Theoretical investigations toward TMEDA-catalyzed [2 + 4] annulation of allenoate with 1-aza-1,3-diene: mechanism, regioselectivity, and role of the catalyst

Abstract

A theoretical investigation on the mechanisms as well as regioselectivity of N,N,N′,N′-tetramethylethane-1,2-diamine (TMEDA)-catalyzed [2 + 4] annulation of allenoate with 1-aza-1,3-diene leading to functionalized pyridines has been performed using density functional theory (DFT). Multiple possible reaction pathways (A–C) have been characterized, and the most favorable pathway C is remarkably different from the mechanism (i.e. pathway A) proposed in Angew. Chem., Int. Ed., 2013, 52, 8584. Generally, there are several steps in the entire catalytic cycle, including activation of allenoate by TMEDA, nucleophilic attack to 1-aza-1,3-diene, intramolecular cyclization, 1,3-hydrogen shift, hydrogen elimination by TMEDA and desulfonation. In pathway A, the 1,3-hydrogen shift is rate-limiting and takes place before the intramolecular cyclization. In the alternative pathway C, cyclization takes place before the 1,3-hydrogen shift, and it is found that TMEDA can function as a proton shuttle to mediate the 1,3-hydrogen shift and lower the energy barrier significantly. The results presented here demonstrate that the catalyst TMEDA can not only serve as a Lewis base to activate allenoate, but also as a Brønsted acid/base to mediate the 1,3-hydrogen shift process, thus accelerating the reaction. Furthermore, the observed regioselectivity is attributed to the more developed negative charge on the α carbon atom of activated allenoate, the stronger C–H⋯π interaction, as well as hydrogen bond interaction between the two fragments. We believe that the present work is helpful to understand the multiple competing pathways for amine-catalyzed annulation reactions of allenoates with electrophiles, and provides valuable insights for predicting the regioselectivity for this kind of reaction.