Type of Resources
The isoxazoline ring has been utilized in many therapeutic agents. For example, it is the key structure in ISO-1, an anti-inflammatory agent with unique anti-Type 1 diabetes activity. There are two primary methods used for the synthesis of isoxazolines: transition metal free cycloadditions and transition metal-mediated cycloadditions and cyclizations. Most transition metal-mediated syntheses employ the use of palladium, gold, silver, or copper complexes as catalysts. The syntheses often require long reaction times and result in low yields with many impurities. In general, mercury-mediated syntheses typically have shorter reaction times and result in products with higher purity. This research investigated the methodological manipulation of four variables for five ortho- and para-substituted oximes in an effort to find the best method to prepare an isoxazoline from a β,γ-unsaturated oxime via a mercury-mediated cyclization. Steric hindrance and electronic effects were observed over the course of the four-step synthetic process. Steric effects were most pronounced in the oximation and cyclization reactions using ortho-methyl and ortho-methoxy substituents. The most successful conditions for the cyclization of oximes were a reaction time of 30 minutes in dichloromethane at room temperature. Mercuric acetate was used in a 1:1 molar ratio with the oxime and resulted in very high yields with minimal byproducts. Catalytic quantities of mercuric acetate were used to show dimerization. The reaction and subsequent 2-isoxazoline were not heat, time, or air sensitive.