Visible-Light-Mediated Carbonyl Alkylative Amination to All-Alkyl α-Tertiary Amino Acid Derivatives

The all-alkyl alpha-tertiary amino acid scaffold represents an important structural feature in many biologically and pharmaceutically relevant molecules. Syntheses of this class of molecule, however, often involve multiple steps and require activating auxiliary groups on the nitrogen atom or tailored building blocks. Here, we report a straightforward, single-step, and modular methodology for the synthesis of all-alkyl alpha-tertiary amino esters. This new strategy uses visible light and a silane reductant to bring about a carbonyl alkylative amination reaction that combines a wide range of primary amines, alpha-ketoesters, and alkyl iodides to form functionally diverse all-alkyl alpha-tertiary amino esters. Bronsted acid-mediated in situ condensation of primary amine and alpha-ketoester delivers the corresponding ketiminium species, which undergoes rapid 1,2-addition of an alkyl radical (generated from an alkyl iodide by the action of visible light and silane reductant) to form an aminium radical cation. Upon a polarity-matched and irreversible hydrogen atom transfer from electron rich silane, the electrophilic aminium radical cation is converted to an all-alkyl alpha-tertiary amino ester product. The benign nature of this process allows for broad scope in all three components and generates structurally and functionally diverse suite of alpha-tertiary amino esters that will likely have widespread use in academic and industrial settings.

Automated summary

This study presents a new method for the straightforward synthesis of all-alkyl alpha-tertiary amino esters in a single step, using visible light and a silane reductant to generate diverse products with broad scope of application.