1-ethylsulfonyl-4-fluorobenzene

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

Procedure: Starting with 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carbaldehyde (115 mg, 0.6 mmol) and 1-ethanesulfonyl-4-fluoro-benzene (226 mg, 1.2 mmol), using a method analogous to the one described for the methyl ester of example 1-1,4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (120 mg, 57%) was obtained as a yellow solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.97, 5.68 Hz, 1H), 7.84 (d, J=9.09 Hz, 2H), 7.33-7.45 (m, 2H), 6.94 (d, J=8.84 Hz, 2H), 3.12 (q, J=7.41 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.45 Hz, 3H). was obtained as a yellow solid which was used in the next step without further purification

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sealed tube containing (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (49 mg, 0.21 mmol), 1-ethanesulfonyl-4-fluoro-benzene (87 mg, 0.427 mmol), and potassium carbonate (73 mg, 0.53 mmol) was evacuated and filled with nitrogen. Anhydrous N,N-dimethylformamide (2 mL) was added. After being stirred at 100° C. overnight, the mixture was cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (67.6 mg, 80%) as a white solid. was evacuated filled with nitrogen Anhydrous N,N-dimethylformamide (2 mL) was added the mixture was cooled to room temperature diluted with water (10 mL) extracted with ethyl acetate (10 mL×2) The combined organic layers were washed with brine (10 mL×3) dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium hydrogen phosphate (14.2 g, 0.1 mol) and sodium sulfite (25.2 g, 0.2 mol) in water (200 mL) was added 4-fluoro-benzenesulfonyl chloride (19.5 g, 0.1 mol). After the mixture was stirred at 60° C. overnight, a solution of bromoethane (32.7 g, 0.3 mol) in acetone (20 mL) was added dropwise, followed by the addition of tetrabutylammonium iodide (3.7 g, 0.01 mol) in one portion. The resulting reaction mixture was stirred at room temperature for 5 days, then diluted with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (elution with 20% ethyl acetate in petroleum ether) to afford 1-ethanesulfonyl-4-fluoro-benzene (11.9 g, 63%) as a yellow oil (reference: Arnold, Leggy A. A., et al., Org. Lett, 6 (2004), 3005-3007). The resulting reaction mixture was stirred at room temperature for 5 days extracted with ethyl acetate (100 mL×3) The combined organic layers were washed with brine dried over sodium sulfate concentrated in vacuo The residue was purified by flash column chromatography (elution with 20% ethyl acetate in petroleum ether)

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

Procedure: Starting with 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carbaldehyde (115 mg, 0.6 mmol) and 1-ethanesulfonyl-4-fluoro-benzene (226 mg, 1.2 mmol), using a method analogous to the one described for the methyl ester of example 1-1,4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (120 mg, 57%) was obtained as a yellow solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.97, 5.68 Hz, 1H), 7.84 (d, J=9.09 Hz, 2H), 7.33-7.45 (m, 2H), 6.94 (d, J=8.84 Hz, 2H), 3.12 (q, J=7.41 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.45 Hz, 3H). was obtained as a yellow solid which was used in the next step without further purification

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sealed tube containing (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (49 mg, 0.21 mmol), 1-ethanesulfonyl-4-fluoro-benzene (87 mg, 0.427 mmol), and potassium carbonate (73 mg, 0.53 mmol) was evacuated and filled with nitrogen. Anhydrous N,N-dimethylformamide (2 mL) was added. After being stirred at 100° C. overnight, the mixture was cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (67.6 mg, 80%) as a white solid. was evacuated filled with nitrogen Anhydrous N,N-dimethylformamide (2 mL) was added the mixture was cooled to room temperature diluted with water (10 mL) extracted with ethyl acetate (10 mL×2) The combined organic layers were washed with brine (10 mL×3) dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium hydrogen phosphate (14.2 g, 0.1 mol) and sodium sulfite (25.2 g, 0.2 mol) in water (200 mL) was added 4-fluoro-benzenesulfonyl chloride (19.5 g, 0.1 mol). After the mixture was stirred at 60° C. overnight, a solution of bromoethane (32.7 g, 0.3 mol) in acetone (20 mL) was added dropwise, followed by the addition of tetrabutylammonium iodide (3.7 g, 0.01 mol) in one portion. The resulting reaction mixture was stirred at room temperature for 5 days, then diluted with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (elution with 20% ethyl acetate in petroleum ether) to afford 1-ethanesulfonyl-4-fluoro-benzene (11.9 g, 63%) as a yellow oil (reference: Arnold, Leggy A. A., et al., Org. Lett, 6 (2004), 3005-3007). The resulting reaction mixture was stirred at room temperature for 5 days extracted with ethyl acetate (100 mL×3) The combined organic layers were washed with brine dried over sodium sulfate concentrated in vacuo The residue was purified by flash column chromatography (elution with 20% ethyl acetate in petroleum ether)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(ethylsulfonyl)-4-fluorobenzene (1.36 mmol, 0.257 g) in sulfuric acid (1.32 ml) was added potassium nitrate (0.243 g) at 80° C. The mixture was stirred at 90° C. for 2 hours. Ice water (5 ml) was added and the mixture was extracted with ethyl acetate (25 ml) and washed with water (20 ml) and brine (10 ml). The organic extracts were combined and dried over sodium sulfate and concentrated. The residue was purified by column chromatography (hexane/ethylacetate 1:3) to give a light yellow solid which was crystallized from methanol. HPLC indicated 98% purity, mp 128-131° C., (0.21 g, 66% yield). 1H NMR (CDCl3): 1.35 (t, 3H, CH3), 3.21 (q, 2H, CH2), 7.55 (t, 1H, Ar—H), 8.21 (m, 1H, Ar—H), 8.64 (d, 1H, Ar—H); MS: 229 M−. Elemental Analysis (C, H, N, F, S) for C8H8FNO4S; calculated C, 41.20; H, 3.46; N, 6.01; F, 8.15; S, 13.75. found C, 41.31; H, 3.35; N, 5.85; F, 8.17; S, 13.53. the mixture was extracted with ethyl acetate (25 ml) washed with water (20 ml) and brine (10 ml) dried over sodium sulfate concentrated The residue was purified by column chromatography (hexane/ethylacetate 1:3) to give a light yellow solid which was crystallized from methanol

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

Procedure: Compound 5e was prepared in analogy to Compound 5a, starting from pipsyl chloride (10 mmol, 3.02 g). A white solid was crystallized from ethyl acetate and hexane. HPLC indicated 100% purity, mp 78-79° C., (0.60 g, 20% yield). 1H NMR (CDCl3): 1.28 (t, 3H, CH3), 3.12 (q, 2H, CH2), 7.63 (d, 2H, Ar—H), 7.96 (d, 2H, Ar—H); MS: 296 M+. Elemental Analysis (C, H, I, S) for C8H9IO2S.0.2C6H14-0.1H2O; calculated C, 35.06; H, 3.83; I, 40.26; S, 10.17. found C, 35.04; H, 3.41; I, 40.32; S, 9.74. A white solid was crystallized from ethyl acetate and hexane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(ethylsulfonyl)-4-fluorobenzene (1.36 mmol, 0.257 g) in sulfuric acid (1.32 ml) was added potassium nitrate (0.243 g) at 80° C. The mixture was stirred at 90° C. for 2 hours. Ice water (5 ml) was added and the mixture was extracted with ethyl acetate (25 ml) and washed with water (20 ml) and brine (10 ml). The organic extracts were combined and dried over sodium sulfate and concentrated. The residue was purified by column chromatography (hexane/ethylacetate 1:3) to give a light yellow solid which was crystallized from methanol. HPLC indicated 98% purity, mp 128-131° C., (0.21 g, 66% yield). 1H NMR (CDCl3): 1.35 (t, 3H, CH3), 3.21 (q, 2H, CH2), 7.55 (t, 1H, Ar—H), 8.21 (m, 1H, Ar—H), 8.64 (d, 1H, Ar—H); MS: 229 M−. Elemental Analysis (C, H, N, F, S) for C8H8FNO4S; calculated C, 41.20; H, 3.46; N, 6.01; F, 8.15; S, 13.75. found C, 41.31; H, 3.35; N, 5.85; F, 8.17; S, 13.53. the mixture was extracted with ethyl acetate (25 ml) washed with water (20 ml) and brine (10 ml) dried over sodium sulfate concentrated The residue was purified by column chromatography (hexane/ethylacetate 1:3) to give a light yellow solid which was crystallized from methanol

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

Procedure: Compound 5e was prepared in analogy to Compound 5a, starting from pipsyl chloride (10 mmol, 3.02 g). A white solid was crystallized from ethyl acetate and hexane. HPLC indicated 100% purity, mp 78-79° C., (0.60 g, 20% yield). 1H NMR (CDCl3): 1.28 (t, 3H, CH3), 3.12 (q, 2H, CH2), 7.63 (d, 2H, Ar—H), 7.96 (d, 2H, Ar—H); MS: 296 M+. Elemental Analysis (C, H, I, S) for C8H9IO2S.0.2C6H14-0.1H2O; calculated C, 35.06; H, 3.83; I, 40.26; S, 10.17. found C, 35.04; H, 3.41; I, 40.32; S, 9.74. A white solid was crystallized from ethyl acetate and hexane

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

Procedure: Starting with 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carbaldehyde (115 mg, 0.6 mmol) and 1-ethanesulfonyl-4-fluoro-benzene (226 mg, 1.2 mmol), using a method analogous to the one described for the methyl ester of example 1-1,4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (120 mg, 57%) was obtained as a yellow solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.97, 5.68 Hz, 1H), 7.84 (d, J=9.09 Hz, 2H), 7.33-7.45 (m, 2H), 6.94 (d, J=8.84 Hz, 2H), 3.12 (q, J=7.41 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.45 Hz, 3H). was obtained as a yellow solid which was used in the next step without further purification

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sealed tube containing (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (49 mg, 0.21 mmol), 1-ethanesulfonyl-4-fluoro-benzene (87 mg, 0.427 mmol), and potassium carbonate (73 mg, 0.53 mmol) was evacuated and filled with nitrogen. Anhydrous N,N-dimethylformamide (2 mL) was added. After being stirred at 100° C. overnight, the mixture was cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (67.6 mg, 80%) as a white solid. was evacuated filled with nitrogen Anhydrous N,N-dimethylformamide (2 mL) was added the mixture was cooled to room temperature diluted with water (10 mL) extracted with ethyl acetate (10 mL×2) The combined organic layers were washed with brine (10 mL×3) dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether)