Thioacylation Achieved by Activation of a Monothiocarboxylic Acid with Phosphorus Reagents

A selection of phosphorus-based coupling reagents have been tested for their ability to activate the ambident nucleophilic monothio acid group as a thiocarbonyl functionality, suitable for use in thioacylations for the formation of thioamides. For these studies the reaction between thioacetic acid and cyclohexylamine to give the corresponding thioamide was chosen as a model. The obtained O/S-selectivities were monitored by the use of P-31 NMR and were found to be dependent on the nature of the phosphorus functionality and on the kind of leaving group involved. Several new analogues of the widely used peptide coupling reagent (benzotriazol-1-yloxy)tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBOP, 1a) were prepared and investigated. Best results were obtained with two new analogues of PyBOP: [(6-nitrobenzotriazol-1-yl)oxy]tris(pyrrolidino)phosphonium hexafluorophosphate (PyNOP, 1b) and [[6-(trifluoromethyl)benzotriazol-1-yl]oxy]tris(pyrrolidino)phosphonium hexafluorophosphate (PyFOP, 1c). Both reagents, containing electron-withdrawing substituents at the benzotriazole ring, secured fast activation of the monothio acid. Other phosphorus reagents, such as bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrOP, 1d), gave an undesired O/S-selectivity, leading to the formation of oxoamides and phosphorus sulfides.