TCFH-NMI: An Emerging Method for Amide Bond Formation and Beyond

N,N,N′,N′-Tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole (TCFH-NMI), a reagent combination for acylation reactions first described in 2018, is gaining recognition and finding applications from research laboratories through to large-scale manufacturing. In this review, we will detail the unique properties of this method for amide bond formation before discussing its extension into the synthesis of esters, ketones, and other functional group transformations. The high reactivity of the N-acyl imidazolium ion, the unique activated ester intermediate accessible by this method, provides for a broad substrate scope under mild conditions. In combination with the favorable safety characteristics of these reagents and ease of isolation provided by the simple water-soluble byproducts, TCFH-NMI should prove an impactful addition to the organic chemists’ toolbox alongside more commonly used amide bond-forming reagents.