2-piperidin-1-ylbenzaldehyde

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

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL), cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68 mmol, 1.0 eq) was added dropwise. After 15 min, a solution of 2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) was added slowly while maintaining the temperature at −20° C. After an additional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution in hexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture was maintained at −20° C. for 90 h using a cryocool apparatus and then cooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8 mmol, 6.0 eq). The cooling bath was removed after the addition and the work-up was carried out once the reaction mixture was at RT. The mixture was poured into a cold solution of saturated NH4Cl and extracted 3X with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to afford a brown oil which was purified by flash chromatography using a mixture consisting of 5% EtOAc-95% hexane as eluent. The desired 2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil (3.74 g, 43% yield). After an additional 15 min The reaction mixture was maintained at −20° C. for 90 h The cooling bath was removed after the addition was at RT The mixture was poured into a cold solution of saturated NH4Cl extracted 3X with EtOAc The combined organic layer was washed with brine dried over anhydrous MgSO4 filtered concentrated to afford a brown oil which was purified by flash chromatography

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the aldehyde 3a (20 g, 161.1 mmol) in dry DMF (160 mL), piperidine (19.1 mL, 193.4 mmol, 1.2 eq) and potassium carbonate (26.73 g, 193.4 mmol, 1.2 eq) were successively added. The suspension was heated at 130° C. for 3 h. The reaction mixture was then poured into cold water and acidified with citric acid up to pH 5. The aqueous layer was extracted 3X with EtOAc and the combined organic extract was successively washed with water, saturated NaHCO3 and brine. After drying the organic extract over MgSO4, filtration and concentration, the desired 2-piperidinobenzaldehyde 3b was isolated as a red oil (28.23 g, 92% yield). The aqueous layer was extracted 3X with EtOAc the combined organic extract was successively washed with water, saturated NaHCO3 and brine After drying the organic extract over MgSO4, filtration and concentration

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the aldehyde 3a (20 g, 161.1 mmol) in dry DMF (160 mL), piperidine (19.1 mL, 193.4 mmol, 1.2 eq) and potassium carbonate (26.73 g, 193.4 mmol, 1.2 eq) were successively added. The suspension was heated at 130° C. for 3 h. The reaction mixture was then poured into cold water and acidified with citric acid up to pH 5. The aqueous layer was extracted 3X with EtOAc and the combined organic extract was successively washed with water, saturated NaHCO3 and brine. After drying the organic extract over MgSO4, filtration and concentration, the desired 2-piperidinobenzaldehyde 3b was isolated as a red oil (28.23 g, 92% yield). The aqueous layer was extracted 3X with EtOAc the combined organic extract was successively washed with water, saturated NaHCO3 and brine After drying the organic extract over MgSO4, filtration and concentration

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

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

Procedure: In a 3 necked round bottom flask (25 ml), equipped with a dropping funnel, reflux condenser and thermometer pocket, placed magnesium turnings (0.254 gm, 10.47 mmol) and flame dried the apparatus. Dry diethyl ether (10 ml.) was added to Mg. Turning, Isobutyl bromide (1.13 ml, 1.45 gm, 10.58 mmol) was taken in 2 ml of dry ether and added drop wise to the Mg turnings. As soon as ether starts boiling (in a few minutes) the reaction was cooled using ice-salt and continued the addition of isobutyl bromide. After complete addition of isobutyl bromide continued for another 20 minutes. o-piperidino benzaldehyde 8 (1.0 gm, 5.29 mmol) in 2 ml of ether was added drop wise at −10° C. After the completion of addition of 8 continued the stirring for 1 hr and the reaction was quenched with ice-cooled saturated ammonium chloride solution (5 ml), the solid separated is filtered off, the filtrate is extracted with ethyl acetate (10×2 ml) dried over sodium sulphate and concentrated to yield 1.36 gm of crude product. The crude product was chromatographed and obtained pure 9 (54.2%). In a 3 necked round bottom flask (25 ml), equipped with a dropping funnel reflux condenser flame dried the apparatus Dry diethyl ether (10 ml.) was added to Mg (in a few minutes) was cooled After the completion of addition of 8 stirring for 1 hr the reaction was quenched with ice- cooled saturated ammonium chloride solution (5 ml) the solid separated is filtered off the filtrate is extracted with ethyl acetate (10×2 ml) dried over sodium sulphate concentrated to yield 1.36 gm of crude product The crude product was chromatographed

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

Procedure: A mixture of o-fluorobenzaldehyde (1.24 gm, 10 mmol), potassium carbonate (2.76 gm, 20 mmol), and piperidine (1.7 gm, 20 mmol) was refluxed in dry DMF for 6 hrs. After the completion of reaction DMF was distilled out at vaccum and 5 ml of water was added to the residue and extracted the product with ethyl acetate (10 ml×2). Organic layer was dried over sodium sulphate and evaporated the solvent to afford 1.8 gm of product (8) (90.5%) 1HNMR CDCl3 (Spectrum 9): 1.68(m, 6H), 3.05(m, 4H), 7.05(m, 2H), 7.45(dd, 1H), 7.75(dd, 1H). was distilled out at vaccum and 5 ml of water was added to the residue extracted the product with ethyl acetate (10 ml×2) Organic layer was dried over sodium sulphate evaporated the solvent

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL), cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68 mmol, 1.0 eq) was added dropwise. After 15 min, a solution of 2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) was added slowly while maintaining the temperature at −20° C. After an additional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution in hexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture was maintained at −20° C. for 90 h using a cryocool apparatus and then cooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8 mmol, 6.0 eq). The cooling bath was removed after the addition and the work-up was carried out once the reaction mixture was at RT. The mixture was poured into a cold solution of saturated NH4Cl and extracted 3X with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to afford a brown oil which was purified by flash chromatography using a mixture consisting of 5% EtOAc-95% hexane as eluent. The desired 2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil (3.74 g, 43% yield). After an additional 15 min The reaction mixture was maintained at −20° C. for 90 h The cooling bath was removed after the addition was at RT The mixture was poured into a cold solution of saturated NH4Cl extracted 3X with EtOAc The combined organic layer was washed with brine dried over anhydrous MgSO4 filtered concentrated to afford a brown oil which was purified by flash chromatography

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the aldehyde 3a (20 g, 161.1 mmol) in dry DMF (160 mL), piperidine (19.1 mL, 193.4 mmol, 1.2 eq) and potassium carbonate (26.73 g, 193.4 mmol, 1.2 eq) were successively added. The suspension was heated at 130° C. for 3 h. The reaction mixture was then poured into cold water and acidified with citric acid up to pH 5. The aqueous layer was extracted 3X with EtOAc and the combined organic extract was successively washed with water, saturated NaHCO3 and brine. After drying the organic extract over MgSO4, filtration and concentration, the desired 2-piperidinobenzaldehyde 3b was isolated as a red oil (28.23 g, 92% yield). The aqueous layer was extracted 3X with EtOAc the combined organic extract was successively washed with water, saturated NaHCO3 and brine After drying the organic extract over MgSO4, filtration and concentration