Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates

Abstract

Palladium complexes supported by (o-biphenyl)P(t-Bu)(2) (3) or (o-biphenyl)PCy(2) (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 degrees C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination.

Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and Structure–Activity Relationships

“…Not only reactions of pyridyl halides, but reactions of quinolinyl, isoquinolinyl and pyrazyl chlorides, bromides and iodides occurred in high yield with catalyst loadings (Table 1, entries 26-27 and 29-31) that are nearly two to three orders of magnitude lower than those reported for the reaction of pyridyl halides with any primary amine. 12 As one comparison, the coupling of benzylamine with 2-chloropyridine occurred in 85% yield with only 10 ppm of the catalyst, corresponding to a turnover number of 85,000 (Table 1, entry 4), whereas the same reaction conducted with 2-(di-t-butylphosphino)biphenyl occurred with 196 turnovers. 12 The steric hindrance of the catalyst did not prohibit reactions of more sterically hindered primary amines.…”

“…12 As one comparison, the coupling of benzylamine with 2-chloropyridine occurred in 85% yield with only 10 ppm of the catalyst, corresponding to a turnover number of 85,000 (Table 1, entry 4), whereas the same reaction conducted with 2-(di-t-butylphosphino)biphenyl occurred with 196 turnovers. 12 The steric hindrance of the catalyst did not prohibit reactions of more sterically hindered primary amines. tert-Butylamine reacted in good yield with 3-chloropyridine ( Enantiomerically enriched amines containing stereogenic centers α to the nitrogen have been shown to undergo racemerization in competition with cross-coupling when Pd(0) and monodendate ligands, such as P(o-tolyl) 3 or PPh 3 , were used as the catalyst.…”

“…12,13,32 Recently, this group compared the two catalyst systems for the reaction of hexylamine with 4-chlorophenol, 32 in part, to assess the importance of chelation on the amination of heteroaryl systems. This reaction conducted with the catalyzed based on Xphos occurred with faster rates and in higher yield than the one we reported using CyPF-t-Bu as ligand.…”

“…The data in this table correspond to reactions under the reported optimal conditions for each of the catalyst systems. 12,66 Reaction of 3-chloropyridine with 1.2 equiv of octylamine in the presence of 0.005 mol % of Pd(OAc) 2 /CyPF-t-Bu afforded a 92% yield of the N-octyl aminopyridine with no side product from diarylation that could be detected by GC/MS or 1 H NMR spectroscopy. In contrast, the reaction conducted with an order of magnitude more catalyst from X-phos ligand 2 (0.05 mol %) led to less than 40% conversion.…”

“…These factors have limited the use of the coupling of amines to produce less expensive intermediates and commodity building blocks. 6,7 (1) Three general classes of reagents react slowly and require high loading of catalyst, even with most of the most recently developed systems: 8 (1) primary alkylamines, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] which form substantial amounts of product from diarylation in the absence of an ortho substituent on the haloarene reagent or an excess of the primary amines; (2) heteroaryl halides, 11,12,15,17,19,[24][25][26][27][28][29][30][31][32] which are important for medicinal chemistry applications, but have reacted more slowly, with narrower scope, and with higher catalyst loadings than aryl halides; and (3) aryl iodides, which react more slowly and provide lower yields than aryl bromides in couplings with amine nucleophiles, 15,17,[33][34][35][36][37][38][39][40][41][42]…”