Progress in Heterocyclic Chemistry, Volume 19

PROGRESS IN HETEROCYCLIC CHEMISTRY Volume 21 Editors GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Ha...

Author: Gordon W. Gribble | J. Joule

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PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 21 Editors

GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and

JOHN A. JOULE The School of Chemistry, The University of Manchester, Manchester, UK

Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo

Elsevier Linacre House, Jordan Hill, Oxford OX2 8DP, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands First edition 2009 Copyright © 2009 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier's Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material. Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. British Library of Cataloguing in Publication Data A catalogue record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. For information on all Elsevier publications visit our web site at books.elsevier.com Printed and bound in Great Britain 09 10 11 12 10 9 8 7 6 5 4 3 2 1 ISBN: 978-0-08-096515-4

xi

Foreword This is the 21st annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2008 on most of the important heterocyclic ring systems. References are incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews. The first, by Steven Collier and colleagues, explores ‘Biocatalytic approaches to chiral heterocycles’, and the second, by Ramachandra Hosmane, discusses ‘Ringexpanded (“fat”) purines and their nucleoside/nucleotide analogues as broad-spectrum therapeutics’. The remaining chapters examine the 2008 literature on the common heterocycles in order of increasing ring size and the heteroatoms present. In the previous volume, Vol. 20, it was not possible to include a chapter on ‘Six-membered ring systems: triazines, tetrazines and fused ring polyaza derivatives’ so this volume has two chapters on this topic: chapter 6.3 (2007) and chapter 6.3 (2008), which cover the 2007 and 2008 literature, respectively. The Index is not fully comprehensive, however the Contents pages list all the subheadings of the chapters that we hope will considerably improve accessibility for readers. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to our colleagues at Elsevier for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modern heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics. Gordon W. Gribble John A. Joule

xii

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2008 - 2009 PROFESSOR M. BRIMBLE (CHAIRMAN) University of Auckland, New Zealand

PROFESSOR D. ST CLAIR BLACK University of New South Wales Australia

PROFESSOR H. HIEMSTRA University of Amsterdam The Netherlands

PROFESSOR M.A. CIUFOLINI University of British Columbia Canada

PROFESSOR D.W.C. MACMILLAN Princeton University USA

PROFESSOR T. FUKUYAMA University of Tokyo Japan

PROFESSOR M. SHIBASAKI University of Tokyo Japan

PROFESSOR A. FÜRSTNER Max Planck Institut Germany

PROFESSOR L. TIETZE University of Göttingen Germany

PROFESSOR R. GRIGG University of Leeds UK

PROFESSOR P. WIPF University of Pittsburgh USA

Information about membership and activities of the International Society of Heterocyclic Chemistry (ISHC) can be found on the WWW at http://webdb.uni-graz.at/~kappeco/ISHC/index.html

1

Chapter 1

Biocatalytic Approaches to Chiral Heterocycles Steven J. Collier, Michael A. K. Vogel, Brian J. Wong and Naga K. Modukuru Codexis Laboratories Singapore [email protected]; [email protected]; [email protected]; [email protected]

1.1

INTRODUCTION

The use of biotransformations to synthesize chiral molecules has been building momentum steadily over the last 15 to 20 years, and biocatalysis is now considered an established approach to such compounds. An increasing number of applications are known, covering a wide array of targets and scales, from microbial oxidation of drug candidates for metabolite profiling studies, to the tonnes per annum commercial manufacture of agrochemical and pharmaceutical intermediates and APIs. Furthermore, with the advent of directed evolution technologies over the last few years, biocatalysis has emerged as a practical alternative for the large scale synthesis of a range of pharmaceutical intermediates including those for blockbuster drugs such as Atorvastatin . Chiral heterocycles are of crucial importance to the development and manufacture of new pharmaceuticals and agrochemicals, as well as in countless smaller scale applications in synthetic, medicinal and natural product chemistry. The goal of this contribution is to review where these important but different areas intersect. A review of this limited size is not and cannot be comprehensive in any way, but is instead geared towards giving a flavor of what has been achieved so far, and to help develop ideas of what could be possible in the future. After a short discussion of some commonly used enzyme classes, the main discussion on synthetic application is subdivided into different heterocycle classes, much along the lines of Progress in Heterocyclic Chemistry as a whole. It should be noted that only examples in which the chirality is part of the heterocyclic ring itself are included; heterocycles with chirality in positions Į-to the ring, or further away are not considered. Sugars and other complex carbohydrates are also generally excluded.

1.2

ENZYME CLASSES DISCUSSED

By far the most familiar and widely used enzymes in biotransformations are lipases, proteases and lactamases, which perform hydrolytic or solvolytic reactions on carboxylic acid derivatives such as esters and amides. Biocatalysts are commonly used as isolated enzymes but in some cases the enzyme is immobilized on a solid support in order to confer greater stability and afford the opportunity for recycling. The reactions are typically easy to perform in either aqueous or organic media, and do not require cofactors to operate. c 2009 Elsevier Limited. All rights reserved.

S.J. Collier et al.

2

Synthetic applications include the hydrolysis or formation of esters, with the latter usually achieved via transesterification of vinyl esters; the vinyl alcohol released tautomerizes to an aldehyde, rendering the reaction essentially irreversible. However, many applications involve kinetic resolution (KR) of racemates, offering a maximum theoretical yield of 50% for a product or unreacted substrate. In instances where the unreacted enantiomer of the substrate can be racemized under the reaction conditions, i.e. dynamic kinetic resolution (DKR), quantitative yields of homochiral products are possible. The hydrolysis or acylation of compounds which bear a centre of symmetry (meso compounds) can also provide quantitative yields of chiral products through desymmetrization. Other useful enzyme classes are known, and can be employed using isolated enzymes or whole cell systems. These include: ketoreductase enzymes (alcohol dehydrogenases) which catalyze the reduction of carbonyl groups to alcohols, or the reverse reaction; amine oxidases and amino acid dehydrogenases which catalyze the oxidation of amines to imines or viceversa; monooxygenases which perform the hydroxylation of unactivated functions, the epoxidation of alkenes, or Baeyer–Villiger type oxidations; and dioxygenases which convert unsaturated carbon functions to syn-diols. Other less common enzyme classes are mentioned periodically in the text. Generic transformations for some of these are shown in the scheme below. An excellent text on the applications of enzymes in asymmetric organic synthesis has been published .

R1

R

X = OR 2, NR 22

X

O

O

Lipase, protease, lactamase

O

1

+

R

X

chiral

chiral

racemic

Kinetic Resolution OH (max yield: 50%)

1

In-situ Racemization

O

O

X

X

Dynamic Kinetic Resolution (max yield 100%)

Lipase, protease

O

O

X

OH chiral

Symmetrical O R racemic

R1

Epoxide hydrolase

R2

OH

O R chiral

X = O: Ketoreductase X = NH: Amine oxidase

X

Meso-desymmetrization (max yield 100%)

+

Kinetic Resolution (max yield: 50%)

OH

R chiral

O XH R1

R2

Baeyer-Villiger Monooxygenase

R

O R O

n chiral

n

The development of directed evolution technologies has facilitated the application of isolated enzyme biocatalysis on a commercial scale, particularly in the field of chiral pharmaceutical intermediates. The technique involves the introduction of mutations into the enzyme protein structure, and the resulting mutants are screened against specific reaction criteria in high throughput format, resulting in the selection of improved (evolved) variants. Thus, the performance of a given wild-type enzyme can be vastly improved in terms of specific activity, substrate specificity, thermostability, enantioselectivity, substrate loading, pH and solvent tolerance, and other factors, ultimately providing a catalyst that can operate competitively on commercial manufacturing scale. Details and examples are referenced here .

Biocatalytic Approaches to Chiral Heterocycles

3

1.3 THREE-MEMBERED RING SYSTEMS 1.3.1 Epoxides The enantioselective epoxidation of alkenes to give chiral epoxides is a well established technique in traditional organic chemistry, with reactions such as the Sharpless-Katzuki, Jacobsen-Katzuki and Shi epoxidations enjoying widespread application. However, it is also possible to epoxidize alkenes using enzymatic methods, often achieving very high enantioselectivity. Commonly, cytochrome P450 enzymes are employed in these reactions, either in whole cell biotransformations or as isolated enzymes, although other enzyme types have also proved useful and, in some cases, complementary. Styrenes are common substrates for enzymatic epoxidations , given the synthetic value of the products, and some examples employing whole cell biotransformation using a styrene monooxygenase expressed in recombinant E. coli are given below. The products were isolated on multigram scale and chemocatalytic routes to the same epoxides could not match the ee’s of the biocatalytic process . The production of several of the examples below was improved by employing cell free isolated enzymes . Furthermore, the enantioselective epoxidation of styrene to (S)-styrene oxide using the styrene monooxygenase (from Pseudomonas sp. strain VLB120) expressed in recombinant E. coli cells has been demonstrated on pilot plant scale, utilizing a two-liquid phase fed batch bioconversion . Directed evolution techniques have been used to increase the performance of a cytochrome P450 BM-3 in reactions that give styrene oxide or substituted analogues and, interestingly, mutations in the protein structure could lead to an inversion of enantioselectivity. Thus, the use of one mutant cytochrome P450BM3 enzyme (F87G mutant) gave (R)-styrene oxide in 92% ee, but a different mutant (A74G/F87V/P386S) gave (S)-styrene oxide in 58% ee. Only three amino acid residues differ in these two mutants; this is a simple but poignant demonstration of the power of directed evolution in enzyme development . recombinant E. coli JM101 (pSPZ10) containing styrene monooxygenase; aq. cell culture, dioctyl phthalate

R

R

O

76.3% yield 99.5% ee

O

74.8% yield 96.7% ee

O

87.2% yield 99.8% ee

Cl

O

O

87.5% yield 99.4% ee

O O

55% yield 98.5% ee

47.9% yield 98.0% ee

A wide range of other epoxides have been prepared enzymatically. For example, (R)propylene oxide can be obtained in up to 85% ee using an alkene monooxygenase from Nocardia coralina B-276 . The same enzyme was found to epoxidize alkylpropenes to give products useful in the synthesis of prostaglandin Ȧ-chains , and also a range of C2 to C18 terminal alkenes, although production rates varied between substrates . The epoxidation of terminal alkenes is favored by Pseudomonas oleovorans whereas internal cis double bonds are epoxidized selectively by chloroperoxidase enzymes and, monoepoxidation of polyenes is readily achieved using xylene monooxygenase and chloroperoxidase . Synthetic applications of such epoxidations include the synthesis of Mevalonolactone and ȕ-blockers such as Metaloprol and Atenolol . Enzymatic epoxidation has also been

S.J. Collier et al.

4

employed to target specific sites in complex substrates bearing more than one potentially reactive centre, a common application being metabolite synthesis. In the examples below, selective cytochrome mediated epoxidation of a single alkene in Carbomycin B gave Carbomycin A . Similarly, monoepoxides of Milbemycins A3, A4 and C were obtained (along with a monohydroxylated product) using whole cell fermentation . O R

R = Pr: 32% yield, 76% ee R = Bu: 55% yield, 90% ee R = Pentyl, 56% yield, 88% ee

Nocar dia coralina whole cell suspension O

Me O

CH O

Me O

N M e2 O

Me O O

HO

O

O O

O

O

OH

Me

O

O OH

O

OC OM e C a rb am yc in A CY P1 0 7C 1

H

R Me

O H

O O H

Me HO

R : e po xi d e:a lc oh o l M e : 4 0 :60 E t: 3 0 :70 M e i -P r: 2 9:7 1

OH

S tre p to my ce s v i o la sc e ns A TC C 3 1 56 0

The kinetic resolution of racemic epoxides with epoxide hydrolases is an effective and well studied approach to chiral oxiranes, giving chiral 1,2-diols as by-products . This reaction clearly has parallels with chemical techniques such as Jacobsen’s hydrolytic kinetic resolution , but in some cases the performance of the enzymatic process far exceeds that of the more traditional synthetic approaches. Interestingly, there are examples in which the diol byproduct is chemically converted to the desired chiral epoxide (or the unreacted epoxide cleaved to the same diol), giving high overall yields and high ee’s for the two step process . Typical examples of epoxides obtained via epoxide hydrolase enzymes are shown below, with the first example being used to prepare (S)-Ibuprofen . Analogues with the following 4substituents: H, F, Cl, Br, CN, NO2, could also be resolved with a range of hydrolytic enzymes.

Biocatalytic Approaches to Chiral Heterocycles O

i-Bu

5

O O

O O Asper gillus niger 35% yield; 95% ee

Cl

Cl

Asper gillus niger 51% yield; 98% ee

O

Solanum t uber osum L. Rhodotor ula glutinis SC 16293 51% yield; 97% ee 45% yield, 99.9% ee Asperigillus niger 16311 45% yield, 97% ee Cl O

O

N Asper gillus niger GBCF 79 43% yield; 99% ee

F F Aspergillus niger 41.5% yield; 99.9% ee

Br Asper gillus niger LCP 521 39% yield; 99.7% ee

The activity and enantioselectivity of epoxide hydrolases has been improved using directed evolution techniques . Enantio- and stereocomplementary hydrolysis has been achieved using different epoxide hydrolases. Different pairings of epoxide and diol could be obtained with different enzymes, resulting from either inversion or retention of configuration during the ring opening . In a related reaction, a racemic epoxide 1 was hydrolyzed in an enantioconvergent reaction (i.e. one enantiomer was hydrolyzed with retention and the other with inversion of configuration), providing an intermediate chlorodiol 2 which cyclized to a single enantiomer of epoxide 3. This was later used in the total synthesis of (+)-pestalotin and a Jamaican rum constituent . My cobacterium paraf f inicum NCIMB 10420

O n-Bu 1 racemic

Cl

OH Cl

HO n-Bu

HO

O

n-Bu 2

3 81% yield 93% ee, >99% de

Epoxide resolution can also be achieved using enzymatic hydrolysis of pendant functionality. For example, lipases perform kinetic resolutions of pendant esters to provide chiral epoxides such as glycidyl butyrate, although the reaction needs to be run beyond 50% to ensure the chiral purity of the desired (R)-glycidyl butyrate is sufficiently high; this approach has been operated on multi-ton scale . A range of alkyl substituted racemic epoxides has been studied in the reaction, and the effect of ester chain length was investigated. Lipase mediated resolution of trans-phenylglycidates 4 (X = CO2Me) was used as an approach to the drug diltiazem. Interestingly, the undesired glycidic acid by-product 5 decomposed spontaneously to an aldehyde and CO2, the former of which was sequestered using bisulfate to prevent it negatively impacting enzyme activity . Following a similar approach, racemic trans-1-aryl-2-cyano epoxides 4 (X = CN) have been resolved using Rhodococcus sp. whole cells, which contain both nitrile hydratase and amidase enzymes. Thus the nitrile hydratase (which typically give poor enantiodiscrimination) hydrates the nitrile of the racemic substrate (giving 4, X = CONH2), and the amidase then performs a kinetic resolution on the amide, producing the unstable acid 5 and the desired chiral amide . Lipase mediated acetylative resolution of

S.J. Collier et al.

6

racemic epoxides, or desymmetrization of meso epoxides has been used in approaches to the natural products epoxydon and cycloepoxydon (proceeding via chiral epoxides 6 and 7, respectively). O

O Ar

4 ra ce m ic

Ar

X

O Y

+

Ar

A rC H 2C H O + CO 2

CO 2 H 5

X = C O 2 Me , Y = CO 2M e ; A r = 4-M e OC 6H 4 ,: 43 .6% y ie ld , 98 % ee (C a nd i d a cy l in d r a ce a l ip a se ) X = C N , Y = C ON H 2 ; A r = Ph , 4 -M e C6 H 4 ,4 -FC 6 H 4 , 4 -C lC 6 H 4 : 4 2 -4 9% yi el d , 9 9 .5% e e (R h o d oc oc cu s s p. AJ 27 0 ce ll s) X = C N , Y = C ON H 2 ; A r = 2-M e C 6H 4, 3 C lC 6 H4 : 6 0-6 1 % yie l d, 3 1.3 -3 9.9 % ee (R h od o c oc cu s sp . AJ 27 0 c el ls )

O

OT BS

TB SO

O

O

O O

H OAc 6 46 % yi el d ~9 9 % ee

H

OH

45 % yi el d ~9 9 % ee Ac yla tiv e K R L i pa se PS

Ac O HO

O

O 7 A cyl a ti ve De s ymm e tr iz ati on L ip as e P S

1.3.2 Aziridines The formation of chiral aziridines via biocatalysis is not widely employed, although a number of examples are known. Lipase mediated kinetic resolution or meso desymmetrization via hydrolysis of esters or acylation of alcohols can provide products in good ee. Another interesting kinetic resolution involves cleavage of an amide bond of a racemic N-acylaziridine, leaving one enantiomer of the amide unreacted . The enantioselective N-acylation of aziridines has also been achieved using dialkyl carbonates and lipase enzymes, with diallyl carbonate giving the best results . Typical products are given below.

Biocatalytic Approaches to Chiral Heterocycles H N

H N HO

OM e

Ph

HO

OMe

O

O O O P ig liv e r es ter as e h yd ro ly ti c K R 9 2% e e 2 7% e e

H N O

Me

Ph OH

H N O

Me

O i mm ob i li ze d P se u d om o na s c ep a ci a l ip a se PS- CII O ac yl ati ve K R 4 9 % y ie ld , 90 % e e 5 1 % y ie ld , 87 % e e 36 % yi el d , 9 5 % e e

O

O OMe

O

Me O

OM e H

OMe

N

A cO

Pr

H N

Me

Ph N

Ph

7

O

O

N

N

OH

H

O

O

Am an o li pa se PS C an d i d a cy li n d r ac e a l ip as e C an d i d a cy li n d r ac e a l ip as e C an d i d a cy li n d r ac e a l ip as e a cy la tive N -a cy la tive KR Am id e h yd r ol ytic K R Am id e h yd r ol ytic K R d e sym me tri za ti o n 4 9 % y ie ld , 84 % e e 3 0 % y ie ld , 95 % e e 3 5 % y ie ld , 90 % e e 9 6% yi el d >9 7% e e

1.3.3 Other Three-Membered Heterocycles Chiral thiiranes have rarely been prepared through biotransformations, although examples do exist. Hydrolytic kinetic resolution with procine pancreatic lipase gave the chiral ester 8 in resonable ee . Chiral thiirane oxide 9 was obtained in good de, using a chloroperoxidase (from Caldariomyces fumago) mediated sulfoxidation, although the ee was poor . (R)-1-Isothiocyanatobutan-2-ol, available through the resolution of racemic 1,2-epoxybutane with thiocyanate, mediated by a halohydrin dehalogenase enzyme from Agrobacterium radiobacter, undergoes a slow rearrangement to the corresponding chiral thiirane . Chiral oxaziridines 10 and 11 have been prepared via kinetic resolution of a pendant ester unit . O O

OS+

S

MeO 2C

8 9 Porcine pancreatic lipase Chloroperoxidase hydrolytic KR 99% yield 71% yield, 80% ee 100% de, 12% ee

N O +

HO2 C

N O

MeO 2C

MeO2 C 10 11 Porcine pancreatic lipase 62% yield 20% yield 36% ee 87% ee

1.4 FOUR-MEMBERED RING SYSTEMS 1.4.1 Azetidines A number of enzymatic approaches to chiral azetidines have been reported, mostly focussing on azetidinones, given their importance in biologically active compounds and as precursors to unnatural amino acids. A wide range of chiral azetidinones have been prepared by the enzymatic resolution of racemates, through cleavage of one enantiomer of the ȕ-

S.J. Collier et al.

8

lactam ring. As one may expect, this transformation has been achieved using lactamases, but lipases have also proved effective . In some cases, the protracted reaction times were required to achieve high conversions. Typical reactions and products are given below. O

R

R

NH

NH

R O

R

C O 2H

R

NH 2

+

R

O n

O

O

NH

n NH

NH

O

n

Et

L ip o la se n = 1 -4 3 6 -4 5% yi e ld 93 -9 9 % e e

C hi ra zy me L- 2 fr om Ca n d i d a a n tar ti c a, ca rr ie r fi xe d 49 % co n ve rsi on 94% ee

50 % co nv er si on 9 9% e e O

O

R

O NH

NH

n

(-) iso m er

L ac tam a se f ro m R h od o co cc u s g lo b e ru l u s (w h ol e c el ls )

H

O

H N O

3 1% yi el d >9 5% e e

n

Li po l as e (i mm o b C AL -B ) n = 1, 2 47 -4 8 % y ie ld 9 9 % ee

NH NH

NH

NH

38 % yie l d >98 % ee

n = 1 -3 L ip o la se (C AL -B) 4 4% yi el d >9 9% e e

O R = H , 4 -Me , 2- , 3 -, 4 -C l, 4- Br, 4 -F C AL -B >=4 1% y ie ld >=9 5 % e e

O

O HN

HN

NH

NH

H O O R h o d oc o ccu s e q u i Li po l as e (C A L- B) L ip o la se (C AL -B) L ip o la se (im mo b CA L -B) L ip o la se (im mo b CA L -B) 40 % yie l d 4 7% yi e ld (re stin g ce ll s) 4 7% yi el d 4 7% yi el d 99 % ee 99% ee 4 0% yi e ld >9 9% e e >9 8% e e 99% ee

Hydrolytic resolution of ester functions of hydroxyazetidinones has also proved to be a successful strategy to chiral azetidinones . The resolved esters 12 were used to to install sidechains on taxol based drugs. Resolution of more remote ester functions has also proved to be a successful strategy, giving the interesting ethynyl azetidonone 13 and gemdiethylazetidinone 14 . In the latter case, the unreacted ester byproduct could be recycled efficiently. Racemic 3-amino-ȕ-lactams have been resolved using carboxylic esters in the presence of penicillin acylase enzymes, providing the corresponding amides, useful intermediates for antibiotics, in excellent ee .


O

OH H

R

9 Et

O

O

NH

OH

Et

O

NH

NH

O 12

O

O

14 13 Lipase PS30 Bacillus subt ilisis SANK 76759 Lipase PS-800 Hydrolytic KR Hydrolytic KR of benzoate Hydrolytic KR of ester 48-49% yield, 99% ee 60% overall yield 95% ee R = Ph: (af ter 3 cycles) 93% ee R = 2-Furyl: R = tBu:

Chiral hydroxyazetidinones (eg 15 and 16) have also been prepared via enzymatic reduction of the corresponding ketones . Different product distributions (including trans-isomers) could be achieved using different enzymes. Other transformations of azetidines are also known. The lipase mediated ammoniolysis of a racemic azetidine ester gave the resolved ester 17 in very high ee, along with the corresponding amide 18 . Also, the diastereoselective 3-hydroxylation of contracted proline analogue 19 was achieved using a Streptomyces species TH1 proline 3-hydroxylase enzyme (the natural reaction for which is the hydroxylation of proline) . HO

Ph

Yeast gene Ybr149w

O

NH

Ph

HO

NH

NH

O

O

O

15 Major product 90% ee

Ph

Yeast gene Yjr096w

16 Major product

CO2 Me

Novozyme 435 (immob CALB) NH3 , tBuOH 35 oC 50-56% conversion

N R

CO2 H NH

+

N R 17 >99% ee

R = CH 2 Ph, PMB, allyl

Proline 3-hydroxylase

HO

CONH 2

CO2 Me N

R 18 80-97% ee

CO2 H NH

19 28% yield

1.4.2 Oxetanes Chiral ȕ-lactones can be prepared via the enzymatic alcoholysis of a racemic substrate, giving a mixture of the desired chiral oxetane, along with the solvolyzed byproduct. A range of chiral oxetanes have been prepared this way using various alcohol nucleophiles and lipase enzymes. One series of these is shown below and a selection of other typical chiral oxetanes prepared using this general approach is also given and others are referenced here . Protracted reaction times were required to achieve high conversions.

S.J. Collier et al.

10

Lipase PS Amano iPr 2 O, 35 oC

R O

R OBn

O

OH O O R = c-C 6H 11, PhCH 2CH 2, Me(CH 2)3 , Me(CH2 )2 , Me 2CHCH 2, CH 2=CH(CH 2) 8, BnOCH2 26-44% yield; 84-99% ee

O

Me

R

+

+ BnOH

Me

O

O

O Lipase PS 38% yield 70% ee

Pr

R

Me Pr O

O

O O

Me

O

O

O

PPL R = n-Pr, i-Pr, n-Bu. n-C 11 H23 Lipase PS 36% yield 50% yield Lipase PS; 27-46% yield; 96% ee 92% ee 70-96% ee

Lipase PS 13% yield 85% ee

O

O Ph

O

O

Me

(S) Tropic acid lactone CAL-B 46% yield >98% ee

CAL-B 99% ee

O

O

O O i-Pr ClF2C Lipase PS CAL-B 39% yield 37% yield 99.9% ee >99% ee

The hydrolysis of remote ester units has also proved a useful approach to chiral oxetanes, 20 and 21, which were used in the preparation of thromboxane agonists . F F

F O

OH OAc

F

OH OAc

O

21 20 Pig liver esterase, hydrolytic KR 24% yield, 100% ee

20% yield, 100% ee

1.4.3 Thietanes There are very few reports of the enzymatic preparation of chiral thietanes and these involve the hydrolytic resolution of ȕ-thiolactones. Very high yields and ee’s were achieved and examples are shown below . R

Pseudomonas cepacia lipase phosphate buffer, cyclohexane

S O

R = Me: 48% yield, 98% ee R = Et: 46% yield, 99% ee

R

R +

S O

HS

OH O


11

1.5 FIVE-MEMBERED RING SYSTEMS 1.5.1 Tetrahydrothiophene Derivatives A number of chiral tetrahydrothiophenes have been prepared using biotransformations. As one would expect, resolutions can be utilized. For example, tetrahydrothiophenones (thiolactones), e.g. 22, can be resolved using lipase enzymes, giving mercaptobutyric acids as byproducts . Simple resolution of pendant esters has also been reported for both tetrahydrothiophenes and their sulfone analogues . Me

Me

O

Candida antarctica lipase O

S 22

+

HS

O S 76% conversion >99% ee O

O

OH

O PhS

PhS S O O

OH Me

O S O O

Novozym e 435 Hydrolytic KR 98% ee (ester and alcohol)

S Lipase PS-800 Triton X-100 Hydrolytic KR 98-99% ee

Enzymatic reductions have also proved useful, and chiral 3-hydroxytetrahydrothiophenes can be obtained via enzymatic reduction of tetrahydrothiophen-3-ones using ketoreductase enzymes or baker’s yeast . Furthermore, (R)-3-hydroxytetrahydrothiophene has been manufactured on a commercial scale from the corresponding ketone using an evolved ketoreductase enzyme derived from Lactobacillus species. The process operated efficiently under mild conditions, using high substrate loadings, and gave high yields of product in very high ee . Dynamic kinetic resolutions have also been employed, giving products with reasonable yield and very high de and ee . O

OH Bakers Yeast

S

CO 2Me

S

CO2Me

64% yield >99% ee >99% de

Aromatic thiophenes and benzothiophenes give interesting cisdihydroxylated products in very high ee upon exposure to the toluene dioxygenase enzymes from Pseudomonas putida UV4. However, the 2-hydroxy group could be racemized via equilibration through a ring open aldehyde.

S.J. Collier et al.

12

P . putida UV4 oxygen

OH

X

OH

OH

Me

OH

OH S 11% yield 3:2 cis:trans 48% ee

X

S

Me

OH

OH

15% yield 4:1 cis:trans >98% ee

OH

S

79% yield 4:1 cis:trans >98% ee

Some more complex transformations have also been reported. For example, a series of thiosugars (eg. 23 and 24) have been prepared from 2-mercaptoacetaldehyde and either glycerol or glycerol phosphate using aldolase enzymes. In the former case, glycerol is converted to glycerol phosphate and then to dihydroxy acetone phosphate. After an aldol reaction, the product was dephosphorylated using an acid phosphatase. In the latter case the mercaptoacetaldehyde was formed in situ by the dissociation of its dimer. The synthesis of 5-thio-D-xylulofuranose 25 was accomplished using a transketolase; the racemic aldehyde was used as a substrate, but only the Denantiomer is accepted by the enzyme .

OH HO OH O P O

S HO

OH 23

OH Aldolase

HS

OH +

77% R = PO3 H2

O

HO

i. Kinase/Dehydrokinase ii. Aldolase

OH HO

SH

O +

HO

OH

O O racemic

O

Transketolase TPP Tris buffer pH 7.5/30 o C 48%

S HO

P OH O

S

70% R =H

OR

O

24

OH

OH OH

OH 25

1.5.2 Tetrahydrofuran Derivatives Chiral tetrahydrofurans are readily accessible using resolutions and desymmetrizations with example products of each given below. Intermediate 26 was used to prepare (-) podophyllotoxin and picrodophyllin . Bicyclic hydroxyfurans have been prepared via lipase mediated acylative desymmetrization of meso diols . Chiral furanones have been prepared by lipase mediated lactonisations. For example, meso-hydroxydiester 27 can undergo a porcine pancreatic lipase catalyzed desymmetrization via lactonization giving (S)-furanone 28 in high optical yield. The (R)-isomer could be obtained using Pseudomonas fluorescens lipase, although ee’s were lower . Treatment of 3,4epoxytetrahydrofuran with an epoxide hydrolase can give the corresponding (3R,4R)-diol . Epoxide hydrolases have also been employed in an elegant enzyme-triggered enantioconvergent cascade reaction. Thus racemic 2,3-disubstituted cis-2-chloroalkyl epoxides 29 can be hydrolyzed enantioconvergently using resting cells of Rhodococcus sp. or Rhodococcus ruber. One enantiomer is cleaved with retention of stereochemistry, the other with inversion, providing a single, stereo-defined chlorodiol intermediate 30, which


13

spontaneously cyclizes to yield chiral 3-hydroxytetrahydrofurans 31 as sole products in good yields and reasonable ee’s . HO

H

O

O

O

O

O

H Lipase from Pseudomonas f luorescens Hydrolytic KR 22% yield, 92% ee

O

O O

OH

Immobilized lipase from P seudomonas cepacia Hydrolytic meso desymmetrization 90% yield, >98% ee; Porcine pancreatic lipase

26 Porcine pancreatic lipase hydrolytic meso desymmetrization 66% yield, 95% ee;

O

Cl

O

O

100%

O

O 28

27 epoxide hydrolase

O

OH OAc

O

OH OAc

-HCl

R

Cl

R 29 Racemic R = Et, n-butyl

OH

OH O

OH (3R,4R) 30

R

(2R,3R) 31 R = Et: 42% conversion, 61% ee R = n-Bu: 79% yield, 86% ee

Enzymatic ketone reductions have also been shown to provide chiral dihydro- and tetrahydrofuran-3-ols in high ee from the corresponding ketones, with either enantiomer accessible through selection of an appropriate variant . Enzymatic reductions of ketones bearing pendant ester groups to chiral alcohols can result in cyclization of the intermediate hydroxyester to give chiral butyrolactones. Enzymes from the yeasts Mucor rouxii or Pichia etchellsi gave excellent yields and ee’s. O

M ucor r ouxii hexane/water

O

RO

OR

O

OR

O O

O

R = Me, Et, n-Pr, i-Pr: 98-100% yield; 94-99% ee O P. etchellsi

O

O

99% ee 90%

O

O

Oxidations have also proved to be valuable and efficient approaches to chiral tetrahydrofuran derivatives. For example, HLADH (horse liver alcohol dehydrogenase) catalyzes the oxidation of meso 1,4-diols 32 to give enantiomerically pure furanones 33 bearing fused rings of varying sizes on multigram scale . Cyclobutene-fused furanones have been prepared using the same approach . Chiral

S.J. Collier et al.

14

dihydrobenzofuran diol 34 was synthesized from benzofuran using toluene dioxygenase .

OH n

OH O

HLADH

n O

O

OH 32

33 n = 1-4: 68-90% yield; 100% ee

OH

34 Toluene dioxygenase from Pseudomonas putida UV4 17% yield, 55% ee 3:2 cis:trans

There are many examples of the synthesis of stereochemically defined Ȗ-butyrolactones, using the enzymatic Baeyer–Villiger oxidation of substituted cyclobutanones with a range of isolated enzymes or whole cell processes. The products of such reactions play a key role in the synthesis of many types of natural products and therapeutic agents (particularly those bearing substituents at the 3-position) . High stereoselectivities and good yields can be obtained using the fungus Cunninghamella echinulata in whole cell processes and the same or similar substrates can be also prepared from isolated Baeyer–Villiger monooxygenases (BVMO), such as cyclohexanone monooxygenases (CHMO), cyclopentanone monooxygenases (CPMO), or 4hydroxyacetophenone monooxygenases (HAPMO) . Bacteria expressing a mutant CHMO (F432S) were tested against a range of ketones in a 24-well microplate, in some cases giving products with high conversion and good ee . An interesting variant of this approach involves the Baeyer–Villiger oxidation of 4-hydroxycyclohexanone, to give (S)-4-hydroxycaprolactone 34 which spontaneously rearranges to give an (S)butyrolactone derivative 35 . The product could be obtained in high yield and good stereoselectivity after screening and directed evolution. R

R

R BVMO

O

BVMO O

O (S)-lactone-derivative Acinetobact er calcoaceticus R = 4-ClC 6H 4, 4-MeC6 H 4, 3,4-(OCH2 O)C6 H3 , 3-MeOC6H4 CH2 : 70-94% yield, 85-100% ee

HO

CHMO r.t. 24 h

O O

(R)-lactone derivative Cunninghamella echinulata NRLL 3655 R = Ph, 4-ClC6 H 4,4-FC6H4, PhCH 2OCH 2: 65-80% yield, 98% ee R = CH2Ot -Bu: 25% yield, >98% ee

HO

O

O

O

O 34

O

HO 35 95% yield, 79% ee


15

1.5.3 Pyrrolidine Derivatives Enzymatic approaches to chiral pyrrolidine derivatives are widespread, with various biotransformation strategies being employed to prepare a wide range of products. A small selection of the many tranformations, including some of the more elegant examples, is given here. Chiral pyrrolidine derivatives are readily accessed via resolution. In the example shown below, a lipase was used to cleave the carbonate function of the undesired enantiomer of a racemic substrate, leaving the chiral carbonate 36, an intermediate to (S)-zoplicone . Protease enzymes have been used to cleave ethyl esters of racemic alkyl and aryl oxalamic pyrrolidines leaving chiral esters in high ee . Lactam 37, an intermediate to the drug Abacavir, was prepared via lactamase mediated resolution of its racemate (R = H) . Protected analogues could be resolved using enzymes such as savinase . Chiral indol-2ones (e.g. 38 and 39) bearing a quaternary stereogenic carbon at the 3-position have been prepared via lipase mediated hydrolytic or acylative meso desymmetrization of diesters or diols respectively . Desymmetrization of meso Ncarboxybenzoyl-3,4-epoxypyrrolidine with an epoxide hydrolase can give the corresponding (3R,4R)- or (3S,4S)-diols .

OH

O N

O N

R

O O

N

Cl N

N O

O

O 36 Can di da a ntar cti ca li p as e- B 5 0% c on vers io n 98% e e

O

O

O

O

O OH O

N R

N R 37 38 39 L ac ta m as e (R = H ) Li p as e OF L ipa se OF or Acy la tiv e d esym me tri zati o n Hyd ro lyti c des ym metriz ati on S a vin a se (R = B oc , A c) R = Bo c, C bz, Ac R = M e, Bo c, Cb z, Ac, M OM, Bn u pto 50 % yi el d 71 -9 3 % yie ld 29 -5 7% yi e ld at l east 9 8% e e 9 7- 99 % ee 98 -9 9% ee

3-Hydroxy-2,3-dihydroisoindolidin-1-ones (hemiaminals) are the core unit of a wide range of naturally occurring substances and bioactive compounds. Racemic N-acylhemiaminals are readily synthesized, and acylative DKR is a straightforward approach to the corresponding enantiopure esters. For example, the acetylation of racemic N-acylhemiaminals 40 mediated by lipase PS (Pseudomonas cepacia), lipase AK (Pseudomonas fluorescens) and lipase QL (Alcaligenes species) exclusively produced the (R)-acetates 41 in high enantiomeric purity and quantitative yields, using isopropenyl acetate as the acyl donor . OH N

Lipase PS, AK or QL Isopropenyl acetate O Hexane, 60-70 o C R

O

quant

OAc O N R O

41 40 R = CH3 : 63% ee; R = Et, Pr, i-Pr, t-Bu, Ph: 95 - >99% ee

S.J. Collier et al.

16

Candida antarctica lipase A is described to catalyze the highly enantioselective DKR of the methyl esters of racemic proline 42 (n = 1) and pipecolic acid 42 (n = 2) (Scheme 1). Vinyl butenoate or 2,2,2-trifluoroethyl butanoate proved to be the best achiral acyl donors . n CO2 Me N H 42

Candida ant ar ct ica lipase-A PrCO2R, MTBE

n

n CO 2Me

CO 2Me

+

N H

N

CH 3CHO, Racemization

O

Pr

n = 1, R = CH=CH2 : 88% yield, 97% ee; R = CH 2CF3: 97% yield, 99% ee n = 2, R = CH=CH2 : 69% yield, 97% ee

Scheme 1 Enzymatic reduction has also proved to be fruitful. For example, ketoreductase enzymes provide chiral pyrrolin-3-ols and pyrrolidin-3-ols in high ee from the corresponding ketones, with either enantiomer accessible through selection of an appropriate variant . In a more interesting example, the asymmetric reduction of the alkene moiety of Nsubstituted maleimides can be conducted by whole cell processes or isolated enzymes. Thus the highly stereo- and diastereoselective reduction of 3-methyl and 3,4-dimethylmaleimides 43 was effected using a cell culture of Marchantia polymorpha . Several reductions of N-substituted maleimides are also described using a plant cell culture of Nicotiana tabacum . The reaction has also been effectively performed using the 12-oxophytodienoate reductase isoenzymes (OPR-1 and OPR-3) from Tomato . The employed system exhibits broad substrate specificity and affords the product in high yields and enantiomeric purity. R2

R1 Enzymatic reduction

R2

R1

O O

N R3 43

O O

N R3

R1 = H, R2 = Me, R3 = 4-MeOC6 H4 : 90% conversion, CH 2Ph: 99% conversion; 99% ee: M. polymorpha; R 1 = H, R2 = Me, R3 = Ph: 99% conversion; 99% ee: N. t abacum; R 1 = Me, R 2 = Me, R 3 = 4-MeOC 6H 4: 77% conversion, Ph: 99% conversion; 99% ee: M. poly mor pha; R1 = Me, R2 = H, R3 = Ph: 100% conversion; 99% ee: N. tabacum;

Enzymatic oxidations are also known. For example, the direct hydroxylation of Nprotected pyrrolidines, 44 (X = CH2) and pyrrolidinones 44 (X = CO) has been achieved using Sphingomonas sp. HXN-200 (using resting cells or a cell free extract), giving 3-hydroxypyrrolidines, or 4-hydroxypyrrolidinones respectively, in moderate yield and ee on gram scale. Crystallization of the products dramatically increased the chiral purity, and with pyrrolidines, a simple change in the nitrogen substituent resulted in a reversal of stereochemistry .


OH

N R (S)-isomer O

Sphingomonas sp. HXN-200 X N R 44

X = CO

Sphingomonas sp. HXN-200 phosphate buffer glucose

17

OH

OH

or N N R R (S)-isomer (R)-isomer

X = CH 2

X R Conversion Enantiomer % ee % ee After Crystallization CH2 COPh 43 (R) 52 95 CH2 CO2CH2Ph 91 (R) 75 98 CH2 CO2Ph 73 (S) 39 96 C=O Bn 68 (S) >99.9 -C=O CO2tBu 46 (S) 92 99.9 Monoamine oxidase (MAO) enzymes convert amines to imines with chiral discrimination. Thus, treating racemic amines with monoamine oxidase enzymes, in the presence of achiral reducing agents can provide chirally pure products. For example, in aqueous buffer solution, the aminoketone 45 cyclises to an achiral iminium ion 46, which is subsequently reduced to racemic amine by NH3-BH3 complex . The (S)-enantiomer 47 is selectively oxidized back to the iminium ion by the monoamine oxidase (from Aspergillus niger). As the cycle repeats, the (R)-amine 48 accumulates, and the product, nicotine, can be obtained in quantitative yield with 99% ee. A similar approach was used to deracemize racemic proline to give L-proline in high yield and ee .

HN

N

NH3 .BH3 phosphate buffer 20 C / 24 h

N

O N

45

H N

N

46

47

Air, MAO-N-5 (resting cells)

N

+

H N

48 quant yield 99% ee

1.5.4 Five-Membered Ring Systems with More Than One Heteroatom A number of chiral five-membered heterocycles bearing two heteroatoms have been prepared using biotransformations. A small selection is given here, and as one would expect, numerous examples involve lipase mediated resolutions or desymmetrizations. Chiral dioxolanes, e.g. 49 and 50, have been prepared through enzymatic desymmetrization reactions, with both configurations available depending on the approach taken (acylative versus hydrolytic) . Chiral isoxazolines such as 51 have been prepared using a lipase mediated DKR, with the racemization step occurring via a reversible Michael reaction . The drug Emtricitabine, 52, a chiral oxathiole, was prepared in excellent ee on multi-kilo scale using a lipase resolution of the corresponding racemic butyrate ester . The opposite (+) enantiomer could be obtained using pig liver esterase . Chiral dithiolane 1-oxide 53, thioxolane-S-oxides and benzo dithiolane 1oxides have been prepared via whole cell asymmetric enzymatic sulfoxidation, with the former being obtained in good ee . Typical products are given below.

S.J. Collier et al.

18 O O

HO

O O

O

OH

OAc 49 Lipase from Pseudomonas f luor escens or P seudomonas cepacia Acylative desymmetrization 90% yield, 99% ee

O

NC

O N O

OH 50 Pseudomonas cepacia lipase Hydrolytic desymmetrization 86% yield, 99% ee

51 Pseudomonas cepacia lipase Hydrolytic DKR of ethyl thioester >99% conversion, 97.6% ee 89% yield, 99.7% ee af ter recryst

O N

O

HO

NH2

S

S

N

F Emtricitabine, 52 Immobilized cholesterol esterase from Candida cy clindicacea hydrolytic KR 31% yield, 98% ee

S O

53 A cinetobact er TD63 whole cells chiral sulfoxidation 87% yield, >95% ee

Chiral oxazolidinones 54 have been prepared from racemic epoxides using an interesting enzymatic transformation. The enzyme halohydrin dehalogenase catalyzes the attack of a range of nucleophiles upon epoxides, and when sodium cyanate is used, the ring opening of one epoxide enantiomer is favored, giving an intermediate isocyanate, which spontaneously cyclizes to give the chiral isoxazolidinone .

R1

O

Halohydrin dehalogenase f rom Agr obacter ium radiobacter , NaOCN, buffer O R1 R2

R2 O O

O

O NH

O

O

NH

44% yield 97% ee

NH 54

O NH

Cl 47% yield 80% ee

O

O

O NH

Br 46% yield 93% ee

O

NH

Cl 47% yield 98% ee

54% yield 69% ee

1.6 SIX-MEMBERED RING SYSTEMS 1.6.1 Piperidines Chiral piperidines have been prepared using a wide range of different biocatalysts. The use of lipase mediated desymmetrizations and kinetic resolutions is widespread with a number of examples given below. Such approaches provided all four diastereomers of 4hydroxypipecolic acid ; chiral piperidine intermediates to the drug paroxetine , and intermediates to the Kishi lactam . Protease enzymes have been used to cleave ethyl esters of racemic alkyl and aryl oxalamic piperidines leaving chiral


19

esters (e.g. 55) in high ee . Lipase mediated DKRs are have also been employed, providing chiral pipecolic acid derivatives . O HO

R

R

O OMe

HO OAc AcO OH N N N Cbz Cbz Bn Lipase from Candida ant ar ct ica Candida cylindracea lipase Lipase from A. niger Acylative desymmetrization Hydrolytic desymmetrization Hydrolytic desymmetrization R = H: 80% yield, 95% ee 25% yield, 80% ee R = H: 82% yield, >98% ee R = OMOM: 76% yield, >98% ee R = OMOM: 83% yield, 96% ee

OH N Boc

Lipase PS/PP Hydrolytic KR 46% yield, 99% ee

OAc

OH N

O

Boc

N

N H HO

Et

O

O OEt Pig liver esterase 55 Lipase PS/PP Hydrolytic KR Hydrolytic desymmetrization Protease from Aspergillus sp. 87% yield, 93% ee Hydrolytic KR 43% yield, >90% ee 49% conversion, 99% ee HOOC

HOOC F

N H

F

N H

O O Candida antar ctica lipase-B Candida antar ctica lipase-A Hydrolytic KR Hydrolytic KR 50% conversion, 99% ee 50% conversion, 99%ee

An interesting DKR approach to chiral tetrahydroisoquinolines is shown below. The amine substrate 56 undergoes racemization in the presence of an iridium catalyst, and a lipase selectively acylates a single enantiomer to give the corresponding carbamate 57 in high yield and good ee . 0.2 mol% [Cp*IrI2 ]2 Candida rugosa lipase Toluene, 40 oC

MeO NH

MeO 56

MeO

O

OPr O

MeO MeO

N

OPr

O 57 86% yield, 96% ee

Enzymatic reductions have also proved to be successful approaches to chiral piperidines. For example, hydroxylated derivatives of the antianxiety drug Buspirone have been accessed using enzymatic reduction of ketone derivative 58 , although other approaches including lipase mediated resolution of an acetoxylated derivative ,

S.J. Collier et al.

20

or direct microbial hydroxylation of Buspirone itself were also demonstrated. (R)-Quinuclidinol 59 has been prepared via enzymatic reduction of the corresponding prochiral ketone . N O O

(R)-Reductase from H ansenula polym orpha SC13845 expressed in E. coli O

N

N

N

N

4 O 6-Ketobuspirone 58

>98% yield >99.9% ee

(S)-Reductase f rom Pseudomonas put ida SC16269 expressed in E . coli O

>98% yield >99.9% ee

N HO

N

O

HO

O

OH

Tropinone reductase-I from Datur a st ramonium 88.4% yield, 98.6% ee N

59

A range of enzymatic oxidations have been used to prepare chiral piperidines. Chiral hydroxylated L-pipecolic acids 60 and 61 can be prepared via highly diastereoselective hydroxylation using proline hydroxylase, cloned and purified from several bacterial sources including Streptomyces sp. . Toluene dioxygenase can convert quinolin-2-one to chiral quinolone diol 62 in high ee . Racemic pipecolic acid has been deracemized using a combination of amine oxidase and reducing agent to give the L-isomer in high yield and ee . OH N H O 60 38% yield >99% ee

OH

Proline 3-Hydroxylase Aqueous, 35 C N H

Proline 4-Hydroxylase OH Aqueous, 35 C O

OH OH N H 62

O

HO N H

OH

O 61 40% yield >99% ee

Toluene dioxygenase from Pseudomonas put ida UV4 10% yield, >98% ee

A scalable route to synthesize chiral piperidines involves the use of both oxidizing and reducing enzymes – an amino acid oxidase and an amino acid dehydrogenase (AADH). For example, L-pipecolic acid, a chiral pharmaceutical intermediate and an important diagnostic marker for epilepsy, is produced in three steps starting from L-lysine (63, X = CH2CH2). Amino acid oxidation by L-lysine oxidase (from Trichoderma viride) affords the corresponding ketoacid 64, which spontaneously cyclizes to form a cyclic imino acid 65. The latter is a substrate for the dehydrogenase (from Pseudomonas putida), giving L-pipecolic acid (66, X = CH2CH2, Scheme 2) . On lab scale, this reaction has reported to give 90% yield and 99.7% ee at 27 g/L lysine loading . It should be noted that


21

this method can also be used to prepare other heterocyclic amino acids from the appropriate open chain amino acid analog. . NH2 X

Amino acid NH2 oxidase OH

NH2 O

X

X

OH

OH N

64 O

X

OH N H 66

O

O 63

Amino acid dehydrogenase

65

O

X = (CH 2 )2, CH 2 , (CH2 )3 , CH2 S, (CH 2) 2S, CH 2O: 99% ee

Scheme 2 1.6.2 Pyrans Chiral pyran derivatives are readily prepared using kinetic resolutions. Two complimentary examples, 67 and 68, are given below, and for the latter of these, the DKR occurred via reversible opening of the hemiacetal to give a transient hydroxyaldehyde . Other resolutions are also known . Bicyclic hydroxypyrans have been prepared via lipase mediated acylative resolution . Mesodesymmetrization was used to prepare the chiral chroman monoacetate 69, an intermediate to (S)-Į-tocotrienol, from the corresponding diol in high ee . Chiral acetamidochroman 70 was prepared using an interesting dynamic kinetic resolution. The corresponding ketoxime was reduced to a racemic amine, which is in constant palladium mediated equilibration. Lipase catalyzed acylation of one enantiomer of the amine gave the chiral acetamide shown in good yield and high ee . F O

O O

OH O

OAc 67

O

OAc 68

CO 2Et

O O

F

Immobilized Lipase PS Immobilized Lipase PS Hydrolytic KR Acylative DKR 3:1 hexane:n-butanol Vinyl acetate 65% conversion >99% conversion >99% ee 76% ee

N N N N Immobilized Lipase PS-30 Hydrolytic KR 48% yield, 98% ee

HO

Bacillus lent us protease Hydrolytic KR 38% yield, >99% ee

NHAc O

OAc

O HO 69 70 Candida antarctica lipase B Candida antarct ica lipase B Hydrolytic desymmetrization Acylative DKR 60% yield, 98% ee 89% yield, 99% ee

Enzymatic reduction and oxidation reactions have also proved to be versatile options. For example, the chiral hydroxytetrahydropyran 71 was prepared in high yield and ee on pilot

S.J. Collier et al.

22

plant scale using an isolated ketoreductase coupled with a glucose/GDH cofactor recycling system . Toluene monooxygenase enzymes can give chiral benzopyran diols 72 and 73 from the corresponding alkenes, in high ee . MeO HO

OMe

OH

OH

OH

OH O 71

Me O Me 73

O 72

Toluene dioxygenase from Pseudomonas put ida UV4 20% yield, >98% ee 18% yield, >98% ee

KRED 101/GDH 101 96-98% yield >99% ee

Chiral tetrahydropyranones are also readily accessible from cyclopentanones using Baeyer–Villigerase enzymes. For example, both wild-type and mutant CHMOs from Acinetobacter sp. catalyze the ring expansion of a range of bicyclic substrates to give the corresponding chiral lactones. Depending on the variant used, the conversion and enantioselectivity varied greatly, as shown . A range of tetrahydropyranones have been prepared this way, some of which are shown below . H

H

O Cl

O

O

O

O

O

H

H > 90% yield 17-94% ee, (-) only

> 90% yield 60-99% ee, (+/-)

O O

1-90% yield 12-92% ee, (+) only

50-90% yield 60-90% ee, (+/-)

CHMO from Acinet obacter sp. H

O O OBn CHMO from Acinetobact er calcoaceticus >85% yield, 96% ee

O

O H CHMO from Brevibacter ium >92% yield, 94% ee

An interesting approach to chiral tetrahydropyrans uses 2-deoxyribose-5-phosphate aldolase (DERA). The native reaction catalyzed by this enzyme involves the condensation of acetaldehyde with D-glyceraldehyde-3-phosphate to form 2-deoxyribose-5-phosphate. DERA has been shown to have the unique ability to accept multiple aldehyde donors in a sequential and stereoselective manner. This feature has been exploited both in the laboratory and on a manufacturing scale to produce a variety of chiral hydroxytetrahydropyrans – several examples of which are shown below . Of particular note is the synthesis of the chlorolactol (74, R1 = Cl) which is an important intermediate for statin drugs such as Atorvastatin (Lipitor) and Rosuvastatin (Crestor). Large-scale production of this compound utilizing the DERA process achieved a throughput of 30 g/L/h with a yield of 89% and an ee and de of 99.9% and 99.8%, respectively .


O

DERA, 20 C O Aq. buffer

O

23

O

R1

OH

R1 OH 74 R 1 = H, N3 : 22-23% yield; R 1 = OMe, CH 2CO2H, Cl: 65-80% yield; O

O

DERA, 20 C Aq. buffer

O

HO

OH

R2

R2

R 2 = OH, N 3, trans-Me:47-60% yield

OH

1.6.3 Thiopyrans Chiral thiopyran derivatives can be produced following similar approaches to pyrans. For example, chiral hydroxytetrahydrothiopyrans can be accessed via enzymatic ketone reduction using alcohol dehydrogenases . Thiopyran dioxide 75, an intermediate in the synthesis of the drug Trusopt, was obtained in high yield and de through alcohol dehydrogenase mediated diastereoselective reduction of the corresponding ketone . Toluene dioxygenase gives chiral benzothiopyran diol 76 in high ee from the corresponding alkene . OH

OH

OH Me

S

S

47% yield 78% ee

34% yield 38% yield 85% ee 65% ee Horse liver alcohol dehydrogenase

OH

O

S

R S Bakers yeast alcohol dehydrogenase R=CH 3 , C2 H 5, C6 H5 32-66% yield, 93-97% ee OH

OR

Bakers yeast alcohol dehydrogenase R=H, CH 3 , C 2H 5, C8 H17 28-86% yield, >98% ee

O

OH

OH OR

S

OH Et

S

S

49% yield 90% ee

OH Me

Et

O

OH S

S O2 75 Alcohol dehydrogenase from Neurospor a cr assa >85% yield, >98% ee

S 76 Toluene dioxygenase f rom Pseudomonas putida UV4 40% yield >98% ee

Again, in direct analogy to tetrahydropyrans, DERA-catalyzed reactions can give chiral tetrahydrothiopyrans. In the case below, a single diastereomer of the thiosugar 77 is produced due to DERA’s exquisite selectivity for 2-hydroxyaldehydes .

S.J. Collier et al.

24

O

S DERA, aq. buffer 48 h, 20 C

O

HS

33% yield

OH

OH

HO OH 77

1.6.4 Six-Membered Heterocycles with More than one Heteroatom A range of chiral six-membered heterocycles which bear more than one heteroatom in the ring are accessible using enzymatic reactions. A small selection is given below, although one could envisage many viable approaches to such compounds. Hydrolase mediated resolutions of racemates are, again, readily employed to access heterocycles bearing chiral alcohol, amine or acid residues. For example, chiral dioxane 78, an intermediate to the natural product leustroducsin, was prepared via acylative desymmetrization of the corresponding meso-diol followed by silylation . Lipases and esterases also act as racemases in that they can catalyze the interconversion between the two enantiomers of a single substrate. Thus, the (2R,3R)-enantiomer of the oxazinol 79 can be ring-opened by commercial Lipase P-800 to give the corresponding aminoketone. The Į-methyl group can be inverted via enolization and upon enzyme-catalyzed ring closure, the (2S,3S)-enantiomer can be obtained. Treatment of an equilibrated mixture with seeds of the desired (2S,3S)-enantiomer results in a crystallization driven transformation, providing the product in 97-98% ee .

O

O

78

Cl OTBS

O

OH

OAc

Lipase AK Acylative Desymmetrization then silylation 86% yield, 90% ee

Cl

Lipase P-800 acetone, water 16 h, 20 C

O

N H

OH

N H 79

Deracemization of racemic amines using chemo-enzymatic synthesis is a powerful approach to chiral amines. For example, the piperazine amino acid 80 (an intermediate for the HIV-protease inhibitor Crixivan) can be prepared using a combination of an amino acid oxidase from porcine kidney (which selectively oxidizes the (S)-carboxylic acid to the corresponding imine) and sodium cyanoborohydride (which reduces the prochiral imine back to the racemate). The resulting (S)-amino acid is then reoxidized to the imine and the cycle continues. The desired L-piperazine-2-carboxylic acid is produced in 86% yield and 99% ee using this elegant one-pot synthesis . Either enantiomer of the same piperazine acid could also be prepared via resolution of the racemic amide using different hydrolase enzymes. Chiral morpholino and thiomorpholino carboxylic acids (66, X = CH2O, CH2S) have been prepared in direct analogy to the route used to prepare L-pipecolic acid (Scheme 2) using a sequence of L-amino acid oxidase then dehydrogenase reactions . Amino acid oxidase f rom P seudomonas put ida aq. buffer, 37 o C, 3 eq NaCNBH 3

H N N H

COOH

H N N COOH H 80


25

In an interesting and unusual reaction, 1,3-dithianes 81 can be oxidized using CHMO enzymes to give the corresponding chiral monosulfoxides 82. Such chiral sulfoxides have proven to be excellent chiral auxiliaries for use in asymmetric syntheses. Selected products are given below, and in all cases, no evidence of bis-sulfoxide formation was noted, although sulfone formation (9 5% e e

N o vo zym e 4 3 5 A cyl ati ve de sy mm etr iza tio n 8 6% yi el d , 9 0 % e e

Cl A cO S

B nO

OH O

OBn

N O

OH O L ip as e FA P-1 5 Hy dr ol yti c KR 4 5 % yie ld , 9 9% e .e

87 Li pa se AK A cyl a ti ve d es ymm e tr iz ati on 8 1 % y ie ld , >99 % ee

OB n

Bn O A cO

O

OH

M PM O Ac O

O MP M O

OH

88

89

L ip a se A K Ac yla tiv e d e sym me tri za tio n 92 % yi el d, 9 2 % e e

Li pa se AK A cyl a ti ve d es ymm e tr iz ati on 7 6 % y ie ld , 94 % ee

Enzymatic reductions have also proved valuable. For example, chiral benzazepinone 90 was prepared by enzymatic ketone reduction with enzymes such as Nocardia salmonicolor and Rhodococcus fascians , although other reductase enzymes may be used for such transformations . Either enantiomer of a range of hydroxyazepanes and oxepanes have been prepared using ketoreductase enzymes . Optically active benzothiazepinones, e.g. 91, have also been prepared by reduction of the corresponding ketones under dynamic conditions . Chiral thiazepino carboxylic acid 66 (X = CH2CH2S) has


27

been prepared in direct analogy to L-pipecolic acid (Scheme 2, above) using a sequence of Lamino acid oxidase then dehydrogenase reactions . H N

O

H N

O

N. salmonicolor phosphate buffer, pH 8

O CF3

OH

85% yield

CF3 90

OMe O

Baker's yeast

S

S

O N H

OMe O

OH N O H 91 85% yield, 99% ee

O

The synthesis of 7-membered chiral lactones or oxepan-2-ones and derivatives thereof, via the enzymatic Baeyer–Villiger oxidation of cyclohexanones is a widely studied reaction. . A classical example of cyclohexanone monooxygenase catalyzed oxidation is shown below, as are other chiral lactones synthesized similarly. Chiral dioxepines, e.g. 92, can also be prepared via the Baeyer–Villiger oxidation of prochiral pyranones utilizing recombinant whole cells of Escherichia coli overexpressing Acinetobacter sp. NCIMB 9871 CHMO , with a typical reaction shown below. O

O CHMO from Acinet obacter sp. NCIMB 9871

O

>99% e.e

O

O O

O

O O

O

O O

O

O

O

Et O O OMe H CHMO from Acinetobacter sp. NCIMB 9871 65% yield >99% ee

76% yield 79% yield 75% ee 95% ee

35% yield >99% ee

22% yield >99% ee

O O 26% yield >99% ee

S.J. Collier et al.

28 R

O

R

CHMO f rom Acinetobacter sp. air, aq. buffer, 20 C

O R

O

O

O

R 92 R = Me: 80% yield, >99% ee; Et: 90% yield, >99% ee; Pr: 19% yield 98% ee; i-Pr/n-Bu: no reaction

1.8 CONCLUSION The preparation of chiral heterocycles using biotransformations is an effective synthetic strategy which can provide high value products with exquisite control of chirality, typically under mild and environmentally benign conditions. Although this review is limited in coverage, the potential of biocatalytic chiral heterocycle synthesis is clear. Furthermore, the development of directed evolution technologies allows rapid optimization of inefficient wild type enzymes, providing superior catalysts that are highly active, selective and robust, and that are commercially attractive alternatives to traditional chiral chemical technologies. Given the increasing access to such evolved catalysts, and the growing acceptance of biocatalysis in the synthetic community, the stage is set for continued growth in this field, with many new and exciting applications waiting to be discovered.

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32 02TL6763 02TL707 02TL7971 03ASC986 03BMCL1479 03CC960 03EP1318200 03JA4048 03JOC4570 03MI357 03MI583 03OL1209 03SL1973 03T4701 03TA1581 03TA3673 03TL2225 03WO006656 03WO016543 04AG(I)2163 04AG(I)4075 04CRV4105 04GC475 04H(63)17 04JA11156 04JMOC245 04JOC12 04JOC2478 04MI981 04OL177 04OL807 04PNA5788 04T525 04T601 04T671 04T717 04TA15 04TA2875 04TA3763 04TA573 04TL7683

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07MI717 07OPRD642 08CBC1048 08MI6 08MI132

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Chapter 2 Ring-Expanded (‘Fat’) Purines and their Nucleoside/Nucleotide Analogues as Broad-Spectrum Therapeutics Ramachandra S. Hosmane Laboratory for Drug Design and Synthesis Department of Chemistry and Biochemistry, University of Maryland, Baltimore County 1000 Hilltop Circle, Baltimore, Maryland 21250, USA [email protected]

2.1.

INTRODUCTION

Purine is a bicyclic, 5:6-fused, aromatic, heterocyclic compound with a 5-membered imidazole ring fused to a 6-membered pyrimidine ring . Although purine itself has never been found in nature, substituted purines like adenine and guanine or their respective nucleoside derivatives, adenosine and guanosine, are the most ubiquitous class of nitrogen heterocycles and play crucial roles in wide variety of functions of living beings . As nucleotides (AMP,GMP), they are the building blocks of nucleic acids (RNA/DNA) . They serve as energy cofactors (ATP, GTP) , as part of coenzymes (NAD/FAD) in oxidation-reduction reactions, as important second messengers in many intracellular signal transduction processes (cAMP/cGMP) , or as direct neurotransmitters by binding to purinergic receptors (adenosine receptors) . Therefore, it is not surprising that analogues of purines have found utility both as chemotherapeutics (antiviral, antibiotic, and anticancer agents) and pharmacodynamic entities (regulation of myocardial oxygen consumption and cardiac blood flow) . While they can act as substrates or inhibitors of enzymes of purine metabolism (ADA, Guanase, HGPRTase, PNPase, etc) to render their chemotherapeutic action , their ability to act as agonists or antagonists of A1/A2A receptors is the basis for modulation of pharmacodynamic property . In addition, they can be excellent probes for elucidation of biochemical mechanisms (e.g. fluorescent ε-adenosine) and biophysical characteristics of nucleic acids (e.g. 8-bromoguanosine) . This review concerns a family of ring-expanded purines, informally referred to as ‘fat’ or f-purines, as well as their nucleoside/nucleotide analogues (RENs/RENTs), which have broad applications in chemistry, biology, and medicine . 2.2. SIGNIFICANCE OF ‘FAT’ PURINES AND THEIR NUCLEOSIDE/ NUCLEOTIDE ANALOGUES

c 2009 Elsevier Limited. All rights reserved.

R.S. Hosmane

36

The definition of ‘fat’ or f-purines is explained (Scheme 1), using guanine (G) as an example. ‘Fat’ purines are largely 5:7-fused ring systems containing an imidazole ring fused to a variety of 7-membered nitrogen heterocycles with amino and/or carbonyl functional groups, and thus can be structurally regarded as ring-expanded purines. When the ring fusion goes beyond the 5:7fused systems, such as 5:8, 5:9 or 5:10, we informally refer to them as ‘super fat’ (sf) purines. The corresponding ring-expanded nucleoside and nucleotide analogues are often referred to as RENs and RENTs. Scheme 1 N

O

O

O NH

NH

N

N

N

NH2 N

N

R

NH2

N R

G

N H

N

HN

NH2

R

fG

sfG

R=H, Ribofuranosyl or 2'-Deoxyribofuranosyl

‘Fat’ purines and their nucleoside and nucleotide analogues are of chemical, biochemical, biophysical and medicinal interest. From a chemical standpoint, their synthesis, structure, stability, acid-base properties, aromaticity, and tautomeric equilibria, are worth exploring. From a biochemical perspective, they are an abundant source of substrates or inhibitors of enzymes of purine metabolism, as well as of those requiring energy cofactors. From a biophysical point of view, they are potentially excellent probes for nucleic acid structure, function, and metabolism. From a medicinal stance, they proved to be anticancer and antiviral agents . They may also have other therapeutic uses, for example, f-purines can be regarded as analogues of the extensively-explored benzodi- and triazepines, a family of powerful pharmaceuticals acting on the central nervous system . Concerning their chemistry, a number of f-purines and their nucleoside/nucleotide analogues (RENs & RENTs) have proved to be synthetically challenging. Although most of them are stable once synthesized, the steps leading to their synthesis are, more often than not, plagued with opportunistic rearrangements as we repeatedly discovered over the years . It is also the experience of others who worked in similar areas since a large number of alleged seven and larger ring heterocycles were later found to be only 5- or 6-ring systems . Therefore, their structures must only be assigned with due caution, preferably by single-crystal X-ray diffraction analyses, unequivocal syntheses or extensive spectroscopic analysis . Secondly, the presence of several N atoms in the heterocyclic ring makes it difficult to predict and plan the specific site of glycosylation a priori, and normally more than one regioisomer is obtained . Syntheses of 2'-deoxy analogues are often complicated further by the formation of both α- and β-anomers for each regioisomer . The theoretical significance of f-purines concerns their novel physicochemical properties, including aromaticity, thermodynamic stability, reactivity, acid-base properties, and tautomeric equilibria.

Ring-Expanded (‘Fat’) Purines and their Nucleoside/Nucleotide Analogues as Broad-Spectrum Therapeutics

37

Biochemically, because of their structural similarity to natural counterparts, f-purines and their nucleoside/-tide analogues (RENs and RENTs) are potentially rich sources of substrates or inhibitors of enzymes of purine metabolism , and of those enzymes requiring energy cofactors such as GTP or ATP. Important precedents for potential substrate/inhibitory activity of ring-expanded nucleosides are provided by nature itself in the form of three naturally-occurring antitumor antibiotics, coformycin and pentostatin (2'-deoxycoformycin) , which contain the 5:7-fused imidazo[4,5-d][1,3]diazepine ring system, and are the strongest known inhibitors of adenosine deaminase (ADA) , and azepinomycin , a non-nucleoside containing the imidazo[4,5-e][1,4]diazepine ring skeleton, which is reported to inhibit guanine deaminase (guanase) (Scheme 2). All three antibiotics possess a tetrahedral geometry at the hydroxyl junction of their seven-membered ring and hence are regarded as transition state analogue inhibitors of ADA and guanase . Not surprisingly, the majority of work done by others in this area has been targeted to either coformycins or their synthetic analogues , with only a few exceptions . By contrast, the RENs and RENTs under study in the Author’s laboratory cover a broad range of both planar and puckered molecules , and as such, can potentially act as substrates and/or inhibitors of a wide variety of enzymes of purine metabolism, besides ADA and guanase. Scheme 2 H

HO N

N

O

N

NH

N NH

N

H

HO

O

NH

OH N H

N N H

N

O HO

HO

OH

OH HO

HO

Coformycin

Azepinomycin

Pentostatin

Biophysically, nucleotides that incorporate steric bulk in their skeleta, as compared with their natural counterparts, offer a unique means of exploring steric and conformational constraints of formation of nucleic acid double helices. Steric bulk is often associated with considerable structural deviations from the natural array. The replacement of a natural nucleotide by a ringexpanded nucleotide (RENT) affects the base-pairing and stacking interactions of nucleic acids. This would have consequent impact upon helical structure, stability, and conformations of single- and double-stranded RNA and DNA helices. Biophysical studies employing RENTs should aid in understanding better the factors and parameters that govern the formation, structure and stability of nucleic acid double helices . Furthermore, because of their unique geometric features coupled with novel electronic, ionizational, and conformational characteristics, RENTs are also potentially excellent probes for nucleic acid triple helices . Therefore, the study of primary and secondary structures of RENs, RENTS, and their polynucleotide derivatives is of both interest and importance . The investigations of primary structures and properties includes topology,

38

R.S. Hosmane

tautomerism, acid-base properties, aromaticity, etc. of heterocyclic rings, and syn/anti baseribose conformations, endo/exo sugar puckers, and α/β-anomeric configurations, etc. of nucleosides . Investigations of secondary structures includes helical formation, stability, and conformations of polynucleotides composed of RENTs, and their potential to form double helices by complementary base-pairing with appropriate pyrimidine partners, and by vertical stacking interactions. The secondary structures of nucleic acids are, in large part, governed by the primary structures of the component nucleotides . Medicinal significance of f-purines, RENs and RENTs is rooted in their structural similarity to natural purines. A vast majority of them have proved to be anticancer or antiviral agents . In searching for a molecular basis of their broad spectrum biological activities, we performed molecular modeling studies, which indeed have provided some very interesting mechanistic notions (Figure 1). Shown in Figure 1A is the Watson-Crick base-pairing array for a representative REN containing an fG as a base (shown in magenta),

Figure 1: (A) Superimposition of fG…C base-pair array (magenta) over natural G…C base-pair (yellow). (B) Comparison of a B-DNA double-helix containing 10 natural nucleotide pairs with that containing the same nucleotides except for an fG residue replacing a G at position 5. [Molecular modeling studies were performed using QUANTA/CHARMm, available from Accelrys Software, Inc., San Diego. Extensive energy minimization was carried out on the two duplexes, employing Adopted Basis Newton-Raphson (ABNR) protocol to the point of convergence with an RMS gradient 30%) between H-2 of the imidazole ring and H-1' of the sugar moiety of 82, the synthesis of which is outlined in Scheme 19 , corroborated its predominantly syn orientation in solution. Indeed, when tested for inhibitory activity against ADA from calf intestinal mucosa, 82 exhibited a Ki of 2.02 ± 0.5 x 10-5, which is several orders of magnitude lower activity than coformycin, as anticipated . Furthermore, nucleoside 84, which lacked the crucial 8-OH group for forming a coordination bond with the active site zinc was completely devoid of activity, supporting the significance of 8-OH in enzyme binding . Efforts are underway to optimize the inhibition potency of 82, while still maintaining its semi-tight binding characteristics with a reversible enzyme inhibition property . (A)

(B) H

OH 1

7 8

HN

N

6 5

2 4

N

5'

O

1'

NH

His 15

N

O

Asp 295

OH

H

H N

H

HN

N3 4' 2'

HO

3'

O

HN

O

O

Zn+2

N

OH His 214

Coformycin: anti OH

O-H

7

HN H

N

H

H

1

8 6

N

HN

1 8

7

5 2

5

4

N H

O H O

2

N

HN 6

dCF

1'

2'

O H

5'

3'

5'

4'

O

3'

O-H

H

4'

OH

HO

Nucleoside 82: syn

O

H

O

2'

1'

O

NH

H

N3

4

N3 O

N

His 17

N

H

O

H H

N

Asp 19

H O

Figure 2: (A) Anti/Syn conformations of coformycin and 82. (B) Observed anti conformation of 2'-deoxycoformycin (dCF or pentostatin) in the crystal X-ray structure of a complex of ADA with dCF

R.S. Hosmane

50 OSi(CH3)3 1. H3C

C

HN

2. TMS-triflate Catalyst 3. OOAc BzO

H N

O

+

HN O

OH

MeOH/H2O

N

N H

N HN O

N H O

N

OH

83

84 10%

NaOMe/MeOH or t-BuNH2/MeOH HN 52 % O OH

OH

N H

2. TMS-triflate Catalyst 3. OOAc BzO BzO

82

OBz

OH N

N

H N

+

BzO

N HO

O BzO

OBz

OBz

81 42%

O NH

N

N H

OBz

OH

27%

N H

O HO

OH

1. H3C

79

H2O-MeOH 51%

O

C

NSi(CH3)3

N HN

70 %

NaBH4

O

HO OH

N H

OH N

N O

NaBH4

O

O NH

N

49

BzO OBz 4. NaOMe/MeOH

N

N H

O

OSi(CH3)3

OH

O

NSi(CH3)3

OBz 80 10%

Scheme 19 2.4.2. Guanine Deaminase (Guanase) Guanine deaminase (GDA) or guanase (EC 3.5.4.3) is an enzyme that catalyzes the hydrolytic deamination of guanine to xanthine. This enzyme has been found in human liver, brain, and kidney . There have been reports of abnormally high levels of serum guanase activity in patients with liver diseases , and so, the elevated enzyme activity has been suggested as a marker of hepatitis and hepatoma . Furthermore, such a high guanase activity is believed to be a biochemical indicator of rejection in liver transplant recipients . Increased levels of guanase have also been detected in cancerous kidney and breast cancer tissues . In addition, patients with multiple sclerosis exhibit significantly elevated levels of guanase activity in their cerebral spinal fluids . These observations suggest that a potent guanase inhibitor is necessary for exploring the biochemical mechanisms of the above metabolic disorders as well to understand the specific physiological role played by guanase, not to mention its potential therapeutic use in treating these disorders. While many studies on guanase inhibition have been reported in the literature, including our own , a potent guanase inhibitor with a submicromolar Ki has yet to be realized. Guanase catalyzes the hydrolysis of guanine 85 to xanthine 87 (Scheme 20) via the tetrahedral intermediate 86 (Scheme 20 ). The X-ray crystal structure of GDA from Bacillus subtilis suggested that the enzyme-catalyzed reaction is assisted by an active site zinc ion (Zn+2) as in ADA, leading to the speculation that the known GDA inhibitor such as azepinomycin 88 may act like a transition state mimic just as coformycins do in case of ADA inhibition described earlier. However, only a moderate inhibition of guanase by 88 has been reported , which suggested somewhat weaker binding of the inhibitor to the enzyme via zinc metal coordination. We hypothesized that this might be due to possible facile elimination of the crucial OH group of 88 as water, assisted by the anchimeric ring NH group. Therefore moving the OH group one carbon away from the ring, as in 89, would alleviate this problem. We further hypothesized that the introduction of a carbonyl group at position-5 of


51

the heterocycle, coupled with the presence of a hydroxymethyl group at position-6, as in 89, would allow excellent coordination of the inhibitor with Zn+2 to form a stable, 6-membered ring structure as shown. The latter would use two of the four metal coordination sites, while the other two would be occupied by two of the three original amino acid residues at the enzyme active site. With this rationale, we synthesized 89 (Scheme 21), starting from 32. O 1 HN 2 H2N

O 6 5

3 N

7 N

N H

N H

O

Guanine (85)

Xanthine (87) H2O

GDA

N

HN 8

9 N 4 H

- NH3 O Cys-83

Cys-86

N

HN

+2

Zn

O

H His-53

N H

H2N

N H

(86)

O O

O

1

1

NH

N

6

N OH H

N H

N H

88

Scheme 20

2

8

NH 7

OH

6

3

N H

N

4

N H

89

H

5

O

2

8

NH 7

OH

6 3

N H

4

N H

H

5

O

89-Zn+2 Complex

Zn+2

R.S. Hosmane

52 O

O N

HO

(1) N

N

O N N

EtO O

(2) H2N-CH(CO2Et)2 N CH2Ph 96%

O2N 32

O

OEt O N

N H

Pd-C/MeOH

90

7

O

8

1

N 2

6

N CH2Ph

H2N

82%

HN

N

N H

H2

N CH2Ph

O2N

O

OEt O

EtO

HO

5

O

91

1) NaH/THF -78 C

N3 H

N4 H

89 NaOR/ROH R = Et or Me

69-70%

Pd(OH)2 AcOH/40 psi

63%

2) Br2

O O

O N

EtO EtO

N

O 2N

O

95

OEt

N PhCH2

- HBr

O O

Br O

N H

7

O

N

OEt O2 N 94

RO

N

HN

8

1

N 2

6 5

O

CH2Ph

LiBH4/THF Super Hydride 0 oC-reflux

N3 CH2Ph

N4 H

H N

EtO MeO EtO O

O2N 96

O O Pd-C (10%) / H2 H N N MeOH EtO MeO N 90% EtO H2N O CH2Ph 97

2 5

N4 H

O

51%

1

N

LiBH4/THF Super Hydride 0 oC-reflux 42% O

O N

NaOMe / MeOH

N

26%

N3 CH2Ph

93

MeOH

O

O

8

6

92 a; R=Et b; R=Me

88%

HO

O 7

HN

HN

MeO MeO2C O

N H

CH2Ph 98

N

Pd(OH)2

N

AcOH

CH2Ph 85%

HN

MeO MeO2C O

N N H

N H

99

Scheme 21 The target 89, along with 93 and 99, were screened against rabbit liver guanase, and were found to possess Ki values of 5.36±0.14 x 10-5 M, 2.01±0.16 M, and 5.4 x 10-4 M, respectively. The values are roughly comparable to the reported IC50 value of 0.5 x 10-5 M for azepinomycin. Further SAR studies are currently in progress in order to enhance the potency without compromising the reversible enzyme binding characteristics of these compounds. 2.4.3. Dual Inhibition of Adenosine Deaminase (ADA) and Guanine Deaminase (GDA) The planar, aromatic heterocycle 37 was of interest for exploration of tautomeric equilibria especially when converted into its nucleoside analogue, as one of the three amino groups would necessarily exist as an imino functionality. Depending upon which one of the three amino groups would assume an imino structure, the nucleoside analogue 100 (Scheme 22) can mimic adenosine, guanosine or iso-guanosine. To resolve this issue, we labeled all three nitrogen atoms of guanidine with N15 and carried out the condensation with 4,5-dicyanoimidazole 39 to obtain the triply labeled 37* . The latter, upon standard Vorbrüggen ribosylation provided the triply labeled 100. The 15N NMR of 100 showed two singlets at ~211 δ (ppm) corresponding to the two labeled ring nitrogen atoms and one triplet (J *N-H= 80 Hz) in the 120-123 δ region corresponding to the labeled exonuclear NH2 group, suggesting that the molecule exists as 100a or 100b or as an equilibrium mixture of the two, but never as 100c. The possible existence of both adenosine- and guanosine-like tautomers in solution for 100 gave rise


53

to the notion that it might be possible to design an inhibitor that could simultaneously inhibit both ADA and GDA. But there was an important difference in substrate requirements of the two enzymes that needed to be reconciled. While the natural substrate for ADA is a nucleoside adenosine, that for GDA is a heterocyclic base guanine. In order to circumvent this problem, we decided to attach an acyclic sugar moiety to 37. Synthesis of such an acyclic nucleoside 107 is outlined in Scheme 23 . Both nucleoside 100 and acyclic nucleoside 107 were bichemically assayed, as before, against both ADA and GDA, and as anticipated, nucleoside 100 was found to be a competitive inhibitor of ADA (Ki = 3.85 x 10-5 M), but not GDA, whereas acyclic nucleoside 107 was found to be a competitive inhibitor of both ADA (Ki = 1.52±0.34 x 10-4 M) and GDA (Ki = 2.97±0.25 x 10-5 M) . NH2 CN

N

N*H

MaOMe

+ H2N*

CN

N*

N

(1) Vorbruggen Ribosylation

H2N*

N*H2 MeOH/heat

N

N*

N H

O OAc

BzO

NH2

39

+

37*

BzO

O-TMS F3 C

N-TMS

OBz

(2) NaOMe/MeOH (3) H3O+

H2N

HN

* N *NH2

N

H2N

* N *NH2

N

N* N

N

N NH

NH2

NH2 O

O HO

HO OH HO 100a

Scheme 22

OH

OH HO

HO

(Adenosine-like)

*NH N*

N*

O HO

* N

N

100b (Guanosine-like)

100c (Iso-Giuanosine-like)

R.S. Hosmane

54 O O

O

HCl

PhCH2OCH2CH2OH

PhCH2OCH2CH2OCH2Cl ClCH2CH2Cl

101 O CH 3 C O B r

+

102

0 oC C H 3C OO C H 2 C H 2O C H 2 B r

O

104

103 NH2 N

OTMS 1).

N

H2 N N

C F 3C

NH2

NTMS

N

N

2).

N H2

P hC H2O C H2 CH 2 O CH 2C l

.

N

H2 N

H S O 3C F 3

N

N

T M S t r i f l a te

O

NH

37

105

TMS triflate

1).

OTMS CF3C NTMS

2).

C H 3C O O C H 2C H 2O C H 2 B r

OCH2Ph Pd C/H2

MeOH

AcOH

NH2 N

N

H2N

.HSO3CF3 N

N NH 106

NH2

H3O+

N

N

H2N N

O

N NH

OCOCH3

. HSO3CF3

107

O OH

Scheme 23

2.4.4. Polynucleotide Phosphorylase Polynucleotide phosphorylase from E. coli is a primer-independent polymerase that converts any nucleoside 5'-diphosphates into the corresponding homopolymers in the presence of Mn+2 . With no requirement for a primer, it was obviously an attractive enzyme for synthesis of ‘fat’ polymers from ring-expanded nucleotides for exploration of some fundamental biophysical properties of nucleic acids, in particular the spatial and conformational constraints for formation of nucleic acid double helices as well as the factors governing their helical structure, stability and conformation. Also, in light of the long-suspected correlation between conformational properties of nucleosides and their observed biological activities, systematic studies continue to be warranted for exploring the little understood interrelationships of nucleoside base-sugar conformations, sugar pucker, ease of in vivo phosphorylation, enzymic polymerization, and biological activity. To this end, we synthesized two ring-expanded nucleoside (REN) analogues 113 and 116, containing the imidazo[4,5e][1,4]diazepine ring system (Scheme 24) . The heterocyclic bases of both RENs were anticipated to be non-planar and non-aromatic but with opposite base-sugar conformations, 113:syn and 116:anti, and thus were considered to be good probes for the intended biophysical evaluations. When the above two target nucleosides 113 and 116 were screened against murine leukemia virus (MuLV) in tissue culture systems, 116 showed potent antiviral activity with an IC50 (inhibitory concentration of the compound required to reduce the viral pathogenicity by 50%) in micromolar range, while 113 was totally devoid of activity . This interesting


55

biological result further elevated our interest in the biophysical properties of these isomeric nucleoside analogues. The single-crystal X-ray structure analysis of the two nucleosides (Figure 3) revealed that the sugar of 113 existed in a syn orientation as dictated by a strong hydrogen bond between the bottom NH of the 7-membered ring the 5'-O of the sugar ring, while the sugar orientation of 113 was anti. This led to a speculation that if the compounds existed in the same preferred conformation in solution, 113 would be less prone to phosphorylation in vivo than 116 since kinases, the enzymes responsible for in vivo phosphorylation of nucleosides to nucleotides, are known to prefer anti orientation . So, if the actual reactive species in vivo is a nucleotide, that would explain the difference in observed biological activities of the two nucleosides. In an attempt to throw more light on the subject, we first investigated the solution conformations of the two RENs using the 1H NMRbased Nuclear Overhauser Effect (NOE) and Circular Dichroism studies . The observed NOE between the imidazole H-2 and the sugar H-1' of 113 was >35% suggesting a highly syn base-sugar conformation, while the same in 116 was 0% consistent with an anti conformation favored by kinases. O

O

HO

N

O2N

SOCl2

N

O 2N

N H

NH2CH2CO2Me

N H

HN

N

O

109

108

O

O

Cl

O2N OMe 110a

N H

O

N

N O2N H OMe 110b

O Baddilly Method

1. AgNO3 2. O Cl BzO OBz BzO 111

MeO

O

N H O O2N

HN

1. PtO2/H2 2. NaOMe

N

N

N

N H

O

112 O BzO

HO

OBz

OH (Syn)

BzO O2N

O

114

MeO

N H 115

113 O

Ribosylation

1. HMDS/CTMS 2. CF3CO2H 3. OAc O Vorbruggen BzO Method OBz BzO

N

HO H

O

N

N

1. PtO2/H2 2. NaOMe

N

N HN

N

O O

O OBz

116 O

(Anti)

BzO OBz

OH HO OH

Scheme 24

56

R.S. Hosmane

Figure 3: Single-crystal X-ray structures of ring-expanded nucleosides 113 and 116 To confirm that the syn/anti conformation indeed plays a role in the observed biological activity, we decided to eliminate the H-bond responsible for the syn conformation by synthesizing the N8methyl derivative of 113, anticipating that the bulky methyl group would not only remove the Hbonding but would also force the conformation to become predominantly anti. The synthesis of the N8-methyl derivative (120) is outlined in Scheme 25 . Indeed, when 120 was assayed against MuLV as before, its antiviral activity was even slightly better than that of 116, thus corroborating the speculated correlation between conformation and biological activity.


O

O

O

O HN

N N

N H

HN

[(i -pr)2SiCl]2O -

DMF/Imidazole

N

HN

HMDS/(NH4)2SO4

N

N H

O

HO

O OSi(Me)3

OH O

O Si O

Syn

O

117

O

OH

Si

Si

O

O NaH/CH3I

HN

Me

118

Si

O N

N O

N

N H

O

OH 113

N

O

O

57

+ -

(n-Bu)4N F

HN

N

N

N O

O

N

Me

O OH

O

(Me)3SiO

119

HO

Si

O Si

O

OH 120 Anti

Scheme 25 We then proceeded to evaluate the difference in conformational features of the nucleic acid homopolymers derived from the two isomeric RENs. To this end, we chemically synthesized the necessary 5'-diphosphate derivatives of 113 and 116 employing standard phosphorylation procedures , and subjected the REN diphosphates 113-DP and 116-DP to polymerization with E.coli polynucleotide phosphorylase in the presence of Mn+2 to form the corresponding homopolymers poly[113-MP] and poly[116-MP] (Scheme 26) . Both diphosphates were found to be substrates for the enzyme, although the yield of the homopolymer obtained from the syn isomer was nearly 50% less than from the anti isomer. The extent of polymerization was determined by (a) the assessment of the inorganic phosphate release from the polymerization reaction, (b) the UV absorbance of the extensively dialyzed product, and (c) determination of the lengths of the homopolymers by gel electrophoresis which indicated polymerization in the 50-mer range . The secondary structures of the homopolymers were determined by UV and CD spectral measurements . A considerable hyperchromic effect was observed upon increase in temperature with the homopolymer poly[116-MP] obtained by the anti isomer, suggesting that it possesses significant secondary structure. In the presence of stoichiometric amounts of spermine, a cation with +4 charge, this homopolymer displayed a very broad absorbance-temperature profile, with a Tm of ~40 ºC and hyperchromicity of ~30-35%, suggesting the presence of intrastrand secondary structure . By contrast, the results obtained with the homopolymer poly[113-MP] obtained from the syn isomer, gave little indication of secondary structure without spermine, and even with spermine, the observed Tm of ~28 ºC and hyperchromicity of 17% or less were considerably lower than those of poly[116-MP]. The CD spectra of the two homopolymers corroborated the above findings by exhibiting a significant Cotton effect only for poly[116-MP]

R.S. Hosmane

58

with a maximum at 283 nm, crossover at 271, and a minimum at 260 nm . Upon addition of a stoichiometric level of spermine, there was a further change in the spectrum with a doubling of the absolute value of the minimum, suggesting a helical structure. By contrast, poly[113-MP] exhibited neither the Cotton effect nor noticeable spectral perturbation upon addition of spermine . POCl3/P(O)(OMe)3

1. Morpholine REN-MP

REN (113 or 116)

REN-DP 2. P(O)(OH)2O- NH+ (n-Bu)3

O

O

HN N N H

O O -

O P

O O

O-

O

Phosphorylase O Mn+2

N

N H

N

N H

O

N

O

O OH

O

P

N

O

OH

O

REN 113-DP

N H

O

O

OH

HO

N

O

O OH

-

HN

N

O

O

O

HN

N

Polynucleotide

O

P

O

HN

O P

O-

P

O-

O

(Syn)

O-

O

n Poly (REN 113-MP)

H

O

H

O

O O

O O P

HO

HN

OH

O-

P O

HN

N

N N HN

N O O

O

REN 116-DP

O

O HO

O

O

O

P

P -

O O

HO

HO

N O

O -

O-

H

N

O O

O

O

N

Phosphorylase Mn+2

N

H N

Polynucleotide

N HN

O

N

N

-

O

O

P O

-

n

(Anti)

O

O

Poly (REN 116-MP)

Scheme 26

2.5.

BIOLOGICAL ACTIVITY

RENs and RENTs, and some of their heterocyclic aglycons turned out to be a goldmine of antiviral and anticancer agents . A host of RENs exhibited potent in vitro broad-spectrum antiviral activity (Table I) against a dozen different viruses , including the hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV),


59

respiratory syncytial virus (RSV), herpes simplex virus types 1 and 2 (HSV-1 & HSV-2), measles virus (MV), rhino virus (RV), influenza A & B viruses (IAV & IBV), Japanese encephalitis virus (JEV), West Nile virus (WNV), severe acute respiratory syndroma (SARS) corona virus, and human immunodeficiency virus (HIV). Table 1: Antiviral Activity of Some Representative RENS REN Structure Virus Antiviral REN Structure Activity (μM) O

Antiviral Activity (μM)

HSV

*EC50= 1.4 SI > 200

Rhino

EC50= 0.20 SI >500

NH2

Measles

EC50= 0.50 SI > 200

NH2

Influenza B

EC50= 65 SI > 150

WNV

EC50=0.51 SI > 195

O

N

NH

N

N

NH2

O

Virus

HBV

*EC50= 0.13 SI > 18,500

N

NH

N

N

NH2

O

HO

121

126

O

O

O P

OH

ONa

NaO HO

O

O NH

N

NH2 N

EBV

N

O HO

NH

N

N

NHCH2CH3

EC50= 8.8 SI > 193

O

N

O

O

127

HO

122

OH HO

HO O

O NH

N

NHPh N

N

O

RSV

O

EC50= 0.10 SI > 1000

NH

N

N

O

123

HO

N

O

HO

128

OH

OH HO

HO O

O NH

N

NH(CH2)11CH3 N

VZV

N

O

O

124

HO

EC50= 2.5 SI >100

N

NH

N

N

O O

OH

PhCH2O

HO

129

O N

NH

N

N

O

O

HO

125

H

HO

NH(CH2)17CH3

HCV

O

EC50= 18 SI > 35

O NH

N

NH(CH2)9CH3

HO N

N

OH

O

130

HO

*EC50=effective concentration of the compound to reduce viral pathogenicity by 50%; SI=selectivity index=ratio of cytotoxic concentration of the compound to kill 50% of the normal cells to that required to kill 50% of the viral cells RENs have also exhibited potent in vitro anticancer activity against 50 different human tumor cell lines, a few of which are listed in Table II, including but not limited to those of the tumors of the breast, lung, prostate, colon, kidney, CNS, skin, ovary, and leukemia. Table 2: Anticancer Activity of Some Representative RENS

R.S. Hosmane

60

REN Structure

H 2N N

N

NH2 N

N

O

HN

100

HO OH HO

O

H N

N

NH N

NH

O

O

132

HO OH HO

O NH

N

NH(CH2)17CH3 N

N

O

O

134

HO OH HO

H

HO

O

O N

NH

N

N

NH(CH2)17CH3

HO

136

O

Tumor (Cell Line)

Antitumor Activity (GI50)* μM

Leukemia (CCRF-CEM) Lung (non-SC) (A549/ATCC) Colon (Colo 205) CNS (SF-295) Melanoma (M14) Ovarian (IGROV1) Renal (UO-31) Prostate (PC-3/Du-45) Breast (MCF-7) Leukemia (K-562) Lung (non-SC) (HOP-62)) Colon (Colo 205) CNS (SF-295) Melanoma (M14) Ovarian (IGROV1) Renal (UO-31) Prostate (PC-3/Du-45) Breast (MCF-7) Lung (non-SC) (A549) (H-460) Breast (MCF-7) Prostate (PC-3) Lung (non-SC) (A549) (H-460) Breast (MCF-7) Prostate (PC-3)

0.12

REN Structure

6.44 1.49

H2N

6.03

N

N

N

N

NH2

1.91

O

HN

Ph(O)CO

131 OC(O)Ph

5.13

Ph(O)CO

6.4 4.46/8.79 1.47 1.79 0.41 1.20

O

H N

N

1.02

NH N

1.81

NH

O

O

Ph(O)CO

133

OC(O)Ph

3.59 Ph(O)CO

5.54 1.61/8.83 1.46 O

4.30 3.0

N

NH

N

N

NH(CH2)17CH3

O

O

HO

135

5.5 HO

3.5 IC50 (μM) 9.1 6.5 19 0.8

H2N N

N

N

N

NH(CH2)17CH3

H2N

37

Tumor (Cell Line)

Antitum or Activity (GI50)* μM

Leukemia (CCRF-CEM) Lung (non-SC) (A549/ATCC) Colon (Colo 205) CNS (SF-295) Melanoma (M14) Ovarian (IGROV1) Renal (UO-31) Prostate (Du-45) Breast (MCF-7) Leukemia (CCRF-CEM) Lung (non-SC) (HOP-92) Colon (Colo 205) CNS (SF-295) Melanoma (M14) Ovarian (IGROV1) Renal (UO-31) Prostate (PC-3/Du-45) Breast (MCF-7) Lung (non-SC) (A549) (H-460) Breast (MCF-7) Prostate (PC-3) Lung (non-SC) (A549) (H-460) Breast (MCF-7) Prostate (PC-3)

2.49 3.43 4.43 1.67 1.71 3.61 6.99 3.05 1.79 1.32 < 0.01 3.78 3.38 6.79 3.54 4.0 2.25/4.01 3.99

2.0 1.5 2.5 2.0 IC50 (μM) 1.70 1.45 2.15 2.01

Ring-Expanded (‘Fat’) Purines and their Nucleoside/Nucleotide Analogues as Broad-Spectrum Therapeutics Ovarian (OVCAR-3)

61

1.17

*GI50=concentration of the compound required to reduce the tumor growth by 50% In view of the observed broad spectrum antiviral and anticancer activities of RENs as listed in Tables 1 and 2, exploring their mechanism of biological activity became an instant interest. To this end, we decided to focus on a few important viruses and cancers using representative RENs. Our mechanistic efforts in the cancer area predominantly involved breast and prostate cancers , the leading causes of cancer mortality in American females and males , respectively. Mechanistic investigations in the viral area mainly targeted flavi viruses, including the hepatitis C (HCV), West Nile (WNV) and Japanese encephalitis (JEV) viruses, and to some extent on hepatitis B (HBV) and human immunodeficiency (HIV) viruses . These are the viruses of current global health priority . With regard to prostate cancer, we explored the in vitro biological effects of RENs 100 and 131 (the latter is perceived to be a prodrug of the former) (see Table 2) in two androgenindependent human prostate cancer cell lines, PC-3 and DU-145 . The studies concentrated on exploring the dose-dependent induction of apoptosis (programmed cell death) in treated cancer cells. The dose response profile of the cytotoxic effects of nucleosides against human prostate cancer cells was investigated. Specifically, PC-3 and DU-145 cells were each treated with increasing concentrations of 100 or 131 (0 - 50 μM) for 2 days, and the cell viability was determined using the Trypan Blue Exclusion assay . The results in each case indicated that the treatment of exponentially growing culture of cells with 100 or 131 for two days leads to marked loss of cell viability in a dose-dependent manner. We further investigated the time course of cytotoxicity of 100 and 131 against androgen-independent prostate cancer cells. After 6 days of treatment of PC-3 and DU-145 cells each with 30 μM concentrations of 100 or 131, ∼98% cell killing was observed . In an attempt to understand the potent anti-breast cancer activity of RENs 100 and 131 in MCF-7 cells (see Table 2), we discovered that these compounds stop cell proliferation, while not seemingly reducing the cell number in treated cultures . We performed further mechanistic studies using the prodrug 131 and found that the compound significantly decreases both RNA and DNA synthesis in MCF-7 cells (see Figures 4 and 5) . It strongly inhibits the cell proliferation, whereas the cell growth assays demonstrated that 131 (MB-1) only slightly decreased the cell number after incubation for either 6 or 24 hours with the compound. The decrease was equivalent to that observed when the cells were incubated with the IC50 concentration for Ara-C. Regardless of the exposure time, combining Ara-C with 131 (10 μM) does not enhance the cell killing, which suggested that both Ara-C and 131 act on the same mechanistic pathway . The observed inhibition of both RNA and DNA synthesis by REN 131 pointed to some intriguing possibilities for its mechanism of action including, but not limited to, (a) it could be phosphorylated in vivo by kinases to its 5'-triphosphate derivative, and subsequently incorporated into nucleic acids during transcription of a DNA/RNA template by a polymerase, and cause double-helical distortion, ultimately leading to chain termination, (b) 131 could bind to an active or allosteric site of the polymerase, either as a nucleoside or nucleotide, and cause competitive or non-competitive inhibition.

62

R.S. Hosmane

Figure 5 (left): Effect of REN 131on MCF-7 cell RNA synthesis. Figure 6 (right): Effect of REN 131 on MCF-7 cell DNA synthesis. MCF-7 cells (5 x 104) were seeded onto 60 mm cell culture plates in Dulbecco’s Modified Eagle’s Medium (DMEM) with 10% FBS. The cells growing in log-phase were exposed to increasing concentrations of 131 for 24 hours at 37 ºC. The cells were then labeled with [3H] thymidine (1 μCi/mL of medium) and incubated for 4 hours. The cells were lysed by 0.1% SDS/PBS and and the level of RNA/DNA synthesis was determined by quantifying the amount of [3H] thymidine present in RNA/DNA by liquid scintillation counting. In order to throw more light on the above subject, we chemically converted 100 (the reactive species of 131 in vivo) to its 5'-triphosphate derivative 137 (Scheme 27), and biochemically screened for inhibition of nucleic acid polymerase activity, employing synthetic DNA oligonucleotide templates and the bacteriophage T7 RNA polymerase as a representative Polymerase . Our results suggest that 137 is a moderate inhibitor of T7 RNA polymerase, and that the 5'-triphosphate moiety of 137 appears to be essential for inhibition as nucleoside 100 alone failed to inhibit the polymerase reaction . Our mechanistic explorations in the viral field largely focused on Flaviviridae, including HCV, WNV, and JEV. We have discovered that the mechanism of action of this family of viruses involves inhibition of viral NTPase/helicase . Helicases are responsible for unwinding duplex RNA and DNA structures by disrupting the hydrogen bonds that keep the two strands together . This process is dependent upon the necessary energy released by hydrolysis of a molecule of nucleoside-5'-triphosphate (NTP) such as ATP or GTP . Our studies pointed to the existence of an allosteric binding site on the viral NTPases/helicases that can be occupied by nucleoside/nucleotide-type molecules such as RENs and inhibit the viral helicase activity . We also found that at low ATP concentrations, the REN-5'-triphosphates bind to the enzyme’s NTP binding site and competitively inhibit the viral NTPase activity . For example, at an ATP concentration equal to 1 x 10-5 KM value of the enzyme, the REN-triphosphate 137 inhibited the WNV NTPase reaction with an IC50 value of 0.15 μM .


63

H2 N

H2 N N

N

NH2 N O

N HN

N

N

N

NH2

(1) POCl3/(OMe)3PO +

(2) (n-Bu)3N/DMF/[(n-Bu)3NH ]2[H2P2O7]

-O

(3) NaI/acetone

HO

NaO

O

P

O

OH OH

100

HO

N

P OH

O O

P

O

OH

137

OH HO

RNA Transcript

17-mer Primer

37-mer DNA Template

HN

O

T7 RNA Polymerase

RNA-DNA Hybrid

Scheme 27 Recently, we have discovered that a number of RENs inhibit both HIV and HCV . The leading RENs in this regard are 135 and 136 (see Table 2), containing a long hydrophobic chain at position-6 of the heterocyclic ring, which practically wiped out the HIV replication in T cells and monocyte-derived macrophages in micromolar concentrations . They were found to potently inhibit the ATP dependent helicase activity of human RNA helicase DDX3 as well as NTPase/helicase activity of HCV . Furthermore, neither of the two RENs exhibited toxicity at therapeutic doses in ex vivo cell culture or in vivo in mice . The dual inhibition of HIV and HCV by RENs has important implications in treating HIV patients infected with HCV. A vast majority of such patients in the US and the Western hemisphere ultimately die of liver cirrhosis and liver carcinoma . This is because the currently available separate therapies for HIV and HCV have unfavorable drug interactions, which lead to exacerbation of both HCV and HIV. Therefore, the drugs that would act against both HCV and HIV are imminently needed, and so, dual-active RENs such as 135 and 136 have good prospects in this regard. RENs 100, 121, and 132 were found to be potent and selective inhibitors of replication of the hepatitis B virus (HBV) in cultured human hepatoblastoma 2.2.15 cells . The most active REN 121 inhibited the synthesis of intracellular HBV replication intermediates and extracellular virion release with 50% effective concentration (EC50) of 0.604 and 0.131μM, respectively, with selectivity indices of >18,500 and >4000, respectively . The toxicity of all three compounds was also measured in rapidly growing human foreskin fibroblast (HFF) cells and Daudi cells by cell proliferation assay. Once again, negligible or no toxicity was observed in both cells . It was also interesting to note that all three RENs, unlike the industrial standard 3TC (2',3'-dideoxy-L-3'-thiacytidine) used for anti-HBV activity, resulted in the reduction of viral protein synthesis, especially that of the core antigen .

2.6.

CONCLUSION

Ring-expanded heterocycles, nucleosides, and nucleotides possess excellent promise as broad-spectrum therapeutics against both cancers and viruses. The promising in vitro data, particularly against prostate and breast cancers, and against viruses, in particular HBV, HCV,

R.S. Hosmane

64

WNV, and HIV, support their further development as drug candidates via extensive animal and clinical studies. 2.7.

ACKNOWLEDGMENTS

This article is dedicated to Dr. Morris J. Robins, J. Rex Goates Professor of Chemistry, Brigham Young University, Provo, Utah on the occasion of his 70th birthday. I am indebted to all my past and present research colleagues whose excellent scientific contributions made writing this review article possible. I also acknowledge the support of the National Institutes of Health (Grant # 1R01 GM087738-01A1), Bethesda, Maryland, and Nabi Biopharmaceuticals, Rockville, Maryland, for unrestricted research grants for the past several years. 2.8.

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Ring-Expanded (‘Fat’) Purines and their Nucleoside/Nucleotide Analogues as Broad-Spectrum Therapeutics 90JMC2818 90JOC5882 90NN297 90NN913 90S1095 91BJC903 91NN1693 91NN819 92NN1137 92NN1175 92PR459 93AR1809 94NN2307 94TL6831 95NN325 95NN455 96BCT189 96JMC277 97AAC1686 97BBR88 97CI212 97H(45)857 97NN1053 98B11949 98B8314 98BMCL3649 98JV6758 98NN1141 98QXX119 98STR89 99BMC2931 99CCR65 99JBC8175 99NN835 99NN837 B-02MI133 B-04MI135 B-06MI103 B-07MI365 B-67MI287 B-67MI93 B-71MI57 B-74MI526 B-77MI130

67

J.W. Daly, I. Hide, P.K. Bridson, J. Med. Chem. 1990, 33, 2818. R.S. Hosmane, A. Bhan, R.L. Karpel Siriwardane, J. Org. Chem., 1990, 55, 5882. W. Saenger, Nucleosides Nucleotides 1990, 9, 297. R.S. Hosmane, A. Bhan, Nucleosides Nucleotides 1990, 9, 913. R.S. Hosmane, V.S. Bhadti, B.B. Lim, Synthesis 1990, 1095. C. Dearden, E. Matutes, D. Catovsky, Br. J. Cancer 1991, 64, 903. R.S. Hosmane, V.P. Vaidya, M.K. Chung, Nucleosides Nucleotides 1991, 10, 1693. R.S. Hosmane, A. Bhan, M. Hulce, H. Zhang, Nucleosides Nucleotides 1991, 10, 819. V.S. Bhadti, A. Bhan, R.S. Hosmane, Nucleosides Nucleotides 1992, 11, 1137. A. Bhan, R.S. Hosmane, Nucleosides Nucleotides 1992, 11, 1175. W.D. Klohs, A.J. Kraker, Pharmacol. Rev. 1992, 44, 459. U. Jehn, M. Gawaz, R. Grunewald, W. Hill, B. Lorenz, O. Stotzer, Anticancer Res 1993, 13, 1809. L. Wang, A. Bhan, R.S. Hosmane, Nucleosides Nucleotides 1994, 13, 2307. A. Bhan, R.S. Hosmane, Tetrahedron Letters 1994, 35, 6831. F.N. Burnett, B.B. Lim, R.S. Hosmane, Nucleosides Nucleotides 1995, 14, 325. A. Bhan, R.S. Hosmane, Nucleosides Nucleotides 1995, 14, 455. O. Canbolat, I. Durak, R. Cetin, M. Kavutcu, S. Demirci, S. Ozturk, Breast Cancer. Res. Treat. 1996, 37, 189. T.J. Marrone, T.P. Straatsma, J.M. Briggs, D.K. Wilson, F.A. Quiocho, J.A. McCammon, J. Med. Chem. 1996, 39, 277. A.E. Eakin, A. Guerra, P.J. Focia, J. Torres-Martinez, S.P. Craig, III, Antimicrob. Agents Chemother. 1997, 41, 1686. R.S. Hosmane, M. Hong, Biochem. Biophys. Res. Commun. 1997, 236, 88. I. Durak, Y. Beduk, M. Kavutcu, O. Suzer, O. Yaman, H.S. Ozturk, O. Canbolat, S. Ulutepe, Cancer Invest. 1997, 15, 212. F.N. Burnett, R.S. Hosmane, Heterocycles 1997, 45, 857. M. Hong, R.S. Hosmane, Nucleosides Nucleotides 1997, 16, 1053. W. Wang, L. Hedstrom, Biochemistry 1998, 37, 11949. Z. Wang, F.A. Quiocho, Biochemistry 1998, 37, 8314. V. Rajappan, R.S. Hosmane, Bioorg. Med. Chem. Lett., 1998, 8, 3649. P. Galinari, D. Brennan, C. Nardi, M. Brunetti, L. Tomei, C. Steinkühler, D.F. R., J. Virol 1998, 72, 6758. V.P. Rajappan, R.S. Hosmane, Nucleosides Nucleotides 1998, 17, 1141. J. Shi, X. Ma, Z. Yang, Qingdao Huagong Xueyuan Xuebao 1998, 19, 119. J.L. Kim, K.A. Morgenstern, J.P. Griffith, M.D. Dwyer, J.A. Thomson, M.A. Murcko, C. Lin, P.R. Caron, Structure (London) 1998, 6, 89. M. Bretner, D. Beckett, R.K. Sood, D.M. Baldisseri, Bioorg. Med. Chem., 1999, 7, 2931. P. Ribeiro, F. Bouaffia, P.Y. Peaud, M. Blanc, B. Salles, G. Salles, B. Coiffier, Cancer 1999, 85, 65. G. Yuan, J.C. Bin, D.J. McKay, F.F. Snyder, J. Biol. Chem. 1999, 274, 8175. V.P. Rajappan, R.S. Hosmane, Nucleosides Nucleotides 1999, 18, 835. M. Bretner, D. Beckett, R.S. Hosmane, Nucleosides Nucleotides 1999, 18, 837. R.S. Hosmane, In Modified Nucleosides: Synthesis and Applications; D. Loakes, Ed.; Research Signpost.: Trivandrum, India, 2002, p 133. R.S. Hosmane, In Kirk-Othmer Encyclopedia of Chemical Technology (5th Edition); A. Seidel, Ed.; John Wiley & Sons: New York, 2004; Vol. 3, p 135. L. Delort, In New Approaches in Nutrition and Cancer 2006, p 103. B.A. Fox, K. Chaudhary, D.J. Bzik, Nucleotides and amino acids, 2007. 365. N. Bargoni, Synthesis and catabolism of purine, 1967, 287. F.L. Rose, Purine Analogs and Related Heterocycles, 1967. 93. J.A. Mntgomery, Antimetabolites. Purines, 1971; Vol. 2, 57. P.O.P. Ts'o, In Basic Principles in Nucleic Acid Chemistry; P.O.P. Ts'o, Ed.; Academic Press: New York, 1974; Vol. 1, p 526. J.F. Henderson, Horiz. Biochem. Biophys. 1977, 4, 130.

68 B-78MI159

B-87MI269 B-87MI280 B-89MI B-99MI233

R.S. Hosmane R.P. Agarwal, S. Cha, G.W. Crabtree R.E. Parks, In Chemistry and Biology of Nucleosides and Nucleotides; R.E. Harmon, R.K. Robins, L.B. Townsend, Eds.; Academic Press: New York, 1978, p 159. W. Saenger, Principles of Nucleic Acid Structure, Pt. 1, 1987. 269 pp. W. Saenger, Principles of Nucleic Acid Structure, Pt. 2, 1987. 280 pp. B.B. Lim, Doctoral Dissertation, University of Maryland Graduate School, 1989. K. Yoon, J. Jendis K. Moelling, In Triple Helix Forming Oligonucleotides 1999, p 233.

69

Chapter 3

Three-Membered Ring Systems Stephen C. Bergmeier Department of Chemistry & Biochemistry, Ohio University, Athens, OH, USA [email protected] David J. Lapinsky Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA [email protected]

3.1

INTRODUCTION

This review covers the chemical literature on epoxides and aziridines for the year 2008. As in previous years, this review is not comprehensive but rather covers a selection of synthetically useful and interesting reactions. Three-membered ring systems, epoxides and aziridines in particular, are excellent synthetic intermediates. This is largely due to their ability to be converted into other functional groups such as diols, diamines, and amino alcohols to name but a few. The chapter has been divided into two sections, one covering epoxides and the other covering aziridines. Each of these sections has been further divided into two additional sections, one on the synthesis of the heterocycle and one on the reactions of the heterocycle. In addition to the usual coverage of epoxides and aziridines, a number of reports on the synthesis and reactions of azirines and oxaziridines are included as well. There is some overlap between methods for the synthesis of epoxides and aziridines and any overlap has been noted in the text.

3.2

EPOXIDES

3.2.1 Preparation of Epoxides The epoxide ring system continues to be one of the most studied heterocyclic ring systems. Its use in ring opening reactions for the synthesis of a variety of substituted alcohols as well as rearrangement reactions make the epoxide ring a highly useful reactive intermediate. Reviews on tandem ketone additions/epoxidation reactions and on the synthesis and reactions of Į-lithiated oxiranes have been reported in the past year. Several new methods for the epoxidation of olefins have been reported in the past year. A key aspect of these reports has been the development of milder and more selective


S.C. Bergmeier and D.J. Lapinsky

70

reaction conditions. Methyltrioxorhenium (MTO), among its many uses, has been shown to be an effective and mild epoxidation catalyst when using H2O2 as the primary oxidant . A very useful aspect of this method is the solvent free reaction conditions. A quinoline based Mo catalyst has been shown to be a useful epoxidation catalyst . Manganese continues to be a popular epoxidation metal. Ionic porphyrin 1 and tetradentate Mn catalyst 2 were both shown to be excellent epoxidation reagents. Both of these catalytic systems worked both with styrene as well as Į,ȕ-unsaturated ketones. It has also been reported that the use of a surfactant in a Jacobsentype epoxidation provides enhanced rate and moderately improved enantioselectivity . R

R conditions

R

R

R

R

R alkene cyclooctene

O

R

conditions

Yield 99%

0.1 mol% MTO, 35% H2O2, 10 mol% 3-methylpyrazole

styrene

97%

cyclooctene

1.7 mol% [PPh4][MoO(O2)2(QO)], 25 mol% NaHCO3, 300 mol% H2O2

73%

styrene

0.5 mol% 1, PhIO

96%

chalcone styrene

54% 0.1 mol% 2, 140 mol% CH3CO3H

91%

cyclohexene

99%

chalcone

88% NMe3 (HS(CH2)2CO2-)5 N N N

Me3N N

N

N Mn (III) N

NMe3

NMe3

Mn

OTf OTf

N 2

1

A very interesting epoxidation reaction using an oxaziridine derived from N-phosphonio imines has been described . The reaction of a catalytic amount of an Nphosphonio imine with oxone provides an oxaziridine intermediate which then carries out the epoxidation of an olefin. This reaction provides very useful levels of regioselectivity. For

Three-Membered Ring Systems

71

example the reaction with 1,4-hexadiene provided the epoxide resulting from reaction at the more substituted olefin in excellent yield. +

10 mol% Ph

N

P(OMe)3

O

200 mol% Oxone K2CO3 84%

A recent review details the use of chiral ketones and chiral iminium salts to catalyze asymmetric epoxidations . A new class of binaphthyl derived iminium ions have been shown to catalyze the epoxidation of styrene and 1,2-dihydronaphthalene with moderate enantioselectivity . A report on an exploration of substrate scope of Shi-type epoxidations has also been published . Shi-type catalysts for epoxidation provide generally poor enantioselectivity for 1,1disubstituted olefins. The use of ketone 3 as a catalyst in such epoxidations provides good yields and improved enantioselectivities with 1,1-disubstituted olefins . O

O

30 mol% 3, Oxone, 1,4-dioxane

O

O N O

O O

3

A variety of enantioselective epoxidation reactions of Į,ȕ-unsaturated ketones catalyzed by chiral amines have been reported. These include quinine 4 and azabicyclo[2.2.1]heptane 5 derived ligands, both of which provide good yields and good levels of enantioselectivity. The alkaloid N-oxide 6 is a new addition to the list of chiral epoxidation reagents . This reagent suffers from low yields and only moderate enantioselectivity. O R2

O

conditions

R1

alkene

R2

conditions

O R1 Yield

% ee

R1 = CH3, R2 = (CH2)2Ph

10 mol% 4, 120 mol% cumene hydroperoxide, 23 °C

88%

97% (3R,4S)

R1 = Ph, R2 = Ph

20 mol% 5, 130 mol% t-butyl hydroperoxide, 6 d

81%

88% (2S,3R)

R1 = Ph, R2 = Ph

200 mol% 6, 100 °C, n-PrCN

26%

82%

Ph

NH2

Ph OH

N N MeO

N H

O N

MeO H

5

MeO

N 6 O

4

H H

O


72

The asymmetric epoxidation of cyclic enones continues to be a problem without a general solution. A recent report on the use of a series of amine catalysts appears applicable to a relatively broad substrate scope . The use of the bisTFA salt of quinine, 7, provided excellent yields and enantioselectivity for a series of substituted cyclohexenones and cycloheptenones.

O

N

10 mol% 7 150 mol% H2O2 ( )n

NH2 •(TFA)2

O

( )n

R

N

O R MeO

n = 1, R = H, 58%, 97:3 n = 1, R = CH3, 70%, 98:2 n = 1, R = Bn, 78, 99:1 n = 2, R = Et, 82%, 99.5:0.5

7

The Darzens and related reactions continue to be useful methods for the synthesis of highly substituted epoxides. A recent report uses benzoyl phosphonates in a Darzens-type reaction to prepare epoxyphosphonates . These reactions provide the transepoxide as the major product, however prolonged treatment with DBU provided the cisepoxide. The reaction of 2-(p-tolylsulfinyl)carbanions with ketones has been shown to be an effective route to highly substituted epoxides . Deprotonation of 8 followed by addition to a ketone leads to a highly diastereoselective addition reaction (>98%). Cyclization of the resulting alkoxide provides excellent yields of the corresponding epoxides. The sulfinyl group can be subsequently removed by treatment with t-BuLi. O

O S

S Tol

O

Tol I

R1

NaHMDS -78 °C, 1 min

R2

O

R1

H

8

R2

Substitution

Yield

Ratio E:Z

R1 = Ph, R2 = Me R1 = i-Pr, R2 = Me R1/R2 = -(CH2)4-

73% 87% 46%

86:14 98:2 -

Rearrangement reactions of alkynyl epoxides continue to be of interest, but the synthesis of the necessary alkynyl epoxides is not always straightforward. The reaction of alkynyl halides with ketones allowed for a facile synthesis of alkynyl epoxides . The reaction is believed to proceed via an initial Į-halogenation of the ketone followed by addition of the alkynyl anion to the ketone, which then leads to the observed alkynyl epoxide via Darzens type reaction. O Ph

R +

Br

R

O

NaOt-Bu Ph

R = Ph, 92% R = n-Bu, 73% R = Et3Si, 42%


73

A mechanistically related approach for the synthesis of epoxides is the use of sulfur ylides. An epoxy annulation reaction for the synthesis of 3,4-epoxypyrrolidines was reported using this strategy . An interesting variation on this theme is a 3-component approach for the synthesis of epoxides and aziridines . The addition of a nucleophile to the vinyl sulfonium salt, in the presence of base, generates an initial sulfur ylide which then reacts with an aldehyde to provide the epoxide. A variety of nucleophiles including amines, thiols, alcohols and malonates, as well as both aromatic and aliphatic aldehydes are viable reaction partners. The yields range from excellent to modest but provide an approximately 1:1 mixture of the cis- and trans-epoxides. Along these same lines, a tandem Michael addition-ylide epoxidation strategy was reported for the synthesis of fused-ring epoxides . O +

NuH

SPh2 + R

Nu R = Ph, Nu = NMeTs, 87% yield R = n-Bu, Nu = NMeTs, 45% yield R = Ph, Nu = SPh, 59% yield R = Ph, Nu = OBn, 77% yield

O

KOt-Bu H

R

Many asymmetric sulfur ylide-based epoxidations use some type of chiral auxiliary. A sulfur ylide approach for epoxide synthesis using chiral catalyst 9 has been reported in the past year . The use of the phosphine oxide 8 and the choice of metal in the chiral ligand proved crucial in obtaining high levels of enantioselectivity. O Ph

CH3

O + H2C S(CH3)2

H3C 5 mol% 8 5 mol% 9 Ph 98%, 96% ee OMe MeO

O

Li O O O = (S)-BINOL La Li HO OH O O O Li 9

PO 3

8

3.2.2

OMe

Reactions of Epoxides

The primary type of epoxide reaction remains the nucleophilic ring-opening reaction. Many of these studies focus on improving regioselectivity and determining milder reaction conditions. A number of interesting developments in the ring opening reaction of epoxides with oxygen nucleophiles have been reported in the past year. Among these is the use of NH2NH2•H2SO4 as a catalyst for opening epoxides with alcohols . This catalyst provides excellent regioselectivity for unsymmetrical epoxides. The reaction of epoxides with a variety of nucleophiles, including H2O, and aniline proceeded in excellent yields when the reaction was carried out in water . The reaction of cyclohexene oxide in water at 60 °C provided an 89% yield of the trans-diol. In addition to the use of water as the nucleophile, this reaction medium can be used for the intramolecular reaction of epoxides with alcohols as shown below. This reaction appears to be another example of the


74

acceleration of an organic reaction in an aqueous media. It is worth noting that this general water mediated reaction works well for aziridines as well as epoxides.

O HO

1) H2O, 60 °C 2) Ac2O 98%

AcO

O H

The intramolecular reaction of an epoxide with an alcohol has been shown to proceed via a 5-endo or a 6-endo pathway depending upon the catalyst used . Reaction of the epoxide with n-Bu4NF in AcOH/H2O, followed by treatment with camphorsulfonic acid provided the coumarin as a 30:1 mixture of trans- and cis-isomers. Alternatively, treatment of the epoxide with just n-Bu4NF provided the dihydrobenzofuran in excellent yield. OBn 1) n-Bu4NF, AcOH, H2O 2) CSA 61% (two steps)

OTBS

O

OBn OBn

n-Bu4NF THF 85%

OBn

BnO

OBn

OBn OBn

O

O

OBn OH

OH

The direct conversion of an epoxide to an acetal is useful as a single step hydrolysis and protection method. Two recent reports use a metal catalyst to effect this transformation. The reaction of styrene oxide with MoO2Cl2 in acetone provides the corresponding acetal in excellent yield . This catalytic system is also useful for the conversion of epoxides to alkoxyalcohols and alkoxyesters. FeCl3 has also been reported to catalyze the same reaction . This method is reported to provide mixtures of isomers and is believed to proceed through an SN1-type mechanism. Both reactions work well with a variety of substrates including both aliphatic and aromatic epoxides.

O

O conditions

O Ph

Ph Conditions

Yield

acetone, 5 mol% MoO2Cl2, 91%

91%

acetone, 5 mol% FeCl3, 92%

92%

Selenium nucleophiles are not common in the ring opening reactions of epoxides. Two recent publications detail methods for the synthesis of ȕ-hydroxy selenides from epoxides. The reaction of PhSeH with stilbene oxide and catalyst 10 yields the ȕ-hydroxy selenide in good yield and with 93% ee . Interestingly when phenyl substituted stilbene oxides are subjected to the same reaction conditions, the reduction product is the major product, proceeding again with excellent enantioselectivity. The use of PhSe-SiMe2t-Bu with


75

a Salen-Cr catalyst also provides good yields of the ring-opened product with good enantioselectivity . With this catalytic system, reduction is not observed when the aromatic rings of the epoxide are similarly substituted.

Ar

OH

OH

O

SePh

Ar

Ar

Ar Ar

Ar Substitution, Yield

Conditions PhSeH, 10 mol% 10

Ar = Ph, 77%, 93% ee Ar = 4-Br-C6H4, 64%, 92% ee

PhSeSiMe2t-Bu, 5 mol% SalenCr•BF4

Ar = Ph, 92%, 92% ee Ar = 4-Br-C6H4, 53%, 72% ee

N

N

t-Bu

t-Bu HO

OH 10

The reaction of epoxides with thiols provides a useful route for the synthesis of hydroxy sulfides. New catalysts for this type of ring opening are always of interest. The use of 10 mol% of borax to catalyze the ring opening of aliphatic epoxides with aryl amines has been shown to be an effective route to the ring opened product . The use of amines to open epoxides is a useful and well-studied route for the synthesis of 1,2-aminoalcohols, an important class of compounds. A variety of new Lewis acid catalysts have been reported in the past year. The use of Bi(OTf)3•4(H2O) in a solvent free system provides excellent yields of the corresponding aminoalcohols . An Al2O3 supported Zn catalyst has been used to prepare aminoalcohols as has a vanadium catalyst with chiral ligand 11 . O

conditions

OH NR2

Conditions

Amine, Yield

1 mol% Bi(OTf)3•4(H2O), μW, 160 °C, neat

cyclohexyl amine, 90% morpholine, 93%

10 mol% Zn(ClO4)2•Al2O3, CH2Cl2

PhNH2, 93% n-BuNH2, 87%

10 mol% VO(Oi-Pr)3, 15 mol% 11

PhNH2, 84%, 62% ee

Me

Me N

N

OH HO 11

A common issue in the ring opening reactions of aryl epoxides is the regiochemistry of nucleophilic attack. With a typical aliphatic epoxide, nucleophiles usually add to the less sterically encumbered carbon of the epoxide. With aryl epoxides, many nucleophiles add to the benzylic position (e.g. 13). The use of Sn(OTf)2 in a solvent free reaction provided


76

generally good yields but a 69:31 mixture of 12 : 13 with pyrrolidine as the nucleophile . This product ratio changes to 0:100, 12 : 13 when an aryl amine (e.g. aniline) is used. Er(OTf)3 in water provides a similar mix of regioisomers with the difference being a much better product distribution (96:4) when an aliphatic amine was used . Y(NO3)3•6(H2O) provides similar yields and product distributions; however an unusual amine, pyrazole gave an excellent yield of product but only a 41:59 ratio of regioisomers . O

NR2

OH

conditions

Ph

NR2

Ph

OH

Ph 13

12 Conditions

Amine, Yield, Ratio 12:13

10 mol% Sn(OTf)2

pyrrolidine, 99%, 25:75 PhNH2, 92%, 0:100

5 mol% Er(OTf)3, H2O

morpholine, 95%, 96:4 PhNH2, 95%, 15:85

1 mol% Y(NO3)3•6(H2O), neat

PhNH2, 81%, 16:84 pyrazole, 92%, 41:59

The large-scale synthesis of (S)-2-hydroxymethyl morpholine from a ring opening/ring closing process has been reported . This reaction involves an initial epoxide ring opening of (S)-epichlorohydrin by N-benzyl ethanolamine. The epoxide is then regenerated and then opened by reaction with the free hydroxyl. A one-pot conversion of an aryl epoxide to an N-alkyl indole has been reported . This transformation proceeds via an epoxide ring opening by an N-alkyl amine followed by an N-arylation and elimination. A very interesting redox reaction of an epoxyaldehyde has been used to prepare 1,2aminoalcohols and the corresponding oxazolidinones . Treatment of an epoxyaldehyde with carbene precursor 14 initiates a redox reaction of the epoxyaldehyde which leads to an epoxide ring opened intermediate. Reaction with an azide source initiates a Curtius rearrangement, which provides the 1,2-aminoalcohol derivative 15 in generally good yield. Inclusion of EtOH in the reaction, as the only change in conditions, generates the oxazolidinone 16. TMSO O R1 R2

CHO

Et3N TMSN3, NaN3 14

R1 2 15 R

H N

1 2 N3 R1 = Ph, R2 = Me, 75%, 4:1 R = Ph, R = Ph, 84%, 2.6:1 R1 = cC6H11, R2 = Me, 78%, 2.7:1 O

O Et3N TMSN3, EtOH, NaN3 14

O R1 16

N

NH R2

R1 = Ph, R2 = Me, 75%, 4:1 R1 = Ph, R2 = Ph, 47%, 1:1 R1 = cC6H11, R2 = Me, 78%, 3:1

N 14

BF4 N C6F5


77

Enolates are not routinely used to open epoxide rings and most examples of this type of reaction are intramolecular. Two interesting examples of intramolecular epoxide ring opening by an enolate have been reported in the past year. The first of these is the intramolecular ring opening of a spiro-epoxide system to provide a bicyclo[3.1.0]hexanone ring system . O

O

HO

NaOH, EtOH 87% (1:1)

O

MeO

MeO

A second example involves the intramolecular cyclization of a malonate anion with an epoxide . Metal-halogen exchange of a bromoepoxide was followed by a conjugate addition to provide an intermediate malonate anion. Subsequent anion addition to the epoxide and formation of a lactone with one of the esters provided the tricyclic product as a mixture of diastereomers. O

Br

O

O

1) n-BuLi 2) CO2Et R CO2Et

O CO2Et

CO2Et CO2Et R

R R = Ph, 60%, 1:1 R = n-Pr, 50%, 67:33

The use of Grignard reagents in epoxide ring opening reactions is a common process. As an example the recently reported reaction of an alkoxy Grignard reagent provides a useful route to homoallylic/allylic alcohols . O R

OH + BrMg

OMgBr

R

OH

R = Bn, 76% R = CH2OTBS, 82%

A related approach, which makes use of a tandem epoxide ring-opening/ring-closing reaction, has been used in the synthesis of spirotenuipesines A and B . The Cucatalyzed Grignard reagent opened the epoxide ring of epichlorohydrin, which is then closed to form a new epoxide ring. Subsequent epoxide opening with an additional Cu-catalyzed Grignard reagent provided the product alcohol. O

Cl +

MgBr 1) cat. CuI 2) NaOH 58%

O

MgBr +

CuI SiMe3 98%

OH SiMe3

A number of examples of epoxides being opened by ʌ-nucleophiles have been reported in the past year. An interesting review comparing 5-exo and 6-endo epoxide opening reactions has been published . Intermolecular examples of this general reaction have largely involved indole as the ʌ-nucleophile. A common theme this past year has been the use of solvent-free conditions. For example the reaction of epoxide 17 with indole using activated silica to catalyze the reaction provides a 74% yield of the epoxide-opened product . This reaction works with substituted indoles and pyrrole as well, although


78

pyrrole provides a 4.6:1 mixture of 2-substituted:3-substituted products. Another solvent-free reaction uses a Ru-catalyst to provide good yields of the epoxide ring-opened product . HN

O 10 eq. Indole, activated SiO2

OH

74%

N N Boc Boc O 17

N N Boc Boc O

An interesting catalyst for epoxide ring opening by indole was designed based on computational evaluations of the catalyst-epoxide complex . This reaction proceeds in excellent yield albeit with a very long reaction time (5-8 days). It is worth noting that 18 also catalyzes the ring opening of epoxides by aniline, thiols and alcohols. Br O 2 + R

Br

10 mol% 18 1.85 M in CH2Cl2 7.2 d

N R1

R2 N R1

CF3 O O F3C

R1 = H, R2 = Me, 89% R1 = Me, R2 = H, 98%

HO

N H

N H

O S Me

18

Intramolecular cyclization reactions of epoxides with ʌ-nucleophiles provide an effective route to a variety of ring systems. The epoxide system 19 can undergo either a 6-endo cyclization or a 5-endo cyclization . Treatment of 19 with excess TFA provides a good yield of lactam 20 via a 6-endo-type of cyclization. Alternatively, simply heating the epoxide in water provides an excellent yield of diastereomeric lactams 21 and 22 via a 5endo process. Ph

Ph Ph

OH N O Me 20

200 mol% TFA t-BuOH, 4Å MS 72%

Ph

OH

N Me 19

OH

Ph

O

O

H2O reflux

Ph

Ph O

H N Me OH

Ph

O

H N Me OH

21 22 30:70, 91% overall

The intramolecular cyclization of the chloroepoxide below provided the cyclized product in good yield . Unsymmetrical ʌ-nucleophiles provide a mixture of regioisomeric products. More electron rich arenes provided improved yields (up to 90%) of the cyclized products.


R

O

79

R

5 mol% AuCl3, 15 mol% AgOTf 6 mol% thiourea

Cl

O

Cl OH

O

R = H, 55% R = OMe, 67%, 5.1:1

A series of studies on a related system determined an optimal Lewis acid for this type of cyclization . The use of FeBr3 with or without AgOTf proved an optimal Lewis acid and provided the t-butyl chromanol in 91% yield. Attempts to prepare a larger ring were quite dependent on the substitution of the nucleophilic aromatic ring. For example the 3,5dimethoxy derivative gave an excellent yield of the benzoxapane ring system while cyclization of the monomethoxy derivative provided only the formacetal. t-Bu

10 mol% FeBr3 •3AgOTf 91%

O O

t-Bu

OH

O

O Ph

O

OMe

O


Ph

OMe

OMe

Ph

O Ph

OMe

HO


O

O

OMe

OMe

O

An extremely useful reaction of epoxides is the reductive ring opening, often with Cp2TiCl2/Zn, followed by a radical reaction. Several examples of these reactions have been reported in the past year. A typical example is the cyclization of the epoxy-aldehyde 23 to form hydroxylated cyclopentanes 24 and 25 in 51% overall yield . An interesting aspect of this system is that the epoxide enantiomer of 23 provided the identical stereoisomeric products.

CHO BnO

OBn OBn 23

OH

OH

O

BnO

BnO Cp2TiCl2, Zn

OH

OH BnO

BnO OBn 24, 41%

OH 25, 10%

The radical derived from this type of reductive ring opening will react with allenes as well as olefins. The intermolecular reaction of these epoxide-derived radicals with the olefin derived from a Baylis-Hillman reaction provided an interesting Į,ȕunsaturated lactone .


80

O OAc CO2Me + R2

R1

O

1) Cp2TiCl 2) H3O+

R1

R1 = H, R2 = 2-(OMe)C6H4CH2, 60% R1 = Ph, R2 = Ph, 51%

O R2

A small library of hydroxymethyl indolines has been prepared by the intramolecular cyclization of an epoxide-derived radical with an aromatic ring. Treatment of epoxide 26 with Cp2TiCl2/Mn followed by hydrogenation provided a series of indolines in good yields . The presence of the methyl group on the epoxide proved to be crucial to the success of the reaction. Desmethyl substrates provided a mixture of indoline and tetrahydroquinoline. O

26

N CO2Et

OH

1) Cp2TiCl2, Mn 2) H2/Pd 65%

N CO2Et

Rearrangement reactions of alkynyl epoxides continue to attract interest due to the variety of new ring systems and rearrangement products obtainable. A rearrangement/dimerization reaction has been reported to convert an alkynyl epoxide to a bisfuran . A wellknown type of rearrangement of alkynyl epoxides is shown below. Treatment of the fused ring epoxide with catalytic PtCl2 provided very good yields of the bicyclic furan derivatives . O

O

10 mol% PtCl2 dioxane/H2O, 100 °C

R

R ( )n

( )n

n = 1, R = Ph, 96% n = 1, R = CH2CH2OH, 79% n = 0, R = Ph, 34% n = 2, R = Ph, 92%

A gold catalyzed rearrangement of alkynyl epoxides has been found to provide divinyl ketones in good yields . O

OAc

O 5 mol% Au(PPh3)Cl/AgSbF6 70%

OAc

While many rearrangement reactions of alkynyl epoxides rely upon transition metal catalysis, a recent report uses ICl to induce the formation of a pyranone . Ph

Ph I OH R O

3.3

AZIRIDINES

ICl, CH3CN/H2O

O

O R

R = Ph, 71% R = i-Pr, 53%


3.3.1

81

Preparation of Aziridines

The catalytic aziridination of alkenes with transition metal species in combination with suitable oxidants and coordinating ligands continues to attract significant attention. With respect to copper catalysis, a variety of aziridines were obtained in good to excellent yields (up to 96%) upon olefin reaction with PhINTs and [Cu(II)(NCCH3)6][Al{OC(CF3)3}4]2 . Likewise, the aziridination of aliphatic alkenes catalyzed by N-heterocyclic carbene copper complexes was reported . As shown below, an efficient protocol for copper-catalyzed olefin aziridination was established using 5-methyl-2pyridinesulfonamide or 2-pyridinesulfonyl azide as the nitrenoid source . This chelation-assisted strategy provided access to a range of aryl aziridines in the absence of external ligands.

N

SO2N3

10 mol% Cu(acac)2 CH3CN 50 °C, 12 h

N LnCu

NSO2(2-Pyr)

R SO2 N

R R = 4-Cl, 69% R = 2-Br, 68% R = 4-OAc, 43%

Cobalt-based catalyst [Co(P1)] was designed on the basis of potential hydrogen-bonding interactions in the metal-nitrene intermediate and shown to effectively aziridinate a variety of aromatic olefins under mild conditions using arylsulfonyl azides . The wide accessibility of arylsulfonyl azides, generation of stable dinitrogen as the only side product, and relatively low cost of cobalt makes this an attractive reaction. Additionally, cobalt(II) complexes of D2-symmetric chiral porphyrins were shown to catalyze asymmetric olefin aziridination using diphenylphosphoryl azide as a nitrene source .

t-Bu

t-Bu

O

O NH

N

N

HN

Co

R N

+ NH O O S Ar N3 Ar = 4-NO2-C6H4

O O S Ar N

N HN

O

O R t-Bu

t-Bu

[Co(P1)]

R = 4-Me, 89% R = 2-Me, 88% R = 4-t-Bu, 98% R = 4-Br, 96% R = 4-CF3, 96%

A catalytic system based on iron(II) triflate, quinaldic acid, and an ionic liquid provided a range of aziridines in good to moderate yields upon treatment of olefins with equimolar amounts of iminoiodinane . Utilization of chiral ligands with this iron-based


82

system also provided access to asymmetric aziridines . Additionally, 27, an iron(II) salt plus 4,4’,4”-trichloro-2,2’:6’,2”-terpyridine, was reported as a highly efficient catalyst for both inter- and intramolecular alkene aziridination . 2+

Cl

5 mol% 27 PhI(OAc)2 40 °C, 12 h

R

Cl

O

SO2NH2

S

Cl

N

O

N

N

N

Fe

R

N R = H, 90% R = Cl, 86%

N N

Cl

Cl

Cl 27

In an effort towards preparing structurally divergent aminoglycosides, a stereocontrolled intramolecular rhodium-catalyzed aziridination of glycal-derived sulfamates was reported . The resulting semistable aziridines were opened with various nucleophiles (C, O, S, and N-based) to selectively give cyclic sulfamate-containing aminosugar derivatives. O O S O NH2 O BzO

O O

10 mol% [Rh2(OAc)4] PhI(OAc)2 MgO, CH2Cl2

Nu

N BzO

BzO

OBz

OBz

O O O S NH O

O S O

Nu OBz

Nu = EtOH, 90% Nu = allyltrimethylsilane, 78% Nu = HS-C6H4-p-Me, 85%

Non-metal catalyzed olefin aziridination conditions continue to be explored. The aziridination of alkenes via direct use of p-toluenesulfonamide, PhI(OAc)2, and I2 under mild conditions was reported . Additionally, stereoselective aziridination of a range of cyclic allylic alcohols using two different chloramine salts, TsNClNa and t-BuSO2NClNa (BusNClNa), was investigated . In general, mixtures cis- and trans-hydroxy aziridines were obtained, however complete cis-diastereoselectivity (>98:2, cis:trans) was observed in the aziridination of 1,3-disubstituted allylic alcohols. R2

R2

OH

R1

R2

OH

TsNClNa•3H2O PhMe3NBr3 MeCN, rt, 12 h cis

OH

NTs +

NTs

R1

R1 trans

R1

R2

Yield of cis

Me

Me

70%

Me

n-Bu

90%

n-Bu

Me

73%


83

A combined theoretical and experimental approach was used to systematically investigate the Bronstead acid-promoted aziridination of electron-deficient olefins . It was found that this reaction proceeds via attack of the internal nitrogen of an azide to the terminal carbon of a protonated olefin. Subsequent intramolecular cyclization of the azido-enol acyclic adduct to the corresponding aziridine is coupled with N2 discharge. During the course of this study, a single-step method for preparing aziridine-2-carboxamides via TfOH-promoted aziridination of acrylamides was established. Given the inability to isolate any triazolines resulting from initial 1,3-dipolar cycloaddition, an analogous mechanism was suggested for the thermal reaction of aryl azides with N-propenoyl (5R)-5-phenyl-4-morpholin-2-one .

H N

Bn N3 +

R

O

H N

TfOH 0 °C to rt CH3CN, 48 h

N

N

N

Bn

OH

R

-N2

H N

BnN

R

O R = H, 72% R = Ph, 53% R = C6H11, 64% R = C12H25, 54%

Along similar mechanistic lines, additional examples of aziridines arriving via azaMichael initiated ring-closure have been reported . Particularly interesting is the phase transfer-catalyzed aziridination of electron-deficient olefins using N-chloro-N-sodio carbamate and the organocatalytic asymmetric aziridination of Į,ȕ-unsaturated ketones . Readily available organocatalyst 28 was reported to promote a domino iminium-enamine intramolecular sequence yielding aziridines with almost complete diastereocontrol (d.r. >19:1) and very high enantioselectivity (up to 99% ee). Ph BocHN COO

Cbz

1.5

OMe

NH3 N H

R N

28

O

OTs Cbz N O H N 20 mol% 28 R NaHCO3 R = pentyl, 93% yield, 96% ee CHCl3 R = Me, 96% yield, 93% ee R = CO2Et, 74% yield, 95% ee

Several examples of aziridines prepared via a 1,2-amino leaving group motif, either generated in situ or as part of the starting material, have been reported . This aziridination strategy traditionally features an amine lone pair or an amide anion facilitating an intramolecular SN2 reaction. A particularly intriguing example is the conversion of ȕ-lactams to 2,3-unsubstituted aziridines upon treatment with LiAlH4 .


84

PhO

R N

OPh

PhO LiAlH4 Et2O, Δ, 2 h

HO

R

R

N

N

O

O

Cl

Cl

R = 4-Cl, 66% R = 4-Me, 62% R = 4-OMe, 85% R = 3-OMe, 81%

In addition to alkenes, imines are tremendously popular aziridine precursors via an azaDarzens or Darzens-like approach. Chiral non-racemic vinyl aziridines with varying substitutions on the alkene were obtained by reaction of (SS)-tert-butylphenylsulfinimine with a range of ylides derived from allyltetrahydrothiophenium salts . Alternatively, addition of N-(2-chloroethylidene)-tert-butylsulfinamide to organocerium reagents provided terminal N-tert-butylsulfinyl aziridines in good yields and diastereomeric ratios . The mechanism and stereoselectivity of an asymmetric aziridination reaction promoted by a bicyclic chiral sulfur ylide was studied using density functional theory method and in a similar light as exemplified below, a report highlighting the asymmetric synthesis of 2,3-disubstituted aziridines utilizing an ylide derived from Eliel’s oxathiane was disclosed . Alternative to the use of sulfur ylides, the synthesis of enantiopure aziridines via iodomethyllithium addition to imines was also reported .

N R1

R2

+ O

S

OTf

NaH, -40 °C or EtP2, -78 °C THF

R2 N

: R1

Ph cis

Ph R1

R2

Base

Yield

t-Bu

Ts

NaH

68%

100 : 0

t-Bu

Ts

EtP2

73%

100 : 0

1-naphthyl

Boc

NaH

75%

2 : 98

1-naphthyl

Boc

EtP2

56%

0 : 100

R2 N R1

Ph trans

cis : trans

The asymmetric aziridination of imines with ethyl diazoacetate mediated by Lewis acid catalysts prepared from the vaulted biphenanthrol (VAPOL) and binaphthol (VANOL) ligands and triphenylborate continues to be explored . It is well known that this type of aziridination traditionally provides predominantly cis aziridines. However, a related trans-selective asymmetric aziridination of diazoacetamides and N-Boc imines organocatalyzed by axially chiral dicarboxylic acid 29 was reported .

Three-Membered Ring Systems O

NBoc + Ar1

Ar2

N H

N2

Boc 5 mol% 29 toluene 0 °C, 2 to 8 h

Ar

N Ar1

O N H

Ar2

Ar1

Ar2

Yield

ee

3-MeO-C6H4

Ph

55%

96%

2-Np

4-MeO-C6H4

71%

99%

4-PivO-C6H4

4-MeO-C6H4

57%

97%

Ph

4-Cl-C6H4

60%

97%

Ar CO2H CO2H

85

Ar = 2,4,6-Me3-C6H2 29

Aziridines can also be synthesized from existing aziridine rings. A particularly interesting and unique example is the following dearomatization reaction of an aryl-substituted silaaziridine upon treatment with benzaldehyde at room temperature . O t-Bu i-Pr

t-Bu

Si N

Ph

t-Bu O t-Bu Si N i-Pr

Ph H

4π electrocyclic

rt

t-Bu O t-Bu Si N

Ph H

i-Pr

>95% (NMR)

Azirines are structurally interesting compounds which represent unsaturated derivatives of N-H aziridines. A short, flexible synthesis of the marine natural product (-)-(Z)-dysidazirine was reported . Asymmetric synthesis of the 2H-azirine carboxylic ester within this antifungal compound was achieved via an alkaloid-mediated Neber reaction. TsO

CO2Me

N CO2Me

( )12

quinidine toluene 84% yield

N ( )12

H2, Lindlar hexanes 52% yield

CO2Me

( )12 N

(-)-Z-Dysidazirine

A general method to prepare polyhydroxylated 3-alkyl-2H-azirines and previously unknown 2-halo-3-alkyl-2H-azirines has been reported . These very intriguing compounds, which may serve as important precursors to more elaborate heterocycles given the known reactivity profile of azirines, were prepared via thermolysis or photochemical reaction of vinyl azides and 1-halovinyl azides.


86 OAc

thermal or photochemical conditions

AcO

Conditions

X

Yield

benzene, reflux

H

85%

450W Hg lamp, rt

F

96%

6:4

benzene, sealed tube, 80 °C

Cl

94%

6:4

450W Hg lamp, rt

Br

95%

6:4

AcO

X O

X

OAc

N3

O

O

N

O

dr

3.3.2 Reactions of Aziridines The reactions of aziridines (like epoxides) are largely dominated by nucleophilic ringopening reactions. Analogously and in this light, a report describing the preparation of stable aziridinium ions and their subsequent ring-opening with various nucleophiles was disclosed . A number of interesting reactions involving oxygen-based nucleophiles, including carbohydrates , have been reported. Asymmetric olefin aziridination using catalytic [Rh2(esp)2] and SESNH2 as a nitrene source was followed by regioselective BF3•Et2O-mediated ring opening with 3-pentanol in a concise synthesis of Tamiflu ((-)-oseltamivir phosphate) . Additionally, an enantioselective ring opening of tetrasubstituted meso-aziridinium ions with alcohol nucleophiles proceeding through a chiral ion pair with a binaphthol-phosphate anion was reported . This reaction was initiated by silver-induced ring closure of ȕ-chloroamines using the Ag salt of a chiral anion as in situ-generated catalyst. Use of insoluble Ag2CO3 as the silver source was essential in order to obtain high enantioselectivity and the authors believe the chiral phosphate acts as a chiral anion phase transfer catalyst to bring silver ion into the organic phase. Ar Ph Ph

Cl

Ph

N

(+/-)

t-BuOH 15 mol% 30 Ag2CO3 toluene 50 °C

N

Ph

Ot-Bu

O O P O O

Ph

N

Ph *

56% yield 92% ee

O O P O OH Ar Ar = 2,4,6-i-Pr3-C6H2 30

Oxazolidinones can be prepared via aziridine ring-opening with carbonyl compounds. A quaternary ammonium bromide covalently bound to polyethylene glycol (PEG6000(NBu3Br)2) was reported to be an efficient and recyclable catalyst for intermolecular cycloaddition of aziridines with CO2 . Enantiopure 1-alkylaziridine-2-


87

carboxamides were sequentially reduced, N-Boc protected, and converted into enantiopure 5(aminomethyl)-1,3-oxazolidin-2-ones via a fully regioselective and stereospecific BF3•Et2Opromoted intramolecular nucleophilic ring-opening . The oxazolidinone shown below in turn served as a precursor to the antibiotic linezolid (Zyvox). Ph

O

Ph N BF3•Et2O

1) LiAlH4 2) Boc2O

N

HN

O

O

NH2

NH

NH

O

Ph

t-BuO

44% yield from the amide

With respect to sulfur-based nucleophiles, moderate to good enantioselectivity was observed in the ring opening of meso-aziridines with benzenethiols using quinine as an organocatalyst . Aziridines were also reported to undergo cyclization with carbon disulfide and isothiocyanates in the presence of organophosphines to provide thiazolidinone derivatives in high yields (up to 98%) . As exemplified below, an unexpected tosyl group transfer was discovered from the reaction of N-tosylimines with aziridines in the presence catalytic amounts of N-heterocyclic carbenes . Cl Ts N

NTs

MesN

NMes

TsHN

SO2Tol-p

10 mol% THF, 70 °C

+ Ph

TsHN

OSOTol-p

+ 30%

27%

Nitrogen-based nucleophiles continue to remain popular in ring-opening reactions of aziridines. An efficient microwave-assisted protocol for ring-opening activated aziridines with resin-bound amines was developed for the synthesis of polyamines and amino acid / peptide derivatives . A novel series of highly efficient organocatalysts for asymmetric aldol reactions was obtained via regio- and stereoselective ring opening of chiral aziridines with azide anions . In a similar light as shown below, the transdiamine functionality within (-)-agelastatin A was introduced by an intramolecular aziridination of an azidoformate followed by regioselective azidation . O O

N N3 CN

160 °C CH2Cl2 sealed tube

O O

N N CN

NaN3 DMF rt

O

CN 92%

O

N N3

N H

61%

Carbon-based nucleophiles continue to be examined in ring opening reactions of aziridines. A communication highlighting the facile synthesis of 1-arenesulfonylazetidines via reacting 1-arenesulfonylaziridines with dimethylsulfoxonium methylide generated under microwave conditions was disclosed . Additionally, the synthesis of optically active aminoethyl-functionalized compounds via organocatalytic ȕ-ketoester ring opening of


88

N-protected aziridines was reported . In a related report, subjection of the Nnosyl aziridine pictured below to a one-pot alkylation/desulfonation/cyclization sequence provided diastereomerically pure tricycle 32 in good yield . Ns N

Cl N N

O

AnRO CO2t-Bu

10 mol% 31 K2CO3 then PhSH

N

CO2t-Bu

An = Anthracenyl R = Adamantoyl

32 71% yield 30:1 dr

31

Several examples of inter- and intramolecular aziridine ring opening using ʌ-nucleophiles have been reported. Iron(III) chloride was found to be a highly effective catalyst for intermolecular Friedel-Crafts reaction of aziridines with electron-rich arenes . An efficient stereoselective synthesis of trans-1-aryl-2-aminotetralins was reported via one-pot Cu(OTf)2-catalyzed aziridination and regioselective intramolecular arylation . With respect to pancratistatin and congeners, a particularly interesting intramolecular cyclization of aziridines with ʌ-nucleophiles has been reported featuring solvent-free silica gel-catalyzed conditions . Likewise, the intramolecular cyclization of ʌnucleophiles with aziridines has been applied towards 6-azabicyclo[3.2.1]octanes and hexahydro-1H-benzo[c]chromen-1-amines (shown below) as structurally relevant natural product scaffolds. An important aspect of this report was to show that N-H and N-alkyl aziridines can participate in intramolecular Friedel-Crafts reactions with arenes. Interestingly, N-Ts aziridines did not work in this system. R

O

R

O B(C6F5)3

N

n-C6H13

N H

n-C6H13

R = H, 80% R = Me, 72% R = OMe, 75%

Lithiated aziridines continue to attract significant attention. The lithiation of mono- and diphenylaziridines was investigated in detail in an effort to understand why monophenylaziridines undergo exclusively or mainly ortho-lithiation while diphenylaziridines are lithiated exclusively at the Į-position of the aziridine ring . Į-Lithiation/electrophile trapping of N-tert-butylsulfinyl aziridine was reported to be a significant reaction due to overcoming previously observed ring-opening and sulfenic acid elimination pathways and controlled stereocenter generation adjacent to nitrogen upon electrophile incorporation . With respect to opening aziridines with organolithium reagents, allylic sulfonamides may be accessed via organolithiummediated conversion of ȕ-alkoxy aziridines . Such an approach was utilized in a formal synthesis of (+)-perhydrohistrionicotoxin .

Three-Membered Ring Systems OH

n-Bu NHBus

OMe NBus

89

n-Bu N n-pent H

steps

n-BuLi THF

73% yield (+)-Perhydrohistrionicotoxin

Vinyl aziridines continue to garner significant attention as precursors to a host of different heterocyclic ring systems. The thermal coupling of vinyl aziridines with phenyl isocyanate was reported to produce predominantly oxazolidinones and in some cases seven-membered ring heterocycles . Photochemical cleavage of bicyclic vinyl aziridines and subsequent [3+2]-cycloaddition with electron-deficient alkenes was investigated as strategy towards accessing the 8-azabicyclo[3.2.1]octane skeleton found within tropane alkaloids . A number of reports highlighting rearrangements of vinyl aziridines were also disclosed, including copper-catalyzed ring expansion to produce 3-pyrrolines , Ni/N-heterocyclic carbene catalyzed rearrangement , and a unique rearrangement of an aziridinofullerene . As shown below, a particularly interesting rearrangement of N-vinyl-2-aryl aziridines was reported to form dihydro[3]benzazepines present within antiproliferative Cephalotaxus esters .

Cs2CO3 1,4-dioxane 100-150 °C

R1 R2

N

R1

N

O

NH

R1 R2

R2

O

O

R1, R2 = H, 30% R1 = H, R2 = OMe, 52% R1, R2 = OCH2O, 68%

Additionally, a novel nitrene-equivalent tandem aziridination/rearrangement reaction of allylic alcohols was reported as an efficient and highly stereoselective approach to various 2quaternary Mannich bases . This methodology serves as an alternative route to conventional vicinal amino-functionalization of alkenes and features a significant accelerating effect with the use of silica gel. O

HO

HO PhthNH2, PhI(OAc)2 CH2Cl2, silica gel

N-Phth NHPhth 99% yield >99% de

With respect to using aziridines as catalysts, an efficient and very fast enantioselective arylation of aromatic aldehydes under microwave flash-heating conditions using conformationally restricted bulky substituted aziridine-2-methanols was reported .


90

Ph

Ph

OH N Tr 10 mol%

O PhB(OH)2 +

R

OH Ph

Et2Zn toluene, μW

R

R = 4-Me, 97% yield, 98% ee R = 2-Me, 98% yield, 93% ee R = 4-Cl, 93% yield, 93% ee R = 2-Me, 88% yield, 98% ee

Reactions employing di-tert-butyldiaziridinone as a nitrogen source continue to be explored. A communication was disclosed describing the catalytic asymmetric diamination of terminal olefins at allylic and homoallylic carbons via formal C-H activation with a catalyst generated from Pd2(dba)3 and a chiral phosphorus amidite ligand . Additionally as shown below, a novel intermolecular α-amination of esters using CuCl and di-tertbutyldiaziridinone was developed for the synthesis of a variety of hydantoins under mild conditions . O

OMe R

+

O

t-Bu

N N

t-Bu

5 mol% CuCl-P(n-Bu)3 CHCl3, 65 °C 12 h

O

t-Bu N

N t-Bu R

O R = H, 79% R = 4-OMe, 73% R = 4-Cl, 78% R = 3-Br, 68%

Interest in the reactivity, stereochemistry, and utility of oxaziridines continues to grow. A report highlighting the stereoselective synthesis of oxaziridines and their subsequent transformation into enantiomerically pure isoxazolidines via [3+2] cycloaddition with aryl ethylenes was disclosed . A related communication investigating cycloadditions of N-sulfonyl nitrones generated by Lewis acid-catalyzed rearrangement of oxaziridines was also reported . N-sulfonyl oxaziridines are susceptible to electrophilic activation using copper(II) catalysts and react with styrenes to produce 1,3-oxazolidines in a formal alkene aminohydroxylation . Additionally as shown below, copper(II)-catalyzed aminohydroxylation of unsymmetrical 1,3-dienes can proceed with both high regio- and chemoselectivity.

+ EtO2C

Ph

O N

5 mol% Cu(TFA)2 10 mol% HMPA SO2Ph

PhO2S

Ph N O

EtO2C 81% isolated yield >20:1 regioselectivity

3.4

REFERENCES

08ACR883 08AG(I)3759 08AG(I)8703 08CC323

M.M. Hussain, P.J. Walsh, Acct. Chem. Res. 2008, 41, 883. B.M. Trost, T. Zhang, Angew. Chem. Int. Ed. 2008, 47, 3759. F. Pesciaioli, F. De Vincentiis, P. Galzerano, G. Bencivenni, G. Bartoli, A. Mazzanti, P. Melchiorre, Angew. Chem. Int. Ed. 2008, 47, 8703. S. Minakata, R. Tsuruoka, T. Nagamachi, M. Komatsu, Chem. Commun. 2008, 3, 323.

Three-Membered Ring Systems 08CC4363 08CC5975 08CC6363 08CR1918 08CR3958 08EJO4647 08JA2920 08JA5408 08JA6070 08JA6610 08JA7220 08JA8134 08JA8590 08JA10076 08JA10078 08JA13538 08JA14380 08JA14984 08JA15228 08JA16838 08JOC948 08JOC1462 08JOC1946 08JOC2270 08JOC2862 08JOC2879 08JOC3566 08JOC3662 08JOC3823 08JOC4116 08JOC4342 08JOC4625 08JOC4709 08JOC5578 08JOC7260 08JOC7852 08JOC8113 08JOC8163 08JOC8992 08JOC9137 08JOC9214 08JOC9411 08JOC9539 08JOC9576 08JOC9727 08MI792 08MI1561 08MI1835 08MI3785 08MI4293

91

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92 08OBC1190 08OBC3186 08OBC3467 08OBC4299 08OL361 08OL881 08OL1497 08OL1501 08OL1569 08OL1947 08OL1935 08OL1995 08OL2095 08OL2151 08OL2291 08OL2461 08OL2493 08OL2781 08OL3275 08OL3453 08OL4384 08OL4457 08OL4943 08OL5023 08OL5269 08OL5429 08OL5457 08S807 08S1404 08S1420 08S2100 08S3160 08SL108 08SL237 08SL453 08SL1381 08SL2119 08SL2191 08SL2856 08SL3149 08SL3234 08T3204 08T3337 08T5013 08T7171 08T9253 08T10239 08T11167 08T11732 08TA231 08TA964

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Three-Membered Ring Systems 08TA2246 08TL500 08TL687 08TL1030 08TL1450 08TL1546 08TL1694 08TL1795 08TL1935 08TL2289 08TL3672 08TL4057 08TL4306 08TL4768 08TL4925 08TL5021 08TL5928 08TL5954 08TL6007 08TL6205 08TL6437 08TL6536 08TL6797 08TL7406

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94

Chapter 4 Four-Membered Ring Systems Benito Alcaide Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid. Spain [email protected] Pedro Almendros Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain [email protected] ______________________________________________________________

4.1

INTRODUCTION

Recently, there has been explosive growth in the research area of four-membered heterocycles, where a non-carbon atom is part of the ring, within many fields of Science, including Organic Chemistry, Inorganic Chemistry, Medicinal Chemistry, and Material Science. Condensing the vast amount of published material during the year 2008 to less than 20 pages is an extremely demanding task. A substantial portion of this material is founded on oxygen- and nitrogen-containing heterocycles, which dominate the field in terms of the number of publications. Our aim is to highlight the current state of the art in the vast area of four-membered heterocyclic chemistry. 4.2

AZETIDINES, AZETINES, AND RELATED SYSTEMS

Recent progress on the chemistry of azetidines, azetines, azetes and related systems has been reviewed in several publications . A new Daphniphyllum alkaloid, calyciphylline J 1 has been isolated . A review on the biosynthesis and taxonomic significance of non-protein amino acids, including azetidine-2-carboxylic acid 2 has been published . The influence of 2-alkyl-2-carboxyazetidines (Aze) on the threedimensional structure of model tetrapeptides R2CO-2-R1Aze-L-Ala-NHMe 3 has been analyzed by molecular modeling, 1H NMR, and FT-IR studies . The synthesis and evaluation of novel azetidine lincosamides 4 have been described . A lead benzamide, bearing both cyanopyridyl and methylazetidinyl moieties, has been identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor . The stereoselective syntheses of cis conformationally constrained glutamate and aspartate analogues, containing an azetidine framework have been accomplished from an azetidin-3-one obtained from (S)-N-tosyl-2-phenylglycine . 3-Aminoazetidine linkers for the synthesis of dendrimers based on melamine have been identified using competition reactions, showing that azetidine is 40 times more reactive than the cyclic, nine-membered ring (C8H17N), and 320 times more reactive than benzylamine


Four-Membered Ring Systems

95

. Cycloreversion of cis- and trans-1,2,3-triphenylazetidine has been achieved by electron transfer . HOOC

H

O

R1

CO2H N

N

N H

N

H N

R2

2

Cl

R2 N

O

O

H 1

O

O

3

N H R1

O S

HO OH

HO

4

A general method has been developed for the synthesis of 1-arylsulfonylazetidines 5 through a one-pot reaction of 1-arylsulfonylaziridines with dimethylsulfoxonium methylide . 2-(Dichloromethylene)azetidines 6 constitute a new class of stable exocyclic enamines, which have been prepared on a multigram scale in good yields through the imination of ȕ-halo ketones, followed by Įƍ,Įƍ-dichlorination and subsequent 1,4dehydrohalogenation . A sequence involving amination, bromination, and baseinduced cyclization of alkyl 2-(bromomethyl)acrylates has been used for the synthesis of alkyl 3-bromoazetidine-3-carboxylates, which are promising synthons as demonstrated by their transformation to 3-aminoazetidine-3-carboxylates . A bicyclic 1,2diazetidine has been located using DFT methods on studying the formal [2ı+2ı+2ʌ] cycloaddition of quadricyclane with dimethyl azodicarboxylate . SO2R3 N +

R2 O SMe2

i

R1

R2 N

R1

R2

R1

Cl

R1 SO2

R3

5 (68–79%)

Cl

N

Cl

Cl

ii

R1

Cl

R1 N

R2

6 (45–62%)

Reagents: i) MW, 160 W, Al2O3, 90 oC. ii) (a) NCS, CCl4, Δ; (b) NaOMe, MeOH, Δ. A one-pot diastereoselective annulation of unmodified Baylis–Hillman adducts with N-arylphosphoramidates to afford 1,2-disubstituted azetidine-3-carbonitriles/carboxylates 7, which are the precursors of biologically versatile azetidine-3-carboxylic acids has been accomplished . The cycloaddition of alkynyl ketones with N-tosylimines catalyzed by the Lewis base 4-dimethylaminopyridine formed completely substituted azetidines 8 in moderate to good yields . Studies at the PM3 level the formation of both 1,4-dihydropyridine and azetidine cycloadducts through cycloadditions of 1,4-diaryl-1-aza-1,3-butadienes with allenic esters, indicate that the transition state for the formation of [4+2] cycloadducts has lower energy, supporting the preferred formation of [4+2] cycloadducts at higher temperature and [2+2] cycloadducts at room temperature . The aza-Michael addition of diethyl N-arylphosphoramidates to chalcones affords diethyl N-aryl-N-(1,3-diaryl-3-oxopropyl)phosphoramidates, which undergo cyclization induced by anions (NCS–, PhS–) of task-specific ionic liquids to functionalized azetidines in excellent yields with high diastereoselectivity. A Lewis base/lanthanum aryl oxide system has been described as suitable for anti-selective Mannichtype reactions of trichloromethyl ketones, affording unique building blocks for azetidine-2carboxylic acids .

B. Alcaide and P. Almendros

96

O OH

EWG

O EWG

Ar1

+ (EtO)2PNHAr2

R

i Ar2

O

N

+

Ar1

n(

ii

)

) N

Ar

ArC=NTs

7 (84–93%)

n(

R

Ts

8 (22–75%)

Reagents: i) NaH, C6H6, 60 oC. ii) DMAP, CH2Cl2, RT. An efficient approach to installing the azetidin-3-yl substituent into aromatic systems, using a nickel-mediated alkylíaryl Suzuki coupling, has been presented . A three-step mechanism involving the formation and rearrangement of the intermediate 9 with an indoline-azetidine spirocyclic core structure was shown by DFT computations to account for the electrophilic cyclization of tryptophan derivatives to hexahydropyrrolo[2,3-b]indoles . The spirocyclic azetidine tert-butyl 1-azaspiro[3.4]oct-6-ene-1-carboxylate has been prepared from 3-choropropionitrile using ring closing metathesis as the key step . A convenient access route to monoprotected 2,6-diazaspiro[3.3]heptane and its participation in Pd-mediated amination reactions to furnish a variety of N-Boc-Nƍ-aryl-2,6diazaspiro[3.3]heptanes 10 has been documented . On treatment with DAST (diethylaminosulfur trifluoride), enantiopure 2-hydroxyalkylazetidines stereospecifically rearrange into 3-fluoropyrrolidines 11 . Similarly, a series of 2-(αhydroxyalkyl)azetidines by treatment with either thionyl chloride or methanesulfonyl chloride in the presence of triethylamine rearrange stereospecifically to 3-(chloro- or methanesulfonyloxy)pyrrolidines . Readily-synthesized, water-stable Pd(II) complexes of azetidine-based tridentate ligands 12 have been proven to be efficient catalysts for the Suzuki–Miyaura coupling reaction . The evaluation of enantiopure N(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol for catalytic asymmetric addition of organozinc reagents to aldehydes has been reported . H HO2C

CO2H

N SeMe N CO2H

9

OH

Boc

Ph

N N 10

Me

F

N

i

N Ar

Ph

R Me

Me

N Me

R

11 (45–81)%

N NHR 12

Reagent: i) DAST, CH2Cl2, RT. Substituted β-amino acids has been prepared from the stable four-membered azetinebased heterocycle 13 . Irradiation of 2-diazo-3-oxochlorins has generated Wolff-rearranged pyrrole ring-contracted azeteoporphyrinoids . A combined experimental and computational study of the conrotatory ring opening of various 3-chloro-2azetines has been carried out . The Pd(0)-catalyzed cyclization of diversely substituted N(allenylmethyl) hydrazines with aryl halides has afforded 1,2-diazetidines 14 bearing two chiral centers in high regio- and diastereoselectively (trans only) . A planar-chiral derivative of 4-pyrrolidinopyridine mediates the [2+2] cycloaddition of ketenes with azo compounds in a convergent manner with good enantioselectivity, thus giving the first catalytic asymmetric synthesis of aza-β-lactams 15 . The fragmentation of a 4-imino-1,2-oxoazetidine under acidic conditions


97

has been described . Nitrosobenzene-mediated CíC bond cleavage reactions and spectral observation of the oxazetidin-4-one ring system 16 has been reported . R2

O R2

N N R1 Ph 13

N H EtO2C

R1 N N CO2Et

i

alkyl CO2Me Ar N N N N CO2Me EtO2C CO2Et O 15 14 R1

Ph N O O 16

Reagents: i) R2I, 5 mol% Pd(PPh3)4, Cs2CO3, MeCN, 80 oC. 4.3

MONOCYCLIC 2-AZETIDINONES (β-LACTAMS)

Reviews addressing recent progress on the synthesis of the β-lactam nucleus have been published . The preparation of β-lactams by [2+2] cycloaddition of ketenes and imines has been reviewed . An essay on Hugo Schiff, Schiff bases, and a century of β-lactam synthesis has appeared . The synthesis and reactivity of silylformylation products derived from alkynes to afford α-silylmethylene βlactams has been reviewed . A review on bifunctional asymmetric catalysis, focusing on cooperative Lewis acid/base systems, for the preparation of different products including β-lactams has been published . The mechanism of the keteneíimine (Staudinger) reaction in its centennial has been reviewed . The mechanism of the reaction between Fischer carbene complexes and imines to produce β-lactams has been studied by a combination of computational (DFT) and experimental methodologies . Densely functionalized 3-substituted 3-hydroxy-β-lactams 17 have been obtained via acyloxyallylation of azetidine-2,3-diones with 3-bromopropenyl acetate or 3bromopropenyl benzoate, in aqueous media promoted by indium under Barbier conditions . The stereochemical course of the Staudinger-like [2+2] cycloaddition of N,Ndialkylhydrazones to N-benzyl-N-(benzyloxycarbonyl)aminoketene can be efficiently controlled by the reaction temperature to afford trans- or cis-cycloadducts as the major products . The disaccharide moiety of the antibiotic mannopeptimycin ε has been synthesized as a (N-phenyl)trifluoroacetimidate donor, and its reactivity was tested in the glycoconjugation of a 4-alkylidene-β-lactam acceptor . Hybrid glycopeptide β-lactam mimetics designed to bind lectins or carbohydrate recognition domains in selectins have been prepared according to a “shape-modulating linker” design using the azideíalkyne “click” cycloaddition reaction . A selection of 3-mono- and 3,3dihalogenated 1,4-diaryl substituted β-lactams has been tested as inhibitors of the serine protease porcine pancreatic elastase . The induction of tumor cell apoptosis by a novel class of N-thiolated β-lactams with structural modifications at N-1 and C-3 of the lactam ring has been described . Mechanistic insights into the inhibition of prostate specific antigens by β-lactams have been reported . Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2Hpentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives which after catalytic hydrogenolysis of the NíO bond under ambient pressure and temperature leads to fluorides of β-amino acids that undergo cyclization to α-trifluoromethylated β-lactams 18 . The copper-catalyzed aerobic oxidative amidation of terminal alkynes for efficient synthesis of ynamides including β-lactam 19 has been reported . A


98

trans-β-lactam was obtained through aminocatalytic enantioselective anti-Mannich reactions of aldehydes with in situ generated N-Boc imines followed by oxidation and cyclization .

H

O

O

AcO HO H O

O i

N O

N O R 17 (45–72%)

R

O

F3 C R1

X F

R2

F ii

O

F3 C

X R1 N

N R3

O

R2 N

R3

O Ph

19

18 (55–97%)

Reagents: i) 3-Bromopropenyl acetate, In, THF/NH4Cl (sat), RT. ii) H2, Pd/C, EtOH, RT, 1 atm. The synthesis of bile acid dimers linked through 1,2,3-triazole and bis-β-lactam and their in vitro have been evaluated for antifungal and antibacterial activity . Bis-β-lactam formation from bisketene-imine cycloadditions has been accomplished . Cu(OAc)2 in combination with K2CO3 is an extremely effective system for promoting the homocoupling of various β-lactam acetylenes to afford C2-symmetrical bis-βlactam-1,3-diynes 20 . 4-Acetoxy-2-azetidinones reacted with organoindium reagent generated in situ from indium and 1,6-dibromo-2,4-hexadiyne in the presence of LiCl in DMF to produce 2-azetidinones 21 selectively, possessing a 1,2,4,5-hexatetraen-3-yl group at C4 . A highly stereoselective synthesis of β-lactams utilizing α-chloroimines as new and powerful chiral inductors has been accomplished . A combined experimental and theoretical study on the cycloaddition reaction between α-bromo vinylketenes and imines to afford 3-bromoalkenylazetidin-2-ones and 3-bromo-4-alkyl-5,6dihydropyridin-2-ones has been carried out . An operationally simple fourstep procedure for the solid-phase synthesis of chiral (3S,4S)-1,3,4,4-tetrasubstituted βlactams has been described . The rapid synthesis of 1,3,4,4-tetrasubstituted βlactams from methyleneaziridines using a four-component reaction has been achieved . A non-cross-linked soluble polystyrene-supported ruthenium catalyst has been used for the intramolecular carbenoid C–H insertion of α-diazoacetamides to generate cis-β-lactams . Light from a mercury vapor high-pressure lamp has been used to induce the photolytic decomposition of α-diazo acetamides in hexane and in nonconventional media such as water or a film to afford the corresponding β-lactams . Intramolecular C–H insertion of diazo-acetamides catalyzed by di-rhodium(II) complexes to generate β-lactams has been demonstrated . N-Heterocyclic carbenes, electrogenerated by electrolysis of imidazolium-based room-temperature ionic liquids, are stable bases that are strong enough to deprotonate bromoamides yielding the azetidin-2-one ring via C–3/C–4 bond formation . The enantioselective synthesis of cis-4-formyl-β-lactams via chiral N-heterocyclic carbene-catalyzed kinetic resolution has been achieved .

R2 2

H H R1

i

R2

R1 H H R2

N

N O

H H R1

R

N

N

O

O 20 (81–100%)

H H OAc

O

H

ii

R

H H N

O

H

21 (45–63%)


99

Reagents: i) Cu(OAc)2, K2CO3, MeCN, RT. ii) 1,6-Dibromo-2,4-hexadiyne, In, LiCl, DMF, RT. A highly stereoselective synthesis of chiral α-amino β-lactams 22 through an ynamide-Kinugasa reaction has been described . N-(4-Methoxy or 4ethoxyphenyl) groups can be oxidatively removed by silica gel supported ceric ammonium nitrate (CANíSiO2) under mild conditions in solution and on column . The chemo- as well as regioselective participation of N-aryl imines as 4π component in azaDielsíAlder reactions with 3-butadienyl-2-azetidinones in the presence of Lewis acid catalysts resulting in novel quinoline derivatives has been described . Regio- and π-facial selective Lewis acid promoted Diels–Alder reactions of α-dienyl-β-lactams leading to the synthesis of diastereomerically pure 1,3,4-trisubstituted-2-azetidinones have been reported . A highly enantioselective synthesis of N-Boc cis-β-lactams through chiral N-heterocyclic carbene-catalyzed Staudinger reaction of arylalkylketenes with a variety of N-tert-butoxycarbonyl arylimines can be achieved . N-Heterocyclic carbenes have promoted the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding β-lactams in good to excellent isolated yields; chiral NHCs give β-lactams in high e.e. after crystallisation . Theoretical calculations on the transition states of the cyclization of 2S-chloropropionyl amino acid derivatives to the corresponding ȕlactams have served to explain the high stereoselectivity of the reaction, and have been the driving force to extend the procedure to the preparation of a Gly-derived 1,3,4-trisubstituted 2-azetidinone in enantiopure form . N-Alkyl β-lactams have been prepared by a palladium-catalyzed [2+2] carbonylative cycloaddition of allyl bromide with heteroarylidene N-alkyl-amines . A general method for the synthesis of 4-alkyliden-2azetidinones 23 via copper-catalyzed intramolecular CíN coupling of 3-bromobut-3enamides has been developed, with 4-exo ring closure fundamentally preferred over other modes of cyclization . O O R1

N

R1 R2

O

O

N

R3

R1 R2

i

+ O

N

N O

Br R3

22 (60–80%)

R1 Br

O

NHR2

ii N

Br O

R2

23 (70–99%)

Reagents: i) 20 mol % CuI, Cy2NMe, MeCN, RT. ii) 5 mol % CuI, Me2NCH2CO2H, THF, reflux. The asymmetric synthesis of difluoro-β-lactams using a menthyl group as a chiral auxiliary, through rhodium-catalyzed Reformatsky-type reaction has been achieved . A two-step protocol for the synthesis of various functionalized gemdifluorinated β-lactams in moderate to good yields has been developed using GilmaníSpeeter and Reformatsky reactions . Decomposition of a diazo β-ketoamide derived from N-trityl serine imidazolide and N-protected acetanilides provided, instead of the expected 3-acyloxindole product, an enantiomerically pure β-lactam . Methyl 3(diethylamino)acrylate, generated in situ from Et2NH and methyl propiolate, on reaction with arylsulfonyl isocyanates afforded exclusively azetidine-2,4-diones in good yields . A synthesis of substituted 3-alkylidene-β-lactams involves a NaOH-promoted intramolecular aza-Michael addition of α-carbamoyl, α-(1-chlorovinyl) ketene-S,S-acetals

100


and subsequent nucleophilic vinylic substitution reaction in alcoholic aqueous media . A selective synthesis of 4-alkylidene-β-lactams from azides and aryloxyacetyl chlorides via a ketenimine-participating one-pot cascade process has been achieved . A RuCl3-catalyzed protocol for the regioselective hydroamidation of amides, including 2-azetidinone, with terminal alkynes has been reported . 3Benzylazetidin-2-ones have been prepared through Negishi cross-coupling of the zinc reagent derived from N-benzyl 3-iodomethyl azetidin-2-one and aryl halides . A route to synthesize 1-nosyl 3,3-dichloro-β-lactams using a Staudinger reaction between N-nosyl imines and dichloroketene has been published . Optically active β-lactams have been synthesized via photochemical intramolecular γ-hydrogen abstraction from thioimides involving a highly-controlled chiral-memory effect . A new one-pot approach to tetrasubstituted pyrroles 24 from β-lactams, relies on the regiocontrolled cyclization of the β-allenamine intermediates derived from the ring opening of 2-azetidinonetethered allenols . Molecular iodine catalyzes the ring expansion of 4oxoazetidine-2-carbaldehydes in the presence of tert-butyldimethyl cyanide to afford protected 5-cyano-3,4-dihydroxypyrrolidin-2-ones 25, through a novel C3–C4 bond cleavage of the β-lactam nucleus . Alkylamino-substituted 2-alkoxy-2-pentenoates, obtained through ring transformation of 4-(2-halo-1,1-dimethylethyl)azetidin-2-ones upon treatment with sodium methoxide in methanol, have been transformed into 5,5-dimethyl-3oxopiperidin-2-ones 26 utilizing an excess of concentrated sulfuric acid . Ring opening of protected 3-aminoalkyl-substituted azetidin-2-ones with O-, N-, or S-nucleophiles led to β,βƍ-diaminocarboxylic esters, amides, and thioesters, respectively . 3-(3-Chloropropyl)-β-lactams have been transformed selectively into transmethyl 1-alkyl-2-arylpiperidine-3-carboxylates upon treatment with hydrogen chloride in methanol then triethylamine in dichloromethane . An efficient synthesis of (3S,4R)-4-benzylamino-3-methoxypiperidine, a useful intermediate for the chiral synthesis of important drug molecule Cisapride and its analogs, from enantiopure 4-formylazetidin-2-one has been described . An approach for the synthesis of hydroxylated 2aminocyclohexanecarboxylic acid stereoisomers from 1,4-cyclohexadiene by the reductive opening of appropriate epoxide intermediates derived from the corresponding bicyclic βlactams has been developed . A β-lactam-based strategy allows the introduction of a nitrogen atom into the carbocycle of an aminocyclopentenecarboxylic ester using lipolase . A solvent-free, vapour-assisted method, for the synthesis of carbocyclic cis β-amino acid enantiomers through the Candida antarctica lipase B-catalysed enantioselective hydrolysis of β-lactams has been developed on a preparative scale . Fluorine-activated β-lactams are acyl donors to N-nucleophiles in the presence of Burkholderia cepacia lipase . A total synthesis of (í)-kainic acid starting from a commercially available 2-azetidinone has been described . The synthesis of the biological relevant N-Boc-(2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl10-phenyldecadenoic acid taking advantage of the base-promoted ring opening of a β-lactam has been completed . 4-Aryl-1-(2-chloroethyl)azetidin-2-ones have been transformed into novel 1-(1-aryl-3-hydroxypropyl)aziridines upon treatment with LiAlH4 . A PtCl2-catalyzed cycloisomerization of N-(2-alkynylphenyl) β-lactams to form benzene-fused pyrrolizinones selectively has been developed . The Aucatalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from N-(pent-2-en-4-ynyl)-β-lactams has been described . An efficient synthesis of hydroxy-substituted cispentacin derivatives starts from a bicyclic β-lactam . The one-pot reaction of β-lactam carbenes with 1-naphthyl or 5-quinolyl isonitriles followed by treatment with aqueous


101

hydrochloride produced benzo[h]-δ-carboline-2,4-diones or pyrido[3,2-h]-δ-carboline-2,4diones, respectively, in moderate yields . R2 OMe N O

R2

R3

R

i

CO2Me

R1O

R1O

R3 N 1 R 24 (49–68%)

O

Me

1

N O

OTBS

O

CN

O

ii O

R2

N R2

N R 26

25 (46–89%)

Reagents: i) MeONa, MeOH, reflux. ii) TBSCN, 10 mol% I2, MeCN, RT. FUSED AND SPIROCYCLIC β-LACTAMS

4.4

The chemistry of cephalosporins and penicillins has been reviewed . The antagonistic interactions between the flavonoids hesperetin and naringenin and β-lactam antibiotics against Staphylococcus aureus have been described . The quantitative retention-activity relationships (QRAR) model of β-lactam antibiotics has been studied . The increased antibacterial activity of β-lactam heterodimers in comparison with their monomeric components has been reported . The reaction of Schiff bases derived from 3-cyano-2,4-diamino thiophene with chloroacetyl chloride afforded spiro-β-lactams . The heterocyclizative crosscoupling between 2-azetidinone-tethered allenols and α-allenic acetates gave β-lactam– dihydrofuran hybrids 27 in good yields . New 3-heterocycle substituted 1,3thiazolidine-derived 4-spiro-β-lactams with a relative trans-configuration have been stereoselectively synthesised by means of a Staudinger ketene–imine reaction . Oxacyclopropane formation gives the highly strained oxiranyl-β-lactam 28, possessing a spirocyclic structure by treatment of a 3-[bromo(nitro)methyl] 3-hydroxy-β-lactam with bases . A novel Pd(II)- catalyzed C෥H lactamization reaction, including the formation of spiro-β-lactams has been achieved .

R2 OH

OAc

O

Me

O + Ar

N O

i

R1

O

O

H O

H

O O

O2N R1

N O

R2

27 (47–75%)

Reagents: i) 5 mol % PdCl2, DMF, 0 oC.

O

Me Ar

N O

PMP 28

Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C 29 which has a spirocyclic β-lactam unit, have been described . The isolation, structural elucidation and biological characterization of phyllostictine A, a new phytotoxic oxatricyclic β-lactam 30, produced in liquid culture by P. cirsii, have been described . Various glutaryl acylase mutants have been evaluated to improve the hydrolysis of cephalosporin C 31 in the absence of hydrogen peroxide . A thermal decarbonylation of penam β-lactams has been developed . Mechanisms for the hydrolysis of nitrocefin and penicillin G have been proposed . β-Lactams have been examined as selective chemical probes for the in vivo labeling of bacterial enzymes involved in cell wall biosynthesis,


102

antibiotic resistance, and virulence . A study of the biosensing process involving fluorophore-labeled β-lactamase as a biosensor for β-lactam antibiotics has been carried out . The resolution of racemic 2-chlorophenyl glycine with immobilized penicillin G acylase has been achieved . O N Br

O

Cl

N

29

R1HN

N Br N H

N

Me Me

R2

S N

O

O

OH

MeO HO 30

CH2R3 CO2H

R1 = (R) HO2C(NH2)CH(CH2)3CO R2 = H, R3 = OAc

31 An approach for synthesizing a series of 2-sulfide carbapenems has been developed using two successive Cu(I)-catalyzed cross-couplings in a single pot . Two different stereocontrolled accesses to new 4-hydroxypipecolic acid analogues 32 with a bicyclic β-lactam structure have been developed by using intramolecular reductive amination or allenic hydroamination reactions in 2-azetidinone-tethered azides . A variety of β-lactams bearing protected polar substituents was generated from chlorosulfonyl isocyanate (CSI)-derived building blocks . 1-Allyl-substituted 4-(2-bromo-1,1dimethylethyl)azetidin-2-ones have been transformed into bicyclic β-lactams through radical cyclization by means of n-tributyltin hydride and AIBN in toluene with excellent diastereocontrol . It has been reported that chlorosulfonyl isocyanate addition to (í)- and (+)-apopinene furnished monoterpene-fused β-lactams in highly regio- and stereospecific reactions . A convenient approach to novel selenium-β-lactams such as 3-selena-1-dethiacephems 33 involved a regioselective iodocyclization . The chemoselective cycloetherification reaction of enallenols under iron-catalyzed conditions resulted in the preparation of bicyclic β-lactams 34 . The stereoselective synthesis of carbapenams via Kinugasa reaction involved cyclic nitrones derived from malic and tartaric acid . A three-step procedure involving imine formation/Staudinger reaction/PausoníKhand cycloaddition enabled the preparation of fusedtricyclic azetidinones from the reaction of N-tosyl-N-allyl ketene with complexed acetals derived from propargylic aldehydes . A CeCl3·7H2O/NaI-promoted synthetic protocol for strained tricyclic β-lactams 35 has been developed from hydrazines . The reaction of 3-arylisoxazoles with LDA in THF at 0 °C afforded syn-2,6diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones (bis-azetidinones), via stereoselective dimerization of an azetidinone anion intermediate . A ring closing metathesis approach to N1–C3 bridged macrocyclic β-lactams has been developed . The synthesis and structural characterization of β-lactam condensed 3-thiaquinolines have been achieved . α,β-Unsaturated aldehydes, including 3-alkyl derivatives, undergo Nheterocyclic carbene (NHC)-catalyzed annulations with N-sulfonyl ketimines to provide bicyclic β-lactams 36 with outstanding diastereo- and enantioselectivity .

Four-Membered Ring Systems R3

TBSO H H

R2 N H

OH Me H N

O 32

R1

R1 N

H

H N

Se

O

O N 33

R2

R2

O

I

34

R1

103

R2 Ar1 O R1 N N O Ar2 35

Ar1 R H S

Ar2 N

O

SO2Ar 36

4.5 OXETANES, DIOXETANES, OXETANEDIONES AND 2-OXETANONES (βLACTONES) The chemistry of oxetanes, dioxetanes, and oxetenes has been reviewed . Reviews on recent progress on four-membered rings with two oxygen atoms the chemistry of 1,2-dioxetanes , carbonyl-olefination with ynolates via oxetene intermediates , cobalt-chemistry including oxetanes and 2-oxetanones have appeared. Progress in the use of second-generation taxoids for tumor-targeting chemotherapy has been reviewed . An account of NMR and synthetic studies establishing the T-taxol conformation as the bioactive tubulin-binding conformation has been published . Vibrational circular dichroism analysis reveals a conformational change of the baccatin III ring of paclitaxel 37 . Paclitaxel-polylactide nanoconjugates have been prepared by the site-specific polymerization of lactide mediated by a paclitaxelmetal complex followed by nanoprecipitation . A method has been developed for the methylation of the C3ƍ amide of taxol C and paclitaxel . Chemo-enzymatic synthesis of ester-linked taxol–oligosaccharide conjugates gives potential prodrugs . Danishefsky’s taxol CD ring key intermediate has been stereoselectivelly synthesized in 15 steps and 11.4% overall yield from a readily available starting material . The design, synthesis, and characterization of triazine dendrimers derivatized with the anticancer agent paclitaxel have been described . The synthesis of new D-seco-C-nor-taxane derivatives in which the D-ring has been deleted and the C-ring has been transformed into a new pentatomic ring, started from baccatin III derivatives . There is rotamer-dependent chemiluminescence in the intramolecular charge-transfer-induced decomposition of bicyclic dioxetanes 38 bearing a hydroxyaryl group . There is a marked difference in singlet-chemiexcitation efficiency between syn-anti isomers of spiro[1,2-dioxetane-3,1ƍ-dihydroisobenzofuran] for intramolecular charge-transfer-induced decomposition . The solvent-promoted chemiluminescent decomposition of a bicyclic dioxetane bearing a 4-(benzothiazol-2-yl)-3hydroxyphenyl moiety has been reported . Spirocyclic oxetanes are analogues of morpholine and also topological siblings of their carbonyl counterparts . A ruthenium-catalyzed synthesis of primary amines directly from alcohols, including aminooxetanes, and ammonia has been achieved under mild conditions . The bicyclic oxetane 39 has been prepared during the total synthesis of the halogenated marine natural product (+)-obtusenyne .


104 AcO

O

O O NH

Ph

O OH

OH O H OAc PhOCO

O

Ph OH

R

HO

Cl

H

t-Bu

O

O

N

O H

38

OTBDPS

39

37

Evidence that the (6–4) photolyase mechanism can proceed through an oxetane intermediate has been found . The synthesis of epi-oxetin 40, an oxetanecontaining β-amino acid, via a serine-derived 2-methyleneoxetane has been accomplished . The synthesis of tetrameric and hexameric carbopeptoids, such as the oxetane hexamer 41, derived from L-ribo 4-(aminomethyl)-oxetan-2-carboxylic acid has been achieved . Investigations into the secondary structural preferences of homooligomers of a new class of sugar amino acids, δ-2,4-cis-oxetane amino acids, have been reported . Mechanistic studies of the copolymerization reaction of oxetane and carbon dioxide to provide aliphatic polycarbonates catalyzed by (salen)CrX complexes have been carried out . (í)-Minlactone has been synthesized using oxetane as a building block . The syntheses of haterumalides NA and NC have been accomplished via the macrocyclization of a chlorovinylidene chromium carbenoid, the preparation of which began with the ring-opening of oxetane, onto a pendant aldehyde . The regioselective ring opening of 2-aryl oxetanes and 2-aryl azetidines with phenols, including catechol, has been achieved by the use of aryl borates in mild and neutral reaction conditions without the aid of any transition metal catalysts . The reductive opening of oxetanes by Cp2TiCl has been investigated by a combined synthetic and computational study . Ȧ-Trichloroalkyl phenyl ethers have been synthesized through a tandem reaction of benzyne with cyclic ethers, including oxetane . The carbonylative polymerization of oxetanes initiated by acetyl cobalt complexes has been reported . Treatment of fused oxetanes bearing a 2-methoxyphenyl moiety with Lewis acids leads to the formation of spirocyclic dihydrobenzofurans through intramolecular attack of an oxygen atom of the proximal phenolic methyl ether . O HO

OH NH2

R2

O

OBn

i

TrHN

iii

ii

O

TrHN

iv

O

O O N H

O

OBn

vi–x

N H

O

OBn

O

O

N H

CO2H

O 40 (2% overall yield from L-serine)

O O

H2N

OBn

O N H

O

OBn

O N H

O

CO2R1

OBn

41

Reagents: i) TMSCl, Et3N, MeOH, TrCl, RT. ii) BOP, Et3N, CH2Cl2, RT. iii) Cp2TiMe2, toluene, 80 oC. iv) DMDO, CH2Cl2, RT. v) DIBAL-H, toluene, –78 oC. vi) Ac2O, pyridine, RT. vii) (a) TFA, RT; (b) Et3N, Boc2O, RT. viii) NaOMe, MeOH, RT. ix) RuCl3, NaIO4, CCl4, MeCN, H2O. x) TFA, CH2Cl2, RT. 2-Nitrophenyl isocyanide is a convertible isocyanide as demonstrated by its feasibility and applicability in an efficient synthesis of the fused γ-lactam β-lactone bicycle of


105

proteasome inhibitor omuralide 42 . An alkylidene carbene 1,5-CH insertion was used as a key step in an enantioselective total syntheses of omuralide, its C7-epimer, and (+)-lactacystin . The synthesis of (–)-salinosporamide A 43 illustrated the synthetic utility of the In(OTf)3-catalyzed cyclization of nitrogen- and oxygen-tethered acetylenic malonic esters . A concise and straightforward total synthesis of (±)-salinosporamide A, based on a biosynthesis model has been accomplished . The total synthesis of salinosporamide A has been achieved through enzymatic desymmetrization, diastereoselective aldol reaction, intramolecular aldol reaction, and intramolecular Reformatsky-type reaction followed by 1,4-reduction, as key reactions . The engineered biosynthesis of antiprotealide and other unnatural salinosporamide proteasome inhibitors has been reported . The mutasynthesis of fluorosalinosporamide, a potent and reversible inhibitor of proteasome, has been described . The synthesis of (±)-vibralactone, (–)-vibralactone 44, and vibralactone C have been accomplished . The synthesis of 2,3- and 3,4methanoamino acid equivalents with stereochemical diversity and their conversion into the tripeptide proteasome inhibitor belactosin A 45 and its highly potent cis-cyclopropane stereoisomer was achieved . A concise stereoselective total synthesis of (í)tetrahydrolipstatin used an Oppolzer’s sultam-directed aldol reaction as the key step . A diastereo and enantioselective synthesis of natural and unnatural nocardiolactone utilised a proline-catalyzed crossed-aldol reaction as the key step . HO O

O Cl

NH Me

NH Me

OH

O

H OH

O

O 42

O

H

O 43

O

O O 44

O

N H

H N HO2C

NH2 O

45

Stereoselective aldol reaction of a homochiral iron octanoyl complex, followed by tandem oxidative decomplexation–cyclisation facilitated the asymmetric syntheses of tetrahydrolipstatin and valilactone . Spiro β-lactone-based proteasome inhibitors have been discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin . A chemical proteomic strategy was applied directly to bacterial proteomes, and β-lactones were identified as important natural product derivatives with a high affinity to various enzyme classes . A multidisciplinary chemical proteomic strategy has been applied and functionalized β-lactones have been identified as potent, cell permeable inhibitors for specific and selective targeting of the key virulence regulator complex ClpP in Staphylococcus aureus . A strategy taking advantage of the cooperative action of aprotic contact ion pair catalysis and Lewis acid catalysis has been used for the catalytic asymmetric selective synthesis of transconfigured 3,4-disubstituted β-lactones . The asymmetric dimerization of disubstituted ketenes catalyzed by N-heterocyclic carbenes afforded β-lactones 46 . The formal cycloaddition of disubstituted ketenes with 2-oxoaldehydes catalyzed by chiral N-heterocyclic carbenes afforded β-lactones 47 with α-quaternary βtertiary stereocenters . Optically active γ-allenoic acids have been synthesized from β-lactones . The one-pot synthesis of piperid-4-ones 48 has been achieved through TiCl4-promoted diketene addition to tosyl imines, followed by reaction with aldehydes . Studies leading to the development of a cascade sequence that generates as many as two CíC bonds, one CíO bond, and three new stereocenters providing


106

substituted tetrahydrofurans from keto β-lactones has been described . The synthesis of N-Boc-Į-halomethyl-Į-alkylglycines that involves cyclization of N-Boc-Į-alkylserines to the corresponding β-lactones under Mitsunobu reaction conditions, followed by ring opening with anhydrous MgX2 has been described . A computational study of the dyotropic rearrangement of α-lactones to β-lactones has been performed . The selective formation of a hydroxy pyroglutamate has been achieved via methanolysis of a bicyclic β-lactone . Dyotropic processes involving unprecedented 1,2-acyl migrations provided access to novel spirocyclic, bridged keto-γ-lactones from a series of fused, tricyclic-β-lactones . Using diketene as a basic reagent, a one-pot, pseudo-five-component reaction for the synthesis of highly substituted bisfuramides has been described . The one-pot synthesis of pyrrolo[2,1-a]isoquinoline-1-carboxamides via a four-component reaction involved diketene . The synthesis of highly functionalized pyrrole derivatives via a four-component reaction of two primary amines and diketene in the presence of nitrostyrene has been accomplished . Sulfonamides and 1,3-oxazine-2,4-diones result from arylsulfonyl isocyanates and diketene . The synthesis from diketene of both hydrazinesubstituted enaminones and 4,5-dihydro-1H-pyrrol-3-carboxamides has also been illustrated . The C1–C8 subunit of biselide E has beeen synthesized starting from a β-lactone . O C i Ar

O C

R R

Ar

Ar

R

O O

Ar1

HO

Ar1 H ii

COAr2

R

R

N

O O

46 (61–74%)

47 (73–99%)

up to 97% ee

up to 99% ee

R1

Ts iii

+ O O

MeO2C R2

N Ts

R1

48 (48–98%)

Reagents: i) 10 mol% NHC, THF, RT. ii) Ar2COCHO, 10 mol% NHC, THF, RT. iii) (a) TiCl4, CH2Cl2, –78 oC, them MeOH; (b) R2CHO, RT; (c) K2CO3, DMF. The ring-opening polymerization (ROP) of racemic β-butyrolactone catalyzed by chromium(III) complexes resulted in poly(hydroxybutyrate) with high molecular weight and with isotacticities of 60–70 % , while the ROP promoted by bis(guanidinate) alkoxide complexes of lanthanides formed syndiotactic poly(hydroxybutyrate) through a chain-end control mechanism . β-Lactones with fluorinated side-chains have been polymerized to form a series of new poly(β-hydroxyalkanoate)s, and their properties were examined with respect to their hydrocarbon analogs .

4.6

THIETANES, β-SULTAMS, AND RELATED SYSTEMS

Recent progress on the chemistry of thietanes, thietes, and four-membered rings with a heteroatom and one sulfur atom has been reviewed in several contributions . The Newman-Kwart OĺS rearrangement of O-aryl thiocarbamates, including the preparation of thietanes has been reviewed . Various 2-alkylidenethietanes 49 have been synthesized by intramolecular nucleophilic substitution reactions at an sp2 carbon of vinyl halides with thiolates . Installing hydroxymethyl substitution at C4 through vinylation and hydroborationíoxidation reactions of the C4 bis-hydroxymethyl derivative of a D-glucose based substrate, and inserting the heteroatom thereafter permitted the formation


107

of spirocyclic nucleosides 50 . A theoretical analysis of the oxidative coupling of two metal-coordinated disulfide species to an S42– rectangle provided the opportunity for reexamination of a number of compounds hitherto considered to be disulfide complexes . Treatment of α-dithiolactones with ethoxycarbonylformonitrile oxide resulted in the formation of 1,2-dithietan-3-ones 51, which can be oxidized to give 4,4-ditert-butyl-1,2-dithietan-3-one 1-oxides 52 R1

O R2

R2

S

i R1

Br

S

R2 R2

S

O

R

Uracil

R RO

49 (30–94%)

OH 50

O N

S

R S

+

ii

R

R S S

iii

O CCO2Et 51 (80–82%)

R

O S S

O 52 (76–78%)

Reagents: i) K2CO3, MeOH, N,N-dimethylimidazolidinone, 120 oC. ii) THF, RT. iii) mCPBA, CH2Cl2, RT. 3-Aryl-3-hydroxy-1-methylazetidine-2-thiones 53 react with HCl in DMSO to give 3methyl-5-aryloxazole-2-thiones through an oxidative rearrangement . NBenzoyl-β-sultam 54 undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis . β-Hydroxysulfinic acids and allylsulfonic acids have been accessed by chemoselective reduction of β-sultones 55 bearing a β-trichloromethyl substituent . The preparation of sulfilimines from the corresponding sulfoxides using the Burgess reagent has been reported to involve the four-membered heterocycle 56 . OH

R

R N S 53

4.7

Me

Ph O S N O O 54

O S O O 55

CCl3

O S Ar O S N 1 R O 56

SILICON AND PHOSPHORUS HETEROCYCLES. MISCELLANEOUS

Recent progress on the chemistry of four-membered heterocyclic rings containing silicon, phosphorous, selenium, tellurium, arsenic, antimony, bismuth, germanium, tin, lead, or boron has been reviewed in several contributions . An overview on nickel-catalyzed transformations with trialkylboranes and silacyclobutanes has appeared . The aromaticity and antiaromaticity of fourmembered P-heterocycles have been reviewed . Donor-free four-membered cyclic silenes, 1,2-disilacyclobut-2-enes 57, were produced from reaction of disilenides with vinylbromides Treatment of silacyclobutanes with enones under palladium catalysis resulted in formal cycloaddition to yield the corresponding eight-membered ring . 6-Oxa-2-silabicyclo[2.2.0]hexanes 58 were obtained via Paternò–Büchi reaction of acyl(allyl)silanes . [2+2] Cycloaddition reactions of P2 with alkenes to give 3,4-dihydro-1,2-diphosphetes 59 have been predicted to proceed via concerted paths . Calculations on 2,4-diborata-1,3-diphosphoniocyclobutane-1,3-diyls have been carried out . Oligomers of 1,3-diphosphacyclobutane-2,4-diyl units have been reported . The synthetic utility of Lawesson’s reagent has been documented


108

. A selenium-based hexameric macrocycle containing four-membered phosphaheterocycles has been prepared . The synthesis and reactivity of several phosphaheterocycles having metallic atoms have been reported . 2-Thia-, 2-selena-, and 2tellura-1,3,4-trisilabicyclo[1.1.0]butanes have been prepared . The synthesis of 1,3-diselenetanes 60 has been achieved . Various azaheterocycles bearing metallic elements have been characterized . The rhodiumcatalyzed oxygenation of 1,5-cyclooctadiene to 4-cyclooctenone with molecular oxygen proceeds via the 2-rhodaoxetane 61 . R1 O Si R1 Si R1 R2 57

4.8

R

P P Si

O 58

R2

Se R1

59

R

Se 60

R

O RhLn 61

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08JA6524 08JA7822 08JA8904 08JA10478 08JA12228 08JA12276 08JA12618 08JA13400 08JA13892 08JA14058 08JA14207 08JA14400 08JA14981 08JA15842 08JA15864 08JAN595 08JOC168 08JOC517 08JOC1264 08JOC1422 08JOC1635 08JOC1704 08JOC2041 08JOC2224 08JOC2367 08JOC3024 08JOC3574 08JOC3975 08JOC4198 08JOC4305 08JOC4504 08JOC4705 08JOC5015 08JOC5183 08JOC5436 08JOC5481 08JOC5926 08JOC6033 08JOC7402 08JOC7837 08JOC8049 08JOC8101 08JOC8104

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112 08JOC8469 08JOC8491 08JOC8791 08JOC8893 08JOC8998 08JOC9545 08JOC9762 08M835 08MI1 08MI2 08MI93 08MI145 08MI219 08MI351 08MI431 08MI443 08MI689 08MI1416 08OBC66 08OBC1108 08OBC1190 08OBC1635 08OBC2782 08OBC3823 08OL77 08OL201 08OL277 08OL369 08OL1267 08OL1401 08OL1417 08OL1711 08OL2199 08OL2227 08OL2737 08OL2877 08OL3259 08OL3319 08OL3477 08OL3525 08OL3571 08OL4037 08OL4239

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Four-Membered Ring Systems 08OL4975 08OL5187 08OL5207 08OL5317 08PS1679 08S429 08S661 08S725 08S1747 08S2074 08S2883 08S3295 08S3537 08S3742 08SL25 08SL108 08SL381 08SL463 08SL539 08SL583 08SL984 08SL1345 08SL1394 08SL1505 08SL1961 08SL2231 08SL2244 08SL2583 08T1002 08T1612 08T1901 08T3701 08T4575 08T4959 08T5036 08T5861 08T6801 08T6973 08T7178 08T7191 08T8659 08T9592 08T9928 08T10465 08T11198 08T11632 08T11839 08TA554

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114 08TA976 08TA984 07TA1005 07TA1857 08TA2296 08TA2363 08TA2620 08TL36 08TL215 08TL327 08TL340 08TL351 08TL601 08TL974 08TL1152 08TL3063 08TL3578 08TL3839 08TL4125 08TL4170 08TL5372 08TL5553 08TL5652 08TL6145 08TL6445 08TL6896 08TL7135 08TL7372

B. Alcaide and P. Almendros B. Lopez-Ortega, S.F. Jenkinson, T.D.W. Claridge, G.W.J. Fleet, Tetrahedron: Asymmetry 2008, 19, 976. T.D.W. Claridge, B. Lopez-Ortega, S.F. Jenkinson, G.W.J. Fleet, Tetrahedron: Asymmetry 2008, 19, 984. E. Forró, F. Fülöp, Tetrahedron: Asymmetry 2008, 19, 1005. X.-G. Li, M. Lähitie, L.T. Kanerva, Tetrahedron: Asymmetry 2008, 19, 1857. Z. Szakonyi, T.A. Martinek, R. Sillanpää, F. Fülöp, Tetrahedron: Asymmetry 2008, 19, 2296. N.W. Fadnavis, A.V. Devi, L.S. Jasti, Tetrahedron: Asymmetry 2008, 19, 2363. S.C. Case-Green, S.G. Davies, P.M. Roberts, A.J. Russell, J.E. Thomson, Tetrahedron: Asymmetry 2008, 19, 2620. T. Shigetomi, K. Okuma, Y. Yokomori, Tetrahedron Lett. 2008, 49, 36. P. Pérez-Faginas, I. Alkorta, M.T. García-López, R. González-Muñiz, Tetrahedron Lett. 2008, 49, 215. G. Kumaraswamy, B. Markondaiah, Tetrahedron Lett. 2008, 49, 327. L. Kiss, B. Kazi, E. Forró, F. Fülöp, Tetrahedron Lett. 2008, 49, 340. A. Alizadeh, A. Rezvanian, L.-G. Zhu, Tetrahedron Lett. 2008, 49, 351. K. Shimoda, H. Hamada, H. Hamada, Tetrahedron Lett. 2008, 49, 601. S.V. Amosova, V.N. Elokhina, A.S. Nakhmanovich, L.I. Larina, A.V. Martynov, B.R. Steele, V.A. Potapov, Tetrahedron Lett. 2008, 49, 974. K.X. Moreno, E.E. Simanek, Tetrahedron Lett. 2008, 49, 1152. K. Okuma, Y. Fukuzaki, A. Nojima, K. Shioji, Y. Yokomori, Tetrahedron Lett. 2008, 49, 3063. S. Nagasaki, S. Inagaki, Tetrahedron Lett. 2008, 49, 3578. A. Tarui, D. Ozaki, N. Nakajima, Y. Yokota, Y.S. Sokeirik, K. Sato, M. Omote, I. Kumadaki, A. Ando, Tetrahedron Lett. 2008, 49, 3839. M.-Y. Lei, K. Fukamizu, Y.-J. Xiao, W.-M. Liu, S. Twiddy, S. Chiba, K. Ando, K. Narasaka, Tetrahedron Lett. 2008, 49, 4125. M. Matsumoto, M. Tanimura, T. Akimoto, N. Watanabe, H.K. Ijuin, Tetrahedron Lett. 2008, 49, 4170. M. Matsumoto, H. Suzuki, Y. Sano, N. Watanabe, H.K. Ijuin, Tetrahedron Lett. 2008, 49, 5372. L.D.S. Yadav, V.K. Rai, Tetrahedron Lett. 2008, 49, 5553. L.D.S. Yadav, V.P. Srivastava, R. Patel, Tetrahedron Lett. 2008, 49, 5652. M. Matsumoto, Y. Takamido, K. Nomura, T. Shiono, N. Watanabe, H.K. Ijuin, Tetrahedron Lett. 2008, 49, 6145. A. Kudaj, A. Olma, Tetrahedron Lett. 2008, 49, 6445. S. Mangelinckx, A. Žukauskaitơ, V. Buinauskaitơ, A. Šaþkus, N. De Kimpe, Tetrahedron Lett. 2008, 49, 6896. N.N.B. Kumar, K.C.K. Swamy, Tetrahedron Lett. 2008, 49, 7135. L.F.R. Gomes, A.F. Trindade, N.R. Candeias, P.M.P. Gois, C.A.M. Afonso, Tetrahedron Lett. 2008, 49, 7372.

115

Chapter 5.1

Five-Membered Ring Systems: Thiophenes and Se/Te Analogues Tomasz Janosik and Jan Bergman Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge, Sweden [email protected], [email protected]

5.1.1 INTRODUCTION The strong and continuously increasing interest in thiophene chemistry is manifested in a multitude of new publications that appeared during the year 2008, where this important heterocycle is represented in research fields such as materials science and medicinal chemistry. Such diverse applications of thiophene derivatives have in turn inspired further studies in thiophene ring synthesis, as well as new developments in modifications of existing thiophene compounds. As in previous years, there are several new reviews available. Although some of these accounts target topics associated with thiophene-based materials, such as layers of oligothiophenes in nanoscale electronic devices , polythiophene semiconductors for transistor applications , annulated oligothiophenes , photochromic thiophene-containing materials , and the use of palladium-catalyzed CH arylation and homocoupling in construction of organic materials , a series of chapters in the most recent edition of Comprehensive Heterocyclic Chemistry are devoted to more fundamental aspects, namely structure , reactivity , ring synthesis , as well as applications . A general review covering the development of organic semiconductors for solution-processable field-effect transistors has also been published, providing numerous references to thiophene-based studies . Finally, a contribution detailing the advances in synthesis of fused thiophenes by the aromatic ortho-Claisen rearrangement has also become available . This chapter provides a survey of selected developments in the field of thiophene chemistry, with sections devoted to thiophene-based materials for special applications, which are now one of the major driving forces for further studies of this versatile class of heterocycles.


T. Janosik and J. Bergman

116

5.1.2 THIOPHENE RING SYNTHESIS For most applications, the well-established methods for thiophene ring synthesis are still in use, but new variations, as well as new annulation strategies are evolving, giving access to products which are not readily obtained by the classical literature routes. The Willgerodt–Kindler conditions have been implemented in, for instance, conversion of the butanone derivative 1 into the fused tricyclic product 2, which involves formation of two new thiophene rings. Co-formation of an isomeric system having the morpholine unit at C-3 of the outer thiophene ring was also observed. The sequence leading to this outcome was suggested to feature an intramolecular nucleophilic aromatic substitution of a thioenolate intermediate . Likewise, 3-(methylthio)thiophene derivatives have been prepared by treatment of suitable 1,4-dicarbonyl compounds bearing a methylthio-group with Lawesson’s reagent, i.e. following a well-known annulation technique . It has also been reported that 1,4dicarbonyl compounds can be converted to thiophenes using H2S in the presence of sulfamic acid as the catalyst . O S8, morpholine, Δ

N

S

N

46%

Cl

N

O

S

1

2

An efficient one-pot protocol has been devised for preparation of 2-aryl-5-nitrothiophene derivatives. As an example, the chloropropenal 3 was initially exposed to sodium sulfide in DMF, followed by reaction with bromonitromethane, and finally, a base-induced annulation, giving the product 4 in good yield .

CHO

Br

1. Na2S·9H2O, DMF 2. BrCH2NO2 3. NaOH, H2O

Br S

71%

NO2

Cl 3

4

The Gewald synthesis has also recently found a new application, involving cyclopropane derivatives as one of the reactants. For example, the substrate 5, which is equivalent to a ketone synthon, was reacted with tert-butyl cyanoacetate in the presence of sulfur and diethylamine, affording the thiophene 6. A related route involving initial opening of the cyclopropane ring using a fluoride source was also performed . NCCH2CO2t-Bu S8, Et2NH, MeOH

CO2Me

TMSO 5

CO2t-Bu MeO2C

66%

S 6

NH2

Five-Membered Ring Systems: Thiophenes and Se/Te Analogues

117

An unusual base-induced cyclization of the dione 7 with glyoxal, followed by acidic workup, gave the unexpected product 8. A plausible mechanistic explanation accounting for this outcome was also suggested . O

O Fe

S

1. HCOCOH, NaOEt 2. HCl

Fe

12%

S

O

O

7

8

Reactions between benzoyl isothiocyanates, ethyl bromopyruvate, and an enaminone derived from 2,4-pentanedione and pyrrolidine, provided access to a set of highly substituted thiophenes in excellent yields . The intermediate 9 could also be transformed rapidly into thiophenes upon annulation with bromoketones under solvent-free conditions, giving the products 10, or with related Į-haloamides, leading to a similar series of derivatives incorporating an amide motif . S

Ar

N

N Ar

O

RCOCH2Br KF-Al2O3, MW

O

62-89%

ROC

9

N

S

O

10

Numerous benzo[b]thiophenes have been synthesized by initial reactions of arylthiols with Įhaloketones in the presence of Na2CO3/SiO2, which gives intermediate Į-sulfanyl ketones, that can be eventually annulated into the target molecules using the combination PPA/SiO2. As an example, the thiol 11 participated in a reaction with 2-chlorocyclohexanone, affording the tetracyclic system 12 in excellent yield .

O SH

Cl

S

Na2CO3/SiO2 PPA/SiO2 87%

11

12

The macrocycle 13, which was prepared from simple thiophene building blocks using a sequence involving multiple metalation and cross-coupling steps, could be transformed into the terthiophene derivative 14 when subjected to Na2S .


118

Na2S MeOCH2CH2OH

Bu

Bu S

38%

S

S

Bu

S

S

13

Bu

14

Cyclization of the molecules 15 in triflic acid, followed by heating in pyridine, afforded the pentacyclic thiophene derivatives 16 in good to excellent yields. The solution processible products were used as semiconductors in fabrication of field-effect transistors . Such strategy has also been used for synthesis of related extended systems . A related approach was used for preparation of highly fluorinated derivatives of this pentacyclic core . O S R

R

S

1. CF3SO3H, P2O5 2. pyridine, reflux

R R S

S O 15a R = H 15b R = Bu

16a R = H (75%) 16b R = Bu (98%)

A convenient synthesis of dinaphthothiophene derivatives has been devised, where the readily available sulfide 17 (easily obtained by heating of naphthalene-2-thiol and 2-naphthol in toluene containing p-TsOH) was irradiated in the presence of iodine, giving the system 18 in good yield. Several substituted or extended derivatives could also be created using this approach .

S hν, I2

S

>79%

17 18

An example of chirality transfer has been observed in a gold-catalyzed synthesis of benzo[b]thiophenes, wherein the precursor 19 underwent annulation into the product 20 (74% ee) with retention of the configuration during the [1,3]-migration. The mechanistic aspects were also discussed, and a possible explanation for this outcome was provided in terms of formation of an intermediate contact ion pair .


119

OTBS Ph

AuCl (10 mol%) PhMe

OTBS

94%

S

S

Ph

19

20

A combination of a Horner–Wadsworth–Emmons olefination, and an ensuing intramolecular annulation/thio-Michael addition, provided the basis for conversion of ȕ-keto-İ-xanthyl phosphonates and aldehydes into thieno[2,3-b]thiopyran-4-ones, as illustrated by preparation of the product 21 from the substrate 22. The sequence is performed in one pot, and can also be extended to ketones . O S

(EtO)2(O)P

OEt

TMS S 22

1. NaH, THF 2. i-PrCHO 3. NaH 85%

O TMS S

S

21

Additional miscellaneous studies resulted in syntheses of thieno[2,3-c]pyrazoles , 4,6-dimethyl-tetrahydro- and hexahydrodibenzothiophene , thieno[2,3-b]indol-2ones , fused thiophene–azulene systems , and thieno[3,2-b]furan derivatives . 5.1.3

REACTIONS OF THIOPHENES

Much effort has been invested in chemical modification of existing thiophene rings over the years, and there are now efficient methods available for preparation of a wide variety of substituted derivatives. However, there is still room for many improvements of the existing approaches, while new types of thiophenes, which are in high demand for instance in materials chemistry, often require completely new strategies. It has been suggested that Zn(OTf)2·6H2O is an efficient catalyst for Friedel–Crafts acylation of thiophenes. For example, the thiophenes 23 underwent conversion to the acyl-derivatives 24 in excellent yields . The sulfonation of meso-tetra(thien-2ƍ-yl)porphyrin has been investigated, leading to the conclusion that under kinetic conditions, 5ƍ-sulfonation is strongly favoured, while heating in sulphuric acid at 130 °C, which corresponds to the thermodynamic conditions, give mainly 4ƍ-sulfonation . Friedel–Crafts type glycosidation involving 2-bromothiophene has been used in construction of 5-substituted thien-2-yl deoxyribonucleosides . In addition, it has been reported that the reaction between dithieno[3,2-b:2ƍ,3ƍd]pyrroles with tetracyanoethylene gives, apart from the expected tricyanovinyl products, also quinoid structures incorporating two dicyanomethylene groups .


120

MeCOCl, CH3NO2, rt Zn(OTf)2·6H2O (10 mol%)

X

S

84-89%

23

Z = H, Cl, Br

X

Ac

S 24

A sequence featuring several different types of reactions has been used in a route to 3fluorothiophene 25, a derivative which is notoriously difficult to prepare. The starting compound 26 was diazotized, followed by heating of the resulting salt, which afforded methyl 3fluorothiophene-2-carboxylate 27. This ester was in turn hydrolyzed to the corresponding acid, and decarboxylated giving the target compound 25 in 49% overall yield . NH2 S

1. NaNO2, HBF4 2. 160-200 °C, sand

CO2Me

62%

S

26

1. NaOH, EtOH 2. barium-promoted copper chromite, quinoline

F CO2Me

F S

78%

27

25

Metalation reactions are extremely useful in modification of thiophenes. This has been exploited in transformation of 3-bromo-4-methoxythiophene 28 into the bicyclic molecule 29, via the intermediate 30. The final product was also subjected to polymerization . In yet another application, two equivalents of 2-lithiothiophene were reacted with one equivalent of methyl formate giving an intermediate alcohol, which was further converted into a dendritic core featuring four thiophene units . Metalation chemistry has also been employed during, for example, syntheses of bromothienyl substituted nucleosides , tetrathia[7]helicenes , thiophene building blocks for new regioregular polythiophenes , and 2-acetyl-4,5-difluorothiophene . In addition, metalated thiophenes have been reacted with phosphorus tribromide, leading to tris(thien-2yl)phosphine derivatives . OH BuLi, THF

MeO

Br O S 28

MeO

NaHSO4 PhMe, Δ

, BF3·OEt2 75%

S 30

72%

O

S 29

It has been reported that the thiophene 31 can be exposed to 2.5 equivalents of BuLi, leading to a dilitihio-intermediate. This was in turn treated sequentially with suitable electrophiles, providing a series of trisubstituted products, for example 32. A set of 12 different thiophenes was prepared regiospecifically in this manner in modest to moderate yields . It should also be mentioned that the reactivity of lithium 2,3-dihydrobenzo[b]thiophene-1-oxide with aldehydes and imines has been the subject of a theoretical study .

Five-Membered Ring Systems: Thiophenes and Se/Te Analogues SMe

1. BuLi (2.5 equiv.), THF, -78 °C 2. TMSCl 3. ClCO2Me

S

63%

121

SMe TMS

31

S

CO2Me

32

Numerous approaches to modification of thiophene compounds involve transition-metalcatalyzed reactions. There are many new developments in this area, as well as new variants of the well-established principles. For example, thiophene-3-boronic acid or the corresponding 2substitued isomer can be coupled with aryl- or heteroarylchlorides in aqueous n-butanol in the presence of Na2PdCl4 and a sulfonated phosphine ligand . Suzuki couplings featuring thiopheneboronic acids have also been employed en route to pyrido[3,4b]thienopyrroles and pyrido[4,3-e]pyridazines . Coupling of benzylic halides with thiophene-3-boronic acid has also been reported . A new approach for iridium-catalyzed borylation of thiophenes via C–H functionalization has been established. In a series of 2-substitued or 2,3-disubstituted substrates, the borylation took place selectively at C-5 in excellent yields. On the other hand, similar reactions involving 3substituted thiophenes proved to be more problematic, sometimes giving rise to mixtures of products. Nevertheless, some transformations proceeded with high selectivity and yield, as illustrated by the borylation of 33, which afforded the useful derivative 34. In a 2,5-disubstituted series of substrates, borylation took place at C-3, and it was also observed that unsymmetrically substituted starting materials usually give mixtures of products. Although these methods are operationally rather cumbersome, they give access to some products which are otherwise difficult to prepare . Likewise, an iridium-catalyzed C–H functionalization protocol for thiophene derivatives using triethylsilane as the reagent has also been reported . CO2Me S 33

HBPin (1.2 equiv.) [Ir(μ2-OMe)(COD)]2 (cat.) dtbpy, n-hexane 95%

CO2Me PinB

S 34

Perarylation of thiophene-3-carboxylic acid has been shown to occur with concomitant decarboxylation. As an example, treatment of the substrate 35 with 1-bromo-4trifluoromethylbenzene in the presence of a palladium catalyst gave the perarylated product 36 in excellent yield. Similar chemistry may also be performed starting from 2,5-diarylthiophene-3carboxylic acids, which leads to products bearing two different types of aryl units . The carboxylic acid functionality has also been used as a removable blocking group during palladium catalyzed vinylation of thiophene derivatives, but such reactions gave mixtures of regioisomers, in contrast to some examples in the pyrrole or indole series . Palladium-catalyzed C–H arylation of structurally interesting thiophene substrates has also been accomplished in the presence of AgNO3–KF as the activator .


122

F3 C Br

CF3

CF3

Pd(OAc)2, PCy3 Cs2CO3, 4 Å MS mesitylene

CO2H

86%

S

S

F3 C

CF3

35

36

Palladium-catalyzed direct arylation has also been utilized as a key feature in an approach to fused polycyclic thiophene-based systems. As an example, the bromide 37 was subjected to a reaction sequence with the aryl iodide 38, providing the product 39. Related thiophene derivatives behaved in the same manner, giving tricyclic products . Yet another route to thiophene-containing fused aromatics relied on a combination of an intramolecular palladium-catalyzed C–H functionalization of thiophene, and an amination, both involving an internal gem-dibromovinyl unit .

O2N

I

Br

S

Pd(OAc)2 (10 mol%) P(2-furyl)3 (20 mol%) norbornene, CH3CN, Δ

S

77%

37

38

39

NO2

A series of interesting silicon-containing heterocycles featuring thiophene units has been accessed by palladium-catalyzed cyclization of 2-(arylsilyl)triflate precursors. In a representative example, the precursor 40 underwent a double cyclization in the presence of a suitable catalytic system, rendering the pentacyclic molecule 41 in excellent yield . TfO

OTf Si i-Pr

Pd(OAc)2 (cat.), PCy3 (cat.) Et2NH, DMA, 100 ºC

Si S i-Pr i-Pr i-Pr

i-Pr Si S i-Pr

85%

40

Si i-Pr i-Pr

41

It has been reported that thiophene-2-silanolates may undergo palladium-catalyzed crosscoupling with aryl halides. For example, the substrate 42 was converted to the product 43 upon initial exposure to base, followed by treatment with ethyl 4-iodobenzoate and Pd2(dba)3·CHCl3 as the catalyst . 1. NaH, PhMe 2. Pd2(dba)3·CHCl3

OH Si Me Me

S 42

I

CO2Et

S CO2Et

78%

43


123

A series of 2-substituted thiophenes have been subjected to palladium-catalyzed vinylation at C-5 under weakly basic conditions in the presence of the reagent combination Pd(OAc)/Cu(OAc)2·H2O/LiOAc. However, the yields were at best moderate . In the course of a study of rhenium-catalyzed hydroarylation of alkynes, acrylates, and isocyanates with heteroaromatics, the imine 44 could be annulated to the bicyclic thiophene-based system 45 by reaction with phenyl isocyanate, followed by treatment with acid. On the other hand, some similar substrates underwent only amidation under these conditions, but not cyclization . t-Bu N PhNCO [ReBr(CO)3(thf)]2 (2.5 mol%) ClCH2CH2Cl, reflux

O

57%

S

Ph N

OH

S

44

45

A rhodium-catalyzed 1,4-addition reaction has been developed for the synthesis of chiral thiophene derivatives from thien-2-yl-zinc bromide 46, as well as some related thienylzinc reagents. As an example, the organometallic species 46 was allowed to react with the lactone 47 in the presence of an appropriate catalyst and a phosphine ligand, affording the derivative 48 . O

[Rh(C2H4)2Cl]2 (cat.) (R,R)-Me-DUPHOS TMSCl, THF, rt

O Br

S

47

ZnX

Br

S

O

76%, 99:1 er

46

48

O

An example of the Nazarov cyclization in the thiophene series has been described. As an example, the substrate 49 was subjected to treatment with a catalytic amount of an iron catalyst, providing the trans-product 50 in good yield. The annulation of numerous related precursors also proceeded in moderate to good yields, with similar stereochemical outcome . A study of palladium-catalyzed annulation of (thien-2-yl)allylcarbamates resulted in synthesis of a series of thieno[2,3-b]pyrroles . Me O

CO2Me FeCl3 (10 mol%) PhMe, 60 ºC

Me S 49

S

80%

CO2Me O 50


124

Some developments involving various unsaturated or oxygenated thiophene derivatives also merit mentioning. For instance, it has been shown that selective alkylation of 2(5H)-thiophene-2one can be performed under Mitsunobu conditions . Various unusual spiroheterocycles, such as 51, have been obtained upon initial reactions of benzo[b]thiophen3(2H)-one 1,1-dioxide 52 with aldehydes, followed by treatment of the resulting intermediates with hexamethylenetetramine (HMTA) . In addition, thioaurones have been shown to undergo rearrangement to thioflavonols under the influence of the reagent combination TFA/Et3SiH . O S O

H N

1. PhCHO, EtOH, DMF 2. HMTA, AcOH, DMF

S

42%

O

O

52

O O S

O PhO 51

The stepwise oxidation of the pentacyclic thiophene system 53 has been evaluated as a tool for controlling the electronic properties of this class of molecules, and it was concluded that initial treatment with 2 equivalents of m-CPBA gives the S,S-dioxide 54 in 45% yield as the major product, along with minor amounts of two isomeric S,S-dioxides. Further oxidation experiments of 54 were also conducted, giving further systems having two oxidized thiophene units . S TIPS

S

O O S

S S 53

S

TIPS

TIPS

S

S S

S

TIPS

54

Additional studies have focussed on development of an acid removable linker for peptide synthesis based on a 5-(4-hydroxyphenyl)-3,4-ethylenedioxythienyl alcohol unit or the application of a similar structural motif as a super acid labile protecting group for peptide chemistry . The generation of nitrenes by photolysis of substituted sulfilimines of dibenzothiophene has also been described . 5.1.4 NON-POLYMERIC THIOPHENE ORGANIC MATERIALS As in previous years, there has been much activity in the field of thiophene-based diarylethene molecules, which can display striking changes in properties upon ring-closure, hence allowing construction of various devices controllable by irradiation. The oxidized system 55, obtained in good yield by oxidation of the corresponding parent molecules by m-CPBA, displayed an interesting feature, which was termed as invisible photochromism. Upon irradiation, the photocyclization of 55 into 56 took place along with a shift of the absorption band to a shorter wavelength in the UV region, without a visible color change .

Five-Membered Ring Systems: Thiophenes and Se/Te Analogues F

F

F

F

F

OF O S

F

O S O

317 nm 284 nm

F

F

F

OF O S

F

125

O S O

55

56

It has been demonstrated that the regulation of human carbonic anhydrase I (hCAI) activity can be accomplished using the specially designed photochromic system 57, via light-induced switching between the low- and high-affinity conformations . The ability of an ethene bearing two terthiophene units to undergo electropolymerization has been blocked by ring-closure upon irradiation .

NH

H2NO2S

HN S

O

S

N Cu

O

57

O

O

O O

The diaryethene 58, which contains a fused thiophene core, has been prepared by Suzuki coupling chemistry, and was also subjected to deeper studies. Upon excitation at 370 nm, strong luminescence was observed, whereas irradiation at 370 nm caused photochromism, giving a purplish red color. It should also be noted that when irradiated, only one of the diarylethene motifs in 58 underwent cyclization. . The photochromic system 59 could be converted to a derivative having two oxidized sulfur units, whereupon the ability to undergo photocyclization was lost. Removal of the oxygen atoms by treatment with NaBH4 led to recovery of the starting molecule, providing a means for controlling the photochromic activity of this molecule . It has also been noted that tetrakis(2-methylthien-3-yl)ethane exhibited the expected photochromic behaviour, whereas one of its tetrakis(methylthio) derivatives underwent rearrangement into a product containing two fused thiopyran rings upon irradiation at high conversion at 350 nm .

S

S

S

S

S S S

S

S

S 58

59

Several studies in this area focussed on diaryethenes containing two thiophene- or benzo[b]thiophene units in conjunction with a central maleimide core . In addition, new systems containing a six-membered aryl unit have been investigated . A macrocycle featuring alternating thiophene and ethylene fragments has also been constructed, and its photochromic properties have been studied . It should also be mentioned that dithienylethenes bearing pyridine rings have been used in modulation of chemical reactivity, by changing the coordinating effects of the pyridine ring nitrogen upon photocyclization or ring-opening . The bis(thien-2-yl)ethene system 60, which carries two conjugated pyridylethynyl fragments, can be rendered unreactive towards light upon protonation of the pyridine nitrogen atoms. However, in the ring-closed state, where the pyridine moieties are not conjugated, the expected photochromic properties were observed both for the unprotonated, and the protonated forms . Yet another study probed the ability of dithienylethenes having chiral or achiral amide motifs to gelate a selected series of solvents . As set of dithienylethenes containing urea units has been subjected to gelation studies . F

F

F

F

F

F

S

S

N

N 60

Moreover, an amphiphilic di(thien-2-yl)ethene system has been evaluated as a tool for imaging living cells , whereas an extended system featuring a perylene bisimide fragment has been employed en route to fluorescent memory devices . A writeby-light/erase-by-heat recording system has also been devised based on a bis(thien-2-yl)ethene core . Incorporation of a dioxaborole ring in a di(thien-2-yl)ethene has enabled modulation of the Lewis acidity of the boron atom by ring closure or ring opening . Additional studies focussed on temperature–light control of the clouding displayed by an oligo(ethylene glycol)-di(thien-2-yl)ethene system , and reversible fluorescence quenching of a di(thien-2-yl)ethene featuring a polythiophene block attached via a bridge containing an aromatic and a 1,2,3-triazole fragment . Many applications involving materials based on low-molecular weight molecules featuring thiophene units have also emerged recently. For example, the crown-ether 61 has been found to display electrochemical recognition for Na+ and Ba2+ ions , whereas studies have also been performed on C2-symmetric cyclophanes featuring a thieno[2,3-b]thiophene unit in conjunction with a bisnaphthol ring . The system 62 has been designed and evaluated as a material for dye-sensitized solar cells . Trimerization of di(thien-2-yl)acetylene and similar precursors has been achieved, affording a set of hexa(thien-2-yl)benzene derivaives, among others the parent system 63, en route to new electroactive materials . In addition, molecules based on tetra(thien-2-yl)benzene scaffolds have also been investigated . There is also a report detailing the synthesis of new thieno[3,4-b]pyrazines for potential electronic applications .


CO2Me

S O

O O

S

S

S

S O

O

O

CO2Me

S

O

127

Ph S

CO2Me

S

S

N Ph

S CN

CO2H

S

S

CO2Me

61

62

63

Various fused aromatics featuring thiophene rings have also attracted much interest recently as materials for electronic devices. The pentacyclic system 64 has been evaluated as an air-stable organic semiconductor . Likewise, organic transistors have been constructed based on the silicon-containing derivatives of an isomeric fused thiophene, for example 65 . Several derivatives of a somewhat related system, in particular 66, have also been subjected to some studies concerning their crystallization properties, and it was found that the fluorinated molecule 66 displayed the ability to form stable, high quality thin films for semiconductor applications . In addition, materials relying on the thienoacenes 67 and 68 have also been subjected to detailed studies as potential semiconductor materials . Finally, the phosphole-containing system 69, as well as a series of derivatives, has been investigated in detail . SiEt3

TIPS

S F

F S

S S 64

C6H13

C6H13

S

S

S

S

C6H13

C6H13 67

TIPS

SiEt3

65

66

C6H13

C6H13 S

S

S

S

C6H13

S

Ph C6H13

68

S

P Ph 69

Ph


128

Further examples of new thiophene-containing molecules displaying potential for various applications may be represented by for instance the systems 70 , 71 , and the trithia[5]helicenes 72 . The structurally relatively simple compound 73 has been evaluated as a material for field-effect transistors . Finally, it should also be mentioned that the molecule 74 may self-assemble into crystalline ribbons, which have been used in fabrication of highly sensitive photodetectors .

N C6H13

C5H11

C5H11

N C6H13

CN

S

S

S

MeO

Ph

Ph

S

S

70 S 72

71

C12H25 S

S

S

S

C12H25

C12H25

C12H25

S S

S

C12H25

73

S 74

C12H25

Two structurally very interesting thiophene derivatives, the heterocirculene 75 (sulflower) and its selenium containing analogue 76 (selenosulflower), have been evaluated as materials for organic field-effect transistors. It was concluded, that more studies are needed in order to better control the growth of films based on these materials . In addition, various aspects concerning thin films of 75 have also been studied . Se

S S

S

S

S

S S

S

S

Se

Se

S

S

S

Se

75

76

5.1.5 THIOPHENE OLIGOMERS AND POLYMERS These fields continue to attract considerable interest, as many oligomeric and polymeric thiophene-containing materials exhibit properties useful for a variety of technical applications.


129

Such molecules, which display increasing structural diversity and complexity, as well as their precursors, can often be accessed using well-established methodology, for example metalations and transition-metal catalyzed reactions. As indicated in the introduction, new reviews covering the fast progress in these areas appear continuously. This section aims only at giving some selected representative examples of new advances, without going into detail. A number of systems based on the 2,2ƍ-bithiophene core have been studied. As an example, the molecule 77 has been investigated as an organic nonlinear optical material . Likewise, studies have also been conducted involving the system 78 , as well as a 2,2ƍ-bithiophene bearing two benzoxazole units with amino acid fragments . N MeO

S

CN

N

S

N

H N

N

N H

S

N

N

77

N

S

N 78

The material 79, as well as some of its derivatives, has been demonstrated to undergo reversible ring-opening rendering a 2,2ƍ-bithiophene by cleavage of the bond between the quinone motifs upon reductive conditions, while oxidative conditions caused regeneration of the system . Moreover, 2,2ƍ-bithiophene units are also present in the silole derivative 80, which displayed electrogenerated chemiluminiscence , bithiophenesilanebased dendrimers , thiophene-containing donor–acceptor [2]rotaxanes , and various alkylthio-endcapped bis(oligothienyl) sulfides . In addition, some partially oxidized thieno[3,2-b]thiophene derivatives having a 2,2ƍ-junction between the thiophene moieties have been shown to exhibit ʌíʌ interactions which are not shown by their non-oxidized analogues . t-Bu

t-Bu

Ph

O

O

Ph

S t-Bu

t-Bu

S

S Si R2

S

S

S 79

80 R = C6H13

During the search for new efficient solvent-free dye-sensitized solar cells, the material 81 has been investigated as a potentially useful sensitizer, along with a closely related system containing a benzenoid unit instead of a benzo[b]thiophene . Tertiophenes terminated by one phosphole unit have been prepared and studied as new materials for optoelectronic applications . Moreover, an interesting ability to form nanostructres featuring channels for ions and holes is displayed by the terthiophene-based material 82 . A terthiophenebased compound involving o-(carboxamido)trifluoroacetophenone units has been devised for sensing of carboxylate anions by fluorescence , while materials based on building


130

blocks consisting of two terthiophene units linked by various moieties, such as disulfide or diacetylene, have been subjected to detailed studies . There is also an example of a terthiophene featuring a central thieno[3,4-b]pyrazine fragment . Conjugation of a terthiophene to a guanosine unit offered a tool for controlling its self-assembly depending on the conditions via hydrogen-bonding interactions between the guanosine units .

C6H13 N

S

S

S

CN

S

C6H13

CO2H

C6H13 81

S

C6H13

O(CH2)12 N

S

N

S

Me

CF3SO3

Me 82

Tuneable light-harvesting has been accomplished using the system 83, which was constructed using metallation/Stille-coupling as the key reactions starting from 2,2ƍ-bithiophene . Oligothiophenes having a bridging unit consisting of a methylenesulfanyl or ethylenesulfanyl unit incorporated in the two central thiophene rings have also been studied, in particular concerning their electronic and thermal properties . Quaterthiophene motifs have also been used as a key structural feature in a tweezer molecule, where the oligothiophenes may form an intramolecular ʌ-dimer upon two-electron oxidation of the system , whereas quaterthiophenes having one or two alkanethiol chains have been submitted to studies concerning their fixation on gold surfaces . Various oligothiophene fragments have also been connected into spider-like systems . AcO(H2C)2

N F2B N

S

S S

N BF2

S

(CH2)2OAc

N

83

The electronegative fluorinated oligomer 84 has been prepared using multiple metalations and couplings, and was found to exhibit high intrinsic electron mobility . Related


131

oligomeric thiophene derivatives featuring fused difluorodioxocylopenetene motifs have also been studied in connection with their application in construction of organic field effect transistors . F

F

F

F

F

F

F

F

F

F

F

F F

S

F F

S

S

S

S F F

F

F

F F

F

F F

S F F

F

F

F

F

F

F

F F

F

F

84

There has also been much activity in the field of polymeric thiophene-based materials, many of which display promising properties for a wide variety of different applications. For example, it has been shown that the performance of the quite popular polymer poly(3,4ethylenedioxythiophene) (PEDOT) 85 in solar cells can be enhanced upon photoelectropolymerization of the corresponding dimer in the presence of the anion TFSIí [(F3CSO2)2Ní] . An enzymatic polymerization of the monomer 3,4ethylenedioxythiophene (EDOT) has been performed in aqueous sodium polystyrenesulfonate solution the presence of 1% terthiophene as the radical mediator . Studies involving synthesis and polymerization of derivatives of the structurally related monomer 3,4ethylenedithiathiophene have also been conducted . O

O S S

n O

O

85

A series of aminoalkylsulfanyl-substituted polythiophenes, which are readily soluble in many common organic solvents have been prepared. As an example, the polymer 86 displayed solubility in methanol, and even in water . The related cationic polythiophene 87 has been utilized in direct visualization of glucose phosphorylation . Alkyl-group containing terthiophene-functionalized metal nanoparticles have been subjected to electropolymerization, producing nanotube composites , whereas the polymerization of gold nanoparticles bearing 5-mercapto-2,2ƍ-bithiophene units has been accomplished on the surface of multiwall carbon nanotubes . It has also been reported that treatment of poly(3-hexylthiophene) with dimethyl sulfate improves many of its properties, such as hole mobility, and stability against photodegradation . In addition, efficient solar cell devices have been designed relying on regioregular poly(3-butylthiophene) nanowires, which can form nanowire networks in conjunction with a fullerene-based ester .


132

(CH2)7NMe2 S

Cl Me

O(CH2)3NMe3

S S

n

S

n

87

86

Supramolecular structures based on the polymer 88 have been studied, also leading to an application in an organic field effect transistor . It has been demonstrated that sequential nickel-catalyzed polymerization of 2-bromo-3-hexyl-5-iodothiophene, followed by 2,5-dibromo-3-phenoxymethylthiophene provides an easily controllable procedure for synthesis of the copolymer 89, which displayed a phase separation, as the alkyl-containing blocks are crystalline, whereas the blocks bearing phenoxymethyl groups are amorphous . In this context, it should also be mentioned that the Kumada catalyst-transfer polymerization of thiophene monomers, dimers, or trimers, has been the subject of a mechanistic study, suggesting that a chain-growth mechanism is in operation during polymerization of bi- or terthiophenes, and that the nickel catalyst undergoes selective transfer along conjugated systems featuring even three thiophene units . C6H13

(CH2)5(CF2)4F Br

S S

n

S

n

C12H25 88

S

H m OPh

89

A number of polymers containing fused thiophene motifs have also been discussed during the reporting period of this chapter. For example, poly(thieno[3,4-b]furan), a new polymer displaying a low band gap, has been prepared and investigated in detail . The polymer 90, a polyelectrolyte, has been prepared in situ by treatment of the appropriate polymeric substrate with trimethylamine in solution . A series of material with thermocleavable ester units have been studied, all affording the same final product 91 . Additional studies focussed on the influence of substituents on the properties of poly(thieno[3,2b]thiophenes) , cyclopentadithiophene polymers incorporating chiral alkyl chains , and tetrathienoacene-containing polymers as soluble semiconductors with high mobility .

Five-Membered Ring Systems: Thiophenes and Se/Te Analogues HO2C

133

CO2H

(CH2)10NMe3 Br S S

N

S S

n

N

S

Br Me3N(H2C)10

S

S

90

S

n

91

Numerous studies have been devoted to copolymers incorporating thiophene units in combination with other structural motifs in their backbone. As an example, the material 92 has been prepared by Stille coupling, and studied with regard to its photovoltaic properties . Further examples of copolymers featuring thiophene rings together with dithieno[3,2-b:2ƍ,3ƍ-d]pyrrole units have been synthesized using palladium-catalyzed coupling, and were used for fabrication of organic field effect transistors . There are more examples of donor/acceptor copolymers incorporating thiophene units in combination with benzo-2,1,3-thiadiazole motifs , as well as additional phenylene rings, as illustrated by the polymer 93 , or indolo[3,2-b]carbazole units . Semiconducting polymers closely related to 93, but lacking the thiadiazole units have also been investigated in detail . C6H13 Et

C6H13

Bu Bu N

N

Et S

S

S 92

S N

S S

S S

S

m N

n C6H13

n S N

C6H13 93

It is also common to construct copolymers based on 3,4-ethylenedioxythiophene (EDOT), as illustrated by, for instance, the metallopolymer 94 . Other examples of EDOTcontaining polymers have been constructed based on 2H-benzo-1,2,3-triazole , or quinoxaline monomers . It has also been shown that conducting 3,4ethylenedioxythiopheneícarbazole copolymers can be obtained upon solid-state conversion of suitable processable poly(arylsilane)precursors .


134

O

O S S

N

n

N

Eu

O

O

O

O

3

94

In addition, new thiophene-based polymers incorporating, for example, such monomer combinations as 9,9-dioctyldibenzosilole and 2,2ƍ-bithiophene , benzo[1,2-b:4,5bƍ]dithiophene and benzo-2,1,3-thiadiazole , fluorene and thieno[2,3-b]thiophene , as well as 2,2ƍ-bithiophene and perfluorobenzene have been reported. A copolymer featuring crystalline poly(3-hexylthiophene) blocks as donors and poly(perylene bisimide acrylate) blocks as acceptors has been devised for transistor applications . Finally, the material 95 has been prepared, and was utilized in near-infrared light-emitting field effect transistors . C8H17 C6H13 S

N S

C12H25

O

O

C12H25 S

N

C6H13

S

n

C8H17 95

5.1.6

THIOPHENE DERIVATIVES IN MEDICINAL CHEMISTRY

The thiophene core is now enjoying some popularity as a subunit of numerous biologically active compounds, where it can sometimes be found in the form of even surprisingly simple derivatives. More complex systems, or such incorporating fused thiophene rings are also rather well-studied. This section aims at highlighting some of the numerous developments that have been reported during the year 2008. During a study towards new inhibitors of the Fe(II)-form of E. coli methionine aminopeptidase, the binding mode of the small molecule 96 to the enzyme was determined using X-ray crystallography. Several related thiophene derivatives prepared using Suzuki crosscoupling methodology, displayed efficient inhibition of four Gram-positive or Gram-negative bacterial strains . A few different types of structures based on the 2(trifluoroacetyl)thiophene core have recently attracted some interest . As an example, the molecule 97, derived from the starting


135

material 5-(trifluoroacetyl)thiophene-2-carboxylic acid, displayed potency as a human histone deacetylase inhibitor . Moreover, the thiophene derivative 98, as well as a set of closely related compounds, was investigated as an inhibitor of tubulin polymerization . MeO Et OH

F3C

O S

N OMe

N

O

S

S O O

OH 96

OMe

97

S

F

O 98

It has been demonstrated that a series of 5-substituted 2-aminothiophenes prepared using the Gewald synthesis as the key step, act as allosteric enhancers of the A1 adenosine receptor. Although a phenyl unit at C-5 was important for high potency, the most active compound of the whole series was the molecule 99, despite a free 5-position . Likewise, the structurally related, larger substance 100 has also been identified as an enhancer of this receptor . The Gewald synthesis has also been employed en route to 5-aryl-2ureidothiophene-3-carboxamides as checkpoint kinase inhibitors . In addition, inhibition of the complement component C1s has been ascribed to a series of thiophenes containing a biphenylsulfonyl motif . The thiophene derivative 101 (begacestat) has been designed for treatment of Alzheimer´s disease .

Ph S 99

NH2

Cl

N

N

CF3

Cl S 100

F3C

HO

O

O

F

NH2

Cl

N H

NH S O O 101

A structurally very simple compound, namely benzo[b]thiophene-2-boronic acid 102 has been found to display powerful activity for inhibition of fatty acid amide hydrolase , whereas yet another simple derivative, the amine 103, obtained by palladiumcatalyzed amination of 3-bromo benzo[b]thiophene, exhibited antifungal effects . Moreover, the system 104, based on a benzo[b]thiophene core, has been evaluated as a histone deacetylase inhibitor . An extended benzo[b]thiophene structure having a 2aminomethylpiperidine fragment was shown to be an urotensin-II receptor antagonist .


136

O

HN N S

B(OH)2

H N

N H

102

S

N

S

H2N

O

103

104

N

The thieno[2,3-c]pyran derivative 105 has been investigated as a thiophene bioisostere of spirocyclic ı receptor ligands, and was found to possess good ı1 affinity . Yet another thiophene fused to an unsaturated heterocycle, namely compound 106, emerged as a lead compound towards new antitubulin agents . From a class of 2alkenylthieno[2,3-b]pyridine-5-carbonitriles, compound 107 was identified as a potent and selective inhibitor of PKCș . Moreover, molecules featuring a thieno[3,2b]pyridine core have been studied as inhibitors of c-Met and VEGFR2 tyrosine kinases . OMe

MeO

Bn N

Me

OMe O OMe

S 105

CN

O

O

H2N

N CO Me 2

N S

N

S 106

N H

107

Various thienopyrimidine-based molecules have also been studied in considerable detail, leading to several new developments. In the thieno[2,3-d]pyrimidine series, there has been activity towards dual thymidilate synthase and dihydrofolate reductase inhibitors, leading for instance to the molecule 108, which displayed good potency , whereas other thieno[2,3-d]pyrimidines have been shown to possess anti-inflammatory and analgesic effects . A number of structurally rather complex thieno[3,2-d]pyrimidines bearing a pyrrolidinyl-acetylenic unit have been shown to exhibit selective inhibition on epidermal growth factor receptor tyrosine kinases . Following the identification of a set of thieno[3,2-d]pyrimidine-4-methanone derivatives as antagonists of human adenosine A2A receptor , a series of 4-arylthieno[3,2-d]pyrimidines were also evaluated in this context, showing some promising effects . Additional thieno[3,2-d]pyrimidine systems have been ascribed potential anticancer properties . Finally, the thieno[3,4-d]pyrimidine-based molecule 109 has been designed as a fluorescent nucleoside analogue for sensing of mismatched pairing .


137

O

S

HN H2N

N

NH

S

O

N

(Et3NH+)4

NO2

O O O O O P O P O P O O O O

Me

S 108

O OH OH

109

A series of 2-aminothieno[3,4-d]pyridazine derivatives, for instance compound 110, have been identified as a new class of adenosine A1 receptor allosteric modulators and antagonists . In addition, thieno[3,2-c][1,2,6]thiadiazine derivatives, such as molecule 111, have been evaluated for anti HIV properties , while a set of benzothieno[2,3d][1,3]thiazine derivatives has been designed aiming at selective inhibition of multidrug resistance-associated proteins . Cl CN O N S O N Bn

N N CO2Et

O H2N

S

S

O 111

110

5.1.7 SELENOPHENES AND TELLUROPHENES Currently, there is relatively little activity in this area compared to the research in thiophene chemistry, which is, to some extent, probably in part due to the relatively limited availability and high cost of commercially available simple selenophenes and tellurophenes. Nevertheless, some new studies have been performed, illustrating that these ring systems still have some importance in certain applications as alternatives to the corresponding thiophene derivatives. A series of enynes 112, which either contain a selenide or telluride moiety, have been shown to undergo copper iodide-catalyzed annulation in the presence of dichalcogenides, giving the selenophenes 113 or tellurophenes 114. Some of the resulting products were employed in crosscoupling reactions, leading to more elaborate structures . Ph RX

YAr

CuI (cat.), ArY2Ar DMSO, 110 °C 42-91%

Ph

X

Ph

Ph 112

R = Bu, Et, Me Y = Se, Te

113 X = Se 114 X = Te


138

Enyne precursors incorporating a selenium moiety, such as 115, have also been converted to selenophenes by initial treatment with butyltellurium tribromide, part of which ends up in the final products, followed by exposure to reductive conditions, as illustrated by synthesis of the heterocycle 116. Most reactions involving similar substrates proceeded in good yields, providing a series of related selenophene derivatives . Ph TeBu

1. BuTeBr3, CH3CN, rt 2. NaBH4, EtOH, rt

BuSe

91%

Ph

Ph

115

Se

Ph

116

The diene 117 served as a starting material incorporating all necessary carbon atoms, leading to the selenophene 118 upon reaction with SeCl2 in the presence of sodium acetate, eventually affording the molecule 119, the selenium analogue of EDOT. This material could be finally converted to poly(3,4-ethylenedioxyselenophene), a highly conductive material .

MeO

OMe

SeCl2, NaOAc C6H14, -78 °C to rt

OMe

MeO

42%

Se 118

117

HOCH2CH2OH, p-TsOH PhMe, 50-55 °C, 12 h 52%

O

O

Se 119

A one-pot sequence for preparation of a series of 3-amino-2-nitroselenophenes 120 has been developed, wherein the precursors 121 were initially exposed to Na2Se giving an intermediate selenolate, followed by treatment with bromonitromethane, and finally a hydroxide mediated cyclization . A similar set of 2-aminoselenophene-3-carbonitriles were converted to tricyclic selenophenopyridines .

R

CN

1. Na2Se, DMF 2. BrCH2NO2 3. NaOH

Cl

57-66%

121

NH2 R

Se

NO2

R = 4-Me/OMe/Cl-C6H4, t-Bu

120

Other studies featuring selenophene ring synthesis encompass conversion of 1-nitroperylene into perylo[1,12-b,c,d]selenophene using elemental selenium in hot NMP , transformation of benzo[c]furan intermediate into the corresponding benzo[c]selenophenes by Woollins’ reagent , preparation of selenophene analogues of the antihypertensive agents milfasartan and eprosartan , and synthesis of 4ƍselenonucleosides . It has also been shown that 3-iodoselenophene derivatives participate in Negishi crosscoupling reactions at room temperature . In addition, two benzo[1,2-b:4,5bƍ]diselenophenes were included in a study of benzodichalcogenophenes bearing perfluoroarene motifs .


139

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Chapter 5.2 Five-Membered Ring Systems: Pyrroles and Benzo Analogs Jonathon S. Russel St. Norbert College, De Pere, WI, 54115, USA [email protected] Erin T. Pelkey and Sarah J. P. Yoon-Miller Hobart and William Smith Colleges, Geneva, NY, 14456, USA [email protected]

5.2.1

INTRODUCTION

The synthesis and chemistry of pyrroles, indoles, and fused ring systems reported during the past year (2008) are included in this monograph. Pyrroles and especially indoles continue to draw a lot of attention from the scientific community due to their prevalence in natural products and wide range of biological and materials science applications. Pyrroles and indoles are treated in separate sections. Review articles and monographs that have appeared in 2008 will be mentioned in the relevant sections. 5.2.2

SYNTHESIS OF PYRROLES

Pyrrole syntheses have been organized systematically into intramolecular and intermolecular approaches, as well as by the location of the new bonds that describe the pyrrole ring forming step (two examples illustrated below). Multi-component reactions and pyrrole syntheses from other heterocycles appear at the end of this section. A review article by Dumitrascu detailed the synthesis of pyrrolo[1,2-b]pyridazines . The syntheses of pyrroles utilizing ruthenium-based methods , and also utilizing the Barton-Zard cyclocondensation , have been reviewed by Cadierno and Ono, respectively. type c N R

5.2.2.1

5.2.2.1 intramolecular

c d

b e

Na R

type bd 5.2.2.2 intermolecular

N R

Intramolecular Approaches to Pyrroles

Intramolecular Type a. The most facile bond disconnection leading to pyrroles involves breaking the ‘a’ bond to nitrogen. Common cyclization strategies include condensations of γ-aminoketones and aldehydes and electrophilic (and metal-mediated) cyclizations of 5-aminopentene and 5aminopentyne derivatives. Group 12 metal-mediated (ZnII, CdII, HgII) cyclization reactions c 2009 Elsevier Limited. All rights reserved.

J.S. Russel et al.

146

of alkyne-substituted enamides gave 2,5-dimethylpyrroles . The De Kimpe group reported a bromocyclization of ketimines leading to 5-alkoxymethyl-2-aryl-3chloropyrroles via pyrrolinium intermediates. An aza-Wacker oxidative cyclization of 5-aminopentene derivatives (e.g., 1) catalyzed by PdII/CuII system led to the formation of 1,2,5-trisubstituted pyrroles (e.g., 2) . Palladium-mediated amino-Heck cyclizations of phosphinyloximes led to the formation of 2,5-disubstituted pyrroles . Ohno and co-workers investigated a palladiumcatalyzed domino cyclization of 1,7-diamino-5-bromohept-3-ynes which gave fused pyrroles (2,7-diazabicyclo[4.3.0]non-5-enes and a hexahydroindole) . PdCl2(PhCN)2 Cu(OTf)2, EtOH

NHBoc Ph

Ph

88% OH 1

N a Me Boc 2

De Kimpe and co-workers reported a novel approach to 3,4-fused pyrroles from the corresponding ortho-bis(aminomethyl)arenes . Treatment of naphthalene 3 with cerium(IV) ammonium nitrate (CAN) led to the formation benzo[f]isoindole-4,9-dione 4 via oxidation of one of the aminomethyl groups into the corresponding aldehyde and subsequent cyclocondensation. 3-Polyfluoroalkylpyrroles were prepared by treatment of aminoethyl vinyl ethers with HCl and the subsequent cyclocondensation of the corresponding γ-aminoketone intermediates that were generated . MeO

HN

t-Bu

H N

MeO

CAN (4 equiv) CH3CN/H2O t-Bu

O

O

a

H N

87%

MeO

N t-Bu t-Bu O

MeO

4

3

Intramolecular Type c. The Cacchi group reported a 5-exo-dig cyclization approach to tri-substituted pyrroles (e.g., 6) by treatment of N-propargylic β-enaminones (e.g., 5) with cesium carbonate . Interestingly, a different mode of ring closure, 6-endo-dig, was in operation upon treatment of 5 with CuBr which led to tri-substituted pyridine 7. O O

O

Me CuBr, DMSO

Me Ph

N 7

60%

Me Me

Ph

N H 5

c

Me

Cs2CO3, DMSO 69%

Ph

N H 6

Ring-closing metathesis has been explored by Donohue for the preparation of simple pyrroles and by Lamaty for the preparation of 2-aryl-3-ketopyrroles . The latter compounds were utilized in a synthesis of pyrrolo[3,2-c]quinolines. In continuing studies by the Beccalli group, heterocycle-fused pyrroles (thieno[3,2-b]pyrroles, thieno[2,3b]pyrroles, and furo[2,3-b]pyrroles) were formed via palladium-catalyzed 5-exo-trig oxidative cyclizations of N-allylaminoheteroarenes .

Five-Membered Ring Systems: Pyrroles and Benzo Analogs

5.2.2.2

147

Intermolecular Approaches to Pyrroles

Intermolecular Type ac. Two related approaches to highly substituted pyrroles from 1,3-dicarbonyl compounds (e.g., 8) were reported by the Narasaka group. Treatment of 8 and ethyl α-azidocinnamate 9 with Cu(NTf2)2 produced tetra-substituted pyrrole 10 . This transformation required the presence of the carboethoxy group. On the other hand, treatment of 8 and vinyl azide 11 with Mn(OAc)3 gave tri-substituted pyrrole 12 via a radical process . N3 c

Ph

a

CO2Et

N H 12

Ph

Me

CO2Et

Ph O

11

Mn(OAc)3, AcOH Me 94%

Ph

N3 9

O OEt 8

c

EtO2C a N H 10

Cu(NTf2)2, MeCN 80%

CO2Et Me

Novel Zn-catalyzed heterocyclization approaches to 1-aminopyrroles from 1,2-diaza-1,3butadienes were reported by Attanasi and Langer . Interestingly, treatment of Danishefsky’s diene 13 with 1,2-diaza-1,3-butadiene 14 in the absence of a Lewis acid led to the formation of 4-acetylpyrrole 15 . O

O OSiMe3

CO2Et +

H2O

Me

76%

N OMe

c

Me

H

a

O N

CO2Et

Me N NHCONH2

NH H2NOC

N H2NOC 14

13

Me

CO2Et

Me

15

A Trofimov reaction (cyclocondensation of ketoximes with acetylene) was employed in the preparation of 2-(1-adamantyl)pyrroles . A large number of highly substituted pyrroles were formed via microwave-assisted heterocyclizations of propargylamines and aldehydes . The mechanism of this domino reaction involved an enamine formation, [3,3]-aza-Claisen rearrangement, and imine-allene cyclization. Functionalized pyrroles were prepared from β-iododehydroamino acid methyl esters by the Queiroz group utilizing a tandem Pd/Cu-mediated Sonogashira alkynylation followed by 5-endo-dig cyclization reminiscent of the Larock heteroannulation . Intermolecular Type ad. Naka and Kondo developed a novel approach to highly substituted pyrroles . Treatment of propargyl silyl ether 16 with a phosphazene base in the presence of imines 17 gave tetra-substituted pyrroles 18. A one-pot, three component reaction that generated 16 in situ was also reported. Ph

Ph Ph

R2 +

OTMS 16

NR1 17

t-Bu-P4, toluene 61-97%

d

Ph

a

N R1 18

R2

An interesting approach to 5-heteroaryl-3-benzoylpyrroles by Ryabukhin employed a cyclocondensation reaction between 3-formylchromones and hetarylmethylamines

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148

. Opatz reported an approach to the lamellarins that involved a cyclocondensation between 1-cyanoisoquinolines and cinnamic esters (modified von MillerPlöchl reaction) . A Knorr-type pyrrole synthesis reported by Huggins allowed for the preparation of pyrrole-2-carboxamides . Intermolecular Type ae. The de novo synthesis of pyrroles through the Paal-Knorr cyclocondensation of 1,4dicarbonyl compounds (and equivalents) with primary amines continues to be an active area of investigation. Novel catalysts examined by De in the context of this reaction include sulfamic acid and praseodymium(III) triflate . The Ley group examined the use of magnesium nitride as a precursor to ammonia for use in the preparation of N-unsubstituted pyrroles . Under microwave irradiation, treatment of diketone 19 with magnesium nitride in the presence of methanol gave pyrrole 20. Pan and Wu developed a synthesis of 3-methylthiopyrroles by the condensation of 2-(methylthio)-1,4diones with ammonium formate . The Gribble group has employed PaalKnorr reactions to prepare a variety of bipyrroles including 2,2’-bipyrroles , 1,2’-bipyrrole 21, and 1,3’-bipyrrole 22 . Bipyrroles 21 and 22 were formed by tin-mediated reductive cyclization of nitropyrroles and succinaldehyde; perhalogenation of 21 gave bipyrrole natural product Q1 . Finally, a novel approach to pyrrolo[1,2-a]benzazepin-6-ones 23 reported by Abonia and co-workers involved a tandem Paal-Knorr cyclocondensation/intramolecular Michael addition of oaminochalcones . O a

O Ph

Me

Mg3N2 MeOH, μW 99%

O 19

Me a N e H 20

O

O

Ne

e

Ph

N N a Me

N Me

Ar

21

22

Michael 23

a

Ne

Liang and co-workers reported an approach to fused pyrroles that involved a tandem gold(III)-catalyzed amination/hydroamination of enynols with sulfonamides . Treatment of enynyol 24 and tosylsulfonamide with HAuCl4 gave fused pyrrole 25. The Bertrand group investigated gold-catalyzed double hydroaminations of hexa-1,5-diynes with ammonia which led to 2,5-disubstituted pyrroles .

OH Ph

HAuCl4•4H2O TsNH2, CH3CN 81%

Ph 24

Ph

a

Ne Ts 25

Ph

Intermolecular Type bd. An important de novo synthesis of 2,3,4-trisubstituted pyrroles involves the cyclocondensation of nitroalkenes (and other electron-deficient alkenes) with activated isocyanides and is often referred to as the Barton-Zard pyrrole synthesis. Ono published a review that details his research group’s utilization of the Barton-Zard pyrrole synthesis in the synthesis of porphyrins and dipyrromethene dyes . An asymmetric variation involving α-isocyano-α-phenylacetates provided entry into optically active dihydropyrroles


149

. A tandem sequence developed by Shin combined a Horner-WadsworthEmmons reaction of aromatic aldehydes (e.g., 26) followed by cyclocondensation with TosMIC 27 providing a one-pot synthesis of 3,4-disubstituted pyrroles (e.g., 28) . The key to this process was using toluene as the solvent. O EtO P EtO

O Ts

OEt

CO2Et

NC 27

CHO sodium t-amylate toluene

b

N H 28

CO2Et

26

d

Multi-component reactions. The cycloaddition of azomethine ylides or their cyclic equivalents (e.g., münchnones or 1,3-oxazolium-5-oxides) with alkynes provides a quick entry into highly substituted pyrroles. A three-component reaction involving α-amidoethers, CO, and alkynes produced pentasubstituted pyrroles via the cycloaddition of in situ generated münchnones . Several studies investigated the use of three- and four-component reactions to prepare highly functionalized pyrroles with selected examples illustrated below. Three-component sequences included the following reactants and products: (a) 1,3-dicarbonyls, arylglyoxals, and ammonium acetate in water producing β-hydroxypyrroles 29 ; (b) 1,3dicarbonyls, 1,2-diaroylacetylenes, and ammonium acetate catalyzed by indium trichloride which gave 3,3’-bipyrroles 30 ; (c) aldose sugars, 1,3-diketones, and arylamines catalyzed by indium trichloride which gave fused pyrroles 31 ; (d) propargyl alcohols, 1,3-dicarbonyls, and primary amines catalyzed by indium trichloride which produced penta-substituted pyrroles ; (e) amino acids, isocyanides, and acetylenedicarboxylates led to 4-hydroxypyrrole-2,3-dicarboxylates ; (f) amino acids, acid chlorides, and acetylenedicarboxylates in basic ionic liquids producing pyrrole3,4-dicarboxylates ; and (g) 1,3-dicarbonyls, aldehydes, and primary amines mediated by low valence titanium (TiCl4/Sm) gave tetra-substituted pyrroles . Four-component sequences included the following reactants and products: (a) two different primary amines, diketene, and nitroalkenes which gave pyrrole-3-carboxamides 32 ; and (b) 1,2-diketones, triphenylphosphine, acetylenedicarboxylates, and ammonium acetate which led to pyrrole-2,3-carboxylates . O R2

HO Ar

N H 29

5.2.2.3

R1

OAc

COR

ROC Me

NH

HN Ar Ar 30

O

O Me

O

Me

R1HN

Ph

AcO N Ar 31

Me

Me

N R2 32

R3

Transformations of Heterocycles and Carbocycles to Pyrroles

This section discusses different routes to pyrroles starting from non-pyrrole heterocycles. The Boger ring contraction of pyridazines to pyrroles was employed by the Rebek group to prepare oxazole-pyrrole-piperazine scaffolds used for probing protein-protein interactions . Debreuil and co-workers published their work on the electrochemical reduction of 3,6-dipyridinylpyridazines to the corresponding pyrroles . The

J.S. Russel et al.

150

Davis group prepared 3-oxopyrrolidines from N-sulfinyl imines and converted them into highly substituted β-hydroxypyrroles . Two different approaches have appeared that utilized azetidinones (β-lactams) as precursors to pyrroles. The Zhang group developed a novel Au-catalyzed domino sequence that converted enyne-tethered azetidinones (e.g., 33) into pyrroles (e.g., 34) . 34 had previously served as a useful intermediate in the synthesis of indolizidine 167B 35. Alcaide and Almendros reported an interesting ring-opening/ring cyclization approach to chiral pyrroles starting from allene-tethered azetidinones . O IPrAuNTf2, THF

N

H

H2, PtO2, 6N HCl

78%

N

N

O 33

34

35

Microwave irradiation improved the transformation of fused furans (e.g., 38) into the corresponding fused pyrroles (e.g., 39) . The fused furans were formed via the Stetter cyclocondensation of 1,3-cyclohexanedione 36 with ethyl 2-bromopyruvate 37. CO2Et

Br

O

O

O CO2H

O 37 O

R-NH2, μW, 120°C

NaOH, MeOH, Δ

O

36

N R 39

38

5.2.3

REACTIONS OF PYRROLES

5.2.3.1

Substitutions at Pyrrole Nitrogen

N-substitution reactions of pyrroles have been explored using a variety of metal catalysts (e.g., Cu). Ma utilized this chemistry in the synthesis of pyrrolo[1,2-a]quinoxalines, a scaffold contained in many clinically important molecules including antipsychotic and antiHIV agents . For example, treatment of pyrrole-2-carboxylate 40 and 2iodotrifluoroacetanilide 41 with CuI/L-proline catalyst led to fused pyrrole 42 in 93% yield via a one-pot coupling/hydrolysis/condensation.

I CO2Me

N H 40

N H

10 mol% CuI 20 mol% L-proline K2CO3, DMSO 80 °C, 25 h

O CF3

93%

N

O NH

41 42

Bryce also utilized modified Ullman conditions in the preparation of N-heteroarylated pyrroles . Treatment of pyrrole and 2-iodo-5-bromopyrazine with CuI in the presence of Cs2CO3 and 1,10-phenanthroline gave the desired N-heteroarylated pyrrole in an 84% yield with complete regioselectivity at the iodine site. Subsequent Suzuki-Miyaura


151

cross-coupling reactions of the bromo substrates gave tris(hetero)arylated scaffolds; these compounds have been used in a wide range of pharmaceuticals, agrochemicals, and organic functional materials. In addition to copper, palladium has also been used to catalyze N-substitution reactions of pyrroles. Kwong studied the palladium-catalyzed amination of aryl mesylates, finding pyrroles to be effective substrates . Finally, N-substitution of pyrroles has been accomplished by carbonylation. Quaranta demonstrated this through a base (DBU, P1-t-Bu, or BTPP) catalyzed carbonylation of pyrrole using carbonic acid diesters . This provided a straightforward, ecofriendly alternative to the traditional synthetic methods based on hazardous phosgene or phosgene-derivatives in the preparation of N-carbonyl derivatives. 5.2.3.2

Substitutions at Pyrrole Carbon

The electron rich pyrrole is readily functionalized utilizing electrophilic aromatic substitution. Mayr demonstrated the reactions of alkyl substituted pyrroles with benzhydrylium ions . It was found that when given the opportunity, electrophilic substitution occurs regioselectively at C3 rather than C2. Friedel-Crafts acylation of N-p-toluenesulfonyl pyrroles has also been reported. Huffman and co-workers discovered that when using weaker Lewis acids, such as EtAlCl2 or Et2AlCl, the 2-acylpyrrole is obtained . However, when using AlCl3, the 3-acyl derivative is the major product. It was found that the regioselective acylation of the pyrrole with AlCl3 is not a Friedel-Crafts acylation, but rather the reaction of an organoaluminum intermediate with an acyl chloride. It is hypothesized that there may be a direct electronic interaction of the electrophilic aluminum atom with an oxygen of the sulfonyl group. This interaction would stabilize the 2-organoaluminium intermediate and decrease the rate of reaction with the acyl halide, thus providing a rationalization for the regioselective formation of the 3-acyl isomers in the acylation of the pyrrole. Chan utilized a gold catalyst in the Friedel-Crafts allylic alkylation of pyrroles with allylic alcohols . Pyrrole 43 was treated with the allylic alcohol 44 in the presence of AuCl3 to give the allylated heteroaromatic adduct 45 in 95% yield. Another example of acylation of pyrroles is seen in the synthesis of pyrrole containing marine natural products, such as the rigidins and lukianol A, by Gupton and co-workers . Highly substituted pyrroles were acylated using microwave accelerated Vilsmeier-Haack reactions.

OH AuCl3, CH2Cl2 N H 43

95%

N H

44 45

Reactions of pyrroles using aldehyde electrophiles have been explored. The Burgess group utilized this chemistry in the synthesis of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes, which are important probes for biotechnology . The use of aldehyde electrophiles can also be seen by Dolphin in the synthesis of unsubstituted β,β’linked diformyl dipyrromethanes, promising precursors for the synthesis of novel polydipyrromethene ligands and N-confused porphyrins . An additional example

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152

of the synthesis of porphyrins was carried out by Kean and co-workers using indium salts . Indium triflate catalyzed the reaction of benzaldehyde and pyrrole in the highest yield (31%) compared to indium tribromide (28%) and indium trichloride (14%). Michael additions of pyrroles have also been studied. Trofimov developed a highly efficient protocol for the Cu(I)-mediated regioselective α-tricyanoethenylation of Nmethylpyrroles . Itoh also studied Michael reactions of pyrroles using ironcatalyzed alkylations with vinyl ketones . This study provides a route to 4,5dialkylated 2-acetylpyrrole. Sibi and co-workers studied the enantioselective Michael addition of methylpyrrole 46 and α-substituted acrylates . Isoxazolidinone 47 was combined with methylpyrrole 46 in the presence of Zn(NTf2)2 and Ph-dbfox ligand 48 to give the desired addition product 49 in an excellent yield (98%) and excellent enantioselectivity (93% ee). A similar reaction was carried out by Du in the asymmetric Friedel-Crafts alkylation of pyrrole with nitroalkenes . This enantioselective Michael addition used Zn(OTf)2 as a Lewis acid and a diphenylamine-tethered bis(oxazoline) ligand.

O

O N N Me 46

O 47

O O

N

N Ph

48

O

Ph

Zn(NTf2)2, 4 Å mol sieves, CH2Cl2, -30 °C 98%

Me N Me

O

O N O

49

In addition to enantioselective Michael additions, stereoselective additions to imines have been carried out with pyrroles. Törok and co-workers synthesized chiral 3,3,3-trifluoro-2(pyrrol-2-yl)-2-amino-propionic acid esters via stereoselective Friedel-Crafts aminoalkylations of pyrrole with glycine derivatives . Similar chemistry was carried out by Gautun with pyrrole and a chiral nonracemic N-sulfinyl imine (a glycine cation equivalent) . Minassian also explored similar reactions with pyrrole and Nbenzylaldonitrones to produce the corresponding N-benzylhydroxylamines . This work also allows access to enantio-enriched non-proteinogenic 2- and 3pyrrolylglycines. Palladium catalyzed cross-coupling reactions play an important role in transformations of pyrroles. Iwao utilized a Suzuki-Miyaura cross-coupling of N-benzenesulfonyl-3,4dibromopyrrole with arylboronic acids to give the corresponding 3,4-diarylpyrroles in high yields . This work can be used to synthesize marine natural products such as the lamellarins. Palladium cross-coupling has also been performed on pyrrole silanolates with aryl iodides by Denmark and co-workers . In addition, directed ortho-metallation of pyrroles to form tetra-substituted 2-aryl-3arylsulfonyl pyrroles has been studied by Demont . Pyrrole 51 was treated with LTMP, followed by I2 to give 2-iodo-3-arylsulfonyl pyrrole 52. Suzuki-Miyaura crosscoupling with phenylboronic acid 53 and phosphine 50 gave the desired 2-phenyl-3arylsulfonyl pyrrole 54 in a 91% overall yield.


P(Cy)2 SO2

Me2N 50

1) LTMP, THF -78 °C 2) I2

B(OH)2

SO2

N SEM

I N SEM

51

52

153

SO2

53 Pd(OAc)2 K3PO4, 50

N SEM

91%

54

Aryl-substitution at the pyrrole carbon can also occur with the help of C-H activation. This was demonstrated by Gaunt in the synthesis of rhazinicine, a pyrrole natural product that stabilizes microtubules . In this example, the Boc-protected pyrrole underwent a one-pot microwave-assisted Ir-catalyzed C-H activation and Suzuki-Miyaura cross-coupling to give the 4-arylpyrrole in good yield. Lautens and co-workers studied the role of norbornene in a domino C-H activation used to construct three carbon-carbon bonds in the synthesis of tetracyclic pyrroles . Aryl iodide 55 was treated with bromoalkyl-aryl alkyne 56 in the presence of PdCl2, TFP, norbornene and Cs2CO3 in CH3CN at 90 °C for 24 h to give tetracyclic pyrrole 57 in an 80% yield.

N

PdCl2, TFP, Cs2CO3 norbornene, CH3CN 90 °C, 24 h

Br I

N

80%

55

56

57

A similar domino reaction was seen by Chang . A copper-catalyzed threecomponent coupling reaction of a terminal alkyne and sulfonylazide with pyrrole gave the 2substituted pyrrole in good yield. Regioselective cyclization of pyrroles has also been studied. Jacobsen and co-workers used a Pictet-Spengler-type reaction to cyclize pyrrole 59 . 59 was treated with methyllithium, followed by 58, acetyl chloride, and TBME to provide the cyclization product 60 in a 77% yield.

C5H11

Me N O

t-Bu S N N H 58

N H Me

N

Ph

N H

O

59

O

1) MeLi, THF, -78 °C 2) 58, AcCl, TBME -78 °C, 48 h 77%

N

O

N H Me 60

Annulations of pyrroles have also been studied by Banwell and co-workers in the synthesis of the lamellarin analogs; they utilized a PIFA-mediated intramolecular oxidative cyclization at C2 to construct the pentacyclic ring system. 5.2.3.3

Functionalization of the Side-Chain

In addition to reactions at the pyrrole carbon, significant advances in the functionalization of pyrrole substituents and side chains have also been reported. Gribble and Fu studied the metal (tin and indium) mediated reductive acylation of 2- and 3-nitropyrroles .

J.S. Russel et al.

154

Treatment of 3-nitropyrrole 61 with maleic anhydride 62 in the presence of tin and AcOH gave substituted maleimide 63 in 75% yield. Cl O NO2

Cl O

N Me

Cl

N

Sn, AcOH, toluene O

O

O N Me

75%

62

61

Cl

63

Ring closing metathesis (RCM) using Grubb’s catalyst is another way to functionalize the side-chain. Savoia used this chemistry in the synthesis of amino pyrrolizidine, compounds with potential activity as glycoside inhibitors and anti-HIV drugs . Oxazolidinone 64 was treated with Grubb’s catalyst II 65 in CH2Cl2 at 40 °C for 4 h to give bicyclic 66 in a 96% yield. König provided another example of RCM with Grubb’s catalyst 65 in the synthesis of ansa pyrrole amino acids . O

O N

N

O Grubb's catalyst II 65 CH2Cl2, 40 °C, 4 h

Ph

O N

N

96%

64

Ph

66

5.2.4

PYRROLE NATURAL PRODUCTS AND MATERIALS

5.2.4.1

Pyrrole Natural Products

A large number of new pyrrole natural products are isolated and identified from marine organisms each year. Bromopyrrole alkaloids nagelamides K-N (e.g., 67) were isolated by the Kobayashi group from the Okinawan marine sponge Agelas . From a different Agelas species, Al-Mourabit and co-workers isolated the structurally related debromodispacamides . Kuramoto and co-workers isolated bromopyrrole alkaloids cylindradines (e.g., 68) from the Japanese marine sponge Axinella cylindratus ; these compounds are structurally related to the phakellin pyrrole natural products. In Streptomyces, the Fenical group found the novel marinopyrroles (e.g., 69), halogenated 1,3’-bipyrroles; these compounds displayed antibiotic activity against methicillin-resistant Staphylococcus aureas . H

Br Br

N H

NH2

H H N

NH

H N

N H

Cl

Br

H N NH

HN

HN

H2N N

Cl O

Br N

O

OH O Cl

OH

N

O 67

SO3

68

Cl 69

Fenical reported the discovery of marineosins (e.g., 70), spiroaminals from a marine actinomycete . Also from a marine actinomycete (NPS12745), Potts and co-


155

workers reported the discovery of lynamicins Q-E (e.g., 71), chlorinated bisindole pyrrole antibiotics . Finally, Gao isolated several pyrrolizidine alkaloids from Ligularia cymbulifera including pyrrole glycoside 72 . H N

H Me H N

CO2Me Cl

Cl

O N

MeO

N H

NH

70

O HO

OH OH

O OH

N

N H

71

O

72

Prodigiosins are tripyrrolic natural products that display antibiotic and anti-cancer activity and have been the subject of significant study. Novel congeners designated prodigiosin R1 and 2-(p-hydroxybenzyl)prodigiosin were isolated from Streptomyces grisoviridis and Psuedoalteromonas rubra, respectively. The biosynthesis of undecylprodiginine has been probed in vivo by the Challis research group . The Leeper group investigated chemoenzymatic synthesis of prodigiosin analogues in Serratia species and E. coli . The novel biological activity and interesting structural variation make bromopyrrole natural products attractive targets for total synthesis. Leighton and Ohfune recently completed short syntheses of manzacidin C 73, while the synthesis of manzacidins was reviewed by Maruoka . Additional total syntheses of bromopyrrole natural products that were reported include: (a) dispyrin by Lindsley and Yamaguchi ; (b) axinellamines by the Baran group ; (c) phakellin and monobromophakellin by Romo ; and (d) agelastatin A by Yoshimitsu . An approach to the oroidin family of natural products was developed by Arndt . The total synthesis of rhazinicine 74 was reported by the Gaunt group; they utilized a direct C-H functionalization to make the pyrrole-aryl bond . Finally, the 3,4-diaryl and 2,3,4-triarylpyrrole natural products collectively known as the lamellarins continue to capture significant interest in the synthetic community and this was reviewed by Hu and co-workers . Total syntheses that have been reported include: (a) lamellarin U trimethyl ether by Opatz ; (b) lamellarins O-R (e.g., 75) by Iwao ; and (c) novel pentacyclic lamellarin analogs by Banwell and Steglich . HO HN

Br N HO2C

NH

O

O Me

OH

O

N H

N

Et

MeO

N

CO2Me

O OH O 73

5.2.4.2

74

75

Pyrrole Materials

Porphyrins and related pyrrole macrocycles occupy an important position in materials science with applications that include photodynamic therapy, molecular recognition (e.g.,

J.S. Russel et al.

156

binding anions), and non-linear optical applications. Reviews of porphyrins (via Barton-Zard pyrrole synthesis) , expanded porphyrins , corroles , phytochrome , and calixpyrroles have appeared in the last year by Ono, Chandrashekar, Paolesse, Inomata, and Sessler, respectively. Pyrroles are integral components of important biomolecular probes known as the BODIPY (boraindacene) dyes. A small sample of the synthesis and chemistry of BODIPY dyes reported during the last year are included here. The Burgess group developed a simple route to preparing symmetrical BODIPY dyes . Treatment of pyrrole-2carboxaldehydes (e.g., 76) with phosphorus oxychloride followed by boron trifluoride led directly to symmetrical boraindacenes (e.g., 77). A highly specific BODIPY dye 78 capable of detecting HOCl was discovered by Yang and co-workers . Non-fluorescent 78 is oxidized to fluorescent quinone 79 in the presence of hypochlorous acid. Methods for alkynylating BODIPY dyes were investigated by the Ziessel group . O

MeO Me

1. POCl3 CHO 2. BF •OEt 3 2

Me

HOCl

NH

N

Me

Me 76

5.2.5

O

OH

Me

B

N

N Me

F F 77

B

N

N

E

E

E

F F 78 non-fluorescent

B

N

E F F 79 fluorescent

SYNTHESIS OF INDOLES

The development of methods for the construction or functionalization of the deceptively simple indole ring system remains an area of intense investigation. And while a goal of this review is to encapsulate advances in the science of indole alkaloid synthesis, it also serves as a reflection of the dedication and ingenuity that characterize efforts in the rapidly evolving discipline of heterocyclic chemistry. As the repertoire of chemical transformations at Nature’s disposal continues to inspire the invention of new synthetic methodology, this survey opens with an illustration of an approach that emanates from a philosophy of biomimetic design and has culminated in an efficient synthesis of the polymeric indole (±)-psychotrimine 82. Accordingly, Newhouse and Baran have described a beautifully simple scheme for the direct quaternization of tryptamine derivatives at C3 via NIS-promoted coupling of indoles with o-iodoaniline, e.g., 80-81 . As the transformation unfolded, the hexahydropyrrolo ring system of the psychotrimine core materialized in diastereoselective fashion. I NH

NHCO2Me N H

Br 80

H

a) Br

a) NIS, Et3N, o-iodoaniline (61-67%)

N H

NHMe

N H NCO2Me

81

R

N H

NCO2Me

psychotrimine 82 R =

N MeHN

The following sections will highlight recent activity in indole ring construction, direct functionalization of the indole core, and the construction of the elaborate frameworks that


157

decorate the diverse family of indole alkaloids. Following a listing of topical reviews on indole chemistry, the remaining indole syntheses will be categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step. In addition, oxindoles, carbazoles, azaindoles, and carbolines will be treated separately. Intramolecular Approaches (type I) c

Intermolecular Approaches (type II) c

type Ia

d e N a H

c

type IIac

d

b

d

b e N a H

b e N a H

Two reviews of works in natural product total synthesis have appeared that house nice examples of indole alkaloid chemistry . A few topical monographs have been published that detail progress in the chemistry of indolocarbazoles , strategies for the synthesis of hexahydropyrroloindoles , and the enzymatic reduction of natural and synthetic quinones with anticancer potential . The syntheses of nomofungin and communesin as well as the welwitindolinones have also been reviewed. 5.2.5.1

Intramolecular Approaches

In the realm of intramolecular cyclizations for indole ring synthesis, considerable attention continues to be directed toward strategies for construction of the N-C2 bond. Nicolaou, Chen, and co-workers have devised an intriguing synthesis for substituted tryptamines, e.g., 86 that begins with nucleophilic addition of ortho-metallated aniline to N-Boc pyrrolidin-3one to afford, after lactone formation, the spiroheterocycle 84. LDA promoted elimination of CO2 from 84 set up indole ring closure via Ia type 5-exo-trig cyclization of aniline nitrogen onto the iminium ion 85 . From o-iodoaniline NBoc

NBoc

a) MeO

OH Boc

O

NBoc

b,c) NH2

MeO O MeO

NH OMe Me

N MeO N OMe Me OMe Me 85 83 84 a) TFA (96%); b) LDA (-CO2, 92%); c) TFA (5-exo-trig, deprotect, 96%).

MeO

N Me 86

The Leimgruber–Batcho indole synthesis, a two step sequence involving o-nitrotoluene deprotonation and condensation onto DMF-acetal followed by reductive cyclization of the resultant β-dialkylamino-o-nitrostyrene derivatives, has been applied by Kan and co-workers for construction of the indole core of (–)-serotobenine . An alternate reductive cyclization strategy has been reported by the Söderberg group for the synthesis of 3-indolecarboxylic acid derivatives from o-nitroalkenes using carbon dioxide as the reducing agent . In one example, palladium-catalyzed N-heteroannulation of 2-(2nitrophenyl)propenoate using Pd(OAc)2/Ph3P in the presence of CO2 afforded methyl 3indolecarboxylate in 91% yield. The transition metal-catalyzed Ia type intramolecular cyclization of o-alkynyl or ovinylanilines continues to find widespread application for indole ring synthesis. A collection of works that share a common theme of 5-endo-dig cyclization of aniline nitrogen onto an

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ortho-pendent alkynyl group has appeared that includes examples of Zn, Pd, Ag, W, Pt, or Cu as metal catalysts, respectively . Stoll and Knöchel have reported the synthesis of highly functionalized indoles via KH-mediated cyclization of o-alkynyl anilines . In the same Ia type cyclization series, an electrochemical-mediated ring closure has been reported by Arcadi, Rossi, and co-workers for the synthesis of 2-substituted indoles . R3

R3 OH R2

R3

R1

N R

R2 CO2Me

R4

a) non-oxidative

R4

NH R 88

R1

87

R2

CO2Me

b)

oxidative

R4

N R1

89

a) PdI2, CO, MeOH (42-88%); b) PdI2, CO, O2, MeOH (45-70%).

As illustrated above, the Gabriele group prepared indole-2-acetic esters via a sequence of Pd-catalyzed 5-exo-dig cyclization of anilines bearing an o-alkynylalcohol substituent followed by carbonylation of the vinyl palladium intermediates, e.g., 88-87 . In the same report, formation of quinoline-3-carboxylic esters 89 was observed as a result of competing 6-endo-dig cyclizations; the ratio of indole to quinoline products was dependent on the nature of alkynyl aniline substrates and oxidative vs. nonoxidative carbonylation conditions. The Flynn group has achieved selective formation of indole or quinoline products using I2 or NIS respectively for an iodocyclization strategy involving ring closure of o-alkynyl imines . In the general class of annulations involving o-vinylanilines, palladium catalyzed Ia type ring closure of gem-dihalovinylanilines has been employed by the Lautens group for the synthesis of a large array of aryl indoles and the Alper group for the synthesis of methyl indole-2-carboxylates . A few examples of aryl azide cyclizations for indole ring synthesis have appeared. Copper-mediated photochemical cyclization of aryl azides onto o-pendent allenes has been reported by Feldman and coworkers for the synthesis of 2,3-cyclopentenyl indoles . The Driver group has prepared 2-arylindoles using rhodium-catalyzed ring closure of aryl azides . A small assortment of indole ring syntheses via Ib type bond installation have been described. Two separate reports have appeared detailing the synthesis of thieno[2,3-b]indoles via cyclization of aryl isothiocyanates. In one report, Saito and co-workers have outlined a novel application of the Pauson–Khand reaction for the synthesis of thieno[2,3-b]indol-2ones . In a separate account, the Butin group observed AlCl3 promoted ring closure of the furan-linked isothiocyanate 90 . The mechanism is proposed to proceed through recyclization of a spiroindolenine intermediate 91 to afford thienoindoles 92 in good yield. R2

R2

R2

O

O S

S R1

N 90

C

N

R1 S AlCl3

91

AlCl3

R1

N H 92 (60-83%)

O


159

As illustrated for the conversion of 93-96 below, an anionic N-Fries rearrangement, involving N-C carbonyl migration of N-pivaloyl substituted 2-iodoanilines 93 has been employed by Lu and coworkers to prepare o-ketoaniline anion 95. Intermediate 95 was trapped in situ with benzyl chloride and transformed to indole 96 in a subsequent step via Ib type cyclization using the McMurry protocol . I

MgCl O

a)

O

N

N

N 94

93

O MgCl

b) c)

N

95

Ph

96

a) iPrMgCl, THF, 0 °C; b) BzCl, rt; c)TiCl3, Zn (McMurry, 82% from 93)

Two other strategies for 1b type bond construction have involved cyclization of a Fischer carbene complex or tin-mediated radical cyclization of N-benzyl-ovinylaniline derivatives . A few examples of Ic type bond construction have been reported that key on Pd-catalyzed intramolecular cyclization. Fuwa, Saski, and co-workers installed the Ic indole bond via palladium-promoted cyclization of N-allenyl anilines to reveal indole-2,3-quinodimethanes that underwent subsequent C2-C3 ring annulation . Two additional examples involved cyclization of o-iodoanilines bearing N-tethered esters (i.e., β-(2-iodoanilino) carboximides) and a Pd-catalyzed oxidative cyclization of Nvinyl aniline derivatives . A series of reports have appeared that describe indole ring synthesis via intramolecular closure of the Ie bond. A microwave-assisted protocol has been developed by Schirok that involved a nucleophilic aromatic substitution of aryl halides by tethered amines in the key Naryl ring-closing step . Karchava and co-workers have employed coppercatalyzed intramolecular amination of aryl bromides to access N-alkyl/N-aryl or N-amino indole-3-carboxylates, respectively . Inamoto, Doi, and coworkers achieved Ie bond construction using Pd-catalyzed activation of aryl C-H with subsequent intramolecular amination . A collection of 3-cyanoindoles has been prepared by Chang, Zhao, and co-workers by means of an FeCl3-mediated intramolecular heterocyclization of alkoxyimino tethered aromatics . As illustrated below, a unique strategy for Ie bond installation has been reported by Androsov who observed base promoted cycloreversion of thiadiazoles 97 followed by amine trapping of the resultant thioketene to afford intermediates 98. Intramolecular ring closure via nucleophilic aromatic substitution lead to the 1,1-dialkylindolium-2-thiolates 99 . N N S

O 2N

Cl

H

R1 N

R2

O2N

K2CO3

Cl

DMF, 12h, 90 °C

97

5.2.5.2

R1 N

98

O 2N R2

S 1R

N S R2

99

Intermolecular Approaches

In the formulation of intermolecular approaches to indole synthesis, the IIac bond disconnection represents a prominent feature of retrosynthetic design. Within this class of

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reactions, the classic Fischer route to indole synthesis, annulation of arylhydrazines with aldehydes or ketones, has served as a template for the development of new synthetic protocols. Accordingly, a variety of strategies for accessing key arylhydrazone intermediates have been reported with the common goal of utilizing Fischer indolization to facilitate fusion of the six-five ring system. Simoneau and Ganem have described a method for indole synthesis that involved treatment of nitriles with Grignard or organolithium reagents to produce metalloimines, sequential addition of arylhydrazines, and, finally, Fischer indolization of the penultimate arylhydrazones . Eilbracht and co-workers prepared β-branched tryptamines using a sequence of hydroformylation of chiral allylic amines, prepared by Ir-catalyzed enantioselective allylic amination, followed by Fischer indole synthesis from the intermediate γ-aminoaldehydes . Hydroamination of terminal alkynes with arylhydrazines has been carried out by the Beller group using titanium or zinc catalysis, respectively to set up Fischer type cyclization . In the realm of type IIac bond installation, indole synthesis via transition metal-catalyzed couplings between anilines and alkynes has received considerable attention. The coupling of unsymmetrical internal alkynes to o-iodoanilines has been reported by Ackermann that involves a one-pot TiCl4-catalyzed hydroamination with sequential palladium-catalyzed azaHeck reaction, e.g., 100 to 102 below . The reactions proceed with good regioselectivity, providing 2-alkyl-3-arylindoles 102 as the predominant products. This reaction series provides a nice complement to Larock’s direct annulation protocol that affords the opposite regioisomeric 2,3-substituted indole products . Cl + NH2 100

Ar

Cl

cat. [Ti]

Ar

Ar cat. [Pd]

N H

Alk 101

Alk

N H

Alk

102

In a related approach that does not require an o-halogen substituent, a rhodium-catalyzed oxidative coupling of acetanilides and unsymmetrical internal alkynes has been employed by the Fagnou group for the synthesis 2-aryl-3-alkylindoles . Working with terminal alkynes, the Tsutsumi group has applied a one-pot combination of heterogeneous and homogeneous Pd-catalysis to promote type IIac indolization to generate 2-arylindoles . In an interesting variation of hydroamination/cyclization chemistry, and the first example of intermolecular heteroannulation of an aromatic urea, Leogane and Lebel prepared indoles from 2-iodobenzoic acids . In the event, the carboxylic acid was converted to an unsymmetrical urea (i.e., an N-carboxamide of aniline) via the Curtius rearrangement followed by palladium-catalyzed hydroamination/cyclization of internal alkynes. A few additional examples of IIac intermolecular strategies include a one-pot procedure for indole and azaindole synthesis via fusion of o-iodophenol, allylamine, an aldehyde, and isocyanide (a tandem Ugi–Smiles/Heck coupling and isomerization sequence) and the coupling of 2-halotrifluoroacetanilides with β-ketoesters using CuI/L-proline in the presence of Cs2CO3 to generate 2-(trifluoromethyl)indoles . A type IIce intermolecular approach has been reported by Jørgensen and co-workers who prepared 3-substituted indoles from 2-bromoiodobenzenes and allylic amines via a sequence of aryl amination and Heck cyclization using Pd-catalysis . Kraus and Guo have reported a synthesis of 2-substituted indoles using a type IIab approach that involved the treatment of 2-aminobenzyl phosphonium salts with aromatic or α,β-unsaturated aldehydes under microwave conditions .


161

N-alkynylation

N p-Tol

N

Bn N-arylation

a)

NH2

O

N

a)

N

O

O

O

O 103

104 a)

105 MeO O OMe

106

, montmorillonite K-10, microwave (85%).

A couple of examples of IIae bond construction have appeared. In one account, the Zhao group prepared 2-amidoindoles 103 via a sequence of selective N-alkynylation (N to sp hybridized C) of a chiral oxazolidinone to afford alkynyl-tethered amides ortho to an aryl halogen, selective palladium catalyzed aromatic animation with primary amines at the ohalogen position (N to sp2 hybridized C), and, finally, 5-endo-dig cyclization of the arylamine substituent onto the o-alkynyl π-system to close the N-C2 bond . In a separate study, Török and co-workers have orchestrated a microwave-assisted synthesis of N-acylindoles 106 on montmorillonite K-10 solid support that involves the fusion of aryl amides 104 and 2,5-dimethoxytetrahydrofuran . 5.2.6

REACTIONS OF INDOLES

5.2.6.1

Pericyclic Transformations

The vast potential for controlled installation of multiple bonds makes pericyclic routes, including sigmatropic rearrangements, cycloadditions, and electrocyclic transformations, attractive for the synthesis and manipulation of the polycyclic frameworks that characterize the indole family of alkaloids. A route toward an insulin mimic has been devised by Xiong and Pirrung that involves Claisen rearrangement of indole kojic acid derivatives 107 . A Claisen rearrangement strategy has also been employed by Kawasaki and co-workers for the total synthesis of hexahydropyrrolo[2,3-b]indole alkaloids . The Rainier group has reported a diastereoselective [3,3]-sigmatropic rearrangement of the sulfonium ylide 108 to afford the C3 quaternary center of an indolenine, which was further manipulated to generate a C3 spirocyclopentane . Zhang and co-workers have constructed furan-fused indole polycyclics 109 via cycloaddition of indole with 1,4-dipoles generated by Aupromoted cyclization of 1-(1-alkynylcyclopropyl) ketones 110 . THPO MeO2C O

MeO2C

Ph

[4+2] Cl

O

H [Au]

O

R N H 107

O

N 108

S Ar

CO2Et

N

110 H

SO2Ph Ph

O 109

As part of a beautiful collection of works on pentacyclic ring systems, the Padwa group has employed carbonyl ylide cycloaddition chemistry in their route toward (±)-aspidophytine , as well as a [4+2]-cycloaddition/rearrangement cascade for the synthesis of Strychnos alkaloids . They also described Rh(II)-catalyzed intramolecular [3+2]-cycloaddition routes toward the Vinca and Tacaman alkaloids .

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A few additional examples of pericyclic strategies include an electrocyclic ring closure by the Ishikura group to set the carbazole framework of olivacine , a hetero Diels-Alder approach to the communesins by George and Adlington , and Ricci utilized a Diels–Alder reaction of vinylindoles leading to tetrahydrocarbazoles . 5.2.6.2

Substitution at C2/C3

An endless stream of literature continues to flow from endeavors to achieve selective functionalization of indole C2 or C3. Within that body of work, various tactics for the installation of aryl or vinyl functionality at indole C2 have been described. In one account, N-methylindole was successfully coupled to iodobenzene by Lebrasseur and Larosa using a ligand-free system of Pd(OAc)2 and Ag2O . Zhang and co-workers employed Pd-catalysis in the presence of Cu to promote regioselective C2 coupling of indole to potassium aryltrifluoroborate salts . An indole-2-boronic acid was coupled to a vinyl iodide in the Nicolaou groups approach to aspidophytine . In a subsequent transformation, a Vilsmeier–Haack reaction was used for C2 to C3 annulation to set four of the five rings that make up the aspidophytine core. Miura and co-workers employed a mixed catalyst system of Pd and Cu to promote oxidative coupling of indole-3-carboxylic acids with alkenes for the synthesis of 2-vinylindoles . direct arylation

+ 2e-, Pb cathode

O H

N

N

N

Cl ortho-alkylation

intramolecular hydroarylation

H N

OH

OMe 111

112

113

Many investigations in the area of C2 substitution have been intimately linked to strategies for ring annulation. Lautens and co-workers have developed a norbornene-mediated Pdcatalyzed alkylation/direct arylation protocol for the synthesis of polycyclic indole and azaindole scaffolds, e.g., 111 . In their synthesis of indole 112, N- to C2 annulation was achieved by Bergman, Ellman, and co-workers who employed Rh-catalysis with phosphoramidite ligands to stitch N-tethered alkenes into indole C2 via directed C-H bond activation (61%, 90% ee) . Kise and co-workers have described an electroreductive intramolecular coupling to afford tricyclic indoline 113 with trans-selectivity in 61% yield . The development of methods for annulation across indole C2-C3 has also received considerable attention. A variation of the heteroaromatic Nazarov cyclization, the acid catalyzed cyclization of heteroaryl vinyl ketones to afford fused cyclopentanones, has been applied by Yadav and Kumar for the synthesis of 2,3-annulated indoles . In that account, indoles bearing cyclopropyl ketones at C3 in place of the traditional vinyl ketones were converted to indole fused cyclohexanones using SnCl4 as Lewis-acid. In another C3 to C2 ring annulation strategy, Evano and co-workers have reported a Cu-catalyzed cyclization of iodotryptophans to generate tetrahydropyrrolo[2,3-b]indoles . Several other approaches to C2 substituted indoles have been disclosed . In the area of indole C3 substitution, an enormous wealth of literature has appeared detailing methodology for the introduction of asymmetric centers alpha to C3. Asymmetric


163

conjugate addition reactions yielding chiral C3-substituted indoles have been directed using a manifold of chiral ligands including a TADDOL-derived phosphonite with Ni catalyst , BINOL-derived phosphoramidite or phosphoric acid ligands , a BINAM-derived chiral imine with Zn catalyst , a few bis(oxazoline) derived ligands , a bis(imidazoline) ligand with Cu catalyst , and soluble star polymers . In one example, Ganesh and Seidel observed enantioselective addition of indoles to nitroalkenes using the quinolinium thioamide catalyst 114 . Ph

Ph BArF24 S HO

N H

Ts

N

Ph

N

HN

Ph

Br

N

NO2

N H

Ph 115

114

OH

OH

Br

116

A few examples of multi-component reaction systems have been described for the synthesis of complex C3 side-chains. Arai and Yokoyama employed an imidazolineaminophenol ligand 115 with Cu catalyst to direct a tandem Friedel–Crafts/Henry reaction . In the event, indole, nitroalkene, and aldehyde were fused to afford C3substituted indole 116 with three contiguous stereocenters with modest diastereoselective control and excellent enantioselectivity (99%) for the major diastereomer. An alternate three component method involving Ti-catalyzed condensation of indoles, aldehydes, and activated carbonyl compounds has been reported by Gérard and co-workers . The Desimoni group observed the unexpected formation of the rearranged aryl indoles 117 (6595%) when attempting a scandium-catalyzed variation of the Paserini reaction for coupling indole, ethyl glyoxylate, and aniline . The Paserini coupling was expected to generate a framework with an N-C bond linkage via indole addition to an imine of aniline. H N

CO2Et

H

R1 N H 117

R2

Ph NH2

unexpected C-C bond

H N Ph R

OH Me

H anti-selectivity

OMe Tips

118

119

Me

In an approach that does not involve a chiral catalyst, the Chung group has reported the diastereoselective Friedel–Crafts alkylation of indoles using chiral α-branched benzylic cations 118 as electrophiles . A preference for anti-substitution with respect to indole substituent and alkyl group (R) of 118 was observed. Basak and Tius used indole to trap the cyclic cation 119 which was prepared via a Nazarov cyclization of the corresponding propargyl vinyl ketone on silica gel . The reaction was used to set a quaternary center in numerous examples of indole-tethered α,β-unsaturated cyclic ketones. Two examples of unnatural amino acid syntheses that have appeared include a Friedel– Crafts aminoalkylation at indole C3 using a chiral imine and triflic acid catalyst or Lewis-acid catalyzed addition of indoles to α,β-dehydroamino esters . As an alternative to Friedel–Crafts chemistry, the Melchiorre group has developed a proline-catalyzed intermolecular α-alkylation of aldehydes to produce chiral C3-substituted indoles . Outside the realm of asymmetric synthesis, a method for Pd-catalyzed C3 allylation of indole with allyl alcohol has been disclosed by the Breit group . The reaction

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164

involved catalysis by a self-assembly of hydrogen-bonded heterocyclic ligands, phosphanylisoquinoline and phosphanylaminopyridine, onto palladium. Synthesis of 3allylindolenines has been reported by Rawal and co-workers . A collection of other works in the general area of C3 substitution includes the following . 5.2.6.3

Substitution at Nitrogen

Work on the development of methods for the functionalization of indole nitrogen has yielded two new reports describing enantioselective processes. In one account, an intramolecular aza-Michael reaction has been used by Bandini, Umani-Ronchi, and coworkers for accessing pyrazino-indoles 120 . The asymmetric transformations proceeded under phase-transfer conditions using chiral Cinchoma ammonium salts. In an alternate report, direct N-alkylation to afford indole 121 using the corresponding tosylate of t-butylpropionate proceeded in very modest yield with good enantioselectivity (>95% ee) . Michael X

R4

O

asymmetric aza-Michael EtO

N *

NBz

N

N

displacement of tosylate

Ot-Bu H

O

CO2R3

R1

R2

O 120

121

CO2R3

122

L.A.-promoted 5-exo-dig.

An interesting route to indoles 122 bearing an indene substituent at nitrogen has been reported by Gao and Wu . The chemistry was carried out under basic conditions using 2-(2-(alkynyl)benzylidene)malonate as the initial Michael acceptor for indole anion followed by an intramolecular cyclization of the malonate anion onto the pendant alkyne with Lewis acid catalysis. Snieckus and co-workers have reported an LDAinduced N-C carbamoyl migration for the generation of indoles substituted with arylamides at C2 from the corresponding N-carbamoylindoles . Methods for the synthesis of N-aryl , N-cyclopropyl , and N-Boc indoles have also appeared. 5.2.6.4

Functionalization of the Benzene Ring

An array of publications have appeared detailing annulation chemistry at the benzenoid ring positions. A Pd-catalyzed domino cyclization reaction of 4-bromoindoles bearing C3 amino allenes has been used by Fujii, Ohno, and co-workers to set the indole 3,4-ring system embedded in the tetracyclic framework of (±)-lysergic acid . Fillion and Dumas prepared indole 4,5-fused cyclic ketones via an intramolecular Friedel–Crafts acylation of 4substituted indoles . Ring construction across indole C6-C7 was achieved by Silva and Craveiro using Friedel–Crafts chemistry. Subsequent manipulation of the resultant cyclic ketone 123 via a thallium(III)-mediated ring contraction afforded the core tricyclic skeleton of (±)-trans-trikentrin A 124 .


165

Cl

Friedel−Crafts

NR 1. Tl(NO3)3, CH3CN 2. NaBH4

N Boc

N Boc

HO

(54%)

MeO2C

124

123

N H

OBn Base

125

Boger and MacMillan have proposed a variation on the putative mechanism for indole C4 spirocyclization leading to cyclopropanone formation in the duocarmycin SA class of alkylating agents . The proposed mechanism for the benzyl protected phenol 125 proceeds through indole N-H deprotonation and the model reaction system affords the corresponding cyclopropane adduct in up to 56% yield. Two examples of N-C7 ring closures include the synthesis of tetracyclic pyrrolo[3,2,1jk]carbazoles via flash vacuum pyrolysis of N-aryl indoles and an aldol cyclization route to the pyrrolo ring juncture of tetracyclic pyrrolo[2,3,1-hi]indoles . A few strategies for manipulation of functionality at indole C5 have been described. As part of a synthetic scheme for the preparation of sulfonamide substituted indoles as potential 5-HT6 receptor ligands, Beller and co-workers have described a palladium-catalyzed amination of 5-bromoindoles . The White group has employed a chelatecontrolled intermolecular oxidative Heck reaction for the direct coupling of indole-5potassium trifluoroborate to the terminal olefin functionality of 4-penten-1-ol with good selectivity for the E-alkene . 5.2.7

INDOLE NATURAL PRODUCTS

5.2.7.1

Natural Products Isolation and Characterization

The tedious work of isolating and characterizing indole natural products remains indispensable as a preliminary step toward unraveling the secrets of Nature’s chemical machinery. Over the past year, endeavors in this area have led to the discovery of new indole alkaloids with a broad spectrum of common structural motifs that include β-carbolines , indolocarbazoles spirooxindoles , ergot type alkaloids numerous variants of pentacyclic fused indolines, e.g., Kopsia or Aspidosperma type alkaloids and brominated indoles . O O

O

O

H N

H

R4 N

H N

NH N

R3

N

NH

H N H scholarisine A 126

R2

N N

HN quinadoline B 127 O

N

1 O R

NO H

N

NH

dictazolines 128

A few new isolates that have promise as targets for intellectual pursuits include the cladoniamides A-G from the actinomycete bacteria Streptomyces uncialis with novel rearranged indolocarbazole scaffolds , the cage-monoterpene scholarisine A

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126 isolated from the fungus Alstonia scholaris , the spiro-quinadoline B fungal metabolite 127 from Aspergillus sp. FKI-1746 , and the bisspiroimidazolidinones 128 from marine sponge Smenospongia cerebriformis . 5.2.7.2

Total Synthesis

The total synthesis of natural products continues to be a marvelous testing ground for the discovery and implementation of chemical methodologies for indole ring synthesis and sidechain modification. In one example, Overman and co-workers employed an oxidative coupling to set the quaternary center alpha to indole C2 in their approach to actinophyllic acid 129 . The key transformation was performed on an early stage precursor to 129 and involved intramolecular Fe(III)-promoted coupling of an indole C3 piperidone enolate and C2 pendent malonate in 60-63% yield. In a separate report from the same group, a chiral (phosphinoaryl)oxazoline was used to promote an asymmetric Heck cyclization to set the C3 quaternary center (indole numbering) of (+)-minfiensine 130 . A subsequent iminium ion cyclization afforded four of the five requisite rings of the hexahydrocarbazole 130. An alternate approach to the same ring system has been reported by Qin and co-workers who used a cyclopropanation strategy for annulation across the indole C2-C3 bond to build the heterocyclic framework of 130 in racemic fashion . An approach to ring construction involving acyl radical chemistry has been developed by the Bennasar group for preparation of the bridged tetracyclic skeletons found within the uleine and Strychnos families of alkaloids, e.g., dasycarpidone 131 . oxidative coupling α to indole C2 H Me N

Heck

HN

OH

HO2C

N O OH

actinophyllic acid 129

N H N iminium ion cyclization minfiensine 130

N H

H acyl radical cyclization dasycarpidone 131 O

A chiral template strategy has been employed by Ishikawa, Saito, and co-workers who have described a domino double Michael–Claisen cyclization sequence for the synthesis of cyclohexane-1,3-diones that house a quaternary center found embedded within a number of natural products including the pentacyclic indole (+)-aspidospermidine . In the case of (+)-aspidospermidine, optical resolution of the core cyclohexane-1,3-dione was achieved via zinc triflate catalyzed enamine formation with (S)-1-phenylethylamine followed by separation of the diastereomers. Using a conceptually appealing synthetic strategy that parallels the reductive contraction of the tetrahydro-1,2-oxazine moiety of FR900482 to a pyrrolo[1,2-a]indole, Johansen and Kerr have accessed the tricyclic core of yuremaine via a diastereoselective N-O bond reduction of 132 followed by an acid catalyzed ring closure of 133 under microwave conditions .


R2

R2

OH

O

CO2Me N H R1 133 >20:1 dr

CO2Me R1

132

R2 b)

a)

OH N

167

N 134

CO2Me

R2

a) 3 equiv SmI2, THF, 3 equiv HMPA/ 40 °C (62-73%). b) TsOH (10mol%)/benzene, microwave, 80 °C (56-95%).

A selection of other targets that have been accessed through total synthesis include the unique tetracycle (±)-mersicarpine bearing a 7-membered cyclic imine , the simple indole tethered oxazalone (-)-indolymycin , (+)-yatakemycin with its characteristic dienone fused cyclopropane ring system , the trimeric indole psychotrime , malabrancheamide alkaloids housing a bicyclo[2.2.2]diazaoctane core , the pentacyclic β-carboline (±)-tacamonine , (-)-alstonerine with its azabicyclo[3.3.1]nonane substructure , pentacyclic (±)-aspidospermidine and the tryptophan derived pyrroloindole roquefortine C , , and an alkaloid from the tunicate Dendrodoa grossularia with a quaternary center stitched into an imidazolone side chain . A few reports on indole side-chain modification that have interesting potential for application to total synthesis include a convenient protocol for the preparation of amino acid (IAA and IPA) conjugates , an enantioselective C-H amination for installation of chirality alpha to C3 , a gold-catalyzed cyclization of indolyl tethered Npropargylamides to produce C3-linked oxazoles or N-C2 fused pyrazinoindolones as a function of solvent , and a cycloaddition route to pandoline-type alkaloids . 5.2.8

OXINDOLES AND SPIROOXINDOLES

The alluring chiral architectures of oxindoles and spirocyclic members of that family continue to inspire efforts toward their synthesis. In one example, the Cook group has reported an enantiospecific synthesis of (+)-alstonisine that involved a stereospecific osmylation across the indole 2,3-π system . In an unrelated investigation, a route to the C10 quaternary center housed within diazonamide A has been reported by Konopelski and co-workers . The key step involved the direct coupling of an oxindole and tryptophan derived aryllead(IV) species. Details of synthetic work on the spirocyclic framework of (±)-welwitindolinone A isonitrile have been documented by the Wood group . O

O

O H

136 Me

N O

Ph

Me

O N O

O

O N

H O O

+

N Me 137

O

Me O

N Me 135

Ph Ph

cycloreversion

N Me 138

H N

O Me H HO O

N H

N Me maremycin A 139

SMe O

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Tamura and co-workers have confirmed the stereochemistry of oxindoles maremycins A 139 and B by setting the C3 quaternary centers via asymmetric cycloaddition chemistry . For example, cycloaddition of the chiral nitrone 136 with isatin derived enone 135 afforded the key spiro intermediate 137 along with the undesired regioisomer 138 as the major product. In one trial, 137 and 138 were prepared from neat starting materials in a ratio of 22:78 in 96% overall yield. A sequence of cycloreversion/re-cycloaddition of 138 allowed for modest conversion (10%) to the minor regioisomer 137. A 50:50 mixture of 137 and 138 was obtained using hexanes as the solvent. An alternate strategy for asymmetric installation of a C3 hydroxyl functionality onto an oxindole scaffold has been reported by the Itoh group who have devised a catalytic asymmetric hydroxylation protocol using molecular oxygen in the presence of a cinchonidine derived phase-transfer catalyst . Chiral N-heterocyclic carbene ligands have been used by Kundig and co-workers for the asymmetric preparation of 3-alkoxy and 3aminooxindoles . A small selection of other published works from the outpouring of literature in this area include an asymmetric synthesis of allyl oxindoles involving an enantioselective Meerwein– Eschenmoser–Claisen rearrangement , an enantioselective synthesis of 3,3disubstituted oxindoles via Pd-catalyzed cyanoamidation , a stereoselective Mannich reaction of 3-substituted oxindoles , selective arylation at oxindole C3 or N using Pd- or Cu-catalysis, respectively , an approach to quaternary 3aminooxindoles via an intramolecular arylation of amino acid enolates , a route to spirocyclic piperidines via electrophile-induced dearomatization and spirocyclization of Narylisonicotinamides , and a stereoselective oxidative rearrangement of 2-aryl tryptamines . 5.2.9

CARBAZOLES

The tricyclic carbazole ring system and polycyclic variants have received significant attention as synthetic targets. Lebold and Kerr have employed a Diels–Alder strategy for regiocontrolled access to the substituted carbazoles clausamines A-D and clausevatine D . The synthesis proceeded with an early-stage cycloaddition between an imine quinone and cyclic diene to afford the tricyclic scaffold 140 that was subjected to Plieninger indolization conditions to strategically set substituents at C4, C5 and C7 (indole numbering) of the desired tetrahydrocarbazole adduct. A total synthesis of (±)-murrayazoline has been reported in which the carbazole moiety of 141 was installed via a double N-arylation of dibromobiphenyl with a key amino-substituted cyclohexenone . Knölker and co-workers built up the carbazole core of clausine L from a substituted aniline and iodobenzene by sequential application of palladium-catalyzed coupling reactions, Buchwald– Hartwig amination and oxidative cyclization . The same group has reported access to the carbazole framework 142 found within euchresifoline using a one-pot Wacker oxidation to stitch together a diarylamine precursor . OH

Plieninger precursor double N-arylation

MeO TsHN 140

Wacker

Diels−Alder N

OMOM N H

141

O

BuchwaldHartwig

O O

142


169

Tsuchimoto, Shirakawa, and co-workers have prepared a diverse series of annulated carbazoles by means of an indium-catalyzed coupling of 2-aryl or 2-heteroarylindoles with propargyl ethers . A one-pot photochemical annulation of 2-chloroindole-3carbaldehydes has been described by the Zhang group for the preparation of tetracyclic benzo[c]carbazoles . Several investigations of indolocarbazole chemistry have also been disclosed . 5.2.10

AZAINDOLES AND CARBOLINES

5.2.10.1

Synthesis of Azaindoles

A variety of different methodologies have been applied for the synthesis of azaindoles. Pujol and co-workers have reported a synthesis of 2-substituted-7-azaindoles via cyclization of 2-amino-3-picoline derivatives . A series of 7-amino-4-azaindoles was prepared by the Palmer group by means of copper iodide catalyzed cyclization of 2-alkynyl-3aminopyridines . In an interesting approach to azaindolines, Wipf and Maciejewski have devised a scheme for 5-azaindoline synthesis that involved reductive intramolecular cyclization of 4-aminopyridine onto an amine-tethered epoxide . 5.2.10.2

Synthesis of Carbolines

A synthesis of γ-carbolines has been developed by the Hu group that involves a microwave-enhanced fusion of N-acetyl-3-bromo-4-piperidone hydrobromide with substituted arylhydrazines . In the event, the initial tricyclic Fischer adducts undergo a spontaneous benzylic type oxidation to afford the fully aromatized carbolines. Microwave conditions have also been employed by the Adib group who prepared 9Hpyrimido[4,5-b]indoles by the annulation of oxindole and arylnitriles . A protocol for the synthesis of trifluoromethyl-α-carbolines has appeared that involved a condensation/cyclization sequence of 2-aminoindole onto a β-diketone . 5.2.10.3

Synthesis of β-Carbolines and THβ-Carbolines

As close descendents of tryptophan, the β-carbolines have a distinctive presence within the diverse family of indole natural products. Accordingly, much attention has been devoted toward the total synthesis of members of this class of alkaloids as well as developmental studies related to the Pictet–Spengler strategy for β-carboline ring construction. The Jacobsen group has completed work on (+)-yohimbine that showcases an enantioselective thiourea-catalyzed acyl-Pictet–Spengler reaction to set a stereocenter alpha to indole C2 . Four additional stereocenters fell into place upon application of an intramolecular Diels–Alder ring closure. Fukuyama and co-workers have described an improved synthesis for the densely functionalized indole core of the eudistomin alkaloids that involved the regioselective introduction of a cyanomethyl group at the 5-position of 2-bromo4-nitroanisole to set up a reductive cyclization . An asymmetric Pictet– Spengler reaction using a chiral hydroxy-α-aminoaldehyde was also described. A few other variations of the Pictet–Spengler methodology have been studied that involve the condensations of tryptophan with α-amino aldehydes or piperonal . An interesting investigation of the mechanism of action of the Pictet–Spengler catalyzing enzyme strictosidine synthase has also appeared .

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A unique preparation of THβ-carbolines 147 has been described by Bondziü and Eilbracht that involved a sequence of hydroformylation of 2,5-dihydropyrrole 144, followed by Fischer indolization with phenylhydrazines . The transformation is proposed to proceed through a 3,3-spiroindoleninium intermediate 146. Ph

N H 143

Ts N

+ NH2 144

Ph

Ph

Ts N

a)

Ph

Ph

Ts N

Ph

Ph

NTs

b) H 145

N N

N H 146

N H 147 (71%)

Ph

a) Rh(acac)(CO2), CO/H2 = 15/10 bar, Ph3P, THF, 100 °C , 3d. b) 4 w % H2SO4, THF. reflux 2h.

England and Padwa have accessed β-carbolines via gold-catalyzed cycloisomerization of indoles bearing an N-propargyl amide moiety at C2 . A microwave-induced electrocyclic transformation was employed by the Hibino group to transform a 1azahexatriene centered about the indole 2,3-bond to the corresponding β-carboline found within (S)-(-)-dichotomine C . 5.2.11

BIOORGANIC CHEMISTRY

Multidisciplinary investigations involving a fusion of techniques from the chemical and biological sciences remain at the forefront of efforts to tap into the logic of biosynthetic processes. A few works in this area include an investigation of the binding of serotonin to the human serotonin transporter , a study of the biosynthetic origin of the thiazolylindole tumor-inhibitory derivative BE-10988 , an investigation of the early enzymatic steps in the biosynthesis of scytonemim, a cyanobacterial sunscreen composed of a dimeric indole scaffold , a report on the action of O2 and FADH2-dependent halogenases in the biosynthetic production of 6,7-dichlorotryptophan, a component of the macrolactone skeleton of the antifungal kutznerides , and double 13C-label incorporation into the bicyclo[2.2.2]diazaoctane core of premalbrancheamide for investigation of the biosynthesis of the fungal metabolite malbrancheamide B . A selection of examples of synthetic studies within the broad realm of medicinal chemistry includes the preparation of an oligodeoxyribonucleotide adduct of the DNA cross-linking agent mitomycin C , the synthesis of a (+)-duocarmycin-like pentagastrin analog for targeted tumor therapy , synthesis and structure activity studies of tryprostatin A, an inhibitor of cancer resistance protein , the preparation of pentacyclic THβ-carbolines, trans-apovincaminates, for probing antioxidant activity as well as effects on cognition , the preparation of pyrrolo[2,3-a]carbazoles for screening as inhibitors of cyclin dependent kinases, key regulators of cell cycle progression , the synthesis of indole cyclopropyl ketones for assessing cannabinoid receptor CB2 activity , the synthesis of a second-generation indomethacin antiinflammatory prodrug , the preparation of a collection of spirooxindole DP2 receptor antagonists for treating allergic and inflammatory diseases and, finally, the synthesis of indolobenzazepinones as inhibitors of tubulin polymerization .


5.2.12

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178 08SL410 08SL897 08SL975 08SL1053 08SL1145 08SL1193 08SL1250 08SL1449 08SL1487 08SL1953 08SL2093 08SL2215 08SL2271 08SL2597 08SL3157 08T328 08T500 08T769 08T809 08T1506 08T2104 08T3005 08T4174 08T4803 08T5246

08T5933 08T6002 08T6884 08T9159 08T10401 08T10714 08T10810 08T11603 08TA435 08TA1339 08TA1883 08TL411 08TL459 08TL1184 08TL3545 08TL3691 08TL4362 08TL4953 08TL7328 08TL7352 08TL7426

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Chapter 5.3 Five-Membered Ring Systems: Furans and Benzofurans Xue-Long Hou Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China. [email protected] Zhen Yang Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing 100871, China. [email protected] Kap-Sun Yeung Bristol-Myers Squibb Research and Development, 5 Research Parkway, P.O.Box 5100, Wallingford, Connecticut 06492, USA. [email protected] Henry N.C. Wong Department of Chemistry, Center of Novel Functional Molecules, Institute of Chinese Medicine and Institute of Molecular Technology for Drug Discovery and Synthesis,† The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. [email protected] and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China. [email protected] † An Area of Excellence of the University Grants Committee (Hong Kong). ___________________________________________________________________________ 5.3.1 INTRODUCTION This article reviews papers that were published in 2008 on reactions and syntheses of furans, benzofurans and their derivatives. Reviews published in 2008 cover the catalytic hydrogenation of furans and benzo[b]furans , preparation of five-membered rings via the translocation-cyclization of vinyl radicals , chemistry of acetogenins , application of singlet oxygen and furans to synthesize polyoxygenated natural products , synthesis of methylenetetrahydrofurans by formal [3+2]

c 2009 Published by Elsevier Limited.

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X.-L. Hou et al.

cycloadditions of propargyl substrates , enantioselective synthesis of dihydrobenzo[c]furans by [2+2+2] cycloaddition , chemistry of spongiane diterpenes that contain tetrahydrofuran or furan moieties , chemistry of marine furanocembranoids , total syntheses of dihydrofuran and tetrahydrofurancontaining azadirachtin , total synthesis of C2-C11 cyclized cembranoids and gold-catalyzed formations of tetrahydrofurans and 2,5-dihydrofurans . Again in 2008, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified. References on compounds whose biological activities were not mentioned are: . Articles on those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons whose biological activities were assessed are: . References on those furan-containing compounds whose biological activities were not mentioned are: . Naturally occurring compounds containing furan skeletons whose biological activities were assessed were mentioned in the following papers: . References of those benzo[b]furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: . References on those naturally occurring compounds containing benzo[b]furan or dihydrobenzo[b]furan skeletons whose biological activities were assessed are: . 5.3.2 REACTIONS 5.3.2.1 Furans Several interesting reactions involving opening of furan rings were reported in 2008. For example, the acidic ring opening of the C-3 furan moiety of an indole depended on the nature of indole nitrogen substitutions. A substrate with a free indole NH provided the ring-opened 1,4diketo-product, whilst an N-tosylated substrate gave no reaction . As depicted below, an electrophilic addition of an isothiocyano group onto the C-2-position of a furan, followed by rearrangement of the intermediate oxoninum ion, generated the thieno[2,3-b]indole product . An analogous reaction of 2-isothiocyanoaryldifurylmethanes furnished 2,4difuryl-4H-3,1-benzothiazines .

Five-Membered Ring Systems: Furans and Benzofurans

181 O

MeO

O

AlCl3 ClCH2CH2Cl 50 °C, 30 min 86%

NCS

MeO N H

S

Addition reactions of 2-silyloxyfurans to various electrophiles continue to be developed. The syn-selective, vinylogous Mukaiyama aldol reaction between 2-trimethylsilyloxyfuran and various aldehydes can be promoted by molecular iodine , and 1 mol% of bismuth triflate . Cyclohexanone also reacted under these conditions. The enantioselectivity of the vinylogous Mukaiyama aldol reaction of 2-trimethylsilyloxyfuran with α-ketoesters was improved using a laponite clay-immoblized chiral bis(oxazoline) copper complex . A highly enantioselective, anti-selective Mukaiyama Michael reaction of 2-trimethylsilyloxyfuran with α-phenylsulfonyl enones was achieved by using a Cu(II)bisoxazoline complex as catalyst . The scope of a silver-catalyzed stereoselective vinylogous Mannich addition of 2-trimethylsilyloxyfurans, as reported in 2006, was expanded to include alkyl-substituted aldimines . The corresponding addition to N-2thienylsulfonylimines, catalyzed by Fessulphos/Cu(I) complex, was also developed . The addition of 2-trimethylsilyloxyfuran to Morita-Baylis-Hillman acetates to form γ-butenolides, first reported in 2004, was rendered enantioselective by the use of a chiral phosphine catalyst . As shown in the following prototypical example, the enantioselectivities and yields were enhanced by the addition of water. O NHCOMe PPh2

O

OAc Ph

+ Me SiO 3

O (2.5 equiv.)

Catalyst

10 mol% Catalyst H2O (6 equiv.) O

PhMe r.t. 94% 94% ee

O H

H Ph

A furan ring was easily reduced to the tetrahydrofuran by transfer hydrogenation using ammonium formate as the hydrogen source . As shown below, oxidation of a furan nucleus by DDQ generated an oxonium ion, which was trapped by the pendant hydroxyl sidechain to form a spirocycle .

OH O Ph

DDQ CH2Cl2 –95 then –80 °C Z / E = 86:14 64%

O O Ph

3

μ -Oxopyranyl and oxopyridinyl molybdenum complexes were prepared via the oxa-and

aza-Achmatowicz reaction on furfuryl alcohols and amines respectively . An Achmatowicz oxidation of furfuryl alcohol under Sharpless kinetic resolution conditions, first

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182

reported in 1988, was adopted as a key step in the total synthesis of the acetogenin, pyranicin . As shown below, the pyranone was obtained as a single diastereomer after reduction. (–)-DIPT Ti(iPrO)4 TBHP CaH2 SiO2

H25C12 O

–20 °C

OBn

HO

F3B.OEt2 iPr SiH 3

O H25C12

H

O

OH OBn

–40 °C 33% d.r. = >20 : 1

O H25C12

H

O

H

OBn

Novel examples of furan cycloadditions reported in 2008 include an intramolecular Diels−Alder reaction between a tertiary amidofuran and a benzofuran . However, the reverse amide analog of the substrate did not undergo such a cycloaddition. An example that demonstrated the effect of a 3-Cl substituent on furan towards Diels−Alder reaction, as indicated by Houk in 2006, is shown below . Cl

CO2Me

Cl

O

+ O

CO2Me

O

100 °C, 10 h 74%

HO

CO2Me CO2Me

As illustrated by the following example, 2-substituted furans participated in a regioselective Diels−Alder reaction with 3-silylbenzynes that were generated from obromophenyl triflates . The regioselectivity could not be explained simply by the steric effect of the bulky silyl group. tBuMe

tBuMe Si 2

OTf Br

O

+

2Si

nBuLi

O nBu

3Sn

PhMe –78 °C, 15–30 min 64%

SnnBu3

A novel palladium-initiated transannular [4+3] cycloaddition between a furan and an allene, as shown in the following model reaction, was examined as a strategy for the synthesis of the ABCD-ring of cortistatin A . A [4+3] cycloaddition of 2-(Boc-amino)furan with oxyallyl cations followed by a base-promoted ring opening of the cycloadducts was developed as an entry to 3-aminotropones . The [4+3] cycloaddition of methyl 2furoate with a nitrogen-stabilized oxyallyl cation, generated from a chiral allenamide, provided a predominant diastereomer as a result of the minimization of dipole interactions between the oxyallyl cation and the furan ester carbonyl group . Exo−cyclization was found to be the preferred pathway of a [2+2] photocycloaddition between a furan 2,3-double bond and the C=N bond of an isoxazoline . The regio- and diastereoselectivity of the


183

Paternò−Büchi [2+2] photocycloaddition of tetrahydrobenzofuranols with benzophenone was dependent on the reaction temperature . Furans containing a ynamide or an alkynyl ether underwent a gold-catalyzed rearrangement to form dihydroindoles, dihydrobenzofurans, tetrahydroquinolines and chromans within minutes . 5.3.2.2 Di- and Tetrahydrofurans As in previous years, the reactivity of dihydrofuran demonstrated in examples published in 2008 derives from its cyclic enol ether and activated double bond. Condensation between 2,3dihydrofuran and phenylhydrazine to form 3-(hydroxy)ethylindole proceeded under catalysis by Montmorillonite-K10 in aqueous media . An aldol-type reaction between 2,3dihydrofuran and glycolaldehyde, as shown below, was employed to synthesize hexahydrofuro[2,3-b]furan-3-ol, a structural element found in certain HIV protease inhibitors . This reaction, catalyzed by a chiral Sn(II)-PyBox complex, provided high diastereoselectivity but poor enantiomeric excess. O

OH

+ O

HO

H

[Sn(S,S)-Ph-PyBox](OTf)2 (2 mol%) (CF3)2CHOH 0 °C to r.t. 63% isolated yield d.s. 93:7, 15% ee

O

OH

O

O H

The activated double bond in 2,5-dihydrofuran participated in a ruthenium-catalyzed [2+2+2] cycloaddition with a 1,6-diyne, forming a tricyclic product in 92% yield . An Yb(OTf)3-catalyzed formal [4+2] cycloaddition between 2,3-dihydrofuran and 3-aminocoumarin-derived aldimines produced cis-fused 1,2,3,4-tetrahydropyrido[2,3c]coumarins . A formal [4+2] cycloaddition of 2,3-dihydrofuran with ohydroxybenzaldimines was catalyzed by iodine to form cis-fused furanobenzopyrans selectively, as shown below . PhHN

NPh H

I2 (2 mol%)

+ O

OH

THF r.t, 2.5 h 96% d.r. = 97 : 3

O

H O H

A hetero−Diels−Alder reaction between 2,3-dihydrofuran and o-quinone methide furnished a cis-fused furopyran. Reaction of o-quinone methide with 2methylenetetrahydrofuran produced a [5,6]-spiroketal as depicted below . O

HO

+

AcO

iPrMgCl

THF –78 °C 76%

O

O

X.-L. Hou et al.

184

2,5-Dimethoxy-2,5-dihydrofuran was transformed in one pot into γ-substituted-γbutenolides via a vinylogous Mukaiyama reaction of the intermediate 2-trimethylsilyloxyfuran. An interesting bromination reaction is illustrated below . Me3SiBr Me3SiOTf Et3N NBS MeO

O

OMe

O

Br

O

CH2Cl2 r.t., then –80 °C 90%

A TiCl4-promoted domino homo-Michael/cyclization/ring cleavage reaction of 3-acetyl5-aryl-4,5-dihydrofurans with 1,3-bis(silyloxy)-1,3-butadienes formed 5-(2-aryl-2haloethyl)salicylates, as demonstrated by the following example . O Me3SiO O

+

OMe

OH

1. TiCl4 (2 equiv.) CH2Cl2 –78 to 20 °C, 18 h

OSiMe3

O OMe

2. HCl (10%) 46%

Ph

Cl Ph

A dyotropic rearrangement of a 2,3-dihydrofuran-5-yl cuprate was used to construct the C11−C14 segment and the C13−C14 trisubstituted (Z)-double bond of discodermolide . As shown in the following example, a tandem ring-opening/ring-closing/cross metathesis of 7-oxanorbornen-2-yl vinyl ether with alkenes, as induced by the Hoveyda−Grubbs catalyst, generated 2,6-dioxabicyclo[3.3.0]octenes, . Substrates with allylic and homoallylic ethers provided 6- and 7-membered ring analogs . O

+ O

H

o-(Me2CHO)PhCH=RuCl2(IMes) (10 mol%) CO2Me

CH2Cl2 40 °C 72%

O

CO2Me

O H

In 2008, important findings regarding the Pd-catalyzed asymmetric Heck reaction of 2,3dihydrofuran were reported. The sense of asymmetric induction of the Heck reaction of 2,3dihydrofuran with triflates to form 2-substituted-2,5-dihydrofurans was found to be dependent on the benzylic substitution of chiral phosphino-oxazoline ligands . The product distribution (i.e. 2,5-dihydrofuran vs 2,3-dihydrofuran) could also be influenced by substitution on chiral cyclopropyl-bridged phosphino-oxazoline ligands . Theoretical studies of the corresponding reaction using a chiral phosphino-thiazole ligand were also reported . Palladium-catalyzed hydroarylation of a 7-oxanorbornene with arenediazonium tetrafluoroborate salts provided exo-products in good yields . The asymmetric ring


185

opening of 7-oxabenzonorbornadienes with aryl boronic acids was catalyzed by a chiral palladacycle, producing products with up to 83% ee . A palladium-catalyzed three-component coupling between 7-oxabenzonorbornadienes, aryl iodides and acetylenes provided 5,6-disubstituted 7-oxabenzonorbornenes, without a ring-opening side reaction . The enantioselectivity of the ring opening of 7-oxabenzonorbornadienes with alkyl Grignard reagents was improved by using a chiral spiro-phosphine ligand under coppercatalyzed conditions . In 2008, tetrahydrofuranyl oxonium ions and tetrahydrofuran-2-yl radicals continued to be exploited in interesting transformations. For example, CH2=CHO abstraction through the intermediacy of a THF oxonium ion was the major reaction between tetrahydrofuran and the aromatic α,α,α-tri-radical, 3,4,5-tridehydropyridinium cation . A THF oxonium ion was produced under Lewis acidic conditions by a 1,2-hydride shift that was subsequently trapped by a nucleophile to furnish a 2,2-disubstituted THF product, as depicted below . nBu

nBu

MsO H

O

H OSitBuMe 2

Me3Al Me2AlCl

nBu

nBu

O

CH2Cl2 86% d.r. 10 : 1

H OSitBuMe 2

A ring opening of tetrahydrofuran was achieved via the formation of THF oxonium ylide from the reaction of THF with an in situ generated metal carbenoid . Another interesting ring opening of tetrahydrofuran by chloromethane derivatives, as shown below, occurred via a THF oxonium ion that was generated from the addition of THF to a benzyne . +

N2

+

O

HCCl2CN Reflux, 5 h 65%

–

CO2

Cl Cl O

CN

As reported in a full account , the ring opening rearrangement of a THF oxonium ylide was the key step in the construction of the oxabicyclo[5.3.1] core of sesquiterpene neoliacinic acid, as illustrated below. OAc Cu(hdacac)2 (2 mol%) H

O N2

O

H

OSi(iPr)3

CH2Cl2 Reflux 69% E:Z=3:2

AcO

OSi(iPr)3

O H

H O

A novel rhodium-catalyzed cross-coupling between tetrahydrofuran and electron-rich styrene derivatives, which probably proceeds via the activation of the C-2-H bond of THF,

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186

furnished a diastereomeric mixture of 2-(2-chloro-2-aryl)ethyltetrahydrofuran products, as represented by the following example . RhCl(PPh3)3 (0.05 equiv.) TiCl4 (4 equiv.) TBHP (1.1 equiv.)

O

O

+ 70 °C 65%

(40 equiv.)

Cl

[60]Fullerene was decorated with a tetrahydrofuran ring through the addition of a tetrahydrofuran-2-yl radical generated by phenylzinc bromide . A tetrahydrofuran2-yl radical was generated by intramolecular hydrogen atom transfer and trapped by an allyl radical to give a C-ketoside . Tetrahydrofuran-2-yl radical also adds to enimines in a 1,4-manner as illustrated below .

O

+

Ph

N

Ts

1. ZnMe2 air THF r.t. 2. NaBH4 MeOH r.t. 76% d.r. = 7 : 3

O H Ph

H N H

Ts

5.3.3 SYNTHESIS 5.3.3.1 Furans A direct, high-yield conversion of cellulose into 5-(chloromethyl)furfural was reported, which can be transformed to the known biofuel ethoxymethyl furfural . A onestep synthesis of dibutyl 2,5-furandicarboxylate in good yield from galactaric acid was documented. Its parent, 2,5-furandicarboxylic acid, is considered to be one of the targets for biorefineries . Mechanistic studies on the degradation of cellulose by ‘endwise peeling’ were described . Several metal-mediated procedures were developed for the synthesis of furans. Thus, reaction of (2-furyl)AlEt2(THF), prepared from 2-furyllithium, with aromatic ketones afforded chiral tertiary 2-furyl alcohols in the presence of a catalytic amount of titanium/BINOL . A full account of the preparation of furans with different substitution patterns using metathesis-based strategy was recorded . This strategy was employed for the synthesis of furan-imbedded (–)-(Z)-deoxypukalide . More detailed studies on the ruthenium/CF3CO2H catalyzed reaction of secondary propargylic alcohols with 1,3diketones were reported. Tetrasubstituted furans were formed when 1,3-cyclohexanediones were used while pyrans were obtained if 1,3-cyclopetanediones were the precursors . In addition to the ruthenium/CF3CO2H system, FeCl3 in refluxing toluene and InCl3 in refluxing chlorobenzene were reported to be effective catalysts for the transformation of secondary propargylic alcohols with 1,3-dicarbonyl compounds into tetrasubstituted furans. Tetraarylfurans were obtained by a palladium-catalyzed


187

reaction of 3-furoic acid with the corresponding aryl bromides . Detailed studies on the multi-component domino synthesis of furo[2,3-c]thiazepines from the reaction of thiazolium salts with substituted ketenes and acetylene dicarboxylates were described . 3-Methylthio-2,5-diarylfurans and 3-methylthio-4-bromo-2,5-diarylfurans were synthesized from 1,4-diketones via a classical Paal–Knorr reaction . The first synthesis of two natural products, (±)-montanin and (±)-teuscorolide having 3furyl groups appeared in 2008 . 3,4-Diiodofuran was utilized in the total synthesis of furan-containing natural product, (–)-halenaquinone . The synthesis of 2,3disubstituted furan-containing natural products, such as (±)-eremopetasidione, was also reported . 2-Substituted furans were synthesized in good to high yields by an intramolecular cyclization of 3-butyne-1,2-diols in the presence of ruthenium-catalyst . catalyst: catalyst (5 mol%) NH4BF4 (10 mol%)

OH

OH

Cl

S

Cp* Ru

O

EtOH 40 °C, 12 h 90%

Cl Cl

Cp* Ru

S Me Me

Cl

Cp* = η5-C5Me5

Palladium-catalyzed cross-coupling of a 2-furylsilanolate with aryl halides delivered the corresponding products in good yields . 1. NaH PhMe O

OH Si 2. Pd(dba)3•CHCl3 (5 mol%) 4-MeOC6H4I Me Me PhMe 50 °C, 24 h 71%

O OMe

Similarly, 3-alkynylfurans were synthesized via a palladium-catalyzed Suzuki coupling of 3-furanboronic acid with bromoalkynes as shown below . Suzuki coupling of 2furanboronic acid with β-bromo unsaturated aldehydes using a palladium catalyst was also reported, which provided β-(2-furyl) unsaturated aldehydes in good yields .

B(OH)2

+ O

Br

Ts N

Boc

N Boc Ts

Pd(PPh3)4 (10 mol%) Ba(OH)2•8H2O (500 mol%) DME-H2O heat, 30 min 62%

O

Functionalization at a 2- or 3-position was realized by the reaction of imines derived from 2- or 3-furfuraldehyde with acetylenes in the presence of [ReBr(CO)3(THF)2] as catalyst.

X.-L. Hou et al.

188

The reaction also took place at the position adjacent to the C=N group of 2,3- and 2,3,5multisubstituted furans . tBu

tBu

ReBr(CO)3(THF)2 (2.5 mol%)

N

+ Me

CO2Me

O

N

CH2ClCH2Cl 15 °C, 24 h 66%

CO2Me

O Me

Platinum-catalyzed tandem cyclization reaction of 1,6-enyne afforded a tetracyclic compound containing a 2,3-disubstituted furan structure, which was used to prepare the tetracyclic core of ent-(+)-nakadomarin A . A novel approach to 2-substituted 3furfurals was realized via an oxidative rearrangement of 3-furfuryl alcohols produced from addition of organometallics to 3-furfural based upon the Achmatowicz reaction as shown in the scheme below . The reaction is also suitable for furan diols obtained from a Sharpless asymmetric dihydroxylation of 3-vinylfurans, and the optical activity of starting materials is retained in the products. HO Bu

O

1. NBS (1.0 equiv.) THF-H2O (4:1) r.t., 4 h 2. 1M HCl (1.5 equiv.) 79%

CHO

O Bu

As can be seen below, coupling of 2-alkyl furans with olefins through C-H activation in the presence of Pd(II) as catalyst provided difurylalkanes predominantly. Difuryl esters were produced when acrylates were used . When Pd(OAc)2–Cu(OAc)2 was the catalyst and the reaction proceeded in HOAc, Heck-type products, namely 5-vinylated furans were obtained .

Ph

Pd(OCOCF3)2 (5 mol%)

+ O

BQ (2 equiv.) HOAc, MeCN r.t., 20 h 70%

Ph

O O

A general and efficient procedure for the synthesis of multi-substituted 3-thio-, seleno-, halo-, aryl- and alkyl-furans from substituted alkynyl- and allenyl ketones via 1,2-migration using gold, copper or other Lewis acids as catalyst. The following is an example of the reaction . In the case of bromoallenyl ketones, gold(I)- and gold(III)-catalysts provided 2bromo- and 3-bromofurans, respectively. A mechanistic study on the regioselectivity was carried out . Another report on the synthesis of 2,4-dihalo-3-thiosubstituted furans via 1,2-migration of 4-thio-but-2-yn-1-ols by using NIS/K2CO3 appeared .


PhS

Ph

CuI

PhS

Bu

O

DMA, Et3N heat 91%

Bu

189

PhS

•

Ph

Bu

O

O

Ph

Trisubstituted furans were prepared by a nucleophlic addition of X-H, including cyclohexa-1,4-diene, amines, alcohols, to a furylcarbene generated from a carbonyl-ene-yne starting material in the presence of Rh2(OAc)4 as a catalyst .

CHO

+

Ph

N H

CO2Me

Me

Rh2(OAc)4 (2.5 mol%) CH2Cl2 r.t., 6 h 69%

O Ph N Me

CO2Me

Another protocol for the synthesis of trisubstituted furans using a carbonyl-ene-yne compound as starting material was documented . In the presence of a gold catalyst, 2-alkynyl-1-cycloalkenecarbaldehydes were converted into trisubstituted furans via gold-carbene intermediates as illustrated below. CHO

O

AuBr3 (5 mol%)

OBn

PhMe r.t., 0.25 h 80% OBn

A gold complex was also used as a catalyst in the reaction of an alkynyl epoxy alcohol to provide bisfurans . This is a substituent-dependent reaction if the substituents on the epoxide are aryl groups, 1,3-diketones instead of furans are produced. OH

Au(PPh3)Cl/AgBF4 (5 mol%) O

H2O (1 equiv.) PhMe 75%

O

O

Di- and tri-substituted furans were provided in moderate to high yields by a goldcatalyzed cyclization-Claisen rearrangement of pent-2-en-4-ynyl allyl ethers .

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190

(p-CF3C6H4)3PAuNTf2 (2 mol%)

O

O

CH2Cl2 r.t., 10 min 78%

Reaction of acetylenic ketones with diazoacetates in the presence of CuI as catalyst afforded trisubstituted furans in moderate to good yields . O

Ph

N2

+ H

Ph

CuI (20 mol%) CO2Et

Ph

ClCH2CH2Cl 90 °C 65%

Ph

O

CO2Et

Regioselective synthesis of multi-substituted furans was realized by employing a coppercatalyzed reaction of bis-propargylic ester via a copper carbene intermediate . The reaction is suitable for the preparation of tetra-substituted furans, and the silane is not necessary when CuBr or CuCl is the catalyst. O

[Cu(MeCN)4]BF4 (5 mol%)

O

H11C5

+ HSiEt3 OEt

EtO2C

CH2Cl2 82%

O

SiEt3 C5H11

A [3+2] annulation of allyl sulfoxides with aldehydes was developed for the synthesis of 2,3,4-trisubstituted furans in good yields . O O Ph MeS

CHO O S Me SMe

Ph NaOH

+ N

EtOH r.t., 1.5 h 85%

MeS

O N

The reaction of 5-oxo-1-ynylphosphonates, produced from alkylation of ketones with 3iodopropynylphosphonates under mild conditions, afforded substituted furans in high yields. The synthesis proceeded in a one-pot manner . O K2CO3 PO(OEt)2

EtOH 96%

O PO(OEt)2


191

Multi-substituted 2-acylfurans were synthesized in good yields through an IBXmediated oxidation-cyclization of cis-2-en-4-yn-1-ols .

IBX (3 equiv.) Ph

HO

Ph

DMSO 90 °C 68%

Ph

O

Ph

O

Platinum-catalyzed cyclization of alkynyl epoxides generated trisubstituted furans in high yields as depicted in the following scheme . A 3-iodo tetrasubstituted furan was obtained in good yield if the reaction was carried out in the presence of NIS. The same transformation can also proceed in the presence of I2/NaHCO3 and without the use of metal catalyst . Bu

Bu

O

O PtCl2 (10 mol%) dioxane-H2O (2:1) r.t., 10 min 83%

Trichlorotriazinetrione, a swimming pool sanitizer, was used as a chloroelectrophilic reagent in the cyclization reaction of alk-3yn-1-ones to deliver chlorofurans in high yields . O O

Cl

Cl

O

O

+

Ph

Cl PhMe 94%

Ph

O

Cl (40 mol%)

The Feist-Benary reaction of 1,3-dicarbonyl compounds with α-haloketones in different ionic liquids was studied. The use of a basic ionic liquid provided dihydrofurans while neutral one afforded furans . O CO2Et

+ Br O

O

[bmim]OH 90%

O HO CO2Et [pmim]Br O

70-75 °C, 4 h 85%

O

CO2Et

O

A full paper reported the zinc chloride-catalyzed transformation of alk-3-yn-1-ones to multisubstituted furans. As illustrated, furopyrimidine nucleosides were prepared using this strategy .

X.-L. Hou et al.

192

O O

HN O

N

ZnCl2 (1.8 equiv)

N

OAc

CH2Cl2 r.t., 20 h 89%

O OAc

O

N

OAc O OAc

As shown below, fluorofurans were produced in good yields via the cyclization reaction of gem-difluorohomopropargyl alcohols mediated by ICl . The iodo substituent in the products was transformed into aryl substituents by Suzuki coupling reaction. Another procedure for the conversion of gem-difluorohomopropargyl alcohols to fluorofurans was also reported by the treatment of alcohols with DBU in THF . 1. ICl (1.5 equiv.) Na2CO3 (1.2 equiv.) THF, μw OBn 5 min

OH Ph

2. silica gel 56%

F F

F Ph

I OBn

O

An efficient palladium-catalyzed three-component Michael addition-cyclization-cross coupling reaction was developed for the preparation of tetrasubstituted furans . O

Ph Cl

+

n-H9C4

Ph

Ph

PdCl2(CH3CN)2 (5 mol%) K2CO3 (4 equiv.)

MeO

MeOH (4 equiv.) MeCN 77%

n-H9C4

O

Ph

Palladium-catalyzed reaction of 3-(1-alkynyl)chromones with aryliodides and alcohols gave rise to the formation of furochromenes in various yields . O

Ph

Ph Pd2(dba)3

+ S O

I i-Pr2NEt-DMF-MeOH 45°C 62%

O

S

O

Reaction of 1-acyl-1-alkynyl cyclopropanes with electrophiles in the presence of MeOH or I2 provided tetrasubstituted furans in good yields .


193

Ph

O

O

I2 (1.1 equiv.) NaHCO3 (3 equiv.) MeOH (10 equiv.) CH2Cl2 92%

Ph I

MeO

A similar starting material was used to produce gold-containing 1,4-dipoles in a [4+2] annulation reaction, providing fully substituted furans in high yields . Pri SO2Ph

Ph

+ N

H

N

ClCH2CH2Cl 70 °C, 15 min 87%

O

N

Ph

PhSO2

IPrAuNTf2 (5 mol%)

Pri N

Au i Pr N CF3O2S SO2CF3

O

Pri

H

IPrAuNTf2

Palladium-catalyzed cyclization-coupling reaction of buta-1,2,3-trienyl carbinols, realized from a SmI2-mediated reaction of epoxypropargyl esters, afforded fully substituted furans in moderate to high yields . CO2Et

1. SmI2 (2.25 equiv.) THF, –5 °C

OAc O CN

2. CH2=CHCO2Et Pd(PPh3)4 (5 mol%) LiCl, Et3N THF-H2O 60 °C 74%

CN

O

A one-pot, multi-component reaction of diamines with diketene and dibenzoylacetylene mediated by PPh3 led to the formation of bisfurans in high yields . Ph O H2N

NH2

+

O

PhOC

COPh (2 equiv.) PPh3 (2 equiv.) CH2Cl2 r.t., 24 h 90%

O

Ph O

Ph O

Ph O

N H

H N

O O

Two reports described the reaction of acetylenedicarboxylate with isocyanides and aromatic carboxylic acids for the synthesis of tetrasubstituted furans . An example is shown below.

X.-L. Hou et al.

194 CO2H

CO2Me

+

NC CH2Cl2 70%

CO2Me

CO2Me

MeO2C

PPh3

+

N H

O

5.3.3.2 Di- and Tetrahydrofurans A report disclosed that tetrahydrofurans were formed through a stereospecific cyclization reaction with inversion of configuration at the allylic carbons when benzyl ether protected polyhydroxylated alkenes containing allylic alcohol, ether or ester functional groups were treated with a mixture of TFA-acetonitrile-toluene . Nucleophilic displacement reaction leading to the formation of jaspine B was also reported . As can be seen in the scheme below, a cage compound was obtained by a Williamson-type reaction . OMe •

MsCl

OH OH

MeO

OMe

CH2Cl2 0 °C

•

OMe Et3N

• OH OMs

MeO

•

CH2Cl2 r.t., 2.5 h 96%

•

O

MeO

•

Other SN2 reactions leading to tetrahydrofuran-containing compounds involving mesylate and iodide as leaving groups have also been recorded. Synthetic studies of cortistatins have been numerous in 2008. Several reports disclosed the formation of the embedded tetrahydrofuran ring making use of a nucleophilic ring cyclization reaction as the pivotal step . The total synthesis of (+)-cortistatin A was reported by Nicolaou, whose team employed an intramolecular Michael addition with subsequent aldol condensation and dehydration to construct the oxygenated ring B as can be seen below . In Shair’s total synthesis of (+)-cortistatin A, the pivotal step for generating the oxygenated B ring was a tandem azaPrins cyclization and transannular etherification . Paquette used Michael addition to construct a tetrahydrofuran ring in his study towards the total synthesis of lancifodilactone G . An intramolecular allylsilane-aldehyde cyclization was reported , and was used in the total synthesis of (–)-aureonitol . O

O

OSiMe2tBu

HO H

O K2CO3

dioxane 125 °C, 12 h 52%

OSiMe2tBu O H

Tetrahydrofuran ring syntheses utilizing nucleophilic attack on oxiranes have been employed in the total synthesis of cis-solamin A , 27-hydroxybullatacin , (–)-goniofupyrone , isolasalosid A , the C10-C22 fragment and the CDEF ring system of pectenotoxin-2


195

, cembrene , cis-sylvaticin . As depicted below, a RuO4-catalyzed oxidative polycyclization of the Cs-symmetric isoprenoid polyene digeranyl led to a mixture of three tetrahydrofuran derivatives , also featuring cascade oxirane-opening as key steps.

HO RuO2•2H2O (20 mol%) NaIO4 (6 equiv.)

O O O H H H H cis/trans/trans (8.4%)

OH

O O H H H cis/trans/cis (5.6%)

OH

EtOAc-MeCN-H2O (3:3:1) HO

H

HO

H

Digeranyl

O

O

O O H H cis/trans (15%)

O

Haloetherification processes also feature in efficient routes for the synthesis of tetrahydrofuran skeletons. Examples published in 2008 include the synthesis of novel nonactic acid analogs , a macrotetrolide , (+)-varitriol , new oxa cages , and a class of COX-2 inhibitors and cytotoxic agents . An asymmetric iodocyclization catalyzed by salen-CrIIICl was also used in the total synthesis of swainsonine , as illustrated in the following scheme. The mechanism of this reaction was also discussed.

TrO

OH

N

+ tBu

1. NCS K2CO3 PhMe –78 °C

N

Cr O Cl O tBu

tBu tBu

(7 mol%)

TrO

I

O

2. I2 (1.2 equiv.) –78 °C, 20 h 90% 93% ee

An etherification route involving the framework of pent-4-en-1-ol as the main precursor can also provide tetrahydrofuran derivatives. Utilizing this protocol, the total synthesis of platensimycin , (±)-paulownin , Woody-Ambery odorants and several 3-oxygenated-cis-2,5-dialkyl-substituted tetrahydrofurans were synthesized. Shi also made use of this process in his quest for 3oxabicyclo[3.1.0]hexane units . A dramatic enhancement of enantioselectivity was observed in the photochirogenic cyclization of 5,5-diphenyl-4-penten-1-ol in near- and supercritical CO2 , a process that may go through a photosensitized cation-radical intermediate. In Baran’s total synthesis of (+)-cortistatin A, the step to construct the oxygenated B ring also involved a cyclization of pent-4-en-1-ol , as shown in the scheme below.

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196 O

AcO

O O

1. MgBr2•Et2O 2,6-(t-Bu)2C5H3N

AcO H AcO OH Me2N

AcO O

2. PPTS H2O 3. K2CO3 82%

H

AcO Me2N

Lactones can be converted into tetrahydrofurans through derivatives such as methyl acetals , lactol acetates and thiol acetals . The scheme below illustrates how a methyl acetal is converted to tetrahydrofuran-containing molecules via intramolecular cyclization processes . AcO

AcO O O

H H

O

PhSO2H H2O OMe 75% OH

AcO

H H

AcO

O OH H H OMe OH

H H

O O H H H

OMe

H OMe

The 3-pentylidene-protected ribosyl fluoride depicted below also underwent an outside attack by nucleophiles to provide substituted tetrahydrofurans . BnO O

O

F O

BnO BF3•Et2O SiMe3 4Å MS CH2Cl2 86%

Nu

BnO O

O O

O

dr >98/2 O

O

As in 2007, several articles reported the construction of tetrahydrofurans by allowing allylsilanes to react with aldehydes in the presence of Lewis acids . This method was used to synthesize 10-hydroxytrilobacin and its three diastereomers as well as the C1-C9 fragment of amphidinolide C . A highly diastereoselective, tandem, three-component synthesis of tetrahydrofurans from ketoaldehydes via silylated β-lactones was reported, and an example is shown below . Moreover, alkynyl alcohols are known to react with various aldehydes via Prins-type cyclization, leading to the formation of 3-tetrahydrofuranylidenes .


OSiiPr3

Me

+ BnO

CHO

S

O

N O

BnO

H

ZnCl2

Me

O

OSiiPr3 Me

H

BnO

O

2. DIBALH CH2Cl2 –78 °C to 0 °C 6h 54% dr >19 : 1

O OBn

O

CH2Cl2 23 °C, 4 h

OBn

1. Et3SiH 0 °C, 12 h

OSiiPr3

BnO

197

OBn Me H

OH

OBn

Improved conditions were reported for the Prins-pinacol rearrangement of cyclohexa1,4-diene derived acetals, using triflic acid. An example is illustrated in the following scheme . A similar reaction was utilized to synthesize (±)-sylvone . Ph O

Ph

O TfOH (5 equiv.) HO

O

HO

H

Ph

O

Ph

Ph 15 min 61%

HO

Ph

H

Ph

O Ph

H

OHC

H

O H

Ph

Ph

Indirectly, tetrahydrofuran rings can be formed through Diels-Alder cycloaddition reactions , and an example is depicted below . Lee achieved the synthesis of the cage-like core of (–)-platensimycin that contains a tetrahydrofuran ring by utilizing a carbonyl ylide cycloaddition approach . Moreover, intramolecular cycloaddition reactions between allyl ethers and trimethylenemethane diyls generated from alkynyl iodonium salts also provided tetrahydrofuran rings in an indirect fashion . Me

Me OMe

OMe

Me Ph3P=CHC(O)Me

H O H OHC

H OPMB

Me MeO

Me Me

H

O

O

PhMe 110 °C 71%

H Me

HH

H OPMB

H Me

HH H OPMB O

O

A diastereoselective synthesis of cis-2,5-disubstituted tetrahydrofurans via a Lewis acid catalyzed [3+2] cycloaddition of donor-acceptor cyclopropanes and aldehydes was reported by Johnson , who also showed that similar reactions can be catalyzed by palladium(0) . An example is depicted below. Intramolecular Pd(0)-catalyzed tetrahydrofuran

X.-L. Hou et al.

198

formation reactions en route to the total synthesis of (+)-oocydin A and jaspine B were postulated to go through π-allyl palladium intermediates. 4-F3CC6H4CHO (6 equiv.) CO2Me Pd2(MeO-dba)3 (0.0125 equiv.) CO2Me

MeO2C

CO2Me

Pd+

– CO2Me

bphen (0.25 equiv.) C 7H 8 rt, 4 h 97%

CO2Me

O

CF3

As can be seen below, the Pd(OAc)2-(S)-SEGPHOS combination catalyzed the enantioselective arylative cyclization of an allenyl aldehyde with p-MeCOC6H4B(OH)2 to afford a 3,4-cis-disubstituted tetrahydrofuran . An intermolecular rhodiumcatalyzed [3+2+2] carbocyclization of alkenylidenecyclopropanes with activated alkynes gave 3,4-cis-fused bicycloheptadienes . The rhodium-catalyzed intramolecular [6+2] cycloaddition of 2-vinylcyclobutanones and alkenes has been studied employing DFT computation . A rhodium-catalyzed Lewis acid-promoted C-H activation process was effective in promoting coupling reactions between tetrahydrofuran and alkenes . Arylzinc reagents are also known to induce the addition of tetrahydrofuran to [60]-fullerene through C-H bond activation . O

• O

CHO

p-MeCOC6H4B(OH)2 (1.5 equiv.) Pd(OAc)2-(S)-SEGPHOS (20 mol%) MeCN 24 h 63% 96% ee

O O

O

Me

OH

PPh2 PPh2

O (S)-SEGPHOS

O

Gagné reported a platinum(II)-mediated oxidative cation polyene cascade cyclization , and an asymmetric version of this reaction is illustrated in the scheme below . Another platinum(II)-catalyzed reaction of γ,δ-ynones with alkenes led to the formation of 8-oxabicyclo[3.2.1]octane frameworks, presumably via platinum-containing carbonyl ylides . P(3,5-Me2C6H4)2

P(3,5-Me2C6H4)2 OH

O

Pt(BF4)2 (10 mol%) AgBF4 (22 mol%) Ph3COMe (resin) (2.1 equiv.) 75% 79% ee

H

Spiroquinolines were realized by a one-pot multicatalytic and multicomponent cascade


199

reaction, as can be seen in the scheme shown below . NH2

OH CHO O

+

NH

O O

HBF4 (1 equiv.) Ph MeCN –30 °C to r.t. 82% (single diastereomer)

O

Ph

O

[PtMe2(cod)] (5 mol%)

+

2,3,4,5-Tetrasubstituted tetrahydrofurans were synthesized from furan via 7oxabicyclo[2.2.1]hept-5-ene-2,3-diols, the key step of these transformations being the 2nd generation Hoveyda-Grubbs ruthenium catalyst-catalyzed ring-opening metathesis–cross metathesis (ROM-CM) sequence in the presence of ethylene . As shown below, gold-catalyzed addition of indole to a 1,6-enyne provided a polycyclic product as a single diastereomer . tBu tBu

Au-NCMe

+ SbF – 6

Au+L

AuL Ph

O

Ph Ph

(5 mol%)

+

H Ph

O

CH2Cl2 rt, 3 h 64%

N H

Ph

H+

H

H

HN

AuL Ph

Ph

–Au+L O H Ph

O+

H Ph

H+

Ph

+O

H Ph

H

H

H

HN

HN

HN

H Ph

O

HN H Ph –H+ Ph

O Me

HN

Intramolecular radical cyclization reactions as key steps have been used to form tetrahydrofuran rings . Examples in this category are Lee’s total syntheses of (+)-monocerin and (–)-amphidinolide E . Titanium(III)-mediated intramolecular radical cyclization of epoxyallene ethers also afforded multifunctional tetrahydrofurans in an exo-mode , while methylenecyclopropanes can be opened by di-n-butyliodotin radical to give homoallyl radicals, whose intramolecular cyclization reaction gave tetrahydrofurans . Di-n-butyliodotin radical also reacted with allenyl compounds to lead to similar cyclizations . A transannular radical cyclization was employed in the synthesis of polycyclic core of platensimycin as shown below . An oxygen-centered radical cyclization onto silyl enol ethers was used to synthesize siloxy-substituted tetrahydrofurans .

X.-L. Hou et al.

200

1. n-Bu3SnH AIBN O PhMe reflux

O O

2. 1N aq. HCl 57%

O Me

SPh

O

O O

•

O Me

Me

Palladium(II)-mediated cycloisomerization of 3-C-alkynyl-allo- and ribofuranose derivatives was investigated by Ramana, whose results indicated the importance of electronic factors on ring closing regioselectivity . The key step in the stereocontrolled synthesis of (±)-nonactic acid was the acid induced intramolecular Michael addition followed by elimination of MeOH . As shown below, reaction of a propargylic carbonate with a 2-substituted cyclohexane-1,3-dione in the presence of a palladium catalyst also led to the formation of a tetrahydrofuran featuring 2,4-dimethylene groups . O OCO2Me

Me

+ O

Pd2(dba)3•CHCl3 (5 mol%) dppf (20 mol%) DMSO 120 °C, 5-30 min 83%

O

Me O

Aqueous asymmetric rhodium-catalyzed Pauson-Khand type cycloaddition of propargyl allyl ethers in the presence of formates was reportedly assisted by microwave irradiation. In this manner, tetrahydrofurans fused with cyclopentenone rings were obtained . A similar asymmetric Pauson-Khand reaction involving CO was also recorded . A high level DFT computation was applied to study the impact of coordination number on the level of diastereocontrol in rhodium-catalyzed Pauson-Khand reactions. Accordingly, experiments were also carried out to assess the effect of CO pressure on the level of diastereocontrol, and the findings were found to support theoretical results . As can be seen in the following scheme, the propargyl allyl ether underwent an asymmetric rhodium-catalyzed reaction with ethyl pyruvate, giving a bicyclic 3-methylenetetrahydrofuran . A similar approach using protected dehydroamino acids led to protected αamino acids bearing a quaternary carbon . When pyruvates were replaced by cyclobutanones, tetrahydrofurans fused with an eight-membered ring were obtained . Variations of these reactions included the use of 1,n-diene-ynes (n = 4-6) where alkyne and alkene moieties are connected by a 1,1-disubstituted alkene , allenebutadiene precursors , and cyclopropene-ynes . Dialkylzincs were able to induce ring cyclization of β-(propargyloxy)enoates, also affording 3methylenetetrahydrofurans . Moreover, a tandem addition/cyclization of carbomotelluroate onto 1,6-enynes was reported to give 3-methylenetetrahydrofurans . Ma reported a controllable gold- or palladium-catalyzed cyclization reaction of 2-(2’,3’-allenyl)acetylacetates, giving 4,5-dihydrofurans with good selectivity .


Ph

O

+

O

[Rh(cod)2]BF4(R)-H8-BINAP (10 mol%)

Me Me

Ph

CO2Et Me O

O

(CH2Cl)2 80 °C, 16 h 67% >99% ee

CO2Et

201

Me

Harada discovered that carbocyclization reactions of ω-iodo- and 1,ω-diiodo-1-alkynes provided 3-methylenetetrahydrofurans without the loss of iodine atoms. It is believed that these reactions went through a carbenoid-chain process as shown in the scheme below . Toluate moiety was found to be a viable radical precursor, promoting a cyclization route to form 3-methylenetetrahydrofurans . Tri-n-butyltin hydride-mediated radical reactions of alkyl halides were performed in a continuous flow microreactor. Within a very short period of time, a key intermediate containing a 3-methylenetetrahydrofuran moiety was obtained in gram scale . Li

Li

I

I

LDA O

I OEt

THF 25-30 °C, 4-7 h 81%

O

I

O

O OEt

OEt

OEt

As shown below, formation of a 4,5-dihydrofuran was achieved by treatment of a furanosyl sulfoxide with n-BuLi . A novel fluorinated nucleoside fused with a 4,5-dihydrofuran ring was realized by treatment of a nucleoside embedded with a 3-butyn-1-ol moiety . An efficient one-pot synthesis of spiro-4,5-dihydrofuran fluorinated products was achieved via [3+2] oxidative cycloaddition reactions mediated by cerium ammonium nitrate between 1,3-dicarbonyl compounds and 9-benzylidene-9H-fluorene or 2(9H-fluorene-9-ylidene)-1-phenylethanone derivatives . 4,5-dihydrofurans were also prepared in a stereoselective manner from readily available enones and α-nitrocarbonyls . O

O

O

O O

SOPh O

n-BuLi THF-hexane –78 °C 79%

O

O HO

A highly diastereoselective and enantioselective formal [4+1] ylide annulation pathway was devised for the synthesis of optically active 4,5-dihydrofurans with cyclopropanes as sideproducts, as illustrated below . Similar reactions of α,β-unsaturated sulfones with arsonium ylides also led to trans-4,5-dihydrofurans .

X.-L. Hou et al.

202

Cl 1. Cs2CO3 DMF –40 °C

Me S CO2Et OH Br 2.

MeOC

COMe

COMe

+

COMe

CO2Et

EtO2C

Me O Cl trans/cis = 15/1 >99 : 1 88% 93% ee

COMe

Cl

A convenient and efficient synthesis of substituted 4,5-dihydrofurans was developed via ring expansion of 1-dimethylaminopropenoyl-1-carbamoyl/benzoyl cyclopropanes . A palladium-catalyzed isomerization of 2-vinylidenehydrofurans afforded also 4,5-dihydrofurans substituted with a 2-vinyl group . A sequential process involving Sonogashira coupling, propargyl-allenyl isomerization, and intramolecular Diels– Alder reaction was also known to give polycyclic molecules with embedded 4,5-dihydrofurans . As can be seen below, an intriguing formal [2+3] cycloaddition promoted by hypervalent iodine reagent led to the formation of products containing both tetrahydrofuran and dihydrofuran rings . OH

O O

O OMe

O

PhI(OAc)2 MeO 36%

H

+

O

O O

O

O

+

H OMe

MeO

6:1

OMe

(±)-2-O-Methylneovibsanin, a naturally occurring molecule containing a 2,5dihydrofuran ring, was synthesized using an intramolecular Michael addition and a concomitant solvolytic attack . An indirect generation of compounds with 2,5-dihydrofuran rings was also achieved by an intramolecular photolytic [4+2] cycloaddition of allene to benzene . The base-promoted endo-mode ring closure of electron-withdrawing group-substituted penta-3,4-dienol provided 2,5-dihydrofurans . Self-condensation of terminal alkynyl ketones via organozinc species afforded also 2,5-dihydrofurans, as is depicted below . O

CF3CO2H Et2Zn CH2I2

O

NO2

CH2Cl2 r.t., 24 h 48%

NO2 O

NO2

Ring-closing metathesis is one of the most convenient methods for preparing 2,5dihydrofurans . In this connection, a fluorous-tagged linker for the parallel


203

synthesis of small molecules that included 2,5-dihydrofuran derivatives using ring-closing metathesis was described . Other organometallic methods for realizing 2,5dihydrofurans include Ma’s palladium(II)-catalyzed coupling-cyclization protocol that led to 4(1’,3’-dien-2-yl)-2,5-dihydrofurans from two 2,3-allenols . Alcaide and Almendros also uncovered that palladium(II) and other noble metal catalysts also catalyzed domino heterocyclization/cross coupling of α-allenols and/or α-allenic esters, leading to functionalized 2,5-dihydrofurans, as shown below . A catalytic enantioselective intermolecular cycloaddition of 2-diazo-3,6diketoester-derived carbonyl ylides with alkynes using chiral dirhodium(II) carboxylates was also recorded PMP O

O

OH

OAc Me

Me

+

•

•

PdCl2 (5 mol%)

Me

Me

O

PMP O

DMF 4h 90%

O

Me Me

5.3.3.3 Benzo[b]furans and Related Compounds A benzo[b]furan-derived cyclicҏβ-amino acid scaffold was utilized as a building block for the synthesis of a diverse set of flavonoid-like probes for identifying the inhibitors of cell motility as shown below . 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives were identified as inhibitors of human pancreatic cancer cells . 2Phenylbenzo[b]furan-3(2H)-one was employed as the starting material for the total synthesis of rocaglamide, being the shortest and most efficient synthetic method so far for the synthesis of this type of molecule . Benzo[b]furan-2-amine reacted with a series of 1,3dielectrophile-based reagents to afford a number of interesting benzofuro[2,3-b]pyridines . MEMO

MEMO

H NR

O MEMO

O H

O H H N PBB Alloc

O

CO2Et NH2

MEMO

O H

SR1

MEMO

O H OAc H NR

H NR O

The reaction of benzofuranyldiazoacetates with 1,3-dienes catalyzed by the dirhodium tetracarboxylate Rh2(R-DOSP)4, generates formal [4+3] cycloadducts with >94% de and 9198% ee. The reaction proceeds via a tandem cyclopropanation/Cope rearrangement followed by a stereoselective tautomerization. This methodology was extended to the formal synthesis of (+)-frondosin B .

X.-L. Hou et al.

204

O Rh MeO2C

N H O Rh SO2Ar 4 Ar = p-C6H4C11-13H23-27

N2 Ph

+

MeO2C

–78 °C to r.t. 68%

O

O Ph (>94% de, 98% ee)

In a diastereoselective total synthesis of (±)-codeine, the key step involved a sequential synthetic transformation, namely lactone ring opening, Michael addition and reduction to afford the morphinan skeleton. This novel approach provides an efficient method for the elaboration of the quaternary carbon at C-13 and for the highly diastereoselective introduction of the C-14 stereogenic center of the morphinan system as depicted below. In a recent formal synthesis of (–)-morphine, the hydroxydibenzo[b]furan was formed using mCPBA which induced an intramolecular etherification via an epoxide opening reaction . A similar strategy was also applied to the total synthesis of (–)-linderol A for the construction of the scaffold of dihydrobenzo[b]furan core . Asymmetric synthesis of ACNO fragment of morphine was also achieved by a palladium-catalyzed intramolecular Heck reaction . O

O BnMeN 1. HNMeBn THF O OMe

BnMeN 13

O 2. LiAlH4 THF reflux 77% (2 steps)

O OMe

MeO OH

NMe2

BnMeN

OMe 14

NMe2

decalin 215 °C

+ O

O

OMe

OMe

A novel and highly stereoselective intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides was applied to the synthesis of structurally diverse tricyclic hexahydrobenzo[3,2-b]pyrroles in high yields as illustrated in the following scheme .

CHO CO2Me MeHNCH CO Et 2 2 O

PhMe reflux 70%

CO2Me

H H O

N Me

CO2Me H

H

Me N

O H

CO2Me CO2Me

As can be seen below, a simple and practical two-step procedure for the preparation of a variety of 2-unsubstituted 1-benzo[b]furan-3-carboxylic acid methyl esters was achieved via copper-catalyzed intramolecular C-O bond formation in good to excellent yields .


CO2Me

CO2Me OH

1. NaH HCO2Me 2. H3O+

Br

205 CO2Me

CuI (10 mol%) K2CO3 DMF 100 °C 87%

Br

90%

O

One-pot oxidative heteroannulations of N-sulfonylanilines with styrenes via a [2+3] cycloaddition allowed the construction of 2-substituted-5-amino-2,3-dihydrobenzo[b]furans . A similar synthetic strategy was reported for the synthesis of 2,3dihydrobenzo[b]furans from phenols and allylsilane . β-Hydroxy-α-tosyloxy esters substituted phenols were also employed as chiral building blocks for the enantioselective synthesis of chiral 2,3-dihydrobenzo[b]furan scaffold . Palladium-catalyzed asymmetric Wacker-type cyclization of o-trisubstituted allylphenols was applied to the synthesis of 2,3-dihydrobenzo[b]furans . OMe

+

O

PhI(O2CCF3)2

OMe

OMe

MeCN TsHN –10 °C to 25 °C 95%

TsHN

1-Substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones were converted into 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzo[b]furan-4-ols as shown below . Treatment of 2-substituted benzoylphosphonates with trialkyl phosphites was found to afford benzo[b]furans via a series of interesting rearrangements . Ph

Ph

H

O O

O

Ph

CH2=S(O)Me2 (2 equiv.)

Ph

H O O H OH

DMF 70%

A total synthesis of the bioactive meroterpenoid natural products frondosin B and frondosin A (formal) from ready available cyclohexanone and gentisic aldehyde dimethyl ether, involved RCM and Lewis acid mediated benzo[b]furan as key steps . OH

HO H

HO

O

HO

H

O

O

BF3•Et2O

p-TsOH

CH2Cl2 0 °C, 5 min 95%

C 6H 6 reflux, 5 h 70%

Frondosin B

Structurally diverse highly substituted benzo[b]furans were made via a BCl3-promoted dehydrative cyclization. .

X.-L. Hou et al.

206 I MeO MeO

O

MeO

tBu

BCl3

tBu

MeO

–78 °C to r.t. 89%

O

OMe

I

OMe

MeO O

MeO

A wide variety of 3-iodobenzo[b]furans were readily prepared by iodocyclization of 2alkynyl-1-(1-ethoxyethoxy)benzenes with the I(coll)2PF6-BF3•Et2O combination . Ph Ph

I(coll)2PF6 (2 equiv.) BF3•Et2O CH2Cl2 r.t., 10 min 95%

O OEE

I Ph Ph +

+

O

N I easily removable

A novel two step synthesis of 2-alkoxymethylbenzo[b]furans was achieved via the palladium-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenols under basic conditions to give 2-methylene-2,3-dihydrobenzo[b]furan-3-ols, followed by acid-catalyzed isomerization or allylic nucleophilic substitution with alcohols as nucleophiles in good yields . OH

PdI2 KI Morpholine MeOH 40 °C 82%

OH

OH H2SO4 O

MeOH-H2O r.t., 15 h 78%

O

OMe

A novel type of Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivative with ethyl acetoacetate was reported to lead rapidly to the scaffold of 2,3dihydrobenzo[b]furans, but the yields were less than 50%. The mechanism of the reaction was proposed in the article .

O

+ MeCOCH2CO2Et

Me3SiOTf (1.0 equiv.) ClCH2CH2Cl 50 °C, 15 h 45%

OH

O Ph

In the total synthesis of rubioncolin B, the key intermediate benzo[b]furan was made by the biomimetic synthesis from substituted 1,4-dioxo-1,4-dihydronaphthalene . An


207

acid-mediated benzo[b]furan formation from substituted o-acetoxyphenylacetylene was also applied to the synthesis of the key intermediate in the formal total synthesis of (–)-kendomycin . O CO2Me

1. CAN (2 equiv.) H2O-MeCN (1:1) 0 °C, 15 min 2. K2CO3 (5 equiv.) DMF 100 °C, 1 h 69% (2 steps)

O

OH CO2Me

O

Structurally diverse furo-pyridines were made by the palladium-catalyzed aryl 4nonafluorobutanesulfonates with terminal acetylenes, followed by Lewis acid-promoted intramolecular furo-pyridine ring formation . A similar strategy was applied to a straightforward synthesis of indole-benzo[b]furan and bis-benzo[b]furan derivatives . nBu

Pd(OAc)2 Ph3P, CuI

OMe F3C

N

nBu

nBu

ONf

i-Pr2NH DMF 61%

tBu

OMe F3C

N

tBu

1. BBr3 CH2Cl2 0 °C

O

2. K2CO3 DMF 80 °C 85%

F3C

N

tBu

As shown below, a simple and efficient synthesis of dihydrobenzo[b]furans was developed using multi-component coupling of salicylaldehyde, and various amines and alkynes. The use of aliphatic alkynes containing a heteroatom is critical to the success of the reaction . A similar synthetic methodology was reported for the facile and efficient synthesis of polyfunctionalized benzo[b]furans via a copper-catalyzed threecomponent coupling reactions from an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine . N CHO

+ OH

+ N H

OH

CuI (30%) MeCN 80 °C, 16 h 94%

O

OH

Two novel synthetic approaches were developed for the syntheses of furo[3,2c]coumarins and chlorofuro[3,2-c]coumarins in good to acceptable yields as shown in the following scheme . Gold-catalyzed tandem annulation of furan-dialkynes was utilized for the formation of benzo[b]furans . A similar type of gold-catalyzed cyclization was also reported to make 2-substituted benzo[b]furans from o-alkynyl phenols .

X.-L. Hou et al.

208 Ph

Ph O

O

Ph

CuCl (20 mol%) O

DMF 90 °C, 20 h 86%

O

O

CuBr (10 mol%) CuCl2 (4.2 equiv.)

Cl

DMF-H2O 75 °C, 10 h 70%

O

O

O

Polysubstituted dibenzo[b]furan derivatives were made by the palladium-catalyzed intramolecular Heck reaction as depicted below . A wide variety of fused [4,5]furo heterocycles could also be constructed by copper-mediated intramolecular cyclizations in good yields . CHO

NO2

CHO Br

NO2

Pd(OAc)2 Na2CO3 DMF 73%

O OMe

O OMe

Angular furanocoumarins could be made by refluxing hydroxycoumarinyl ketone with methyl γ-bromocrotonate in dry acetone in the presence of anhydrous K2CO3 . MeO2C O

Me

HO

Me

BrCH2

O

Me

O

O

CO2Me

O

K2CO3 (anhyd.) Me2CO reflux, 8 h 65%

O

Me

An efficient synthetic approach was developed for the synthesis of 2,3-disubstituted benzo[b]furans: the reaction proceeded via an initial Claisen rearrangement followed by ring closure as illustrated below . N-Acyliminium-initiated aromatic π-cyclization was applied to the construction of a wide variety of benzo[b]furan-based tetra- and pentacyclic lactams .

F3C

O F

CsF F3C F

N,N-diethylaniline reflux 73%

F Me O F


209

Carbodiimides reacted with secondary amines, phenols or alcohols in the presence of a catalytic amount of K2CO3 or sodium alkoxide to give 2-substituted benzofuro[3,2d]pyrimidin-4(3H)-ones . O

O

EtNH2

CO2Et

O CO2Et

N C NAr

89%

NEt

NHEt

N

O

N NHAr

NHAr NaOEt 90% O

O NAr

N NHEt

A palladium-catalyzed double annulaton reaction was applied to the construction of polysubstituted benzo[1,2-b:5,4-b’]difurans and benzo[1,2-b:4,5-b’]difurans from bis(allyloxy)bis(alkynyl)benzenes . O

Pd2(dba)3 (5 mol%) Ph3P

O

Bu

Bu

DMF 60 °C, 9 h 665

O

O

Bu

Bu

As can be seen in the following scheme, a practical synthesis of lespedezol was achieved in 33% yield for four steps starting with the formation of a substituted chalcone. The key step is an acid-catalyzed ketalization followed by dehydration . Total synthesis of wedelolactone was also achieved via a similar synthetic strategy . MeO

O

O HO

HCl (cat.) 3Å MS

OH

HC(OMe)3 MeOH reflux 71%

MeO

O

O OH

Corsifuran A was realized in an enantiomerically pure form using copper-catalyzed intramolecular etherification as a key step .

X.-L. Hou et al.

210

Br

CuCl (5 mol%) NaH

OMe

MeO OMe

PhMe reflux 76%

OMe HO

O Corsifuran A

In a synthetic study toward the total synthesis of lancifodilactone F, the key intermediate dihydrobenzo[b]furan-based was made via a [2+2] ketene cycloaddition reaction as the only diastereoisomer . Me 1. (COCl)2 PhMe O

O

H

Me

2. Et3N 77%

CO2H

O

A novel synthetic approach for the synthesis of 3-acyl-benzo[b]furans was developed by reaction of iodonium ylides with the in situ generated benzyne derived from o-silylaryl triflates and CsF as illustrated below . A convenient method for the synthesis of 2-bromo-3-aroyl-benzo[b]furans by a palladium-catalyzed coupling reaction between 1-aryl-3silylpropynones and substituted 2-iodophenols has been developed .

+ OTf

CO2Me

O

SiMe3

CO2Me

Me

CsF (3 equiv.) Me MeCN Ar r.t., 4.5 h 88%

IPh

O

Intramolecular carbolithiation of alkynes was applied to the regioselective synthesis of 3-(2,2-diethoxyethylidene)-2,3-dihydrobenzo[b]furan with exclusive anti selectivity, this stereochemical outcome was verified by DFT computational study . EtO

OEt

OEt EtO

Br

n-BuLi (1 equiv.)

O

THF –78 °C

OEt Li

O

H2O or EtOD 84-88%

EtO

H(D)

O (100% E)

In the total synthesis of laurentristich-4-ol, the key feature was the regio- and stereoselective synthesis of 2,3-dihydrobenzo[b]furan-based spirocyclic ether . A similar scaffold could also be made by Lewis acid-mediated oxetane ring opening reaction .

Five-Membered Ring Systems: Furans and Benzofurans AcO

O Me O

Me

SmI2

AcO

HMPA-THF 0 °C 66%

Me

211

O HO Me

In a model study towards the synthesis of aflatoxin B2, a tricyclic 2,3dihydrobenzo[b]furan was made by utilizing the Dötz benzannulation reaction .

O

OH

H

H

Cr(CO)5 O

+ MeO

SitBuMe

2

OEt

H

O H

THF 80 °C 31%

SitBuMe2

O

OMe OEt

1-(2-Benzo[b]furoyl)guaiazulene derivatives were synthesized by the condensation of 3-(chloroacetyl)guaiazulene with salicylaldehyde under mild conditions with good yields . OHC

K2CO3

+ Cl

MeCN reflux, 8 h 65%

HO

O

O

O

As shown below, palladium-catalyzed enolate arylation was used in one-pot syntheses of a wide variety of benzo[b]furans, in moderate to excellent yields. The illustrated example further demonstrates its use in the synthesis of natural product eupomatenoid . 1. Pd(OAc)2 (±)-DTBPB NaO-t-Bu

O Cl

Br

+ OH

Me

Me Cl OMe

OMe

2. CF3CO2H CH2Cl2 43%

O

The tricyclic core of the cyclopentabenzo[b]furans were made in an efficient and stereoselective manner utilizing a sequential intramolecular silyl vinylketene formation/[4+1] annulation. This type of scaffold could be applied to the total synthesis of naturally occurring rocaglamides .

X.-L. Hou et al.

212 OMe iPr Si 3

(CO)5Cr

iPr

iPr

3Si

O

OMe

C6H6 65 °C, 2 h

O

1. PhCHN2 Et2O 0 °C to r.t. 18 h

• O

2. CAN MeOH 0 °C to r.t. 30 min 81%

O

O

OMe

3Si

5.3.3.4 Benzo[c]furans and Related Compounds Warrener’s 3,6-di(2-pyridyl)tetrazine method is by far the most reliable and efficient method for the preparation of benzo[c]furans. Benzo[c]furans prepared in this way were allowed to react with α,β-unsaturated sulfones . As shown below, another way in which a series of π-extended 1,1’-bi(benzo[c]furans)s can be made in one pot is by a photochemical exocyclic [2+2+2] cycloaddition starting from bis[o(arylcarbonyl)phenyl]acetylenes .

Ar

hν (385 nm)

O O

Ar

O Ar

THF 62-90%

Ar

O

1,3-diarylbenzo[c]furans can also be converted to 1,3-diarylbenzo[c]selenophenes using Woollins reagent, while the starting 1,3-diarylbenzo[c]furans were synthesized by reacting 3methoxyphthalide with two equivalents of aryl Grignard reagents with subsequent acid treatment . Similar conversion of o-aroylbenzaldehyde to benzo[c]furans was also recorded . Derivatives of benzo[c]furans have been utilized as reactive Diels– Alder dienes in the synthesis of anthraquinones as well as a functionalized heptacene . 1,3-diphenylbenzo[c]furan has also been used to trap 3-substituted 1-chlorocyclopropenes and donor-acceptor cyclopropanes in [4+3] cycloaddition reactions as depicted in the scheme below. Near-infrared fluorophores containing benzo[c]furan subunits have also been reported . O

Ph

Ph CO2Et

+

O

CO2Et Ph

Yb(OTf)3 (5 mol%) CH2Cl2 reflux, 9 h 85% exo : endo = 56 : 44

Ph exo

Ph

O CO2Et CO2Et Ph

Ph

+

CO2Et CO2Et

Ph

Ph endo

An efficient route for the synthesis of 1,3-dihydrobenzo[c]furans based on an iodinemediated cyclization of 2-vinylbenzyl alcohols was reported . As can be seen below, diols can be converted into 1,3-dihydrobenzo[c]furans via a tandem oxidation-reduction


213

method employing a cocktail of MnO2/Et3SiH/CF3CO2H . Oxa-Pictet-Spengler synthesis of hydroxyphthalans was achieved by reacting hydroxybenzyl alcohols with benzaldehydes. The hydroxy groups of benzyl alcohols are proposed to affect the course of the reaction .

OH OH OMe

MnO2 Et3SiH CF3CO2H CH2Cl2 –5 °C to 0 °C, 1 h 86%

O OMe

The release of steric strain was important in an unusual intramolecular nucleophilic aromatic substitution, leading to the formation of a naphthofuran as depicted below . The enantioselective addition of organozinc reagents to 2-alkynyl benzaldehydes and the subsequent cyclization were reported to give chiral 1,3dihydrobenzo[c]furans featuring alkylidene substituents . A mechanistic study of the gold-catalyzed synthesis of 1,3-dihydrohydroxybenzo[c]furans from ω-alkynyl furans was reported .

OH NaH

I

O

THF reflux 32%

Rhodium-catalyzed [2+2+2] cycloaddition reactions involving dipropargyl ethers and unsaturated partners such as alkynes and alkenes led to the formation of polysubstituted 1,3dihydrobenzo[c]furans. An example is illustrated in the scheme below . Other alkynes and alkenes include alkynylamides , 1,3-diynes , aryl isocyanates , enol ethers and enol acetates , dialkynylphosphine oxides , (2-deoxy-D-ribofuranosyl)alkynes and maleimide . Ruthenium catalysts , iridium catalysts , nickel catalysts and palladium catalysts have all been reported to give similar results. S Ph O

P(c-C6H11)2

+

[RhCl(cod)]2 (5 mol%) AgBF4 (10 mol%) BINAP (10 mol%)

Ph

S P(c-C6H11)2

O

Ph Ph

ClCH2CH2Cl reflux 58%

Ph Ph

Reductive ring opening of substituted 1,3-dihydrobenzo[c]furans was achieved by treatment with lithium and a catalytic amount of DTBB, leading to the formation of the corresponding functionalized organolithium intermediates in a regioselective manner. Further

X.-L. Hou et al.

214

reactions of these intermediates with electrophiles gave benzylic alcohols . An example is shown below. tBu

Li (10 equiv.) DTBB (5 mol%) O THF –78 to –50 °C

Ph

Ph

t-BuCHO Li OLi –78 °C Ph 58%

OH

OH

As can be seen in the scheme below, Diels–Alder reaction between a dibromoanthracene and the oxygen-bridged compound gave an endoxide whose acid dehydration reaction afforded the extended bifunctional triptycene . On the other hand, gold-catalyzed [4+3] annulation of oxabicyclic benzenes with 2-substituted allylsilanes gave mixtures of bicyclic products through tandem allylation and cyclization .

Me

Me

Br

+

Me

Br

Me

O

Br Me

1. xylene 160 °C

Me

2. p-TsOH 120 °C 52%

Br Me

Me

Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoE/P-10/01). XLH acknowledges with thanks support from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. KSY thanks Dr Nicholas A. Meanwell for support. 5.3.4 REFERENCES 08ASC1531 08AGE34 08AGE342 08AGE891 08AGE944 08AGE951 08AGE1107 08AGE1312 08AGE1903 08AGE2178 08AGE2869 08AGE3410 08AGE3762 08AGE4009 08AGE4903 08AGE5026

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Five-Membered Ring Systems: Furans and Benzofurans 08JOC585 08JOC612 08JOC730 08JOC882 08JOC1040 08JOC1131 08JOC1320 08JOC1440 08JOC1649 08JOC2554 08JOC2753 08JOC2886 08JOC2947 08JOC2951 08JOC3377 08JOC4732 08JOC5311 08JOC5776 08JOC5852 08JOC5881 08JOC6268 08JOC6753 08JOC6909 08JOC7336 08JOC7467 08JOC7526 08JOC7616 08JOC7625 08JOC7721 08JOC7985 08JOC8089 08JOC8120 08JOC8331 08JOC8437 08JOC9219 08JOC9544 08JOC10276 08NPR298 08OBC1317 08OBC1665

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Five-Membered Ring Systems: Furans and Benzofurans 08OM3996 08OM6393 08P225 08P271 08P445 08P553 08P1173 08P1227 08P1242 08P1319 08P1384 08P1782 08P2088 08P2374 08S1094 08S1545 08S1729 08S1783 08S1788 08S2278 08S2617 08S2707 08S2929 08S3389 08S3516 08S3615 08S3742 08SL25 08SL94 08SL126 08SL242 08SL343 08SL555 08SL739 08SL837 08SL911 08SL1076 08SL1145 08SL1376 08SL1553 08SL1724 08SL1897 08SL2046 08SL2069 08SL2299 08SL2389 08SL2508

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E. Thiery, D. Harakat, J. Le Bras, J. Muzart, Organometallics 2008, 27, 3996. M. Rubina, W.M. Sherrill, M. Rubin, Organometallics 2008, 27, 6393. Y.-H. Lu, B.-L. Wei, H.-H. Ko, C.-N. Lin, Phytochemistry 2008, 69, 225. H. Zhang, O.A. Odeku, X.-N. Wang, J.M. Yue, Phytochemistry 2008, 69, 271. L.G. Felippe, D.C. Baldoqui, M.J. Kato, V. da S. Bolzani, E.F. Guimarães, R.M.B. Cicarelli, M. Furlan, Phytochemistry 2008, 69, 445. S.-G. Cao, A.J. Al-Rehaily, P. Brodie, J.H. Wisse, E. Moniz, S. Malone, D.G.I. Kingston, Phytochemistry 2008, 69, 553. S.-H. Lam, J.-M. Chen, C.-J. Kang, C.-H. Chen, S.-S. Lee, Phytochemistry 2008, 69, 1173. C. Bassarello, T. Muzashvili, A. Skhirtladze, E. Kemertelidze, C. Pizza, S. Piacente, Phytochemistry 2008, 69, 1227. O. Yodsaoue, S. Cheenpracha, C. Karalai, C. Ponglimanont, S. Chantrapromma, H.-K. Fun, A. Kanjana-Opas, Phytochemistry 2008, 69, 1242. X.-N. Wang, C.-Q. Fan, S. Yin, L.-S. Gan, J.-M. Yue, Phytochemistry 2008, 69, 1319. P.K. Cheplogoi, D.A. Mulholland, P.H. Coombes, M. Randrianarivelojosia, Phytochemistry 2008, 69, 1384. N.T. Kipassa, T. Iwagawa, H. Okamura, M. Doe, Y. Morimoto, M. Nakatani, Phytochemistry 2008, 69, 1782. H.-X. Wang, C.-M. Liu, Q. Liu, K. Gao, Phytochemistry 2008, 69, 2088. R.B. Teponno, A.L. Tapondjou, E. Abou-Mansour, H. Stoeckli-Evans, P. Tane, L. Barboni, Phytochemistry 2008, 69, 2374. K. Kobayashi, K. Hashimoto, S. Fukamachi, H. Konishi, Synthesis 2008, 1094. D. Enders, A. Hieronymi, G. Raabe, Synthesis 2008, 1545. X. Yang, L. Zhu, Y. Zhou, Z. Li, H. Zhai, Synthesis 2008, 1729. C.V. Ramana, S.B. Narute, R.G. Gonnade, R.S. Patil, Synthesis 2008, 1783. A. Alizedeh, S. Rostamnia, L.-G. Zhu, Synthesis 2008, 1788. D. Enders, V. Terteryan, J. Palecek, Synthesis 2008, 2278. S. Mann, V. Sarli, A. Giannis, Synthesis 2008, 2617. A.S.K. Hashmi, E. Enns, T.M. Frost, S. Schäfer, W. Frey, F. Rominger, Synthesis 2008, 2707. A. Alizdeh, Q. Oskuyan, S. Rostamnia, A. Ghanbari-Niaki, A.R. Mohebbi, Synthesis 2008, 2929. L. Coutable, C. Saluzzo, Synthesis 2008, 3389. A. Aljarilla, J. Plumet, Synthesis 2008, 3516. J. Rybácek, J. Závada, P. Holy, Synthesis 2008, 3615. A. Alizadeh, A. Hosseinpour, S. Rostamnia, Synthesis 2008, 3742. R.J. Boxall, R.S. Graingerm, C.S. Aricò, L. Ferris, Synlett 2008, 25. H. Berber, P.-O. Delaye, C. Mirand, Synlett 2008, 94. C.G. Nasveschuk, T. Rovis, Synlett 2008, 126. S.J. Gharpure, S.K. Porwal, Synlett 2008, 242. V.O. Iaroshenko, U. Groth, N.V. Kryvokhyzha, S. Obeid, A.A. Tolmachev, T. Wesch, Synlett 2008, 343. H. Yang, S. Kim, Synlett 2008, 555. J.E. Antoline, R.P. Hsung, Synlett 2008, 739. D.K. Mohapatra, H. Rahaman, Synlett 2008, 837. R. Rincón, J. Plumet, Synlett 2008, 911. D. Bérard, L. Racicot, C. Sabot, S. Canesi, Synlett 2008, 1076. A.V. Butlin, F.A. Tsiunchik, V.T. Abaev, V.E. Zavodnik, Synlett 2008, 1145. L.X. Alvarez, B. Bessières, J. Einhorn, Synlett 2008, 1376. H.W. Lee, F.Y. Kwong, A.S.C. Chan, Synlett 2008, 1553. K. Tanaka, Y. Takahashi, T. Suda, M. Hirano, Synlett 2008, 1724. R.-V. Nguyen, C.-J. Li, Synlett 2008, 1897. R. Zimmer, M. Taszarek, L. Schefzig, H.-U. Reissig, Synlett 2008, 2046. I. Kim, H.-K. Na, K.R. Kim, S.G. Kim, G.H. Lee, Synlett 2008, 2069. L.-W. Hsin, L.T. Chang, H.-L. Liou, Synlett 2008, 2299. F. Dènés, F. Beaufils, P. Renaud, Synlett 2008, 2389. G. Bartoli, S. Cacchi, G. Fabrizi, A. Goggiamani, Synlett 2008, 2508.

222 08SL2547 08SL2993 08SL3046 08T53 08T163 08T219 08T445 08T809 08T821 08T847 08T936 08T1603 08T2329 08T2740 08T3661 08T4162 08T4183 08T4275 08T5200 08T5974 08T5982 08T6215 08T6289 08T6341 08T7258 08T7511 08T7537 08T7992 08T8952 08T9136 08T9413 08T10267 08T11086 08T11185 08T11193 08T11296 08T11313 08T11860 08TA209 08TL20 08TL57 08TL165 08TL226 08TL358 08TL500 08TL782 08TL799

X.-L. Hou et al. P. Li, Z. Cai, G. Zhao, S.-Z. Zhu, Synlett 2008, 2547. B.-J. Zhao, J.-B. Chang, Q. Wang, Y.-F. Du, K. Zhao, Synlett 2008, 2993. W.-H. Ji, Y.-M. Pan, S.-Y. Zhao, Z.-P. Zhan, Synlett 2008, 3046. V. Fiandanese, D. Bottalico, G. Marchese, A. Punzi, Tetrahedron 2008, 64, 53. W.-G. Cao, H. Zhang, J. Chen, X.-H. Zhou, M. Shao, M.C. McMills, Tetrahedron 2008, 64, 163. C.V. Ramana, R. Mallik, R.G. Gonnade, Tetrahedron 2008, 64, 219. M.A. González, Tetrahedron 2008, 64, 445. T.J. Donohoe, N.M. Kershaw, A.J. Orr, K.M.P. Wheelhouse, L.P. Fishlock, A.R. Lacy, M. Binham, P.A. Procopiou, Tetrahedron 2008, 64, 809. T. Shibata, S. Yoshida, Y. Arai, M. Otsuka, K. Endo, Tetrahedron 2008, 64, 821. Y. Yamamoto, K. Hattori, Tetrahedron 2008, 64, 847. S.A. Eastham, S.P. Ingham, M.R. Hallett, J. Herbert, A. Modi, T. Morley, J.E. Painter, P. Patel, P. Quayle, D.C. Ricketts, J. Raftery, Tetrahedron 2008, 64, 936. Z.-Y. Chen, S.C. Sinha, Tetrahedron 2008, 64, 1603. Y.-K. Cheong, P. Duncanson, D.v. Griffiths, Tetrahedron 2008, 64, 2329. M.Ikoma, M. Oikawa, M. Sasaki, Tetrahedron 2008, 64, 2740. C.-F. Chang, L.-Y. Yang, S.-W. Chang, Y.-T. Fang, Y.-J. Lee, Tetrahedron 2008, 64, 3661. S.K. Das, G. Panda, Tetrahedron 2008, 64, 4162. R. Garzelli, S. Samaritani, C. Malanga, Tetrahedron 2008, 64, 4183. D. García, F. Foubelo, M. Yus, Tetrahedron 2008, 64, 4275. P. Novák, S. Cíhalová, M. Otmar, M. Hocek, M. Kotora, Tetrahedron 2008, 64, 5200. Y. Kuninobu, K. Kikuchi, Y. Tokunage, Y. Nishina, K. Takai, Tetrahedron 2008, 64, 5974. A. Maehara, T. Satoh, M. Miura, Tetrahedron 2008, 64, 5982. M.M. Montero-Campillo, J. Rodríguez-Otero, E.M. Cabaleiro-Lago, Tetrahedron 2008, 64, 6215. K. Tanaka, M. Takahashi, H. Imase, T. Osaka, K. Noguchi, M. Hirano, Tetrahedron 2008, 64, 6289. K.W.L. Yong, A. Jankam, J.N.A. Hooper, A. Suksamrarn, M.J. Garson, Tetrahedron 2008, 64, 6341. K.-i. Yamada, H. Umeki, M. Maekawa, Y. Yamamoto, T. Akindele, M. Nakano, K. Tomioka, Tetrahedron 2008, 64, 7258. C.-P. Chuang, K.-P. Chen, Y.-L. Hsu, A.-I. Tsai, S.-T. Liu, Tetrahedron 2008, 64, 7511. D. Bérard, M.-A. Giroux, L. Racicot, C. Sabot, S. Canesi, Tetrahedron 2008, 64, 7537. P. Amaladass, N.S. Kumar, A.K. Mohanakrishnan, Tetrahedron 2008, 64, 7992. R. Grigg, V. Scidharan, D.A. Sykes, Tetrahedron 2008, 64, 8952. M. Tori, Y. Okamoto, K. Tachikawa, K. Mihara, A. Watanabe, M. Sakaoku, S. Takaoka, M. Tanaka, X. Gong, C. Kuroda, M. Hattori, R. Hanai, Tetrahedron 2008, 64, 9136. F. Wang, G. Yang, Y.-J. Zhang, W. Zhang, Tetrahedron 2008, 64, 9413. R.N. Ram, N. Kumar, Tetrahedron 2008, 64, 10267. S. Kitagaki, T. Kawamura, D. Shibata, C. Mukai, Tetrahedron 2008, 64, 11086. V. Piccialli, N. Borbone, G. Oliviero, Tetrahedron 2008, 64, 11185. A. Hiranrat, W. Mahabusarakam, Tetrahedron 2008, 64, 11193. L. Coutable, K. Adil, C. Saluzzo, Tetrahedron 2008, 64, 11296. Y. Ichikawa, K. Matsunaga, T. Masuda, H. Kotsuki, K. Nakano, Tetrahedron 2008, 64, 11313. N. Mantrand, P. Renaud, Tetrahedron 2008, 64, 11860. K. Venkatesan, K.V. Srinivasan, Tetrahedron: Asymmetry 2008, 19, 209. A.V. Butin, S.K. Smirnov, I.V. Trushkov, Tetrahedron Lett. 2008, 49, 20. H.T. Bonge, T. Hansen, Tetrahedron Lett. 2008, 49, 57. L.-X. Shao, M.-H. Qi, M. Shi, Tetrahedron Lett. 2008, 49, 165. H. Zhou, J. Yao, G. Liu, Tetrahedron Lett. 2008, 49, 226. H. Tanimoto, R. Saito, N. Chida, Tetrahedron Lett. 2008, 49, 358. L.-B. Xu, X. Huang, Tetrahedron Lett. 2008, 49, 500. H. Konno, Y. Okuno, H. Makabe, K. Nosaka, A. Onishi, Y. Abe, A. Sugimoto, K. Akaji, Tetrahedron Lett. 2008, 49, 782. R.N. Ram, N. Kumar, Tetrahedron Lett. 2008, 49, 799.

Five-Membered Ring Systems: Furans and Benzofurans 08TL980 08TL1461 08TL1627 08TL1678 08TL1738 08TL2359 08TL2469 08TL2514 08TL2799 08TL3063 08TL3335 08TL3409 08TL3437 08TL3648 08TL3963 08TL3967 08TL4110 08TL4192 08TL4260 08TL4276 08TL4313 08TL4446 08TL4613 08TL4652 08TL5021 08TL5179 08TL5208 08TL5238 08TL5271 08TL5618 08TL5683 08TL5693 08TL5931 08TL6245 08TL6282 08TL6437 08TL6597 08TL6610 08TL6613 08TL6701 08TL6784 08TL7113 08TL7191 08TL7260 08TL7364

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M. Passiniemi, A.M.P. Koskinen, Tetrahedron Lett. 2008, 49, 980. K. Samanta, G.K. Kar, A.K. Sarkar, Tetrahedron Lett. 2008, 49, 1461. N.D. Yadav, M. Yamashita, M. Nagahama, T. Inaba, T. Sawaki, I. Kawasaki, A. Kurume, S. Ohta, Tetrahedron Lett. 2008, 49, 1627. M. Yoshida, M. Higuchi, K. Shishido, Tetrahedron Lett. 2008, 49, 1678. E. Liktor-Busa, A. Simon, G. Tóth, M. Báthori, Tetrahedron Lett. 2008, 49, 1738. X. Huang, W. Fu, M. Miao, Tetrahedron Lett. 2008, 49, 2359. S.K. Nandy, J. Liu, A.A. Padmapriya, Tetrahedron Lett. 2008, 49, 2469. P.J. Jervis, B.M. Kariuki, L.R. Cox, Tetrahedron Lett. 2008, 49, 2514. N. Tanaka, Y. Kashiwada, M. Sekiya, Y. Ikeshiro, Y. Takaishi, Tetrahedron Lett. 2008, 49, 2799. K. Okuma, Y. Fukuzaki, A. Nojima, K. Shioji, Y. Yokomori, Tetrahedron Lett. 2008, 49, 3063. P.R. Singh, M.P. Surpur, S.B. Patil, Tetrahedron Lett. 2008, 49, 3335. A.K. Ghosh, J. Takayama, Tetrahedron Lett. 2008, 49, 3409. N. Sakai, N. Uchida, t. Konakahara, Tetrahedron Lett. 2008, 49, 3437. H. Jayasuriya, K.B. Herath, J.G. Ondeyka, D.L. Zink, B. Burgess, J. Wang, S.B. Singh, Tetrahedron Lett. 2008, 49, 3648. S. Giboulot, A. Pérez-Luna, C. Botuha, F. Ferreira, F. Chemla, Tetrahedron Lett. 2008, 49, 3963. M. Spadafora, M. Mehiri, A. Burger, R. Benhida, Tetrahedron Lett. 2008, 49, 3967. X. Feng, Z. Tan, D. Chen, Y. Shen, C.-C. Guo, J. Xiang, C. Zhu, Tetrahedron Lett. 2008, 49, 4110. T. Yamada, M. Doi, H. Shigeta, Y. Muroga, S. Hosoe, A. Numata, R. Tanaka, Tetrahedron Lett. 2008, 49, 4192. V.S.P.R. Lingam, R. Vinodkumar, K. Mukkanti, A. Thomas, B. Bopalan, Tetrahedron Lett. 2008, 49, 4260. K. Mohamad, Y. Hirasawa, C.S. Lim, K. Awang, A.H.A. Hadi, K. Takeya, H. Morita, Tetrahedron Lett. 2008, 49, 4276. C. Seger, S. Pointinger, H. Greger, O. Hofer, Tetrahedron Lett. 2008, 49, 4313. M. Butters, M.C. Elliott, J. Hill-Cousins, J.S. Paine, A.W.J. Westwood, Tetrahedron Lett. 2008, 49, 4446. B.C. Ranu, L. Adak, S. Banerjee, Tetrahedron Lett. 2008, 49, 4613. K. Cao, Y.-J. Jiang, S.-Y. Zhang, C.-A. Fan, Y.-Q. Tu, Y.-J. Pan, Tetrahedron Lett. 2008, 49, 4652. M. Yoshida, M. Al-Amin, K. Matsuda, K. Shishido, Tetrahedron Lett. 2008, 49, 5021. A. Martin, I. Pérez-Martin, L.M. Qunitanal, E. Suárez, Tetrahedron Lett. 2008, 49, 5179. J. Wang, F.-X. Xu, X.-F. Lin, Y.-G. Wang, Tetrahedron Lett. 2008, 49, 5208. K.J. Quinn, J.M. Curto, E.E. Faherty, C.M. Cammaranto, Tetrahedron Lett. 2008, 49, 5238. Y.-D. Zhou, Q.-F. Xu, H.-B. Zhai, Tetrahedron Lett. 2008, 49, 5271. M. Lau, P. Langer, Tetrahedron Lett. 2008, 49, 5618. J.S. Yadav, B.V. Subba Reddy, G. Narasimhulu, G. Satheesh, Tetrahedron Lett. 2008, 49, 5683. H.-Y. Lee, Y. Yoon, Y.-H. Lim, Y. Lee, Tetrahedron Lett. 2008, 49, 5693. D.T. Craft, B.W. Gung, Tetrahedron Lett. 2008, 49, 5931. S.R. Angle, I. Choi, Tetrahedron Lett. 2008, 49, 6245. M.-K. Na, D.A.F. Meujo, D. Kevin, M.T. Hamann, M. Anderson, R.T. Hill, Tetrahedron Lett. 2008, 49, 6282. L.-Z. Dai, M. Shi, Tetrahedron Lett. 2008, 49, 6437. I. Kim, S.-H. Lee, S. Lee, Tetrahedron Lett. 2008, 49, 6597. M.-J. Dai, S.J. Danishefsky, Tetrahedron Lett. 2008, 49, 6610. M.-J. Dai, Z. Wang, S.J. Danishefsky, Tetrahedron Lett. 2008, 49, 6613. B. Panda, T.K. Sarkar, Tetrahedron Lett. 2008, 49, 6701. G.J. Florence, r. Cadou, Tetrahedron Lett. 2008, 49, 6784. G. Mehta, N.S. Likhite, Tetrahedron Lett. 2008, 49, 7113. A.G. Guzii, T.N. Makarieva, V.A. Denisenko, P.S. Dmitrenok, Y.V. Burtseva, V.B. Krasokhin, V.A. Stonik, Tetrahedron Lett. 2008, 49, 7191. G. Savitha, R. Sudhakar, P.T. Perumal, Tetrahedron Lett. 2008, 49, 7260. L. Zhao, G. Cheng, Y. Hu, Tetrahedron Lett. 2008, 49, 7364.

224

Chapter 5.4 Five-Membered Ring Systems: With More than One N Atom Larry Yet AMRI, Singapore [email protected]

_________________________________________________________________________ 5.4.1

INTRODUCTION

The synthesis and chemistry of pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles were actively pursued in 2008. The solid-phase and combinatorial chemistry of these ring systems seemed to have disappeared compared to past years. No attempt has been made to incorporate all the exciting chemistry and biological applications that were published this year. 5.4.2

PYRAZOLES AND RING-FUSED DERIVATIVES

A review on the synthesis of 4-iodopyrazoles was published . A microreview was written on recent advances in the chemistry of indazoles . A review on the reaction of trifluoromethyl-ȕ-diketones with hydrazines and hydroxylamine in the synthesis of trifluoromethylpyrazole and isoxazole derivatives was published . Theoretical calculations have been carried out on 3,3’-dimethyl-1,10diphenyl-5,5’-bi-1H-pyrazole to evaluate its usefulness as a molecular balance to measure ππ stacking . Hydrazine additions to 1,3-difunctional groups is the most common method for the preparation of pyrazoles. 2-Alkyn-1-ones 1 were converted to substituted 1-acyl-5-hydroxy4,5-dihydro-1H-pyrazoles 2, which underwent dehydration and iodination in the presence of iodine monochloride and lithium carbonate at room temperature to provide 1-acyl-4-iodo-1Hpyrazoles 3 . Pyrazoles 5 were prepared by the reaction of 1,3-diketones 4 with hydrazines catalyzed by polystyrene supported sulfonic acid (PSSA), which proceeded efficiently in water in the absence of any organic solvent at room temperature within 1–2 min . Condensation between alkyl acetoacetates 6 and hydrazine hydrochloride in alcoholic solvents delivered 3-alkoxypyrazoles 7 . The regioselectivity of the condensation of electronically unsymmetrical 1,3-diaryl-1,3-diketones with 2hydrazinopyridine and 2,6-bis hydrazinopyridine to form N-(2-pyridyl)-3,5-diarylpyrazoles was studied . A series of 5-amino-1-aroylpyrazoles 9 were synthesized directly by the reaction of β-aminocrotononitrile 8 with some structures containing the hydrazine moiety (X-NHNH2) by refluxing ethanol in presence of sodium acetate . Reactions of Cbz-enaminone 10 with hydrazine hydrochlorides under microwave irradiation afforded intermediates 11, which were deprotected with HBr-AcOH to give a library of 4-(2aminoethyl)-1H-pyrazol-5-ols 12 . 12-Tungstophosphoric acid (H3PW12O40) was c 2009 Elsevier Limited. All rights reserved.

Five-Membered Ring Systems: With More than One N Atom

225

found to be an efficient and recyclable catalyst in promoting a chemo- and regioselective condensation of hydrazines and hydrazides with various 1,3-dicarbonyl compounds in pure water at room temperature to afford pyrazoles in high yields . 4-Substituted 1Hpyrazole-5-carboxylates were prepared from the cyclocondensation reaction of enaminodiketones with tert-butylhydrazine hydrochlorides or with carboxymethylhydrazine . A convenient one-pot procedure for the synthesis of 3,5-disubstituted pyrazoles by condensation of chalcones, hydrazine hydrate and sulfur in ethanol under microwave irradiation was reported . The preparation of N-methylpyrazoles with 1,3-diketones with methylhydrazine in 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3hexafluoro-2-propanol (HFIP) as solvents dramatically increased the regioselectivity in the pyrazole formation . NH 2 NHAc, PhMe

O R1 2

R

80 °C

R1

53–95%

HO

Ac N N

O

CH2 Cl2

R1

O

N NH 3

R R2

NH2 NH2 •HCl, R1 OH

8

COBn N O

R1 O

reflux, 8 h

R3 R2

9–55%

6

NH 2

X = H, Et, Cl

X 5

72–92%

O

R O

10

R1 = Me, Et, i-Pr, Bn R2 = H, Et, Bn, F R3 = Me, CO 2Et, CF3

7 Me

CN NH 2NHX, NaOAc•H 2O EtOH, ref lux, 2 h

N

80–98%

RNHNH 2•HCl EtOH, microwave

N

R N

N X 9

NH2

HOAc

N

R N

OH

50 °C 16–75%

R = H, Me, Bn, Ar, 3-pyridazinyl

X = COAr, C(S)NH 2

HBr OH

120 °C Me2 N

R2 = Ar, COR

R1

25 °C, 1–2 min

4

1

2 3 R

R1 = Me, OEt

N N

PSSA, H 2O

X

I

0–96%

Ac N N

R2

R 2NHNH 2

O

ICl, Li2 CO3

2 2 R

R1 = R2 = alkyl, Ar

1

R1

11

NHCO2 Bn

12

NH 2

Hydrazones are useful intermediates in the preparation of pyrazoles. Two general protocols were developed for the regioselective synthesis of 1,3,5-tri- and 1,3,4,5tetrasubstituted pyrazoles 15 by the reaction of electron-deficient N-arylhydrazones 13 with nitroolefins 14 . A silver(I)-catalyzed intramolecular facile regioselective formation of 1,3- and 1,5-disubstituted and 1,3,5-trisubstituted pyrazoles 17 from propargyl N-sulfonylhydrazones 16 was disclosed in which a migration of sulfonyl groups (Ts, Ms) was observed . Select C(α),N-phenylhydrazones were dilithiated with excess lithium diisopropylamide to their dianion-type intermediates followed

L. Yet

226

by condensation with methyl hydrogen phthalate and the resulting C-acylated hydrazones were not isolated but acid cyclized directly to afford substituted 2-(1-phenyl-1H-pyrazol-5yl)benzoic acids . Select C(α)-N-carbo-tert-butoxyhydrazones were dilithiated with excess lithium diisopropylamide followed by condensation with methyl 2(aminosulfonyl)benzoate, acid cyclization, hydrolysis and decarboxylation to yield new 2(1H-pyrazol-5-yl)benzenesulfonamides . A novel high-yielding and regioselective method to prepare N-methylpyrazole derivatives was reported by reaction of an N-Boc-and N-Me-substituted hydrazone with an aromatic alkyl ester . The onepot cyclization of hydrazone dianions with diethyl oxalate allowed a convenient synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates . Arylamines were diazotized and coupled with various active methylene compounds such as cyanoacetamide, cyanoacetophenone, malononitrile, and ethyl cyanoacetate, resulting into αarylhydrazononitriles 18, which were cyclized with α-bromoketones or esters 19 to give 4amino-1-aryl-3,5-substituted-1H-pyrazoles 20 . A novel one-pot procedure for the synthesis of limited accessible pyrazoles through the in situ generation of a monohydrazone of cyclic 1,3-diones and subsequent cyclization with N,Ndimethylformamide dimethyl acetal was disclosed .

N 2

R

CF3CH2 OH, TFA (10 equiv)

NHR 1

NO 2

R3

+

R4

H

or

R2 R4

R3

ethylene glycol, 120–150 °C, air

14

13

R1 N N

25–75 °C, air

R1 = Me, Ph, Ar R2 = Ar R3 = Ar, 2-thiophenyl R4 = H, Me

15

19–81%

R3

R2

N Ts N

AgSbF 6, CH 2Cl2 R2

Ts

20 °C, 3 h R3

65–98%

R1

R 1 = H, Me N

R

N

1

R 2 = H, Me, Ph R 3 = Ph, styrenyl, alkyl

17

16

18-cr-6, KOH, CH3 CN or PhMe NNHAr R1

CN 18

+

60–70 °C, 2–2.5 h R2

Br 19

or TBHSO4 , KOH, CH 2Cl2

R1

NH2

N

R2

R1 = CONH 2 , COPh,

60–70 °C, 3–3.5 h

N Ar

35–94%

20

CN, CO2 Et R2 = CO 2Et, COPh

Trifluoromethyl-containing pyrazoles were synthesized via Yb(PFO)3-catalyzed threecomponent condensations of aromatic hydrazines, aldehydes, and ethyl trifluoroacetoacetate followed by IBX-mediated oxidation of pyrazolines . One-pot synthesis of fully substituted pyrazoles was accomplished from three-component condensations of phenylhydrazines, aldehydes, and 1,3-dicarbonyl compounds using Yb(PFO)3 catalyst under solvent-free conditions . Alkyne precursors have reacted with different reagents intramolecularly and intermolecularly in the preparation of various pyrazole derivatives. 5-Endo-dig cyclizations of N-nitroso derivatives of homopropargylic amines 21, catalyzed by silver nitrate on silica gel, proceeded smoothly at ambient temperature in chlorinated solvents to give essentially quantitative yields of the corresponding pyrazole-N-oxides 22, which upon deoxygenation with phosphorus(III) chloride gave excellent yields of the related N-alkylpyrazoles 23 in a regiospecific manner . Substituted arylhydrazines reacted with 3-butynol 24 in the presence of a catalytic amount of zinc triflate to give pyrazolines 25, which were easily


227

oxidized in a one-pot procedure to the corresponding pyrazoles 26 . The palladium-catalyzed four-component coupling of halides 27, phenylacetylene 28, molybdenum hexacarbonyl and hydrazine monohydrate was shown to be an efficient method for the construction of highly substituted pyrazoles 29 in a one-pot process . A novel one-pot and three-component synthesis of dialkyl 5-(alkylamino)-1-aryl-1H-pyrazole3,4-dicarboxylates 33 was accomplished by the addition of isocyanides 30 to dialkyl acetylenedicarboxylates 31, and trapped by hydrazinecarboxamides 32 . Acid chlorides 34 coupled with terminal alkynes 35 to give α,β-unsaturated ynones and in situ converted into pyrazoles 36 by the cycloaddition with hydrazines . These similar reagents and conditions were also performed under microwave radiation to give the same substituted pyrazoles by other authors . The reaction of α,β-acetylenic χ-hydroxynitriles with thiosemicarbazide under mild conditions proceeded chemo-, regioand stereoselectively to give atypically so far inaccessible tri-functionalized (amino, hydroxyl and thioamide groups) pyrazoles . AgNO 3 (10 mol%), SiO 2 (20 mol%) R2

N

CHCl3 or CH2 Cl2 , 20 °C, 6–8 h

NO

R1

R1 21

R2

>95% R3

= i-Bu, Ph;

R2

= Bn, n-Pr, allyl;

60 °C, 2 h

N

THF, 100 °C, 24 h 52–98%

N N

R3

R1

92–99%

22

Zn(OTf)2 (5 mol%)

R2

PCl3, CHCl3

Me

ArNHNH2

24

R3

R1

R 3 = Bu, Ph, (CH2 )2 OTBDPS

HO

O N N

23

Me HOAc, air N

50 °C, 24–72 h

N Ar 25

48–67%

N Ar 26

NH2NH2 •H 2 O, Mo(CO)6 , Pd(OAc)2 RX + 27

Ph

0–54%

CO2 R2 + ArHNHN 31

29

acetone, 25 °C, 36 h

O

30

R

R= Ph, Ar, 3-pyridyl, Bn

28

R1 NC + R 2 O2C

N NH

CuI, Pt-Bu3 , Cs 2 CO 3, 80 °C, 18 h

Ph

NHPh

R2 O2 C

R 1 = t -Bu, Cy, 1,1,3,3,-

32

R 1HN

tetramethylbutyl

CO2 R2 N

R = Me, Et

N Ar

60–72%

33

2

1. PdCl2 (PPh3 )2 , CuI, Et3N, THF 2. R 3NHNH 2

O

R1

1

R1

Cl + 34

R = Ph, Ar, 2-f uryl

R2 35

R 2 = Ph, 2-naphthyl 3

R =H 15–85%

N

N R3

R2

36

Diazo or diazonium compounds have been used as precursors in the preparation of pyrazoles and indazoles. The [3+2] cycloaddition of a variety of diazo compounds with o(trimethylsilyl)aryl triflates 37 in the presence of CsF or TBAF at room temperature provided

L. Yet

228

a very direct, efficient approach to a wide range of substituted indazoles in good to excellent yields under mild reaction conditions. Simple diazomethane derivatives afford Nunsubstituted indazole 39 while a dicarbonyl-containing diazo compound underwent carbonyl migration to afford 1-acyl or 1-alkoxycarbonyl indazoles 38 selectively . A new method for the synthesis of substituted 4-amino-1-arylpyrazoles 42 was described starting from β-enaminones 40 and variously substituted benzenediazonium tetrafluoroborates 41 . A facile, InCl3 and/or DABCO mediated 1,3-dipolar cycloaddition of ethyl diazoacetate with various activated olefins 43 under solvent-free conditions at ambient temperature to afford 3, 5-disubstituted pyrazolines 44 and pyrazoles in moderate to good yields was reported . O EtO

O

Me

O N

TMS

CsF, MeCN

N H 3C 38

N2 CHCO2Et

N

TBAF, THF

OTf

90%

O

CO 2Et

OEt N2

N H

85%

37

39

O R1

NHR3 R2

O R1

+ ArN2 BF4 41

40

NHR 3

R1 = Et, cyclopropyl, Ph

NaOAc N

CH2 Cl2 40–80%

R2 = Me, Ph, Et

R2

N Ar

R3 = Me, Ph

42

CO2 Et R

CO2 Et (CN)

N 2CHCO 2Et, DABCO or InCl3 neat, 25 °C

N H

R

46–97%

43

R = H, CH(R')OH

(NC) EtO2C

N

R' = H, alkyl, aryl

44

Substituted 1H-pyrazoles 46 were synthesized under Vilsmeier conditions from 1carbamoyl, 1-oximyl cyclopropanes 45 via sequential ring-opening, chlorovinylation, and intramolecular aza-cyclization . Treatment of 5-methyl-4-nitroisoxazole 47 with phenyl- and methylhydrazine followed by oxidation of the corresponding 4-amino-5nitro-1H-pyrazoles 48 with hydrogen peroxide gave 4,5-dinitro-1H-pyrazoles 49 . Ar

NOH O R

NHAr 45

RNHNH2 , H 2O

O 2N

reflux, 1 h H 3C

O 47

N

or RNHNH 2, EtOH reflux, 15 h

N N

POCl3 , DMF 38–56% R = Me, Ph

R

Cl CH 2CH2 Cl 46

O2N H 2N

Me

H2 O2 , H 2SO4 0–25 °C, 16 h

N R 48

N

40–81% R = H, Me, Ph

O2 N O2 N

Me

N R 49

N


229

Triphenylphosphine-promoted reactions of the allenylphosphonates with diisopropylazodicarboxylate or diethylazodicarboxylate led to phosphonopyrazoles . Cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alkyl[aryl]-2-ones with semicarbazide hydrochloride in the presence of pyridine in methanol and water under microwave irradiation afforded 3-alkyl[aryl]-1-carboxamides-5-trichloromethyl-5-hydroxy4,5-dihydro-lH-pyrazoles . The facile regiospecific and one-pot synthesis of 2(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4,6-diarylpyrimidines was described involving a [3+2] and [3+3] cyclocondensation between the α,β-unsaturated ketones and aminoguanidine bicarbonate . 3-Phenyl-1-(thiophen-2-yl)prop-2-en-1-one obtained by Claisen– Schmidt condensation of 2-acetyl thiophene with benzaldehyde was converted into 2,3dibromo-3-phenyl-1-(thiophen-2-yl)propan-1-one, which on treatment with various thiosemicarbazides in the presence of triethylamine in absolute ethanol yielded the corresponding hydroxy pyrazolines . The stereoselective synthesis of either trans- or cis-3,5-disubstituted pyrazolidines was accomplished via Pd-catalyzed carboamination reactions of unsaturated hydrazine derivatives . Efficient and general domino reaction of 2-acylaziridines with the Huisgen zwitterions to furnish 2-pyrazoline rings was described . Baylis-Hillman bromides have been successfully employed as a valuable source of 1,3-dipoles for cycloaddition onto dialkyl azodicarboxylates under the influence of dimethyl sulfide and potassium carbonate to provide functionalized dihydropyrazole derivatives in a simple one-pot [3+2] annulation strategy . Several approaches have been investigated for the preparation of indazoles. A copper(I)catalyzed intramolecular amination reaction of aryl hydrazones 50 using CuI, KOH, and 1,4dioxane at 105 °C for the preparation of 1-aryl-1H-indazoles 51 was described . The synthesis of 1H-indazoles 53 was achieved from o-aminobenzoximes 52 by the selective activation of the oxime in the presence of the amino group using a slight excess of methanesulfonyl chloride and triethylamine . Reaction of thioamides 54 with excess hydrazine was a convenient method for the preparation of 3-aminoindazoles and 3amino-7-azaindazoles 55 . Copper-catalyzed intramolecular C-N bond formation of 2-halobenzohydrazides afforded 1-alkyl- and aryl-substituted indazolones . CH=NNHAr R

CuI (5 mol%), KOH (2 equiv) 1,4-dioxane, 1,10-phenanthroline 100–105 °C, 5 h

X

R

63–90%

50

51

X = Cl, Br NOH

R1

R1

R3

MsCl (1.2 equiv), Et3 N (2 equiv) CH2 Cl2

NHR2

R3

N

35–87%

52

53

S R1

R2

NH2 NH 2 , DMSO 16–86%

X 54

N R2

R2

R1

N N H

X

N N Ar

R 1 =H R 2 = H, Me, Et, Bn, 2-furyl R 3 = H, Me, allyl, Ms, Ts

C = CH, N R 1 = H, F, OMe R 2 = NHR, NR'R''

55

A modular approach for the regiocontrolled preparation of pyrazoles bearing substituents on all three carbon atoms was described . In this approach, the use of a switchable metal-directing group enabled sequential direct lithiation of the 3- and 5-positions

L. Yet

230

of the pyrazole ring. Pyrazole boronic esters obtained from these lithiated intermediates underwent efficient Suzuki cross-coupling under the developed nonaqueous conditions which minimized undesirable protolytic deboronation. Halogenation of the 4-position provided the means for substitution at the remaining carbon atom. Arylpyrazoles were ortho-selectively arylated with aryl bromides with ruthenium complexes . Facile decarbonylation of the 4-formyl group in 5-alkyl amino pyrazoles 56 was seen when reacted with catalytic p-toluenesulfonic acid in methanol under microwave irradiation to provide parent 4H-pyrazoles 57 in good yields . 4-Nitropyrazole 58 underwent Mitsunobu reactions with primary and secondary alcohols to give 1-alkyl-4nitropyrazoles followed by subsequent nitro reduction to afford 1-alkyl-4-aminopyrazoles 59 . Silver and zinc salts were found to efficiently catalyze the addition of an N-H bond of pyrazoles to alkynes .

N

R2 N

R1

NR3 R4

p-TsOH•H 2O, MeOH

N

R2 N

1. PPh 3, DBAD,

microwave, 120 °C

CHO

47–99%

56

R

NH O2 N

1

THF

N

NR3 R4

57

MeOH 58

N

2. H2 , Pd/C, 59–91%

N R H2 N

59

Pyrazoles 60 were converted in a practical green manner to 4-iodopyrazoles 61 using only 0.5 equiv of iodine and 0.6 equiv of hydrogen peroxide generating water as the only reaction by-product . Deprotonation of N-phenylpyrazole using an in situ mixture of ZnCl2/TMEDA (0.5 equiv) and lithium 2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature followed by trapping with iodine regioselectively gave 5-iodo-Nphenylpyrazole . R3 N R

2

N R1 60

R3

I2 (0.5 equiv), H 2O 2 (0.6 equiv) H2 O 63–100%

R 1 = H, Me, Ph

I R

2

N N R1 61

R 2 = H, Me, NH2 R 3 = H, Me, NH2

N-(1H-7-indazolyl)pyridinones were prepared by the condensation of 2-pyrone derivatives with 7-aminoindazole in the presence of acid medium . The reaction of 5-amino-2-phenyl-3,4-dihydro-3H-pyrazol-3-one with activated lactams (lactam ethers, lactam acetals, and methylthioalkylidene iminium salts) occurred on the active methylene group of 5-amino-2-phenyl-3,4-dihydro-3H-pyrazol-3-one to furnish cyclic enamines, 5amino-4-(2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-ones and 5-amino-4-(1methyl-2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-ones . An electrochemically induced catalytic tandem Knoevenagel–Michael reaction of two equivalents of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one with various aromatic aldehydes in ethanol in an undivided cell in the presence of sodium bromide as an electrolyte results in the formation of the corresponding 4,4’-(arylmethylene)bis(1H-pyrazol-5-ols) . The regioselective N-aryl or O-aryl copper-catalyzed coupling of a tautomeric pyrazolone/pyrazole with 2-halopyridines was investigated . Alkyl radicals have been cyclized onto pyrazoles using Bu3SnH-, (TMS)3SiH- and Bu3GeH-mediated aromatic homolytic substitution for the synthesis of bicyclic Nheterocycles . The synthesis of dipyridopyrazole and pyridopyrazolopyrazine derivatives both of which incorporate a 3-aryl moiety was achieved by intramolecular radical arylation of pyridinium N-aminides using tris(trimethylsilyl)silane and azobisisobutyronitrile .


231

Many methods for the preparation of pyrazole-fused ring systems were published. A facile synthesis of 5H-indazolo[3,2-b]benzo[d]-1,3-oxazines 62 via one-pot intramolecular bis-heterocyclizations was reported . An efficient synthesis of pyrazolo[4,3c]quinolin-4-ones 63 was achieved by the photocyclization of 5-chloro-N-phenyl-1Hpyrazole-4-carboxamides . A simple and practical six-step synthesis of new 1methyl-1H-thieno[2,3-c]pyrazoles 64 from 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester was reported . A convenient synthesis of a series of pyrazolo[3,4-b]pyridine and pyrazolo[5,1-c][1,2,4]triazine derivatives incorporating a pyrimidine moiety via the reactions of the versatile, readily accessible 3-oxo-N-(pyrimid-2-yl)butanamide was described . Tacrine analogs derived from N-aryl-5-amino-4-cyanopyrazoles by a Friedlander type reaction was published . A novel approach to one-pot synthesis of dihydrofuro[3’,4’:5,6]pyrido[2,3-c]pyrazoles 65 and indeno[2’,1:5,6]pyrido[2,3c]pyrazole 66 were investigated using organocatalysts that were recyclable . Regio- and chemoselective multicomponent protocols for the synthesis of 1,4,6,7,8,9hexahydro-1H-pyrazolo[3,4-b]quinolin-5-ones, 5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin8-ones, and 5α-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones starting from 5-amino-3-phenylpyrazole, cyclic 1,3-dicarbonyl compounds and aromatic aldehydes was disclosed . Several novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]and -[4,5-g]indazoles and their 6-alkyl and 8-alkyl derivatives were synthesized from 5-nitro and 6-nitroindazoles in a three-step route involving the regioselective cyclization of thioureidoindazoles and indazolyl dithiocarbamates as the key steps . An environmentally benign four-component reaction in aqueous medium at room temperature was developed for the synthesis of 6-amino-5-cyano-3-methyl-4-aryl/heteroaryl-2H,4Hdihydropyrano[2,3-c]pyrazoles 67 . Three series of 3,7-bis(arylazo)-6-methyl2-phenyl-1H-imidazo-[1,2-b]pyrazoles were prepared starting from N-aryl 2-oxo-2phenylethanehydrazonoyl bromides and 5-amino-4-arylazo-3-methylpyrazoles . Regioselective synthesis of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones by the cyclization of 3-acyl-4-methoxy-1-methylquinolinones with hydrazines was reported . General high-yielding microwave-assisted organic synthesis protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines 68 and pyrazolo[3,4-b]pyrimidines 69 were described . Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier–Haack conditions. 4,5- and 6,7-Dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives . Diazafulvenium methides were generated under microwave irradiation from 2,2-dioxo-1H,3H-pyrazolo[1,5c]thiazoles which underwent sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8π+2π] cycloaddition to give pyrazole derivatives . Reaction of 4,6dichloropyrimidine-5-carbaldehyde with various substituted hydrazines provided 1alkylpyrazolo[5,4-d]pyrimidines . A series of 6-(2-hydroxybenzoyl)-5-methyl7-phenylpyrazolo[1,5-a]pyrimidines were synthesized directly by the solvent-free reaction between 5-amino-1H-pyrazoles and 3-benzoyl-2-methyl-4H-chromen-4-one . Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1b][1,2,4]triazoles via desulfurization ring contraction was described . A facile and efficient preparation of pyrazoloquinolin-4-ones [phenyliodine(III)bis(trifluoroacetate)] promoted cyclization reaction was described . Reaction of 6-acetyl-7-(2dimethylaminovinyl)pyrazolo[1,5-a]pyrimidine with 1,3- and 1,4-bisnucleophiles provided entry to new pyrazolo[1,5-a]quinazolines . Cycloaddition of pyridine N-imine with 6-alkyl-4-oxohex-5-ynoates followed by condensation with hydrazine provided entry to 6-(pyrazolo[1,5-a]pyridine-3-yl)pyridazinones . 2-Phenyl-3-piperidin-1-yl acrylonitrile was utilized for the synthesis of pyrazolo[5,1-c][1,2,4]triazine derivatives

L. Yet

232

. 1-Aryl or alkyl-substituted-4-arylazamethylene-6-arylpyrazolo[5,4-d]-1,3,oxazines were synthesized from the acylation of (5-amino-1-substituted-pyrazolo-4-yl)-Ncarboxamides . 4-Acetyl-5-methyl-1-phenyl-1H-pyrazole was employed in the synthesis of pyrazolo[3,4-d]pyridazines . A green and efficient synthesis of furo[3,4-e]pyrazolo[3,4-b]pyridine derivatives in water under microwave irradiation without catalyst was reported . The synthesis of pyrazolo[3,4-b]pyridines using ammonium acetate as green reagents in multicomponent reactions was disclosed . 7-Substituted-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-ones were conveniently prepared by direct diazotization of 5-aminopyrazole-4-carbonitriles . The syntheses of derivatives of five new ring systems: pyrazolo[1,5-a:4,3b’]dipyridine, pyrazolo[1,5-a:3,4-c]dipyridine, pyrido[3’,2’:3,4]pyrazolo[1,5-a]pyrimidine, pyrazolo[1’,2’:2,3][1,2,3]triazolo[4,5-b]pyridine, and pyrazolo[1’,2’:1,2][1,2,3]triazolo[4,5c]pyridine was reported . One-pot synthesis of pyrazolo[3,4-c]pyridazines were derived from potassium cyanoacetahydroxamate . A one-pot atom and step economic synthesis of pyrazolo[4’,3’:5,6]pyrido[2,3-d]pyrimidine derivatives was reported . Pyrazolo[4,3-d]pyrimidines, pyrazolo[4,3-d]triazolino[4,3-a]pyrimidines, and pyrazolo[1,5-a]pyrimidines were all prepared from 2-[4-(3-oxobenzo[f]-2H-chromen-2yl)-1,3-thiazol-2-yl]ethanenitrile . Reaction of 2-substituted 3-dimethylamino2-propenenitriles with hydrazine hydrate afforded 3-substituted-1H-4-pyrazole carbonitriles and with 5-methyl-1H-pyrazol-3-amine to give 7-substituted pyrazolo[1,5-a]pyrimidine-6carbonitriles and 2-substituted-5-aminopyrazolo[1,5-a]pyrimidines . A facile synthesis of 4-aryl-5-alkoxycarbonyl-6-hydroxy-6-methyl-4,5,6,7-tetrahydro-3-hydroxy-2(pyridin-2-yl)indazoles and their NMR characterizations was reported . 2Benzylbenzothiazoles were easily N-aminated by tosyl hydroxylamine, and the obtained Namino salts were reacted with ethyl orthoformate to give pyrazolo[5,1-b][1,3]benzothiazoles . Pyrazolo[3,4-b]pyridines were synthesized by the reaction between 5aminopyrazoles and diethylethoxymethylenemalonate . R1

R1

N N

R

2

N

N

62

R

R2 R3

N Ph

O

Me

O

Me N N

O

Me

CO 2Et

64

CN N Ph

N 66

N

O 67

O N H 65 NR 1R 2

R Ar2

N N

HN

N

O

N N Ph

OH

R 63

R

Me

S

NH 2

N Ar1 68

N

N N Ar

N 69

The facile solution and solid-phase synthesis of 1-pyrazol-3-ylbenzimidazoles from 4fluoro-3-nitrobenzoate derivatives and 5(3)-amino-3(5)-subtituted-1H-pyrazoles were reported . 5.4.3

IMIDAZOLES AND RING-FUSED DERIVATIVES

Various methods were reported for the synthesis of imidazoles. InCl3•3H2O was found to be a mild and effective catalyst for the efficient, one-pot, three-component synthesis of 2,4,5trisubstituted imidazoles 71 from benzoin 70, aldehydes, and ammonium acetate at room temperature . Silica-supported boron trifluoride (BF3•SiO2) was a reusable catalyst for the synthesis of 1,2,4,5-tetrasubstituted imidazoles 73 using benzil 72, aromatic aldehydes and amines in the presence of ammonium acetate .


R2 CHO, NH 4OAc R1

O

ArCHO, RNH 2, NH 4OAc

InCl3•H 2O (10 mol%)

R1

R1

O

Ph, 4-MeC 6H4

R1

57–82%

O

Ph

BF3 •SiO 2 (37 mol%)

N

neat, 140 °C R2

N H 71

R 2 = alkyl, Ph, Ar

70

Ph

N

MeOH, 25 °C R1 =

233

Ph

O

Ph

R = Bn, Me, Cy, Ph 80–93%

72

Ar

N R 73

A novel four-component reaction of alkoxyallenes with imines, iodine, and nitriles provided highly substituted imidazole derivatives in high overall yields . Nitriles 74 were converted to imidates 75 under alkaline catalysis and then reactions of 75 in situ with aminoacetaldehyde derivatives 76 brought about a one-pot preparation of 2-substituted imidazoles 78 after hydrolysis of 77 . A new and easy synthesis of substituted benzimidazoles and imidazoles based on the reaction of imidates with diamine derivatives was reported . Addition of substituted amino alcohols 80 to a thioamide 79 and subsequent oxidation with PDC led to tri- and tetrasubstituted imidazoles 81 . Regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio-1Himidazole provided entry to 1,2,4- and 1,2,5-trisubstituted imidazoles . OR2

H 2N

OR 2 HOAc, 50 °C R 1CN

NH

30%NaOMe in MeOH

74

R1

76

OMe 2-thiophenyl, thiazolyl R2 = Me, Et 75

6N HCl

NH

R 1 = Ar, pyridyl, primidinyl, R1

N H

OR 2 OR 2

S 1. Ph

N H 79

80

, HgCl2, CH 3 CN

Ph

F 2. f ilter, then PDC, 60 °C R 1 = Me, cyclopropyl, (CH2 )n CF3 , t -Bu, Ph R 2 = H, Me, Ph, Ar 64–87%

R

N H 78

R2

R1 NH2

OH

45–99%

N

77

R2 R1

ref lux

N

N

81

F

Several methods were available for the synthesis of 2-aminoimidazole derivatives. αHaloketones 82 and N-acetylguanidine 83 under microwave irradiation afforded N-(1Himidazol-2-yl)acetamides 84 followed by deacetylation to give di- and monosubstituted 2aminoimidazoles 85 . A new divergent and efficient synthesis of substituted 2aminoimidazoles was developed starting from the readily available 2-aminopyrimidines and α-bromocarbonyl compounds using conventional heating or microwave irradiation . Fluoroalkylated 2-ylamino-imidazoles were synthesized by reaction of 3amino-5-phenyl-1,2,4-oxadiazole with fluorinated β-dicarbonyl compounds and subsequent base-induced Boultone-Katritzky rearrangement of the isolated β-enaminocarbonyl intermediate . A short and efficient route to 1,4-substituted-2-aminoimidazole alkaloids starting from the easily accessible 2-alkylaminopyrimidines and α-bromoaldehydes was reported . Guanylation of amidinothioureas 86 using mercury(II) chloride as a thiophile yielded amidinoguanidines 87 which reacted with various phenacyl bromides 88 under mild conditions to afford 1-aryl-2-arylamino-4-alkyl/phenyl-5-aroyl-1H-imidazoles 89 in moderate to good yields .

L. Yet

234

1. 20% H 2SO 4, EtOH, CH 3CN

O Br

R1 R2

NAc +

H 2N

microwave

R1

N

2. 5M KOH, MeOH

N H

R2

10 min

83

82

microwave, 10 min

N NHAc

100 °C

NH 2

R1

R1 = Me, Ph, Ar

N H

R2

R2 = H, Me, Ph

84

NH2

85

88–98%

R 1 NH 2, HgCl2 Et3 N, DMF R1 HN

R 1 = Ph, 4-ClC 6 H4 , 4-MeC 6 H4

NEt2 S

R 1N

2

R = Me, Ph, n-Bu

R2

R1

R 3 = 4-ClC6 H4 , 4-MeC6 H4

86

NEt2 NH

R2

87

65–80% O R3

R2

Br 88

DBU, CH 3CN 25 °C, 12 h 55–68%

N R 1HN

N R1 89

R3 O

Silica sulfuric acid-activated poly-1,3,-dichloro-5-methyl-5(4’-vinylphenyl)hydantoin was an effective reagent for the oxidation of 1,3,5-trisubstituted 2-pyrazolines both under microwave irradiation and thermal conditions to give the corresponding pyrazoles . 5-Methyl-5(4’-vinylphenyl)hydantoin was an effective reagent for the oxidation of 1,3,5-trisubstituted 2-pyrazolines pyrazoles under microwave irradiation with in situ generation of NO+ and NO2+, respectively, from sodium nitrite and sodium nitrate in acetic acid . N-Tosyl-N’-propargylureas underwent reaction with AuCl3 to give the corresponding dihydroimidazolone . A simple and efficient method was developed for the synthesis of 2-imidazolines through a one-pot reaction of various nitriles with ethylenediamine in the presence of sodium hydrosulfide as catalyst . A new synthetic approach towards 1-alkoxy-2-aminoimidazolines used N-alkoxy-N-(2-aminoethyl)2-nitrobenzenesulfonamides as nucleophile reagents for the reaction with isothiocyanate . A simple strategy for the synthesis of highly substituted 2-imidazolines starting from terminal alkynes, sulfonyl azides, and N-unsubstituted aziridines via two steps with high regioselectivity was described . 3-(Ethoxycarbonylmethylene)-2(arylimino)-imidazol-4-ones were synthesized selectively by reaction of α-amino ester with carbodiimides, which were obtained from aza-Wittig reaction of iminophosphoranes with aromatic isocyanates . Stereoselective preparation of unsymmetrically protected 2-alkylidene-1,3-imidazolidines was achieved by the reaction of N,N’-protected ethylenediamine, bromopropynamide, and potassium phosphate in hot DMF . Various 2-imidazolines were prepared in high yields by reaction of aldehydes and ethylenediamines with 1,3-diiodo-5,5-dimethylhydantoin . Many similar methods were published for the synthesis of 2-substituted-benzimidazoles 90 from o-phenylenediamines 91 and they are shown in the table below. An efficient method for the synthesis of benzimidazoles via cascade reactions of o-haloacetoanilide derivatives with amidine hydrochlorides with 10 mol% CuBr as the catalyst, Cs2CO3 as the base, and DMSO as the solvent with no required ligand was reported . A highly selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles from the reaction of ophenylenediamines and aromatic aldehydes in the presence of metal hydrogen sulfates


235

[M(HSO4)n] in water and also under solvent-free conditions in good to excellent yields . An environmentally benign method for the rapid and selective synthesis of 2aryl-1-arylmethyl-1H-1,3-benzimidazoles by the reaction of o-phenylenediamines and aromatic aldehydes in the presence of 1-methylimidazolium triflouroacetate ([Hmim]TFA) at room temperature under aqueous conditions was described . The facile generation of novel 1,2,5,6-tetrasubstituted benzimidazoles starting from 5-chloro-4-iodo-2nitroaniline was reported . NH 2 Condit ions

R1

N R2

R1

NH 2 90

91

Condi tions

N H Ref erence

ArCHO, 4-methoxyTEMPO, O2 , xylene, 120 °C

08AG(E)9330

ArCHO, H2 O2 , CAN, neat, 50 °C

08JOC6835

ArCHO, NH 4 OAc, EtOH, 80°C

08SC1128

ArCHO, N-hyroxyphthalimide, Co(OAc) 2, air,

08SC3500

CH 3CN, 25 °C RCHO, PEG-400, neat, 110 °C

08TL6237

RCH=CBr 2, DABCO, NMP, 100 °C

08TL7284

ArCHO, T(o-Cl)PPFe(III)Cl, EtOH, 25 °C

08EJO4126

ArCHO, sulfonic acid, functionalized silica,

08JHC1499

CH 2Cl2, O2 , 25 °C ArCHO, p-TsOH or N,N-dimethylaniline, graphite,

08JHC1293

EtOH, 75 °C ArCHO, trichloroisocyanuric acid, 1,4 dioxane, 25 °C

08JHC1203

ArCHO, activated carbon, O2 , xylenes, 115 °C

08H(75)415

2-Azidoaniline 92 reacted with aldehydes to form imines 93 which underwent iron catalysis to give 2-arylbenzimidazoles 94 . Tosylation of N-aryl amidoxime 95 in the presence of triethylamine produced the corresponding benzimidazoles 96 in high yields . A rapid and efficient one-pot method for the synthesis of 2-(Nsubstituted)aminobenzimidazoles 99 from o-phenylenediamines 97 and dithiocarbamates 98 with catalytic CuO was published . A highly efficient one-step and versatile method for the synthesis of 2-(indolizin-2-yl)benzimidazoles was developed on the basis of the novel ring contraction of 3-arylchloromethyl- and alkylchloromethylquinoxalin-2-ones with α-picoline . Cyclodehydration with phosphorus oxychloride with 1,2phenylenediamines 100 provided 2-trifluoroethylbenzimidazoles 101 in good yields . Nafion®-H, a perfluoroalkanesulfonic acid resin was found to be a suitable solid acid catalyst with high selectivity and catalytic activity for the one-pot synthesis of fluorinated benzimidazolines . Aromatic (phenols, anilines, and thiophenols) and alkyl nucleophiles (amines and thiols) reacted with 2-methylsulfonyl benzimidazole under solvent-free conditions to generate a variety of 2-substituted benzimidazoles . Reductive cyclization of 2-nitroanilines with orthoesters in the presence of Pd/C in methanol at room temperature promoted by a catalytic amount of acetic acid afforded benzimidazole derivatives .

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236

ArCHO

NH2

N

MgSO 4

R N3

N3

25 °C

92

N H 95

R

H

36–98%

N Ar

R N H

93

NOH

R1

4A MS, 40 °C

R

CH2 Cl2

FeBr2 (30 mol%)

Ar

N

Ts 2O, Et3N

R2

R1

CHCl3

2

94

N H

59–98%

R 1 = H, OMe, I, SMe R 2 = 2-pyridyl, Ph, Cy

96

R3 R1

K2CO3 (2 equiv),

R3

NH 2

S

+ R2

R4

NH 2

98

97

N H

CuO (0.2 equiv)

H N

R2

N

R4 NH

DMF, 60 °C, 1–2 h

SMe

R1

69–92%

99

NH2 NHR1

N

1. CF 3CH2 COCl 2. POCl3

R2 100

R 1 = H, Me, Ph, i-Pr

R2 N 1 101 R

67–97%

CF3

R 2 = H, CO2 Me, OMe

An efficient and convenient method was developed for preparing N-substituted 1,3dihydrobenzimidazol-2-ones 103 from Nƍ-substituted N-(2-halophenyl)ureas 102 via a CuI/DBU-catalyzed cyclization in DMSO under microwave heating . The copper-catalyzed-TMEDA intramolecular N-arylation of 2-bromoarylureas 104 performed in water provided the benzo[d]imidazolones 103 . CuI, TMEDA

CuI (10 mol%), DBU X R N H 102

R N

DMSO, microwave O

120 °C, 20 min NHR2

X = I, Br;

R1

R1

59–93%

R 1 = Bn, allyl, O

=H

N H

R2 = Ar, allyl, 2-thiophenyl

H2 O, 120 °C

2

103

Bu, Et R = H, F, OMe, NO 2

Br R1 N

O NH 2

R2 104

51–92%

Various reactions of imidazoles were published. Trifluoroacylation of imidazole and benzimidazole derivatives with trifluoroacetic anhydride resulted in trifluoromethylcontaining ketones substituted at the 2-position of the heterocycle . 2(Trifluoroacetyl)imidazoles reacted with methyl acrylate and acrylonitrile under Baylis– Hillman conditions to afford heterocyclic trifluoromethyl-containing allylic alcohols . 1-Substituted imidazoles 105 were C(2)-vinylated with 3-phenyl-2propynenitrile 106 at room temperature without catalyst and solvent to afford 3-(1-organyl1H-imidazol-2-yl)-3-phenyl-2-propenenitriles 107 mainly as (Z)-isomers . The ionic liquid 1-ethyl-3-methylimidazolium fluoride hydrofluoride, [C2mim][F]xHF, was synthesized through a solventless route that excluded halogen metathesis . Chiral room temperature ionic liquids containing a carbohydrate moiety linked by the anomeric centre to an N-methylimidazolium group were synthesized . Ionic liquids with 1-alkyl-3-methyl-imidazolium cations reacted at C-2 with cellulose at its


237

reducing end forming a carbon–carbon bond . Highly enantioselective Michael addition of cyclohexanone to aryl nitroolefins in the presence of an ionic liquid anchored pyrrolidine and trifluoroacetic acid generated the corresponding adducts in high yields with excellent diastereoselectivities and enantioselectivities . Various pyridine-Noxides 108 were converted to their corresponding α-imidazoloheteroarenes 110 in good yield by treatment with sulfuryl diimidazole 109 in nonpolar solvents at elevated temperatures . N-1H,1H-Perfluoroalkylation and regioselective C-perfluoroalkylation of imidazoles were obtained using the corresponding hypervalent iodonium salts . A synthesis of potassium 4-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2carboxylate was demonstrated where the carboxylate group was introduced via bromine– magnesium exchange on a SEM-protected cyanoimidazole followed by reaction with ethyl cyanoformate . 25 °C, 20–24 h

N N R 105

+

Ph

N

56–88%

CN

N R

R = Me, Et, Am, 106

Ph, allyl

Ph

NC 107

O R

+ N O 108

N

O S

PhMe

N N

N 109

ref lux

R N

42–86% 110

N N

There were plenty of published examples of metal-catalyzed reactions of imidazoles, benzimidazoles and fused imidazole ring systems. Per-6-amino-β-cyclodextrin (per-6ABCD), acting simultaneously as a supramolecular ligand for CuI and host for aryl bromides, catalyzed N-arylation of imidazole with aryl bromides 111 to yield imidazoles 112 under mild conditions . Cu2O was found to be an efficient and economical metal catalyst in the Ullmann cross-coupling reaction of vinyl bromides and chlorides 113 with imidazoles or benzimidazoles 114 to give access to 115 . The system Cu2O/ethyl 2-oxocyclohexanecarboxylate showed high catalytic activity in acetonitrile at 80– 90 °C. A cross-coupling reaction of imidazoles 116 with bromoalkynes 117 in the presence of a catalytic amount of CuI provided access to N-(1-alkynyl)imidazoles 119 in the presence of 1,3-diketone 118 was reported . The synthesis of a 2-aminoimidazole library for antibiofilm screening utilizing the Sonogashira reaction was reported . The direct arylation of benzimidazole 120 with aryl iodides was effectively promoted by CuI with use of PPh3 and Na2CO3 as ligand and base, respectively, in DMF to produce the corresponding 2-arylated benzimidazole 121 in good yields . A series of 2-arylbenzimidazoles 123 was synthesized via microwave-mediated Suzuki– Miyaura coupling of 2-chlorobenzimidazoles 122 with either arylboronic acids or aryltrifluoroborate salts without protection of the nitrogen . Synthesis of 3alkenylimidazo[1,2-a]pyridines 126 in high to moderate yields by microwave direct palladium-catalyzed C–H alkenylation between bromoalkenes 125 and imidazo[1,2a]pyridines 124 . New, potentially bioactive, imidazopyridine derivatives were synthesized in a highly efficient synthesis in four steps from 2-amino-3,5-dibromopyridine using microwave-assisted double Suzuki–Miyaura cross-coupling methodology . A general and efficient synthesis of 5-aryl imidazo[1,5-a]pyrazines 128 by palladiumcatalyzed coupling of the corresponding 8-substituted derivatives 127 with aryl halides was described . A general Pd-catalyzed protocol was developed for the arylation of

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238

known 2-phenylimidazo[1,2-a]pyridin-3-amines and 2-phenylimidazo[1,2-a]pyrazin-3amines 129 with various electron-deficient aryl and heteroaryl halides to give aminated products 130 . Addition of imidazole to the activated double bond of the intermediate acrylimidazole in the reaction between diverse acrylic acids and different amines promoted by CDI led to a synthesis of β-imidazolylpropionamides . Palladium-catalyzed direct C-5 arylation of 1-methyl-1H-imidazole with aryl bromides furnished entry to regioselective synthesis of 4,5-diaryl-1-methyl-1H-imidazoles . N,N’-Phenylmethylenediacetamides were efficient ligands in the coppercatalyzed coupling reaction of aryl halides with imidazoles and benzimidazoles . N-THP protected 5-(1H)-imidazolyl boronic acid pinacol ester and its use in Suzuki crosscoupling reactions with a wide range of (het)aryl halides provided 4(5)-(het)aryl-1Himidazoles . imidazole, CuI Br R

R

K2CO3 , DMSO, 110 °C 81–98%

111

R1

R2

+

R1

CH 3CN, Cs2 CO 3

N R2

85–130 °C

N

N

45–99%

114

113

112

Cu 2O, β-keto ester

H N

X

115

X =Br, Cl O

R1

O

R2

+ N H 116

N

R1

118

N

R 1 = H, Me, Ph, 4-FC 6H 4

N

CuI (5 mol%), Cs2 CO3 (2 equiv)

Br

R 2 = Ph, TIPS, n-C6 H 12 ,

4A MS, 1,4-dioxane, 50 °C

117

N

N

Per-6-ABCD (6 mol%)

CH 2OTBDMS

119

15–90%

R2

ArB(OH)2 or N

120

Ar-BF 3K

ArI, CuI, PPh3

R= OMe, H, Cl, Br, N Me CO2Me, CN 15–89%

N

N

Na2 CO 3, DMF

Cl

Ar 121

N H

N Me

PdCl2 (PPh3 )

N

K2 CO 3 CH3 CN

N H

Ar

microwave

122

123

150 °C 0–88%

Br

N X

N 124

R1

R4

125 R2 R3 Pd(OAc)2 (20 mol%), AsPh3 (40 mol%) Ag2 CO3 , Et3 N, DMF, microwave, 130 °C X = H, Cl; R1 = H, Ph; R 2 = R3 = R4 = H, Me, Ph 26–71%

N N

X 126

R2

R1 R4 R3

Five-Membered Ring Systems: With More than One N Atom ArBr, Pd(OAc)2

X

X

(t-Bu)2 PMe•HBF4

N N 127

N

N

Cs 2CO3 , DMF 45–89% X = NH 2, NMe 2,

N

Ar 128

Ar(Het)X, Pd(OAc) 2

N

N X

N

120-130 °C Me

239

Me 129

Ph

BINAP, Cs 2CO3 100 °C, 16 h

130

5–82%

OMe, Ar

Ph

N

PhMe, sealed tube NH 2

N

X

NHAr(Het)

X= CH, N

Imidazole-containing compounds were utilized as reagents for various synthetic transformations. The direct and catalytic kinetic resolution of racemic carboxylic acids bearing a Brønsted base such as O-protected α-hydroxy carboxylic acids and N-protected αamino acids was accomplished through an L-histidine-derived sulfonamide 131 induced enantioselective esterification reaction with tert-butyl alcohol . 2[(Imidazolyl)thiomethyl]pyrrolidine 132 was utilized as a trifunctional organocatalyst for the highly asymmetric Michael addition of ketones to nitroolefins . Catalyst 133, an ion pair consisting of a hydrophilic cation and a lipophilic anion, was effective in the asymmetric aldol reaction under aqueous biphasic conditions to give enantioselectivities and anti-diastereoselectivities up to >99% . Efficient synthesis of ethyl 2-thioxo2,3-dihydro-1,3-oxazole-5-carboxylates or ethyl 5-methyl-2-thioxo-2,3-dihydro-1,3-oxazole4-carboxylates were prepared from ammonium thiocyanate, acid chlorides, and ethyl bromopyruvate or ethyl 2-chlroacetoacetate in the presence of N-methylimidazole 134 . A kinetic study of Michael addition catalyzed by N-methylimidazole 134 in ionic liquids was investigated .

i-Pr

i-Pr O2 S

O NH

i-Pr OTBDPS 131

O

N N Me

Me N

N H

S 132

Tf2 N

N

N

O

N

N H

N (HO)3 Si

133

OH

N Me 134

Many methods were developed for the synthesis of imidazole fused-ring systems. The interaction of methyl 2,4-dioxo-2H-3,1-benzoxazine-1(4H)-acetate, 1-(3,3-dimethyl-2oxobutyl)- and 1-(2-oxopropyl)-2H-3,1-benzoxazine-2,4(1H)-diones with substituted acetonitriles, XCH2CN (X = CN, hetaryl) in the presence of acetic acid and sodium acetate, afforded imidazo[1,2-a]quinoline-2,5(1H,3H)-diones, 2-tert-butyl- and 2-methylimidazo[1,2a]quinolin-5(3H)-ones . Pyrido[2’,1’:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones was obtained by a microwave-assisted three-component reaction between 2-aminopyridines, pisocyanides, and 2-carboxybenzaldehydes under acidic conditions . Toluenesulfonic acid catalyzed the one-pot, three-component synthesis of 3aminoimidazo[1,2-a]pyridines and pyrazines through a condensation reaction of a 2aminoazine, an aldehyde, and an isocyanide at room temperature . A convenient and clean water-mediated synthesis of a series of 4-amino-2-aryl-1,2-dihydropyrimido[1,2a]benzimidazoles was reported . A practical and facile one-pot approach for the synthesis of 7-trifluoromethyl-substituted imidazo[4,5-b]pyridines by the reaction of in situ generated 5-aminoimidazole and a 1,3-CCC-biselectrophile . Microwaveassisted, solvent-free condensation of 2-aminopyrimidine with aldehydes and isonitriles gave the desired 3-aminoimidazo[1,2-a]pyrimidine products with good to excellent regioselectivity . An efficient, one-pot, multicomponent synthesis of 3-amino-2arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2arylimidazo[1,2-a]pyrimidines was described . Two synthetic routes to the versatile 3,5-dihydroimidazo[4,5-d]pyridazin-4-ones were developed . A convenient four-step preparation route to novel 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones

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240

135 from methyl phenylglyoxylate was published . Azepino and azocino[1,2a]benzimidazoles were obtained either by treatment of 1-nitrophenyl-2-azacycloalkanes via a one-pot catalytic hydrogenation/acetylation or by treatment of the acetamides generated in the latter reaction with performic acid . N-Substituted 5-piperazin-1-yl-1,3,4thiadiazol-2-amines underwent reactions with aldehydes and isocyanides to give 2-piperazin1-ylimidazo[2,1-b][1,3,4]thiadiazoles 136 when such reaction was promoted by an equimolar quantity of trimethylsilyl chloride in aprotic medium. The reaction of 2-imino-3-(2propynyl)-1,3-benzothiazole with various iodobenzenes in the presence of a palladium catalyst led to the production of 2-benzylimidazo[2,1-b][1,3]benzothiazoles 137 . The reaction of 2-amino-1-(2-propynyl)pyridinium bromide with various iodobenzenes, catalyzed by Pd–Cu, led to the formation of 2-benzylimidazo[1,2-a]pyridines 138 . The first synthesis of a novel 5:7:5-fused heterocyclic ring system 139, a diimidazodiazepine was reported . Two highly efficient and general one-pot annulation reactions were described for the synthesis of imidazopyridine derivatives 140 . ortho-Metalation of imidazo[1,2-a]pyridines provided synthesis of substituted imidazo[1,2-h][1,7]naphthyridines 141 . A direct microwave-assisted one-pot Beckmann rearrangement of 3-acyl-2-(alkylamino)quinolin-4-(1H)-ones in ethanol/pyridine provided 2,3-dialkylimidazo[4,5-b]quinolin-9-ols 142 . 6(Arylmethyl)imidazo[1,2-a]pyrimidin-7-ylamines were derived from allylamine derivatives afforded by the Baylis-Hillman acetate of substituted benzaldehydes and heterocyclic aldehydes from treatment with cyanamide . Multicomponent reaction between 2-aminobenzimidazole, benzaldehydes and imidazoline-2,4,5-trione provided entry to 9Himidazo[1,2-a][1,3]benzimidazoles under solvent-free conditions . Threecomponent condensation of 2-aminopyrimidines, isocyanides and 4-hydroxybenzaldehyes furnished 3-amino-2-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidine derivatives . 4,5-Diphenylimidazole-2-thione reacted with 1-chloro-2,3-epoxypropane and 1bromopropene to give imidazo[2,1-b]thiazine and thiazole . Cyclocondensation of o-phenylenediamine with 3-bromopropionic acid in polyphosphoric acid followed by bromination and reaction with aryl nitriles and aryl isocyanates yielded 1arylpyrimido[1,6-a]benzimidazoles and 2-arylpyrimido[1,6-a]benzimidazol-3-ones, respectively . 8-Hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid and ethyl 8-hydroxyimidazo[1,2-a]pyridine-2-carboxylate were prepared via cyclization of 2aminopyridin-3-ol with bromopyruvic acid and ethyl bromopyruvate, respectively . The recyclization of 3-formylchromones promoted by chlorotrimethylsilane with 1-amino-1H-imidazoles resulted in imidazo[1,5-b]pyridazines . Synthesis of 3-nitroimidazo[1,2-a]pyridine derivatives was acheived by SRN1 reactions . O N N

NHR3

Ph R1 N Cl

S

N

N N S

135

CH2 Ar N

R2 N

N N

136

CH 2 Ar

N

S

138

137

OMe Me O HN Ar N

N N

N

O

N

N

NH

OH Me

N R1

R2 N

N N H

N

139

140

Ar

141

142

N R3


241

An efficient method for solid-phase synthesis of benzimidazole libraries by microwaveassisted condensation of resin-bound esters with 1,2-phenylenediamines was developed . Chemical stability and reactivity of a bifunctional polymer conjugate containing an ortho-amino arylamide linkage have been successfully exploited to achieve a parallel synthesis of methoxycarbonylated head–tail bis-benzimidazoles .

5.4.4

1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES

A Highlight on the copper-free azide-alkyne cycloadditions with new insights and perspectives was published . Substituent effects in the 1,3-dipolar cycloadditions of azides with alkenes and alkynes were investigated with the high accuracy CBS-QB3 method . Click chemistry includes a range of reactions that proceed in high yield under ambient conditions, preferably in water, with regioselectivity and a broad tolerance of functional groups. The copper-catalyzed 1,3-dipolar cycloaddition reaction of azides and acetylenes to give 1,2,3-triazoles is known as the “cream of the crop” of all click reactions. Alkynes 143 underwent a copper(I)-catalyzed cycloaddition with sodium azide and formaldehyde with sodium ascorbate to yield 2-hydroxymethyl-2H-1,2,3-triazoles 144; the hydroxymethyl group could be removed, providing convenient access to NH-1,2,3-triazoles . The reaction of alkynyl sulfoximines 145 with in situ prepared organic azides in water– dichloromethane under reflux afforded sulfoximidoyl-substituted triazoles 146 by Huisgen 1,3-dipolar cycloaddition . 1,3-Dipolar cycloadditions of organic azides to terminal alkynes to give 1,4-disubstituted-1,2,3-triazoles by a dicopper-substituted silicotungstate was reported . A copper-catalyzed click reaction of organic azides with terminal alkynes 147 followed by direct arylation provided a modular syntheses of highly functionalized 1,2,3-triazoles 148 . N-Propynoyl (5R)-5phenylmorpholin-2-one underwent non-regioselective cycloaddition with aromatic azides to furnish mixtures of the corresponding triazoles . A series of CuI-immobilized polymeric supports having quaternary ammonium salts were prepared as recyclable heterogeneous catalysts with evaluation of their ability in Cu(I)-catalyzed Huisgen’s 1,3dipolar cycloaddition of azides and terminal alkynes . A novel SiO2–NHC– Cu(I) was used as a highly efficient catalyst for [3+2] cycloaddition of organic azides and terminal alkynes to generate the corresponding regiospecific 1,4-disubstituted 1,2,3-triazoles in excellent yields under solvent-free reaction conditions at room temperature . A new catalytic system based on copper(I)-doped Wyoming montmorillonite was used to prepare 1,4-disubstituted-1,2,3-triazoles from azides and alkynes . 1Monosubstituted-1,2,3-triazoles were prepared from two-step one-pot deprotection/click additions of trimethylsilylacetylene . The copper-catalyzed 1,3-dipolar cycloaddition of 4-butoxyphenyl azide with 2-,3-, or 4-ethynylpyridine furnished 1,4-diaryl1,2,3-triazoles . ‘Click’ cycloaddition catalysts, copper(I) and copper(II)tris(triazolylmethyl)amine complexes were effective in the synthesis of various 1,2,3-triazoles . The copper(I) complex [Cu(C186tren)]Br (C186tren = tris(2dioctadecylaminoethyl)amine) exhibited good catalytic behavior in the cycloaddition of azides with terminal or internal alkynes to give 1,4-disubstituted-1,2,3-traizole derivatives . Copper(I)-exchanged zeolites were developed as effective catalysts for the click reaction . A series of 1,2,3-triazoles were synthesized through unexpected cyclization of vinyl azides bearing electron-withdrawing groups . Two reports have shown that biomolecules labeled with azides underwent copper-free click chemistry . Azides and alkynes were transformed into 1,4disubstituted-1,2,3-triazoles by copper-catalyzed click reaction followed by subsequent alkylation afforded 1,3,4-trisubstituted-1,2,3-triazoles salts as ionic liquids .

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242

NaN 3 , HCHO R

CuSO 4 (5 mol%) sodium ascorbate (20 mol%)

R

N

HOAc 143

N

1,4-dioxane, 25 °C

N OH

67–95%

144

R 3 Br, NaN 3 H2 O, CH 2Cl2 N Ts R2

reflux, 3 h Ts N R1 S O

R1 S O N

1

R = Me, Ph, 4-MeC6 H 4

R2

R 2 = Bu, CH2 OMe, t-Bu, Ph

N

R 3 = Bn, Ar, Ph(CH 2) n

146

145

N R3

0–73% 1. R 2N 3, CuI (10 mol%), R1

N R1 N N Ar R2 148

DMF, 60 ºC

H

2. ArI, LiOt -Bu, DMF, 140 ºC

147

63–84%

R 1 = n-Bu, Ph R 2 = n-Oct, Bn

Ruthenium catalysts can be used as alternatives to the usual copper catalysts. In the presence of catalytic Cp*RuCl(PPh3)2 or Cp*RuCl(COD), primary and secondary azides reacted with a broad range of terminal alkynes containing a range of functionalities selectively producing 1,5-disubstituted-1,2,3-triazoles . 1,3-Dipolar cycloaddition of trifluoromethylated propargylic alcohols 149 with azides in the presence of catalytic [Cp*RuCl2]n afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3triazoles 150 in high yields . 1

R R2 OH

F3 C 149

[Cp *RuCl2] n , R3 N 3

R1 R 2 OH

F3 C

THF, reflux

N

85–95%

N

N R3

R 1 = R 2 = (CH 2 )5 R 1 = H, R 2 = Ph, styrenyl

150

Organic azides have also been generated in situ and reacted with alkynes in one-pot reactions. Terminal alkynes reacted with benzyl- or alkyl halides and sodium azide in the presence of a copper(I) catalyst immobilized on 3-aminopropyl- or 3-[(2aminoethyl)amino]propyl-functionalized silica gel in ethanol to exclusively generate the corresponding regiospecific 1,4-disubstituted 1,2,3-triazoles in good to excellent yields . The practical and efficient one-pot azidation of anilines 151 with the reagent combination t-BuONO and trimethylsilyl azide under microwave irradiation significantly enhanced the rate of formation of 1,4-disubstituted-1,2,3-triazoles 152 from in situ generated azides .

NH 2

1. t-BuONO, TMSN 3 , CH3 CN

N N

2. CuSO4 •5H2 O, sodium

N

ascorbate, H2 O, R2

R1 151

80–99%

R2

R 1 = H, CN, NO 2, I R 2 = Cy, Ac, CO 2Et,

1

R

152

Ar, 3-thiophenyl


243

Other methods of 1,2,3-triazole synthesis were also published. Combrestastin 1,5disubstituted-1,2,3-triazoles 154 were prepared from aryl azides and α-keto phosphorus ylides 153 . A Lewis base-catalyzed three-component cascade reaction of nitroethylenes 155 with aryl aldehydes 156 with L-proline provided the synthesis of 4,5disubstituted-1,2,3-(NH)-triazoles 157 . A variety of substituted benzotriazoles 159 were prepared by the [3+2] cycloaddition of azides to benzynes generated from aryl triflates 158 and cesium fluoride . β-Hydroxy-1,2,3triazoles 161 from in situ generated 1,2-azidols synthesized from epoxides 160 underwent two sequential click reactions in very high yields with high regioselectivity using Cu(OAc)2•H2O as a catalyst in water at ambient temperature . Cyanoformazans 162 were treated with hydroxylamine hydrochloride to give 1,2,3-triazole derivatives 163 . Arylhydrazononitriles were useful building blocks in the synthesis of benzothiazolyl-1,2,3-triazole amines and 1,2,3-triazol-4-yl-1,3,4-thiadiazol-5-ylamines . O PPh2 Py

MeO

90 °C

MeO

N N N Ar

MeO

ArN3 , PhMe

MeO OMe 154

OMe 153

R1 H

NO2 R2

R1

R2

Ar +

NaN3 , L-proline (0.2 equiv)

ArCHO 156

155

N

DMSO, 25 ºC, 8–10 h 55–89%

R1 = R2 = alkyl, ar y

N N H 157

NaN3 , H 2O R2

RN3 , CsF TMS Z

Z

20–100% OTf 158

R = Ph, Ar, Bn, alkyl

Ar

N N

CN N

162

O

N

CH3 CN, 25 °C

N N 159 R

NH2 OH•HCl 60–62%

R2

R = Ph, CH 2OPh,

cyclohexene oxide R1 R2 = Ar, CH 2 OH, CMe2 OH 160 R1 76–99%

EtOAc, NaOAc NHAr

, CuI

1

Ar N N

N N N OH 161

NH2

N

N N Ar 163

1,2,3-Triazoles was converted to other structures. Rh(II) complexes catalyzed the ring opening of N-sulfonyl-1,2,3-triazoles 164 which upon reaction with nitriles, produced Nsulfonylimidazoles 165 . 1,2,3-Triazole participated in L-proline catalyzed reactions with benzoketones 166 and paraformaldehyde to give Mannich adducts 167 . Efficient post-triazole regioselective N-2 arylation to give 169 was developed from C-4, C-5 disubstituted-1,2,3-NH-triazoles 168 . Three different approaches were investigated including SNAr, Cu(I) catalyzed aryl amidation and Cu(II) mediated boronic acid coupling. 1-(1H-1,2,3-triazol-1-yl)propanone was coupled with aryldiazonium

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244

salts yielding arylhydrazones, which upon gas phase pyrolysis produced n-arylamino-2acetylimidazoles and 2-acetylimidazoles . Regioselective synthesis of either 1H- or 2H-1,2,3-triazoles via Michael addition to Į,ȕ-unsaturated ketones was investigated . R1

R1

N R 3CN N Rh 2(OAc) 4 N SO2 R2 42–94%

( )n 3

R N SO2R 2 165

164

1,2,3-triazole, (HCHO) n

N R

L-proline, DMSO

( )n R

60–80 °C 166

O

O

n = 0, 2

N N N

167

12–82%

ArF or ArCl, base or R1

ArB(OH) 2, Cu(OAc)2 (20 mol%) N NH

R2

N 168

O2 , 1 atm, 50 °C, 12 h or ArI, CuCl (10 mol%), L-proline (20 mol%),

R1

N N Ar

R2

N 169

110°C, 24 h (or microwave, 160 °C, 30 min) 50–95%

“Click” chemistry was very active in various fields this year. This is particularly evident in the carbohydrate, nucleotide, and nucleoside arenas. The click chemistry of a sugar azide with a sugar acetylene was carried out in 10 ionic liquids as well as in standard molecular solvents such as toluene and DMF to give the 1,4-disubstituted triazole-linked C-disaccharide . A heterocyclic nucleoside analog library of uracils N1 tethered to 1,2,3triazoles was constructed by solid-phase organic synthesis via click chemistry . A new triazole-linked analog of DNA (TLDNA) was designed and synthesized using click chemistry . The activity of three copper(I)-based catalytic systems in the preparation of various 1,2,3-triazolyl-carbanucleosides via the Huisgen azide–alkyne 1,3dipolar cycloaddition was presented . Compounds belonging to a new type of furo[2,3-d]pyrimidine nucleoside conjugated with carbohydrate were synthesized by Sonogashira coupling and ‘click chemistry’ . The synthesis of 1,4- and 1,5disubstituted-1,2,3-triazolo-nucleosides from various alkynes with 1’-azido-2’,3’,5’-tri-Oacetylribose using either copper-catalyzed azide-alkyne cycloaddition or ruthenium-catalyzed azide-alkyne cycloaddition was reported . Novel nucleobase-modified cADPR mimics were synthesized by the application of click chemistry . Conversion of amino iron oxides to carbohydrates and protein derived nanoparticles through a combination of diazol transfer and azide-alkyne click chemistry was disclosed . An efficient synthesis of triazolo-fused carbohydrate mimetics was published . A series of per-O-acetyl-glycose-Fmoc-L-Asp(O-t-Bu) derivatives and tert-butyl per-O-acetyl-glycose(S)-3-fluorenylmethyloxycarbamidobutyrates were prepared by copper-catalyzed 1,3-dipolar cycloaddition of fully acetylated propargyl 1-thioglycosides (gluco, galacto, manno and rhamno series) and Fmoc-LAsp(O-t-Bu)propargyl amide with tert-butyl (S)-4-azido-3fluorenylmethyloxycarbamidobutyrate, 2,3,4,6-tri-O-acetyl-glycosyl azides and ethyl 2,3,4tri-O-acetyl-6-azido-6-deoxy-1-thioglycosides(gluco, galacto, manno series), respectively . A general approach to the synthesis of nucleoside conjugates containing carborane and metallocarborane complexes based on click chemistry was published . Conjugation of nucleosides and nucleotides were achieved by copper(I)catalyzed [3+2] cycloaddition of in near quantitative yield . Click chemistry was applied to supramolecular and polymeric type structures. Two new ȕ-cyclodextrins (ȕ-CDs) modified with chromophore were synthesized in high yields through Huisgen 1,3-dipolar cycloaddition . A tetraazido calix[4]arene derivative was


245

allowed to react with ethynyl tetra-O-benzyl-C-galactoside via click chemistry in three different ionic liquids at 80 °C by thermal and microwave irradiation to give a triazole-linked tetra-C-galactosyl-calix[4]arene . Homo- and heterodimers of α-, β-, and χcyclodextrin were prepared by microwave-promoted Huisgen cycloaddition . The first report on the simultaneous copper(I)-catalyzed azide-alkyne cycloaddition and living radical polymerization was published . Cu(I)-catalyzed 1,3-dipolar cycloaddition of meso-ethynyl Zn(II) porphyrin with benzyl azide efficiently provided meso1-benzyl-1H-1,2,3-triazolyl Zn(II) porphyrin which assembled to form a slipped cofacial dimer by the complementary coordination of the triazole nitrogen atom at the 3-position to the zinc center of a second porphyrin moiety both in the solid and solution states . 1,2,3-Triazole CH···Cl contacts guide anion binding and concomitant folding in 1,4-diaryl triazole oligomers was reported . The synthesis of molecular knots based on the click chemistry platform was published . Click chemistry was employed in dendrimer designs . The applicability of the copper(I)catalyzed click reaction of terminal trialkynes with triazides to the synthesis of cagelike triazole compounds was determined . A novel step growth polymerization A-B strategy based on the click chemistry polyaddition of tailor-made α-azide-ω-alkyne low molar mass monomers was developed, leading to polytriazole polymers with tunable structures and properties . A novel biomass-based polymer was prepared from lignin-derived stable metabolic intermediate by copper(I)-catalyzed azide-alkyne click chemistry . C60 derivatives bearing either terminal alkyne or azide functional groups were prepared and used as building blocks under the copper mediated Huisgen 1,3dipolar cycloaddition conditions . The elusive heterofullerine C58N2 family of compounds were prepared from the thermal heating of its 1,2,3-triazolo intermediates . A series of Frechet-type dendron functionalized [60]fullerene derivatives that bore a 1,2,3-triazole linkage group, referred to as triazole-linked dendro[60]fullerenes, were prepared via a modular synthetic protocol based on a Cu-catalyzed [3+2] cycloaddition reaction . Click chemistry also found applications in peptides and peptidomimetics. Piperidinefunctionalized-1,4-disubstituted-1,2,3-triazoles, prepared by click chemistry, were conceived as “minimalist” mimics of peptidic β -turn structures . A click chemistry approach to assembly of proline mimetic libraries containing 1,4-substituted-1,2,3-triazoles was published . A series of novel triazolophanes containing peptidic and nonpeptidic backbones was reported based on click chemistry . The area of fluorescent probes was exploited by click chemistry also. A fluorogenic ‘click’ reaction of azidoanthracene derivatives was reported . A new multichromophoric cyclodextrin substituted with benzothiadiazoyl-triazole moiety was synthesized by a one-pot click reaction between azido-cyclodextrin and TMS-ethynyl benzothiadiazole in the presence of TBAF; this fluorescent chemosensor exhibited a high selectivity to Ni2+ among a series of cations in acetonitrile solution . The Cu(I)catalyzed azide-alkyne cycloaddition reaction was used to synthesize an anthracene-based fluorescent compound that underwent strong fluorescence quenching in the presence of Cu(II) . A copper(I)-catalyzed 1,3-dipolar cycloaddition reaction was used to prepare a potentially photoactivatable series of mono and disubstituted-1,2,3-triazolyl coumarins . Isomeric charge-transfer push-pull chromophores using 1,2,3triazol-diyl as conjugative π-linkers were studied experimentally and computationally . 1,2,3-Triazole probes found click chemistry applications to the study of biological systems. Triazole-linked azithromycin was used as chemical probe for the inhibitory effects on Pseudomonas aeruginosa . A panel of 198 P4-diversified aldehyde and vinyl sulfone inhibitors was successfully synthesized via click chemistry and these were screened against caspase-3- and -7 for inhibition . A panel of small moleculebased MMP inhibitors containing rhodanine warheads was assembled using “one-pot” click chemistry . The design and incorporation of triazole-containing metal-chelating

246

L. Yet

systems into biomolecules of diagnostic and therapeutic interest was reported . The synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold was reported . (S)-2-Azido-1-(pchlorophenyl)ethanols reacted with alkynes employing click chemistry to afford high yields of optically pure triazole-containing α-adrenergic receptor blocker analogs with potential biological activity . A straightforward approach to macrocycles having four estrone-derived nuclei by the sequential Cu-catalyzed Huisgen azide-alkyne cycloadditionGlaser-Eglington Cu homocoupling were developed . Click chemistry was also applied to the synthesis of useful catalysts. Novel cinchonine ammonium salt derivatives were prepared by 1,3-dipolar cycloaddition and their chiral catalytic efficacy was investigated in the asymmetric alkylation of Ndiphenylmethyleneglycine t-butyl ester in the water phase . (S)-Pyrrolidin-2ylmethyl-1,2,3-triazolium salts were synthesized as new ionic liquids via click reaction and alkylation which were found to be excellent recyclable catalysts in enantioselective Michael additions to nitrostyrenes in excess of carbonyl compounds as reactant and as solvent providing high yields and stereoselectivities . The attachment of multiple triazole moieties and perfluoroalkyl chains to TEMPO promoted emulsion formation in dichloromethane/water giving a highly active and easily recoverable catalyst for the oxidation of alcohols . Other non-general applications of click chemistry were also reported. 2-Benzylsulfanyl4-chloro-6-(trimethylsilyl)ethynyl-1,3,5-triazine was used to obtain phosphoric acid mono{4-[4-(4-amino-6-benzylsulfanyl-1,3,5-triazin-2-yl)-1,2,3-triazol-1-yl]-phenyl}ester via click chemistry by Huisgen 1,3-dipolar cycloaddition reaction . [11C]Methyl azide ([11C]MeA) was reacted with [11C]methyl iodide ([11C]MeI) in situ with an azide-donor and used it in the synthesis of 11C-labeled 1,2,3-triazoles . Several applications of benzotriazole mediated methodology to different synthetic transformations were reported. N-Protected-(aminoacyl)benzotriazoles converted heterocyclic amines under microwave irradiation into N-substituted amides in good yields . The bis-addition of arylhydrazines to α,β-unsaturated-N-acylbenzotriazoles to form heterocyclic compounds was achieved in refluxing THF using triethylamine as promoter to give a highly regioselective synthesis of 2-aryl-substituted pyrazolidin-3-ones in moderate to good yields . 1-(Benzotriazole-1-yl)alkyl esters underwent samarium diiodide mediated cross-coupling with aldehydes or ketones to afford β-(benzotriazole-1-yl)alcohols 2 with the selective removal of acyloxy over benzotriazolyl . 1Carbamoyl-1H-benzotriazole, an effective carbamoyl chloride substitute, and a range of its analogs were synthesized in good yields in two very simple steps from 1,2-diaminobenzene . N-(4-Arylazobenzoyl)-1H-benzotriazoles reacted with amino acids and amines to give azo-dye labeled amino acids and amines . Flash vacuum pyrolysis of 1-acylbenzotriazole phenylhydrazones gave benzonitriles, aniline and 2arylbenzimidazole derivatives . Some fused-1,2,3-triazole systems were reported. Structurally diverse tricyclic 1,2,3triazoles 170 were synthesized via a sequential epoxide ring-opening with azide, Opropargylation and intramolecular azide-alkyne cycloaddition . A facile entry to 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones from amines and α-amino acids was reported . 2-(2-[1-(3-substitutedphenyl)-1H-1,2,3-triazol-4-yl]ethyl)-1Hbenzo[d]imidazole derivatives were prepared from o-phenylenediamine with 3-(1-(3substituted phenyl)-1H-1,2,3-triazol-4-yl)proprionic acid . 3-Alkyl-5-phenyl3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones 171 were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature . Starting from N,N-disubstituted propargylamines, through a one-pot sequential 1,3-dipolar cycloaddition/Pd-catalyzed arylation, polyheterocyclic systems 172 were obtained in only one step . Derivatives of the new ring system


247

pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidines 173 were synthesized by a Dimroth rearrangement reaction .

Me

R1 N N N N

Ar

O

O R2

N

N

N R

N

N N

N ( )n N

171

170

O

N

Y

N N

Ph

N

R= Boc, Me

N R1

R

N H

N

R2

173

Y = CH, N 172

An efficient synthesis of N-benzyl-1H-benzotriazoles utilizing a two-step reductive amination reaction on solid supports was achieved .

5.4.5

1,2,4- TRIAZOLES AND RING-FUSED DERIVATIVES

Various synthetic protocols were reported for the preparation of 1,2,4-triazoles and derivatives thereof. Direct transamination of N,N-dimethylformamide azine dihydrochloride 174 with various amines provided a series of 4-substituted-1,2,4-triazoles 175 . Treatment of N-methylcarbonyl-, N-phenylthioamido-, and N-cyano- iminoethers with perfluoroalkylated hydrazines led to 1-perfluoroalkyl-5-methyl-1,2,4-triazoles, 1perfluoroalkyl-5-phenylamino-1,2,4-triazoles, and 1-perfluoroalkyl-5-amino-1,2,4-triazoles in good yields . 3-N,N-Dialkylamino-1,2,4-triazoles 178 were synthesized from S-methylisothioureas 176 and acyl hdyrazides 177 in moderate to good yields . Ring-opening reaction of (Z)-2-methyl-4-arylmethylene-5(4H)-oxazolones with hydrazides proceeded to give (Z)-2-(3-methyl-5-substituted 1,2,4-triazol-4-yl)-3-aryl-2-propenoic acids . Aromatic diaminomethylenehydrazones were reacted with bis(methylthio)methylenemalononitrile to give 5-aryl-1-benzyl-3-dimethylamino-1H-1,2,4triazoles . A synthesis of trisubstituted 1,2,4-triazoles via a cyclization of hydrazonamides was described . •2HCl N N N

N

174

SMe R1

N R2

N 176

R3

+

H2 N

(10:1) N H 177

R4

N N

40–75%

THF/HOAc

O

RNH 2 PhH, ref lux

ref lux 33–72%

R1 N R2

175

N N N R3 178

N R

R 1 = R 2 = piperidinyl derivative 4

R

R 3 = Ar, CH2 Ar, pyridyl R 4 = Me, CH2 NHBoc, CH 2Ar, CH2 OMe

There are some literature reports on the reactions of 1,2,4-triazoles. A variety of sixmembered ring annulated 1,2,4-triazoles 181 were synthesized in moderate yields from bromoethyl-1,2,4-triazole 179 and aryl iodides 180 via a one-pot norbornene-mediated palladium-catalyzed sequence whereby an alkyl-aryl bond and and an aryl-heteroaryl bond are successively formed through two C-H bond activations . An efficient synthesis of furanone derivatives via the multicomponent reaction involving 1,2,4triazolylidene carbene, dimethyl acetylenedicarboxylates, and aldehydes was described . Conversion of (1H)-1,2,4-triazole to its sodium salt with methanolic sodium methoxide followed by reaction with iodomethane was published as a practical methylation procedure . The addition of 1,2,4-triazole to Baylis–Hillman acetates 182

L. Yet

248

mediated by triethylamine dramatically accelerated under solvent-free conditions to afford (E)-1,2,4-triazole-substituted alkenes 183 . The microwave-assisted reactions of 4-amino-5-mercapto-3-substituent-1,2,4-triazoles 184 with benzoyl chloride and arylaldehydes under solvent-free conditions afforded 3-substituted-6-phenyl-1,2,4triazolo[3,4-b]-1,3,4-thiadiazoles 185 and 4-arylideneamino-5-mercapto-3-substituted-1,2,4triazoles 186, respectively . 4-Methyl-4H-1,2,4-triazole-3-thiol 187 underwent aminomethylations, chloromethylation and acylation to give 4-methyl-1-substituted-1H1,2,4-triazole-5(4H)-thiones 188 . 5-Functionalized 1,2,4-triazolium ylides were prepared from N,N-disubstituted carbohydrazonamides under microwave irradiation . 1-Tert-butyl-3,4-diaryl-1,2,4-triazol-5-ylidenes reacted with malonic ester to afford heterocyclic zwitterionic compounds . Pd(OAc)2 R1

N

I

CH3 CN, 90 ºC R2 180

179

181 O

O

1

neat, 25 ºC

R2

R

O

42–90%

N

R 1 = Ar, Het, R 2 = Me, Et 182

R1

N 185

Ph

R1

67–89% R 1 = alkyl, aryl

N N SH N CH 3 187

N

R 2CHO N N

microwave S

R2

N

183

PhCOCl

N N

R2

N N

32–47%

1,2,4-triazole, Et 3N

OAc O R1

N

Cs 2 CO 3, norbornene

Br +

N N

R1

tri-2-f urylphosphine

N N

microwave

SH N NH2

R

81–92% R2

1

= alkyl, aryl

N N 186

184

SH R2

R HCHO + RNH 2 or HCHO + HCl or Ac2 O

N N S N CH 3

R = CH 2 NHR, CH 2 Cl, Ac

188

The use of 1,2,4-triazole reagents in synthetic operations was described. Triazolium catalyst 189 was utilized in the synthesis of 1,2-amino alcohols via azidation of epoxy aldehydes where modest asymmetric induction was achieved . NPentafluorophenyl triazolium tetrafluoroborate salt 190 was found to be useful catalyst in the asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates . Chiral catalyst 191 promoted the intramolecular Stetter cyclization of an aldehyde onto a vinylphosphine oxide or vinylphosphonate Michael acceptor . Chiral triazolium salt 192 was successfully employed in the hetero Diels-Alder reactions of α-chloroaldehyde bisulfite adducts with various oxodienes under biphasic reaction conditions with high levels of enantioselectivity . N-heterocyclic catalyst 193 promoted O to C carboxyl transfer on a range of indolyl and benzofuranyl carbonates . Carbene of 193 promoted the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding β-lactams . Chiral triazolium catalyst 194 was found to be efficient in the formal [2+2] cycloaddition reactions of alkyl(aryl)ketenes with 2-


249

oxoaldehydes to afford β-lactones with α-quaternary-β-tertiary stereocenters in high yields with good diastereoselectivities and excellent enantioselectivities . The asymmetric Michael addition of aromatic heterocyclic aldehydes to arylidenemalonates catalyzed by N-heterocyclic carbene 195 was disclosed . Catalyst 195 was effective in intermolecular Stetter reaction to give 1,4-diketones . Pyrido[1,2a][1,2,4]triazol-3-ylidenes 196 were identified as a new family of stable annulated Nheterocyclic carebenes which found applications in catalytic benzoin condensations and transesterifications at ambient temperature . N-Heterocyclic carbene catalyst 197 catalyzed the oxidation of unactivated aldehydes to esters with manganese(IV)oxide in excellent yields .

R

O

BF 4 N

N N

189 R = H 190 R = Bn

C6 F5

N

N X N R

N N R1

BF4

N

N R2

N

X N R2 Me N

N Me N I

R1

191 R = C6 F5 , X = BF4 193 R 1 = H, R 2 = Ph 196 X = BF 4, PF6 194 R 1 = CPh2 OTBS, R 2 = Ph 192 R = Mes, X = Cl

197

195 R 1 = CH2 OTBDPS, R 2 = Bn

Structurally unique 1,2,4-triazole fused-ring systems were reported. 2,7Diaminosubstituted-1,2,4-triazolo[1,5-a]pyrimidine-6-carbonitriles 198 were prepared by solid-phase synthesis . 7-Amido-[1,2,4]triazolo[1,5-a]pyrimidines 199 were prepared using halogen–metal exchange of the chloro or iodo precursor . A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones and Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines . An efficient and convenient electrosynthesis of thioheterocyclic compounds 200 was described via a onepot, two-component condensation of 3-substituted-5-mercapto1,2,4-triazoles with acetylenedicarboxylic acid esters . 7-Trichloromethyl-1,2,4triazolo[1,5-a][1,3,5]triazin-5-amine was aminated efficiently with replacement of the trichloromethyl group to give 7-amino-substituted-1,2,4-triazolo[1,5-a][1,3,5]triazin-5amines 201 . A novel series of 2,4-disubstituted-1,2,4-triazolo[1,5-a]quinazolin-5(4H)-ones were prepared by Dimroth rearrangement of their respective isomers namely 1,4-disubstituted[1,2,4]triazolo[4,3-a]-quinazolin-5(4H)-ones. . A series of 4-(4-ethylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones 202 were synthesized by the cyclization of 2-hydrazino intermediate with various electrophiles . Cyclization of 4-amino-3-propargylmercato-1,2,4-triazole with heteropolyacids afforded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 203 . A series of novel 6-aryl-3-(1,2,3,4-tetrahydroxybutanol-1-yl)-7H-1,2,4-triazolo[3,4b][1,3,4]thiadiazines were easily synthesized in high yields by means of the reactions of 4amino-5-(1,2,3,4-tetrahydroxybutyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione with substituted ω-bromo- and ω-chloroacetophones . 3-Phenylthieno[3,2-e][1,2,4]triazolo[4,3c]pyrimidines and 3-phenylthieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines were easily synthesized by the oxidative cyclization of thienopyrimidinyl hydrazones using iodobenzene diacetate . The multicomponent reactions of 3-amino-1,2,4-triazoles with phenylpyruvic acids and aromatic aldehydes led to 5-aryl-7-hydroxy-6-phenyl-4,5,6,7tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acids . 2’-Substituted5’,6’,7’,8’-tetrahydro-4’H-{spiro[cyclohexane-1,9’-[1,2,4]triaozlo[5,1-b]}quinazolines 204 were synthesized by condensation of 3-substituted-5-amino-1,2,4-triazoles with 2cyclohexylidene cyclohexanone in DMF . A series of new fluorine-containing 1,2,4-triazolopyrimidines resulted from one-pot reactions of 3,5-diamino-1H-1,2,4-triazole-1carboximidamide hydrochloride with fluoro-1,3-diketones . A convenient synthesis of 2,4-disubstituted-1,2,4-triazolo[1,5-a]quinazolin-5(4H)-ones 205 were prepared

L. Yet

250

by Dimroth rearrangement of 1,4-disubstituted-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones . R2

R 1HN

N

R3

RHN N

N N

N N

N

N

N 198

R1

O C 6F3 H 2

H

N

N N

N 199

Ph S

N

202

N

NH 2

= Me, Et

CH 3

N

N

N N

N

N

O H N

R

N

N N

201

200 R 1 = Me, Ph

Et

O

R

CO2 R2

Cl R2

N

NR 1R 2

O

N

R

S

N N N

203

N N

N H 204

205

Ph N R

A backbone amide linker strategy was used for the solid-phase synthesis of triazolecontaining cyclic tetra- and pentapeptides .

5.4.6

TETRAZOLES AND RING-FUSED DERIVATIVES

The first study of the protonated, neutral form of tetrazoles as potent anion recognition elements that emulated the disfavored anti conformations of carboxylic acids was disclosed . The most common preparation of tetrazoles is the reaction of nitriles with azides. The [3+2] cycloaddition of various nitriles 206 and trimethylsilyl azide proceeded smoothly in the presence of copper(II) oxide in DMF/MeOH mixture to give the corresponding 5-substituted1H-tetrazoles 207 in good yields . A series of di-, tri-, and tetra-tetrazoloalkanes were synthesized from the corresponding nitrile and sodium azide which was further alkylated to give hydroxyl terminated chains for possible use as high energy oligomers . Aliphatic azidonitriles separated by three or four carbon atoms underwent facile Lewis acid-induced cycloadditions to give bicyclic tetrazoles in the presence of trimethylsilyl cyanide and boron trifluoride etherate in nitromethane . This was extended to 3-azido-2-aryl-1,3-dioxolanes 208 and the corresponding 1,3-dioxanes to give a series of diversely functionalized novel oxabicyclic tetrazoles 209 . Click azide-nitrile cycloaddition reactions were utilized as a new ligation tool for the synthesis of tetrazoletethered C-glycosyl α-amino acids . Ugi four-component condensation between methyl o-formylbenzoates 210, amines 211, isocyanides 212, and trimethylsilyl azide afforded the Ugi adducts 213, which were cyclized to the tetrazolylisoindolinones 214 with sodium ethoxide in ethanol . Tetrazole-fused glycosides and nucleosides were synthesized from the intramolecular 1,3-dipolar cycloaddition reaction of the azide and cyano groups .

R CN 206

TMSN3 , Cu2 O (2.5 mol%) DMF/MeOH, 80 ºC R = Ar, alkyl, Bn, Ts 36–96%

R

H N N N

N

207

Five-Membered Ring Systems: With More than One N Atom R1 O

O

N3

R1

TMSCN

R2

R2

N

BF3 •OEt2

N

MeNO 2, 0 °C

251

R 1 = R 2 = Me, (CH 2) 5

O

N N

R 1 = H, CH2 Br; R2 = Me, Ar

OH

29–94% 209

208 CHO +

R1

R2 NH2

CO2 Me

R3 NC

+

211

R1 210

212

N N R3 N N

N N N R N NHR2

NaOEt

N R2

EtOH

R

CO 2Me R1 213

MeOH 25 °C, 2 d

3

1

TMSCN

R1

R1

68–92%

= H, OMe;

R2

= Ar, Bn, Me;

O R1 214

R 3 = Bn, Cy, Ar

Interests in heterocyclic energetic materials were reported for compounds containing the tetrazole structure. For example, 1,5-diaminotetrazoles 218 were synthesized by the in situ reaction of cyanogen azide 216 with monosubstituted hydrazine derivatives 215 via intermediate 217 as part of a program towards development of energetic materials 90%

Fc

OH

N OAc

S

R 20

19

R 21

Fc = ferrocenyl; R = aryl, CO2Et

A series of trisubstituted thiazole derivatives 31 has been prepared via a four-component tandem protocol . Reaction of acid chloride 24 with ammonium thiocyanate generates acetyl isothiocyanate 27, which, upon treatment with ethyl bromopyruvate and tetramethylthiourea, provides thiazoles 31 in good yields. The reaction presumably starts with intermediate 25. Elimination of HBr generates carbanion 26, which undergoes a nucleophilic attack at 27 to give 28. Ring closure and subsequent elimination of water produces thiazole 31. S Me

Br

Me N N Me Me 22

CO2Et +

+ O

23

R

Me

Cl

NH4SCN

+

O 24

N

Me Br H

Me

78-90%

N Me

25

O EtO2C Me N Me

O N

S N Me

S

R

N

O 29

Br

CO2Et OH Me N R

Me N

Me

N Me

S 30

S

O

S 28

NCS O

S CO2Et

Me N Me

27

Me

Me N

Me N Me

O

Me N R

N Me

N Me

S 31

S

O

CO2Et

S 26

CO2Et 78-90%

O

-HBr R

R

Me N

Me

Me

CO2Et

S

R = aryl, alkyl

O

Y.-J. Wu and B.V. Yang

264

α-Diazoketones 32 undergo smooth coupling with thiourea in the presence of copper(II) triflate to produce 2-aminothiazoles 35 . The reaction may proceed via initial formation of an imine 33 followed by sulfur insertion resulting in the formation of 2aminothiazoles 35. O Cu(OTf)2

N

H2N

R thiourea

N2

S

32

R

R

R 85-96%

N H2N

N2

33

N

N2

S

H2N

S 35

34

Oxidation of thiazolines represents another common approach to thiazoles. For example, treatment of thiazoline 36, available by DAST induced ring closure (vide infra), with bromotrichloromethane and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), generates thiazole 37 without racemization . This thiazole serves as an advanced intermediate in the synthesis of thiopeptide antibiotics GE2270A, GE2270T, and GE2270C1. Oxidation of thiazoline 38, also prepared from its acyclic precursor using DAST (vide infra), is effected with manganese dioxide at room temperature to give cyclopeptide YM-216391 . CO2Me

CO2Me S

S

N

N

BrCCl3, DBU

N

N >69%

N N

S

S

MeO2C

N

OTBS NHBoc

N H

S

i-Pr

O

NH

N

NH

N

O

MnO2

Et

N

OTBS NHBoc

37 O

O

N

S

S

MeO2C

O

O

O

N

36

i-Pr

N

S

N H

N

O

NH

N

NH

N

Et Me O

N O H 38

N S

O

55% Me O

N O

O

N S

(-)-YM-216391

Thiazoles can also be derived from 1,4-dicarbonyl compounds, which are available through the N-H insertion reaction of rhodium carbenoids. For example, the dirhodium(II) carboxylate-catalyzed reaction of diazocarbonyl compound 40 in the presence of primary amide 39 leads to the formation of α-acylaminoketone 41, which is converted into thiazole 42 by treatment with Lawesson’s reagent . Thiazole 42 serves as one of the six thiazole building blocks in the total synthesis of thiopeptide antibiotics GE2270A. GE2270T, and GE2270C1. Thiazole 44 is also obtained from diketone 43 using Lawesson’s reagent .

Five-Membered Ring Systems: With N and S (Se) Atoms

i-Pr

O NH2

BocHN

i-Pr

Rh2(OAc)4

N2

+ MeO

O

H N

BocHN

54%

CO2Et

39

265

O

40

41

O

BnO2C

H N O

Me

N

BocHN

N S

BnO2C

45%

58% i-Pr

NHBoc Lawesson's CO2Me reagent

OMe

O

Lawesson's reagent BocNH

CO2Et

S

CO2Me

CO2Et

Me

43

OMe 42

44

Cyclocondensation of thiazadiene 45 with α-haloketones 46 provides a new approach to glucosylamino thiazoles 49 . The intermediate cycloadduct 47 undergoes cyclization and spontaneous deamination to afford aminosugars 49. In this process, the β anomeric configuration is fully preserved, and only 1,2-trans glucosidic linkage is formed. : NMe2

NMe2

O Et3N

N

R

HN S Sugar 45

NMe2

N

X X = Br, Cl

HN S Sugar

46

S HN Sugar

R

OAc

O

S HN Sugar

R 48

47

N

O

N O

Sugar = AcO AcO

R

O

78% (R = p-ClPh) 62% (R = CF3) 74% (R = Me)

OAc

49

5.5.2.2 Synthesis of Fused Thiazoles A series of 2-arylbenzothiazoles 53 has been synthesized from 2-methylthio-N(arenylidene)anilines 50 by means of flash vacuum pyrolyses or photolyses . According to the proposed mechanism, elimination of a methyl radical from 50 is followed by cyclization of the resulting thiophenoxyl radical 51 to give a nitrogen radical 52. This radical is then aromatized to benzothiazole 53. SMe N Ar 50

FVP or hυ

S

. -Me

N

S Ar N Ar

51

52

-H 40-98%

S Ar N 53

The Jacobson thioanilide radical cyclization has been frequently used for the synthesis of benzothiazoles as shown by the preparation of benzothiazole derivative 55 . The harsh reaction conditions (K3Fe(CN)6, NaOH, H2O, EtOH, 90°C) commonly used for the


266

Jaconson benzothiazole formation can be overcome by two new methods. The first one uses phenyliodine(III)bis(trifluoroacetate) (PIFA) in trifluoroethanol or cerium ammonium nitrate (CAN) in aqueous acetonitrile at room temperature , and the other one involves a palladium-catalyzed C-H functionalization/C-S bond formation sequence . K3Fe(CN)6, NaOH, H2O, Δ

S

S NO2

N H

MeO

NO2

54 R1

PhI(OCOCF3)2, CF3CH2OH

S

2

R

Ph

N H

N

MeO

56

55 R1 R

or CAN

H S

-H

S

2

R2

Ph N

Ph

N H

58

57

R1

-H

R1

S R2

9-98%

Ph N 59 PdX2 or PdCl2(cod) (10 mol%) CuI (50 mol%), Bu4NBr (2 equiv)

S

R

60

N H

R'

S R N

R' DMSO/NMP, 23-90%

61

2-Benzylimidazo[2,1-b][1,3]benzothiazoles 66 are prepared through a palladium-catalyzed heteroannulation of acetylenic compounds 63 . Reaction of 2-imino-3-(2propynyl)-1,3-benzothiazole 63 with aryl iodides and triethylamine in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide gives 2-substituted imidazo[2,1-b][1,3]benzothiazoles 66 in moderate to high yields. Ar Br

N

N NH2

S

NH

(PPh3)2PdCl2, Et3N, CuI, DMF

N NH S

S 63

62

64 Ar Ar

N

C 55-87%

N

S 66

H

N NH S

65

Kaufmann-type aminothiazole formation has been utilized for the synthesis of novel thiazolomorphinans . Treatment of 1-aminocodeine 67 with potassium thiocyanate and bromine in acetic acid under microwave irradiation provides aminothiazole codeine 71. The reaction probably proceeds via thiyl radical 69, which undergoes 1,5homolytic radical cyclization followed by aromatization of radical 70 to give thiazole 71.


267

OH

OH

H

OH H

KSCN, Br2, HOAc, MW

Me N

H

Me N

Me N Br2

O

O

O [HSCN] HN H2N

OMe

N

OMe H2N

67

S

H2N

68

OMe . S

69

OH

OH

H

H

Me N

Me N

54%

O

O .

OMe

N H2N

5.5.2.3

OMe

N

S

S H2N

71

70

Synthesis of Thiazolines

Thiazolines can be obtained through cyclodehydration of the compounds bearing C(=S)NH-C-C-OH moiety (β-hydroxy thioamide). The utility of this strategy is demonstrated in the total synthesis of cyclopeptide YM-216391 and thiopeptide antibiotics GE2270A, GE2270T, and GE2270C1 . Exposure of β-hydroxy thioamides 72 and 73 with DAST brings about intramolecular cyclization to provide thiazolines 36 and (-)YM-216391, respectively, in good yields. CO2Me S

CO2Me S

N

N

DAST N

N

HO N

N

S

S

S

MeO2C

HN

N N

OTBS NHBoc

O

i-Pr

N H

S

i-Pr

O

NH

N

NH

N

O

DAST

Et

N 36

O

O

N

S

S

MeO2C

72 O

O

>69%

N H

N

O

NH

N

NH

N

Et Me O

N

HN

O H HO

S 73

O

89% Me O

N O H

N S 38

O

OTBS NHBoc


268

Kelly’s biomimetic methodology, first reported in 2003 , has become one of the most reliable routes to thiazolines. In this approach, the phosphorus-activated amide carbonyl group undergoes nucleophilic attack by the cysteine thiol group to provide the thiazoline moiety (see 75a/b). Kelly’s thiazoline formation has been applied to the total syntheses of cyclic depsipeptide largazole, a new antitumor natural product isolated in 2008 (vide infra), by two independent groups . Thus, amides 74a/b are treated with triphenylphosphine oxide and triflic anhydride to provide thiazoline esters 76a/b in good yields. STr O S

Me CO2Me

N H

N

O

Me CO2Me

N

S

a: R = NHFmoc b: R = N3

74a/b

R

(TfO)Ph3P

Ph3P(O), Tf2O

Tr S

S 90%

N

S

N

CO2Me

N R

75a/b

R

Me

76a/b

The same thiazoline-thiazole 76a is also prepared using Ishihara’s thiazoline formation method . The double dehydrative cyclization of tripeptide 77 is effected with a catalytic amount of ammonium permanganate in refluxing toluene to give (bis)thiazoline 78, which is readily oxidized to 76a . SH O O

NH

S

Me

HS N H

(NH4)2MnO4

CO2Me

S

NHFmoc

S

Me N

BrCCl3, CO2Me DBU

N

N

S

CO2Me

N

40%

NHFmoc

NHFmoc 78

77

Me

76a

Pattenden’s approach to thiazolines, first reported in 1993 , has been applied to the synthesis of largazole by four independent laboratories . Cyclocondensation of α-methylcysteine hydrochloride 79a with nitrile 80 under optimized conditions (phosphate buffer pH 5.95, methanol, 70 °C, 2 h) results in thiazoline-thiazole acid 81a in quantitative yield. Interestingly, when α-methylcysteine methyl ester hydrochloride 79b is used instead of the acid 79a under different conditions (Et3N, EtOH, 50 °C, 72 h), a significant lower yield of thiazoline-thiazole ester 81b is obtained.

Me RO2C

NH2•HCl 79a/b

5.5.2.4

NC

SH +

N

99% (81a) 51% (81b)

S NHBoc

80

a: R = H b: R = Me

Me RO2C

S N N 81a/b

S NHBoc

Reactions of Thiazoles and Fused Derivatives

2-Aminothiazoles 82, upon diazotization and treatment with sodium nitrite, give 2nitrothiazoles 83. These compounds are further nitrated with trifluoroacetyl nitrate to generate


269

dinitrothiazoles 84 . These compounds are useful building blocks for medicinal chemistry. aq HBF4, NaNO2; NaNO2, Cu

N R

NH2

S 82

R

28% (R = H) 21% (R = Me)

S 83

O2N

NH4NO3, TFA, TFAA

N NO2

N R

34% (R = H) 91% (R = Me)

S 84

NO2

Trifluoroacylation of thiazole 85 and benzothiazole with trifluoroacetic anhydride and triethylamine results in the formation of trifluoroacetylthiazoles 88 and 89, respectively, in good yields . It is postulated that the acylation occurs via the intermediate heterocyclic ylide 87. O

O Me N

N

S 85

CF3

Et3N

S

TFAA, Et3N 99%

N

CF3

N

72%

S

S 87

S 86 N

Me

Me

Me

TFAA, Et3N

N S 89

88

CF3 O

CF3 O

2-Iodobenzothiazole 90 is prepared from benzothiazole by deprotonation using an in situ mixture of ZnCl2•TMEDA and lithium 2,2,6,6-tetramethylpiperidine (LiTMP) followed by trapping with iodine . When CdCl2•TMEDA is used instead of ZnCl2•TMEDA, the yield is increased to 97% . However, a mixture of two iodides 91 and 92 is obtained from simple thiazole. S N

S N

MCl2•TMEDA (0.5 equiv), LiTMP (1.5 equiv); I2

S I N

73% (M = Zn) 97% (M = Cd) MCl2•TMEDA (0.5 equiv), LiTMP (1.5 equiv); I2

90 I

S I N 91

S

+

I N 92

Two palladium-mediated methodologies for the direct C-2 arylation of thiazole analogs have been reported. The first one involves t-butyl 4-thiazolecarboxylate 93 . Thus, the C-2 arylation of 93 with aryl or heteroaryl halides is carried out using P(o-tol)3 as ligand, cesium carbonate as base and a catalytic amount of palladium acetate in DMF at 110 °C. The other one employs palladium bis(2,2,6,6-tetramethyl-3,5,heptanedionate) (Pd(TMHD)2) as an efficient catalyst . The 2-substituted thiazoles 97 undergo palladium-catalyzed C-5 arylations with aryl triflates to give the C-5 substitited thiazoles 98 .


270 O t-BuO

N

Pd(OAc)2 (5 mol%) P(o-tol)3 or JohnPhos (10 mol%) Cs2CO3 (2 equiv)

O t-BuO

N

Ar-X (1 equiv) 36-95%

S 93 S

Ar-X, Pd(TMHD)2, K3PO4, NMP

N

40-86%

S 94

Ar

S Ar N 96

95 S 2

R N

R1

ArOTf, PPh3, KOAc or Cs2CO3 37-64%

97

Ar

S

R1 = H, Me R2 = alkyl, CN

R2 R1

N 98

Despite many recent advances in the direct arylation of thiazoles, regioselective C2 and C5 arylation can still be problematic, and a high yielding C4 arylation remains unavailable . To this end, regioslective arylation of thiazole N-oxides has been developed. The thiazole oxides are readily prepared from thiazoles by treatment with mCPBA or H2O2 in the presence of catalytic MeReO3, and the N-oxide moiety can be easily deoxygenated via zinc powder in aqueous ammonium chloride . The N-oxide group not only increases reactivity in direct arylation at all positions of thiazole ring but also provides a reliable C2 > C5 > C4 arylation activity order. Treatment of an aryl halide with thiazole Noxide 99 in the presence of palladium acetate, biphenyl ligand 100, pivalic acid (PivOH), and potassium carbonate in toluene at room temperature results in C2 arylation to give 101 as the exclusive product. These are rare examples of direct C-2 arylation occurring under such mild conditions. When the C2 position is blocked, the thiazole N-oxide 101 can then undergo selective C5 arylation using palladium acetate, t-Bu3PHBF4, and potassium carbonate in toluene at 70 °C. Interestingly, addition of pivalic acid to the C5 arylation reactions is

H

Ar1-I, Pd(OAc)2 (5 mol%), ligand 100 (10 mol%),

O N

H

H

S 99

Cs2CO3 (1.5 equiv), PivOH (20 mol%) 69-84%

O N

H H

Ar2-Br, Pd(OAc)2 (5 mol%), t-Bu3PHBF4 (5 mol%), K2CO3 (1.5 equiv)

80-86%

Ar2

Ar2

64-84%

O N

H Ar2

S 102

Zn powder, NH4Cl

64-72% Ar

Ar1

S 103

3

Ar3-Br, Pd(OAc)2 (5 mol%), PPh3 (15 mol%), K2CO3 (2 equiv)

O N

Ar3

O N S

Ar1 104

Ar1

S 101

Ar1

NMe2 PPh2 100


271

detrimental to the C5/C4 selectivity. The optimal C4 arylation conditions include palladium aceatate in the presence of triphenylphosphine and potassium carbonate in toluene at 110 °C. This represents the first examples of arylation at C4 of the thiazole ring system. This arylation approach using thiazole N-oxides permits an exhaustive functionalization of the azole core: first at C2 (99 to 101), followed by C5 (101 to 102) and C4 (102 to 103). The Vorbrüggen method is a well known N-glycosylation procedure that involves coupling between silylated forms of nitrogen or amide-containing heterocycles and activated sugars, in the presence of a Lewis acid. In this modified version, the C2 position is activated in 2(trimethylsilyl)thiazole, and treatment of this thiazole with tetra-O-acetylribose 105 and tin(IV) chloride furnishes the β-thiazole-C-nucleoside 106 . However, simple unactivated thiazoles fails to react with 105. The modified Vorbrüggen reaction may have potential for the ribosylation of deactivated heteroaryls including thiazoles. O

AcO

N

OAC

N +

AcO

OAc

TMS

S

O

AcO

SnCl4

S

74% AcO

105

OAc

106

A facile intramolecular C(sp3)-H bond activation with Pd(II) has been disclosed . Reaction of bis(thiazole) 107 with palladium acetate results in the exclusive formation of an organometallic Pd(II) complex 108 with C-H activated t-butyl group and a hemilabile S-coordinated thiazole donor in cis-position. This complex may be useful for reactivity studies and for the visualization of proposed reaction intermediates in modern palladium catalyzed reactions.

N S

N Bu-t

N H

Pd(OAc)2

N S N t-Bu 107

78%

N S

N

N

N Pd N Bu-t Me

S

Me 108

1,3-Dipolar addition of thiazolium azomethine ylides to enantiomerically pure cyclic and acyclic vinyl sulfoxides provides efficient access to polyfunctionalized pyrrolo[2,1b][1,3]thiazoles in a highly regio- and stereoselective fashion . Treatment of furanone 110 with ylide derived from thiazolium salt 109 delivers the anti-endo adduct 111 as a single isomer, while the reaction with acyclic vinyl sulfoxide 112 proceeds in a completely stereoselective and regioselective manner to afford 113 in almost quantitative yield. The sulfoxide group is the main controller of the endo selectivity of both reactions as well as of the π-facial selectivity in the reaction with (Z)-3-p-tolylsulfinylacrylonitrile 112. In contrast, the π-facial selectivity in the reaction with 110 is mainly determined by the configuration at C-5, affording the anti adduct 111 with respect to the ethoxy group.


272 :

Tol S H S(O) O

R

N

Me

NC O

O

R 110

O

EtO2C

O

S

OEt 111

:

Tol

OEt

R

H

S

H CN

112 N

Me

N

Me

DBU, 84% R = (CH2)2OH

H

S

Tol S O

CO2Et

Br 109

DBU, 100%

S(O)Tol

EtO2C

R = (CH2)2OAc

113

The thiazolium-mediated three-component reaction of thiazolium salts 114, disubstituted ketenes 117 (generated in situ from acetyl chlorides 115), and dimethyl acetylenedicarboxylate (DMAD) provides a facile synthesis of polusubstituted furo[2,3c]thiazepines 120 . The reaction pathway may involve the sequential nucleophilic addition of thiazol-2-ylidene 116 with ketene 117 and DMAD to form the spirocyclic intermediate 118 through the formation of two C-C bonds and a C-O bond. This intermediate undergoes either [1,3]-sigmatropic sulfur shift or selective ring opening followed by 7-endo-trig cyclization to produce thiazepine 120. R4

R2

O

S

Cl

+

Me X

N R1

i-Pr2NEt

+ R3

R4

115

114

CO2Me 31-87%

CO2Me

2

R

S

R3 O CO2Me

Me 120

N R1

CO2Me 59-88%

1,3-S shift R3 R4

R2

S Me 116

N R1

..

117 C O

2

R CO2Me Me

R2

R3

S 1

MeO2C

R4

118

R4

R3

Me O

R1

N

R MeO2C

S

CO2Me

N

MeO2C

O CO2Me

119

R1 = Me, Et, Bn; R2 = H, Me, AcO(CH2)2; R3 = Me, Et, i-Pr, Ph; R4 = aryl, Me, Et; X = Br, I

5.5.2.5

Thiazole Intermediates in Synthesis

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is demonstrated in a recent enantioselective synthesis of the macrocyclic core of (-)-pladienolide B . Addition of aldehyde 122 to the titanium enolate solution of N-propionyl thiazolidinethione 121 produces aldol product 123 as the major isomer (diastereomeric ratio (dr) = 4 : 1). Asymmetric aldol reactions with chlorotitanium enolates derived from the indene-based thiazolidinethiones have been recently conducted . Propionate and acetate aldol reactions with various aldehydes deliver adducts with high diastereoselectivity. This new chiral auxiliary is more economic than other sterically encumbered ones, and may find use in process chemistry. This methodology has been applied twice in a formal synthesis of the auriside aglycon . Addition of aldehyde 125 to the enolate solution of 124 leads to aldol product 126 as a single diastereomer. The second aldol reaction with aldehyde 127 also proceeds with good diastereoselectivity (dr = 9 : 1). Both aldol reactions using


273

indene-based thiazolidinethione chiral auxiliary establishes two of the three chiral centers present in the auriside aglycon. AcO S S

O N

AcO Me

S

+

S

OH

O

123

OH

S

N

OTBS Me

125

Me

TiCl4, sparteine 86%

O N

N

OTBS

Me Me

S

O

Bn

122 OHC

S

89% dr = 4:1

CHO

Bn

121

S

TiCl4, DIPEA, CH2Cl2

Me

Me

126

Me S

OHC

Br

S

127

O

OH

N

Br

124 TiCl4, sparteine 74% dr = 9:1

128

The sodium enolate of N-propionyl thiazolidinethione 129 undergoes enantioselective Michael addition-elimination with (E)- and (Z)-ethyl 3-iodoacrylate to give α,β-unsaturated esters 131 and 133, respectively, with full retention of the initial E or Z configuration . The optimized conditions include 9 : 1 mixture of dichloromethane and THF as the media and -78 °C as the reaction temeprature. Boron, titanium, and lithium enolates are also explored, but sodium enolate is optimal in terms of yield and stereochemical control.

130 S S

O N

S

CO2Et

I

S

129

CO2Et

N

NaHMDS Bn

Et I

Bn

O

S

132 CO2Et S

Me 131

95% yield >99% E >97:3 (R/S)

O N

NaHMDS

Me Bn

CO2Et

93% yield >99% Z >97:3 (R/S)

133

The Julia olefination reaction involving alkylsulfonyl benzothiazoles remains one of the most effective methods for the stereoselective formation of olefins. The power of this reaction is reflected in the synthesis of bryostatins . Deprotonation of the sulfone 135 with LHMDS and subsequent addition to aldehyde 134 gives the (E)-alkene 136 in 71% yield, with no (Z)-isomer being isolated. The Julia olefination reaction is also featured twice in a recent total synthesis of (+)-myxothiazol . Coupling of sulfone 137 with aldehyde 138 using LHMDS produces a 3.2 : 1 mixture of E and Z isomers, of which the E


274

isomer 139 is isolated in 59% yield. Oxidation of 139 affords sulfone 140, which undergoes another Julia olefination with (2E)-4-methylpentenal 141 to give (+)-myxothiazol A. The Julia olefination reaction involving alkylsulfonyl benzothiazoles has also been applied to the synthesis of the myxobateria metabolites crocacins A-D and spirastrellolide A methyl ester . Me H

TIPSO H

O

O O

MeMe OBn

OTBS

O O S

N

H

TIPSO

134

CHO S

Me

H H

O

OBn H OTBS

LiHMDS

OTES

OTES TBSO Me

Me

71%

OTBS

Me

O

MeMe

OTBDPS

+

Me

O

OSEM

OSEM Me TIPSO

Me

OTBS

136

135

N N

S

N

N

138

S S Me O O

137 O O S

LHMDS

H2O2, Mo7O24(NH4)6 N

S N

S 140

CHO H2N

O

141

S

77%

N

59%

N

S

S

N

S

i-Pr

S N 139

Me

i-Pr Me

OMe OMe

OMe OMe

Me

i-Pr

OHC

S

OTBS

TIPSO

S S

OTBDPS

LHMDS 61%

H2N

O Me

N S

myxothiazol A

S N

i-Pr Me

There are several new methodologies based on the Julia olefination reaction. For example, 2-(fluoro(phenylsulfonyl)methylsulfonyl)benzo[d]thiazole 142 reacts with a variety of aldehydes in the presence of DBU to furnish phenyl (α-fluoro)vinyl sulfones 143 . An efficient synthesis of α-fluoro acrylonitriles 145 also takes advantage of the Julia olefination of aldehydes with α-fluoro (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile 144 .

Five-Membered Ring Systems: With N and S (Se) Atoms S OO O O S S N F 142 S OO S CN N F 144

5.5.2.6

O O S

R

RCHO, DBU H

59-94%

143 R

RCHO, DBU

F

CN

R = alkyl, aryl, heteroaryl

H

76-97%

275

145

F

Thiazole- and Thiazolium-Catalyzed Reactions

The N-heterocyclic carbenes derived from thiazolium ions are used to catalyze the oxidative esterification of aryl aldehydes with methanol . Treatment of aryl aldehydes with azobenzene, 3-benzyl-4-methylthiazolium bromide 146 and methanol in the presence of 5% mol triethylamine provides methyl esters 149. The reaction pathway includes oxidation of the Breslow intermediate 147 with azobenzene to give 2-benzoyl thiazolium ion 148, which transfers its acyl group to methanol to furnish methyl ester 149 and regenerate catalyst 146.

S

Me

Ph-N=N-Ph, ArCHO, Et3N, MeOH

Me N Br Bn 146

S

Me S

N Bn

O

46-97%

N Bn

Ar

16-97%

Ar

OH 147

Ar

O

OMe 149

148

The N-heterocyclic carbene (NHC) catalyzed carbonyl anion addition reactions have been extensively investigated, but in contrast, the corresponding nucleophilic addition reactions to unactivated olefins have received considerably less attention. Recently, NHCs generated in situ from thiazolium salts 151 have been applied to intramolecular nucleophilic addition reactions . For example, treatment of aryl aldehydes 150 with 151 (25 mol%) and DBU at 160°C affords benzofuranones 154 in good yields. Y

Y

Me

Y

Me

S

N Me

S

N Me OH Ph

S Me 151 I

CHO R O 150

Ph

N Me

DBU 92-99%

Y = (CH2)2OH

OH Ph

R O 152

R O

Me

O Ph R O

Me

154

153

Benzotetramisole (BTM) has been identified as an effective catalyst for the kinetic resolution of 2,2-difluoro-3-hydroxy-3-aryl-propionates 155 . Homobenzotetramisole (HBTM), a ring expanded analog of BTM, displays higher catalytic activity and a different structure-activity profile . This catalyst is effective in the kinetic resolution of secondary benzylic alcohols, especially the 2-aryl substituted cycloalkanols 156.


276 S N

S

OH N

Ar

N

F F 155

Ph

BTM

Ar N

CO2Et

( )n

n = 1, 2 OH

Ph 156

HBTM

Asymmetric hydrogenation of trisubstituted aryl alkenes and aryl alkene esters using iridium-phosphine cyclic thiazole complexes 157 was previously reported . Recently, the acyclic analogs of 158 have been synthesized and evaluated . In general, these acyclic catalysts are as reactive and selective as their cyclic counterparts for the asymmetric hydrogenation of various trisubstituted olefins. BArF

BArF

Ph2 P Ir

Ph2 P Ir

N Ph

R1

H

Ph

S

S 158

157

R3

32-97% ee

N

R

R2

R = Bn, Me, allyl

BArF = tetrakis(3,5-di-trifluoromethylphenyl)borate

R2 H R1

H2, 158 (0.5 mol%) R3 H H

A series of ruthenium olefin metathesis catalysts coordinated with thiazol-2-ylidene ligands 159 has been prepared . These phosphine-free catalysts are more stable than their phosphine-containing counterparts, and they are competent catalysts for ring-closing metathesis, cross metathesis, and ring-opening metathesis polymerization. Me Ar N Cl i-Pr

5.5.2.7

Me S Cl Ru O

Ar = phenyl, substituted phenyl 159

New Thiazole-Containing Natural Products

Thiazomycin A, a potent thiazolyl peptide antibiotic, has been isolated from Amycolatopsis fastidiosa by a thiazolyl peptide specific chemical screening . This peptide carries modification in the oxazolidine ring of the amino sugar moiety. Thiazomycin A is a specific inhibitor of protein synthesis (IC50 0.7 μg/mL) and a potent Gram-positive antibacterial agent with minimum inhibitory concentration (MIC) in the 0.002-0.25 μg/mL range. Philipimycin is the other thiazolyl peptide discovered from Actinoplanes philippinensis MA7347 . This compound also shows strong antibacterial activities against Gram-positive bacteria including MRSA and exhibits MIC values in the range of 0.015-1 μg/mL. Philipimycin is effective in vivo in a mouse model of S. aureus infection exhibiting an ED50 value of 8.4 mg/kg. Both thiazomycin A and philipimycin are structurally related to the previously known thiazolyl peptides, nocathiacin I and thiazomycin. Perhaps largazole is the most interesting and important thiazole-containing compound discovered in 2008 . This marine natural product is isolated in scarce amounts from cyanobacteria of the genus Symploca. It consists of a potentially strained 16-membered macrocycle possessing a dense combination of unusual structural features, including a


277

substituted 4-methylthiazoline linearly fused to a thiazole and (S)-3-hydroxy-7-mercaptohept4-enoic acid unit. Interestingly, this unit is an essential motif in several cytotoxic natural products, including FK228, FR901375, and spiruchostatin, all of which are known histone deacetylase inhibitors (HDACi) . The biological evaluation of largazole and its key analogs suggests that histone deacetylases (HDACs) are molecular targets of largazole, and largazole is a class I HDAC inhibitor. Largazole is a prodrug: largazole thio is the active drug. The combination of cap group and the zinc-binding motif present in this thio provides the most potent and selective HDACi reported to date. The molecular scaffold of largazole presents another macrocyclic template from which more active and selective isoform-selective HDAC inhibitors can be designed and synthesized. OH

O

S

Me O

N

NH

N

S

R1 =

NMe2 Me OH

O Me

N

O

O

Me

N

S

O

1

N

OH

Me O

N

thiazomycin

N

OMe S

Me

O N H

O

Me

R =

O

NH O

O

HN

nocathiacin I

Me

S

NH

HO

H2N

N

O

R1 = R1O

O

OH

Me N Me

Me O

thiazomycin A

O

S N

NH

N

S

O Me

N

O

S

NH

HO

O

2 O R O

HN Me

H2N

N

N

NH O

S

R2 =

O NH

N

OMe S

OMe O

O

OH OMe

O O

O i-Pr O

O n-Hep

Me

NH

S

N O

S

O N H

largazole

i-Pr

N

lipase or esterase

O

S HS Zn+2 HDAC

Me OH

O

philipimycin

N H HO

Me

Me O OMe OMe O

Me

NH

S N N

O

O

N H largazole thiol

S


278 5.5.2.8

Synthesis of Thiazole-Containing Natural Products

The potent biological activity and selectivity of largazole (vide supra) for cancer cells have stimulated significant interest in its synthesis, and seven total syntheses have already been reported in 2008 . Preliminary structure-activity relationship studies on largazole have also been undertaken . Syntheses of other thiazole-containing natural products include: amythiamicins A, B, and C , scleritodermin A , GE2270A , GE2270A, GE2270T, GE2270C1 , (-)-dysithiazolamide , (+)-myxothiazol A , YM-216391 , and patellamide A . Synthetic studies on nosiheptide have also been initiated . R2 O S

R3 O

N

N N

i-Pr

N H

O

HN

N

NH

N

S

NH

MeHN

O

S

Me

YM-216391

N

N

N

S

i-Pr

S

O H NH

H

O

N

N

O O O

O

NH

Me O

OH O

N

N

Et

Ph

S

S N

NH2

N

N

O

O

O

CHCl2

R1 Cl2HC

GE2270 A (R1 = CH2OMe; R2 = R3 = H) GE2270C (R = H; R2 = R3 = H) GE2270T (R1 = CH2OMe; R2, R3 = C=C)

Me

Me N Me

S

N

NH

O

Et

O

OH (-)-dysithiazolamide S

N H

O

O

O

O

O

N O

S N

O Et

HN

N

Me

Me

NH Et

i-Pr

O

Me

N

O

Me

Me

HN

scleritodermin A

Et

N

O O

NH O

OMe NHSO3Na

N N

S

HN O i-Pr

patellamide

O

Five-Membered Ring Systems: With N and S (Se) Atoms R S

R=

O

N

N

O N

N

i-Pr

N

S

amythiamicin A

N O

S

N

NH2

O

HN

O

OH

S O

O O

O

NH

MeHN

S

i-Pr

Me

amythiamicin B

NH O

N

N

N

N

O

NH

H

NH2

S O

O O

Me

HO

S

HN

OH

N

S

OO

N

NH

N

S

O

OH N

Me

O

O

Me

HN H

N

O

S

amythiamicin C

N HN

O

H N

279

H S

N S

O NH2

HN

O NH

5.5.2.9

nosiheptide

Pharmaceutically Interesting Thiazoles

A number of biologically important thiazole analogs have been disclosed. For example, TMC435350 is a cyclopentane-containing macrocyclic inhibitor of the hepatitis C virus NS3/4A protease . This compound is currently being evaluated in the clinics. BMS-640994, a potent and selective p38α MAP kinase inhibitor, has demonstrated oral efficacy in rodent models of acute and chronic inflammation . PSNGK1 has been developed as a potent glucokinase activator for the treatment of diabetes . MB06322 is an orally bioavailable phosphoramidase-sensitive prodrug for the treatment of type 2 diabetes . PC190723 has been identified as an inhibitor of FtsZ with potent and selective anti-Staphylococcal activity (FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian β-tubulin that polymerizes and assembles into a ring to initiate cell division). This compound serves as a lead for optimization into a new anti-staphylococcal therapy . H2N

N

O

S i-Bu

CO2Et O P N Me H HN CO2Et

H N

O

S N

N

Me MB06322

JNJ27265732

O OH


280

F

O

O

O

N

NH2

H N O S

i-Pr

O

N

F

N

O

S F

Me

N

PSN-GK1

S

O

MeO O

N N

H N

Me

H N

S Et

O

Cl NHMe

S

Me

O

NH

O O N S H

O

N

PC190723

O

TMC435350

BMS-640994

5.5.3

ISOTHIAZOLES

5.5.3.1

Synthesis of Isothiazoles

A facile synthesis of 2,3-dihydroisothiazole-3-ones 164 and 3-thione 165 utilizes the readily available cyanomonothio-carbonylmalonamides 160 or the cyanodithio congener 161 . The key step involves formation of the highly reactive thioenols 162 or 163 in ethyl acetate, and the succeeding oxidative intramolecular annulation to form a new N-S bond affording 164 or 165, respectively. NHR2

NC

NHR2

NC

CN

X EtOAc/Air

R1HN

X

S X

160 (X = O) 161 (X = S)

SH NHR1 162 (X = O) 163 (X = S)

R1

N

S

NHR2

164 (X = O) Yields: 53-79% 165 (X = S) Yield: 76%

X= O, R1 = H, Me, R2 = Ph, 1-Naph, i-Pr, t-Bu; X= S, R1 = H, R2 = Ph

A divergent approach to new sultams features intramolecular Baylis-Hillman reactions of the readily prepared N-(2-oxoethyl)vinylsulfonamides 167 . TBS-deprotection of vinylsulfonamide 166 with HCl and subsequent Dess-Martin oxidation yield the aldehyde 167, which undergoes smooth Baylis-Hillman reaction, affording vinyl sultams 168 in excellent yields with moderate to good levels of diastereoselectivity. The TBS-protected prolinol-derived vinyl sulfonamide 170, under the aforementioned orthogonal conditions, generates the bicyclic sultam 171 with excellent diastereoselective ratio (97:3). The method has been extended to the secondary alcohol 172, leading to the unique bicyclic vinyl sultam 173 through a keto vinyl sulfonamide. O

O S

N

TBSO

R2 R1

166

1. HCl 2. DMP

O

O S

N

R2

OHC R1 167

DABCO 67-72% (overall yield) dr = 62:38 to 90:10

O

O S 2 N R +

HO R1 168 (major)

O

O S 2 N R

HO R1 169 (minor)


1. HCl 2. DMP 3. DABCO

O

O S

N

70% dr = 97:3

TBSO

O

O Ar

O

O S N

S TBSO

O Ar S N H

O

1. HCl; 2. PCC (70% 2 steps)

N

3. DABCO (53%) HO dr = >95:5

HO

170

281

171

172

173

R1 = i-Pr, i-Bu, Bn; R2 = CH2CH=CH2, Bn, CH2Ph(o-Br), CH2CCH; Ar = p-Cl-Ph

Synthesis of 5-carboxylate substituted sultam 175 has been achieved through the alkylation of methyl 2-(N-phenylsulfamoyl)acetate 174 with 1,2-dibromoethane in a dilute solution of K2CO3-DMF . O O BrCH2CH2Br K2CO3, DMF S N H 18-86% CO2Me

R

O O S CO2Me N

R

174

R = H, 2-Me, 4-Me, 4-Cl, 2.6-Di-Me, 4-CO2Et

175

A rapid synthesis of benzosultam-3-acetic acid derivative 180 has engaged a domino Heck–aza-Michael reaction . The one-pot, sequential three-component process affords diverse benzosultams 180 from ortho-bromobenzenesulfonyl chlorides 176, amines 177 and Michael acceptors 179. O S Cl Br

R1

O

R2NH2 177 Et3N, DMF

O

NHR2 Br

R1

176

Pd2(dba)3• CHCl3 Et3N, Bu4NCl, 110 °C 74-95%

O S

R3 O

178

O

O S N R2

R1 COR3

180

179

R1 = H, F ; R2 = c-C5H9, c-C6H11, C8H17, Bn, 4-Cl-Ph, 4-MeO-Ph; R3 = Me, OH, OMe, OEt, NH2

Polyfunctionalized benzo[d]sultams 183 and 182, containing an α-amino acid unit, have been prepared from the corresponding open chain sulfonamides 181 by either complementary solid-liquid phase transfer catalysis (SL-PTC) with TEBA (triethylbenzylammonium chloride) or homogeneous protocols . The cyclization step proceeds through the intramolecular nucleophilic displacement of an aromatic fluorine atom. F

O

O

F

S

F

F F 181

N H

Ph

F CO2Me

DBU F MeCN 98% F

O

O S NH

F Ph 183

F RX, MeCN K2CO3, TEBA

F

82-100%

F

CO2Me

RX, base, TEBA, DMSO ( 20-94%) X = I, Br; R = C1-C4 alkyl , Bn, Allyl; base = K2CO3, Cs2CO3 or Na2CO3

O

O S N R

F

Ph 182

CO2Me


282

A series of saccharin derivatives of amino acids 185 has been conveniently synthesized using the H5IO6-CrO3 oxidation system . Racemisation of the amino acid moiety has not been detected, albeit with less than optimal yields. O

O S

1

R

Me

O

R2

N H

CrO3, H5IO6, Ac2O, MeCN, rt OMe

O S

1

R

R2

N OMe

8-40%

O

O O

184 185 R1 = 6-NO2, 6-Br, 6-F, 5-MeO; R2 = (S)-Me, (S)-iPr, (S)-Ph, (R)-iPr, (R)-CH2CH2CO2Me

A novel aziridine sultam 188 is obtained through an unexpected internal SN2 displacement pathway in an attempt to prepare the δ-sultam 189 . 1. (MeO)2P(O)Cl O O S Boc N-methylNH N imidazole (97%)

O

O S

OBn

2. FeCl3 (60%) 187

186

5.5.3.2

S

N

Bn

OBn

OBn

H

OPO(OMe)2

188

189 (not detected)

OPO(OMe)2

OH OBn

O

O

BnBr O O S Cs2CO3 N 100%

Reactions of Isothiazoles

N-Heterocyclic carbenes-catalyzed homoenolate addition to saccharin-derived ketimines 191 provides a simple and convenient solution to the synthesis of stereochemically defined tricyclic γ-lactam 193 with broad scope and low catalyst loadings . The use of IMes•HCl precatalyst 192 and DBU proves most effective for the formation of lactams predominantly with the two substituents at cis orientation. The possible reaction pathway invokes enal-catalyst adduct 194, which forms an ene-like transition state with 191. The presumed six-membered cyclic transition state could be stabilized by hydrogen bond to the sulfonyl oxygen and allows for the concomitant transfer of the acyl proton to the imine nitrogen atom and formation of the new carbon-carbon bond. O

O S

O

1

HO H

H+ N

R

190

R2

N N

R1

R3 191

Mes

N

O O

S NH R2 R1

R1

N Cl N Mes

O

R2 193

1

Cl

194

55-98% cis/trans = >20:1 to 1:1

192 (0.5 mol%) DBU, DCM, 25 0C O O O S N

R3

R3

N N Mes

Cl N

N

R3

195

R = H, Me, Pr, 1-propenyl, Ph, substituted Ph, 2-furyl R2 = Ph, substituted Ph, heteroaryl, Me, Bu; R3 = H, Me, OMe

R3

R2

Mes

Cl

N N H R1 N S N O O H O ene-like addition

R2

Mes

NH R1 S O O O H

Cl N N N

tautomerization


283

An efficient and fast N-benzylation of saccharin 196 has been accomplished with benzyl chloride in the presence of K2CO3 and a phase transfer catalyst under solvent free condition . N-Allylation of saccharin 196 has been achieved through a new oxidative amination of unactivated alkyl olefins with high regioselectivity . Reaction of saccharin 196 and alkene 198 with Pd(OAc)2 under oxygen atmosphere (6 atm) in the presence of the basic resin D301(OH), 4ǖ molecular sieves and maleic anhydride (MA) appears to proceed by allylic C-H activation and subsequent nucleophilic attack at the C-1 position of an intermediate π-allylpalladium species resulting in the (E)-allylic amination product 199 and the corresponding alkene isomers. Neither the enimide 200a (C2-amination) nor the branched allylimide 200b (C3 amination) is detected. O O S NH 196

PhCH2Cl, Bu4NBr K2CO3, 100 °C 48%

O

197

O

1

3

O O S N

R 198 Pd(OAc)2, D301(OH) 2

MA, 4Å MS, O2 58-85%

not detected O O R S N 3

O O S N

199

O

200b O O O S 2 N

R nonallylic isomers

+

(C1 amination) ratio: 56:44 to 100:0

O 200a

R

R = C8H17, C5H11, CH2OPh, CH2OBz, CH2CH2OAc, CH2CH2OBz, CH2CH2CO2i-Pr, Ph

N-Phthalimidyl-saccharins (3-oxosultam) 206 can be accessed by a sequence of oxidation reactions from N,N’-linked isothiazolium perchlorates 203 with hydrogen peroxide, or MMPP/PDC (magnesium monoperoxyphthalate/pyridinium dichromate) . NAmino-phthalimide 201 reacts with thiocyanate 202 in glacial acetic acid in the presence of perchloric acid forming the N,N’-linked isothiazolium salt 203. The first stage of the reaction produces hydrazonium salt, which then undergoes cyclization giving rise to isothiazole 203.

O

NH2 N O

201

R1

CHO R1

R2 SCN 202 HOAc, HClO4 89-93%

2

R

R1 H

H2O2 N R AcOH

OOH N R

S ClO4 203

R2

R1 H 44-51%

N R S O O

R2

S 204

205

MMPP 50 °C R1 = R2 = Me R1, R2 = (CH2)4 O R=

N O

80 °C

R1

R1 H N R

R2

S O 207

OOH

93-98% R2

OH

R1 PDC N R 79-82%

S O O 208

R2

O

O

N N S O O

O 206

Aza-ortho-xylylenes 211, generated by thermal extrusion of sulphur dioxide from cyclopenteno-spiro-benzisothiazoline 2,2-dioxides 210, undergo [1,5]-sigmatropic hydrogen shift leading to unstable arylcyclopentadienes 214 that can be trapped with dienophiles 215 to form arylnorbornenes 216 as a diastereomeric mixture .


284

R2 N R1

Z

O S O

R2

Cl

Cl

N S

NaOH, DMSO

R1

53-75%

209

Z

R2 N

O O

R1

Z

210

211

2

R

Br

N NaOH, DMSO

S Z

R1

(R2 = H)

O RCM, Grubbs II O 73-85%

212 R1 Z Y

Y

X

215 R1

28-85%

NH 216 R2

R2

R2

NH

NH R1

Z

X

Z 213

214

A one-pot synthesis has been developed for the pilot-scale manufacturing of a new antiarthritic drug candidate, sultam 220 (S-2474) . This route consisting of only two reactions gives an overall yield of 84% with excellent E-selectivity. The mechanism for the E-selective dehydration relies on the unique character of the phenol derivative 219 that can easily form the quinone methide intermediate 222. Dehydration proceeds through the phenoxide anions threo-isomer 221a and erythro-isomer 221b, both of which would give the same intermediate 222. The dihedral angle energy of the proposed quinone methide LiO t-Bu

CHO

HO t-Bu 217

LDA, DMI

t-Bu

O O S N Et

LiO

O O S N Et

H2O 50-90 °C 84% E-selective dehydration

t-Bu 219 (Li salt of phenol)

O O S N Et

t-Bu HO t-Bu 220 E-isomer

218 t-Bu O HO H Et

H t-Bu O

t-Bu threo-221a

N S O O t-Bu

X H

H

O S O N Et

H t-Bu H

223 O

OH O O S N Et

t-Bu Z-isomer

erythro-221b 221 (phenoxide anions)

H t-Bu O t-Bu 222

H O O S N Et


285

intermediate 223 which leads to Z-isomer is higher than that of the intermediate 222 which leads to E-isomer due to the steric hindrance of the sulfonyl and the aryl groups. If the mechanism is a normal E2 elimination, the Z-isomer would have been produced by antielimination of the threo-isomer 221a. 5.5.3.3

Isothiazoles as Auxiliaries and Reagents in Organic Syntheses

Oppolzer’s camphor sultam, a well known chiral auxiliary, has been applied to the synthesis of β2-homotryptophane 229 via the aminomethylation of chiral silyl enol ether 225 using the highly reactive iminium ion 226 . Silylation-aminomethylation of the 3-indolylpropanoic acid derivative 224 yields 227 as a single diastereomer, which gives rise to N-Boc-β2-homotryptophane 229 after subsequent deprotection, saponification, Boc-protection and final debenzylation of the indole nitrogen under the Birch condition. The β2-homolysine derivative 233 is prepared as a single diastereomer under the similar aminomethylation condition starting with bromide 230, wherein the bromo is replaced with di-tert-butyl iminodicarboxylate 232 after the aminomethylation reaction. TMSO O

X TMSOTf NEt3

N

S O O

N Bn

1. CH2=NBn2 CF3CO2 226 2. TBAF 88%

N Bn

Xs

BocNH 1. H2, Pd(OH)2/C 2. LiOH 3. Boc2O, LiOH

Xs

N Bn

225

224

227

O

BocNH OH Na, NH3 THF, -50 °C

O OH

81%

65% N Bn

N H 229

228 1. TMSOTf, NEt3 O Br

O

2. CH2=NBn2 N

S O O

230

O

Bn2N s

CF3CO2 226 3. TBAF 76%

Xs

Bn2N Br 231

HN(Boc)2 232 NaH DMF Bn2N 68% (Boc)2N

O Xs

233

Asymmetric conjugate addition of linear aliphatic Grignard reagents to aryl substituted α,β unsaturated carbonyl compounds 234 derived from Oppolzer’s (2R)-bornane-10,2-sultam has been achieved with great regioselectivity and good to excellent diastereoselectivity . Application of this methodology is highlighted in the preparation of a series of chiral triazole analogs (R)-237 . Employing (2S)-bornane-10,2-sultam in a similar fashion results in (S)-240 triazole analogs.


286

H

O

O

S

O

NaBH4 XR Ar 78-92% 1,4/1,2 product = >20:1 235 (3R) (2 steps) de% 82-98 RMgX

Ar

N

O

234

XR O S O O N

RMgX (79-87%)

Ar

238

XS

OH R

R

O

1,4/1,2 = >20:1 de% 70-98

R

XS

Ar

Ar

N

1.CBr4, PPh3 (76-91%)

N

2. triazole (68-87%)

236

N

R Ar

237

1. NaBH4 (87-93%) 2. CBr4, PPh3 (71-90%)

N N

R

N

3. triazole (63-80%)

Ar 240

239 (3S)

Ar = Ph, 4-F-, 4-Cl-, 4-OMe-, 4-Me-Ph; R = Et, n-Pr, n-Bu; X = Br, Cl.

(2R)-N-Propenoylbornane-2,10-sultam 244 has been widely used as a dienophile in DielsAlder and 1,3-dipolar cycloaddition reactions. However, access to a large amount of 244 is restricted mainly because of the lack of a convenient preparation using the inexpensive sulfonic acid 241 as a starting material. Thus, an improved procedure has been developed . Conversion of 241 to the sulfonyl chloride completes in neat SOCl2 with a nearly quantitative yield. Treating the crude chloride with NH4OH and refluxing the obtained sulfonamide with Amberlyst in toluene for 4 hours afford the crude imine 242, which can be crystallized from ethanol as white crystals. Imine 242 is cleanly reduced to sulfonamide 243 with LiAlH4. While the direct N-acylation gives poor yield, the N-trimethylsilyl derivative, prepared by stirring a mixture of 243, TMSCl and triethylamine in benzene-MeCN, reacts with propenyl chloride and CuCl2 in refluxing benzene to provide 244 in 87% yield. H

O SO3H

H

1. SOCl2 NH4OH, 0 °C 2. Amberlyst 15 toluene, reflux 75%

N

S O

LiAlH4 THF reflux

TMSCl, Et3N, propenyl chloride CuCl2

H O

NH benzene, reflux S 87% O O

85%

O

242

241

H

S O

243

N O 244

Other applications of Oppolzer’s sultams include diastereoselective alkylation of (2phenyl-thiazol-4-yl)-acetic acid derivative , alkylation of 4,4-difluoro-3-enoic acid derivative , and asymmetric aldol reaction in the synthesis of (-)tetrahydrolipstatin . 5.5.3.4 Pharmaceutically Interesting Isothiazoles Several biologically active isothiazoles and their saturated and/or oxygenated analogs were reported in 2008. Benzisothiazole has been incorporated into SHP-2 (SH2 domain-

HN N

O

N S

OCH3 O

S O 245

NH O

N S

R

246

OH O

O S

N

R = 4-Et2N-phenyl, N 4-biphenyl, NH 2-naphthyl 247


287

containing tyrosine phosphatase) inhibitor 245 , isothiazole into HIV-1 integrase inhibitor 246 , and sultam into CDK (cyclin-dependent kinase) inhibitors 247 . 5.5.4

THIADIAZOLES AND SELENODIAZOLES

5.5.4.1

Syntheses of Thiadiazoles and Selenodiazoles

An efficient one-pot procedure provides easy access to 3-substituted-5-amino-1,2,4thiadiazoles . Amidine 248 reacts with isothiocyanate 249 in the presence of Hünig’s base in DMF at room temperature for 12 h followed by the addition of DIAD (diisopropyl azodicarboxylate) provides amino-thiadiazole 250 in good to excellent yields. This procedure works well for a broad range of isothiocyanates and amidines with a high compatibility for various functional groups, proving to be a potentially widely applicable methodology. R2NCS 249 Hunig base

NH R1

NH2 HCl 248

NH 1

R

S 2

N H

NHR

N S DIAD 42-97% R1 N

NHR2

250

Ph

R1 = Ph, 2-Py, 4-Py, c-Pr, t-Bu, 1-adamantyl R2 = Ph, substituted Ph, 2-naphthyl, cyclohexyl, BocNH(CH2)6

Microwave-enhanced reaction with expeditious and eco-friendly advantages has been applied for the synthesis of a number of 1,3,4-thiadiazole derivatives. 3-Substituted-6-phenyl1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles 252 are easily prepared by the microwave-assisted reactions of 4-amino-5-merecapto-triazoles 251 with benzoyl chloride without catalyst and under solvent-free condition . (1,3,4-Thiazol-2-yl)hydrazones 255 are efficiently synthesized by the reaction of benzaldehyde thiocarbohydrazone 253 with aromatic acids 254 using silica-supported dichlorophosphate as a recoverable dehydrant under microwave irradiation . Rapid access to 1,3,4-thiadiazoles 258 can be achieved by a onepot solvent free microwave-assisted synthesis through condensation of acid hydrazide 256 and triethyl orthoalkanates 257 using phosphorus pentasulfide in alumina as an efficient thioating agent . N N R

N

SH

NH2 251

PhCOCl μW

N N R

67-89%

N N 252

S

R = Me, Et, Pr, Ph, substituted Ph, PhCH2

Ph

SiO2

CHO S

NHNH2 NHNH2 1

1

R

O Cl P O Cl

R

253

CO2H NHNH2 254 R2 N S N μW 8 min H R1 81-90%

R1 = H, 4-OMe; R2 = H, 2-Me, 3-Me, 4-OMe, 3-Cl, 4-Cl

N N N 255

N H

S R2


288 NHNH2 2

O + R C(OEt)3 1

R

256

P4S10 / Al2O3 120 0C, μW

R1

R1 = H, F, OMe, 2-furyl, 2-thienyl, 4-pyridyl; R2 = H, Et, Ph

N N

65-72%

257

R2

S

258

N-Phenyl thioamide 259 condenses easily with N-phenyl hydrazonoyl chloride 260 to give dihydro-1,3,4-thiadiazole 262 when boiling in ethanol in the presence of triethylamine . NC

CN

NC

CN R

Ph PhHN

R

NNHPh Cl 260

NC

S

NHPh

-PhNH2 65-79%

Ph

NC NC

261

259

S

NC

N NHPh

NC

R

S

N Ph

N

Ph

262

N R = Ph, 4-Cl-Ph, S

O

The Hurd-Mori and Lalezari cyclizations of α-methylene ketones are by far the most widely used routes to 1,2,3-thiadiazole and 1,2,3-selenodiazole, respectively. Novel 1,2,3and 1,2,4-thiadiazolylnitrones, 268 and 275, have been prepared as potential neuronprotective agents . Formation of the 1,2,3-thiadiazole ester 266 takes place with a HurdMori cylcization of acylhydrazone 265, prepared from condensation of ethyl acetoacetate 263 with methyl carbazate 264. A reduction/oxidation sequence transforms ester 266 into aldehyde 267, which combines with N-substituted hydroxylamine in the presence of NaHCO3 to give the desired nitrones 268. 1,2,4-Thiadiazolenitrones 275 are derived from aldehyde 274 in a similar manner. Synthesis of 274 involves a key intermediate nitrile sulfide 271, generated in situ through thermolysis of the 1,3,4-oxathiazol-2-one 270. Treatment of the intermediate 271 with ethyl cyanoformate 272 yields ester 273 via a 1,3-dipolar cycloaddition process, and subsequent reduction / oxidation leads to aldehyde 274. O 264

O O MeO

N

NHNH2 25%

OEt

NH-CO2Me O SOCl2 N N S OEt

265

263 O SCl

RCONH2 269

O R

O R

275

N S

CN 272

N

65-92% R

R'NHOH NaHCO3 48-81% O

271

CHO R'NHOH

H

R

S N 274

CO2Et 1. NaBH4 2. MnO2 27-44%

CHO

N N S 267

EtO

140 - 160 °C S decalin N 270

N R'

N N S

18%

266 O

O Cl

1. NaBH4 CO2Et 2. MnO2

N R

S N 273

R = Ph, 4-Cl-Ph, 4-OMe-Ph, 3,5-di-t-Bu-4-OH-Ph; R' = t-Bu, cyclohexyl, benzyl

N R'

N N S

H 268


289

A solid phase approach of the Hurd-Mori reaction is established in the synthesis of 1,2,3thiadiazole derivatives 279 . The acylhydrazine resin 276 reacts with excess ketone 277 in the presence of acetic acid to give the resin-bound acylhydrazones 278. After Hurd-Mori type cleavage using thionyl chloride, various 1,2,3-thiadiazoles 279 are obtained with good yields. The released acylchloride resin 280 is reusable by transforming to the acylhydrazine resin 276 either by direct reaction with hydrazine hydrate or through a methyl ester after treatment with methanol. H2NHN O

R1COCH2R2 277 HOAc,EtOH

R1

O R

276

O

85-94%

R2

278

N N

SOCl2 CH2Cl2

NHN

R1 279

O S

R2

+

Cl R 280

= Merrifield resin R=

1

R = Me, Et, Pr, Ph, substituted Ph R2 = H, CH3, PhCO, CO2Et; R1, R2 = -(CH2)4 -

O

Application of Lalezari reactions is highlighted in the synthesis of a novel 1,2,3selenodiazole containing heterocycle system 284 . Naphthopyran 281 reacts with semicarbazide 282 to give semicarbazone 283, and oxidative cyclization of 283 with selenium dioxide affords selenodiazole 284.

O

O

NH2 282

O

N H

R2

N O

R1 R

281 R = H, Br ; R1 = H, Br ; R2 = H, CH3

5.5.4.2

SeO2

R2 O

87-92%

94-97% R1

N Se N

NH2

NHNH2 R2

O

R1 R 283

R

284

Reactions of Thiadiazoles and Selenodiazoles

1,2,3-Selenodiazoles are versatile intermediates for the preparation of alkynes. A novel method for the synthesis of highly substituted pyrrole derivatives 292/293 utilizes 1,2,3selenodiazoles 288 as precursors of 1,3-enynes 289, and their subsequent reactivity toward diaryl nitrones 290 . Reaction of semicarbazone 286 with selenium dioxide yields both selenodiazole 288 and 1,3-enyne 289. Selenodiazole 288 results from oxidation of the initial Lalezari cyclization product 287 with excess selenium dioxide, and enyne 289 is generated following the thermal decomposition of 288. The dipolar addition of nitrone 290 with enyne 289 proceeds in a [3 + 4] fashion creating an unstable seven membered intermediate 291 which undergoes a rearrangement to give pyrrole diastereomers 292 and 293. The dipolar addition of diarylnitrone 290 with selenodiazole 288 also leads to diastereomers 292 and 293 in a similar ratio to that obtained from cycloaddition with enyne 289, indicating that elimination of nitrogen and selenium would have occurred in selenodiazole 288 prior to the cycloaddition.


290

O NC O

NHNH2

CO2Et

Ar1

O

Ar2

NH2 282

MeCO2Na

285

N N H Ar2

Ar1

NC

Ar2

N Se N

CO2Et

H N Ar3 O 290

SeO2

Se Ar2

NC

CO2Et

287 Ph

Ar1

O

O N

Ph

Ar1

N H

Ar3

Ar2

Ar3 Ar2

CO2Et Ar2 NC 291

Ar1 CO2Et NC 289 (23-28% yield)

N

Ar1

CO2Et 286

Ph

NC Ar1 288 (31-36% yield) +

N

NH2

Y

X 292 (X = CO2Et, Y = CN): 28-46% 293 (X = CN, Y = CO2Et): 24-38%

Ar1 = Ph, 4-Cl-Ph Ar2 = Ph, 4-Cl-Ph, 4-OMe-Ph Ar3 = 4-Cl-Ph, 4-OMe-Ph

Imidazo[2,1-b][1,3,4]thiadiazoles have attracted increased attention during recent years because of their interesting biological properties. A Groebke–Blackburn type MCR (multicomponent reaction) using TMSCl as a promoter renders imidazob-thiadiazole 297 in fair to good yields . The optimized protocol involves heating amine 294 and aldehyde 295 in MeCN for 2h, and mixing the resulting imine with an equimolar amount of TMSCl in dichloromethane for 30 minutes followed by treating with a solution of isocyanide 296 (1 equiv) in MeCN at 70 °C overnight. 2-Amino-imidazo-thiadiazoles 302 can be easily prepared via chemoselective replacement of the 2-Br substituent of dibromide 301 with primary and secondary amines (or hydrazine) .

R1 N

N N

N

S

NHR3

1. R2CHO 295 2. TMSCl (1 equiv)

R1 N

N

3

S

3. R NC 296 56-92%

NH2

294

N N

R2 N

297

R1 = allyl, PhCH2, 2-PyCH2, substituted PhCH2, substituted acetyl, 4-F-PhCO, t-BuNHCO, MeOCH2CH2NHCO, (pyrrolidin-1-yl)-COCH2 R2 = Ph, substituted Ph; R3 = cyclopentyl, t-butyl

Condensation of amino-thiadiazole 298 with α-bromoacetophenone 299 in boiling nbutanol forms imino-thiadiazole which undergoes a spontaneous ring closure and the HBr elimination to give 2-bromo-imidazo-thiadiazole 300. The nucleophilic substitution of dibromide 301, obtained from bromination of 300, is highly chemoselective: even excess amount of amines do not provoke an attack on C-5. Br

Br

Br

2

S S H2N

N O + N Ph

298 1

N N

n-BuOH Br

Br2 80%

N

N

58%

299 2

Ph 300 1

S

2

N N

Br 1 NHR1R2 R

5 Br

N 2 60-85% R

Ph 301

R = H, CH3; R = CH3, NH2; R , R = -(CH2)5-, -(CH2)2-O-(CH2)2-

N N S 302

Ph N


291

A concise synthesis of trifluoroacetyl-thiadiazole 306 features a Regel-Büchel acylation employing trifluoroacetic anhydride and triethylamine . The acylation involves an initial N-acylation followed by an intramolecular rearrangement via the bipolar ylide 305. COCF3 N N CF3CO2 S Ph

CF3

S

Ph

OCOCF3

O

N N

toluene

303

COCF3 N N

Et3N

acyl transfer 56%

S

Ph

304

CF3

N N S

Ph

O

306

305

1,2-Diamino-4,5-phthalodinitrile 310 has emerged as a convenient starting material inter alia for functionalized phthalocyanines and porphyrazines. A new and reliable synthesis is based on the reductive desulfurisation of 5,6-dicyano-benzothiadiazole 309 . Diamine 307 is converted to benzothiadiazole 308 upon treatment with thionyl chloride in refluxing dichloromethane. The Rosenmund von Braun reaction with copper(I) cyanide converts dibromide 308 to dicyano-benzothiadiazole 309, which undergoes desulfurisation to give 310 upon exposure to an excess of sodium borohydride. Br

NH2

SOCl2, Br Et3N

N

Br

NH2

66%

N

S

Br

307

5.5.4.3

CuCN DMF

NC

N

66%

NC

N

NaBH4 NC EtOH

S

308

NH2 NH2

NC

53%

309

310

Pharmaceutically Interesting Thiadiazoles

There has been growing interest in the search for biologically active thiadiazoles and their saturated and/or oxygenated analogs in recent years. 1,2,4-Thiadiazoles have been incorporated into dual agonist of PPARα/β (peroxisome proliferators-activated receptors α and β) 311 , DPP-IV (dipeptidyl peptidase IV) inhibitor 312 and inhibitor of fatty acid amide hydrolase 313 , 1,2,5-thiadiazolidin-1-oxide into CXCR2/CXCR1 (CXC-chemokine receptors 2 and 1) antagonists 314 , 1,2,5-thiadiazolidin-1,1-dioxide into oxazolidinone antibacterial agent 315 , 1,2,3-thiadiazoles into CRAC (Ca2+ release-activated Ca2+) channel inhibitors 316 and HIV-1 NNRT (non-nucleoside reverse transcriptase) inhibitor 317 . Imidazo-thiadiazoles 318 have been identified as a novel class of COX-2 (cyclooxygenase-2) inhibitor . N S

O

Cl

CO2H

N

S 311 N

O S

N H

312

O Ph

N

R

2

R

OH 2

i

314a R = Et, R = Pr 314b R1 = iBu, R2 = H

N S

N

1

1

S N

Cl

O

O

N

N

S N

NH N

O N

O

O O S N HN

N

N

O NHAc

N

F 315

O

313 NHPh


292

R1 F3C

N N N

NH

R

O

S

Cl S

N S N

NH

NO2

O

R2

N N

317

SO2CH3 N

S

Cl

316a R = Me 316b R = CN

5.5.5

N

318a R1 = H, R2 = CF3 318b R1 =OCH3, R2 = SO2NH2

1,3-SELENAZOLES, 1,3-SELENADOLIDINES AND 1,3-TELLURAZOLES

2-Aminoselenazoles have been prepared via a solid-state reaction under the modified Hantzsch condition . A mixture of α-bromo-ketone 319, selenourea 320 and CuPy2Cl2 as a Lewis acid catalyst is ground with a pestle and mortar to afford 2-aminoselenazole 321. O

O Br

R

O 319

H2N

O

CuPy2Cl2 (solvent free)

O + NH2

87-96%

O N NH2

R

320

321

Se

R = H, 8-Br, 8-Me, 6,8-di-Br, 6,8-di-Cl, 5,6-(-Ch=CH-CH=CH-)

5.5.7

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294 08JMC6150 08JOC177 08JOC578 08JOC1386 08JOC2323 08JOC6686 08JOC8206 08JOC8484 08JOMC2982 08OBC169 08OBC366 08OBC1994 08OL65 08OL617 08OL1115 08OL2175 08OL2191 08OL2223 08OL2821 08OL2909 08OL2951 08OL3363 08OL3595 08OL3765 08OL3907 08OL4021 08OL4621 08OL5147 08OPPI209 08OPRD442 08S699 08S948 08S1133 08S1179 08SCI1673

08SC3311 08SC3422 08SC4407 08SL999 08SL2379 08SL2465 08SL2483 08T4332 08T4880 08T5019 08T5629 08T6494 08T7741 08T8797 08T10388 08TL327

Y.-J. Wu and B.V. Yang W. Porcal, P. Hernandez, M. Gonzalez, A. Ferreira, C. Olea-Azar, H. Cerecetto, A. Castro, J. Med. Chem. 2008, 51, 6150. J. L’Helgoual’s, A. Seggio, F. Chevallier, M. Yonehara, E. Jeanneau, M. Uchiyama, F. Mongin, J. Org. Chem. 2008, 73, 177. H. Ding, Y. Zhang, M. Bian, W. Yao, C. Ma, J. Org. Chem. 2008, 73, 578. A. Basheer, Z. Rappoport, J. Org. Chem. 2008, 73, 1386. S. Saravanan, I.A. Azath, S. Muthusubramanian, J. Org. Chem. 2008, 73, 2323. M. Penso, D. Albanese, D. Landini, V. Lupi, A. Tagliabue, J. Org. Chem. 2008, 73, 6686. M. Del Solar, A.K. Ghosh, B. Zajc, J. Org. Chem. 2008, 73, 8206. J.L.G. Ruano, A. Fraile, M.R. Martin, G. Gonzalez, C. Fajardo, J. Org. Chem. 2008, 73, 8484. A. Wrona, J. Zakrzewski, L. Jerzykiewicz, K. Nakatani, , J. Orgnamet. Chem. 2008, 693, 2982. J. Roger, H. Doucet, Org. Biomol. Chem. 2008, 6, 169. P.P. Cheruku, A. Paptchikhine, M. Ali, J. Neudorfl, P.G. Anderson, Org. Biomol. Chem. 2008, 6, 366. J. Deeley, A. Bertram, G. Pattenden, Org. Biomol. Chem. 2008, 6, 1994. J. Esteban, A.M. Costa, I. Gmez, J. Vilarrasa, Org. Lett. 2008, 10, 65. A. Osorio-Lozada, H.F. Olivo, Org. Lett. 2008, 10, 617. V.B. Birman, X. Li, Org. Lett. 2008, 9, 1115. A. Drda, R.G. Soengas, M.I. Nieto, C. Jimenez, J. Rodriguez, Org. Lett. 2008, 10, 2175. R. Tello-Aburto, H.F. Olivo, Org. Lett. 2008, 10, 2191. M. Jimenez-Hopkins, P.R. Hanson, Org. Lett. 2008, 10, 2223. P.R. Skaanderup, T. Jsensen, Org. Lett. 2008, 10, 2821 T. Martin, C. Verrier, C. Hoarau, F. Marsais, Org. Lett. 2008, 10, 2909. A. Zhou, P.R. Hanson, Org. Lett. 2008, 10, 2951. M.S. Kabir, M.L. Van Linn, A. Monte, J.M. Cook, Org. Lett. 2008, 10, 3363. C.G. Nasveschuk, D. Ungermannova, X. Liu, A.J. Phillips, Org. Lett. 2008, 10, 3595. S. Liu, Y. Cui, F. Nan, , Org. Lett. 2008, 10, 3765. A.K. Ghosh, S. Kulkarni, Org. Lett. 2008, 10, 3907. Y. Yiong, Y. Liu, S. R. Byeon, H. Kim, H. Luesch, J. Hong, Org. Lett. 2008, 10, 4021. P. Garcia-Reynaga, M.S. VanNieuwenhze, Org. Lett. 2008, 10, 4621. K. Inamoto, C. Hasegawa, K. Hiroya, T. Doi, Org. Lett. 2008, 10, 5147. J.K. Laha, Org. Prep. Proced. Int. 2008, 40, 209. K. Oda, T. Hida, T. Sakata, M. Nagai, Y. Sugata, T. Masui, H. Nogusa, Org. Process Res. Dev. 2008, 12, 442. A.R. Katritzky, A.V. Vakulenko, J. Sivapackiam, B. Draghici, R. Damavarapu, Synthesis 2008, 699. P.V. Khodakovskiy, D.M. Volochnyuk, D.M. Panov, I.I. Pervak, E.V. Zarudnitskii, O.V. Shishkin, A.A. Yurchenko, A. Shivanyuk, A.A. Tolmachev, Synthesis 2008, 6, 948. V.M. Zakharova, C.M. Gonzalez Tanarro, M. Guetschow, L. Hennig, J. Sieler, B. Schulze, Synthesis 2008, 1133. C. Burmester, R. Faust, Synthesis 2008, 1179. D.J. Haydon, N.R. Stokes, R. Ure, G. Galbraith, J.M. Bennett, D.R. Brown, P.J. Baker, V.V. Barynin, D.W. Rice, S.E. Sedelnikova, J.R. Heal, J.M. Sheridan, S.T. Aiwale, P.K. Chauhan, A. Srivastava, A. Taneja, I. Collins, J. Errington, L.G. Czaplewski, Science 2008, 321, 1673. Y. Bai, G. Zhao, C. Li, S. Zhao, Z. Shi, Synth. Commun. 2008, 38, 3311. Z. Jakopin, M.S. Dolenc, Synth. Commun. 2008, 38, 3422. Z. Liu, Y. Mu, J. Lin, Y. Chen, Synth. Commun. 2008, 38, 4407. M. He, A.K. Ghosh, B. Zajc, Synlett 2008, 999. Q. Ren, L. Dai, H. Zhang, W. Tan, Z. Xu, T. Ye, Synlett 2008, 2379. H. Modrzejewska, K. Wojciechowski, Synlett 2008, 16, 2465 Y. Numajiri, T. Takahashi, M. Takagi, K. Shin-ya, T. Doi, Synlett 2008, 2483. T. Narumi, K. Tomita, E. Inokuchi, K. Kobayashi, S. Oishi, H. Ohno, N. Fujii, Tetrahedron 2008, 64, 4332. J.T. Feutrill, M.J. Lilly, J.M. White, M.A. Rizzacasa, Tetrahedron 2008, 64, 4880. T.M. Potewar, S.A. Ingale, K.V. Srinivasan, Tetrahedron 2008, 64, 5019. X. Cao, F. Liu, W. Lu, G. Chen, G.-A. Yu, S.H. Liu, Tetrahedron 2008, 64, 5629. H. Zhou, Q. Xu, P. Chen, Tetrahedron 2008, 64, 6494. N.K. Downer-Riley, Y.A. Jackson, Tetrahedron 2008, 64, 7741. J. He, S. Tang, J. Liu, Y. Su, X. Pan, X. She, Tetrahedron 2008, 64, 8797. L. Giran, S. Berenyi, A. Sipos, Tetrahedron 2008, 64, 10388. G. Kumaraswamy, B. Markondaiah, Tetrahedron Lett. 2008, 49, 327.

Five-Membered Ring Systems: With N and S (Se) Atoms 08TL1045 08TL2381 08TL2869 08TL3273 08TL3682 08TL3967 08TL4003 08TL4145 08TL4707 08TL5241 08TL6188 08TL6352 08TL7024

295

N.S. Nandurkar, M.J. Bhanushali, M.D. Bhor, B.M. Bhanage, Tetrahedron Lett. 2008, 49, 1045. J.S. Yadav, B.V.S. Reddy, Y.G. Rao, A.V. Narsaiah, Tetrahedron Lett. 2008, 49, 2381. Y.-J. Wu, Y. Zhang, Tetrahedron Lett. 2008, 49, 2869. V. Kikelj, P. Setzer, K. Julienne, J. Meslin, D. Deniaud, Tetrahedron Lett. 2008, 49, 3273. Q. Qiao, R. Dominique, R. Goodnow Jr, Tetrahedron Lett. 2008, 49, 3682. M. Spadafora, M. Mehiri, A. Burger, R. Benhida, Tetrahedron Lett. 2008, 49, 3967. C. Noonan, L. Baragwanath, S.J. Connon, Tetrahedron Lett. 2008, 49, 4003. C. Chou, P. Yu, B. Wang, Tetrahedron Lett. 2008, 49, 4145. R. Moumne, M. Larregola, Y. Boutadla, S. Lavielle, P. Karoyan, Tetrahedron Lett. 2008, 49, 4704. M. Krasavin, S. Tsirulnikov, M. Nikulnikov, V. Kysil, A. Ivachtchenko, Tetrahedron Lett. 2008, 49, 5241. M. Bakherad, H. Nasr-Isfahani, A. Keivanloo, G. Sang, Tetrahedron Lett. 2008, 49, 6188. J. V. Allen, A. P. Green, S. Hardy, N. M. Heron, A. T. L. Lee, E. J. Thomas, Tetrahedron Lett. 2008, 49, 6352. Y. Iwaki, M. Kaneko, H. Akita, Tetrahedron Lett. 2008, 49, 7024.

296

Chapter 5.6 Five-Membered Ring Systems: With O & S (Se, Te) Atoms

R. Alan Aitken University of St. Andrews, UK (e-mail: [email protected])

5.6.1

1,3-DIOXOLES AND DIOXOLANES

New catalysts and conditions for the reaction of carbonyl compounds with ethanediol to give 2-substituted 1,3-dioxolanes include iodine in a polyethylene glycol-based ionic liquid , the aluminium-functionalised ethylene oxide/propylene oxide block copolymer Al-SBA-15 , indium triflate , the combination of microwave irradiation with a Dean and Stark trap , and the heteropolyphosphotungstic acid Cs2.2H0.8PW12O40 which is especially effective for ketalisation of isatin to give the spiro dioxolanes 1 . Conditions to convert the ketone function in isoricinoleic acid derivatives such as CH3(CH2)4C≡C(CH2)2CO(CH2)7CO2Me into the corresponding dioxolane (and similarly the 1,3-oxathiolane and 1,3-dithiolane) without affecting the triple bond have been described . The conversion of epoxides 2 into dioxolanes 3 by reaction with acetone can be efficiently catalysed by phosphomolybdic acid or MoO2Cl2 and this transformation has been extended to epoxides bound to both calixarenes and functionalised C60 . The reaction of terminal alkynes, RC≡CH, with ethanediol and a gold(I) catalyst to give dioxolanes 4 has been developed and the similar reaction of substituted catechols with alkynes, RC≡CR, to give benzodioxoles 5 is efficiently catalysed by Ru3(CO)12 . Reaction of propylene oxide with CO2 to give 4-methyl-1,3-dioxolan-2-one can be catalysed by polyethylene glycol-supported quaternary phosphonium salts . O

O

O

O

R

1

N H

R1

Me2CO R2

Me

Me

O

O

R1

2

R2

3

R

O

Me

O

4

O R1 O

R R

5

1 2 Reaction of diazo esters, R CH2C(N2)CO2R , with aromatic aldehydes is efficiently catalysed t by Rh2(Bu CO2)4 to give dioxolanes 6 as the main products with very little β-elimination product (R1CH=CHCO2R2) . The carbonyl ylides derived from 2-aryl-3,3dicyanooxiranes undergo 1,3-dipolar cycloaddition to the keto carbonyl function of α-keto esters and isatins to give dioxolanes 7 the relative stereochemistry of which has been


Five-Membered Ring Systems: With O & S (Se, Te) Atoms

297

determined by X-ray diffraction and rationalised computationally . The stepwise construction of triacyldioxolanes 8 has been described and interaction of a synthetic equivalent of CF3C≡C– with carbonyl compounds gives the (Z)-4trifluoroethylidene-1,3-dioxolanes 9 . An improved synthesis of the Na+,K+ATP-ase inhibitor ustalic acid 10 found in mushrooms has been described . Ph R1

O

Ar

O

CO2R2 Ar

O

CN CN R1

O

Ar

7

6

O

COR1

O

COR2

R1OC

R2

R1 R2 F3C

O

O R2

8

O

CO2H

O

CO2H

R1

Ph

9

10

New X-ray structures reported for dioxolanes include compound 1 (R = 5-Cl) which is a potential anti-convulsant , the camphor-derived sulfone 11 , the diamide 12 and the bis(imidazolidinethione) 13 . A detailed 13 C NMR study of 1,3-dioxolan-4-ones has appeared , and the synthesis and chiroptical properties of sugar-derived naphthylethylidene ketals such as 14 have been reported . SO2Ph

Me

O

Me O

11 O

Me Me

CO2But

NH2

Me

O

O

NH2

Me

O

O

Me

16

CO2R O N (Me)

CONMe2 COR

18 R1O R

CHO CF3

17

MeO

N

NMe

S

N

O Me AcO

O O

O

NMe

Me

NO2

15

O

13

Me

O

O

S

O

12

F3C

O

O

F

14

Me Me

Et

O

Et

O

O P O Me Me

S

19

Me

O

Me

O

Ph

O PPh2

20

The radical addition of dioxolane to tert-butyl trifluoromethacrylate to give 15 has been described , and asymmetric Michael addition of both 1,3-dioxolan-4-yl and -2-yl radicals has been investigated . A theoretical study on reactivity of CH2=C(NO)NMe2 includes its cycloaddition to 2-methylene-1,3-dioxolane . There have again been many developments in the use of chiral dioxolanes in asymmetric synthesis. Tartaric acid-derived keto amides 16 can be used to obtain chiral α-trifluoromethyl α-alkoxy aldehydes 17 and asymmetric aziridination of dioxolane-containing nitroalkenes to give products such as 18 has been reported . The origin of enantioselectivity in the TADDOL-catalysed hetero Diels-Alder reaction has been examined theoretically . The TADDOL-like phosphonite 19 is an excellent ligand in the rhodium-catalysed asymmetric hydrogenative coupling of aldehydes to methyl vinyl ketone . Hydrostannylation of TADDOL diacrylates occurs in an unexpected way to give eleven-membered ring products . Enantiomerically pure dioxolane

R.A. Aitken

298

phosphine oxides such as 20 have been prepared and the X-ray structure of 20 is reported . Bismuth triflate is effective in catalysing allylation of dioxolanes . Ring opening of the dioxolane 21 with ethylenediamine takes an unusual course to afford a 1,4-diazepine product . Oxidative cleavage of 2-aryldioxolanes 22 using dimethyldioxirane affords the hydroxyalkyl benzoates 23 and InCl3 in aqueous acetonitrile is effective in cleaving 2,2-dimethyl-1,3-dioxolanes to the corresponding diols without affecting other acid-labile groups . Me

Me

O O

HO

Me

O O

Ar

O O

Me Me

O

Me

21 Me

CHO Me

R

Ar

O HO

O

22 O

Me

F

O

O

Me

F

O

24

O O

F

O N

R O N H O

23

O

O

OH OCF3

25

S

27

26

A study of salt effects on the electronic properties of donor-acceptor complexes includes the complex of benzobis(dioxole) 24 with DDQ and a spectroscopic and theoretical study on copolymers of tetrafluoroethylene with 25 has appeared . The hydroxynaphthoquinone ketal 26 has been found to affect tubulin assembly and biocidal activity has been claimed for compounds such as 27 as well as related oxathiolanes and dithiolanes .

5.6.2

1,3-DITHIOLES AND DITHIOLANES

The reaction of carbonyl compounds with ethanedithiol to give 2-substituted 1,3-dithiolanes can be achieved using alumina-supported sulfuric acid or ferric hydrogen sulfate Fe(HSO4)3 . Direct conversion of ethylene carbonate into ethylene trithiocarbonate 28 using CS2 and catalytic lithium chloride in a one-pot process has been reported , the new diselenolane 29 is formed, as a mixture of diastereomers, by reacting divinyl selenide with SeBr2 and a multi-step route suitable for large scale synthesis of the 1,3-diselenole-2-selenone 30 has been patented . Br

S S S

28

Me

Se

Se Se

Se

29

Br

Me

Se

30

O S S O

S HX

S Pri

Me

31

32

Intramolecular Michael-type addition in chiral dithiolane disulfoxides 31 has been reported and the menthone-derived spiro dithiolane 32 has been converted into a disulfoxide and a sulfone-sulfoxide both of whose X-ray structures were determined . The monosulfoxide 33 of BEDT-TTF has been prepared by direct oxidation using a chiral oxaziridine and its X-ray structure and electrochemistry examined . Trapping of benzyne by a range of dithiolactones leads to spiro benzodithioles such as 34 and a Fischer carbene complex has been used in the


299

stereospecific synthesis of (E)-dithioles 35 . Reaction of the caesium salt of "dmit" 36 with Ph3SnCH2I unexpectedly leads to 1,2-dithiole-3-thione products . New X-ray structures of dithiolones and dithiolethiones reported include those of 37 and 38, the latter of which exhibits second harmonic generation , 39 and compound 40 containing fused five- and thirteeen-membered rings . A gold(I) complex of 41 has been described and silver complexes of both tetrakis(2-cyanoethylthio)TTF and 4,5-bis(methylthio)-1,3-dithiole-2thione have been reported . Treatment of 2-alkynyl-1,3-dithiolanes 42 with butyllithium followed by an aromatic aldehyde allows formation of enynes 43 in an overall process equivalent to Wittig reaction of the alkynyl ketone . S

O S

S S

S

Me S

S

S

33 S

X

X X

S

37 X = O 38 X = S

S

S

S

S

Ph

S

35

S

S– Cs+

S

S– Cs+

36 R1

R1

S

S

S

S

S S

34

S

S

R1

Me 2 Me R

S

S

S

Me

S S

39 X = Br 41 X = OH

Ar

S

S

R2 S

40

R2

42

43

Tetrathiafulvalene (TTF) has been used as a matrix for MALDI mass spectrometric analysis of pigments and the aromaticity of TTF cations has been studied computationally . Three new polymorphic forms of dibenzo-TTF have been identified . A detailed 1H, 13C and 77Se NMR study of tetraselenafulvalenes 44–46 has appeared . New TTF-based charge transfer salts reported include (BEDT-TTF)2+ cyanurate– , (TTF)2+ SbCl6– and (Me4TTF)+ BF4– , (47)2•Mn[N(CN)2]3 which is superconducting at 0.3 kbar , (48)2+ PF6– + – and (Me2TTF)2 X (X = Cl, Br, I) . A variety of silylated TTFs bearing SiMe2H, SiPh2H and SiMe2SiMe3 groups have been prepared and their X-ray structures and cyclic voltammetry described . R R

Se

Se

X

Se

Se

X

S S

44 R = H, X = O 45 R = Me, X = O 46 R = Me, X = S PrS

S

S

Se

Se

S

Se

Se

S

47

S

S

49

N H

S

O

S

S

O

S

AcN

NAc S

N

S

O

48 S

Me PrS

Me

Me

S

Me

S

S

NMe

S

51 Me

S

S

Me

S

S

N H O NH

S

50

O

N

NMe2

52

A benzimidazole-fused TTF 49 has been reported and new pyrrole-fused TTFs such as 50 are of interest for organic field effect transistors . The radical anion salts of pyrimidine-fused TTFs 51 and 52 have been evaluated as single component organic conductors .

R.A. Aitken

300

There has been considerable interest in TTF-containing ligands and their binding to metals. The X-ray structure and cyclic voltammetry behaviour of 53 have been described 2+ and binding of 54 to Pb has been examined . Tetrakis(pyridyl) and (pyrazinyl)TTFs 55 have been prepared and ethynylbipyridine-linked TTFs such as 56 have been prepared and their binding to ruthenium studied . The pyridine-containing vinylogous TTF derivative 57 has been reported to complex to ZnCl2 and the bipyridylmethylenedithiole unit 58 has been used to form complexes containing rhenium and another metal such as Au or Pt or a crown ether or anthracene unit . The extended TTF derivative 59 containing a crown ether has been examined as a redox-responsive ligand by electrochemistry in the presence of Na+ and Ba2+ and TTF derivative 60 has 2+ been evaluated as a receptor for electrochemical recognition of Cd . Me

S

S

Me

S

S

53 X

X

S

S

S

S

S

S

S

S

S

S

S

S

55 X = CH or N

X

S

Ph

S

MeS

S

X

S

S

S

57

S

56

S

S

N

S

S

O O

S

S

S

60

O

O

O

58 N H

S S

N MeO2C

H N

N Me

S

N

O

MeS

S

LnRe

N

N S

S

N

S

Ph

N N

54

Me S

N

S S

S N N

N

Ph2 P S Pt P S Ph2

N

S S

S

CO2Me CO2Me MeO2C

59

O

New TTF-type donors reported include dithiin-fused compounds such as 61 , the polyether-containing compound 62 whose X-ray structure has been determined and a range of extended compounds 63 . There have also been reports on TTF-containing porphyrins , phthalocyanins , "molecular clips" and bent-core liquid crystals , TTF-modified DNA and an unusual TTF dimerisation process within a TTF-containing rotaxane . A polymer with pendant TTFs and an acceptor main chain has been studied . Alkyne-containing extended TTFs such as 64 and 65 have been described and several studies on "molecular wires" have appeared . A ternary hybrid framework made up of EDT-TTF 66, 1,4bis(iodoethynyl)benzene and (Ph4P+)4 [Re6Se8CN6]4– has been described and dithioles are the active groups in a redox-responsive molecular rotor and a 2+ Hg -gated molecular switch . A "molecular arithmetic" function has been claimed for pyridylthiazolyl-TTF 67 and TTF-oxadiazole diads have been examined as photoconducting materials .


Ph

S

S

S

S

Ph

S

S

S

S

Ph

S

S

S

S

Ph

S

S

S

S

R1 R1

61

62

S S

S

S

S

S

63

S

R2

S

R2

CO2Me MeO2C

S

301

O

OMe

O

OMe

O O SR

RS S

S

CO2Me MeO2C

S

S S

Pri3Si

SiPri3

S S

S S

CO2Me

MeO2C

CO2Me

MeO2C

64 S

S

S

S

S

S

66

S

S

S

S

S

S

SR

RS N N

S

65

OMe

67

Highlights in supramolecular chemistry involving TTF derivatives include encapsulation of C60 by TTF-containing dendrimers and attachment of extended TTFs to C60 both covalently and by crown ether / cation interactions . A range of new donor–acceptor compounds have been developed involving TTF or extended TTF donors attached to perylene or quinones and 1,3-dithiole-based diads have also been examined electrochemically and for second-order non-linear optics . The conformational properties of synthetic cannabinoid ligand 68 that has analgesic properties have been evaluated using molecular mechanics .

5.6.3

1,3-OXATHIOLES AND OXATHIOLANES

Reaction of carbonyl compounds with 2-mercaptoethanol to give 2-substituted 1,3oxathiolanes proceeds efficiently using either an alumina-supported sulfuric acid catalyst or a sulfonic acid-containing ionic liquid under solvent-free conditions . Reaction of epoxides 69 with CS2, catalysed either by sodium hydride in methanol or hydrotalcite , gives the oxathiolanethiones 70, and an efficient synthesis of 2-imino-1,3-oxathiolanes has been described together with the X-ray structure of one example 71 . Syntheses of the 1,3-oxaselenolane 72 and 1,3thiaselenolane 73 from the corresponding epoxide(episulfide) have been described . Synthesis, conformational calculations and detailed 1H NMR studies have been

R.A. Aitken

302

13 reported for a range of simple 1,3-oxathiolane S-oxides and a C NMR study of 1,3-oxathiolan-5-ones has appeared . The oxathiolanone 74 has been used as a source of the -SCH2CO- fragment in the Biginelli reaction , similar multicomponent reactions and, in addition, to nitrostyrenes . A series of pyrrolidine-containing oxathiolane S-oxides 75 have been evaluated as muscarinic antagonists .

Me

R H

H Me Me

R

OH

O C6H13n

S

S

68

Ph

S

Me

O

O

N H Me

74

5.6.4

Se

S R1 R2 S O

H O

Me

O

S

70

75

Me

72 X = O 73 X = S

71 O R

Me

X

N

S

69 O

O

O O OH Me

R

Me

76

77

1,2-DIOXOLANES

Asymmetric conversion of α,β-unsaturated ketones 76 into the "peroxyhemiketals" 77 is achieved in good e.e. using H2O2 and a cinchona-alkaloid derived chiral ammonium salt and further examples of dioxolanes with promising anti-malarial activity have been reported including the hybrid chloroquine structure 78 .

5.6.5

1,2-DITHIOLES AND DITHIOLANES

A synthesis of 3-methyl-1,2-dithiolane from 1,3-dibromobutane under phase-transfer conditions has been described and the synthesis, structure and spectra of 5amino-4-cyano-1,2-dithiole-3-thione 79 have been reported . The X-ray structure of 80, formed by nitration of a di-t-butyl naphthodithiole, has been reported , and a theoretical study of the Se–Se NMR coupling in systems such as 81 H N

O O

NC

82

S

78 S S

N Me

S S

Me

83

Se Se But

O2N

O S S

S S

S

NH

84

Cl Et

H2N

S

79

S

Te Te

O

85

NO2 NO2

R

80

81

S

S R

S

S

86 R = Me 87 R = SBu

S

O Pr2HC

O

88 has appeared . A theoretical study of electron structure in cyclic disulfides includes treatment of 82 . Dithiolanes 83 and 84 have been identified in


303

the anal gland secretion of the long-tailed weasel . The spirobicyclic 1,2ditellurolane 85 adds oxidatively to Pt(0) complexes giving new mono- and di-nuclear Pt(II) complexes . Solvatochromic effects are reported for Cr(CO)5 complexes of dithiolethiones such as 86 and 87 and compound 88 is reported to be active as a histone deacetylase inhibitor .

5.6.6

1,2-OXATHIOLES AND OXATHIOLANES

A detailed study on the reactivity of 4-amino-1,2-oxathiole S,S-dioxides 89 has appeared . R1 CH2Ph

H2N

O

O S O2

R2

S S

Me

S

R1 R2

Me

Me R1

90 S

O R2

S S

Me

94

93

5.6.7

Me O

O

89 R1 R2

O O

O R3 O HO

91

NH O

O

Me NH2

Me

O S

O

Me O

92 S

Me

S S

95

THREE HETEROATOMS

The conversion of the 1,2,3-trioxolane to the 1,2,4-trioxolane has been observed spectroscopically for the first time in a kinetic study of the ozonolysis of tetramethylethylene . A theoretical estimation of the energy barriers in 1,3-dipolar cycloaddition of ozone to ethene and ethyne has appeared . A series of cyclic ozonides 90 have been prepared and evaluated as potential herbicides and a major metabolite from the anti-malarial 1,2,4-trixolane OZ277 has been identified as the hydroxylation product 91 . Ring-opening polymerisation of the 1,3,2dioxathiolan-4-one S-oxide 92 leads to poly(hydroxyisobutyrate) . A new simple procedure for conversion of ketones, R1R2CO, into 1,2,4-trithiolanes 93 involves bubbling an excess of H2S through a chloroform solution in the presence of iodine . A range of biaryl-fused 1,2,3-trithioles have been prepared and their atropisomerism studied and 1,2,3-trithiole-fused phthalocyanins and their nickel complexes have been reported . Fragmentation of 1,2,4-trithiolanes under flash vacuum pyrolysis conditions leads mainly to formation of a thione and a dithiirane which may then rearrange . The 1,2,3-trithiolane 94 has been identified as a poorly volatile organic component of garlic while the dimethyl-1,2,4-trithiolane 95 has been identified in onions .

5.6.8

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08CPC2406 08CPL(453)136 08CPL(458)276 08EJI4728

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08T3287 08T3751 08T5285 08T5873 08T7902 08T8449

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308

Chapter 5.7

Five-Membered Ring Systems with O & N Atoms

Stefano Cicchi, Franca M. Cordero, Donatella Giomi Università degli Studi di Firenze, Italy [email protected]

5.7.1

ISOXAZOLES

The uncatalyzed, thermal 1,3-dipolar cycloadditions (1,3-DC) of alkynes and nitrile oxides are rarely used in isoxazole synthesis due to several shortcomings (poor regioselectivity, low yields, side products formation) related to the relatively high reactivity of nitrile oxides and the general inertness of alkynes. On the other hand, 3,4-di- and 3,4,5-trisubstituted isoxazoles 1 and 2a,b were obtained with excellent regioselectivity at room temperature by a ruthenium(II)-catalyzed 1,3-DC of nitrile oxides, generated in situ from hydroximoyl chlorides, and terminal and internal alkynes, respectively. Coordination to the ruthenium atom effectively changes the polarity of the 1,3-dipole, determining a different regioselectivity with respect to thermal and Cu(I)-catalyzed processes . R1

O

R2

R1 = Ar, styryl, Et, CH2CH2Ph R2 = Ar, HO-C6H10, CH2NR2, CH2CH2CN, CMe2OAr

Ph

R2

R1 N

a)

O

R1

Cl N

R3

OH

a)

R1

HO Ph

a): [Cp*RuCl(cod)] 5 mol%, NEt3, 1,2-dichloroethane, rt, 10 h

R2 = Me3Si, alkyl, Ar, Het, CH2OTHP R3 = Ar, Het

R1

O Cl

+

R2

N

O

OH Ph

O

2b 83-99% R3

a)

O

2a 68-71%

1 67-93%

O

R3

N

a)

R3 = Me, OMe

R1 = Ar, Het, styryl, t-Bu, cyclopropyl

Ph

Cl N

R1 R2

O R3

R1

OH

b)

a): PdCl2(PPh3)2 2 mol%, CuI 4 mol%, NEt3, THF, rt, 1h b): NEt3, MW, 90 °C , 30 min

N

O

R2

3 12-78%

A three-component synthesis of 3,4,5-trisubstituted isoxazoles with a flexible substitution c 2009 Elsevier Limited. All rights reserved.


309

pattern has been reported. The consecutive Sonogashira coupling of acid chlorides with terminal alkynes followed by microwave-assisted 1,3-DC of in situ generated nitrile oxides gave isoxazoles 3 in moderate to good yields . A facile one-pot regioselective synthesis of 3,5-disubstituted isoxazoles was achieved through a sequence of reactions involving bromination of electron-deficient alkenes to 1,1-disubstituted bromoalkenes, 1,3DC with in situ generated nitrile oxides, and loss of HBr from the intermediate bromo isoxazolines . Solid-phase organic synthesis was exploited to prepare a heterocyclic nucleoside analogue library of uracils, N-1 or N-3 tethered to isoxazoles (or isoxazolines) 4a and 4b, through 1,3DC of nitrile oxides with resin-bound N1/N3-propargyl (or allyl) 5,6-dihydrouracils . 1,3-DC of pyrimidinyl nitrile oxides and alkynes afforded 4-(isoxazol-3yl)pyrimidines 5 while novel isoxazole-linked steroidal glycoconjugates 6 were obtained from a novel in situ generated steroidal nitrile oxide and appropriate propargyl ethers of sugars . R3 O N R1

N

N O

R2 O O

R3

N R2

N O 4a

OSugar

3

R

R N

N R1

O

N O 1

N

N O

O

NHR2

4b

5

AcO 6

The iodocyclization of O-methyloximes of 2-alkyn-1-ones led to 4-iodoisoxazoles 7, converted into 3,4,5-trisubstituted isoxazoles 8 via Pd-catalyzed reactions. The Pd-catalyzed processes were adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries affording a diverse 51-member library of compounds 8 . N

R1 = Ar

OMe

R1

R2 = Ar, alkyl

N

ICl CH2Cl2

R1

R2

N

OH O

R2 cat. Pd reagent

I 7

POCl3 NHAr CH2Cl2, rt

R

O

N R

R = Me, Ph

N

O

X = Ar, CONR2, R3,

1

R X Ar 8 8-83% (87-100% purity)

OH POCl 2 O NHAr CH2CH2Cl

R2

N O HOPOCl2

NHAr

R

CH2CH2Cl 9 75-93%

In the presence of POCl3/CH2Cl2, fully substituted isoxazoles 9 were obtained from cyclopropyl oximes via ring-opening and intramolecular nucleophilic vinylic substitution . R2

O

R1

R2

O RF

R2

O 10

NH2OH MeOH, rt

R1 R2

R1 = H, Me, Cl, NO2 R2 = H, Me

O

R2

O RF

OH N OH

O N

R1 R2

RF = CF3, CF2H, (CF2)2H

O

OH RF

11 40-72%

S. Cicchi et al.

310

Reaction of 3-(polyfluoroacyl)chromones 10 with hydroxylamine proceeded via nucleophilic 1,4-addition and opening of the pyrone ring followed by cyclization to 4(polyfluoroalkyl)-4H-chromeno[3,4-d]isoxazol-4-ols 11 . 2-Nitrosobenzonitrile reacted efficiently with tri- and tetrasubstituted alkenes via tandem nitroso-ene/intramolecular cyclization to give 1-substituted benzo[c]isoxazol-3(1H)-imines, such as 12, in very good yields . N

O N

N

OH

N O

N

THF, rt

NH

81% 12

A multicomponent synthesis of polyfunctionalized cyclopropanes from commercially available materials, 3,5-dimethyl-4-nitroisoxazole 13, an aromatic aldehyde 14, and a suitable chloroketone like 15, involved a sequential Knoevenagel-Michael-cyclization process in the presence of an amine catalyst to give in high combined yields 16, as 1:1 diastereomeric mixtures resolved by column chromatography . 3-Methyl-4-nitro-5styrylisoxazoles, obtained from reaction of 13 and 14, were also exploited for the synthesis of isoxazolyl aziridines and for N,O-heteroatom interchange on the isoxazole core through reaction with hydroxylamine . NO2

NO2 N

O +

O

Ar

13

O

piperidine CO2Et

+ 14

15

N

EtOH

CO2Et

O

Ar 16 59-92%

Cl

COMe

The Rh2(OAc)4-catalyzed reactions of various isoxazoles with methyl phenyldiazoacetate 17 gave 2H-1,3-oxazines 19 through a ring expansion probably involving ylide intermediates 18 . Operating with the rhodium carbenoid derived from vinyldiazomethanes 20, the one-pot synthesis of highly functionalized 1,4-dihydropyridines 21 and pyridines 22 was performed via isoxazole ring expansion followed by a rearrangement/tautomerization/oxidation sequence. A wide variety of substituents are compatible with these processes . CO2Me N2 Ph

+ CO2Me

N O R1

Rh2(OAc)2 R3

17

-N2

1

3

R

R1

N2 R3

R1 R2 20

N + R4

O

R5 Rh (OAc) 2 2 toluene R4 60 °C, -N2

O

R3 N

O

19 67-96% R1

R4

N H

R1

O R2

R5 R5 toluene reflux

R3 R2

R2

R2

O

R1

R 18

CO2Me

N

N O

CH2Cl2, reflux

R2

Ph

Ph

R3 rt 21

R2

DDQ R5 R4

N

R3

22 31-84%


311

A two-step protocol involving 1) the N-methylation of isoxazoles and 2) the smooth oxidation of the resulting isoxazolium salts 23 with NaOCl, followed by hydrolysis, provided an effective entry to α-hydroxy β-diketones 24. Application of this strategy to polycyclic substrates, such as the enantiomerically enriched isoxazole (R)-25 (98% ee), allowed a stereoselective approach to angular cis-diols, like 27, preserving the enantiomeric purity. These conditions proved to be applicable to more complex polycyclic isoxazolium salts with good yields and cis-diastereoselectivities related to the attack of the oxidant from the convex face of the polycyclic systems . Moreover, operating with BF3.OEt2 and different O, S, and C-nucleophiles, the isoxazole-assisted SN1 substitution of the hydroxy group in α-ketols of type 25 allowed a facile introduction of angular substituents in polycyclic structures .

R1

BF4N O

Me3O+BF4-

N O

R3 CH Cl rt R1 2 2,

R2 R1, R3 = Me, Ph, t-Bu OBn N

XR3

R2 23 76-97%

O

OBn N

N O O

aq NaOCl MeCN 0 °C, 10 min

BF4O

a)

R1

O

H2O R3

R3 HO

R2 R2 = H, Me, Ph, CO2Et

OBn O

O

R1 R2

24 62-84%

O OH

O S

b), c)

O N

π

S OH O (R)−25 (98% ee)

O 26

OH

OH O 27 71% (98% ee)

28

Ph

a): Me3O+BF4-, MS 4 Å, CH2Cl2, rt; b): aq NaOCl, MeCN/H2O, pH 8.7, 0 °C, 10 min; c): 0.5 M HCl

A new family of isoxazolopyridobicyclooxacalix[4]arenes of potential interest for hostguest interactions was synthesized from phloroglucinol and 4,6-dichloro-3methylisoxazolo[4,5-c]pyridines . An efficient synthetic method toward enantiomerically pure (isoxazole-isoxazoline) hybrid ligands based on an unsymmetrical spiro[4.5]decane backbone has been reported . A series of benzo[d]isoxazol-3-ol derivatives were synthesized and evaluated as D-amino acid oxidase inhibitors . The Knoevenagel reaction of ω-dithiafulvenylpolyenals and isoxazolones led to merocyanines 28 that are strongly polarized and show good second-order nonlinear optical responses . 5.7.2 ISOXAZOLINES Nitrile oxides generated in situ by oxidation of aldoximes with iodosobenzene in neutral water undergo inter- and intramolecular 1,3-DC with alkenes to afford 2-isoxazolines in good yields. For example, the glycal-aldoxime 29 was converted into the optically pure tricyclic isoxazoline 30 in 64% yield by treatment with PhIO in a cetyltrimethylammonium bromide (CTAB) micellar system . O

O

NOH

AllO

PhIO, CTAB AllO H2O, rt, 3 h

AllO

29

O

AllO

O 30 64%

N

O

S. Cicchi et al.

312

3-Substituted-4-hydroxyisoxazoline N-oxides were used as synthetic equivalents of nitrile oxides in the synthesis of 2-isoxazolines. Cyclic nitronates such as 31 react with electron– deficient alkenes to give bicyclic isoxazolidines 32 that undergo fragmentation to 33 and hydroxyacetaldehyde under acidic conditions . O

O

O N

O N

R2 R1 +

R2 BF3·OEt2 (0.1 equiv)

neat, rt CHCl3, rt (10 equiv) 2-4 d R1 1h HO 31 OH 32 1 2 quant; dr = 69:23:8 a: R = Me; R = CN b: R1 = CO2Et; R2 = CO2Me 96%; dr = 74:19:7

F3B

O N

HO

R1

R1 33

O

H

R2

CHO

R2

O O N

88% 94%

A catalytic cascade synthesis of 2-isoxazoline N-oxides was developed through prolinecatalyzed nitroalkene activation. For example, nitroalkene 34 reacts with an excess of vinyl ester 35 in the presence of a catalytic amount of proline and one equivalent of NaOAc to afford adduct 36 in 65-88% yield. In all the examined cases, a complete transdiastereoselectivity was observed, whereas enantioselectivity was negligible. A mechanism that rationalizes the formation of 36 was proposed .

OAc

NO2 + R

2 Ph 1 equiv 34 NO2 Ar

2 equiv mol 35

+

H N N

O

N O Ph

DMSO, rt, 10 h Ph

HO H

CO2R 37

proline (20%) NaOAc (1 equiv mol)

Br

Cs2CO3 H2O (traces) THF 0 °C

36 O

R N O

RO2C

39 38 CO2Et R = Me, Ar = 2-MeOC6H4 (54%); 4-FC6H4 (77%) R = Bn, Ar = Ph (65%); 4-MeOC6H4 (75%); 4-MeC6H4 (77%); 2-furyl (67%)

R = H (88%) Me (76%) Et (71%) Bn (65%)

CO2Et

Ar dr > 99 :1 ee ≥ 99%

Optically pure 2-isoxazoline N-oxides were prepared by conjugate addition of enantiopure ylides to nitroolefins followed by cyclization. In particular, the reaction of the ammonium salt 38 derived from cinchonidine with 3-aryl- and 3-heteroaryl-2-nitro acrylates 37 in the presence of Cs2CO3 afforded isoxazoline N-oxides 39 with up to 99% ee and trans/cis diastereomeric ratio higher than 99%. The diastereomeric cinchonine-derived salt afforded ent-39 with the same selectivity . Isoxazoline ent-39 (R = Me, Ar = Ph) was employed in the formal synthesis of the natural bicyclic amide dehydroclausenamide . The scope and limit of the synthesis of 2-isoxazolines by condensation of primary nitro compounds with alkenes catalyzed by a copper/base system was thoroughly investigated. In particular a catalytic amount of N-methylpiperidine and copper or Cu(OAc)2 was shown to promote the smooth formation of variously substituted isoxazolines avoiding the use of stoichiometric polluting reagents . Several 5-arylmethylisoxazolines such as 40 were prepared in good yields by palladiumcatalyzed cascade reactions of aryl bromides with β,γ-unsaturated oximes. The 2-isoxazolines were then converted into β-hydroxy ketones by treatment with iron and ammonium chloride.


313

The reported reducing conditions are well tolerated by several functional groups including the C=C double bond. For example, the conjugated 3-vinyl 2-isoxazoline 40 was selectively converted into the unsaturated β-hydroxy ketone 41 in good yield . The enantioselective synthesis of 3,5-disubstituted 2-isoxazolines by cyclization of β,γunsaturated oximes in the presence of an enantiopure palladium complex and the kinetic resolution of racemic 2-isoxazolines by enantioselective reduction of the C=N double bond mediated by chiral oxazaborolidines have been investigated . Ar Br Pd2(dba)3 (1 mol%) Xantphos (1 mol%) NaOt-Bu, toluene 105 °C Ph

NOH Ph Ar = 3,4-Cl2C6H3

O R

N

+

H

N

O Ar

40 78%

N

O

OH Ar

Ph

EtOH, H2O 80 °C

PhNH2Me (PhO)2PO2 (20 mol%)

OH

O

Fe NH4Cl

41 86%

O

R

+

42 55-86%

toluene, 0 °C, 6-15.5 h

R = Me, n-Pr, Ph(CH2)2, BnOCH2, c-Hex, PMBO(CH2)2, TBDPSO(CH2)4, MeO2C

(CH2)3

3-Unsubstituted 2-isoxazolines 42 were prepared by reaction of aliphatic α,β-unsaturated aldehydes with oximes in the presence of catalytic amounts of an anilinium salt. The process is believed to occur through an initial iminium-catalyzed conjugate addition of oxime to the unsaturated aldehyde followed by hydrolysis of the formed O-alkyloxime and cyclization . Novel nucleoside analogues containing the isoxazolidine ring system have been recently described . R2

TfO

R1 O

N t-Bu 43

n-BuLi THF −78 °C

+ R

t-Bu N O

R2

Br

44

R1

R2 Zn AcOH rt

R

R1

t-Bu NH H O

R 45

R1

Δ

R2

R2

R1

O

O

R

R

46

The 1,3-DC of several α,β-unsaturated nitrones 43 and arynes generated in situ from 2bromoaryl triflates 44 was studied. The N-tert-butyl benzoisoxazolines 45 were then converted into polysubstituted 4a,8a-dihydro-2H-chromenes 46 through an efficient N–O bond reduction-elimination–electrocyclization sequence . A study on photoreactivity of some 5-alkylidene- and 5-alkylideneamine-2,5dihydroisoxazoles has been reported . 5.7.3 ISOXAZOLIDINES New syntheses and applications of isoxazolidine derivatives have been recently described. Holmes reported a total synthesis of the spirocyclic piperidine alkaloid histrionicotoxin 285A (51) based upon the nitrone dipolar cycloreversion/cycloaddition approach and elaboration of the isoxazolidine adduct. In particular, isoxazolidine 47 was subjected to a microwave (MW) thermally induced 1,3-dipolar cycloreversion to generate the enantiopure nitrone 48 which

S. Cicchi et al.

314

spontaneously underwent intramolecular cycloaddition to the tricyclic isoxazolidine 49. Suitable side-chain structural modification afforded 50 which was converted into 51 by selective reduction of the isoxazolidine N–O bond with SmI2 . CN TBDPSO

TBDPSO

MW 184 °C

N O 47 Ph

CN

N O 48 •

TBDPSO

CN

N

• SmI2

11 steps N

16%

O

78%

85%

50

49

N H

THF

O

51 HO

Just as in the case of isoxazoles and isoxazolines, the isoxazolidine ring has been used in the synthesis of new modified nucleosides. Commonly, two different synthetic approaches were followed i.e. the condensation of 5-acetoxyisoxazolidines with silylated nucleobases (Vorbrüggen nucleosidation) and the direct cycloaddition of nitrones with vinyl and allyl nucleobases . Mutarotation studies on enantiopure 5-hydroxy isoxazolidinyl-3-phosphonates have been reported . Isoxazolidine-modified monolayer protected gold nanoparticle 53 were prepared efficiently via interfacial 1,3-DC of maleimide-modified nanoparticles 52 with nitrones. The reaction proceeds within 10–60 min under high pressure conditions whereas it is very slow at atmospheric pressure .

Au

S S

( )9 ( )9

O N

R'

O N

R

S

Au

(15 equiv)

S

( )9 ( )9

O N

11000 atm, 10−60 min, CH2Cl2

52 O R = Ph; R' = Ph, 4-O2NC6H4, 4-MeOC6H4 R = Me; R' = Ph, 1,3-benzodioxol-5-yl

Ar F3C

Me N O

H2 (1 atm) Pd/C

53 O R = 4-MeC6H4; R' = 1H-indol-3-yl, 3-furyl R = 4-MeOC6H4; R' = H, R = Bn; R' = Ph

Me

Me NH

Ar

OH

− HF

EtOH, rt, 1 h F F F3C X 54 F X F X = H, F; Ar = 4-MeC6H4, 4-MeOC6H4, 2-thienyl

NH O

Ar F3C

− HF

F

R'

Ar NMe F3C

X

O N R

O 55 62-97% X

Cycloadducts of nitrones with hexafluoro- and 1,1,3,3,3-pentafluoro-1-propene smoothly undergo ring contraction to β-lactams when subjected to hydrogenolysis of the N-O bond. The primary reduction product spontaneously eliminates HF to provide an acyl fluoride which cyclises affording the fluorinated β-lactam 55. Starting from cyclic nitrones, the process gave bicyclic azetidinones. The major drawback of the approach was the formation in many cases of inseparable diastereomeric mixtures of isoxazolidines 54 and lactams 55 . 3,3-Difluoro-5-[(4-methylphenyl)sulfonyl]-tetrahydro-4-pyridinols 58 were prepared by the two-step sequence 1,3-DC – thermal rearrangement (Brandi-Guarna reaction) starting


315

from the fluorinated methylenecyclopropane 56 and acyclic nitrones. At 50 °C, the 1,3-DC afforded the difluoro-substituted 5-spirocyclopropane isoxazolidines 57 with high selectivity and good yields (55-95%) when petroleum ether was used as solvent. By heating at 100 °C, the mixture of nitrone and 56 was directly converted into 58 with high yields (69-82%) and complete regioselectivity . Ar Ts Me

Ts

56

Ts

Ar

Ar

F

O

petroleum ether 100 °C, 8 h

F F

N

O

F N Me O F

F

N Me O F

57

N Ar Me 58 69-82%

Ts = 4-MeC6H4-SO2; Ar = Ph (70%), 4-O2NC6H4 (79%), 4-MeOC6H4 (82%), 4-BrC6H4 (75%), 4-ClC6H4 (69%), PhCH=CH (70%) BnO

BnO

OBn

OBn

H OBn

H

N O 60

125 C xylenes 12 h 95%

N OBn O

BnO

OBn

SmI2 THF 75%

59

H N OBn H HO 61

Ts

F

Ar N Me

F

OH

F

Ts

Pd(OAc)2 (10 mol%) O2 (5 Atm)

BnO

OBn H

Py (2 equiv) OBn N toluene, 80 °C

O 60/62 (1:1)

95%

The thermal rearrangement of adducts of cyclic nitrones and bicyclopropylidene such as 59 afforded 3-spirocyclopropane-4-tetrahydropyridones like 60 in good yield. In addition, the isoxazolidine N–O bond could be selectively reduced by SmI2 to give a bicyclopropyl 1,3amino alcohol which underwent a Pd(II)-catalyzed cascade rearrangement to 3spirocyclopropanedihydro- and tetrahydropyrid-4-one. For example, 61 afforded a 1:1 mixture of 60 and 62 in 95% yield. A mechanism was proposed to rationalize the formation of the two different products . A study of the cycloaddition of nitrones to strained cyclopropenes and the subsequent transformation of the isoxazolidine cycloadducts was reported . Selectivity aspects of some Lewis acid catalyzed nitrone cycloadditions have been examined. In 1,3-DC of nitrones with α,β-unsaturated aldehydes catalyzed by chiral bistitanium complexes, regio- and stereoselectivity were significantly enhanced by the presence of a sterically bulky group such as diphenylmethyl on the nitrone nitrogen. The results are consistent with a kinetic destabilization of the Lewis-acid-nitrone complex by steric repulsion . Chiral Cu(II)- and Mn(II)- or Mg(II)-bis-oxazolines efficiently catalyze the cycloaddition of nitrones with α'-phosphoric enones and alkenoyl oxazolidinones, respectively . 4-Methylene-substituted isoxazolidines were prepared by catalyzed 1,3-DC of a D-glyceraldehyde-derived nitrone with methoxyallenes. The diastereofacial selectivity of the cycloaddition could be controlled by the nature of the Lewis acid. Finally, the adducts were converted into α-methylene-β-amino acid esters by redox ringopening of the isoxazolidine ring . Ns Ph

+

Ns N O

5 Å MS Ph 63 23 °C Ns = 4-O2NC6H4-SO2 H

O N

TiCl4 (10 mol%) Ph

H O N

PhSH, K2CO3 Ph

95% dr >10:1

MeCN/DMF − 25 °C

Ph

Ph 78%

S. Cicchi et al.

316

N-Nosyl isoxazolidines were prepared by Lewis acid catalyzed cycloaddition of N-nosyl nitrones generated in situ from N-nosyl oxaziridines such as 63. The nosyl group could be removed by treatment with thiophenol and carbonate without affecting the isoxazolidine ring. In contrast, sodium napthalenide caused the selective cleavage of the N-O bond without cleavage of the nosyl moiety . The reaction of optically active oxaziridines with aryl ethenes afforded enantiopure isoxazolidines with a 70-75% diastereoselectivity . N

TBSO

R1 BF2 CO2Et N

CO2Et BF3·OEt2 (2.2. equiv) O

(CH2Cl)2, 60 °C

64

O NH

R2 R1

CO2Et R2

Oxime-olefin cycloaddition could be a useful approach to N-unsubstituted isoxazolidines but often requires high temperature conditions because of thermodynamically unfavourable oxime-nitrone tautomerization. By treatment with BF3·OEt2, O-tert-butyldimethylsilyloximes such as 64 give N-boranonitrones which undergo inter- and intramolecular cycloaddition with alkenes under mild conditions. Stereochemical and mechanistic aspects of this methodology have been recently investigated by Tamura and co-workers . Nitrones were generated in situ from nitrosobenzenes and styrenes and directly trapped with electron-deficient alkenes to afford 5-substituted isoxazolidines such as 65 with high regioselectivity and good yield . N Ph

O +

+ Ph

O

EWG MeCN, MS 4 Å 0 °C-rt, 7 h

N O +

O O

Ph N O 65

O

N

O +

EWG EWG = CHO (86%), CO2Me (78%), CONMe2 (82%), COEt (74%),CN (65%), 2-oxo-1,3-oxazolidine-3-carbonyl (81%) O

O

PKR

O

toluene O O O rt, 2 h rac-66 (2 equiv) 67 (1 equiv) 68 (1 equiv)

H O 69 64% O

+ O

O O

N O

O

H O O 70 68%

Levoglucosenone (67) and isolevoglucosenone (68) were used as quasienantiomers in an effective parallel kinetic resolution (PKR) of racemic nitrone 66 . The stereoselectivity was complete as demonstrated by the exclusive formation of the two cycloadducts 69 and 70. The separated isoxazolidines 69 and 70 were used in the synthesis of imino-C-disaccarides. Some theoretical studies of 1,3-DC reactions have been reported including the cycloaddition of cyclic nitrones with unsaturated lactones and vinyl ethers , the effect of Lewis acid coordination in the cycloaddition of nitrones with cinnamonitrile , and the site selectivity in successive 1,3-DCs of meso-porphyrin with N-methylnitrone and azomethine ylide . R N O

MeO2C

1) Yb(OTf)3 (5 mol%) 2) RCHO

MeO2C 73

H

MeO2C H2N

O 71

R CO2Me

1) RCHO

MeO2C

2) Yb(OTf)3 (5 mol%)

MeO2C

N O

72

H

The intramolecular reaction of oxime ethers and cyclopropane diesters under Yb(OTf)3


317

catalysis affords hexahydropyrrolo[1,2-b]isoxazoles 72 with high diastereoselectivity. Both aliphatic and aromatic aldehydes can be used in the formation of oxime from hydroxylamine 71. Altering the order of aldehyde and catalyst addition leads to the selective formation of diastereoisomers 73 . The methodology was applied to the total synthesis of the alkaloid (–)-allosecurinine . 5.7.4 OXAZOLES Most of the effort has been devoted to the synthesis of natural compounds possessing one, or more, oxazole rings as well as structural analogues. New total syntheses of (−)-inthomycin , (+)-phorboxazole , (−)ulapualide A , siphonazole , neopeltide ariakemicin A , and YM-216391, a cyclopeptide containing oxazole rings , were described. O N

MeO

O

O

O

O

HO

(−)-inthomycin B

O

NH2

N O

O

O

neopeltide

HO

H2N MeO

MeO

O

O H N

N

MeO OH

O ariakemicin A

O

siphonazole

O

H N

O

N

O

N

NH

O

O

NH

At the same time also some structural analogues were synthesized as, for example, a derivative of westiellamide in which the oxazoline rings are substituited by oxazole rings or analogues of biologically active cyclopeptides containing oxazoles . A new procedure for assembling an oxazole ring uses the catalysis of Pd(II)complexes to induce the cyclization of propargylamides 74 to 5-oxazole carbaldehydes 75 in moderate yields . O R

PdCl2(MeCN)2 N H

benzoquinone R = alkyl, aryl

74 O

TfOH

N OH 76

-H2O

R

O N

CHO 75 37-61 % O

TfO-

N H 77 TfO

O

C 6H6

N Ph

78 98 %

The tricyclic oxazole derivative 76 can act as a superelectrophile, thus when treated with trifluoromethanesulfonic acid compound 76 formed the dication 77 which reacted with

S. Cicchi et al.

318

aromatic compounds, including benzene itself, used as solvent, affording compound 78 . Some examples of derivatization of oxazoles were described. A very efficient and wide in scope arylation and heteroarylation reaction of ethyl oxazole-4-carboxylate 79 was optimized using Pd-complexes. The reaction was applied to a large number of substrates affording good yields of the oxazole ester derivatives 80 which were finally decarboxylated to oxazoles 81 . Starting from 5-substituted oxazoles, a ligandless microwave-assisted Pd/Cu-catalyzed arylation of oxazoles was also accomplished . The use of PdCl(dppb)(C3H5) as catalyst allowed the arylation on C-2 of several oxazoles and benzoxazoles in good yields .

EtO2C

1) Ar2X 2) Ar5X

N O 79

catalyst

EtO2C

N

-CO2

O

Ar5

N

LiOH

Ar2

Ar2 Ar5

O 81

80 29-98 %

Ph

catalyst: 5% Pd(OAc)2, 10% P(o-tol)3 Pd2(dba)3 (5 mol%) Ph PCy3 (10 mol%) N K2CO3, DMF

Ph O I

N O

B

O

O Ph

N

O Pd2(dba)3, (5 mol%)

O

PCy3 (10 mol %) K2CO3, DMF

150 °C

150 °C N

O

I I 82

83

N

Ph

84 46%

Bu3Sn

O Ph

N O

O N

N

Ph 85

Ph 86 60%

Aryl triflates were found to be useful reagents for the palladium catalyzed direct arylation of benzoxazoles, the best conditions being the use of Pd(OAc)2, PPh3 and DMF as solvent . Dihalo oxazoles were used in a regioselective palladium cross-coupling with the aim of obtaining a trisoxazole. The first step is a regioselective Suzuki-Miyaura cross coupling of the 2,4-dihalooxazole 83 followed by a Stille coupling to afford trisoxazoles 86 . 5.7.5 OXAZOLINES Interest in the discovery and application of effective asymmetric catalysts is still very high in both academic and industrial settings and the understanding of the relationship between catalyst structure and enantioselectivity is very important to design new catalysts. Linear free energy relationships have been constructed by quantitatively correlating steric parameters, associated to the ligand-substituent size, and enantiomeric ratio for enantioselective carbonyl allylation reactions using modular oxazoline ligands . A review summarizing some approaches to realize complete reversal of enantioselectivity using a single chiral source by changing reaction conditions has been reported .


a), (S)-88 R

X

O

a), (S)-87

ROTf

X

R

ROTf

63-100% 10-89% ee (S)

R1 = i-Pr, t-Bu, Ph

N PPh2

X

46-100% 60-95% ee (R)

X = O, NCO2Me

319

R1

(S)-87 O

R2 = i-Pr, t-Bu

R = Ar, cyclohexenyl N PPh2

a): Pd(dba)2 (3 mol%), L* (6 mol%), i-Pr2NEt, THF or C6H6 or toluene, 60 or 80 °C

R2

(S)-88

A series of benzylic substituted P,N-ligands 87 and 88 have been synthesized; their Pdcomplexes showed high catalytic activity and enantioselectivity in the asymmetric intermolecular Heck reaction of 2,3-dihydrofuran and N-carbomethoxy-2,3-dihydropyrrole with various triflates. A dramatic switch in enantioselectivity is realized using ligands with and without substituents at the benzylic position. Ligands 87 without substituents gave products in (R)-configuration while ligands 88 with methyl substituents resulted in (S)configuration products. In most cases high enantioselectivities were achieved. Density functional theory calculations on the reaction mechanism and X-ray analysis of some Pdcomplexes provided a rational explanation for the observed results . Novel chiral cyclopropane-based PHOX ligands 89 were synthesized. The introduction of a strained cycle reduced conformational fluctuations of the metallacycle allowing excellent enantioselectivities in the Pd-catalyzed asymmetric intermolecular Heck reaction, as well as enantiodivergency resulting from subtle modifications to the ligand structure . R1

Ph (S) (S)

t-Bu2P

O N

89

R1

R2

R1 R1

R2 NO P N R2

R1

O N t-Bu 90

O O P O O

O

N O R1

R2 91

O

O

R

R2 R3

N N S R O 92

R2

A new class of bis(N-arylamino)phosphine-oxazolines 90 was prepared from chiral 1,2diamines and exploited for efficient iridium-catalyzed asymmetric hydrogenations of olefins . Pyranoside phosphite-oxazolines 91 found efficient application in the same reaction and also in the synthesis of a series of stabilized palladium nanoparticles that were applied in allylic alkylation and Heck reactions . A library of phosphite-oxazoline ligands in which the phosphite and oxazoline moieties are connected by a chiral alkyl backbone chain was synthesized and screened in Pd-catalyzed allylic substitution reactions . Chiral spiro iridium/phosphine-oxazoline complexes Ir-SIPHOX were applied in asymmetric hydrogenation of α,β-unsaturated carboxylic acids to produce α-substituted enantiopure carboxylic acids with exceptionally high enantioselectivity (up to 99.4% ee) and reactivity . Planar chiral ruthenocene-based phosphine-oxazoline ligands were easily synthesized and applied in the transfer hydrogenation of ketones . The development and application of optically active ferrocenyloxazolinylphosphines (FOXAPs) to catalytic asymmetric reactions has been reviewed . Aryl-bridged C1-symmetric oxazolinyl sulfoximines 92, with (S)-configuration at sulfur, were prepared in 65-78% overall

S. Cicchi et al.

320

yields and applied in Cu-catalyzed asymmetric Mukaiyama aldol reactions of various enol silyl ethers with methyl pyruvate to give α-hydroxy esters with up to 94% ee in 21-98% yields . Chiral ditopic Pybox ligands with amine or phosphine oxide functions at the 4-position of the oxazoline rings were conveniently prepared from a common Pybox precursor . Starting from D-glucosamine, a new carbohydrate-based pyridyl bis(oxazoline) 93, was applied in Cu(I)-catalyzed alkynylation of imines with enantioselectivities up to 99% . New 3-O-modified carbohydrate bis(oxazolines) (glucoBox) have been prepared.

O O AcO AcO

O

N N

OAc

N AcO

93 glucoPybox

R3 R3

O OAc OAc

O

R1 R1 B O N

R2

H

N R2

94-H boraBox

O

R3 R3

N

Li/H

B O

N N O

95 Li/H[ToM]

Chiral anionic boron-bridged bis(oxazolines) (boraBox) ligands, with alkyl or aryl substituents at the oxazoline rings and the boron atom, have been synthesized from 2oxazolines and haloboranes, characterized in their protonated form 94-H, as well as Pd and Cu complexes, and applied in copper-catalyzed allylic oxidation reactions . The same procedure allowed the synthesis of the first oxazoline-based scorpionate ligand 95, tris(4,4-dimethyl-2-oxazolinyl)phenylborate [ToM]- with Li+ or H+ as counterion , while the exploitation of the C3 chirality of tris(oxazolinyl)ethanes (trisox) in asymmetric catalysis has been reviewed . Asymmetric Friedel–Crafts alkylations of indoles with activated alkenes have been performed with up to 99% ee in the presence of a Sc(III)-Pybox complex and Cu(II)-complexes of Box and azaBox ligands, through careful tuning of the ligand/metal ratio . Anyway, the considerable drawbacks associated with the use of chiral bis(oxazolines)metal complexes (requirement of relatively large quantity of catalyst, high cost, and a low turnover number) determined many efforts towards the development of heterogeneous systems by anchoring homogeneous catalysts onto stationary supports such as organic crosslinked polymers or inorganic materials. For instance, aza-bis(oxazoline) was easily immobilized on siliceous mesocellular foam offering good enantioselectivity and excellent recyclability and the use of Pt-catalyzed hydrosilylation chemistry of silicones simplified the preparation of Box ligands covalently bound to an insoluble poly(dimethylsiloxane) matrix, applied in different copper-catalyzed asymmetric reactions with high levels of enantioselectivity (91-99% ee) . Surface effects are probably responsible for enhanced stereoselectivity in Mukaiyama aldol reactions catalyzed by a claysupported bis(oxazoline)-copper complex . Self-supported copper coordination polymers based on a new kind of ditopic chiral ligand bearing two azabis(oxazoline) moieties combined the advantages of homogeneous and heterogeneous enantioselective catalysis: in cyclopropanation reactions, the polymer became soluble in the reaction conditions but precipitated after reaction completion, allowing easy recovery and efficient reuse up to 14 times . Moreover, a chiral C2-symmetric Box-Cu(II) complex, immobilized in hydrophobic ionic liquids such as [Bmim]PF6 and [Bmim]SbF6, was successfully used in asymmetric hetero Diels–Alder reactions: a remarkable acceleration was observed in


321

[Bmim]PF6 and the complex was recovered and recycled up to eight times with almost the same reactivity and selectivity . A bis-oxazoline was activated towards a highly selective aerobic oxygenation by metal complexation with Zn(ClO)4.6H2O. The oxidation allowed the self-assembly of a highly ordered metallamacrocycle, a cyclic Zn4O4 tetramer, which displayed catalytic phosphatase activity . 2-Aryl trans-4,5-diphenyloxazolines 96 promoted dearomatizing stereoselective nucleophilic addition to simple benzenoid rings without metal complexation, provided N,N'dimethylpropyleneurea (DMPU) was used to activate the organolithium nucleophile. Upon lithiation and quenching with MeI, cyclohexadienes 97 were isolated as single stereo- and regioisomers. Their conversion into highly functionalized cyclohexene and cyclohexanone derivatives allowed the synthesis of carbocyclic sugar analogues 98 in six to eight steps . Ph

Ph

O

N

Ph 1. RLi, THF DMPU (6 equiv) -78 °C

O

96

HO

X

R = i-Pr, s-Bu, t-Bu X = H, 4-Ph, 3-OMe, 4-OMe

HO

N R

2. MeI

X

Ph

R = i-Pr X = 4-OMe

HO

OH OH

98 33-43% overall

97 17-81%

The condensation of fluorinated (and non-fluorinated) nitriles with enolates generated from 2-alkyl oxazolines 99 afforded β-enamino acid derivatives 100 transformed into uracil derivatives 101 by treatment with triphosgene followed by oxazoline ring-opening with nucleophiles . R2

R2 1. LDA,THF, -78 °C

N O 99

NH2

N

2. RFCN, -78 °C to rt

R1 3. aq NH Cl 4

R1 = H, Me R2 = H, Ph

O

RF

R2

1. (Cl3CO)2O, Et3N, THF, rt

Cl

O N

NH

2. aq HCl O

RF R1 101 83-91%

R1

100 60-93%

2-Bromo-4-substituted oxazolines 102 underwent an unprecedented thermal rearrangement to the corresponding 2-bromoisocyanates 103, isolated in good yields and suitable for further synthetic transformations . A simple and efficient procedure for the synthesis of β-seleno and β-thio amides 105 via the ring-opening of chiral 2-oxazolines 104 in the presence of indium metal has been developed . Moreover, a reduction of 2-substituted oxazolines 106 to alcohols 107 was performed in a two-step, one-pot procedure, using methyl chloroformate and lithium borohydride . Δ

O Br N 102

R1 R2

1 R2YYR2 R

R1

Br R1

OCN

N

R1 = H, Me R2 = Me, i-Pr, Ph

In0/RX

Ph dioxane, Δ

R2 103 85-90%

O

104

HN

O YR2 Ph

O 105 40-98%

R1 = i-Pr, i-Bu, Ph, Bn Y = Se, S

R N 106

a), b) OH R THF or toluene 107 54-96%

R = Alkyl, Ar, Het a): ClCO2Me, 65-100 °C b): LiBH4/MeOH, 0°C-rt

S. Cicchi et al.

322

2'-Arylspiro[cyclopropane-1,4'-oxazoline]carboxylates 110 were conveniently synthesized by Michael addition of carboxamides 109 under basic conditions to methyl 2-chloro-2cyclopropylideneacetate 108 with subsequent ring closure. The corresponding free carboxylic acids 111 were obtained by hydrolysis and exploited in different coupling reactions . Treatment of alkenes with NBS, a nitrile, NaHCO3 and water in the presence of Cu(OTf)2 or Zn(OTf)2 furnished oxazolines 112 in one-pot and good yields . A one-step synthesis of 4-fluoro-3-oxazolines 113 has been performed via a three-component reaction involving diarylmethanimines, trifluoroacetophenones, and CF2Br2 . Fluorinated 2-phenyl-2-oxazolines 116 were synthesized from fluorinated acid chlorides 114 and chloroethylamine hydrochloride through amides 115 by elimination of HCl. Oxazolines 116 were subjected to microwave-assisted polymerization towards compounds 117 in nitromethane at 140 °C, with methyl tosylate as initiator . O

Cl

+ CO2Me Ar 108

NH2

X

R3CN, H2O (1.2 equiv), rt

Cl

H3N

114

F2-5

H N

O

Cl

COCl

R2

R1 O

HO2C

89-93%

110

N

R2

O

R3

NH

N

113

115

40-90%

F2-5

THF, rt 43-86%

CF3 Ar3

OH n

N ArF 116

F

O

KOH or KOt-Bu

CH2Cl2, NEt3, 0 °C

N O

112 51-72%

Cl

111

Ar1 Ar2

R1

R3

Ar

O

2. AcOH, rt

MeO2C

51-81%

109

N

Ar 1. aq NaOH

O

0 °C to rt

M(OTf)2 (0.05 equiv), NBS (1.2 equiv), 2 R NaHCO3 (1.2 equiv),

R1

N

NaH, MeCN

F2-5

O 117

5.7.6 OXAZOLIDINES The oxazolidine ring always attracts the attention of groups interested in providing new methods for its synthesis. N-Tosyloxycarbamates 118 in the presence of an inorganic base and rhodium(II) dimer complex catalyst 119, form metal nitrenes which undergo C-H insertion reactions. This procedure allows the amination of ethereal, benzylic, tertiary, secondary and even primary C-H bonds. In its intramolecular version this reaction can afford substituted oxazolidinones 120 . O

R2 R1

H N

O 118

O

[Rh2(tpa)4] 119 OTs

K2CO3, CH2Cl2, 25 °C 9 examples, 41- 92 %

HN R2

O

R1 120

N-Sulfonyl oxaziridines are susceptible to electrophilic activation using a copper(II)catalyst and, under these conditions, react with olefins and dienes. These latter substrates show a high selectivity towards monoaminohydroxylation as exemplified by the reaction of cyclopentadiene 121 with 2-benzenesulfonyl-3-phenyl oxaziridine 122 .

Five-Membered Ring Systems with O & N Atoms Cu(TFA)2 5% HMPA 10%

O N

+

O2S Ph Ph 122

121

323 SO2Ph

N

CH2Cl2, rt

123

84%

Ph

O

Unactivated 1-aryl or 1-alkylaziridine-2-carboxamides 124 were reduced and protected to afford 2-(Boc-aminomethyl)aziridines 125. These substrates underwent a stereo- and regioselective BF3.Et2O catalyzed ring expansion to afford phenylaminomethyl substituted oxazolidin-2-one 126 . 1) LiAlH4 2) Boc2O

Ph N

124 CONH2

Ph N

125 O

O

BF3·Et2O NH

Ot-Bu

THF, reflux

Ph N

HN 126

BF3

O

O 45%

NHPh

BF3 NPh

NH Ot-Bu

O

H N

t-Bu O

H

N-Alkyl-2-arylaziridines were converted into 5-aryl oxazolidin-2-ones by treatment with quaternary ammonium bromide functionalized polyethylene glycol PEG6000(NBu3Br)2 in substoichiometric ratio (25 mol%) under a CO atmosphere. The reaction proceeded with high yield and selectivity under organic solvent free conditions . The enzyme halohydrin dehalogenase catalyzed the enantioselective ring opening of terminal epoxides 127 in the presence of cyanate as nucleophile, affording enantioenriched 5substituted oxazolidin-2-ones 128 with good yield and selectivity. Although limited in scope, only a small number of similar substrates were efficiently transformed; this was the first example of a biocatalytic conversion of epoxides into oxazolidinones .

O 1

R R2

127

O

haloydrin dehalogenase O NaOCN, buffer

1

NH

yield 44-47% ee 80-98%

R 128 R2 R1 = H, Me; R2 = Me, Cl, Br

An enzyme (hydroxynitrile liase) was also used in the synthesis of new ferrocenyloxazolidin-2-ones that found application as chiral auxiliaries . The known transformation of triazolines 130, obtained by 1,3-DC reactions of electron deficient olefins 129, into oxazolidine diones 131, is accelerated by Brønsted acids. A detailed study of the mechanism was reported evidencing the role of triflic acid in the cycloaddition step and that of water in the final transformation .

S. Cicchi et al.

324

O

129

O N Bn

TfOH BnN3

OMe

O

Ph

N Bn

N N N 130

CH3CN -20 to 25°C

HN

O OMe

Bn O

NBn O 131 O 92%

Oxazolidine and oxazolidinone derivatives have found wide application as chiral auxiliaries. Quite novel results were obtained with fluorinated oxazolidines. Fluorinated oxazolidines (Fox) were used as chiral auxiliaries for the stereoselective alkylation of amide enolates. A striking difference of selectivity was found between the use of trans-Fox 132 and cis-Fox 133, the latter affording a much lower stereoselectivity. O

O

CF3 1) NaHMDS, THF N

85 %

Ph

O

N O Bn Ph 134 dr > 99 : 1

2) BnBr

O

CF3

132

O

CF3 1) NaHMDS, THF N

O

N O Bn Ph 135 dr 69 : 31

2) BnBr 85 %

Ph

CF3

133

This difference was rationalized, also through a theoretical study, by the synergy of the interactions of the sodium cation (derived from the base NaHDMS) with the aromatic ring and with the fluorine atoms of the side-chain. These two interactions rigidify the reactant geometry . Some other examples of use of the oxazolidine ring as chiral lingand or chiral auxiliary were published The 2,3-oxazolidinone protected thioglycoside 136 was used as a glycosyl donor in a glycosylation procedure that overcomes the known difficulties of selectivity and yield often associated with this reaction. Most interestingly, it is possible, through a preactivation protocol and the use of a hindered base, to obtain selectively the β or α anomer of the corresponding glycoside 137a,b . OAc O

AcO O O

OAc 1) preactivation protocol + TTBP AcO OR 2) ROH O

N Ac 137a

83-98% 11 examples

O

OAc O STol

N Ac 136

1) preactivation protocol AcO 2) ROH O

O

N OR O 137bAc

81-90% 11 examples

Preactivation protocol: 1) benzenesulfinyl morpholine, Tf2O, CH2Cl2, -73 C TTBP: 2,4,6-tri-(tert-butyl)pyrimidine

Sometimes it is difficult to translate reactions performed in solution onto solid phase, however the alkylation of a polymer-supported Evans oxazolidinone was optimized introducing the use of a cleavable linker and carefully tuning the reaction conditions . O N

O

1) KHMDS, Et2O 8 min, -78 °C 2) E-X, 10 min, -78°C

O N

8 examples, ee 73-96 % 138

O

139

O E O


325

Enantioenriched substituted valines 139 were obtained from the valine derived oxazolidine-5-one 138. The ‘memory of chirality’, due to the high rotation barrier of tertiary amides, allowed the alkylation of 138 with several electrophiles giving products with an enantiomeric excess ranging from 73 to 96% . Enantiopure oxazolidin-5-ones have been also employed in a double stereodifferentiation aldol addition with N-(tertbutylsulfinyl)imines CO2Et

O

Ph

N

[Rh(COD)Cl]2/KI 5%

140

O

H2 (5 atm), CO (5 atm) toluene, 180 °C

O N

O Ph

O

N Ph 141 97 %

N-(Ethoxycarbonylmethyl)oxazolidines 140 underwent a reductive ring expansion, under the catalysis of a rhodium complex, to afford N-methylmorpholin-2-ones 141. The reaction proceeded under an atmosphere of carbon monoxide and hydrogen. The proposed mechanism suggests the intermediacy of an iminium ion . A very simple procedure for the decarboxylative isomerization of 5-unsubstituted N-acyl2-oxazolidinones 142 to 2-oxazolines 143 was developed. The starting N-acyl-2oxazolidinones were ring-opened by lithium iodide and decarboxylated in the presence of a mild proton source, NH4Cl. Finally in the presence of an amine base, DBU, 2-oxazolines were obtained. This procedure avoids the use of high temperatures or the use of metal catalysts . O O

1) LiI, NH4Cl 2) DBU, CH2Cl2, rt

O N

142

R

Bn

45-82 % R = aryl, alkyl

R O

N

143

Bn

N-Acyloxazolidinone derivatives can undergo a samarium diiodide mediated coupling with electron-deficient alkenes. This reaction has been applied to the synthesis of peptidyl ketones 145 starting from N-peptidyl oxazolidin-2-ones 144 . O TrtHN FmocHN 144 O

O H N

O

O N

Bn

X

O SmI2 (6 equiv.) H2O (8equiv.) THF, -78 °C

TrtHN

H N

O

FmocHN X 145 O Bn X = ester, amide, nitrile 47-85%

The same reagent was used to transform N-acyl oxazolidin-2-ones into the corresponding esters, by removal of the oxazolidinone group, in a wide-scope and efficient reaction which allowed also the recovery of the oxazolidinone . Finally the natural product (−)quinocarcin, containing an oxazolidine ring, was synthesized .

S. Cicchi et al.

326

CO2H H NMe

N OMe

O

)-quinocarcin

5.7.7 OXADIAZOLES The 1,2,4-oxadiazole system is commonly found in bioactive molecules. A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles 146 from readily available aryl nitriles, hydroxylamine, and acyl chlorides has been applied in a single continuous microreactor sequence. In this way, a multiday, multistep preparative procedure was shortened to a matter of minutes, demonstrating proof-of-concept for the rapid synthesis of libraries of molecules based on this system . Development of a kilogram-scale synthesis of the tartrate of cis-LC15-0133, a potent dipeptidyl peptidase IV inhibitor, has been reported . F OH R1CN

NH2OH.HCl R1 H nig's base

OH R2COCl

NH2

DMF R1

N

R2

= Ar, Het

R1

N

R2

NH

N N

N

N O

DMF

O O 146 40-60%

= Ar, Het, Alkyl

O

t-Bu

cis-LC15-0133

Bipolar dendritic molecules composed of carbazole-based donors and 1,3,4-oxadiazolebased acceptors have been synthesized and their ability in photoinduced electron transfer processes studied . 2-Amino-1,3,4-oxadiazoles 149 were prepared by amination of 1,3,4-oxadiazol-2-ones 147 with primary and secondary amines in the presence of benzotriazol-1yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) as activating agent. The process presumably occurs by formation of the intermediates 148 and affords the products 149 in high yields under mild conditions . R1

O

O

N N 147

H

R2R3NH BOP, DIPEA DMF, rt

R1

O

OP(NMe2)3

1

R

N N 148

HNR2R3

HMPA

O N N

R3 N R2

149

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328 08JOC1088 08JOC1099 08JOC1192 08JOC1999 08JOC2396 08JOC3278 08JOC3288 08JOC3303 08JOC4320 08JOC4709 08JOC4746 08JOC5436 08JOC5890 08JOC7164 08JOC7219 08JOC7383 08JOC7775 08JOC8376 08JOC9181 08JOM(693)135 08JOM(693)3563 08OBC169 08OBC1478 08OBC1994 08OBC3908 08OL65 08OL305 08OL885 08OL917 08OL1357 08OL1573 08OL1691 08OL1695 08OL1755 08OL1935 08OL2417 08OL2481 08OL3211 08OL4113 08OL4227 08OL4995 08OM2399 08OM6393 08OPRD626 08S293 08S1233

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Five-Membered Ring Systems with O & N Atoms 08S3361 08SL89 08SL827 08SL919 08SL1211 08SL1483 08SL1747 08SL1989 08SL3036 08T477 08T1813 08T1853 08T3111 08T3541 08T3561 08T4778 08T5583 08T6901 08T7877 08T7937 08T8078 08T10244 08TA279 08TA838 08TA1204 08TA1660 08TA2140 08TA2246 08TA2492 08TA2519 08TL764 08TL941 08TL1237 08TL2069 08TL4153 08TL6224 08TL6613 08TL6707 08TL7406

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Chapter 6.1 Six-Membered Ring Systems: Pyridine and Benzo Derivatives Darrin W. Hoppera, Aimee L. Crombieb, Jeremy J. Clemensa, and Soojin Kwona Chemical Sciences, Wyeth Research, Pearl River, NY, USA b Chemical Sciences, Wyeth Research, Collegeville, PA, USA [email protected], [email protected], [email protected], and [email protected]

a

6.1.1 INTRODUCTION Much attention has been focused on developing the chemistry of pyridines and their benzo derivatives due to their unique chemical, biological and electronic properties. In particular, efforts have been directed towards establishing more efficient, practical and environmentally friendly procedures involving these molecules . A number of reviews highlighting preparations and reactions of pyridines and their benzo derivatives were published in 2008 (e.g., synthesis of pyridines by transition metal-catalyzed [2+2+2] cycloadditions , syntheses of quinoline and quinolineannulated ring systems , chemistry and SAR of indolo[3,2-b]quinolines , quinoline, quinazoline and acridone alkaloids ). In addition, there have been two reviews highlighting the synthesis of substituted piperidines. One review focused on the stereoselective syntheses of trans-3,4-substituted piperidines in the literature . The other paper reviewed pharmaceutically active compounds containing a disubstituted piperidine framework . The following chapter is a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were described in 2008. It will cover selected advances in the field and serve as an update to the previous review.

6.1.2 PYRIDINES 6.1.2.1 Preparation of Pyridines Cyclocondensations and related polar cyclizations are the most widely used methods for preparing pyridines, dihydropyridines, and pyridinones. The reactions are routinely employed in the synthesis of biologically important pyridines and those of interest in c 2009 Elsevier Limited. All rights reserved.

Six-Membered Ring Systems: Pyridine and Benzo Derivatives

331

material sciences . Several of the polar cyclization strategies involve aminolysis of pyranones , electrophilic aromatic substitution reactions and addition/elimination processes . In general, these reactions are catalyzed by base, as well as Brønsted and Lewis acids (e.g., AlCl3 , ZnCl2 , ZnBr2 , Ba(NO3)2 , CeCl3 , and AuCl3 or AuSbF6 . Pyridine-forming polar cyclizations can also be promoted with KF/Al2O3 , chiral phosphonic acid , sodium 1-dodecanesulfate , TMSCl , K-10 clay , or photolysis . In addition, many employ the use of the Vilsmeier reagent (POCl3 or PBr3/DMF) to produce halo-substituted pyridine derivatives . Recently, efforts have been directed towards utilizing multicomponent cyclocondensation reactions as one-pot procedures to conveniently synthesize a variety of pyridine derivatives in an efficient manner . In addition, much attention has been focused towards improving efficiency with the incorporation of microwave technology and solid phase synthesis , and towards developing more environmentally friendly protocols . For example, a novel green method for synthesizing pyridine derivatives conducted in ionic liquid has been described . The reaction of aldehydes 1 with dihydroindenylidine malononitrile 2 catalyzed with 10 mol% of malononitrile leads to indeno[2,1-c]pyridines 3 in excellent yields. The ionic liquid can be reused several times without significant loss of activity making this one-pot procedure even more environmentally friendly. NC O Ar

10 mol% malononitrile

NC N

+ [bmim+][BF4-] 90 °C, 8-14 h

H 1

CN

2

79-90%

Ar 3

Another novel approach to a single-step polar cyclization synthesis of highly substituted pyridines has been reported . The strategy involves a TMSCl-promoted [3+2+1] intermolecular cyclization of functionalized enamines 4, N,N-dimethylformamide diethyl acetal 5, and alkynes 6 to produce 2,3,4,5-tetrasubstituted pyridines 7. The reaction proceeds cleanly under mild conditions and in good to excellent yields.

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332

CO2R1

Me2NCH(OEt)2 + R1O2C

2 equiv

2 equiv

1. Me3SiCl (2 equiv) MeCN, rt, 10 min 2.

R2 4

R2

CO2R1 CO2R1

R3

N 55-98%

3

5

6

R NH2 MeCN, rt, 30 min

7

The Hantzsch synthesis of pyridine is a cyclocondensation method of considerable importance. This route classically involves the condensation of four components, including two molecules of ȕ-carbonyl compounds, an aldehyde, and ammonia (or an equivalent) to form 1,4-dihydropyridines, which can be aromatized into pyridines . Recent efforts have been focused on developing more environmentally friendly conditions, including those that are performed in the absence of organic solvent . For example, a practical multicomponent synthesis of symmetrical and unsymmetrical 1,4-dihydropyridines in aqueous micelles catalyzed by PTSA under ultrasonic irradiation has recently been reported . As shown below, reaction of aldehydes 8 with two equivalents of alkyl or aryl acetoacetate esters 9 and ammonium acetate leads to highly substituted dihydropyridines 10 in excellent yields. The strategy can also be applied to the synthesis of polyhydroquinoline derivatives when cyclic 1,3-diketones are utilized as substrates. R1 R1CHO

O

COOR2

Me 8

NH4OAc, PTSA

O

+

9

SDS, H2O ultrasound 90-97%

2

COOR2

R OOC Me

N H

Me

10

Aromatization methods that convert hydropyridines and pyridinones to pyridines continue to be optimized. In particular, efforts to develop efficient and more environmentally friendly oxidizing agents for aromatizing Hantzsch 1,4-dihydropyridines have been underway. Some recent examples include the use of t-butylhydroperoxide catalyzed by iron (III) phthalocyanine chloride in room temperature aromatizations of dihydropyridines and a urea-hydrogen peroxide adduct as oxidant catalyzed by molecular iodine . In addition, the photochemical aromatization of dihydropyridines was also recently reported . Other, more traditional hydropyridine-type oxidizing procedures include the use of DDQ , cerium (IV) ammonium nitrate , cerium (IV) sulfate , nitric oxide , sulfur , MnO2 , NaIO4 , KMnO4 , chloroanil , palladium , silica gel and air 99% Cl PCy3 Ph R = H, 1.5 h, ethylene atm, 96% Ru-I

Nelson and co-workers designed a novel fluorous-tagged linker that can be used in parallel synthesis and purified by fluorous-solid-phase extraction (F-SPE) . In the final step, a cyclization-release strategy was used where functionalized heterocycles such as tetrahydropyridines were liberated by a RCM reaction. Use of a light-fluorous tagged derivative of the Grubbs−Hoveyda second generation catalyst, Ru-III, allowed for facile purification of the desired heterocycles from the linker and catalyst. Domino metathesis reactions were used to generate new multi-fused piperidine-containing systems. The first total syntheses of lepadins F and G were achieved by Blechert et al. using a tandem ene–yne–ene RCM . The regioselectivity of this reaction was controlled by the coordinative effect of the allylic alcohol for the initial carbene formation. The authors noted that although all three ruthenium catalysts, Ru-I, Ru-II, and Ru-III were attempted, the least stable Ru-I provided the final product in highest yield with the absence of side-products, even under elevated reaction temperatures (60 °C). Oikawa and co-workers demonstrated that an allylic amine appended to the 5-position of 7-oxanobornene could undergo a domino metathesis reaction to reveal structurally diverse cis-fused tricyclic heterocycles that contained a dehydropiperidine ring . The same authors later revealed that the domino metathesis of oxanorbornene 172 could be directed by a neighboring carbonyl group, to generate fused-tetrahydropyridine 173 . Although Ru stabilization by carbonyl oxygens usually leads to loss of reactivity, the unique cis-fused pyrrolidone ring reduced the strength of the Ru-O binding. In both papers, the oxanobornene starting material was rapidly assembled by the Diels–Alder reaction.


NHBn H O

PMBN

O

H Ru-III, benzene OAc 11 h, rt 97%

O H

H 172

PMBN O H H NsN

NsN

NHBn

NHBn H

O O

O

PMBN

OAc

355

MesN

O

Cl Ru Cl O

[Ru]

O H

H

H

NMes

NsN

173

Ru-III

Taking advantage of the ability of Ru-II to induce isomerization of double bonds, PérezCastells et al. combined metathesis and isomerization with a cyclopropanation reaction to generate cyclopropane-fused piperidinones . After completion of the RCM– isomerization sequence, ethyl diazoacetate was added slowly over 8 h to afford cyclopropane-fused piperidine lactams. Xiao and co-workers took advantage the Lewis acidity of the ruthenium catalysts to effect a metathesis-hydroarylation sequence of indole 174 with crotonaldehyde 175 to generate carbazole 176 . OHC N Ts

MesN

Ru-II, DCE

+

O

N 174

N Ts

reflux 85%

N

175

NMes

Cl Ru Cl PCy3 Ph Ru-II

176

Non-ruthenium catalysts can also be used in cycloisomerization reactions to afford piperidine ring structures. Kambe et al. reported an intramolecular vinylchalcogenation reaction using alkynes 177 to generate piperidine lactams 178 in high yields . A platinum catalyst was used in this reaction to catalyze the cis-vinylthiolation and selenation of 177 with high E/Z stereoselectivity. Density functional theory (DFT) calculations suggested that the reaction proceeded through a seven-membered seleno-platinum transition state. Brummond et al. disclosed a mild rhodium-catalyzed allenic Alder-ene-type reaction of allenamides 179 to generate trienes 180 . Catalysis of the ene-yne cyclization reaction was also studied using gold and nickel complexes. PhY O

O

toluene reflux 78-95% R2 Y = S, Se 177

O

O

Pt(PPh3)4 1

R N

O

R1N

YPh R2 178

N

4

·

R Me R3

179

[Rh(CO)2Cl]2 O

R4

N

toluene, rt 68-95%

R3 180

Several groups studied the addition of amine sources to unsaturated bonds by an intramolecular hydroamination reaction. Hartwig et al. disclosed a versatile rhodiumcatalyzed hydroamination of terminal and internal alkenes with primary and secondary amines that tolerated a variety of common functional groups . Other catalysts that were capable of facilitating this transformation included Hg(OTf)2 and an yttrium complex . Intramolecular hydroamination onto alkynes were catalyzed by palladium and gold to generate tetrahydropyridines. Similarly, Alcaide et al. disclosed a regioselective intramolecular 5-exo-dig cyclization of an

D.W. Hopper et al.

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amine to the central carbon of an allene to afford a ȕ-lactam-fused tetrahydropyridine ring . A novel palladium-catalyzed diamination of alkenes 181 furnished fusedpiperidines 182 by utilizing copper chloride as an oxidant . NCO2R2 NH R1 R1

NCO2R2

Pd(OAc)2, CuCl2 2

NHCO2R

K3CO3, DMF 88-99%

R1

NCO2R2

N

R1 H

181

182

Ohno et al. reported a palladium-catalyzed bromoalkyne-diamine domino cyclization of 1,7-diamino-5-bromohept-3-yne derivatives using Pd(PPh3)4 and NaH to provide pyrrolidinetetrahydropyridine-fused bicycles in high yields . The same authors disclosed a similar zipper-mode cascade reaction of allenic bromoalkenylamine derivatives 183 to afford bis-tetrahydropyridine-fused bicycles 184 in high yields . This chemistry was utilized in an efficient synthesis of (±)-lysergic acid . R MTs N

· Br

R

Pd2dba3, TBAF NHTs

183

MeCN 75-91%

MTs

N

Ts

N 184

Palladium-catalyzed carbon-carbon bond-forming reactions were frequently used to form the piperidine ring. Intramolecular Heck coupling of an amine-tethered vinyliodide with a cycloheptene ring formed the bridged piperidine of ervitsine . This cyclization required the addition of a catalytic amount of phenol to afford a cleaner product with higher yield. In a related transformation, Overman et al. used an intramolecular Heck coupling of an enolate with a vinyl iodide to construct the final piperidine ring of (+)-minfiensine . Tsukamoto and Kondo reported a novel cascade reaction in which 4substituted tetrahydropyridines were generated in an arylative cyclization reaction . Both alkynes 185 and allenes 186 could be treated with formaldehyde and organoboronic acids to afford tetrahydropyridines 187 in a single step. R2 2

·

R B(OH)2, "Pd"

NHBn

H2C=O, 50 °C 63-88%

or R1

NHBn 185

R1

186

R1

N Bn 187

"Pd" = Pd(PPh3)4 or PdCp(η3-C3H5) and PPh(c-C6H11)2

Radical cyclization was applied in the synthesis of novel piperidine-containing products. Callier-DuBlanchet and co-workers elaborated on their total syntheses of aspidospermidine and 13-deoxyserratine in which the key cyclizations hinged on a 6-endo amidyl radical cascade . These authors found that installing a chlorine directing group, which would be removed under the reaction conditions, inhibited the undesired 5-exo closure. The synthesis of mersicarpine was accomplished by an intramolecular Mn(OAc)2-mediated oxidation/radical cyclization of N-acylindoline with a malonic acid side chain to form the dihydropyridoindoline . Intramolecular cyclization of 1-indole alkanones could be achieved by electroreduction using a Pb cathode in an undivided cell containing Et4NOTs


357

as the electrolyte . A previously unsuccessful 6-exo amidyl radical cyclization of pentenyl amides 188 was realized to form piperidines 189 when the vinyl position was substituted with either a halogen or heteroatom (O and S) . In the absence of these vinyl substitutions, a mixture of the 5-exo and 6-endo products was observed. O

O R

N SPh

188

X

Bu3SnH AIBN, 80 °C 60-90%

R

N

X

X = H, Me 5-exo predominates X = Cl, OMe, SEt only 189 observed

189

Nucleophilic displacement of leaving groups is still a common route to constructing piperidine cores. A one-pot cyclization of diols with amines via bis-triflate intermediates was reported . Concellón et al. reported a highly enantioselective double ring opening of C2-symmetric diepoxides with primary amines in the presence of LiClO4 to generate 4amino-3,5-dihydroxypiperidines . Intramolecular ring opening of ȕ-lactams with acidic methanol followed by intramolecular cyclization of the newly exposed amine by displacement of a terminal alkyl chloride afforded trans-2,3-disubstituted piperidine rings in high yield . A previously underutilized, low yielding cyclization of unprotected amino alcohols with thionyl chloride was significantly improved . Slow, inverse addition of the amino alcohol 190 to a solution of SOCl2 in solvent, followed by quenching with NaOH furnished piperidine 191 in high yield. This inverse addition allowed for rapid protonation of the nucleophilic amine, thus preventing N-sulfinylation. (SOCl)2, (MeOCH2)2 H N

HO

then aq. NaOH 92%

190

N 191

Intramolecular cyclization of an oxirane-containing enamide 192 under acidic conditions gave the 6-endo piperidine product 193 while the same substrate in refluxing water afforded the 5-exo pyrrolidine ring 194 . Both products could be formed efficiently in a highly stereospecific manner. Ar1

OH

Ar2 HO

O N Me 194

H2O reflux 68-93%

O Ar

1

Ar1

Ar2

O

TFA, t-BuOH N Me

4Å MS, reflux 50-86% 192

Ar2

OH N Me

O 193

Smith and Williams were able to repeat the conversion of d-quinotoxine to quinine, which had been reported by Paul Rabe and Karl Kindler in 1918, thus validating the classical formal total synthesis of quinine by Robert Woodword and William von Eggers that had been under suspicion for eighty years. A key step in this conversion involved bromination of the piperidine nitrogen with sodium hypobromite, followed by enolate displacement of the bromide to generate the quinuclidine ring . Cyclization via reductive amination, utilizing various hydride sources, continued to receive attention. L-Sorbose was converted to (+)-1-epi-castanospermine in 11 steps in which the final transformation entailed reduction of an azide and reduction of the resulting piperidine imine in one-pot by palladium-catalyzed hydrogenation . Rao and Rafi reported a novel reductive cyclization of 1,5-keto oximes in refluxing sodium borohydride

D.W. Hopper et al.

358

and acetic acid to afford piperidine N-oxides . Enantioselective syntheses of piperidines 195 were achieved in two steps by Michael addition of aldehydes to γ-keto-Į,ȕunsaturated ester 196 using diarylprolinol ether 197 as an organic catalyst, followed by stereoselective bis-reductive amination of the 1,5-ketoaldehyde intermediate .

EtO2C

COCH3 196

1. RCH2CHO, 197, HOAc, MeOH 2. BnNH2, NaBH(OAc)3, HOAc 57-69%, >96% ee

CO2Et R N Bn 195

OTMS Ph N H Ph 197

Another method frequently utilized in the preparation of piperidines is the reduction of the corresponding pyridine ring. Piras et al. were able to improve the hydrogenation of pyridine in a microwave by pre-reduction of the PtO2 catalyst in acetic acid under a H2 atmosphere at 50 °C prior to addition of the substrate . These conditions gave products in high yields in less than one hour of exposure and were compatible with acid-labile functional groups, such as acetals and t-butyl carbamates. Zhou and co-workers achieved an Ircatalyzed asymmetric reduction of 7,8-dihydroquinolin-5(6H)-ones in high yields and high enantiomeric excess . Other trisubstituted pyridines and pyridines with electron-withdrawing substituents at the 3-position gave either no reaction or poor enantioselectivity. Piperidine lactams are commonly generated by construction of the amide bond either from the corresponding lactone or from the linear precursor. Larhed et al. published an acid-free lactamization of lactones and primary amines by heating to 220 °C via microwave irradiation in an ionic liquid, [bmim]BF4 . Reaction of racemic γ-lactones with isocyanates in the presence of a BINAP-derived phosphine ligand resulted in a palladiumcatalyzed formation of 3,3-disubstituted 2-piperidones with high enantioselectivity . Pittman et al. were able to condense two equivalents of 1,3-diacid chlorides with one equivalent of 2-methylimidazoline or 2-methyl-1,4,5,6-tetrahydropyrimidine in refluxing triethylamine and acetonitrile to generate highly functionalized 1,8naphthyridinetetraones through a double amide bond formation reaction . Another novel route to piperidine lactams involved the radical addition of alkyl iodides to oxime ethers followed by an intramolecular lactamization cascade . The Prins reaction was applied in the synthesis of piperidine rings. Treatment of homoallylic amines and aldehydes with gallium (III) iodide and molecular iodine generated 4-iodopiperidines through an aza-Prins reaction under mild conditions . Another aza-Prins reaction was carried out in an ionic liquid, Et4NF·5HF, to furnish 4fluoropiperidine rings . Murty and co-workers disclosed a novel aza-Prins reaction between N-protected homoallylic amines and epoxides using bismuth (III) chloride as a mild catalyst to assemble 4-chloropiperidine derivatives in high yields . Cariou et al. were able to show that the diastereoselectivity of the Prins reaction of 198 could be influenced by adjusting the temperature and acid used in the reaction . Low temperature cyclization catalyzed by HCl proceeded under kinetic control to afford the 4,5-cis-piperidine 199 while cyclization catalyzed by MeAlCl2 proceeded under thermodynamic control to afford the 4,5-trans-piperidine 200.


Bn

Ts N

Bn

conc. HCl CH2Cl2, −78 °C 81%

OH 199

Ts N

MeAlCl2

Bn

CHCl3, 40 °C 64%

O

359 Ts N

OH 200

198

The Pictet–Spengler reaction remains a popular method for the synthesis of ȕ-carbolines. Efforts have been made to improve the diastereoselectivity of the reaction including using nitromethane as solvent , adjusting the acidity of the reaction by using bromoacetic acid , and using new catalysts such as BINOL-phosphoric acid and molecular iodine . Cascade reactions that culminate in the Pictet–Spengler reaction have also been explored, as exemplified in the tandem hydroformylation-Pictet–Spengler reaction of tryptamine 201 with olefins 202 to provide carbolines 203 in high yields . NH2

R3

50/10 bar CO/H2 Rh(acac)(CO)2

R2

CSA, CH2Cl2 46-99%

+ N H 201

R1

202

NH N H R1 203

R3 R2

Other methods to synthesize ȕ-carbolines include the use of an intramolecular metallocarbenoid cyclization onto the indole scaffold using Rh2(OAc)4 as a catalyst and a one-pot hydroformylation-Fischer indole sequence that results in the rearrangement of a 3,3-spiroindoleninium cation to form the piperidine ring from a dihydropyrrole . Raheem, Thiara and Jacobsen reported a chiral, N-acyl Pictet–Spengler-type reaction of pyrrole nucleophiles onto lactams using a chiral thioureapyrrole catalyst . Intramolecular aza-Michael additions provide facile access to the formation of piperidines and have thus been often used in their synthesis. Takeuchi et al. found that intramolecular conjugate addition of carbamate-protected amines onto Ȗ-alkoxy substituted (E)-Į,ȕunsaturated ketones under basic conditions (K2CO3) afforded cis-2,3-disubstituted piperidines while the more uncommon Lewis acidic conditions (BCl3) selectively afforded trans-2,3disubstituted piperidines . Liu, Hong and Weinreb reported a stereoselective conjugate addition of a pyrrolidine nitrogen onto an intramolecular enone to establish the piperidine ring in the total synthesis of (–)-secu’amamine . Asymmetric intramolecular Michael addition of a benzyl carbamate onto an Į,ȕ-unsaturated aldehyde was reported by Carter et al. using a diaryl TMS-prolinol catalyst to provide a 2-substituted piperidine in 95% ee after NaBH4 reduction of the aldehyde . Staudinger reduction of 1,2-azido alcohols resulted in formation of an intermediate aziridine, which cyclized onto an Į,ȕ-unsaturated ester upon exposure to methanol to furnish 1azabicyclo[4.1.0]heptanes with good diastereoselectivity (9:1) . Nitroenamines were also viable Michael acceptors in the construction of novel tetrahydropyridine-fused azaheterocycles and tetrahydropyridine-fused 1,3-diazaheterocycles . Trost et al. reported that readily accessible propargylic alcohols such as 204 could be converted into 2-substituted piperidines 205 through a redox isomerizationintramolecular Michael addition cascade upon treatment with a ruthenium complex, indium triflate and camphorsulphonic acid . This atom-economical reaction is highly tolerant to a wide variety of functional groups, such as aromatic rings, esters and ethers.

D.W. Hopper et al.

360 R

IndRu(PPh3)2Cl, CSA

O

OH 204

N Ts

In(OTf)3, THF, reflux 68-80%

NHTs

R

R = H, 77% R = CH2OBn, 80%

205

Intramolecular attack of cyclic iminiums can give rise to complex multicyclic ring systems. Cyclic imides that were tethered to indoles and benzofurans underwent partial reduction with lithium triethylborohydride and the resulting acyliminium species was attacked by the pi nucleophile upon treatment with TsOH to generate novel tetracyclic and pentacyclic piperidine lactams . A similar reaction in which the acyliminium ion, generated by an intramolecular condensation of an amide and ketone, was also attacked by pi nucleophiles tethered to the ketone to furnish spirocyclic piperidine lactams . This cyclization was mediated by solid supported Si-TsOH. Lévesque and Bélanger disclosed that cyclic iminiums generated by intramolecular Vilsmeier–Haack cyclizations of the enol ether group of 206 with the primary amide underwent a 1,3-dipolar cyclization to generate the piperidine-fused tricyclic alkaloids such as 207 in high yield . In a similar vein, the cyclic iminium derived from an intramolecular Vilsmeier–Haack cyclization of a silyl enol ether with an activated amide underwent a second halide-promoted alkyne addition to generate the bridged-fused tricyclic core of alkaloid securinol B .

OEt O

O N

O

OMe

OEt H

O

1. DTBMP, Tf2O PhCl

O

OMe

H N H

2. DIPEA, reflux 77%, 8:1 dr

206

O

+ diast. 207

Continuing with the theme of carbonyl chemistry, a number of piperidine syntheses involved intramolecular cyclization via alkylation of an enolate with an electrophile. Kawabata et al. developed a direct method for asymmetric alkylation of Į-amino acid derivatives without the aid of external chiral sources by taking advantage of the substrate’s memory of chirality . Intramolecular asymmetric cyclization of 6-membered rings was achieved by simple treatment with KOH in DMSO at 20 °C. Serine derivatives, that are prone to ȕ-elimination and epimerization, were successfully alkylated with minimal epimerization using CsOH in DMSO . Kozlowski et al. described an interesting umpolung addition of 4-chlorobutyl Grignard to the nitrogen of Į-iminoester 208 to yield cyclic Į-amino acid derivative 209 .

Ph

NPMP OMe O 208

1. Cl

MgBr THF, –78 °C to rt

2. DMF, rt 66%

N

PMP CO2Me

Ph 209

Intramolecular aldol reactions involving substrates with reactive functional groups that are connected through an amine tether can contribute to the formation of a piperidine core. Lam et al. revealed that Į,ȕ-unsaturated amides such as 210 can undergo a reductive aldol reaction in the presence of a Ni catalyst and diethylzinc to afford piperidine lactams 211 .


361

The same substrate can undergo an alkylative aldol reaction when employing a cobalt catalyst and trialkylaluminum as the alkylating reagent to yield piperidine lactams 212 . O 1

R

N

Bn

Ni(acac)2 up to 99% >9:1 dr

2

R HO 211

O

Et2Zn R1

O R2

N Bn

R

Co(acac)2 H2O

210

H

O

1

R R3Al, THF up to 98% >19:1 dr

N

Bn

2

R HO 212

Mannich reactions can be considered the aza version of the aldol reaction. Double Mannich reactions of ȕ-ketoesters with bisaminol ethers yielded highly functional 3,3,5,5tetrasubstituted-4-piperidones upon treatment with trichloromethane silane as a Lewis acid . Intramolecular Mannich reactions using ȕ-amino ketals afforded novel 2-(2pyridyl)-6-isopropyl-cis-piperidines as bidentate ligands for Suzuki cross-coupling reactions , as well as novel Į-trifluoromethyl-4-piperidones . Chiral 7-oxo2-enimides, prepared by a Cope-rearrangement, underwent a proline-catalyzed Mannich-azaMichael cascade reaction with glyoxyl imines to furnish highly substituted pipecolic esters with excellent stereocontrol . An intramolecular nitro-Mannich-lactamization cascade with Ȗ-nitromalonates 213 and cyclic imines 214 afforded complex multi ring-fused structures 215 with high stereoselectivity .

213

NO2

Ph

O2N MeO2C O O

R2 + R1

N X X = CH2, O 214

H2O, 70 °C n

58-91% up to >99:1 dr

Ph X 215

N n O O

R2 R1

Highlighting ring expansion of pyrrolidine rings is the novel conversion of 2(bromomethyl)pyrrolidines to the corresponding piperidin-3-ones upon heating in the presence of K2CO3 and DMSO . This ring expansion-oxidation transformation is thought to occur through an aziridinium salt which is opened up by nucleophilic addition of DMSO, followed by proton abstraction to form the ketone. Jida and Ollivier disclosed a similar ring opening of azabicyclo[3.1.0]hexan-1-ols with either a two-step ferric chloride/sodium acetate sequence or by using bis(sym-collidine)iodine hexafluorophosphate to afford chiral dihydropyridin-3-ones . Many multicomponent reactions (MCRs) have been reported in 2008. Yadav and Kapoor formed 3-amino-2(1H)-pyridinones through a CeCl3·7H2O/NaI-promoted [3+2+1] coupling of a chalcone, 2-phenyl-1,3-oxazolon-5-one and an amine . The same authors also reported a similar reaction with 2-methyl-2-phenyl-1,3-oxathiolan-5-one to generate the 3-mercapto-2(1H)-pyridinone derivatives in an excess of 78% yield . In the presence of Yb(OTf)3 and AgOTf, two equivalents of dimethylmalonate and two equivalents of O-benzyloxime combine to form trimethyl-3,5,5-pyridinone tricarboxylate in quantitative yield . Marazano et al. reported a novel “Chichibabin-like” 3-component MCR of aldehydes, benzylamine hydrochloride and acrolein to reveal tetrahydropyridines after reduction or cyanation of the dihydropyridinium salt . This chemistry was used to model a biosynthetic approach to the synthesis of manzamine alkaloids. Lhommet and co-workers published a one-pot, three-component condensation of acrolein, (S)phenylglycinol and 1,3-dicarbonyl compounds to afford chiral oxazolo-tetrahydropyridine fused bicycles . Combination of arylaldehydes 216, arylamines 217 and 1,3-

D.W. Hopper et al.

362

carbonyl compounds 218 in the presence of bromodimethylsulfonium bromide resulted in 3component Mannich products 219 when R1 was non-enolizable and 5-component Mannichaza-Diels–Alder transformations when R1 = Me to reveal highly functionalized tetrahydropyridines 220 . Ar2

NH O

Ar1

OR, Ph O

R1

Ar1CHO O 216 Me2S BrBr 1 + R R1 = OR, Ph Ar2NH2 217 +

219

Ar2

O

-

+

2

Me2S BrBr

-

NH

O OR2

OR

1

R = Me

Ar1

218

N Ar2

Ar1 220

6.1.5.2 Reactions of Piperidines A lot of effort has been focused on Į-substitution of piperidine rings through an Į-anionic intermediate. In an effort to create a chiral Į-center, Coldham et al. used dynamic resolution of N-Boc-2-lithiopiperidine in the presence of chiral diamino-alkoxide ligands to produce enantiometrically enriched 2-substituted piperidines . Zinc transmetalation of the Į-lithiated intermediate of N-Boc piperidine 221 followed by a palladium-catalyzed Negishi-type coupling using a tri-t-butylphosphine ligand allowed direct access to 2-aryl substituted piperidines 222 in good yields . Bahde and Rychnovsky demonstrated that reductive lithiation of N-benzyl-2-cyanopiperidine 223 with lithium 4,4´di-t-butylphenylide (LiDBB) and intramolecular carbolithiation afforded piperidine spirocycle 224 . This spiroannulation reaction was also possible using alkynes and allylic methoxy ethers on the piperidine to construct both 5- and 6-membered rings. s-BuLi, TMEDA

1. LiDBB N

then ZnCl2, then ArBr N Boc Pd(OAc)2, t-BuP•HBF4 51-75% 221

N Ar Boc 222

Bn

CN 223

2. MeOH 67%

N Bn 224

Addition of nucleophiles to the Į-position of piperidines through Į-oxidation continued to be explored. Intramolecular C-H amine insertion of a sulfamoyloxymethyl arm at the 6position of N-tosyl-2-sulfamoyloxylmethyl piperidine was achieved by treatment with PhI(OAc)2 and a rhodium catalyst . Exposure of the bridged intermediate to allyl- or propargylsilanes yielded 2,6-disubstituted piperidine rings. Onomura et al. reported a highly regioselective Į-methoxylation of Į-substituted N-cyanopiperidines using a Lewis acid-catalyzed electrochemical oxidation to furnish 2,2-disubstituted piperidines . Efficient Į-cyanation of N-carbonyl protected piperidines was achieved by site isolation of the anode and polymer-supported PS-NMe3CN during the electrochemical oxidation reaction . Atobe et al. disclosed a novel system that used acoustic emulsification by ultrasonication to allow for efficient electrochemical anodic substitution of Nmethylcarbamate piperidine with the immiscible allylsilane nucleophile to provide the corresponding 2-allyl-substituted piperidine . Several methods to cleave the C-C bond of piperidine rings to form linear compounds were reported. An efficient route to 2-benzyltryptamines was achieved in high yields by cleavage of the piperidine C-N bond of 1-aryl substituted ȕ-carbolines by hydrogenation under standard Pd/C conditions . These carbolines were assembled by Pictet– Spengler cyclization of tryptamine with substituted benzaldehyde derivatives. Oxidative cleavage of N-carbamate protected piperidines 225 with sodium nitrite in trifluoroacetic acid


363

formed ring-opened Ȧ-amino carboxylic acids 226 in high yield . Similar Ȧamino carboxylic acids were synthesized by RuO4-promoted oxidative cleavage of N-Boc protected 1,2,3,4-tetrahydropyridines . Comins et al. were able to optimize the von Braun reaction to induce ring opening of 2-phenylpiperidines 227 to the linear cyanamide derivatives 228 with retention of all chiral centers . R2 3

R4 225

R2 NaNO2

R

N CO2R1

H2O, TFA 42-98%

R3

OR CO2H CHO

R4

N 1 226 CO2R

Me

BrCN Ph

Me

N

98%

NC

OR

Br

N

Ph

227

228

Palladium-catalyzed coupling reactions of piperidine derivatives were also in abundance in 2008. Georg and co-workers were able to arylate 2,3-dihydropyridin-4-one 229 directly to form 230 by using organotrifluoroborates in a palladium-catalyzed coupling reaction . Interestingly, aryltrifluoroborates containing halides were tolerant to these reaction conditions. 4-Piperidinones were converted to N-tosylhydrazone enamides in situ and coupled with arylchlorides and arylbromides in a palladium catalyzed reaction using XPhos as a ligand . Unprotected N-H groups on the piperidinone did not hinder the high efficiency of this reaction. Prandi et al. disclosed that triflates prepared from Nprotected piperidine lactams underwent a palladium-catalyzed aminocarbonylation with carbon monoxide and N-methoxy-N-methylamine to afford novel 2-Weinreb amide derived tetrahydropyridines . Onomura et al. were able to introduce aldehydes, ketones and imines to the 4-position of N-benzoyl-2,3-dehydro-4-acetoxypiperidines using catalytic Pd(OAc)2 and excess diethylzinc . Only minor amounts of the 2substituted regioisomer were observed. Charette et al. described a regioselective arylation of tetrahydropyridines 231 at the less common ȕ-position to afford the coupled product 232 . This reaction was tolerant to a variety of functional groups and heterocycles. Ar O

O Pd(OAc)2, Cu(OAc)2 N Bn 229

K2CO3, t-BuOH, HOAc DMSO, Ar-BF3K 27-97%

Ar N Bn 230

N Ph

Me N O 231

ArI, Pd(dppf)Cl2 Ag3PO4, NaOAc DMF 32-84%

N Ph

Me N O 232

6.1.6 REFERENCES 08AG(I)1736 08AG(I)2458 08AG(I)2489 08AG(I)4012 08AG(I)4695 08AG(I)4851 08AG(I)5418 08AG(I)5836 08AG(I)6286

A.C. Smith, R.M. Williams, Angew. Chem. Int. Ed. 2008, 47, 1736. J. Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao, L.-Z. Gong, Angew. Chem. Int. Ed. 2008, 47, 2458. J.-r. Chen, C.-F. Li, X.-L. An, J.-J. Zhang, X.-Y. Zhu, W.-J. Xiao, Angew. Chem. Int. Ed. 2008, 47, 2489. Y. Hayashi, H. Gotoh, R. Masui, H. Ishikawa, Angew. Chem. Int. Ed. 2008, 47, 4012. K.L. Billingsley, S.L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 4695. H. Tsukamoto, Y. Kondo, Angew. Chem. Int. Ed. 2008, 47, 4851. J.-C. Wypych, T.M. Nguyen, P. Nuhant, M. Benechie, C. Marazano, Angew. Chem. Int. Ed. 2008, 47, 5418. M. Rueping, A.P. Antonchick, Angew. Chem. Int. Ed. 2008, 47, 5836. V.N. Kozhevnikov, B. Donnio, D.W. Bruce, Angew. Chem. Int. Ed. 2008, 47, 6286.

364 08AG(I)6594 08AG(I)6674 08AG(I)7044 08AG(I)8059 08AG(I)8246 08BMC601 08BMC1493 08BMC1738 08BMC2367 08BMC3261 08BMC3825 08BMC4551 08BMC9276 08BMC9349 08BMC9660 08BMCL188

08BMCL405 08BMCL409 08BMCL1407

08BMCL1795 08BMCL2194 08BMCL2206

08BMCL2211 08BMCL2355 08BMCL2878 08BMCL3178

08BMCL3856

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08JMC7614 08JMC7777 08JOC312 08JOC327 08JOC630 08JOC830 08JOC1154 08JOC1169 08JOC1468 08JOC1586 08JOC1635 08JOC1752 08JOC1852 08JOC1906 08JOC1941 08JOC1954 08JOC2224 08JOC2442 08JOC2641 08JOC2753 08JOC2943 08JOC3088 08JOC3236 08JOC3281 08JOC3497

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Six-Membered Ring Systems: Pyridine and Benzo Derivatives 08JOC3589 08JOC3928 08JOC3954 08JOC3996 08JOC4101 08JOC4568 08JOC4740 08JOC4971 08JOC5110 08JOC5135 08JOC5155 08JOC5170 08JOC5558 08JOC5658 08JOC6025 08JOC6048 08JOC6166 08JOC6355 08JOC6405 08JOC6425 08JOC6793 08JOC6899 08JOC6905 08JOC7096 08JOC7102 08JOC7390 08JOC7451 08JOC7721 08JOC7731 08JOC8398 08JOC8437 08JOC8608 08JOC8619 08JOC8627 08JOC9061 08JOC9326 08JOC9372 08JOC9504 08JOC9610 08JOC9698 08JOC9744 08JOC9765 08JOM1572 08MRMC538 08NPR166

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370 08OBC175 08OBC739 08OBC1293 08OBC1938 08OBC2679 08OBC3337 08OBC4059 08OL221 08OL285 08OL321 08OL325 08OL345 08OL597 08OL673 08OL781 08OL815 08OL1071 08OL1151 08OL1171 08OL1231 08OL1329 08OL1333 08OL1437 08OL1577 08OL1967 08OL2159 08OL2307 08OL2369 08OL2461 08OL2537 08OL2621 08OL2629 08OL2657 08OL2701 08OL2657 08OL2857 08OL2897 08OL2939 08OL3089 08OL3255 08OL3263 08OL3417 08OL3433 08OL3485 08OL3535 08OL3563 08OL3567 08OL3661 08OL3883 08OL3923 08OL4017 08OL4117 08OL4267

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Six-Membered Ring Systems: Pyridine and Benzo Derivatives 08OL4383 08OL4501 08OL4617 08OL4705 08OL4791 08OL4939 08OL5083 08OL5111

08OL5187 08OL5239 08OL5289 08OL5329 08OL5425 08OPRD411 08S69 08S201 08S225 08S320 08S369 08S479 08S573 08S1541 08S1575 08S1600 08S1688 08S1703 08S1861 08S1902 08S1948 08S2337 08S2561 08S2764 08S3065 08S3081 08S3131 08S3273 08SC666 08SC754 08SC1168 08SC1355 08SC1579 08SC1662 08SC1808 08SC1896 08SC1984 08SC2584 08SC3003 08SC3170

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372 08SC3201 08SC3523 08SC4321 08SC4426 08SL77 08SL233 08SL263 08SL343 08SL359 08SL529 08SL655 08SL667 08SL695 08SL883 08SL924 08SL1125 08SL1159 08SL1185 08SL1243 08SL1250 08SL1305 08SL1309 08SL1357 08SL1361 08SL1459 08SL1647 08SL1719 08SL1724 08SL1989 08SL1999 08SL2093 08SL2257 08SL2303 08SL2334 08SL2348 08SL2479 08SL2571 08SL2579 08SL2601 08SL2629 08SL2647 08SL2674 08SL2705 08T487 08T1351 08T1671 08T1879 08T2425 08T2740 08T2755 08T2997

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Six-Membered Ring Systems: Pyridine and Benzo Derivatives 08T3176 08T3190 08T3236 08T3483 08T3935 08T4011 08T4037 08T4575 08T4803 08T4985 08T4999 08T5139 08T5291 08T5545 08T5649 08T7143 08T7273 08T7574 08T7626 08T7910 08T7914 08T8202 08T8952 08T8963 08T9309 08T9368 08T9561 08T9567 08T9705 08T9937 08T9947 08T10004 08T10172 08T10681 08T10867 08T11180 08TA131 08TA435 08TA1572 08TL250 08TL265 08TL437 08TL481 08TL723 08TL832

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374 08TL1141 08TL1301 08TL1469 08TL1492 08TL1510 08TL1670 08TL1706 08TL1768 08TL1777 08TL1948 08TL2074 08TL2578 08TL2689 08TL2865 08TL3330 08TL3368 08TL3757 08TL3785 08TL4029 08TL4349 08TL4369 08TL4437 08TL4579 08TL4720 08TL4840 08TL4922 08TL5108 08TL5366 08TL5531 08TL5990 08TL6039 08TL6104 08TL6134 08TL6231 08TL6556 08TL6728 08TL6850 08TL6901

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375

Chapter 6.2

Six-Membered Ring Systems: Diazines and Benzo Derivatives Amelia Manlove and Michael P. Groziak California State University East Bay, Hayward, CA, USA [email protected]

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6.2.1 INTRODUCTION The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the Xray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible.

6.2.2 REVIEWS AND GENERAL STUDIES A review of pyrrolo[1,2-b]pyridazines (1) was compiled to supplement Kuhla and Lombardino’s earlier review of the same topic . A description of advances in pyrimidine synthesis included new versions of conventional condensations as well as novel syntheses that utilize the intramolecular cyclization of reactive intermediates . Pyrimidine regulation, metabolism and metabolic disorders were once again examined in detail . Lithium dialkylamide deprotonations were reviewed as means of functionalizing diazines and their benzo derivatives . A description of the transformation of diazines into cycloalkyl[b]pyridines via bridged intermediates (e.g., 2) was published . Calculated (B3PW91/6-311++G(d,p)//B3PW91/6-311++G(d,p)) spin-spin carbon-carbon couplings across one, two, or three bonds were found to be in good agreement with experimental values for diazine systems . Three photon energy levels were used to study the photoionization fragmentation pathways of a variety of diazines. While some fragments were visible in the mass spectra of all the diazines, differences in fragment abundance is thought to suggest considerable intramolecular rearrangements . An elucidation of the structure-


A. Manlove and M.P. Groziak

376

activity relationships of 2,6-disubstituted pyrazines and 4,6-disubstituted pyrimidines against CK2α and CK2Į' pointed to pyrazine derivatives with (pyrrol-3-yl)acetic acid and monosubstituted aniline moieties as potent inhibitors . A novel set of diazine-bridged rhenium (I) coordination complexes displayed room temperature photoluminescent emissions in the range of 579-620 nm . Pyrimidine and pyridazine were used in monodentate ligand substitutions to create rhenium(IV) anions with tetrabutylammonium counterions that were analyzed by magnetometry and voltammetry . Substituting triflic anhydride for methyl chloroformate as the activating agents in reactions of diazines with bis(TMS)ketene acetals gave similar products with one major exception; under these conditions, pyridazine reacted to form γ-lactone 3 directly . A one-pot, multi-component synthesis required no solvents to give imines of 3-amino-2-arylimidazo[1,2a]pyrazines and 3-amino-2-arylimidazo[1,2-a]pyrimidines (e.g., 4) . Pyrazinothienopyrimidines (5) and pyrazinothienotriazolopyrimidinones were prepared in intra- and intermolecular aza-Wittig reactions , while pyrimidinylthiopyridazines were prepared as potential antimicrobial therapies . Pyrimidines and pyrazines were also popular synthetic targets for their non-linear optical, fluorescence and liquid crystalline properties . O2 N N N

N N +

N

NO2

N N

N

1

NO2

H N 2

Me

I

Me O

O N N COOMe 3

NHAr

Ar N

N

N N

N Ar

4

N N

N NH2 O

S 5

6.2.3 PYRIDAZINES AND BENZO DERIVATIVES A wide variety of theoretical and experimental techniques were used to study pyridazines in 2008. One QSAR study of pyridazinones showed correlations between δE, log P and the fungicidal properties of the molecules , while another concerned pyridazine derivatives and provided a predictive model of antitubercular activity . The photochemical behavior of 3,6-bis(styryl)pyridazines was found to include a stereoisomerization mechanism that could make these molecules useful in imaging technologies . Ionization spectroscopy and EOM-CCSD calculations were used to hypothesize a partial delocalization of the S1-S0 excitation of pyridazine . A kinetic study of the thermal and light-assisted dimerization of 3-(p-bromophenyl)pyridazinium benzoyl methylide (6) supports a multistep mechanism for the reaction . Pyridazines were once again useful in preparing Schiff-base ligands, in silver(I) complexes with bis-bidentate ligands . A new pyridazine ligand, benzil (4-benzyl-6-phenyl-pyridazin-3-yl)hydrazone (7), was found to

Six-Membered Ring Systems: Diazines and Benzo Derivatives

377

form mononuclear coordination complexes with a variety of transition and lanthanide elements . Iron(III) complexes with derivatized pyridazine ligands were immobilized in NaY zeolite by a bacterial biofilm biosorption process; such complexes are expected to perform as catalysts under mild conditions . O N Br

NH+

-H

2C

O 6

PhCH2 N HN N N 7

6.2.3.1 Syntheses Hydrohydrazinations were widely used in the preparation of pyridazines. One-pot Nalkylations and hydrazinations gave 5-alkyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-ones and 1,4(5H)-diones . A zinc chloride-mediated hydrohydrazination of 4-pentynoic acid gave aryl-substituted 4,5-dihydro-3-(2H)-pyridazinones (8) . A hydrohydrazination of 2-(diethoxyphosphoryl)-4-oxoalkanoates followed by a Horner-Wadsworth-Emmons olefination gave a series of disubstituted pyridazin-3(2H)-ones . Pyridazinoindoles were synthesized from ethyl 3-formyl-substituted-1H-indole-2-carboxylates and arylhydrazines , while cyclopropane ring-fused pyridazinones (9) were prepared in a stereoselective hydrohydrazination . Formazans were used in microwave-assisted cycloadditions to produce aminoazothienopyridazinones and aminoazophthalazines . Two convenient large-scale hydrohydrazine syntheses of disubstituted 3,5dihydroimidazo[4,5-d]pyridazin-4-ones 10 and 11 were developed for use in making DPP-4 inhibitor BI 1356, each rendering chromatographic purification unnecessary . Novel pyridine N-imine cycloadditions with alkyne-substituted γ-keto acids were followed by hydrazine condensation to produce 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazinones . Likewise, condensation of hydrazine onto γ-lactones led to a wide variety of substituted 3(2H)pyridazinones . Elsewhere, 6-substituted 5-hydroxy-3-oxo-2,3-dihydropyridazine-4-carboxylates were prepared in good yields via an intramolecular Dieckmann cyclization . Convenient cyclizations of a wide range of pyridazines and other heterocycles from 3-oxo-N-(pyrimid-2yl)butanamide were reported . A recyclization of 3-formylchromones with Naminoimidazoles in the presence of trimethylsilyl chloride produced a series of imidazo[1,5b]pyridazines . The synthesis of pyridazines functionalized with amino acid moieties (e.g., 12) proceeded simply via a Tebbe olefination followed by a Diels-Alder reaction with tetrazine . Twenty-eight 3,6-di(2-pyridyl)pyridazines were synthesized from alkynes and 3,6-di(2-pyridyl)-1,2,4,5-tetrazine using an inverse electron demand Diels-Alder reaction scheme . Finally, pyrazolo[3,4-c]pyridazines were formed unexpectedly in a one-pot reaction of ethyl 2-arylhydrazono-3-oxobutyrates with potassium cyanoacetohydroxamate .


378

COOH

R N H

+

NH2

R

ZnCl2, THF

N

100 °C, 24 h

N

Me

O 8

F 3C O

CN

H

NC NH2NH2•H2O

H

CO2CH3 O

DME

R

9

N

HN N

Br N

N Me

10

O

OMe

O

Tebbe reagent N Boc THF, -40 °C

N Boc

H N

HN N

N

N Me BI 1356

OMe

O

N

N

N

R

Me

O

Me

O

NH N

F3C

N NH2

MeO

N N

OMe

O

N N

O

dioxane, rt.

Br N Me 11

CO2Me N N CO2Me

N Boc

12

6.2.3.2 Reactions Pyridazinium bromides (13) were prepared from pyridazine and used to form the N-ylides (14) as in situ intermediates in the formation of fused-pyridazine cycloadducts (15) . Another study detailed the functionalization of pyridazinylboronic acids and esters in a directed ortho metalation-boronation procedure leading to heterocycle-disubstituted pyrazinones (16) . A variety of aryl-substituted 1H-pyridazino[1,2-a]indazole-1,6,9(2H,11H)triones were prepared via a one-pot synthesis, and tested for antibacterial activity . The synthesis of fluorescent pyrrolo[1,2-b]pyridazines utilized a cycloaddition of alkyne dipolarophiles with 1,3-oxazolo[3,2-b]pyridazinium 2-oxides . One-pot SuzukiMiyaura cross-coupling reactions gave dual arylations of 6-chloro-2-chloromethylimidazo[1,2b]pyridazine . In another Suzuki-Miyaura reaction, asymmetrically 5,6disubstituted pyridazinones (17) were prepared with microwave irradiation . Elsewhere, an investigation into 3- and 6-functionalizations of imidazo[1,2-b]pyridazines utilized a variety of other palladium cross-coupling reactions along with SNAr reactions to attach heteroatoms at the 6-position .


O N N Br

CHCHOC6H4R

H

13

O

Ph N

N N

Et3N

379

H

Me

N

Me N N

O O

COC6H4R

O

15

14 O

Ar

O NH N

Ar 16

R1

N R2

N N Cl

R3

R O

Ar-B(OH)2 5 mol % Pd MW 135-140 °C 30 min

R1

N R2

N N

R3

Ar 17

6.2.3.3 Applications A number of studies addressed pyridazine derivatives, with cores 18 and 19, as potential treatments for hepatitis A and hepatitis C . Hexahydropyridazine 20 was found to be an inhibitor of cathepsin K, showing dose-dependent reduction of bone resorption in osteoclasts , while a series of 3,5-dihydroimidazo[4,5-d]pyridazin-4-ones were discovered to be formidable inhibitors of DPP-4 . Pyrrolo[2,3-d]pyridazine CS-526 (21), was shown to be a potent suppressor of gastric acid secretion that, importantly, does not cause post-treatment hypersecretion . Pyrazolo[1,5-b]pyridazines were synthesized as anti-tumor treatments that target cyclin dependent kinase . In two separate studies, pyridazinones (22 and 23) showed promising anti-viral properties against both wild-type and mutant strains of HIV . Arylethyl- and arylethenyl-pyridazinones were prepared and investigated as anti-inflammatory COX-2 inhibitors . Investigations into fluorinated pyridazinones found 24 to be a promising cardiac radiotracer . Pyridazinone derivatives with known anti-inflammatory properties were found to also act as antioxidants at micromolar concentrations . Structure-activity relationships were elucidated for (3-oxo-3-phenylprop-1-en-1-yl)-substituted pyridazin-3(2H)-ones as antiplatelet agents as well as for pyridazinone-substituted phenylalanine amides as α4 integrin antagonists . Pyridazinone derivatives such as 25 and 26 were designed and synthesized as potential vasorelaxant drugs . Incorporation of aminosubstituted imidazo[4,5-d]pyridazinones into nucleosides gave purine nucleoside analogs 27 and 28 that show potent inhibition of adenosine deaminase; the ribonucleoside analogs (27b and 28b) also showed excellent potential as breast cancer therapies . In the non-biomedical field, a set of 4-(3-trifluoromethylphenyl)pyridazines were found to perform well as bleaching herbicides . Finally, oxadiazolyl 3(2H)-pyridazinone (29) was shown to inhibit larval development in Pseudaletia separata armyworms by interfering with carbohydrate digestion .


380

R1

OH

O N S O

N

N N R2

HN

N

N

R3

N

O

N

O Me

S R 19

O

O

H N

Me 20

18 R2 R3 R4 O F

N

N N

R1

Me

F

22

Me

OH

O

R

EtO2C

N

Cl O

O

NH

N HN

25

N H

24

O Me

23

O

O

N N

NH

Cl O

O

N

O

Me

21

Me3C

NC

N N R5

N

N

CN N

NH

OH

Me

CH2OCH2CH218F

N

Me

26

O

NH2 N

N NH

N HO O OH R 27a, R=H b, R=OH

N

O

NH N

N HO O

NH2

O HN N

H N N O

OH R

29

28a, R=H b, R=OH

6.2.4 PYRIMIDINES AND BENZO DERIVATIVES A review in 2008 covered the recent advances in the synthesis of pyrimidines . Two computationally-focused studies were published. A high-level one focused on the energies and structures of 2-pyrimidinethiol 30a, 4-methyl-2-pyrimidinethiol 30b, 5-methyl-2pyrimidinethiol 30c, and 4,6-dimethylpyrimidinethiol 30d, and their dimers, disulfides, sulfenyl radicals, and tautomers . In another, the higher formation yields measured in the ultrafast photoinduced formation of cyclobutane thymine dimers (31) with respect to those of cytosine (32) were explained, shedding light on the frequencies of these dimer formations in UVirradiated DNA .

Six-Membered Ring Systems: Diazines and Benzo Derivatives R1

N

SH N

R2 R3

381

O O H 2N NH2 30a, R1 = R2 = R3 = H; MeMe H H 1 2 3 b, R = Me, R = R = H; HN NH N N c, R1 = R3 = H, R2 = Me; O O O N N N N d, R1 = R3 = Me, R2 = H O H H H H 31

32

Spectroscopic aspects of pyrimidines were investigated in a good number of studies. Bisazodianil compounds based on pyrimidinyl azo hydroxybenzaldehydes and primary aliphatic diamines were prepared and analyzed by UV/Vis, IR and 1H NMR. In this study, the change in the absorption spectra with varying pH was utilized to calculate acid dissociation constants. Moreover, the important bands of IR and signals of the 1H NMR spectra were assigned. Finally, the fluorescence spectra of the compounds were examined . Complete and unambiguous 1H, 13C, and 15N NMR chemical shift assignments of the pyrimidine-β-carboline natural product alkaloids annomontine, methoxyannomontine, and N-hydroxyannomontine (3335, respectively) were performed . Diode laser transient absorption spectroscopy was used to examine the CO2 collision-induced relaxation of laser-excited vibrationally hot pyrimidine . The C 1s and N 1s Auger spectra of pyrimidine, 2-chloropyrimidine, and 5-bromopyrimidine were measured in an electron impact experiment at 1000 eV, and these spectra were thoroughly analyzed and interpreted . The collision induced dissociation of deprotonated guanine was studied by using sequential ion trap tandem mass spectrometry and isotopically labeled guanine analogs. The mechanisms of pyrimidine ring opening and closure prior to the decomposition of deprotonated guanine was elucidated . The IR spectral and structural changes induced by mono- and dideprotonation of 5,5-diethyl-(1H,3H,5H)-pyrimidinetrione (the sedative drug Veronal) were studied by spectroscopic experiments and ab initio computations . Finally, the low pKa value (33) at C6 of the 1-methyl-2,4-dimethoxypyrimidinium ion 36 was found to be nearly identical to that in the related N-methyl-2-methoxypyridinium 37 and N-methyl-4-methoxypyridinium ions 38 in aqueous solution . R2

OMe

OMe N N R1 N H2N

N R1

N

R2

33, = =H MeO 34, R1 = H, R2 = OCH3 35, R1 = OH, R2 = H

N Me 36

MeO

N Me 37

N Me 38

X-ray crystallographic analysis was the central focus of a good number of pyrimidine investigations. Analysis of 7-ethyl-7-hydroxy-5-phenyl-5H-tetrahydrothiazolo[3,2-a]pyrimidine prepared by condensation of 2-aminothiazoline with the appropriate α,β-unsaturated ketone revealed only one diastereomer of the 5R variant in the solid state . Structures of the closely related 3-(4-chlorophenyl)-2-(diisopropylamino)-1-benzofuro[3,2-d]pyrimidin-4(3H)-one 39 , 3-butyl-2-propylamino-1-benzothieno[3,2-d]pyrimidin-4(3H)-one 40 , and 3-phenyl-2-(prop-2-ynyloxy)-1-benzofuro[3,2-d]pyrimidin-4(3H)-one 41 were reported, as was that of somewhat related 3-benzyl-1-butylimidazo[1,2-


382

a]benzothieno[3,2-d]pyrimidine-2,5(1H,3H)-dione 42 . Solid-state structures of the ethyl esters of 2-benzylsulfanyl-7-(2-chlorophenyl)-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5a]pyrimidine-6-carboxylate 43 and 5-chloromethyl-2-methylsulfanyl-7-phenyl4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylate 44 were reported, as were those of 2-(dimethylsila)pyrimidine derivatives . Cl

O O

O

N N

O

N

N

N H

N

N

39

41

H N N

O

O

N N N

N

N

O

H N

Cl O

S

N N N

S

O

Cl

42

O

N

40

O S

O

S

44

43

A new symmetrical "Leonard/trimethylene linker" isopropyl analog 1,3-bis(4-isopropoxy-6methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane 45 was studied by both 1H NMR and X-ray crystallography. It was found to have an atypical structure attributed to the bulk of the isopropyl groups . N-(4,6-Dimethylpyrimidin-2-yl)-N'-(3-trifluoromethylphenyl)guanidine 46a , N-monomethylated 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4(pyridin-3-yl)pyrimidin-2-yl)urea 46b , and a pyrimidinophane with two uracil moieties were each investigated by X-ray methods, as was the recognition of aromatic dicarboxylic acids by substituted amino-pyrimidines . Finally, ureido pyrimidinediones with Ph, 1-naphthyl and 2-naphthyl substituents (47a-c, respectively) were found to form stable dimers via quadruple H-bonding . Whereas 47a and 47c used the DDAA pattern shown, the 1-naphthyl derivative 47b was found to exist as an unexpected tautomer in the solid state, and used a DADA pattern for dimerization instead. N N O Me S N O N OPri

R1

OPri

N

Me NH

N

N

N N

F3C

O S O Me 45

O R

N

N

N

D H DH

N R2

O

N A

N

Me

46a, R1 = R2 = H; b, R1 = CF3, R2 = Me

O H

N H

A

47a, R = Ph; b, R = 1-naphthyl; c, R = 2-naphthyl


383

Pyrimidine X-ray structural reports of an organometallic nature included networks of Ag(I) and Hg(II) complexes of two constitutional isomers, bis[4-(3-pyridyl)pyrimidinylthiomethyl]benzenes 48 and 49 , Sn(IV) complexes with 2-mercapto-4methylpyrimidine used to study their influence upon the catalytic peroxidation of linoleic acid by the enzyme lipoxygenase , and a trinuclear-based Cu(II) compound containing N(pyrimidin-2-yl)acetamide and dicyanamide ligands . Binuclear Cu(II) complexes and Mn(II) and Co(III) complexes of two pyrimidine-derived Schiff base ligands were solved crystallographically and were evaluated for their magnetic properties. Chlorocadmate(II) salts of 1,2,4-triazolo-[1,5-a]pyrimidine 50a and its 5,7dimethylated derivative 50b were prepared and studied by X-ray. These heterocycles were found to be protonated at N3 in both cases . In a related study, five Cu(II) salts of these same two heterocycles were examined by X-ray. They were found to be monodentately coordinated via their N3 in all cases . In the Pt(II) complex transPt(Me(PhCH2)SO)(pyrimidine)I2, the C-atom of the CH3 group was found to lie in the Pt(II) plane while the pyrimidine ligands were perpendicular to it . N

N N

N

S

S

N

N

N N

N

S

S

N

N

48

N

49 R

N

N N N

50a, R = H; b, R = Me

R

6.2.4.1 Syntheses Microwave-accelerated chemistry continued to be a popular way to synthesize pyrimidines in 2009, and in particular, solvent-free approaches. One was the preparation of 32 various pyrazolo[3,4-d]pyrimidines 53 using hydrazine and N4-substituted 2,4-diamino-6-chloro-5carbaldehydes 52, themselves prepared by aminating 2-amino-4,6-dichloropyrimidine-5carbaldehyde 51 derived from 6-aminouracil . Another was an approach to similar substituted pyrazolo[3,4-d]pyrimidines . Two of the products were characterized by X-ray diffraction in the latter report. Another was an approach to a series of 8 6-(2hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines 56 using 5-amino-1H-pyrazoles 54 and 3-benzoyl-2-methyl-4H-chromen-4-one 55 as co-reactants . And still another was an approach to pyrrolo[2,3-d]pyrimidine-annulated pyrano[5,6-c]coumarin/[6,5c]chromones 59a,b by an intramolecular hetero Diels-Alder reaction starting from 1,3-dimethyl1-pyrrolo[2,3-a]pyrimidine-2,4-diones 57a,b and 1,3-diones 58 .


384 OH N H2N

N

OH

DMF

CHO HNR1R2

N H 2N

N

NH2

O

MW

NR1R2

N

R O

O

O

O

N

O

Me

CHO + N Me

MW

N

O

R1

R2

O 56

O H

N

O

NR1R2

Me

Ph

O

O

N

N N

MW

55

Me

H2N

53

N

Ph

N

52

Me

+

N N H 54

CHO NH2NH2

N

Et3N H2N EtOH heat

Cl

51

R

HN N

Cl

Cl POCl3

N Me

OH

O

N

O H

58

2 R1 R

59a,b

57a, R1 = H, R2 = Ph; b, R1 = R2 = Me

Not all of the microwave-assisted protocols were solvent-free. One was developed for the synthesis of pyrazolo[1,5-a]- and [3,4-d]pyrimidines (59 and 60, respectively) , while another was developed for the ligand-free Suzuki cross-coupling reactions of dihalopyrimidines . Poly-substituted pyrido[2,3-d]pyrimidines were obtained from a microwave-assisted multicomponent reaction , and the three-component reaction of benzaldehydes, malononitrile, and N-unsubstituted amidines to form 4-aminopyrimidine-5carbonitriles 61 was conducted in water at reflux or by using microwave heating . Finally, a three-component microwave-assisted synthesis of benzo[1',2':6,7]quinolino[2,3d]pyrimidines was developed based on the condensation of an aromatic aldehyde, 2hydroxynaphthalene-1,4-dione, and 2,6-diaminopyrimidin-4-one in the mixed solvent system of acetic acid and glycol . NR3R4 R2

N N R1

CN N

N

MW 82-99%

N R1

NH2

4 steps

N

N N R1

MW 35-55%

59

N 60

R1 R1CHO + CH2(CN)2 +

NH•HCl

NaOAc

CN

N R2

NH2

aq. EtOH heat (46-82%) R2 or MW (67-96%)

N 61,

NH2 R1

= substituted Ph; R2 = Ph or NH2


385

Some syntheses of pyrimidines relied upon catalyzed reactions, and often that catalyst was a metal. 2-Arylthio-4-quinazolinone and 2-arylthiothieno[2,3-d]pyrimidin-4-one methanesulfonamides were shown to undergo efficient coupling with aryl iodides in the presence of a powdery Cu(s)/CuI catalyst . A Cu-catalyzed benzyloxylation of 5-halopyrimidines 62 gave derivatives 63 for catalytic hydrogenation leading to substituted 5-pyrimindinol antioxidants, among others . This method was extended to the preparation of 5pyrimidinamines by using BnNH2 instead of BnOH. A one-pot, four-component reaction involving the Pd-catalyzed coupling of a halide, a terminal alkyne, Mo(CO)6, and either a hydrazine or amidine was demonstrated to be an efficient route to highly substituted pyrimidines, as well as pyrazoles . Tetrasubstituted pyrimidines were prepared from readily available Biginelli 3,4-dihydropyrimidin-2(1H)-ones by a sequence of dehydrogenation, chlorination, and Pd-catalyzed Suzuki or Sonogashira coupling reactions. The products were screened for antifungal activity . Suzuki-Miyaura cross-coupling reactions were used to prepare star- and banana-shaped oligomers with a pyrimidine central core and ʌconjugated arms consisting of aromatic rings bearing electron-donor substituents . InCl3 was found to be an efficient catalyst for the intramolecular aza Diels-Alder cyclization reaction of aldimines derived from aldehyde 64 to give pyrrolo[2,3-d]pyrimidineannulated tetrahydroquinolines 65 , and indazole regioisomers such as 3-amino-4(trifluoromethyl)-6-phenyl-1H-indazole-7-carbonitrile and 3-amino-6-(trifluoromethyl)-4phenyl-1H-indazole-7-carbonitrile were independently reacted with formaldehyde followed by Diels-Alder reaction with unsymmetrical, symmetrical, and cyclic electron-rich olefins in presence of GdCl3 as catalyst to give pyrimidine fused indazoles, respectively. The reaction was concerted and an exclusive product formed .

R

10 equiv. BnOH, 1.5 equiv. Cs2CO3

I (Br)

N

10 mol % CuI, R 20 mol % 1,10-phenanthroline, toluene, 110 °C, 24 h

N

62 (R =NMe2, NH2, OMe, OH, Et, Cl, Br, CN, NO2) O Me O

R

N

CHO N Me

N

64

+ H 2N

20 mol % Me InCl3 N

R = H, Me, OMe, Cl, Br, NO2

CH3CN

O

OBn

N N 63

O H H N N Me

N H

R

65 (+ trans isomer)

Syntheses using nonmetal catalysts were also reported. A one-step multicomponent preparation of pyrimidines was developed based on the SiCl4-catalyzed reaction of aldehydes, 1,3-dicarbonyl compounds, and urea or thiourea . A three-component acid-catalyzed condensation of an aryl aldehyde, a 1,3-dicarbonyl compound, and cyanamide produced a series of twenty-one 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidines 66 , and a one-pot base-catalyzed heterocyclization of 2-amino-5-phenyl-3-furancarbonitrile with isothiocyanates gave new furo[2,3-d]pyrimidines . Carbodiimides derived from aza-Wittig reactions of an iminophosphorane with aryl isocyanates reacted with secondary amines, phenols


386

or alcohols in the presence of catalytic amts. of K2CO3 or sodium alkoxide to give 2-substituted benzofuro[3,2-d]pyrimidin-4(3H)-ones . Finally, the KF/Al2O3-catalyzed reaction of 1,3-diaryl-2-propen-1-ones and 2,6-diamino-4-hydroxypyrimidine gave 5,7-diarylpyrido[2,3d]pyrimidines upon air oxidation . O R1CHO + 2 H2NCN +

HCl, NaOAc

R2 R3

R1

O

O

R2

EtOH, 78° C 4h

NH R3 66

N H

N

CN

One-pot, multistep or multicomponent reactions were once again an efficient way to synthesize pyrimidines. For example, 5- and 6-substituted 2-phenyl-3H-pyrimidin-4-ones were easily obtained in a one-pot fashion by the reaction of 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones with benzamidine hydrochloride . A one-pot synthesis of 5-benzyl-4(3H)pyrimidinones was developed via N-formylation of primary allylamines in the presence of neat H2NCHO followed by HCO2NH4-mediated cyclization. The products could be transformed into 4-pyridinamines . A one-pot regioselective preparation of 2H-[1,2,4]thiadiazolo[2,3a]pyrimidines was developed, and the course of the reaction was analyzed by semi-empirical MO methods . An X-ray crystal structure of one of the products was determined. A one-pot, three-component synthesis of fused bicyclic 2,3-diarylpyrimidin-4(3H)-ones was developed based on a key step involving a Lewis acid-assisted cyclization . A greener, three-component protocol for the preparation of pyrimido[4,5-b]quinolines and indeno[2',1':5,6]pyrido[2,3-d]pyrimidines was developed by condensing aldehydes, 6aminopyrimidine-2,4-dione, and 5,5-dimethyl-1,3-cyclohexanedione or 1,3-indanedione in the ionic liquid 1-n-butyl-3-methylimidazolium bromide . A one-pot synthesis of 4alkoxy-5,6-dihydrofuro- and -thieno[2,3-d]pyrimidines was developed based on the reaction of 2-benzamido-4,5-dihydro-3-furan- and -3-thiophenecarbonitriles with EtOH or MeOH in the presence of ZnCl2/NEt3 . Pyrrolo[2,3-d]pyrimidines were among the fused pyrimidines accessed by a one-pot three-component condensation of aryl aldehydes, urea or guanidine, and various heterocycles , and a three-component, one-pot, solvent-free synthesis of pyrimido[4,5-d]pyrimidine-2,4-diones was developed by condensing 6-amino-1,3dimethyluracil, aldehydes, and S-benzylisothiourea hydrochloride . Finally, a convenient synthesis of substituted imidazo[1,2-a]pyrimidin-7-ylamines 67 from allylamines and cyanamide was reported . The allylamines were obtained via Baylis-Hillman reaction of substituted benzaldehydes and heterocyclic aldehydes. Interestingly, the allylamines generated from heterocyclic aldehydes underwent a one-pot reaction, whereas those derived from other aldehydes reacted by a two-step procedure.

CH(OMe)2 1. aq. AcOH R

H2N

CN NH2

CN NH R = aryl, heteraryl

R

N

N

N

NaOMe

2. HCl (one-pot) 1. aq. AcOH; 2. HCl (one-pot)

RCH2

N N 67


387

Condensation reactions were popular ones for constructing pyrimidines. Ureidopyrroles 68 were condensed directly with aryl aldehydes in the presence of TFA to give pyrrolo[3,2d]pyrimidines 69a-d . An efficient soluble polymer-supported synthesis of 5arylidenepyrimidinones using aniline as a traceless linker was developed . In that synthesis, aldehydes were attached to PEG-bound aniline via their imine, and after a PEGpromoted Suzuki coupling reaction for diversification, Knoevenagel condensation was used as the cleavage strategy. (E)-3-(N,N-Dimethylamino)-1-(3-methylthiazolo[3,2-a]benzimidazol-2yl)prop-2-en-1-one, prepared by condensing 1-(3-methylthiazolo[3,2-a]benzimidazol-2yl)ethanone with DMFDMA, was treated either with 5-amino-3-phenyl-1H-pyrazole or 3-amino1,2,4-(1H)-triazole to give pyrazolo[1,5-a]pyrimidines and 1,2,4-triazolo[1,5-a]pyrimidines, or with 6-aminopyrimidines to give pyrido[2,3-d]pyrimidines . Cyclocondensation of thioglycolic acid with methylene-bis-(N-cyclohexylidene-N-pyrimidine) gave methylene-bispyrimidinyl-spiro-4-thiazolidinones which were evaluated for antibacterial and antifungal activities . Cyclocondensation of 4-isothiocyanato-4-methylpentan-2-one with 1,2-diaminocyclohexane, 3-amino-2-naphthol, 1-amino-2-naphthol•HCl, 3-amino-2-naphthoate, 1,3-diamino-2-hydroxypropane, and 1,3-diaminoguanidine•HCl or of 3-isothiocyanatobutanal with 1,2-diaminocyclohexane and 1,3-diaminoguanidine•HCl gave the corresponding fused perhydropyrimidine-2-thiones . CO2Bn Bn O

NH

CO2Bn 4-R-C6H4CHO (10 equiv.)

N NHBn 68

TFA (3 equiv.) 140 °C, 1.5 h

R1 O

NH N N R3

R

69a, R = H (55%); b, R = Me (63%); c, R = MeO (53%); d, R = NO2 (28%)

Cyclization routes were also developed for preparing pyrimidines. A parallel solution-phase synthesis of substituted thieno[2,3-d]pyrimidin-6-carboxylic acids was developed, based on the dry HCl-mediated cyclization of 2-aminothiophen-3,5-dicarboxylates with nitriles . 5-(2-Hydroxybenzoyl)pyrimidines and heterofused analogs were prepared by Me3SiCl-promoted recyclization of 3-formylchromones with 1,3-NCN-binucleophiles . Cyclization of 3-formylchromone with 2-methylpyrimidin-4(3H)-ones promoted by Me3SiCl led to fused pyrido[1,2-a]pyrimidin-4-ones . Methyl-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylates were prepared by sequential cyclization of 2-aminopyridine-1-oxides with DMAD . New tricyclic pyrimidine-fused 8-membered heterocycles like pyrimidobenzodiazocines were prepared via iminium ion cyclization in pyrimidinediamines containing electron-rich aromatic rings . Pyrazolo[4,3-e][1,2,4]triazolo[4,3c]pyrimidines 71 were obtained by the oxidative cyclization of aldehyde N-(1,3diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones 70. A Dimroth rearrangement of the products generated pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines 72 . The first catalystfree tandem acetalization/5-exo-dig cyclization reaction of 6-phenylethynylpyrimidine-5-


388

carbaldehydes led to the development of a new synthesis of 5,7-dihydrofuro[3,4-d]pyrimidines . The stereoselective synthesis of a benzyl-octahydropyrazino[1,2-a]pyrimidin-6one was developed based on an intramolecular acyliminium ion cyclization . 3Phenylthiazolo[4,5-d]pyrimidine-2-thiones were obtained by cyclization of 4-amino-5alkyl(aryl) carboxamido-2,3-dihydrothiazolo-2-thione with aryl aldehydes . The products were characterized by IR, 1H NMR, and 13C NMR, and they were evaluated in an antitumor screening assay.

Ph

HN

N 70

R

R Ph

N

N N Ph

N

N N N

N N Ph

N 71

Ph

N N

R

N

N N Ph

N 72

1-Aryl-2-oxo-indano[3,2-d]pyrimido[1,2-b]pyrimidines were prepared via Michael addition of 2-aminopyrimidine to 2-(arylidene)-indan-1,3-diones, they were characterized by IR, 1H NMR, and 13C NMR, and their antibacterial and antifungal activities were also investigated . 2-(Alkylamino)-1,4,5,6-tetrahydropyrimidin-4-ones were prepared from N-alkyl βamino acid esters by a guanidinylation reaction employing a sulfonyl-activated thiourea . 2-Substituted benzo[3',2':5,6]thiopyrano[4,3-d]pyrimidines were derived from the key intermediate 3-(dimethylaminomethylene)-7-methoxy-2,3-dihydrobenzo[3',2':5,6]thiopyran4(4H)-one . 2-Amino substituted thieno[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)ones were prepared from carbodiimides derived from a mono(iminophosphorane) and aryl isocyanates , and 2,3-diaminothieno[2,3-d]pyrimidin-4(3H)-ones were obtained from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-carboxylates, themselves obtained from the corresponding 2-amino-thiophene-3-carboxylates and HC(OEt)3 and NaN3 . 2,3Dicyano-imidazo[1,2-a]pyrimidines were synthesized from 4-hydroxy-6-methylpyran-2-one and 2-amino-4,5-dicyanoimidazole . 5-Alkyl/arylamino- and 5,7-dialkyl/arylaminopyrido[2,3-d]pyrimidine-2,4-diones were generated from the corresponding 5,7-dichloropyrido[2,3-d]pyrimidine-2,4-diones by a regioselective amination reaction . 5Amino-2-(methoxymethyl)pyrimidine was transformed into pyrrolo[2,3-d]pyrimidines with various substituents on N1 and C2 , and 6-amino-5-(3,4-dihydroxyphenyl)pyrimidine was prepared electrochemically by oxidation of catechol in the presence of 4(6)-aminouracil . A one-step direct synthesis of pyrimidines and quinazolines from N-vinyl and N-aryl amides was developed. It consists of amide activation with Tf2O/2-chloropyridine followed by nitrile addition and annulation . A cascade reaction of aminopyrimidines with N-alkylated amino acids was developed for the preparation of tetrahydropyrimido[4,5-d]pyrimidines . A common precursor was used to prepare pyrido[1,2-f]pyrimidine, pyrazolo[3,4b]pyrido[1,2-f]pyrimidine, 6-(4-substituted styryl)pyrimidine, pyrido[4,3-d]pyrimidine, pyrimido[5,4-d]pyridazine, and substituted-6-(thien-2-yl)pyrimidines . A regioselective synthesis of 5-amino-6-arylamino-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones was developed, based on tandem aza-Wittig and annulation reactions of iminophosphorane, aromatic isocyanates, and hydrazine. X-ray and antifungal activity analyses were performed


389

. A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines was developed, based on a carboxamide-mediated internal C6 activation the 2-chloro-4-anilino-1H-pyrrolo[2,3d]pyrimidine precursors . Functionalized pyrimidines were obtained from unprotected, bio-renewable aldoses via an aza-Michael addition of aromatic amines aldose-derived 1,3-oxazin-2-ones followed by dehydrative ring transformation to 4-polyhydroxyalkylpyrimidin-2-ones . Highly conjugated arylpropenylidene-1,3-diazin-2-ones were prepared in a Paterno-Büchi reaction by photoreaction of 5-fluoro-1,3-dimethyluracil with 1-methoxynaphthalenes . Highly functionalized pyrimidinyl arylglycines 75 were prepared by a three-step sequence consisting of Mitsunobu O-alkylation of 2-(benzylsulfanyl)-4(3H)-pyrimidinones 73 with N-Boc βaminoalcohols, Petasis reaction using glyoxylic and phenylboronic acids, and displacement of the activated sulfur with morpholine . Some of the products of the first step were found to undergo spontaneous Smiles rearrangements to corresponding pyrimidinyl-4-amines 74. In a multistep route starting from 2-chloro-5-(chloromethyl)pyridine, 3-[(6-chloropyridin-3yl)methyl]-6-substituted-6,7-dihydro-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-imines were prepared. These weakly fungicidal and insecticidal compounds were characterized by 1H NMR and elemental analyses, and also in some cases by IR, 13C NMR, MS, and X-ray . R2 1. HO O Mitsunobu

HN BnS

N

R1

2. TFA

H N

R3

N Boc

O

R3

R2

N BnS

R2

N

R3 Smiles

R1

OH

N

N BnS

R1

N

73

74 HO2C-CO2H PhB(OH)2

Petasis

08T5226

Ph N

O

Ph

R3

N

N O

R3

R2

N

R1

CO2H N

O

R2

N BnS

CO2H

N

R1

75

Starting from a polystyrene-supported 4-hydroxy-2-methoxybenzaldehyde, a multistep process was developed for the preparation of 2,7-diamino-substituted [1,2,4]triazolo[1,5a]pyrimidine-6-carbonitriles . Tetrahydropyrimidin-2-one-5-carboxylate was prepared by an efficient modification of the Hofmann rearrangement . The fusion of 5-bromouracil with anilines followed by coupling with a benzyl halide led to 1,5-disubstituted pyrimidine-2,4-diones . The reaction of 3-nitropyran-2-one N-functionalized amidines and primary amines led to 4-(nitromethylene)-1,4-dihydropyrimidines, viewed as pyrimidine nucleoside analogs . The reaction of α,β-unsaturated acetals with aryl nitriles in the presence of the LICKOR (LochmanníSchlosser) superbase (n-BuLi/t-BuOK) gave pyrimidines . Finally, the 14C-labeling of 1H-pyrazolo[3,4-d]pyrimidine and related


390

[4.3.0]-bicyclic pyrimidino systems was achieved using sodium [14C]formate. The natural product 8-aza-7-deaza-5'-[14C]noraristeromycin was prepared by this method .

6.2.4.2 Reactions 2-Imino-7-methyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones, prepared via cyclization from 2-alkylthio-6-methyl-4-oxopyrimidin-3(4H)-yl]acetonitriles, were converted to 7methylimidazo[1,2-a]pyrimidine-2,5-[1H,3H]-diones via hydrolysis, or 7-methyl-2-aminoimidazo[1,2-a]pyrimidin-5(3H)-ones via reaction with amines . 5-Dienylpyrimidinones were shown to undergo a regioselective imino Diels-Alder reaction with N-aryl imines in the presence of MgBr2 as a Lewis acid catalyst to generate quinolines and benzoquinolines . 5,6-Diamino-2-phenylpyrimidin-4(3H)-ones underwent nitrosative cyclization with nitrous acid to give 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)ones . 6-Amino-1-methyl-2-thiouracil 76a and 6-amino-1-benzyluracil 76b were found to condense with aromatic aldehydes under acidic conditions to give different products . The former gave 5-arylmethylenebis(1-methyl-6-amino-2-thiouracils) 77a-f but the latter gave the tricyclic 1,3,6,8,9-pentaazaanthracenes 78a-f. 6-(Diazomethyl)-1,3bis(methoxymethyl)uracil, prepared from the corresponding aldehyde by hydrazone formation and oxidation, was transformed into pyrazolo[4,3-d]pyrimidine-5,7-diones by thermolysis and deprotection . 6,7-Dihydropyrazolo[1,5-a]pyrimidines underwent regioselective formylation under Vilsmeier-Haack conditions to give 4,7-dihydropyrazolo[1,5-a]pyrimidine3,6-dicarbaldehydes . O

O

HN X

ArCHO N R

NH2

76a, R = Me, X = S; b, R = Bn, X = O

abs. EtOH, HCl, 23 °C or AcOH, 115 °C

O CHAr

HN

Ar

O NH

HN

and S

N Me

NH2

O 2

N Bn

77a-f

N H

N Bn

O

78a-f a, Ar = Ph; b, Ar = 4-FC6H4; c, Ar = 2-MeOC6H4; d, Ar = 3-MeOC6H4; e, Ar = 4-HOC6H4; f, Ar = 2,4-Cl2C6H3

A halogen-metal exchange approach to 7-amido-[1,2,4]triazolo[1,5-a]pyrimidines was developed , and a cyclization reaction of 6-aminopyrido[2,3-d]pyrimidines with benzoyl chlorides generated 2-aryloxazolo[5',4':4,5]pyrido[2,3-d]pyrimidines . The conditions for this reaction were studied by differential scanning calorimetry (DSC). In an unprecedented cascade transformation, ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4tetrahydropyrimidine-5-carboxylate (79) was shown to generate diethyl 9-methyl-5-methylene3,11-dioxo-2,3,4,5,6a,7,10,11-octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]triazocine6,8(1H)-dicarboxylate (80) when treated with NaH or other strong bases like DBU and KOH . The structure of heterocycle 80 was solved by a detailed analysis of the 1H and


391

13

C NMR spectra in DMSO-d6, DMSO-d6 + D2O, and C5D5N, and of 1H,1H-COSY, 1H,13CHSQC, and 1H,13C-HMBC data. The n-Bu3SnH-AIBN mediated aryl radical cyclization of various 8-[(2-bromophenoxy)methyl]-1,3-dimethyl-2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones and 1-[(2-bromophenoxy)methyl]-3,5- dihydropyrano[2,3-c]coumarins was investigated . N-Methyl-4-(methylthio)thieno[2,3-d]pyrimidinium salts, prepared by one of two routes, were found to undergo NaOMe-catalyzed condensation with active methylene compounds like CH2(CN)2 and EtO2CCH2CN to afford N-methyl-4ylidenethieno[2,3-d]pyrimidines . Oxidation of 3,4-dihydropyrimidin-2(1H)-ones from a Biginelli reaction using an activated charcoal/O2 system led to functionalized pyrimidin2(1H)-ones . The Pd-catalyzed cyclization of 5-(4-aryloxybut-2-ynyloxy)uracils was found to proceed via an unusual [1,3] aryloxy shift followed by 6-endo-dig cyclization and a [1,3] prototropic shift to give uracil-annulated pyrano heterocycles . Primary, secondary, and tertiary aminated uracils and thymines were prepared via chloranil-mediated oxidative amination of the corresponding cuprated pyrimidines, in turn obtained via magnesiations , and pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidines were obtained via a Dimroth rearrangement from the corresponding angular isomers . EtO2C

EtO2C

CH2Cl

EtO2C H

2 NaH 2 Me

NH

Me

NH CH3CN 23 °C , 7.5 h (78%)

HN O 79

N

HN

O

N H

O 80

Regio- and chemoselective magnesiations of pyrimidines with TMPMgCl•LiCl gave highly functionalized pyrimidines upon treatment with electrophiles . The 2-cyanomethyl derivative of imidazo[1,2-a]pyrimidine was obtained, and the reactivity of its methylene group was explored . The cyclization reaction of 3-allyl-2-thiouracils with ICl followed by HI elimination led to thiazolo[3,2-a]pyrimidin-5-ones . An elimination reaction mechanism consistent with the kinetics was proposed. Two pyrimido[4,5-c]isoquinoline-7,10quinones 82a,b were obtained from acylhydroquinones and 1,3-dimethyl-5-aminouracil (81), and their cycloaddition reactions with 1-trimethylsilyloxybutadiene and 1-dimethylamino-3-methyl1-azabutadiene were investigated . Tetracycles 83a-d were produced in a highly regioselective manner. COR1 O

O N

H2N

N Me 81

Me HO O

Me N

O

N

OH

Ag2O, CH2Cl2 23 °C 86%, R = Me; 61%, R = H

Me

O

= Me; 82a, b, R1 = H

N X R2

R1 R1

O

X R3 R2

N O

Me N

R3 O

R1

O Me

N O

R1

83a, = Me, X = CH, R2 = OSiMe3, R3 = H; b, R1 = H, X = CH, R2 = OSiMe3, R3 = H; c, R1 = Me, X = N, R2 = NMe2, R3 = Me; d, R1 = H, X = N, R2 = NMe2, R3 = Me


392

The gas-phase acidity and proton affinity properties of thymine, cytosine, and 1methylcytosine were examined by both computational and experimental methods . The hydrolysis mechanism of N,N-dimethyl-N'-(2-oxo-1,2-dihydro-pyrimidinyl)formamidine was investigated in the gas phase and simulated in aqueous solution by a hybrid density functional theory computational study . The kinetics of association of ureidopyrimidinone dimers, in either 4(1H)-keto or pyrimidin-4-ol form, with 2,7-diamido-1,8naphthyridine into a complementary heterodimer was investigated . The regioisomeric product distribution in the reaction of 6-methyl-2-thiouracil with bromodiethyl malonate, bromomalononitrile, and 2-(bromomethyl)benzonitrile were investigated using a combination of 1H NMR and computational methods . The reaction of 6-acetyl-7-(2dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines with 1,3- and 1,4-bisnucleophiles was investigated, generating new polycyclic heterocycles . The tautomers of the protonated forms of 1-amino-5-benzoyl-4-phenyl-1H-pyrimidine-2-one and -2-thione were investigated by UV-vis spectroscopy . The triplet-triplet energy-transfer process which may proceed through hydrogen bonds was investigated using phosphorescence quenching and flash photolysis experiments with a 2-ureido-4(1H)-pyrimidinone self-complementary quadruple H-bonded assembly . Finally, the key step in the synthesis of a novel anti-HIV drug was shown to proceed via an unprecedented stepwise radical pair rearrangement mechanism proceeding through intermediate 84 . O MeO2C

N H

N H2N

O

MeO2C

CO2Me CO2Me

N

N H H

N

H 84

H

CO2Me

O

CO2Me MeO2C

H N

OH

HN N

CO2Me

6.2.4.3 Applications One pyrimidine-based application reported was the development of a new series of push-pull compounds containing a pyrido[4,3-d]pyrimidine central core for their potential use as nonlinear optical (NLO) materials . They were prepared via a metalation/cross-coupling route. In another application, the analysis of the solid-state and solution structures of macrocycles consisting of a pyrimidine ring and an aza- or thiapolymethylene bridge connecting N1 and N3 was undertaken . Finally, cationic dimeric pyrimidinic surfactants were prepared, and the aggregation and catalytic properties of systems based on these and polyethyleneimine were studied . Many more of the applications reported for pyrimidines focused on their metal complexes. A new 2-dimensional Mn(II) coordination polymer with mixed pyrimidine-2-carboxylate and oxalate bridges was prepared, and its structure and magnetic properties were examined . Similarly, linear tri- and tetra-copper chains containing anions of N,N'bis(pyrimidine-2-yl)formamidine were prepared for an examination of their solid-state structural and magnetic properties . Also, Mn(II) coordination polymers 86-89 containing the bridging ligand pyrimidine-4,6-dicarboxylate (85, pmdc) were prepared. Depending on the reaction conditions of temperature and solvent, either 1-D chains or 2-D layers were obtained. Their thermal, magnetic, and adsorption properties were studied, and antiferromagnetic


393

properties were discovered . Isostructural Zn, Cu, Ni, Co, and Mn complexes with 5-(4-[N-t-butyl-N-aminoxyl]phenyl)pyrimidine were prepared, and their magnetic and EPR spectral characteristics were studied . In similar investigations, Co(II) and Cu(II) complexes with deprotonated N-[2'-(4-methyl)pyrimidinyl]-2-nitrobenzenesulfonylurea were prepared and their structures characterized by IR spectroscopy, elemental analysis, and X-ray diffraction , Co(II) and Ni(II) complexes containing 4-amino-1,3-dimethyl-2,6pyrimidinedione Schiff-base ligands with various benzaldehydes were prepared and characterized by elemental analysis, molar conductance, magnetic moment, thermal and XRPD analysis, and IR, 1H NMR, and mass and solid reflectance spectroscopy , and Co(II) and Cu(II) complexes of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (the antimicrobial drug trimethoprim) were synthesized and characterized by elemental analysis, UVvis and IR spectroscopy, magnetic susceptibility measurements, and EPR . HO2C

CO2H N

Mn2+ [Mn(pmdc)]•2H2O 3D polymer 86

DMF 110 °C

N 85

Mn2+ H2O 20 °C

{[Mn(pmdc)(H2O)3]•2H2O}n 1D polymer 87

{[Mn(pmdc)2(H2O)5]•2H2O}n 1D polymer 88

{[Mn(pmdc)(H2O)]•H2O}n 2D polymer 89

N-(4-Amino-1-methyl-5-nitroso-6-oxo-1,6-dihydropyrimidin-2-yl)-(S)-glutamic acid was prepared, protonated, and complexed with Cd(II), Zn(II), Cu(II), and Mn(II) in an attempt to develop this ligand into one which could extract these metals from aqueous solution after being adsorbed onto activated charcoal . The X-ray structure of the Cd complex was determined. Pd and Pt complexes with 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5a]pyrimidine (HmtpO, an analog of the naturally occurring purine hypoxanthine) were prepared, X-ray structures were obtained, and DNA adduct formations were studied . Mononuclear mixed ligand complexes of Ni(II) and Ce(III) ions with 4-(3-methoxy-4hydroxybenzylideneamino)-1,3-dimethyl-2,6-pyrimidinedione and other N/O donor ligands were prepared and characterized by elemental analysis, molar conductance, IR, mass, and solid reflectance spectroscopy, and magnetic moment measurements and thermal analysis . The azo dye 4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylazo)benzene-1,3-diol was prepared, characterized, and was used to form complexes with Co(II), Ni(II), and Cu(II). The complexes were characterized by a variety of techniques, including thermal analyses (TGA and DTA) . The Heck coupling capability of new Pd(II) complexes containing pyrimidinefunctionalized N-heterocyclic carbenes was investigated in a study which included X-ray analysis and catalyst evaluation . The reaction of [RuHCl(CO)(PPh3)3] with pyrimidine gave the complex [RuHCl(CO)(PPh3)2(C4H4N2)] which was characterized by IR and UV-vis spectroscopies and X-ray crystallography . The reaction of the lanthanide metallocene allyl complexes, (C5Me5)2Ln(η3-CH2CHCH2)(THF) (Ln = Ce, Sm, Y) with 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine 90 (Hhpp) was used to prepare a series of metallocene complexes 91 . X-ray crystallography revealed isomorphous structures regardless of the size of the metal. Finally, two porous Zeolite-like metal-organic frameworks with 4,6-pyrimidinedicarboxylate (C6N2O4H2) or 2-pyrimidinecarboxylate (C5H3N2O2) bridging


394

ligands were prepared, and their ion exchange and H2 sorption properties were examined . These Zeolite-like frameworks were characterized and formulated by X-ray as and Cd(C5H3N2O2)2(C4N2H10)0.35(H2O)5.36, [In(C6N2O4H2)2Na0.36K1.28](NO3)0.64(H2O)2.1 respectively. Their study assists in the development of candidates for H2 storage at room temperature and moderate pressure.

N

N

+

Ln

N

O

Ln N H

N N

90

91

As usual, many biological applications were reported for pyrimidines. In a series of three papers, the extensive development of 2-amino-N-pyrimidin-4-ylacetamides into adenosine A2a receptor antagonists was described , and in another series of three papers focusing on the same type of antagonists, the development of thieno[3,2d]pyrimidine-4-methanone, 4-arylthieno[3,2-d]pyrimidines, pyrazolo[3,4-d]pyrimidines, and pyrrolo[2,3-d]pyrimidines was described . NPyrimidinyl-2-phenoxyacetamides were also examined as adenosine A2a receptor antagonists last year . The extensive development and discovery of 2-(1H-indazol-4-yl)-6-(4methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (92, GDC0941), a class I phosphatidylinositol-3-kinase (PI3K) inhibiting anticancer agent , (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid 93 (BMS-644950), a potential HMG-CoA reductase inhibitor replacement for the statin drugs , and N4-(2,3-dimethyl-2Hindazol-6-yl)-N4-methyl-N2-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine (94), the potent VEGF receptor (VEGFR) inhibiting anticancer agent known as pazopanib were related. O N S

N

N O Me

N

N S

O

92

N N H

Six-Membered Ring Systems: Diazines and Benzo Derivatives F

Me N N

OH OH N

CO2H

N

395

N N Me

N

Me

NH

N N Me

N Me

N

Pri

Me 93

SO2NH2

94

The development of pyrimidines as kinase inhibitors continued in 2008. Among those developed for the inhibition of tyrosine kinases were 1,2,4-triazolo[4,3-c]- and -[1,5c]pyrimidines , 7-aminopyrazolo[1,5-a]pyrimidines , imidazo[1,2c]pyrimidines , 3-alkoxy-1H-pyrazolo[3,4-d]pyrimidines , 4amino-6-benzimidazole-pyrimidines , imidazole-vinyl-pyrimidines , indeno[1,2-d]pyrido[1,2-a]pyrimidines , substituted pyrrolo[2,3d]pyrimidines , and pyrido[2,3-d]pyrimidin-5-ones . Still others included 6,7-dihydro-4H-pyrazolo-[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-diones as Aurora kinase A inhibitors , 3-(pyrimidin-4-yl)-7-azaindoles (meriolins—chemical hybrids between meridianin and variolin natural products) and AZD5597 (an imidazole pyrimidine amide) as cyclin-dependent kinase (CDK) inhibitors, 4-(4aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective protein kinase B inhibitors , 4-amino-5,6-diaryl-furo[2,3-d]pyrimidines as glycogen synthase kinase-3 inhibitors , 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as ErbB-2/EGFR dual kinase inhibitors , N1-(4-substituted-benzyl)-pyrimidines as Mycobacterium tuberculosis thymidine monophosphate kinase inhibitors , and a 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidinediamine as a dual EGFR/HER2 kinase inhibitor . Pyrazolo-pyrimidines were developed as p38α MAP kinase inhibitors, and the X-ray crystal structure of analog 95 bound to unphosphorylated p38α was obtained . Finally, the dependence of Janus kinase 3 (Jak3) inhibition on the stereochemistry of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile was investigated by the synthesis and evaluation of all four stereoisomers of the drug. Only the 3R,4R isomer had Jak3-dependent blocking of STAT5 (signal transducers and activators of transcription 5) phosphorylation . Me H N

HN O

N

N N

N O

N 95

Receptor antagonism was the goal of still other investigations with pyrimidines. Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines were examined as histamine H4 receptor


396

antagonists . Of the compounds prepared, 4-((3R)-3-aminopyrrolidin-1-yl)-6,7dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine (96, A-943931), combined the best features of the series in a single molecule and is an excellent tool for probing H4 pharmacology. 2-Alkyl-4-aryl-pyrimidine-fused heterocycles as selective histamine 5-HT2α antagonists , 5-(phenylethynyl)pyrimidines as mGluR5 allosteric antagonists , substituted aryl pyrimidines as TRPV1 antagonists , and heteroaryl-substituted 4-(1H-pyrazol-1-yl)-5,6-dihydro-1H-pyrrolo-[2,3-d]pyrimidines as corticotropin-releasing factor receptor-1 (CRF1) antagonists . Thieno[2,3d]pyrimidines were prepared as 5-HT3 receptor ligands , and pyrazolo[1,5a]pyrimidines were prepared as c-Src inhibitors . NH2 N

N

N

NH2

96

2,4-Diamino-5-alkyl-substituted-7H-pyrrolo[2,3-d]pyrimidines were examined as dihydrofolate reductase (DHFR) inhibitors , while both 2-amino-4-oxo-5arylthio-substituted-6-methylthieno[2,3-d]pyrimidines and 2-amino-4-oxo-5substituted-6-methylpyrrolo[3,2-d]pyrimidines were examined as dual thymidylate synthase and DHFR inhibitors. 2-(4-Methylsulfonylphenyl)pyrimidines were prepared as COX-2 cyclooxygenase inhibitors , pyrido[3,4-d]pyrimidin-4-ones as matrix metalloproteinase-13 (MMP-13) inhibitors , 5H-thiazolo[3,2-a]pyrimidines as acetylcholinesterase inhibitors , 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamides as STAT6 (signal transducers and activators of transcription 6) inhibitors , 6-substituted 5-alkyl-2-(arylcarbonyl-methylthio)pyrimidin-4(3H)ones 97 as non-nucleoside HIV-1 reverse transcriptase inhibitors , and pyrimidine and quinolone conjugates as dual inhibitors of HIV reverse transcriptase and integrase . Bicyclic pyrimidinones were prepared as HIV-1 integrase inhibitors , and 5-alkyl-6-benzyl-2-(2-oxo-2-phenylethyl-sulfanyl)pyrimidin-4(3H)-ones as anti-HIV1 agents . O R3

H S O

R1

N

R2 N 97, R1 = H, Me, Et, i-Pr, s-Bu; R2 = 2,6-Cl2, 2-Cl-6-F, 2,6-F2; R3 = H, F, OMe

A series of 1-(2-pyrimidinyl)piperazines were synthesized as potential antianxiety, antidepressant, and antipsychotic agents , and 2,4,6-functionalized pyrido[2,3d]pyrimidines were synthesized as cytotoxic agents . The SAR of pyrazolo[3,4-


397

d]pyrimidines as mGluR4 positive allosteric modulators was investigated , 2thioxo-N3-aminothieno[2,3-d]pyrimidines were prepared as antiinflammatory and analgesic agents , 5-(1,3,4-oxadiazol-2-yl)pyrimidines were prepared as selective FLT3 inhibitors , and pyrazolo[3,4-d]pyrimidines were prepared as Abl-inhibiting antiproliferative antileukemic agents . Heterocycles linked to pyrimidine via a sulfur were prepared as potential antimicrobials and antifungal agents , and 1,2,4-triazolo[1,5-a]pyrimidines were developed both as antifungal agents and as antimicrobials . A one-pot synthesis of eight pyrazolo[3,4-d]pyrimidine antimycobacterial agents was reported . 2-(2Aroylaroxy)-4,6-dimethoxypyrimidines characterized by IR, NMR, and mass spec, were prepared as anti-inflammatory agents from 2-methylsulfonyl-4,6-dimethoxypyrimidine and 2hydroxybenzophenones . Pyrimidine benzamide-based compounds were developed as thrombopoietin receptor agonists, and the agonism-inducing conformation was probed using X-ray, NMR, and computational methods . Pyrimidine-based inhibitors of the Ca2+/calmodulin-dependant kinase CaMKIIδ like 98 were identified, and computational analyses provided an understanding of the probable mode of binding . Substituted 18F-labeled pyrazolo[1,5-a]pyrimidines were among the compounds synthesized and evaluated for the study of the peripheral benzodiazepine receptor using positron emission tomography (PET) imaging . Finally, in the EtOAc extract of the sponge Acanthostrongylophora ingens, a new pyrimidine-β-carboline alkaloid named acanthomine A was discovered. Its unambiguous structure was established by extensive NMR spectroscopic (1H, 13C, 1H-1H COSY, HMQC, HMBC) and mass spectrometric analyses . N Cl

N H

N

H N

NH2

98

6.2.5 PYRAZINES AND BENZO DERIVATIVES A kinetic and mechanistic study of pyrazinium dichromate oxidations identified the formation of a symmetric cyclic chromate ester as the rate-determining step . The kinetics of pyrazinium chlorochromate oxidation of cyclic alcohols to cyclic ketones in acetic acid indicated that the reaction is first order with respect to each of the three components . A rate equation was derived in a study of the kinetics of pyrazinamide oxidation by bromamine-T in perchloric acid . Gaussian03 was used to assign the vibrational frequencies in the IR spectrum of 6-chloro-N-o-tolylpyrazine-2-carboxamide (99) . A detailed vibrational analysis of the anti-tubercular drug pyrazinamide discussed both FTIR and FT Raman spectra . A new photoelectron spectroscopic study of the 3s Rydberg and cationic states of pyrazine showed finer vibrational structure than previous work . A computational and spectroscopic study of molecular interactions between pyrazine and solvents found hydrogen bonding interactions even aprotic solvents . An experimental and computational study of pyrazine in supercritical xenon defined the solvent local number density with high internal consistency . Experimental hydrophobicity constants were


398

determined for pyrazine derivatives . Two distinct surface-hopping procedures were used to analyze the nonadiabatic dynamics of pyrazine . Crystal structures were determined for 1-aminopyrazinium mesitylenesulfonate derivatives , and for N-(2-pyridylmethyl)-2-pyrazinecarboxamide . Pyrazines were again useful as ligands in coordination complexes. Heterometallic (Re2-Ni or compounds with pyrazine ligands were prepared from a Re2-Cu) pentachloro(pyrazine)rhenate(IV) complex . A linear chain coordination polymer consisting of distorted octahedral CuF2(H2O)2(pyrazine) became square-net 2D structures via F•••H-O hydrogen bonding . Pyrazine-2,3-dicarboxylate was used as bidentate ligands along with water, N,N’-dimethylethylenediamine and 1,10-phenanthroline in distorted octahedral copper(II) complexes . Pyrazine-2,3-dicarboxylate was used for the first time as a monodentate ligand, in copper(II) complexes , but elsewhere monodentate pyrazine-2-carboxylic acid ligands in cyanooxo molybdenum(IV) complexes were found to undergo slow rearrangement to the corresponding bidentate carboxylate anion . Novel photoluminescent Cd(II) and Zn(II) complexes contained 3,5-dimethyl2,6-pyrazinedicarboxylic acid ligands . Seven pyrazinohydroxamic acidcontaining copper(II)-lanthanide(III) 15-metallacrown-5 complexes (100) were synthesized that contain multiple Lewis acid and Lewis base moieties around the periphery of the crown structure . Pyrazinyltriazine ligands were complexed with Re(V) and Re(VI) . Newly prepared Ag(I) 1D coordination polymers contained 1-(2pyrazinyl)piperazine ligands . The physical chemistry of Eu(III) and Tb(III) complexes of pyrazine-2-carboxylates was studied via luminescence and vibrational spectroscopy . Platinum(II) mixed-ligand complexes of pyrazine and pyridines were characterized by IR and 195Pt, 1H, and 13C NMR spectroscopy . An X-ray crystallographic study of {FeII(pyrazine)[Pt(CN)4]} revealed that the compound crystallizes similarly in both high and low spin states . N N

O Cl

N

NH Me

N

99

N

N Cu N O N O N Cu O Cu N O O Ln N N O O Cu N Cu O N O N O

N

(NO3)3

N 100, Ln=Gd(III), La(III)

Pyrazine was used as a bridging ligand in Zn(II) and Cd(II) linear coordination polymers , in 2D antiferromagnetic copper(II) lattices , and in an extended 3D nickel metavanadate complex . Pyrazines were shown by X-ray diffraction to function as pillars cross-linking 2D sheets in a nickel(II) coordination polymer with non-linear optical properties . A first-principle study of Cu(HCO2)(NO3)(pyrazine) indicated


399

that the spin delocalization effect of the two bridging ligands produce a ferromagnetic interaction . Zero-, one-, and three-dimensional coordination complexes were formed from copper(II), water, triflates, and pyrazine or 2-methylpyrazine, but showed no long-range magnetic ordering . A series of alkyl-substituted pyrazines were used as bridging ligands in geometrically-varied one-dimensional copper(II) complexes , and in one- and two-dimensional zinc(II) complexes . Silver(I) complex polymers of the gem-diol hydrate of dipyrazin-2-ylmethanone (101) were prepared and characterized, one of which contained an unusual Ag(I) atom with a coordination number of five . Iron(II) and iron(III) complexes of pyrazine-2-carboxylate showed catalytic behavior in the oxidation of hydrocarbons that depended strongly on the nature of the complex that formed in solution . Pyrazinedicarboxylic acids were used as ligands in several new selfassembling thorium(IV) coordination polymers , in a one-dimensional Ni(II) zigzag coordination polymer , in a two-dimensional cadmium coordination polymer , and in Co(II), Mn(II), Nd(III), Eu(III) coordination complexes and polymers . Pyrazine mono-, di- and tricarboxylate ligands showed pentadentate coordination in trinuclear copper(II) complexes . Three-dimensional polymers of bis(ȝ-aqua)di(ȝpyrazine-2,3,5,6- tetracarboxylate)tetracalcium(II) were shown by X-ray crystallography to give the calcium atoms a coordination number of seven . Meanwhile, a study of the complexes formed from uranyl nitrate and pyrazinetetracarboxylic acid demonstrated the great versatility of this ligand, which was found to coordinate with up to seven metal atoms . 1-(Pyrazin-2-yl)-pyridin-2(1H)-one bridged metal centers in a 2D Cd(II) coordination polymer , while 2,3,5,6-tetrakis(2-pyridyl)pyrazine ligands bridged Ru(II) and Pt(II) centers in linear bimetallic complexes . Pyrazine ring-fused tetrathiafulvalene ligands (102) produced copper(II) complexes with antiferromagnetic and semiconducting properties . Ab initio calculations were published on cobalt(II) complexes of pyrazine dioxide showing ferromagnetic interactions . Another ab initio study concerned [Mn2(dpp)2(H2O)2Cl4]•2H2O, dpp = 2,3-bis(2-pyridyl)pyrazine, which confirmed the semiconducting properties of the compound and indicated the existence of a stable ferromagnetic ground state . Finally, an ab initio study revealed that pyrazine becomes a more potent binder of anions when complexed to Ag(I) . O N N 101

N

N

S

S

N

N

S

S

102

6.2.5.1 Syntheses During an attempted synthesis of a substituted mannopyranose, the highly-substituted 2,3,4triacetoxy-1-[5-(1,2,3,4-tetraacetoxybutyl)pyrazin-2-yl]butyl acetate (103) was inadvertently formed . 2H-Pyrido[2,3-b]pyrrolo[2,3-e]pyrazin-2-ones were prepared regioselectively from 2,3-diaminopyridine and 1-aryl-4-(phenylhydroxymethylidene)pyrrolidine-2,3,5-triones . A solid-phase supported, double cyclodehydration of peptides (104) gave pyrazino[2,1-b]quinazoline-3,6-diones (105) in the presence of a zinc triflate


400

catalyst . A variety of polycyclic pyrazines were prepared via aminations of 2,3dihydrobenzo[de]chromene-7,8-dione . Aza-Michael reactions were used to give high enantioselective yields in the formation of pyrazino-indol-1-ones in the presence of a phasetransfer catalyst . A regioselective three-step route gave 5-substituted 4,5,6,7tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones (106) starting from amines and amino acids without the use of chromatographic purification . A one-pot, three-component reaction gave 3-aminoimidazo[1,2-a]pyrazines easily . Condensations of 1,2diamines with 1,2-diketones gave highly-delocalized acene-like compounds with many rectilinearly fused aromatic rings and up to 6 pyrazine rings . A Smiles rearrangement was useful in the synthesis of pyrido[2,3-e]pyrrolo[1,2-a]pyrazines . The conformationally constrained (9a±)-octahydropyrido[1,2-a]pyrazine-(3S)carboxylate, a bicyclic amino acid analog, was found to be stable and amenable to conventional methods of peptide synthesis , while elsewhere a new route to pyrazine cyclodipeptides was achieved via enaminones . Cyclopenta[b]pyrazines have been incorporated into new purinyl-1'-homocarbanucleosides (e.g., 107) which may find use as HIV reverse transcriptase inhibitors . A variety of newly-synthesized 5-alkyl-2ferrocenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-ones (108) were tested for cell growth inhibition on A549 cells . A synthetic route to 2,3-disubstituted thieno[3,4b]pyrazines was developed with the aim of creating a class of compounds with functionalizationdependent tunable band gaps . Me O

Me O

Me O

O

O

N O

O

O Me Me

O

O O

O

103

O Me Me

O

O

NH

N

DMF, heat

105

104

R2

O

N

Zn(OTf)2

NH2

O

R1

O

O

N H NH

N O

R1

O

Me O

R2

HO O R

N N N

N

N N N

106

Fe

N

N

N Cl

107 N

N

108

O

R

N

6.2.5.2 Reactions A simple two-step synthetic route was designed to produce 6-methylpyrazine-2-yl-amines via malonic ester and amination reactions involving two successive decarboxylations . Several reactions of 2,5-bis(chloromethyl)pyrazine and 2,3,5,6-tetrakis(chloromethyl)pyrazine with alkoxide salts gave as the major product pyrazine acetals (109) over the expected substitution products (110) . The mechanism of formation of the pyrazine acetals is


401

hypothesized to involve a 2,5-dimethylene-2,5-dihydropyrazine intermediate. A synthetic route to highly substituted pyrazinamides involved an oxidation and elimination of HCN as the key step . Symmetrically substituted pyrazino- and quinoxalinobarrelenes were shown to undergo high-yield photorearrangements to produce semibullvalenes such as 111 . Imidazo[1,5-a]pyrazines (112) were arylated directly at the 5-position in a Heck-type palladiumcatalyzed reaction . A four-component Ugi/Smiles coupling gave substituted amino-pyrazines with synthetically viable yields . A microwave-assisted Smiles rearrangement produced 3-anilinopyrazin-2(1H)-ones and 3-anilinoquinoxalin-2(1H)-ones from disubstituted pyrazines . Microwave-assisted routes were developed for the synthesis of 5-chloro-3-(dimethylamino)pyrazin-2(1H)-ones and for the synthesis of asymmetrically-substituted pyrazines from PMB-protected 3,5-dichloro-2(1H)-pyrazinones (113) . 3,5-Dichloropyrazinones were reacted with a variety of anilines prior to a microwave-assisted intramolecular cyclization, giving substituted pyrazino[1,2-a]benzimidazol1(2H)ones such as 114 . N

NaOR Cl N

Cl

N

RO

OR

CO2Me CO2Me

+

Me

N

ROH or THF

N

N

OR 109

OR

110 111

R = Me, Et, t-Bu

N N CN NC

X N N H

N

Ar-Br Pd(OAc)2

(t-Bu)2PMe•HBF4 Cs2CO3 Me

112, X = NH2, NMe2, OMe, Ar'

X

OMe

N N Ar

N

Cl

O

Me

N

N

O

Ar N

N N

F

Cl Cl

113

F

114

6.2.5.3 Applications In a promising new study, pyrazine derivative T-705 prevented mortality in rodents infected with the normally fatal West Nile virus . An investigation of 4-oxo-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides found compound 115 to inhibit HIV-1 replication in vitro at nanomolar doses . Pyrazines and pyrazinamides were again tested for antimycobacterial activity . A series of novel (E)-N'-(1-(pyrazin-2-yl)ethylidene)benzohydrazides (116) were prepared for use in iron overload disease as chelators that form redox-inert complexes . Apoptosis was induced in lung cancer cells treated with 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)one derivatives (117) . Highly substituted pyrazino[1,2-b]-isoquinoline-4-ones such as 118a,b were tested for antitumor activity, with several displaying either cytostatic or apoptotic effects in vitro . The hypothesized protective effects of Maillard reaction metabolites were supported in a study which found that pyrazinoic acids reduced the invasiveness of human hepatocellular carcinoma cells in vitro . Other studies of the


402

formation of pyrazines as Maillard products included asparagine- and 1,3dihydroxyacetone and 2-oxopropanal-containing model systems . O F

N

Me NH2

MeNHCO N N H N

Me N

OH

N

T-705

O

HO N Fe

N F

OMe

OMe

R1

O OPri

O OR2

118a, R1 = OH, R2 = Bn b, R1 = H, R2 = (E)-COCH=CHPh

N C(CH3)3

O

N

MeO

117, R =

H

N

N R

N

Ph

O 115 Me

O

H N

116

OMe N

N

Cl

OMe

A predictive QSAR model was developed for pyrazine-pyridine biheteroaryl compounds as inhibitors of a growth factor receptor (VEGFR-2) . Pyrazinones were useful as prolyl oligopeptidase inhibitors . 1,1-Diphenylhexahydrooxazolo[3,4-a]pyrazin-3ones were synthesized and the structure-activity relationships with respect to neuropeptide S inhibition demonstrated the importance of an urea moiety at the 7-position of the molecule ; one such compound (119) showed potent neuropeptide S antagonism . 2-(3,4,5-Trimethoxyphenylamino)-6-(3-acetamidophenyl)pyrazine (120) served as the lead compound in a study of pyrazine derivatives as micro- or nanomolar inhibitors of the serine/threonine kinase BRAF . Pyrrolo[1,2-a]pyrazines were studied as noncompetitive and selective antagonists of mGluR5 . Cis-3-(3-azetidin-1ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (121) was among the imidazo[1,5-a]pyrazines found to inhibit IGF-IR in vitro . An optimization study addressed the efficacy of pyrazinoindolones as inhibitors of MAPKAP-K2 . Substituted imidazo[1,2-a]pyrazines (122) were found to be potent inhibitors of hog H+/K+-ATPase gastric acid pump . A zinc complex of 2,5-di-[2-(3,5-bis(2pyridylmethyl)amine-4-hydroxyphenyl)ethylene]pyrazine shows promise as a fluorescent protein sensor . Ligand substitution of 2,3-bis(2-pyridyl)pyrazine caused rubidium(II) terpyridine complexes to become DNA-photocleaving agents in the presence of oxygen . Fluorescent pyrazine 123 is expected to be useful as a label for thymine-based single-point mutations in duplex DNA . Pyrazinamide derivative 124 was discovered as a potent member of the neonicotinoid agonist class of insecticides . Pyrazines also found several new uses outside the biochemical and biomedical fields. Poly(thieno[3,4-b]pyrazine)s and poly(acenaphtho[1,2-b]thieno[3,4-e]pyrazine) were found to be


403

low band gap conjugation polymers in three separate studies . Indenopyrazines were synthesized as deep-blue emitters . A series of novel 2,5-bis(2-benzoazolyl)pyrazines such as 125 were prepared as anion-sensing fluorescent dyes . The chemiluminescent compound MCLA (2-methyl-6-(4-methoxyphenyl)imidazo[l,2-a]pyrazin-3(7H)-one, 126) was shown to have a detection limit of about 50 pM for superoxide in seawater and was used successfully for this purpose in the field . Finally, tetrakis-2,3-[5,6-di-(2-pyridyl)pyrazine]porphyrazinatopalladium(II) species were analyzed as photosensitizing agents and producers of singlet oxygen (1O2) . OMe N

O N H F

H N

Me

N N

119

N

O O N

N Cl

N

N

O

N

N

NC

N 123

122

124

N

N

N N H

H N

N

N

H2N

NH2 Cl

N

S

121 N

OMe

N

R

N

NH2

N H

120

O

N

OMe

MeO

N 125

N N H

N 126

N Me O

6.2.6 REFERENCES 08AAC1522 08AF521 08AG(I)3238 08AG(I)4134 08ANC1215 08AP28 08AP223 08AP294 08AP333

08AP418

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412 08MI412 08MI429 08MI447 08MI595 08MI693 08MI891 08MI893 08MI1222 08MI1481 08MI1610 08MI1689 08MI1854 08MI2147 08MI2921 08MI3866 08MI6105 08MI6567 08MI6836 08MIL50 08MM4576 08MRC69 08NNN547 08NNN800 08NPC175 08OBC175 08OBC739 08OBC1197 08OBC1849 08OL849 08OL889 08OL1715 08OL2497 08OL2757 08OL2923 08OL3513 08OL4473 08POL552 08POL593 08POL617 08POL623 08POL717 08POL2035

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Six-Membered Ring Systems: Diazines and Benzo Derivatives 08POL2167 08POL2341 08POL2349 08POL2471 08POL2519 08POL2643 08POL2650 08POL2779 08POL3318 08S101 08S358 08S369 08S823 08S1069 08S1397 08SA(A)175 08SA(A)534 08SA(A)725 08SA(A)793 08SA(A)1127 08SC723 08SC1090 08SC1896 08SC3170 08SL100 08SL702 08SL813 08SL1693 08T1333 08T1430 08T2605 08T2783 08T2801 08T3017 08T3372 08T5023 08T5226 08T6372 08T6551 08T6670 08T8128 08T8907 08T9052 08T9515 08T9885 08T10214 08T10339

413

H.-Z. Dong, H.-B. Zhu, X. Liu, S.-H. Gou, Polyhedron 2008, 27, 2167. N. Koyama, T. Ishida, T. Nogami, T. Kogane, Polyhedron 2008, 27, 2341. E.V. Govor, A.B. Lysenko, A.N. Chernega, J.A.K. Howard, A.A. Mokhir, J. Sieler, K.V. Domasevitch, Polyhedron 2008, 27, 2349. O.Z. Yesilel, A. Mutlu, O. Buyukgungor, Polyhedron 2008, 27, 2471. S. Gupta, S. Pal, A.K. Barik, A. Hazra, S. Roy, T.N. Mandal, S.-M. Peng, G.-H. Lee, M.S. El Fallah, J. Tercero, S.K. Kar, Polyhedron 2008, 27, 2519. D. Matoga, J. Szklarzewicz, K. Lewinski, Polyhedron 2008, 27, 2643. J.L. Manson, J. Donovan, B. Twamley, Polyhedron 2008, 27, 2650. C.R. Maldonado, M. Quiros, J.M. Salas, Polyhedron 2008, 27, 2779. M.N. Xanthopoulou, N. Kourkoumelis, S.K. Hadjikakou, N. Hadjiliadis, M. Kubicki, S. Karkabounas, T. Bakas, Polyhedron 2008, 27, 3318. S. Nag, S. Madapa, S. Batra, Synthesis 2008, 101. N. Zanatta, L. Fantinel, R.V. Lourega, H.G. Bonacorso, M.A.P. Martins, Synthesis 2008, 358. S. Tu, C. Li, F. Shi, D. Zhou, Q. Shao, L. Cao, B. Jiang, Synthesis 2008, 369. M.D. Hill, M. Movassaghi, Synthesis 2008, 823. A.S. Plaskon, S.V. Ryabukhin, D.M. Volochnyuk, A.A. Tolmachev, Synthesis 2008, 1069. G. Blanco, J.M. Quintela, C. Peinador, Synthesis 2008, 1397. H. Kilic, Spectrochim. Acta, Part A 2008, 1, 175. M. Gaber, K.Y. El-Baradie, Y.S.Y.El-Sayed, Spectrochim. Acta, Part A 2008, 2, 534. Y.S. Mary, H.T. Varghese, C.Y. Panicker, M. Dolezal, Spectrochim. Acta, Part A 2008, 71A, 725. R. Wang, Q. Li, R. Wu, G. Wu, Z. Yu, Spectrochim. Acta, Part A 2008, 70A, 793. F.-Y. Wu, F.-Y. Xie, Y.-M. Wu, J.-I. Hong, Spectrochim. Acta, Part A 2008, 70A, 1127. A. Perdicaro, G. Granata, A. Marrazzo, A, Santagati, Synth. Commun. 2008, 38, 723. A. Shaabani, E. Soleimani, A. Maleki, J. Moghimi-Rad, Synth. Commun. 2008, 38, 1090. X.-S. Wang, M.-M. Zhang, Q. Li, C.-S. Yao, S.-J. Tu, Synth. Commun. 2008, 38, 1896. N.A. Kheder, Y.N. Mabkhot, A.M. Farag, Synth. Commun. 2008, 38, 3170. J.P. Stonehouse, D.S. Chekmarev, N.V. Ivanova, S. Lang, G. Pairaudeau, N. Smith, M.J. Stocks, S.I. Sviridov, L.M. Utkina, Synlett 2008, 1, 100. S.M. So, C.-E. Yeom, S.M. Cho, S.Y. Choi, Y.K. Chung, B.M. Kim, Synlett 2008, 702. F. Dumitrascu, M.R. Caira, B. Draghici, M.T. Caproiu, D.G. Dumitrescu, Synlett 2008, 813. I. Cikotiene, M. Morkunas, D. Motiejaitis, S. Rudys, A. Brukstus, Synlett 2008, 11, 1693. G. Blanco, J.M. Quintela, C. Peinador, Tetrahedron 2008, 64, 1333. N.T. Pokhodylo, V.S. Matiychuk, M.D. Obushak, Tetrahedron 2008, 64, 1430. A. Sharma, V.P. Mehta, E. Van der Eycken, Tetrahedron 2008, 64, 2605. S. Achelle, Y. Ramondenc, G. Dupas, N. Ple, Tetrahedron 2008, 64, 2783. J. Wagger, U. Groselj, A. Meden, J. Svete, B. Stanovnik, Tetrahedron 2008, 64, 2801. G. Bhargava, C. Mohan, M.P. Mahajan, Tetrahedron 2008, 64, 3017. R. Hulme, O.D.P. Zamora, E.J. Mota, M.A. Pasten, R. Contreras-Rojas, R. Miranda, I. ValenciaHernandez, J. Correa-Basurto, J. Trujillo-Ferrara, F. Delgado, Tetrahedron 2008, 64, 3372. C. Ramalingan, Y.-W. Kwak, Tetrahedron 2008, 64, 5023. D. Font, M. Heras, J.M. Villalgordo, Tetrahedron 2008, 64, 5226. F. Montel, C. Lamberth, P.M.J. Jung, Tetrahedron 2008, 64, 6372. T. Lifka, G. Zerban, P. Seus, A. Oehlhof, H. Meier, Tetrahedron 2008, 64, 6551. W. Cao, H. Zhang, J. Chen, H. Deng, M. Shao, L. Lei, J. Qian, Y. Zhu, Tetrahedron 2008, 64, 6670. J. Alen, K. Robeyns, W.M. De Borggraeve, L. Van Meervelt, F. Compernolle, Tetrahedron 2008, 64, 8128. A.-C. Chen, S.-Y. Lin, N.R. Villarante, G.J. Chuang, T.-C. Wu, C.-C. Liao, Tetrahedron 2008, 64, 8907. M.-G. Liu, Y.-G. Hu, M.-W. Ding, Tetrahedron 2008, 64, 9052. M.-C. Tseng, Y.-H. Chu, Tetrahedron 2008, 64, 9515. R. Islam, N. Ashida, T. Nagamatsu, Tetrahedron 2008, 64, 9885. A.R. Gholap, K.S. Toti, F. Shirazi, M.V. Deshpande, K.V. Srinivasan, Tetrahedron 2008, 64, 10214. A.S. Shawali, H.M. Hassaneen, N.K. Shurrab, Tetrahedron 2008, 64, 10339.

414 08T10681 08T10754 08T11067 08TL305 08TL703 08TL710 08TL811 08TL903 08TL1725 08TL1812 08TL1832 08TL1931 08TL2316 08TL2377 08TL2472 08TL2519 08TL2583 08TL2689 08TL2761 08TL3208 08TL3257 08TL4099 08TL4405 08TL4607 08TL5125 08TL5283 08TL6254 08TL6556

A. Manlove and M.P. Groziak M. Adib, E. Sheibani, H.R. Bijanzadeh, L.-G. Zhu, Tetrahedron 2008, 64, 10681. H. Meier, T. Lifka, P. Seus, A. Oehlhof, S. Hillmann, Tetrahedron 2008, 64, 10754. A. Contini, E. Erba, P. Trimarco, Tetrahedron 2008, 64, 11067. R.N. Daniels, K. Kim, E.P. Lebois, H. Muchalski, M. Hughes, C.W. Lindsley, Tetrahedron Lett. 2008, 49, 305. J.A. Valderrama, D. Vasquez, Tetrahedron Lett. 2008, 49, 703. S.S.H. Davarani, N.S. Fumani, H. Arvin-Nezhad, F. Moradi, Tetrahedron Lett. 2008, 49, 710. D.E. Murphy, P.S. Dragovich, B.K. Ayida, T.M. Bertolini, L.-S. Li, F. Ruebsam, N.S. Stankovic, Z. Sun, J. Zhao, Y. Zhou, Tetrahedron Lett. 2008, 49, 811. E. Mann, L. Moisan, J.-L. Hou, J. Rebek, Tetrahedron Lett. 2008, 49, 903. K. Yang, X. He, H.-s. Choi, Z. Wang, D.H. Woodmansee, H. Liu, Tetrahedron Lett. 2008, 49, 1725. E. Ramesh, R. Raghunathan, Tetrahedron Lett. 2008, 49, 1812. F. Christopher Bi, G.E. Aspnes, A. Guzman-Perez, D.P. Walker, Tetrahedron Lett. 2008, 49, 1832. M. Eckhardt, N. Hauel, E. Langkopf, F. Himmelsbach, Tetrahedron Lett. 2008, 49, 1931. B.J. Min, X. Gu, T. Yamamoto, R.R. Petrov, H. Qu, Y.S. Lee, V.J. Hruby, Tetrahedron Lett. 2008, 49, 2316. L.D.S. Yadav, C. Awasthi, V.K. Rai, A. Rai, Tetrahedron Lett. 2008, 49, 2377. A. El Akkaoui, J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Tetrahedron Lett. 2008, 49, 2472. Y. Eda, Y. Odazaki, A. Mizutani, Y.N. Ito, T. Kawato, Tetrahedron Lett. 2008, 49, 2519. E. Ramesh, R. Raghunathan, Tetrahedron Lett. 2008, 49, 2583. J. Quiroga, J. Trilleras, B. Insuasty, R. Abonia, M. Nogueras, J. Cobo, Tetrahedron Lett. 2008, 49, 2689. J. Li, J. Kou, X. Luo, E. Fan, Tetrahedron Lett. 2008, 49, 2761. A. Barthelon, A. Dos Santos, L. El Kaim, L. Grimaud, Tetrahedron Lett. 2008, 49, 3208. J. Quiroga, J. Trilleras, B. Insuasty, R. Abonia, M. Nogueras, A. Marchal, J. Cobo, Tetrahedron Lett. 2008, 49, 3257. A.D. Shutalev, A.A. Fesenko, D.A. Cheshkov, D.V. Goliguzov, Tetrahedron Lett. 2008, 49, 4099. K.C. Majumdar, B. Sinha, B. Chattopadhyay, K. Ray, Tetrahedron Lett. 2008, 49, 4405. K. Alex, A. Tillack, N. Schwarz, M. Beller, Tetrahedron Lett. 2008, 49, 4607. A. Lauria, I. Abbate, C. Patella, N. Gambino, A. Silvestri, G. Barone, A.M. Almerico, Tetrahedron Lett. 2008, 49, 5125. P. Mizar, B. Myrboh, Tetrahedron Lett. 2008, 49, 5283. J. Quiroga, J. Portilla, R. Abonia, B. Insuasty, M. Nogueras, J. Cobo, Tetrahedron Lett. 2008, 49, 6254. O.D. Kinzel, R.G. Ball, M. Donghi, C.K. Maguire, E. Muraglia, S. Pesci, M. Rowley, V. Summa, Tetrahedron Lett. 2008, 49, 6556.

415

Chapter 6.3 (2007)

Triazines, Tetrazines and Fused Ring Polyaza Systems Dmitry N. Kozhevnikova,b and Valery N. Kozhevnikovc Institute of Organic Synthesis, Ural Division of RAS, 20, S. Kovalevskoy Str., 620041 Ekaterinburg, Russia b Urals State Technical University, Mira 19, Ekaterinburg, 620002, Russia c University of York, Heslington, York, YO10 5DD, UK e-mail: [email protected]

a

6.3.1

TRIAZINES

6.3.1.1 1,2,3-Triazines Computational studies of hydrogenation and photodissociation have been carried out. Theoretical studies of complexes of benzene with 1,2,3triazine, 1,2,4-triazine, 1,3,5-triazine and 1,2,4,5-tetrazine have been reported . New nematodocides, tetrahydrobenzotriazines 1 were synthesized by BuLi induced cyclization of triazene 2 followed by reaction with an electrophile . X NH2

1. [HNO2]

N

N

N

1. BuLi 2. Electrophile

2. HNMe2 85%

N

2

8-76%

N N

R

1 X = O, S R = Alkyl, HNAr

6.3.1.2 1,2,4-Triazines One-pot reactions of 1,2-diketones, acid hydrazides, and ammonium acetate in the Bronsted acidic ionic liquid, 1-butylimidazolium tetrafluoroborate, yielded 3,5,6-trisubstituted-1,2,4triazines . Mesoporous graphitic C3N4 was successfully employed as an effective catalyst for the cyclotrimerisation of acetonitrile to 3,5,6-trimethyl-1,2,4-triazine . 3,3'-Dimethyl-5,5'-bis(1,2,4-triazine) 3 was synthesized in one step from acetamidrazone by cyclisation with monomeric glyoxal under strongly basic conditions. Acetamidrazone can


D.N. Kozhevnikov and V.N. Kozhevnikov

416

be obtained from acetamidine by reaction with hydrazine/hydroquinone (1/1) inclusion complex or with pure hydrazine hydrate . O NH

N2H2 H2O

N H

NH2

N

O

NH NH2

N N

N

KOH 55%

N

3

N

Co-ordination of [Ru-(C6H6)Cl2]2 with the product of the condensation of benzil dihydrazone with 2-formylpyridine and 2-acetylpyridine was found to promote the formation of 5,6-diphenyl-3-(pyridin-2-yl)-1,2,4-triazine as its cationic Ru-complex 4. The reaction proceeds via electrocyclic cyclisation of 5 to dihydrotriazine 6, followed by the aromatization of 6 by elimination of the imine . + Ru Cl

N N

Ph

N N N

Ph

Ru Cl

N N H

N 5

+

+

N

Ph

N N

Ph

Ru Cl

N N

Ph

N

Ph HN

N 6

N

N 4

Chiral (up to 91% ee) 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones were obtained in high yields by enantioselective diethylzinc addition to the exocyclic C=N bond of 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones using chiral ligands or polymers. Reductive cleavage of the 1,2,4-triazinyl ring provided the corresponding chiral benzylic amines without significant loss of enantiomeric purity . One of the most useful and widely used properties of 1,2,4-triazines is their use as dienes in pyridine synthesis by inverse electron demand Diels–Alder reaction. Thus, an elegant reaction between readily-available 1,2,4-triazines 7 and in situ formed enamine, proceeds through (i) an inverse electron demand Diels–Alder (D–A) reaction, (ii) nitrogen extrusion by a retro-D–A reaction, and (iii) an intramolecular D–A reaction and leads to polycyclic product 8 in high yields. The structure of 8 was confirmed by X-ray crystallography. In this multi-step process, the use of a cyclic enamine (derived from cyclopentanone and diallylamine) produces a tetracyclic product with the formation of four new C–C bonds and five new stereogenic centres in a regio- and diastereo-selective process . All three components (i.e. 1,2,4triazine, carbonyl component and allylic (or homoallylic) amine) can be diversified to yield a wide variety of polycyclic compounds.

Triazines, Tetrazines and Fused Ring Polyaza Systems

R

R

7

R R

N

1

n

N

N

R

R 4 R

6

R

3

N H

R

2

R

O 1

5

R

4

R

7

7

8

8

2

417

R

N

R R

5

( )n 3

N 1

3

8

R

( )n N 6 R R

R

7

(iii)

R

R

2

N R6

R 4 R

5

8

(i, ii) n = 1, 2

A new, straightforward procedure based on similar aza D–A reaction of 5-phenyl-3pyridyl-1,2,4-triazine with enamines was described for the preparation of highly substituted pyridines, e.g. 6-phenyl-2-pyridylcyclopenteno[c]pyridine . The method includes aromatization of the intermediate dihydropyridines by treatment with silica gel. The value of this procedure has been demonstrated with a one-step synthesis of an E-ring-modified estrone. The aza D–A reaction of unsubstituted 1,2,4-triazine 9 with 1-(4-phenylcyclohex-1-en-1yl)pyrrolidine 10 gave 7-phenyl-5,6,7,8-tetrahydroisoquinoline 11, a key intermediate in the synthesis of tetrahydroimidazo[2,1-a]isoquinolines 12, inhibitors of gastric acid secretion. The transformation of 11 into 12 included Chichibabin amination of pyridine 11 followed by cyclisation of aminopyridine 13 with chloroacetone or 3-bromobutanone. O N

N

+

CHCl3

Ph

Ph

NaNH2

R

60 oC

N

84% 9

Hal

Ph N

Ph 10

N 11

59%

R = H, Me N 13

NH2

N

N

66-81% R 12

The inverse electron demand D–A reactions of 3-pyridyl-6-ethoxycarbonyl-1,2,4-triazines 14 with 2,5-norbornadiene were found to be effective for the synthesis of 2,2'-bipyridine-5carboxylates 15. To access triazines 14, a convenient method for the synthesis of Į,ȕdiketoesters 18 from Į-chloro-ȕ-ketoesters 16 and through intermediate formation of picolinates 18, has been suggested. Į,ȕ-Diketoesters 18 were generated in situ from compounds 17 in reaction with Cu(OAc)2 and further reacted with amidrazone 19 to give targeted pyridyltriazines 14 .


418

Py

H2N

O

COOEt

Cl O

O

COOEt

O

R

R 16

N

R

N

O

R

EtOOC

N

R N

14

COOEt

N NH 19

18

17

EtOOC

O

H N

N N

15

Aryl-substituted 6-phenyl-2,2'-bipyridines, known C^N^N-ligands for the synthesis of cyclometallated PtII complexes, were obtained starting from triazine 20 using the arylacetylenes as dienophiles. Thus, heating 5-phenyl-3-pyridyl-1,2,4-triazine 20 (obtained from pyridine-2-amidrazone and phenylglyoxal) with a variety of arylacetylenes in odichlorobenzene afforded a mixture of regioisomers 4-aryl-6-phenyl-2,2'-bipyridines 21 and 5aryl-6-phenyl-2,2'-bipyridines 22 . Stericaly hindered metasubstituted bipyridines 21 were the major products (20–86% isolated yields), while yields of para-isomers 22 did not exceed 18%. The observed regioselectivity of the reaction was explained by π-π interactions in the transition state between the arylacetylene and the external pyridine rings. This hypothesis was confirmed by exclusive formation of the para isomers in the reaction of triazine 20 with nonaromatic dienophiles 3,3-dimethylbut-1-yne and 3dimethylaminoprop-1-yne. Ar N

Ar Ar

N

+

N N 20

N

N

N

N 21

22

5-18%

20-86%

First examples of liquid crystalline 2,2':6',6''-terpyridines have been obtained by D–A reaction of 2,6-bis(6-aryl-1,2,4-triazin-3-yl)pyridines with norbornadiene or 1-morpholinocyclopentene . Incorporation of cyclopenteno units was found to drastically influence the mesomorphic properties. Substituted 2,3-dihydrofuro[2,3-b]pyridines 23 (n = 0) and 3,4-dihydro-2H-pyrano[2,3b]pyridines 23 (n = 1) have been synthesized from 1,2,4-triazines using intramolecular inverse electron demand Diels–Alder reactions . Starting 1,2,4-triazine 24 bearing an appropriate alkynyl substituent at position 3 was obtained by reaction of 3-methylsulfanyl1,2,4-triazine 25 with hydroxyalkene, which was followed by ozonolysis of propenyloxy- or butenyloxytriazines 26 and addition of ethynylmagnesium bromide to the intermediate


419

aldehyde. Microwave activation of the cycloaddition reaction proved to be very efficient and allowed shorter reaction times.

N Ph

HO

N

N 25

SO2Me

N

n

Ph

n = 0, 1

(i) O3, Me2S

N

N

O

(ii)

n

MgBr

26 OH

N Ph

N

N

OH O

( )n Ph

n

24

N

O

23

The high electrophilicity of the 1,2,4-triazine ring can be used for direct introduction of various substituents through nucleophilic substitution of hydrogen (SNH). Thus, reaction of 5,6-bis(4-methoxyphenyl)-1,2,4-triazine 27 with lithium ferrocene gave 3-ferrocenyl-5,6-bis(4methoxyphenyl)-1,2,4-triazine 28 in 67% yield. Addition of an oxidizing agent, dichlorodicyanoquinone (DDQ), is necessary for aromatization of the intermediate σ-adduct 29 . Li Fe Ar Ar Ar

N

N

Ar

N

NH H

N

N 27

Ar

N

Ar

N

DDQ

Fe 29

N

Fe 28

Ar = 4-MeOC6H4

A similar methodology was used for introduction of an ethynyl group into a 1,2,4-triazine ring. Thus, addition of lithium phenylacetylide to 3-methyl-1,2,4-triazine followed by oxidation of the σ-adduct with K3FeCN6 afforded 3-methyl-5-phenylethynyl-1,2,4-triazine in 17% yield. More successful nucleophilic substitutions of a methylsulfonyl group in 5-methyl3-methylsulfonyl-1,2,4-triazine with lithium arylacetylides resulted in a series of 5-methyl-3arylethynyl-1,2,4-triazines as inhibitors of human mGluR5-mediated intracellular calcium mobilization . Heating phenylhydrazones of 5-acyl-1,2,4-triazines resulted in intramolecular SNH reactions to give fused pyrazolo[4,3-e][1,2,4]triazines . Derivatives of 1,2,4-triazine find application as ligands in analytical and coordination chemistry. For example, new complexes of 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine with copper , rhenium and ruthenium , as well a copper complex of 3,3'-dimethyl-5,5'-bis(1,2,4-triazine) were synthesized and characterized by X-ray crystallography. A ruthenium complex of 2,6-bis(5,6-diisobutyl-1,2,4triazin-3-yl)pyridine was used as catalyst in hydrogenation of ketones . 6-


420

Methy-4-{[1-(1H-pyrrol-2-yl)methylidene]amino}-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)one was used as a suitable ionophore in an electrode and showed a very good response to the presence of ytterbium in a wide concentration range . 6-Methyl-4-{[1-(2thienyl)methylidene]amino}3-thioxo-3,4-dihydro-1,2,4-triazin-5-(2H)-one, has been reported as a new carrier for a gadolinium ion-selective electrode . An Fe3+-selective and sensitive PVC membrane sensor has been developed using 4-amino-6-methyl-3methylmercapto-1,2,4-triazin-5-one .

6.3.1.3

1,3,5-Triazines

2,4,6-Tri(4-pyridyl)-1,3,5-triazine (tpt) was extensively used as tridentate ligand for a variety of complexes, e.g. rhodium and iridium , ruthenium , copper and molybdenum . Reactions of AgX with 2,4,6-tri(2-pyridyl)-1,3,5-trazine yielded 3D highly symmetric isostructural coordination polymers . A novel pentadentate ligand, 2,4-bis[6-(2pyridyl)-2-pyridyl]-6-(4-bromophenyl)-1,3,5-triazine, was synthesized and structural reorganisation in the electrochemical oxidation of its dinuclear, double helical Cu(I) complex was studied . Zinc and ruthenium complexes of 6-aryl-2,4-(2-pyridyl)-1,3,5triazines were obtained and their luminescence was studied . The reaction of 2,4,6-tri(pyridyl)-1,3,5-triazine and copper(II) salts in DMF/water (1:1) resulted in the hydrolysis of the triazine and formation of the anions of bis(2pyridylcarbonyl)amide and bis(2-pyridylamine)amide, isolated as their copper complexes . A series of primary alcohols and aldehydes were treated with iodine in aqueous ammonia under microwave irradiation to give intermediate nitriles, which underwent [2 + 3] cycloaddition with dicyandiamide to afford high yields of the corresponding 6R-2,4-diamino1,3,5-triazines . 2,4,6-Trifluoro-1,3,5-triazine 30 has been used in a total synthesis of cruentarene A to obtain 31, the acid fluoride of a substituted benzoic acid . F

OH MeO

Ph

O Si

Ph Bu

F

OMe O

N

N

OMe O

N 30

F

F MeO

Ph

O Si

Ph Bu 31

Highly nitrogenated polymer 32 was obtained from 2,4,6-tricyano-1,3,5-terpyidine 33 following a typical tetrazine synthesis procedure. However, only partial oxidation of the intermediate dihydrotetrazines took place .


421 . . .

F

F

CN NaCN

N

N N

F

N

N NC

30

N

CN

33

N ..

.

N N

N N

N

N

N N

H N

N N

N

NH

N

32

...

Inverse-electron demand Diels-Alder reactions of 1,3,5-triazines 34 and 2-aminopyrroles 35 gave pyrrolo[2,3-d]pyrimidine 36 . COOEt N EtOOC

COOEt RT

N

+

H2N

COOEt

N 34

N R

N EtOOC

40%

35

N

N R

36

The wide spectrum of potential activity of 1,3,5-triazines is reflected in the number of publications in 2007. A library of ureido-linked compounds containing the 1,3,5-triazine moiety has been tested for antibacterial and antifungal activity . 4-Carbamoyl-5(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1-ȕ-D-ribofuranoside showed dual inhibitory activity against WNV and HCV NTPase/helicase . A platinum complex of 2,4,6-tri(2-pyridyl)-1,3,5-trazine showed cytotoxic activity . Platinum(II) complexes of pyridine sulfide derivatives of 1,3,5-triazine exhibited activity against a human breast cancer cell line . Oligodipeptide, oligodeoxydipeptide, or oligodipeptoid backbones tagged with a 2,4diamino-1,3,5-triazine (e.g. derived from 37) pair strongly with complementary DNA and RNA . N N DBU N OH

1. O HOOC

NH2 N

O NHBoc

N

O

Ph 2.

H2N

H N NH

NH2 NH

H2N

N

O NHBoc

Ph

37

2-Amino- and 2-alkylamino-1,3,5-triazines were obtained by oxidative (alkyl)amination of 1,3,5-triazine in ammonia-ethanol or alkylamine-ethanol with AgPy2MnO4 as an oxidant . A combinatorial library of potential cleavage agents for soluble oligomers of amyloid ȕpeptides was created on the basis of a 1,3,5-triazine-bearing fragment of a Co(III)-cyclen complex as active part, and various other auxilary moieties .


422

Amide coupling reactions with 2-chloro-4,6-bis[(perfluorooctyl)propyloxy]-1,3,5-triazine or 2,4-dichloro-6-(perfluorooctyl)propyloxy-1,3,5-triazine was used in plate-to-plate gravity fluorous solid-phase extraction (F-SPE) for solution-phase library purification . The application of cyanuric chloride in different organic reactions has been the subject of several papers, including a review . It has been used for promotion of aniline acylation by acetic acid , as dehydrating reagent in the synthesis of nitriles and in the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles as peptidomimetic building blocks . Cyanuric chloride was found to mediate the regio- and stereoselective ring opening of epoxides in water in the presence of morpholine to afford the corresponding β-chlorohydrins in excellent yields . An efficient solvent-free method for the direct conversion of carboxylic acids to primary, secondary, tertiary alkyl, and aromatic amides in the presence of the corresponding ammonium salts, silica-supported 2,4,6trichloro-1,3,5-triazine, and triethylamine was described . N-Methyl-N-4,6-dimethoxy-1,3,5-triazin-2-yl morpholinium salts (DMTMM) derived from 2-chloro-4,6-dimethoxy-1,3,5-triazine were widely used as condensing reagents in amide synthesis . Synthesis of N-glycosyl amino acids with DMTMM as coupling agent has been reported . Chemoselective and stereospecific O-activation of 2'-deoxynucleoside 38 with DMTMM 39 resulted in formation with retention of configuration of 5'-O-DMT-2'-deoxynucleoside 40. Active esters 40 are convenient intermediates for hydrolytic interconversion of RP-38 into SP-38 . OMe N +

N DMTO

N

Me

B O

O

N

39

DMTO

S O

DMTO

H2O S P

98% retention

P

B

O

BF4O

O Me

OMe

Me

N O N

Rp-38

40

OMe N

DBU

O

inversion

B

O

S P

Me

O Sp-38

OMe

2,4-Dimethoxy-6-thienyl-1,3,5-triazine 41 was obtained via a Suzuki-Miyaura crosscoupling reaction of thienyl-2-boronic acid 42 and 2-chloro-4,6-dimethoxy-1,3,5-triazine 43 . OMe

OMe N MeO

N N 42

+ Cl

Ph2(acac)Pd

HO B HO

S 43

N MeO

N N

S

41

A number of functionalized tetraoxacalix[2]arene[2]triazines including chiral examples were synthesized using a fragment coupling strategy and their response to fluoride anion was studied .


423

A chlorotriazine polymer bearing two alkoxy substituents (Poly-O-Trz–Cl) and alkoxy and amino substituents (Poly-N-Trz–Cl) at the 4- and 6-positions was prepared as a polymer-type dehydrocondensing reagent .

6.3.2

TETRAZINES

Stabilization energies for aromatic molecules of various types including tetrazine were calculated . Anioníʌ interactions in tetrazine were theoretically studied . Complexes of unsubstituted 1,2,4,5-tetrazine with ruthenium and 3,6-di(2pyridyl)-1,2,4,5-tetrazine (DPT) with mercury and platinum have been obtained. Reduced 1,2,4,5-tetrazines serve as two-point hydrogen-bonding acceptors for thiourea. This hostíguest system does not exhibit significant binding in the neutral state, making the complex an electrochemical “on/off” switch . The reaction of the nucleophilic carbene derived from 1,3-dimesityl-imidazolium tetrafluoroborate 44 and dipyrazolyltetrazine 45 gave a new unprecedented compound 46 in excellent yield .

N N N N

N N N

+

Mes N

BF4-

K2CO3

N Mes

MeCN

+

96%

N 44 45

N Mes

Mes N

Mes = Mesityl

N N

N N O 46

Nucleophilic substitution of a methylthio group in reaction of 2,6-bis(methylthio)-1,2,4,5tetrazine followed by palladium-catalyzed copper-mediated cross-coupling reactions with a wide range of boronic acids and organotin derivatives led to unsymmetrically substituted aryltetrazines in moderate to good yields . The inverse electron demand Diels–Alder (D–A) reaction remains the most important reactivity of tetrazines. Reactions of 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (DPT) 47 with derivatives of naphthalene 1,4-endoxides 48 to generate fused benzo[c]furans 49. Trapping 49 with various dienophiles, e.g. naphthaquinone 50 , ethynyl tolyl sulfone , fullerene C60 led to functionalized fused ring systems, e.g. 51.


424

O Py

N N

N 47

N O

Py O

51

O

O

O

50

49

48

A similar approach was used for the synthesis of 2-pentafluorosulfanylnaphthalene by a D– A, retro-D–A sequence in the reaction of 2-pentafluorosulfanylbenzobarralene with DPT . A straightforward procedure based on the aza D–A reaction of 3,6-diphenyl-1,2,4,5tetrazine with enamines obtained in situ was described for the preparation of substituted pyridazines, e.g. 3,6-diphenylcyclopenteno[d]pyridazine . Substituted dimethyl pyridazine-3,6-dicarboxylates were obtained by the reaction of dimethyl 1,2,4,5tetrazine-3,6-dicarboxylate with enamines generated from aldehydes and pyrrolidine or with alkyl acetylenes . The [4+2] cycloaddition of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 52 with sugar Cacetylenic dienophiles 53 and 54 yielded pyridazine C-sugars 55 and 56 respectively. Treatment of 55-56 with Zn in AcOH gave pyrrole C-analogs 57 and 58 . Ph

O BnO

COOMe BnO

53

Ph

OBn

N N

O 56%

BnO

COOMe N N

BnO

OBn

COOMe Ph

Zn

NH

O AcOH

COOMe

BnO

COOMe BnO

OBn

55

N N COOMe

52 BnO

57

Ph O

BnO OBn 54 OBn 70%

COOMe Ph BnO

N N

O

COOMe OBn

BnO OBn

COOMe Ph Zn BnO

NH

O

COOMe OBn

AcOH BnO OBn

56

58

1,2,4,5-Tetrazines bearing different substituents (H, OMe, COOMe, CF3, Ph) were used in the synthesis of caged polycyclic pagodanes – dodecahedrane through [4+2] cycloaddition of corresponding benzo/ene to tetrazine, followed by benzo/pyridazino [6+6] photocycloadditions . Other examples of the use of DPT in [4+2] cycloaddition for synthesis of electron donor– acceptor dyads possessing rigid polynorbornene frameworks have been published .


425

The [4+2] cycloaddition of 3,6-dipyrazolyl-1,2,4,5-tetrazine 59 with alkynylboronates 60 afforded 3,6-dipyrazolylpyridazine-3-boronates 61 .

N N N N

N N N

N O

B

O

84% R

N

60

59

O B O

N N

+

N

N

R N

61

Synthesis of novel dispiroheterocyclic systems 62 has been reported by D–A reaction of tetrazines 63 with spiro dienophiles 64. The reaction proceeds at the exocyclic double C,Cbond of 64 with excellent selectivity and 84–98% de and 45–81% yields . H N

R R N N

N N N

O

+

R 45-81% 84-98% de

X

R

O X

64

63

62

R = Py, COOMe

X = O, NHAr

Intramolecular [4+2] cycloaddition of an indole to a tetrazine ring has been reported for 1benzyl-2-(2-(1,2,4,5-tetrazin-3-ylamino)-phenyl)indole 65, which was obtained by a substitution reaction on methylsulfanyltetrazine with lithium 1-benzyl-2-(2aminophenyl)indole. Heating of 65 in Ac2O gave tricyclic product 66, which formed chains in the crystal state (according to X-ray crystallography) due to intermolecular H-bonds .

Ph N N

N

NH2 N N

N N SO2Me

BuLi

Ph

N

OAc

N N

H

NH 63%

63%

Ac N N N Ac

N Ph

65

66


426 6.3.3

FUSED [6]+[5] POLYAZA SYSTEMS

6.3.3.1 Triazino and tetrazino [6+5] fused systems Aniviral activity and cytotoxicities of methyl and ethyl 2-(4-oxo-8-aryl-2H-3,4,6,7tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetates have been studied . Synthesis of 3-(2-hydroxyethoxymethyl)-1-methyl-1H-pyrazolo[4,3-e][1,2,4]triazine as azaanalog of N-methylated acycloformycin A has been reported . Synthesis of 8-substituted pyrazolo[1,5-a][1,3,5]triazines by palladium-catalyzed crosscoupling reactions of 8-iodopyrazolo[1,5-a]-1,3,5-triazines has been reported . A Sonogashira/copper(I)-catalyzed heteroannulation sequence was developed to convert 3,5diamino-6-chloro-1,2,4-triazines 67 (obtained by selective substitution of chlorine atoms in trichlorotriazine 68) to the corresponding 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazine 69 derivatives in good yields . Cl

N

Cl

N

BnNH2

Cl

N

BnNH

N

N Cl

90%

HNR1R2

Cl

N

BnNH

N

N Cl

57-96%

67 R

R

3

N N 1 R

R

2

66

3

N BnNH

N

N

N N 1 R

R

R

2

50-82%

N

3

N Bn

N

N 1 R

R

2

68

Cyclisation reactions of 7-hydrazinotetrazolo[1,5-b][1,2,4]triazines with mono- and dicarbonyl compounds afforded various tricyclic heterocyclic systems . A series of 5-substituted 1,3-dimethyl-pyrazolo[4,3-e][1,2,4]triazines was obtained by intramolecular oxidative cyclization of 5-hydrazinopyrazole derived from 5-chloro-1,3dimethyl-4-nitropyrazole . 3-Allylsulfanyl-2-arylazo-3-cycloalkylaminoacrylonitriles 69 undergo cyclization to afford the novel heterocyclic system 1,4,6,7,8,8a-hexahydropyrrolo[2,1-c][1,2,4]-triazine-4-thione 70, via a number of consecutive pericyclic reactions .

CN

Ar

N N

[1,5]H

N Ar

HN N

CN

CN

CN S

S +

N

S

S Ar

N N

69 1,2,4-triazine ring formation via tert-Amino effect

N

-

Ar

thio-Claisen rearrangement

N N

N

70

Reduction of the azido group in ethyl 4-azido-3-aryl-1-phenyl-1H-pyrazolo[3,4-b]pyridine5-carboxylates gave ethyl 4-amino-3-aryl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates as expected .


427

A convenient synthesis of new 5-azapurine derivatives, regioisomeric 5-amino-6,7dihydro- and 7-amino-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines, was developed using benzhydrazide as starting material . 5,7-Diamino[1,2,4]triazolo[1,5-a][1,3,5]triazines were synthesized by cyclocondensation of 3(5)-amino-1,2,4-triazoles with cyanoguanidine .

6.3.3.2 Purines Purine nucleosides and related structures have not been included. The role of purines in the mammalian central nervous system has been reviewed . Purines were widely used as ligands for various metals, e.g. cadmium , magnesium and manganese , platinum and palladium . Interligand interactions involved in the molecular recognition between copper(II) complexes and adenine or related purines have been analyzed . Anioníʌ interactions in bisadenine derivatives with ZnCl4 and HgCl4 have been crystallographicaly and theoretically studied . 2,2'-Bipyridine modified adenine derivatives and their application in sequence-selective DNA-osmium complexation have been reported . Reaction of 1,3-dimethyl-5,6-diaminouracil with the appropriate carboxylic acid in the presence of a carbodiimide followed by imidazole ring closure in basic medium and 7Nmethylation with excess of iodomethane gave (E)-8-styrylcaffeines exhibiting inhibition of monoamine oxidase B . Regiocontrolled solid-phase synthesis of a 2,6,8,9-tetrasubstituted purines 71 through onresin elaboration of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine 72 has been described. Substitution of chlorine and methylsulfonyl (after oxidation of the methylthio group) followed by reduction of the nitro group gave a series of resin-loaded tetraaminopyrimidines 73. Final cyclisation with orthoesters and cleavage gave a library of 2,6,8,9-tetrasubstituted purines 71 .

N

R

1

NO2 R2NH2

N S

N

N

Cl

R

N S

N

72

N

N 73

N NO2

1. Oxone

NH 2 R

2. R3NH2

1

N NH2 R4C(OEt) 3

N HN 3 R

R

1

NH 2 R

N

TFA

N 2 R

CrCl2

NH 2 R

HN R

N

NO2

N HN 3 R

1

1

N

N HN 3 R

R

R

R

N

N

4

HN 3 R

1

R N 71

N 2 R

4


428

A series of guanylsulfonamides 74 was synthesized by reductive aminoformylation of 2amino-5-nitro-6-Ar-3H-pyrimidin-4-one 75 and subsequent intramolecular ring condensation as key steps . O HN H2N

N

O

O NO2 Ar-NH2 Cl

NO2 Zn/HCOOH

HN

H2N

N 75

HN

H2N

NH Ar

O

H N

H+

O NH Ar

N

N

HN H2N

N

N Ar

74

Y X Ar = N SO2

9-Phenyl-9H-purin-6-amine derivatives have been synthesized by reaction of 5-amino-1phenyl-1H-imidazole-4-carbonitrile with HC(OEt)3 followed by reaction with ammonia . Products of condensation of S-methylpseudothiourea with alkyl or aryl isocyanates were used as exotic cyclizing agents in reactions of 5,6-diaminopyrimidine to give purines bearing a urea residue at position 8 . Electron inverse Diels–Alder reaction of 2,4,6-tritrifluoromethyl-1,3,5-triazine 76 and 5methyl-1,2-dimethylimidazole 77 resulted in 2,6-bistrifluoromethylpurine 78 . CF3 N CF3

CF3

N

N

+ CF3

N

Me H2N

76

N

N

N Me

CF3

Me N Me

N

77

78

N,N-Dialkyladenine derivatives were prepared starting from 5-amino-4cyanoformimidoylimidazoles and dimethylformamide diethyl acetal . Syntheses of carbovir-related cis-[2-(9H-purin-9-yl)-3-cyclopentene]-1-methanols 79, and their antiviral activity, have been reported . Cl

Cl NH2

N N

HO

H N

HC(OEt)3 35%

N

N

N

N

HO 79

Regioselectivity in the palladium(0)-catalyzed cross-coupling of various amides with 2,6dihalogenopurines, in comparison with comparable SNAr processes, have been studied . Thus, in 6-chloro-2-iodopurine 80 the chlorine was substituted with deprotonated amide to give 2-amidopurine 81, while Pd(0)-catalyzed cross-coupling involved the iodine yielding 6-amidopurine 82. In 6-chloro-2-fluoropurine 83 nucleophilic substitution


429

of fluorine atom took place under strongly basic conditions (NaH), while Pd(0)-catalysis resulted in Cl/amide exchange . Cl

O NH2

R Cl N

N I

N

R

Pd(0)

N H

NaH 82 O

80

HN

X

N

N

N F

NH2 R Pd(0)

N

N

35-56%

R

Cl

98% ee on recryst.)

30

O

Scheme 47 R6 6

X

R R4 5 R

1

HO2C +

OCO2Me

R

Pd(PPh3)4 (5 mol%) •

R3

R2 R3

X

R1

MeNO2, 60 oC R2 Scheme 48

R4 O R5

11 examples, 54 - 87%

O

Alkynyl benzylic esters 31 undergo a Bi-catalysed intramolecular carbo-oxycarbonylation that leads to 3,4-dihydropyran-2-ones (Scheme 49) and is extendable to isocoumarin synthesis . Ring closing metathesis continues to be of value in the construction of derivatives of 5,6-dihydropyran-2-ones which feature as fragments of natural products . 1-Alkynyl-2,3-epoxyalcohols 32 are rapidly converted into 3-spiro-linked 5-iodo-2,3dihydropyran-4-ones on treatment with an electrophilic iodine species. The synthesis can also be effected by Au-catalysis . The products, which arise from a tandem heterocyclisation and 1,2-alkyl shift, are readily elaborated through Pd coupling methodology (Scheme 50) .

Not only does AuCl catalyse the 6-endo-dig cyclisation of difluorinated ȕ-hydroxy ynones to 2,3-dihydropyran-4-ones, but also concomitant 5-halogenation occurs in the presence of Hal+ reagents through interception of a gold intermediate species (Scheme 51) .

J.D. Hepworth and B.M. Heron

472

6.4.2.6

Coumarins

A variety of 4-arylcoumarins, including naturally-occurring examples, have been obtained by the Cu-catalysed hydroarylation of protected 2-hydroxyphenylpropynoates with arylboronic acids (Scheme 52) and Pd(II) catalyses the dicarbonylation of 2-(1hydroxyprop-2-ynyl)phenols which leads to 3-[(alkoxycarbonyl)methyl]coumarins (Scheme 53) .

Under the influence of Au-catalysis, the cyclisation of aryl propynoates to coumarins is spontaneously followed by an oxidative coupling which results in the formation of dicoumarins with high regioselectivity (Scheme 54) . AuCl3 (5 mol%), AgOTf (15 mol%)

1

R

R1

o

O

O

1,2-DCE, 60 C

+ O

R1 O

O

9 examples, 8 - 40% Scheme 54

O

2

9 examples, 13 - 67%

Salicylaldehydes are the basis of many coumarin syntheses and new and improved methods continue to appear. Their reaction with formylcyclopropane 1,1-diesters is catalysed by N-heterocyclic carbenes and leads to 3-malonyl derivatives of coumarins through a domino-redox-esterification and cyclisation procedure (Scheme 55) . 3-Alkenylcoumarins, some of which show gelating properties, are readily obtained by treatment with Į,ȕ-unsaturated acid chlorides through O-acylation and an isomerisationprompted condensation (Scheme 56) . R1

EtO2C

CHO

CO2Et

+ OH

imidazolium salt (20 mol%) DABCO, DBU o

CHO

THF, N2, 55 C Scheme 55

R1

CO2Et

CO2Et O O 14 examples, 51 - 94%

Six-Membered Ring Systems: With O and/or S Atoms

473

3-Aminocoumarins result from the Suzuki coupling of 2-(pinacolboronate)phenol with methyl 2-(protected amino)-3-bromopropenoates (Scheme 57) . Their value in the synthesis of pyrido[2,3-c]coumarins through a Povarov reaction is described .

Coumarins form 1:2 host-guest complexes with cucurbit[8]uril and the restricted space in the nanoenvironment allows control of subsequent photochemical dimerisation. Thus, irradiation in water preferentially generates the head-to-tail adducts, with 6- or 7- polar or non-polar substituents affording the syn- or anti-adducts respectively . Control of the stereochemistry of the [2+2] cycloaddition of a coumarin-3-carboxamide with alkenes has been achieved with high ee using the homochirality in the crystal generated by spontaneous crystallisation in the photocycloaddition reaction. Photoracemisation in the singlet excited state is prevented by the addition of a triplet sensitiser . Of related interest is the detailed study of the photocyclodimerisation of some methyl dihydropyranones A one-pot double annulation leads directly to dibenzo[c,h]coumarins when 3-substituted phthalides react with cinnamate-based Michael acceptors in the presence of base (Scheme 58) .

In a development of the Rh-catalysed synthesis of 4-methyldihydrocoumarins 3-substituted 3-(2-hydroxyphenyl)cyclobutanones undergo a Pd-catalysed reaction with aryl halides to give 4-substituted 4-benzyl-3,4-dihydrocoumarins (Scheme 59) . R1 2

R

O +

ArBr

Pd2(dba)3.CHCl3 (1 mol%) [HP(tBu)3]BF4, K2CO3

R1

Ar

2

R

1,4-dioxane, 100 oC

OH

O O 10 examples, 61 - 93% Scheme 59

The synthesis of dihydrocoumarins from phenols and cinnamoyl chloride is improved in both yield and ease when carried out under microwave irradiation in the presence of montmorillonite K10 and a Friedel–Crafts reaction is also involved in the

474


formation of dihydrocoumarins from Į-hydroxyketene-S,S-acetals with phenols by way of an alkylation and intramolecular cyclisation (Scheme 60). However, when R2 = CN a hydrolytic elimination does not occur and the product is a 3-cyano-4H-chromene .

Isocoumarins result from the decarbonylative addition of phthalic anhydrides to alkynes effected by Lewis acid and Ni catalysis and 2-(arylethynyl)aryl esters undergo a 6-endo-dig cyclisation to isocoumarins under the combined influence of a Brønsted and a Lewis acid, with or without microwave assistance . A TsOH-promoted annulation under microwave irradiation is also efficient and under these conditions, the analogous benzyl alcohol gives the isochromene (Scheme 61) .

2-Alkynylbenzaldehydes afford dihydroisocoumarins with high enantioselectivity in a Rh-catalysed [4+2] annulation with acyl phosphonates (Scheme 62) and cyclic 1,2-dicarbonyl compounds give the 3,3-spirocyclic isocoumarins with good ee and yields .

3-Aryldihydroisocoumarins are formed through a TiCl4-mediated [3+3] cyclisation of 1-aryl-1-hydroxy-5-silyloxy-4-en-3-ones with 1,3-bis(silyloxy)buta-1,3-dienes (Scheme 63) . Similar products, including several naturally occurring examples, have been obtained through a radical-initiated Barbier reaction between benzaldehydes and ethyl 2-bromomethylbenzoate .

6.4.2.7 Chromones 2-But-2-ynoyl aryl O-carbamates e.g. 33 are a source of chromone 3- and 8-carboxamides through treatment with LTMP alone or sequentially with s-BuLi, or with LDA, respectively. The use of the stronger base is considered to involve initial ortho-carbamoyl deprotonation.


475

The 3-substituted chromones arise from generation of a cumulenolate and subsequent intramolecular Fries rearrangement and Michael addition (Scheme 64) .

The value of 3-acylchromones in synthetic chemistry continues to be recognised and has been reviewed . Routes to isoxazoles , pyridines , quinolines and pyrimidines have been described, while annulation of a second pyran ring has been achieved by reaction with coumarin-4-acetic acids leading to pyrano[3,2-c]chromenes and the [4,3-b] isomeric system results from an enantioselective asymmetric [4+2] cycloaddition of electron poor alkynes (Scheme 65) . CO2R3

O CHO R1

+

O PBu3 or PPh3 PhMe, rt, 4 - 8 h

R2

O

Scheme 65

O

R1

R2 CO2R3 11 examples, 60 - 99% O

Elaboration of chromones includes a direct 5-amination of 5-trifluoromethanesulfonyloxyflavones , the gem-dimethylcyclopropanation using triisopropylsulfoxonium tetrafluoroborate (Scheme 66) and the conversion of flavones into 3-hydroxyflavanones via the epoxide . O

O +

O

S O

NaH BF4

DMF, rt, 3 h 95% Scheme 66

O

A study of the synthesis of 3-substituted chroman-4-ones and their sulfur analogues by the intramolecular Stetter reaction has comprehensively assessed the significance of catalyst, structure of reactants and reaction conditions on the yield and enantioselectivity of the products (Scheme 67) . Both vinylphosphine oxide and vinylphosphonate have been incorporated into the Michael acceptor moiety and fluorous and camphor-derived thiazolium catalysts have been developed.

Chiral N,N-dioxide Ni(II) catalysts have been developed to effect the asymmetric intramolecular oxa-Michael addition of Į,ȕ-unsaturated ketones and esters which lead to chromanones (Scheme 68) .


476

The synthesis of chromanones through the Lewis acid-catalysed addition of 2-ethynylphenols to aldehydes proceeds via a chalcone (Scheme 69) .

6.4.2.8 Xanthones and Xanthenes 9-Aryl-2,6,7-trihydroxyxanthen-3-one dyes are readily obtained in a one-pot reaction between an aromatic aldehyde and 1,2,4-triacetoxybenzene followed by peroxosulfate oxidation of the resulting polyhydroxytriarylmethane and rhodamine dyes have been incorporated into polymer networks . Formation of dibenzo[a,j]xanthenes from 2-naphthol and benzaldehydes can be achieved in ionic liquids catalysed by Yb(OTf)3 and using silica sulfuric acid without solvent . The relative leaving group ability in SNAr reactions allows control of the regioselectivity of the cyclisation of 2-hydroxybenzophenones to xanthones. Whereas 2-alkoxy-6-fluoro derivatives yield the 1-alkoxyxanthones exclusively, varying amounts of 1-alkoxy- and 1chloro-xanthones are obtained from the 2-alkoxy-6-chloro-2ƍ-hydroxybenzophenones (Scheme 70) . MeO

O

MeO

OH

X

solvent heat

X

O

Cs2CO3

O

+ O X = F, 99% X = Cl, 8% X = Cl, 62% Scheme 70

O X = F, 0% (MeOH) X = Cl, 90% (MeOH) X = Cl, 37% (DMF)

Benzo[c]xanthones are readily obtained by the UV-initiated cyclisation of 2-benzylidene1-tetralones in which cis – trans isomerisation prompts an oxa-6ʌ electrocyclisation and a subsequent singlet oxygen ene reaction (Scheme 71) .


477

The Cu(II)/(-)sparteine-catalysed oxidative ȕ,ȕ-phenolic coupling of styrenylphenols is followed by a spontaneous Diels–Alder reaction which leads to high yields of benzoxanthen2-ones, including the lignin natural product carpanone, as single diastereomers. By varying the conditions, conjugate addition of the solvent MeOH can occur which introduces a further stereocentre (Scheme 72) .

6.4.3 HETEROCYCLES CONTAINING ONE SULFUR ATOM 6.4.3.1 Thiopyrans and analogues The thermolysis of Į-phosphorylmethyl tetrazolyl sulfoxides in the presence of 2,3-dimethylbuta-1,3-diene leads to 3,6-dihydro-2H-thiopyran 1-oxides either alone or admixed with the corresponding thiopyran resulting from dehydration of the oxide (Scheme 73) . O Ph S N N N N

O P Ph Ph +

1,4-dioxane sealed tube, 140 oC, 2 h

S O

P

Ph 28%

O + Ph

S

P

O Ph

Ph 27%

Scheme 73

Thiones derived from either malonates or Meldrum’s acid afford dihydrothiopyrans on reaction with 1,3-dienes, for which a stepwise mechanism proceeding via a thiiranium zwitterionic intermediate is proposed. Preference is shown for the 5- rather than the 4-methyl isomer, consistent with Cį-=Sį+ polarisation (Scheme 74) . 2-Diphenylphosphinoyl-3,4-dihydrothiopyrans are formed by a diastereoselective tandem Michael – intramolecular Horner–Wittig sequence involving chalcones and bis(diphenylphosphinoylmethyl)sulfide (Scheme 75) .


478 O Ph2P

S

O PPh2

(i) NaH, THF, Ar (ii) Ar1

Ar2

Ar1

12 examples, 77 - 88%

O Ar2

S

P(O)Ph2

Scheme 75

3,6-Dihydrothiopyran 1-oxides, obtained by chemoselective oxidation, yield 4-substituted 3,4-dihydrothiopyran through regioselective nucleophilic attack at the Ȗ-position of the ȕ,Ȗ-unsaturated thionium ion generated under Pummerer reaction conditions (Scheme 76) .

Although only moderate yields of 3-methoxycarbonyl-2H-thiochromenes result from the reaction of Baylis–Hilman acetates with Na2S, the route is simple and utilises readily available substrates (Scheme 77) .

A highly diastereo- and enantioselective synthesis of thiochromenes features a domino thia-Michael – aldol reaction between enals and 2'-mercaptoacetophenone effected by chiral pyrrolidine-based catalysts (Scheme 78) and 2-iminothiochromenes result from a Cu-catalysed one-pot reaction between 2-mercaptobenzaldehyde, phenylethyne and arylsulfonyl azides; a ketenimine intermediate is proposed (Scheme 79) .

O

O +

SH

R1

Ar (20 mol%) Ar N H OTMS Ar = 3,3-(CF3)2C6H3 4-NO2C6H4CO2H (20 mol%) PhMe, -25 oC, 64 h

O

HO

S

R1

9 examples, 68 - 98%, 96 - >99% de

Scheme 78

Lithiation of the azulene sulfone 35 occurs preferentially in the p-tolyl function and promotes cyclisation at the 8-position leading to the thianaphtho[3,2,1-cd]azulene 7,7-dioxide 36 . Treatment of 1-trifluoromethyl-3,3-bis(arylthio)propan-1,1-diols with concentrated sulfuric acid invokes a 1,3-sulfanyl migration which leads to 2,4-bridged thiochromans 37 . The (4H-thiochromen-4-ylidene)-3H-chromen-2,4-diones 38 derived from 4-hydroxycoumarin and thioflavone function as reversible redox switches .


479

Ar1

Ph S

LTMP

SO2

THF, -100 oC 48% SO2Tol TMS 35

O S Ar1

S

O

CF3

O

37

36

38

A double Michael cascade sequence catalysed by a cinchona derivative between ȕ-nitrostyrenes and 3-(2-mercaptophenyl)prop-2-enoic acids provides an excellent enantioand diastereoselective route to 2,3,4-trisubstituted thiochromans (Scheme 80) and a cinchona-based catalyst effects the enantioselective formation of tetrasubstituted thiochroman-4-ols from 2-mercaptobenzaldehyde and benzylidene malonates which involves a tandem Michael – Knoevenagel reaction (Scheme 81) .

2-(2-Methoxyvinyl)thiobenzamides 39, obtained from 2-lithio-ȕ-methoxystyrenes by reaction with isothiocyanates, cyclise to 1-imino-3-methoxyisothiochromans . An allenyl dication incorporating two thioxanthene units 40 has been shown to contain hexacoordinate carbon which is thought to be electron rich and hypervalent . Friedel–Crafts acylation of terminal alkynes and subsequent cyclisation of the resulting dichlorovinyl ketones through two C–S bond formations provides a route to 2,3-dihydrothiopyran-4-ones (Scheme 82) and the same products result from the Pd/Cu-catalysed reaction of Į,ȕ-unsaturated thioesters with propargyl alcohols . R2

R2

S

1

R1

OMe

R

conc. HI

OMe

0 oC - rt

MeO MeO

S

3

CSNHR 39

R1

O CH2Cl

+ Cl 2

R

OMe OMe

NR3 10 examples, 52 - 84%

O

•

S

CH2Cl

(ii)

R2

2

R1

Cl

40

O

(i) R

R1

S

Reagents: (i) AlCl3, CH2Cl2; (ii) NaSH, Me2CO, 0 - 25 oC Scheme 82


480


C-Acylation of the N-hydroxysuccinimide ester 41, derived from thiosalicylic acid, with an activated methylene compound and subsequent ring closure provides a route to thiocoumarins and thiochromones depending on the nature of the substrate .

A photolabile protecting group for alcohols, amines and acids is based on the thiochromone 1,1-dioxide system . 6.4.4 HETEROCYCLES CONTAINING TWO OR MORE OXYGEN ATOMS 6.4.4.1 Dioxins and Dioxanes Trioxa[4.4.3]propellanes result from the Mn(III)-catalysed aerobic oxidation of cyclic 1,3-dicarbonyl compounds with 1,1-diarylethenes (Scheme 83). In cases where the dioxabicyclic intermediates were obtained, a further cyclisation could be achieved using a Lewis acid-catalyst . 2,5,7,10-Tetraoxapropellane 42 is formed in the acidcatalysed reaction between indane-1,2-dione and ethandiol .

The stable spiro-bisperoxyketals 43 have been obtained by the intramolecular cyclisation of bisperoxyketones and by the intramolecular alkylation of 1,1-bis(hydroperoxides) . Molecular rods of up to 3 nm length based on spiro-linked 1,3-dioxane units and showing good solubility in CH2Cl2 have been obtained by coupling [1,3]dioxolo[4,5f][1,3]benzodioxole with diols . Treatment of 1,2-dioxines with phosphonate nucleophiles results in a cyclopropanation cascade reaction and the formation of substituted cyclopropyl ketones and thence the corresponding carboxylic acids by Baeyer-Villiger oxidation. Furthermore, use of phosphonoglycines allowed the synthesis of ȕ-cyclopropyl amino acid derivatives (Scheme 84) .

A Ti-mediated pinacol cross coupling reaction between o-hydroxy benzaldehydes and acetophenones and o-phthalaldehyde gives direct access to the tetracyclic nucleus of the integrastatins (Scheme 85) .

Six-Membered Ring Systems: With O and/or S Atoms O R2

R1

CHO

Mg(Hg), TiCl4

+

o

THF, 0 C

CHO

OH

R2

481 OH O

1

R


O Scheme 85

Alkylidene derivatives of Meldrum’s acid undergo a Rh-catalysed 1,4-addition of vinyl stannanes. Subsequent Pd-catalysed intramolecular O-alkylation leads to tetrahydrofuranones while the presence of a Lewis acid ensures C-alkylation and cyclopropanes result; both modes occur with good diastereoselectivity (Scheme 86) .

2,3-Dihydro-1,4-benzodioxins are formed when 2-iodophenols react with epoxides. A Cu-catalysed cyclisation of the initial ring-opened adduct is postulated (Scheme 87) .

The regioselectivity of the cycloaddition of sinapyl alcohol 44 to o-quinones which leads to 1,4-benzodioxanes is controlled by the location of an alkoxy group in the latter , a device utilised in a total synthesis of cleomiscosin C . OTBS

OMe

OMe O

O OMe

+ O

O

THF, rt 83%

O

O

O

O

OTBS OMe

OH OMe

OH OMe

44

6.4.5 HETEROCYCLES CONTAINING TWO OR MORE SULFUR ATOMS 6.4.5.1 Dithianes and Trithianes Under phase transfer conditions, 1,4-dibromobutanes react with a mixture of Na2S and sulfur to give high yields of 1,2-dithianes and oxidation of butan-1,4-dithiol with N-t-butyl-N-chlorocyanamide affords the same disulfide .


482

Aldehydes and ketones undergo an efficient Lewis base-catalysed addition to 2-trimethylsilyl-1,3-dithiane to afford the Į-hydroxy dithiane (Scheme 88) and stereoselective nucleophilic addition to 2-alkylidene-1,3-dithiane 1,3-dioxides has been studied . An efficient polymer-assisted dithiane hydrolysis has been reported .

6.4.6

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488 08S2739 08S3279 08S3356 08SC8 08SC274 08SC2459 08SL129 08SL329 08SL575 08SL867 08SL871 08SL940 08SL1017 08SL1091 08SL1175 08SL1353 08SL1643 08SL1825 08SL1910 08SL2500 08SL2583 08SL3167 08SL3234 08T412 08T487 08T664 08T797 08T874 08T1487 08T1792 08T2683 08T2997 08T3103 08T3253 08T3405 08T3589 08T4511 08T5055 08T5139 08T5416 08T5454 08T5491 08T5728 08T6015

J.D. Hepworth and B.M. Heron J.S. Yadav, B.V.S. Reddy, T. Maity, G.G.K.S.N. Kumar, Synthesis 2008, 2739. M.G. Edwards, R.J. Paxton, D.S. Pugh, A.C. Whitwood, R.J.K. Taylor, Synthesis 2008, 3279. A. Aponick, B. Biannic, Synthesis 2008, 3356. J.A. Hyatt, Synth. Commun. 2008, 38, 8. A. Shaabani, A.H. Rezayan, A. Sarvary, A. Rahmati, Synth. Commun. 2008, 38, 274. A. Raghotham, T. Lavanya, P.P. Reddy, Synth. Commun. 2008, 38, 2459. E. Gorobets, M. Parvez, B.A. Keay, Synlett 2008, 129. M.P. Healy, A.F. Parsons, J.G.T. Rawlinson, Synlett 2008, 329. M. Bruder, C.J. Moody, Synlett 2008, 575. M.A. Brimble, J.S. Gibson, J.J.P. Sejberg, J. Sperry, Synlett 2008, 867. H. Jiang, S. Zhu, Synlett 2008, 871. Y. Zhang, J. Xue, Z. Xin, Z. Xie, Y. Li, Synlett 2008, 940. Y. Zhao, X.-J. Wang, J.-T. Liu, Synlett 2008, 1017. Z. Zhang, Y. Ma, Y. Zhao, Synlett 2008, 1091. J.S. Yadav, B.V.S. Reddy, S.S. Mandal, A.K. Basak, C. Madavi, A.C. Kunwar, Synlett 2008, 1175. Y. Huang, T.R.R. Pettus, Synlett 2008, 1353. L. Xia, Y.R. Lee, Synlett 2008, 1643. C.-N. Huang, R.-R. Chuang, P.-Y. Kuo, D.-Y. Yang, Synlett 2008, 1825. J. Sperry, M.A. Brimble, Synlett 2008, 1910. C.D. Bray, Synlett 2008, 2500. A.-F. Salit, M. Barbazanges, F. Miege, M.-H. Larraufie, C. Meyer, J. Cossy, Synlett 2008, 2583. C. Valla, A. Baeza, F. Menges, A. Pfaltz, Synlett 2008, 3167. Y. Hirooka, M. Nitta, T. Furuta, T. Kan, Synlett 2008, 3234. J. Jacobs, S. Claessens, N. De Kimpe, Tetrahedron 2008, 64, 412. S.-L. Cui, J. Wang, Y.-G. Wang, Tetrahedron 2008, 64, 487. I. Kim, S.G. Kim, J. Choi, G.H. Lee, Tetrahedron 2008, 64, 664. C.M. Grisé, E.M. Rodrigue, L. Barriault, Tetrahedron, 2008, 64, 797. T.E. Hurst, T.J. Miles, C.J. Moody, Tetrahedron 2008, 64, 874. L.-W. Ye, X. Han, X.-L. Sun, Y. Tang, Tetrahedron 2008, 64, 1487. A.C. Razus, C. Pavel, O. Lehadus, S. Nica, L. Birzan, Tetrahedron 2008, 64, 1792. I. Larrosa, P. Romea, F. Urpí, Tetrahedron 2008, 64, 2683. V.Y. Sosnovskikh, R.A. Irgashev, M.I. Kodess, Tetrahedron 2008, 64, 2997. B. Furman, M. Dziedzic, I. Justyniak, Tetrahedron 2008, 64, 3103. S. Ray, A. Patra, D. Mal, Tetrahedron 2008, 64, 3253. V. Singh, U.M. Krishna, Vikrant, G.K. Trivedi, Tetrahedron 2008, 64, 3405. H. Morita, S. Tashiro, M. Takeda, K. Fujimori, N. Yamada, M.C. Sheikh, H. Kawaguchi, Tetrahedron 2008, 64, 3589. V. Singh, S. Batra, Tetrahedron 2008, 64, 4511. V.Y. Korotaev, V.Y. Sosnovskikh, I.B. Kutyashev, A.Y. Barkov, E.G. Matochkina, M.I. Kodess, Tetrahedron 2008, 64, 5055. M.J.R.P. Queiroz, A.S. Abreu, R.C. Calhelha, M.S.D. Carvalho, P.M.T. Ferreira, Tetrahedron 2008, 64, 5139. M.A. Rashid, N. Rasool, B. Appel, M. Adeel, V. Karapetyan, S. Mkrtchyan, H. Reinke, C. Fischer, P. Langer, Tetrahedron 2008, 64, 5416. S. Kikionis, V. McKee, J. Markopoulos, O. Igglessi-Markopoulou, Tetrahedron 2008, 64, 5454. W. Zhong, Y. Zhao, W. Su, Tetrahedron 2008, 64, 5491. S. Song, L. Song, B. Dai, H. Yi, G. Jin, S. Zhu, M. Shao, Tetrahedron 2008, 64, 5728. M. Lafrance, D. Lapointe, K. Fagnou, Tetrahedron 2008, 64, 6015.

Six-Membered Ring Systems: With O and/or S Atoms 08T6935 08T7324 08T7561 08T7877 08T9646 08T10148 08T10172 08T10924 08T11050 08T11243 08TL62 08TL445 08TL516 08TL520 08TL851 08TL1523 08TL1578 08TL1870 08TL1899 08TL2558

08TL2974 08TL3242 08TL3283 08TL3391 08TL3419 08TL4102 08TL4178 08TL4329 08TL4390 08TL4405 08TL4516 08TL4648 08TL4697 08TL5376 08TL5400 08TL5449

489

G.S. Creech, X.-F. Zhu, B. Fonovic, T. Dudding, O. Kwon, Tetrahedron 2008, 64, 6935. G. Liu, X. Lu, Tetrahedron, 2008, 64, 7324. R. Bernini, E. Mincione, G. Provenzano, G. Fabrizi, S. Tempesta, M. Pasqaletti, Tetrahedron 2008, 64, 7561. V.Y. Sosnovskikh, V.S. Moshkin, M.I. Kodess, Tetrahedron 2008, 64, 7877. M. Lácová, H. Stankoviþová, A. Boháþ, B. Kotzianová, Tetrahedron 2008, 64, 9646. Y.-W. Dong, G.-W. Wang, L. Wang, Tetrahedron 2008, 64, 10148. V.Y. Sosnovskikh, I.A. Khalymbadzha, R.A. Irgashev, P.A. Slepukhin, Tetrahedron 2008, 64, 10172. M.V. Khoshkholgh, S. Balalaie, R. Gleiter, F. Rominger, Tetrahedron 2008, 64, 10924. S.K. Mandal, S.C. Roy, Tetrahedron 2008, 64, 11050. C. Lecoutey, C. Fossey, L. Demuynck, F. Lefoulon, F. Fabis, Tetrahedron 2008, 64, 11243. M. Hellal, J.-J. Bourguignon, F.J.-J. Bihel, Tetrahedron Lett. 2008, 49, 62. C.V. Ramana, S.B. Suryawanshi, Tetrahedron Lett. 2008, 49, 445. J.D. Neighbors, N.R. Mente, K.D. Boss, D.W. Zehnder II, D.F. Wiemer, Tetrahedron Lett. 2008, 49, 516. S.U. Sonavane, M. Chidambaram, S. Khalil, J. Almog, Y. Sasson, Tetrahedron Lett. 2008, 49, 520. R. Jana, S. Samanta, J. K. Ray, Tetrahedron Lett. 2008, 49, 851. J. Pospíšil, I.E. Markó, Tetrahedron Lett. 2008, 49, 1523. F. Liu, T. Evans, B.C. Das, Tetrahedron Lett. 2008, 49, 1578. J. Almog, N. Stepanov, F. Dubnikova, Tetrahedron Lett. 2008, 49, 1870. R. Dodda, T. Mandal, C.-G. Zhao, Tetrahedron Lett. 2008, 49, 1899. A. Kuboki, T. Yamamoto, M. Taira, T. Arishige, R. Konishi, M. Hamabata, M. Shirahama, T. Hiramatsu, K. Kuyama, S. Ohira, Tetrahedron Lett. 2008, 49, 2558. S.J. Gharpure, A.M. Sathiyanarayanan, P. Jonnalagadda, Tetrahedron Lett. 2008, 49, 2974. T. Katagiri, K. Fujiwara, H. Kawai, T. Suzuki, Tetrahedron Lett. 2008, 49, 3242. Y.R. Lee, L. Xia, Tetrahedron Lett. 2008, 49, 3283. W. Su, D. Yang, C. Jin, B. Zhang, Tetrahedron Lett. 2008, 49, 3391. K.C. Majumdar, S. Chakravorty, N. De, Tetrahedron Lett. 2008, 49, 3419. S.K. Kwon, S. Kou, H.N. Kim, X. Chen, H. Hwang, S.-W. Nam, S.H. Kim, K.M.K. Swamy, S. Park, J. Yoon, Tetrahedron Lett. 2008, 49, 4102. X. Zhang, Y. Shiraishi, T. Hirai, Tetrahedron Lett. 2008, 49, 4178. M. Denancé, R. Legay, A.-C. Gaumont, M. Gulea, Tetrahedron Lett. 2008, 49, 4329. X. Yu, Q. Ding, W Wang, J. Wu, Tetrahedron Lett. 2008, 49, 4390. K.C. Majumdar, B. Sinha, B. Chattopadhyay, K. Ray, Tetrahedron Lett. 2008, 49, 4405. A. Kuboki, C. Maeda, T. Arishige, K. Kuyama, M. Hamabata, S. Ohira, Tetrahedron Lett. 2008, 49, 4516. V.S. Matiychuk, R.B. Lesyk, M.D. Obushak, A. Gzella, D.V. Atamanyuk, Y.V. Ostapiuk, A.P. Kryshchyshyn, Tetrahedron Lett. 2008, 49, 4648. X. Chen, Z. Li, Y. Xiang, A. Tong, Tetrahedron Lett. 2008, 49, 4697. V.Y. Korotaev, V.Y. Sosnovskikh, I.B. Kutyashev, A.Y. Barkov, Y.V. Shklyaev, Tetrahedron Lett. 2008, 49, 5376. M. Sher, A. Ali, H. Reinke, P. Langer, Tetrahedron Lett. 2008, 49, 5400. C. Lherbet, D. Soupaya, C. Baudoin-Dehoux, C. André, C. Blonski, P. Hoffmann, Tetrahedron Lett. 2008, 49, 5449.

490 08TL5727 08TL5782 08TL6279 08TL6856 08TL7153 08TL7194

J.D. Hepworth and B.M. Heron G. Sabitha, M. Bhikshapathi, S. Nayak, J.S. Yadav, R. Ravi, A.C. Kunwar, Tetrahedron Lett. 2008, 49, 5727. C.C. Silveira, F. Rinaldi, M.M. Bassaco, T.S. Kaufman, Tetrahedron Lett. 2008, 49, 5782. N.R. Curtis, J.C. Prodger, G. Rassias, A.J. Walker, Tetrahedron Lett. 2008, 49, 6279. V.Y. Sosnovskikh, V.S. Moshkin, M.I. Kodess, Tetrahedron Lett. 2008, 49, 6856. S. Samanta, H. Mohapatra, R. Jana, J.K. Ray, Tetrahedron Lett. 2008, 49, 7153. S. Makarem, A.A. Mohammadi, A.R. Fakhari, Tetrahedron Lett. 2008, 49, 7194.

491

Chapter 7 Seven-Membered Rings Jason A. Smith School of Chemistry, University of Tasmania, Hobart, Tasmania, 7001, AUSTRALIA [email protected] Peter P. Molesworth School of Chemistry, University of Tasmania, Hobart, Tasmania, 7001, AUSTRALIA [email protected] John H. Ryan CSIRO Division of Molecular and Health Technologies, Clayton, Victoria, 3168, AUSTRALIA [email protected]

7.1

INTRODUCTION

This chapter summarises the chemistry of seven-membered heterocycles and puts particular emphasis on research focussing on the construction and reactions of these heterocyclic systems. A continued trend has been to use seven-membered heterocyclic motifs in derivatives of biologically active molecules and a summary of the key advancements in pharmacological activity of these derivatives has been included. A review concentrating on the major synthetic methods for the synthesis of all reported isomers of 1,2-, 1,3- and 1,4-benzoxazepines was published as well as a review on 1,2benzothiazepines as pharmacophores . 7.2

SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM

7.2.1

Azepines and derivatives

Azepines and heterocyclic fused derivatives were formed in good to moderate yields by the reaction of an enamine like 1 with γ-bromo esters 2. The intermediate enamine esters undergo a 7-exo-trig cyclisation to yield the 4-oxoazepines 3 .


J.A. Smith et al.

492

CO2Me

CO2Me + MeO2C

NH Bn

(i)

Br(CH2)3CO2Et

1

MeO2C

2

O

N Bn

CO2Et

N Bn

CO2Et

MeO2C

MeO2C MeO2C

MeO2C N Bn

3

Reagents: (i) neat, 120 oC, 46%

Gold(III) compounds were reported to catalyse a [4+3] annulation from propargyl ester 4 and α,β-unsaturated imines 5 . The mechanism is postulated to involve formation of a gold carbenoid species followed by nucleophilic addition of the imine and subsequent nucleophilic cyclisation. The reaction was very tolerant of functional groups, including bromine and olefins, resulting in highly substituted azepines 6. Ph BzO

N

+ Ph

4

Ph

(i)

5

BzO

N

Ph

6

Reagents: (i) PicAuCl2 5 mol%, CH2Cl2, rt, 65%

1,5-Aminoalkyne 7 was shown to undergo zirconium catalysed cyclisation to give the corresponding azepine 8 in excellent yield . NH2 (i) 7

Ph

N

Ph

8

Reagents: (i) Zr cat. 5 mol%, benzene-d6, 75 oC, 93%

Two approaches to the azepine core of the fungal metabolite balanol 9 were reported, one using metathesis as the key step , the other using an oxidative cleavage/reductive amination from a chiral cyclohexane-diol 10 that was obtained from the chemoenzymatic oxidation of bromobenzene .

Seven-Membered Rings

493 CO2H

HO HO R O HO

O

N

HO

N

O O O

(i)-(ii) 11

O O

N

Bn

OH

HN

12 balanol 9 R= p-C6H4-OBn Reagents: (i) NaIO4, acetone, H2O; (ii) Bn-NH2, NaCNBH3, AcOH, molecular sieves, MeOH, -78 oC-rt, 64% Br

10

OH

O

O

HO

HO

R

O

The chiral azepine 14 was synthesised from phenylalanine by way of the alkenyl amine derivative 13 that underwent oxidative cleavage and intramolecular reductive amination . Reductive amination was the method used for formation of the azepine 14 as a derivative of deoxynorjirimycin .

OH

Ph

Ph HN Cbz

OH

(i)-(ii) N Cbz

13

14

Reagents: (i) OsO4, NaIO4, THF/H2O quant.; (ii) H2, Pd/C, EtOH, 89%

Constrained phenylalanine derivatives were synthesised via an ene-yne metathesis that not only formed the azepine ring 16 but gave a diene that was transformed into the fused benzoazepine 17 . MeO2C MeO2C (i) N Ts

CO2Et

(ii)-(iii) N Ts

15 2nd gen.,

Reagents: (i) Grubb's toluene, 100 39%; (iii) DDQ, toluene, reflux, 50%

CO2Et oC,

16

N Ts

CO2Et

17

24h, 54%; (ii) DMAD, toluene, reflux,

7.2.2 Fused azepines and derivatives The rhodium(I)-catalysed cycloisomerisation of bicyclobutanes 18 with a tethered N-allylamine resulted in the formation of the cyclopropane fused azepine 19 in good yield with excellent diastereoselectivity .

J.A. Smith et al.

494 Ts

N

Ts

(i)

Ph

N

Ph

18

19

Reagents: (i) [Rh(CO)2Cl] 5 mol%, dppe 10 mol%, PhMe,110 oC, 77%

The key seven-membered ring of the stemona alkaloids was formed in good yield by exploiting [5+2] photocycloaddition . The key to good yields was the use of a custom high flow-rate/low volume continuous flow photoreactor to minimise product degradation allowing formation of gram quantities of the key intermediate 21 in the synthesis of (±)-neostenine 22. O O

O H

O H

O (i)

H N

O

Cl

H

O

H

H

H N

O

Cl

H

H

H O

20

N H

O 21

Cl Reagents: (i) hν, 400W Hg lamp, flow reactor, 63%

Cl

H

22 (±)- neostenine

Grubbs methodology was successfully exploited to construct the pyrido[1,2-a]azepine core 24 of stemocurtisinol . HO

HO (i)

Ph

N

O

N

23

O 24

Reagents: (i) Grubb's 2nd gen. 13 mol%, p-benzoquinone 0.88 equiv, CH2Cl2, rt, 85%

Indole-fused azepines were synthesised by a tungsten or rhenium photocatalysed cyclisation of the o-dialkylamino alkynes 25 followed by 1,2-alkyl migration to yield the tricyclic derivative 26 . N

(i) 25 CH3

N

CH3

26

Reagents: (i) [ReBr(CO)5] 10 mol%, Mol. Sieves, toluene, hν, rt, 85%

Copper-mediated cyclisation of sulfonamides onto cyclohexenyl bromides occurred in good yield to afford a fused azepine and oxazepines in good to excellent yields .


Br

NHTs

495

Ts N

(i)

27

28

Reagents: (i) CuI/DMEDA (1:2) 40 mol%, dioxane, 100 oC, 96%

Cycloaddition reactions have been used to generate azepines both directly and indirectly. Reaction of nitrile oxides with a tethered alkene yields isoxazole fused azepines while direct formation of the azepine 30 was achieved via a [4+3] cycloaddition of an azomethine ylide to the triply linked Ni(II) diporphyrin in 41% . The reaction results in another link between the two porphyrins by joining of two pyrrole systems. Ar

Ar

N

N

N

Ni

Ar N

Ar N

Ni N

N

(i)

Ar

N

29 Ar Ar Reagents: (i) CH3NHCH2CO2H, CH2O, toluene, reflux, 41%

H

H

N

N

Ni

Ar N

N

CH3 N

Ar

N Ni

N

Ar

N

Ar N

Ar

30

The use of chiral fused benzazepines has received a great deal of attention as organocatalysts with applications in the amination of α-cyanoketones and β-keto esters , aminohydroxylation of aldehydes , aldol , hydroamination , addition of alkylzincs to aldehydes as well as chiral proton sponges . The general structures of these organocatalysts are represented by structures 31-33.

R' N N R"

N R" N

R"' 31

32

33

7.2.3 Benzoazepines and derivatives Enantiopure benzoazepines were synthesised by treatment of the keto-acid 34 with (R)phenylglycinol to give two diastereomers (35 and 36) separable by chromatography . Reductive cleavage occurred with retention of configuration and debenzylation to

J.A. Smith et al.

496

yield both enantiomers of 2-methyl-3-benzazepine. The azepine adducts were also alkylated and deprotected to yield 2-methyl-5-benzyl derivatives. H3C O

CH3 (i)

N

O

H 3C O N

Ph

O 35

CO2H 34

O

Ph 36

Reagents: (i) (R)-phenylglycinol, toluene, reflux, 3 d, 72% (35:36 = 52:48)

Dibenzoazepines 38 were formed by a coupled Buchwald amination of o-alkylanilines 37 and remote metallation. In general, α-deprotonation occurs in preference to ortho-lithiation yielding azepine derivatives . O

NMe2 O N Me

(i) Me

N Me

37

38

Reagents: (i) LDA (2-4 equiv), THF, 0 oC, 95%

Annulation onto a phenyl ring is still one of the most common routes to benzazepines and includes Friedel–Crafts acylation , nucleophilic aromatic substitution , modified Ullman-Goldberg aryl amination , hypervalent iodine mediated cyclisation of a phenol , Heck cyclisation in a formal synthesis of (-)-cephalotaxine and bis cyclisation of two aryl moieties onto an acetal to yield two new benzofused azepine rings in compound 40 . H3CO

O

O

H3CO (i)

N

H3CO H3CO

OCH3

N H3CO

OCH3 OCH3 39

Reagents: (i) H2SO4/AcOH, 0

oC-rt,

40 H3CO

41%

OCH3

Flash vacuum pyrolysis of the N-allyl and N-benzyl dibenzoazepines results in ring contraction to yield pyrrolocarbazole 42 with a 63% yield for gram scale reaction of the N-allyl derivative 41 at 950°C. The mechanism is reported to involve homolytic cleavage, cyclisation, ring opening and final ring closure . (i) N

N 41

Reagents: (i) FVP, 950

7.2.4

42 oC,

63%

Oxepine and fused derivatives


497

The marine natural product (+)-isolaurepan 44 was produced in good yield by reductive cyclisation of a ȕ-keto-alcohol 43 using TMSOTf and triethyl silane . OH (i) O O

44

43 Reagents: (i) Et3SiH, TMSOTf, CH2Cl2, 0 °C, 1 h, 84%

Intramolecular silyl-Prins cyclisation was used to produce a series of 3-vinylidene oxepines, in good to high yield and stereoselectivity while ruthenium(I)-catalysed carbocyclisation of allenyl allyl ethers was employed to synthesise a library of unique oxepine containing compounds in moderate yields . SiMe3 (i) PhCHO OH

O 45

Et

Ph 46

Reagents: (i) Me3SiOTf, Et2O,-78 °C, 2-4 h, 92%, 97% ee

Intramolecular Heck cyclisation of appropriately substituted brominated allyl ethers 47 gave access to a series of 2-phenyl substituted oxepines 48 in moderate yields .

Br (i) O

O 47

48

Reagents: (i) Pd(OAc)2 5 mol%, Cs2CO3, PPh3, TBAC, DMF, 80-85 °C, 2 h, 80%

An advanced precursor for the synthesis of a diterpenoid, zoapatanol 51 isolated from the Mexican plant Montanoa tomentosa, was produced by conversion of a substituted furanone 49 to a bicyclic lactone by selective deprotection and cyclisation yielding the lactone fused oxepine 50 . O

OBn O

TBDPSO H3CO 49

O

(i) BnO

O O

50

O

O OCH3

OH HO

zoapatanol 51

Reagents: (i) TBAF, THF, rt, 85%

Base-promoted ring closure was used to prepare the oxepine 53 from (Ȧ-hydroxyalkyl) allene 52. The 7-endo-dig cyclisation produced 53 as the sole product .

J.A. Smith et al.

498 O HO

O (i)

OBn

OBn O

52

53

Reagents: (i) t-BuOK, t-BuOH, rt, 5 min, 77%

The reaction of a β-silyloxy allene 54 with aldehydes in the presence of hexamethylditin and a palladium complex yielded oxepine 55 when exposed to TMSOTf. Choice of solvent was key to ensure production of oxepines as the tetrahydrofuran derivative 56 formed when dichloromethane was substituted for tetrahydrofuran . SnMe3 (i)

Ph

(ii) Ph

Ph O

Ph

O

OTMS

55 Ph

54

56

Reagents: (i) (π-allyl)2Pd2Cl2, (Me3Sn)2, 0oC, 3 h then PhCH2CHO, TMSOTf, -40 oC, CH2Cl2, rt, 71%; (ii) as for (i) except THF instead of CH2Cl2, 83%

The addition of an alcohol onto a tethered Michael acceptor was used to synthesise substituted oxepines 58 by reaction of 57 with pyridinium salts and by the intramolecular conjugate addition of (Ȧ-hydroxyalkyl)(ȕ-sulfoxide)alkenes . O

O (i)

HO CO2t-Bu

O

57 Reagents: (i) Py.AcOH, CH2Cl2, rt, 78%

CO2t-Bu 58

The Cope rearrangement was used to prepare a range of substituted oxepines 60 in moderate to excellent yields (55-99%) . O

O

CF3

CF3

(i) 59

Ph

Ph 60

Reagents: (i) CCl4, 100 °C, 12 h, 93%.

Ring closing metathesis continues to be a popular method for the preparation of oxepine ring systems due to the ease that precursors can be synthesised through simple alkylation of alcohols to tether two alkenes. During 2008 examples of RCM include formation of a fused oxepine ring to complete a short synthesis of ptaeroxylin, a chromone from the sneezewood tree Ptaeroxylon obliguum and the synthesis of highly substituted benzoxepines from o-allyl phenolic derivatives. Quinoline derivatives with oxepines annulated to either the heterocyclic or carbocyclic rings have also been reported. Oxepines


499

were prepared from the corresponding diene ethers with one example being incorporated as a motif in HIV protease inhibitors . Ring closing metathesis has again been crucial in the syntheses of toxins responsible for ciguatera seafood poisoning as reported for both the Y ring of maitotoxin and D ring of ciguatoxin prepared using 2nd generation Grubbs catalyst. A partial synthesis of yessotoxin and the preparation of tetra-, hepta-, and decacyclic ethers was also reported. Dibenzoxepines have been prepared by cyclocarbopalladation yielding a vinyl palladium species, which undergoes subsequent coupling with methylboronic acid to yield the product 62 . Benzopyridyloxepines were prepared in a similar manner but with a syn diboration of an alkyne followed by a sequence of inter- and intramolecular Suzuki reactions . O O

(i)

I

61

NO2

NO2

62

Reagents: (i) PdCl2(dppf).CH2Cl2 3 mol%, CH3B(OH)2, Cs2CO3, dioxane/water (4:1), 90 °C, 12 h, 76%

An investigation into Lewis acid promoted Prins cyclisation of 2-allylphenols 63 showed that aluminium(III) chloride gave significantly improved yields, leading to the production of a series of spiro chlorobenzoxepines 64 in good yields . Cl H3CO

H3CO

(i)

O

OH 63

64

Reagents: (i) Adamantanone, AlCl3, CH2Cl2, -10-0 °C, 8 h, 81%

Cyclisation of compounds such as 65 promoted by p-toluenesulfonic acid gave a series of benzoxepines 68 in moderate to good yields. The method was found to be tolerant of both electron-donating and electron-withdrawing substituents . CO2Me OH

CO2Me (i)

CN 65

Reagents: (i) PTSA, toluene, reflux, 2 h, 78%

O

O

66

J.A. Smith et al.

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The fused oxepine derivative 68 instead of the desired oxonine was the unexpected major product when a selenoacetal 67 was treated with titanium(IV) chloride and triethylsilane. The unusual bicyclic structure was confirmed by X-ray crystallography . PhSe TBSO MeO PhSe

O

(i)

OTBDPS

OTBDPS O

TBSO

67

68

Reagents: (i) TiCl4, Et3SiH, -78 °C, then MeOH, 59%.

Formation of the dibenzoxepine core using an intramolecular Ullman biaryl ether coupling was the key step in the synthesis of the biologically active plant metabolite bublophylol-B 70 . Br HO

OBn

H3CO

(i)-(ii)

OH O O

O 69

O

O

bulbophylol-B 70

Reagents: (i) CuBr.DMS, NaH, Py, 120 °C, 89%; (ii) H2, Pd/C, EtOH, 95%

The conversion of benzyl glycidyl ethers 71 to benzoxepines 72 was studied screening various Lewis acids, with the combination catalysts of FeBr3/3AgOTf and AuCl3/3AgOTf being the most reliable . O

O

OMe

O

(i)

HO OMe

OMe 71

72

MeO

Reagents: (i) BF3.Et2O cat. 30 mol %, CH2Cl2, -78 °C, 15 min., 80%

Hydrofluoric acid in acetonitrile was used to achieve the synthesis of dibenzoxepines as biaryl substrates for the inhibition of microtubule assembly. Deprotection of the alcohol 73 and cyclisation to form the oxepine ring 74 occurred concomitantly . OH

HO R1

R1 MeO

OH OTES

MeO

73 OMe

(i)

O

MeO MeO

74 MeO

R1 = H, Me, Et, n-Pr

Reagents: (i) 40% HF (aq)/CH3CN (1:5), 20 °C, 48 h, 71-97%

The fused oxepine E ring in the partial synthesis of the adriatoxin polyether ring system was achieved using olefinic ester cyclisation .


501

O O

Ph H

O

O

O O

O (i)

O

Ph 75

H

O

O H

O

76

H

Reagents: (i) TiCl4, TMEDA, Zn, PbCl2, THF, CH2Cl2, CH3CH2Br, 65%

The oxepine motif was by far the most common seven-membered heterocycle reported in new natural products that have been isolated and characterised. A 3,4-dihydroxyoxepine was isolated from Turraea pubescens . Six limonoids containing fused oxepines were isolated from the stem bark of Cedrela odorata . Four novel fused chromone-3-oxepines 77 were isolated from the endophytic fungi Chalara sp. . A brominated dibenzoxepine assigned as 78 was isolated from marine red alga Polysiphonia urceolata and chlorinated derivatives isolated from the plant endophytic fungus Pestalatiopsis adusta . HO MeO

O O

HO

OH

Br

O

O

R

R = H or OH O

HO

77

Br

78

HO

7.2.5

Thiepine and fused derivatives

Thiepine derivatives 80 were synthesised via a MARDi cascade, a Michael-Aldol-retro-Dieckmann reaction of the 3-oxotetrahydrothiophene 79 with acrolein . Azepines and oxepines were also formed by reaction of the corresponding 3-oxo-4-methoxycarbonyl pyrroline and tetrahydrofuran derivatives. CO2Me O (i)

O S

S

CO2Me 79

MeO2C

80

Reagents: (i) K2CO3, MeOH, rt, 20 h, 55%

7.3

SEVEN-MEMBERED SYSTEMS CONTAINING TWO HETEROATOMS

7.3.1

Diazepines and fused derivatives

The synthesis of diazepines remains of great interest in the development of biologically active compounds and coverage of the entire field in 2008 is beyond the scope of this review, therefore we have chosen to focus on articles where synthesis is the major outcome. The [1,2]diazepino[4,5-b]indole derivatives 83 were produced by a condensation reaction of pyranoindoles 81 with methyl hydrazine 82 .

J.A. Smith et al.

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O

O O N R1 81

N N

(i)

+

H2NNHMe 82

R2

N R1 83

Me

R2

Reagents: (i) PhBr, reflux, 20 min

Bis-alkylation of N,N-diarylamidines 85 with 1,4-dihaloalkanes or Į,Į′-dibromoxylene 84 gave amidinium salts which readily underwent anion exchange reactions to afford the monocyclic or bicyclic amidinium tetrafluoroborate salts 86, respectively. Deprotonation of the amidinium salts 86 with strong base afforded the corresponding 1,3-diazepanyl carbene species 87, which were isolated as stable white solids . Ar N

X X

+

Ar

BF4

H HN Ar

84

Ar N

(i)-(ii)

N

(iii)

N

N Ar

85

Ar

86

87

Reagents: (i) K2CO3, MeCN, reflux; (ii) NaBF4, CH3CN/H2O; (iii) KN(SiMe3)2, THF

Subjecting benzothiadiazine 1,1-dioxides 88 to either iodocyclisation or aminomercuration/demercuration afforded diazepine-fused benzothiadiazine 1,1-dioxides 89 or 90 respectively . O

O S N

O (i)

N N R1 89

I

O

O S N

N

(CH2)3 NHR1 88

(ii)-(iii)

O S N

N N R1 90

Reagents: (i) 3.0 equiv. I2, K2CO3, CH2Cl2, rt; (ii) 1.0 equiv. Hg(OAc)2, CH2Cl2, rt; (iii) aq. NaOH; NaBH4

Selective sulfurisation of benzo[e]pyrrolo[1,2-a][1,4]diazepine 91 with Lawesson’s reagent gave monothiolactam 92, which underwent mercuric chloride promoted amination with amino alkyl esters to afford amidines 93, followed by cyclisation to give the annulated (including 1,3diazepanylated) pyrrolobenzo[1,4]diazepines 94 (n = 1-3) . Related aminations of monothiolactam 92 were promoted by mercuric chloride, bismuth nitrate or N-heterocyclic carbenes .

Seven-Membered Rings O

O

O

N

N

O N

(i)

N

(ii)

H O 91

N H

503

N H

Reagents: (i) Lawesson's reagent; (ii) H3 (iv) aq. HCl

H S

N+-(CH

(iii)-(iv) H N N H 93 EtO2C (CH2)n

92 2)n-CO2Et,

N O

H N 94 (CH2)n

HgCl2, Et3N; (iii) 2N NaOH, 2:1 dioxane: H2O;

The Beckmann rearrangement continues to be favoured for the preparation of 1,4-diazepane-5ones from piperidine-4-one oximes. Examples include formation of a 1,4-diazapan-5-one analogue 95 of the antibiotic Linezolid and mesitylenesulfonyl chloride promoted formation of 2,7-diphenyl-1,4-diazepin-5-ones 96 . O O

N

N

O O

H N

R1 O

R2 Ph

F 95

N Boc

NH R3 R4 N Ph Me 96

An alternative ring-expansion reaction of ketones with hydroxyalkyl azides by Lewis acid promotion has been further explored for the synthesis of diazepanes. The reaction of piperidone 97 with hydroxyethylazide 98 and boron trifluoride etherate afforded bicyclic iminium ether 99. Iminium ether 99 underwent efficient addition reactions with a variety of nucleophiles to afford 1,4-diazepin-5-ones 100, which have potential utility in peptidomimetics . This chemistry was developed into a three-component reaction for producing 1,4-diazepin-5-ones from piperidones, hydroxyalkyl azides and various nucleophiles and demonstrated by production of a 128-member library of Ȗ-turn like peptidomimetics . O

O + N Bn

97

HO

N3

98

(i) N Bn

X

O N+ BF4

N

(ii)

99

Reagents: (i) BF3.OEt2, CH2Cl2, 0 oC to rt; (ii) NaX, DMF, 70 oC, 24 h.

N Bn

100

X = N3. CN, SPh, OPh, F, I

The caprazamycins have been shown to exhibit activity against gram-positive bacteria and in vitro activity against Mycobacterium tuberculosis and efforts are underway to prepare analogues to study structure activity relationships. The diazepanyl ring of pamitoyl caprazol was prepared by hydrogenolysis of the advanced synthetic intermediate, the CBz-protected amine 101, followed by intramolecular reductive amination to afford amine 102. A reductive amination reaction of amine 102 and formaldehyde gave the N-methyl derivative 103. Full deprotection of precursor 103 was achieved with aqueous acid, affording palmitoyl caprazol 104 .

J.A. Smith et al.

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O

O

O BzCHN Me O N OHC H O O O CO2tBu O O H3C 14

N

O

NHBoc

O H3 C (i)-(ii)

O

O

O

NHBoc

96%, 2 steps

14

R

O

tBuO C 2

NH

N N Me

O

H

N

O

O NH

O

O

101

O

O

O

102 R = H

O

(iii), 77%

103 R = Me Reagents: (i) 1 atm H2, Pd black, i-PrOH, rt (ii) NaBH(OAc)3, AcOH, EtOAc, rt (iii) (CHO)n, NaBH(OAc)3, AcOH, EtOAc (iv) aq. TFA, THF

(iv), quant.

HO

HO NH2

O H3C 14

Me

O

HO2C

N N Me

O

O

H O HO

O N

O NH

HO

O

104

A similar reductive amination ring-closing reaction was used in the solid-phase synthesis of 1,3,4,5-tetrasubstituted 1,4-diazepin-2-ones 106 on Wang resins . R1

R1 N O

O NHBoc

O R2

(i)-(iii)

N O

NH

O

105

R2

106

Reagents: (i) 1:1 TFA:CH2Cl2; (ii) Et3N,CH2Cl2; (iii) NaBH3CN, 1% AcOH, THF

To overcome problems associated with cyclisation to form medium-sized rings, an auxiliarybased method was developed and applied to the synthesis of chiral 1,4-diazepan-2,5-diones. The Boc-amine of the medium-sized lactams 107 was deprotected with TFA then treatment with sodium bicarbonate revealed a free amino residue that underwent cyclisation to form the bis lactams 108. Removal of the auxiliary with TFA and anisole produced the chiral diazepanediones 109 .

Seven-Membered Rings Ar

Boc N

OH

MeO

OiPr O

(i)-(ii)

O

HN O

505 Ar

Ar O

iPrO

O

(iii)

HN

N

NH

NH

O

O

MeO 107

108

Reagents: (i) TFA/CH2Cl2; (ii) NaHCO3, EtOAc; (iii) TFA, anisole, 60

109

oC.

A dialkylation cyclisation reaction of N,N′-ditosylethylenediamine 110 with N-Boc-serinol dimesylate 111 promoted by cesium carbonate, using either ultrasound and microwave assistance in acetonitrile or solvent-free conditions afforded 6-amino-1,4-diazepane 112 . An alkylation/acylation cyclisation reaction of 1,1-dimethyl-1,3-propylenediamine 113 with ethyl chloroacetate 114 afforded 1,1-dimethyl-3-oxo-1,4-diazepan-1-ium chloride .

MsO

O

NHBoc OMs 111 +

NH2

Ts NH HN Ts

O

114 + NH2 NMe2

(i) or (ii) Ts N

Cl

EtO

N Ts

(i)

HN

N

Cl

65%

112

115 113

110

Reagents: (i) EtOH, reflux, 50 h.

Reagents: (i) Cs2CO3, MeCN, ultrasound (120W), 3 min; MW 150 oC, 2 h; (ii) neat, MW (600W), 20min

Tandem N-benzylation and ring-opening of aziridines 117 by 2-acetamidobenzylbromide 116 gives bromide intermediate 118 which undergoes triethylamine-promoted intramolecular alkylation reaction to produce benzo-1,4-diazepine derivatives 119 . O NHCOCF3 R

MeO2C +

(i) N

Br

NH

117

CF3

O CO2Me

R

(ii)

N

CO2Me

R Br

N

Ar 116

CF3

Ar

118

Reagents: (i) MeCN, reflux, 1h; (ii) Et3N (2 equiv.), MeCN, reflux, 12h

N Ar 119 10 examples 25 - 71% yield

A palladium-catalysed domino intramolecular N-arylation/intermolecular C-C bond formation was developed for the preparation of functionalised benzo-1,4-diazepine-2,5-diones. An Ugi four-component reaction using 2-iodobenzyl isonitrile 120, 2-iodobenzoic acid 121, aldehydes and amines provided the bis-iodoaryl cyclisation precursor 122. In the presence of 5 mol% Pd(OAc)2, under ligandless conditions, the bis-iodoaryl compound 122 underwent Ugi reaction with olefins (e.g. dihydrofuran) to afford benzo-1,4-diazepine-2,5-diones 123 .

J.A. Smith et al.

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I

O

I

HO2C

H N

(i)

+ I 120

R1

121

R1CHO,

R2NH

Reagents: (i) KOAc (2 equiv.), 120 oC

I

(ii)

N R2

O

NC

O

O

N R2

122

2,

N

R1 O

123

Ugi reactions: (ii) 2,3-dihydrofuran, Pd(OAc)2 (5 mol%)

A tandem Ugi multi-component reaction and Fe(0) reduction with microwave assistance was used in the synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3ones. Choice of 2-nitrobenzaldehydes 124 and amines as Ugi reagents led to C2, N4, C5 substituted benzodiazepinone 125 whereas 2-nitrobenzylamines 126 and aldehydes led to C2, N4-substitution 127 . H N

R4

R1

CHO 124

O N O

NO2

R1

R2

R2-NH

NHR3

Fe(0)

O

R2

HO

R4

NH2 126

R3-NC

2

NO2

H N

R4

R2

O N

R1-CHO

R1

Fe(0)

80-85% dr > 1.5:1

70-80% 125 dr > 20:1

O NHR3

127

Bromination of alkene 128 gave a mixture of dibrominated diazocine 129 and diazepine isomer 130. The proposed mechanism involves neighbouring group participation of the tosylamide nitrogen on the initially formed bromonium ion 131 with formation of an aziridinium ion intermediate 132 that can undergo ring opening with bromide ion to give either of the observed products . Ts N

Ts N

(i)

Ts N

Br

Br

+ N Ts 128

N Ts 129 Ts N

Br

Ts N Br+

N Ts 131 Reagents: (i) Br2

N Ts 130

Br N Ts 132

Br


507

Conversion of 1,2-phenylenediamine 133 into 1,5-benzodiazepine derivatives continues to be an area of significant interest. Examples include: - a multicomponent reaction of 133 with ketones, isocyanides and water which yields 1,5benzodiazepine-2-carboxamides 134 , - a three component reaction with aromatic aldehydes and ȕ-ketoesters involving Ȗ-selective C-C bond formation of ȕ-ketoesters producing 1,5-benzodiazepine derivatives 135 , - 1,4- and 1,2-addition reactions of 133 and 2-aminothiophenol with Į,ȕ-unsaturated Nacylbenzotriazoles to afford 1,5-benzodiazepin-2-ones 136 and 1,5-benzothiazepin-4-one derivatives, respectively , - condensation with chalcones to afford dihydro-1,5-benzodiazepine derivatives 137 uncatalysed or catalysed by Ga(OTf)3 in acetonitrile , - condensation with 1,3-diketones to afford 1,5-benzodiazepine derivatives 138, catalysed by 12tungstophosphoric acid (H3PW12O40) in water or polystyrene supported sulfonic acid in water , - condensation with two equivalents of a ketone to afford dihydro-1,5-benzodiazepine derivatives 139, catalysed by RuCl3.xH2O neat , or with Ga(OTf)3 in acetonitrile , K-10 montmorillonite, at 80°C in CH2Cl2 , , alumina supported 12tungstophosphoric acid, neat or alum [KAl(SO4)2.12H2O], neat . R5 NH H O N R3 R4

NH2 NH2

MeO2C H N

N H R3 R4 134

133 H N

N H

Ar

O

N R H 136

Ar 135 1 H R N

R

N

H N

R2 R2

N 137

HO

N

N

138

139

R1

A number of reports described the synthesis of 1,4-benzodiazepine-2,5-dione systems from 2aminobenzoyl synthons and Į-amino acids. Condensation of protected spiro(fructose)-proline 140 with isatoic anhydrides 141 gave spiro(fructose)pyrrolobenzodiazepinedione 142. Hydrogenolysis of tri-O-benzyl protected triol 142 gave water-soluble chimeric scaffolds 143 that were studied for GABAA receptor affinity. R1O

BnO BnO

O O NH

BnO

O 140

CO2H

X

O

+

(i)

O R1O R1O

N R 141

X

N H O

N R (ii)

Reagents: (i) DMF, reflux; (ii) H2, Pd(OH)2, MeOH/EtOAc

142 R1 = Bn 143 R1 = H

J.A. Smith et al.

508

Other examples include solid-phase synthesis of 1,4-benzodiazepin-2,5-diones 144 and 145 as potential building blocks for dipeptide or ȕ-turn mimetics. O

O

O XH

N

N R2

R1

R2

R3

R4 N R1

N O H 144 X = NH, O

O

145

Enantiomerically pure 5-arylpyrrolo[2,1-c][1,4]benzodiazepines were prepared starting with coupling of 2-aminobenzophenones 146 with L-Boc-proline 147 to give amide 148. Deprotection with TFA afforded the amino ketone 149 and reduction of the ketone with sodium borohydride followed by thermal ring closure afforded the pyrrolodiazepanone 150. Reduction of lactam 150 provided the target octahydro-5-arylpyrrolobenzodiazepine 151 as a mixture of cis and trans isomers . H HO2C

NH2 R1

O

H O

N Boc

147

NH R1

H N

N R (iii)-(iv)

X H

R1 N H

O

(i) R2 R2

146

R2 (ii)

148 R = Boc

(v)

150 X = O

149 R = H 151 X = H,H Reagents: (i) IBCF, Et3N, THF, 0 oC; (ii) TFA, CH2Cl2, rt; (iii) NaBH4, EtOH, rt; (iv) DCB, 180 oC; (v) LiAlH4

The reduction of aryl azides 153 generated amines in situ that underwent intramolecular imine formation to give pyrrolo[2,1-c][1,4]benzodiazepine-5-ones 152. Similar reduction of azide 154 proceeded via lactamisation to give pyrrolo[2,1-c]1,4]benzodiazepine-5,11-diones 155 . R1

H N

R2

O H N

O

(i) R3

152 Reagents: (i) BF3.OEt2, NaI.

X=H

R1 R2

X

O N3

(i) N

O 153 X = H 154 X = OMe

R3

X = OMe

R1

H N

R2

O H N

O

R3

155

On heating in xylenes under reflux, amino esters 156 underwent lactamisation resulting in pyrrolo[1,2-a][1,4]benzodiazepine-6-ones 157. The lactam 157 was reduced with lithium


509

aluminium hydride to give the corresponding 5,6-dihydropyrrolo[1,2-a][1,4]benzodiazepine 158 . OMe

H N

OMe

OMe

N

N

(i)

CO2Me

OMe

N X

MeO

MeO

OMe

156

OMe

157 X = O (ii)

158 X = H,H

Reagents: (i) xylene, reflux; (ii) LiAlH4, toluene, ether

An Ugi multicomponent reaction of pyrroline 159 (derived from L-glutamic acid) with benzyl isocyanide and carboxylic acid 160 gave an N-acyl-2,5-disubstituted pyrrolidine. Side-chain manipulation of the TBDMS ether into the carboxymethyl derivative 161 then lactamisation afforded hexahydro-pyrrolo[1,2-a][1,4]diazepine-1,5-dione 162 . H N Bn

(i-iv)

TBDMSO

MeO2C

N

CBz 159

N

(v)

HN

O N H

O

H N Bn

O N O O

161

162

Reagents: (i) BnNC, CBzNH(CH2)2CO2H 160, rt, 1-2 h; (ii) HF, MeCN, rt; (iii) Jones oxidation, acetone, 0 oC; (iv) CH2N2, THF, 0 oC; (v) H2, Pd/C, MeOH, rt; (vi) tBuOH, Et3N, 0.2M, reflux

A diastereoselective Pictet-Spengler reaction was used to prepare pyrrolo[3,2-e][1,4]diazepin-2ones of interest as potential peptide turn mimics. Amination/aromatisation of the previously reported pyrrolidinone 163 gave 4-benzylaminopyrrole 164. Coupling of aminopyrrole 164 with N-protected Į-amino acids, followed by deprotection afforded amino-substituted pyrroles 165. Pictet-Spengler reaction of 3-amino pyrroles 165 with various aldehydes resulted in formation of desired pyrrolodiazepinones 166 . O (i) CO2Me N PhF 163

O

O

BnHN (ii-iv) N H

CO2Me 164

R1

NBn NH3Cl

N H

(v) CO2Me 165

NBn

R1 HN R2

N H

CO2Me 166

Reagents: (i) BnNH2, p-TsOH.H2O, THF; (ii) FmocNHCHR1CO2H, (Cl3CO)2CO, 2,3,6-collidine, THF; (iii) piperidine, DMF; (iv) HCl, THF; (v) R2CHO, TFA, PhMe, 70 oC, 4 oC, molecular sieves, sealed tube.

A solvent-free, stereoselective three-component reaction of cyclopentyl ȕ-ketoamide 168, aryl aldehydes and ethylene diamine (or cyclohexane-1,2-diamine) 167 resulted in octahydrocyclopenta[e][1,4]diazepines (or cyclohexyl-fused analogues) 169 .

J.A. Smith et al.

510

O

O

+ H2 N

(i) HN

NR2

NH2 167

NH CONR2

Ar

168

169

Reagents: (i) ArCHO, 120 oC, 4h

Benzoindolodiazepines were prepared by a copper(I)-catalysed domino three-component reaction. Thus, in the presence of copper(I) iodide, N-mesyl-2-ethynylaniline 170, paraformaldehyde and 2-bromobenzylamines 171 underwent tandem Mannich-type reaction and cyclization to form an indole intermediate 172. Addition of sodium methoxide deprotected the indole nitrogen allowing N-arylation to proceed to give 173. The reaction with pyridine and thiophene analogues of 171 led to pyridine- and thiophene-fused analogues .

NHMs

N Ms Br

(i)

RHN

+

N-R

(ii)

N

N R

Br

170

171

172

173

Reagents: (i) (HCHO)n, CuI (2.5 mol%), dioxane; (ii) NaOMe

Deprotonation of bis(pyridinium) salt 174 results in bispyridinylidene 175, a very powerful neutral organic two electron donor . I

I N

Me2N

N

174

N

(i)

NMe2

N

175

Me2N

NMe2

Reagents: (i) NaH, DMF

A copper-catalysed amination and intramolecular cyclisation of 2-aminophenones 176 and 2amino-iodobenzenes 177 results in dibenzo[b,e]-1,4-diazepines 178 . R1

R1 R2

O NH2 176

H2N R3

+ I

177

Reagents: (i) Cu2O, K2CO3, xylene, 145 oC

(i)

N R2 N H

R3 178


511

Amino-anilinopyridines 179 underwent Bischler-Napieralski type cyclisation to form libraries of pyridobenzodiazepine analogues 180 . R1

R1 NH2

X

(i)

R4

N

X

R3 Y

N R2 179

Y

X=CH, Y=N or X=N, Y= H

N R2 180

R3

Reagents: R4CO2H, POCl3, MeCN, reflux.

A nevirapine analogue was prepared on pilot scale by chlorination of hydroxyacid 181 followed by reaction with 3-amino-2-chloropyridine to afford amide 182. Treatment of bis(chloropyridine) 182 with ethylamine afforded the monosubstituted pyridine derivative 183 which underwent cyclisation and amide N-methylation to give the nevirapine core scaffold 184. Arylbromide 184 was transformed via a novel one-pot palladium-catalysed arylation into aryl ethanol 185 then further transformed into the nevirapine analogue 186 . HO2C

Br

HO

O (i)-(ii)

N

N

Cl 181

Me N N

N Et

O (v)-(vii) Br

N

N

O Br

N H Cl

N

Me N

O

N Et

N

(iii)

Br

N H EtHN

Cl 182

OH

184

N

N

N

Me N

O

N Et

N

185

(iv)

183

O N

O 186

Reagents: (i) SOCl2; (ii) 3-amino-2-chloropyridine, NaHCO3, MeCN; (iii) EtNH2, THF; (iv) NaHDMS, THF, MeI; (v) CH2(CN)CO2iPr, Pd(OAc)2, PPh3, NaH/oil, PhMe, 100 oC; (vi) aq. NaOH, 80 oC; (vii) HCl/THF, NaBH4, diglyme, 0 oC to rt.

An intramolecular C2-arylation of an indole derivative 187 afforded an indolo-fused benzodiazepinone 188 .

(i)

Br N

N Et

Et N Bn 187

O

N O Bn 188

Reagents: (i) 10% Pd(OAc)2, 10% PCy3.HBF4, NaOtBu, PhMe, μwave, 110 oC, 15 min

J.A. Smith et al.

512

Reactions of thiones 189, formed by a three-component reaction of ketones, ethyl trifluoroacetate and cyanothioacetamide, with N-chloroacetylglycine afforded pyridothiophenyldiazepines 190. Related reactions with N-chloroacetylproline produced pyridothiophenyl(pyrrolo)diazepine 191 . O

O

CF3

(i)-(ii)

R1 R2

CF3 R1

NH S

N

R2

O

(iv)-(v)

CN

R1

N

R2

S 189

N H

190

CF3

N

S

O 191

Reagents: (i) N-chloroacetylglycine, KOH, EtOH; (ii) reflux; (iii) N-chloroacetylproline, KOH, DMF; (iv) KOH, EtOH, reflux.

Tetrahydro-1,5-benzodiazepin-2-thiones 192 undergo condensation with aromatic bromoketones to afford thiazolium[3,2-a][1,5]benzodiazepine derivatives 193 .

Į-

Ar H N

S

S

Br N

(i)

R2

R2

N R1OC

N R1OC

192

193

Reagents: (i) BrCH2COAr, 2-butanone, reflux.

Monoacylation of 1,4-diazepane 194 was achieved in a flow system by ionic immobilisation of the diamine on a sulfonic acid functionalised silica gel 195, acylation with the appropriate reagent then liberation of the product 196 with methanolic ammonia . SO3H HN

NH

O

(i)-(iv)

+

HN

Si 194

195

N OtBu 196

Reagents: (i) solvent rinse (ii) (tBuOCO)2O (iii) solvent rinse (iv) NH3/MeOH

Catalytic asymmetric deprotonation of N-Boc-pyrrolidine 197 with s-BuLi, catalytic (-)-sparteine and diazepane analogue of TMEDA, 198, as stoichiometric second ligand resulted in an 86:14 enantiomeric ratio of silylated pyrrolidine 199 .

N Boc 197

+

N

N 198

(i)-(ii)

SiMe3 N Boc 199

Reagents: (i) sBuLi (1.6 equiv.), (-)-sparteine (0.3 equiv.), 198 (1.3 equiv.), Et2O, -78 oC, 4h; (ii) Me3SiCl.


513

7.3.2 Dioxepines, dithiepines and fused derivatives The reaction of terminal acetylenes with 2,2'-dihydroxybiphenyl 200 and 1,5pentandiol with Lewis acids yields the dioxepines 201 and 203. The method was also applicable to the formation of dithiepines . O O

OH OH

(i) O

200

CH3 Ph

(i)

201

Reagents: (i) InCl3 or ZrCl4, 202 (excess), 60

202 oC

O 203

Reagents: (i) 1,5-pentandiol, AuPPh3Cl, AgBF4, toluene, 100 oC

Desymmetrisation of allylic meso-dioxepine 204 yielded chiral dienes 205 in up to 70% ee . PMBO O

(i)

PMBO

O HO

O 204

205

Reagents: (i) s-BuLi, sparteine, dimethoxymethane, -78

oC

The diastereoselective ring contraction of 1,3-dioxepines 206 with Lewis acids gave highly substituted tetrahydrofurans 207 in good yields . The choice of Lewis acid gave some control over which diastereomer predominated. CHO

O O 206

(i) O

O O major isomer

207

Reagents: (i) TMSOTf, MeCN, -40 oC, 1 h, 94% (95:5:

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