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Domino Nitro Reduction-Friedlander Heterocyclization for the Preparation of Quinolines.

ABSTRACT: The Friedländer synthesis offers efficient access to substituted quinolines from 2-aminobenzaldehydes and activated ketones in the presence of a base. The disadvantage of this procedure lies in the fact that relatively few 2-aminobenzaldehyde derivatives are readily available. To overcome this problem, we report a modification of this process involving the in situ reduction of 2-nitrobenzaldehydes with Fe/AcOH in the presence of active methylene compounds (AMCs) to produce substituted quinolines in high yields. The conditions are mild enough to tolerate a wide range of functionality in both reacting partners and promote reactions not only with phenyl and benzyl ketones, but also with β-keto-esters, β-keto-nitriles, β-keto-sulfones and β-diketones. The reaction of 2-nitroaromatic ketones with unsymmetrical AMCs is less reliable, giving a competitive formation of substituted quinolin-2(1H)-ones from the cyclization of the Z Knoevenagel intermediate which appears to be favored when certain large groups are adjacent to the AMC ketone carbonyl.

SUBMITTER: Fobi K

PROVIDER: S-EPMC9268355 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Styryl quinolines are biologically active compounds with properties largely depending on the substituents on the styryl and quinoline rings. The supramolecular aspects of this class of compounds are rarely explored. In this study, two new series of styryl quinoline derivatives, bearing -OH and -NO2 groups at the eighthposition of the quinoline ring and -SCH3, -OCH3, and -Br groups on the styryl ring, have been developed, and their structural, supramolecular, and cytotoxic properties have been analyzed. Crystallographic analyses revealed the exciting substituent-dependent structural and supramolecular features of these compounds. In general, the 8 -OH substituted derivatives (SA series) exhibited a non-planar molecular geometry having larger dihedral angles (5.75-59.3°) between the planes of the aromatic rings. At the same time, the 8 -NO2 substituted derivatives (SB series) exhibited a more or less planar molecular geometry, as revealed by the smaller dihedral angles (1.32-3.45°) between the aromatic rings. Multiple O-H···O, C-H···O, O-H···N, and π-π stacking interactions among the molecules lead to fascinating supramolecular architectures such as hydrogen-bonded triple helices, zig-zag 1D chains, π-π stacked infinite chains, and so forth in their crystal lattice. Hirshfeld surface analyses confirmed the existence of strong π-π stacking and other weak bonding interactions in these compounds. The preliminary cytotoxic properties of SA and SB series compounds were evaluated against the human cervical cancer cell lines (HeLa cells), which further highlighted the roles of functional substituents on the aromatic rings. The SA series compounds with the -OH substituent on the quinoline ring exhibited better cytotoxicity than the SB series compounds with a -NO2 substituent. Similarly, the electron-withdrawing group -Br on the styryl ring enhanced the cytotoxicity in both series. The IC50 values were 2.52-4.69 and 2.897-10.37 μM, respectively, for the SA and SB series compounds. Compound S3A having -OH and -Br groups on the quinoline and styryl ring, respectively, exhibited the best IC50 value of 2.52 μM among all the compounds tested. These findings confirm the relevance of the hydroxyl group in the eighth position of quinoline. In short, the present study attempts to provide a systematic analysis of the effects of aromatic ring substituents on the structural, supramolecular, and cytotoxic properties of styryl quinolines for the first time.

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Domino Nitro Reduction-Friedlander Heterocyclization for the Preparation of Quinolines.

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