methyl 5-fluoro-2-hydroxybenzoate

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

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

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

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

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

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

Procedure: With exclusion of oxygen, 27.1 g (159.28 mmol) of methyl 5-fluoro-2-hydroxybenzoate are initially charged in 500 ml of dry THF and cooled to 0° C. With cooling, 238 ml (238 mmol) of a 1 M solution of lithium aluminum hydride in THF are then slowly added dropwise, and the mixture is then stirred at 0° C. for 1 hour and then at RT overnight. After the reaction has gone to completion, saturated ammonium chloride solution is added and the mixture is taken up in dichloromethane. The organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed under reduced pressure. The crude product is purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1). This gives 18.0 g (126.6 mmol, 79% of theory) of a colorless solid. With cooling at RT overnight is added The organic phase is separated off dried over sodium sulfate After filtration the solvent is removed under reduced pressure The crude product is purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 5-fluorosalicylate (3.93 g, 23.1 mmol) in dry N,N-dimethylformamide (30 ml) was added sodium hydride (1.1 g, 50% oil dispersion). After hydrogen gas evolution had ceased, the mixture was cooled in an ice-bath, and dimethylthiocarbamoyl chloride (3.71 g, 30.0 mmol) was added. The mixture was stirred at 80° C. for one hour, cooled, and poured into water (100 ml). The product was extracted with diethyl ether (2×), and the combined organic extracts were washed with water, 5% aqueous potassium hydroxide, water, dried (sodium sulfate), and evaporated. The solid obtained was recrystallized from diethyl ether-hexane to afford 3.16 g (53%) of O-2-carbomethoxy-4-fluorophenyl dimethylthiocarbamate. The 90 MHz NMR spectrum in chloroform-d was in accord with the desired structure. the mixture was cooled in an ice-bath cooled The product was extracted with diethyl ether (2×) the combined organic extracts were washed with water, 5% aqueous potassium hydroxide, water dried (sodium sulfate) evaporated The solid obtained was recrystallized from diethyl ether-hexane

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

Procedure: To a solution of methyl 5-fluoro-2-hydroxybenzoate (1.0 g, 5.88 mmol), (R)-(−)-pent-4-en-2-ol (1.210 ml, 11.76 mmol) and triphenylphosphine (2.004 g, 7.64 mmol) in THF (14 ml) was added dropwise DIAD (1.486 ml, 7.64 mmol) and the resulting solution was stirred at rt. After 20 h, the reaction was diluted with Et2O and washed with 1N NaOH, water (3×'s) and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV) to give methyl 5-fluoro-2-(pent-4-en-2-yloxy)benzoate (1.1331 g, 4.76 mmol, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.7, 3.3 Hz, 1H), 7.15 (ddd, J=8.9, 7.7, 3.4 Hz, 1H), 6.96 (dd, J=9.0, 4.2 Hz, 1H), 6.02-5.79 (m, 1H), 5.20-5.06 (m, 2H), 4.50-4.34 (m, 1H), 3.90 (s, 3H), 2.60-2.32 (m, 2H), 1.34 (d, J=6.1 Hz, 3H). washed with 1N NaOH, water (3×'s) and brine The organic phase was dried (Na2SO4) filtered concentrated The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV)

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

Procedure: To a solution of methyl 5-fluoro-2-hydroxybenzoate (1.0 g, 5.88 mmol), (R)-(−)-pent-4-en-2-ol (1.210 ml, 11.76 mmol) and triphenylphosphine (2.004 g, 7.64 mmol) in THF (14 ml) was added dropwise DIAD (1.486 ml, 7.64 mmol) and the resulting solution was stirred at rt. After 20 h, the reaction was diluted with Et2O and washed with 1N NaOH, water (3×'s) and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV) to give methyl 5-fluoro-2-(pent-4-en-2-yloxy)benzoate (1.1331 g, 4.76 mmol, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.7, 3.3 Hz, 1H), 7.15 (ddd, J=8.9, 7.7, 3.4 Hz, 1H), 6.96 (dd, J=9.0, 4.2 Hz, 1H), 6.02-5.79 (m, 1H), 5.20-5.06 (m, 2H), 4.50-4.34 (m, 1H), 3.90 (s, 3H), 2.60-2.32 (m, 2H), 1.34 (d, J=6.1 Hz, 3H). washed with 1N NaOH, water (3×'s) and brine The organic phase was dried (Na2SO4) filtered concentrated The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-fluoro-2-hydroxybenzoate (2.65 g, 15.6 mmo.) and 1-fluoro-2-nitrobenzene (2.02 g, 14.2 mmol) were dissolved in acetonitrile (30 mL) and cesium carbonate (6.10 g, 18.7 mmol) was added. The reaction mixture was stirred at 80° C. for 60 hours. The mixture was cooled down to room temperature and poured into ethyl acetate. This organic mixture was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography with 10-20% ethyl acetate in hexanes and triturated in ethanol to afford the title compound 18 (3.49 g, 84%) as white solid. LRMS (ESI): (calc) 291.05. (found) 292.2 (MS)+. The mixture was cooled down to room temperature This organic mixture was washed with water and brine dried over sodium sulfate filtered evaporated The crude was purified by flash chromatography with 10-20% ethyl acetate in hexanes triturated in ethanol

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

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