3-溴-4-碘三氟甲苯

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A microwave vial was charged with INTERMEDIATE M (0.573 g, 1.372 mmol), Xantphos (0.159 g, 0.274 mmol), 2-bromo-1-iodo-4-trifluoromethyl-benzene (0.722 g, 2.059 mmol), Pd2(dba)3 (0.126 g, 0.137 mmol) and sodium tert-butoxide (0.264 g, 2.74 mmol). The mixture was diluted with toluene (13.72 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 30 minutes. The reaction was diluted with water, and washed with DCM. The organics were dried using a phase separator, and concentrated under a vacuum. The material was then purified via silica gel MPLC, eluting with 0 to 50% ethyl acetate in heptanes to yield 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light yellow solid. purged with nitrogen The reaction was diluted with water washed with DCM The organics were dried concentrated under a vacuum The material was then purified via silica gel MPLC eluting with 0 to 50% ethyl acetate in heptanes

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A microwave vial was charged with INTERMEDIATE M (0.573 g, 1.372 mmol), Xantphos (0.159 g, 0.274 mmol), 2-bromo-1-iodo-4-trifluoromethyl-benzene (0.722 g, 2.059 mmol), Pd2(dba)3 (0.126 g, 0.137 mmol) and sodium tert-butoxide (0.264 g, 2.74 mmol). The mixture was diluted with toluene (13.72 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 30 minutes. The reaction was diluted with water, and washed with DCM. The organics were dried using a phase separator, and concentrated under a vacuum. The material was then purified via silica gel MPLC, eluting with 0 to 50% ethyl acetate in heptanes to yield 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light yellow solid. purged with nitrogen The reaction was diluted with water washed with DCM The organics were dried concentrated under a vacuum The material was then purified via silica gel MPLC eluting with 0 to 50% ethyl acetate in heptanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared from 4-methyl-benzenethiol and 3-bromo-4-iodo-benzotrifluoride.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-1-iodo-4-trifluoromethyl-benzene.

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of tris(dibenzylidene)dipalladium(0) (Pd2dba3, 0.183 g, 0.2 mmol) and bis(2-diphenylphosphinophenyl)ether (DPEphos, 0.215 g, 0.2 mmol) in toluene (80 mL) was added 3-bromo-4-iodobenzotrifluoride (7.02 g, 20 mmol; prepared from 2-bromo-4-trifluoromethyl-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753), 4-chlorothiophenol (2.89 g, 20 mmol) and potassium tert-butoxide (2.46 g, 22 mmol) at room temperature (rt). The reaction mixture was stirred for 2.5 h at 100° C. and then cooled to room temperature (rt) and filtered through celite. The solvent was evaporated off and the crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8) to produce 4.53 g (81%) of 1-bromo-2-(4-chloro-phenylsulfanyl)-5-(trifluoromethyl)-benzene as an oil. at room temperature (rt) cooled to room temperature (rt) filtered through celite The solvent was evaporated off the crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared from 4-methyl-benzenethiol and 3-bromo-4-iodo-benzotrifluoride.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-1-iodo-4-trifluoromethyl-benzene.

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of tris(dibenzylidene)dipalladium(0) (Pd2dba3, 0.183 g, 0.2 mmol) and bis(2-diphenylphosphinophenyl)ether (DPEphos, 0.215 g, 0.2 mmol) in toluene (80 mL) was added 3-bromo-4-iodobenzotrifluoride (7.02 g, 20 mmol; prepared from 2-bromo-4-trifluoromethyl-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753), 4-chlorothiophenol (2.89 g, 20 mmol) and potassium tert-butoxide (2.46 g, 22 mmol) at room temperature (rt). The reaction mixture was stirred for 2.5 h at 100° C. and then cooled to room temperature (rt) and filtered through celite. The solvent was evaporated off and the crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8) to produce 4.53 g (81%) of 1-bromo-2-(4-chloro-phenylsulfanyl)-5-(trifluoromethyl)-benzene as an oil. at room temperature (rt) cooled to room temperature (rt) filtered through celite The solvent was evaporated off the crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8)

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of Pd(PPh3)4 (Strem Chemicals Inc., Newburyport, Mass., 0.804 g, 0.696 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (Matrix Scientific, Columbia, S.C., 3.05 g, 8.70 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.500 g, 6.96 mmol), and potassium carbonate (4.81 g, 34.8 mmol) in 14 mL dioxane and 6 mL water was heated to 100° C. overnight. LC/MS showed about 50% conversion, so the reaction mixture was transferred to a microwave vial, and was heated to 130° C. in a microwave reactor for 3 hours. The reaction mixture was diluted with EtOAc, washed with water then brine, the organics dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 30% EtOAc/heptane) gave tert-butyl 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.73 g, 5.98 mmol). washed with water brine, the organics dried over MgSO4 concentrated Purification of the resulting residue by silica gel column chromatography (0 to 30% EtOAc/heptane)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.500 g, 0.876 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (0.769 g, 2.191 mmol), potassium phosphate (0.651 g, 3.07 mmol), and PdCl2(dppf)-CH2Cl2 (0.072 g, 0.088 mmol). DMF (5.84 ml), and the vial was flushed with argon, sealed, and stirred at 60° C. for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (silica gel, gradient elution 0 to 100% EtOAc:Hexanes) to afford 3-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.255 g, 0.382 mmol, 43.6% yield) as an off-white solid. m/z (ESI) 667.0 (M+H)+. DMF (5.84 ml), and the vial was flushed with argon sealed The reaction was diluted with ethyl acetate washed with water The aqueous layer was extracted with ethyl acetate the combined organic layers were washed with brine dried with sodium sulfate filtered concentrated The material was purified via column chromatography (silica gel, gradient elution 0 to 100% EtOAc:Hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of xantphos (0.277 g, 0.479 mmol), Pd2(dba)3 (0.146 g, 0.160 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (Oakwood Chemical, 1.232 g, 3.51 mmol), (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (1.000 g, 3.19 mmol), and potassium phosphate (2.032 g, 9.57 mmol) in 10 mL dioxane was heated to 90° C. for 5 hours. The reaction mixture was diluted with water and extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was used in the next step without purification. m/z (ESI) 536.0 (M+H)+. extracted with DCM The organics were dried over MgSO4 concentrated The crude residue was used in the next step without purification

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A reaction vessel was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2 sulfonamide (Intermediate E) (4 g, 7.05 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (4.95 g, 14.10 mmol) and Pd(dppf)Cl2 DCM (1.151 g, 1.410 mmol). Dioxane (35.2 mL) and t-butanol (35.2 mL) were added to the reaction mixture followed by sodium carbonate in water (1.9 M) (11.13 mL, 21.15 mmol). The reaction vial was then swept with nitrogen and sealed with a screw cap. The resulting mixture was then heated to 50° C. and stirred for 4 hours. LC/MS indicated that the product was formed. The resulting mixture was transferred to a separatory funnel containing water and the aqueous layer was washed three times with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to a dark oil which was purified by MPLC using 120 g silica gel column eluting with 0 to 70% EtOAc in heptane) to afford 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (3.27 g, 4.92 mmol) as a white solid. m/z (ESI) 685.8 [M+Na]+. sealed with a screw cap was formed The resulting mixture was transferred to a separatory funnel the aqueous layer was washed three times with DCM dried with MgSO4 filtered concentrated to a dark oil which was purified by MPLC eluting with 0 to 70% EtOAc in heptane)