Aldehyde synthesis (via alkene):

 

To a mixture of alkene coumpound (284 mg, 0.72 mmol) in t-BuOH (1.8 mL) and THF (0.6 mL) at room temperature was added N-methylmorpholine N-oxide (337 mg, 1.44 mmol) followed by osmium tetroxide (0.027 mL, 0.022 mmol). The mixture was stirred at room temperature overnight. The reaction was then diluted with phosphate buffer (pH 7, 5 mL). Sodium periodate (693 mg, 3.24 mmol) was then added and the cloudy solution was stirred vigorously for 2 hours. Next it was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give aldehyde compound as a yellow solid (251 mg, 88%).

 

Patent reference: WO2010056564 (Merck)

Aldehyde synthesis (via alkene):

 

Oxalyl chloride (99%, 0.39 mL, 4.4 mmol) was added drop-wise to a -78 °C solution of dimethyl sulfoxide (0.83 ml, 8.9 mmoi) in dichloromethane (5 mL). After 20 minutes, a solution of benzyl (2S,4R)-4-[(3- fluorophenyl)amino]-4-{hydroxymethyl)-2-methylpiperidine-1-carboxylate (1.10 g, 2.95 mmol) in dichloromethane (5 ml) was slowly added. After an additional 20 minutes, triethylamine (99%, 1.86 mL. 11.8 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The reaction was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the product as an oil. Yield: 600 mg, 1.62 mmol, 55%.

 

Patent reference: WO2010058333 (Pfizer)

Swern oxidation

Aldehyde synthesis (via cyanide): 

 

A 200 mL round bottom flask was charged with a magnetic stir bar, 3-ethoxy-2- fluorobenzonitrile (1.000 g, 6.05 mmol), and anhydrous toluene (12.92 ml). The solution was placed under argon and cooled to 0°C with an ice bath. DIBAL-H (7.27 ml, 7.27 mmol) (1M in PhMe) was then added drop wise via syringe and the reaction was allowed to stir to rt overnight. To this mixture was added 10 % HCl until the solution reached a pH of ~ 2. The resulting mixture was then left to stir for 0.5 h. and was then poured into a separatory funnel and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:4) as eluent to provide pure 3-ethoxy-2-fluorobenzaldehyde (0.810 g, 80 %).

 

Patent reference: WO2010001169 (Astrazeneca)

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