Anti-Markovnikov alcohols via epoxide hydrogenation through cooperative catalysis

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Science  24 May 2019:
Vol. 364, Issue 6442, pp. 764-767
DOI: 10.1126/science.aaw3913

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Markovnikov falls to chromium and titanium

Ring opening of strained triangular epoxides is a versatile method for making alcohols. However, these reactions are limited by their tendency to leave the oxygen on the more heavily substituted carbon, in accord with the Markovnikov rule. Yao et al. now show that a pair of catalysts working cooperatively can invert this selectivity pattern. A titanium catalyst pries the ring open while a chromium catalyst activates and delivers hydrogen. In an unusual mechanistic twist, the chromium complex appears to deliver a hydrogen atom, a proton, and an electron at different stages of the cycle.

Science, this issue p. 764


The opening of epoxides typically requires electrophilic activation, and subsequent nucleophilic (SN2) attack on the less substituted carbon leads to alcohols with Markovnikov regioselectivity. We describe a cooperative catalysis approach to anti-Markovnikov alcohols by combining titanocene-catalyzed epoxide opening with chromium-catalyzed hydrogen activation and radical reduction. The titanocene enforces the anti-Markovnikov regioselectivity by forming the more highly substituted radical. The chromium catalyst sequentially transfers a hydrogen atom, proton, and electron from molecular hydrogen, avoiding a hydride transfer to the undesired site and resulting in 100% atom economy. Each step of the interconnected catalytic cycles was confirmed separately.

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