Elsevier

Tetrahedron

Volume 58, Issue 27, 1 July 2002, Pages 5513-5523
Tetrahedron

Acyl hydrazines as precursors to acyl radicals

https://doi.org/10.1016/S0040-4020(02)00490-8Get rights and content

Abstract

The use of acyl hydrazines (hydrazides) as precursors for the stoichiometric generation of acyl radicals is explored. Two classes of substrates are examined: unsubstituted acyl hydrazines and acyl hydrazines substituted with a leaving group (2-nitrobenzenesulfonyl or ‘nosyl’). Both types are successfully converted to acyl radicals, and are then trapped by nitroxide radicals to give acyloxyamine products. Cyclization reactions are demonstrated for both classes of substrates. A low temperature modification of the McFayden–Stevens reaction is also developed.

Introduction

The use of acyl radical methodology as a tool for the formation of carbon–carbon bonds, and particularly in the construction of carbon ring systems has been an important development in modern synthetic organic chemistry.1 Today a number of successful methods of generating acyl radicals have been developed, and have been utilized in organic synthesis. The most widely studied method is the stannane reduction of selenoesters,2 based on a radical chain mechanism. Likewise, carbonylation of organohalides in a tin-mediated chain sequence has been developed by Ryu.3 These methods suffer from toxicity and disposal issues associated with the use of organotin reagents and their resulting waste products. A number of techniques have been developed to circumvent these problems, including the use of tris(trimethylsilyl)silane,4 water soluble tin hydride reagents,5 fluorous tin hydride reagents,6 and solid phase tin hydride reagents.7 Other methods of generating acyl radicals have also been developed that avoid the use of organotin reagents altogether. Examples of these methods are the oxidation of aryl diazonium-tethered thioesters8 and the photolysis of substrates such as thioxanthates,9 acyl cobalt salen species,10 and telluroesters.11

The alkyl or acyl hydrazine functional group is characterized by an N–N single bond connected to an alkyl carbon atom or a carbonyl group, respectively. Acyl hydrazines are also known as hydrazides, and the general class of carbon-substituted hydrazines are also referred to as carbohydrazines. Much is known about the structure and reactivity of carbohydrazines, and this class of functional groups has been reviewed.12 Two distinct categories of carbohydrazines are considered in this discussion: unsubstituted (R–NHNH2) and those substituted with a leaving group (R–NHNH–X or R–NX–NH2).

The oxidative conversion of unsubstituted alkyl hydrazines to alkyl radicals was first demonstrated by Corey et al. in a strategy for preparing hindered optically active amines derived from borneol.13 This method of generating radicals has been used extensively in our laboratory to study stereoselective trapping of nitroxides at prochiral carbon centers,14 and has also been used in the synthesis of initiators for nitroxide-mediated ‘living’ free-radical polymerization.15 Alkyl hydrazines substituted with leaving groups have also been shown to be precursors to alkyl radicals: Myers et al. have demonstrated that alkyl hydrazines substituted with a 2-nitrobenzenesulfonyl (‘nosyl’ or ‘Ns’) group spontaneously degrade to alkyl radicals.16 The mechanism for the generation of alkyl radicals from unsubstituted and nosyl-substituted alkyl hydrazines involves the initial formation of a reactive alkyl diazene17 intermediate (R–NN–H) followed by degradation with loss of nitrogen to afford the carbon radical. There is evidence that acyl radicals generated from acyl hydrazines may play a part in the enzyme-mediated mechanism of action of isoniazid, a widely utilized antituberculosis drug.18

Herein the generation and utilization of acyl radicals from acyl hydrazine precursors is explored. Acyl hydrazines are attractive precursors to acyl radicals as they can be prepared easily from inexpensive reagents, and often exist as stable crystalline species. Reported here are results in the generation of acyl radicals from unsubstituted acyl hydrazines and from nosyl-substituted acyl hydrazines. Direct trapping of the acyl radicals is first demonstrated, followed by examples of cyclization reactions.

Section snippets

Acyl radicals from unsubstituted acyl hydrazines

The first task at hand was the preparation of unsubstituted acyl hydrazine substrates. The most commonly reported method in the literature is the direct hydrazinolysis of methyl esters. For example, methyl benzoate (1) was reacted with hydrazine monohydrate to generate benzhydrazide (2) (Scheme 1). This method is unattractive due to the toxicity and explosiveness of hydrazine, and because a large excess is generally required. The use of hydrazine can be circumvented by using a two-step protocol

Conclusion

In summary, a new method for the generation of acyl radicals has been developed that utilizes either unsubstituted acyl hydrazines or nosyl-substituted acyl hydrazines. With both classes of substrates, the simple generation of acyl radicals was demonstrated initially, followed by application to cyclization reactions. This method differs from selenoester, telluroester and carbonylation methodology, in that the acyl radical is generated in a stoichiometric fashion, and is trapped by a nitroxide

General

All reactions were carried out under an atmosphere of argon. Solvents for radical trapping experiments were degassed by passing argon through them for at least 15 min prior to use. Tetrahydrofuran (THF) was freshly distilled from sodium/benzophenone ketyl. Sonication was carried out in a Fisher FS-14 cleaning bath. Slow reagent addition was performed using a Sage Instruments syringe pump (model 355) with gas tight Hamilton syringes. Analytical thin layer chromatography (TLC) was carried out

Acknowledgements

We would like to thank the National Science Foundation (CHE 9527647 and CHE 0078852) for financial support. Frank Rivera and Armando Jimenez also gratefully acknowledge support from the National Institute of Health program ‘Bridges to the Future’ (GM 51765).

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