Synthesis and Biological Activity of 8-(Dialkylamino)-3-aryl-6-oxo-2,4-dicyanobicyclo[3.2.1]octane-2,4-dicarboxylic Acid
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hesis and Biological Activity of 8-(Dialkylamino)-3-aryl6-oxo-2,4-dicyanobicyclo[3.2.1]octane-2,4-dicarboxylic Acids Diethyl Esters A. I. Ismiyeva,*, M. Shoaiba, V. V. Dotsenkob,c, K. G. Ganbarova, A. A. Israilovaa, and A. M. Magerramova a Baku
State University, Baku, AZ1148 Azerbaijan State University, Krasnodar, 350040 Russia c North Caucasus University, Stavropol, 355009 Russia *e-mail: [email protected] b Kuban
Received January 3, 2020; revised February 25, 2020; accepted February 28, 2020
Abstract—Cascade reaction of 2 equiv. of furfural (or equimolar amounts of furfural and aromatic aldehyde) with secondary amines and ethyl cyanoacetate afforded diethyl esters of 8-(dialkylamino)-3-aryl-6-oxo-2,4-dicyanobicyclo[3.2.1]octane-2,4-dicarboxylic acids with yields of 37–54%. Antimicrobial activity of a number of obtained compounds in vitro was studied, and biological activity in silico was analyzed. The obtained bicyclo[3.2.1]octanes are inactive or exhibit weak fungicidal activity, but exhibit moderate bactericidal effect. Keywords: furfural, Stenhouse salts, Nazarov reaction, aza-Piancatelli rearrangement, bicyclo[3.2.1]octane
DOI: 10.1134/S1070363220080071 Compounds containing bicyclo[3.2.1]octane fragment are the object of constant attention of researchers [1, 2]. Over the past 5 years, a number of works have appeared (see, for example, [3–7]) devoted to the development of new approaches to the synthesis of substituted derivatives of bicyclo[3.2.1]octane. This attention is primarily due to an interesting and a broad profile of biological activity. Thus, some bicyclo[3.2.1]octanes are inhibitors of the carriers of dopamine and serotonin [8, 9], as well as substances with anticancer effects [10]. Bicyclooctane is the scaffold of a number of natural bioactive terpenes, neolignans, alkaloids, sesquiterpenoids and their synthetic analogs [2, 11–13]. Continuing the studies of reactions of carbo- and heterocyclization of methylene-active compounds [14–18], herein we reported the synthesis of functional derivatives of bicyclo[3.2.1]octane through sequential reaction of furfural with secondary amines and cyanoacetic ester, as well as biological activity of the obtained compounds. We have previously shown that a similar reaction involving isopropyl cyanoacetate led to the formation of bicyclooctanes 1 in moderate yields (Scheme 1) [17].
It was found that cyanoacetic acid diethyl ester reacts with furfural (2 equiv.) and secondary amines similarly to isopropyl cyanoacetate to form 8-(R2N)-6oxo-3-(2-furyl)-2,4-dicyanobicyclo[3.2.1]octane-2,4dicarboxylic acids diethyl esters 2а–2c in moderate yields (37–45%, Scheme 2). The sequential introduction of furfural and a secondary amine into the reaction, and then cyanoacetic ester and aromatic aldehyde allowed obtaining compounds 2d–2g in 43–54% yields. Structure and composition of compounds 2a–2g were confirmed by IR, NMR spectroscopy and elemental analysis data. A plausible mechanism of this cascade reaction includes the formation of Stenhouse salt 3 through the aza-Piancatelli-
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