cyclohexane-1,2-dione

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

Procedure: Follow a procedure similar to that of Preparation 2 except use 1,2-cyclohexanedione (1.0099 g, 9.0065 mmol); 2,6-diphenylaniline (2.2258 g, 9.0731 mmol); toluene (22 mL); p-toluenesulfonic acid monohydrate (0.0859 g, 0.4516 mmol); reflux reaction mixture for 2.3 hours; to isolate 3.5678 g of a brown thick oil. Purify the thick oil be chromatography using a Biotage SNAP 50 g KP-Sil column, loading the thick oil with small amount of 4% ethyl acetate/96% hexanes and 100% ethyl acetate and eluting with a gradient of 4-8% ethyl acetate in hexanes to afford after isolation 1.1388 g (37.2%) of the 2-((1,1′:3′,1″-terphenyl)-2′-ylamino)-2-cyclohexen-1-one as a yellow thick oil. of Preparation 2 reflux reaction mixture for 2.3 hours

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

Procedure: Synthesis based on literature modified procedure (Ōhashi, M.; Takahashi, T.; Inoue, S.; Sato, K. Bulletin Chemical Society of Japan, 1975; 48:1892). A 500-mL round-bottomed flask is equipped with a Dean Stark, condenser, stir bar and gas inlet (N2 gas atmosphere). The flask is charged with of 1,2-cyclohexanedione (15.14 g, 135.00 mmol), morpholine (14.82 g, 170.10 mmol) and toluene (330 mL). The resulting yellow solution is heated to reflux for 5 hours. Heating is stopped and about 3.0 mL of water are collected on the Dean Stark. The brown solution is decanted away from a thick oil and rinsed with toluene. The solution is concentrated under high vacuum to afford 23.33 g (95.34% yield) of title compound of Preparation 2 as a brown solid. Synthesis A 500-mL round-bottomed flask is equipped with a Dean Stark, condenser The resulting yellow solution is heated to reflux for 5 hours Heating about 3.0 mL of water are collected on the Dean Stark The brown solution is decanted away from a thick oil rinsed with toluene The solution is concentrated under high vacuum to afford

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

Procedure: Synthesis based on literature procedure (Gates, D. P.; Svejda, S. A. Onate, E.; Killian, C. M.; Johnson, L. K.; White, P. S.; Brookhart M. Macromolecules, 2000; 33:2320-2334.). Cyclohexane-1,2-dione (2.062 g, 18.39 mmol) and 2,6-diisopropylaniline (6.52 g, 36.78 mmol) are dissolved in 70 mL of methanol. To this solution is added 1 mL of formic acid and the mixture is stirred for 3 days at room temperature. Precipitated white crystalline solid is collected on the frit, washed with methanol (2×15 mL) and dried under reduced pressure to give 4.1 g (51.8% yield) of title compound of Preparation 1. Synthesis Precipitated white crystalline solid is collected on the frit washed with methanol (2×15 mL) dried under reduced pressure to give

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

Procedure: 0.80 g (2.1 mmol) of 4-benzoyloxy-5,8-dimethyl-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid in 30 ml of methylene chloride was admixed with 2 drops of N,N-dimethylformamide and 1.69 g (13.3 mmol) of oxalyl chloride, and the mixture was boiled under reflux for 3.5 h. The solvents were subsequently stripped off using a rotary evaporator, and the residue was taken up in 100 ml of methylene chloride and, at 0° C., admixed with 0.25 g (2.2 mmol) of cyclohexanedione and 0.44 g (7.4 mmol) of triethylamine. The mixture was stirred at room temperature for 4 h and subsequently concentrated using a rotary evaporator, and the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1). under reflux for 3.5 h a rotary evaporator was taken up in 100 ml of methylene chloride and, at 0° C. subsequently concentrated a rotary evaporator the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1)

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

Procedure: 0.56 g (1.2 mmol) of 4-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy}-5,8-dimethyl-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid in 30 ml of methylene chloride was admixed with 2 drops of N,N-dimethylformamide and 0.48 g (3.8 mmol) of oxalyl chloride, and the mixture was boiled under reflux for 3.5 h. The solvents were subsequently stripped off using a rotary evaporator and the residue was taken up in 100 ml of methylene chloride and, at 0° C., admixed with 0.15 g (1.4 mmol) of cyclohexanedione and 0.22 g (3.7 mmol) of triethylamine. The mixture was stirred at room temperature for 4 h and subsequently concentrated using a rotary evaporator, and the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1). under reflux for 3.5 h a rotary evaporator was taken up in 100 ml of methylene chloride and, at 0° C. subsequently concentrated a rotary evaporator the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1)

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

Procedure: 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid was prepared according to a modified literature procedure 1. To a stirring solution of potassium hydroxide (28.06 g, 0.5 mol) in methanol (100 mL) under Nitrogen at 0° C. was added dropwise a solution of cyclohexanedione (56.07 g, 0.5 mol) in methanol (100 mL). The mixture was stirred at 0° C. for 0.5 h, then a solution of ethyl bromopyruvate (66 mL, 0.525 mol) in methanol (100 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 17 h, a 50% aqueous sodium hydroxide solution (60 mL) was added dropwise and stirring continued an additional 7 h. After dilution with water, the solution was acididfied and the methanol removed in vacuo. Ice water was added and the precipitate filtered and dried in vacuo to afford 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid. 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid was prepared to stir at ambient temperature for 17 h stirring continued an additional 7 h the methanol removed in vacuo Ice water was added the precipitate filtered dried in vacuo

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

Procedure: Allyl bromide (195 g., 1.62 mol.) was added over a 15 minute period to a stirred ice-cold mixture of cyclohexanedione (165 g., 1.47 mol.), copperbronze (4.5 g.), and 330 ml. of 20% by weight aqueous potassium hydroxide. After 6 hours, the reaction was mixed with 1500 ml. of a 5% by weight aqueous sodium hydroxide solution and 1000 ml. of ethyl ether, filtered and the separated water layer acidified with 4N aqueous hydrochloric acid to pH 1. A brown solid (188 g.) formed upon refrigeration at 0° C. The solid was taken up in ethyl acetate and the solution was washed with water (3 × 150 ml.), dried (MgSO4), treated with charcoal, and condensed until turbid. Upon cooling, 126 g. (57%) of 2-allyl-1,3-cyclohexanedione was collected, m.p. 125°-127° C. the reaction was mixed with 1500 ml of ethyl ether, filtered A brown solid (188 g.) formed upon refrigeration at 0° C the solution was washed with water (3 × 150 ml.) dried (MgSO4) treated with charcoal, and condensed until turbid Upon cooling (57%) of 2-allyl-1,3-cyclohexanedione was collected

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

Procedure: 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared according to the following procedure. Potassium hydroxide (345 g, 6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in methyl alcohol (1.2 L), dissolved using gentle heat, is added dropwise to the cold, stirred KOH solution over 2 h. A solution of ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is then added dropwise over 3 h. The reaction mixture is allowed to reach ambient temperature and stirred an additional 14.5 h. While cooling the reaction mixture via a water bath, a solution of sodium hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise over 2.5 h. After stirring at ambient temperature for 15.5 h, the reaction mixture is cooled in an ice water bath, 500 g of ice added, and the resulting mixture is then acidified with concentrated hydrochloric acid (ca 1 L) to pH 1. The reaction mixture is concentrated in vacuo, 1 L of ice is added, and the precipitate filtered, washed with ice water (3×200 mL), and then dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (560 g). m.p. 137-138° C. 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared then cooled in an ice water bath is added dropwise to the cold to reach ambient temperature While cooling the reaction mixture via a water bath After stirring at ambient temperature for 15.5 h the reaction mixture is cooled in an ice water bath The reaction mixture is concentrated in vacuo, 1 L of ice is added the precipitate filtered washed with ice water (3×200 mL) dried in a vacuum oven at 75° C.

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

Procedure: Add methyl 2-(2-oxopropylthio)acetate (35.4 g, 183.2 mmol) to a freshly prepared solution of solid sodium (8.78 g, 381.5 mmol) in dry MeOH (300 mL) at 0° C., followed by addition of a solution of cyclohexane-1,2-dione (20 g, 152.6 mmol) in MeOH (30 mL). Stir the mixture at 0° C. for 30 min and then at 50-60° C. for additional 1.5 hour. Remove the solvent under vacuum and dilute the residue with water (100 mL). Extract the aqueous mixture with ethyl acetate (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (50:1 to 30:1) to afford methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate as a white solid (10 g, 27.6%). MS (m/z): 239 (M+1). at 50-60° C. for additional 1.5 hour Remove the solvent under vacuum dilute the residue with water (100 mL) Extract the aqueous mixture with ethyl acetate (100 mL×3) The combined organic layers are washed with brine dried over anhydrous Na2SO4 evaporated under vacuum Purify the residue by a flash column on silica gel eluting with PE

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

Procedure: A methanol (30 ml) solution of cyclohexane-1,2-dione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) with cooling below -30° C., and aqueous 12.5N-NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 minutes and was further stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture, and sodium bicarbonate (15 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product. (19.7 g, yield: 82.1%). with cooling below -30° C. was further stirred at room temperature for 3 hours was added after 10 minutes stirring the solvent then being distilled off in vacuo The residue, to which was added water was extracted three times with chloroform the extract was dried with anhydrous magnesium sulfate concentrated in vacuo The residue was recrystallized from acetone to obtain the product

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

Procedure: 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared according to the following procedure. Potassium hydroxide (345 g, 6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in methyl alcohol (1.2 L), dissolved using gentle heat, is added dropwise to the cold, stirred KOH solution over 2 h. A solution of ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is then added dropwise over 3 h. The reaction mixture is allowed to reach ambient temperature and stirred an additional 14.5 h. While cooling the reaction mixture via a water bath, a solution of sodium hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise over 2.5 h. After stirring at ambient temperature for 15.5 h, the reaction mixture is cooled in an ice water bath, 500 g of ice added, and the resulting mixture is then acidified with concentrated hydrochloric acid (ca 1 L) to pH 1. The reaction mixture is concentrated in vacuo, 1 L of ice is added, and the precipitate filtered, washed with ice water (3×200 mL), and then dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (560 g). m.p. 137-138° C. 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared then cooled in an ice water bath is added dropwise to the cold to reach ambient temperature While cooling the reaction mixture via a water bath After stirring at ambient temperature for 15.5 h the reaction mixture is cooled in an ice water bath The reaction mixture is concentrated in vacuo, 1 L of ice is added the precipitate filtered washed with ice water (3×200 mL) dried in a vacuum oven at 75° C.

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

Procedure: 1.04 g (3.0 mmol) of 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoic acid are introduced into 50 ml of dichloromethane together with 0.37 g (3.3 mmol) of cyclohexanedione and treated with 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide. After stirring at room temperature for 16 hours, the precipitate is filtered off with suction and the filtrate is washed with water. After the removal of the solvent, 1.22 g (92% of theory) of 3-oxo-1-cyclohexenyl 2-chloro-3-(5-methoxymethylisoxazol-3 yl)-4-methyl-sulfonylbenzoate are obtained as a yellowish, partly crystalline oil. the precipitate is filtered off with suction the filtrate is washed with water After the removal of the solvent, 1.22 g (92% of theory) of 3-oxo-1-cyclohexenyl 2-chloro-3-(5-methoxymethylisoxazol-3 yl)-4-methyl-sulfonylbenzoate are obtained as a yellowish, partly crystalline oil