Aldehyde synthesis from alkene

Aldehydes can be synthesized from alkenes by oxidation using ozonolysis, wacker oxidation and in some cases oxidation by KMnO₄ in THF can lead to formation of aldehyde.

Procedure:

Ozonolysis

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)

Wacker oxidation (general procedure)

 Palladium(II) acetate (0.2 mmol), benzoquinone (9 mmol), and the inorganic acid (HCl, HClO₄, HBF₄, H₂SO₄, or HNO₃, 0.1 M) were dissolved in acetonitrile/water (7:1 v/v, 50 mL). The solution was deoxygenated by purging with argon for at least 30 min and stirred vigorously until the Pd(OAc)₂ had dissolved. The olefin (10 mmol) was then added to the flask (by syringe), and the reaction mixture was stirred for 10 min. The products were separated from the catalyst by extraction into hexane or diethyl ether, washed with 30% aqueous sodium hydroxide, water and concentrated to a residue.

Reference:  J. Org. Chem. 55, 2924-2927 (1990)

KMnO₄ in THF oxidation

 4-Formyl-2,2-dimethyl-1H-1,5-benzodiazepine (2, R1=R4)

To a solution of 10 g (0.036 mol) of 1 in 300 mL of THF was added 10 g (0.063 mol) of KMnO₄ dissolved in 100 mL of water, over a period of 3.5 h in small portions. The reaction mixture was allowed to warm up to 40 °C. After the addition was finished, the brown precipitate was filtered, and the filtrate was concentrated and extracted with diethyl ether. After drying, the organic phase was concentrated and the resulting oil crystallized from diisopropyl ether: 7 g (78.7%); mp 102-104°C.

Above procedure can be used to synthesize all of the other aldehydes listed in Table I. Solubility of the starting material determines the THF/H₂O ratio. In case of low solubility, a few preliminary tests should be made to determine the minimum amount of THF.

Attention: Usage of neat THF or addition of solid KMnO₄ may lead to an explosion and therefore must be avoided.

4-(2-Phenylvinyl)-2,2-dimethyl-1H-1,5-benzodiazepine (1, R1=R4, R2=H, R3=Ph)

A solution of 10 g (0.053 mol) of 2,2,4-trimethyl-1H-1,5-benzodiazepine, 5.63 g (0.053 mol) of benzaldehyde, and 0.5 g of ammonium acetate in 100 mL benzene was refluxed for 4 h and then concentrated. The resulting oil is crystallized from diisopropyl ether: 12.1 g (82.4%); mp 134-136°C.

Refrence: P. Viski, Z. Szeverenyi, and L. I. Simandi J. Org. Chem. 51, 3213-3214 (1986)