Remote N-H activation of indole aldehydes: an investigation of the mechanism, origin of selectivities, and role of the catalyst

In this study, a density functional theory (DFT) method was utilised to predict the reaction mechanism of N-heterocyclic carbene ( NHC )-catalysed remote N-H activation in indole aldehydes for the synthesis of enantiomerically enriched oxazinoindole derivatives. Simulation results indicate that the mechanism involves six energetically feasible stages: (a) chemo-selective nucleophilic addition of NHC to indole aldehydes, (b) N , N -diisopropylethylamine ( DIEA ) and protonated DIEA-assisted simultaneous proton shifts for the generation of Breslow intermediates, (c) oxidation of Breslow intermediates, (d) another DIEA -assisted intermolecular proton shift for the formation of reactive aza- o -quinone methide (aza- o -QM) analogues, (e) stereo-selective [4+2]-cycloaddition of aza- o -QM to a ketonic moiety, and (f) regeneration of NHC with simultaneous formation of the desired product. Chemo- and stereo-selectivity of the titled reaction was analysed by adopting several well-known DFT tools. Conceptual DFT-derived reactivity indices and the frontier molecular orbitals (FMOs) were analysed comprehensively to unravel the real role of NHC in this proposed catalytic cycle. Besides NHC , DIEA and DIEA-H + were found to play crucial roles in lowering the activation energy barrier of different proton transfer stages. This investigation may help in the rational designing of other NHC -catalysed novel organic transformations. Density functional theory investigation on the N-heterocyclic carbene-catalysed synthesis of oxazinoindole derivatives via N-H activation of indole aldehydes.