Knoevenagel-Cyclization Cascade Reactions of Substituted 5,6-Dihydro-2H-Pyran Derivatives

Király, Sándor Balázs and Bényei, Attila and Lisztes, Erika and Bíró, Tamás and Tóth, Balázs István and Kurtán, Tibor (2021) Knoevenagel-Cyclization Cascade Reactions of Substituted 5,6-Dihydro-2H-Pyran Derivatives. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2021 (45). pp. 6161-6170. ISSN 1434-193X

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Abstract

The diastereoselective domino-Knoevenagel-IMHDA reactions of 5,6-dihydro-2H-pyran derivatives containing an o-formylaryl amine or ether moiety were performed with active methylene reagents. In the spiro heterocyclic products representing a novel skeleton, a tetrahydroquinoline or chroman unit is fused with two pyran rings and the bridgehead carbon atoms are chirality centers formed diastereoselectively. Depending on the substitution pattern, a domino Knoevenagel-[1,5]-hydride shiftcyclization sequence was identified as a competing pathway, which resulted in the formation of tetrahydroquinoline derivatives with a 5,6-dihydro-2H-pyran-3-yl substituent. The relative configurations of the products were determined by means of the characteristic NOE correlations and single crystal X-ray diffraction analysis. Antiproliferative activity assays of two products against A2780 and WM35 human cancer cell lines showed low micromolar IC50 values down to 2.99 μM.

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