Synthesis of 4-Amino-6-aryl-2-sulfanylpyridine-3,5-dicarbonitriles
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Synthesis of 4-Amino-6-aryl-2-sulfanylpyridine-3,5-dicarbonitriles I. N. Bardasova,*, A. Yu. Alekseevaa, D. L. Mikhailova, А. I. Ershovaa, and O. V. Ershova a Ul’yanov
Chuvash State University, Cheboksary, 428015 Russia *e-mail: [email protected]
Received March 13, 2020; revised March 20, 2020; accepted March 22, 2020
Abstract—4-Amino-6-aryl-2-sulfanylpyridine-3,5-dicarbonitriles were obtained in two ways: by nucleophilic substitution of the halogen atom in 2-halopyridines under the action of thiols and by alkylation of pyridine2-thiones with alkyl halides. Keywords: pyridines, thiols, alkylation, nucleophilic substitution
DOI: 10.1134/S1070428020080230 Pyridines bearing a sulfanyl group in the α position present interest as potential biologically active compounds. Among them special focus can be given to 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles, because some of them were found to exhibit antimictobial [1, 2], anticancer [3, 4], and antiviral activity [5]. Some 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles were tested as inhibitors of PrPSc replication [6], a protein which, according to modern views, is responsible for infectious prion diseases. Two main synthetic approaches to 2-amino-6sulfanylpyridine-3,5-dicarbonitriles are known. The first involves reaction of thiols with 2-halopyridines [1, 7] and the second, S-alkylation of pyridine-2(1H)thione derivatives [4, 8, 9]. In the present work we synthesized previously unknown 4-amino-6-aryl-2-sulfanylpyridine-3,5-dicarbonitriles 1. The latter are positional isomers of known 6-amino-4-aryl-2-sulfanylpyridine-3,5-dicarbonitriles [1–3]. To synthesize the target compounds, we chose to mutually complementary approaches. The first is based on the use of 4-amino-6-aryl-2-bromopyridine3,5-dicarbonitriles 2. The latter were synthesized from the corresponding arylmethylidene derivatives of malononitrile dimer and HBr in the presence of an oxidant [10]. We previously showed that halogen in bromopyridines 2 is readily substituted by an amino
group to form the corresponding 2-(alkylamino)pyridines and observed solid-state fluorescence of these compounds [11]. Continuing this research we found that the reaction of 4-amino-6-aryl-2-bromopyridine3,5-dicarbonitriles 2 with thiols in 1,4-dioxane in the presence of triethylamine at 80°C formed 4-amino-6aryl-2-sulfanylpyridine-3,5-dicarbonitriles 1 in yields of 37–89% (Scheme 1). It was shown that this reaction was catalyzed by different organic and inorganic bases, but the highest yields of products were obtained with triethylamine. The second approach made use of pyridine-2thiones 3. The latter were synthesized by treatment of arylmethylidene derivatives of malononitrile dimer with elemental sulfur [12]. The target 4-amino-6-aryl-2sulfanylpyridine-3,5-dicarbonitriles 1 were synthesized by the reaction of 4-amino-6-aryl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles with alkyl iodides at room temperature in DMF in the presence of Cs2CO3 (Scheme 2). The yields of compounds 1 were 25–85%. Thus, we deve
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