2025/12/09 by James A. Schwindeman, Alex Kosanovich, Timothy Kwok +7 · 1 voice
Chemistry · Engineering · Environmental Science · #Advanced Physical and Chemical Molecular Interactions #Chemistry and Chemical Engineering #Innovative Microfluidic and Catalytic Techniques Innovation
paper · pdf · doi:10.1021/acs.oprd.5c00473
openalex created_date 2025/12/09 · openalex publication_date 2025/12/09 · openalex updated_date 2026/07/22
Nitrogen insertion has emerged as a powerful strategy for converting five-membered rings into six-membered nitrogencontaining heterocycles.Morandi and co-workers from Switzerland reported a continuous-flow adaptation of their previously developed nitrogen insertion methodology, addressing the safety and scalability limitations associated with the batch process (Chem.Commun., DOI: 10.1039/d5cc03194j).A key factor for success is the in situ formation of ammonium carbonate by combining methanolic ammonia with gaseous carbon dioxide, along with the establishment of a Taylor flow regime that prevents clogging caused by solid accumulation.To enable rapid fine-tuning of conditions for each substrate, the authors designed a modular six-feed flow setup, including two feeds dedicated to in-line quenching (dibutyl sulfide and nitrogen).A broad range of five-membered heterocycles, such as TBS-protected indoles and pyrroles as well as indenes and cyclopentadienes, were successfully converted into the corresponding azaarenes in modest to high yields.The method also tolerates various functional groups such as halogens, amides, and alcohols, and its scalability was demonstrated by a gram-scale synthesis example.