A general carbonyl alkylative amination for tertiary amine synthesis facilitated by visible light

Abstract

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and smallmolecule biological probes ^{1, 2} continues to stimulate enormous efforts towards their streamlined synthesis ^{3– 9} . Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl reductive amination ³ : comprising two elementary steps, condensation of a secondary alkylamine with an aliphatic aldehyde forms an all alkyl-iminium ion, which is reduced by a hydride reagent. Chemists have sought to develop direct strategies for a ‘higher order’ variant of this reaction via the union of an alkyl fragment with an in-situ generated all alkyl-iminium ion ^{10– 14} . However, despite more than 70 years of research, the successful realization of a ‘carbonyl alkylative amination’ has remained elusive. Herein, we report that a practical and general solution can be accomplished by the addition of alkyl-radicals to all alkyl-iminium ions. The process is facilitated by visible-light and a silane reducing agent, which, together with the other reaction components, trigger a distinct radical initiation step to establish a chain process. An attractive feature of this operationally straightforward, metal-free and modular transformation is the unbiased nature of tertiary amines that arise from the traceless union of aldehydes and secondary amines with alkyl-halides. As such, the structural and functional diversity within these classes of abundant feedstocks provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.