Synthesis of Symmetrical Bis-Benzimidazole, Bis-Benzoxazole, and Bis-Benzothiazole Derivatives via Double Cyclocondensation of EDTA with ortho-Substituted Anilines

Abstract

A series of symmetrical bis-benzimidazole, bis-benzoxazole, and bis-benzothiazole derivatives were synthesized through a double Phillips-type cyclocondensation between ethylenediaminetetraacetic acid (EDTA) and a set of ortho-substituted aniline precursors. EDTA serves as a polycarboxylic substrate enabling the simultaneous formation of two heterocyclic rings in a single step under strong acidic conditions. Structural elucidation of the ten obtained compounds was confirmed by 1H and 13C NMR spectroscopy, HRMS, and comparison with reported data. The observed molecular masses and NMR profiles unambiguously support the formation of bis-heterocyclic structures. Yields ranged from 49% to 73% depending on the nature of the heteroatom (O, S, or N), reflecting the higher nucleophilicity of sulfur leading to improved cyclization efficiency. Corrected synthetic schemes and a mechanistic rationale are presented.