MICROREVIEW The Use of Tosylhydrazone Salts as a Safe Alternative for Handling Diazo Compounds and Their Applications in Organic Synthesis J. Robin Fulton,[a] Varinder K. Aggarwal,*[b] and Javier de Vicente[b] Keywords: Diazo compounds / Hydrazones / Bamford–Stevens reaction / Epoxidation / Aziridination / Cyclopropanation / Olefination / Pyrazoles / Homologation / Ether synthesis Diazo compounds are useful synthetic intermediates in or- induced to react directly with alkenes or alkynes to synthe- ganic synthesis but, due to their toxicity and unpredictable size pyrazoles or with aldehydes to generate ketones. Alter- explosive behaviour, their unique reactivity has not been natively, diazo compounds can react with transition metals fully exploited and their use on large scale has been avoided. capable of carbene transfer reactions. We have shown the We have developed a reliable method that generates diazo usefulness of this chemistry in a number of different transfor- compounds in situ. Our approach is based on the Bamford– mations, such as Wittig olefination reactions and the sulfur Stevens reaction, which utilizes tosylhydrazone salts as diazo ylide mediated epoxidation, as well as aziridination and cy- precursors. In the presence of phase-transfer-catalysts (PTC), clopropanation chemistry as applied toward the synthesis of we found that tosylhydrazone salts can be cleanly converted more complicated molecules. to diazo compounds under mild reaction conditions and in a (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, wide range of solvents. These diazo compounds can then be Germany, 2005) Introduction to be taken into account when synthesising and working with them.[4] The toxicity of diazo compounds is due to Diazo compounds are inherently dangerous.[1–3] Their their acid-catalyzed decomposition to form carbocations, toxicity and tendency to explode are indeed serious hazards which are able to alkylate deoxynucleic acids. This is espe- [a] Department of Chemistry, cially acute when handling volatile diazo compounds. For University of Sussex instance, diazomethane is reported to be a strong respira- Falmer, Brighton, BN1 9QJ, UK tory irritant that can cause asthmatic symptoms as well as [b] School of Chemistry, Bristol University, [5] Cantock’s Close, Bristol, BS8 1TS, UK pulmonary edema. There has been one reported fatality E-mail: [email protected] of diazomethane poisoning in humans and the high acute J. Robin Fulton was born in Wichita, Kansas, and moved to Seattle, Washington, when she was 11. She received a B.S/B.S in chemistry and biochemistry from the University of Washington in 1995 and a PhD in Chemistry from the University of California, Berkeley in 2000 where she studied organometallic chemistry under the supervision of Professor Robert G. Bergman. After a postdoctoral studies in environ- mental chemistry at the University of Colorado, she moved to England and did further postdoctoral studies with Professor Varinder K. Aggarwal at the University of Bristol investigating new methodologies for the use of diazo compounds in organic synthesis. In 2004, she started a permanent lectureship position at the University of Sussex where she currently holds a Leverhulme Early Career Fellowship. Varinder K. Aggarwal was born in Kalianpur in North India in 1961 and emigrated to the United Kingdom in 1963. He received his B.A. (1983) and Ph.D. (1986) from Cambridge University, the latter under the guidance of Dr. Stuart Warren. He was subsequently awarded a Harkness Fellowship and carried out postdoctoral work with Professor Gilbert Stork at Columbia University, NY (1986–1988). He returned to a lectureship at Bath University and in 1991 moved to Sheffield University, where in 1997, he was promoted to Professor of Organic Chemistry. In 2000, he moved to the University of Bristol to take up the Chair of Synthetic Chemistry. He is recipient of the AstraZeneca award, Pfizer Awards, GlaxoWelcome award, Novartis lectureship, RSC Hickinbottom Fellowship, Nuffield Fellowship, RSC Corday Morgan Medal the Liebigs Lectureship, RSC Green Chemistry Award, and AstraZenecaDistinguished Lecturer award. Javier de Vicente was born in Madrid in 1974. He studied chemistry at the Autonoma University of Madrid, receiving his B.S. degree in 1997 and his MS degree in 1999 under the supervision of Professor Juan Carlos Carretero. For his Ph.D. degree, he studied with Professor. Varinder K. Aggarwal at the University of Bristol, developing user-friendly synthetic processes using diazo compounds generated in situ. He is currently conducting postdoctoral studies with Professor Scott D. Rychnovsky at the University of California, Irvine, and his work focuses on the synthesis of natural polyhydroxy structures. MICROREVIEWS: This feature introduces the readers to the authors’ research through a concise overview of the selected topic. Reference to important work from others in the field is included. Eur. J. Org. Chem. 2005, 1479–1492 DOI: 10.1002/ejoc.200400700 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1479 MICROREVIEW J. R. Fulton, V. K. Aggarwal, J. de Vicente toxicity to cats has also been described. The potentially vi- olent behaviour of diazomethane has also been well docu- mented. Several researchers have reported diazomethane explosions resulting from contact with sharp surfaces, such as etched or scratch flasks or upon warming on ambient to elevated temperatures.[6] De Boer and Backer also reported that most explosions occur during distillation. In addition, Scheme 1. Resonance structures of aliphatic and ester substituted diazo compounds. diazomethane has been reported to react exothermically with Drierite® (calcium sulfate). Trimethylsilyldiazomethane is remarkably more stable compounds will alkylate amines and aziridinate im- than diazomethane and has led to investigations on its use ines.[14,15] Diazo compounds are also the preferred precur- in synthesis as a stable and safe substitute of diazometh- sors of metallocarbenes and carbenoids.[13,16–19] They can ane.[7] Diazoesters are considered to be much safer than di- react with a wide number of transition metal complexes azomethane due to the resonance stabilization of the ester capable of transferring carbenes, and such diazo com- functional group (although only estimated to be around pounds can be used for a variety of different transforma- 16 kJ/mol) (Scheme 1).[8] These compounds can still deto- tions, including carbene insertion reactions into C–H,[20] nate, albeit under much more forcing conditions, such as Si–H, N–H, O–H, and S–H bonds,[13] sulfur ylide mediated exposure to heat or concentrated sulfuric acid.[9] In ad- epoxidation, aziridination or cyclopropanation reactions dition, the health hazards associated with ethyl diazoacetate (the latter can also occur directly) in addition to Wittig- are much reduced, partially due to its significantly higher type transformations.[21,22] Despite diverse reactivity, diazo boiling point. The toxicity of aliphatic and aromatic diazo compounds are generally avoided in an industrial setting compounds has not been studied in the same detail; how- due to their unpredictable explosive behaviour. Only re- ever, these compounds are assumed to be toxic (due to the cently has the thermo-chemistry and the detonation proper- pathways previously discussed) and are also explosive. On ties of ethyl diazoacetate have been studied and large scale a personal account, one of the authors’ co-workers experi- chemistry of ethyl diazoacetate has shown limited enced an explosion during a distillation of phenyldiazo- use.[9,23–25] With regards to diazomethane, only one patent methane. Fortunately, the impact of the explosion was mini- has described the production of diazomethane on a large mal as the reaction vessel was placed behind a glass shield. scale[26] and methods for the continuous process of diazo- Despite their danger, the synthetic utility of diazo com- methane have also been described.[27,28] To the best of our pounds cannot be overlooked.[10–12] Diazo compounds have knowledge, there has been no large scale production of an unique reactivity due to their 1,3-dipole and ylide nat- more complex aliphatic non-diazocarbonyl compounds. ure.[13] They can react directly with organic substrates, such The synthetic utility of diazo compounds and their lim- as in the alkylation of acidic alcohols and carboxylic acids, ited use in industry has evolved a recent drive to develop homologation of carbonyl compounds, 1,3-dipolar addition safer alternative methods for using diazo compounds; either onto alkynes and preparation of diazoketones from acyl ha- generating them in situ or using an alternative source of lides (Scheme 2). In the presence of a Lewis-acid, diazo carbene equivalents and precursors. This review will focus Scheme 2. Some of the most useful transformations of diazo compounds (LA = Lewis acid). 1480 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org Eur. J. Org. Chem. 2005, 1479–1492 Tosylhydrazone Salts as a Safe Alternative for Handling Diazo Compounds MICROREVIEW Scheme 3. Catalytic epoxidation (X = O), aziridination (X = NTs), and cyclopropanation (X = CH2COY) mediated by sulfur ylides. on the in situ generation of diazo compounds from tosylhy- ines[41] or cyclopropanes (Scheme 3).[42] Unfortunately, fur- drazone compounds. It is noteworthy that other alternatives ther applicability and potential commercial success of this such as the use of phenyliodonium ylides, N-aziridinyl- new methodology was thwarted by the need