A Unified Phosgene-Free Carbonylation Using CO2 for the Synthesis of Ureas, Carbamates, Carbonates, Amides, and Formamides

Abstract

Phosgene remains a privileged reagent for carbonylation; however, its extreme toxicity and stringent regulatory controls often restrict its routine and broad application. Herein, we describe a unified CO2-based carbonylation platform for the synthesis of ureas, (thio)carbamates, (thio)carbonates, amides, and formamides under mild, metal-free conditions. The method employs readily available phosphorus(V) activators to generate transient phosphorus-activated carbonyl species that selectively react with amines, alcohols, thiols, hydrides, and organometallic reagents, enabling a one-pot, three-component protocol that telescopes multi-step phosgene-based sequences into a single operation. This approach eliminates the need for phosgene and other preactivated carbonylating reagents. Mechanistic studies are most consistent with the involvement of a transient phosphorus-mediated carbonylating species, conceptually analogous to electrophilic carbonyl transfer in biological systems, although its precise identity remains unresolved. The synthetic utility of the platform is demonstrated by the 25 g synthesis of the anticancer drug sorafenib using POCl3 as the activator. By harnessing CO2 as a C1 synthon, this strategy addresses a long-standing challenge in electrophilic carbonylation and provides an operationally simple and complementary alternative to phosgene-based methods.