Computational determination of pyrrolopyridine formation rates via the intramolecular inverse diels–alder reaction of pyrazine derivatives

A systematic computational study of the intramolecular inverse electron-demand Diels-Alder (IEDDA) reactions of 2-aminopyrazine derivatives and following retro-Diels-Alder (rDA) reactions is disclosed, including an examination of the impact of N, C3 and C6 substituents. The computations are carried out employing DFT and high-level coupled-cluster methods. The IEDDA cycloaddition transition state exhibits the highest activation barrier and is therefore the rate-determining step. N substituents were found to exhibit a remarkable impact on the cycloaddition reactivity of the 2-aminopyrazine without altering, and even more enhancing, the intrinsic cycloaddition regioselectivity. Moreover, the study revealed that the reaction can be predictably modulated by a C3 or C6 substituent and portends extensive synthetic utility for a target pyrrolopyridine scaffolds.