Transition-metal-free three-component synthesis of α-tertiary trifluoromethyl phosphonates from CF3 diazo compounds

Abstract

α-Trifluoromethylated phosphonates are highly valued in medicinal chemistry and functional materials, yet their efficient synthesis remains challenging. Herein, we report a practical, transition-metal-free strategy for the rapid assembly of this important class of scaffolds via a one-pot, three-component reaction, using α-trifluoromethyl diazo compounds as key precursors together with readily accessible H-phosphites and benzyl bromides or alkyl halides. This mild reaction proceeds through a base-promoted, ordered nucleophilic attack sequence, enabling the simultaneous formation of C-C and C-P bonds and affording products bearing congested, fully substituted carbon centers in high yields (up to 98%). The selected products were predicted to have favorable pharmacokinetic properties based on in silico ADME analysis. This work provides a general synthetic route to α-trifluoromethylated phosphonates and highlights their broad application prospects in drug discovery and functional materials development.