1-cyclobutylethanone

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g). sealed tube The reaction was cooled partitioned in water (20 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on 2×40 g SiO2 cartridges

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

Procedure: To a solution of cyclobutyl methyl ketone (4 g, 40.8 mmol) in MeOH (60 mL) was added sodium methoxide (3.3 g, 61.2 mmol) at rt. After a 5 min stirring, dimethyl oxalate (4.8 g, 40.8 mmol) was added. The reaction mixture was stirred for 3 h at rt and concentrated. The residue was taked up in diluted HCl and extracted with EtOAc. The organic layers were concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 9:1) to provide 4 g of the title compound. Rf=0.46 (hexane/EtOAc, 1:1); 1H NMR (300 MHz, CDCl3) δ ppm 1.70-2.40 (m, 6H), 3.58 (quintet, 1H), 3.85 (s, 3H), 6.54 (s, 1H), 13.8-15.0 (br. s, 1H). The reaction mixture was stirred for 3 h at rt concentrated extracted with EtOAc The organic layers were concentrated The residue was purified by silica gel column chromatography (hexane/EtOAc, 9:1)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g). sealed tube The reaction was cooled partitioned in water (20 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on 2×40 g SiO2 cartridges

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g). sealed tube The reaction was cooled partitioned in water (20 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on 2×40 g SiO2 cartridges

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g). sealed tube The reaction was cooled partitioned in water (20 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on 2×40 g SiO2 cartridges

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g). sealed tube The reaction was cooled partitioned in water (20 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on 2×40 g SiO2 cartridges

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250-mL round-bottom flask equipped with a thermometer, drying tube (calcium chloride) was charged with 10.0 g (0.1019 mol) of cyclobutyl methyl ketone (SEA C Lot 01) and 80 mL of methanol. The mixture was cooled to 5° C., and 0.8 mL of a 30% solution of hydrogen bromide in acetic acid was added, followed by 5.0 mL (0.09705 mol) of bromine, during a period of 10 min, while the temperature of the slight exotherm was maintained at about 5° C. The mixture was stirred for 4 hours at 5° C. (Decolorization from dark brown to light orange occurred after 75 minutes). To this mixture was added dropwise 10.0 mL of water, with cooling in an ice bath (the temperature rose from 5° to 10° C.). After the addition, the mixture was stirred at room temperature for a period of 45 minutes. To this mixture was added 20.45 g (0.0968 mol) of crude compound of Example 1 as a powdered solid which dissolved gradually with concomitant decolorization of the yellow solution. The reaction temperature during the addition of the compound of Example 1 was maintained at 30° C. by an ice bath. The mixture was stirred at room temperature overnight. At that time, the compound of Example 1 was no longer detectable (TLC, Merck silica gel 60, F-254; 95:5 ethyl acetate-methanol). The mixture was rendered basic with concentrated ammonium hydroxide solution while the temperature was maintained at 20° C. with an ice bath and was then evaporated. The residue was taken up in 150 mL of ethyl acetate. This solution was washed with 100 mL of water and the aqueous phase was reextracted with 75 mL of ethyl acetate. 50 mL of brine was used to wash, in succession, the first and the second ethyl acetate solutions. The ethyl acetate solutions were combined and dried over sodium sulfate. After solvent evaporation and drying at 60° C. at 10 torr, there was obtained 28 g of crude [(4-cyclobutyl-2-thiazolyl)methyl]phosphonic acid diethyl ester as a dark oil, 99.83% pure (HPLC); 100% yield based on the compound of Example 1 used. A 250-mL round-bottom flask equipped with a thermometer drying tube (calcium chloride) was maintained at about 5° C with cooling in an ice bath (the temperature rose from 5° to 10° C. After the addition the mixture was stirred at room temperature for a period of 45 minutes dissolved gradually with concomitant decolorization of the yellow solution was maintained at 30° C. by an ice bath The mixture was stirred at room temperature overnight was maintained at 20° C. with an ice bath was then evaporated This solution was washed with 100 mL of water to wash, in succession dried over sodium sulfate After solvent evaporation drying at 60° C. at 10 torr

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

Procedure: To a slurry of compound A4 (400 mg, 0.860 mmol), sodium acetate (212 mg, 2.58 mmol), and magnesium sulfate (1 g) in anhydrous N,N-dimethylformamide (5 mL) was added 1-cyclobutylethanone (253 mg, 2.57 mmol). After stirring at room temperature for 5 min, sodium triacetoxyborohydride (911 mg, 4.30 mmol) was added. The reaction mixture was then heated at 50° C. for 20 h. After this time, the reaction mixture was cooled to room temperature and diluted with saturated aqueous sodium bicarbonate (10 mL), methanol (5 mL), methylene chloride (20 mL), and water (10 mL). The layers were separated and the aqueous layer back extracted with 20% methanol/methylene chloride (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 2% to 6% methanol/methylene chloride to afford compound (+/−)-C1 as a white solid (199 mg, 53%): MS (M+H) 433. The reaction mixture was then heated at 50° C. for 20 h After this time, the reaction mixture was cooled to room temperature The layers were separated the aqueous layer back extracted with 20% methanol/methylene chloride (2×30 mL) The combined organic layers were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash column chromatography on silica gel eluting with 2% to 6% methanol/methylene chloride

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

Procedure: Ethanol (4.39 mL, 75.2 mmol) was added dropwise to a suspension of sodium hydride (0.607 g, 15.2 mmol, 60% in mineral oil) in a flask that was held in an ice bath. Ten minutes after complete addition, a mixture of 1-cyclobutylethanone (1.5 mL, 14 mmol, Aldrich) and diethyl oxalate (2.01 g, 13.8 mmol, Aldrich) was added dropwise. After stirring overnight, 4.0M sulfuric acid in water (0.00759 L, 30.4 mmol) was added. The product was extracted into diethyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The material was used without further purification in Step B. was held in an ice bath Ten minutes after complete addition was added dropwise The product was extracted into diethyl ether The combined organic extracts were washed with water and brine dried over sodium sulfate filtered concentrated The material was used without further purification in Step B

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

Procedure: To a solution of cyclobutyl methyl ketone (4 g, 40.8 mmol) in MeOH (60 mL) was added sodium methoxide (3.3 g, 61.2 mmol) at rt. After a 5 min stirring, dimethyl oxalate (4.8 g, 40.8 mmol) was added. The reaction mixture was stirred for 3 h at rt and concentrated. The residue was taked up in diluted HCl and extracted with EtOAc. The organic layers were concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 9:1) to provide 4 g of the title compound. Rf=0.46 (hexane/EtOAc, 1:1); 1H NMR (300 MHz, CDCl3) δ ppm 1.70-2.40 (m, 6H), 3.58 (quintet, 1H), 3.85 (s, 3H), 6.54 (s, 1H), 13.8-15.0 (br. s, 1H). The reaction mixture was stirred for 3 h at rt concentrated extracted with EtOAc The organic layers were concentrated The residue was purified by silica gel column chromatography (hexane/EtOAc, 9:1)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (Example 60, 4.18 mmol, 1.05 g), cyclobutylmethylketone (5.23 mmol, 0.57 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.50 mmol, 0.31 g), tris(dibenzylideneacetone)dipalladium(0) (0.21 mmol, 0.19 g), and potassium t-butoxide (6.27 mmol, 0.70 g) was heated in a single mode microwave synthesizer to 130° C. for 1 h in a 10 mL microwave sealed tube. The reaction was cooled and partitioned in water (20 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on 2×40 g SiO2 cartridges stacked using a 0-20% ethyl acetate/hexanes gradient to give 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.98 g). sealed tube The reaction was cooled partitioned in water (20 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on 2×40 g SiO2 cartridges