Abstract
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 β-H elimination from the Csp3‒[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 Csp3‒Csp3/Csp3‒Csp2 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.
Highlights
Installation of fluorine into pharmaceutically relevant molecules plays a vital role in their properties of biology or medicinal chemistry
The installation of fluorine into bioactive molecules uniquely plays a vital role in their properties of relevance to biology or medicinal chemistry[58,59,60,61,62,63], major advances in transition-metal-catalyzed fluoroalkylation have been achieved in recent years[64,65,66,67,68]
We initiated our studies by optimizing reaction conditions for the envisioned cobalt-catalyzed regioselective three-component coupling of alkenylarene (2a) with bromodifluoroacetate (1a) and phenylzinc pivalate (3a, PhZnOPiv)
Summary
Installation of fluorine into pharmaceutically relevant molecules plays a vital role in their properties of biology or medicinal chemistry. These organozinc reagents, including (hetero)aryl[17,18,19,20,21,22], alkynyl[23,24], and alkyl zinc pivalates[25], exhibited good reactivity in Pd-catalyzed cross-coupling reactions with unsaturated halides, which further proved to be broadly applicable for the late-stage functionalizations of biologically active molecules[26].
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