Organic Synthesis

Preparation of 3,5-diphenylisooxazoline


The Diels-Alder reaction is a cycloaddition involving six π electrons – four of them coming from a diene and two from a dienophile. An analogous reaction called 1,3-dipolar or Huisgen cycloaddition appear between 1,3 dipolar species and alkenes. Instead of six-membered ring formation (the Diels-Alder reaction), a five-memebered ring is formed as it can be seen on the picture below.


Nitrile oxides are told to react easily with an alkene (a dipolarophile) generating heterocyclic products called isoxazolines. Nitrile oxides can be prepared in situ by oxidation of starting oxime. In this reaction syn-benzaldehyde oxime will be prepared and used as a starting oxime for the cycloaddition. The reaction yields 3,5-diphenylisooxazoline.


Other compounds including nitrones, azides, diazomethane and ozone (ozonolysis) can act as 1,3-dipoles due to the resonance structures. Two possible products can be prepared. The regioselectivity depends on electronic and and steric effects mainly.


a) Prepration of syn-benzaldehyde oxime
Sodium hydroxide (3.5 g, 87 mmol) was dissolved in 30 mL of distilled water in 100 mL Erlenmayer flask. The solution was cooled down in an ice-bath. Benzaldehyde (5.1 mL, 50 mmol) was added regurarly along with hydroxylamine hydrochloride (4.2 g, 60 mmol) in small portions (5 minutes interval). The reaction mixture was stirred vigorously. After all benzaldehyde has been consumped the mixture was stirred for another 10 minutes and then neutralized with glacial acetic acid. The mixture was extracted with ether (2×30 mL). Organic phases were combined, dried over anhydrous magnesium(II) sulphate and filtrated. The solvent was distilled off using rotary evaporator. The crude product was weighted and used in the next step. Yield: 68.4 %.

b) Preparation of 3,5-diphenylisooxazoline
Styrene (2.9 mL, 25 mmol) and triethylamine (0.3 mL, 2 mmol) were dissolved in 15 mL of dichloromethane. Under constant stirring syn-benzaldehyde oxime (2.5 g) was added dropwise from a Pasteur pipet over 15 minutes to the mixture. After the addition the mixture was stirred for another 45 minutes. The lower organic phase was separated and the aqueous layer was extracted with another 15 mL of dichloromethane. The organic phases were combined together, dried over anhydrous magnesium(II) sulphate, filtered and the solvent was distilled off. The product was cooled down and crystallized. The crude product was weighted. Yield: 69.6 %.