Synthesis and Biological Activity of 2-Aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides
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hesis and Biological Activity of 2-Aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides N. V. Nosovaa, D. D. Lezhninaa, O. N. Geina, V. V. Novikovaa, and V. L. Geina,* a Perm
State Pharmaceutical Academy, Perm, 614990 Russia *e-mail: [email protected]
Received May 16, 2020; revised May 16, 2020; accepted May 31, 2020
Abstract—The reaction of unsubstituted acetoacetamide with aromatic aldehydes in ethanol in the presence of piperidine gave 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides and 4-aryl-5-acetyl-2-hydroxy2-methyl-6-oxopiperidine-3-carboxamides. Structures of the obtained compounds were proved using IR, 1H and 13C NMR spectroscopy methods. The synthesized compounds were tested for antimicrobial and analgesic activities. Keywords: 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides, acetoacetamide, aromatic aldehydes, antimicrobial activity, analgesic activity, toxicity
DOI: 10.1134/S1070363220100011 Functionalized cyclohexanones are polyfunctional compounds containing ester or amide moieties, a hydroxyl group, and an aromatic substituent. Recently, an effective procedure has been developed for the preparation of 6-oxocyclohexane-1,3-dicarboxamides under basic catalysis conditions [1]. Among the obtained compounds, substances possessing weak antimicrobial activity and a pronounced analgesic effect were found [2–6]. It has been previously shown that the reaction of acetylacetone, alkyl acetoacetate or N-substituted acetoacetamide with aromatic aldehydes under basic catalysis conditions yield 3-aryl-2,4-diacetyl-5hydroxy-5-methylcyclohexanones, 2-aryl-6-hydroxy6-methyl-4-oxocyclohexane-1,3-dicarboxylates and 2-aryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3dicarboxamides [5, 7–9]. Among the substances obtained, compounds with various types of biological activity have been found [5, 7]. The reaction of N-unsubstituted acetoacetic acid amide with aromatic aldehydes in ethanol in the presence of piperidine as a catalyst furnished 2-aryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3dicarboxamides [1]. Other direction of the cyclization has been found when reacting acetoacetic acid amides with aromatic aldehydes. Thus, functionalized piperidin2-ones were obtained in the case of ortho-substituted aldehydes bearing a bulky substituent in position 2 of the aromatic ring [1], as well as when using Lewis acids as a catalyst [10].
In order to obtain new biologically active compounds and to establish the effect of the nature and position of the substituent in the aromatic aldehyde on the reaction outcome, we continued to study this reaction. A series of new 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3dicarboxamides 1а–1f was synthesized when carrying out diketone condensation of acetoacetamide with para- and meta-substituted aromatic aldehydes in a 2 : 1 ratio in ethanol (Scheme 1). It was found that the cyclization occurs with the participation of the amide group to form 4-aryl-5-acetyl2-hydroxy-2-methyl-6-oxopiperidine-3-carboxamides 2а–2d when 2-bromobenzaldehyde was used as the carbonyl comp
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