peri-Interactions in 1,8-bis(dimethylamino)naphthalene ortho-ketimine cations facilitate [1,5]-hydride shift: selective synthesis of 1,2,3,4-tetrahydrobenzo[h]quinazolines

Selective heterocyclization leading to 1,2,3,4-tetrahydrobenzo[h]quinazolines from ortho-ketimines of 1,8-bis(dimethylamino)naphthalene (DmanIms) under acid catalysis has been revealed. In contrast to the rather unreactive N,N-dimethylaniline ortho-ketimine, DmanIms readily undergo this transformation without an additional catalyst. This distinction in the reactivity underscores the importance of the second peri-NMe2 group in DmanIms, which facilitates a [1,5]-hydride shift and the subsequent cyclization. The cascade of peri-interactions emerging between 1-NMe2 and 8-NMe2 groups has been identified as a reason for the catalytic effect: (1) the hydrogen bond in the DmanIm dication constrains 1-NMe2 in the desired position providing proximity of reaction centers, (2) the repulsion of the lone pairs of 8-NMe2 group and unrelaxed 1-NMe2 group arising right after deprotonation process reduces the Gibbs free energy of activation (ΔG‡) for the straight hydride shift, and (3) the electrostatic interaction between 8-NMe2 and the charged N=CH2+ group in the intermediate increases the ΔG‡ for the reverse hydride shift.

Org. Biomol. Chem. 2022, 20, 4559–4568