Indole-3-carbaldehydes Arylhydrazones as Multisite C-Nucleophiles in the Reactions with Quinazoline
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le-3-carbaldehydes Arylhydrazones as Multisite C-Nucleophiles in the Reactions with Quinazoline Yu. A. Azeva,*, O. S. Koptyaevaa, O. S. Eltsova, Yu. A. Yakovlevaa, A. N. Tsmokalyuka, A. V. Ivoilovaa, E. A. Seliverstovaa, T. A. Pospelovaa, and V. A. Bakuleva a Ural
Federal University, Yekaterinburg, 620002 Russia *e-mail: [email protected]
Received April 15, 2020; revised April 15, 2020; accepted April 25, 2020
Abstract—C,C-Coupling of indole-3-carbaldehyde arylhydrazones with quinazoline in trifluoroacetic acid has occurred at position 5 or 7′ of the hydrazone molecule and has afforded the σ-adducts. The C,C-coupling has been accompanied by a change in the E-configuration of the C=N bond of the starting hydrazones to the Z-configuration in the formed quinazoline trifluoroacetyl hydrazides. Keywords: arylhydrazones, indole-3-carbaldehydes, C,C-coupling, quinazoline, trifluoro hydrazides
DOI: 10.1134/S1070363220090030 Quinazoline core is a part of natural alkaloids [1, 2]. The derivatives of quinazoline include the compounds revealing various types of biological activity, including antimicrobial, antiallergic, hypotonic, antiviral [3], antitumor [4], and radioprotective [5] ones. The addition of C-nucleophiles at 3-methylquinazolinium iodide yielding 4-substituted 3,4-dihydroquinazolines has been reported [6]. Furthermore, it has been found that unsubstituted quinazoline reacts with indole, 5-methyl-2-phenylpyrazol-3-one, 1,3-dimethylbarbituric acid, and pyrogallol in the presence of an acid, resulting in the 4-σ-adducts [7]. The examples of quinazoline arylation with 1,3,5-trimetoxybenzene, 1-(4-metoxybenzylidene)-2-phenylhydrazine, and o-phenylenediamines have been described [8]. Efficient quinazoline-based drugs can be prepared via varying the substituents (pharmacophore fragments) in these compounds, which allows tuning of their physicochemical properties (hydrophilicity and lipophilicity), bioavailability, and activity. Indole core is a constituent of tryptophane and its metabolites as well as certain natural alkaloids and antibiotics [9]. Indole derivatives have revealed antitumor, antiviral, antiinflammatory, antidepressant, and other types of activity [10]. We continue to develop methods for the synthesis of biologically active derivatives of quinoxaline [7]. At
present, atom economic processes that correspond to the principles of green chemistry are the most promising [11]. The reactions of nucleophilic C‒C coupling are among them, since they can proceed under conditions of acid catalysis (without the use of metal catalysts) and are theoretically waste-free [12, 13]. In this study, phenylhydrazones of indole-3carbaldehydes 3а–3e were used as nucleophiles which were prepared by short-term heating of indole-3-carbaldehydes 1a, 1b with phenylhydrazines 2a–2d in aqueous ethanol in the presence of HCl (Scheme 1). The structure of the obtained compounds was confirmed using 1 Н and 13 С NMR spectroscopy, mass spectrometry, and the 2D experiments: 1H‒13C gHSQC/gHMBC and 1H‒15N gHMBC. In the case of arylhydrazones,
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