1,4-dibromo-2,5-difluorobenzene

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

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

Procedure: To a solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in anhydrous Et2O (60 mL) at −78° C. (dry ice/acetone bath) was added n-BuLi (7.72 mL, 19.31 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 minutes (min) (light yellow color), then TMSCl (2.59 mL, 20.23 mmol) was added. The reaction mixture was allowed to slowly warm to 20° C. and was stirred for 12 h. The reaction mixture was poured into a saturated (satd) aqueous (aq) ammonium chloride solution (NH4Cl; 150 mL), and the crude product was extracted with Et2O (3×). The combined organic layers were washed with satd aq NaCl, dried over MgSO4, filtered and concentrated (orange/brown oil). The residue was purified by column chromatography (silica gel (SiO2), eluting with hexanes) to afford the title compound as a colorless oil (4.17 g, 86%): 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J=7.1, 5.1 Hz, 1H), 7.09 (dd, J=8.0, 4.4 Hz, 1H), 0.31 (d, J=0.9 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −105.42, −115.48; EIMS m/z 266. to slowly warm to 20° C. was stirred for 12 h the crude product was extracted with Et2O (3×) The combined organic layers were washed with satd aq NaCl dried over MgSO4 filtered concentrated (orange/brown oil) The residue was purified by column chromatography (silica gel (SiO2), eluting with hexanes)

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 16.55 g (60.85 mmol) 1,4-dibromo-2,5-difluorobenzene in 400 ml of ethyl ether stirred at -75° C. under an argon atmosphere was treated dropwise with 24.3 ml of 2.5 M n-butyl lithium in hexane. The mixture was let warm to -50° C. and treated dropwise with a solution of 11.00 g (64.33 mmol) 1-ethoxycarbonyl-4-piperidone in 100 ml ethyl ether. After stirring a further 0.25 hour, the mixture was let warm to room temperature and extracted with ammonium chloride solution. The organic layer was dried (MgSO4), evaporated and the crude product chromatographed on a silica gel column and crystallized from toluene hexane to afford the title compound, mp 133°-136° C. the mixture was let warm to room temperature extracted with ammonium chloride solution The organic layer was dried (MgSO4) evaporated the crude product chromatographed on a silica gel column crystallized from toluene hexane

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 16.55 g (60.85 mmol) 1,4-dibromo-2,5-difluorobenzene in 400 ml of ethyl ether stirred at -75° C. under an argon atmosphere was treated dropwise with 24.3 ml of 2.5 M n-butyl lithium in hexane. The mixture was let warm to -50° C. and treated dropwise with a solution of 11.00 g (64.33 mmol) 1-ethoxycarbonyl-4-piperidone in 100 ml ethyl ether. After stirring a further 0.25 hour, the mixture was let warm to room temperature and extracted with ammonium chloride solution. The organic layer was dried (MgSO4), evaporated and the crude product chromatographed on a silica gel column and crystallized from toluene hexane to afford the title compound, mp 133°-136° C. the mixture was let warm to room temperature extracted with ammonium chloride solution The organic layer was dried (MgSO4) evaporated the crude product chromatographed on a silica gel column crystallized from toluene hexane

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

Procedure: A solution of 27.2 g (0.1 mole) of 1,4-dibromo-2,5-difluorobenzene in 200 ml of ether was blanketed with argon and cooled to -78° C. To this mixture was added 42 ml of n-butyl lithium (2.4 M; 0.10 mole) dropwise via an addition funnel. The solution was stirred at -78° C. for 15 minutes, then allowed to warm to -45° C. To the anion was added 13 ml of 3-ethoxy-2-cyclopentenone (0.10 mole); the solution was kept at -45° for 30 minutes and was then warmed slowly to room temperature. The mixture was poured into 250 ml of 1 N hydrochloric acid, stirred for 30 minutes, and extracted with ethyl acetate; the organic phases were combined, washed with water, dried over magnesium sulfate, and concentrated. The crude product was purified via silica gel chromatography using an 80:20 chloroform ethyl acetate mixture to give 14.2 g of the desired product; mp 129°-131° C. to warm to -45° C the solution was kept at -45° for 30 minutes was then warmed slowly to room temperature stirred for 30 minutes extracted with ethyl acetate washed with water dried over magnesium sulfate concentrated The crude product was purified via silica gel chromatography

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2.72 g (10 mmoles) of 1,4-dibromo-2,5-difluorobenzene in 50 ml of ethyl ether, under an argon atmosphere stirred at -75° C., was treated dropwise with 4.2 ml of 2.5 M n-butyl lithium (hexane solution). The mixture was treated dropwise with a solution of 1.20 g (10.6 mmoles) of N-methyl-4-piperidone in 10 ml of ethyl ether, stirred a further 0.75 hours at -75° C., let warm to -30° C., and poured into a solution of 0.56 g (10.5 mmoles) ammonium chloride in 15 ml of water. The ether layer was washed with two 10 ml portions of water, dried (MgSO4), and evaporated to give 2.85 g of crude product which was purified by chromatography on a column of silica gel and crystallized to give 1.30 g of the title compound; mp 133°-135° C. let warm to -30° C. The ether layer was washed with two 10 ml portions of water dried (MgSO4) evaporated to give 2.85 g of crude product which was purified by chromatography on a column of silica gel crystallized

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

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1,4-dibromo-2,5-difluorobenzene (600 mg, 2.21 mmol) in dry Et2O (8 mL) was added to a n-BuLi (0.88 mL of a 2.5M solution in hexanes, 2.20 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (530 mg, 2.24 mmol) was dissolved in dry THF (20 mL) and treated with BH3.Me2S complex (1.0 M in THF, 4.5 mL, 4.50 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 3:1 to 1:1) to give the title compound as a white solid. TLC:rf (1:1 EA-hept)=0.53. was added to warm up to rt was added The layers separated layer dried over MgSO4 filtered the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid treated with BH3 at 0° C The reaction mixture was then warmed to 50° C. stirred at this temperature until completion of the reaction The mixture was cooled to 0° C. The layers were separated the aq. layer extracted with EA (3×) extracts were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The crude residue was purified by FC (hept-EA 3:1 to 1:1)

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

Procedure: The Compound 12AQ was prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester using the procedure as described for the preparation of Compound 4-(2-fluoro-4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester but using 1,4-dibromo-2,5-difluoro-benzene in place of 4-bromo-2-fluoro-1-iodobenzene.

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

Procedure: The Compound 12AQ was prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester using the procedure as described for the preparation of Compound 4-(2-fluoro-4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester but using 1,4-dibromo-2,5-difluoro-benzene in place of 4-bromo-2-fluoro-1-iodobenzene.

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

Procedure: n-Butyl lithium (3.6 ml, 7.7 mmol) was added drop wise to a solution of 1,4-dibromo-2,5-difluoro-benzene (2 g, 7.35 mmol) in dry ether at −78° C. under nitrogen atmosphere and the resulting mixture was stirred at −78° C. for 30 minutes. This was followed by the addition of DMF (0.85 ml, 11.03 mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600 mg of the product (37% yield). The resultant was stirred at room temperature for 1 hour The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride The organic layer was concentrated purified by column chromatography on silica gel (2% ethyl acetate in hexane)

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

Procedure: n-Butyl lithium (3.6 ml, 7.7 mmol) was added drop wise to a solution of 1,4-dibromo-2,5-difluoro-benzene (2 g, 7.35 mmol) in dry ether at −78° C. under nitrogen atmosphere and the resulting mixture was stirred at −78° C. for 30 minutes. This was followed by the addition of DMF (0.85 ml, 11.03 mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600 mg of the product (37% yield). The resultant was stirred at room temperature for 1 hour The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride The organic layer was concentrated purified by column chromatography on silica gel (2% ethyl acetate in hexane)

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

Procedure: A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol). The solution was stirred at −78° C. for 30 min, then was treated with a piece of dry ice. The cooling bath was removed after 5 min and the mixture was stirred for another 30 min while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCO3. The combined aqueous phases were acidified with 1M aqueous HCl, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53% yield). The cooling bath was removed after 5 min the mixture was stirred for another 30 min while warming to room temperature The mixture was diluted with EtOAc and water The organic phase was separated washed twice with saturated aqueous NaHCO3 extracted twice with DCM the combined organic phases were dried concentrated