Direct aminolysis of methyl esters with ammonia in continuous flow through Bayesian optimization†

Amides play a crucial role in the pharmaceutical, animal health and agrochemical industry. Despite the availability of various catalytic systems and coupling reagents, many methods suffered from long reaction times and poor atom economy. The direct synthesis of primary amides remained particularly challenging due to the limited availability of suitable nitrogen sources. In this study, continuous flow technology was explored as a process-intensification approach for the direct amidation of methyl esters to produce primary amides. Methanolic ammonia was employed as a nitrogen source to enhance process efficiency while circumventing the limitations of aqueous ammonia and the hazards of gaseous ammonia. Seventeen substrates were screened to assess their aminolysis reactivity under these conditions. As a proof of concept, methyl picolinate was selected for continuous flow optimization using Bayesian optimization. Therefore, a custom-designed high-pressure, high-temperature continuous flow reactor was utilized to achieve efficient, safe and scalable synthesis (200 °C, 50 bar).