Advances in Heterocyclic Chemistry, Volume 96

EDITORIAL ADVISORY BOARD A. T. Balaban, Bucharest, Romania M. Begtrup, Copenhagen, Denmark A. J. Boulton, Norwich, Engl...

Author: Alan R. Katritzky

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EDITORIAL ADVISORY BOARD A. T. Balaban, Bucharest, Romania M. Begtrup, Copenhagen, Denmark A. J. Boulton, Norwich, England J. Elguero, Madrid, Spain A. P. Krapcho, Burlington, Vermont E. Lukevics, Riga, Latvia A. P. Marchand, Denton, Texas V. I. Minkin, Rostov-on-Don, Russia C. A. Ramsden, Keele, England J. Schantl, Innsbruck, Austria E. F. V. Scriven, Gainesville, Florida B. Stanovnik, Ljubljana, Slovenia Y. Yamamoto, Sendai, Japan J. A. Zoltewicz, Gainesville, Florida

Advances in

HETEROCYCLIC CHEMISTRY VOLUME

96 Editor

ALAN R. KATRITZKY, FRS Kenan Professor of Chemistry Department of Chemistry University of Florida Gainesville, Florida

Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San Francisco Singapore Sydney Tokyo Academic Press is an imprint of Elsevier

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First edition 2008 Copyright r 2008 Elsevier Inc. 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:// www.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 ISBN: 978-0-12-374433-3 ISSN: 0065-2725

For information on all Academic Press publications visit our website at books.elsevier.com Printed and bound in USA 08 09 10 11 12 10 9 8 7 6 5 4 3 2 1

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the author’s contribution begins. Tatiana N. Borisova (81) Organic Chemistry Department, Russian Peoples Friendship University, 6, Miklukho-Maklaya Street, Moscow 117198, Russia Navneet Kaur (123) Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India L.S. Konstantinova (175) N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia Larisa N. Kulikova (81) Organic Chemistry Department, Russian Peoples Friendship University, 6, Miklukho-Maklaya Street, Moscow 117198, Russia Subodh Kumar (123) Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India O.A. Rakitin (175) N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia Harjit Singh (123) Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India D.O. Tymoshenko (1) Department of Medicinal Chemistry, AMRI, 26 Corporate Circle, Albany, NY 12203, USA

vii

viii

Contributors

Alexey V. Varlamov (81) Organic Chemistry Department, Russian Peoples Friendship University, 6, Miklukho-Maklaya Street, Moscow 117198, Russia Leonid G. Voskressensky (81) Organic Chemistry Department, Russian Peoples Friendship University, 6, Miklukho-Maklaya Street, Moscow 117198, Russia

PREFACE

Benzoheteropines with fused pyrrole, furan, and thiophene rings, of great interest because of their biological activity, are surveyed by Dr. D.O. Tymoshenko of the Albany Molecular Research Institute, New York. These compound classes were considered in both the first and second editions of Comprehensive Heterocyclic Chemistry as part of a host of related multi-atom heterocyclic systems. Other specialized reviews have appeared. However, the present survey is the first comprehensive treatment. The synthesis of hetero annulated azocines is treated by L.G. Voskressensky, L.N Kulikova, T.N. Borisova, A.V. Varlamov (all of Russian Peoples Friendship University, Moscow). While azocino-[4,3-b]indoles have been studied because many alkaloids contain this ring system; the present survey covers all six isomeric azocinoindoles. S. Kumar, N. Kaur, and H. Singh (Guru Nanak Dev University, Amritsar, India) have followed up their review entitled Syntheses, Structures and Interactions of Heterocalixarenes in Volume 89 of Advances in Heterocyclic Chemistry with a new consideration of metallacalixarenes and their organo-inorganic hybrid molecular architectures. The final chapter in this volume covers the use of sulfur monochloride in the synthesis of heterocyclic compounds and is by O.A. Rakitin and L.S. Konstantinova (Zelinsky Institute, Moscow, Russia). It includes a survey of the extensive work carried out by these authors and other friends and associates of the late Charles Rees on heterocycles containing heterocycles with up to five sulfur atoms and often many nitrogen atoms. In addition, the chapter also shows how sulfur monochloride may be used advantageously in the synthesis of other sulfur heterocycles. Alan R. Katritzky Gainesville, Florida

ix

CHAPT ER

1 Benzoheteropines with Fused Pyrrole, Furan and Thiophene Rings D.O. Tymoshenko

Contents

1. Introduction 1.1 Scope of the review 1.2 Structural types and nomenclature 2. Benzoheteropine Rings with One Heteroatom 2.1 Benzazepines 2.2 Benzoxepines 2.3 Benzothiepines 3. Benzoheteropine Rings with Two Heteroatoms on the Heteropine ring 3.1 Benzodiazepines 3.2 Benzoxazepines 3.3 Benzothiazepines 4. Systems with More than Two Atoms on the Heteropine Ring and Miscellaneous Ring Systems 4.1 Benzotriazepines 4.2 Pyrrolo-benzothiadiazepines 4.3 Miscellaneous ring systems 5. Reactivity of Benzoheteropines with Fused Five-Membered Rings 5.1 Reactivity of the rings 5.2 Reactivity of substituents 6. Properties of Benzoheteropines with Fused Five-Membered Rings 6.1 Theoretical methods 6.2 Experimental methods 7. Important Compounds and Applications References

2 2 2 3 3 21 26 29 29 40 43 49 49 51 53 54 54 61 67 67 68 69 71

Department of Medicinal Chemistry, AMRI, 26 Corporate Circle, Albany, NY 12203, USA Advances in Heterocyclic Chemistry, Volume 96 ISSN 0065-2725, DOI 10.1016/S0065-2725(07)00001-3

r 2008 Elsevier Inc. All rights reserved

1

2

D.O. Tymoshenko

1. INTRODUCTION 1.1 Scope of the review Heteropines received much attention, primarily because of continuous interest in the psychopharmacological activity of their bicyclic and tricyclic derivatives. Tricyclic heteropine ring systems have been reviewed in the first (1984CHECI(7)593) and second (1996CHEC-II(9)1) editions of Comprehensive Heterocyclic Chemistry, where they were treated with other azepine, thiepine, oxepine and related multiheteroatom systems. Synthesis, structures, reactivity and applications of tricyclic heteropines have been a part of the general indole (2001MI361) and seven-membered rings (1994PHC301, 1995PHC294, 1996PHC298, 1997PHC318, 1998PHC320, 1999PHC319, 2000PHC339, 2001PHC340, 2003PHC385, 2004PHC431, 2005PHC389) discussions. The specialized review (1993H601) surveyed the synthesis of 1,5-benzodiazepines with three-, four- and fivemembered rings fused to different positions of the 1,5-benzodiazepine skeleton. Synthesis of DNA-interactive pyrrole[2,l-c][1,4]benzodiazepines (1994CR433) and medicinal chemistry aspects of the novel thieno benzodiazepine antipsychotic Olanzapine (1997MI1743) have been reviewed. Current work is focused on the benzoheteropines with the fused pyrrole (or indole), thiophene or furan rings, i.e., ortho-fused 6 + 7 + 5 ring systems with carbons only on the six-membered ring, one heteroatom on the five-membered ring and one or more heteroatoms on the seven-membered ring. The variety of heteroatoms is limited to nitrogen, oxygen and sulfur. Several examples of the related cyclic systems with the other heteroatom distribution or peri-fusion are briefly summarized in Section 4.3. The current first specialized review covers synthetic, reactivity and structural aspects reported from the late 1989 until 2007.

1.2 Structural types and nomenclature The main surveyed structural types are depicted in Figure 1. They are based on the parent carbocyclic benzoazulene core (Q ¼ A ¼ carbon) which produces a Q

Q Q

A

A

A A 1

Q

A A 2

A A 3 A

A

A Q A A

A A

4

5

Figure 1 Main structural types.

A

Q

A A 6

Benzoheteropines with Fused Pyrrole, Furan and Thiophene Rings

N A

A A

7

A

N A A

8

A

N A

A

9

N

3

A A A

10

Figure 2 Benzopyrrolo[1,2-a]azepine types.

total of three benzo[e]azulenes 1–3 and three benzo[f ]azulenes 4–6. The tricyclic ring systems discussed in this review can be generated by defining of the query atoms A (A ¼ C, N, O or S) and Q (Q ¼ N, O or S) of the parent ring. The special case of the fusion of a five-membered ring to the benzoheteropine ring occurs when the pyrrole or indole N1 and C2 atoms serve as fusion sites (Figure 2). The resultant benzopyrrolo[1,2-a]azepines differ by the position of the fused benzo ring and are listed in the order of benzo[c]pyrrolo[1,2-a]- (7), benzo[d]pyrrolo[1,2-a]- (8), benzo[e]pyrrolo[1,2-a]- (9) and benzo[f ]pyrrolo[1,2-a](10) azepines, respectively. The nomenclature and numbering used above are recommended by IUPAC (1998PAC143), and they can be further applied to the other cyclic systems with one or more heteroatoms on the heteropine ring using the order of preference rules. Thus, fusion of pyrrole (54), furan (71) or thiophene (78) with azepine (43), oxepine (67) or thiepine (78) results in chemical names in which the parent heterocycle has the lowest preference number and is cited last in the name (preference numbers from Appendix II (1998PAC143) are in brackets). Explanation of the fusion descriptors can be found in the IUPAC recommendations (1998PAC143) and were exemplified in CHEC-I (1984CHEC-1(1)7). Particular types of seven-membered rings and their fused derivatives are reviewed in the order of nitrogen-, oxygen- and sulfur-containing heteropines, following the same heteroatom order for the five-membered fused rings. Thus, synthesis of benzazepines is discussed in Section 2.1 in the order of fused pyrrole, furan and thiophene derivatives. Discussion of pyrrole, furan and thiophene fused to oxepine and thiepine rings is organized in a similar manner in Sections 2.2 and 2.3, respectively. Section 3 describes the diheteropine systems in the order of benzodiazepines, benzoxazepines and benzothiazepines, followed by benzodioxepines, benzoxathiepines and benzodithiepines. Section 4 deals with the systems with more than two heteroatoms on the heteropine ring and miscellaneous related ring systems.

2. BENZOHETEROPINE RINGS WITH ONE HETEROATOM 2.1 Benzazepines 2.1.1 Benzazepines with fused pyrrole ring Two major types of transformations are usually used for the synthesis of benzazepines with the fused pyrrole and indole rings. Construction of the

4

D.O. Tymoshenko

benzazepine ring by formation of C–C or C–N bonds is most common for the preparation of pyrrole fused systems, while a Fischer synthesis is widely used for the attachment of an indole ring to a preformed benzazepinone. Several other methods, usually involving annulation of a pyrrole ring onto a pre-formed benzazepine, have been developed. Syntheses of benzopyrrolo[1,2]azepines, in which pyrrole or indole N1 and C2 atoms serve as fusion sites, are considered separately in Section 2.1.1.5.

2.1.1.1 Construction of the azepine ring by C–C bond formation. The Heck-type cyclization of amides 11, easily available by amide bond coupling (EDCI, DMAP) between the corresponding indolo- and pyrrolo-[2,3-b]pyridine-carboxylic acids and 2-iodobenzylamine, is effective in the presence of Pd(OAc)2/PPh3 catalyst and silver carbonate base and leads to excellent yields of the corresponding azepinones 12 (Equation (1) (2005TL8177)).

R X

Pd(OAc)2, PPh3, AgCO3, DMF, 100 °C, 2 h

Boc N

O

O R

(1)

I

Y

Boc N

Y

X

11

12

#

R

X

Y

Yield of 12, %

11a, 12a 11b, 12b 11c, 12c 11d, 12d

H OMe H H

CH CH N CH

N-SO2 Ph N-SO2 Ph N-SO2 Ph S

92 96 86 100

Suitable amide derivatives of pyrrole- and indole-2-caroxylic acids 13 result in good yields of 5,6-dihydrobenzo[c]pyrrolo[3,2-e]azepin-4(3H)-one 14a and its indole analog 14c (Equation (2) (2005TL8177)). R2 R1

O X N Boc

Pd(OAc)2, PPh3, AgCO3, DMF, 100 °C, 2 h

Boc N

O

(2)

X

I R1

R2 14a-d

13a-d #

R1, R 2

X

Yield of 14, %

13a, 14a 13b, 14b 13c, 14c 13d, 14d

R1 = R2 = H -CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-

N-EOM N-Boc N-EOM S

70 0 96 82

5


Similarly, 2-iodoanilides of indolyl acetic acid 15 lead to the corresponding 7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-ones 16 (Equation (3) (2005TL8177)). Contrary to N-phenylsulfonyl derivatives 11a,b and EOM protected species 13a,c, Boc-derivatives 14b and 15a do not tolerate these reaction conditions, and their fast decomposition has been observed. Pd(OAc)2, PPh3, AgCO3, DMF, 100 °C, 2 h

O N R2

O N

R2

(3) I

N R1

16a-c

15a-c #

R1

15a, 16a 15b, 16b 15c, 16c

Me Boc Me Me EOM EOM

R2

N R1

Yield of 16, % 0 89 92

Conversion of 2-chloroacetamides 17 into iodoacetamides by iodide exchange followed by reaction with Bu3SnH in the presence of AIBN affords 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-ones 18 as products of free radical cyclization (Equation (4) (2005T5489)). Low (8–25%) yields of azepinones 18 are observed in toluene medium, and they are usually accompanied with the product of spiro cyclization 19 and isomeric compound 20. Yields of the paullone 18 can be increased to 25–52% at higher temperatures (boiling mesitylene). O R

O Bn N R N H

N

Cl

Bn O N

N H

1. NaI, MeCN

R

18

2. Bu3SnH, AIBN toluene or mesitylene, reflux

NH

O N

Bn

Bn

(4)

19

N

17 R

20

A new route to the benz[5,6]azepino[4,3-b]indole ring has been developed from easily available 3-formyl indole derivatives 21 (Scheme 1 (2005TL377)). Intermediate azomethine ylides are generated from aldehydes in refluxing xylene using decarboxylative condensation with sarcosine or N-benzyl glycine. Further 1,7-electrocyclization followed by 1,5-hydrogen shift leads to products 22a–b in good yields. In the case of methyl sarcosinate (R ¼ Me, E ¼ COOMe)

6

D.O. Tymoshenko

R N

O R3 R4

MeNHCH2COOH or BnNHCH2COOH

N R1

R2

E

3

R

R4

xylene, reflux R2

N R1

21 R N

R N

E

3

R

E

R3 R4 R2

R4

N R1

R2

N R1

22a R = Me, E = H, 46−61%; 22b R = Bn, E = H, 38−46%; 22c R = Me, E = COOMe, 15−18;

Scheme 1

H N X 24

S X = CO, AlCl3

N H

NCS X

MeNO2, rt, 6 h, 53% 23

H N

K2CO3, DMF rt, 3 h

H N

X = CO, 90% X = CH2, 92%

X

S N

25

Scheme 2

decarboxylation does not occur and the corresponding ester derivatives 22c (E ¼ COOMe) were isolated in 15–18% yields. Isothiocyanate 23 (X ¼ CO), when treated with AlCl3 in nitromethane undergoes ring closure by an intramolecular electrophilic substitution between C3 of the pyrrole ring and the isothiocyanate group to afford pyrrolo[3,2-c][1]benzazepine10(1H)-one-4(5H)-thione 24 (Scheme 2 (2005BMCL3220, 1998MI197)).

2.1.1.2 Construction of the azepine ring by C–N bond formation. Indole 26, readily available by the palladium-catalyzed, two-step, one-pot borylation/ Suzuki coupling reaction, undergoes cyclization under basic conditions to yield paullone 27 (Scheme 3 (2002JOC1199)). Basic hydrolysis of 28 followed by treatment with hydrochloric acid gives the primary amide 29. Further lactamization can be achieved after controlled heating in concentrated sulfuric acid to produce norsecorhazinilam analog 30 (Scheme 4 (2000TL5853)).

7


CN

NH2 O

H2O, Ba(OH)2, 100 °C, 1 h

Br

B N H

O

62%

O

NC

NH NaOH N H HN 2

MeOH/H2O; reflux, 51%

26

NH 27

Scheme 3

MeOOC

Me Et N Et

Me Et N Et

1. 50% aq NaOH, MeOH, reflux, 3 h

CONH2

CN 2. 10% aq. HCl, rt 15 min, 100%

BocHN

28

H2SO4, reflux, 10 min, 100%

Me Et N

Et

O

NH

H2N

29

30

Scheme 4

Reduction of nitro compound 31 with hydrazine hydrate/Raney nickel affords an amine, which produces pyrrolo-benzazepine 32 under intramolecular amide bond coupling (Equation (5) (1996BCF251). Me N

COOH

1. NH2NH2/Ni Raney 2. CMC, CH2Cl2, rt, 60%

Me N

O NH

O –

(5)

+

N O

31

32

Reaction of N-benzoyl isoindolin-1-one with 2-lithio-1-phenylsulfonylindole takes place at both lactam and acyclic carbonyl groups generating a separatable 4:3 mixture of ketone 33 with 2-benzoyl-1-phenylsulfonylindole. When the reaction is allowed to proceed for longer than ca. 15 min, cyclized product 34 is formed as the result of an intramolecular nucleophilic substitution. Compound 34 can be obtained from the isolated ketone 33 in good yield on exposure to NaH in refluxing THF (Scheme 5 (1996TL4283)). 2-Aminobenzonitrile 35a produces the corresponding indolo benzazepine 36a when reacted with o-carboxymethyl bromoacetophenone in refluxing DMF

8

D.O. Tymoshenko

O R N COPh N SO2Ph

N

PhOCHN 1. NaH, THF, reflux, R = COPh, 89% N O SO2Ph

n-BuLi, THF,

− 78 °C, 38%

2. NaOH, MeOH, reflux, R = H, 80%

33

N O SO2Ph

34

Scheme 5

CN CN

DMF, reflux X

XH 35a X = o -NO2C6H4CONH; 35b X = NHAc; 35c X = O

O

COOMe O HN

NH2 X

COOMe X

O

O 36a X = o -NO2C6H4CONH, 82%; 36b X = NH, 62%; 36c X = O, 36%

Scheme 6

(Scheme 6 (1991JHC379)). Interestingly, N-acetyl derivative 35b affords N-unsubstituted compound 36b in 62% yield. Hydrogenation of unsaturated nitro compound 37 (10% Pd/C, toluene) gives a saturated amino intermediate that can be treated with PTSA under Dean–Stark conditions to give the target keto isomer of cryptoheptine 38 in a 44% two-step yield (Scheme 7 (2000JNP643)). 1-Phenylsulfonyl-2-[2u-acetamido-5u-methylbenzoyl]-indole when reacted with chloromethyl methyl ether in acetic acid at room temperature affords 2,5-dimethyl7-phenylsulfonyl-5,6-dihydroindolo[2,3-c]benzazepin-12-one (2005AX(E)o2410).

2.1.1.3 Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-1H-benzo[b]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed

9


O2N

1. H2, Pd/C, toluene 2. p-TSA, toluene, Dean-Stark trap

O O

HN

N

EtONa, O2 O

N Me

O

N Me

N Me

38

39

37

Scheme 7 R2

R2

HN

O

HN

ArNHNH2

RHal, NaH, THF R1

R1 N H

R1

H2SO4, AcOH, O 70 °C

40

N H

N R 42

O

41, R1 = 2-Br; 2,3-(OCH3)2; 4-OCH3 R2 = H, Hal, OCH3, Alk, CF3, CN, NO2

O

RHal, KOH, acetone

1. P2S5, NaHCO3, THF, 67% 2. MeI, NaH, THF, 44% R1 = H, R2 = 9-Br

R2 Br HN

N

Br RNH2 R = OH, 83% R = NH2, 36%

NHR 45

HN

N

SMe

43

R

N

N H

O

44

Scheme 8

by indole ring formation on treatment with sulfuric acid. Other examples of such transformations, including reaction conditions and yields are listed in Table 1. The protic acid procedure affords products in 33–74% yields, while successful attempts using Lewis acid catalyzed (1993JMC2908, 1992AG(E)1060) or thermal (2005MI541) conditions also has been reported. The Fisher synthesis tolerates diverse substitution including vinyl and allyl (2005EJM655), phthalimide protected amino (2005MI541), nitrile and ester (2005MI541), methoxy (2002AP311), thiomethyl and sulfonamide (2004AP486) derivatives.

2.1.1.4 Miscellaneous reactions. Pyrrolo-benzazepinedione 50 has been synthesized by a Schmidt type rearrangement and ring enlargement of diketone 49

H H 9-Br 11-Cl 9-Cl H H 9-OMe 9-OMe, 10-CH2NR2 9-Br 9-Br 9-NO2 9-NO2 9-NO2 9-NO2 9-SO2NH2 9-SMe 9-CF3

H 2-Br H H H H H 3-Cl 3-Cl 2-vinyl 2-allyl 2-o-C6H4(CO)2N-(CH2)4 2-o-C6H4(CO)2N-CH2CHQCH CH2CH2CN CH2CH2COOMe 2-OMe 2-OMe 2-I

9

10

Indole

Substitution on the ring

Synthesis of indolobenzoheteropines

Benzo

Table 1

8

1

6 5

X NH

NH

12

CQO CQO CQO CQO CQO CQO CQO CH2 CH2 CQO CQO CQO CQO CQO CQO CQO CQO CQO

X

7

11

3

H2SO4, AcOH, 70 1C, 1 h H2SO4, AcOH, 70 1C, 1 h H2SO4, AcOH, 70 1C, 1 h H2SO4, AcOH, 70 1C, 1 h H2SO4, AcOH, 70 1C, 1 h ZnCl2 ZnCl2, 170 1C, 5 min HCl, EtOH, reflux, 18 h HCl, EtOH, reflux, 18 h H2SO4, AcOH, 70 1C, 2 h H2SO4, AcOH, 70 1C, 2 h Ph2O, reflux, 2 h Ph2O, reflux, 2 h Ph2O, reflux, 2 h Ph2O, reflux, 2 h H2SO4, AcOH, 70 1C, 1 h H2SO4, AcOH, 70 1C, 1 h H2SO4, AcOH, 70 1C, 1 h

Conditions

4

2

70 63 58 62 83 7.5 85 53 49 52 62 55 70 72 56 58 82 50

Yield (%)

1992AP297 1992AP297 1992AP297 1992AP297 1992AP297 1993JMC2908 1992AG(E)1060 1994CPB1084 1994EJM107 2005EJM655 2005EJM655 2005MI541 2005MI541 2005MI541 2005MI541 2004AP486 2004AP486 2000BMCL567

References

10 D.O. Tymoshenko


R1 N

O

R1 N

TosMIC

O

MeI, K2CO3, DMF

R1 N

O

N Me

NH O

NaH, DMSO-ether R1 = H, 45%; R1 = Me, 57%

11

1

O

46

R = H, 77% R1 = Me, 100%

47

48

MeI, NaH, THF, R1 = Me, 100%

O HN

O

O

NaN3, H2SO4

N Me

N Me O O 50

49

Scheme 9

Br t-BuOK N Ac

N Ac 51

52

X

X

X 53 N H 54

N H 55

Scheme 10

(Scheme 9 (1996SC1839)). Alternatively, this cyclic system has been synthesized by TosMIC addition to 1H-1-benzazepine-2,5-dione 46. Reaction of N-acetyl-10-bromodibenzazepine 51 with potassium tert-butoxide yields the reactive intermediate 52 that reacts with N-methyl pyrrole 53 (X ¼ NMe) used as a solvent to produce a mixture of Diels–Alder/retro Diels–Alder adduct 54 with the Michael by-product 55 (X ¼ NMe, Scheme 10 (1994JHC293)). The condensation of dichloride 57 with the dianion of N-methyl orthotolylamide 56 affords pyrrolo[2,3-d]-[2]benzazepin-6(1H)-one 58 (R ¼ p-tolyl). The product 58 contains four rather than just two imino groups. This can be explained

12

D.O. Tymoshenko

Cl R

N

N

R

O NHMe

O

O

Cl

N

N

57

N R N R

N R NH

BuLi, THF

Me

Me

Me

N R

R 56

N R 58

Scheme 11 O X

COOMe COOMe N

PMB O

O

N Me

60

O

PMB N DMAD

O O

O toluene, sealed tube, 180 °C, 3 h 53%

N Me

59

X

O

N PMB O

toluene, sealed tube, 180 °C , 1 h

O N

Me

61a X = O, 57%; 61b X = NMe, 87%

Scheme 12

by condensation of the enamine function of the initial 1:1 product with a second molecule of the bis(imidoyl) chloride 57 (Scheme 11 (2001EJO1503, 1998SL399)). The unusual annulation of a substituted phenyl ring through [4 + 2] cycloaddition of vinyl compound 59 with dimethyl acetylenedicarboxylate (DMAD) as dienophile affords indolo benzazepine 60 in 53% yield, while a similar reaction with N-methyl-maleimide or maleic anhydride yields tetracyclic 61a,b in 53–87% yield (Scheme 12 (2003T6659)). Intramolecular oxidative palladium couplings of alkenylamino indoles allow the preparation of azepinoindole derivatives in high yields (2005MI707).

2.1.1.5 Benzopyrrolo[1,2]azepines. Syntheses of benzopyrrolo[1,2]azepines in which pyrrole or indole N1 and C2 atoms serve as fusion sites usually involve preforming the N-substituted pyrrole derivatives followed by intramolecular cyclization. Few examples of the intramolecular electrophilic substitution on a C2pyrrole site have been reported for benzo[f ]pyrrolo[1,2-a]azepinones. Thus, treatment of acid 62 with phosphorous pentachloride results in Friedel–Crafts product 63 (Scheme 13 (2000T9351)). Similarly, benzo[f ]pyrrolo[1,2-a]azepinone 68 (R ¼ Ph; X ¼ CH2) can be obtained from the corresponding acid 67 via intramolecular Friedel–Crafts acylation (Scheme 14 (2002JMC4276)).

13


HOOC

Ph

Ph PCl5, DCE

Li-n-BuBH3, −78 °C, 92%

O

89%

Ph OH

N

N 62

N

63

64 NaBH4, MeOH, 91%

H2, Pd/C 89%

Ph

Ph

OH

O N

N

65

66

Scheme 13

R COOH X

X X

PCl5 N

N

N

Et2NCOCl R

R

X = CH2

O O

O

NEt2 68

67

69

Scheme 14

Intramolecular electrophilic reactions of substituted pyrrole-2-carboxylic acids or their amides lead to benzo[d]pyrrolo[1,2-a]azepinones. Acid 70 in this fashion undergoes Friedel–Crafts cyclization to furnish fused azepine 71 in good yield (Equation (6) (2000JOC2479)). OMe

MeO OMe

MeO

MeO OH

MeO

Eaton's acid, 68%

O

MeO N

(6) OMe

MeO N 70 71 MeO

OMe

O

OMe

14

D.O. Tymoshenko

Likewise, aryllithiums generated by lithium–iodine exchange undergo intramolecular cyclization to give pyrrolo-azepine 72. The best results were obtained when Weinreb (R1 ¼ Me, R2 ¼ OMe) or morpholine amides were used as internal electrophiles, resulting in 66 and 70% yields, respectively (Equation (7) (2005T3311)). R1 2 N R N

O

O n-BuLi

N

I

OMe

(7)

OMe

MeO

OMe

72

Several azepine ring constructions have been reported using palladium catalyzed C–C bond formation. Palladium catalyzed cyclizations of substituted tryptamine derivatives 73 lead to benzo[d]pyrrolo[1,2-a]azepinones 74 (Equation (8) (2000JMC1050)). NHCOR2

NHCOR2

R1

Pd(PPh3)4 Br N

R1

(8)

AcOK

N 74

73

R I

H

PdCl2, norbornene, trifurylphoshine, Cs2CO3

N Br

H

75

H N

I

R R N

77

76

Scheme 15

15


A variety of substituted seven-membered annulated pyrroles can be synthesized in a one-step process in good yields from readily accessible N-bromoalkyl pyrroles 75 and aryl iodides. The synthesis is based on a palladium-catalyzed/ norbornene-mediated sequential coupling reaction involving an aromatic sp2 C–H functionalization as the key step. The proposed mechanism suggests that ortho-alkylation with the formation of intermediate 76 most likely precedes aryl–heteroaryl coupling (Scheme 15 (2006OL2043)). Reaction of the radical derived from substituted 2-bromo indole 78 leads in moderate (37%) yield to benzo[d]pyrrolo[1,2-a]azepinone 79 along with 32% of the reduction product 80. The process occurs via radical addition to the benzene ring followed by rearomatization (Equation (9) (2000TL4209)). O

O

O

Bu3SnH, AIBN Br

H

N Ph

N

N

79

80

78

Ph

(9)

A similar synthetic transformation has been reported for a variety of substituted indole annulated rings (2005JA13148, 2006OL3601). Synthesis of benzo[e]pyrrolo[1,2-a]azepinone 82 was accomplished by palladium catalyzed ring closure of ketone 81 (Scheme 16 (2005JMC1705)). Palladium catalyzed reaction of iodo 84 with allene is an example of a 5 + 2 ring formation and gives access to the fused benzo[d]pyrrolo[1,2-a]azepinone O Me

N

Pd2(dba)3 DPPF t-BuONa

O

N Br 81

82 1. TMSOTf 2. N-Me-piperazine Me N N

N 83

Scheme 16

16

D.O. Tymoshenko

derivatives 85 in 48–73% yield (Equation (10) (2000T6585)).

N R

N R

Pd(0), allene

N H

(10)

N I 84

85

A one-step method has been developed for elaboration of fused indole 87 via a palladium-catalyzed intramolecular indolization of 2-chloroaniline 86 bearing tethered acetylene (Equation (11) (2006OL3573)). Cl

Bu

Pd(OAc)2, ligand, K2CO3, NMP

NH O

(11)

N

Bu 87

86

1,3-Dipolar cycloaddition is another route to benzopyrrolo[1,2-a]azepines by pyrrole ring formation. The azomethine ylide derived from imine 88 and difluorocarbene adds to DMAD to produce dimethyl 3-fluoro-9H-dibenzo[c,f ]pyrrolo[1,2-a]azepine-1,2-dicarboxylate 89 in 20% yield (Equation (12) (2000JCS(P1)231)). DMAD, CBr2F2, Pb N F

N

(12)

H3COOC 88

89

COOCH3

2.1.2 Benzazepines with fused furan ring An example of the direct annulation of the furan ring onto the benzazepine core has been reported by Cann and co-workers (1990JHC1839). Reaction of N-acetyl-10-bromodibenzazepine 51 with potassium tert-butoxide yields the reactive intermediate 52. It further reacts as a dienophile with furan 53 (X ¼ O) to produce 8H-furo[3,4-d]dibenz[b,f ]azepine 54 as a sole product (X ¼ O, Scheme 10, Section 2.1.1.4). Intramolecular C–C bond formation in the furan precursor is the main synthetic method for furobenzazepines. 2-Hydroxybenzonitrile 35c produces the corresponding benzofuran benzazepine dione 36c when reacted with o-carboxymethyl bromoacetophenone in refluxing DMF (Scheme 6, Section 2.1.1.2 (1991JHC379)). Alternatively, benzofurobenzazepinone 91 can be synthesized starting from benzofuran amino ester 90 by intramolecular acylation


17

(Equation (13) (1991JHC379)).

AcN

O

HN

1. NaOH, H2O

O

2. DCC, CH2Cl2; 3. NaOH, EtOH

OC3H7

(13)

O O

90

91

Benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione 93 has been reported as a product of cyclization of acid 92 (Equation (14), 2002MI353). MeO

COOH O

MeO

O

MeO

O

PPA MeO

(14)

N

N

O

Me

Me

93 O

92

In situ generation of azomethine imines from furan-3-carbaldehyde and N,N’-disubstituted hydrazines followed by cycloaddition to N-methylmaleimide results in a 2.8:1 mixture of pyrazolidines 94 and 95 (X ¼ O) separatable by chromatography. Further Pd(0) catalyzed cyclization involving the aldehyde and hydrazine moieties leads to the formation of benzoxepines 96 and 97 (X ¼ O) in good yield (Scheme 17 (2003T4451)). The cascade ketene imine [2 + 2] cycloaddition and palladium catalyzed cyclization is a convenient route to furoazepine 98 (X ¼ O) with the fused b-lactam

O H H

Me N

H N COOMe N

hydrazine, N-Me-maleimide, xylene, reflux, 19 h

X

N H

H N

N

O H

N COOMe

X

X

O

O H H

O

Me N

94

95

I

I

Pd(0), TlOAc, xylene, 100 °C, 19h

O H H

COOMe

I X

Me N

O

H N COOMe N

O H H X

97

96

Scheme 17

Me N

N

O H

N COOMe

18

D.O. Tymoshenko

moiety obtained in 52% yield (Scheme 18 (1995TL9053)). Introduction of the furan moiety into aldehyde counterpart gives corresponding 99 (X ¼ O) in 60% yield.

2.1.3 Benzazepines with fused thiophene ring 2.1.3.1 Construction of the azepine ring by C–C bond formation. Thieno[2]benzazepine with the annulated isoindole ring 101 is the product of acidcatalyzed cyclization of hydroxylactam 100 obtained in 88% yield (Scheme 19 (1997JHC1495, 1997TL1041)). Similar fused derivatives were synthesized starting from succinimide and tetramethyl succinimide, to give thieno benzazepines in 80 and 85% yields, correspondingly.

I

BnO

•

I H H

O

N

N

benzene, reflux, 4 h, 80%

X

OBn

N

PPh3, toluene, reflux, 24 h

O

X

H H OBn

Pd(OAc)2

O

X 98

X

Br N

H H OBn N O

X 99

Scheme 18

O Br

OH

Steps O

CH2Cl2, rt, 24 h 88%

Br

S

N

TFA

N

S

S 101

100

Scheme 19

S

S MeSO3H

OH

N

CH2Cl2, reflux

N n

S

BF3 etherate, BH3 SMe2, THF, reflux N n

O

n

O 102

103a n = 1, 80% 103b n = 2, 99%

Scheme 20

104a n = 1, 61% 104b n = 2, 71%

19


Tetracyclic benzo[f ]-4-oxopyrrolo[1,2-a]thieno[3,2-c]azepine 103a, as well as its piperidone homolog 103b, can be prepared through intramolecular N-acyliminium ion cyclization of hydroxylactams 102 (Scheme 20 (2001H1519)). The synthesis of thieno[3,2-c]benzazepine derivative 106b has been reported by Friedel–Crafts intramolecular cyclization of isocyanates 105 (Equation (15) (2002S355)). Noteworthy, lactam 106b is formed in 51% yield, while dione 106a can not be obtained due to the electron-withdrawing effect of the carbonyl group. NCO X

S

AlCl3, 1,2-dichlorobenzene, 100 °C Me

O HN X

S

(15)

Me

106a X = CO, 0%; 106b X = CH2, 51%

105

The cyclization of diene conjugated nitrile ylides in which the conjugated system consists of a benzene ring and a five-membered heterocyclic ring provides an effective route to unsaturated heterocycle-fused benzazepines. Thus, nitrile ylide 107 undergoes smooth cyclization onto the substituent at the 6 position without considerable competition from cyclization onto the unsubstituted phenyl group at the 2 position, providing thieno benzazepine 108 in 98% yield (Scheme 21 (1991CC658, 1995JCS(P1)2565)). Several other examples of a thieno benzazepine synthesized from substituted thieno aryls through nitrile ylides have been reported (1994JCS(P1)1193). Similar to furo derivatives, cascade ketene imine [2 + 2] cycloaddition and palladium catalyzed cyclization gives thieno benzazepines 98 and 99 (X ¼ S) with the fused b-lactam moiety in 65 and 66% yields, correspondingly (Scheme 18, Section 2.1.2 (1995TL9053)). The Heck-type cyclization in the presence of Pd(OAc)2/PPh3 catalyst and silver carbonate base leads to good to excellent yields of the corresponding thieno benzoazepinones 12d and 14d (see Equations (1) and (2), Section 2.1.1.1 (2005TL8177)). Similar to the furobenzazepine derivatives (Scheme 17, Section 2.1.2), thieno benzazepines 96 and 97 (X ¼ S) were synthesized in good yields by a multistep procedure involving in situ generation of azomethine imines from thiene3-carbaldehyde and N,Nu-disubstituted hydrazines followed by cycloaddition to

S NH Ph

O

1. SOCl2

S

2. t-BuOK

N Ph 107

Scheme 21

S Ph N Ph 108

20

D.O. Tymoshenko

N-methylmaleimide and Pd(0) catalyzed cyclization of the intermediate pyrazolidines (2003T4451). Thieno benzazepine 109 was synthesized in moderate yield by oxidative biaryl-coupling using the hypervalent iodine reagent phenyliodine(III)bis (trifluoroacetate) (PIFA) and BF3 OEt2 as the activating agent in methylene chloride (Equation (16) (2002T8581)).

MeO MeO

S N

PIFA, BF3 OEt2, CH2Cl2, 47%

S MeO

(16)

N

MeO

COCF3

COCF3 109

2.1.3.2 Construction of the azepine ring by C–N bond formation. Aranapakam et al. synthesized 5,10-dihydro-4H-benzo[b]thieno[2,3-e]azepine 111 and 4Hbenzo[b]thieno[3,2-e]azepin-10(9H)-one 113 (X ¼ CO) starting from the corresponding tributylstannyl derivatives 110 and 112, which react with 2-nitrobenzyl bromide and [(Ph)3P]4Pd. Sequential deprotection and reductive cyclization were carried out in one step with zinc and aqueous acetic acid (Scheme 22 (1999BMCL1733)). The synthesis of thieno[3,2-c]benzazepine-1,6-dione by treatment of 3-methylamino-3-methylthio-1-phenylthioxopropene with 2-hydroxy-1,4-benzoquinone, which serves as enolizable cyclic ketone, has been reported (2000JOC3690).

O O Sn(Bu3)

S

Br O N+ O– Pd(PPh3)4, toluene, reflux, 24 h,

O O O N+ O–

S

H N

Zn, AcOH, 80 °C S

111

110

Br N O S Sn(Bu3)

N

+O

N O–

O S

Pd(PPh3)4, toluene, reflux, 24 h,

112

Scheme 22

O N+ O–

1. Zn, AcOH, 80 °C, X = CO 2. LiAlH4, THF, reflux, X = CH2

H X N S

113

21


O HN

OHC

O

OHC KOH, EtOH

S

O

114

O

HN

S

60%

NaBH4 69%

S

O

115

O

Me

HN

N

MeI, NaH, THF

67%

83 %

S

OH

116

O SiEt3H

HN

S

117

118

Scheme 23

O

NC

85%

NC S

S, morpholine, EtOH, reflux

malononitrile, TEA, EtOH

N Ts

NH2

CN

N Ts 119

90%

N Ts 120

Scheme 24

2.1.3.3 Miscellaneous reactions. Double aldol condensation of phthalic dialdehyde with thieno azepinedione 114 results in a 60% yield of naphtho derivative 115 (Scheme 23 (1999PHA645)). Fusion of a functionalized thiophene ring to a benzazepine can be achieved by a two-step procedure through the dinitrile intermediate 119 (Scheme 24 (2005IJC(B)1257)).

2.2 Benzoxepines 2.2.1 Benzoxepines with fused pyrrole ring Lactonization of the suitable hydroxy acids or their derivatives is the most common synthetic method for benzoxepinenones with fused pyrrole rings. Therefore, reduction of the formyl group in the ester aldehyde 121 with sodium borohydride gives a mixture of alcohol 122 (80% yield) and lactone 123 (19%). Further heating of the open-chain product 122 in refluxing ethanol affords cyclic lactone 123 quantitatively (Scheme 25 (1998T11079)). Cyclic lactone 125 has been observed as the only minor product of reduction of ketone 124 under thermal conditions. Stepwise reaction under mild conditions

22

D.O. Tymoshenko

O

HO NaBH4 COOEt

O

COOEt

N Me

N O Me

N Me

121

EtOH, reflux

122

123

Scheme 25

produces oxepinone 125 in 88% yield (Equation (17) (1993H1287)). O O

1. NaBH4, rt COOMe

N Ac

O

(17)

2. Na2CO3, rt N H 125

124

Pyrrolidinone 126 and salicylic aldehyde in acetic acid under microwave irradiation gives in dioxopyrrolo[3,4-c]benzoxepine 127 as a mixture with phenyl chromeno[2,3-b]pyrrole 128 (8 and 13% yields, correspondingly, Equation (18) (2006T6018)). O O O

OH

Ph

O O

NH AcOH, reflux

O 126

Ph

COOEt

NH

Ph O

O

(18)

N

128

127

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-b]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). HO

O

SO2Ph N

H N

O NaOH, EtOH O

129

130

(19)


COOMe

23

COOMe O2

N Me

N Me

131

132 OH

COOMe

O

OH

O N Me

COOMe

O

N Me

N Me

134

133

COOMe

135

Scheme 26

Diels–Alder reaction of 3-vinylindole 131 with aryne in the presence of air gives, besides primary Diels–Alder product 132, the methyl 12-methyl-12H-[3]benzoxepino[1,2-b]indole-5-carboxylate 135. This can be explained by the formation of 1,2-dioxetane 133, its cyclo reversion and final intramolecular cyclization of dienol 134 or its tautomers (Scheme 26 (1996JCS(P1)1767)). The synthesis of cyclic ethers 137 was achieved by a Fischer indole synthesis starting from cyclic keto arylhydrazones generated in situ from 4-(hydroxymethylene)-3,4-dihydrobenzo[b]oxepin-5(2H)-one 136 and the corresponding diazonium salt (Equation (20), 1993JHC1481). O

HO 1. p-RC6H4N2Cl; 2. HCl, EtOH

O

H N

(20) O 136

O

R

137

Several methods for the synthesis of indolo benzoxepines with the peri-fusion have been reported. A route to 3,4-fused indoles by two consecutive palladiumcatalyzed reactions and an intramolecular Heck reaction followed by a reductive N-heteroannulation has been described (Scheme 27 (2005T3637)). In the case of the 1-butene 138a (R ¼ CH2CH2) the corresponding nitro oxepine 139 and indolo oxepine 140 are the products of the sequence. Reaction of the substituted vinyl styrene 138b (R ¼ o-C6H4) is more complex, giving an unseparatable mixture. Sequential reductive annulation results in a mixture of indolo benzoxepine 141 and dibenzo[b,f ]oxocin-10-amine 142. A peri-fused system can be synthesized by diaryl copper-catalyzed ether coupling accomplished utilizing (CuOTf)2 PhMe in pyridine (Equation (21) (2004JOC4527)). This protocol produces several annulated ring systems and gives

24

D.O. Tymoshenko

O

R

1. Pd(OAc)2, TEA, P(o-tolyl)3

Br

2. Pd2(dba)3; phenanthroline; CO(4 atm); R = o-C6H4

NO2 138a R = CH2CH2; 138b R = o-C6H4

O

O

N H

NH2

141

142

Pd(OAc)2, TEA, P(o -tolyl)3; R = (CH2)2 Pd2(dba)3; phenanthroline; CO(4 atm)

O

O

N H

NO2 139

140

Scheme 27

straightforward access to the natural product aristoyagonine 143. O

O

N Me

N Me Cu(OTf)2, toluene

MeO OH Br

Cs2CO3, pyridine OMe OMe

MeO O

(21) OMe

MeO 143

Alternative strategies to the aristoyagonine molecular structure (2002ARK62, 1996TL9357) and its synthetic analogs (1992JOC2029, 1990TL6247) have been reported. 1-Tosyl-4,6-dinitroindoline 144 undergoes under basic conditions condensation with salicylic aldehyde followed by intramolecular nitro group substitution to afford mono nitro compound 145 in 75% yield (Scheme 28 (2003RCB759)). Further refluxing in benzene in the presence of DBU gives isomerization product 146 in 82% yield.

2.2.2 Benzoxepines with fused furan ring The synthesis of these rings involves annulation of the furan ring onto the preformed benzoxepine core or intramolecular oxepine C–C bond formation of the furan precursors. Thus, 2-methyldibenzo[b,f ]furo[2,3-d]oxepines 148 (R ¼ H, Cl)

25


O

NO2

O

OH N Ts

O2N

piperidine, benzene

N Ts

O2N

144

O

DBU, benzene

N Ts

O2N 146

145

Scheme 28 HO O R

1. ClCH2COMe NaH, DMSO O

O 1. NBS, Bz2O2 or Pb(OAc)4

R

2. TSA, benzene

2. LAH

O

147

O R O 149

148

Scheme 29

R O R

I Ph R

R

O O

150

Me

O

CH

R

O

Cu(acac)2 O

151

O

I Ph

R O

30−52% O

Me

Me

152

Scheme 30

are readily available by reaction of 11H-dibenzo[b,f ]oxepine-10-ones 147 and chloroacetone through an intermediate diketone not shown (Scheme 29 (2006JHC749)). Alternative furan ring fusion involves the reactions of phenyliodonium ylides of cyclic seven-membered b-diketones with alkynes. These processes lead under mild conditions to cyclization products 152. The high regioselectivity can be explained by the formation of dipolar intermediate 151 favored by the predominant enolization of the carbonyl adjacent to phenyl ring. Terminal alkynes react in the similar fashion, although, in this case, mixtures of regioisomers have been reported due to steric hindrance in the intermediate enol (Scheme 30 (1993JOC4885)). The next two examples illustrate intramolecular oxepine C–C bond formation of the furan precursors. Palladium catalyzed intramolecular arylation of 153

26

D.O. Tymoshenko

affords furano oxepine 154 in good yield (Equation (22) (2005JOC7679)). Ph

Ph

O I

Cs2CO3, DMA Pd-catalyst

O

(22)

76%

O

O

153

154

Ruthenium catalyzed intramolecular propargylation leads to furobenzoxepines 155 in moderate to good yields (Equation (23), 2006EJO881). R OH R

[CpRuCl(μ2-SMe)]2

O

O

R

10 mol % NH4BF4

O

(23)

R O

155, R = H, Me, Cl 40−93%

In a manner similar to that of 1-tosyl-4,6-dinitroindoline (see Scheme 28, Section 2.2.1), 4,6-dinitrobenzofuran undergoes condensation with salicylic aldehyde under basic conditions followed by nitro group substitution/cyclization to afford a mono nitro compound with peri-fusion of the benzofuran ring in 68% yield (2005CHE796).

2.2.3 Benzoxepines with fused thiophene ring Flash vacuum pyrolysis of oxiranes 156, accessible by a two-step procedure, results in carbonyl ylides 157, conjugated with a diene system formed by benzene and heterocyclic substituents R. They further undergo 1,7-electrocyclization and subsequent 1,5-sigmatropic hydrogen shift to give oxepines 158 and 159 (Scheme 31 (1997JCS(P1)3025, 1996JCS(P1)515)). Benzopyran 160 reacts with 2,3-dichloro-1,4-naphthoquinone by substitution of both chlorine atoms. The unstable primary adduct 161 undergoes ring expansion of oxirane 162 to produce thieno benzoxipine 163 in 70% yield (Scheme 32 (1994JCS(P1)2191)).

2.3 Benzothiepines 2.3.1 Benzothiepines with fused pyrrole ring Chiral pyrrolo[d]thiepine 166 can be obtained efficiently in 63% yield starting from N-alkylated maleimide 164. Successive Michael addition of phenethyl thiol and regioselective reduction are followed by spontaneous loss of hydrogen by N-acyliminium intermediates 165 and p-aromatic intermolecular a-amidoalkylation

27


R

S

R R = thien-3-yl COOMe

COOMe

O

O

O COOMe

156

158

157

1. Suzuki 2. Darzen condensation

R = thien-2-yl

B(OH)2

S COOMe

O

O 159

Scheme 31 NH2 O

S

Cl

NH2 O

O TEA

S

Cl

CN OH

Cl

NH

THF, reflux

O

O

160

Cl

161

NH2

NH2 O

S

O

S

CN

O

O

CN

O O 163

162

Scheme 32

cyclization (Scheme 33). An alternative pathway, which involves isomerization of 165, results in 22% of the open chain separable byproduct 167 (2001TL573). 2-(3-Indolylthio)phenylacetic acid 168 in 50% polyphosphate ester in methylene chloride at room temperature affords 169 as a major product in 65% yield. In hot polyphosphoric acid (PPA) cyclized 169 and 170 were formed in 15 and 21% yields, respectively, due to the partial isomerization. Heating in PPA for a prolonged period gives a 90% yield of 170 as a sole product of

28

D.O. Tymoshenko

O 1. PhCH2CH2SH; 2. NaBH4; 3. TFA

O N

N Ph

S

Ph O 164

165

O

O

N

N Ph

S

Ph

S

166

167

Scheme 33

isomerization/cyclization (Equation (24) (1999JHC643)). COOMe

S

N H 168

polyphosphate ester in CH2Cl2 or PPA

S N H

O

S O

169

(24)

N H 170

Treatment of substituted pyrrole 171a (R ¼ pyrrol-2-yl) with triphosgene and triethylamine leads to pyrrolo-benzothiazepine 172 in 35% yield (Scheme 34 (1994MI283)). Similarly, substituted pyrrole 171b (R ¼ N-Me-pyrrol-3-yl) produces pyrrolo-benzothiazepine 175. An indole ring can be fused to a benzothiepine via Fisher synthesis to give benzothiepino[5,4-b]indole (2006BMCL3233).

2.3.2 Benzothiepines with fused thiophene ring Dithioacetals derived from heteropine 177 smoothly react with methylene iodide in the presence of a zinc–copper couple in refluxing ether to give the corresponding fused thiophenes 178. The suggested mechanism involves formation of an ylide which undergoes intramolecular aldol-type condensation assisted by coordination of zinc with a carbonyl followed by demethylation of the S-methylthiophenium species (Scheme 35 (1989TL3093)).

29


H N

O R S

NH2

O

(CCl3CO)2CO

H N

MeI, K2CO3 S

R = pyrrol-2-yl N H

171a R = pyrrol-2-yl; 171b R = N-Me-pyrrol-3-yl

S N Me

172

173

1. MeI, t-BuOK; 2. H2O2

(CCl3CO)2CO R = N-Me-pyrrol-3-yl

S

O O S

H2O2

O

N N H

N Me

O

175

S N O O Me 174

Me

N H

Me N

O

176

Scheme 34

R

X

R

X

R

X

CH2I2, Zn-Cu O MeS

SMe ether, reflux 61−63%

SMe O IZn

S

Me

SMe S

I

177

178

Scheme 35

3. BENZOHETEROPINE RINGS WITH TWO HETEROATOMS ON THE HETEROPINE RING 3.1 Benzodiazepines 3.1.1 Benzodiazepines with fused pyrrole ring The synthetic chemistry for these targets has been most extensively developed for benzopyrrolo[1,2]diazepines. It includes annulation of the pyrrole ring to a pre-formed benzodiazepine core, intramolecular cyclizations of non-cyclic precursors and 6 + 1 and 4 + 3 dicomponent cyclizations. Similar approaches have been reported for a few systems with other fusion modes, and they are surveyed at the end of each section.

3.1.1.1 Annulation of the pyrrole ring. o-Aminoketone 179, bearing the protected aldehyde moiety, can be smoothly reacted with substituted phenyl alanines and transformed into 1,4-benzodiazepinones 180 with a fused pyrrole ring (Scheme 36 (1992BMCL1639)).

30

D.O. Tymoshenko

O

OH

O

N

i-iii

O NH2

N H

179

N

iv-v

R

R = p -C6H4OBn

N

O

O

180

vi

181

R = Ph

O

N

182

N H

HO

O

i, BocNHCHRCOOH, NMM, i -BuOCOCl; ii, HCl (g), then 1N NaOH; iii, oxalic acid, H2O; iv, BrCH2CH2C6H4OBn, DMF, NaH; v, CHCl3, TMSI; vi, POCl3, DMF

Scheme 36

The high-pressure carbonylation of dimeric palladium derivatives 183 (R ¼ Me or cyclopropyl) in ethanol or methanol/chloroform leads in moderate yields to fused isoindoles 184 as mixtures with their alkoxy derivatives 185, easily separated by flash chromatography (Equation (25) (1991JOM371)). R N

R N

O

R N

O

O

CO, ROH N Cl Pd

Cl

Cl

H

N O

Cl

N RO

O

(25)

2

183

184

185

3.1.1.2 Intramolecular cyclizations. Intramolecular cyclizations of electronrich chloroacetyl indoles leads to indolo[1,2-d][1,4]benzodiazepin-6-one 20 as a result of a side nucleophilic cyclization at the indole nitrogen (Equation (4), Section 2.1.1.1 (2005T5489)).


31

Imidazo[2,1-a]isoindolone 187 is the product of an intramolecular a-aza-amidoalkylation of N-acyliminium species 186. Nevertheless, when the b-substituent is an aromatic moiety, a competing a-amidoalkylation takes place and isoindolo[1,4]benzodiazepine 188 is obtained under thermodynamic control (Scheme 37 (2004T11029)). N-Aryl isoindolo[2,1-b][2,4]benzodiazepines 190 (Scheme 38, R ¼ Ar) can be obtained by an intramolecular acylation of amino acids 189 in acetic anhydride (1998T1497). O

N

O

TFA

HN

NH

N

neat

186

188

TFA (cat.) or AcOH (cat.) CH2Cl2, rt

O

O

N

N

HN

N

OH

187

Scheme 37 1. SOCl2; 2. RNH2; 3. Hydrolysis

O O N

O

O O N

OH

OH

NH R

188

189 1. Hydrolysis 2. SOCl2

Ac2O

O

O O N Cl

R = aryl

Cl

1. RNH2; 2. PTSA. toluene R = alkyl

N N R O

191

190

Scheme 38

32

D.O. Tymoshenko

O

O

N

PPh, toluene, reflux

O N3

87%

N O N PPh3

191

O N N 192

Scheme 39

6,11-Dihydro-13H-isoindolo[2,1-b][2,4]benzodiazepin-13-one 192 has been reported as a product of the tandem Staudinger/aza-Wittig reaction of azidoimide 191 (Scheme 39 (1989CC602)). Reduction of nitro derivative 193 with tin (II) chloride leads to aldehyde 194 in 45% yield (Equation (26) (2005T5831)). Cl

O

O

Cl

SnCl2, HCl

N

Cl

O Cl

N N

45% –

O

(26)

N+ O 193

194

The precursor of ( + )-anthramycin, pyrrolo-benzodiazepine 196, can be synthesized by deprotection, acylation and reductive cyclization of pyrrolidine derivative 195, obtained by enyne metathesis (Scheme 40 (2004T9649)). Pyrrolo-benzodiazepine 199 with controlled stereochemistry has been prepared from the corresponding protected amino alcohol 198 in good yield (Scheme 41 (2003CC1688)). Reductive ring closure of 1-(2-nitrobenzyl)-2-pyrrole carbaldehyde 200 results in pyrrolo[2,1-c][1,4]benzodiazepine 201 (Scheme 42 (1999BMCL1737)). On the other hand, oxo derivative 203 can be synthesized starting from aldehyde 200 through a nitrile formation/cyclizations multistep sequence. The alternate synthetic strategy included reduction of the intermediate acid (R ¼ H) or ester (R ¼ Et) 205 followed by CDI or thermal cyclization (1992JHC1005).

33


1. TMSI H

2. Me

N Cbz

MeOOC 195

OBn

O H

O H

OAc

AcO

N

NO2

catalyst, 91%

O

COCl 3. Zn, AcOH 93% OBn H N

Me

OBn H N

Me

196 OBn H N

Me

steps

O H N

N O

O

OAc

O

197

O

Scheme 40 Alloc NH

MeO

C6H5I(OAc)2, TEMPO

O

MeO

OH N

Alloc N

MeO

N

MeO

84%

OH H

R

O 198 R Pd(PPh3)4 80%

N

MeO

H N

MeO O 199

R

Scheme 41

N O

N

H2, Pd/C

+O

200

N

N H

1. NH2OH; 2. POCl3; 3. H2, Pd/C; 4. KOH

N O–

N

RCOCl

O

201

R 202

X = CH2 X N N

1. (morpholyl)2POCl; 2. NH2NHCHO N

N 204

X = CH2, SO2

R = H; X = CH2 1. H2, Pd/C; 2. Im2CO

X N N H 203

Scheme 42

O

ROOC

R = Et; X = CH2, SO2; 1. H2, Pd/C; 2. 2-HO-Py

205

N X N+ O–

O

34

D.O. Tymoshenko

The pyrrole derivative of carbonyl azide 206 undergoes thermal Curtius rearrangement into isocyanate, which spontaneously cyclizes into pyrrolodiazepinone 207 (Equation (27) (1991JHC1911)). CON3 AcOH N

N

62%

NH

(27)

O 206

207

Ketoester 208 derived from 1-(2-nitrophenyl)-1H-pyrrole and ethyl oxalyl chloride can be selectively reduced at the keto group with zinc iodide and sodium cyanoborohydride. Further reduction of the nitro group and cyclization to lactam 209 has been accomplished by treatment with stannous chloride in refluxing ethanol (Scheme 43 (2003BMCL2195)). Sequential Mannich reaction of ester 210a or nitrile 210b, alkylation and displacement of quaternary ammonium salt affords azides 211. Further hydrogenation can be followed by intramolecular cyclization under basic conditions into pyrrolo-benzodiazepinone 212 (Scheme 44 (1994JHC1317, 1994S164)). Aminomethyl substituted pyrrolo-benzdiazepine can be formed from the Cbz-protected precursor 214 and further reduced into tetrahydro derivative 215. Alternatively, the unsubstituted ring in 217 has been synthesized by a Bischler– Napieralski method (Scheme 45 (1993JHC749). 5,6-Dihydro-4H-benzo[f ]pyrrolo[1,2-a][1,4]diazepin-4-one 220 is a product of reductive cyclizations of ester nitrile 219a (R1 ¼ COOMe, R2 ¼ CN), while amido

COOEt –

O

O N+

N O

1. ZnI2, NaCNBH3; 2. SnCl2

N

O

1. BH3-Me2S 2. RCOCl TEA, CH2Cl2

N

NH

N O

208

202

209

Scheme 43 1. CH2O, NHMe2; 2. MeI; 3. NaN3

N

N3 1. H2, Pd/C; 2. EtONa N

R R 210a R = COOEt; 210b R = CN

N HN

211

Scheme 44

R = COOEt, X = O; R = CN, X = NH

X 212a, b

R

35


H N

NH2

NHCbz

Cbz-Gly O N

EDCI

1. POCl3 2. NaBH4; 3. H2, Pd/C

N

213

H2N H N N 215

214

1. RCHO; 2. MnO2

1. HCOOEt; 2. POCl3

R

N N

TosMIC

N

N N

N N

N 217

218

216

Scheme 45

R1 NaBH4, CoCl2

O

N

N HN

1

R2

R = COOMe; R2 = CN

219a, b

220

R1 = CONH2; R2 = COOMe

O

N

1. Br(CH2)4Cl; 2. N-Ar-piperazine; 3. LAH

Ar

N

N N

HN

N 4

O 221

222

Scheme 46

ester 219b (R1 ¼ CONH2, R2 ¼ COOMe) can is cyclized into the corresponding benzodiazepine dione 221 (Scheme 46 (1993MI249)). Intramolecular cyclization is the final step in the preparation of the scaffold for a 66-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine library (2007JCC437).

36

D.O. Tymoshenko

Solid-phase synthesis of a 210 member library of pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones has been reported (2007JCC29).

3.1.1.3 6 + 1 cyclizations. A number of pyrrolo-benzodiazepines with the spiro piperidine moiety have been reported (Scheme 47 (1992JHC241)). Their synthesis included direct reaction of (2-(1H-pyrrol-1-yl)phenyl)methanamine with 4-piperidone or its N-substituted derivatives to afford spiro[piperidine-4,11u-pyrrolo[2,1-c][1,4]benzodiazepines 223 in 55–79% yields. Alternatively, ortho-aminomethyl derivatives 224 under the same reaction conditions give 5u,6u-dihydrospiro[piperidine-4, 4u-pyrrolo[1,2-a][1,4]benzodiazepines 225 (1990SC3537). H2N NH2

X N

O

N

X N

224

N

NH

HN N R

maleic acid, EtOH N R 223

reflux

maleic acid, EtOH N R

reflux

225

Scheme 47 O O Me N HN EtOCO

COOEt

EtOCO

O

COOEt

N NH

213

+

OEt

+

H , EtOH

H , EtOH

Me COOEt

226

229 1. Boc2O; 2. NaOH; 3. BnNH2; CDI

1. PhNCO; 2. H2, Pd/C

PhNCO

N N O Ph

Boc

N N

O

N

O

N Bn

O 227

N

N

228

Scheme 48

O

Me

N O 230

Ph


N

37

1. LAH; 2. RCHO NH

N

N

R 231

232 MnO2

N

N

R 233

Scheme 49

Similarly, amine 213 affords carboxy substituted diazepine derivatives 226 and 229 from ethyl 3-oxo-4-(propionyloxy)butanoate and ethyl acetoacetate, respectively (Scheme 48 (1993JHC897)). Tetrahydro pyrrolo-benzodiazepine 232 is a product of a two-step sequence starting from nitrile 231 (Scheme 49 (2005BMCL3453)). A multicomponent reaction of aldehyde acid 234 with isonitriles and amines in methanol at 40 1C leads to novel pyrrolo[1,2-a][1,4]diazepines 235 in 75–85% yields (Equation (28), 2005JOC1478). Cl

Cl COOH N O

O

R1NH2; R2NC

N R1

N O

234

(28)

NH R2

235

A Bischler–Napieralski intramolecular cyclization involving aryl acetyl chlorides in phosphoryl chloride affords 4-arylmethyl-4H-pyrrolo[l,2-a][1,4]benzodiazepines 236 (Scheme 50 (1995EJM593)). Direct acylation of imines 238 produces stable hydroxyl substituted pyrrolobenzodiazepines 239 (Equation (29) (1993TL1929)).

38

D.O. Tymoshenko

Ar

Ar N

1. ArCH2COCl

N

N

1. NaBH4

N

N Me

NH2 2. CH2O, H2, Pd/C

2. POCl3 236

237

Scheme 50

N

N

Ac2O (R = Me) NH

R N OH

or RCOCl

Ar

(29)

Ar

238

239

NH2 O

O

Ar

NH2 OH

HN

X

NH

ArCHO

NH2

O

AcOH, MeOH 240

H N

X

NH 241

Scheme 51

N-Alkyl isoindolo[2,1-b][2,4]benzodiazepines 190 (R ¼ alkyl, Scheme 38, Section 3.1.1.2) are synthesized by an intramolecular N-acyliminium ion–amide reaction (1997TL2985, 1998T1497). Isothiocyanates 23 undergo under basic conditions in DMF ring closure by an intramolecular substitution between N1 of the pyrrole ring and isothiocyanate group to afford benzo[f ]pyrrolo[1,2-c] [1,3]diazepine-5-thiones 25 (Scheme 2, Section 2.1.1.1 (2005BMCL3220)). A two-step route to tetrahydrobenzo[b]pyrrolo[3,4-e][1,4]diazepinone 241 (X ¼ NH) starting from 4-hydroxy pyrrolone 240 has been reported (Scheme 51 (1991KFZ16)).

3.1.1.4 4 + 3 cyclizations. Isoindolo[2,1-b][2,4]benzodiazepin-6-ones 242 are easily accessible from isoindolin-1-imine and phthalic dichloride or o-chloromethyl benzoyl chloride (Equation (30) (1993PHA812)). The structural assignment of 242b (X ¼ CH2) was based on NMR data and comparisons with those of known benzodiazepinones. COCl NH NH

X Cl

O N N X

(30) 242a X = CO, 70% 242b X = CH2; 51%

39


O

NH2

O

NH2 Cy

O

N

AcOH, reflux, 91%

O

Cy

Cy

N

N

O

O 245

244

243

1. POCl3 2. NHR2

RCOCl, TEA

O

NaH, DMF, 25%

H N

N N

N

NEt2 HBr

Br

O

R R N

Cy

MeI, NaH, DMF 72%

N

N

Me

Me N

O

H N

OEt

Cy

O O

O 246

Cy

N

N

H N N

N O

NEt2

R 248

247a R = Ph, 79%; 247b R = ClCH2, 69%

Scheme 52

Pyrrolo-benzodiazepine dione 244 can be obtained from the ketoester 243 in refluxing AcOH in high yield (Scheme 52 (1991ZOR1951, 1992CE649, 1996PHA548, 2005H2451)). The diazepine with fused pyrrole ring 250c is the product of the condensation of ortho-phenylenediamine with pyrrole carbaldehyde 249 in 36% yield (Equation (31) (2006T6018)). X

O COOCH3

NH2 Cl

N Bn

Ph

piperidine, EtOH

249

COOCH3

N X

N Bn

Ph

(31)

250a X = O, 38%; 250b X = S, 45%; 250c X = NH, 36%

3.1.2 Benzodiazepines with fused furan ring Reaction of 4-benzoyl-3-hydroxy-2(5H)-furanone with 1,2-phenylenediamine results in a low yield of diazepine 251 (Figure 3 (1991JHC1501)).

3.1.3 Benzodiazepines with fused thiophene ring Thieno benzodiazepine 253 is available in two steps starting from o-nitro halobenzenes and a thieno amino nitrile through intermediate 252 (Scheme 53 (1997BMCL25)).

40

D.O. Tymoshenko

Ph

N N H

O O

251

Figure 3 NC R1

NO2

H2N

S

R2

R1

NO2 SnCl2, HCl, EtOH NH

X

LiOH, DMSO

NC

S 252

R2 Me N

R1

N N H

NH2 N -Me-piperazine S

R2

toluene, DMSO

253

R1

N N H

N

S

R2

254

Scheme 53

As for benzo[b]pyrrolo[3,4-e][1,4]diazepin-3(4H)-ones 241, a fused thiophene (X ¼ S) can be synthesized using a two-step reaction sequence (Scheme 51, Section 3.1.1.3 (1991CE495)).

3.2 Benzoxazepines 3.2.1 Benzoxazepines with fused pyrrole ring 3.2.1.1 Pyrrolo[1,2]oxazepines. Piperidine derivatives of pyrrolo-benzoxazepine 257 have been reported starting with Vilsmeier formylation of pyrrole 255, followed by a reaction with Grignard reagents derived from N-substituted 4-chloropiperidine (R ¼ Me, Bn). Resulting alcohol 256 undergoes cyclizations in the presence of sodium hydride (Scheme 54 (1993JHC177)). The corresponding dimethylamino derivative 258 can be constructed in the similar manner. Benzopyrrolo[1,2]oxazepines 68 (X ¼ O) can be obtained from the corresponding acids 67 by an intramolecular Friedel–Crafts acylation (Scheme 14, Section 2.1.1.5 (1996JMC3435, 2002JMC4276)). Similarly, pyrrolo-benzoxazepines 261 are accessible by intramolecular Friedel–Crafts cyclization of acids 260

41


F

Ph 1. DMF/POCl3

N

N R

HO Ph

F

O NaH

N

2. Grignard

255

N R Ph

N

256

257

1. ClCH2CN, ZnCl2; 2. NHMe2 Me F

N Me O

Ph

Me

1. NaBH4 2. NaH

O Ph

N

N Me 1. EtOCOCl 2. NaOH

O Ph

N

HN Me

N

259

258

Scheme 54

Et O N

Ar

O

COOH O

PCl5 N

Et Ar

1. NBS, AIBN 2. Wittig

N

Et

O

Ar = p -MeC6H4

O 260

262

261

Ph

Scheme 55

(Scheme 55 (2005JMC7153, 1999JMC4462, 1996JMC2672)). This methodology was further extended to the derivatives of 261 substituted on the benzo ring (2005JMC4367). One-step reduction of aldehyde and ester functions in intermediate 263a (R1 ¼ Me, R2 ¼ H) results in a di-alcohol, which, when treated with P2O5, undergoes cyclization into oxazepine 264 (Scheme 56 (2005BMCL2515)). Similarly, this reaction sequence can start from monoester 263b (R1 ¼ H, R2 ¼ OH (2001JCS(P1)1039)). N-(2-Hydroxymethylphenyl)pyrrole is prone to selective a-metalation with n-BuLi-potassium tert-butoxide. Trapping the formed anion with a variety of electrophiles and treatment of the crude products with silica gel in toluene results in pyrrolo-benzoxazepines 266 and pyrrolo-benzoxazepinone 267 (Scheme 57 (1994T2071)). N-Phenylpyrrole generates a di-lithio derivative which after trapping with acetone and treatment with silica gel produces tetramethyl pyrrolo-benzoxazepine

42

D.O. Tymoshenko

OH R

O

R COOR1

N

1. LAH; 2. P2O5, toluene

steps N

N

R2

O

R = NO2

N O

O 264

263a R1 = Me, R2 = H; 263b R1 = Me, R2 = OH

265

Scheme 56

N O R1

1. n-BuLi, t-BuOK

O

2. R1R2CO R2

N

1. n-BuLi, t-BuOK

N

2. CO2 3. TSA/Py

OH

O

266

267

Scheme 57

268 (Equation (32) (1993T10271)). Me N

1. n-BuLi, TMEDA 2. acetone 3. silica gel

N

Me O Me

(32) Me 268

3.2.1.2 Pyrrolo-benzoxazepines with other fusion modes. As with diazepine, benzoxazepine with the fused pyrrole ring 250a can be prepared by condensing ortho-amino phenol (X ¼ O) with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4 (2006T6018)). 1-[2-Aryloxyethyl]-5-benzotriazolyl-2-pyrrolidinones 269 (X ¼ O) and the corresponding isoindolinones (not depicted) undergo Lewis acid mediated cyclizations to 1,4-benzoxazepines 270 (X ¼ O) (Equation (33) (2001JOC5590)). X O X

N

Bt TiCl4

N O

269

270

(33)

43


OH O

O

N

1. EtOH 2. DMF

Cl

H2, Pd/C; AcOH, Ac2O

O

NH2 CHO

NH

O

OAc 271

272

273

Scheme 58

COOCH3

COOCH3

COOCH3

S H3COOC

Lawesson s reagent

S

Fe, AcOH

O

O

O NH

R

S

O

NO2 R

274

S

N H R

275

276

N -Me-piperazine R = COOMe

R1 O

1. NaNO2 N H

H2N

S

S

O

O

2. HPF6 83%

278

NH F

O 2. N -Me-piperazine R=F

279

S

O

1. POCl3, P2O5

N R

N N

Me

277

Scheme 59

3.2.2 Benzoxazepines with fused furan ring Benzo[b]benzofuro[2,3-f ][1,4]oxazepine 272 is the sole product obtained from chloro aldehyde 271 and o-aminophenol (Scheme 58 (2001JHC383)).

3.2.3 Benzoxazepines with fused thiophene ring Nitro ester 274 undergoes reduction with iron in acetic acid to afford thieno benzoxazepine 275 (Scheme 59 (1994JHC1053)). An alternative route to 275 by the intramolecular formation of a Cthiene–O bond has been reported (2002JHC163).

3.3 Benzothiazepines 3.3.1 Benzothiazepines with fused pyrrole ring 3.3.1.1 Pyrrolo[1,2]thiazepines. Hydroxy lactam 280a (n ¼ m ¼ 1), upon treatment with neat TFA at room temperature gives a 20:1 mixture of benzothiazepines 283 and 284 in overall 94% yield. In contrast, 280b (n ¼ 2, m ¼ 0) produces

44

D.O. Tymoshenko

O OH

N

TFA N

n

O

S

S

m

n = 2; m = 0

N m

280

S

n

O 281

282

n=m=1

O

O

N

N

S

S 284

283

Scheme 60

N

S O

X

X = Se, (CuOTf)2C6H6; 12% X = O, no reaction

O

O

1. NaIO4, MeOH; 2. TFAA; 40%

N

N S

285

S

286

Scheme 61

benzo[1,4]thiazepine 282 in an excellent yield of 95% (Scheme 60 (2005EJO2758)). The regioselectivity of the process can be explained by the formation of the bicyclic onium intermediate 281. Intramolecular electrophilic cyclization of methyl selenoate gives only a 12% yield of benzo[f ]pyrrolo[2,1-b][1,3]thiazepin-9(10H)-one 285, while cyclization of an acetate derivative under a variety of the conditions failed (Scheme 61 (1998JMC3763)). An alternate route from pyrrole ketones 286 by oxidation and TFAA induced cyclization proved to be advantageous providing a 40% yield of 285. Treatment of cycloadduct 287, obtained from a dibenzo thiazinylium intermediate and a diene, with base affords dibenzo[d,f ]pyrrolo[2,1-b][1,3]thiazepine 290 in 58% yield. The proposed mechanism involves formation of ylide intermediate 288 which undergoes intramolecular rearrangement into dihydro derivative 289 and spontaneous oxidative aromatization (Scheme 62 (1999TL95)). A new method for the preparation of pyrrolo[2,1-c][1,4]benzothiazepine 292 starting from aldehyde 291 with an intramolecular Mitsunobu cyclization in the last step has been reported (Scheme 63 (1999T1479)). A disadvantage of this procedure is the redox nature of the Mitsunobu reaction, which is responsible for a side oxidation of the thiol group and poor isolated yields of the product.

45


Me Me TFAA, LiBF4 S

N H

O

N

S BF4−

MeONa or LDA

N

S

BF4-

N

S Me

Me 287

Me

288

Me

[O]

S

S N

N

Me

Me 289

Me

Me

290

Scheme 62

N O

1. NaBH4 ; 2. Na, DMAA 3. DIAD, PPh3 30%

SMe

N S

291

1. Cl3CCOCl; 2. ADDP, TBP 3. MeONa/MeOH

N

4. LiOH 5. Ph2O, 250 °C

SCH2OAc 293

292

Scheme 63

The alternate route starting from 293 provides the target compound in improved 58% yield. Preliminary acetylation of thiol 294 followed by a displacement step, using 2 equiv. of MeONa or NaH in DMF/benzene, gives tricycle 295 in 25% yield (Equation (34) (1996T7745)). F

S

1. Ac2O N

Ph 294

N

2. NaOMe or NaH SH

Ph 295

(34)

46

D.O. Tymoshenko

F MeONa N

SAc

70%

S

1. m -CPBA; 2. Ac2O S

N

40−70%

R

N

R

Ph 296

298

297

Scheme 64

Pyrrolo[2,1-c][1,4]benzothiazepine 297 (R ¼ Ph) has been prepared by an intramolecular nucleophilic displacement of acetyl derivative 296 (Scheme 64 (1992H51)). The same compound and its aryl (R ¼ Ar (1992H51)) and carboethoxy or cyano (R ¼ COOEt or CN (1990H1291)) analogs can also be obtained by a Pummerer rearrangement-cyclization of sulfinyl precursor 298. Pyrrolo[1,2]thiazepine 68 (R ¼ Ph; X ¼ S) can be obtained from the corresponding acid 67 via an intramolecular Friedel–Crafts acylation (Scheme 14, Section 2.1.1.5 (1997EJM241, 1996JMC2672, 1994JMC4100, 1994JMC1427)).

3.3.1.2 Pyrrolo-benzothiazepines with other fusion modes. Thiazepine with fused pyrrole ring 250b can be prepared by condensing ortho-amino thiophenol with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4 (2006T6018)). Pyrrolo[3,4-c][1,5]-benzothiazepin-3-ones 300 are available from ketoester 299 by a three-step sequence which includes hydrolysis and decarboxylation, aldol condensation and cyclization with o-aminothiophenol (Equation (35) (1993CE773)). O

O

O Cy

COOCH3

N

1. HCl Cy N 2. ArCHO 3. o -HSC6H4NH2

299

H N S Ar

(35)

300

Two types of benzothiazepines with fused indole rings 301 and 302 (Figure 4) have been reported as products of a Fischer indole type synthesis (1993EJM659). 3-Arylthioindole-2-carboxylic acids 303, obtained from aryl disulfides and indole-2-carboxylic acids, afford tetracyclic 5H-indolo-[3,2-b][1,5]benzothiazepin6(7H)-ones 304 on treatment with EDC–DMAP (Scheme 65 (1998MI139)). 2H-Pyrrolo[3,4-b][1,5]benzothiazepine 307 can be obtained by thermal cyclization of pyrrole aminoester 308 (R ¼ Et) in the presence of 2-hydroxypyridine (Scheme 66 (1998SC2517, 2005FES385)). An analogous transformation has been reported for the corresponding pyrrole amino acid 308 (R ¼ H) (1990BCJ1617). Alternatively, dihydro analog 309 can be obtained starting from nitro ketone 306 by reductive cyclization (1998SC2517).

47


R3 N

S R1

S R2

N H

R3 N

R1

O

R2

N

301

Me

302

Figure 4

R2 H2N

S S

HOOC

NH2

COOH

H2N

N H

S

NH

EDC, DMAP

NaH

R1 R1

R1

R2

303 O O

H N

HN

HN H2O2 S O O

S R1

H N

R1

R2 304

R2

305

Scheme 65

H N

NO2 O S O

Cl

Cl

O

O

HN Me

306

NH

S

O S

Cl

O

O

NH

ROOC

308

R1X, K2CO3

H N

O

2-HOPy

307

H2, Pd/C; R = Me

Cl

H2N

O

LAH N

S O

309

H N

R

R1

R=H

Cl

O

O 2

1. R X, t-BuOK N

S O

310

Scheme 66

R1

2. Lewasson s Cl reagent

R2 N

O

311

S

N

S O

R1

48

D.O. Tymoshenko

OH

O Me

N

O S

S

NaBH4

PPA

O Me

COOH

S N S O O

Me

313

312

XCH2CH2NR2; NaOH, TEBA Br or 1. BrCH2CH2OH, PTSA; 2. R2NH

1. NH2OH.HCl; 2. XCH2CH2NR2; NaOH, TEBA Br R

S N S O O 314

R N R

N R O

N O

Me

N S O O

Me

S 315

S N S O O 316

Scheme 67

Benzo[c]thieno[3,2-f ][1,2]thiazepin-4(9H)-one 313 is the product obtained from acid 312 on dehydration (Scheme 67 (1997JHC1191, 1998PHA130, 1993JHC1509)). A similar transformation has been reported for the preparation of an isomeric to 313 benzo[c]thieno[3,4-f ][1,2]thiazepin-10(5H)-one (not depicted in the Scheme). 1-[2-Arylthioethyl]-5-benzotriazolyl-2-pyrrolidinones 269 (X ¼ S, Equation (33), Section 3.2.1.2) and the corresponding isoindolinones (not depicted) undergo Lewis acid mediated cyclizations to 1,4-benzothiazepines 270 (X ¼ S) (2001JOC5590).

3.3.2 Benzothiazepines with fused furan ring A convenient preparation has been reported for benzofuran annulated 2-phenyl-1,5-benzothiazepine derivatives 318 by oxidative cyclocondensation of phenolic diketones 317 with o-aminothiophenol in DMSO (Equation (36) (2000M393)). SH OH O

O Ar

NH2

S

O N

DMSO, reflux 317

Ar

318

(36)

49


Furobenzothiazepines 320 can be prepared by a Bischler–Napieralski method from ester ureas 319 (Equation (37) (1999JHC819)). R R N NH

N

S O

O

R N R

POCl3, P2O5

COOCH3

(37)

reflux

S

O

COOCH3

320

319

3.3.3 Benzothiazepines with fused thiophene ring 2-(2-Nitrophenyl)-thiochroman-4-one 321 upon treatment with SnCl2 in ethanol does not give the expected aniline derivative. Instead, ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate 322 is produced in high yield. The presumed mechanism involves addition of an hydroxylamine intermediate to the ketone carbonyl, followed by a tin-mediated pinacol-type rearrangement with preferred migration of the phenyl substituent and ethanolysis of the intermediate amide (Scheme 68 (2002JOC8662)). Syntheses of benzo[f ]thieno[3,2-b][1,4]thiazepin-9(10H)-one 323 (2001BMC1123) and thieno[3,4-b]-[1,4]benzothiazepine 324 (Figure 5 (1999JHC659)) start from the corresponding open chain amino acids.

4. SYSTEMS WITH MORE THAN TWO ATOMS ON THE HETEROPINE RING AND MISCELLANEOUS RING SYSTEMS 4.1 Benzotriazepines Phthalimide 325 when refluxed with triethylphosphite yields iminophosphorane that further transforms into 5H-isoindolo[1,2-b][1,3,4]benzotriazepin-5-one 326 O O

HO S

COOEt

O

O– N+ SnCl2

S

EtOH

NH

S S

S

S N H

321

322

Scheme 68 O

O

NH

NH

O

S O

O

S

S

S O 324

323

Figure 5

COOCH3

50

D.O. Tymoshenko

in 57% yield (Equation (38) (1990TL6561)). O

O N N3

Et3PO, toluene reflux, 57%

N

N

N

(38)

N

O

326

325

Pyrrolo[1,2-b][1,2,5]benzotriazepin-11-one 329 is the product of a sequence starting from N-(2-nitrophenyl)-1H-pyrrol-1-amine 327. The pathway included alkylation, reduction of the nitro group, formation of the isocyanate from intermediate 328 and intramolecular thermal cyclization (Scheme 69 (2000JHC1539)). Similar to pyrrolo-benzodiazepines, pyrrolo-benzotriazepines 225 (X ¼ NMe) with a spiro piperidine moiety have been reported (Scheme 47, Section 3.1.1.3 (1992JHC241)). Their synthesis included direct reaction of hydrazine 224 (X ¼ NMe) with N-substituted 4-piperidones to afford 225 in 42–63% yields. Reductive cyclization of nitro amine 330 with zinc in boiling aqueous sodium hydroxide afforded pyrrolo[2,l-d][1,2,5]benzotriazepine 332 in 30% yield. The proposed mechanism (Scheme 70) involves an intramolecular coupling between amino and in situ generated nitroso groups to give intermediate 331. The latter loses water under the strongly basic conditions and azo intermediate (not shown on the scheme) further undergoes prototropic interconversion to cyclic hydrazone 332 (1996T10751).

O N+

O–

NH N

1. EtBr, TBAHS CH2Cl2, aq. NaOH

NH2

2. FeSO4, NH3

N N

327

1. triphosgene

H N

2. AcOH, Δ

N N

O

329

328

Scheme 69

NH2 N

Zn, NaOH

N

O2N

330

NH N OH

331

Scheme 70

N

332

N NH


51

(i) (ii) H N X (iii) S N O O 333

Figure 6

4.2 Pyrrolo-benzothiadiazepines Syntheses of this class of compounds usually involve 1,2,5-thiadiazepine ring 333 (Figure 6) which is stable in the S-oxidized form and structurally represents cyclic pyrrole N-sulfonyl derivatives. Most of the synthetic strategies include formation of an S–Npyrrole bond in the early stages. A final cyclization step typically includes (i) intramolecular cyclization by creation of an N–X bond from a suitable pyrrole precursor or (ii) a 6 + 1 type cyclization that involves dielectrophilic species to form linker X and utilizes the nucleophilicity of the phenyl amino group and of the pyrrole ring at C2. Intramolecular processes with the formation of the X–C2pyrrole bond (iii) are rarer. Reduction of nitro glyoxylic ester 334 with iron powder in acetic acid into pyrrolo-benzothiadiazepine 335 represents a type (i) intramolecular cyclization (Equation (39) (1996JHC2019)). O NO2 O O O S N

334

OEt O

Fe, AcOH

N S N O O

OEt

(39)

335

Formation of the similar pyrrolo-benzothiadiazepinone dioxide 337 from amino hydrazide 336 occurs with a loss of hydrazine when reacted with 2-hydroxypyridine or glacial acetic acid (Scheme 71 (2000H2163)). Similar rings can be synthesized starting from the corresponding esters 338 (1996BMC837, 1997FES323). Fused cyclic system 340 can be obtained by type (i) reaction through the reduction of the nitro aldehyde intermediate 339 and its sequential cyclization in acetic acid. Alternate type (iii) process starts from the corresponding formamide 341 that can be cyclized with phosphorus oxychloride by a Bischler–Napieralski reaction (Scheme 72 (1994JHC1033)). Another example of type (iii) intramolecular cyclization is the final step of a multistep synthesis of a series of substituted pyrrolo-benzothiadiazepines 344

52

H2NHNOC

D.O. Tymoshenko

O

NH2

O S

H N

2-HOPy or

N AcOH

Cl

O

Cl

336

NH2 O O S N

O 2-HOPy

S N O

COOEt

Cl

338

337

Scheme 71

NO2

N

O S O

N

Fe, AcOH

NHCHO

POCl3

S N O O

O

S N O O 341

340

339

TosMIC n-BuLi

1. MeNO2; 2. H2, Ni-Raney

H2N H N

N 1. TEOF 2. MnO2

N S N O O

S N O O

343

342

Scheme 72

(Equation (40) (2004TL7553)). O O S N NH

R R

POCl3

O O S N

R N

R R

(40) R

O 344

Type (ii) cyclizations are more common. Thus, acid derivatives of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide 346 and 347 have been prepared from amino sulfonyl pyrrole 345 with acetal (2006JMC5840) or the semiacetal (1994JHC867) of ethyl glyoxalate or ethyl 2,2-diethoxy propionate (1996FES425) in the presence of PTSA catalyst in boiling absolute ethanol by a Pictet–Spengler type of reaction (Scheme 73). Reduction of nitro derivative 351 followed by reaction with diethyl 2-oxosuccinate affords diester 352 (Scheme 74 (1994SC2685)).

53


Bn

O

NH2

H N

(MeO)2CHCOOEt S N O O

EtOH, PTSA, reflux

S N O O

346 1. (MeO)2CHCH2COOEt EtOH, PTSA, 1. LiOH reflux 2. LiOH 2. LAH, AlCl3

1. LAH 2. H2, Pd/C

O H N

OH

S N O O

NH

OH N

S N O O

347

O

N S N O O 349

345

H N

N

O

OEt 1. BrCH COBr 2 2. BnNH2

S N O O 350

348

Scheme 73

O O N+

O–

S N 351

COOEt

1. m -CPBA 2. Hydrolysis 3. EDC, DMAP

1. Fe, AcOH

H N

2.

S N

O

352

353

EtOOC

O COOEt

COOEt

N

COOEt

S N O

Scheme 74

As with pyrrolo-benzodiazepine (1992JHC1005), oxo derivative of pyrrolobenzothiadiazepine 203 (X ¼ SO2) can be synthesized by the thermal cyclization of intermediate 205 (Scheme 42, Section 3.1.1.2 (1992SC1433)).

4.3 Miscellaneous ring systems Several other types of rings related to the reviewed cyclic systems have been reported (Figure 7). Structurally similar, most are out of the scope of the current review although they give insight into the possible diversity. Most of the systems described in this section have been synthesized using the methods mentioned above and the reader is referred to the individual references for this information. Syntheses of furano thiazepinones 354 by intramolecular Friedel–Crafts cyclizations have been reported (1995CPB2064). Examples of other benzoheteropines with fused five-membered rings include annulated oxazoles 355 (1993JOC4885), and pyrazoles 356 (1996AP352, 1997JHC1191, 1998PHA130, 2003FES1), as well as pyridines 357 (1995CPB2064) and 358 (1994JCS(P1)1193),

54

D.O. Tymoshenko

R H N

O

O

O Me O S N

N

R O

S

COOCH3

O

O

354

Me

N

O

Me 356

355 O

R

SR N

H N

N

O

H N

O

N

R Me

CN

R

N

R

N

N

Ph 357

N

Cl

Ph

Ar

360

359

358 O

O

O

HN

HN

R

R

N

S N H

N H

N

S 363

362

361 O R

HN

N

S

H N

R

COOCH3

R N H

S 364

N H

S 365

366

Figure 7

and pyrones 359 (1989JHC1299) and 360 (1999SC3561). Five-membered rings fused to cores other than benzoheteropines are represented by pyrido azepines 361 and 362 (2004BMCL413), and benzothiophene derivative 363 (1994JCR(S)295). Thieno[3u,2u:2,3]azepino[4,5-b]indol-5(4H)-one 364 (1992AP297, 2004BMCL413) as well as peri fused 365 (2002H1831) and 366 (2003H73) have been reported.

5. REACTIVITY OF BENZOHETEROPINES WITH FUSED FIVE-MEMBERED RINGS 5.1 Reactivity of the rings 5.1.1 Electrophilic attack on ring carbons Electrophilic substitution on position 2 of pyrrolo[1,2]benzoheteropines is the most common example of this type of transformation. Thus,

55


N N

TEA, CH2Cl2

N

CH2O, NHMe2

N

N

N H

N O

R

201

O 368

367 R

S SnBu3 Pd(PPh3)4

(SnBu3)2; Pd(PPh3)4 N N

N

ArBr N

N S

O

O

Ar

O

Bu3Sn

369

N

Pd(PPh3)4

371

370

Scheme 75

10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine 367 undergoes reaction with formaline and dimethylamine in acetic acid (2005BMCL5003) or tetramethyl diaminomethane (2000BMCL783) to form dimethylaminomethyl derivatives 368 (Scheme 75). Similar reactions were performed using the corresponding secondary amines and paraformaldehyde to afford Mannich products in 60–80% yields (2000BMCL783). Reaction of phenyl-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine 297 (R ¼ Ph) with paraformaldehyde and 1-methylpiperazine dihydrochloride in methanol occurs on the 2-pyrrole position and affords Mannich product 372 (Equation (41) (1999JMC3334)). Me

N N

N

R

CH2O, N-Me-piperazine

(41) N

S 297

372

R

S

Analogous dimethylamino derivatives of this ring with different substitution patterns on the thiazepine ring have been reported (1996T7745). Formylation of 5H-benzo[f ]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one 180 pyrrole ring with POCl3/DMF is known (Scheme 36, Section 3.1.1.1 (1992BMCL1639)). Formyation of pyrrolo-benzothiazepine can be accomplished using POCl3/ PhNMeCHO (Scheme 76 (2004JMC143)). The monoaldehyde 375 (R1 ¼ H) is

56

D.O. Tymoshenko

Me N

Me N

N

O N-Me-piperazine

R

N

R N

N TMSOTf

S

N

S

S 376

374

373

PhNMeCHO/POCl3; 1. NaBH4; (i) 1.3 eq., R1 = H; 2. PBr3 ; 1 3. N-Me-piperazine (ii) 2 eq., R = CHO Me N

R1 = H

1. NH2NHTs 2. NaBH4, i-PrOH

Me N

N

Me N

N

R

R1 O

R N

N

S

N

1. NH2NH2 2. t-BuOK R

N

1

R =H

S

377

O

R

Me

S 378

375

Scheme 76 Ar

1. NaBH4 2. I2 /PPh3 3. KOH

Ar EtOCOCOCl

N 379

Ar

N

N

pyridine 380

O

O EtO

O

381 HO

Scheme 77

prepared using 1.3 equiv. of the formylating agent, while exposure to 2 equiv. of the reagent provided the 1,10-diformylated derivative (R1 ¼ CHO). Syntheses of a series of pyrrolo-benzazepine acetic acids 381 have been reported (Scheme 77 (1994MI385)). They include acylation of the core heterocycle with ethoxy oxalyl chloride in the first step to afford ketoesters 380. This sequence can also be successfully applied to a pyrrolo-benzothiazepine ring system. Reaction of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepines 202 with trichloroacetylchloride results in trichloromethyl keto derivatives 382 (Scheme 78 (2000BMCL783)). An example of electrophilic substitution on position C2 of the fused furan has been reported for 8H-furo[3,4-d]dibenz[b,f ]azepine, which reacts with t-butyl hypochlorite to afford a mono chlorinated furan ring product (1995H431).

57


O N

R 202

O 1. NaOH 2. EDC, HNR2

N

Cl3CCOCl

O

R

R N

R

N

N

N O

CCl3

N 382

O

R

383

Scheme 78

5.1.2 Electrophilic attack on ring heteroatoms This kind of reactivity is usually limited to substitution on the nitrogen of benzazepine ring and the nitrogen of pyrrole (or indole) fused to the heteropine core. Electrophilic substitution of a pyrrolo-benzazepine depends on the nature of the electrophile, base and solvent and can be fine tuned. Thus, N-alkylation of indolo benzazepinones 41 (Scheme 8, Section 2.1.1.3 (1999JMC2909)) proceeds selectively on the azepinone nitrogen in THF in the presence of sodium hydride, while in acetone with potassium hydroxide it gives exclusively indolo N1 substituted products 44. Acylation of this ring system with Boc anhydride gives a product substituted on both nitrogens in methylene chloride in the presence of DMAP. Application of large excess of the Boc2O in NaH/THF leads to a tri-substituted product of N5, N12 and C7 alkylation (1999JMC2909). Similarly, methylation of pyrrolo-benzothiazepines 172 (Scheme 34, Section 2.3.1 (1994MI283)) and 307 (Scheme 66, Section 3.3.1.2 (2005FES385)) with methyl iodide in acetone in the presence of potassium carbonate proceeds regioselectively and produces N-methyl pyrrole derivatives as sole products. Methylation on the thiazepine ring nitrogen requires stronger base, i.e. potassium tert-butoxide, to give dimethyl 174 and 311, respectively. Alkylation of pyrrolo-benzodiazepine dione 244 with methyl iodide occurs on both positions N9 and C10a, while reaction with 2-bromo diethylaminoethane leads to the low yield of the 4-substituted 248. Acylations with benzoyl and 2-chloroacetyl chlorides are directed exclusively to position 4 to afford 247 (Scheme 52, Section 3.1.1.4 (1992CE649, 2005H2451)). Alkylation of 5H-benzo[f ]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one with a substituted phenethyl bromide has been reported (Scheme 36, Section 3.1.1.1 (1992BMCL1639)). Electrophilic substitutions of rings with a single N-nucleophilic site proceed smoothly. Thus, indolo benzazepine 36a, protected on the indole ring, and benzoxepine 36c are easily methylated on the benzazepine nitrogen (Scheme 79 (1991JHC379)). Other examples of mono-alkylation include thieno azepinone 118 (Scheme 23, Section 2.1.3.3 (1999PHA645)), benzodiazepine dione 221 (Scheme 46, Section 3.1.1.2 (1993MI249)) and 7,12-dihydro-6H-[1]benzothiepino[5,4-b]indole (2006BMCL3233).

58

D.O. Tymoshenko

O

O MeI, NaH, DMF

HN

X

N

X

O

36a, c

X = o-NO2C6H4CONH, Et2NCH2CH2NH2, DMF, rt, 2 h, 96%;

Me

O

384a X = o -NO2C6H4CONH,

O Me N

N H

O

385

73%; 384b X = O, 73%

Scheme 79

The reactivity of N-nucleophilic sites of other fused heteropines towards acylating agents is similar to pyrrolo-benzazepines described at the beginning of this chapter. Pyrrolo[2,1-c][1,4]benzodiazepine 201 with acid chlorides (CH2Cl2/TEA, at room temperature) gives amide 202 (Schemes 42 and 43, Section 3.1.1.2 (1999BMCL1737) and (2003BMCL2195), correspondingly). Compounds 111 and 113 undergo smooth acylation on the azepine nitrogen with 4-(2-methylbenzoylamino)benzoic acid chloride to give amides (Scheme 22, Section 2.1.3.2 (1999BMCL1733)). 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine 201 gives amides 367 by reacting with acid chlorides in the presence of triethylamine in methylene chloride (Scheme 75, Section 5.1.1 (2005BMCL5003, 1998JMC2442, 2000BMCL783)). Reductive formylation of dihydro compounds derived from 4-arylmethyl pyrrolo-benzodiazepines 236 with formaldehyde in a Parr apparatus yields N-methyl 237 (Scheme 50, Section 3.1.1.3 (1995EJM593)). Carboxy substituted diazepines 226 and 229 react with phenyl isocyanate to afford pyrimido diones 227 and 230, correspondingly (Scheme 48, Section 3.1.1.3 (1993JHC897)). N-Hydroxymethylation on an indole ring annulated to benzazepinone, as well as formation of the corresponding carbamate and urea, has been described (2004MI1076).

5.1.3 Reactions with nucleophiles Fusion of the imidazole ring to pyrrolo-benzothiadiazepine 340 can be achieved by straightforward TosMIC cycloaddition approach (Scheme 72, Section 4.2 (1994JHC1033)). An alternative sequence starts with the addition of nitromethane to the C–N double bond on the thiadiazepine ring, nitro group reduction and manganese oxide oxidation of the intermediate dihydroimidazole derived from amine 342 and triethyl ortho formate.

5.1.4 Reduction The most general of this type of transformation is the reduction of lactam carbonyls on five- or seven-membered rings. Examples also include the reduction of C–C or C–N double bonds on the azepine ring. Therefore, reaction of a pyrrolidone carbonyl with BF3 O(C2H5)2/BH3 S(CH3)2 provides tetracyclic benzo[f ]pyrrolo[1,2-a]thieno[3,2-c]azepine 104a in good yield (Scheme 20, Section 2.1.3.1 (2001H1519)). Lithium aluminum hydride is the usual reactant of choice for the reduction of a lactam carbonyl on an azepinone ring


59

(see Scheme 66, Section 3.3.1.2 and Scheme 46, Section 3.1.1.2 for examples (1998SC2517) and (1993MI249), correspondingly). Reduction of the azepinone ring in 63 can be accomplished selectively. Thus, hydrogenation results in selective 1,4-reduction of the enone moiety and furnishes the corresponding saturated ketone 65. Selective enone 1,2-reduction can be performed with n-BuLi–BH3 to produce allylic alcohol 64. Reduction with borohydride is non-selective and gives saturated hydroxyl compound 66 (Scheme 13, Section 2.1.1.5 (2000T9351)). 4-Arylmethyl-4H-pyrrolo[l,2-a][1,4]benzodiazepines 236 can be transformed with sodium borohydride to corresponding derivatives reduced at the imine double bond (Scheme 50, Section 3.1.1.3 (1995EJM593)). Contrary to the stable azepines and diazepines, benzo[b]benzofuro[2,3-f ][1,4]oxazepine 272 undergoes ring cleavage under reductive conditions in the acetic acid/acetic anhydride to afford open chain acetoxy amine 273 (Scheme 58, Section 3.2.2 (2001JHC383)).

5.1.5 Oxidation Oxidation on the sulfur atom of pyrrolo-benzothiazepine 175 (Scheme 34, Section 2.3.1 (1994MI283)), indolo benzothiazepine (Scheme 65, Section 3.3.1.2 (1998MI139)) and pyrrolo-benzothiadiazepine (Scheme 74, Section 4.2 (1994SC2685)) proceeds smoothly with hydrogen peroxide in acetic acid or with MCPBA to afford cyclic sulfones in good yields. Treatment of the keto isomer of cryptoheptine with sodium ethoxide in ethanol leads to fast enolization followed by formation of 5-methylindolo[3,2-b][1]benzazepin-7(5H)-one 39 as an oxidation product (Scheme 7, Section 2.1.1.2 (2000JNP643)). Tetrahydro pyrrolo-benzodiazepine 232 can be oxidized with manganese (IV) oxide to imino analog 233 (Scheme 49, Section 3.1.1.3 (2005BMCL3453)).

5.1.6 Intramolecular ring transformation reactions This type of transformation usually involves contraction of a seven-membered ring into a thermodynamically more stable five- or six-membered ring. Bromination of lactone 386 followed by oxidation with trimethylamine oxide in DMSO resulted in rearranged 387 in poor, 7% yield (Equation (42) (2001H91)). O MeO MeO

O O 386

O

1. NBS 2. Me3NO, DMSO

MeO

O

MeO

O

(42)

O

387

Benzo[e]thieno[3,2-b]thiepin-10(5H)-one 388 under Schmidt conditions undergoes a ring contraction into 2-benzylthieno[3,2-d]isothiazol-3(2H)-one 390 through initial intermediate 389 by nitrogen loss and intramolecular nucleophilic

60

D.O. Tymoshenko

attack of the sulfur on the imminium nitrogen. Interestingly, a similar transformation for isomeric thieno thiepinones 391 and 392 is accompanied with the loss of the methylene thiophene moiety to produce benzo[d]isothiazol-3(2H)-one 393 (Scheme 80 (1991JHC1881)). Hexahydro pyrrolo-benzdiazepinetrione 394 in boiling phosphorous oxychloride produces 3,5-dichlorobenzo[h][1,6]naphthyridine 396 as rearrangement product of trichloride 395 (Scheme 81 (2003JHC255)). The suggested mechanism includes thermal aromatization in the final step. A similar transformation for hydroxyl derivative 397 requires initial dehydration with mesytyl chloride/pyridine followed by rearrangement to 398 (Scheme 82 (1997TL2271)). NaN3, H2SO4

S

S

S NH

35% S

S

O 388

O

O 391

393 NaN3, H2SO4

NaN3, H2SO4

45%

S

S S

−N2 S

S

S

N Ph

N OH N+ N–

O

O

389

392

390, 47%

Scheme 80 H N

O H

POCl3, pyridine microwave, 90 min

N

N

O

O

Cl

N

Cl

Cl 394

395

Cl

N

Cl

N H

N

N

Cl

396

Scheme 81

Cl

Cl

61


H N

O H

H N

MsCl, Py N

POCl3 N

OH

O

O

O

397

H N

Cl

N N

N

Cl

Cl 398

Scheme 82

N

N H N NH2

Cl

N H2NNH2

O 401

N

MeNH2

O

N O 399

N 400

N H

Me

Scheme 83

11-Chloropyrrolo[2,1-c]-[1,4]benzodiazepines 399 are readily accessible from 2-hydroxypyrrolo[2,1-c][1,4]benzodiazepines in refluxing thionyl chloride. Further reaction with methyl amine gives imino benzoxazine 400, while quinazoline 401 is the product of hydrazinolysis (Scheme 83). In contrast, reactions with dimethyl amine and ammonia lead to open chain products of diazepine ring cleavage on CO–Npyrrole bond (2001TL5183).

5.2 Reactivity of substituents 5.2.1 Reactivity of substituents attached to ring carbon atoms 5.2.1.1 Alkyl groups and further carbon functional groups. p-Tolyl derivative of pyrrolo-benzoxazepine can be brominated with NBS and further submitted to a Wittig reaction to afford unsaturated 262 (Scheme 55, Section 3.2.1.1 (2005JMC7153)). Trichloromethyl keto derivatives 382 (Scheme 78, Section 5.1.1) undergo hydrolysis with sodium hydroxide in aqueous THF to produce acids in overall yields of 60–70%. Coupling of the acids with amines leads directly to amides 383 in 80–90% yield (2000BMCL783). Oxidation of the methyl group in position 2 of the 1,8-dioxadibenzo[e,h]azulene system proceeds smoothly resulting in aldehydes. Further LAH reduction gives alcohols 149 in 35–83% yields (Scheme 29, Section 2.2.2 (2006JHC749)).

62

D.O. Tymoshenko

1. KH, Tf2O 2. CO, Pd(PPh3)4

O N

Ph

N

Ph

MeLi

O

O Ph

N

OMe

O 402

403

Me

O

O

404

LAH

AcBr

O

O Ph

N

Ph

N

O

OH 406

405

O

Scheme 84

O H N S N O O 407

O X R

HXR, X = O, NH EDC, DMAP

H N S N O O 347

O OH

TFAA

N S N O O 408

Scheme 85

The ester derivative of pyrrolo-benzoxazepine 403 (Scheme 84) has been transformed into ketone 404 with methyl lithium, while ester 406 was synthesized by esterification with acetyl bromide of alcohol 405, prepared by LAH reduction of 403 (1996JMC3435). Di-carboxy substituted diazepine 226 results in spiro 228 after Boc-protection, hydrolysis, CDI activation and imide formation (Scheme 48, Section 3.1.1.3 (1993JHC897)). The conjugated ester group of ( + )-anthramycin derivative 197 can be constructed by cross-metathesis of pyrrolo-benzodiazepine 196 (Scheme 40, Section 3.1.1.2 (2004T9649)). Lithium hydroxide hydrolysis of the ester of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide 346 afforded the acid, subsequently reduced with lithium aluminum hydride-aluminum chloride to alcohol 348 (Scheme 73, Section 4.2 (2006JMC5840)). Pyrrolo[1,2-b][1,2,5]benzothiadiazepine acid 347 gives easy access to a variety of esters and amides 407, while treatment with TFAA produces fused lactam 408 (Scheme 85 (1996FES425)).

63


H N

H N

O H2O2 (35%), MeCN, K2CO3, EtOH, r.t.

O n

n

O

HN

HN R

R

410

411a R = CF3, n = 0, 31%; 411b R = Br, n = 0, 38%; 413c R = Br, n = 1, 26%

n = 0; tributylvinyltin, PdCl2(PPh3)2, DMF 91% H N

H N

O

O

1

R CH=CH2 Pd(AcO)2; PPh3; TEA, DMF

I

R1 HN CF3

HN R

409

R1

413

Mg, R1 = CN

CH

PdCl2(PPh3)2; CuI, TEA H N

H N

O

O

NC R1

HN

HN

CF3

CF3 414

412

Scheme 86

Diester 352 (Scheme 74, Section 4.2 (1994SC2685)) after the sulfur atom oxidation undergoes hydrolysis and intramolecular acylation to the pyrrolothiadiazepine 353 with a fused lactam ring. Examples of transformations on the side-chains attached to a benzo ring have been reported. Epoxidation of the double bond in vinyl and allyl derivatives of paullone 410 can be achieved with a hydrogen peroxide/nitrile mixture (Scheme 86 (2005EJM655)). The saturated analogue 414 has been prepared upon refluxing the acrylonitrile 413 with magnesium turnings in methanol (2000BMCL567).

5.2.1.2 Amino and imino groups. Amino thieno benzoxepine 163 (Scheme 32, Section 2.2.3) can be smoothly transformed into the corresponding amides and urea (1994JCS(P1)2191). The dimethylamino substituted pyrrolo-benzoxazepine

64

D.O. Tymoshenko

258 gives mono methyl derivative 259 with ethyl chloro formate followed by basic hydrolysis of the intermediate carbamate (Scheme 54, Section 3.2.1.1 (1993JHC177)). Amino methyl substituted pyrrolo-benzodiazepine 215 forms a cyclic aminal with aldehydes that can be further oxidized with MnO2 to fused 3-substituted imidazole 216. Alternatively, cyclic imine 217 can be submitted to TosMIC cyclization to afford unsubstituted 9H-benzo[e]imidazo[5,1-c]pyrrolo[1,2-a][1,4]diazepine 218 (Scheme 45, Section 3.1.1.2 (1993JHC749)). The amino group of 10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine 253 can be substituted with N-methyl piperazine by direct amination under thermal conditions (Scheme 53, Section 3.1.3 (1997BMCL25)). 7-Aminobenzo[b]thieno[2,3-f ][1,4]oxazepin-10(9H)-one 278 forms 7-fluoro derivative 279 by a standard diazotation/fluorination procedure (Scheme 59, Section 3.2.3 (1992AF896, 2002JHC163)). Elaboration of the nitro group in 264 (R ¼ NO2) has been reported and it leads, after multistep transformation, to alcohol 265 (Scheme 56, Section 3.2.1.1 (2005BMCL2515)). An alternate route to fuse an imidazole to a pyrrolo-benzothiadiazepine includes side-chain nitro reduction and manganese oxide oxidation of the dihydroimidazole derived from amine 342 and triethyl ortho formate (Scheme 72, Section 4.2 (1994JHC1033)).

5.2.1.3 Hydroxy and oxo groups and other O-linked groups. Treatment of the potassium enolate of the pyrrolo-benzazepine and benzoxepine ketones 68 with the N,N-diethylcarbamyl chloride gives carbamates 69 (Scheme 14, Section 2.1.1.5 (2002JMC4276)). A similar modification has been reported for a benzopyrrolo[1,2]thiazepine (1997EJM241). Reaction of indolo benzazepinone 27 with phosphorus pentasulfide yields 91% of the corresponding thione 415 (Scheme 87 (1993LA1141)). Reduction of the keto group in naphtho derivative 115 with sodium borohydride results in 69% of the alcohol 116 (Scheme 23, Section 2.1.3.3 (1999PHA645)). Further triethylsilane reduction gives 117 in 67% yield. Synthesis of a series of pyrrolobenzazepine and pyrrolo-benzothiazepine acetic acids (Scheme 77, Section 5.1.1 (1994MI385)) includes reduction of ketoesters 380 into corresponding hydroxyl esters, subsequent deoxygenation with iodine/PPh3 and hydrolysis. O H N

O P4S10

H N

S

R

R NH2 N H 416

N N

32−72%

HN

HN

27

415

Scheme 87

HN 417

N


S

S

(EtO)2POCH2COOEt, NaH, THF S

70%, ~1:1 ratio

S

65

EtOOC

O

420

391 n -BuLi, R = n -Bu, 91% RMgX, X = p -C6H4NMe2, 66%

NaBH4, TFA 89%

S

S

S

S 418

HO R 419

Scheme 88

The 1-isopropoxymethyl derivative of pyrrolo-benzothiazepine 376 can be obtained from aldehyde 375 through the tosyl hydrazone followed by reduction with sodium borohydride in 2-propanol. 1-Methyl substituted 378 is available from aldehyde 375 and hydrazine monohydrate followed by potassium tertbutoxide (Scheme 76, Section 5.1.1 (2004JMC143)). Reduction of the keto group in thieno thiepinone 391 proceeds smoothly to give thiepine 418. Reactions of the carbonyl group with strong nucleophiles give alcohols 419 in good yields. A Wittig–Horner reaction of 391 results in the substituted acrylic ester 420 as a separatable mixture of E- and Z-isomers formed in approximately a 1:1 ratio (Scheme 88 (1992JHC1789)). Benzo[e]thieno[3,2-b]thiepin-10(5H)-one 388 can be smoothly reduced with sodium borohydride to the corresponding alcohol, which forms the chloro substituted compound under standard treatment with thionyl chloride (1991CPB2564). Dihydro derivatives of pyrrolo-benzothiazepine 377 have been reported starting from ketone 373 by a carbonyl reduction, bromination and amination sequence (Scheme 76, Section 5.1.1 (1998JMC3763, 2002JMC344, 2004JMC143)). Treatment of the azepinone ring with TMS triflate followed by amination affords piperazine 83 (Scheme 16, Section 2.1.1.5 (2005JMC1705)). Likewise, benzothiazepines 374 can be prepared from ketones 373 with N-alkylpiperazines and N-methylhomopiperazine in the presence of trimethylsilyl triflate (Scheme 76, Section 5.1.1 (2002JMC344, 2004JMC143)). Fusion of a 1,2,4-triazole ring to pyrrolo-benzodiazepine (1992JHC1005) and pyrrolo-benzothiadiazepine (1992SC1433) rings has been reported starting from oxo 203 and included formation of the phosphonic imidate with formyl hydrazine (Scheme 42, Section 3.1.1.2). The lactam carbonyl of 2H-pyrrolo[3,4-b][1,5]benzothiazepinone 310 undergoes an O–S exchange with Lewasson’s reagent to afford benzothiazepine thiones 311 (Scheme 66, Section 3.3.1.2 (2005FES385)).

66

D.O. Tymoshenko

Formation of thiolactam 276 and its direct amination with N-methyl piperazine (1994JHC1053) is one of the routes to piprerazines 277 (Scheme 59, Section 3.2.3 (1992AF896, 2002JHC163)). Alternatively, 7-fluorobenzo[b]thieno[2,3-f ][1,4]oxazepin-10(9H)-one 279 undergoes chlorination and sequential amination to 277. The lactam moiety of pyrrolo-benzdiazepine dione 244 can be transformed into the corresponding cyclic imidoyl chloride and further reacted with anilines and aliphatic amines to afford amines 246 (Scheme 52, Section 3.1.1.4 (1996PHA548)). Pyrrolo-benzoxazepine 402 (Scheme 84, Section 5.2.1.1) gives ester 403 through the triflate intermediate by reaction with carbon monoxide and methanol in the presence of tetrakis(triphenylphosphine)palladium (1996JMC3435). Transformations on the keto group of benzo[c]thieno[3,2-f ][1,2]thiazepin4(9H)-one 313 and isomeric benzo[c]thieno[3,4-f ][1,2]thiazepin-10(5H)-one (not depicted in the Scheme) include reduction with sodium borohydride to afford alcohol 314 and formation of oximes (Scheme 67, Section 3.3.1.2 (1997JHC1191, 1998PHA130)). The later can be further O-alkylated to 2-aminoethyl 315 (2003FES1, 1996AP352). Similarly, substituted 2-aminoethyl ethers 316 were synthesized using two alternative routes (2000JHC389).

5.2.1.4 S-Linked groups. Thiomethyl 43 with hydroxyl amine or hydrazine hydrate affords 45 by displacement of the thiomethyl group (Scheme 8, Section 2.1.1.3 (2006IC1945)). Oxidation of a thiomethyl group in indolo azepines to a sulfoxide and a sulfone has been reported (2004AP486). Thione 415 with a variety of hydrazides 416 under thermal conditions (n-butanol, reflux) gives fused triazoles 417 in moderate to good yields as the products of a substitution/cyclization sequence (Scheme 87, Section 5.2.1.3 (1993LA1141)). 5.2.1.5 Halogen atoms. The introduction of side-chains on 9-trifluoromethylpaullone 409 can be accomplished applying a Stille coupling (Scheme 86, Section 5.2.1.1 (2005EJM655)). Similarly, a Heck reaction of iodo 409 with terminal alkenes under standard conditions affords 2-substituted paullones 413 exclusively as E-isomers. The reaction of terminal alkynes with 409 in the presence of cuprous iodide and a palladium catalyst in triethylamine furnishes the 2-alkynyl-paullones 412 (2000BMCL567).

5.2.2 Reactivity of substituents attached to ring heteroatoms 5.2.2.1 Alkyl groups and further carbon functional groups. The N-2-nitrobenzoyl derivative of indolo benzazepine 384a can be easily deprotected on the indole nitrogen by treatment with N,N-diethylaminoethylamine in DMF at room temperature (Scheme 79, Section 5.1.2 (1991JHC379)). The iodo benzamide derivative of pyrrolo[2,1-c][1,4]benzodiazepine 367 (R ¼ I, Scheme 75, Section 5.1.1) reacts with bis(tributyl)tin, lithium chloride and tetrakis(triphenylphosphine) palladium(0) in refluxing dioxane to yield the stannyl derivative 370. The latter couples with substituted aryl bromides in the presence of


67

(PPh3)4Pd(0) in boiling toluene to yield 371. Similarly, 369 is accessible by a Stille coupling of 367 with 2-stannyl substituted thiophene (2005BMCL5003). O-Debenzylation on the side-chain with TMSI to produce substituted benzo[f ]pyrrolo[1,2-d][1,4]diazepinone 181 has been reported (Scheme 36, Section 3.1.1.1 (1992BMCL1639)). The ester derivative of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide 346 can be bromoacylated and further reacted with benzylamine and reduced to a four-ring system with an annulated piperazine ring (Scheme 73, Section 4.2 (1994JHC867)).

5.2.2.2 Amino, imino and other N-linked groups. Benzazepines 34 with acyl substituent on the azepine nitrogen are cleanly deprotected using NaOH in refluxing methanol (Scheme 5, Section 2.1.1.2 (1996TL4283)). Cbz-Protected ester 421 undergoes deprotection/cyclization by hydrogenation of the intermediate amide to furnish diazepino pyrrolo-benzodiazepinedione 422 (Equation (43) (1992JMC4533)). N

N

COOEt

O N

N O

H2, Pd/C

NHCbz

421

NH

(43)

O 422

The N-4-chlorobutyl benzodiazepine dione 221 (Scheme 46, Section 3.1.1.2 (1993MI249)) gives the piperazine derivative after amination with N-methyl piperazine. Condensation of substituted hydrazine 45 (R ¼ NH2, Scheme 8, Section 2.1.1.3) with 2-hydroxybenzaldehyde in methanol produces the corresponding hydrazone (2006IC1945).

6. PROPERTIES OF BENZOHETEROPINES WITH FUSED FIVE-MEMBERED RINGS 6.1 Theoretical methods Semiempirical and molecular mechanics calculations have been widely used. Thus, conformation of indolo benzazepine 423 (Figure 8) with its conjugated benzo and indole rings has been studied by molecular mechanics (MMX force field). Its planarity was estimated from a calculation of dihedral angle t1234; the value of ca. 221 is due to strain as contributed by azepine ring. This characteristic was further compared to that of the open-chain and six-membered

68

D.O. Tymoshenko

OMe HN 2 3

Cl

1

4

N H

423

Figure 8

analogs and to the experimental pKa and clogP values (1994CPB1084, 1994EJM107). Molecular mechanics calculations on two 6-arylpyrrolo[2,l-d][1,5]benzothiazepines (1995JMC4730) confirmed that binding to a mitochondrial benzodiazepine receptor depends on conformational strain as well as on specific repulsive interactions involving their side-chains. Semiempirical molecular orbital calculations performed for a set of pyrrolobenzodiazepines using MNDO and AM1 were used for the interpretation of their mass-spectroscopic data (1996MI653).

6.2 Experimental methods 6.2.1 X-ray Studies of the solid phase conformations of fused heteropines are useful for the prediction of their pharmacophore derived conformations. The crystal structure of 2,5-dimethyl-7-phenylsulfonyl-5,6-dihydroindolo[2,3-c]benzazepin-12-one has been reported (2005AX(E)o2410). This compound crystallizes with two independent molecules in the asymmetric unit, related by a non-crystallographic twofold rotational axis. The two molecules differ in the relative orientations of the phenyl sulfonyl group and the indole ring. In both molecules the sevenmembered ring adopts a distorted boat conformation. The molecular packing is stabilized by C–H?p and C–H?O interactions. Likewise, a boat conformation of the seven-membered ring has been reported for thieno benzodiazepines (2004AX(E)o66, 2003AX(E)o1367) and their hydrates and solvates (2005AX(E)o2720, 2004AX(E)o69). The benzene and thiophene systems, fused with the central 1,5-diazepine ring, are planar, and the dihedral angle between the planes of these two aromatic rings is 124.3(2)1 for the methanol solvate and 1181 for the methanol solvate hydrate (2004AX(E)o69, 2003AX(E)o1367). X-ray structural data have identified the conformations responsible for receptor binding for a series of 6-arylpyrrolo[2,l-d][1,5]benzothiazepines (1995JMC4730). Crystal structures of methyl 12-methyl-12H-[3]benzoxepino[1,2-b]indole-5-carboxylate 135 (1996JCS(P1)1767), benzoxepino[4,3-b]indole (1993AX(C)2126), and natural furobenzoxepine (1990JCR(S)114) have been reported.


69

6.2.2 Spectroscopic methods NMR, UV and IR spectroscopies are routinely used for the characterization of the majority of reviewed systems and the reader is referred to the individual references for this information. The special cases of structure elucidation of a secondary metabolite of the Chinese drug Danshen (Salvia miltiorrhiza Bunge) by 1 H NMR (1990JOC3537) and of homocryptolepinone by HMQC, IDR-HMQCTOCSY and HMBC experiments (1995JHC1631) are worth mentioning. Mass spectrometry is suitable for the identification of pyrrolo-benzodiazepines and the differentiation of their isomers (1996MI653). A structural distinction can be made easily from their mass spectra or the metastable massanalyzed ion kinetic energy (MIKE) spectra, produced by their molecular or most intense fragment ions. Established fragmentation pathways have been supported by MNDO and AM1 semiempirical calculations.

7. IMPORTANT COMPOUNDS AND APPLICATIONS Heteropines with fused five-membered rings are structural blocks of valuable natural products and their synthetic analogs. Latonduines 424 A (R ¼ H) and B (R ¼ COOH) (Figure 9), two new alkaloids with pyrrolo-pyridoazepinone heterocyclic skeletons, have been isolated from the Indonesian marine sponge Stylissa carteri (2003OL2735). Cyclic anhydride 425 is a secondary metabolite of the Chinese drug Danshen (S. miltiorrhiza Bunge) widely used to treat coronary heart diseases, particularly angina pectoris and myocardial infarction. This drug also has sedative and tranquilizing effects and is also being used to treat neurasthenic insomnia (1990JCR(S)114, 1990JOC3537). Cularinoids are a group of isoquinoline alkaloids isolated from the plant families Fumariaceae, particularly the genus Sarcocapnos enneaphylla. Their distinguishing structural feature is a benzoxepine nucleus, and aristoyagonine 143 is the only example to date of a natural cularine alkaloid incorporating a fivemembered lactam (1996TL9357, 2004JOC4527). Homocryptolepinone 426 (Figure 10) was isolated from the extracts of the indigenous Ghanaian medicinal plant Cryptolepis sanguinolenta (1995JHC1631), as well as the alkaloid cryptoheptine 427 that was identified in other related H2N

O

N

Br

O

NH2

R Br

O N H

NH

O

O 424

425

Figure 9

70

D.O. Tymoshenko

Me N

Me

N O

OH H N

OH

N Me

N Me

426

427

OH H NH2

N O

O

428

Figure 10

Cryptolepis species, extracts of which are used in traditional medicine in Central and West Africa (1996TL4283, 2000JNP643). Benzoheteropines with fused five-membered rings represent bi-(hetero)aryl molecules that bind to many proteins and, therefore, are found in almost any therapeutic class. The broad scope of the biological activities of the reviewed class of heteropines is represented by analgetics (1989FES109, 1995EJM593), antibacterial (2005BMCL2515, 1993EJM659), antifungal (2005BMCL3453), antimalarial (1994EJM107), antihistaminic (1991CCC2482, 1994CCC667), and anti-inflammatory (1990FES817) agents. Applications in psychopharmacology include antidepressants (1990FES1265, 1990FES7, 1992JMC4533, 1995CPB2064, 1996AP352, 1998PHA130, 2000JHC389, 2003FES1), antipsychotics (1992AF896, 1994MI845, 1997BMCL25, 1998JMC3763, 2002JMC344, 2003AX(E)o1367, 2004AX(E)o66, 2004AX(E)o69, 2004JMC143, 2005AX(E)o2410, 2005AX(E)o2720, 2005RJBC378, 2001JMC1603) and anxiolytics (1991KFZ16, 1992FES987, 1993MI249). The neurological drug class is represented by nootropics (1990SC3537), memory enhancing mitochondrial DBI receptor complex ligands (1992AG(E)1060, 1993JMC2908, 1994JMC1427, 1995JMC4730, 1996JMC3435, 1997EJM241, 2002JMC4276) and cerebrovascular agents (1991CPB2564). ( + )-Anthramycin 428 and related antitumor antibiotics are produced by Streptomyces species (1994CR433). Several other synthetic subclasses of antitumor agents (1993MI173, 1999PHA645, 2001BMC1123, 2005BMCL3220, 2005EJM655, 2006IC1945), including apoptotics (2001MI704, 2005JMC4367, 2006JMC5840) and CDK inhibitors (1999JMC2909, 2000BMCL567, 2002AP311, 2004AP486, 2004MI1076, 2005JCI1282, 2005MI541) have been reported. Selective arginine vasopressin V2 antagonists correct the fluid retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injuries, lung disease and hyponatremia (1998JMC2442, 1999BMCL1733, 1999BMCL1737, 2003BMCL2195, 2000BMCL695, 2000BMCL783, 2001PAC1401, 2002BMCL3081, 2004BMCL2747, 2004BMCL3363, 2005BMCL5003, 2006BMCL954). Development of antiviral agents (2002EJM3) included HIV-1 non-nucleoside reverse transcriptase (1992BMCL1639, 1994MI283, 1996BMC837, 1996FES425, 1996JMC2672, 1997FES323, 1998MI127, 1998MI139, 1999JMC4462, 2000JHC1539, 2005FES385, 2005JMC7153) and HIV-1 integrase (1999JMC3334, 2002BMC4169, 2004BMCL1447, 2005JMC1496) inhibitors. These data have been further


71

summarized in a neural network computational model for in silico HIV-1 activity prediction (2006JMC1118). Selective glycogen synthase kinase inhibitors (2004BMCL413), cardiovascular agents (1996JMC2922) and inhibitors of tubulin assembly (1996BCF251, 2000TL5853) of the fused benzoheteropine type have been reported.

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1994CR433 1994EJM107 1994JCR(S)295 1994JCS(P1)1193 1994JCS(P1)2191 1994JHC293 1994JHC867 1994JHC1033 1994JHC1053 1994JHC1317 1994JMC1427

1994JMC4100 1994MI283 1994MI385 1994MI845 1994PHC301 1994S164 1994SC2685 1994T2071 1995CPB2064 1995EJM593 1995H431 1995JCS(P1)2565 1995JHC1631 1995JMC4730

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CHAPT ER

2 Synthesis of Heteroannulated Azocine Derivatives Leonid G. Voskressensky, Larisa N. Kulikova, Tatiana N. Borisova and Alexey V. Varlamov

Contents

1. Introduction 2. Hydrogenated Azocinoindoles: Natural Sources, Synthesis and Reactivity 2.1 Natural alkaloids based on azocinoindoles 2.2 Synthesis of hydrogenated azocinoindoles 2.3 Reactivity of hydrogenated azocinoindoles 3. Synthesis of Pyrimidoazocines 4. Synthesis of Hydrogenated Thienoazocines 4.1 Synthesis of thieno[2,3-d ]azocines 4.2 Synthesis of thieno[3,2-d ]azocines 4.3 Synthesis of thieno[3,2-b]azocines 4.4 Synthesis of thienoazocines of different coupling 4.5 Synthesis of bisthienoazocines 5. Synthesis of Hydrogenated Thienobenzazocines 6. Synthesis of Hydrogenated Benzothienoazocines 7. Synthesis of Furoazocines 8. Synthesis of Thiazoloazocines 9. Tandem Enlargement of the Six-Membered Ring in Heteroannulated Tetrahydropyridines under the Action of Activated Alkynes – A General Method for the Synthesis of Condensed Azocines References

82 82 82 86 97 100 101 102 103 103 105 105 106 110 112 112

116 118

Organic Chemistry Department, Russian Peoples Friendship University, 6, Miklukho-Maklaya Street, Moscow 117198, Russia Advances in Heterocyclic Chemistry, Volume 96 ISSN 0065-2725, DOI 10.1016/S0065-2725(07)00002-5


81

82

L.G. Voskressensky et al.

1. INTRODUCTION The chemistry of heteroannulated azocines has not been explored in detail owing to the lack of efficient methods for their synthesis. The exception is azocinoindoles, which have been investigated extensively due to the host of alkaloids with an azocinoindole fragment in their structure.

2. HYDROGENATED AZOCINOINDOLES: NATURAL SOURCES, SYNTHESIS AND REACTIVITY Theoretically, the existence of six isomeric azocinoindoles in which an azocine ring is annulated with a pyrrole fragment, is possible.

N

N

N

N H

N H

N H

1

2

3

N N N H 4

N N H

N H 5

6

A large number of articles are devoted to various aspects of azocino[4,3-b]indoles 2 chemistry. There are several publications on the synthesis and reactivity of the derivatives 3, 4 and 5. But, up to now, there has been no detailed work on azocinoindoles 1 and 6.

2.1 Natural alkaloids based on azocinoindoles 2.1.1 Alkaloids containing an azocino[4,3-b]indole fragment The first papers on the extraction of alkaloids containing an azocinoindole fragment 2 and the elucidation of their structure go back to the 1950–1960s. Alkaloid uleine (7a), isolated (57HCA1189) from the roots and bark of the SouthAmerican Aspidosperma ulei tree contains an a-vinylindole fragment (59JA4433). Its structural analogs, dasycarpidone (7b) and nordasycarpidone (7c), also extracted from raw plant material (64E363), are assigned to the group of acetylindole alkaloids.

83

Synthesis of Heteroannulated Azocine Derivatives

R1 N

N

N

H

H N H MeO2C

R

N H

N H

O

MeO2C

O 9

8 7a R=CH2, R1=Me 7b R= O, R1=Me 7c R=O, R1=H

In succeeding decades reports on the extraction of these alkaloids from other plants have appeared (00MI208, 76P1093). Hydrogenated azocine fragments also can be found in the structures of some indole alkaloids of vallesamine, for example, angustilobine A (8) and angustilobine B (9), extracted from the leaves of Alstonia angustiloba (87JNP714, 89P1241). Related alkaloids 19,20-Z-vallesamine (10a) and 19,20-E-vallesamine (10b) have been extracted from the leaves of Alstonia scholaris (87H(26)413), from the bark of Tabernaemontana dichotoma (85P2097) and from cell cultures Tabernaemontana divaricata (88MI393). N

N R1 N H MeO2C

N H

R CH2OH

10a R=H, R1=Me 10b R=Me, R1=H

O CO2Me 11

Alstonamine (11) – a pentacyclic alkaloid with a hydrogenated azocino[4,3-b]indole fragment – has been isolated from the leaves of this plant (87P2139). Brafouedine (12) and isobrafouedine (13), two alkaloids isolated in minor amounts from the bark of the rhizome of Strychnos dintlagei (86JNP452), and Epchrosine (14), a metabolite of cell cultures Ochrosia elliptica Labill (86MI147, 86MI381), have similar structures. N

N

N

OH N H

CH3

OH Me H

N H

O

O N H

Me 12

13

14

H

Me

84


The related alkaloids ervaticine (15) and apparicine (16a) have been isolated from the leaves of Ervatamia coronaria (85H(23)2975) and from the wood of Vallesia antillana (77MI249), respectively. The latter exhibits high antibacterial activity. Subsequently, 16(S)-hydroxy-16,22-dihydroapparicine (16b) was isolated from the leaves of T. dichotoma (84JNP835). Me N

N N

O

CHMe N H

N H

Me 15

R1

N H

R 17

16a R′R1- =CH2 16b R=OH, R1=Me

O

Me

Gilbertin (17), isolated from the bark of Aspidosperma gilbertii, is assigned to another type of indole alkaloid (82TL5395). The above structures are not the only examples of alkaloids containing the azocino[4,3-b]indole fragment but, only those most interesting from our point of view will be discussed here. More detailed information on the general topic can be found elsewhere (74MI219, 94CH(25)261).

2.1.2 Alkaloids with an azocinoindole fragment of different coupling Only a few papers on the isolation of alkaloids with an azocinoindole fragment other than [4,3-b] coupling have appeared. Three indole alkaloids (lundurine A (18), lundurine B (19), lundurine C (20)) bearing the octahydroazocino[5,4-b]indole fragment have been extracted from the leaves of Kopsia tenuis. Their structures have been established from spectral data (95TL759). All are tryptamine derivatives with an annulated cyclopentyl fragment. O N N Me

Me

O

O N

N

MeO2C

MeO2C 18

19 N N

Me

R

R

O R=CO2Me

N N MeO2C

R 20

21


85

Alkaloid Lapidilectine A (21) has a basically similar carbon chain. A series has been isolated from the wood and leaves of Kopsia lapidilecta. (92TL2493, 93JNP1134). Bis-indole alkaloids, Tenuisines A (22), B (22a) and C (23) were isolated from ethanol extracts of the leaves of K. tenuis later (96TL8811, 97T12661). R1

O Me

N

O

O R1

N

R

MeO2C

O

N O

O

Me

22 R=H, R1=CH2 22a R=OMe, R1=CH2 23 R=H, R1=O

N

R

MeO2C

One of the indole diketopiperazines 24, metabolite Aspergillus Ustus from mold spores forming in corn grains, has a pentacyclic structure with an azocino[5,4-b]indole fragment (73T107). N O O N

N HO

H

Et

N H

N H 24

25

Pandine (25), bearing the azocino[5,4-b]indole fragment, has been isolated from Pandaca caducifolia (74TL3119). Its structure has been determined spectroscopically and corroborated by chemical transformations. There are several publications on the isolation of indole alkaloids with the hydrogenated azocino[3,4-b]indole fragment from different plants. For example, nareline (26) (77HCA1419) and alschomine (27) (89CPB887, 90P3547) were extracted at different times from the leaves and wood of A. scholaris. Later, the isolation of derivatives 26 from other plants was reported (94P1737). N

O O N

N

MeO

OH

H N O

MeOOC Me

COOMe

Me 26

27

86


The alkaloid aspidodasycarpine (28), known since the 1960s (64TL3899), has been isolated from other plants in succeeding years (68P2045, 83JNP708). The nitrogen atom in its azocane fragment is not substituted, a phenomenon quite unique for this type of alkaloid. H N

H N O

Me

MeOOC CH2OH 28

2.2 Synthesis of hydrogenated azocinoindoles 2.2.1 Synthesis of hydrogenated azocino[4,3-b]indoles Most publications on the synthesis of hydrogenated azocinoindoles have involved attempts to synthesize known alkaloids and their derivatives. Early studies on the successful synthesis of racemic alkaloids uleine (7a) and dasycarpidone (7b) were conducted mainly in the 1960s. Dolby and Biere carried out acidic cyclization of indolyl-substituted amino acid 29 resulting in the formation of 7b in poor yield. In the last stage they isolated epimer 7b – (7) epidasycarpidone (30) with 55% yield (Scheme 1). Using 30 as a starting material they also synthesized a racemic form of epimer 7a – (7)epiuleine (31) (Scheme 2; 70JOC3843). Kametani (71JOC1291) used a completely different approach to the synthesis of 29 (and correspondingly 7b, 30 and 31). The reaction between 3-indolylmagnesium bromide and 3-ethyl-4-carbomethoxypyridine N-oxide gave a mixture of 3-pyridylindoles 32a and 32b, separated chromatographically and converted into the corresponding methiodides with subsequent catalytic COOH N

N +

4 steps

PPA, 80−90 °C

CH3CH2CH(Br)COCl

N H 29 Me H

N H N H

O 55% 30

Scheme 1

0.7%

7b

87


Me H

Me

N

MeLi/THF

H

Al 2O3/ Δ

H

30

N H

97%

N H

77%

HO Me

CH2

N H

31

Scheme 2

COOMe

COOMe

+ N

i, ii, iii

N

R 32a R=3-indolyl; R1=H 32b R=H, R1= 3-indolyl

BrMg

O

32a

R1

N

PPA

29

7a - 12% 31 - 6 %

Me H

N

R2

Me N

i,ii,iii

R1

PPA

H

COOH

O N H 33a (6%) R1=Et, R2=H 33b (3.5%) R1=H, R2=Et

32b N H

29a

i: CH3I/MeOH, reflux; ii: H2/CH3OH/Adams cat, iii: KOH/EtOH/H2O, reflux, 3h

Scheme 3

reduction and saponification to amino acid 29 and its isomer 29a. On heating with polyphosphoric acid, the latter were converted into 7a and 31 and their 33a and 33b isomers, respectively. The yields were not better than ca. 12% (Scheme 3). Subsequently (71CPB1424), the same authors modified the synthesis, arriving at a better stereoselectivity and higher yield of the target product. Using heteroannulation with palladium catalyst to form intermediate 32a, they obtained the corresponding azocinoindole 7c in a high yield (Scheme 4; 97JOC3158). About the same time a number of publications appeared on the complete synthesis of 7a, 7b, 30 and 31 using a different approach to build the alkaloid framework (Scheme 5; 68MI364, 68MI584, 69JCA(C)2738). Phenylhydrazone 34 under Fischer reaction conditions was converted into indole 34a with subsequent successive transformations to pentacyclic derivative 35. Its acid-initiated rearrangement led to the formation of 7b and 30 in a ratio of 1:5. While 7b and

88


CO2Me

H

N

N

HN

2 steps

PdCl2(PPh3)2,

+

O

CO2Me

N

ZnCl

H

Br

42%

N

S O 32a

O

22% N H

S O

O

7c

Scheme 4

N

N PPA

O HN

35% N

O

O

i,ii,iii,iv N

NH N

34

34a

35

AcOH(50%) 100 °C

Me H

N

7b (5%) 7a (31%) CH2I2/Mg/Hg

H N H

36

O

31 (29%) 30 (25%)

i: CH3I, EtOH; ii: NaBH4 (excess), MeOH,r.t, 2h, (yield 81%), iii: MnO2/CH2Cl2, r.t., 30 min., (yield 78%); iv: Na/DMSO/95 ° C, 36h, (yield 30%)

Scheme 5

30 with methylene diiodide in the presence of magnesium amalgam gave uleine (7a) and epiuleine (31) correspondingly, a similar procedure gave (36)-de-ethyldasycarpidone. The first publications on the successful stereospecific synthesis of uleine (7a) and epiuleine (31) appeared in 1971 (71JA2492). Using 31 as an example, the key step lies in the formation of transoid piperidone 37, whose conformational stability allows the subsequent transformations to be carried out stereoselectively (Scheme 6). Later methods of stereoselective synthesis of alkaloids 30, 31 and their derivatives differ mainly in the construction of the conformationally stable intermediate with a 3-(2-piperidyl) substituted indole fragment (type 38). In the


H2N

CHO

+

66% O

H

H

NaOH N H

N HN

O 37 H i ii iii iv

CHO N LiAlH4/glyme 31

89

CHO

H

v

N

84% HN

HN

H

O 38

i: (CH3CO)2O/HCOOH, r.t., yield 87%; ii: KCCK/THF −20 °C,13 h, yield 50%; iii: Hg(CH3COO)2/CH3COOH , 2 days, yield 67%; iv: Li/liq.ammonia, yield 72%; v: BF3xEt2O, CH2Cl2, yield 70%

Scheme 6 Me NC

N

H

N

+

N H

Me

HN

O

R

H

Me

39 H+

O R = Me

O

31

Scheme 7

publications (81TL331, 83T3683, 82JOC2435), the authors used acid-initiated condensation of 2-cyano-D-3-piperideines 39 with indole to achieve this result (Scheme 7). A similar approach, used for the synthesis of the isomeric alkaloids 33a and 33b, has been described in more recent work (85JOC1516, 89TL5659; Scheme 8). In Ref. 80TL839, the main stage of the synthesis is the reaction of endoperoxide 40 with indole, initiated by tin chloride (II). The total yield of 31 is 10% (Scheme 9). The derivatives of 2-azabicyclo[3.3.1]nonanes (morphane) (41) can also be used to build the framework of alkaloids with the azocino[4,3-b]indole fragment. 7-(2-Nitrophenyl)-substituted azabicyclononanone 42 obtained from N-benzylpiperidone-4 (seven stages, total yield (10%)) under the conditions of reductive cyclization has been converted into N-benzylhexahydroazocino[4,3-b]indole 43 (Scheme 10; 88T2087).

90


R NC

R

N

N

+

COOMe

N

78%

MgI

HN

COOMe EtMgBr CuI, −20 °C R

H

N

R

R2 H

R1

H

PPA

R1

R2 N

COOMe HN

O N H 33a (17%) R=Me, R1=Et, R2=H 33b (18%) R=Me, R1=H, R2=Et

Scheme 8 Cbz N OO

+

N H

H

3 steps

Me TsOH/CHCl 3

N HN

R

32%

O H

Me

40 O R = Me

O

Scheme 9

N

41 Bn

H

N NO2 O

70%

Bn

H

Fe/AcOH

N HN

H 43 H

42

Scheme 10

31

91


The Fischer indolization of bicycloketones of the morphane series often has been used for the synthesis of the corresponding azocinoindoles (89TL3841, 90TL2449, 92LA461). Thus, bicyclic ketone 44, under Fischer conditions, has been transformed into azocinoindole 45 in moderate yields (94JOC3939; Scheme 11). Blechert et al. have proposed a new effective approach to the synthesis of different indole alkaloids using cation domino reactions (95S592, 97AGE1474). The total yield of uleine (7a), produced on the basis of this concept, is 32%, which is quite unique in the synthesis of polycyclic indole alkaloids. Note that this is the total yield, starting from cyclohexenone 46; the yield of the key step of the synthesis – the cyclization of carbazole 47 into 7a is 95% (Scheme 12). A more recent publication (96H(43)15) reports the synthesis of tetracyclic derivative azocino[4,3-b]indole 49 using an intramolecular aldol condensation of carbazole 48. The possible elaboration of effective synthetic methods of the

Bn

H Bn NC

Me

HCl/H2O

N

69%

N

O

1. PhNHNH2 2. AcOH

Bn N

HN

26%

H 44

Et

Me H

45

Me

H

O

Scheme 11

ii, iii, iv

i

O

v

Me

OH

O

N H

O

46

HCOOH, r.t.

vi, vii

Me

Me N N H

O

OH

OH N H

Me

N

7a 95%

OAc 47

i: 1) a) EtMgBr, CuI, Me2S, THF b) Allyl bromide, HMPTA, (yield 60%) 2)NaH, glyme, HCOOEt (yield 95%); ii: PhN2Cl (yield 85%); iii: HCOOH (yield 86%); iv: NaOMe, MeOH, r.t, 12-14 d (yield 99%), v: 1)OsO4, NaIO4, MTBE, H2O 2)MeNHOH, NaCNBH3, i PrOH (yield 85%); vi: MeLi, THF, −20°C (yield 98%) ; vii: Ac2O, pyridine, r.t. (yield 99%)

Scheme 12

92


starting compounds for this synthesis (00JHC11, 02JHC315) makes it appear promising (Scheme 13). Other methods for the synthesis of indole alkaloids of the uleine type and related compounds are based on the use of 2-(1,3-dithian-2-yl)indoles (89TL6761, 93AQ(89)149, 94T6585, 95TL1693, 89H(29)2121, 96T3563), Friedel–Crafts intermolecular annulation of 2-indolylpiperidine-4-carboxylic acids (94TL7123), nucleophilic addition of indolyl-2-acetic acid esters to pyridine salts (94T5233) and intermolecular cyclization of 4-(indolylmethyl)piperidines catalyzed by mercury acetate (88H(27)2883, 85T1753). Enantiocontrolled syntheses have been used allowing optically active derivatives (97MI765, 95T10759, 00MI400, 03T1691) to be obtained. Further information can be found in the specialized paper (01MI(57)235). In one of the few publications not directly connected with the synthesis of alkaloids, an original method for the formation of hexahydroazocino[4,3-b]indoles using a Mannich intermolecular reaction of the corresponding 2-(N-R-aminobutyl)indoles 50 has been reported (Scheme 14; 87JCS(P1)1599). O Bz N

H

N

Bz

OH

NaH/THF H

58% N H

O

N H

O

48

49

Scheme 13

NHBz THF\−70 °C Li

N S O

+

O

LiAlH4/THF, reflux

N Bz

72%

N

O O

O

63%

S O

Bn N HCHO\CH3COOH glym, r.t NHBn N H

OH

96%

N H

OH 51

50

Scheme 14

93


2.2.2 Synthesis of hydrogenated azocinoindoles of different couplings In Ref. 95TL3511 the authors have suggested an ingenious method for hexahydroazocino[4,5-b]indoles 52 from readily available tetrahydro-g-carbolines. In the first stage, a dibenzyl salt of the corresponding carboline is cleaved in the presence of methyl cyanoacetate and a strong base. This reaction is widely used in ‘‘gramine’’ chemistry. Reductive cyclization of the resulting b-cyanoethyl derivative followed by debenzylation leads to the formation of azocinoindole 52 (Scheme 15). The preparation of azocino[5,4-b]indole 54 using photoisomerization of pyrrolo[1,2-a]indole 53 has been described (83T3657) giving the product in 36% yield (Scheme 16). Epoxyhexahydroazocino[5,4-b]indole 56 (in the original paper mistakenly related to azocino[5,6-b]indoles) has been obtained in 60% yield by a Meisenheimer rearrangement of the N-oxide of azetopyrido[3,4-b]indole 55 (91CL1781; Scheme 17).

CN

MeO2C

Bn N Bn R1

CO2Me

R1

Br

Bn N H

70−85%

N H 1 R = H, OMe

NH

R1

ii

i

30−40%

N

N H

Bn

52

i: NCCH2CO2Me, NaH, THF; ii: H2, Pd/C, AcOH, 48 h

Scheme 15

NH

NH2

O hν

N 53

36%

O

N H

54

Scheme 16

N N

Et

mCPBA, CH2Cl2/r.t

Et

O

CO2Me

N

N

CO2Me

Me

Me 55

56

Scheme 17

94


NH RCHO, PhH reflux N H

11−73%

N R

N H 58

57

Scheme 18

A number of azocino[3,4-b]indoles derivatives 58, analogs of b-carbolines, have been synthesized by the Pictet–Spengler reaction using 3-piperidylindole 57 as the starting material (98TL1441, 01T2039). The products were isolated in various yields as mixtures of distereoisomers. The ratio of stereoisomers depended on the aldehyde used (Scheme 18).

2.2.3 Methods for the synthesis of azocino[4,5,6-cd]indoles The first method for the preparation of tetrahydroazocino[4,5,6-cd]indoles was reported in 1966. In succeeding years, this reaction came to be known as the Witkop photocyclization. Azocino[4,5,6-cd]indoles 61 and 62 have been obtained from the corresponding N-chloroacetyl derivatives of tryptamine and melatonine with the help of photocyclization. Further, lactam 62 has been reduced to 8-methoxy-3,4,6, 7-tetrahydro-1H,5H-azocino[4,5,6-cd]indole (63) under the action of B2H6 (69JMC(12)636; Scheme 19). In succeeding years, the Witkop photocyclization has been widely used for the synthesis of similar compounds. For example, the dichloroacetyl derivative of tryptophane in the presence of sodium azide under the conditions of photocyclization (93JA813) produces 7-azidoazocinoindole 65 in 49% yield (Scheme 20). The preparation of lactams 68 and 69 from the corresponding dichloramides 66 and 67 in acetonitrile under UV light in 43% and 42% yields, respectively, has been reported. But with dichloramide 67, carried out under similar conditions in aqueous acetonitrile, in addition to the mixture of diastereoisomers of azocinoindole 70 (54%), azepinoindole 71 (25%) was also obtained (92JCS(P1)823, 92JCS(P1)797; Scheme 21). When aqueous acetonitrile was used as solvent for the dichloroacetyl derivative of tryptophane 66 under Witkop cyclization conditions, two products were also obtained: azocino[4,5,6-cd]indole 68 in 16% yield and lactone 72 in 46% yield. Thereafter, in the reduction of major lactone 72 by sodium borohydride, 7-hydroxy-7-isopropylazocinoindol-4-yl-methanol 73 (42%) and a mixture of lactone diastereomers 74 in the ratio 1:1 (35%) were produced (Scheme 22). The authors have shown that changing the hydroxyl group in the 8-position to an azide group causes transformation of the azocine ring into azocinoindole 75 under UV light. This leads to the exocyclic amine 76 and the product of azocine fragment enlargement, diazonino[4,3,2-cd]indole 77 (Scheme 23).

95


H O NH

R

hν

N B2H6

R

O N H

H

N

H3CO

H2C Cl

N H

59 R=H 60 R=OCH3

N H

61 R=H 62 R=OCH3

63

Scheme 19

H

CO2CH3

O

NH

CO2CH3

N

N3

hν O

N H

Cl

NaN3

CH Cl

N H

64

65

Scheme 20

H

R

O

R

N

NH hν

O Cl Cl

N H

C

MeCN N H

66 R=CO2Me 67 R=CH2OH

hν

68 R=CO2Me 69 R=CH2OH

MeCN H2O H

O

N

OH O

HO + N H

N H

71

70

Scheme 21

NH O

96


O

R O

NH

hν

NH

O N H

Cl Cl

C

MeCN H2O

68

+

O N H

66 R=CO2Me

72

NaBH4 H O

OH

N

OH

O

HO

NH O + N H

N H

73

74

Scheme 22

H O

N

O

H O

OH hν

R

N

N

OH

N +

MeCN N H 70 + 73 R=OH

N H i

75 R=N3

H N

OH

76

N H 77

i: NaN3, CF3CO2H, CHCl 3

Scheme 23

Anderson and Lavton in 1977 described vinyl modification of the Witkop cyclization to give azecino[4,5,6-cd]indole 79 from tryptophane 78. But later it was proven that the product was, indeed, azocino[4,5,6-cd]indole 80 (99TL8443). The same photocyclization has been used for trichlorobutenamide 81 with the resulting formation of azocinoindole 82 instead of the expected 83 (Scheme 24). A multi-stage synthesis of azocino[4,5,6-cd]indoles has been suggested (03MI3519). From 4-bromoindole (84) with the help of successive transformations (among them the Vilsmeier–Haack reaction, Henry nitroaldole condensation, lithium aluminum hydride reduction and insertion of an allyl fragment), indole 85 has been produced in 18% yield. The cyclization of the latter on palladium

97


O

O

H

NH

NH

O

Cl CO2CH3 N H

79

N H

78

O

80 O

Cl NH

H

NH Cl

O Cl

Cl

Cl hν

83

CO2CH3

hν

N H

N H

N

CO2CH3

N

Cl

N H 81

N H 82

Scheme 24

catalyst gives 86 and 87 with eight- and nine-membered rings. The alternate method, which includes cyanomethylation, N-Boc-protection and further reductive amination, leads to the formation of indole 88 in 28% yield, which under further cyclization produces azocinoindole 89 (30%) (Scheme 25).

2.3 Reactivity of hydrogenated azocinoindoles One of the main reasons for investigating the reactivity of azocinoindoles is connected with the synthesis of pentacyclic indole alkaloids of the Strychnos group. In Refs. 98JOC7547, 90TL3453, 92JOC5792 and 85AQ277, N-(dimethylthio)ethyl and N-dimethoxyethyl derivatives of hexahydroazocino[4,3-b]indole 90–93 under the action of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) form pentacyclic compounds 94. Their further reduction results in strychnine, tubopholine, tubopholidine and other analogs (Scheme 26). A different approach to the derivation of Strychnos-type pentacyclic alkaloids has been used (85T2557). Photocyclization of N-chloroacetyl derivative 99 takes place in position 4 of the indole core (but not in position 2, as expected) to form 100 (Scheme 27). The rearrangement of hexahydroazocino[4,3-b]indole 101 into pyrrolo[3,2-a]carbazole 102 under Wolff–Kishner reaction conditions is also described in the publication (Scheme 28; 84H(22)561). The reaction is a special case of cleavage of compounds related to gramine.

98


N

Bn

Bn

Bn

N

N

Br

Br

ii

i

+ N H

N H

84

N H

85

87

N Br

N H 86

CH3

CH3

N

Br

CN iii

ii

N

N Boc

N H

Boc 88

89

(i) POCl3, DMFA; MeNO2, NH4OAc; LiAlH4,THF; PhCHO, NaBH(OAc)3, DCM-THF; AllylBr, MeCN. (ii) 25 mol % Pd(OAc)2, 55 mol % P(o-Tol)3, NEt3, MeCN (iii) DIBALH, DCM; AllylNHMe, NaBH(OAc)3, DCM.

Scheme 25

R R

SEt

H

[H]

DMTSF

N HN

H

N

HN

N R2

R2

R2

H R 1

90 R=MeS, R1=R2=H 91 R=MeS, R1=Et R2=H 92 R=MeS, R1=H R2=Et 93 R=MeO, R1=R2=H

H

N

H R 1

H R 1

94

95 Tubofoline 96 Tubofolidine 97 19, 20-Dihydroakuamicine 98 Tubifoline

Scheme 26

The acetate derivative of alkaloid uleine (104) obtained from its N-oxide 103 with acetyl chloride also undergoes cleavage by sodium borohydride, giving carbazole 105 in high yield (85LA2073; Scheme 29). In the reduction of 7a (83JNP206) it was shown that, on hydroboration only the expected hydroxymethyl derivative 106 is formed while the reduction in the presence of lithium aluminum hydride leads to the formation of a mixture of two derivatives 107 and 108 (Scheme 30).

99


O Cl

H

O

N

H hν

N HN

HN

40% H H

99

100

Scheme 27

H

H N

N2H4 *H2O, KOH

HN O 101

N H

N H

79% H

102

Scheme 28

Cl Me

H HN

Me OCOCH 3 N NaBH4, −50 °C

H

N O CH3COCl HN

H N H

90% H

N Me OCOCH3

H 104

103

105

Scheme 29 Me N

H Me Me H

N H

N H

1. BF3 , NaBH4 2. NaOH(aq), H2O2

N H

1. LiAlH4 2. H2O

107 ( 34%)

7a

Me N

H

CH2OH

Me

106 (24%) N H

Scheme 30

H

H OH 108 (34%)

100


N Bn

O +

N H

O

O

CO2Me

109

110

Bn

Bn

O

N

O

N O

O 97% N H

N H

CO2Me

CO2Me

111

Scheme 31

In another publication by the same authors, the possible transformation of 7a into 102 and 108 by different microorganisms was studied and confirmed (83JNP211). Unusual recyclizations of hexahydroazocino[4,5-b]indole derivatives under the action of aliphatic aldehydes have been described (01JOC5303). Thus, azocinoindole 109, in the presence of aldehyde 110, has been transformed into tetracyclic 111 in quantitative yield and isolated as a mixture of two diastereoisomers (Scheme 31). The spectral characteristics of heterocycles examined in this paper are certain to be useful to chemists working in this field. Voluminous data on the NMR spectra of indole alkaloids containing the azocine fragment can be found in special publications (87MI377, 83JNP200).

3. SYNTHESIS OF PYRIMIDOAZOCINES Only two examples of the synthesis pyrimidoazocines have been described. In Ref. 82JHC1257, a three-stage synthesis of a new heterocycle system, pyrimido[5,4-c]benz[1]azocine, has been proposed. Condensation of 4-methyl2-phenyl-5-pyrimidincarboxylate (112) with 3,4-dimethoxy-6-nitrobenzaldehyde (113) led to the substituted alkene 114, which, after catalytic hydrogenation of the nitro group on Raney nickel and subsequent intramolecular cyclization of product 115, was converted into pyrimidobenz[1]azocine 116 (Scheme 32). Pyrimidobenzomorphane 119, has been obtained by [4+2] cycloaddition of enamine 118, produced from the bicyclic ketone 117 and pyrrolidine, to 1,3,5-triazine (82TL4559; Scheme 33).


CO2Et O2N

N N

i

+

Me

CO2Et

N

OMe

101

OMe

N OHC

OMe

112

O2N

114

113

OMe

ii O NH

OMe

N

CO2Et

N iii

OMe

N N

OMe 116

H2N

115

i: PhMe, pTSA, 44% ii: H2/Ni, 71% iii: NaH, PhMe, 45%

Scheme 32

O N CO2Me

N

C6H6

+ N H

N CO2Me

118

117

1,3,5-triazine N N

119

N CO2Me

Scheme 33

4. SYNTHESIS OF HYDROGENATED THIENOAZOCINES There are data on the synthesis of only six isomers of thienoazocines.

N

N

S

S

S [3,2-b]

N

[3,2-c]

[3,2-d]

OMe

102


N N N

S

S

[2,3-c]

[2,3-d]

S [3,4-d]

4.1 Synthesis of thieno[2,3-d ]azocines In recent years much attention has been paid to the synthesis of benzomorphane heteroanalogs in which a benzene ring has been replaced by a heteroaromatic one. Syntheses of substituted thieno[3,2-f ]morphanes (derivatives of thieno[2,3-d]azocine) described in Ref. 75JHC651 consists of the condensation of cyanopyridines 120 with 2-thienyllithium, reduction of the resulting ketones into thienylmethylpyridines, quaternization and reduction of the quaternary salts with sodium borohydride to form piperidines 124 and 125. Intramolecular cyclization of the latter leads to the formation of thieno[2,3-d]azocines 126 (Scheme 34).

O NC

N +

R1

N

S

S

Li

R2

R1

KOH, NH2NH2

N

S R1

R2

CH3

CH3

122 50−55%

121 70−90%

120

R2 CH3

MeX CH3

CH3

CH3

N

S

N

S

NaBH4

+ R1

CH3

CH3 124

125 48% HBr CH3 N

S

R1 CH3

X

R2

R1

R2

N

S

126 a R1=R2=H 49% b R1=CH3 R2=H 45% c R1=H R2=CH3 67%

R2

Scheme 34

R1 123 65−90%

R2 CH3


103

R1 COOMe

NH2

Me +

S

O

NH2

OH

R1 NH

Me

R1 Me

OH

R1

S

R2X

N

Me

127 21−34%

S

HBr

R1

R2

128 a R1=R2=Me 31% b R1=Me,R2=Bn 91% c R1=Et,R2=Bn 84%

R1 Me

Me +

S

N

R2

129 a R1=R2=Me 35% b R1=Me R2=Bn 46% c R1=Et R2=Bn 56%

S

N

R2

130 R1=Et R2=Bn 9%

Scheme 35

In (91H(32)107) the key stage of thieno[2,3-d]azocines 129 and 130 formation is the intramolecular cyclization of 2-thienylmethyltetrahydropyridines by HBr, resulting from dehydration of piperidols 128 (Scheme 35). The synthesis of compound 135 (Scheme 12) includes the production of isoquinoline 132 via a Bischler–Napieralski reaction, its reduction and alkylation on the nitrogen atom followed by cyclization of N-alkyl derivatives 134 in the presence of acids (83JHC1477; Scheme 36).

4.2 Synthesis of thieno[3,2-d ]azocines For the synthesis of isomeric thieno[3,2-d]azocines 138, intramolecular cyclization of 2-thienyltetrahydropyridines 137 has been used (74JHC853; Scheme 37).

4.3 Synthesis of thieno[3,2-b]azocines Esters of amino thienyldionic acids 140 served as starting compounds for the synthesis of thienoazocine 142 (76HCA104) produced in 87% yield by refluxing the hydrochloride of dicarboxylic acid 141, first obtained by the ester 139 hydrolysis (Scheme 38). Thieno[3,2-b]azocines can also be produced (01JCS(P1)2774) from arylthioketene S,N-acetals 143 and trimethylsilyl ethers of enoles (Scheme 39).

104


N

NH

NH2

O

S

+

NH

S

S 80%

94% COCl 132

131

S

133

S 48% HBr

N

R

S

N R 135 a CH3 (43,5%) b Bn (43%)

134 a CH3 84% b Bn 83%

Scheme 36

CH3

R1

Br

1) Mg / THF 2) NaBH4 /EtOH

R2 +

N S

N

S CH3

O3S

48% HBr

N S

R2 R1

CH3 137 (a-b) 32%

136 (a-b)

CH3

R2 R1

138 a R1=R2=CH3 81% b R1=C6H5 R2 =H 43%

Scheme 37

O HO H3CO2C

N

HN

ROC

NH2

HCl/ether R′O2C

141 S

(CH2)4

S

(CH2)4 CO2R′′

CO2CH3 139

140 a R′=R′′=Me b R′=Me R′′=H 141 R′=R′′=H

Scheme 38

S 142 R = OH (87%)


OTMS Ar

SR′′

O Me

1. Hg(OAc)2 CH2Cl2

N

2. TASF

+ S

105

NHR′

Ph

S

143 Ar =Ph R′=R′′=Me

144 28−30%

Scheme 39 CH3 N S H3C N H3C

X

NaNH2, NH3 liq. 66%

S

145

146

X N CH3 CH3

NaNH2, NH3 liq. 80%

S

N

S

CH3 148

147

Scheme 40

4.4 Synthesis of thienoazocines of different coupling An effective method of hexahydrothieno[3,2-c]- and [2,3-c]azocines 146 and 148 syntheses involving a Sommelet–Hauser rearrangement of 1,1-dimethyl-2-(2- or 3-thienyl)pyrrolidine salts 145 and 147 under the action of NaNH2 in liquid ammonia has been described (87SC935; Scheme 40). Thieno[3,4-d]azocine (78JHC193) 152 is formed as a result of intramolecular cyclization of 2-thienyltetrahydropyridine 151 produced by the interaction of pyridine quaternary salts 149 and thienylmagnesiumbromide with subsequent reduction. Under the action of the cyanogenbromide thienoazocines 152 are converted into their NH derivatives 153, subsequent alkylation allows the introduction of pharmacophoric substituents into the molecule (Scheme 41).

4.5 Synthesis of bisthienoazocines The bisthieno[2,3-c:3u,2u-f]azocine 157 containing a bicyclic azocine fragment has been obtained for the first time by cyclization of N,N-bis-(thienyl-2-methyl)valine ester 156 with organolithium compounds (Scheme 42). Compound 156 has been formed by the alkylation of valine ester with thienylmethylbromide in acetonitrile in the presence of potash (98SL1355). Maffrand (80H(14)321) has worked out the general strategy for the synthesis of bisthienoazocines with a bicyclic azocine fragment based on the

106


Me

Me

Me

Me

Me + N

NaBH4

Me

MgCl S

S

MeOH N

X

Me

R

Me

R 150

149 Me

Me

Me

Me

Me

HBr 47%

Me

BrCN S

S

S AcOH

N Me

151

Me

Me Me

NH

N R Me

Me

R

153 (51%)

152 a R=Me (57%) b R=Bn (60%)

Me a R= CH2CH=CH2 (61%) b R= CH2CH=CMe2 (40%) c R= CH2CH2Ph (87%) (48%)

d R=

RX or 1) R'COX 2) LiAlH4 (R=CH2R')

Me Me

S N R Me

154

Scheme 41

R

R

CO2Alk

Br Br

2 S

155

CO2Alk

Br NH2

Br

43

MeCN/K 2CO3

S

HO R′Li/THF/−100 °C

N S

156

R′=n-Bu or t-Bu S

R

S

N

157 R = i-Pr (53%)

Scheme 42

thienomethylation of hydroxy- and methoxytetrahydrothieno[2,3-c]pyridines 158 and 159 and subsequent cyclization of N-thienomethyl derivatives 160–162 into azocines 163–165 (Scheme 43). In a more recent paper (80H(14)325) quaternary salts were obtained from bisthienoazocines 163 and 164 and MeI or (Me)2SO4. Their interaction with bases under Hofmann conditions gave in all cases the corresponding vinyl derivatives 166–168 in high yields (Scheme 44).

5. SYNTHESIS OF HYDROGENATED THIENOBENZAZOCINES One method for the synthesis of thienobenzazocines is bicyclization of N-thienylmethyl-N-arylmethylaminoethanal diethylacetal 169 with substituted aryl


107

Br

S NH

K 2CO3/ DMF

N

6N HCl

N S

S OCH3

S

163

160

Br

OCH3

S

S

158

S

N K 2CO3/ DMF

6N HCl

N

59%

S

S

164

OCH3 161

Br S

NH

S

S

S

N

S

6N HCl

OH

165

OH

159

162

Scheme 43

CH3 N S

S

166

96%

167

95%

168

90%

163 CH3 N i S S CH3 165

S N

61%

K 2CO3/ DMF

164

S

S

66%

S

N

S

i- KOH 30%(MeOH), reflux, atm.N2

Scheme 44

108


radicals in trifluoromethanesulfonic acid at room temperature. The corresponding thienobenzazocine 170 has been obtained in 85% yield (86CPB1888; Scheme 45). The cyclization of aminoethanal acetal can be carried out in various acids. Thus, 171a–c, produced by the alkylation of the corresponding N–H derivatives with meta-methoxy-substituted benzylhalides, transform into thieno[3,2-d][2]benzazocines 172a–c with 6N HCl (80H(14)321; Scheme 46). With compounds 173 and 159, the above method gives thieno[2,3-d][2]benzazocine isomer 176 (80H(14)321; Scheme 47). Cl

EtO OEt

CF3SO3H S

N Ar′

N

85% Ar′′

169

170

Ar′ = 2-thienyl Ar′′ = p-Cl-Ph

Scheme 45 R′

OCH3 R′′

N

R′ OCH3 N

6N HCl

R′′

R′′′ S

S

OMe OMe

R′′′ 172 (a-c)

171 a R′=R′′=R′′′=H b R′=R′′′=H R′′=CH3O c R′=R′′=CH3O R′′′=H

Scheme 46 OCH3

S

NH

S

N 41%

173

OCH3 OCH3

OCH3

OCH3 OCH3

S

N

174 S

NH

OH 159

S

176

OCH3

N

71%

OH 175

Scheme 47

109


By an analogous scheme, thienobenzazocine 172 has been synthesized from methoxytetrahydrothienopyridine 158, which undergoes further transformation into the vinyl derivative 177 under Hofmann conditions in quantitative yield (Scheme 48). Thieno[3,2-c][1]benzazocines 179 and 180 have been obtained by Beckmann rearrangement of benzo[4,3]cyclohepta[1,2-b]thiophen-4-one oxime 178 (71HCA283; Scheme 49). Thienobenzazocine 179 is formed regioselectively in 65–93% yield when the rearrangement is carried out in PPA or PPA in xylene. The use of H2SO4 or PCl5 gives a mixture of regioisomers 179:180 in ratios from 90:10 to 60:40. The Schmidt reaction forms only thienobenzazocine 179 in 25–65% yield from benzo[4,3]cyclohepta[1,2-b]thiophen-4-one 181 (Scheme 50). The same thienobenzazocine 179 is produced in 65% yield when O-tosyloxime 182 is boiled in acetone (Scheme 50). Azocine 183 can be synthesized in high yields by reduction of the carbonyl group in thienobenzazocine 179 by lithium aluminum hydride to a methylene group. N-Alkylation and N-acylation of azocines 179 and 183 carried out under

OCH3 NH

K 2CO3/ DMF 3-CH3O-C6H4CH2Cl

N 6N HCl

87%

S

S

OCH3

87%

OCH3

158 CH3 N

KOH 30% MeOH

OCH3 N

S

98% S

OCH3 177

172

Scheme 48

S

PPA S R

90 −130 °C

R

R

HN O

HON 178 R = H, Cl

S +

179

Scheme 49

NH O 180

110


S

NaN3, H2SO4

S

CH2Cl 2

R

S R

R

HN

N

O

O

O 181

179

Ts

182

R = H, Cl

Scheme 50

S R

S

LiAlH4 R

HN O

HN 183

179

NaNH2 ClR′

NaNH2 ClR′ S

S R

R

N R′

O 185

O

R′=CH2CH2NH2, CH2CH2NMe2, CH2CH2-N

N R′

184

, CH2CH2NHMe, (CH2)3NMe2,

O (CH2)3NEt2, (CH2)3NMe(Bn), COCH2Cl, COCH2CH2Cl, COCH2NHMe, COCH2-N

N Me

R = H,Cl

Scheme 51

the action of alkyl halides and chloroanhydrides in the presence of sodium amide, led to the formation of thienobenzazocines 184 and 185 (Scheme 51). Thieno[4,3,2-fg]benz[1]azocine 187 is produced in high yield (79MI397) from oxime 186 by Beckman rearrangement in PPA. Transformations of amide and thioamide groups of azocines 187 and 188, lead to derivatives 189–192, as shown in Scheme 52.

6. SYNTHESIS OF HYDROGENATED BENZOTHIENOAZOCINES A mixture of benzothieno[2,3-d]- and benzothieno[3,2-d]-azocines (194 and 195) is produced in 43% overall yield by the Beckmann rearrangement of the mixture of oxime isomers 193 with phosphorus pentoxide in dichloromethane (90JCS(P1)1083; Scheme 53).

111


HON

O

H N

PPA

H N

P2S5

87, 5%

66% S

S

S Et

186

188

187

Et

Et

EtO3BF4

CH3I

97%

OEt

SMe

56%

N

N 54%

PCl 5 NaN3 S

S

191 Et

Et N

CH2(CN)2 Cu

S

N 26%

N

N

NC CN

S

H N

190 Et

S

192 Et

Scheme 52

O OH

NH

N S P2O5

H N

194

43%

O

S 193 S 195

Scheme 53

189

112


7. SYNTHESIS OF FUROAZOCINES Few publications are available on the synthesis of furoazocines. Curtius reaction of ester 196 in benzyl alcohol leads to benzylurethane 197, which by hydrolysis and catalytic reduction gives amine 198 (72JCS(P1)878, 69JCS(C)2235). The primary amino group of compound 198 was converted into dimethylamino using the Eschweiler reaction, and then selectively quaterniz. Hofmann cleavage of this salt then leads to furo[4,3,2-fg]benzazocine 199 (Scheme 54). Later reports (81JCS(P1)1969, 73JCA(CC)657) describe [3,2] sigmatropic rearrangements of bicyclic quaternary salt 200 into allene 201, under the action of NaH in DMSO at room temperature. Allene 201 is converted into furoazocine 202 by prototropic rearrangement (Scheme 55). Cyclization (92ZN(B)1403) of 2-(N-pentenylaminopropyl)benzoquinone 203 in the presence of perchloric acid gives azocine perchlorate 204 (61%), from which azocine is isolated in 64% yield. The azocine ring closure takes place via nucleophilic addition of the enamine fragment to the benzoquinone ring (Scheme 56).

8. SYNTHESIS OF THIAZOLOAZOCINES Cyclization of azocane 2-oxo-3-p-methoxybenzamide 205 with phosphorus pentasulfide gives thiazolo[5,4-b]azocine 206 (94JHC877; Scheme 57). H3CO

H3CO BnOH O

H3CO i or ii

O

O NCH3

NCH3 H3CO

H3CO CO2Et 196

NCH3 H3CO

NHCO2CH2Ph 197

NH2 1) MeI exc. 2) Ag 2O, EtOH

198

H3CO

O i: HCl/EtOH ii: H2/Pd/C-10%

NCH3

OCH3 199

Scheme 54

113


NaH/DMSO

Br

N

N

N 99%

Ph

O

C

O

Ph

Ph

O

Me

200

201

202

Scheme 55

O

CH3

O

CH3

N H

HClO4 20 °C

O

NH

H3C

H3C

CH3

O O

O

203 CH3

H

ClO4

N

CH3

ClO4

OH

CH3 N

H3C O H3C

HO

H

O

CH3

CH3

O

204 61%

Scheme 56

H2/Pd/C

NaN3 Br DMF NH

O

N3 NH

O

NH

O

P2S5 N R NH

H N

RCOCl NH2 Et N/THF 3

EtOH

S

206 39%

Scheme 57

NH

R

OO

205 R = 4-MeO-C6H4

114


Isomeric hexahydro[1,3]thiazolo[4,5-b]azocine 208 is formed in the reaction between 3-bromo-2-oxoazocane 207 and thioamide in ethanol (96CPB2070; Scheme 58). An ingenious multi-step synthesis of oxo[1,3]thiazolo[5,4-f ]azocine 214 is based on the transformations of ethyl tetrahydro[1,3]benzothiazolyl acetate 209 (81CPB1780; Scheme 59). Under the action of methylamine, 209 cyclizes to thiazolo[4,5-e]indolone 210 which, through compounds 211 and 212, converts into quaternary salt 213. The key stage of the process is the efficient rearrangement of this salt into thiazoloazocine under the action of alcoholic base. Wittig reaction of azocine 214 with triphenylmethylenphosphane gives methylene derivative 215. In contrast, under Wolff–Kishner reaction conditions 214 was transformed into azocine 216a. Catalytic hydrogenation of the methylene

H N

O Br

H N

N

RCSNH2

R

EtOH

R = p-OCH3-C6H4

S

207

208

Scheme 58

CH3NH2 MeOH

S N H3C

O CH2CO2Et

78%

S OH N H3C

209

NCH3 210

p-TsOH PhMe

S N H3C

88%

O

NCH3

211

O LiAlH4

H S

Br

O N H3C

NCH3

Br

EtOH/NaOH S −10 °C N H3C

NCH3

72%

NCH3

N

O

96%

S N H3C

Br 213

S

Br 2 CH2Cl 2 −60 °C

CH3 214

Scheme 59

212

NCH3


115

group of compound 215 leads to a mixture of thiazolo[5,4-d]azocines 216b,c isomers in 75% yield (82CPB4378; Scheme 60). 2-Aza-2-benzoylbicyclo[3.3.1]nonan-8-one (217) has been used for the synthesis of isomeric thiazolo[4,5-c]azocine 221 (83CPB2094). Bromination of 217 in the a-position by pyridinium dibromide hydrobromide and condensation of bromoketone 218 with thiourea leads to aminothiazoloazocine 219. Successive deamination of 219, the removal of N-benzoyl protection and methylation gives the target azocine 221 (Scheme 61). [1,3]Thiazolo[5,4-c]azocine 228 was synthesized from 222 (Scheme 62). The process includes reduction of the carbonyl group of 222, dehydration of the alcohol 223 formed, reduction of the nitrile group, followed by the protection of

214

S

NCH3

N

CH2

NCH3

S

H2/Pd-C

R′ N

R CH3

CH3 215

216 a R=R′=H b R=CH3, R′=H c R=H, R′′=CH3

Scheme 60

S N Br 2

HBr

AcOH

O N

97%

Br

H2N THF

O

H2N N

79%

N

Bz

S

NH2

N

Bz

217

Bz 219

218

HNO2 Ca(H2PO2)2 1) HCl 2) HCHO-HCOOH

S

70%

N

S N

N

N

H3C

Bz

221

Scheme 61

220 63%

116


O S R N

CH2CN

222 a R=NH2 b R=Cl c R=H OH

222 c

S

NaBH4 EtOH

TsOH toluene

N

CH2CN 87%

N

223

Me

S

LiAlH4 THF

S

CH2CN

65%

NH2

N

224

225

N Me

N

R N

SR

CHCl 3

S

72%

N

NHR PhSeCl (CH2Cl 2), 0 °Ñ CF3CO2Ag 91%

226 Ph 3SnH toluene(dry) 99%

R N

S

SePh

N

227 Me N

S

LiAlH4 THF(dry)

S

N

84%

N

228 R = p-methoxybenzyloxycarbonyl

Scheme 62

the resulting amino group. N-Aryl-substituted dihydrobenzothiazole 226 is cyclized into thiazoloazocine 227 by benzeneselenenyl chloride. Successive deselenization of azocine 227 and reduction of the benzyloxycarbonyl group yield the target [1,3]thiazolo[5,4-c]azocine 228.

9. TANDEM ENLARGEMENT OF THE SIX-MEMBERED RING IN HETEROANNULATED TETRAHYDROPYRIDINES UNDER THE ACTION OF ACTIVATED ALKYNES – A GENERAL METHOD FOR THE SYNTHESIS OF CONDENSED AZOCINES Tetrahydropyrrolo[3,2-c]pyridines 229 undergo enlargement of the six-membered ring by dimethylacetylene dicarboxylate (DMAD) in acetonitrile, yielding pyrrolo[2,3-d]azocines in moderate yield (02TL6767; Scheme 63).

117


E

R R

2

N

R′ NH

DMAD

E

20−42%

R2

R R′

N

NH

R

R 229

230

R=Me or H, R′=H, COCF3, CHO, R2=Me or Bn, E=COOMe

Scheme 63

R3

MeOOC

R2 N

R1 N

N H

R

NH 1

N H

R 3

R

2

R

231

O

R

R

N

N

R1

233

232

R3 O N

R1

S 234

R2

N

R

R R1

O Ar

R2

235

Scheme 64

This reaction was later used successfully for the synthesis of annulated azocines including tetrahydroazocino[4,5-b] 231 – and azocino[5,4-b]indoles 232 (04EJO(14)3128), tetrahydropyrimido[4,5-d]azocines 233 (06TL999), tetrahydrobenzo[b]thieno[3,2-d]azocines 234 (05CH944) and tetrahydrobenzo[d]azocines 235 (06TL4585; Scheme 64). A plausible mechanism for the ring expansion (Scheme 65) proceeds via an intermediate zwitterion A, resulting from Michael addition of the tertiary nitrogen to the alkyne. Cleavage of the C(1)–N bond occurs via formation of the six-membered transition state B in which a molecule of alcohol facilitates the SN reaction. Some azocine derivatives, synthesized via this protocol, exhibited acetylcholinesterase (AChE) inhibitory activity (06MI7205). Thus, hydrogenated heteroannulated azocines, while relatively little known, are of interest for potential biological activity and their synthesis has attracted attention.

118


COOMe O

COOMe O R

N

R NH

N

R1

NH

N

MeOH

R1

N A

MeOOC

Me MeOOC

O H +δ1

O NH

O

R N +δ

NH R1

N

R

N

N

R1

233

B

Scheme 65

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98JOC7547 90TL3453 92JOC5792 85AQ277 85T2557 84H(22)561 85LA2073 83JNP206 83JNP211 01JOC5303 87MI377 83JNP200 82JHC1257 82TL4559 75JHC651 91H(32)107 83JHC1477 74JHC853 76HCA104 01JCS(P1)2774 87SC935 78JHC193 98SL1355 80H(14)325 86CPB1888 80H(14)321 71HCA283 79MI397 90JCS(P1)1083 72JCS(P1)878 69JCS(C)2235 81JCS(P1)1969 73JCA(CC)657 92ZN(B)1403 94JHC877

121

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96CPB2070 81CPB1780 82CPB4378 83CPB2094 02TL6767

04EJO(14)3128 06TL999 05CH944 06TL4585 06MI7205

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CHAPT ER

3 Metallacalixarenes: Organo-Inorganic Hybrid Molecular Architectures Subodh Kumar, Navneet Kaur and Harjit Singh

Contents

1. Introduction 2. Metallacalixarenes Derived from Nucleobases 2.1 General 2.2 Metallacalixarenes based on pyrimidine nucleobases 2.3 Metallacalixarenes based on purine nucleobases 3. Metallacalixarenes Derived from Model Heterocycles 3.1 General 3.2 Metallacalixarenes based on pyrimidines 3.3 Metallacalixarenes based on imidazoles and benzimidazoles 3.4 Metallacalixarenes derived from 2,2’-bipyrazine and 4,7-phenanthroline 4. Conclusions List of Abbreviations Acknowledgement References

123 126 126 126 131 150 150 150 157 165 169 170 171 171

1. INTRODUCTION The application of the concept of molecular recognition, the cornerstone of biological operations invoking biomolecular interactions, when extended into the realm of design of abiotic receptors of synthetic origin provides molecular architectures of functional materials having catalyzing, sensing, conducting, stabilizing, transporting, etc. abilities (95MI1). Among three generations of synthetic receptors, calix[n]arenes 1, a category of m-cyclophanes elaborating a cyclic array of aromatic phenolic rings joined at 1,3- positions by methylene bridges are marked for their ability to undergo structural diversifications and thereby display versatile binding characters. This uniqueness is characterized Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India Advances in Heterocyclic Chemistry, Volume 96 ISSN 0065-2725, DOI 10.1016/S0065-2725(07)00003-7


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R

R R

R

R

R

R

R

R OH

HO

HO

OH

OH

R partial cone

HO

R

R R cone

R

OH

OH OH

OH OH HO

OH OH OH HO

R

1,3-alternate

R 1,2-alternate

Figure 1 Conformations of calixarenes.

by: (i) a core of aromatic rings (p-electron rich cavity) providing p-cation, p–p, CHyp, etc. interactions, (ii) derivatization at rims generating varied possibilities of receptor designs capable of crown-type bindings, and (iii) tunability of the cavity with respect to its size (n ¼ 4, 5, 6,y), depth, and conformation such as a cone, partial cone, and 1,2-/1,3- alternate geometry (Figure 1, 98MI1). The replacement of phenolic unit(s) of calix[n]arenes by heterocyclic ring(s) constituting heterocalixarenes (e.g., 2 calix[4]pyrrole), further adds to their molecular recognition potential by enhancing an electron-rich (pyrrole) or imparting an electron-deficient (pyridine) cavity of p-electron character which can further be tuned by substitution and ring transformation reactions of the heterocyclic rings and by the influence of the heteroatom(s) (2005AHC67). The replacement of methylene bridges of a calix[n]arene by heteroatom(s) and of appropriate heterocalixarene by metal species provides, respectively, heteracalix[n] arene (e.g. 3 thiacalix[4]arene) (2004JOC1675) and metallacalixarene 4 ([Pt(en)UH-N1,N3]4+ 4 ; UH ¼ uracil monoanion and en ¼ 1,2-diaminoethane) (2001CCR219). The latter constitutes a self-assembled product of the monomeric complex cis[(en)Pt(H2O) (UH-N1,N3)]. Hence in the nomenclature ‘metallacalixarene’, it is presumed that for binding with a metallic specie, the organic linker would always be an appropriate heterocyclic ring and a metallacalixarene system would be a metal analog of a heterocalixarene. O NH2 Z

Z OH

NH

OH HO OH Z

N H

Z

Pt

HN H N

N O H2 N

N

OH N

NH2

N

HO N

OH N

N

NH2

O Pt NH2 H2N

O

2

Pt

OH

H2N Pt

1 Z = CH2 3Z=S

H2N

N

4

Metallacalixarenes

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Structurally, metallacalixarenes constitute organo-inorganic hybrids where heterocyclic organic species with appropriately oriented donor nitrogens are linked in a self-assembled manner with inorganic metallic species to form functional entities which being positively charged can show anion-sensing ability. The presence of heterocyclic moieties and other functionalities (QO, OH, NHR etc.) can induce interactions with additional metal ions. Due to the presence of metal ions, these materials can possess magnetic, optical, catalytic, and structural properties intrinsic to the metal ions and the rigid voids enable the reversible absorption of gases such as nitrogen and ammonia (2001JA383, 2003POL3051). Moreover, as in heterocalixarenes, changes in organic linkers in metallacalixarenes, can induce a varied flexibility (geometry) and nuclearity (tri-, tetra-, hexameric etc.) influencing their interactive capability. Evidently, these structural features empower metallacalixarenes to provide a category of synthetic receptors which holds unique promise in the creation of newer functional materials. In the comprehensive review on metallacalixarenes (2001CCR219, 99CCR653, 2005JSSC2436, 2002CCR199, 2003OM2166), in the absence of any rigorous nomenclature such as that in calixarenes (98MI1), the metallacalixarenes have been represented as their molecular units with an inbuilt provision for abbreviated heterocyclic component(s) with binding sites. Thus, the representation of 4 above indicates that four (en)PtII linkers are joined to four uracil moieties at their 1,3 positions to form the cyclic tetramer. For forming metallacalixarenes, 1,3-heterocycles having at least two angularly disposed ligating nitrogens (Figure 2) are employed and a prominent use has been made of nucleobases such as uracil, adenine, guanine, hypoxanthine etc. The model heterocycles 2,2u-bipyrazine and 4,7-phenanthroline having similar inbuilt angular ligating character have also been used. Thus metallacalixarenes derived from nucleobases and model heterocycles are categorized accordingly and discussed in separate sections. The presentation has also been titled and subtitled with respect to the various heterocyclic and/or metal component(s) used and the synthesis, structures, and binding characters of various metallacalixarenes formed from them have been elaborated.

1

1

N

N 3

3

N7

N1

9

3

N H Purine

N

N Pyrimidine

4

N

1

1′

N

N

N1 3

N H Imidazole 4

N

N H Benzimidazole 7

N

4′

N

2,2′-Bipyrazine

4,7-Phenanthroline

Figure 2 Structures of parent heterocyclic molecules used for elaborating metallacalixarenes.

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2. METALLACALIXARENES DERIVED FROM NUCLEOBASES 2.1 General Nucleobases have pyrimidine and purine (a combination of pyrimidine and imidazole) heterocyclic nuclei which have two ligating nitrogens placed in angular directions. The angular dispositions of pyrimidine, imidazole, and 1,7-purine nitrogens respectively being 1201, 1501, and 901 impart to these bases, heteroatom-induced endocyclic donor ability towards metals which drive selfassembly processes to form macrocyclic systems. The metallacalixarenes formed from nucleobases and various metal salts are discussed with respect to each base.

2.2 Metallacalixarenes based on pyrimidine nucleobases Uracil based ‘Pt Blues’, cis-[(en)PtCl(UH-N1)] formed from (en)PtCl2 and uracil (UH2), on reaction with aqueous silver nitrate (81IC4326) gave [(en)Pt(UH-N1) H2O]+ which tetramerized to cyclic complex [(en)Pt(UH-N1,N3)]4+ (5) and 4 crystallized as its nitrate salt (92JCS(CC)1385, 94JA616). Though similar PtII, PdII based cyclic products derived from the nucleobases guanine (92JA10647, 89IC2067) and theophyline (88AGE1160) were already reported, a clear-cut analogy of such a self-assembled chemical entity with a classical calixarene was drawn by Lippert for the first time. He assigned these systems the nomenclature ‘metallacalixarenes’ (92JCS(CC)1385, 94JA616). This contribution has focused attention and visibility on this category of organo-inorganic hybrid receptor systems in which the metal-binding endocyclic sites are invariably nitrogens preferably meta oriented. The abbreviation of a parent species shows the number of ionizable protons on nitrogen. On protonation or deprotonation the same abbreviation with increase or decrease in number of protons is given (Figure 3). The tetranuclear product 5 in its X-ray structure depicts a 1,3-alternating arrangement in which oppositely placed uracil pairs have identical orientation with their O(2) groups on the same side. The hydrogen bonds between O(2)–O(4) of adjacent uracil units impart stability to this arrangement. In its crystals, tetranuclear cations are stacked producing a long channel and nitrate anions connect the cations via H-bonds involving NH2 of (en). In solution 5 through rotation around a Pt–N bond by the uracil moiety through the annulus, achieves cone conformation 6 (1H NMR, X-ray). This phenomenon is influenced both by O

O HN 3 O

1

N H Uracil (UH2) Monoanion (UH) Dianion (U)

HN 3 1

6

CH3

N H Thymine (TH2) Monoanion (TH) Dianion (T) O

N NH

O HN1 3 NH S

NH2

Ligand (H2L1) Monoanion (HL1) Dianion (L1)

Figure 3 Structures of the pyrimidine nucleobases used in elaborating metallacalixarenes.

Metallacalixarenes

127

Figure 4 Effect of pH on conformational changes between 5 and 6.

the pH and the presence of additional metal ions (Figure 4). In aqueous NaOH at pH 8, 5 forms its freely water-soluble alkali adduct 7 which on heating at 40 1C is partially (66%) converted to cone conformation 8. This equilibrium is dependent on the nature of the base employed. Using Mg(OD)2 100% conversion to cone conformer 8 is observed. The adduct 8 on acidification affords 6 (cone conformation of 5) where its four C(2)–OH units act as proton donors and acceptors as in classical calixarenes. Despite its four-fold positive charge, metallacalixarenes 5 and 6 exhibit high basicity of the exocyclic O and react with metal cations in various stoichiometries depending on the nature of the metal ion and the original conformation of the metallacalixarene. 1,3-Alternate conformer 5 coordinates to four additional divalent metal ions to give octanuclear [(en)Pt(U-N1,N3,O2,O4)CuCl(H2O)2]4Cl4 (9) and [(en)Pt(U-N1,N3,O2,O4)M(H2O)3]4(SO4)4 (10) (Figure 5) (M ¼ a, Ni; b, Cu; c, Co; d, Zn) (97AGE1296, 2000EJI147). The X-ray structures of 9, 10b, and 10d show that the 1,3-alternate conformation of 5 is retained in the octanuclear complexes. In each one of these complexes, the uracil ring binds with four metal centers and carries PtII at N(1), N(3) and M at O(2), O(4) of two adjacent dianionic moieties. The uracil rings at opposite side are not exactly parallel. The spatial disposition of the four heterometals in the molecular box is 1,3-alternate, with a

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Figure 5 X-ray crystal structures of (a) [(en)Pt(U-N1,N3,O2,O4)CuCl(H2O)2]4Cl4 (9) and (b) [(en)Pt(U-N1,N3,O2,O4) M(H2O)3]4(SO4)4 (10) (M ¼ CuII, ZnII). (Reprinted with permission from 2000EJI147, Copyright 2000, Wiley.)

OH2

2+

H2O M

O

O O

(a)

2+

OH2 OH2

O N La O

O

O

O

O

O

O

(b)

Figure 6 Schematic presentation of cone conformers of (a) 12 and (b) 13.

˚ from the plane defined by the four platinum centers. displacement of ~1.9 A Similarly, 1,3-alternate conformer 5 with cis-PtII(NH3)2 and (en)PtII salts undergoes deprotonation of UH moieties to form [(en)PtUPt(en)/(NH3)2]8+ 4 which in the presence of an excess of NaCl or NaCN lose Pt units bound to O(4) and O(2). Despite the high thermodynamic stability of free [Pt(CN)4]2, the platinum units bound to N(1) and (N3) are not dissociated. In the presence of excess AgNO3, 5 forms an octanuclear complex [(en)Pt(UH)Ag]4(NO3)8 4H2O (11), which from its partially resolved X-ray structure has been assigned a pinched cone conformation where four AgI centers bind to the uracil O(2) donor atoms of the four uracil monoanions. On addition of NaCl, all four AgI dissociate to give 6. However, the cone conformer of [(en)Pt(UH-N1,N3)]4+ 4 , i.e. 6, on addition of one equivalent of ZnII, BeII, or LaIII salts undergoes deprotonation from four uracil units to form {[(en)PtU]4ZnSO4}(12a), {[(en)PtU]4Be}2+ (12b) and {[(en)PtU]4La}(NO3)3 (13) (Figure 6) (99IC426). 1H NMR and ESIMS show that in

Metallacalixarenes

129

the case of complexes 12a and 12b, the two exocyclic O atoms of the two base constituents are bridged by metal and the other two O are H-bonded via a coordinated water molecule thus stabilizing the cone conformation. In the case of 13, the tetradendate binding of LaIII to a cone conformer with nitrate anion binding at the exo side of the LaIII has been suggested by 1H NMR and mass spectral data (99IC426). Metallacalixarenes 6 and 12 having a cone conformation are capable of binding with RSO (R ¼ aliphatic or aromatic) anions in water. These 3 associations arise due to a cooperative effect between well-structured hydrophobic cavities and electrostatic interactions between positively charged cavities and the anionic guest (99IC426). In 13, coordination of LaIII to the cone causes flattening of the cavity incapacitating it for guest inclusion. All complexes with 1,3-alternate conformations and Pt4Ag4 complex (11) having a pinched cone conformation, despite their high positive charge do not incorporate anions because of the narrowness of the inner cavity. In unique distinction from classical calix[4]arene which is isolated in a cone conformation, the uracil–Pt based metallacalixarene 5 is isolated in a 1,3-alternate conformation and has a high affinity for metal ions despite its positively charged nature. Its cone conformer 6 as well as its further derived positively charged complexes 12 bind anions also (99IC426). The host–anion complexation is maximized when the stability of the metalated species is optimized. Thus 12a shows maximum interactions with anions at pH ~7.4 and remains stable between pH 3 and 8 and 12b shows anion complexation only at pHo5, a pH range in which 12b is stable. The cis-platin analog [(dpk)PtCl2], prepared by treating 2,2u-dipyridylketone (dpk) with K2PtCl4, on reaction with AgNO3 and subsequently with uracil or thymine gave pentanuclear PtII complexes [(dpk)2(dpkOH2)3Pt5(U)3](BF4) (NO3)3 8H2O (14), [(dpk)2(dpkOH2)3Pt5(U)3](PF6)(NO3)3 9H2O (15), and [(dpk)2 (dpkOH2)3Pt5(T)3](ClO4)2(NO3)2 8H2O (16). Here, the three dianionic nucleobases are bridged through three PtII(2), PtII(3), and PtII(5) centers chelated to (dpkOH2) to form the trinuclear calix[3]arene segment (2004AGE1300). The other two PtII centers are coordinated to the oxygen atoms of nucleobases, the other potential metal-binding sites. PtII(4) is bound through O(2) oxygens of nucleobases ‘a’ and ‘b’ and PtII(1) is bound through O(4) oxygens of nucleobases ‘a’ and ‘c’ (Figure 7). As a result, the nucleobase ‘a’ coordinates to four PtII centers utilizing all N- and O- donor atoms and two other nucleobases ‘b’ and ‘c’ coordinate to three PtII centers (Figure 7). The modified nucleobase H2L1, generated in situ from 2-thiouracil4-aldehyde and diethylene triamine, undergoes self-assembly with cobaltII trifluoromethane sulfonate to form a tetrameric species [Co(L1)]4+ 4 (CF3SO3)4 8H2O (17) (Figure 8). In this complex four nitrogens including the N(1) of uracil are coordinated to one cobalt whereas the other uracil N(3) and S are bound to an adjacent CoIII. The cyclic tetramer constitutes a highly extended form of metallacalixarene where the uracil nitrogens are linked through CoIII (94JCS(CC)1773). It elaborates a columnar cavity at its centre with adjacent Co–Co ˚. separation of 5.54 A

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Figure 7 X-ray crystal structure of [(dpk)2(dpkOH2)3Pt5(U)3]4+ (14). (Reprinted with permission from 2004AGE1300, Copyright 2004, Wiley.)

Figure 8 ORTEP diagram of [Co(L1)]4+ 4 (CF3SO3)4 8H2O (17). (Reprinted with permission from 94JCS(CC)1773, Copyright 1994, Royal Society of Chemistry.)

131

Metallacalixarenes

2.3 Metallacalixarenes based on purine nucleobases Purine nucleobases having four inbuilt endocyclic nitrogens [N(1), N(3), N(7), N(9)] and additional exocyclic oxo, amino, or thione moieties at positions 2 and/or 6 (Figure 9) display versatile ligating abilities towards metal ions and generate a variety of new chemical entities. For forming metalla macrocycles, various combinations of two nitrogen sites mostly at positions 1,7; 7,9; 3,9 and in some cases even three nitrogen sites of purine bases react with metal salts, their complexes, or organometallics. However, further cooperative binding with additional exocyclic O, N, or S is also realized. Here, various modes of

N N R

NH2

N

N

N 18

O− MeO P O 19G R = O

O HO

(5′-MeAMP)

O NH

N

19A R = H(AdH) 19B R = Me(9-MeAd) 19C R = allyl(9-allAd) 19D R = Et(9-EtAd)

N 19

R

18A R = H (PuH) 18B R = Me (9-MePu)

N

N

N

N

NH2

R

20 20A R = H (GuH2) 20B R = Me(9-MeGuH) 20C R = ribose(Guo)

OH

OH

O− 19E R = −O P O (5′-AMP) O

HO O

OH

OH

19F R = (3′-AMP)

HO O

HO

(

HO O− O O P O 19H R = O (5′-ADP) O P O− HO O− − O O O P O 19I R = O (5′-ATP) O P O− HO 2 − O

O

19D R = (Ado)

HO

OH

O− O P O− O

O

N

NH

N R

N

21

N H

21A R = H (HxH2) 21B R = Me (9-MeHxH) O− O P O O (5′-IMP)

21C

S

O

N

−

N N Me

23 23 (ThpH)

O

Me

N

O

N R

NH

N

R′

22

22A R, R′ = H (6-PutH2) 22B R = H, R′ = NH2 (6-PutH2A2) 22C R = H, R′ - OH (6-PutH2O2) 22D R = ribose R′ = H (6-PutHrb)

OH HO

21D

(

O− O O P O O O P O− HO 2 − O

(5′-ITP)

OH

Figure 9 Structures of the purine nucleobases used in elaborating metallacalixarenes.

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S. Kumar et al.

interactions of purine 18 (PuH), adenine 19 (AdH), guanine 20 (GuH2), hypoxanthine 21 (HxH2), 6-thiopurine 22 (6-PutH2), theophylline 23 (ThpH) (Figure 9) with metal ions resulting in the formation of metallacalixarenes of varied nuclearity are detailed. With multiple possibilities of combinations of coordinating sites, the binding modes of purine bases and the nuclearities of their metallacalixarene products, depend mostly on the coordination geometries of the linker metals. Hence the presentation has been sub-classified in respect to metal coordinatives, discussed in the order Pt, Pt–Ag, or Pt–Hg, Pd, Ag, Cu, Cd, and Co and various organometallics.

2.3.1 Metal coordinatives The reaction of the sodium salt of theophylline with [Me3Pt(H2O)3]2SO4 (24) in water formed a trimeric product [Me3Pt(Thp-N7,O6;N9)]3 (25) (Figure 10a), m.p. 110 1C (79JCS(CC)324). This structure has been postulated on the basis of its 1H NMR and osmometrically determined molecular weight. On refluxing K(Thp) and 24 in water, the product [Me3Pt(Thp-N7,O6;N9)]6 (26), m.p.W215 1C, was formed. In its X-ray structure (Figure 10b), 26 revealed a hexameric metallacalixarene species in which Me3Pt groups are coordinated in a cis fashion to N(7) and N(9) of the two neighboring thp monoanions. The interaction of O6 of thp with PtIV completes its distorted octahederal coordination (88AGE1160). 6-Thiopurines 22A–22C on reaction with [(tacn)CoCl3], in presence of sodium hydroxide, undergo deprotonation to produce initially monomeric [(tacn)Co (22-N,S)Cl]+ which on subsequent deprotonation undergo self-assembly to form trimeric and/or tetrameric complexes (Scheme 1). Whereas 22A forms a mixture

Figure 10 (a) The postulated structure of 25 (b) X-ray crystal structure of [Me3Pt (Thp-N7,O6;N9)]6 (26). (Reprinted with permission from 79JCS(CC)324, Copyright 1979, Royal Society of Chemistry; 88AGE1160, Copyright 1988, Wiley.)

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Metallacalixarenes

N N N

HN

N

Cl Co

N

+ Cl

Cl

S HN

N NaOH N

N

N

N Self-assembly

Co N

N

S Cl

N

N

Co

Co

N

N

N

N

S N

NaOH

N

N Co

N N

S

n

27 n = 3 28 n = 4

Scheme 1

Synthesis of trimer 27 and tetramer 28.

Figure 11 X-ray crystal structure of tetramer [(tacn)Co(6-put-N7,S6;N9)]4+ 4 (28A). (Reprinted with permission from 98IC5611, Copyright 1998, American Chemical Society.)

of trimeric [(tacn)Co(6-put-N7,S6;N9)]3+ (27) and tetrameric [(tacn)Co(6-put3 N7,S6;N9)]4+ (28A) complexes, both 22B and 22C give tetrameric [(tacn)Co 4 4+ (6-putA2-N7,S6;N9)]4+ 4 (28B) and [(tacn)Co(6-putO2-N7,S6;N9)]4 (28C), respectively (98IC5611). The X-ray structures of 28A (Figure 11) and 28B reveal that all these thiopurines act as tridentate ligands via S, N(7), and N(9); where S and N(7) bind to one CoIII and are bridged to another CoIII through N(9).

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In neutral aqueous solution, cis-[(PMe3)2Pt(m-OH)]2(NO3)2 reacts with 9-MeGuH (20B) to form a mixture of products from which a cyclic hexamer cis-[(PMe3)2Pt(9-MeGu-N1;N7)]6(NO3)6 18H2O (29) was crystallized (95IC1745). In the X-ray structure of 29 (Figure 12), six cis-(PMe3)2PtII units are symmetrically bridged by deprotonated guanine ligands through their N(1) and N(7) atoms. The purine rings are alternately disposed above and below the mean plane passing through the metal atoms and the adjacent metal atoms are disposed ˚. alternately in two parallel planes separated by 0.34 A Using metal entities such as trans-a2PtCl2 (a ¼ NH3 or CH3NH2) or AgI or Hg(NO3)2 displaying linear coordination geometries, metallacalixarenes having the same or mixed nucleobases as well as metal bridges have been reported. Lippert (98IC5044) crosslinked two cations trans-[(NH3)2Pt(9-MeAd-N7) (9-MeGuH-N7)]2+ (30) by trans-(CH3NH2)2PtII through the N(1) position of 9-MeAd (19B) units to form U-shaped trinuclear trans,trans,trans-{(CH3NH2)2Pt

Figure 12 X-ray crystal structure of the cation of cis-[(PMe3)2Pt(9-MeGu-N1;N7)]6 (NO3)6 18H2O (29). (Reprinted with permission from 95IC1745, Copyright 1995, American Chemical Society.)

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(-9-MeAd-N1;N7)2[(NH3)2Pt(9-MeGuH-N7)]2}(NO3)6 6.25H2O (31) (Scheme 2, Figure 13a). Intramolecular H-bonding between exocyclic N(6) and O(6) groups of the two purines remains as observed in the case of starting compound 30. However, in solution, 31 exists in an equilibrium between U and S forms (1H and R1

H3C N

N

N H2N

N H

Pt N

R1 O N H2 30

N CH3 N

+

N

CH3 N N

R2 Cl Pt Cl R2

CH3 N N

N R2 CH3 R2 N CH3 N N N Pt N 1 N Pt N N R N R1 R2 R2 Pt 1HN Hg(NO3)2 Pt 1 NH2 Hg NH N N R H2N R OH 1 N 2 R1 O H2O R 1 N O Pt R1 O R Pt O N N N N Hg N N H3C H3C NH N HN N N N NH Hg HN N NH2 N H2N CH3 CH3 ONO2 32 31 R1 = NH3; R2 = CH3NH2

Scheme 2

Synthesis of 31 and 32.

(a)

(b)

Figure 13 X-ray crystal structures of the cations of (a) trans,trans,trans-{(CH3NH2)2Pt(-9-MeAdN1;N7)2 [(NH3)2Pt(9-MeGuH-N7)]2}(NO3)6 6.25H2O (31) and (b) trans,trans,trans-{(CH3NH2)2PtHg (H2O)2 [(9-MeAd-N1,N6;N7)(NH3)2Pt(9-MeGu-N1,N2;N7)]2Hg2(ONO2)} (NO3)5 13H2O (32). (Reprinted with permission from 98IC5044, Copyright 1998, American Chemical Society.)

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Pt-NMR data) with rotation about the Pt(2)–9-MeAd–N(1) bonds. Complex 31, on reaction with Hg(NO3)2 in aqueous solution, formed quantitatively the mixed metallacalixarene trans,trans,trans-{(CH3NH2)2PtHg(H2O)2[(9-MeAd-N1,N6;N7) (NH3)2Pt(9-MeGu-N1,N2;N7)]2Hg2(ONO2)}(NO3)5 13H2O (32) (Scheme 2, Figure 13b). In this process, the guanine undergoes di-deprotonation at N(1) and its exo-NH2 and adenine undergoes deprotonation at its exo-NH2 to form respective 9-MeGu and 9-MeAd. One HgII crosslinks (with deprotonation) N(1) positions of two 9-MeGu and two additional HgII ions ligate the exocyclic NH of either two 9-MeGu or two N-MeAd. Uniquely, here 9-MeGu is linked through the three nitrogens N(1), N(2), and N(7) and this approach unlike selfassembly involves cyclometallation of a U-shaped precursor 31. Ignoring the extra HgII ions bound to the exocyclic groups of nucleobases, nuclear three PtII, and one HgII bridges generate a molecular rectangle, a variant of molecular squares which utilize cis metal entities and colinearity of suitable ligands in their formation (98IC5044). 1H and 195Pt NMR studies also verify the cyclic structure in solution. Another interesting mixed rectangular tetrameric metallacalixarene from 9-MeAd (19B), 9-MeHxH (21B), trans-(NH3)2PtII, and AgI involving pairwise N(1),N(7)–PtII and N(1),N(1)–AgI coordination is reported (2002SupC189). The complex trans-[(NH3)2Pt(9-MeAd-N7)(9-MeHxH-N7)](NO3)2 H2O in the presence of AgNO3 in aqueous solution undergoes deprotonation at N(1) of 21B and the resulting specie undergoes cyclodimerization to form trans[{(NH3)2Pt(9-MeAd-N1;N7)(9-MeHx-N1;N7) Ag(NO3)(H2O)}2Ag](NO3)3 6H2O (33) (Figure 14) which is further coordinated intermolecularly by AgI ions to form an infinite array of quartets. The water molecules are located between adjacent quartets and adopt a cyclic water hexamer structure in a chair conformation (2002SupC189). 9-Methylpurine (18B) and trans-[(NH3)2Pt(OH)Cl] H2O (34) in HClO4 formed the 1:1 complex trans-[(NH3)2Pt(9-MePu-N7)Cl]ClO4 (35), which in the presence of AgNO3 through self-assembly provides a mixture of a molecular square [trans-{(NH3)2 Pt(9-MePu-N1;N7)}]4(ClO4)8 6H2O (36) and a molecular triangle [trans-{(NH3)2Pt(9-MePu-N1;N7)}]3(ClO4)6 3H2O (37) in 0.6:1 ratio (1H NMR) (Scheme 3). By using sulfate anions as template, this ratio changes to 2.5:1 with an enhanced rate of formation of 36 and 37. In the X-ray structures (Figure 15) of both 36 and 37, the purine ligands and PtII atoms are essentially coplanar and the amine ligands are perpendicular to this plane. The tetramer 36 represents the first example of a true purine square with four metal entities at the periphery and alternate N(1),N(7) coordination. Both these compounds have affinity for sulfate anions which is more pronounced in case of 36 (Ka ¼ 7.271.2 104 M1) than in 37 (Ka ¼ 9.970.6 103 M1) (2006AGE147). An unprecedented tetrameric metallacalixarene derived from a single nucleobase 9-allAd (19C) and a single intervening AgI ion and which is embedded in a unique polymeric network, [Ag(9-allAd-N1;N3,N7)]x(NO3)x (38), has recently been reported (2006JA400). The crystalline product 38, obtained in a meticulously performed reaction of 19C with AgNO3 in 50% aqueous methanol, in its X-ray structure (Figure 16) revealed a distorted rectangle where four 19C

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Figure 14 X-ray crystal structure of the cation of trans-[{(NH3)2Pt(9-MeAd-N1;N7) (9-MeHx-N1;N7)Ag(NO3)(H2O)}2Ag](NO3)3 6H2O (33). (Reprinted with permission from 2002SupC189, Copyright 2002, Taylor and Francis Inc.)

molecules are linked to intervening AgI ions atoms consecutively through their N(7),N(1); N(7),N(3) sites. Each silver bridge is further tethered to an additional adenine unit through the third endocyclic nitrogen and thus is coordinated to three different endocyclic nitrogens N(1), N(3), and N(7) of three 9-allyladenine molecules (2006JA400), a rare case of the 3N coordination mode of a 9-substituted adenine. The interactions of guanosine and its monophosphate with [(en)Pd(NO3)2] in D2O, when spectrally monitored, supported the formation of tetrameric adducts having N7–Pd–N1 linkages between adjacent guanine rings (89IC2067). The formation of a similar adduct was noticed in the reaction of [(en)Pd(NO3)2] with inosine monophosphate. Hydrogen bonding from amino groups of en and phosphate groups stabilized these adducts (89IC2067). The reaction of adenine and silver perchlorate in HClO4 gave the first cyclic diadeninium disilver perchlorate monohydrate [Ag2(1-AdH+2 -N3;N9)2](ClO4)4 H2O (39) which may be visualized as the smallest and earliest known dimeric metallacalixarene system (77IC2469). In the X-ray structure of 39 (Figure 17), silver bridging is evident at N(3) and N(9) sites and N(3)–Ag–N(9) angle is 164.11. Adenine (19A) (73IC1166, 69AX(B)1480, 71JCS(A)2167) and hypoxanthine (21A) (70AX(B)1609) have been found to react with CuII salts to form robust 3D systems which display a confluence of two dimeric metallacalixarenes bridged

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NH3

NH3 OH2

H2O

H3N Pt

H3N +1

Pt NH3

H3N

−H2O

Pt

N N

N

+1

N

N

H3N

Pt

N NH3

N N

N

Pt

N NH3

N

H3N

N

N

Pt

H3N

H3N

Pt

NH3

N

N N

H3N

NH3

N

N

Pt

−H2O

N

N

N

N

H3N

−H2O

NH3

N

N

Pt

N

N N

NH3

NH3

N

N

N

N

N

N

N

N

Pt

N

H3N

−H2O

N

N

H2O N

X2

N

N

N

H3N

NH3 N

Pt

N

37

H3N Pt

N N

NH3

NH3 N

N

N

N

N

H3N

N

36

Scheme 3 Synthesis of tetramer 36 and trimer 37.

around CuII. Both nucleobases act as bidentate ligands and bind to CuII via their N(3) and N(9) nitrogens. In the X-ray structure of [Cu2(AdH-N3;N9)4(H2O)2] (ClO4)4 (40) (Figure 18) formed from 19A and copper perchlorate at pH 4, each CuII is surrounded by two N(3) and two N(9) atoms, one from each of the four different adenine molecules and one oxygen atom of a water molecule (73IC1166). Thus 40 represents a confluence of two dimeric metallacalixarenes having common CuII bridges, in which four nitrogen atoms coordinated to a given CuII are coplanar but the metal is displaced from that plane. The perchlorate anion and the lattice water molecules are held together in an intricate network of hydrogen bonds. Similar structures had earlier been proposed for [Cu2(Ad-N3;N9)4(H2O)2]6H2O (69AX(B)1480) and [Cu2(AdH-N3;N9)4Cl2]Cl2 6H2O (71JCS(A)2167). Hypoxanthine and copper chloride in aqueous HCl at pH 4 form [Cu2(HxH2)4Cl2]2Cl2 6H2O (41) (70AX(B)1609), the X-ray structure of which is similar to its AdH analog 40. The reaction of monosodium salt of adenosine-5u-monophosphoric acid (19E) (AMP) with cadmium nitrate in the presence of nitric acid formed a binuclear

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Figure 15 X-ray crystal structure of the cations of (a) [trans-{(NH3)2Pt(9-MePu-N1;N7)}]4 ClO4)8 6H2O (36) and (b) [trans-{(NH3)2Pt(9-MePu-N1;N7)}]3 (ClO4)6 3H2O (37). (Reprinted with permission from 2006AGE147, Copyright 2006, Wiley.)

Figure 16 X-ray crystal structure of polymeric [Ag(9-allAd-N1;N3,N7)]xx+ (38). (Reprinted with permission from 2006JA400, Copyright 2006, American Chemical Society.)

complex [Cd(AdH+2 -N3;N9)(NO3)2 H2O]2(NO3)2 (42). Its X-ray structure (Figure 19; 81IC356) shows water bridged nitrated cadmium atoms each of which is coordinated to the N(3) atom of one adenine moiety and to the N(9) of a centrosymmetrically related second adenine moiety. The water molecules in this

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NH2 H

N

H N

N N Ag Ag N N N

N H

H

NH2 39

[Ag2(1-AdH+2-N3;N9)2](ClO4)4 H2O

Figure 17 X-ray structure of from 77IC2469, Copyright 1977, American Chemical Society.)

(39). (Reprinted with permission

Figure 18 X-ray crystal structure of the cation of [Cu2(AdH-N3;N9)4(H2O)2](ClO4)4 (40). (Reprinted with permission from 73IC1166, Copyright 1973, American Chemical Society.)

structure serve as bridging ligands connecting two cadmium atoms. Each nitrate ion not bound to the metal is attached to the dimeric cation as a hydrogen bond acceptor and all hydrogens of the adenine ring as well as those of water molecules appear to participate in this network of hydrogen bonds. A comparison of these nucleobase-derived metallacalixarenes with natural nucleobase-derived tetrands may be advisable. In the non-natural quartets formed by interconnection of uracil, purine or its derived nucleobases with coordinative metals, the cationic character lies on the metals in the periphery and anions are bound in the cavity. In natural tetrands of these nucleobases, the hydrogen bonds interconnect the bases and the structures are stabilized by a cation located in the centre whereas phosphate groups located in the periphery carry negative charge (2005AGE668). As against the existence of only natural

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Figure 19 X-ray crystal structure of the cation of [Cd(AdH+2-N3;N9)(NO3)2 H2O]2(NO3)2 (42). (Reprinted with permission from 81IC356, Copyright 1981, American Chemical Society.)

quartets, metallacalixarenes with different nuclearity (dimer, trimer, hexamer etc.) are also realized in the non-natural mode.

2.3.2 Organometallics The interactions of nucleobases with metal complexes as a consequence of the drug activity potential of the resulting products have been extensively investigated. In quite a few cases because of the availability of angular ligating profiles, the products have cyclic organo-inorganic hybrid structures constituting metallacalixarenes. In a similar manner, the use of organometallics in triggering self-assembly with appropriate nucleobases to constitute corresponding metallacalixarenes has been argued and investigated. Fish et al. (2003OM2166) pioneered these investigations and are responsible for initiating and advocating a focused attention of practitioners of organometallic chemistry towards this intriguing

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new area of bioorganometallic chemistry. The reactions of Rh, Ru, and Ir based organometallics with nucleobases, reported so far, are detailed here in respect to the metallic linkers.

2.3.2.1 Rhodium organometallics. The water soluble (Z5-pentamethylcyclopentadienyl)-rhodium aqua complex [CpRh(H2O)2(OTf)2]x (43) reacts with 9-MeAd (19B) in D2O at pD 7.2 to form an unprecedented racemic trimeric metallacalixarene [CpRh(9-MeAd-N1;N6,N7)]3(OTf)3 (44) (Figure 20) (92JA10647). The X-ray structure of one of its enantiomers shows each CpRhIII bound to N(1) and N(6), N(7) of adjacent 9-MeAd monoanions. It displays a triangular dome like structure with three Cp groups stretching out from the top of the dome, three Me groups pointing to the bottom, three 9-MeAd planes forming the surrounding shell and three RhIII cations embedded in the top of the dome. The formation of this 12-membered cyclic trimer is evidently triggered by the ability of the CpRhIII cation to act as an azaphile with a favorable geometry of N(1) poised to form the third bond to CpRhIII of an adjacent [CpRh(9-MeAd-N1;N6,N7)](OTf) moiety. The 1H NMR spectrum of 44 shows the upfield shift of H(2) and downfield shift of H(8) signals of 9-MeAd moieties, as compared with the parent system. This parameter constitutes a convenient diagnostic tool for monitoring the formation and structural assignment of analogous trimeric cyclic metallacalixarene systems (92JA10647). The reaction of 43 with adenosine (Ado) in H2O at pH 7.1 provided a complex which could not be purified. Its 1H NMR analysis showed it to be a mixture of two

Figure 20 (a) Schematic presentation of 44 (R ¼ Me) (b) X-ray crystal structure of the cation of [CpRh(9-MeAd-N1;N6,N7)]3(OTf)3 (44). (Reprinted with permission from 92JA10647, 95JA3631, Copyright 1992 and 1995, American Chemical Society.)

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diastereomers of trimeric cyclic metallacalixarene [CpRh(Ado-N1; N6,N7)]3(OTf)3 (45) (92JA10647, 96JA4993, 93IC4119). Similar reactions of 43 with 2u-deoxyadenosine and 2u,3u-dideoxyadenosine gave respective trimers 46 and 47 in good yields (95JA3631, 96JA4993). Adenosine 5u-monophosphate (19E, 5u-AMP) and 43 formed a mixture of mononuclear and dinuclear complexes and diastereomers of trimer in low yields (93IC4119). 1H and 31P NMR spectra of the mixture showed that 5u-P(O)2QO group because of its competition with N(1) and NH(6) for CpRhIII site significantly inhibited cyclic trimer formation. Further, the methylation of the 5u-phosphato group in 19G (5u-MeAMP), mitigated such a competition and on reaction with 43 formed only the cyclic trimer [CpRh(5u-MeAMP-N1;N6,N7)]3(OTf)3 (48) (93IC4119). On prolonged equilibration at pH 7.7, time-dependent 1H NMR monitoring showed the enhancement of the ratio of diastereomers of 48 from 1:1 to 6:1. Such diastereoselectivity differences among 19D, 19E, and 19G based trimers could be attributed to a more pronounced steric effect of the ester group on ribose which dramatically allowed resolution of one trimeric diastereomer in preference to the other to occur over time by equilibration between the two possible forms. The reaction of 43 with 3u-AMP (19F), a positional isomer of 5u-AMP formed mainly the cyclic trimer, and only a minor amount of a dimer (93IC4119). So both methylation of one of the oxygens of –P(O)2QO or moving it away from N(7) and NH(6) prevented its competition for reaction at the RhIII center and favored trimer formation. The trimer 46 has found utility as a new aqueous 1H NMR shift reagent via a host– guest molecular recognition process by non-covalent p–p and hydrophobic interactions with a variety of water-soluble organic substrates (98JOC7151). On 1H NMR monitoring of the reaction of nicotine adenine dinucleotide (NAD+), an important co-factor in enzymatic reactions, with 43 at pH 6, the formation of two unique diastereomeric cyclic trimeric metallacalixarene systems 49, in a self-assembly mode, was evident (1999JOM(589)66). These products have a narrow stability range at pH 6 and decompose at lower or higher pH. The complex 49 was neither electroactive nor it was possible to convert it to the corresponding NADH-based system (1999JOM(589)66). The molecular recognition ability of these unique adenine based organometallic metallacalixarene hosts for some biologically important guests has been extensively investigated using complexation induced 1H NMR chemical shifts of both the guests and hosts, markedly in aqueous medium at pH 7.2 (96JA4993, 95JA3631). The cyclic trimers 44–48 recognize aromatic amino acids and several aliphatic amino acids with relatively long hydrophobic side chains by invoking p–p and/or hydrophobic host–guest interactions. It is further realized that molecular recognition of amino acids occurs inside the cavities of the hosts and hydrogen bonding, steric, conformational, and electronic factors also influence the recognition process (96JA4993, 95JA3631). In an intriguing study, in order to understand the role of water in the above molecular recognition modes, soft electrospray ionization mass spectrometry has been used to extend the same interactions in the gas phase for all the above hosts and guests (97CC2135). In a subtle comparison using L-tryptophan as the guest, it was found that just as in water, 46 was also the best host in the gas phase. The recognition process

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here is found to occur predominantly via non-covalent p–p interactions whereas hydrophobic forces apparently remain weak or non-existent. Guanosine (20C, Guo) reacted with 43 at pH 5.4 to provide a monomeric complex [CpRh(Guo)(H2O)(OH)](OTf) (92JA10647). The bonding differences between Ado and Guo for 43 reflect on the geometry of N(7) and exocyclic NH2(6) positions for 5-membered ring chelate formation via a condensation reaction of the exocyclic NH2(6) group with a reactive CpRh hydroxyl species (92JA10647). In order to delineate the steric role of NH2(2) and any role of the carbonyl group at C(6) and pH, the reactions of 43 with 9-ethylguanine and 9-methyl/ethylhypoxathine were studied. The reaction of 9-ethylguanine with in situ generated [CpRh(MeOH)3](OTf)2 formed [CpRh(9-EtGu-N7)(CH3OH)2] (OTf)2, invoking exclusive N(7) binding. The lack of cyclic trimer formation even over a pH range (93IC4677) clearly implied a dominant steric role of the exocyclic NH2(2) in inhibiting cyclic trimer formation. 9-Methylhypoxanthine (21B), like 9-ethylguanine also formed [CpRh(N79-MeHxH)(CH3OH)2](OTf)2. Its N(7) coordination mode was verified by its X-ray structure. The 1H NMR monitoring of its aqueous solution over a pH range showed that at pH 6.45, this complex changes to an unprecedented cyclic trimer [CpRh(9-MeHx-N1;N7,O6]3+ 3 (50) (Figure 21) (93IC4677) but it could not be isolated. It invoked (N7, O6) 5-membered ring formation, where the C6 carbonyl on 9-MeHx facilitated cyclometallation like C6-NH2 of Ado (93IC4677). However, at pH 10.2 a dimer [{CpRh[Z1(N1)-9-MeHx](m-OH)}2] was formed. Its X-ray structure displayed a unique N(1) binding mode for 9-MeHx and intramolecular hydrogen bonding between OH groups and O6 of nucleobase (95AGE1514). The reaction of 9-ethylhypoxanthine with 43 at pH 6.1 formed the trimeric metallacalixarene [CpRh(9-EtHx-N1;N7,O6)]3(OTf)3 (51). Its X-ray structure

Figure 21 Solution phase structure of 50. (Reprinted with permission from 93IC4677, Copyright 1993, American Chemical Society.)

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displayed a triangular dome like cavity where three Cp groups stretch out from the top of the dome, three ethyl groups point to the bottom, three hypoxanthine planes form the surrounding shell, and three Rh atoms are embedded on the top of the dome (95AGE1514). The self-assembling reaction between 43 and 6-thiopurine ribose (22D, 6-PutHrb) having a ligating skeleton similar to adenosine except that NH2(6) of adenosine is replaced by a thione group, forms a hexanuclear metallacalixarene system [CpRh(6-Putrb-N1;N7,S6)]6(CF3SO3)6 (52). Its X-ray structure reveals coordination by N(1) and N(7) of neighboring molecules of 22D and the thione S binds Rh to form a five member chelate ring. Six RhIII ions are crystallographically independent and six purine rings are arranged on the six planes of a cube, thus forming an unprecedented cubic cavity. Three ribose groups collect together towards each side of the longest cubic diagonal (2001AGE2268).

2.3.2.2 Ruthenium organometallics. Adenine (19A) and [(Z6-C6H6)RuCl2]2 (53) in a 2:1 molar reaction in aqueous solution formed a tetrameric product [(Z6-C6H6)RuCl(AdH-N7;N9)]4Cl4 (54). Its X-ray structure showed an N(7), N(9) bridging mode of adjacent adenine ligands. In the reaction of 6-methylaminoadenine (6-MeAdH) with 53 in methanol in the presence of sodium methoxide, analogous metallacalixarene [(Z6-C6H6)RuCl(6-MeAdN7;N9)]4 (55) was formed (93ICA15) (Figure 22). The reaction of [(Z6-p-cymene)RuCl2]2 (56) with adenine in water formed the tetrameric system [(Z6-p-cymene)Ru(Ad-N6,N7;N9)]4(CF3SO3)4 (57). In its X-ray structure (Figure 23a), 57 exhibits crystallographic S4 symmetry and N(9) and N(6), N(7) bridging modes for the adjacent adenine ligands with Ru linkers. The observation of N(7), N(9) bridging in 54 and 55 suggests that initial displacement of N(9) proton by Ru linker fragment might be leading to enhancement of the basicity of the second imidazole nitrogen N(7). In the absence of any other suitable ligand, metallation of N(6) through formation of a 5-membered ring provides additional stabilization of N(7), N(9) binding (97ICA85). The N(6) metallation also causes an upfield shift (1H NMR) of the adenine ring protons as compared with the free base. This unique N(9); N(6), N(7) binding mode prompted investigation of N(9) substituted adenine derivatives with RuII linkers. Similar reaction of 56 with 9-EtAd (19D) formed a trinuclear system [(Z6-cymene)Ru(9-EtAd-N1;N6,N7)]3(CF3SO3)3 (58) (97ICA85). Its X-ray structure (Figure 23b) showed that N(6),N(7) participate in formation of a five-member chelate ring and due to the non-availability of N(9), the N(1) of the adjacent nucleobase coordinates with RuII to form the trinuclear cation with N(1); N(6),N(7) bridging mode. A similar binding mode has been also observed in 44 (92JA10647). Trimer formation is accompanied by dramatic chemical shifts in H(2) (downfield) and H(8) (upfield) protons of 9-EtAd moiety in 58 in comparison to free 19D. The 1H NMR monitoring of the progress of the reaction also provides conclusive evidence for similar formation of trimeric adenosine complex [(Z6-C6H6)Ru(Ado)]3(CF3SO3)3 (59) from reaction of 56, adenosine, and Ag(CF3SO3) (97JCS(DT)2191).

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Figure 22 X-ray crystal structure of [(Z6-C6H6)RuCl(6-MeAd)]4 (55). (Reprinted with permission from 93ICA15, Copyright 1993, Elsevier.)

In reactions of (Z6-arene)RuII fragments with nucleotides, macrochelation involving additional bindings with phosphate oxygens could compete with cyclic self-assembled oligomer formation. The reaction of [(Z6-p-cymene)Ru(Me2CO)3]2+ with 5u-H2AMP in acetone gave [(Z6-p-cymene)Ru(5u-HAMP)]3(CF3SO3)3 which on slow evaporation of its aqueous solution formed crystals of [(Z6-pcymene)Ru(5u-AMP-N1;N6,N7)]3 7.5H2O (60) (97JCS(DT)2191). The X-ray structure (Figure 24) of its RusRusRus diastereomer established a pronounced degree of conformational flexibility in the sugar and phosphate residues. In the 1H NMR monitored reaction of [Ru(Z6-C6H6)(D2O)3]2+ with 5u-AMP (19E), in the pH range 3.30–9.18, the predominant formation of cyclic trimers of the type [(Z6C6H6)Ru (5u-AMP-N1;N6,N7)]3 invoking N(1); N(6), N(7) binding of adjacent adenosine molecules was evident (97JCS(DT)2191). In contrast to 5u-AMP, cyclic trimers were not observed in more strongly acidic solution for equilibrium system [(Z6-C6H6)Ru(5u-ATP)]2 and constituted minor species even at neutral or higher pH values. 31P NMR confirmed that macrochelates constitute the dominant species in acidic solution. Time-dependant 1H NMR studies for [(Z6-C6H6)Ru(5u-ADP)] indicated that initial macrochelation of this nucleotide was followed by cleavage of the b-phosphate group and formation of cyclic trimers of 5u-AMP.

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Figure 23 X-ray crystal structure of the cation of (a) [(Z6-p-cymene)Ru(Ad-N6,N7;N9)]4 (CF3SO3)4 (57) (b) [(Z6-cymene)Ru(9-EtAd-N1;N6,N7)]3(CF3SO3)3 (58). (Reprinted with permission from 97ICA85, Copyright 1997, Elsevier.)

Figure 24 X-ray crystal structure of [(Z6-p-cymene)Ru(5u-AMP)]3 7.5H2O (60). (Reprinted with permission from 97JCS(DT)2191, Copyright 1997, Royal Society of Chemistry.)

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Figure 25 X-ray crystal structure of the cation of [(Z6-C6H6)Ru(HxH-N7;N9)(H2O)]4 (CF3SO3)4 (61). (Reprinted with permission from 2000ICA115, Copyright 2000, Elsevier.)

In the 1H NMR monitored reactions of guanosine 5u-mono, di and triphosphates with [Ru(Z6-C6H6)(D2O)3]2+ between pH 3.69 and 8.38, formation of only 1:1 and 2:1 complexes and macrochelates involving N(7) and oxygens of phosphate groups have been realized (97JCS(DT)2191). Hypoxanthine (HxH2) and [(Z6-C6H6)Ru(H2O)3](CF3SO3)2 reacted to form tetrameric metallacalixarene [(Z6-C6H6)Ru(HxH-N7;N9)(H2O)]4(CF3SO3)4 (61). Its X-ray structure (Figure 25) showed N(7), N(9) binding of adjacent HxH molecules to the RuII bridge (2000ICA115). It revealed crystallographic S4 symmetry and participation of exocyclic HxH oxygens in intramolecular hydrogen bonds to the coordinated water ligands.

2.3.2.3 Iridium organometallics. The reactions of [CpIr(H2O)](CF3SO3)2 (62) with adenine (19A) and 9-ethyladenine (19D) gave respective tetra and trinuclear products [CpIr(Ad-N9;N6,N7)]4(CF3SO3)4 (63) and [CpIr(9-EtAd-N1;N6,N7)]3 (CF3SO3)3 (64). In their X-ray structures (Figure 26a and b) (2000ICA115) the former exhibits an N(9); N(6),N(7) coordination mode for the bridging adenine ligands and the latter an N(1); N(6),N(7) binding pattern of adjacent 9-EtAd molecules. In these metallacalixarenes again, in the 1H NMR spectra, substantial upfield and downfield shifts respectively for purine H(2) and H(8) are diagnostic of cyclic oligomerization. Equimolar equilibrium systems of 62 with 19E and 19I showed exclusive formation of analogous diastereomeric trimers in the pH range 3.5–9.0.

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Figure 26 X-ray structure of the cation of (a) [CpIr(Ad-N9;N6,N7)]4(CF3SO3)4 (63) (b) [CpIr (9-EtAd-N1;N6,N7)]3(CF3SO3)3 (64). (Reprinted with permission from 2000ICA115, Copyright 2000, Elsevier.)

Figure 27 X-ray structure of the cation of [CpIr(GuH)(H2O)]4(CF3SO3)4 (65). (Reprinted with permission from 2000ICA115, Copyright 2000, Elsevier.)

The reactions of 62 with guanine (GuH2) and hypoxanthine (HxH2) provided respective tetramers [CpIr(GuH-N7;N9)(H2O)]4(CF3SO3)4 (65) and [CpIr(HxH)(H2O)]4 (CF3SO3)4 (66) in which O(6) participated only in outersphere coordination through O6–H–O interactions to the water ligand. The N(7),

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N(9) coordination mode of adjacent molecules of GuH in 65 has been confirmed by its X-ray structure (Figure 27) (2000ICA115). In weakly acidic equilibrium systems of 62 and 5u-IMP (21C) or 5u-ITP (21D), two cyclic, presumably trimeric oligomers with respectively N(1); N(7),O(6) (67) and N(1); N(7), O (H2O) (68) binding patterns of adjacently placed nucleobases were present in an approximately 1:1 ratio. The phosphate coordination was absent in the case of this Ir species in the presence of purine nucleoside 5u-triphosphate (2000ICA115). 6-Thiopurine ribose (22D) reacted with 62 to form cyclic hexameric complex [CpIr(6-Putrb)]6(CF3SO3)6, similar to 52 (2001AGE2268).

3. METALLACALIXARENES DERIVED FROM MODEL HETEROCYCLES 3.1 General Simulation of the self-assembly reactions of nucleobases and appropriate metallic components in structurally simpler heterocyclic models elaborating similar structural set-up of two appropriately oriented binding sites would provide a broader perspective to this approach of generating new metallacalixarene-based chemical architectures of relevance in devising functional materials. Evidently, the first choice was pyrimidine and imidazole systems as these are constituents of nucleobases. However, heterocyclic systems such as 2,2u-bipyrazine and 4,7-phenanthroline also elaborate two angularly placed coordinating nitrogens. The reactions of these four categories of heterocycles with various metallic components are detailed here.

3.2 Metallacalixarenes based on pyrimidines 1

N

1

N 3N

OH

3

N 4 OH

1

Me

OH

N 6

3

N

2-pymoH

4-pymoH

Me 2-dmpymoH

69

70

71

1

N 3

N

pym 72

The deoxyuracil derivatives-2-hydroxypyrimidine (69) (2-pymoH), 4-hydroxypyrimidine (70) (4-pymoH), 4,6-dimethyl-2-hydroxypyrimidine (71) (2-dmpymoH), and pyrimidine (72) (pym), shown here as the minor tautomer, have provided metallacalixarenes having closer resemblance to classical calixarenes, as compared with those obtained from uracil. The reactions of [(en)M(H2O)2](NO3)2 (M ¼ PdII and PtII) with 2-pymoH in water gave tetranuclear metallacalixarenes [(en)Pd(2-pymo-N1;N3)]4(NO3)4 (73) and [(en)Pt(2-pymo-N1;N3)]4(NO3)2 (74) (2000IC2301). As compared with uracil-based systems, the appearance of one set of resonances for each of pyrimidine H, in their 1H NMR spectra showed fast

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Figure 28 (a) X-ray structure of complexes 73 and 74 (M ¼ PdII or PtII) (b) perspective view of the interaction between [Cu(H2O)6]2+ and a tetranuclear [(en)Pt(2-pymo-N1;N3)]4+ 4 in 75. (Reprinted with permission from 2000IC2301, Copyright 2000, American Chemical Society.)

rotation around M–N bonds and rapid conformational changes in solution. In the solid state, X-ray structures display a 1,3-alternate arrangement of 2-pymo residues (Figure 28a) where nitrate anions are H-bonded through en NH2 and their stacking produces long channels. Metallacalixarenes 73 and 74, despite their high positive charge, are unable to include anions, as the cavity is too small ˚ ] to permit the inclusion of guest molecules. [C5–C5 separation of ~4.3 A In contrast to [(en)Pt(UH-N1,N3)]4+ 4 (NO3)4 (5), there is no evidence of the interaction (1H NMR) of either soft (PtII, PdII) or hard (NaI, BaII, LaIII) metal ions with 73 or 74, which could be attributed to the low basicity of 2-oxo oxygens of pyrimidine residues. The recrystallization of 73 from ~1 M HClO4 gave the adduct {[(en)Pt(2-pymo-N1;N3)]4(ClO4)4}2 [H20O8](ClO4)4 in which HClO4 does not protonate the oxygens of 2-pymo residues and [H20O8]4+ (ClO4)4 is sandwiched between two tetranuclear cations as a result of multiple H-bonding interactions with the oxo surface of two metallacalix[4]arenes. Again, a pinchedcone conformation of the 2-pymo residues is realized. Metallacalixarene 74 and Cu(ClO4)2 6H2O formed 2:1 adduct, [(en)Pt(2-pymo-N1;N3)]4(ClO4)4}2 [Cu(H2O)6] (ClO4)2 9H2O (75) (Figure 28b) in which CuII does not coordinate directly to the oxo surface of the metallacalix[4]arene but interacts strongly through H-bonding between the water molecules coordinated to the CuII center and the oxo-surfaces of the two metallacalix[4]arene 74 units. As a consequence, the 1,3-alternate conformation of 74 switches to a pinched cone conformation (2000IC2301) in ˚ ), while which two 2-pymo residues are too close (C5–C5 separation of 3.63(3) A ˚ the other two 2-pymo residues are 10.45(3) A apart, making it unsuitable for inclusion of a guest molecule. The conformationally flexible metallacalixarene [(en)Pd(2-dmpymo)]4+ 4 , formed by self-assembly of 2-dmpymoH and [(en)Pd(H2O)2]2+, reacts with Gd(NO3)3 in aqueous solution to form {Gd(NO3)2(H2O)[(en)Pd(2-dmpymoN1;N3)]4}5+(NO3)5 8H2O (76). Its X-ray structure (Figure 29) shows that the

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Figure 29 X-ray structure of the cation of {Gd(NO3)2(H2O)[(en)Pd(2-dmpymo-N1;N3)]4} (NO3)5 8H2O (76). (Reprinted with permission from 2000CC235, Copyright 2000, Royal Society of Chemistry.)

large-sized GdIII is bound to four oxygens of 2-dmpymo moieties and all the 2-dmpymo residues are oriented in the same direction affording a cone ˚ and 10.64(2) A ˚ separation between two opposite conformation with 7.82(2) A 2-dmpymo residues (2000CC235). The water molecule coordinated to the GdIII center and included in the metallacalixarene cavity, alters the hydrophobic character of the cavity and allows the inclusion of an additional water molecule and a nitrate anion inside the cavity. The 1:1 reactions between [(R,R-dach)Pd(H2O)2]2+ or [(S,S-dach)Pd(H2O)2]+2 with 2-pymoH, 4-pymoH, and 2-dmpymoH provided corresponding enantiopure tetrameric metallacalixarenes of general formula [(R,R-/S,S-dach)Pd (2-pymo-N1;N3)]4(NO3)4 14H2O (77a/77b) (Figure 30a); [(R,R-/S,S-dach)Pd (4-pymo-N1;N3)]4(NO3)4 12H2O (78a/78b); [(R,R-/S,S-dach)Pd(2-dmpymoN1;N3)]4(NO3)4 10H2O (79a/79b) (2003CEJ4414). In the case of reactions with 2-dmpyoH, the crystallizations from dilute solutions gave respective metallacalix[6]arenes [(R,R-/S,S- dach)Pd(2-dmpymo-N1;N3)]6(NO3)6 (80a/80b) (Figure 30b). On 1H NMR monitoring of the self-assembly process, the formation of 80a/80b could also be noticed along with their respective tetrameric species. Also, on heating above 60 1C, 80a/80b underwent conversion to the entropically favored tetrameric products 79a/79b. Thus it has been possible to engineer the size and functionalization of the metallacalixarenes by appropriate choice of the reaction conditions and pyrimidine derivatives. Tetranuclear 77–79 and hexanuclear 80 systems, in their X-ray structures, show respective 1,3 and 1,3,5 alternate arrangements and the latter was folded because of the hydrophobic interactions between methyl protons and 2-dmpymo

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Figure 30 X-ray crystal structure of the cation of (a) [(S,S-dach)Pd(2-pymo-N1;N3)]4 (NO3)4 14H2O (77b) (b) [(S,S-dach)Pd(2-dmpymo-N1;N3)]6 (NO3)6 (80b). (Reprinted with permission from 2003CEJ4414, Copyright 2003, Wiley.)

p- electrons. Both 77a and 77b on co-crystallization with NaNO3 and La(NO3)3 gave {Na[(dach)Pd(2-pymo-N1;N3)]4}(NO3)5 (81) and {La[(dach)Pd(2-pymoN1;N3)]4}(NO3)7 (82). In 81, two hydrated NaI ions were found in the asymmetric units composed of two crystallographically independent tetranuclear cations. Only one of the two NaI ions was bound directly to one exocyclic pyrimidine oxygen atom of parent 1,3- tetramer 77. 77a and 77b on reactions with lanthanum salts gave adducts and implied a 1,3-alternate to cone conformational change during complexation. In contrast, the non-formation of adducts of LaIII with 78 and 79 could be attributed to the sterically hindered rotation about the Pd–N bonds between bulky methyl substituents and dach. Only 79a and 79b showed selective molecular recognition of adenosine 5u-monophosphate among adenosine, guanosine, thymidine, and cytidine 5u-monophosphates. These results point to the possibility of employing metallacalixarenes as selective metal-based DNA-binding drugs (2003CEJ4414). In a unique self-assembly process, [Pd(bu2bipy)(thf)2]BF 4 /CF3SO3 reacted with 4-pymoH under basic conditions to form trimeric products [(bu2bipy)Pd (4-pymo-N1;N3)]3X3 (83a) (X ¼ BF4), 83b (X ¼ CF3SO3) (2002IC3967) (Scheme 4). On reaction with tetrabutylammonium perchlorate/nitrate, 83a provided 83c/83d. The steric bulk of the bu2bipy chelating ligand probably forced the Pd to form a trimer as in the case of chelation with dach where the tetrameric product was formed (2000IC2301). In solution phase (1H NMR), the presence of six resonances in the aromatic region, two in the t-butyl region for the bu2bipy ligand showed non-equivalence of the two pyridyl rings. These signals along with three resonances for 4-pymo ligands were consistent with structure 83a. In the X-ray structure of 83a, each of the three PdII centres is bound to four nitrogen atoms adopting a slightly distorted square planer coordination ˚ edges. geometry (Figure 31) and an almost perfect equatorial triangle with 5.88 A

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3+ 2+

OH

OH N Pd N

Cl AgBF4 or

N

Cl AgO3SCF3

N

Pd

(BF4− )2 or (CF3SO3− )2

N

N

N Pd

N

N N

Pd N

N HO

N N

(X − )3 N

N base

OH N

= bu2bipy

N

N Pd N

83 83a X = BF4 83b X = CF3SO3 83c X = ClO4 83d X = NO3

Scheme 4 Synthesis of metallacalixarenes 83.

Figure 31 X-ray crystal structure of the cation of [(bu2bipy)Pd(4-pymo-N1;N3)]3 (BF4)3 (83a). (Reprinted with permission from 2002IC3967, Copyright 2002, American Chemical Society.)

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The 4-pymo rings are placed in the same direction (syn, syn, syn) at angles of 68.71, 69.81, and 68.71 with respect to the Pd3 plane to form the cone conformation of the metallacalix[4]arene 83a whereas related trimers formed from imidazolate and benzimidazolate ligands have the syn, anti, anti conformation (99AGE669, 92JCS(CC)321). The bowl formed by the three 4-pymo residues of 83a is too small to accommodate guest molecules but the opposite side of the bowl, the open cavity defined by the [(bu2bipy)Pd]2+ residues, can accommodate one of the three tetrafluoroborate anions with three of the fluorine atoms directed towards the cationic PdII centers. In addition, three fluorine atoms also form weak C–HyF H-bonds with three C(2)–H groups of the 4-pymo residues. The 1H NMR titrations of 83a with various anions have revealed that weakly binding anions such as HSO 4 , NO3 , ClO4 , and CF3SO3 bind in the open cavity on the opposite side of the cone cavity of the 83a whereas strongly binding anions H2PO 4 , CH3COO , Cl , Br cleave 83a (2002IC3967). The combinations of pyrimidine endocyclic N (1201) with linear metal fragments mostly form polymeric materials but formation of tetra and hexameric metallacalixarenes have also been reported (2005JSSC2436). The reaction of 2-pymoH with AgNO3 in acetonitrile in the presence of Et3N gave hexameric metallacalixarene [Ag(2-pymo-N1;N3)]6 (84). It also has been obtained from zigzag polymeric [Ag(2-pymo)]N 2NH2O (85) either by thermal treatment or by its reaction with HC(OEt)3 (97IC5648). The reversibility of the latter process has been realized by quantitative formation of 85 on stirring 84 in wet acetone (Scheme 5). XRPD analysis reveals non-planarity of the six 2-pymo ligands about the hexagonal Ag6 with dihedral angles between adjacent 2-pymo rings of about 20 or 701. Apparently the large cavity in the center of the hexamer is occupied by the tails of non-planar molecules. Another hexagonal system [Cu(2-pymo-N1;N3)]6 (86) has been identified in the grooves of polymeric [Cu(2-pymo-N1;N3)]N formed from [Cu(MeCN)4]BF4 and 2-pymoH (69) (98AGE3366). However, the reactions of CuY2 [Y ¼ Cl, NO3, (SO4)1/2] with 69 in the presence of MX (M ¼ NH4, CH3NH3, Li, K, Rb; X ¼ ClO4, BF4, PF6) gave highly crystalline materials of formula [Cu(2-pymo-N1;N3)2] (MX)1/3(H2O)4/3 (87). In 87, CuII ions are coordinated to four nitrogen donor atoms of four different 2-pymo moieties, each one symmetrically bridging two Cu centers (2001JA383). In this way, tetranuclear and hexanuclear molecular boxes analogous to calix[n]arenes (n ¼ 4, 6) along with planar hexanuclear [Ag(2-pymo)]n . 2nH2O

AgNO3 + 2-pymoH

acetone HC(OEt)3 H2 O

[Ag(2-pymo)]6

Scheme 5

Reversibility between various [Ag(2-pymo)]x derivatives.

[Ag(2-pymo)]x

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Figure 32 The X-ray crystal structure of a segment from 87 NH4ClO4 polymer framework. (Reprinted with permission from 2001JA383, Copyright 2001, American Chemical Society.)

molecular hexagons are generated. These three structural motifs are interlocked to give a highly symmetric three dimensional framework that acts as a host for NH4ClO4. The [Cu(2-pymo)2]N framework in 87 NH4ClO4 (Figure 32) accounts for ~80% of the total volume in the unit cell and the remaining ~20% is filled with ˚ diameter are defined NH4 and ClO4 ions and water molecules. The pores of 8.1 A by planar [Cu6(2-pymo-N1;N3)6] molecular hexagons and contain an NH4 cation ˚ and two water molecules. Each of these pores connects two cavities of ~14 A diameter in which two ClO4 anions are included. Organo-inorganic molecular architecture 87 elaborates rich host–guest chemistry. The facile exchange of ammonium in 87 NH4ClO4 with LiI, NaI, KI, and RbI on treatment with aqueous solutions of perchlorates gave respective 87 MClO4 clatharates. However, exchange of NH+4 with CsI, alkaline earth and lanthanides could not occur. Nitrogen sorption at 77 K by empty host 87 reveals its microporous nature with BET surface area of 200 m2 g1. Hydrated 87 loses water on heating and when exposed to moist air regenerates the original hydrated material. Likewise, 87 NH4ClO4 loses ammonia upon heating, giving the corresponding activated acidic material 87 HClO4 which upon exposure to gaseous ammonia regenerates 87 NH4ClO4. Similarly, 3D polymeric [Cu(4-pymo-N1;N3)2 nH2O]N framework, formed from 4-pymoH and CuX2 in the presence of NH3, reversibly absorbs N2 and water vapors with minimal structural changes (2003POL3051). In a skillfully performed reaction of pyrimidine (72) with AgNO3, [Ag(PymN1;N3)]4(NO3)4 (88) was formed. Its X-ray crystal structure shows tetrameric cyclic self-assembly forming supramolecular 1:1 AgI:pyrimidine squares ˚ ] which exist in planar sheets with each square face to face stacked [3.8 3.8 A

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Figure 33 (a) The supramolecular squares of 88 showing face-to-face stacking to six other squares. (b) The supramolecular structure of 89 with vertically cross linked pym units. (Reprinted with permission from 98CC215, Copyright 1998, Royal Society of Chemistry.)

to six other squares (Figure 33a). The nitrate ions are inside the open channel structure which facilitates the exchange with other anions (98CC215). The crystals of 88 on suspending in methanolic NH4 99TcO4 underwent exchange of nitrate ions with TcO 4 . The crystallization of AgClO4 with Pym gave 1D coordination polymer [Ag2.5(Pym-N1;N3)3][ClO4]2.5 (89), having supramolecular squares similar to 88 but these squares are crosslinked by a dimeric pymo unit vertically in a stair case fashion (Figure 33b).

3.3 Metallacalixarenes based on imidazoles and benzimidazoles The imidazole ring, an ubiquitous ligand in chemical and biological systems, has two angularly disposed ligating nitrogen atoms (1501) and reacts with appropriate metal complexes or organometallics in a self-assembled manner to form corresponding metallacalixarenes. Thus [Cu(ImH)2(OAc)2], obtained in situ from imidazole (ImH) and Cu(OAc)2, on reaction with 1,4,7-trimethyl-1,4, 7-triazacyclononane (L2) followed by treatment with sodium perchlorate formed an imidazolate bridged trinuclear complex [(L2)3Cu3(Im-N1;N3)3](ClO4)3 (90), a CuII analogue of calix[3]imidazole (93IC888). In its X-ray structure (Figure 34a), each CuII is placed at the corner of an equilateral triangle with the ˚ and is coordinated to N(1) and N(3) of adjacently Cu–Cu separation of 5.92 A placed nearly planar imidazoles and three nitrogens of the cyclic amine (92JCS(CC)321). On replacing the tricyclic amine L2 with 1,4,7-triazacyclononane (L3), the same reaction provided the tetranuclear system [(L3)4Cu4 (Im-N1;N3)4](ClO4)4 2H2O (91). Its X-ray structure (Figure 34b) showed that the four CuII ions lie in a plane and form an approximate parallelogram with sides ˚ and 5.99 A ˚ (93IC888). These complexes are of interest from a magneto 5.89 A structural and a bio modeling standpoint. The complex 90 constitutes a firstgeneration model for the active site of ascorbate oxidase and both 90 and 91 display antiferromagnetic character. Using benzimidazole (BzimH) as the non-linear bridging motif, luminescent platinum(II) trimeric systems [Pt(thpy)(Bzim)]3 (92) and [Pt(bzqn)(bzim)]3 (93) have been synthesized from sodium benzimidazolate and luminescent

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Figure 34 X-ray crystal structures of cations of (a) [(L2)3Cu3(Im-N1;N3)3](ClO4)3 (90) (b) [(L3)4Cu4(Im-N1;N3)4](ClO4)4 3H2O (91). (Reprinted with permission from 92JCS(CC)321, Copyright 1992, Royal Society of Chemistry; 93IC888, Copyright 1993, American Chemical Society.)

cyclometalated PtII precursors [Pt(thpy)(thpyH)Cl] and [n-Bu4N][Pt(bzqn)Cl2], respectively (99AGE669). The trimeric nature of 92, consisting of alternating thpy vertices and benzimidazole edges has been confirmed by X-ray crystallography (Figure 35). The bzim groups are oriented in syn, anti, anti (two-up, one-down) fashion to create a partial cone conformation. From the mean plane through the Pt atoms, the angle to the syn bzim units is 601, while the inclination of the anti one is 771. In the above synthetic approaches, monomers undergoing self-assembly have been generated in situ only. In an alternate approach, preformed monomeric CuII complexes of multidendate Schiff base ligands containing imidazole, stabilized as protonated species and having potential donor–acceptor character, act as self complementary building blocks and under basic conditions through coordination of the imidazolate nitrogen of one unit to CuII ion of the adjacent unit, generate CuII analogs of calix[4]imidazole (2002CCR199). Here, an appropriate choice of bulky ligands such as L4–8 (Figure 36) imposing steric restrictions to facilitate cyclic self-assembly is evident. In the monomeric copper complexes with one donor and one acceptor sites per molecule, the assembly structure is easily predictable but in the case of multiple donor and/or acceptor sites, such a prediction could be difficult. The mononuclear CuII complex [Cu(HL4)Cl]ClO4, formed from 4-formylimidazole, N,N-dimethyl-propane-1,3-diamine, CuCl2 H2O and NaClO4, on treatment with Et3N formed [(CuL4)4](ClO4)4 (94) (93JCS(DT)2157). Its X-ray structure (Figure 37) shows a cyclic tetranuclear molecule in which each imidazolate nitrogen atom coordinates axially to the CuII ion of the adjacent unit. The reactions of CuCl2 2H2O with Schiff bases HL5a and HL5b gave monomeric complexes [Cu(HL5a)Cl2] (95) and [Cu(HL5b)Cl2] (96) as light green

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Figure 35 X-ray structure of [Pt(thpy)(bzim)]3 (92). (Reprinted with permission from 99AG669, Copyright 1999, Wiley.)

R

R HN

HN

N

N N HL4

R HN

R

N

HL5a, R = H HL5b, R = CH3

HL6a, R = CH3 HL6b, R = Ph

R1 (CH2)m

N

N

N

N

N H2L7a, R = H H2L7b, R = CH3

Figure 36

N

N

N

H N

N

HN

N

N

Structures of ligands L4–L8.

N H

N

(CH2)n

m, n, R1, R2 H2L , 3, 4, H, CH3 H2L8b, 3, 4, H, Ph H2L8c, 3, 3, CH3, Ph H2L8d, 2, 3, H, CH3 8a

N

N 2

R2 R

H2L8a-8d

NH

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Figure 37 X-ray structure of the cation of [(CuL4)4](ClO4)4 (94). (Reprinted with permission from 93JCS(DT)2157, Copyright 1993, Royal Society of Chemistry.)

crystals. The complex 95 on sequential treatment with sodium hydroxide and sodium perchlorate through self-assembly formed tetrameric metallacalixarene [{Cu(L5a)}4]4+ (97). On using 96, having a 2-methyl group on a pyridine unit, a bluecoloured hexameric metallacalixarene, [{Cu(L5b)}6](ClO4)6 (98) was formed and clearly indicated the role of steric bulk on the ligand in determining the nuclearity of the self-assembled system (2002CCR199). On treatment with HCl, 98 showed a visibly reversible interconversion to 96. Its X-ray structure shows a tubular shape ˚ ). A constriction in the middle of the with a cylindrical cavity (radius ~4 A cylindrical cavity delineates two half-cavities (97AGE1860). The protonated monomeric PdII complex [Pd(HL5b)Cl]Cl (99), formed in a manner similar to that of 96, on treatment with NaOH and NaClO4 formed the self-assembled deprotonated cyclic tetramer [{Pd(L5b)}4](ClO4)4 (100) (97AGE1860). Thus, the metal ion also determines the nuclearity of the oligomeric species through its coordinative requirements. + HN

N

H3C Cl Pd N N 99

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The monomeric copper complexes 101 and 102 obtained from 2-aminoethylpyridine, 2-Me (L6a)/Ph (L6b)-4-formylimidazole and CuCl2, again constitute modular building units able to induce self-assembly via formation of metalimidazolate coordination bonds. On treatment with base, 101 and 102 respectively gave [Cu4(L6a)4](ClO4)4 (103) (Figure 38a) and [Cu6(L6b)6](ClO4)6 (104) (Figure 38b) which could be converted to [Cu6(L6b)6](PF6)6 (105). Their structures have been confirmed through X-ray structural analysis and FAB-MS spectra (99IC1165). It may be seen that as in the case of the pyridine unit in L5, the substitution profile of the imidazole unit in L6, also tunes the nuclearity of self- assembled structures. The cyclic structures of 103, 104 (Figure 38b) reveal that 2-imidazolate substituents of adjacent modular units orient themselves in directions opposite to each other resulting in face-to-face disposition of substituents of alternating units imposing steric repulsion, also evident in space filling models. Thus a hexanuclear structure is more favorable in the case of 104 having phenyl substituents. The monomers [Cu(H2L7a)]NO3 (106) and [Cu(H2L7b)Cl]NO3 (107) obtained by 2:1 condensations of corresponding 4-formylimidazole with 1,4-diaminobutane and copper salts, in their X-ray structures reveal a bent butterfly shape imposing non-equivalence of two imidazoline moieties (98IC3553). On base induced self-assembly, 106 having unsubstituted imidazoles formed an infinite zig-zag chain but 107 having 2-methylsubstituted imidazoles gave cyclic product [Cu(HL7b)]4(NO3)2Cl2 1.25H2O (108) which could also be further deprotonated. The difference in these modes of self-assembly has been explained due to the non-equivalence of two imidazoles with respect to their deprotonation process

Figure 38 X-ray crystal structures of the cations of (a) [Cu4(L6a)4](ClO4)4 (103); (b) [Cu6(L6b)6](ClO4)6 (104). (Reprinted with permission from 99IC1165, Copyright 1999, American Chemical Society.)

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and thereby oligomerization. In its X-ray structure, 108 (Figure 39) consists of an imidazolate-bridged cyclic tetranuclear molecule described as a molecular square with two nitrate and two chloride anions and water molecules (98IC3553). The strand-type protonated complexes [Cu(H2L8a–d)](ClO4)2 xH2O of pentadendate Schiff-base ligands containing two imidazole groups were synthesized from appropriate triamine cap, 4-formylimidazole derivative and CuCl2 (99IC3513). The monodeprotonated copper complexes of HL8a–c contain one imidazole and one imidazolate groups per unit and are clockwise or anticlockwise enantiomorphs due to the spiral arrangement of the ligand around the CuII ion. These function as chiral building components for self-assembly process resulting from the formation of hydrogen bonds between the imidazole and imidazolate groups of adjacent units to yield 1D zigzag-chain structures. In a unique manner, [Cu(H2L8d)]2+ complex on deprotonation forms [Cu(HL8d)4] (ClO4)4 16H2O (109) (Figure 40) where four [Cu(HL8d)] units are bridged into a tetranuclear cyclic structure. The most interesting feature of 109 is the formation of a hexahydropyrimidine ring derived from the parent ligand H2L8d involving base induced partial dissociation of the secondary amine followed by its attack on an imine carbon resulting in ligand rearrangement to a

Figure 39 X-ray crystal structure of the cation of [Cu(HL7b)]4(NO3)2Cl2 1.25H2O (108). (Reprinted with permission from 98IC3553, Copyright 1998, American Chemical Society.)

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Figure 40 X-ray crystal structure of (a) the cation of [Cu(HL8d)4](ClO4)4 16H2O (109) and (b) a schematic presentation of 109. (Reprinted with permission from 99IC3513, Copyright 1999, American Chemical Society.)

Figure 41 X-ray crystal structure of [Au(Gly-L-His)]4 (110). (Reprinted with permission from 92IC1983, Copyright 1992, American Chemical Society.)

hexahydropyrimidine ring. Thus while mononuclear precursor [Cu(H2L8d)] is pentacoordinated, the ligand in 109 is tetradentate. The mononuclear complex [Au(gly-L-his)Cl]Cl 3H2O formed from H[AuCl4] and gly-L-his HCl at pH 1.5–2, unlike all other cases where alkaline conditions are essential for oligomerization, readily forms the cyclic tetramer [Au(Gly-L-His)]4 (110) at pH 6–7 (92IC1983). In the X-ray structure of 110 (Figure 41), each AuIII is surrounded by the three nitrogen donor set as in the

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precursor and a fourth nitrogen of the deprotonated imidazole ring and four water molecules interact both inside and outside the molecule. Imidazole-4-carboxylic acid (ImacH2) (111) on reaction with [CpRhCl2]2 in the presence of Ag2O as base formed a metallacalixarene [CpRh-(ImacN1;N3,O4)]4 (112). Its 1H NMR is highly symmetrical and single crystal X-ray structure (Figure 42, Scheme 6) reveals it as a tetrameric self-assembly in which the two-fold deprotonated ligands bridge the CpRh fragments. Overall, the complex displays S4 symmetry and the 5-membered N, O- chelate ring is nearly planar (2004IC1609). In a different complementary approach, a self-assembled monomeric bridged dicopper(II) cation 114, formed from bpimH (113) and CuII, on condensation with bidentate imidazolate formed the tetranuclear metallacalixarene

Figure 42 X-ray structure of [CpRh-(Imac-N1;N3,O4)]4 (112). (Reprinted with permission from 2004IC1609, Copyright 2004, American Chemical Society.)

O 2 Rh Cl Cl + O OH 4 HN

N O Rh 2

4 Ag2O

O

−8 AgCl

N

N

N N Rh O

N N

N

O 111 112

Scheme 6 Synthesis of [CpRh-(Imac-N1;N3,O4)]4 (112).

O Rh

O N Rh

O

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N

N

113

4+

N

N

N

NH

bpimH

N 3+

N H

N

N N

N

N N Cu N

N N Cu N

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N

Cu N

N

N

N

N

Cu N N

N

Cu N N

Cu N

115 114

Scheme 7

Synthesis of metallacalixarene [Cu2(bpim)(Im-N1;N3)]2(NO3)4 4H2O (115).

[Cu2(bpim)(Im-N1;N3)]2 (NO3)4 4H2O (115) (Scheme 7). Here, two sets of alternately placed imidazole nuclei are in different environments. Metallacalixarene 115 is unstable at both high and low pH but 114 is stable in pH range 3.5 to 11.5 (81IC2933).

3.4 Metallacalixarenes derived from 2,2u-bipyrazine and 4,7-phenanthroline Some flexible organic ligands with at least two angularly disposed binding nitrogen donors react with metal salts to generate monomeric species having structural prerequisites for undergoing cyclic self-assembly. 2,2u-Bipyrazine (bpz) and 4,7-phenanthroline (4,7-phen) constitute two such species and have been used to create metal bridged cyclic oligomers in which organic ligands are not strictly 1,3- or meta linked as in calixarenes. But due to similarity of their structural set-up with calixarenes, these oligomers have been termed as metallacalixarenes (2005JSSC2436). The synthesis, structures, and anion interactions of these systems are elaborated here.

3.4.1 Metallacalixarenes based on 2,2u-bipyrazine 2,2u-Bipyrazine (bpz), through rotation around its C(2)–C(2u) bond elaborate cis and trans conformers. Cis-bpz on reaction with (en)PdII formed only a mononuclear chelate [(en)Pd(bpz-N1;N1u)](ClO4)2 (116) (98AGE119, 2000JA1381) but with (en)PtII mainly via N(4),N(4u) metal coordination formed a unique trimeric cyclic system [(en)Pt(bpz-N4,N4u)]3(NO3)6 (117), alongwith a minor amount of [(en)Pt(bpz-N1,N1u)](NO3)2 (118). The former, on prolonged heating in water quantitatively gave 118 (2000JA1381). 1H NMR of metallacalixarene 117 revealed a number of interconvertible conformations in solution but crystallized in only an all trans rotamer. The formation of two types of structures with all trans and all cis conformations of bpz ligands have been triggered by the nature of the counter anion. In the X-ray structure of [(en)Pt(bpz-N4,N4u)]3(NO3)2(PF6)4 (117a) (Figure 43), cations with an all trans conformation and an all cis conformation

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Figure 43 X-ray crystal structure of the cation of [(en)Pt(bpz-N4,N4u)]3(NO3)2(PF6)4 (117a). (Reprinted with permission from 2000JA1381, Copyright 2000, American Chemical Society.)

Figure 44 X-ray crystal structure of the cation of [(en)Pt(cis-bpz-N4,N4u)]3(NO3)2(ClO4)4 2H2O (117b). (Reprinted with permission from 2000JA1381, Copyright 2000, American Chemical Society.)

of bpz ligands crystallize side-by-side. The three Pt atoms linked through N(4) atoms form an approximately equilateral triangle. In [(en)Pt(cis-bpz-N4,N4u)]3 (NO3)2(ClO4)4 2H2O (117b) (Figure 44), one of the bpz ligands is roughly planar while the other two are more strongly twisted. The structure of 117b looks more like a vase or a double cone, when the en ligands are considered (2000JA1381). The anions interact differently in both cis and trans isomers of bpz-based metallacalixarenes 117a and 117b and these interactions may be responsible for stabilizing or even inducing a particular rotamer structure (2000JA1381). In all trans rotamers 117 and 117a, NO 3 lies outside the cavity of the triangle and has no interaction with the metallacalixarene but in rotamer 117a having both NO 3 and PF 6 anions, PF6 lies within the cavity (2000JA1381). In the all cis isomer 117b, both NO 3 and ClO4 anions are bound in the cavity with NO3 lying approximately in the Pt3 plane revealing PtyO interactions and ClO4 lies above the Pt3 plane. The all cis triangles in both 117a and 117b behave as versatile hosts

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for anions, incorporating trigonal planar NO 3 , tetrahedral ClO4 , and octahedral PF6 and even a combination of both NO3 and ClO4 anions (2000JA1381). Metallacalixarene 117 readily chelated with (en)PdII to generate a hexanuclear Pt3Pd3 complex [(en)Pt(N4;N4u-bpz-N1;N1u)Pd(en)]3(NO3)4(PF6)8 (119) (99AGE168, 2000JA 1381). Its X-ray structure reveals that while the three Pt atoms form an equilateral triangle, the Pd triangle at the rim is irregular and larger. In a similar way a Pt6 vase has been formed from 117 and [(en)Pt(H2O)2]2+. In contrast, hexanuclear [{(en)Pd(N4,N4u-bpz-N1,N1u)Pd(en)}3](NO3)4(PF6)8 5H2O and [{(en) Pd(N4;N4u-bpz-N1;N1u)Pt(en)}3](NO3)7(PF6)5 9.75H2O have been obtained by reactions of 116 and 118 with [(en)Pd(H2O)2]2+ (2000JA1381). However 116, on reaction with trans-(NH3)2PtII forms an isomeric Pd3Pt3 complex [{(en)Pd}2.5 (N1;N1u-bpz-N4;N4u)3{(NH3)2Pt}3](ClO4)6(NO3)5 5H2O (120) in which PtII links N(4),N(4u) and PdII binds N(1),N(1u) (99CC675). In the X-ray structure of 120 (Figure 45), both the Pd3 and Pt3 triangles are close to equilateral with Pd–Pd and ˚. Pt–Pt distances being 13.5 and 7.6 A Metallacalixarene 119 simultaneously encapsulates both NO 3 and PF6 anions, the nitrate being in the centre of the Pt3 triangle with its oxygens pointing to acidic PtII atoms and PF 6 is located in the centre of the antiprism on top of the nitrate ion (99AGE168). It is also a receptor for many other anions but binds SO2 4 strongly and also encapsulates ClO4 in the center of the cation and aggregates in the solid state in such a way as to form long channels containing a string of ClO 4 ions (99CC675). In the reactions of 117b with silver salts, higher nuclearity products [(117b)2Ag2]14+ with molecular formula [{(en)Pt(N4;N4u-bpz-N1;N1u)}3AgNO3]2 (NO3)8(PF6)4 15.5H2O (121) and [(117b)2Ag3]15+ AgNO3 with molecular

Figure 45 X-ray structure of the cation of [{(en)Pd}2.5(N1;N1u-bpz-N4;N4u)3{(NH3)2Pt}3](ClO4)6 (NO3)5 5H2O (120). (Reprinted with permission from 99CC675, Copyright 1999, Royal Society of Chemistry.)

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formula [{(en)Pt(N4;N4u-bpz-N1;N1u)}3(AgNO3)1.5]2(NO3)12AgNO3 22H2O (122) have been formed by respective bridging of two Pt3 triangles with two and three silver ions via N1, N1u positions (2000JA1381). The container complex 122 represents the inorganic version of an organic carceplex and has both one AgI cation and five nitrate anions incorporated in its interior.

3.4.2 Metallacalixarenes based on 4,7-phenanthroline On the basis of its geometrical coordination requirements, 4,7-phenanthroline (phen) constitutes a ligand which can be considered as an extended pyrimidine ring. The cyclic self-assembled metallic systems based on phen and designated as metallacalixarenes have been obtained and their interactions with anions have been studied. Trimeric metallacalixarenes [(en)Pd(phen)]3(NO3)6 (123) and [(en)Pt(phen)]3 (NO3)6 (124) have been formed from phen and [(en)Pd/Pt(NO3)2] (2003AGE686) (Scheme 8). In its X-ray structure, 123 reveals a calix[3]arene bowl with a cone conformation in which the three [(en)Pd]2+ bridges of the phen backbone constitute an almost equilateral triangle which in aqueous solution binds sulfate ion more strongly than nitrate ion (2003AGE686). The reactions of [(R,R- and S,S-dach)Pd(NO3)2] and 4,7-phenanthroline in aqueous media formed trinuclear cyclic species [(R,R-dach)Pd(phen-N4;N7)]6+ (125) and [(S,S-dach)Pd(phen3 N4;N7)]6+ (126) (2004DT1563). The X-ray structure of 125 confirms its trinuclear 3 nature with N(4), N(7) bridging mode. The suitability of the extended aromatic nature of phen for p–p interactions and the rigid cone arrangements in the ˚ molecular vases of 123, 124, and 125 with upper ring opening of ca. 8.5 A facilitated inclusion of mononucleotide guest molecules. Nucleotides induced decomposition of these metallacaliarenes gave acyclic adducts of the type [a2Pd(phen)(mononucleotide)]+ (2004DT1563). For modulation of the size and shape of these metallacalixarene cavities, combinations of various pyrimidine and phen ligands have been used to form heterotopic metallacalixarenes. The multicomponent reactions of 3:1:2 mixture of [(en)PdII], pyrimidine, and phen preferably formed heterotopic trimeric species [(en)3Pd3(L-N1;N3)(phen-N4;N7)2]5+ (127) (L, a ¼ 2-pymo, b ¼ 2-mpymo,

Scheme 8 Schematic formation of phen-based trimeric metallacalixarenes 123–126. (Reprinted with permission from 2004DT1563, Copyright 2004, Royal Society of Chemistry.)

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Figure 46 X-ray structures of the cations of (a) [(en)3Pd3 (2-dmpyo-N1;N3)(phen-N4;N7)2]5+ (NO3)5 (127c) and (b) [(en)4Pd4(2-pymo-N1;N3)2(phen-N4;N7)2]6+(NO3)6 (129). (Reprinted with permission from 2004DT2780, Copyright 2004, Royal Society of Chemistry.)

c ¼ 2-dmpymo) and not the homotopic species. Heterotopic metallacalixarenes 127 were also obtained by the reaction of a 3:8 mixture of homotropic systems [(en)Pd(phen-N4;N7)]3(NO3)4 (123) and [(en)Pd(L-N1;N3)]4(NO3)4 (128) (2004DT2780). In its X-ray structure (Figure 46a), 127c reveals an irregular triangle exhibiting a pinched-cone conformation. The reaction of a 2:1:1 mixture of [(en)Pd]2+, 2-pymo, and phen formed the tetranuclear metallacalixarene [(en)4Pd4(2-pymo-N1;N3)2(phen-N4;N7)2]6+ (129). Its X-ray structure (Figure 46b) shows a 1,3- alternate conformation with alternately placed pymo and phen moieties and the metal ions constituted the vertices of a parallelogram, rather than those of a rectangle. The reaction of a 3:4 mixture of homotropic species 128 (L ¼ 2-pymo) and 123 formed hexanuclear metallacalixarene [(en)6Pd6(2-pymo-N1;N3)4(phen-N4;N7)2]8+ (130) (2004DT2780). The host–guest interaction studies of these metallacalixarenes showed their ability to interact with both cationic as well as with anionic species (2004DT2780).

4. CONCLUSIONS This account of an infant discipline of metallacalixarenes, the metallo-version of heterocalixarenes and a unique category of organo-inorganic hybrid systems elaborates many of their distinctive features with respect to other synthetic receptors. Their metallic components are primarily responsible for the multifold positive charge of the species which visibly constitute attractive hosts for anions so significant in biological reactions. The intrinsic magneto-electrical and structural contribution of metals could impart in metallacalixarenes such unusual features in target functional materials. An abundant use of nucleobases in their designs which is bye and large non-existent in parent heterocalixarenes points to

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their relevance in mimicking supramolecular phenomenon in biological systems. Despite their positively charged nature, depending upon their heterocyclic component profiles, metallacalixarenes also interact with metal cations. As against the existence of nucleobase derived natural tetrands stabilized by a central metal ion, analogous metallacliaxrenes having desired metal components, nuclearity, and thereby cavity size compatible for even bigger biological anions, can be formed. Such unusual features evidently open up new vistas of research aimed at newer materials. But it calls for a focused and multifaceted collaborative approach coordinating design, synthesis and evaluation work. That only four model heterocycles have so far been used in evolving metallacalixarenes, points to the lack of awareness amongst practitioners of heterocyclic chemistry. It is hoped that their involvement in the exploration of this interfacial area will prove increasingly fruitful.

LIST OF ABBREVIATIONS AdH Ado 5u-ADP 9-AllAd 3u-AMP 5u-AMP 5u-ATP bpz bu2bipy BzimH bzqnH Cp dach 2-dmpymoH dpk en 9-EtAd GuH2 Guo HxH2 ImacH2 ImH 5u-IMP 5u-ITP 9-MeAd 5u-MeAMP 9-MeGuH 9-MeHxH 9-MePu

Adenine Adenosine Adenosine-5u-diphosphate 9-allyladenine Adenosine-3u-monophosphate Adenosine-5u-monophosphate Adenosine-5u-triphosphate 2,2u-bipyrazine 4-(t-butyl)-2,2u-bipyridine Benzimidazole 7,8-benzoquinoline Z5-pentamethylcyclopentadienyl 1,2-diaminocyclohexane 4,6-dimethyl-2-hydroxypyrimidine 2,2u-dipyridylketone 1,2-diaminoethane 9-ethyladenine Guanine Guanosine Hypoxanthine Imidazole-4-carboxylic acid Imidazole Ionosine-5u-monophosphate Ionosine-5u-triphosphate 9-methyladenine Adenosine-5u-monophosphate methyl ester 9-methylguanine 9-methylhypoxanthine 9-methylpurine

Metallacalixarenes

2-MpymoH NAD+ phen PuH 6-PutH2 6-PutH2A2 6-PutH2O2 6-PutHrb pym 2-pymoH 4-pymoH T tacn TH TH2 thf ThpH thpyH U UH UH2

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4-methyl-2-hydroxypyrimidine Nicotine adenine dinucleotide 4,7-phenanthroline Purine 6-thiopurine 2-amino-6-thiopurine 2-hydroxy-6-thiopurine 6-thiopurine-9-ribose Pyrimidine 2-hydroxypyrimidine 4-hydroxypyrimidine Thymine dianion Triazacyclononane Thymine monoanion Thymine Tetrahydrofuran Theophylline 2(2u-thienyl)pyridine Uracil dianion Uracil monoanion Uracil

ACKNOWLEDGEMENT We thank CSIR and INSA, New Delhi, India for financial support.

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CHAPT ER

4 Sulfur Monochloride in the Synthesis of Heterocyclic Compounds$ O.A. Rakitin and L.S. Konstantinova

Contents

1. Introduction 2. Heterocycles without Sulfur Atoms 3. Heterocycles with One Sulfur Atom 3.1 Thiophenes 3.2 1,2,5-Thiadiazoles 3.3 1,2- and 1,4-Thiazines 3.4 Other heterocycles with one sulfur atom 4. Heterocycles with Two Sulfur Atoms 4.1 1,2-Dithioles 4.2 1,2,3-Dithiazoles 4.3 1,2- and 1,4-Dithiines 4.4 Other heterocycles with two sulfur atoms 5. Heterocycles with Three Sulfur Atoms 6. Heterocycles with Four Sulfur Atoms 7. Heterocycles with Five Sulfur Atoms 7.1 1,2,3,4,5-Pentathiepins 7.2 Other heterocycles with five sulfur atoms 8. Heterocycles with Six or More Sulfur Atoms 9. Conclusions References

175 177 178 179 180 185 187 190 191 198 205 206 208 210 213 213 220 221 224 224

1. INTRODUCTION Sulfur chlorides are important reagents in organic synthesis (1982AHC55, 1998MI145, 1999JPR99, 2006EJO849). Many are known SnCl2 (n ¼ 1–12); some $

Dedicated to the late Professor Charles W. Rees – our teacher and coworker.

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia Advances in Heterocyclic Chemistry, Volume 96 ISSN 0065-2725, DOI 10.1016/S0065-2725(07)00004-9


175

176

O.A. Rakitin and L.S. Konstantinova

can be isolated (1969ZAAC241, 1972ZN(B)1006, 1984JOC1043, 1996ZAAC1594). Only two, sulfur dichloride (SCl2) and sulfur monochloride (S2Cl2), are commercially available. However, sulfur dichloride is unstable and has to be purified before using (B-2001MI). Sulfur monochloride is sufficiently stable and can be kept in dark bottles resulting in slight decomposition giving small amounts of sulfur chloride and sulfur. Sulfur monochloride shows versatile reactivity. It is an extremely powerful chlorinating agent for perchlorination of aromatic compounds (1960JA4294, 1992JOC5712), yet chemists rarely use it because there are many other chlorinating agents which allow higher yields. The sulfurating ability of sulfur monochloride is more important. Many inorganic sulfur reagents can be prepared from it (see e.g., 1991ZN5, 1996ZAAC557, 1994ZAAC632). However, both the chlorinating and sulfurating ability of sulfur monochloride can take place simultaneously and this diminishes its value as a sulfurating agent. Numerous attempts have been undertaken to prepare a sulfurating reagent (Scheme 1) with carbon, nitrogen, oxygen or sulfur leaving groups to replace the chlorine atom (1978JA1222, 1990SL473, 1998TL2467, 2001JOM173, 2002TL499 and many others). But these disulfides 1 do not substitute for sulfur monochloride, and so S2Cl2 has ranked among the best sulfur transfer reagents in inorganic and organic chemistry since its discovery in the late 1800s (1860LA266). Sulfur monochloride plays an important role with its ability to cyclize organic substances into a heterocyclic ring. The main feature of this reagent appears to be the addition of two sulfur atoms inserted between carbon–carbon or carbon– heteroatom bonds to produce heterocycles with two bound sulfur atoms. Yet, often it adds one, three, four, five, six and even more sulfur atoms, sometimes bonded together, sometimes not. These syntheses cannot be explained only by disproportioning of sulfur monochloride into sulfur dichloride and sulfur followed by the generation of higher sulfur chlorides (Scheme 2), as explained (1978JA1222). The role of S2Cl2 seems to be crucial. The results of most of the reactions (heterocycle ring size and yield) discussed in this review depend largely on conditions (solvent, temperature and conversion time)

R1 S S

Cl + R1H

S S

R1

Cl 1 R1 = Ar, NR22, OR2, SR2

Scheme 1

S2Cl2

SCl2 + 1/8 S8 + 1/8S8

S2Cl2

−1/8S8

+ 1/8S8 S3Cl2

−1/8S8

Scheme 2

S4Cl2

SnCl2

S2Cl2 in the Synthesis of Heterocyclic Compounds

177

as well as on activating compounds (most often tertiary amines) added to the reaction mixture. Few general mechanisms can explain the full variety of heterocyclic syntheses, and therefore we will give special attention to mechanistic explanations even when they have not been proven. This review is divided into sections depending on the quantity of sulfur atoms in the formed heterocycle. We have examined all the literature data for the last 150 years up to March 2007, including the latest achievements concerning 1,2,3-dithiazoles fused with other heterocycles. We do not discuss the Herz reaction since it is well known and has been reviewed (1957CRV1011). A few reviews on the synthesis of heterocycles with sulfur chlorides have been published (1998MI145, 1999JPR99, 2006EJO849). They do not give the full scope of the reactivity and synthetic utility of sulfur monochloride.

2. HETEROCYCLES WITHOUT SULFUR ATOMS Semicarbazones 2 were converted into their corresponding mono-, di- and trisubstituted 2,4-dihydro-1,2,4-triazol-3-ones 3 (Scheme 3; 1986JHC881). The reaction was carried out in refluxing acetic acid and ethyl acetate; triazolones 3 were isolated in good yields (Table 1). Thiosemicarbazone 4 reacted in a similar manner to give 1,2,4-triazole-3-one 5 in good yield (1986JHC881), whereas at lower temperature (40 1C), unexpectedly, 2-methylamino-5-phenyl-1,3,4-thiadiazole 6 was isolated in low yield (Scheme 4). The proposed mechanism includes the addition of sulfur monochloride to the N–H bond of semicarbazone or thiosemicarbazone with the formation of an N–S–S–Cl intermediate followed by its cyclization into the triazole or thiadiazole ring with the extrusion of two sulfur atoms and HCl. 1,3,4-Oxadiazoline-2-thione 7 was obtained in low yield from 2-benzoyl-1, 1-dimethylhydrazine and sulfur monochloride by similar process (1967J CS(C)2636). 1,1,4,4-Tetramethyltetrazane 8 was the major product (Scheme 5). The addition of one equivalent of sulfur monochloride to two equivalents of 2-aminocinnamates 9 in chlorobenzene followed by brief refluxing produced diethyl 2,5-diaryl-3,4-pyrroledicarboxylates 10 in 36–52% yields (1984JOC4780). The mechanism was described and expected intermediates 11 and 12 were isolated under less stringent conditions (see Section 3.3; Scheme 6). R2 N N R1

R2 O + S2Cl2

HN R3 2

Scheme 3

N N R1

N R3 3

O

178

Table 1


Yields and melting points of 2,4-dihydro-1,2,4-triazol-3-ones

R1

R2

R3

Yield (%)

Mp (1C)

Ph 4-MeC6H4 4-ClC6H4 2-HOC6H4 Ph Ph Ph Ph Ph Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4

H H H H Ph Ph Ph Ph Ph Ph Ph Ph Ph

H H H H H Et Prn Bun Ph 3-NO2C6H4 2,5-Cl2C6H3 Ph Ph

62 64 51 70 32 52 54 68 72 68 81 80 68

323 334 380 (dec) 330 234–236 80 82 70 221 160 161–162 174 188

N NH Ph

115 °

C

N NH S + S2Cl2

Ph

O

N Me 5, 75%

40 °C

HN Me

N N Ph

4

NHMe

S 6, 10%

Scheme 4 O Me

Ph

N N Me

O Ph

+ S2Cl2 Me2N

N N

Me

NMe2 Ph

N N

+ Ph

O

S

O 8, 50%

7

Scheme 5

3. HETEROCYCLES WITH ONE SULFUR ATOM Sulfur monochloride can add one sulfur atom to a molecule and these transformations usually suggest the extrusion of sulfur dichloride or another sulfur atom with contraction of the heterocycle to a more stable (often heteroaromatic) ring.


Ar Ar

S2Cl2

H2N

CO2Et

H2N H2N

9

CO2Et EtO2C

S

H

CO2Et Ar N NH2

Ar

CO2Et

Ar

S

179

11 Ar = Ph, 3-CF3C6H4 EtO2C

S

Ar

N

H

EtO2C

CO2Et

Ar

Ar

12

CO2Et Ar

N H 10

Scheme 6

R

catalyst + S2Cl2

high temp

R

S

R = Me, Et

Scheme 7

3.1 Thiophenes Compounds with double and triple bonds react with sulfur monochloride to cyclize into a thiophene ring. The most vigorous method for preparing thiophenes is a reaction of 2-alkylbuta-1,3-dienes with sulfur monochloride at high temperature in the presence of a catalyst (1989JPP01066179, 2005CNP1583741; Scheme 7). Yields are moderate. Surprisingly, in this case, sulfur monochloride did not act as a chlorinating agent. Benzyne generated from 2-carboxybenzenediazonium chloride reacted with sulfur monochloride to give dibenzothiophene 13 (8–10%) and thiantherene 14 (26–35%) (1989SUL83). A mechanism involving the addition of sulfur monochloride to benzyne with the formation of betaine 15 followed by the elimination of SCl2 to afford benzothiirene 16 and a further reaction with another benzyne molecule or dimerization to thianthrene 14 is given in Scheme 8. 3-(3,4-Dimethoxyphenyl)prop-2-ynoic acid reacted with sulfur monochloride in the presence of pyridine to give low yields of substituted 1-benzothiophenes 17 and 18 (1979AJC833; Scheme 9). A thiophene ring can also be produced from two methylene groups. Here 2,5-dicarbethoxy-3,4-dicyanomethylthiophene 19 reacted with sulfur monochloride to give tetrasubstituted thieno[3,4-c]thiophene 20 in moderate yield (2002JOC2453). A mechanism for the thiophene 20 formation was proposed and 1,2-dithiine derivative 21 was likely to be an intermediate (Scheme 10) because sulfur monochloride gave higher yields of 20 than SCl2. At the next step (21-20), sulfur monochloride apparently acted as an oxidant.

180


N2Cl

Cl S+

S2Cl2

heat

_

S

Cl S

S Cl Cl

CO2H 15 S

−SCl2

+ S

16

13

x2 S S 14

Scheme 8 Cl

Cl MeO

CO2H + S2Cl2

MeO

1. Py 2. MeOH

Cl

MeO

MeO

CO2Me

CO2Me + S

MeO

S

MeO

18, 7%

17, 7%

Scheme 9 NC + S2Cl2

S MeO2C

CN

MeO2C

NC 19

Et3N

S S

S MeO2C

CN 21

MeO2C −“H 2S

“

MeO2C

S

CN S

MeO2C

CN

20, 44%

Scheme 10

A variety of zirconium metallocycles was used to produce thiophenes, its dihydro and tetrahydro derivatives and also isothiazoles (1994JA1880, 2003JA4199) through their reactions with sulfur and selenium halides. Surprisingly, higher yields were obtained with sulfur monochloride as compared to SCl2, although one sulfur was added to the metallocycle molecule (Scheme 11). The reaction conditions were mild (1 h at 25 1C) and yields ranged from moderate to high.

3.2 1,2,5-Thiadiazoles An overall strategy for the synthesis of 1,2,5-thiadiazoles from the acyclic N–C–C–N grouping and sulfur monochloride was proposed in 1967 (1967JOC2823). The N–C function could vary over oxidation levels of amine, imine, cyanide, oxime and nitroso derivatives. Aliphatic and aromatic compounds having these functionalities in many combinations reacted with sulfur monochloride to form appropriately substituted or fused 1,2,5-thiadiazoles. Based on this model, a large


Me

Me

ZrCp2 + S2Cl2

S

Me

C6F5

Me 55%

Ph

Ph

C6F5

ZrCp2 + S2Cl2 C6F5

181

S C6F5

Ph Me

Ph 76% Me

ZrCp2 + S2Cl2

S 48%

ZrCp2 + S2Cl2

S 46%

Me

Me

ZrCp2 + S2Cl2

S

N

N 22%

Scheme 11

R1

R2 + S2Cl2

H2N

NH2

DMF

R1 N

R2 S 22

N

a R1 = R2 = H b R1 = R2 = Me c R1 = H, R2 = CO2H d R1, R2 = (CH2)4

Scheme 12

number of readily available acyclic and aromatic compounds serve as starting materials, including 1,2-diamines, a-aminoamidines, a-aminonitriles, alkyl cyanoformamidates, heterocyclic o-nitrosoamines, a-nitrosonitriles, a-dioximes and cyanogen. One sulfur atom is added because of the inherent stability of aromatic 1,2,5-thiadiazoles which is the driving force for their formation (1967JOC2823). Yields vary from 30% to 90%.

3.2.1 From 1,2-diamines Ethylenediamine and some of its 1,2-dialkyl derivatives are easily transformed into the corresponding 1,2,5-thiadiazoles 22 with sulfur monochloride in DMF at room temperature (1967JOC2823; Scheme 12).

182


NH2 + S2Cl2

N

DMF

S N

NH2

23, 81% N

NH2 + S2Cl2

S N

N

N

N

N

S

NH2

S

24, 59%

Scheme 13 R H2N

O NH2

+ S2Cl2

DMF

R = Prn, Pri, Bun, Bui, Ph, Bn, CH2CH2CO2Et

R N

OH S

N

25, 40−60%

Scheme 14

In the presence of FeCl3 and chlorine, ethylenediamine dihydrochloride formed 3,4-dichloro-1,2,5-thiadiazole (74%) (1989DDP271425). Aromatic and heteroaromatic o-diamines were also converted in high yields to fused thiadiazoles 23 and 24 under the same conditions (Scheme 13; 1967JOC2823, 1975JOC2749). 2-Aminoacid amides are suitable synthons for transformation to 3-hydroxythiadiazoles 25 (1967JOC2823, 1984WOP8402525) in moderate yields (Scheme 14). Clycinamide gave 4-chloro-1,2,5-thiadiazol-3-ol (1993JPP05140133) in a reaction with sulfur monochloride. Sulfur monochloride and N1- (26) or N2- (27) substituted amides of 2-aminoacids afforded different 1,2,5-thiadiazole derivatives: 1,2,5-thiadiazol-3(2H)-ones 28 (1979NLP7712033, 1992CHP680220, 1994JPP06306063) and mesoionic 1,2,5-thiadiazolium-3-olates 29 (1981JCS(P1)1033; Scheme 15).

3.2.2 From ethyl oxamimidate and 2-aminoacetamidine Compounds containing an a-aminoimidate fragment (HNQC–C–NH2) as in ethyl 2-amino-2-oxoethanimidoate 30 and 2-aminoethanimidamide 31 reacted with sulfur monochloride to give, respectively, 4-ethoxy-1,2,5-thiadiazol-3-ol (32) and 3-amino-1,2,5-thiadiazol (33) (1967JOC2823; Scheme 16). Yields were moderate.

3.2.3 From aminonitriles a-Aminonitriles are a convenient starting material for the preparation of 1,2,5-thiadiazoles. The amine must be primary and bear at least one a-hydrogen atom. Thus, treatment of unsubstituted a-aminonitrile and its aromatic and heterocyclic derivatives with sulfur monochloride in DMF at room temperature


R1

O

R1

DMF, r.t. + S2Cl2

N

HN R2

H2N

26

183

O S

N R2

28, 56−81%

R1 = Me, H R2 = 4-MeC6H4, 4-MeOC6H4, 4-ButC6H4, CH(Me)Ph, (CH2)11Me

_

R1 1

R

O

1. DMF, 60 °C, 2h

+ S2Cl2 2

R NH

+ R2 N

2. Et3N

NH2

O S

N

29, 59−98%

27 1

R = Ph, 4-MeOC6H4, 4-ClC6H4 R2 = Me, C6H11(cyclo)

Scheme 15

EtO

O

DMF

EtO

OH

+ S2Cl2 HN

NH2

N

30

N

S

32, 51%

H2N

DMF

H2N

+ S2Cl2 HN

N

NH2

S

N

33, 66%

31

Scheme 16

R

DMF CN + S2Cl2

H2N

rt

R = H, Ph, 3-pyridine

R N

Cl S

N

34, 45−74%

Scheme 17

afforded 3-chloro-1,2,5-thiadiazoles 34 in moderate yields (1967JOC2823, 1995WOP9505174, 1999JMC1999; Scheme 17). A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable; this includes the formation of the N-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). Similarly, 1-cyanoformamide can be converted into 4-chloro-1,2,5-thiadiazol3-ol 35 upon treatment with sulfur monochloride (1967JOC2823; Scheme 19).

184


R CN H2N

S2Cl2 − HCl

R HN

R

N S

S

,, ,, − S HN Cl

Cl S

R

S2Cl2 Cl S

N

R

Cl

S N S N

−S2, −HCl

N

Cl S

N

34

Scheme 18 O

DMF CN + S2Cl2

H2N

HO

rt

Cl

N

S

N

35, 88%

Scheme 19

DMF

RO CN + S2Cl2 HN

rt

R = Me, Et, Prn, Pri, Bn, pentyl, hexyl

RO N

Cl S

N

36, 79−95%

Scheme 20

DMF NC CN + S2Cl2

80 °C

Cl N

Cl S

N

37, 90%

Scheme 21

3.2.4 From nitriles and oximes Treatment of cyanoimidates, easily obtained from cyanogen and alcohols in the presence of triethylamine, gave with sulfur monochloride the corresponding 4-chloro-1,2,5-thiadiazoles 36 in good-to-moderate yields (1967JOC2823, 1998JMC379; Scheme 20). Cyanogen itself is reported to react smoothly with sulfur monochloride to form 3,4-dichloro-1,2,5-thiadiazole 37. The reaction was not exothermic and was readily run by passing cyanogens into an S2Cl2 solution in dimethylformamide at 80 1C (1967JOC2823; Scheme 21). Cyanooximes are less desirable starting materials for the synthesis of 1,2,5-thiadiazoles. Yields of 3-chloro derivatives 38 were low (1967JOC2823, 1992WOP9203433; Scheme 22). The reaction of a-dioximes with sulfur monochloride is usually complex and leads to a mixture of various heterocycles including 1,2,5-thiadiazoles, their N-oxides 39 and sometimes 1,2,5-oxadiazoles (1967JOC2823, 1970JOC1165). Yields are low (Scheme 23).

185


R

R

DMF

Cl

CN + S2Cl2 N OH

N

S

N

38, 15% R = Ph,

N

Scheme 22

R1

R2

DMF + S2Cl2

HO N

N OH

R1 N

r.t.

R2 S

N

23−38% 1

R1 +

N

R1

R2 S

N O

39, 3−5%

+

N

R2 O

N

3%

2

R = R = Me, Ph

R1, R2 =

,

Scheme 23

3.2.5 From o-aminonitrosoheterocycles o-Aminonitrosoheterocyclic compounds were used in a selective synthesis of fused 1,2,5-thiadiazole N-oxides by a reaction with sulfur monochloride. Various nitrogen and sulfur–nitrogen heterocycles were employed and the yields varied from excellent to moderate (1996KGS997, 1998KGS1130, 2005ZOB493; Scheme 24). The reaction was carried out using both aromatic and non-aromatic heterocycles, yet it is difficult to predict how this method will work for particular classes of heterocyclic compounds. Although no information on the conversion mechanism was cited, it is easy to imagine the addition of sulfur monochloride to the amino group with the formation of an N–S–S–Cl derivative followed by the extrusion of hydrogen chloride and sulfur and the generation of the 1,2,5-thiadiazole-N-oxide ring.

3.3 1,2- and 1,4-Thiazines The reaction of 3-aminocinnamates 9 with sulfur monochloride leading to tetrasubstituted pyrroles 10 (see Section 2) can be stopped at the formation of 2H-1,4-thiazines 12 by the inverse addition of sulfur monochloride to compound 9. Yields of thiazines 12 may reach 58–77% (1984JOC4780; see Scheme 6). Treatment of dicyano compound 41 with sulfur monochloride, N-ethyldiisopropylethylamine and N-chlorosuccinimide in tetrahydrofuran at 0 1C for 3 days led to condensed 1,2-thiazine 42 in low yield (10%) together with polychlorinated

186


NO

O N S N

DMF + S2Cl2

Het NH2

Het r.t. or 60 °C

40, 37−85% O R =

Het

O

NH2

N

N

N ,

O R1

, H2N

N

H2N

N

,

S

N

R = H, Me, CH2CH2OH

Scheme 24

+ S2Cl2

Cl S

EtNPr i2, NCS

S

S N

S N

CN NC

NC 41

Cl

NC

Cl 44

Cl

Cl S

NC

S N Cl

−S

Cl Cl

S N NC 42, 10%

Cl

CN NC 43, 70%

Scheme 25

derivative 43 as the main product (70%) (1999JCS(P1)1023). A reasonable pathway for the conversion of dicyanide 41 into thiazine 42 includes the sulfur monochloride addition to the nitrile bond followed by cyclization onto an activated allylic position yielding either dithiazepine 44 or directly, with a loss of sulfur, the thiazine ring. A standard chlorination–dehydrochlorination process followed by the sulfur extrusion gave planar and formally aromatic product 42 (Scheme 25). Cyclobutanone oxime 45 reacted with the same mixture to give cyclopenta1,2-thiazine 46 in low yield together with two other unexpected 10-p pseudoazelenes 47 and 48 (1996JOC9178). Benzo derivative 49 of oxime 45 afforded analogous benzo product 50 together with methylenoindene 51 in high yield. The simplest mechanism for oxime 45 conversion into 1,2-thiazine 46 could involve an initial ketoxime fragmentation of the abnormal (second-order) Beckmann type, presumably induced by sulfur monochloride. Cyclobutane ring opening would give nitrile 52 that could react through the S2Cl2 addition to the nitrile with further cyclization and give a seven-membered dithiazepine ring which, by a dehydrogenation and chlorination sequence, would give fully

187


Cl

OH N + S2Cl2

CN

EtNPr i2, NCS

Cl N S S

N

S2Cl2

S S

Cl

Cl

Cl N S S

+[Cl] −HCl

Cl

52

45

Cl Cl

Cl

−S

Cl N S

Cl Cl

Cl

NC

Cl

Cl

Cl S

Cl S

Cl 47, 6%

46, 10%

OH N

Cl 48, 10%

Cl CN

i

49

S

Cl S

Cl 53

+ S2Cl2

CN

N S

EtNPr 2, NCS

Cl 50, 33%

+

Cl Cl 51, 62%

Scheme 26

chlorinated product 53. This is formally a 12-p system that upon the electrocyclization of the seven-membered ring to a fused 6-3 system followed by sulfur loss would give thiazine 46 (Scheme 26).

3.4 Other heterocycles with one sulfur atom Three-, five-, six- and seven-membered heterocycles containing one sulfur atom, except for those described above, can be obtained from various organic substances and sulfur monochloride. Unexpectedly, treatment of di-tert-butyl- and di-1-adamantylacetylenes with sulfur monochloride afforded dichlorothiiranes 54 in good yields (2002HAC424). Expected 1,2-dithietanes 55 were not formed even as trace amounts. The initial step might be the addition of sulfur monochloride to the acetylenes to produce adduct 56. The preferred configuration of 56 might be as shown in Scheme 27 in order to avoid steric repulsions between the bulky substituent R and the S–C group. As a result, exclusive three-membered ring formation gives thiirane 54 with sulfur atom elimination (Scheme 27). A series of five-membered heterocycles with two and three heteroatoms were synthesized. 4-Hydroxyisothiazoles 57 were prepared from a-amino ketones with sulfur monochloride (1968BCJ959). Polar solvents, especially N,N-dimethylformamide, were preferable (Scheme 28). In a similar reaction of 1-amino-1-phenyl2-propanone with sulfur monochloride 5-chlorinated isothiazole 58 was obtained in high yield.

188


Cl r.t.

R + S2Cl2

R

R

S S

Cl

R

Cl

Cl

R

R

54, 56%

56 R = But, 1-Adamantyl

S

S S R

Cl Cl R 55

Scheme 27

R1

R1

O + S2Cl2

r.t.

R2

H2N

Ph

OH

OH

DMF N

S

N

R2

57, 9−44%

R1, R2 = Me, Ph

S

Cl

58, 70%

Scheme 28

H N

NH2 + S2Cl2 +N H

H N

Me DMF

+N H

Me _ ClO4

60

S N Me _ ClO4

59, 64%

Scheme 29

H N R

NH2 S

+ S2Cl2

60 °C

N NH2

R S 61, 90−98%

R = 4-OMe, 2-Cl

Scheme 30

Condensed isothiazole 59 was isolated from o-aminomethyldiazepin 60 and sulfur monochloride (1996KGS997; Scheme 29). Substituted 2-aminobenzothiazoles 61 can be prepared from N-arylthioureas with sulfur monochloride (1976DEP2601700). Yields are almost quantitative (Scheme 30). 2,4,5-Trichlorothiazole was generated using 62 with sulfur monochloride (1976DEP2451632; Scheme 31). Hydrazones are useful materials for the synthesis of thiadiazoles. Benzaldehyde hydrazone and its derivatives substituted in the aromatic ring with sulfur monochloride in the presence of DBU gave 2,5-diaryl-1,3,4-thiadiazoles 63 in


Cl

40−50 °C

ClCH2CHCl-N=CCl2 + S2Cl2

189

N Cl

73%

Cl

S

62

Scheme 31 Ar N2 Ar N + S2Cl2 NH2

H

DBU

Ar

Ar N N Sn

H

−N2; −Sn-1

H S

H

Ar = 4-XC6H4 X = H, MeO, F, Cl, Br, CF3 N N

Ar H

S

N N

Ar Ar

H

S

Ar

63, 28−73%

Scheme 32

N HN SO2Tol

R2 1

R2

R1

R1

R = H, Me R2 = Me, Ph

+ S2Cl2

r.t.

R2 Cl

S

N N

64, 13−27%

+ S

N N

1

65, R = H, 6−18%

Scheme 33

moderate-to-good yields (2004S1929). The mechanism included the formation of arenecarbothialdehydes by a nucleophilic attack of hydrazone at S2Cl2 affording unstable N-thionitrosoimine followed by extrusion of nitrogen, and independent production of diazoalkane by the oxidation of the hydrazone with S2Cl2. Finally, the reaction between the two intermediate molecules led to corresponding 1,3, 4-thiadiazoline which was then oxidized to thiadiazole 63 (Scheme 32). 1,2,3-Thiadiazoles 64 and 65 can be prepared in good yields from a,b-unsaturated p-tolylhydrazones (1981G289). The reaction is not regioselective and usually gives a mixture of two isomers (Scheme 33). Treatment of 1,5-cyclopentadiene with sulfur monochloride and then with sulfuryl chloride provided high yields of 2,6-dichloro-9-thiabicyclo[3.3.1]nonane 66 containing a six-membered tetrahydrothiopyran ring (2006MI212). The formation of thiopyran 66 is assumed by the authors to be the result of the reversible elimination–addition of SCl2, which is in equilibrium with sulfur monochloride, and of the high thermodynamic stability of 66 relative to the other monomeric and oligomeric sulfur dichloride addition products (Scheme 34). Resonance-stabilized bis-thiadiazinylpyridine 67 can be prepared from bifunctional amidine 68 and sulfur monochloride followed by treatment of

190


S

1. S2Cl2 2. SO2Cl2

Cl Cl 66, 95%

Scheme 34

Ph

N

N

N

NH2

Ph NH2

Ph + S2Cl2

68

N N

S +

H N

N S

Cl

Ph N Cl

1. NOSbF6 2. Proton Sponge Ph N

_

_ N

N S +

Ph

N S

N

Cl 67

Scheme 35

Ar

Me

+ S2Cl2

Pyridine

Ar N

NOH 71

Ar S

N

69, 54%

Ar = 4-NO2C6H4

O

O NH Pyridine But + S2Cl2 NH t O Bu 72

But N S N But

O 70, 69%

O +

But N S3 N But

O 73, 9%

Scheme 36

the insoluble chloride with NOSbF6 and Proton Sponge (2005CC1218; Scheme 35). Structurally similar seven-membered dihydro-1,2,7-thiadiazepine 69 and 1,2,7-thiadiazepan-3,6-dione 70 were obtained by an unexpected dimerization of acetoxime 71 (1997BSB605) and a ring closure of dicarboxamide 72 (1995CC1449). Curiously, the reaction of sulfur monochloride containing two sulfur atoms in both cases led to the insertion of one sulfur atom to the sevenmembered ring or three sulfur atoms to the by-product 73 in the second reaction, but not two sulfurs (Scheme 36).

4. HETEROCYCLES WITH TWO SULFUR ATOMS Heterocycles with two sulfur atoms obtained from sulfur monochloride, for example, 1,2-dithioles, 1,2,3-dithiazoles and 1,2-dithiines, are the most anticipated compounds because they are obtained by a direct insertion of two sulfur atoms during heterocyclic molecule construction. But even in that case some

191


unexpected transformations, such as the formation of an adjacent heterocyclic ring, may accompany the main process.

4.1 1,2-Dithioles 4.1.1 From isopropylamines This approach to the synthesis of 1,2-dithioles from tertiary isopropylamines was discovered and elaborated by Charles Rees and coworkers in the late 1990s and in the beginning of this century. They commenced when N-ethyldiisopropylamine (Hu¨nig’s base), having been initially used as an ‘‘inert’’ base, was found to react with sulfur monochloride and 1,4-diazabicyclo[2.2.2]octane (DABCO) to give an unexpected and novel multisulfur–nitrogen system – bis[1,2]dithiolo[1,4]thiazine 74 (1997AG(E)281). In this one-pot conversion of Hu¨nig’s base into tricycle 74, 14 isopropyl C–H bonds were replaced by 10 C–S and 2 C–C double bonds, while the ethyl group remained intact. This is a striking example of high selectivity between primary and secondary N-alkyl groups in a competitive reaction (Scheme 37). Other bis[1,2]dithiolo[1,4]thiazines 75 and 76 can be also selectively obtained by the reaction of Hu¨nig’s base with sulfur monochloride through the addition of oxygen donors such as cyclopentadienylacetic or formic acid (1998JOC2189; Scheme 38). When the reaction of Hu¨nig’s base with sulfur monochloride was performed in boiling chlorobenzene, the corresponding bis[1,2]dithiolopyrroles 77–79 were formed by sulfur extrusion from intermediates 74–76 (Scheme 39). The transformation of Hu¨nig’s base into bis[1,2]dithiolo[1,4]thiazines 74–76 and pyrroles 77–79 requires some 15 or so separate reaction steps, as estimated, from the formation of dithiole rings. A mechanistic pathway for the formation of all products was proposed (1998JOC2189; Scheme 40). The first step was the oxidation of the isopropyl group in Hu¨nig’s base by S2Cl2 (or its reactive complex with DABCO) to give more stable iminium ion 80, as generally occurs in the Me Me Me

N Me

Me

S + S2Cl2

S N

DABCO S

S S

Me

S

S 74, 40%

Scheme 37

Me O

Me O

N

1. S2Cl2, DABCO S

S S

S

Me

S

2. HCO2H

Me

N

O 1. S2Cl2, DABCO S

Me 2.

Me

Me

76, 42%

Scheme 38

S N S

S CO2H

S

S

75, 42%

192


Me O S

Me S

1. S2Cl2, DABCO in C6H5Cl

S

2. HCO2H, reflux

N S

S

1. S2Cl2, DABCO in C6H5Cl

Me Me

N

Me

Me

S S

2. reflux

Me

S

N S

S

S

77, 42%

78, 25% 1. S2Cl2, DABCO in C6H5Cl 2. HCO2H, reflux Me O

O

N

S

S

S

S

79, 42%

Scheme 39

N

+N

+ S2Cl2

− HCl − 1/4S8 Cl

S2Cl2

Cl

Cl

S+ S Cl _

S

S 85

S

S2Cl2

N S+ S

S 84

2Cl

heat

X

X S

S S

82

Cl

Cl

N _

2Cl

S S

81

X

S+

N

− HCl

+S

N +S

Cl

repeat

N

83

− HCl

_ 80

S2Cl2

N

S

S

74−76

−S X = O, S

S

− HCl _ − 1/8S8

X

N S

S

S

77−79

Scheme 40

oxidation of tertiary amines (1991COS221). Further deprotonation of 80 gave enamine 81 which reacted with S2Cl2 to give 1,2-dithiole 82 which led to 3-chlorodithiolium salt 83. The dithiolium ring in this compound is expected to be stable and the whole sequence could then be repeated to transform the other isopropyl group in a similar manner to give dithiolium salt 84. This could cyclize to tricyclic species 85 by a further reaction with S2Cl2 with a loss of sulfur. 3,5-Dichloro-bis-dithiolium salt 85 presumably was the key intermediate and reacted with sulfur and oxygen nucleophiles to give heterocycles 74–79. With a view to furthering the investigations of the substituted diisopropylamines reaction with sulfur monochloride, Rees and coworkers synthesized a number of tricyclic bis-dithiolothiazines (1999JOC5010, 2000JCS(P1)3421), including the parent members.

193


Treatment of N-(2-chloroethyl)diisopropylamine with sulfur monochloride in tetrahydrofuran followed by the addition of phosphorus pentasulfide with heating under reflux gave dithiolothiazine 86 (1999JOC5010). Bis-dithiolium salt 87, which analogously formed disalt 84, in the presence of P4S10 gave intermediate 88 which could then cyclize to give partially saturated thiazine 89, after further chlorination. Salt 89 converted into final product 86 with more P4S10 (Scheme 41). 3,5-Dichloro-bis-dithiolium salt 85 obtained from N-ethyldiisopropylamine, S2Cl2 and DABCO in chloroform at room temperature reacted with arenesulfonamides and their N,N-dichloro derivatives with the formation of N,Nu-bis(arylsulfonyl)dithiolothiazine diimines 90 in modest yields (2001JCS(P1)2409; Scheme 42). The reaction of Hu¨nig’s base, sulfur monochloride and toluene-p-sulfonhydrazide under the same conditions is more complex and gives monohydrazone 91 in low yield (2001JCS(P1)2409; Scheme 43). The reaction of N-alkyldiisopropylamines with sulfur monochloride and DABCO, deficient with respect to S2Cl2, prevented the formation of the 1,4-thiazine ring and led apparently to salts 84 which were then chlorinated by excess S2Cl2 and next treated with formic acid to give N,N-bis(5-chloro3-oxo[1,2]dithiol-4-yl)amines 92 together with the corresponding bis-dithiolothiazines 76, although in low yields (1999JCS(P1)2237; Scheme 44).

Cl

Cl

SH Cl

Cl N

S+

+S S

S 87

N

P4S10

88

S

S P4S10

N

N S

_

S

_ 2Cl

S S

+S S

S

S

2Cl

S

Cl

S+

+S

_

S S S2Cl2

Cl

Cl

P4S10

N

+ S2Cl2

S

Cl

S 86

89

Scheme 41

Cl N

+ S2Cl2

DABCO

Cl N S+

+S S

S

S 85

Ar = Ph, 4-MeC6H4

Scheme 42

ArSO2NH2 or ArSO2NCl2 _ 2Cl

ArO2SN

N

NSO2Ar

S

S S

S

S

90 12 −14% from ArSO2NH2 42 − 48% from ArSO2NCl2

194


S N

+ S2Cl2

NNHSO2Ar

N

1. S2Cl2, DABCO S

2. ArSO2NHNH2

S S

S

S

91, 11% Ar = 4-MeC6H4

Scheme 43

R N

R N

Cl + S2Cl2

DABCO

Cl

S

S 84 O

R N

Cl

_

S+ S

S

2Cl

Cl Cl

2Cl

_

O R = Et, PhCH2, ClCH2CH2, PhSCH2CH2 etc

S

S S

S

R N

Cl +S

S+

+S

HCO2H

S2Cl2

Cl Cl 92, 7−22%

Scheme 44

R N

R N

S

+ S2Cl2

S HS

R = Et , CH2Ph, CH2CH2CO2Et , CH2CH2CN, CH2CH2N3

S

93, 11−37%

+

R N

S S S 94

Scheme 45

In all the reactions discussed in this section, both isopropyl groups were transformed into a 1,2-dithiole ring. When N-alkyldiisopropylamines and sulfur monochloride were mixed in chloroform in the absence of another base, that is, DABCO, two monocyclic dithiole-3-thiones 93 and 94 were isolated. 5-Mercapto derivative 93 was the main product in all the cases examined (2001MC165, 2006RCB143; Scheme 45). Two other N-substituted diisopropylamines (RQCH2CH2Cl and CH2CH2Phth) in the same reaction gave dithiolothiazine 95 which had apparently resulted from the HCl or phthalimide extrusion from 5-mercapto-1,2-dithiole-3-thiones 94 (Scheme 46). 5-Mercaptodithiole thiones 93 were treated with sulfur monochloride and DABCO under conditions for the synthesis of tricyclic bis-dithiolothiazines from substituted diisopropylamines (see Scheme 38). Unexpectedly, in all the cases 5-chloro-1,2-dithiole-3-ones 96 were formed in high yields (2006RCB143; Scheme 47).


195

X

N

2. HCO2H

S

S

1. S2Cl2, 0 °C

N

N S X

HS

S

S

− HX

S

94

O

S

95, 21−33%

N

X = Cl,

O

Scheme 46 R N

S + S2Cl2

S HS

R N

1. DABCO

S

O S

2. HCO2H Cl

93

S

R = CH2Ph, CH2CH2CO2Et, CH2CH2CN, CH2CH2N3

96, 77−94% O

R N

S

S

S S

S

S

Scheme 47 O Me N O

+ S2Cl2 N R

Me

O

1. DABCO N

2. Et3N O

R = Pr i, neopentyl

S

S S

N R

Cl

97, 30−43%

Scheme 48

5-Chlorodithioles 96 can also be prepared from a reaction of N-alkyldiisopropylamines, sulfur monochloride and DABCO followed by the addition of formic acid (2001MC165). Structurally similar 5-chloro-1,2-dithiole-3-thiones 97 were obtained upon treatment of N-(2-phthalimidoethyl)-N-alkylisopropylamines with sulfur monochloride and DABCO and a final reaction with triethylamine (2003OL929). The stability of thiones 97 is explained by the dipole–dipole interaction between the electron-rich 1,2-dithiole-3-thione ring and electron-poor phthalimido groups (Scheme 48). The reaction of diisopropyl sulfide with sulfur monochloride and DABCO afforded 1,2-dithiolo-3-thiones 98 and 99 (1999JOC4376). Dithiole ring formation had been assumed to be similar to that produced from tertiary diisopropylamines. However, in the case of diisopropyl sulfide only one isopropyl group was

196


Me

Me

Me

Me S

Me

Me

Me

DABCO

+ S2Cl2

S

S S Me

Me

Me

S Me

S

+

Me S

S

S

S

S S S 99, 19%

98, 33%

S

S S

S

Scheme 49

N N

N

N

+ S2Cl2 R

DABCO S S

R

100

101, 20−27%

R = Me, Ph

Scheme 50

Cl

N OSiMe 3 EtNPr i2, NCS + S2Cl2

CN

S2Cl2 S

Cl 13%

S Cl

103 CN

S2Cl2

102 20%

EtNPr i2, NCS

Scheme 51

activated by the initial sulfide atom; this activation was suppressed when isopropyl sulfide was bonded to a dithiolthione group (Scheme 49).

4.1.2 From other sources A general strategy for the synthesis of 1,2-dithioles is the addition of two sulfur atoms to the CHQCH–CH– group; also, non-ethylenic CH groups should be activated. Elemental sulfur is obviously the best reagent although sulfur monochloride is sometimes used. Treatment of a,b-unsaturated hydrazones 100 with sulfur monochloride gave 3-imino-1,2-dithioles 101 in low yields (1985ZC400; Scheme 50). 1-(Cyanomethyl)cyclopentene reacted with sulfur monochloride, Hu¨nig’s base and N-chlorosuccinimide to form perchlorinated cyclopenta-1,2-dithiole 102 (1996JOC9178). The same product was obtained from cis-bicyclo[3.2.0]hepten6-one oxime, and in that case its formation was explained by the initial abnormal Beckmann rearrangement of the oxime to cyanide 103 followed by cyclization, extensive chlorination and dehydrochlorination (Scheme 51).


O

O

Cl CO2H

+ S2Cl2

EtNPr i2, NCS

Cl

S

Cl

THF

197

S Cl 104, 22%

Scheme 52

Cl S2Cl2 CO2H

S S

EtNPr i2, NCS

S S Cl

HO2C Cl

,,

Cl+

,,

Cl

S S Cl

Cl

Cl

Cl

CO2H

Cl S S

S S+ O

Cl 106

105, 51%

Scheme 53

Cyclopentenylacetic acid when treated with sulfur monochloride, Hu¨nig’s base and N-chlorosuccinimide in tetrahydrofuran gave trichlorocyclopenta[1,2]dithiole ester 104, a product of heterocyclic ring formation, chlorination and dehydrochlorination and, unexpectedly, the conversion of the acid in THF into its 4-chlorobutyl ester (1999JCS(P1)1023; Scheme 52). Under the same conditions indenylacetic acid afforded four crystalline products, the major being tricyclic 1,2-dithiolone 105 (1999JCS(P1)1023). While the indenylacetic acid conversion into 105 was not predicted, a pathway to it can be easily envisaged (Scheme 53) based on the demonstrated propensity of sulfur monochloride, NCS and Hu¨nig’s base to form 1,2-dithiole rings with activated allylic systems followed by extensive chlorination–dehydrochlorination that resulted in fully unsaturated and chlorinated products. This suggests acid group loss caused by decarboxylation and, probably, the formation of 3-chloro1,2-dithiolium chloride 106 which then reacts with some external oxygen nucleophile. Pentathiepinopyrroles 107 react with complex 108 obtained from sulfur monochloride and DABCO to give bis(dithiolo)pyrroles 109 in high yields (2005OL5725). Although pentathiepin rings and methyl groups are normally unreactive toward S2Cl2–DABCO at room temperature, pyrroles 107 react in an extensive cascade sequence. Presumably, the electron-releasing pyrrole nitrogen activated 107 to attack either the pentathiepin ring or a methyl group by the electrophilic reagent (Scheme 54).

198


S S

S

S S +

Me

N R 107

+

N

_ S Cl

Me 108

S

S

N S

N R

S

Cl

S

S S

109, 74−85% N

R = Me, Et, Pr n, Pr i, CH2Ph

N + S2Cl2

Scheme 54

H2N NH2

+ S2Cl2

N S

Ph3Sb S + 111

S +

N S 2Cl

N S

S

_

S

N S

110, 47%

Scheme 55

4.2 1,2,3-Dithiazoles 4.2.1 From amines A synthesis of benzofused 1,2,3-dithiazolium (Herz) salts by the action of sulfur monochloride on arylamines is the best-known synthesis of this class. Although it has been known for over 80 years (1922DEP360690), it is still in use. This chemistry was reviewed (1957CRV1011) and therefore here we describe the synthesis of heteroannulated 1,2,3-dithiazolium salts and new achievements in their preparation. Bis(1,2,3-dithiazoles) represent a new and potentially valuable class of heterocycles. A notable development is the ‘‘double Herz condensation’’ of 2,6-diaminonaphthalenes with sulfur monochloride which afforded naphthobis[1,2,3]dithiazole 110 after reduction of di-Herz salt 111 with triphenylantimony (1998CC1939; Scheme 55). Double Herz condensation of N-alkylated 2,6-diaminopyridinium salts with sulfur monochloride is an effective procedure for the preparation of bis[1,2,3]dithiazolopyridinium salts 112 (2004CM1564) that were readily reduced to the corresponding dithiazolyl radicals 113 by decamethylferrocene (Scheme 56). When 4-unsubstituted pyridinium salts were used, simultaneous chlorination accompanies the dithiazolium rings formation to give chlorinated salts 114 and radicals 115 after reduction in high yields (2002CC2562, 2003JA14394; Scheme 57). A few examples of the Herz reaction are known where the amino group is in the heterocyclic (thiophene) ring and thienodithiazolium salt 117 may be formed even if the carboxy group is in the ortho-position to the amino group in the heterocycle substituted by the dithiazole ring (1976KGS1355, 1979KGS447; Scheme 58).

199


H2N

R1 N+

NH2

N + S2Cl2

R2 OTf

R1 N

N

S S

S

_

OTf

R2 112

R1 = Me, Et R2 = Me, Ph

N

+ Cp*2Fe S

R1 N

S S

_

N .

S

S

R2 113, 56−58%

Scheme 56

H2N

R N+

NH2 + S2Cl2 OTf

R N

N

N

S

+ Cp*2Fe S

S

S

_

OTf

Cl 114

R = Me, Et

N S S

_

R N

N .

S

S

Cl 115, 64−83%

Scheme 57 NH3Cl

N S+ S _ Cl S

+ S2Cl2 S

116, 95% CO2H

S S2Cl2

Ph

S

NH2

72%

Ph

S

S+ N _ Cl

S2Cl2 65%

Ph

N

N

H N

N

N

S

S

NH3Cl

117

Scheme 58

N

N

NH2

N

N

SH

S2Cl2

S

S

S

118

Scheme 59

A series of condensed 1,2,3-dithiazoles were prepared by Oakley and coworkers from o-aminoaromatic and heterocyclic thiols and S2Cl2. This approach is more beneficial than a common Herz reaction that fails when applied to some aromatic amines, especially to phenylenediamines (1999JA969; Scheme 59). A two-step synthesis of quinoxaline-1,2,3-dithiazolium chloride 119 utilized quinoxaline aminothiol 120 and a mixture of sulfur monochloride and chlorine with further treatment of intermediate 121 with S2Cl2 (2001CJC1352; Scheme 60).

200


Cl N

NH2

N

SH

S2Cl2/Cl2 Cl

120

Cl N

N

N

S Cl

121, 66%

S Cl

Cl

S2Cl2

N

N

N

S

S Cl

Cl

_

119, 82%

Scheme 60

H2N

NH2

1. S2Cl2

N S

2. Ph3Sb HS

S

SH

N S

S

122, 60% Cl HS

NH2

1. S2Cl2

S

N

N

S

S

S H2N

SH

2. Ph3Sb

123, 49% H2N

N

NH2

HS

H N

N

S2Cl2

S S

SH

N +

S S

Cl 124, 75%

Cl

_

Scheme 61

R1

R2 + S2Cl2

H2N

Et3N

C(O)R3

R1, R2 = (CH2)3, (CH2)4, R3 = OEt R1 = Me, Ph, R2 = Me, R3 = Me, OEt

R2

R1 N

C(O)R3 S

S

125, 35−83%

Scheme 62

A great advantage of this method is the synthesis of bis(1,2,3-dithiazoles) from diaminodithiols (1997JA12136, 1999CM164, 2000JA7602). Reduction of radical cations formed with Ph3Sb led to neutral heterocycles 122 and 123 as air-stable crystalline solids (Scheme 61). Activated enamines are expected to be useful precursors for 1,2,3-dithiazoles. In fact, the reaction of b-ketoenamines with sulfur monochloride gave 5H-1,2,3-dithiazoles 125 via intramolecular cyclization of an intermediate N-thiosulfinylamine with the possibility of its isolation (1981H803, 1981BCJ3541; Scheme 62). Treatment of enamines 126 with sulfur monochloride and methanol afforded 5-methoxydithiazoles 127 in moderate yield. Remarkably, the reaction without methanol under the same conditions gave no products. The formation of


Me

Me + S2Cl2 H2N

N

Et3N

C(O)R 126

C(O)R S

S+ Cl

OMe C(O)R

Me

MeOH

N

_

201

S

S

127, 35−53%

128 R = Me, OEt

Scheme 63

R + S2Cl2 H2N

R

Et3N

N

Cl2

SO2F

R = H(CF2)5, C3F7

Cl S

S+ Cl

_

129, 68−71%

Scheme 64

R1

X

R1

R2

X

R2

R1

X

R2

+ S2Cl2 HON

NOH

N

S S O

N

130, 15−30%

N

O S O

N

131

X = CH2, CHMe, CM2, CHPh, CH(2-furyl), CH(2-thienyl), S, S(O), SO2 R1 = R2 = H, Me, Ph

Scheme 65

dithiazoles 127 can be explained as a methanolysis of the intermediate dithiazolium salt 128 (Scheme 63). Dithiazolium salts 129 were successfully isolated in the reaction of fluorinated enamines with sulfur monochloride; yields were high (1993ZOR491; Scheme 64).

4.2.2 From oximes A synthesis of annulated oxadithiadiazapentalene 130 can be achieved by the cyclization of 1,3-dioximes with sulfur monochloride. Moderate yields were accompanied by a small amount of dioxathiadiazapentalene 131. Although yields of pentalenes 130 were from low to moderate, it still is the most convenient route to all known compounds of this class (1979BSF199, 1984USP4440564, 1985JPP62036388, 1985JCS(P2)1797; Scheme 65). The single known N-oxide of 1,2,3-dithiazole 132 was isolated from cyclic oxime 133 and sulfur monochloride (1985TL189; Scheme 66). In other reactions, 1,2,3-dithiazole N-oxides were proposed as intermediates which underwent deoxygenation. Thus, 1-oximino-3-phenylindene formed 1,2,3-dithiazole 134 (1992JHC639, 1993JCS(P1)769; Scheme 67). This reaction was extended further to cyclopentenone and cyclopentanone oximes (Scheme 68). The greatest improvement in the syntheses was the use of N-ethyldiisopropylamine (Hu¨nig’s base) that led to the highest yields of

202


But

But S + S2Cl2 NOH

But

S N O

But

133

132

Scheme 66 Ph

Ph + S2Cl2

S N S

NOH

134, 60%

Scheme 67 Cl + S2Cl2

EtNPr i2, NCS

S S

Cl THF

NOH

N

EtNPr i2, NCS

+ S2Cl2

THF

NOH

Cl 135, 25%

Scheme 68

EtNPr i2

S S N

13%

+ S2Cl2 NOH

Cl2-5

EtNPr i2, NCS

S

21%

N

S Cl4-5 137

136

Scheme 69

dithiazoles 134 (80%) and 135 (25%). The introduction of chlorine atoms into the five-membered ring, for example, dithiazole 135, demonstrated a chlorinating capacity of sulfur monochloride and its role as an oxidant in the case of cyclopentanone and cyclopentenone oximes. Multiple chlorination, dehydrochlorination and oxidation steps in the formation of 135 suggest a complex multistage mechanism which makes the reaction sensitive to reaction conditions and may be responsible for lower yields. Where the carbon ring is protected with substituents (Schemes 66 and 67), chlorination is prevented. A reaction with seven-membered cyclic oximes proceeded similarly to give cyclopenta-1,2,3-dithiazoles 136 and 137 (1993JCS(P1)769; Scheme 69). For chlorination, up to 15 equivalents of sulfur monochloride were used and polychlorination was assisted by N-chlorosuccinimide. A similar reaction gave dithiazole 139 (Scheme 70) with acyclic a,b-unsaturated oxime 138.


203

Cl Ph

Ph

i

Ph

EtNPr 2

+ S2Cl2

Ph

N

S S 139, 23%

HON 138

Scheme 70

R R

S2Cl2, EtN(Pri)2

N S

Cl S

NOH Cl R = CH2CH2CN

140, 47%

Scheme 71

O R1

R1

S2Cl2, EtN(Pri)2, NCS, THF

R2 HO

O R4

R3

R5

S N S

N

R3 = Cl, But, Me, Pri, Me, ClCH2 R4 = Cl, Cl, Me, Pri, Me, Me R5 = H, Cl, H, H, Me, Cl

141

1

R = H, Cl, But, Me, Pri, Me R2 = H, H, H, H, H, Me O

O Cl

N S

S N S 142

S Cl 143

Scheme 72

Cyclopenta-1,2,3-dithiazole 140 was formed through a reaction of 2-substituted cyclopentanone oximes and S2Cl2 (Scheme 71; 2001CC403). Exhaustive chlorination accompanied this reaction as in the case of other cyclopentadithioles (see above). 6H-1,2,3-Benzodithiazol-6-ones 141 were prepared from p-benzoquinone4-oximes, S2Cl2, N-ethyldiisopropylamine and NCS (1998T223; Scheme 72). Some ring chlorination occurred and 2,6-substituents were retained in the products except for the tert-butyl group, which was replaced by chlorine. 1,4-Naphthoquinone 4-oxime and 1,2-naphthoquinone 2-oxime similarly gave dithiazole derivatives 142 and 143 (1998T223). A possible synthesis of the extensively studied 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) analogs (see next section) was found in the reaction of acetophenone oxime and its 4-nitro derivative with S2Cl2 (1994H1827, 1997BSB605; Scheme 73).

204


Ar

Ar

Cl

S2Cl2 N

N

HO

_ S+ Cl S 144

Ar = Ph, 4-NO2C6H4

Scheme 73 R RCH2CN + S2Cl2

+S

Cl S

N

Cl

_

R = Cl, Br, CN, MeS, C6F5, Ph, 4-MeOC6H4, 4-NO2C6H4

145, 20−85%

Scheme 74

R RCH2CN

S2Cl2 R

CN + S2Cl2

Cl

Cl Cl R S

S

Cl N

H S

Cl Cl

N

S

R +S

Cl

Cl

R S

Cl S

N

H

Cl S

N

Cl

_

145

Scheme 75

4.2.3 From nitriles An extensively studied and highly important 1,2,3-dithiazole – 4,5-dichloro-1,2, 3-dithiazol-1-ium chloride (Appel salt) 145 (R ¼ Cl) – was first prepared by Appel and coworkers in 1985 by chlorination of chloroacetonitrile by sulfur monochloride in dichloromethane (1985CB1632) and it has been the most convenient procedure to date. Appel salt can be obtained also by prolonged chlorination of acetonitrile itself, or by the sulfur monochloride reaction with ethylamine; the yields and experimental conditions were not disclosed (1985PS277). Recently, a series of mono-substituted acetonitriles were converted to 5-substituted-4-chloro-1,2,3-dithiazolium chlorides 145 (1999CC531, 2005MI346; Scheme 74). Where the 5-substitutent was not a good leaving group, chloride salts were converted into the corresponding perchlorates sufficiently stable to be characterized. Various mechanisms can be envisaged for the conversion of substituted acetonitriles into dithiazolium salt 145, yet no firm evidence has been given. The first step could be the chlorination of acetonitrile by sulfur monochloride, as demonstrated for acetonitrile itself (1985CB1632) and for phenylacetonitrile (1939ZOK1329). This could be followed by sulfur monochloride addition to the cyano group, cyclization and ionization (Scheme 75).


205

Cl

NC

CN + S Cl 2 2

Bu4NCl

Cl

N S

CH2Cl2, rt

Cl

_ N S+ Cl 146, 78% S

Scheme 76

Ar

Cl

Me N + S2Cl2

NH Cl

O

CN

O

Bu4NCl

Me

N

N

O

O

CH2Cl2, rt Cl

N S

Ar 147

148

Scheme 77 N S O + S2Cl2

60−70 °C

R

N Cl

S+

S

Cl

_

149, 15−35%

R = Cl, Br, I, NO2

Scheme 78

Glutaronitrile reacted with sulfur monochloride to afford isothiazolyldithiazolium chloride 146 by an unknown mechanism (2002CC1872; Scheme 76). Bicyclic oxathiadiazapentalene 147 was prepared from acetonitrile derivative 148 with sulfur monochloride under the same conditions (1981USP4260624; Scheme 77).

4.2.4 From other sources 6-Chloro-3H-1,2,3-benzodithiazolium chloride 149 can be prepared from p-substituted N-sulfinylanilines and sulfur monochloride when the substituent R is a good leaving group (1967RRC427; Scheme 78). Nu-Arylthiocarbamoyl-N,N-dialkylamidines 150 are useful intermediates for many heterocyclic systems (1996T8413), one being a reaction with sulfur monochloride that led to dithiazoles 151 (Scheme 79).

4.3 1,2- and 1,4-Dithiines The synthesis of 1,4-dithiines from arenes and heteroarenes has been known for more than 100 years. The reaction of quinoline and sulfur monochloride gave dithiodiquinoline 152 (R1 ¼ R2 ¼ H) (1896JPR340). The structure of such compounds has been correctly identified only recently (1976PJC785, 1997JCR(S)435; Scheme 80).

206


NH

H N

NR22 S

NR22

N

Pyridine + S2Cl2

1

S S

1

R

N

R

151, 44−84%

150 1

R = 3-NO2, 4-NO2, 4-Cl, 4-Br, 4-Me, 4-OMe R2 = Et, Pr, Bu, allyl

Scheme 79 R2 N 2

R

R1

N

S

R1 = R2 = H R1 = Me, R2 = H R1 = H, R2 = Me

S

+ S2Cl2 R1

N 152 R2

R1

Scheme 80

R

AlCl3

R

S

R

S

R

+ S2Cl2 R

R

153, 10−90%

R = H, OMe, OEt

Scheme 81

The preparation of thianthrene 153 (R ¼ H) from benzene, sulfur monochloride and aluminum chloride is the most inexpensive and simple method (1921LA265, 1956JA2163, 1976DEP2549435), also used for the preparation of other thianthrenes 153 (1972JCS(P1)1687; Scheme 81). Only two examples of the 1,2-dithiine synthesis from biphenyls are known (1996NJC1031), although this transformation is the expected one. Dibenzodithiin 155 was formed in a reaction of 3,3u, 4,4u, 5,5u-hexamethylbiphenyl 154 with sulfur monochloride at low (0–5 1C) temperature. At room temperature the main product was bis[1,2]dithiine 156. Surprisingly, monodithiine 155 did not convert to bisdithiine 156 after treatment with S2Cl2, and this probably implies that the addition of two sulfur monochloride molecules to biphenyl 154 took place simultaneously (Scheme 82).

4.4 Other heterocycles with two sulfur atoms The insertion of two sulfur atoms between two carbons separated by one or two other atoms is an expected process, albeit examples of these transformations are few.


MeO

OMe

MeO MeO

0−5 °C

OMe

MeO

rt MeO

OMe S S

OMe

155, 88%

OMe + S2Cl2

MeO

207

MeO

OMe 154

S S

OMe

MeO MeO

OMe S S

+ 155, 22.5%

OMe

156, 58%

Scheme 82 OH

O O

O Pyridine

N

N

N S N S

+ S2Cl2

O

O HO

O 158, 65%

157

Scheme 83

Me O

N

CO2Et O N

NaH, dioxane + S2Cl2

Me CO2Et

CO2Et O N Sn N O Me CO2Et

Me

n=2, 160, 17% n=4, 161, 9%

159

Scheme 84

Pyrazinodiindole 157 reacted with sulfur monochloride and pyridine to give epi-dithio derivative 158 (an aromatic analog of arantins) (1977JOC948; Scheme 83). A similar transformation of piperazindione 159 led to disulfide 160 and tetrasulfide 161, also isolated in somewhat lower yield (1971TL3127; Scheme 84). Another interesting reaction is the formation of epi-dithiooxaanthracenones from alkylydene-bisphenols (1988HCA1101). Bicyclic 1,3,4-oxadithiolane 163 – a rare ozonide analog in which two oxygen atoms are replaced by two sulfur atoms – was obtained by intramolecular cyclization of monohydrazone 162 with sulfur monochloride in the presence of triethylamine. No mechanism was given (1992CC7; Scheme 85). 1,2,3,5-Dithiadiazolyl radicals are considered to be organic molecular magnets and conductors and therefore chemists display increasing interest. Treatment of

208


Ph

O Ph

N NH2 + S Cl Me 2 2 Me

Me Me

S S

Ph Me

Et3N

O

Me

Ph Me Me

163, 56%

162

Scheme 85

Cl S

H2N+ S H2N

Ar 164

H S N

Cl S N S

+ S2Cl2 S N Cl S

Ar

−HCl − “S”

S S N

Ar −“S”

Ar = Ph, 4-ClC6H4, 4-CF3C6H4, 4-MeC6H4, 4-MeOC6H4, 2,4-(NO2)2C6H3

Ar S N +S N _ Cl S 165, 55−73%

Scheme 86

S-benzyl-iso-thiuronium chlorides 164 with sulfur monochloride provides a convenient method for preparing S-benzyl-1,2,3,5-dithiadiazolium chlorides 165 (2002ARK224). Based on the formation of similar products from amidines and guanidines with sulfur dichloride, the authors proposed a mechanism which included the addition of two S2Cl2 molecules to amidine 164 followed by HCl and sulfur extrusion (Scheme 86). The preparation of tris(1,2,3,5-dithiadiazolyl)-1,3,5-triazine 166 was achieved through treatment of tricyanotriazine in refluxing sulfur monochloride in the presence of excess ammonium chloride. Reduction of the trication with triphenylantimony yielded triradical 167 (1993IC1554; Scheme 87). Interestingly, the usual strategy for the preparation of 1,2,3,5-dithiadiazolyls through amidines and their analogs failed. A new class of sulfurated heterocycles – dithiadiazaphospholidine S-oxides 170 – was obtained by treatment of phosphonic diamide 168 with sulfur monochloride; its precursor heterocycle 169 was detected in the mixture. However, it was found to be susceptible to oxidation and only S-oxide 170 was isolated (1995CC1449; Scheme 88).

5. HETEROCYCLES WITH THREE SULFUR ATOMS Non-symmetric isomers of benzotrithiadiazepine 173 were prepared by 1:1 condensation of azathienes 171 with sulfur monochloride followed by intramolecular ortho-cyclization of intermediate 172 (2001CC1774). In the case of meta-substituted

209


S S N + N

CN N NC

N N

NH4Cl

+ S2Cl2

N

Ph3Sb

N

N S + S N

CN

S S . N N N

N + S N S _ 3Cl

N 166

N S

N N

N

.

.

S N

S

N S 167, 12%

Scheme 87

O Ph t But P Bu N N H H

+ S2Cl2

O Ph Bu N P N But S S t

Pyridine

168

O Ph Bu N P N But S S+ _ O

[O]

t

170, 83%

169

Scheme 88

R

R N

S

S S N N S

R

+ S2Cl2 N

N

S

−HCl

N

SiMe3

SSCl

171

173, 3−10%

172

R = H, Br Me S S N + S N

+ S2Cl2 Me

N

S

N

Me SiMe3

174, 4.5%

171, R = 3-Me

S S N N S 175, 2.5%

Scheme 89

N

N S

N H 176

N S

+ S2Cl2 N H

SSCl Cl

177

−HCl

S N S

S 178, 30%

Cl

Scheme 90

precursor 171 (R ¼ 3–Me), cyclization was not regioselective and led predominantly to 7-methyl substituted derivative 174 (Scheme 89). 2-Allylthiobenzimidazole 176 reacted with sulfur monochloride to give trithiazepinobenzimidazole 178 (2002MI317). The formation of intermediate 177 by S2Cl2 addition to the double allylic bond was proposed (Scheme 90).

210


6. HETEROCYCLES WITH FOUR SULFUR ATOMS Heterocycles containing four consecutive sulfurs and one or two carbons, or two S–S bonds separated by carbon atoms are commonly prepared. A reaction of sterically hindered hydrazone 179 with sulfur monochloride led to disubstituted tetrathiolane 180 in low yield together with 1-adamantyltert-butyl thioketone 181 as the main product (1996CC2681; Scheme 91). If a diluted solution of dithiole 182 and sulfur monochloride in ether were mixed at low temperature, tetrathiane 183 was formed in low yield (1995JOC8056). The precipitation and purification of the final product were achieved by cooling the mixture to 78 1C (Scheme 92). Bis-titanocene complex 184 reacted with one equivalent of sulfur monochloride to give intermediate mono-titanocene 185 which, upon treatment with ethane-1,2-disulfenyl chloride, transformed to bicyclic sulfur–carbon heterocycle 186 (1991CB2141; Scheme 93). An unusual seven-membered diazaphosphatetrathia heterocycle (190) containing a chain of four sulfur atoms was obtained using diaryl or dialkyl phenyl phosphonamide 187 with sulfur monochloride in the presence of pyridine base (1993CC1684). A mechanism of the formation of 190 remains unclear but 190 was possibly formed via expected disulfide 188 which might be in equilibrium with bis(thionitroxide) 189 and the latter, in turn, could then further react with S2Cl2 (Scheme 94). The extension sulfur chain was explained by the S2Cl2 addition and But Ad

N + S2Cl2 NH2

−78 to + 20 °C

But Ad

179

S S S S

But +

S Ad 181, 46%

180, 5.5%

Ad = 1-adamantyl

Scheme 91

SH

S

+ S2Cl2

S S S

SH 182

183, 10%

Scheme 92

S Cp2Ti

TiCp2 + S2Cl2 S

S

ClS S + S S ClS

S

S S

184 Cp = cyclopentadienyl

Cp2Ti S 185

Scheme 93

S S

S S

S S

S S

186, 20%


O Ph R N P N R S. S .

O Ph R N P N R S S

O Ph R P R + S Cl 2 2 N N H H 187

2S2Cl2

R

− SCl2

189

188

211

O PhR P N N S S S S

190, 24−25%

t

R = Bu , Ph

Scheme 94 O

O NHR NHR O

+ S2Cl2

−HCl O

191 O

NHR S2Cl2 S2

RHN

NHR

−HCl

−HCl

191 NHR

193

O

RHN S2 RHN O

O 194

O

R N S S

Cl O

O

RHN

O

O NHR NR S S

NHR

RHN(O)C

S S

C(O)NHR

R N

RHN(O)C

S S

C(O)NHR

S

S

Cl 192, 77−92%

O

R = Pr, Pri, CH2Ph, Ph, 4-MeC6H4

Scheme 95 O

O S S O + S2Cl2

O

O S S O 195, 82%

Scheme 96

SCl2 loss, similar to how it was explained for the formation of pentathiepins (2005OBC3496) (see Section 7.1). Although the first report on the reaction of sulfur monochloride with compounds containing active methylene groups had been published more than 120 years ago (1885CB2090), correct structures of the isolated products were proved only 28 years ago (1980CJC1233). The reaction of N,Nu-dialkyl- and diarylmalonodiamides 191 with sulfur monochloride gave symmetrically substituted 1,2,4,5-tetrathianes 192 (Scheme 95). The reaction was apparently initiated by N-sulfenylation and the possible intermediate formation of 1,2,3-dithiazolidine 193 followed by the addition of the second diamide molecule with the formation of disulfide 194 and a final rearrangement to tetrathiane 192. Tetrathiane 195, similar in structure, was prepared by treatment of 3(2H)benzofuranone with sulfur monochloride (1996T1961; Scheme 96).

212


RO

RO

S S

OR

RO

S S

OR

RO

S S

OR

RO

S S

OR

+ S2Cl2 RO i

R = Me, Et, Pr etc

197, R = H, Me, 29−33%

196, 16−65%

Scheme 97

R R Et

Et

R R Et

Et N H

N H

S2Cl2

S

N H

N H

S

−78 °C

S

H N

H N

S

R = H, Me

Et

Et R R 198, 34%

Scheme 98

S2Cl2 NH

HN

−78 °C

S S

NH

HN

NH

HN

S S

199, 27%

Scheme 99

Other heterocyclic compounds containing four sulfur atoms – tetrathiocines 196, 197 – were synthesized from activated aromatic compounds, in particular 1,2-dialkoxybenzenes or 2,3-dialkoxynaphthalenes, and sulfur monochloride in acetic acid in fairly good yields (1989PS111; Scheme 97). Biphenyl 154 treated with S2Cl2 under the same conditions yielded 1,2-dithiines (see Section 4.3). A reaction of a,au-free pyrroles under argon at 78 1C with sulfur monochloride furnished disulfide-linked oligopyrrolic macrocycles 198 and 199 (2005CC2122; Schemes 98 and 99). It is noteworthy that S2Cl2 under the identical reaction conditions may lead to products containing sets of three sulfur atoms (see Section 8). These systems bear an important analogy to known carbon-linked oligopyrrole macrocycles. They or their putative congeners may play a role as ligands in cation complexation or as receptors for anion recognition. An iron-catalyzed reaction between bis(2,4-dimethoxyphenyl)sulfide and sulfur monochloride in dilute chloroform led to a mixture of metacyclophanes in

213


OMe

OMe

OMe S + S2Cl2

MeO

OMe S S

Fe, 7 d at rt

+ MeO

OMe

OMe S

OMe

MeO

OMe

S OMe 200, 7%

S MeO

OMe S

S

MeO

S

OMe

OMe

OMe

201, 6%

Scheme 100

low yield. Tetrathiacyclophanes with three (200) or four (201) phenyl rings were the major products (1981JCS(P1)718; Scheme 100).

7. HETEROCYCLES WITH FIVE SULFUR ATOMS 7.1 1,2,3,4,5-Pentathiepins One of the simplest routes to pentathiepins is a reaction of 1,2-dithioles or their salts with sulfur monochloride. There are few examples where the starting material is dithiol salt (1980JOC5122, 1994IC4537, 1995T2533, 1999AM758; Schemes 101–104). Isothiazolopentathiepin 202 was generated almost quantitatively (1980JOC5122); with hexalithium hexamercaptobenzene, the combined product yield was also very high but the major product was tristrithiole 204 (1995T2533). Only one pentathiepin ring was built (203), trithiole rings being more preferably formed in this situation. Further examples of this reaction where a dithiolate is generated in situ are shown in Schemes 105–111 (1981USP4275073, 1985JA3871, 1993JOC4522, 1993JA7017, 1994JOC5955, 1994MI101, 1995JA7261, 2001CC403). An unusual synthesis of pentathiepins fused to another heterocyclic ring was discovered recently by Rees and coworkers (2002CC1204). Treatment of nucleophilic heterocycles such as pyrroles and thiophenes and their tetrahydro derivatives with sulfur monochloride and a base (usually 1,4-diazabicyclooctane, DABCO) provided a simple one-pot synthesis of condensed mono- and bis-pentathiepins, sometimes in surprisingly good yields (2005OBC3496). N-Methylpyrrole and its 2-chloro and 2,5-dichloro derivatives all gave the same dichloropentathiepin 214a (Scheme 112).

214


NC

S

_

S

NC + S2Cl2

_ N

S S

S

S

S

N

2 Na+

S S

202, 98%

Scheme 101

S S S

SLi LiS

SLi

S S S S S

+ S2Cl2 LiS

SLi

S S S

SLi

S S S

S S

+ S

S S S

204, 74%

203, 20%

Scheme 102

S

S

S

S

S

S

S

S

_ _

S

S

S

S

S

S

+ S2Cl2

2 NH4

+

S S S S S

205, 27%

Scheme 103

S

S

S

S

S

_

S S

Zn2+ + S2Cl2 _

S

S S S S S

206, 58%

Scheme 104

OMe MeO

SAlk

Na

MeO

OMe Na+ _ S S Cl MeO 2 2

SAlk NH3 R

S R

OMe S S S S S

_

Na+

R 207

R = CH2CH2NHC(O)OCH2CH2SiMe3

Alk = a Prn, 28% b Bun, 47%

Scheme 105

N-Methyl-, N-ethyl, N-isopropyl- and N-tert-butyl-pyrrolidines, which are readily available from the reaction of dichloro- or dibromobutanes and their corresponding amines, all gave N-alkyl dichloropentathiepinopyrroles 214 as the main products in low-to-moderate yield (16–31%). Additionally,


SBut

Me

S S S S S

Me

S2Cl2

SH

208, 86%

Scheme 106

OMe

OMe SBut

MeO

S S S S S

MeO

S2Cl2

SBut

NHBoc

NHBoc 209, 59%

Scheme 107

R1

R1

R1 2

R

R2

S

SH

OR4 S

S2Cl2

R2

S S S S S

SH R3

R3

R3

210 a R1 = R2 = R3 = H, R4 = Bu b R1 = Me, R2 = R3 = H, R4 = Bu c R1 = R2 = OMe, R3 = CH2CH2NHBoc, R4 = CH2CH2CMe2

Scheme 108

CH2CH2CN N S

Cl Li2S S

Cl

CH2CH2CN N S

SLi S

NCCH2CH2

S S S S S

S2Cl2 N S S

SLi

211

Scheme 109

Br

S2Cl2

S

S Br

S S

SH BuLi S8

S SH

S

S S

212, 2%

Scheme 110

215

216


_ SCH2Ph

Na/NH3

Me N N

S Me N

Me N

_

N

SCH2Ph

S S

S2Cl2

S

N

2Na+

S

S S

213, 21%

Scheme 111

S2Cl2 N Me

50%

S

S S Cl

S S

N Me

S2Cl2 60−70% Cl

Cl

R

N Me R = Cl R=H

214a

Scheme 112

S S

S2Cl2

S

S S

S S +

N R

Cl

a b c d

N R 214

Cl

N R

S

S S S S

215 R = Me, 5%

+

Cl

N R

S

S S

216 R = Et, 23%

R = Me 31% R = Et 29% R = Pri 16% R = But 31%

Scheme 113

N-methylpyrrolidine gave a small amount (5%) of unchlorinated compound 215 with the pentathiepin ring fused across the 2,3-pyrrole bond and N-ethylpyrrolidine gave a higher percentage (23%) of product 216 fused similarly to the former but chlorinated in the free a-position of the pyrrole (Scheme 113). N-Isopropylpyrrolidine gave an unexpected mixture of two pentathiepins with the N-isopropyl groups remaining intact, dichloromonopentathiepin 214c and bispentathiepin 217 (Scheme 114). The latter, a yellow oil, is believed to be the first bispentathiepin reported (2004CRV2617). Thiophene gave a mixture of oligomers without pentathiepin products; apparently the ring is very reactive toward S2Cl2 and about a half of its hydrogen atoms, judging from NMR spectra, appeared to be substituted by sulfur. A reduced ratio of S2Cl2 and DABCO did not improve the situation but simply afforded similar oligomers in lower yield. Tetrahydrothiophene gave pentathiepin 218 and the yield increased as the S2Cl2–DABCO mixture was reduced from a sixfold excess (24%) to a fourfold excess (39%) (Scheme 115), which suggests

217


S2Cl2 N

S S

DABCO

S S

S S S

N

S

S S

S S

S

S S

+

Cl

217, 31%

Cl

N

214c, 16%

Scheme 114 S S

S2Cl2 DABCO

S

S

S

S S

218, 39%

Scheme 115

N

N + S2Cl2

N

+

N S

DABCO

N

+

N S

_ S Cl

DABCO

N

_

Cl 219

+

N

S 2Cl 220

Scheme 116

a possible conversion of 218 to a mixture of oligomers; indeed in a blank experiment, 218 reacted with S2Cl2 to give such a mixture. Too little is known about the nature of these reactions, although possible overall reaction pathways, including dehydrogenation of tetrahydroaromatics, chlorination and sulfuration of aromatics and their conversion into SSCl derivatives, and the pentathiepin ring formation, were proposed. Other aromatic heterocycles, such as indoles and furan, did not yield pentathiepin products under these conditions. Also, where there was more than one site for fusion of the new polysulfur ring, these reactions were not regioselective and were sensitive to the nature of the heterocycle and conditions (2005OBC3496, 2004MC91). Recently it was found that a mixture of equimolar amounts of S2Cl2 and DABCO in chloroform, stored for 48 h at 0 1C or 1 h at room temperature before use, formed complexes 219 (1:1 mixture of S2Cl2 and DABCO) and 220 (1:2 mixture of S2Cl2 and DABCO) (2004MC91; Scheme 116). These complexes could exhibit different reactivities, since 219 is a potential Cl+ and +S–SCl source and could be an electrophilic chlorinating and sulfurating agent, while 220 should react only as the latter. A reaction of N-alkyl-and N-phenyl-2,5-disubstituted pyrroles with complex 219 at 0 1C gave the best yields of the corresponding pentathiepins 221 under conditions which include treatment with non-premixed sulfur monochloride and DABCO and with complex 220 (2005OL5725; Scheme 117). Treatment of N-alkyl-pyrrolidines and -indoles with a fivefold excess of complex 220 in chloroform for 48 h at room temperature gave regioselectively

218


R2

0 °C

+

N

+

R2

N R1

N S Cl

R1 = Me, Et, Prn, Pri, Bn R2 = Me, Ph

S S

_ S Cl

S

S S

R2

2

R N 1 R 221, 36−62%

219

Scheme 117

+

+

N

N S

N

S

N R

S S

48h

+

N

S S

r.t.

S N R 222, 29−61%

_

R = Me, Et, Pri, But

2Cl 220 +

N S

N +

+

N

S

N

_

N R

S S

48h r.t. N R

2Cl 220

S

S S

223, 51−62%

R = Me, Et

Scheme 118

S S

EtNPri2/S2Cl2 Me

X

Me

48 h,−10 °C

Me

S

X

S S Me

224 X = 225 S, 13% 226 O, 11%

Scheme 119

N-alkyl-1,2,3,4,5-pentathiepinopyrroles 222 and indoles 223 in moderate yields (2004MC91; Scheme 118). Even milder conditions were used for the preparation of thienopentathiepin 225 and pentathiepinofuran 226 from the corresponding heterocycles 224 (2006MC289). These heterocycles with sulfur monochloride and N-ethyldiisopropylamine at low (10 1C) temperature gave pentathiepins 225 and 226 although in low yields (Scheme 119). The various, complex, cascade reactions described above converted simple saturated and aromatic heterocycles into polycyclic pentathiepins and their chlorinated and rearranged derivatives; this strikingly illustrates the extensive reactivity of S2Cl2 and its complexes with bases, particularly DABCO. This reactivity encompassed dehydrogenation of tetrahydroaromatics, chlorination and sulfuration of aromatics and their conversion into SSCl derivatives,


219

pentathiepin ring formation and pentathiepin-to-pentathiepin rearrangements. It was also proposed that –SnCl chains could be extended to give –S(n+1)Cl chains by the S2Cl2 addition and SCl2 loss and, ultimately, the thermodynamically stable (2004CRV2617) pentathiepin ring. A typical mechanism is presented in Scheme 120 (2005OBC3496). Sulfur monochloride was successfully used for the preparation of pentathiepino-fused poly(N-methylpyrrole) from the corresponding polymer (2005MI345). With triethylamine in toluene, S2Cl2 converted indane derivative 227, probably activated by the enedithio group, into pentathiepin 228 in low yield (1974JCS(P1)447; Scheme 121). More curious and unexpected reactions were observed when complex 219 was heated with triethylamine often used as an ‘‘inert’’ base in many reactions with sulfur monochloride. Thienopentathiepin 229 (30%) together with heptathiocane 230 (10%) were produced; their polysulfur rings had the anticipated chair and crown conformations, respectively (2003OL1939; Scheme 122). Similar reactions were observed with other tertiary N-ethylamines though in lower yields. Despite rather low yields in most instances, the products were prepared in one pot and from cheap starting materials. The thiophene ring of 229 was built from two ethyl groups with a new C–C bond established between two formally unactivated methyl groups; the pentathiepin ring was fused onto S2Cl2 N Me

N Me

S2Cl2

base +

_

Cl + S Cl S S S Cl

N Me

N Me

−SCl2

S2Cl2 +

base

N S-SCl Me

N Me S2Cl2

N Me

S3 Cl

−SCl2

S2Cl2 S4 Cl

N Me

Cl S S N Me

S

S S

S S −HCl N Me

S

S S

Scheme 120

S

S

S2Cl2

S S

S S

S

Et3N S

S

228, 14%

227

Scheme 121

H

−SCl2

base S2Cl2

220


Et2N +

DABCO

N S

Et3N + N

_ S Cl

S S S + Et2N S S

S

CHCl3

Cl

Et2N

S

S

S S S

230, 10%

229, 30%

219

S

S

Scheme 122

CH3

CH3 +

Ph

N OH

N OH

S S

S2Cl2

Ph

S

S S

NH2 Ph

N H

OH

Ph

231, 2%

Scheme 123

R Ph

N + S2Cl2 NH2

−78−20 °C

R = 1-adamantyl, But, Ph

R S S

R S S S + Ph S S 232, 4−11%

R S + Ph S S S Ph 233, 3−7%

R O +

15−63%

S Ph 15−63%

Scheme 124

thiophene as in the above transformations (see Schemes 112–115, 117–120). Mechanisms were proposed. Pyrrolopentathiepin 231 was found as a minor by-product in a curious and completely unexpected reaction of acetophenone oxime and sulfur monochloride in the presence of pyridine and o-aminophenol (1997BSB605; Scheme 123). A possible mechanism was suggested.

7.2 Other heterocycles with five sulfur atoms Treatment of hydrazones derived from 1-adamantyl phenyl ketone, pivalophenone and benzophenone with sulfur monochloride gave pentathianes 232 and hexathianes 233 along with the corresponding ketones and thioketones as the main products (1997H255; Scheme 124). Surprisingly, under these conditions di-tert-butyl ketone hydrazone afforded 1,1-di-tert-butyltetrathiolane in very low yield (2%) (see similar reaction in Scheme 91). A reaction of dithiadiazocanes 234 with sulfur monochloride gave a novel macrocyclic polysulfide, 1,2,3,5,7-pentathiocanes 235, in moderate-to-high yields (2002CL90). The NMR monitoring of this reaction suggested that a plausible route involved the formation of an oxidative transannular S–S bond in a thermally stable secondary species, a symmetrical dithiadication 236, followed by

221


S N Ar + S2Cl2

Ar N

Ar N

S 234

+ S S +

,, N Ar

Ar N

S S

S

,, S8

236

Ar N

S S S

S 235, 18−72%

Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4

Scheme 125

subsequent removal of half of the product 236 by the attack of some nucleophiles derived from elemental sulfur formed from sulfur monochloride (Scheme 125).

8. HETEROCYCLES WITH SIX OR MORE SULFUR ATOMS Hexathiaspirododecane 237 containing six sulfur atoms in the ring was prepared from titanocene complex 238 with sulfur monochloride (1996ZAAC1594). The structure of 237 had a chair conformation as identified by X-ray analysis (Scheme 126). A new sulfurimide heterocycle with six sulfurs – octyl hexathiazepane 239 – was obtained from titanocene complex 240 in high yield (1998AG(E)492; Scheme 127). Sulfur monochloride reacted with another titanocene complex 241 to give nonasulfur imide 242. The reaction proceeded smoothly at room temperature (1996AG(E)2537; Scheme 128). Treatment of 3,4-diethylpyrrole with a,au-free positions using sulfur monochloride under argon at 78 1C gave macrocycle 243 where two pyrrole rings were linked by two chains of three sulfur atoms (2005CC2122; Scheme 129). The mechanism is unknown. However, it is noteworthy that under identical conditions sulfur monochloride gave products with a different number of bridging sulfur atoms depending on the pyrrole structure (see also Schemes 98 and 99). Various aromatic compounds were intensively studied in reactions with sulfur monochloride to achieve macrocyclic multisulfur oligomers. A highdilution methodology was usually used which often led to the selective formation of cyclic products. 1,4-Dialkoxybenzenes reacted with sulfur monochloride in the presence of Montmorrilonite-K catalyst to give macrocycles 244 in surprisingly moderate yields (1972JCS(P1)1687; Scheme 130). The structure of these compounds was confirmed by transformation to the corresponding dithiols or disulfonyl dichlorides. The iron-catalyzed reaction of 1,3-dimethoxybenzene with sulfur monochloride in dilute chloroform gave two polysulfur heterocycles 245 and 246 with six sulfur atoms in the molecule, yields were very low (1979JCS(P1)1712; Scheme 131). The structure of compounds 245 and 246 was confirmed by mass and NMR spectroscopy.

222


S S

S S

S S

TiCp2 + S2Cl2 S S

S S


237, 51%

Scheme 126

S S Oct N

TiCp2 + S2Cl2

20 °C

S S

S S S Oct N S S S


239, 91%

Scheme 127

Cp2TiS7NH + S2Cl2 241

rt

S HN S

S S

S S S

+ Cp2TiCl2

S S 242, 54%

Scheme 128

EtEt

Et Et Et

Et

N H

Et N H

S S S

S2Cl2 −78 °C

Et

Et

N H

N H

H N

H N

S S S

Et

EtEt 243, 21%

Scheme 129

OR

S + S2Cl2

Montmorrilonite-K

RO

S

S

S

RO OR

OR

S

R = Me, Et

S

S

OR S

244, 52−59%

Scheme 130

223


OMe

OMe S S

MeO MeO + S2Cl2

S S S

OMe

Fe

+ MeO

OMe S

MeO

OMe

S S S

S S

OMe

S

MeO 245, 5%

OMe 246, 1.5%

Scheme 131

Me

Me S S

Me + S2Cl2

Me

FeCl3 Me 18%

S

Me

Me Me Me Me

Me S Me

Me Me FeCl3

Me

S

Me

18% Me Me

Me S S Me

Me 247

Scheme 132

Treatment of mesitylene or dimesityl sulfide with sulfur monochloride led to the same polysulfur macrocycle 247; yields in both cases were identical (1977T337; Scheme 132). These investigations continue because these macrocyclic oligomers are promising reactive intermediates for the synthesis of high-performance linear aromatic polymers by ring-opening polymerization. Pseudo high-dilution conditions which were achieved by a slow addition of diphenyl derivatives 248 to the sulfur monochloride and iron powder catalyst led to a mixture of oligomers 249 in almost quantitative yield (1998MI6469, 2004MI735, 2004CNP1470511). MALDI-TOF mass-spectra showed that repeated cyclization units ranged from two to seven and a unit of the macrocyclic (arylene multisulfide) oligomers had from one to seven sulfur atoms (Scheme 133). Polysubstituted benzene-1,3-dithioles are employed in the synthesis of polysulfur-bridged metacyclophanes. Surprisingly, the quantity of sulfur atoms inserted into the polycyclic ring may vary significantly. For example, when 4,6-dimethoxybenzene-1,3-dithiol was used in the reaction with sulfur monochloride, only one product with six sulfur atoms 245 was isolated (1979JCS(P1)1712). Mesitylene-2,4-dithiol gave two oligomers, an unsymmetrical hexathiametacyclophane 250 as the major product accompanied by minor amounts of higher homolog 251. Compounds 250 and 251 were produced in equal yields by using sulfur dichloride instead of S2Cl2 (1980T3095; Scheme 134).

224


Fe

H Ar H + S2Cl2

Sx n

Ar Ar

x = 1-7 y = 1-7 n = 1-3

Sy n

249

248 Ar =

O

H2 C

S Me

Me

Me

Me

S2

Scheme 133

Me

Me Me

Me

SH

SH

+ S2Cl2 Me

S S2 S Me Me S Sn S

Me

Me

n = 0, 250, 50% n = 1, 251, 5%

Scheme 134

9. CONCLUSIONS The reactions described show that sulfur monochloride is an important reagent for the synthesis of heterocycles with various numbers of sulfur atoms and even without sulfur. An important feature of this reagent is that it can add not only two sulfur atoms to the molecule, as might be expected, but also one, three, four, five or even more atoms, and the structure of the final compound often depends on its stability. Recent developments in the use of sulfur monochloride include the discovery of its ability to form complexes with organic bases and of the significant difference in reactivity of these complexes from S2Cl2. A selective synthesis of particular heterocycles requires accurate conditions (temperature, solvent, catalyst and base).

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1998JOC2189 1998KGS1130 1998MI145 1998MI6469 1998T223 1998TL2467 1999AM758 1999CC531 1999CM164 1999JA969 1999JCS(P1)1023

227

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228


1999JCS(P1)2237

1999JMC1999

1999JOC4376 1999JOC5010 1999JPR99 2000JA7602 2000JCS(P1)3421 2001CC403 2001CC1774 2001CJC1352 2001JCS(P1)2409

2001JOM173 2001MC165 B-2001MI 2002ARK224 2002CC1204 2002CC1872 2002CC2562 2002CL90 2002HAC424 2002JOC2453 2002MI317 2002TL499 2003JA4199 2003JA14394

2003OL929

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2003OL1939 2004CM1564 2004CNP1470511 2004CRV2617 2004MC91 2004MI735 2004S1929 2005CC1218

2005CC2122 2005CNP1583741 2005MI345 2005MI346 2005OBC3496 2005OL5725 2005ZOB493 2006EJO849 2006MC289 2006MI212 2006RCB143

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SUBJECT INDEX Acetophenone oxime, reaction with sulfur monochloride, 190 reaction with sulfur dichloride, 203 N-Acetyl-10-bromodibenzazepine, reaction with potassium tert-butoxide and N-methyl pyrrole, 11 reactions, 16 5,5-Adamantyl-t-butyl tetrathiolane, 210 Adenine-based organometallic metallacalixarenes as hosts for some biologicals, 143 Adenine, reaction with metal ions to form metallacalixarenes, 132 reaction with cupric ions, 138 reaction with iridium complexes, 148 reaction with ruthenium complexes, 145 reaction with silver perchlorate in perchloric acid, 137 Adenosine 5u-monophosphate, reaction with rhodium complexes, 143 selective binding by metallacalixarenes, 153 Adenosine-5u-monophosphoric acid, reaction with cadmium salts, 138 N-Alkylated 2,6-diaminopyridinium salts, reaction with sulfur monochloride, 198 N-Alkylation of indolo benzazepinones, 57 2-Alkylbuta-1,3-dienes, reaction with sulfur monochloride, 179 N-Alkyldichloropentathiepinopyrroles, synthesis, 214 N-Alkyl(phenyl)-2,5-disubstituted pyrroles, 217 N-Alkylindoles, reaction with sulfur monochlorides, 217 N-Alkylisoindolo[2,1-b][2,4]benzodiazepines, 38 N-Alkyl-1,2,3,4,5-pentathiepinoindoles, synthesis, 218 N-Alkyl-1,2,3,4,5-pentathiepinopyrroles, synthesis, 218 N-Alkylpyrrolidines, reactions with sulfur monochlorides, 214, 217 Alkylydene-bisphenols, reaction with sulfur monochloride, 207 2-Alkynyl-paullones, 66 9-Allyladenosine, in tetrameric metallacalixarene with silver ions, 137 2-Allylthiobenzimidazole, reaction with sulfur monochloride, 209 Alstonamine, isolation, 83

2-Aminoacid amides, conversion to 3-hydroxythiadiazoles, 182 o-Aminoaromatic thiols, reaction with sulfur dichloride, 199 2-Aminobenzonitrile, reaction with o-carboxymethyl bromoacetophenone, 7 2-Aminobenzothiazoles, synthesis, 188 7-Aminobenzo[b]thieno[2,3-f ][1,4]oxazepin10(9H)-one, conversion to fluoro derivatives, 64 2-(N-R-Aminobutyl)indoles, in synthesis of hexahydroazocino[4,3-b]-indoles, 92 2-Aminocinnamates, reaction with sulfur monochlorides, 177 3-Aminocinnamates, reaction with sulfur monochloride, 185 2-Aminoethanimidamide, reaction with sulfur monochloride, 182 2-Aminoethylpyridine, reaction with 4-formylimidazole and cuprous chloride, 161 o-Aminoheterocyclic thiols, reaction with sulfur dichloride, 199 a-Aminoketones, reaction with sulfur monochloride, 187 o-Aminomethyldiazepine, reaction with sulfur monochloride, 188 a-Aminonitriles, in preparation of 1,2, 5-thiadiazoles, 182 o-Aminonitrosoheterocyclic compounds, in synthesis of fused 1,2,5-thiadiazole N-oxides, 185 2-(2u-Aminophenyl)-3-indoleacetonitrile, cyclisation, 6 1-Amino-1-phenyl-2-propanone, reaction with sulfur monochloride, 187 3-Amino-1,2,5-thiadiazol, formation, 182 Aminothienobenzoxepines, acylation, 64 o-Aminothiophenol reaction with phenolic diketones, 48 Angustilobine A, isolation, 83 Angustilobine B, isolation, 83 Annulated oxadithiadiazapentalenes, synthesis, 201 (+)Anthramycin, 70 (+)Anthramycin, precursor, 32 Apparicine, isolation, 84

231

232

Subject Index

Arenecarbothialdehydes, formation by a nucleophilic attack of hydrazone at sulfur dichloride, 189 Aristoyagonine, synthesis, 24 isolation, 69 5-Aryl-7-alkyl-7-hydroxypyrrolo[1,2-d] [1,4]benzodiazepines, 37 Arylamines, reaction with sulfur monochloride, 198 N-Arylisoindolo[2,1-b][2,4]benzodiazepines, 31 4-Arylmethylpyrrolobenzodiazepines, reaction with formaldehyde, 58 4-Arylmethyl-4H-pyrrolo[l,2-a] [1,4]benzodiazepines, formation, 37 reaction with sodium borohydride, 59 1-[2-Aryloxyethyl]-5-benzotriazolyl2-pyrrolidinones, 42 C2-Arylpyrrolo[2,1-c][1,4]benzodiazepine library, 35 6-Arylpyrrolo[2,l-d][1,5]benzothiazepines, molecular mechanics calculations, 67 structure, 68 Nu-Arylthiocarbamoyl-N,N-dialkylamidines, reaction with sulfur monochloride, 205 1-[2-Arylthioethyl]-5-benzotriazolyl-2pyrrolidinones, in formation of 1, 4-benzothiazepines, 48 3-Arylthioindole-2-carboxylic acids, in formation of tetracyclic 5H-indolo-[3,2-b] [1,5]benzothiazepin-6(7H)-ones, 46 Arylthioketene-S,N-acetals, reaction with trimethylsilyl ethers of enols, 103 N-Arylthioureas, reaction with sulfur monochloride, 188 Aspidodasycarpine, isolation, 86 2-Aza-2-benzoylbicyclo[3.3.1]nonan-8-one, in synthesis of thiazolo[4,5-c]azocines, 115 2-Azabicyclo[3.3.1]nonanes, in synthesis of alkaloids, 89 Azepinoindole, synthesis, 94 Azetopyrido[3,4-b]indole-N-oxide, Meisenheimer rearrangement, 93 7-Azidoazocinoindole, synthesis, 94 Azocane 2-oxo-3-p-methoxybenzamide, cyclisation with phosphorus pentasulfide to thiazolo[5,4-b]azocine, 112 Azocinoindoles, synthesis, 94 Azocino[4,3-b]indole fragments, found in alkaloids, 84 synthesis, 91 Azocino[4,5,6-cd]indoles, synthesis, 96 Azocino[5,4-b]indole fragment, found in alkaloids, 85 by photoisomerization of pyrrolo[1,2-a] indoles, 93

Benzaldehyde hydrazone, reaction with sulfur monochloride, 188 1H-1-Benzazepine-2,5-dione, reaction with TosMIC, 11 Benz[5,6]azepino[4,3-b]indoles, formation, 5 Benzene, reaction with sulfur monochloride, 206 Benzimidazole, in luminescent palladium complexes, 157 Benzo[b]benzofuro[2,3-f ][1,4]oxazepine, 43 ring cleavage, 59 Benzo[4,3]cyclohepta[1,2-b]thiophen-4-one oxime, Beckmann rearrangement to thieno[3,2-c][1]benzazocines, 109 6H-1,2,3-Benzodithiazol-6-ones, synthesis, 203 Benzofuran annulated 2-phenyl-1, 5-benzothiazepine derivatives, formation, 48 3(2H)-Benzofuranone, reaction with sulfur monochloride, 211 Benzofuro[2,3-c][1]benzazepin-6,12-dione, 17 Benzofurobenzazepinones, 16 Benzofused 1,2,3-dithiazolium salts, synthesis, 198 9H-Benzo[e]imidazo[5,1-c]pyrrolo[1,2-a] [1,4]-diazepine, 64 Benzo[d]isothiazol-3(2H)-one, formation, 60 Benzo[f ]-4-oxopyrrolo[1,2-a]thieno[3,2-c] azepines, formation, 19 Benzo[c]pyrrolo[1,2-a]azepines, structure, 3 Benzo[d]pyrrolo[1,2-a]azepines, structure, 3 formation, 14–15 Benzo[e]pyrrolo[1,2-a]azepines, structure, 3 Benzo[f ]pyrrolo[1,2-a]azepines, structure, 3 Benzo[e]pyrrolo[1,2-a]azepinone, formation, 15 Benzo[f ]pyrrolo[1,2-a]azepinones, preparations and reactions, 12 Benzopyrrolo[1,2]diazepines, 29 5H-Benzo[f ]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one, formylation, 55 alkylation with substituted phenethyl bromides, 57 Benzo[f]pyrrolo[1,2-c][1,3]diazepin-5-thiones, 38 Benzopyrrolo[1,2]oxazepines, formation, 40 Benzo[f ]pyrrolo[2,1-b][1,3]thiazepin-9(10H)-one, 44 Benzo[f ]pyrrolo[1,2-a]thieno[3,2-c]azepine, formation, 58 p-Benzoquinone-4-oximes, reaction with sulfur dichlorides, 203 Benzo-2,1,3-thiadiazine, synthesis, 182 Benzo[1,4]thiazepine, synthesis, 44 4H-Benzo[b]thieno[3,2-e]azepin-10(9H)-one, formation, 20 Benzothieno[2,3-d]azocines, 110 Benzothieno[3,2-d]azocines, 110

Subject Index

10H-Benzo[b]thieno[2,3-e][1,4]diazepin-4-amine, displacement of amino group by other amines, 64 Benzo[b]thieno[3,4-e][1,4]diazepin-3(4H)-ones, 40 Benzo[c]thieno[3,2-f ][1,2]thiazepin-4(9H)-one, formation, 48 reactions of keto group, 66 Benzo[c]thieno[3,4-f ][1,2]thiazepin-10(5H)-one, formation, 48 reaction of keto group, 66 Benzo[f ]thieno[3,2-b][1,4]thiazepin-9(10H)-one, synthesis, 49 Benzo[e]thieno[3,2-b]thiepin-10(5H)-one, ring contraction, 59 reduction, 65 Benzothiepino[2,3-b]indole, formation, 28 Benzothiepino[5,4-b]indole, formation, 28 1-Benzothiophenes, formation, 179 Benzotrithiadiazepine, preparation of isomers, 208 Benzoxepino[4,3-b]indole, 22 crystal structure, 68 2-Benzoyl-1,1-dimethylhydrazine, conversion to 1,3,4-oxadiazoline-2-thione, 177 4-Benzoyl-3-hydroxy-2(5H)-furanone, reaction with 1,2-phenylenediamine, 39 N-Benzoylisoindolin-1-one, reaction with 2-lithio-1-phenylsulfonylindole, 7 S-Benzyl-1,2,3,5-dithiadiazolium chlorides, synthesis, 208 N-Benzylglycine, reaction with formyl indoles, 5 N-Benzylhexahydroazocino[4,3-b]-indole, synthesis, 89 4-(N-Benzyl-N-isopropyl)amino-5-mercapto1,2-dithiole-3-one, synthesis, 194 4-(N-Benzyl-N-isopropyl)amino-5-mercapto1,2-dithiole-3-thione, synthesis, 194 S-Benzyl-isothiuronium chlorides, reaction with sulfur monochloride, 208 N-(2u-Benzylmercaptobenzyl)pyrrole, cyclisation via Pummerer reaction, 46 2-Benzylthieno[3,2-d]isothiazol-3(2H)-one, formation, 59 Benzyne, generated from 2-carboxybenzenediazonium chloride, reacted with sulfur monochloride, 179 Bicyclic 1,3,4-oxadithiolane, synthesis, 207 Bicyclic oxathiadiazapentalenes, synthesis, 205 2,2u-Bipyrazine, in formation of metallacalixarenes, 165 N,Nu-Bis(arylsulfonyl)-dithiolothiazine diimines, synthesis, 193 N,N-Bis(5-chloro-3-oxo[1,2]dithiol-4-yl)amines, synthesis, 193

233

Bis(2,4-dimethoxyphenyl)sulfide, reaction with sulfur monochloride, 212 Bis(1,2,3-dithiazoles), synthesis, 198, 200 Bis[1,2,3]dithiazolopyridinium salts, synthesis, 198 Bis[1,2]dithiine, synthesis, 206 Bis(dithiolo)pyrroles, 197 Bis[1,2]dithiolopyrroles, synthesis, 190 Bisdithiolothiazines, synthesis, 193 Bis[1,2]dithiolo[1,4]thiazine, 190 Bispentathiepin, synthesis, 216 Bisthiadiazinylpyridine, 189 Bisthieno[2,3-c:3u,2u-f ]azocine, synthesis, 105 Bisthienoazocines, synthesis, 105 quaternary salts, 106 N,N-Bis(thienyl-2-methyl)valine ester, cyclisation with organolithium compounds, 105 Bistitanocene complex, reaction with sulfur monochloride, 210 Brafouedine, isolation, 83 N-(2u-Bromobenzyl)-2-acetylpyrrole, in formation of benzo[e]pyrrolo[1,2-a] azepinone, 15 2-Bromo-3-bromomethylthiophene, in formation of thieno[2]benzazepines, 18 4-Bromoindole, in synthesis of azocino[4,5,6-cd] indoles, 96 3-Bromo-2-oxoazocane, reaction with thioamide, 114 N-(3u-Bromopropyl)pyrrole, reaction with aryliodides, 15 9-Bromo-6-thiomethylindolo[3,2-d] benzazepine, reactions of thiomethyl group, 66 t-Butyladamantylhydrazone, reaction with sulfur monochloride, 210 Calix[n]arenes, 123 2-Calix[4]pyrrole, 124 N-(2u-Carbonylazidobenzyl)pyrrole, Curtius rearrangement and cyclisation, 34 2-Carboxybenzenediazonium chloride, generation of benzyne, 179 2-(2u-Chloracetamidophenyl)indole, cyclisation, 5 5-Chlorinated isothiazoles, 187 Chloroacetone, reaction with 11H-dibenzo[b,f ] oxepine-10-ones, 25 Chloroacetonitrile, reaction with sulfur monochloride, 204 6-Chloro-3H-1,2,3-benzodithiazolium chloride, 205 3-Chloro-6,7-dihydro-8-methoxyindolo[3,2-b] benzazepine, theoretical studies of conformation, 67 5-Chloro-1,2-dithiole-3-ones, 194

234

Subject Index

5-Chloro-1,2-dithiole-3-thiones, synthesis, 195 3-Chloro-1,2-dithiolium chloride, 197 N-(2-Chloroethyl)diisopropylamine, reaction with sulfur monochloride, 193 2-Chloro-N-methylpyrrole, reaction with sulfur monochloride, 213 11-Chloropyrrolo[2,1-c][1,4]benzodiazepines, formation, 61 3-Chloro-1,2,5-thiadiazoles, synthesis, 183–184 4-Chloro-1,2,5-thiadiazoles, synthesis, 184 4-Chloro-1,2,5-thiadiazol-3-ol, synthesis, 182–183 Cobalt(II)trifluoromethane sulfonate formation of a tetrameric species with 2-thiouracil4-aldehyde and diethylene triamine, 129 Condensed 1,2,3-dithiazoles, preparation, 199 Cryptoheptine, 8 Cularinoids, isolation, 69 1-Cyanoformamide, conversion to 4-chloro1,2,5-thiadiazol-3-ol, 183 Cyanogen, reaction with sulfur monochloride, 184 Cyanoimidates, reaction with sulfur monochloride, 184 1-(Cyanomethyl)cyclopentene, reaction with sulfur monochloride, 196 Cyanooximes, reaction with sulfur monochloride, 184 N-(2u-Cyanophenyl)pyrrole, in formation of tetrahydropyrrolobenzodiazepines, 37 2-Cyano-D-3-piperideines, reaction with indole, 89 Cyanopyridines, reaction with 2-thienyllithium, 102 Cyclobutanone oxime, reaction with sulfur monochloride, 186 1,5-Cyclopentadiene, conversion to 2, 6-dichloro-9-thiabicyclo[3.3.1]nonane, 189 Cyclopenta-1,2,3-dithiazoles, synthesis, 202–203 Cyclopenta-1,2-thiazine, formation, 186 Cyclopentenylacetic acid, reaction with sulfur monochloride, 197 Danshen, structure of metabolite, 69 Dasycarpidone, isolation, 82 synthesis, 86 De-ethyldasycarpidone, synthesis, 88 2u-Deoxyadenosine, reaction with rhodium complexes, 143 Di-1-adamantylacetylenes with sulfur monochloride, 187 1,2-Dialkoxybenzenes, reaction with sulfur monochloride, 212 1,4-Dialkoxybenzenes, reaction with sulfur monochloride, 221

2,3-Dialkoxynaphthalenes, reaction with sulfur monochloride, 212 N,Nu-Dialkylmalonodiamides, reaction with sulfur monochloride, 211 Dialkylphenylphosphonamide, reaction with sulfur monochloride, 210 Diaminodithiols, in formation of bis (1,2,3-dithiazoles), 200 2,6-Diaminonaphthalenes, reaction with sulfur monochloride, 198 3,6-Diaryl-dihydro-1,2,7-thiadiazepine, synthesis, 190 N,Nu-Diarylmalonodiamides, reaction with sulfur monochloride, 211 Diarylphenylphosphonamide, reaction with sulfur monochloride, 210 2,5-Diaryl-1,3,4-thiadiazoles, synthesis, 188 Diazaphosphatetrathia heterocycle, synthesis, 210 Diazepinopyrrolo-benzodiazepinediones, formation, 67 Diazonino[4,3,2-cd]indole, synthesis, 94 Dibenzodithiin, synthesis, 206 11H-Dibenzo[b,f ]oxepine-10-ones, reaction with chloroacetone, 25 Dibenzo[b,f ]oxocin-10-amines, formation,23 Dibenzo[d,f ]pyrrolo[2,1-b][1,3]thiazepine, formation, 44 Dibenzothiophene, formation, 179 Di-t-butylacetylenes with sulfur monochloride, 187 Di-t-butylketone hydrazone, reaction with sulfur monochloride, 220 N,Nu-Di-t-butylphthalamide, reaction with sulfur monochloride, 190 1,1-Di-t-butyltetrathiolane, synthesis, 220 2,5-Dicarbethoxy-3,4-dicyanomethylthiophene, reaction with sulfur monochloride, 179 1,5-Dicarbomethoxy-4-(2u-nitrophenoxy) thiophene, cyclisation, 43 3,5-Dichlorobenzo[h][1,6]naphthyridine, 60 3,5-Dichloro-bis-dithiolium salt, 192–193 4,5-Dichloro-1,2,3-dithiazolium chloride, synthesis, 203–204 1,3-Dichloro-2-formyl-5-hydropyrrolo[1,2-c] [1,4]benzodiazepine, 32 2,5-Dichloro-N-methylpyrrole, reaction with sulfur monochloride, 214 Dichloromonopentathiepin, synthesis, 216 2,3-Dichloro-1,4-naphthoquinone, reaction with benzopyrans, 26 Dichloropentathiepin, synthesis, 213 2,6-Dichloro-9-thiabicyclo[3.3.1]nonane, synthesis, 189 3,4-Dichloro-1,2,5-thiadiazole, synthesis, 182, 184 Dichlorothiiranes, synthesis, 187

Subject Index

2u,3u-Dideoxyadenosine, reaction with rhodium complexes, 143 Diethyl 2,5-diaryl-3,4-pyrroledicarboxylates, formation, 177 Diethylene triamine, reaction with 2-thiouracil4-aldehyde and self-assembly with cobalt(II)trifluoromethane sulfonate to form a tetrameric species, 129 3,4-Diethylpyrrole, reaction with sulfur monochloride, 221 3,4-Dihydro-1H-benzo[b]azepine-2,5-diones, reaction with arylhydrazines, 8 5,6-Dihydrobenzo[c]indolo[3,2-e]azepin-4(3H)one, formation, 4 5,6-Dihydrobenzo[c]pyrrolo[3,2-e]azepin4(3H)-one, formation, 4 5,6-Dihydro-4H-benzo[f]pyrrolo[1,2-a] [1,4]diazepin-4-one, 34 5,10-Dihydro-4H-benzo[b]thieno[2,3-e]azepine, formation, 20 7,12-Dihydro-6H-[1]benzothiepino[5,4-b] indole, monoalkylation, 57 7,12-Dihydroindolo[3,2-d][1]benzazepin-6(5H)ones, formation, 5 6,11-Dihydro-13H-isoindolo[2,1-b] [2,4]benzodiazepin-13-one, 32 2,3-Dihydro-5-methylisothiazolo[3,4-f ] [1,4]diazepine, synthesis, 188 10,11-Dihydro-5H-pyrrolo[2,1-c] [1,4]benzodiazepine, reaction with formaline and dimethylamine, 55 reaction with trichloroacetylchloride, 56 reaction with acid chlorides, 58 5u,6u-Dihydrospiro[piperidine-4,4u-pyrrolo[1,2-a] [1,4]benzodiazepines, 36 2,4-Dihydro-1,2,4-triazol-3-ones, formation, 177 Diisopropyl sulfide, reaction with sulfur monochloride, 195 Dimesityl sulfide, reaction with sulfur monochloride, 223 1,3-Dimethoxybenzene, reaction with sulfur monochloride, 221 4,6-Dimethoxybenzene-1,3-dithiol, reaction with sulfur monochloride, 223 3,4-Dimethoxy-6-nitrobenzaldehyde, condensation with 4-methyl-2-phenyl5-pyrimidincarboxylate, 100 3-(3,4-Dimethoxyphenyl)prop-2-ynoic acid, reaction with sulfur monochloride, 179 Dimethylacetylene dicarboxylate, reaction with tetrahydropyrrolo[3,2-c]pyridines, 116 Dimethyl 3-fluoro-9H-dibenzo[c,f ]-pyrrolo[1,2-a] azepine-1,2-dicarboxylate, 16 4,6-Dimethyl-2-hydroxypyrimidine, formation of metallacalixarenes, 150

235

Dimethyl(methylthio)sulfonium tetrafluoroborate, in synthesis of pentacyclic compound from hexahydroazocino[4,3-b]indole, 97 2,5-Dimethyl-7-phenylsulfonyl-5, 6-dihydroindolo[2,3-c]benzazepin-12-one, formation, 8 crystal structure, 68 N,N-Dimethylpropane-1,3-diamine, with 4-formylimidazole in formation of copper complexes, 158 1,1-Dimethyl-2-(2- or 3-thienyl)pyrrolidine salts, Sommelet–Hauser rearrangement 105 N-(Dimethylthio)ethyl and N-dimethoxyethyl derivatives of hexahydroazocino[4,3-b] indole, in formation of pentacyclic compounds, 97 4,6-Dinitrobenzofuran, condensation with salicylic aldehyde, 26 1,8-Dioxadibenzo[e,h]azulenes, oxidation of 2-methyl groups, 61 Dioxathiadiazapentalene, synthesis, 201 1,3-Dioximes, cyclisation with sulfur monochloride, 201 Dioxopyrrolo[3,4-c]benzoxepine, 22 2,2u-Dipyridylketone, in formation of metallacalixarenes, 129 Disulfide-linked oligopyrrolic macrocycles, synthesis, 212 Dithiadiazaphospholidine S-oxides, synthesis, 208 Dithiadiazocanes, reaction with sulfur monochloride, 220 2-(1,3-Dithian-2-yl)indoles, in synthesis of uleine alkaloids, 92 5H-1,2,3-Dithiazoles, 200 Dithiodiquinoline, synthesis, 205 4-Dithiomethylmethylenebenzazepin-5-one, reaction with methylene iodide, 28 Enamines, reaction with sulfur monochloride, 200 Epchrosine, isolation, 83 (+/-)-Epidasycarpidone, synthesis, 86 Epidithiooxaanthracenones, synthesis, 207 (+/-)-Epiuleine, synthesis, 86, 88 Epoxyhexahydroazocino[5,4-b]indole, synthesis, 93 Ervaticine, isolation, 84 Esters of aminothienyldionic acids, in synthesis of thienoazocines, 103 Esters of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide, reduction, 62 reactions, 67 4-Ethoxy-1,2,5-thiadiazol-3-ol, formation, 182

236

Subject Index

9-Ethyladenine, formation of ruthenium metallacalixarenes, 145 reaction with iridium complexes, 148 Ethyl 2-amino-2-oxoethanimidoate, reaction with sulfur monochloride, 182 3-Ethyl-4-carbomethoxypyridine N-oxide, reaction with 3-indolylmagnesium bromide, 86 Ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin11-ylacetate, synthesis, 49 N-Ethyldiisopropylamine, reaction with sulfur monochloride, 191 reaction with sulfur dichloride, 193 Ethylenediamine, reaction with sulfur monochloride, 181 Ethylenediamine dihydrochloride, reaction with sulfur monochloride, ferric chloride and chlorine, 182 9-Ethylguanine, reaction with rhodium complexes, 144 Ethyl N-(2u-nitrophenylsulfonyl)pyrrole2-glyoxylate, reductive cyclisation, 51 Ethyl tetrahydro[1,3]benzothiazolyl acetate, transformations to oxo[1,3]thiazolo[5,4-f ] azocine, 114 7-Fluorobenzo[b]thieno[2,3-f ][1,4]oxazepin10(9H)-one, formation, 64 chlorination and sequential amination, 66 Formylation reactions of polycyclic heterocycles, 55 8-Formylbenzo[d]pyrrolo[1,2-a]azepinone, formation, 15 4-Formylimidazole, reaction with N, N-dimethyl-propane-1,3-diamine and copper salts, 158 reaction with 2-aminoethylpyridine and cuprous chloride, 161 reaction with 1,4-diaminobutane and copper salts, 161 Furan-3-carbaldehyde, reaction with N,N’-disubstituted hydrazines and cycloadditions, 18 Furanooxepines, 26 Furo[4,3,2-fg]benzazocines, 112 Furobenzoxepines, 26 crystal structure, 68 Furobenzthiazepines, synthesis, 49 8H-Furo[3,4-d]dibenz[b,f ]azepines, formation, 16 reaction with t-butyl hypochlorite, 56 Fused 1,2,5-thiadiazole N-oxides, synthesis, 185 Gilbertin, isolation, 84 Glutaronitrile, reaction with sulfur monochloride, 205

Glycinamide, formation of 4-chloro-1,2, 5-thiadiazol-3-ol, 182 Gold metallacalixarenes, 163 Guanine, reaction with metal ions to form metallacalixarenes, 132 reaction with iridium complexes, 148 Guanine-based platinum metallacalixarenes, 126 Guanosine, reaction with rhodium complexes, 144 Guanosine 5u-mono, di and triphosphates, reaction with ruthenium complexes monitored by NMR, 148 Heterocalix[n]arenes, 124 Heterocalixarenes, 124 Hexahydroazocino[4,3-b]-indoles, from 2-(N-R-aminobutyl)indoles, 92 conversion to pyrrolo[3,2-a]carbazole under Wolff–Kishner reaction conditions, 97 derivatives in formation of pentacyclic compounds, 97 derivatives, recyclisation under the action of aliphatic aldehydes, 100 from tetrahydro-g-carbolines, 93 Hexahydropyrrolo-benzdiazepinetrione, reaction with phosphorous oxychloride, 60 Hexahydro[1,3]thiazolo[4,5-b]azocine, synthesis, 114 Hexahydrothieno[2,3-c]azocines, syntheses involving a Sommelet–Hauser rearrangement of 1,1-dimethyl-2-(2- or 3-thienyl)pyrrolidine salts, 105 Hexahydrothieno[3,2-c]azocines, syntheses involving a Sommelet–Hauser rearrangement of 1,1-dimethyl-2-(2- or 3-thienyl)pyrrolidine salts, 105 3,3u,4,4u,5,5u-Hexamethylbiphenyl, reaction with sulfur monochloride, 206 Hexanuclear platinum-palladium complexes, 167 Hexathiaspirododecane, synthesis, 221 Homocryptolepinone, isolation and structure, 69 Host-guest chemistry in metallacalixarenes, 156 Hunig’s base, see N-Ethyldiisopropylamine, Hydrazones derived from 1-adamantyl phenyl ketone, reaction with sulfur monochloride, 220 Hydrazones derived from benzophenone, reaction with sulfur monochloride, 220 Hydrazones derived from pivalophenone, reaction with sulfur monochloride, 220 Hydrazones, reaction with sulfur dichloride, 189 Hydrogenated azocino[3,4-b]indole fragments found in alkaloids, 85

Subject Index

2-Hydroxy-1,4-benzoquinone, reaction with 3-methylamino-3-methylthio1-phenylthioxopropene, 20 16(S)-Hydroxy-16,22-dihydroapparicine, isolation, 84 7-Hydroxy-7-isopropylazocinoindol4-yl-methanol, synthesis, 94 4-Hydroxyisothiazoles, synthesis, 187 4-(Hydroxymethylene)-3, 4-dihydrobenzo[b]oxepin-5(2H)-one, reaction with arylhydrazines and Fischer indole synthesis, 23 N-(2-Hydroxymethylphenyl)pyrrole, in formation of pyrrolo-benzoxazepines and pyrrolo-benzoxazepinones, 41 2-Hydroxypyrimidine, formation of metallacalixarenes, 150 reaction with palladium complexes, 152 reaction with silver nitrate, 155 4-Hydroxypyrimidine, formation of metallacalixarenes, 150 reaction with palladium complexes, 152 2-Hydroxypyrrolo[2,1-c][1,4]benzodiazepines, reaction with thionyl chloride, 61 Hydroxytetrahydrothieno[2,3-c]pyridines, thienomethylation, 106 3-Hydroxythiadiazoles, formation, 182 Hypoxanthine, reaction with metal ions to form metallacalixarenes, 132 in formation of tetrameric metallacalixarenes with ruthenium complexes, 148 formation of iridium complexes, 148 reaction with cupric ions, 138 Imidazo[2,1-a]isoindolone, 31 Imidazole, in formation of metallacalixarenes, 157 Imidazole-4-carboxylic acid, in formation of rhuthenium complexes, 164 3-Imino-1,2-dithioles, 196 Indenylacetic acid, reaction with sulfur monochloride, 197 3-Indoleaceto-(2u-iodo)anilide, cyclisation to 7,12-dihydroindolo[3,2-d][1]benzazepin6(5H)-ones, 5 Indolo[3,2-c]benzazepin-7,12-diones, formation, 8 Indolo[3,2-d]benzazepin-11-thione, formation, 64 Indolo[1,2-d][1,4]benzodiazepin-6-one, 30 Indolobenzothiazepines, formation, 44 5H-Indolo[3,2-b][1,5]benzothiazepin-6(7H)ones, 46 Indolo[2,3-b]pyridine-carboxylic acids, reaction with 2-iodobenzylamine and Heck reaction, 4

237

3-Indolylmagnesium bromide, reaction with 3ethyl-4-carbomethoxypyridine N-oxide, 86 2-Indolylpiperidine-4-carboxylic acids, in synthesis of uleine alkaloids, 92 2-(3-Indolylthio)phenylacetic acid, cyclisation, 27 2-Iodobenzylamine, reaction with indolo-[2,3-b] pyridine-carboxylic acids and pyrrolo[2,3-b]pyridine-carboxylic acids, 4 N-2u-(2v-Iodo-3,4-dimethoxyphenyl)ethyl2-carboxamidopyrrole, cyclisation to pyrroloazepines, 14 Isobrafouedine, isolation, 83 Isoindolin-1-imine, reaction with phthalic dichloride, 38 Isoindolo[1,2-a]benzodiazepines, 30 Isoindolo[1,4]benzodiazepine, 31 Isoindolo[2,1-b][2,4]benzodiazepin-6-ones, formation, 38 5H-Isoindolo[1,2-b][1,3,4]benzotriazepin-5-one, synthesis, 49 N-Isopropylpyrrolidine, reaction with sulfur monochloride, 216 4-Isopropylthio-5-isopropyldisulfyl-1, 2-dithiolo-3-thiones, 195 Isothiazolyldithiazolium chloride, 205 b-Ketoenamines, reaction with sulfur monochloride, 200 Lapidilectine A, isolation, 85 Latonduines A and b, isolation, 69 2-Lithio-1-phenylsulfonylindole, reaction with N-benzoyl isoindolin-1-one, 7 Lundurine A, B and C, isolation, 84 5-Mercaptodithiole thiones, reaction with sulfur monochlorides, 194 5-Mercapto1,2-dithiole-3-thiones, 194 Mesitylene-2,4-dithiol, reaction with sulfur monochloride, 223 Mesitylenesulfide, reaction with sulfur monochloride, 223 Mesoionic 1,2,5-thiadiazolium-3-olates, synthesis, 182 Metal-based DNA-binding drugs from metallacalixarenes, 153 Metallacalix[4]arenes, structures, 151 Metallacalixarene, 124 reviews, 125 as selective metal-based DNA-binding drugs, 153 5-Methoxydithiazoles, synthesis, 200 8-Methoxy-3,4,6,7-tetrahydro-1H,5H-azocino [4,5,6-cd]indole, synthesis, 94 Methoxytetrahydrothienopyridine, in preparation of thienobenzazocine, 109

238

Subject Index

Methoxytetrahydrothieno[2,3-c]pyridines, thienomethylation, 106 9-Methyladenine, formation of metallacalixarenes, 134 formation of metallacalixarenes with trans amino complexes of platinum, 136 reaction with Z5-pentamethylcyclopentadienyl-rhodium aqua complex, 142 6-Methylaminoadenine, formation of ruthenium metallacalixarenes, 145 3-Methylamino-3-methylthio1-phenylthioxopropene, reaction with 2-hydroxy-1,4-benzoquinone, 20 2-Methylamino-5-phenyl-1,3,4-thiadiazole, synthesis, 177 Methylation of pyrrolo-benzodiazepine diones, 57 Methylation of pyrrolo-benzothiazepines, 57 Methyl-6-benzyl-7-phenylpyrrolo[1,2-b] [1,5]benzodiazepine-8-carboxylate, 39 2-Methyldibenzo[b,f ]furo[2,3-d]oxepines, 24 1-Methyl-2-(1u,1u-diethylacetamido)3-(2u-anilino)pyrrole, cyclisation, 7 9-Methylguanine, reaction with platinum complexes, 134 9-Methyl(ethyl)hypoxanthine, reaction with rhodium complexes, 144 5-Methylindolo[3,2-b]-[1]benzazepin-7(5H)-one, formation, 59 Methyl 12-methyl-12H-[3]-benzoxepino[1,2-b] indole-5-carboxylate, 23 crystal structure, 68 1-Methyl-3-(2u-nitrophenyl)-4-methyl-5-tbutylpyrrole-2-carboxylic acid, reductive cyclisation, 7 4-Methyl-2-phenyl-5-pyrimidinecarboxylate, condensation with 3,4-dimethoxy6-nitrobenzaldehyde, 100 Methyl-9-phenylpyrrolo[2,1-d]benzoxazepine6-carboxylate, reactions of ester, 62 1-Methyl-5-phenyl-1,2,4-triazol-2-one, synthesis, 177 N-Methylpyrrole, reaction with sulfur monochloride, 213 Methyl pyrrolidin-2,3-dione-4-carboxylate, in formation of pyrrolo[3,4-c][1,5]benzothiazepin-3-ones, 46 Methyl 2-[2-(3u-thienyl)phenyl]oxirane, flash vacuum pyrolysis, 26 Mixed metallacalixarenes with platinum and mercury and 9-methyladenine, 136 Monodeprotonated copper complexes containing one imidazole and one imidazolate group, structure, 162 Monosodium salt of adenosine-5umonophosphoric acid, reaction with

cadmium nitrate in the presence of nitric acid, 138 Mono-substituted acetonitriles, reaction with sulfur monochlorides, 204 Naphthobis[1,2,3]dithiazole, synthesis, 198 1,2-Naphthoquinone 2-oxime, reaction with sulfur dichloride, 203 1,4-Naphthoquinone 4-oxime, reaction with sulfur dichloride, 203 Nicotine adenine dinucleotide, reaction with rhodium complexes, 143 1-(2-Nitrobenzyl)-2-pyrrole carbaldehyde, reductive ring closure, 34 N-(2-Nitrophenyl)-2-aminomethylpyrrole, 50 N-(2-Nitrophenyl)-1H-pyrrol-1-amine, conversion to pyrrolo[1,2-b] [1,2,5]benzotriazepin-11-one, 50 1-(2-Nitrophenyl)-1H-pyrrole, reaction with ethyl oxalyl chloride and cyclisation, 34 7-(2-Nitrophenyl)-substituted azabicyclononanone, synthesis, 89 2-(2-Nitrophenyl)-thiochroman-4-one, reduction, 49 Nordasycarpidone, isolation, 82 Norsecorhazinilam analogs, formation, 6 Octahydroazocino[5,4-b]-indole fragments, found in alkaloids, 84 Octanuclear metallacalixarenes, 127 Octyl hexathiazepane, synthesis, 221 1,3,4-Oxadiazoline-2-thione, from 2-benzoyl1,1-dimethylhydrazine, 177 N-Oxide of 1,2,3-dithiazole, synthesis, 201 1-Oximino-3-phenylindene, synthesis, 201 Oxo[1,3]thiazolo[5,4-f ]azocine, synthesis, 114 Pandine, isolation, 85 Paullone, 63 synthesis, 6 (Z5-Pentamethylcyclopentadienyl)-rhodium aqua complex, reaction with 9-MeAd, 142 Pentathiepin, synthesis, 213, 216 Pentathiepinofuran, synthesis, 218 Pentathiepino-fused poly(N-methylpyrrole), synthesis, 219 Pentathiepinopyrroles, 197 1,2,3,5,7-Pentathiocanes, synthesis, 220 2-(N-Pentenylaminopropyl)benzoquinone, cyclization, 112 Perchlorinated cyclopenta-1,2-dithiole, synthesis, 196 4,7-Phenanthroline, in formation of metallacalixarenes, 165, 168 Phenolic diketones, reaction with o-aminothiophenol, 48

Subject Index

7-Phenylbenzo[f ]pyrrolo[1,2-a]azepin-6-one, reduction, 59 1,2-Phenylenediamine, reaction with 4-benzoyl-3-hydroxy-2(5H)-furanone, 39 reaction with pyrrole carbaldehyde, 39 reaction with sulfur monochloride, 182 2-Phenyl-3-formylindole, reaction with sarcosine and ring closure, 5 8-Phenylindeno[5,4-a][1,2,3]dithiazole, synthesis, 201 Phenyliodonium ylides of cyclic sevenmembered a-diketones, reaction with alkynes, 25 N-Phenylpyrrole, in formation of tetramethyl pyrrolo-benzoxazepine, 41 5-Phenylpyrrolo[2,1-c]][1,4]benzothiazepines, 45 reaction with paraformaldehyde and 1-methylpiperazine dihydrochloride, 55 N-(3u-Phenylpropyl)-2-bromo-3-formylindole, radical cyclisation, 15 1-Phenylsulfonyl-2-[2u-acetamido-5umethylbenzoyl]-indole reaction with chloromethyl methyl ether, 8 1-Phenylsulfonylindolo[3,2-c]benzazepin10-one, formation, 7 2-Phenyl-4,5,6,7-tetrahydro-4(2u-iodobenzyloxy)benzofuran, palladium catalysed cyclisation, 26 Phthalic dialdehyde, reaction with thieno azepinedione, 21 N-(2-Phthalimidoethyl)-N-alkylisopropylamines, reaction with sulfur monochloride, 195 4-Piperidone, reaction with (2-(1H-pyrrol-1-yl) phenyl)methanamine, 36 3-Piperidylindole, in synthesis of azocino[3,4-b] indoles, 94 Polysubstituted benzene-1,3-dithioles, in the synthesis of polysulfur-bridged metacyclophanes, 223 Polysulfur-bridged metacyclophanes, synthesis, 223 Propyl-3-N-acetyl-N-benzylaminobenzofuran2-carboxylate, in formation of benzofurobenzazepinones, 16 Purine, reaction with metal ions to form metallacalixarenes, 132 Pyrazinodiindole, reaction with sulfur monochloride, 207 Pyrimidine, formation of metallacalixarenes, 150 reaction with silver nitrate, 156 Pyrimidoazocines, synthesis, 100 Pyrimido[5,4-c]benz[1]azocine, synthesis, 100 Pyrimidobenzomorphane, synthesis, 100 Pyrroloazepines, formation, 14

239

Pyrrolo[2,3-d]azocines, synthesis, 116 Pyrrolobenzazepines, formation, 7 Pyrrolobenzazepinediones, synthesis, 9 Pyrrolo[2,3-d][2]benzazepin-6(1H)-one, 11 Pyrrolo[3,2-c][1]benzazepine-10(1H)-one4(5H)-thione, 6 Pyrrolobenzodiazepines, synthesis, 32 calculations using MNDO and AM1, 68 Pyrrolo[4,5-a]benzodiazepines, 30 Pyrrolo[2,1-c][1,4]benzodiazepines, formation, 34 reaction with acid chlorides, 58 Pyrrolo[1,2-d][1,4]benzodiazepin-4,6-dione, 35 Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione, library formation, 36 Pyrrolo[1,2-d][1,4]benzodiazepin-5-one, 34 Pyrrolo[1,2-d][1,5]benzodiazepin-9-one, 34 Pyrrolobenzothiadiazepines, formation, 51 Pyrrolobenzothiadiazepinone dioxides, formation, 51 Pyrrolobenzothiazepines, oxidation on sulfur, 59 2H-Pyrrolo[3,4-b][1,5]benzothiazepines, 46 Pyrrolo[2,1-c][1,4]benzothiazepine, formation, 44, 46 Pyrrolo[1,2-b][1,2,5]benzothiadiazepine acids, reactions of acid groups, 62 Pyrrolo[1,2-b][1,2,5]benzothiadiazepine7-carboethoxy-7-carboethoxymethyl, 52 Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5, 5-dioxide acid derivatives, 52 2H-Pyrrolo[3,4-b][1,5]benzothiazepinone, reaction with Lewasson’s reagent, 65 Pyrrolo[3,4-c][1,5]benzothiazepin-3-ones, formation, 46 Pyrrolobenzotriazepines, formation, 50 Pyrrolo[2,l-d][1,2,5]benzotriazepine, 50 Pyrrolo[1,2-b][1,2,5]benzotriazepin-11-one, from N-(2-nitrophenyl)-1H-pyrrol1-amine, 50 Pyrrolobenzoxazepines, formation, 41 Pyrrolo[2,1-d][1,4]benzoxazepines, 42 Pyrrolobenzoxazepinones, formation, 40–41 Pyrrolo[3,2-a]carbazole, synthesis, 97 Pyrrolo[1,2-a][1,4]diazepines, formation, 37 Pyrrolodiazepinone, 34 Pyrrolo[1,2-a]indole, photoisomerization to azocino[5,4-b]indoles, 93 Pyrrolopentathiepin, synthesis, 220 Pyrrolo[2,3-b]pyridine-carboxylic acids, reaction with 2-iodobenzylamine followed by Heck Reaction, 4 Pyrrolo[1,2]thiazepines, formation, 46 Pyrrolo[d]thiepines, 26 2-(2u-Pyrrolyl)-4-methyliminobenzoxazine, 61

240

Subject Index

2-(2u-Pyrroloyl)phenylisothiocyanate, cyclisation, 6 (2-(1H-Pyrrol-1-yl)phenyl)methanamine, reaction with 4-piperidones, 36 Quinoline, reaction with sulfur monochloride, 205 Quinoxaline aminothiol, reaction with sulfur monochloride, 199 Quinoxaline-1,2,3-dithiazolium chloride, synthesis, 199 Salicylic aldehyde, reaction with 1-tosyl-4, 6-dinitroindoline, 24 reaction with 4,6-dinitrobenzofuran, 26 Sarcosine, reaction with formyl indoles, 5 Semicarbazones, formation of mono-, di- and trisubstituted 2,4-dihydro-1,2,4-triazol3-ones, 177 Sommelet–Hauser rearrangement of 1, 1-dimethyl-2-(2- or 3-thienyl)pyrrolidine salts, 105 Spiro-piperidine-4,11u-pyrrolo[2,1-c][1,4]benzodiazepines, 36 Strychnine, synthesis, 97 Substituted benzo[f ]pyrrolo[1,2-d] [1,4]diazepinones, 67 5-Substituted-4-chloro-1,2,3-dithiazolium chlorides, synthesis, 204 2-Substituted cyclopentanone oximes, reaction with sulfur dichloride, 203 2-Substituted paullones, 66 p-Substituted N-sulfinylanilines, reaction with sulfur monochloride, 205 Sulfur dichloride, stability and use in synthesis, 176 Sulfur monochloride, stability and use in synthesis, 176 perchlorination of aromatic compounds, 176 simultaneously sulfurating and chlorinating activity, 176 Tenuisines A, B and C, isolation, 85 Tetrahydroazocino[4,5,6-cd]indoles, synthesis, 94 Tetrahydroazocino[4,5-b]indoles, synthesis, 117 Tetrahydroazocino[5,4-b]indoles, synthesis, 117 Tetrahydrobenzo[d]azocines, synthesis, 117 Tetrahydrobenzo[b]pyrrolo[3,4-e] [1,4]diazepinone, 38 Tetrahydrobenzo[b]thieno[3,2-d]azocines, synthesis, 117 Tetrahydro-g-carbolines, from hexahydroazocino[4,5-b]indoles, 93 Tetrahydropyrimido[4,5-d]azocines, synthesis, 117

Tetrahydropyrrolobenzodiazepines, formation, 37 oxidation, 59 Tetrahydropyrrolo[3,2-c]pyridines, ring enlargements, 116 Tetrahydrothiophene, reaction with sulfur monochloride, 216 Tetrameric metallacalixarene, derived from 9-allyladenosine and silver ions, 137 Tetramethylpyrrolo-benzoxazepine, 41 1,1,4,4-Tetramethyltetrazane, synthesis, 177 Tetranuclear metallacalixarene involving palladium, 2-hydroxypyrimidine and phenanthroline, 169 Tetrasubstituted thieno[3,4-c]thiophene, synthesis, 179 Tetrathiacyclophanes, synthesis, 213 1,2,4,5-Tetrathianes, synthesis, 211 Theophylline, reaction with metal ions to form metallacalixarenes, 132 reaction of sodium salt with platinum complexes, 132 Theophylline-based platinum metallacalixarenes, 126 3-Thiacalix[4]arene, 124 1,2,7-Thiadiazepan-3,6-dione, synthesis, 190 1,2,5-Thiadiazoles, synthesis, 180, 182 1,2,5-Thiadiazol-3(2H)-ones, synthesis, 182 Thianthrene, formation, 179 synthesis, 206 2H-1,4-Thiazines, synthesis, 185 Thiazolo[4,5-c]azocines, synthesis, 115 Thiazolo[5,4-b]azocine, synthesis, 112 [1,3]-Thiazolo[5,4-c]azocine, synthesis, 115 Thiazolo[5,4-d]azocines, synthesis, 115 Thienoazepinedione, reaction with phthalic dialdehyde, 21 Thieno[3u2u:2,3]azepino[4,5-b]indol-5(4H)-one, synthesis, 54 Thienoazocines, 103 Thieno[2,3-d]azocine, 102 Thieno[3,2-b]azocines, from arylthioketeneS,N-acetals and trimethylsilyl ethers of enols, 103 Thieno[3,2-d]azocines, synthesis, 103 Thieno[3,4-d]azocine, synthesis by intramolecular cyclization of 2-thienyltetrahydropyridine, 105 Thieno[3,2-c]benzazepines, formation, 19 Thieno[3,2-c]benzazepine-1,6-dione, formation, 20 Thienobenzazocines, 108 Thieno[2,3-d][2]benzazocines, 108 Thieno[3,2-c][1]benzazocines, synthesis, 109 Thieno[3,2-d][2]benzazocines, 108 Thieno[4,3,2-fg]benz[1]azocine, synthesis, 110

Subject Index

Thienobenzodiazepines, boat conformations, 68 Thieno[3,4-b][1,4]benzothiazepine, synthesis, 49 Thieno[1,2-b][1,5]diazepines, formation, 39 Thieno[3,2-f ]morphanes, synthesis as analogues of morphine, 102 Thienopentathiepin, synthesis, 218 2-Thienyllithium, reaction with cyanopyridines, 102 N-Thienylmethyl-N-arylmethylaminoethanal diethylacetal, bicyclization, 106 Thienylmethylbromide, reaction with valine ester, 105 2-Thienylmethyltetrahydropyridines, intramolecular cyclization, 103 2-Thienyltetrahydropyridines, intramolecular cyclization, 103, 105 Thiophenes, synthesis, 179 6-Thiopurine, reaction with metal ions to form metallacalixarenes, 132 reaction with cobalt complexes, 132 6-Thiopurine ribose, reaction with rhodium complexes, 145 reaction with iridium complexes, 150 Thiosemicarbazone, formation of triazolones, 177 2-Thiouracil-4-aldehyde, reaction with diethylene triamine, and self-assembly with cobalt(II) trifluoromethane sulfonate to form a tetrameric species, 129 1-Tosyl-4,6-dinitroindoline, reaction with salicylic aldehyde and cyclisation, 24 1,4,7-Triazacyclononane, as a ligand in metallacalixarenes, 157 Trichlorocyclopenta[1,2]-dithiole ester, synthesis, 197 2,4,5-Trichlorothiazole, synthesis, 188 Tricyanotriazine, reaction with sulfur monochloride, 208 Tricyclic bis-dithiolothiazines, 192 Tricyclic 1,2-dithiolone, synthesis, 197

241

N-Trifluoroacetyl-N-(3,4,-dimethoxybenzyl)2-aminomethylthiophene, in formation of thienobenzazepines, 20 9-Trifluoromethylpaullone, Stille reactions, 66 Trimeric metallacalixarenes involving phenanthroline, 168 Trimethylsilyl ethers of enols, reaction with arylthioketene-S,N-acetals, 103 1,4,7-Trimethyl-1,4,7-triazacyclononane, as a ligand in metallacalixarenes, 157 Tris(1,2,3,5-dithiadiazolyl)-1,3,5-triazine, synthesis, 208 Trithiazepinobenzimidazole, synthesis, 209 Tryptamine derivatives, cyclisation to benzo[d]pyrrolo[1,2-a]azepinones, 14 Tubopholidine, synthesis, 97 Tubopholine, synthesis, 97 Uleine, isolation, 82 synthesis, 86, 88 Uleine acetate, formation and cleavage, 98 a,b-Unsaturated hydrazones, reaction with sulfur monochloride, 196 Uracil-based platinum metallacalixarenes, synthesis and conformations based on X-ray crystallography, 126 basicity and reaction with metal ions, 127 cone conformations binding to sulfonate anions, 129 deprotonations, 128 reaction with silver nitrate, 128 Valine ester, condensation with thienylmethylbromide, 105 19,20-Z-Vallesamine, isolation, 83 19,20-E-Vallesamine, isolation, 83 Wolff–Kishner reactions in synthesis of pyrrolocarbazoles, 97 Zirconium metallocycles, in synthesis of thiophenes, 180

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