A concise one-pot synthesis of flavones by cyclisation of o-(alkynon-1-yl)phenols
Khalid Widyan
A
Abstract
A concise one-pot process for producing flavones and 2-alkyl-4H-benzopyran-4-one from a variety of salicylic acylbenzotriazoles is described. The in situ generation of o-(alkynon-1-yl)phenols in the ionic liquid 1-butyl-3-methylimidazoliumtetrafluoroborate ([BMIM][BF4]) is also described in this work. Three rounds of usage of the ionic liquid are possible without a noticeable decrease in efficiency.
Keywords: benzopyranone, flavones, green chemistry, ionic liquid, ionic liquid recycling, N-(o-hydroxyarylacyl)benzotriazoles, o-(alkynon-1-yl)phenols, one-pot synthesis.
References
1 Nandi S, Jamatia R, Sarkar R, Sarkar FK, Alam S, Pal AK. One-pot multicomponent reaction: a highly versatile strategy for the construction of valuable nitrogen-containing heterocycles. ChemistrySelect 2022; 7: e202201901.
| Crossref | Google Scholar |
2 Ma X, Zhang W. Recent developments in one-pot stepwise synthesis (OPSS) of small molecules. iScience 2022; 25: 105005.
| Google Scholar |
3 Leonte D, Ungureanu D, Zaharia V. Flavones and related compounds: synthesis and biological activity. Molecules 2023; 28: 6528.
| Crossref | Google Scholar | PubMed |
4 Kshatriya R, Jejurkar VP, Saha S. In memory of Prof. Venkataraman: recent advances in the synthetic methodologies of flavones. Tetrahedron 2018; 74: 811-833.
| Crossref | Google Scholar |
5 Khadem S, Marles RJ. Chromone and flavonoid alkaloids: occurrence and bioactivity. Molecules 2012; 17: 191-206.
| Crossref | Google Scholar |
6 Lv XH, Liu H, Ren ZL, Wang W, Tang F, Cao HQ. Design, synthesis and biological evaluation of novel flavone Mannich base derivatives as potential antibacterial agents. Mol Divers 2019; 23: 299-306.
| Crossref | Google Scholar | PubMed |
7 Chagas MdSS, Behrens MD, Moragas-Tellis CJ, Penedo GXM, Silva AR, Gonçalves-de-Albuquerque CF. Flavonols and flavones as potential anti-inflammatory, antioxidant, and antibacterial compounds. Oxid Med Cell Longev 2022; 2022: 9966750.
| Crossref | Google Scholar |
8 Fujimoto KJ, Nema D, Ninomiya M, Koketsu M, Sadanari H, Takemoto M, Daikoku T, Murayama T. An in silico-designed flavone derivative, 6-fluoro-4'-hydroxy-3',5'-dimetoxyflavone, has a greater anti-human cytomegalovirus effect than ganciclovir in infected cells. Antivir Res 2018; 154: 10-16.
| Crossref | Google Scholar | PubMed |
9 Abou Baker DH. An ethnopharmacological review on the therapeutical properties of flavonoids and their mechanisms of actions: a comprehensive review based on up to date knowledge. Toxicol Rep 2022; 9: 445-469.
| Crossref | Google Scholar | PubMed |
10 Melrose J, Smith MM. Natural and semi-synthetic flavonoid anti-SARS-CoV-2 agents for the treatment of Long COVID-19 disease and neurodegenerative disorders of cognitive decline. Front Biosci (Elite Ed) 2022; 14(4): 27.
| Crossref | Google Scholar | PubMed |
11 Khdera HA, Saad SY, Moustapha A, Kandil F. Synthesis of new flavonoid derivatives based on 3-hydroxy-4′-dimethylamino flavone and study the activity of some of them as antifungal. Heliyon 2022; 8: e12062.
| Crossref | Google Scholar | PubMed |
12 Górniak I, Bartoszewski R, Króliczewski J. Comprehensive review of antimicrobial activities of plant flavonoids. Phytochem Rev 2019; 18: 241-272.
| Crossref | Google Scholar |
13 Bennardi DO, Ruiz DM, Romanelli GP, Baronetti GT, Thomas HJ, Autino JC. Efficient microwave solvent-free synthesis of flavones, chromones, coumarins and dihydrocoumarins. Lett Org Chem 2008; 5: 607-615.
| Crossref | Google Scholar |
14 Melrose J. The potential of flavonoids and flavonoid metabolites in the treatment of neurodegenerative pathology in disorders of cognitive decline. Antioxidants 2023; 12: 663.
| Crossref | Google Scholar | PubMed |
15 Reis J, Gaspar A, Milhazes N, Borges F. Chromone as a privileged scaffold in drug discovery: recent advances. J Med Chem 2017; 60: 7941-7957.
| Crossref | Google Scholar | PubMed |
16 Chen S, Wang X, Cheng Y, Gao H, Chen X. A review of classification, biosynthesis, biological activities and potential applications of flavonoids. Molecules 2023; 28: 4982.
| Crossref | Google Scholar | PubMed |
17 Stanek F, Stodulski M. Mild and efficient organocatalytic method for the synthesis of flavones. Tetrahedron Lett 2016; 57: 3841-3843.
| Crossref | Google Scholar |
18 Pérez M, Ruiz D, Autino J, Sathicq A, Romanelli G. A very simple solvent-free method for the synthesis of 2-arylchromones using KHSO4 as a recyclable catalyst. C R Chim 2016; 19: 551-555.
| Crossref | Google Scholar |
19 Pontes O, Costa M, Santos F, Sampaio-Marques B, Dias T, Ludovico P, Baltazar F, Proença F. Exploitation of new chalcones and 4H-chromenes as agents for cancer treatment. Eur J Med Chem 2018; 157: 101-114.
| Crossref | Google Scholar | PubMed |
20 Ares JJ, Outt PE, Kakodkar SV, Buss RC, Geiger JC. A convenient large-scale synthesis of 5-methoxyflavone and its application to analog preparation. J Org Chem 1993; 58: 7903-7905.
| Crossref | Google Scholar |
21 Tsukayama M, Kawamura Y, Ishizuka T, Hayas S, Torii F. Improved, rapid and efficient synthesis of polymethoxyflavones under microwave irradiation and their inhibitory effects on melanogenesis. Heterocycles 2003; 60: 2775-2784.
| Crossref | Google Scholar |
22 Kabalka GW, Mereddy AR. Microwave-assisted synthesis of functionalized flavones and chromones. Tetrahedron Lett 2005; 46: 6315-6317.
| Crossref | Google Scholar |
23 Zubaidha PK, Hashmi AM, Bhosale RS. FeCl3 catalyzed dehydrative cyclisation of 1,3-(diaryl diketones) to flavones. Heterocycl Commun 2005; 11: 97-100.
| Crossref | Google Scholar |
24 Hoshino Y, Oohinata T, Takeno N. The direct preparation of flavones from 2′-hydroxychalcones using disulfides. Bull Chem Soc Jpn 1986; 59: 2351-2352.
| Crossref | Google Scholar |
25 Selepe MA, van Heerden FR. Application of the Suzuki–Miyaura reaction in the synthesis of flavonoids. Molecules 2013; 18: 4739-4765.
| Crossref | Google Scholar | PubMed |
26 Du Z, Ng H, Zhang K, Zeng H, Wang J. Ionic liquid mediated Cu-catalyzed cascade oxa-Michael-oxidation: efficient synthesis of flavones under mild reaction conditions. J Org Biomol Chem 2011; 9: 6930-6933.
| Crossref | Google Scholar | PubMed |
27 Jung JC, Min JP, Park OS. A highly practical route to 2-methylchromones from 2-acetoxybenzoic acids. Synth Commun 2001; 31: 1837-1845.
| Crossref | Google Scholar |
28 Fan X, He C, Ji M, Sun X, Luo H, Li C, Tong H, Zhang W, Sun Z, Chu W. Visible light-induced deoxygenation/cyclization of salicylic acid derivatives and aryl acetylene for the synthesis of flavonoids. Chem Commun 2022; 58: 6348-6351.
| Crossref | Google Scholar | PubMed |
29 Baruah S, Kaishap PP, Gogoi S. Ru(II)-Catalyzed C-H activation and annulation of salicylaldehydes with monosubstituted and disubstituted alkynes. Chem Commun 2016; 52: 13004-13007.
| Crossref | Google Scholar | PubMed |
30 Miao H, Yang Z. Regiospecific carbonylative annulation of iodophenol acetates and acetylenes to construct the flavones by a new catalyst of palladium–thiourea–DPPP complex. Org Lett 2000; 2: 1765-1768.
| Crossref | Google Scholar | PubMed |
31 Xu S, Sun H, Zhuang M, Zheng S, Jian Y, Zhang W, Gao Z. Divergent synthesis of flavones and aurones via base-controlled regioselective palladium catalyzed carbonylative cyclization. Mol Catal 2018; 452: 264-270.
| Crossref | Google Scholar |
32 Zhu F, Wang Z, Li Y, Wu XF. Iridium-catalyzed and ligand-controlled carbonylative synthesis of flavones from simple phenols and internal alkynes. Chem Eur J 2017; 23: 3276-3279.
| Crossref | Google Scholar | PubMed |
33 Wu XF, Neumann H, Beller M. Palladium-catalyzed carbonylation reaction of aryl bromides with 2-hydroxyacetophenones to form flavones. Chem Eur J 2012; 18: 12595-12598.
| Crossref | Google Scholar | PubMed |
34 Baldwin JE, Thomas RC, Kruse LI, Silberman L. Rules for ring closure: ring formation by conjugate addition of oxygen nucleophiles. J Org Chem 1977; 42: 3846-3852.
| Crossref | Google Scholar |
35 García H, Iborra S, Primo J, Miranda MA. 6-Endo-dig vs. 5-exo-dig ring closure in o-hydroxyaryl phenylethynyl ketones. A new approach to the synthesis of flavones and aurones. J Org Chem 1986; 51: 4432-4436.
| Crossref | Google Scholar |
36 Brennan CM, Johnson CD, McDonnell PD. Ring closure to ynone systems: 5- and 6-endo- and -exo-dig modes. J Chem Soc Perkin Trans 1989; 2: 957-961.
| Crossref | Google Scholar |
37 Awuah E, Capretta A. Access to flavones via a microwave-assisted, one-pot Sonogashira-carbonylation-annulation reaction. Org Lett 2009; 11: 3210-3213.
| Crossref | Google Scholar | PubMed |
38 Garcia H, Iborra S, Primo J. 6-Endo-dig vs. 5-exo-dig ring closure in o-hydroxyaryl phenylethynyl ketones. A new approach to the synthesis of flavones and aurones. J Org Chem 1986; 51: 4432-4436.
| Crossref | Google Scholar |
39 Alabugin IV, Gilmore K, Manoharan M. Rules for anionic and radical ring closure of alkynes. J Am Chem Soc 2011; 133: 12608-12623.
| Crossref | Google Scholar | PubMed |
40 Yoshida M, Fujino Y, Doi T. Synthesis of γ-benzopyranone by TfOH-promoted regioselective cyclization of o-alkynoylphenols. Org Lett 2011; 13: 4526-4529.
| Crossref | Google Scholar | PubMed |
41 Yoshida M, Fujino Y, Saito K, Doi T. Regioselective synthesis of flavone derivatives via DMAP-catalyzed cyclization of o-alkynoylphenols. Tetrahedron 2011; 67: 9993-9997.
| Crossref | Google Scholar |
42 Lee JI, Kim HN. Synthesis of flavones by thallium(III) p-tosylate-catalyzed regioselective cyclization of o-(alkynon-1-yl)phenols. Bull Korean Chem Soc 2018; 39: 1113-1116.
| Crossref | Google Scholar |
43 Lee JI. Novel synthesis of flavones by regioselective cyclization of 1-(2-hydroxyphenyl)-3-phenyl-2-propyn-1-ones derived from 2-hydroxybenzoic acids. Bull Korean Chem Soc 2017; 38: 675-678.
| Crossref | Google Scholar |
44 Bhat AS, Whetstone JL, Brueggemeier RW. Novel synthetic routes suitable for constructing benzopyrone combinatorial libraries. Tetrahedron Lett 1999; 40: 2469-2472.
| Crossref | Google Scholar |
45 Chuang D-W, El-Shazly M, Balaji B, Chung Y-M, Chang F-R, Wu Y-C. Synthesis of flavones and γ-benzopyranones using mild sonogashira coupling and 18-crown-6 ether mediated 6-endo cyclization. Eur J Org Chem 2012; 2012(24): 4533-4540.
| Crossref | Google Scholar |
46 Katritzky AR, Singh SK, Cai C, Bobrov S. Direct synthesis of esters and amides from unprotected hydroxyaromatic and -aliphatic carboxylic acids. J Org Chem 2006; 71: 3364-3374.
| Crossref | Google Scholar | PubMed |
47 Katritzky AR, Singh SK, Akhmedova R, Cai C, Bobrov S. Efficient synthesis of 1,3-benzodioxin-4-one and benzoxazine-2,4-diones. Arkivoc 2007; 6: 6-13.
| Google Scholar |
48 Katritzky AR, Le KNB, Mohapatra PP. Synthesis of aliphatic hydroxyaryl ketones or (hetero)aryl hydroxyaryl ketones by acylation of organometallic reagents. Synthesis 2007; 2007(20): 3141-3146.
| Crossref | Google Scholar |
49 Katritzky AR, Widyan K, Kirichenko K. Preparation of polyfunctional acyl azides. J Org Chem 2007; 72: 5802-5804.
| Crossref | Google Scholar | PubMed |
50 Widyan K. An improved synthesis of polyfunctional acyl azides in PEG 400. Org Prep Proced Int 2021; 53: 120-126.
| Crossref | Google Scholar |
51 Widyan K. Acylation of terminal alkynes with N-acylbenzotriazole: synthesis of conjugated ynones in ionic liquids. Monatsh Chem 2023; 154: 645-649.
| Crossref | Google Scholar |
52 Widyan K. 3,5-Disubstituted-1H-pyrazoles: sequential syntheses from N-acylbenzotriazoles, alkynes, and hydrazine in ionic liquid. Chem Pap 2025; 79: 1649-1655.
| Crossref | Google Scholar |
53 Hsieh AY, Haines RS, Harper JB. Effects of ionic liquids on the nucleofugality of dimethyl sulfide. J Org Chem 2024; 89: 14929-14939.
| Crossref | Google Scholar | PubMed |
54 Hsieh AY, Haines RS, Harper JB. Effects of ionic liquids on the nucleofugality of bromide. J Org Chem 2024; 89: 6247-6256.
| Crossref | Google Scholar | PubMed |
55 Hsieh AY, Haines RS, Harper JB. The effects of ionic liquids on the ethanolysis of a chloroacenaphthene. Evaluation of the effectiveness of nucleofugality data to predict reaction outcome. RSC Adv 2023; 13: 21036-21043.
| Crossref | Google Scholar | PubMed |
56 Coney MD, Morris DC, Gilbert A, Prescott SW, Haines RS, Harper JB. Effects of ionic liquids on the nucleofugality of chloride. J Org Chem 2022; 87: 1767-1779.
| Crossref | Google Scholar | PubMed |