4.8 Article

Pd-Catalyzed Synthesis of Densely Functionalized Cyclopropyl Vinyl Sulfides Reveals the Origin of High Selectivity in a Fundamental Alkyne Insertion Step

Journal

ACS CATALYSIS
Volume 10, Issue 17, Pages 9872-9888

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acscatal.0c02053

Keywords

alkyne insertion; regioselectivity; hydrothiolation; homogeneous catalysis; Markovnikov addition

Funding

  1. Agilent Technologies through an Agilent Fellowship

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Catalytic atom-economic hydrothiolation of cyclopropyl acetylenes was developed. Using Pd/NHC complex as a precatalyst, regioselective addition of thiols to cyclopropyl acetylenes was successfully performed, leading to densely functionalized compounds in excellent selectivity (up to 99:1) and high yields (up to 99%). Formation of Markovnikov-type products by insertion of alkyne into the Pd-S bond was confirmed experimentally. Molecular dynamics of the alkyne insertion into the Pd-S bond was performed computationally to identify key factors controlling the remarkable regioselectivity of this process. The fundamental question of how a small difference in activation energies can result in very high regioselectivity has been addressed by experimental methods combined with computational modeling. We show that the insertion of alkyne into the Pd-S bond proceeds by an asynchronous mechanism, which starts with metal-carbon binding and resolves into diverse transient structures. We further demonstrate that dynamic involvement of these structures ensures regioselectivity of the entire process, thus providing a mechanistic link that has long been missing. Alkyne insertion into the metal-heteroatom bond is a fundamental elementary step and a corner stone of catalysis and organometallic chemistry that works for a large variety of metals and heteroatoms. Mastering its Markovnikov vs anti-Markovnikov selectivity provides powerful opportunities for the design of selective functionalization routes.

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