Preparation of halogenated derivatives of thiazolo[5,4‐d]thiazole via direct electrophilic aromatic substitution

Chlorination and bromination reactions of thiazolo5,4‐d]thiazole led to the generation of its mono‐ and dihalogenated derivatives. These are the first instances of successful direct electrophilic aromatic substitution in the thiazolo5,4‐d]thiazole ring system. X‐ray analysis demonstrates that both 2‐bromothiazolo5,4‐d]‐thiazole and 2,5‐dibromothiazolo5,4‐d]thiazole are planar structures, with strongly manifested π‐stacking in the solid state. Theoretical analysis of the pyridine‐catalyzed halogenation (MP2/6‐31+G(d) and B3LYP/6‐31+G(d) calculations) reveals that introduction of one halogen actually leads to a slightly enhanced reactivity towards further halogenation. Several halogenation mechanisms have been investigated: 1) The direct C‐halogenation with N‐halopyridine as electrophile; 2) C‐halogenation via intermediate N‐halogenation, and 3) C‐halogenation following an addition ‐ elimination pathway, with intermediate formation of a cyclic halonium ion. The theoretical studies suggest that the direct C‐halogenation is the favored mechanism.