Organozinc pivalates for cobalt-catalyzed difluoroalkylarylation of alkenes

Installation of fluorine into pharmaceutically relevant molecules plays a vital role in their properties of biology or medicinal chemistry. Direct difunctionalization of alkenes and 1,3-dienes to achieve fluorinated compounds through transition-metal catalysis is challenging, due to the facile beta -H elimination from the Csp(3)[M] intermediate. Here we report a cobalt-catalyzed regioselective difluoroalkylarylation of both activated and unactivated alkenes with solid arylzinc pivalates and difluoroalkyl bromides through a cascade Csp(3)Csp(3)/Csp(3)Csp(2) bond formation under mild reaction conditions. Indeed, a wide range of functional groups on difluoroalkyl bromides, olefins, 1,3-dienes as well as (hetero)arylzinc pivalates are well tolerated by the cobalt-catalyst, thus furnishing three-component coupling products in good yields and with high regio- and diastereoselectivity. Kinetic experiments comparing arylzinc pivalates and conventional arylzinc halides highlight the unique reactivity of these organozinc pivalates. Mechanistic studies strongly support that the reaction involves direct halogen atom abstraction via single electron transfer to difluoroalkyl bromides from the in situ formed cobalt(I) species, thus realizing a Co(I)/Co(II)/Co(III) catalytic cycle. Transition metal-catalyzed regioselective difunctionalizations of alkenes with two different functional groups are useful for preparing organic compounds, but the construction of two new C-C bonds is challenging. Here, the authors report cobalt-catalyzed regioselective difluoroalkylarylation of alkenes with solid arylzinc pivalates and difluoroalkyl bromides, through a cascade Csp(3) Csp(3)/Csp(3) Csp(2) bond formation.

Automated summary

The installation of fluorine into pharmaceutically relevant molecules through the direct difunctionalization of alkenes and 1,3-dienes using transition-metal catalysis is challenging due to beta -H elimination from the Csp(3)[M] intermediate. This study reports a cobalt-catalyzed regioselective difluoroalkylarylation of alkenes with solid arylzinc pivalates and difluoroalkyl bromides, showcasing good yields and high regio- and diastereoselectivity. The unique reactivity of organozinc pivalates was highlighted in comparison to conventional arylzinc halides, supporting a Co(I)/Co(II)/Co(III) catalytic cycle involving direct halogen atom abstraction via single electron transfer.