Regiodivergent Synthesis of Benzothiazole-Based Isosorbide Imidates by Oxidative N-Heterocyclic Carbene Catalysis

A novel N-heterocyclic carbene (NHC)-promoted regiodivergent protocol for exo (2-OH) and endo (5-OH) isosorbide (IS) imidates synthesis is described. The disclosed strategy allows the straightforward synthesis of monoimidate-isosorbides (MIIs) endowed with the biologically relevant benzothiazole (BTA) moiety under mild oxidative conditions, starting from easy-accessible aldimines. Process optimization encompassed the use of stoichiometric diquinone as well as atmospheric oxygen as oxidant species, focusing on reaction dichotomy between oxidative and oxygenative pathways. The reaction scope was investigated on a representative selection of BTA-containing aldimines and further extended to congeners bearing different biologically pivotal N-heterocyclic rings (benzoxazole, thiazole and isoxazole), observing good levels of yield (up to 87 %) and regioselectivity (exo/endo up to 10.0; endo/exo up to 7.0). Furthermore, the employment of an immobilized-NHC under heterogeneous conditions was assessed, showing satisfactory selectivity towards exo-MIIs (exo/endo=3.8). Overall, the methodology presented provided an unprecedented collection of high value-added products with potential applications in different fields.

Automated summary

A novel NHC-promoted synthesis method for biologically active isosorbide imidates was described. The method allows the easy synthesis of different benzothiazole products by using accessible aldimines and oxidative conditions.