2,3-dihydropyran-6-one

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: 4-(4-Trifluoromethylphenyl)tetrahydropyran-2-one (995 mg) derived by the same method as in Preparation Example 2-10 from 4-(trifluoromethyl)phenylboronic acid (5.29 g) and 5,6-dihydro-2H-pyran-2-one was dissolved in tetrahydrofuran (10 mL). The solution was added dropwise at −78° C. to a lithium diisopropylamide solution previously prepared from n-butyllithium (3.91 mL) and diisopropylamine (1.46 mL) in tetrahydrofuran (30 mL). After stirring at the same temperature for 30 minutes, iodomethane (760 μL) and hexamethylphosphoramide (1.77 mL) were added and stirring was continued. After stirring for 30 minutes, the reaction solution was gradually heated to room temperature over three hours and 20 minutes. The reaction was terminated with saturated ammonium chloride aqueous solution. The organic layer was washed with brine and then dried over magnesium sulfate. Removal under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (500 mg). stirring After stirring for 30 minutes The reaction was terminated with saturated ammonium chloride aqueous solution The organic layer was washed with brine dried over magnesium sulfate Removal under reduced pressure gave an oil The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%)

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

Procedure: (Acetylacetonato)bis(ethylene)rhodium (I) (180 mg) was dissolved in 1,4-dioxane (144 mL). Racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene) (867 mg) was added at room temperature, followed by stirring for 30 minutes. Subsequently, water (14.4 mL) and 3-(trifluoromethyl)phenylboronic acid (5.29 g) were added, followed by stirring for 10 minutes. Then, 5,6-dihydro-2H-pyran-2-one (2 mL) was added and the mixture was reacted at 100° C. for 12 hours. The reaction solution was partitioned with ethyl acetate and water. Then, the organic layer was washed with a saturated sodium bicarbonate solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 60%) to obtain the title compound (2.5 g). by stirring for 10 minutes the mixture was reacted at 100° C. for 12 hours The reaction solution was partitioned with ethyl acetate and water Then, the organic layer was washed with a saturated sodium bicarbonate solution dried over magnesium sulfate Concentration under reduced pressure gave an oil The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 60%)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (2.0 g, Reference Example 12), 5,6-dihydro-pyran-2-one (1.1 g), tetrakis(triphenylphosphine)palladium(0) and triethylamine (2.2 g) in dimethylformamide (5 ml) was stirred at about 95° C. in a sealed vessel under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the layers separated, and the organic layer washed with sodium bicarbonate solution, then dried, and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3,v/v) to give the title compound as a brown oil, 1.2 g. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid the layers separated the organic layer washed with sodium bicarbonate solution dried evaporated The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3,v/v)

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5,6-Dihydro-2H-pyran-2-one (1.0 g, 10.2 mmol) was dissolved in 3 ml of a 33% solution of methylamine in ethanol and heated to 55° C. overnight. The solvent was evaporated, the residue dissolved in methanol (20 ml) and conc. HCl (20 ml) and the mixture heated at 95° C. for 2.5 h. The mixture was evaporated to dryness, the residue dissolved in THF (20 ml), dichloromethane (20 ml) and triethylamine (3 ml) and a solution of [2,1,3]-benzoxadiazole-5-carboxylic acid chloride (2.0 g, 11 mmol), in dichloromethane (5 ml), added. After stirring the mixture for 0.75 h, the mixture was washed with 1N HCl and conc. NaHCO3 solution, dried over sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column using ethyl acetate/hexane/dichloromethane (70:20:10), to give N-methyl-N-(2-oxotetrahydro-2H-pyran-4-yl)-[2,1,3]-benzoxadiazole-5-carboxamide as white solid after crystallization from dichloromethane/methanol (0.21 g). Mp=169-171° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.97 (d, J=9.0 Hz, 1H); 7.90 (s, 1H); 7.40 (d, J=9.0 Hz, 1H); 5.10-4.40 (m, 3H); 3.01 (s, 3H); 3.00-2.74 (m, 2H) and 2.60-2.10 ppm (s, 2H). The solvent was evaporated the residue dissolved in methanol (20 ml) conc. HCl (20 ml) and the mixture heated at 95° C. for 2.5 h The mixture was evaporated to dryness the residue dissolved in THF (20 ml) the mixture was washed with 1N HCl and conc. NaHCO3 solution dried over sodium sulfate concentrated under vacuum The residue was purified on a silica gel column

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (3.36 g, 60 mmoles) was added to a stirred solution of 5,6-dihydro-2H-pyran-2-one (4.9 g, 50 mmoles) in water (45 ml) at 5° C. The solution was allowed to warm to 20° C. and stirred for 21/2 hours then evaporated to residue in a vacuum. The residue was flushed with isopropanol (2×50 ml) and dried in a vacuum at 50° C. over P2O5. This solid was slurried in dry dimethylformamide (30 ml) and methyl iodide (34.2 g, 240 mmol) added. The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g). The mixture was extracted with diethyl ether (4×50 ml) and the extracts washed with aqueous sodium chloride (50 ml) and dried (Na2SO4). Solvent removal in a vacuum afforded methyl (Z)-5-hydroxy-2-pentenoate as a colourless oil (4.1 g, 63% yield). The oil was dissolved in dichloromethane (40 ml) with N,N-dimethylaminopyridine (0.1 g) and treated with acetyl chloride (2.75 g, 35 mmoles) in dichloromethane (10 ml) added over 5 minutes at 5° C. The resulting slurry was allowed to warm to room temperature then quenched by the addition of water (40 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (40 ml) and the organic extracts combined, washed with hydrochloric acid (0.5M, 2×50 ml) then water (2×50 ml), and dried (Na 2SO4). Solvent removal in a vacuum followed by Kugelrohr distillation afforded methyl (Z)-5-acetoxy-2-pentenoate as a colourless oil (4.1 g, 76%) b.p. 75° C./0.1 mbar (Found: C, 55.60, H, 7.00 C8H12O4 requires C, 55.80; H, 7.00%). then evaporated to residue in a vacuum The residue was flushed with isopropanol (2×50 ml) dried in a vacuum at 50° C. over P2O5 The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g) The mixture was extracted with diethyl ether (4×50 ml) the extracts washed with aqueous sodium chloride (50 ml) dried (Na2SO4) Solvent removal in a vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (3.36 g, 60 mmoles) was added to a stirred solution of 5,6-dihydro-2H-pyran-2-one (4.9 g, 50 mmoles) in water (45 ml) at 5° C. The solution was allowed to warm to 20° C. and stirred for 21/2 hours then evaporated to residue in a vacuum. The residue was flushed with isopropanol (2×50 ml) and dried in a vacuum at 50° C. over P2O5. This solid was slurried in dry dimethylformamide (30 ml) and methyl iodide (34.2 g, 240 mmol) added. The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g). The mixture was extracted with diethyl ether (4×50 ml) and the extracts washed with aqueous sodium chloride (50 ml) and dried (Na2SO4). Solvent removal in a vacuum afforded methyl (Z)-5-hydroxy-2-pentenoate as a colourless oil (4.1 g, 63% yield). The oil was dissolved in dichloromethane (40 ml) with N,N-dimethylaminopyridine (0.1 g) and treated with acetyl chloride (2.75 g, 35 mmoles) in dichloromethane (10 ml) added over 5 minutes at 5° C. The resulting slurry was allowed to warm to room temperature then quenched by the addition of water (40 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (40 ml) and the organic extracts combined, washed with hydrochloric acid (0.5M, 2×50 ml) then water (2×50 ml), and dried (Na 2SO4). Solvent removal in a vacuum followed by Kugelrohr distillation afforded methyl (Z)-5-acetoxy-2-pentenoate as a colourless oil (4.1 g, 76%) b.p. 75° C./0.1 mbar (Found: C, 55.60, H, 7.00 C8H12O4 requires C, 55.80; H, 7.00%). then evaporated to residue in a vacuum The residue was flushed with isopropanol (2×50 ml) dried in a vacuum at 50° C. over P2O5 The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g) The mixture was extracted with diethyl ether (4×50 ml) the extracts washed with aqueous sodium chloride (50 ml) dried (Na2SO4) Solvent removal in a vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (3.36 g, 60 mmoles) was added to a stirred solution of 5,6-dihydro-2H-pyran-2-one (4.9 g, 50 mmoles) in water (45 ml) at 5° C. The solution was allowed to warm to 20° C. and stirred for 21/2 hours then evaporated to residue in a vacuum. The residue was flushed with isopropanol (2×50 ml) and dried in a vacuum at 50° C. over P2O5. This solid was slurried in dry dimethylformamide (30 ml) and methyl iodide (34.2 g, 240 mmol) added. The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g). The mixture was extracted with diethyl ether (4×50 ml) and the extracts washed with aqueous sodium chloride (50 ml) and dried (Na2SO4). Solvent removal in a vacuum afforded methyl (Z)-5-hydroxy-2-pentenoate as a colourless oil (4.1 g, 63% yield). The oil was dissolved in dichloromethane (40 ml) with N,N-dimethylaminopyridine (0.1 g) and treated with acetyl chloride (2.75 g, 35 mmoles) in dichloromethane (10 ml) added over 5 minutes at 5° C. The resulting slurry was allowed to warm to room temperature then quenched by the addition of water (40 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (40 ml) and the organic extracts combined, washed with hydrochloric acid (0.5M, 2×50 ml) then water (2×50 ml), and dried (Na2SO4). Solvent removal in a vacuum followed by Kugelrohr distillation afforded methyl (Z)-5-acetoxy-2-pentenoate as a colourless oil (4.1 g, 76%) b.p. 75° C./0.1 mbar (Found: C, 55.60, H, 7.00 C8H12O4 requires C, 55.80; H, 7.00%). then evaporated to residue in a vacuum The residue was flushed with isopropanol (2×50 ml) dried in a vacuum at 50° C. over P2O5 The slurry was stirred for 18 hours at 20° C. then quenched by the addition of ice (20 g) The mixture was extracted with diethyl ether (4×50 ml) the extracts washed with aqueous sodium chloride (50 ml) dried (Na2SO4) Solvent removal in a vacuum

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

Procedure: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 8.39 mL, 56.1 mmol) was added to a stirred mixture of tosylmethyl isocyanide (10.95 g, 56.1 mmol) in tetrahydrofuran (THF, 56 mL) at 0° C. After 15 minutes, to the mixture was added 5,6-dihydro-2H-pyran-2-one (5 g, 51 mmol). The mixture was then stirred at room temperature for 2 hours. The reaction was quenched with brine and extracted with THF several times. The combined extracts were dried (sodium sulfate), filter and concentrated to give 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one. The reaction was quenched with brine extracted with THF several times The combined extracts were dried (sodium sulfate) filter concentrated