1-methylcyclohexan-1-ol

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

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

Procedure: 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3%). HPLC ret. time 3.00 min, 10-99% CH3CN, 5 min run; ESI-MS 224.2 m/z (MH+). Overall yield (3%)

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

Procedure: 4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2C2 (250 mL×3). The organic layer was washed with saturated a.q NaHCO3, dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil −47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (m, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H). The reaction mixture was then extracted by CH2C2 (250 mL×3) The organic layer was washed with saturated a.q NaHCO3 dried over MgSO4 evaporated under vacuum The residue was purified by column chromatography on silica gel

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

Procedure: 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3%). HPLC ret. time 3.00 min, 10-99% CH3CN, 5 min run; ESI-MS 224.2 m/z (MH+). Overall yield (3%)

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

Procedure: 4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2Cl2 (250 mLx3). The organic layer was washed with saturated a.q NaHCO3., dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil—47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (M, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H). The reaction mixture was then extracted by CH2Cl2 (250 mLx3) The organic layer was washed with saturated a.q NaHCO3 , dried over MgSO4 evaporated under vacuum The residue was purified by column chromatography on silica gel

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

Procedure: 1-methylcyclohexanol (30 g, 0.26 mol) was placed in a 100 mL three necked round bottomed flask and was stirred. The flask was cooled in a brine/ice bath, dropping funnel fitted and fitted with a static N2 supply. The dropping funnel was charged with 98% sulfuric acid (16.14 ml) and water (6.45 ml) giving a 70% sulfuric acid solution. This was added dropwise to the 1-methylcyclohexanol and stirring continued to give a viscous brown mixture. The bath was recharged with ice/brine, dropping funnel rinsed with water and recharged with 35% hydrogen peroxide (6.98 mL, 0.125 mol) and added dropwise. The solution separated into two phases. Cyclohexanol (150 mL) was added and the mixture was transferred to a separating funnel. The aqueous fraction was extracted with another portion of cyclohexane (150 ml) and the combined organic fractions washed with 1M NaOH (2×100 mL), water (2×150 mL), dried and evaporated to give a viscous colourless oil. (12.98 g). The oil was sorbed onto silica gel then placed on a silica gel column and eluted with cyclohexane. After evaporation at reduced pressure 0.7 g colourless oil of di(1-methyl-cyclohexyl)peroxide was obtained. 13C-NMR (CDCl3) δ 22.45, 25.01, 25.95, 35.39, 78.58 to give a viscous brown mixture rinsed with water added dropwise The solution separated into two phases Cyclohexanol (150 mL) was added the mixture was transferred to a separating funnel The aqueous fraction was extracted with another portion of cyclohexane (150 ml) the combined organic fractions washed with 1M NaOH (2×100 mL), water (2×150 mL) dried evaporated to give a viscous colourless oil eluted with cyclohexane After evaporation at reduced pressure 0.7 g colourless oil of di(1-methyl-cyclohexyl)peroxide was obtained

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

Procedure: 1-methylcyclohexanol (30 g, 0.26 mol) was placed in a 100 mL three necked round bottomed flask and was stirred. The flask was cooled in a brine/ice bath, dropping funnel fitted and fitted with a static N2 supply. The dropping funnel was charged with 98% sulfuric acid (16.14 ml) and water (6.45 ml) giving a 70% sulfuric acid solution. This was added dropwise to the 1-methylcyclohexanol and stirring continued to give a viscous brown mixture. The bath was recharged with ice/brine, dropping funnel rinsed with water and recharged with 35% hydrogen peroxide (6.98 mL, 0.125 mol) and added dropwise. The solution separated into two phases. Cyclohexanol (150 mL) was added and the mixture was transferred to a separating funnel. The aqueous fraction was extracted with another portion of cyclohexane (150 ml) and the combined organic fractions washed with 1M NaOH (2×100 mL), water (2×150 mL), dried and evaporated to give a viscous colourless oil. (12.98 g). The oil was sorbed onto silica gel then placed on a silica gel column and eluted with cyclohexane. After evaporation at reduced pressure 0.7 g colourless oil of di(1-methyl-cyclohexyl)peroxide was obtained. 13C-NMR (CDCl3) δ 22.45, 25.01, 25.95, 35.39, 78.58 to give a viscous brown mixture rinsed with water added dropwise The solution separated into two phases Cyclohexanol (150 mL) was added the mixture was transferred to a separating funnel The aqueous fraction was extracted with another portion of cyclohexane (150 ml) the combined organic fractions washed with 1M NaOH (2×100 mL), water (2×150 mL) dried evaporated to give a viscous colourless oil eluted with cyclohexane After evaporation at reduced pressure 0.7 g colourless oil of di(1-methyl-cyclohexyl)peroxide was obtained

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

Procedure: A mixture of 1-methylcyclohexanol (100.00 g, 0.876 mol) and 4-bromophenol (101.01 g, 0.584 mol) in CH2Cl2 (1.0 L) and H2SO4 (44 mL) was heated to reflux for 4 days. The mixture was cooled to RT. The reaction was poured in a separatory funnel and washed with water, 0.5 N NaHCO3 (till neutralized), brine and dried (MgSO4). The mixture was filtered, evaporated and the residue was purified on silica gel (eluant: hexane: CH2Cl2, 4:1) to give a total amount of 2-(1-methylcyclohexyl)-4-bromoanisole as an oil (29.70 g, 13%). 1H NMR (300 MHz, CDCl3): δ 1.30 (s, 3H), 1.30–1.70 (m, 8 H), 2.00–2.15 (m, 2H), 4.87 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 7.15 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H). was heated to reflux for 4 days The reaction was poured in a separatory funnel washed with water, 0.5 N NaHCO3 (till neutralized), brine dried (MgSO4) The mixture was filtered evaporated the residue was purified on silica gel (eluant: hexane: CH2Cl2, 4:1)

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

Procedure: 4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2C1-2(250 mL×3). The organic layer was washed with saturated a.q NaHCO3., dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil—47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (m, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H). The reaction mixture was then extracted by CH2C1-2(250 mL×3) The organic layer was washed with saturated a.q NaHCO3 , dried over MgSO4 evaporated under vacuum The residue was purified by column chromatography on silica gel

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

Procedure: 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3%). HPLC ret. time 3.00 min, 10-99% CH3CN, 5 min run; ESI-MS 224.2 m/z (MH+). Overall yield (3%)

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

Procedure: 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3%). HPLC ret. time 3.00 min, 10-99% CH3CN, 5 min run; ESI-MS 224.2 m/z (MH+). Overall yield (3%)

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

Procedure: 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3%). HPLC ret. time 3.00 min, 10-99% CH3CN, 5 min run; ESI-MS 224.2 m/z (MH+). Overall yield (3%)