转自：康龙化成

Efficient Aminations of Aryl Halides by a Cu(II) Catalyst

Christina N. Pierson, Teresa Horak, Willi M. Amberg, Ritwika Ray, Guodong Rao, Timothy M. Pinkhassik, Serena M. Fantasia, Stephan M. Rummelt, Kurt Püntener, R. David Britt, and John F. Hartwig*

Department of Chemistry, University of California, Berkeley, California 94720, United States

—J. Am. Chem. Soc., 2025, doi:org/10.1021/jacs.5c05210.

Recommended by Bingbing Chang_MC5 and Shi Li_MOC

KEYWORDS:Cu catalysis, C-N coupling (反应类型), C(sp2)-N (成键类型), aryl bromide, hydrazine hydrate, amines (原料), aryl amines (产物)

ABSTRACT:Aminations of aryl halides catalyzed by copper complexes with ancillary ligands have become valuable for the formation of anilines, and the mechanisms for these reactions have been shown to occur by a Cu(I)/(III) cycle. Prof. John F. Hartwig et al. show that the coupling of aryl and heteroaryl bromides with a range of nitrogen nucleophiles, including hydrazine hydrate and complex amines, occurs with copper and a simple dianionic, dimethylpyrrole-based oxalohydrazido ligand by a cycle in which Cu(II) complexes of this ligand are the resting state and an active, low-valent, catalytic intermediate. These couplings involving Cu(II) occur in many cases with just 0.1−0.2 mol % catalyst and take place under air, due to the absence of Cu(I) that is less stable to disproportionation and to air. Kinetic profiles and EPR spectroscopy of reactions initiated with Cu(I) and Cu(II) precursors provide strong evidence that both systems react through an active Cu(II) complex, thereby indicating that a recently uncovered mechanistic manifold for copper-catalyzed couplings of phenoxides with oxalamide ligands is also followed for the coupling of nitrogen nucleophiles catalyzed by copper complexes of oxalohydrazido ligands.

Background

Optimization of the reaction conditions

Synthetic scope

Proposed mechanism

Prof. John F. Hartwig et al. reported a Cu(II)-catalyzed amination of aryl and heteroaryl halides with a variety of nitrogen nucleophiles, including primary amines and hydrazine hydrate, under exceptionally low catalyst loadings and operationally simple conditions.The process employs a dianionic dimethylpyrrole-based oxalohydrazido ligand to stabilize Cu(II) species, enabling couplings to proceed under air with broad functional group tolerance and high turnover numbers. Mechanistic investigations, including kinetic studies and EPR spectroscopy, provided strong evidence for a catalytic cycle involving Cu(II) as both the resting and active species, with oxidative addition of aryl halides to Cu(II) followed by reductive elimination to form C-N bonds. The methodology demonstrated excellent scalability and was applied to the synthesis of medicinally relevant compounds, such as flupirtine and bromazine derivatives. The air-stable, highly active Cu(II) catalyst system offers significant advantages for industrial applications and expands the mechanistic understanding of copper-catalyzed cross-coupling reactions.

（转自：康龙化成）