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

## TL;DR

This paper introduces a new method using ZnCr-based catalysts to efficiently and sustainably synthesize tetrazole and kynurenic acid-based drug candidates from nitriles.

## Contribution

The first use of ZnCr-based LDH/MMO catalysts for tetrazole synthesis with high efficiency and reusability under sustainable conditions.

## Key findings

- Zn3Cr-LDH achieved 60–95% conversion of nitriles to tetrazoles with high selectivity.
- The catalyst retained over 80% conversion and 100% selectivity after five reuse cycles.
- Four new kynurenic acid nitriles were synthesized and characterized for potential neuroprotective applications.

## Abstract

For the first time,
Zn/Cr-containing layered double hydroxides
(LDH) and mixed metal oxides (MMO) were applied in the synthesis of
5-substituted 1H-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
x
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.