Exploring the Role of Aminocatalysis in the Dearomatization and Regioselectivity of Heteroaromatic Aldehydes.

ABSTRACT

Heteroaromatic aldehydes have recently received a lot of attention as a scaffold for aminocatalytic functionalization as they allow for the construction of remote stereocenters and highly complex heterocyclic compounds. In this paper, we employ computational methods (M06-2X/cc-pVTZ//M06-2X/6-31 + G(d,p) and MP2/cc-pVTZ//M06-2X/6-31 + G(d,p)) to examine the abilities of secondary amines to activate several model heteroaromatic aldehydes by promoting loss of aromaticity and formation of the reactive trienamine intermediate. The hyperhomodesmotic equations used to assess the energy penalty for dearomatization show that the formation of the iminium ion decreases the energy cost for dearomatization, especially when X = O and S. Furthermore, we also investigated the role that the catalyst and heteroatom may have on the orbital coefficients of the various positions of the trienamine intermediary in order to better understand and/or predict the regioselectivity these systems may showcase. Synergistic effects between the catalyst and the heteroatom of the aromatic ring were observed to increase electron density at the most remote positions of several of the model systems studied.