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

preprint
submitted on 15.10.2020 and posted on 16.10.2020 by Mingyu Liu, Tianhua Tang, Omar Apolinar, Rei Matsuura, Carl Busacca, Bo Qu, Daniel Fandrick, Olga Zatolochnaya, Chris Senanayake, Jinhua Song, Keary Engle
Selective carbon–carbon (C–C) bond formation in chemical synthesis generally requires pre-functionalized building blocks. However, the requisite pre-functionalization steps undermine the efficiency of multi-step synthetic sequences, 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 pre-functionalized building blocks. This method is facilitated by a tailored P,N-ligand that enables regioselective coupling and suppresses secondary E/Z-isomerization of the product. The transformation enables several classes of unactivated internal acceptor alkynes to 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. The reaction is scalable and can operate effectively with 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.

Funding

NIH-R35GM125052

NSF-DBI-1759544

NSF-DGE-1842471

Honjo International Scholarship

Nankai University College of Chemistry for an International Research Scholarship

History

Email Address of Submitting Author

keary@scripps.edu

Institution

The Scripps Research Institute

Country

USA

ORCID For Submitting Author

0000-0003-2767-6556

Declaration of Conflict of Interest

No conflict of interest.

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