Uses
Exceptional ligands for Pd-catalyzed amination and amidation of aryl sulfonates. XPHOS is used as a regent in the synthesis of novel [1,2,4]triazolo[4,3-a]pyrazine derivatives as potential selective c-met inhibitors with improved pharmacokinetic properties.
Synthesis
Under nitrogen protection, 200 mL of tetrahydrofuran (THF) and 31 g of 2-bromo-1,3,5-triisopropylbenzene were added to a 1 L three-necked flask. The reaction mixture was cooled to 0 °C and 46 mL of a 2.5 M hexane solution of n-butyllithium was slowly added dropwise. After the dropwise addition was completed, the reaction continued to be stirred at 0 °C for 1 hour. Subsequently, 24.6 g of 1,2-dibromobenzene was slowly added dropwise at the same temperature. After completion of the dropwise addition, the reaction was continued at 0°C for 1 hour. Next, 42 mL of 2.5 M hexane solution of n-butyllithium was added dropwise to the reaction mixture at 0 °C. After the dropwise addition was completed, the reaction was continued with stirring at 0 °C for 1 hour. Then, 26.7 g of dicyclohexylphosphonium chloride was slowly added dropwise and the reaction mixture was allowed to warm up to room temperature naturally and the reaction was continued to be stirred for 2 hours. Upon completion of the reaction, 200 mL of saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction under the cooling of an ice bath. After performing phase separation, the organic phase was concentrated and crystallized by adding methanol. The solid was collected by filtration to afford 44.5 g of a white crystalline product of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl in 89% yield.
