4-chloro-3-fluorophenol

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:; See reaction.notes.procedure_details.

Procedure: Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-chloro-3-fluorophenol, the title compound was obtained (33%): 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H), 7.52-7.41 (m, 2H), 7.23 (t, 1H), 6.96 (d, 1H), 6.84 (d, 1H), 6.80 (d, 1H), 4.15 (s, 1H), 3.79-3.58 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 346 (M−17), 386 (M+23).

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

Procedure: 4-chloro-3-fluorophenol (2.38 g, 16.2 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.524 g, 1.62 mmol) was added. HNO3 70% (2.1 mL, 32 mmol) was diluted with H2O (18.9 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.29 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 8.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=10.6 Hz, 1H). This solution was added to the reaction mixture which extracted with DCM (3×) The combined organic layers were dried over MgSO4 filtered concentrated in vacuo chromatographed

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

Procedure: The general procedure of Example 3 was repeated using 4-chloro-3-fluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product. obtaining the intended product

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

Procedure: The general procedure of Example 3 was repeated using 4-chloro-3-fluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product. obtaining the intended product

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

Procedure: To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz). to stir for overnight at RT was added was extracted with ethyl acetate (3×15 mL) the resulting organic layer was washed with water, brine dried

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

Procedure: 3-Fluoro-4-chlorophenol (1.78 g, 12.1 mmol) was dissolved in methanol (40 mL). Sodium iodide (3.63 g, 24.2 mmol) and sodium hydroxide (0.97 g, 24.2 mmol) was added, and the solution was cooled to 0° C. Aqueous sodium hypochlorite (6.0% NaOCl, 24.2 mmol) was added dropwise over 75 minutes at 0-3° C. The resulting slurry was stirred for 1 h at 0-2° C. and allowed to warm up to room temperature overnight. White precipitates were observed. The mixture was adjusted to pH 7 using 1M aqueous HCl while stirring. The aqueous layer was extracted with ether for three times and the ether layer was washed with aq sodium thiosulfate, brine, the organic layers were dried with MgSO4. The solvent was removed under reduced pressure to afford the residue which was purified by flash column chromatography on silica gel (Hexanes:Ethyl acetate 1:1 to afford the desired product (1.60 g, 64% yield). 1H NMR: 6.84 (d, 1H, J=9.9 Hz), 7.67 (d, 1H, J=8.1 Hz). to warm up to room temperature overnight White precipitates while stirring The aqueous layer was extracted with ether for three times the ether layer was washed with aq sodium thiosulfate, brine the organic layers were dried with MgSO4 The solvent was removed under reduced pressure to afford the residue which was purified by flash column chromatography on silica gel (Hexanes:Ethyl acetate 1:1

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

Procedure: The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3-fluorophenol.

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

Procedure: The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 4-chloro-3-fluorophenol.

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

Procedure: The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 4-chloro-3-fluorophenol.