Stereoselective Addition of Nucleophiles to Aziridinyl-2-carboxaldimine

Abstract

Commercial success to produce both enantiomers of aziridine-2-carboxylates in optically pure forms prompts us to extend their synthetic utilities for the preparation of enantiopure nitrogen containing molecules. In last few years we have studied with chiral aziridine-2-carboxylates to provide enantiomerically pure αor β-amino ester and their derivatives. Synthetic study has been extended to construct diamine compounds based on the reaction with the substrate, aziridinyl-2-carboxaldimine. Recently we successfully prepared aminomethylaziridine and 4,5-disubstitued imidazolidin-2-ones by the addition of organomagnesium reagents to aziridinyl-2-carboxaldimine. The additions of alkyland arylmagnesium reagents to the chiral [1'(R)-αmethylbenzyl]aziridine-2(R)-carboxaldimine were highly stereoselective in most cases with chelation controlled transition states. The subsequent treatment of theses adducts with triphosgen and NaH afforded enantiopure 5-alkylor 5aryl-4-chloromethylimidazolidin-2-ones. The utility of imines can be expanded by the addition of the nucleophiles other than organometallic reagents as shown in Scheme 1. In this report we would like to describe the recent success to introduce carbon nucleophiles other than alkylmetal reagents and their stereochemical outcomes with the mechanistic implications. The addition of nitrile to imine as in Strecker reaction was achieved using cyanotrimethylsilane (4) that reacted with activated imines. The substrate we used, [1'(R)-α-methylbenzyl]aziridine-2(R)-carboxaldimine (1) was inert without any additives. Reaction in CH2Cl2 with 50 mol% of BF3·OEt2 at room temperature in 3 hr yielded the products as a diastereomeric mixture (5 and 6) with the ratio of 69 : 31 in 91% yield (entry 1). Two diastereomers were inseparable by chromatography and treated with triphosgen and NaH in THF to yield enantiopure 5-cyano-4-chloromethylimidazolidin-2-ones. The stereochemistry of two products were determined by the comparison of coupling constant of two imidazoline ring protons at C-3 and C-4. The coupling constant was observed as 2.6 Hz for the major product and 7.5 Hz for the minor product which were corresponding to trans and cis configurations respectively. This informed us that the major product is threo isomer from re face attack of the coming nucleophile to the substrate. Trials to improve the diastereoselectivity by changing Lewis acids such as ZnCl2, Sc(OTf)3, Ti(Oi-Pr)4, TMSTf, CeCl3 were not successful to show similar stereoselectivity in a little lower yield. When we used CsF that is known to be a good catalyst in the addition of imine, the reaction produced a little better ratio as 78 : 22 in 75% yield (entry 2). It is also noteworthy that the reaction with TMSCl as an additive gave Dedicated to professor Yong Hae Kim on the occasion of his 65th birthday. Co-Corresponding Authors: H.-J. Ha (hjha@hufs.ac.kr), W. K. Lee (wonkoo@sogang.ac.kr) Scheme 1 Table 1. The addition of nucleophiles to chiral (p-methoxyphenyl)[1'(R)-α-methylbenzyl]aziridine-2(R)-ylmethylene]amine