A DFT Mechanistic\nStudy\non the Aza-Aldol Reaction\nof Boron Aza-Enolates: Relative Stability of Six-Membered Transition\nState and Its Relevance to the Coordination Mode of the Leaving Group

The\nmechanism of the aza-aldol reaction between boron aza-enolate\nand benzaldehyde is investigated by using density functional theory\ncalculations. The result shows that the <i>syn</i>-<i>E</i> isomer is preferentially formed, consistent with experimental\nobservations. The six-membered ring transition state (TS) with the\nboat form leads to the <i>E</i> isomer, while the more unstable\nchair TS does to the <i>Z</i> isomer. The preference of\nthe <i>syn</i> isomer is determined by the interactions\nbetween the substituents of aza-enolate and benzaldehyde. Structural\ndistortion and intrinsic reaction coordinate analyses of simplified\nmodel systems provide insights into the origin of the relative stability\nof the rate-determining TS with boat and chair forms. The boat TS\nis an early TS; thus, minimal structural distortions of the reactant\nare required to reach this TS. The Lewis pair interactions between\nthe boron and imine groups during B–N elimination also influenced\nthe relative stability of the TSs. This interaction involves the nitrogen\nlone pair in the boat TS, while the π(NC) orbital is\ninvolved in the chair TS. The Lewis pair with the lone pair stabilizes\nthe TS more than that with the π orbital. The boron aza-enolate\nwith 9-BBN generates an ate complex and forms C–C bonds sequentially,\nwhereas that with Bpin does not generate an ate complex and exhibits\nthe concerted formation of B–O and C–C bonds. Thus,\nthe higher electrophilicity of boron such as 9-BBN enhances the reactivity\nby facilitating the formation of the ate complex. A reaction design\nis proposed to reverse the <i>syn</i>/<i>anti</i> selectivity. Proof-of-concept DFT calculations suggested that the\nmodification of the imine group would change the relative stability\nof the boat/chair TSs and give the <i>anti</i>-product.