3-phenyloxolan-2-one

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

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

Procedure: 2,3,4,5,6,7-Hexahydro-1H-azepine (3.36 g, 33.9 mmol) in 1,2-dichloroethane (10 ml) was added to a cooled (ice/water) solution of triethylamine (4.68 g, 46.2 mmol) and aluminium trichloride (4.52 g, 33.9 mmol) in 1,2-dichloroethane (70 ml). A solution of 2-phenylbutyrolactone (5.00 g, 30.8 mmol) in 1,2-dichloroethane (50 ml) was added to the cooled reaction mixture and stirring continued overnight. The reaction mixture was poured into water (150 ml), basified with 2M-NaOH, and washed with ethyl acetate (3×80 ml). The combined organic phases were washed with brine (80 ml) and water (80 ml), dried (MgSO4), and concentrated in vacuo to afford a brown oil which partially solidified on standing. The crude product was chromatographed on silica gel, eluting with ethyl acetate to give the title compound as an oil (2.68 g, 33.3%). washed with ethyl acetate (3×80 ml) The combined organic phases were washed with brine (80 ml) and water (80 ml) dried (MgSO4) concentrated in vacuo to afford a brown oil which The crude product was chromatographed on silica gel eluting with ethyl acetate

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

Procedure: 2,3,4,5,6,7-Hexahydro-1H-azepine (3.36 g, 33.9 mmol) in 1,2-dichloroethane (10 ml) was added to a cooled (ice/water) solution of triethylamine (4.68 g, 46.2 mmol) and aluminium trichloride (4.52 g, 33.9 mmol) in 1,2-dichloroethane (70 ml). A solution of 2-phenylbutyrolactone (5.00 g, 30.8 mmol) in 1,2-dichloroethane (50 ml) was added to the cooled reaction mixture and stirring continued overnight. The reaction mixture was poured into water (150 ml), basified with 2M-NaOH, and washed with ethyl acetate (3×80 ml). The combined organic phases were washed with brine (80 ml) and water (80 ml), dried (MgSO4), and concentrated in vacuo to afford a brown oil which partially solidified on standing. The crude product was chromatographed on silica gel, eluting with ethyl acetate to give the title compound as an oil (2.68 g, 33.3%). washed with ethyl acetate (3×80 ml) The combined organic phases were washed with brine (80 ml) and water (80 ml) dried (MgSO4) concentrated in vacuo to afford a brown oil which The crude product was chromatographed on silica gel eluting with ethyl acetate

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

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

Procedure: To a solution of 3-methoxy-thiophenol (1.4 g, 0.01 mol) and 2-phenylbutyrolactone 2a (1.5 g, 0.0093 mol, (Tetrahedron 47, (8) 1525-40, 1991) in DMF (10.0 mL) were added potassium carbonate (1.4 g, 0.01 mol) and 18-crown-C (0.05 g), and the mixture was heated at 75° C. for 12 h under an atmosphere of argon. The reaction mixture was cooled, and partioned between 5% citric acid (25 mL) and ethylacetate (50 mL). The organic phase was washed with water (2×25 mL), dried dried (Na2SO4) and concentrated under reduced pressure to give a yellow syrup. This was purified by silica gel flash chromatography using 20% EtOAc in hexane. Fractions containing the desired acid as monitored by ES mass spectrometry, [m/z=303 (M+H)] were combined and concentrated. This material was dissolved in EtOH (5 mL), added 4N HCl/dioxane (5.0 mL) and stirred at room temperature for 1 h, and at 70° C. for 1 h. The resulting solution was concentrated to dryness and the residue was purified by silica gel flash chromatography using 20% EtOAc in hexane to give 1.2 g (40%) of the desired ester as a pale yellow liquid: 1H-NMR (400 Mz, CDCl3) δ 7.35-7.15 (m, 5H), 6.87 (m, m 1H), 6.85 (m, 1H), 6.70(m, 1H), 4.02 (m, 2H), 3.77 (m, 3H), 3.18 (d, 2H, J=7.2 Hz), 2.92 (dd, 1H, J=6.4 Hz), 2.65 (dd, 1H, J=8.0 Hz), and 1.11 (t, 3H, J=6.8 Hz); ES-MS m/z 331 (M+H)+; HR-MS Calcd C19H23O3S 331.1100, found 331.1377. The reaction mixture was cooled The organic phase was washed with water (2×25 mL) dried dried (Na2SO4) concentrated under reduced pressure to give a yellow syrup This was purified by silica gel flash chromatography Fractions containing the desired acid concentrated This material was dissolved in EtOH (5 mL) added 4N HCl/dioxane (5.0 mL) at 70° C. for 1 h The resulting solution was concentrated to dryness the residue was purified by silica gel flash chromatography

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

Procedure: To a solution of 3-methoxy-thiophenol (1.4 g, 0.01 mol) and 2-phenylbutyrolactone 2a (1.5 g, 0.0093 mol, (Tetrahedron 47, (8) 1525-40, 1991) in DMF (10.0 mL) were added potassium carbonate (1.4 g, 0.01 mol) and 18-crown-C (0.05 g), and the mixture was heated at 75° C. for 12 h under an atmosphere of argon. The reaction mixture was cooled, and partioned between 5% citric acid (25 mL) and ethylacetate (50 mL). The organic phase was washed with water (2×25 mL), dried dried (Na2SO4) and concentrated under reduced pressure to give a yellow syrup. This was purified by silica gel flash chromatography using 20% EtOAc in hexane. Fractions containing the desired acid as monitored by ES mass spectrometry, [m/z=303 (M+H)] were combined and concentrated. This material was dissolved in EtOH (5 mL), added 4N HCl/dioxane (5.0 mL) and stirred at room temperature for 1 h, and at 70° C. for 1 h. The resulting solution was concentrated to dryness and the residue was purified by silica gel flash chromatography using 20% EtOAc in hexane to give 1.2 g (40%) of the desired ester as a pale yellow liquid: 1H-NMR (400 Mz, CDCl3) δ 7.35-7.15 (m, 5H), 6.87 (m, m 1H), 6.85 (m, 1H), 6.70(m, 1H), 4.02 (m, 2H), 3.77 (m, 3H), 3.18 (d, 2H, J=7.2 Hz), 2.92 (dd, 1H, J=6.4 Hz), 2.65 (dd, 1H, J=8.0 Hz), and 1.11 (t, 3H, J=6.8 Hz); ES-MS m/z 331 (M+H)+; HR-MS Calcd C19H23O3S 331.1100, found 331.1377. The reaction mixture was cooled The organic phase was washed with water (2×25 mL) dried dried (Na2SO4) concentrated under reduced pressure to give a yellow syrup This was purified by silica gel flash chromatography Fractions containing the desired acid concentrated This material was dissolved in EtOH (5 mL) added 4N HCl/dioxane (5.0 mL) at 70° C. for 1 h The resulting solution was concentrated to dryness the residue was purified by silica gel flash chromatography

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

Procedure: Butyl lithium (62.5 mL of 1.6M solution in hexanes) was treated dropwise with a solution of diisopropylamine (14.0 mL) in THF (200 mL) at −20° C. and the resulted mixture was stirred for additional 30 min at the same temperature. After that the mixture was cooled to −90° C., treated dropwise with a solution of 2-phenyl-γ-butyrolactone (11.0 g) in THF (50 mL) and then stirred for 45 min at the same temperature. Next the reaction mixture was treated dropwise with a solution of chloromethyl methyl ether (8.05 g) in THF (50 mL), stirred for additional 10 min, then allowed to slowly warm-up to room temperature and stirred at this temperature for 16 h. Subsequently the reaction mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid. The formed organic phase was separated and the aqueous phase was extracted with chloroform. The combined organic phases were washed with saturated aqueous solution of potassium bicarbonate, then water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.5 g (82%) of the title compound. stirred for 45 min at the same temperature stirred for additional 10 min to slowly warm-up to room temperature stirred at this temperature for 16 h Subsequently the reaction mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid The formed organic phase was separated the aqueous phase was extracted with chloroform The combined organic phases were washed with saturated aqueous solution of potassium bicarbonate water, dried over magnesium sulfate filtered concentrated on a rotary evaporator distilled in vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of potassium tert-butoxide (12.3 g) in toluene (200 mL) was treated dropwise with a mixture of phenylacetonitrile (12.9 g) and (2-bromoethoxy)trimethyl-silane (23.8 g) at room temperature. Upon completion of the addition, the reaction mixture was refluxed for 5 h, then cooled to room temperature and quenched by pouring onto a mixture of ice and water. The formed organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 2-phenyl-4-trimethylsilanyloxy-butyronitrile. The obtained butyronitrile derivative was redissolved in a mixture of ethanol (40 mL) and 70% aqueous sulfuric acid (40 mL), stirred at 50° C. for 3 h and, after cooling to room temperature, diluted with water (150 mL). The resulted organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, then with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.0 g (62%) of the title compound. after cooling to room temperature The resulted organic phase was separated the aqueous phase was extracted with benzene The combined organic phases were washed with water with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate filtered concentrated on a rotary evaporator distilled in vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of potassium tert-butoxide (12.3 g) in toluene (200 mL) was treated dropwise with a mixture of phenylacetonitrile (12.9 g) and (2-bromoethoxy)trimethyl-silane (23.8 g) at room temperature. Upon completion of the addition, the reaction mixture was refluxed for 5 h, then cooled to room temperature and quenched by pouring onto a mixture of ice and water. The formed organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 2-phenyl-4-trimethylsilanyloxy-butyronitrile. The obtained butyronitrile derivative was redissolved in a mixture of ethanol (40 mL) and 70% aqueous sulfuric acid (40 mL), stirred at 50° C. for 3 h and, after cooling to room temperature, diluted with water (150 mL). The resulted organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, then with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.0 g (62%) of the title compound. after cooling to room temperature The resulted organic phase was separated the aqueous phase was extracted with benzene The combined organic phases were washed with water with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate filtered concentrated on a rotary evaporator distilled in vacuum

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

Procedure: To a solution of 3-methoxy-thiophenol (1.4 g, 0.01 mol) and 2-phenylbutyro-lactone 2a (1.5 g, 0.0093 mol, (Tetrahedron 47, (8) 1525-40, 1991) in DMF (10.0 mL) were added potassium carbonate (1.4 g, 0.01 mol) and 18-crown-C (0.05 g), and the mixture was heated at 75° C. for 12 h under an atmosphere of argon. The reaction mixture was cooled, and partioned between 5% citric acid (25 mL) and ethylacetate (50 mL). The organic phase was washed with water (2×25 mL), dried dried (Na2SO4) and concentrated under reduced pressure to give a yellow syrup. This was purified by silica gel flash chromatography using 20% EtOAc in hexane. Fractions containing the desired acid as monitored by ES mass spectrometry, [m/z=303 (M+H)] were combined and concentrated. This material was dissolved in EtOH (5 mL), added 4N HCl/dioxane (5.0 mL) and stirred at room temperature for 1 h, and at 70° C. for 1 h. The resulting solution was concentrated to dryness and the residue was purified by silica gel flash chromatography using 20% EtOAc in hexane to give 1.2 g (40%) of the desired ester as a pale yellow liquid: 1H-NMR (400 Mz, CDCl3) δ 7.35-7.15 (m, 5H), 6.87 (m, m 1H), 6.85 (m, 1H), 6.70 (m, 1H), 4.02 (m, 2H), 3.77 (m, 3H), 3.18 (d, 2H, J=7.2 Hz), 2.92 (dd, 1H, J=6.4 Hz), 2.65 (dd, 1H, J=8.0 Hz), and 1.11 (t, 3H, J=6.8 Hz); ES-MS m/z 331 (M+H)+; HR-MS Calcd C19H23O3S 331.1100, found 331.1377. The reaction mixture was cooled The organic phase was washed with water (2×25 mL) dried dried (Na2SO4) concentrated under reduced pressure to give a yellow syrup This was purified by silica gel flash chromatography Fractions containing the desired acid concentrated This material was dissolved in EtOH (5 mL) added 4N HCl/dioxane (5.0 mL) at 70° C. for 1 h The resulting solution was concentrated to dryness the residue was purified by silica gel flash chromatography

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

Procedure: The product of Example 3 (14.5 g, 90 mM) in 48% of HBr/acetic acid (100 ml) was left at room temperature overnight. The reaction was poured onto water (500 ml) and extracted with IPE 2x). The organic phase was washed with water, dried and evaporated to give the crystalline product (22 g) m.p. (cyclohexane). The reaction was poured onto water (500 ml) extracted with IPE 2x) The organic phase was washed with water dried evaporated

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

Procedure: The product of Example 2 (837 g, 2.6M) methanol (1.5 l) and 40% aq. NaOH (1 l, 10M) were heated to reflux for 2 hours. The reaction was then cooled to room temperature and acidified with conc. HCl (1l). The reaction was left as room temperature overnight and then extracted with methyl tert.butyl ether (1 l,500 ml). The extracts were washed with aq. Na2CO3, dried and evaporated to give the title compound(376 g, 89%). to reflux for 2 hours extracted with methyl tert.butyl ether (1 l,500 ml) The extracts were washed with aq. Na2CO3 dried evaporated