Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

Selective
carbon–carbon (C–C) bond formation in chemical
synthesis generally requires prefunctionalized building blocks. However,
the requisite prefunctionalization steps undermine the overall efficiency
of synthetic sequences that rely on such reactions, which is particularly
problematic in large-scale applications, such as in the commercial
production of pharmaceuticals. Herein, we describe a selective and
catalytic method for synthesizing 1,3-enynes without prefunctionalized
building blocks. In this transformation several classes of unactivated
internal acceptor alkynes can be coupled with terminal donor alkynes
to deliver 1,3-enynes in a highly regio- and stereoselective manner.
The scope of compatible acceptor alkynes includes propargyl alcohols,
(homo)­propargyl amine derivatives, and (homo)­propargyl carboxamides.
This method is facilitated by a tailored P,N-ligand that enables regioselective
addition and suppresses secondary E/Z-isomerization of the product. The reaction is scalable and can operate
effectively with as low as 0.5 mol % catalyst loading. The products
are versatile intermediates that can participate in various downstream
transformations. We also present preliminary mechanistic experiments
that are consistent with a redox-neutral Pd­(II) catalytic cycle.