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2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid

2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid molbank Short Note 2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid Boris V. Lichitsky, Andrey N. Komogortsev * and Valeriya G. Melekhina N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky Pr., 47, 119991 Moscow, Russia; blich2006@mail.ru (B.V.L.); melekhinavg@gmail.com (V.G.M.) * Correspondence: dna5@mail.ru Abstract: We elaborated a convenient one-step approach for the synthesis of previously unknown 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. The suggested protocol includes the multicomponent reaction of acetovanillone, 4-methoxyphenylglyoxal and Meldrum’s acid. We have demonstrated that the considered reaction is a one-pot telescoped process including the preliminary condensation of the components in MeCN followed by acid-catalyzed cyclization. 1 13 The structure of the synthesized product was confirmed by H, C-NMR spectroscopy and high- resolution mass-spectrometry. Keywords: acetovanillone; arylglyoxal; meldrum’s acid; multicomponent reaction 1. Introduction Acetovanillone (Apocynin) is a natural organic compound structurally related to vanillin found in plant sources [1,2]. Acetovanillone has a wide spectrum of biological Citation: Lichitsky, B.V.; activity. For example, apocynin can influence the immune system through the inhibition Komogortsev, A.N.; Melekhina, V.G. of NADPH oxidase [3–11]. Besides that, acetovanillone is used as an anti-arthritic [12,13] 2-(5-Acetyl-7-methoxy-2-(4- and anti-asthmatic agent [14]. Additionally, apocynin can be employed for the treatment methoxyphenyl)benzofuran-3- of bowel diseases [15] and atherosclerosis [16]. Finally, it was shown that this compound yl)acetic Acid. Molbank 2022, 2022, displays significant activity against amyotrophic lateral sclerosis [17]. In this regard, the M1357. https://doi.org/10.3390/ preparation of synthetic derivatives of acetovanillone, which may also have various biolog- M1357 ical activities, is of considerable interest. Academic Editor: Nicholas Previously, we proposed a general method for the preparation of condensed furylacetic E. Leadbeater acids based on a multicomponent reaction of hydroxyl derivatives with arylglyoxals and Meldrum’s acid [18–24]. It should be noted that the considered method allows one to syn- Received: 17 March 2022 thesize the wide range of furylacetic acids from the diverse phenols. We assumed that the Accepted: 24 March 2022 presented approach could be applied to obtain the condensed acetovanillone derivatives. Published: 1 April 2022 Publisher’s Note: MDPI stays neutral 2. Results and Discussion with regard to jurisdictional claims in In the present paper, we describe a multicomponent reaction of acetovanillone published maps and institutional affil- 1, 4-methoxyphenylglyoxal 2 and Meldrum’s acid 3 leading to 2-(5-acetyl-7-methoxy- iations. 2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid 4 unknown in the literature (Scheme 1). It was shown that the studied reaction was a one-pot telescoped two stage process. The first step involves the condensation of the starting components in acetonitrile in the presence of triethylamine. Note that the initial stage of the process can be carried out under mild Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. conditions at room temperature due to the high solubility of acetovanillone 1. In this This article is an open access article case, the reaction proceeds rather slowly, and a complete conversion of apocynin 1 was distributed under the terms and observed in 48 h. At the same time, our attempts to accelerate the process by increasing the conditions of the Creative Commons temperature of the first stage led to a significant decrease in the yield of the target product 4. Attribution (CC BY) license (https:// It should be mentioned that the final step of the reaction involves intramolecular cyclization creativecommons.org/licenses/by/ in a mixture of hydrochloric and acetic acids. As was shown previously, these conditions 4.0/). Molbank 2022, 2022, M1357. https://doi.org/10.3390/M1357 https://www.mdpi.com/journal/molbank Molbank 2022, 2022, x FOR PEER REVIEW 2 of 5 Molbank 2022, 2022, x FOR PEER REVIEW 2 of 5 Molbank 2022, 2022, M1357 2 of 4 4. It should be mentioned that the final step of the reaction involves intramolecular cy- 4. It should be mentioned that the final step of the reaction involves intramolecular cy- clization in a mixture of hydrochloric and acetic acids. As was shown previously, these clization in a mixture of hydrochloric and acetic acids. As was shown previously, these are optimal for the last stage of the process [18–24]. Thus, the presented approach allows conditions are optimal for the last stage of the process [18−24]. Thus, the presented ap- conditions are optimal for the last stage of the process [18−24]. Thus, the presented ap- one to obtain the target product 4 in a 62% yield. proach allows one to obtain the target product 4 in a 62% yield. proach allows one to obtain the target product 4 in a 62% yield. Scheme 1. Synthesis of 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid 4. Scheme 1 Scheme 1. . Synthesis of 2-(5-a Synthesis of 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic cetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid acid 4 4.. The assumed pathway of the considered reaction is shown in Scheme 2. At first, The assumed pathway of the considered reaction is shown in Scheme 2. At first, the The assumed pathway of the considered reaction is shown in Scheme 2. At first, the the condensation of 4-methoxyphenylglyoxal 2 with Meldrum’s acid 3 results in unstable condensation of 4-methoxyphenylglyoxal 2 with Meldrum’s acid 3 results in unstable Mi- condensation of 4-methoxyphenylglyoxal 2 with Meldrum’s acid 3 results in unstable Mi- Michael acceptor A. Then, the interaction of acetovanillone anion B with aroylmethylene chael acceptor A. Then, the interaction of acetovanillone anion B with aroylmethylene de- chael acceptor A. Then, the interaction of acetovanillone anion B with aroylmethylene de- derivative A leads to adduct D. At the next step, intermediate D cyclizes into -ketoacid F rivative A leads to adduct D. At the next step, intermediate D cyclizes into γ-ketoacid F rivative A leads to adduct D. At the next step, intermediate D cyclizes into γ-ketoacid F with the elimination of acetone and CO molecules. Finally, the target furylacetic acid 4 is with the elimination of acetone and CO 2 2 molecules. Finally, the target furylacetic acid 4 is with the elimination of acetone and CO2 molecules. Finally, the target furylacetic acid 4 is formed as a result of an acid-catalyzed intramolecular cyclization of compound F. formed as a result of an acid-catalyzed intramolecular cyclization of compound F. formed as a result of an acid-catalyzed intramolecular cyclization of compound F. Scheme 2. The assumed reaction pathway for the formation of compound 4. Scheme 2. The assumed reaction pathway for the formation of compound 4. Scheme 2. The assumed reaction pathway for the formation of compound 4. The synthesized 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic The synthesized 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic The synthesized 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic 1 13 acid 4 is the solid crystalline compound, whose structure was confirmed by 1 H, 13 C NMR 1 13 acid 4 is the solid crystalline compound, whose structure was confirmed by H, C NMR acid 4 is the solid crystalline compound, whose structure was confirmed by H, C NMR spectroscopy and high-resolution mass-spectrometry. 1 H NMR spectra of the product 4 spectroscopy and high-resolution mass-spectrometry. H NMR spectra of the product 4 spectroscopy and high-resolution mass-spectrometry. H NMR spectra of the product 4 contain characteristic signals of the protons of the carboxymethylene fragment in the re- contain characteristic signals of the protons of the carboxymethylene fragment in the re- contain characteristic signals of the protons of the carboxymethylene fragment in the region gion δ 3.89 ppm and 12.57 ppm. The remaining signals are also in good agreement with gion δ 3.89 ppm and 12.57 ppm. The remaining signals are also in good agreement with 3.89 ppm and 12.57 ppm. The remaining signals are also in good agreement with the the presented structure. the presented structure. presented structure. In summary, we suggested an efficient method for the modification of naturally oc- In summary, we suggested an efficient method for the modification of naturally oc- In summary, we suggested an efficient method for the modification of naturally curring acetovanillone. The considered approach allows one to synthesize the previously curring acetovanillone. The considered approach allows one to synthesize the previously occurring acetovanillone. The considered approach allows one to synthesize the previ- unknown 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. The u ously nknown 2- unknown (5-a2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic cetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. acid. The studied reaction is based on the multicomponent condensation of acetovanillone, 4-meth- st The udie studied d reactir on is eaction based is o based n the mu on the ltico multicomponent mponent condensat condensation ion of acetovan of acetovanillone, illone, 4-meth- 4-methoxyphenylglyoxal and Meldrum’s acid. The advantages of this protocol are the ap- plication of readily available starting compounds, an atom economy and an easy work-up Molbank 2022, 2022, M1357 3 of 4 procedure, which can avoid chromatographic purification. The structure of the synthesized 1 13 product was confirmed by H, C-NMR spectroscopy and high-resolution mass-spectrometry. 3. Materials and Methods All starting chemicals and solvents were commercially available and were used as received. NMR spectra were recorded with Bruker DRX 300 (300 MHz) spectrometers (Billerica, MA, USA) in DMSO-d . Chemical shifts (ppm) were given relative to solvent 1 13 signals (DMSO-d : 2.50 ppm ( H NMR) and 39.52 ppm ( C NMR)). High-resolution mass spectra (HRMS) were obtained on a Bruker micrOTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray ionization (ESI). The melting points were determined on a Kofler hot stage (Dresden, Germany). IR spectra were recorded on a Bruker ALPHA (Santa Barbara, CA, USA) spectrophotometer in a KBr pellet. Experimental Procedure for the Synthesis of 2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid 4 A mixture of acetovanillone 1 (3 mmol, 0.5 g), 4-methoxyphenylglyoxal hydrate 2 (5 mmol, 0.91 g), Meldrum’s acid 3 (6 mmol, 0.86 g), and Et N (7 mmol, 1 mL) in 6 mL of MeCN was kept for 48 h at room temperature. Then, 2 mL AcOH was added, and the reaction mixture was evaporated in vacuo. 3 mL of conc. HCl and 5 mL of AcOH were added to the residue, and the solution was refluxed for 15 min. The resulting mixture was stirred for 2 h at room temperature and left overnight. The formed precipitate was collected by filtration and washed with 50% aqueous AcOH (3  7 mL). To remove traces of HCl and AcOH, the precipitate was kept for 24 h in water (50 mL) at room temperature, collected by filtration, and washed with water (3  10 mL). Beige powder; yield 62% (0.66 g, 1.9 mmol); mp 193–195 C. H NMR (300 MHz, DMSO-d )  12.57 (br.s, 1H), 7.96 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.45 (s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 4.02 (s, 3H), 3.89 (s, 2H), 3.83 (s, 3H), 2.64 (s, 3H). C NMR (75 MHz, DMSO-d )  197.25, 171.84, 159.93, 153.25, 144.77, 144.59, 133.36, 131.57, 128.26, 121.85, 114.59, 114.18, 109.34, 106.01, 55.99, 55.33, 29.94, 26.79. IR spectrum (KBr), , cm : 3418, 3089, 3056, 3000, 2980, 2945, 2841, 2706, 2596, 2361, 2341, 2042, 1852, 1720, 1646, 1615, 1589, 1512, 1481, 1466, 1422, 1391, 1321, 1302, 1260, 1218, 1178, 1088, 1053, 1026. HRMS (ESI-TOF) m/z: [M + H] Calcld for C H O 355.1176; 20 18 6 Found 355.1173. 1 13 Supplementary Materials: The following are available online: copies of H, C-NMR, mass and IR spectra for compound 4. Figure S1: H NMR spectrum (300 MHz) of compound 4 in DMSO-d6; 13 1 Figure S2: C { H} NMR spectrum (75 MHz) of compound 4 in DMSO-d6; Figure S3: HRMS for compound 4; Figure S4: IR spectrum for compound 4. Author Contributions: A.N.K.—conceptualization, synthesis, spectroscopic analysis and writing the manuscript. B.V.L.—conceptualization, synthesis, spectroscopic analysis and writing the manuscript. V.G.M.—conceptualization, synthesis, spectroscopic analysis and writing the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The data for the compounds presented in this study are available in the Supplementary Materials of this article. Conflicts of Interest: The authors declare no conflict of interest. References 1. Debnath, P.; Rathore, S.; Walia, S.; Kumar, M.; Devi, R.; Kumar, R. Picrorhiza Kurroa: A Promising Traditional Therapeutic Herb from Higher Altitude of Western Himalayas. J. Herb. Med. 2020, 23, 100358. [CrossRef] 2. 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APPA (Apocynin and Paeonol) Modulates Pathological Aspects of Human Neutrophil Function, without Supressing Antimicrobial Ability, and Inhibits TNF Expression and Signalling. Inflammopharmacology 2020, 28, 1223–1235. [CrossRef] [PubMed] 7. Montes-Rivera, J.O.; Tamay-Cach, F.; Quintana-Pérez, J.C.; Guevara-Salazar, J.A.; Trujillo-Ferrara, J.G.; Del Valle-Mondragón, L.; Arellano-Mendoza, M.G. Apocynin Combined with Drugs as Coadjuvant Could Be Employed to Prevent and/or Treat the Chronic Kidney Disease. Ren. Fail. 2018, 40, 92–98. [CrossRef] 8. Boshtam, M.; Kouhpayeh, S.; Amini, F.; Azizi, Y.; Najaflu, M.; Shariati, L.; Khanahmad, H. Anti-Inflammatory Effects of Apocynin: A Narrative Review of the Evidence. Life 2021, 14, 997–1010. [CrossRef] 9. Abdelmageed, M.E.; El-Awady, M.S.; Suddek, G.M. Apocynin Ameliorates Endotoxin-Induced Acute Lung Injury in Rats. Int. Immunopharmacol. 2016, 30, 163–170. [CrossRef] 10. Wang, K.; Li, L.; Song, Y.; Ye, X.; Fu, S.; Jiang, J.; Li, S. Improvement of Pharmacokinetics Behavior of Apocynin by Nitrone Derivatization: Comparative Pharmacokinetics of Nitrone-Apocynin and Its Parent Apocynin in Rats. PLoS ONE 2013, 8, e70189. [CrossRef] 11. Choi, S.H.; Suh, G.J.; Kwon, W.Y.; Kim, K.S.; Park, M.J.; Kim, T.; Ko, J.I. Apocynin Suppressed the Nuclear Factor-KB Pathway and Attenuated Lung Injury in a Rat Hemorrhagic Shock Model. J. Trauma Acute Care Surg. 2017, 82, 566–574. [CrossRef] [PubMed] 12. ‘T Hart, B.A.; Simons, J.M.; Shoshan, K.-S.; Bakker, N.P.M.; Labadie, R.P. Antiarthritic Activity of the Newly Developed Neutrophil Oxidative Burst Antagonist Apocynin. Free Radic. Biol. Med. 1990, 9, 127–131. [CrossRef] 13. ‘T Hart, B.A.; Copray, S.; Philippens, I. Apocynin, a Low Molecular Oral Treatment for Neurodegenerative Disease. BioMed Res. Int. 2014, 2014, 298020. [CrossRef] [PubMed] 14. Van den Worm, E.; Beukelman, C.J.; Van den Berg, A.J.J.; Kroes, B.H.; Labadie, R.P.; Van Dijk, H. Effects of Methoxylation of Apocynin and Analogs on the Inhibition of Reactive Oxygen Species Production by Stimulated Human Neutrophils. Eur. J. Pharmacol. 2001, 433, 225–230. [CrossRef] 15. Palmen, M.; Beukelman, C.; Mooij, R.; Pena, A.; Vonrees, E. Anti-Inflammatory Effect of Apocynin, a Plant-Derived NADPH Oxidase Antagonist, in Acute Experimental Colitis. Neth. J. Med. 1995, 47, A41. [CrossRef] 16. Pandey, A.; Kour, K.; Bani, S.; Suri, K.A.; Satti, N.K.; Sharma, P.; Qazi, G.N. Amelioration of Adjuvant Induced Arthritis by Apocynin: Amelioration of adjuvant induced arthritis by apocynin. Phytother. Res. 2009, 23, 1462–1468. [CrossRef] [PubMed] 17. Harraz, M.M.; Marden, J.J.; Zhou, W.; Zhang, Y.; Williams, A.; Sharov, V.S.; Nelson, K.; Luo, M.; Paulson, H.; Schöneich, C.; et al. SOD1 Mutations Disrupt Redox-Sensitive Rac Regulation of NADPH Oxidase in a Familial ALS Model. J. Clin. Investig. 2008, 118, JCI34060. [CrossRef] 18. Komogortsev, A.N.; Lichitsky, B.V.; Melekhina, V.G. Straightforward One-Step Approach towards Novel Derivatives of 9-Oxo- 5,6,7,9-Tetrahydrobenzo[9,10]Heptaleno[3,2-b]Furan-12-Yl)Acetic Acid Based on the Multicomponent Reaction of Colchiceine, Arylglyoxals and Meldrum’s Acid. Tetrahedron Lett. 2021, 78, 153292. [CrossRef] 19. Gorbunov, Y.O.; Lichitsky, B.V.; Komogortsev, A.N.; Mityanov, V.S.; Dudinov, A.A.; Krayushkin, M.M. Synthesis of Condensed Furylacetic Acids Based on Multicomponent Condensation of Heterocyclic Enols with Arylglyoxals and Meldrum’s Acid. Chem. Heterocycl. Compd. 2018, 54, 692–695. [CrossRef] 20. Komogortsev, A.N.; Lichitsky, B.V.; Tretyakov, A.D.; Dudinov, A.A.; Krayushkin, M.M. Investigation of the Multicomponent Reaction of 5-Hydroxy-2-Methyl-4H-Pyran-4-One with Carbonyl Compounds and Meldrum’s Acid. Chem. Heterocycl. Compd. 2019, 55, 818–822. [CrossRef] 21. Lichitsky, B.V.; Melekhina, V.G.; Komogortsev, A.N.; Minyaev, M.E. A New Multicomponent Approach to the Synthesis of Substituted Furan-2(5H)-Ones Containing 4H-Chromen-4-One Fragment. Tetrahedron Lett. 2020, 61, 152602. [CrossRef] 22. Lichitsky, B.V.; Tretyakov, A.D.; Komogortsev, A.N.; Mityanov, V.S.; Dudinov, A.A.; Gorbunov, Y.O.; Daeva, E.D.; Krayushkin, M.M. Synthesis of Substituted Benzofuran-3-Ylacetic Acids Based on Three-Component Condensation of Polyalkoxyphenols, Arylglyoxals and Meldrum’s Acid. Mendeleev Commun. 2019, 29, 587–588. [CrossRef] 23. Lichitsky, B.V.; Komogortsev, A.N.; Melekhina, V.G. 2-(2-(4-Methoxyphenyl)Furo[3,2-h]Quinolin-3-Yl)Acetic Acid. Molbank 2022, 2022, M1315. [CrossRef] 24. Lichitsky, B.V.; Komogortsev, A.N.; Melekhina, V.G. 2-(2-(4-Methoxyphenyl)-4,9-Dimethyl-7-Oxo-7H-Furo[2,3-f ]Chromen-3- Yl)Acetic Acid. Molbank 2021, 2021, M1304. [CrossRef] http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molbank Multidisciplinary Digital Publishing Institute

2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid

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Abstract

molbank Short Note 2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid Boris V. Lichitsky, Andrey N. Komogortsev * and Valeriya G. Melekhina N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky Pr., 47, 119991 Moscow, Russia; blich2006@mail.ru (B.V.L.); melekhinavg@gmail.com (V.G.M.) * Correspondence: dna5@mail.ru Abstract: We elaborated a convenient one-step approach for the synthesis of previously unknown 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. The suggested protocol includes the multicomponent reaction of acetovanillone, 4-methoxyphenylglyoxal and Meldrum’s acid. We have demonstrated that the considered reaction is a one-pot telescoped process including the preliminary condensation of the components in MeCN followed by acid-catalyzed cyclization. 1 13 The structure of the synthesized product was confirmed by H, C-NMR spectroscopy and high- resolution mass-spectrometry. Keywords: acetovanillone; arylglyoxal; meldrum’s acid; multicomponent reaction 1. Introduction Acetovanillone (Apocynin) is a natural organic compound structurally related to vanillin found in plant sources [1,2]. Acetovanillone has a wide spectrum of biological Citation: Lichitsky, B.V.; activity. For example, apocynin can influence the immune system through the inhibition Komogortsev, A.N.; Melekhina, V.G. of NADPH oxidase [3–11]. Besides that, acetovanillone is used as an anti-arthritic [12,13] 2-(5-Acetyl-7-methoxy-2-(4- and anti-asthmatic agent [14]. Additionally, apocynin can be employed for the treatment methoxyphenyl)benzofuran-3- of bowel diseases [15] and atherosclerosis [16]. Finally, it was shown that this compound yl)acetic Acid. Molbank 2022, 2022, displays significant activity against amyotrophic lateral sclerosis [17]. In this regard, the M1357. https://doi.org/10.3390/ preparation of synthetic derivatives of acetovanillone, which may also have various biolog- M1357 ical activities, is of considerable interest. Academic Editor: Nicholas Previously, we proposed a general method for the preparation of condensed furylacetic E. Leadbeater acids based on a multicomponent reaction of hydroxyl derivatives with arylglyoxals and Meldrum’s acid [18–24]. It should be noted that the considered method allows one to syn- Received: 17 March 2022 thesize the wide range of furylacetic acids from the diverse phenols. We assumed that the Accepted: 24 March 2022 presented approach could be applied to obtain the condensed acetovanillone derivatives. Published: 1 April 2022 Publisher’s Note: MDPI stays neutral 2. Results and Discussion with regard to jurisdictional claims in In the present paper, we describe a multicomponent reaction of acetovanillone published maps and institutional affil- 1, 4-methoxyphenylglyoxal 2 and Meldrum’s acid 3 leading to 2-(5-acetyl-7-methoxy- iations. 2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid 4 unknown in the literature (Scheme 1). It was shown that the studied reaction was a one-pot telescoped two stage process. The first step involves the condensation of the starting components in acetonitrile in the presence of triethylamine. Note that the initial stage of the process can be carried out under mild Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. conditions at room temperature due to the high solubility of acetovanillone 1. In this This article is an open access article case, the reaction proceeds rather slowly, and a complete conversion of apocynin 1 was distributed under the terms and observed in 48 h. At the same time, our attempts to accelerate the process by increasing the conditions of the Creative Commons temperature of the first stage led to a significant decrease in the yield of the target product 4. Attribution (CC BY) license (https:// It should be mentioned that the final step of the reaction involves intramolecular cyclization creativecommons.org/licenses/by/ in a mixture of hydrochloric and acetic acids. As was shown previously, these conditions 4.0/). Molbank 2022, 2022, M1357. https://doi.org/10.3390/M1357 https://www.mdpi.com/journal/molbank Molbank 2022, 2022, x FOR PEER REVIEW 2 of 5 Molbank 2022, 2022, x FOR PEER REVIEW 2 of 5 Molbank 2022, 2022, M1357 2 of 4 4. It should be mentioned that the final step of the reaction involves intramolecular cy- 4. It should be mentioned that the final step of the reaction involves intramolecular cy- clization in a mixture of hydrochloric and acetic acids. As was shown previously, these clization in a mixture of hydrochloric and acetic acids. As was shown previously, these are optimal for the last stage of the process [18–24]. Thus, the presented approach allows conditions are optimal for the last stage of the process [18−24]. Thus, the presented ap- conditions are optimal for the last stage of the process [18−24]. Thus, the presented ap- one to obtain the target product 4 in a 62% yield. proach allows one to obtain the target product 4 in a 62% yield. proach allows one to obtain the target product 4 in a 62% yield. Scheme 1. Synthesis of 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid 4. Scheme 1 Scheme 1. . Synthesis of 2-(5-a Synthesis of 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic cetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid acid 4 4.. The assumed pathway of the considered reaction is shown in Scheme 2. At first, The assumed pathway of the considered reaction is shown in Scheme 2. At first, the The assumed pathway of the considered reaction is shown in Scheme 2. At first, the the condensation of 4-methoxyphenylglyoxal 2 with Meldrum’s acid 3 results in unstable condensation of 4-methoxyphenylglyoxal 2 with Meldrum’s acid 3 results in unstable Mi- condensation of 4-methoxyphenylglyoxal 2 with Meldrum’s acid 3 results in unstable Mi- Michael acceptor A. Then, the interaction of acetovanillone anion B with aroylmethylene chael acceptor A. Then, the interaction of acetovanillone anion B with aroylmethylene de- chael acceptor A. Then, the interaction of acetovanillone anion B with aroylmethylene de- derivative A leads to adduct D. At the next step, intermediate D cyclizes into -ketoacid F rivative A leads to adduct D. At the next step, intermediate D cyclizes into γ-ketoacid F rivative A leads to adduct D. At the next step, intermediate D cyclizes into γ-ketoacid F with the elimination of acetone and CO molecules. Finally, the target furylacetic acid 4 is with the elimination of acetone and CO 2 2 molecules. Finally, the target furylacetic acid 4 is with the elimination of acetone and CO2 molecules. Finally, the target furylacetic acid 4 is formed as a result of an acid-catalyzed intramolecular cyclization of compound F. formed as a result of an acid-catalyzed intramolecular cyclization of compound F. formed as a result of an acid-catalyzed intramolecular cyclization of compound F. Scheme 2. The assumed reaction pathway for the formation of compound 4. Scheme 2. The assumed reaction pathway for the formation of compound 4. Scheme 2. The assumed reaction pathway for the formation of compound 4. The synthesized 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic The synthesized 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic The synthesized 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic 1 13 acid 4 is the solid crystalline compound, whose structure was confirmed by 1 H, 13 C NMR 1 13 acid 4 is the solid crystalline compound, whose structure was confirmed by H, C NMR acid 4 is the solid crystalline compound, whose structure was confirmed by H, C NMR spectroscopy and high-resolution mass-spectrometry. 1 H NMR spectra of the product 4 spectroscopy and high-resolution mass-spectrometry. H NMR spectra of the product 4 spectroscopy and high-resolution mass-spectrometry. H NMR spectra of the product 4 contain characteristic signals of the protons of the carboxymethylene fragment in the re- contain characteristic signals of the protons of the carboxymethylene fragment in the re- contain characteristic signals of the protons of the carboxymethylene fragment in the region gion δ 3.89 ppm and 12.57 ppm. The remaining signals are also in good agreement with gion δ 3.89 ppm and 12.57 ppm. The remaining signals are also in good agreement with 3.89 ppm and 12.57 ppm. The remaining signals are also in good agreement with the the presented structure. the presented structure. presented structure. In summary, we suggested an efficient method for the modification of naturally oc- In summary, we suggested an efficient method for the modification of naturally oc- In summary, we suggested an efficient method for the modification of naturally curring acetovanillone. The considered approach allows one to synthesize the previously curring acetovanillone. The considered approach allows one to synthesize the previously occurring acetovanillone. The considered approach allows one to synthesize the previ- unknown 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. The u ously nknown 2- unknown (5-a2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic cetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. acid. The studied reaction is based on the multicomponent condensation of acetovanillone, 4-meth- st The udie studied d reactir on is eaction based is o based n the mu on the ltico multicomponent mponent condensat condensation ion of acetovan of acetovanillone, illone, 4-meth- 4-methoxyphenylglyoxal and Meldrum’s acid. The advantages of this protocol are the ap- plication of readily available starting compounds, an atom economy and an easy work-up Molbank 2022, 2022, M1357 3 of 4 procedure, which can avoid chromatographic purification. The structure of the synthesized 1 13 product was confirmed by H, C-NMR spectroscopy and high-resolution mass-spectrometry. 3. Materials and Methods All starting chemicals and solvents were commercially available and were used as received. NMR spectra were recorded with Bruker DRX 300 (300 MHz) spectrometers (Billerica, MA, USA) in DMSO-d . Chemical shifts (ppm) were given relative to solvent 1 13 signals (DMSO-d : 2.50 ppm ( H NMR) and 39.52 ppm ( C NMR)). High-resolution mass spectra (HRMS) were obtained on a Bruker micrOTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray ionization (ESI). The melting points were determined on a Kofler hot stage (Dresden, Germany). IR spectra were recorded on a Bruker ALPHA (Santa Barbara, CA, USA) spectrophotometer in a KBr pellet. Experimental Procedure for the Synthesis of 2-(5-Acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic Acid 4 A mixture of acetovanillone 1 (3 mmol, 0.5 g), 4-methoxyphenylglyoxal hydrate 2 (5 mmol, 0.91 g), Meldrum’s acid 3 (6 mmol, 0.86 g), and Et N (7 mmol, 1 mL) in 6 mL of MeCN was kept for 48 h at room temperature. Then, 2 mL AcOH was added, and the reaction mixture was evaporated in vacuo. 3 mL of conc. HCl and 5 mL of AcOH were added to the residue, and the solution was refluxed for 15 min. The resulting mixture was stirred for 2 h at room temperature and left overnight. The formed precipitate was collected by filtration and washed with 50% aqueous AcOH (3  7 mL). To remove traces of HCl and AcOH, the precipitate was kept for 24 h in water (50 mL) at room temperature, collected by filtration, and washed with water (3  10 mL). Beige powder; yield 62% (0.66 g, 1.9 mmol); mp 193–195 C. H NMR (300 MHz, DMSO-d )  12.57 (br.s, 1H), 7.96 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.45 (s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 4.02 (s, 3H), 3.89 (s, 2H), 3.83 (s, 3H), 2.64 (s, 3H). C NMR (75 MHz, DMSO-d )  197.25, 171.84, 159.93, 153.25, 144.77, 144.59, 133.36, 131.57, 128.26, 121.85, 114.59, 114.18, 109.34, 106.01, 55.99, 55.33, 29.94, 26.79. IR spectrum (KBr), , cm : 3418, 3089, 3056, 3000, 2980, 2945, 2841, 2706, 2596, 2361, 2341, 2042, 1852, 1720, 1646, 1615, 1589, 1512, 1481, 1466, 1422, 1391, 1321, 1302, 1260, 1218, 1178, 1088, 1053, 1026. HRMS (ESI-TOF) m/z: [M + H] Calcld for C H O 355.1176; 20 18 6 Found 355.1173. 1 13 Supplementary Materials: The following are available online: copies of H, C-NMR, mass and IR spectra for compound 4. Figure S1: H NMR spectrum (300 MHz) of compound 4 in DMSO-d6; 13 1 Figure S2: C { H} NMR spectrum (75 MHz) of compound 4 in DMSO-d6; Figure S3: HRMS for compound 4; Figure S4: IR spectrum for compound 4. 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Journal

Molbank – Multidisciplinary Digital Publishing Institute

Published: Apr 1, 2022

Keywords: acetovanillone; arylglyoxal; meldrum’s acid; multicomponent reaction

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