Open AccessAtom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes
Author(s) -
Mingyu Li,
Tianhua Tang,
Omar Apolinar,
Rei Matsuura,
Carl A. Busacca,
Bo Qu,
Daniel R. Fandrick,
Olga V. Zatolochnaya,
Chris H. Senanayake,
Jinhua J. Song,
Keary M. Engle
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.0c12565
Subject(s) - chemistry , propargyl , isomerization , catalysis , combinatorial chemistry , regioselectivity , catalytic cycle , acceptor , propargyl alcohol , ligand (biochemistry) , stereoselectivity , alkyne , organic chemistry , biochemistry , physics , receptor , condensed matter physics
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.