Reduction of 2-chloro-N-phenylpropanamide and 2-methyl-N-phenylaziridine with lithium aluminium hydride

Abstract

The reduction of 2-chloro-N-phenylpropanamide with LiAlH(4) has been re-examined. In contrast to previous findings, we obtain in almost equal quantities two amines from this reaction, namely N-propylaniline and the rearranged product N-isopropylaniline. 2-Methyl-N-phenylaziridine is an intermediate in the reduction and can be isolated from reactions with less LiAlH(4). Reduction of 2-methyl-N-phenylaziridine itself proceeds non-regioselectively to provide a mixture of propyl- and isopropylanilines. Formation of the amines by reduction of the aziridine is much slower than formation by reduction of the 2-chloropropanamide, which indicates that Lewis acid catalysis (by aluminium chlorohydrides) facilitates the reduction of the aziridine. In addition, Lewis acid catalysis increases the relative yield of the propylamine product. The reduction of 2-chloro-N-phenylpropanamide furnishes 2-phenylamino-1-propanol as a by-product, rather than the previously proposed 1-phenylamino-2-propanol.

Stereoselective synthesis of trans- and cis-2-aryl-3-(hydroxymethyl)aziridines through transformation of 4-aryl-3-chloro-β-lactams and study of their ring opening

“…The LiAlH 4 -induced ring opening of aziridines without additional N-activation is surprising and has not been described before in the literature, apart from a recent paper in which the partial and non-regioselective LiAlH 4 -promoted ring opening of 2-methyl-1phenylaziridine is reported. 20 Besides that report, only indirect Scheme 2 evidence for the reduction of aziridines by LiAlH 4 , deduced from several experiments in which aziridines were assumed to be intermediates, is available in the literature. 21 The hydride-induced ring opening of aziridines is indeed peculiar, as several methods are known for the formation of aziridines by LiAlH 4 reduction of suitable substrates.…”

Microwave-assisted regioselective ring opening of non-activated aziridines by lithium aluminium hydride

“…29 Subsequently, reductive ring opening takes place via nucleophilic attack of a hydride ion (from LiAlH 4 ) at the less substituted carbon atom of the aziridine moiety in intermediates Scheme 1 3. Apparently, the reducing agent acts both as the activator of the aziridine ring (through coordination of aluminium with nitrogen 5, 14 ) and as the provider of the nucleophile (hydride) which opens up the ring at the less hindered position (Scheme 1). However, the alternative mechanistic pathway comprising an initial hydride attack at the less hindered position of the aziridine moiety of 2-(bromomethyl)aziridines 1, yielding the ring opened intermediates, and their subsequent ring closure towards 2methylaziridines 3, should not be neglected.…”

“…The intermediacy of aziridines in direct, non-regioselective ring opening reactions by LiAlH 4 has been proposed in an early paper, in which the reduction of N-(1,1-dichloro-2-alkylidene)anilines was investigated, 12 and was also deduced indirectly from the experiments of Suzuki. 13 In addition, in one recent report, 14 the reduction of 2-methyl-1phenylaziridine with LiAlH 4 in THF yielded a mixture of ring opened amines (derived from hydride attack at both the more and the less hindered aziridine carbon atom in a 1 : 2 ratio, respectively) yet was shown to be slow and not complete after heating under reflux for 20 h. Furthermore, the contribution of the electronwithdrawing effect of the phenyl group at the nitrogen, facilitating ring opening of the aziridine moiety, should not be neglected.…”

Synthesis of α-Hydroxyl Amides via Direct Amidation of Lactic Acid at Solvent- and Catalyst-Free Conditions

“…8 The stepwise nucleophilic acylation and hydrolysis of α-chloroamides [Eqn (3), Scheme 1] has also been reported. 9 These methods have led to the synthesis of useful α-hydroxyl amide products. However, the requirement for the prior synthesis of the substrates limits their use.…”