Accessing trifluoromethylated SuFEx-able pyrazole via distortion-accelerated 1,3-dipolar cycloadditions

Abstract

Fluorinated pyrazoles are valuable scaffolds with wide-ranging applications in medicinal chemistry, agrochemistry and materials science. We report the 1,3-dipolar cycloaddition of 2,2,2-trifluorodiazoethane and 1-bromoethene-1-sulfonyl fluoride for the concise synthesis of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride. Computational analysis revealed that lowered distortion energies account for increased reactivity relative to other stabilized diazo compounds. The resulting trifluoromethylated pyrazole contains a SuFEx-able click handle, enabling orthogonal diversification pathways for diversity-oriented clicking. Together, these features support rapid functionalization and efficient access to structurally diverse analogs, offering a versatile platform for expansion of chemical space geared towards the development of bioactive molecules.