Thermocatalytic Transformation of Nitriles Utilizing Pristine and Calcined ZnCr Layered Double Hydroxides for the Synthesis of Various Tetrazole- and Kynurenic Acid-Based Drug Candidates

For the first time, Zn/Cr-containing layered double hydroxides (LDH) and mixed metal oxides (MMO) were applied in the synthesis of 5-substituted 1<i>H</i>-tetrazole heterocycles from different aromatic nitriles and TMSN₃ (trimethylsilyl azide) as a less explosive/toxic and easily recoverable azide source. Effects of the nitrile concentration, reaction time, temperature, catalyst loading, and amount of N₃ ^- source were carefully investigated to achieve high yields and selective tetrazole formation under the most sustainable conditions. Both Zn _<i>x</i> Cr-LDH and -MMO (prepared based on thermogravimetric analysis) catalyst forms were efficient in the reaction (achieving between 60 and 95% conversion), and Zn₃Cr-LDH tolerated nitriles containing different electron-withdrawing and -donating substituents well. The catalyst was recycled five times and characterized by X-ray diffractometry, transmission, and scanning electron microscopy with energy-dispersive X-ray analysis, infrared, and Raman spectroscopic techniques. Based on the tests, excellent catalyst reusability results (over 80% conversion and 100% selectivity even at the fifth use) were due to the robustness of the catalytic surface. The performance of zinc-rich Zn₃Cr-LDH catalyst rivaled that of many extreme and noticeably expensive metal-containing materials (Cu, Pd, La), and it was also highly effective for use in DMSO solvent approved for medical research. For the extension of tetrazole synthesis, four new nitriles of kynurenic acid (glutamate receptor antagonists, potential neuroprotective agents with modified blood-brain barrier permeability) were synthesized and fully characterized by nuclear magnetic resonance and mass spectroscopic analyses.