4-(methoxymethylidene)-1,1-dimethylcyclohexane

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

Procedure: The compounds listed in the Examples 54, 55 and 56 below were made starting from a common cyclohexanone precursor. For the synthesis of the compounds in Examples 54 and 55 below, 4,4-dimethylcyclohexanone was converted by a four-step process into 1-(4,4-dimethylcyclohexyl)ethanone. The 4-step process is similar to that given in Example 53: the Wittig reagent generated as in Example 53 from (methoxymethyl)triphenylphosphonium chloride and NaH in THF was used to form the corresponding enol ether product from 4,4-dimethylcyclohexanone: (4-methoxymethylene-1,1-dimethyl-cyclohexane). This enol ether was hydrolyzed using TFA:DCM to generate the corresponding aldehyde. This aldehyde was treated with MeMgBr in THF/Et2O to give a methylcarbinol derivative which was then oxidized using PCC in DCM to give the desired 1-(4,4-dimethylcyclohexyl)ethanone. Also in an analogous fashion to the process disclosed in Example 53, this ketone was then treated with pyrrolidone hydrotribromide to give the 2-bromoketone derivative, and this bromoketone intermediate was subsequently treated with the appropriate thiourea derivatives in MeOH to produce the products shown in Examples 54 and 55 after hydrolysis of the esters, purification of the acids, and generation of the sodium carboxylate salts.

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

Procedure: A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g, 0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred at room temperature for 24 hr. The reaction mixture was diluted with a mixture of ethyl ether, hexanes, brine and water. The mixture was separated and the aqueous phase was extracted with ethyl ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde as a yellow oil, used without further purification. The mixture was separated the aqueous phase was extracted with ethyl ether The combined organic phase was washed with brine dried over Na2SO4 concentrated in vacuo

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

Procedure: A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g, 0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred at room temperature for 24 hr. The reaction mixture was diluted with a mixture of ethyl ether, hexanes, brine and water. The mixture was separated and the aqueous phase was extracted with ethyl ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde as a yellow oil, used without further purification. The mixture was separated the aqueous phase was extracted with ethyl ether The combined organic phase was washed with brine dried over Na2SO4 concentrated in vacuo

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

Procedure: To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (s, 6H); 1.27 (m, 5H); 1.95 (m, 2H); 2.18 (m, 2H); 3.52 (s, 3H). cooled to −78° C. After 1 hr at −78° C. the mixture was slowly warmed to 0° C. stirred at room temperature for 48 hr Layers were separated the aqueous phase was extracted with ethyl acetate Combined organics were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was triturated with hexanes, solids were removed by filtration the filtrated was concentrated in vacuo The residue was dissolved in dichloromethane (40 mL) PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added the mixture was stirred at room temperature for 24 hr Resin was removed by filtration washed (CH2Cl2, MeOH, CH2Cl2) Combined filtrate/washings were concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-BuLi (2.6 M in hexane, 2.3 mL, 5.94 mmol) was added dropwisely to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.04 g, 5.94 mmol) in THF (20 mL) at −78° C. and stirred for 10 min at the same temperature and then stirred for 2.5 h at room temperature. The reaction mixture was cooled down to −78° C., a solution of 4,4-dimethylcyclohexanone (500 mg, 3.96 mmol) in THF (5 mL) was added slowly at −78° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for overnight. The reaction mixture was quenched with sat. NaHCO3 aq. (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil. The crude product was used for next step without purification. stirred for 2.5 h at room temperature to warm to room temperature stirred at room temperature for overnight The reaction mixture was quenched with sat. NaHCO3 aq. (20 mL) extracted with EtOAc The combined organic layers were dried over anhydrous Na2SO4 concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil The crude product was used for next step without purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-BuLi (2.6 M in hexane, 2.3 mL, 5.94 mmol) was added dropwisely to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.04 g, 5.94 mmol) in THF (20 mL) at −78° C. and stirred for 10 min at the same temperature and then stirred for 2.5 h at room temperature. The reaction mixture was cooled down to −78° C., a solution of 4,4-dimethylcyclohexanone (500 mg, 3.96 mmol) in THF (5 mL) was added slowly at −78° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for overnight. The reaction mixture was quenched with sat. NaHCO3 aq. (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil. The crude product was used for next step without purification. stirred for 2.5 h at room temperature to warm to room temperature stirred at room temperature for overnight The reaction mixture was quenched with sat. NaHCO3 aq. (20 mL) extracted with EtOAc The combined organic layers were dried over anhydrous Na2SO4 concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil The crude product was used for next step without purification

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

Procedure: A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g, 0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred at room temperature for 24 hr. The reaction mixture was diluted with a mixture of ethyl ether, hexanes, brine and water. The mixture was separated and the aqueous phase was extracted with ethyl ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde as a yellow oil, used without further purification. The mixture was separated the aqueous phase was extracted with ethyl ether The combined organic phase was washed with brine dried over Na2SO4 concentrated in vacuo

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

Procedure: To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil. cooled to −78° C. After 1 hr at −78° C. the mixture was slowly warmed to 0° C. stirred at room temperature for 48 hr Layers were separated the aqueous phase was extracted with ethyl acetate Combined organics were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was triturated with hexanes, solids were removed by filtration the filtrated was concentrated in vacuo The residue was dissolved in dichloromethane (40 mL) PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added the mixture was stirred at room temperature for 24 hr Resin was removed by filtration washed (CH2Cl2, MeOH, CH2Cl2) Combined filtrate/washings were concentrated in vacuo

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

Procedure: A solution of flask 4-(methoxymethylene)-1,1-dimethylcyclohexane (2.3 g, 14.9 mmol) in a 4:1 THF/2N HCl mixture (100 mL) was refluxed fo(1 hour. The volatile was removed in vacuo and the residue was cooled to 0°C. and neutralized with 1N NaOH and extracted with Et2O (3×60 mL). The organic layer was washed with water (50 mL), brine (60 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography with hexane-DCM 10% linear gradient as eluant to give the title compound as clear oil. 1H NMR (400 MHz, CDCl3) δ 9.64 (d, J=1.6 Hz, 1H), 2.19-2.12 (m, 1H), 1.79-1.72 (m, 2H), 1.59-1.40 (m, 5H), 1.25-1.18 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H). No ionization by LCMS. 1 hour The volatile was removed in vacuo extracted with Et2O (3×60 mL) The organic layer was washed with water (50 mL), brine (60 mL) dried over sodium sulfate filtered concentrated The residue was purified by chromatography with hexane-DCM 10% linear gradient as eluant

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

Procedure: The compounds listed in the Examples 54, 55 and 56 below were made starting from a common cyclohexanone precursor. For the synthesis of the compounds in Examples 54 and 55 below, 4,4-dimethylcyclohexanone was converted by a four-step process into 1-(4,4-dimethylcyclohexyl)ethanone. The 4-step process is similar to that given in Example 53: the Wittig reagent generated as in Example 53 from (methoxymethyl)triphenylphosphonium chloride and NaH in THF was used to form the corresponding enol ether product from 4,4-dimethylcyclohexanone: (4-methoxymethylene-1,1-dimethyl-cyclohexane). This enol ether was hydrolyzed using TFA:DCM to generate the corresponding aldehyde. This aldehyde was treated with MeMgBr in THF/Et2O to give a methylcarbinol derivative which was then oxidized using PCC in DCM to give the desired 1-(4,4-dimethylcyclohexyl)ethanone. Also in an analogous fashion to the process disclosed in Example 53, this ketone was then treated with pyrrolidone hydrotribromide to give the 2-bromoketone derivative, and this bromoketone intermediate was subsequently treated with the appropriate thiourea derivatives in MeOH to produce the products shown in Examples 54 and 55 after hydrolysis of the esters, purification of the acids, and generation of the sodium carboxylate salts.

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

Procedure: A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g, 0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred at room temperature for 24 hr. The reaction mixture was diluted with a mixture of ethyl ether, hexanes, brine and water. The mixture was separated and the aqueous phase was extracted with ethyl ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde as a yellow oil, used without further purification. The mixture was separated the aqueous phase was extracted with ethyl ether The combined organic phase was washed with brine dried over Na2SO4 concentrated in vacuo

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

Procedure: To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (s, 6H); 1.27 (m, 5H); 1.95 (m, 2H); 2.18 (m, 2H); 3.52 (s, 3H). cooled to −78° C. After 1 hr at −78° C. the mixture was slowly warmed to 0° C. stirred at room temperature for 48 hr Layers were separated the aqueous phase was extracted with ethyl acetate Combined organics were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was triturated with hexanes, solids were removed by filtration the filtrated was concentrated in vacuo The residue was dissolved in dichloromethane (40 mL) PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added the mixture was stirred at room temperature for 24 hr Resin was removed by filtration washed (CH2Cl2, MeOH, CH2Cl2) Combined filtrate/washings were concentrated in vacuo