Synthesis of Tyramine-Derived Aromatic Amides as Building Blocks for Tripodal Phosphorothioates and Star-Shaped Hexakis(aryloxy)cyclotriphosphazenes

Abstract

Tyramine combines a nucleophilic primary amine and a phenolic hydroxyl group in one small molecule, which makes it a convenient bifunctional building block. In this work, four aromatic carboxylic acids (benzoic, 2-naphthoic, indole-2-carboxylic and nicotinic acid) were coupled chemoselectively with tyramine using EDC/HOBt in DMF at room temperature. The coupling gave the N-(4-hydroxyphenethyl)amides 1a–1d in 86–90% yield with the phenolic OH left free. The phenol was then used as a nucleophile towards two phosphorus cores in dry THF with anhydrous cesium carbonate as the base. With phosphorothioyl trichloride, substitution of all three P–Cl bonds gave the tripodal phosphorothioate triesters 2a–2d (85–89%). With hexachlorocyclotriphosphazene, replacement of all six chlorine atoms gave the star-shaped hexakis(aryloxy)cyclotriphosphazenes 3a–3d (84–86%). Both phosphorylation steps proceeded at room temperature, and the products were purified by simple precipitation from dichloromethane into pentane, without chromatography. All twelve compounds were characterized by FT-IR, ¹H and ¹³C NMR spectroscopy, HRMS and elemental analysis. The mild, modular route gives access to multivalent molecules that display three or six identical aryl amide units on a central phosphorus scaffold, and these compounds are now available for biological and materials evaluation.