Reductive Aza-Pauson-Khand Reaction of Nitriles

• Published in: Journal of the American Chemical Society Vol. 145; no. 19; pp. 10463 - 10469
• Main Authors: Huang, Hong-Gui, Zheng, Yu-Qing, Zhong, Dayou, Deng, Jiang-Lian, Liu, Wen-Bo
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17-05-2023
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.3c01656

γ-Lactams are valuable heterocycles in synthetic chemistry and drug development. Here, we report a reductive aza-Pauson-Khand reaction (aza-PKR) of an alkyne, a nitrile, and Co2(CO)8. A wide array of bicyclic α,β-unsaturated γ-lactams containing two adjacent stereocenters, including an all-carbon quaternary center, from alkyne-tethered malononitriles are efficiently accessed in high diastereoselectivity. Preliminary mechanistic investigations by experiments and DFT calculations reveal that the reaction undergoes an aza-PKR process followed by a in situ reduction. The reducing reagent generated in situ from water also provides a practical tool for deuterium incorporation into the γ-position of lactams using D2O as the deuterium source. This study represents a new mode for [2 + 2 + 1] cycloaddition that enables the direct use of nitrile in aza-heterocycle synthesis.