Environment-Friendly Synthesis of Indoline Derivates Using Flow Chemistry Techniques

Flow chemistry proved to be a valuable technique to improve the discovery chemistry route to melanin-concentrating hormone receptor 1 (MCHr1) antagonists with 1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole scaffold. Novel, one-step heterogeneous catalytic hydrogenation for the synthesis of ethyl 2-(2,3-dihydro-1H-indol-2-yl) acetate was developed from ethyl 4-(2-nitrophenyl)-3-oxobutanoate to avoid commonly used reducing chemicals. The N-alkylation reaction of the indoline nitrogen was also optimised using a purpose-built flow reactor and design of experiments. Applying the optimal set of parameters allowed us to decrease almost ten-fold the excess of carcinogenic 1,2-dibromoethane. Additionally, nearly complete conversion was achieved in a fraction of the original reaction time (30 min vs. 4 days); therefore, the productivity (space time yield) of the flow reactor system is proved to be ca. 200 times more than the batch process.