Synthesis of linear hetarenochromones based on 7-hydroxy-6-formyl(acetyl)chromones




6-formyl(acetyl)-7-hydroxychromones, annulation, furo[3, 2-g]chromones, chromeno[6, 7-d]isoxazoles, pyrano[3


Fused chromones are attracting increasing attention as novel therapeutic agents due to their wide distribution in nature, effective bioactivities and low toxicity. 6-Carbonyl-7-hydroxychromones proved to be versatile synthons for the synthesis of linear hetarenochromones by annulation of heterocycle to the chromone core. The present review is focused on the syntheses of furo[3,2-g]chromones, pyrano[3,2-g]chromones and some of their N-containing analogues, namely chromeno[6,7-d]isoxazoles, pyrano[3’,2’:6,7]chromeno[4,3-b]pyridine-5,11-diones and pyrano[3’,2’:6,7]chromeno[4,3-c]pyridine-5,11-diones based on the 7-hydroxy-6-formylchromones or 7-hydroxy-6-acetylchromones and shows the current state of research to date. The methods for the synthesis of the starting 7-hydroxy-6-formylchromones and 7-hydroxy-6-acetylchromones have been also mentioned. The biological activity of naturally occurring and modified synthetic linear hetarenochromones has been also represented.


Sharma S, Kumar S, Chand K, Kathuria A, Gupta A, Jain R. An Update on Natural Occurrence and Biological Activity of Chromones. Current Medicinal Chemistry 2011;18(25):3825-3852.

Keri R, Budagumpi S, Pai R, Balakrishna R. Chromones as a privileged scaffold in drug discovery: A review. European Journal of Medicinal Chemistry 2014;78:340-374.

Mohsin N, Irfan M, Hassan S, Saleem U. Current Strategies in Development of New Chromone Derivatives with Diversified Pharmacological Activities: A Review. Pharmaceutical Chemistry Journal 2020;54(3):241-257.

Edwards , Howell . The chromones: history, chemistry and clinical development. A tribute to the work of Dr R. E. C. Altounyan. Clinical & Experimental Allergy 2000;30(6):756-774.

El-Desoky E, Al-Shihry S. Synthesis and reactions of some new benzopyranone derivatives with potential biological activities. Journal of Heterocyclic Chemistry 2008;45(6):1855-1864.

Lozinskii O, Shokol T, Khilya V. Synthesis and biological activity of chromones annelated at the C(7)–C(8) bond with heterocycles (review). Chemistry of Heterocyclic Compounds 2011;47(9):1055-1077.

Shokol T, Lozinski O, Gorbulenko N, Khilya V. The synthesis of angular heteroarenochromones based on 7-hydroxy-8-carbonylchromones. French-Ukrainian Journal of Chemistry 2017;5(2):68-94.

Zhu Y, Yan K, Tu G. Two homoisoflavones from Ophiopogon japonicus. Phytochemistry 1987;26(10):2873-2874.

Zhou C, Zou L, Mo J, Wang X, Yang B, He Q, Gan L. Homoisoflavonoids fromOphiopogon japonicus. Helvetica Chimica Acta 2013;96(7):1397-1405.

Liu Z, Zheng X, Wang Y, Tang M, Chen S, Zhang F, Li L, Zhang C, Sun Y. Lignans and isoflavonoids from the stems of Pisonia umbellifera. RSC Advances 2018;8(29):16383-16391.

Schönberg A, Badran N, Starkowsky N. Furo-chromones and -Coumarins. VII. Degradation of Visnagin, Khellin and Related Substances; Experiments with Chromic Acid and Hydrogen Peroxide; and a Synthesis of Eugenitin. Journal of the American Chemical Society 1953;75(20):4992-4995.

Gammill R, Nash S. Catalytic osmylation and oxypalladation of khellin. Two useful methods for furan ring degradation. Replacement of the furan ring by an isoxazole ring.. Tetrahedron Letters 1984;25(28):2953-2956.

Gammill R, Nash S. Oxymetallation of khellin. Solvomercuration, osmylation, and palladium-catalyzed oxidation of the furan ring in khellin. The synthesis of highly oxygenated chromones and 2-substituted furochromones. The Journal of Organic Chemistry 1986;51(16):3116-3123.

Ragab F, Yahya T, El-Naa M, Arafa R. Design, synthesis and structure–activity relationship of novel semi-synthetic flavonoids as antiproliferative agents. European Journal of Medicinal Chemistry 2014;82:506-520.

Schönberg A, Badran N, Starkowsky N. Furo-chromones and -Coumarins. XIV. 2-(3'-Pyridyl) Analogs of Khellin and Visnagin. Journal of the American Chemical Society 1955;77(20):5439-5440.

Jayaprakash Rao Y, David Krupadanam GL. A facile synthesis of 7,8/6,7 fused pyrano[4,3-b]pyridinochromones and evaluation of antibacterial activity. Indian J. Chem., Sect. B. 2000;39(8):610–613.

Murti V, Seshadri T, Sundaresan V, Venkataramani B. Formylation of polyhydroxy flavones and chromones. Proceedings of the Indian Academy of Sciences - Section A 1959;50(3):192-195.

Mohan SB, Murti VVS. Duff Reaction with Flavones: Formation of Homobiflavones. Indian J. Chem. Sect. B. 1982;21(9):887–888.

Shokol TV, Gorbulenko NV, Khilya VP. Synthesis of 7-Hydroxy-2,8-dimethyl-4-oxo-3-phenoxy-4H-6-chromenecarbaldehide. Bulletin of Taras Shevchenko National University of Kyiv. Chemistry., 2018;(1(55)):54-57.

Shokol T, Gorbulenko N, Frasinyuk M, Khilya V. Synthesis of 7-Hydroxy-8-Methyl-4'-Methoxy-6-Formylisoflavone and Linear Hetarenochromones Based on It. Chemistry of Natural Compounds 2020;56(3):420-422.

Rodighiero P, Pastorini G, Chilin A, Manzini P, Guiotto A. Synthesis of some methylfurochromones as potential photochemotherapeutic agents. Journal of Heterocyclic Chemistry 1988;25(2):527-533.

Dorofeenko G, Tkachenko V. Synthesis of 4-alkoxybenzopyrylium salts and chromones. Chemistry of Heterocyclic Compounds 1972;8(8):935-938.

Oganesyan ET, Vasilenko YuK, Khachatryan M.M, Pyshchev AI. Synthesis of flavones with hypolipidemic activity. Pharm. Chem. J. 1990;23(11):927–931.

Khalil N, Bishr M, Desouky S, Salama O. Ammi Visnaga L., a Potential Medicinal Plant: A Review. Molecules 2020;25(2):301.

Abu-Hashem A, El-Shazly M. Synthesis, reactions and biological activities of furochromones: A review. European Journal of Medicinal Chemistry 2015;90:633-665.

Travaini M, Sosa G, Ceccarelli E, Walter H, Cantrell C, Carrillo N, Dayan F, Meepagala K, Duke S. Khellin and Visnagin, Furanochromones fromAmmi visnaga(L.) Lam., as Potential Bioherbicides. Journal of Agricultural and Food Chemistry 2016;64(50):9475-9487.

Murti V, Seshadri T. Nuclear oxidation in flavones and related compounds. Proceedings of the Indian Academy of Sciences - Section A 1949;30(3):107-113.

Briggs MTD, Duncan GLS, Thornber CW, Cooper CR. The preparation of flavones and their derivatives. Part I. Flavones and 4-thioflavones. J. Chem. Res., Miniprint 1982, 2461−2487.

Hishmat OH, El-Diwani HI, Melek FR, El-Sahrawi HM, El-Shabrawi O. Synthesis and pharmacological activity of benzodipyran derivatives. Indian J. Chem. Sect. B 1996;35(1):30–35.

Duan Y, Jiang Y, Guo F, Chen L, Xu L, Zhang W, Liu B. The antitumor activity of naturally occurring chromones: A review. Fitoterapia 2019;135:114-129.

Alves I, Abreu L, Costa C, Le Hyaric M, Guedes M, Soares M, Bezerra D, Velozo E. Pyranochromones fromDictyoloma vandellianumA.Jussand Their Cytotoxic Evaluation. Chemistry & Biodiversity 2017;14(3):e1600276.

Gonzalez A, Darias V, Estevez E, Vivas J. Chemotherapeutic Study of Chromones from Spanish Cneoraceae. Planta Medica 1983;47(01):56-58.

Moreira W, Lima M, Ferreira A, Ferreira I, Nakamura C. Chemical constituents from the roots of Spathelia excelsa and their antiprotozoal activity. Journal of the Brazilian Chemical Society 2009;20(6):1089–1094.

Nixon NS, Scheinmann F, Suschitzky JL. Reactions of Allene-1,3-dicarboxylic Esters and Acids/ Part 3. New Chromene, chromone, Quinolone, α-Pyrone and Coumarin Syntheses. J. Chem. Res, Synop. 1984;12:380–381.

Mustafa A, Starkovsky NA, Zaki M. Experiments with Furochromones and -coumarins. Synthesis of α-Pyronochromone Derivatives from Visnagin and α-Pyronocoumarin from Bergapten. The Journal of Organic Chemistry 1961;26(2):523-526.

Hishmat O, El-Ebrashi N, El-Naem S, Abd El Rahman A. Convenient Syntheses of Some Substituted 5H, 11H-Pyrano[3′,2′ : 6,7][1] benzopyrano[3,4-c]pyridines and 7,9-Dioxa-3,4,6-triazabenzo[de]naphthacenes. Synthesis 1982;1982(12):1075-1077.

Gohar A-KMN, Abdel-Latif FF, El-Ktatny MS. Synthesis of Benzo<1,2-b:5,4-b'>dipyran Derivatives. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1987;26(1-12):274–276.

Hishmat OH, Khalil KHM, Abdel Galil FM, El-Naem ShI, Magd-El-Din AA. Benzodipyrans of expected biological activity. Pharmazie. 1989;44 (11):793–794.

Hishmat O, Khalil K, El-Naem S, el-Rahman A. Synthesis of Pyranobenzopyranopyridines and Benzodipyran Derivatives. Zeitschrift für Naturforschung B 1986;41(2):252-258.

Abdel-Aziem A, El-Sawy E, Kirsch G. Convenient synthesis of linear 2H,6H-pyrano[3,2-g] chromenes from natural occurring compound; visnagin. Synthetic Communications 2019;49(24):3419-3425.

El Bialy S, Gouda M. Cyanoacetamide in heterocyclic chemistry: Synthesis, antitumor and antioxidant activities of some new benzothiophenes. Journal of Heterocyclic Chemistry 2011;48(6):1280-1286.

Farag A, Abd-Alrahman S, Ahmed G, Ammar R, Ammar Y, Abbas S. Synthesis of Some Azoles Incorporating a Sulfonamide Moiety as Anticonvulsant Agents. Archiv der Pharmazie 2012;345(9):703-712.

Gouda M. Synthesis and Antioxidant Activity of a Novel Series of Pyrazolotriazine, Coumarin, Oxoazinone, and Pyrazinopyrimidine Derivatives. Archiv der Pharmazie 2013;346(8):626-634.

Hishmat OH, Khalil KhMA, El-Naem ShE, Rahman, Abd El-Rahman AH. Synthesis of Some Substituted Pyranobenzopyranopyridines and Benzodipyrans. Indian J. Chem., Sect. B. 1986;25:897–900.

Gohar A-KMN, Abdel-Latif FF. Synthesis of Benzo<1,2-b;5,4-b'>dipyran Derivatives (Part II). Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1987;26(1-12):363–365.

Yakout El-SMA. Preparation of New Chromone Derivatives of Molluscicidal and Antitumour Activities. Egypt. J. Chem. 2002;45(6):1029-1042.

Maigali S, Arief M, EL-Hussieny M, Soliman F. Chemistry of Phosphorus Ylides. Part 34 Synthesis of Chromenone Phosphanylidene and Cyclobutylidene Derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements 2012;187(2):190-204.

Soliman F, Khalil K, Elnaem S. Chemistry of Phosphorus Ylides 9. Reactions with Phosphacumulenes III. Synthesis of Benzodipyrans from the Reaction of Ketenylidene- and Thioketenylidenetriphenylphosphorane with Formylbenzopyran Derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements 1991;60(3-4):183-187.

Atta S, Hafez T, Mahran M. Organophosphorus Chemistry 25. The Utilization of Wittig Reagents in Lactone Ring Formation. Application to the Synthesis of Linear Furocoumarins and pyranocoumarins. Phosphorus, Sulfur, and Silicon and the Related Elements 1993;80(1-4):109-116.

Bodendiek S, Mahieux C, Hänsel W, Wulff H. 4-Phenoxybutoxy-substituted heterocycles – A structure–activity relationship study of blockers of the lymphocyte potassium channel Kv1.3. European Journal of Medicinal Chemistry 2009;44(5):1838-1852.

Houghton P, Hairong Y. Novel Chromone Alkaloids fromSchumanniophyton magnificum. Planta Medica 1985;51(01):23-27.

Houghton P, Woldemariam T, Khan A, Burke A, Mahmood N. Antiviral activity of natural and semi-synthetic chromone alkaloids. Antiviral Research 1994;25(3-4):235-244.

Houghton P, Osibogun I, Woldemariam T, Jones K. Heteronuclear NMR Studies of the Chromone Alkaloids and Revision of the Structure of Some Piperidino-Chromone Alkaloids. Planta Medica 1995;61(02):154-157.

Kelly T, Kim M. Synthesis of schumanniophytine and isoschumanniophytine. The Journal of Organic Chemistry 1992;57(5):1593-1597.