title: Mechanism for the regioselective asymmetric addition of grignard reagents to malimides: A computational exploration.
abstract: We present a systematic theoretical investigation on the addition reaction of Grignard reagents to malimides to understand its mechanism as well as the origin of its regio- and diastereo-selectivity. The computations carried out at a hybrid density functional B3LYP/6-31G* level of theory reveal that (i) the addition of Grignard reagents with N,O-dimethylmalimide (1-methyl-3-methoxypyrrolidine-2,5-dione) occurs regioselectively at the alpha-carbonyl (C1) by passing through a cis-alpha-chelated precursor and affords stereoselectively cis-addition product, in qualitative agreement with the previous experimental observations; (ii) such regioselectivity is ascribed to the preferential chelation of Grignard reagent to the alpha-carbonyl (C1) over the coordination to the alpha-carbonyl (C4); (iii) its unusual trans-addition, in sharp contrast to the Cram chelation-type stereoselectivity for the reaction of aliphatic alpha- or beta-alkoxy carbonyl compounds, is due primarily to the rigidity of the five-membered ring skeleton of the malimide that favors the formation of the cis-alpha-chelated precursor; and (iv) poor regioselectivity is predicted for the reaction of O-TBDMS-protected malimide (1-benzyl-3-(tert-butyldimethylsilyloxy)pyrrolidine-2,5-dione) with Grignard reagent and can be ascribed to the large steric repulsion of the bulky TBDMS group and the electronic effects of the silyl group that remarkably destabilizes the alpha-chelated precursors and the corresponding transition states.
authors.affiliation: Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Ye
authors.forename: Pei-Qiang
authors.initials: PQ
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Lu