phenyl(piperidin-1-yl)methanone

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

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

Conditions: temp:80.01; pressure:0.00; stir:

Procedure: In an argon filled glove box, a 5.0 mL wheaton microreactor was charged with [Ir(cod)(OMe)]2 (1.98 mg, 1.5 mol%), L1 ligand (2.1 mg, 3.5 mol%), B2pin2 (50.8 mg, 1.0 equiv.), KOtBu (1.0 mg, 4.5 mol%) and dry THF (1.0 mL). The reaction mixture was stirred for 2 minutes at room temperature. To this mixture, phenyl(piperidin-1-yl)methanone (37.8 mg, 0.2 mmol) was added. The microreactor was capped with a teflon pressure cap and placed into pre-heated aluminum block at 80 oC. The reaction mixture was stirred for 12 h. After completion (judged by GC/MS), THF was removed under reduced pressure and chromatographic separation with silica gel (15% ethyl acetate in hexane as eluent) gave the meta-borylated product 4h (42.2 mg, 67%) as white solid. Spectral data are in accordance with the reported data.

Conditions: temp:25.01; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:

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

Procedure: To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+(found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602). before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL) The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+(found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602). before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL) The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+ (found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602). before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL) The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL) dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (115.35 g, 480 mmol) and toluene (100 mL) were added to a mixture of benzoylpiperidine (95.4 g, 1.05 equivalents) and phosphorus oxychloride (88 mL, 147 g, 0.96 equivalents), which had been stirred at 25° C. for 1 hour. An additional 100 mL toluene was added. The suspension was heated to a temperature of 40° C. to 45° C. for 4 hours. The resulting syrup was transferred into a rapidly stirring solution of sodium hydroxide (180 g, 4.5 mol), piperidine (1.0 mL), and water (650 mL). The temperature was maintained at 25° C. to 35° C. and the mixture was stirred for 1 hour. A mixture of toluene (100 mL), water (50 mL), and sodium hydroxide (12 g, 300 mmol) was added to the reaction flask, and the entire reaction mixture was stirred at 25° C. for 1 hour. The suspension was then heated to 75° C. and the layers were separated. The organic layer was cooled to 60° C. and hexane (100 mL) was slowly added, and the solution slowly stirred and cooled to −15° C. The precipitate was filtered, washed with toluene/hexane (150 mL, 2:1 v/v) and then with hexane (150 mL), and dried under vacuum at 25° C. to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (138.01 g, 83.5% yield). The suspension was heated to a temperature of 40° C. to 45° C. for 4 hours The temperature was maintained at 25° C. to 35° C. the mixture was stirred for 1 hour was added to the reaction flask the entire reaction mixture was stirred at 25° C. for 1 hour The suspension was then heated to 75° C. the layers were separated The organic layer was cooled to 60° C. hexane (100 mL) was slowly added the solution slowly stirred cooled to −15° C The precipitate was filtered washed with toluene/hexane (150 mL, 2:1 v/v) with hexane (150 mL), and dried under vacuum at 25° C.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (115.35 g, 480 mmol) and toluene (100 mL) were added to a mixture of benzoylpiperidine (95.4 g, 1.05 equivalents) and phosphorus oxychloride (88 mL, 147 g, 0.96 equivalents), which had been stirred at 25° C. for 1 hour. An additional 100 mL toluene was added. The suspension was heated to a temperature of 40° C. to 45° C. for 4 hours. The resulting syrup was transferred into a rapidly stirring solution of sodium hydroxide (180 g, 4.5 mol), piperidine (1.0 mL), and water (650 mL). The temperature was maintained at 25° C. to 35° C. and the mixture was stirred for 1 hour. A mixture of toluene (100 mL), water (50 mL), and sodium hydroxide (12 g, 300 mmol) was added to the reaction flask, and the entire reaction mixture was stirred at 25° C. for 1 hour. The suspension was then heated to 75° C. and the layers were separated. The organic layer was cooled to 60° C. and hexane (100 mL) was slowly added, and the solution slowly stirred and cooled to −15° C. The precipitate was filtered, washed with toluene/hexane (150 mL, 2:1 v/v) and then with hexane (150 mL), and dried under vacuum at 25° C. to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (138.01 g, 83.5% yield). The suspension was heated to a temperature of 40° C. to 45° C. for 4 hours The temperature was maintained at 25° C. to 35° C. the mixture was stirred for 1 hour was added to the reaction flask the entire reaction mixture was stirred at 25° C. for 1 hour The suspension was then heated to 75° C. the layers were separated The organic layer was cooled to 60° C. hexane (100 mL) was slowly added the solution slowly stirred cooled to −15° C The precipitate was filtered washed with toluene/hexane (150 mL, 2:1 v/v) with hexane (150 mL), and dried under vacuum at 25° C.

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

Procedure: Benzoyl chloride (500 mL, 606 g, 4.3 mol) was added dropwise to a rapidly stirring mixture of piperidine (426 mL, 367 g, 4.3 mol), sodium hydroxide (190 g, 4.7 mol, 1.1 equivalents), toluene (1 L), and water (1.7 L) over a period of 70 minutes. After the addition was complete, the mixture was stirred at 25° C. for one hour. The organic and aqueous phases were separated, and the organic phase was washed with 2N hydrochloric acid (2×100 mL), concentrated by rotary evaporation, and distilled under vacuum to yield benzoylpiperidine as a colorless liquid which crystallized on standing. (779 g, 95% yield, bp 169° C. to 171° C.). After the addition the mixture was stirred at 25° C. for one hour The organic and aqueous phases were separated the organic phase was washed with 2N hydrochloric acid (2×100 mL) concentrated by rotary evaporation distilled under vacuum

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