Carbonyl Alkylative Amination

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The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes continues to stimulate enormous efforts towards their streamlined synthesis. Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl reductive amination: 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. In this regard, scientists 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 alkyl-iminium ion. However, despite more than 70 years of research, the successful realization of such a 'carbonyl alkylative amination' has remained elusive. We aim to develop a practical and general solution to this long-standing synthetic challenge, accomplished by addition of alkyl radicals to all alkyl-iminium ions. The carbonyl alkylative amination process will be mediated by the action of visible light and a silane reducing agent, establishing a chain process that permits the combination of aldehydes and secondary amines with alkyl halides. A particularly distinctive feature of this modular transformation will be the unbiased nature of tertiary amine products that arise from the traceless union of aldehyde and alkyl halide building blocks with a wide range of secondary amines. As such, the structural and functional diversity inherent within these classes of abundant feedstocks will facilitate a versatile strategy for the streamlined synthesis of complex tertiary amine products, many of which would be non-trivial to produce via currently established methods.