Selective Amination of Polyhalopyridines Catalyzed by a Palladium-Xantphos Complex

Reaction Scheme


Amination of 5-bromo-2-chloropyridine (1a) catalyzed by a palladium-Xantphos complex predominately gives 5-amino-2-chloropyridine product 3a in 96% isolated yield and excellent chemoselectivity (3a/4a-97:3). Amination of 2,5-dibromopyridine under the same conditions exclusively affords 2-amino-5-bromopyridine 4a.



5-Bromo-2-chloropyridine (1a) (250.1 mg, 1.3 mmol, 1.3 equiv.) and 1-N-Boc piperazine (2a) (186.3 mg, 1 mmol, 1.0 equiv.) were combined in the reaction flask. Dry toluene was added, followed by NaOtBu (144.0 mg, 1.5 mmol, 1.5 equiv.), Pd2(dba)3 (18.3 mg, 0.02 mmol, 0.02 equiv.) and XantPhos (34.7 mg, 0.06 mmol, 0.06 equiv.). The mixture was evacuated and purged with N2 (3 cycles), then heated to 95-100 �C under N2 for 3 hours. The conversion and selectivity were determined by HPLC analysis. After the reaction went to completion, the reaction mixture was then cooled down to room temperature, diluted with EtOAc (20 mL) and washed with water (5 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel.



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