Regio- and Stereoselective Hydroalkynylation of Internal Alkynes with Terminal Alkynes by Half-Sandwich Rare-Earth Catalysts

The regio- and stereoselective hydroalkynylation of internal alkynes with terminal alkynes is of great interest and importance as a straightforward route for synthesizing multisubstituted 1,3-enynes. However, this transformation often suffers from regio- and stereoselectivity issues when working with unsymmetrical internal alkynes. Herein, we report for the first time the regio- and syn-stereoselective hydroalkynylation of a variety of heteroatom-functionalized unsymmetrical internal alkynes including homopropargyl ethers, thioethers, and tertiary amines with terminal alkynes by half-sandwich rare-earth catalysts. This protocol provides an atom-efficient and straightforward route for the synthesis of a new family of heteroatom (O, S, or N)-functionalized 1,3-enynes, featuring 100% atom-efficiency, broad substrate scope, and high regio- and syn-stereoselectivity (>19:1 r.r. and >19:1 syn/anti). The mechanistic details have been elucidated by deuterium-labeling experiments, control experiments, and isolation and transformations of key reaction intermediates, revealing that the reaction proceeded through the C(sp)-H deprotonation of a terminal alkyne by a half-sandwich scandium alkyl species to form a catalytically active dimeric half-sandwich scandium tetraalkynyl species followed by heteroatom-assisted insertion of internal alkyne into the Sc-alkynyl bond and the subsequent protonolysis of the resulting Sc-alkenyl bond with another terminal alkyne molecule. The coordination of the heteroatom (O, S, or N) of internal alkynes to the catalyst metal center plays a critically important role in achieving a high level of reactivity and regio- and stereoselectivity. Remarkably, the catalytically active dimeric half-sandwich scandium tetraalkynyl species can be recovered and reused, constituting the first example of a recyclable catalyst system for the hydroalkynylation of internal alkynes.