Lactams. XIII Alkylation of lactim ethers: A novel synthetic route to N-(2-arylethyl)lactams from N-unsubstituted lactams.

Abstract

Treatment of the lactim ethers (10a-d, 11a-c), prepared from N-unsubstituted 5-, 6-, and 7-membered lactams (6a-d), with phenacyl bromide or 3, 4-dimethoxyphenacyl bromide in N, N-dimethylformamide at 60°for 1-6 hr furnished the corresponding N-substituted lactams (21a-d, 22a-c) in good yields. Conversion of the lactam ketones (21a-d, 22a-c) into the N-(2-arylethyl) lactams (25a-d, 26a-c) through the lactam alcohols (23a-d, 24a-c) was effected in excellent overall yields by NaBH4 reduction followed by catalytic hydrogenolysis. In contrast, the alkylations of O-methylvalerolactim (10b) or O-ethylvalerolactim (11b) with less reactive alkyl halides (relative to phenacyl bromide) such as MeI, EtI, PhCH2Br, PhCH2CH2Br, and 3, 4-(MeO)2C6H3CH2CH2Br were found to give mixtures of the normally N-alkylated 2-piperidones and N-methyl-or N-ethyl-2-piperidone presumed to have formed by the O→N methyl or ethyl migration during the reactions. Alkylations of the δ-valerolactam anion with 2-arylethyl bromide or its equivalents could afford the corresponding N-substituted 2-piperidones, but in unacceptable yields.