Nickel-Catalyzed Reductive Coupling of γ-Metalated Ketones with Unactivated Alkyl Bromides

Abstract

A nickel-catalyzed reductive cross-coupling reaction of aryl cyclopropyl ketones with easily accessible unactivated alkyl bromides to access aryl alkyl ketones has been developed. This strategy facilitates access to various of γ-alkyl-substituted ketones via ring opening of cyclopropyl ketones (26 examples, 50–90% yield). Initial mechanistic studies revealed that the reaction proceeds via radical cleavage of the alkyl bromide.

Nickel-Catalyzed Cross-Electrophile Coupling of 1,2,3-Benzotriazin-4(3H)-ones with Aryl Bromides

“…Motivated by our previous studies on nickel-catalyzed cross-electrophile coupling reactions, ,, we initiated our research by choosing Ni(COD) 2 /bipy as catalyst precursors and 3-methylbenzo[ d ][1,2,3]triazin-4(3 H )-one 1a and bromobenzene 2a as model substrates. Zn powder was employed as the reductant, with N,N -dimethylacetamide (DMA) as the solvent at 60 °C for 12 h. We were pleased to find that the denitrogenative ortho -arylated product 3aa was produced in 56% isolated yield (Table , entry 1).…”

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

“…While nickel complexes with electron-rich, monodentate ligands promote oxidative addition of cyclopropyl ketones to form metalacyclic intermediates that are useful in ring-expansion reactions with unsaturated π-systems, these metalacyclic intermediates appear to be unreactive for Negishi crosscoupling reactions 9−13 and only couple with alkyl radicals to form monofunctionalized products. 75,76 Other mechanistic approaches, such as photoredox and metalloradical ringopening, 19−22 have not yet been demonstrated to afford net difunctionalized products. Fujisawa reported the first example of net ring-opening difunctionalization of cyclopropyl ketones, using Ni(acac) 3 as the catalyst without any added ancillary ligand (Scheme 2B).…”

“…Sterically hindered zinc reagents, such as orthosubstituted arylzincs and 2°alkyl zinc reagents, coupled in low yields under these conditions. Comparison with related ringopening alkylations that proceed via nickeladihydropyran (Scheme 4C), reported after our initial disclosure of these results, 27,75,76 are informative on how mechanistic differences can lead to differences in reactivity and scope. Those reactions are able to couple alkyl bromides instead of alkylzinc reagents, but are limited to monofunctionalization (γ-functionalization) of aryl cyclopropyl ketones.…”

“…Those reactions are able to couple alkyl bromides instead of alkylzinc reagents, but are limited to monofunctionalization (γ-functionalization) of aryl cyclopropyl ketones. 75,76 We anticipate that future studies will shed further light on how these differences arise and how existing limitations might be overcome.…”

Iron-Catalyzed Reductive Ring Opening/gem-Difluoroallylation of Cyclopropyl Ketones

“…Therefore, only specific types of cyclopropyl ketones, such as nonsubstituted, β,β-disubstituted, and β-aryl substituted ones, are suitable substrates for highly regioselective ring opening reactions. In the past decade, considerable efforts by organic chemists have been devoted to developing highly regioselective ring opening/expansion reactions of cyclopropyl ketones under mild conditions, and two complementary strategies regarding the regiocontrol have been established: (1) ring opening initiated by oxidative addition with a low-valent metal, in which the less-substiuted site of the cyclopropane is favored due to steric hindrance; − (2) ketyl radical-mediated ring opening reactions, in which the more-substituted site of the cyclopropane is preferred owing to the generation of more stable carbon-centered radicals (Scheme A). − Relying on the latter strategy, Yoon et al developed lanthanide/photococatalyzed regio- and stereoselective [3 + 2] cycloaddition of cyclopropyl ketones and olefins. , A similar enantioselective variant was reported by Lin et al using a chiral redox-active Ti-salen complex as the catalyst . Furthermore, Procter et al successfully applied phenyl acetylenes as the coupling partner in the samarium-catalyzed diastereoselective [3 + 2] cycloaddition with cyclopropyl ketones .…”