 (d, J = 8.2 Hz, 1H, ArH in Bt), 8.22 (d, J = 8.0 Hz, 1H, ArH in Bt). 13C NMR (CDCl3) 18.1, 38.5, 50.3, 54.1, 67.1, 114.3, 120.4, 126.6, 127.4, 128.1, 128.2, 128.5, 128.6, 129.2, 130.8, 131.0, 135.0, 136.0, 146.0, 156.0, 170.2, 172.1. Anal. Calcd for C26H25N5O4: C, 66.23; H, 5.34; N, 14.85. Found: C, 66.25; H, 5.37; N, 14.29. 5.4.2 General procedure for the Preparation of 5.2a i 5.4a f 5.4a' and 5.5a b N -Acylbenzotriazoles ( 5.1a d 5.3a b ) (0.5 mmol) were added at room temperature to a solution of -amino acid (0.5 mmol) in a solution of CH3CN (7 mL) and H2O (3 mL) in the presence of Et3N (0.6 mmol). The reaction mi xture was then stirred at room temperature until the starting material was completely consumed (10 40 min for dipeptides, 30 120 min for tripeptides, 120 240 min for tetrapeptides). After 1 mL of 6 N HCl was added, the solution was concentrat ed under reduced pressu re. The residue was extracted with EtOAc (20 mL), washed with 6N HCl (5 mL) and brin e (10 mL), and then dried (anhydrous MgSO4). Evaporation of the solvent ga ve the desired product in pure form, which was recrystallized further from CHCl3/hexanes.

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83 (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino } propanoyl)amino]-3-phenylpropanoic acid (Z-Ala-Phe-OH, 5.2a): [02OL4005][94JOC7503] Colorless microcrystals (90%), mp 122 124 oC (lit.[ 94JOC7503] 126 127 oC): [ ]25 D = +4.1o ( c 1.3, CH2Cl2) [lit.[02OL4005] [ ]25 D = +4.2o ( c 1.3, CH2Cl2)]; 1H NMR (DMSOd6) 1.16 (d, J = 7.0 Hz, 3H, CHCH 3), 2.92 (dd, J = 13.6, 8.5 Hz, 1H, CHCH 2Ph), 3.05 (dd, J = 13.6, 4.9 Hz, 1H, CHCH 2Ph), 4.04 4.10 (m, 1H, NCH CO), 4.38 4.45 (m, 1H, NCH CO), 5.00 (s, 2H, OCH 2Ph), 7.23 7.45 (m, 11H, ArH and NH ), 8.05 (d, J = 7.4 Hz, 1H, NH). One exchangeable proton is missing. 13C NMR (DMSOd6) 18.1, 36.5, 49.8, 53.2, 65.3, 126.3, 127.6, 127.7, 128.0, 128.2, 129.1, 136.9, 137.3, 155.4, 172.3, 172.6. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino } propanoyl)amino]-3-hydroxypropanoic acid (Z-Ala-Ser-OH, 5.2b): [84JCS(P1)2439] Colorless microcrystals (85%), mp 192 194 oC (lit.[84JCS(P1)2439] 194 196 oC): [ ]25 D = +21.1o ( c 0.4, DMF) [(lit.[84JCS(P1)2439] [ ]25 D = +21.1o ( c 0.4, DMF)]; 1H NMR (DMSOd6) 1.22 (d, J = 7.1 Hz, 3H, CHCH 3), 3.60 3.75 (m, 2H, CHCH 2OH), 4.13 4.18 (m, 1H, NCH CO), 4.25 4.28 (m, 1H, NCH CO) 5.02 (s, 2H, OCH 2Ph), 7.35 (s, 5H), 7.36 7.48 (m, 1H, OH), 7.91 8.00 (m, 2H, NH 2), One exchangeable proton is missing. 13C NMR (DMSOd6) 18.2, 49.8, 54.4, 61.2, 65.3, 127.6, 128.2, 128.2, 136.9, 155.5, 171.8, 172.5. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]a mino} propanoyl)amino]-3-(1 H -indol3-yl)propanoic acid (Z-Ala-Try-OH, 5.2c): [88JHC1265] Colorless microcrystals (97%), mp 154 155 oC: [ ]25 D = +8.1o ( c 1.6, MeOH); 1H NMR (DMSOd6) 1.19 (d, J = 7.0 Hz, 3H, CHCH 3), 3.07 (dd, J = 15.0, 8.7 Hz, 1H, CHCH 2), 3.18 (dd, J = 15.0, 5.0 Hz, 1H, CHCH 2), 4.11 (apparent q, J 7.1 Hz, 1H, NCH CO), 4.44 4.51 (m, 1H, NCH CO), 4.98 (d, J = 12.6 Hz, 1H, OCH 2Ph), 5.04 (d, J = 12.6 Hz, 1H, OCH 2Ph), 6.98

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84 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.26 7.46 (m, 8H), 7.53 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H, NH), 10.9 (s, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 18.1, 26.9, 49.8, 52.7, 65.3, 109.5, 111.2, 118.1, 118.3, 120.8, 123.6, 127.2, 127.6, 128.2, 136.0, 136.9, 155.5, 172.4, 173.1. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino}-3-methylbutanoyl)amino]-3phenylpropanoic acid (Z-Val-Phe-OH, 5.2d): [83LAC1712] Colorless microcrystals (98%), mp 166 167 oC (lit.[83LAC1712] 167 168 oC): [ ]25 D = 13.0o ( c 1.0, MeOH) [(lit [83LAC1712] [ ]25 D = 13.3o ( c 1.0, MeOH)]; 1H NMR (DMSOd6) 0.78 0.82 (m, 6H, CH 3 2), 1.87 1.99 (m, 1H, CHCH (CH3)2), 2.89 (dd, J = 12.6, 9.0 Hz, 1H, CHCH2 Ph), 3.05 (dd, J = 12.6, 5.2 Hz, 1H, CHCH2 Ph), 3.85 3.91 (m, 1H, NCH CO), 4.41 4.48 (m, 1H, NCH CO), 5.03 (s, 2H, OCH 2Ph), 7.18 7.35 (m, 11H, ArH and NH ), 8.17 (d, J = 7.7 Hz, 1H, NH ). One exchangeable proton is missing. 13C NMR (DMSOd6) 18.0, 19.0, 30.4, 36.7, 53.2, 59.9, 65.3, 126.3, 127.5, 127.7, 128.0, 128.2, 129.0, 137.0, 137.4, 155.9, 171.0, 172.7. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino}-3-methylbutanoyl)amino]-3(1 H -indol-3-yl)propanoic acid (Z-Val-Try-OH, 5.2e): [96BP1051][68JCS(C)1208] Colorless microcrystals (96%), mp 187 188 oC (lit.[96BP1051] 135 137 oC): [ ]25 D = 6.4o ( c 1.5, MeOH) [(lit.[68JCS(C)1208] [ ]25 D = 6.0o ( c 2.63, MeOH)]; 1H NMR (DMSOd6) 0.80 0.85 (m, 6H, CH 3 2), 1.91 1.98 (m, 1H, CHCH (CH3)2), 2.99 (dd, J = 13.8, 9.0 Hz, 1H, CHCH 2-3-indolyl), 3.05 (dd, J = 13.8, 5.2 Hz, 1H, CHCH 2-3indolyl), 3.90 3.95 (m, 1H, NCH CO), 4.44 4.60 (m, 1H, NCH CO), 5.00 (d, J = 12.5 Hz, 1H, OCH 2Ph), 5.06 (d, J = 12.5 Hz, 1H, OCH 2Ph), 6.97 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 7.18 7.37 (m, 8H), 7.53 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 7.4 Hz, 1H, NH ),

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85 10.86 (br s, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 18.0, 19.1, 27.1, 30.5, 52.8, 59.9, 65.4, 109.7, 111.3, 118.1, 118.3, 120.9, 123.6, 127.2, 127.6, 127.7, 128.3, 136.1, 137.1, 156.0, 171.2, 173.2. Anal. Calcd for C24H27N3O5: C, 65.89; H, 6.22; N, 9.60. Found: C, 65.92; H, 6.33; N, 9.58. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino] propanoic acid (Z-Phe-Ala-OH, 5.2f): [82TL3831] Colorless micr ocrystals (96%), mp 157 158 oC (lit.[82TL3831] 153 154 oC): [ ]25 D = 9.5o ( c 1.0, EtOH) [(lit.[82TL3831] [ ]25 D = 10.0o ( c 1.90, EtOH)]; 1H NMR 1.36 (d, J = 7.0 Hz, 3H, CHCH 3), 3.05 (d, J = 6.2 Hz, 2H, CHCH 2Ph), 4.47 4.52 (m, 2H, NCH CO 2), 5.13 (d, J = 12.5 Hz, 1H, OCH 2Ph), 5.18 (d, J = 12.5 Hz, 1H, OCH 2Ph), 5.63 (d, J = 5.6 Hz, 1H, NH), 6.65 (br s, 1H, NH), 7.15 7.36 (m, 10H), 8.80 (br s, 1H, CO2H ). 13C NMR 17.1, 37.4, 47.5, 55.9, 65.1, 126.2, 127.4, 127.6, 128.0, 128.3, 129.2, 137.0, 138.2, 155.8, 171.4, 174.0. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]-3methylbutanoic acid (Z-Phe-Val-OH, 5.2g): [67LAC227] Colorless microcrystals (95%), mp 140 142 oC (lit.[67LAC227] 149 151 oC): [ ]25 D = 6.2o ( c 2.0, MeOH) [(lit.[67LAC227] [ ]22 D = 6.3o ( c 2.0, MeOH)]; 1H NMR (DMSOd6) 0.90 (d, J = 5.2 Hz, 6H, CH 3 2), 2.05 2.11 (m, 1H, CHCH (CH3)2), 2.69 2.77 (m, 1H, CHCH 2Ph), 2.98 3.02 (m, 1H, CHCH 2Ph), 4.17 4.22 (m, 1H, NCH CO), 4.36 4.41 (m, 1H, NCH CO), 4.94 (s, 2H, OCH 2Ph), 7.19 7.53 (m, 11H, ArH and NH ), 8.07 8.09 (m, 2H, NH and CO2H ). 13C NMR (DMSOd6) 17.9, 19.0, 29.9, 37.3, 55.8, 57.1, 65.1, 126.1, 127.3, 127.6, 127.9, 128.2, 129.1, 136.9, 138.0, 155.7, 171.8, 172.8. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]-3phenylpropanoic acid (Z-Phe-Phe-OH, 5.2h): [79CB2145][91S35] Colorless

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86 microcrystals (98%), mp 141 142 oC (lit.[91S35] 138 139 oC): [ ]25 D = 6.7o ( c 1.3, MeOH); 1H NMR (DMSOd6) 2.67 2.75 (m, 1H, CHCH 2Ph), 2.93 3.14 (m, 3H, CHCH 2Ph), 4.31 4.34 (m, 1H, NCH CO), 4.49 4.5.1 (m, 1H, NCH CO), 4.94 (s, 2H, OCH2Ph), 7.12 7.51 (m, 16H), 8.10 (br s, 1H, CO2H ), 8.32 (d, J = 7.6 Hz, 1H, NH ). 13C NMR (DMSOd6) 36.6, 37.3, 53.4, 55.9, 65.1, 126.1, 126.4, 127.3, 127.6, 127.9, 128.1, 128.2, 129.1, 136.9, 137.3, 138.0, 155.7, 171.5, 172.7. (2 S )-2-[((2 S )-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]-3hydroxypropanoic acid (Z-Phe-Ser-OH, 5.2i): [91LAC165] Colorless microcrystals (96%), mp 140 141 oC (lit.[91LAC165] 137 oC): [ ]25 D = +0.6o ( c 1.0, MeOH) (lit.[91LAC165] [ ]22 D = +0.6o ( c 1.0, MeOH); 1H NMR (DMSOd6) 2.73 (t, J = 12.6 Hz, 1H, CHCH 2Ph), 3.06 3.10 (m, 1H, CHCH 2Ph), 3.67 (dd, J = 10.3, 3.3 Hz, 1H, CHCH 2OH), 3.78 (dd, J = 10.3, 4.5 Hz, 1H, CHCH 2OH), 4.32 4.42 (m, 2H, NCH CO 2), 4.93 (s, 2H, OCH 2Ph), 7.24 7.46 (m, 10H), 7.52 (d, J = 8.8 Hz, 1H, NH ), 8.32 (d, J = 7.7 Hz, 1H, NH ), Two exchangeable protons (OH and CO2H ) are missing. 13C NMR (DMSOd6) 37.4, 54.6, 55.9, 61.2, 65.1, 126.1, 127.3, 127.6, 127.9, 128.2, 129.2, 136.9, 138.1, 155.7, 171.7, 171.8. (5 S ,11 S )-11-Isobutyl-5-methyl-3,6,9-tri oxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid (Z-A la-Gly-Leu-OH, 5.4a): Colorless microcrystals (93%), mp 150.5 151.5 oC: [ ]25 D = 13.8o ( c 1.3, MeOH); 1H NMR (DMSOd6) 0.83 (d, J = 6.2 Hz, 3H, CH 3), 0.87 (d, J = 6.3 Hz, 3H, CH 3), 1.20 (d, J = 7.2 Hz, 3H, CH 3), 1.52 1.64 (m, 3H, CH 2CH (CH3)2), 3.72 (d, J = 5.4 Hz, 2H, NCH 2CO), 4.02 4.07 (m, 1H, NCH CO), 4.21 4.29 (m, 1H, NCH CO), 4.99 (d, J = 12.6 Hz, 1H, OCH 2Ph), 5.06 (d, J =

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87 12.6 Hz, 1H, OCH 2Ph), 7.36 (s, 5H), 7.55 (d, J = 7.0 Hz, 1H, NH ), 7.91 (d, J = 7.8 Hz, 1H, NH ), 8.17 (br s, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 17.8, 21.3, 22.7, 24.1, 41.7, 50.0, 65.3, 127.7, 127.7, 128.2, 136.8, 155.7, 168.5, 172.6, 173.8. Anal. Calcd for C19H27N3O6: C, 58.00; H, 6.92; N, 10.68. Found: C, 58.21; H, 7.01; N, 10.59. (11 S )-11-Isobutyl-5-methyl-3,6,9-trioxo1-phenyl-2-oxa-4,7,10-triazadodecan12-oic acid (ZDL -Ala-Gly-Leu-OH, 5.4a+5.4a ): Colorless microcrystals (94%), mp 101 105 oC. 1H NMR (DMSOd6) 0.83 (d, J = 6.2, 3H), 0.88 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 7.2 Hz, 3H), 1.52 1.62 (m, 3H), 3.72 (d, J = 5.1 Hz, 2H), 4.02 4.07 (m, 1H), 4.24 4.26 (m, 1H), 4.99 (d, J = 12.6 Hz, 1H), 5.05 (d, J = 12.6 Hz, 1H), 7.28 7.46 (m, 5H), 7.55 (d, J = 7.0 Hz, 1H), 7.90 7.97 (m, 1H), 81.4 8.17 (m, 1H). 13C NMR (DMSOd6) 17.8, 21.3, 22.7, 24.1, 41.7, 50.1, 50.2, 65.4, 127.7, 127.7, 128.3, 136.8, 155.8, 168.6, 172.7, 173.8. Anal. Calcd for C19H27N3O6: C, 58.00; H, 6.92; N, 10.68. Found: C, 58.43; H, 6.99; N, 10.66. (5 S 11 S )-11-Isobutyl-5-isopropyl-3,6,9-tr ioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid (Z-V al-Gly-Leu-OH, 5.4b): Colorless microcrystals (85%), mp 131.5 132.5 oC: [ ]25 D = 17.1o ( c 1.4, MeOH); 1H NMR (DMSOd6) 0.82 0.88 (m, 12H, CH 3 4), 1.49 1.66 (m, 3H, CH 2CH (CH3)2), 1.93 2.02 (m, 1H, CHCH (CH3)2), 3.73 (d, J = 5.4 Hz, 2H, NCH 2CO), 3.85 (apparent t, J 7.7 Hz, 1H, NCH CO), 4.25 (apparent q, J 7.7 Hz, 1H, NCH CO), 5.01 (d, J = 12.6 Hz, 1H, OCH 2Ph), 5.07 (d, J = 12.6 Hz, 1H, OCH 2Ph), 7.30 7.40 (m, 6H, ArH and NH ), 7.95 (d, J = 8.0 Hz, 1H, NH ), 8.21 (t, J = 5.4 Hz, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 18.1, 19.1, 21.3, 22.7, 24.1, 29.9, 41.6, 50.0, 60.3, 65.3, 127.6, 127.7, 128.2, 136.9, 156.2,

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88 168.5, 171.4, 173.8. Anal. Calcd for C21H31N3O6: C, 59.84; H, 7.41; N, 9.97. Found: C, 60.13; H, 7.64; N, 9.94. (5 S )-5-Benzyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,1 0-triazadodecan-12-oic acid (ZPhe-Gly-Gly-OH, 5.4c): [89CCC784] Colorless microcrystals (98%), mp 120 122 oC. (lit.[89CCC784] 122 125 oC): [ ]25 D = 21.4o ( c 1.4, DMF) [lit.[89CCC784] [ ]15 D = – 11.8o ( c 1.0, DMF); 1H NMR (DMSOd6) 2.76 (t, J = 12.3 Hz, 1H, CHCH 2Ph), 3.03 3.08 (m, 1H, CHCH 2Ph), 3.78 (s, 4H, NCH 2CO 2), 4.31 (br s, 1H, NCH CO), 4.94 (s, 2H, OCH 2Ph), 7.25 7.40 (m, 11H, ArH and NH ), 7.56 (d, J = 7.8 Hz, 1H, NH ), 8.11 (br s, 1H, NH ), 8.35 (br s, 1H, CO2H ). 13C NMR (DMSOd6) 37.4, 40.6, 41.9, 56.2, 65.3, 126.2, 127.4, 127.6, 128.0, 128.3, 129.2, 137.0, 138.1, 155.9, 169.0, 171.1, 171.8. (5 S 8 S 11 S )-5-Benzyl-8,11-dimethyl-3,6,9-tr ioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid (Z -Phe-Ala-Ala-OH, 5.4d): [69ABB311] Colorless microcrystals (92%), mp 180 180 oC. (lit.[69ABB311] 187.5 188.5 oC): [ ]25 D = 15.0o ( c 1.0, DMF). 1H NMR (DMSOd6) 1.23 1.29 (m, 6H, CH 3 2), 2.66 2.75 (m, 1H, CHCH 2Ph), 3.00 3.05 (m, 1H, CHCH 2Ph), 4.17 4.35 (m, 3H, NCH CO 3), 4.93 (s, 2H, OCH 2Ph), 7.19 7.33 (m, 10H), 7.51 (d, J = 8.7 Hz, 1H, NH ), 8.14 (br s, 1H, NH ), 8.17 (br s, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 17.1, 18.2, 37.3, 47.4, 47.8, 55.9, 65.1, 126.1, 127.3, 127.5, 127.9, 128.2, 129.1, 136.9, 138.1, 155.8, 171.1, 171.7, 173.9. (5 S 8 S 11 S )-5-Benzyl-11-(hydroxymethyl)-8-m ethyl-3,6,9-trioxo-1-phenyl-2oxa-4,7,10-triazadodecan-12-oic acid (Z-Phe-Ala-Ser-OH, 5.4e): Colorless microcrystals (94%), mp 185.5 186.5 oC: [ ]25 D = 1.4o ( c 1.1, DMF); 1H NMR (DMSOd6) 1.26 (d, J = 7.0 Hz, 3H, CHCH 3), 2.68 2.76 (m, 1H, CHCH 2Ph),

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89 3.01 3.10 (m, 1H, CHCH 2Ph), 3.62 3.76 (m, 2H, CHCH 2OH), 4.24 4.34 (m, 2H, NCH CO 2), 4.26 4.48 (m, 1H, NCH CO), 4.92 4.94 (m, 2H, OCH 2Ph), 7.20 7.34 (m, 10H), 7.53 (d, J = 8.8 Hz, 1H, NH ), 8.04 (d, J = 7.7 Hz, 1H, NH ), 8.19 (d, J = 7.4 Hz, 1H, NH ), Two exchangeable protons (OH and CO2H ) are missing. 13C NMR (DMSOd6) 18.3, 37.3, 47.9, 54.5, 56.0, 61.2, 65.1, 126.1, 127.3, 127.6, 127.9, 128.2, 129.1, 136.9, 138.1, 155.8, 171.1, 171.7, 172.1. Anal. Calcd for C23H27N3O7: C, 60.38; H, 5.95; N, 9.18. Found: C, 59.84; H, 6.06; N, 9.10. (5 S 8 S 11 S )-8-Benzyl-11-(1 H -indol-3-ylmethyl)-5-methyl-3,6,9-trioxo-1phenyl-2-oxa-4,7,10-triaza dodecan-12-oi c acid (Z-Ala-Phe-Try-OH, 5.4f): Colorless microcrystals (95%), mp 203 204 oC: [ ]25 D = 6.9o ( c 0.6, DMF); 1H NMR (DMSOd6) 1.11 (d, J = 7.0 Hz, 3H, CHCH 3), 2.77 2.85 (m, 1H, CHCH 2Ar), 2.98 3.23 (m, 3H, CHCH 2Ar), 4.00 (t, J = 7.2 Hz, 1H, NCH CO), 4.45 4.60 (m, 2H, NCH CO 2), 4.97 (d, J = 12.5 Hz, 1H, OCH 2Ph), 5.03 (d, J = 12.5 Hz, 1H, OCH 2Ph), 6.98 (t, J = 7.1 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.18 7.21 (m, 6H), 7.33 7.41 (m, 7H), 7.53 (d, J = 7.7 Hz, 1H, NH ), 8.01 (d, J = 8.0 Hz, 1H, NH ), 8.32 (d, J = 5.6 Hz, 1H, NH ), 11.0 (br s, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 18.1, 27.0, 37.5, 50.1, 53.0, 53.6, 65.4, 109.5, 111.4, 118.1, 118.3, 120.8, 123.8, 126.1, 127.2, 127.7, 127.9, 128.3, 129.3, 136.0, 136.9, 137.6, 155.5, 170.9, 172.1, 173.0. HRMS m/z calcd for C19H27N3O6 557.2400 (M), found 557.2400. (5 S 8 S 14 S )-14-Isobutyl-5-benzyl-8-methyl -3,6,9,12-tetraoxo-1-phenyl-2-oxa4,7,10,13-tetraazapentadecan-15-oic acid (Z-Phe-Ala-Gly-Leu-OH, 5.5a): Colorless microcrystals (86%), mp 207.5 208.5 oC: [ ]25 D = 11.2o ( c 1.2, DMF); 1H NMR (DMSOd6) 0.83 (d, J = 6.3 Hz, 3H, CH(CH 3)2), 0.88 (d, J = 6.3 Hz, 3H, CH(CH 3)2),

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90 1.14 1.24 (m, 1H, CH2CH (CH3)2), 1.24 (d, J = 6.8 Hz, 2H, CH 2CH(CH 3)2), 1.48 1.66 (m, 3H, CHCH 3), 2.68 2.77 (m, 1H, CHCH 2Ph), 3.00 3.08 (m, 1H, CHCH 2Ph), 3.74 (d, J = 5.4 Hz, 2H, NCH 2CO), 4.20 4.36 (m, 3H, NCH CO 3), 4.94 (s, 2H, OCH 2Ph), 7.19 7.36 (m, 10H), 7.51 (d, J = 8.5 Hz, 1H, NH ), 8.02 (d, J = 8.0 Hz, 1H, NH ), 8.07 (t, J = 5.4 Hz, 1H, NH ), 8.22 (d, J = 6.9 Hz, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 18.1, 21.3, 22.7, 24.1, 37.3, 41.6, 48.3, 50.0, 55.9, 65.1, 126.1, 127.3, 127.6, 127.9, 128.2, 129.1, 136.9, 138.0, 155.8, 168.4, 171.2, 172.2, 173.8. Anal. Calcd for C28H36N4O7: C, 62.21; H, 6.71; N, 10.36. Found: C, 62.01; H, 6.78; N, 10.36. (5 S 8 S 14 S )-14-Isobutyl-8-benzyl-5-methyl -3,6,9,12-tetraoxo-1-phenyl-2-oxa4,7,10,13-tetraazapentadecan-15-oic acid (Z-Ala-Phe-Gly-Leu-OH, 5.5b): Colorless microcrystals (85%), mp 149 150 oC: [ ]25 D = 26.6o ( c 1.1, DMF); 1H NMR (DMSOd6) 0.84 (d, J = 6.3 Hz, 3H, CH(CH 3)2), 0.89 (d, J = 6.3 Hz, 3H, CH(CH 3)2), 1.12 (d, J = 7.0 Hz, 3H, CHCH 3), 1.49 1.65 (m, 3H, CH 2CH (CH3)2), 2.86 (dd, J = 13.1, 6.3 Hz, 1H, CHCH 2Ph), 3.04 (dd, J = 13.1, 4.0 Hz, 1H, CHCH 2Ph), 3.74 (d, J = 5.4 Hz, 2H, NCH 2CO), 3.96 4.06 (m, 1H, NCH CO), 4.25 (apparent q, J 7.4 Hz, 1H, NCH CO), 4.50 (br s, 1H, NCH CO), 4.98 (d, J = 12.4 Hz, 1H, OCH 2Ph), 5.04 (d, J = 12.4 Hz, 1H, OCH 2Ph), 7.14 7.28 (m, 5H), 7.30 7.42 (m, 6H, ArH and NH ), 7.96 (d, J = 7.9 Hz, 1H, NH ), 8.01 (d, J = 8.0 Hz, 1H, NH ), 8.23 (t, J = 5.4 Hz, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSOd6) 17.9, 21.3, 22.7, 24.1, 37.3, 41.6, 50.1, 53.7, 65.4, 126.1, 127.7, 127.9, 128.2, 129.1, 136.8, 137.6, 155.6, 168.4, 171.0, 172.2, 173.9. HRMS m/z calcd for C28H36N4O7 541.2662 (M), found 541.2662.

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91 5.4.3 Preparation of Boc-Protecte d dipeptide from Boc-Phe-Bt. Boc-Phe-Ala-OH was prepared by the pr ocedure used for preparation of 5.2a i This experiment showed that Boc-protected pe ptides can also be prepared in this method. (2 S )-2-({(2 S )-2-[( tert -Butoxycarbonyl)amino]-3-phenylpropanoyl}amino) propanoic acid (Boc-Phe-Ala-OH, 5.6): [97S1499] White powder (98%), mp 90 93 oC (lit.[97S1499] 96 oC): [ ]25 D = +9.8o ( c 2.0, MeOH) [lit.[97S1499] [ ]25 D = +11.62 ( c 2.00, MeOH)]; 1H NMR (DMSOd6) 1.22 (d, J = 7.2 Hz, 3H, CHCH 3), 1.30 (s, 9H, C(CH 3)3), 2.69 2.78 (m, 1H, CHCH 2Ph), 2.90 2.97 (m, 1H, CHCH 2Ph), 4.20 4.27 (m, 2H, NCH CO 2), 6.84 6.90 (m, 1H, NH), 7.19 7.29 (m, 5H ), 8.17 8.25 (m, 1H, NH ), One exchangeable proton is missing. 13C NMR (DMSO-d6) 17.5, 28.2, 37.9, 47.5, 55.4, 78.0, 126.2, 128.0, 129.3, 138.0, 155.1, 171.2, 174.0.

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92 CHAPTER 6 REGIOSELECTIVE C -ACYLATION OF PYRROLES, INDOLES, 2METHYLFURAN AND THIOPHENE USING N -ACYLBENZOTRIAZOLES 6.1 Introduction The Friedel-Crafts reaction is one of the most important reactions in synthetic organic chemistry to form a new C-C bond. Ge neral methods for the introduction of an acyl substituent at C-2 of pyrro les include reactions with acid chlorides, Vilsmeier-Haack reagents, [77Pyrroles] [ 70JCS(C)2563] seleno-esters,[ 80JACS860] thiol-esters [81TL4647] nitrilium salts, [85TL 4649] [96CHC44] and the use of -(dimethylamino)--pyrrolylacetonitrile [88J OC6115] or pyrrylmagnesium halide[76S281] precursors. Similar synthesis of 3-acylpyrro les requires the presence of st erically or electronically effective directing substituents on the nitrogen atom. [85TL5035] [90JOC6317] [85CJC896] The most common methods for th e preparation of 3-acylindoles include Friedel-Crafts [85JOC5451] [00OL1485] or Vilsmeier-Haack [70Indoles] [72CHC116] acylations; use of nitrilium, [96CHC44] [92SC2077] [65JOC2534] dialkoxy carbenium, [86LAC1621] or N -(-haloacyl)pyridinium [73T971] sa lts and the acylation of indole magnesium [69AHC43] [87TL 3741] or zinc [97SC2125] [9 0T6061] reagents. However, there are limitations asso ciated with the literature methods : selective direct Friedel-Crafts acylations of electron-rich heterocycles may require the presence of an electronwithdrawing substituent to avoid diacylati on, or mixtures of isomers. [70Indoles] [79TL2505] [87JOC2209] [81JOC8 39] Some heterocycles are se nsitive to acids such as

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93 HCl. Vilsmeier-Haack acylations ar e mostly limited to formamide and alkylcarboxamides. [72CHC116] For the Friedel-Crafts reaction of furans and thiophenes, some Friedel-Crafts reactions are complicated by the high reactiv ity of these heterocy clic rings under strong Lewis acid conditions. [68YakuZasshi997] Syntheses of acylthiophenes have been reported using carboxylic acid chlo rides and catalysis with AlCl3 [89JMC409] and SnCl4. [53JACS1115] Other previously reported met hods require special reagents and/or give low to moderate yields. [89JOM379] [99JCS(P1)2661] [81CL1135] [66JOC2149] [85JOC130] N -Acylbenzotriazoles have been previ ously reported by us as mild neutral N acylating agents for the prep aration of primary, seconda ry and tertiary amides, [00JOC8210] and specifically for formylation, [95S503] and trifluoroacylation. [97JOC726] We have also used N -acylbenzotriazoles for the O -acylation of aldehydes, [99JHC777] and for regioselective C -acylation of ketone enolates into -diketones. [00JOC3679] We now apply N -acylbenzotriazoles fo r mild regioselective C -acylations of pyrroles, indoles, 2-methylfuran and thiophe ne, including preparations of several acylpyrroles and -indoles not easily available by known methods. 6.2 Results and Discussion 6.2.1 Preparation of N -Acylbenzotriazoles. The present work concentrated on (i) pr eviously less studied arylcarbonyl or heterocyclocarbonyl examples as compared to the more common alkylcarbonyl derivatives and (ii) cases where the co rresponding acyl chlori des are unstable or inconvenient to prepare, for example, 4-diethylaminobenzoyl, indolyl-3-carboxyl or pyrrolyl-2-carboxyl derivatives. The starting N -acylbenzotriazoles 6.1a j with aryl or

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94 heterocyclic groups (R = 4-to lyl, 4-diethylaminophenyl, 4-nitr ophenyl, 2-furyl, 2-pyridyl, 2-indolyl, 2-pyrrolyl, 4-anisyl, benzyl, or 1-naphthyl) were prepared from the corresponding carboxylic acids by treatment with 1-(methylsulfonyl)benzotriazole following the earlier reported one-ste p general procedure. [00JOC3679] 6.2.2 Preparation of 2-Acylpyrroles. Regioselectivity in the acylation of py rroles is a function of the Lewis acid, [83JOC3214] reaction solvent, [01OL1005] a nd the acylating agent. [77Pyrroles] Accordingly, we studied the effect of these parameters to optimize the reaction conditions. Our initial results on the acylation of pyrrole using 1 H -1,2,3-benzotriazolyl(4methylphenyl)methanone ( 6.1a ) in the presence of ZnBr2 as the Lewis acid in dichloroethane gave low re gioselectivity: a 3:1 ratio of 2and 3-isomers (4methylphenyl)(1 H -pyrrol-2-yl)methanone and (4-methylphenyl)(1 H -pyrrol-3yl)methanone, respectively, was detected in the reaction mixture after 3 h by 1H NMR analysis of an aliquot. This ratio changed to 5:1 on contin uing the reaction for 12 h and the mixture of 2-, 3-isomers was obtained in a combined yield of 75%. No diacylation products were formed under these reaction condi tions. Formation of mixtures of 2and 3isomers in the acylation of pyrroles and th e interconversion of the isomers has been observed previously. [81JOC839] The use of TiCl4 as the Lewis acid proved to be beneficial: the acylati on of pyrrole using 1 H -1,2,3-benzotriazolyl(4methylphenyl)methanone ( 6.1a ) in dichloromethane produced exclusively the 2-isomer, (4-methylphenyl)(1 H -pyrrol-2-yl)methanone ( 6.3a ) in 87% yield in a short reaction time of 2 h. No formation of the 3-isomer was detected in the crude reaction mixture by 1H NMR. Thus, a set of appropriate reaction conditions was developed for the regioselective 2-acylation of pyrroles using N -acylbenzotriazoles.

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95 The above optimized reaction conditions were used for the synthe sis of a variety of 2-acylpyrroles. Reactions of unsubstituted pyrrole ( 6.2 ) with N -acylbenzotriazoles 6.1b g gave 2-acylpyrroles 6.3b g in 21 % yields. Similar results were obtained when N -methylpyrrole ( 6.4 ) was acylated under thes e reaction conditions: the corresponding 2-acylated N -methylpyrroles 6.5a g were produced in 51 % yields. Again, no formation of the 3-isomer was de tected in the crude reaction mixtures. Structures 6.3a g and 6.5a g are supported by their 1H and 13C NMR spectra and microanalysis or HRMS data. These results i llustrate the general applicability of this method for the preparation of 2-acyl pyrroles under mild conditions (25 oC) and short reaction times (2 h). In comparison, lite rature procedures for the known compounds usually require the preparati on of morpholides prior to acy lation, and may result in low regioselectivity, or require long reaction times (25 45 h) (Table 6-1). [77JOC4248] [82JHC1493] N X RCOBt TiCl4N X R O 6.2 : X = H 6.4 : X = Me + 6.1a-g CH2Cl225oC, 2 h 6.3 : X = H 6.5 : X = Me Scheme 6-1. 2-Acylation of pyrrole ( 6.2 ) and 1-methylpyrrole ( 6.4 ) using N Acylbenzotriazoles 6.1a g

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96 Table 6-1. Preparation of 2-acylated pyrrole ( 6.2 ) and 1-methylpyrrole ( 6.4 ) Reactant R Product (Yield %)a Previous work 6.2 + 6.1a 4-CH3C6H4 6.3a (87) [77JOC4248]b 6.2 + 6.1b 4-NO2C6H4 6.3b (60) [77JOC4248]b 6.2 + 6.1c 4-Et2NC6H4 6.3c (21) -6.2 + 6.1d 2-furyl 6.3d (91) [81TL4647]c 6.2 + 6.1e 2-pyridyl 6.3e (47) [90JAFC1260]d 6.2 + 6.1f 2-indolyl 6.3f (39) -6.2 + 6.1g 2-pyrrolyl 6.3g (38) [01JMC4509]e 6.4 + 6.1a 4-CH3C6H4 6.5a (90) [82JHC1493]f 6.4 + 6.1b 4-NO2C6H4 6.5b (74) [95CA286086]g 6.4 + 6.1c 4-Et2NC6H4 6.5c (51) -6.4 + 6.1d 2-furyl 6.5d (94) [82SC1121]h 6.4 + 6.1e 2-pyridyl 6.5e (54) [02CA102279]i 6.4 + 6.1f 2-indolyl 6.5f (56) -6.4 + 6.1g 2-pyrrolyl 6.5g (75) -aIsolated yield; bA = morpholide (freshly prepared from acid chloride and equimolar mixture of morpholine and triethylamine), 4CH3C6H4COA / POCl3, 20 h, 25 oC; c2-furoyl-S-2-pyridyl, MeMgCl (90%); d2-PyridylCOCl/AlCl3 (62%); e2,2 -Dipyrrylthioketone/KOH/H2O2 (76%);f4-CH3C6H4COA / POCl3, A = morpholide, 45 h, 25 oC (65%); g4NO2C6H4COCl ,18 h refluxing in toluene (73%); h N -methyl-2pyrrolylCOOH, (CF3CO)2O, phosphonic resin. (76%); i2-PyridylCOCl.HCl/ 3N NaOH (34%). 6.2.3 Preparation of 3-Acylpyrroles. Regioselective synthesis of 3-acyl-1 H -pyrroles have until recently been timeconsuming and problematic, requiring indir ect methods. [85S353] The most effective device has been the use of a bulky group on the nitrogen atom: t -butyldimethylsilyl (TBDMS) [85TL5035] and especi ally triisopropylsilyl (TIPS) [90JOC6317] groups allow easy 3-acylation of pyrroles as sterically effective, stable and easily cleavable Nsubstituents. Accordingly, following Tidwell and Muchowski, we have utilized the N triisopropylsilyl substituent for the preparation of 3-acylpyrroles using N acylbenzotriazoles as the acylati ng agents. Thus, TIPS-pyrrole ( 6.6 ) was prepared from the sodium salt of pyrrole and triisopropyl silyl chloride in 90% yield. [90JOC6317]

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97 Reaction of 6.6 with N -acylbenzotriazoles 6.1a g in the presence of TiCl4 produced exclusively the corr esponding 3-acylated N -triisopropylsilylpyrroles 6.7a g in 54 92% yields, except 6.7f which could not be isolated in a pure form. 3-Acylated N triisopropylsilylpyrroles 6.7a e and 6.7g are all novel compounds and have been fully characterized by 1H and 13C NMR spectroscopy and elemental analysis or high resolution mass spectrometry (Table 6-2). Fluoride ion induced desilylation [90JOC6317] of 3acylated N -triisopropylsilylpyrrole 6.7a occured readily at room temperature to give (4methylphenyl)(1 H -pyrrol-3-yl)methanone ( 6.8a ) in 98 % yield. N Si( i -Pr)3RCOBt TiCl4N Si( i -Pr)3O R ( 7a ) N H O R 6.6 + 6.1a-g CH2Cl225oC, 2 h 6.7 6.8 98% Bu4NF Scheme 6-2. 3-Acylation of TIPS-pyrrole ( 6.6 ) using N -acylbenzotriazoles 6.1a g Table 6-2. Preparation of 3-acylated TIPS-pyrrole ( 6.6 ). Reactants R Product (Yield %)a 6.6 + 6.1a 4-CH3C6H4 6.7a (92) 6.6 + 6.1b 4-NO2C6H4 6.7b (72) 6.6 + 6.1c 4-Et2NC6H4 6.7c (90) 6.6 + 6.1d 2-furyl 6.7d (89) 6.6 + 6.1e 2-pyridyl 6.7e (54) 6.6 + 6.1f 2-indolyl 6.7f ( -)b 6.6 + 6.1g 2-pyrrolyl 6.7g (78) aIsolated yield; bcould not be isolated in a pure form. 6.2.4 Preparation of 3-Acylindoles. The method developed above for the 2-acylation of pyrroles and N -methylpyrroles was then applied to the acyla tion of unsubstituted indole ( 6.9 ). 3-Acylindoles 6.10a g were obtained exclusively and in go od yields in reac tions of indole ( 6.9 ) with N -

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98 acylbenzotriazoles 6.1a g in the presence of TiCl4. Similarly, reactions of N methylindole ( 6.11 ) gave the corresponding acylated N -methylindoles 6.12a g in 27 92% yields (Table 6-3). Novel 3-acylate d indoles were characterized by their 1H and 13C NMR spectra and elemental analysis. Th e complications obser ved earlier in the acylation of unsubstituted indole, such as si multaneous formation of 1-acylated and/or 1,3-diacylated products were ab sent. [70Indoles] [72CHC116] Our method also removes the possibility of decomposition or self-polym erization of indole commonly observed due to the release of HC l when acyl chlorides are employed. [01OL1005] N X RCOBt TiCl4N X 6.9 : X = H 6.11 : X = Me + 6.1a-g CH2Cl225oC, 2 h 6.10 : X = H 6.12 : X = Me O R Scheme 6-3. 3-Acylation of indole ( 6.9 ) and 1-methylindole ( 6.11 ) using N Acylbenzotriazoles 6.1a g Table 6-3. Preparation of 3-acylated indole ( 6.9 ) and 1-methylindole ( 6.11 ). Reactants R Product (Yield %)a Previous work 6.9+6.1a 4-CH3C6H4 6.10a (88) [65CA10415b]b 6.9 + 6.1b 4-NO2C6H4 6.10b (66) [01CPB799]c 6.9 + 6.1c 4-Et2NC6H4 6.10c (43) -6.9 + 6.1d 2-furyl 6.10d (64) [00OL1485]d 6.9 + 6.1e 2-pyridyl 6.10e (73) [77JOC1213]e 6.9 + 6.1f 2-indolyl 6.10f (86) [02CA336939]f 6.9 + 6.1g 2-pyrrolyl 6.10g (15) -6.11 + 6.1a 4-CH3C6H4 6.12a (92) [97H347]g 6.11 + 6.1b 4-NO2C6H4 6.12b (74) -6.11 + 6.1c 4-Et2NC6H4 6.12c (79) -6.11 + 6.1d 2-furyl 6.12d (90) -6.11 + 6.1e 2-pyridyl 6.12e (70) -6.11 + 6.1f 2-indolyl 6.12f (27) -6.11 + 6.1g 2-pyrrolyl 6.12g (48) -

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99 Table 6-3 contd. aIsolated yield; bEtMgI/4-CH3C6H4COCl (65%); c4-NO2C6H4COCl/AlCl3 (34%); d2-furylCO2H/Et2AlCl (91%); eDDQ oxidation of 3-(2-pyridylmethyl)indole (48%); ffrom bis( N -phenylsulfonylindol-2-yl) derivativel; g4CH3C6H4COCl/AlCl3. 6.2.5 Synthesis of 2-Acyl-5-methylfurans The C-acylation proceeds with TiCl4 catalysis at 25 35 oC or by heating up to 90 oC in dichloroethane with ZnBr2. As shown in Table 6-4, when 4-methylphenyl6.1a 4diethylaminophenylacylbenzotriazole 6.1c or benzyl6.1i were used with ZnBr2, higher yields of the corresponding acylfurans 6.14a (84%), 6.14b (98%) and 6.14e (68%) were obtained as compared to using TiCl4. On the other hand, 2-pyridylacyl6.1e or 4methoxybenzoylbenzotriazole 6.1h or gave higher yields of 6.14c (54%) and 6.14d (81%) with TiCl4 as compared to using ZnBr2. 2-Acylfurans 6.14a-e were characterized by 1H and 13C NMR spectroscopy and also by elemental analysis for novel 6.14b O R-COBt O COR + Lewis acid 6.1a,c,e,h,i 6.14a-e 6.13 Scheme 6-4. C-Acylation of 2-methylfuran. Table 6-4. Preparation of 2-acylated 2-methylfuran. R Lewis acid temp. (oC) time (h) yielda (%) Previous work 4-CH3C6H4( 6.1a ) ZnBr2 90 3.5 6.14a (94)b [90JHC1131]c 4-Et2NC6H4( 6.1c ) ZnBr2 90 3.5 6.14b (98)d,e -2-pyridyl( 6.1e ) TiCl4 35 12 6.14c (54)f,g [70Indoles]h 4-MeOC6H4( 6.1h ) TiCl4 22 3.5 6.14d (81)i [90JHC1131]j C6H5CH2( 6.1i ) ZnBr2 90 12 6.14e (68) [88JOC6115]k aIsolated yield; b Yield with TiCl4 was 63%.; c4-CH3C6H4COCl (59%); d Yield with TiCl4 was 49 %; e mp 66-67 oC; fYield with ZnBr2 was 20%.; gmp 52-53 (lit. mp 52-53 oC); h 2Cyanopyridine/ n -BuLi; iYield with ZnBr2 was 75%; j4-MeOC6H4COCl/AlCl3 (40%); kCoupling of 4-methyl-2-furanyl acid chloride with C6H5CH2Br/Pd(Ph3)2Cl2 (81%).

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100 6.2.6 Synthesis of 2-Acylthiophenes Using the method developed for the prepara tion of 2-acylfurans, the preparation of 2-acylthiophenes was carried out. As shown in Table 6-5, 4-methylphenyl6.1a 4diethylaminophenyl6.1c benzyl6.1i or 1-naphthyl-acylbenzotriazole 6.1j in the presence of ZnBr2 gave the acylthiophenes 6.16a 6.16b 6.16d and 6.16e in 89, 58, 80, and 97% yields, respectively. In the presence of TiCl4, (4-methoxyphenyl)(2thienyl)methanone ( 6.16c ) was obtained in 78% yield (Table 6-5). S R-COBt S COR + Lewis acid 6.1a,c,h,i,j 6.16a-e 6.15 Scheme 6-5. C-Acylation of Thiophene Table 6-5. Preparation of 2-acylated thiophene. R Lewis acid temp. (oC) time (h) yielda (%) Previous work 4-CH3C6H4 ( 6.1a ) ZnBr2 90 3.5 6.16a (89)b [77JOC4248]c 4-Et2NC6H4 ( 6.1c ) ZnBr2 90 3.5 6.16b (58)d -4-MeO-C6H4 ( 6.1h ) TiCl4 22 3.5 6.16c (78) [92SC2077]e C6H5CH2 ( 6.1i ) ZnBr2 90 12 6.16d (80) [85TL5035]f 1-naphthyl ( 6.1j ) ZnBr2 90 24 6.16e (97) [86LAC1621]g aIsolated yield; bYield with TiCl4 was 65%; c4-CH3C6H4COCl/AlCl3 (59%); dYield with TiCl4 was 10%; e4-CH3C6H4COCl/AlCl3 (67%); fC6H5CH2Br/KF; gNaphthoyloxytrichlorosilane/AlCl3 (69%) 6.3 Conclusion In summary, we have introduced a conveni ent and general met hod for direct access to isomerically pure 2-acylpyrroles, 3-acylp yrroles or 3-acylindoles under mild reaction conditions using readily available N -acylbenzotriazoles.. In a ddition, this method offers a convenient route for the prepar ation of 2-acyl-5-methylfurans and 2-acylthiophenes. Use

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101 of N -acylbenzotriazoles 1c f g illustrate the preparation of acyl derivatives not easily available by other methods. 6.4 Experimental Section Melting points are uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 (with TMS for 1H and chloroform-d for 13C as the internal reference) unless specified otherwise. 6.4.1 General Procedure for the Preparation of N -Acylbenzotriazoles 6.1a g A mixture of aromatic or hete roaromatic acid (20 mmol), 1(methylsulfonyl)benzotriazole [00JOC8210] (20 mmol) and tr iethylamine (4.0 mL, 28 mmol) was dissolved in THF (120 mL) a nd the solution was heated under reflux overnight (except for 6.1f which required heating at 40 oC for 2 days). The solvent was evaporated under reduced pressu re and the residue was dissolved in chloroform. Aqueous work-up gave the crude product that was recrystallized to give pure N -acylbenzotriazoles 6.1a g 1 H -1,2,3-Benzotriazol-1-yl(4-me thylphenyl)methanone (6.1a): colorless prisms (from ethanol); mp 123 124 oC (Lit.[00JOC8210] mp 123 124 oC); yield, 91%. 1 H -1,2,3-Benzotriazol-1-yl(4-nitrophenyl)methanone (6.1b): yellow needles (from chloroform/ hexanes); mp 192 193 oC (Lit.[00JOC8210] mp 193 194 oC); yield, 81%. 1 H -1,2,3-Benzotriazol-1-yl[4-(diethyl amino)phenyl]methanone (6.1c): yellow needles (from ethanol/hexanes); mp 85 87 oC (Lit.[00JOC8210] mp 86 87 oC); yield, 87%.

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102 1 H -1,2,3-Benzotriazol-1-yl(2 -furyl)methanone (6.1d): yellow needles (from methanol); mp 171 173 oC (Lit.[92T7817] mp 172 174 oC); yield, 91%. 1 H -1,2,3-Benzotriazol-1-yl(2-py ridyl)methanone (6.1e): yellow microcrystals (from chloroform/hexanes); mp 95 97 oC (Lit.[92T7817] mp 97 100 oC); yield, 95%. 1 H -1,2,3-Benzotriazol-1-yl(1 H -indol-2-yl)methanone (6.1f): yellowish microcrystals (from chloroform); mp 215 216 oC; yield, 36%; 1H NMR (DMSO-d6) 7.13 7.22 (m, 1H), 7.36 7.44 (m, 1H), 7.59 7.71 (m, 2H), 7.78 7.90 (m, 2H), 8.04 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 12.5 (s, 1H); 13C NMR (DMSOd6) 112.9, 114.5, 114.5, 120.1, 120.8, 123.2, 126.4, 126.5, 126.8, 127.0, 130.7, 131.8, 138.4, 144.9, 158.4. Anal. Calcd for C15H10N4O: C, 68.69; H, 3.84; N, 21.36. Found: C, 68.63; H, 3.87; N, 21.36. 1 H -1,2,3-Benzotriazol-1-yl(1 H -pyrrol-2-yl)methanone (6.1g): yellow prisms (from methanol); mp 159 oC (Lit.[92T7817] mp 161 162 oC); yield, 86%. 1 H -1,2,3-Benzotriazol-1-yl(4 -methoxyphenyl)methanone (6.1h): colorless flakes (from ethanol); yield: 72%; m.p. 96 97 oC (Lit.[99JCS(P1)2661] mp 96 97 oC). 1 -(1H-1,2,3-Benzotriazol-1-yl)-2 -phenyl-1-ethanone (6.1i): white crystals (from CH2Cl2/hexanes); Yield: 84%; m.p. 65 66 oC (Lit.[99JCS(P1)2661] mp 66 67 oC). 1 H -1,2,3-Benzotriazol-1-yl(1-naphthyl)methanone (6.1j): white microcrystals (from benzene); Yield: 88%; m.p. 136 137 oC (Lit.[99JCS(P1)2661] mp 136 137 oC). 6.4.2 General Procedure for C -Acylation of Pyrroles ( 6.2 6.4 6.6 ) or Indoles ( 6.9 6.11 ) using N -Acylbenzotriazoles 6.1a g TiCl4 (1.0M in CH2Cl2, 4 mL, 4 mmol) was added to a mixture of pyrrole ( 6.2 6.4 6.6 ) or indole ( 6.9 6.11 ) (2.5 mmol) and N -acylbenzotriazole (2.0 mmol) in CH2Cl2

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103 (15mL), and the mixture was stirred for a sp ecified time and temperature (see Tables 61 3 for details). The reaction was quenched by adding MeOH (2 mL). The solvents were evaporated under reduced pressure a nd the residue was subjected to column chromatography on silica-gel using hexanes/ethyl acetate (2:1) as the eluent to give the C -acylated pyrroles 6.3a g 6.5a g 6.7a g or indoles 6.10a g 6.12a g in pure form. (4-Methylphenyl)(1 H -pyrrol-2-yl)methanone (6.3a): white needles (from ethanol); mp 116 117 oC (Lit.[77JOC4248] mp 118 119 oC); yield, 87%; 1H NMR 2.47 (s, 3H), 6.32 6.34 (m, 1H), 6.89 (s, 1H), 7.14 (d, J = 0.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 10.00 (br s, 1H); 13C NMR 21.6, 110.8, 119.1, 125.0, 129.0, 129.1, 131.2, 135.6, 142.4, 184.6. (4-Nitrophenyl)(1 H -pyrrol-2-yl)methanone (6.3b): brown microcrystals (from ethanol); mp 160 161 oC (Lit.[77JOC4248] mp 160 162 oC); yield, 60%; 1H NMR (DMSO-d6) 6.34 (s, 1H), 6.83 (s, 1H), 7.32 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 8.36 (d, J = 8.4 Hz, 2H), 12.2 (br s, 1H); 13C NMR (DMSO-d6) 110.8, 120.5, 123.6, 127.7, 129.8, 130.2, 144.0, 149.0, 181.8. [4-(Diethylamino)phenyl](1 H -pyrrol-2-yl)methanone (6.3c): yellowish plates (from chloroform/ hexanes); mp 100 101 oC; yield, 21%; 1H NMR 1.22 (t, J = 7.1 Hz, 6H), 3.44 (q, J = 7.1 Hz, 4H), 6.31 6.33 (m, 1H), 6.68 (d, J = 9.1 Hz, 2H), 6.91 (s, 1H), 7.07 (s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 9.70 (br s, 1H); 13C NMR 12.5, 44.5, 110.2, 110.4, 117.0, 123.4, 124.7, 131.5, 131.6, 150.7, 182.9. Anal. Calcd for C15H18N2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.71; H, 7.71; N, 11.69. 2-Furyl(1 H -pyrrol-2-yl)methanone (6.3d): [81TL4647] white needles (from chloroform/ hexanes); mp 69 oC; yield, 91%; 1H NMR 6.35 6.37 (m, 1H), 6.56 6.57

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104 (m, 1H), 7.15 (d, J = 0.9 Hz, 1H), 7.37 (d, J = 3.4 Hz, 1H), 7.41 (s, 1H), 7.64 (s, 1H), 10.4 (br s, 1H); 13C NMR 111.2, 112.1, 117.6, 118.4, 125.5, 130.0, 145.9, 152.7, 170.6. 2-Pyridinyl(1 H -pyrrol-2-yl)methanone (6.3e): reddish prisms (from chloroform/hexanes); mp 70 71 oC (Lit.[90JAFC1260] mp 65 67 oC); yield, 47%; 1H NMR 6.37 (dd, J = 6.1, 2.4 Hz, 1H), 7.12 (br s, 1H), 7.45 7.50 (m, 2H), 7.90 (td, J = 7.8, 1.4 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.70 (d, J = 4.4 Hz, 1H), 11.6 (br s, 1H); 13C NMR 111.0, 119.7, 124.0, 124.8, 126.2, 132.0, 137.2, 148.0, 155.3, 177.8 1 H -Indol-2-yl(1 H -pyrrol-2-yl)methanone (6.3f): brown microcrystals (from chloroform/ hexanes); 168 172 oC; yield, 39%; 1H NMR 6.37 6.40 (m, 1H), 7.13 7.18 (m, 2H), 7.28 7.34 (m, 2H), 7.42 7.46 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 9.68 (br s, 1H), 10.1 (br s, 1H); 13C NMR 109.2, 111.3, 112.1, 117.3, 120.8, 122.9, 125.0, 125.7, 127.9, 130.7, 134.2, 137.0, 174.8. HRMS calcd for C13H10N2O 210.0793, found 210.0793. Di(1 H -pyrrol-2-yl)methanone (6.3g): reddish microcrystals (from chloroform/hexanes); mp 150 152 oC (Lit.[01JMC4509] mp 157 159 oC); yield, 47%; 1H NMR 6.32 6.35 (m, 2H), 7.08 (s, 2H), 7.16 (s, 2H), 10.2 (br s, 2H); 13C NMR 110.9, 116.2, 124.2, 130.5, 173.1 (4-Methylphenyl)(1-methyl-1 H -pyrrol-2-yl)methanone (6.5a): [82JHC1493] colorless oil; yield, 90%; 1H NMR 2.42 (s, 3H), 4.02 (s, 3H), 6.14 (dd, J = 4.1, 2.4 Hz, 1H), 6.73 (dd, J = 4.4, 1.5 Hz, 1H), 6.88 6.93 (m, 1H), 7.25 (d, J = 7.9 Hz, 2H), 7.72 (d, 7.9 Hz, 2H); 13C NMR 21.5, 37.2, 107.9, 122.3, 128.6, 129.3, 130.5, 131.1, 137.1, 141.8, 185.9. (1-Methyl-1 H -pyrrol-2-yl)(4-nitroph enyl)methanone (6.5b): white needles (from ethanol); mp 147 148 oC (Lit [95CA286086] mp 148 150 oC); yield, 74%; 1H

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105 NMR 4.06 (s, 3H), 6.19 (dd, J = 3.6, 1.5 Hz, 1H), 6.69 (dd, J = 4.1, 1.3 Hz, 1H), 7.00 (br s, 1H), 7.92 (d, J = 8.7 Hz, 2H), 8.31 (d, J = 8.7 Hz, 2H); 13C NMR 37.5, 108.8, 123.3, 123.6, 129.8, 132.7, 145.3, 149.2, 183.6. [4-(Diethylamino)phenyl](1-methyl-1 H -pyrrol-2-yl)methanone (6.5c): yellowish prisms (from hexanes); mp 82 83 oC; yield, 51%; 1H NMR 1.21 (t, J = 7.0 Hz, 6H), 3.42 (q, J = 7.0 Hz, 4H), 3.97 (s, 3H), 6.13 6.15 (m, 1H), 6.65 (d, J = 8.8 Hz, 2H), 6.73 (dd, J = 3.8, 1.2 Hz, 1H), 6.84 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H); 13C NMR 12.5, 36.9, 44.5, 107.3, 110.0, 120.3, 126.2, 129.7, 131.0, 132.0, 150.5, 184.7. Anal. Calcd for C16H20N2O: C, 74.97; H, 7.86; N, 10.93. Found: C, 74.92; H, 8.21; N, 10.87. 2-Furyl(1-methyl-1 H -pyrrol-2-yl)methanone (6.5d): colorless oil; yield, 94%; 1H NMR 4.00 (s, 3H), 6.20 (dd, J = 4.1, 1.6 Hz, 1H), 6.54 (dd, J = 3.2, 1.4 Hz, 1H), 6.90 (s, 1H), 7.22 (d, J = 3.5 Hz, 1H), 7.29 (dd, J = 4.1, 1.5 Hz, 1H), 7.62 (s, 1H); 13C NMR 37.5, 108.4, 111.8, 117.5, 120.9, 129.3, 131.4, 145.6, 153.2, 171.9. Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.93; H, 5.15; N, 8.27. (1-Methyl-1 H -pyrrol-2-yl)(2-pyrid inyl)methanone (6.5e): [02CA102279] colorless oil; yield, 54%; 1H NMR 4.06 (s, 3H), 6.19 (dd, J = 4.1, 2.5 Hz, 1H), 6.94 (br s, 1H), 7.30 (dd, J = 4.1, 1.4 Hz, 1H), 7.40 7.44 (m, 1H), 7.83 (td, J = 7.6, 1.2 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H); 13C NMR 37.8, 108.6, 123.6, 124.7, 125.4, 129.6, 132.1, 136.7, 148.3, 156.7, 182.7 1 H -Indol-2-yl(1-methyl-1 H -pyrrol-2-yl)methanone (6.5f): reddish prisms (from ethanol); mp 129 oC; yield, 51%; 1H NMR 4.02 (s, 3H), 6.23 (dd, J = 4.1, 2.5 Hz, 1H), 6.94 (s, 1H), 7.13-7.26 (m, 3H), 7.33 (t, J = 7.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 9.57 (br s, 1H); 13C NMR 37.1, 108.5, 109.7, 111.9, 120.7,

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106 122.8, 125.5, 127.8, 130.3, 131.2, 135.6, 137.0, 176.4. Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.72; H, 5.54; N, 12.20. (1-Methyl-1 H -pyrrol-2-yl)(1 H -pyrrol-2-yl)methanone (6.5g): reddish prisms (from chloroform/ hexanes); mp 131 oC; yield, 75%; 1H NMR 3.97 (s, 3H), 6.18 (dd, J = 4.0, 2.4 Hz, 1H), 6.31 (dd, J = 6.1, 2.6 Hz, 1H), 6.87 (br s, 1H), 6.97 (br s, 1H), 7.05 7.07 (m, 2H), 9.90 (br s, 1H); 13C NMR 36.8, 108.1, 110.4, 116.8, 119.4, 123.8, 130.2, 130.3, 131.9, 174.8. Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C, 69.17; H, 5.79; N, 16.16. (4-Methylphenyl)[1-(triisopropylsilyl)-1 H -pyrrol-3-yl]methanone (6.7a): white prisms (from hexanes); mp 82 oC; yield, 92%; 1H NMR 1.16 (d, J = 7.4 Hz, 18H), 1.47 .55 (m, 3H), 2.48 (s, 3H), 6.84 6.85 (m, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.38 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H); 13C NMR 11.5, 17.6, 21.5, 112.4, 125.3, 126.9, 128.8, 129.2, 131.6, 137.5, 141.7, 190.7. Anal. Calcd for C21H31NOSi: C, 73.84; H, 9.15; N, 4.10. Found: C, 73.97; H, 5.79; N, 16.16. (4-Nitrophenyl)[1-(triisopropylsilyl)-1 H -pyrrol-3-yl]methanone (6.7b): yellow prisms (from hexanes); mp 131 oC; yield, 72%; 1H NMR 1.12 (d, J = 7.4 Hz, 18H), 1.43 1.51 (m, 3H), 6.76 6.77 (m, 1H), 6.81 6.83 (m, 1H), 7.33 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 8.32 (d, J = 8.7 Hz, 2H); 13C NMR 11.4, 17.6, 112.2, 123.4, 126.1, 126.2, 129.6, 132.3, 145.6, 149.3, 188.8. Anal. Calcd for C20H28N2O3Si: C, 64.48; H, 7.58; N, 7.52. Found: C, 64.84; H, 7.88; N, 7.46. [4-(Diethylamino)phenyl][1-(triisopropylsilyl)-1 H -pyrrol-3-yl]methanone (6.7c): yellow prisms (from hexanes); mp 103 oC; yield, 90%; 1H NMR 1.11 (d, J = 7.4 Hz, 18H), 1.20 (t, J = 7.1 Hz, 6H), 1.42 1.50 (m, 3H), 3.42 (q, J = 7.1 Hz, 4H),

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107 6.66 (d, J = 8.9 Hz, 2H), 6.76 6.80 (m, 2H), 7.33 (s, 1H), 7.87 (d, J = 8.9 Hz, 2H); 13C NMR 11.4, 12.5, 17.6, 44.3, 109.9, 112.4, 124.7, 126.6, 127.1, 130.3, 131.7, 150.2, 189.2. Anal. Calcd for C24H38N2OSi: C, 72.31; H, 9.61; N, 7.03. Found: C, 72.71; H, 10.08; N, 6.94. 2-Furyl[1-(triisopropylsilyl)-1 H -pyrrol-3-yl]methanone (6.7d): yellow prisms (from hexanes); mp 76 oC; yield, 89%; 1H NMR 1.13 (d, J = 7.5 Hz, 18H), 1.45 1.53 (m, 3H), 6.55 (dd, J = 4.5, 1.7 Hz, 1H), 6.77 6.79 (m, 1H), 6.99 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 3.0 Hz, 1H), 7.62 (d, J = 0.7 Hz, 1H), 7.73 (s, 1H); 13C NMR 11.5, 17.6, 111.8, 111.9, 116.9, 125.2, 125.8, 131.4, 145.2, 154.1, 176.6. Anal. Calcd for C18H27NO2Si: C, 68.09; H, 8.57; N, 4.41. Found: C, 68.52; H, 9.40; N, 4.34. 2-Pyridinyl[1-(triisopropylsilyl)-1 H -pyrrol-3-yl]methanone (6.7e): reddish plates (from hexanes); mp 82 oC; yield, 54%; 1H NMR 1.13 (d, J = 7.5 Hz, 18H), 1.44 1.55 (m, 3H), 6.76 6.78 (m, 1H), 7.08 7.09 (m, 1H), 7.39 7.44 (m, 1H), 7.84 (t, J = 7.8 Hz, 1H), 8.06 8.09 (m, 2H), 8.69 8.71 (m, 1H); 13C NMR 11.5, 17.7, 113.0, 123.6, 124.9, 125.6, 134.4, 136.7, 148.3, 156.5, 187.2. Anal. Calcd for C19H28N2OSi: C, 69.46; H, 8.59; N, 8.53. Found: C, 69.62; H, 8.90; N, 8.49. 1 H -Pyrrol-2-yl[1-(tri isopropylsilyl)-1 H -pyrrol-3-yl]methanone (6.7g): white needles (from hexanes); mp 115 oC; yield, 78%; 1H NMR 1.12 (d, J = 7.4 Hz, 18H), 1.42 1.55 (m, 3H), 6.30 6.33 (m, 1H), 6.78 6.80 (m, 1H), 6.89 (br s, 1H), 6.98 (br s, 1H), 7.06 (br s, 1H), 7.54 (s, 1H), 9.85 (br s, 1H); 13C NMR 11.5, 17.7, 110.3, 111.5, 115.6, 123.3, 125.2, 126.4, 129.9, 132.3, 179.0. Anal. Calcd for C18H28N2OSi : C, 68.30; H, 8.92; N, 8.85. Found: C, 68.53; H, 9.25; N, 8.82.

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108 (4-Methylphenyl)(1 H -pyrrol-3-yl)methanone (6.8a). To a solution of (4methylphenyl)[1-(triisopropylsilyl)-1 H -pyrrol-3-yl]methanone (7a) (0.100 g, 0.29 mmol) in dry THF (2mL), tetran -butylammonium fluoride ( 0.078 g, 0.30 mmol) was added at 25 oC. After 5 min. stirring, THF was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. Aqueous wo rk-up followed by recrystallization gave (4methylphenyl)(1 H -pyrrol-3-yl)methanone (8a) in 98 % yield as white microcrystals (from toluene/hexanes); mp 127 128 oC (Lit.[98JHC1345] mp 130 oC); 1H NMR 2.42 (s, 3H), 6.75 (s, 1H), 6.81 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 9.20 (br s, 1H); 13C NMR 21.5, 110.4, 119.4, 124.7, 125.5, 128.8, 129.1, 137.2, 142.0, 191.1. (1 H -Indol-3-yl(4-methylphenyl)methanone (6.10a): white microcrystals (from ethanol); mp 179 180oC (Lit.[65CA10415b] mp 179 81 oC); yield, 92%; 1H NMR 2.42 (s, 3H), 7.24 7.30 (m, 4H), 7.37 7.40 (m, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 8.39 8.42 (m, 1H), 9.61 (br s, 1H); 13C NMR 21.5, 111.6, 116.8, 122.2, 122.6, 123.8, 126.4, 128.9,, 129.0, 134.2, 136.5, 137.8, 141.9, 191.8. 1 H -Indol-3-yl(4-nitrophenyl)methanone (6.10b): [01CPB799] yellow microcrystals (from ethanol); mp 232 233 oC; yield, 66%; 1H NMR (DMSO-d6) 7.26 7.30 (m, 2H), 7.53 7.58 (m, 1H), 8.00 .02 (m, 3H), 8.24 (m, 1H), 8.37 (d, J = 8.0 Hz, 2H), 12.2 (br s, 1H); 13C NMR (DMSO-d6) 112.4. 114.8, 121.4, 122.4, 123.5, 123.7, 126.0, 129.6, 136.8, 136.9, 146.0, 148.7, 188.2. [4-(Diethylamino)phenyl](1 H -indol-3-yl)methanone (6.10c): yellow microcrystals (from ethanol); mp 249 250 oC; yield, 66%; 1H NMR 1.14 (t, J = 7.0 Hz, 6H), 3.42 (q, J = 7.0 Hz, 4H), 6.73 (d, J = 8.9 Hz, 2H), 7.16 7.25 (m, 2H), 7.50 (d, J =

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109 7.2 Hz, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 2.9 Hz, 1H), 8.20 (d, J = 7.0 Hz, 1H), 11.9 (s, 1H); 13C NMR 12.4, 43.8, 110.2, 112.0, 115.3, 121.2, 121.5, 122.6, 126.5, 126.7, 131.0, 133.4, 136.5, 149.9, 188.1. Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 77.86; H, 6.99; N, 9.53. 2-Furyl(1 H -indol-3-yl)methanone (6.10d): [00OL1485] white microcrystals (from ethanol); mp 181 182 oC; yield, 64%; 1H NMR 6.57 6.59 (m, 1H), 7.28 7.36 (m, 3H), 7.43 7.46 (m, 1H), 7.61 (s, 1H), 8.41 (s, 1H), 8.54 8.57 (m, 1H), 9.15 (br s, 1H); 13C NMR 111.4, 112.1, 115.6, 116.6, 122.6, 122.8, 123.9, 126.7, 133.2, 135.9, 145.0, 154.3, 176.8. 1 H -Indol-3-yl(2-pyridinyl)methanone (6.10e): white prisms (from benzene); mp 187 188 oC (Lit.77JOC1213] mp 189 190 oC); yield, 73%; 1H NMR (DMSO-d6) 7.24 7.28 (m, 2H), 7.53 7.56 (m, 1H), 7.60 7.64 (m, 1H), 8.02 8.04 (m, 2H), 8.40 8.42 (m, 1H), 8.76 (d, J = 7.7 Hz, 1H), 8.84 (s, 1H), 12.1 (br s, 1H); 13C NMR (DMSO-d6) 112.2, 113.7, 121.7, 122.1, 122.9, 123.0, 126.1, 126.9, 136.1, 137.4, 137.9, 148.5, 156.2, 186.1. 1 H -Indol-2-yl(1 H -indol-3-yl)methanone (6.10f): brownish microcrystals (from chloroform/ hexanes); mp 258 260 oC (Lit.[02CA336939] mp 260 261 oC); yield, 86%; 1H NMR (DMSOd6) 7.09 (t, J = 7.2 Hz, 1H), 7.12 7.29 (m, 3H), 7.36 (d, J = 1.4 Hz, 1H), 7.50 7.56 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 8.30 8.34 (m, 1H), 8.48 (d, J = 3.1 Hz, 1H), 11.8 (s, 1H), 12.1 (s, 1H); 13C NMR (DMSO-d6) 107.1, 112.1, 112.4, 114.9, 119.8, 121.4, 121.6, 122.1, 122.9, 124.2, 126.3, 127.2, 133.7, 136.2, 136.4, 137.0, 180.4. 1 H -Indol-3-yl(1 H -pyrrol-2-yl)methanone (6.10g): reddish plates (from chloroform/hexanes); mp 226 228 oC; yield, 15%; 1H NMR (DMSOd6) 6.24 (br s,

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110 1H), 7.02 (br s, 1H), 7.08 (br s, 1H), 7.09 7.25 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 8.25 8.27 (m, 2H), 11.8 (br s, 1H), 11.9 (br s, 1H); 13C NMR (DMSO-d6) 109.4, 111.9, 114.7, 114.8, 121.1, 121.4, 122.6, 123.6, 126.5, 131.9, 132.1, 136.3, 178.5. Anal. Calcd for C13H10N2O: C, 74.27; H, 4.79; N, 13.32. Found: C, 74.05; H, 4.66; N, 13.30. (1-Methyl-1 H -indol-3-yl)(4-methylphenyl)methanone (6.12a): [97H347] reddish needles (from ethanol); mp 139 140 oC; yield, 92%; 1H NMR 2.42 (s, 3H), 3.80 (s, 3H), 7.26 (d, J = 7.9 Hz, 2H), 7.31 7.33 (m, 3H), 7.50 (s, 1H), 7.71 (d, J = 7.9 Hz, 2H), 8.39 8.43 (m, 1H); 13C NMR 21.5, 33.4, 109.5, 115.6, 122.5, 122.6, 123.4, 127.2, 128.8, 128.9, 137.4, 137.5, 138.1, 141.5, 190.6. (1-Methyl-1 H -indol-3-yl)(4-nitrophenyl)methanone (6.12b): white prisms (from ethanol); mp 183 184 oC; yield, 15%; 1H NMR (DMSOd6) 3.88 (s, 3H), 7.30 7.38 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.6 Hz, 2H), 8.04 (s, 1H), 8.29 (d, J = 7.0 Hz, 1H), 8.35 (d, J = 8.6 Hz, 2H); 13C NMR (DMSO-d6) 33.3, 110.9, 113.6, 121.6, 122.7, 123.5, 123.6, 126.4, 129.5, 137.5, 140.4, 145.9, 148.6, 187.6. Anal. Calcd for C16H12N2O3: C, 68.56; H, 4.32; N, 9.99. Found: C, 68.37; H, 4.22; N, 9.82. [4-(Diethylamino)phenyl](1-methyl-1 H -indol-3-yl)methanone (6.12c): yellowish needles (from chloroform/hexanes); mp 115 116 oC; yield, 79%; 1H NMR 1.20 (t, J = 7.1 Hz, 6H), 3.41 (q, J = 7.1 Hz, 4H), 3.79 (s, 3H), 6.66 (d, J = 8.9 Hz, 2H), 7.27 7.33 (m, 3H), 7.55 (s, 1H), 7.82 (d, J = 8.9 Hz, 2H), 8.34 8.37 (m, 1H); 13C NMR 12.5, 33.3, 44.4, 109.3, 110.1, 115.8, 121.8, 122.6, 123.0, 127.2, 127.5, 131.4, 136.0, 137.2, 150.2, 189.1. Anal. Calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found: C, 78.18; H, 7.37; N, 9.13.

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111 2-Furyl(1-methyl-1 H -indol-3-yl)methanone (6.12d): yellowish prisms (from chloroform/ hexanes); mp 124 125 oC; yield, 90%; 1H NMR 3.80 (s, 3H), 6.54 (dd, J = 3.4, 1.6 Hz, 1H), 7.27 7.33 (m, 4H), 7.57 (s, 1H), 8.17 (s, 1H), 8.52 8.55 (m, 1H); 13C NMR 33.5, 109.5, 111.9, 113.8, 116.0, 122.6, 122.7, 123.4, 127.5, 136.9, 137.2, 144.6, 154.5, 176.0. Anal. Calcd for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found: C, 74.46; H, 4.83; N, 6.14. (1-Methyl-1 H -indol-3-yl)(2-pyridinyl)methanone (6.12e): reddish microcrystals (from ethanol); mp 107 108 oC; yield, 70%; 1H NMR 3.84 (s. 3H), 7.33 7.36 (m, 3H), 7.40 7.45 (m, 1H), 7.83 7.89 (m, 1H), 8.16 (d, J = 7.7 Hz, 1H), 8.60 8.63 (m, 1H), 8.68 8.71 (m, 2H); 13C NMR 33.5, 109.5, 113.7, 122.8, 122.9, 123.3, 123.5, 125.6, 128.1, 136.9, 137.0, 140.5, 148.0, 156.7, 186.2. Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C, 75.95; H, 5.01; N, 11.76. 1 H -Indol-2-yl(1-methyl-1 H -indol-3-yl)methanone (6.12f): yellowish microcrystals (from ethyl acetate/hexanes); mp 185 186 oC; yield, 27%; 1H NMR 3.88 (s, 3H), 7.13 7.20 (m, 2H), 7.29 7.37 (m, 4H), 7.51 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 8.49 8.52 (m, 1H), 9.85 (br s, 1H); 13C NMR 33.6, 107.9, 109.7, 112.2, 115.3, 120.6, 122.5, 122.6, 123.6, 125.2, 127.2, 127.8, 135.9, 136.2, 136.9, 137.4, 180.7. Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C, 78.67; H, 5.29; N, 10.02. (1-Methyl-1 H -indol-3-yl)(1 H -pyrrol-2-yl)methanone (6.12g): yellowish microcrystals (from chloroform/hexanes); mp 130 131 oC; yield, 48%; 1H NMR 3.87 (s, 3H), 6.31 6.34 (m, 1H), 6.95 (br s, 1H), 7.10 (br s, 1H), 7.28 7.37 (m, 3H), 7.86 (s, 1H), 8.40 8.43 (m, 1H), 10.0 (br s, 1H); 13C NMR 33.5, 109.5, 110.2, 114.9, 115.0,

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112 122.2, 122.5, 123.2, 123.3, 127.3, 132.4, 134.9, 137.3, 178.9. Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.87; H, 5.43; N, 12.37. 6.4.3 General Procedure for C-Acylation of 2-Methylfuran and Thiophene using N Acylbenzotriazoles 6.1a, c, e, h, i, j. To the mixture of 2-methylfuran or thiophene (2.5 mmol) and N-acylbenzotriazole (2.0 mmol) in CH2Cl2 (15mL), TiCl4 (1.0M in CH2Cl2, 4 mL, 4 mmol) or ZnBr2 (4 mmol) was added and the mixture was stirred for a specified time and temperature (see Tables 6-1~6-2 for details). The reaction was quenched by adding MeOH (2 mL). The solvents were evaporated under reduced pr essure and the residue was subjected to column chromatography on silica-gel using hexa nes/ethyl acetate (2:1) as the eluent to give the C-acylated furan 6.14a e or thiophene 6.16a f (5-Methyl-2-furyl)(4-methylphenyl)methanone (6.14a): yellow oil; yield, 94%; 1H NMR 2.43 (s, 3H), 2.45 (s, 3H), 6.20 (d, J = 3.3 Hz, 1H), 7.10 (d, J = 3.3 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H). 13C NMR 14.1, 21.6, 108.9, 122.4, 129.0, 129.2, 134.9, 142.9, 151.0, 158.4, 181.9. [4-(Diethylamino)phe nyl](5-methyl-2-fury l)methanone (6.14b): yellow needles; yield, 98%; mp 66 67 oC. 1H NMR 1.21 (t, J = 7.0 Hz, 6H), 2.44 (s, 3H), 3.43 (q, J = 7.0 Hz, 4H), 6.17 (d, J = 2.6 Hz, 1H), 6.67 (d, J = 9.1 Hz, 2H), 7.08 (d, J = 3.3 Hz, 1H), 7.96 (d, J = 9.1 Hz, 2H). 13C NMR 12.5, 14.1, 44.5, 108.4, 110.2, 120.3, 124.1, 131.9, 150.9, 151.8, 156.8, 180.2. Anal. Calcd for C16H19NO2 (Mr = 257.34): C 74.68, H 7.44, N 5.44 %; found: C 74.81, H 7.56, N 5.42 %. (5-Methyl-2-furyl)(2-pyridinyl)methanone (6.14c): brown solid; yield, 54%; m.p. 52 53 oC (Lit.[01JCS(P1)1853] m.p. 52 53 oC). 1H NMR 2.46 (s, 3H), 6.25 (d, J = 3.5 Hz, 1H), 7.44 7.48 (m, 1H), 7.83 7.89 (m, 1H), 7.97 (d, J = 3.5 Hz, 1H), 8.14 (d, J

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113 = 7.8 Hz, 1H), 8.70 (d, J = 4.2 Hz, 1H). 13C NMR 14.1, 109.4, 123.7, 126.3, 126.4, 136.8, 148.4, 150.0, 154.2, 159.2, 178.4. (4-Methoxyphenyl)(5-methyl-2-furyl)methanone (6.14d): yellow oil; yield, 81%. 1H NMR 2.45 (s, 3H), 3.88 (s, 3H), 6.20 (dd, J = 0.8, 3.4 Hz, 1H), 6.95 6.99 (m, 2H), 7.10 (d, J = 3.4 Hz, 1H), 7.95 7.99 (m, 2H). 13C NMR 14.1, 55.4, 108.8, 113.6, 121.8, 130.2, 131.4, 151.2, 158.0, 163.0, 180.8. 2-Phenyl-1-(5-methyl-2-fu ryl)-1-ethanone (6.14e): yellow oil; yield, 68%. 1H NMR 2.39 (s, 3H), 4.05 (s, 2H), 6.14 (d, J = 3.5 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 7.20 7.32 (m, 5H). 13C NMR 14.0, 45.1, 109.1, 120.0, 126.8, 128.6, 129.4, 134.5, 151.0, 158.0, 185.8. (4-Methylphenyl)(2-thienyl)methanone (6.16a): white solid; yield, 89%; m.p. 72 74 oC (Lit.[53JACS1115] m.p. 75 76 oC). 1H NMR 2.41 (s, 3H), 7.11 7.14 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 3.7 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H). 13C NMR 21.4, 127.7, 128.9, 129.2, 133.7, 134.3, 135.2, 142.9, 143.6, 187.7. [4-(Diethylamino)phenyl](2 -thienyl)methanone (6.16b): yellowish gummy solid; yield, 58%. 1H NMR 1.22 (t, J = 7.0, 6H), 3.44 (q, J = 7.0, 4H), 6.70 (d, J = 9.1 Hz, 2H), 7.13 (dd, J = 3.7, 4.8, 1H), 7.61 (dd, J = 0.9, 4.9, 1H), 7.65 (dd, J = 0.9, 3.7, 1H), 7.89 (d, J = 9.1, 2H). 13C NMR 12.5, 44.5, 110.1, 124.4, 127.4, 131.9, 132.2, 132.7, 144.5, 151.0, 185.8. Anal. Calcd. For C15H17NOS (Mr = 259.37): C 69.46, H 6.61, N 5.40 %; found: C 69.03, H 7.70, N 5.32 %. (4-Methoxyphenyl)(2-thienyl)methanone (6.16c): brown solid; yield, 78%; m.p. 73 74 oC (Lit.[73JACS4599] m.p. 73.4 74.0 oC). 1H NMR 3.89 (s, 3H), 6.98 (d, J = 8.9 Hz, 2H), 7.15 (dd, J = 3.9, 4.8 Hz, 1H), 7.63 7.64 (m, 1H), 7.68 (dd, J = 0.8, 4.9 Hz,

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114 1H), 7.91 (d, J = 8.9 Hz, 2H). 13C NMR 55.4, 113.6, 127.7, 130.6, 131.5, 133.4, 134.0, 143.7, 163.0, 186.8. 2-Phenyl-1-(2-thienyl)-1-ethanone (6.16d): gummy solid; yield, 80%. 1H NMR 4.16 (s, 2H), 7.08 (t, J = 4.4 Hz, 1H), 7.22 7.33 (m, 5H), 7.58 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 3.7 Hz, 1H). 13C NMR 46.2, 126.9, 128.1, 128.6, 129.3, 132.6, 134.0, 134.2, 143.7, 190.3. 1-Naphthyl(2-thienyl)methanone (6.16e): yellow oil[59ZOK3873]; yield, 97%. 1H NMR 7.10 (t, J = 3.8 Hz, 1H), 7.46 7.56 (m, 4H), 7.71 7.75 (m, 2H), 7.89 7.92 (m, 1H), 7.99 (d, J = 8.3 Hz, 1H), 8.15 8.18 (m, 1H). 13C NMR 124.2, 125.4, 126.5, 127.0, 127.2, 128.1, 128.3, 130.5, 131.2, 133.7, 135.0, 135.6, 136.1, 145.3, 189.6.

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115 LIST OF REFERENCES The reference citation system employed throughout this dissertation is from “ Comprehensive Heterocyclic Chemistry II ” (Vol.1); Pergamon Press: New York, 1996 (Eds. Katritzky, A. R.; Rees, C. W. and Scriven, E.). Each time a reference is cited, a numbe r-letter code is designated to the corresponding reference with the first two (o r four if the reference is before 1910’s) number indicating the year fo llowed by the letter code of th e journal and the page number in the end. Additional notes to this reference system are as follows: (i) Each reference code is followed by the conventional literatu re citation in the ACS style. (ii) Journals which are published in more than one part include in the abbreviation cited the appropriate part. (iii) Less commonly used books and journals ar e still abbreviated as using initials of the journal name. (iv) The list of the reference is arranged according to the designated code in the order of (a)year; (b)journal in alphabe tical order; (c)part number or volume number if it is included in the code; (d)page number. (v) Project number is used to code the unpublished results.

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116 [1898CB3248] Bischoff, C. A. Chem. Ber. 1898 31 3248. [1901CB1504] Scholtz, M.; Jaross, K. Chem. Ber. 1901 34 1504. [21JCS1537] Morgan, G. T.; Challenor, W. A. P. J. Chem. Soc. 1921 1537. [40JACS1960] Degnan, W. M.; Pope, F. B. J. Am. Chem. Soc. 1940 62 1960. [49JOC952] Donia, R. A.; Shotton, J. A. ; Bentz, L. O.; Smith, Jr., G. E. P. J. Org. Chem. 1949 14 952. [51JACS5553] Vaughan, J. R., Jr.; Osato, R. L. J. Am. Chem. Soc 1951 73 5553. [53JACS1115] Spurlock, J. J. J. Am. Chem. Soc 1953 75 1115. [55JACS6662] Joullie, M. M. J. Am. Chem. Soc. 1955 77 6662. [55JCS3010] Crombie, L.; Hooper, K. C. J. Chem. Soc. 1955 3010. [59LAC120] Jaenicke, L.; Brode, E. Liebigs Ann. Chem. 1959 624 120. [62JOC3315] Rahman, A.; Medrano, M. A.; Jeanneret, B. E. J. Org. Chem. 1962 27 3315. [63SpecActs509] Myquist, R. A. Spectrochim. Acta. 1963 19 509. [64JACS1839] Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J. Am. Chem. Soc 1964 86 1839. [65CA10415b] N. V. Koninklijke Pharmaceutische Fabrieken voorheen BrocadesStheeman & Pharmacia Belg. Pat. 637352, 1964; Chem. Abstr. 1965 62, 10415b. [65JOC2534] Powers, J. C. J. Org. Chem. 1965 30 2534. [66JOC2149] Mohrbacher, B. J.; Paragamian, V.; Carson, E. L.; Puma, B. M.; Rasmussen, C. R. J. Org. Chem 1966 31 2149. [67LAC227] Schnabel, von E.; Klostermeyer, H.; Dahlmans, J.; Zahn, H. Liebigs Ann. Chem 1967 707 227. [68JCS(C)1208] Pettit, G. R.; Gupta, S. K. J. Chem. Soc. (C) 1968 1208. [68TL3185] Rimpler, M; Schoberl, A. Tetrahedron Lett. 1968 3185. [68YakuZasshi997] Yohina, S.; Tanaka, A.; Yamamoto, K. Yakugaku Zasshi 1968 88 997.

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117 [69ABB311] Morihara, K.; Oka, T.; Tsuzuki, H. Arch. Biochem. Biophys 1969 135 311. [69AHC43] Heacock, R. A.; Kasparek, S. In Advances in Heterocyclic Chemistry ; Katritzky, A. R.; Boulton, A. J., Eds.; Academic Press: New York, 1969; pp 43. [70Indoles] Sundberg, R. J. In The Chemistry of Indoles; Academic Press: New York, 1970. [70JCS(C)2563] Candy, C. F.; Jone s, R. A.; Wright, P. H. J. Chem. Soc. C 1970 2563. [70JMC1212] Crank, G.; Harding, D. R. K.; Szinai, S. S. J. Med. Chem. 1970 13 1212. [70JMC1215] Crank, G.; Harding, D. R. K.; Szinai, S. S. J. Med. Chem. 1970 13 1215. [71CC733] Gilman, N. W. J. Chem. Soc., Chem. Commun. 1971 733. [72AJC1341] Beveridge, S.; Huppatz, J. L. Aust. J. Chem. 1972 25 1341. [72CHC116] Remers, W. A.; Brown, R. K. In The Chemistry of Heterocyclic Compounds ; Houlihan, W. J., Ed.; John Wiley: New York, 1972; Vol. 25, pp 116. [72JPS1235] Matin, S. B.; Rowland, M. J. Pharm. Sci. 1972 61 1235. [73SC185] Rubottom, G. M.; Pichardo, J. L. Synth. Commun. 1973 3 185. [73T971] Bergman, J.; Backvall, J.-E.; Lindstrom, J.-O. Tetrahedron 1973 29 971. [75JHC995] Sunjic, V.; Kajfez, F.; Blazev ic, N.; Oklobdzija, M.; Mildner, P. J. Heterocycl. Chem. 1975 12 995. [75TL1219] Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett 1975 1219. [76S281] Patterson, J. M. Synthesis 1976 281. [77CA155653q] Schwan, T. J. US Pat. 4,001,245, 1977; Chem. Abstr. 1977 86 155653q. [77JOC1213] Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977 42 1213. [77JOC4248] White, J.; McGillivray, G. J. Org. Chem. 1977 42 4248.

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118 [77LAC956] Kliegel, W.; Franckenstein, G.-H. Liebigs Ann. Chem. 1977 956. [77Pyrroles] Jones, R. A.; Bean, G. P. In The Chemistry of Pyrroles; Academic Press: New York, 1977; pp 151. [78JPS718] Schwan, T. J.; Goldenberg, M. M.; IIse, A. C. J. Pharm. Sci. 1978 67 718. [79CB2145] Kunz, H.; Buchholz, M. Chem. Ber 1979 112 2145. [79JMC1340] Schaaf, T. K.; Hess, H. J. Med. Chem. 1979 22 1340. [79JOC4536] Houghten, R. A.; Simpson, R. A.; Hanson, R. N.; Rapoport, H. J. Org. Chem. 1979 44 4536. [79Peptide] Gross, M.; Meienhofer, J. The Peptides ; Academic Press: New York, 1979. [79TL2505] Belanger, P. Tetrahedron Lett. 1979 2505. [80JACS860] Kozikowski, A. P.; Ames, A. J. Am. Chem. Soc. 1980 102 860. [80JACS4537] Hegarty, A. F.; McCarthy, D. G. J. Am. Chem. Soc 1980 102 4537. [80JOC3640] Glass, R. S.; Duchek, J. R.; Prabhu, U. D. G.; Setzer, W. N.; Wilson, G. S. J. Org. Chem. 1980 45 3640. [80JOM141] Gasparini, J. P.; Gassend R.; Maire, J. C.; Elguero, J. J. Organomet. Chem. 1980 188 141. [81CL1135] Sato, T.; Naruse, K. ; Enokiya, M.; Fujisawa, T. Chem. Lett 1981 1135. [81JOC839] Carson, J. R.; Davis, N. M. J. Org. Chem. 1981 46 839. [81TL4647] Nicolaou, K. C.; Claremon, D. A.; Papahatjis, D. P. Tetrahedron Lett. 1981 22 4647. [82CC1282] Soai, K.; Komiya, K.; Shigem atsu, Y.; Hasegawa, H.; Ookawa, A. J. Chem. Soc., Chem. Commun. 1982 1282. [82JHC1493] Artico, M.; Corelli, F.; Massa, S.; Stefancich, G. J. Heterocycl. Chem. 1982 19 1493. [82SC1121] Fayed, S.; Delmas, M.; Gaset, A. Synth. Commun. 1982 12 1121. [82TL3831] Wasserman, H. H.; Lu, T.-J. Tetrahedron Lett. 1982 23 3831.

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119 [83JOC3214] Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org. Chem. 1983 48 3214. [83LAC1712] Waldmann, H.; Kunz, H. Liebigs Ann. Chem 1983 1712. [84BCS(Jpn)3203] Harada, K.; Munegumi, T. Bull. Chem. Soc. Jpn. 1984 57 3203. [84CL1603] Yamamoto, K.; Rehman, S. U. Chem. Lett. 1984 1603. [84JCS(P1)2439] Nagao, Y.; Miyasaka, T.; Seno, K.; Fujita, E.; Shibata, D.; Doi, E. J. Chem. Soc. Perkin trans 1 1984 2439. [84S572] Dourtoglou, V.; Gross, B. Synthesis 1984 572. [85CJC896] Anderson, H. J.; Loader, C. E.; Xu, R. X.; Le, N.; Gogan, N. J.; McDonald, R.; Edwards, L. G. Can. J. Chem. 1985 63 896. [85JCS(P1)769] Soai, K.; Hasegawa, H. J. Chem. Soc., Perkin Trans. 1 1985 769. [85JOC130] Ricci, A.; Degl’Innocenti, A.; Chimichi, S.; Fiorenza, M.; Rossini, G. J. Org. Chem 1985 50 130. [85JOC5451] Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985 50 5451. [85S353] Anderson, H. J.; Loader, C. E. Synthesis 1985 353. [85T611] Polonski, T. Tetrahedron 1985 41 611. [85TL4649] Eyley, S. C.; Giles, R. G.; Heaney, H. Tetrahedron Lett. 1985 26 4649. [85TL5035] Simchen, G.; Majchrzak, M. W. Tetrahedron Lett. 1985 26 5035. [86AG(Int)565] Matsumoto, K.; Hashimoto, S.; Otani, S. Angew. Chem. Int. Ed. Engl. 1986 25 565. [86CL737] Tani, K.; Tanigawa E.; Tatsuno, Y.; Otsuka, S. Chem. Lett. 1986 737. [86JOC2228] Bates, H. A.; Condulis, N.; Stein, N. L. J. Org. Chem. 1986 51 2228. [86LAC1621] Pindur, U.; Flo, C.; Akgun, E.; Tunali, M. Liebigs Ann. Chem. 1986 1621. [86S657] Lambert, J. B.; Huseland, D. E.; Wang, G.-T. Synthesis 1986 657. [86TL1921] Shin, J. M.; Kim, Y. H. Tetrahedron Lett. 1986 27 1921.

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120 [87CL2021] Kawanami, Y.; Fujita, I.; Ta niguchi, Y.; Katsuki, T.; Yamaguchi, M. Chem. Lett. 1987 2021. [87JOC2209] Harsanyi, M. C.; Norris, R. K. J. Org. Chem. 1987 52 2209. [87JOC5288] Davis, F. A.; Ulatowski, T. G.; Haque, M. S. J. Org. Chem. 1987 52 5288. [87S236] Schmidt, U.; Utz, R.; Lieberkn echt, A.; Griesser, H.; Potzolli, B.; Bahr, J.; Wagner, K.; Fischer, P. Synthesis 1987 236. [87TL3741] Bergman, J.; Venemalm, L. Tetrahedron Lett. 1987 28 3741. [88JCS(P1)1939] Harvey, I. W.; McFarlane, M. D.; Moody, D. J.; Smith, D. M. J. Chem. Soc., Perkin Trans. 1 1988 1939. [88JHC555] Beck, J. R.; Lynch, M. P.; Wright, F. L. J. Heterocyclic Chem. 1988 25 555. [88JHC1265] Letellier, S.; Fleury, B.; Terreilles, J.; Previero, A. J. Heterocycl. Chem 1988 25 1265. [88JOC685] Doedens, R. J.; Meier, G. P.; Overman, L. E. J. Org. Chem. 1988 53 685. [88JOC6115] Bray, B. L.; Muchowski, J. M. J. Org. Chem. 1988 53 6115. [88TL3675] Hatat, C.; Karim, A.; Kokel, N.; Mortreux, A.; Petit, F. Tetrahedron Lett. 1988 29 3675. [89CCC784] Ovchinnikov, M. V.; Be spalova, Z. D.; Molokoedov, A. S.; Revenko, I. V.; Sepetov, N. F.; Isakova, O. L.; Titov, M. I. Collect. Czech. Chem. Commun 1989 54 784. [89JCS(P1)225] Katritzky, A. R.; Yannakopoul ou, K.; Lue, P.; Rasala, D.; Urogdi, L. J. Chem. Soc., Perkin Trans. 1 1989 225. [89JHC901] Hashida, Y.; Imai, A.; Sekiguchi, S. J. Heterocycl. Chem. 1989, 26 901. [89JMC409] Kruse, L. I.; Ladd, D. L.; Ha rrsch, P. B.; McCabe, F. L.; Mong, S.M.; Faucette, L.; Johnson, R. J. Med. Chem 1989 32 409. [89JOM379] Bumagin, N. A.; More, P. G.; Beletskaya, I. P. J. Organomet. Chem 1989 365 379. [89Prac.Org.Chem.] Vogel, A. Practical Organic Chemistry Langman Scientific & Technical and Wiley: New York, 1989, pp 708-710.

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121 [89S37] Chen, S.-T.; Wu, S.-H.; Wang, K.-T. Synthesis 1989 37. [89TL2771] Cossy, J.; Pale-Grosdemange, C. Tetrahedron Lett. 1989 30 2771. [90BCS(Jpn)1894] Fujisawa, T.; Ukaji, Y.; Funabora, M.; Yamashita, M.; Sato, T. Bull. Chem. Soc. Jpn. 1990 63 1894. [90CC1321] Solodin, I.; Goldberg, Y.; Zelcans, G.; Lukevics, E. J. Chem. Soc., Chem. Commun. 1990 1321. [90CCC540] Niopas, I.; Smail, G. A. Collect. Czech. Chem. Commun. 1990 55 540. [90CJC446] Katritzky, A. R.; Rachwal, S.; Wu. J. Can. J. Chem. 1990 68 446. [90JACS9651] Carpino, L. A.; Sadat-Aal aee, D.; Chao, H. G.; DeSelms, R. H. J. Am. Chem. Soc 1990 112 9651. [90JAFC1260] Rao, K. V.; Reddy, G. C. J. Agric. Food Chem. 1990 38 1260. [90JCS(P1)541] Katritzky, A. R.; Pilarski, B.; Urogdi, L. J. Chem. Soc., Perkin Trans. 1 1990 541. [90JHC1131] Massa, S.; Di Santo, R.; Artico, M. J. Heterocycl. Chem. 1990 27 1131. [90JOC1772] Parrinello, G.; Mlhaupt, R. J. Org. Chem. 1990 55 1772. [90JOC6317] Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.; Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990 55 6317. [90T5665] Sharma, G. V. M.; Shekharam, T.; Upender, V. Tetrahedron 1990 46 5665. [90T6061] Bergman, J.; Venemalm, L. Tetrahedron 1990 46 6061. [90TL205] Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett 1990 31 205. [91CSP] Jones, J. The Chemical Synthesis of Peptides ; Clarendon Press: Oxford, UK, 1991. [91JCS(P1)119] Niopas, I.; Smail, G. A. J. Chem. Soc., Perkin Trans. 1 1991 119. [91JOC2611] Carpino, L. A.; Mansour, E.-S. M. E.; Sadat-Aalaee, D. J. Org. Chem 1991 56 2611. [91LAC165] Braun, P.; Waldmann, H.; Vogt, W.; Kunz, H. Liebigs Ann. Chem 1991 165.

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122 [91S35] Iwamura, M.; Hodota, C.; Ishibashi, M. Synlett 1991 35. [91T2683] Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron 1991 47 2683. [92Adv.Org.Chem] March, J. Advanced Organic Chemistry Fourth Edition. John Wiley & Sons: New York, 1992, pp 416-425. [92SC2077] Allen, M. S.; Hamaker, L. K.; La Loggia, A. J.; Cook, J. M. Synth. Commun. 1992 22 2077. [92T7817] Katritzky, A. R.; Shobana, N.; Pe rnak, J.; Afridi, A. S.; Fan, W. Q. Tetrahedron 1992 48 7817. [92T10233] Raju, N.; Ramalingam, K.; Nowotnik, D. P. Tetrahedron 1992 48 10233. [93JHC381] Katritzky, A. R.; Lan, X.; Zhang, Z. J. Heterocycl. Chem. 1993 30 381. [93PR913] Rogers, J. A.; Choi, Y. W. Pharm. Res. 1993 10 913. [93SC2919] Rivera, A.; Gallo, G. I. ; Gayon, M. E.; Joseph-Nathan, P. Synth. Commun. 1993 23 2921. [94EJP223] Sakuta, H.; Okamoto, K. Eur. J. Pharm. 1994 259 223. [94JOC7503] Gibson, F. S.; Park, M. S.; Rapoport, H. J. Org. Chem 1994 59 7503. [94T11113] Strunz, G. M.; Finlay, H. Tetrahedron 1994 50 11113. [95CA286086] Carmosin, R. J.; Carson, J. R.; Pitis, P. US Pat. 5418236, 1995; Chem. Abstr. 1995 123, 286086. [95CR2115] Wipf, P. Chem. Rev. 1995 95 2115. [95JACS7379] Jung, M. E.; D’Amico D. C. J. Am. Chem. Soc. 1995 117 7379. [95S503] Katritzky, A. R.; Chang, H.-X.; Yang, B. Synthesis 1995 503. [95SC3701] Benedetti-Doctorovich, V. ; Huang, F.-Y.; Lambropoulos, J.; Burgess, E. M.; Zalkow, L. H. Synth. Commun. 1995 25 3701. [96BP1051] Carmona, A. K.; Juliano, L. Biochem. Pharmaco. 1996 51 1051. [96CHC44] Black, D. St. C. In Comprehensive Heterocyclic Chemistry ; Katritzky, A. R.; Rees, C. W.; Sc riven, E. F. V., Eds.; Pergamon Press: New York, 1996; Vol. 2, pp 44.

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123 [96EJP273] Olmos, G.; Ribera, J.; Garc i a-Sevilla, J. A. Eur. J. Pharm. 1996 310 273. [96HAC365] Katritzky, A. R.; Soleiman, M.; Yang, B. Heteroatom Chem. 1996 7 365. [96JMC3483] Sharma, V.; Cranksha w, C. L.; Piwnica-Worms, D. J. Med. Chem. 1996 39 3483. [96NN1459] Dineva, M. A.; Petkov, D. D. Nucleosides Nucleotides 1996 15 1459. [96PCJ690] Shchegel’skii, V. F.; Sokol ov, V. V.; Shataeva, G. A.; Fetisov, V. I. Pharm. Chem. J. (Engl. Transl.) 1996 30 690; Khim. Farm. Zh. (Russian) 1996 30 26. [96TL937] Dressman, B. A.; Spangle, L. A.; Kaldor S. W. Tetrahedron Lett. 1996 37 937. [97CR2243] Humphrey, J. M.; Chamberlin, A. R Chem. Rev 1997 97 2243. [97H347] Wang, S.-F.; Chuang, C.-P. Heterocycles 1997 45 347. [97Janti100] Barrett, D.; Terasawa, T.; Okuda, S.; Kawabata, K.; Yasuda, N. J. Antibiot. 1997 50 100. [97JOC726] Katritzky, A. R.; Yang, B.; Semenzin, D. J. Org. Chem. 1997 62 726. [97S1499] Gewehr, M.; Kunz, H. Synthesis 1997 1499. [97SC361] Cai, M.-Z.; Song, C.-S.; Huang, X. Synth. Commun. 1997 27 361. [97SC2125] Yang, C.; Patel, H. H.; Ku, Y.-Y.; Shah, R.; Sawick, D. Synth. Commun. 1997 27 2125. [98Azolides] Staab, H. A.; Bauer, H.; Schneider, K. M. Azolides in Organic Synthesis and Biochemistry WILEY-VCH: Germany, 1998, pp129-205. [98B13893] Sage, C. R.; Michelitsch, M. D.; Stout, T. J.; Biermann, D.; Nissen, R.; Finer-Moore, J.; Stroud, R. M. Biochemistry 1998 37 13893. [98CJC549] He, H.-Y.; Qu, Y.-L.; Zhao, C.-X. Chin. J. Chem. 1998 16 549. [98CR409] Katritzky, A. R.; Lan, X.; Yang, J.; Denisko, O. V. Chem. Rev 1998 98 409. [98CR763] Fletcher, M. D.; Campbell, M. M. Chem. Rev 1998 98 763.

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124 [98JCR(M)701] Fetter, J.; Bertha, F.; Vasarhelyi, H.; Kajtar-Peredy, M. J. Chem. Res. (M) 1998 701. [98S153] Katritzky, A. R.; Levell, J. R.; Pleynet, D. P. M. Synthesis 1998 153. [98SC1625] Orelli, L. R.; Salerno, A. ; Hedrera, M. E.; Perillo, I. A. Synth. Commun. 1998 28 1625. [99CA52421k] Sierra, M. L.; Pianetti, P. M. C. PCT Int. Appl. WO 98 56,790, 1998; Chem. Abstr. 1999 130 52421k. [99CA184961s] Kukkola, P. J.; Robinson, L. A.; Sakaki, J.; Nakajima, M. PCT Int. Appl. WO 99 42,443, 1999; Chem. Abstr. 1999 131 184961s. [99JCS(P1)2661] Kang, S.-K.; Ryu, H.-C.; Lee, S.-W. J. Chem. Soc., Perkin Trans. 1999 1 2661. [99JHC777] Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl. Chem. 1999 36 777. [99TA255] Katritzky, A. R.; CoboDomingo, J.; Yang, B.; Steel, P. J. Tetrahedron: Asymmetry 1999 10 255. [99TL2501] Wang, W.; McMurray, J. S. Tetrahedron Lett. 1999 40 2501. [00CPB729] Chang-Fong, J.; Benamour, K.; Szymonski, B.; Thomasson, F.; Morand, J.-M.; Cussac, M. Chem. Pharm. Bull. 2000 48 729. [00HCA2607] Wasserman, H. H.; Chen, J.-H.; Xia, M. Helv. Chim. Acta 2000 83 2607. [00JHC57] Salerno, A.; Hedrera, M. E.; D Accorso, N. B.; Alho, M. M.; Perillo, I. A. J. Heterocycl. Chem. 2000 37 57. [00JOC3679] Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65 3679. [00JOC3683] Katritzky, A. R.; Qiu, G.; He, H.-Y.; Yang, B. J. Org. Chem. 2000 65 3683. [00JOC4364] Katritzky, A. R.; Meht a, S.; He, H.-Y.; Cui, X. J. Org. Chem. 2000 65 4364. [00JOC8210] Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem 2000 65 8210. [00OL1485] Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000 2 1485.

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125 [00TL37] Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000 41 37. [01CPB799] Sawada, K.; Okada, S.; Kuroda, A.; Watanabe, S.; Sawada, Y.; Tanaka, H. Chem. Pharm. Bull. 2001 49 799. [01JCS(P1)1767] Katritzky, A. R.; Xu, Y.-J.; He, H.-Y.; Steel, P. J. J. Chem. Soc., Perkin Trans. 1 2001 1767. [01JMC4509] Shi, D.-F.; Wheelhouse, R. T.; Sun, D.; Hurley, L. H. J. Med. Chem. 2001 44 4509. [01JOC148] Katritzky, A. R. ; Mehta, S.; He, H.-Y. J. Org. Chem. 2001 66 148. [01OL1005] Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001 3 1005. [01OL2793] Carpino, L. A.; Ferrer, F. J Org. Lett 2001 3 2793. [01S1811] Kienhfer, A. Synlett 2001 1811. [01SPP] Goodman, M.; Felix, A. ; Moroder, L.; Toniolo, C. Synthesis of Peptides and Peptidomimetics (E22a and E22b): New York, 2001. [01TA2427] Katritzky, A. R.; He, H.-Y.; Jiang, R.; Long, Q. Tetrahedron: Asymmetry 2001 12 2427. [02ARK(viii)134] Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.; Akhmedov, N. G. Arkivoc 2002 viii 134. [02CA102279] Carson, J. R.; Pitis, P. M. PCT Int. Appl. 0202521, 2002; Chem. Abstr. 2002 136 102279. [02CA336939] Mahboobi, S.; Kuhr, S.; Pongratz, H.; Popp, A.; Hufsky, H.; Bohmer, F.; Teller, S.; Uecker, A.; Beckers, T. US Pat. 6407102, 2002; Chem. Abstr. 2002 131, 336939. [02JOC3109] Katritzky, A. R.; Suzuki, K.; He, H.-Y. J. Org. Chem. 2002 67 3109. [02OL4005] Palomo, C.; Palomo, A. L. ; Palomo, F.; Mielgo, A. Org. Lett. 2002 4 4005. [02T7851] Konda-Yamada, Y.; Okada, C.; Yoshida, K.; Umeda, Y.; Arima, S.; Sato, N.; Kai, T.; Takayanagi, H.; Harigaya, Y. Tetrahedron 2002 58, 7851.

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126 [02TA933] Katritzky, A. R.; He, H.-Y.; Verma, A. K. Tetrahedron: Asymmetry 2002 13 933. [02TL7717] Gagnon, P.; Huang, X.; Therrien, E.; Keillor, J. W. Tetrahedron Lett 2002 43 7717. [03JOC4932] Katritzky, A. R.; A bdel-Fattah, A. A. A.; Wang, M. J. Org. Chem 2003 68 493. [03JOC5720] Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org. Chem 2003 68 5720. [03OL2793] Baek, B.-H.; Lee, M.-R.; Kim, K.-Y.; Cho, U.-I.; Boo, D. W.; Shin, I. Org. Lett 2003 5 971. [03S2795] Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003 2795. [04CCA175] Katritzky, A. R.; Suzuki, K.; Singh, S. K. Croat. Chem. Acta 2004 77 175.

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127 BIOGRAPHICAL SKETCH Kazuyuki Suzuki was born in November 25, 1973, in Fukushima, Japan. He worked under the supervision of professor Yo shito Takeuchi in Kanagawa University, where he received his Bachelor of Scien ce in March 1993 and Master of Science in March 1997. He joined the University of Florida Center of He terocyclic Compounds supervised by Professor Alan R. Katritz ky in August 2000, and started his Ph.D program in the Chemistry Department of the Un iversity of Florida in January 2001.


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Title: Benzotriazole-Mediated Syntheses of Heterocyclic Compounds and Acylations Utilizing N-Acylbenzotriazoles
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Title: Benzotriazole-Mediated Syntheses of Heterocyclic Compounds and Acylations Utilizing N-Acylbenzotriazoles
Physical Description: Mixed Material
Copyright Date: 2008

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BENZOTRIAZOLE-MEDIATED SYNTHESES OF HETEROCYCLIC COMPOUNDS
AND ACYLATIONS UTILIZING N-ACYLBENZOTRIAZOLES















By

KAZUYUKI SUZUKI


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

UNIVERSITY OF FLORIDA


2004

































Copyright 2004

by

Kazuyuki Suzuki

































This document is dedicated to my family, my father Toshio Suzuki, my mother Mitsue
Suzuki, .my sister Hiroko Inamura, and my brother Shin-ichi Suzuki.















ACKNOWLEDGMENTS

Things that I have heard, things that I have seen, things that I have thought are my

valuable experience. Things that I have suffered are my treasures. They will guide me to

a certain conclusion. Here, I sincerely give my acknowledgments to those who helped me

pursue my Ph.D.

My deepest gratitude goes to my supervisor, Professor Alan R. Katritzky, and I

greatly thank my committee members, Dr. William R. Dolbier, Dr. Ion Ghiviriga, Dr.

Vaneica Young, and Dr. Hartmut Derendorf.

I cannot thank my wife, Yoko Suzuki, enough for her support and patience. I give

special thanks to my parents for supporting and letting me do whatever I believe is right.

Finally, I thank my friends, who always inspire me.
















TABLE OF CONTENTS


page

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

LIST OF TABLES .............. .......... .. ....... ........... ....... ix

LIST OF SCHEMES ............................................... ......... ....... x

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

CHAPTER

1 GENERAL INTRODUCTION ............................................................................. 1

2 CONVENIENT SYNTHESIS OF UNSYMMETRICAL IMIDAZOLIDINES ..........4

2 .1 In tro d u ctio n ........... ................................................................ .. 4
2.2 Results and Discussion ............................ ....... .. ...... ..............6
2.2.1 Preparation of 1-Substituted-3-benzotriazolylmethylimidazolidines
2 .9 a c .................................. .......... .. ............ ....... ....... ............... .. 6
2.2.2 Nucleophilic Substitutions of 2.9a-c with NaBH4, Grignard Reagents,
Sodium Cyanide, Benzenethiol and Triethyl Phosphite. (cf. Scheme 2-2) .......7
2.2.3 Syntheses of Optically Active Imidazolidines. (cf. Scheme 2-3)...............8
2.2.4 Modification of the 2-Position of the Imidazolidine Ring. ......................10
2.2.5 Preparation of 1-Methyl-3-substituted-2,3-dihydro-l1H-benzimidazoles
2 .2 8 2 .2 9 ................................................... ................ 1 1
2.3 C conclusion ................................................................. ..... ..........13
2 .4 E x p erim mental S section ....................................................................... ...............13
2.4.1 General Procedure for the Preparation of 1-Substituted-3-
(benzotriazolylmethyl) Imidazolidines 2.9a-c .............................................13
2.4.2 Procedure for Reduction of 2.9a with NaBH4.......................................15
2.4.4 General Procedure for the Nucleophilic Substitutions of 2.9a-c with
G rignard R agents. .............. .. ............................ ........... ..... ........ ... 15
2.4.5 General Procedure for the Reaction of 2.9a-c with NaCN.....................18
2.4.6 Procedure for the Nucleophilic Substitution of 2.9a with
B enzenethiol. ............................................... ........ ....... .................... 20
2.4.7 Procedure for the Nucleophilic Substitution of 2.9a with Triethyl
Phosphite........... .. ..................................................................... 20









2.4.8 General Procedure for the Preparation of Chiral Diamines 2.18a-c
from N-Boc-a-am ino Acids 2.15a-c.................................. .................. .....21
2.4.9 General Procedure for the Preparation of Optically Active
Imidazolidines 2.20a-d, 2.21, 2.22. ........................................ ........ ..........22
2.4.10 Procedure for the Preparation of the Bt Intermediate 2.24 and its
Substitution w ith N aCN ........................................ .......................................26
2.4.11 Procedure for the Preparation of 1-Substituted-3-methyl-2,3-dihydro-
1H -benzim idazoles 2.28, 2.29 .................................................................. 27
2.4.12 Procedure for the Preparation of 2-(2-Anilinoanilino)acetonitrile
(2.31) .................................... ................... .............. ........... 29

3 NOVEL SYNTHESES OF HEXAHYDROIMIDAZO[1,5-B]ISOQUINOLINES
AND TETRAHYDROIMIDAZO[1,5-B]ISOQUINOLIN-1(5H)-ONES VIA
IM INIUM CATION CYCLIZATION S ........................................ .....................30

3.1 Introduction........................................................................ ....... ...... 30
3.2 R results and D iscu ssion .............. .... ... .........................................................3 1
3.2.1 Preparation of Chiral Diamines 3.11a-c from N-Boc-Phe-OH (3.7).........31
3.2.2 Syntheses of 1,2,3,5,10,10a-Hexahydroimidazo[1,5-b]isoquinolines
3 .1 a c .................................. ............ ........... .............. .. .. ................ 3 2
3.2.3 Syntheses of 2,3,10,10a-Tetrahydroimidazo[1,5-b]isoquinolin-l(5H)-
ones 3.15a-c. (c.f Schem e 3-3) .................................... ... ........ ............33
3.2.4 Syntheses of Chiral 3-Substituted-2,3,10,10a-tetrahydroimidazo[1,5-
b]isoquinolin-l(5H)-ones 3.18a-c. (c.f. Scheme 3-4)..................................34
3.2.5 Attempts to Synthesize 1,2a,3,4a,5,9b-Hexahydrobenzo[g]imidazo
[2,1,5-cd]indolizin-4(2H)-one (3.23).............. ................... ..... ............37
3 .3 C o n clu sio n ...................................... ............................. ................ 3 8
3.4 Experim mental Section................... ......... .. ..... ... .... ........................... 38
3.4.1 General Procedure for the Preparation of Chiral a-Amino-amides
3.10a-c and Diamines 3.11a-c from N-Boc-Phe-OH (3.7)..........................39
3.4.2 General Procedure for the Preparation of Benzotriazolyl intermediates
3 .1 2 a c ...................... ...... ...... ...... .. ... .. ........ ............... 3 9
3.4.3 General Procedure for the Preparation of 1,2,3,5,10,10a-
Hexahydroimidazo[1,5-b]isoquinolines 3.1a-c...........................................40
3.4.4 General Procedure for the Preparation of Benzotriazolyl Intermediates
3.13 and 3.14a- c .................................. .............................. .................. .. 42
3.4.5 General Procedure for the Preparation of 2,3,10,10a-
Tetrahydroimidazo[1,5-b]isoquinolin- 1(5H)-ones 3.15a-c. .........................44
3.4.6 General Procedure for the Preparation of 2,3,5-Tri sub stituted-tetrahydro-
4H -im idazol-4-ones 3.16a-c .......................................................................45
3.4.7 General Procedure for the Preparation of Bt intermediates 3.17a-c
and 3.17'a.............. ......... .. ............ .............................. ................. 46
3.4.8 General Procedure for the Lewis Acid Promoted Cyclization of 3.17a-c
and 3.17'a ................ ..... ... .......... ...... .. ....... .. ..... ..........48
3.4.9 Procedure for the Preparation of Bt intermediate 3.22.............................50









4 N-ACYLBENZOTRIAZOLES: NEUTRAL ACYLATING REAGENTS FOR
THE PREPARATION OF PRIMARY, SECONDARY AND TERTIARY
A M ID E S ........................................................... ................ 5 2

4.1 Introduction ............... .... .................... ..........................52
4.2 R results and D discussion ................................................................................. 53
4.2.1 Preparation of N-Acylbenzotriazoles 4.2a-q........................ .................53
4.2.2 Preparation of Primary Amides 4.3a-n from N-Acylbenzotriazoles
4.2 w ith A m m onia. ................ ... .. ... .. ..... .. .. .. .... .................... 55
4.2.3 Preparation of Secondary Amides 4.4a-j from N-Acylbenzotriazoles 4.2
w ith Prim ary A m ines .................................................................... ... 56
4.2.4 Preparation of Tertiary Amides 5a-k from N-Acylbenzotriazoles 4.2
w ith Secondary Am ines. ....................... ................ .... ............... 57
4.2.5 Preparation of a-Hydroxyamides using BtSO2CH3. ...............................58
4.2.6 Preparation of 1-(1H-1,2,3-Benzotriazol-l-yl)-2,2,3,3,4,4,4-
heptafluorobutan-1-one (4.8) and its Perfluoroacylation with Primary and
Secondary A m ines. .......................... ........ ........................... ...... ............59
4.3 Conclusion .................................................................... ......... 61
4.4 E xperim mental Section ............................. ................................................... 61
4.4.1 Modified procedure for the Preparation ofN-(1-
m ethanesulfonyl)benzotriazole (4.1) ....................................... ............... .... 61
4.4.2 General procedure for the Preparation of N-Acylbenzotriazoles 4.2........62
4.4.3 General procedure for the Reaction of N-Acylbenzotriazoles 4.2 with
A queous am m onia. ................... ...................... .... ........ .. ....... ............ 65
4.4.4 General procedure for the Reaction of N-Acylbenzotriazoles 4.2 with
P rim ary am ines. .................... ...... ......... ... ............................... ... 65
4.4.5 General procedure for the Reaction of N-Acylbenzotriazoles 4.2 with
Secondary am ines. ..................... .... ....... .. ...... ........ .........................67
4.4.6 General procedure for the Preparation of a-Hydroxyamides.....................68
4.4.7 Preparation of 1-(1H-1,2,3-Benzotriazol-l-yl)-2,2,3,3,4,4,4-
heptafluorobutan-1-one (4.8) ..................................................... .................69
4.4.8 General Procedure for the Reaction 4.8 with Primary and Secondary
am in es. ....................................................... ................ 6 9

5 HIGHLY DIASTEREOSELECTIVE PEPTIDE CHAIN EXTENSIONS OF
UNPROTECTED AMINO ACIDS WITH N-(Z-a-AMINOACYL)
B E N Z O T R IA Z O L E S ........................................................................ ...................7 1

5.1 Introduction .................................. ..............................................7 1
5.2 R results and D discussion .................. .... ... .............................. ............... 73
5.2.1 Preparation of N-(Z-Aminoacyl)benzotriazoles from N-Cbz-Amino
a c id s 5 .1 a d .................................................... ................ 7 3
5.2.2 Preparation of N-Z-Dipeptides ..................................................................75
5.2.3 Preparation of N-Acylbenzotriazoles derived from N-Z-Dipeptides..........76
5.2.4 Preparation of N-Z-Tripeptides. ........................... ............... 77
5.2.5 Preparation of N-Z-Tetrapeptides.............. ..............................................78









5.3 Conclusion ..................................................................... ......... 78
5.4 E xperim mental Section ................... ......... ........... ......... ........................ 79
5.4.1 General procedure for the Preparation of 5.1a-d and 5.3a-b....................79
5.4.2 General procedure for the Preparation of 5.2a-i, 5.4a-f, 5.4a', and
5.5a-b ............................................. ........................... ............... 82
5.4.3 Preparation of Boc-Protected dipeptide from Boc-Phe-Bt........................91

6 REGIOSELECTIVE C-ACYLATION OF PYRROLES, INDOLES, 2-
METHYLFURAN AND THIOPHENE USING N-ACYLBENZOTRIAZOLES .....92

6.1 Introduction ............... ........... ....................... .........................92
6.2 R results and D discussion .............. ................................. .............................. 93
6.2.1 Preparation of N-Acylbenzotriazoles .......................................................93
6.2.2 Preparation of 2-Acylpyrroles. ............. ............................ ............... .94
6.2.3 Preparation of 3-Acylpyrroles. ..................................................... 96
6.2.4 Preparation of 3-Acylindoles............................................. ............... 97
6.2.5 Synthesis of 2-Acyl-5-methylfurans....................................................99
6.2.6 Synthesis of 2-A cylthiophenes.............................................................. 100
6.3 Conclusion ............................................... 100
6.4 Experimental Section........................... ..... .................101
6.4.1 General Procedure for the Preparation of N-Acylbenzotriazoles
6.1a- g. ........................ ..... .... ...... ..... ............. ..... . 10 1
6.4.2 General Procedure for C-Acylation of Pyrroles (6.2, 6.4, 6.6) or
Indoles (6.9, 6.11) Using N-Acylbenzotriazoles 6.1a-g. ............................102
6.4.3 General Procedure for C-Acylation of 2-methylfuran and thiophene
Using N-Acylbenzotriazoles 6.1a, c, e, h, i, j................... ...................112

LIST OF REFEREN CES ........................................................... .. ............... 115

BIOGRAPHICAL SKETCH ............................................................. ............... 127
















LIST OF TABLES


Table pge

2-1 Preparation of 1,3-disubstituted imidazolidines 2.11a-1 ........................................

4-1 Preparation ofN-acylbenzotriazoles 4.2a-q........ .......... ........................... 55

4-2 Preparation of primary amides 4.3a-n ............... .... ......... .................. 56

4-3 Preparation of secondary amides 4.4a-j ....................................... ............... 57

4-4 Preparation of tertiary amides 4.5a-k.............. .................. ........... ............... 58

5-1 Conversion of N-Z-a-amino acids into N-(Z-aminoacyl)benzotriazoles ...............74

5-2 Preparation of N-Z-dipeptides from N-(Z-aminoacyl)benzotriazoles and
unprotected am ino acids ................................................. .............................. 76

5-3 Conversion of N-Cbz-dipeptides into N-(Z-dipeptidoyl)benzotriazoles ................77

5-4 Preparation of N-Cbz-tripeptides. ........................................ ........................ 78

5-5 Preparation of N-Z-tetrapeptides from dipeptidoylbenzotriazoles and an
unprotected dipeptide. ..................................................................... ...................78

6-1 Preparation of 2-acylated pyrrole (6.2) and 1-methylpyrrole (6.4)........................96

6-2 Preparation of 3-acylated TIPS-pyrrole (6.6)............................ .. ...............97

6-3 Preparation of 3-acylated indole (6.9) and 1-methylindole (6.11). .....................98

6-4 Preparation of 2-acylated 2-methylfuran................... ....... ..... .. ............. 99

6-5 Preparation of 2-acylated thiophene......... ......... ..... ....... .. ............... 100
















LIST OF SCHEMES


Scheme p

1-1 Isomers of the N-substituted benzotriazoles ............ ...... .. ....................1

1-2 The formation of imnium cation and benzotriazole anion ........................................2

1-3 Conversion of carboxylic acid into N-acylbenzotriazole ........................................3

2-1 Previously reported methods for imidazolidines....................... ............... 5

2-2 Nucleophilic substation to unsymmetrical imidazolidines............... ............ 6

2-3 Preparation of optically active imidazolidines............................ ............. ..9

2-4 Modification of the 2-position of the imidazolidine ring................................... 11

2-5 Preparation of benzim idazoles ........................................ ........................... 12

3-1 Intramolecular cyclizations utilizing Lewis acid-activated benzotriazole ..............31

3-2 Synthesis of 2-substituted hexahydroimidazo[1,5-b]isoquinolines .............................32

3-3 Synthesis of tetrahydroimidazo[1,5-b]isoquinolin- 1(5H)-ones ...............................34

3-4 Syntheses of chiral 3-substituted tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-
o n e s ............................................................................. 3 6

3-5 Isomerization of chiral 3-substituted tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-
o n e s ............................................................................. 3 6

3-6 Attempts to synthesize 1,2a,3,4a,5,9b-hexahydrobenzo[g]imidazo[2,1,5-
cd]indolizin-4(2H )-one......... ........................... ...... .................. ............... 37

4-1 Preparation of N-acylbenzotriazoles and amides ............................................. 55

4-2 Reaction of BtSO2CH3 with 2-hydroxy-2-phenylacetic acid ................................59

4-3 Synthesis of perfluoroalkylated amides ....................................... ............... .60

5-1 Coupling reactions with N-(Z-aminoacyl)benzotriazoles.............. ... .............73









5-2 1H NMR spectra of compound 5.2f (left) and racemized 5.2f (right) in
C D C 13 (C H 3 signal in L -A la) ......................................................... .....................75

6-1 2-Acylation of pyrrole (6.2) and 1-methylpyrrole (6.4) using
N -A cylbenzotriazoles 6.1a-g ....................................................... ...... ......... 95

6-2 3-Acylation of TIPS-pyrrole (6.6) using N-acylbenzotriazoles 6.1a-g .................97

6-3 3-Acylation of indole (6.9) and 1-methylindole (6.11) using
N -A cylbenzotriazoles 6.1a-g ....................................................... ...... ......... 98

6-4 C-Acylation of 2-methylfuran .......................... .............. ...... ........... 99

6-5 C-A cylation of Thiophene.......................... ................................. ............... 100















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

BENZOTRIAZOLE-MEDIATED SYNTHESES OF HETEROCYCLIC COMPOUNDS
AND ACYLATIONS UTILIZING N-ACYLBENZOTRIAZOLES



By

Kazuyuki Suzuki

December 2004

Chair: Alan R. Katritzky
Major Department: Chemistry

1H-Benzotriazole is a versatile synthetic auxiliary, and has widely been applied to

many organic syntheses. In our continuous work on the methodology, we have developed

convenient and efficient methods for preparation of heterocyclic compounds.

In chapter 2, formation of imidazolidine rings by the Mannich reaction involving

1H-benzotriazole as a neucleophile is described, and followed by nucleophilic

substitution of the benzotriazole group utilizing Grignard reagents to give unsymmetrical

imidazolidines.

In chapter 3, the study of the imidazolidines was further expanded to preparation of

multi-cyclic compounds hexahydroimidazo[1,5-b]isoquinolines and tetrahydroimidazo-

[1,5-b]isoquinolin-1(5H)-ones. These heterocycles are synthesized via iminium cation

cyclizations in the presence of AlC13.









In chapter 4, N-acylbenzotriazole is introduced as neutral acylating reagents for the

preparation of primary, secondary, and tertiary amides. Reaction of N-acylbenzotriazoles

with various amines under mild conditions is discussed.

In chapter 5, syntheses of di-, tri-, and tetra-peptides is demonstrated utilizing N-(Z-

aminoacyl)benzotriazoles with unprotected amino acids in aqueous solution. N-(Z-

Aminoacyl)benzotriazoles are prepared from N-Z-amino acids and an intermediate

obtained by reaction of 1H-benzotriazole and thionyl chloride.

In chapter 6, N-acylbenzotriazoles are applied to C-acylation under Friedel-Crafts

conditions using heterocyclic compounds such as pyrrole, N-methylpyrrole, indole, N-

methylindole, 2-methylfuran, and thiophene. This method provides heteroaromatic

ketones, and is especially useful when the acid chlorides corresponding to N-

acylbenzotriazoles are not readily available.















CHAPTER 1
GENERAL INTRODUCTION

The benzotriazole chemistry has been studied intensively in our group, and its

various utilities have been reported. [98CR409]

1H-Benzotriazole is an excellent synthetic auxiliary and acts as a leaving group,

electron-withdrawing group, and even an electron-donating group (Scheme 1-1). As

another aspect of a good auxiliary, the benzotriazole group is readily removed from the

reaction mixture by simply washing with base due to the acidity (pKa 8.2) of 1H-

benzotriazole. Moreover, 1H-benzotriazole is an inexpensive, stable compound that is

soluble in common organic solvents such as ethanol, benzene, chloroform, and DMF.

-N -N '- N

X N N
y ^Y

R H
1.1 1.2 1.3
Leaving group Activating CH Electron donor
to proton loss
Scheme 1-1. Isomers of the N-substituted benzotriazoles

As a good synthetic auxiliary, there should be several characteristics including the

advantages mentioned above. It has been shown to be an excellent leaving group when

attached to a-carbon atom adjacent to hetero-atoms such as N, 0, and S. Unlike

halogens, the benzotriazole group rarely leaves if there is no hetero-atom at the a-carbon

atom. It is also a good leaving group when attached to a carbonyl group to form N-

acylbenzotriazoles, which are efficient N-acylating reagents. The benzotriazole group can









be used as an activating group for ca-hydrogen (adjacent CH). Furthermore, the

benzotriazole group is easily removed by washing with a basic aqueous solution such as

sodium carbonate and sodium hydroxide solution when products are stable in the basic

solutions. If products are not stable towards base, but stable to an acid wash, 2-4N

hydrochloric acid solution can be used. Another important aspect of the benzotriazole

group is that it is stable during various synthetic operations. It must be introduced at the

beginning of the sequence and may be carried through several reactions.

This dissertation includes reactions of Bt-C-N type compounds for the nucleophilic

substitution, and reactions of N-acylbenzotriazoles for formation of simple amides,

peptide coupling and Friedel-Crafts type reaction. N-Substituted benzotirazole

derivatives (Bt-C-N) have shown electron-acceptor properties, which lead to the

formation of imnium cation and benzotriazole anion (Scheme 1-2).

In chapter 2, formation of imidazolidine rings by the Mannich reaction involving

1H-benzotriazole as a nucleophile is described, and followed by nucleophilic substitution

of benzotriazole group to give unsymmetrical imidazolidines. Symmetrical,

unsymmetrical, and optically active imidazolidines were synthesized by the method using

Grignard reagents, triethyl phosphite and sodium cyanide.


Bt = N
N1N


R'\ Bt R + N
N-/ N= + N |
R" R" N-

1.4 1.5

Scheme 1-2. The formation of imnium cation and benzotriazole anion









In Chapter 3, the study of the imidazolidines was extended to the preparation of

multi-cyclic compounds hexahydroimidazo[1,5-b]isoquinolines and

tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones. These heterocycles are synthesized via

iminium cation cyclizations in the presence of AlC13.

N-Acybenzotriazoles are versatile neutral acylating reagents. N-Acylation is

discussed in Chapter 4 for the preparation of primary, secondary and tertiary amides.

N-Protected (aminoacyl)benzotriazoles are N-acylbenzotriazoles derived from N-

protected amino acids, and they are utilized for peptide coupling using unprotected amino

acids in aqueous solution (Chapter 5).

O 0
R O R4 N-Acylbenzotriazole
OH Bt
1.6

R0 RO
R R, N-Protected
P H OH P H Bt (aminoacyl)benzotriazole
Pg-NH OH Pg-NH Bt

Pg = protecting group 1.7

Scheme 1-3. Conversion of carboxylic acid into N-acylbenzotriazole

N-Acylbenzotriazoles can be applied to a Friedel-Crafts reaction. In the presence of

a Lewis acid, the reaction was carried out to give various ketones with heterocycles such

as pyrrole, indole, furan and thiophene (Chepter 6). This method is especially

advantageous when the corresponding acid chlorides are not readily available.














CHAPTER 2
CONVENIENT SYNTHESIS OF UNSYMMETRICAL IMIDAZOLIDINES

2.1 Introduction

Imidazolidines have attracted attention due to their important role as building

blocks in the synthesis of biologically active compounds. [96JMC3483] [96EJP273]

[98B13893] [00CPB729] [93PR913] [94EJP223] [70JMC1212] [70JMC1215] Early

symmetrical imidazolidines prepared by condensation of N,N'-diaryl-1,2-ethanediamines

with formaldehyde were reported by Bischoff et al. [1898CB3248] in 1898 and by

Scholtz et al. [1901CB1504] in 1901. Since their work, preparation of other symmetrical

imidazolidines including 1,3-diarylimidazolidines [59LAC120] and 1,3-

dialkylimidazolidines from N,N'-dialkyl- 1,2-ethanediamines [49JOC952] was

demonstrated using the same methodology. Other methods were also reported: i) the

reduction of symmetrical cyclic ureas with LiA1H4, [86JOC2228] ii) reactions of 1,3,6,8-

tetraazatricyclo[4.4.1.13'8]dodecane with p-substituted phenols, [93SC2919] and iii) the

Mannich reaction of 1,2-ethanediamine, benzotriazole and formaldehyde followed by

nucleophilic substitutions with the Grignard reagents. [90JCS(P1)541]

On the other hand, few syntheses of unsymmetrical N,N'-disubstituted

imidazolidines have been reported. Kliegel et al. demonstrated in 1977 that preparation of

1-phenyl-3-alkylimidazolidines by reactions of formaldehyde with N-alkyl-N'-phenyl-

1,2-ethanediamines previously prepared by the condensation of f-aminosulfonic acids

and primary amines. [77LAC956] Lambert synthesized unsymmetrical imidazolidines









from diethyl oxalate with primary amines in three-steps involving LiAlH4 reduction of

the corresponding oxamides to unsymmetrical N,N'-disubstituted-1,2-ethanediamines and

condensation with formaldehyde. [86S657] Perillo et al. [00JHC57] recently prepared 1-

benzyl-3-arylimidazolidines from formaldehyde and N-benzyl-N'-aryl-1,2-

ethanediamines, produced by BH3 reduction of the corresponding N-benzoyl-N'-aryl- 1,2-

ethanediamines. [98SC1625]

R1 and R2 alkyll or aryl) groups are generally introduced when N,N'-disubstituted-

1,2-ethanediamines are prepared in the protocols mentioned above. However, the

methods limit the efficiency and the productivity for preparation of a wide variety of

imidazolidines. N-Substituted benzotriazoles have been reported as useful synthetic

precursors due to the easy replacement of the benzotriazole group as a leaving group via

nucleophilic substitution, elimination, reduction, cyclization, etc.[98CR409] We now

report a simple and efficient way to prepare novel unsymmetrical imidazolidines, and

optically active imidazolidines in good to excellent yields and extend this methodology to

the preparation of 2,3-dihydro-1H-benzimidazoles using benzotriazole as a synthetic

auxiliary.

SBt Bt
R1-N N-R2 \,N Ny
H H HCHO RMgX 2.3
S2.3
2.2 (R1 = R2) Bt = benzotriazolyl
RlN N-R2
HHO 2.1 "HCHO
H 4 steps
SArl-N NYPh
2O0 O H H
PhN R2 2.6, Y = H2
H H EtO OEt BH3 E 2.6, Y = H2
2.4 2.5 2.7, Y = C=O

Scheme 2-1. Previously reported methods for imidazolidines










2.2 Results and Discussion

2.2.1 Preparation of 1-Substituted-3-benzotriazolvlmethylimidazolidines 2.9a-c.

Mannich condensation of N-substituted-1,2-ethanediamines 2.8a-c with 1

equivalent of benzotriazole and 2 equivalents of formaldehyde (37% aqueous solution) in

MeOH/H20 at room temperature gave 1-substituted-3-benzotriazolylmethyl-

imidazolidines 2.9a-c in 96%, 85% and 92% yields, respectively (Scheme 2-2).

Compound 2.9a was initially obtained solely as the Bt1 isomer, but in CDC13 it gradually

changes to a mixture of Bt1 and Bt2 isomers in ca. 5.6:1 ratio after 3 days. Compounds

2.9b,c were obtained as mixtures of Bt1 and Bt2 isomers, each in ca. 5:1 ratio. Based on

our previous results, which showed little difference in the reactivity of Bt1 and Bt2

isomers, [91T2683] [01JOC148] 2.9b,c were used directly as mixtures for the subsequent

reactions. In the 13C NMR spectrum of 2.9a, the signal of 145.8 ppm is believed to

contain two carbons, since it changes to two signals (145.0 and 146.0 ppm, respectively)

in DMSO-d6. Benzotriazolyl intermediates 2.9a-c were used as crude products for the

subsequent reactions.

\ BtH, 2 HCHO Bt
1 1Bt
R -N N-H R1-N N Ph-N \N.Me
H H 1
2.8a, R = Ph 2.9a, R = Ph 2.10
2.8b, R1 = Et 2.9b, R1 = Et
2.8c, R1 = PhCH2 2.9c, R1 = PhCH



R2 Et
R1-N\ N_ PhN NN 'OEt
2.11a-I R1_N \N N PhN N /SPh 2.14

2.12a, R1 =Ph 2.13
2.12b, R = Et i) NaBH4(R =Ph); ii) R2MgX; iii) NaCN;
2.12c, R1 = PhCH2 iv) PhSH/NaH (R1 = Ph); v) P(OEt)3/ZnBr2 (R1 = Ph)

Scheme 2-2. Nucleophilic substitution to unsymmetrical imidazolidines









Table 2-1. Preparation of 1,3-Disubstituted Imidazolidines 2.11a-1
2.11 R R2 a Yield (%) Methodb
a Ph n-Bu 80 A; 1.4 eq of GRc
b Ph CH2CH2Ph 96 A; 1.2 eq of GR
c Ph CH2Ph 96 A; 2.0 eq of GR
d Ph C6H40Me-p 81 A; 1.2 eq of GR
e Ph C-CPh 80 A; 1.2 eq of GR
f Ph CH=CH2 75 A; 1.2 eq of GR
g Et CH2Ph 75 B; 2.0 eq of GR
h Et C6H4Me-p 71 B; 2.0 eq of GR
i PhCH2 CH2C6H5 79 B; 2.0 eq of GR
j PhCH2 CH=CH2 63 B; 2.0 eq of GR
k PhCH2 C-CPh 65 B; 1.2 eq of GR
1 PhCH2 n-C5H11 80 B; 1.6 eq of GR
aR2MgBr was used except for 2.11c,g when PhCH2MgC1 was used.; bMethod A: in
THF (10 mL), rt, 0.5 h, then reflux 1 h; Method B: in toluene (10 mL), rt, 0.5 h, then
1 h at 50 C.; CGR = Grignard reagent.


2.2.2 Nucleophilic Substitutions of 2.9a-c with NaBH4, Grignard Reagents, Sodium
Cyanide, Benzenethiol and Triethyl Phosphite. (cf Scheme 2-2)

Treatment of 2.9a with 2 equivalents of sodium borohydride in refluxing THF

replaced the Bt group with hydrogen to give 1-phenyl-3-methylimidazolidine (2.10) in

96% yield. The methylene protons between two nitrogen atoms in 2.10 appeared at 3.97

ppm as a singlet.

We previously reported that the benzotriazolyl group attached to a nitrogen is easily

replaced by nucleophiles. [89JCS(P1)225] [00JOC4364] [00JOC3683] Nucleophilic

substitutions of 2.9a-c with alkyl-, vinyl-, aryl- and phenylethynyl-magnesium bromide

and, for the preparation of 2.11c,g, benzyl magnesium chloride, in dry THF or toluene

furnished novel unsymmetrical 1,3-disubstituted imidazolidines 2.11a-1 in 63-96%

yields. The isolated yields and reaction conditions for 2.11 are summarized in Table 1.

Compounds 2.11g-1 were easily decomposed on silica gel, so they were isolated by

neutral aluminum oxide column chromatography. The structures of 2.11a-1 were









supported by their 1H, 13C NMR spectra and microanalyses or HRMS results. The

methylene groups between the two nitrogens in 2.11a-f appeared at around 4.0 ppm as

singlets.

The benzotriazolyl group in 2.9a-c can be substituted by cyano anion to give 2-(3-

substituted-1-imidazolidinyl)acetonitriles 2.12a-c in 77-97% yields. Reaction of 2.9a

with benzenethiol in the presence of sodium hydride produced 1-phenyl-3-(phenyl-

thiomethyl)imidazolidine (2.13) in 66% yield. The benzotriazolyl group in 2.9a was

replaced in the presence of ZnBr2 by a P-nucleophile (triethyl phosphite) to afford diethyl

(3-phenyl-l-imidazolidinyl)methylphosphonate (2.14) in 70% yield. The Lewis acid

ZnBr2 facilitates loss of the benzotriazolyl anion to form an iminium cation, which is then

attacked by the P-nucleophile. [00JOC3683] Thus, various useful functionalities were

introduced to the imidazolidine ring system via nucleophilic substitution of the

benzotriazolyl group.

2.2.3 Syntheses of Optically Active Imidazolidines. (cf. Scheme 2-3)

We further investigated the preparation of optically active imidazolidines starting

from commercially available N-Boc-a-amino acids 2.15a-c. Based on our recent

paper,[01JCS(P1)1767] a-amino amides 2.17a-c were easily obtained in two steps from

the optically active N-Boc-a-amino acids 2.15a-c (R3 = Me, i-Bu, or PhCH2) and 4-

methylphenylamine. Crombie and Hooper reduced 2-amino-N-phenylpropanamide with

LiA1H4 to 2-aminopropylaniline without reporting a detailed procedure.[55JCS3010] We

found that refluxing of 2.17b (R3 = i-Bu) with 3 equiv of LiAlH4 in dry THF for 1 day

gave a 1:1 mixture of 2.17b and 2.18b. When 6 equiv of LiAlH4 in dry THF for 2 days

was used, reduction of 2.17a-c afforded chiral diamines 2.18a-c in more than 90%









yields. Intermediates 2.16a-c, 2.17a-c and 2.18a-c were all used as crude products

without further purification for subsequent reactions.

Reaction of diamines 2.18a-c with benzotriazole and formaldehyde generated

benzotriazol-1-yl intermediates 2.19a-c in 85%, 93% and 93% yields, respectively.

Nucleophilic substitution of 2.19a-c by Grignard reagents, triethyl phosphite or sodium

cyanide gave optically active imidazolidines 2.20a-d, 2.21 or 2.22 in 66-99% yields.

The structures of 2.20-22 are supported by their 1H, 13C NMR spectra and microanalyses.

The two diastereotopic methylene hydrogens at the 5-position appear at different

chemical shifts due to the chirality at postion-4. For 2.20a, 2.21, irradiation of the annular

CH3 caused a positive NOE effect for one of the methylene hydrogens at 5-position; thus

this hydrogen at a higher field is assigned to be the anti-hydrogen Ha. We did not attempt

to assign Ha and Hb for 2.20b-d, 2.22 because of their overlap with other protons, but we

believe that their anti-Ha would be upfield by analogy to what was observed for 2.20a

and 2.21.

R3 O R3 O R3 O

BocNH OH p-MeC6H4NH2 BocNH NHC6H4Me-p H2N NHC6H4Me-p
2.15a-c 2.16a-c 2.17a-c


R3 BtH, R3
LiAIH4 2 HCHO Bt1
SH2N NHC6H4Me-p N N/N 'C6H4Me-p
2.18a-c 2.19a-c
Scheme 2-3. Preparation of optically active imidazolidines










Scheme 2-3 contd.


R3

Bti
Bt NN N'C6H4Me-p

2.19a-c

NaCN R3 = PhCH2


PhH2C Ha

NC H N
NC N -~~ C6H4Me-p

2.22


R4MgBr





P(OEt)3
ZnBr2
R3 = Me


R3 Ha
4 1llHb
-N~/ NC6H4Me-p

2.201 R3 R4
a Me allyl
b i-Bu CH=CH2
c i-Bu C6H4Me-p
d CH2Ph C CPh


Me Ha
EtO. I Hb
EtO- N /NC6H4Me-p
2.21


i) CICOOBu-i, N-methylmorpholine; ii) HCI/Et20 (2 M); iii) aq. NaOH

2.2.4 Modification of the 2-Position of the Imidazolidine Ring.

Following a previously reported procedure, [90JOC1772] 4-nitrophenyl group was

introduced onto the imidazolidine ring at the 2-position by the reaction of N-ethyl-1,2-

ethanediamine with 4-nitrobenzaldehyde using azeotropic distillation. To avoid the

formation of chain tautomers due to possible ring-chain tautomerism, [90JOC1772] we

did not attempt to use N-phenyl-1,2-ethanediamine (2.8a) as the starting material.

Compound 2.23 exists only in its cyclic form since no spectral evidence for the open

tautomer was observed.

Reaction of 2.23 with 1 equiv of benzotriazole and formaldehyde gave the Bt

intermediate 2.24, which was treated with sodium cyanide to afford 2-[3-ethyl-2-(4-

nitrophenyl)-1-imidazolidinyl]acetonitrile (2.25) in 92% yield (Scheme 2-4).










Et-N NH i Et-N N
Et-N N.H
H H C6H4NO2-P C6H4NO2-p

2.8b 2.23 2.24, R = Bt
NaCN .
2.25, R = CN
i) p-O2NC6H4CHO; ii) BtH, HCHO

Scheme 2-4. Modification of the 2-position of the imidazolidine ring

2.2.5 Preparation of 1-Methyl-3-substituted-2,3-dihydro-l1H-benzimidazoles 2.28, 2.29.

2,3-Dihydro-1H-benzimidazoles are usually prepared by condensation of the

corresponding N,N'-disubstituted-1,2-benzenediamines with formaldehyde.[21JCS1537]

[88JCS(P1)1939] We reported the formation of 1,3-bis(benzotriazolylmethyl)-2,3-

dihydro- 1H-benzimidazole by treatment of 1,2-benzenediamines with 1H-benzotriazole

and formaldehyde. [90CJC446] We found that condensation of N-methyl-1,2-

benzenediamine (2.26a) with benzotriazole and 2 equiv of formaldehyde produced Bt

intermediate 2.27 in 85% yield (Scheme 2-5). Compound 2.27 was obtained as a mixture

of Bt and Bt2 isomers in ca. 5.9:1 ratio, which was used directly for the subsequent

reactions.

Reaction of 2.27 with vinyl magnesium bromide was found to give unidentifiable

products probably opening the five-membered ring. The weaker nucleophile, vinyl zinc

bromide (prepared from vinyl magnesium bromide and zinc chloride), gave 1-allyl-3-

methyl-2,3-dihydro-1H-benzimidazole (2.28) in 83% yield. Compound 2.28 is extremely

sensitive to silica gel or neutral A1203; it was finally purified by flash column

chromatography on basic A1203. It also easily decomposes in CDC13 with disappearance

of the NCH2N methylene group, so NMR analysis was performed in DMSO-d6.

Treatment of 2.27 with 2 equiv of NaCN produced 94% yield of 2-(3-methyl-2,3-










dihydro-1H-benzimidazol-l-yl)acetonitrile (2.29), which was also purified by flash

column chromatography on basic A1203. Compounds 2.28 and 2.29 are both labile to air,

so are used in situ for other transformations, since their crude NMR spectra and GC

analyses show more than 90% purity. In the absence of mechanistic studies, a possible

reason for instability is that compounds 2.28 and 2.29 are readily oxidized.

Condensation of 2.26b (R = Ph) with benzotriazole and formaldehyde (1 or 2

equiv) only generated the acyclic intermediate 2.30 possibly due to the increased steric

hindrance caused by the PhNHAr fragment. The Bt group in 2.30 was further substituted

by cyanide anion to give 2-(2-anilinoanilino)acetonitrile (2.31) in 77% yield.


I /
R-N N-
H H
Bt Me
HCHOXR=




2Bt7
Me-N N 2
2.27


CH2=CHZnBr/





Me-N N


NaCN





Me-N\ N


2.28

Scheme 2-5. Preparation of benzimidazoles


2.29


2.26a, R = Me
2.26b, R = Ph
H


BtH R = Ph
HCHO


SBt
Ph-N N--_
H H
2.30

SNaCN




CN
,CN Ph-N N N
H H

2.31









2.3 Conclusion

In summary, an efficient method has been developed for the preparation of

unsymmetrical imidazolidines and 2,3-dihydro-1H-benzimidazoles via Mannich reactions

of diamines with benzotriazole and formaldehyde, followed by nucleophilic substitution

of the benzotriazolyl group with other functionalities. Compared to the previous methods

(multi-step and low yields) for the preparation of unsymmetrical imidazolidines,

[86S657] [77LAC956] [00JHC57] our method needs only two steps, utilizes easily

available starting materials, and generally affords the desired products in good to

excellent yields.

2.4 Experimental Section

THF or toluene was distilled from sodium-benzophenone prior to use. Melting

points are uncorrected. 1H, 13C NMR spectra were recorded (300 MHz and 75 MHz

respectively) in CDC13 (with TMS for 1H and chloroform-d for 13C as the internal

reference), unless otherwise stated. Elemental analyses were performed on a Carlo Erba-

1106 instrument. Optical rotation values were measured with the use of the sodium D

line. Column chromatography was performed on silica gel (200-425 mesh), neutral

alumina (60-325 mesh) or basic alumina (60-325 mesh). All of the reactions were

carried out under N2.

2.4.1 General Procedure for the Preparation of 1-Substituted-3-(benzotriazolvlmethyl)
Imidazolidines 2.9a-c.

A mixture of a N-substituted-1,2-ethanediamine 2.8a-c (3.0 mmol), BtH (0.36 g,

3.0 mmol), and formaldehyde (37% aqueous solution, 0.49 g, 6 mmol) in CH3OH/H20

(10 mL/5 mL) was stirred for 4 h at 20 OC. For 2.9a, the precipitate formed was filtered

and washed with cool Et20. For 2.9b,c, the mixture was extracted with EtOAc, the









organic fraction was washed with 1 M NaOH, brine and dried over anhyd Na2SO4.

Removal of solvents in vacuo gave 2.9b,c as oil. Bt intermediates 2.9a-c were used as

crude products for the subsequent reactions.

1-(1H-1,2,3-Benzotriazolylmethyl)-3-phenylimidazolidine (2.9a): white

microcrystals (from CHC13/hexanes); yield, 96%; mp 123-124 OC; 1H NMR 6 3.20 (t, J=

6.1 Hz, 2H), 3.35 (t, J= 6.1 Hz, 2H), 4.24 (s, 2H), 5.62 (s, 2H, BtlCH2), 6.43 (d, J= 7.9

Hz, 2H), 6.70 (t, J= 7.2 Hz, 1H), 7.19 (t, J= 7.7 Hz, 2H), 7.37 (t, J= 7.5 Hz, 1H), 7.51

(t, J= 7.5 Hz, 1H), 7.65 (d, J= 8.2 Hz, 1H), 8.06 (d, J= 8.4 Hz, 1H); 13C NMR 6 45.9,

49.6, 64.4, 67.0 (Bt1CH2), 109.6, 111.6, 116.8, 119.9, 124.1, 127.7, 129.1, 133.4, 145.8,

145.8. Anal. Calcd for C16H17N5: C, 68.79; H, 6.13; N, 25.07. Found: C, 68.96; H, 6.18;

N, 25.13.

1-Benzotriazolylmethyl-3-ethylimidazolidine (2.9b): colorless oil; obtained as a

mixture of Bt1 and Bt2 isomers in 5:1 ratio (only 1H and 13C NMR data for the Bt1 isomer

are presented); yield, 90%; 1H NMR 6 (Bt1) 1.06 (t, J= 7.1 Hz, 3H), 2.48 (q, J= 7.1 Hz,

2H), 2.74 (t, J= 7.2 Hz, 2H), 3.11 (t, J= 6.8 Hz, 2H), 3.64 (s, 2H), 5.57 (s, 2H),

7.34-7.39 (m, 1H), 7.46 (t, J= 7.2 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 8.06 (d, J= 8.3 Hz,

1H); 13C NMR 6 (Bt1) 13.8, 48.4, 48.9, 52.1, 65.4, 73.1, 109.8, 119.8, 123.9, 127.5,

133.5, 145.9. Anal. Calcd for C12H17N5: N, 30.28. Found: N, 30.20.

1-Benzotriazolylmethyl-3-benzylimidazolidine (2.9c): yellowish oil; obtained as

a mixture of Bt1 and Bt2 isomers in 5:1 ratio (only 1H and 13C NMR data for the Bt1

isomer are presented); yield, 92%; 1H NMR 6 (Bt1) 2.70 (t, J= 7.1 Hz, 2H), 3.12 (t, J=

7.1 Hz, 2H), 3.56 (s, 2H), 3.61 (s, 2H), 5.54 (s, 2H), 7.18-7.36 (m, 7H), 7.59 (d, J= 8.2

Hz, 1H), 8.05 (d, J= 8.2 Hz, 1H); 13C NMR 6 (Bt1) 48.8, 52.2, 58.4, 65.5, 73.2, 109.7,









118.2, 119.8, 123.8, 127.0, 127.4, 128.1, 133.4, 138.4, 145.9. Anal. Calcd for C17H19N5:

H, 6.53; N, 23.87. Found: H, 6.24; N, 23.70.

2.4.2 Procedure for Reduction of 2.9a with NaBH4.

A mixture of 2.9a (0.28 g, 1 mmol) and NaBH4 (0.076 g, 2 mmol) was refluxed in

dry THF (10 mL) overnight. After removal of the solvent in vacuo, the residue was

diluted with EtOAc. The organic extracts were washed with 1 M NaOH, brine, and dried

over anhyd MgSO4. Evaporation of the solvent in vacuo gave 1-methyl-3-

phenylimidazolidine (2.10).

1-Methyl-3-phenylimidazolidine (2.10): colorless flakes (from Et20); yield, 96%;

mp 33-34 C (mp lit[77LAC956] 32-34 C); 1H NMR 6 2.48 (s, 3H), 2.96 (t, J= 6.3 Hz,

2H), 3.42 (t, J= 6.3 Hz, 2H), 3.97 (s, 2H), 6.53 (d, J= 7.8 Hz, 2H), 6.69 (t, J= 7.3 Hz,

1H), 7.23 (t, J= 7.3 Hz, 2H); 13C NMR 6 40.8, 46.3, 54.8, 71.8, 111.4, 116.1, 129.2,

146.4.

2.4.4 General Procedure for the Nucleophilic Substitutions of 2.9a-c with Grignard
Reagents.

To a solution of 1-substituted-3-(benzotriazolylmethyl)imidazolidine 2.9a-c (1.0

mmol) in dry THF or toluene (10 mL) at 0 OC, an appropriate Grignard reagent was

added dropwise. The amount of the Grignard reagent and the subsequent reaction

conditions are collected in Table 1. After being cooled, the mixture was quenched with

water and extracted with Et20. The combined extracts were washed with 1 M NaOH,

brine, and dried over anhyd MgSO4. After removal of solvents in vacuo, the residue was

purified by column chromatography (silica gel) with hexanes/EtOAc as an eluent to give

1,3-disubstituted-imidazolidine 2.11a-f. Compounds 2.11g-1 were purified by neutral

A1203 column chromatography.









1-Pentyl-3-phenylimidazolidine (2.11a): colorless oil; yield, 80%; 1H NMR 6

0.91 (t, J= 6.3 Hz, 3H), 1.34-1.40 (m, 4H), 1.53-1.58 (m, 2H), 2.55 (t, J= 7.5 Hz, 2H),

2.95 (t, J= 6.3 Hz, 2H), 3.40 (t, J= 6.3 Hz, 2H), 3.98 (s, 2H), 6.48 (d, J= 8.2 Hz, 2H),

6.68 (t, J= 7.3 Hz, 1H), 7.22 (t, J= 7.7 Hz, 2H); 13C NMR 6 14.0, 22.6, 28.5, 29.6, 46.1,

52.9, 54.7, 70.3, 111.3, 116.0, 129.1, 146.4. Anal. Calcd for C14H22N2: C, 77.01; H,

10.16; N, 12.83. Found: C, 77.30; H, 10.49; N, 13.14.

1-Phenyl-3-(3-phenylpropyl)imidazolidine (2.11b): yellow oil; yield, 96%; 1H

NMR 6 1.85-1.93 (m, 2H), 2.58 (t, J= 7.0 Hz, 2H), 2.70 (t, J= 7.4 Hz, 2H), 2.94 (t, J=

6.2 Hz, 2H), 3.39 (t, J= 6.2 Hz, 2H), 3.98 (s, 2H), 6.48 (d, J= 7.7 Hz, 2H), 6.68 (t, J=

7.3 Hz, 1H), 7.18-7.31 (m, 7H); 13C NMR 6 30.3, 33.5, 46.1, 52.8, 53.9, 70.3, 111.4,

116.1, 125.8, 128.3, 128.4, 129.1, 141.9, 146.4. Anal. Calcd for CisH22N2: C, 81.16; H,

8.32; N, 10.52. Found: C, 81.39; H, 8.61; N, 10.50.

1-Phenethyl-3-phenylimidazolidine (2.11c): white microcrystals (from EtOH);

yield, 96%; mp 77-78 OC; 1H NMR 6 2.83-2.90 (m, 4H), 3.03 (t, J = 6.2 Hz, 2H), 3.42

(t, J= 6.2 Hz, 2H), 4.06 (s, 2H), 6.45-6.51 (m, 2H), 6.67-6.73 (m, 1H), 7.19-7.33 (m,

7H); 13C NMR 6 35.5, 46.2, 53.0, 56.4, 70.4, 111.4, 116.3, 126.2, 128.5, 128.6, 129.2,

139.8, 146.4. Anal. Calcd for C17H20N2: C, 80.91; H, 7.99; N, 11.10. Found: C, 80.76; H,

8.05; N, 11.15.

1-(4-Methoxybenzyl)-3-phenylimidazolidine (2.11d): white needles (from

CH30H); yield, 81%; mp 80-81 OC; 1H NMR 6 3.01 (t, J= 6.2 Hz, 2H), 3.43 (t, J= 6.2

Hz, 2H), 3.70 (s, 2H), 3.81 (s, 3H), 3.99 (s, 2H), 6.46 (d, J= 8.2 Hz, 2H), 6.70 (t, J= 8.0

Hz, 1H), 6.88 (d, J= 8.7 Hz, 2H), 7.21 (t, J= 8.0 Hz, 2H), 7.30 (d, J= 8.5 Hz, 2H); 13C

NMR 6 46.1, 52.6, 55.3, 58.1, 69.9, 111.4, 113.8, 116.1, 129.1, 129.9, 130.3, 146.4,









158.8. Anal. Calcd for C17H20N20: C, 76.09; H, 7.51; N, 10.44. Found: C, 75.85; H, 8.00;

N, 10.60. HRMS Calcd for C17H20N20 268.1576 (M), found 268.1574.

1-Phenyl-3-phenylethyn-2-ylimidazolidine (2.11e): orange prisms; yield, 80%;

mp 68-69 C; H NMR 6 3.18 (t, J= 6.2 Hz, 2H), 3.47 (t, J= 6.2 Hz, 2H), 3.76 (s, 2H),

4.20 (s, 2H), 6.52 (d, J= 7.9 Hz, 2H), 6.71 (t, J= 7.3 Hz, 1H), 7.21-7.41 (m, 5H),

7.41-7.44 (m, 2H); 13C NMR 6 42.6, 46.2, 51.4, 68.8, 84.2, 85.1, 111.5, 116.3, 122.7,

128.2, 129.2, 131.7, 146.3. Anal. Calcd for ClsH18N2: C, 82.41; H, 6.92; N, 10.68. Found:

C, 82.68; H, 7.18; N, 10.78.

1-Allyl-3-phenylimidazolidine (2.11f): yellow oil; yield, 75%; H NMR 6 2.99 (t,

J= 6.2 Hz, 2H), 3.21-3.24 (m, 2H), 3.39 (t, J= 6.2 Hz, 2H), 4.00 (s, 2H), 5.14-5.29 (m,

2H), 5.89-5.98 (m, 1H), 6.47-6.50 (m, 2H), 6.66-6.71 (m, 1H), 7.19-7.24 (m, 2H); 3C

NMR 6 45.9, 52.5, 57.4, 69.9, 111.4, 116.1, 117.5, 129.1, 135.2, 146.4. Anal. Calcd for

C12H16N2: C, 76.56; H, 8.57; N, 14.88. Found: C, 76.25; H, 8.63; N, 15.07.

1-Ethyl-3-phenethylimidazolidine (2.11g): colorless oil; yield, 75%; 1H NMR 6

1.10 (t, J= 7.5 Hz, 3H), 2.56 (q, J= 7.4 Hz, 2H), 2.78-2.86 (m, 8H). 3.46 (s, 2H),

7.19-7.31 (m, 5H); 13C NMR 6 14.1, 35.8, 49.3, 52.2, 52.5, 57.4, 76.4, 126.0, 128.3,

128.6, 140.1. Anal. Calcd for C13H20N2: C, 76.42; H, 9.87. Found: C, 76.53; H, 9.77.

1-Ethyl-3-(4-methylbenzyl)imidazolidine (2.11h): yellowish oil; yield, 71%; 1H

NMR 6 1.08 (t, J= 7.3 Hz, 3H), 2.33 (s, 4H), 2.50-2.57 (m, 2H), 2.81 (s, 3H), 3.39 (s,

2H), 3.67 (s, 2H), 7.12 (d, J= 7.7 Hz, 2H), 7.24 (d, J= 7.7 Hz, 2H); 13C NMR 6 14.0,

21.0, 49.1, 52.2, 52.3, 59.3, 76.3, 128.4, 128.9, 136.2, 136.5. Anal. Calcd for C13H20N2:

C, 76.42; H, 9.87. Found: C, 76.65; H, 10.34. HRMS Calcd for C13H21N2 205.1704

(M+1), found 205.1693.









1-Benzyl-3-phenethylimidazolidine (2.11i): colorless oil; yield, 79%; 1H NMR 6

2.76 (br s, 4H), 2.84 (br s, 4H), 3.44 (s, 2H), 3.70 (s, 2H), 7.19-7.33 (m, 10H); 13C NMR

6 35.8, 52.3, 52.5, 57.1, 59.5, 76.5, 126.0, 126.9, 128.2, 128.3, 128.4, 128.5, 139.2, 140.1.

Anal. Calcd for ClsH22N2: C, 81.16; H, 8.32; N, 10.52. Found: C, 81.21; H, 8.63; N,

10.31.

1-Allyl-3-benzylimidazolidine (2.11j): colorless oil; yield, 63%; 1H NMR 6 2.83

(s, 4H), 3.17 (d, J= 6.2 Hz, 2H), 3.41 (s, 2H), 3.71 (s, 2H), 5.08 (d, J= 10.1 Hz, 1H),

5.18 (dd, J= 17.1, 2.4 Hz, 1H), 5.84-5.93 (m, 1H), 7.24-7.37 (m, 5H); 13C NMR 6 52.1,

52.4, 58.2, 59.4, 76.2, 116.8, 126.9, 128.2, 128.5, 135.9, 139.2. Anal. Calcd for C13H18N2:

C, 77.18; H, 8.97; N, 13.85. Found: C, 76.85; H, 9.29; N, 13.65.

1-Benzyl-3-(3-phenyl-2-propynyl)imidazolidine (2.11k): brown oil; yield, 65%;

H NMR 6 2.87 (t, J= 6.2 Hz, 2H), 3.01 (t, J= 6.4 Hz, 2H), 3.58 (s, 2H), 3.64 (s, 2H),

3.74 (s, 2H), 7.24-7.43 (m, 10H); 13C NMR 6 43.1, 50.8, 52.6, 59.3, 75.0, 84.2, 85.3,

123.0, 126.9, 128.0, 128.1, 128.2, 128.4, 131.6, 139.1. Anal. Calcd for C19H20N2: C,

82.57; H, 7.29; N, 10.14. Found: C, 82.25; H, 7.64; N, 9.99.

1-Benzyl-3-hexylimidazolidine (2.111): yellow oil; yield, 80%; 1H NMR 6 0.88 (t,

J= 6.7 Hz, 3H), 1.28 (br s, 6H), 1.45 (br s, 2H), 2.47 (t, J= 7.5 Hz, 2H), 2.81 (s, 4H),

3.39 (s, 2H), 3.70 (s, 2H), 7.23-7.36 (m, 5H); 13C NMR 6 14.0, 22.5, 27.1, 29.0, 31.7,

52.3, 52.5, 55.5, 59.6, 76.6, 126.8, 128.1, 128.4, 139.2. Anal. Calcd for C19H20N2: N,

11.37. Found: N, 11.44. HRMS Calcd for C16H27N2 247.2174 (M+1), found 247.2171.

2.4.5 General Procedure for the Reaction of 2.9a-c with NaCN.

A mixture of 2.9a-c (1.0 mmol) and NaCN (0.050 g, 1.0 mmol) in DMSO (5 mL)

was stirred at 25 C for 20 h. The mixture was poured into 20 mL water. For 2.12a, the









precipitate formed was filtered to give white powder, which was recrystallized from

EtOH. For 2.12b,c, the mixture was extracted with CH2C12, and the organic extracts were

washed with 1 M NaOH, water, brine, and dried over anhyd MgSO4. After removal of the

solvent in vacuo, the residue was purified by column chromatography to give 2.12b,c.

2-(3-Phenyl-l-imidazolidinyl)acetonitrile (2.12a): white microcrystals (from

EtOH); yield, 77%; mp 65-66 C; 1HNMR 6 3.15 (t, J= 6.2 Hz, 2H), 3.49 (t, J= 6.2 Hz,

2H), 3.74 (s, 2H), 4.15 (s, 2H), 6.51 (d, J= 8.1 Hz, 2H), 6.75 (t, J= 7.3 Hz, 1H), 7.25 (t,

J= 7.9 Hz, 2H); 13C NMR 6 40.6, 46.2, 51.3, 68.6, 111.7, 114.9, 117.0, 129.3, 145.9.

Anal. Calcd for CllH13N3: C, 70.56; H, 7.00; N, 22.44. Found: C, 70.31; H, 7.14; N,

22.45.

2-(3-Ethyl-l-imidazolidinyl)acetonitrile (2.12b): separated by flash basic A1203

column chromatography with CH2C12 as an eluent; colorless oil; yield, 90%; 1H NMR 6

1.11 (t, J= 7.2 Hz, 3H), 2.56 (q, J= 7.2 Hz, 2H), 2.85 (t, J= 6.6 Hz, 2H), 2.98 (t, J= 6.6

Hz, 2H), 3.51 (s, 2H), 3.65 (s, 2H); 13C NMR 6 13.9, 41.2, 48.6, 50.5, 52.0, 74.5, 115.6.

HRMS Calcd for C7H13N3 139.1109 (M), found 139.1105.

2-(3-Benzyl-l-imidazolidinyl)acetonitrile (2.12c): separated by flash silica gel

column chromatography with hexanes/EtOAc (7:3) as an eluent; colorless oil; yield,

97%; H NMR 6 2.85-2.89 (m, 2H), 2.95-3.00 (m, 2H), 3.47 (s, 2H), 3.59 (s, 2H), 3.70

(s, 2H), 7.24-7.36 (m, 5H); 13C NMR 6 41.2, 50.5, 52.2, 58.6, 74.4, 115.6, 127.0, 128.2,

128.3, 138.5. Anal. Calcd for C12H15N3: C, 71.61; H, 7.51; N, 20.88. Found: C, 71.26; H,

7.41; N, 21.11.









2.4.6 Procedure for the Nucleophilic Substitution of 2.9a with Benzenethiol.

To a solution ofbenzenethiol (0.13 g, 1.2 mmol) in dry THF (10 mL), NaH (60%

in mineral oil, 0.05 g, 1.3 mmol) was added, and the mixture was stirred at 20 OC for 10

min. One drop of methanol was added to quench excess NaH and then 2.9a (0.28 g, 1.0

mmol) was added. The mixture was refluxed for 38 h. After removal of THF under

reduced pressure, the residue was extracted with Et20. The organic extracts were washed

with 2 M NaOH, brine and dried over anhyd MgSO4. The desired compound was purified

by column chromatography with hexanes/EtOAc (4:1) as an eluent.

1-Phenyl-3-(phenylthiomethyl)imidazolidine (2.13): white flakes (from CH3OH);

yield, 66%; mp 64-65 OC; 1HNMR 6 3.12 (t, J= 6.2 Hz, 2H), 3.99 (t, J= 6.3 Hz, 2H),

4.14 (s, 2H), 4.55 (s, 2H), 6.43-6.46 (m, 2H), 6.70 (t, J= 7.3 Hz, 1H), 7.18-7.30 (m,

5H), 7.45-7.48 (m, 2H); 13C NMR 6 46.3, 49.6, 60.2, 67.1, 111.6, 116.4, 126.6, 129.0,

129.2, 130.9, 137.1, 146.2. Anal. Calcd for C16Hs1N2S: C, 71.07; H, 6.71; N, 10.36.

Found: C, 71.09; H, 6.88; N, 10.30.

2.4.7 Procedure for the Nucleophilic Substitution of 2.9a with Triethyl Phosphite.

To a solution of 2.9a (0.28 g, 1.0 mmol) in dry CH2C2 (20 mL) at 0 oC, ZnBr2

(0.22 g, 1.0 mmol) and triethyl phosphite (0.34 mL, 2.0 mmol) were added sequentially.

The reaction mixture was stirred at 0 OC for 2 h and at room temperature overnight. After

extraction with CH2C2, the combined organic layers were washed with 1 M NaOH, brine

and dried over anhyd MgSO4. After removal of the solvent in vacuo, the desired product

was purified by column chromatography with hexanes/EtOAc (4:1) as an eluent.

Diethyl (3-Phenyl-l-imidazolidinyl)methylphosphonate (2.14): yellowish oil;

yield, 70%; 1HNMR 6 1.36 (t, J= 7.0 Hz, 6H), 3.02 (d, J= 12.5 Hz, 2H), 3.17 (t, J= 6.3









Hz, 2H), 3.41 (t, J= 6.1 Hz, 2H), 4.05-4.23 (m, 6H), 6.50 (d, J= 8.2 Hz, 2H), 6.71 (t, J

= 7.3 Hz, 1H), 7.23 (t, J= 7.7 Hz, 2H); 13C NMR 6 16.5 (d, J= 5.3 Hz), 45.8, 50.2 (d, J=

167.3 Hz), 54.7 (d, J= 10.6 Hz), 62.3 (d, J= 6.4 Hz), 71.5 (d, J= 12.7 Hz), 111.5, 116.4,

129.2, 146.2. Anal. Calcd for C14H23N203P: C, 56.37; H, 7.77; N, 9.39. Found: C, 56.39;

H, 7.89; N, 9.59.

2.4.8 General Procedure for the Preparation of Chiral Diamines 2.18a-c from N-Boc-a-
amino Acids 2.15a-c.

a-Amino amides 17a-c were obtained according to our recent paper.

[01JCS(P1)1767] Therefore, we did not obtain these elemental analyses.

A mixture of 2.17a-c (3 mmol) and LiA1H4 (powder, 0.68 g, 18 mmol) in dry THF

(30 mL) was refluxed for 2 days. The mixture was slowly quenched with water under ice-

bath. The precipitate formed was filtered off and washed with CH2C12. The combined

filtration was washed with 1M NaOH, brine and dried over anhydrous K2CO3. Removal

of solvents afforded diamine 2.18a-c, which was directly used for the subsequent

reaction. GC analyses show that the purity of 2.18a-c is more than 90%.

(2S)-NA-(4-Methylphenyl)-1,2-propanediamine (2.18a): yellowish oil; yield,

96%; 1H NMR 6 1.20 (d, J= 7.1 Hz, 3H), 1.20-1.80 (br s, 2H), 2.31 (s, 3H), 2.90 (dd, J

= 12.1, 8.0 Hz, 1H), 3.14-3.22 (m, 2H), 3.80-4.25 (br s, 1H), 6.62 (d, J= 8.4 Hz, 2H),

7.05 (d, J= 8.1 Hz, 2H); 13C NMR 6 20.1, 21.8, 45.9, 52.3, 112.8, 126.1, 129.5, 146.0.

(2S)-4-Methyl-NA-(4-methylphenyl)-1,2-pentanediamine (2.18b): colorless oil;

yield, 93%; 1HNMR 6 0.91 (d, J= 6.5 Hz, 3H), 0.95 (d, J= 6.6 Hz, 3H), 1.28 (t, J= 6.7

Hz, 2H), 1.20-1.40 (br s, 2H), 1.70-1.81 (m, 1H), 2.24 (s, 3H), 2.79 (dd, J= 11.8, 8.7

Hz, 1H), 3.00-3.08 (m, 1H), 3.13-3.20 (m, 1H), 3.80-4.10 (br s, 1H), 6.56 (d, J= 8.1









Hz, 2H), 7.00 (d, J= 8.0 Hz, 2H); 13C NMR 6 20.3, 22.1, 23.5, 24.7, 45.7, 48.4, 51.3,

113.1, 126.5, 129.7, 146.3.

(2S)-NA-(4-Methylphenyl)-3-phenyl-1,2-propanediamine (2.18c): yellowish oil;

yield, 94%; 1HNMR 6 1.02-1.40 (br s, 2H), 2.23 (s, 3H), 2.56 (dd, J= 13.3, 8.4 Hz, 1H),

2.78-2.94 (m, 2H), 3.18-3.27 (m, 2H), 3.90-4.05 (br s, 1H), 6.53 (d, J= 8.2 Hz, 2H),

6.97 (d, J= 8.0 Hz, 2H), 7.18-7.32 (m, 5H); "3C NMR 6 20.3, 42.7, 50.3, 52.1, 113.0,

126.3, 126.5, 128.4, 129.1, 129.6, 138.7, 146.1.

2.4.9 General Procedure for the Preparation of Optically Active Imidazolidines 2.20a-d,
2.21, 2.22.

To a solution of a diamine 2.18a-c (3.0 mmol), BtH (0.36 g, 3.0 mmol) in

CH30H/H20 (10 mL/5 mL), formaldehyde (37% aqueous solution, 0.49 g, 6 mmol) was

added, and the reaction mixture was stirred for 4 h at 20 OC. The precipitate formed was

filtered and washed with cool Et20 to give 2.19a-c. After dried under reduced pressure at

30 C for 24 h, the products were crystallized out from appropriate solvents described

below.

To a solution of 2.19a-c (1.0 mmol) in dry THF (15 mL), an appropriate Grignard

reagent (1.2 mmol) in THF was added dropwise. The reaction mixture was stirred at

room temperature for 30 min and then refluxed for 1 h. The same work-up as used for the

preparation of 2.11 gave 2.20a-d, which was purified by flash column chromatography

(silica gel).

The same procedure as used for the preparation of 2.14 and 2.12b afforded 2.21

and 2.22, respectively.









1-{[(5S)-5-Methyl-3-(4-methylphenyl)tetrahydro-1H-imidazol-l-yl]methyl}-

1H-1,2,3-benzotriazole (2.19a): colorless microcrystals (from EtOH); yield, 85%; mp

129-130 oC; [a]25D = -16.2 (c 1.71, CHC13); 1H NMR 6 1.41 (d, J= 6.1 Hz, 3H), 2.21 (s,

3H), 3.02 (t, J= 8.1 Hz, 1H), 3.25-3.31 (m, 1H), 3.45 (t, J= 7.3 Hz, 1H), 4.13, 4.38 (AB,

J= 4.1 Hz, 2H), 5.64 (d, J= 3.5 Hz, 2H), 6.34 (d, J= 8.5 Hz, 2H), 7.00 (d, J= 8.2 Hz,

2H), 7.38 (t, J= 7.2 Hz, 1H), 7.52 (t, J= 7.5 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 8.07 (d, J

= 8.4 Hz, 1H); 13C NMR 6 16.9, 20.2, 54.1, 54.6, 61.8, 68.1, 109.5, 111.7, 120.0, 124.0,

126.0, 127.7, 129.7, 133.6, 143.9, 145.9. Anal. Calcd for C18H21Ns: C, 70.33; H, 6.89; N,

22.78. Found: C, 70.24; H, 7.11; N, 22.95.

1- { [(5S)-5-Isobutyl-3-(4-methylphenyl)tetrahydro-1H-imidazol- -yl] methyl}-

1H-1,2,3-benzotriazole (2.19b): colorless microcrystals (from hexanes/EtOAc); yield,

93%; mp 103-104 OC; [a]25D= +4.8 (c 1.62, CHC13); 1HNMR 6 0.92 (d, J= 6.3 Hz, 3H),

0.93 (d, J= 6.3 Hz, 3H), 1.37-1.46 (m, 1H), 1.61-1.72 (m, 1H), 1.76-1.84 (m, 1H), 2.22

(s, 3H), 2.99 (t, J= 7.5 Hz, 1H), 3.29-3.33 (m, 1H), 3.49 (t, J= 7.5 Hz, 1H), 4.19, 4.31

(AB, J= 4.8 Hz, 2H), 5.61 (d, J= 2.8 Hz, 2H), 6.37 (d, J= 8.0 Hz, 2H), 7.00 (d, J= 8.0

Hz, 2H), 7.38 (t, J= 7.5 Hz, 1H), 7.51 (t, J= 7.5 Hz, 1H), 7.66 (d, J= 8.2 Hz, 1H), 8.07

(d, J= 8.4 Hz, 1H); 13C NMR 6 20.3, 22.3, 23.5, 25.7, 41.9, 52.5, 58.1, 63.5, 67.9, 109.7,

112.0, 120.0, 124.0, 126.1, 127.6, 129.7, 133.5, 144.0, 146.0. Anal. Calcd for C21H27N5:

C, 72.17; H, 7.79; N, 20.04. Found: C, 72.39; H, 7.82; N, 20.23.

1-{[(5S)-5-Benzyl-3-(4-methylphenyl)tetrahydro-1H-imidazol- -yl]methyl}-

1H-1,2,3-benzotriazole (2.19c): white microcrystals (from EtOH); yield, 93%; mp

94-95 OC; [a]25D= +1.8 (c 1.70, CHC13); 1H NMR 6 2.21 (s, 3H), 2.74 (dd, J= 13.2, 8.3

Hz, 1H), 3.08 (t,J= 7.6 Hz, 1H), 3.22-3.31 (m, 2H), 3.58-3.63 (m, 1H), 4.24, 4.39 (AB,









J= 5.0 Hz, 2H), 5.56, 5.67 (AB, J= 13.7 Hz, 2H), 6.35 (d, J= 8.4 Hz, 2H), 6.98 (d, J=

8.1 Hz, 2H), 7.22-7.40 (m, 6H), 7.45-7.49 (m, 2H), 8.05 (d, J= 8.2 Hz, 1H); 13C NMR 6

20.3, 39.2, 52.2, 61.2, 63.7, 68.2, 109.7, 112.3, 120.0, 124.0, 126.4, 126.6, 127.7, 128.6,

129.0, 129.6, 133.5, 138.1, 144.0, 145.9. Anal. Calcd for C24H25N5: C, 75.17; H, 6.57; N,

18.26. Found: C, 74.95; H, 6.77; N, 18.29.

(4S)-3-(3-Butenyl)-4-methyl-l-(4-methylphenyl)tetrahydro- 1H-imidazole

(2.20a): yellowish oil; yield, 94%; []25D = +111 (c 2.17, CHC13); 1H NMR 6 1.20 (d, J=

6.0 Hz, 3H), 2.24 (s, 3H), 2.30-2.37 (m, 3H), 2.82-2.94 (m, 2H), 3.02 (t, J= 8.2 Hz, 1H,

Ha), 3.44 (t, J= 7.4 Hz, 1H, Hb), 3.68, 4.43 (AB, J= 4.1 Hz, 2H), 5.04 (d, J= 10.2 Hz,

1H), 5.11 (d, J= 17.0 Hz, 1H), 5.79-5.92 (m, 1H), 6.40 (d, J= 8.4 Hz, 2H), 7.02 (d, J=

8.2 Hz, 2H); 13C NMR 6 16.8, 20.2, 33.2, 51.8, 53.9, 58.7, 70.8, 111.3, 115.8, 125.1,

129.6, 136.3, 144.3. Anal. Calcd for C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C,

78.05; H, 9.63; N, 11.99.

(4S)-3-Allyl-4-isobutyl-1-(4-methylphenyl)tetrahydro-1H-imidazole (2.20b):

yellowish oil; yield, 78%; [a]25D = +28.7 (c 1.67, CHC13); 1H NMR 6 0.93 (d, J= 6.5 Hz,

3H), 0.95 (d, J= 6.5 Hz, 3H), 1.30-1.40 (m, 1H), 1.53-1.69 (m, 2H), 2.24 (s, 3H),

2.91-3.05 (m, 3H), 3.47-3.54 (m, 2H), 3.73, 4.31 (AB, J= 5.1 Hz, 2H), 5.15 (d, J= 10.2

Hz, 1H), 5.25 (d, J= 17.0 Hz, 1H), 5.87-6.00 (m, 1H), 6.41 (d, J= 8.4 Hz, 2H), 7.03 (d,

J= 8.2 Hz, 2H); 13C NMR 6 20.3, 22.3, 23.7, 25.8, 41.9, 52.5, 56.1, 61.4, 70.3, 111.6,

117.4, 125.3, 129.6, 135.6, 144.5. Anal. Calcd for C17H26N2: C, 79.02; H, 10.14; N,

10.84. Found: C, 78.79; H, 9.84; N, 10.70.

(4S)-4-Isobutyl-3-(4-methylbenzyl)-l-(4-methylphenyl)tetrahydro-lH-

imidazole (2.20c): yellowish oil; yield, 85%; [a]25D = +74.9 (c 2.50, CHC13); 1H NMR 6









0.94 (d, J= 5.9 Hz, 6H), 1.41-1.46 (m, 1H), 1.63-1.76 (m, 2H), 2.22 (s, 3H), 2.34 (s,

3H), 2.99-3.09 (m, 1H), 3.06 (q, J= 7.6 Hz, 1H), 3.37, 4.02 (AB, J= 13.0 Hz, 2H), 3.55

(dd, J= 7.4, 6.6 Hz, 1H), 3.68, 4.15 (AB, J= 5.1 Hz, 2H), 6.35 (d, J= 8.4 Hz, 2H), 6.98

(d, J= 8.3 Hz, 2H), 7.13 (d, J= 7.7 Hz, 2H), 7.25 (d, J= 7.8 Hz, 2H); 13C NMR 6 20.3,

21.1, 22.4, 23.7, 25.9, 42.0, 52.6, 57.0, 61.6, 70.4, 111.6, 125.2, 128.6, 129.0, 129.6,

135.8, 136.7, 144.5. Anal. Calcd for C22H30N2: C, 81.94; H, 9.38; N, 8.69. Found: C,

81.66; H, 9.58; N, 8.72.

(4S)-4-Benzyl-l-(4-methylphenyl)-3-(3-phenyl-2-propynyl)tetrahydro-1H-

imidazole (2.20d): pale brown prism; yield, 66%; mp 91-92 OC; []25D = +6.8 (c 1.51,

CHC13); 1H NMR 6 2.23 (s, 3H), 2.68 (dd, J= 13.3, 9.2 Hz, 1H), 3.13-3.20 (m, 2H),

3.30-3.35 (m, 1H), 3.47-3.52 (m, 1H), 3.83 (d, J= 17.7 Hz, 2H), 4.17, 4.45 (AB, J= 4.2

Hz, 2H), 6.40 (d, J= 8.2 Hz, 2H), 7.01 (d, J= 8.2 Hz, 2H), 7.21-7.33 (m, 8H), 7.41-7.43

(m, 2H); 13C NMR 6 20.3, 38.6, 40.4, 52.4, 62.0, 69.8, 83.8, 85.4, 111.7, 122.0, 125.5,

126.4, 128.2, 128.3, 128.5, 129.0, 129.6, 131.7, 138.5, 144.3. Anal. Calcd for C26H26N2:

C, 85.21; H, 7.15; N, 7.64. Found: C, 85.16; H, 7.16; N, 7.99.

Diethyl [(5S)-5-methyl-3-(4-methylphenyl)tetrahydro-1H-imidazol-1-

yl]methylphosphonate (2.21): yellowish oil; yield, 90%; [a]25D= +50.6 (c 1.58, CHC13);

1HNMR 6 1.22 (d, J= 5.4 Hz, 3H), 1.35 (t, J= 7.0 Hz, 6H), 2.24 (s, 3H), 2.77 (dd, J=

15.1, 6.6 Hz, 1H, Ha), 2.98-3.02 (m, 2H), 3.20 (dd, J= 17.7, 15.1 Hz, 1H, Hb), 3.46-3.47

(m, 1H), 3.87, 4.65 (AB, J= 4.7 Hz, 2H), 4.12-4.22 (m, 4H), 6.42 (d, J= 8.4 Hz, 2H),

7.03 (d, J= 8.4 Hz, 2H); 13C NMR 6 16.4 (d, J= 5.7 Hz), 16.5 (d, J= 5.7 Hz), 16.7, 20.2,

47.8 (d, J= 167.2 Hz), 53.4, 60.1 (d, J= 17.8 Hz), 61.9 (d, J= 6.3 Hz), 62.5 (d, J= 6.3









Hz), 71.9 (d, J= 2.3 Hz), 111.5, 125.4, 129.6, 144.2. Anal. Calcd for C16H27N203P: C,

58.88; H, 8.34; N, 8.58. Found: C, 58.58; H, 8.33; N, 8.60.

2-[(5S)-5-Benzyl-3-(4-methylphenyl)tetrahydro-1H-imidazol-1-yl]acetonitrile

(2.22): yellowish flakes (from EtOH); yield, 99%; mp 76-77 OC; [a]25D = +40.4 (c 1.98,

CHC13); 1H NMR 6 2.23 (s, 3H), 2.71 (dd, J= 13.0, 7.1 Hz, 1H), 2.98 (dd, J= 13.3, 5.1

Hz, 1H), 3.14 (br s, 1H), 3.36-3.41 (m, 2H), 3.63 (s, 2H), 4.05, 4.37 (AB, J= 4.0 Hz,

2H), 6.38 (d, J= 8.4 Hz, 2H), 7.02 (d, J= 8.2 Hz, 2H), 7.21-7.35 (m, 5H); 13C NMR 6

20.2, 38.6, 38.9, 52.3, 62.1, 69.9, 111.9, 114.8, 126.2, 126.7, 128.6, 128.8, 129.6, 137.5,

143.7. Anal. Calcd for C19H21N3: C, 78.31; H, 7.26; N, 14.42. Found: C, 78.45; H, 7.45;

N, 14.11.

2.4.10 Procedure for the Preparation of the Bt Intermediate 2.24 and its Substitution with
NaCN.

A mixture of 1-ethyl-2-(4-nitrophenyl)imidazolidine (2.23, 0.66 g, 3.0 mmol), BtH

(0.36 g, 3.0 mmol), formaldehyde (37% aq solution; 0.25 g, 3.0 mmol) in CH30OHH20

(10/4 mL) was stirred at room temperature for 24 h. The precipitate formed was filtered

and recrystallized from EtOH to give 2.24.

A mixture of 2.24 (0.35 g, 1.0 mmol) and NaCN (0.10 g, 2.0 mmol) was stirred in

DMSO (3 mL) at 25 OC for 24 hours. The mixture was diluted with CH2C12, washed with

water and dried over anhyd MgSO4. After removal of the solvent in vacuo, the residue

was purified by flash basic A1203 column chromatography with hexanes/EtOAc (6:4) as

an eluent to afford 2.25.

1-{[3-Ethyl-2-(4-nitrophenyl)-1-imidazolidinyl]methyl}-1H-1,2,3-benzotriazole

(2.24): pale yellow microcrystals (from EtOH); yield, 85%; mp 121-122 OC; 1H NMR 6

0.92 (t, J= 7.2 Hz, 3H), 2.06-2.13 (m, 1H), 2.29-2.42 (m, 2H), 3.10-3.17 (m, 1H),









3.33-3.40 (m, 1H), 3.51 (q, J= 7.4 Hz, 1H), 4.11 (s, 1H), 5.29, 5.45 (AB, J= 14.0 Hz,

2H), 7.34-7.39 (m, 2H), 7.48 (t, J= 7.1 Hz, 1H), 7.75 (d, J= 8.5 Hz, 2H), 8.04 (d, J=

7.4 Hz, 1H), 8.21 (d,J= 8.7 Hz, 2H); 13C NMR 6 13.4, 46.4, 48.1, 50.6, 62.2, 83.4,

109.4, 119.9, 123.4, 124.0, 127.6, 130.2, 133.6, 145.6, 147.4, 148.3. Anal. Calcd for

C18H20N602: C, 61.35; H, 5.72; N, 23.85. Found: C, 61.29; H, 5.83; N, 23.90.

2-[3-Ethyl-2-(4-nitrophenyl)-l-imidazolidinyl]acetonitrile (2.25): Brown oil;

yield, 92%; 1HNMR 6 1.00 (t, J= 7.2 Hz, 3H), 2.22-2.34 (m, 1H), 2.42-2.54 (m, 1H),

2.62-2.71 (m, 1H), 2.99-3.06 (m, 1H), 3.24 (d, J= 17.6 Hz, 1H), 3.39-3.54 (m, 2H),

3.57 (d, J= 17.7 Hz, 1H), 3.92 (s, 1H), 7.67 (d, J= 8.6 Hz, 2H), 8.23 (d, J= 8.6 Hz, 2H);

13C NMR 6 13.4, 39.0, 46.5, 49.5, 50.2, 85.4, 115.0, 123.7, 129.9, 146.4, 148.6. Anal.

Calcd for C13H16N402: C, 59.99; H, 6.20; N, 21.52. Found: C, 59.93; H, 6.17; N, 21.80.

2.4.11 Procedure for the Preparation of 1-Substituted-3-methvl-2,3-dihydro-1H-
benzimidazoles 2.28, 2.29.

A mixture of N-(2-aminophenyl)-N-methylamine (2.26a, 0.37 g, 3.0 mmol), BtH

(0.36 g, 3.0 mmol), formaldehyde (37% aq solution; 0.49 g, 6 mmol) in CH30OHH20 (10

mL/4 mL) was stirred at room temperature overnight. Then an additional 10 mL water

was added and the mixture was stirred for 1 h. The precipitate formed was filtered and

washed with cool ethanol to give 27.

To a solution of vinyl magnesium bromide (2.0 M in THF; 0.7 mL, 1.4 mmol) at 0

C, ZnCl2 (0.5 M in Et20; 3.0 mL, 1.5 mmol) and a solution of 2.27 (0.26 g, 1.0 mmol) in

dry THF (10 mL) was added subsequently. The reaction mixture was stirred for 20 min at

room temperature, and then refluxed for 2 h. After cooling, the mixture was quenched

with water, and extracted with CH2C12. The organic extracts were washed with 1M

NaOH, water, brine, and dried over anhydrous K2CO3. Evaporation of the solvent in









reduced pressure gave the crude product 2.28, which was purified by flash column

chromatography on basic A1203 with hexanes/ethyl acetate (8:2).

The same procedure as used for the preparation of 2.25 afforded 2.29.

1-Benzotriazolylmethyl-3-methyl-2,3-dihydro-1H-benzimidazole (2.27):

obtained as a mixture of Bt1 and Bt2 isomers in ca. 6:1 ratio (only 1H, 13C NMR data for

the Bt1 isomer are presented); white microcrystals (from CH30H); yield, 85%; mp

122-124 C; H NMR 6 (Bt1) 2.66 (s, 3H), 4.61 (s, 2H), 5.96 (s, 2H), 6.38-6.41 (m, 1H),

6.67-6.77 (m, 2H), 6.81-6.83 (m, 1H), 7.34-7.39 (m, 1H), 7.46 (t, J= 7.2 Hz, 1H), 7.58

(d, J= 8.0 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H); 13C NMR 6 (Bt1) 34.0, 60.2, 76.0, 106.6,

106.7, 109.7, 118.8, 119.9, 120.8, 124.1, 127.8, 132.7, 138.6, 142.9, 146.1. Anal. Calcd

for C15H15N5: C, 67.90; H, 5.70; N, 26.40. Found: C, 67.72; H, 5.46; N, 26.40.

1-Allyl-3-methyl-2,3-dihydro-1H-benzimidazole (2.28): Rf= 0.70 [eluent:

hexanes/CH2C2 = 7:3; A1203 TLC plate (Aldrich, Cat No. Z23421-4)]; extremely labile

to air; yellowish oil; yield, 83%; 1H NMR (DMSO-d6) 6 2.64 (s, 3H), 2.79 (d, J= 6.1 Hz,

2H), 4.29 (s, 2H), 5.19 (d, J= 12.1, 2.1 Hz, 1H), 5.30 (dd, J= 17.2, 2.0 Hz, 1H),

5.84-5.94 (m, 1H), 6.38-6.45 (m, 2H), 6.50-6.55 (m, 2H); 13C NMR (DMSO-d6) 6 34.0,

50.4, 77.5, 105.8, 106.2, 117.5, 118.5, 118.7, 134.1, 141.9, 143.2; GC-MS (EI): 174

(M+).

2-(3-Methyl-2,3-dihydro-1H-benzimidazol-l-yl)acetonitrile (2.29): Rf= 0.70

[eluent: hexanes/CH2C2 = 7:3; A1203 TLC plate (Aldrich, Cat No. Z23421-4)]; separated

by flash basic A1203 column chromatography with CH2C12 as an eluent; extremely labile

to air; brown oil; yield, 94%; 1H NMR (DMSO-d6) 6 2.72 (s, 3H), 4.38 (s, 2H), 4.46 (s,

2H), 6.55 (d, J= 7.2 Hz, 1H), 6.65-6.78 (m, 3H); 13C NMR (DMSO-d6) 6 34.0, 35.4,









76.7, 106.7, 115.9, 118.7, 120.8, 139.4, 143.3; GC-MS (EI): 173 (M+). Anal. Calcd for

C1loH1N3: H, 6.40; N, 24.26. Found: H, 6.54; N, 24.16.

2.4.12 Procedure for the Preparation of 2-(2-Anilinoanilino)acetonitrile (2.31).

The same procedure as used for the preparation of 2.24 and 2.25 gave compounds

2.30 and 2.31, respectively.

N-(1H-1,2,3-Benzotriazol- -ylmethyl)-Ni-phenyl-1,2-benzenediamine (2.30):

white microcrystals; yield, 92%; mp 146-147 OC; 1H NMR 6 5.18 (s, 1H), 5.51 (t, J= 6.8

Hz, 1H), 6.07 (d, J= 7.0 Hz, 2H), 6.85 (d, J= 7.9 Hz, 2H), 6.78-6.85 (m, 2H),

7.05-7.16 (m, 5H), 7.31-7.42 (m, 2H), 7.49 (d, J= 7.9 Hz, 1H), 8.03 (d, J= 8.2 Hz, 1H);

13C NMR 6 57.9, 109.9, 112.8, 115.2, 119.6, 120.0, 120.1, 124.0, 126.1, 126.8, 127.4,

128.8, 129.3, 132.3, 141.2, 145.6, 146.4. Anal. Calcd for C19H17N5: C, 72.36; H, 5.43; N,

22.21. Found: C, 72.47; H, 5.79; N, 22.27.

2-(2-Anilinoanilino)acetonitrile (2.31): separated by basic A1203 flash column

chromatography; yellow plates (from ethanol/hexanes); yield, 77%; mp 102-103 OC; 1H

NMR 6 4.08 (d, J= 7.0 Hz, 2H), 4.55 (t, J= 6.7 Hz, 1H), 5.13 (s, 1H), 6.68 (d, J= 7.8

Hz, 2H), 6.81-6.90 (m, 3H), 7.15-7.25 (m, 4H); 13C NMR 6 32.4, 111.9, 115.2, 116.8,

119.8, 120.2, 125.7, 126.5, 129.3, 129.4, 141.2, 145.3. Anal. Calcd for C14H13N3: C,

75.31; H, 5.87; N, 18.82. Found: C, 75.60; H, 5.65; N, 18.89.














CHAPTER 3
NOVEL SYNTHESES OF HEXAHYDROIMIDAZO[1,5-b]ISOQUINOLINES AND
TETRAHYDROIMIDAZO[1,5-b]ISOQUINOLIN-1(5H)-ONES VIA IMINIUM
CATION CYCLIZATIONS

3.1 Introduction

Following our recent syntheses of optically active imidazolidines 3.6 from N-Boc-

a-amino-acids, [02JOC3109] we have now developed routes to novel tricyclic

1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolines 3.1 and 2,3,10,10a-

tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones 3.2. The nearest known analogs of 3.1

and 3.2 are 10,10a-dihydroimidazo[ 1,5-b]isoquinoline- 1,3(2H, 5H)-diones 3.3, which are

of interest as inhibitors of inflammation, [77CA155653q] [78JPS718] apoprotein B-100

biosynthesis, [99CA52421k] and matrix-degrading metalloproteinase. [99CA184961s]

The parent compound 3.3 (R1 = R2 = R3 = H) was obtained by cyclization of

1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid with KOCN. [77CA155653q]

[78JPS718] Significant synthetic activity to prepare derivatives of 3 has involved (i) N-

alkylation of 3.3 (R1 = R2 = R3 = H) with N-(2-chloroethyl)piperidine; [77CA155653q]

[78JPS718] (ii) Mannich condensation of 3.3 (R1 = R2 = R3 = H) with formaldehyde and

secondary amines; [90CCC540] (iii) modification of 3.3 (R1 = H, alkyl or Ph, R2 = R3 =

H) via bromination and nucleophilic substitution. [99CA52421k] [91JCS(P1)119]

Additional analogs of 3.3 have been made by (iv) solid phase supported intramolecular

cyclization of N-Z-a-amino-amides. [96TL937]

Optically active imidazolidines 3.6 were synthesized by Mannich condensations of

chiral diamines 3.4 with benzotriazole and formaldehyde, followed by nucleophilic









substitutions of the benzotriazolyl group in 3.5. [02JOC3109] Previous syntheses of 1,4-

dihydro-3(2H)-isoquinolinones, [93JHC381] tetrahydro[1,3]oxazolo[3,4-b]isoquinolin-3-

ones [99TA255] and tetrahydroisoquinolines [01TA2427] by intramolecular cyclizations

utilizing Lewis acid-activated benzotriazole as a leaving group, suggested a route to 3.1

by iminium cation Lewis acid promoted cyclizations of intermediates 3.5 (Scheme 3-1).

Success of the methodology led to its extension to prepare 2,3,10,10a-tetrahydro-

imidazo[1,5-b]isoquinolin- 1 (5H)-ones 3.2.

0 R2 0

N-R N-R1 I N-R1
Ni/ N N
R2 R3 O
3.1 3.2 3.3


Ph BtH Ph Ph-
2 HCHO Nu-
H-N NR N NR N N'R
H H Bt Nu
3.4 3.5 3.6

L.A. -Bt

-H+
BtH = benzotriazole 3[ 1 -~ 3.1
5N+ NR

X

Scheme 3-1. Intramolecular cyclizations utilizing Lewis acid-activated benzotriazole

3.2 Results and Discussion

3.2.1 Preparation of Chiral Diamines 3.11a-c from N-Boc-Phe-OH (3.7).

N-Boc-a-amino-amides 3.9a-c were readily obtained from optically active N-Boc-

Phe-OH (3.7) and primary amines 3.8a-c (R =p-CH3C6H4, c-C6H11 or PhCH2) using the

mixed anhydride method. [01JCS(P1)1767] [00TL37] We previously used excess









HCl/EtOAc to remove the Boc protecting group (usually needs 12-24 h until the

disappearance of 3.9). [02JOC3109] [01JCS(P1)1767] We now find that 8 equiv of

CF3COOH in dry CH2C12 efficiently removes N-Boc in 2-5 h giving the a-amino-amides

3.10a-c in >88% yields. Treatment of 3.10a-c with 6 equiv of LiAlH4 in refluxing THF

for 2 days afforded chiral diamines 3.11a-c in >90% yields. Intermediates 3.9a-c,

3.10a-c and 3.11a-c were all used as crude products for the subsequent reactions.

Ph
Ph + RNH2 Ph O

BocNH OH BocNH NHR H2N NHR
3.7 3.8a-c 3.9a-c 3.10a-c

iv

N-R h Ph
IN- N-R Bt, / \ / \
N R BtN- N-R H2N NHR

3.1a-c 3.12a-c 3.11a-c

a, R = p-MeC6H4; b, R = c-C6H11; c, R = PhCH2

i) CICOOBu-i, N-methylmorpholine; ii) CF3COOH; iii) aq. NaOH
iv) LiAIH4; v) BtH, 2 HCHO (aq.); vi) AIC13

Scheme 3-2. Synthesis of 2-substituted hexahydroimidazo[1,5-b]isoquinolines

3.2.2 Syntheses of 1,2,3,5,10,10a-Hexahydroimidazo[ 1,5-b]isoquinolines 3.1a-c.

Mannich condensation of chiral diamines 3.11a-c with 1 equiv of benzotriazole

and 2 equiv of formaldehyde (37% aqueous solution) in an aqueous solution at 25 C

gave benzotriazolyl intermediates 3.12a-c in 93%, 96% and 90% yields, respectively.

Compounds 3.12a,c were obtained solely as benzotriazol-1-yl isomers; 3.12b was

obtained as a mixture of Bt and Bt2 isomers in ca. 26:1 ratio.









Treatment of crude 3.12a-c with 3 equiv of AiC13 in refluxing CH2C12 afforded 2-

substituted- 1,2,3,5,10,10a-hexahydroimidazo[ 1,5-b]isoquinolines 3.1a-c (Scheme 3-2).

The structures of 3.1a-c are supported by their 1H, 13C NMR spectra and microanalyses.

Lewis acid AiC13 facilitates loss of the benzotriazolyl anion to form an iminium cation,

which then undergoes intramolecular cyclization to afford 3.1a-c.

3.2.3 Syntheses of 2,3,10,10a-Tetrahydroimidazo[1,5-b]isoquinolin-l(51H)-ones 3.15a-c.
(c.f. Scheme 3-3)

The reaction of a-amino-amide 3.10a with benzotriazole and formaldehyde in

aqueous solution at 25 C did not produce the desired cyclized compound 3.14a; instead

acyclic 3.13 was obtained in 92% yield, due to the lower nucleophilic activity of amide

nitrogen. Therefore, stronger conditions using azeotropic distillation with

paraformaldehyde was applied and Bt intermediates 3.14a-c were prepared in 92%, 91%

and 94% yields, respectively. Attempts to purify 3.14a-c by column chromatography

failed due to their significant decomposition on silica gel. Therefore, compounds 3.14a-c

were used directly for the subsequent cyclizations.

The treatment of 3.14a-c with 3 equiv of A1C13 in refluxing CH2C12 gave

2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin- 1(5H)-ones 3.15a-c in 82%, 83% and

78% yields, respectively. The structures of 3.15a-c are supported by the their 1H, 13C

NMR spectra and microanalyses. The two methylene protons at the 5-position in 3.15a-c

appear at 3.7-4.0 ppm as a typical AB system with JAB = 14 Hz.

We attempted direct treatment of a-amino-amide 3.10a with excess

paraformaldehyde in the presence of AlC13, but could not isolate any desired tricyclic

3.15a. This result highlighted the necessity of using the benzotriazole.









BtH
Ph- O aq. HCHO Ph O

H2N NHR R = C6H4Me-p Bt CH2NH NHC6H4Me-p
3.10a-c 3.13
BtH (CH20), AIC13
(CH20)n


Bt, ` N
N /N R 3

3.14a-c 3.15a-c

a, R = p-MeC6H4; b, R = c-C6H11; c, R = PhCH2

Scheme 3-3. Synthesis of tetrahydroimidazo[1,5-b]isoquinolin- 1 (5H)-ones

3.2.4 Syntheses of Chiral 3-Substituted-2,3,10,1 Oa-tetrahvdroimidazo[1,5-b]isoquinolin-
1(5H)-ones 3.18a-c. (c.f. Scheme 3-4)

We further investigated the modification of 2,3,10,10a-tetrahydroimidazo[1,5-

b]isoquinolin-1(5H)-ones 3.15 at 3-position. In agreement with the previous reactions of

a-amino-amides and aldehydes, [85T611] [75JHC995] we obtained 3.16b,c exclusively

as the trans-isomers; however, trans-3.16a was isolated in 38% yield together with the

corresponding cis-3.16'a in 31% isolated yield. The absolute configurations of trans-

3.16a-c and cis-3.16'a were determined by NOE experiments. For example, a strong

positive NOE effect between H(2) (5.81 ppm, s) and H(5) (4.00 ppm, t) in 16'a confirms

its cis-configuration. For trans-16a-c, no positive NOE effect was observed between

H(2) and H(5); however, small but distinct NOE effects between H(2) and PhCH2 at the

5-position proved their trans-configurations.

Reaction of 3.16a-c with benzotriazole and aqueous formaldehyde readily gave Bt

intermediates 3.17a-c, which were directly treated with AlC13 to furnish enantiopure

trans-3-substituted-2,3,10,10a-tetrahydroimidazo[ 1,5-b]isoquinolin- (5H)-ones 3.18a-c.









The same route from cis-3.16'a led to enantiopure cis-3.18'a. The 1H NMR spectra show

that NCHN (5.68 ppm, d) in trans-3.18a appears at a lower field than NCHN (5.32 ppm,

d) in cis-3.18'a. The positive NOE effect of H(3) and H(10a) in 3.18'a also confirms its

cis-configuration.

We attempted reactions of 3.16a-c with paraformaldehyde and AlC13 in the

absence of benzotriazole. The crude NMR spectra of the products showed a mixture of

trans-3.18a-c and cis-3.18'a-c in a ratio ranging from 4:1 to 5:1. It is impossible to

separate trans-3.18a-c and cis-3.18'a-c by column chromatography due to their very

close Rf values on alumina or silica gel TLC plate. This result indicates the possible

Lewis acid promoted ring opening and closing of the five-membered ring in 3.16a-c. We

further treated trans-3.16a with AlC13 only, and did observe the formation of cis-3.16'a in

1:4 ratio.

We have suggested two recemization processes; 1) the nitrogen at position-1 may

coordinate with AlC13 to form intermediate A, which undergoes ring opening to generate

an iminium cation intermediate B. The lone electron pair of the nitrogen in B attacks the

iminium cation from above (I) or below (II) the plane, leading to trans-3.16a and cis-

3.16'a, respectively (Scheme 3-5, left). 2) The oxygen may coordinate with AlC13 to form

intermediate C. The a-hydrogen would leave to form the enolate intermediate D, which

lead to the racemization for the formation of 3.16"a (Scheme 3-5, right).











Ph- O

H2N NHR
3.10a-c


PhCHO
-----------------


(CH20)n b
AIC13 /


Ph H2O


S3.16ah-
3.16a-ca


SBtH
HCHO
0 Ph
N-R AIC13 Bt
N3NR Bt. N NR

Ph H PIh H
3.18a-c 3.17a-c


a, R = p-MeC6H4; b, R = c-C6H11; c, R = PhCH2

a For trans-16a, the cis-16'a was isolated in 31% yield.
b This route resulted in a mixture of trans-18a-c and cis-18'a-c
in a ratio range from 4:1 to 5:1.

Scheme 3-4. Syntheses of chiral 3-substituted tetrahydroimidazo[1,5-b]isoquinolin-
1(5H)-ones


AICd3 Ph O
H*N N.NAr
H Ph


3.16'a


H N N
H( -Ar

3.16a

I IC1


AICd3 Ph-,,
H-N( N'Ar
Ph" H
3.16"a
f


a Ar = p-MeC6H4; Reflux of only trans-16a resulted in
a mixture of trans-16a and cis-16'a in ca. 4:1 ratio.

Scheme 3-5. Isomerization of chiral 3-substituted tetrahydroimidazo[1,5-b]isoquinolin-
1(5H)-ones


Ph^O
H N 'Ar
PW H
3.16a

AlICl3


\1









3.2.5 Attempts to Synthesize 1,2a,3,4a,5,9b-Hexahydrobenzo[g]imidazo[2,1,5-
cdlindolizin-4(2H)-one (3.23).

We recently reported reaction of succindialdehyde (3.19) with benzotriazole and N-

phenylethylenediamine leading to 1-phenyl-5-(benzotriazol-1-yl)hexahydro-1H-

pyrrolo[1,2-a]imidazole 3.20. The benzotriazolyl group at the 5-position in 3.20 is readily

removed by nucleophilic substitutions with Grignard reagents, allylsilanes, silyl enol

ethers, or triethyl phosphite to furnish novel 1-phenyl-5-substituted-hexahydro-1H-

pyrrolo[1,2-a]imidazoles 3.21 [Nu = alkyl, aryl, allyl and P(O)(OEt)2] (Scheme 3-6).

[00JOC3683] Since chiral diamines 3.11a-c were readily obtained in high yields, our

initial idea intended to use chiral diamine 3.11a instead of N-phenylethylenediamine, in

order to control the two new chiral centers at 5- and 7a-positions. Subsequent treatment

of Bt intermediates 3.22 was supposed to undergo intramolecular cyclizations at the

tethered phenyl group to give 3.23.




CHOCHO H2N HNPh Bt N NPh Nu- Nu N NPh
BtH "I
3.19 3.20 3.21
11a, BtH

Ph
NOE H3 AIC3 H
ABtI3 N
Bt N C6H4Me-p N N-C6H4Me-p
C H5\ /H7a /H7a

3.22 (de > 99%) 3.23

Scheme 3-6. Attempts to synthesize 1,2a,3,4a,5,9b-hexahydrobenzo[g]imidazo[2,1,5-
cd]indolizin-4(2H)-one









Reaction of chiral diamine 3.11a with succindialdehyde (3.19, obtained by

treatment of 2,5-dimethoxytetrahydrofuran with 0.1 M HC1) and benzotriazole in CH2C12

at room temperature for 24 h readily afforded Bt intermediate 3.22 as a single enantiomer

in 81% yield (Scheme 3-6). The stereochemistry of 3.22 was determined by NOE NMR

experiments. H NMR spectra of 3.22 show that H(3), H(7a) and H(5) appear at 3.7 ppm

multipleet, 5.1 ppm (doublet-doublet) and 6.0 ppm (triplet), respectively. A significant

positive NOE effect was observed between H(3) and H(5), and no NOE effect was

observed between H(7a) with either H(3) or H(5). Thus, NOE analysis demonstrates that

H(3) and H(5) in 3.22 are in a cis-orientation whereas H(3) and H(7a) are in trans-

orientation.

Treatment of 3.22 with 2 equiv of AlC13 did not afford the desired 3.23, but gave a

decomposed mixture possibly due to the labile NCHN moiety in the presence of a Lewis

acid.

3.3 Conclusion

In summary, starting from easily available N-Boc-a-amino-acids, we have

developed an efficient method for the preparation of novel enantiopure 1,2,3,5,10,10a-

hexahydroimidazo[1,5-b]isoquinolines 3.1a-c, 2,3,10,1 a-tetrahydroimidazo[ 1,5-

b]isoquinolin-l(5H)-ones 3.15a-c and 3.18a-c via Lewis acid promoted iminium cation

intramolecular cyclizations.

3.4 Experimental Section

Column chromatography was performed on silica gel (200-425 mesh). All of

reactions were carried out under nitrogen.









3.4.1 General Procedure for the Preparation of Chiral a-Amino-amides 3.10a-c and
Diamines 3.11a-c from N-Boc-Phe-OH (3.7).

a-Amino-amides 3.10a-c and diamines 3.11a-c were prepared from N-Boc-Phe-

OH (3.7) and primary amines 3.8a-c according to our recent paper. [02JOC3109]

[01JCS(P1)1767] [02TA933]

3.4.2 General Procedure for the Preparation of Benzotriazolyl intermediates 3.12a-c.

A mixture of a diamine 3.11a-c (3.0 mmol), BtH (0.36 g, 3.0 mmol) and

formaldehyde (37% aqueous solution, 0.49 g, 6 mmol) in CH3OH/H20 (10 mL/5 mL)

was stirred at 25 C for 4 h. The precipitate formed was filtered and washed with cool

Et20 to give 3.12a-c, which was used directly for the subsequent reactions. For

microanalyses and optical activity, crude 3.12a-c was recrystallized from appropriate

solvents.

1- [(5S)-5-Benzyl-3-(4-methylphenyl)tetrahydro-1H-imidazol- -yl]methyl}-

1H-1,2,3-benzotriazole (3.12a): white microcrystals (from EtOH); yield, 93%; mp

94-95 OC; [a]25 D= +1.8 (c 1.70, CHC13); 1H NMR 6 2.21 (s, 3H), 2.74 (dd, J= 13.2, 8.3

Hz, 1H), 3.08 (t,J= 7.6 Hz, 1H), 3.22-3.31 (m, 2H), 3.58-3.63 (m, 1H), 4.24, 4.39 (AB,

J= 5.0 Hz, 2H), 5.56, 5.67 (AB, J= 13.7 Hz, 2H), 6.35 (d, J= 8.4 Hz, 2H), 6.98 (d, J=

8.1 Hz, 2H), 7.22-7.40 (m, 6H), 7.48 (d, J= 3.6 Hz, 2H), 8.05 (d, J= 8.2 Hz, 1H); 13C

NMR 6 20.3, 39.2, 52.2, 61.2, 63.7, 68.2, 109.7, 112.3, 120.0, 124.0, 126.4, 126.6, 127.7,

128.6, 129.0, 129.7, 133.5, 138.1, 144.0, 146.0. Anal. Calcd for C24H25N5: C, 75.17; H,

6.57; N, 18.26. Found: C, 74.95; H, 6.77; N, 18.29.

1-{[(5S)-5-Benzyl-3-cyclohexyltetrahydro-1H-imidazol- -yl]methyl}

benzotriazole (3.12b): obtained as a mixture ofBt1 and Bt2 isomers in 26:1 ratio, and









NMR data are reported for the major Bt1 isomer; white needles (from EtOH); yield, 90%;

mp 94-95 C; []25D = +30.5 (c 1.64, CHC13); 1H NMR 6 1.02-1.14 (m, 5H), 1.53-1.67

(m, 5H), 1.90 (br s, 1H), 2.41 (dd, J= 8.8, 6.8 Hz, 1H), 2.65-2.77 (m, 2H), 2.99 (dd, J=

13.4, 6.1 Hz, 1H), 3.43-3.48 (m, 1H), 3.70 (s, 2H), 5.31, 5.49 (AB, J= 13.5 Hz, 2H),

7.20-7.48 (m, 8H), 8.04 (d, J= 8.2 Hz, 1H); 13C NMR 6 24.4, 24.6, 25.8, 31.6, 31.7,

41.1, 56.3, 61.4, 61.5, 65.1, 72.3, 109.8, 119.8, 123.8, 126.3, 127.3, 128.4, 129.1, 133.4,

138.8, 145.8. Anal. Calcd for C23H29N5: C, 73.57; H, 7.78; N, 18.65. Found: C, 73.94; H,

8.17; N, 18.77.

1-{[(5S)-3,5-Dibenzyltetrahydro-1H-imidazol-1-yl]methyl}-lH-1,2,3-

benzotriazole (3.12c): white microcrystals (from EtOH); yield, 96%; mp 81-82 C;

[a]25D= +40.8 (c 1.87, CHC13); 1H NMR 6 2.34 (dd, J= 9.4, 6.5 Hz, 1H), 2.67-2.81 (m,

2H), 2.92 (dd, J= 13.2, 6.6 Hz, 1H), 3.42, 3.52 (AB, J= 13.2 Hz, 2H), 3.52-3.60 (m,

1H), 3.62, 3.70 (AB, J= 6.3 Hz, 2H), 5.38, 5.43 (AB, J= 13.6 Hz, 2H), 7.12-7.45 (m,

13H), 8.05 (d, J= 8.1 Hz, 1H); 13C NMR 6 41.3, 57.8, 58.6, 61.8, 65.5, 73.9, 109.8,

119.8, 123.8, 126.3, 127.0, 127.3, 128.2, 128.3, 128.4, 129.2, 133.4, 138.3, 138.8, 145.9.

Anal. Calcd for C24H25N5: C, 75.17; H, 6.57; N, 18.26. Found: C, 75.03; H, 6.32; N,

18.30.

3.4.3 General Procedure for the Preparation of 1,2,3,5,10,10a-Hexahvdroimidazo[ 1,5-
blisoquinolines 3.1a-c.

A mixture of 3.12a-c (1.0 mmol) and anhyd AlC13 (0.40 g, 3.0 mmol) was stirred

in dry CH2C12 (20 mL) refluxing for 12 h. After cooling, the reaction mixture was added

CH2C12 (30 mL) and the organic layer was washed with 2 M NaOH, brine and dried over

anhydrous K2CO3. After removal of the solvent in reduced pressure, the crude product









was purified by column chromatography with hexanes/EtOAc (3:1 to 1:1) as an eluent to

give 3.1a-c.

(10aS)-2-(4-Methylphenyl)-1,2,3,5,10,10a-hexahydroimidazo[1,5-

b]isoquinoline (3.1a): colorless microcrystals (from hexanes/CHC13); yield, 76%; mp

189-190 C; []25D = -50.3 (c 1.68, CHC13); 1H NMR 6 2.26 (s, 3H), 2.91-3.06 (m, 3H),

3.24 (t, J= 8.2 Hz, 1H), 3.62-3.70 (m, 2H), 3.84 (d, J= 3.6 Hz, 1H), 4.18 (d, J= 14.4

Hz, 1H), 4.60 (d, J= 3.6 Hz, 1H), 6.45 (d, J= 8.5 Hz, 2H), 7.05-7.19 (m, 6H); 13C NMR

20.3, 33.2, 52.8, 53.0, 59.2, 71.1, 111.3, 125.3, 126.0, 126.5, 126.8, 129.1, 129.7, 133.5,

134.0, 144.3. Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60. Found: C, 81.61; H,

7.88; N, 10.71.

(10aS)-2-Cyclohexyl-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline

(3.1b): colorless prism (from hexanes/CHCl3); yield, 77%; mp 101-102 OC; [a]25D

-35.5 (c 1.66, CHC13); 1H NMR 6 1.24 (br s, 5H), 1.56-1.62 (m, 1H), 1.74 (br s, 2H),

1.88 (br s, 2H), 2.31 (br s, 1H), 2.63 (t, J= 8.4 Hz, 1H), 2.76-2.93 (m, 3H), 3.17 (dd, J=

8.4, 5.5 Hz, 1H), 3.43 (d, J= 4.6 Hz, 1H), 3.56, 4.02 (AB, J= 14.3 Hz, 2H), 4.03 (d, J=

4.6 Hz, 1H), 7.04-7.26 (m, 4H); 13C NMR 6 24.7, 24.8, 26.0, 31.6, 32.2, 33.5, 52.9, 56.0,

58.8, 62.2, 74.1, 125.7, 126.2, 126.7, 129.0, 134.4, 134.8. Anal. Calcd for C17H24N2: C,

79.64; H, 9.44; N, 10.93. Found: C, 79.94; H, 9.69; N, 10.87.

(10aS)-2-Benzyl-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline (3.1c):

white needles (from hexanes/EtOH); yield, 85%; mp 73-74 OC; []25D = -30.3 (c 1.77,

CHC13); 1H NMR 6 2.64 (t, J= 8.7 Hz, 1H), 2.77-2.95 (m, 3H), 3.21 (dd, J= 8.7, 5.7 Hz,

1H), 3.43, 3.93 (AB, J= 5.4 Hz, 2H), 3.55, 3.99 (AB, J= 14.2 Hz, 2H), 3.84 (s, 2H),

7.04-7.16 (m, 4H), 7.23-7.39 (m, 5H); 13C NMR 6 33.5, 52.6, 59.0, 59.1, 60.6, 76.5,









125.9, 126.4, 126.7, 127.0, 128.3, 128.5, 128.9, 134.4, 134.7, 139.4. Anal. Calcd for

Ci8H20N2: C, 81.78; H, 7.63; N, 10.60. Found: C, 81.52; H, 7.37; N, 10.65.

3.4.4 General Procedure for the Preparation of Benzotriazolvl Intermediates 3.13 and
3.14a-c.

Using the same procedure as for the preparation of 3.12a-c, reaction of 3.10a with

benzotriazole and aqueous formaldehyde (1 or 2 equiv) led to 3.13.

(2S)-2-[(1H-1,2,3-Benzotriazol-1-ylmethyl)amino]-N-(4-methylphenyl)-3-

phenylpropanamide (3.13): white microcrystals (from CH30H); yield, 92%; mp

136-137 OC; [a]25D = -74.5 (c 1.76, CHC13); 1H NMR 6 2.32 (s, 3H), 2.70 (br s, 1H),

2.79 (dd, J= 13.8, 8.7 Hz, 1H), 3.01 (dd, J= 14.1, 4.8 Hz, 1H), 3.61 (dd, J= 8.4, 4.5 Hz,

1H), 5.41-5.53 (m, 2H), 6.87-6.89 (m, 2H), 7.08-7.14 (m, 5H), 7.33-7.40 (m, 4H), 7.44

(d, J= 7.8 Hz, 1H), 8.04 (d, J= 8.7 Hz, 1H), 8.67 (s, 1H); 13CNMR 6 20.8, 39.0, 60.9,

61.3, 108.8, 119.7, 120.1, 124.1, 127.0, 127.8, 128.6, 128.7, 129.4, 132.5, 134.1, 134.6,

135.9, 146.0, 170.2. Anal. Calcd for C23H23N50: C, 71.67; H, 6.01; N, 18.17. Found: C,

71.60; H, 6.25; N, 18.29.

A mixture of 3.10a-c (2.0 mmol), BtH (0.48 g, 4.0 mmol) and paraformaldehyde

(0.18 g, 6.0 mmol) withp-TsOH'H20 (0.08 g, 0.4 mmol) was stirred in refluxing benzene

(25 mL) using a Dean-Stark apparatus for 2 h. After cooling, benzene was evaporated and

toluene (25 mL) was added, and then the mixture was refluxed for another 1 h. The

mixture was washed with 2 M NaOH. The aqueous phase was extracted with EtOAc and

the combined organic phase was washed with water, brine, and dried over anhyd K2CO3.

Removal of solvent under reduced pressure gave crude 3.14a-c, which were used directly

for the subsequent reactions. Attempt to purify 3.14a-c failed due to their significant

decomposition on silica gel.









(5S)-1-(Benzotriazolylmethyl)-5-benzyl-3-(4-methylphenyl)tetrahydro-4H-

imidazol-4-one (3.14a): obtained as a mixture of Bt1 and Bt2 isomers in 3:1 ratio, and

NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 92%; 1H NMR 6

2.29 (s, 3H), 3.09 (dd, J= 14.2, 7.4 Hz, 1H), 3.35 (dd, J= 14.2, 3.9 Hz, 1H), 3.91 (dd, J=

7.3, 3.8 Hz, 1H), 4.63, 4.85 (AB, J= 5.6 Hz, 2H), 5.41 (s, 2H), 7.06-7.46 (m, 12H), 8.04

(d, J= 8.2 Hz, 1H).

(5S)-1-(Benzotriazolylmethyl)-5-benzyl-3-cyclohexyltetrahydro-4H-imidazol-

4-one (3.14b): obtained as a mixture of Bt1 and Bt2 isomers in 4:1 ratio, and NMR data

are reported for the major Bt1 isomer; yellowish oil; yield, 91%; 1H NMR 6 0.90-1.40

(m, 6H), 1.50-1.80 (m, 4H), 2.95 (dd, J= 13.9, 7.4 Hz, 1H), 3.24 (dd, J= 13.8, 3.4 Hz,

1H), 3.70-3.81 (m, 2H), 4.21, 4.43 (AB, J= 5.6 Hz, 2H), 5.31 (d, J= 4.8 Hz, 2H), 7.11

(d, J= 8.1 Hz, 1H), 7.27-7.45 (m, 7H), 8.04 (d, J= 8.1 Hz, 1H).

(5S)-1-(Benzotriazolylmethyl)-3,5-dibenzyltetrahydro-4H-imidazol-4-one

(3.14c): obtained as a mixture of Bt1 and Bt2 isomers in 5:1 ratio, and NMR data are

reported for the major Bt1 isomer; pale brown oil; yield, 94%; 1H NMR 6 3.04 (dd, J=

14.0, 6.8 Hz, 1H), 3.29 (dd, J= 14.0, 3.7 Hz, 1H), 3.87-3.90 (m, 1H), 4.09, 4.57 (AB, J

10.7 Hz, 2H), 4.11-4.13 (m, 1H), 4.32 (d, J= 5.2 Hz, 1H), 5.35 (s, 2H), 6.91-6.93 (m,

2H), 7.11-7.45 (m, 11H), 8.05 (d, J= 8.1 Hz, 1H); 13C NMR 6 37.4, 44.9, 62.9, 63.3,

65.1, 109.1, 120.0, 124.2, 126.8, 127.5, 127.7, 127.9, 128.5, 128.7, 130.0, 133.4, 134.9,

137.3, 145.7, 170.6.









3.4.5 General Procedure for the Preparation of 2,3,10,10a-Tetrahydroimidazo[ 1,5-
blisoquinolin-1(SH)-ones 3.15a-c.

Treatment of crude 3.14a-c with 3 equiv of AlC13 afforded 3.15a-c using the same

procedure as for the preparation of 3.1a-c. The isolated yields of 3.15a-c were based on

a-amino-amides 3.10a-c.

(10aS)-2-(4-Methylphenyl)-2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-

1(5H)-one (3.15a): colorless needles; yield, 82%; mp 185-186 OC; [a]25D = -62.7 (c

1.66, CHC13); 1H NMR 6 2.32 (s, 3H), 3.04-3.21 (m, 2H), 3.38-3.43 (m, 1H), 3.83, 4.05

(AB, J= 14.0 Hz, 2H), 4.48 (dd, J= 4.8, 1.6 Hz, 1H), 4.76 (d, J= 5.0 Hz, 1H), 7.10-7.21

(m, 6H), 7.44 (d, J= 8.5 Hz, 2H); 13C NMR 6 20.8, 29.9, 52.3, 61.4, 69.6, 119.2, 126.2,

126.6, 126.9, 129.4, 129.5, 133.3, 133.7, 134.5, 135.0, 170.9. Anal. Calcd for C18H18N20:

C, 77.67; H, 6.52; N, 10.06. Found: C, 77.48; H, 6.54; N, 10.10.

(10aS)-2-Cyclohexyl-2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-l(5H)-

one (3.15b): colorless microcrystals; yield, 83%; mp 72-73 OC; []25D = -89.8 (c 1.75,

CHC13); 1H NMR 6 1.03-1.16 (m, 1H), 1.23-1.42 (m, 4H), 1.66-1.82 (m, 5H), 2.98 (AB

dd, J= 15.6, 9.6 Hz, 1H), 3.10 (AB dd, J= 15.6, 4.8 Hz, 1H), 3.28 (dd, J= 9.2, 4.8 Hz,

1H), 3.78, 3.96 (AB, J= 14.1 Hz, 2H), 3.90-3.95 (m, 1H), 4.04 (dd, J= 4.8, 2.1 Hz, 1H),

4.36 (d, J= 4.8 Hz, 1H), 7.08-7.10 (m, 1H), 7.17-7.20 (m, 3H); 13C NMR 6 25.2, 25.2,

25.4, 29.8, 30.2, 30.6, 49.9, 52.3, 60.9, 65.1, 126.1, 126.5, 126.8, 129.3, 133.6, 133.9,

171.3; HRMS m/z calcd for C17H22N20 270.1732 (M), found 270.1738. Anal. Calcd for

C17H22N20: C, 75.52; N, 10.36. Found: C, 75.18; N, 10.32.

(10aS)-2-Benzyl-2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-l(5H)-one

(3.15c): colorless prism; yield, 78%; mp 50-51 oC; [a]25D= -64.8 (c 1.66, CHC13); 1H









NMR 6 3.10 (d, J= 6.6 Hz, 2H), 3.49 (t, J= 6.9 Hz, 1H), 3.77, 3.84 (AB, J= 14.5 Hz,

2H), 4.05 (dd, J= 5.2, 1.8 Hz, 1H), 4.12 (d, J= 5.0 Hz, 1H), 4.29, 4.65 (AB, J= 15.3 Hz,

2H), 7.02-7.15 (m, 3H), 7.16-7.27 (m, 6H); 13C NMR 6 30.0, 44.8, 52.4, 60.4, 68.4,

126.3, 126.6, 127.0, 127.5, 127.6, 128.7, 129.2, 133.8, 134.4, 135.6, 172.3. Anal. Calcd

for Ci8H18N20: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.50; H, 6.83; N, 10.09.

3.4.6 General Procedure for the Preparation of 2,3,5-Trisubstituted-tetrahydro-4H-
imidazol-4-ones 3.16a-c.

A mixture of a-amino-amide 3.10a-c (2.0 mmol), benzaldehyde (0.27 g, 2 mmol)

and p-TsOH (0.4 mmol) in CH3OH (15 mL) with anhydrous Na2SO4 (3.0 g) was stirred

refluxing for 12 hours. After evaporation of CH3OH under reduced pressure, the reaction

mixture was diluted with EtOAc. The organic phase was washed with 2 M NaOH, water,

brine, and dried over anhyd K2CO3. After removal of solvent in vacuo, the residue was

purified by column chromatography with hexanes/EtOAc (6:4) as an eluent to give trans-

3.16a and cis-3.16'a, and trans-3.16b,c.

(2R,5S)-5-Benzyl-3-(4-methylphenyl)-2-phenyltetrahydro-4H-imidazol-4-one

(3.16a): yellowish microcrystals; yield, 38%; mp 106-107 OC; [a]25D= -52.5 (c 1.86,

CHC13); 1H NMR 6 1.70 (br s, 1H), 2.24 (s, 3H), 3.09-3.21(m, 2H), 4.13 (t, J= 5.5 Hz,

1H), 5.55 (s, 1H), 7.03, 7.11 (AB, J= 8.5 Hz, 4H), 7.22-7.32 (m, 10H); 13C NMR 6 20.8,

38.0, 60.2, 77.1, 122.0, 126.4, 126.8, 128.5, 128.8, 128.9, 129.4, 129.8, 134.2, 135.1,

137.3, 139.4, 173.7. Anal. Calcd for C23H22N20: C, 80.67; H, 6.48; N, 8.18. Found: C,

80.39; H, 6.51; N, 7.94.

(2S,5S)-5-Benzyl-3-(4-methylphenyl)-2-phenyltetrahydro-4H-imidazol-4-one

(3.16'a): yellowish microcrystals; yield, 31%; mp 97-98 OC; [a]25D = -29.8 (c 1.58,









CHCl3); 1H NMR 6 1.88 (br s, 1H), 2.20 (s, 3H), 3.17 (dd, J= 14.1, 4.8 Hz, 1H), 3.40

(dd, J= 14.1, 5.4 Hz, 1H), 4.00 (t, J= 4.6 Hz, 1H), 5.81 (s, 1H), 6.81 (d, J= 7.0 Hz, 2H),

6.98-7.33 (m, 12H); 13C NMR 6 20.9, 36.6, 60.9, 77.2, 122.8, 127.0, 127.1, 128.8, 128.9,

129.1, 129.3, 129.9, 134.0, 135.3, 136.4, 138.5, 174.0. Anal. Calcd for C23H22N20: C,

80.67; H, 6.48; N, 8.18. Found: C, 80.40; H, 6.30; N, 8.28.

(2R,5S)-5-Benzyl-3-cyclohexyl-2-phenyltetrahydro-4H-imidazol-4-one (3.16b):

colorless microcrystals; yield, 69%; mp 92-93 C; []25D= -32.2 (c 1.81, CHC13); 1H

NMR 6 0.87-0.99 (m, 2H), 1.07-1.28 (m, 2H), 1.43-1.61 (m, 5H), 1.65-1.70 (m, 1H),

1.99 (br s, 1H), 2.90 (dd, J= 13.5, 7.5 Hz, 1H), 3.13 (dd, J= 13.6, 3.9 Hz, 1H),

3.53-3.64 (m, 1H), 4.07-4.11 (m, 1H), 5.16 (s, 1H), 7.20-7.34 (m, 10H); 13C NMR 6

25.1, 25.6, 25.7, 29.9, 30.9, 38.7, 52.8, 59.7, 75.0, 126.4, 126.5, 128.3, 128.8, 129.0,

129.7, 137.8, 141.9, 173.6. Anal. Calcd for C22H26N20: C, 79.00; H, 7.84; N, 8.38.

Found: C, 78.55; H, 7.99; N, 8.29.

(2R,5S)-3,5-Dibenzyl-2-phenyltetrahydro-4H-imidazol-4-one (3.16c): colorless

needles (from hexanes/EtOAc); yield, 74%; mp 128-129 C; []25D= -19.7 (c 1.73,

CHC13); 1H NMR 6 2.15 (br s, 1H), 3.04 (AB dd, J= 13.8, 6.9 Hz, 1H), 3.16 (AB dd, J=

13.8, 4.2 Hz, 1H), 3.46, 5.02 (AB, J= 14.9 Hz, 2H), 4.17 (br s, 1H), 4.96 (s, 1H),

6.85-6.87 (m, 2H), 7.14-7.36 (m, 13H); 13C NMR 6 38.1, 43.9, 59.8, 74.8, 126.7, 126.8,

127.5, 128.0, 128.5, 128.6, 129.1, 129.2, 129.8, 135.5, 137.2, 139.3, 173.6. Anal. Calcd

for C23H22N20: C, 80.67; H, 6.48; N, 8.18. Found: C, 80.31; H, 6.63; N, 8.13.

3.4.7 General Procedure for the Preparation of Bt intermediates 3.17a-c and 3.17'a.

A mixture of 3.16a-c or 3.16'a (1.0 mmol), benzotriazole (0.14 g, 1.2mmol) and

formaldehyde (37% aq. solution, 0.12 g, 1.5 mmol) was stirred in CH30H (15 mL) at 25









C overnight. After evaporation of CH30H, EtOAc was added to the mixture. The

organic phase was washed with 1 M NaOH aqueous solution, brine, water, and dried over

anhyd K2CO3. Removal of solvent in vacuo gave essentially pure 3.17a and 3.17'a, which

were purified by recrystallization for analytical purposes. Attempts to purify 3.17b,c

(both obtained as sticky oil) by column chromatography (silica gel) failed, thus they were

used directly for the subsequent reaction as crude products.

(2R,5S)-l-(1H-1,2,3-Benzotriazol-l-ylmethyl)-5-benzyl-3-(4-methylphenyl)-2-

phenyltetrahydro-4H-imidazol-4-one (3.17a): white needles (from EtOH); yield, 89%;

mp 153-154 C; [a]25D= -20.4 (c 1.80, CHC13); 1HNMR 6 2.19 (s, 3H), 3.30-3.43 (m,

2H), 4.46 (br s, 1H), 5.34, 5.65 (AB, J= 13.8 Hz, 2H), 5.45 (d, J= 2.1 Hz, 1H, NCHN),

6.84-6.97 (m, 5H), 7.08-7.32 (m, 12H), 7.98-8.01 (m, 1H); 13C NMR 6 20.8, 36.3, 60.2,

63.2, 80.1, 109.7, 119.7, 123.6, 123.9, 126.8, 127.2, 128.0, 128.5, 128.8, 129.4, 129.6,

129.8, 132.3, 132.9, 135.9, 136.0, 136.7, 145.9, 170.6. Anal. Calcd for C30H27N50: C,

76.09; H, 5.75; N, 14.79. Found: C, 75.74; H, 6.01; N, 14.69.

(2S,5S)-1-(Benzotriazolylmethyl)-5-benzyl-3-(4-methylphenyl)-2-

phenyltetrahydro-4H-imidazol-4-one (3.17'a): obtained as a mixture of Bt1 and Bt2

isomers in 17:1 ratio, and NMR data are reported for the major Bt1 isomer; white prism

(from EtOH); yield, 85%; mp 197-198 C; [a]25D =-185 (c 1.56, CHC13); 1H NMR 6

2.16 (s, 3H), 3.38 (AB dd, J= 14.0, 4.4 Hz, 1H), 3.47 (AB dd, J= 14.0, 4.4 Hz, 1H), 4.08

(br s, 1H), 5.34, 5.46 (AB, J= 14.8 Hz, 2H), 5.82 (s, 1H, NCHN), 6.84 (d, J= 8.2 Hz,

2H), 6.88-6.96 (m, 4H), 7.13-7.36 (m, 4H), 7.40-7.50 (m, 7H), 8.11 (d, J= 8.1 Hz, 1H);

13C NMR 6 20.9, 36.9, 58.9, 61.6, 77.8, 108.8, 120.2, 124.2, 124.5, 126.8, 128.0, 128.4,









128.5, 128.9, 129.3, 129.4, 130.5, 132.5, 134.0, 136.3, 136.7, 137.1, 145.6, 169.5. Anal.

Calcd for C30H27N50: C, 76.09; H, 5.75; N, 14.79. Found: C, 75.84; H, 5.96; N, 14.54.

(2R,5S)- -(Benzotriazolylmethyl)-5-benzyl-3-cyclohexyl-2-phenyltetrahydro-

4H-imidazol-4-one (3.17b): obtained as a mixture of Bt1 and Bt2 isomers in 10:1 ratio,

and NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 94%; 1H NMR

6 0.85-1.07 (m, 2H), 1.12-1.26 (m, 2H), 1.40-1.72 (m, 6H), 3.20-3.30 (m, 2H),

3.40-3.60 (m, 1H), 4.40 (s, 1H), 5.15 (s, 1H), 5.24, 5.41 (AB, J= 13.6 Hz, 2H),

7.09-7.45 (m, 12H), 7.55 (d,J= 8.1 Hz, 1H), 8.03 (d,J= 8.1 Hz, 1H).

(2R,5S)- -(Benzotriazolylmethyl)-5-benzyl-3-benzyl-2-phenyltetrahydro-4H-

imidazol-4-one (3.17c): obtained as a mixture of Bt1 and Bt2 isomers in 7:1 ratio, and

NMR data are reported for the major Bt1 isomer; yellowish oil; yield, 95%; 1H NMR 6

3.21-3.35 (m, 2H), 4.60 (d, J= 3.3 Hz, 1H), 5.01-5.07 (m, 2H), 5.05 (d, J= 2.1 Hz, 1H),

5.30, 5.55 (AB, J= 14.2 Hz, 2H), 6.58 (d, J= 7.0 Hz, 2H), 6.90-7.38 (m, 16H), 7.95 (d,

J= 8.1 Hz, 1H).

3.4.8 General Procedure for the Lewis Acid Promoted Cyclization of 3.17a-c and 3.17'a.

Using the same procedure as for the preparation of 3.1a-c, treatment of 3.17a-c

and 3.17'a with 3 equiv of AlC13 afforded 3.18a-c and 3.18'a. After work-up, all of the

products were obtained as essentially NMR pure solids, which were recrystallized from

EtOH for analytical purposes.

(3R,10aS)-2-(4-Methylphenyl)-3-phenyl-2,3,10,10a-tetrahydroimidazo[1,5-

b]isoquinolin-1(5H)-one (3.18a): colorless needles (from EtOH); yield, 91%; mp

189-190 C; [a]25D = -79.2 (c 1.83, CHC13); 1H NMR 6 2.22 (s, 3H), 3.14 (d, J= 6.9 Hz,

2H), 3.62, 3.81 (AB, J= 14.7 Hz, 2H), 4.02 (td, J= 7.0, 1.4 Hz, 1H), 5.68 (d, J= 1.4 Hz,









1H, NCHN), 7.00-7.08 (m, 3H), 7.15-7.28 (m, 5H), 7.32-7.39 (m, 5H); 13C NMR

20.8, 30.0, 49.6, 58.3, 81.9, 122.4, 124.2, 126.3, 126.6, 127.0, 127.3, 128.8, 129.1, 129.4,

133.9, 134.0, 134.5, 135.3, 136.7, 172.3. Anal. Calcd for C24H22N20: C, 81.32; H, 6.26;

N, 7.90. Found: C, 81.07; H, 6.53; N, 7.97.

(3S,10aS)-2-(4-Methylphenyl)-3-phenyl-2,3,10,10a-tetrahydroimidazo[1,5-

b]isoquinolin-1(5H)-one (3.18'a): colorless needles (from EtOH); yield, 91%; mp

212.5-213 C; [a]25D= -83.9 (c 1.59, CHC13); 1H NMR 6 2.22 (s, 3H), 3.22-3.35 (m,

2H), 3.44 (ddd, J= 10.8, 4.2, 2.2 Hz, 1H), 3.79 (s, 2H), 5.32 (d, J= 2.1 Hz, 1H, NCHN),

6.97-7.11 (m, 5H), 7.11-7.33 (m, 6H), 7.40-7.43 (m, 2H); 13C NMR 6 20.9, 30.8, 50.6,

60.8, 82.7, 124.2, 126.1, 126.6, 126.8, 128.4, 128.9, 129.3, 129.4, 129.8, 133.3, 133.4,

133.7, 135.6, 136.1, 171.4. Anal. Calcd for C24H22N20: C, 81.32; H, 6.26; N, 7.90.

Found: C, 81.07; H, 6.61; N, 8.04.

(3R,10aS)-2-Cyclohexyl-3-phenyl-2,3,10,10a-tetrahydroimidazo[1,5-

b]isoquinolin-1(5H)-one (3.18b): white microcrystals (from EtOH); yield, 78%; mp

150-151 OC; [a]25D= -66.6 (c 1.79, CHCl3); 1H NMR 6 0.84-1.00 (m, 2H), 1.11-1.26

(m, 2H), 1.40-1.72 (m, 6H), 2.80-3.12 (m, 2H), 3.47, 3.64 (AB, J= 14.5 Hz, 2H),

3.60-3.70 (m, 1H), 3.86-3.91 (m, 1H), 5.19 (s, 1H, NCHN), 7.02 (d, J= 6.4 Hz, 1H),

7.12-7.41 (m, 8H); 13C NMR 6 25.1, 25.6, 25.7. 30.1, 30.3. 31.1, 49.6, 52.4, 58.1, 79.4,

126.1, 126.5, 126.9, 127.4, 128.7, 129.0, 131.7, 134.1, 134.7, 138.8, 172.7; HRMS m/z

calcd for C23H26N20 346.2045 (M), found 346.2042. Anal. Calcd for C23H26N20: N,

8.09. Found: N, 8.05.

(3R,10aS)-2-Benzyl-3-phenyl-2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-

1(5H)-one (3.18c): white needles; yield, 78%; mp 108-109 OC; []25D = +65.1 (c 1.23,









CHC13); 1H NMR 6 3.05 (dd, J= 15.2, 6.7 Hz, 1H), 3.22 (dd, J= 15.2, 4.8 Hz, 1H), 3.29,

4.99 (AB, J= 15.2 Hz, 2H), 3.58, 3.81 (AB, J= 15.2 Hz, 2H), 4.24 (br t, J= 4.7 Hz, 1H),

4.66 (d, J= 2.3 Hz, 1H, NCHN), 6.53 (d, J= 7.0 Hz, 2H), 7.02-7.39 (m, 12H); 13C NMR

6 29.9, 43.4, 50.1, 59.2, 80.5, 126.5, 127.1, 127.2, 127.3, 127.5, 128.4, 128.5, 128.6,

128.8, 129.2, 134.6, 134.9, 135.6, 138.1, 172.9. Anal. Calcd for C24H22N20: C, 81.32; H,

6.26; N, 7.90. Found: C, 81.16; H, 6.38; N, 7.87.

3.4.9 Procedure for the preparation of Bt intermediate 3.22.

A mixture of 2,5-dimethoxytetrahydrofuran (0.66 g, 5.1 mmol) and HC1 aqueous

solution (0.1 M, 20 mL) was heated to 100 OC for 45 mins, then cooled to room

temperature. CH2C12 (40 mL), benzotriazole (0.61 g, 5.1 mmol) and diamine 3.11a (1.20

g, 5 mmol) were added successively and stirred at room temperature for 24 h. The

reaction mixture was washed with 1 M NaOH and the aqueous phase was extracted with

CH2C12. The combined organic phase was washed with brine and dried over anhyd

Na2SO4. After removal of the solvent in vacuo, the residue was purified by column

chromatography with hexanes/EtOAc (3:1) as an eluent to give 3.22. However,

subsequent treatment of 3.22 with AlC13 did not afford the desired tetracyclic compound

3.23.

(3S,5R,7aS)-5-Benzotriazolyl-3-benzyl- -(4-methylphenyl)hexahydro- 1H-

pyrrolo[1,2-a]imidazole (3.22): obtained as a mixture of Bt1 and Bt2 isomers in 4.5:1

ratio, and NMR data are reported for the major Bt1 isomer; colorless needles (from

CHCl3/Et20); mp 145-146 OC; [ca]25D= -4.2 (c 1.37, CHC13); 1H NMR 6 2.06-2.17 (m,

1H), 2.29 (s, 3H), 2.45-2.64 (m, 5H), 3.18 (dd, J= 9.2, 4.0 Hz, 1H), 3.70-3.80 [m, 1H,

H(3)], 3.85 (dd, J= 9.2, 6.5 Hz, 1H), 5.10 (dd, J= 5.3, 4.0 Hz, 1H, NCHN), 6.02 (t, J=






51


7.0 Hz, 1H, BtCHN), 6.58 (d, J= 8.3 Hz, 2H), 6.79-6.82 (m, 2H), 6.92-6.98 (m, 3H),

7.10 (d, J= 8.1 Hz, 2H), 7.32-7.36 (m, 2H), 7.61-7.64 (m, 1H), 8.00-8.03 (m, 1H); 13C

NMR 6 20.2, 30.6, 30.9, 41.0, 52.8, 63.7, 79.2, 81.6, 111.5, 113.5, 119.6, 123.6, 125.9,

126.7, 126.8, 127.8, 128.4, 129.7, 131.2, 137.8, 143.9, 146.6. Anal. Calcd for C26H27N5:

C, 76.25; H, 6.65; N, 17.10. Found: C, 76.05; H, 6.88; N, 17.03.














CHAPTER 4
N-ACYLBENZOTRIAZOLES: NEUTRAL ACYLATING REAGENTS FOR THE
PREPARATION OF PRIMARY, SECONDARY AND TERTIARY AMIDES

4.1 Introduction

Common routes to primary, secondary and tertiary amides mostly involve the

treatment of activated derivatives of acids, especially acyl halides, acid anhydrides or

esters, with ammonia, primary and secondary amines. [89Prac.Org.Chem.] However,

limitations are associated with these methods. Reactions of ammonia or amines with acyl

halides are highly exothermic. Acid anhydrides, especially cyclic anhydrides, easily form

imides with ammonia and primary amines. Acylations of ammonia, primary and

secondary amines by esters frequently require strongly basic catalysts and/or high

pressure. Reactions of carboxylic acids themselves with ammonia or amines are seldom

of preparative value. [92Adv.Org.Chem] Other preparations of primary amides include

the activation of carboxylic acids using 1-hydroxybenzotriazole (HOBt) and N,N'-

dicyclohexylcarbodiimide (DCC) [89S37] or the treatment of carboxylic acids with

ammonium chloride, tertiary amine and coupling agents typically used in peptide

synthesis. [99TL2501] With these last two methods, difficulties can arise from the

insolubility of starting materials and products or by competitive hydrolysis of the

activated carboxyl group.

As recently documented by Staab, Bauer and Schneider, [98Azolides] acyl-azolides

in general, and N-acylimidazoles in particular, are efficient acylating reagents. They have

been widely reacted with ammonia or primary amines to give the corresponding primary









[80JOC3640] [79JOC4536] [79JMC1340] [88JHC555] [95JACS7379] or secondary

amides. [88JOC685] [94T11113] [92T10233] [95SC3701] [90T5665] [89JHC901]

[68TL3185] The classical azolide method normally involves two steps (which can,

however, be combined in one-pot): i) reaction of the free carboxylic acid at 20 OC with

(usually) 1,1'-carbonyldiimidazole (CDI) in a 1:1 molar ratio to form the carboxylic acid

imidazole via elimination of CO2 and imidazole; ii) after CO2 evolution has ceased,

addition of an equimolar amount of amine. Thus, two molar equivalents of the imidazole

moieties are used. Furthermore, relatively few reports have been reported for reactions of

N-acylimidazoles with secondary amines.

N-Acylbenzotriazoles have been used as acylating agents in our group specifically

for formylation, [95S503] trifluoroacylation [97JOC726] and to provide oxamides

[98S153]; and by others in isolated applications. [98JCR(M)701] [96NN1459]

[97Janti 100] We now report a simple, mild and general procedure for the preparation of

primary, secondary and tertiary amides. Carboxylic acids are converted in a one-pot

reaction into N-acylbenzotriazoles and subsequently treated with ammonia, primary, or

secondary amines. This methodology should be particularly applicable to solid-phase

syntheses.

4.2 Results and Discussion

4.2.1 Preparation of N-Acylbenzotriazoles 4.2a-q.

1-(Trimethylsilyl)benzotriazole, readily available from benzotriazole and N,N-

bis(trimethylsilyl)amine, [80JOM141] was previously reacted with methanesulfonyl

chloride to generate N-(1-methanesulfonyl)benzotriazole (4.1) in 60% yield. [92T7817]

We now find that compound 4.1 is produced in 89% yield by direct treatment of

benzotriazole with methanesulfonyl chloride in the presence of pyridine.









N-Acylbenzotriazoles 4.2a-m with R as aryl groups were readily prepared in

72%-92% yields by the previously reported reaction ofN-(1-methanesulfonyl)

benzotriazole (4.1) with arene carboxylic acids (Scheme 4-1). [92T7817] We previously

synthesized N-(alkanecarbonyl)- or N-(arylacetyl)-benzotriazoles 4.2 (R = alkyl,

arylmethyl) by the reaction of benzotriazole with alkanecarbonyl chlorides [92T7817] or

arylacetyl chlorides [96HAC365] in the presence of triethylamine. The reported yields of

4.2o, 4.2p and 4.2q are 80%, 80% and 79%, respectively. [92T7817] [96HAC365] We

now find that N-(alkanecarbonyl)benzotriazoles 4.2o, 4.2p and 4.2q can be obtained in

84%, 89% and 83% yield, respectively, from the corresponding aliphatic carboxylic acids

and BtSO2CH3 in the presence of triethylamine (Scheme 4-1). The mechanism for the

formation of N-acylbenzotriazoles 4.2 involves attack of the carboxylate (formed in the

presence of triethylamine) on the sulfur atom of 4.1 followed by the departure of

benzotriazole anion to give the intermediate RCOOSO2CH3. Then, addition of the

benzotriazole anion to the carbonyl carbon and elimination of alkanesulfonate affords the

final products 4.2. The N-Acylbenzotriazoles 4.2a-q are listed in Table 4-1. The diverse

carboxylic acids used include aromatic, heteroaromatic and aliphatic. Novel structures

4.2b-f and 4.21-n were supported by 1H, 13C NMR spectra and microanalysis.









Bt SO2CH3 (4.1) RCOOSO2CH3
RCOOH + RCOBt1

R = aryl Et3N Bt- Et3NH 4.2a-q
or alkyl



Bt N NH40H RNH2 R2R3NH
Bt' =I NI N


RCONH2 RCONHR1 RCONR2R3
4.3a-n 4.4a-j 4.5a-k

Scheme 4-1. Preparation of N-acylbenzotriazoles and amides

Table 4-1. Preparation ofN-acylbenzotriazoles 4.2a-q
4.2 R Yield (%) mp (C) mpht (C)
a C6H5 89 112-113 112-11311
b 2-CH30C6H4 72 96-97
c 3-ClC6H4 74 120-121
d 4-Et2NC6H4 85 86-87
e 4-02NC6H4 83 193-194
f 4-C1C6H4 74 138-139
g 4-CH3C6H4 91 123-124 123-12411
h 2-furanyl 92 171-173 172-17411
i 2-pyridyl 91 98-100 97-10011
j 3-pyridyl 88 87-89 86-8911
k 4-pyridyl 84 149-151 148-15011
1 1-naphthyl 88 136-137
m 2-pyrazinyl 76 146-147
n PhCH2CH2 84 63-64
o PhCH2 84 65-66 66-6712
p Ph2CH 89 88-89 106-10712
q n-C4H9 83 42-44 42-4411
"Novel compound


4.2.2 Preparation of Primary Amides 4.3a-n from N-Acvlbenzotriazoles 4.2 with
Ammonia.

Direct treatment ofN-acylbenzotriazoles 4.2a-e and 4.2h-q with excess ammonium

hydroxide (30% aqueous solution) in EtOH/THF (1:1) at room temperature for 2-4 h

gave crude products, which were recrystallized from benzene to afford pure primary

amides 4.3a-n (Scheme 4-1). The yields and melting points including the literature









melting points, for the primary amides 4.3a-n are summarized in Table 4-2; mps and

spectra of the products are in accord with literature data. The benzotriazole by-product

(BtH, pKa= 8.2 [98CR409]) formed in these reactions dissolved in the excess aqueous

ammonia solution.

Table 4-2. Preparation of primary amides 4.3a-n
4.3 R Yield (%) mp (OC) mpa (OC)
a C6H5 100 128-130 130
b 2-CH30C6H4 100 128-129 129
c 3-C1C6H4 87 134-135 134
d 4-NO2C6H4 100 199-200 201
e 2-furanyl 100 142-143 142-143
f 1-naphthyl 100 201-202 202
g 2-pyridyl 100 107-108 107-109
h 3-pyridyl 100 128-130 129-130
i 4-pyridyl 100 155-156 155-156
j 2-pyrazinyl 100 188-189 189-191
k PhCH2 100 158-159 157-158
1 PhCH2CH2 85 104-105 105
m Ph2CH 90 168-169 167-168
n n-C4H9 72 104-105 106
aCadogan J. I. G. et al, Dictionary of Organic Compounds; Sixth edition,
Chapman & Hall, London, UK.; 4.3a, B-0-00069; 4.3b, M-0-00635; 4.3c, C-
0-00557; 4.3d, N-0-00821; 4.3e, F-0-01325; 4.3f, N-0-00046; 4.3g, P-0-
03885; 4.3h, P-0-03881; 4.3i, P- 0-03887; 4.3j, P-0-03652; 4.3k, P-0-01232;
4.31, P-0-02416; 4.3m, D-0-11687; 4.3n, P-0-00666.


4.2.3 Preparation of Secondary Amides 4.4a-j from N-Acylbenzotriazoles 4.2 with
Primary Amines.

Treatment of N-acylbenzotriazoles 4.2 with one equiv. of primary amines in THF at

room temperature for 4 h furnished the corresponding secondary amides 4.4a-j in

70%-100% yields (Scheme 4-1 and Table 4-3). After dilution of the concentrated residue

in ethyl acetate, the by-product, 1H-benzotriazole, was easily washed away by a 2 M

NaOH aqueous solution, and simple removal of EtOAc in vacuo gave secondary amides

4.4a-j, which were recrystallized from appropriate solvents to afford pure products. The









primary amines used include aryl amines (phenyl, 4-nitrophenyl) and alkylamines (n-

butyl, cyclo-hexyl, sec-butyl and tert-butyl).

Table 4-3. Preparation of secondary amides 4.4a-j
4.4 R RI Yield (%) mp (oC) mplit (OC)
a 4-C1C6H4 EtCH(CH3) 95 82-83
b 4-C1C6H4 C6H5 75 195-197 195-196[97SC361]
c 4-Et2NC6H4 n-C4H9 92 73-74 b
d C6H5 t-C4H9 75 133-134 134-135[73SC185]
e 2-furanyl n-C4H9 94 40-41 40-41[40JACS1960]
f 1-naphthyl n-C4H9 92 92-93 b
g 2-pyridyl 4-CH30C6H4 83 86-87 b
h 4-pyridyl EtCH(CH3) 100 50-52 b
i 2-pyrazinyl (CH3)3C 100 87-88 b
j Ph2CH C6H5 70 117-118 117-118[62JOC3315]
aIR spectrum data of 4.4a were given in ref. [63 SpecActs509]; bNovel compound.


4.2.4 Preparation of Tertiary Amides 5a-k from N-Acylbenzotriazoles 4.2 with
Secondary Amines.

When 1H-1,2,3-benzotriazol-l-yl(4-chlorophenyl)methanone was reacted with

tetrahydro-1H-pyrrole at room temperature in EtOH, the crude 1H NMR spectrum

showed that the isolated product was a mixture of (4-chlorophenyl)(tetrahydro-1H-

pyrrol-1-yl)methanone and ethyl 4-chlorobenzoate with a ratio of 9:1. The use of THF

avoided the formation of esters by-products.

Treatment of N-acylbenzotriazoles 4.2 with one equiv. of secondary amines in THF

at room temperature produced the corresponding tertiary amides 4.5a and 4.5d-k in good

to excellent yields (Scheme 4-1 and Table 4-4). However, when using N-ethyl-N-(1-

methylethyl)amine or N,N-bis(1-methylethyl)amine as a secondary amine, no desired N-

ethyl-4-methyl-N-(1-methylethyl) or 4-methyl-N,N-bis(1-methylethyl)benzamide (4.5b or

4.5c) was isolated, probably due to the heavily hindered nitrogen. Reaction of less

hindered N,N-diethylamine with 1H- 1,2,3-benzotriazol- 1-yl(4-methylphenyl)methanone









(4.2g) produced N,N-diethyl-4-methylbenzamide (4.5a) in moderate yield (44%). A

moderate yield (51%) was also obtained for N,N-diethylfuran-2-amine (4.5g) from N,N-

diethylamine. These results show that the cyclic aliphatic amines, e.g., tetrahydro-1H-

pyrrole, produce the secondary amides in much better yields than the acyclic aliphatic

amines, e.g., N,N-diethylamine.

Table 4-4. Preparation of tertiary amides 4.5a-k
4.5 R R2 R3 Yield (%) mp (oC) mplit'(C)
a 4-CH3C6H4 C2H5 C2H5 44 oil oil
b 4-CH3C6H4 i-Pr C2H5 0
c 4-CH3C6H4 i-Pr i-Pr 0
d 4-02NC6H4 -(CH2)4- 96 73-74 b
e C6H5 -(CH2)4- 100 oil oil[86AG(Int)565]
f 2-CH30C6H4 -(CH2)4- 98 oil b
g 2-furanyl C2H5 C2H5 51 oil oil[71CC733]
h 1-naphthyl -(CH2)4- 94 51-52 b
i 4-pyridinyl -(CH2)4- 100 oil b
j PhCH2 -(CH2)4- 99 oil oil[89TL2771]
k Ph2CH -(CH2)5- 68 114-116 b
"Cadogan J. I. G. et al, Dictionary of Organic Compounds, Sixth edition, Chapman & Hall, London, UK.
4.5a, M-01138; bNovel compound.


4.2.5 Preparation of a-Hydroxyamides using BtSO2CH3.

Development of synthetic methods for a-hydroxyamides has attracted considerable

interest, since they include valuable therapeutic agents and also possess synthetic utility.

General routes to a-hydroxyamides include: i) the reduction of a-keto-amides with

sodium borohydride, [82CC1282] [85JCS(P1)769] [90CC1321] with other metal

borohydrides, such as LiBEt3H, KBEt3H and Zn(BH4)2 [87CL2021] or with magnesium-

or titanium-based reagents; [90BCS(Jpn)1894] ii) the hydrogenation of a-keto-amides in

the presence of palladium on charcoal [84BCS(Jpn)3203] or neutral rhodium (I)

complexes [84CL1603] [86CL737] [88TL3675]; iii) the oxidation of acyclic, tetra-

substituted amide-enolates by oxaziridines with yields of around 50%. [87JOC5288]









Methods i) and ii) need a-keto-amides prepared, e.g., from a-ketoacids [85JCS(P1)769]

or a-keto-acyl chlorides. [90CC1321] The only previous direct conversion of a-

hydroxycarboxylic acids to a-hydroxyamides is their reaction with N-sulfinylamines

(RNSO). [86TL1921]

After reaction of BtSO2CH3 with 2-hydroxy-2-phenylacetic acid (4.6) in the

presence of triethyl amine, we failed to isolate the corresponding a-hydroxy-N-

acylbenzotriazoles probably due to their instability. However, when one equiv. of aniline

or 4-methylaniline was added into the mixture obtained by refluxing 4.6, BtSO2CH3 and

Et3N in dry THF for about 20 min, a-hydroxyamides 4.7a and 4.7b were obtained in

68% and 72% yields, respectively (Scheme 4-2). Products 4.7a and 4.7b were not formed

in the absence of BtSO2CH3. When n-butylamine or pyrrolidine was used as the amine

reactant, no desired products were obtained. The role of BtSO2CH3 is the same as with

other reactions.

i) BtSO2CH3
OH OH
C-COOH Et3N/ C-CONHR
H ii) RNH2 H

DL-4.6 4.7a, R = C6H5
4.7b, R = 4-CH3C6H4

Scheme 4-2. Reaction of BtSO2CH3 with 2-hydroxy-2-phenylacetic acid

4.2.6 Preparation of 1-(1H- 1,2,3-Benzotriazol- -yl)-2,2,3,3,4,4,4-heptafluorobutan- 1-one
(4.8) and its Perfluoroacylation with Primary and Secondary Amines.

In 1997, we reported (trifluoroacetyl)benzotriazole as a convenient

trifluoroacetylating agent for amines and alcohols. [97JOC726] (Trifluoroacetyl)-

benzotriazole was prepared by the reaction of benzotriazole with trifluoroacetic

anhydride [(CF3CO)20] and, thus, trifluoroacetic acid was formed as a byproduct. The









analogous preparation of perfluoroacylbenzotriazoles, e.g., 1-(1H-1,2,3-benzotriazol-l-

yl)-2,2,3,3,4,4,4-heptafluorobutan-1-one (4.8) from n-(C3F7CO)20, means that half of the

carbon-fluorine moiety is not utilized.

No reaction occurred between BtSO2CH3 and n-C3F7COOH in the presence of

Et3N. However, reaction of 1-(trimethylsilyl)benzotriazole (BtTMS) with one equiv. of

2,2,3,3,4,4,4-heptafluorobutanoyl chloride (n-C3F7COC1) gave 4.8 in 86% yield (NMR

yield) as the sole Bt1 isomer, together with byproduct BtH, due to the easy hydrolysis of

BtTMS. The 1H NMR spectrum of the mixture shows the molar ratio of 4.8 to BtH is

about 6:1. Attempts to obtain the pure 4.8 by washing with aqueous sodium hydroxide

solution to remove BtH failed because of rapid hydrolysis of 4.8. Compound 4.8 cannot

be separated from BtH by column, as they have almost identical Rf values. Nevertheless,

the presence of BtH should not affect the perfluoroacylation of amines with n-C3F7COBt

(4.8), which will also generate benzotriazole as a byproduct. Therefore, the mixture of 4.8

and BtH was used for the subsequent reactions without separation, and indeed treatment

of primary and secondary amines with 4.8 readily produced the perfluoroalkylated

amides 4.9a-d in good yields (Scheme 4-3).

BtTMS R1R2NH CF ,N12
n-C3F7COCI BtTM n-C3F7COBt n-C3F7CONRR2
4.8 4.9 R1 R2
a 4-CH3C6H4 H
b PhCH(CH3) H
c -(CH2)4-
d -(CH2)20(CH2)2-


Scheme 4-3. Synthesis of perfluoroalkylated amides









4.3 Conclusion

In summary, a simple and efficient method for the preparation of primary,

secondary and tertiary amides has been developed by the treatment of N-

acylbenzotriazoles with ammonia, primary and secondary amines, respectively.

Advantages of this procedure include: 1) The neutral reaction conditions are useful for

ammoniation and amination of compounds possessing acid- or base-sensitive

substituents; 2) the use of acyl chlorides is avoided; 3) most N-acylbenzotriazoles can be

recrystallized and are stable to storage over months; 4) work-up is very simple; 5)

primary, secondary and tertiary amides are generally obtained in good to excellent yields;

6) the method can be extended to c-hydroxyamides and perfluoroalkylated amides.

4.4 Experimental Section

H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 NMR

spectrometer in CDC13 (with TMS for 1H and CDC13 for 13C as the internal reference). 19F

NMR spectra were recorded on a 300 NMR spectrometer at 282 MHz in CDC13 with

CFC13 as an internal reference.

4.4.1 Modified procedure for the Preparation of N-(1-Methanesulfonvl)benzotriazole
(4.1).

To an ice-cold solution of benzotriazole (11.9 g, 0.10 mol) and pyridine (12.0 g,

0.16 mol) in dry toluene (120 mL), was added dropwise methylsulfonyl chloride (9.3 mL,

0.12 mol) in toluene (30 mL). The mixture was then stirred overnight at room

temperature. AcOEt (150 mL) and H20 (100 mL) were added. The organic layer was

separated and successively washed with water, brine and dried over anhydrous MgSO4.

Removal of solvents in vacuo gave a solid, which was recrystallized from benzene to









afford N-(1-methanesulfonyl)benzotriazole (4.1) (17.5 g, 89 %) as colorless needles [mp

110-112 C (mp [92TL7817] [72AJC1341] 110-112 C)].

4.4.2 General procedure for the Preparation of N-Acylbenzotriazoles 4.2.

A mixture of aromatic or aliphatic acid (10.0 mmol) and 1-(methylsulfonyl)-

benzotriazole 4.1 (1.97 g, 10.0 mmol), triethylamine (2.0 mL, 14.0 mmol) were heated in

refluxing THF (50 mL) overnight. The solvent was evaporated and the residue was

dissolved in chloroform (100 mL). The organic layer was washed with water, dried over

anhydrous MgSO4 and evaporated to give a crude product, which was recrystallized from

an appropriate solvent to give pure N-(arylcarbonyl)- or N-(alkanecarbonyl)benzotriazole

4.2a-q.

1H-1,2,3-Benzotriazol-l-yl(2-methoxyphenyl)methanone (4.2b): yield, 72%;

Colorless flake (recrystallized from ethanol); mp 96-97 OC; 1H NMR 6 8.38 (d, J= 8.4

Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.69 (t, J= 7.5 Hz, 1H), 7.63-7.50 (m, 3H), 7.14-7.05

(m, 2H), 3.77 (s, 3H); 13C NMR 6 166.9 (C=O), 157.8, 146.0, 133.5, 131.4, 130.2, 130.1,

126.1, 122.6, 120.4, 120.0, 114.4, 111.7, 55.7 (CH3). Anal. Calcd for C14HllN302: C,

66.38; H, 4.38; N, 16.60. Found: C, 66.53; H, 4.41; N, 16.66.

1H-1,2,3-Benzotriazol-l-yl(3-chlorophenyl)methanone (4.2c): yield, 74%;

Colorless needles (recrystallized from chloroform/hexane); mp 120-121 OC; 1H NMR 6

8.38 (d, J= 8.4 Hz, 1H), 8.20-8.11 (m, 3H), 7.75-7.65 (m, 2H), 7.60-7.53 (m, 2H); 13C

NMR 6 165.3 (C=O), 145.7, 134.6, 133.6, 133.1, 132.1, 131.5, 130.6, 129.8, 129.7,

126.6, 120.3, 114.7. Anal. Calcd for C13HsC1N30: C, 60.60; H, 3.13; N, 16.31. Found: C,

60.75; H, 3.01; N, 16.38.









1H-1,2,3-Benzotriazol-l-yl[4-(diethylamino)phenyl]methanone (4.2d): yield,

85%; Yellow needles (recrystallized from ethanol/hexane); mp 86-87 C; 1H NMR 6

8.34 (d, J= 8.4 Hz, 1H), 8.23 (d, J= 9.3 Hz, 2H), 8.14 (d, J= 8.4 Hz, 1H), 7.64 (t, J=

7.6 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 6.73 (d, J= 9.0 Hz, 2H), 3.47 (q, J= 7.1 Hz, 4H),

1.24 (t, J= 7.0 Hz, 6H); 13C NMR 6 165.2 (C=O), 151.9, 145.5, 134.8, 132.9, 129.6,

125.6, 119.8, 116.3, 114.8, 110.3, 44.6 (CH2), 12.5 (CH3). Anal. Calcd for C17H18N40: C,

69.37; H, 6.16; N, 19.03. Found: C, 69.50; H, 6.37; N, 19.16.

1H-1,2,3-Benzotriazol-l-yl(4-nitrophenyl)methanone (4.2e): yield, 83%; Yellow

needles (recrystallized from chloroform/hexane); mp 193-194 OC; 1H NMR 6 8.45-8.30

(m, 5H), 8.20 (d, J= 8.4 Hz, 1H), 7.77 (t, J= 8.1 Hz, 1H), 7.61 (t, J= 8.1 Hz, 1H); 13C

NMR 6 165.0 (C=O), 145.9, 136.9, 132.6, 132.0, 131.0, 127.0, 123.7, 123.5, 120.5,

114.8. Anal. Calcd for C13H8N403: C, 58.20; H, 3.01; N, 20.90. Found: C, 58.21; H, 2.89;

N, 20.95.

1H-1,2,3-Benzotriazol-l-yl(4-chlorophenyl)methanone (4.2f): yield, 74%;

Colorless needles (recrystallized from chloroform/hexane); mp 138-139 OC; 1H NMR 6

8.38 (d, J= 8.1 Hz, 1H), 8.22-8.16 (m, 3H), 7.72 (t, J= 7.5 Hz, 1H), 7.58-7.54 (m, 3H);

13C NMR 6 165.6 (C=O), 145.7, 140.4, 133.2, 132.2, 130.6, 129.7, 128.8, 126.5, 120.3,

114.8. Anal. Calcd for C13HsClN30: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.51; H,

3.02; N, 16.43.

1H-1,2,3-Benzotriazol-l-yl(1-naphthyl)methanone (4.21): yield, 88%; Colorless

needles (recrystallized from benzene); mp 136.5-137.5 OC; 1H NMR 6 8.50 (d, J= 8.4

Hz, 1H), 8.20-8.11 (m, 3H), 7.99-7.94 (m, 2H), 7.76 (t, J= 7.5 Hz, 1H), 7.65-7.56 (m,

4H); 13C NMR 6 167.6 (C=O), 146.2, 133.6, 133.0, 132.0, 131.0, 130.5, 130.2, 129.3,









128.7, 127.9, 126.7, 126.5, 124.7, 124.3, 120.3, 114.7. Anal. Calcd for C17H11N30: C,

74.71; H, 4.06; N, 15.38. Found: C, 74.57; H, 4.14; N, 15.38.

1H-1,2,3-Benzotriazol-l-yl(2-pyrazinyl)methanone (4.2m): yield, 76%; Pale red

needles (recrystallized from chloroform/hexane); mp 146-147 OC; 1H NMR 6 9.35 (s,

1H), 8.89-8.87 (m, 2H), 8.41 (d, J= 6.0 Hz, 1H), 8.20 (d, J= 6.0 Hz, 1H), 7.65 (t, J=

7.8 Hz, 1H), 7.60 (t, J= 7.8 Hz, 1H); 13C NMR 6 163.7 (C=O), 147.5, 146.7, 145.8,

144.4, 131.7, 130.9, 126.9, 120.5, 114.5. Anal. Calcd for CllH7N50: C, 58.67; H, 3.13;

N, 31.10. Found: C, 58.72; H, 3.11; N, 31.27.

1-(1H-1,2,3-Benzotriazol-l-yl)-3-phenyl-l-propanone (4.2n): yield, 84%;

Colorless needles (recrystallized from chloroform/hexane); mp 63-64 OC; 1H NMR 6

8.18 (d, J= 8.3 Hz, 1H), 8.01 (d, J= 8.3 Hz, 1H), 7.55 (t, J= 7.5 Hz, 1H), 7.40 (t, J= 7.5

Hz, 1H), 7.28-7.26 (m, 3H), 7.20-7.17(m, 2H), 3.70 (t, J= 7.6 Hz, 2H), 3.18 (t, J= 7.6

Hz, 2H); 13C NMR 6 171.3 (C=O), 145.8, 139.6, 130.7, 130.0, 128.4, 128.2, 126.2, 125.8,

119.8, 114.0, 36.8, 29.8. Anal. Calcd for C15H13N30: C, 71.70; H, 5.21; N, 16.72. Found:

C, 71.48; H, 5.35; N, 16.77.

1-(1H-1,2,3-Benzotriazol-l-yl)-2,2-diphenyl-l-ethanone (4.2p): yield, 89%;

Colorless needles; mp 88-89 OC (mp[96HAC365] 106-107 OC); 1H NMR 6 8.32 (d, J=

8.4 Hz, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.62 (dd, J= 7.3, 7.3 Hz, 1H), 7.50-7.35 (m, 5H),

7.32-7.25 (m, 6H), 6.82 (s, 1H); 13C NMR 6 171.2 (C=O), 146.3, 137.4, 131.2, 130.4,

128.9, 128.8, 127.7, 126.3, 120.2, 114.5, 55.8 (CH).









4.4.3 General procedure for the Reaction of N-Acylbenzotriazoles 4.2 with Aqueous
ammonia.

The N-acylbenzotriazole 4.2 (2.5 mmol) was stirred with ammonium hydroxide

(30% aqueous solution, 5 mL, 43 mmol) in EtOH (5 mL) and THF (5 mL) at room

temperature for 2-4 h. After evaporation of solvents in vacuo, the residue was added 2 M

NaOH (20 mL) and extracted with EtOAc. The combined organic layers were dried over

anhydrous MgSO4. Evaporation of the solvent gave a solid, which was recrystallized

from benzene to afford the pure primary amide 4.3a-n. The isolated yields, melting points

and the reported melting points of 4.3a-n are summarized in Table 4-2.

4.4.4 General procedure for the Reaction of N-Acylbenzotriazoles 4.2 with Primary
amines.

The N-acylbenzotriazole 4.2 (1 mmol) was stirred with the appropriate primary

amine (1 mmol) in THF (10 mL) at room temperature for 4 h. After evaporation of

solvents in vacuo, the residue was added to 2 M NaOH (20 mL) and the product was

extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4.

Evaporation of the solvent gave a secondary amide 4.4a-j, which was recrystallized from

appropriate solvents.

N-Butyl-4-(diethylamino)benzamide (4.4c): yield, 92%; Yellow crystals

(recrystallized from benzene/hexane); H NMR 6 7.63 (d, J= 8.9 Hz, 2H), 6.62 (d, J=

8.9 Hz, 2H), 5.93 (br s, 1H), 3.46-3.54 (m, 6H), 1.62-1.53 (m, 2H), 1.43-1.36 (m, 2H),

1.18 (t,J= 7.0 Hz, 6H), 0.95 (t,J= 7.3 Hz, 3H); 13C NMR 6 167.3(C=0), 149.7, 128.5,

120.5, 110.3, 44.3, 39.5, 31.9, 20.1, 13.7, 12.4. HRMS Calcd for C15H25N20: 249.1967

(M+1), found: 249.1974.









N-Butyl-1-naphthamide (4.4f): yield, 92%; Colorless needles (recrystallized from

benzene); 1HNMR 6 8.23-8.20 (m, 1H), 7.84-7.78 (m, 2H), 7.49-7.45 (m, 3H),

7.36-7.31 (m, 1H), 6.28 (br s, 1H), 3.37 (t, J= 6.1 Hz, 2H), 1.58-1.51 (m, 2H),

1.39-1.32 (m, 2H), 0.90 (t, J= 7.1 Hz, 3H); 13C NMR 6 169.5 (C=O), 134.7, 133.5,

130.2, 130.0, 128.1, 126.8, 126.2, 125.3, 124.6, 124.5, 39.6, 31.5, 20.0, 13.7. Anal. Calcd

for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.24; H, 7.68; N, 6.11.

N-(4-Methoxyphenyl)-2-pyridinecarboxamide (4.4g): yield, 83%; Colorless

needles (recrystallized from benzene/hexane); 1H NMR 6 9.95 (s, 1H), 8.59 (d, J= 4.5

Hz, 1H), 8.29 (d, J= 7.5 Hz, 1H), 7.91-7.85 (m, 1H), 7.73-7.69 (m, 2H), 7.48-7.43 (m,

1H), 6.94-6.90 (m, 2H), 3.80 (s, 3H); 3C NMR 6 161.7 (C=O), 156.3, 149.7, 147.9,

137.6, 130.8, 126.2, 122.2, 121.2, 114.1, 55.4. Anal. Calcd for C13H12N202: C, 68.41; H,

5.30; N, 12.27. Found: C, 68.56; H, 5.38; N, 12.36.

N-(1-Methylpropyl)pyridine-4-carboxamide (4.4h): yield, 100%; Colorless

needles (recrystallized from benzene/hexane); 1H NMR 6 8.73 (dd, J = 4.4, 1.6 Hz, 2H),

7.61 (dd, J= 4.4, 1.6 Hz, 2H), 6.16 (br s, 1H), 4.18-4.08 (m, 1H), 1.64-1.55 (m, 2H),

1.24 (d, J 6.6 Hz, 3H), 0.97 (t, J= 7.4 Hz, 3H); 13C NMR 6 165.0 (C=O), 150.0, 142.1,

121.0, 47.4, 29.3, 20.1, 10.4. HRMS Calcd for C10H15N20: 179.1184 (M+1), found:

179.1184.

N-(tert-Butyl)-2-pyrazinecarboxamide (4.4i): yield, 100%; Colorless flakes

(recrystallized from benzene); 1H NMR 6 9.39 (d, J= 1.3 Hz, 1H), 8.72 (d, J= 2.5 Hz,

1H), 8.49 (dd, J= 1.5, 1.5 Hz, 1H), 7.75 (br s, 1H), 1.50 (s, 9H); 13C NMR 6 161.9

(C=O), 146.8, 145.1 143.9, 142.1, 51.2, 28.6. Anal. Calcd for C9H13N30: C, 60.32; H,

7.31; N, 23.45. Found: C, 60.16; H, 7.63; N, 23.28.









4.4.5 General procedure for the Reaction of N-Acylbenzotriazoles 4.2 with Secondary
amines.

The same procedure as used in the preparation of the secondary amides 4.4

afforded pure tertiary amides 4.5a-k.

(4-Nitrophenyl)(tetrahydro-lH-pyrrol-l-yl)methanone (4.5d): yield, 96%; light

yellow solid; 1H NMR 6 8.17 (dd, J= 8.4, 2.0 Hz, 2H), 7.62 (dd, J= 8.4, 2.0 Hz, 2H),

3.56 (t, J= 6.3 Hz, 2H), 3.30 (t, J= 6.0 Hz, 2H), 1.99-1.74 (m, 4H); 13C NMR 6 167.0

(C=O), 148.0, 142.9, 127.9, 123.3, 49.1, 46.1, 26.1, 24.1. Anal. Calcd for CllH12N203: C,

59.99; H, 5.49; N, 12.72. Found: C, 59.85; H, 5.54; N, 12.69.

(2-Methoxyphenyl)(tetrahydro-1H-pyrrol-l-yl)methanone (4.5f): yield, 98%;

Yellow oil; H NMR 6 7.36-7.25 (m, 2H), 7.00-6.90 (m, 2H), 3.82 (s, 3H), 3.65 (t, J=

6.3 Hz, 2H), 3.22 (t, J= 6.3 Hz, 2H), 1.97-1.83 (m, 4H); 13C NMR 6 167.7 (C=O),

155.0, 130.2, 127.5, 127.3, 120.6, 110.9, 55.4, 47.5, 45.3, 25.6, 24.4. HRMS Calcd for

C12H16N02: 206.1181 (M+1), found: 206.1178.

1-Naphthyl(tetrahydro-1H-pyrrol-l-yl)methanone (4.5h): yield, 94%; Colorless

needles (recrystallized from benzene/hexane); 1H NMR 6 7.88-7.84 (m, 3H), 7.53-7.43

(m, 4H), 3.79 (t, J= 6.9 Hz, 2H), 3.11 (t, J= 6.9 Hz, 2H), 2.01-1.94 (m, 2H), 1.83-1.78

(m, 2H); 13C NMR 6 169.1 (C=O), 135.6, 133.4, 129.0, 128.9, 128.2, 126.8, 126.1, 125.0,

124.7, 123.5, 48.4, 45.5, 25.9, 24.5. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N,

6.22. Found: C, 79.86; H, 6.84; N, 6.14.

4-Pyridinyl(tetrahydro-1H-pyrrol-l-yl)methanone (4.5i): yield, 100%; Yellow

oil; 1H NMR 6 8.73-8.71 (m, 2H), 7.43-7.40 (m, 2H), 3.68 (t, J= 6.9 Hz, 2H), 3.40 (t, J









= 6.9 Hz, 2H), 2.05-1.88 (m, 4H); 13C NMR 6 167.1 (C=O), 150.0, 144.5, 121.2, 49.2,

46.3, 26.2, 24.2. HRMS Calcd for C10H13N20: 177.1028 (M+1), found: 177.1017.

2,2-Diphenyl-l-piperidino-l-ethanone (4.5k): yield, 68%; Colorless needles

(recrystallized from benzene); H NMR 6 7.32-7.20 (m, 10H), 5.22 (s, 1H), 3.64-3.61

(m, 2H), 3.41-3.37 (m, 2H), 1.55-1.53 (m, 4H), 1.30-1.20 (m, 2H); 13C NMR 6 169.9

(C=O), 139.7, 129.0, 128.4, 126.8, 54.7, 49.0, 43.2, 26.0, 25.5, 24.4. Anal. Calcd for

C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.69; H, 7.76; N, 5.02.

4.4.6 General procedure for the preparation of a-hydroxyamides.

A mixture of BtSO2CH3 (0.49 g, 2.5 mmol), 2-hydroxy-2-phenylacetic acid (0.38 g,

2.5 mmol) and Et3N (0.35 g, 3.5 mmol) was heated under reflux in dry THF for about 20

min, then an appropriate amine (2.5 mmol) was added and the mixture was refluxed for

18 h. After being concentrated, EtOAc (50 mL) was added and the organic phase was

washed with 2 M NaOH, dried over anhyd MgSO4. Removal of the solvent gave a solid,

which was recrystallized from CHC13 to furnish a-hydroxyamide 4.7a-b.

2-Hydroxy-N,2-diphenylacetamide (4.7a): yield, 68%; Colorless flakes; mp

143-144 C (mp[86TL1921] 150-151 C); H NMR 6 9.08 (br s, 1H), 7.59-7.51 (m,

2H), 7.49-7.40 (m, 2H), 7.40-7.20 (m, 5H), 7.07 (t, J= 7.4 Hz, 1H), 6.07 (br s, 1H), 5.13

(s, 1H); 13C NMR 6 170.5 (C=O), 139.7, 137.2, 128.4, 127.9, 127.6, 126.3, 123.7, 119.2,

73.8. Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.72; H, 5.91;

N, 6.14.

2-Hydroxy-N-(4-methylphenyl)-2-phenylacetamide (4.7b): yield, 72%;

Colorless flakes; mp 169-170 C (mp[86TL1921] 170-172 C); H NMR 6 9.02 (br s,

1H), 7.53-7.45 (m, 4H), 7.37-7.24 (m, 1H), 7.33 (d, J= 7.5 Hz, 2H), 7.09 (d, J= 8.3 Hz,









2H), 6.11 (d, J= 4.4 Hz, 1H), 5.14 (d, J= 4.2 Hz, 1H), 2.29 (s, 3H); 13C NMR 6 170.2

(C=O), 139.9, 134.7, 133.1, 128.8, 127.8, 127.5, 126.3, 119.1, 73.7, 20.3. Anal. Calcd for

C15H15N02: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.43; H, 6.63; N, 5.77.

4.4.7 Preparation of 1-(1H- 1,2,3-Benzotriazol- -yl)-2,2,3,3,4,4,4-heptafluorobutan- 1-one
(4.8).

To a solution of BtTMS (1.9 g, 10 mmol) in dry THF (20 mL) under argon, was

added dropwise n-C3F7COCl (2.3 g, 10 mmol). The mixture was stirred at rt for 3 h.

Then, removal of the solvent afforded C3F7COBt (4.8), together with byproduct BtH. The

1H NMR spectrum of the mixture shows that the molar ratio of these two compounds is

6:1.

1-(1H-1,2,3-Benzotriazol-1-yl)-2,2,3,3,4,4,4-heptafluorobutan-1-one (4.8): white

powder (a mixture with benzotriazole with ratio as 6:1); Yield determined by 1H NMR,

86%; 1H NMR 6 8.28 (d, J = 8.1 Hz, 1H), 8.22 (d, J= 8.1 Hz, 1H), 7.79 (t, J= 7.2 Hz,

1H), 7.65 (t, J= 7.2 Hz, 1H); 19F NMR 6 -80.7 (t, J= 9.3 Hz, 3F, CF3), -112.5 -112.7

(m, 2F, -CF2CO-), -124.8 (s, 2F, -CF2-).

4.4.8 General Procedure for the Reaction 4.8 with Primary and Secondary amines.

The mixture of 4.8 and BtH (212 mg, 0.63 mmol of 4.8) and an appropriate amine

(0.63 mmol) was stirred at rt for 6 h. After being concentrated, the mixture was washed

with 2 M NaOH and extracted with EtOAc (20 mL x 2). The organic phase was dried

over anhyd MgSO4. Removal of the solvent in vacuo afforded perfluoroalkylated amide

4.9a-d. The isolated yields of 4.9a-d were based on n-C3F7COBt.

2,2,3,3,4,4,4-Heptafluoro-N-(4-methylphenyl)butanamide (4.9a):[96PCJ690]

yield, 90%; Colorless needles; mp 99-100 oC; 1H NMR 6 10.03 (br s, 1H), 7.55 (d, J=

8.3 Hz, 2H), 7.16 (d, J= 8.1 Hz, 2H), 2.33 (s, 3H); 19F NMR 6 -81.0 (t, J= 8.2 Hz, 3F,









CF3), -120.2--120.3 (m, 2F, -CF2CO-), -127.3 (s, 2F, -CF2-). Anal. Calcd for

CllH8NF70: C, 43.58; H, 2.66; N, 4.62. Found: C, 43.25; H, 2.86; N, 4.82.

2,2,3,3,4,4,4-Heptafluoro-N-(1-phenylethyl)butanamide (4.9b): yield, 87%;

Colorless needles; mp 91-92 C (mp[72JPS1235] 89-90 C); 1H NMR 6 7.41-7.30 (m,

5H), 6.65 (br s, 1H), 5.19 (q, J= 7.2 Hz, 1H), 1.58 (d, J= 6.9 Hz, 3H); 19F NMR 6 -81.1

(t, J= 8.2 Hz, 3F, CF3), -121.2 -121.3 (m, 2F, -CF2CO-), -127.5 (s, 2F, -CF2-). Anal.

Calcd for C12H10NF70: C, 45.44; H, 3.18; N, 4.42. Found: C, 45.65; H, 3.56; N, 4.32.

2,2,3,3,4,4,4-Heptafluoro-l-tetrahydro-1H-pyrrol-1-ylbutan-1-one (4.9c):

colorless oil, bp[55JACS6662] 65 C/2 mmHg; Yield, 88%; 1H NMR 6 3.71-3.67 (m,

2H), 3.66-3.59 (m, 2H), 2.06-1.99 (m, 2H), 1.97-1.88 (m, 2H); 19F NMR 6 -80.7 (t, J=

9.3 Hz, 3F, CF3), -116.0 -116.1 (m, 2F, -CF2CO-), -126.6 (s, 2F, -CF2-).

2,2,3,3,4,4,4-Heptafluoro-1-tetrahydro-4H-1,4-oxazin-4-ylbutan-1-one (4.9d):

colorless oil, bp[98CJC549] 90 C/10 mmHg; Yield, 85%; 1H NMR 6 3.80-3.65 (m,

8H); 19F NMR 6 -80.3 (t, J= 9.3 Hz, 3F, CF3), -112.3 -112.4 (m, 2F, -CF2CO-), -126.3

(s, 2F, -CF2-).














CHAPTER 5
HIGHLY DIASTEREOSELECTIVE PEPTIDE CHAIN EXTENSIONS OF
UNPROTECTED AMINO ACIDS WITH N-(Z-a-AMINOACYL)BENZOTRIAZOLES

5.1 Introduction

The many coupling reagents [79Peptide] [01SPP] developed for the formation of

amide bonds in the synthesis of biologically active peptides and their analogs

[95CR2115] [97CR2243] [98CR763] include: (i) carbodiimides in combination with

additives such as 1-hydroxybenzotriazole (HOBt), [02T7851] [030L2793] 1-hydroxy-7-

azabenzotriazole (HOAt) and analogs [010L2793] or N-hydroxysuccinimide (HOSu);

[64JACS1839] (ii) phosphonium [75TL1219] [90TL205] and uronium salts [84S572]

[01S1811] of HOBt or HOAt; (iii) N-acylazoles such as 1,1'-carbonylbis(1H-imidazole)

(CDI); [00HCA2607] (iv) mixed anhydrides; [51JACS5553] or (v) carboxylic acid

fluorides. [90JACS9651] [91JOC2611]

A commonly encountered problem in peptide synthesis is epimerization of the

amino acid component during activation of the carboxylic acid group. Many of the

coupling reagents require prior protection and subsequent deprotection of various amino

acid functional groups. [91CSP] Coupling reactions with such reagents are frequently

moisture sensitive. Furthermore, isolation and purification processes often involve

column chromatography due to the formation of by-products from the coupling reagents.

The literature reveals that the reactions of N-protected C-activated amino acids

with unprotected amino acids have been less explored than their reactions with C-

protected amino acids. In 1980 Hegarty et al. reported peptide coupling of unprotected









amino acids with imidoyl halides RC(:NNR'2)X (derivatives of acid hydrazides) as

condensation reagents; they observed 1.0-21.0% of racemization at pH 7.2-9.3.

[80JACS4537] N-Hydroxysuccinimide esters of amino acids couple with unprotected

amino acids in dioxane in the presence of sodium hydroxide. [87S236] Recent one-pot,

two-step preparations of di- and tripeptides coupled unprotected amino acids in aqueous

acetonitrile with p-nitrophenyl esters of N-protected amino acids in 15-98% yields, with

high retention of chirality. [02TL7717]

N-Acylbenzotriazoles are efficient neutral coupling reagents for: (i) preparation of

primary, secondary, and tertiary amides; [00JOC8210] (ii) C-acylation of pyrroles and

indoles, [03JOC5720] 2-methylfuran and thiophene; [04CCA175] (iii) acylation of

primary and secondary alkyl cyanides. [03JOC4932]

N-Acylbenzotriazoles are sufficiently reactive to form amide bonds at ambient

temperature, but stable enough to resist side reactions. We previously prepared amino-

amides from 1-(ca-Boc-aminoacyl)benzotriazoles and amines in 82-99% yields with no

detectable racemization. [02ARK(viii)134] Advantageously, N-acylbenzotriazoles are

usually crystalline and can be stored at room temperature for long periods. We report

herein the preparation of N-terminal protected peptides by reactions of N-

acylbenzotriazoles with unprotected amino acids in aqueous/organic solvents in a broadly

applicable, simple and efficient coupling method (Scheme 5-1).










R O 0
R O i) R1 O ii R2
Z-NH HN
Z-NH OH Z-NH Bt O
HO
5.1a-d 5.2a-i

iv) iii)

Ri 0 Ri 0
NHHN R1
Z-NH HN- O / Z-NH HN-
0 v) R vi) o
HN Z NH HN- HN

HO Bt HO HN
5.4a-f, 5.4a' 0 5.3a-b 0 5.5a-b

Z= benzyloxycarbonyl R1 = CH3, CH(CH3)2, CH2Ph
R2 = H, CH3, CH(CH3)2, CH2Ph, CH2OH, CH2(indol-3-yl)
Bt= benzotriazol--yl R3 = H, CH3, CH2CH(CH3)2, CH2OH, CH2(indol-3-yl)
R4 = CH2CH(CH3)2

Scheme 5-1. Coupling reactions with N-(Z-a-aminoacyl)benzotriazoles

i) SOC12, BtH at 25 C, ii) Unprotected amino acid, Et3N in CH3CN/H20. iii) SOC12, BtH

at 0 C, iv) Gly-Leu-OH or Gly-Gly-OH, Et3N in CH3CN/H20, v) Unprotected amino

acid, Et3N in CH3CN/H20. vi) Gly-Leu-OH, Et3N in CH3CN/H20.

5.2 Results and Discussion

5.2.1 Preparation of N-(Z-Aminoacyl)benzotriazoles from N-Z-Amino acids 5.1a-d.

The Z group is a favorite protecting group due to (i) its stability towards both acidic

and basic conditions, (ii) easy purification of solid Z-protected amino acids and peptides,

and (iii) its ready cleavage by hydrogenation. [01SPP] [02TL7717] The Boc group is also

a popular protecting group, [64JACS1839] [97S1499] but is not preferred under strongly

acidic conditions.

Chiral 1-(c-Boc-aminoacyl)benzotriazoles were previously prepared by the reaction of

BtSO2Me with Boc-protected amino acids in refluxing THF in the presence of Et3N with









no detectable racemization. [02ARK(viii)134] Although Z-Ala-OH and Z-Phe-OH

produced the corresponding N-acylbenzotriazole derivatives with 15-50% of

racemization under these conditions, our recently developed mild alternative procedure

for the preparation of N-acylbenzotriazoles proved beneficial. [03 S2795] Under this

protocol, the N-Z-amino acid was reacted with four equivalents of benzotriazole and one

equivalent of SOC12 in CH2C12 at room temperature for 2 h to give N-(Z-

aminoacyl)benzotriazoles 5.1a-d in 85-95% yields; compounds la-c were obtained with

minimal racemization (Table 5-1).

Table 5-1. Conversion of N-Z-a-amino acids into (N-Z-aminoacyl) benzotriazoles
compound yield (%) mp (C) [a]D25
Z-Ala-Bt (5.1a) 95 114-115 -0.8
Z-Val-Bt (5.1b) 91 73-74 -32.5
Z-Phe-Bt (5.1c) 88 151-152 +18.6
Z-DL-Ala-Bt (5.1d) 94 112-113 --


To test the optical purity of N-(Z-aminoacyl)benzotriazoles 5.1a-c prepared by the

above procedure with commercially available, enantiomerically pure unprotected amino

acids, [03S2795] we performed 1H NMR analysis of the crude dipeptides 5.2. Thus, Z-

DL-Ala-L-Phe-OH prepared by coupling Z-DL-Ala-Bt (5.1d) with L-Phe-OH showed

two separate doublets for the methyl protons at 1.25 and 1.20 ppm corresponding to the

LL- and DL-diastereomers, respectively. In comparison, Z-L-Ala-L-Phe-OH (5.2a)

prepared by the coupling of Z-L-Ala-Bt (5.1a) with L-Phe-OH showed a single doublet in

the 1H NMR spectrum at 1.25 ppm. Similarly, partially racemized Z-L-Phe-Bt with L-Ala

formed two diastereomers (Z-DL-Phe-L-Ala-OH) with signals at 1.32 and 1.23 ppm in

the 1H NMR spectrum while Z-L-Phe-L-Ala-OH (5.2f) prepared from Z-L-Phe-Bt (5.1c)

and L-Ala-OH showed a single doublet for the methyl group at 1.32 ppm (see Fig. 5-1).










Compounds 5.1a-d are novel compounds which were fully characterized by 1H and 13C

NMR spectroscopy and elemental analysis.


(S, S)

SN CH3
H NH
H 0
OH


1


l N (RS, S)
z 0
N CH3
H NH
OH

(S,S)


(R, S)







1


Fig.5-2 1H NMR spectra of compound 5.2f (left) and racemized 5.2f (right) in CDC13
(CH3 signal in L-Ala)

5.2.2 Preparation of N-Z-Dipeptides.

Coupling reactions of 5.1a-d were carried out with diverse unprotected amino

acids in partially aqueous solution (CH3CN/H20) in the presence of Et3N for 10 to 40

min. After washing with 6 N HC1, the resulting peptides 5.2a-i were obtained in 85-98%

yields (Table 5-2). The crude products were estimated to be >95% pure and the absence

of epimerization was established by 1H NMR experiments. Thus, Z-L-Phe-Bt (5.1c) was

reacted with racemic DL-Ala-OH. While enantiopure Z-L-Phe-L-Ala-OH (5.2f) showed

the methyl group on the alanine fragment at 1.32 ppm as a doublet, the methyl groups in









diastereomers Z-L-Phe-D-Ala-OH and Z-L-Phe-L-Ala-OH resonated at 1.23 and 1.32

ppm, respectively. Furthermore, the dipeptides were analyzed by HPLC (detection at 254

nm, flow rate 1.0 mL/min, and solvents 50/50 MeOH/H20 contained 0.1% TFA); while

Z-L-Phe-DL-Ala-OH gave two peaks at 15.1 and 19.8 min, Z-L-Phe-L-Ala-OH (5.2f)

showed a only single peak at 15.1 min. This result confirmed minimal epimerization in

the reaction.

Table 5-2. Preparation of N-Z-dipeptides from (N-Z-aminoacyl)benzotriazoles and
unprotected amino acids.
RCOBt amino Product yield Ref.
reactant acid (%)

5.1a Phe Z-Ala-Phe-OH (5.2a) 90 [020L4005]
5.1a Ser Z-Ala-Ser-OH (5.2b) 85 [84JCS(P1)2439]
5.1a Try Z-Ala-Trp-OH (5.2c) 97 [84JCS(P1)2439]
5.1b Phe Z-Val-Phe-OH (5.2d) 98 [83LAC1712]
5.1b Try Z-Val-Try-OH (5.2e) 96 [96BP1051]
5.1c Ala Z-Phe-Ala-OH (5.2f) 98 [68JCS(C)1208]
5.1c Val Z-Phe-Val-OH (5.2g) 95 [82TL3831]
5.1c Phe Z-Phe-Phe-OH (5.2h) 98 [67LAC227]
5.1c Ser Z-Phe-Ser-OH (5.2i) 96 [02TL7717]


5.2.3 Preparation of N-Acylbenzotriazoles derived from N-Z-Dipeptides.

Z-Phe-Ala-Bt (5.3a) and Z-Ala-Phe-Bt (5.3b) were prepared from N-Z-protected

dipeptides by reaction with benzotriazole and SOC12 at 0 C for 2 h. This reaction

proceeded at 0 C without visible racemization (i.e. <5.0% as indicated by 1H NMR of

the crude products), and gave 5.3a and 5.3b in 85% and 95% yields, respectively (Table

5-3). However, at 25 C, 5-15% racemization was observed: the methyl group in Z-L-

Phe-DL-Ala-Bt showed peaks at 1.58 ppm (LL) and 1.47 ppm (LD). Compound 5.3a and

5.3b are novel compounds and were fully characterized by 1H and 13C NMR

spectroscopy and elemental analysis.









Table 5-3. Conversion of N-Z-dipeptides into N-(Z-dipeptidoyl)benzotriazoles.
Compound yield (%) mp (C) [a]D25
Z-Phe-Ala-Bt (5.3a) 85 180-181 -57.1
Z-Ala-Phe-Bt (5.3b) 90 148-149 -8.7

5.2.4 Preparation of N-Z-Tripeptides.

Tripeptides 5.4a-f were prepared according to two different protocols: (i) reactions

of N-acylbenzotriazole derivatives of N-Z-protected amino acids 5.1a, 5.1b, and 5.1c

with free dipeptides, Gly-L-Leu-OH and Gly-Gly-OH, and (ii) reactions of N-

acylbenzotriazole derivatives of N-Z-protected dipeptides 5.3a and 5.3b with free amino

acids (see Scheme 5-1 and Table 5-3). The reaction conditions were similar to those

described above for the preparation of the dipeptides 5.2a-i, but longer reaction times

(around 30 to 120 min) were required. After work-up as described above for the

preparation of the dipeptides 5.2a-i, the enantiopure tripeptides 5.4a-f were obtained in

85-98% yields (Table 5-4). In order to check the enantiopurity, a racemic mixture of Z-

L-Ala-Gly-L-Leu-OH (5.4a) and Z-D-Ala-Gly-L-Leu-OH (5.4a') was prepared from

racemic compound 5.1d with Gly-L-Leu-OH for comparison with the enantiopure

tripeptide 5.4a. The 1H NMR of the mixture (5.4a+5.4a') showed broadened peaks for

protons of two methyl groups in the iso-butyl group and complicated multiplets for three

NH protons (7.55, 7.91 and 8.17 ppm) while 5.4a gave two sharp doublets for the two

methyl groups and two doublets and a broad singlet for the NH protons. In the 13C NMR

spectrum, the 5.4a-5.4a' mixture of diastereomers gave separate signals at 50.0 (from Z-

L-Ala-Gly-L-Leu-OH, 5.4a) and 50.2 ppm (from Z-D-Ala-Gly-L-Leu-OH, 5.4a'), but

many other signals from 5.4a and 5.4a' overlapped. Moreover, HPLC was utilized to

confirm the negligible racemization; 5.4a showed a single peak at 11.7 min when a

mixture of 5.4a and 5.4b showed two peaks at 11.7 and 14.1 min (detection at 230 and









254 nm, flow rate 1.0 mL/min, and solvents 50/50 MeOH/H20 containing 0.1% TFA).

Tripeptides 5.4b, 5.4e, and 5.4f are novel compounds, and were characterized by 1H and

13C NMR spectroscopy, elemental analysis, and optical rotation.

Table 5-4. Preparation of N-Z-tripeptides (i) from N-(Z-aminoacyl)benzotriazoles and
unprotected dipeptides (with 5.1a-c) (ii) from N-(Z-
dipeptidoyl)benzotriazoles and unprotected amino acids (with 5.3a and 5.3b).
RCOBt amino acid Product yield Ref.
reactant or dipeptide (%)

5.1a Gly-Leu Z-Ala-Gly-Leu-OH (5.4a) 93 --
5.1d Gly-Leu Z-DL-Ala-Gly-Leu-OH (5.4a+5.4a') 94
5.1b Gly-Leu Z-Val-Gly-Leu-OH (5.4b) 85 [79CB2145]
5.1c Gly-Gyl Z-Phe-Gly-Gly-OH (5.4c) 98 [91SL35]
5.3a Ala Z-Phe-Ala-Ala-OH (5.4d) 92
5.3a Ser Z-Phe-Ala-Ser-OH (5.4e) 94
5.3b Try Z-Ala-Phe-Try-OH (5.4f) 95


5.2.5 Preparation of N-Z-Tetrapeptides.

Reactions of 5.3a and 5.3b with Gly-L-Leu-OH for 2-4 h gave tetrapeptides 5.5a

and 5.5b in 86% and 85% yields, respectively (Table 5-5). These novel compounds were

characterized by 1H and 13C NMR spectroscopy, elemental analysis, and optical rotation.

Table 5-5. Preparation of N-Z-tetrapeptides from N-(Z-dipeptidoyl)benzotriazoles and an
unprotected dipeptide.
RCOBt dipeptide Product yield
reactant (%)
5.3a Gly-Leu Z-Phe-Ala-Gly-Leu-OH (5.5a) 86
5.3b Gly-Leu Z-Ala-Phe-Gly-Leu-OH (5.5b) 85

5.3 Conclusion

In summary, N-acylbenzotriazoles derived from N-protected amino acids or

peptides have been introduced as new coupling reagents. The peptide coupling reaction

utilizing the N-acylbenzotriazole derivatives and unprotected amino acids proceeds with

minimal epimerization in partially aqueous solution under mild conditions.









5.4 Experimental Section

Melting points were determined on a capillary point apparatus equipped with a

digital thermometer. NMR spectra were recorded in CDC13 or DMSO-d6 with TMS for

1H (300 MHz) and 13C (75 MHz) as the internal reference unless specified otherwise. The

HPLC was performed with Chirobiotic T column 4.6 x 250 mm, detection at 254 nm,

flow rate 1.0 mL/min, and solvents (MeOH/H20 contained 0.1% TFA). THF was

distilled from sodium metal in the presence of benzophenone under nitrogen atmosphere

immediately prior to use. Amino acids and peptides are L-configuration unless specified

otherwise.

5.4.1 General procedure for the Preparation of 5.1a-d and 5.3a-b.

For preparation of 5.1a-d and 5.3a-b, thionyl chloride (5 mmol) was added to a

solution of 1H-benzotriazole (20 mmol) in dry THF (15 mL) at 25 C, and the reaction

mixture was stirred for 20 min. To the reaction mixture, N-protected amino acid (5

mmol) dissolved in dry THF (5 mL) was added dropwise, and stirred for 1 hour at 25 C.

For compounds 5.3a and 5.3b, the reaction mixture was cooled to 0 oC, and N-Z-

dipeptide (5 mmol) dissolved in dry THF (5 mL) was added dropwise, and stirred at 0 C

for 2 hours. The reaction mixture was concentrated under reduced pressure, and the

residue was purified by column chromatography (EtOAc:Hexanes = 1:1 for 5.1a-d,

CHCl3:Hexanes = 1:1 for 5.3a and 5.3b) to give the desired product. Further purification

was performed by recrystallization from CHC13/hexanes for the purpose of elemental

analysis. Crude 5.1a-d can be purified by washing with 5% Na2CO3 solution to remove

BtH, instead of column chromatography.









Benzyl N-[(1S)-2-(1H-1,2,3-benzotriazol-1-yl)-l-methyl-2-oxoethyl]carbam-ate

(Z-Ala-Bt, 5.1a): Colorless fine needles (95%), mp 114-115 oC: [a]25D = -0.80 (c 1.8,

CHC13); 1H NMR (CDC13) 6 1.69 (d, J= 7.0 Hz, 3H, CH3), 5.11 (d, J= 12.2 Hz, 1H, O

OCH2Ph), 5.17 (d, J= 12.2 Hz, 1H, OCH2Ph), 5.69 (d, J= 7.6 Hz, 1H, NH), 5.78-5.84

(m, 1H, NCHCO), 7.14 (br s, 1H, ArH), 7.36-7.42 (m, 4H), 7.50-7.55 (m, 1H, ArH in

Bt), 7.67 (td, J= 8.1, 0.8 Hz, 1H, ArH in Bt), 8.13 (d, J= 8.2 Hz, 1H, ArH in Bt), 8.26

(d, J= 8.1 Hz, 1H, ArH in Bt). 13C NMR (CDC13) 6 19.0, 50.5, 67.2, 114.3, 120.3, 126.5,

128.1, 128.2, 128.5, 130.7, 131.1, 136.0, 146.0, 155.6, 172.2. Anal. Calcd for

C17H16N403: C, 62.95; H, 4.97; N, 17.27. Found: C, 63.21; H, 4.88; N, 17.40.

Benzyl N-[(1S)-1-(1H-1,2,3-benzotriazol-1-ylcarbo-nyl)-2-methylpropyl]-

carbamate (Z-Val-Bt, 5.1b): Colorless needles (91%), mp 73-74 oC: []25D = -32.50 (c

2.0, CHC13); 1HNMR (CDC13) 6 0.97 (d, J= 6.8 Hz, 3H, CHCH3), 1.13 (d, J= 6.8 Hz,

3H, CHCH3), 2.48-2.54 (m, 1H, CHCH(CH3)2), 5.13 (d, J= 12.4 Hz, 1H, OCH2Ph), 5.16

(d, J= 12.4 Hz, 1H, OCH2Ph), 5.68 (d, J= 9.0 Hz, 1H, NH), 5.77 (dd, J= 9.0, 4.5 Hz,

1H, NCHCO), 7.15 (br s, 1H, ArH), 7.36 (br s, 4H, ArH), 7.50-7.55 (m, 1H, ArH in Bt),

7.64-7.69 (m, 1H, ArH in Bt), 8.13 (d, J= 8.3 Hz, 1H, ArH in Bt), 8.27 (d, J= 8.2 Hz,

1H, ArH in Bt). 13C NMR (CDC13) 6 16.9, 19.6, 31.6, 59.4, 67.3, 114.3, 120.3, 126.4,

128.1, 128.5, 130.6, 131.0, 136.0, 146.0, 156.2, 171.5. Anal. Calcd for C19H20N403: C,

64.76; H, 5.72; N, 15.90. Found: C, 64.82; H, 5.77; N, 15.80.

Benzyl N- [(1S)-2-(1H-1 ,2,3-benzotriazol- 1-yl)- 1-benzyl-2-oxoethyl] carbamate

(Z-Phe-Bt, 5.1c): Colorless plates (89%), mp 151-152 C: [a]25D = +18.60 (c 2.0,

CHC13); H NMR (CDC13) 6 3.23 (dd, J= 13.9, 7.7 Hz, 1H, CHCH2Ph), 3.49 (dd, J=

13.9, 4.9 Hz, 1H, CHCH2Ph), 5.09 (s, 2H, OCH2Ph), 5.51 (d, J= 8.2 Hz, 1H, NH),









6.05-6.10 (m, 1H, NCHCO), 7.12-7.14 (m, 2H), 7.23-7.33 (m, 8H), 7.53-7.58 (m, 1H,

ArH in Bt), 7.66-7.72 (m, 1H, ArH in Bt), 8.16 (d, J= 8.1 Hz, 1H, ArH in Bt), 8.24 (d, J

= 8.1 Hz, 1H, ArH in Bt). 13C NMR (CDC13)6 38.8, 55.6, 67.2, 114.3, 120.4, 126.6,

127.4, 128.1, 128.5, 128.7, 129.2, 130.8, 134.9, 146.0, 155.7, 170.8. Anal. Calcd for

C23H20N403: C, 68.99; H, 5.03; N, 13.99. Found: C, 69.19; H, 5.11; N, 14.05.

Benzyl N-[2-(1H-1 ,2,3-benzotriazol-l-yl)-l-methyl-2-oxoethyl]carbamate (Z-

DL-Ala-Bt, 5.1d): Colorless crystals (94%), mp 112-113 oC; H NMR (CDC13) 6 1.69

(d, J= 7.0 Hz, 3H, CH3), 5.11 (d, J= 12.2 Hz, 1H, OCH2Ph), 5.17 (d, J= 12.2 Hz, 1H,

OCH2Ph), 5.69 (d, J= 7.6 Hz, 1H, NH), 5.78-5.84 (m, 1H, NCHCO), 7.14 (br s, 1H),

7.36 (s, 4H), 7.50-7.55 (m, 1H, ArH in Bt), 7.64-7.70 (m, 1H, ArH in Bt), 8.13 (d, J=

8.2 Hz, 1H, ArH in Bt), 8.26 (d, J= 8.1 Hz, 1H, ArH in Bt). 13C NMR (CDC13) 6 38.8,

55.6, 67.2, 114.3, 120.4, 126.6, 127.4, 128.1, 128.5, 128.7, 129.2, 130.8, 130.9, 134.9,

135.9, 146.0, 155.7, 170.8. Anal. Calcd for C17H16N403: C, 62.95; H, 4.97; N, 17.27.

Found: C, 63.24; H, 4.96; N, 17.26.

Benzyl N-((1S)-2-{[(1S)-2-(1H-1,2,3-benzotriazol-l-yl)-l-methyl-2-oxoethyl]

amino}-l-benzyl-2-oxoethyl) carbamate (Z-Phe-Ala-Bt, 5.3a): Colorless needles

(85%), mp 180-181 oC: [a]25D = -57.1 (c 0.83, CHC13); 1H NMR (DMSO-d6) 6 1.61 (d,

J= 7.1 Hz, 3H, CHCH3), 2.70-2.78 (m, 1H, CHCH2Ph), 3.07 (dd, J= 13.6, 3.0 Hz, 1H,

CHCH2Ph), 4.34-4.41 (m, 1H, NCHCO), 4.93 (s, 2H, OCH2Ph), 5.63 (apparent q, J=

6.5 Hz, 1H, NCHCO), 7.21-7.35 (m, 10H), 7.55 (d, J= 8.8 Hz, 1H, NH), 7.65 (t, J= 7.6

Hz, 1H, ArH in Bt), 7.82 (t, J= 7.7 Hz, 1H, ArH in Bt), 8.25 (d, J= 8.3 Hz, 1H, ArH in

Bt), 8.31 (d, J= 8.4 Hz, 1H, ArH in Bt), 9.02 (d, J= 5.5 Hz, 1H, NH). 13C NMR (DMSO-

d6)6 16.6, 37.3, 48.6, 55.6, 65.1, 113.9, 120.1, 126.2, 126.6, 127.4, 127.6, 127.9, 128.2,









129.1, 130.6, 131.0, 136.9, 137.9, 145.3, 155.8, 171.7, 172.0. Anal. Calcd for

C26H25N504: C, 66.23; H, 5.34; N, 14.85. Found: C, 65.80; H, 5.48; N, 14.52.

Benzyl N-((1S)-2-{[(1S)-2-(1H-1,2,3-benzotriazol-1-yl)-l-benzyl-2-oxoethyl]

amino}-l-methyl-2-oxoethyl) carbamate (Z-Ala-Phe-Bt, 5.3b): Colorless

microcrystals (90%), mp 148-149 C: []25D = -8.70 (c 2.0, CHC13); 1H NMR (CDC13) 6

1.34 (d, J= 7.0 Hz, 3H, CHCH3), 3.22 (dd, J= 14.0, 7.8 Hz, 1H, CHCH2Ph), 3.47 (dd, J

= 14.0, 4.8 Hz, 1H, CHCH2Ph), 4.30-4.33 (m, 1H, NCHCO), 5.07 (d, J= 12.2 Hz, 1H,

OCH2Ph), 5.13 (d, J= 12.2 Hz, 1H, OCH2Ph), 5.34 (d, J= 6.2 Hz, 1H, NH), 6.20-6.23

(m, 1H, NCHCO), 7.04-7.35 (m, 11H), 7.51-7.57 (m, 1H, ArH in Bt), 7.65-7.70 (m, 1H,

ArH in Bt), 8.15 (d, J= 8.2 Hz, 1H, ArH in Bt), 8.22 (d, J= 8.0 Hz, 1H, ArH in Bt). 13C

NMR (CDCl3)6 18.1, 38.5, 50.3, 54.1, 67.1, 114.3, 120.4, 126.6, 127.4, 128.1, 128.2,

128.5, 128.6, 129.2, 130.8, 131.0, 135.0, 136.0, 146.0, 156.0, 170.2, 172.1. Anal. Calcd

for C26H25N504: C, 66.23; H, 5.34; N, 14.85. Found: C, 66.25; H, 5.37; N, 14.29.

5.4.2 General procedure for the Preparation of 5.2a-i, 5.4a-f, 5.4a', and 5.5a-b.

N-Acylbenzotriazoles (5.1a-d, 5.3a-b) (0.5 mmol) were added at room

temperature to a solution of a-amino acid (0.5 mmol) in a solution of CH3CN (7 mL) and

H20 (3 mL) in the presence of Et3N (0.6 mmol). The reaction mixture was then stirred at

room temperature until the starting material was completely consumed (10-40 min for

dipeptides, 30-120 min for tripeptides, 120-240 min for tetrapeptides). After 1 mL of 6

N HC1 was added, the solution was concentrated under reduced pressure. The residue was

extracted with EtOAc (20 mL), washed with 6N HC1 (5 mL) and brine (10 mL), and then

dried (anhydrous MgSO4). Evaporation of the solvent gave the desired product in pure

form, which was recrystallized further from CHC13/hexanes.









(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino} propanoyl)amino]-3-phenyl-

propanoic acid (Z-Ala-Phe-OH, 5.2a):[020L4005][94JOC7503] Colorless

microcrystals (90%), mp 122-124 C (lit.[ 94JOC7503] 126-127 oC): [a]25D = +4.10 (c

1.3, CH2C2) [lit.[020L4005] [a]25D = +4.20 (c 1.3, CH2C12); 1H NMR (DMSO-d6) 6

1.16 (d, J= 7.0 Hz, 3H, CHCH3), 2.92 (dd, J= 13.6, 8.5 Hz, 1H, CHCH2Ph), 3.05 (dd, J

= 13.6, 4.9 Hz, 1H, CHCH2Ph), 4.04-4.10 (m, 1H, NCHCO), 4.38-4.45 (m, 1H,

NCHCO), 5.00 (s, 2H, OCH2Ph), 7.23-7.45 (m, 11H, ArH and NH), 8.05 (d, J= 7.4 Hz,

1H, NH). One exchangeable proton is missing. 13C NMR (DMSO-d) 6 18.1, 36.5, 49.8,

53.2, 65.3, 126.3, 127.6, 127.7, 128.0, 128.2, 129.1, 136.9, 137.3, 155.4, 172.3, 172.6.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino} propanoyl)amino]-3-hydroxy-

propanoic acid (Z-Ala-Ser-OH, 5.2b):[84JCS(P1)2439] Colorless microcrystals (85%),

mp 192-194 oC (lit.[84JCS(P1)2439] 194-196 oC): []25D = +21.1 (c 0.4, DMF)

[(lit.[84JCS(Pl)2439] [a]25D = +21.1 (c 0.4, DMF)]; 1H NMR (DMSO-d6) 6 1.22 (d, J=

7.1 Hz, 3H, CHCH3), 3.60-3.75 (m, 2H, CHCH20H), 4.13-4.18 (m, 1H, NCHCO),

4.25-4.28 (m, 1H, NCHCO) 5.02 (s, 2H, OCH2Ph), 7.35 (s, 5H), 7.36-7.48 (m, 1H, OH),

7.91-8.00 (m, 2H, NHx2), One exchangeable proton is missing. 13C NMR (DMSO-d) 6

18.2, 49.8, 54.4, 61.2, 65.3, 127.6, 128.2, 128.2, 136.9, 155.5, 171.8, 172.5.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino} propanoyl)amino]-3-(1H-indol-

3-yl)propanoic acid (Z-Ala-Try-OH, 5.2c):[88JHC1265] Colorless microcrystals

(97%), mp 154-155 oC: [a]25D = +8.10 (c 1.6, MeOH); H NMR (DMSO-d6) 6 1.19 (d, J

= 7.0 Hz, 3H, CHCH3), 3.07 (dd, J= 15.0, 8.7 Hz, 1H, CHCH2), 3.18 (dd, J= 15.0, 5.0

Hz, 1H, CHCH2), 4.11 (apparent q, J& 7.1 Hz, 1H, NCHCO), 4.44-4.51 (m, 1H,

NCHCO), 4.98 (d, J= 12.6 Hz, 1H, OCH2Ph), 5.04 (d, J= 12.6 Hz, 1H, OCH2Ph), 6.98









(t, J= 7.2 Hz, 1H), 7.07 (t, J= 7.2 Hz, 1H), 7.26-7.46 (m, 8H), 7.53 (d, J= 7.7 Hz, 1H),

8.06 (d, J= 7.7 Hz, 1H, NH), 10.9 (s, 1H, NH), One exchangeable proton is missing. 13C

NMR (DMSO-d6) 6 18.1, 26.9, 49.8, 52.7, 65.3, 109.5, 111.2, 118.1, 118.3, 120.8, 123.6,

127.2, 127.6, 128.2, 136.0, 136.9, 155.5, 172.4, 173.1.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-methylbutanoyl)amino]-3-

phenylpropanoic acid (Z-Val-Phe-OH, 5.2d):[83LAC1712] Colorless microcrystals

(98%), mp 166-167 C (lit.[83LAC1712] 167-168 C): [a]25D = -13.00 (c 1.0, MeOH)

[(lit.[83LAC1712] [a]25D = -13.30 (c 1.0, MeOH)]; 1H NMR (DMSO-d6) 6 0.78-0.82

(m, 6H, CH3x2), 1.87-1.99 (m, 1H, CHCH(CH3)2), 2.89 (dd, J= 12.6, 9.0 Hz, 1H,

CHCH2Ph), 3.05 (dd, J= 12.6, 5.2 Hz, 1H, CHCH2Ph), 3.85-3.91 (m, 1H, NCHCO),

4.41-4.48 (m, 1H, NCHCO), 5.03 (s, 2H, OCH2Ph), 7.18-7.35 (m, 11H, ArH and NH),

8.17 (d, J= 7.7 Hz, 1H, NH). One exchangeable proton is missing. 13C NMR (DMSO-d6)

6 18.0, 19.0, 30.4, 36.7, 53.2, 59.9, 65.3, 126.3, 127.5, 127.7, 128.0, 128.2, 129.0, 137.0,

137.4, 155.9, 171.0, 172.7.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-methylbutanoyl)amino]-3-

(1H-indol-3-yl)propanoic acid (Z-Val-Try-OH, 5.2e):[96BP1051][68JCS(C)1208]

Colorless microcrystals (96%), mp 187-188 oC (lit.[96BP1051] 135-137 oC): []25D =

-6.40 (c 1.5, MeOH) [(lit.[68JCS(C)1208] [a]25D = -6.00 (c 2.63, MeOH)]; H NMR

(DMSO-d6) 6 0.80-0.85 (m, 6H, CH3x2), 1.91-1.98 (m, 1H, CHCH(CH3)2), 2.99 (dd, J

= 13.8, 9.0 Hz, 1H, CHCH2-3-indolyl), 3.05 (dd, J= 13.8, 5.2 Hz, 1H, CHCH2-3-

indolyl), 3.90-3.95 (m, 1H, NCHCO), 4.44-4.60 (m, 1H, NCHCO), 5.00 (d, J= 12.5 Hz,

1H, OCH2Ph), 5.06 (d, J= 12.5 Hz, 1H, OCH2Ph), 6.97 (t, J= 7.3 Hz, 1H), 7.06 (t, J=

7.3 Hz, 1H), 7.18-7.37 (m, 8H), 7.53 (d, J= 7.7 Hz, 1H), 8.16 (d, J= 7.4 Hz, 1H, NH),









10.86 (br s, 1H, NH), One exchangeable proton is missing. 13C NMR (DMSO-d) 6 18.0,

19.1, 27.1, 30.5, 52.8, 59.9, 65.4, 109.7, 111.3, 118.1, 118.3, 120.9, 123.6, 127.2, 127.6,

127.7, 128.3, 136.1, 137.1, 156.0, 171.2, 173.2. Anal. Calcd for C24H27N305: C, 65.89; H,

6.22; N, 9.60. Found: C, 65.92; H, 6.33; N, 9.58.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]

propanoic acid (Z-Phe-Ala-OH, 5.2f):[82TL3831] Colorless microcrystals (96%), mp

157-158 C (lit.[82TL3831] 153-154 oC): [a]25D = -9.50 (c 1.0, EtOH) [(lit.[82TL3831]

[a]25D = -10.00 (c 1.90, EtOH)]; 1HNMR 6 1.36 (d, J= 7.0 Hz, 3H, CHCH3), 3.05 (d, J

= 6.2 Hz, 2H, CHCH2Ph), 4.47-4.52 (m, 2H, NCHCOx2), 5.13 (d, J= 12.5 Hz, 1H,

OCH2Ph), 5.18 (d, J= 12.5 Hz, 1H, OCH2Ph), 5.63 (d, J= 5.6 Hz, 1H, NH), 6.65 (br s,

1H, NH), 7.15-7.36 (m, 10H), 8.80 (br s, 1H, CO2H). 13C NMR 6 17.1, 37.4, 47.5, 55.9,

65.1, 126.2, 127.4, 127.6, 128.0, 128.3, 129.2, 137.0, 138.2, 155.8, 171.4, 174.0.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]-3-

methylbutanoic acid (Z-Phe-Val-OH, 5.2g):[67LAC227] Colorless microcrystals

(95%), mp 140-142 oC (lit.[67LAC227] 149-151 oC): [a]25D = -6.20 (c 2.0, MeOH)

[(lit.[67LAC227] [a]22D = -6.30 (c 2.0, MeOH)]; 1H NMR (DMSO-d6) 6 0.90 (d, J= 5.2

Hz, 6H, CH3x2), 2.05-2.11 (m, 1H, CHCH(CH3)2), 2.69-2.77 (m, 1H, CHCH2Ph),

2.98-3.02 (m, 1H, CHCH2Ph), 4.17-4.22 (m, 1H, NCHCO), 4.36-4.41 (m, 1H,

NCHCO), 4.94 (s, 2H, OCH2Ph), 7.19-7.53 (m, 11H, ArH and NH), 8.07-8.09 (m, 2H,

NH and CO2H). 13C NMR (DMSO-d6) 6 17.9, 19.0, 29.9, 37.3, 55.8, 57.1, 65.1, 126.1,

127.3, 127.6, 127.9, 128.2, 129.1, 136.9, 138.0, 155.7, 171.8, 172.8.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]-3-

phenylpropanoic acid (Z-Phe-Phe-OH, 5.2h):[79CB2145][91S35] Colorless









microcrystals (98%), mp 141-142 C (lit.[91S35] 138-139 oC): [a]25D = -6.70 (c 1.3,

MeOH); 1H NMR (DMSO-d6) 6 2.67-2.75 (m, 1H, CHCH2Ph), 2.93-3.14 (m, 3H,

CHCH2Ph), 4.31-4.34 (m, 1H, NCHCO), 4.49-4.5.1 (m, 1H, NCHCO), 4.94 (s, 2H,

OCH2Ph), 7.12-7.51 (m, 16H), 8.10 (br s, 1H, CO2H), 8.32 (d, J= 7.6 Hz, 1H, NH). 13C

NMR (DMSO-d6) 6 36.6, 37.3, 53.4, 55.9, 65.1, 126.1, 126.4, 127.3, 127.6, 127.9, 128.1,

128.2, 129.1, 136.9, 137.3, 138.0, 155.7, 171.5, 172.7.

(2S)-2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpropanoyl)amino]-3-

hydroxypropanoic acid (Z-Phe-Ser-OH, 5.2i):[91LAC165] Colorless microcrystals

(96%), mp 140-141 oC (lit.[91LAC165] 137 oC): [a]25D = +0.60 (c 1.0, MeOH)

(lit.[91LAC165] [a]22D = +0.60 (c 1.0, MeOH); H NMR (DMSO-d6) 6 2.73 (t, J= 12.6

Hz, 1H, CHCH2Ph), 3.06-3.10 (m, 1H, CHCH2Ph), 3.67 (dd, J= 10.3, 3.3 Hz, 1H,

CHCH2OH), 3.78 (dd, J= 10.3, 4.5 Hz, 1H, CHCH2OH), 4.32-4.42 (m, 2H,

NCHCOx2), 4.93 (s, 2H, OCH2Ph), 7.24-7.46 (m, 10H), 7.52 (d, J= 8.8 Hz, 1H, NH),

8.32 (d, J= 7.7 Hz, 1H, NH), Two exchangeable protons (OH and CO2H) are missing.

13C NMR (DMSO-d6) 6 37.4, 54.6, 55.9, 61.2, 65.1, 126.1, 127.3, 127.6, 127.9, 128.2,

129.2, 136.9, 138.1, 155.7, 171.7, 171.8.

(5S,11 S)- 11-Isobutyl-5-methyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triaza-

dodecan-12-oic acid (Z-Ala-Gly-Leu-OH, 5.4a): Colorless microcrystals (93%), mp

150.5-151.5 oC: [a]25D = -13.80 (c 1.3, MeOH); H NMR (DMSO-d6) 6 0.83 (d, J= 6.2

Hz, 3H, CH3), 0.87 (d, J= 6.3 Hz, 3H, CH3), 1.20 (d, J= 7.2 Hz, 3H, CH3), 1.52-1.64

(m, 3H, CH2CH(CH3)2), 3.72 (d, J = 5.4 Hz, 2H, NCH2CO), 4.02-4.07 (m, 1H,

NCHCO), 4.21-4.29 (m, 1H, NCHCO), 4.99 (d, J= 12.6 Hz, 1H, OCH2Ph), 5.06 (d, J=









12.6 Hz, 1H, OCH2Ph), 7.36 (s, 5H), 7.55 (d, J= 7.0 Hz, 1H, NH), 7.91 (d, J= 7.8 Hz,

1H, NH), 8.17 (br s, 1H, NH), One exchangeable proton is missing. 13C NMR (DMSO-

d6) 6 17.8, 21.3, 22.7, 24.1, 41.7, 50.0, 65.3, 127.7, 127.7, 128.2, 136.8, 155.7, 168.5,

172.6, 173.8. Anal. Calcd for C19H27N306: C, 58.00; H, 6.92; N, 10.68. Found: C, 58.21;

H, 7.01; N, 10.59.

(11S)-l11-Isobutyl-5-methyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-

12-oic acid (Z-DL-Ala-Gly-Leu-OH, 5.4a+5.4a'): Colorless microcrystals (94%), mp

101-105 oC. 1HNMR (DMSO-d6) 6 0.83 (d, J= 6.2, 3H), 0.88 (d, J= 6.3 Hz, 3H), 1.21

(d, J= 7.2 Hz, 3H), 1.52-1.62 (m, 3H), 3.72 (d, J= 5.1 Hz, 2H), 4.02-4.07 (m, 1H),

4.24-4.26 (m, 1H), 4.99 (d, J = 12.6 Hz, 1H), 5.05 (d, J= 12.6 Hz, 1H), 7.28-7.46 (m,

5H), 7.55 (d, J= 7.0 Hz, 1H), 7.90-7.97 (m, 1H), 81.4-8.17 (m, 1H). 13C NMR

(DMSO-d6) 6 17.8, 21.3, 22.7, 24.1, 41.7, 50.1, 50.2, 65.4, 127.7, 127.7, 128.3, 136.8,

155.8, 168.6, 172.7, 173.8. Anal. Calcd for C19H27N306: C, 58.00; H, 6.92; N, 10.68.

Found: C, 58.43; H, 6.99; N, 10.66.

(5S, 11S)-l1-Isobutyl-5-isopropyl-3,6,9-trioxo-l-phenyl-2-oxa-4,7,10-triaza-

dodecan-12-oic acid (Z-Val-Gly-Leu-OH, 5.4b): Colorless microcrystals (85%), mp

131.5-132.5 oC: [a]25D = -17.10 (c 1.4, MeOH); H NMR (DMSO-d6) 6 0.82-0.88 (m,

12H, CH3x4), 1.49-1.66 (m, 3H, CH2CH(CH3)2), 1.93-2.02 (m, 1H, CHCH(CH3)2), 3.73

(d, J= 5.4 Hz, 2H, NCH2CO), 3.85 (apparent t, J& 7.7 Hz, 1H, NCHCO), 4.25 (apparent

q, J& 7.7 Hz, 1H, NCHCO), 5.01 (d, J= 12.6 Hz, 1H, OCH2Ph), 5.07 (d, J= 12.6 Hz,

1H, OCH2Ph), 7.30-7.40 (m, 6H, ArH and NH), 7.95 (d, J= 8.0 Hz, 1H, NH), 8.21 (t, J

= 5.4 Hz, 1H, NH), One exchangeable proton is missing. 13C NMR (DMSO-d6) 6 18.1,

19.1, 21.3, 22.7, 24.1, 29.9, 41.6, 50.0, 60.3, 65.3, 127.6, 127.7, 128.2, 136.9, 156.2,