Cumulenes in Click Reactions

Home , Heterocumulene

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HENRI ULRICH

A John Wiley and Sons, Ltd., Publication

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Cumulenes in Click Reactions

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Cumulenes in Click Reactions

HENRI ULRICH

A John Wiley and Sons, Ltd., Publication

iii P1: OTE/OTE/SPH P2: OTE FM JWBK368-Ulrich October 5, 2009 9:26 Printer: Yet to come

This edition ﬁrst published 2009 C 2009 John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data Ulrich, Henri, 1925Ð Cumulenes in click reactions / Henri Ulrich. p. cm. Includes bibliographical references and index. ISBN 978-0-470-77932-3 (cloth) 1. Alkenes. 2. Chemical reactions. I. Title. QD305.H7U54 2009 547.412Ðdc22 2009033775

A catalogue record for this book is available from the British Library. ISBN 978-0-470-77932-3 Set in 10/12pt Times by Aptara Inc., New Delhi, India Printed and bound in Great Britain by CPI Antony Rowe, Chippenham, Wiltshire

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Contents

Preface ix Acknowledgements xi

1 General Introduction 1 References 12

2 1-Carbon Cumulenes 13 2.1 Sulﬁnes, R2C S O13 2.1.1 Introduction 13 2.1.2 Dimerization Reactions 14 2.1.3 Cycloaddition Reactions 15 References 23 2.2 Sulfenes, R2C S(O) O25 2.2.1 Introduction 25 2.2.2 Dimerization Reactions 26 2.2.3 Cycloaddition Reactions 26 References 32 2.3 Other 1-Carbon Cumulenes 33 2.3.1 Thiocarbonyl S-Imides 33 2.3.2 Thiocarbonyl S-Sulﬁdes 37 2.3.3 1-Aza-2-azoniaallene Salts 39 References 44

3 2-Carbon Cumulenes 45 3.1 Carbon Oxides, O C O, :C O45 3.1.1 Introduction 45 3.1.2 Cycloaddition Reactions 47 3.1.3 Insertion Reactions 60 References 61 3.2 Carbon Sulﬁdes, S C S, S C O64 3.2.1 Introduction 64 3.2.2 Cycloaddition Reactions 65 3.2.3 Insertion Reactions 75 References 77 3.3 Carbon Nitrides 79 3.3.1 Isocyanates, RN C O79 References 156

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3.3.2 Isothiocyanates, RN C S 168 References 194 3.3.3 Carbodiimides, RN C NR 197 References 232 3.4 Center Carbon Phosphorallenes, P C P 236 3.4.1 Introduction 236 3.4.2 Dimerization Reactions 236 3.4.3 Cycloaddition Reactions 238 References 241

4 1,2-Dicarbon Cumulenes 243 4.1 Ketenes, R2C C O 243 4.1.1 Introduction 243 4.1.2 Dimerization Reactions 244 4.1.3 Trimerization Reactions 252 4.1.4 Cycloaddition Reactions 254 References 312 4.2 Thioketenes, R2C C S 321 4.2.1 Introduction 321 4.2.2 Dimerization Reactions 322 4.2.3 Cycloaddition Reactions 323 References 335 4.3 Ketenimines, R2C C NR 337 4.3.1 Introduction 337 4.3.2 Dimerization Reactions 337 4.3.3 Cycloaddition Reactions 339 References 363 4.4 1-Silaallenes, R2C C Si 366 4.4.1 Introduction 366 4.4.2 Dimerization Reactions 366 4.4.3 Cycloaddition Reactions 367 References 368 4.5 1-Phosphaallenes, R2C C P 368 4.5.1 Introduction 368 4.5.2 Dimerization Reactions 369 4.5.3 Cycloaddition Reactions 370 References 376 4.6 Other Metal Allenes 377 4.6.1 Introduction 377 4.6.2 Cycloaddition Reactions 378 References 389

5 1,3-Dicarbon Cumulenes 391 5.1 Thiocarbonyl S-ylides, R2C S CH2 391 + 5.2 2-Azaallenium Salts, R2C N CR2 394 + 5.3 1-Oxa-3-azoniabutatriene Salts, R2C N C O 395 P1: OTE/OTE/SPH P2: OTE FM JWBK368-Ulrich October 5, 2009 9:26 Printer: Yet to come

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+ 5.4 1-Thia-3-azabutatriene Salts, R2C N C S 396 5.5 Phosphorus Ylides 397 References 397

6 1,2,3-Tricarbon Cumulenes 399 6.1 Allenes, R2C C CR2 399 6.1.1 Introduction 399 6.1.2 Dimerization Reactions 402 6.1.3 Oligomerization Reactions 410 6.1.4 Cycloaddition Reactions 412 References 456 6.2 [3] Cumulenes, R2C C C CR2 462 6.2.1 Introduction 462 6.2.2 Dimerization Reactions 462 6.2.3 Trimerization Reactions 464 6.2.4 Cycloaddition Reactions 465 References 468 6.3 [4] Cumulenes, R2C C C C CR2 469 6.3.1 Introduction 469 6.3.2 Dimerization Reactions 469 6.3.3 Cycloaddition Reactions 470 References 470 6.4 [5] Cumulenes, R2C C C C C CR2 470 6.4.1 Introduction 470 6.4.2 Dimerization Reactions 471 6.4.3 Cycloaddition Reactions 472 References 473

7 Noncarbon Cumulenes 475 7.1 Azides, RN N N 475 7.1.1 Introduction 475 7.1.2 Oligomers 476 7.1.3 [3+2] Cycloaddition Reactions 477 References 492 7.1.4 Some Applications in Modiﬁcations of Biopolymers 495 Application References 499 7.2 Triazaallenium Salts, RN N+ NR 501 7.2.1 Introduction 501 7.2.2 Cycloaddition Reactions 501 References 502 7.3 Sulfur Oxides 503 7.3.1 Introduction 503 7.3.2 Sulfur Dioxide, O S O 504 7.3.3 Sulfur Trioxide, O SO2 510 References 515 P1: OTE/OTE/SPH P2: OTE FM JWBK368-Ulrich October 5, 2009 9:26 Printer: Yet to come

viii Contents

7.4 Sulfur Nitrides 517 7.4.1 N-Sulﬁnylamines, RN S O and N-Thiosulﬁnylamines, RN S S 517 7.4.2 Sulfurdiimines, RN S NR 526 7.4.3 N-Sulfonylamines, RN SO2 and Hexavalent Sulfurdiimides 529 7.4.4 Dithionitronium Salts, S N+ N 533 References 536 7.5 Cationic Boron Cumulenes, R2N B NR 538 7.5.1 Introduction 538 7.5.2 Cycloadditions 539 References 540

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Preface

The advent of azide/alkyne ‘click’ chemistry, reintroduced by Sharpless and Meldal earlier this century, has prompted an avalanche of publications in the fields of biochemistry, material science and biopolymers. As of 2008, more than 1000 publications on this subject are listed on the Sharpless website. I have noticed that gradually other [3+2] and [4+2] cycloaddition reactions are included, indicating that cycloaddition chemistry is useful for construction and modification of biopolymers. Especially, the [3+2] ‘Huisgen’ chemistry is useful because in addition to azides many other 1,3-dipolar species react with dipolarophiles at room temperature and the yields often approach quantitative. There is also renewed interest in [4+2] DielsÐAlder chemistry. The Nobel Laureates involved in cycloaddition chemistry include Sharpless (2001), Staudinger (1953), Diels and Alder (1950) and Wittig (1979) and today’s emphasis on green chemistry has accelerated research in this field. For example, cycloaddition reactions of carbon dioxide could be of interest for sequestering of greenhouse gases. In addition, sulfur dioxide readily undergoes cycloaddition reactions with dienes. I was first introduced to more exotic azide chemistry during my research work at Ohio State University in the early 1950s where we synthesized highly explosive oligo azides. Soon afterwards, at the former Donald S Gilmore Research Laboratories of the Upjohn Company in North Haven, Connecticut, working on isocyanates and carbodiimides, I realized the enormous potential of these cumulenes for high-yielding addition reactions. In 1967, I published a book on Cycloaddition Reactions of Heterocumulenes and in the following forty years a wealth of new information has become available. Especially, highly reactive 1,3-dipolar compounds generated in situ, such as 1-aza-2-azoniaallene salts (Chapter 2, Section 2.3.3), triazaallenium salts (Chapter 7, Section 7.2) and dithionitronium salts (Chapter 7, Section 7.4.4), react readily with numerous dipolarophiles to form [3+2] cycloadducts in very high yield. In addition, ring-opening of three-remembered ring compounds generates 1,3-dipolar species, which readily react with suitable dipolarophiles. Some of these reactions can be conducted in the absence of solvents. Photochemical intramolecular cyclization reactions of allenes occur at room temperature in the solid state in quantitative yields, indicating their enormous potential for green chemistry. The cumulenes discussed in this book are subdivided into carbon- and noncarbon cumulenes, and the 1-carbon cumulenes (sulfines, sulfenes, thiocarbonyl S-imides and thiocarbonyl S-sulfides) are excellent dipolar species. The 2-carbon or the center-carbon cumulenes (carbon dioxide and carbon sulfides) are less reactive but their imides (isocyanates, isothiocyantes and carbodiimides) readily participate in many of the discussed reactions. The 1,2-dicarbon cumulenes (ketenes, thioketenes and ketenimenes) similarly participate in cycloaddition reactions, as well as the more exotic 1,2-dicarbon cumulenes (1-silaalene, 1-phosphaallene and other metal allenes). In contrast, 1,3-dicarbon cumulenes are only

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x Preface

minor participants but thiocarbonyl S-ylides (Chapter 5, Section 5.1) as well as 2- azaallenium salts (Chapter 5, Section 5.2) are excellent 1,3-dipolar reagents. Tricarbon cumulenes, such as allenes (Chapter 6, Section 6.1) and the higher allenes (Chapter 6, Sections 6.2 to 6.4) also participate readily in inter- and intramolecular cycloaddition reactions. Last, but not least, non-carbon cumulenes (azides, sulfur oxides and sulfur nitrides) are highly reactive in cycloaddition reactions. This present text should prove valuable to researchers and technologists in organic, bioorganic and polymer chemistry, especially in the emerging ﬁelds of proteomics and nanotechnology.

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Acknowledgements

I would like to acknowledge the contributions of many of my friends and colleagues in the global chemistry community, especially Dr Frank Seela, formerly at the University of Osnabruck, Dr Gert Kolllenz, formerly at the Karl Franzen University of Graz and Dr Ernst Schaumann, the Technical University of Clausthal-Zellerfeld. In addition, Drs Mloston, Alvarez, Maslivets, Vogel and Jochims have provided numerous reprints of their work in cycloaddition reactions. Dr Huisgen, the pioneer of dipolar cycloaddition reactions, also provided valuable input. In my earlier work on isocyanates and carbodiimides the valuable contributions of Professor Dr W von Eggers-Doering, formerly at Harvard University, are gratefully acknowledged. Last but not least, I would like to thank my wife Franziska for her patience, constant encouragement and support of this undertaking.

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1 General Introduction

Click chemistry, as introduced by Kolb and Sharpless in 2001 1, relates mainly to the Cu(i) catalyzed [3+2] cycloaddition reaction of azides with alkynes. This copper catalyzed cycloaddition reaction is highly useful for attaching ﬂuorescent or other markers to a wide variety of biomolecules. Although azides are often unstable at elevated temperatures, they are stable at physiological conditions, have no intrinsic toxicity and have extraordinary chemical selectivity. Proteins and glycans have already been labeled with azides in laboratory mice using enzyme inhibitors and sugar azides. Azides have cumulative double bonds and they are only a small section of the cumulenes encountered in organic chemistry. Cumulenes are often not stable at room temperature and they are isolated as their cyclic dimers, formed in a click reaction. In this case a [2+2] cycloaddition reaction occurs, and often no catalyst is required. Some of the more exotic cumulenes are matrix isolated at low temperatures. For example, alkyliminopropa- dienones, RN C C C O, the mono imides of carbon suboxide, are unstable. However, the neopentyl-, mesityl- and o-t-butylphenyl derivatives can be isolated at room temperature and their nucleophilic reactions provide a wide variety of heterocyclic compounds 2. Several of the early Nobel prize winners were involved in the click reactions of cumulenes. For example, the [2+2] cycloaddition reaction of ketenes and imines to give β-lactames is often referred too as the Staudinger reaction. Another Nobel Laureate, Shee- han, has used this reaction to synthesize penicillin antibiotics. The reaction of iminophosphoranes with other cumulenes is called the azaÐWittig reaction. Also, Wittig received the Nobel Prize for his pioneering work in phosphorous chemistry. The [3+2] cycloaddition reactions, which include the cycloaddition of azides to alkynes named by Sharpless, also a Nobel Laureate, as a click reaction, are sometimes referred to as Huisgen reactions. Rolf Huisgen has extensively investigated the [3+2] dipolar cycloaddition reactions 3.The[4+2] cycloaddition reactions are called DielsÐAlder reactions, again named after two early Nobel Laureates. The best example of a click polymerization reaction is the polyaddition reaction of diisocyanates with dioles or polyols to produce polyurethanes. This reaction was discovered

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2 Cumulenes in Click Reactions

by Otto Bayer, at the IG Farben Laboratories (now Bayer AG) in 1937, and today the world wide consumption of polyurethanes exceeds 10 million tons per annum. In the formation of polyurethanes no solvents are required, the yields are quantitative and most reactions are conducted at room temperature. An exception is the RIM (reaction injection molding) of automotive bumpers which is conducted at elevated temperatures to increase the production rate. When this polymerization is conducted continously in an extruder, the finished polymers are extruded, chopped and collected in drums. An example is the production of thermoplastic segmented polyurethane elastomers, appropriately sold by Dow under the tradename ‘Pellethane’ 4. In the reaction of thermoset reaction polymers spray technology is also applied. For example, flexible polyurethane foams are continuously produced in buns and semirigid and rigid insulation foams are directly sprayed onto the substrate. Dendritic polymers are also constructed by reacting 1,3,5-benzene triisocyanate with amines 5. Copolymerization reactions of cumulenes are also of some significance. For example, copolymerization of carbon monoxide with alkenes affords polyketones, which are biodegradable and they also could undergo subsequent crosslinking reactions on the carbonyl group. When carbon dioxide is copolymerized with alkenes, polyesters are obtained. The polyaddition reactions of diketenes with diols to produce polyesters is not used, because of the tendency of ketenes to undergo dimerization reactions. Also, sulfur dioxide can be copolymerized with alkenes to produce polysulfones. Some of the cumulenes undergo homo-polymerization reactions. The homo-polymers derived from isocyanates and carbodiimides are of no commercial value because the homopolymers ‘unzip’ on heating. Intractable thermoset polymers are obtained from carbon suboxide or carbon disulfide. More often the click reaction is used in the modification of biopolymers. An example is sugar-derived imaging in live animals. Glycans in live zebrafish embryos light up when the embryos are fed azide-derived sugars and are subsequently treated with difluori- nated cyclooctyne derived probes 6. Elastin-like hybrid polymers, based on the reaction of azide-terminated poly (ethylene oxide) (PEO) and alkyne functionalized peptides, are also developed. These polymers are intended to grow new vocal cords 7. The cyclodimerization reaction of cumulenes is their most common click reaction, especially when the monomers are not stable at room temperature. Some of the cyclodimers serve as a ready source of the monomers, which are generated in situ and are trapped with suitable reagents. Sometimes, the retro reactions provide new cumulenes. In this book the latter reactions are referred to as ‘exchange reactions’. Cyclodimerization reactions can occur across either one of the cumulative double bonds giving rise to the formation of head-to-head or head-to-tail cyclodimers. The stable head- to-tail cyclodimers of ketenes and the head-to-head cyclodimers of isocyanates are good examples and only one type of cyclodimer is formed. In contrast, allenes often provide mixtures of cyclodimers. A ‘super-click reaction’ is observed in the cyclodimerization of bis-allenes, which occurs at room temperature in the solid state upon irradiation to give the cyclodimers in quantitative yields 8. The first example of a cumulene click reaction, the cyclodimerization of phenyl isocyanate, was reported by Hofmann in 1860 9. In later years numerous cycloaddition reactions of cumulenes with a wide variety of double or triple bonded substrates were observed 10. In addition to the cycloaddition reactions of cumulenes their insertion reactions into numerous single bonds also often proceed at room temperature in high yields 10. In fact, P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

General Introduction 3

even some nucleophilic reactions of cumulenes can be considered to involve click reactions, i.e. they occur at room temperature, sometimes without a solvent to produce linear reaction products in quantitative yields. Perhaps the most important click reaction in chemistry is the neutralization of an acid by a base which can be conducted at room temperature, often in water and the yields are always quantitative. The most general definition of click chemistry is a reaction which proceeds at room temperature, often without a solvent or catalyst, to give the reaction product in close to quantitative yields. The yields in the reactions in this book are by no means optimized, but they often approach quantitative. As an industrial chemist I am well aware that yields can be dramatically increased with modest process development efforts. Sometimes, a change of reaction temperature can have a dramatic effect, as demonstrated by Wilson and Fu who obtained a < 2 % yield of β-lactones in their [2+2] cycloaddition reaction of ketenes with aldehydes at room temperature, while at −78 ◦C a 92 % yield of the cycloadduct is obtained 11. The yields shown in the selected examples in this book are often the higher yields reported by the authors. More comprehensive lists can be found in my relatively recent books on isocyanates 12 and carbodiimides 13. Of course, comprehensive lists of cycloadducts of heterocumulenes are also found in my 1967 book 10. Huisgen’s introduction of the dipolar [3+2] cycloaddition reaction has provided an enormous variety of synthetically useful click reactions. The example quoted by Kolb and Sharpless 1 is ‘only the tip of the iceberg’. Over 1000 literature references on this reaction were reported in recent years. I had summarized the cycloaddition reactions of heterocumulenes in 1967 10, but in the meantime many new cumulenes have emerged and the cycloaddition reactions of carbon cumulenes, such as allenes, butatrienes and higher cumulenes, are also well investigated. The cycloaddition reactions of cumulenes generally produce three- to six-membered ring compounds, which often cannot be obtained in a one-step reaction. When the cumulene or the substrate contain metal to carbon bonds, metallacycles are readily produced. Organometalic compounds are readily obtained in the insertion reactions of the cumulenes. In the latter reactions, linear compounds are obtained. Click chemistry therefore can provide not only a vast number of cyclic compounds but also numerous linear compounds and even linear and crosslinked polymers which have commercial significance. Often the initially formed bonds at low temperature are not the ones that are isolated at room temperature. Also the electronic configurations play a part in product formation. For example, in the [2+2] cycloaddition reaction involving two carbodiimides the more nucleophilic carbodiimide attacks the more electrophilic carbodiimide giving rise to the formation of only one reaction product. The latter reactions proceed stepwise, while sometimes concerted reactions are observed. Sterical hindrance also plays an important role in product formation. We have utilized N-methyl-N-t-butylcarbodiimide as a probe in de- termining the structure of the derived cycloadducts, because the reaction always proceeds via addition across the C N bond with the methyl substituent. For example, in the [2+2] cycloaddition reaction with benzoyl isocyanate the reaction proceeds across the C O bond of the isocyanate, because t-butyl isocyanate is the only product generated in the retro reaction 14. By definition, cumulenes are compounds with double bonds adjacent to each other. The parent compound of carbon cumulenes is allene, CH2 C CH2, in which the center as well P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

4 Cumulenes in Click Reactions

as the terminal atoms are carbon. Extension of the double bonded system produces the higher cumulenes and often the number of double bonds are used to identify the higher cumulenes. When one or more of the atoms in the cumulative system are hetero atoms, such as oxygen, nitrogen, sulfur or selenium, they are known as heterocumulenes. The carbon containing heterocumulenes are sometimes referred to as heteroallenes. I have organized the cumulenes according to the number of carbon atoms in the cumulative system. In Chapter 2 I have treated the cumulenes with one carbon atom in the beginning of the cumulative system. With the exception of the 1-aza-2-azoniaallene salts, the compounds are sulfur derivatives. The thiocarbonyl S-sulfides are excellent 1,3-dipoles, which participate in numerous [3+2] cycloaddition reactions. Huisgen has reviewed their chemistry in 1997 15. In Chapter 3 the cumulenes with a center carbon atom are treated, which include the carbon oxides, carbon sulfides and carbon nitrides (isocyanates, isothiocyanates and carbodiimides). In this chapter the chemistry of carbon dioxide is of considerable interest, because the sequestering of carbon dioxide is a major problem in coping with global warming. The chemistry of isocyanates relates to polyurethanes, which are major industrial polymers, and carbodiimides play an important role in proteomics, the building blocks of life. Center carbon phosphaallenes and diarsaallenes are also treated in Chapter 3. The 1,2- dicarbon cumulenes are described in Chapter 4, which encompass the ketenes, thioketenes, ketenimines, 1-silaallenes, 1-phosphaallenes, as well as some metal allenes. In Chapter 5 the 1,3-dicarbon cumulenes, which are not too well known, are treated, and in Chapter 6 the ‘all-carbon’ cumulenes are summarized. This chapter encompasses the allenes and the higher carbon cumulenes. Higher carbon cumulenes have been detected in interstellar space by microwave spectroscopy, and in recent years many of the higher carbon monoxides, C2O to C6O and carbon dioxides, carbon monosulfides and carbon disulfides, have been matrix isolated at low temperatures. The carbon monoxides and carbon monosulfides have a linear carbene like structure. Finally in Chapter 7 the non-carbon cumulenes are described. This latter chapter includes the azides. Cationic cumulenes are also known, and especially the azaallenium salts are known for their 1,3-dipolar character. These cationic cumulene salts undergo numerous [3+2] cycloaddition reactions with suitable dipolarophiles to give five-membered ring heterocycles, often in quantitative yields. The cycloaddition reactions of all of the cumulenes under discussion are of considerable importance because in almost all cases only one compound is isolated in high yield. This renders these reactions as the most useful method to synthesize cyclic or heterocyclic compounds, which are often otherwise difficult to synthesize. The first book on the reactions of carbon cumulenes, treating the cycloaddition reactions of ketenes in depth, was written by Staudinger in 1912 16. Staudinger already realized that cycloaddition reactions of ketenes are common, and often ketenes were only isolated as cyclodimers. The cyclodimers of isocyanates became prominent in the development of polyurethanes in the IG Farben Laboratory in Leverkusen, Germany in the early 1930s 17, and the cyclotrimerization of diisocyanates led to the development of polyisocyanurate foams, with thermal stability superior to rigid polyurethane foams in the 1960s. Today, polyisocyanurate foams are used in the insulation of the fuel tank of the space shuttle. Also, carbodiimide derived cellular plastics with improved thermal stability are of interest 18.In recent years, cumulene derived polymers became of interest as one-dimensional molecular wires. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

General Introduction 5

The chemical reactivity of the cumulenes under discussion ranges from highly reactive species to almost inert compounds. While some cumulenes can only be generated in a matrix at low temperatures, others are indefinitely stable at room temperature. For example, sulfines and sulfenes are only generated in situ, but some cumulenes with bulky substituents are sometimes isolated at room temperature: for example, :C C S was detected in interstellar space by microwave spectroscopy, and its spectrum was later verified by matrix isolation spectroscopy. In contrast, some cumulenes, such as carbon dioxide and carbon disulfide, are often used as solvents in organic reactions or in the extraction of natural products. The reactivity of some center carbon heterocumulenes in nucleophilic reactions is as follows: isocyanates > ketenes > carbodiimides > isothiocyanates. However these reactivities do not relate to the reactivities in cycloaddition reactions. Often reactive cumulenes are isolated as their cyclodimers. Aromatic diisocyanates are more reactive than aliphatic diisocyanates in nucleophilic as well as cycloaddition reactions. Substituents attached to the cumulative system can influence their reactivity. The effect of the substituents can be both steric or electronic. For example, steric hindrance is often applied to stabilize a cumulene system, which normally cannot be isolated. For example, 2,4,6-trimethyl-phenyl groups are used in phosphorus cumulenes for this purpose, and 2,4,6-trichlorophenyl groups are used to stabilize 1,3-diaza-2-azaallenium cations. Also, ortho methyl groups in phenyl substituents are often sufficient to prevent cycloaddition reactions. An example is the selective dimerization of 2,4-tolylene diisocyanate involving the isocyanate group para to the methyl group. In methyl-t-butylcarbodiimide the [2+2] cycloaddition reactions proceed across the less hindered C N bond. Also, substituents attached to phenyl groups in aromatic cumulenes influence their reactivity. For example in isocyanates electron withdrawing groups increase the electrophilicity of the center carbon atom, whereas electron donating groups reduce the electrophilicity. The reactivity of isocyanates in cycloaddition reactions is greatly enhanced in carbonyl-, thiocarbonyl-, imidoyl- and sulfonyl-isocyanates. While the sulfonyl isocyanates undergo [2+2] cycloaddition reactions readily, they do not undergo cyclodi- or trimerization reactions. The reactivity of ketenes in cycloaddition reactions is as follows: diphenylketene > dimethylketene > butylethylketene > ketene 19. The mechanism of the cycloaddition reactions of cumulenes involve concerted one-step processes as well as two-step processes, and both types of mechanisms are encountered. It seems that concerted processes are more the exception, and ionic linear 1:1 intermediates are sometimes trapped in cycloaddition reactions. The sometimes encountered [2+2+2] six-membered ring cycloadducts exemplify the stepwise reactions. The cycloaddition reactions are subdivided into di-, tri- and oligomerization reactions, [2+1]-, [2+2]-, [3+2]- and [4+2] cycloaddition reactions and other cycloaddition reactions. The insertion reactions into single bonds are also discussed. The cyclodimerization or cyclotrimerization reactions are special examples of the [2+2] and the [2+2+2] cycloaddition reactions, respectively. The cumulenes vary in their tendency to undergo these reactions. The highly reactive species, such as sulfines, sulfenes, thioketenes, carbon suboxide and some ketenes, are not stable in their monomeric form. Other cumulenes have an intermediate reactivity, i.e. they can be obtained in the monomeric state at room temperature and only heat or added catalysts cause di- or trimerization reactions. In this group, with de- creasing order of reactivity, are allenes, phosphorus cumulenes, isocyanates, carbodiimides and isothiocyanates. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

6 Cumulenes in Click Reactions

In the cumulative systems, X C Y(X= CR2,NR;Y= O, S, NR), in RP C X(X= O, S, NR) and in R3P C C X(X= O, NR) three types of dimeric species are visualized. When the cycloaddition reaction proceeds across the C X double bond the cyclodimer 1 is formed. When the reaction proceeds across the C Y bonds the cyclodimer 2 is obtained and when the reaction proceeds across both bonds the asymmetric cyclodimer 3 is isolated.

y x y x y x x y y y x x 1 2 3

The cyclodimers 1 and 2 have an axis of symmetry, because dissociation in both directions affords the same products. Cyclodimer 3 has no axis of symmetry and cleavage in both possible directions affords different products. All three types of cyclodimers are encountered in the cumulenes X C Y and the asymmetric dimers often undergo thermolysis contrary to their mode of formation. A typical example is cyclodimer 3 derived from dimethylketene, which affords tetramethylallene and carbon dioxide on thermolysis. In the cycloaddition reaction of higher cumulenes different types of cyclodimers are encountered. In [3] cumulenes the cycloaddition can occur across the center bonds to form [4] radialenes 4 or across their end groups to give cyclodimers 5 and 6.

R RR R RR • • • R2 R2 R2 R2 • R R 45 6

Radialenes are also obtained from [5] cumulenes. Pentatetraenes dimerize across their end double bonds to form 7 or one of the center double bonds to give 8.

RR R R • • R R

• • R R

• R2 R2 • R R R R 78

As a general rule ketenes undergo non-catalyzed [2+2] cycloaddition reactions across their C C bonds, with the exception of ketene itself. In contrast, disubstituted thioketenes undergo cyclodimerization across their C S bonds. Mono substituted thioketenes undergo dimerization via a [3+2] cycloaddition reaction, also involving the C S bonds. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

General Introduction 7

N-Isothiocyanatodimethylamine 9 dimerizes at room temperature in less than one minute via a [3+2] cycloaddition to give 10, which rearranges in solution to form 11 20.

Me N N MeN N 2 Me2NN C S S S S SMe N N

NMe2 NMe2 91011 Another type of dimerization is observed in heterocumulenes, having the cumulative system attached to a carbonyl-, thiocarbonyl- or an imidoyl-group. Although these heterocumulenes can dimerize via a [2+2] cycloaddition sequence, more often a DielsÐAlder-like [4+2] cycloaddition reaction occurs giving rise to the formation of six-membered ring heterocyclic dimers. Often these heterocumulenes are only generated in situ because they undergo rapid dimerization at room temperature. An example is the dimerization of thioa- cyl isocyanates in which the heterocumulene reacts as diene and dienophile to give the cyclodimer 12 21.

S O S O • NRN R N N + R S R S O O 12 Thermal dissociation of the cyclodimers often generates the reactive monomers. Dimeric intermediates are also postulated as intermediates in the exchange reaction of similar and different cumulenes. In these reactions thermal equilibria are established via [2+2] cycloaddition sequences. For example, in the heating of an isocyanate with a differently substituted carbodiimide a four-membered ring intermediate 13 is generated, which can either regenerate the starting materials or form a new set of heterocumulenes. When one of the new products is constantly removed from the reaction mixture (for example, the lowest boiling R1N C O) the reaction produces the new set of heterocumulenes exclusively 22.

O RN C O + R1N C NR1 RN R1N C O + RN C NR1 NR1 R1N 13 Upon addition of a second equivalent of RN C O the sequence can be repeated, and the ﬁnal product is RN C NR. The conversion of two equivalents of isocyanate into carbodiimide and carbon dioxide also involves an asymmetric isocyanate dimer as an intermediate. The cyclotrimerization of carbon cumulenes is usually initiated by heat or catalysis. Especially, the use of a catalyst assures that trimerization can be accomplished in quantitative yields. The base catalyzed cyclotrimerization reaction seems to be limited to ketenes, isocyanates, isothiocyanates and carbodiimides. In the trialkylphosphine catalyzed trimerization of methyl isocyanate an asymmetric trimer is obtained. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

8 Cumulenes in Click Reactions

Interesting is the participation of sulfonyl isocyanates and sulfonyl carbodiimides in mixed trimerization reactions although these monomers do not undergo cyclotrimerization reactions themselves. For example, dicyclohexylcarbodiimide reacts with two equivalents of N-p-toluenesulfonyl-N-cyclohexylcarbodiimide to give the six membered ring [2+2+2] cycloadduct 14 in 93 % yield 23.

NR 1 1 RN NSO2 R RN C NR + 2 R SO2N C NR RN N NR 1 SO2 R 14

In cycloaddition reactions of carbon cumulenes with suitable substrates, [2+1], [2+2], [3+2] and [4+2] cycloaddition reactions giving rise to the formation of cyclic compounds are observed. In general, [2+1] cycloaddition reactions afford three-membered ring compounds with an attached double bond, and sometimes the initially formed cycloadducts rearrange to form an isomeric three-membered ring cycloadduct. An example is the addition of diphenylcarbene to dialkylthioketenes where the initially formed cycloadduct 15 on photolysis produces the isomer 16, with bulky substituents on the three-membered ring 24.

R2 1 2 R R C 1 S 1 2 + S R R R C C S :CPh2 Ph Ph Ph Ph

15 16

The carbenes, incuding carbon monoxide and isocyanides, readily participate in these cycloaddition reactions and because of their lone pair of electrons they can be considered to be pseudocumulenes. Also, [4+1] cycloadditions of carbon monoxide or isocyanides to 1,3-dienes are observed to afford ﬁve-membered ring cycloadducts 17, often in high yields.

+ :C X X

A similar reaction, resulting in the formation of ﬁve-membered ring sulfur heterocycles 18, is the cheletropic addition of sulfur dioxide to 1,3-dienes.

O + :SO S 2 O 18 P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

General Introduction 9

The lone pair of electrons on sulfur dioxide can also participate in free radical annulation reactions with formation of sulfolanes 19.

+ SO O 2 • S ( ) ( ) SO ( ) n • n 2 n O 19

Carbon cumulenes undergo [2+2] cycloaddition reaction with numerous double or triple bonded substrates to give four-membered ring cycloadducts. Examples of cycloaddition to C≡C, C C, C O, C N, C S, N O, N N. N S. S O, P C, P O, P N and P S bonds are known. When the two adjacent double bonds in the cumulenes are different, cycloaddition across either one of the double bonds occurs, and sometimes addition across both bonds is observed. However, more often the cycloaddition reactions follow only one pathway. As a general rule, in ketenes the non-catalyzed cycloaddition occurs preferentially across the C C bond, whereas catalyzed cycloaddition reactions proceed across the C O bond. In thioketenes, isothiocyanates and sulfenes addition mainly occurs across the C S bond. In isocyanates addition across the C N bond is preferred. The cycloaddition to isolated C C bonds is generally slow, and only highly reactive species, such as sulfonyl isocyanates, react well. The cycloaddition to activated olefins, such as allenes, cyclopentadiene, styrene etc., occurs more readily and many sulfonyl isocyanates and ketenes react at room temperature. The less reactive olefins, such as ethylene, react in the presence of nickel (0) compounds to give five-membered ring metallacycles. Substitution of the olefins by amino or alkoxy groups increases their reactivity in cycloaddition reactions. The approximate order of reactivity is: vinyl ethers < enamines < ketene O,O-acetals < ketene N,N-acetals < tetraalkoxyethylene or tetraaminoethylene. In [2+2] cycloaddition reactions of carbon cumulenes, often only one four-membered ring compound is obtained. This reaction is of considerable importance in the synthesis of β- lactams from ketenes and C N double bond containing substrates. The β-lactam structure is present in a variety of antibiotics. Also, β-thiolactams are obtained from thioketenes and imines. The obtained four-membered ring cycloadducts sometimes rearrange to more stable linear products. When the substrate has β-hydrogen atoms attached to the cumulative system, rearrangement to the linear product is the preferred mode of reaction. Also, fragmentation of the initially formed cycloadduct is sometimes observed. Compounds containing phosphorous double bonds are special cases, because the reaction with heterocumulenes across C OorC S bonds affords phosphorous oxides or sulfides with generation of a new double bond. These reactions are generally referred to as Staudinger or Wittig reactions. A well known example is the azaÐWittig reaction involving iminophosphoranes and isocyanates. A concerted four-centered transition state is postulated in order to explain the retention of configuration observed in these reactions. The P N bonds in heterocyclic compounds often undergo [2+2] cycloaddition reactions with heterocumulenes. The cumulative double bonds in cumulenes can also participate in [2+2] cycloaddition reactions with the same or another cumulene to give rise to the formation of four-membered ring cycloadducts. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

10 Cumulenes in Click Reactions

The general nature of these reactions was first recognized by Staudinger and his coworkers in the reaction of ketenes with olefins. Huisgen and his coworkers 25 demonstrated that the cycloaddition reaction of diphenylketene with vinyl ethers is stereospecific, indicating a concerted one-step mechanism. However, more often the [2+2] cycloaddition reactions proceed in a stepwise fashion. In recent examples it was demonstrated that the initial reaction of ketenes with several substrates produces adducts which are different from the isolated ones (see Chapter 4, Section 4.1.4.2) 26. Also switter ionic intermediates are detected by low temperature spectroscopy. For example, Machiguchi and coworkers 27 have detected the formation of 1,4-switter ionic species as intermediates in the reaction of bis(trifluoromethyl)ketene with ethyl vinyl ether. Also in the reaction of a carbodiimide with diphenylketene in liquid sulfur dioxide the [2+2+1] cycloadduct 21 is obtained by trapping the linear adduct 20 28.

NR NR C RN RN C NR + Ph C C O RN + SO O 2 2 O S O O CPh2 Ph Ph 20 21 The linear ionic intermediate can also be intercepted with either one of the reagents, for example, in the cycloaddition reaction of ketenes with aliphatic imines (Chapter 4, Section 4.1.4.2). Sometimes [2+2+2] cycloadducts resulting from the reaction of the initially formed linear adduct with either one of the reagents are observed. The basicity of the imine plays a role because aliphatic imines react in this manner, while aromatic imines produce the four-membered ring [2+2] cycloadducts 29. Substituents attached to the cumulenes can influence the mechanism of the cycloaddition reactions by rendering one molecule more nucleophilic and thereby deciding the course of the addition, i.e. determine which molecule is the electron donor to attack the electrophilic center of the other molecule 30. The [3+2] cycloaddition reactions of cumulenes as 1,3-dipolarophiles are also well known. Huisgen in 1963 3 demonstrated the wide scope of the dipolar [3+2] cycloaddition reactions, which often proceed in high yields, and consequently these reactions rival the DielsÐAlder reactions as valuable synthetic tools. The oldest example of a [3+2] cycloaddition reaction is the reaction of isocyanates with nitrones, discovered by Beckmann in 1890 31, but the general character of this reaction was discovered much later. Because of the dual character of heterocumulenes, such as isocyanates, the reaction can occur across either one of the double bonds and sometimes both reaction products are isolated. In general, the [3+2] cycloaddition reaction proceeds across the same double bonds, which also participate in the [2+2] cycloaddition reactions. Ketenes react predominantly across their C C bonds, isocyanates across their C N bonds and sulfenes across their C S bonds. The 1,3-dipolar systems involved in the cycloaddition reaction with cumulenes include azides, nitrile oxides, nitrile imines, nitrones, azomethine imines and diazo compounds. However, some 1,3-dipolar systems are also generated in the reaction of precursors with catalysts. Examples include the reaction of alkylene oxides, alkylene sulfides and alkylene carbonates with heterocumulenes. Carbon cumulenes also participate as 1,3-dipols in [3+2] cycloaddition reactions. Examples include thiocarbonyl sulfides, R2C S S, and 1-aza-2- azoniaallenes. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

General Introduction 11

The [4+2] cycloaddition reaction of dienes with dienophiles, which is generally known as the DielsÐAlder reaction, is one of the most useful reactions in synthetic organic chemistry. Many examples of carbon cumulenes participating as dienes, dienophiles, or both, are known. Even aryl substituted cumulenes sometimes react as dienes in [4+2] cycloaddition reactions. A 1,4-dipolar cycloaddition reaction also affords six-membered ring cycloadducts. For example, a 1,4-dipol can be generated in the reaction of ketenes with N-heterocycles, such as pyridine. The generated dipol 22 undergoes cycloaddition reaction with a second molecule of the ketene to give the cycloadduct 23. Staudinger had assigned structure 23 to the cycloadducts but later work demonstrated that part of the cycloadducts had the isomeric structure 24.

+ N R or N R R C C O + + R2C C O 2 N N R R O O R O O CR O 2 R R R 22 23 24 I have also included in this book the insertion reactions of carbon cumulenes into polarized metal single bonds, which can be perceived as an initial [2+2] cycloaddition, which subsequently rearranges to give a linear adduct. The reactivity of the metal substituent appears to be NR2 > OR > SR. When the metal compound contains several reactive groups, stepwise insertion occurs. For example, Sn(OR)4 reacts with phenyl isocyanate to give the tetracarbamate Sn[N(Ph)COOR]4. Mixed insertion products are obtained using different isocyanates. In the insertion reactions of carbodiimides sometimes ionic cyclic amidinate complexes are formed. A variety of other cyclization reactions are also observed with many of the carbon cumulenes. Especially, allenes and ketenes undergo many of these reactions and gold catalysis has achieved a new dimension in selectivity. From bis-allenes, complex natural products, such as 18,19 norsteroids, are generated in one step. In order to monitor the cycloaddition reactions of carbon cumulenes infrared spectroscopy is most useful, because their asymmetric stretching absorption at approximately 2300Ð1900 cm−1 occurs in a region which is relatively undisturbed. Although fundamen- tally four vibrations can be visualized in the linear cumulene system (two stretching and two bending vibrations) only the stretching vibrations are of signiﬁcance, and often the symmetric stretching absorptions of cumulenes at approximately 1400Ð1100 cm−1 are too weak to be recognized because of the proximity of methyl and methylene absorptions in this region. Proton magnetic resonance spectroscopy can also be used to identify carbon cumulenes. The protons attached to the same carbon atom to which the cumulene group is attached are deshielded by the cumulene group and the chemical shifts of these protons are suf- ﬁciently separated from that of ordinary alkyl protons to allow characterization and also quantitization. Of course, this method is only of value in the aliphatic series because in aryl substituted cumulenes only β protons are present and the deshielding effect is minimized. The reactions shown in this book, up to 2008, are only examples to demonstrate the general scope of cumulene click reactions. New reactions are being reported constantly and many new reactions are expected to be discovered at an ever increasing rate. P1: IFM c01 JWBK368-Ulrich October 5, 2009 7:49 Printer: Yet to come

12 Cumulenes in Click Reactions

References

1. H.C. Kolb, M.G. Finn and K.B. Sharpless, Angew. Chem. Int. Ed. 40, 2004 (2001). 2. H. Bibas, D.W.J. Moloney, R. Neumann, M. Shtaiwi, P.V. Bernhardt and C. Wentrup, J. Org. Chem. 67, 2619 (2002). 3. R. Huisgen, Angew.Chem.Int.Ed.2, 565 (1963). 4. H.W. Bonk, A.A. Sadarnopoli, H. Ulrich and A.A.R. Sayigh, J. Elastoplastics 3, 157 (1971). 5. S.J. Atkinson, V. Ellis, S.E. Boyd and C.L. Brown, New J. Chem. 31, 155 (2007). 6. C&EN, May 5, 2008, p. 8. 7. C&EN, September 22, 2008, p. 80. 8. F. Toda, Eur. J. Org. Chem. 1377 (2000). 9. A.W. Hofmann, Chem. Ber. 3, 761 (1860). 10. H. Ulrich, Cycloaddition Reactions of Heterocumulenes, Academic Press, New York, USA, 1967. 11. J.E. Wilson and G.C. Fu, Angew. Chem. Int. Ed. 43, 6358 (2004). 12. H. Ulrich, Chemistry and Technology of Isocyanates, John Wiley & Sons Ltd, Chichester, UK, 1996. 13. H. Ulrich, Chemistry and Technology of Carbodiimides, John Wiley & Sons Ltd, Chichester, UK, 2007. 14. H. Ulrich, B. Tucker and A.A.R. Sayigh, J. Am. Chem. Soc. 94, 3484 (1972). 15. R. Huisgen and J. Rapp, Tetrahedron 53, 939 (1997). 16. H. Staudinger, Die Ketene, Enke, Stuttgart, Germany, 1912. 17. O. Bayer, Angew. Chem. A59, 257 (1947). 18. H. Ulrich and H.R. Reymore, J. Cell. Plast. 21, 350 (1985). 19. J.C. Martin, P. Gott, V.W. Goodlett and R.H. Hasek, J. Org. Chem. 30, 4309 (1965). 20. U. Anthoni, C. Larsen and P.H. Nielsen, Acta Chem. Scand. 22, 309 (1986). 21. J. Goerdeler and H. Schenk, Angew. Chem. 75, 675 (1963). 22. W. Neumann and P. Fischer, Angew. Chem. Int. Ed. 1, 621 (1962). 23. H. Ulrich, B. Tucker, F.A. Stuber and A.A.R. Sayigh, J. Org. Chem. 34, 2250 (1969). 24. E. Schaumann, Tetrahedron 44, 1827 (1988). 25. R. Huisgen, L. Feiler and G. Binsch, Angew.Chem.Int.Ed.3, 753 (1964). 26. T. Machiguchi, J. Okamoto, J. Takachi, T. Hasegawa, S. Yamabe and T. Minato, J. Am. Chem. Soc. 125, 14446 (2003). 27. T. Machiguchi, J. Okamoto, Y. Morita, T. Hasegawa, S. Yamabe and T. Minota, J. Am. Chem. Soc. 128, 44 (2006). 28. W.T. Brady and E.D. Dorsey, J. Org. Chem. 35, 2732 (1970). 29. H. Ulrich, Acc. Chem. Res. 2, 186 (1969). 30. H. Ulrich, R. Richter and B. Tucker, J. Heterocyclic Chem. 24, 1121 (1987). 31. E. Beckmann, Ber. Dtsch. Chem. Ges. 23, 1680 (1890). P1: IFM c02 JWBK368-Ulrich October 9, 2009 15:14 Printer: Yet to come

2 1-Carbon Cumulenes

2.1 Sulﬁnes, R2C S O

2.1.1 Introduction Sulfines are non-linear sulfur centered heterocumulenes with the general structure RR1C S O. Sulfines are considered to be analogs of sulfur dioxide, in which one oxygen atom is replaced by a carbon atom. Sulfines are unstable at room temperature, and they are usually generated in situ. Aromatic substituted sulfines are generally more stable than the aliphatic substituted species. For example, 9-sulfinylfluoren is obtained in 75 % yield by the dehydrochlorination of the corresponding sulfinyl chloride. In the oxidation of tropothione with m-chloroperbenzoic acid below −60 ◦C the red tropothione S-oxide, a stable sulfine, is obtained, also in 75 % yield 1. Some halogenated sulfines are also stable at room temperature. Review articles on sulfines were written by Opitz in 1967 2, Zwanenburg in 1982 3, 1985 4, 1988 5 and 1989 6 and by Block in 1981 7. The chemistry of thiosulfines was reviewed by Huisgen and Rapp in 1997 8. Sulfines are usually presented by combinations of the neutral (R2C S O), the ylene + − + (R2C S ÐO ) and the ylide (R2CÐS O) resonance structures. The molecular structure of sulfines, particularly the non-linearity of the C S Osys- tem, was established by X-ray crystallography (CÐS, 1.62 A:û S-O, 1.46 A:û CSO, angle 114◦). The electronic charge distribution was calculated for the parent sulfine and mono and dihalogen substituted sulfines using ab initio methods 9. The charge on sulfur and oxygen remains almost constant (S, +0.63 0.03: O, −0.69 0.01) by varying the substituents on carbon, whereas the charge on carbon exhibits a strong influence. The non-linearity of the COS function is also deduced from the H1 NMR spectra of ortho protons in diarylsulfines syn to the COS system, which absorp at lower fields by ca. 0.6 ppm rela- tive to the almost unperturbed anti-ortho protons 10. The same deshielding is observed in E-phenyl(phenylthio)sulfine, whereas in the Z isomer all aromatic protons absorb at the same δ-value 11. The infrared spectra of sulfines show two characteristic absorptions in the

Cumulenes in Click Reactions Henri Ulrich C 2009 John Wiley & Sons, Ltd P1: IFM c02 JWBK368-Ulrich October 9, 2009 15:14 Printer: Yet to come

14 Cumulenes in Click Reactions

sulfoxide region from 1000 to 1150 cm−1. The UV absorption of the CSO chromophore is observed at about 270 nm 12. The stable arylsulfines have IR absorptions at 1019Ð1078 cm−1 and at 1093Ð1128 cm−1, respectively. Historically, sulfines were first prepared in 1923 by Wedekind and coworkers 13,who reacted campher-10-sulfonyl chloride with pyridine. The sulfine structure of the reaction product was confirmed by King and Durst in 1963 using spectroscopic evidence 14. In 1938 Kitamura oxidized thioamides with hydrogen peroxide, but assigned an imino sulfenic acid structure to the reaction product 15. Walter, in 1960, showed that the correct structure 16 was that of an aminosulfine (RC(NH2) S O) . During the reinvestigation of Wedekind’s work, King and Durst discovered that sulfines can exist as stable geometrical isomers. The assignment of the E- and Z-geometry was made by means of NMR spectroscopy 17. Ethylsulfine (propanethial S-oxide) was spectroscopically identical to the natural onion lachrymatory factor 18. The configuration of the natural ethylsulfine was established to be Z by the anisotropic deshielding effect of the CSO group on the C(1)ÐH in combination with benzene induced shifts 19. The lachrymatory effect of sulfines diminishes when the substituent is more bulky; t-butylsulfine is devoid of lachtymatory activity. Also, 2,3- dimethylbutanedithial S,S-dioxide, a disulfine, was isolated from an onion extract 20. The click chemistry, involving sulfines, is encountered in their [3+2] and [4+2] cycloaddition reactions which afford five- and six-membered ring heterocycles, often in high yields. Examples of the [2+1] and the [2+2] cycloaddition reactions of sulfines are hardly known. Thiosulfines, R2C S S, are also not stable and rearrangement to thiocarboxylic esters seems to be faster than reaction with alkynes or norbornadiene 21. However, numerous [3+2] cycloaddition reactions, in which the C S S system reacts as a 1,3-dipolar species are known (see Section 2.3.2). Thione S-imides, the nitrogen homologues of sulfines, also undergo mainly [3+2] and [4+2] cycloaddition reactions (see Section 2.3.1.2).

2.1.2 Dimerization Reactions In contrast to the sulfenes, the [2+2] cycloaddition reactions of sulfines are not well known. The dimerization of ethylsulfine gives rise to a four-membered ring trans-3,4-diethyl-1,2- dithietane 1,1-dioxide, which is not the result of a [2+2] cycloaddition 22. Similarly, reaction of trimethylsilylmethanesulfinyl chloride with triethylamine affords the sulfine 1, which on standing at room temperature for several days gives 42 % of trans-3,4-bis(trimethylsilyl)- 1,2-dithietane 1,1-dioxide, 2 23.

SO2 Me3Si Me3SiCH2SOCI + Et3N [Me3SiCH S O] Me3Si S 1 2

The dimer of trifluoromethylsulfine is obtained in the thermal generation of the sulfine from the anthracene adduct 24. Also, the cyclic dimers of γ -acetylenic-β,β-disubstituted thioaldehyde S-oxides are isolated in their generation from allenic sulfinates with vinyl magnesium bromide 25. P1: IFM c02 JWBK368-Ulrich October 9, 2009 15:14 Printer: Yet to come

1-Carbon Cumulenes 15

The mechanism of formation of the dithietane 1,1-dioxide dimers involves an opposite [3+2] cycloaddition to form 3, which subsequently rearranges to give 4 . 26

S S R2 R2C S O R2 O R SO 2 SO2 R2

3 4

2.1.3 Cycloaddition Reactions 2.1.3.1 [2+1] Cycloaddition Reactions Diphenylsulﬁne reacts with dichlorocarbene to give the [2+1] cycloadduct 5 in 18 % yield 27.

Ph O S Ph2C S O + :CCl2 Ph

Cl Cl

2.1.3.2 [2+2] Cycloaddition Reactions The [2+2] cycloadditions to sulﬁnes have not, as yet, been observed. However, singlet oxygen addition occurs across the C S bond of sulﬁnes with formation of ketones and sulfur dioxide 28.

2.1.3.3 [3+2] Cycloaddition Reactions Sulfines participate as dipolar species in numerous [3+2] cycloaddition reactions. Huisgen has labelled sulfines as ‘superdipolarophiles’. For example, generation of benzonitrile oxide in the presence of diarlsulfines affords the [3+2] cycloadducts in a regiospecific reaction. The formed 1,4,2-oxathiazole S-oxides 6 are obtained in 50Ð88 % yield 29.

R S Ph

R2C S O + PhC N–O R O N 6

The cycloadducts are thermally labile and, on heating in reﬂuxing xylene, extrusion of sulfur monoxide with formation of diarylketones and benzonitrile is observed. P1: IFM c02 JWBK368-Ulrich October 9, 2009 15:14 Printer: Yet to come

16 Cumulenes in Click Reactions

However, in the reaction of bis(trifluoromethyl)sulfine 7 with benzonitrile oxide, 3- phenyl-4,4-bis(trifluoromethyl)-1,5,2-oxathiazol 5-oxide 8 is obtained in 57 % yield 30.

CF S 3 O (CF3)2C S O + PhC N–O CF 3 N Ph

7 8

The corresponding 1,5,2-oxathiazole S-oxide is also obtained in the reaction of fluorene- sulfine and benzonitrile oxide 29. In a similar manner diphenylnitrilimines, generated in situ, react with diarylsulfines to give 1,3,4-thiadiazoline S-oxides 9 in 62Ð85 % yield in a stereospecific reaction 31.

R S Ph R C S O + PhC N–NPh 2 R N N Ph 9

The orientation in cycloaddition reactions of nitrile oxides and imines with heterodipo- larophiles obeys the principle of maximum gain in σ-bond energy 32. This means that the reactants join in such a manner that the best compensation for the π-bond energy lost is achieved in the combined energy of the two newly formed σ-bonds. The cycloaddition of diphenylsulﬁne with the nitrile ylide 10 affords 2-thiazoline S- oxides 11 33.

Ph S Ph Ph C S O + PhC N–CHPhNO -p 2 2 Ph N

O2N 10 11

The reactions of sulfines with C-phenyl-N-methylnitrone is more complicated 34.For example, sulfine and this dipole react in a molar ratio of 2:1. The initially formed 1:1 adduct loses sulfur dioxide providing a dipolar species which reacts with the second molecule of the sulfine. Diphenylsulfine reacts with ammonium azide to give diphenyldiazomethane in 88 % yield 35. Apparently the cycloadduct reverses to give the isolated product. Also, some mesoionic compounds undergo a [3+2] cycloaddition reaction with diaryl- or arylchlorosulfines. Munchenone,¬ an oxazolium-5-olate 12, reacts with arylchlorosulfine