key: cord-0948668-nxfl64t9
authors: Shatokhin, S. S.; Tuskaev, V. A.; Gagieva, S. Ch.; Oganesyan, É. T.
title: Synthesis of heterocyclic analogs of isoflavone and homoisoflavone based on 3-formylchromone
date: 2021-07-14
journal: Russ Chem Bull
DOI: 10.1007/s11172-021-3183-6
sha: 5fe713091173248a85c0f640d7f9c150b8b03756
doc_id: 948668
cord_uid: nxfl64t9

The review is focused on recent developments of chemistry of synthetic analogs of natural compounds, isoflavone and homoisoflavone. The possible synthetic strategies to access heterocyclic analogs of these compounds starting from readily available 3-formylchromone and its derivatives (3-cyanochromone, 2-amino-3-formylchromone) and products of its condensation with simplest C- and N-nucleophiles are discussed. The structural features of the reaction products that depend on the nature of the reaction medium, structure of the starting compounds, and reagent ratio are considered. Particular attention is given to the application of the modern strategies of organic synthesis, namely green chemistry approaches, click reactions, domino reactions, etc. Examples of compounds of this group most promising for clinical application due to wide and pronounced pharmacological effects are given.

The search for new eff ective and safe drugs by rational synthesis of biologically active compounds has been a most important aim of modern medicinal chemistry for many years. One of the directions of this search is the modifi cation of natural biologically active substances. 1-4 From this viewpoint, 4H-chromen-4-one derivatives that are a subclass of fl avonoids, secondary metabolites of plants, are of great interest. The convenient precursors for the synthesis of heterocyclic analogs and homologs of isofl avones are 3-formylchromones (1) and, in particular compound 1a (R = H).

To date, more than 8000 natural and synthetic fl avonoids are described. 5 These compounds exhibit a wide range of biological activities along with low toxicity (see, for example, reviews 6-11 ). Reviews 12-14 are focused on the potential of diff erent natural compounds, including fl avonoids, to combat COVID- 19. In the fl avonoid class, derivatives of 3-phenylchromone also called isofl avonoids are of considerable interest. 15, 16 The structures of isofl avones and their heterocyclic analogs that are currently used in clinical practice or under clinical trials are show n below. Isofl avone genistein 2 is an active ingredient of the dietary supplements (Menoril ® ) used for alleviating menopausal symptoms. 17 Synthetic isofl avone iprifl avone 3 is used to inhibit bone resorption and to prevent bone and cartilage degeneration. 18 2´,6-Dichloro-7-meth oxy isofl avone (4) effi ciently induces keratinocyte migration and could be used in wound healing compositions. 19 Furan isofl avone analogs 5 showed antituberculosis activity against reference strain H37Rv of Mycobacterium tuberculosis. The authors believe that the cell wall lipoproteins of M. tuberculosis are the major target for these compounds. 20 (Chromon-3-yl)triazolylmethane derivative 6 showed antimycobacterial activity similar to that of Rifampicin. 21 The most known methods for the synthesis of isofl avone heterocyclic analogs involve preliminary synthesis hetaryl desoxybenzoins and their subsequent cyclization. 15, 16, 22, 23 This approach is very time-and labor-consuming when applied for the library synthesis of new isofl avone derivatives. Another strategy is the C-C bond formation between the chromone fragment and 3-positioned cyclic substituent by the cross coupling reactions. 24-28 This is very important to note that 3-formylchromones have three reactive centers, i.e., an aldehyde group, an electrophilic C(2) atom, and a carbonyl group at C(4) that provide possibility to modify the structures of the starting compounds (the reactivity of compounds 1 is discussed in reviews 29-34 ). The reactivity of the simplest chromone derivatives, viz. 3-cyanochromone 35,36 and 2-aminochromone-3-carboxaldehyde, 37 was reviewed earlier. Depen ding on the reactive center of the starting compound involved in the reaction with nucleophile, 3-formylchromones can either undergo recyclization to hetaryl-substituted phenols, or produce benzopyran-fused systems, or participate in the reactions occurring with the retention of the initial heterocycle. The present review is mainly focused on this last type of the reactions.

Three-component reaction of 3-formylchromones 1, alkyl isocyanides, and acetylenedicarboxylates gave the furan-substituted isofl avones 7, cyclopenta[b]chromene-dicarboxylates 8 or their mixtures (Scheme 1). 38 The direction of the reaction depends on both the nature of the substituents in 3-formylchromone 1 and the structure of acetylenedicarboxylate. The presence of electron-releasing substituents in the chromone ring system and the use of methyl acetylenedicarboxylate both facilitated the formation of isofl avone hetero analogs 7. In contrast, the presence of electron-withdrawing substituents in chromone and the use of ethyl acetylenedicarboxylate led to predominant formation of the fused derivatives 8.

The reaction of 3-formylchromones 1 (R 1 = H, Me; R 2 = H), alkyl isocyanides (R 3 = Bu t , cyclo-C 6 H 11 ), and methyl acetylenedicarboxylate in polyethylene glycol 400 (PEG-400) at room temperature gave selectively furan isofl avone analogs 7 in 75-90% yields. 39 When acetylenedicarboxylate was replaced with cinnamic and benzoic acids, 2-acyloxy-2-(chromon-3-yl)acetamides 9 were obtained. 40 Three-component reaction of 3-formylchromones 1, isocyanide, and either 4-hydroxycoumarin (10) or 4-hydroxy-6-methylpyran-2-one (11) in refl uxing toluene for 2 h gave furocoumarin and furopyranone isofl avone derivatives 12 (Scheme 2). 41 The authors suggest that the reaction proceeded as [4+1] cycloaddition of isocyanide to the Knoevenagel adduct 13 that generated in the reaction of 3-formylchromones 1 with compounds 10 and 11. 41 Product 12 exists in the more stable enamine form.

If primary aromatic amines were employed in this reaction instead of isocyanides, 5-oxofuran derivatives 14 were synthesized (Scheme 3). 42 The authors believed the reaction proceeds as follows. Initially, acetylenedicarboxylate reacted with amine to give dimethyl (E)-2anilinobut-2-enedicarboxylate that further added to the aldehyde group of 6-formylfurochromone 1b.

Some furochromone derivatives 14 demonstrated in vitro cytotoxicity against hepatocellular carcinoma (HEPG2) and breast cancer (MCF7) cell line similar to that of the commonly used chemotherapeutic agents, 5-Fluorouracil and Doxorubicin, and in vivo against N-methyl-N-nitrosourea-induced breast cancer in rats. 42 Four-component condensation of 3-formylchromones 1, Meldrum´s acid, alkyl isocyanide, and alcohol resulted in succinimide derivatives 15 (Scheme 4). 43 The reaction proceeded at room temperature chemo-and regioselectively to give products 15 in reasonable yields.

This approach is tolerated to a wide variety of the substituents R 2 and R 3 , while the use of methanol promoted the pyrrolidone ring opening to give amido diesters 16 43 (see Scheme 4) .

Pseudo three-component reaction of 3-formylchromones 1 and isocyanides aff orded furo [3,4-b] chromones 17 in high yields (Scheme 5). 44 The authors suppose that cycloaddition of isocyanide to the position 2 of formylchromones 1 followed by condensation of the generated adduct with the second molecule of aldehyde 1.

3-Formylchromone 1a reacted with glycine derivatives in refl uxing toluene in the presence of catalytic amounts of p-toluenesulfonic acid (TsOH) to give either pyridine derivatives 18 or substituted pyrroles 19-21 (Scheme 6). 45 The reaction of 3-formylchromone 1a with ethyl glycinate aff orded a mixture of compounds 18a and 19a. When -aminoacetonitrile was used instead of ethyl glycinate, the reaction selectively gave compound 18b. Both alanine ethyl ester and phenylglycine ethyl ester reacted with 3-formylchromone 1a to give pyrrole 20. Under these conditions, N-methylglycine aff orded pyrrole 21.

The authors suggested the mechanisms leading to compounds 18-21. 45 In particular, they proposed almost all possibilities of formation of compounds 18a and 19a via successive addition of both nucleophilic centers of ethyl glycinate to the position 2 and the aldehyde group of 3-formylchromone 1a. The authors believe that pyrrole 20 is resulted from the following reaction sequence. The reaction of the starting amine with aldehyde 1a gave the Schiff base that eliminated -keto acid and aff orded 3-aminomethylchromone, the last compound further reacted with the second molecule of aldehyde 1a to give 20.

Later, 46 the results obtained and the mechanisms of the reactions of 3-fromylchromone 1a with amino acid deriv atives proposed by Suschitzky and coworkers 45 were revised.

The reaction of compound 1a with methyl glycinate hydrochloride (22) in the presence of K 2 CO 3 at a ratio 1a : 22 : K 2 CO 3 of 1 : 1 : 0.5 in refl uxing toluene aff orded 3-aza-9-xanthene 23 (12%) along with salicyloylpyridine 18c (21%) and salicyloylpyrrole 19b (R = COOMe) (8%) (Scheme 7). 46 No product 23 is formed in this reaction performed with excesses of hydrochloride 22 and K 2 CO 3 (5 equiv. each).

The key intermediate in the reaction of 3-formylchromone 1a with N-methylglycine is azomethine ylide. Formation of intermediate 24 was supported by the synthesis of a series of N-methylpyrrolidine derivatives by 1,3-dipolar cycloaddition of different dipolarophiles (Scheme 8). [46] [47] [48] The reaction in refl uxing toluene with N-phenylmaleimide as a dipolarophile gave a mixture of cis/trans diastereomers 25 and pyrrole 21. 46 Under similar conditions, the three-component condensation of 3-formylchromone 1a, N-methylglycine, and fullerene C 60 resulted in unique fullerene-chromone dyad 26. 47 Tomé and coworkers assumed that combining two structural moieties with antioxidant activity, namely, fullerene and chromone cores, is a promising approach to pharmacologically active compounds. The reaction of 3-formylchromones 1 with N-methylglycine in a ratio of 1 : 1 in refl uxing DMF gave a mixture of 1-methyl-2,5-dihydropyrrol-2-ylchromones 27 and the products of deformylation of the starting 3-formylchromones, compounds 

Reagents and conditions: i. K 2 CO 3 , toluene, refl ux.

28 (see Scheme 8) . 48 No increase in the yield of compounds 27 was achieved when 2 equiv. of formylchromones 1 were used. The authors believe that products 27 are resulted from [3+2] cycloaddition of compounds 1 to intermediates 24. Dimethyl fumarate, 1,4-naphthoquinone, and dimethyl acetylenedicarboxylate were found unreactive in 1,3-dipolar cycloaddition reaction with intermediates 24. Under these conditions, only 1-methyl-3-salicyloylpyrrole 21 was formed. 46 In the absence of dipolarophile, the main product in the reaction of 3-formylchromone 1a with N-methylglycine (2.5 equiv.) was pyrrole 21 (80%). 46 Apparently, the formation of 21 is a result of 1,5-electrocyclization of azomethine ylide 24 followed by the pyranone ring opening. The minor product in this reaction was chromonopyrrole 29 (Scheme 9). The authors suggested that compound 29 is formed via the 1,3-cycloaddition of ylide 24 to compound 1a. The yield of product 29 could be increased to 50% reacting 3-formylchromone 1a with N-methylglycine in a 10 : 1 ratio. 46 The reaction of 3-formylchromone 1a, DL-alanine, and dimethyl fumarate in MeOH in the presence of catalytic amounts of AcOH selectively gave diastereomer 30. When fumaronitrile was used as a dipolarophile, a 4.5 : 1 mixture of diastereomers 31a and 31b was obtained in 61% yield (Scheme 10). 49 The course of the reaction of primary hetaryl methaneamines with 3-formylchromone 1a in the presence of TMSCl strongly depends on the reagent ratio. 5-Hetaryl-3-(2-hydroxybenzoyl)-1H-pyrrols 32 were obtained using a molar ratio 1a : amine of 1 : 2, while at a molar ratio 1a : amine of 2 : 1 the only reaction products were chromenopyrrole isofl avone analogs 33 (Scheme 11). 50 The reaction of 3-formylchromone 1a with secondary hetarylmethaneamines is independent of the reagent molar ratio and gives N-substituted salicyloylpyrroles 34 in 61-99% yields (Scheme 12). Ryabukhin and coworkers postulated two possible mechanisms of the TMSCl-activated reaction. 50 First, TMSCl can activate 3-formylchromone 1a via addition to the carbonyl oxygen at C(4). This reaction after some transformation may result in salicyloylpyrroles 32 and 34. Another possible activation route involves addition of TMSCl to the aldehyde group of compound 1a. This reaction pathway could give rise to derivatives 33 as well as to salicyloylpyrroles 32 and 34.

Pyrazoline and pyrazole derivatives of isofl avone analogs can be synthesized by cyclization of chromones bearing 3-positioned ,-unsaturated moiety with either di-starting compounds 40 were synthesized by the SnCl 2 -catalyzed reaction of 3-formylchromones 1 with bromonitromethane followed by acetylation and -elimination reactions.

Compound 41 bearing the pyrocatechol moiety (R 1 = = R 2 = H, R 3 = R 4 = OH) showed antioxidant activity comparable with that of tocopherol and -glucosidase inhibitory activity. It was found that introduction of the hydroxy groups into the chromone core did not significantly increase free radical scavenging activity. 55 The imidazole isofl avone analogs 42 were synthesized by condensation of 3-formylchromones 1 with 1,2-dicarbonyl compounds in glacial AcOH in the presence of ammonium acetate. 56-63 Scheme 15 exemplifi es the synthesis of imidazolyl chromones 42. 56, 57 The role of 1,2-dicarbonyl compound could be played by o-quinones (1,2-naphthoquinone, 9,10-phenanthrenequinone, and substituted isatines) (Scheme 16). 64 The synthesized compounds 43 and 44 were evaluated for their antimicrobial, antifungal, and antioxidant activities. It was shown that glucosidated derivatives 44 are more active than their analogs 43 unsubstituted at the position 7 of the chromone ring.

2-(6-Methyl-3-chromonyl)imidazo [4,5-f ] [1, 10] phenanthrolines 45 were synthesized by condensation of 3-formylchromones 1 with 1,10-phenanth roline-5,6-dione. Compounds 45 were used as the ligands for the synthesis of ruthenium(II) complexes 46 (Scheme 17). 60-63, 65 It was found that ruthenium complexes 46 can intercalate into DNA base pairs and cleave DNA upon irradiation. Thus, complexes 46 after incubation with pBR322 DNA plasmid and irradiation at 365 nm effi ciently cleave supercoiled form of the circular plasmid DNA to nickedcircular form. 52 The reaction of ketone 35 with hydrazine hydrate in DMF 53 and the reaction of ,-dihalo carbonyl derivatives of chromone 38 with hydrazine 54 both aff orded 3-(pyrazol-5-yl) chromone derivatives 39 (see Scheme 13) . Some pyrazolylchromone derivatives 39 were active against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Salmonella typhimurium) bacteria and fungi strains (Candida albicans, Aspergillus niger, and Aspergillus fumigatus). 53, 54 The treatment of nitrovinylchromones 40 with the generated in situ aromatic aldehyde N-methylhydrazones gave pyrazole isofl avone analogs 41 (Scheme 14). 55 The -Hydroxyiminoketones 47 reacted with 3-formylchromone 1a to give 3-(1-hydroxyimidazol-2-yl)chromones 48 (Scheme 18). 66 X-Ray diff raction studies indicated that in solid state compounds 48 existed as N-oxide tautomers 48´. Compounds 48 were reduced to the corresponding imidazolyl chromones 49 by treatment of PPh 3 in glacial AcOH. The three-component reaction of compounds 1a, 47, and benzylamine gave N-benzyl(chromenyl)imidazole N-oxide 50 (see Scheme 18) . 66 The reaction of compound 1a with dimedone monoxime gave rise to the fused derivative 51. 

The TMSCl-promoted addition of the amino acid derivatives to 3-formylchromone 1a could result in either the products of [3+3] cyclocondensation involving the pyrone ring opening or [4+1] recyclization products, 2-chromonylpyrazolidin-5-ones 52 and 53 (Scheme 19). 50

Reagents and conditions: i. TMSCl (4 equiv.), DMF, 100 C, 15 h.

The structure of the product of the reaction of 3-formylchromone 1a with o-phenylenediamine was controversial for several years (Scheme 20). Thus, Fitton and coworkers 67 suggested that the reaction of compound 1a

with o-phenylenediamine in chloroform at room temperature aff orded benzodiazepinone 54, while Ghosh and Khan 68 assigned the Schiff base structure 55 to the product of this reaction in refl uxing EtOH. To the products obtained by oxidation of compound 54 with chloranil in refl uxing xylene 67 and heterocyclization of compound 55 in refl uxing AcOH, 68 the structure of benzo [b] chromeno-[2,3-e] [1, 4] diazepin-13(6H)-one (56) was attributed. Later, Winkler and coworkers suggested 69 that the reaction of 1a with o-phenylenediamine gives dihydrotetraaza [14] annulene 57 and unambiguously confi rmed 70 this structure by X-ray diff raction analysis. A product of oxidation of compound 57 in refl uxing AcOH was found to be 3-(benzimidazol-2-yl)chromone 58 (see Scheme 20) . 69 In order to shorten the reaction time and increase the yields of 3-(benzimidazol-2-yl)chromones 58, the reaction of compound 1 with o-phenylenediamine was performed in the presence of the following catalysts: 3 mol.% of vanadyl sulfate (yield 78% for 8 h) 71 , 1 equiv. of (bromodimethyl)sulfonium bromide (yield 82% for 4 h), 72 and propanesulfonic acid-functionalized silica (yield 84% for 1 h). 73 It is of note that the synthesis of the fused benzodiazepine compounds of type 56 from 2-methyl(phenyl)amino-3formylchromone was described by Ishar and coworkers. 74 Sosnovskikh and coworkers 75 showed that the reaction of o-phenylenediamine with both 3-cyanochromone 59 and 2-amino-3-formylchromone 60 selectively gives (iminomethyl)chromone 61a (Scheme 21). Refl uxing of imine 61a in AcOH for 3 h aff orded 3-(benzimidazol-2-

Reagents and conditions: i. CHCl 3 , ~20 C; ii. chloranil, xylene, refl ux, 15 h; iii. EtOH, refl ux, 1 h; iv. AcOH, refl ux, 4 h. only the self-condensation product, chromonopyrimidine 62 (see Scheme 21). 75, 76 3-Formylthiochromone 63 reacted with o-phenylenediamines and 2-aminothiophenols to give 3-(benzimidazol-2-yl)thiochromones 64. In the case of 2-aminophenol, the reaction yielded the Schiff base 65 (Scheme 22). 77 Condensation of compound 1a with 2-aminothiophenol afforded 3-(benzothiazol-2-yl)chromone 66 (Scheme 23). 78 Structure of product 66 was confi rmed by X-ray analysis. Compound 66 was suggested as chemosensor for cyanide ions, it selectively reacted with the cyanide ions to give disulfi de 67.

The reaction of formylchromones 1 with N-phenylhydr oxylamine gave rise to nitrones 68 that readily reacted with diff erent dipolarophiles 79-84 to aff ord N-phenyl-3-(chromon-3-yl)isoxazolidines 69-71 (Scheme 24). 79,80, 82 The reaction of nitrone 68 with 2 equiv. of dimethyl acetylenedicarboxylate is controlled by the nature of the substituent at the nitrogen atom (Scheme 25). 85 Thus, the alkyl substituents at the nitrogen atom favor the [3+2] cycloaddition of nitrone 68 to dimethyl acetylenedicarb- Reagents and conditions: i. NaOH, H 2 O; ii. EtOH or benzene, refl ux; iii. AcOH, refl ux.

Conditions: i. EtOH (anhydr.), refl ux, 6 h.

yl) chromone 58. It is interesting to note, that refl uxing of anil 61b synthesized by the reaction of compound 60 with 2-aminophenol gave no the expected 1,3-benzoxazole but oxylate to give dihydroisoxasole derivatives 72, whereas N-phenyl derivatives selectively produce the fused compounds 73. It is of note that the highest yields of compounds 73 were achieved in the presence of 1.2 equiv. of PPh 3 but additives of PPh 3 have no eff ect on the yield of compounds 72.

Treatment of 3-formylchromones 1 with hydroxylamine in acidic media gave substituted 3-cyanochromones 59.

The AlCl 3 -catalyzed reaction of compounds 59 with sodi um azide resulted in 3-(1H-tetrazol-5-yl)chromones 74 with antiallergic activity (Scheme 26). 86- 91 2-Substituted 3-(1H-tetrazol-5-yl)chromones 76 show antimicrobial activity against S. aureus, E. coli, B. subtilis, Pseudomonas aeruginosa and antifungal activity against C. albicans and A. niger with minimal inhibitory concentrations comparable with that of the reference drugs More convenient synthetic approach to compounds 75 that allows widely vary aryl and hetaryl substituents in the oxadiazole moiety is intramolecular cyclization of (3-formylchromone)aroyl hydrazides 77. This reaction can be enabled by treatment of compounds 75 with either bromine and sodium acetate in basic medium 94,95 or diacetoxyiodobenzene in dichloromethane 96 (Scheme 27). The replacement of primary amine with aromatic 1,2-diamine led to the fused derivatives 81 with thiazolidine moiety (Scheme 29). 100 It was found that antimicrobial activity of compounds 81 is lower than that of the reference drugs Ciprofl oxacin and Griseofulvin.

3-Formylchromones 1 reacted with 2 equiv. of thiobenzamide in refl uxing toluene to give 3-(5-phenyl-3H- [1, 2, 4] dithiazol-3-yl)chromones 82. 101 Under these acid under microwave irradiation conditions gave imidazo[1,2-a]pyridine isofl avone analogs 84 (Scheme 30). 102 Instead of microwave activation, this reaction can be performed in an eutectic mixture of choline chloride and urea (1 : 2) that also plays the role of an organocatalyst. 103 3-Aminothiazoles and 2-aminobenzothiazoles in this reaction produced derivatives of imidazo [ Scheme 30) . 104 The prolonged refl ux of a mixture of 2-amino-3-formylchromone 60, isocyanide, and 2-aminopyridine, 2-aminopyrazine or 2-aminopyrimidine in MeOH in the presence of TsOH/ZnCl 2 resulted in derivatives 87-89 (Scheme 31). 105

Synthetic approaches to pyridine isofl avone analogs were briefl y outlined in previous Section (see Schemes 6 and 7) .

The Hantzsch reaction involving 3-formylchromones 1 proceeded ambiguously. In the early works, 106 structure of 1,4-dihydropyridine 90 was ascribed to the product of the reaction of compound 1 with ethyl acetoacetate and liquid ammonia in methanol. However, later 107 these The Groebke-Blackburn-Bienaymé three component reaction between 3-formylchromones 1, 2-aminoazine (2-aminopyridine), and isocyanide in methanol in the presence of catalytic amounts of InCl 3 and chloroacetic results were revised. The structure of the reaction product is determined by the nature of the CH acidic component (Scheme 32). 107 Thus, under the Hantzsch reaction conditions 3-formylchromones 1 reacted with acetoacetic acid esters and ammonia to give benzopyranopyridines 91. These products were also obtained by the reaction of compounds 1 with enamines derived by treatment of the corresponding dicarbonyl compounds with liquid ammonia in refl uxing alcohol. The reaction of 3-formylchromone 1 with acetylacetone, diethyl malonate, ethyl cyanoacetate and ammonia (or ammonium acetate) aff orded salicyloylpyridines 92. 107 Recently, several attempts have been made to develop the synthesis procedures to access 1,4-dihydropyrid-ine isofl avone analogs. The solvent-free reaction of 3-formylchromone 1, ethyl acetoacetate, and ammonium acetate catalyzed with Wells-Dawson heteropolyacids H 6 P 2 W 18 O 62 •24H 2 O gave a mixture of the corresponding dihydropyridines 90 and 5-salicyloylpyridines 92. 108 However, under these conditions the main reaction products were salicyloylpyridines 92. The use of the Bi 2 WO 6 nano particles to catalyze this reaction in aqueous media at room temperature gave rise to dihydropyridine 90 (R 1 = H, R 2 = Et) in 92% yield. 109 Firuzi and coworkers 110 described the similar reaction of 6(7)-hydroxy-3-formylchromones with -ketoesters and ammonium acetate, which in the presence of Ba(NO 3 ) 2 as a catalyst in refl uxing EtOH gave the corresponding hydroxy derivatives 93

Cy is cyclo-C 6 H 11 . in 62-66% yields. Acylation of hydroxy derivatives 93 with acetic and hexanoic anhydrides furnished compounds 94. It was found that derivatives 94 inhibit β-secretase (BACE-1), an aspartyl protease responsible for amyloid- production and one of the promising targets in the treatment of Alzheimer´s disease. The derivatives bearing the substituents at the position 7 of the chromone ring system were found more active than 6-substituted analogs. Moreover, the 7-acetyl-substituted derivatives were more active than 7-hexanoyloxy analogs. The most potent BACE-1 inhibitor was 7-acetoxy derivative 94 (R 1 = 7-OAc, R 2 = Et, R 3 = Me) with 51.32% enzyme inhibition at 10 mol L -1 .

Gorlitzer and Michels 111 reported that 3-formylchromone 1a reacted with aminocrotonates to give mixtures of isomeric dihydropyridines 90 and 95 (Scheme 33), however more recent publications contradict this result. Thus, Ryabukhin and coworkers 112 obtained only product 90 (R = Et) in 76% yield by performing this reaction in DMF in the presence of the four-fold excess of TMSCl under ultrasound activation conditions.

The amount of the side salicyloylpyridines 92 could be reduced by step-by-step synthesis of 1,4-dihydropyridine derivatives. 113 Variation of the CH-acidic components in the Hantzsch synthesis provided a wide structural variety of 1,4-dihydropyridine isofl avone analogs. For instance, the microwaveassisted condensation of 3-formylchromone 1a with 3-methyl-1-phenylpyrazol-5(4H)-one (2 equiv.) and ammonium acetate in PEG-400 resulted in the fused system 96. Compound 96 showed antimicrobial activity comparable to that of the reference drug Penicillin and moderate antifungal activity. 114 Derivative 97 was synthesized by the reaction of 6-formylfurochromone 1b, malononitrile, and ammonium acetate. 115 Unsymmetrical 1,4-dihydropyridines can be obtain ed by the Hantzsch synthesis using two diff erent di carbonyl compounds. Thus, Arumugam and Perumal 116 successfully synthesized tetrahydroquinoline derivative 98 (in 93% yield) by four-component condensation of 3-formylchromone 1a, dimedone, methyl acetoacetate, and ammonium acetate. Condensation of 3-for m yl chromones 1, 2-aminochromone as an amine, and dimedone or 1,3-cyclohexanedione as a C-nucleophile gave the fused systems, 11-(chromon-3-yl)-8,9-dihydro-6H-chromeno[2,3-b]quinolin-10,12(7H,11H)-diones 99 (Scheme 35). 117 The highest yields of the target products were achieved by carrying out the reactions in 0.5 M aqueous sodium dodecyl sulfate (SDS). The authors suggested 117 that a plausible mechanism leading to compounds 99 involved the condensation of formylchromones 1 with CH acid (dimedone or 1,3-cyclohexanedione), 1,4-addition of enamine (2-aminochromone) to the Knoevenagel adduct, and subsequent cyclization.

Successive treatment of compounds 1 with malononitrile and cyanoacetic acid hydrazide gave compounds 100a-c whatever reaction sequence was used (Scheme 36). [118] [119] [120] Diaminodihydropyridines 100 were the starting compounds for the synthesis of a large series of isofl avone hetero analogs. Thus, the reaction of compound 100c with acetic anhydride, ethyl formate, 6-chloro-3-formylchromone (1, R = 6-Cl), and chromone-3-carboxylic acid yielded [1, 2, 4] 120 Ali and Ibrahim 120 examined antimicrobial activity of the synthesized compounds and found that the highest activity is exhibited by compounds 102-104.

The reaction of 3-formylchromone 1a, aromatic amine, and 1-vinylpyrrolidin-2-one in aqueous MeCN catalyzed by 5 mol.% of ceric ammonium nitrate (CAN) aff orded tetrahydroquinolines 112. Condensation of 2-amino-3-formylchromone 60 with 5-hydroxydopamine gave tetrahydroquinoline isofl avone analog 114. 122 The iodine-catalyzed reaction of compound 1a with tryptamine (the Pictet-Spengler reac-

Ar = 4-ClC 6 H 4 tion) furnished 1,2,3,4-tetrahydrocarboline isofl avone analog 115. 123 Tetrahydropyrimidine isofl avone analogs can be synthesized by the Biginelli reaction. Thus, the three-component condensation of 3-formylchromones 1, urea, and -ketoesters was used to synthesize a series of (chromonyl)- 126 showed that antibacterial activity of compounds 117 against E. coli 1411 is comparable to that of the reference drug Cycloserine and its antifungal activity is equal to that of the standard drug Miconazole.

Tetrahydropyrimidine isofl avone analogs can be synthesized by the solvent-free Biginelli-type reaction catal yzed by either sulfated silica tungstic acid 127 or TsOH 128 (Scheme 41). The reaction of 3-formylchromones 1, urea, and ethyl cyanoacetate or phenylacetic acid aff orded compounds 118. The use of ethyl acetoacetate gave rise to product 119. 6-Formylfurochromone 1b similarly reacted with acetoacetic esters and acetylacetone to give the corresponding products 120 (see Scheme 41) . The yields and purity of the target products could be enhanced by performing the reaction under microwave irradiation conditions. The reaction of formylchromones 1 with aromatic acid amino amides can be employed for the synthesis of quinazoline derivatives. Thus, upon heating of formylchromones 1 with either 2-aminobenzamide in DMSO for 20 h 133 or 2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide in DMF for 3 h 134 under aerobic conditions, the initially formed dihydroquinolines are oxidized to give quinazolinones 124 133 and 125. 134 The solvent-free Lewis acid-catalyzed reaction of compound 1a, primary aromatic amine, and isatoic anhydride aff orded N-phenyl-2,3-dihydroquinazolinones 126. Siddiqui and coworkers demonstrated that LaCl 3 supported on nano sized silica (nano-SiO 2 ) most effi ciently catalyzed this reaction (Scheme 42). 135 Four-component condensation between 3-formylchromone 1a, isatoic anhydride, hydrazine, and 2-sulfobenzimide that is used as a source of the sulfonamide moiety gave rise to (chromonyl)quinazolinones 127 (Scheme 43). 136 The reaction was performed under solvent-free conditions using propylsulfonic acid-functionalized mesoporous silica (SBA-Pr-SO 3 H) as a catalyst.

Compounds 128, the adducts of 3-formylchromones 1 with Meldrum's acid, reacted with substituted amides and anthranilic acid hydrazides under acid catalysis conditions to produce N-substituted 2,3-dihydroquinazol inones 129 in 48-84% yields (Scheme 44). 137 The same reaction under basic catalysis conditions gave rise to pyridin-2-one derivatives 130 (Scheme 44). 137 Acid-catalyzed condensation of 3-formylchromones 1 with 2-aminophenylpyrrole resulted in 4,5-di hydropyrrolo [1,2-a]quinoxaline isoflavone analogs 131 (Scheme 45). 138,139 Using AcOH as a catalyst, pyrrolo-[1,2-a] quinoxaline 131a was obtained in 86% yield. 138 Rashidi et al. 139 reported the synthesis of compound 131b in aqueous media under catalysis with ionic liquid [PPy] HSO 4 supported on nano-sized silica ([PPy]HSO 4 •nano-SiO 2 ). Under these conditions, 98% yield of the target product 131b was achieved. Tang and coworkers 140 expanded the substrate scope of this reaction and used 1-(2-aminophenyl)-3-methylindole as a substrate and N-oxoammonium salt [TEMPO] + PF 6 as a catalyst. Under these conditions, the reaction produced 5,6-di hydroindolo[1,2-a]quinoxaline 132 in 86% yield (see Scheme 45) . 140 Dihydropyrazinones 134 were synthesized by the reaction of 3-formylchromone 1a, isocyanides, substituted anilines, and 2-azidoacetic acid (Scheme 46). 141 Bazgir and coworkers 141 believe that the four-component Ugi reaction initially produced intermediates 133 that further underwent PPh 3 -catalyzed intramolecular aza-Wittig cyclization.

Dihydroquinoxaline isofl avone analogs 135 were synthesized by three-component TsOH-catalyzed condensa-tion of compound 1b, o-phenylenediamine, and isocyanates (Scheme 47). 142 The reaction of 3-formylchromone 1a with 2 equiv. of dimedone 136a in pyridine at room temperature followed by treatment with concentrated HCl and recrystallization from EtOH acidifi ed with HCl gave 3-(3,3,6,6-tetra- H (131a, 132) , Cl (131b); R 2 = R 3 = R 4 = H (131a,b);

Reagents, conditions, and yields: i (for 131a). AcOH (cat.), EtOH, 50 C, 5-10 min, 86%; ii (for 131b). Deshmukh and coworkers 144 studied the reaction of 3-formylchromones 1 with (hetero)cyclic 1,3-dicarbonyl compounds 136a-g (Scheme 49). The reaction was carried out at a ratio 1 : 136 of 1 : 2 in 50% aqueous EtOH in the presence of (±)-camphorsulfonic acid as a catalyst. The reaction of 3-formylchromones 1 with active methylene compounds 136a-e gave pyrone isofl avone analogs 137, while the reaction of compounds 1 with barbituric acid (136f) and 1,3-indanedione (136g) gave rise to only the corresponding Knoevenagel adducts 138 that do not react with the second molecule of active methylene compound.

The functionalized pyran isofl avone analogs 139 and 140 were synthesized by three-component reaction involving 3-formylchromone 1a, malononitrile and either di- 

medone or β-naphthol in the presence of bismuth tungstate as a catalyst (Scheme 50). 109 Panja et al. 145 

Reagents and conditions: i. Bi 2 WO 6 (5 equiv.), H 2 O, ~20 C, 10 min.

Cy is cyclohexyl. Similarly to 2´-hydroxychalcones, compounds 143 that were synthesized by condensation of 3-formylchromones 1 with substituted 2-hydroxyacetophenones underwent cyclization to give chromenochromone derivatives 144. 146 Intramolecular cyclization of derivatives 143 resulting in 2,3´-bischromones is also known. 147, 148 Thus, microwave-assisted reaction of compounds 143 with CuBr 2 gave rise to 3-bromo-substituted 2,3´-bischromones 145. 147 2,3´-Bischromones 146 were synthesized by prolonged refl ux of compounds 143 with selenium dioxide in isoamyl alcohol (Scheme 52). 148 Gabr and coworkers 149 demonstrated that the product of condensation of 6-chloro-3-formylchromone with 4-acetyl-5,6-diphenylpyridazin-3(2H)-one in the presence of piperidine underwent similar cyclization to give compound 147.

Isofl avone analogs with seven-membered heterocycles can be synthesized by the reaction of the chromone derivatives 148 bearing enone moiety with binucleophiles. Albanese et al. 152 demonstrated that the use of perfl uorinated solvents, e.g., hexafl uoropropan-2-ol, allows increasing the product yields. The authors believe that due to its high acidity hexafl uoropropan-2-ol can activate both the carbonyl and thiol groups via hydrogen bonding and behave as a proton shuttle.

Three-component condensation of 3-formylchromones 1, o-phenylenediamine, and 3-acetyl-4-hydroxycoumarin catalyzed by nano silica-supported N-propylsulfamic acid resulted in 4-hydroxy-3-[2-(4-oxo-4Hchromen-3-yl)-2,3-dihydro-1H-benzo[b] [1, 4] diaze pin-4-yl]-2H-chromen-2-ones 151. 154 The use of dimed one as a CH acidic component gave rise to the fused 3,3-dimethyl-11-(4-oxo-4H-chromen-3-yl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e] [1, 4] diazepin-1-ones 152. 155 The reaction requires no solvent and can be also catalyzed by silica-supported Fe(OTs) 3 . 

Homoisofl avonoids are the homologs of isofl avonoids and constitute a small family of natural oxygen heterocycles, the derivatives of 3-benzylchromone (chromanone) or 3-benzylidenechromanone. These compounds show antioxidant, anti-infl ammatory, antimutagen, antimicrobial, and antiviral activities. Some natural homoisofl avonoids show the cytostatic eff ects against diff erent cancer cell lines and inhibit angiogenesis. It was also found 157 that these compounds are capable of inhibiting phosphodiesterases type IV and V. Despite the extensive studies over the last decades in chemistry of benz--pyrone derivatives, homoisofl avones are far less explored.

The simplest synthetic approach to 3-[di(hetaryl)methyl]-4H-chromen-4-ones is the reaction of nucleophilic (-rich) heterocycles (indoles, pyrroles) with 3-formylchromones 1. [158] [159] [160] [161] [162] [163] [164] Thus, Sosnovskikh and coworkers 158,163 described the synthesis of 3-[di(1H-indol-3-yl)methyl]-4H-chromen-4-ones 156a-h. Solvent-and catalyst-free reaction of 3-formylchromones 1 with excess (3 equiv.) of indole, 1-methylindole, or 2-methylindole gave the target products 156a-h in the yields from moderate to high (51-79%). 158 The authors emphasized that the poorly separable mixtures were obtained when the reactions were carried out in solvent or under both acidic and basic catalytic conditions; while, the presence of electron-withdrawing substituents in the chromone ring system facilitated polymerization of the reaction mixture. Compound 156i was synthesized in butanol in the presence of perchloric acid as a catalyst. 158 Product 156j was prepared by heating the corresponding reagents in aqueous medium. 158 Compounds 156 were synthesized but in lower yields using 1 equiv. of indoles. 163 (162) . 162 Microwaveassisted indium trifl ate-catalyzed reaction of 3-formylchromone 1a, substituted indoles, and anilines gave rise to 3-[(1H-indol-3-yl)(arylamino)methyl]-4H-chromen-4-ones 163 in 70-83% yields and the corresponding (chromon-3-yl)bis(indol-3-yl)methanes 156 as the side products. 167 Prajapati and coworkers 167 believe that imines generated by the reaction of 3-formylchromone 1a and anilines underwent the nucleophilic attack with indole to give the target products 163 but competitive elimination of amine followed by the condensation of intermediates with the second indole molecule led to the minor products 156.

The four-component condensation of 3-formylchromones 1, anilines, isocyanides, and azidotrimethylsilane Compounds 164 show antiprotozoal activity against Entamoeba histolytica, Giardia lamblia, and Trichomona vaginalis. Despite the fact that activity of compounds 164 was lower than that of the reference drug Metronidazole, they are regarded as suitable alternatives for the antiparasitic treatment of metronidazole-resistant strains. 168 Fluoro-and iodo-substituted derivatives 164 exhibited the highest antimicrobial (P. aeruginosa and S. aureus), antiprotozoal (E. histolytica), and antifungal (Sporothrix schenckii, C. albicans, and Candida tropicalis) activities. 169 Mehrparvar et al. 170 demonstrated the possibility to introduce the carbonyl group into the (chromonyl)hetarylmethane core. The successive treatment of 3-formylchromones 1 with Meldrum's acid, 4-hydroxycoumarin (10) or 4-hydroxy-6-methylpyran-2-one (11) 

This diff erence in the structure of the products Mehrparvar et al. 170 rationalized by the relative ease of addition of primary alcohols to the ketene moiety of the intermediates formed by the Michael addition of deprotonated form of 4-hydroxycoumarin 10 and 4-hydroxy-6-methylpyran-2-one 11 to the Knoevenagel intermediates and subsequent elimination of acetone. The Knoevenalgel adducts are resulted from the reaction of 3-formylchromone and Meldrum´s acid. When the reaction was carried out in propan-2-ol no addition of alcohol to ketene occurred. As the authors suggested, the hydroxy group of 4-hydroxycoumarin played a role of nucleophile. Its addition to ketene and subsequent decarboxylation gave rise to lactone 166. 170 3-[(2-Oxo-5-arylfuran-3(2H)-ylidene)methyl]-4Hchromen-4-ones 167a-d were synthesized by the reaction of 3-formylchromones 1 with β-aroylpropionic acids, and (chlorosulfi nyloxy)-N,N-dimethylmethaneiminium chlor ide (154) (Scheme 60). 171, 172 The treatment of (furanylidene)methylchromenone 167d with ammonium acetate in EtOH gave pyrrolone 168. The structure of the product formed in the reaction of compound 167d with hydrazine is determined by the solvent nature. In benzene, [(phenylpyridazin-4-yl)methyl]chromenone 169 is formed, while in ethanol [(phenylpyridazin-4-yl)methyl]quinolinone 170 was obtained. The reaction of compound 167d with phenylhydrazine aff orded chromylidene pyridazinone deriv ative 171 (see Scheme 60). 172 Derivatives 167d and 168-171 showed moderate antimicrobial activity. The most promising compound 167d inhibited the growth of E. coli and S. aureus, however its activity was lower than that of amoxicillin. Compound 167d also exhibited antifungal activity against C. albicans. 172 Venkateswararao et al. 173 It is of note that derivatives of type 175 (R 1 = R 2 = H) are the main products of the reaction of 3-formylchromone 1a with iron pentacarbonyl (2 equiv.) and hexamethapol (4 equiv.). 174 Compounds 174 and 175 were evaluated for their ability to inhibit the growth of the following cancer cell lines: prostate cancer PC-3, lung adenocarcinoma NCI-H23, breast cancer MDA-MB-231, colorectal adenocarcinoma HCT-15, gastric cancer NUGC-3, and renal adenocarcinoma ACHN. 173 It was found that the most active compounds contain cyclohexylmethoxy group at the position 5 of one of the chromone cores and electron-releasing substituents (Me, OMe) or hydrogen-bonding groups (OH) at the position 7 of another. Reduction of the Reagents and conditions: i. 1) CH 2 Cl 2 , 0 C, 2) Et 3 N, 20 C, 5 h; ii. AcONH 4 (4 equiv.), EtOH (anhydrous), refl ux, 2 h; iii. NH 2 NH 2 •H 2 O, benzene, refl ux, 2 h; iv. NH 2 NH 2 •H 2 O (2 equiv.), EtOH (anhydrous), 20 C, 4 h or refl ux, 1 h; v. PhNH 2 NH 2 , EtOH (anhydrous), refl ux, 30 min. double bond in one of the chromone moieties decreased the activity. 173 2-Aryl-and alkylamino-substituted 3,3´-methyl enebis[2-aryl(alkyl)amino-4H-chromen-4-ones] 176 were synthesized by heating 3-formylchromones bearing 2-positioned secondary amino group with the formaldehyde excess in DMF in the presence of secondary amine (piperidine or diethylamine). 175 Condensation of 3-formylchromones 1 (R = H, Br) and 2-amino-3-formylchromones (60) with chromanone in EtOH in the presence of piperidine gave the corresponding (E)-3-[(4-oxochroman-3-ylidene)methyl]-4H-chromen-4-ones 177. 176 Compounds 177 (and especially 2-amino derivatives) binds with calf thymus DNA presumably by intercalation. Amino derivative 177 (R 1 = H, R 2 = NH 2 ) also effi ciently inhibit acetylcholinesterase being only slightly inferior to reference drug Tacrine. 177 It is of note that compounds 179 were also synthesized by the piperidine-catalyzed reaction of -ketoacid 178 with the corresponding 3-cyanochromones. 177 Condensation of 3-formylchromones 1 with benzofuran-2-ones, benzofuran-3-ones, naphthofuran-2-ones, and naphthofuran-3-ones produced the corresponding derivatives 180-183 that can be regarded as chromonebased aurone analogs. 178,179 Anticancer activity of compounds 180-183 was tested in vitro against the murine L1210 leukemia cell line. Compound 183 (R = H) was found to be most active with IC 50 = 1.6 mol L -1 . 178 Among the synthetic aurone analogs evaluated against K562 chronic myeloid leukemia cells, derivative 181 (R 1 = 6-Me, R 2 = Me) was found the most active. the K562 cell cycle in G1 phase and induced about 24% apoptosis. 179 The replacement of the chromone moiety with coumarin core aff orded compounds 184 capable of blocking the cell cycle in G2 phase. 179 The (Z)-3-[(4-oxo-4H-chromen-3-yl)methylene]indolin-2-one derivatives 185 were synthesized by condensation of 3-formylchromones 1 with indolinones. 180, 181 Compound 185a showed pronounced anticancer activity inhibiting growth of 60 human cancer cell lines with the average GI 50 values of 3.2 mol L -1 . 180 Compounds 185b,c were found to be selective inhibitors of cyclooxygenase-2 (IC 50 of 29-20 mol L -1 , selectivity indices of 46 and 337, respectively). Compound 185b exhibited an analgesic potential higher than Diclofenac. 181 Compounds 188 are the agonists of PPAR- receptors activation of which lowers the glucose level in blood at type 2 diabetes. Compounds 188 were as eff ective in lowering the blood glucose level as the standard drug Pioglitazone. The authors noted that derivatives 188 exhibit no hepatotoxicity, which is the major drawback encountered for such commercial thiazolidinone antidiabetic drugs as Pioglitazone and Rosiglitazone. Compounds 189 with the reduced double bond at the chromone core were found inactive. 184

From the data summarized in the present review, one can conclude the high promise of the development of chemistry of heterocyclic analogs of natural compounds, isofl avone and homoisofl avone, based on readily available and highly reactive 3-formylchromone. The developed synthetic approaches are not limited only to the construction of heterocyclic cores based on the formyl group. The reactions are often accompanied by diff erent recyclizations involving the C(2) nucleophilic center. This forms the basis for multicomponent reactions and allows the library synthesis of heterocyclic isofl avonoid analogs and thus accelerated the search for the most promising compounds in terms of biological activity. Additional synthetic pos-sibilities are off ered by the use of the simplest 3-formylchromone derivatives, namely, 3-cyanochromone, 2-amino-3-formylchromone, and the products of its condensation with C-and N-nucleophiles, as the starting materials. The considered synthetic approaches allow environmentally friendly synthesis of low-toxic compounds showing a wide spectrum of pharmacological activity.

The Handbook of Medicinal Chemistry: Principles and Practice

Prirodnye i modifi tsirovannye isofl avonoidy [Natural and Chemically

Izbrannye metody sintesa i modifi catsii geterocyclov [Selected Methods of Synthesis and Modifi cation of Heterocycles

Access to Flavonoids through Cross-Coupling Reactions

This work was fi nancially supported by the Russian Foundation for Basic Research (Project No. 19-13-50232).This work does not involve human participants and an imal subjects.The authors declare no competing interests.

Condensation of 3-formylchromone 1a with hydantoin, thiohydantoin, and thiazolidin-2,4-diones gave derivatives 186a-c showing insulinotropic activity. At concentration of 1 g mL -1 in the presence of 5.6 mol L -1 glucose, these compounds are able to increase insulin release; however, their activity is lower than that of glibenclamide. 182 Dundar and coworkers 183 synthesized a large series of adducts of 6-methyl-3-formylchromone 1 (R = 6-Me) with hydantoin, thiohydantoin, and thiazolidin-2,4-dione, for example, compounds 186d-f. As promising insulinotropic agents, derivatives 186g-j and 187 alkylated at the N(3) nitrogen atom and thioxo group were also synthesized. 182,183