title: Conversion of five-, six-, and seven-membered lactams to racemic or scalemic 2-substituted heterocycles by amidoalkylation.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Madan
authors.forename: Peter
authors.initials: P
authors.lastname: Milano
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Eddings
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gawley
mesh_terms: D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D007769:Lactams / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D006571:Heterocyclic Compounds; D007769:Lactams