Premium
Environmentally Friendly Synthesis of Indoline Derivatives using Flow‐Chemistry Techniques
Author(s) -
Örkényi Róbert,
Beke Gyula,
Riethmüller Eszter,
Szakács Zoltán,
Kóti János,
Faigl Ferenc,
Éles János,
Greiner István
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201700849
Subject(s) - chemistry , flow chemistry , indoline , yield (engineering) , alkylation , catalysis , indole test , combinatorial chemistry , organic chemistry , environmentally friendly , thermodynamics , ecology , physics , biology
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.