Dipolar cycloaddition of N-aryl-C-(2,2-dichloro-1-phenylcyclopropyl)nitrones to N-arylmaleimides

Abstract

1,3-Dipolar cycloaddition of N-aryl-C- (2,2-dichloro-1-phenylcyclopropyl)nitrones to N-arylmaleimides stereoselectively gives substituted pyrrolo [3,4-d]isoxazolidines as mixtures of two diastereoisomers differing by configuration at the C 1′ atom of the cyclopropane ring in the substituent on C 3 . Substituents in the aromatic rings of the initial nitrone and maleimide do not affect the stereochemistry of the process.1,3-Dipolar cycloaddition of nitrones to unsaturated compounds underlies one of the most important methods for building up five-membered heterocyclic systems [1]. A necessary condition for the synthesis of compounds with required properties is the possibility to control the reaction stereochemistry, which may be achieved by proper selection of the corresponding substrates and reaction conditions (solvent and catalyst). It is known that in reactions of C,N-diaryl nitrones with N-arylmaleimides the ratio of the resulting endo/exo diastereoisomers changes from 1.4 to 3.9, depending on the substituent in the aromatic ring of the initial nitrone and mealeimide [2]. Enhanced diastereoselectivity was observed in reactions of C-aryl-N-(arylmethyl)nitrones with maleimides having both electronwithdrawing and electron-donating substituents in the aromatic ring of the imide [3], as well as with o,o′-disubstituted N-arylmaleimides due to increase of steric interaction in the transition state [4]. The selectivity of cycloaddition also changed in the presence of ZnBr 2 [3] and upon variation of the solvent [5].Compounds containing a cyclopropyl group attract interest due to broad spectrum of their biologically important properties [6,7]. However, published data on cycloaddition of nitrones having a cyclopropyl group to unsaturated compounds are very limited [8,9], whereas nitrones containing a geminal dihalocyclopropane fragment have not been reported. We previously found that nitrones react with compounds possessing a strained three-membered ring (e.g., cyclopropenes [10] and 2-methylidenecyclopropane-1,3-dicarboxylates [11]) to form adducts which readily undergo secondary processes involving opening of the strained ring.In the present work we examined the reaction of N-aryl-C-(2,2-dichloro-1-phenylcyclopropyl)nitrones Ia-Ic with N-arylmaleimides IIa-IIe. Nitrones Ia-Ic were synthesized by reaction of 2,2-dichloro-1-phenylcyclopropane-1-carbaldehyde with N-arylhydroxylamines. Nitrones readily undergo hydrolysis, and their 1 H NMR spectra recorded after several hours contained signals from protons of the corresponding aromatic amine and initial aldehyde. The steric configuration of nitrones Ia-Ic was determined on the basis of the NOESY spectrum of compound Ic which displayed cross peaks between the 3-H proton and ortho-protons in both aromatic rings, as well as between one orthoproton in the unsubstituted aromatic ring and one proton in the cyclopropane fragment (see the structure shown below). These findings allowed us to assign Z-configuration at the C=N bond of nitrone Ic.In the reaction of nitrones Ia-Ic with...