Umpolung of Amine Reactivity. Nucleophilic α‐(Secondary Amino)‐alkylation via Metalated Nitrosamines

Abstract

There are basically two kinds of hetero atoms in organic molecules: one kind confers electrophilic character upon the carbon atom to which it is bound, and the other kind turns it into a nucleophilic site. The development of methods permitting transitions between the two resulting categories of reagents has become an important task of modern organic synthesis. The scope of such umpolung of the reactivity of functional groups is discussed for the case of amines as an example. A method of preparing masked α‐secondary amino carbanions consists in nitrosation of the secondary amine, followed by metalation of the resulting nitrosamine α‐to the nitrogen, reaction with electrophiles, and subsequent denitrosation. Many examples are given for each of these steps which illustrate the wide scope of the overall synthetic operation (electrophilic substitution at the α‐C atom of the secondary amine). Preliminary applications and a method for avoiding the handling of nitrosamines are presented, and the report concludes with a brief account of the significance of nitrosamines in the study of carcinogenesis and mutagenesis.