3-Quinuclidone hydrochloride
An example of the experimental procedure of the Dieckmann condensation is exemplified by the synthesis of 3-quinuclidone hydrochloride. This preparation involves two steps. In the first step, 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine is treated with potassium ethoxide in refluxing toluene leading to the formation of the bridgehead bicyclic system via the Dieckmann condensation. In the second step, the intermediate is decarboxylated via treatment with concentrated hydrochloric acid.
Experimental:
3-Quinuclidone hydrochloride
1. Dieckmann Condensation:
Freshly cut potassium (40 g, 1.03 mol) is added to 165 mL of dry toluene under inert atmosphere. The mixture is heated at reflux until the potassium has melted. Absolute ethanol (63 mL, 49.3 g, 1.07 mol) is then added over 30 minutes to the rapidly stirred solution at reflux. Upon the disappearance of the potassium metal, the temperature of the reaction mixture is raised to 130 °C and 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine (100 g, 0.411 mol) in 250 mL of dry toluene is added dropwise over 2 hours.
After heating at 130 °C for an additional 3 hours, the reaction mixture is cooled to 0 °C followed by slow addition of 250 mL 10M hydrochloric acid. The resulting mixture is then extracted with 10M hydrochloric acid (2X125 mL).
2. Decarboxylation:
The combined aqueous fractions are heated at reflux for 15 hours followed by the addition of 5 g of activated charcoal. The resulting mixture is then filtered and evaporated to dryness in vacuo. The crude product is then dissolved in 150 mL of water and saturated aqueous potassium carbonate is added very slowly to avoid foaming until the solution has become basic. The resulting solution is then treated with solid potassium carbonate until a slurry is obtained, followed by extraction with diethyl ether (4X200 mL). The combined organic fractions are then treated with calcined potassium carbonate. After 60 minutes the mixture is filtered and concentrated in vacuo. The resulting solid is then treated with 75 g of ice and 10M hydrochloric acid (65 mL, 75 g) followed by evaporation to dryness. The resulting material is then purified via recrystallization from hot water and boiling isopropanol.