Stereochemical Aspects of T3P Amidations

Propanephosphonic acid anhydride (T3P) is a process-friendly commercial reagent that is useful for direct carboxamide formation from the carboxylic acid and amine components. For amidation reactions of certain tetrahydroisoquinolonic carboxylic acids and electron-poor anilines, the phosphonate carboxylate mixed anhydride intermediate evidently eliminates under basic conditions to give a ketene, whose addition reaction in turn leads to a mixture of diastereomeric amide products. For example, 1,4-diazabicyclo­[2,2,2]­octane, used as the base, provides mostly the 3,4-cis product, whereas N-methylimidazole leads efficiently to the 3,4-trans product. A mechanistic rationale, along with compelling evidence for the intermediate ketene, is provided, as are several examples of the efficient T3P-mediated preparation of carboxamides that are of interest as active antimalarials.