Enantioselective aza-Friedel–Crafts alkylation of aniline derivatives with cyclic N-sulfonyl α-ketiminoesters: the effect of catalyst confinement and the rationale behind the high enantioselectivity

Abstract

Transition metal complex-catalyzed enantioselective aza-Friedel–Crafts alkylation of ketimines with aniline derivatives has been problematic due to the relatively low reactivity of these reactants. Herein, we will show that using structurally confined Ni(II) complexes as the catalysts, the reaction mechanism of the aza-Friedel–Crafts reactions was altered and highly efficient asymmetric aza-Friedel–Crafts alkylations of anilines with cyclic N-sulfonyl α-ketiminoesters were realized. In the presence of 0.1–0.5 mol% of nickel complex bearing structurally confined binaphthyl-proline-imidazoline-based chiral ligand L8, the reactions proceeded smoothly under mild conditions, affording the desired α-quaternary amino esters in up to 96% yield with up to 99% ee. Both N,N-disubstituted and N-monosubstituted aniline derivatives were tolerated in the transformations. Gram-scale reaction and functional group transformations of the product have been achieved. Preliminary DFT and isotope effect studies suggest that, unlike the traditional Friedel–Crafts alkylations of aromatic compounds in which the electrophilic attack on the aryl rings is the key step, aromatization of the aza-Friedel–Crafts intermediate also plays a key role in achieving high enantioselectivity in the reactions.