On the Regioselectivity of the Gould–Jacobs Reaction: Gas‐Phase Versus Solution‐Phase Thermolysis

A detailed investigation of the regioselectivity in the thermal cyclization of (pyridyl)aminomethylenemalonates both in the gas- and solution phase is presented. Flash vacuum pyrolysis (FVP) as a gas-phase thermolysis technique is used to study the Gould-Jacobs reaction at temperatures between 450-650 degrees C, while different solution-phase heating techniques (reflux, microwave, and continuous flow) were employed at 260-350 degrees C. Depending on the position of the substituent in the pyridine moiety and the applied thermolysis technique, the regioselectivity of the cyclization can be controlled either in favor of the kinetic (pyridopyrimidinone) or the thermodynamic (naphthyridinone) product. Under FVP conditions, 6-substituted pyridopyrimidinones were obtained in high regioselectivity, which was not demonstrated before under standard Gould-Jacobs reaction conditions. DFT calculations have been additionally performed to provide further insights into the mechanistic pathways of this specific Gould-Jacobs reaction.