N -Hydroxymethylation of 3-Aryl-2-cyanoprop-2-enethioamides
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droxymethylation of 3-Aryl-2-cyanoprop-2-enethioamides V. V. Dotsenkoa,b,*, E. A. Chigorinac,d, and S. G. Krivokolyskoa a Kuban
State University, Krasnodar, 350040 Russia North Caucasus Federal University, Stavropol, 355009 Russia c National Research Center “Kurchatov Institute”–IREA, Moscow, 107076 Russia d National Research Center “Kurchatov Institute,” Moscow, 123182 Russia *e-mail: [email protected] b
Received April 4, 2020; revised April 4, 2020; accepted April 14, 2020
Abstract—Hydroxymethylation of (E)-3-aryl-2-cyanoprop-2-enethioamides with an aqueous alcoholic solution of formaldehyde has afforded (E)-3-aryl-N-(hydroxymethyl)-2-cyanoprop-2-enethioamides. The predictive analysis of the biological activity of the obtained compounds in silico has been carried out. Keywords: 2-cyanoethanethioamide, (E)-3-aryl-2-cyanoprop-2-enethioamides, N-hydroxymethylation, N-(hydroxymethyl)thioamides, Mannich reaction
DOI: 10.1134/S107036322008006X The products of 2-cyanoethanethioamide 1 condensation with aldehydes—(Е)-3-aryl-2-cyanoacrylthioamides 2 (3-aryl-2-cyanoprop-2-enerhioamides)—have been recognized as readily available and multipurpose precursors in the chemistry of S,N-compounds [1–3], primarily of the heterocyclic series: derivatives of thiophene, thienoazines, 1,3,5-thiadiazine, etc. [4–11]. Unsaturated thioamides 2 readily form the derivatives of hexahydropyrimido[4,3-b][1,3,5]thiadiazine 3 [12–15] or decahydropyrimido[4ʹ,5ʹ:4,5]pyrimido[2,1-b][1,3,5]thiadiazine 4 [16] as a result of cascade transformations under the Mannich reaction conditions (Scheme 1). The derivatives of 1,3,5-thiadiazine exhibit broad range of biological activity and utilitarian properties [10, 11, 17–19], therefore, the development of facile methods of synthesis of fused 1,3,5-thiadiazine is a topical issue. The first stage likely consists in N-aminomethylation of thioamides 2, followed by cyclization of N-(aminomethyl)thioamides 5 into perhydropyrimidines 7 and then closing of 1,3,5-thiadiazine cycle. However, N-hydroxymethylation affording N-(hydrohymethyl)thioamides 6 at the first stage cannot be ruled out. None of the intermediates 5–7 has been isolated. Herein we investigated the interaction of formaldehyde with 3-aryl-2-cyanoacrylthioamides 2 as a possible route to N-(hydroxymethyl)thioamides 6, promising thioamidoalkylating agents and possible intermediates in the synthesis of 1,3,5-thiadiazine heterocycles.
N-(Hydroxymethyl)thioamides are relatively readily formed from formaldehyde and thioamides containing primary or secondary amino groups, often in the presence of base [20–28]. These compounds exhibit enhanced hydrophilicity (in comparison with thioamides) and can be used as bidentate ligands for the creation of sorbents selective with respect to heavy metals ions [29–31], thioamidoalkylating agents [20, 24–25, 32–34], and as the reagents in the synthesis of derivatives of 1,3-thiazine 8 [26, 35, 36], 1,2,4-dithiazoles 9 (with pronounced fungicide action) [37–39], 6H-1,3,5-oxathiazine 10 [27, 40], 4H-1,3,5-dithiazine
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