6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6,6-dimethyl-4-methylene-bicyclo[3.1.1]heptan-2-one (2(10)pinen-4-one, 6.8 g, 45.3 mmol) in dry methanol (300 mL) under a nitrogen atmosphere was cooled to −78° C. in a dry ice/acetone bath. The stirred reaction was treated with ozone for 20 minutes, during which time the solution turned a light blue color, indicating accumulation of ozone and completion of the reaction. The reaction was purged with oxygen (5 minutes), followed by nitrogen (10 minutes) at −78° C., and then dimethyl sulfide (5.0 ml, 68.2 mmole) was added dropwise via a syringe. The resulting reaction mixture was stirred overnight, during which time it came up to room temperature. Methanol was removed on a rotary evaporator, and the residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by column chromatography on silica gel (20% ethyl acetate/hexane) to gave the desired product as a white solid (5.7 g; 83% yield), mp=80–81° C.; MS (−) ESI m/z=151 (M−H)−. The stirred reaction The reaction was purged with oxygen (5 minutes) followed by nitrogen (10 minutes) at −78° C. The resulting reaction mixture came up to room temperature Methanol was removed on a rotary evaporator the residue was partitioned between ethyl acetate (300 mL) and water (300 mL) The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL) the combined organic layers were dried over anhydrous sodium sulfate concentrated on a rotary evaporator

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6,6-dimethyl-4-methylene-bicyclo[3.1.1]heptan-2-one (2(10)pinen-4-one, 6.8 g, 45.3 mmol) in dry methanol (300 mL) under a nitrogen atmosphere was cooled to −78° C. in a dry ice/acetone bath. The stirred reaction was treated with ozone for 20 minutes, during which time the solution turned a light blue color, indicating accumulation of ozone and completion of the reaction. The reaction was purged with oxygen (5 minutes), followed by nitrogen (10 minutes) at −78° C., and then dimethyl sulfide (5.0 ml, 68.2 mmole) was added dropwise via a syringe. The resulting reaction mixture was stirred overnight, during which time it came up to room temperature. Methanol was removed on a rotary evaporator, and the residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by column chromatography on silica gel (20% ethyl acetate/hexane) to gave the desired product as a white solid (5.7 g; 83% yield), mp=80–81° C.; MS (−) ESI m/z=151 (M−H)−. The stirred reaction The reaction was purged with oxygen (5 minutes) followed by nitrogen (10 minutes) at −78° C. The resulting reaction mixture came up to room temperature Methanol was removed on a rotary evaporator the residue was partitioned between ethyl acetate (300 mL) and water (300 mL) The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL) the combined organic layers were dried over anhydrous sodium sulfate concentrated on a rotary evaporator

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-4′-chloro-4-ethyl-2′-fluorobiphenyl (0.213 g, 0.68 mmol) is added to a mixture of 6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione (0.124 g, 0.81 mmol), powdered potassium phosphate (0.316 g, 1.49 mmol), palladium (II) acetate (0.008 g, 0.034 mmol) and (2-dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.024 g, 0.051 mmol) in degassed 1,2-(2.5 ml) and the mixture is stirred and heated to 160° C. for 1 hour under microwave irradiation. The mixture is cooled to room temperature, diluted with ethyl acetate and washed with 2 M aqueous hydrochloric acid. The organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in N,N-dimethylformamide (2 ml) and purified by preparative reverse-phase HPLC. Fractions containing the desired product are taken up in ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, filtered and the fitrate is evaporated under reduced pressure to give 3-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)-6,6-dimethylbicyclo[3.1.1]-heptane-2,4-dione. in degassed 1,2-(2.5 ml) The mixture is cooled to room temperature diluted with ethyl acetate washed with 2 M aqueous hydrochloric acid The organic phase is washed with brine dried over anhydrous magnesium sulfate filtered the filtrate is evaporated under reduced pressure purified by preparative reverse-phase HPLC Fractions containing the desired product washed with brine dried over anhydrous magnesium sulfate filtered the fitrate is evaporated under reduced pressure

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-4′-chloro-4-ethylbiphenyl (0.200 g, 0.68 mmol) is added to a mixture of 6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione (0.124 g, 0.81 mmol), prepared by the method of W. Childers et al., US2006/0004108, powdered potassium phosphate (0.316 g, 1.49 mmol), palladium (II) acetate (0.008 g, 0.034 mmol) and (2-dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.024 g, 0.051 mmol) in degassed 1,2-dimethoxyethane (2 ml) and the mixture is stirred and heated to 160° C. for 1 hour under microwave irradiation. The mixture is cooled to room temperature, diluted with ethyl acetate and washed with 2 M aqueous hydrochloric acid. The organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in N,N-dimethylformamide (2 ml) and purified by preparative reverse-phase HPLC to give 3-(4′-chloro-4-ethylbiphen-3-yl)-6,6-dimethylbicyclo[3.1.1]heptane-2,4-dione. prepared by the method of W The mixture is cooled to room temperature washed with 2 M aqueous hydrochloric acid The organic phase is washed with brine dried over anhydrous magnesium sulfate filtered the filtrate is evaporated under reduced pressure purified by preparative reverse-phase HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6,6-dimethyl-4-methylene-bicyclo[3.1.1]heptan-2-one (2(10)pinen-4-one, 6.8 g, 45.3 mmol) in dry methanol (300 mL) under a nitrogen atmosphere was cooled to −78° C. in a dry ice/acetone bath. The stirred reaction was treated with ozone for 20 minutes, during which time the solution turned a light blue color, indicating accumulation of ozone and completion of the reaction. The reaction was purged with oxygen (5 minutes), followed by nitrogen (10 minutes) at −78° C., and then dimethyl sulfide (5.0 ml, 68.2 mmole) was added dropwise via a syringe. The resulting reaction mixture was stirred overnight, during which time it came up to room temperature. Methanol was removed on a rotary evaporator, and the residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by column chromatography on silica gel (20% ethyl acetate/hexane) to gave the desired product as a white solid (5.7 g; 83% yield), mp=80–81° C.; MS (−) ESI m/z=151 (M−H)−. The stirred reaction The reaction was purged with oxygen (5 minutes) followed by nitrogen (10 minutes) at −78° C. The resulting reaction mixture came up to room temperature Methanol was removed on a rotary evaporator the residue was partitioned between ethyl acetate (300 mL) and water (300 mL) The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL) the combined organic layers were dried over anhydrous sodium sulfate concentrated on a rotary evaporator