4,4-dimethylcyclohexane-1,3-dione

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4,4-dimethylcyclohexane-1,3-dione (6.28 g, 45 mmol), 5-bromo-2-ethylphenyl lead triacetate (28 g, 49 mmol) and dimethylaminopyridine (27.4 g, 0.22 mol) under nitrogen are added anhydrous chloroform (300 ml) and toluene (75 ml). The reaction mixture is heated at 80° C. for 2 hours and then allowed to cool to room temperature overnight. 2M Aqueous hydrochloric acid (750 ml) and dichloromethane (500 ml) are added and the mixture is filtered through diatomaceous earth, washing through with more dichloromethane (250 ml). The two layers are separated and the aqueous phase is extracted with dichloromethane (500 ml). The organic layers are combined and washed with 2M aqueous hydrochloric acid (1000 ml) and then brine (1000 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by preparative normal phase chromatography to give 2-(5-bromo-2-ethylphenyl)-4,4-dimethylcyclohexane-1,3-dione (6.78 g). to cool to room temperature overnight the mixture is filtered through diatomaceous earth washing through with more dichloromethane (250 ml) The two layers are separated the aqueous phase is extracted with dichloromethane (500 ml) washed with 2M aqueous hydrochloric acid (1000 ml) brine (1000 ml), dried over anhydrous magnesium sulfate filtered the filtrate is evaporated under reduced pressure The residue is purified by preparative normal phase chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4,4-dimethyl-1,3-cyclohexanedione (0.21 g, 1.5 mmol), 4′-chloro-4-ethylbiphen-3-yllead triacetate (1.0 g, 1.7 mmol) and dimethylaminopyridine (0.93 g, 7.6 mmol) is added anhydrous chloroform (11 ml) and anhydrous toluene (2.8 ml). The reaction mixture is heated at 80° C. for 4 hours and then cooled to room temperature. The mixture is diluted with dichloromethane (50 ml) and 2M aqueous hydrochloric acid (50 ml) and filtered through diatomaceous earth. The filtrate is partitioned, the aqueous layer is extracted with dichloromethane (50 ml) and the organic extracts are combined, washed with 2M aqueous hydrochloric acid (50 ml), brine (50 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by preparative reverse phase HPLC to give 2-(4′-chloro-4-ethylbiphen-3-yl)-4,4-dimethyl-1,3-cyclohexanedione. cooled to room temperature filtered through diatomaceous earth The filtrate is partitioned the aqueous layer is extracted with dichloromethane (50 ml) washed with 2M aqueous hydrochloric acid (50 ml), brine (50 ml) dried over anhydrous magnesium sulfate filtered the filtrate is evaporated under reduced pressure The crude product is purified by preparative reverse phase HPLC

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

Procedure: A 50-mL single neck round bottom flask was charged with 4-cyanophenyl 4-methylbenzoate (2.65 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was refluxed for 6 hours. Volatiles were stripped from the reaction mixture and the residue was partitioned between diethyl ether (100 mL) and water (50 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (30 mL), then water (10 mL), then brine (10 mL). All aqueous layers were combined and 1N hydrochloric acid was added to pH 1. The resulting oil was extracted into dichloromethane (30 mL, 2×15 mL). The dichloromethane layers were combined, dried over magnesium sulfate, filtered and stripped to a brown oil (3.57 g). The crude product was chromatographed on silica gel (200 g), eluting with hexanes-ethyl acetate (4:1). Fractions containing pure product were concentrated to a yellow oil (2.08 g), which was crystallized from hexanes to afford the title compound as off-white crystals, 1.35 g (46.8%), m.p. 78-79° C. 1H NMR (DMSO-d6): δ 1.08 (s, 6), 1.84 (m, 2), 2.36 (s, 3), 2.61 (m, 2), 7.26 (d, 2), 7.60 (d, 2). the mixture was refluxed for 6 hours the residue was partitioned between diethyl ether (100 mL) and water (50 mL) The organic layer was extracted with saturated aqueous sodium bicarbonate (30 mL) 1N hydrochloric acid was added to pH 1 The resulting oil was extracted into dichloromethane (30 mL, 2×15 mL) dried over magnesium sulfate filtered The crude product was chromatographed on silica gel (200 g) eluting with hexanes-ethyl acetate (4:1) Fractions containing pure product were concentrated to a yellow oil (2.08 g), which was crystallized from hexanes

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

Procedure: A 50-mL single neck round bottom flask was charged with 4-nitrophenyl acetate (2.03 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was stirred for 2 hours at ambient temperature. NMR analysis of an aliquot showed that 43% of the starting acetate was still unreacted. The mixture was then refluxed for 2 hours after which time NMR analysis of an aliquot showed no starting acetate remaining. The mixture was then refluxed for 2 hours after which time NMR analysis of an aliquot

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

Procedure: 4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis. with cooling the organic phase was washed with 150 ml 5% Na2CO3 four times extracted with methylene chloride dried concentrated to yield 25.3 g of crude product The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH

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

Procedure: The subtitle compound was prepared according to the procedure of example 2 using hydroxyacetophenone instead of acetol and 4,4-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione in step1.

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

Procedure: The subtitle compound was prepared according to the procedure of example 2 using 1-hydroxy-2-butanone instead of acetol and 4,4-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione in step1.

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

Procedure: 4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis. with cooling the organic phase was washed with 150 ml 5% Na2CO3 four times extracted with methylene chloride dried concentrated to yield 25.3 g of crude product The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH

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

Procedure: 4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis. with cooling the organic phase was washed with 150 ml 5% Na2CO3 four times extracted with methylene chloride dried concentrated to yield 25.3 g of crude product The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH

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

Procedure: A mixture of 4,4-dimethylcyclohexane-1,3-dione (563 mg, 4.02 mmol), 3-(trifluoromethyl)aniline (500 μL, 645 mg, 4.02 mmol), Ytterbium(III) trifluormethanesulfonate (12.5 mg, 20 μmol, 0.5 mol %) and N,N-dimethylformamide (2.5 mL) is stirred at room temperature over night. Methanol and water are added and the mixture is filtered. The precipitate is washed with water and dried under reduced pressure. Yield: 654 mg; ESI mass spectrum [M+H]+=284, Retention time HPLC: 1.18 min (Z005—001). the mixture is filtered The precipitate is washed with water dried under reduced pressure 1.18 min (Z005—001)