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Tailored quinones support high-turnover Pd catalysts for oxidative C–H arylation with O2

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Science  18 Dec 2020:
Vol. 370, Issue 6523, pp. 1454-1460
DOI: 10.1126/science.abd1085

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A subtle balancing act for quinones

Palladium catalysis is widely used in drug synthesis to form carbon-carbon bonds, but typically both carbon centers need to be activated ahead of time. Although introducing oxygen as an oxidant diminishes the need for preactivation, the catalysis then tends to be less efficient, especially in the case of arene coupling. Salazar et al. pinpointed the role of quinone co-catalysts in these processes and determined that after accelerating carbon-carbon bond formation, the quinone slows down catalyst reoxidation by oxygen. Appending bulky substituents to the quinone struck a better balance and substantially enhanced catalytic efficiency.

Science, this issue p. 1454

Abstract

Palladium(II)-catalyzed carbon-hydrogen (C–H) oxidation reactions could streamline the synthesis of pharmaceuticals, agrochemicals, and other complex organic molecules. Existing methods, however, commonly exhibit poor catalyst performance with high palladium (Pd) loading (e.g., 10 mole %) and a need for (super)stoichiometric quantities of undesirable oxidants, such as benzoquinone and silver(I) salts. The present study probes the mechanism of a representative Pd-catalyzed oxidative C–H arylation reaction and elucidates mechanistic features that undermine catalyst performance, including substrate-consuming side reactions and sequestration of the catalyst as an inactive species. Systematic tuning of the quinone cocatalyst overcomes these deleterious features. Use of 2,5-di-tert-butyl-p-benzoquinone enables efficient use of molecular oxygen as the oxidant, high reaction yields, and >1900 turnovers by the Pd catalyst.

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