Synthesis of tertiary alkyl amines via photoinduced copper-catalysed nucleophilic substitution

Abstract

In view of the high propensity of tertiary alkyl amines to be bioactive, the development of new methods for their synthesis is an important challenge. Transition-metal catalysis has the potential to greatly expand the scope of nucleophilic substitution reactions of alkyl electrophiles; unfortunately, in the case of alkyl amines as nucleophiles, only one success has been described so far: the selective mono-alkylation of primary amines to form secondary amines. Here, using photoinduced copper catalysis, we report the synthesis of tertiary alkyl amines from secondary amines and unactivated alkyl electrophiles, two readily available coupling partners. Utilizing an array of tools, we have analysed the mechanism of this process; specifically, we have structurally characterized the three principal copper-based intermediates that are detected during catalysis and provided support for the key steps of the proposed catalytic cycle, including the coupling of a copper(II)–amine intermediate with an alkyl radical to form a C–N bond. Alkyl amines are found in a wide array of bioactive compounds, making strategies for their synthesis very important. Now, a method has been developed to synthesize tertiary alkyl amines via photoinduced, copper-catalysed nucleophilic substitution of unactivated alkyl halides by secondary alkyl amines, with key copper intermediates elucidated in a detailed mechanistic study.