Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation.

Abstract

There is evidence to suggest that increasing the level of saturation (that is, the number of sp³-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline¹. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates². Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination³. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines^4-7. In particular, processes that transform accessible feedstocks into sp³-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp³)-C(sp³) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.