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).