2-methylidene-1-azabicyclo[2.2.2]octan-3-one

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

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

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

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

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

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

Procedure: 2-Methylenequinuclidin-3-one (17.8 g, 0.13 mol, 1 eq) is dissolved in 40 mL MeOH in a Parr hydrogenation bottle. A THF slurry of 10% Pd/C (0.57 g) is added. The mixture is hydrogenated for 45 min at 45 psi, recharging as needed. The mixture is filtered through a pad of Celite. The Celite is washed with excess MeOH. The solution is concentrated to give a solid and a yellow oil. The mixture is taken up in ether, filtered and concentrated to provide 16.2 g (90%) of 2-methylquinuclidin-3-one. MS (ESI) for C8H13NO m/z 140.2 (M+). The mixture is filtered through a pad of Celite The Celite is washed with excess MeOH The solution is concentrated to give a solid filtered concentrated

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

Procedure: A mixture of 2-methylene-3-quinuclidinone dihydrate hydrochloride (27.2 g, 0.13 mol, 1 eq) and K2CO3 (86.0 g, 0.62 mol, 4.8 eq) is dissolved in 130 mL water and 250 mL CH2Cl2 and stirred vigorously. After 3 days, the layers are separated and the aqueous layer is extracted with CH2Cl2. The combined organic layers are dried (MgSO4), filtered and concentrated to give 17.8 g (100%) of 2-methylenequinuclidin3-one as a yellow oil. MS (ESI) for C8H11NO m/z 138.1 (M+). the layers are separated the aqueous layer is extracted with CH2Cl2 The combined organic layers are dried (MgSO4) filtered concentrated

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

Procedure: A reaction flask containing 2-methylenequinuclidin-3-one (6.86 g, 50 mmoles) and a magnetic stir bar was charged with piperidine (12 ml, 120 mmoles). The mixture was stirred at room temperature for 18 hours, and the mixture was added to hexane (300 ml). The solution was filtered through Celite® and the filtrate was concentrated in vacuo (maximum temperature 60° C.) to provide 11.03 g (99%) of the product as a pale yellow solid, mp 34°-37° C. The solution was filtered through Celite® the filtrate was concentrated in vacuo (maximum temperature 60° C.)

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

Procedure: To a solution prepared from 3 g sodium metal in 100 ml absolute methanol there was added 45 g methyl benzyl ketone. The resulting solution was refluxed for 30 minutes, cooled to 0° C. and 39 g 2-methylene-3-quinuclidinone was added. The solution was stirred at ambient temperature during 48 hours, neutralized by the addition of 3 ml acetic acid and the solvents were removed under reduced pressure. There was obtained a crude oil which was extracted with chloroform. After evaporation of the solvent there was obtained 52 g (a yield of 60%) of the desired product, M.P. from acetone, 125.7° C. Treatment with hydrochloric acid gave the corresponding hydrochloride salt, M.P. above 300° C. (dec.). The resulting solution was refluxed for 30 minutes the solvents were removed under reduced pressure There was obtained a crude oil which was extracted with chloroform After evaporation of the solvent there

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

Procedure: To a solution prepared from 3 g sodium metal in 100 ml absolute methanol there was added 45 g methyl benzyl ketone. The resulting solution was refluxed for 30 minutes, cooled to 0° C. and 39 g 2-methylene-3-quinuclidinone was added. The solution was stirred at ambient temperature during 48 hours, neutralized by the addition of 3 ml acetic acid and the solvents were removed under reduced pressure. There was obtained a crude oil which was extracted with chloroform. After evaporation of the solvent there was obtained 52 g (a yield of 60%) of the desired product, M.P. from acetone, 125.7° C. Treatment with hydrochloric acid gave the corresponding hydrochloride salt, M.P. above 300° C. (dec.). The resulting solution was refluxed for 30 minutes the solvents were removed under reduced pressure There was obtained a crude oil which was extracted with chloroform After evaporation of the solvent there

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

Procedure: Ethyl phenylacetate, 49.2 g was added to a solution of sodium ethoxide previously prepared from metallic sodium, 2.9 g and ethanol, 100 ml. The mixture was cooled to 5°, then a solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml. was added dropwise and with stirring. After 16 hours at room temperature, the solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml. was added to the residue and the mixture was extracted with chloroform. Evaporation of this solvent gave ethyl (3-oxoquinuclidin-2-yl)methylphenylacetate, 54 g (60%); b.p. 195°-200° at 1 mm Hg; m.p. of methiodide salt, 194.7-195.6°. The mixture was cooled to 5° was added dropwise then subjected to evaporation at reduced pressure was added to the residue the mixture was extracted with chloroform Evaporation of this solvent

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

Procedure: Ethanolic sodium ethoxide, previously prepared from 2.9 g of metallic sodium and 100 ml of ethanol, was added to diethyl methyl-malonate, 50 g, and the mixture was refluxed for 30 min. then cooled to 5°. A solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml, was then added dropwise and with stirring. After 16 hrs. at room temperature, the resulting solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml was added and the mixture was extracted with chloroform. Evaporation of this solvent gave diethyl (3-oxo quinuclidin-2-yl)-methyl-methylmalonate, 72 g (81%), m.p., 58.4° (from petroleum ether). the mixture was refluxed for 30 min. then cooled to 5° at room temperature then subjected to evaporation at reduced pressure Water, 100 ml was added the mixture was extracted with chloroform Evaporation of this solvent