Synthesis of antiaromatic thiazinoindolizines based on electrophilic cyclizations of indolizine-5-thione
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Synthesis of antiaromatic thiazinoindolizines based on electrophilic cyclizations of indolizine-5-thione Eugene V. Babaev1,2*, Aleksandra А. Nevskaya1, Ilya V. Dlynnikh1, Victor B. Rybakov1 1
Lomonosov Moscow State University, 1, Build. 3, Moscow 119992, Russia; e-mail: [email protected] 2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., Moscow 119991, Russia Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(7), 942–948
Submitted May 13, 2020 Accepted after revision July 20, 2020
Alkylation of indolizinethione at the sulfur atom by the action of RCOCH2Br (R = Me, Ar, CO2Me, OEt) leads to thioethers, and subsequent closure of the thiazine ring of which leads to the formation of stable antiaromatic thiazino[4,3,2-cd]indolizines. Keywords: thiazino[4,3,2-cd]indolizine, thioethers, 5-thioxo-3,5-dihydroindolizine, alkylation, cyclization, X-ray structural analysis.
tautomerism made it possible to expect the manifestation of binucleophilic properties by these thiones in reactions with α-halogencarbonyl compounds (across the S atom and the C-3 position), and therefore, suggested the possibility of an alternative cyclization of the thiazinoindolizine system with the closure of the six-membered ring via path b (Fig. 1). This work is devoted to the study of this approach. The target 7-methyl-5-thioxo-3,5-dihydroindolizine6-carbonitrile was synthesized in three steps from the available N-phenacyl derivative of pyridin-2-one, easily obtained by phenacylation of the Guareschi pyridone (Scheme 1). All steps – the closure of the 7-methyl-5-oxo3,5-dihydroindolizine-6-carbonitrile ring, its conversion to 5-chloro-7-methylindolizine-6-carbonitrile by the action of POCl3, and the conversion of the latter into 7-methyl5-thioxo-3,5-dihydroindolizine-6-carbonitrile by the action of thiourea in 98% yield – proceeded smoothly according to the described procedure.3 To study the subsequent reactions, 7-methyl-5-thioxo-3,5-dihydroindolizine-6-carbonitrile was converted into sodium salt 1. It turned out that the reaction of the sodium salt of thione 1 with 4-chloro- and 4-methoxyphenacyl bromides gave the expected products of S-alkylation 2a,b, respectively (Scheme 2). Their 1H NMR spectra contain singlet signals of the SCH2 group protons at 4.44 and
Indolizines annulated at peri positions 3 and 5 with the thiazine ring (Fig. 1) are very interesting from the point of view of theory. Although they do not meet the aromaticity criteria due to the peri structure of the entire π-system,1 these heterocycles nevertheless should be antiaromatic along the perimeter, decaying into a 12π-electron thiopentadiene fragment and a lone pair of the nodal nitrogen atom, which is not conjugated with the perimeter. The literature describes two examples of the synthesis of these tricycles,2 and both approaches included path a (Fig. 1) of constructing the 5+6+6 system, that is, the attachment of a five-membered fragment. Relatively recently, we proposed a simple method for the synthesis of indoli
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