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.