Expanding the Chemical Space: Functionalized Ethynyl Oxazoles as Versatile Reagents for the Click Chemistry

The limited availability of synthetic techniques and methods, coupled with the sensitivity of the oxazole ring, has restricted the use of ethynyl-substituted oxazoles in drug design, despite their potential advantages. In this study, we present our extensive experience in oxazole chemistry through a comprehensive analysis of the oxazole core’s tolerance to various reaction conditions for selective modifications. Additionally, we aimed to optimize synthetic protocols to develop efficient methods scalable to multigram quantities in a single run. We also sought to identify mild, tolerant approaches to address the instability of the oxazole ring and manage potential side reactions. Our work led to the development of an efficient approach for performing click reactions on ethynyl heterocycles, resulting in excellent yields and a straightforward purification process. This opens up a largely unexplored space for incorporating small molecule oxazoles into drug targets via click reactions with various azides. These findings could significantly advance oxazole chemistry and their integration into drug development programs.