Metal‐Free Synthetic Approach to 3‐Monosubstituted Unsymmetrical 1,2,4,5‐Tetrazines Useful for Bioorthogonal 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. Using this novel approach 11 3‐aryl/alkyl 1,2,4,5‐tetrazines were prepared in excellent yields (up to 75 %). The mechanism of this new reaction, including the role of DCM in the tetrazine ring formation, has been investigated by 13 C labeling of DCM, and is also presented and discussed as well as the photophysical and electrochemical properties.