Olefin difunctionalization reactions are an essential part of the modern synthetic organic chemist’s toolkit and have been exploited for the synthesis of natural products and pharmaceutical compounds. The regiochemistry of the products is usually controlled by the steric and electronic properties of the substrate (Scheme 1a-c).<br/>In the Engle group, we recently demonstrated the use of directing groups for the regioncontrolled hydroamination, hydrochlorination and hydrocarbofunctionalization of alkenes and alkynes by intercepting a Wacker-type intermediate with a Brønsted acid. These reactions proceed in high yields under relatively mild conditions. Regiocontrol is achieved through formation of a stable, five-membered palladacyle <b>A</b>, which has been isolated and characterized by X-ray crystallography (Scheme 2a). The directing groups are easily cleavable, allowing access to a wide range of synthetically useful products. We now report that through systematic tuning of the directing group either the Markovnikov or the anti-Markovnikov product can be obtained under otherwise identical reaction condition (Scheme 2b). We attribute this regiochemical divergence to differences in stability in the putative palladacycle intermediates. These results expand the synthetic toolkit to include directed alkene/alkyne functionalization reactions that have heretofore proven elusive and lay the groundwork for the development of ligand-controlled regioselective alkene functionalization reactions.

Tuning the regioselectivity of alkene/alkyne functionalization via a directing group strategy

253rd National Meeting (2017)

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