Development of a Mild and Efficient Process for Ir-Catalyzed N‑Alkylation of 4‑Bromopyridin-2-amine with a Primary Alcohol via Borrowing Hydrogen

• Published in: Organic process research & development Vol. 28; no. 8; pp. 3414 - 3422
• Main Authors: Nimmagadda, Sri Krishna, Kalidindi, Srinivas, Bondigela, Siva Sankar, Korapati, Satish, Dasgupta, Debottam, Malik, Noormohamed Abdul, Rao, Prakasa, Maity, Prantik, Coombs, John R., Hay, Michael, Simmons, Eric M., Mukherjee, Sabuj, Vaidyanathan, Rajappa, Eastgate, Martin D., González-Bobes, Francisco
• Format: Journal Article
• Language: English
• Published: American Chemical Society 16-08-2024
• Subjects: C−N bond formation; borrowing hydrogen; hydrogen autotransfer; N-alkylation
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.4c00269

We report herein the development and scale up of an Ir-catalyzed N-alkylation reaction between a 4-bromopyridin-2-amine (1) and (4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)­bicyclo[2.2.2]­octan-1-yl)­methanol (2) proceeding via a borrowing hydrogen process. The traditional approach of alcohol oxidation followed by reductive amination posed challenges that are attributed to the poor nucleophilicity of the 2-aminopyridine derivative (1) resulting in lower isolated yields. Several catalysts and bases were evaluated for the successful N-alkylation of 1 with 2, and an Ir (III) catalyst in combination with LiOt-Bu as a base was found to provide optimal conversion. The borrowing hydrogen process was successfully demonstrated on a 1.5 kg scale and afforded >70% yield of 3 without the need for a sealed reactor or any other specialized equipment.