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 ,, ,, ,, and , 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 (-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 -/-/-/-based nucleophile, the corresponding -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.