Photoinduced [3+2] Cycloaddition of Carbenes and Nitriles: A Versatile Approach to Oxazole Synthesis

We have developed a photoinduced protocol for the synthesis of pharmaceutically important oxazole molecules using diazo- and nitrile-containing reactants. The process involves the initial photolysis of the diazo compound to afford singlet carbenes, which are tapped by nitriles in a [3+2] cycloaddition fashion to give substituted oxazoles. With di-nitrile compounds, useful bis-oxazoles were obtained. The applicability of the transformation is showcased through the expedient synthesis of small-molecule drugs and biologically relevant molecules such as felbinac, pimprinine, texamine, ugnenenazole etc. The protocol is also useful for the generation of 2H and 13C isotope labelled oxazoles. Merging photolysis with continuous-flow chemistry was demonstrated for scaling up the reaction. The non-requirement of metal catalysis or photosensitizers to harness the light energy with blue light sufficing the execution of the reaction makes it a versatile and general protocol for the synthesis of structurally diverse oxazoles Utilizing singlet carbenes, we developed a versatile method for [3+2] cycloaddition with diverse nitriles to yield substituted oxazoles. Our approach can be extended to bis-oxazoles, isotope-labeled oxazoles, drug diversification, as well as natural product and drug synthesis. Integration of photolysis with continuous-flow chemistry demonstrated applicability, scalability, and robustness for oxazole synthesis.+image

Automated summary

We have developed a photoinduced protocol for the synthesis of pharmaceutically important oxazole molecules using diazo- and nitrile-containing reactants. The process involves the initial photolysis of the diazo compound to afford singlet carbenes, which are tapped by nitriles in a [3+2] cycloaddition fashion to give substituted oxazoles. The protocol is applicable for the synthesis of diverse oxazoles and can be used for drug synthesis and isotope labeling.