Stereochemical Aspects of T3P Amidations

21 Feb 2017

Zheng Wang, Robert D. Barrows, Thomas J. Emge, and Spencer Knapp

Organic Process Research and Development

DOI: 10.1021/acs.oprd.7b00046

Abstract

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 Nmethylimidazole 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.
 
Read the full article on ACS Publications.