Development of a Safer Continuous Flow Process for B2(OH)4‑Mediated Chemoselective Reduction of Nitroarenes to Anilines

• Published in: Organic process research & development Vol. 28; no. 10; pp. 3847 - 3857
• Main Authors: Revu, Omkar, Vasilev, Maksim, Gajula, Praveen, Kalikinidi, Nageswara Rao, Gadi, Madhusudhan Reddy, Zhao, Huiping, Gamage, Shanika M. P., Hibbert, Graham, Ravikumar, Ongolu, Gummidi, Lalitha, Nasipireddy, Venkatarathnam, Vinodini, Arun, Bietsch, Jonathan, Wang, Zhirui, Brown, Jack D., Sirasani, Gopal, Armstrong, Joseph D., Gangu, Aravind S., Qu, Bo, Senanayake, Chris H.
• Format: Journal Article
• Language: English
• Published: American Chemical Society 18.10.2024
• Subjects: process safety; nitro reduction; chemoselective reduction; B2(OH)4; tetrahydroxydiboron; continuous flow chemistry
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.4c00267

Tetrahydroxydiboron [B2(OH)4] is a chemoselective reducing reagent for nitro reductions in the presence of other labile functional groups. However, there are significant process safety challenges associated with the application of this reducing reagent, including rapid heat release and thermal instability of B2(OH)4 in aprotic polar solvents. Herein, we report the development of a safer continuous flow process applying B2(OH)4-mediated chemoselective nitro reduction conditions. The safety challenges were addressed by employing continuous flow technology along with identifying a suitable protic cosolvent EtOH. Functional group tolerance toward cyano groups, halides, carboxylic acids, olefins, imines, and benzylic alcohols was demonstrated in flow with higher reaction yield compared to that in batch synthesis. The modified reaction conditions provide a potentially scalable approach to widespread applications of this key transformation for the generation of highly functionalized diversified aniline derivatives.