9-methyl-9-azabicyclo[3.3.1]nonan-3-one

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

Procedure: A 5-liter 3-necked flask was charged with 140 grams of 50% aqueous glutaric dialdehyde (Aldrich, 0.7 moles), 630 ml of water and 70.7 grams of CH3NH2.HCl (1.036 moles) which was first dissolved in 700 ml of water, 116.6 grams of acetonedicarboxylic acid (0.8 moles) which had been dissolved in 1162 ml of water, and a solution of 123.2 sodium phosphate dibasic and 10.22 grams of NaOH dissolved in 280 ml of water. The heterogeneous orange solution was stirred at room temperature for 24 hours during which time the evolution of CO2 (g) was noted.

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

Procedure: A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) d 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+ formed This solid was collected by filtration rinsed with additional methanol (2×10 mL) dried under vacuum for 1 h

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

Procedure: A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+ formed This solid was collected by filtration rinsed with additional methanol (2×10 mL) dried under vacuum for 1 h

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

Procedure: A 5-liter 3-necked flask was charged with 140 grams of 50% aqueous glutaric dialdehyde (Aldrich, 0.7 moles), 630 ml of water and 70.7 grams of CH3NH2.HCl (1.036 moles) which was first dissolved in 700 ml of water, 116.6 grams of acetonedicarboxylic acid (0.8 moles) which had been dissolved in 1162 ml of water, and a solution of 123.2 sodium phosphate dibasic and 10.22 grams of NaOH dissolved in 280 ml of water. The heterogeneous orange solution was stirred at room temperature for 24 hours during which time the evolution of CO2 (g) was noted.

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

Procedure: A 5-liter 3-necked flask was charged with 140 grams of 50% aqueous glutaric dialdehyde (Aldrich, 0.7 moles), 630 ml of water and 70.7 grams of CH3NH2.HCl (1.036 moles) which was first dissolved in 700 ml of water, 116.6 grams of acetonedicarboxylic acid (0.8 moles) which had been dissolved in 1162 ml of water, and a solution of 123.2 sodium phosphate dibasic and 10.22 grams of NaOH dissolved in 280 ml of water. The heterogeneous orange solution was stirred at room temperature for 24 hours during which time the evolution of CO2 (g) was noted.

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

Procedure: To a 250 mL RB flask were added 9-methyl-9-azabicyclo[3.3.1]nonan-3-one (10 g), NH2OH.HCl (5.26 g), NaOAc.3H2O (10.26 g), EtOH (56 mL), and H2O (26 mL). The mixture was refluxed for 1.5 h and cooled to RT. Solvents were removed and the residue was partitioned between aqueous K2CO3 (3M) and CHCl3. The organic phase was separated and the aqueous phase extracted twice with CHCl3. The combined CHCl3 solution was washed once with brine, dried over Na2SO4, filtered, and evaporated to a brownish oil, which solidified upon standing. The solid was transferred to a 500 mL Parr flask. To this were added Raney-Ni (6.2 g, wet) and NH3 solution in MeOH (150 mL), made by bubbling NH3 into MeOH for 20 min. This mixture was hydrogenated under a pressure of 40-45 psi of H2 at RT for 18 h. The mixture was filtered through a pad of Celite. All volatiles were removed on a rotary evaporator. EtOH (50 mL) was added to the residue and then evaporated to give an I-1 as an oil (9.5 g, 94%). This crude product contained two isomers, and was used without further purification. The mixture was refluxed for 1.5 h Solvents were removed the residue was partitioned between aqueous K2CO3 (3M) and CHCl3 The organic phase was separated the aqueous phase extracted twice with CHCl3 The combined CHCl3 solution was washed once with brine dried over Na2SO4 filtered evaporated to a brownish oil, which To this were added Raney-Ni (6.2 g, wet) and NH3 solution in MeOH (150 mL) by bubbling NH3 into MeOH for 20 min The mixture was filtered through a pad of Celite All volatiles were removed on a rotary evaporator EtOH (50 mL) was added to the residue evaporated

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

Procedure: The synthesis of arylethenyl-substituted 8-azabicyclo[3.2.1]octanes and arylethynyl-substituted 8-azabicyclo[3.2.1]octanes are accomplished in a manner similar to that described for arylethenyl-substituted 7-azabicyclo[2.2.1]heptanes and arylethynyl-substituted 7-azabicyclo[2.2.1]heptanes. Treatment of pseudopelletierine (N-methyl-9-azabicyclo[3.3.1]nonan-3-one) as described earlier for tropinone (Daly et al. Eur. J. Pharmacol. 321:189-194 (1997)) will generate ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate. Pseudopelletierine is made according to Howell et al., Org. Syn. Coll. Vol IV: 816-819 (1963). Reduction of ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate with diisobutylaluminum hydride and subsequent reaction of the 6-formyl derivative with diethyl (5-isoxazolylmethyl)phosphonate and n-butylithium will provide mixture of ethyl (E)- and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole-8-carboxylate. Separation of the isomers followed by deprotection will provide (E)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole. The other methods described previously for the preparation of five-membered heterocycle analogues of ethenyl-substituted 7-azabicyclo[2.2.1]heptanes may be applied similarly. will provide Separation of the isomers

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

Procedure: To a solution of pseudopelletierine (52 g, 0.34 mol) in toluene (220 mL) at 50° C. was added anhydrous potassium carbonate (1.0 g), followed by the slow addition of trichloroethylchloroformate (79 g, 0.37 mol). After addition was completed (30 minutes), triethylamine (10 mL) was added. The reaction was allowed to cool to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and 1N hydrochloric acid (200 mL). After the organic layer was washed with 1N hydrochloric acid (100 mL), it was washed with aqueous 10% sodium hydroxide (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford a beige solid which was triturated with hexane (300 mL) to afford 81.4 g of crystalline solid (76% yield); mp 95°-96° C. after recrystallization from ethyl acetate-hexane. Anal. (C11H14C13NO3). After addition was added After the organic layer was washed with 1N hydrochloric acid (100 mL), it was washed with aqueous 10% sodium hydroxide (100 mL) The organic layer was dried over anhydrous sodium sulfate filtered concentrated to afford a beige solid which was triturated with hexane (300 mL)

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

Procedure: The synthesis of arylethenyl-substituted 8-azabicyclo[3.2.1]octanes and arylethynyl-substituted 8-azabicyclo[3.2.1]octanes are accomplished in a manner similar to that described for arylethenyl-substituted 7-azabicyclo[2.2.1]heptanes and arylethynyl-substituted 7-azabicyclo[2.2.1]heptanes. Treatment of pseudopelletierine (N-methyl-9-azabicyclo[3.3.1]nonan-3-one) as described earlier for tropinone (Daly et al. Eur. J. Pharmacol. 321:189-194 (1997)) will generate ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate. Pseudopelletierine is made according to Howell et al., Org. Syn. Coll. Vol IV: 816-819 (1963). Reduction of ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate with diisobutylaluminum hydride and subsequent reaction of the 6-formyl derivative with diethyl (5-isoxazolylmethyl)phosphonate and n-butylithium will provide mixture of ethyl (E)- and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole-8-carboxylate. Separation of the isomers followed by deprotection will provide (E)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole. The other methods described previously for the preparation of five-membered heterocycle analogues of ethenyl-substituted 7-azabicyclo[2.2.1]heptanes may be applied similarly. will provide Separation of the isomers

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

Procedure: A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) d 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+ formed This solid was collected by filtration rinsed with additional methanol (2×10 mL) dried under vacuum for 1 h

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

Procedure: A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+ formed This solid was collected by filtration rinsed with additional methanol (2×10 mL) dried under vacuum for 1 h

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

Procedure: A 5-liter 3-necked flask was charged with 140 grams of 50% aqueous glutaric dialdehyde (Aldrich, 0.7 moles), 630 ml of water and 70.7 grams of CH3NH2.HCl (1.036 moles) which was first dissolved in 700 ml of water, 116.6 grams of acetonedicarboxylic acid (0.8 moles) which had been dissolved in 1162 ml of water, and a solution of 123.2 sodium phosphate dibasic and 10.22 grams of NaOH dissolved in 280 ml of water. The heterogeneous orange solution was stirred at room temperature for 24 hours during which time the evolution of CO2 (g) was noted.