4-(Methylsulfonyl)cyclohexanone

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

Procedure: A solution containing (buta-1,3-dien-2-yloxy)(trimethyl)silane (12.5 ml, 70.7 mmol) in toluene (50 ml), was treated with (methylsulfonyl)ethene (4.1 ml, 47.1 mmol) and heated under reflux for 76 hours. After which time, the reaction mixture was cooled to room temperature and concentrated in-vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 (120 ml) and filtered through Celite®. The filtrate was concentrated in-vacuo and the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water). It was then treated with TFA (2.0 ml). The reaction mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 25 hours. The reaction mixture was concentrated in-vacuo and the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera to give the title compound 1.2 g (14%) as a thick yellow oil. LC-MS 94%, 0.39 min (3.5 minute LC-MS method), m/z=177.0 (ELS visible only). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.24-3.32 (m, 1H) 2.94 (s, 3H) 2.62-2.70 (m, 2H) 2.50-2.56 (m, 2H) 2.38-2.45 (m, 2H) 2.07-2.18 (m, 2H). heated under reflux for 76 hours concentrated in-vacuo to give a yellow oil filtered through Celite® The filtrate was concentrated in-vacuo the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water) It was then treated with TFA (2.0 ml) at room temperature for 25 hours The reaction mixture was concentrated in-vacuo the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera

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

Procedure: A solution containing (buta-1,3-dien-2-yloxy)(trimethyl)silane (12.5 ml, 70.7 mmol) in toluene (50 ml), was treated with (methylsulfonyl)ethene (4.1 ml, 47.1 mmol) and heated under reflux for 76 hours. After which time, the reaction mixture was cooled to room temperature and concentrated in-vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 (120 ml) and filtered through Celite®. The filtrate was concentrated in-vacuo and the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water). It was then treated with TFA (2.0 ml). The reaction mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 25 hours. The reaction mixture was concentrated in-vacuo and the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera to give the title compound 1.2 g (14%) as a thick yellow oil. LC-MS 94%, 0.39 min (3.5 minute LC-MS method), m/z=177.0 (ELS visible only). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.24-3.32 (m, 1H) 2.94 (s, 3H) 2.62-2.70 (m, 2H) 2.50-2.56 (m, 2H) 2.38-2.45 (m, 2H) 2.07-2.18 (m, 2H). heated under reflux for 76 hours concentrated in-vacuo to give a yellow oil filtered through Celite® The filtrate was concentrated in-vacuo the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water) It was then treated with TFA (2.0 ml) at room temperature for 25 hours The reaction mixture was concentrated in-vacuo the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera

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

Procedure: A solution containing (buta-1,3-dien-2-yloxy)(trimethyl)silane (12.5 ml, 70.7 mmol) in toluene (50 ml), was treated with (methylsulfonyl)ethene (4.1 ml, 47.1 mmol) and heated under reflux for 76 hours. After which time, the reaction mixture was cooled to room temperature and concentrated in-vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 (120 ml) and filtered through Celite®. The filtrate was concentrated in-vacuo and the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water). It was then treated with TFA (2.0 ml). The reaction mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 25 hours. The reaction mixture was concentrated in-vacuo and the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera to give the title compound 1.2 g (14%) as a thick yellow oil. LC-MS 94%, 0.39 min (3.5 minute LC-MS method), m/z=177.0 (ELS visible only). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.24-3.32 (m, 1H) 2.94 (s, 3H) 2.62-2.70 (m, 2H) 2.50-2.56 (m, 2H) 2.38-2.45 (m, 2H) 2.07-2.18 (m, 2H). heated under reflux for 76 hours concentrated in-vacuo to give a yellow oil filtered through Celite® The filtrate was concentrated in-vacuo the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water) It was then treated with TFA (2.0 ml) at room temperature for 25 hours The reaction mixture was concentrated in-vacuo the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a dry pressure resistant vessel of 20 ml, 1.0 g (5.20 mmole) 4-methanesulphonylcyclohexanone, 0.56 g (5.20 mmole) 2-picolylamine, 0.89 g (10.4 mmole) acetone cyanhydrin and 1.06 g (10.4 mmole) triethylamine were dissolved in 16 ml dry methanol. The vessel was closed and heated for 50 hours at 100° C. Methanol was evaporated and the residue was re-dissolved in dichloromethane, washed with a saturated NaHCO3 solution, dried over MgSO4, filtered and evaporated. The residue was further purified by means of column chromatography. 7-(pyridin-3-ylmethyl)-7-aza-bicyclo[2.2.1]heptane-1-carbonitrile (structural formula below) was thus obtained in a 69% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, infrared (IR) spectrophotometry and mass spectrum (MSES) as follows. The vessel was closed Methanol was evaporated the residue was re-dissolved in dichloromethane washed with a saturated NaHCO3 solution dried over MgSO4 filtered evaporated The residue was further purified by means of column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a dry pressure resistant vessel of 20 ml, 1.0 g (5.20 mmole) 4-methanesulphonylcyclohexanone, 0.56 g (5.20 mmole) 3-picolylamine, 0.89 g (10.4 mmole) acetonecyanohydrin and 1.06 g (10.4 mmole) triethylamine were dissolved in 16 ml dry methanol. The vessel was closed and heated for 50 hours at 100° C. Methanol was then evaporated and the residue was redissolved in dichloromethane, washed with a saturated NaHCO3 solution, dried over MgSO4, filtered and evaporated. The residue was further purified by means of column chromatography. 7-(pyridin-3-ylmethyl)-7-aza-bicyclo[2.2.1]heptane-1-carbonitrile (structural formula below) was thus obtained in a 50% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, infrared (IR) spectrophotometry and mass spectrum (MSES) as follows: The vessel was closed Methanol was then evaporated the residue was redissolved in dichloromethane washed with a saturated NaHCO3 solution dried over MgSO4 filtered evaporated The residue was further purified by means of column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This synthesis was performed according to scheme 2, with details as follows. In a dry, pressure resistant vessel of 20 ml, 1.25 g (6.5 mmole) 4-methanesulfonylcyclohexanone 9, 0.89 g (6.5 mmole) 4-methoxybenzylamine, 1.11 g (13 mmole) acetone cyanohydrine and 1.32 g (13 mmole) triethylamine were dissolved in 16 ml dry methanol. The vessel was closed and heated to 100° C. for 50 hours. Methanol was evaporated and the residue was redissolved in dichloromethane. The solution was washed with a saturated NaHCO3 solution and dried over MgSO4. After filtration of the solids, the volatile components were evaporated. 7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptane-1-carbonitrile 6a was obtained as a brown oil in a 97% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, and mass spectrum (MSES) as follows: The vessel was closed Methanol was evaporated the residue was redissolved in dichloromethane The solution was washed with a saturated NaHCO3 solution dried over MgSO4 After filtration of the solids the volatile components were evaporated