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

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.