Introduction
2-(2-Chlorophenyl)-2-hydroxycyclohexanone (cas 1823362-29-3) is a precursor in simple Ketamine synthesis. This synthesis has less step than classical Ketamine synthesis from cyclopentyl bromide and o-chlorobenzonitrile and a little bit bigger yield. Moreover, you can ship 2-(2-Chlorophenyl)-2-hydroxycyclohexanone as legal substance overseas.
Equipment and glassware:
- 3 L Round bottom flask;
- 2 L or 100 mL Three-neck round bottom flask (Depends on Method 1 or 2);
- Retort stand and clamp for securing apparatus;
- Magnetic stirrer with heating plate;
- Glass rod and spatula;
- Rotovap machine;
- Flash chromatography kit (middle column and silica gel 60 ± 120 mesh);
- Vacuum source;
- Reflux condenser;
- Nitrogen balloon ~15-20 L (1 barr);
- 500 mL Drip funnel;
- 1 L Separatory funnel;
- 250 mL x2; 500 mL x2; 1 L x2; 5 L x2 Beakers;
- Ice water bath;
- Dean–Stark apparatus;
- TLC kit;
- Laboratory scale (0.01-100 g is suitable) [depends on synthesis load];
- pH indicator paper;
- Boiling chips;
- 1 L and 150 mL Measuring cylinders;
- Five crystals of Iodine (I2);
- 3.65 g, 150 mmol Magnesium (Mg) ;
- 1250 mL dry tetrahydrofuran (THF);
- 23.90 g, 125 mmol 1-Bromo-2-chlorobenzene (1);
- 9.80 g, 100 mmol Cyclohexanone;
- ~50 g Ammonium chloride (NH4Cl);
- ~1.2 L Distilled water (H2O);
- ~50 g Sodium chloride;
- ~200 g Magnesium sulfate (MgSO4) anhydrous;
- ~ 1200 mL Hexane;
- ~ 120 mL Ethyl acetate;
- 520 mL Acetone;
- 12.5 mL Acetic acid;
- 16.60 g, 105 mmol Potassium permanganate (KMnO4);
- ~ 200 mL Sulfuric acid (H2SO4) 12.5% aq. solution;
- 10.20 g, 120 mmol Sodium nitrate (NaNO3);
- 800 mL Diethyl ether (Et2O);
- ~200 mL Sodium hydroxide aq. (NaOH);
- Method A:
- 2.10 g, 11 mmol p-toluenesulfonic acid (PTSA);
- 500 mL Toluene;
- 1.5 L Dichloromethane;
- 500 mL Sodium bicarbonate, 10 % aq. (NaHCO3);
- Method B:
- 0.80 g, 2.0 mmol 1-Methyl-3-[2-(dimethyl-4-sulfobutyl-ammonium) ethane] imidazolium hydrogen sulfate [MSIHS];
Procedure
Synthesis of 1-(2-chlorophenyl)-cyclohexane1-ol (3)
Five crystals of iodine were added to a mixture of magnesium (3.65 g, 150 mmol) in 3 L Round bottom flask with 500 mL dry tetrahydrofuran (THF). The mixture was refluxed for 2 h under N2 atmosphere and was cooled to room temperature. The solution of 1-bromo-2-chlorobenzene (1) (23.90 g, 125 mmol) in 250 mL dry THF was added dropwise to the mixture. The reaction mixture was stirred again at room temperature for 2 h under N2 atmosphere. Subsequently, a solution of cyclohexanone (9.80 g, 100 mmol) in 500 mL THF was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 24 h under N2. Then, it was poured to a mixture of crashed ice and ammonium chloride. The organic layer was separated and washed with water and brine. It was dried over anhydrous MgSO4 . The solvent was evaporated by a rotary evaporator to generate 1-(2-chlorophenyl)-cyclohexan-1-ol (3) as a crude product. Purifying the product by a silica gel column chromatography (20:3 hexane/ethyl acetate) produce pure alcohol as oily yellow liquid with 82 % yield.
Synthesis of 1-(2-chlorophenyl)-cyclohexene (4)
Method A: Synthesis of 1-(2-chlorophenyl)-cyclohexene (4) in the presence of p-toluenesulfonic acid (PTSA): The synthesized alcohol (3) (21.05 g, 100 mmol), p-toluenesulfonic acid (2.10 g, 11 mmol) and 500 mL toluene were added to a 2 L three-neck flask equipped with a reflux condenser and the Dean–Stark apparatus. The reaction mixture was stirred at 110 °C for 10 h under N2 atmosphere. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, toluene was removed by rotary evaporator under reduced pressure. Further, 1.5 L dichloromethane and 500 mL NaHCO3 (10 %) were added. The organic layer was separated and dried over anhydrous MgSO4. Finally, by evaporating the solvent and purifying with silica gel column chromatography (hexane), 1-(2-chlorophenyl)-cyclohexene was obtained as a pure colorless liquid (88 % yield).
Method B: Synthesis of 1-(2-chlorophenyl)-cyclohexene (4) in the presence of 1-methyl-3-[2-(dimethyl-4-sulfobutyl-ammonium) ethane] imidazolium hydrogen sulfate: The synthesized alcohol (3) (21.05 g, 100 mmol) and 1-methyl-3-[2-(dimethyl-4-sulfobutyl-ammonium) ethane] imidazolium hydrogen sulfate [MSIHS] (0.80 g, 2.0 mmol) were charged to a 100 mL three-neck flask equipped with a reflux condenser and a Dean-Stark apparatus. Further, it was heated up to 90 °C and maintained at the same temperature for 30 min. The progress of the reaction was monitored by TLC. The product (1-(2-chlorophenyl)-cyclohexene) was separated simply by extraction with hexane (2 x 25 mL) and dried over anhydrous MgSO4 . Finally, by evaporation of the solvent and purifying with a silica gel column chromatography, (hexane), 1-(2-chlorophenyl)-cyclohexene (4) was obtained as a pure colorless liquid (97 % yield).
Method A: Synthesis of 1-(2-chlorophenyl)-cyclohexene (4) in the presence of p-toluenesulfonic acid (PTSA): The synthesized alcohol (3) (21.05 g, 100 mmol), p-toluenesulfonic acid (2.10 g, 11 mmol) and 500 mL toluene were added to a 2 L three-neck flask equipped with a reflux condenser and the Dean–Stark apparatus. The reaction mixture was stirred at 110 °C for 10 h under N2 atmosphere. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, toluene was removed by rotary evaporator under reduced pressure. Further, 1.5 L dichloromethane and 500 mL NaHCO3 (10 %) were added. The organic layer was separated and dried over anhydrous MgSO4. Finally, by evaporating the solvent and purifying with silica gel column chromatography (hexane), 1-(2-chlorophenyl)-cyclohexene was obtained as a pure colorless liquid (88 % yield).
Method B: Synthesis of 1-(2-chlorophenyl)-cyclohexene (4) in the presence of 1-methyl-3-[2-(dimethyl-4-sulfobutyl-ammonium) ethane] imidazolium hydrogen sulfate: The synthesized alcohol (3) (21.05 g, 100 mmol) and 1-methyl-3-[2-(dimethyl-4-sulfobutyl-ammonium) ethane] imidazolium hydrogen sulfate [MSIHS] (0.80 g, 2.0 mmol) were charged to a 100 mL three-neck flask equipped with a reflux condenser and a Dean-Stark apparatus. Further, it was heated up to 90 °C and maintained at the same temperature for 30 min. The progress of the reaction was monitored by TLC. The product (1-(2-chlorophenyl)-cyclohexene) was separated simply by extraction with hexane (2 x 25 mL) and dried over anhydrous MgSO4 . Finally, by evaporation of the solvent and purifying with a silica gel column chromatography, (hexane), 1-(2-chlorophenyl)-cyclohexene (4) was obtained as a pure colorless liquid (97 % yield).
Synthesis of 2-(2-chlorophenyl)-2-hydroxycyclohexane-1-one (5)
The 1-(2-chlorophenyl)-cyclohexene (4) (14.40 g, 75 mmol) was added to a mixture of 150 mL H2O and 370 mL acetone in 3 L round bottom flask. Further, acetic acid (12.5 mL) was added to the reaction mixture and stirred for 45 min at room temperature. Then KMnO4 (16.60 g, 105 mmol) dissolved in 37.5 mL of H2O and 150 mL of acetone was added dropwise to the reaction mixture. The mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. Subsequently, a solution of sulfuric acid:H2O (75:600 or 12.5%) was slowly added and stirred for 30 min at room temperature. NaNO3 (10.20 g, 120 mmol) was then added and stirred for 30 min at room temperature, and 800 mL of diethyl ether was added. The organic layer was neutralized with NaOH. After separation of the organic layer, it was dried with MgSO4. Finally, evaporation of the solvent via rotary evaporator and purifying the product via silica gel column chromatography (20:3 hexane/ethyl acetate) produced 2-(2-chlorophenyl)-2-hydroxy cyclohexan-1-one (5) as yellow liquid (yield, 85 %).
The 1-(2-chlorophenyl)-cyclohexene (4) (14.40 g, 75 mmol) was added to a mixture of 150 mL H2O and 370 mL acetone in 3 L round bottom flask. Further, acetic acid (12.5 mL) was added to the reaction mixture and stirred for 45 min at room temperature. Then KMnO4 (16.60 g, 105 mmol) dissolved in 37.5 mL of H2O and 150 mL of acetone was added dropwise to the reaction mixture. The mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. Subsequently, a solution of sulfuric acid:H2O (75:600 or 12.5%) was slowly added and stirred for 30 min at room temperature. NaNO3 (10.20 g, 120 mmol) was then added and stirred for 30 min at room temperature, and 800 mL of diethyl ether was added. The organic layer was neutralized with NaOH. After separation of the organic layer, it was dried with MgSO4. Finally, evaporation of the solvent via rotary evaporator and purifying the product via silica gel column chromatography (20:3 hexane/ethyl acetate) produced 2-(2-chlorophenyl)-2-hydroxy cyclohexan-1-one (5) as yellow liquid (yield, 85 %).
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