1,4-difluoro-2-methoxybenzene

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

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

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

Procedure: 35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to returnto ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product. to returnto ambient temperature extraction The extracts were washed dried concentrated to dryness under reduced pressure

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

Procedure: 35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to returnto ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product. to returnto ambient temperature extraction The extracts were washed dried concentrated to dryness under reduced pressure

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

Procedure: A solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to a stirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30 ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g ; 0.026 mol) in dry THF (50 ml). The reaction temperature was allowed to raise to room temperature and then stirring was maintained at room temperature for 30 min. Pd(OAc)2 (8 mg; 0.2 mol %) was added, followed by ethyl cis-3-bromoacrylate (3.58 g ; 0.02 mol). The reaction mixture was placed in preheated oil bath and heated under reflux for 1 h. The resulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) of DIBAL (1M solution in hexanes) was added dropwise. The stirring was continued at −78 C for 2 h and 1 h at room temperature. The reaction was quenched with water and all solids were dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, brine and evaporated in vacuo. The residue was Kugelrohr distilled (1.5×10−2 mbar, 150 C) to give 3.7 g (92%) of crude (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains ˜6% of other regioisomers. The crude product was used in the next step without further purification. was maintained at room temperature for 30 min The reaction mixture was placed in preheated oil bath heated under reflux for 1 h The resulting reaction mixture was added dropwise The reaction was quenched with water all solids were dissolved by addition of HCl The organic phase was diluted with ether separated washed with 5N HCl, brine evaporated in vacuo distilled (1.5×10−2 mbar, 150 C)

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

Procedure: A solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to a stirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30 ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g ; 0.026 mol) in dry THF (50 ml). The reaction temperature was allowed to raise to room temperature and then stirring was maintained at room temperature for 30 min. Pd(OAc)2 (8 mg; 0.2 mol %) was added, followed by ethyl cis-3-bromoacrylate (3.58 g ; 0.02 mol). The reaction mixture was placed in preheated oil bath and heated under reflux for 1 h. The resulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) of DIBAL (1M solution in hexanes) was added dropwise. The stirring was continued at −78 C for 2 h and 1 h at room temperature. The reaction was quenched with water and all solids were dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, brine and evaporated in vacuo. The residue was Kugelrohr distilled (1.5×10−2 mbar, 150 C) to give 3.7 g (92%) of crude (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains ˜6% of other regioisomers. The crude product was used in the next step without further purification. was maintained at room temperature for 30 min The reaction mixture was placed in preheated oil bath heated under reflux for 1 h The resulting reaction mixture was added dropwise The reaction was quenched with water all solids were dissolved by addition of HCl The organic phase was diluted with ether separated washed with 5N HCl, brine evaporated in vacuo distilled (1.5×10−2 mbar, 150 C)

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

Procedure: solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to a stirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30 ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g; 0.026 mol) in dry THF (50 ml). The reaction temperature was allowed to raise to room temperature and then stirring was maintained at room temperature for 30 min. Pd(OAc)2 (8 mg; 0.2 mol %) was added, followed by ethyl cis-3-bromoacrylate (3.58 g; 0.02 mol). The reaction mixture was placed in preheated oil bath and heated under reflux for 1 h. The resulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) of DIBAL (1M solution in hexanes) was added dropwise. The stirring was continued at −78 C for 2 h and 1 h at room temperature. The reaction was quenched with water and all solids were dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, brine and evaporated in vacuo. The residue was Kugelrohr distilled (1.5×10−2 mbar, 150 C) to give 3.7 g (92%) of crude (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains˜6% of other regioisomers. The crude product was used in the next step without further purification. was maintained at room temperature for 30 min The reaction mixture was placed in preheated oil bath heated under reflux for 1 h The resulting reaction mixture was added dropwise The reaction was quenched with water all solids were dissolved by addition of HCl The organic phase was diluted with ether separated washed with 5N HCl, brine evaporated in vacuo distilled (1.5×10−2 mbar, 150 C)

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

Procedure: solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to a stirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30 ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g; 0.026 mol) in dry THF (50 ml). The reaction temperature was allowed to raise to room temperature and then stirring was maintained at room temperature for 30 min. Pd(OAc)2 (8 mg; 0.2 mol %) was added, followed by ethyl cis-3-bromoacrylate (3.58 g; 0.02 mol). The reaction mixture was placed in preheated oil bath and heated under reflux for 1 h. The resulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) of DIBAL (1M solution in hexanes) was added dropwise. The stirring was continued at −78 C for 2 h and 1 h at room temperature. The reaction was quenched with water and all solids were dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, brine and evaporated in vacuo. The residue was Kugelrohr distilled (1.5×10−2 mbar, 150 C) to give 3.7 g (92%) of crude (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains˜6% of other regioisomers. The crude product was used in the next step without further purification. was maintained at room temperature for 30 min The reaction mixture was placed in preheated oil bath heated under reflux for 1 h The resulting reaction mixture was added dropwise The reaction was quenched with water all solids were dissolved by addition of HCl The organic phase was diluted with ether separated washed with 5N HCl, brine evaporated in vacuo distilled (1.5×10−2 mbar, 150 C)

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

Procedure: A solution of 1,4-difluoro-2-methoxybenzene (i-6a) (2.88 g, 20 mmol) in THF (5 mL) was added to a solution of LDA freshly prepared from n-BuLi (10M solution in hexane, 2.2 mL, 22 mmol) and diisopropylamine (2.28 g, 22.8 mmol) in THF (20 mL) at −60° C. After 30 min, a freshly prepared solution of CO2 in diethyl ether (20 mL) was quickly added. Then aq. H2SO4 was added, and the resulting precipitate was collected and washed with H2O, and dried to give the title compound (i-6b) as white crystals. LCMS (ESI) calc'd for C8H6F2O3 [M+H]+: 189. found: 189. the resulting precipitate was collected washed with H2O dried

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

Procedure: A solution of 1,4-difluoro-2-methoxybenzene (i-6a) (2.88 g, 20 mmol) in THF (5 mL) was added to a solution of LDA freshly prepared from n-BuLi (10M solution in hexane, 2.2 mL, 22 mmol) and diisopropylamine (2.28 g, 22.8 mmol) in THF (20 mL) at −60° C. After 30 min, a freshly prepared solution of CO2 in diethyl ether (20 mL) was quickly added. Then aq. H2SO4 was added, and the resulting precipitate was collected and washed with H2O, and dried to give the title compound (i-6b) as white crystals. LCMS (ESI) calc'd for C8H6F2O3 [M+H]+: 189. found: 189. the resulting precipitate was collected washed with H2O dried

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

Procedure: 35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to return to ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product. to return to ambient temperature extraction The extracts were washed dried concentrated to dryness under reduced pressure

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

Procedure: 35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to return to ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product. to return to ambient temperature extraction The extracts were washed dried concentrated to dryness under reduced pressure