3-bromo-2-fluorobenzaldehyde

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol), potassium carbonate (4.0 g, 30 mmol) and 2-methyl-2-propanethiol (5.5 mL, 49 mmol) in dry DMF (25 mL) was heated to 110° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, added to water (100 mL) and extracted with DCM (3×50 mL). The combined organic fractions were washed with water (50 mL), dried, and evaporated to afford 6.7 g (98%) of the crude title compound which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 1.31 (s, 9H), 7.26-7.41 (m, 1H), 7.93-7.99 (m, 2H), 10.73 (s, 1H). The reaction mixture was cooled to RT extracted with DCM (3×50 mL) The combined organic fractions were washed with water (50 mL) dried evaporated

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

Procedure: Using 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde, 8.2 g (205.7 mmol) of sodium hydride (60% pure) and 16.0 g (150.9 mmol) of methyl mercaptoacetate,

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

Procedure: Reaction of 3-bromo-2-fluorobenzaldehyde with acetonitrile gave 3-(3-bromo-2-fluorophenyl)-3-hydroxypropanenitrile as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J=7.2 Hz, 2H), 7.11 (td, J=7.6, 0.4 Hz, 1H), 5.37 (dd, J=6.8, 4.4 Hz, 1H), 2.73-2.91 (m, 2H).

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

Procedure: Starting from 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde, by general method A with 8.2 g (205.7 mmol) of sodium hydride (60% in liquid paraffin) and 16.0 g (150.9 mmol) of methyl mercaptoacetate, 20.57 g of a mixture of the title compound and the corresponding acid (about 1:1) is obtained.

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

Procedure: A solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 31.5 mL) was added to an ice-bath cooled, stirred slurry of (methoxymethyl)triphenylphosphonium chloride (5.07 g) in tetrahydrofuran (50 mL) keeping the temperature of the reaction mixture below 10° C. The mixture was stirred for 30 min. A solution of 3-bromo-2-fluorobenzaldehyde (2 g) in THF (5+3 mL) was added dropwise and the cold bath was removed. The mixture was stirred at ambient temperature for 1.5 h. The mixture was quenched with saturated ammonium chloride solution and extracted into ethyl acetate (70 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford crude product. Ether (50 mL) was added and the mixture was left overnight in the fridge. The solid was filtered off and the filtrate was concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in isohexane to afford the subtitled compound (1.84 g) as a liquid. (5:3 mixture of isomers). 1H NMR (300 MHz, CDCl3) δ (a mixture of isomers) 7.98 (ddd, J=1.5, 7.1 and 8.4 Hz, 1H), 7.36-7.18 (m, 3H), 7.17 (d, J=13.1 Hz, 2H), 7.00-6.88 (m, 2H), 6.28 (d, J=7.1 Hz, 1H), 5.85 (d, J=13.1 Hz, 1H), 5.47 (d, J=7.1 Hz, 1H), 3.81 (d, J=6.5 Hz, 3H), 3.72 (d, J=6.5 Hz, 3H). cooled the temperature of the reaction mixture below 10° C the cold bath was removed The mixture was stirred at ambient temperature for 1.5 h The mixture was quenched with saturated ammonium chloride solution extracted into ethyl acetate (70 mL) The organic phase was washed with brine dried over magnesium sulfate filtered evaporated to afford crude product the mixture was left overnight in the fridge The solid was filtered off the filtrate was concentrated The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in isohexane

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

Procedure: To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, and then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and additional (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol) was added. The mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with DCM. The layers were separated and the aqueous phase extracted twice with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of DCM and purified via silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min) gave the title compound (1.22 g, 3.92 mmol, 80% yield) as a pale yellow liquid. 1H NMR (400 MHz, CD3OD) δ 7.54-7.40 (m, 2H), 7.35-7.23 (m, 2H), 7.09-6.90 (m, 3H), 6.38 (s, 1H), 4.12 (q, J=7.0 Hz, 1H), 3.76 (s, 3H). to warm to room temperature The reaction mixture was cooled to 0° C. to warm to room temperature overnight The reaction was quenched with a saturated aqueous solution of NH4Cl The reaction mixture was diluted with DCM The layers were separated the aqueous phase extracted twice with DCM dried over Na2SO4 filtered concentrated to afford a yellow residue purified via silica gel chromatography an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min)

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

Procedure: To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, and then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and additional (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol) was added. The mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with DCM. The layers were separated and the aqueous phase extracted twice with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of DCM and purified via silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min) gave the title compound (1.22 g, 3.92 mmol, 80% yield) as a pale yellow liquid. 1H NMR (400 MHz, CD3OD) δ 7.54-7.40 (m, 2H), 7.35-7.23 (m, 2H), 7.09-6.90 (m, 3H), 6.38 (s, 1H), 4.12 (q, J=7.0 Hz, 1H), 3.76 (s, 3H). to warm to room temperature The reaction mixture was cooled to 0° C. to warm to room temperature overnight The reaction was quenched with a saturated aqueous solution of NH4Cl The reaction mixture was diluted with DCM The layers were separated the aqueous phase extracted twice with DCM dried over Na2SO4 filtered concentrated to afford a yellow residue purified via silica gel chromatography an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min)

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

Procedure: To a stirring solution of 1-chloro-2-iodobenzene (7.05 g, 29.6 mmol) in tetrahydrofuran (Volume: 15 mL) at −15° C. was added isopropylmagnesium chloride (17.24 mL, 34.5 mmol). The mixture was allowed to stir for 30 minutes, at which time 3-bromo-2-fluorobenzaldehyde (5 g, 24.63 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was extracted with EtOAc (3×). The organics were combined, rinsed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (7.5 g, 96%). was added The reaction was quenched with saturated aqueous NH4Cl The reaction mixture was extracted with EtOAc (3×) rinsed with brine dried over Na2SO4 filtered concentrated

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

Procedure: To a solution of 3-bromo-2-fluorobenzaldehyde (1.5 g, 7.39 mmol) in THF (Volume: 32.1 ml) cooled to 0° C. was added (4-fluoro-2-methoxyphenyl) magnesium bromide (17.73 ml, 8.87 mmol). After 50 min, additional (4-fluoro-2-methoxyphenyl)magnesium bromide (17.73 ml, 8.87 mmol) was added. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 30 min, tr=17 min) gave the title compound (2.10 g, 6.06 mmol, 82% yield) as a colorless liquid. The reaction was quenched with a saturated aqueous solution of NH4Cl The reaction mixture was diluted with CH2Cl2 The layers were separated the aqueous phase extracted with CH2Cl2 (2×) dried over Na2SO4 filtered concentrated to afford a yellow residue to be chromatographed Purification of the crude material by silica gel chromatography an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 30 min, tr=17 min)

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

Procedure: To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (5-fluoro-2-methoxyphenyl)magnesium bromide in THF (11.82 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature. The reaction mixture was then re-cooled to 0° C. and additional (5-fluoro-2-methoxyphenyl) magnesium bromide in THF (11.82 mL, 5.91 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl and diluted with CH2Cl2. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 20 min, tr=17.5 min) gave the title compound (1.62 g, 4.92 mmol, 100% yield) as a colorless liquid. to warm to room temperature The reaction mixture was then re-cooled to 0° C. to warm to room temperature overnight The reaction was quenched with a saturated aqueous solution of NH4Cl diluted with CH2Cl2 The layers were separated the aqueous phase was extracted with CH2Cl2 (2×) dried over Na2SO4 filtered concentrated to afford a yellow residue to be chromatographed Purification of the crude material by silica gel chromatography an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 20 min, tr=17.5 min)

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

Procedure: A solution of pyridazine (0.078 mL, 1.075 mmol) in THF (2.0 mL) and a solution of 3-bromo-2-fluorobenzaldehyde (0.200 g, 0.985 mmol) in THF (2.0 mL) were added simultaneously to a cold solution of LTMP at −78° C. The mixture was stirred at −78° C. for 4 h, followed by the addition of excess of HCl/EtOH/THF. The solution was allowed to warm to room temperature, then treated with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (0.254 g, 0.897 mmol, 100% yield) as a yellow residue. to warm to room temperature extracted with CH2Cl2 (3×) dried over Na2SO4 filtered concentrated