FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2021, VOLUME 09, ISSUE 01) Synthesis of linear hetarenochromones based on 7-hydroxy-6- formyl(acetyl)chromones Tetyana Shokol*, Natalia Gorbulenko, Volodymyr Khilya Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska Street, 64/13, Kyiv 01601, Ukraine} [email protected] Keywords: 6-formyl(acetyl)-7-hydroxychromones, annulation, furo[3,2-g]chromones, chromeno[6,7-d]isoxazoles, pyrano[3,2-g]chromones. 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. ________________________________________________________________________________ Introduction by furochromone and pyranochromone Chromone derivatives represent an derivatives. Benzopyranones and important class of naturally occurring furobenzopyranones are compounds of compounds belonging to the flavonoid family considerable significance owing to their wide with a wide range of biological activities and spread occurrence in plants and their potential low toxicity [1]. Their structural diversity and as important pharmaceuticals in the treatment high pharmacological potency made them a of renal colic, anginal syndromes, whooping privileged scaffold in drug discovery [2, 3]. cough, peptic ulcer, in photochemotherapy The first chromone to be used in pure treatment of a variety of skin diseases such as form in clinical practice was a linear psoriasis, vitiligo, mycosis fungoides, as furochromone khellin [4]. Natural antiviral, antitumor, antiproliferation and hetarenochromones are represented primarily CNS agents [5]. 70 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2021, VOLUME 09, ISSUE 01) Design of hetarenochromones can be hetarenochromones have been highlited in accomplished both by annulation of reviews [6, 7]. heterocycle to the chromone core and by We present here the current state of annulation of γ-pyrone cycle to the research on the synthesis of linear benzohetarene system. ortho-Hydroxy- hetarenochromones namely furo[3,2- formyl(acetyl)chromones are treated as g]chromones, pyrano[3,2-g]chromones and attractive starting materials for the synthesis some of their N-containing analogues based of angular and linear hetarenochromones by on the 7-hydroxy-6-formyl- and 7-hydroxy-6- the first route. The syntheses of angular acetylchromones (Scheme 1). Scheme 1. Hetarenochromones based on of 6-formyl(acetyl)-7-hydroxychromones 1. Synthesis of 6-formyl- and 6-acetyl-7- 5,7-dihydroxy-3-(4-methoxybenzyl)-8- hydroxychromones methyl-4-oxo-4H-6-chromenecarbaldehyde It is interesting to note that several (1) and 3-(1,3-benzodioxol-5-ylmethyl)-5,7- 7-hydroxy-6-formylchromones were isolated dihydroxy-8-methyl-4-oxo-4H-6- from natural sources. Two homoisoflavones: chromenecarbaldehyde (2), the former 71 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2021, VOLUME 09, ISSUE 01) showing marked cytotoxic activity against lung cancer cells being isolated from the roots of Ophiopodon japonicus [8, 9] (Figure 1). Me Me HO O HO O O O Scheme 2. Oxidation of visnagin (4) and khellin (5) OH O OH O 1 2 O Oxidation of visnagin (4) with chromic acid OMe O afforded the hydroxy aldehyde 6 in good yield Me HO O [11]. However, treatment of khellin (5) with OH O chromic acid under identical conditions (and OH O modifications thereof) failed to yield 3 Pisonone H hydroxyaldehyde 7 [13]. The failure of the above oxidation is perhaps not surprising Figure 1. Natural 6-formyl-7-hydroxychromones from when one considers that chromic acid is Ophiopodon japonicus and Pisonia umbellifera known to effect oxidative demethylation of certain p-methoxy aromatics to yield quinones 5,7,2'-Trihydroxy-6-formylisoflavone (3), [13]. Oxidation of khellin with mercuric(II) named as pisonone H, was identified in a nitrate (Hg(NO3)2) in aqueous THF followed study of the stems of Pisonia umbellifera by treatment with sodium metaperiodate used in Chinese folk medicine and tested for (NaIO4) afforded hydroxy aldehyde 7 in 24 % anti-inflammatory and cytotoxic activity[10] yield. Catalytic osmylation of khellin, using (Figure 1). o NaIO4 to reoxidize the osmium, in THF at 50 Usually, 7-hydroxy-6- C afforded hydroxy aldehyde 7 in 73 % yield formylchromones are synthesized by [12, 13]. oxidation of natural linear furochromones: 6-Formyl-7-hydroxychromones (8) visnagin (4) and khellin (5) and their synthetic can also be obtained from 7- analogues [11-15] (Scheme 2). hydroxychromones (9) via the Duff reaction (method A) by heating them with hexamethylene tetramine (from 1 equiv. [16] to 7 equiv. [17]) in glacial acetic acid at 100oC for 6-8 h followed by hydrolysis with 72 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2021, VOLUME 09, ISSUE 01) hot HCl and water (1:1) when heating for 15- hydroxychromones (9) can be used in this 30 min (Scheme 3). The Duff’s method has reaction. With more complex molecules been used successfully in a number of cases especially having a larger number of free [16-18], however certain difficulties arise in hydroxyls groups in their structure, namely the implementation of the reaction. Due to the nor-wogonin (9 R1=Ph, R2=H, R3=R4=OH) low activity of position 6 in 7- and 5,7,8-trihydroxy-2-methylchromone, it hydroxychromones towards electrophilic did not work and no aldehyde could be attack, only 8-substituted 7- obtained [17]. Scheme 3. The synthesis of 6-formyl-7-hydroxychromones via the Duff reaction Another embodiment of 6-formyl-7- hydrochloride of the aminomethyl derivative hydroxychromones (8) synthesis (method B) 10 was isolated [19]. starting from 6-aminomethyl derivatives of The synthesis of 6-acetyl-7- 7-hydroxychromones (10) under modified hydroxychromones was realized via Duff reaction conditions, namely refluxing acetylation of 8-substituted-7- 10 with 2 equiv. of hexamethylene tetramine hydroxychromones with acetic anhydride in AcOH for 3-6 h followed by acid containing anhydrous sodium acetate hydrolysis, has been reported in [19, 20] followed by Friss rearrangement with (Scheme 3). It should be noted that carrying anhydrous aluminium chloride, as shown in out this reaction while heating in a water bath the Scheme 4 for 6-acetyl-7-hydroxy-2,3,8- (100oC) did not lead to the desired result. trimethyl-chromone (11) [21]. Under these conditions, only the 73 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2021, VOLUME 09, ISSUE 01) Scheme 4. The synthesis of 6-acetyl-7-hydroxy-2,3,8-trimethylchromone The reaction of [22] (Scheme 5). Reaction of 12 with resodiacetylacetophenone (12) with ethyl aromatic aldehydes in ethyl orthoformate orthoformate (6 equiv.) in the presence of followed by boiling in DMF and dilution with 70 % perchloric acid gave 4- water resulted in 6-acetyl-7-hydroxyflavones alkoxybenzopyrylium salt 13, which was 15 with hypolipidemic activity [23] (Scheme converted to 6-acetyl-7-hydroxychromone 14 5). in almost quantitative yield on refluxing water Scheme 5. The synthesis of 6-acetyl-7-hydroxychromones from 4-alkoxybenzopyrylium salts 6-Formyl- and 6-acetyl-7- chromeno[4,3-b]pyridines and hydroxychromones have been extensively pyrano[3’,2’:6,7]chromeno[4,3-c]pyridines. used in the synthesis of chromones, annulated 2. Chromones annulated with five- with five- and six-membered heterocycles, membered heterocycles namely furo[3,2-g]chromones, dioxolo[4,5- 2.1. Furo[3,2-g]chromones g]chromones, chromeno[6,7-d]isoxazoles, Khellin and visnagin (Scheme 2) are pyrano[3,2-g]chromones, pyrano[3’,2’:6,7]- the most famous natural linear furo[3,2- g]chromones found in fruits and seeds of 74 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2021, VOLUME 09, ISSUE 01) Ammi visnaga, a plant belonging to the family A facile synthesis of kellin (5) was Umbelliferae [24]. They were shown to implemented in 1949 starting from 2-methyl- possess phototoxic and genotoxic activities 5,7-dihydroxychromone (16) in 7 steps. The against various kinds of microorganisms, approach relied on formylation of 5-hydroxy- phototherapeutic properties similar to those of 8-methoxy-7-O-carbomethoxy-methyl-2- the psoralen, but with substantially lower methylchromone (17) with hexamine in phototoxic and DNA damaging effects, glacial acetic acid solution yielding the 6- herbicidal and vasodilating activity. These formyl derivative 18, followed by complete results support their application in the photo- methylation to the key intermediate aldehydo- chemotherapeutic treatment of vitiligo and ester 19 and gentle alkali hydrolysis to psoriasis, usefulness in the treatment of aldehydo-acid 20 which when boiled with spasmodic conditions like asthma and acetic anhydride and sodium acetate formed intestinal colic and also for certain diseased the furan ring with the simultaneous evolution conditions of the heart and their potential as of carbon dioxide [27] (Scheme 6). bioherbicides or lead molecules for the development of new medicines [25-27]. Scheme 6. The synthesis of kellin An alternative approach was realized presence of K2CO3 in refluxing acetone [13]. by Gammill et al to obtain aldehydo-ester 21. Treatment of 21 with 1 equiv of sodium It was synthesized upon alkylation of 5,8- methoxide in methanol cleanly afforded 2- dimethoxy-7-hydroxy-2-methyl-6-formyl- ethoxycarbonylkellin (22) in 54% yield [13] chromone 7 with ethyl bromoacetate in the (Scheme 6).