Abstract
Despite remarkable recent advances in transition-metal-catalyzed C(sp3)−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary-C(sp3)−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp3) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert-alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials.
Highlights
Despite remarkable recent advances in transition-metal-catalyzed C(sp3)−C cross-coupling reactions, there remain challenging bond formations
A selection of alkyl halides was employed to react with α-trifluoromethylstyrene 2a
Mn proved superior to Zn, B2pin[2], diethoxymethylsilane and HCOONa, which are commonly employed in reductive cross-coupling reactions (Supplementary Table 4)
Summary
Despite remarkable recent advances in transition-metal-catalyzed C(sp3)−C cross-coupling reactions, there remain challenging bond formations. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis This strategy is complementary to the existing coupling protocols with tert-alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from available starting materials. With our continuing interest in remote functionalization, we have uncovered a mechanistically distinct and highly regioselective migratory 3,3-difluoroallylation[68,69,70,71] of unactivated alkyl bromides at tertiary carbon centers This undirected tert-C(sp3)−H functionalization nicely complements existing methods for all-carbon quaternary center construction, especially when tertiary alkyl halide/metal reagents are not readily available or not stable. We demonstrate that unactivated primary and secondary alkyl bromides are competent precursors for generating tertiary alkyl coupling partners via Ni–H-mediated chain-walking (Fig. 1e)
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