3-Nitro-2-phenyl-2-trifluoromethyl-2 H -chromenes in reactions with azomethine ylides from isatins and (thia)proline: sy
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3-Nitro-2-phenyl-2-trifluoromethyl-2H-chromenes in reactions with azomethine ylides from isatins and (thia)proline: synthesis of spiro[chromeno(thia)pyrrolizidine-11,3'-oxindoles] Igor B. Kutyashev1, Ivan А. Kochnev1, Anastasiya А. Cherepkova1, Nikolay S. Zimnitskiy1, Alexey Yu. Barkov1, Vladislav Yu. Korotaev1*, Vyacheslav Ya. Sosnovskikh1 1
Institute of Natural Sciences and Mathematics of Ural Federal University named after the first President of Russia B. N. Yeltsin, 51 Lenina Ave., Yekaterinburg 620000, Russia; е-mail: [email protected] Submitted March 19, 2020 Accepted April 18, 2020
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(10), 1302–1313
1,3-Dipolar cycloaddition of stabilized azomethine ylides generated in situ from isatins and proline to 3-nitro-2-phenyl-2-trifluoromethyl2H-chromenes in i-PrOH proceeds stereoselectively at room temperature and leads to the formation of hexahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3'-indolin]-2'-ones with the cis arrangement of the trifluoromethyl group and the nitro group. A similar reaction with the participation of thiaproline-based ylides at 50°С leads to mixtures of diastereomeric tetrahydro-6H,9H-spiro[chromeno[3',4':3,4]pyrrolo[1,2-c]thiazole11,3'-indolin]-2'-ones with a predominance of the cis- or trans-isomer. The stereochemistry of the obtained products was confirmed by the NOESY experiment and X-ray structural analysis. Keywords: 3-nitro-2-phenyl-2-trifluoromethyl-2H-chromenes, spiro[chromeno(thia)pyrrolizidine-11,3'-oxindoles], 1,3-dipolar cycloaddition, stabilized azomethine ylides.
Due to the presence of a β-nitrostyrene fragment in the molecule, 3-nitro-2H-chromenes exhibit high biological activity and are widely used as precursors for the preparation of condensed chromene and chromane derivatives.1 Thus, 3-nitro-2-trifluoromethyl-2H-chromene (TIM-38) and 6-bromo-3-nitro-2-trifluoromethyl-2H-chromene (1) have proven themselves as inhibitors of the P2Y6 receptor due to the ability to react with cysteine fragments in proteins via the Michael addition and are promising antiinflammatory drugs.2a 3-Nitro-2H-chromenes BENC-511 and DHM25 inhibit phosphoinositide-3-kinases (PI3K) and possess antitumor activity against cells of various cancer 0009-3122/20/56(10)-1302©2020 Springer Science+Business Media, LLC
lines.2b,c Also in this case, the activity of chromenes is due to the increased electrophilicity of the double bond. Indian scientists have found that condensed N-phenyl-substituted chromeno[3,4-b]pyrroles obtained by the three-component reaction of 2-aryl-3-nitro-2H-chromene with acetylacetone and aniline under microwave irradiation exhibit antibacterial activity.2d Recently, we demonstrated that 6-trifluoromethylspiro[chromenopyrrolidine-1,3'-oxindoles], the products of (3+2) cycloaddition of ylides from isatins and sarcosine to 3-nitro-2-trifluoromethyl-2H-chromenes possess pronounced cytotoxic activity against human cervical cancer HeLa cells2e (Fig. 1). 1302
Chemistry of Heterocyclic Compounds 2020, 56(10), 1302–1313
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