Environmentally Friendly Synthesis of Indoline Derivatives using Flow‐Chemistry Techniques

Abstract

Flow chemistry proved to be a valuable technique to improve the synthesis route to melanin‐concentrating hormone receptor 1 (MCHr1) antagonists with the 1 H ,2 H ,3 H ,4 H ,5 H ‐[1,4]diazepino[1,7‐ a ]indole scaffold. A one‐step route for the heterogeneous catalytic hydrogenation of ethyl 4‐(2‐nitrophenyl)‐3‐oxobutanoate for the synthesis of ethyl 2‐(2,3‐dihydro‐1 H ‐indol‐2‐yl)acetate was developed, and the use of common reducing chemicals was avoided. N ‐Alkylation of the indoline nitrogen atom was also optimized by using a purpose‐built flow reactor and by design of experiment (DoE). Applying an optimal set of parameters allowed us to decrease the amount of carcinogenic 1,2‐dibromoethane used by a factor of 10. Additionally, nearly complete conversion was achieved in a fraction of the original reaction time (30 min vs. 4 d); therefore, the productivity (space‐time yield) of the flow‐reactor system was proven to be ca. 200 times higher than that of the batch process.