摘要：David J.Bernhardson, Ian Hotham,* Liam S.Sharninghausen, Robert A. Singer, and Daniel W.Widlicka

转自：康龙化成

Cu-Catalyzed Coupling of Aryl Halides Utilizing Ammonia and Hydroxypicolinamide Ligands

David J. Bernhardson, Ian Hotham,* Liam S. Sharninghausen, Robert A. Singer, and Daniel W. Widlicka

Chemical Research and Development, Groton Laboratories Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States

—Org. Process Res. Dev., 2025, doi:org/10.1021/acs.oprd.5c00101.

Recommended by Bingbing Chang_ MC5

KEYWORDS: Cu catalysis, C-N coupling (反应类型), C(sp2)-N (成键类型), aryl bromide, aryl iodide, Ammonia,amine (原料), aryl amines (产物), 6-hydroxypicolinamide, DMPS(其他)

ABSTRACT: The hydroxypicolinamide family of ligands has previously demonstrated utility in Cu-catalyzed C-N couplings and hydroxylation of heteroarylhalides. The application of these ligands has been extended to the coupling of ammonia with aryl bromides and iodides using the dimethoxy picolinamide scaffold (DMPS) ligand. By tailoring reaction conditions, Cu-DMPS provides high reactivity and selectivity toward amination over hydroxylation. Utilizing aqueous ammonia or anhydrous ammonia with K3PO4 in MeOH provides robust conversion of bromides and iodides to the corresponding aryl amines. Additionally, this catalytic system gives efficient C-N couplings with simple primary amines by using the same general reaction conditions.

Synthetic scope

Amination of aryl iodides

Ian Hotham et al. extended the utility of the hydroxypicolinamide family of ligands to amination of heteroaryl halides. DMPS was previously reported to be an effective ligand for hydroxylation; this report demonstrates that selectivity for amination over hydroxylation can be achieved with the same ligand by tailoring the reaction conditions. The development of this catalyst system has provided mild and robust reaction conditions with bromide coupling at 65 ℃and iodides at 25 ℃. Depending on the reactants, inexpensive aqueous ammoniacan be used as the ammonia source or ammonia in MeOH can be employed for anhydrous reaction conditions. These reaction conditions have been shown to be scalable up to 10 g with minimal pressure build up (20-30 psi) for bromides and general laboratory glassware can be used for iodides. The hydroxypicolinamide family of ligands may be applied and optimized for more complex substrates to directly access primary and secondary aryl amines.

来源：新浪财经