Project 5 Background

Isoxazoles are five-membered heteroaromatic compounds that contain adjacent oxygen and nitrogen atoms. Many isoxazole-containing compounds are known to exhibit potent biological activities, including anticancer, antibacterial, antifungal, antiviral, anti-tuberculosis, and antiflammatory. Some examples of these compounds are illustrated in Figure 1.

Figure 1. Some examples of biologically active isoxazoles. Sulfisoxazole (1) is an antibiotic used to treat a range of severe bacterial infections. Oxacillin (2) is a penicillin antibiotic most often used to treat resistant staphylococci infections. Compound 3 was reported as a potential prodrug to treat tuberculosis infections. KRIBB3 (4) shows significant anti-tumor activity against a variety of cancers.

KRIBB3 (4) is a relatively simple 4,5-diarylisoxazole that displays significant antitumor activity against colon, prostate, breast, and lung cancers. This compound and similar isoxazole analogs may be attractive candidates forĀ  clinical applications.

A University of Richmond undergraduate researcher recently demonstrated an effective method for preparing the simplest KRIBB3 analog, 4,5-diphenylisoxazole (Figure 2). Although the synthesis involves four reaction steps, it is accomplished by performing two sequential “one-pot” syntheses. In a one-pot synthesis, the reactant undergoes successive chemical transformations in the same reaction vessel, thereby increasing the efficiency of the overall process.

Figure 2. Synthesis of 4,5-diphenylisoxazole (10) via two one-pot reaction sequences.

The synthesis begins with the condensation of acetophenone 5 and benzaldehyde 6 to generate chalcone 7, which is not isolated. Addition of hydrogen peroxide to the reaction flask oxidizes 7 to chalcone epoxide 8, which is isolated and purified by recrystallization. In the second series of reactions, copper (II) trifluoromethanesulfonate (a.k.a. “copper triflate”) behaves as a Lewis acid to initiate an interesting rearrangement of 8 to ketoaldehyde 9. Condensation of 9 with hydroxylamine hydrochloride produces the isoxazole 10.

In Project 5, your class will investigate the scope of the methodology outlined in Figure 2. Each lab group will attempt to prepare a different 4,5-diarylisoxazole by applying the procedure to a different pair of aryl ketone and aryl aldehyde starting materials. To plan your synthesis, complete the Project 5 Experiment Design Plan and bring a printed copy to lab the week of 11/1-11/5. After your instructor approves your plan, and you may begin lab work. You will have 3 weeks of lab time to complete complete the reactions, gather data, ask questions, and prepare for your presentation.