7-oxa-3-azabicyclo[4.1.0]heptan-3-yl(phenyl)methanone

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

Procedure: The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).

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

Procedure: Into a solution of 10 (2.27 g, 12.1 mmol) in CH2Cl2 (20 mL), a solution of 3-chloroperoxybenzoic acid (5.43 g, 77% pure, 24.3 mmol) in CH2Cl2 (40 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. After the reaction was complete as determined by TLC (hexane/ethyl acetate, 1/1, v/v), saturated Na2CO3 solution (50 mL) was added into the reaction vial slowly with stirring. The reaction mixture was stirred for 30 min. The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using hexane/ethyl acetate (3/1, v/v) as the mobile phase to afford the product as a sticky oil (1.54 g, 62%). 1H NMR (CDCl3): δ 2.04-2.18 (m, 2H), 3.09-4.40 (m, 6H), 7.28-7.47 (m, 5H). with stirring The reaction mixture was stirred for 30 min The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL) dried over Na2SO4 concentrated under reduced pressure The crude product was purified by silica gel column chromatograph

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

Procedure: Into a solution of 10 (2.27 g, 12.1 mmol) in CH2Cl2 (20 mL), a solution of 3-chloroperoxybenzoic acid (5.43 g, 77% pure, 24.3 mmol) in CH2Cl2 (40 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. After the reaction was complete as determined by TLC (hexane/ethyl acetate, 1/1, v/v), saturated Na2CO3 solution (50 mL) was added into the reaction vial slowly with stirring. The reaction mixture was stirred for 30 min. The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using hexane/ethyl acetate (3/1, v/v) as the mobile phase to afford the product as a sticky oil (1.54 g, 62%). 1H NMR (CDCl3): δ 2.04-2.18 (m, 2H), 3.09-4.40 (m, 6H), 7.28-7.47 (m, 5H). with stirring The reaction mixture was stirred for 30 min The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL) dried over Na2SO4 concentrated under reduced pressure The crude product was purified by silica gel column chromatograph

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethynyl magnesium chloride in THF (5 mmole) at 0° C., is added dropwise a solution of 40 (5.8 mmole) in THF. The mixture is allowed to stir at 0-10° C. for 1 hour, then at room temperature for an additional hour and then heated with gentle reflux for 30 mm. The reaction mixture is added to ice-water and the formed precipitate, Mg(OH)2, is dissolved in 30% H2SO4. The product formed is extracted repeatedly with methylene chloride. Standard work-up and flash chromatography affords 54. at room temperature for an additional hour heated with gentle reflux for 30 mm The product formed is extracted repeatedly with methylene chloride

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

Procedure: A solution of metachloroperbenzoic acid (12 mmole) in methylene chloride is added dropwise to a solution of 39 at 4 C. The reaction mixture is allowed to stir overnight at room temperature. It is made basic and then extracted with methylene chloride. Following work-up and flash chromatography affords 40. extracted with methylene chloride

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

Procedure: The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).

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

Procedure: Into a solution of 10 (2.27 g, 12.1 mmol) in CH2Cl2 (20 mL), a solution of 3-chloroperoxybenzoic acid (5.43 g, 77% pure, 24.3 mmol) in CH2Cl2 (40 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. After the reaction was complete as determined by TLC (hexane/ethyl acetate, 1/1, v/v), saturated Na2CO3 solution (50 mL) was added into the reaction vial slowly with stirring. The reaction mixture was stirred for 30 min. The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using hexane/ethyl acetate (3/1, v/v) as the mobile phase to afford the product as a sticky oil (1.54 g, 62%). 1H NMR (CDCl3): δ 2.04-2.18 (m, 2H), 3.09-4.40 (m, 6H), 7.28-7.47 (m, 5H). with stirring The reaction mixture was stirred for 30 min The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL) dried over Na2SO4 concentrated under reduced pressure The crude product was purified by silica gel column chromatograph

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethynyl magnesium chloride in THF (5 mmole) at 0° C., is added dropwise a solution of 40 (5.8 mmole) in THF. The mixture is allowed to stir at 0-10° C. for 1 hour, then at room temperature for an additional hour and then heated with gentle reflux for 30 mm. The reaction mixture is added to ice-water and the formed precipitate, Mg(OH)2, is dissolved in 30% H2SO4. The product formed is extracted repeatedly with methylene chloride. Standard work-up and flash chromatography affords 54. at room temperature for an additional hour heated with gentle reflux for 30 mm The product formed is extracted repeatedly with methylene chloride

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

Procedure: A solution of metachloroperbenzoic acid (12 mmole) in methylene chloride is added dropwise to a solution of 39 at 4 C. The reaction mixture is allowed to stir overnight at room temperature. It is made basic and then extracted with methylene chloride. Following work-up and flash chromatography affords 40. extracted with methylene chloride

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

Procedure: The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).

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

Procedure: Into a solution of 10 (2.27 g, 12.1 mmol) in CH2Cl2 (20 mL), a solution of 3-chloroperoxybenzoic acid (5.43 g, 77% pure, 24.3 mmol) in CH2Cl2 (40 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. After the reaction was complete as determined by TLC (hexane/ethyl acetate, 1/1, v/v), saturated Na2CO3 solution (50 mL) was added into the reaction vial slowly with stirring. The reaction mixture was stirred for 30 min. The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using hexane/ethyl acetate (3/1, v/v) as the mobile phase to afford the product as a sticky oil (1.54 g, 62%). 1H NMR (CDCl3): δ 2.04-2.18 (m, 2H), 3.09-4.40 (m, 6H), 7.28-7.47 (m, 5H). with stirring The reaction mixture was stirred for 30 min The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL) dried over Na2SO4 concentrated under reduced pressure The crude product was purified by silica gel column chromatograph