3,7,7-trimethylbicyclo[4.1.0]hept-3-ene

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg methyl trioxorhenium was dissolved in 30% aqueous hydrogen peroxide (19 ml) and cooled to 0° C. internal in a 250 ml, 3-necked flask. A solution was separately prepared from 1,3-dioxolane (89 ml), the carene mixture (11 g), and pyridine (9 ml). This was also cooled to 0° C. internal. While stirring the cold aqueous solution vigorously, the cold dioxolane solution was added over 70 minutes, keeping the exothermic reaction at 0-5° C. After three hours, NaCl solution (20 ml) was added and the layers were separated. The aqueous layer was extracted once with dioxolane (25 ml). The organics were combined. Aqueous pH 5.8 buffer solution (275 ml) was added and stirred vigorously at room temperature for 1 hour, then 30° C. for 2.5 hours. The reaction was transferred to a separating funnel and washed once with heptane (100 ml). NaCl (43 g) was added to the aqueous layer and stirred for 30 min. The aqueous layer was extracted with ethyl acetate (1×100 ml, 2×250 ml). The ethyl acetate extracts were combined, dried over Na2SO4, and concentrated in vacuo to solid (2 g). The solid was dissolved in hot ethyl acetate. Heptane was added and the solution was allowed to cool with stirring and then cooled to 0° C. The solid was collected by vacuum filtration and washed with hexane. After drying under vacuum, 1.1 g (+)-p-menth-2-ene-diol (6.5% yield from (+)-3-carene) was obtained. This was also cooled to 0° C. internal the exothermic reaction at 0-5° C the layers were separated The aqueous layer was extracted once with dioxolane (25 ml) Aqueous pH 5.8 buffer solution (275 ml) was added stirred vigorously at room temperature for 1 hour 30° C. for 2.5 hours The reaction was transferred to a separating funnel washed once with heptane (100 ml) NaCl (43 g) was added to the aqueous layer stirred for 30 min The aqueous layer was extracted with ethyl acetate (1×100 ml, 2×250 ml) dried over Na2SO4 concentrated in vacuo to solid (2 g) The solid was dissolved in hot ethyl acetate Heptane was added to cool with stirring cooled to 0° C The solid was collected by vacuum filtration washed with hexane After drying under vacuum

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

Procedure: The starting material 2-caren-4-one can be produced from commercially available, optically pure (+)-3-carene. The (+)-3-carene is treated with nitrosyl chloride followed by the addition of powdered sodium carbonate. The resulting 2-caren-4-one oxime is then treated with sodium bisulfite in aqueous ethanol to yield 2-caren-4-one, the desired starting product for the inventive process.

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

Procedure: Δ-3-carene was epoxidized by the above-described procedure, using Di(acetate)3 as catalyst (1% based on the weight of Δ-3-carene) and ethyl acetate as solvent (volume ratio solvent to Δ-3-carene 3:1). The final mol ratio propionaldehyde to Δ-3-carene was 1.5:1, oxygen was bubbled through at a rate of 8 liters/hour, and reaction time was 4 hours. was bubbled through at a rate of 8 liters/hour, and reaction time

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

Procedure: To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxane (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL), and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. 1H NMR (CDCl3): δ 4.05 (dd, J=7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J=10.0, 14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H). extracted with diethyl ether (500 mL) The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL) dried over Na2SO4 The solvent is removed under reduced pressure the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1

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

Procedure: To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxane (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL), and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. 1H NMR (CDCl3): δ 4.05 (dd, J=7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J=10.0, 14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H). extracted with diethyl ether (500 mL) The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL) dried over Na2SO4 The solvent is removed under reduced pressure the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1

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

Procedure: To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxan (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL), and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. 1H NMR(CDCl3): δ 4.05 (dd, J=7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J=10.0, 14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H). extracted with diethyl ether (500 mL) The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL) dried over Na2SO4 The solvent is removed under reduced pressure the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1

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

Procedure: To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxan (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL), and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. 1H NMR(CDCl3): δ 4.05 (dd, J=7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J=10.0, 14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H). extracted with diethyl ether (500 mL) The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL) dried over Na2SO4 The solvent is removed under reduced pressure the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1

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

Procedure: A suspension of (+)-3-carene (4.09 g, 30 mmol), CaCO3 (3.90 g, 39 mmol) and NBS (6.94 g, 39 mmol) in water (15 mL) and 1,4-dioxane (30 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (75 mL) and extracted with Et2O (100 mL). The organic layer washed with water (3×50 mL), saturated Na2S2O3 aq. (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide compound C22-1 (4.53 g, 65%) as a white solid. extracted with Et2O (100 mL) The organic layer washed with water (3×50 mL), saturated Na2S2O3 aq. (50 mL) dried over MgSO4 concentrated under reduced pressure The residue was purified by silicagel chromatography (10% EtOAc/hexane as eluent) to provide compound C22-1 (4.53 g, 65%) as a white solid

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

Procedure: The condensation of cyanoacetic acid and 4-formylcarane obtained via the Prins reaction of 3-carene as described in Annalen 613, p. 43 (1958), was carried out according to the procedure of Example 3A. Yield 73% of the isomeric mixture 3-(3,7,7-trimethylbicyclo [4.1.0]heptylidene-4)propanenitrile and 3-(3,7,7-trimethylbicyclo [4.1.0]heptyl-4)acrylonitrile, b.p. 99°-103° C. at 0.6 mm Hg, nD20 =1.4950, with metallic, woody, rosy odour.

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

Procedure: To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxan (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL), and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. 1H NMR (CDCl3): δ 4.05 (dd, J=7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J=10.0, 14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H). extracted with diethyl ether (500 mL) The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL) dried over Na2SO4 The solvent is removed under reduced pressure the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg methyl trioxorhenium was dissolved in 30% aqueous hydrogen peroxide (19 ml) and cooled to 0° C. internal in a 250 ml, 3-necked flask. A solution was separately prepared from 1,3-dioxolane (89 ml), the carene mixture (11 g), and pyridine (9 ml). This was also cooled to 0° C. internal. While stirring the cold aqueous solution vigorously, the cold dioxolane solution was added over 70 minutes, keeping the exothermic reaction at 0-5° C. After three hours, NaCl solution (20 ml) was added and the layers were separated. The aqueous layer was extracted once with dioxolane (25 ml). The organics were combined. Aqueous pH 5.8 buffer solution (275 ml) was added and stirred vigorously at room temperature for 1 hour, then 30° C. for 2.5 hours. The reaction was transferred to a separating funnel and washed once with heptane (100 ml). NaCl (43 g) was added to the aqueous layer and stirred for 30 min. The aqueous layer was extracted with ethyl acetate (1×100 ml, 2×250 ml). The ethyl acetate extracts were combined, dried over Na2SO4, and concentrated in vacuo to solid (2 g). The solid was dissolved in hot ethyl acetate. Heptane was added and the solution was allowed to cool with stirring and then cooled to 0° C. The solid was collected by vacuum filtration and washed with hexane. After drying under vacuum, 1.1 g (+)-p-menth-2-ene-diol (6.5% yield from (+)-3-carene) was obtained. This was also cooled to 0° C. internal the exothermic reaction at 0-5° C the layers were separated The aqueous layer was extracted once with dioxolane (25 ml) Aqueous pH 5.8 buffer solution (275 ml) was added stirred vigorously at room temperature for 1 hour 30° C. for 2.5 hours The reaction was transferred to a separating funnel washed once with heptane (100 ml) NaCl (43 g) was added to the aqueous layer stirred for 30 min The aqueous layer was extracted with ethyl acetate (1×100 ml, 2×250 ml) dried over Na2SO4 concentrated in vacuo to solid (2 g) The solid was dissolved in hot ethyl acetate Heptane was added to cool with stirring cooled to 0° C The solid was collected by vacuum filtration washed with hexane After drying under vacuum

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

Procedure: The starting material 2-caren-4-one can be produced from commercially available, optically pure (+)-3-carene. The (+)-3-carene is treated with nitrosyl chloride followed by the addition of powdered sodium carbonate. The resulting 2-caren-4-one oxime is then treated with sodium bisulfite in aqueous ethanol to yield 2-caren-4-one, the desired starting product for the inventive process.