Comparative Computational Study on the Robinson–Gabriel Synthesis and Bischler–Napieralski Reaction: Density Functional Theory Investigation of T3P‐Mediated Ring Closure

Previously, this study reported novel and efficient methods for the Bischler–Napieralski and Robinson–Gabriel reactions of tryptamides under microwave conditions using propylphosphonic anhydride (T3P). Furthermore, it presents the first computational study on Bischler–Napieralski reaction of N b ‐benzoyltryptamine with T3P leading to 1‐phenyl‐3,4‐dihydro‐β‐carboline. Here, it provides the detailed comparison of both T3P promoted reactions that actually lead to different products in case of a small change in the substrate. To reveal the effect of the substrate structure, density functional theory (DFT) computations have been performed on the two model tryptamides leading to three different product molecules. The computed mechanistic pathways correspond to the experimental observations and explain why the oxoalkyl tryptamide derivative selectively reacts in a Robinson–Gabriel cyclization (highest activation Gibbs free energy is 194.9 kJ mol −1 ) and does not give any Bischler–Napieralski product (highest activation Gibbs free energy of the pathway is 269.4 kJ mol −1 ). It can also be understood why high temperature is required for both reactions. It is the first occasion in the literature that these two reactions are compared by DFT calculations.