I. Hotham et al, Org. Process Res. Dev. 2025, 29, 1554–1559
https://doi.org/10.1021/acs.oprd.5c00101
The standard go-too method for coupling ammonium salts and ammonia or ammonia surrogates with aryl halides is palladium catalysis. Copper catalysis has become much more competitive over the past few years, driven largely by the development of activating ligands. A recent paper by Hotham and a team at Pfizer describes a detailed investigation into the Cu-catalysed coupling of aryl halides with ammonia and primary amines using hydroxypicolinamide ligands, in particular the the dimethoxy picolinamide scaffold (DMPS). The ligand family was previously applied to Cu-mediated C–N and C–O bond formation; here, its utility is extended to amination using either aqueous or anhydrous ammonia. The DMPS ligand was identified using a comprehensive ligand screen focusing on optimal conversion and selectivity for C–N coupling over competing hydroxylation. Further optimisation yielded a high yielding reaction with low Cu loading (1-2 mol%). The protocol tolerates a wide range of (hetero)aryl bromides and iodides, including electron-rich, electron-deficient, and sterically hindered substrates, as well as various functional groups. Selective activation of aryl iodides over other halides was observed under mild conditions (25 °C). The system was shown to be applicable to other small primary amines and was demonstrated on multigram scale with minimal pressure build-up, The paper suggeststhat electronic and steric features of the DMPS ligand contribute to its efficacy, potentially through secondary coordination effects. This represents an operationally simple approach to aryl amines via Cu-catalysed C–N coupling.
- Cu-mediated Ullmann-type cross-coupling and industrial applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes: D. Ma et al, Org. Process Res. Dev. 2022, 26, 1690–1750
- Palladium-catalyzed amination of aryl halides with aqueous ammonia and hydroxide base enabled by ligand development: J. Hartwig et al, J. Am. Chem. Soc. 2024, 146, 19414–19424
- Cu-catalyzed couplings of heteroaryl primary amines and (hetero)aryl bromides with 6-hydroxypicolinamide ligands: R. Singer et al, Org. Process Res. Dev. 2019, 23, 1538–1551
