Fluorinated Pyrones, Chromones and Coumarins

Sosnovskikh, Vyacheslav Ya.

doi:10.1007/978-3-319-04435-4_5

Vyacheslav Ya. Sosnovskikh²

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8 Citations

Abstract

The synthesis, reactivity and applications of fluorinated α- and γ-pyrones, chromones and coumarins are reviewed. The literature data clearly indicate that these heterocycles are very attractive building blocks for the synthesis of various heterocyclic compounds containing the R^F group. This chapter reviews the significant advances in this area, highlighting new and interesting trifluoromethylated derivatives and their novel transformations. The bibliography includes 204 references.

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Chemistry of Fluorinated Indoles

Fluorinated Indolizines

Chemistry of Fluorinated Pyrroles

Keywords

1 Fluorinated 4-Pyrones

4H-Pyran-4-ones (4-pyranones, 4-pyrones, γ-pyrones) containing polyfluoroalkyl substituents, especially the CF₃ group, serve as key precursors to a variety of fluorinated pyridine derivatives having a wide range of biological activities. For example, 2,6-bis(trifluoromethyl)-4-pyridols have been found useful as herbicides and fungicides as disclosed in patent literature [1a, b]. Certain 2-aryl-6-tri(di)fluoromethyl-4-pyrones selectively inhibit COX-2 in preference to COX-1 and are useful in the treatment of COX-2 mediated diseases, such as inflammation, pain, fever, and asthma with fewer side effects [1c]. Due to the powerful electron-withdrawing ability of R^F groups the insertion of polyfluoroalkyl substituents into the 2-position of 4-pyrone activates these molecules and dramatic differences in the reactivity of 2-alkyl(aryl)- and 2-(polyfluoroalkyl)-4-pyrones with respect to nucleophilic reagents are observed.

1.1 Synthesis of 2-(Polyfluoroalkyl)-4-Pyrones

In addition to the considerable variety of methods for the synthesis of non-fluorinated γ-pyrones [2], Tyvorskii and co-workers have described three new procedures, which produced 2-(perfluoroalkyl)-4-pyrones. One of them is a convenient two-step synthesis of 5-substituted 2-(perfluoroalkyl)-4H-pyran-4-ones 2 by dehydration of 2,3-dihydro-3-hydroxy-6-(perfluoroalkyl)-4H-pyran-4-ones 1 prepared by condensation of 2-acetyloxiranes with ethyl perfluoroalkanoates [3]. The reaction of dihydropyranones 1 with thionyl chloride in pyridine provides the desired pyrones 2 in 61–79 % yields with 10–15 % of chlorine-containing dihydropyrones 3. Pure compounds 2 were prepared in good yields by the treatment of 1 with SOCl₂ followed by reflux of the crude products in Et₃N [4] (Scheme 1).

Additionally, unsubstituted and 6-substituted 2-(perfluoroalkyl)-4H-pyran-4-ones 4 have been prepared using alkyl enolates derived from β-dicarbonyl compounds. The reaction of acetylacetone enol ether with ethyl perfluoroalkanoates in the presence of t-BuOK, followed by p-TsOH catalyzed cyclization in benzene afforded pyrones 4a,b in 57–75 % yields. Similarly, the parent compounds 4c,d were obtained from the formylacetone derivative in 40–64 % yields [4]. Analogue 4e was accessible in low yield from the corresponding triketone [5] (Scheme 2).

The alternative way to 5-aryl substituted γ-pyrone 2a,b is based on the readily available aminoenones 5a,b. Reaction of 5a,b with ethyl trifluoroacetate in the presence of t-BuOK afforded enamino diketones 6a,b cyclized to pyrones 2a,b [6]. Compounds 6b and 2b are starting materials for the preparation of 4-pyridones exhibited potent antimalarial activity [5] (Scheme 3).

The ready availability of pyrones 2 and the enhanced reactivity at their α-position have made them the starting materials of choice for the synthesis of 2-(trifluoromethyl)-4-pyridinols 7 by reaction with ammonia or methylamine [6–8] (Scheme 4).

Trifluoromethylated pyrones can also be prepared from acyl chlorides by reaction with pyridine and trifluoroacetic anhydride followed by capture of the intermediate trifluoroacyl ketene 8 with suitable reagents. Thus, addition of N-cyclohexenylmorpholine to the intermediate from palmitoyl chloride gave pyrone 9 as the major product, accompanied by amide 10. Ethyl vinyl ether yielded pyrones 11a and 11b (through β-elimination of ethanol) [9] (Scheme 5).

Acylketene methodology [10] was also developed for the synthesis of 4-pyrones bearing a polyfluoroalkylthio substituent. The reaction of ethyl trifluoroacetoacetate with fluoroalkanesulfenyl chlorides afforded compounds 12 (Scheme 6).

The latter reacting with P₂O₅ gave rise to fluoroalkylthio(trifluoroacetyl)ketenes 13, which were demonstrated to act as heterodienes in the Diels–Alder reaction with phenylacetylene to form 4-pyrones 14 [11]. Langer et al. reported that the Me₃SiOTf-mediated cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes 15 with 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one resulted in the formation of trifluoromethylated pyran-4-ones 16 [12] (Scheme 7).

Condensation of 2-acetyldimedone with ethyl trifluoroacetate in the presence of LiH afforded tetraketone 17 in 65 % yield existing in CDCl₃ as an equilibrium mixture of 17a and 17b. In a mixture of DMSO-d ₆ and CCl₄, 17 occurs as cyclic hemiketal 17c (95 %) and open forms 17a and 17b (5 %). Treatment of 17 with concentrated H₂SO₄ at ~20 °C for 5 h afforded the carbofused 4-pyrone 18 [13] (Scheme 8).

If dehydroacetic acid is used as the methylene component in the condensation with R^FCO₂Et under the same conditions, the reaction gives fluorine-containing pyrones 19, which underwent cyclization to 2-(polyfluoroalkyl)-7-methylpyrano[4,3-b]pyran-4,5-diones (20) on treatment with H₂SO₄ [14].

The reaction of ethyl 2,4-dioxopentanoate with ethyl trifluoroacetate in the presence of NaOEt leads to ester 21a. This ester is smoothly hydrolyzed to acid 21b by reflux in 20 % HCl, whereas its treatment with 20 % ammonia depending on conditions applied affords amides 22 and 23 in high yields [15]. Decarboxylation of 6-(trifluoromethyl)comanic acid (21b) gave 2-(trifluoromethyl)-4H-pyran-4-one (4c) [4, 16] (Scheme 9).

1.2 Reactions of 2-(Polyfluoroalkyl)-4-Pyrones

Obydennov and Usachev have reported [17] that 2-R^F-4-pyrones 21a–d react with aniline and o-aminophenol under acidic conditions to give the corresponding 2-RF-1-aryl-4-pyridones 24. Their reaction with o-phenylenediamine in the presence of HCl gave R^F-bearing benzodiazepines 25 and quinoxalin-2-ones 26 (Scheme 10).

In the absence of a strong acid, compounds 27 can be prepared as a mixture of two tautomers (R^F=CF₃, 27: 27′ = 21: 79; R^F=CF₂H, 27: 27′ = 65: 35) from the reaction of 6-R^F-comanic acids 21b,d with o-phenylenediamine. To transform 27′ into more conjugated tautomers 27 the mixtures were heated in DMSO at 80–120 °C. Under the same conditions reaction of pyrone 21b with o-aminophenol led to the formation of benzo[b][1,4]oxazin-2-one 28 [17] (Scheme 11).

It was also reported that acid 21b reacts regioselectively with phenylhydrazine in water to give 1-phenylpyrazole-3-carboxylic acid 29. Similar reaction in dioxane leads to 1-phenylpyrazole-5-carboxylic acid 30. A strong solvent influence on the reaction route was also found for 6-(trifluoromethyl)comanic acid derivatives 21a and 22 [18]. The reaction of 21b with N₂H₄ · 2HCl (2.2 equiv.) in water gave a mixture of regioisomeric pyrazoles from which 3-(trifluoromethyl)pyrazole 31 was isolated in 30 % yield. Phenylhydrazones 29 and 30 as well as phenylhydrazone from pyrazole 31 were converted into 3-(pyrazolyl)indoles 32 and 33, and indole-2-carboxylic acid 34, by heating in MeSO₃H with P₂O₅ [19] (Scheme 12).

Pyrones 21a,b react with aminoguanidine to give 5-CF₃-pyrazolo[1,5-c]pyrimidines 35a,b as the major products, while the reaction of their precursor, ethyl 7,7,7-trifluoro-2,4,6-trioxoheptanoate (36), with the same polynucleophile gave regioisomeric 2-CF₃-pyrazolo[1,5-c]pyrimidines 37. On the other hand, the reaction of 21a and 36 with thiosemicarbazide affords 38 and 39 in low yield [20] (Scheme 13).

Dehydration of pyronecarboxamide 22 with trifluoroacetic anhydride in the presence of pyridine leads to the formation of 2-cyano-6-(trifluoromethyl)-4-pyrone (40) in 61 % yield. The reactions of this cyanopyrone with N-nucleophiles can proceed with or without substitution of the cyano group to give a wide range of novel trifluoromethylated compounds. Thus, cyanopyrone 40 easily reacted with aliphatic and aromatic amines in EtOH at −20 °C and o-phenylenediamine in acetic acid to produce carbamoylated aminoenones 41 and benzimidazole 42. Treatment of 41 with DMF-DMA in toluene under ambient conditions for 24 h gave 4-pyridone-3-carboxamides 41a in 31–68 % yields. The regiochemistry of the reactions of 40 with hydrazine and phenylhydrazine in EtOH is similar to those observed in the case of the amine attack. These reactions afforded derivatives of 2-(3-trifluoromethylpyrazol-5-yl)acetic acid 43, whereas the reaction with phenylhydrazine in toluene resulted in the formation of phenylhydrazone 44 in 33 % yield. The reaction between 40 and hydroxylamine in ethanol proceeds by the nucleophilic addition to the cyano group to give amidoxime 45. Heating this compound with trifluoroacetic anhydride in the presence of pyridine gave pyrone 46 in high yield [21] (Scheme 14).

1.3 Synthesis and Reactions of 2,6-bis(Polyfluoroalkyl)-4-Pyrones

The first synthesis of 4-pyrone derivatives with two CF₃ groups was reported in 1988 by Lee and co-workers [22]. Acetone dicarboxylic acid monomethyl ester 47 reacted with isobutylene in sulfuric acid to form 48. Subsequent reaction with MgCl₂ and trifluoroacetic anhydride led to pyrone 49. This compound was converted to the monoester 50, which gave pyrone 51. The latter was reacted with ammonia in methanol to form 4-hydroxypyridine 52 [22] (Scheme 15).

Diester 53 was obtained by the one-pot transformation of a magnesium diacetonedicarboxylate complex using trifluoroacetic anhydride [23] (Scheme 16).

Babu et al. reported that 3-acetoxy-4,4,4-trifluoro-2-butenoates (54) undergo self-condensation at 100 °C in presence of catalytic amounts of zinc chloride to yield 2,6-bis(trifluoromethyl)-4-pyrones 55. These compounds were further converted to the corresponding pyridine derivatives 56 via ammonolysis [24] (Scheme 17).

A variety of procedures have been used to obtain the 2,6-bis(polyfluoroalkyl)-4-pyrones 57 from the corresponding 1,3,5-triketones [H₂SO₄, PPA, HCl/MeOH, (Me₃SiO)₃PO]. Ethyl polyphosphate appeared to be the most effective dehydrating agent with regard to the isolation and yield of products formed [25] (Scheme 18).

Pyrazolo[1,5-a]pyrimidine 58 and its hydrated form were obtained by reaction of 5-amino-3-methylpyrazole with 2,6-bis(trifluoromethyl)-4-pyrone (57) [26] (Scheme 19).

Polyfluoroalkyl-substituted 4-pyrones 57 react with salicylaldehydes in the presence of piperidine and p-TsOH to give a wide variety of fused 2H-chromenes 59 and 60. Compounds 59 were obtained as mixtures of the corresponding trans- and cis-isomers in variable proportions, depending on the nature of the starting materials and catalysts. This annulation proceeds by a tandem intermolecular oxa-Michael addition and subsequent intramolecular Mannich condensation [27] (Scheme 20).

2 Fluorinated 2-Pyrones

Most reports concerning 2H-pyran-2-ones (α-pyrones) involve non-fluorinated derivatives, which perform important biological functions in nature and have unlimited synthetic potential for the construction of a variety of arenes and heteroarenes [28]. However, very few deal with 2-pyrones containing fluoroalkyl groups. It is evident that the C-2, C-4 and C-6 positions of the 2-pyranone ring are electrophilic in nature and prone to nucleophilic attack. The presence of polyfluoroalkyl substituents on the pyrone ring favours these reactions. At the same time, R^F-containing 2-pyrones behave as cyclic dienes in cycloadditions.

2.1 Synthesis and Reactions of 6-(Polyfluoroalkyl)-2-Pyrones

The ethyl 6-(trifluoromethyl)-2-pyrone-3-carboxylate (61) was prepared by condensation of trifluoroacetone with diethyl ethoxymethylenemalonate, followed by cyclization of intermediate diethyl β-acylethylidenemalonate. This pyrone was used for the preparation of cage derivatives to explore their usefulness as antiviral agents. Reaction of 61 with ethylene at high pressure afforded ester 62. Hydrogenation of 62 yielded the corresponding alkyl bicyclo[2.2.2]octane-l-carboxylate, which was hydrolyzed to 63. The latter was converted into bicyclo[2.2.2]octan-l-amine hydrochloride 64 via the Schmidt reaction [29] (Scheme 21).

6-(Trifluoromethyl)-2-pyrone (65) was prepared in 65 % yield by reaction of 2-pyrone-6-carboxylic acid with SF₄–HF at 100 °C. Chloromethylation with bis(chloromethyl) ether and sulfuric acid at 75 °C gave an inseparable mixture of mono- and bis(chloromethyl)pyranones. However, when the mixture was treated with phenylcopper-dimethyl sulfide in THF at 35 °C, only 66 reacted, giving the desired pyrone 67 as one of the perspective inactivators of α-Chymotrypsin [30] (Scheme 22).

Dealkoxylation of trifluoroacetoacetic ester by P₂O₅ leads to trifluoroacetylketene, which quickly dimerizes to hexafluorodehydroacetic acid 68. The reaction of 68 with NaHCO₃ leads to the formation of 2-pyrone 69 [31] (Scheme 22).

Gerus et al. reported that heating of β-alkoxyvinyl ketones 70 and N-acylglycines in acetic anhydride gave the corresponding 3-(acylamino)-6-(polyfluoroalkyl)-2H-pyran-2-ones (71) [32]. Reactions of thiazole 72 with enones 70 gave products 73 in good to high yields as a result of acylvinylation of the active methylene group. Products 73 were cyclized to pyrones 74 by heating in acetic anhydride [33] (Scheme 23).

The reactions of 2H-pyran-2-one 71a with O– and N-nucleophiles were studied and a series of trifluoromethyl-containing oxazolone and pyridone derivatives were synthesized. The oxazolone 75, which can exist in two tautomeric forms, can be obtained by heating of 71a with KOH in DMF and subsequent acidification. When 71a was dissolved in aqueous 1N NaOH, a yellow solution of salt 76 was formed. After acidification of the solution with HCl, hydroxypyrone 77 precipitated. The pyridones 78 were obtained by heating 71a with ammonia or alkylamines [32, 34] (Scheme 24).

The key step of the synthesis of new δ-(polyfluoroalkyl)-δ-hydroxy-α-amino acids 81 was the hydrogenation of 2H-pyran-2-ones 71 to the tetrahydropyrones 79, which were transformed into the corresponding benzoylamino acid esters 80 by methanolysis. In all cases mixtures of diastereomeric esters 80 were formed, careful treatment of which with 15 % HCl gave a mixture of the diastereomeric benzoylamino acids 81. The latter are of interest as analogues of 2-amino-5-hydroxyvaleric acid and glutamic acid [35] (Scheme 25).

The propensity of α-pyrones to undergo the Diels-Alder reaction makes them useful for syntheses of highly substituted aromatics and biphenyls. A practical method for the regioselective synthesis of the N-benzoyl-4-(polyfluoroalkyl)anilines 82 by thermal Diels–Alder cycloaddition of 71 with fluorostyrenes and acetylenes was described. Free 4-(polyfluoroalkyl)anilines were smoothly formed in good yields by DBU-assisted deprotection. In the case of the reactions of pyrone 71a with isobutyl vinyl ethers and cyclic vinyl ethers, compounds 83 and 84 were obtained, respectively [36] (Scheme 26).

The Cu-catalysed (3–6 mol%) addition of 1,1,1-trichloro-2,2,2-trifluoroethane to methyl itaconate leads to the 1: 1 adduct 85 in 57 % yield. Double HCl elimination with triethylamine affords the diene 86 (Z/E = 17:83). Refluxing of 86 in mesitylene leads to elimination of MeCl and formation of 87 in 62 % yield [37] (Scheme 27).

The presence of the carbomethoxy and trifluoromethyl groups in the diene system of the pyrone 87 increases its electrophilicity and its ability to undergo Diels-Alder reactions with inverse electron demand. The reaction of 87 with 1-(N-pyrrolidino)-1-cyclopentene at 30 °C gives rise to the tricyclic lactone 88. When 88 is treated with HCl/dioxane, the indane derivative 89 is obtained. This compound was prepared directly in the reaction of 87 with l-(trimethylsilyloxy)cyclopentene at 180 °C in 90 % yield. More reactive tetramethoxyethylene adds at 100 °C to 87 to afford 90. With 2,5-dihydrofuran at 130 °C, 91a is formed as the sole isomer. Endo-adducts of this type result also with cyclopentene (91b, 120 °C), cyclooctene (91c, 150 °C), and indene (91d, 80 °C). All four possible regio- and stereoisomers can be identified in the reaction of 87 with vinylacetate at 150 °C (79 % yield) (Scheme 28).

Another feature of 2-pyrone 87 is its ability to undergo Diels-Alder reactions with acetylenes. The cycloadducts decarboxylate spontaneously to form benzene rings bearing the CF₃ group. The substitution pattern is determined by the regioselectivity of the [4 + 2] cycloaddition step. Thus, the reaction of 87 with 1-(N,N-diethylamino)-1-propyne takes place at 0 °C to produce 92 as a single isomer. Less electron rich acetylenes require heating at 140–200 °C. Treatment of 87 with acetylene at 200 °C leads to 93, while with dimethyl acetylenedicarboxylate triester 94 is formed [37] (Scheme 28).

Our group reported that treatment of 1-aryl-4,4,4-trifluorobutane-1,3-diones with PCl₅ and then with sodium diethyl malonate afforded ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates (95) in moderate yields. These compounds can be converted in high yields to 2H-pyran-2-ones 96 by refluxing in aqueous acetic acid with H₂SO₄ [38]. Pyrones 95 and 96 react with sodium azide to produce highly functionalized (Z)-CF₃-1,2,3-triazoles 97 and 98 [39a] (Scheme 29).

The reaction of 95 (Ar=Ph) with NH₄OAc in refluxing aqueous DMF, involving loss of the ethoxycarbonyl group at the 3-position, afforded the pyridinol derivative 99a, while the solvent-free inverse electron-demand Diels-Alder reaction with 2,3-dihydrofuran gave bicyclic lactone 100 in 61 % yield. Treatment of 95 with H₂SO₄ at 110–125 °C afforded the intramolecular Friedel-Crafts acylation products 101, which are the first representatives of a novel polynuclear fused heterocyclic system. Due to the presence of antiaromatic cyclopentadienone fragment compound 101 (R=H) showed high reactivity to weak nucleophiles such as water leading to the formation of 102 [38a]. 2-(Trifluoromethyl)-6H-pyrano[3,4-c]quinoline-4,5-diones 99b can be obtained from pyrones 95 and 101 via the Schmidt reaction in moderate yields. When pyranocarbostyrils 99b were heated in DMSO with NaN₃ at 120 °C for 3 h, triazoles 99c were obtained in good yields and presumably arise via ring-opening of the initially formed fused intermediate [38b] (Scheme 30).

Very recently, the concise synthesis of a range of disubstituted 2-pyrones 96 from (thiophenyl)acetic acids and readily available trifluoromethyl enones via an isothiourea mediated one-pot Michael addition/lactonization/thiol elimination sequence has been demonstrated. Derivatization of these reactive pyrones to generate additional high-value products was next investigated and compounds 96a–c were prepared in good yields [39b] (Scheme 31).

Gerster and Maas reported that heating 4-trifluoroacetyl-substituted münchnone and the propyne iminium triflates in acetonitrile solution at 150 °C (closed vessel) under microwave irradiation furnished the (6-oxo-2-trifluoromethyl-6H-pyran-3-yl)arylidene iminium salts 103 [40] (Scheme 32).

2.2 Synthesis of 4-(Perfluoroalkyl)-2-Pyrones

In contrast to 6-(perfluoroalkyl)-2-pyrones, only one method for the preparation of 4-(perfluoroalkyl)-2-pyrones has been described [41]. It was established that the reaction of methyl 2-perfluoroalkynoates with aroylmethyltriphenyl phosphonium bromide in the presence K₂CO₃ in dichloromethane at room temperature gave methyl 4-aroyl-2-triphenylphosphoranylidene-3-(perfluoroalkyl)-3-butenoates 104 in excellent yields. 6-Aryl-4-(perfluoroalkyl)-2-pyrones 105 and methyl 4-aroyl-3-(perfluoroalkyl)-3-butenoates 106 were obtained in moderate to high yield by hydrolysis of phosphoranes 104 with hot aqueous methanol in a sealed tube. The butenoates 106 were isolated chromatographically as mixtures of Z and E isomers, the ratios of which were estimated by ¹H NMR. Reaction mechanism was proposed to account for the formation of products 104–106 [41] (Scheme 33).

2.3 Miscellaneous

Fluorinated α-pyrones were obtained from perfluoroacryloyl fluoride and perfluoromethacryloyl fluoride by reaction with arylacetylenes and methyl ketones. The arylacetylene route involves a [4 + 2] cycloadduct, followed by a 1,3 fluoride ion shift to 107 and hydrolysis to the pyrone 108. The methyl ketone route may involve addition of enols to the fluorinated double bond, ring closure through the enol form of the resulting 1,5-diketone, and loss of HF [42a] (Scheme 34).

The synthesis and chemistry of perfluoroacylketene 110 are described by England [42b]. Hexafluoropropene dimerizes under CsF catalysis. Heating the resulting mixture in a sealed vessel to 150 °C yields the thermodynamic dimer 109, from which compound 110 was prepared in good yield (Scheme 35).

Cesium fluoride catalyst in tetraglyme without heating caused the acylketene 110 to dimerize to 111. When heated with catalytic amounts of cesium fluoride in tetraglyme 110 gave the pyronopyrone 112a (from 3 mol of 110 with loss of 2 mol of C₂F₅COF). Hydrolysis of 112a by sulfuric acid gave 112b. The acylketene 110 also reacted with phenyl- and butylacetylenes to give pyrones 113. Although acetylene was not reacted with 110, the corresponding product 113 (R=H) was obtained by reaction with vinyl acetate with simultaneous loss of acetic acid. Compound 110 added readily to the C=C bond in ketene with proton migration to give a mixture of hydroxypyrone 114a and the acetylated product 114b. These products could be interconverted by hydrolysis of 114b in sulfuric acid and by acetylation of 114a with ketene [42b] (Scheme 35).

The chemistry of compound 115, prepared from the reaction of hexafluoropropene with sulfur and potassium fluoride in DMF, is similar to 110. Diels-Alder addition of 115 to vinyl acetate was accompanied by loss of acetic acid to give the parent pyrone 116 (R=H). The reaction of 115 with butyl- and phenylacetylenes gave 116 (R=Bu, Ph). Addition of 115 to the C=C bond of ketene was accompanied by a 1,3 hydrogen shift to produce the hydroxypyrone and its acetylated product 117. In the presence of a weak base such as dimethylacetamide or dimethylpropionamide, 115 underwent a self-condensation reaction with loss of CO₂ to give the pyrone 118; this reaction was not observed for 110 [43] (Scheme 36).

England and Krespan reported that ketene 119 reacted exothermically with ketene at very low temperature to give β-lactone 120a, which was readily dimerized by base to give α-pyrone 121, a reaction analogous to the formation of dehydroacetic acid from diketene. Lactone 120a also reacted with another equivalent of ketene 119 in the presence of zinc chloride as catalyst to give the insertion product 122. Methylketene, like ketene, reacted with 119 to give a mixed lactone 120b, the reaction of which with another mole of 119 in the presence of zinc chloride gave γ-pyrone 123. Reaction of 123 with sodium methoxide replaced two fluorine atoms to give the dimethoxypyrone 124, methanol gave the keto diester 125 [44] (Scheme 37).

A synthetic entry to 2-acyl-1,3-dimethyl-6-(trifluoromethyl)-1H-pyrano[4,3-b]pyrrol-4-ones 126 in high yields has been developed via ring closure of pyrrole-2-acetic acid derivatives with trifluoroacetic anhydride at reflux [45a]. Under the same conditions trifluoromethylated dihydropyridinecarboxylates were converted via compounds 127 into pyrano[4,3-b]pyridine-3-carboxylates 128 in low yields [45b] (Scheme 38).

The butenolide, 3-(trifluoromethyl)-2H-furo[2,3-c]pyran-2-one, was obtained by treatment of 3-iodo-2H-furo[2,3-c]pyran-2-one with trifluromethyltriethylsilane in the presence of copper iodide and potassium fluoride in 1-methyl-2-pyrrolidinone [45c].

3 Fluorinated Chromones

Chromones (4H-chromen-4-ones, 4H-1-benzopyran-4-ones) are naturally occurring oxygen-containing heterocycles which perform important biological functions in nature [46]. Many chromone derivatives, including flavones and 2-(trifluoromethyl)chromones, exhibit various types of biological activity and find use as valuable synthetic intermediates in the preparation of pharmacologically relevant products and new heterocyclic systems [47–49]. There are a number of methods available for preparing chromones, however, the most common methods involve Claisen condensation of 2-hydroxyacetophenones with esters or Baker-Venkataraman rearrangement of 2-acyloxyacetophenones. The ensuing diketone is then cyclized under strongly acidic conditions to furnish chromones. These compounds possess two strong electrophilic centers (carbon atoms С-2 and С-4) and their reactions with nucleophiles start predominantly with attack of the С-2 atom (1,4-addition) and are accompanied by pyrone ring-opening to form an intermediate capable of undergoing intramolecular heterocyclizations. Alternatively, the initial attack can also occur at C-4 (1,2-addition) [46].

3.1 Synthesis of 2-(Polyfluoroalkyl)Chromones

The first representatives of 2-(trifluoromethyl)chromones were obtained in 1951 by condensation of substituted 2-hydroxyacetophenones with ethyl trifluoroacetate in the presence of sodium followed by dehydration of the initially formed β-diketones in an acid medium [50]. It has long been considered [51] that these diketones have a linear keto-enol structure 129a; however, subsequently, it has been found on the basis of ¹H NMR data [52] that they exist as cyclic semiketals 129b both in solutions and in crystals. Cyclisation is facilitated by the presence of the electron-withdrawing trifluoromethyl group in the side chain and the hydroxy group in the ortho-position of the benzene ring. Refluxing of 2-hydroxychromanones 129b in ethanol [50] or acetic acid [53, 54] in the presence of concentrated HCl results in 2-(polyfluoroalkyl)chromones 130 (Scheme 39).

Modification of natural products by replacing an alkyl group by a polyfluoroalkyl group has long attracted the attention of researchers, because the electron-withdrawing effect of the fluorinated substituent entails electron density redistribution in the molecule and thus changes its reactivity with respect to nucleophilic reagents [55]. In this connection, of obvious interest is the synthesis of 7-(polyfluoroalkyl)norkhellins 131 [56, 57], which are fluorinated analogues of natural furochromone khellin (active substance of the plant Ammi visnaga L., known for its therapeutic properties since antiquity), because it opens up the way for the preparation of a broad range of fluorine-containing heterocycles that incorporate the benzofuran fragment and are potentially biologically active (Scheme 40).

Fluorokhellins 131 were prepared by the reaction of khellinone with R^FCO₂Et in the presence of LiH followed by dehydration of the condensation products, which exist as furochromanones A in crystals and in DMSO-d ₆ solutions. In CDCl₃, these compounds (except for R^F=CF₃) are mixtures of tautomers A–C. Irrespective of length of the fluoroalkyl group, cyclic form A predominates (50–78 %), while the content of the diketone form C usually does not exceed 8 % [57].

If 2-hydroxyacetophenone analogues such as 3-acetyl-4,6-dimethyl-2-pyridone and 4-acetyl-5-hydroxy-3-methyl-1-phenylpyrazole are used as the methylene component in the condensation with R^FCO₂Et in the presence of LiH in THF or dioxane, the reaction gives the corresponding R^F-containing β-diketones 132 and 134, whose dehydration under the action of concentrated H₂SO₄ affords 8-aza-2-(polyfluoroalkyl)chromones 133 [58] and 6-(polyfluoroalkyl)-3-methyl-1-phenylpyrano[2,3-c]pyrazol-4(1H)-ones 135 [59] (Scheme 41).

Recently, 2-(trifluoromethyl)chromones 130 have been prepared by the reaction of 2-hydroxyacetophenones with trifluoroacetic anhydride in pyridine (80 °C, 3 h, yields 79–98 %) [60]. Due to the low solubility of phenolates, derivatives hydroxylated at the benzene ring are synthesized using the Kostanecki–Robinson method. Thus, 7-hydroxy-2-(trifluoromethyl)chromone was obtained in 68 % yield by heating 2,4-dihydroxyacetophenone with trifluoroacetic anhydride and sodium trifluoroacetate [49]. In addition to these protocols, other methods for the synthesis of chromones 130 have also been developed. For example, the reaction of 2-hydroxyacetophenone with trifluoroacetonitrile affords aminoenone 136. Unlike diketones 128, this compound exists in the open form as Z-isomer having a coplanar s-cis-conformation stabilised by an intramolecular hydrogen bond [61]. However, the products of condensation of CF₃CN with sterically hindered 2-hydroxy-4,6-dimethylacetophenone and 1-acetyl-2-naphthol exist predominantly as 2-aminochroman-4-ones 137 and 138 due to unfavourable interactions between the vinylic hydrogen atom and the ortho-substituent in the benzene ring [62]. In an acid medium, compounds 136–138 are converted into 130 in high yields (Scheme 42).

The condensation of ketimines, prepared from 2-hydroxyacetophenones and primary amines, with R^FCO₂Et in the presence of LiH yields aminovinyl ketones 139 with γ-arrangement of the NHR and R^F groups, which exist only in the open form. In an ethanol solution of HCl, these compounds cyclise to 2-(polyfluoroalkyl)-4H-chromene-4-iminium salts 140, which can be neutralised with ammonia to form 2-(polyfluoroalkyl)-4H-chromene-4-imines 141. On treatment with aqueous acetic acid, compounds 139 and 141 are hydrolysed to chromanones 129, which can be easily converted into chromones 130 [63] (Scheme 43).

The reactions of polyfluoroalk-2-ynoic acids with a fivefold excess of ArOH and KOH in an aqueous solution are stereoselective and result in (Z)-β-(polyfluoroalkyl)-β-aryloxyacrylic acids 142. On treatment with concentrated H₂SO₄, these compounds are converted into 2-R^F-chromones 130 [64]. A similar approach to the synthesis of 2-R^F-chromones 130 has been described in a study [65], in which ethyl 2,2-dihydropolyfluorocarboxylates were used as the starting substrates. They were made to react with phenols in the presence of Et₃N in MeCN at 60 °C, which gave ethers 143, most often, as mixtures of Z- and E-isomers. When heated with polyphosphoric acid (PPA) at 170 °C, they were converted into chromones 130 in high yields (Scheme 44).

The oxidation of enals 144 using sodium chlorite and hydrogen peroxide under mild conditions gave the corresponding acids 145. When acids 145 were treated with polyphosphoric acid at high temperatures, the desired chromones 130 were obtained in predominantly very high yields [66] (Scheme 45).

3.2 Reactions of 2-(Polyfluoroalkyl)Chromones

In recent years, our research group has examined the chemistry of 2-(polyfluoroalkyl)chromones 130 and a number of features of these compounds important from the synthetic standpoint have been found. This allowed chromones 130 to be recommended as readily accessible highly reactive substrates for the synthesis of various heterocyclic derivatives including R^F-containing compounds with a potential biological activity [46b]. The NMR, vibrational, electronic, and structural properties of 6-nitro- and 6-amino-2-(trifluoromethyl)chromones were discussed and assigned with the assistance of DFT calculations [67a].

3.2.1 Nitration and Hydrogenation

2-(Trifluoromethyl)chromone 130a unsubstituted in the benzene ring, like its non-fluorinated analogues, is smoothly nitrated at the 6-position yielding 6-nitro-2-(trifluoromethyl)chromone (146a). On heating with a mixture of nitric and sulfuric acids, 6-, 7- and 8-substituted 2-(trifluoromethyl)chromones are nitrated into the positions, which is in line with the directing effect of substituents, giving rise to the corresponding nitro derivatives 146b–g [54, 67–69] (Scheme 46).

Reduction of 2-(polyfluoroalkyl)chromones 130 by sodium borohydride in methanol gives cis-2-(polyfluoroalkyl)chroman-4-oles 147 in high yields, which were easily oxidized under the action of chromic acid into 2-(polyfluoroalkyl)chroman-4-ones 148. Selective reduction of chromone 130a can be achieved by using of diisobutylaluminium hydride. In this case, 2-(trifluoromethyl)chroman-4-one (148a, R^F=CF₃) and 2-(trifluoromethyl)-4H-chromen-4-ol (149) were obtained. Dehydration of chromanol 147a (R^F=CF₃) gave 2-(trifluoromethyl)-2H-chromene (150) [70]. Chromanones 148, which easily react at both the carbonyl carbon atom and α-methylene group, are of interest as the starting materials for the preparation of novel R^F-containing chromans derivatives. Thus, they react with hydroxylamine, hydrazine hydrate, benzaldehyde on reflux in ethanol and with an excess of dimethylformamide dimethylacetal to give oximes and hydrazones 151 as well as methylidene derivatives 152 [70]. Application of the Ritter reaction conditions to chroman-4-ols 147 gave 4-(acylamino)-2-(polyfluoroalkyl)chromans (153) in excellent yields. This reaction was stereoselective and chromanes 153 were obtained as mixtures of trans- and cis-isomers (trans/cis = 84/16–94/6) without the formation of any side products [71]. Treatment of an alcoholic solution of 148 with an excess of isopropyl nitrite and concentrated hydrochloric acid at 0–80 °C for 3 h gave 3-hydroxychromones 154 in good yields [72] (Scheme 47).

3.2.2 Reactions with Mono-, Di- and Triamines

In 1981, an attempt at using 6-methyl-2-(trifluoromethyl)chromone (130) as a protective group in the peptide synthesis was made, which showed for the first time that secondary amines (dimethylamine and piperidine) add reversibly to the C-2 atom without opening of the pyrone ring to give unstable compounds 155 (in the case of sterically hindered diethylamine, the reaction does not proceed). However, even mere mixing of 6-methylchromone 130 with primary amines (ethyl- and propylamines) induces opening of the pyrone ring to give aminoenones 156. A similar transformation takes place for ethyl glycinate in MeCN [73]. Subsequently, the significance of the steric factor in the reactions of 130 with ammonia and primary amines was also demonstrated for other examples (Scheme 48).

The nature of the substituent at the 5-position of the chromone system influences the form of existence of the reaction products, which can be either ring or open. The attack by the amine on the C-2 atom of 130 for R¹=H is accompanied by the pyrone ring opening and yields aminoenones 157; when R¹ ≠ H, the process stops after the nucleophilic addition of the amine to give stable chromanones 158 [74] (Scheme 49).

A change in the direction of nucleophilic attack has been found in a study of the reaction between chromones 130a–g unsubstituted in the benzene ring and 2-aminoethanol at room temperature. This amine easily yields aminovinyl ketones 159a–d, however the reaction with 130e–g leads to imines 160e–g [75, 76] (Scheme 50).

Unlike non-fluorinated chromones, whose reactions with ethylenediamine (EDA) give complex mixtures of products [77], the reactions of 2-R^F-chromones 130 give rise to 5-(2-hydroxyaryl)-7-(polyfluoroalkyl)-2,3-dihydro-1H-1,4-diazepines (161) in excellent yields. The reaction is accompanied by opening of the pyrone ring with the initial formation of aminovinyl ketones 162 (in equilibrium with imidazolidines 163) and cyclization to dihydrodiazepines 161 [78, 79]. Compounds 161 exist in CDCl₃ as the 1H-7-R^F-tautomers due to the formation of an intramolecular hydrogen bond between the phenolic proton and the imine nitrogen atom of the heterocycle. This conclusion was based on the values of the ³ J _H,F coupling constants, which are 2.8–4.5 Hz for molecules with the HCF₂CF₂–C(X)=C fragments, where X=O, N [80] (Scheme 51).

With diethylenetriamine (DETA), chromones 130 are converted into 5-(2-hydroxyaryl)-7-(polyfluoroalkyl)-1,4,8-triazabicyclo[5.3.0]dec-4-enes (164) (35–91 %), which represent the cyclic form of dihydrodiazepines containing a 2-aminoethyl group at the nitrogen atom located most closely to the fluorinated group. The first step is nucleophilic addition of the primary amino group to the C-2 atom accompanied by opening of the pyrone ring yielding N-substituted aminovinyl ketones, which further cyclise to triazabicyclic products 164 with participation of both electrophilic centres [81]. It should be emphasised that the formation of 164 is typical only of 2-R^F-chromones and R^F-aminovinyl ketones [82], where the R^F group substantially increases the reactivity of the carbon atom that carries this group. On keeping in ethanol for a week, compound 164 (R^F=(CF₂)₂H, R=MeO) isomerises into dihydrodiazepine 165 [83] (Scheme 52).

Thus, the reaction of 2-R^F-chromones with amines usually starts with the attack by the amino group on the C-2 atom. In the case of secondary amines or in the presence of a substituent at the 5-position, the reaction can stop after 1,4-nucleophilic addition; however, in most cases, it is accompanied by pyrone ring opening giving the corresponding aminovinyl ketones, whose structural features and subsequent transformations provide a variety of products. An exception is the reaction of 2-RF-chromones with 2-aminoethanol pointing to the possibility of an attack by the amine on the carbonyl group.

3.2.3 Reactions with Hydrazines, Hydroxylamine, Amidines and Sodium Azide

The reactions of chromanones 129 and chromones 130 with hydrazine hydrate resulted in the formation of 3(5)-(2-hydroxyaryl)-5(3)-polyfluoroalkylpyrazoles that have a planar conformation and mainly exist as 1H-5-R^F-tautomers 166a in CDCl₃ and as 1H-3-R^F-tautomers 167a in DMSO. The reaction with phenylhydrazine allows one to synthesise regioisomeric 5-R^F-pyrazole 166b from 129 and 3-RF-pyrazoles 167b from 130. With methylhydrazine, only the 3-R^F-regioisomers 167c are formed. Under mild conditions, the reaction of 129 with hydrazines can be arrested after the formation of dihydropyrazoles 168 [84a]. Reactions of CF3-pyrazole 166a (R¹=H) with various 2-chloro-3-nitropyridines via nucleophilic aromatic substitution followed by denitrocyclization gave benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepines in 50–60 % yields (Scheme 53).

The reaction of chromanones 129 with hydroxylamine gave oximes existing in the ring isoxazoline form 169 [53]. Under similar conditions, chromones 130 react at the C-2 atom rather than at the oxo group and give isomeric oximes 170, which do not tend to cyclise, unlike the aliphatic analogues [85]. The change in the direction of the nucleophilic attack on passing from 129 to 130 makes it possible to obtain regioisomeric 5-R^F-isoxazoles 171 (refluxing of 169 in toluene with SOCl₂) and 3-R^F-isoxazoles 172 (refluxing of 170 in AcOH with HCl) (Scheme 54). Azachromones 133 react with amines, hydrazines and hydroxylamine similarly [86].

Substituted 2-R^F-chromones are effective in the reaction with amidines to create R^F-containing pyrimidine derivatives. Reflux of chromones 130 with benzamidine hydrochloride or guanidinium nitrate in the presence of KOH yielded the pyrimidines 173 in moderate to high yields [87] (Scheme 55).

The reaction is applicable to the 8-aza-5,7-dimethyl-2-(trifluoromethyl)chromone (133a) to afford the corresponding pyrimidines with 2-pyridone substituent [87].

Salicyloyltriazoles 174 were prepared by the reaction of 2-CF₃-chromones 130 with sodium azide. It should be noted that on replacement of the CF₃ group by H, CF₂H or (CF₂)₂H, the reaction does not take place. Furthermore, without an electron-withdrawing group at the 6-position the reaction slows down to such an extent that 2-(trifluoromethyl)chromone 130a is recovered unchanged [88] (Scheme 56).

The reactivity of the pyrone ring with respect to NaN₃ can be increased by replacement of the C=O group by the C=NR group. It was shown [88] that the presence of an electron-withdrawing group in the benzene ring is not obligatory for chromene-4-imines 141, and they easily react with NaN₃ in the presence of AcOH to give aryltriazolylketone imines 175 due to protonation of C=N bond (Scheme 57).

Hydrolysis of imines 175 affords triazoles 174, which could not be synthesised from the corresponding 2-CF₃-chromones. Since the transformations 139 → 141 and 141 → 174 proceed via common iminium intermediate 140, it comes as no surprise that aminovinyl ketones 139 are converted under these conditions into triazoles 174 as easily as chromene-4-imines 141 [88].

3.2.4 Reactions with Alkyl Mercaptoacetates

One of the most unexpected reactions of 2-CF₃-chromones 130 is the reaction with ethyl mercaptoacetate in the presence of Et₃N, which results in 176 and diethyl 3,4-dithiaadipate via redox process. This reaction can be accomplished only with 2-CF₃-chromones. Most likely, it starts with the formation of 177, subsequent reductive opening leads to 178 cyclizing to dihydrothienocoumarin 176 [89]. The reaction of alkyl mercaptoacetates with fluorokhellins 131 stops after the formation of products 179. Only under rigorous conditions (sealed tube, 150 °C), norkhellins 131 were converted into 180 [57, 90] (Scheme 58).

The reaction of 8-aza-5,7-dimethyl-2-(trifluoromethyl)chromone (133a) with alkyl mercaptoacetates afforded bicycles 181a,b. When the reaction time and the amount of Et₃N were increased, acyclic derivatives 182a,b were isolated [91]. A similar reaction of pyranopyrazole 135 proceeds at the C-6 atom followed by pyrone ring opening and intramolecular condensation of the aldol type to give compound 183, from which heterofused coumarin 184 was obtained [59] (Scheme 59).

Selective oxidation of dihydrothienocoumarins 176 gives rise to highly reactive substrates, namely, sulfoxides 185 (NO₂, CHCl₃) and sulfones 186 (H₂O₂, AcOH). Under Pummerer rearrangement conditions, sulfoxides 185 produce thienocoumarins 187 [89b]. Sulfones 186 are transformed into 3-hydrazino-6-(2-hydroxyaryl)pyridazines 188 by the action with hydrazine hydrate [92]. Previously, these pharmaceutically valuable products providing the basis for a series of 3-hydrazinopyridazine drugs [93], were synthesised in seven steps starting from phenols and succinic anhydride [94]. Multistep mechanism of this transformation is given below (Scheme 60).

3.2.5 Reactions with C-Nucleophiles

Trimethyl(trifluoromethyl)silane (Ruppert’s reagent) easily reacts with α,β-unsaturated carbonyl compounds yielding the corresponding trifluoromethylated alcohols [95]. The reaction of CF₃SiMe₃ with 2-CF₃-chromones 130 is the first example of preparative 1,4-trifluoromethylation of the α,β-enone system, which leads to trimethylsilyl ethers 189 giving after acid hydrolysis 2,2-bis(trifluoromethyl)chroman-4-ones 190 [96]. Chromone 130a reacts with ethyl malonate and ethyl cyanoacetate to give methylidene derivatives of 4H-chromene 191a,b. Subsequent reaction with CF₃SiMe₃ in the presence of Me₄NF involves nucleophilic 1,6-addition to the conjugated systems to produce, through acid hydrolysis of intermediate 192, 2H-chromenes 193a,b [97] (Scheme 61).

2-Methyl-2-(trifluoromethyl)chroman-4-ones 194a,b were obtained in good yields by reaction of chromene-4-imines 141 with malonic acid, which acts as methylating agent via addition-decarboxylation-hydrolysis sequence [98] (Scheme 62).

The reactions of 2-CF₃-chromones 130 with dilithiooximes proceed via nucleophilic 1,2-addition to give β-hydroxy oximes 195a–d and, on acidification, 4H-chromene-4-spiro-5′-isoxazolines 196a–d. The isoxazoline ring in 196 undergoes opening under the action of concentrated H₂SO₄, yielding oximes 197a–c. Their nitrosation leads to 198a,b, while the Beckmann rearrangement, to α,β-unsaturated amides 199. The latter are also formed from 196 using PCl₅ [99] (Scheme 63).

Analogous reactions of acetophenone dimethylhydrazone and acetophenone ethoxycarbonylhydrazone with chromone 130a gave β-hydroxy hydrazone 200 and spiropyrazoline 201, which are also 1,2-adducts. In contrast, acetophenone and acetophenone anil behaved differently under the same conditions giving via 1,4-addition chromanone 202 [99, 100] (Scheme 64).

It was also found that 2-R^F-chromones 130 react with N-(1-arylethylidene)-2-propanamines to afford pyridines 203 in moderate yields. Using this reaction, pyridine 203a was obtained, demethylation of which to 2,6-bis(2-hydroxyphenyl)-4-(trifluoromethyl)pyridine (203b) was achieved by heating with 48 % HBr at 200 °C [87]. When a mixture of chromones 130 with (isopropylidene)isopropylamine was refluxed without solvent for 10 h, anilines 204 were obtained [101] (Scheme 65).

The reaction of 6-nitro-2-R^F-chromones 130 with 1,3,3-trimethyl-3,4-dihydroisoquinolines affords chiral zwitter-ions 205 in 35–82 % yields. This reaction is typical only for 6-nitro derivatives and includes the nucleophilic attack of the enamine tautomer of dihydroisoquinoline to C-2 atom of 130 followed by ring opening and intramolecular cyclization at the keto group with elimination of H₂O. Cleavage of the Me₂C–N bond, resulting in the formation of isomers 206, takes place on heating or in the presence of H₂SO₄ [102] (Scheme 66).

We also found that 2-R^F-chromones 130 react with salicylaldehydes in the presence of piperidine to afford 207 via oxa-Michael addition followed by intramolecular Mannich condensation [27]. Treatment of 130 with pyridoxal hydrochloride in the presence of NaOH (2.6 equiv.) gave oxepines 208 in moderate yields. In this case, the reaction proceeded at the alcoholic hydroxyl. Interestingly, using 1.3 equiv. of NaOH, it was possible to obtain 209 [103] (Scheme 67).

Recently, Sosnovskikh et al. reported that 2-(trifluoromethyl)chromones 130 reacted with two molecules of ethyl cyanoacetate, yielding benzo[c]chromene-8-carbonitriles 210. A similar base-mediated reaction of 130 with diethyl malonate gave carboxylates 211. These products are formed through nucleophilic attack followed by Claisen condensation (intermediate A), intramolecular cyclization and dehydration (intermediate B), and then by aromatization (after hydrolysis and decarboxylation) through involvement of the phenolic hydroxy group. At the same time, chromone 130a reacts with cyanoacetamide, N-methyl cyanoacetamide, and cyanoacetohydrazide in the presence of sodium ethoxide, affording 2-pyridones 212 in good yields [104] (Scheme 68).

In conclusion, it should be noted that the trifluoromethyl group occupies a special place among polyfluorinated substituents, because the most interesting and peculiar transformations with N-, S- and C-nucleophiles can be carried out only for 2-CF₃-chromones and their derivatives. Most of the reaction described in this chapter are typical only for 2-R^F-chromones and does not occur when the R^F group is replaced by the methyl or trichloromethyl group [46b].

3.3 3-Substituted 2-(Polyfluoroalkyl)Chromones

3.3.1 Synthesis of 3-Substituted 2-(Trifluoromethyl)Chromones

Preparation of 3-aryl and 3-hetaryl-2-(trifluoromethyl)chromones 214 was achieved by reaction of trifluoroacetic anhydride with pyridine solutions of ketones 213 [105]. This simple and effective procedure was also used for the synthesis of 7-hydroxy-2-(trifluoromethyl)chromone-3-carbonitrile (214, X=CN), from which 7-hydroxy-2-(trifluoromethyl)chromone-3-carboxamide (214, X=CONH₂) was obtained. These compounds are useful for preventing allergic and asthmatic symptoms [106]. The same procedure was employed for the preparation of isoflavones 215 and 216 which are potent dual PPARα and γ agonists [107]. By heating ω-phenylresacetophenone with (CF₃CO)₂O and sodium trifluoroacetate isoflavone 217 was prepared with the intent to study antihypertensive activity [48]. The reactions of isoflavones containing a trifluoromethyl group at the 2-position have been reviewed previously [108] (Scheme 69).

2-Hydroxy-3-(methoxycarbonyl)propiophenone is easily converted into chromones 218a,b through DBU assisted Baker-Venkataraman reaction with perfluoroalkanoyl anhydrides in pyridine [109]. The strength of the trifluoroacetic anhydride as acylating agent and the electron delocalization toward the carbonyl oxygen promoted by the para-methoxyl group favor the over trifluoracetylation of an intermediate, which ultimately produce 219 in excellent yield [60] (Scheme 70).

The reaction of o-fluorobenzoyl chloride with β-ketoesters in the presence of NaH has been proposed as a method for the synthesis of 2-methylchromone-3-carboxylic acid and its esters. In particular, this reaction proved to be suitable for the preparation of ethyl 2-(trifluoromethyl)chromone-3-carboxylate (220) [110] (Scheme 71).

Derivatives of 4-hydroxy-2-(trifluoromethyl)-4H-chromene 221 were obtained via condensation of salicylaldehydes with methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate [111] or methyl 2-perfluoroalkynoates [112]. Treatment of 221 with Sarrett reagent in CH₂Cl₂ generated chromones 220 in high yields [111] (Scheme 72).

3-(Trifluoromethyl)flavonoid derivatives 222 were prepared by trifluoromethylation of 3-iodoflavonoids with FSO₂CF₂CO₂Me/CuI. Other C ring and B ring trifluoromethylated flavones were also prepared. All the compounds were tested for their effect on the U2OS cell cycle. Bistrifluoromethylated apigenin derivative 223 showed the strongest activity [113]. Chrysin derivatives 224 and 225 were tested in vitro against human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma (HT-29) cells [114] (Scheme 73).

3.3.2 Reactions of 3-Substituted 2-(Polyfluoroalkyl)Chromones

When treated with chlorine in the light (CCl₄, ~60 °C, 1 h), chromones 130 add a chlorine molecule at the double bond of the pyrone ring and, after elimination of HCl, they are converted into 3-chlorochromones 226a, which are readily nitrated to give 3-chloro-6-nitrochromones 226b [67, 115] (Scheme 74).

3-Chlorochromones 226 react with hydrazine dihydrochloride to give 4-chloropyrazoles 227 in good yields [115]. It is the first example of a reaction of 3-halochromone with a nucleophile with retention of the halogen atom in the reaction product. When chromones 226 are refluxed with hydroxylamine, contraction of the pyrone ring to the furan ring, typical of 2-unsubstituted 3-halochromones, takes place to give benzofurans 228 [116]. The reactions involve intermediate A resulting from the attack of the NH₂ group on the C-2 atom with the pyrone ring opening. This is followed by either an intramolecular Ad_N-E reaction between the C=O and NH₂ groups (X=NH₂) or nucleophilic substitution of the phenolic hydroxyl for the chlorine atom (X=OH) [116] (Scheme 74).

When 3-cyano-2-(polyfluoroalkyl)chromones 229, prepared from 3-(polyfluoroacyl)chromones 230 (see Sect. 3.4.1), were treated with H₂SO₄, amides 231 were obtained in high yields. Heterocyclization of 229 with hydrazines, hydroxylamine and acetamidine resulted in pyrazoles 232, 5-aminoisoxazole oxime 233, and pyrimidin-5-ones 234 in variable yields [117] (Scheme 75).

We found that 154a smoothly reacts with an excess of MeI (refluxing acetone) and Ac₂O–Py to produce the expected 3-methoxy- and 3-acetoxy-2-(trifluoromethyl)chromones in high yields. Treatment of 235 with primary amines and hydrazine gave only the corresponding ammonium salts 236 [72] (Scheme 76).

Chromones 220 were converted to 2-trifluoromethyl-substituted benzoxepins 238 through cyclopropanation and Lewis acid-catalyzed ring opening of 237 [111] (Scheme 77).

3.4 3-(Polyfluoroacyl)- and 2-(Trifluoroacetyl)Chromones

3.4.1 Synthesis and Reactions of 3-(Polyfluoroacyl)Chromones

3-(Polyfluoroacyl)chromones 230 containing a β-dicarbonyl fragment and a masked formyl group are highly reactive R^F-containing building blocks [118]. There has been only two reports on the preparation of 230 by trifluoroacetylation of 3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one with trifluoroacetic anhydride or N-(trifluoroacetyl)imidazole [119] and by formylation of 2-hydroxy-2-(polyfluoroalkyl)chroman-4-ones 129 using diethoxymethyl acetate [120] (Scheme 78).

It should be taken into account that these compounds easily add a water molecule at the carbonyl group and exist as a mixture with their hydrates 230′ [121]. Pure 230a was obtained from a mixture of keto and hydrate forms using P₂O₅ [122]. Heteroanalogues 239–241 were obtained similarly in high yields [59, 121, 123].

As expected, the reaction of chromones 230 with alkyl orthoformates catalyzed with HCl or p-TsOH resulted in the formation of hemiketals 242. The reaction of 230 with primary amines afforded chromanones 243 in good yields [121] (Scheme 79).

Chromones 230 smoothly react with indole and N-methylindole in refluxing pyridine resulting in the formation of 244 as mixtures of Z- and E-isomers [124]. These reactions include the nucleophilic 1,4-addition of the amine or indole with concomitant opening of the pyrone ring and subsequent intramolecular cyclization of the intermediate at the R^FCO group [125].

Reactions of 3-(polyfluoroacyl)chromones 230 with hydrazine hydrate and methylhydrazine proceed via nucleophilic 1,4-addition followed by opening of the pyrone ring and heterocyclization at polyfluroacyl group into 4-(2-hydroxyaroyl)-3-(polyfluoroalkyl)pyrazoles 245 or aroyl group into 4-(polyfluoroalkyl)-2,4-dihydrochromeno[4,3-c]pyrazol-4-oles 246 [126] (Scheme 80).

Similar reaction of 230 with hydroxylamine proceeds via 1,4-addition and subsequent cyclization to 247 in good yields. On treatment with trifluoroacetic acid, the isoxazole ring of this fused heterocyclic system opens to give 3-cyano-2-R^F-chromones 229 (see Sect. 3.3.2). On the other hand, oximation of 230 with hydroxylamine hydrochloride occurs either at the C=O group connected to the R^F group or at the C-2 atom to give chromones 248 and isoxazole 249, respectively. The former were converted to isoxazoles 250 by heating in DMSO [127] (Scheme 80). Treatment of chromones 230 with amidine and guanidine gave 5-salicyloyl-4-(polyfluoroalkyl)pyrimidines 251 in variable yields, from which the corresponding 4-(trifluoromethyl)pyrimidine-5-carboxylic acids, a new class of potent ryanodine receptor activators, were obtained under Dakin reaction conditions [128] (Scheme 81).

Reactions of chromones 230 with acetoacetamide and ethyl acetoacetate in ethanol in the presence of ammonium acetate proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent cyclization to 252. Similar reaction with β-aminocrotononitrile gave 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyridine-3-carbonitriles (253a) [129]. Three-component reaction between chromones 230, dimedone, and AcONH₄ is accompanied by detrifluoroacetylation and leads to 254 in low yields [130] (Scheme 82).

Chromone 230a reacts with heterocyclic amines 255 giving four types of products, depending on the nature of the 1,3-C,N-dinucleophile and the solvent. The reaction of heterocycles 255a,i,j,l with 230a gave the corresponding fused pyridines 257 as the main products, while in the case of 255e–h the formation of chromeno[4,3-b]pyridines 258 was preferred. At the same time, aminoheterocycles 255b,k,m–o in DMF gave mainly chromanones 256. Reactions of 255a–e, performed in glacial acetic acid yielded preferably products 257 and 259, which represent fused pyridines with a trifluoromethyl group located in the α- or γ-position. It clearly appears that the less aromatic heterocycles 255a–j,l have a proclivity to form fused pyridines 257–259 [131] (Scheme 83).

While enamines react with chromones 230 mainly at the R^FCO group to produce pyridine derivatives, reactions of dimethyl acetonedicarboxylate with 230 took an entirely different course and gave a series of 6H-benzo[c]chromenes 260 in good yields. This heterocyclic system certainly is the product of the primary 1,4-addition followed by the pyrone ring-opening, attack of the second CH₂ group to the carbonyl bound with the aromatic cycle, and ring-closure involving the phenolic hydroxyl and R^FСО group [132] (Scheme 84).

3-(Polyfluoroacyl)chromones 230 undergo heterodiene cycloaddition to 3,4-dihydro-2Н-pyran, 2,3-dihydrofuran and ethyl vinyl ether under mild conditions, producing novel fused pyranes 261 and 262 with high stereoselectivity and in good yields. Some of these pyranes were transformed into 2-R^F-containing pyridines on treatment with ammonium acetate in ethanol [133] (Scheme 85).

3.4.2 Synthesis and Reactions of 2-(Trifluoroacetyl)Chromones

We found that methyl 2-methoxytetrafluoropropionate reacted with 2-hydroxyacetophenones under Claisen reaction conditions (NaOEt or LiH) affording chromones 264 in high yields. Deprotection of chromones 265 was carried out using 96 % H₂SO₄ and SiO₂, to afford 2-(trifluoroacetyl)chromones 265, which were prone to form hydrates [134] (Scheme 86).

Chromone 265 (R=H) behaves as a latent 1,2-diketone, having a masked aroyl fragment at the 3-position, and reacts with ethylenediamine and o-phenylenediamine to give 266 and 267a,b (two tautomeric forms) in good yields. This chromone reacted smoothly with indole to produce the expected adduct 268. These results clearly indicate that C-2 of 265, due to the electron-withdrawing effect of the CF₃CO group, is very susceptible to nucleophilic attack [134] (Scheme 87).

4 Ring-Fluorinated Chromones and Coumarins

4.1 Synthesis of Ring-Fluorinated Chromones and Coumarins

Ring-fluorinated chromone carboxylic acids are very interesting compounds being oxygen analogues of the fluoroquinolone antibiotics. It is well-known that polyfluoroaryl β-dicarbonyl compounds are useful in this area because the nucleophilic replacement of their ortho-fluorine atom leads to the formation of chromone structures. Such behaviour has been found in the reactions of pentafluoroaromatic β-ketoesters [135] and β-diketones [135, 136] and also in the synthesis of 2-substituted 3-ethoxycarbonyl-5,6,7,8-tetrafluorochromones 269a–d through the reaction of pentafluorobenzoyl and pentafluorophenylacetyl chlorides with β-ketoesters in the presence of magnesium ethoxide. On hydrolysis, 269d gave 2-pentafluorobenzyl-5,6,7,8-tetrafluorochromone (270) [135, 137] (Scheme 88).

Saloutin et al. reported [138] that the self-condensation of ethyl pentafluorobenzoylacetate (271) on refluxing without any catalyst leads to the formation of compound 272 in 37 % yield, acid hydrolysis of which gave 2-pentafluorobenzoylmethyl-5,6,7,8-tetrafluorochromone (273). Other routes for preparing some new ring-fluorinated chromones have been performed from the 2-ethoxymethylene pentafluorobenzoylacetic ester (274) and also via intramolecular cyclization of ethyl pentafluorobenzoylpyruvate (275). The reaction of ester 271 with ethyl orthoformate results in the formation of compound 274, which was refluxed with water to form 3-ethoxycarbonyl-5,6,7,8-tetrafluorochromone (276). The latter was hydrolyzed under acidic conditions to give carboxylic acid 277, sublimation of which produced 5,6,7,8-tetrafluorochromone (278). This compound was derived directly from ester 276 in boiling acetic acid [138]. Pentafluoroacetophenone reacts with diethyl oxalate in the presence of LiH to give ethyl pentafluorobenzoylpyruvate (275), which can be isolated through its copper(II) chelate. Ester 275 is stable at room temperature, but is converted by heat to give 2-ethoxycarbonyl-5,6,7,8-tetrafluorochromone (279) in quantitative yield. The latter under acidic hydrolysis gave tetrafluorochromone (280), sublimation of which at 230–250 °C produced chromone 278 [138]. Pentafluoroacetophenone also reacts with Vilsmeier reagent to give chromone 278 and its 3-formyl derivative depending on the conditions [139] (Scheme 89).

Heating diketone 281, containing an easily replaceable fluorine atom in the ortho-position to the carbonyl group, with urea results in 2-(trifluoromethyl)-5,6,7,8-tetrafluorochromone (282) [140]. Perfluoroflavones 283a,b were obtained from the reactions of bis(pentafluorobenzoyl)- and fluorobis(pentafluorobenzoyl)-methanes with methyl- and phenylhydrazines [136]. 3-Fluoroflavone 284a and its 6-substituted derivatives were prepared from appropriate flavones by electrochemical fluorination with Et₄NF · 4HF or Et₃N · 3HF. Anodic fluorination of flavones affords mono- (284a), di- (284b) and tri- (284c) fluoro derivatives, whose ratio depends on the type of salt used and the temperature of electrolysis. 3-Fluoroflavones 284a are formed upon dehydrofluorination of 284b under the action of Et₃N, while trifluoro derivatives 284c are the products of further fluorination of 284a. The yields of 284a vary over a broad range (25–63 %) [141] (Scheme 90).

Formation of perfluoro-4-methylcoumarin 285 has been reported from perfluoro-3-methylindenone, in which the carbonyl group is involved in reaction with H₂O₂ in the HF–SbF₅ system [142a]. Perfluoro-1-ethylindan heated with excess of SiO₂ in SbF₅ at 75 °C and then treated with water, gives isocoumarin 286a in high yield. Perfluoro-3-ethylindan-1-one is converted, under the action of SbF₅ at 70 °C, to perfluoro-3,4-dimethylisocoumarin 286b [142b, c] (Scheme 91).

4.2 Reactions of Ring-Fluorinated Chromones and Coumarins

The reactions of chromones with amines is known to afford the corresponding aminoenones at the C-2 atom [46]. In contrast, chromone 279 reacts with cyclohexylamine, morpholine, N-methylpiperazine, and piperidine without pyrone ring opening to give compounds 287a–d. Similar reaction with methylamine furnishes compound 288, which results from reaction at the ethoxycarbonyl group and nucleophilic displacement of the fluorine atom at the 7-position of the heterocycle. At the same time, ammonia and aniline does not react with 279. The reaction of 279 with ethylenediamine gave piperazinone 289 [143]. Refluxing of 279 with o-phenylenediamine in toluene for 18 h in the presence of BF₃ · Et₂O results in the formation of quinoxalinone 290a [144]. On treatment with o-aminophenol chromone 279 gave benzoxazinone 290b in low yield [145, 146] (Scheme 92).

The reaction of chromone 269a with hydroxylamine affords isoxazole 291a, which could only arise from addition of the N-nucleophile at the C-2 position of the heterocycle. This compound was subjected to cyclization on refluxing under acidic conditions to give benzopyranoisoxazole 292a. A similar reaction of chromone 269a with hydrazine hydrate gave the corresponding pyrazole 291b. When 291b was heated with a boiling mixture of concentrated acetic and hydrochloric acids, benzopyranopyrazole 292b was obtained [147a]. Chromone 269a also reacts with ammonium hydroxide at room temperature to give a mixture of aminoenone 293a and its cyclic derivative 294a. The latter can be derived from 293a by refluxing with ammonium hydroxide. When 269a was heated with ammonium hydroxide, only 294a was obtained. Similar reaction of 269a with benzylamine also proceeds at the C-2 position and gives substituted aminoenone 293b, which was then subjected to cyclization to produce coumarin 294b without any catalyst or solvent at 100 °C. Both keto-enamino and imino-enol isomers are possible in structures 293 and 294, however keto-enamino form is preferred [147b, c]. Under acidic conditions, aminoenone 293a was hydrolyzed to give 2-methyl-5,6,7,8-tetrafluorochromone (295), which was also obtained from 3-carboxy-2-methyl-5,6,7,8-tetrafluorochromone and compound 294a by alkaline and subsequent acidic treatment. When 294a was treated with diluted H₂SO₄, coumarin 296 was obtained. The latter was treated with concentrated H₂SO₄ to give 4-hydroxy-5,6,7,8-tetrafluorocoumarin (297) [147a] (Scheme 93).

4-Hydroxycoumarin 297 was found to react with о-phenylenediamine on refluxing in toluene to form product 298 existing as a mixture of tautomers А and B. Under similar conditions, 3-acetyl-4-hydroxycoumarin 296 reacts with о-phenylenediamine to form a mixture of products from which benzodiazepine-2-one 299 and compound 298 can be isolated. The former was also obtained in 65 % yield by the reaction of 3-acetimidoyl-4-hydroxycoumarin 294a [148a] (Scheme 94).

The reactions of 4-hydroxy-5,6,7,8-tetrafluorocoumarine derivatives with ammonia and morpholine involve aromatic nucleophilic substitution of fluorine atoms at the 7-position as the main process [148b].

5 Fluorinated Coumarins

Derivatives of 2H-1-benzopyran-2-one, also known as coumarins, are prominent natural products possessing a wide range of valuable physiological activities. Many coumarin derivatives exert anticoagulant, antitumor, antiviral, antiinflammatory and antioxidant effects, as well as antimicrobial and enzyme inhibition properties [47a, 149]. In addition, they represent useful synthetic building blocks in organic and medicinal chemistry, and have also found application as photosensitisers, fluorescent and laser dyes [150]. 7-Amino-4-(trifluoromethyl)coumarins, the important class of laser dyes for the “blue-green” region, are strongly fluorescent in polar solvents, and their fluorescence properties depend on the electron-donating ability of the 7-amino group [151].

5.1 Synthesis and Application of Polyfluoroalkylated Coumarins

5.1.1 3-Unsubstituted 4-(Polyfluoroalkyl)Coumarins

Coumarins have been synthesized by several routes, including Pechmann, Perkin, Knoevenagel and Wittig reactions. The reaction of various phenols with β-ketoesters in the presence of an acid catalyst, an example of the Pechmann reaction, has been extensively used in the synthesis of 4-substituted coumarins. With ethyl 4,4,4-trifluoroacetoacetate [152] and electron-rich phenols, the reaction affords, almost invariable, 4-(trifluoromethyl)coumarins 300 bearing different electron-donating substituents at the benzene ring [50, 153, 154].

Various derivatives of 7-hydroxy- and 7-amino-4-(trifluoromethyl)coumarins 300 are readily prepared by the Pechmann reaction using zinc chloride as the condensing agent [155]. Recently, there have been reports on the use of ZrCl₄ [156], AgOTf and molecular iodine [157], InCl₃ [158], Sc(OTf)₃ [159] and TiCl₄ [160] as Lewis acids for the synthesis of 4-CF₃-coumarins 300. A 30-membered library of 4-substituted coumarins has been synthesized in a microwave-assisted Pechmann reaction using neat trifluoroacetic acid both as an acidic reagent and a reaction medium [161]. Fused 4-(trifluoromethyl)coumarins 301a–d, including 4-CF3-psoralen 301c, were obtained in the presence of an acid catalyst such as ZnCl₂, methanesulfonic acid or sulfuric acid [162–165] (Scheme 95).

Synthesis and purification of 7-amino-4-(trifluoromethyl)courmarin (300a) (R = 7–NH₂, R^F=CF₃, Coumarin 151) from 3-aminophenol by the Pechmann reaction was first reported in 1980 [166]. Two byproducts, 7-hydroxy-4-(trifluoromethyl-2-quinolone (302) and 2-ethoxy-7-hydroxy-4-(trifluoromethyl)quinoline (303), were also isolated and identified. The synthesis of benzene ring fluorinated 7-hydroxy-4-methyl- and 7-hydroxy-4-(trifluoromethyl)coumarins 304 in 45–80 % yields was reported by Sun et al. by the condensation of fluorinated resorcinols with ethyl acetoacetate and ethyl trifluoroacetoacetate in methanesulfonic acid at ~20 °C [167]. 4-Fluorocoumarins 305a were obtained from the corresponding 4-chlorocoumarins by a halogen-exchange reaction [168a]. The reaction of (Z)-2-fluoro-3-methoxyprop-2-enoyl chloride with phenol gave 3-fluorocoumarin 305b [168b]. Dmowski reported facile preparation of 3-fluoro-4-hydroxycoumarins 305c by treatment of o-hydroxy-2,3,3,3-tetrafluoropropiophenone with aqueous KOH and NH₃ [168c, d] (Scheme 96).

Reaction of 3-aminophenylpivalate with 3-acetoxy-3-methyl-l-butyne in the presence of CuCl afforded the corresponding propargyl aniline, which could be cyclized to 306 by treatment with catalytic CuC1 in refluxing THF. Reduction of the olefin by catalytic hydrogenation, deprotection of the phenol, and Pechmann cyclization using ethyl trifluoroacetoacetate mediated by zinc chloride in ethanol, afforded coumarin 307, the 1-oxa version of 4-(trifluoromethyl)-2(1H)-piperidino[3,2-g]quinolinone, typified by the lead human androgen receptor antagonist LG120907. A series of 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor [169] (Scheme 97).

It was shown that the base-catalyzed cyclization of 308, prepared from 300b and chloroacetone, gave difurocoumarin 309 in high yield [170]. Coumarin 300b was also reacted with crotonic acid in the presence of PPA to offer the corresponding angular chromanone, which was further condensed with 1,1-diethoxy-3-methyl-2-butene under microwave irradiation to produce the target tetracyclic dipyranocoumarin 310 as a potential anti-HIV-1 agent [171]. Reaction of 7-aminocoumarin 300a with diethyl ethoxymethylenemalonate led to the condensation intermediate (the Gould-Jacobs reaction), thermal cyclization of which gave the desired tricyclic ester 311a. This ester was hydrolyzed to the corresponding benzopyranopyridine carboxylic acid 311b, which was found to possess high antimicrobial activity against Gram-positive microorganism [172] (Scheme 98).

5.1.2 3-Substituted 4-(Trifluoromethyl)Coumarins

Resorcinol and 5-methylresorcinol react with 3-oxo-2-aryl-4,4,4-trifluorobutyronitrile using ZnCl₂ in dibutyl ether under the Hoesch reaction conditions to give a low yield of coumarins 312. However, the related reaction with m-methoxyphenol was found to produce poor yields of 312 and 313 [173] (Scheme 99).

3-Aryl-7-(diethylamino)-4-(trifluoromethyl)coumarins 314 were synthesized as a result of the photoreaction of 7-(diethylamino)-4-(trifluoromethyl)coumarin (300c) with iodobenzene and 3,4-dimethoxyiodobenzene in acetonitrile. It was established that the electron-withdrawing CF₃ group and addition of triethylamine accelerate photosubstitution [174] (Scheme 100).

Ethyl 2-(p-fluorobenzyl)trifluoroacetoacetate reacted with resorcinol in 70 % sulfuric acid at 100 °C to provide coumarin 315a. Upon treatment with N,N-dimethylcarbamoyl chloride in the presence of NaH, this compound was readily converted into the corresponding N,N-dimethylcarbamate 316a, which was tested as a TNF-α inhibitor [175]. A similar reaction of resorcinol with diethyl trifluoroacetosuccinate in PPA gave compound 315b, from which 316b as CYP2C9 substrates responsible for the metabolism of drugs were obtained [176] (Scheme 101).

Voznyi et al. reported that condensation of 4-(trifluoroacetyl)resorcinol 317 (R=H) with cyanoacetic ester occurs at 100–150 °C and is accompanied by closure of the pyrane ring and formation 318 as a result of condensation of 319 with cyanoacetic ester, followed by hydrolysis of the cyano group and decarboxylation [177]. When the trimethylsilyl derivative 317 (R=Me₃Si) was heated with cyanoacetic ester, it was possible to increase the yield of compound 319 from 10–12 % to 79–82 %. The synthesis of 320 was realized by a similar method [178] (Scheme 102).

Similarly, reaction of 321 with cyanoacetic ester and potassium carbonate gave the benzopyrane 322. When ketone 321 was treated with monoethyl malonate, triethylamine and phenyl phosphorodichloridate, the required coumarin 323a was obtained and subsequent alkaline hydrolysis gave the acid 323b [179] (Scheme 103).

Huang et al. reported that coumarins and thiocoumarin react with perfluoroalkyl iodides in the presence of sodium hydroxymethanesulfinate (Rongalite) to give 3-(polyfluoroalkyl)coumarins 324a,b selectively and under mild conditions. A free-radical mechanism was proposed for the reaction [180]. The regioselective reaction of 3-unsubstituted coumarins with bis(perfluoroalkanoyl)peroxides also affords 3-(perfluoroalkyl)coumarins 324c. Though the introduction of perfluoroalkyl groups into the 3-position of coumarins lowers the fluorescence intensities, the derivatives 324c are much more stable towards UV irradiation than 3-unsubstituted coumarins [181] (Scheme 104).

5.1.3 Applications of 7-Amino-4-(Trifluoromethyl)Coumarin Derivatives

7-Amino-4-(trifluoromethyl)coumarin (300a) is strongly fluorescent in polar solvents and its ¹⁹F NMR spectrum shows only a singlet peak without any coupling to intramolecular protons. Thus, coumarin 300a has been utilized as a reporter group that is active in both fluorescence measurement and ¹⁹F magnetic resonance imaging [182].

The photophysical properties of fluoroionophores composed of a laser dye, Coumarin 153, linked to azacrowns have been reported. The changes in the photophysical properties upon complexation with alkali and alkaline-earth metal cations are due to the direct interaction between the cation and the carbonyl group of the coumarin. Of particular interest is the bis-coumarin 325, which exhibits specific changes in quantum yield according to the size of the cation [183]. Mizukami et al. reported a novel fluorescent anion sensor 326 that works in neutral aqueous solution for bioanalytical application. This molecule contains 7-amino-4-(trifluoromethyl)coumarin (300a) as a fluorescent reporter and Cd(II)-1,4,7,10-tetraazacyclododecane as an anion host. In neutral aqueous solution, Cd(II) of 326 is coordinated by the four nitrogen atoms of cyclen and the aromatic amino group of coumarin [184]. A colorimetric and fluorescent cyanide probe based on 4-(trifluoromethyl)coumarin 327 displays rapid response and high selectivity for cyanide over other common anions [185]. In order to develop coordination complexes that can be used as selective probes, fluorescent agents and inorganic medicinal agents, the design, synthesis, characterization and X-ray structure of new water-soluble monofunctional Pt(II) complexes with useful spectroscopic properties for assessing metal binding to biomolecules were investigated. Complex 328 was designed to allow the fluorophore group, coumarin 300a, to be attached to metal centers through the diethylenetriamine moiety [186]. Proline-substituted coumarin derivatives, such as compound 329, were prepared and used as environment-sensitive fluorescence probes. Phosphorylation and dephosphorylation of tyrosine derivatives labeled with the coumarin–proline conjugate induced marked changes in fluorescence intensity allowing phosphatase activity to be monitored [187] (Scheme 105).

A coumarin-based derivative 330, a highly selective and sensitive turn-on fluorogenic probe for the detection of hydrosulfate anion in aqueous solution, has been designed and synthesized. This compound exhibits a unique fluorescence change in the presence of the HSO₄ ⁻ ion and with high selectivity over other anions [188]. Compounds 331 were synthesized from 1-azulenecarboxaldehyde and 7-amino-4-(trifluoromethyl)coumarin (300a) and a very fast vibrational cooling process of azulene was studied by the transient absorption method using molecular integrated systems with a molecular thermometer. This is the first attempt to use the molecular heater–molecular thermometer integrated system for investigating the thermalization process from the solvent side [189] (Scheme 106).

To probe the steric requirements for deacylation, lysine-derived small molecule substrates, including coumarin derivative 332, were synthesized and their structure-reactivity relationships with various histone deacetylases were examined. It was found that compound 332, prepared from the corresponding lysine derivative and coumarin 300a in pyridine in the presence of POCl₃, is selectively deacetylated by HDAC6 in preference to HDAC1 and HDAC3. This indicated that the structure of N-Boc and trifluoromethyl coumaryl amide of 332 is selectively recognized by HDAC6 [190]. Suzuki et al. have identified novel HDAC6-selective inhibitors whose designs were based on the structure of the HDAC6-selective substrate 332. Thus, compound 333, in which the acetamide of 332 is replaced by a thioester function, was obtained from the corresponding bromide and thioisobutyric acid under alkaline conditions [191] (Scheme 106).

Novel calix[4]arene-based anion sensor 334 with two coumarin units attached via amido functions acting also as binding sites was described. This compound may be considered as a potential fluorescent chemosensor for F⁻. Reference calixarene 335 was also synthesized and its 1,3-alternate conformation was deduced from the ¹H NMR spectrum [192] (Scheme 107).

5.1.4 Applications of 7-Hydroxy-4-(Trifluoromethyl)Coumarin Derivatives

One-step reaction of 7-hydroxy-4-(trifluoromethyl)coumarin (300c) with TIPS-Cl provided compound 336 in 67 % yield, which was used to detect fluoride anions in organic and aqueous media, utilizing the specific affinity of fluoride anion to silicon [193]. Eighteen new fluorogenic analogues of organophosphorus nerve agents were synthesised and characterised. They included analogues of tabun, sarin, cyclosarin, and soman, with the 7-hydroxy-4-(trifluoromethyl)coumarin leaving group, for example, compound 337. These analogues inhibited acetylcholinesterase effectively in vitro and therefore have potential as tools for the identification of novel organophosphatases in biological systems [194]. A series of potent and highly subtype-selective PPARα agonists was identified through a systematic SAR study. Based on the results of superior in vivo efficacy in the two animal models, coumarin 338 was characterized in pharmacokinetic studies in three preclinical animal species. It exhibited low plasma clearance, good oral bioavailability, and no significant off-target activity was observed for 338. Unfortunately, the results for the stability studies of compound 338 indicated the lactone ring stability issues [195]. Bis-4-(trifluoromethyl)-7-hydroxycoumarins 339 (n = 0, 1) ended mono and diethyleneglycols were prepared starting from bis(3-hydroxyphenyl)glycols by Pechmann condensation using ethyl trifluoroacetoacetate. Accordingly, coumarin 300c was converted to bis-coumarin ended three and tetraethylenglycol derivatives 339 (n = 2, 3) by reacting with three and tetraethyleneglycols dichlorides in Na₂CO₃/DMF. The Li⁺, Na⁺ and Rb⁺ metal/ligand selectivities of cation binding behaviour of products in acetonitrile were studied with steady state fluorescence spectroscopy [196] (Scheme 108).

Woo et al. synthesized and examined coumarin sulfamates 340, of which 4-methylcoumarin 7-O–sulfamate was found to be the most effective nonsteroidal E1-STS inhibitors [197]. The coupling between the fluorescence properties of the (trifluoromethyl)coumarino fluorophore and the protolytic state of the ion binding moiety of two fluorescent cryptands 341 is investigated. The experimental results obtained with 341 indicate that the diprotonated state of the fluorescent cryptands exhibit a comparatively high quantum yield around 0.6 and are characterized by a single lifetime around 5.4 ns [198]. Coumarin 342, a fluorescent analogue of farnesyl pyrophosphate (FPP), was prepared and utilized to study ligand interactions with E. coli UPPs [199]. To explore the structural requirements of (+)-cis-khellactone derivatives as novel anti-HIV agents, 24 monosubstituted 3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives, including compound 343, were synthesized asymmetrically [200]. The metabolism of 7-benzyloxy-4-(trifluoromethyl)coumarin to 7-hydroxy-4-(trifluoromethyl)coumarin (300a) was studied in human liver microsomal preparations and in cDNA-expressed human cytochrome P450 (CYP) isoforms [201] (Scheme 109).

5.2 Synthesis and Reactions of 3-(Trifluoroacetyl)Coumarins

A series of ethyl 2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylates (344) was obtained in high yields via the Knoevenagel condensation of salicylaldehydes with ethyl trifluoroacetoacetate in the presence of piperidinium acetate. The subsequent recyclization of these chromenes proceeds smoothly in refluxing chlorobenzene in the presence of p-toluenesulfonic acid affording 3-(trifluoroacetyl)coumarins (345) in good yields [202]. These compounds were also prone to the facile and reversible covalent hydrate formation [120] (Scheme 110).

4-Chloro-3-(trifluoroacetyl)coumarin (346) was synthesized via direct TMSCl-mediated acylation of 4-hydroxycoumarin with trifluoroacetic anhydride (TFAA) followed by the treatment with POCl₃ [203] (Scheme 111).

Iaroshenko et al. reported that the reaction of 346 with anilines is a two-step method, which affords via substitution products 347 a set of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones (348) in concentrated H₂SO₄ at 70 °C in high yields [203] (Scheme 112).

Coumarin 346 also reacts with electron-rich aminoheterocycles, dimethyl 1,3-acetonedicarboxylate, hydrazines, alkyl thioglycolates, and methyl sarcosinate to give a variety of 3,4-heteroannulated coumarins 349a–h with an excellent regioselectivity and in moderate to high yields (41–85 %) [204] (Scheme 113).

Treatment of 346 with dimethyl 1,3-acetonedicarboxylate in dioxane in the presence of triethylamine at reflux gave the expected benzo[c]coumarin 350, whereas the reaction with methyl thioglycolate in dichloromethane at room temperature resulted in the formation of thienocoumarin 351 [204] (Scheme 114).

6 Conclusion

Analysis of the published data demonstrates that of the diverse fluorine-containing pyrones, chromones and coumarins, 2-(trifluoromethyl)-4-pyrones and 2-(polyfluoroalkyl)chromones, as well as 3-(polyfluoroacyl)chromones and chromones with the perfluorinated benzene ring have now been studied most comprehensively. Data on 3-fluoro- and 3-(trifluoromethyl)chromones and coumarins are quite scarce. Despite the ready accessibility of polyfluoroalkylated pyrones and chromones, these compounds have long remained out of sight of chemists engaged in synthesis, and their systematic study has started only in recent years. Nevertheless, it is already clear that these compounds and, in particular, trifluoromethylated analogues of natural oxygen-containing heterocycles are valuable substrates for the synthesis of diverse partially fluorinated heterocycles with a potential biological activity. Indeed, a polyfluoroalkyl group present at the C-2 atom of the pyrone system entails dramatic changes in the reactivity of this ring, which is manifested as a bunch of new transformations uncharacteristic of non-fluorinated analogues. In addition, the introduction of a polyfluoroacyl group into the 3-position of the chromone system also changes crucially the reactivity of the pyrone ring with respect to nucleophiles and stipulates the broad synthetic potential of 2-unsubstituted 3-(polyfluoroacyl)chromones. The diversity of properties of these compounds is due to the fact that, being actually highly reactive geminally activated alkenes with a good leaving group at the β-carbon atom, they acquire the ability to undergo additional reactions related to opening and transformation of the γ-pyrone ring.

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Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000, Ekaterinburg, Russian Federation
Vyacheslav Ya. Sosnovskikh

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Vyacheslav Ya. Sosnovskikh
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Correspondence to Vyacheslav Ya. Sosnovskikh .

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Department of Chemistry, Moscow State University, Moscow, Russia
Valentine Nenajdenko

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Sosnovskikh, V.Y. (2014). Fluorinated Pyrones, Chromones and Coumarins. In: Nenajdenko, V. (eds) Fluorine in Heterocyclic Chemistry Volume 2. Springer, Cham. https://doi.org/10.1007/978-3-319-04435-4_5

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DOI: https://doi.org/10.1007/978-3-319-04435-4_5
Published: 13 June 2014
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-04434-7
Online ISBN: 978-3-319-04435-4
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)

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