Synthesis of Aminophenylpolycarbonitriles from Arylidenemalononitriles by the Michael Reaction
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Synthesis of Aminophenylpolycarbonitriles from Arylidenemalononitriles by the Michael Reaction M. A. Maryasova,*, V. V. Davydovaa, O. E. Nasakina, S. A. Shteingoltsb, and O. A. Lodochnikovab a
b
I.N. Ulyanov Chuvash State University, Cheboksary, 428015 Russia A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences, Kazan, 420088 Russia *e-mail: [email protected] Received February 20, 2020; revised February 20, 2020; accepted February 27, 2020
Abstract—The reactions of arylidenemalononitriles with malononitrile, methyl cyanoacetate and cyanoacetamide yielded aminophenyldi- and tricarbonitriles. Formation of these compounds occurs through the dehydrocyanation step of the corresponding aminohexenepolycarbonitriles. Keywords: arylidenemalononitriles, malononitrile, aminophenylcarbonitriles, 4-aminocyclohex-4-ene-1,1,3,3,5pentacarbonitrile, SK2 inhibitors
DOI: 10.1134/S1070363220080289 Cycloaddition reactions are widely used in organic synthesis. The Michael reaction can also be used to obtain cyclic products [1–3]. Previously, 4-aminocyclohex4-ene-1,1,3,3,5-pentacarbonitriles have been obtained by reacting malononitrile with two equivalents of arylidenemalononitrile in the presence of a base [4]. Structurally similar compounds have been also prepared through the reaction of malononitrile with levulinic and succinic aldehydes [5]. Aminophenylpolycycarbonitriles are precursors of inhibitors or modulators of protein kinase SK2 activity, which are used to treat tumor diseases, infections, degenerative processes (Alzheimer’s and Parkinson’s
diseases) [6]. In addition, a number of compounds with an aminophenylcarbonitrile moiety exhibit antiinflammatory [7, 8] and antimicrobial activity [9]. In order to optimize the methods for the synthesis of this type of polycarbonitrile compounds, we studied the reactions of vinylidene cyanide 1а and arylidenemalononitriles 1b–1e with malononitrile 2а, cyanoacetamide 2b, and methyl cyanoacetate 2c (Scheme 1). The reactions were carried out in ethanol in the presence of triethylamine with heating (40–50°С) for 3–4 h. As a result, the corresponding aminophenyldi- and -tricarbonitriles 4a–4h were obtained in 55–84% yields.
Scheme 1.
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MARYASOV et al. Scheme 2.
In the case of the reaction of vinylidene cyanide 1а with malononitrile 2а, 4-aminocyclohex-4-ene1,1,3,3,5-pentacarbonitrile 3а was initially isolated, which was subsequently easily oxidized to 2-aminobenzo1,3,5-tricarbonitrile 4а. This confirms the fact that in the case of arylidenemalononitriles 1b–1e, the reaction proceeds through the stage of formation of aminocyclohexenecarbonitriles followed by dehydrocyanation. Structure of compound 3а was confirmed by the single crystal X-ray diffraction analysis (Fig. 1). The X-ray diffraction data obtained by us at 150 K are generally similar to those obtained earlier at 293 K [10]. In the crystal, the six-membered ring of the molecule is in the six-membered envelope conformation: the С2–6 at
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