1,4-dibromo-2-fluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. solution of 1,4-dibromo-2-fluorobenzene (4 g, 15.75 mmol) in THF (52.5 mL) was added a solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol). The reaction mixture was stirred at −78° C. for 30 min 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.21 mL, 15.75 mmol) was then added, and the mixture was stirred at −78° C. for an additional 1 h. A solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol) was then added, followed after 30 min by TMSCl (4.03 mL, 31.5 mmol). The reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. The mixture was then poured into a half saturated NH4Cl solution (300 mL), and the crude product was extracted with Et2O (3×). The combined organic layers were dried over MgSO4, filtered, concentrated and dried in vacuo to afford the title compound as a yellow oil (4.87 g, 11.92 mmol, 76% yield based on a 72% purity): 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J=7.2, 6.0 Hz, 1H), 7.26 (dt, J=7.2, 1.2 Hz, 1H), 7.16 (dd, J=9.6, 0.4 Hz, 1H), 1.36 (s, 12H), 0.26 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −104.02; EIMS m/z 294. was then added to warm slowly to room temperature was stirred overnight the crude product was extracted with Et2O (3×) The combined organic layers were dried over MgSO4 filtered concentrated dried in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium (n-BuLi, 2.5 Molar (M) in hexanes; 900 microliters (μL), 2.2 millimoles (mmol), 1.1 equivalents (equiv)) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (500 milligrams (mg), 2.0 mmol, 1.0 equiv) in diethyl ether (Et2O; 10 milliliters (mL)) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 2 hours (h). Chlorotrimethylsilane (TMSCl; 300 μL, 2.4 mmol, 1.2 equiv) was added, and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and was stirred for 72 h. The reaction mixture was diluted with water (H2O; 50 mL) and was extracted with dichloromethane (CH2Cl2; 3×50 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow oil (350 mg, 71%): IR (thin film) 3068 (w), 2955 (m), 2927 (m), 2855 (w), 1598 (w), 1567 (w) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.49 (m, 3H), 0.30 (s, 9H). to slowly warm to 23° C. was stirred for 72 h was extracted with dichloromethane (CH2Cl2; 3×50 mL) The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered concentrated by rotary evaporation

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of DL-proline (576 mg, 5 mmol) in 10/1 DMF-H2O (7.5 ml) at RT were added CuI (48 mg, 0.25 mmol), Pd(PPh3)4 (290 mg, 0.25 mmol), K2CO3 (690 mg, 5 mmol), NEt3 (1.4 ml, 10 mmol), triethylammonium bromide (158 mg, 0.75 mmol), and 1,4-dibromo-2-fluorobenzene. The resulting mixture was stirred in a sealed tube at 120° C. for 48 hours. The reaction mixture was cooled to room temperature and poured onto saturated K2CO3 /Et2O. The aqueous layer was extracted 3× with Et2O. The pH of the aqueous layer was adjusted to 4 and extracted 3× with EtOAc. The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to produce title compound which was used without further purification: LCMS (M+1)=287. ##STR393## The reaction mixture was cooled to room temperature The aqueous layer was extracted 3× with Et2O extracted 3× with EtOAc The combined organics were washed with brine dried over MgSO4 concentrated in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of DL-proline (576 mg, 5 mmol) in 10/1 DMF-H2O (7.5 ml) at RT were added CuI (48 mg, 0.25 mmol), Pd(PPh3)4 (290 mg, 0.25 mmol), K2CO3 (690 mg, 5 mmol), NEt3 (1.4 ml, 10 mmol), triethylammonium bromide (158 mg, 0.75 mmol), and 1,4-dibromo-2-fluorobenzene. The resulting mixture was stirred in a sealed tube at 120° C. for 48 hours. The reaction mixture was cooled to room temperature and poured onto saturated K2CO3 /Et2O. The aqueous layer was extracted 3× with Et2O. The pH of the aqueous layer was adjusted to 4 and extracted 3× with EtOAc. The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to produce title compound which was used without further purification: LCMS (M+1)=287. ##STR393## The reaction mixture was cooled to room temperature The aqueous layer was extracted 3× with Et2O extracted 3× with EtOAc The combined organics were washed with brine dried over MgSO4 concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2.5 M solution of n-butyllithium (3.5 mL, 8.5 mmol, 1.1 equiv) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (2.0 g, 7.9 mmol, 1.0 equiv) in tetrahydrofuran (26 mL) at −78° C. The resulting bright yellow solution was stirred at −78° C. for 15 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 mL, 8.7 mmol, 1.1 equiv) was added and the resulting pale yellow solution was stirred at −78° C. for 30 m. A 2.5 M solution of n-butyllithium (3.5 mL, 8.5 mmol, 1.1 equiv) was added and the resulting yellow/brown solution was stirred at −78° C. for 15 m. Chlorotrimethylsilane (2.2 mL, 17 mmol, 2.2 equiv) was added and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and stirred for 18 h. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow powder (2.3 g, 99%): IR (thin film) 3058 (w), 2981 (s), 2932 (m), 1615 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J=7.5, 6 Hz, 1H), 7.26 (m, 1H), 7.16 (d, J=7.5 Hz, 1H), 1.34 (s, 12H), 0.23 (s, 9H). the resulting pale yellow solution was stirred at −78° C. for 30 m the resulting yellow/brown solution was stirred at −78° C. for 15 m to slowly warm to 23° C. stirred for 18 h extracted with dichloromethane (2×100 mL) The combined organic layers were dried (magnesium sulfate), gravity filtered concentrated by rotary evaporation

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butylmagnesium chloride (3.49 mmol) in 2.05M tetrahydrofuran solution (1.70 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.45M hexane (4.85 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. To the suspension was added dropwise a toluene solution (25 mL) containing ice-cooled 1,4-dibromo-2-fluorobenzene (2.54 g, 10.0 mmol) over a period of 10 minutes, while keeping the temperature below 5° C. The resultant yellowish suspension was stirred at 0° C. for one hour, and N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto. The mixture was stirred at 0° C. for 30 minutes, and 1M aqueous acetic acid solution (15 mL) was added. The reaction mixture was extracted twice with ethyl acetate (15 mL). The organic extracts were combined, and 20% aqueous sodium hydrogen sulfite solution (5 mL) was added at room temperature. The mixture was stirred vigorously at room temperature for one hour. The aqueous phase was separated, washed with ethyl acetate (15 mL), adjusted to pH 10 with 6N sodium hydroxide solution, and extracted twice with ethyl acetate (25 ml). The organic extracts were combined, washed successively with aqueous ammonium chloride saturated solution (10 mL) and saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give the title compound (1.666 g, 82% yield) as an almost colorless crystalline solid. to give a suspension containing ice- the temperature below 5° C The resultant yellowish suspension was stirred at 0° C. for one hour The mixture was stirred at 0° C. for 30 minutes The reaction mixture was extracted twice with ethyl acetate (15 mL) 20% aqueous sodium hydrogen sulfite solution (5 mL) was added at room temperature The mixture was stirred vigorously at room temperature for one hour The aqueous phase was separated washed with ethyl acetate (15 mL) extracted twice with ethyl acetate (25 ml) washed successively with aqueous ammonium chloride saturated solution (10 mL) and saturated aqueous sodium chloride (10 mL) dried over magnesium sulfate concentrated to dryness under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. solution of 1,4-dibromo-2-fluorobenzene (4 g, 15.75 mmol) in THF (52.5 mL) was added a solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol). The reaction mixture was stirred at −78° C. for 30 min 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.21 mL, 15.75 mmol) was then added, and the mixture was stirred at −78° C. for an additional 1 h. A solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol) was then added, followed after 30 min by TMSCl (4.03 mL, 31.5 mmol). The reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. The mixture was then poured into a half saturated NH4Cl solution (300 mL), and the crude product was extracted with Et2O (3×). The combined organic layers were dried over MgSO4, filtered, concentrated and dried in vacuo to afford the title compound as a yellow oil (4.87 g, 11.92 mmol, 76% yield based on a 72% purity): 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J=7.2, 6.0 Hz, 1H), 7.26 (dt, J=7.2, 1.2 Hz, 1H), 7.16 (dd, J=9.6, 0.4 Hz, 1H), 1.36 (s, 12H), 0.26 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −104.02; EIMS m/z 294. was then added to warm slowly to room temperature was stirred overnight the crude product was extracted with Et2O (3×) The combined organic layers were dried over MgSO4 filtered concentrated dried in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. solution of 1,4-dibromo-2-fluorobenzene (4 g, 15.75 mmol) in THF (52.5 mL) was added a solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol). The reaction mixture was stirred at −78° C. for 30 min 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.21 mL, 15.75 mmol) was then added, and the mixture was stirred at −78° C. for an additional 1 h. A solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol) was then added, followed after 30 min by TMSCl (4.03 mL, 31.5 mmol). The reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. The mixture was then poured into a half saturated NH4Cl solution (300 mL), and the crude product was extracted with Et2O (3×). The combined organic layers were dried over MgSO4, filtered, concentrated and dried in vacuo to afford the title compound as a yellow oil (4.87 g, 11.92 mmol, 76% yield based on a 72% purity): 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J=7.2, 6.0 Hz, 1H), 7.26 (dt, J=7.2, 1.2 Hz, 1H), 7.16 (dd, J=9.6, 0.4 Hz, 1H), 1.36 (s, 12H), 0.26 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −104.02; EIMS m/z 294. was then added to warm slowly to room temperature was stirred overnight the crude product was extracted with Et2O (3×) The combined organic layers were dried over MgSO4 filtered concentrated dried in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium (n-BuLi, 2.5 Molar (M) in hexanes; 900 microliters (μL), 2.2 millimoles (mmol), 1.1 equivalents (equiv)) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (500 milligrams (mg), 2.0 mmol, 1.0 equiv) in diethyl ether (Et2O; 10 milliliters (mL)) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 2 hours (h). Chlorotrimethylsilane (TMSCl; 300 μL, 2.4 mmol, 1.2 equiv) was added, and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and was stirred for 72 h. The reaction mixture was diluted with water (H2O; 50 mL) and was extracted with dichloromethane (CH2Cl2; 3×50 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow oil (350 mg, 71%): IR (thin film) 3068 (w), 2955 (m), 2927 (m), 2855 (w), 1598 (w), 1567 (w) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.49 (m, 3H), 0.30 (s, 9H). to slowly warm to 23° C. was stirred for 72 h was extracted with dichloromethane (CH2Cl2; 3×50 mL) The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered concentrated by rotary evaporation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium (n-BuLi, 2.5 Molar (M) in hexanes; 900 microliters (μL), 2.2 millimoles (mmol), 1.1 equivalents (equiv)) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (500 milligrams (mg), 2.0 mmol, 1.0 equiv) in diethyl ether (Et2O; 10 milliliters (mL)) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 2 hours (h). Chlorotrimethylsilane (TMSCl; 300 μL, 2.4 mmol, 1.2 equiv) was added, and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and was stirred for 72 h. The reaction mixture was diluted with water (H2O; 50 mL) and was extracted with dichloromethane (CH2Cl2; 3×50 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow oil (350 mg, 71%): IR (thin film) 3068 (w), 2955 (m), 2927 (m), 2855 (w), 1598 (w), 1567 (w) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.49 (m, 3H), 0.30 (s, 9H). to slowly warm to 23° C. was stirred for 72 h was extracted with dichloromethane (CH2Cl2; 3×50 mL) The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered concentrated by rotary evaporation

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

Procedure: Into a 100 mL single neck flask were placed 1,4-dibromo-2-fluorobenzene (2.35 g, 9.2 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.645 g, 0.92 mmol), tributyt (1-ethoxyvinyl)tin (10 g, 27.7 mmol), in THF (50 mL), and the mixture was heated at reflux while stirring for 18 hours. The reaction was cooled to room temperature and poured into 5N HCl (20 mL). The product was extracted with EtOAc and the organic layer was separated and washed twice with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 90:10 to provide the intermediate title compound, 1-(4-acetyl-2-fluorophenyl)ethan-1-one, (1.65 g, 100%) as a solid. Electron spray M.S. 180.9 (M*) Into a 100 mL single neck flask were placed at reflux The product was extracted with EtOAc the organic layer was separated washed twice with water dried over anhydrous Na2SO4 filtered concentrated under reduced vacuum The resulting semi-solid was purified via flash chromatography (Silica gel, isocratic) eluting with a solvent of Hexanes/EtOAc 90:10