Metal-Free Synthetic Approach to 3-Monosubstituted Unsymmetrical 1,2,4,5-Tetrazines Useful for Bio-orthogonal Reactions

A facile, efficient and metal-free synthetic approach to 3-monosubstituted unsymmetrical 1,2,4,5-tetrazines is presented. Dichloromethane (DCM) is for the first time recognized as a novel reagent in the synthetic chemistry of tetrazines. Eleven 3-aryl/alkyl 1,2,4,5-tetrazines were prepared in excellent yields (up to 75%) through this novel approach. The mechanism of this new reaction, including the role of DCM in the tetrazine ring formation, has been investigated by DCM¹³C labeling, and is also presented and discussed as well as the photophysical and electrochemical properties.