2,5-difluoro-4-formylbenzonitrile

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,5-difluoro-4-formylbenzonitrile (Preparation 20, 280 mg, 1.68 mmol) in ethanol (8 mL) was cooled to 0° C. in an ice/water bath. Sodium borohydride (63.4 mg, 1.68 mmol) was added and the reaction stirred at 0-5° C. for 5 hours. The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) and extracted with EtOAc (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a yellow oil, which crystallised on standing (182 mg, 64%). The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) extracted with EtOAc (25 mL) The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) dried over sodium sulphate concentrated in vacuo

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

Procedure: n-Butyllithium solution (1.6 M in hexanes, 8.75 mL, 14 mmol) was added dropwise to a solution of methyl methylthiomethyl sulfoxide (1.58 g, 12.7 mmol) in THF (25 mL) at −78° C. After 30 minutes at −78° C., 2,4,5-trifluorobenzonitrile (commercial, 1 g, 6.35 mmol) was added dropwise. The solution was then allowed to warm to room temperature, and stirred for 18 hours under a nitrogen atmosphere. The deep red reaction mixture was poured into water (75 mL), and extracted with EtOAc (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated to yield a brown oil. The oil was redissolved in THF (15 mL) and concentrated sulphuric acid (4.1 mL, 77.2 mmol) and water (4 mL) were added. After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over magnesium sulphate, and evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM to afford the title compound as a yellow oil (280 mg, 26%). The deep red reaction mixture extracted with EtOAc (2×75 mL) The combined organics were dried over magnesium sulphate evaporated to yield a brown oil After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) extracted with EtOAc (2×50 mL) The combined organic extracts were dried over magnesium sulphate evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM

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

Procedure: n-Butyllithium solution (1.6 M in hexanes, 8.75 mL, 14 mmol) was added dropwise to a solution of methyl methylthiomethyl sulfoxide (1.58 g, 12.7 mmol) in THF (25 mL) at −78° C. After 30 minutes at −78° C., 2,4,5-trifluorobenzonitrile (commercial, 1 g, 6.35 mmol) was added dropwise. The solution was then allowed to warm to room temperature, and stirred for 18 hours under a nitrogen atmosphere. The deep red reaction mixture was poured into water (75 mL), and extracted with EtOAc (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated to yield a brown oil. The oil was redissolved in THF (15 mL) and concentrated sulphuric acid (4.1 mL, 77.2 mmol) and water (4 mL) were added. After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over magnesium sulphate, and evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM to afford the title compound as a yellow oil (280 mg, 26%). The deep red reaction mixture extracted with EtOAc (2×75 mL) The combined organics were dried over magnesium sulphate evaporated to yield a brown oil After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) extracted with EtOAc (2×50 mL) The combined organic extracts were dried over magnesium sulphate evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM

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

Procedure: 2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase was washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. cooled on an ice bath The mixture was extracted three times with diethyl ether the combined ethereal phase was washed with water dried (Na2SO4) evaporated The crude product crystallised soon could be used without further purification

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

Procedure: 2,5-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.8 g, 0.0107 mol; see step (i) above) was dissolved in 100 mL of THF and 6.5 g of concentrated sulfuric acid was added. The mixture was left at room temperature for 6 days and subsequently poured into 500 mL of water. Extraction three times with diethyl ether followed and the combined ethereal phase was washed several times with water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel using heptane:EtOAc (8:2). Yield: 1.2 g (67%). The position of the formyl group was established by use of 13C NMR. The carbon signals from the fluorinated carbons at 160.1 and 158.4 respectively, were doublets and not quartets, which they would have been if the formyl group had been in the 2-position. Extraction three times with diethyl ether the combined ethereal phase was washed several times with water dried (Na2SO4) evaporated chromatographed on silica gel

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

Procedure: 2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. Yield: 3.1 g (85%). cooled on an ice bath The mixture was extracted three times with diethyl ether the combined ethereal phase washed with water dried (Na2SO4) evaporated The crude product crystallised soon could be used without further purification

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

Procedure: 2,5-Difluoro-4-[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.8 g, 0.0107 mol; see step (i) above) was dissolved in 100 mL of THF and 6.5 g of concentrated sulfuric acid was added. The mixture was left at room temperature for 6 days and subsequently poured into 500 mL of water. Extraction three times with diethyl ether followed and the combined ethereal phase washed several times with water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel using heptane:EtOAc (8:2). Yield: 1.2 g (67%). The position of the formyl group was established by use of 13C NMR. The carbon signals from the fluorinated carbons at 160.1 and 158.4 respectively were doublets and not quartets, which they would have been if the formyl group had been in the 2-position. Extraction three times with diethyl ether the combined ethereal phase washed several times with water dried (Na2SO4) evaporated chromatographed on silica gel

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

Procedure: 2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase was washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. cooled on an ice bath The mixture was extracted three times with diethyl ether the combined ethereal phase was washed with water dried (Na2SO4) evaporated The crude product crystallised soon could be used without further purification

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

Procedure: 2,5-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.8 g, 0.0107 mol; see step (i) above) was dissolved in 100 mL of THF and 6.5 g of concentrated sulfuric acid was added. The mixture was left at room temperature for 6 days and subsequently poured into 500 mL of water. Extraction three times with diethyl ether followed and the combined ethereal phase was washed several times with water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel using heptane:EtOAc (8:2). Yield: 1.2 g (67%). The position of the formyl group was established by use of 13C NMR. The carbon signals from the fluorinated carbons at 160.1 and 158.4 respectively were doublets and not quartets, which they would have been if the formyl group had been in the 2-position. Extraction three times with diethyl ether the combined ethereal phase was washed several times with water dried (Na2SO4) evaporated chromatographed on silica gel

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,5-difluoro-4-formylbenzonitrile (Preparation 20, 280 mg, 1.68 mmol) in ethanol (8 mL) was cooled to 0° C. in an ice/water bath. Sodium borohydride (63.4 mg, 1.68 mmol) was added and the reaction stirred at 0-5° C. for 5 hours. The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) and extracted with EtOAc (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a yellow oil, which crystallised on standing (182 mg, 64%). The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) extracted with EtOAc (25 mL) The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) dried over sodium sulphate concentrated in vacuo

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

Procedure: n-Butyllithium solution (1.6 M in hexanes, 8.75 mL, 14 mmol) was added dropwise to a solution of methyl methylthiomethyl sulfoxide (1.58 g, 12.7 mmol) in THF (25 mL) at −78° C. After 30 minutes at −78° C., 2,4,5-trifluorobenzonitrile (commercial, 1 g, 6.35 mmol) was added dropwise. The solution was then allowed to warm to room temperature, and stirred for 18 hours under a nitrogen atmosphere. The deep red reaction mixture was poured into water (75 mL), and extracted with EtOAc (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated to yield a brown oil. The oil was redissolved in THF (15 mL) and concentrated sulphuric acid (4.1 mL, 77.2 mmol) and water (4 mL) were added. After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over magnesium sulphate, and evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM to afford the title compound as a yellow oil (280 mg, 26%). The deep red reaction mixture extracted with EtOAc (2×75 mL) The combined organics were dried over magnesium sulphate evaporated to yield a brown oil After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) extracted with EtOAc (2×50 mL) The combined organic extracts were dried over magnesium sulphate evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM