Abstract
Design and implementation of the first (asymmetric) Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes (VCPs) with alkyl halides and aryl Grignard reagents has been realized via a mechanistically driven approach. Mechanistic studies support the diffusion of alkyl radical intermediates out of the solvent cage to participate in an intra- or intermolecular radical cascade with a range of VCPs followed by re-entering the Fe radical cross-coupling cycle to undergo (stereo)selective C(sp2)–C(sp3) bond formation. This work provides a proof-of-concept of the use of vinyl cyclopropanes as synthetically useful 1,5-synthons in Fe-catalyzed conjunctive cross-couplings with alkyl halides and aryl/vinyl Grignard reagents. Overall, we provide new design principles for Fe-mediated radical processes and underscore the potential of using combined computations and experiments to accelerate the development of challenging transformations.
Highlights
Iron-catalyzed C–C cross-coupling reactions have attracted much attention due to the higher abundance, costeffectiveness, and lower toxicity of iron in comparison to precious transition metals.[1]
More experimental studies are needed to assess the validity of the computational models, and the mechanism likely depends on subtle changes to the alkyl halide, Grignard, and ligand structures. Based on these mechanistic studies, we envisage diverting the reactivity from the Fe radical crosscoupling catalytic cycle to a programmed intra- and intermolecular radical cascade with vinyl cyclopropanes, leading to a new alkyl radical that could re-enter the catalytic cycle and undergo stereoselective C(sp2)–C(sp3) bond formation
We hypothesize that upon radical formation and in the presence of a pendant vinyl cyclopropane (Scheme 2; right), we could divert reactivity from the crosscoupling cycle to promote an intra-molecular radical cascade reaction
Summary
Iron-catalyzed C–C cross-coupling reactions have attracted much attention due to the higher abundance, costeffectiveness, and lower toxicity of iron in comparison to precious transition metals.[1]. In 2017, parallel quantum mechanical studies in our lab[23] and by Morokuma[24] were reported on the mechanism of chiral bisphosphine cross-coupling reactions between a-chloro esters and aryl Grignard reagents These studies revealed a mechanism involving halogen abstraction by an aryl Fe(I) complex, leading to an alkyl radical and halo aryl Fe(II) species (Scheme 2; circled). More experimental studies (i.e., spectroscopic and kinetic) are needed to assess the validity of the computational models, and the mechanism likely depends on subtle changes to the alkyl halide, Grignard, and ligand structures Based on these mechanistic studies, we envisage diverting the reactivity from the Fe radical crosscoupling catalytic cycle (black) to a programmed intra- and intermolecular radical cascade (red) with vinyl cyclopropanes, leading to a new alkyl radical that could re-enter the catalytic cycle and undergo stereoselective C(sp2)–C(sp3) bond formation. Given that most of the transition-metal catalyzed cascade reactions terminate with C–H bond formation[25] and fail to control the stereoselectivity at the termination step, if successful, this approach could lead to a rapid increase in molecular diversity
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