P-METHYLPHENYLACETALDEHYDE

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 ethyl 4-methylphenylacetate (0.89 g, 5.0 mmol) in dry methylene chloride (5 ml) cooled to −78° C. under nitrogen was added drop-wise 1.1 M di-isobutyl-aluminum hydride in toluene (4.5 ml, 5 mmol), keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (40 ml), and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (40 ml). The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give 7.1 g of 4-methylphenylacetaldehyde as a volatile liquid: 1H NMR (CDCl3) 9.73 (1H, t, J 2.5 Hz), 7.17 (2H, m), 7.12 (2H, m), 3.64 (2H, d, J 2.5 Hz), 2.35 (3H, s). To a stirred mixture of benzyl (trans-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)carbamate (524 mg, 1.5 mmol), triethylsilane (0.36 ml, 260 mg, 2.25 mmol), and bismuth tribromide (45 mg, 0.10 mmol), in anhydrous acetonitrile (7.5 ml), was added the freshly prepared 4-methylphenylacetaldehyde (460 mg, approx. 2.2 mmol) slowly, keeping the temperature at or below 25° C. After stirring for 4 h, the reaction was quenched with half-saturated sodium bicarbonate (30 ml) and ethyl acetate (25 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (3×8 ml), and the filtrate layers were separated. The organic layer was washed with one-fifth saturated brine (8 ml) and water (8 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a heterogeneous oil (1.19 g). The oil was chromatographed on silica gel, eluting with ethyl acetate:hexane (5:95 increasing to 25:75) to give a white solid. The solid was triturated with ethyl acetate:hexane (20:80), filtered off and dried to give benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 55%) as a white solid. A second crop was obtained from the mother liquor (34 mg, 6%). the internal temperature below −68° C When the addition the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml) The mixture was filtered through filter aid the pad was washed with ethyl acetate (40 ml) the filtrate layers were separated The aqueous layer was extracted with ethyl acetate (40 ml) The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml) dried (sodium sulfate) filtered the solvent evaporated under reduced pressure

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

Procedure: To a solution of ethyl 4-methylphenylacetate (0.89 g, 5.0 mmol) in dry methylene chloride (5 ml) cooled to −78° C. under nitrogen was added drop-wise 1.1 M di-isobutyl-aluminum hydride in toluene (4.5 ml, 5 mmol), keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (40 ml), and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (40 ml). The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give 7.1 g of 4-methylphenylacetaldehyde as a volatile liquid: 1H NMR (CDCl3) 9.73 (1H, t, J 2.5 Hz), 7.17 (2H, m), 7.12 (2H, m), 3.64 (2H, d, J 2.5 Hz), 2.35 (3H, s). To a stirred mixture of benzyl (trans-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)carbamate (524 mg, 1.5 mmol), triethylsilane (0.36 ml, 260 mg, 2.25 mmol), and bismuth tribromide (45 mg, 0.10 mmol), in anhydrous acetonitrile (7.5 ml), was added the freshly prepared 4-methylphenylacetaldehyde (460 mg, approx. 2.2 mmol) slowly, keeping the temperature at or below 25° C. After stirring for 4 h, the reaction was quenched with half-saturated sodium bicarbonate (30 ml) and ethyl acetate (25 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (3×8 ml), and the filtrate layers were separated. The organic layer was washed with one-fifth saturated brine (8 ml) and water (8 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a heterogeneous oil (1.19 g). The oil was chromatographed on silica gel, eluting with ethyl acetate:hexane (5:95 increasing to 25:75) to give a white solid. The solid was triturated with ethyl acetate:hexane (20:80), filtered off and dried to give benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 55%) as a white solid. A second crop was obtained from the mother liquor (34 mg, 6%). the internal temperature below −68° C When the addition the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml) The mixture was filtered through filter aid the pad was washed with ethyl acetate (40 ml) the filtrate layers were separated The aqueous layer was extracted with ethyl acetate (40 ml) The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml) dried (sodium sulfate) filtered the solvent evaporated under reduced pressure

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

Procedure: At 10° C., p-tolyl-acetaldehyde (11.0 g, 82 mmol) is added to a mixture of POCl3 (20 mL, 230 mmol) and DMF (20 mL). The mixture is stirred at rt for 2 h before the reaction is quenched by adding water/ice and NaOAc and extracted with DCM (2×200 mL). The solvent of the organic extract is evaporated and the product is purified by CC on silica gel eluting with heptane:EA 9:1. The resulting oil (1.95 g) is dissolved in ethanol (5 mL) and then added dropwise to a freshly prepared solution of Na (370 mg, 16.2 mmol) and ethyl-2-mercaptoacetate (1.95 g, 16.2 mmol) in ethanol (20 mL). The reaction mixture is stirred at it for 72 h, diluted with water (100 mL) and extracted with EA (2×150 mL). The organic extracts are dried over MgSO4 and evaporated. CC on silica gel eluting with heptane:EA 5:1 gives 4-p-tolyl-thiopene-2-carboxylic acid ethyl ester (850 mg). This ester is dissolved in ethanol (10 mL) and 3 M aq. NaOH (5 mL) and the mixture is refluxed for 2 h. The reaction mixture is acidified and extracted with DCM. The organic extract is dried over MgSO4 and the solvent is evaporated to give 4-p-tolyl-thiophene-2-carboxylic acid (580 mg) as a solid; LC-MS: tR=0.91 min, [M+1+CH3CN]+=260.16, 1H NMR (CDCl3): δ 8.14 (s, 1H), 7.70 (s, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 7.05 (s br, 1H), 2.39 (s, 3H). is quenched by adding water/ice and NaOAc extracted with DCM (2×200 mL) The solvent of the organic extract is evaporated the product is purified by CC on silica gel eluting with heptane:EA 9:1 The resulting oil (1.95 g) is dissolved in ethanol (5 mL) The reaction mixture is stirred at it for 72 h extracted with EA (2×150 mL) The organic extracts are dried over MgSO4 evaporated

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

Procedure: 2.57 g of aldehyde 37 is introduced into 300 ml of methylene chloride under nitrogen, and 6.5 ml of triethylamine and 7.1 g of Eschenmoser's salt are added at 0° C. After 2.5 hours at 0° C., saturated ammonium chloride solution is added, extracted with methylene chloride, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil. extracted with methylene chloride washed with sodium chloride solution dried on sodium sulfate concentrated by evaporation The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil

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

Procedure: To a solution of ethyl 4-methylphenylacetate (0.89 g, 5.0 mmol) in dry methylene chloride (5 ml) cooled to −78° C. under nitrogen was added drop-wise 1.1 M di-isobutyl-aluminum hydride in toluene (4.5 ml, 5 mmol), keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (40 ml), and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (40 ml). The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give 7.1 g of 4-methylphenylacetaldehyde as a volatile liquid: 1H NMR (CDCl3) 9.73 (1H, t, J 2.5 Hz), 7.17 (2H, m), 7.12 (2H, m), 3.64 (2H, d, J 2.5 Hz), 2.35 (3H, s). To a stirred mixture of benzyl (trans-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)carbamate (524 mg, 1.5 mmol), triethylsilane (0.36 ml, 260 mg, 2.25 mmol), and bismuth tribromide (45 mg, 0.10 mmol), in anhydrous acetonitrile (7.5 ml), was added the freshly prepared 4-methylphenylacetaldehyde (460 mg, approx. 2.2 mmol) slowly, keeping the temperature at or below 25° C. After stirring for 4 h, the reaction was quenched with half-saturated sodium bicarbonate (30 ml) and ethyl acetate (25 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (3×8 ml), and the filtrate layers were separated. The organic layer was washed with one-fifth saturated brine (8 ml) and water (8 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a heterogeneous oil (1.19 g). The oil was chromatographed on silica gel, eluting with ethyl acetate:hexane (5:95 increasing to 25:75) to give a white solid. The solid was triturated with ethyl acetate:hexane (20:80), filtered off and dried to give benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 55%) as a white solid. A second crop was obtained from the mother liquor (34 mg, 6%). the internal temperature below −68° C When the addition the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml) The mixture was filtered through filter aid the pad was washed with ethyl acetate (40 ml) the filtrate layers were separated The aqueous layer was extracted with ethyl acetate (40 ml) The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml) dried (sodium sulfate) filtered the solvent evaporated under reduced pressure

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

Procedure: The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and p-Tolyl-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 380; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.1259.

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

Procedure: 2.57 g of aldehyde 37 is introduced into 300 ml of methylene chloride under nitrogen, and 6.5 ml of triethylamine and 7.1 g of Eschenmoser's salt are added at 0° C. After 2.5 hours at 0° C., saturated ammonium chloride solution is added, extracted with methylene chloride, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil. extracted with methylene chloride washed with sodium chloride solution dried on sodium sulfate concentrated by evaporation The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil

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

Procedure: 2.57 g of aldehyde 37 is introduced into 300 ml of methylene chloride under nitrogen, and 6.5 ml of triethylamine and 7.1 g of Eschenmoser's salt are added at 0° C. After 2.5 hours at 0° C., saturated ammonium chloride solution is added, extracted with methylene chloride, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil. extracted with methylene chloride washed with sodium chloride solution dried on sodium sulfate concentrated by evaporation The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil

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

Procedure: In the like manner as Example 1, 26.4 g of p-methylphenylacetaldehyde as an aldehyde and 2.3 g of sulfuric acid were used. The oxidation was done by using 125 g of 12% aqueous solution of sodium hypochlorite at temperatures of -10° to -12° C., which was followed by the hydrogenation to obtain p-methylphenylacetic acid. at temperatures of -10° to -12° C., which

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

Procedure: 2.57 g of aldehyde 37 is introduced into 300 ml of methylene chloride under nitrogen, and 6.5 ml of triethylamine and 7.1 g of Eschenmoser's salt are added at 0° C. After 2.5 hours at 0° C., saturated ammonium chloride solution is added, extracted with methylene chloride, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil. extracted with methylene chloride washed with sodium chloride solution dried on sodium sulfate concentrated by evaporation The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil