1-(2-hydroxy-3-propan-2-ylphenyl)ethanone

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: To a solution of Example 13A (2.048 g, 11.5 mmol) in ethanol (60 mL)was added diethyl oxalate (3.43 mL, 25.3 mmol) and sodium ethoxide (21% in EtOH, 12.9 mL, 34.5 mmol) and the mixture was refluxed for 30 minutes. The mixture was cooled to ambient temperature, partitioned between diethyl ether (150 mL) and water (150 mL). Hydrochloric acid (12N, 3 mL) was added and the separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 8-isopropyl-4-oxo-4H-chromene-2-carboxylate. After dissolving the intermediate in acetic acid (45 mL) and 12N hydrochloric acid (7.5 mL), the mixture was heated to reflux for 5.5 hours then cooled to ambient temperature. Water (400 mL) was added and the mixture was extracted with ethyl acetate (400 mL). The combined organic layers were washed with water (400 mL) and brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and vacuum dried overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (d, 6H), 3.56 (m, 1H), 6.91 (s, 1H), 7.48 (t, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H). MS (ESI) m/z 232.94 (M+H)+. the mixture was refluxed for 30 minutes partitioned between diethyl ether (150 mL) and water (150 mL) Hydrochloric acid (12N, 3 mL) was added the separated organic layer was washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxy-3-isopropylbenzoic acid (Aldrich, 4.0 g, 22.2 mmol) was dissolved in tetrahydrofuran (20 mL), chilled to −75° C., and methyllithium (1.6M in diethyl ether, 42 mL, 66.6 mmol) was added. The mixture stirred overnight at ambient temperature. The mixture was quenched with methanol (50 mL), concentrate under reduced pressure, and ethyl acetate (200 mL) was added. The mixture was washed with 1N hydrochloric acid (200 mL), water (200 mL), and brine and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (d, 6H), 2.64 (s, 3H), 3.39 (m, 1H), 6.87 (t, 1H), 7.41 (dd, 1H), 7.59 (dd, 1H), 12.69 (s, 1H). MS (DCI) m/z 179.07 (M+H)+. The mixture was quenched with methanol (50 mL) concentrate under reduced pressure, and ethyl acetate (200 mL) was added The mixture was washed with 1N hydrochloric acid (200 mL), water (200 mL), and brine the organic layer was dried over anhydrous sodium sulfate filtered concentrate under reduced pressure The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane

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

Procedure: To a solution of Example 13A (2.048 g, 11.5 mmol) in ethanol (60 mL) was added diethyl oxalate (3.43 mL, 25.3 mmol) and sodium ethoxide (21% in EtOH, 12.9 mL, 34.5 mmol) and the mixture was refluxed for 30 minutes. The mixture was cooled to ambient temperature, partitioned between diethyl ether (150 mL) and water (150 mL). Hydrochloric acid (12N, 3 mL) was added and the separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 8-isopropyl-4-oxo-4H-chromene-2-carboxylate. After dissolving the intermediate in acetic acid (45 mL) and 12N hydrochloric acid (7.5 mL), the mixture was heated to reflux for 5.5 hours then cooled to ambient temperature. Water (400 mL) was added and the mixture was extracted with ethyl acetate (400 mL). The combined organic layers were washed with water (400 mL) and brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and vacuum dried overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (d, 6H), 3.56 (m, 1H), 6.91 (s, 1H), 7.48 (t, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H). MS (ESI) m/z 232.94 (M+H)+. the mixture was refluxed for 30 minutes partitioned between diethyl ether (150 mL) and water (150 mL) Hydrochloric acid (12N, 3 mL) was added the separated organic layer was washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxy-3-isopropylbenzoic acid (Aldrich, 4.0 g, 22.2 mmol) was dissolved in tetrahydrofuran (20 mL), chilled to −75° C., and methyllithium (1.6M in diethyl ether, 42 mL, 66.6 mmol) was added. The mixture stirred overnight at ambient temperature. The mixture was quenched with methanol (50 mL), concentrate under reduced pressure, and ethyl acetate (200 mL) was added. The mixture was washed with 1N hydrochloric acid (200 mL), water (200 mL), and brine and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (d, 6H), 2.64 (s, 3H), 3.39 (m, 1H), 6.87 (t, 1H), 7.41 (dd, 1H), 7.59 (dd, 1H), 12.69 (s, 1H). MS (DCI) m/z 179.07 (M+H)+. The mixture was quenched with methanol (50 mL) concentrate under reduced pressure, and ethyl acetate (200 mL) was added The mixture was washed with 1N hydrochloric acid (200 mL), water (200 mL), and brine the organic layer was dried over anhydrous sodium sulfate filtered concentrate under reduced pressure The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane