Preparation of octahydro-2H-chromen-4-ol with analgesic activity from isopulegol and thiophene-2-carbaldehyde in the presence of acid-modified clays

AYu Sidorenko, AV Kravtsova, Johan Wärnå, Atte Aho, I. Heinmaa, IV Il’ina, OV Ardashov, KP Volcho, NF Salakhutdinov, Dmitry Murzin, VE Agabekov

Research output: Contribution to journalArticleScientificpeer-review

25 Citations (Scopus)


Prins reaction of (−)-isopulegol with thiophene-2-carbaldehyde to physiologically active substituted octahydro-2H-chromenol (as 4R and 4S diastereomers) was studied in the presence of commercial montmorillonites K-10 and K-30, acid-treated illite and glauconite clays as well as synthetic aluminosilicate AS-36 without of any solvent and in cyclohexane solution. The effect of the reaction temperature, catalyst/reagents ratio, solids drying conditions, and the initial concentrations of reagents on the yield of the desired chromenol and selectivity to diastereomers formation was studied for the first time. The catalysts were characterized by XRF, XRD, MAS NMR, FTIR with pyridine and nitrogen low-temperature sorption methods In the absence of any solvent after 1 h 70.8–99.0% conversion of isopulegol depending on the catalyst was achieved with 78.5–82.0% overall selectivity to octahydro-2H-chromenol. Ratio of 4R/4S diastereomers increased from 3.7 to 4.9 with decrease of the acid sites concentration in the catalyst from 153 to 47 μmol/g. The overall selectivity to chromenol and 4R/4S ratio increased with decreasing the drying temperature of illite clay which indicates preferable formation of 4R isomer in the presence of weak Brønsted acid sites. In cyclohexane as a solvent at same substrate conversion the yield of octahydro-2H-chromenol on illite clay decreases with a decrease in the catalyst/reagents ratio. At 50% isopulegol conversion the 4R/4S ratio increased from 5.7 to 6.8 with a decrease in the initial concentration of reagents from 0.5 to 0.05 mol/l, while the overall selectivity to chromenol decreased from 84.9 to 76.1%. It is established that formation of chromenol and dehydration byproducts (chromenes) occurs both in consecutive and parallel pathways, with only 4R diastereomer undergoing dehydrated. Kinetic modeling was performed to describe quantitatively observed regularities for the first time. Acid-modified illite L-1 clay is a promising catalyst for the synthesis of octahydro-2H-chromenol exhibiting analgesic activity.

Original languageUndefined/Unknown
Pages (from-to)139–148
JournalMolecular Catalysis
Publication statusPublished - 2018
MoE publication typeA1 Journal article-refereed

Cite this