An efficient method for the synthesis of 2-alkyl- and 2-aryl pyrrolidines, piperidines, and azepanes from lactams, in either racemic or enantiopure form, is presented. The lactam nitrogens are acylated with either Boc anhydride or trans-cumylcyclohexyl (TCC) chloroformate. Selective reduction of the lactam carbonyl to the carbinolamide is followed by treatment with benzotriazole. Substitution of the benzotriazole is accomplished by treatment with organometallics, yielding the 2-substituted heterocycles. With TCC, up to 90% diastereoselectivity is achieved. After diastereomer purification, reductive removal of the auxiliary affords enantiopure 2-substituted heterocycles. A mechanistic hypothesis is presented that details the conformational equilibria of the key step.

Pyridine derivatives R 0380Conversion of Five-, Six-, and Seven-Membered Lactams to Racemic or Scalemic 2-Substituted Heterocycles by Amidoalkylation. -The process offers an efficient route to racemic and enantiopure 2-substituted pyrrolidines, piperidines, and azepanes. -(MADAN, S.; MILANO, P.; EDDINGS, D. B.; GAWLEY*, R. E.; J. Org. Chem. 70 (2005) 8, 3066-3071; Dep. Chem. Biochem., Univ. Ark., Fayetteville, AR 72701, USA; Eng.) -Jannicke 37-138