Copper-Catalyzed C-N Bond Coupling Approach to Highly Substituted Oxazoles

Significance

A modular and practical synthesis of highly substituted oxazoles is reported. The route starts with a Cu-catalyzed amidation of vinyl halides, the second step being an intramolecular cyclization promoted by iodine. For the second step, a variety of different iodine sources as well as different bases were studied. Iodine combined with 2 equivalents of K₂CO₃ at 80 °C was found to be optimal, whereas other procedures gave lower yields and/or various byproducts. Addition of an acid (PTSA) was required in some cases to achieve isomerization to the desired oxazole. This stepwise process was then translated into a sequential process which showed similar efficiency. The scope was well-studied: Electron-donating and -withdrawing groups were tolerated and the yields were good. A limitation of this process is that mono- or disubstituted oxazoles gave complex mixtures or decomposition products. The authors tried to redeem this drawback by successfully testing a domino Cu-catalyzed C-N/C-O bond-forming reaction employing a 1,2-dihaloalkene substrate (Route B).

Comment

Oxazoles are ubiquitous in a variety of natural products (Z. Jin Nat. Prod. Rep. 2006, 23, 464) displaying biological activities such as cytotoxic, antifungal, antibacterial, antitumor, and antiviral activities (see review below) as well as being important synthetic intermediates. Classical methods for their preparation include the Cornforth protocol (J. W. Cornforth, R. H. Cornforth J. Chem. Soc. 1947, 96) and Robinson-Gabriel-type reactions (P. Wipf, C. P. Miller J. Org. Chem. 1993, 58, 3604), which have largely been replaced by newer metal-catalyzed approaches (M. P. Kumar, R.-S. Liu J. Org. Chem. 2006, 71, 4951). The reported procedure provides a valuable addition due to its efficiency, mild conditions, and the ready availability of starting materials. A drawback of the method is the unsuccesful synthesis of mono- or disubstituted oxazoles, which can be circumvented by using dihaloalkenes but these substrates are not readily available.

Review

E. Riego et al. Synthesis 2005, 1907.