HFIP-Mediated, Highly Chemo-, Regio-, and Stereoselective Hydrofunctionalizations of Ynamides: Access to Stereodefined Alkenes Bearing Drugs and Natural Products.

We disclose a sustainable and versatile synthetic strategy for the highly chemo-, regio-, and stereoselective hydrofunctionalizations of ynamides, through its activation by a solvent, HFIP, to access a wide variety of stereodefined ketene N , N , N , O , N , S , and N , Se acetals in high yield at room temperature. The reaction proceeded through the formation of the reactive keteniminium ion intermediate, formed via protonation at the β-carbon of ynamide by HFIP, followed by an attack of a nucleophile ( syn -addition) at the α-carbon. When ynamides are treated with only HFIP at room temperature, the HFIP addition products of ynamides are formed in a 100% atom-economic fashion; however, in the presence of a stronger N -/ O -/ S -/ Se -based nucleophile, the corresponding syn -hydroheterofunctionalized products are formed. Notably, HFIP played multiple roles, such as a reagent, in particular, a Brønsted acid, nucleophile, as well as solvent. Interestingly, HFIP is found to be unique for this transformation. Notably, this strategy is utilized for the late-stage functionalization of several marketed drugs and natural products, and it also enables the connection of two different drugs or a drug and a natural product through chemical bonds. Significantly, HFIP was recovered after the reaction and reused for consecutive reactions.