NEW 2,5-BIS(2-ETHYLHEXYL)- PYRROLO[3,4-c]PYRROLE-1,4(2H,5H)-DIONE-2,2’-BIPYRIDINE-BASED CO-POLYMER, SYNTHESIS, PHOTOPHYSICAL PROPERTIES AND RESPONSE TO METAL CATIONS Chimica Techno Acta LETTER published by Ural Federal University 2022, vol. 9(1), No. 20229103 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.1.03 1 of 3 Features of –C–C– coupling of quinoxaline-2-one with ethyl acetoacetate under acid catalysis Yu.A. Azev *, O.S. Koptyaeva, A.A. Mkrtchyan, T.A. Pospelova Ural Federal University, 620002 Mira st., 19, Ekaterinburg, Russia * Corresponding author: azural@yandex.ru This short communication (letter) belongs to the Regular Issue. © 2021, The Authors. This article is published in open access form under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract Quinoxalin-2-one (1) reacts with ethyl acetoacetate in trifluoroacetic acid (TFA) to form 3-(2-oxopropylideno)-3,4-dihydroquinoxaline-2- one (2) and 3-(3-oxo-3,4- dihydroquinoxaline-2-(1H)- ylidene)methylquinoxaline-2-(1H)-one (3). The reaction product 3 was also obtained by heating the compound 1 with acetone in the presence of TFA. Keywords quinoxaline-2-one ethyl acetoacetate nucleophilic substitution of hydrogen vicarious substitution acid catalysis Received: 16.11.2021 Revised: 11.01.2022 Accepted: 11.01.2022 Available online: 14.01.2022 Key findings ● The replacement of hydrogen led to the formation of water, which activated the process of cleavage of the dicarbonyl group of 3-(2-oxopropylideno)-3,4-dihydroquinoxaline-2-one. The acyl group of com pound 3-(2-oxopropylideno)-3,4-dihydroquinoxaline-2-one was "vicarious" in this reaction. ● The formation of 3-(3-oxo-3,4-dihydroquinoxaline-2-(1H)-ylidene) methylquinoxaline-2-(1H)-one was the result of C,C-coupling of compounds quinoxaline-2-one and 3-(2-oxopropylideno)-3,4- dihydroquinoxaline-2-one, similarly to the reaction of quinoxaline-2-one 1 with acetone. 1. Introduction Compounds with various types of biological activity were found among quinoxaline derivatives. [1, 2] Quinoxidine and Dioxidine were used as antimicrobial agents [3]. The features of the synthesis and biological activity of quinoxaline derivatives are described in the review [4]. It was previously reported that quinoxaline salts interact with acetylacetone or ethyl acetoacetate in the presence of base catalysis (diethyl and triethylamines) to form 3a,4,9,9a-tetrahydro-endo-furo[2,3-b]quinoxalines [5]. The authors of the article [6] described the cyclization of 1,3-bis(silyl-enol-ethers) and quinoxaline with the for- mation of 6-alkylidene-2,3-benzo-1,4-diaza-7- oxobicyclo[4,3,0]non-2-yenes. There were known exam- ples of hydrogen substitution in the heterocyclic nucleus of quinoxaline when the reactions with various C-nucleophiles were carried out in the presence of acid. As a result, –C–C-coupling products were obtained [7]. Recently [8] it was found that quinoxaline-2-one react- ed with acetylacetone, benzylacetone, and heptane-3,5- dione when heated in TFA to form derivatives 6а,7- dihydropyrido[1,2-a]quinoxaline-6,8-dione. Examples of reactions of aliphatic aldehydes with quinoxalin-2-one in the presence of acid with the for- mation of 6-oxidopyrido[1,2-a]quinoxalinium zwitter ions were published [9]. It was also previously found that when quinoxalin-2- one and phenylhydrazine hydrazones are heated in buta- nol in the presence of TFA, hydrogen substitution products are formed [10]. It should be noted that there have been no data on –C–C– coupling of quinoxaline-2-one with esters of β-dicarbonyl acids in the literature. 2. Experimental Unless otherwise indicated, all common reagents and sol- vents were used from commercial suppliers without fur- ther purification. The reaction progress and purity of the obtained com- pounds were controlled by thin layer chromatography http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.1.03 https://orcid.org/0000-0002-4414-559X http://creativecommons.org/licenses/by/4.0/ Chimica Techno Acta 2022, vol. 9(1), No. 20229103 LETTER 2 of 3 (TLC) method on Sorbfil UV-254 plates, using visualization under UV light. Melting points were determined on a Stu- art SMP10 melting point apparatus. 1H, 13C and 19F NMR spectra were acquired on Bruker Avance-400 and Bruker Avance NEO–600 spectrometers in DMSO-d6 solutions, using TMS as internal reference for 1H and 13C NMR or CFCl3 for 19F NMR. Mass-spectra (EI, 70 eV) were recorded on MicrOTOF-Q instrument (Bruker Daltonics) at 250 °C. Elemental analysis was performed using a Perkin- Elmer 2400 Series II CHNS/O analyzer. 2.1. Reaction of quinoxaline-2-one 1 with ethyl acetoacetate A mixture of quinoxaline-2-one (1) (0.2 mmol) and ethyl acetoacetate (0.6 mmol) was refluxed in 2.0 ml of TFA at 110 ℃ in a sealed vessel for 50 hours. The solvent was re- moved in vacuo. The precipitate was dissolved in ethanol (3.0 ml). The alcoholic solution was treated with water (2.0 ml) followed by treatment with 15% NH4OH solution to pH 7–8 with the formation of a precipitate. The precipi- tate of the mixture of reaction products was filtered off. 3-(2-Oxopropylidene)-3,4-dihydroquinoxaline-2-one (2) was isolated using preparative chromatography (Rf = 0.156, Silica gel Kiselgel 60 PF 254, chloroform). Yield 35%, m.p. 267–268 °С ([11] 267 °С). 1H NMR (400 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.06 (s, 1H), 7.08–7.13 (m, 3H), 7.37–7.40 (m, 1H), 11.86 (s, 1H), 12.96 (s, 1H). MS (IR, 70 эВ), m/z (Iотн, %): 202 (M+, 100), 187 (М-15, 98), 159 (М-43, 60). Found, %: С 65.28; Н 4.99; N 13.88. C11H10N2O2. Calculated, %: С 65.34; Н 4.98; N 13.85. 3 - ( 3 - o x o - 3 , 4 - d i h y d r o q u i n o x a l i n e - 2 - ( 1 H ) - ylidene)methylquinoxaline-2-(1H)-one (3) was isolated by preparative chromatography (Rf = 0). Yield 5%, m.p. >300 °С. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (s, 1H), 7.16–7.21 (m, 6H), 7.71–7.73 (m, 2H), 11.93 (s, 2H), 13.62 (s, 1H). 13С NMR (101 MHz, DMSO-d6) δ 88.91, 99.49, 115.16, 121.09, 123.29, 125.18, 128.28, 128.54, 147.03, 155.71. MS (EI, 70 eV), m/z (Iотн, %): 304 (M+, 100), 276 (18), 248 (27). Found, %: С 67.13; Н 3.99; N 18.38. C17H12N4O2. Calculated, %: С 67.10; Н 3.97; N 18.41. 2.2. Reaction of quinoxaline-2-one 1 with acetone 0.5 mmol of quinoxaline-2-one (1) was heated with 0.6 mmol of acetone in a mixture of butanol (2 ml) and TFA (0.5 ml) at 110 °C in a sealed vessel for 25 hours. The solvent was removed in vacuo. The precipitate was sus- pended in ethanol (3 ml) and filtered off. The resulting precipitate of 3-(3-oxo-3,4-dihydroquinoxaline-2(1H)- ylidene) methylquinoxaline-2-(1H)-one (3) was recrystal- lized from DMSO and dried. Yield 30%. The melting point and spectral characteris- tics of the reaction product were similar to those obtained in the product of the interaction of quinoxaline-2-one (1) with ethyl acetoacetate. 3. Results and discussion While developing effective methods for the functionaliza- tion of quinoxaline-2-one, we investigated the interactions of quinoxaline-2-one with ethyl acetoacetate under acid catalysis. We found that heating the reagents in TFA re- sulted in the formation of 3-(2-oxopropylideno)-3,4- dihydroquinoxaline-2-one 2 (Scheme 1). The mass spectrum of compound 2, in addition to the molecular ion peak, contained intense peaks of ions with molecular weights of 187 (М–СН3) and 159 (М–СОСН3). These peaks were formed during the decomposition of ketones, which were characteristic of these compounds in common (Scheme 2). The singlet of the protons of the methyl group in the NMR spectrum of compound 2 in DMSO-d6 was observed at 2.3 ppm. The signal of the proton of the methine group of the enamine fragment was observed at 6.2 ppm. Scheme 1 The formation of 3-(2-oxopropylideno)-3,4-dihydroquinoxaline-2-one 2 Chimica Techno Acta 2022, vol. 9(1), No. 20229103 LETTER 3 of 3 Scheme 2 The decomposition of ketones to form molecular ions It could be assumed that the formation of the reaction product 2 proceeded through a number of stages: nucleo- philic substitution of hydrogen, hydrolysis of the ester group, and decarboxylation with the formation of the final product. Obviously, the replacement of hydrogen led to the for- mation of water, which activated the process of cleavage of the dicarbonyl group of compound 2. In addition to the compound 2, 3-(3-oxo-3,4- dihydroquinoxaline-2-(1H)-ylidene) methylquinoxaline-2- (1H)-one 3 was found in the reaction products. In the mass spectrum of compound 3, an intense peak with m/z 304 was observed. It corresponded to the pro- posed structure. The 1H NMR spectrum of compound 3 contained the characteristic signal of the proton of the enamine frag- ment at 6.9 ppm. A two-proton singlet of two amide NH-groups was observed at 11.9 ppm. The singlet of the NH group of the quinazoline nucleus appeared in a weak field at 13.7 ppm. The shift of this signal was apparently due to the presence of a hydrogen bond between the NH group of quinazoline and the N-atom of another quinoxa- line nucleus. The formation of compound 3 was the result of –C–C– coupling of quinoxaline-2-one 1 with a new C-nucleophilic agent, which was formed during the reaction, compound 2. Apparently, the acyl group of compound 2 was "vicari- ous" in this process. The ompound 3 was also obtained by heating the com- pound 1 in acetone in the presence of TFA. Obviously, the formation of 3 was the result of C,C-coupling of the compounds 1 and 2, similarly to the reaction of quinoxaline-2-one 1 with acetone. 4. Conclusions In conclusion, it should be noted that the synthesis of al- kylated derivatives of quinoxaline-2-one was carried out earlier [11] by the interaction of 1,2-dihydroquinoxaline 4-oxide with active methylene compounds in the presence of piperidine. Nevertheless, direct alkylation of quinoxa- line-2-one with ethyl acetoacetate under conditions of acid catalysis was described by us for the first time. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References 1. Barlin GB. The Chemistry of Heterocyclic Compounds: The Pyrazines. New York: Wiley-VCH; 1982. 687 p. doi:10.1002/9780470187173 2. Cheeseman GWN, Cookson RF. The Chemistry of Heterocyclic Compounds: The Condensed Pyrazines. New York: Wiley-VCH; 1979. 843 p. 3. Mashkovsky MD. Lekarstvennyye sredstva [Medicines]. Mos- cow: Nauka; 1993. 347 p. Russian. 4. 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