Introduction
The silylation of (1) by a mixture of trimethylchlorosilane and NaI in the presence of Et3N in MeCN leads to the formation of 2-trimethylsilyloxy-3-methyl-1,3-butadiene (2) in an 82.3% yield. By carrying out the reaction in a MeCN solution with addition of NaI, it is possible to increase considerably the yield of the desired silyloxy-diene (2) in comparison with. We found that the addition of acetaldehyde acetals to (2) in the presence of ZnCl2 as catalyst proceeds under the conditions of a 1,2-dienic system with the formation of 5-alkoxy-2-methyl-1-hexene-3-ones (3) in a yield of 60-68%. The latter, when reacted with MeNH2 in an aqueous-alcoholic medium, readily convert into ketone (4). It was noted that a methoxy derivative (3) reacts readily with MeNH2., forming piperidone (4) in a 72-80% yield. A new improved three-step path of synthesis of (4) starting from methyl isopropenyl ketone with an overall yield at the 3rd stage of 40-44% was developed.
Carrying out the addition reaction of phenyllithium to 1,2,5-trimethylpiperidone-4 (4) at -10°C and -40°C leads to an increase in the yield of Promedol (5) to 45% and 49%, respectively, but at these temperatures amount of side reactions is still quite large. When the temperature drops to -70°C, the selectivity of the process sharply increases and, hence, the yield of Promedol (5) increases up to 87% as well. A further temperature decrease does not lead to a significant increase in yield, and is limited by the freezing point of diethyl ether. Carrying out the reaction at a temperature of -70°C and an equimolar ratio of phenyllithium and 1,2,5-trimethylpiperidone-4 (4) leads only to a slight decrease in the yield of Promedol, which indirectly indicates an almost complete suppression of side reactions at this temperature. The relatively low yield of promedol when using phenylmagnesium bromide is explained by its lower reactivity compared to phenyllithium.
Carrying out the addition reaction of phenyllithium to 1,2,5-trimethylpiperidone-4 (4) at -10°C and -40°C leads to an increase in the yield of Promedol (5) to 45% and 49%, respectively, but at these temperatures amount of side reactions is still quite large. When the temperature drops to -70°C, the selectivity of the process sharply increases and, hence, the yield of Promedol (5) increases up to 87% as well. A further temperature decrease does not lead to a significant increase in yield, and is limited by the freezing point of diethyl ether. Carrying out the reaction at a temperature of -70°C and an equimolar ratio of phenyllithium and 1,2,5-trimethylpiperidone-4 (4) leads only to a slight decrease in the yield of Promedol, which indirectly indicates an almost complete suppression of side reactions at this temperature. The relatively low yield of promedol when using phenylmagnesium bromide is explained by its lower reactivity compared to phenyllithium.
Equipment and glassware:
- 500 mL, 2 L and/or 5 L three necked round bottom flasks;
- 50 mL Pear shaped flask;
- Laboratory grade thermometer(s) (-100°C to 200°C) with flask adapter;
- Heated magnetic stirrer;
- Conventional funnel;
- Filter paper;
- Laboratory scale (0.1 — 500 g is suitable);
- 100 mL Drip funnel;
- Reflux condenser;
- 1 L Buchner flask and funnel;
- 1 L and/or 5 L Separating funnels;
- 1000 mL x2; 500 mL x2; 200 mL x2; 100 mL x2 Beakers;
- 250 mL, 500 mL and 1000 mL Erlenmeyer flasks;
- Retort stand and clamp for securing apparatus;
- Vacuum distillation setup;
- Rotary evaporator;
- Vacuum source;
- pH indicator paper;
- Nitrogen or Argon balloon 10-20 L is enough — optional;
- Water bath;
- Dewar bath — optional;
- Glass rod.
Reagents:
- 24.3 g (0.16 mole) Sodium iodide (NaI);
- 16 g (0.12 mole) Methyl isopropenyl ketone;
- 80 mL Acetonitrile (MeCN);
- 16.3 g (0.16 mole) Triethylamine (Et3N);
- 17.5 g (0.16 mole) of Me3SiCl;
- ~100 g Sodium bicarbonate (NaHCO3);
- ~300 mL Pentane;
- ~2 L Distilled water;
- ~200 g Magnesium sulphate anhydrous (MgSO4);
- ~200 g Potassium carbonate anhydrous (K2CO3) — optional;
- 90 g (1 mole) Acetaldehyde dimethylacetal;
- 295 mL Zinc Cloride (ZnCl2) 15% anhydrous ethyl acetate solution;
- ~ 700 mL Diethyl ether (Et2O);
- 5 mL (0.032 mole) Methylamine (MeNH2) 20% aqueous solution;
- 3.5 mL Methanole (MeOH);
- ~250 mL Hydrochloric acid (HCl) 18% aq solution;
- ~ 100 g Sodium hydroxide (NaOH);
- 1100 mL of a 1 M Phenyllithium in diethyl ether solution;
- Dry ice (solid CO2) to make -78°С — optional;
- 209 g Propionyl chloride;
- ~1500 mL Benzene;
- 500 mL 2-Propanol;
1,2,5-Trimethyl-4-phenyl-4-piperidol Propionate Hydrochloride:
Boiling Point: 348.2 °C at 760 mm Hg;
Melting Point: 221 - 222 °C;
Molecular Weight: 311.847 g/mole;
Density: N/A;
CAS Number: 125-80-4.
Procedure
2-Trimethylsilyloxy-3-methyl-1,3-butadiene (2)
In a 500 mL three necked round bottom flasks a 24.3 g portion (0.16 mole) of calcined NaI was added with vigorous stirring to a mixture of 16 g (0.12 mole) of methyl isopropenyl ketone (1), 80 mL of MeCN and 16.3 g (0.16 mole) of Et3N, and then 17.5 g (0.16 mole) of Me3SiCl was added dropwise. The reaction mixture was stirred for 15 min at 25°С, and then for 1 h at 70°С with reflux condenser, then was cooled, and 120 mL of a saturated solution of NaHCO3 was added. The precipitate was filtered off through Buchner flask and funnel, the organic layer was thoroughly extracted with pentane, the extract was washed with water, and dried over MgSO4. After distillation, 15.3 g (82.3%) of (2) was obtained, bp 42°С (20 mm Hg) in the form of a mobile colorless liquid.
In a 500 mL three necked round bottom flasks a 24.3 g portion (0.16 mole) of calcined NaI was added with vigorous stirring to a mixture of 16 g (0.12 mole) of methyl isopropenyl ketone (1), 80 mL of MeCN and 16.3 g (0.16 mole) of Et3N, and then 17.5 g (0.16 mole) of Me3SiCl was added dropwise. The reaction mixture was stirred for 15 min at 25°С, and then for 1 h at 70°С with reflux condenser, then was cooled, and 120 mL of a saturated solution of NaHCO3 was added. The precipitate was filtered off through Buchner flask and funnel, the organic layer was thoroughly extracted with pentane, the extract was washed with water, and dried over MgSO4. After distillation, 15.3 g (82.3%) of (2) was obtained, bp 42°С (20 mm Hg) in the form of a mobile colorless liquid.
5-Methoxy-2-methyl-l-hexen-3-one (3)
A 100.3 g portion (0.66 mole) of (2) was added dropwise during of 40 min to a mixture of 90 g (1 mole) of acetaldehyde dimethylacetal and 295 mL of a 15% solution of ZnCl2 in anhydrous ethyl acetate. A spontaneous warming up of the mixture to 35°С was observed. The reaction mixture was stirred for 1 h at 40°С, then was cooled to 20 °С and treated with a saturated solution of NaHCO3 (500 mL). The organic layer was separated, and the aqueous layer was thoroughly extracted with ether. The combined organic layer and ether extracts were dried over K2CO3 (or MgSO4). After distillation of the product, 62 g (68.2 %) of 5-methoxy-2-methyl-1-hexen-3-one (3) was obtained, bp 77 С (10 mm Hg).
A 100.3 g portion (0.66 mole) of (2) was added dropwise during of 40 min to a mixture of 90 g (1 mole) of acetaldehyde dimethylacetal and 295 mL of a 15% solution of ZnCl2 in anhydrous ethyl acetate. A spontaneous warming up of the mixture to 35°С was observed. The reaction mixture was stirred for 1 h at 40°С, then was cooled to 20 °С and treated with a saturated solution of NaHCO3 (500 mL). The organic layer was separated, and the aqueous layer was thoroughly extracted with ether. The combined organic layer and ether extracts were dried over K2CO3 (or MgSO4). After distillation of the product, 62 g (68.2 %) of 5-methoxy-2-methyl-1-hexen-3-one (3) was obtained, bp 77 С (10 mm Hg).
1,2,5-Trimethyi-4-piperidone (4)
A mixture of 3.4 g (0.024 mole) of (3), 5 ml of a 20% aqueous solution of MeNH2 (0.032 mole) and 3.5 mL of MeOH was heated in a sealed ampule (or tightly closed flask) at 60°С in water bath for 4 h. The mixture was then cooled, acidified with 18% HCl to an acid reaction, MeOH was evaporated off under a slight vacuum, and the reaction mixture was extracted with ether to remove neutral products. The mixture was then cooled and treated with a solid alkali (NaOH/KOH), and extracted thoroughly with ether. The ether extract was dried over MgSO4. After distillation, 2.4 g (71.2 %) of (4) was obtained, bp 82 С (10 mm Hg).
A mixture of 3.4 g (0.024 mole) of (3), 5 ml of a 20% aqueous solution of MeNH2 (0.032 mole) and 3.5 mL of MeOH was heated in a sealed ampule (or tightly closed flask) at 60°С in water bath for 4 h. The mixture was then cooled, acidified with 18% HCl to an acid reaction, MeOH was evaporated off under a slight vacuum, and the reaction mixture was extracted with ether to remove neutral products. The mixture was then cooled and treated with a solid alkali (NaOH/KOH), and extracted thoroughly with ether. The ether extract was dried over MgSO4. After distillation, 2.4 g (71.2 %) of (4) was obtained, bp 82 С (10 mm Hg).
1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine hydrochloride (5)
The molar ratio of 1,2,5-trimethylpiperidone-4 (4) and phenyllithium is 1:1.1. To 1100 mL of a 1 M solution of phenyllithium in diethyl ether, in an inert atmosphere, at a temperature of -70 °C, add a solution of 141 g of 1,2,5-Trimethylpiperidin-4-one (4) in 200 mL of dry diethyl ether. After stirring at -70°C for 2 hours, 112 g of propionyl chloride are added, the temperature is raised to 20-25°C and stirred for 1 hour. Then the reaction mass is carefully acidified with dilute hydrochloric acid, the ether layer is separated, the water layer is extracted with benzene (2×100 mL). 1 L of benzene is added to the aqueous layer and alkalinized with 20% sodium hydroxide solution to pH 10-11. The benzene layer is separated, the aqueous layer is extracted with benzene (2×200 mL). The solvent is distilled off from the combined benzene extract, the residue is distilled in a vacuum of (1 mm Hg), collecting a fraction in the range of 120-148°C (at 1 mm Hg). The distillate is dissolved in 800 mL of benzene, 97 g of propionyl chloride are added, and the reaction mass is left at room temperature for 12 hours. The formed precipitate was separated by filtration, washed with benzene, dried, and recrystallized from 2-propanol. 271.0 g of 1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine hydrochloride (5) are obtained. Yield 86.9%.
The molar ratio of 1,2,5-trimethylpiperidone-4 (4) and phenyllithium is 1:1.1. To 1100 mL of a 1 M solution of phenyllithium in diethyl ether, in an inert atmosphere, at a temperature of -70 °C, add a solution of 141 g of 1,2,5-Trimethylpiperidin-4-one (4) in 200 mL of dry diethyl ether. After stirring at -70°C for 2 hours, 112 g of propionyl chloride are added, the temperature is raised to 20-25°C and stirred for 1 hour. Then the reaction mass is carefully acidified with dilute hydrochloric acid, the ether layer is separated, the water layer is extracted with benzene (2×100 mL). 1 L of benzene is added to the aqueous layer and alkalinized with 20% sodium hydroxide solution to pH 10-11. The benzene layer is separated, the aqueous layer is extracted with benzene (2×200 mL). The solvent is distilled off from the combined benzene extract, the residue is distilled in a vacuum of (1 mm Hg), collecting a fraction in the range of 120-148°C (at 1 mm Hg). The distillate is dissolved in 800 mL of benzene, 97 g of propionyl chloride are added, and the reaction mass is left at room temperature for 12 hours. The formed precipitate was separated by filtration, washed with benzene, dried, and recrystallized from 2-propanol. 271.0 g of 1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine hydrochloride (5) are obtained. Yield 86.9%.
You can choose not to create a reduced temperature and an inert atmosphere for the reaction, but the yield of the reaction will be reduced (read the Introduction).
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