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

• Published in: Journal of the American Chemical Society 2021-01, Vol.143 (3), p.1598-1609
• Main Authors: Blackwell, J. Henry, Kumar, Roopender, Gaunt, Matthew J
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.0c12162

The all-alkyl α-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 α-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, α-ketoesters, and alkyl iodides to form functionally diverse all-alkyl α-tertiary amino esters. Brønsted acid-mediated in situ condensation of primary amine and α-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 α-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 α-tertiary amino esters that will likely have widespread use in academic and industrial settings.