Advances in Strained and Interesting Organic Molecules, Volume 8, Volume 8

ADVANCES IN STRAINED AND INTERESTING ORGANIC MOLECULES

Volume 8

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ADVANCES IN STRAINED AND INTERESTING ORGANIC MOLECULES

Editor: BRIAN HALTON School of Chemical and Physical Sciences Victoria University of Wellington

VOLUME 8

Al PRESS INC. Stamford, Connecticut

Copyright © 2000 by JAI PRESSINC 100 Prospect Street Stamford, Connecticut 06904-0811 All rights reserved. No part of this publication may be reproduced, stored on a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, filming, recording, or otherwise without prior permission in writing from the publisher. ISBN: 0-7623-0631-9 ISSN: 1061-8902 Manufactured in the United States of America

CONTENTS LIST OF CONTRIBUTORS

vi i

PREFACE Brian Halton

ix

NATURAL AND NON-NATURAL PLANAR CARBON NETWORKS: FROM MONOMERIC MODELS TO OLlGOMERlC SUBSTRUCTURES Michael M . Haley and W. Brad Wan

1

RECENT DEVELOPMENTS IN STRAINED CYCLIC ALLENES Metin Balci and Yavuz Taskesenligil

43

STRAIN AND STRUCTURE OF STERICALLY CONGESTED TRIPLET CARBENES Hideo Tomioka

83

SYNTHESIS AND CHEMISTRY OF STRAINED CARBOHYDRATES: OXABICYCL0[4.1 .O]HEPTANES Ghislaine S. Cousins and John 0. Hoberg

113

EXPLOITING THE STRAIN IN 12.2.1IBICYCLIC SYSTEMS IN POLYMER AND SYNTHETIC ORGANIC C HEMISTRY Michael North

145

AZlRlNES AND AZlRlDlNES REVISITED Kuriya Madavu Lokanatha Rai and Alfred Hassner

187

INDEX

259

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LIST OF CONTRIBUTORS Metin Balci

Department of Chemistry Middle EastTechnical University Ankara, Turkey

Ghislaine 5. Cousins

School of Chemical and Physical Sciences Victoria University of Wellington Wellington, New Zealand

Michael M. Haley

Department of Chemistry University of Oregon Eugene, Oregon

Alfred Hassner

Department of Chemistry Bar-Ilan University Ramat-Gan, Israel

John O. Hoberg

School of Chemical and Physical Sciences Victoria University of Wellington Wellington, New Zealand

Michael North

Department of Chemistry King's College London, England

Kuriya Madavu Lokanatha Rai

Department of Chemistry University of Mysore Mysore, India

Yavuz Taskesenligil

Department of Chemistry Ataturk University Erzurum, Turkey

Hideo Tomioka

Chemistry Department for Materials Mie University Tsu, Mie, Japan vii

viii W. Brad Wan

LIST OF CONTRIBUTORS Department of Chemistry University of Oregon Eugene, Oregon

PREFACE The past year has seen the publication of the first Supplement to this Series under the editorship of Professor K. K. Laali and this signals our wish to provide timely collections under independent editorship from, for example, important international symposia. Carbocyclic and Heterocyclic Cage Compounds and Their Building Blocks appeared in June as the first Supplement of the past century---I sincerely hope that the next Supplement will not be the last of the present one! The present Volume, which comprises six chapters and involves ten authors from seven countries, provides a pot pourri of interesting strained and not so strained molecules and their use----or abuseBin the widest sense. Haley and Wan of the University of Oregon give a position summary of planar carbon networks. Their discourse commences with graphite and outlines methods now brought to bear on the synthesis of oligophenylenes, their conversions into polycyclic aromatic hydrocarbons such as "supernaphthalene" and "supertriphenylene," and the need to avoid alkyne "mismatch" that can lead to non-planarizable products. Next come polyphenylenes (or polybiphenylenes) that can be expected to link in a linear and an angular manner; the elegance and beauty of the cobalt-mediated cyclotrimerization of alkynes is displayed in its full glory. Graphynes (from hexaethynylbenzenes and dehydrobenzo[ 12]annulenes) and graphdiynes (which have advanced notably from Haley's in situ protiodesilylation/alkynylation protocol) are followed by the tetraethynylcyclobutadiene and tetraethynylethene motifs in what is a well rounded state-of-the-art summary of the field.

x

PREFACE

Chapter 2 introduces our first authors from Turkey. Balci and his student Taskesenligil address the field of strained allenes by considering the five- to nine-membered ring derivatives and then discuss bicyclic analogues. The developments of the past 10 years are put into good perspective and it is noteworthy that matrix technology has yet to be brought to bear on the characterization of cyclopenta- 1,2-diene. While cyclohexa- 1,2-dienes are easily intercepted by cycloaddition, studies on heteroatom-substituted derivatives are more recent. The synthetic potential of these strained cyclic heteroallenes is explored and the biological activity of the compounds addressed. Metal complexation of cyclohexa- 1,2-dienes provides sufficiently stable crystals for structural study and the results are presented. Despite the lower ring strain of the cyclohepta-1,2-dienes effective routes to the compounds have only recently been developed, but it is only with the higher homologue, 1-tert-butylcycloocta-1,2-diene, that stability at 20 ~ is achieved. The generation of an allene in the bicyclo[3.2.1 ] framework has been accomplished and the details of this elegant chemistry are provided. The contribution by Tomioka of Mie University on his studies of sterically congested triplet carbenes fits well in this Series. He provides an easily understood introduction to the nature of carbene geometry and the use of ESR spectroscopy in deducing carbene structure before describing the relationship of strain to structure in triplet carbenes. First, diarylcarbenes are presented and then the discussion focuses on ortho-subsfltuted diphenylcarbenes before considering more sterically congested polybromo, triptycyl, and anthryl derivatives. The use of strained molecules in the synthesis of important new compounds of a natural and nonnatural nature continues through the remainder of the Volume. My Colleague Hoberg (a recent arrival in the antipodes from the United States) and his student Cousins provide a timely contribution on strained carbohydrates. Their discussion follows the fusion of the carbohydrate with a cyclopropane, an oxirane, an aziridine, and a thiirane (episulfide), and the discussion encompasses the methods of formation and selectivity, as well as the chemistry of the newly formed ring systems. Examples of reactions and rearrangements that lead to new products and naturally occurring materials are presented. In particular, ring expansions into oxepanes and the development of electrophilic opening of the three-membered ring with high diastereoselectivities at the anomeric center show the potential for the cyclopropanes. The stereocontrolled opening of carbohydrate epoxides with oxygen nucleophiles leads to oligosaccharides and nucleosides while nitrogen and carbon analogues likewise effect stereospecific opening that have an obvious appeal in synthesis. Carbohydrate aziridines are comparatively recent but they can lead to amino-sugars through ring cleavage. In comparison the thiirane derivatives are few and this area appears to be one for future exploitation. The fifth chapter, by North of King's College, London, describes recent, elegant work that has led to controlled cleavage of the bicyclo[2.2.1 ]heptene (norbornene)

Preface

xi

ring system thereby providing stereocontroUed access to natural products and to polymer systems. The strain present in the bicyclic framework is used to advantage in providing synthetic polymers via the "Ring Opening Metathesis Polymerization"----or ROMP reaction. In this way amino acid, amino ester, peptide, and nucleic-acid base-containing polymers have been generated in living processes. In comparison, ozonolysis of enantiomerically pure norbornene-derived amido acids has provided a concise synthesis of enantiomericaUy pure cyclopentane derivatives in which all of the substituents are syn to each other and ready for elaboration into target molecules. The final chapter provides the first and a much sought after contribution to the series on small-ring nitrogen heterocycles. Hassner and Rai describe the developments in the chemistry of azirines and aziridines and their contribution fills an obvious gap in-our coverage. The detailed chapter opens with a discussion of the structure and spectroscopic properties before moving on to the synthesis and reactions 1H-azirines, 3,3-dimethylamino-2H-azirines, and aziridines. The preparation of azirines from vinyl azides and oximes is followed by a description of the first chiral synthesis of the cytotoxic (R)-(-)-dysidazirine. A notable strength of the chapter is in the full description of the chemistry of the azirines that is provided. The 3-(dimethylamino)azirines have value because of their easy transformation into a wide variety of heterocycles of particular importance, e.g. imidazolones and oxadiazocines, and their transformation into peptide and depsipeptide derivatives is nicely described. The aziridines are similarly treated and after a good synopsis of the synthetic methodologies the chemistry of the heterocycle that leads to important pseudo-sugars, imino-sugars, and natural products is provided. The section concludes with a discussion on the metabolism and cytotoxicity of natural and synthetic aziridines. Brian Halton Series Editor

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NATU RAL AN D NON-NATU RAL PLANAR CARBON NETWORKS: FROM MONOMERIC MODELS TO OLIGOMERIC SUBSTRUCTURES

Michael M. Haley and W. Brad Wan

1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Graphite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Subunits via Intramolecular D i e l s - A l d e r Reaction . . . . . . . . . . . . . 2.2 Subunits via Alkyne Cyclotrimerization . . . . . . . . . . . . . . . . . . 2.3 Subunits via Intermolecular D i e l s - A l d e r Reaction . . . . . . . . . . . . . Poly(phenylene) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Biphenylene Dimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Oligo(phenylene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Graphyne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Hexaethynylbenzenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Dehydrobenzo[ 12] annulenes . . . . . . . . . . . . . . . . . . . . . . . . Graphdiyne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Hexabutadiynylbenzenes . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Dehydrobenzo[ 18]annulenes . . . . . . . . . . . . . . . . . . . . . . . .

Advances in Strained and Interesting Organic Molecules Volume 8, pages 1--41. Copyright 9 2000 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1.7623-0631-9

2 3 5 8 9 13 13 14 17 18 20 24 25 25

2

MICHAEL M. HALEY and W. BRAD WAN

6. 7. 8. 9.

Poly(tetraethynylcyclobutadiene) . . . . . . . . . . . . . . . . . . . . . . . . Poly(tetraethynylethene) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Ethynyl-Linked Networks . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31 33 36 37 37 38

1. INTRODUCTION For thousands of years the only recognized crystalline forms of carbon were graphite and diamond. Only recently though have these forms found important technological uses [1]. Graphite, comprised of planar sheets of sp2-hybridized carbon atoms, is used in pencils, as a solid lubricant, as a moderator in nuclear reactors, as a component in electrodes, and as a reinforcement material in carbon fiber composites [2]. Diamond, a three-dimensional network of sp3-hybridized carbon atoms, is used in jewelry and as drilling heads in the petrochemical industry. More recently, diamond thin films generated by vapor deposition methods have been used extensively as protective coatings of tools and materials and in electronic devices [3]. Despite the rapidly emerging importance of these carbon allotropes, the study of other carbon-rich systems has been limited for most of the 20th century. A visionary in the field of nonnatural carbon phases was Alexandru Balaban. In 1968, a group of theoreticians led by Balaban published an article in which they put forth a variety of imaginative and aesthetically attractive two- and three-dimensional carbon allotropes, e.g. 1-3 [4]. Although formation of many of these structures is energetically prohibitive, e.g. 1, some networks seemed more reasonable and thus potentially might be within the realm of synthetic endeavors. Over the next 20+ years, numerous two- and three-dimensional all-carbon networks were proposed in the literature, many of which were predicted to exhibit interesting electrical, optical, and structural properties [5]. Nevertheless, synthetic efforts towards the assembly of these nonnatural carbon phases, as well as toward expanded substructures, were lacking. The landmark event that invigorated the study of carbon allotropes was the isolation and confirmation of the structure of C6o (buckminsterfullerene) in 1990

l

2

3

Planar Carbon Networks

3

[6]. Although postulated by Smalley and Kroto in 1985 [7], it was not until 5 years later that Kr~itschmer and Huffman reported the isolation of macroscopic amounts of material, from which they were able to ascertain the now well-established truncated icosahedron structure [8]. Over the ensuing decade since their report, a plethora of publications has appeared dealing with a burgeoning number of carbon-rich and all-carbon molecules. A vast majority of the research has centered on the construction of monomeric and oligomeric substructures of nonnatural sp 2 and/or sp carbon networks. Several reviews have recently appeared from the leading protagonists in some of the respective subareas [9]; therefore, the scope of this review will be limited to selected key examples and more recent studies of planar carbon allotropes and associated model substructures. Three-dimensional systems, which have received only cursory examination [10], will not be discussed.

2. GRAPHITE Given the aforementioned uses of graphite (4), it is not surprising that this natural allotrope is the most heavily studied all-carbon structure [2]. The class of molecules that most resembles graphite (and thus could be considered as a subunit) is the benzenoid polycyclic aromatic hydrocarbons (PAHs). PAHs themselves have been intensively investigated for well over a century [ 11]. Although a wide array of small and intermediate size PAHs are known, e.g. triphenylene, coronene (5), and ovalene, only recently has access to large PAHs been achieved by MiJllen and co-workers [12]. Using very straightforward chemistry, the Mtillen team has assembled a variety of expanded graphitic topologies with excellent efficiency. The driving force behind their work has been the preparation of materials with interesting electrical and/or optoelectronic properties. The inherent thermal stability of the PAHs has allowed for the physisorption of highly ordered monolayers which may be imaged by means of scanning tunneling microscopy (STM) [13]. Furthermore, the PAHs have been shown to form discotic liquid-crystalline mesophases, which may lead to a wealth of technologically important applications [14]. These model graphite topologies of well-defined structure may lead to a better understanding of the materials science of soot, graphite, fullerenes, and nanotubes.

4

$

4

MICHAEL M. HALEY and W. BRAD WAN

According to Mtillen, there are four basic "modes" or methods of constructing PAHs and these are summarized in Figure 1 [12]. The most direct and intuitive method is the dimerization or fusion of smaller benzenoid PAH fragments (Figure 1, path A); however, PAHs are seldom reactive in this manner. The use of forcing conditions is often necessary and results in nonspecific and/or nonordered linkages between the components, which is clearly undesirable for the construction of well-defined substructures. The addition of a C 2 or a C 4 fragment (Figure 1, paths B and C, respectively) at specific target sites is not difficult. However, in virtually all cases, the result of such an addition is the annelation of a nonaromatic ring, which does not contribute to the overall benzenoid motif. An alternative method for the formation of benzenoid PAHs is intramolecular cyclodehydrogenation of suitable PAH precursors (Figure 1, path D). An ideal oligophenylene precursor has the correct number of benzene rings in close proximity and with acceptable spatial arrangement. This approach, which does not alter the number of carbon atoms in the macromolecular system, has proven to be the most efficient method for PAH assembly (vide infra) [12].

Path A

v

dimerization

+

I

,

PathB

__

Addition of C2 fragment

Addition of C4 fragment

Path D

cyclodehydrogenation

Figure 1. Four possible modes for PAH construction.

Planar Carbon Networks

5

Oxidative cyclodehydrogenation can be achieved using a variety of Lewis acid catalysts combined with oxidants, e.g. vanadium(V) or thallium(llI) with 0 2 [15], zero-valent metals, e.g. K or Pt [16], as well as by photochemical routes [17]. Another method employs an A1CI3 melt that is combined with atmospheric oxygen in order to fuse aromatic components [18]. Most of these traditional routes have s~gnificant drawbacks. High temperatures are required to drive these reactions, and the result is often decomposition and/or unpredictable rearrangement. The reactions often result in incomplete cyclization with difficulty in separating the partially cyclized materials. In the 1960s Kovacic was able to polymerize benzene and its derivatives under relatively mild conditions, utilizing A1C13or FeC13 in concert with atmospheric oxygen to catalyze the formation of aryl-aryl bonds [ 19]. This method was somewhat successful but not very selective; the result was an uncontrolled mixture of ortho and meta branching. By subtle modification of Kovacic's mild conditions (use of CuC12/A1C13 or CuSO2CF3/AIC13 as the catalytic system), the Mtillen team has been able to complete the synthesis of a family of large graphitic, all-benzenoid PAH structures [ 12].

2.1

S u b u n i t s via

Intramolecular Diels-Alder

Reaction

Mtillen and co-workers have developed three fundamental approaches of synthesizing oligophenylenes, which serve as the precursors for PAHs. The first approach involves an intramolecular [4+2] cycloaddition of suitable phenylenevinylene derivatives. A representative example of this strategy is the preparation of 6 (Scheme 1) [20]. The coupling partners 7 and 8 were constructed with relative ease via Wittig reaction of 2-iodobenzyltriphenylphosphonium chloride with benzaldehyde and cinnamaldehyde, respectively. The individual components were heated briefly in toluene at 110 ~ with a catalytic amount of iodine and in the absence of light to convert the mixture of isomers into the thermodynamically more stable

b 1oo%

+

75% 7

8

9

e _

d 77%

75%10

11

Scheme I. Reagents: (a)i] 7, BuLi, THF,-78 ~

6

ii] ZnBr2, THF,-78 ~ iii] 8, Pd2(dba)3, THF, -78 to 25 ~ (b) toluene, 100 ~ (c) DDQ, benzene, 78 ~ (d) AICI3, CuCl2, CS2, 25 ~

6

MICHAEL M. HALEY and W. BRAD WAN

(E) form. Aryl-aryl cross-coupling of 7 with 8 was accomplished according to the method of Knochel et al. in 75% yield [21]. Once constructed, intermediate 9 was heated at 100 ~ in toluene to induce an intramolecular Diels-Alder reaction, providing i0. The central ring was aromatized upon treatment with DDQ to give PAH precursor 11 in 75% yield. Oxidative cyclodehydrogenation of 11 could be accomplished by reduction with a potassium mirror for several days followed by oxidation with iodine in toluene in 47% yield; a superior method was use of modified Kovacic conditions (CuCI2/AIC13 in CS2), achieving the same transformarion in 77% yield. More importantly, this latter method was amenable to scaled-up reactions. Utilizing analogous chemistry, polyene 12 could be assembled from 8 and diiodide 13 (Scheme 2) [20]. In order to avoid the possibility of premature Diels-Alder reaction, the cross-coupling step was performed at a lower temperature and thus resulted in the lower isolated yield (32%). Heating 12 at 100 ~ in toluene induced the double [4+2] cycloaddition and subsequent aromatization with DDQ gave 14 in 92% yield. Oxidative cyclodehydrogenation furnished a hydrocarbon that was characterized by its molecular weight from laser desorption time-of-flight mass spectrometry (LDTOF-MS). Two factors, however, complicated PAH identification: (1) the starting arene can exist as two rotomers (14a,b) which upon cyclodehydrogenation can lead to the formation of two different C54

,T

r '

) 12

Scheme 2. Reagents: (a)i] 8, BuLi, THF, -78 ~

14b

Ifi

ii] ZnBr2, THF, -78 ~ iii] 13, Pd2(dba)3, THF, -78 to 25 ~ (b) toluene, 100 ~ (c) DDQ, 1,1,2,2-tetrachloroethane, 140 ~ (d) AICI3, CuCI2, CS2, 25 ~

Planar Carbon Networks

7

topologies (15 and 16). This dilemma illustrates the need for careful consideration of the starting polyene structure, and (2) PAHs are known to exhibit extremely poor solubility. This recurring problem made it impossible to determine the ratio of 15 to 16. In fact, poor solubility limited most PAH product characterization primarily to TOF-MS experiments and solid-state techniques. In order to assure the formation of 15 exclusively, an alternate synthesis was devised in which the central core of the arene precursor is in a fixed geometry prior to cyclodehydrogenation (Scheme 3) [22]. Suzuki cross-coupling of dibromide 17 with 18 gave stilbenoid 19 in excellent yield (92%) and with no evidence of premature cyclization. Heating 19 in 1,1,2,2-tetrachloroethane induced the double intramolecular Diels-Alder reaction, providing 20 in essentially quantitative yield. Treatment with DDQ gave 21 in 96% yield. Unlike 14, the central benzene moiety of this PAH precursor cannot rotate and so oxidative cyclodehydrogenation provided PAH 15 as the sole compound in essentially quantitative yield. Judicious placement of the ene-diene moieties in the starting stilbenoids can lead to a variety of topologies. For example, reversal of the substituents in 17 and 18 provided 22, which upon similar elaboration gave the C54 isomer 23 [22]. Although traditional spectroscopic techniques were generally ineffective due to low solubility, other methods for structural characterization could be utilized as the PAHs displayed remarkable thermal stability. For example, deposition of 15 at 450 ~ under ultrahigh vacuum onto a MoS 2 surface produced well-ordered layers of

I Br

a

b

92%

17

18

e

I

98%

19

~

d

v

96%

20

99%

21

15

Scheme3. Reagents:(a) Pd(PPh3)4,toluene, EtOH, H20, reflux; (b) 1,1,2,2-tetrachlo-

roethane, 135 oC; (c) DDQ, 1,1,2,2-tetrachloroethane, 135 oC; (d) AICI3, CuCI2, CS2,

25 ~

8

MICHAEL M. HALEY and W. BRAD WAN

22

23

the PAH from which the unit mesh could be derived by low-energy electron diffraction [22]. The area of the mesh (ca. 200 A) corresponded roughly to the van der Waals area of the planar PAH. STM analysis of the deposited material clearly showed planar molecules of rhombic shape closely packed in an ordered arrangement on the substrate.

2.2 Subunitsvia Alkyne Cyclotrimerization As previously mentioned, the ideal precursor for an all-benzenoid PAH is an oligophenylene with the benzene rings in good spatial agreement. One of the most elementary compounds that matches this description is hexaphenylbenzene (24, R = H). The preparation of 24 via hexaaryl substitution of hexahalobenzene is exceedingly difficult [23]. A much more convenient route to 24 is the cobaltmediated cyclotrimerization [24] of 1,2-diphenylethyne (also known as tolane, 25), as shown in Scheme 4 [13]. The cyclization conditions are sufficiently mild to tolerate both halogen and alkyl substituents on the phenyl rings. The tolane derivatives are readily assembled by Pd-catalyzed alkynylation of an appropriate iodobenzene and allow the introduction of solubilizing substituents. This method is restricted, however, to producing identically substituted PAH precursors. Another

3

R~~j~,R _ a 92%

_

R

b ~

R

49%

] 25

24

26

(R ==H, ~.~-~, tBu)

(R - H. n-alkyl,tBu)

Scheme 4. Reagents: (a) Co2(CO)8, dioxane, 100 ~

C52, 25 ~

5 d; (b) Cu(OSO2CF3)2, AICI3,

Planar Carbon Networks

9

drawback is that inclusion of the alkyl groups complicates the cyclodehydrogenation reaction. The substituted oligophenylenes also undergo alkyl group migration, dealkylation, and chlorination. Fortunately these deleterious side reactions can be suppressed by use of a weaker Lewis acid. For example, the yield of 26 increased from 49% using A1C13 to 95% using FeC13 [25]. In addition to standard spectroscopic techniques, PAH 26 (R = C12H25) was visualized using STM [ 12]. As with 15, the macromolecule packed in a highly ordered manner. Interestingly, several long-chain alkyl derivatives of 26 displayed discotic liquid crystalline behavior, an unusual result for a pure hydrocarbon. The columnar mesophases formed by 26 exhibited extremely broad temperature ranges [13]. ,

2.3 Subunits via Intermolecular Diels-Alder Reaction The construction of differently substituted derivatives of 26 required an alternative synthesis of 24. The Mtillen team developed an intermolecular Diels-Alder approach in which cycloaddition of tetraarylcyclopentadienones (tetracyclones, e.g. 27) with tolanes and subsequent extrusion of carbon monoxide led directly to the hexaphenylbenzene structure 24 (Scheme 5) [25]. The requisite tetracyclones are readily prepared via well-established transformations [26] and are much more

R

~

r

a, b ~ 60%

2 R R

d

27

2

2 R

[~

R

R

R

R

R

r

>95% R

R

26

24

(R, R', R2- 14,n-,dkyi,tBu, halollcn) Scheme 5. Reagents: (a) BuLi, THF, -78 ~

(b) 1,4-dimethylpiperazine-2,3-dione; (c) Fe(CO)5, NaOH, CH2CI2, H20, dodecyltrimethylammonium bromide; (d) KOH, EtOH, reflux, 3 h; (e) 25, Ph20, 250 ~ 3-6 h; (f) Cu(OSO2CF3)2,AICI3, CS2, 25 ~

Z <~

-r'

_I

<~ -I-

Q T"--

,t~

A

H

~

II

I t.,,sl

U P,,,l "r" (,.3

u_

u

A

o

(,,.3

(,.3

o

+u ,,A

t-

O

c

LI.

~O

,,+u

m.o

_.m~

Planar Carbon Networks

11

amenable to the introduction of assorted substituents. Cycloaddition of 24 to 25, decarbonylation, and cyclodehydrogenation gave PAH 26, which has been nicknamed "superbenzene" The tetracyclone-based route has proved to be a powerful and versatile synthetic strategy. The one-pot reaction installs five new phenyl rings at each alkyne. For example, alkynes 28 and 29 can be transformed into "supernaphthalene" (30) and "supertriphenylene" (31), respectively (Scheme 6) [27]. Using analogous chemistry, hydrocarbons 32-35 have been assembled [27,28]. Proper choice of alkyne can lead to a wide variety of oligophenylenes, which in turn can be cyclodehydrogenated to PAHs of unprecedented shape and size. Alkyne "mismatch" produces oligophenylenes which in theory are "nonplanarizable." In certain instances, skeletal rearrangement can lead to planarized PAHs [29]. For example,PAH 36 can be formed from either oligophenylene 37 or 38 (Scheme 7). The latter molecule undergoes a 1,2-phenyl shift during Lewis acidcatalyzed cyclodehydrogenation in order to relieve steric strain between aromatic rings, thus leading to formation of thermodynamically more stable 36. The ultimate example of the cyclodehydrogenation method is the construction of the C222 PAH 39 (Scheme 8) [27]. Utilizing a combination of the tetracyclone strategy and the cyclotrimerization strategy, triyne 40 could be converted into freely

32 (R ,,H. n-CI2H~)

34

33 (R - H, tBu)

35

12

MICHAEL M. HALEY and W. BRAD WAN

O

-

s [ 97%

s [ 95%

37

0/

38

36 2 days; (b) Cu(OSO2CF3)2, AICI3, CS2, 23 ~ 2 days; (c) CuCI2, AICI3, CS2, 25 ~ 2 days. Scheme 7. Reagents: (a) 27, Ph20, 220 ~

66%

71%

r

41

39

Scheme 8. Reagents: (a) 27, Ph20, 190 ~ 11h; (b) Co2(CO)8, dioxane, I00 ~ 5 days; (c) Cu(OSO2CF3)2, AICI3, CS2, 25 ~ 2 days.

Planar Carbon Networks

13

soluble oligophenylene 41, which contained 37 aromatic rings. Cyclodehydrogenation with A1C13/Cu(OTf)2 produced a black solid impervious to all common solvents. Analysis by TOF-MS showed a broad peak in the mass range expected for 39; however, proof of complete removal of the 108 hydrogen atoms to form 39 was not possible due to signal broadening. Additionally, PAHs of this size are at the limits of detection for the MS instrument. The Mtillen group's ability to build the requisite oligophenylene precursors has exceeded their ability to manipulate and characterize the resultant products. Nevertheless, work continues on the preparation and characterization of even larger graphite fragments.

3.

POLY(PHENYLENE)

In addition to graphite and networks 1-3, a wide array of other sp2-hybridized carbon allotropes can be envisaged. Two such networks are linear and angular polyphenylene structures 42 and 43, respectively. It is noteworthy that 43 was one of the networks proposed by Balaban et al. in 1968 [4]. The angular network has an estimated heat of formation of ca. 22 kcal/g-atom C, which is considerably higher than that of graphite and diamond (0 and 0.4 kcal/gatom C, respectively) [30]. As a result of the strain inherent in the cyclobutane rings, both of these "high-energy" networks may be susceptible to facile rearrangement into the aforementioned natural allotropes, i.e. graphitization.

3.1 Biphenylene Dimer Biphenylene, the simplest structural motif contained within 42 and 43, has been synthesized numerous times since its original discovery in 1941. The most convenient method is dimerization of benzyne with isolated yields up to 35% for this single-step reaction [31 ]. Derivatized biphenylenes, on the other hand, are much more difficult to construct. In order to prepare "2 x 2" macrocyclic fragment 44 of linear network 42, Rajca and co-workers had to first synthesize the dibromo-

J:

41

43

14

MICHAEL M. HALEY and W. BRAD WAN

30%"

30%

~r

~r 30-34%R

46

4'7

45

44 (R=H, d3u)

Scheme 9. Reagents:(a) i] BuLi, ether, -78 ~ 2 h, ii] CuBr2,-78 to 25 ~ (b) i] BuLi,

ether,-78 ~

2 h, ii] CuCN,-78 to 25 ~

iii] 02,-78 ~

biphenylene 45 via symmetrical aryl-aryl coupling steps (Scheme 9) [32]. Li/I exchange on 46 followed by copper-mediated oxidative dimerization gave 47 in ca. 30% yield. Li/Br exchange (2 equiv) of 47, conversion to a cuprate with CuCN, and treatment with gaseous oxygen furnished the biphenylene 45 in similar yield. This molecule was dimerized using a final Li/Br exchange and copper-mediated oxidative coupling. Although the synthetic route was clearly inefficient (ca. 3% overall yield), physical studies of 44 (R = t-Bu) provided important information, in that it was shown to exist as three polymorphs in the solid state. X-ray crystallography of two of these phases showed bond alternation similar to that observed in biphenylene and slight distortion of the tetraphenylene core from planarity (dihedral angle <12~ The latter effect was attributed to repulsive intrastack contacts in both polymorphs involving the tert-butyl groups. X-ray quality crystals of the parent hydrocarbon (44, R = H) were not obtained.

3.20ligo(phenylene)s The Vollhardt group has been the principle protagonists in the syntheses of larger linear, angular, and triangular substructures of 42 and 43. The Berkeley team has produced a remarkable variety of molecules using the cobalt-mediated cyclotrimerization of alkynes as the key reaction [24]. Structures 48-54 are representative examples, with the linear molecules as subunits of 42 and the angular and triangular molecules as subunits of 43. The construction of these molecules as well as discussion of their properties has been reviewed recently in this Series [33]. The sole topology missing from the various phenylene models is the zigzag variant; however, earlier this year Vollhardt et al. reported the preparation of 55 (Scheme 10; the abbreviation "Th" for thexyl (1,1,2-trimethyl) is used here and throughout) and 56 (Scheme 11) [34]. Like much of Mtillen's work (vide infra), one of the keys to successful phenylene construction was judicious choice of the coupling partners. In Vollhardt's case, the preparation of the requisite alkynes for cyclization often times was a challenge. Fortunately, the discovery of conditions

Planar Carbon Networks

15

R

M c 3 S i ~ R

R

Mc3Si

48

R

49

(g = rt SiMe3)

(R = H, SilVlc3)

M c 3 S i ~ S i M c 3 M c 3 S i ~ S i M c 3 50

$1

53

52

54 (R = H, SiMe3)

that allowed selective, stepwise alkynylation of 1,2,3,4-tetrabromobenzene (57) permitted the assembly of several ct,(o-polyynes useful for further elaboration [35]. For example, the pentayne 58 was quickly and efficiently prepared in three steps from 57 (Scheme 10). Cyclization of 58 with bis(trimethylsilyl)ethyne mediated by CpCo(CO)2 furnished phenylene 55 (R = SiMe3), albeit in low yield (15%) and protiodesilylation with trifluoroacetic acid gave the parent zigzag [4] hydrocarbon.

ThM~Si

Br Br Br~-(Br~

Br~.iBr ~ a

66%

-

B

r

~

b,c

33%

57

15% 58

9 I ' R=Silvlc3 55 74% ~ R- H

Scheme lO. Reagents: (a) o-(HC--C)C6H4(C:---CSiMe2Th), PdCI2(PPh3)2, Cul, Et3N,

50 ~ 24 h; (b) Me3SiC:-----CH, PdCI2(PPh3)2, Cul, piperidine, 100 ~ 7 days; (c) Bu4N+F-, THF, 2 h; (d) Me3SiC--CSiMe3, CpCo(CO)2, h~,, 10 h; (e) CF3CO2H, CHCI3, 12h.

16

MICHAEL M. HALEY and W. BRAD WAN

Similarly, the zigzag topology of 56 was prepared from the hexayne 59 (Scheme 11) [34]. As expected, the spectral data of both zigzag structures bear a striking resemblance to those found in their angular counterparts [33]. X-ray crystal structures revealed, as found in their angular isomers, pronounced bond alternation (ca. 0.08/~) in the interior benzene moieties of 55 and 56, as well as marked deviations from planarity. An extreme example of angular phenylenes would be the macrocyclic substructure 60 of network 43 that is known as "antikekulene" [35]. Vollhardt and co-workers recently reported the synthesis of the nonayne macrocycle 61, which not only is a potential precursor of the circular oligophenylene 60 but also serves as a model substructure for the all-carbon network graphyne (see Section 4). As before, the assembly of 61 proceeded via selective functionalization of tetrabromobenzene (57) (Scheme 12). Intramolecular [CpCo(CO)2]-induced cyclotrimerization of 61 afforded the cyclic angular triphenylene derivative 62 in low to moderate yield, depending on the alkyne substituents. The second cyclization was accomplished at elevated temperature (160 ~ to produce the pentaphenylene derivative 63. Although the final cyclization to give the corresponding antikekulene structure 60 has not yet been achieved, the spectral data of partially cyclized structures 62 and 63 suggest "superdelocalization" of the antiaromatic ring currents in these molecules due to inclusion of the bridging alkyne units [35]. This finding supports Balaban's predictions that both substructure 60 and networks 42 and 43 would exhibit similar if not enhanced delocalization, giving rise to interesting electronic properties. SiMe2Th

Br-~Br Br Br

R

a

~

Br~r

SiMe2Th

~

b,r

50-80%R

59 (R- H, Ph,Pr)

R R

56 (R- H, Ph,Pr)

Scheme 11. Reagents: (a) o-(HC~C)C6H4(C~CSiMe2Th), PdCI2(PPh3)2, Cul, Et3N,

50 ~ 24 h; (b) RC=CH, PdCI2(PPh3)2,Cul, piperidine, 100 ~ 7 days; (c) Bu4N+F-, THF, 2 h; (d) Me3SiC=CSiMe3, CpCo(CO)2, h~ 10 h.

Planar Carbon Networks

~

r

a

_

17

Br

b

~

r

r

57 RR

R

g

f

36%

62

61

(R - Pr', 14%) (R CH2C6I-Ii !, 45%) -

R

R

6.t (R-Pr, 14%) (R - CH2Cd~,, 4o%)

R

R

60

Scheme 12. Reagents: (a) RC~CH, PdCI2(PPh3)2, Cul, Et3N, 23-60 ~

3 days; (b) Me3SiC=---CH, PdCI2(PPh3)2, Cul, Et3N, 100 ~ 4 h-2.5 days; (c) BuLl, Et20,-78 ~ 30 rain; (d) 12, Et20,-78 to 23 ~ (e) K2CO3, MeOH, or NaOH, MeOH, or BuaN+F-, THF, 1 h; (f) CuCI, NH4OH, EtOH, pyridine, g, 6 h; (g) CpCo(CO)2, m-xylene, A, hv, 20 min; (h) CpCo(CO)2, 1,2,4-trichlorobenzene, 160 *C, 3 h.

4. GRAPHYNE As with purely sp2-hybridized networks, a plethora of planar allotropes combining sp and sp 2 carbon atoms can be envisaged. For example, replacement of one-third of the carbon-carbon bonds of graphite (4) with ethyne units results in the formation of a network composed entirely of phenyl rings and triple bonds, dubbed graphyne (64). In their seminal paper predicting structural, thermodynamic, and electronic properties for planar sheets equally occupied by sp and sp 2 carbon atoms, Baughman et al. postulated that 64 would exhibit interesting nonlinear optical behavior [36]. Furthermore, alkali metal charge-transfer complexes of 64 were expected to be metallic. Accompanying the interesting materials properties, gra-

18

MICHAEL M. HALEY and W. BRAD WAN

r 0 ---..0.... 65

64

phyne was also predicted to be a large bandgap semiconductor (Eg = 1.2 eV). The calculated heat of formation [A~ for 64 is 14.2 kcal/g-atom C, which is comparable to the experimentally determined values for C60 and C70 (10.16 and 9.65 kcal/g-atom C, respectively) [37]. Despite this thermodynamic instability, the crystalline fullerenes are kinetically stable molecules, and require high-temperature and high-pressure conditions to force their conversion to the more stable forms of graphite and diamond. Hence it can be argued that graphyne might exhibit analogous kinetic stability and thus be resistant to graphitization. Synthetic accessibility is the primary deterrent to graphyne-related research. Controlled oligotrimerization of cyclo[ 12]carbon (65)could conceivably be a route to 64, but the synthesis (detection) of 65 outside a mass spectrometer has proved elusive [38]. Very recent reviews by Diederich [39] and Tobe [40] detail the preparative strategies used for the cyclo[n]carbons.

4.1 Hexaethynylbenzenes The simplest graphyne substructure that is within the realm of synthetic accessibility is hexaethynylbenzene, which can be viewed as an acetylenic scaffold off of which graphyne mimics can be built. The parent hydrocarbon 66 (R = H) was first prepared by Vollhardt et al. in 1986 using Sonogashira cross-coupling between hexabromobenzene and trimethylsilylethyne followed by protiodesilylation [41]. The resultant molecule proved to be highly sensitive to both heat and oxygen, a common problem found in perethynylated n systems. Not surprisingly, this instability has limited studies utilizing 66 (R = H). Since the initial report, a number of hexaethynylbenzene derivatives have been prepared which incorporate D6h (67) [42], Dab (68) [43], and C2v (69) [44] symmetries. The preparations of the last two systems require considerably more involved syntheses. For example, the topology of 68 is derived from mesitylene (Scheme 13). This molecule can readily be converted into tribromotrialdehyde 70.

Planar Carbon Networks

19 R R

R

R

R

R

R

R R

R 67 (R = H, Pent, Hex, Hept)

66

(R = H, SiMe3,tBu) R! R 2 ~

Ri

R2

R l ~

Rl"W !2 "~'RI

RI"~

68

Me

Mr

Me 85%

!1 "~R2 69

(R1- SiMr R2 = Ph) (R1- SiEt3; R2 - H, Br,p-C6H4NO2)

Me

Br~

Br

Me

Me

Br

(R1- SiiPt3,/Bu; R2 = H)

Br

b ~ 80%

Br,v ~ Br ~ Br Br Br

Ph.~ d

55-65%"OHC CHO HO Br

e

86%

Br Ph Br~Brlb

CHO Ph

Ph 71 Ph

Br

89% g -

Me3Si~ Phr"

Br

r

88%

-- O H C ~ O

70

f 95%

R2

SiMe3

IhI-

"-Ph SiMe3

68

Scheme 13. Reagents: (a) Br2, Fe; (b) Br2, h~ (c)i] KOAc, DMF, ii] KOH, H20; (d)

PCC; (e) PhC~CH, PdCI2(PPh3)2,Cul, i-Pr2NEt; (f) PPh3,Zn, CBr4, CH2CI2; (g) i] LDA, THF,-78 ~ ii] Me3SiCI.

20

MICHAEL M. HALEY and W. BRAD WAN

The first set of substituted alkynes is installed via Pd-catalyzed cross-coupling to give 71, while the second set is formed via the Corey-Fuchs procedure followed by trapping with an electrophile. Of the series 66-69, the most "advanced" graphyne subunits are the hexakis(arylethynyl)benzenes (67). Also prepared from hexabromobenzene, molecule 67 (R = H) was found to have a large third-order nonlinear susceptibility, a property already predicted for the bulk graphyne network (vide supra) [42b]. The incorporation of long alkyl chains on the exterior phenyl tings of 67 produced molecules that exhibited discotic liquid crystalline behavior [42a].

4.2 Dehydrobenzo[12]annulenes An alternative method to use of acetylenic scaffolding is to prepare macrocyclic segments as network mimics. Dehydrobenzoannulenes [45] are a class of molecules that are well suited for this purpose. In addition to being substructures of synthetic carbon allotropes, dehydrobenzoannulenes have garnered tremendous interest in recent years as ligands for organometallic chemistry, as hosts for binding guest molecules, as probes for investigating weak induced ring currents, and as precursors to fullerenes, "bucky" tubes, "bucky" onions, and other carbon-rich materials [46]. More importantly, the annulenic compounds tend to be more stable to heat, light, and oxygen. In the specific case of graphyne, hexadehydrotribenzo[ 12]annulene (72) is the smallest macrocyclic unit. Triyne 72 has been synthesized in a variety of ways [47] over the 30+ years since its initial preparation [48]. Nevertheless, an improved version of the original approach remains the easiest and most direct route. Cu-mediated intermolecular cyclotrimerization of alkyne 73 furnishes annulene 72 in 47% yield along with an 8% yield of tetramer 74 and traces of hexamer (Scheme 14) [49]. The cyclotrimerization strategy has provided many other annulenic systems, including a hexa(methoxy) analogue of 72 [50] as well as nonayne 61 (Scheme 12, p. 17) [35], a more "evolved" graphyne subunit. The concomitant isolation of tetramer and hexamer along with 72 highlights a major drawback of the intermolecular strategy. While simple in execution, the unavoidable pitfall of the synthesis is formation of other cyclooligomeric products. Depending upon the substituents, trimeric [49], tetrameric [38], or even highly

ck

b,r

[~

73

+

72 (47%)

Scheme 14. Reagents:(a)i] KOt-Bu, BuLi, THF,-78 ~

74 (8%)

ii] MgBr2-Et20, iii] 12, iv] 1 M HCl; (b) CuSO4, NH2OH.HCl, NH4OH, EtOH; (c) pyridine, reflux.

Planar Carbon Networks

21

strained dimeric species [51] can predominate. Owing to their similarity in composition, structure, and solubility, it is often difficult (or impossible) to isolate a specific macrocycle from the product mixture. This problem is exacerbated for larger diacetylenic macrocycles (vide infra). Ready access to 72 has allowed detailed exploration of its chemistry by the Youngs group. Reactions with transition metal complexes have led to a number of structures in which 72 participates as a ligand. For example, treatment with dicobaltoctacarbonyl yielded the 66 electron cluster 75 [52]. An alternative mode of metal bonding was observed with the Ni(0) complex 76, generated from a benzene solution of Ni(COD)2 and 72 [53]. The distance from the center of the macrocycle to the center of the carbon-carbon triple bonds is ca. 1.2/~; thus, 72 provides a good environment for 7t-alkyne transition metal bonding. Due to this sizable hole, the nickel atom of 76 was able to reside in the plane of the macrocycle. Depending on the stoichiometry of the copper triflate used, either 77 or 78 could be isolated [54]. Use of the slightly larger silver cation gave rise to a sandwich complex that exists as a mixture of two conformers in the solid state; 79 depicts the eclipsed form [55]. Treatment of annulene 72 with lithium induced the collapse of the 12-membered ring, giving the helical fulvalene dianion derivative Li20'ISTIS-C24H14) (80), the structure of which was confirmed by X-ray analysis of its complex with TMEDA [56]. The dianion could be treated with methanol to generate the neutral parent compound (81, R = H) or quenched with other electrophiles such as chlorotrimethylsilane to generate the corresponding helical adducts, e.g. 81 (R = SiMe3) [56]. An analogous type of lithium-induced "zipper" cyclization was observed with tetramer 74 [57]. In order to minimize the formation of side products, [12]annulene 72 can be constructed via an intramolecular approach [58]. Sequential Sonogashira coupling

(CO)3Co~.~./. Co(CO)3 " ?~Co~- -"

75

CR/~SO2CF3

R

R

76 (R -- H. OMe)

(F3CO2SO

OSO2CF3) ~

-

~

Cu(OSO2CF3) 77

78

79

+

22

MICHAEL M. HALEY and W. BRAD WAN

80

81 - H, SilVlc3)

reactions and manipulation of iodines masked as triazenes [59] represent most of the chemistry involved in Scheme 15. Using these proven methods, diyne 82 and subsequently triyne 83 can be assembled easily. Iodination, desilylation, and intramolecular alkynylation with Pd(dba)2 under high dilution conditions furnished 72 as the sole product. Although this route required six more steps from commercially available materials, the overall yield was 35% as opposed to the reported 24% for Scheme 14. More importantly, larger cyclooligomeric macrocycles were not detected, facilitating product isolation and purification. The intramolecular cyclization strategy is indispensable for the construction of more complex substructures of the graphyne network, such as bis-macrocycle 84 (Scheme 16), which is otherwise impossible to synthesize by intermolecular routes [58]. Using the same general sequence of reactions, hexayne precursor 85 ~was prepared efficiently. Intramolecular cyclization gave, after vacuum sublimation, a yellow solid that proved to be sparingly soluble in common organic solvents. Despite this problem, mass spectrometry, IR, and UV-vis data confirmed the formation of 84. Although it came to be expected for larger graphyne mimics, the

I

2

a, b

.iMc3 !

96%

82%

t2

d

/~.SiMe3 C C

88%

98%

SiMe3

~ N3Et2 82

c, f _

~

= SiMe3

73%

c, d, g

69% 83

72

Scheme 15. Reagents: (a)i] HCI, NaNO2, ii] K2CO3, Et2NH; (b) Me3SiC~CH, PdCI2(PPh3)2, Cul, Et3N; (c) Mel, 120 ~ (d) K2CO3, MeOH; (e) PdCI2(PPh3)2, Cul, Et3N; (f) N,N-Diethyl-o-ethynylphenyltriazene, PdCI2(PPh3)2,Cul, Et3N; (g) Pd(dba)2, PPh3, Cul, Et3N.

23

Planar Carbon Networks

~t2r~ 3

82

85

84

Scheme 16. Reagents"(a) K2CO3, MeOH, THF; (b) 1,5-dibromo-2,4-diiodobenzene,

PdCI2(PPh3)2, Cul, Et3N; (c) Me3SiC~CH, PdCI2(PPh3)2,Cul, Et3N; (d) Mel, 120 ~ (e) Pd(dba)2, PPh3, Cul, Et3N.

severity of the solubility problem was surprising at this stage. It is probable that the low yield of the cyclization step (<15%) is due mainly to this complication. Repetition of the synthetic sequence with solubilizing substituents on the arenes has failed so far to furnish derivatives of 84. Anticipating that solubility problems might be encountered during the preparation of bis-macrocycle 86, precursors with tea-butyl substituents were prepared (Scheme 17) [58]. Treatment of commercially available 4-tert-butylaniline with

tBu

tl~u

87

h.i . 25%

Me~3~S s~

ild~

d,f,j _

~t2

14%

p~

Scheme 17. Reagents:(a) BnEt3N+ICI~, CaCO3, CH2CI2, MeOH; (b)i] NaNO2, HCI,

MeCN, H20, ii] Et2NH, K2CO3, H20; (c) Me3SiC~CH, PdCI2(PPh3)2,Cul, Et3N; (d) Mel, 120 ~ (e) i-Pr3SiC~CH, PdCI2(PPh3)2,Cul, Et3N; (f) K2CO3, THF, MeOH; (g) N,N-Diethyl-o-ioclophenyltriazene, PdCI2(PPh3)2,Cul, Et3N; (h) Bu4N+F-, THF, EtOH; (i) 87, PdCI2(PPh3)2,Cul, Et3N; (j) Pd(dba)2, PPh3, Cul, Et3N.

24

MICHAEL M. HALEY and W. BRAD WAN

(BnNEt3)+IC1] [60] provided 2,6-diiodo-4-tert-butylaniline in high yield under mild conditions. This in turn was transformed into intermediate 87. Following a synthetic pathway analogous to Schemes 15 and 16, the diamond-shaped subunit 86 was assembled in 0.6% overall yield from 13 steps. Attempts to obtain X-ray diffracting crystals of the bright yellow solid were unsuccessful; nevertheless, the spectral properties agreed fully with the proposed structure. Although bis-macrocycles 84 and 86 represent the largest substructures of graphyne to date, insufficient quantities of these compounds have precluded reliable correlation studies relating size with physical properties. 5.

GRAPHDIYNE

Extension of the linkages of graphyne by an additional triple bond generates another theoretical sp-sp 2 carbon allotrope called graphdiyne (88). Recent calculations predict 88 to retain all of the properties of graphyne, e.g. high third-order nonlinear optical susceptibility, conductivity, or superconductivity when doped with alkali metals, and enhanced redox activity [61 ]. In addition, the extra alkyne unit increases the pore size of the network to approximately 2.5/~. This may make through-sheet transport of smaller ions possible, and thus there exists a potential method of dopant storage which is unavailable to graphite, namely intrasheet intercalation [61 ]. Analogous to graphyne, the synthetic routes to network 88 are beyond the limits of current methods. Whereas controlled oligotrimerization of cyclo[18]carbon (89) could conceivably fiamish 88, attempts to generate macroscopic amounts of this material have been unsuccessful [39,40]. Ideally, hexaethynylbenzene (66, R = H) would also be a suitable monomer

It

88

119

25

Planar Carbon Networks

for 88. Instead of ordered polymerization via Cu-mediated oxidative acetylenic coupling, the aforementioned instability problems result in random cross-linking and incomplete cross-coupling, thus eliminating scaffold 66 as a viable network precursor. Additionally, defects from incomplete reductive elimination of the copper and from intersheet coupling are possible.

5.1 Hexabutadiynylbenzenes Building on their earlier success, the Vollhardt group reported the preparation of three hexabutadiynylbenzene derivatives 90 in 1992 [62]. Again starting with hexabromobenzene, Sonogashira coupling provided the molecules in low to modest yield. Attempts to prepare the parent hydrocarbon by protiodesilylation failed due to its instability. A more "advanced" graphdiyne model (91) was recently synthesized from hexaiodobenzene and p-t-butylphenylbutadiyne in 42% yield using the highly reactive catalyst Pd[P(o-tol)3]2 [63]. 5.2 Dehydrobenzo[18]annulenes The best strategy for reliable correlation of structure and properties becomes the preparation and characterization of well-defined macrocyclic "oligomer" segments. By monitoring a variety of physical properties as a function of oligomer size, extrapolation towards the behavior of the bulk network may be possible. The smallest stable macrocyclic substructure of network 88 is dodecadehydrotribenzo[18]annulene (92, R = H), which has been pursued as a synthetic target since the late 1950s [64]. Analogous to [12]annulene 72, the primary approach to the preparation of 92 and its derivatives has been through the cyclooligomerization route. Cu-mediated cyclization of an o-diethynylbenzene generates the desired macrocycle in low to moderate yield; however, the trimeric structure must be separated from a mixture of cyclooligomers (Scheme 18). Whereas it is possible to

R II

tBu

tBu

R

R R

tBu~

~

~~tBu

tBu 90

(R - tBu,SbPr3,SiMc2Th)

91

26

MICHAEL M. HALEY and W. BRAD WAN R R~..~

ffH H-

R

R

R

R

Cu(I) or

Cu(II)

R I

I

~ R

R

R

93

92

R --- H

35%

0*,4

0*,4

R = nBu

31%

21%

9',4

R -- ODr162

17%

33%

26%

Scheme 18.

manipulate the ratio of dimer, trimer, and tetramer by varying the reaction conditions, i.e. concentration, temperature, catalyst, solvent, etc., a mixture is almost always isolated. Surprisingly, the exception to this is formation of the parent macrocycle 92 (R = H). The only compound identified from the reaction was the highly strained dimer 93 (R = H) [64]. However, inclusion of alkyl or alkoxy groups on the starting diethynylarene did produce a mixture of products from which structure 92 (R = alkyl, alkoxy) could sometimes be isolated in pure form, but only after repeated chromatography and/or recrystallization [65]. Despite possible synthetic and purification shortcomings, the vast majority of related compounds found in the literature have been prepared in this fashion. One of the most recent examples is the formation of the perethynylated derivative 94 by Rubin et al. (Scheme 19), a"highly evolved" graphdiyne subunit [44]. Alkynylation of acetal 95 with tert-butylethyne followed by hydrolysis gave the cyclopentadienone 96 [66]. Cycloaddition of this with diethoxybutynal and subsequent liberation of CO produced arene 97. Sequential dibromomethylenation followed by elimination afforded hexayne 69 (R 1 = t-Bu; R 2 = H) in 5% overall yield from 95. Cyclooligomerization of 69 under Hay coupling conditions gave predominantly dimer 98 (25% yield) and a mixture of trimer 94 and tetramer 99 (13% combined yield) that proved inseparable; thus, the chemical and physical properties of the expanded system 94 are as yet unknown. Analogous to the synthesis of larger graphyne substructures, utilization of an intramolecular cyclization in macrocycle construction assures the formation of a single product. However, such an approach necessitates the manipulation of phenylbutadiyne moieties, which are typically highly reactive species and thus difficult to manipulate. Haley et al. have recently developed a method for coupling reactive phenylbutadiyne derivatives with iodoarenes by means of an in situ deprotection of the sensitive terminal alkynyl groups under typical Sonogashira coupling conditions [67]. Illustrative of this intramolecular route is the successful synthesis of 92

Planar Carbon Networks

B,, Mo Bf-~rDMr

a

27

~

B~

tBu

Me

b

=

87% tBu~ ~ "IC)Me.tBu 82%

tBu

tBu~

c

tBu" ~...,Bu 61%

95

96

tB

tBu d,e

tB

.

r

tBu

Br

Eli

d,f

tBu"-

H

_ tBt~

~'~'H

tlJU

tLlu

97

69

tBu..

cB

flu ..tBu i'~

t u

.j .,-,~.,,.. mu t B u ~ t Ia tBu

tBul

!

9a (n--0) 25% 94 (n=l)l 13% 99 (n=2)J

-In

Scheme 19. Reagents: (a) t-BuC~CH, PdCI2(PPh3)2, Cul, i-Pr2NH; (b) CF3COOH, CH2CI2, H20 25 ~ (c) 4,4-Diethoxy-2-butynal, toluene, reflux; (d) CBr4, PPh3, CH2CI2, 5iO2; (e) LDA, THF,-78 ~ if) CuCI, TMEDA, acetone, 02.

(R = H) (Scheme 20) [68]. Sequential cross-coupling of trimethylsilyl-1,3-butadiyne and (triisopropylsilyl)ethyne furnished triyne 100 in 73% combined yield. Under pseudo-high dilution conditions, the smaller, more labile SiMea-grou p was deprotected in situ and the resultant butadiyne was coupled to 1,2-diiodobenzene in 71% yield. Protiodesilylation of 101 with Bu4NF followed by oxidative dimerization with Cu(OAc)2 in pyridine furnished 92 (R = H) as the sole product in modest yield (ca. 30-35%). The in situ protiodesilylation/alkynylation protocol has proved to be versatile and has led to the preparation of a large family of derivatized [ 18]annulenes [69] as well as other dehydrobenzoannulene topologies [45,67,70]. The Haley method has made possible the preparation and characterization of considerably larger graphdiyne substructures, such as macrocycles 102-105

28

MICHAEL M. HALEY and W. BRAD WAN

~'B

~~,, r

73%

c SiiPr3

100

"~~,~3~Pl"d,e -

=

71%

92 (R = H)

31% I01

Reagents: (a) Me3SiC_CC~CH, PdCI2(PPh3)2, Cul, Et3N; (b) I"Pr3SiC=CH, PdCI2(PPh3)2, Cul, Et3N; (c) o-diiodobenzene, PdCI2(PPh3)2, Cul, KOH, Et3N, THF; (d) Bu4N+F-, THF, EtOH; (e) Cu(OAc)2, CuCI, pyridine.

Scheme 20.

[68,71 ]. Based on the poor solubility of 92 (R = H), the incorporation of solubilizing alkyl chains was deemed necessary. Thus preparation of the fundamental precursors needed for construction of 102-105 is shown in Scheme 21. Treatment of 4-decylaniline with 1 equiv of(BnNEt3)+IC12 followed by diazotization and trapping with diethylamine gave triazene 106 in 92% yield. Palladium-catalyzed alkynylation with triisopropylsilylacetylene, conversion of the triazene moiety into an iodine, and a second alkynylation produced triyne 107 (X = H) in 84% yield. The structurally similar tetrayne 108 was constructed in ca. 60% overall yield following the same pathway, with the exception of using 2 equiv of the appropriate reagents in steps a and c.

D

c

~

D

c

102

m

c

c

10,3

m

104

I05

Planar Carbon Networks

29 iiiM9

~2

a,b

bl3Et2e,d

~SiiPr3

X~I

X

e

X

SiiPr3

D~e 106 (X---I-I)

107 (x = H) 108 (X = C--CSiiPr3',

Scheme 21. Reagents: (a) BnEt3N+ICI~,CaCO3, CH2CI2, MeOH, (b) i] NaNO2, HCI, MeCN, H20, ii] Et2NH, K2CO3, H20; (c) i-Pr3SiC~CH, PdCI2(PPh3)2, Cul, Et3N; (d) Mel, 120~ (e) Me3SiC~CC-------CH,PdCI2(PPh3)2, Cul, Et3N.

Bis-macrocycles 102 and 103 were prepared fTom 1,2,4,5- and 1,2,3,4-tetraiodobenzene, respectively, via the in situ protiodesilylation/alkynylation sequence using excess triyne 107 (Scheme 22) [68,71]. Deprotection of the tetracoupled products with fluoride ion followed by double intramolecular oxidative coupling with Cu(OAc)2 produced graphdiyne models 102 and 103 in 41% and 17% overall yield, respectively. The lower isolated yield of 103 is attributed to the presence of two possible cyclization pathways: (1) double cyclization of the outermost appendages affording the desired macrocycle, and (2) single cyclization of the inner appendages and subsequent oligomerization/polymerization of free alkynes in the intermediate species. Analogous to the observations of Vollhardt with the corresponding tetrabromide, 1,2,3,4-tetraiodobenzene undergoes selective, stepwise alkynylation. Two equivalents of triyne 107 were attached at positions 1 and 4, producing the desired para-subsfituted diiodohexayne 109 (Scheme 23) [71]. Addition of tetrayne 108 at the remaining iodines furnished the (x,c0-polyyne 110. Removal of the triisopropylsilyl groups and oxidative intramolecular coupling gave tris-macrocycle 104 as an amorphous yellow solid in 23% overall yield. The improved cyclization yield of 104 versus that for 103 (65 vs. 30%) is likely due to avoiding the polymerization

102

4 .s, c, d .

41%

" ~.

~

siiPr3 .

b- d

17%

~

103

107 Scheme 22. Reagents:(a) 1,2,4,5-tetraiodobenzene, PdCI2(PPh3)2,Cul, KOH, Et3N, THF, 60 ~ (b) 1,2,3,4-tetraiodobenzene, PdCI2(PPh3)2,Cul, KOH, Et3N, THF, 60 ~ (c) Bu4N+F-, THF, EtOH; (d) Cu(OAc)2, CuCI, pyridine.

30

MICHAEL M. HALEY and W. BRAD WAN

II II 66%

b - 9-

c,d

52'

65%

~

104

II II 1r 109

110

Scheme 23. Reagents: (a) 107, PdCI2(PPh3)2,Cul, KOH, Et3N, THF, 25 ~ (b) 108, PdCI2(PPh3)2, Cul, KOH, Et3N, THF, 60 ~ (c) Bu4N+F-, THF, EtOH; (d) Cu(OAc)2,

CuCI, pyridine.

scenario described above for 103; intramolecular coupling of the appendages of desilylated 110 can lead to formation of only a single product. Construction of the "diamond" substructure 105, although in appearance a symmetrically "simpler" structure, was more difficult. Cross-coupling of triazene

60~ i~c

Hi (x = I)

35% ~

SiiPr3

~12 C

d,c

11%

105

113 Scheme 24. Reagents: (a) 100, PdCI2(PPh3)2,Cul, KOH, Et3N, THF, 25

~ (b) Mel, 120 ~ (c) 108, PdCI2(PPh3)2,Cul, KOH, Et3N, THF, 60 ~ (d) Bu4N+F-, THF, EtOH; (e) Cu(OAc)2, CuCI, pyridine.

Planar Carbon Networks

31

114

111 with 2 equiv of tfiyne 100 (see Scheme 20) and subsequent treatment with iodomethane at 120 ~ afforded iodohexayne 112 in 60% yield (Scheme 24). Installation of tetrayne 108 at the iodine site of 112 via the in situ protiodesilylation/alkynylation protocol produced polyyne 113 in 35% yield. Desilylation with Bu4N§ - followed by Cu-mediated intramolecular oxidative cyclization gave 105 as a pale yellow solid in 11% yield. The low yield of 105 is likely due to difficulties in manipulating the product; apparently, the two decyl chains do not impart enough solubilizing influence of the large, rigid planar core. Macromolecules 102-105 represent the most complete graphdiyne fragments synthesized to date. Although detailed studies of their physical properties are not yet complete, the bright yellow molecules are highly fluorescent and have cut-offs in their electronic absorption spectra around 450 nm. As with all other dehydrobenzo[ 18]annulene derivatives [69], 102-105 exhibit small but distinct downfield shifts (ca. 0.2-0.3 ppm) of the aromatic protons upon cyclization, indicating the presence of a weak diatropic ring current in the 18-membered ring [70,72]. Comparison of the two proton resonance on the central tetrasubstituted benzene ring of 103 with 104 reveals a slight downfield shift of the protons (At = 0.06 ppm). Whether this is due to the presence of"superdelocalization" in tris-macrocycle 104 is debatable. Graphdiyne fragment 114 is an extremely advanced substructure whose construction is now feasible employing the techniques and methodologies discussed above and its assembly in the future should help answer this and other questions.

6. POLY(TETRAETHYNYLCYCLOB UTADI EN E) Another allotrope possessing 1"1 sp:sp 2 carbon atoms is network 115, based on tetraethynylcyclobutadiene (116). The corresponding 2:1 sp:sp 2 network 117 would be the cyclobutadiene analogue of graphdiyne (88) (see p. 24). The inherent instability of cyclobutadiene likely precludes formation of the all-carbon network, so coordination of a 14-electron organometallic fragment, e.g. CoCp, Fe(CO) 3,

32

MICHAEL M. HALEY and W. BRAD WAN

'-

II

II

II

i 115

....

116

,I 117

should be necessary. Unfortunately, the metal now introduces stereochemical problems (vide infra); thus, metallated networks 115 and 117 are depicted as all-syn for clarity. The Bunz group has been the leading advocate of 7r-complexed, ethynylated species and has prepared an impressive array of linear, angular, and cyclic structures. Compounds 118-121 are representative examples of their efforts. The construction of these molecules as well as discussion of their properties has been reviewed recently [73] and consequently, only a few salient examples are presented herein. Pd-catalyzed cross-coupling of known tetraiodide 122 with ethynylstannanes has permitted the construction of tetraethynyl models such as 123 bearing a variety of substituents and these are generally isolated in greater than 80% yield [74]. The most interesting of these molecules is complex 124 [75], which possesses five Fe(CO) 3 fragments and thus is an "evolved" subunit of network 115. Macrocyclic structures are also attainable from such n complexes (Scheme 25). For example, Cu-mediated oxidative cyclization of diyne 125 produced the ex-

(OC)3F~Fe(CO)3 118

119

M

e

3

S

~

SiMe3 120 n"0-8

121

~ SiMe3 SiMe3

Planar Carbon Networks

33

~ Fe(CO)3

R

l~ 9

~

)3

122

123

"~Fr

124

(R = tBu, SiMc3, Ph, CmCtBu)

C

S i M e ' ~ Cu(OAr

Me3Si

iMe3

PC~siMe3

;iMr 3 M e ~I1" ~~iMe_3 ~pC~ ]~'-SiMe3 i

CoCp

Me,Si~Si~169

MealS"

~gpC~

~--SiMe3 iMe3

125

126

127

Scheme 25.

pected cyclooligomeric mixture, this time as a combination of trimer 126 (25%), tetramer 127 (41%), and the pentamer (13%) [76]. This mixture was further complicated by formation of diastereomers of each product. Nevertheless, careful separation by size exclusion chromatography (SEC) and HPLC permitted identification of the two and four diastereomers of 126 and 127, respectively.

7. POLY(TETRAETHYNYLETH EN E) One of the simplest structural motifs that can be incorporated into a nonnatural planar phase is tetraethynylethene (TEE). Unlike previous alkynic systems, the lower symmetry of the molecule translates into the formation of multiple topologies upon controlled oxidative polymerization. Networks 128 and 129 are two possible arrangements. Tetraethynylethene was first prepared by Diederich et al. in 1991 (Scheme 26) [77]. Dibromomethylidenation of known ketone 130 followed by Pd(0)-catalyzed alkynylation of 131 provided the fully-protected and stable TEE derivatives 132. Similar to hexaethynylbenzene, TEE is highly reactive. Protiodesilylation of 132 (R = SiMe3) with K2CO3 in MeOH cleanly afforded the parent hydrocarbon, which precipitated as a white solid from pentane at -25 ~ but rapidly decomposed upon

34

MICHAEL M. HALEY and W. BRAD WAN ,d.

i

II II

128

129

warming to 20 ~ In fact, the pure solid was found to be explosive. Attempts to generate networks from this smallest repeatable subunit have been unsuccessful. The general strategy for TEE synthesis has been exceedingly productive. The Diederich group has prepared an ever-burgeoning family of substituted TEEs with various combinations and arrangements of protecting and/or pendant groups [78]. Numerous accounts of their work have appeared; therefore, only those systems that can be viewed as network mimics will be discussed herein. Although TEE itself is unstable, mono- and dideprotected TEE derivatives are moderately stable compounds that can undergo further synthetic elaboration. For example, the (Z) dideprotected TEE 133 can be cyclized readily to give macrocycles 134 and 135 (Scheme 27) [79]. Ideally, macrocycle 135 might be polymerized into network 129. The challenge was the preparation of a TEE derivative with the proper substituents, viz. 133, the synthesis of which was considerably more involved. Diol 136, prepared from mucochloric acid by exhaustive reduction, was protected as the cyclic orthoester, which was then subjected to Pd-catalyzed alkynylation to give 137. Cleavage of the orthoester group upon treatment with DIBAL-H followed by sequential introduction of the two dibromoalkene moieties provided the tetrabromo derivative 138 as an acid- and light-sensitive material. Dehydrobromination with LDA followed by quenching with saturated NH4C1 solution gave TEE 133 in ca. R

Me3S

SiMe3 130

65%

Me3Si" 131

61-88%

"'SiMe3

R

Me3S

SiMe3 132

(R = SiMe3,SiiPr3, Ph) Scheme

25 ~

26. Reagents: (a) CBr4, PPh3; (b) Pd(PPh3)4,CuI, RC_CH, BuNH2, benzene,

Planar Carbon Networks

CroH

a,b 56%

35

iPr3Si~,f,.O _ ~ M r aPr3S

e

iPr3Si~H

94%

iPr3Si~--

d 77%

OCH2OMe

137

r d _ tPr3S~~ 33%-

f

fl~r3Si~ Br~Br

iPraSI,~~H al'r3Sir 133

138

d ~ r 3 S ~ zl~r3Si""

- -

Siipr3 + "Si~Pr3

tPr3S~t-~l_~SiiPr3 iPr3Si"

134

"'H

SiiPr3 135

Scheme 27. Reagents: (a) (Me30)3CH, CSA, CH2CI2; (b) i-Pr3SiC--CH, PdCI2(PPh3)2, Cul, BuNH2, benzene; (c) DIBAL-H, CH2CI2; (d) i] PDC, CH2CI2, ii] CBr4, PPh3, Zn; (e) B-bromocatecholborane, CH2CI2; (f)i] LDA, THF, ii] NH4CI.

10% overall yield. Solutions of 133 in hexane or benzene appear to be reasonably stable, but decomposition occurs rapidly upon concentration. (Z)-Diprote~ted TEE 133 was subjected to oxidative Hay coupling to give a mixture of dimer 134 and trimer 135. The yields and ratio of which varied depending on the dilution factor of the reaction. Whereas 134 proved to be somewhat unstable in concentrated solutions due to the strained 12-membered ring, the 18-membered 135 was completely stable both in solution and in the solid state. Similar to the parent TEE and most other perethynylated systems, 134 and 135 are very unstable upon desilylation, even when stored in the dark at -20 ~ Attempts to obtain charactedzable two-dimensional all-carbon network structures by oxidafive polymerization have failed thus far [78]. The largest macrocyclic fragment of network 129 is the expanded hexaradialene 139. This molecule, together with the tetrameric structure 140, can be prepared from TEE derivative 141 via sequential, kinetically controlled protiodesilylation (Scheme 28) [80]. These radialenes are highly stable and highly soluble due to the presence of the bulky i-Pr3Si groups. Compound 139 possesses a macrocyclic ring of ca. 22 A in diameter and this is rivaled in size only by graphdiyne models 91 and 102-105. The extremely large size and high stability of these systems bode well for the preparation of even larger acetylenic structures.

36

MICHAEL M. HALEY and W. BRAD WAN

.•

Et3S

a,b

SiMe3

24%

i P r 3 S t ~ ~ Siipr3

r

Et3Si~

68%

"~SiMe3 141

iPr3St~~SiiPr3 iPr3Si~iiPr3

c, d

I I ~ r 3 S i ~ iPr3Si"

yL

iPr3Si,'=

SiiPr .SiiPr3Jn

"~SiiPr3

139 (n-- 1, 10%) 140 (n - 3, 13%) Scheme 28. Reagents:(a) CBr4, PPh3; (b) PdCI2(PPh3)2, Cul, hPr3SiC=CH, hPr2NEt,

benzene; (c) 1 M NaOH, MeOH, THF; (d) Cu(OAc)2, pyridine, benzene; (e) K2CO3, MeOH, THF.

8. MISCELLANEOUS ETHYNYL-LINKED NETWORKS A variety of other planar sp2-hybridized molecules can be utilized as the core from which nonnatural carbon allotropes can be ~tilt. For instance, expansion of the tetraethynylethene motif of 128 by two carbon atoms should lead to the corresponding butatriene network 143. This allotrope, in theory, could be prepared from a tetraethynylbutatriene scaffold (142, Scheme 29) [81]. Alternatively, use of [3]radialene as the core unit would lead

R 130

R

e,b 142 (R- SiMr 55%) (R- Si/Pr3,42%)

143 Scheme 29. Reagents:(a) BuLi, Et20; (b) Cul, DBU,-110 to 20 ~

Planar Carbon Networks

Mc3S~

3/

a, b 93%

M9 i ~

SiMr

c "r 5*/.

Dt

Mr162 Mr

r162 Mr

....... ~.

$iMr

144

145

Scheme 30. Reagents: (a) MeMgBr, THF; (b) Me3SiC~CCH2Br, Cul, 50 ~ 3 h; (c) t-BuLl, THF, -78 ~ (d) tetrachlorocyclopropene,-78 ~ (e) DDQ,-78 to 20 ~ to topologically interesting network 145, derived from the hexaethynyl system 144 (Scheme 30) [82]. Although syntheses of both "monomers" have been achieved, the recurring problem of instability encountered upon protiodesilylation of perethynylated systems has prevented further studies.

9. CONCLUSION Tremendous strides have been made over the last 10 years on the construction of monomeric model systems and more advanced macrocyclic segments of natural and nonnaaual carbon aUotropes. A vast majority of these successes can be attributed to the discovery of high-quality synthetic proceAures. Intrinsic to the work discussed in this review has been the extensive development and utilization of Pd-catalyzed crosscoupling reactions for the formation of carbon--carbon single bonds between sp and sp 2 centers. Despite these advances, chemists have a long way to go due to recurring and vexing problems. Issues concerning the stability of perethynylated monomers, the ability to develop ordered polymerization reactions, and the characterization of the resultant, often insoluble products must be addressed and overcome (or at least minimized) if the field is to continue to grow. Nevertheless, if the rapid expansion of this area over the last decade is any indication, the 21st century holds tremendous promise for the discovery and/or synthesis of new phases of carbon.

ACKNOWLEDGMENTS We wish to thank our talented graduate and undergraduate co-workers whose names appear in the literature for their many contributions to the results detailed in this review. Financial

38

MICHAEL M. HALEY and W. BRAD WAN

support of our research efforts in this area has been graciously provided by the National Science Foundation, the Petroleum Research Fund (administered by the American Chemical Society), The Camille and Henry Dreyfus Foundation (Camille Dreyfus Teacher-Scholar Award to M.M.H. 1998-2003), and the U.S. Department of Education (GAANN fellowship to W.B.W.).

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Planar Carbon Networks

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[16] Jaworek, W. and V6gtle, E, Chem. Ber., 124 (1991) 347; Koch, K.-H. and MOllen, K., Chem. Ber., 124 (1991) 2091; Copeland, P. G., Dean, R. E., and McNeil, D., J. Chem. Soc., (1960) 1689. [171 Bushby, R. J. and Hardy, C., J. Chem. Soc., Perkin Trans. 1, (1986) 721; Sato, T., Goto, Y., and Hata, K., Bull. Chem. Soc. Jpn., 40 (1967) 1994; Sato, T., Shimada, S., and Hata, K., ibid., 44 (1971) 2484: Liu, L. B., Yang, B. W., Katz, T. J., and Poindexter, M. K., J. Org. Chem., 56 (1991) 3769. [18] Allen, C. E H. and Pingert, E P., J. Am. Chem. Soc., 64 (1942) 1365. [19] Kovacic, P. and Jones, M. B., Chem. Rev., 87 (1987) 357, and references cited therein. [20] MUller, M., Mauerman-Dull, H., Wagner, M., Enkelmann, V., and MOllen, K., Angew. Chem., Int. Ed. Engi.,34 (1995) 1583. [21] Sidduri,A., Rozema, M. J.,and Knochel, P.,J.Org. Chem., 58 (1993) 2694. [22] MUller, M., Petersen,J.,Strohmaier,R., Gunther, C., Karl, N., and MUllen, K., Angew. Chem., Int. Ed. Engl., 35 (1996) 886. [23] Hendel, W., Khan, Z. H., and Schmidt, W., Tetrahedron, 42 (1986) 1127. [24] Vollhardt, K. P. C., Angew. Chem., Int. Ed. Engl., 23 (1984) 539. [25] Berresheim, A. J., MOiler, M., and MUllen, K., Chem. Rev., 99 (1999), 1747. [26] Ogliaruso, M. A., Romanelli, M. G., and Becker, E. I., Chem. Rev., 65 (1965) 261; MttellerWesterhoff, U. T. and Zhou M., J. Org. Chem., 59 (1994) 4988; Kimura, Y., Tomita, Y., Nakanishi, S., and Otsuji, Y., Chem. Lett., (1979) 321; des Abbayes, H., Clement, J., Laurent, P., Tanguy, G., and Thilmont, N., Organometallics, 7 (1988) 2293. [27] lyer, V. S., Wehmeier, M., Brand, J. D., Keegstra, M. A., and MOllen, K., Angew. Chem., Int. Ed. Engl., 36 (1997) 1604. [28] Morgenroth, E, Reuther, E., and Mttllen, K., Angew. Chem., Int. Ed. Engl., 36 (1997) 631. [29] MUller, M., lyer, V. S., Kubel, C., Enkelmann, V., and M011en, K., Angew. Chem., Int. Ed. Engl., 36 (1997) 1607. [30] Diederich, E and Rubin, Y., Angew. Chem., Int. Ed. Engl., 31 (1992) 1101. [31] Inter alia: Hoffmann, R. W., Dehydrobenzene and Cycloalkynes, Academic: New York, 1967; Berry, R. S., Spoles, G. N., and Stiles, R. M., J. Am. Chem. Soc., 82 (1960) 5240; Logullo, E M., Seitz, A. H., and Friedman, L. In Baumgarten, H. E. (Ed.), Organic Syntheses, Coll. Vol. V, Wiley: New York, 1973, p. 54; Heaney, H., Mann, E G., and Millar, I. T., J. Chem. Soc., (1956) 4692. [32] Rajca, A., Safronov, A., Rajca, S., Ross, C. R., and Stezowski, J. J., J. Am. Chem. Soc., 118 (1996) 7272. [33] Vollhardt, K. P. C. and Molder, D. L. In Halton, B. (Ed.), Advances in Strain in Organic Chemistry, Vol. 5, JAl Press: Greenwich, 1996, p. 121. [34] Eickmeier, C., Holmes, D., Junga, H., Matzger, A. J., Scherhag, E, Shim, M., and Vollhardt, K. P. C., Angew. Chem., Int. Ed. Engl., 38 (1999) 800. [35] Eickmeier, C., Junga, H., Matzger, A. J., Scherhag, E, Shim, M., and Vollhardt, K. P. C., Angew. Chem., Int. Ed. Engl., 36 (1997) 2103. [36] Baughman, R. H., Eckhardt, H., and Kert~sz, M. J., J. Chem. Phys., 87 (1987) 6687. [37] Beckhaus, H.-D., Rackhardt, C., Kao, M., Diederich, E, and Foote, C. S., Angew. Chem., Int. Ed. Engl., 31 (1992) 63; Beckhaus, H.-D., Verevkin, S., R0ckhardt, C., Diederich, E, Thilgen, C., ter Meer, H.-U., Mohn, H., and M0ller, W., ibid., 33 (1994) 996. [38] Tobe, Y., Matsumoto, H., Naemura, K., Achiba, Y., and Wakabayashi, T., Angew. Chem., Int. Ed. Engl., 35 (1996) 1800. [391 Diederich, E and Gobbi, L., Top. Curr. Chem., 201 (1999) 43. [40] Tobe, Y. In Halton, B. (Ed.), Advances in Strained and Interesting Organic Molecules, Vol. 7, JAI Press: Greenwich, 1999, p. 153. [411 Diercks, R., Armstrong, J., Boese, R., and Vollhardt, K. P. C., Angew. Chem., Int. Ed. Engl., 25 (1986) 268. [42] Praefcke, K., Kohne, B., and Singer, D., Angew. Chem., Int. Ed. Engl., 29 (1990) 177; Kondo, K., Yasuda, S., Sakaguchi, T., and Miya, M., J. Chem. Soc., Chem. Commun., (1995) 55.

40

MICHAEL M. HALEY and W. BRAD WAN

[43] Anthony, J. E., Khan, S. I., and Rubin, Y., Tetrabedron Lett., 38 (1997) 3499. [44] Tovar, J. D., Jux, N., Jatrosson, T., Khan, S. I., and Rubin, Y., J. Org. Chem., 62 (1997) 3432; Tobe, Y., Kubota, K., and Naemura, K., ibid., 62 (1997) 3430. [45] Haley, M. M., Synlett, (1998) 557. [46] Haley, M. M., Pak, J. J., and Brand, S. C., Top. Curt. Chem., 201 (1999) 81. [47] Barton, J. W. and Shephard, M. K., Tetrahedron Lett., 25 (1984) 4967; Diercks, R. and Vollhardt, K. E C., J. Am. Chem. Soe., 108 (1986) 3150; Huynh, C. and Linstrumelle, G., Tetrahedron, 44 (1988) 6337; Iyoda, M., Vorasingha, A., Kuwatani, Y., and Yoshida, M., Tetrahedron Lett., 39 (1998) 4701. [48] Campbell, I. D., Eglinton, G., Henderson, W., and Raphael, R. A., J. Chem. Sot., Chem. Commun., (1966) 87; Staab, H. A. and Graf, E, Tetrahedron Lett., (1966) 751; Staab, H. A. and Graf, E, Chem. Ber., 103 (1970) 1107; Imgartinger, H., Leiserowitz, L., and Schmidt, G. M. J., ibid., 103 (1970) 1119. [49] Solooki, D., Ferrara, J. D., Malaba, D., Bradshaw, J. D., Tessier, C. A., and Youngs, W. J., Inorg. Synth., 31 (1997) 122. [50] Kinder, J. D, Tessier, C. A., and Youngs, W. J., Synlett, (1993) 149. [51] Charkraborty, M., Tessier, C.A., and Youngs, W. J., J. Org. Chem., 64 (1999) 2947. [52] Djebli, A., Ferrara, J. D., Tessier-Youngs, C., and Youngs, W. J., J. Chem. Soc., Chem. Commun., (1988) 548. [53] Ferrara, J. D., Tessier-Youngs, C., and Youngs, W. J., J. Am. Chem. Sot., 107 (1985) 6719; Ferrara, J. D., Tanaka, A. A., Fierro, C., Tessier-Youngs, C., and Youngs, W. J., OrganometaUics, 8 (1989) 2089; Youngs, W. J., Kinder, J. D., Bradshaw, J. D., and Tessier, C. A., ibid., 12 (1993) 2406. [54] Ferrara, J. D., Tessier-Youngs, C., and Youngs, W. J., Organometallics, 6 (1987) 676; Ferrara, J. D., Tessier-Youngs, C., and Youngs, W. J., Inorg. Chem., 27 (1988) 2201. [55] Ferrara, J. D., Djebli, A., Tessier-Youngs, C., and Youngs, W. J., J. Am. Chem. Sot., 110 (1988) 647. [56] Youngs, W. J., Djebli, A., and Tessier, C. A., Organometallics, 10 (1991) 2089; Malaba, D., Djebli, A., Chert, L., Zarate, E. A., Tessier, C. A., and Youngs, W. J., ibid., 12 (1993) 1266. [57] Bradshaw, J. D., Solooki, D., Tessier, C. A., and Youngs, W. J., J. Am. Chem. Soc., 116 (1994) 3177. [58] Haley, M. M., Kehoe, J. M., and Kiley, J. H., submitted. [59] Moore, J. S., Weinstein, E. J., and Wu, Z. Y., Tetrahedron Lett., 32 (1991) 2465. [60] Kajigaeshi, S., Kakinami, T., Yamasaki, H., Fujisaki, S., and Okamoto, T., Bull. Chem. Soc. Jpn., 61 (1988) 118. [61] Narita, N., Nagai, S., Suzuki, S., and Nakao, K., Phys. Rev. B, 58 (1998) 11009. [62] Boese, R., Green, J. R., Mittendorf, J., Molder, D. L., and Vollhardt, K. E C., Angew. Chem., Int. Ed. Engl., 31 (1992) 1643. [63] Wan, W. B. and Haley, M. M., unpublished results. [64] Eglinton, G. and Galbraith, A. R., Proc. Chem. Sot., (1957) 350; Behr, O. M., Eglinton, G., and Raphael, R. A., Chem. & Ind., (1959)699; Eglinton, G. and Galbraith, A. R., J. Chem. Sot., (1960) 3614. [65] Zhou, Q., Carroll, E J., and Swager, T. M., J. Org. Chem., 59 (1994) 1294. [66] Tobe, Y., Kubota, K., and Naemura, K., J. Org. Chem., 62 (1997) 3430. [67] Haley, M. M., Bell, M. L., English, J. J., Johnson, C. A., and Weakley, T. J. R., J. Am. Chem. Sot., 119 (1997) 2956. [68] Haley, M. M., Pak, J. J., and Brand, S. C., Angew. Chem., Int. Ed. Engl., 36 (1997) 836. [69] Pak, J. J., Weakley, T. J. R., and Haley, M. M., J. Am. Chem. Soc., 121 (1999) 8182. [70] Wan, W. B., Kimball, D. B., and Hale),, M. M., Tetrabedron Lett, 39 (1998) 6795. [71] Wan, W. B., Brand, S. C., Pak, J. J., and Haley, M. M., submitted. [72] Matzger, A. J. and Vollhardt, K. E C., Tetrahedron Lett., 39 (1998) 6791. [73] Bunz, U. H. E, Top. Curt. Chem., 201 (1999) 131.

Planar Carbon Networks

41

[74] Bunz, U. H. E and Enkelmann, V., Angew. Chem., Int. Ed. Engl., 32 (1993) 1653. [75] Bunz, U. H. E and Enkelmann, V., Organometallics, 13 (1994) 3823. [76] Altmann, M., Friedrich, J., Beer, F., Reuter, R., Enkelmann, V., and Bunz, U. H. E, J. Am. Chem. Sot., 119 (1997) 1472. [77] Rubin, Y., Knobler, C. B., and Diederich, E, Angew. Chem., Int. Ed. Engl., 30 (1991) 698. [78] Tykwinski, R. R. and Diederich, E, Liebigs AnnJRecueil, (1997) 649, and references cited therein. [79] Anthony, J., Knobler, C. B., and Diederich, E, Angew. Chem., Int. Ed. Engl., 32 (1993) 406; Anthony, J.; Boldi, A. M.; Boudon, C., Gisselbrecht, J.-P., Gross, M., Seiler, P., Knobler, C. B., and Diederich, E, Helv. Chim. Acta, 78 (1995) 797. [80] Boldi, A. M. and Diederich, E, Angew. Chem., Int. Ed. Engl., 33 (1994) 468. [81] van Loon, J. D., Seiler, P., and Diederich, E, Angew. Chem., Int. Ed. Engl., 32 (1993) 1187. [82] Lange, T., Gramlich, V., Amrein, W., Diederich, E, Gross, M., Boudon, C., and Gisselbrecht, J.-P., Angew. Chem., Int. Ed. Engl., 34 (1995) 805.

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RECENT DEVELOPMENTS IN STRAINED CYCLIC ALLENES

Metin Balci and Yavuz Taskesenligil 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Five-Membered-Ring Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Six-Membered-Ring Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Six-Membered-Ring Heteroallenes . . . . . . . . . . . . . . . . . . . . . 3.2 Six-Membered-Ring Allene Complexes . . . . . . . . . . . . . . . . . . 4. Seven-Membered-Ring Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Eight-Membered-Ring Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Nine-Membered-Ring Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Bicyclic Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43 45 47 50 59 60 64 67 69 75 78

1. INTRODUCTION The equilibrium geometry for allene is linear with orthogonal pairs of substituents. An aUene incorporated into a carbocyclic ring of nine or more carbon atoms is relatively unstrained [ 1-5]. Cyclonona- 1,2-diene (5) is a distillable liquid [6], while

Advances in Strained and Interesting Organic Molecules Volume 8, pages 43--81. Copyright O 2000 by JAI Press Inc. All rights of reproduction In any form reserved. ISBN: 1.7623-0631-9 43

44

METIN BALCI and YAVUZ TASKESENLIGIL

0 1

() 0 2

3

4

5

cycloocta-1,2-diene (4) rapidly dimerizes at room temperature [7] and its IH NMR spectrum has been measured a t - 6 0 ~ [8]. However, if the ring size is decreased, the linear perpendicular allene will be twisted and bent until, at some point, the energy gained by rt bonding in the two double bonds will be insufficient to offset the increased strain. Furthermore, ring constraints will exert torsion toward a planar arrangement of ligands. Therefore, one of the fundamental questions is the influence of ring size on the barrier to n-bond rotation. Cyclohepta-1,2-diene (3) and its derivatives have been generated and chemically trapped [7]. Balci and Jones [9] provided evidence for the allenic structure by isolation of optically active cycloadducts. Considerable controversy has arisen over the structure of cyclohexa-l,2-diene (2). Structures proposed to date consist of chiral 2 zwitterionic 6 and 7, and triplet or singlet diradical 8, and 9. On the basis of extensive studies of its chemistry, Bottini et al. [ 10] preferred initial formation of a bent, twisted allene which rapidly isomerizes to the diradical 8 that is the active agent in both [2+2] and [2+4] cycloadditions [11 ]. Moore and Moser [ 12] and Greenberg and Liebman [5] proposed zwitterion 6 for cyclohexa1,2-diene, a contention that has found support in INDO calculations by Dillon and Underwood [13]. Balci and Jones [9] performed some experiments in which optically active cyclohexa-l,2-diene (2) was successfully trapped by diphenylisobenzofuran (DPIBF) and they suggested that at around 80 ~ conversion of the nonplanar form of 2 into a symmetrical isomer (presumably 6) competes with its reaction with the allene trap. Later, Wentrup [14] trapped pyrolytically generated cyclohexa-1,2-diene in an argon matrix at 11 K. Its infrared spectrum showed a characteristic absorption at 1886 cm -1, which is shifted only 70 cm -1 from that of a normal allene. More recently, Johnson et al. [ 15,16] have applied ab initio SCF, MCSCF and Mrller-Plesset calculations to cyclohexa-l,2-diene (2) and cyclopenta-l,2-diene (1). The former is calculated to prefer a chiral allenic structure, cf. 2, with a barrier to inversion of ca. 15 kcal/mol, whereas cyclopenta1,2-diene (1) is predicted to have an inversion barrier of 2-5 kcal/mol with a chiral equilibrium geometry. Furthermore, Johnson et al. [ 17] have predicted the follow-

,.

2

6

7

,.

8

9

(lo,l

Strained Cyclic Allenes

"%

9

H

..

"H

1

2

:H

3

"H

~ ' .

4

45

"H

5

ing order among the possible electronic configurations for bent planar allene: 7 > 6 > 9 > 8 (ground state); the zwitterions 6 and 7 are excited states. Tapia et al. [18] has shown by using ab initio molecular orbital calculations that the bending potential is soft for the first 20 ~resulting in only ca. 4 kcal/mol of estimated strain which then rises steeply from greater bending. In smaller cyclic allenes, ring constraints increase bending, torsion, and strain. Again, Johnson et al. [16] have predicted from MNDO calculations that the strain increases with decreasing ring size (30, 20, 15, and 10 kcal/mol for five- to eight-membered-ring allenes, respectively). Predicted bending angles and out-of-plane torsional angles from MNDO calculations [16] are given above. Yavari has estimated a 14 kcal/mol of total strain energy in 4 by force-field methods [19]. The present review covers the recent developments on cyclic strained aUenes through the last 10 years with a natural organization based on ring size. The synthesis and chemical reactions of strained allenes are presented throughout.

2. FIVE-MEMBERED-RING ALLENES Cyclopenta-1,2-diene (1) still remains as an elusive compound. Favorskii [20] first attempted to synthesize this strained compound by treatment of dibromide 10 with metallic sodium and isolated cyclopenta-l,3-diene (11). Base-promoted elimination reaction of the corresponding vinylbromide 12 resulted in the formation of 13 that was trapped by suitable reagents (Scheme 1). More recently, Ceylan et al. [21 ] have applied fluoride ion-promoted elimination of a [3-halogenosilane [22] to 15 and zinc-catalyzed elimination [23] to 14 to

0 1

10

1

12

Scheme 1.

11

13

46

METIN BALCI and YAVUZ TASKESENLIGIL

~ 8r

Br _

Zn, DMSO,85~

~

14

Br

Br

Br

(+)16 Br

Br

meso-I 7

~/KF

15 Scheme 2.

generate the highly strained cyclopenta-l,2-diene (1) (Scheme 2). Reaction of 15 with tetrabutylammonium fluoride (BuaNF) and KF under different conditions resulted in the formation of two isomeric Wurtz-like condensation products 16 and 17. On the other hand, treatment of 14 with activated zinc again gave the same isomeric mixture of 16 and 17 instead of cyclopenta- 1,2-diene (1). Another attempt to generate a substituted cyclopenta-l,2-diene was made by Tolbert and Johnson and their co-workers [24]. Photoexcitation of an allyl anion increases its charge density at C2. Substitution at this position by an efficient leaving group provides a route to an allene [25]. Unfortunately, irradiation of 19 did not provide any evidence for the formation of the expected 1-phenylcyclopenta- 1,2diene (20) (Scheme 3) and the starting material was recovered. It has been assumed that the anion does not undergo elimination because of the increased strain in 20.

18

19

20

Scheme 3.

Benzene 20

21

22

Scheme 4.

23

Strained Cyclic Allenes

47

The base-promoted elimination reaction of 21 with the even better leaving group, iodine, did not result in the formation of 20 (Scheme 4); the starting material was recovered. At elevated temperatures, reduction product 22 and 1,2-diphenylcyclopent-l-ene (23) were obtained in yields of 22 and 23%, respectively [26].

3. SIX-MEMBERED-RING ALLENES Enormous effort has been devoted toward the synthesis of cyclohexa- 1,2-diene (2). There are at least 10 different synthetic methods leading to 2 that have already been summarized in the excellent review of Johnson [ 1]. Shakespeare and Johnson [27] recently described a new and presumably general route to cyclic allenes as shown in Scheme 5. The fluoride-induced elimination of bromo-organosilane 24 yielded cyclohexa1,2-diene (2) which was trapped successfully by DPIBF to yield the two stereoisomeric cycloadducts 25 and 26 in a ratio identical with that previously reported [28,29]. Treatment of 24 with tetrabutylammonium fluoride in THF afforded the same trapping products 25 and 26 [22]. This methodology was applied successfully to generate cyclic butatrienes. Reaction of 27 with CsF in DMSO in the presence of DPIBF afforded the crystalline adduct 29 [27]. The formation of 29 indicates the generation of the highly strained intermediate 28 which is trapped at the most strained double bond (Scheme 6). A photochemical approach to strained cyclic allenes has been developed by Tolbert and Johnson and their co-workers [24] and it was applied successfully to 30a,b to generate the substituted six-membered-ring allenes 31a, and 31b (Scheme 7). These allenes were trapped successfully with furan and DPIBE Confirmation of the allene structure 31a was obtained by an independent generation from treatment of 33 with MeLi in the presence of DPIBE Allene 31 cycloadds regiospeBr

Ph DPIBF

24

2

25

+

Ph

C( 26

Scheme 5.

h

fl

48

METIN BALCI and YAVUZ TASKESENLIGIL S02CF3

Ph

$i(M9

=[0]

27

DPIBF 24o)e"Ph

28

29

Scheme 6.

cifically and displays high stereoselectivity. AM 1 calculations indicate it to have a chiral allenic structure with a C1-C2-C3 angle of 134 ~ [24]. The first example of a molecule containing a cyclohexa- 1,2,4-triene was reported by Miller and S ~ [ 3 0 ] . The "isoaromatic compound" 36 was synthesized by dehydrobromination of 35 with potassium tert-butoxide in the presence of DPIBF and the cycloadducts 37 and 38 were obtained in a 3:2 ratio (Scheme 8). Reaction of 35 with KOBu-t in the absence of DPIBF resulted in the formation of enol ether 39 with no evidence for the formation of the conjugated isomer. Most recently, Christi et al. [31] have succeeded in generating cyclohexa-l,2,4triene (41) and its benzo derivative 44 (Scheme 9). For the synthesis of the suitable starting materials 40 [32,33] and 43 [34] they added bromofluorocarbene to cyclopentadiene and indene, respectively. Reaction of 40 and 43 with methyllithium causes Br-Li exchange and this is followed by the loss of LiE Ring expansion leads to the conjugated cyclic allenes 41 and 44 which were successfully trapped with styrene, butadiene, cyclopentadiene, and furan. The reactivities of the different n bonds in 41 and 44 are different. El Ph

R

hv ,

P

-'"

Furan u,,..._

,,....

PC h

>450 nm

30a, R=H 30h, R=Ph

3 la, R=H 311~ R=Ph

Ph

Ph MeLi Br 33

32a, R=H 321~ R=Ph

0~

31a Scheme 7.

H

Strained Cyclic Allenes

49 h

Ti-IF

20%

H3C" "CH3

35

H3C

~

"CH3

36

+

37

-t Ph

Ph

H3

38

39

H:

Scheme 8.

Cyclohexa-1,2,4-triene (41) reacts exclusively at the conjugated allene ~ bond in the [2+4] cycloaddition and this has been explained by the more favorable frontier orbital energies in comparison to those of the nonconjugated allene rt bond. However, the selectivity of 44 needs to be confirmed by further investigations. Janoschek [35] has employed the semiempirical AM1 method to answer some structural questions concerning 41 and 2. A chiral structure with C l symmetry was proposed for the local energy minimum. The dihedral angles H - C 1 - C 2 - C 3 and C 1 - C 2 - C 3 - H were found with an average value of-161 ~ (-180 ~ corresponds to a planar allene structure). The C1-C2-C3 angle of 132.4 ~ indicates considerable Pl Ph MeLi

-25~

40

IOl

,-,

/

65%

41

(

42 P

Ph

43

44 Scheme 9.

H

45

50

METIN BALCI and YAVUZ TASKESENLIGIL

41

2

ring strain. Optical activity for the calculated structure of 41 can be expected only if the activation barrier to racemization is high enough; Janoschek has calculated a value of 2 kcal/mol for this barrier. This value is too small and rules out the observation of optical activity. Application of the same calculation method to 2 gave a higher activation energy of 8.7 kcal/mol for racemization which is in good agreement with the results of earlier semiempirical and ab initio calculations (5.7 and 12.1 kcal/mol, respectively) [ 16]. Strained cyclic cumulenes are interesting not only in view of their structural properties. They gain importance also as intermediates in the [2+4] cycloadditions. The intramolecular [2+4] cycloaddition of conjugated enynes provides an efficient and general route to aromatic and dihydroaromatic compounds. Recently, Danheiser et al. [36] and Johnson et al. [37] have shown computational and experimental evidence for the formation of cyclic allenes in the Diels-Alder reactions of Scheme 10. On thermolysis in toluene at 180 ~ the enediyne 49 that contains electron-withdrawing substituents produced product 51 via a concerted cycloaddition reaction that passes through a strained allene or a diradical 52 [36]. Especially the observation that thermolysis of 49 in carbon tetrachloride produced a chlorine-incorporated by-product, supports a concerted pathway involving the intermediacy of the diradical 52 that is possibly derived from cyclic allene 50. Of particular significance was the observation that these reactions can be conducted at or below 0 ~ in the presence of protic and Lewis acid. Johnson et al. [37] have studied gas-phase reactions of 46, 53, and 58 at 600 ~ The product distributions indicated the formation of the highly strained cummulenes 47, 54, and 59, respectively, as the possible intermediates. Furthermore ab initio calculations support the existence of [2+4] cycloaddition reactions in which an enyne or diyne acts as the diene unit. Moreover, it was estimated (from model semiempirical calculations) that intramolecular reaction would diminish AG in each case by 4--5 kcal/mol because of the lowered activation entropy.

3.1 Six-Membered-Ring Heteroallenes Six-membered carbocyclic allenes have been studied extensively. However, very little is known about heteroatom derivatives of cyclohexa-1,2-diene. Oxa-derivatives of 2 are the best known among strained six-membered-ring heteroallenes. Christi et al. have applied Doering-Moore-Skattebr reactions for generating of the oxaallene 65 [38]. As potential precursors for 65 they started from 6,6-dichloro(63) and 6,6-dibromo-3-oxabieyclo[3.1.0]hexanes (64) (Scheme 11). Contrary to earlier reports [39,40], they generated oxaallene 65 and trapped it with various dienes to give [2+4] cycloaddition products, e.g. 66 and 67. Furthermore, they

Strained Cyclic Allenes

>

51

__6oo (90%) 46

47

48

,,o~

~" ~~. ~ To,,~ L ~..~. 49

~o tl

[ ._.

//

--

5,,,,.52%,

1

oooc '3

53

"--

54

55(58%)

56(16%)

57(17%

~

m

> 58

59

60 (65%)+ 61 (4%)

62(3%) Scheme 10.

suggested that oxaallene 65 should be more bent and more highly strained than cyclohexa- 1,2-diene (2) because of the smaller covalent radius of the oxygen atom. The conjugated oxaallene 69 was generated and intercepted by the same methodology as described above for 65, again by Christi and Braun [41 ]. The best results

52

METIN BALCI and YAVUZ TASKESENLIGIL

~

Ci

MeLi

--//~"

[0]

h

6'

21%

64

67 Scheme 11.

were obtained by the reaction of the bromofluoro compound 68 with methyllithium (Scheme 12). An interesting feature of these trapping experiments was the observation of different chemoselectivity. [2+4] Cycloaddition reactions with the allene take place exclusively at the double bond most remote from the oxygen atom, whereas [2+2] cycloaddition reactions prefer the enol ether double bond. In the case of the [2+4] cycloaddition reaction the electron-pure double bond, which is that more remote from the oxygen atom, will react preferentially with electron-rich dienes. For the formation of the [2+2] cycloaddition products a two-step mechanism involving diradical intermediates was suggested [42,43]. OxaaUene 69 was generated by Ruzziconi et al. [44] independently by reacting 5-bromo-3,4-dihydro-2H-pyran (72) with potassium tert-butoxide in the presence of 18-crown-6 in dimethylsulfoxide and it was trapped with various dienes and dienophiles; these workers also observed the same stereoselectivity. However, they proposed a certain asynchronous [2s+2s+2s] cycloaddition mechanism [45,46] for the [2+2] cycloaddition products on the basis of the observed retention of the dienophile

~

_/

G'r-r x

Br 70

31-37%

68

69

Furan ~

2,4-dimethylfuran R=H, CH3 71 Scheme 12.

R

Strained Cyclic Allenes

53

.._ Various [2+2] and [2+4] trapping products 72

69

configuration in the cycloadducts. The most convenient way to generate strained cyclic aUenes is the reaction of the corresponding vinyl halides with a strong classical base [2]. Strained cyclic allenes generated in this way can undergo different reactions; namely, dimerization, reaction with base, and interception with dienes and dienophiles. From extensive studies with various bases, Cauber6 et al. [47,48] have shown that halocyclohexenes generate mainly cyclohexynes by using non-nucleophilic complex bases. In contrast, nucleophilic complex bases strongly favor cyclohexa-1,2diene (2). Cauber6 et al. [49,50] have generated 69 by reacting 72 with cyclohexanone enolate as activating agent for sodium amide, and intercepted it with cyclohexanone enolate in [2+2] cycloaddition to give 73, 74, and 75 (Scheme 13). The formation of 75 can be explained by attack of enolate at C3, the central allene carbon atom. This methodology shows the synthetic potential of strained cyclic allenes in the synthesis of polycyclic oxygenated heterocycles. The chemistry of 69 shows that it reacts at positions 2, 3, and 4 with tert-butoxide [51 ] and at position 3 and 4 with enolates depending on the nature of the latter [49,50]. The observation that the terminal carbon atom will be attacked preferentially by a larger cycloalkanone ring is remarkable. The involvement of the terminal allene carbon, C4, indicates a polarization of 69 as shown below by 69a. In fact this situation corresponds to the meta-directing effect of electron-withdrawing groups in arynic chemistry. Recently Christi and Drinkuth [52] have synthesized the benzo analogue 76 of 69 by reacting 3-bromo-2H-chromene with potassium tert-butoxide. Allene 76 was

n,§ 9

THF~[O

DME 72

H

69 +

73

~

I

§ 74

Scheme 13.

54

METIN BALCl and YAVUZ TASKESENLIGIL

()

0'0 Co0"O'o t~

69

t~

69a

76

76a

intercepted by furan and styrene in cycloaddition reactions to give 77 and 78, whereas reaction with KOBu-t/HOBu-t provided 79 (Scheme 14). The exclusive formation of 79 in 79% yield shows that nucleophilic attack occurs at C2 of 76 with a high degree of efficiency and selectivity. This has been explained on the basis of a higher degree of polarization of 76 compared to 69. In all probability, resonance structure 76a has more contribution to the ground state of 76. The first isodihydropyridine 80, an aza derivative of 2, has been recently generated from 6,6-dibromo-3-phenyl-3-azabicyclo[3.1.0]hexane with methyllithium (Scheme 15) [53]. In the presence of buta-l,3-diene, furan, or cyclopenta-l,3-diene, 80 was trapped successfully to give the [2+2] and [2+4] cycloaddition products 81 and 82. An interesting and attractive way for the generation of a small-ring cummulene is from the reaction of atomic carbon with a smaU-ring heterocycle. Recently, Shevlin et al. have postulated aza- and thiacyclohexatrienes 83 and 84 as intermediates in the reaction of atomic carbon with pyrroles [54,55] and thiophene [56], respectively. Reaction of arc-generated carbon with thiophene 85 at 77 K provided two new products, 90 and 91, in a ratio of 2.5:1 (Scheme 16). Thiophenes 90 and 91 likely result from the reaction of parent 85 with the carbenes 88 and 89. These carbenes can arise by a simple C - H insertion by a carbon atom on 85. However, the reaction of lac atoms with 85 using the same conditions revealed that 91 is labeled in the 2'- and 6-positions in a 5:1 ratio while 90 is labeled exclusively in the 6-position. These labeling experiments clearly demonstrate that carbenes 88 and 89 have been

T,~OtB u 79% 79

59% 77

76 Ph

41%

----/

tt 78

Scheme 14.

Ph

55

Strained Cyclic Allenes

MeLi .20oc~ Pit-"

PIr--'N

~

81

82

X - 0 or CH2

Scheme 15.

0

o/ C)

I R

I R

83 R-H

83a R-H

R-CH3

84

R=CI-13

84a

--H

H

O

c ~,

85

88

86

1 @ 91

IO

0C._-CH89 ~~"90b 6

"S" Scheme 16.

56

METIN BALCI and YAVUZ TASKESENLIGIL

92

93

produced by the "cummulene-to-carbene" rearrangement of the initially formed allene 87. Similar interconversion of cycloheptatetraene 92 and phenylcarbene (93) along the C7H6 energy surface has been well studied experimentally [57] and theoretically [58-60]. These results, which demonstrate that atomic carbon reacts with thiophene and generates intermediate 87, is in marked contrast to the reaction of atomic carbon with pyrrole [54,55]. The reaction of atomic carbon with N-methylpyrrole (94b) at 77 K generates the N-methyl-3-dehydropyridinium ylide 83a (R = Me) which can be trapped with added hydrogen halides or carbon dioxide. The addition of carbon dioxide is strong evidence for the ylide 83a rather than the cumulene form 83. The reasons for the differing reactivity of atomic carbon with pyrrole and thiophene are not completely clear. However, the regioselectivity of carbon reactions have been rationalized by attack of carbon at the point of highest electron density in the HOMO [61]. Synthetic potential of strained cyclic heteoallenes has been nicely demonstrated by Elliott et al. [62]. It has been shown that a leaving group at C3 in cefotaxime 96a is not essential for antimicrobial activity [63] as Burton et al. replaced the metabolically unstable acetoxy group of 96a by a cyclic ether as in 96b and shOwed that this compound retains cefotaxime-like activity [64]. Upon this finding, Elliott et al. [65,66] studied the reaction of cephalosporin triflates 97 with various dienophiles in the presence of base and obtained the 2,3-fused cyclobutanes 99 and cyclobutene analogues (Scheme 17). Reactions of

c Cryt, I

K

- - - - - - - .

R

94 a) R=H

95 a) R=H

b) R=CH3

b) R=CH3 ]OMe N~

U~ IQI 83a

R

R

R=H

83 a) K=H

R=CI-13

b) R=CH3

a) R I. CH2OAc

96

CO2Na

b)R-

Strained Cyclic Allenes

57 R

e~zNEt _

l

10•N• OTf CO2MB-p

MB-p

R

97 p-MB = p-methoxybenzyl R = PhCH2CONH

p-MBO2C ~ 100

Scheme 17.

98 with dienes (furan, pyrrole) resulted in the formation of the [2+4] cycloaddition products, e.g. 100. These reactions have been rationalized by invoking the intermediacy of the strained cyclic heteroallene 98. Cycloallene 98 undergoes an orbital symmetry allowed concerted [2+2] cycloaddition reaction as reported in the case of 69. The fact that olefins with electron-donating or electron-withdrawing substituents give rise to products with the same regiochemistry indicates that di-ionic intermediates are not involved. The [2+4] cycloadditions take place at the less electron-rich 3,4-double bond to give 100. However, when cephalosporin r triflate 101 was treated with i-Pr2NEt in the presence of furan, 103 was isolated in 62% yield as the sole product contrary to the reaction of 97. The oxidation state of sulfur determines the regiochemistry of the addition. In the case of sulfide 97 this is the 3,4-double bond, whereas in the sulfoxide 101 the 2,3-double bond is more electron-deficient.

CO2MB-p 101

COzMB-p 102

pMB = p-methoxybenzyl R ,, PhCH2CONH e , c ,CH3 H3C,, ,,Si_ H3C~i~si

104

O32MB-p 103

58

METIN BALCl and YAVUZ TASKESENLIGIL

Me3Si~ SiMr Li\ ,Li a(siMeD3a Me--.Si,, ,,Si~-lvle R'CH2"c~'C'-R n-BuLi~ R~'C-C-C" R ~ 9 0 % / Si Me R ---Si(CH3)3 9

105

107

106

P h ~ P h n-BuLi Li\ ,,Li (CllVlc2Si)2SiPh2 I I H3C--Si,, .,,Si--CH3 Ph'CH2"c----C--Ph ph/C=C=C'ph 11% H,CJph/Si~ph'CH3 108

109

110

Scheme 18.

Independently, Cainelli et al. [67] and Torii et al. [68] have also postulated the intermediacy of cephalosporin allenes 98 to account for the observed products of their reactions [69]. The recent finding that the tetrasilacyclohexyne 104 is a stable liquid at room temperature [70] prompted Barton et al. [71] and Ando et al. [72] to synthesize strained cyclic allenes containing silicon atoms, namely 107 and 110, respectively (Scheme 18). When 1,3-bis(trimethylsilyl)prop- 1-yne (105) was converted into the dianion 106 and then quenched with 1,3-dichlorosilane cyclic allene 107 was formed. Allene 107 is a stable liquid in the absence of oxygen and is extraordinarily unreactive. It does not react even with DPIBF at 180 ~ Ando et al. [72] have applied a similar approach to the synthesis of 110 which is a stable crystalline compound whose structure has been determined. The bond angle on the sp carbon C1-C2-C3 was found to be highly strained (161 ~ from linear geometry, but the longer bond lengths of the skeletal Si-Si (2.35-2.38/~) in 110 and 111 release the strain caused by allenic moiety to a greater extent. Allene 111 was also prepared and it too is a stable solid whose structure was analyzed by X-ray crystallography. The allene unit is bent to 166.4 ~ and the dihedral angle, as defined by the Sil-C1-C2 and Si2-C3-C2 planes, is a remarkable 64.6 ~ This value is even less than the previous record of 72.4 ~ measured in octa-

Ph ph

121.5

I Ph

Ph

110

Ph

Ph

111

Strained Cyclic Allenes

59

H3C

CH3

C.H3

cazrcl~

PM~ .._ 53~ 8ff-

-60 to - 10~C

v

113

112

ZrCp2 I I PM~

114

Scheme 19. sila[4.4]betweenallene [73]. The terminal allenic carbon is considerably rehybridized with the internal Si-C--C angle of 104.8 ~ allowing the accommodation of the six-membered ring.

3.2 Six-Membered-RingAIleneComplexes Jones et al. [74] have recently reported 114 as the first metal complex of a six-membered-ring allene (Scheme 19). Reaction of CP2ZrCI 2 (Cp = cyclopentadiene) with 112 resulted in the formation of 113. Conversion of 113 into zirconocene complex 114 was completed at 53 ~ in 71% yield. Methyl-substituted cycloalkene was used to prevent formation of cyclohexyne as previously reported [75]. The crystal structure of 114 shows that the six-membered ring is bent by 54.9 ~ The angle (157.0 ~ that the plane containing atom Zr, C1, and C2 form with the plane connecting atoms C1, C2, and C3 deviates significantly from 180 ~ This success in the synthesis of 114 prompted Jones et al. to apply the same methodology to the preparation of a zirconocene complex of a cyclohexa-l,2,3triene. In order to block alkyne formation they introduced a phenyl ring at C1 of 28 and 115 was a successful synthon for 116 (Scheme 20) [76]. The zirconocene Ph

Ph

O 28

~,,'~ZrCpz

117

120.8~ ~ 115

IpMe3 116

--ZrCp2

118 Scheme 20.

60

METIN BALCI and YAVUZ TASKESENLIGIL

complex of 1-phenylcyclohexa- 1,3-diene 116 is a yellow and air-sensitive solid. Its X-ray crystallographic analysis indicates that the internal bond angles of the butatriene moiety, C1-C2-C3 and C1-C2-C6 are 124.4 ~ and 120.8 ~ respectively. These two bonds angles are identical to those reported for the benzyne complex 117 (122.1 ~ and 120.2~ which may be represented as a resonance hybrid that includes the cyclic butatriene canonical form 118 [75].

4. SEVEN-MEMBERED-RING ALLENES Ring opening of annelated cyclopropylidenes via the Doering-Moore-Skattebr method is often employed for the synthesis of cyclic allenes [77]. This method is the most efficient for generation of cyclohexa- 1,2-diene (2) [78] but, paradoxically, was not successful for the higher homologue 3. Moore et al. [79] isolated a mixture of tricyclic hydrocarbons 121 and 122 in 40% yield from the reaction of 7,7-dibromobicyclo[4.1.0]heptane (120) with methyllithium (Scheme 21). Krbrich and Goyert [80] suggested a carbenoid structure for the reaction intermediate and free carbene was assumed to be involved in the formation of 121 and 122 in ether [81]. However, the Doering-Moore-Skattebr method does succeed for the methoxy-derivative 123 [82] and [2+2] dimer 125 was isolated in 85% yield. High-temperature thermolysis of exo(endo)-7-bromo-7-(trimethylstannyl)-bicyclo[4.1.0]heptane (126) in benzene (162 ~ afforded the cyclohepta-l,2-diene dimer 127 [83]. The mechanism of this reaction was established by running the reaction in different solvents and the involvement of a free carbene was postulated as the precursor for allene formation. More recently, Bettinger and Schleyer et al. [84,85] elucidated the ring-opening reactions of carbenes 128-132 to the corresponding acyclic and cyclic allenes using density functional theory and ab initio quantum mechanical computations. For parent cyclopropylidene (128), the barrier to ring opening leading to allene was found to be -5 kcal/mol. In the case of the cis-cyclopropylidene 129 this value is lowered to 0.5 kcal/mol and this contrasts Br

MeLi

Br

0

119

G,Q 121

122

Br 120

Scheme 21.

3

Strained Cyclic Allenes Br,~

61

Br

pCH 3

OCH3 Meli

123 Me,jSn

78%

3

(

124

) 125

Br

126

3

127

CH3 H3C ~ 3

128

129

130

131

132

with its trans-isomer 130 (4 kcal/mol) which is very similar to that of 128 where the transition state occurs "later" along the reaction coordinate. Isomerization of 131 to cyclohexa-l,2-diene (2) proceeds almost spontaneously, as in the case of cis-dimethylcyclopropylidene (129) with a barrier of only 0.5 kcal/mol. However, the activation barrier of 132 for the isomerization to cyclohepta-1,2-diene (3) was found to be 14.6 kcal/mol. The half-chair conformation of the cyclohexane ring in 132 is not suitable for the ring-opening reaction and the needed change to the chair conformation during the reaction is responsible for the higher activation barrier. On the other hand, the activation barriers for intramolecular CH insertions to form 121 and 122 (Scheme 21) were found to be 9.1 and 6.4 kcal/mol, respectively. These calculations are in complete agreement with the product distribution formed by Doering-Moore-Skattebr reactions of 119 and 120. Since the Doering-MooreSkattebr method fails to generate seven-membered-ring allenes, Balci et al, [86] applied classical base-supported elimination using appropriate halocycloalkenes to generate benzannelated derivatives. Vinylbromide 134 was synthesized in three steps starting from the dibromocyclopropane 133 (Scheme 22). Subsequent dehydrobromination with potassium tert-butoxide in THF gave the dimer of 135, viz. 136, in 20% yield. In order to distinguish between the head-to-head and head-to-tail dimers, 136 was reacted with the tetracyanoethylene (TCNE) to give 137 whose structure was established by NMR and X-ray analysis. Analogous dehydrobromination of 138 provided 140 instead of the expected seven-membered-ring allene 139 likely from primarily double-bond isomerization followed by a rapid ~-elimination [86].

62

METIN BALCI and YAVUZ TASKESENLIGIL

nr Br

1)AgNOj,H20,A

2)PB.3.

"~

~---- ~

1

3) t+i.+,.]ti 133

134

1351

CNCN _

137

136

138

140

139

Scheme 22.

Christi et al. [87] have applied the Doering-Moore-Skatteb;~l method to 141 and isolated the C - H insertion product 143 and the unexpected allene dimer 142 in 19 and 20% yields, respectively. It is likely that the annelation of benzene to the seven-membered ring changes the conformation of the ring in a manner that is suitable for the opening of the cyclopropylidene carbene. Probably the activation barrier for the formation of allene is decreased and has a similar value to that of the insertion reaction and this is reflected by the product distribution. Cycloheptatetraene 92 is the best studied cyclic allene which plays a central role in C7H6 interconversions (Scheme 23) [ 1,59]. Recent ab initio calculations [59] at the G2(MP2,SVP) and B-LYP/6-311+G(3df,2p)+ZPVE levels predict a chiral equilibrium geometry in agreement with experimental evidence for chirality [88]. Allene 92 is 67 kJ/mol more stable than phenylcarbene 93. Interconversion of 93 and 92 is predicted to have a moderate activation barrier with the involvement of the stable bicyclic intermediate 144. Rearrangement of 144 to singlet carbene 93 has a significant barrier of 69 kJ/mol, while ring expansion of 144 to 92 has a barrier Br

Ph Ph 141

142 20%

143 ]9%

Strained Cyclic Allenes

93

63

144

92a

92b

Scheme 23. of only 8 kJ/mol. Therefore, an experimental observation of 144 will be impossible. The calculated C--C bond length and CCC angle for the allene unit in 92 are 1.337 /1, and 146.2 ~ respectively. B-LYP/6-31 G* calculations predict a C----C=C stretching frequency of 1813 cm -1 that is consistent with the experimentally determined IR absorptions of 1824 and 1816 cm -1 [89]. Reaction of 1-bromocycloheptene (145) with KOBu-t in the presence of (Ph3P)3Pt has been reported to give reasonable yields of the Pt(0) complex 147 of cyclic allene 3 [8]. Adduct 147 was thought to havearisen from simple trapping of the free allene. However, Jones et al. [90] reinvestigated the reaction in different solvents and with different bases and concluded that 147 arises from dehydrobromination of the initially formed 7t complex 146 rather than from trapping of the free cyclohepta- 1,2-diene. Jones et al. [74] also succeeded in generating the first (trimethylphosphine)zirconocene complex 148 of 3-methylcyclohepta- 1,2-diene; the seven-membered ring is bent by 48 ~. Br

Br

- pt(Pph3)3

145

.~

146

147

CH3

PMe 3 148

64

METIN 13ALCI and YAVUZ TASKESENLIGIL

5. EIGHT-MEMBERED-RING ALLENES The four eight-membered-ring allenes 4 and 149-151 represent the range of compounds known and the last two are stable compounds. Parent cycloocta-1,2diene (4) was first synthesized in 1961 by Ball and Landor [7] who reported that it undergoes rapid dimerization to dimer 152. A reinvestigation of the dimerization of 4 by K6nig et al. [91 ] indicated the presence of the C-H insertion product 153 and two carbene addition products 154 and 155. The trans configuration at the four-membered ring of 152 was determined by X-ray crystallographic analysis of the Diels-Alder product obtained by reaction with tetracyanoethylene. The 1-methyl derivative 149 has greater kinetic stability than 4 and it dimerizes with a half-life time of 10-15 min at ambient temperature [1,91]. The three [2+2] cycloaddition products 156-158 have been isolated but only the stereochemistry of 156 was determined by X-ray structure analysis of its Diels-Alder adduct with tetracyanoethylene [91 ]. 1-tert-Butylcycloocta-l,2-diene (150) is the only eight-membered cycloallene stable at 20 ~ [92]. In contrast to parent 4 and methyl-derivative 149, allene 150 did not dimerize, even on prolonged standing at ambient temperature. All these reported examples show that the cyclic allenes 2, 3, and 4 and their derivatives dimerize rapidly to give usual products, namely, the C2-symmetric 1,2-bismethylidenecyclobutane derivatives. However, 1-phenylcycloocta-l,2diene (151) [93], generated by application of the Doering-Moore-Skattebr method to dibromocarbene adduct 159, dimerizes in an unusual manner to give product 160 (Scheme 24). The structure of 160 was confirmed by an X-ray structure analysis. It is now well established that cyclic allenes dimerize by way of a diradical.

0 4

149

152

150

153

151

154

C.H3

H

155

H

H

CH3CH3 156

157

158

Strained Cyclic Allenes

~Br ~,

65

MeLi Br

.40oC

50-60%

159

151 160

Scheme 24.

The formation of 160 can be rationalized by formation of the diradical 161 as the intermediate. The fast collapse of 161 to 160 is probably caused by the conformation of the eight-membered tings placing the reaction centers in suitable positions. An interesting cycloocta-l,2-diene derivative is 163 that contains a propellane subunit. It was recently synthesized by Kreuzholz and Szeimies [94] starting from the allenic tautomer 162 in 59% yield, but an attempted distillation led to complete polymerization. The chirality of cycloocta-1,2-diene (4) and that of several 1-alkyl derivatives was proved by gas chromatography on a stationary phase prepared from modified cyclodextrin [91,95]. Recently, Roth and Bastigkeit [96] determined the activation parameters for the racemization of cycloocta-l,2,5-triene (AH* 39.8 kcal/mol) despite the pronounced tendency of this molecule to dimerize. Cycloocta-l,2,3triene (166) has been prepared for the first time starting from two different compounds, viz. 164 and 165 (Scheme 25) [97]. The final strained ~r bond was introduced by fluoride-induced vicinal elimination of trimethylsilyl and chloride in 164, and by magnesium-induced dehalogenation in 165. Furthermore, the kinetic stability of 166 in solution has been demonstrated and the total strain energy is estimated to be 17.7 kcal/mol.

161

iPh CH--C~C~Li 59%

CH2-..CH2..~CH2C! 162

163

66

METIN BALCI and YAVUZ TASKESENLIGIL

~ - . . . - ~ T M S DMSO, 40~

CI

164

165

166 , 49% Ph CH3

,,~

14%

c 2) Ph

CH3 167

168 Scheme 25.

Photochemical reactions of cyclic allenes have been studied systematically [98]. Price and Johnson studied the photochemical behavior of the isolable eightmembered-ring allene, 1-tert-butylcycloocta-l,2-diene (150) (Scheme 26) [99]. Direct irradiation in pentane at 254 nm affords 169 as the major product. Formation of this product has been attributed to initial 1,2-hydrogen migration in the excited state to give a vinylcarbene, independent generation of which gave a similar product distribution. However, the benzene-sensitized triplet reaction of 150 afforded products of hydrogen abstraction at the tea-butyl group or the ring methylenes. Irradiation of 150 in oxygenated solutions gave 1-tert-butylcycloheptene, probably from extrusion of carbon monoxide from an intermediate cyclopropanone. Similar results have been observed by photolysis of 1-methylcycloocta-1,2-diene (149) [100]. Recently, the [3.3] sigmatropic ring expansion of cyclic thionocarbonates has been successfully applied to the synthesis of medium-membered heterocyclic allenes [ 101]. Kurihara et al. [ 102] rearranged the six-membered thionocarbonates

~

(CH3)3hv 2 54 n'--""~m ~

150

C(CH3)3 +

169 76%

171 5%

172 4% Scheme 26.

170 I0%

173 2%

Strained Cyclic Allenes

67

Benzene reflux,

(Me)3 176 R=CH3 92% 177 R=Ph 63%

174 R ~ H 3 175 R=Ph Scheme 27.

CH3 64% y

178

179

R RI S.iMe3

R/

180

R =Me

174 and 175 (Scheme 27) in refluxing benzene to the stable and pure eight-membered heterocyclic allenes 176 and 177 that contain divalent sulfur and oxygen atoms in 92 and 63% yields, respectively. The MNDO-optimized structure indicates the allene moiety in 176 to be bent and strained. The bond angle on the sp carbon C = C = C is bent from linearity to 170.1 ~ The synthesis of allene 178 lacking a bulky substituent has also been achieved. The isolated product was the [2+2] cycloaddition product 179 whose structure as the head-to-head dimer was determined by X-ray analysis. As anticipated, the eight-membered silacycloallene 180 does not show any evidence of notable strain, is quite stable, and requires no special treatment in handling [71].

6. NINE-MEMBERED-RING ALLENES Cyclonona-1,2-diene (5) is a distillable liquid [6] and its dimerization takes place only at 130 ~ [ 103]. However, 1-phenylcyclonona- 1,2-diene (181) which has been

68

METIN BALCI and YAVUZ TASKESENLIGIL

Ph

PhPh

181

~)

cis-182

H

Sn2Mc6, Po~

SnM~

~ ~~-SnMe3 + ~ S n M c 3

] 2h

80 ~

trans-182

SnMe3 cis-183 > 9s %

trans-183 < 2 %

generated by application of the Doering-Moore-Skattebr method to 1-phenylcyclooctene [ 104] dimerizes slowly at room temperature to give cis- and trans-182 in a 1:1 ratio. Stable cyclo-l,2-dienes can be converted into synthetically promising compounds. For example, it has been demonstrated recently [ 105] that reaction of parent cyclonona-1,2-diene (5) with Sn2Me6 and [Pd(Ph3)4] in the absence of solvent at 80 ~ provides in excellent yield cis- and trans-183. These compounds furnish useful doubly functionalized medium-ring cycloalkenes. The photochemistry of cyclonona-l,2-diene (5) was reported by Ward and Karafiath as early as 1969 [ 106]. Benzene-sensitized irradiation in the vapor phase resulted in the formation of 185 (Scheme 28) while direct irradiation furnished four C 9 isomers from which only 185 was characterized. Gilbert et al. [ 107] reported the formation of 188 and 189 in benzene solution. However, Stierman and Johnson [108] reinvestigated the photochemical reaction of 5 and characterized other products as bieyclo[6.1.0]non-9-ene (186) and cyclononyne (187) (Scheme 28).

0

hV [(3

bcnzcn~ vapor

51

185

184

benzene,

solution

186

188

189 Scheme 28.

187

69

Strained Cyclic Allenes

pentanc 190

191 26%

192 22%

~CH3+~ CH3

193 1o%

+(~/CH3

(+~~ /~CH3 i,''~'~" PC~H3 194 3%

195 40/,

197 <5%

198

19624%

Scheme 29.

Recently, Johnson et al. [ 109] studied the photoreaction of 1-methylcyclonona1,2-diene (190), which was synthesized by the Doering-Moore-Skattebr method, in order to determine the substituent effect on the mechanism. Direct irradiation of 190 afforded as primary products the seven isomers 191-197 (Scheme 29). In contrast to the apparently concerted reaction of 5, methyl derivative 190 seems to favor vinylcarbene intermediates.

7. BICYCLIC ALLENES Bergman and Rajadhyaksha [110] have reported that dehydrobromination of 199 gives the acetylenic compound 202 in the absence of a trapping agent. The same compound was also observed from thermal decomposition of 203 (Scheme 30). The authors suggested the homoaromatic zwitterionic structure 200 as a plausible precursor of 202. This reactive intermediate undergoes facile [3.3] sigmatropic rearrangement to alkyne 202. Evidence for the allenic structure 201 rather than zwitterion 200 was provided by Balci and Jones [ 111] who generated the strained bicyclic allene 201 by base-promoted dehydrobromination of 199, and trapped it with DPIBF. The formation of optically active products from dehydrobromination with an optically active base implied the intermediacy of 201 with a twisted allene structure. The optical activity decreased with increasing reaction temperature which suggests facile racemization. Subsequent MNDO calculations on 201 showed a strongly bent, chiral structure, although the racemization barrier was not accurately estimated [ 16]. Balci and Harmandar [ 112] investigated the fate of allene 201 when

70

METIN BALCI and YAVUZ TASKESENLIGIL

~~.~Br

KOBu-t

.."

DMSO

or

199

p,31s h i n /

20 A

/ ~H

U 202

203 Scheme 30.

the remote double bond in bromo-compound 199 is deactivated by benzosubstitution. For the synthesis of the required 6,7-benzo analogue 205 of 199, vinylbromide 204 was synthesized and subjected to dehydrobromination with potassium tert-butoxide in the presence of DPIBF as a trapping agent (Scheme 31). Five products, 206-210, were isolated from this reaction. The formation of 206, 207, and 208 was reasonably explained by the intermediacy of the strained bicyclic allene 205 which is trapped by DPIBF, but isomer 211 was not found among the products. It is believed that 211 undergoes facile isomerization to the less strained alcohol 209. The formation of ketone 210 was explained by addition of tea-butanol or tert-butoxide ion to the central carbon atom of allene 205, followed by hydrolysis. On the basis of these results the authors concluded that the dehydrobromination of 204 gives rise to the strained bicyclic allene 205 which, unlike 201, does not isomerize further to the ring-opened alkyne 213 because involvement of the remote double bond is impeded by the stability of the aromatic ring (Scheme 32). 1-Bromocyclohexene and 1-bromocycloheptene form tricyclic hydrocarbons on dehydrobromination and these arise from dimerization of the intermediate cycloalka-1,2-dienes 2 and 3. In contrast, the reaction of 205 with potassium tert-butoxide did not form any dimerization product. In the absence of DPIBF, enol ether 212 (Scheme 32) was formed as the sole product. Balci and Harmandar proposed an alternate mechanism for the formation of cycloadducts 206-208 as shown in Scheme 33 [112]. According to this mechanism the dehydrobromination of 204 yields the bicyclic alkyne 214 which cycloadds DPIBF to give 215. The base-promoted isomerization of the double bonds of 215 would give the observed adducts 206-208 (Scheme 33, route b).

Strained Cyclic Allenes

71

KOBu-t/THF Br

DPIBF

Ph

reflux

204

205

Ph

+

F~ +

207

208

211

H

~

O 210

209 Scheme 31.

In order to distinguish between the two possible mechanisms, Balci et al. [ 113] recently investigated the generation and trapping Of the alkyne 214 by alternate procedures. Alkyne 214 was generated by the base-induced rearrangement of the bromomethylidene compound 216 (Scheme 34). When 216 was subjected to dehydrobromination with potassium tert-butoxide in the presence of DPIBF, a mixture of products 218a, and 218b was obtained. The same products were also

~ t

204

Br reflux

KOBu-~rI'HE

.v

~-205

d'a, 213

Scheme 32.

~OBu.t 212

72

METIN BALCI and YAVUZ TASKESENLIGIL

r o u te a ,,

Br

205

204

/

I

base ~rou te b

DPIBF

T

214

I

DP|BF

ba~

I

215 Scheme 33.

isolated by debromination of 217 with tert-butyllithium in the presence of DPIBF [ 114]. Repetition of this last reaction with two moles of potassium tert-butoxJde under identical conditions afforded a reaction mixture consisting of 206-210. This is the same reaction mixture as was obtained previously [ 112] from the reaction of 204 with potassium tert-butoxide. These two experiments indicate that the alkyne 214 initially reacts with DPIBF to give the syn- and anti-isomers 218a and 218b which then isomerize completely to the allene-like adducts 206-210 in the presence of excess base. The identical product distribution from the two different reactions, implies that the intermediates must have the same structure. Since the allene intermediate cannot be generated from the base-promoted reaction of 216, it was concluded that the intermediate is the alkyne 214. This is calculated to be 11 kcal/mol (MOPAC) and 16 kcal/mol (PCMODEL) more stable than the allene 205 [113]. Even with these results allene formation cannot be excluded in the base-promoted reaction of 204. In order to reveal whether the real intermediate in the dehydrobromination of 204 is 205 or 214 it was necessary to undertake another independent generation of alkyne 214 where the formation of allene 205 was excluded. For this

Strained Cyclic Allenes

73

t-BuLi/THF ~

KOBu-t(lmol)

Br

"78~ Br

O-IBr 214

216

217

DPIBF

I~

~~

0 218b

I

,

I

206-210

Scheme 34.

reason, chloroalkene 219 was synthesized and submitted to dehydrochlorination with potassium tert-butoxide [ 115]. In contrast to expectation, the base-promoted reaction of 219 did not form the alkyne intermediate 214 or its derived enol ether 212. Instead allyl ether 220 was isolated as the sole product of reaction (Scheme 35). It was suggested that prototropic rearrangement of the chloro alkene 219 to the corresponding allyl chloride is followed by nucleophilic displacement of the chlorine atom by tert-butoxide and that this is responsible for this conversion. At this stage the question "what is the real intermediate in the base-promoted reaction of vinylbromide 204?" still remained open. In order to solve this problem, the 4,4-dideuterio derivative 221 was synthesized and its dehydrobromination reaction studied [116]. Formation of allene intermediate 223 by dehydrobromination of 221 would result in the scrambling of deuterium atoms; however, alkyne formation will give product 222 which, after trapping with DPIBF and double bond isomerization, will have deuterium located at the double bond. Unfortunately, substrate 221 undergoes H/D exchange reaction before HBr elimination. After the failure of this attempt to determine the real structure of the intermediate an attempt was made to force the system to undergo allene formation by replacing the double bond proton in 204 by an alkyl group. Thus the 2-methyl derivative 225

74

METIN BALCI and YAVUZ TASKESENLIGIL

reflux

KOBu-t/T HF._

219

"~

(31

-t

~Bu.t

// 214

212

Scheme 35.

[114] was synthesized from 2,3-dibromobenzonorbornadiene (224) (Scheme 36) [117]. No reaction was observed when 225 was subjected to dehydrobromination with potassium tert-butoxide under the same reaction conditions as reported for 204. When the more drastic conditions of diglyme at 170 ~ were employed, dehydrobromination occurred and the exocyclic olefin 226 was formed; primarily base abstracts a hydrogen atom from the methyl group [ 114]. This result indicates that 225 has no tendency for dehydrobromination to form allene 227 (Scheme 36). The chemistry of Scheme 36 was repeated using the phenyl derivative 228 so as to prevent proton abstraction from the methyl group. It was synthesized and submitted to the base-supported dehydrobromination reaction whereupon enol ether 230 was isolated in 16% yield [ 114]. This result indicates the formation of allene 229 which is trapped by tert-butoxide ion. Another attempt to generate 205 was made using zinc-catalyzed elimination of the dibromide 231 [23]. The reaction afforded two isomeric Wurtz-like condensation products, 232 and 233, in 16% yield. Not even a trace of the expected allene dimerization product was detected in this reaction.

?

?

KoBU'UTHF

222

Sr

.._

KOBu-Cr HF

221 I KOBu-FTHF Deuterium-scrambling

223

Strained Cyclic Allenes

75

B~i~ - i ~

224

~ CH3 ~

ur

KOBu-t THF // "-

"Br

225

~CH3 227

I KOBu-t/diglyme 170~

~

2

226

Scheme 36.

Ph KOBu-t Br

Ph KOBu-t..._

THF

Bu-t

16%

228

229

Zn/DMSO Br 1lO~

230

H Br

+

231

(+)232

(meso)-233

8. MISCELLANEOUS Doubly bridged cyclic allenes, namely "betweenallene" or "screw[2]ene" have also been subjects of interest for their molecular chirality [ 118]. The fact that siliconsilicon bonds release ring strain prompted Ando et al. [72] and Barton et al. [73] independently to synthesize octasila[4.4]betweenallene 234 from the reaction of dichlorooctamethyltetrasilane with hexachloropropene in the presence of magnesium [72] or with dilithioallene [73] as shown in Scheme 37. X-ray crystallographic analysis of 234 shows that the allenic sp carbon is almost linear, although in the case of 235 it is slightly bent. Cyclic-strained allenes containing -SCO 2 units in the range of 8- to 11-membered rings were synthesized by [3.3] sigmatropic rearrangement of the appropriate alkynyl cyclic thionocarbonate [ 119]. This methodology has been applied successfully to the synthesis of an antifungal constituent of a Sapium Japonicum.

76

METIN BALCI and YAVUZ TASKESENLIGIL Me,, ~Si--Si,,

CI3C-CCI=CCI2 + Cl -Si(Me2)4_CI

si

"si"

Me

Mg,THF

Me/ ~C=C=C/ "lVle

34%

Me" "~Si---~,, "Me 234

Scheme 37.

A new synthetic method for medium-sized cyclic allenes was developed on the basis of a. C-C bond cleavage directed by removal of a silyl group (Scheme 38) [ 120]; the dissociation of the enol triflate moeity into the vinyl cation is assumed as the rate determining step. Finn et al. [ 121 ] have developed some Ti(IV)-substituted phosphorus methylides as "doubly oxophilic" reagents for the condensation of nonenolizable aldehydes to 1,3-disubstituted allenes. As an extension of this work, the cyclization ofdicarbonyl compounds 243 have been studied to generate medium-size cyclic allenes 244 [122]. The resulting cyclic allene 224 (n = x) has been characterized by X-ray diffraction. Ab initio molecular orbital calculations of diallenes 245-248 have been performed to study their energies and conformational strained structures [ 123]. Five, four, and two geometries [(+)- and meso-isomers] have been found at the potential minima for the cyclic diallenes 245-248. In the case of the nine-, eight-, and seven-membered cyclic compounds 246-248 the (+)-isomers have lower potential energies. However for 245 it is the meso-isomer that has the lower energy. This

Me

,/I "=

Si--Si~ Me |lie

Me Me

235 R

(CH2RnI ~ )

[3.3]

R1

;C--C_-C/

(CH2).

236

R

~S

237 28-66%

Strained Cyclic Allenes

77

TMS 180~

imidazole .--- ~ C DMF,3h, 150'C

"rF'SO

Tf'SO

238

24076%

239 82%

TIPSITriisopropylsilyl

T•,

< ~ ~

imidazolr .-- ~ DMF,3h, 150~C

C

OMeOTf

OMe

241

242 60% Scheme 38.

result is consistent with the experimental fact that only meso-245 has been characterized [ 124]. Yavari et al. [ 125-127] have calculated molecular structures of 249 and 250 using iterative molecular mechanics calculations while AM1 semiempirical SCF-MO calculations were also used for cyclonona-1,2,4,5-tetraene 249. They found four conformations and two transition states for conformational interconversions but the

(.CH2)n

(C,H2)n

0/

ClIO OHC

~0---i~~

C=C--

(M~N)3P----'CI'I'2 3 NaN(SiMr 2

243

244

H H C=C=C,. ~_.'C_C_C/~ _

H

_

H

H "c=c=cH

[-0=0.2 H

245

246

Hc~C~cH

Hc~C~cH

247

248

<

>

C=C=C~ C~c~c._.J 249

C~ 250

I

>

78

METIN BALCI and YAVUZ TASKESENLIGIL

calculated strain energies for the ground state conformations of both diastereomers are reported to have similar values.

REFERENCES [1] Johnson, R. P.,Chem. Rev., 89 (1989) 11 II. [2] Johnson, R. P. In Thummel, R. P. (Ed.)Advances in Theoret~'caUyInterestingMolecules, Vol. I, JAI Press Inc.:Greenwich, CT, 1989, p. 401. [3] Landor, S. R. (Ed.) The Chemistry of the Allenes,Vols. I-3, Academic Press:New York, 1982. [4] Dykstra, C. E., Schaefer,H. F. In Patai,S. (Ed.),The Chemistry ofKetenes, Allenes, and Related Compounds, Wiley: New York, 1980, p. I. [5] Greenberg, A., and Liebman, J.L.,StrainedOrganic Molecules, Academic Press:New York, 1978, p. 126. [6] Blomquist, A. T., Burger, R. E. Jr.,Liu, L. H., Bohrer, J. C., Sucsy, A. C., and Kleis, C., J. Am. Chem. Soc., 73 (1951) 5510. [7] Ball, W. J. and Landor, S. R., Proc. Chem. Soc., London, (1961) 143. [8] Wisser, J. P. and Ramakers, J. E., J. Chem. Soc., Chem. Commun. (1972) 178. [9] Balci, M. and Jones, W. M., J. Am. Chem. Soc., I02 (1980) 7607. [10] Bottini,A. T., Corson, E P.,Fitzgerald,R., and Frost,K. A., Tetrahedron, 28 (1972) 2883. [11] Bottini,A. T., Hilton,L. L., and Plott,J.,Tetrahedron, 31 (I975) 1997. [12] Moore, W. R. and Moser, W., J. Am. Chem. Soc., 92 (I970) 5469. [13] Dillon, P. W. and Underwood, G. R., J. Am. Chem. Soc., 96 (1974) 779. [14] Wentrup, C., Gross, G., Maquestiau, A., and Flammery, R., Angew. Chem., Int.Ed. Engl., 27 (1983) 542. [15] Schmidt, M. W., Angus, R. O., and Johnson, R. P., J. Am. Chem. Sot., 104 (1982) 6838. [16] Angus, R. O., Schmidt, M. W., and Johnson, R. P., J. Am. Chem. Soc., 107 (1985) 532. [17] Lam, B. and Johnson, R. P., J. Am. Chem. Sot., 105 (1983) 7479. [18] Andres, J., Cardenas, R., and Tapia, O., J. Chem. Sot., Perkin Trans. 2, (1985) 363. [19] Yavari, I., J. Mol. Struct. (Theochem.), 65 (1980) 169. [20] Favorskii, A. E., J. Gen. Chem. USSR (Engl. Transl.), 6 (1936) 720. [21] Ceylan, M., Secen, H., and Stitbeyaz, Y., J. Chem. Res. (S), (1997) 293. [22] SUtbeyaz,Y., Ceylan, M., and Secen, H., J. Chem. Res. (S), (1993) 70. [23] Taskesenligil, Y., TOmer, E, and Balci, M., Turk. J. Chem., 19 (1995) 305. [24] Tolbert, M. L., Islam, M. N., Johnson, R. P., Loisella, P. M., and Shakespeare, W. C., J. Am. Chem. Soc., 112 (1990) 6416. [25] Tolbert, M. L. and Siddiqui, S., J. Am. Chem. Soc., 106 (1984) 5538. [26] Balci, M., Ceylan, M., Secen, H., and Stitbeyaz, Y., unpublished results. [27] Shakespeare, W. C. and Johnson, R. P., J. Am. Chem. Sot., 112 (1990) 8578. [28] Wittig, G. and Fritze, P., Angew. Chem., Int. Ed. Engl., 5 (1966) 846. [29] Wittig, G. and Fritze, P., Justus Liebigs Ann. Chem., 82 (1968) 711. [30] Miller, B. and Sift, X., J. Am. Chem. Sot., 109 (1987) 578. [31] Christi, M., Braun, M., and Mtiller, G., Angew. Chem., Int. Ed. Engl., 31 (1992) 473. [32] Hamos, S., Tivakornpannarai, S., and Waali, E. E., Tetrahedron Lett., 27 (1986) 3701. [33] Christi, M. and Schreck, M., Chem. Bet., 120 (1987) 915. [34] Christi, M. and Braun, M., Chem. Ber., 122 (1989) 1939. [35] Janoschek, R., Angew. Chem., Int. Ed. Engl., 31 (1992) 476. [36] Danheiser, R. L., Gould, A. E., Praclilla, E, and Helgason, A., J. Org. Chem., 59 (1994) 5514. [37] Burrell, R. C., Daoust, K. J., Bradley, A. Z., DiRic.o, K. J., and Johnson, R. P., J. Am. Chem. Sot., 118 (1996) 4218. [38] Schreck, M. and Christi, M., Angew. Chem., Int. Ed. Engl., 99 (1987) 692.

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Moore, W. R. and Moser, W. R., J. Am. Chem. Sor 92 (1970) 5469. Moore, W. R., Ward, H. R., and Merritt, R. E, J. Am. Chem. Sor 83 (1961) 2019. K6brich, G. and Goyert, W., T e t r ~ n , 24 (1968) 4327. Backes, J. and Brinker, U. In Eegitz, M. (Ed.), Methoden der Organischen Chemie (Houben-Weyl), Thieme Verlag: Stuttgart, E19b, 1989, p. 400. [82] Taylor, K. G., Hobbs, W. E., Clark, M. S., and Chancy, J., J. Org. Chem., 37 (1972) 2436. [83] Warner, P. M., Herold, R. D., Chu, I., and Lessman, J., J. Org. Chem., 53 (1985) 942. [84] Bettinger, H. E, Schleyer, P. v. R., Schreiner, P. R., and Schaefer III, H. E,J. Org. Chem., 62 (1997) 9267. [851 Bettinger, H. E, Schleyer, P. v. R., Schreiner, P. R., and Schaefer IIl, H. E, J. Phys. Chem., 100 (1996) 16147. [86] Yildiz, Y. K., Sefen, H., Krawiec, M., Watson, W. H., and Balci, M., J. Org. Chem., 58 (1993) 5355. [87] Jelinek-Fink, H., Christi, M., Peters, E. M., Peters, K., and Schnering, H. G. v., Chem. Ber., 124 (1991) 2569. [88] Harris, J. W. and Jones, W. M., J. Am. Chem. Sot., 104 (1982) 7329. [89] Matzinger, S., Bally, T., Patterson, E. V., and McMahon, R. J., J. Am. Chem. Sot., 118 (1996) 1535. [90] Lu, Z., Abboud, K. A., and Jones, W. M., Organometallics, 12 (1993) 1471. [91] Pietruska, J., K6nig, W. A., Maelger, H., and Kopf, J., Chem. Ber., 126 (1993) 159. [92] Price, J. D. and Johnson, R. P., Tetrahedron Lea., 27 (1986) 4679. [93] Christi, M., Rudolph, M., Peters, E. M., Petrs, K., and Schnering, H. G. v., Angew. Chem., Int. Ed. Engl., 34 (1995) 2730. .~ [94] Kreuzholz, R. and Szeimies, G., Liebigs Ann./Recueil, (1997) 1131. [95] Pietruska, J., Hochmuth, D. H., Gehrcke, B., Icheln, D., Runge, T., and K6nig, W. A., Tetrahedron: Asymmetry, 3 (1992) 661. [96] Roth, W. R. and Bastigkeit, T., Liebigs Ann., (1996) 2171. [97] Hemandez, S., Kirehhoff, M. M., Swartz, S. G., and Johnson, R. P., Tetrahedron Lett., 37 (1996) 4907. ,~ [98] Johnson, R. P., Org. Photochem., 7 (1985) 75. [99] Price, J. D. and Johnson, R. P., J. Org. Chem., 56 (1991) 6372. [lOO] Stierman, T. J., Shakespeare, W. C., and Johnson, R. P., J. Org. Chem., 55 (1990) 1043. [lOl] Harusawa, S., Kase, N., Yoneda, R., and Kurihara, T., Tetrahedron Lett., 35 (1994) 1255. [1o2] Harusawa, S., Moriyama, H., Ohishi, H., Yoneda, R., and Kurihara, T., Heterocycles, 38 (1994) 1975. [los] Skatteb~l, L. and Solomon, S., J. Am. Chem. Soc., 87 (1965) 4506. [lO4] Christi, M., Moigno, D., Peters, E-M., Peters, K., and Schnefing, H. G. v., Liebigs Ann./Recueil, (1997) 1791. ~, : [lO51 Kwetkat, K., Riches, B. H., Ropsset, J-M., Breeknell, D. J., Byriel, K., Kennard, C. H. L., Young, D. J., Schneider, U., Mitchell, T. N., and Kitehing, W., Chem. Commun., (1996) 773. [lO6] Ward, H. R. and Karafiath, E., J. Am. Chem. Soe., 91 (1969) 7475. [107] Betridge, J. C., Fotrester, J., Foulger, B. E., and Gilbert, A., J. Chem. Soe., Perkin Trans. 1, (1980) 2425. [1081 Stierman, T. J. and Johnson, R. E, J. Am. Chem. Soe., 107 (1985) 3971. [~091 Stierman, T. J., Shakespeare, W., and Johnson, R. E, J. Org. Chem., 55 (1990) 1043. [110] Bergman, R. G. and Rajadhyaksha, V. J., J. Am. Chem. Soe., 92 (1970) 2163. [1111 Balei, M. and Jones, W. M., J. Am. Chem. Soe., 103 (1981) 2874. [112] Balei, M. and Harmandar, M., T e t r ~ n Lea., 25 (1984) 237. [1131 Taskesenligil, Y., Kashyap, R. E, Watson, W. H., and Bald, M., J. Org. Chem., 58 (1993) 3216. [1141 Tilrner, E, Taskesenligil, Y., and Balei, M., unpublished results. [1151 TUrner, E, Taskesenligil, Y., Dastan, A., and Balci, M., Aust. J. Chem., 49 (1996) 599.

Strained Cyclic Allenes

81

[116] Taskesenligil, Y., Tamer, E, Kazaz, C., and Balci, M., Turk. J. Chem., in press. [117] Cossu, S., De Lucchi, O., Lucchini, V., Valle, G., Bald, M., Dastan, A., and Demirci, B., Tetrahedron Lett, 38 (1997) 5319. [1181 Farina, M. and Morandi, C., Tetrahedron Lett., 30 (1974) 1819. [119] Harusawa, S., Moriyama, H., Kase, N., Ohishi, H., Yonexta, R., and Kurihare, T., Tetrahedron, 51 (1995) 6475. [120] Sugai, M., Tanino, K., and Kuwajima, I., Synlett, (1997) 461. [121] Reynolds, K. A., Dopico, P. G., Sundermann, M. J., Hughes, K. A., and Finn, M. G., J. Org. Chem., 58 (1993) 1298. [122] Brody, S. B., Williams, R. M., and Finn, M. G., J. Am. Chem. Soc., 119 (1997) 3429. [123] Shimizu, T., Kamigata, N., and Ikuta, S., J. Mol. Struct. (Theochem.) 369 (1996) 127. [124] Dehmlow, E. V. and Stiehm, I'., Tetrahedron Lea., 31 (1990) 1841. [125] Yavari, I., Baharfar, R., and Asghari, S., J. Mol. Struct. (Theochem.) 283 (1993) 277. [126] Yavari, I., Asghari, S., and Shaabani, A., J. Mol. Struct. (Theochem.) 309 (1994) 53. [127] Yavari, I., Baharfar, R., and Nori-Shargh, D., J. Mol. Struct. (Theochem.) 393 (1997) 167.

This Page Intentionally Left Blank

STRAI N AN D STRUCTU RE OF STERICALLY CONGESTED TRIPLET CARBENES

H ideo Tom ioka

1. 2. 3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relationship between Structure and Ground-State Multiplicities . . . . . . . . . EPR Spectroscopy of Triplet Carbenes . . . . . . . . . . . . . . . . . . . . . . 3.1 The Zero-Field Splitting . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Triplet Carbene Structure and ZFS Parameters . . . . . . . . . . . . . . . Strain and Structure of Triplet Carbenes . . . . . . . . . . . . . . . . . . . . . 4.1 Diarylcarbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Diphenylcarbenes Bearing ortho Substituents . . . . . . . . . . . . . . . 4.3 Effect of Triptycyl Group . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Advances in Strained and Interesting Organic Molecules Volume 8, pages 83-112. Copyright 9 2000 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-7623-0631-9 83

84 84 86 86 90 94 95 97 106 109 110 110

84

HIDEO TOMIOKA

1. INTRODUCTION Since bis(m-phenylenecarbene) was shown to have a quintet ground state in 1967 [1], triplet diphenylcarbene units have served as the source of electron spins in constructing high-spin molecules as models for purely organic ferromagnetics [2]. Thus, poly(m-phenylenecarbenes) have been studied most systematically inter alia and are accepted as the highest spin organic molecules [3,4]. The highly transient nature of the species [5], however, is an inherent drawback for further extension to usable magnetic materials. In this light, it is highly desirable to synthesize persistent triplet carbenes [6] and then to connect them in a ferromagnetic fashion with an appropriate topological coupler [7]. In order to achieve this purpose, it is important to reveal the relationship between the structure and stability of triplet carbenes. Electron paramagnetic resonance (EPR) spectroscopy in a rigid matrix at low temperature is an especially useful technique in this regard as it is expected to provide valuable information on the molecular and electronic structures of triplet carbenes [8]. In this chapter, we wish to describe the research along this line, where EPR data of a series of triplet carbenes are systematically analyzed and discussed in terms of structural features so as to understand how the structures of triplet carbenes are affected by electronic and steric effects. We will first discuss briefly the relationship between structure and ground-state multiplicities of carbenes, and then describe the type of information that can be obtained from matrix isolation EPR spectroscopy. This will be followed by the main topics, namely the structures of triplet carbenes that are "forced" to become less bent mainly by steric crowding around the carbenic center. 11

RELATIONSHIP BETWEEN STRUCTURE AND GROUND-STATE MULTIPLICITIES

The carbene carbon atom is linked to two adjacent groups by covalent bonds, and it possesses two nonbonding electrons that may have their spins antiparallel (singlet state) or parallel (triplet state) [9]. If the carbene unit were linear, it should have two degenerate p orbitals, and Hund's first rule would predict a triplet ground state. If the carbene unit is not linear the two orbitals become different. The orbital perpendicular to the plane defined by the three atoms is designated as p, while that parallel to this plane is called o. Actually most carbenes are not linear and so the ground-state multiplicity depends upon the relative energy of the singlet and triplet states. The four lowest energy configurations of a carbene have an electronic configuration described as olp 1, o2, or p2. The triplet state has a olp 1 configuration, while the oa is generally thought to be the lowest configuration for the singlets (Figure 1). In a singlet state, the electron-electron coulombic repulsion would be severe, since two electrons are constrained to the same small molecular orbital (MO). On

Congested TripletCarbenes

85

H

H ~

H

,

T H

Linear

-t-CBent

(~2

T o~pl

Figure 1. Linear methylene with two degenerate p orbitals and bent methylene with a (~ and a p orbital.

the other hand, the triplet configuration is stabilized by relief of the coulomb repulsion, although one pays a price for separation of the electrons into different MOs. Thus, the magnitude of the energy difference between the triplet and singlet states (the singlet-triplet splitting, AGsT) is roughly equal to the electron-electron repulsion minus the energy required to promote an electron from the a- to the p-nonbonding orbital. In other words, as the energy separation between a and p states increases, the promotion energy becomes large enough to overcome the repulsion energy, while if the spacing is small, the species will still have a triplet ground state. The small difference between the energies of SOand T 1 may easily be overturned by the effects of substituents on the carbene center. The factors that influence the spacing can be analyzed in terms of electronic and steric effects. An electron-donating substituent raises the energy of the p orbital, thereby increasing the separation of the p and a orbitals. The ground state of such a carbene becomes a singlet. Many carbenes in this class are known. The most familiar ones are the halocarbenes. On the other hand, an electron-withdrawing group lowers the p - o gap and the ground state for such carbenes is expected to be T 1. From a valence-bond viewpoint, this means that electron-donor groups stabilize the electrophilic singlet carbene more than they do the radical-like triplet, and that electron-withdrawing groups destabilize the singlet and lead to a greater AGsT [ 10]. The magnitude of AGsT is expected to be sensitive to the carbon-carbene-carbon bond angle. A linear carbene has two degenerate p orbitals and this is calculated to provide the maximum value of AGsT.Bending of the bond angle removes the orbital degeneracy and reduces AGsT.As the carbon-carbene-carbon bond angle is further contracted, the o orbital picks up more s-character and consequently moves even lower in energy. The smaller the bond angle, the more energy it takes to promote an electron from the c~ to the p orbital and the smaller AGsT becomes. This is shown more quantitatively by calculation for methylene. The calculations predict that the energy of singlet methylene will drop below that of the triplet state for carbenes with bond angles less than about 906. On the other hand, theory also suggests that opening of the central angle strongly destabilizes the singlet state, but

86

HIDEO TOMIOKA

requires very little additional energy for the triplet, thus making AGsT larger [11 ]. In accordance with this prediction, cyclopropenylidene has been shown to have a singlet ground state [12], while di(adamantyl)carbene has been shown to have a triplet ground state [ 13].

3. EPR SPECTROSCOPY OF TRIPLET CARBENES 3.1 The Zero-Field Splitting The electron has the spin S = 1/2, which in a magnetic field is allowed to take the spin quantum number m s = +1/2. For one or more unpaired electrons, one defines the total spin multiplicity as 2S + 1. One unpaired electron has the spin multiplicity 2.1/2+1 = 2, and the system is called a doublet, corresponding to the two values of m s. Two unpaired electrons, as in triplet carbenes, have the spin multiplicity 2.1 + 1 = 3 (triplet) and it has three values of the spin magnetic quantum number, ms=l, 0, and -1. The three components (1, 0, -1) of the triplet state correspond to three different possibilities for the magnetic quantumnumber m s. Each of these possibilities corresponds to a stable state, i.e. one of the three components of a triplet, which is defined as T§ - o~1~ 2, T_ - 131~2' and T O- tx1132, for m s = 1, -1, and 0, respectively, where ct and 13 refer to the spin vectors. This means that the m s = 1 and m s = -1 states correspond to the two electronic magnets being oriented in the same direction where they repel each other, while the m s = 0 state behaves much like a singlet state, the two electronic magnets being antiparallel and therefore attracting each other. In contrast to the two energy levels of a doublet (radical), which are degenerate unless an external field is applied, the three levels of a triplet are split even in the absence of an external magnetic field since a dipole coupling of the two spins creates an internal magnetic field in the molecule, which splits the energy levels. The ms=0 level is stabilized and the m s = 1 and -1 levels are destabilized. This energy separation is called D (Figure 2). Each electron moves in the magnetic field of the other. If the molecule has less than cylindrical symmetry there will be two different values of the internal field. These fields do not affect the m s = 0 level, which has no overall spin. They cause, however, a further splitting of the m s = 1 and m s = -1 levels. This splitting is called E. In contrast to the energy levels of a doublet, which are degenerate unless an external magnetic field is applied, these splittings persist in the absence of an external magnetic field, and hence the constants D and E are termed zero-field splitting (ZFS) parameters (Figure 2). Each energy level is associated with a principal magnetic axis in the molecule because its energy will not change with magnetic field when the field is parallel to that axis. Triplet EPR spectroscopy provides a direct measure of the distribution of spins in the molecule. The magnitude of this splitting is, however, very small and so an external field is applied to bring the transition into the microwave range. When an external magnetic field H is applied, the energy difference between the m s = 1 and m s = -1

Congested Triplet Carbenes

87

Energy o -

ms=

t 2z I n s = ",

1 -1

%%%%%~ /D

ms=0

Figure 2. Zero-field splitting in the triplet state.

levels will increase, but the energy of the ms = 0 level remains unchanged. Thus the three levels split as shown in Figure 3. The selection rule that allows transitions usually has ~trns = +1. One would expect then two EPR transition for a triplet [14,15]. However, the exact transition frequency seen depends on the orientation of the internal principal magnetic axes of the triplet carbene with respect to the external magnetic field. Thus, one might expect an infinite number of possible orientations for a randomly oriented sample. Fortunately, though, one observes selectively those structures that have one of their principal magnetic axes nearly aligned with the external field. Since there are three magnetic axes, and two transitions for each of the canonical orientations, one expects 3 x 2 = 6 lines for a triplet spectrum. The lines appear in pairs, according to whether they arise from structures which have the x, y or z principal magnetic axis nearly aligned with the external field.

/

J

ms =

I (Tt)

m, = 0 (To)

~ ~

4 ~n = I

ms =-I (T.z) I

o

Figure 3. Energy levels of the triplet in a magnetic field (H).

-

//

88

HIDEO TOMIOKA

Figure 4 shows the theoretical EPR spectrum of a randomly oriented triplet species [ 15]. The values of D and E are calculated from the values of x, y, and z by using the relationships x = D I 3 - E, y = D I 3 + E, a n d z = - 2 D I 3 . D and E are obtained in gauss from the spectrum, but usually they are converted to energy units (cm -l) and reported as ID/hcl and IE/hcl. The absolute value signs indicate the fact that D can be positive or negative, and the sign is not known. b)

t

. . . .

-

I-

f

:!

-- --

ll

!

I

,'

i

2,000

D

A

-'iY'--'V ....

1,000

4 2D

'lf--r 1,

4,000

3,000

_

__

|

5,000

G

a)

-

I | _

_

J1

_

l-

l---4 II II

.J',

12D D+3E D-3E

/

ii" ',!

l! t

o

-

!

~,o0o

|

I

I

~,oo0 ~

3,000

_

t

I

4iooo s,ooo

G Figure 4. Theoretical EPR spectrum of randomly oriented triplet species. (a) E~ O, (b) E = O.

Congested Triplet Carbenes

89

The E value describes the smallest splitting and relates to the molecular symmetry of the triplet. In a structure with threefold or higher symmetry, two of the triplet sublevels will be degenerate, producing a value of zero for E. In this case, the middle pairs of lines collapse to one pair and produce a four-line spectrum [Figure 4(b)]. In addition to the six (E ~ 0) or four (E = 0) lines described above, an extra line sometime appears at much lower frequencies as indicated by dashed line in Figure 4. This line corresponds to Ams = 2 transitions between the two outer triplet sublevels. It is a critical line because its presence unambiguously signals that one is observing a triplet state. In a simple model, the ZFS parameters D and E for a triplet depend on the distance between electrons with parallel spins as given by Eq. 1: D = ~" g2gt2 ~

, E = ~- g21a2

(1)

In this equation r is the distance between the two spins and x, y, and z are the component of r along the x, y, and z axes, respectively. As mentioned before, these parameters describe the separation of the three energy levels when no external magnetic field is present. Each energy level is associated with a principal magnetic axis in the molecule because its energy is not changed with magnetic field when the field is parallel to that axis. The parameter D measures the magnetic dipole interaction along thez axis and is related to the average 1/r3 as shown above. A high value of D implies a large spin-spin interaction and a close proximity of the two spins. The parameter E, on the other hand, is a measure of the difference between similar magnetic dipole interactions along the x and y axes. A consequence of this is that a molecule with three different axes should have a finite E, whereas this quantity vanishes for linear molecules with degenerate p orbitals. More plainly, the more the two electrons are delocalized in carbenes with conjugated r systems, the smaller the value the repulsive interaction D will be. On the other hand, increasing the bond angle at the carbene center leads to a higher p-orbital contribution and a smaller value for E. Although the values D and E depend on the electronic distribution, it has been shown that there is a good correlation between the E/D ratio and the bond angle at the divalent carbon atom. However, one should be aware that the ratio of E/D is not always a reliable guide to the structure of triplet carbenes. For instance, diphenylcarbene and fiuorenylidene have very different geometries but almost exactly the same D and E values [8]. If one really wants to learn about the geometry, one must label the carbene carbon with t3C and measure the hyperfine coupling constants. The other difference between triplet and doublet EPR spectroscopy concerns the nature of the samples used. Free radical spectra are typically taken in fluid media and are thus nicely isotropic. However, triplet spectra generally require rigid samples. In order to obtain the appropriate information on the interaction of the

90

HIDEO TOMIOKA

unpaired spins in the triplet state molecule, it is necessary to prevent rapid rotation of the molecule. Carbenes are usually generated by photolysis of an appropriate precursor, e.g. the diazo compound, in a suitable inert rigid matrix at low temperature. Here, the matrix is expected to prevent the highly reactive molecules from reacting either with themselves or the carbene precursor. The low temperature also prevents rapid free rotation and suppresses the reactivity of the triplet species. The intensity of an EPR signal depends on the magnitude of the magnetic susceptibility, Z. For a simple paramagnetic system, a Curie plot, a plot of Z versus 1/T, should be linear. This means that the intensity becomes smaller as the temperature is raised. Deviations from linearity could indicate a temperature dependent equilibrium between a triplet and a singlet. Conversely, a linear Curie plot is taken as evidence for a triplet ground state, but this requires that the carbene be stable to a certain extent at elevated temperature.

3.2 Triplet Carbene Structure and ZFS Parameters From the above it can be seen that ZFS parameters provide information on the molecular and electronic structures of triplet carbenes. We will see here how the parameters change systematically by examining a series of sterically less perturbed triplet carbenes.

3.2.1 Effects of Carbenic Substituents Some D and E values for typical triplet carbenes are collected in Table 1 [ 16-18]. The ZFS parameters for methylene [16], the parent compound of all carbenes, clearly indicated that it has bent structure. A bond angle of 136 ~ is estimated [16b] which is in good agreement with most theoretical calculations [9b]. Introduction of aryl groups on methylene results in a significant decrease in D values; thus D decreases from 0.69 to 0.515 on going from methylene to phenylcarbene (PC) [17]. The D values decrease further as the aromatic ring is changed from phenyl to naphthyl to anthryl (Table 1) [18]. These trends are interpreted in terms of an increase in spin delocalization into the aromatic rings. It is interesting to note here that there are only small changes in E/D values among the monoarylcarbenes listed, indicating that the central bond angle of the carbenes is not affected significantly by change in the nature of the aromatic ring.

3.2.2 Effects of Remote Substituents Effects ofpara-subsfituents on the ESR spectrum of triplet diphenylcarbenes (1; 3DPCs) have been investigated (Table 2) [19]. Two trends become obvious when the D values are compared for para- and para, para'-disubstituted DPCs. First, substitution generally causes a decrease in D from that in the parent molecule. This is obviously due to extended g delocalization of spin density. Second, the decrease in D is largest when 3DPC is substituted with one p-electron-withdrawing group

Congested Triplet Carbenes

91

Table 1. Zero-Field Splitting Parameters a for Some Typical Triplet Carbenes D(cm- I)

Carbenes H,~," H

~H

E(cm- t)

E/D

Ref.

0.69

0.003

0.004 b

16

0.5150 0.518

0.0251 0.024

0.04873 c 0.046 d

17

(Z') 0.4347 (E) 0.4555

0.0208 0.0202

0.0478 0.0443

18 18

(Z) 0.4926 (E) 0.4711

0.0209 0.0243

0.0424 0.0516

18 18

0.3008

0.0132

0.0439

18

0.4055

0.0194

0.0478

17

(PC)

"FH

~

(1-NC) H (2-NC)

(AC)

(DPC) Notes: "Measured in benzophenone at 77 K unless otherwise noted.

bMeasured in xenon at 4.2 K. CMeasured in p-dichlorobenzene at 77 K. dMeasured in fluorolube glass at 77 K.

and one p'-electron-donating group. The decrease in D in these unsymmetrically disubstituted 3DPC is always larger than that predicted by taking the sum of the effects in the independent mono-substituted derivatives. These observations are explained in terms of merostabilization, a term first suggested by Katritzky [20] to describe increased delocalization in radicals for which reasonable charge-separated resonance structures can be drawn (Scheme 1). These charge-separated resonance structures contribute only in unsymmetrically disubstituted DPCs containing strong electron-withdrawing and electron-donating groups.

92

HIDEO TOMIOKA

Table 2. Zero-Field Splitting Parameters a for para, para'-Disubstituted Diphenylcarbenes (1) [19]

Substituent X

Y

D(cm-I)

E(crn-I)

H

H

H OMe H CN H NMe 2 H NO 2 CN CN NO 2 NO 2

OMe OMe CN CN NMe 2 NMe 2 NO 2 NO 2 OMe NMe 2 OMe NMe 2

0.4088 0.4043 0.4022 0.3906 0.3879 0.3876 0.3 748 0.3778 0.3773

0.0170 0.0191 0.0189 0.0193 0.0178 0.0168 b 0.0180 c 0.01 73 d 0.01 77 b 0.0172 0.0163 d 0.0172 b 0.0164 b

0.3774 0.3.518 0.3611 0.3351

Notes: aMeasuredin 4 19 methylcyclohexane isopentane 9 matrix unless otherwise noted. bMeasured in tetrahydrofuran matrix. CMeasured in 4 19methylcyclohexane tetrahydrofuran 9 matrix. ~ salt was used.

M e 2 N . ~ ] ~ ~

NO2

Me2

I

0

§

Me2

+

.I

0

Scheme 1.

0

=0

93

Congested Triplet Carbenes 3.2.3 Geometrical Isomerism

Triplet carbenes whose divalent carbon atom is substituted with a n sp 2 hybridized carbon atom may exist in two rotomeric forms which are stable at very low temperatures. In favorable cases, ESR spectra of these carbenes exhibit two sets of triplet signals with sufficiently different ZFS parameters. The magnitude of the ZFS parameters D is largely determined by the spin-spin dipolar interaction of the two electrons at the divalent carbon atom. Accordingly, the fraction of the g spin density located at the carbenic center can be estimated from the D value of the carbene. In spite of the predominance of this one-center interaction, the spin density at atoms several bonds removed from the divalent carbon atom can also have a significant effect on the ZFS parameters. This was first-observed for the pairs of 1- and 2-naphthylcarbenes in 1965 [18], and since then reports of isomerism in triplet carbenes have appeared with increasing frequency, where two sets of triplet signals having similar but non-identical ZFS parameters are observed [21 ]. The spectra are assigned to the two conformations of the carbene in which the a orbital at the divalent carbon and the aromatic moiety are coplanar. When the distribution of the spin in the n orbital is unsymmetric, the dipole spin-spin interaction of the ~ electron with the electron localized in the a orbital is different for the two conformations. Consequently, the ZFS parameters will be different and in cases where the differences are sufficiently large, it is possible to observe the spectra of the two isomers. The assignment of the ZFS parameters to specific conformer is made possible by a point spin model [21], with individual contributions, D i, due to n spin densities, Pi, at the individual carbon atoms, C i, viz.,

where r i is the distance between the divalent carbon, Cdi, and a carbon, C i, bearing = spin density and zi is the z coordinate of C i. As mentioned above, carbenes will have noticeable secondary contributions to ID/hcl due to the nearest carbons with g-electron spin densities. Take 2-naphthylcarbene for instance (Scheme 2). The n-electron density at the 1-position is twice that at the 3-position (03 = 1/2Pl). For

(E)-2-NC

(Z)-2- NC Scheme 2.

94

HIDEO TOMIOKA

the (E)-isomer, C1 lies close to the z axis so that r is approximately parallel to z. Hence, Zl = rl, and D i o~ Pi/-~l~i = Pi

(3)

causing a noticeable negative contribution to ID/hcl. A similar inspection of the (Z)-isomer shows that C3 lies close to the z axis (% = r3), whereas C1 is far from the z axis (z 1 > rl). Therefore, the negative contribution to ID/hcl is smaller. Based on these considerations, the (E)-conformer must have the smaller ID/hcl value (see Table 1).

3.2.4 Effects of Host Matrix The effects of the host matrix on the geometry of a triplet carbene have been studied extensively for 3DPC [ 17,22]. The ZFS parameters obtained in a series of matrices indicate that the magnitudes of D and E show a small dependence on the nature of the host matrix. The ZFS parameters from measurement in single crystals of benzophenone and 1,1-diphenylethene differ appreciably from each other. These observations are interpreted as suggesting a possible difference in the geometry of the diphenylcarbene in these two matrices. However, it is noted that use of the linear diphenylethyne as the matrix results in a set of ZFS parameters having essentially identical values to those in other hosts. Further, the use of other precursors for DPC, such as diazidodiphenylmethane [23] and tetraphenyloxirane [24], have provided essentially the same ZFS parameters in the ESR experiments. Thus the influence of the host is not overwhelming at least for usual triplet carbenes.

4. STRAIN AND STRUCTURE OF TRIPLET CARBENES Bending of the molecule would remove the degeneracy of the p orbitals and convert them to A 1 and B 1 orbitals of the C2v group. Therefore, bent molecules could be singlet states. However, it is not at all obvious that the energy minimum of the triplet state would inevitably have the linear configuration, although such has sometimes been assumed to be the case. Because bending would be accompanied by rehybridization, the relative amounts of s and p character in both the bonding and the nonbonding orbitals would change with consequential changes to the binding energies of both the bonding and the nonbonding electrons. If the levels of the A 1 and B 1 orbitals are close together, relief of electron-electron repulsion might very easily be enough to compensate for the promotion energy required to put one unshared electron in the higher orbital allowing the bent molecule to be a triplet [llc]. In accordance with those theoretical considerations, the ZFS parameters of typical triplet carbenes thus far described suggest that most of these carbenes favor

Congested Triplet Carbenes

95

a bent structure at least in a rigid matrix. This is also true in solution at ambient temperature. In other words, a linear structure is thermodynamically less stable for most triplet carbenes but becomes favored when perturbation is large enough to compensate for the hybridization energy. We will see in this section how the structure of triplet carbenes is perturbed either sterically or electronically.

4.1 Diarylcarbenes INDO calculations on DPC have been carried out [ 11 a] on several geometrical conformations by changing the values of three variable parameters; these are the angle ((x) between the two bonds joining the carbene carbon to the phenyl tings ( C - C - C ) and two angles (01 and 02) each being the dihedral angle between one of the rings and the central plane, i.e. the plane containing (x. The state of 3DPC calculated to be the most stable is a linear triplet ((x = 180 ~ with rings at 90 ~ to each other. However, an energy of <3 kcal/mol, which is smaller than warranted by the accuracy of the calculations, separates it from a continuum of states in which rings can rotate freely and the molecule can bend to almost 145 ~ In accordance with this expectation, electron nuclear double resonance (ENDOR) experiments on 3DPC in single crystals of 1,1-diphenylethene suggest that the molecule is nonlinear with (x of 140-155 ~ and twisted under these conditions [25]. The E/D values determined for 3DPC are essentially similar with those for monophenylcarbene under identical conditions. This implies that the second phenyl ring shows little steric effects on the geometry of carbene even though a decrease in D values suggest a higher degree of spin delocalization within the aromatic system (Table 3) [26-31].

Table 3. Zero-Field Splitting Parameters for Diarylcarbenes Ar-C-Ar' Carbenes Ar

Af

Matrixa

Ph

Ph

(DPC)

1-Np 1-Np

Ph 1-Np

(1-2) (1-3)

2-Np

Ph

(2-2)

2-Np

2-Np

(2-3)

9-An

9-An

(4)

T(K)

D(cm-1) E(cm-1)

MTHF

77 77 77 15 80 77

MTHF

77

DAK

4

0.4055 0.401 0.353 0.3157 0.2609 0.3898 0.4044 0.3832 0.3971 0.113

BP fluorol MTHF MTHF

(E) (Z) (E) (Z)

0.0194 0.0186 0.016 0.0109 0.0051 0.0195 0.0168 0.0182 0.0158 0.0011

E/ D

Ref.

0.0478 0.0464 0.0453 0.0345 0.0195 0.050 0.0415 0.0475 0.0398 0.0097

17 26 27 28 28 29 29 30 30 31

Note: aBP= Benzophenone;fluorol = fluorolube glass; MTHF = 2-methyltetrahydrofuran; DAK = di(9-anthryl)

ketone.

96

HIDEO TOMIOKA

The situation changes slightly when a naphthyl (Np) group is introduced. For phenyl(2-naphthyl)carbenes (2-2), for instance, two rotational isomers are detected and assigned. In the (E)-isomer, EID value is similar with 3pc and 3DPC, again implying similar bond angles. On the other hand, the (Z)-isomer exhibits a slightly smaller EID value. This can be interpreted in terms of a slight difference in the steric interaction between aromatic hydrogens. Thus the interaction of the ortho-hydrogen atom on the phenyl ring with 1-H on the naphthyl ring is slightly more tight than that with 3-H as 1-H is buttressed by the per/-hydrogen atom. Similar trends are noted for the EID value between the two isomers of di(2-naphthyl)carbenes (2-3) [30]. The role of the H - H interaction between the two aryl rings in diarylcarbenes is more clear in 1-naphthyl(aryl)carbenes. Thus, only one set of triplet signals is observed in the EPR spectra of 1-naphthyl(phenyl)- (1-2) [27] and di(1naphthyl)carbenes (1-3) [28]. It may be that the difference in the ZFS parameters between the two rotomers is too small to be resolved by EPR under these conditions. A more likely possibility is ascribable to steric factors. It has been shown by a kinetic analysis that (E)-isomer of 31-NC is probably lower in energy than the (Z)-isomer [32], probably because of the steric interaction of the per/-hydrogen with the carbenic hydrogen. In 1-naphthyl(aryl)carbenes, this hydrogen is replaced with an aromatic ring and hence steric repulsion with the per/-hydrogen in the (Z)-isomer is expected to be much more severe than the H - H interaction in 31-NC. Therefore the energy difference between the two isomers becomes large enough to form the more stable isomer almost exclusively. A more significant decrease in EID is observed for di(1-naphthyl)carbene (1-3) [28]; the EID value is 0.0345 in MTHF at 15 K and is to be compared with the values observed for other naphthylcarbenes. Interestingly, a new set of triplet signal with a smaller EID value ascribable to the linear configuration of 31-3 is observed at the expense of the original peaks when the matrix is annealed to ca. 80 K. This observation is interpreted in terms of steric strain in triplet carbenes [28]. Thus, when the carbene is formed in rigid matrices at low temperatures, it should have the bent geometry dictated (presumably) by that of the precursor, and even if the thermodynamically most stable geometry of the carbene is different from those at the birth, the rigidity of the matrix prevents it from assuming its minimum energy geometry. However, when the matrix is softened on annealing, the carbene relaxes to a structure which is closer to linear as evidenced by the substantial reduction in E. The small reductions in D are also consistent with this picture since they indicate that the unpaired electrons are more efficiently delocalized in the relaxed geometry. Since E values for 3DPC are essentially insensitive to the matrix (suggesting that the carbene has achieved its relaxed geometry regardless of the environment) the observations indicate that the carbene undergoes expansion of the central C - C - C angle to gain relief from steric compression in soft matrices or upon an annealing of harder matrices.

Congested TripletCarbenes

97

Similar dependence of the ZFS parameters on the rigidity of matrices is observed for many other sterically congested triplet carbenes (vide infra) and hence can be considered as an indication of steric strain in triplet carbenes. A further increase in delocalization of the spin density as well as steric hindrance between the two aromatic tings is expected as 1-naphthyl groups are replaced with 9-anthryl groups. Thus, dramatic decrease in the ZFS parameters are observed for di(9-anthryl)carbene (34) [31 ]. When formed in di(9-anthryl) ketone matrices at 4 K, it shows very small values for both D (0.113 cm -1) and E (0.0011 cm-1). Annealing the matrix allows the carbene to adopt its minimum geometry which is completely linear; the value of E has dropped to zero. The observations mean that there is extensive delocalization of the unpaired electrons into the anthryl portions and that the carbene carbon has allenic character. The substituents at either end of the central three-carbon-atom group then lie in perpendicular planes.

4.2 Diphenylcarbenes Bearing ortho Substituents ENDOR studies of 3DPC in matrices have shown that the carbene has a triplet ground state with a central C - C - C angle of 148 ~ and a dihedral angle of 35 ~ between the phenyl rings [25]. Theoretical studies suggest that, even though a linear and perpendicular structure is the most stable, it is separated only by 3 kcal/mol from a continuum of states in which tings can rotate freely and the molecule can bend to almost 145 ~ [lla]. This suggests that the introduction of substituents at ortho positions of 3DPC is expected to exert a significant effect on the stable geometries of the triplet state.

4.2.1 Polymethylated Diphenylcarbenes ESR studies of the triplet states of DPC bearing a series of methyl groups show that increasing ortho substitution leads to an expansion of the C - C - C angle [33]. Thus, as summarized in Table 4, D and E values decrease with increasing steric crowding in the carbenes, i.e. on going from DPC, (2,4,6-trimethylphenyl)phenylcarbene (Sa), (2,4,6-trimethylphenyl)(2-methylphenyl)carbene (Sb) to dimesitylcarbene ($c) and reflect the steric influence of o-methyl groups which force an expansion of the central angle. Although the change in E is relatively small compared to the experimental error, it is accompanied by a clear reduction in D. This indicates that the electrons are becoming more delocalized and is consistent with the concept of angular expansion upon o-methyl substitution. Probably the most striking difference between sterically unperturbed and perturbed DPC is in the temperature dependence of their ESR spectra. The D and E values for Sb, for instance, show a marked and irreversible reduction as the temperature is increased from 4 to ca. 70 K. In the case of 5c, the E value (in crn-1) becomes close to zero. It indicates that, on wanning, the carbene relaxes to a structure with an expanded C - C - C angle.

98

HIDEO TOMIOKA

Table 4. Zero-Field Splitting Parameters a for Polymethylated Diphenylcarbenes

Ar-C-Ar' (5)[33] Carbenes Ar

At

2,4,6-Me3C6H 2 (Sa)

C6H5

2,4,6-Me3C6H 2 (Sb)

2-MeC6H4

2,4,6-Me3C6H 2 (5c)

2,4,6-Me3C6H2

Notes:

T(iO

D(cm- I)

E(cm- 1)

E/ D

4 68

0.3863 0.3856

0.0165 0.0160

0.0427 0.0415

4 68

0.3919 0.3769

0.0150 0.0133

0.0383 0.0354

0.3561 0.3489

0.0125 0.0083

0.0351 0.0240

6b

77c

aMeasuredin MTHF matrix unlessotherwisenoted. bMeasured in isopentane-ethylether matrix. CMeasuredafter annealing.

5a

5b

5c

The D and E values for 5a, on the other hand, show no change with temperature. Therefore, the minimum energy geometry of 5a has a smaller C - C - C angle than that in 5b and 5c and that the matrix provides sufficient space for it to achieve that geometry at all temperatures. A further decrease in EID values is observed when more methyl groups are introduced on the aromatic tings of di(2,6-dimethylphenyl)carbene (Table 5) [34,35]. This can be interpreted as reflecting the difference in the extent of steric

Table S. Zero-Field Splitting Parameters a and Kinetic Data b for Polymethylated Diphenylcarbenes Ar2C: (5) [35]

Carbenes DPC 5c 5d 5e

Ar C6H5 2,4,6-Me3C6H 2

2,3,5,6-Me4C6H Me5C6

O(cm-1)

E(cm-1)

E/ D

ki(s- I)

0.4053 0.3551 0.3805 0.3636

0.0190 0.0116 0.0106 0.0095

0.0469 0.0326 0.0279 0.0260

-1.5 2.2 4.1

Notes'. aMeasuredin MTHF at 77 K. bMeasured in degassedbenzeneat 20 *C.

tl/2(ms] 0.002 160 410 180

Congested Triplet Carbenes

99

crowding around the carbenic centers between those carbenes. It is well known that, in 1,2-disubstituted benzene derivatives, introduction of substituents in the 3-position exerts a very large effect on the rate of appropriate reactions and the data are considered in the light of the importance of bond bending; 3-substituents buttress 2-substituents [36]. Thus, in 5d, each of the four ortho-methyl groups around the carbene center is buttressed by four additional meta-methyl groups. Therefore the carbene center in 5d is surrounded by the ortho-methyl groups much more tightly than in 5c. The ortho-methyl group in 5e is buttressed more effectively since four meta-methyl groups are buttressed by the two para-methyl groups in this case [37]. The chemistry of these carbenes ($c-e) observed in solution at room temperature is also in accord with the interpretation of the EPR results in the matrix at low temperature (Scheme 3). Product analysis studies reveal unusual chemical properties of these carbenes. Most diarylcarbenes generated in a relatively unreactive solvent, e.g. benzene, react with the parent diazo compound to give an azine.

hv = R'

R

~

"

~

R

R' R

R

5

5(N2)

r R=H, R'=Me d: R=Me, R'=H e: R=R'=Me R R' R

R

R'

R

+

R' R

R

R

ye~d (%) 6

7

c

94

6

d

29

41

5

79

9

Scheme 3.

I O0

HIDEO TOMIOKA

solvent, e.g. benzene, react with the parent diazo compound to give an azine. Dimesitylcarbene (5e) generated by irradiation of di(2,4,6-trimethylphenyl)diazomethane 5e(N2) in degassed benzene at 15 ~ affords tetra(aryl)ethylene (6e), as a result of dimerization of the carbene, and benzocyclobutene (Te) formed by attack at an ortho-methyl group [38]. The chemistry found for 5e is therefore in sharp contrast with that found for other diarylcarbenes and reflects its strained structure. Probably dimesitylcarbene (Se) has a geometry that effectively maximizes the triplet-singlet energy gap. The steric interactions of the methyl groups disfavor ring rotation and reduction of the central C - C - C bond angle which, in turn, could provide a pathway for intersystem crossing from the triplet to singlet, thereby preventing the formation of azine. Moreover, other reactions of the carbene require substantial activation energy due to the steric influence of the methyl groups. Consequently a carbene-carbene combination reaction and attack at the orthomethyl groups become significant reaction pathways. Although the same two products are formed in the reaction of 5d and 5e under identical conditions, the product distributions are significantly different. In the case of 5e, for instance, 6e is formed as the main product. Benzocyclobutene formation increases as more methyl groups are introduced and it becomes the major product at the expense of 6 in the reaction of 5e [35]. These observations suggest that, as the ortho-methyl groups are buttressed more effectively, they are brought much closer to the carbene, and hence the carbene is more easily trapped by the methyl groups before it undergoes dimerization. Laser flash photolysis (LFP) [35] studies provide more direct and quantitative support to this interpretation. LFP of 5e(N2) in degassed benzene gives a transient absorption ascribable to triplet carbene 35e at 320 to 330 nm, coincidental with the laser pulse. The decay kinetics of the transient shows that, as the absorption of 35e decays, a new absorption at 370 nm ascribable to orthoquinodimethane (8e) appears, and the decay of 35e is kinetically correlated with the growth of orthoquinodimethane (Scheme 4). From the decay curve, a half-life (tl/2) of 35c is estimated to be approximately 160 ms, which is some 5 orders of magnitude longer lived than parent 3DPC. The study reveals that the carbene center is quite well protected from external reagents by the four ortho-methyl groups and becomes exceptionally long-lived for an arylcarbene. The growth rate (ki) of the orthoquinodimethane is equal to the rate of intramolecular hydrogen abstraction of triplet carbene and is estimated to be 1.5 s-1 under these conditions. Similar measurements done for the carbenes 35d and 35e show that ki increases as more methyl groups are introduced (Table 5). These spectroscopic studies corroborate the trend observed in the product analysis studies (vide supra). Thus, ortho-methyl groups lead 3DPC to have a geometry that effectively maximizes the triplet-singlet energy gap, and hence 3DPC becomes persistent. As more methyl groups are introduced on the aromatic ring, the carbene angle of the 3DPC is widened giving a more favorable geometry that increases AGsT. Thus, didurylcarbene is shown to be longer lived than 2a. However, as the

101

Congested Triplet Carbenes

7

~,

R'

R' R

R

Scheme 4.

methyl groups are brought much closer to the carbenic center by the buttressing methyl groups, the carbenic center comes to interact more easily with the o-methyl groups. Thus, decamethyldiphenylcarbene (5e) comes to be trapped by the o-methyl groups to generate orthoquinodimethane (8e) more efficiently and hence becomes shorter lived again in spite of its more linear geometry. Optimized geometries calculated for a series of polymethylated monophenylcarbenes with PM3-ROHF/CI(4x4) reveal that the distance between the carbenic carbon and the ortho-methyl carbon atom for mesityl-, duryl-, and pentamethylphenylcarbenes decrease from 285 to 278 pm.

4.2.2 Polybrominated Diphenylcarbenes A bromo group is expected to exert more profound effects on the geometry of 3DPC than methyl when introduced at the ortho positions since, while the van der Waals radius of bromine is similar to that of methyl (Br: 195 pm; Me: 200 pm), the C-Br bond length (185 pm) is significantly longer than that of C-CH 3 (150 pm), suggesting that o-bromo groups can interact with each other more effectively [39]. The ZFS parameters obtained for di(2,4-dibromo-6-tert-butylphenyl)carbene (9a) in MTHF at 77 K are IDI = 0.3966 cm -l, IE1 = 0.0311 cm -1 and E/D = 0.0784. Contrary to expectation, this value is significantly larger than that of dimesitylcarbene (5c) (E/D = 0.0326), and even parent 3DPC (E/D = 0.0469). However, the ZFS parameters of this carbene undergo a marked reduction as the temperature of matrix is raised; upon annealing, the x and y lines of the spectrum move closer together, resulting in essentially zero E value. The observation suggests that 39a undergoes substantial geometrical change upon annealing as is observed for many other sterically congested triplet carbenes. A similar reduction in the E value is also observed when the carbene is generated in a "soft" matrix, e.g. 3-methylpentane (Table 6) [40,41]. Despite the rather large E/D value for 39a in a matrix at low temperature, LFP studies in solution at room temperature show that this carbene is fairly stable. The carbene is shown to decay in second-order fashion and the rough lifetime is estimated in the form of its half-life, tu2, to be 16 s [41]. This is approximately 100 times the lifetime of dimesitylcarbene 5c. These observations suggest that 39a also

102

HIDEO TOMIOKA

Table 6. Zero-Field Splitting Parameters a and Kinetic Data b for Polymethylated Diphenylcarbenes Ar2C: (9) [41,42]

Carbenes

Ar

9a

2,6-Br2-4JBuC6H 2

9b

2,3,6-Br3-4-tBuC6 H

D(cm-1)

E(cm-1)

0.3966

0.0311 --.0 0.012

0.4421

0.600

E~ D

tl/2(s)

0.0784 --0c 0.020 c

16 18

Notes. aMeasured in MTHF at 77 K.

bMeasured in degassed benzene at 20 *C. CMeasured in 3-MP at 77 K. Br

Br

X

X g

a:

X=H,

b: X-Br

has a geometry that maximizes AGsT , disfavors a pathway for intersystem crossing for the triplet to singlet, and protects the carbene center quite well from external reagents. Since the buttressing groups are shown to play an important role in the ortho substituent effect on the geometry of polymethylated DPCs (5), similar effects are also expected for polybrominated DPCs. The observations are, however, somewhat contrary to expectation. The ZFS parameters observed in MTHF at 77 K for 39b having two additional bromine groups at the meta positions are similar with those obtained for 39a under identical conditions (Table 6) [42]. In a soft matrix, i.e. 3-MP, where carbenes can relax to a more stable geometry even at 77 K, the E value of 39a is essentially zero, while in 39b it is still significant indicating that 39b is more bent than 39a. This is the exact reverse of that observed with polymethylated DPCs, where E values decrease as more methyl groups are introduced on the aromatic rings. Kinetic measurements in solution at room temperature by using LFP indicate that decay rates of 39b and 39a are essentially the same under the same conditions. The observations suggest that the buttressing effect which exerts significant effect on the geometry and reactivity of polymethylated DPCs shows little influence on those of polybrominated DPCs. Semiempirical calculations provide some clues to the interpretation of these rather puzzling results. The optimized geometry of polybrominated DPCs calculated by PM3-UHF suggests that 39a has an almost linear structure (a = 170.82~ and that the dihedral angle between the two phenyl tings in 39b (0 = 88.94 ~ is smaller than that in 39a (0 = 88.94~ This is in accord with the ESR data.

Congested Triplet Carbenes

103

Interestingly, the distances from the carbene carbon to the two ortho-bromine groups are marginally different; the distance of 322.8 pm to the 2-bromine in 39b (which should be buttressed by the 3-bromine group) is longer than that to the 6-bromine atom (300.7 pm). This latter distance in 39a is 305.7 pm. Therefore the carbenic center in 39b is considered not to be protected so tightly as expected. A closer inspection of the geometry reveals that benzene ring in 39b is distorted, probably due to steric repulsion between the two adjacent bromine groups at 2- and 3-positions, and that the two bromine groups are tilted by ca. 2 ~ one up and one down with respect to the benzene plane. Therefore, the buttressed 2-bromine group is forced to move away from the carbenic center and hence cannot block it from external reagents more effectively than the unbuttressed 6-bromine group. These effects can be ascribed to the differences in shape and size of a methyl and bromine group. The bromine substituent is spherically symmetrical and therefore interacts with another with little directional factor. Thus, the benzene ring is forced to be distorted when two bromine groups are introduced at the adjacent positions. On the other hand, a hydrogen atom bonded to carbon in a methyl group is only conically symmetrical and the interaction potential of this hydrogen atom with another atom will depend on the particular point on the C - H bond that the other atom approaches. Therefore two methyl groups at adjacent positions can be accepted on the benzene ring without causing severe distortion simply by rotating each with respect to the other to minimize the interaction potential. This will result in the restraint of free rotation of the ortho-methyl group and bring it closer and fighter around the carbenic center.

4.2.3 Effects of Other ortho Substituents on the Structure of D iphenylcarbenes Effects of other ortho substituents on the structure and reactivity of diphenylcarbenes are summarized in Table 7. The effect of chlorine groups on the central C - C - C bond angle of 3DPC is smaller compared to that of methyl and bromine groups as judged by larger E/D values observed for the polychlorinated DPCs 10 and 11 [43] as opposed to those for polymethylated 5 and brominated 9 analogues. The observation is in accord with the order of the van der Waals radius of those ortho substituents. The lifetimes of 310 and 311 in solution at room temperature are also significantly smaller than those of 35 and 39 and reflect the sterical crowding around the carbene center [44]. The effect of isopropyl and ten-butyl groups on the structure and reactivity of 3DPCs is intriguing. Thus, the EID values for (2,4,6-tri-isopropylphenyl)phenylcarbene (12) in a "hard" matrix, i.e. MTHF, are significantly smaller than those for (2,4,6-trimethylphenyl)phenylcarbene (see 5a in Table 4, p. 98) and undergo considerable reduction when generated in a "soft" matrix, i.e. 3-MP [45]. These observations suggest that the isopropyl group is large enough to influence signifi-

Table Z

Carbenes

o

Zero-Field Splitting Parameters a and Kinetic Data b for Substituted Diphenylcarbenes Ar-C-Ar"

Ar

At'

10 11 12

2,4,6-C13C6H 2 ClsC 2,4,6-ipr3C6 H

2,4,6-Cl3C6H2 ClsC C6Hs

13

2,4,6JBu3C6H 2

C6Hs

D(cm-1) 0.371 0.409 0.408 0.375 0.341 0.340

Notes: aMeasuredin MTHF at 77 K.

bMeasured in degassedbenzene at 20 ~ CMeasuredin 3-MP at 77 K. CI

CI

R

R

R

10: R=H

12: R=ipr

11: R=CI

13: R=tBu

E(cm-1) 0.0133 0.0140 0.0150 0.0094 ---0 --0

E/ D 0.0353 0.0341 0.0367 0.0249 c -0 -0 c

t l/2@)(ms)

Ref.

18 24 (0.13)

43,44 43,44 45

(0.12)

35,46

Congested Triplet Carbenes

105

cantly the central bond angle even if introduced only on to only one of the two phenyl groups. The E value for (2,4,6-tri-tert-butylphenyl)phenylcarbene (313) is essentially zero not only in MTHF but also in 3-MP at 77 K [46]. The result can be interpreted as indicating that the geometry of the diazo precursor is already fairly linear due to the steric hindrance of tert-butyl groups. However, it is less likely that the precursor with linear diazo carbon can exist as a stable molecule. An alternative explanation then is that the steric compression of 313 is so large that it undergoes expansion of the angle even in rigid matrix at low temperature. It is also possible that the bulk of the tert-butyl group provides space for 313 to achieve the stable geometry more easily even in rigid matrix. Although 313 is shown to have the thermodynamically most favorable structure for a triplet, its stability is disappointingly low. The lifetime of 313 in solution at room temperature is 3 and 5 orders of magnitude shorter than 35c and 39a, respectively [35,47]. This is ascribable to the kinetic instability of 313. Due to the voracious appetite of carbenes for electrons, they can react even with very poor sources of electrons such as C - H bonds. Thus, the major product from 313 is 4,6-di-tert-butyl-l,l-dimethyl-3-phenylindan (14) formed as a result of intramolecular hydrogen abstraction of the carbene from the C - H bonds of an orthoten-butyl group (Scheme 5). It is interesting to note that the lifetime in solution is not decreased at all when ortho-tert-butyl groups are replaced with an isopropyl group, even though a rather significant increase in E/D is noted in the matrix [45]. This can be interpreted in terms of the balance between thermodynamic and kinetic stability. The larger E/D values for 312 as opposed to 313 suggest that the two methyl groups of the isopropyl functions in 312 are directing opposite to the carbenic carbon probably to avoid steric interaction. In solution, the methyl group can rotate but this conformation is expected to be more stable than the others where the methyl group is directing toward the carbene center. Product analysis supports the idea. Thus not only 4,6-di-isopropyl-l-methyl-3-phenylindan (15), formed as a result of hydrogen abstraction from the methyl group, but also (4,6-di-isopropyl-2-isopropenylphenyl)-phenylmethane (16), obviously formed by hydrogen abstraction from the methine followed by H migration, is produced in the reaction of 312 (Scheme 6).

hv

. N2-~ Ph

13

Scheme 5.

14

106

HIDEO TOMIOKA

hv -N212

Ph 15

16 Scheme 6.

Thus the proximity and probability of active hydrogen atoms of ortho-alkyl groups in 312 are significantly smaller than those in 313 and hence 312 is less prone to trapping by ortho-alkyl groups. The methyl groups of an isopropyl function are thus protecting the carbenic center from external reagents.

4.3 Effect of Triptycyl Group We saw above that diarylcarbenes undergo the expansion of a central C - C - C bond angle as a result of steric interaction between the substituents on the aromatic ring. Thus the decrease in E value is accompanied by a clear reduction in D, suggesting that the electrons are becoming more delocalized as angular expansion proceeds. One may expect that the delocalization of the electron significantly stabilizes triplet carbenes as, for instance, in the case of radicals. In order to understand how the structure and reactivity of triplet carbenes are affected by steric and electronic effects, the relationship between structures and reactivities of triplet arylcarbenes has been investigated systematically for a series of 9-triptycyl(aryl)earbenes. Here the triptycyl (Trp) group is expected to cause a steric effect while the aryl groups, ranging from phenyl to 9-anthryl, will stabilize the triplet carbene by accepting the unpaired electrons. The results are summarized in Table 8 [48,49]. Comparison of ZFS parameters for triptycyl(phenyl)carbene (17a) with phenylcarbene (PC in Table 1, p. 91) reveals the very small difference in D values between the two. This is not surprising as little 7t interaction between the unpaired electrons

Congested Triplet Carbenes

107

Table 8. Zero-Field Splitting Parametersa and Kinetic Data b for Triptycyl(aryl)carbenes Trp-~-Ar 17 [48,49] Carbenes

Ar

17a 17b

Ph 1-Np

17C

2-Np (E)

(Z) 17d

9-An

D(cm-I)

E(cm-I)

E/ D

tl/2(x)(ms)

0.510 0.455 0.475 0.491 0.348

0.0288 0.0237

0.0564 0.0522

0.84 21

0.0289

0.0608

0.0258 0.0075

0.0524 0.0215

1.1

0.28

Notes: aMeasured in MTHF at 77 K.

bMeasured in degassed benzene at 20 *C.

o

r

a: Ar=Ph b: Ar=l-Naphthyl c: Ar=2-Naphthyl d: Ar=9-Anthryl

17

and the benzenoid rings of the triptycyl group is expected. A slight increase in E values on going from PC to 17a is rather unexpected, but is interpreted as indicating that steric interaction between Ph and Trp groups in 17a is negligible as the three phenyl rings on the tertiary carbon atom in the Trp are held back tightly, allowing little interference with the phenyl ring on the carbenic carbon. It is interesting to note that a more significant decrease both in D and E values is observed on going from PC to DPC than to 17a. The observation suggests that delocalization of the spin plays a more important role in changing the structure of the triplet carbene than the steric interaction. Similar changes in ZFS parameters are observed for naphthylcarbene (NC) systems. Again very small changes in the D values and slight increase in the E values are noted as one changes the substituent from H to Trp, not only in the 2- but also in the 1-NC systems. The observation suggests that the 1-naphthyl group in 17b is located in the cavity of the triptycene moiety in order to avoid an interaction between the per/-hydrogen atoms, although the per/-hydrogen on the 1-naphthyl group potentially can interact with those on the Trp group. The EPR spectrum of triptycyl(2-naphthyl)carbene (17c) consists of two sets of triplet peaks and is assignable to (Z)- and (E)-rotomers, while only one set of triplet signals is observed in the EPR spectra of the corresponding 1-isomer (17b) under the same conditions. It may be that the difference in ZFS parameters between the two rotomers is too small to be resolved by EPR.

108

HIDEO TOMIOKA

The more likely explanation is ascribable to steric factors. It has been shown by a kinetic analysis that the (Z)-isomer of 1-NC is probably higher in energy than the (E)-isomer probably because of steric interaction between the peri-hydrogen and the hydrogen on the carbene carbon [32]. In 17b, this hydrogen is replaced with the bridgehead tertiary carbon and hence steric repulsion with the peri-hydrogen in the (Z)-isomer is expected to be much more severe than the H - H interaction in (Z)-1-NC. Therefore the energy difference between the two isomers becomes large enough to form the more stable isomer almost exclusively. When the Trp group is replaced to Ph and Np, i.e. on going from 17b to 1-2 and 1-3, and 17e to 2-2 and 2-3, respectively, significant decreases both in the D and E values are again observed obviously due to extended r~ delocalization. The effects of the Trp group on 9-anthrylcarbene are somewhat different from those observed with the former two carbenes. The most notable change in this case is a rather significant decrease in the E value. This can be interpreted in terms of a steric interaction between the peri-hydrogen and bridgehead carbon, as advanced above. The anthryl group has per/-hydrogens both at the 1- and 8-positions and therefore cannot avoid steric interaction with the bridgehead carbon. Although triptycyl(9-anthryl)carbene (17d) exhibits the smallest E/D values among the triplet triptycyl(aryl)carbenes studied, a much more significant reduction in the ZFS parameters is observed for di(9-anthryl)carbene 4 which is suggested to have an almost completely linear and perpendicular geometry in which extensive delocalization of the unpaired electrons into the anthryl positions is proposed (vide supra). Since the anthryl group is planar and considerably less bulky than the triptycyl group, the fact that 4 has a more linear and perpendicular structure than 17d clearly suggests that n delocalization of the unpaired electrons plays a more dominant role in determining the structures of triplet carbenes than does steric effects. Kinetic data in solution at room temperature reveals an interesting aspect of the relationship between structures and reactivities of triplet carbenes [48]. The lifetime of triptycyl(phenyl)carbene (317a), for instance, is some 3 to 4 orders of magnitude greater than that of "parent" phenylcarbene (PC, x - 200 ns). This stabilization by a Trp group originates mostly from kinetic factors since no significant change in the structure of triplet carbene is observed at least in matrix at low temperature (vide supra). It is interesting to note that 317a is approximately 103 times longer-lived than 3DPC which must undergo significant thermodynamic stabilization as judged by the considerable decrease in the ZFS parameters. These results indicate that kinetic stabilization plays a dominant role in stabilizing triplet carbenes. Similar trends are observed for the naphthylcarbene systems. Triptycyl(1naphthyl)carbene (317b), for instance, has a lifetime of 21 ms, which is 105 times longer lived than the parent 1-NC, and 103 times longer lived even than di(1naphthyl)carbene (31-3) which must undergo significant thermodynamic stabilization from the two naphthyl groups in addition to kinetic stabilization resulting from steric repulsion between the two per/-hydrogen atoms. These observations again

Congested TripletCarbenes

109

support the idea that kinetic stabilization plays a much more important role than thermodynamic factors in increasing the lifetime of triplet carbenes. 9-Anthrylcarbene is considered to be the most stable among the mono-arylcarbenes studied since the carbene center is shielded by the two peri-hydrogen atoms and the unpaired electrons are extensively delocalized into the anthryl ring, and hence it is expected to be protected quite well once a Trp is introduced on the 9-position. ZFS parameters in the matrix support these ideas. Contrary to this expectation, the lifetime of 317d is found to be shorter than most of its naphthyl analogues (317b and 317c), and even shorter than phenyl derivative 317a. A possible explanation for this rather unexpected decrease in lifetime resides in an extensive delocalization of the unpaired electrons into anthryl ring. Since the carbenic center in 317d is effectively shielded from external reagents, by the two and three peri-h'y&ogens on the aromatic and triptycyl rings, respectively, simple reaction at the carbenic center must suffer from severe steric hindrance. The carbene is then forced to react at the aromatic tings where the unpaired electrons are delocalized. Such reactions are expected to become more facile as the number of fused aromatic tings is increased; the loss of the resonance energy as a result of such reaction on the first aromatic ring is estimated to decrease from 36 to 25 to 11 kcal/mol on going from benzene to naphthalene to anthracene. While the carbene center is shielded more effectively on going from 317a to 317d, the extent of rc delocalization of the unpaired electrons and the facility of the reaction at the aromatic sites are increased in the same order. The steric and electronic factors are operating in opposite directions.

5. CONCLUSION AND PERSPECTIVES In the present review, we have shown how triplet arylcarbenes undergo changes in their molecular and electronic structures by electronic and steric perturbations. It has been shown that electronic effects, i.e. n delocalization of the unpaired electrons, show a dominant role in changing electronic structure as judged by a large reduction in the D values for many arylcarbenes as opposed to those for alkylcarbenes. Steric effects, i.e. steric hinderance between the substituents around carbene centers, exhibit crucial role in expanding the central C - C - C bond angle especially for triplet carbenes in which n delocalization is less extended. Interestingly, sterically perturbed triplet carbenes undergo further expansion of the central bond angle as matrices become soft. This is considered to be an indication of steric strain in these triplet carbenes. The expansion of the central bond angle is usually accompanied by n delocalization of the unpaired electrons as evidenced by concomitant decrease in the D values. It is obvious that this increase in the extent of ~ delocalization assists the geometrical change upon softening the matrix since such expansion of this magnitude has not been observed for a sterically crowded dialkylcarbene.

110

HIDEO TOMIOKA

hydrogens makes the carbenes adopt less bent and more perpendicular geometries, which are favored by extensive n delocalization of the unpaired electrons. Both steric and electronic effects operate in the same directions. An almost completely linear and perpendicular structure, which was once believed to be most probable structure of a triplet carbene, is seen in di(9-anthryl)carbene 4. An examination of the relationship between the structure and stability of a triplet carbene reveals the complicated nature of this exotic species. The g delocalization is an important factor in stabilizing a triplet carbene, as judged by the increased lifetime on going from phenylcarbene (0.2 gs) to diphenylcarbene (2 Its). However, as the extent of g delocalization increases, the reaction sites of the triplet carbene spread over the molecule and eventually the carbene becomes more reactive. For instance, di(9-anthryl)carbene decays faster than monophenylcarbene. Steric factors play a more dominant role in increasing the lifetime of triplet carbenes. This is clearly demonstrated by systematic studies of a series of diphenylcarbenes bearing a various ortho substituents as a steric protector. The ZFS parameters of these carbenes suggest that they do not have completely linear and perpendicular structure, which is supposed to be the ideal geometry for the thermodynamically most stable triplet species. Nevertheless, the kinetic study indicates that these carbenes survive several orders of magnitude longer than "parent" diphenylcarbene. These considerations provide a guiding principle to construct stable triplet carbenes. A diarylcarbene with a moderate extension of g delocalization is desired as a prototype system. Kinetic protectors should be bulky since the carbene carbon has only two modifiable groups in which steric groups can be introduced. More importantly, they should be unreactive toward triplet the carbene center since its intrinsic reactivity is not suppressed to such an extent that the carbene center becomes essentially unreactive to, for instance, C - H bonds.

ACKNOWLEDGMENTS Many thanks go to Dr. Katsuyuki Hirai for his very careful spectroscopic measurements, Professors Shigeru Murata, Takeji Takui, and Koichi Itoh for their enlightening discussions, and to my students named in the references and those currently in my group for their time-consuming and painstaking efforts. I also appreciate the support of the Ministry of Education, Science and Culture, Japan Nagase Science and Technology Foundation, and Mitsubishi Foundation for this research.

REFERENCES AND NOTES [1] (a) ltoh, K., Chem. Phys. Lett., 1 (1967) 235; (b) Wasserman, E., Murray, R. W., Yager, W. A., Trozzolo, A. M., and Smolinski,G., J. Am. Chem. Soc., 89 (1967) 5076. [2] lwamura,H., Adv. Phys. Org. Chem., 26 (1990) 179. [3] Mataga,N., Theor. Chim. Acta, 10 (1968) 372.

Congested Triplet Carbenes

111

[31 Mataga, N., Theor. Chim. Acta, 10 (1968) 372. [4] Matsuda, K., Nakamura, N., Inoue, K., Koga, N., and Iwamura, H., Bull. Chem. Soc. Jpn., 68 (1996) 1483, and references cited therein. [51 The lifetime of triplet diphenylcarhene is estimated to be only 2 gs in solution at room temperature: Hadel, L. M., Maloney, V. M., Platz, M. S., McGimpsey, W. G., and Scaino, J. C., J. Phys. Chem., 90 (1986) 2488. [61 For reviews of persistent triplet carbenes, see (a) Tomioka, H., Ace. Chem. Res., 30 (1997) 315; (b) Tomioka, H., In Brinker, U. (Ed.),Advances in Carbene Chemistry, Vol. 2, JAI Press: Stamford, 1998, p. 175-214. [7] Tomioka, H., Hattori, M., Hirai, K., Sato, K., Shiomi, D., Takui, T., and Itoh, K., J. Am. Chem. Soc., 120(1998) 1106. [8] For review of the EPR spectra of triplet carbenes, see: Sander, W., Bucher, G., and Wierlacher, S., Chem. Rev., 93 (1993) 1583. [9] For reviews of carbene chemistry, see (a) Regitz, M. (Ed.), Carbene (oide), Carbine (Huben-Weyl), Vol. E196, Thieme: Stuttgart, 1989; (b) Wentrup, C., Reactive Molecules, Wiley: New York, 1984, Ch. 4; (c) Moss, R. A. and Jones, M., Jr. (Eds.), Carbenes, Vols. I and II, Wiley: New York, 1973, 1975; (d) Kirmse, W., Carbene Chemistry, 2nd edn., Academic Press: New York, 1971. [10] For discussion of substituent effect on AGsT, see: Schuster, G. B., Adv. Phys. Org. Chem., 22 (1986)311. [111 (a) Metcalfe, J. and Halevi, E. A., J. Chem. Soc., Perkin Trans. 2, (1997) 364; (b) Hoffman, R., Zeiss, G. D., and VanDine, G. W., J. Am. Chem. Sot., 90 (1968) 1485; (c) Walsh, A. D., J. Chem. Sot., (1953) 2260. [12] Reisenauer, H. P., Maier, G., Riemann, A., and Hoffmann, R. W., Angew. Chem., Int. Ed. Engl., 23 (1984) 641. [13] Myers, D. R., Senthilnathan, V. P., Platz, M. S., and Jones, M., Jr., J. Am. Chem. Soc., 108 (1986) 4232. [14] For more detail description of EPR, see: Carrington, A. and McLachlan, A. D., Introduction to Magnetic Resonance, Harper International: New York, 1967; Wertz, J. E. and BoRon, J. R., Electron Spin Resonance, McGraw-Hill: New York, 1972. [15] Wasserman, E., Snyder, L. C., and Yager, W. A., J. Chem. Phys., 41 (1964) 1763; Wasserman, E., Prog. Phys. Org. Chem., 8 (1971) 319. [16] (a) Bernheim, R. A., Bernard, H. W., Wang, P. S., Wood, L. S., and Skell, P. S., J. Chem. Phys., 53 (1970) 1280; (b) Wasserman, E., Yager, W. A., and Kuck, V., Chem. Phys. Lett., 7 (1970) 409. [17] Wasserman, E., Trozzolo, A. M., and Yager, W. A., J. Chem. Phys., 40 (1964) 2408. [18] Trozzolo, A. M., Wasserman, E., and Yager, W., J. Am. Chem. Soc., 87 (1965) 129. [19] Humphreys, R. W. R. and Arnold, D. R., Can. J. Chem., 57 (1979) 2652; Arnold, D. R. and Humphreys, W. R., J. Chem. Soc., Chem. Commun., (1978) 181. [20] Baldock, R. W., Hudson, P., and Katritzky, A. R., J. Chem. Sot., Perkin Trans. 1, (1974) 1422; Katrizloj, A. R., ibid., (1974) 1427. [21] (a) Hutton, R. S., Manion, M. L., Roth, H. D., and Wasserman, E., J. Am. Chem. Sot., 96 (1974) 4680; (b) HuRon, R. S. and Roth, H. D., ibid., 100 (1978) 4324; (c) Hutton, R. S. and Roth, H. D., ibid., 104 (1982) 7395; (d) Roth, H. D. and Hutton, R. S., Tetrahedron, 41 (1982) 1564. [22] Hutchinson, C. A., Jr., J. Phys. Chem., 71 (1967) 203. [23] Barash, L., Wasserman, E., and Yager, W. A., J. Am. Chem. Sot., 89 (1967) 3931. [24] Trozzolo, A. M., Yager, W. A., Griffin, G. W., Kristinsson, H., and Sarkar, I., J. Am. Chem. Soc., 89 (1967) 3357. [25] Hutchinson, C. A., Jr. and Kohler, B. E., J. Chem. Phys., 51 (1969) 3327. [26] Trozzolo, A. M., Murray, R. W., and Wasserman, E., J. Am. Chem. Sot., 84 (1962) 4990. [27] Fujiwara, Y., Sakaki, M., Tanimoto, Y., and Itoh, M., Chem. Phys. Lett., 146 (1988) 133. [281 Tukada, H., Sugawara, T., Murata, S., and lwamura, H., Tetrahedron Lett., 27 (1986) 235.

112

HIDEO TOMIOKA

[29] (a) Maloney, V. and Platz, M. S., J. Phys. Org. Chem., 3 (1990) 135; (b) Roth, H. D. and Platz, M. S., ibid., 9 (1996) 252. [30] Tomioka, H., Koshiyama, K., and Hirai, K., to be published. [31] (a) Wasserman, E., Kuck, V. J., Yager, W. A., Hutton, R. S., Greene, E D., Abegg, V. P., and Weinshenker, N. M., J. Am. Chem. Soc., 93 (1971) 6335; (b) Astles, D. J., Girard, M., Griller, D., Kolt, R. J., and Wayner, D. D. M., J. Org. Chem., 53 (1988) 6053. [32] Senthilnathan, V. P. and Platz, M. S., J. Am. Chem. Soc., 103 (1981) 5503. [33] Gilbert, B. C., Griller, D., and Narzan, A. S., J. Org. Chem., 50 (1985) 4738. [34] Tomioka, H., Okada, H., Watanabe, T., and Hirai, K., Angew. Chem., Int. Ed. Engl., 33 (1994) 873. [35] Tomioka, H., Okada, H., Watanabe, T., Banno, K., Komatsu, K., and Hirai, K., J. Am. Chem. Soc., 119 (1997) 1582. [36] Westheimer, E H., In Newman, M. S. (Ed.), Steric Effects in Organic Chemistry,Wiley: New York, 1956, pp. 523-555. [37] For buttressing effect in carbene chemistry, see: Tomioka, H., Kimoto, K., Murata, H., and Izawa, Y., J. Chem. Sot., Perkin Trans. 1, (1991) 471. [38] Zimmerman, H. E. and Paskovich, D. H., J. Am. Chem. Soc., 86 (1964) 2149. [39] Gordon, A. J. and Ford, R. A., The Chemist's Companion, Wiley: New York, 1972. [40] Tomioka, H., Watanabe, T., Hirai, K., Furukawa, K., Takui, T., and Itoh, K., J. Am. Chem. Soc., 117 (1995) 6376. [41] Tomioka, H., Hattori, M., Hirai, K., and Murata, S., J. Am. Chem. Soc., 118 (1996) 8723. [42] Tomioka, H., Watanabe, T., Hattori, M., Nomura, N., and Hirai, K., to be published. [43] Tomioka, H., Maemura, T., and Hirai, K., to be published. [44] Tomioka, H., Hirai, K., and Nakayama, T., J. Am. Chem. Sot., 115 (1993) 1295. [45] Tomioka, H., Yasuda, K., and Hirai, K., to be published. [46] Tomioka, H., Ishikawa, Y., and Hirai, K., to be published. [47] Tomioka, H. and Hirai, K., Chem. Lea., (1994) 503. [48] Tomioka, H., Nakajima, J., Mizuno, H., Sone, T., and Hirai, K., J. Am. Chem. Sot., 117 (1995) 11355. [49] Tomioka, H., Nakajima, J., Mizuno, H., Iiba, E., and Hirai, K., Can. J. Chem., 77 (1999) 1066.

SYNTHESIS AND CHEMISTRY OF STRAI N ED CARBOHYDRATES: OXABICYCLO[4.1.0]H EPTANES

Ghislaine S. Cousins and John O. Hoberg

1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Carbohydrate Cyclopropanes . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Formation of Cyclopropanated Carbohydrates . . . . . . . . . . . . . . 2.2 Chemistry of Cyclopropanated Carbohydrates . . . . . . . . . . . . . . Carbohydrate Oxiranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Epoxidations of Carbohydrates . . . . . . . . . . . . . . . . . . . . . . 3.2 Chemistry of Carbohydrate Oxiranes . . . . . . . . . . . . . . . . . . . Carbohydrate Aziridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Aziridination of Carbohydrates . . . . . . . . . . . . . . . . . . . . . . 4.2 Chemistry of Carbohydrate Aziridines . . . . . . . . . . . . . . . . . . Carbohydrate Thiiranes (Episulfides) . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Advances in Strained and Interesting Organic Molecules Volume 8, pages 113-143. Copyright 9 2000 by JAI Press Inc. All fights of reproduction In any form reserved. ISBN: 1-7623-0631-9

113

114 115 115 122 130 130 132 137 137 137 138 140

114

GHISLAINE S. COUSINS and JOHN O. HOBERG

1. INTRODUCTION The present chapter presents an overview of the effects of combining carbohydrates with strained systems. The use of strained systems fused into a carbohydrate provides for an interesting mix of highly reactive systems with the optical activity inherent in carbohydrates. Thus, one may envisage the use of the chemistry normally associated with strained rings in conjunction with enantiopure building blocks. This combination has started to generate much interest as an increasing number of reports on "strained" carbohydrates have appeared in the synthesis of bioactive compounds and the development of new synthetic methods. The inherent optical activity in carbohydrates allows for asymmetric synthesis without the need for expensive chiral reagents, chiral catalysts, or wasteful separation techniques. Furthermore, unlike traditional chemicals that are petroleum-derived, carbohydrates are a natural and renewable resource making them an environmentally attractive alternative for use in synthesis. Traditionally carbohydrates have been considered difficult to work with as a number of protection and deprotection reactions can be necessary to effect a given transformation. This is perhaps due to the fact that each hydroxyl group represents a unique chemical environment. Carbohydrates with a fused three-membered ring, however, usually start with two less of these hydroxyl groups thereby making the use of the carbohydrate very facile. Although the need for protection is still somewhat true, new methods, reagents, and the commercial availability of unsaturated carbohydrates (glycals) have allowed for convenient use of the carbohydrates as discussed below. As an example, Danishefsky has used a cyclopropanated pseudo-carbohydrate in the synthesis of the brystatin (1) as shown in Figure 1. Finally, while a full coverage of the material cannot be undertaken, it is hoped that the reader will gain considerable understanding of various methods used to form the bicyclic carbohydrate and the current state of its subsequent transformations. The outline which follows presents the synthesis of the strained carbohydrate and this is followed by its chemistry and any other interesting properties. We have

BnO,...~

BnO..~9 i

OH

,,,,'_.v..~~Me OH

Figure1.

H- g~oHO" 1

Strained Carbohydrates

115

chosen to start with the synthesis and chemistry of carbohydrate-fused cyclopropanes and follow this with oxiranes, aziridenes, and finally episulfides (thiiranes).

2. CARBOHYDRATE CYCLOPROPANES 2.1 Formation of Cyclopropanated Carbohydrates Several classical methods are normally used in the formation of cyclopropanated carbohydrates. Due to the accessibility of 1,2-unsaturated carbohydrates (glycals) these substrates are generally used for reaction with carbenes. The three commonly used methods for the cyclopropanation of such substrates are the Simmons-Smith reaction, transition metal-catalyzed decomposition of diazo compounds, and cyclopropanation using dihalocarbenes. In this section each 'of these areas is reviewed and some other novel cyclopropanation reactions are also included.

2.1.1 The Simmons-Smith Reaction The Simmons-Smith reaction is an effective means for converting alkenes into cyclopropanes by use of diiodomethane and a zinc/copper couple. This is believed to transfer the methylene group from the organometallic reagent and it can do so in a stereospecific manner with allylic alcohols [ 1]. The cyclopropanation (Scheme 1) is directed to a specific face through complexation of the zinc atom and it has been shown to produce cyclopropanes with diastereoselectivities as high as 300:1 or better. An alternative reagent is the Furukawa modification, which uses a diethylzinc reagent instead of the metallic couple. This modification is used extensively with carbohydrates, as it is more reproducible and especially convenient. At present a wide variety of protected glycals have been cyclopropanated using this strategy as shown in Scheme 2 and excellent yields and selectivities have been reported. The efficiency of the Furukawa modification on glycals has been demonstrated with the formation of cyclopropanes 2, where yields of up to 96% and diastereoselectivities of >250:1 are obtained [2]. As expected the syn'diastereomer, in which the cyclopropane ring is syn to the OR 3 group, is formed. Cyclopropanation of the tri-tert-butyldimethylsilylglycal failed presumably because of the increased size of the tert-butyldimethylsilyl group. Alternatively, the classic

RO'" "~

+

H'C~I

RO~',~

OR

RO" "~ OR

Scheme 1.

116

GHISLAINE S. COUSINS and JOHN O. HOBERG R~

CH212 R

Et2Zn OR 3

~ RO" y OR

2 R1 = R2 = R3 = Bn R I = R 2 = R 3= Me R1 = TBS, R2 = R3 = H

..

AcO" y OAc 3

R1 R2 =CMe2, R3 = H R I=R2=SitBu2, R3 =H R1 = R2 - R3 = TBS

Scheme 2.

Simmons-Smith reaction with only a slight modification can be used. Nagarajan and co-workers used acetyl chloride as an activator for several benzylated glycal systems. With this modification, they reported yields of a single cyclopropyl adduct greater than 80% [3]. An unexpected result for the triacetyl-protected glycal was reported by Lorica and this produces 3 as the major product in 38% yield [4]. The authors attribute the stereoselectivity to steric hindrance of the upper face by the acetate groups. Thus it appears that an appropriate protecting group is critical for a stereodirected cyclopropanation. The effectiveness of the directed cyclopropanation with carbohydrates can further be seen with the glycals of Scheme 3. Synthesis ofcyclopropane 4 was achieved stereospecifically in 93% yield [5] while the formation of 5 (R3 = H) produced an equal mixture ofdiastereomeric cyclopropanes [6]. Additionally, a method has been reported which alleviates the problem associated with acetate protecting groups [2]. Thus cyclopropanation of the diol depicted in Scheme 3 (R 1 = Me; R 2 = R 3 = OH) with Et2Zn/CH2I2 followed by quenching in situ with Ac20 provides the diacetylprotected 6 in 85% yield and 8:1 selectivity; in situ protection is required for isolation as the diol is water soluble and is lost upon aqueous workup. Cyclopropanation of 2,3- and 4,5-unsaturated carbohydrates has also been reported and is shown in Scheme 4. Fraser-Reid and co-workers devised a strategy for the formation of either isomer from a 2,3-unsaturated carbohydrate using the classic Simmons-Smith Zn/Cu couple [7]. In the formation of 7a with the cyclopropane anti to the ethoxy group, the hydroxy group at C4 was oxidized with manganese dioxide prior to cyclopropanation; yields ranged from 22 to 93%. Formation of 7b involved initial formation of the cyclopropane, presumably directed by the C4 hydroxy group and then oxidation with ruthenium oxide. Overall yields for these two steps in this strategy ranged from 45 to 80%. One example of the cyclopropanation of a 4,5-glycal has been reported [8]. Synthesis of 8 was performed by the Furukawa modification that provided a mixture of diastereoisomers in a combined yield of 74%. In an attempt to improve the diastereoselectivity of the reaction, the system was modified by switching from the diacetate protecting groups to the acetinide. Cyclopropane 9 was then formed as

Strained Carbohydrates

BnO~.

117

MOMO.,.~ | ,~r, , . . ~ . O . ~ ' , ~ ~ . ~ OTBDS " ~ OTBS

ii::( 6H

ii

II::` 6Ac

Scheme3. the exclusive isomer, presumably by complexation of the zinc to the acetinide oxygen.

RO~.,,OEt ~ 7a

RO~ '~ ,/.,,OEt OH ,O .

~ Ro~ ' Ov]."',O ~Eto"

R = CPh3 or H

7b

OH

OTBS

Ac OAc

~ R = Ac

"OR

OR

R = CMe2

8

O-~ 9

Scheme4. 2.1.2 Cyclopropanation Using Diazo Compounds Cyclopropanated sugars formed from the reaction of glycals with diazo compounds are not as common as those from the Simmons-Smith reaction, perhaps due to the hazards associated with diazo compounds. This reaction occurs by the metal-catalyzed decomposition of the diazo compound to nitrogen and a carbene which adds to the alkene forming the cyclopropane. The initial example of diazocyclopropanation of a sugar used triacetylglucal (triacetylglucose) but a low yield of cyclopropane 10 (Scheme 5) was obtained and no stereochemistry was reported [9]. Recent studies have improved upon this reaction and high diastereoselectivities and yields have been reported. The improve-

118

GHISLAINE S. COUSINS and JOHN O. HOBERG

AcO~.. O'~CO2Et

AcO" y

OAc

H

..0~._ol "H

10

EDA

Cu

I

I

R,O" "I ~

OR3

13

BnO~co2Et BnO

0 H R 1 0 ~ . . . I ' J " ~ CO2Et

Rh2(OAc), R20"" " ~ ~H OR3 11 R1 = R2 = R3 =TBS RI=R2=R3 =TIPS RI=R2 R3 =Bn R1 = R2 = R3 = Ac RI=TBS, R2=R3=Ac R1 = TBS, R2 = R3 = H

H 12

Scheme 5.

ment in selectivities have been attained through the use of sterically bulky protecting groups to block one face of the molecule and this enables diazo cycloadditions to give good-to-excellent selectivities. For example, increasing the steric size at R 3 from an acetate to a tert-butyldimethylsilyl group gave increased selectivity in the formation of 11 (Scheme 5) [10]. In these reactions, the addition of ethyl diazoacetate (EDA) to a solution of the glycal and 1 mol% of a metal catalyst produced yields of up to 89% and diastereoselectivities as high as 45:1:1:1. The highest conversions were obtained with rhodium acetate as the catalyst. Again use of the appropriate protecting groups is crucial as the use of R 3 = H fails to cyclopropanate. Similar results were attained by van Boom and co-workers in which a variety of pyranose and furanose ring systems 12 as well as disaccharides were cyclopropanated [11]. Copper powder has been used as an alternative in the cyclopropanation reaction. In these investigations, Henry and Fraser-Reid found that the use of EDA, 5 equiv of copper and methyl butyl ether as a solvent led to 13 in 90% yield with a diastereomeric excess of 3.3 : 1 [12]. Low yields of the cyclopropane were obtained when the tert-butyldimethylsilyl protecting group was replaced with benzyl or acetate groups.

2.1.3 Cyclopropanation Using Dihalocarbenes Another alternative to the Simmons-Smith reaction for cyclopropanation is the addition of a dihalocarbene to the glycal. Like the diazo cyclopropanation, this

Strained Carbohydrates

119

reaction is sterically directed and is traditionally carded out in chloroform and the presence of a strong base. The resulting dichlorocyclopropane (Scheme 6) can be isolated or reduced with lithium aluminum hydride to form the non-halogenated cyclopropane. Thus, using this strategy one may obtain the cyclopropane with an unsubstituted methylene center with stereochemistry opposite to that of the Simmons-Smith cyclopropanation. Additionally, an important factor in these cyclopropanations is the use of a phase-transfer catalyst, such as cetyltrimethylammonium chloride, which enables the process to be a viable synthetic route. If the cyclopropanation is performed without the use of the catalyst, dramatic decreases in yields are normally observed. The initial use of this strategy was reported by Brimacombe and co-workers using a trimethyl-protected glycal (Scheme 7) [13]. A single isomer of dichlorocyclopropane 14a was obtained in 82% yield and reductive dechlorination by lithium aluminum hydride provided 14b in 59%. This methodology was extended also to a furanose example. Weber and Hall also used this strategy to produce cyclopropane 15 in 69% yield with only one stereoisomer being formed [ 14]. The formation of a single isomer seems to be unique to the 2-methoxy-2-methyl-substituted pyran o BnO'~U"~

LiAIH4 _

:CCI2

BnO,,,',~H OBn

BnO,,"'~H "Cl OBn

OBn

Scheme 6. R=Me R = Bn

RO~T"~O"~ .. ..,CI

RO""L',~"':'(<'CI " RO~"" RO""~ O~:(' OR

OR

14a

14b

1

i: oi i /

MeO. 0

Ro'~O'I..::<
RO"'y" OR

"i

Br 15

16

Scheme 7.

H

I

H H

120

GHISLAINE S. COUSINS and JOHN O. HOBERG

however, since a mixture of isomers is obtained when 2-methoxy-3,4-dihydro-2Hpyran is cyclopropanated. Further use of this strategy was not realized until recently when Nagarajan and co-workers reported their work on a series of glycals [3]. Using benzyl-protected glucal, galactal, and rhamnal derivatives, excellent yields of the cyclopropanes (84-95%) were obtained as a single isomer. Subsequent reductive dehalogenation furnished the cyclopropanes 14 in 68-78% yield (Scheme 7). More recently Nagarajan has extended this to the formation of dibromocyclopropanes 16 [15]. However, simply replacing chloroform with bromoform will not achieve the desired cyclopropanation; reducing the amount of the alkali and using excess potassium fluoride are necessary to obtain good yields. The stereoselectivity of the reaction again gave one isomer in the case of the glucal and galactal derivatives but a 7:1 ratio was observed for the rhamnal substrate.

2.1.4 Additional Sugar Cyclopropanes The use of sulfur ylids for the cyclopropanation of glycals has also been reported, although sparingly. This lack of use would appear to be due to the number of transformations needed to obtain the required Michael acceptor. However, in the 1970s a series of papers were published on the cyclopropanation of unsaturated pyranosides containing a vinyl nitro group (Scheme 8) [16]. Cyclopropanation of 2,3-unsaturated glycals with dimethyloxosulfonium methylide in dimethylsulfoxide produced the desired nitrocyclopropanes 17 (R = H) in 75% yield. However, a minor amount of 18 can also be formed depending on the solvent, the type of ylid, and the reaction conditions. Furthermore, the stereochemistry of the anomeric methoxyl group greatly changes the outcome, as use of an o~-anomer results in formation of 18 as the major product [ 17]. Similarly, Fitzsimmons and Fraser-Reid reported the formation of 19 in 64% using the same strategy (Scheme 9) [18]. The sulfur ylid was used after the addition of diazomethane failed to cyclopropanate this system. Once again, the stereochemistry exhibited in both of these examples is sterically directed, apparently by the anomeric ether group as both cyclopropanes 17 and 19 are formed as a single diastereomer.

H

H

O2NR ' - ~ R'

R=R'=H R=Me, R'=CO2Et

17

18 R = H, CO2Et

Scheme8.

121

Strained Carbohydrates

OAc

~i,i0..,,OEt

0 ~ "

OAc Me2S=CHCO2Et-O~

,,OEt

19 C02Et Scheme 9.

Two other examples of the formation of cyclopropanated sugars are worth mentioning. Expanding on the 1,4-addition chemistry, Fraser-Reid used the unsaturated sugar 20 as the acceptor in the benzophenone-sensitized addition of methanol to form hydroxide 21 (Scheme 10) [ 19]. Subsequent treatment with para-toluenesulfonyl chloride (PTSA) in pyridine provided the tosylate which undergoes intramolecular attack to produce cyclopropane 22. Modest to good yields in the formation of 21 were reported (50-75%), while the second step gave a near quantitative yield. An alternative is the conversion of epoxides into cyclopropanes and this has also been developed. Reckendorf and Kamprath-Scholtz first published this in 1968, in which they treated the epoxide 23 with ethyl diethoxyphosphorylacetate and sodium hydride over 3 days [20]. Formation of 24 was accomplished, however, as a mixture with the starting epoxide. Due to the difficulty of separating 24 from the starting epoxide, the mixture was hydrolyzed and then separated thereby providing the acid 24 (R = OH) in 46% yield.

~ ,R1 ~0

.OR1

OR1

"'OR3oR2Ph2CO~ "]ii'~~ ~'"IO" ~ "OR3 PTSCI O~i "'OR3 350nm )~'v~ -'"'~"OR2 pyridine~ 0~ 7 " 0 ....OR2 " o21 H 20 22 R2 = H, R3 = Et R2 = R3 = Me

OCH

C6Hs'"LO""""<"O

o

(EtO)zPOCHzCO2EtNaH " CeHs,~ ''" COR

23

24 R = OH, OEt

Scheme 10.

122

GHISLAINES.COUSINSandJOHNO. HOBERG 2.2 Chemistryof CyclopropanatedCarbohydrates

Although methods for the formation of cyclopropanated carbohydrates have been developed quite thoroughly, development of the chemistry of these molecules is still in the early stages. The majority of the chemistry that has been undertaken on these systems usually occurs at the cyclopropane ring and involves opening of the cyclopropane. The other main area of interest involves ring expansion of the carbohydrate moiety which leads to the formation of seven-membered oxacycles. The chemistry of cyclopropanated carbohydrates is presented under the heading of ring expansions of the carbohydrate and ring opening of the cyclopropane, but a few miscellaneous rearrangements are presented.

2.2.1 Ring Expansions In the mid-1990s, we began to investigate the chemistry of cyclopropanated carbohydrates and rationalized that these substrates would be amenable to ring expansion [2]. This premise was based on the well-known Lewis acid-catalyzed rearrangement of unsaturated sugars as shown in Scheme 11 [21]. In view of the strain present in the cyclopropane ring, it was speculated that upon treatment with a Lewis acid and a nucleophile, a cyclopropanated sugar would undergo ring expansion to provide the corresponding oxacycle (oxepane). The initial studies did indeed provide a ring-expanded product although in an unexpected form as illustrated in Scheme 12. Treatment of the cyclopropane with trimethylsilyl triflate (TMSOTf) in the presence of an external nucleophile produced only the bicyclic product 25; separate reaction without the external nucleophile gave 25 in 78% yield. In order to eliminate the intramolecular attack that led to 25, a 6-deoxy derivative was used. Ring expansion was successful and produced

OR ~ RO'"

LewisAcid =

RO"

Nu.

R

@.

OR ~ C~

OR ~(~ O~,.~

LewisAcid.

OR ~ ~

RO

Scheme 11.

OR O~,.~~ Nu R

Nu:~

ORI~..0. _, " ~ ~ O Nu

RO

123

Strained Carbohydrates

TBSO~. 0 " ~

TMSCN

AcO"" " ~

10% TMSOTf

AcO

CH3CN

AcO'"" 25

Me~O~~> TMSCN ~ 40%TMSOTf AcO" H CH3CN AcO

ON

26

Scheme 12.

the oxepane 26 but only in 49% yield. A 30:1 mixture of diastereomers was observed for this reaction which is presumed to involve attack of the cyanide ion from the less-hindered face of the incipient oxonium ion. More recently we reported an improvement on this strategy involving a more stable protecting group for the C6 alcohol [22]. The silyl-functionalized 27 provides robust protection at C4 and C6 and leaves the hydroxy moiety at C3 available for further elaboration (Scheme 13) [23]. Cyclopropanation occurs in 96% yield with 250:1 selectivity, and when followed by acetylation and ring expansion it provides the oxepanes 28 in yields ranging from 67 to 93%. A side product in this reaction is diene 29 (0-12%) but it could be formed selectively in 81% yield. The diastereoselectivity of 29 was very poor with a 2:1 ratio the highest recorded. The poor selectivity of the reaction was believed to be due to a planar geometry in the intermediate oxonium ion. While no applications of this methodology to the synthesis of natural products have been reported, this strategy offers access to the naturally occurring seven-membered ring systems such as rogiolenyne and others [24]. Similar types of ring expansions using cyclopropanated sugars have also been reported. Nagarajan used the dibromocyclopropane 16 in a solvolytic ring expansion to produce the oxepanes 30 (Scheme 14) [ 15]. This reaction is believed to occur through loss of an endo halogen forming the allyl cation, which is then captured by

O~1/O~ tBu2Sl~o,,,-L~ OH 27

1) CH21z,EtzZn 2) Ac20 OAc

R3SiNuc_ TMSOTf MeCN

+ 28

Scheme 13.

29

124

GHISLAINE S. COUSINS and JOHN O. HOBERG Br Br

BnO" ' ~

K2CO3 MeOH

OBn

~

L BnO

BnO

16

30

))~' )'~OAc OAc

AIBN

~/'qOAc

+

OAc

Me"'""T" "OAc OAc

31

32

Scheme 14.

a nucleophilic solvent. The oxepanes were isolated as a mixture of anomers with yields ranging from 55 to 70%. The regioselectivity of the reaction can be rationalized by stabilization of the positive charge with the adjacent oxygen atom to provide a stabilized oxonium ion. Gurjar and co-workers have also reported the formation of oxepanes via a ring expansion reaction, although as a side product in the formation of an exocyclic methylene moiety [8]. In the proposed radical induced ring opening, the oxepane 31 and pyranose derivative 32 were obtained in a combined 93% yield and 2:3 ratio, respectively. The separation of these two were reported to be difficult and therefore subjected to hydroboration-oxidation and protection of the resulting alcohol; separation was then feasible. Ring expansions of cyclopropyl sulfides in a furanose system have also been reported (Scheme 15) [25]. Treatment of 33 with cerium(IV) ammonium nitrate (CAN) and tetramethylammonium chloride gave rise to the chlorinated products 34 and 35, each as a single isomer in a 1:1 ratio and combined yield of 67-83%. Use of a 13-ethyl group resulted in no ring opening and this was believed to be due to steric hindrance of the ethyl group in the approach of the chloride anion. Additionally, the conversion of 35 into 34 could be achieved in modest yield by treatment with p-toluenesulfonic acid. This strategy could, in principle, provide entry into the Dactomelyne group of halogenated natural products [26].

9

.,

R"" "O" ' ~ "

CI

"OH

~

:

L R"" "O"'~w" "OHJ

33

OMe

R'''O~OI-I 34

Scheme 15.

CI

35

Strained Carbohydrates

125

2.2.2 Electrophilic Ring Opening Cyclopropanated carbohydrates are ideally suited for electrophilic ring opening and a substantial amount of investigation has been in this area. Since the cyclopropanation reaction forms a pseudo-cyclopropylcarbinol assemblage, the potential for rearrangement reactions are numerous [27]. The reaction sequence that applies to the majority of the ring openings reported is shown in Scheme 16 where the formation of the oxonium ion intermediate leads to nucleophile attack and formation of substituted sugars. The use of mercury(H) ion to catalyze the opening of various cyclopropanes has been reported [28], and Heathcock used this strategy in the reaction of cyclopropanated sugars and the synthesis of a C2-methyl-D-glucal [29]. Thus treatment of sugar 36 with mercury trifluoroacetate in the presence of water provides the organomercurial 37 as a mixture of anomers (Scheme 17). Reductive cleavage of the organomercurial with tributyltin hydride produces the C2 methyl-substituted 38 in a combined yield of 81%. The ct/13selectivity at the anomeric center was only 4:1 but it could be increased to over 10:1 with the use of methanol. Finally, reaction of 38 with methanesulfonic anhydride and triethylamine induces elimination leading to the 2-C-methyl-D-glucal. Another example of a metal-induced ring opening, developed by Madsen, uses catalytic amounts of the platinum complex, Zeise's dimer (Scheme 18) [30]. The ring opening was achieved with a variety of alcohols to produce C2-branched glycosides 39 from the simple methyl glycoside (R = Me) to more complex disaccharides. Yields ranged from 50 to 97% and very high diastereoselectivities could be obtained at the anomeric center. The t~-glycoside, favored by the anomeric effect, was the major product regardless of the stereochemistry of the starting cyclopropane. Furthermore, the scope of the reaction was shown to be very extensive as a wide variety of cyclopropanated sugars were successfully transformed. A suggested reaction sequence involves oxidative addition of the platinum to the cyclopropane to provide a platinacyclobutane (Scheme 18). Polarization of the C1-Pt bond provides a stabilized oxonium ion which undergoes nucleophilic attack with the alcohol. Subsequent reductive elimination produces the C2branched glycoside and regenerates the Pt(II) catalyst. Also worth mentioning is that formation of C-glycosides were achieved as well. Use of electron-rich phenols

RO R(

+

RO

RO O"~O ~R E

Nuc RO l~o " ~~ N . ucE OR

FRO

E',,.

Scheme 16.

126

GHISLAINE S. COUSINS and JOHN O. HOBERG

BnO

O ~~"'

Bn

Hg(OT2 f'.

OBn 36

H20/THF

BnO

BnO

~OyOH

Bu3SnH= ..~.O~ ,OH BnO,,.K , , . ~ HgOTf AIBN BnO,,.-,,i,- ..CH 3 OBn OBn 37 38 Scheme 17.

provides the corresponding glycosyl arene in modest yield, presumably by way of an initial oxygen attack and then a Fries-type rearrangement [31 ]. Another recently developed strategy for the ring opening of the cyclopropane moiety was reported by Danishefsky and co-workers [5,32]. This solvolytic strategy used N-iodosuccinimide (NIS) for the oxidative opening and was developed for the synthesis of epothilones A and B (Scheme 19). Treatment of the sugar with excess NIS in methanol produces the methyl glycoside 40 which was reductively reduced with tributyltin hydride to produce 41 in a combined 80% yield. Elaboration and eventual cleavage of glycoside 41 provided the acyclic aldehyde which was incorporated as the C3 to C9 portion of epothilone A. Several variations of this strategy have appeared since the original report by Danishefsky, and many synthetically useful transformations have been developed. Both Ley [33] and Nagarajan [34] have reported work on the conversion of the diastereomeric cyclopropanes 42 and 44 using NBS as well as NIS as shown in Scheme 20. Yields of up to 72% and a stereospecific selection for the ct-anomer were reported in the slow formation of 43. However, conversion of 44 into 45 occurs rapidly but gives a mixture of anomers. Nagarajan attributed this difference in reactivity and selection to an SN2-type ring opening in the more sterically hindered 42 producing the more

BnO

BnO"

// .el. ..el 4,',p CI.~ t'cl'Pt~,~ = OBn

/ ~~~PtCl2

ROH

CH2CI2

BnO

.,~. O .,,,OR

BnO""~CH3 OBn 39

~0~::._-Pt-

Scheme 18.

.~..,~~ PtCI2 I

127

Strained Carbohydrates

BnO.-.~

~

~..,'O'~,,,"'--'~ NIS (7eq) ,,,,."...~,~ M'eO"H OH

BnO~..,,O..~M e ,"'"~y ~-~1

BnO.~ Bu3SnHAIBN

,,O~~Me OH

OH

40

41

~ - H 0,,,~0 ; n.,,vH

H3

-_

~S*w,.

I "OH EpothiloneA Scheme 19.

favored s-glycoside, while in the formation of 45 ring opening is unhindered and could involve an SNl-type pathway. In addition to this work, Nagarajan has extended the methodology to the formation of disaccharides halogenated at C2 by inclusion of sugar alcohols in the reaction [35]. Reported yields for the formation of these disaccharides range from 60 to 66% but the selectivity was only 2:1.

BnO

BnO

Oo~.~ Bn OBn

42

NBSorNIS = ROH 40-72%

BnO BnO"

~/O

.,,,OR

B n O ~

x

OBn

43

Ki ~176

BnO NBS or NIS D ROH OBn

44

66-91%

BnO,,"y".,,/x OBn 45

Scheme 20.

128

GHISLAINES. COUSINSand JOHN O. HOBERG

Several other variations of this ring opening strategy have been reported and these are collected in Scheme 21. Reaction of the cyclopropanated sugars with iodoniumdi(s-collidine) tetrafluoroborate in dioxan/water leads to formation of the (xmethylidenevalerolactones 46 in yields ranging from 41 to 82% [36]. This reaction was shown to proceed through the intermediate iodide 47 that undergoes elimination and oxidation. As part of their synthesis of (-)-A-23187 (Calimycin), Boeckman and co-workers reported the ring opening and intramolecular attack to form the spiroacetal 48 in 55% yield as a single diastereomer from a diastereomeric

BnO

O ~0

Bn

BnO

dioxane-H20 ,, [s-collidine]21§CI0460-70~C

.OH

Bn~

I

B n O 00~ Bn

0

OBn 46

//

47

,, ....

RO~O~~,~' ," ~....'~OTBDPS

~ o,.

pTSOH-H20

TBDPS 48

AcO AcO" y "H OAc

30%HBr in AcOH

49

AcO

Oy.r

AcO,,,.~P.....~CO2Et

50

Scheme 21.

129

Strained Carbohydrates

OR

OR

RO o ~

I::"('"CH2OH

OR

~~.0

Ph:)P, DEAD

,.OPN

ArCO2H

ON

\

RO

RO

/

51

+

l

O=PPh3 L

R

OR Scheme 22.

mixture of cyclopropanes [6,37]. Unlike the previous ring openings, however, acidic conditions with p-toluenesulfonic acid were able to induce successful ring opening. A final example of an electrophilic ring opening was accomplished on the ester substituted cyclopropane 49 [ 10]. The pyranosyl bromide 50 was isolated in 38% yield with a 13"1 13:ct-selectivity; however bromide substitution of the C3 acetate also occurred.

HO

oe C:

CI H CI 52

MeO

O

.Ag -""

O ~ c H 53

Scheme 23.

I

130

GHISLAINES. COUSINSand JOHN O. HOBERG BF ~,,~O~.,,,OMe

PhCO0" " ~ . , , M e R

Br

L

N-methylcarbazole _ Mg(ClO4)2, H20 hv

_o ..,,OMe

R

54 R = H, C02Et Scheme24.

2.2.3 Miscellaneous Rearrangements Several novel rearrangements of cyclopropanated sugars have been reported. These again include ring opening of the cyclopropane as well as a ring opening of the carbohydrate unit. For example, using standard Mitsunobu conditions and para-nitrobenzoic acid Henry and Fraser-Reid generated the vinylglycosides 51 in over 90% yield (Scheme 22) [12]. Selectivity for the reaction was modest with only 1:1 to 2.7:1 mixtures being formed. Presumably, this reaction proceeds through an SNl-type pathway, thus giving the observed ratios. A rare example of the chemistry that can be carried out on 4,5-cyclopropanated sugar-like systems was reported by Hall (Scheme 23) [ 14]. Simple acid hydrolysis of the acetal moiety of Scheme 23 provided the dichlorocyclopropanol 52 in 93% yield. Alternatively, solvolysis in silver acetate/acetic acid produced the acyclic vinylchloride 53 in 68% yield. Presumably, silver-induced removal of a chlorine results in rearrangement to provide 53. A final example is the photochemically induced ring opening of the 2,3-cyclopropane of Scheme 24 that produces 54 [38]. Yields of 86% for 54 (R = CO2Et ) and 67% for 54 (R = H) were obtained.

3. CARBOHYDRATE OXIRANES

3.1 Epoxidationsof Carbohydrates In 1922 Brigl [39] reported the first glycal epoxidation using triacetylglucal. However, the method was not general and the study of these substrates lay dormant until recently. Lately the chemistry of these oxiranes has attracted considerable attention due to the ease with which these substrates can be formed by use of dimethyldioxirane (DMD) as the epoxidant (Scheme 25). Danishefsky and Halcomb reported the epoxidation of a series of glycals using this reagent to produce the oxiranes 55 in high stereoselectivity and excellent yields [40]. For example, 55 [R = Me~BuSi fiBS)] was obtained as one isomer in 100% yield, and the use of a benzyl group also gave high stereoselection (20:1) in 99% yield. However, triace-

131

Strained Carbohydrates

RO"" "~ (DMD) OR ~,~ O~<Me 55

NO"' " ~

~,~

~~~,Mo

56

RE)'"~OR

55

55

55

Scheme 25.

tylglucal produced a mixture of isomers of 55 (R = Ac) in modest yield. Thus one may reason that use of protecting groups which are of a nonparticipatory nature should be used for obtaining high diastereoselectivity. The DMD reagent can be modified as reported by Yang and co-workers [41]. Use of methyl(trifluoromethyl)dioxirane, generated in situ, was shown to be efficient in the epoxidation of a tripivaloyl-protected glycal. Finally, the use of resin-bound fluorodioxiranes has also been developed [42]. This strategy enables the reuse of the resin and still produces high yields of the oxirane. An alternative approach to glycal epoxidation, which provides the opposite isomer, involves the formation and cyclization of bromohydrins [43]. Formation of a bromohydrin using N-bromoacetamide in aqueous tetrahydrofuran occurs in yields as high as 100%; however little selectivity is obtained. Cyclization using sodium hydride produced predominantly the [3-epoxide 56 in 30-50% yield. Although the use of DMD is very attractive, a drawback is the low concentration of the reagent solutions that must be used thus making scale-up difficult. Several solutions to this problem have been developed. For example, Chiappe, Bellucci, and co-workers reported the use of Camps [44] reagent, m-chloroperoxybenzoic acid/potassium fluoride [45]. Excellent yields of 80 to 95% were obtained in the formation of the oxirane 55; however selectivity suffered as ratios from 4:1 to 20:1 resulted. Additionally, Resnati and co-workers have reported the use of cis-2,3perfluorodialkyloxaziridines to perform the epoxidation [46]. Modest-to-complete diastereoselection was reported with yields of greater than 90%.

132

GHISLAINE S. COUSINS and JOHN O. HOBERG

A final method is the use of transition metals, which are known to catalyze the epoxidation of a variety of alkenes, but until recently these methods have not been applicable to unsaturated sugars. A recent report by Che and co-workers has addressed this need with the use of a ruthenium porphyrin complex [47]. Treatment of either triacetyl- or tribenzylglucal with C12pyNO and a ruthenium(II) catalyst provides only the tx-epoxide 55 in 77 and 55% yield, respectively. 3.2 Chemistry of Carbohydrate Oxiranes

A typical use of 1,2-epoxysugars in carbohydrate and organic chemistry involves ring opening of the oxirane moiety. In view of the acetal configuration of the carbohydrate oxirane, these molecules are ideally set up for preferential nucleophilic attack at the anomeric center. This leads to formation of a new bond at the anomeric center and generation of a 2-hydroxyl moiety.

3.2.1 RingOpening with Oxygen Nucleophiles A widely used reaction to effect ring opening is with alcohols and a multitude of reports on its use in the synthesis of natural product and biologically active compounds have been published [48]. A specific example of this reaction is the use of these glycosyl donors in the construction of oligosaccharides and nucleosides (Scheme 26). Treatment of the oxirane with alcohol 57 in the presence of a Lewis acid results in the formation of disaccharides such as 58 in good to excellent yields and with exclusive formation of 13-glycosidic bonds [49]. In the example shown, reiteration of the sequence by epoxidation of the glycal moiety in the disaccharide followed by attack of Null, can provide oligosaccharides in a stereoselective and high yielding manner [50]. A useful elaboration of this ring opening is the epoxidation of an allylglucopyranoside, which was shown to be asymmetrically induced by the sugar moiety as shown in Scheme 27 [51 ]. In this strategy, ring opening of the 1,2-epoxysugar with allyl alcohol provides the allylglucopyranoside 59. Epoxidation of the allyl side chain with m-CPBA provided the oxirane 60 in 80% yield and 9:1 distereoselectivity. Subsequent nucleophilic openings of the newly formed epoxide in 60 were also carried out.

RO"" ~

OR

"

"~

Scheme 26.

o

StrainedCarbohydrates , ~.,~i ''O

133

0

HO~

=

o

0 , 0 ~ ~~.,,O H

MCPBA ~'"OH

59

60

Scheme 27.

3.2.2 Ring Opening with Nitrogen Nucleophiles N-glycosidations of oxiranes have also been reported. Using Vorbruggen-like reaction conditions [52] and bis(siloxy)imidates as the nucleophile, the nucleosides 61 are produced in good to high yields (Scheme 28) [53]. Once again, stereospecificity can and is obtained in these reactions. Given the useful role of nonnatural nucleosides in antiviral therapy, access to this series of compounds is of notable appeal. Other methods for the formation of N-glycosidic bonds using this system have been reported and applied to the synthesis of natural products [54]. For example, the sodium salts of indoles have been used in the three-membered ring opening to produce indole-13-N-glycosides which have been shown to exhibit antitumor activity. An interesting alternative in the ring opening of the oxirane is the use of a Ritter-type solvolysis (Scheme 29) [55]. Treatment of the oxirane with zinc chloride in acetonitrile produces the oxazolines 62 in 23-53% yields [56]. Presumably, the initially formed equatorial anomer undergoes an inversion to produce the axial anomer which is captured by the proximal ct-hydroxy group. The oxazoline is then subsequently hydrolyzed to the corresponding aminoacetate. Other ring openings with nitrogen nucleophiles have been achieved with the use of lithium azide [57]. Treatment of epoxides with lithium azido(hydrido)(di-isobutyl)aluminate (DIBAH-LiN 3) again results in regioselective attack of the azido group at the anomeric carbon atom to form a vicinal azidoalcohol; yields in this reaction range from 65 to 92%.

H O O N

9 RO"" "~ OR"

.C o TMSO,,,L~J

ZnGI2 38 -84%

RO"" ~ " "OH OR 61

Scheme28.

134

GHISLAINE S. COUSINS and JOHN O. HOBERG MeCN ZnC!2

RO" " 1 f " ON

R o ' " y ....o OR

62

1

1

IR0~0"~ ....N+"~r Me .~.,,. Ro,~O,~N~~ ~o."y

R o ' " " C ....oAc OR

....o- z~

OR

.o."-y

Me "][

....o- znC,. I

OR

J

Scheme 29.

3.2.3 Ring Opening with Carbon Nucleophiles Complementary to the above O- and N-glycosides are the formation of 13-C-glycosides through the use of carbon nucleophiles as shown in Scheme 30. Thus Czernecki and Bellosta reported the formation of the C-glycosides 63 in 25 to 90% yields from variously substituted oxiranes using methyl- and phenylcuprates [58], while van Boom and co-workers used an excess of sodium di-tert-butyl

RO"' y

....OAc OR

63

1. R2CuLi 2. Ac20

R1 = TMS (51%) R1 = nPr (55%) R1 = CH2OTHP (76%) R1 = sugar

RO"" " ~ ' OR

"••(CO2tBu)2

Ro.~OTCH(CO2tBu)2

RO'" y

RO"'y

....OH

....OH OR

OR

65

64

Scheme 30.

135

Strained Carbohydrates

RO+RO"" "~'" "~O~''O 'R

ClZn

F.o o c,

R1 ~

[ RO""O~OR''OZn --- R1 "----"

65

Figure 2.

malonate and zinc chloride for the formation of analogue 64 [59]. On the basis of these findings van Boom has extended the ring opening with alkynyl anions, although with dissimilar results [60]. Modest-to-good yields of a single isomer of 65 were obtained for a series of substituted alkynes and this also provided for the coupling of sugar units. A rational for the observed diastereoselectivity is shown in Figure 2, in which an alkynyl-zinc complex reacts with the sugar oxirane to produce the ~chloride complex A. Intramolecular o~-directed delivery of the alkynyl moiety leads to formation of the observed stereochemistry in 65. Other reports for the formation of C-glycosides involve the use of Grignard reagents [61] or allylstannanes [62]. In both cases, the use of a Lewis acid such as zinc chloride improved the yields and selectivity of the reaction. Several applications of these ring-opened C-glycosides in the synthesis of natural products have been reported. One example uses an iterative approach to the synthesis of ethers in fused ring systems and has been developed by Rainier and co-workers (Scheme 31) [63]. The strategy involves ring opening with an organometallic acetal to form 66 which cyclizes with loss of methanol under catalysis. Initial reactions using a Grignard reagent as the metal species gave yields of

OMe RO~.. O3".;:O M""v~OMe Ro,.. T

OR

'

OMe Ro'~O'~"~OMe Ro,.....E--..,o.

OR

PPTS

,eat

RO

OH RO 67

66

Ph H2 OR

RO ~

O ~ OR 68

Scheme 31.

I. NaHoC3HsBr

RO~O'~ RO 69

136

GHISLAINE S. COUSINS and JOHN O. HOBERG

29-51% and low selectivity; however the in situ transformation of the Grignard to an organocuprate reagent increased the yields to >60% and the selectivity to 6:1. Subsequent in situ elimination of alcohol provides the trans-fused polyether 67 which can be subjected to further epoxidations and cyclizations. The result is an efficient two-flask formation of bioactive natural products. Similarly, the ring opening with lithium acetylide developed by van Boom provides a complementary method for the polyether synthesis [64]. Ring opening followed by reduction of the alkynyl group with the Lindlar catalyst gave the (E)-olefin 68. Allylation of the 2-hydroxy group with allyl bromide affords the necessary diene for cyclization to 69 via ring closing metathesis.

3.2.4 MiscellaneousRing Opening Several additional types of ring-opening reactions of epoxysugars have been reported. For example, treatment of an epoxide with tetrabutylammonium fluoride induces ring opening to produce the fluorosugar 70 (Scheme 32) [65]. Alternatively, the use of sodium phenylthiolate or (triphenylstannyl)lithium provided the thioglycosides 71 [66] and the glucopyranosylstannanes 72 [67] in reasonable yields. The formation of the stannane 72 is of synthetic interest since transmetallation with butyllithium leads to an inversion of polarity at the anomeric center. This is of synthetic appeal since most of the reactions that occur at the anomeric center of a sugar involve nucleophilic attack at an electrophilic carbon. Therefore, formation of the anion and quenching of it with electrophiles opens new avenues in sugar chemistry. Further elaboration of the chemistry of the pyranosylstannanes has been developed through the use of Pd/Cu cocatalyzed cross-couplings [68]. For instance,

RO

.

NaSPh OR

OH

BuLl

....o.

or LiSnPh3 70

71; X = S P h 72; X = S n P h 3

72

,o Oy,

o ~ Ro,,.v o,, ....

OR

Scheme 32.

E+

R O , , . y .. 0 H OR

137

Strained Carbohydrates

coupling with thiolchloroformates results in the formation of the thiol carbamates and provides for another means for the formation of C-glycosides. Finally, hydride addition has been achieved also providing an efficient route to anhydroalditols [69].

4. CARBOHYDRATE AZIRIDINES 4.1 Aziridination of Carbohydrates The synthesis and use of carbohydrate aziridines (epimines) has not been studied in detail and the compounds were unknown prior to 1960. They are, however, potentially useful intermediates for the synthesis of diamino- [70] aminohalo- [71 ], aminodideoxy- and unsaturated [72] sugars via ring-opening reactions with nucleophiles. Several methods for the preparation of the aziridines are available [73]; however the most heavily used method involves attack of an amino group on a trans-vicinal sulfonyloxy moiety, e.g. mesylate [74]. The specific example of Scheme 33 shows the reduction of the benzamide 73 with lithium aluminum hydride which is followed by internal nucleophilic attack to produce 74. Similar strategies have been used on 2-azidosulfonyloxysugars [75]. Alternatively, the preparation of 1,2-aziridines from the corresponding glycal would appear to be an attractive route. Methodology for the generation and in situ reaction of these species have been reported [76], however isolation of the 1,2-aziridine has not been accomplished and it is not discussed in detail here. These methods involve reaction of the 1,2-unsaturated sugar with either a transition metal reagent, ([saltmen]MnN), or H2SO2Ph in the presence of a nucleophile, thus undergoing nucleophilic opening to provide the C2 amino derivative.

4.2 Chemistry of Carbohydrate Aziridines As mentioned above, the aziridines are useful precursors for aminosugars via ring opening. The aziridines have been shown to undergo stereoselective opening, giving predominantly one isomer, normally that resulting from trans-diardal opening. These derivatives have been studied with a view to the synthesis of methyl- and dimethylaminosugars, such as are found as constituents of antibiotics [77]. For example, treatment of the aziridine 74 (R = H) with iodomethane in silver carbonate produces the N-methylaziridine 75 (Scheme 34) which is unreactive towards ring

RO..,~O...,,OMe

LiAIH4

RO,"~",NHBz OMs 73

RO~.. RO'"~'O""ill,OMe 74

Scheme 33.

138

GHISLAINE S. COUSINS and JOHN O. HOBERG

R OR~O. '." ~OR .,,OMe

Mel

AgCO3

_-- ROR ~ i , , O M e ., -

(R = H)

74

Me

1. Mel .. R C~R. .o , ,O. ~ ,,OMe . Nuc

2. Nuc

22 - 56%

75

NMe2

76

Scheme 34.

HNO3 U~:~ 78 Ar

.

'~

RO,,'~,,,~

(R = COAr) 77

79

Scheme 35.

opening. Ring opening is accomplished by formation of the quaternary salt with additional iodomethane and subsequent nucleophilic attack to produce the C3 aminosugar 76 [78]. Additional ring-opening reactions of 74 include that with tetrabutylammonium fluoride to produce a C2 fluorosugar in 40% yield [79], and treatment with sodium azide to provide a C2 azidosugar (56%) [80]. In each of these examples, nitrogen protecting groups such as dinitrophenyl, benzoyl, and tosylate are used, thus alleviating the need to form the quaternary salt [81 ]. Further reactions of the aziridines include ring expansion to form oxazolines and the deamination of the carbohydrate to give an unsaturated sugar. Treatment of the N-benzoylaziridine 77 with sodium iodide in dimethylformamide produces the corresponding oxazoline 78 in 20-48% yields (Scheme 35) [82] while deamination to unsaturated glyca179 has been accomplished in up to 80% yield [83].

5. CARBOHYDRATE THIIRANES (EPISULFIDES) A limited amount of work has been reported on the synthesis and chemistry of (episulfide) sugars and only a few examples are presented here. This limited amount of work is perhaps due to the cumbersome methods initially used for their formation. A typical synthesis of the episulfide is the formation of epoxide 80 (Scheme 36) followed by reaction with dithioacids of phosphorus, such as 2-mercapto-5,5dimethyl-2-thioxo-1,3,2-dioxaphosphorinane [84]. The thiirane 81 is obtained as a single isomer in a yield of 47% from the mannose epoxide shown; alternatively the allose isomer (epoxide down) can be likewise transformed in 85% yield. Presumably, the reaction proceeds via formation of adduct 82 which undergoes phosphorus migration and episulfide formation.

Strained Carbohydrates

139

oleO..,,OMe

O MeCN -

O .,,OMe

Ph"'"

-., -

80

81

"-. F

.,ooe

/ s,, ,o---~/

82

Scheme 36.

An alternative route to episulfide sugars is through the triflate sugar 83 (Scheme 37) [85]. Nucleophilic displacement of the triflate with potassium thioacetate provides the thioepoxide 84 quantitatively. This was converted into the episulfide 85 in 95% yield by deacetylation and nucleophilic opening of the epoxide. Again, the same reaction sequence was carried out on the diastereomer of 83 (TfO and epoxide down) in 90% overall yield. Interestingly, both of these episulphides

.,,OBn

TfO

0

.,,OBn

SAc'"" 83

0

MeOH

-

- ,'

84

85

Scheme 37. ~~ o ~ ~

, ~rS~, OBn

OBn

OBn

\ f~o~~_o~l ~ ~ Scheme 38.

,,OBn H

140

GHISLAINE S. COUSINS and JOHN O. HOBERG

display high inhibitorial activity on a proteinase isolated from Saccharomonospora

canescens. A final exam pl e of thiirane formation is from the reaction of an intermediate episulfonium ion in the formation of glucopyranosides ( S c h e m e 38) [86]. In situ generation of 86 from the benzylated glycal shown with tosyl chloride and tetrachlorostannane produces the intermediate episulfonium ion. Trapping of 86 with a vinyl ether and nucleophile provides 87 as the f - i s o m e r in yields ranging from 18 to 95% with ratios as high as 95:5.

REFERENCES AND NOTES [1] Hoveyda, A. H.o Evans, D. A., and Fu, G. C., Chem. Rev., 93 (1993) 1307; Molander, G. A. and Harring, L. S., J. Org. Chem., 54 (1989) 3525; Poulter, C. D., Friedrich, E. C., and Winstein, S., J. Am. Chem. Soc., 91 (1969) 6892; March, J.,AdvancedOrganic Chemistry,4th edn., John Wiley & Sons: New York, 1992. [2] Hoberg, J. O. and Bozell, J. J., Tetrahedron Lea., 36 (1995) 6831. [3] Murali, R., Ramana, C. V., and Nagarajan, M., J. Chem. Soc., Chem. Commun., (1995) 217. [41 Albano-Garcia, E. L., Akkolario, E. M., and Lorica, R. G., Nat. Appl. Sci. Bull., 31 (1979) 61. [5] Bertinato, P., Meng, D., Balog, A., Su, D., Kamenecka, T., Sorensen, E. J., and Danishefsky, S. J., J. Am. Chem. Soc., 119 (1997) 10073. [6] Boeckman, R. K., Charette, A. B., Asberom, T., and Johnston, B. H., J. Am. Chem. Soc., 109 (1987) 7553. [7] Fraser-Reid, B. and Carthy, B. J., Can. J. Chem., 50 (1972) 2928. [8] Gurjar, M. K., Chakrabarti, A., Venkateswara Rao, B., and Kumar, P., Tetrahedron Lett., 38 (1997) 6885. [91 Baidzhigitova, E. A., Afanasev, V. A., and Dolgii, I. E., Izv. Akad. Nauk. Kirg. SSR, (1981) 50. [I0] Hoberg, J. O. and Claffey, D. J., Tetrahedron Lea., 37 (1996) 2533. [11] Timmers, C. M., Leeuwenburgh, M. A., Verheijen, J. C., van der Marel, G. A., and van Boom, J. H., Tetrahedron Asym., 7 (1996) 49. [12] Henry, K. J. and Fraser-Reid, B., Tetrahedron Lett., 36 (1995) 8901. [13] Brimacombe, J. S., Evans, M. E., Forbes, E. J., Foster, A. B., and Webber, J. M., Carbohydr. Res., 4 (1967) 239. [14] Weber, G. E and Hall, S. S., J. Org. Chem., 44 (1979) 447. [15] Ramana, C. V., Murali, R., and Nagarajan, M., J. Org. Chem., 62 (1997) 7694. [16] Sakakibara, T., Takamoto, T., Sudoh, R., and Hakagawa, T., Chem. Lett., (1972) 1219; Sakakibara, T., Sudoh, R., and Nakagawa, T., Bull. Chem. Soc. Jpn., 51 (1978) 1189. [17] Sakakibara, T. and Sudoh, R., Bull. Chem. Soc. Jpn., 51 (1978) 1193; Sakakibara, T. and Sudoh, R., J. Chem. Sot., Chem. Commun., (1977) 7. [18] Fitzsimmons, B. J. and Fraser-Reid, B., Tetrahedron, 40 (1984) 1279. [19] Fraser-Reid, B., Holder, N. L., Hicks, D. R., and Walker, D. U, Can. J. Chem., 55 (1977) 3978. [20] zu Reckendorf, W. M. and Kamprath-Scholtz, U., Angew. Chem., Int. Ed. Engl., 7 (1968) 142. [21] Toshima, K., Ishizuka, T., and Matsuo, G., Tetrahedron Lett. 35 (1994) 5673. [221 Hoberg, J. O., J. Org. Chem., 62 (1997) 6615. [23] Hoberg, J. O., Carbohydr. Res., 300 (1997) 356. [24] Guella, G., Helv. Chim. Acta, 75 (1992) 310; Fukuzawa, A. and Masamune, T., Tetrahedron Lett., 22(1981)4081. [25] Takemoto, Y. and Ibuka,T., Tetrahedron Lett., 39 (1998) 7545. [26] Grimvall, A. and de Leer, E. W. B., Naturally Produced Organohalogens, Kluwer Academic Publishers: The Netherlands, 1995.

5trained Carbohydrates

141

[27] Wenkert, E., MueUer, R. A., Reardon, E. J. Jr., Sathe, S. S., Scharf, D. J., and Tosi, G., J. Am. Chem. Soc., 92 (1987) 7428. [281 Collum, D. B., Still, W. C., and Mohamadi, E, J. Am. Chem. Soc., 108 (1986) 2094, and references cited therein. [29] Scott, R. W. and Heathcock, C. H., Carbohydr. Res., 291 (1996) 205. [301 Beyer, J. and Madsen, R., J. Am. Chem. Soc., 120 (1998) 12137. [311 Mahling, J.-A., Jung, K.-H., and Schrnidt, R. R., Liebig's Ann. Chem., (1995) 461. [321 Bertinato, P., Sorensen, E. J., Meng, D., and Danishefsky, S. J., J. Org. Chem., 61 (1996) 8000. [331 One example of the conversion of 44 using NIS and MeOH was reportedmsee: Femandez-Megia, E., Gourlaouen, S., Ley, S. V., and Rowlands, G. J., Synlett, (1998) 991. [34] For a thorough study on this system with additional work on the formation of levoglucosan-type structures see ref. 15. [35] Ramana C. V. and Nagarajan, M., Carbohydr. Lctt., 3 (1998) ll7. [36] Ramana, C. V. and Nagarajan, M., Synlett, (1997) 763. [37] Bocckman, R.,_Charette, A., Asbcrom, T., Johnston, B., J. Am. Chem. Soc., 109 (1987) 7553. [38] Clive, D. and Daigneault, S., J. Org. Chem., 56 (1991) 3801. [39] Brigl, P. Z., Physiol. Chem., 122 (1922) 257. [40] Halcomb, R. L. and Danishefsky, S. J., J. Am. Chem. Soc., l l l (1989) 6661; Adam, W., Hadjiarapoglou, L., and Wang, X., Tetrahedron Lctt., 32 (1991) 1295. [41] Yang, D., Wong, M.-K., and Yip, Y.-C., J. Org. Chem., 60 (1995) 3887. [421 Bochlow, T. R., Buxton, P. C., Grocock, E. L., Marples, B. A., and Waddington, V. L., Tetrahedron Lett., 39 (1998) 1839. [431 Marzabadi, C. H. and Spilling, C. D., J. Org. Chem., 58 (1993) 3761. [441 Camps, E, Coil, J., Messeguer, A., and Pujol, E, J. Org. Chem., 47 (1982) 5402. [451 Bellucci, G., Catelani, G., Chiappe, C., and D'Andrea, E, Tetrahedron Lett., 35 (1994) 8433; Bellucci, G., Chiappe, C., and D'Andrea, E, Tetrahedron Asym., 6 (1995) 221; Chiappe, C., Moro, G. L., and Munforte, P., ibid., 8 (1997) 2311. [46] Cavicchioli, M., Mele, A., Montanari, V., and Resnati, G., J. Chem. Soc., Chem. Commun., (1995) 901. [471 Liu, C.-J., Yu, W.-Y., Li, S.-G., and Che, C.-M., J. Org. Chem., 63 (1998) 7364. [481 Delgado, A. and Clardy, J., J. Org. Chem., 58 (1993) 2862; Randolph, J. T. and Danishefsky, S., J. Am. Chem. Soc., 117 (1995) 5693; Danishefsky, S., Behar, V., Randolph, J. T., and Lloyd, K. O., ibid., 117 (1995) 5701; Lorimer, S. D., Mawson, S. D., Perry, N. B., and Weavers, R. T., Tetrahedron, 51 (1995) 7287; Park, T. K., Kim, I. J., and Danishefsky, S., Tetrahedron Lett., 36 (1995) 9089; Broddefalk, J., Bergquist, K.-E., and Kihlberg, J., Tetrahedron, 54 (1998) 12047. [49] Gervay, J. and Danishefsky, S., J. Org. Chem., (1991) 5448 - see also reference 40a. For additional ring-opening reactions with alcohols see: Chiappe, C., Moro, G. L., and Munforte, P., Tetrahedron, 53 (1997) 10471; Matsushita, Y., Sugamoto, K., Kita, Y., and Matsui, T., Tetrahedron Lett., 38 (1997) 8709. [5o1 Liu, K. K.-C. and Danishefsky, S.,J. Org. Chem., 59 (1994) 1892; Liu, K. K.-C. and Danishefsky, S., ibid., 59 (1994) 1895; Lu, P.-P., Hindsgaul, O., Li, H., and Palcic, M. M., Can. J. Chem., 75 (1997) 790; Tunmers, C. M., Wigchert, C. M., Leeuwenburgh, M. A., van der Marel, G. A., and van Boom, J. H., Eur. J. Org. Chem., (1998) 91; Kwon, O. and Danishefsky, S., J. Am. Chem. Soc., 120 (1998) 1588; Randolph, J. T. and Danishefsky, S., J. Am. Chem. Soc., 115 (1993) 8473. [511 Bellucci, G., Catelani, G., Chiappe, C., D' Andrea, E, and Grigo, G., Tetrahedron Asym., 8 (1997) 765; Chiappe, C., Crotti, P., Menichetti, E., and Pineschi, M., ibid., 9 (1998) 4079. [521 Niedballa, U. and Vorbruggen, H., J. Org. Chem., 39 (1974) 3654. [531 Chow, K. and Danishefsky, S., J. Org. Chem., 55 (1990) 4211. [541 Gallant, M., Link, J. T., and Danishefsky, S., J. Org. Chem., 58 (1993) 343; Faul, M. M., Winneroski, L. L., and Krumrich, C. A., ibid., 64 (1999), 2465. [551 Ritter, J. J. and Minieri, P. P., J. Am. Chem. Soc., 70 (1948) 4045.

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GHISLAINE S. COUSINS and JOHN O. HOBERG

[56] Gordon, D. M. and Danishefsky, S., J. Org. Chem., 56 (1991) 3713. [57] Lee, G. S., Min, H. K., and Chung, B. Y., Tetrahedron Lett., 40 (1999) 543. [581 Bellosta, V. and Czemecki, S., J. Chem. Soc., Chem. Commun., (1989) 199; Bellosta, V. and Czemecki, S., Carbohydr. Res., 244 (1993) 275. [59] Timmers, C. M., Dekker, M., Buijsman, R. C., van der Marel, G. A., Ethell, B., Anderson, G., Burchell, B., Mulder, G. J., and van Boom, J. H., Bioorg. Med. Chem. Lea., (1999) in press. [60] Leeuwenburgh, M. A., Timmers, C. M., van der Marel, G. A., van Boom, J. H., Mallet, J.-M., and Sinay, P. G., Tetrahedron Lett., 38 (1997) 6251. [61] Best, W. M., Ferro, V., Harle, J., Stick, R. V., and Tilbrook, D. M. G., Aust. J. Chem., 50 (1997) 463. [621 Evans, D. A., Trotter, B. W., and Cote, B., Tetrahedron Lett., 39 (1998) 1709. [63] Rainier, J. D. and Allwein, S. P., Tetrahedron Lea., 39 (1998) 9601, J. Org. Chem., 63 (1998) 5310. [641 Leeuwenburgh, M. A., Overkleeft, M. A., Herman, S., van der Marel, G. A., Gijsbert, A., and van Boom, J. H., Synett., 11 (1997) 1263. [651 Gordon, D. M. and Danishefsky, S., Carbohydr. Res., 206 (1990) 361; Park, T. K., Peterson, J. M., and Danishefsky, S., Tetrahedron Lea., 35 (1994) 2671; Berkowitz, D. B., Danishefsky, S., and Schulte, G. K., J. Am. Chem. Soc., 114 (1992) 4518; see also ref. 50b. [66] Walford, C., Jackson, R. E W., Rees, N. H., Clegg, W., and Heath, S. L., Chem. Commun., (1997) 1855; see also ref. 43. [67] Frey, O., Hoffmann, M., Wlttmann, V., Kessler, H., Uhlmann, P., and Vasella, A., Helv. Chim. Acta, 77 (1994) 2060; Burkhart, E, Hoffmann, M., and Kessler, H., Tetrahedron Lett., 39 (1998) 7699. [68] Belosludtsev, Y. Y., Bhatt, R. K., and Falck, J. R., Tetrahedron Lea., 36 (1995) 5881. [69] Flaherty, T. M. and Gervay, J., Tetrahedron Lea., 37 (1996) 961. [70] Guthrie, R. D. and Murphy, D., J. Chem. Soc., (1965) 3828. [71] Buss, D. H., Hough, L., and Richardson, A. C., J. Chem. Soc., (1965) 2736; Ali, Y., Richardson, A. C., Gibbs, C. E, and Hough, L., Carbohydr. Res., 7 (1968), 255. [72] Guthrie, R. D. and King, D., Carbohydr. Res., 3 (1966), 128. [73] Christensen, J. E. and Goodman, L., J. Am. Chem. Soc., 82 (1960) 4738; Guthrie, R. D. and Murphy, D., J. Chem. Soc., (1963) 5288; Buss, D. H., Hough, L., and Richardson, A. C., J. Chem. Soc., (1963) 5295; Barford, A. D. and Richardson, A. C., Carbohydr. Res., 4 (1967) 408. [74] Gibbs, C. E, Hough, L., Richardson, A. C., and Tjebbes, J., Carbohydr. Res., 8 (1968) 405. [75] Pinter, I., Kovacs, J., Messmer, A., Kalman, A., Toth, G., Lindberg, B. K., Carbohydr. Res., 72 (1979) 289; Guthrie, R. D. and Liebmann, J. A., J. Chem. Soc., Perkin Trans. 1, (1974) 650. [76] Du Bois, J., Tomooka, C. S., Hong, J., and Carreira, E. M., J. Am. Chem. Soc., 119 (1997) 3179; Griffith, D. A. and Danishefsky, S. J., ibid., 112 (1990) 5811; Griffith, D. A. and Danishefsky, S. J., ibid., 113 (1991) 5863; Griffith, D. A. and Danishefsky, S. J., ibid., 118 (1996) 9526. [77] Dutcher, J. D., Adv. Carbohydr. Chem., 18 (1963) 259. [78] Gibbs, C. E and Hough, L., Carbohydr. Res., 18 (1971) 363; zu Rechendorf, W. M. and Lenzen, H. J., Tetrahedron Lett., 38 (1979) 3657. [79] Baptistella, L. H. B., Marsaioli, A. J., Filho, J. D. S., Oliveira, G. G., Oliveira, A. B., Dessinges, A., Castillon, S., Olesker, A., Thang, T. T., and Lukacs, G., Carbohydr. Res., 140 (1985) 51. [801 zu Reckendorf, W. M. and Lenzen, H.-J., Liebigs Ann. Chem., (1985) 477, (1982) 265. [81] For an additional example using a thio anion see: Hashimoto, H., Shimada, K., and Horito, S., Tetrahedron Lea., 34 (1993) 4953. [82] El Shafei, Z. M. and Guthrie, R. D., J. Chem. Soc., Perkin Trans. l, (1970) 843; Guthrie, R. D. and Williams, G. J., ibid., (1976) 801. [83] Guthrie, R. D. and King, D., Carbohydr. Res., 3 (1966) 128. [84] Kudelska, W. and Michalska, M., Carbohydr. Res., 83 (1980) 43; Kudelska, W., Michalska, M., and Swiatek, A., ibid., 90 (1981) 1; Michalska, M., Brzezinska, E., and Lipka, P., J. Am. Chem. Soc., 113 (1991) 7945.

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143

[85] AI-Qawasmeh, R. A., Abdel-Jalil, R. J., AI-Tel, T. H., Thurmer, R., and Voelter, W., Tetrahedron Lett., 39 (1998) 8257. [86] Smoliakova, I. P., Han, M., Gong, J., Caple, R., and Smit, W. A., Tetrahedron 55 (1999) 4559 and references cited therein.

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EXPLOITING THE STRAIN IN [2.2.1]BICYCLIC SYSTEMS IN POLYMER AN D SYNTH ETIC ORGAN IC CHEMISTRY

Michael North

1.

2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 1.1 Origin of the Strain in Norbomene Systems . . . . . . . . . . . . . . . 147 1.2 Desymmetrization of Anhydrides by Proline Derivatives . . . . . . . . 148 Ring Opening Metathesis Polymerization of Norbomene Derivatives . . . . . 150 2.1 Mechanism of ROMP . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 2.2 Background to Our Work . . . . . . . . . . . . . . . . . . . . . . . . . 153 2.3 ROMP of Amino Acid-Derived Norbomenes . . . . . . . . . . . . . . . 155 2.4 ROMP of Peptide-Derived Norbomenes . . . . . . . . . . . . . . . . . 160 2.5 ROMP of Nucleic Acid Derivatives . . . . . . . . . . . . . . . . . . . . 163 2.6 ROMP of Miscellaneous [2.2.1 ]Bicycloalkenes . . . . . . . . . . . . . 165 Synthesis of Highly Substituted Cyclopentanes . . . . . . . . . . . . . . . . . 168 3.1 Synthesis of All-syn-Tetrasubstituted, EnantiomericaUy Pure Cyclopentanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 3.2 Synthesis of Pentasubstituted, Enantiomerically Pure Cyclopentanes . . 176 3.3 On the Difference in Reactivity between the Tetra- and Pentasubstituted Cyclopentane Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . 179

Advances in Strained and Interesting Organic Molecules Volume 8, pages 145-185. Copyright 9 2000 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-7623-0631-9

145

146

MICHAEL NORTH Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Note on Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

181 182 182

1. INTRODUCTION The norbornene, or bicyclo[2.2.1]hept-2-ene, (1) ring system is a strained ring system which is in many ways ideally suited for exploitation in organic synthesis. Among the features of this class of compounds are: 9 Ease of synthesis by Diels-Alder reactions, particularly if the dienophile bears electron-withdrawing substituents (Scheme 1). 9 Conformational rigidity which results in well-defined locations for substituents. 9 The presence of an alkene bond where further chemistry can be carried out. 9 A strain energy of approximately 100 ld/mol. This chapter will illustrate the ways in which the strain energy present in norbornene systems can be exploited to produce compounds which are useful in the fields of polymer chemistry, synthetic organic chemistry, and bioorganic chemistry. Emphasis is placed on results obtained within my laboratory, though reference is also made to other work carried out in this area. The starting materials for most of the studies described in the following pages are the anhydrides 2 and 3 which are readily available by the Diels-Alder reaction between cyclopentadiene and maleic anhydride. This reaction can be controlled to give either the endo-isomer 2 as the kinetic product of the reaction [1], or the exo-anhydride 3 the thermodynamic product [2]. Alternatively, anhydride 2 can be isomerized to anhydride 3 by heating to 180 ~ (Scheme 2). Before the chemistry associated with the ring opening of norbomenes is described, the remainder of this Introduction will discuss the origin of the strain in norbornenes, and introduce some background chemistry which is needed for the chemistry covered in Section 3.

1

X Y Y

Scheme 1.

Exploiting the Strain in [2.2.1]Bicyclic Systems

147

180~

o ckionnetioC1 ~

+

S 0

tchoenTo l~ namic o

o 3

2

Scheme 2.

1.1 Origin of the Strain in Norbornene Systems For monocyclic ring systems, it is well known that five and six-membered rings are strain free [3]. At first sight therefore, it may be surprising that norbornene should have a strain energy of ca. 100 kJ/mol, a value which is comparable with those of cyclobutane and cyclopropane (115 and 110 kJ/mol, respectively [4]). However, the rigid, bicyclic framework of norbornene enforces considerable distortions in the C - C - C bond angles as shown in Figure 1. Thus, the C - C - C bond angle around the CH 2 bridge is reduced by 17 ~ and the C - C = C bond angle is reduced by 13 ~ from the preferred bond angles for sp 3- and sp2-hybridized carbon atoms, respectively [5]. In addition, the six-membered ring of the norbornenes is constrained to a boat conformation which forces the substituents on C2 and C3 (X and Y in Figure 1t) to eclipse one another. The net effect of these bond distortions and eclipsing interactions is to give the norbomene ring system a considerable strain energy. If any one of the carbon-carbon bonds in a norbornene ring is broken, then all of this strain energy is released since the product will be an unstrained, monocyclic cyclopentane or cyclohexane. The

107

~

92~

104~

Y

Figure 1. Bond angles and eclipsing substituents in norbornene derivatives.

148

MICHAEL NORTH

easiest bond to break is the double bond, since this can be achieved by metathesis (Section 2) or ozonolysis (Section 3).

1.2 Desymmetrizationof Anhydridesby Proline Derivatives Despite containing four stereocenters, anhydrides 2 and 3 are achiral meso compounds since they possess a plane of symmetry. The two carbonyl groups of compounds 2/3 which lie on opposite sides of the plane of symmetry are enantiotopic. As a result, achiral nucleophiles will react at the same rate with both carbonyls of the anhydride since the transitions states for the two reactions will be enantiomeric and so of equal energy. Chiral nucleophiles however, may react more rapidly with one of the carbonyls than the other since in this case the transition states are diastereomeric. This provides a route for converting achiral anhydrides 2 and 3 into enantiomerically pure carboxylic acids which possess four or more stereocenters. A number of examples of this desymmetrization reaction employing a range of chiral alcohols or amines as the nucleophile have been reported in the literature [6]. In 1995, we showed that methyl (S)-prolinate (4) could be used as the chiral nucleophile in this reaction [7], and that excellent asymmetric induction was obtained under mild reaction conditions (Scheme 3). Thus, anhydride 2 was converted into diastereomerically pure acid 5, and anhydride 3 gave acid 6 as a 10:1 ratio of diastereomers, the major isomer being that shown in Scheme 3. Subsequent work [8] showed that a wide range of cyclic meso-anhydrides could be desymmetrized in this way, though the best diastereomeric excesses were obtained with anhydrides derived from [2.2.1]bicyclic ring systems (Figure 2). It was also possible

2

H

0

5

4

R= Me, tBu

-

0

&

~

tt

3

6 Scheme 3.

COzR

Exploiting the Strain in [2.2.1]Bicyclic Systems H O

149 ,O

/...-'~,,. ~ H .O ....

>50: I

I0: I

2

I0: I

3

O

O

O

H

O

O

O

6:1

9:1

4:1


0

0

0

4:1

4:1

0

0

""'....

>50:1

Figure 2. Desymmetrization of meso-anhydrides by methyl (S)-prolinate. The ratio below each anhydride is the diastereoselectivity, and the arrow indicates the carbonyl which is attacked bythe amine. In the final example, it has not been determined which carbonyl is attacked but this is assumed to be the one indicated by the broken arrow by analogy with the other structures. to use the ten-butyl rather than methyl ester of proline with only minor changes to the diastereoselectivity. The stereochemistry of the major diastereomer of the acid obtained fTom anhy&ides containing [2.2.1]bicyclic ring systems can be predicted from the model shown in Figure 3. Thus, reaction occurs on the less-hindered face of both the anhydride and proline ester, and occurs at the anhydride carbonyl which avoids steric interactions between the proline ester and the anhydride. In addition to the work which will be discussed in Section 3, the desymmetrization of meso-anhy&ides by proline esters has been employed in the synthesis of conformationally constrained peptides [9] and conformationally constrained protease inhibitors [ 10].

150

MICHAEL NORTH X o

0

COOMe

Figure 3. Model to predict the major diastereomer of the acid formed by the desymmetrization of anhydrides containing a [2.2.1 ]bicyclic ring system. 0

RING OPENING METATHESIS POLYMERIZATION OF NORBORNENE DERIVATIVES

Olefin metathesis refers to the process whereby the carbon-carbon double bonds of two alkenes are formally broken to give reactive intermediates which can then reassemble to form new alkenes as shown in Scheme 4. When applied to cyclic alkenes, one possible outcome of this reaction is the formation of a polymer with concomitant ring opening, a process which is referred to as ring opening metathesis polymerization (ROMP) [ 11]. Neither ROMP nor olefin metathesis in general occur spontaneously, a catalyst or initiator is required and many transition metal complexes or mixtures of transition metal complexes have been discovered which will induce this reaction. The nature of the true catalytic species derived from these transition metal complexes is generally not known; however a major breakthrough in this area was the discovery that metal alkylidene complexes could be used as metathesis catalysts. Rl~]]~+RI R

R2

R~~./R 3 R4~ ~R 4

[ metathesis catalyst

R~'/R4 / R2R4 R4

ROMP initiator~ Scheme 4.

Exploiting the Strain in [2.2.11Bicyclic Systems

151

~)Cy3 H Cl-.,.,u ,,... C l " 1~ ~ P h

FCy3 RO

7 R = Me3C 8 R = (CF3)Me2C 9 R = (CF3)2MeC

Cy = cyclohexyl 10

Among the many metal alkylidene complexes investigated for olefin metathesis, the molybdenum complexes 7-9 discovered by Schrock's group [12] and the ruthenium complex 10 report by Grubbs and co-workers [13] have been widely used. Complexes 7-9 are highly air and moisture sensitive, can only be used in nonprotic solvents, and are not compatible with substrates containing protic functional groups or ketones but are highly reactive olefin metathesis initiators. In contrast, complex 10 is comparatively stable to air and moisture, can be used in protic solvents (including water), and tolerates a wide range of functional groups in the substrate. This complex is however, much less reactive as a metathesis initiator than complexes 7-9, which is significant for ROMP where tens or hundreds of metathesis reactions need to be carded out consecutively to construct the polymer chain. For other types of olefin metathesis (e.g. ring-closing metathesis), the lower reactivity of complex 10 is less significant since it is possible to use high concentrations of the catalyst and correspondingly low turnover numbers to obtain the desired metathesis reaction in a short period of time. Hence, the discovery of complex 10 and its tolerance of air, moisture, and functional groups has led to an explosion of interest in olefin metathesis in organic synthesis [14]. Although many cyclic alkenes undergo ROMP [15], the metathesis process is reversible so high yields of polymeric materials are obtained only if the polymer is thermodynamically more stable than the monomer. For this reason, strained alkenes are particularly good monomers for ROMP, and the ease of synthesis of norbornene derivatives combined with the strain energy of this ring system means that most work has been carded out on the ROMP of norbornene derived monomers [16].

2.1 Mechanism of ROMP A general mechanism for ROMP has been determined as shown in Scheme 5 [17]. Thus, a [2+2] cycloaddition reaction between the metal alkylidene complex and the cyclic alkene generates a metallocyclobutane intermediate 11. A retro [2+2] cycloaddition reaction then generates a new metal alkylidene complex 12, with concomitant ring opening of the cyclic alkene. Alkylidene complex 12 can react

152

MICHAEL NORTH

with another molecule of the cyclic alkene to form a new metallocyclobutane intermediate which can again ring open to form a further metal alkylidene complex. This process can be continued indefinitely until a polymer is formed. Molybdenum complexes 7 - 9 function directly as the metal alkylidene complex, but ruthenium complex 10 first coordinates to the alkene to form a six-coordinate complex and then dissociates a phosphine ligand prior to formation of the metallocyclobutane [18]. There are a number of important consequences of the mechanism shown in Scheme 5: 1. The stereochemistry of the metallocyclobutane determines the stereochemistry of the alkene formed during the ROMP process. In particular, if the substituents (R and H in structure 11) are syn to one another, then the alkene will have the cis geometry while if the substituents are anti, then the trans-alkene will be formed. For molybdenum complexes 7-9, it is possible to control the stereochemistry of the metallocyclobutane and hence the stereochemistry of the alkene in the polymer by variation of the alkoxide ligands. As the ligands become more electron-withdrawing, i.e. as the number of fluorine atoms in the ligands increases, the percentage of cis-alkenes in the polymer increases [19]. 2. Each [2+2] cycloaddition/retrocycloaddition cycle shown in Scheme 5 generates a new metal alkylidene complex which can act as a ROMP initiator. Provided air, moisture, and impurities are rigorously excluded from the reaction mixture, these metal alkylidene complexes are stable, so there are no termination reactions associated with this polymerization. Hence, once the polymerization is initiated, it will continue until all of the monomer has been consumed. If further monomer is then added, the polymerization will

R

H

R\

/ H

M

----

12

11

R\

B

/H

R

)rl Scheme 5.

\

/

H

Exploiting the Strain in [2.2.11Bicyclic Systems

153

restart, with the new monomer units being added to the end of existing polymer chains. If the second monomer is different from the first, then a block copolymer will be produced. In principle, many different monomers can be added sequentially to the polymerization mixture allowing the synthesis of polymers composed of blocks of different monomers. 3. The rate of initiation of the polymer (ki) is the rate of formation of metal alkylidene 12, i.e. the rate of the first ROMP cycle. All subsequent cycles are propagation steps and can be assumed to proceed at approximately the same rate (kp). If ki >> kp, then all of the polymer chains will start growing at approximately the same time and they will all grow at the same rate, so that when all of the monomer has been consumed they will all have the same length and a monodisperse polymer will be formed. In practice, no ROMP initiator is known for which ki >> kp, but provided ki = kp, then a polymer with a narrow molecular weight distribution is obtained. It should be noted however, that all of the steps in ROMP are reversible, so the molecular weight distribution of the polymer tends to increase with time as monomer units are depolymerized from the polymer chains [20]. 4. When the polymerization is complete, it is necessary to destroy the remaining metal alkylidene complexes to obtain a stable, metal-free polymer. For polymers formed using initiators 7-9, this is usually achieved using benzaldehyde to give a polymer with a benzylidene end-group. Ruthenium alkylidene complexes, however, do not react with aldehydes, so the polymerizations are quenched with ethyl vinyl ether to give a polymer with a methylene end-group. Thus the nature of the ROMP mechanism allows the preparation of polymers with a much greater degree of control over the polymer structure than can be achieved by classical polymerization methods. The molecular weight of the polymer is determined directly by the monomer to initiator ratio, the polymer is formed with a narrow molecular weight distribution, the stereochemistry of the double bonds within the polymer can be influenced, block copolymers can be prepared, and reactive end-groups can be introduced onto the polymer chains.

2.2 Background to Our Work A 1997 review of ROMP [11 ] details approximately 200 bicyclo[2.2.1]heptane derivatives which have been found to undergo ROMP. The majority of these monomers however, contain only relatively unreactive functional groups such as alkyl groups, aryl rings, halides, or esters. We were interested in using ROMP methodology to prepare biomimetic polymers derived from amino acids or nucleicacid bases. These compounds contain a wide variety of functional groups, so the ROMP of these compounds was expected to test the versatility of the available ROMP initiators. In this respect, it should be noted that at the start of our work in 1993, molybdenum-based initiators 7-9 were known, but the ruthenium-based

MICHAEL NORTH

154

/ .-~M

T

ROMP

i

" R - . J ......

T

T

T

H

head to tail polymerization M

RO.P

T

R

.

--:'

T

-

H

head to head polymerization Scheme 6.

initiator 10 which is more tolerant of functional groups had not been discovered. In addition, the amino acid-derived monomers would be chiral and enantiomerically pure, thus allowing the synthesis of nonracemic polymers. Concurrently with our work, the ROMP of carbohydrate-derived monomers was being investigated elsewhere [21 ]. One problem with ROMP is that if the monomers are unsymmetrical, then they can be polymerize~ in two ways: head-to-tail or head-to-head [22] as shown in Scheme 6. While head-to-tail polymerization is normally favored for steric reasons, the occasional incorporation of heM-to-head units would result in an undesirable lack of uniformity in the polymers. Hence, we elected to base our monomer units around imides of general structure 13 (endo- and exo-isomers) since for monomers bearing identical substituents on C2 and C3, the problem of head-to-tail versus head-to-head polymerization does not occur.

o

R O 13

Exploiting the Strain in [2.2.1]Bicyclic Systems

155

2.3 ROMP of Amino Acid-Derived Norbornenes The simplest monomers which could be polymerized to give polymers analogous to proteins have structures 14 and 15 corresponding to the endo- and exo-isomers of the monomers, respectively. In these monomers, the acid group of the amino acid has been protected as a methyl ester since a free carboxylate group would be incompatible with the molybdenum-based initiators 7-9. Monomers 14a-i/15a-i could be readily prepared on 100 gram scale from anhydrides 2/3 as shown in Scheme 7 [23] and monomers 14b-i/15b-i were optically active. That no racemization was to be expected in the majority of cases during this synthesis was shown by analysis of compounds 14c/15c. These monomers are derived from the amino acid isoleucine which contains two stereocenters. Thus, in this case, epimerization of the tx-stereocenter would generate a pair of diastereomers which would be distinguishable by NMR. In the event, monomers 14c/15c gave a single set of peaks in both their 1H and 13C NMR spectra. Hence, it appeared that for "normal" amino acids the route outlined in Scheme 7 would form the monomers without racemization. Monomers 14i/15i which are derived from the amino acid cystine also contain two stereocenters, and in this case the 1H and 13C NMR spectra of the monomers showed two sets of peaks indicating that partial racemization had occurred during

R

0 2

yNyR 0 14a-i

CI~

CO2Me

Et3N / toluene I A

0 3

a) R = H b) R = Me c) R = CH(Me)Et d) R = CHMe2 e) R = CH2CHMe 2 0 R = CH2Ph g) R = Ph h) R = CH2OH i) R --- [CH2S] 2

Scheme 7.

0 R

0 15a-i

CO2Me

156

MICHAEL NORTH

o

+ cI

NZco M o

"

O 2, 3

O I

~O2Me

eOH / HCl

2, 14 (endo) 3, 15 (exo)

O

g) R = P h i) R = [CH2S] 2

R O

CO2Me

14g,i / 15g,i Scheme B.

the synthesis. Cystine derivatives are known to be particularly prone to racemization as the a-hydrogen is more acidic than that of other amino acids [24], and the reaction conditions required for the formation of monomers 14i/15i require heating to 100 ~ in the presence of triethylamine. Similarly, the a-hydrogen of phenylglycine, from which monomers 14g/15g are derived, is particularly acidic [24], so partial racemization was expected during the synthesis of these monomers as well. In order to allow the synthesis of enantiomerically pure monomers 14g, i/15g,i, an alternative synthesis of the monomers was developed as shown in Scheme 8. This two step synthesis avoids heating the reaction mixture and was found to give monomers 14g,i/15g,i without racemization [25]. Monomer 16 which contains a thermally unstable 7-oxanorbomene ring could also be prepared from exo-7-oxonorbom-5-ene-2,3-dicarboxylic anhydride by the route shown in Scheme 8.

O Me 0

C02Mc

16

Exploiting the Strain in [2.2.1]Bicyclic Systems

157

Preliminary investigations have so far been carried out on the polymerization of monomers 14a-c,f,g and 15a-c,f,g using initiators 7-10. In each case investigated, polymeric material was obtained; however monomers 14a-c and 15a-c were selected for a more detailed study [26] and only the polymerization of these monomers will be discussed here. Monomers 14a/15a are derived from the simplest amino acid~glycine, monomers 14b/15b from the simplest chiral amino a c i d ~ alanine, while monomers 14e/15c are derived from the amino acid with the largest side chain~isoleucine. Thus, these six monomers were expected to allow the scope of the polymerization with respect to the size of the amino acid to be investigated. Selected analytical data for these polymerizations are given in Table 1, and in each case a 1H NMR signal corresponding to a propagating alkylidene compound was observed prior to quenching the polymerizations with benzaldehyde, and the isolated polymers had narrow molecular weight distributions (as judged by the polydispersity index which would be 1.00 for a completely monodisperse sample [27]). Both of these properties are indicators that the polymerizations were carried out under living polymerization conditions. In the case of polymers derived from

Table 1. Selected Physical Data for Polymers Derived from Monomers 14a-c and 15a-c

Monomer

Initiator

Propagating Alkylidene %cis i~) Double Bonds

Specific Rotation

Polydispersity Index

14a

7

11.9

19

--

1.27

14a 14a 15a

8 9 7

11.8 12.3 11.4

24 36

---

5

--

1.21 1.27 1.12

15a

8

12.4

46

~

1.21

15a

9

13.0

71

~

1.23

15a

10

19.6

13

~

1.48

14b

7

11.9

10

-52

1.28

14b

8

12.4

10

-50

1.20

14b 15b 15b 15b 15b 14c 14c 14c 15c 15c 15c 15c

9

13.0

10

-51

1.10

7 8 9 10 7 8 9 7 8 9 10

11.5 11.9 12.4 19.6 11.7 12.1 12.7 11.5 11.9 12.4 19.8

7 43 73 16 8 6 12 <5 55 77 15

-31 -35 -30 -35 -79 -72 -67 -57 -61 -59 -59

1.27 1.51 1.07 1.22 1.44 1.25 1.05 1.27 1.17 1.23 1.11

158

MICHAEL NORTH

monomers 15a-e, the percentage of cis-alkenes within the polymer was determined by the structure of the initiator, with initiators 7 and 10 giving polymers with only a very low percentage of cis-alkenes while initiator 9 gave polymers containing predominantly cis-alkenes. By contrast, monomers 14a-c show little variation of the percentage of cis double bonds in the polymer with initiators 7-9, an effect which can be accounted for by the much slower rate of polymerization of these monomers [19]. These monomers were also polymerized only very slowly by initiator 10, and the polymerizations did not proceed to completion. It is well known that endo-isomers of norbornenes are more sterically hindered than the exo-isomers and hence are polymerized more slowly [28]. Finally, polymers derived from optically active monomers were themselves optically active, and the specific rotation of-the polymers was not significantly dependent upon the percentage of cis double bonds in the polymer. One unexpected property of the polymers derived from monomer 15a (and only of the polymers derived from this monomer) was the ability of the polymers to absorb alkanes. Thus, methane, pentane, hexane, heptane, octane, decane, dodecane, 2,2-dimethylpropane, 2,2,4-trimethylpentane, and cyclohexane were all absorbed by the polymer, and released only at temperatures above 150 ~ the glass transition temperature of the polymer. The amount of hydrocarbon which can be incorporated into the polymer depends on the structure of the alkane, and varies from 3 mol% for pentane and 2,2-dimethylpropane up to 42 mol% for cyclohexane and 2,2,4-trimethylpentane. The absorption seems to be specific for nonpolar hydrocarbons however, since no absorption of ethene, 1-hexene, benzene, methanol, 1-hexanol, 1-fluorohexane, 1-chlorohexane, acetone, or carbon dioxide was observed. This alkane incorporation was independent of the initiator used and hence did not depend upon the cis/trans alkene ratio, but it did depend upon the stereochemistry of the monomer since no such effect was observed for polymers derived from monomer 14a. The alkane incorporation also depended upon the molecular weight of the polymer, since hexane absorption was only observed for polymers with molecular weights (Mn) greater than 16,000. It has not been possible to determine the cause of the hydrocarbon absorption, but it is thought that the alkane

Table 2. Selected Physical Data for Block Copolymers Derived from Monomers

14b, c and 15a

First Monomer (mol%) 15a (55) 15a (56) 14b (51)

Second Monomer (mol%) 14b (45) 14c (44) 14c (49)

%cisDouble Bonds <10 <10 <10

Calculated Specific Rotation -24 -34 -65

Actual S p e c i f i c Polydispersity Rotation Index -29 -35 -64

1.13 1.32 1.63

Exploiting the Strain in [2.2.1]Bicyclic Systems

159

a) R=H b) R = Me c) R = CH(Me)Et 0

C02H

17a-c

is held in voids within the polymer and that in polymers derived from monomers 15b,c, these voids may be occupied by the amino acid side chains. A series of block copolymers derived from monomers 14a-c and 15a-c have also been prepared using initiator 7 [29]. The block copolymers were prepared by first mixing initiator 7 and the first monomer, then when the polymerization was complete, adding the second monomer and allowing the polymerization to proceed. Selected analytical data for three of these polymers is given in Table 2. In each case, the block copolymers had narrow molecular weight distributions, and were composed predominantly of trans double bonds. The specific rotations of the polymers were found to match closely the predicted specific rotations calculated on the basis of the specific rotations of the homopolymers (Table 1) and the proportion of each monomer in the block copolymer. No alkane incorporation was observed in any of the block copolymers, even those derived from monomer 15a. Since the ruthenium initiator 10 is known to be tolerant of protic functional groups, the polymerization of acid-containing monomers 17a-e was also investigated using this initiator [30]. Monomers 17a-r were prepared by essentially the same method as that used to prepare the corresponding methyl esters (Scheme 7) [23]. In view of the known lower reactivity of the endo-isomers of norbornene derivatives, and the low activity of initiator 10 compared to initiators 7-9, only the exo-isomers of the monomers were investigated. Monomers 17a-e were all polymerized by initiator 10, and selected data for the polymers is given in Table 3. These data show that all of the monomers were polymerized by a living process, and the properties of the polymers were very similar to those of the polymers derived from the corresponding amino ester-derived monomers 15a-e. It was also possible to

Table 3.

Monomer 17a 17b 17c

Selected Physical Data for Polymers Derived from Monomers 17a-c and Initiator 10

Propagating Alkylidene (8)

19.6 19.6 19.7

%cis Double Bonds SpecificRotation 13 15 16

-

-

-31 -52

Polydispersity Index 1.33 1.35 1.37

160

MICHAEL NORTH

prepare a series of block copolymers derived from two of the monomers 17a-c, or one of monomers 17a-c and one of monomers 15a-e. Again, the properties of the polymers were analogous to those of the block copolymers derived from monomers 14a-c/15a-c [29].

2.4 ROMP of Peptide-Derived Norbornenes Having shown that monomers derived from a single amino acid could be polymerized using initiators 7-10, the next step in the preparation of biomimetic polymers was to investigate the polymerization of polymers containing a peptide unit. The monomers required for this work (18a-e) were prepared from the glycine derivative 17a as shown in Scheme 9. Thus conversion of acid 17a to the corresponding acid chloride 19 was achieved by reaction with oxalyl chloride/DME Subsequent treatment of acid chloride 19 with an amino acid methyl ester or dipeptide methyl ester then gave the desired monomers [31 ]. Glycine was chosen as the N-terminal amino acid for each of these polymers for three reasons:

o

o

CICOCOCl / C02H DMF --

COCl

0

o

17a

19

HCI. RHNC

' HRCO2Me ~

HCI H-Phe-Phe-OMe / [ r:. :~

~

~

CO-Phe-Phe-OMe N R

O

CO2Me O

18a-d

18e 18a: R = H, R' = CH3 18b: R = H, R' = CH2Ph 18(:: R = H, R'= Ph 18d: R-R' = CH2CH2CH2 Scheme 9.

Exploiting the Strain in [2.2.1]Bicyclic Systems

161

1. There was no danger of racemization during the preparation of acid chloride 19. 2. Glycine is the smallest amino acid and hence would limit steric congestion around the norbornene ring. 3. The >NCH2-grou p provides a readily recognized and characteristic signal in the 1H NMR spectrum of the polymers and so aids in their characterization. Each of monomers 18a-e was polymerized using initiators 7-9. The polymers derived from monomer 18a were rather insoluble, but all other monomers gave soluble polymers which could be characterized. Selected analytical data for these polymers is given in Table 4 and, as these data show, the polymers were all obtained by a living process since a 1H NMR signal corresponding to a propagating alkylidene entity was observed and the isolated polymers had narrow molecular weight distributions. The polymers were all optically active, and the percentage of cis-alkene units in the polymers increased as the number of fluorine atoms in the initiator increased [ 19]. Thus, it was clear that increasing the length of the peptide attached to the norbornenr did not inhibit the ROMP of the monomers, and the molybdenum-based initiators 7-9 were compatible with the secondary amide bonds present in compounds 18a-e. Ongoing work in this area is concerned with the preparation and polymerization of norbornenes attached to longer peptides which are known to adopt specific conformations such as an tz-helix or a [3-sheet. As a final test of the ability of ROMP to tolerate sensitive functional groups present in peptides, the synthesis and p01ymefization of the penicillin-derived

Table 4. Selected Physical Data for Polymers Derived from Monomers 18b-e Monomer

Initiator

Propagating Alkylidene %cis (8) Double Bonds

Specific Rotation

Polydispersity Index

18b 18b 18b 18c 18c 18c 18d

7 8 9 7 8 9 7

11.6 12.0 12.4 11.6 12.0 12.4 11.6

8 44 69 13 57 74 9

+79 +59 +63 +61 +57 +56 -64

1.34 1.56 1.26 1.03 1.39 1.03 1.1 7

18d 18d 18e 18e 18e

8 9 7 8 9

12.0 12.6 11.6 12.2 12.5

45 71 a a a

-56 -58 +24 +27 +19

1.13 1.13 1.04 1.03 1.03

Noter aThepercentageof cis-alkenesin the polymer could not be determined due to signal overlap in the NMR spectra.

162

MICHAEL NORTH

monomers 20 and 21 was investigated. In view of the strained nature of the [3.2.0]bicyclic ring system present in the penicillin nucleus, and the ease with which nucleophiles are known to react with penicillins [32], compounds 20/21 were expected to provide a stringent test of the capabilities of ROMP. In addition,

0

C02H

H ~ S

..."CH3

0 17a

DCC/ N-hydroxysuccinimide

~_.~'~ 0

~/o

MeC(OSiMe3)=NSiMe3

%., o~

H H

cii~ ....co~s~o~

o//-~---"

0

1 o

/J-~

O"

L

....

"CO2SiMe3

2O

H20

o

o/J-~ 21

Scheme 10.

L.....call

Exploiting the Strain in [2.2.1]Bicyclic Systems

163

polymers prepared from monomers related to 21 could have applications including slow release agents for antibiotics, antibiotic impregnated bandages for the treatment of surface wounds, and the ability to deliver multiple copies of an antibiotic simultaneously thus helping to overcome problems associated with bacteria becoming resistant to antibiotics. The synthesis of monomers 20 and 21 is shown in Scheme 10 [33], and had to be carded out under very mild conditions to avoid decomposition of the penicillin ring. The acid functionality of 6-aminopenicillanic acid was first protected as a trimethylsilyl ester [34], and then reacted with the N-hydroxysuccinimide ester of glycine derivative 17a to give monomer 20. Treatment of compound 20 with water produced the carboxylic acid-containing monomer 21. Both monomers 20 and 21 were polymerized by treatment with the ruthenium-based initiator 10 and gave, after aqueous workup, the same insoluble polymer which could be characterized by electrospray mass spectrometry. Thus, a polymer sample prepared using 10 equiv of monomer 21 was found to contain chains containing between 8 and 17 monomer units. The IR spectra of the polymers showed characteristic 13-1actam carbonyl absorption at 1770 cm -1 [35], showing that the 13-1actam ring had survived intact during the polymerization. The polymerization of monomer 20 could be monitored by 1H NMR, and a signal at 19.4 ppm corresponding to a propagating alkylidene unit was observed, indicating that the polymerization of this monomer was a living process.

2.5 ROMP of Nucleic Acid Derivatives A number of synthetic applications for polymers derived from nucleic acids could be anticipated. These include the preparation of novel adhesives, exploiting the specific hydrogen-bonding interactions between complementary nucleic-acid bases [36], and the development of new pharmaceuticals. Thus, a synthetic polymer containing a sequence of nucleic-acid bases which are complementary to the bases found within the DNA/RNA of a virus might exhibit antiviral activity. Similarly, if the polymer contains a sequence of bases which are complementary to a part of a gene which is activated in tumor cells, then the polymer may exhibit anticancer properties. In view of the high degree of control over the properties of the polymer

0

o

Figure 4. General structure of the monomers derived from nucleic-acid bases.

164

MICHAEL NORTH

that can be obtained by ROME and the ability to prepare block copolymers, we decided to investigate the ROMP of norbornenes attached to a nucleic-acid base. The structure of the monomers used for this work is shown in Figure 4. The compounds consist of three parts: a polymerizable norbornene unit, a linker unit the length of which can be varied to allow intermolecular hydrogen bonding, and

0

0

11

H2NCH2CH

O

0

"

24

0

H2NCH2CH2NHCPh~ '~...~O O 3

NHCPh3 O CF3CO2~

...e~O H2NCH2CH2NH~

If

0 2

0 23a (endo)

HN~f

EDC

0

_ 0 . . ~.~

22a (o~o)

22b (exo) Scheme 11.

j.O

Exploiting the Strain in [2.2.1]Bicyclic Systems

165

a nucleic-acid base connected through the same nitrogen atom that is used to connect the bases to the sugar in DNA [36]. The simplest of the four bases found in DNA is thymine, and the synthesis of monomers 22a,b which incorporate this base are shown in Scheme 11 [37]. Reaction of anhydride 2 with excess ethylenediamine gave monoamine 23a; however reaction of anhydride 3 with ethylenediamine always gave di-adduct 24 as the only product. Similar di-adducts were obtained when anhydride 3 was reacted with other (z,c0-diamines. This problem was eventually overcome by reacting anhydride 3 with N-(triphenylmethyl)ethylenediamine followed by cleavage of the triphenylmethyl protecting group by treatment with acid to give monoamine 23b. Treatment of amines 23a,b with thymine acetic acid [38] then gave monomers 22a,b. Monomers 22a,b were both polymerized by the ROMP initiator 10 to give the corresponding homopolymers. The propagating alkylidene hydrogen atom of the polymers could be detected by 1H NMR spectroscopy, and the isolated polymers had narrow molecular weight distributions (polydispersity index 1.07) as determined by MALDI-TOF mass spectrometry. Interestingly, if the polymerization reactions were quenched by exposure to oxygen rather than the usual treatment with ethyl vinyl ether, then polymeric material containing an aldehyde end-group was obtained. The reactivity of aldehydes should allow these polymers to be further modified, for example by attachment to a solid support or by the introduction of other functional groups at one end of the polymer chain. It was also possible to introduce aldehyde end-groups onto the polymers prepared from amino ester- and amino acid-containing norbornenes (as discussed in Section 2.3), provided that these were prepared using initiator 10 rather than initiators 7-9 [39]. Attempts to extend this chemistry to monomers derived from other nucleic-acid bases has been hampered by the poor solubility of the products. Monomers analogous to 22a,b derived from adenine, cytosine, and guanine have all been prepared, but none of these compounds was sufficiently soluble in any organic solvent to undergo ROMP when treated with initiator 10 [40]. Work on modifying the nature of the linker to make the monomers more lipophilic is currently in progress.

2.6 ROMP of Miscellaneous [2.2.1]Bicycloalkenes The rate at which bicyclo[2.2.1 ]heptene derivatives undergo ROMP is related to the amount of strain present in the bicyclic ring system. In general, the more strained the monomer, the more rapidly it is polymerized. Increasing the rate of polymerization should decrease the polydispersity of the polymer by reducing the reaction time and hence preventing depolymerization [20]. Since norbomadienes are more strained than norbomenes due to the additional two sp 2 hybridized carbon atoms, it was of interest to prepare norbornadiene derivatives of amino acids and investigate their ROMP [41 ]. Norbomadiene derivatives cannot exhibit endo/exo isomer-

166

MICHAEL NORTH

ism and so the synthesis of these compounds was expected to be shorter and more straightforward than the synthesis of the exo-isomers of the norbomene derivatives. All attempts to prepare norbornadiene imides of amino esters analogous to compounds 14/15 have been unsuccessful, since it has proven impossible to form the imide ring under a range of reaction conditions. However, monomer 25 was prepared by the route shown in Scheme 12 [42]. Thus a Diels-Alder reaction between cyclopentadiene and but-2-yn-1,4-dioic acid gave the known diacid 26 [43], which when reacted with 2 equiv of dicyclohexylcarbodiimide and 2 equiv of glycine methyl ester gave diglycine derivative 25. The ROMP of monomer 25 was carried out using initiator 10 and provided a polymer in which only the disubstituted double bond of the norbornadiene ring had undergone metathesis as expected on the basis of previous work on the ROMP of norbornadiene derivatives [44]. Another class of compounds which have given interesting results during ROMP are the 2,3-diazanorborn-5-ene derivatives 27a,b and 28a, b [45]. These monomers are readily prepared by Diels-Alder reactions [46] (Scheme 13), and their conformations have previously been investigated by 1H NMR spectroscopy [47]. Thus, compounds 27a,b are known to exist as an interconverting mixture of the trans, exo-cis, and endo-cis conformations as shown in Figure 5. The trans conformation consists of a pair of enantiomers and has the highest population, with the exo-cis CO2H

C>,,I,

CO2H

26

O2H

I

DCC/ H2NCH2CO2Me

COHNCH2CO2Me ONHCH2CO2Me 25

I

I0

MeO2CH2CHNOC Scheme 12.

COHNCH2CO2Me

167

Exploiting the Strain in [2.2.1]Bicyclic Systems

__.CC~R/

1~1~,0

RO2C~/E/

'NN~CO2R

CO2R O 27a R = Et 27b R = tBu

21~a R = Ph

~I~b R = Me Scheme 13.

conformation having the second highest conformation and the endo-cis conformation the lowest population. Similarly, compounds 28a,b exist as an equilibrium mixture of exo- and endo-isomers, with the exo-isomer predominating. In view of their ease of preparation and the high population of trans and/or exo conformations, it was anticipated that compounds 27a,b and 28a,b would be excellent monomers for ROMP. In the event, monomers 27a,b and 28a,b were polymerized only by the more reactive of the molybdenum based ROMP initiators. Only monomer 27b could be polymerized by all three initiators 7-9. The corresponding diethyl ester 27a was polymerized only by initiators 8 and 9, and the imide-based monomers 28a,b could be polymerized only by the most reactive molybdenum based initiator, viz. 9. None of these monomers could be polymerized by the ruthenium-based initiator 10. The

/ff•/}•CO2R 1~

._ N

~~~CO~R CO2R

CO2R trans

exo-c is

Figure 5.

Conformationsof monomers27a,b.

I CO2R CO2R e ndo-c is

168

MICHAEL NORTH

Table 5. SelectedPhysical Data for Polymers Derived from Monomers 27a,b and

28a, b

Monomer

Initiator

27a 27a 27b 27b 27b 28a 28b

Notr

8 9 7 8 9 9 9

Propagating Alkylidene (8)

%cis Double Bonds

Polydispersity Index

11.1 11.7 10.6 11.0 11.6 12.4 12.4

69 84 14 66 84 89 87

1.26 1.26 1.10 1.19 1.37 1.08 a

aNo molecular weight data could be obtained for this polymer due to its abnormal elution from the gel permeation chromatography columns.

low reactivity of monomers 27a,b/2$a,b may reflect a reduction in the strain of 2,3-diazanornornene derivatives compared to norbornenes due to the nitrogen-nitrogen bond being longer than a carbon-carbon bond. However, when these monomers did polymerize they behaved very similarly to the parent norbornene systems. Thus, in each case 1H NMR spectroscopy showed the presence of a propagating alkylidene entity, and the isolated polymers had narrow molecular weight distributions (Table 5). The percentage of cis double bonds in the polymers also increased as the degree of fluorination of the initiator increased [ 19]. In conclusion, so far in this project we have shown that the well-defined metal alkylidene complexes 7-10 can be used to initiate the ROMP of a variety of bicyclo[2.2.1 ]heptene derivatives, many of which contain pendant groups of biological significance. The resulting homopolymers and block copolymers have been characterized, and our ongoing work in this area is aimed at further refining the structures of the monomers and polymers, and investigating the biological and biomimetic properties of the latter. 11

SYNTHESIS OF HIGHLY SUBSTITUTED CYCLOPENTANES

Cyclopentane rings are widely found in natural and unnatural products [48]. In contrast to the situation with cyclohexane tings, however, cyclopentane derivatives usually do not adopt a single well-defined conformation. Rather, cyclopentane derivatives are often fluxional, existing as a rapidly interconverting mixture of envelope and twist conformations [3]. As a result, the synthesis of stereoisomerically pure cyclopentane derivatives is more complex than the synthesis of the corresponding cyclohexane analogues. One approach which has been developed

Exploiting the Strain in [2.2.1]Bicyclic Systems

169

for the synthesis of diastereomerically pure cyclopentane derivatives is the use of a conformationally rigid norbornene derivative as a cyclopentane precursor. Substituents can be introduced onto the norbornene ring, and cleavage of a suitable bond in the bicyclic framework then leads to a cyclopentane of defined stereochemistry. Probably the best known example of this approach is the prostaglandin synthesis developed by Corey and co-workers [49] which is outlined in Scheme 14. The synthesis (in its original form) starts with a Diels-Alder reaction between 5-methoxymethylcyclopenta-l,3-diene and 2-chloroacrylonitrile to form norbornene 29 which could then be hydrolyzed to norbornenone 30. This two-step procedure effectively fixes the relative stereochemistry of three substituents on the cyclopentene ring. The masked cyclopentene ring is next revealed by a two-step procedure consisting of a regioselective Baeyer-Villiger reaction followed by hydrolysis of the resulting lactone to give cyclopentene 31. Subsequent manipulation of compound 31 led to the racemic prostaglandin (PGF2ct).

MeO L

+ OMe

Cu(BF4)2~ CN

CI

Ci CN 29

~

KOH

OMe

MeO 1) MCPBA

HO2C/--......

.....OH ~ 2) NaOH O 30

31

HO

i-io

r

v

HO PGF2(x Scheme 14.

170

MICHAEL NORTH

OHC

/CO~H

2.....llill

o-:

-N d

.o2R

.

o

0I

N

CO2Rl

32

Scheme 15.

In Corey's prostaglandin synthesis, it is the C1-C2 bond of a norbom-5-ene derivative that is cleaved to reveal a cyclopentene. We were attracted to the concept of breaking the alkene bond of acid 5 (and derivatives of acid 5 bearing a substituent at C7) by ozonolysis [50] to give enantio- and diastereomerically pure cyclopentane derivatives 32 which would be suitable for subsequent modification (Scheme 15). In order for this synthesis to be useful, it was anticipated that some way would need to be found to distinguish between the two aldehyde groups present in compound 32, and it was hoped to achieve this by exploiting a regioselective cyclization between the carboxylic acid group and one of the aldehydes. The remainder of this Section will outline the successful implementation of this synthetic strategy for the synthesis of highly substituted cyclopentane derivatives.

3.1 Synthesisof AII-syn-Tetrasubstituted, Enantiomerically Pure Cyclopentanes Ozonolysis of acid 5 with ozone in either dichloromcthane or methanol followed by a reductive workup with dimethylsulfide gave an equilibrating mixture of two compounds [51,52]. Spectroscopic analysis revealed that these compounds each contained a single aldehyde, a hemiacctal, and no carboxylic acid. Hence, the structure could be assigned as either the epimeric [3.3.0]bicyclic hemiacetals 33a,b, or the [3.2.1]bicyclic bemiacetals 34a,b (Scheme 16), though it was not possible to distinguish between these. The structures have been assigned tentatively as the [3.3.0]bicyclic compounds 33a,b on the basis of subsequent results and because molecular mechanics calculations [53] suggested that the [3.3.0]bicyclic ring system should be thermodynamically more stable than the [3.2.1] analogue. Whatever the actual structures of the hemiacetals, it was clear that the two aldehydes arising from the ozonolysis had been distinguished spontaneously by the carboxylic acid group. In order to allow the preparation of a single compound which could be more fully characterized, the reduction of bemiacetals 33a,b was investigated. Treatment of the epimeric mixture with sodium borohydride followed by acid catalyzed lactonization on silica gel gave the [3.2.1]bicyclic lactone 35 as the sole product. On

171

Exploiting the Strain in [2.2.1]Bicyclic Systems

standing in chloroform, or more rapidly on treatment with p-toluenesulfonic acid, lactone 35 isomerized to [3.3.0]bicyclic lactone 36. The structure of lactones 35 and 36 could not be assigned on the basis of their NMR spectra, but that of lactone 36 was secured by X-ray crystallography, and the structure of lactone 35 was determined from the structure of the corresponding p-bromobenzoate 37. To prove that no isomerization occurred during the esterification, lactone 36 was also converted into p-bromobenzoate 38 as shown in Scheme 16.

fO2Me

i

o

/--o

02H .CO2Me 03 / Me2S

"IY 0

0

C02Me 0

5 33a, b

34a,b

1) NaBH4 2) SiO2

O2Me O

_~ tt 0 'OH 0

CO2Me 36

~

BrC6H4COCI / Et3N

\

o

OC~r

~

35

BrC6H4COCI / Et3N

CO2M~ O

38

37

Scheme 16.

CHO

172

MICHAEL NORTH

The initial formation of the strained [3.2.1]bicyclic lactone 35 during the reduction of hemiacetals 33a,b can be explained by the mechanism shown in Scheme 17 [52]. Thus, the hemiacetal acts as a "semi-protecting" group for one of the two latent aldehydes of compounds 33a,b, so that the other aldehyde is reduced first. The resulting alkoxide then lactonizes (probably assisted by a Lewis acid generated in situ from the sodium borohydride), forming the [3.2.1]bicyclic ring system and revealing the other aldehyde which is subsequently reduced to the corresponding alcohol, giving lactone 35. Whatever the mechanism of this reaction, the ability to produce either lactone 35 or its isomer 36 achieved the goal of distinguishing between the two carbonyl groups formed during the ozonolysis, and it was expected to allow subsequent chemistry to be carried out selectively at either alcohol group. Having developed a concise synthesis of isomeric lactones 35 and 36, the re-oxidation of the unprotected alcohol group was investigated in the expectation that subsequent addition of an organometallic reagent to the aldehyde would occur diastereoselectively, thus establishing an additional stereocenter into the carbon framework. In the event, the oxidation of the unstrained [3.3.0]bicyclic lactone 36 to aldehyde 39 occurred without difficulty when carded out under Swern conditions (Scheme 18) [54]. That aldehyde 39 still contained a [3.3.0]bicyclic ring system was established by its reduction back to lactone 36. Attempts to oxidize the strained [3.2.1 ]bicyclic lactone 35 under the same conditions, however, gave the mono- and dialdehydes 39 and 40 as the only products. An alternative structure for dialdehyde 40, namely the ~ketosulfoxide 41, at first appeared to be likely. However, this structure for the product was discounted due to the absence of a ketone carbonyl resonance in the 13C NMR spectrum, the absence of a sulfoxide stretch in the IR spectrum, and from comparison of the chemical shift of the SCH 2 protons with literature precedent for ~-ketosulfoxides [55] and methylthiomethyl esters [56]. The formation of aldehyde 39 during this reaction can be explained by isomerization of lactone 35 to lactone 36 under the acidic reaction conditions. Dialdehyde 40 appears to form as a result of a Pummerer rearrangement converting DMSO into

HO~..O,

FO2Mc

II~"~,.~,O\

0

33a,b

C02Me

00

02 c

O

~

CHO

N~LBI~

35

Scheme 17.

Exploiting the Strain in [2.2.1]Bicyclic Systems

-

173

i

..__.-

HOH

"l O 36

Me2SO / Et3N / CO2MeCICOCOCi O

O 39

]02Me

CO2Me

IVIES> CICOCOCI / Me2SO / / Et3N

.~

CH20H

0

.....---O

OHC

o.c

35

0~0

"f " fCO2Me

O 4O

Scheme 18.

chloromethyl methylthioether, a process for which there is literature precedent [57]. Electrophilic attack by chloromethyl methylthioether at the strained lactone carbonyl oxygen atom and ring opening by DMSO would then generate intermediate 42 (Scheme 19), which could be converted into the observed dialdehyde 40 by standard Swem oxidations. This mechanism requires 3 equiv of DMSO, and this corresponds to the amount that is used under standard Swern oxidation conditions [54]. When the oxidation of lactone 35 was carried out using fewer than three equiv of DMSO, the only effect was to increase the amount of aldehyde 39 at the expense of dialdehyde 40.

o . c =.

Otto

.--

O 41

0

CO2Me

174

MICHAEL NORTH

Me2SO + CICOCOCI

~O2Me

1

FO2Me O

o

',,..

e-'='O ~

O

CH2OH

r

35

OttC

H20H

1 HOH2C

OHC.

C1|

~ O

O'k=..=o

O 40

CO2Me

9 e ~ S , N CI

O

CO2Me

42 Scheme 19.

The addition of organometallic reagents to aldehyde 39 turned out to be disappointing and no asymmetric induction was observed. However, the addition of organometallic reagents to hemiacetals 33a,b was more rewarding. Hemiacetals 33a,b contain a free aldehyde group, and an aldehyde which has been "semi-protected" as a hemiacetal. Thus we required an organometallic reagent that would react regio- and diastereoselectively with the free aldehyde. Grignard and organolithium reagents were found to be unsuitable, but the use of allylindium was more successful. Allylindium is an interesting organometallic reagent which can be generated from allyl bromide and indium in dilute hydrochloric acid [58], and it is known to undergo highly chemo- and diastereoselective additions to carbonyl groups [59]. Reaction of hemiacetals 33a, b with 1 equiv of allylindium in aqueous solvent gave acetal 43 as a single stereoisomer as shown in Scheme 20 [52]. The tricyclic structure of acetal 43 was determined spectroscopically, though the configuration of the newly created stereocenter could be determined only after reduction and lactonization to give dilactone 44, the structure of which was determined by X-ray crystallography. Dilactone 44 contains five contiguous stereocenters and a number of functional groups which are expected to make it a versatile building

175

Exploiting the Strain in [2.2.1]Bicyclk Systems

i

~

--O

In (1 eq.) / allyl-Br OHC

O 33a,b

CO2Me

...

~,....

.

O

a

.

j-

m

o

,IN@

OH

~

MeO2 43 1) NaBI~ 2) p-MeC6H4SO3 H

In(2 eq.)/ allyl-Br

.

O

CO2Me 44

45

p-MeC~SO3H

....C( 46 Scheme 20.

block for the construction of cyclopentane derivatives. It can be prepared in a completely stereocontrolled manner from the achiral anhydride 5 in just four steps. The removal of the methyl prolinate chiral auxiliary under mild conditions by acid-catalyzed lactonization is also notable in the preparation of dilactone 44. The "semi-protected" nature of the second aldehyde in hemiacetals 33a,b was demonstrated by the addition of 2 equiv of allylindium to compounds 33a,b. In this

176

MICHAEL NORTH

allyl group is added to the front (s0-face of the aldehyde

Ill" allyl !

CO2Me

Figure 6. Explanation of the asymmetric induction observed during the addition of allylindium to hemiacetals 33a,b. case, an allyl group was added to each aldehyde, giving lactone 45 as the major product along with 20% of a diastereomeric product. The stereochemistry oflactone 45 was again determined after acid catalyzed lactonization to dilactone 46, an achiral m e s o compound. The symmetrical nature of compound 46 was apparent from its NMR spectra and from the fact that it was optically inactive. The asymmetric induction observed during the synthesis of compounds 43 and 45 is consistent with a chelation controlled addition of the allyl group (Figure 6), similar to the chelation control observed in other reactions of allylindium [59]. Thus, the indium ion is complexed to the aldehyde and amide carbonyl groups so that the re-face of the aldehyde is blocked by the cyclic hemiacetal unit, and the allyl group is directed to the si-face of the aldehyde. The addition of allylindium to the second aldehyde in the formation of lactone 45 is less diastereoselective, presumably because there is no longer a cyclic hemiacetal present to completely block one face.

3.2 Synthesisof Pentasubstituted, Enantiomerically Pure Cyclopentanes Section 3.1 demonstrated that the desymmetrization/ozonolysis approach to cyclopentanes could be used to provide a rapid and highly stereocontrolled access to enantiomerically pure derivatives, with four substituents all located syn to one another. In particular, lactones 44 and 45 are expected to find use in subsequent work aimed at the synthesis of target molecules. It was therefore of interest to explore the possibility of extending this chemistry to the preparation of pentasubstituted cyclopentanes in which all of the substituents are located syn to one another. This would require the use of a 7-substituted norborn-5-ene-2,3-dicarboxylic acid anhydride in which the substituent in the 7-position was a n t i to the anhydride. Compounds with just this stereochemistry are obtained from the Diels-Alder reaction between 5-substituted cyclopenta-l,3-dienes and maleic anhydride [60]. We elected to employ a trimethylsilyl group as the fifth substituent since the required anhydride 47 is a known compound [61] which can be prepared by the Diels-Alder reaction between 5-trimethylsilylcyclopenta-l,3-diene [62] and

Exploiting the Strain in [2.2.1]Bicyclic Systems

177

maleic anhydride. The silyl group can be transformed into a variety of other functional groups [63] and its steric bulk was expected to test the limits of the methodology. Treatment of anhydride 47 with methyl (S)-prolinate gave a 3:1 ratio of diastereomeric acids [52], with the major isomer being assumed to have structure 48 by analogy with all other endo-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid anhydrides studied in this reaction to date [7,8]. Ozonolysis of acid 48 gave a pair of epimers which were assigned structures 49a,b (Scheme 21) from the absence of any aldehyde signals in their 1H or 13C NMR spectra, but the presence of peaks which could be assigned to both acetal and hemiacetal units, along with an OH stretch in the IR spectrum. The formation of tricyclic hemiacetals 49a,b rather than the bicyclic hemiacetals 33a,b was the first suggestion that the introduction of a

Me3

.,(3)-Pto-OMe ._

"~CO2Hco2M e

)

O 47

~

48

O3 / Me2S

Me3Si " " ~ " ~

Me3Si~[

~ N ~

- (tCICO)2 /

50

.

u H~Oo~N~

e

49a,b

~ p-MeC6H4SO3H Me3Si'~~',-i

Scheme 21.

-

178

MICHAEL NORTH

fifth substituent was going to have a marked effect on the chemistry of the resulting cyclopentane derivatives. The tricyclic ring system present in compounds 49a,b is remarkably stable. Thus oxidation under Swem conditions [54] gave the tricyclic dilactone 50, and, to our surprise, treatment of hemiacetals 49a,b with p-toluenesulfonic acid resulted in lactonization with elimination of the proline unit to give the achiral tetracycle 51, albeit in only 36% yield. Molecular models of compounds 50 and 51 showed them to be appreciably strained, partly because the six-membered ring of compound 51 is constrained to a boat conformation. The structure of compound 51 is particularly interesting since one face of this compound is devoid of functionality while the other face contains five oxygen atoms all in rigidly fixed locations as emphasized in the space-filling diagram shown in Figure 7. Hence, compound 51 and related compounds would appear to have potential as metal-ion complexing agents, and this is currently being investigated. Reduction of hemiacetals 49a,b with sodium borohydride did result in opening of the tricyr ring system to give the [3.3.0]bicyclic lactone 52 which could be further lactonized to achiral dilactone 53 (Scheme 22). Interestingly, a [3.2.1 ]bicyclic lactone analogous to lactone 35 was never detected during this reduction. Treatment of hemiacetals 49a,b with potassium carbonate catalyzed the ring opening of the tricyclic framework and epimerization of the stereocenters adjacent

Figure 7. A space-filling model of dilactone 51. Oxygen atoms are shown in black, carbon a dark grey, and silicon and hydrogen in pale grey.

Exploiting the Strain in [2.2.1]Bicyclic Systems Me3Si~l

179

~

.:'~(~.._

i

...--o

..........

49a,b

52

~K2CO3

Mc3Si..... ~ OHC

~p-MeC6I-I4SO3H

~,.CO2H

[

~

Mc3Si........." ~ '

]

1F

O

CChMe

.S4

-

O

~"O 53

Scheme 22.

to the aldehyde groups to give dialdehyde 54. The structure is based on the presence of two aldehyde signals in the 1H and laC NMR spectra, and an acid group in the IR spectrum. This implies that both aldehydes must be anti to the acid group to prevent hemiacetal formation and, since the protons adjacent to aldehydes will be much more acidic than those next to acid (which will exist as its potassium salt under the reaction conditions), this implies that the dialdehyde has structure 54. The formation of dialdehyde 54 opens the possibility of preparing highly substituted cyclopentanes in which the substituents are not all syn to one another. Finally, the reaction of hemiacetals 49a,b with allylindium was investigated. However, even when only 1 equiv was employed, the only isolated products were dilactones 51 and 55 (Scheme 23). It appears that under the acidic reaction condition, the cyclization of hemiacetals 49a,b to dilactone 51 is so facile that it competes with the addition of allylindium to the hemiacetal, so that there is always sufficient allylindium present for a double addition to occur. However, dilactone 55 was formed as a single stereoisomer which was identified as the meso-isomer on the basis of the symmetry evident in its I'~IR spectra, and its lack of optical activity.

3.3 On the Difference in Reactivity between the Tetra- and Pentasubstituted Cyclopentane Derivatives Comparison of the results presented in Sections 3.1 and 3.2 above shows that while the tetrasubstituted cyclopentane derivatives tend to cyclize only to bicyclic

180

MICHAEL NORTH

i Me3Si~'~

7o

Me3Si.........~ "

/1

o
allyl-Br / In / HCI _

49a,b

55

Me3Si'~'~ I

/1

"J"o 51 Scheme 23.

systems, the pentasubstituted derivatives usually cyclize to tri- or even tetracyclic systems. The origin of this difference in reactivity can be traced to the effect that a trimethylsilyl substituent has on the conformation of a cyclopentane ring. Most cyclopentane derivatives are fluxional compounds in which there is a rapid interchange between the 10 possible envelopes and 10 twist conformations [3]. It is known, however, that for monosubstituted cyclopentanes the most stable single conformation is that in which the substituent is pseudoequatorial at the flap position of an envelope conformation (see Figure 8) [64]. In view of the large volume occupied by a trimethylsilyl group (cf. Figure 7), it seems likely that for each of compounds 49-55 the minimum energy conformation will be that in which the trimethylsilyl group is located at the pseudoequatorial flap position of the cyclopentane ring. While other conformers will still be accessible, they will be at a much higher energy than the minimum energy conformation, and so will have only very low populations. Thus, the trimethylsilyl group acts as a "conformational anchor"

H H

H

Figure 8. Predicted minimum energy conformation of a monosubstituted cyclopen-

tane.

Exploiting the Strain in [2.2.1]Bicyclic Systems

181

M e 3 S i ~

~

"OH

MeO2C~

Figure 9. The predicted minimum energy conformation of the trimethylsilylsubstituted cyclopentane derivatives. Arrows show cyclizations which are facile due to the conformation of the molecules.

here in the same way that a tea-butyl group acts as a conformational anchor in cyclohexane chemistry [3]. The effect of the trimethylsilyl group adopting the pseudoequatorial flap position in compounds 49-55 is to force the other four substituents to all adopt pseudoaxial positions around the base of the envelope as shown in Figure 9. Substituents in these positions are brought close together and this is ideal for cyclization reactions. In the absence of a trimethylsilyl substituent, viz. 33a,b, 36, 39, 40, and 45, the compounds are likely to be fluxional with each of the substituents adopting the pseudoequatorial flap position in turn. The origin of the difference in reactivity between the tetra- and pentasubstituted systems can then be traced to an entropic effect as the pentasubstituted systems exist predominantly as a single conformation prior to cyclization; there is no decrease in entropy brought about by the cyclization. For the tetrasubstituted systems, however, cyclization would result in a conformationally more rigid product, and hence a decrease in the entropy of the system. Evidently, the enthalpy of cyclization is insufficient to overcome this decrease in entropy and so the tetrasubstituted systems are less prone to cyclization than the pentasubstituted cyclopentane analogues.

ACKNOWLEDGMENTS The work described in Section 2 of this Chapter was carried out in collaboration with the group of Prof. Vernon C. Gibson at Imperial College, London. I would like to thank him and all of his co-workers, along with the numerous undergraduate students, visiting Erasmus exchange students, postgraduate students and postdoctoral research fellows whose work I have summarized. All of the work in Section 3 of this Chapter was carded out by a single Ph.D. student, Dr. Iwan G. Jones. Financial support for the work has been provided by the EPSRC, BBSRC, EU, and Peboc Division of Eastman Chemicals Ltd.; without their support none of these studies could have been carried out.

182

MICHAEL NORTH

NOTE ON NOMENCLATURE tFor consistency and ease of comparison, all substituted norbornenes discussed in this chapter have been numbered so that the sp 2 hybridized carbon atoms are C4 and C5, respectively.

REFERENCES AND NOTES [1] Fechtel, G., J. Prakt. Chem., 324 (1982) 1037. [2] Craig, D., J. Am. Chem. Sor 73 (1951) 4889. [3] Eliel, E. L. and Wilen, S. H., Stereochemistry of Organic Compounds, Wiley: Chichester, 1994, Chap. 11. [4] See p. 677 of ref. [3]. [5] Min, ]'., Benet-Buchholz, J., and Boese, R., Chem. Commun., (1998) 2751. [6] For recent examples see: Romagnoli, R., Roos, E. C., Hiemstra, H., Moolenaar, M. J., Speckamp, W. N., Kaptein, B., and Schoemaker, H. E., Tetrahedron Lett., 35 (1994) 1087; Matsuki, K., Inoue, H., and Takeda, M., ibid., 34 (1993) 1167; Metz, E, Tetrahedron, 45 (1989) 7311; Harada, T., Wada, I., and Oku, A., J. Org. Chem., 54 (1989) 2599; Imado, H., Ishizuka, T., and Kunieda, T., Tetrahedron Lett., 36 (1995) 931; Ward, R. S., Pelter, A., Edwards, M. I., and Gilmore, J., Tetrahedron: Asymm., 6 (1995) 843; Ozegowski, R., Kunath, A., and Schick, H., ibid., 6 (1995) 1191; Luna, H., Prasad, K., and Repic, O., ibid., 5 (1994) 303; Suda, Y., Yago, S., Shiro, M., and Taguchi, T., Chem. Lett., (1992) 389; Asensio, G., Andreu, C., and Marco, J. A., Chem. Ber., 125 (1992) 2233; Janssen, A. J. M., Klunder, A. J. H., and Zwanenburg, B., Tetrahedron, 47 (1991) 5513; Ohtani, M., Matsuura, T., Watanabe, E, and Narisada, M., J. Org. Chem., 56 (1991) 4120; Janssen, A. J. M., Klunder, A. J. H., and Zwanenburg, B., Tetrahedron Lett., 31 (1990) 7219; Aitken, R. A. and Gopal, J., Tetrahedron: Asymm., 1 (1990) 517; Harada, T., Wada, I., and Oku, A., J. Org. Chem., 54 (1989) 2599. [7] North, M. and Zagotto, G., Synlett, (1995) 639. [8] Albers, T., Biagini, S. C., Hibbs, D. E., Hursthouse, M. B., Malik, K. M. A., North, M., Uriarte, E., and Zagotto, G., Synthesis, (1996) 393; Jones, I. G., Jones, W., North, M., Teijeira, M., and Uriarm, E., Tetrahedron Lett., 38 (1997) 889. [9] Jones, I. G., Jones, W., and North, M., Synlett, (1997) 63; Jones, I. G. and North, M., Letters in Peptide Science, 5 (1998) 171; Hibbs, D. E., Hursthouse, M. B., Jones, I. G., Jones, W., Malik, K. M. A., and North, M., J. Org. Chem., 63 (1998) 1496; Jones, I. G., Jones, W., and North, M., ibid., 63 (1998) 1505; l-Iibbs, D. E., Hursthouse, M. B., Jones, I. G., Jones, W., Malik, K. M. A., and North, M., Tetrahedron, 53 (1997) 17417. [10] Jones, I. G., Jones, W., and North, M., Tetrahedron, 55 (1999) 279. [11] For a comprehensive review of olefin metathesis including ROMP covering the literature published up to 1996 see: lvin, K. J. and Mol, J. C., Olefin Metathesis and Metathesis Polymerization, Academic Press: London, 1997. [12] Schrock, R. R., Murdzek, J. S., Bazan, G. C., Robbins, J., DiMare, M., and O'Reagan, M., J. Am. Chem. Sot., 112 (1990) 3875; Bazan, G. C., Khosravi, E., Schrock, R. R., Feast, W. J., Gibson, V. C., O'Reagan, M. B., Thomas, J. K., and Davis, W. M., ibid., 112 (1990) 8378; Bazan, G. C., Schrock, R. R., Cho, H.-N., and Gibson, V. C., Macromolecules, 24 (1991) 4495. [13] Schwab, P., France, M. B., Ziller, J. W., and Grubbs, R. H., Angew. Chem., Int. Ed. Engl., 34 (1995) 2039; Schwab, P., Grubbs, R. H., and Ziller, J. W., J. Am. Chem. Soc., 118 (1996) 100. [14] For recent reviews see: lvin, K. J., J. Mol. Catal., A, Chemical, 133 (1998) 1; Schuster, M. and Blechert, S., Angew. Chem., Int. Ed. Engl., 36 (1997) 2036; Grubbs, R. H., Miller, S. J., and Fu, G. C., Acc. Chem. Res., 28 (1995) 446; Schmalz, H.-G., Angew. Chem., Int. Ed. Engl., 34 (1995) 1833.

Exploiting the Strain in [2.2.1]Bicyclic Systems

183

[151 See Chaps. 11-13 of ref. [ 11]. [16] See pp. 294--339 of ref. [11]. [171 Herrison, J. L. and Chauvin, Y., Makromol. Chem., 141 (1970) 161. For a detailed account of the evidence that has been accumulated to support this mechanism see Chap. 3 of ref. I11 ].

[18] Dias, E. L., Nguyen, S. T., and Grubbs, R. H., J. Am. Chem. Sot., 119 (1997) 3887. [19] Oskam, J. H., and Schrock, R. R.,J. Am. Chem. Sor 115 (1993) 11831. [20] See Chap. 16 of ref. [11]. [21] Mortell, K. H., Gingras, M., and Kiessling, L. L., J. Am. Chem. Soc., 116 (1994) 12053; Fraser, C., and Grubbs, R. H., Macromolecules, 28 (1995) 7248; Mortell, K. H., Weatherman, R. V., and Kiessling, L. L., J. Am. Chem. Sor l l8 (1996) 2297; Nomura, K. and Schrock, R. R., Macromolecules, 29 (1996) 540. [22] See p. 255-259 of ref. [l 1]. [23] Biagini, S. C., Bush, S. M., Gibson, V. C., Mazzariol, L., North, M., Teasdale, W. G., Williams, C. M., Zagotto, G., and Zamuner, D., Tetrahedron, 51 (1995) 7247. [24] Bodansky, M., Principles of Peptide Synthesis, 2nd edn., Springer-Verlag: London, 1993, Chap. 5. [25] The structure of monomer 141 was rigorously established by X-ray crystallography: North, M., Hursthouse, M. B., and Malik, K. M. A., Acta Crystallogr. Sect. C, (1997) 1701. [26] Coles, M. P., Gibson, V. C., Mazzariol, L., North, M., Teasdale, W. G., Williams, C. M., and Zamuner, D., J. Chem. Soc., Chem. Commun. (1994) 2505; Biagini, S. C., Coles, M. P., Gibson, V. C., Giles, M. R., Marshall, E. L., and North, M., Polymer, 39 (1998) 1007. [27] The polydispersity index is defined as the ratio of the weight average molecular weight of a polymer to the number average molecular weight. For a monodisperse polymer, the two molecular weights will be equal and so the polydispersity index will be exactly one. [28] See p. 312 of ref. [11]. [29] Biagini, S. C. G., Gibson, V. C., Giles, M. R., and North, M., manuscript in preparation. [30] Biagini, S. C. G., Gibson, V. C., Giles, M. R., and North, M., manuscript in preparation. [31] Biagini, S. C. G., Davies, R. G., Gibson, V. C., Giles, M. R., Marshall, E. L., North, M., and Robson, D. A., Chem. Commun., (1999) 235. [32] Simmonds, R. J., Chemistry of Biomolecules an Introduction, Royal Society of Chemistry: Cambridge, 1992, p. 220. [33] Biagini, S. C. G., Gibson, V. C., Giles, M. R., Marshall, E. L., and North, M., Chem. Commun., (1997) 1097. [34] Berry, P. D., Brown, A. C., Hanson, J. C., Kaura, A. C., Milner, P. H., Moores, C. J., Quick, J. K., Saunders, R. N., Southgate, R., and Whittall, N., Tetrahedron Lett., 32 (1991) 2683. [35] Silverstein, R. M., Bassler, G. C., and Morrill, T. C., Spectrometric Identification of Organic Compounds, 5th edn., Wiley: Chichester, 1991, Chap. 3. [36] For a survey of the structure of DNA including the nature of the hydrogen bonding that can be observed between the bases see: Sinden, R. D., DNA Structure and Function, Academic: London, 1994. [371 Gibson, V. C., Marshall, E. L., North, M., Robson, D. A., and Williams, P. J., Chem. Commun., (1997) 1095. [38] Kosynkina, L., Wang, W., and Liang, T. C., Tetrahedron Lett., 35 (1994) 5173. [39] Biagini, S. C. G., Gibson, V. C., North, M., and Robson, D. A., unpublished results. [40] Biagini, S. C. G., Davies, R. G., Gibson, V. C., North, M., Robson, D. A., and Williams, P. J., unpublished results. [41] For a survey of the ROMP of other norbornadienes see pp. 316-327 of ref. [11]. [42] Davies, R. G., Gibson, V. C., North, M., and Robson, D. A., unpublished results. [43] Williams, R. V., Sung, C.-L. A., Kurtz, H. A., and Harris, T. M., Tetrahedron Lett., 29 (1988) 19; Anderson, M. R., Brown, R. F. C., Browne, N. R., Eastwood, F. W., FaUon, G. D., Gan, D. P. C., Pullin, A. D. E., and Staffa, A. C., Aust. J. Chem., 43 (1990) 549.

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[44] See p. 316 ofref. [11]. [45] Davies, R. G., Gibson, V. C., North, M., and Robson, D. A., Polymer Commun., 40 (1999), 5239. [46] Cohen, S. G., Zand, R., and Steel, C., J. Am. Chem. Soc., 83 (1961) 2895; Carpino, L. A., Terry,

[47]

[48]

[49]

[50] [52]

[53] [54] [55] [56] [57]

[58] [59]

[60]

[61] [62] [63]

P. H., and Crowley, P. J., J. Org. Chem., 26 (1961) 4336; Cookson, R. C., Gilani, S. S. H., and Stevens, I. D. R., Tetrahedron Lett., (1962) 615; Cookson, R. C., Gilani, S. S. H., and Stevens, I. D. R., J. Chem. Soc., C, (1967) 1905; Olsen, H. and Snyder, J. P., J. Am. Chem. Soc., 99 (1977) 1524. Breliere, J. C. and Lehn, J. M., J. Chem. Soc., Chem. Commun., (1965) 426; Wager, J., Wojnarowski, W., Anderson, J. E., and Lehn, J. M., Tetrahedron, 25 (1969) 657; Nomura, Y., Masai, N., and Takeuchi, Y., J. Chem. Soc., Chem. Commun., (1975) 307; Agmon, I., Kaftory, M., Nelsen, S. F., and Blackstock, S. C., J. Am. Chem. Soc., 108 (1986) 4477. For selected examples see: Tropea, J. E., Kaushal, G. P., Pastuszak, I., Mitchell, M., Aoyagi, T., Molyneux, R. J., and Elbein, A. D., Biochemistry, 29 (1990) 10062; Aoyagi, T., Yamamoto, T., Kojiri, K., Morisha, H., Nagai, M., Hamada, M., Takeuchi, T., and Umezawa, H., J. Antibiot., 42 (1989) 883; Scarborough Jr., R. M., Toder, B. H., and Smith III, A. B., J. Am. Chem. Soc., 102 (1980) 3904; Altmann, K.-H., Kesselring, R., Francotte, E., and Rihs, G., Tetrahedron Lett., 35 (1994) 2331; Ando, O., Satake, H., Itoi, K., Sato, A., Nakajima, M., Takahashi, S., and Haruyama, H., J. Antibiot., 44 (1991) 1165. Corey, E. J., Weinshenker, N. M., Schaaf, T. K., and Huber, W., J. Am. Chem. Soc., 91 (1969) 5675. For a review of this work and subsequent modifications to the original procedure see: Nicolaou, K. C. and Sorensen, E. J., Classics in Total Synthesis, VCH: Cambridge, 1996, Chap. 5. Razumovskii, Z., Ozone and its Reactions with Organic Compounds, Elsevier: New York, 1984. Jones, I. G., Jones, W., and North, M., Synlett, (1997) 1478. Hibbs, D. E., Hursthouse, M. B., Jones, I. G., Jones, W., Malik, K. M. A., and North, M., J. Org. Chem., 64 (1999), 5413. Jones, I. G. and North, M., unpublished results. Calculations were carded out using the MM+ force field as implemented within Hyperchem. Mancuso, A. J., Huang, S.-L., and Swern, D., J. Org. Chem., 43 (1978) 2480. Drewe, J. A. and Groundwater, P. W., J. Chem. Soc., Perkin Trans. 1, (1997) 601. Kukla, M. J., Tetrahedron Lett., 23 (1982) 4539. Bordwell, E G. and Pitt, B. M., J. Am. Chem. Soc., 77 (1955) 572; Amonoo-Neizer, E. H., Ray, S. R., Shaw, R. A., and Smith, B. C., J. Chem. Soc., (1965) 6250; Thea, S. and Cevasco, G., J. Org. Chem., 53 (1988) 4121. For reviews on the use of organometallic reagents, including organoindium reagents, in aqueous solvent systems see: Chan, T. H., Li, C.-J., Lee, M. C., and Wei, Z. Y., Can. J. Chem., 72 (1994) 1181; Li, C.-J., Tetrahedron, 52 (1996) 5643. Paquette, L. A. and Lobben, P. C., J. Am. Chem. Soc., 118 (1996) 1917; Paquette, L. A. and Mitzel, T. M., ibid., 118 (1996) 1931; Paquette, L. A., Mitzel, T. M., Isaac, M. B., Crasto, C. E, and Schomer, W. W., J. Org. Chem., 62 (1997) 4293; Isaac, M. B. and Paquette, L. A., ibid., 62 (1997) 5333; Bemadelli, P. and Paquette, L. A., ibid., 62 (1997) 8284. Gilman, G., J. Org. Chem., 22 (1957) 250; Moberg, C. and Nilsson, M., J. Organomet. Chem., 49 (1973) 243; Nzabemwita, G., Kolani, B., and Jousseaume, B., Tetrahedron Lett., 30 (1989) 2207; Tolbert, L. M., Gregory, J. C., and Brock, C. P., J. Org. Chem., 50 (1985) 548; Ishida, M., Aoyama, I'., Beniya, Y., Yamabe, S., Kato, S., and Inagaki, S., Bull. Chem. Soc. Jpn., 66 (1993) 3430. Magnus, P., Cairns, P. M., and Moursounidis, J., J. Am. Chem. Soc., 109 (1987) 2469. Kraihanzel, C. S. and Losee, M. L., J. Am. Chem. Soc., 90 (1968) 4701; Ranganathan, D., Rao, C. B., Ranganathan, S., Mehrotra, A. K., and lyengar, R., J. Org. Chem., 45 (1980) 1185. Carpino, L. A. and Sau, A. C., J. Chem. Soc., Chem. Commun., (1979) 514; Boschelli, D., Takemasa, T., Nishitani, Y., and Masamune, S., Tetrahedron Lea., 26 (1985) 5239; Landais, Y., Tetrahedron, 52 (1996) 7599; Chow, H.-E and Fleming, I., Tetrahedron Lett., 26 (1985) 397;

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Fleming, I., and Kilbum, J. D., J. Chem. Sot., Chem. Commun., (1986) 1198; Polniaszek, R. P. and DiUard, L. W., J. Org. Chem., 57 (1992) 4103; Roush, W. R. and (;rover, E T., Tetrahedron, 48 (1992) 1981; Hart, D. J. and Krishnamurthy, R., J. Org. Chem., 57 (1992) 4457; Fleming, I., Henning, R., Parker, D. C., Plaut, H. E., and Sanderson, E E. J., J. Chem. Soc., Perkin Trans. 1, (1995) 317. [64] Fuchs, B. In Eliel, E. L. and Allinger, N. L. (Eds.), Topics in Stereochemistry,Vol. 10, Wiley: Chichester, 1978, Chap. 1.

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AZlRINES AND AZlRIDINES REVISITED

Kuriya Madavu Lokanatha Rai and Alfred Hassner

1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Theoretical Considerations . . . . . . . . . . . . . . . . . . . . . . . . 2.2 N M R Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Infrared Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Electronic Absorption Spectroscopy . . . . . . . . . . . . . . . . . . . 2.5 Microwave Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of 1-Azirines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Azirines from Vinyl/Aryl Azides . . . . . . . . . . . . . . . . . . . . . 3.2 Azirines from Oximes . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Optically Active Azirines . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Miscellaneous Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Rearrangement of Molecules via Azirine Intermediate . . . . . . . . . . 4.2 Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 1,3-Dipolar Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Intramolecular 1,3-Dipolar Cycloaddition . . . . . . . . . . . . . . . . 4.5 [4+2] Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 3-Dimethylamino-2H-Azirines . . . . . . . . . . . . . . . . . . . . . . . . .

Advances in Strained and Interesting Organic Molecules Volume 8, pages 187-257. Copyright 0 2000 by JAI Press Inc. All rights of reproduction In any form reserved. ISBN: 1-7623-/}631-9

187

188 188 188 190 190 191 191 191 191 193 193 195 197 197 199 203 207 214 218 221

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KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

5.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 5.2 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 6. Aziridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 6.1 Synthesis of Aziridines from Alkenes . . . . . . . . . . . . . . . . . . . 231 6.2 Synthesis of Aziridines from Imines . . . . . . . . . . . . . . . . . . . . 235 6.3 Aziridines from Azirines . . . . . . . . . . . . . . . . . . . . . . . . . . 238 6.4 Miscellaneous Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . 238 6.5 Ring-Opening Reactions of Aziridines . . . . . . . . . . . . . . . . . . 239 6.6 Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 6.7 Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 247 6.8 Metabolism of Aziridines and the Mechanism of Their Cytotoxicity . . . 248 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

1. INTRODUCTION Azirine and its dihydro derivative, aziridine, can be regarded as representative of the first and most simple of all N-heterocyclic systems, one which is characterized by the presence of two carbon atoms and one nitrogen in a three-membered ring. In this chapter we are mainly using the nomenclature of 2H-azirine for 1 and 1H-azirine for 2a (X = NH). Alternate names such as ethylenimines for aziridine, 1-azirine for 2H-azirine, and 2-azirine for 1H-azirine will be encountered in the literature. The chemistry of small-ring heterocycles has flourished with considerable intensity in the past decade or two because of its theoretical, mechanistic, synthetic, and biological applications. A number of reviews on the chemistry of aziridines and azirines have appeared during this period [ 1-12]. The theoretical and mechanistic interests are associated with the structure, stability and inherent strain energy of the azirines, and the ability of the system to direct in several distinct ways the course of many mechanistically significant reactions. 2H-Azirines are reactive and versatile substrate because of certain inherent features within their structure. These include high ring strain, a reactive rt bond, a lone pair of electrons on the nitrogen, and the ability to undergo ring cleavage on thermal or photochemical excitation to give such reactive fugitive species as a vinylnitrene, iminocarbene, and nitrile ylide. Azirines have been shown to be the discrete intermediates in the Hoch-Campbell synthesis of N-unsubstituted aziridines [2].

2. STRUCTURE 2.1 Theoretical Considerations The structure and relative stabilities of the parent heterocycles have been the subject of considerable attention. Recent ab initio MO calculations [3,4] predict for 2H-azirine (1), in which an overall Cs symmetry is assumed, a carbon-carbon bond shorter and carbon-nitrogen longer than those commonly encountered in acyclic molecules, a-Bridged 7t orbitals are characterized in the three-center bond that often

Azirines and Aziridines Revisited

189

occurs in electron-sufficient small-ring compounds made of atoms such as C, N, O, S, P, and Si. This bonding pattern proves efficient in explaining bond length changes and strain energies in the three-membered rings [13]. It was also shown that explanations based on this type of orbital are compatible with a number of other theoretical models in the literature and that the application of the o-bridged r~-bonding concept helps extend these models and would make them useful. For the 1H-azirine (2a, X = NH) in which Cs symmetry and nonplanarity of the nitrogen substituents were considered, calculations show the C-N bond in 2a, (X = NH) to be slightly longer and the Ce: bond shorter than that in cyclopropene (1.128/~). The degree of nonplanarity about nitrogen is predicted to be a ca. 72 ~ a value which is significantly larger than that calculated for the 2H-azirine ring. It has been suggested that as a planar species, the 1H-azirine ring is unstable because of the antiaromatic character, which will result in complete delocalization of the electrons. The existence of ring strain, nitrogen lone,pair interaction, or both, seem to be crucial to the absence of aromaticity in this kind of system [14,15]. The nonaromatic character of 1H-azirines is confirmed by resonance energies of the opposite sign to that predicted for benzene, as well as the barrier to nitrogen inversion.

A

/k

Cyclopropenyl anion (2b, X = CH) is the smallest antiaromatic carbocyclic system with 4n electrons [16]. The isoelectronic heterocyclic species such as 1H-azirine, oxirene and thierene are also elusive species and are detected only in rigid matrices as short-lived intermediates [17]. The lack of stability in the cyclopropenyl anion and analogous heterocyclic species is attributed to antiaromaticity in this system [ 16]. The low-lying status of three-membered ring systems has been investigated by configuration interaction (CI) calculation using the SINDOI method. Though the ground state is moderately or highly antiaromatic in the cyclopropenyl anion, azirine, oxirene, and thierene, these species exhibit moderate aromaticity in the excited states [ 18]. Incorporation of a heteroatom into a multiple bond generally lowers its nucleophilicity due to change in hybridization. Still reaction with an aryne can occur to give a zwitterion which may collapse to a four-membered ring or undergo further reaction. For instance, reaction of azirine with benzyne leads to 2,3-diphenylindole [ 19]. Calculation by the SCF-MO LACO method for determining the thermodynamic stabilities and reactivity of the antiaromatic 1H-azirine heterocycles indicated that protonation of 1H-azirines occurs at a carbon atom, in analogy with enamines, and the resulting cation is transformed into N-protonated 2H-azirines [20]. MO calcu-

190

KURIYA MADAVU LOKANATHA PAl and ALFRED HASSNER

lations show 1H-azirines to be approximately 30 kcal/mol less stable than 2H-azirines [21 ]. The structure of the potentially aromatic azirinyl cation (C2H2N§ [22] and the azirinyl radical cation [23] have also been studied by semiempirical and ab initio MO methods. Theoretical studies have been used to investigate the complexation of H and metal ions to aziridine, 1H-azirine and 2H-azirine. Such studies allow a ranking of the relative basicity of these three heterocycles: 1H-azirine > aziridine > 2H-azirine [24]. The high basicity of the hypothetical 1H-azirine is proposed to be due to alleviation of the antiaromatic character of the neutral heterocycle.

2.2 NMR Spectroscopy The general aspects of 1H, lSC, and 15N NMR spectroscopy of 2H-azirines have been well reviewed [2-4,10]. On the basis of NMR spectra and X-ray structure determination, it was found that the five-membered ring of a spiro-fused azirine is commonly locked in the envelope conformation and is stabilized by the interaction between a quinazoline nitrogen (N-3) p orbital and a bonded p orbital of the adjacent azirine carbon atom [25], while the six-membered ring of fused azirines has the twist-boat conformation [26]. In lSN NMR the signals for the ring nitrogen appear upfield from those for the nitrogen atom of acyclic imines and show that the azirine ring exerted a stronger -I effect than the cyano group [27].

2.3 Infrared Spectroscopy IR spectroscopy is more useful for the characterization of 2H-azirines as they exhibit absorption very characteristic of the unsaturated ring. Alkyl and aryl substitution at C2 give rise to intense absorption (C~stretching) at 1770 and 1740 cm -l, respectively. The fused ring of 2,3-hexamethylene-2H-azirines shows the C ~ stretching at 1760 cm -1 [28]. Azirines bearing no substituent at C2 exhibit C ~ absorption in the region commonly observed for those of normal acyclic imines (ca. 1650 cm-1). The IR spectrum of 1H-azirine has been calculated using MO methods. Regitz et al. [29] reported the matrix isolation of 1H-azirines 3 and 4 which were characterized by their C-C stretching frequencies at 1880-1890 and 1867 cm -l, respectively.

\--/

/VVh

\.

CN

CN

3

4

Azirines and Aziridines Revisited

191

2.4 Electronic Absorption Spectroscopy The UV absorption spectra of 3-alkyl-2H-azirines show a weak absorption at about 230 nm (e, ca. 100), while 3-aryl-2H-azirines exhibit a stronger absorption at about 245 nm (e, ca. 13,000-20,000) with an inflection at about 285 nm for the ~* n ---) transition (e, ca. 1000) [2-4] The parent compound 2H-azirine shows an absorption at 229 nm [30]. Multiphoton ionization of 2,3-diphenyl-l-azirine has been reported for nanosound laser excitation at 248 and 193 nm and compared with electron impact ionization [31]. The dependance of the ion intensity on the laser intensity shows that the formation of the parent ion and some of the more prominent fragments require the absorption of two photons per molecule. Other fragment ions are produced after'the absorption of these photons. The results of the absorbed photon energy are corroborated by ionization and appearance energies obtained on calibrated electron impact ionization. Pure metastable ion spectra were obtained both by the defocusing method and by direct analysis of daughter ions produced by the electron impact ionization and also by multiphoton ionization. The multiphoton absorption has been shown to proceed via two different excitation pathways.

2.5 Microwave Spectroscopy The microwave spectrum of 3-methyl-2H-azirine produced by pyrolyzing Nchloro-2-methylazirine was measured [32]. The identification of this new unstable molecule was based on a comparison of observed molecular composition and that determined from an ab initio calculation. The rotational axis are A = 22338.04(4), B = 6618.622(9) and C = 5464.442(7) MHz, respectively. The dipole moments are a = 1.90(5) and b = 1.86(5) D from the analysis of the Stark effect. The potential barrier to internal rotation of the methyl group was determined by the principal axis method (PAM) to be V3 = 1315(10) cal mo1-1.

3. SYNTHESIS OF 1-AZIRINES Extensive reviews coveting many synthetic and mechanistic aspects of reactions leading to the synthesis of 2H-azirines have been published in recent years [4,6,9]. These include the modified Neber reaction, thermolysis and photolysis of vinyl azides and isoxazoles, and thermolysis of oxazaphosphines [2]. Only those reactions to which a measure of generality and/or uniqueness can be assigned are outlined in the following discussion.

3.1 Azirinesfrom Vinyl/Aryl Azides Hassner and Fowler have reported the preparation of a number of 2H-azirines in good to excellent yields by photolysis of corresponding vinyl azides at 3500/~ [33]. Several mechanistic pathways can be postulated for the formation of 2H-azirine

192

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

from the thermolysis of a vinyl azide. One attractive pathway involves formation of a transient vinylnitrene species by loss of molecular nitrogen from the thermally or photolytically excited vinyl azides. If the 2H-azirine is formed from a singlet nitrene, the conversion is a symmetry-allowed conrotatory electrocyclization. Although evidence for the intermediacy of a nitrene in the formation of 2H-azirines is not available, the formation of certain side products provides some support for the transient existence of the fugitive species. For example, the formation of keteimine, indole, and dihydropyrazine can be reasonably assumed to arise from intermediate nitrene species. The thermolysis and photolysis of vinyl azides have been utilized extensively for the preparation of 2H-azirines [3]. For instance, photolysis of 1-azidocyclooctene gave 9-azabicyclo[6.1.0]non-1 (9)-ene (5) in 93% yield [33]. Very recently Moraietz and Sander were able to generate 7-azabicyclo[4.1.0]hepta-2,4,6-triene (6) by selective irradiation of corresponding phenyl azide at 444 nm in the presence of solid argon [34], while at 366 nm the azirine reverted back to nitrene.

~

3

hv

N 5

6

An evaluation of the reported thermolyses of cyclic and acyclic vinyl azides [ R ( N 3 ) C ~ ' ] led to the empirical generalization that when R is aryl, alkyl, a heteroatom, or even an alkoxy carbonyl, thermolysis usually results in the formation of 2H-azirines [35]. Three major pathways have been proposed for these transformations [35]: (1) loss of nitrogen occurring concertedly with ring formation, (2) the intermediacy of a vinyl nitrene (presumably a singlet) which can undergo a symmetry allowed electrocyclic closure to azirine, and (3) intramolecular [3+2] cycloaddition of the azido group to the double bond, followed by loss of nitrogen from the intermediate triazole. Access to a vast number of aziridines and 2H-azirines has been gained through the cyclization of vicinal haloalkyl isocyanates and haloalkyl azides. In turn these are prepared by the addition of iodine isocyanate and iodine azide (and to lesser extent bromine and chloride azides) to alkenes [1,4]. Various substituted (3-azido-1-alkenyl)phosphonates [(R 10)2P(O)CR21~I-I(N3)R 3] or their equilibrium mixture with the regioisomeric 2-azidophosphonates [(RIO)2P(O)CR2(Na)CHI~4R 3] have been synthesized from allylic or y-hydroxy phosphonate by the Mitsunobu reaction with TPP/DEAD/HN 3. These azides were converted into (2H-azirine-2-yl)methylphosphonates upon treatment in toluene with DBU as catalyst [36]. The transformation proceeds via base-catalyzed rearrangement to (3-azido-2-alkenyl)phosphonates and subsequent thermolysis.

Azirines and Aziridines Revisited

193

3.2 Azirines from Oximes One of the more important approaches to 2H-azirines involves a base-induced cycloelimination reaction of suitably functionalizcd ketone derivatives. An example of this cyclo elimination involves the Neber rearrangement of oxime tosylates, or the conversion of quaternary salts of hydrazones or of N-haloamines to 2H-azirines, which are subsequently hydrolyzed to aminoketones (Eq. 1) [37]. From mechanistic studies on the Neber reaction, a 2H-azirine has been shown to be a distinct intermediate formed by the closure of a vinyl nitrene. The evidence for the vinylnitrene intermediacy has resulted from the reported lack of stereospecificity in converting the (E)- and (Z)-isomers of O-tosyloximes to the same oc-aminoketones. Although a vinylnitrene has been suggested as a possible intermediate in the thermal and photochemical preparations of the azirine ring from vinyl azides, direct evidence for such a species is lacking. In this context, the configurational stereospecificity in a modified Neber reaction has been studied with an oxime carbamate in order to elucidate the mechanism of the reaction. Thus oxidation of (E)-ct,ccbis(methylthio)oxime carbamate (7) with KMnO 4 or MCPBA yields functionalized 2H-azirine derivatives 8 or 9 exclusively (Scheme 1) [38]. On the other hand, reaction of the corresponding (Z)-isomer 10 results only in oxidation at sulfur (Scheme 2). These observations imply that the involvement of a vinylnitrene intermediate is unlikely in the conversion of the oxime carbamates into 2H-azirines.

Base

~-

v

/

H20 -

.~

(1)

Y = OTs; NMe3X; ElHassner et al. [39] described a useful route for the synthesis of azirines from ct-bromoketoximcs, which involves protection of ketoximes followed by phosphine substitution and deprotection via an oxazaphospholine intermediate. The mild deprotection of the oxime ethers involves intramolecular assistance by a phosphonium group. For instance, the protection of readily available cc-bromooximes in the form of ketals permits clean SN2 substitution by Ph3P to produce 11, which can be deprotected under mild conditions (trace of aqueous acid in chloroform for 20 min at 25 ~ to generate the salts 12. These phosphonium salts are readily converted to oxazophospholines 13 which, in turn, can be thermolyzed to 1-azidnes (Scheme 3).

3.3 Optically Active Azirines Optically active 2H-azirine-2-carboxylic esters 15 were prepared either by a two-step process involving N-chlorination of 14 with tea-butyl hypochlorite and a

194

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

M

~~J~4nO4

r

PBA

7

~SMo tlut

/~~,/S02Me

"SO2Mr

Scheme 1.

KMnO4 , . , ~ S Me uut \S Me

MCPBA

1

10 Me ,•,•s t~uL ~SO2Me

Me SO2Me Scheme 2.

~

/OH

Me~OMe

r

- H+

...,.0~

)Me PPh3 =

.....0. ~ 1~

,1,Ph3Br

Br

z~

Me

~

,,oH Ph3

13 Scheme 3.

Et3N

Br" ,~fPh3

~ 12

Azirines and Aziridines Revisited

195

subsequent dehydrochlorination with base [40] or by Swem oxidation (Eq. 2) [41]. For both cis- and trans-azJridine esters, Swern oxidation gives regioselective introduction of the double bond, which is not conjugated with the ester function. Furthermore, treatment of optically active aziridine 16 with LDA/MeI affords the enantiomericaUy pure 2H-azirine-2-carboxylic ester 17 (Eq. 3) which represents the first assymetrie synthesis of cytotoxic (R)(-)-dysidazirine [42]. Dysidazirine, an azacyclopropane isolated from the marine sponge Dysidea fragilis is cytotoxic to L1210 cells at 0.27 ug/mL and it inhibited the growth of gram-negative bacteria (P. aeruginosa) and yeast at a minimum concentration of 4 ug/disk in a standard paper disk assay [43]. Azirinomycin, an azacyclopropane antibiotic, isolated from a strain of the soil bacterium streptomyces aureus bears a structural similarity to dysidazirine [44]. .....COOEt

RN

.....COOEt (2)

14

15

~ O O E t

~ O O E t

I

"Is 16

(3)

17

A new, convenient and good yielding route towards optically active azirine carboxylate esters, using a modified Neber reaction, involves the conversion of the tosylated oxime of [$-ketoesters with chiral bases such as cinchona alkaloids and in particular quinidine and dihydroquinidine. Bases lacking hydroxyl functions, e.g. spartine, brucine and strychnine, show no selectivity at all [45].

3.4 Miscellaneous Syntheses Oxidation of aminoquinazolines 18 (n = 2, R = H, Me; n = 3, R = H) with lead tetraacetate in dichloromethane results in the intramolecular addition of an N-nitrene to the triple bond in each case and azirines 19 are isolated [25].

,/ R 18

19

196

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

Methyl benzoisoxazolyl acetates reacted with Nail, Me3COK, or MeONa in DMF to give 60-90% of azirines [46], while thermolysis of isoxazole 20 at high temperature provided the isomeric azirine 21 and its 2-epimer [47]. ~.OCH3

~~-OCH3

20

21

Similar photoinduced isomerizations have also been observed with several isoxazoles, but yields are generally very low [4]. Both the thermal and photochemical rearrangement are believed to proceed via an initial homolytic cleavage of the weak N-O bond followed by ketone formation and 1,3-diradical reunion. Photolysis of pyridophanes 22 (n = 2-6) in the presence of oxygen gave pyrrolophanes 23, the azirines 24, and nitriles. Thermolysis of 24 followed by reduction gave 23 [48]. Oxazophospholine, prepared by the 1,3-dipolar cycloaddition of nitrile oxide to arylidinephosphoranes, have been used as precursor to 2H-azirines which are not easily accessible through the more general vinyl azide decomposition route (Scheme 4) [4]. Piquet et al. [49] reported the synthesis of 2-phosphino-2H-azirines by the reaction of [bis(dicyclohexylamino)phosphino]trimethylsilylcarbene with benzonitrile in 81% yield.

22

23

§

R--C ~N--(~

+

24

PPh 3

3

~=C=N--R R"

R"

Scheme 4.

h

Azirines and Aziridines Revisited

197

Enantiopure sulfimine, (S)-p-tolylS(O)NtgI-IPh was employed in a Darzen's-type synthesis of the aziridine-2-phosphonate 25. This was then transformed into an aminophosphonate and the first enantiopure examples of azirinylphosphonates 26 and 27 [50]. o~-Oxophosphonium ylides react with N-chloro- or -bromosuccinimide in the presence of azidotrimethylsilane giving the corresponding haloazidoalkenes with elimination of triphenylphosphine oxide. These compounds were then converted into 2H-azirines on heating in heptanes [51]. Ph ....... ~,,~(OEt)2 "~

FL....

25

/~(OEt)2

26

Ph,,,

3(OEt)2

27

4. REACTIONS 2H-Azirines are capable of acting in many reactions as nucleophiles as well as electrophiles [2], as 2rt components in thermal cycloadditions, and as 4n components in photochemical cycloadditions. These reactions can be regarded in general terms as involving the participation of the C~, C-C, and C-N bonds of the azirine ring [4].

4.1 Rearrangementof Molecules via Azirine Intermediate To this category belong all rearrangements which involve the interchange of annular atoms [52]. They are best known in the field of isoxazoles, e.g. 28, which are converted thermally or (better) photochemically into oxazoles, e.g. 31. The reactions occur by a ring contraction-ring expansion mechanism and proceed via acylazirines 29, which isomerize to nitrile ylides 30 and then close to oxazoles 31 (Scheme 5) [53]. Although it is generally accepted that the ring contraction step involves a homolytic cleavage of the weak O-N bond, a concerted mechanism for the thermal process has also been proposed. In many cases, the azirines have been isolated and then converted into oxazoles under different conditions. For instance, irradiation of 3,5-diphenylisoxazole (28, R l = R 3 = Ph, R 2 = H) in ether with 253.7

R

R'

2|

R

0

R

21

~

Scheme 5.

31

198

KURIYA MADAVU LOKANATHA PAl and ALFRED HASSNER

nm light, and interruption of the reaction before completion, led to the isolation of 3-benzoyl-2-phenyl-1-azirine. This compound could be transformed into the corresponding oxazole by further irradiation with 253.7 nm light or converted back to the isoxazole with light >334 nm. At relatively high temperatures (-200 ~ Singh and Ulmann found that 3-benzoyl-2-phenyl-l-azirine can be converted into 3,5diphenylisoxazole. It is likely that at this temperature the azirine and isoxazole are in equilibrium, as evidenced by the preparation of several 1-azirine-3-carboxylates from the corresponding 5-alkoxy-3-aryl-isoxazoles [54]. 2-Amino- 1-azirine can be prepared by the thermolysis or photolysis of amino-substituted isoxazoles [55]. The formation of the isoxazole was suggested to occur via the nrt* state of the carbonyl chromophore. Oxazole formation was attributed to selective excitation of the nrc state of the azirine ring. In a related case, Schmid et al. reported on the photoisomerization of the 2-isoxazoline 32 into oxazoline 35 (Scheme 6) [56]. The reaction is thought to proceed via the transient azirine 33. This intermediate was not isolated but was suggested to undergo rapid ring opening to nitrile ylide 34, which then cyclized to the observed photoproduct via an intramolecular 1,3-dipolar cycloaddition reaction (Scheme 6). The related 4-phenyl-2-oxa-3-azabicyclo[3.2.0]hept-3-ene (36) undergoes a similar photochemical rearrangement to produce 2-phenyl- 1,3-oxazepine (38) [57]. This reaction has been proposed to involve azirine 37 as intermediate which subsequently cyclizes to the observed product (Scheme 7). When the chain between the azirine ring and the aldehyde is less than two carbon atoms in length no cycloadduct was obtained. In this case, the "two-plane" orientation approach of the linear nitrile ylide and the 7t system is too difficult to attain and other competing processes occur. Rearrangements of this type are not limited to isoxazoles, but have

hv 32

~

~

~

33

35 Scheme 6.

36

p

37 Scheme 7.

38

AziHnes and Aziridines Revisited

199

39

4O Scheme 8.

also been reported for pyrazoles which isomerize to imidazoles. Although not recognized so far, this highly unstable three-membered ring probably isomerizes into a dipolar species prior to recyclization [52]. A unique case with involvement of two-side chaffa atoms from the 5-position is the thermal isomerization of some 5-hydrazinoisoxazoles 39 into 4-aminopyrazoline-5-ones 40. The reaction most probably proceeds via an azirine and a bicyclic compound as intermediates (Scheme 8) [52]. Similarly photolysis of t~-naphthyltriazoles gave in good yield the expected benzo[g]indoles and rearranged indoles. These reactions are explained by a mechanism in which the less stable carbene intermediate rearranges to the more stable isomer via a 1H-azirine intermediate in competition with its direct cyclization [58].

4.2 Ring Expansion Preparations of 2-amino-3H-azepines utilize the deoxygenation of nitroso- and nitroarenes [6], or photolysis of the aryl azides (Scheme 9) [59] or naphthyl azide in the presence of an amine [6]. The in situ reaction pathway for ring expansion as proposed by Huisgen and co-workers is outlined for photolysis of aryl azides and involves the generation of an electron-deficient nitrene; this is held to be in dynamic equilibrium with the benzoazirine. The strongest evidence to date for the intermediacy of an azirine is the observation that photolysis of phenyl azide in ethanethiol affords o-thioethoxyaniline in 39% yield, presumably from nucleophilic trapping of the azirine intermediate (Scheme 10) [60]. Similarly, nucleophilic addition of an amine to the reactive imine bond of the azirine intermediate, followed by electrocyclic ring opening of the azanorcaradiene, was thought to give initially a 1Hazepine, which subsequently rearranged to the more stable 3H-tautomer. The data presented demonstrated that mono- and bicyclic aryl azides follow the same chemistry with the substituent controlling the observed product distribution. The rearrangement of singlet phenylnitrene (41) to 1-azacyclohepta-l,2,4,6tetraene (43) (Scheme 11) has been studied computationally [61], using the CASSCF and CASPT2N methods in conjunction with the 6-31G*, cc-pVDZ and 6-31G(2d,p) basis sets. Ring expansion from the 1A2 state of 41 is predicted to occur in two steps via azabicyclo[4.1.0]hept-2,4,6-triene (42) as intermediate. The rearrangement of 41 to 42 is estimated to have a barrier of ca. 6 kcal/mol and to be rate-determining. Azirine 42 is unlikely to be detected because of the small

200

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

3 r

NHCOCH3

COCH3

~NHCOCH3

- ,NHCOCF3

NHCOCF3

(X'F 3

Scheme 9.

calculated barrier (ca. 3 kcal/mol) to its rearrangement to 43. At the CASPT2N/631G(2d,p)//CASSCF(8.8)/6-31G* = ZPE level of theory, the reaction 41 --->43 on the lowest singlet potential energy surface is calculated to be exothermic by 1.6 kcal/mol. This reaction is predicted to be ca. 19 kcal/mol less exothermic but to have a barrier ca. 9 kcal/mol lower than the analogous ring expansion of phenylcarbene to cyclohepta- 1,2,4,6-tetraene. Ketoazirines formed by the reaction of sodium azide with tetra- or pentaphenylpyrrilium salts at room temperature undergo rearrangement at 100 ~ to afford 1,3-oxazepine derivatives (Eq. 4) [62].

P

~

p

R

h

P.h

h (4)

p h ~ p +

h

"-

Ph

When azirine 44 was heated in xylene at 140 ~ for 10 h, the pyrrole 45 and the pyridine 46 were isolated. These transformations can be best rationalized in terms of an equilibration of the azirine with a transient vinylnitrene which subsequently rearranges as shown in Scheme 12 [3]. Thermolysis of 2H-azirines bearing an aldehyde or imine substituent at C2 leads to the formation of isoxazoles and pyrazoles, respectively, while 2H-azirine bearing aromatic substituents produce indoles by electrocyclization of the intermediate vinylnitrene with the aromatic ring [ 10]. Thermal cleavage of the C-C bond of 2H-azirines is less common than C2-N bond cleavage as it requires a substantially higher temperature. These reactions are believed to proceed via iminocarbene intermediates which undergo a 1,4-hydrogen

N3

H

. . . .

~ Scheme TO.

~SEt

Azirines and Aziridines Revisited

201

;O 41

43

42

Scheme 11.

transfer to yield 2-aza-1,3-butadienes. The dienes which are formed often participate in subsequent intra- and intermolecular cyclization reactions. Scheme 13 shows an example where electrocyclization of the azabutadiene leads to a dihydroquinoline [ 10]. Regioselectivity during thermal or photochemical rearrangements and metalmediated rearrangement are illustrated by the example involving azirines in Scheme 13, in Eq. 5 [63], in Eq. 6 [64], and in Scheme 14 [65] and Scheme 15 [66]. In the rearrangement of azirines the stereochemistry of the alkene determines the regiochemistry of the rearrangement.

.qPh=280 p c.o,, Pk

-Ph

I ~ '" COOMe

(5)

1 ~ Mo(CO)(~

p

COOMe

H

Ph

Ph I

COOEr

OOEt

46

ph~OOEt

N:.

COOEt

1

44 H I

p~Me

=__p~Me 4S "COOEt .?COOEt Scheme 12.

OOE

(6)

202

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

/

Ph

Scheme 13.

A possible mechanism for the conversion of azirine to imides by molybdenumcatalyzed addition of carbanions involve the initial coordination of the nitrogen lone pair to molybdenum. This would give 47, which can then react with the carbanion to give 48 (Scheme 16). Intramolecular cyclization of 48 by ethoxide ion replacement would afford the bicyclic 13-1actam49, which on hydrogen migration and ring scission would give the metal-complexed five-membered ring heterocyclic complex 50. Conversion of 50 into 51 in situ may take place via hydration followed by dehydration (Scheme 16) [67]. Treatment of the 1-azirine 52 with catalytic quantifies of dichlorobis(benzonitrile)palladium(II) gave a quantitative yield of the indole 53 (Eq. 7). This transformation proceeds through the intermediacy of a 2:1 azirine-palladium chloride complex. Conversion of the azirine ring into indole under uncatalyzed thermolytic condition provides a mechanistically interesting comparison with the Pd(II)catalyzed conversions. The C-N bond cleavage in the latter is apparently accelerated as a result of the coordination of the azirine to palladium [4]. ~,.,

Pd(II)

H

~

~

R (7)

R

52

53

Ph Ph

N XX '~

ZX x~-.~ J Ph ~ or hv - ~ h ~

Scheme 14.

Ph Fe(CO)6 "-

Azirines and Aziridines Revisited

203

M~

[Rh(CO)2Cl]2

~A~A r

Scheme 15.

Thermolysis of a vinyl azide affords an azirine which can be captured in situ with an enaminoketone. This reaction sequence was developed into a new general method for the preparation of nonsymmetrical pyrazines and applied to the synthesis of cephalostatin analogs with high biological activity [68]. A [l+2]-cycloaddition reaction of a phosphinocarbene with benzonitrile in toluene gave a phosphinyl azirine in 85% yield, which on dichloro(p-cymene)ruthenium-catalyzed ring expansion gave an azaphosphonate (Eq. 8) [69]. R2

=. SiMe3

(8)

~Ph

Ru(ll) ~

i'R2

SiMe3

4.3 1,3-Dipolar Cycloaddition 1-Azirines undergo irreversible ring opening on electronic excitation to give nitrile ylides as reactive intermediates [4]. For instance, photolysis and successive y-radiolysis of biphenylazirine at 77 K resulted in the formation of a novel intermediate with an absorption maximum at 425 nm. This was produced by one-electron reduction of the nitrile ylide Bp-C§ (Bp = biphenyl) [70].

CH(COOEt)2

EtOOC~ . ~ ~-~

i

P~"~' 49

OOEt

EtOoe~COOEt ~ t r % ~ - ~176

Mo(CO)6 -v

H ...... H ""s

Ph

"~'Mo(CO)6 50

51

Scheme 16.

48

204

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

The intermediate was also produced by photochemical ring opening of the azirine radical anion. Nitrile ylides may be classified as nitrilium betaines, a class of 1,3-dipole containing a central nitrogen atom and a g bond orthogonal to the 4g allyl system. They can be intercepted with a wide variety of dipolarophiles to form five-membered heterocyclic rings. Irradiation of the n-g* bond of an aryl substituted azirine ring at 280 nm leads to the opening of the ring and to the formation of ylide Ph-C=N§ (54). This ylide is readily trapped with a dipolarophile such as acrylonitrile forming the trans-pyrolidine 55 in 90% yield and 10% of its cis-isomer 56 (Scheme 17) [71]. Alternatively, imines react with 54 to form imidazolines [72]. The reaction of 54 with appropriate aldehydes affords the oxazoline 57 while reactions with imines yield imidazolines. If there is no sufficiently reactive dipolarophile available to trap the nitrile ylide, it reacts further with the azirine to form diazabicycles 58 (Scheme 17) [73]. On the other hand, irradiation under conditions of photochemical electron transfer (PET) leads to a different ratio of products. Irradiation of the electron acceptor 1,4-naphthalenedicarbonitrile (DCN) with 350 nm light enables an electron to be transferred from the arylazirine to the excited sensitizer. The resulting azirine radical cation opens spontaneously to the linear azaallenyl radical cation, e.g. 59 (Scheme 18). This species does not react in a concerted manner as does the ylide 54, but instead adds quantitatively via 60 in a multistep process to a reagent like acrylonitrile (Scheme 18). This indicates that the reaction follows a pathway that is different from that in the absence of a PET scavenger. Experiments with 2,2,2-trifluoroethanol revealed the formation of two trapping intermediates 61 and 62, under PET conditions, while direct irradiation led to the formation of 62 only [74]. With the PET promoted [3+2] cycloaddition of azirine, it should be possible to synthesize bridged heterophane compounds using bicyclic azirines 63 as starting material. Azirines 63 with n = 5, 6, or 10 are converted into imidazophanes 64 when reacted with imines; with DMAD 63 forms pyrrolophanes 65 (Scheme 19) [75].

/~ Pl( "Ph ~

Ph~~..Ph /Ph Ph-C+-C%

~~~"Pphh 58

55 "CN I

56

57

Scheme 17.

Azirines and Aziridines Revisited

DeN

~

205

hv

h~+N / P h P =(2 \ H

DCN*

~

'~"'CN

P~

PhC=+N=C/ Ph \ H + DCN

~N60

59 ~ - D C N

P . cH2cF3

/

PhC-N-C -

+

DCN

\H

P~/OCH2CF3 61

Ph

H

62

Scheme 18.

However, irradiation of the tricyclic bisazirine 66 with DMAD does not furnish a [2+2] pyrrolophane but only compound 67 in 15% yield (Eq. 9) [75]. The formation of 67 and the complete absence of any [2+2] pyrrollophane or a monoannulated product suggests that 67 is formed by a transannular reaction after the PET-sensitized opening of the first azirine ring.

DCN

.~ (9)

DEAD 66

67

Porphyrins may be formally regarded as [ 1.1.1.1 ]pyrrollophanes. A tetrakisazirine 68 derived from cyclododecane should be a useful alternative for the preparation of these important natural systems. Indeed, the reaction of 68 with DEAD affords porphyrin 69 in 6% yield with eight ester groups E (Eq. 10) [76]. E

.,DCN : DEAD

(10) E/

68

69

xE

206

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

H2)n

" -

~H2)n

H2)n

Pr Pr 64

65 Scheme 19.

Upon irradiation, 2,3-diphenyl-2H-azirine adds to C6o yielding 1,9-(3,4-dihydro2,5-diphenyl-2H-pyrrolo)fullerene-60. Mechanistic studies revealed that two reaction pathways lead to the adduct, viz. the classic 1,3-dipolar cycloaddition via the nitrile ylide (direct irradiation) or a route via the 2-azaallenyl radical cation (sensitized by PET) [77]. The photocyclization of acylazirines with electrondeficient alkenes to produce 1-pyrrolines [4] exhibits all the characteristics of a concerted reaction, including stereospecificity and regioselectivity. 1,3-Dipolar addition proceeds via a two-phase orientation complex when the dipole and dipolarophile approach each other in parallel planes [4]. For the case of diphenylazirine and methyl acrylate, two possible orientation complexes exist leading to 70 and 71 (Scheme 20). The interaction of substituent groups in the syn product 70 can be attractive (g-overlap, dipole-dipole interaction) or of a repulsive nature (van der Waals strain). Both effects are negligible in the corresponding anti complex that gives 71. The rate of the product formation depends on the interplay of steric and electronic effects in the transition state of the 1,3-dipolar addition and emphasizes

Ph.C-N=C~/II 7: + ,.;"Ph

~

P

i

. oo o "COOMe

70 p

!

h ~ N ~ h .,~

~COOM~ \H

.,~

"~OOMe 71 Scheme 20.

Azirines and Aziridines Revisited

207

IR

R

,

-

,

h

Scheme 21.

the important role this effect has in controlling the stereochemical distribution of the products obtained. Frontier molecular orbital (FMO) theory [3] correctly rationalizes the regioselectivity of most 1,3-dipolar cycloadditions. When nitrile ylides are used as 1,3-dipoles, it is the dipole highest occupied molecular orbit (HOMO) and dipolarophile lowest occupied molecular orbital (LUMO) interaction that stabilizes the transition state. The favored cycloadduct is that formed by union of the atoms with the largest orbital coefficient in the dipole HOMO and dipolarophile LUMO. In the HOMO of the nitrile ylides under consideration, the electron density at the disubstituted carbon atom is somewhat greater than that at the trisubstituted carbon [78]. In electron-deficient olefins the largest coefficient in the LUMO is on the unsubstituted carbon atom. This treatment adequately explains the photochemical reaction of diphenylazirine with methyl acrylate to produce only the 4-substituted regioisomer. Padwa [78] explained the mixture of cycloadducts in the reaction of 2-phenyl-1-azirine with methyl methacrylate (CH2=CMe-CO2Me) by a lowering of the LUMO coefficient at the unsubstituted carbon atom of the dipolarophile by the presence of the methyl group. Apparently the terminal coefficient in the LUMO of methyl methacrylate is not nearly the same as for methyl acrylate, resulting in the observed loss of regioselectivity. Photolysis of biphenylazirines in the absence of an alkene leads to rearrangement via a 1,3-dipolar cycloaddition of the nitrile ylide with the aromatic ring. This forms fused azepine derivatives while in the presence of an alkene pyrrole derivatives are formed (Scheme 21) [79].

4.4 Intramolecular 1,3-Dipolar Cycloaddition The cycloaddition of a 2H-azirine with a simple olefin produces a 1-pyrroline, while a rearranged isomer can be formed when the alkene and azirine moieties are suitably positioned in the same molecule [80]. This intramolecular cycloaddition

208

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

was first observed by Padwa et al. [81] using 2-vinyl-substituted azirines. Irradiation of 72 in benzene affords the 2,3-disubstituted pyrrole 73 while thermolysis gives the 2,5-disubstituted pyrrole 74 (Scheme 22). Photolysis of 75 proceeds similarly and gives 1,2-diphenylimidazole 76 as the exclusive photochemical product, while thermal reaction affords the isomeric 1,3-diphenyl pyrazole 77 as the only product (Scheme 23). The evidence obtained clearly indicates that the photorearrangements of 72 and 73 proceed by a mechanism which involves a nitrile ylide intermediate. This conclusion was reached by irradiating 72 in the presence of ethyl acrylate as trapping reagent; under these conditions the formation of 73 is entirely suppressed. Intramolecular r of the nitrile ylide intermediate 78 followed by a [ 1,5] H shift in the initially formed five-membered ring readily accounts for the formation of 73 (Scheme 24). On the other hand, the thermal transformation observed with this system has been rationalize~ in terms of an equilibration of the 2H-azirine with a transient vinylnitrene 79 which subsequently rearranges to the 2,5-disubstituted pyrrole 74. In contrast to the photochemical results encountered with 72, the presence of a (Z)-styryl side chain at the 2-position of the azirine 80 leads to ring expansion and gives benzazepine 82 (Scheme 25) [4,80]. ,The 2-[2-(ctand [3-naphthyl)vinyl]-3-phenyl-2H-azirine behaves similarly and the reaction proceeds with complete regiospecificity. The photocatalysis of the isomeric (E)styrylazirine follows an entirely different course and produces 2,3-diphenylpyrrole as the major product (Eq. 11) [4]. The results indicate that opening of the azirine ring followed by intramolecular cyclizaton proceeds at a faster rate than (Z)-(E) isomerization about the carbon-carbon double bond. The preference for cyelization of 81 to a seven-membered ring was attributed to stereoelectronic factors. Closure of the linear dipolar intermediate 81 obtained from 80 occurs more easily via a seven-membered transition state and leads to the preferential formation of the benzazepine 82. Cyclization of the nitrile ylide derived from the (E)-isomer to a seven-membered ring is precluded on structural grounds and formation of 2,5diphenyl pyrrole occurs instead.

-_ P hH

(11)

Padwa and Carlson [82] found that irradiation of 2-allyl-2-methyl-3-phenyl-2Hazirine (83) gave 3-methyl-1-phenyl-2-azabicyclo[3.1.0]hex-2-ene (84) as the exclusive photoproduct (Eq. 12). The photoreaction of the closely related azirine 85 produced azabicyclohexene 86 (Eq. 13) while azirine 87 gave the rearranged compound 88. Upon standing at room temperature 88 epimerized to the thermodynamically more stable exo-isomer 89 (Scheme 26).

Azirines and Aziridines Revbited

209 P

p~R

~

hv

ZX

~-,Ph

/-i 74

73

72 Scheme 22.

P hv

A

I

h

Ph 77

Ph 76

75 Scheme 23.

P~~_.~ - ~

72

73

78

P

~:

~"COOMe 79

74

Scheme 24.

P~Ph 80

r

81

Scheme 25.

82

210

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

"

(12) 83

84

Ph (13) 85

86

The formation of photoproducts 84, 86, and 88 was found to be completely suppressed when the irradiation was carried out in the presence of methyl acrylate. The only product formed under these conditions was the usual 1-pyrroline. Padwa and Carlson [82] have pointed out that bimolecular 1,3-dipolar addition proceeds via a "two-plane" orientation complex in which the dipole and dipolarophilr approach each other in parallel planes [80]. In order to achieve this type of transition state, the linear nitrile ylide derived from the irradiation of these allylazirines must first bend. This involves disruption of the orthogonal n bond at some moderate energy cost but leaves the allyl anion n system undisturbed. The cycloaddition of 83, 85, and 87 with added dipolarophiles proceeds in the same fashion and affords 1-pyrroline derivatives as the primary cycloadduct. Molecular models of the allyl-substituted nitrile ylides indicate that the normal "two-plane" orientation approach of the linear nitrile ylide and the allyl n system is impossible as a result of the geometric restriction imposed. Product formation is possible, however, if the linear geometry species subsequently undergoes 1,1-cycloaddition with the neighboring dofible bond. The most favorable transition state for this 1,1-cycloaddition is one in which the ~ orbitals of the nitrile ylide and those of the olefinic double bond are orthogonal. This orthogonality could, in principle, permit the occurrence of a concerted orbital symmetry allowed [co2s+ ~2a] process and thus accommodate the formation of a thermodynamically less-favored endo-isomer 88 (Scheme 27). Me

87

88

Scheme 26.

H

89

Azirines and Aziridines Revbited

211

P Mo PtL

_._._ H.....~ h \ 88

Scheme 27.

Irradiation of the analogous azirine 90 also produces the azabicyclohexene 88 (Scheme 28) [80]. This observation indicates that the 1,1-cycloaddition process is stereoselective but not stereospecific. A reasonable explanation to account for the observed stereoselectivity is that the 1,1-cycloaddition process occurs by initial attack of the carbon on the terminal position of the double bond. Such an attack will generate the six-membered ring dipole 91 which contains a secondary carbocation as well as the azallyl anion. Collapse of this new 1,3-dipole to the thermodynamically favored exo-product 89 will result in a severe torsional barrier closure. On the other hand, collapse to the thermodynamically less favored endo-isomer 88 moves the phenyl and methyl groups increasingly further apart and will account for the formation of the less stable product. Supporting evidence for this suggestion was obtained by irradiating the isomeric 3-methyl-2H-azirinr system 92 (Scheme 29); photolysis results in quantitative formation of azabicyclohexenr 84 the same azabicyclohexene that was formed from the irradiation of 83. A combined experiment showed that 84 and 92 were not interconverted under the photolytic condition. The formation of 84 from 92 involves preferential generation of the six-membered ring dipole 95. Thus cyclization of the initially formed carbene 93 generates 95 which close to azabicyclohexene 84. The same six-membered dipole is also formed from azirinr 83. Thus, the selectivity

P or 87

~

i

M

+

90

B0~

/

Me

M•e...

89 "not observed" Scheme 28.

88 "observed"

91

212

KURIYA MADAVU LOKANATHA PAl and ALFRED HASSNER

~ .x~h

#•..••r 92

Ph +

93

95

84

+

83

94

Scheme 29.

observed with 87 and 88 as well as the regiospecificity encountered with azirine 83 and 92 can be attributed to a two-step cyclization path which involves a six-membered ring dipole. When the chain between the azirine ring and the alkene moiety is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine 96 gave 1-pyrroline 97 quantitatively (Scheme 30) [78]. In this case the methylene chain is sufficiently long to allow the dipole and olefinic portion to approach each other in a parallel plane. An electrondeficient alkene has the largest coefficient on the unsubstituted carbon in the LUMO. In order to predict regioselectivity in the photocycloaddition of arylazirines, the relative magnitudes of the coefficients in the HOMO of the nitrile ylide must be known. The photoconversion of arylazirines to alkoxymines, e.g. 98, indicates that in the HOMO of the nitrile ylide the electron density at the disubstituted carbon is greater than at the trisubstituted carbon atom (Eq. 14) [4]. With this conclusion, all of the regiochemical data found in the photoaddition of arylazirines with dipolarophiles can be explained. hv

=- Ph_C=~=C_ "' 'R' - ' ~ / R Ph_C=N_Cx~,M e j -K'

(14)

H 98

Irradiation of arylazirines with alkenes of low dipolarophilic activity produced no photoadducts but instead gave dimers. Originally it was reported that photolysis of phenylazirines gave azabicyclo[3.1.0]pentanes but the dimer actually isolated was subsequently shown to be a diazabicyclo[3.1.0]hexane. In the absence of an added dipolarophile the photochemically generated nitrile ylide simply adds to the ground-state azirine molecule [4]. The photochemical addition of azirines to the carbonyl group of aldehydes, ketones, and esters is also completely regiospecific. Besides the formation of isomeric oxazolines from azirine and ethyl cyanoacetate,

Azirines and Aziridines Revisited

hv

213

/Ph Ph-C--N=C~ ~-- + ('CH2)3

96

P 97

Scheme 30.

there is also formed the imidazole from addition to C_=N in the expected regioselective manner [4]. Open-chain substrates for intramolecular cycloadditions have been examined with the alkene chain attached at the disubstituted azirine carbon. If the intervening tether is sufficiently long (three atoms), only 1,3-cycloaddifion is observed [78]. Photolysis of azirine 99 gave a fused bicyclic dihydropyrrole in 81% yield (Scheme 31). This result is rationalized from normal concerted cycloaddition of an intermediate azomethine ylide. Proof for the intermediate dipole was obtained by trapping the latter as a pyrrole with DMAD. The homologous azirine 100 with a one-atom bridge gave quite different results. Photolysis led to the 4,5-fused dihydropyrrole 101. The isomeric azirine 102 also led to 100, but the initial product included dihydropyrrole 103 which apparently was converted into 101 as photolysis continued. Azirines 100 and 102 are not interconvertible and the postulated independent and discrete azomethine ylides were trapped with methyl trifluoroacetate. The formation of dihydropyrrole 101 was based on a two-step cycloaddition process involving a common diradical intermediate (Scheme 32) [83]. The observation of 103 from photolysis of 102 but not 100 can be explained based on extinction coefficient differences. Azirine 100 has a higher extinction coefficient than does 102 and so the initial product 103 can be optically pumped to 101 with a low-extinction coefficient. Azirine 100 also has a low-extinction coefficient and any 103 that formed from it would be optically pumped to 101 before observation. The azomethine ylide formed by photolysis of the corresponding azirine 104, cyclized exclusively to the 1,3-cycloaddition product in 75% yield (Eq. 15) [84].

~

~

hv (15)

104

The electronic effect has been rationalized based on the degree of linearity of the azomethine ylide. Electron-donating groups should make the dipole more bent while electron-attracting groups should make it more linear [84]. It has been reasoned that the more linear the dipole, the better the concerted 1,3-dipolar

214

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER P

hv

99

Scheme 31.

cycloaddition process. An electron-attracting group on the terminal carbon atom of the dipolarophile also favors 1,3-dipolar cycloaddition presumably by speeding up the concerted process [85].

4.5 [4+2] Cycloadditions The strained carbon-nitrogen double bond of a 2H-azirine is much more reactive than that of a normal imine [3]. Thus the 27t electrons of the carbon nitrogen double bond of an azirine can participate in thermal symmetry allowed [4+2] cycloaddidons with a wide variety of substituents such as cyclopentadienones, isobenzofurans, triazines, and tetrazines [ 1]; cycloaddition also occurs with heteroannulenes such as ketones, ketimines, isocyanates, and carbon disulfide. It is also possible for the 27t electrons of 1-azirines to participate in ene reactions. Hassner and Anderson reported one of the first examples of cycloaddition of 1-azirine 105 with cyclopentadienone 106 to give the 3H-azepine 109 (Scheme 33) [1]. The first step of the reaction involves a [4+2] cycloaddition to give the endo-product 107. Cheletropic ejection of carbon monoxide then furnishes the azanorcaradiene 108. This material undergoes a disrotatory electrocyclic ring opening followed by a supra_facial [1,5] H shift to the thermodynamically most stable 3H-azepine ring. 1,3-Diphenylisobenzofuran has been reported to react with

:

Ph

100

-,,C_N=C ./'Fh[

T 103

101

Scheme 32.

102

Azirines and Aziridines Revisited

215

N Pb" 105

106

107

P

h

p

h

~

~. Ph

109

108

Scheme 33.

azirine 105 in refluxing toluene to give cycloadduct 110. This primary product of [4+2] cycloaddition possesses the exo configuration (Eq. 16) [86]. Ph (16) 105

110

Recently Gilchrist et al. [87] showed that 2-aryl-2H-azirine-3-carboxylates react as dienophiles with cyclopentadiene, 1,3-r and 2,3-dimethylbuta1,3-diene at 50 ~ to give products 111, 112, 113, respectively, of [4+2] cycloaddition to the carbon-nitrogen double bond. The cycloaddifions are endo-selective except with furan, and the reactions consistently show the same regioselectivity of addition in which the more nucleophilir tenmnus of the diene combines with the carbon atom of the carbon-nitrogen double bond [88]. The products are fused aziridine esters. The Diels-Alder reaction should be capable of extension to other activated azirinvs, t-Butyl-2H-azidne-3-carboxylate generated in situ by thermolysis of tert-butyl-2-azidoacrylate undergoes Diels-Alder cycloaddition reaction to several dienes. Addition to a chiral diene is highly diastereoselective [89].

OOMe 111

OOMe 112

~ ~ Z ) M e 113

2"16

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

Irradiation of a 1"1 mixture of azirine and 6,6-dimethylfulvene provides cycloadducts 114 and 115 in a ratio of 3:1 (Scheme 34) via nitrile ylide cycloaddition. The major adduct was quite labile and rapidly rearranged to two new species that were simple isomers of the original cycloadduct with respect to the cyclopentadiene double bond regiochemistry [90]. The orientation of the reaction pattern in adduct 114 is consistent with the preferential bonding of the position with the highest orbital coefficient in the fulvene LUMO to the position with highest coefficient in the dipole HOMO. 6,6-Dimethylfulvene was observed to be totally inert when exposed to a nitrile ylide in an effort to induce a cycloaddition between the two reactants. This lack of reactivity was attributed to a significant variation of the fulvene LUMO energy resulting in a decreased frontier orbital interaction. The reaction of the cyclobutadienc diester 116 with 2H-azirine 117 (R = Ph, p-C1C6H4-, or Me3C-, R" = H; R = Ph or, NMePh, R' = H; R = Ph or, R' = NMePh) gave oxaazatricyclic compounds 118 via [4+2] cycloaddition involving one ester carbonyl. Under thermal conditions, cleavage of isobutylene from 118 led to formation of the tricyclic lactone 119 which rearranges to the Dewar pyridine 120 [91 ].

..d Coo X~

116

R' 117

118

x,

Ph

120

119

Treatment of azirine 121a-c with 1 or 2 equiv of diphenylketene in ether at 25 ~ for 6h affords diadduct 123a-c the formation of which is probably accounted for by the greater reactivity of an azirinium ion. Thus formation of 122 and subsequent regioselective ring closure at the more electronegative oxygen rather than carbon accounts for product (Scheme 35) [92]. In comparison, the azirine 121d reacts with diphenylketene to give 126 in low yield via the intermediates 124 and 125 (Scheme 36). The aziridinium ion intermediate 124 is stabilized by conjugation

._ ~ P h 114 Scheme 34.

+ ~Ph 115

Azirines and Aziridines Revisited

217

Ph Ph2C=C=O

p

R' R O ~ P h 2

121

a) R, R'=H

122

b) R=I-I,R'=CH3

h

c)R, R'=CH3

P CPh2 123

Scheme 35.

with the phenyl substituent at C3. Hence ring closure of 124 to 125 can occur before a second molecule of ketene reacts as in the formation of 122. The methanophthalazine 127 is a propellene that contains an electron-rich cyclohexadiene and an electron-deficient diamadiene system within the same molecule. The highly strained amirines 128 [RR' = (CH2)n (n = 4-6) and R = Et, R' = Me] prepared from the corresponding vinyl amides, underwent in situ cycloaddition to the diamadiene system of added 127 to furnish the corresponding stable polycyclic azo compounds 129 (Scheme 37); these possess exo configuration of the annulated amiridine. Attack apparently occurred from the less-hindered face anti to the methano bridge of 127 with high stereo- and regioselectivity [93]. UV irradiation of tricarbonyl(cycloheptatriene)chromium(0) and 2-phenyl-1azirine through pyrex at 0 ~ led to 7-aza-8-phenylbicyclo[4.3.1 ]deca-2,4,7-triene via a [6+3] cycloaddifion to the cycloheptatriene ring (Scheme 38) [94]. Ph ,_~_ h

Ph

h••I

+

P

Ph2C=C=O

h

121d

124

I

125

126

Scheme 36.

218

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

F3 I

CF3 127

129

128

Scheme 37.

2H-Azirines are known to be relatively unreactive towards simple isocyanates [ 1]. However, benzoyl, thiobenzoyl, and p-tolylsulfonyl isocyanates were found to undergo thermal symmetry allowed [,t4s + n2s], [n2s + ,t2a], and [n2s + ,t2s + n2s] pericylic reactions while chlorosulfonyl isocyanates (CSI) react with 2H-azirines at-78 ~ to form [2+2+2] cycloadducts. The tricyclic aziridine derivatives undergo CSI extrusion reactions and subsequent oxidation to the corresponding pyrazines

[95]. A

+

~

.~0

~r--cO

"co Scheme

38.

4.6 Miscellaneous Reactions

The 4oz electronic system of a nitrile oxide can participate in 1,3-dipolar cycloaddition with an azirine forming a carbodiimide. A possible mechanism for its formation assumes initial 1,3-dipolar cycloaddition between the nitrile oxide and the azirine. Ring cleavage of the bicyclic adduct, or its valence tautomer, is followed by 1,2-migration of the R group of the nitrile oxide via a Beckmann-type rearrangement to give the carbodiimide (Scheme 39) [96].

"~h

Ph-CO-CH-N=C=N-R

~..

n

Scheme 39.

Ph-CO-CH-N=C-I~/':

Azirines and Aziridines Revisited

219

Arylazirines 130 (R = H, Me, OMe, Br; R' = H, Me) when treated with aryl-substituted chloromethyl sulfones, p-R"C6H4SO2CH2C1 (R" = H, Me, or C1) or the equivalent sulfoxides (p-R"C6H4SOCI-I2C1) in the presence of BuLi in THF a t - 7 8 ~ gave functionalized azabicyclo[1.1.0]butanes (n = 1,2) (Eq. 17) [97]. These reactions proceed via nucleophilic addition of the lithiated chlorosulfone or chlorosulfoxides generated in situ to the C--N bond of the azirine followed by intramolecular cyclization. ,R

(17) 130

131

The 1-azirines 132 (R = H or Me) reacted with hydrazine or phenylhydrazine in methanol to produce hexahydropyrrolopyrazolines 133, (R = H or Me, R' = H or Ph). The process may involve intramolecular interception of an unstable 4-aminopyrazoline intermediate resulting from C--N bond cleavage. In DMSO, reaction of 132 with formamidine, guanidine and hydrazine affords an imidazole, pyrimidine, and amino-S-triazine and triazole as a consequence of C-C bond cleavage in an aziridine intermediate (Scheme 40). The intermediacy of tautomers may account for the diversity of products [98]. Fluroalkyl (F-alkyl) chains perturb the reactivity of the substrate in an often unpredictable way. F-alkylazirine and aziridinecarboxylates were prepared from F-alkenyl esters in 80 and 60% yield, respectively, and were found to display reactions different from those of their hydrocarbon analogues. These F-alkylazirines give addition products easily but resist ring opening, while F-alkylaziridines are extremely stable, both towards nucleophilic and electrophilic reagents, irrespective of the medium used [99]. The metal complexes and metal reactions of azirines have been reviewed [2]. Stable complexes of silver, platinum, palladium, and zinc are also known. The reactions of azirines with tungsten or molybdenum complexes provide ring-opened compounds via initial complexation of the azirine nitrogen with the metal [ 100]. The products, metal imido complexes, are essentially a result of the complexation of a vinylnitrene to the metal. The reaction of a 2,2-dimethyl-3-phenyl-2H-azirine with molybdenum carbonyl in the presence of an alkyne produces 2H-pyrroles [ 10]. Exposure of an azirine to carbon monoxide in the presence of a catalytic amount of [Pd(PPh3)4] gave a bicyclie 13-1actam[ 101 ], while carbonylation of 2-arylazirines under mild condition (5 *C) in the presence of [Rh2(CO)4C12] gave vinylisocyanates in high yield [ 102]. These products can be isolated, or more conveniently converted to carbamates or ureas by reaction with alcohols or amines. The stereospecific synthesis of imides involves the reaction of azirines with activated methylidene compounds in the presence of a catalytic amount of molybdenum hexacarbonyl

220

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER R'

Ph ..R

H

~

2Ntt2

!

-132NR -H H

H I HN.~.~,~COOMe R' Ph

~

I

R'

R

R = R'=H

I

Ph

R

R=Me R'=NH2

I

P.h

Ph H2 Scheme 40.

[ 103]. A variety of other insertion reactions, dimerizations, intramolecular cyclizations, and intermolecular addition of azirines are known to be promoted by transition metals [10]. An antitumor agent, the cephalostatin analogue 134 was produced in 63% yield by cyclocondensation of 2,3-diphenylazirine with 1713acetoxy-2-aminoandrost- 1-en-3-one (Scheme 4 l) [ 104]. The mild base-promoted reaction of methyl 2-phenyl- 1-azirine-3-acetate with carbonyl compounds provides a new and simple route to 1,3-oxazolines which are formed in good yield by the electrophilic trapping of an imino anion produced by C-N bond cleavage in the 1-azirine enolate intermediate [105]. The treatment of enantiomerically pure L-sedne-derived N-carbobenzoxy- or N-(9-fluorenemethoxy)carbonylazirine dicarboxylates with indoles in the presence of a stoichiometric amount of Sc(O3SCF3) 3 in dichloromethane at 0 ~ or room Ac H2

Ac 0oc "~

Ph 134

Scheme 41.

Azirines and Aziriclines Revisited

A~

\

221

+ Null m'XCOOMe

Nwr

~__.XCOOMe

135

136 c

TCNE -Null 137 Scheme 42.

temperature gives aryl-substituted and aryl-protected tryptophanes in good yields [ 106]. The polyfunctional 1-azirine-3-methylacrylates 135 serve as valuable starting materials in a new approach to an aza-1,3-diene system (Scheme 42) [ 107]. Reaction of 135 with pyrazole, imidazole, and simple alcohols under mild base-catalyzed condition affords 2-aza-l,3-diene derivatives 136 containing a potential leaving group at the 1-position. Azadiene 136 undergoes the hetero-DielsAlder reaction with an electron-deficient dienophiles like TCNE to yield the cycloadduct 137 in good yield.

5. 3-DIMETHYLAMINO-2H-AZIRIN ES 3-Dimethylamino-2H-azirines are known to be the valuable synthetic intermediates for a wide variety of uses [108,109]. Indeed they undergo reaction with different substrates containing acidic protons. For instance, reaction with activated phenols [110] and heterocycles with acidic NH groups [111] lead to different types of heterocycles of special importance. Structural similarity with natural amino acids and the high reactivity of 3-amino-2H-azirines [ 112-115] suggests a wide possibility for synthesis of various classes of organic compounds including peptides and depsipeptide derivatives. For example, the reaction with carboxylic acids and amino acids affords ot,cx-disubstimted-r acid derivatives. This last reaction is the starting point for the development of the so-called azirine/oxazoline method for the synthesis of dipeptides [ 116], linear oligopeptides [ 117], depsipeptides [ 118], and cyclic peptides [ 119] containing ot,0t-disubstituted ~-amino acids as well as for the synthesis of peptaibols [ 114].

222

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

5.1 Synthesis The most general synthesis of 3-amino-2H-azirines bearing two substituents at C2 is based on the procedure described by Ren and Ghosez [120] in which r are allowed to react with sodium azide (see Scheme 43). Amidation of EtOCOCH2CN with RNH 2 followed by treatment with NH2OH afforded an oxime. The tosylate of this oxime was transformed into an azirine when treated with sodium methoxide [ 121 ]. Recently optically active (2R,3R), (2S,3R), (2S,3S), and (2R,3S)-3-amino-2H-azirines were prepared in high optical yield by means of a modified Neber reaction using amino acid derivatives of chiral substrates derived from phenylglycine ethyl ester [ 122]. Thus optically active peptide 139 possessing a 3-amino-2H-azirine ring system was conveniently prepared in good yield by the reaction of a base with imine 138, bearing a leaving group on the imine nitrogen atom as well as at least one r next to the imine (Eq. 18). EtOOG..

0

NH2

H

(18) 138

139

The synthesis of the heterospirocyclic 3-amino-2H-azirine 140 [ 110], as well as of other 2,2-substituted or 2-monosubstituted 3-amino-2H-azirines [ 123,124] was carried out from the reaction between an amide enolate and diphenylphosphorochloridate followed by reaction with sodium azide (Scheme 43) [ 124]. The yields obtained are excellent and the method is suitable for large scale preparation. The complexation/decomposition procedure with PdC12 has been shown to be a very useful method for the purification of 140.

~=-~

h LD^_ -

Li+ ~~Oe=..F h

~

0'hO)2PCi ~

I...,,.OPh O-Li§

~~hl,,Op

h

~-+ (PhO)2POLi HMe 140

.,,,.Ph

Hr __~'-'Ph

"Me

Me

Scheme 43.

Azirines and Aziridines Revisited

223

5.2 Reactions

Cleavage of the azirine double bond leads to a synthon which can be considered an amino acid equivalent. The reactions of 2,2-dialkyl-3-amino-2H-azirines 141 with carboxylic acids yields N-acylamino acid amides, which can be converted by a selective amide cleavage to the corresponding N-acylamino acids. 2-Oxazolinc5-ones are intermediates in this amide cleavage (Scheme 44). The reaction sequence has been used for the extension of pepfide chains as well as for a number of heterocyclic syntheses. Likewise, the desired synthesis of a cyclic depsipeptide and lactone proceeds by a direct amide cyclization process via a 2-oxazoline-5-one intermediate. The selective amide cleavage was also applied to a novel method for the resolution of enanfiomeric amino acid derivatives [113]. The reaction Of the 2,2-dialkyl-3-amino-2H-azirine 141 (R = R' - Me) and the 1,3-oxadiazolidine-2,4-dione 142 in acetonitrile at room temperature leads to 3,4-dihydro-3-(2-hydroxyacyl)-2H-imidazol-2-one 144 in good yield [125]. A reaction pathway proceeding via ring enlargement of the bicyclic zwittcrion 143, followed by transannular ring contraction is proposed for the formation of 144 (Scheme 45). This mechanism is in accord with the result of the reaction of 142 and 141 in which the azirine nitrogen atom is labeled; in the isolated product only (N3) is labeled. The analogous reaction of 141 and 1,3-thiazolin-2,4-dione is more complex. Besides the expected 3,4-dihydro-3-(2-mercaptoacetyl)-2H-imidazol-2-onc, 5amino-3,4-dihydro-2H-imidazol-2-ones, and/or N-(1,4-thiazin-2-ylidcnc) arc formed. The analogous reactions of 3-amino-2H-azirine 141 with 1,3-thiazolidin2-thione (145, X=S) and 1,3-oxazolidin-2-thione (145, X=O) lead to the corresponding imidazole derivatives 146 (Scheme 46) [ 126]. Under similar conditions the reaction of 141 with 4-substituted-4-phenyl-2-(trifluoromethyl)-l,3-oxazol5(4H)-ones 147 afforded 5-dimethylamino-3,6-dihydropyrazine-2(1H)-ones 148 (Scheme 47) [127], whereas no reaction could be observed between 141 and R'O

Mc N

R~

141 R' 0 n

!

M ~ . . ~ OR 1~Ir 1r "R

Me" ~le Scheme 44.

224

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

+

141

142

lr

H 144

Scheme 45.

2-alkyl-4-phenyl-2(trifluoromethyl)-l,3-oxazol-5(2H)-ones or 4,4-dibenzyl-2phenyl-l,3-oxazol-5(4H)-one [128]. The formation of 148 is rationalized by nucleophilic attack of 141 on 147. The failure of 4,4-dibenzyl-2-phenyl-1,3-oxazol-5(4H)-one to react showed that only activated 1,3-oxazol-5(4H)-ones bearing an electron-with&awing substituent react as electrophiles with 141. The reaction of azirine 141 with 1,3-benzoxazol-2(3H)-thione, which can be considered an NH acidic heterocyclic compound (pKa 7.3), in acetonitrile followed by hydrolysis led to the formation of 3-(2-hydroxyphenyl)-2-thiohydantoins 149 (Scheme 48) [ 129]. In the last few years, Heimgartner et al. [130] have shown that NH acidic heterocycles 150 with PKa-- 8 react with 141 via ring expansion of the three-membered ring. In some examples, heterocycles 150 are enlarged by the three azirine atoms to give (n + 3)-membered heterocycles of the type 151 via the zwitterionic intermediate 152 (Scheme 49) [131 ]. This reaction has been effected with 1,2-thiazol-3(2H)-one-l,l-dioxide and 1,2-thiazolidin-2-one-l,l-dioxide (n = 5) [132], four- and five-membered cyclic imides [133], with 1,2-oxazolidin-3-one (n - 5) [134], with 12-thiazolidin-2,4-dione (n = 5) [135], and with 2H-1,2,4-thiadiazin-

~

+ 141 /

\

/

145 146 Scheme 46.

225

Azirines and Aziridines Revisited

Ph ~ F 3

_I ~ + 141

h

,. ,

147

148

Scheme 47.

3(4H)-one-1,1,-dioxide (n = 6) [136]. With these examples, it was demonstrated that this ring enlargement gives medium sized heterocycles in high yield. The reaction of azirine 141 with 2,4-disubstituted-l,3-oxazol-5(4H)-ones 153 leads to a novel ring enlargement to the 4,5-dihydropyridine-2(3H)-one system 155. Several side products were observed in this reaction. Two different mechanisms for the formation of 155 are proposed, either 141 undergoes a nucleophilic addition to the open chain ketone tautomer of 154 (Scheme 50) or via reaction of 153 as a CH acidic compound (Scheme 51) [ 131]. Azirines 141 (R : Me, R' = Me, CHMe 2, vinyl or allyl) underwent ring enlargement with isoxazolidinones to give 63-97% of oxadiazoeines [135] while 141 (R : R ' = Me) isoxazolidine-2-thione in aeetonitrile gave imidazothiazolethione 156 and thiazolylallylthioureas 157. In comparison the last reaction in isopropanol at 60 ~ gave 157 as the only product (Scheme 52). In a polar solvent 156 isomerizes to 157. Hydrolysis of 156 and 157 gave thiohydantoins 158 [137]. The reaction of 141 (R = R' = Me) with a barbitudc acid derivative gives 2-[5-(dimethylamino)-4,4-dimethyl-4H-imidazol-2-yl]acetamide (159, R = R' = Me). The formation of 159 proceeds via loss of carbon dioxide and the formation of a zwittedonie intermediate. Thermolysis of 159 gave 2-alkyl-5-(dimethylamino)-4,4-dimethyl-4H-imidazole or the tautomeric 2-alkylidine derivative via

..N /

~

S

+

141

149

Scheme 48.

226

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

~ +

141

~ ~ +

150

~

~.~~--

152

151

Scheme 49.

,

+

153

~N/

,

~ R'

NHCOR

oo,.

H

,

.-"

R'

~

,~, ~.

154

NHCOR

155 Scheme 50.

[

\

IMe ~_~~Me

.,,.N--

141

153

_ -----Iw

+

NHCOR Oo,..

..-" R e

155 Scheme 51.

'~R

Azirines and Aziridines Revisited

227

H 156

157

H 158

Scheme 52.

loss of HNCO. A reaction of 141 with barbituric acid was not observed in the presence of alcohols or morpholines. Instead, formation of 2-alkoxy-2-(dimethylamino)azirinium ion precedes ring opening as observed [138].

Ro~NH2 159

Reaction of 141 with the N-sulfonylalkylamine 160a,b provides 1,2,5-thiadiazoles 161a,b (Scheme 53) whereas N-carbonylsulfonylamines 160c-f results primarily in 1,2,3-oxathiazoles 162c-f which isomerize to the corresponding thiadiazoles 161c-f on treatment with silica gel at room temperature. In contrast, use of 2-alkyl-3-dimethylamino-2-phenyl-2H-azirine in the reaction with the sulfonamide and N-sulfonylcarbamates leads to mixture of thiadiazoles and oxathiazoles along with isomeric acrylimine 163 [ 139]. After activation by protonation or complexation with BF 3, azirine 141 reacts with the amino group of an ~-amino acid ester to give a 2,6-dihydro-5-aminopyrazine2H-one 164 by ring enlargement (Scheme 54) [140], while with BF 3 primary amines gave r Similarly reaction of 141 with ethyl nitroacetates in refluxing MeCN affords 4-amino-l,5-dihydro-2H-pyrrole-2-ones and 3,6diamino-4,5-dihydropyrazines, the dimerized product of 141. Thus ethyl nitroacetate reacts with 141 as a CH acidic compound by charge transfer and bond formation via nucleophilic attack of deprotonated ethyl nitroacetate onto the amidinium carbon atom of protonated azirine 141 (Scheme 55) [141 ].

228

KURIYA MADAVU LOKANATHA PAl and ALFRED HASSNER

.O. Ph ,, R'O~N " ~ " R--N--~DO +

P~,~" + Me2N~ ~0

~ ,~Mo~_

~--~=NR

0 ~ ~ N'

141

160

a - Pri; b = Bui,

161

+

162

-SO2--NHCOR Me2

c =Bz; d = cinnamoyl;

e = COOMe; f = COOPr

163

Scheme 53.

, 141

+

H+

- " - ' ~ " ~ ~H+ ' -

~./NH2

~L

\

_~.C--COOMe

+

~

e2

164

Scheme 54.

! 141 +

H+

~

~ + -

O2NCH2COOEt .....

H

=~

/ N N2o M e 2 _

Scheme 55.

H~~E t

~o2

AzMnes and Aziridines Revisited

229 H

~NMe2

NMe2

H2N~NMe 2

166

Scheme 56.

Reaction of 141 with salicylohydrazide in MeCN at 80 ~ afforded 2H,5H- 1,2,4triazine 165 and 1,3,4-oxadiazole derivative 166 (Scheme 56) [ 142]. Tripeptide 167 containing a 2,2-disubstituted a-amino acid and ethyl p-aminobenzoate were synthesized in high yield by application of the azirine/oxazoline method. In this versatile approach for the incorporation of disubstituted residues into the peptide chain, N-protected peptides or amino acids were coupled with 2,2-dialkyl-3-amino2H-azirines after the selective hydrolysis of the newly formed amide bond at the C-terminus and further condensation with amino components via in situ generated oxazol-(4H)-ones in the presence of additives. A comparison with the conventional procedure clearly demonstrated the advantage of this new method that works equally well with I]-branched cyclic- or cyclic-disubstituted amino acids (Scheme 57)[143].

R~

~ NMe2 BocN~e2

+ BocN~''COOEt 141

3NHCl ~THF/H20 R"~IH2

R

0

H2N~ ~ i ~ , ''OH

H

Scheme 57.

OOEt

230

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

6. AZIRIDINES Aziridines [144] are very interesting heterocyclic compounds, some of which are found in nature in unusual natural products that display strong biological activity that is intimately associated with the reactivity of the strained heterocycles. For example, mitomycins A, B, and C together with porfiromycin (168) and mitiromycin (169) [145] represent an important class of naturally occurring mitosanes, isolated from soil extracts of Streptomyces verticillatus [146]. These mitosanes exhibit both antitumor and antibiotic activity, their antitumor properties resulting from their ability to cross-link DNA [145]. Structure-activity relationships have identified the presence of the aziridine ring as essential for such antitumor activity, and a vast amount of work has concentrated on synthesizing derivatives of these natural products with increased potency [147].

Z 168

169

Mitomycin A. X=~3Me,Y=Me, Z=H

Mitiromycin

Mitomycin B. X=OMe, Y-H, Z=Me Mitomycin C. X--NH2, Y--Me,Z=H Porfiromycin A. X--NH2, Y-Me, Z-Me

A further class of biologically active aziridine derivatives such as azirinomycins A and B (170) [ 148], isolated from the fermentation broth of Streptomyces griseofuscus, and (+)-FR900482 (171) [149], from the culture broth of Streptomyces sandaensis, exhibit exceptionally potent antitumor activity against various types of mammalian solid tumors. A number of synthetic aziridines have also been shown to exhibit useful biological properties. For example, 2-(4-amino-4-carboxybutyl)aziridine-2-carboxylic acid (172) is a potent irreversible inhibitor of the bacterial enzyme diaminopimelic acid epimerase [150], while 2-(3-carboxypropyl)aziridine-2-carboxylic acid (173) is an irreversible inhibitor of glutamate racemase [ 151 ]. M

H

R

170 Azinomycin A: R=H; AzinomycinB: R=CHO

~ H .,,,,OCONH2

171

Azirines and Aziridines Revisited

H~OOH 172

HOO~A~COOH

231

173

Novel antitumor agents related to mitosanes and mitomycins have recently been synthesized and demonstrated to possess activity against a variety of cancers [ 152]. Thus, aziridines are worthy targets for the synthetic organic chemist, and it is essential that efficient methods exist for the facile synthesis of a range of structurally diverse aziridines, with the added requirement that the available methods should also allow enantioselective azifidine formation. Since their discovery by Gabriel in 1888, aziridines have attracted much attention as starting materials for further transformations, Recently, the chemistry of enantiomerically pure substituted aziridines has been the target of extensive research [ 153]. Like other three-membered rings, aziridines are highly strained and this renders them susceptible to ring-opening reactions [5]. By suitable choice of substituents on the carbon and nitrogen atoms, excellent stereo- and regiocontrol can be attained in opening the ring with a wide variety of nucleophiles including organometallic reagents; this makes chiral aziridines useful substrates for the synthesis of important biologically active species including alkaloids, amino acids, and I~lactam antibiotics. In particular, the ringopening reactions of enantiomerically pure aziridine-2-carboxylate have been the most popular since the reaction provides either enantiomerically pure t~-amino or ffamino esters many of which are considered biologically important compounds [154].

6.1 Synthesisof Aziridines from Alkenes Aziridincs are valuable intermediates in organic synthesis and, in addition to the classical synthesis via addition of INCO [ 155] or of IN 3 [ 156] to olefins, new routes to their preparation have been the focus of recent investigations with an emphasis on metal-catalyzed processes [ 157]. Copper salts including CuOTf and Cu(OTf) 2 were shown by Evans [ 158] to be effective at catalyzing the aziridination reaction between [N-(p-tolylsulfonyl)iminc]phenyliodinane (PhI--NTs) and a wide range of electron-rich and electron-poor olefins; copper nitrenes of general structure XnCu--NTs were proposed as intermediates. Recently available nitrene precursors increase the utility of the Evans asymmetric synthesis of aziridines from olefins, with the olefin as the limiting component. The aziridine derivatives were obtained in moderate to excellent yields and with enantioselectivity up to 95% ee [ 159]. The aziridination process is stereospecific with alkyl-substitutexi olefins. However, while addition to (E)-stilbene generated the trans-aTdddine, addition to (Z)-stilbene was accompanied by partial loss of the olefin geometry. Jacobson [ 160] proposed that this observation is best explained by involving two different mechanisms in which an alkyl-substituted olefin reacts via a concerted mechanism, whereas an alkene bearing aryl substituents undergoes a stepwise process. A radical interme-

232

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

diate was proposed with these latter substituents which are capable of providing stabilization (Scheme 58). Rotation about the C-N bond prior to ring closure by formation of the second bond accounts for the formation of a trans-aziridine from a (Z)-olefin. Transition metal-ligand complexes isolated from either chiral 1-phenyl-2-[(4S)phenyl-4,5-dihydrooxazol-2-yl]propen-2-ol or 1-phenyl-2-[(4S)-phenyl-4,5-dihydrooxazol-2-yl]vinyl-p-tosylamine and copper are highly active catalysts for the asymmetric aziridination of styrene giving the corresponding N-tosylaziridine in excellent yields and with enantiomeric excess at 15-34% [ 161 ]. Copper-exchanged zeolite Y is shown to be an efficient catalyst for the aziridination employing PhI--NTs as the nitrogen source [ 162]. Aziridines were prepared by the reaction of unsaturated compounds with a nitrene donor in the presence of an acidic zeolitic material impregnated or exchanged with ions of groups VRA, VIII, IB, and IIB elements [ 163]. Asymmetric aziridination may be effected by treating the catalyst with a chiral modifier such as a 4,4'-disubstituted bis(oxazoline) before contact with the nitrene donor. Thus methyl cinnamate, PhI=NTs and zeolite Y exchanged with copper acetate, were stirred for 24 h in acetonitrile to give 84% of aziridine derivative. In contrast to many homogeneous aziridinations, a high product yield can be achieved without the use of excess alkene. Significant progress has been made in the development of an enantioselective aziridination reaction. Prabhakar et al. [164] reported a new catalytic enantioselective method for N-arylaziridines based on the quarternary salts of cinchona alkaloids as phase-transfer catalysts. The parent bis(benzylidenediamino)cyclohexane in association with Cu(OTf), 174, exhibited moderate catalytic activity and enantioselectivity in the aziridination of alkenes [165]. Significant improvement in selectivity was observed with substituted bis-benzylidine derivatives and bis(2,6-dichlorobenzylidenediamino)cyclohexane afforded best results with regard to both catalyst lifetime and selectivity. High enantiomeric excess was obtained with (Z)-olefins, although the reaction was not stereospecific. Evans [ 166] reported that copper complexes of chiral bis(dihydrooxazole) 175 were also very effective for enantioselective aziridination of styrene in terms of yield and diastereo- and enantioselectivity. The manganese(III) bis(benzylidenediamino)ethane complex 176 was less effective. A newly designed chiral manganese(III) [Salen] complex was found to be an effective catalyst for

Ar

R

Ar

Ar

R

Coil aps

.~

+

Ts-"~

Rotation

Ar

"]3STs

p~

s o"

Scheme 58.

Azirines and Aziridines Revisited

233

asymmetric aziridination of styrene derivatives showing high asymmetric induction [167,168].

=•H.•H 174 XffiOTf 177 X=PF6

~

175

Ph Ph

R-Ph/tBu

176

Several features of the reaction mechanism have been elucidated. Evidence to support the existence of a discrete (diamine)Cu=NTs species as the catalyst was put forward by Jacobson [ 169]. A copper nitrene solution generated under photochemical conditions from tosyl azide in the presence of 177 gave the same ee with styrene as did the reaction of PhI=NTs with 177. Furthermore, similar levels of enantioselectivity were observed in CuPFt-catalyzed aziridination or in cyclopropanation using ethyl diazoacetate when the same ligands were employed. Several observations support the intermediacy of a copper species in the +2 oxidation state. Evans observed similar enantioselectivity with Cu(OTf) 2 or Cu(OTf). In addition, the iodine(IU) reagent was shown to be an oxidant for Cu(I). The UV spectrum of a solution of the ligand, and Cu(OTf) taken after treatment with the iodine reagent was indistinguishable from that of a solution of Cu(OTf) 2. The Cu(I) complex (FeNN)Cu(O3SCF3)[FeNN=NN'-bis(ferrocenylmethylene)1,2-ethanediamine] catalyzed nitrene transfer from PhI=NTs to alkenes to produce aziridines in high yield [170]. The Rh2(OAc)4-catalyzed decomposition of [N-(pnitrobenzenesulfonyl)imino phenyliodinane] (PhI--NNs) in the presence of olefins affords aziridines. The aziridination of (Z)-methylstyrene and (Z)-hex-2-ene is stereospecific [ 171]. When anhydrous chloramine-T was added to an acetonitrile solution of alkenes in the presence of various CuC1 catalysts and MS-5A, the corresponding aziridines were obtained in moderate to good yields [ 172]. This appears to be the first bonafide case, using chloramine-T, where the transition metal center is directly involved in the aziridine synthesis. Recently Ando et al. [173] showed that iodine acts as an effective catalyst for the aziridination of alkenes utilizing chloramine-T as nitrogen base. For instance, when 2 equiv of styrene were added to chloramine-T in the presence of a catalytic amount of iodine in a 1"1 solvent mixture of acetonitrile and neutral buffer, the corresponding aziridine was obtained in 91% yield. A wide range of bromine sources (e.g. ZnBr 2, HgBr 2, FeBr 2, CuBr 2, Br 2, NBS) act as catalysts for the aziridination of simple olefins using chloramine-T [ 174]. Initially the olefins react with the Br+ source (Br-X) to give the bromonium ion 178, which then suffers benzylic opening by TsNC1- forming ffbromo-N-chlorosul-

234

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

fonamide. Attack of Br- or TsNC1- on the N-C1 group in the intermediate 179 generate the anion 180 and a Br-X species. Expulsion of Br- from anion 180 finally yields the aziridine 181 and the regenerated Br-X species (vide supra) is ready to initiate another turn of the catalytic cycle (Scheme 59). The reaction of tx,ffunsaturated esters with ethoxycarbonyl nitrene, generated by o~-elimination from MsONHCO2Et by CaO as base and in a heterogeneous medium, led to the preparation of aziridine-1,2-dicarboxylates in good yield. The same reaction does not take place using triethylamine as base under homogeneous conditions [175]. Chiral 3'-benzyloxaminoimides are suitable precursors of 3'-alkylaziridine-2-carboxylates, which are obtained via chiral titanium or aluminium enolates. 1,4-Addition of ammonia to chiral tx-haloamides in DMSO is a diastereoselective and high-yielding procedure to obtain optically active transaziridines [176]. For instance Cardillo et al. synthesized benzylaziridine-2-carboxylates by conjugate addition of ammonia to tx,13-unsaturated chiral imides followed by treatment with lithium benzyloxide [176]. Aziridine-2-imides are prepared both in high yield and with high diastereoselectivity from chiral 3'-benzyloxaminoimides by treatment with triethylamine in the presence of either TiC14 or A1Me2C1 [ 177,178]. A mechanistic study by means of AM 1 calculations suggests that the complete trans diastereoselectivity can be attributed to the preferred conformations displayed by the intermediate cyclic enolate in which the alkyl group and the leaving group are trans to each other. In the synthesis of 3'-unsubstituted aziridines, diastereoselectivity is lower probably owing to the absence of the substituent in position 3. Diastereoselective aziridination of vinylsilanes (PhCH=CH-SiR3; R = Me, Et, Ph) with enantiopure-3-acetoxyaminoquinazolinone (Q*NHOAr gave the corresponding aziridines. Desilylative elimination of the quinazolinone Q* from these aziridines by CsF in the presence of cyanide ion led to an NH-aziridine of 83% ee, via the in situ-generated 3-phenylazirine intermediate (Scheme 60) [179]. Reaction of naphthalene with 3-acetoxyaminoquinazoli-

%.

/=x

.~

Ph

P~"~/"Me

Me

Ts ph/

181 Br-X

X=Cl,TsNCI,Br, etc ~

Br

H%..

....

-

Tg

180

T/ 179 Scheme 59.

Br

S T

X'Me 178

s~r

Azirines and Aziridines Revisited

235

1

Ph-CH=CH-SiMe3 R'

Q*NIIOAc

Scheme 60.

nones in the presence of hexamethyldisilazane afforded the corresponding monoaziridine,which on heating in benzene serves as an aziridinatingagent for alkenes [180]. The presence of the quinazolin-4(3H)-one ring (Q*) in N-(Q*)-aziridines facilitatesring opening by nuclcophiles. Removal of the Q* from enantiopure ring-opened products gives useful chirons [181 ]. The activatedaziridines182 were prepared by the addition of iodine isocyanatc to either cyclohexene or cyclopcntene followed by treatment with potassium t-butoxidein dimethylformamide in 85 and 75%, respectively[182]. In the presence of Lewis acid catalysts,alkyldiazoacetatesadd nucleophilicallyto N-methylidcncimine equivalents from hexahydro-l,3,5-triazineto give adducts 183. When nitrogen is released from these adducts 3-unsubstitutcd aziridine-2-carboxylatesarc formed. The same reaction for the chiralN-methylideneimine equivalent derived from 1,3,5-tris(R)-,or 1,3,5-tris(S)-phenylethylhexahydro-1,3,5-triazinesyielded a diastereomeric mixture of N-phcnylethylaziridine-2-carboxylates (Scheme 61) [183]. (~t~-Boc

182

a: n=0; b: n=l

6.2 Synthesisof Aziridines from Imines Olefination, cyclopropanation, and epoxidation via an ylide route are fields of extensive research. In comparison, ylide aziridination has attracted little attention due to the low reactivity of imines towards attack by ylides compared with the reactivity of carbonyl compounds or Michael acceptors. Aziridination by addition of carbenoids [ 184] or ylides [ 185] to C--N double bonds has been demonstrated as a synthetic strategy for asymmetric aziridination in recent years and is regarded as an alternative methodology to the reaction between nitrenoids and a carbon-

236

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

R LA

H

~COOR'

I

TiC4

l

t

LA

COOR' 183

Scheme 61.

carbon double bond [186]. Among the potential advantages of this approach are the synthetic accessibility of imines and diazocarbonyl compounds, the high reaction efficiency (the only side product being nitrogen), and the inherent convergence associated with coupling two potentially complex fragments. However, the ylide and carbenoid methodologies can only be applied to an activated imine; that is to carbon-nitrogen double bonds carrying an N-electron-withdrawing group (Eq. 19). H/P"/'C=Nx,X + N2CHR'

~

~ R ' I X

(19)

Hou et al. [ 187] synthesized ~-phenylvinylaziridines from the reaction of N-sulfonylimines and cinnamyl bromide mediated by a catalytic amount of dimethylsulfide in the presence of solid potassium carbonate in acetonitrile at ambient temperature. Recently the same group demonstrated an efficient method for the preparation of various a-unsaturated substituted prop-2-ynylic and aUylic sulfonium ylides in the presence of BF3.OEt2 with high cis selectivity [188]. This extends the scope of the ylide route to aziridination without the need to prepare N-EWG imines, and it can be applied also to cyclic imines. Brookehart et al. [ 189] described the use of BF3-(OEt)2, A1CI3, and TiC14 for the synthesis of aziridines from the reaction of ethyl diazoacetate with imines, while Agarwal et al. [ 190] used a combination of sulfur ylide and metal complexes for asymmetric aziridination. It has been found that for metal-catalyzed reactions of imines with diazoacetate [191], both main group complexes--such as BF3-OEt2; early- and late-transition metal complexes, such as TiCl2(O-pri)2 , Cu(OTf) 2 and Zn(OTf)2; and rare earth metal complexes, such as Yb(OTf)3--can catalyze the formation of aziridines. The aziridination gives mainly cis-aTJddines as the major diastereomer, but the selectivity is dependent on the substrate, catalyst, and solvent. Zn(OTf) 2 and Yb(OTf) 3 have been shown to be general catalysts for the formation of various aziridines using different imines and a variety of reaction conditions.

237

Azirines and Aziridines Revisited

Both Zn(OTf)2 and Yb(OTf)3, as well as other Lewis acids, in combination with various chiral ligands, have been tested as catalysts for the formation of optically active aziridines, but only low ees were obtained. The Zn(OTf) 2- and Yb(OTf)3catalyzed reactions have been investigated for imines having both electron-donating and electron-withdrawing substituents, and in reactions containing diethyl fumarate as a trapping agent, in attempts to obtain insight into the mechanism of aziridination [191]. Recently Sudalai et al. [192] demonstrated that Rh(HI) montmorillonite K10 is an efficient and reusable catalyst for imine aziridination using methyl diazoacetate as the carbene precursor. Reaction of N-sulfonylimines with N,N-dialkylcarbamoylmethyl dimethylsulfonium bromides in the presence of solid potassiumhydroxide gives aziridinyl carboxamides in good yield (Eq. 20) [ 193]. cis-~nyl- and cis-ethynylaziridines are furnished in high yields and in high stereoselectively by aziridination of N-aryl and N-alkylimines with S-ylides in the presence of a Lewis acid catalyst (Scheme 62) [194].

4-

Ar

"kT]l~ tlDtt

Me2S~ Br" v

~

+ ArCH=NTs

KOH ..~ -Me2S ..-

\

~N~

"NRT," I

(20)

Ts

Reaction of boron enolates, derived from ten-butyl tx-halothioacetate and bearing menthone derived chiral ligands, with imines led with excellent diastereo- and enantiocontrol to a syn-cz-halo-~aminothioester that can be converted into the corresponding aziridine by simple ring closure during LAH reduction [ 195]. A key precursor of the antibiotic (+)-thiamphenicol and (-)-floffenicol was synthesized in this manner. Under phase transfer or low temperature conditions, the ylide generated from (Me3SiC_=CCH2S+Ph2)(CIO4) readily reacts with N-sulfonylimines to give alkyne-substituted aziridines in excellent yields, but with low to moderate cis/trans selectivity [196]. When using butyllithium as the base to generate the ylide at low temperature, the product with an intact silyl protecting

Ph2 R

4A Mol. Seive

+ BuLi

THF,-7$oC--

CIO4

\ I-I""

/H +

LA = Me3SiCI or BF3:OEt2 S c h e m e 62.

238

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

group is obtained, whereas potassium tert-butoxide leads to desilylated product. With CaCO 3 as the base, dimethylsulfonium salts show much better cis/trans selectivity (>98.2) than the diphenylsulfonium salts. The asymmetric version of the above aziridination reactions using camphor-derived sulfonium salts give chiral aziridines with ee values up to 85%. Both (2R,3S)-(-)- and (2S,3R)-(+)-ethynylaziridines can be prepared. The i r o n - c o n t a i n i n g Lewis acid [(C~C5Hs)Fe(CO)2(THF)]+[BF4] - was found to be an effective catalyst for aziridination with yields up to 95% from compounds with diazo functionality and a variety of substituted N-benzyilideneimines with N-aryl or N-alkyl groups. The reaction is believed to proceed through an electrophilic iminium ion intermediate [ 197]. Monocarbonyliodinium ylides, generated in situ from 2-acetoxyvinyliodinium salts via an ester exchange reaction with EtOLi, undergo an alkylidine transfer reaction to activated imines to yield 2-acylaziridines in good yields. The stereochemical outcome of this aziridination was shown to be dependent on both the activating group of the imines and the reaction solvent [ 198]. For instance, the aziridination of N-(2,4,6-trimethylbenzenesulfonyl)imine in THF affords cisaziridine as a major product while that of N-benzoylimine in THF-DMSO or THF give the trans-isomer stereoselectively.

6.3 Aziridines from Azirines Nucleophilic attack on azirines at the C3-N double bond has proven to be a useful method for the preparation of substituted aziddines [2,4]. The carbon-nitrogen double bond is more electrophilic than that of a normal imine due to the strain of the three-membered ring. Direct stereoselective [ 199] additions have been reported with a number of strong nucleophiles, including LAH, NaBH 4, sulfur ylides, alkoxides, Grignard reagents, amines, nitrones, etc. For instance, the highly stereoselective addition of methylmagnesium bromide to 2H-azirines resulted in the first synthesis of unsymmetrical 3,3-disubstituted aziridine-2-carboxylic esters and it represents a particularly general route to these valuable materials [199]. Selective hydrogenation of these aziridines results in a new methodology for the enantioselective synthesis of substituted or-amino acid esters.

6.4 Miscellaneous Syntheses The efficient single-step transformation of chiral N-protected-[3-amino alcohols into the corresponding aziridinr consists of treatment with tosyl chloride and an excess of powdered potassium hydroxide in dry ether followed by reflux [200]. The Lewis acid catalyst, [n5-(C6H5)Fe(CO)2(THF)]+[BF4] - was found to be effective for the preparation of aziridines [201]. This new method provides a facile, one step route to predominantly cis-aziridines with yields up to 95% from diazo compounds with a variety of substituents and N-benzylidineimines possessing N-allcyl or N-aryl groups. The reaction is believed to proceed through an electrophilic iminium ion intermediate. The enantiomerically pure aziddine derivatives of

Azirines and Aziridines Revbited

239

[3-D-glucopyranosides were obtained by regioselective azidolysis of 2",3'-epoxide derivatives of aUyl-3,4,6-tri-O-benzyl-~D-glucopyranosides followed by cyclization of the corresponding azido alcohols by means of the triphenylphosphine protocol [202]. Treatment of the allylmesylate of N-protected-2-alkyl-4-amino-(E)-2-alkene-1ols with sodium hydride in dimethylformamide yields exclusively the corresponding trans-2-alkenyl-3-alkylaz~dJnes. In contrast exposure of the methyl carbonate ofN-protected-2-alkyl-4-amino-(E)-2-alkene- 1-ols to Pd(PPh3) 4 in THF or dioxane predominantly gives the corresponding cis-2-alkenyl-3-alkylaz~dines [203]. The conversion of 9,10:12,13-diepoxyoctadeconates with sodium azide and ammonium chloride in wet ethanol yielded 9(10),12(13)-diazido-10(9),13(12)-dihydroxyoctadeconates in the first step as a regioisomeric mixture. Further reaction with Ph3P led-tocis,cis-9,10,12,13-diepirr6nooctadeconates, fatty acid derivatives that contain aziridine functionalities [204]. Aminoallenes, (S,as)Me2CHCH(NHMts)CH----C--CMe (Mts=2,4,6-Me3C6H2SO2) reacted with Pd(PPh3)4/K,2CO3 and an aryl halide, e.g. iodobenzene, to give aziridine 183 [205]. M~

Mts

183

6.5 Ring-Opening Reactions of Aziridines As a consequence of the ring strain present in aziridines and related threemembered rings, ring-opening reactions are a dominant feature of their chemistry. Synthesis of or-amino acids has become increasingly important in recent years and this has led into the development of a large variety of new synthetic methods. A useful general synthetic entry to chiral amino acids would be to react a suitably substituted, optically pure, aziridine-2-carboxylates with a variety of nucleophiles. Reaction at the ~-carbon atom would give the desired protected a-amino acids, whereas reaction at the cz-carbon atom would yield [3-amino acids [5]. Regiospecific ring opening at the ~-carbon atom of such aziridine esters to yield useful products has been successful using heteronucleophiles such as sulfur nucleophiles, oxygen nucleophiles, nitrogen nucleophiles, carbon nucleophiles, and halides [206,207]. Most of the aziridines which undergo direct nucleophilic ring opening bear strong electron-accepting groups on nitrogen, viz. RCO, RSO 2, CN, Ar, etc. Those aziridines which do not bear such functionality require very strong nucleophiles or vigorous reaction conditions for ring opening. It is possible that some of these last examples actually involve general acid catalysts. Competition can occur between atta_.ck on the ring and the carbonyl group of an aziridine and this presents a complication in the synthetic utilization of such a reaction [208].

240

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

The ring opening of activated aziridines by amines requires elevated temperatures; the introduction of an amino group is generally best realized by nucleophilic ring opening by sodium azide [209,210]. The yterbium triflate-catalyzed aminolysis of N-protected aziridines such as tert-butoxycarbonyl-, tosyl-, and benzylaziridines has been reported recently to proceed smoothly with primary or secondary amines [211]. Actually both N-Boc and the N-benzyl-bis-aziridines 184 react with primary amines 185 (R = alkyl) in the presence of 10% yterbium triflate. Nucleophilic ring opening takes place regioselectively at the primary carbon leading to an tx-diamino intermediate, able to cyclize via both nitrogen atoms to give either the pyrrolidine 186 [212], the piperidine 181 [213], or the piperidine 188 (Scheme 63), Nucleophilic opening of the aziridine 184 by aminoglucose 185 (R = glucose) in refluxing THF led to a mixture of glucosyl-substituted pyrrolidine 186 and both piperidines 187 and 188. The nucleophilic opening of bis-aziridines with a thio- or aminosugar is an efficient method for the synthesis of pseudodisaccharides, while tricyclic aziridines using C, O, N, S, or X-containing nucleophiles provided the oxazolidinones in good yield with high selectivity [214]. In all cases, nucleophilic attack occurred exclusively at the least-substituted carbon of the aziridine ring. A novel intramolecular 6-exo opening of a terminal Boc-protected aziridine ring by a strategically located amino group in the molecule to furnish a key intermediate with a requisite deoxyaminoimino sugar framework led to the synthesis of ~1,7diamino- 1,2,6,7-tetradeoxy-imino-l>glycero-D-iodo-heptitol [215]. Sulfonate esters of aziridinemethanols are converted to allylic amines by treatment with telluride ion obtained by reduction of elemental tellurium [216]. In the course of the reaction, tellurium(0) is re-formed and may be reused. Thetelludde reaction yields optically active allyl amines from optically active aziridinomethanols and, in contrast to many ring openings of aziridines by nucleophiles, activation by an electron-withdrawing substituent on nitrogen is not necessary.

'"~)BBZ+ KNH2 ,, z

OBz p H ~ B

P~...OBz ~

185

184

1 B~

187 %

. . . . . . . . NItP P

186

Scheme 63.

z

Azirines and Aziridines Revisited

241

Tert-Butyl N-tert-butoxycarbonyla~ridine-2-carboxylate and tert-butyl N-tertbutoxycarbonylaziridine-2-carboxamide were synthesized starting from serine and were found to react with Grignard reagents under copper catalysis to give protected a-amino acids in moderate to good yields [217]. a-Amino acids or [3-amino acids are conveniently prepared by regio- and stereoselective ring-opening reactions of 3-substituted-N-ethoxycarbonylaziridine-2-carboxylate by MgBr2 or NaX respectively [218]. Investigations into the ring opening with Grignard reagents under copper catalysis demonstrated that N-Boc-activated aziridines reacted with better regioselectivity than the corresponding N-sulfonamide-activated aziridines [219]. By treatment with organocopper reagents, -cis-N-acfivated-3-alkyl-2-vinylaziridines provided exclusively 189 aUyl amines in high yields, presumably via an anti SN2' reaction pathway. On the other hand, under identical condition, -trans-N-activated-3-alkyl-2-vinylaziridines gave a 85-95% mixture of 189 and 190 allylamines (Scheme 64) [220]. Oppolzer and Flashkamp [221] used a chiral aziridine in an enantioselective total synthesis of pumiliotoxin-C. This elegant piece of work allowed unambiguous assignment of the absolute configuration of the natural product and was also one of the first applications of an organometallic reagent for the ring opening of an activated aziridine leading to natural products. The naturally occurring amino acids (S)-~-pyrazolylalanine and (S)-quisquetic acid were synthesized via the nucleophilic ring opening of an optically active aziridine by pyrazole and 1,2,4-oxadiazolidine-3,5-dione, respectively [222]. The reaction of trans-N-arylsulfonyl-2-alkenyl-3-alkylaziridine with organocopper reagents gives a mixture of two or three products. The corresponding cis-2,3-disubstituted isomer provides a highly efficient route to synthetically important non-racemic (E)-allylamines [223]. It is also found that the reaction proceeAs via the well known anti SN2' pathway. trans-3-(2-Aminocyclopentyl)indoles and trans-3-(2-anunocyclohexyl)indoles have been prepared stereoselectively by the nucleophilic ring-opening reaction of 192 and the lower order magnesium cuprate 191 generated from the corresponding indole magnesium bromides (Scheme 65) [182].

189

189

Scheme 64.

190

242

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

Scheme 65.

N-Tosylphenylaziridines were opened regioselectively by allylsilanes in the presence of BF3.E~O to give u in reasonable yields via a formal [3+2] cycloaddition (Scheme 66) [224], while methylideneaziridines were opened with chloroformate or acid chlorides to functionalized enamines under mild conditions [225]. BF3-induced reaction of an aziridinocyclopropane resulted in a rearrangement via a cyclopropyl carbinyl cation intermediate to give either bicyclic compound 193 or monocycle 194 (Scheme 67) [226].

Scheme 66.

The reductive opening of N-phenylaziridines or chiral aziridines with an excess of lithium powder in the presence of a catalytic amount of naphthalene (15 tool%) at -78 ~ leads to the corresponding N-lithio-2-1ithioethylamine. This reacts with different electrophilic reagents to afford the expected product, viz. PhNHCI~CH2X [227]. Optically active aziridines can be used as precursors in the synthesis of several enantiopure amide-containing surfactants [228]. Acylation of the aziridines is a well-known method for both the activation of the aziridine ring and the introduction of a hydrocarbon chain. The regioselectivity of the ring-opening reactions using dibenzyl phosphate could be controlled by varying the reaction temperature. Application of high pressures (12 kbar) for the ring opening of activated aziridines with imidazole led to the efficient formation of the desired surfactant with complete regioselectivity [228]. Aziridines are used extensively as monomers for the preparation of polymers [229]. Aziridine itself is polymerized under acidic conditions to provide

243

Azirines and Aziridines Revisited

I; l" Ph

L S02Ph

.l

$02Ph 193

194

Scheme 67.

poly(ethylenimine) or PEI. Two general modes of polymerization have been noted with aziridines. The first is the activated chain mode wherein the aziridine end of the growing polymer is protonated and attacked by a molecule of the monomer. In the second mode, the terminal amine attacks a protonated aziridine monomer. In the polymerization of functionalized aziridines, substitution generally occurs at the least substituted carbon of the ring. The polymerization of N-alkylaziridines can be initiated by either acid or alkyl halides. Chiral aziridino alcohols have been applied as ligands for the enantioselective addition of alkylzinc reagents to N-(diphenylphosphinoyl)imines [230]. Reaction of 1,3-di-tert-butylaziridinone (195, R = R' = Bu-t) and similar aziridinones with thiosemicarbazide affords, as one product, a compound devoid of sulfur, viz. a substituted N-aminoimidazolinone 196 by selective cleavage of the acyl nitrogen bond. Compound 196 underwent a novel, acid-catalyzed rearrangement to a 3' imino-hexahydro-l,2,6-triazolin-6-one 197, which can be obtained also by treatment of 195 with hydrazine followed by BrCN; again this involves selective cleavage of the acyl-nitrogen bond (Scheme 68) [231]. Cr(NBu-t)C13(dme)-catalyzed ring opening of N-tosylaziridines with tdmethylsilyl azide and addition of molecular sieves to the reaction mixture improve both the yield and the regioselectivity of the aziridine ring opening [232]. Various aziridines react with N20 4 (2 ecluiv) in the presence of tdethylamine in dry tetrahydrofuran under argon atmosphere to give the corresponding ethylene in excellent yield [233].

6.6 Ring Expansion Various cis- and trans-2,3-trisubsfituted vinylaziridines have been prepared from the corresponding cis- and trans-epoxy alcohols and used as substitutes in the [2,3] aza-Wittig rearrangement [234]. With trans-2,3-trisubstitutexi vinylaziridines having a tert-butyl ester moiety as an anion-stabilizing group the [2,3] rearrangement to the corresponding cis-2,6-disubsfitutext tetrahydropyddine is with complete selectivity (Scheme 69). Moreover, the key step for the enantioselective total synthesis of indolizidine 209D (198) involves an analogous [2,3] aza-Wittig rearrangement that yields the cis-2,6-disubsfitutexl tctrahyclropyddine in 90% yield as the only detectable diastereomer [235]. The stereochemical outcome of these

244

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

19s

O

R~

NH _1

NH2

R"

"NH

~ .H+ NNI-I 2~

R ~

NH2

2

R~"" ~NI-I 196

197

Scheme 68.

transformations was explained by invoking a transition-state geometry that closely resembles that calculated for the parent [2,3] Wittig rearrangement in allylic ethers.

198 It has been shown that the stereochemical outcome of the reaction can be controlled by a judicious choice of anion stabilizing group [236]. For instance, the anionic rearrangement of vinylaziridines 199 (R = Me) gives the corresponding 1-pyrrolines exclusively. The probable mechanism for the formation of 1-pyrrolines involves the generation of a propargylic anion from 199, with opening of the aziridine ring to form the corresponding allylic anion (Scheme 70). Intramolecular

"-

Scheme 69.

l~""~'~OOtBu

Azirines and Aziridines Revisited

245

:~.- II ~

s-BuLi,Trr ~N~TMS -78oc "- L

- N~TMS

-

LB

t.

199

D20

LBu.... II" rMs 200

Scheme 70.

addition of this anion to the alkyne moiety then gives a vinylic anion, which is quenched by D20 to give 1-pyrrolines. In contrast the unsubstituted vinyl group (199, R = H) or the (E)-methyl substituted derivative gives the 2,6 disubstituted tetrahydropyridines are the major products. Michael addition of a vinylaziridine to an acrylate produces an azepine ring system after an intramolecular SNi reaction as shown in Scheme 71 [237]. Vinylaziridines undergo reaction with electrophilic alkynes and olefins to produce seven-membered azepine derivatives. With 13-nitrostyrenes, however, a novel rearrangement occurs, presumably via an ene reaction as 201 is formed (Scheme 72); the structure is proved by X-ray diffraction studies [238]. Ring expansion of N-arenesulfonylaziridine 202 occurred with dimethylsulfonium methylide to afford N-arenesulfonylazetidines 203 (Eq. 21). cis-Azfiridines yield trans-azetidines and trans-az~dines yield cis-azetidines via an Srq2-type reaction with intramolecular nucleophilic substitution [239]. SO2Ar ,..-"

--,,,

ArO2S. DMSO

"-

8"'

/

R'

(21)

R' 202

203

Ring opening of 1-azabicyclo[1.1.0]butane 204 with Olah's reagent (pyridine, 10H~ gives ready access to the cis-3-fluoroazefidines 205, which could be isomerized quantitatively into the trans-isomer 206 (Scheme 73) [240]. This last compound is also obtained from 204 with hydrogen fluoride. Nonregioselective ring

R/~q.

[ + ~OOEt OEt Scheme 71.

~

OEt

246

R ~

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

••rsph

+O2NI; P h

-+

_1.~

H

h

/ h

Ph 201

NO2

Scheme 72.

opening of 2-(hydroxymethyl)aziridine occurs by means lithium diisopropylamide to give amino alcohols 207 and 208, the latter being transformed into stercochemically pure azetidine 209 by PPh3/DEAD (Scheme 74) [241]. Functionalized j3-1actams are synthesized by carbonylativc ring expansion of the silylated (hydroxymethyl)aziridines catalyzed by dicobalt octacarbonyl, a process that proceeds with inversion of configuration [242]. N-Acylaziridines undergo NaI-catalyzed rearrangement to afford oxazole derivatives [243] while Lewis acid-catalyzed addition of aziridines to ketenimines gives substituted pyrrolidinimines in 47-87% yields [244]. The hard Lewis acid LiClO4 proved to be superior to the soft [Pd(CN)2PdCI2] affording higher yields under mild condition. The reaction is regioselective and occurs with complete stereoselectivity using [Pd(CN)2PdCI2], and with a small amount of racemization in case of LiC104. A quantitative regio- and stereocontrolled ring expansion of an aziridine to an oxazoline, followed by a mild ring-opening reaction, allows one to determine the absolute stereochemistry of the aziridine and suggests a simple procedure for the stereocontrolled synthesis of [3-hydroxy-r acid [176]. The formation of different pyrrolidine derivatives in the phototransformation of some substituted aziridinyl maleate and aziridinyl fumarates could be understood in terms of an azomethine ylide intermediate. This is thought to undergo facile 1,2-rearrangement Ph

Ph

Ph h

Py, HF =

=

....Ph

h 204

205

\

206

/ Scheme 73.

AzMnes and Aziridines Revisited

247

--OH l~rITs Mo2CuI.,i,LiL \ ' ~ , ~,,OH + -75oc, RT

~~~t

207

H~~~H

~

H 208 F

209

Scheme 74.

leading to a Schiff's base and subsequent cyclization followed by further transformations [245]. The Bamford-Stevens reaction of cis-az~dinyl ketone tosylhydrazones gave 1,6-dihydro-l,2,3-triazines and proceeded without elimination of nitrogen. The reaction was induced by a slight excess of sodium hydride or sodium ethoxide. When a large amount of sodium ethoxide was used, 1-isopropylamino3,5-diphenylpyrazole was formed from the corresponding substrate [246]. The regio- and stereoselective carbonylation of an optically active vinylaziridine catalyzed by tris(dibenzylideneacetone)dipaUadium(0)-chloroform complex yielded an optically active ~lactarn in moderate yield [247]. An analogous conversion, involving reaction with cuprate, oxidation, and ring closure, has been reported for 2-(hydroxymethyl)aziridines [248]. Carbonylation of nonactivated aziridines [249] takes place by treating the aziridine first with LiI and then with Ni(CO)4, followed by workup with iodine. In this reaction, it is the less substituted carbon-nitrogen bond which is carbonylated with net retention of configuration and it affords moderate yields of the ~lactam. Carbonylation of aziridines catalyzed by cobalt octacarbonyl [250] under CO pressure resulted in inversion of configuration as the active catalyst, cobaltoctacarbonyl anion, induces nucleophilic ring opening of the heterocycle. The re#o- and stereospecificity of the reaction resulted in the synthesis of the first highly strained trans-7-azabicyclo[4.2.0]octan-8-one derivatives. 6.7

Miscellaneous Reactions

Aziridines with a 2-sulfonyl- [251] 2-cyano- [252] or 2-bcnzotriazole [253] group react with r to give pyrrolines via [4+3] cyclization of the derived azomethine ylides and loss of the functional group. In all these reactions, the C2-C3 bond undergoes scission and the ethyne component becomes the C3 and C4 of the pyrrole ring. Asymmetric borane reduction of acetophenone using a 1,3,2-oxazolidine derived from an aziridine-2-tertiary alcohol yielded the 1-phenylethanol in high optical yield [254]. An r underwent ring expansion on heating to afford a dihydrofuran via an alkylidinecarbene, whereas heating of r and r afforded ringexpanded cyclic ethers via alkyl carbenes (Scheme 75) [255].

248

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

Scheme 75.

6.8 Metabolism of Aziridines and the Mechanism of Their Cytotoxicity Aziridine derivatives, especially carbazilquinone and mitomycin C, are used extensively as antitumor agents [6,256]. RecentlY, aziridine-carboxylic acid derivatives have also been reported as immunomodulators. Unfortunately, in spite of their usefulness, these aziridines generally display potent carcinogenic and cytotoxic properties. The carcinogenic properties of these compounds are thought to be mediated by the alkylation of DNA or other cellular macromolecules. Diaziridinylquinones are bifunctional alkylating agents that form interstrand cross-links with DNA [257]. A variety of symmetrically substituted diaziridinylbenzoquinones have been examined for DNA cross-linking properties [258]. In general the crosslinking efficiency of these agents is increased by reduction of the quinone to the hydroquinone or by lowering the pH. Substituents can alter electron density in the benzoquinone ring and reactivity of the aziridines. For example, 2,5-diaziridinyl1,4-benzoquinones (DZQ) can cross-link DNA at pH 7.2, whereas the 3,6-dimethyl-substituted analogue (MeDZQ) required enzymatic reduction at the same pH [259]. Reductive activity can also alter the sequential selectivity of these agents. For instance, the hydroquinone form of DZQ cross-links preferentially at the 5'-GC or the 5'-GNNC sites, whereas the hydroquinone of MeDZQ prefer 5'-GNC sites [260]. Diaziridinylquinones cross-link DNA in the major groove between the N7 atom of the dG residues on opposite strands of the duplex [261], an ideal location for targeted delivery by Triflex-forming oligonucleotides (TFOs). The interstrand DNA cross-linking observed for 3,6-dialkyl-substituted diaziridinylquinones when linked to the TFO shows the advantage of sequence-specific targeting [262]. The analogous reagent from the dimethyl-substituted compound (MeDZQ) required enzymatic reduction for DNA cross-linking [263]. This hybridization-driven reactivity is presumably due to the higher effective local concentration of alkylating agent at the targeted site, but other reactions in the major groove may contribute. Molecular modeling structures show that the interstrand cross-linking by diaziridinylquinones at the 5'-GAC flanking sequence can be accompanied with little distortion of the B-DNA structure. This is in contrast with nitrogen mustard-mediated cross-linking that require some reduction in helical twist at the preferential cross-link site [264]. Diaziridinylquinones TFOs may be apparent in gene therapy of cell lines (chemosensitized) as DNA can be modified. They may also be used as rare DNA cutting agents. In addition, the diaziridinylquinone-activated ester 210 is suitable for conjugation with a variety of amine-containing targeting ligands for evaluation as possible anticancer agents [262].

Azirines and Aziridines Revisited

249

~I~CH2)4CO2TPP 210 A diaziridinylspermine analogue, 1,12-diaziridinyl-4,9-diazododecane (NSC 667005), was synthesized as a bisallcylating agent with a polyamine backbone. DNA cross-linking was detected in the reaction of linearized pBR322 DNA with 1,12-diaziridinyl-4,9-diazododecane at a concentration comparable with that required for cross-linking by two nitrogen mustard drugs, mechlorethamine and melphalan [263]. While studying the biological characteristics of aziridines, strong cytotoxicity was observed in some specific aziridines which were susceptible to fragmentation reactions by chemical oxidation. This suggested that the product of the fragmentation plays an important role in the cytotoxic activity of aziridines. In 1976, Hata et al. [265] observed that aziridine derivatives underwent fragmentation in rat liver microsomes to generate olefinic and nitrosoalkane products. They also observed that aziridines generating higher yields of olefin and nitrosoalkane in the microsomal mixture were more cytotoxic against L-1210 mouse leukemia and HeLa cells. By comparison, aziridines resistant to the fragmentation showed no cytotoxicity. Aryl- or alkylaziridines are transported across cell membranes and then transformed into N-oxides by cellular oxidases followed by fragmentation to produce nitroso compounds. The nitroso compounds inhibit mitochondrial respiration by decomposition of the ATP-generating system to cause cell death. The antagonistic interaction of diaziridine and aziridines against L-1210 mouse leukemia cells reinforced this hypothesis. In order to improve the unfavorable character of aziridine derivatives as drugs, the introduction of electron-withdrawing groups into the aziridine ring could be promising. This is because the electronic effect of these groups may depress the basicity of the ring nitrogen and consequently depress the possibility of fragmentation of the aziridines by oxidases. The rationale for this comes from the fact that several aziridines that bear a benzoquinone moiety on the nitrogen atom, or a carboxylic group on the ring carbon, such as aziridinecarboxylic acids, have been used as antineoplastic agents without serious cytotoxicity. Recently, it was observed that nitrogen mustards can be converted into aziridines via chloroethylamines,

Scheme 76.

250

KURIYA MADAVU LOKANATHA RAI and ALFRED HASSNER

which are formed by the elimination of one of their chloroethylene groups during metabolism in microsomal or isolated hepatocyte suspensions [266]. Thus the cytotoxicity of nitrogen mustards can also be discussed with consideration of the mechanism of the oxidative fragmentation of the aziridines generated (Scheme 76).

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252

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259. Lee, C.-S., HaRley, J. A., Berardinr M. D., Bultler, J., Siegel, D., Ross, D., and Gibson, N. W., Biochemistry, 31 (1992) 3019. 260. Berardinr M. D., Souhami, R. L., Lr162C.-S., Gibson, N. W., Bultler, J., and Hartley, J. A., Biochemistry, 32 (1993) 3306. 261. Alley, S. C., Bramold, K. A., and Hopkins, P. B., J. Am. Chem. See., 116 (1994) 2734; Alley, S. C. and Hopkins, P. B., Chem. Res. Toxicol., 7 (1994) 666. 262. Reed, M. W., Wald, A., and Meyer, R. B., J. Am. Chem. See., 120 (1998) 9729. 263. Li, Y., Eiseman, J. L., Jentz, D. L., Rogers, E A., Pan, S. S., Hu, L.-T., Egorin, M. J., and Caller),, P. S., J. Med. Chem., 39 (1996) 339. 264. Millard, J. J., Raucher, S., and Hopkins, P. B., J. Am. Chem. See., 112 (1990) 2459. 265. Hata, Y., Watanahe, M., Matsubara, T., and Touchi, A., J. Am. Chem. See., 98 (1976) 6033. 266. Watanabr M., Tonda, K., Hirata, M., and Hata, Y., Biochem. Biophys. Res. Commun., 112 (1983) 356.

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INDEX

Antikekulene, 16 Azirines and aziridines revisited, 187257 aziridines, 230-250 as antitumor agents, 230-231,248 asymmetric aziridination of styrene, 232-233 from azirines, 238 azirinomycins, 230 biological properties of, 230 carcinogenic properties, 248-250 chloramine-T, use of, 233 cytotoxic properties, 248-250 definition, 230 diaziridinylquinones, 248 Evans asymmetric synthesis, 231 as immunomodulators, 248 metabolism of and mechanism of cytotoxicity, 248-250 mitosanes, 230 as monomers for preparation of polymers, 242-243 reactions, miscellaneous, 247 ring expansion, 243-247 ring-opening reactions of, 239243 syntheses, miscellaneous, 238239 synthesis of from alkenes, 231-235 259

synthesis of from imines, 235-238 synthesis of from olefins, 231 3-dimethylamino-2H-azirines, 221229 azirine/oxazoline method, 221, 229 reactions, 223-229 as synthetic intermediates, 221 synthesis, 222 introduction, 188 1H-azirine and 2H-azirine, 188 intermediaries in Hoch-Campbell synthesis of N-unsubstituted aziridines, azirines as, 188 reactions, 197-221 [4+2] cycloadditions, 214-218 1,3-dipolar cycloaddition, 203207 HOMO and LUMO interaction, 207 intramolecular 1.3-dipolar cycloaddition, 207-214 isoxazoles, 197-198 metal complexes and reactions, 219-220 miscellaneous, 218-221 nitrilium betaines, 204 pyrazoles, 199

260

INDEX

rearrangement of molecules via azirine intermediate, 197-199 ring expansion, 199-203 "two-plane" orientation complex, 210 structure, 188-191 bonding pattern, 188-189 electronic absorption spectroscopy, 191 infrared spectroscopy, 190 microwave spectroscopy, 191 NMR spectroscopy, 190 SCF-MO LACO method, using, 189-190 SINDOI method, using, 189 Stark effect, 191 theoretical considerations, 188190 synthesis of 1-azirines, 191-197 azirinomycin, 195 dysidazirine, 195 miscellaneous syntheses, 195-197 Neber reaction, 191, 193 optically active azirines, 193-195 oxazophospholine, 196 from oximes, 193 from vinyl/aryl azides, 191-192

chemistry of cyclopropanated carbohydrates, 122-130 electrophilic ring opening, 129 miscellaneous rearrangements, 130 oxepane, 122-124 ring expansions, 122-124 Zeise's dimer, 125 formation of cyclopropanated carbohydrates. 115-121 diazo compounds, using, 115, 117-118 dihalocarbenes, using, 115, I 18119 epoxides, conversion of into cyclopropanes, 121 ethyl diazoacetate (EDA), use of, 118 Furukawa modification, 115-116 phase-transfer catalyst, use of, 119 Simmons-Smith reaction, 115117 sugar cyclopropanes, additional, 119-121 glycals, 115-121

[2.2.1] Bicyclic systems in polymer and synthetic organic chemistry, exploiting strain in, 145185 (see also Norbornene systems) Biphenylene, 13-14 Buckminsterfullerene, isolation of and confirmation of structure of, 2-3

Dehydrobenzoannulenes, 20-24, 25-31 Diamond, 2 Diarylcarbenes, 95-97 Diaziridinylquinones, 248 Diels-Alder reaction, 5-8, 9-13, 50, 64, 146, 166, 169, 176, 215, 221 Doering-Moore-Skattebr method, 50, 60-62, 64, 68, 69

C60, isolation and confirmation of structure of, 2-3 Cycloheptatetraene, 62-63 Cyclopropanes, carbohydrate, 115-130

Electron paramagnetic resonance (EPR) spectroscopy, 84 Electronic absorption spectroscopy, 191 ENDOR experiments, 95, 97

Index

Frontier molecular orbital (FMO) theory, 207 Furukawa modification, 115-116 Glycals, 114, 115-121 Graphdiyne, 24-31 (see also Natural and non-natural planar) Graphite, 2, 3-13 (see also Natural and non-natural planar) Graphyne, 16, 17-24 (see also Natural and non-natural planar) Halocarbenes, 85 Hay coupling, 26 Hexaethynylbenzenes, 18-20 Infrared spectroscopy, 190 Isoxazoles, 197-198 Laser flash photolysis (LFP), 100 MALDI-TOF mass spectrometry, 165 Merostabilization, 91 Microwave spectroscopy, 191 Natural and non-natural planar carbon networks, 1-41 conclusion, 37 ethynyl-linked networks, miscellaneous, 36-37 graphdiyne, 24-31 dehydrobenzo[ 18]annulenes, 2531 hexabutadiynylbenzenes, 25 graphite, 3-13 alkyne :mismatch," products of, 11 C222 PAH, construction of, 11-13 most heavily studied all-carbon structure, 3 PAHs, 3-13 (see also PAHs) subunits via alkyne cyclotfimerization, 8-9

261

subunits via intermolecular DielsAlder reaction, 9-13 subunits via intramolecular DielsAlder reaction, 5-8 "superbenzene," 11 tolane, 8 graphyne, 16, 17-24 dehydrobenzo[ 12]annulenes, 2024 hexaethynylbenzenes, 18-20 Sonogashira coupling, 18, 21-22, 25 introduction, 2-3 buckminsterfullerene, isolation and confirmation of structure of, 2-3 graphite and diamond, 2 icosahedron structure, 3 poly(phenylene), 13-17 angular, 13 antikekulene, 16 biphenylene dimer, 13-14 graphyne, 16, 17-24 (see also Graphyne) linear, 13 oligo(phenylene0s, 14-17 zigzag variant, 14-16 poly(tetraethynylcyclobutadiene), 31-33 poly(tetraethynylethene) (TEE), 3336 Neber reaction, 191,193, 195, 222 Nitrilium betaines, 204 NMR spectroscopy, 190 Norbornene systems, exploiting strain in, 145-185 cyclopentanes, highly substituted, synthesis of, 168-181 difference in reactivity between tetra- and pentasubstituted derivatives, 179-181 fluxional, 168, 180, 181 hemiacetals, 170-176, 178-179

262

of pentasubstituted, enantiomerically pure cyclopentanes, 176-179 prostaglandin synthesis, 169-170 Swern oxidations, 172-173, 178 of all-syn-tetrasubstituted, enantiomerically pure cyclopentanes, 170-176 introduction, 146-150 desymmetrization of anhydrides by proline derivatives, 148150 features, 146 origin of strain in, 147-148 ring opening metathesis polymerization (ROMP) of derivatives, 150-168 alkane incorporation, 158-159 of amino acid-derived norbomenes, 155-160 background, 153-154 initiators, 150-153 mechanism of, 151-153 of miscellaneous [2.2.1] bicy cloalkenes, 165-168 of nucleic acid derivatives, 163165 olefin metathesis, 150 of peptide-derived norbornenes, 160-163 problem with, 154 Oligo(phenylene)s, 14-17 Orthoquinodimethane, 100-101 Oxepanes, 122-124 Oxiranes, carbohydrate, 130-137 bromohydrins, formation and cyclization of, 131 chemistry of, 132-137 C- glycosides, 135 miscellaneous ring opening, 136137 oxazolines, 133

INDEX

ring opening with carbon nucleophiles, 134-136 ring opening with. nitrogen nucleophiles, 133-134 ring opening with oxygen nucleophiles, 132 Ritter-type solvolysis, 133 dimethyldioxirane (DMD), use of, 130-131 epoxidations of, 130-132 PAHs, 3-13 C222, construction of, 11-13 discotic liquid-crystalline mesophases, formation of, 3 modes of constructing, four, 4-5 Planar carbon networks, 1-41 (see also Natural and non-natural planar carbon) Polyphenylene structures, 13-17 (see also Natural and non-natural planar carbon) Pyrazoles, 199 ROMP reaction, 150-168 (see also Norbomene) Scanning tunneling microscopy (STM), 3 Simmons-Smith reaction, 115-117 Sonogashira coupling, 18, 21-22, 25, 26 Stark effect, 191 Strained carbohydrates, synthesis and chemistry of, 113-143 aziridines (epimines), 137-138 aziridination oL 137 chemistry of, 137-138 cyclopropanes, 115-130 (see also Cyclopropanes) chemistry of, formation of cyclopropanated carbohydrates, 121 introduction, 114-115

263

Index

difficulty in working with, 114 glycals, 114, 115-121 oxiranes, 130-137 (see also Oxiranes) chemistry of, 132-137 epoxidations of carbohydrates, 130-132 thiiranes (episulfides), 138-140 Strained cyclic allenes, recent developments in, 43-81 bicyclic, 69-75 eight-membered ring, 64-67 five-membered-ring, 45-47 cyclopenta- 1,2-diene, 45 introduction, 43-45 miscellaneous, 75-78 betweenallene, 75 screw[2]ene, 75 nine-membered-ring, 67-69 seven-membered ring, 60-63 cycloheptatetraene, 62-63 Doering-Moore-Skattebr method, 50, 60-62, 64, 68, 69 six-membered-ring, 47-60 allene complexes, 59-60 cyclohexa- 1,2-diene, 47 heteroallenes, 50-59 "Superbenzene," 11 Swern oxidations, 172-173, 178, 195 TEEs, 33-36 Tetraethynylcyclobutadiene, 31-33 Tetraethynylethene (TEE), 33-36 Triplet carbenes, sterically congested, strain and structure of, 83-112 conclusion and perspectives, 109110 EPR spectroscopy of, 86-94 carbenic substituents, effects of, 90 doublet, 86 geometric isomerism, 93-94 host matrix, effects of, 94

merostabilization, 91 remote substituents, effects of, 90-92 structure and ZFS parameters, 9094 theoretical spectrum, 88 zero-field splitting (ZFS), 86-90 introduction, 84 electron paramagnetic resonance (EPR) spectroscopy, 84 strain and structure of, 94-109 It delocalization, 106-107, 110 diarylcarbenes, 95-97 diphenylcarbenes bearing ortho substituents, 97-106 ENDOR studies, 95, 97 kinetic stabilization, 108-109 laser flash photolysis (LFP) studies, 100 naphthylcarbene systems, 108109 ortho substituents, other, effects of on structure, 103-106, 110 orthoquinodimethane, 100-101 per/-hydrogen atoms, 107-108, 110 polybrominated diphenylcarbenes, 101-103 polymethylated diphenylcarbenes, 97-101 triptycyl (Trp) group, effect of, 106-109 structure and ground-state multiplicities, relationship between, 84-86 halocarbenes, 85 methylene, 85-86, 90 singlet state, 84 triplet state, 84, 85 Wittig reaction, 5,243-244 Zeise's dimer, 125

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