Facile Synthesis of Hydroxyformamidines by the N-Oxidation of Their Corresponding Formamidines

Abstract

The N-oxidation of N,N¢-disubstituted amidines with MCPBA (m-chloroperoxibenzoic acid) affords a mild, rapid, and efficient route to the corresponding hydroxyamidines This novel synthetic route for the preparation of N,N¢-disubstituted hydroxyamidines provides an attractive alternative to the classical one. It was found that the efficiency of the N-oxidation reaction, and the stability of the hydroxyformamidines are influenced by the substitution on the N,N¢-diaryl rings, for example, higher yields (up to 92%) and more stable products are obtained for the compounds bearing substituents in the 2,6-positions of the phenyl rings. 1 H NMR and 13 C NMR, HRMS and/or elemental analysis were used to characterize the products. N,N¢-Disubstituted hydroxyamidines/amidoximes have been studied for their biological activity (antituberculars, hypotensives), their pharmacological properties (bactericidal, fungicidal, local anaesthetics), 1 and also as precursors in the synthesis of cyclic compounds. 2 Their propensity to form stable five-membered chelate rings with metal ions was exploited for tracing metals in analytical chemistry. 3 They also show good electronic delocalization through the ligand backbone and have interesting design possibilities as far as multiple functionalization is concerned. Due to these properties, the N,N¢-disubstituted hydroxyamidines/amidoximes and their mononuclear complexes are interesting candidates for incorporation into supramolecular assemblies based on coordination chemistry and hydrogen bonding. They could also present potential applications in catalysis, as recently many catalysts containing N,O-bidentate ligands have been developed. 4 Surprisingly, none of these aspects of their chemistry have received much attention in the literature. In this context, our main objective is to synthesize and characterize N,N¢-diaryl-N-hydroxyamidine ligands and their different metal complexes, in order to study their properties and their possible applications in the above-mentioned fields. We have developed and optimized a new route for the synthesis of the hydroxyamidines -the N-oxidation of the parent amidines with MCPBA -as a more efficient alternative to the classical one (Scheme 1). We report herein the results obtained using different functionalized formamidines 2a-i as substrates (Scheme 2) Generally, hydroxyamidines are prepared from the corresponding carboxylic acids, aniline, and hydroxyaniline, Scheme 1 Synthesis of hydroxyamidines via a classic route 5