1-bromo-4-(1,1,2,2,2-pentafluoroethoxy)benzene

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 9:1 DMF/H2O (50 mL) was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into H2O, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with hexanes (100 mL). The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole (7.0 g, 61% based on starting triazole) as an off-white solid: mp 130-132° C.; ESIMS m/z 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with hexanes (100 mL) The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dry 2 L round bottomed flask fitted with an overhead mechanical stirrer, nitrogen inlet, thermometer, and reflux condenser were added 1 bromo-4-(perfluoroethoxy)-benzene (100 g, 344 mmol), benzophenone hydrazone (74.2 g, 378 mmol), and (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP, 4.28 g, 6.87 mmol), and the mixture was suspended in anhydrous toluene (500 mL). To exclude oxygen, argon was sparged into the mixture for ten minutes (min) prior to and during the addition of palladium (II) acetate (Pd(OAc)2, 1.54 g, 6.87 mmol) and sodium tert-butoxide (NaOtBu, 49.5 g, 515 mmol), which was added in portions. The argon sparge was halted and the brown mixture was warmed to 100° C. and stirred for 3 h. The reaction was cooled to RT and poured into water (500 mL) and the aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water, washed with saturated aqueous NaCI, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by flash column chromatography using 0-100% (v/v) EtOAc/hexanes as eluent to give the title compound as a red oil (123.3 g, 88%): 1H NMR (400 MHz, CDCI3) δ 5 7.63-7.56 (m, 4H), 7.55 (t, J=1.5 Hz, 1H), 7.51 (d, J=4.7 Hz, 1H), 7.36-7.26 (m, 5H), 7.13-7.04 (m, 4H); 19F NMR (376 MHz, CDCI3) 5-85.94, −87.84; 13C NMR (101 MHz, CDCI3) δ 145.23, 143.46, 141.24, 138.06, 132.53, 129.74, 129.41, 129.03, 128.30, 128.23, 126.57, 122.82, 113.45. To a dry 2 L round bottomed flask fitted with an overhead mechanical stirrer, nitrogen inlet thermometer, and reflux condenser was sparged into the mixture for ten minutes (min) was added in portions The argon sparge The reaction was cooled to RT poured into water (500 mL) the aqueous mixture was extracted with EtOAc (3×200 mL) The combined organic extracts were washed with water washed with saturated aqueous NaCI dried over anhydrous MgSO4 filtered concentrated under reduced pressure on a rotary evaporator The crude product was purified by flash column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dry 2 L round bottomed flask fitted with an overhead mechanical stirrer, nitrogen inlet, thermometer, and reflux condenser were added 1 bromo-4-(perfluoroethoxy)-benzene (100 g, 344 mmol), benzophenone hydrazone (74.2 g, 378 mmol), and (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP, 4.28 g, 6.87 mmol), and the mixture was suspended in anhydrous toluene (500 mL). To exclude oxygen, argon was sparged into the mixture for ten minutes (min) prior to and during the addition of palladium (II) acetate (Pd(OAc)2, 1.54 g, 6.87 mmol) and sodium tert-butoxide (NaOtBu, 49.5 g, 515 mmol), which was added in portions. The argon sparge was halted and the brown mixture was warmed to 100° C. and stirred for 3 h. The reaction was cooled to RT and poured into water (500 mL) and the aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water, washed with saturated aqueous NaCI, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by flash column chromatography using 0-100% (v/v) EtOAc/hexanes as eluent to give the title compound as a red oil (123.3 g, 88%): 1H NMR (400 MHz, CDCI3) δ 5 7.63-7.56 (m, 4H), 7.55 (t, J=1.5 Hz, 1H), 7.51 (d, J=4.7 Hz, 1H), 7.36-7.26 (m, 5H), 7.13-7.04 (m, 4H); 19F NMR (376 MHz, CDCI3) 5-85.94, −87.84; 13C NMR (101 MHz, CDCI3) δ 145.23, 143.46, 141.24, 138.06, 132.53, 129.74, 129.41, 129.03, 128.30, 128.23, 126.57, 122.82, 113.45. To a dry 2 L round bottomed flask fitted with an overhead mechanical stirrer, nitrogen inlet thermometer, and reflux condenser was sparged into the mixture for ten minutes (min) was added in portions The argon sparge The reaction was cooled to RT poured into water (500 mL) the aqueous mixture was extracted with EtOAc (3×200 mL) The combined organic extracts were washed with water washed with saturated aqueous NaCI dried over anhydrous MgSO4 filtered concentrated under reduced pressure on a rotary evaporator The crude product was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an oven-dried 500-mL round bottom flask equipped with a stirring bar was added 1-bromo-4-(perfluoroethoxy)benzene (9.35 g, 32.1 mmol) and anhydrous THF (200 mL). The flask was placed under nitrogen and cooled in an ice bath for 10 min. A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min. The ice bath was removed after 1 hour, and the reaction was warmed to room temperature and stirred overnight. GC/MS showed the presence of starting material. The reaction was cooled in an ice bath and 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added. The ice bath was removed after 20 min and stirred at room temperature for 9 hours. Ethyl chloroformate (3.4 mL, 35.3 mmol) was added in a slow, steady stream. The reaction was warmed slightly during the addition and was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes) to provide ethyl 4-(perfluoroethoxy)benzoate as a yellow liquid (4.58 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −86.05, −87.84; ESIMS m/z 284 ([M+11]+). To an oven-dried 500-mL round bottom flask equipped with a stirring bar cooled in an ice bath for 10 min A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min The ice bath was removed after 1 hour The reaction was cooled in an ice bath 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added The ice bath was removed after 20 min stirred at room temperature for 9 hours The reaction was warmed slightly during the addition was stirred at room temperature overnight washed with saturated aqueous ammonium chloride The aqueous layer was extracted three times with EtOAc The organic layers were dried over anhydrous sodium sulfate filtered concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an oven-dried 500-mL round bottom flask equipped with a stirring bar was added 1-bromo-4-(perfluoroethoxy)benzene (9.35 g, 32.1 mmol) and anhydrous THF (200 mL). The flask was placed under nitrogen and cooled in an ice bath for 10 min. A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min. The ice bath was removed after 1 hour, and the reaction was warmed to room temperature and stirred overnight. GC/MS showed the presence of starting material. The reaction was cooled in an ice bath and 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added. The ice bath was removed after 20 min and stirred at room temperature for 9 hours. Ethyl chloroformate (3.4 mL, 35.3 mmol) was added in a slow, steady stream. The reaction was warmed slightly during the addition and was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes) to provide ethyl 4-(perfluoroethoxy)benzoate as a yellow liquid (4.58 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −86.05, −87.84; ESIMS m/z 284 ([M+11]+). To an oven-dried 500-mL round bottom flask equipped with a stirring bar cooled in an ice bath for 10 min A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min The ice bath was removed after 1 hour The reaction was cooled in an ice bath 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added The ice bath was removed after 20 min stirred at room temperature for 9 hours The reaction was warmed slightly during the addition was stirred at room temperature overnight washed with saturated aqueous ammonium chloride The aqueous layer was extracted three times with EtOAc The organic layers were dried over anhydrous sodium sulfate filtered concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 50 mL of 9:1 DMF/H2O was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with 100 mL of hexanes. The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 7.0 g (61% based on starting triazole) of 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole as an off-white solid, mp 130-132° C.; ESIMS 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with 100 mL of hexanes The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 50 mL of 9:1 DMF/H2O was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with 100 mL of hexanes. The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 7.0 g (61% based on starting triazole) of 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole as an off-white solid, mp 130-132° C.; ESIMS 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with 100 mL of hexanes The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]-triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 50 mL of 9:1 DMF/H2O was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with 100 mL of hexanes. The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 7.0 g (61% based on starting triazole) of 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]-triazole as an off-white solid, mp 130-132° C.; ESIMS 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with 100 mL of hexanes The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 9:1 DMF/H2O (50 mL) was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with hexanes (100 mL). The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole (7.0 g, 61% based on starting triazole) as an off-white solid: mp 130-132° C.; ESIMS m/z 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with hexanes (100 mL) The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 9:1 DMF/H2O (50 mL) was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into H2O, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with hexanes (100 mL). The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole (7.0 g, 61% based on starting triazole) as an off-white solid: mp 130-132° C.; ESIMS m/z 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with hexanes (100 mL) The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 9:1 DMF/H2O (50 mL) was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with hexanes (100 mL). The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole (7.0 g, 61% based on starting triazole) as an off-white solid: mp 130-132° C.; ESIMS m/z 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with hexanes (100 mL) The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol), 4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs2CO3 (25 g, 77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4 mmol) in 9:1 DMF/H2O (50 mL) was stirred vigorously and heated to 130° C. (internal temperature) for 20 h. The solution was then cooled, poured into H2O, and acidified with 2 N HCl to pH 2. Ether (250 mL) was then added and the solution was shaken and filtered before separating layers. The organic layer was dried and concentrated, and the resulting gummy solid was heated with hexanes (100 mL). The hot hexane layer was decanted from insoluble residue, the resulting solution cooled to 0° C. and the precipitated solid was filtered and air-dried to furnish 1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole (7.0 g, 61% based on starting triazole) as an off-white solid: mp 130-132° C.; ESIMS m/z 370.8 (M+H). The solution was then cooled filtered before separating layers The organic layer was dried concentrated the resulting gummy solid was heated with hexanes (100 mL) The hot hexane layer was decanted from insoluble residue the resulting solution cooled to 0° C. the precipitated solid was filtered air-dried