1-溴-2-碘-4-(三氟甲基)苯

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

实验步骤: A solution of Cl2Pd(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 1.157 g, 1.416 mmol), (n-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (8.76 ml, 28.3 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (9.94 g, 28.3 mmol), and potassium phosphate (36.1 g, 170 mmol) in 100 mL dioxane, 40 mL water was heated to 100° C. 3 hours. LC/MS showed complete consumption of starting material. Isoquinolin-5-ylboronic acid (4.90 g, 28.3 mmol) and Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 1.003 g, 1.416 mmol) were added, and the reaction mixture was again heated to 100° C. for an additional hour. The reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether. The organics were washed with water, then brine, dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.80 g, 21.56 mmol). 3 hours consumption of starting material to cool to room temperature The organics were washed with water brine, dried over MgSO4 concentrated Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of pd(ph3p)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-4-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 6 mL water was heated to 120° C. overnight. Additional portions of pyridin-4-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. The reaction mixture was then poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (3.054 g, 10.11 mmol, 41.4% yield) as a white solid. [M+H]+=303.9 was extracted with DCM The organics were then concentrated Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane)

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

实验步骤: A solution of Cl2Pd(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 1.157 g, 1.416 mmol), (n-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Maybridge Chemicals, Cornwall, UK, 8.76 ml, 28.3 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (Combi-Blocks, San Diego, Calif., 9.94 g, 28.3 mmol), and potassium phosphate (36.1 g, 170 mmol) in 100 mL dioxane and 40 mL water was heated to 100° C. for 3 hours. LC/MS showed clean conversion to tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate. To the resulting mixture was added isoquinolin-5-ylboronic acid (Sigma-Aldrich, St. Louis, Mo., 4.90 g, 28.3 mmol) and Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 1.003 g, 1.416 mmol). The reaction mixture was again heated to 100° C. an additional hour before the reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether. The organics were washed with water, then brine, dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.80 g, 21.56 mmol). to cool to room temperature The organics were washed with water brine, dried over MgSO4 concentrated Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane)

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

实验步骤: A solution of 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.408 ml, 8.55 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific, Logan, Utah, 2.78 g, 8.98 mmol), Pd(dppf)Cl2—CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 0.349 g, 0.427 mmol), and potassium carbonate (2.052 g, 34.2 mmol) in dioxane (32.1 ml) and water (10.69 ml) was stirred at 70° C. for three hours. (LC-MS MH+ 430.1) 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 dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (silica gel 80 g, gradient elution 0 to 100% Et2O:Heptane) to afford tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (2.54 g, 6.25 mmol) as a light yellow oil. [M+H]+=428.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.69 (d, J=8.3 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.41-7.36 (m, 1H), 5.69 (br. s., 1H), 4.08 (q, J=2.7 Hz, 2H), 3.66 (t, J=5.6 Hz, 2H), 2.48-2.40 (m, 2H), 1.52 (s, 9H) washed with water The aqueous layer was extracted with ethyl acetate the combined organic layers were dried with sodium sulfate filtered concentrated The material was purified via column chromatography (silica gel 80 g, gradient elution 0 to 100% Et2O:Heptane)

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

实验步骤: A 75-mL pressure vessel was charged with 1-bromo-2-iodo-4-(trifluoromethyl)benzene (2.015 g, 5.74 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, St. Louis, Mo., 1.374 g, 6.60 mmol), potassium phosphate (2.438 g, 11.48 mmol), and PdCl2(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 0.469 g, 0.574 mmol). The vessel was flushed with Ar (g), then DMF (19.14 ml) was added. The vial was sealed and placed in an 80° C. oil bath for 2 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on an 80 g silica gel column to give 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (1.001 g, 3.28 mmol) as a yellow solid. [M+H]+=307.0. The vessel was flushed with Ar (g) DMF (19.14 ml) was added The vial was sealed placed in an 80° C. for 2 hours The mixture was diluted with water extracted with EtOAc (3×) The combined organic extracts were washed with brine dried over sodium sulfate filtered concentrated The residue was chromatographed on an 80 g silica gel column

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

实验步骤: A solution of 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.598 ml, 9.70 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.00 g, 9.70 mmol), Pd(dppf)-CH2Cl2 adduct (0.396 g, 0.485 mmol), and potassium carbonate (2.329 g, 38.8 mmol) in 1,4-dioxane (36.4 ml) and water (12.13 ml) was stirred at 70° C. for 18 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 dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (Redi-Sep Gold 80 g silica gel column (Teledyne Isco, Lincoln, Nebr.), gradient elution 0 to 100% Et2O:Heptane) to afford tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a light yellow oil. m/z (ESI) 428.1 (M+Na)+. washed with water The aqueous layer was extracted with ethyl acetate the combined organic layers were dried with sodium sulfate filtered concentrated The material was purified via column chromatography (Redi-Sep Gold 80 g silica gel column (Teledyne Isco, Lincoln, Nebr.), gradient elution 0 to 100% Et2O:Heptane)

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

实验步骤: A round-bottom flask was charged with 1-bromo-2-iodo-4-(trifluoromethyl)benzene (5.00 g, 14.25 mmol), 1-methyl-1h-pyrazole-5-boronic acid pinacol ester (3.41 g, 16.39 mmol), potassium phosphate (6.05 g, 28.5 mmol) and PdCl2(dppf)-CH2Cl2 (1.164 g, 1.425 mmol). The flask was flushed with Ar, and DMF (47.5 ml) was then added. The flask was sealed, heated to 60° C. for 12 h, then stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organics were washed with brine, dried, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 100% EtOAc/Heptane) to yield 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (2.956 g, 9.69 mmol, 68.0% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ=8.06 (td, J=0.7, 8.1 Hz, 1 H), 7.86-7.73 (m, 2 H), 7.53 (d, J=2.0 Hz, 1 H), 6.41 (d, J=2.0 Hz, 1 H), 3.64 (s, 3 H). m/z (ESI) 305.0 (M+H)+. The flask was flushed with Ar, and DMF (47.5 ml) was then added The flask was sealed The mixture was diluted with water extracted with EtOAc (3×) The combined organics were washed with brine dried concentrated in vacuo The crude product was purified by chromatography on silica gel (0 to 100% EtOAc/Heptane)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of Pd(Ph3P)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-3-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 16 mL water was heated to 120° C. overnight. LC/MS showed incomplete conversion, so an additional portion of pyridin-3-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. LC/MS showed no further conversion, so the reaction mixture was poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by column chromatography (0-100% EtOAc/heptane) gave 3-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (5.150 g, 17.05 mmol, 69.8% yield) as a yellow solid. m/z (ESI) 303.9 (M+H)+. was extracted with DCM The organics were then concentrated Purification of the crude residue by column chromatography (0-100% EtOAc/heptane)

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

实验步骤: A solution of PdCl2(dppf)-CH2Cl2 adduct (0.349 g, 0.427 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.500 g, 4.27 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (ASW MedChem, Inc., New Brunswick, N.J., 1.893 g, 6.41 mmol), and potassium carbonate (3.54 g, 25.6 mmol) in 15 mL dioxane/7.5 mL water was heated to 100° C. for 1 hour. LC/MS showed product, so the reaction mixture was cooled to room temperature and the aqueous layer was removed. The organics were concentrated then purified directly by reverse phase column chromatography [Redisep Gold C18, 20-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding tert-butyl 3-(2-bromo-5-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.040 g, 2.65 mmol, 62.0% yield). m/z (ESI) 413.9 (M+Na)+. the aqueous layer was removed The organics were concentrated then purified directly by reverse phase column chromatography [Redisep Gold C18, 20-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

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

实验步骤: A solution of PdCl2(dppf)-CH2Cl2 adduct (0.233 g, 0.285 mmol), 1-methyl-2-(tributylstannyl)imidazole (2.189 ml, 6.84 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (0.919 ml, 5.70 mmol), and potassium fluoride (1.656 g, 28.5 mmol) in 6 mL DMF was heated to 80° C. overnight. LC/MS showed product, so the reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 2-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-imidazole (1.122 g, 3.68 mmol, 64.5% yield). m/z (ESI) 307.2 (M+H)+. was extracted with DCM The organics were dried over MgSO4 concentrated Purification of the crude residue by silica gel column chromatography (0 to 100% EtOAc/heptane)

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

实验步骤: A solution of Pd(Ph3P)4 (0.986 g, 0.854 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (2.000 g, 8.96 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.377 ml, 8.54 mmol), and potassium phosphate (5.44 g, 25.6 mmol) in 20 mL dioxane 10 mL water was heated to 90° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 97% EtOAc/heptane, 3% MeOH) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine. m/z (ESI) 320.1 (M+H)+. extracted with DCM The organics were dried over MgSO4 concentrated Purification of the crude residue by silica gel column chromatography (0 to 97% EtOAc/heptane, 3% MeOH)

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

实验步骤: A solution of PdCl2(dppf)-CH2Cl2 adduct (0.582 g, 0.712 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.63 g, 14.96 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (2.298 ml, 14.25 mmol), and potassium phosphate (9.07 g, 42.7 mmol) in 50 mL dioxane/25 mL water was heated to 80° C. for 2 hours. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-30% EtOAc/heptane) gave tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (4.05 g, 9.97 mmol, 70.0% yield) as a clear oil. m/z (ESI) 430.2 (M+Na)+. was extracted with DCM The organics were dried over MgSO4 concentrated Purification of the crude residue by silica gel column chromatography (0-30% EtOAc/heptane)