Identifying viable synthetic routes from side channels in automated reaction-path searches

Automated reaction-path search methods based on quantum chemical calculations from a single equilibrium structure have revolutionized the exploration of chemical reaction networks, uncovering numerous unexpected and often computationally imaginary side pathways. Although these routes have traditionally often been dismissed as unrealistic or mere byproduct-formation pathways, they represent an untapped source of novel synthetic information. Here, we propose a “network editing” strategy to systematically identify and exploit these latent pathways. In this approach, the kinetically dominant pathways are removed from the generated reaction-path network and kinetic simulations are performed on the edited network, allowing the detection of masked side reactions. Guided by these theoretical predictions, we have developed viable synthetic routes by replacing a reactive substituent with an unreactive one to deliberately trigger the formation of the desired byproduct. Case studies, including the development of an arylcarboxylation of N-allylaniline derivatives via the CO2 radical anion (CO2•−) to access five- and six-membered N-heterocycles, demonstrate how computational tools can inspire and advance contemporary synthetic organic chemistry. Automated reaction-path search methods based on quantum chemical calculations from a single equilibrium structure can provide novel synthetic information. Here, the authors propose a network editing strategy to identify masked side reactions by removing kinetically dominant pathways, demonstrating its application to the development of synthetic routes that replace a reactive substituent with an unreactive one to trigger the formation of the desired byproduct, such as the arylcarboxylation of N-allylaniline derivatives via the CO2 radical anion to access five- and six-membered N-heterocycles.