Polyfluorinated benzoic acids as promising reagents for organic synthesis and medicinal chemistry

Benzoic acid and its derivatives are widely used as stabilizers, catalysts and reagents in the production of coolants, solvents, plastics, textiles, pesticides, paper, dyes, pharmaceuticals, as well as preservatives and flavourings for food and cosmetics[1, 2]. A separate area of application for such compounds is pharmaceuticals. This is because benzoic acid per se occurs naturally in many plants and is a by-product in the biosynthesis of various secondary metabolites[3, 4]. Benzoic acid and its sodium salt are part of many pharmaceutical preparations and mixtures. For example, acerbine is used as an antiseptic, amsterol and thermopsis are used to treat coughs, the combined preparation caffeine – sodium benzoate is a psychostimulant, etc.

The significance of substituted benzoic acids and their derivatives for medical applications is invaluable. Commercially important benzamide drugs include the analgesics ethenzamide and procainamide, the antidepressant moclobemide, the antiemetics bromopride and cisapride, the neuroleptics sulpiride and tiapride, the diagnostic agent 4-aminohippuric acid, the cytostatics imatinib and procarbazine, and the antiparkinsonian drug raclopride. The group of pharmacologically important drugs that are esters of benzoic acids is even larger and more diverse in both composition and use.

2-Hydroxybenzoic acid and its derivatives, commonly known as salicylates, deserve special attention as they are among the longest-lasting drugs on the pharmaceutical market. Aspirin, methyl salicylate, trolamine salicylate, salsalate, acelisin, etc.[5] are entered in the register of clinically used non-steroidal anti-inflammatory drugs. By modifying the structure of salicylic acid, it has been possible to tune the biological action of its derivatives, which have shown new types of activity. The introduction of an amino group at positions 4 and 3 led to the antituberculosis drug PASA (p-aminosalicylic acid)[6] and the antiulcer drug mesalazine[7, 8], respectively. The importance of salicylic acid as a phenolic phytohormone that regulates plant physiological processes[9] should not be overlooked, and its derivatives are used to reduce the incidence of viral, bacterial and fungal infections in various crops[10-13].

Due to their wide demand, benzoic acid derivatives, including salicylates, occupy leading positions in organic synthesis as building blocks for the preparation of a variety of open-chain[5, 14-17], as well as carbo- and heterocyclic compounds[18-21]. In addition, benzoates and salicylates are widely used as ligands in coordination chemistry[22, 23] and as analytical reagents[24-26].

Polyfluorobenzoic acids can also play an important role in solving various applied problems, as the introduction of fluorine atoms into organic compounds is effectively and successfully used in chemistry to modulate the physicochemical and biological properties of the resulting products. Due to specific possibilities of chemical modification, fluorinecontaining compounds, especially polyfluoroaromatic compounds, occupy an important place in organic synthesis[27-29]; they are in great demand as reagents for the preparation of valuable organic products for use in technology, medicine and agriculture[30]. The enormous potential of such derivatives in targeted drug development is confirmed by the fact that ~30% of drugs contain at least one fluorine atom in their molecules, often as a substituent in the aromatic ring[31-39]. Examples include fluoroquinolone antibiotics (levofloxacin, ciprofloxacin, sparfloxacin, etc.), antifungal agents (fluconazole, voriconazole) and hypoglycemic agents (sitagliptin) (Figure 1). Salicylate derivatives are not neglected either. For example, diflunisal, which contains fluorine, has twice the anti-inflammatory effect of aspirin and is less irritating to the mucous membranes of the gastrointestinal tract[40]. Fluoroaromatic products are also widely used in agrochemicals: for example, diflufenican, flutriafol, flusilazole are used as herbicides, and polyfluorobenzoyl ureas (diflubenzuron, chlorfluazuron, teflubenzuron, flufenoxuron) and ethoxazole are used as insecticides[41, 42].

Figure 1

Polyfluoroarene-based pharmaceutical drugs and insecticides.

In addition, polyfluoroarenes have been used to obtain liquid crystals[43] and polymers, including dendrimers[44, 45], which can be used to fabricate matrices for organic light-emitting diodes (OLEDs) (Figure 2).

Figure 2

Polyfluoroarene-based functional materials.

Given the practical importance of polyfluorobenzoic acids and the great prospects for their chemical modification, there was a need to address these aspects in a single review, as no data on these compounds have been summarized and analyzed to date. The present review aims to fill this gap by presenting the chemical properties and assessing the potential applications of polyfluorobenzoic acids and their derivatives, including polyfluorosalicylic acid analogues, mainly in the field of medicinal chemistry. From a synthetic point of view, polyfluorobenzoic acids have clear potential for modifications, since in addition to the transformations of the carboxyl group and the aromatic core, which are also inherent in their nonfluorinated analogues, they are characterized by reactions involving the polyfluoroaromatic ring due to the activation of the C – F bond[28].

The most common ways to modify polyfluorobenzoic acids are the preparation of esters and amides therefrom. This is due not only to the relative simplicity of such reactions, but also to their great potential for the synthesis of a variety of biologically active products. The esters are mainly prepared using the classical esterification reaction by heating the reagents in excess alcohol in the presence of an acid catalyst[46-54]. Polyfluorobenzoic acid amides are preferably obtained directly from acids using peptide synthesis reagents (RPS) such as PyBOB (benzotriazol1-yloxytripyrrolidinophosphonium hexafluorophosphate), HATU (hexafluorophosphate azabenzotriazole tetramethyluronium), HOBt (N-hydroxybenzotriazole), DCC (1,3-dicyclohexylcarbodiimide) and others[55-60] or from their acid chlorides[60-67] in the presence of organic bases (pyridine, triethylamine, diisopropylethylamine (DIPEA), etc.) or without them (Scheme 1).

Scheme 1

The pool of alcohols and amines involved in such transformations is quite large, so we have confined ourselves to referring to current publications on the subject. Other methods for the synthesis of esters and amides and for the preparation of compounds of practical importance are discussed in more detail below. For example, 2-methoxy-2-oxo-1-phenylethyl pentafluorobenzoate was obtained in moderate yield by the reaction of pentafluorobenzoic acid and methyl phenyldiazoacetate in the presence of tropylium tetrafluoroborate (Trop) (Scheme 2)[68].

Scheme 2

The use of alkylating agents such as diazomethane[69], methyl iodide[70, 71], dimethyl sulfate[72] or ethyl iodide[73] in reactions with polyfluorosalicylic acids provided an approach to alkyl 2-alkoxypolyfluorobenzoates (Scheme 3). Partial hydrolysis of combined diesters was used to obtain ortho-alkoxy-substituted polyfluorobenzoic acids. For example, alkali treatment of methyl 2-methoxy-3,5,6-trifluorobenzoate and ethyl 2-ethoxy3,5-difluorobenzoate gives 2-methoxy-3,5,6-trifluorobenzoic acid[74] and 2-ethoxy-3,5-difluorobenzoic acid[73], respectively.

Scheme 3

Polyfluorosalicylic acids readily form acetylpolyfluorosalicylic acids under the action of acetic anhydride (Scheme 4; T is heating)[51, 75].

Scheme 4

In vivo tests have revealed a moderate anti-inflammatory effect of fluorinated analogues of aspirin and methyl 3,4,5-trifluorosalicylate[51]. In addition, fluorinated acetylsalicylic acids have a marked analgesic effect, superior not only to aspirin but also to diclofenac.

Hexadecanyl- and 10-chlorodecanyl-substituted tetrafluorosalicylates, synthesized from tetrafluorosalicylic acid and the appropriate alcohols by boiling in benzene over Amberlite IR120 ion exchange resin (Scheme 5), have properties that allow them to be considered as potential antifriction additives for advanced motor oils[76].

Scheme 5

The reaction of polyfluorobenzoic acids with [3-bromo-1-(3chloro-2-pyridyl)-1H-pyrazol-5-yl]methanol in the presence of DCC gave [3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl]methylpolyfluorobenzoates (Scheme 6), the difluoro derivative of which has insecticidal activity against the cabbage pests Plutella xylostella and Spodoptera frugiperda[77].

Scheme 6

Among the O-substituted esters of difluorosalicylic acid, biologically active compounds have been identified such as 6-[(4,6-dimethoxypyrimidin-2-yl)oxy]-2,3-difluorobenzoic acid and its methyl ester (1), which have herbicidal activity[78], and methyl 2-[phenyl(pyrrolidin-3-yl)methoxy]-3,5-difluorobenzoate 2, which are serotonin and noradrenaline reuptake inhibitors[79].

Structures 1, 2

Selective alkylation of 4,6-dihydroxy-2,3,5-trifluorobenzoic acid via the 4-hydroxyl group was carried out. For this purpose, the dihydroxy acid was first treated with pentafluorophenyltrifluoroacetate to afford pentafluorophenyl ester, which was further reacted with paraformaldehyde[80] or acetaldehyde[81] in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to give 7-hydroxy-5,6,8-trifluoro-4H-benzo[d][1,3]dioxin-4-ones (Scheme 7). The latter compounds were coupled with O-(4methoxytetrahydropyran-4-yl)-2'-deoxyuridine under Mitsunobu conditions to give O-(5-hydroxy-4-carboxy-2,3,6-trifluorophenyl)-2'-deoxyuridine in moderate yield (see Scheme 7, path a)[82, 83]. Treatment of benzo[d][1,3]dioxin-4ones with alkyl bromides and subsequent passing the intermediates through an ion exchange resin column furnished the target 4-alkoxy-substituted 3,5,6-trifluorosalicylic acids (path b)[80, 81]. O-(5-Hydroxy-4-carboxy-2,3,6-trifluorophenyl)-2'-deoxyuridine and similar acids containing geranyl- or farnesyl-substituted units showed inhibitory activity against Ras protein farnesyl transferase and geranylgeranyl transferase I, one of the key enzymes involved in proliferative processes[80, 82].

Scheme 7

An original method for the synthesis of 6-(6-hydroxy-3,5difluorobenzamido)hexanoic acid has been developed[84]. First, 3,5-difluorosalicylic acid was refluxed in xylene in the presence of a small excess of acetic anhydride, resulting in oligosalicylate which was reacted with aminocaproic acid without isolation (Scheme 8).

Scheme 8

Rearrangements of nitrone derivatives have also been used to prepare polyfluorosalicylic acid amides. For example, α-pentafluorophenyl-N-phenylnitrones form tetrafluorosalicylic acid arylamides on heating in DMF under acidic conditions[85] or on refluxing in toluene[86] (Scheme 9).

Scheme 9

The EDC-mediated condensation of 2-methoxymethoxy-3,6-difluorobenzoic acid with 3-amino-2-ethyl-N-(3-fluorophenylethyl)but-2-enamide in the presence of hydroxybenzotriazole was used to synthesize amide A, the cyclization of which in the presence of alkali gave 2-(2-hydroxy-3,6-difluorophenyl-6-methyl-3-[2-(3-fluorophenyl)ethyl]-5-ethyl-4(3H)-pyrimidone (Scheme 10)[87].

Scheme 10

The methyl esters of perfluoro-3,4,5-trifluorosalicylic acid have been shown to react with ammonia in methanol on heating to give the corresponding amides, which are converted to acids when heated in hydrochloric acid solution (Scheme 11)[88]. 3,4,5-Trifluorosalicylic acid amide in the in vivo tests showed a pronounced analgesic effect in the hot plate test along with low acute toxicity.

Scheme 11

In contrast to reactions with ammonia, polyfluorosalicylate esters form stable salts in reactions with diethylamine (Scheme 12)[89]. At the same time, polyfluorosalicylic acid ethyl esters give N,N-diethylammonium 2-hydroxypolyfluorobenzoates and methyltetrafluorosalicylate gives N,N-diethylammonium 6-methoxycarbonyl-2,3,4-trifluorophenolate. However, methyl tetrafluorosalicylate forms the same product as its ethyl counterpart.

Scheme 12

The reaction of 3,4-difluorosalicylic acid methyl ester with 2,2-diphenylethylamine at 110 °C yields N-(2,2-diphenylethyl)2-hydroxy-3,4-difluorobenzamide (Scheme 13), which selectively inhibits dihydroorotate dehydrogenase, an enzyme of the malaria parasite Plasmodium falciparum, at micromolar concentrations[90].

Scheme 13

Based on 4,5-difluorosalicylic acid and 2-methoxy-4,5-difluorobenzoic acid, conjugates with tacrine linked via an amidoalkylene spacer have been obtained (Scheme 14). Such products are able to inhibit acetyl-(AChE) and butyrylcholinesterase at micromolar concentrations and block AChE-induced β-amyloid aggregation, as well as have antioxidant and metal chelating properties, allowing them to be considered as promising multitarget agents for the treatment of Alzheimer’s disease[91].

Scheme 14

By the reaction of tetrafluorophthalic anhydride with primary (cyclo)alkylamines[92] or with aminobarbituric acid derivatives[93, 94], a series of 2,3,4,5-tetrafluorobenzamides with antiangiogenic properties have been obtained (Scheme 15).

Scheme 15

A large number of publications, most of them patents, are devoted to polyfluorosalicylate amides, which have different biological effects depending on the variation of the amide moiety. For example, 3,4-difluorosalicylic acid amide (3) has been patented as an antagonist of M 3-muscarinic receptors, which is promising for the development of a drug for the treatment of asthma and chronic obstructive pulmonary disease[95, 96]. The patent[97] describes (±) N-(2-hydroxy-5-oxo-7oxabicyclo[4.1.0]hept-3-en-3-yl)-2-methoxy-3,4-difluorobenzamide (4), which is capable of inhibiting the transcription factor NF-κB, dysregulation of which triggers inflammatory processes, autoimmune diseases, viral infections and cancer. 2-(6-Hydroxy-2,4-difluorobenzamido)-5-(morpholin-4-ylsulfonyl)-thiophene-3-carboxamide (5) has been proposed as a therapeutic agent for the treatment of cystic fibrosis[98]. Amides 6 showed antiproliferative activity against 22RV1 and LNaP95 cancer cells causing prostatitis[62, 63]. N-[3-Chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxy-3,5-difluorobenzamide (7) showed properties as an inhibitor of human pancreatic lipase[58], the same compound is claimed in a patent[99] as a potential treatment for dengue fever.

Structures 3 – 16

A number of polyfluorosalicylic acid amides 8 have been patented as anticoagulants[100]. Alen et al.[101] propose to use the sepiapterin reductase inhibitor (6-azaspiro[3.4]octan-6-yl) (6-hydroxy-2,4-difluorophenyl)methanone (9) to create new potent analgesics. Polyfluorinated N-([4-oxo-6-fluoro-7(cyclohexylamino)-1-cyclopentyl-1,4-dihydroquinolin-3-yl] methyl)-2-hydroxybenzamides 10 have been claimed as inhibitors of platelet aggregation and P2Y12 receptors[102]. Salicylamide 11, which contains a polynuclear heterocyclic moiety, has been shown to be an effective inhibitor of B-cell lymphoma protein 6 (BCL-6)[57].

Polyfluorobenzoic acid amides also proved to be a convenient platform for the generation of promising physiologically active compounds. For example, N-{4-[3-(1-methyl-1H-imidazol-2yl)-3-oxoprop-1-en-1-yl]phenyl}-2,3,4,5,6-pentafluorobenzamide 12 has anticancer activity against HCT-116 and NCI-H522 cell lines[103], and polyfluoro-substituted amides 13 bearing a coumarin residue 67 showed activity against the MCF-7, T47D, MDA-MB-231 and SkBr3 cancer cell lines in the micromolar concentration range. N-[4-(Hydroxycarbamoyl)benzyl]-2,3,4,5,6-pentafluorobenzamide (14) was found to be a selective inhibitor of histone deacetylase 6 (HDAC6), which causes hematological malignancies. N-(5-Sulfamoyl-2,3-dihydro-1H-inden-2-yl)-2,3,4,5,6-pentafluorobenzamide (15) has moderate anticonvulsant activity[104], while pentafluorobenzamide 16 with a polynuclear amine moiety has shown activity against MCF-7 breast cancer cell cultures and the adriamycin-resistant MCF-7/ADR cell line[105].

The development of biologically active amides based on substituted polyfluorosalicylic acids proved promising. For example, [2-(4-bromo-2-fluorobenzylcarbamoyl)-4,5-difluorophenoxy)]acetic acid (17) was patented as a potent inhibitor of human aldose reductase 2 (hALR2), an enzyme responsible for complications in diabetes mellitus[106]. N-(3-Carbamoyl-4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3,4-trifluorobenzamide 18 was found to be a Na_v1.8 sodium channel blocker[107]. (S)-2-tert-Butoxy-2-[6-methyl-1-(2-methoxy-3,6-difluorobenzoyl)-4-(p-methylphenyl)-2,3-dihydroindol-5-yl]acetic acid (19) and (S)-2-tert-butoxy-2-[6-methyl-1-(2-methoxy-3,4-difluorobenzoyl)-4-(5-methyl-8-fluorochroman-6-yl)-2,3-dihydroindol-5-yl]acetic acid (20) showed properties of potent inhibitors of human immunodeficiency virus (HIV-1)[108].

Structures 17 – 20

To summarize, the above data indicate the prospects for the development of new methods for the synthesis of amides and esters of polyfluorobenzoic and polyfluorosalicylic acids as privileged scaffolds for medicinal chemistry.

The reduction of the carboxyl function in polyfluorobenzoic acids is used to obtain polyfluoroaryl-substituted benzyl alcohols. A number of methods are reported for the synthesis of pentafluorobenzyl alcohol by reduction of the carboxyl group in pentafluorobenzoic acid with zinc(II) borohydride, generated in situ from zinc(II) chloride and sodium borohydride[109], using a catalytic system consisting of zinc(II) acetate, phenyl silane and N-methylmorpholine[110], and in the presence of titanium(IV) chloride and borazane[111] (Scheme 16). Using lithium aluminium hydride, this process is also accompanied by reductive defluorination to give 2,3,5,6-tetrafluorobenzyl alcohol[109].

Scheme 16

The carboxyl group in polyfluorobenzoic acids can be sequentially converted into alcohol and aldehyde functions. Thus, reduction of the carboxyl substituent in difluorosalicylic acids with LiAlH₄ (see [112, 113]) or BH₃ · Me₂S (see [114]) affords 3,5-difluoro-, 3,4-difluoro- and 4,5-difluoro-2-(hydroxymethyl)phenols (Scheme 17). Oxidation of alcohols with pyridinium chlorochromate (PCC) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) opened the way to difluorosalicylic aldehydes[113, 114].

Scheme 17

Decarboxylation of polyfluorobenzoic acids is used to produce polyfluorobenzenes. For example, it has been shown that polyfluorobenzoic acids can be decarboxylated by heating in a sealed ampoule in the presence of Cu₂O and 1,10-phenanthroline (phen) (Scheme 18)[115].

Scheme 18

The synthesis of polyfluorobenzenes is also accessible by heating polyfluorobenzoic acids in a toluene – water mixture in the presence of the catalytic system [(COD)Rh(OH)₂ – 1,3-bis(diphenylphosphino)propane (DPPP) and a base (NaOH) (Scheme 19)[116].

Scheme 19

The use of polyfluorosalicylic acids in decarboxylation reactions is an effective approach to polyfluorophenols which are difficult to obtain. Thermal decarboxylation of perfluoro(see [117]) and 3,5,6-trifluorosalicylic acids[117, 118] is carried out in a sealed ampoule at temperatures of 270 – 300 °C for 3 – 7 h (Scheme 20) to give 2,3,4,5-tetrafluoro-2,4,5-trifluorophenols.

Scheme 20

Depending on the conditions, decarboxylation of 2,6-dimethoxy-3,4,5-trifluorobenzoic acid affords 4,5,6-trifluororesorcin or its dimethyl ester (Scheme 21)[119].

Scheme 21

Modern approaches to the modification of polyfluorobenzoic acids or their salts, which have been actively developed in recent years, are metal-catalyzed decarboxylative cross-coupling reactions used for the synthesis of biaryl or aryl-hetaryl derivatives. A process has been proposed for the preparation of a variety of biaryl compounds (Scheme 22), based on the reaction of potassium polyfluorobenzoates with (het)aryl halides or triflates in the presence of the catalytic system Pd(OAc)₂ (0.01 – 0.04 equiv.) – PCy₃ or P(o-Tol)₃ (0.02 – 0.08 equiv.)[120]. The same research group[121] showed that cheaper copper(I) iodide could be used in this reaction. However, (het)aryl chlorides could not be involved in the cross-coupling under these conditions, so this process was successfully carried out for (het)aryl iodides and bromides in the presence of phen as a ligand. Notably, the highest yields of products were reached with pentafluorobenzoic acid, whereas a decrease in the number of fluorine atoms often led to a decrease in the yield of the target biaryls, down to trace amounts.

Scheme 22

Copper(I) iodide immobilized on a solid support (mesoporous MCM-41) and functionalized with the phen ligand was proposed as a renewable catalyst for the cross-coupling of potassium salts of polyfluorobenzoic acids with aryl halides (Scheme 23)[122]. This method not only allows the catalyst to be recovered many times without a significant decrease in the yield of the target product, but also increases the yield of biaryls based on di- or trifluorobenzoic acids.

Scheme 23

For the cross-coupling of potassium polyfluorobenzoates with (het)aryl halides or pseudohalides, the Ni(COD)₂ catalyst was also used in the presence of Bu₃^tP · HBF₄, 1,1'-(diphenylphosphino)ferrocene (DPPF) or 2-[2-(dicyclohexylphosphino)phenyl]-1-methyl-1H-indol (CM-Phos) as phosphine ligands (Scheme 24)[123].

Scheme 24

The Ni(COD)₂ catalyst was also utilized in the synthesis of biaryls or diarylmethanes via the reaction of potassium polyfluorobenzoates with arylpivalates, arylsulfamates or arylmethylpivalates, but in this case it was necessary to add zinc(II) acetate to the reaction mixture (Scheme 25)[124]. It was also found that in the absence of the second aryl reagent, decarboxylation of potassium pentafluorobenzoate gives pentafluorobenzene.

Scheme 25

It has been shown[125] that zinc salts of polyfluorobenzoic acids can be effectively used in the decarboxylative crosscoupling, and the reaction with (poly)aryl bromides or nonaflates runs in the presence of the catalyst Pd(PPh₃)₄ under milder conditions (heating up to 60 °C) (Scheme 26). This approach provided the preparation of a large number of bis- and polyaryl derivatives (Figure 3).

Figure 3

Examplary polyaryl structures obtained by the cross-coupling reaction (see Scheme 26).

Scheme 26

Polyfluorobenzoic acids per se have also been involved in decarboxylative cross-coupling reactions, but these have been carried out under Suzuki conditions using arylboronic acids, palladium(II) trifluoroacetate as catalyst and silver(II) carbonate as the base[126]. At the same time, the replacement of the catalyst with copper(II) triflate in the reaction of 4-methoxy-2,6-difluorobenzoic acid with phenylboronic acid gave O-phenylsubstituted 4-methoxy-2,6-difluorobenzoate (Scheme 27).

Scheme 27

In addition, polyfluorobenzoic acids can undergo Pdcatalyzed C – H functionalization with (het)arenes (Scheme 28) such as benzene and its substituted analogues[127, 128], (benzo)thiazoles[127], 4-methylfuran[129], 4-substituted thiophenes[128, 130] and indole[131]. The reaction requires the presence of a silver(II) carbonate base and sometimes the addition of a phosphonium ligand. As a result of these processes, the range of known polyfluorinated biaryl and aryl-hetaryl derivatives has been greatly expanded.

Scheme 28

The use of N-methylpyridinium iodide and its benzoanalogues in the C – H functionalization of polyfluorobenzoic acids promoted by CuBr₂ and the phase transfer catalyst tetra-n-butylammonium bromide (TBAB) in the synthesis of 2-polyfluorophenylpyridines, 2,6-difluorophenylpyridine and 1-polyfluorophenyl(iso)quinolines has been described (Scheme 29)[132].

Scheme 29

It has been shown that polyfluorobenzoic acids or their salts can undergo decarboxylative cross-coupling with (benz)oxazoles in the presence of a nickel catalyst, NiCl₂(PCy₃)[133] or Ni(OTf)₂ (see [134]), to give 2-polyfluorophenyl(benz)oxazoles (Scheme 30).

Scheme 30

Polyfluorobenzoic acids were found to undergo self-coupling with double decarboxylation in the presence of palladium[135] or copper[136] catalysts to furnish symmetrical polyfluorobiaryls (Scheme 31).

Scheme 31

In addition, polyfluorobenzoic acids can undergo crosscoupling with other (het)arylcarboxylic acids under the action of the PdCl₂ – PPh₃ catalytic system in the presence of silver(II) carbonate, leading to asymmetric biaryl or aryl-hetaryl derivatives (Scheme 32)[135]. The moderate yields of the target products are explained by the formation of symmetric biaryl byproducts.

Scheme 32

The pool of reagents subjected to cross-coupling reactions with polyfluorobenzoic acids and their potassium salts has been extended by the use of styrenes. Such transformations were carried out under the catalysis of Pd(O₂CCF₃)₂ in the presence of Ag₂CO₃ to produce styryl-polyfluorobenzenes (Scheme 33)[137]. It should be noted that these reactions are sometimes accompanied by decarboxylation of the starting polyfluorobenzoic acids, which decreases the yield of the target products.

Scheme 33

1,2,3,4,5-Pentafluorostilbene was obtained from potassium pentafluorobenzoate and (2-bromoethyl)benzene in the presence of the CuI – phen catalytic system (Scheme 34)[121].

Scheme 34

The outcome of the reaction of polyfluorobenzoic acids with α,β-unsaturated carbonyl compounds in the presence of the catalyst [(COD)Rh(OH)]₂ and NaOH base depends on the phosphonium ligand used. Thus, in the case of (4R,5R)-(–)-4,5-bis(diphenylphosphanylmethyl)-2,2-dimethyl-1,3-dioxolane (DIOP), mainly alkyl 3-(polyfluorophenyl)prop-2-enoates or 3-(polyfluorophenyl)prop-2-enamides are formed[116], whereas the use of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) gives alkyl-3-(polyfluorophenyl)propanoates or 3-(polyfluorophenyl)propanamides (Scheme 35)[138].

Scheme 35

It was shown that polyfluorobenzoic acids react with allyl acetate when heated in a mixture of DMSO – dioxane in the presence of catalysts Pd(OAc)₂, Cu₂O and oxidant Ag₂CO₃ to form a mixture of 3-(polyfluorophenyl)allyl acetate (as E,Z-isomers) and 2-(polyfluorophenyl)allyl acetate in a ratio of ca. 20 : 1 (Scheme 36)[139].

Scheme 36

However, attempts to use butadiene in the cross-coupling reaction with polyfluorobenzoic acids in the presence of the catalytic system [Rh(COD)Cl]₂–tri(2-furyl) phosphine (TFP) resulted only in the formation of esters, (but-3-en-2-yl)polyfluorobenzoates (Scheme 37)[140].

Scheme 37

Summarizing the information given in this Section, it can be concluded that metal-catalyzed cross-coupling reactions of polyfluorobenzoic acids provide access to a diversity of (het)aryl-containing polyfluoroarenes.

In addition to cross-coupling, polyfluorobenzoic acids are known to undergo decarboxylative thiolation, halogenation and acylation reactions and also combinations of these transformations with cross-coupling.

In the reaction of pentafluorobenzoic acid and thiophenol mediated by the CuI – phen system, in addition to thiolation, nucleophilic substitution of the fluorine atom in the para position occurs to afford (perfluoro-1,4-phenylene) bis(phenylsulfane) (Scheme 38)[141].

Scheme 38

The potassium salts of polyfluorobenzoic acids undergo a decarboxylative acylation with (het)aroyl fluorides to give the corresponding biaryl ketones or aryl-hetaryl ketones (Scheme 39)[142], without the need for catalysts and/or bases.

Scheme 39

Polyfluorobenzoic acids undergo halogenation along with decarboxylation by sequential treatment first with a Bu₃^t PAuCl complex in the presence of Ag₂O and then with halosuccinimides[143] using TBAB[144] or iodine[145] under the action of a base (K₃PO₄) (Scheme 40).

Scheme 40

It was shown that consecutive reactions of iodination of 2,6-difluorobenzoic acid with iodine and cross-coupling of the intermediate with pentafluorobenzoic acid under the action of the CuI – phen catalytic system give 2,2',3,4,5,6,6,6'-heptafluoro-1,1'-biphenyl (Scheme 41)[145].

Scheme 41

An original synthetic approach to fluorinated biaryls, styrylpolyfluorobenzenes and arylethynylpentafluorobenzenes based on pentafluorobenzoic esters of ketoximes by cleavage of O – N, С–С bonds and subsequent arylation followed by decarboxylation has been proposed (Scheme 42)[146].

Scheme 42

Metal-catalyzed reactions of pentafluorobenzoyl oximes, in which the polyfluorobenzoic acid residue acts as an auxiliary group to generate the iminyl radical, have been reported (Scheme 43). The subsequent transformations include several directions, which are discussed in detail in the review articles: for example, aza-Heck cyclization[147-156], as well as functionalization of C(sp³) – C(sp³) and C(sp³) – H bonds[156-159]. The realization of transformations involving pentafluorobenzoate as the leaving group opens up possibilities for the synthesis of a wide range of open-chain and heterocyclic compounds.

Scheme 43

To conclude, the analysis of the data considered in this Section shows that the decarboxylation of polyfluorobenzoic acids can be used to introduce new groups of different nature into the molecule.

Partially fluorinated benzoic acids and their derivatives can undergo C – H functionalization reactions that are also typical of non-fluorinated analogues. Thus, a method has been proposed for the selective Pd-catalyzed ortho-hydroxylation of difluorobenzoic acids with hydrogen peroxide in the presence of [2-methyl-2-(6-oxo-1,6-dihydropyridin-2-yl]propanoic acid (L3) to give the corresponding difluorosalicylic acids (Scheme 44)[113].

Scheme 44

A series of substituted biaryls have been synthesized by the C – H functionalization reaction of di- and trifluorobenzamides with aryl bromides, using palladium(II) chloride as a catalyst (Scheme 45)[160]. It should be noted that the arylation proceeds regioselectively, exclusively to the ortho position relative to the two fluorine atoms in the benzene ring.

Scheme 45

3,5-Difluorobenzamide reacts with 2-bromobenzyl bromides in the presence of palladium(II) acetate to give 2-(2-bromobenzyl)-3,5-difluorobenzamides (Scheme 46)[161].

Scheme 46

It has been shown that N-disubstituted di(trifluorobenzamides) can also undergo a Pd-catalyzed C – H functionalization with ethyl acrylate to yield ethyl 3-{3-[(4-nitrophenylsulfonyl) (2-cyanophenethyl)carbamoyl]-2,4-difluorophenyl}acrylates 21 (Scheme 47)[162].

Scheme 47

Methods for the selective reductive hydrodefluorination at the para-position of polyfluorobenzoic acids by treatment with zinc in liquid[163, 164] or aqueous ammonia[165] have been reported (Scheme 48). The use of the reductive sodium – liquid ammonia system in this reaction produces a mixture of (fluoro)benzoic acids[163, 164].

Scheme 48

The esters and amides of pentafluorobenzoic acid undergo selective monohydrodefluorination at para position in DMSO when treated with sodium borohydride (Scheme 49)[166].

Scheme 49

A similar process for esters has also been carried out under photocatalytic conditions in the presence of Ir(ppy)₃ complex (ppy is 2-phenylpyridine)[167] but in this case, the yields of products were somewhat lower. Methyl 4-amino-2,3,5,6-tetrafluorobenzoate is characterized by selective dehydrodefluorination of the ortho-fluorine atom to give methyl 4-amino-3,5,6-trifluorobenzoate[167].

Treatment of pentafluobenzoic acid solution with zinc in the presence of 0.01 equiv. of the NiCl₂ – 2,2'-bipyridine (bipy) system leads to selective reductive hydrodefluorination of the ortho-fluorine atom and formation of 2,3,4,5-tetrafluorobenzoic acid. With 0.05 equiv. of this system, hydrodefluorination of both ortho-fluorine atoms takes place to give 3,4,5-tetrafluorobenzoic acid (Scheme 50)[168]. It should be noted that the regioselectivity of the process reduces dramatically when pentafluorobenzoic acid ethyl ester or amide is involved in this reaction, since incomplete conversion of the starting materials is observed, and in both cases a mixture of ortho- and para- defluorinated products is formed.

Scheme 50

The selective monohydrodefluorination of the ortho-fluorine atom in pentafluorobenzoic acid and in 2,6-difluorobenzoic acid in THF by heating in the presence of 0.2 equiv. of ytterbium(II) complex YbCp₂(DME) (Cp is cyclopentadienyl, DME is 1,2-dimethoxyethane), 2 equiv. of magnesium and 0.02 equiv. of iodine has been described (Scheme 51)[169].

Scheme 51

By varying the reaction conditions, including the amount of a base (DIPEA) and the reaction temperature, Kharbanda and Weaver 115 succeeded in carrying out mono-, di- and trihydrodefluorination in methyl pentafluorobenzoate to obtain the corresponding methyl esters of 2,3,5,6-tetrafluoro-, 2,3,5-trifluoro-3,5-difluorobenzoic acids (Scheme 52). Methyl 2,3,5,6-tetrafluorobenzoate was further subjected to Pdcatalyzed C – H functionalization mediated with 1-iodo-3,5-dimethyl- or (3-chloroprop-1-en-1-yl)benzenes to give the corresponding 4-substituted products.

Scheme 52

It should be noted that the transformations of arylamides of pentafluorobenzoic acids under similar conditions are less selective because the reaction produces mixtures of mono- and dihydrodefluorinated derivatives 22 – 26. The ratio of these products depends not only on the amount of DIPEA and water, but also on the structure of the aryl moiety (Scheme 53)[115].

Scheme 53

Under similar conditions, a photocatalytic cross-coupling of polyfluorobenzoate esters with (het)arenes was carried out without isolating the hydrodefluorinated intermediate, resulting in the synthesis of biaryl derivatives and 4-(pyrrol-3-yl)substituted methyl esters of 2,3,5,6-tetrafluorobenzoic acid (Scheme 54)[170].

Scheme 54

To summarize, the conditions for selective para- and ortho- hydrodefluorination of polyfluorobenzoic acids, their esters and amides are described, and the possibility of polyhydrodefluorination reactions is also demonstrated.

For the modification of polyfluorobenzoic acids, their esters and amides, the nucleophilic aromatic substitution of fluorine atoms (S_NAr^F) reactions, which allow the introduction of various moieties, including pharmacophore ones, into the polyfluorobenzoate molecule, have great potential.

It has been shown that the fluorine atom in the para position of pentafluorobenzoic acid or its esters is easily substituted under the action of various nucleophilic reagents such as sodium methoxide, sodium methanethiolate, hydrazine[171], sodium hydrosulfide[172], mercaptoethanol[173], imidazole[174] (Scheme 55). However, the reaction of pentafluorobenzoic acid with an ethanol solution of methylamine or dimethylamine produces a mixture of products from which para- and ortho-N-(di)methylsubstituted tetrafluorobenzoic acids could be isolated[171], with the starting acid not reacting with aqueous ammonia.

Scheme 55

Reactions of polyfluorobenzoic acids via the S_NAr^F mechanism are actively used to introduce the hydroxyl function, and the search for selective methods of para- and ortho- hydroxylation has become the main trend of such studies. Of particular interest is the development of approaches to o-hydroxypolyfluorobenzoic acids as fluorinated analogues of salicylic acid.

Fluorine atoms in polyfluorobenzoic acids can be easily replaced with the OH group in 1,3-dimethylimidazolidin-2-one (DMI) upon heating with alkali[175-177]. Not only the number of fluorine atoms in the benzene ring, but also their position affects the process selectivity. Thus, when 2,4-difluoro-2,3,4-trifluorobenzoic acids are treated with sodium hydroxide, the content of the resulting ortho-hydroxy isomers in the mixture reaches 99 and 99.8%, respectively, and their isolated yield is almost quantitative (95%) (Scheme 56, Table 1)[177]. Under similar conditions, in 2,4,6-trifluorobenzoic acid, only one of the ortho-fluorine atoms is predominantly substituted and the ratio of ortho- to para-isomers reaches 97 : 3. The reaction of 2,4,5-trifluorobenzoic acid with alkali is less selective, the ratio of ortho- to para-isomers being 72 : 28. The authors of patents[178, 179] claim that, under similar conditions, 2,4,5-trifluorobenzoic acid is selectively converted to 4,5-difluorosalicylic acid, although no convincing evidence of the structure of the product is provided, except for the ¹H NMR spectrum, which is not very informative in this case. If the number of fluorine atoms is increased to 4 or 5, the process becomes even less selective, since 2,3,4,5-tetrafluorobenzoic acid in this reaction gives a mixture of products in the ratio 67 : 33, whereas the reaction of pentafluorobenzoic acid with NaOH furnishes only a hard-to-separate mixture of products[177] (see Scheme 56 and Table 1). It should be noted that the 3,4,5-trifluoroand tetrafluorosalicylic acids thus synthesized could not be isolated in pure form.

Scheme 56

Table 1

\[ \]

Products of hydroxylation of fluorobenzoic acids (see Scheme 56).

(1)

A similar method is used for the preparation of the isomeric 3,4-difluoro- (see [55, 57, 180-182]) and 2,4-difluorosalicylic acids[183].

3,5-Difluorosalicylic acid was synthesized by the reaction between 2,3,5-trifluorobenzoic acid and alkali on heating in DMSO (Scheme 57)[70, 172].

Scheme 57

It should be noted that this acid can be used as an additive to herbicides such as paraquat and atrazine to increase their efficacy against tobacco mosaic virus and reduce their toxic effect on tobacco[184-188].

Our research group[119, 189] found a selective ortho-substitution of the fluorine atom in pentafluorobenzoic acid under the action of magnesium methoxide. As a result, 2-methoxytetrafluorobenzoic acid is formed, which is hydrolyzed in situ to tetrafluorosalicylic acid in 42% yield (Scheme 58). The proposed mechanism of methoxylation involves the initial formation of intermediate I through the addition of magnesium methoxide to the carboxyl group. Due to the specific coordinating ability of the magnesium atom, the fluoride ion is eliminated on heating and the methoxide anion is subsequently attached to the ortho-position of intermediate II[119]. For pentafluoro (see [190]) and 2,3,5,6-tetrafluorobenzoic acids[51], the optimum conditions for the selective substitution of one of the ortho-fluorine atoms were chosen including the use of 2.5 equiv. of Mg(OMe)₂ in boiling toluene and 3.5 equiv. of Mg(OMe)₂ when heating in diglyme. The mixtures of the resulting methoxy-substituted acids II were treated with PCl₅, which made possible to separate the corresponding 2-methoxypolyfluorobenzoic acid chlorides by distillation. Treatment of the latter with 48% HBr solution gave tetrafluoro- and 3,5,6-trifluorosalicylic acids (see Scheme 58). Hydrolysis of 2-methoxy-3,4,5,6-tetrafluorobenzoic acid chloride with 20% NaOH solution at room temperature afforded 2-methoxytetrafluorobenzoic acid in individual form[190].

Scheme 58

When pentafluorobenzoic acid is reacted with 12 equiv. of magnesium methoxide on heating in toluene or diglyme, both ortho-fluorine atoms are substituted to give 2,6-dimethoxy-3,4,5-trifluorobenzoic acid (see Scheme 58).

In the case of polyfluorobenzoic acids with only one ortho- fluorine atom, the synthesis is not complicated by the formation of disubstitution by-products, and the mono-ortho-methoxylation proceeds selectively, providing virtually quantitative yields of the target polyfluorosalicylic acids (Scheme 59)[190].

Scheme 59

In our opinion, this method is the most promising approach to polyfluorosalicylic acids, especially to those containing more than three fluorine atoms in the benzene ring, because of the simplicity of the equipment and the availability of starting compounds. This approach allows not only to obtain high purity polyfluorosalicylic acids in good yields, but also to produce them for biological studies. It should be noted that tetrafluoro-, 3,4-difluoro- and 4,5-difluorosalicylic acid[190] has a pronounced antimycobacterial activity against Mycobactérium tuberculosis H₃₇Rv, M. avium, M. terrae and multidrug-resistant (MDR) strains, with a minimum inhibitory concentration (MIC) ranging from 0.7 to 1.5 mg ml ^–1. Moreover, tetrafluorosalicylic acid has a weak antifungal activity against pathogenic fungi of the genus Trichophiton (MIC = 25 – 50 mg ml^–1). Tetrafluoro-, 3,4,5-trifluoro-, 3,5,6-trifluorosalicylic acids and 2-methoxy derivatives of tetrafluoro- and 3,4,5-trifluorosalicylic acids showed anti-inflammatory activity in the carrageenan-induced paw edema test in vivo comparable to that of aspirin[51]. The same compounds and 4,5-difluorosalicylic acid showed analgesic activity in the hot plate test. In vitro tests have shown that their mechanism of action as potential non-steroidal anti-inflammatory agents is due to inhibition of cyclooxygenase-1 (COX-1).

In studying the reactions of ethyl pentafluorobenzoate with sodium ethoxide at room temperature, it was found that the selectivity of the fluorine atom substitution can be adjusted by varying the ratio of ethanol to diethyl ether (Scheme 60)[191]. It should be noted that the reaction of pentafluorobenzoic acid methyl ester with sodium methoxide is less selective, since even in excess of methanol a 53 : 48 mixture of ortho- and para- methoxy-substituted isomers is formed[192].

Scheme 60

Methyl 4-methyl-2,3,5,6-tetrafluorobenzoate reacts with sodium methoxide to give a 6-methoxy derivative (Scheme 61)[193, 194].The authors report high yields of the ortho- substituted ester and deny the formation of by-products, but the patent[193] uses the preparative chromatography to purify the final product, which casts doubt on the above data. At the same time, it was found that when the methyl ester of 4-benzylamino-2,3,5,6-tetrafluorobenzoic acid was treated with sodium methoxide, even at room temperature, both ortho-fluorine atoms were readily substituted to give a dimethoxy ester (see Scheme 61)[195, 196].

Scheme 61

Benzyl pentafluorobenzoate can undergo double nucleophilic substitution of ortho- and para-fluorine atoms under the action of benzyl alcohol in THF in the presence of potassium tert-butoxide to give a 2,4-disubstituted ether but this process is not selective and is accompanied by the formation of a 2,4,6-trisubstituted product (Scheme 62)[81]. The same compounds can be obtained by the analogous reaction of the benzyl 4-benzyloxy-2,3,5,6-tetrafluorobenzoate[80]. Hydrogenolysis of benzyl 2,4-bis(benzyloxy)-3,5,6-trifluorobenzoate gives 4,6-dihydroxy-2,3,5-trifluorobenzoic acid[80, 81].

Scheme 62

Under the action of sodium azide, the fluorine atom in the para position of pentafluorobenzoic acid esters is easily replaced by the azide group upon heating in aqueous acetone (Scheme 63)[197]. The introduction of the azide function is promising for subsequent modifications since it can be selectively reduced to the amino group with tin(II) chloride[198, 199] or copper(II) sulfate in the presence of sodium ascorbate[200] to give 4-amino-2,3,5,6-tetrafluorobenzoic acid or its methyl ester. 4-Azido-2,3,5,6-tetrafluorobenzoic acid[201] and its methyl ester[202] undergo a Staudinger reaction with triarylphosphines to give 4-[(triarylphosphoranylidene)amino] derivatives. For 4-azido-substituted tetrafluorobenzoates, azide-alkyne addition reactions have been studied, leading to the synthesis of a series of 4-(1,2,3-triazol-1-yl)-2,3,5,6-tetrafluorobenzoic acids[203-210]. In addition, transformations of methyl 4-azidotetrafluorobenzothiazole in [3+2] cycloaddition reactions with aldehydes[211, 212] and thioacetic acid (TAA)[213] to give amides, and with enamines[214, 215] to give amidines have been described (see Scheme 63).

Scheme 63

As shown above, esters of polyfluorosalicylic acids react with ammonia to give the corresponding amides (see Scheme 11). In this context, the synthesis of 4-aminopolyfluorosalicylic acids[88] is achieved through the preliminary preparation of 4-azidopolyfluorosalicylates by substitution of the fluorine atom at the activated 4-position with sodium azide. The reduction of the azide function was carried out under the action of zinc metal in the presence of NH₄Cl in refluxing methanol to give methyl 4-amino-2-hydroxy-2,3,5-trifluoro(or 3,5-difluoro)-benzoates, the hydrolysis of which afforded the corresponding benzoic acids (Scheme 64). 4-Amino-3,5-difluorosalicylic acid, a fluorinated analogue of the well-known anti-tuberculosis drug PASA, has been shown to inhibit the growth of M. tuberculosis H₃₇Rv, M. avium and M. terrae strains and to inhibit the growth of MDR strains (MIC = 1.5 mg ml^–1), whereas PASA in the similar concentration only inhibits the growth of Mycobacterium tuberculosis H₃₇Rv[88].

Scheme 64

(Poly)fluorobenzoic acids with different heterocyclic substituents have been obtained by S_NAr^F reactions. Studying the reaction of polyfluorosalicylic acid esters with cyclic amines showed that the outcome of the transformation depends on the substrate structure, the temperature regime, the nature of the solvent and the amine moiety[53]. For example, reactions esters of tetrafluoro- and 3,4,5-trifluorosalicylic acids with morpholine or N-methylpiperazine in DMSO at room temperature lead to 4-substituted products, methyl 4-(morpholin-4-yl)polyfluoromethyl- and methyl 4-(N-methylpiperazin-1-yl)tetrafluorosalicylates (Scheme 65, path 1). When similar processes are carried out by heating in DMSO or acetonitrile in the presence of DIPEA, not only substitution of the fluorine atom at the 4-position occurs, but also hydrolysis of the ester functionality, affording N-cycloamino-substituted polyfluorosalicylic acids MTFA, MDFA, PTFA, PDFA (path 2). Reactions of polyfluorosalicylic acid esters with morpholine, carried out at a lower temperature (50 °C), provided the selective preparation of 4-(morpholin-1-yl)polyfluorosalicylamides (path 3). 2,4,5-Trifluoro-3-(morpholin-4-yl)phenol was obtained by treating the corresponding acid or amide with 48% HBr solution.

Scheme 65

Methyl polyfluorosalicylates react with pyrrolidine on heating in DMSO or acetonitrile in the presence of DIPEA to give 4-(pyrrolidin-1-yl)polyfluorosalicylic acids[53] as a result of substitution of the fluorine atom at the 4-position and hydrolysis of the ester group (Scheme 66). In contrast to this transformation, the same esters only react with L-proline when heated with DIPEA to give methyl 4-(proline-1-yl)polyfluorosalicylates.

Scheme 66

Substitution to the morpholine moiety was also carried out for methyl 2-methoxy-3,4,5-trifluorobenzoate when the reaction was carried out in refluxing acetonitrile, giving methyl 2-methoxy-4-(morpholin-4-yl)-3,5-difluorobenzoate (Scheme 67)[53]. Methyl 2-methoxy-4,5-difluorobenzoate, treated with tert-butylpiperazine-1-carboxylate on heating in DMF in the presence of K₂CO₃, also readily undergoes substitution of the fluorine atom in the para position to give tert-butyl 4-(5-methoxy-4-methoxycarbonyl-2-fluorophenyl)piperazine1-carboxylate[216].

Scheme 67

Ethyl 4,5-difluorosalicylate reacts with morpholine in DMSO at room temperature with substitution of the fluorine atom in the 4-position to give ethyl 2-hydroxy-4-(morpholin-4-yl)-5-fluorobenzoate (Scheme 68, path 1), and on heating, the ester moiety is also involved in this reaction in addition to this process. As a result, [2-hydroxy-4-(morpholin-4-yl)-5-fluorophenyl](morpholin-1-yl)methanone (path 2) was isolated, the hydrolysis of which in 48% HBr solution leads to decarboxylation and the formation of 3-(morpholin-4-yl)-4-fluorophenol[53]. When heated with N-methylpiperazin in DMSO, this ester forms 2-hydroxy4-(N-methylpiperazin-1-yl)-3-fluorobenzoic acid (PMFA) (path 3).

Scheme 68

The reaction of methyl 3,4-difluorosalicylate with morpholine in DMSO at room temperature led to the corresponding unsubstituted amide (Scheme 69, path 1), and after heating a mixture of this amide with 4-(morpholin-4-yl)-substituted amide in a ratio of 1 : 0.4 was isolated (path 2)[53]. When methyl 3,4-difluorosalicylate reacts with N-methylpiperazine in acetonitrile under heating, the main process is hydrolysis of the ester functionality to 3,4-difluorosalicylic acid, and the content of the substitution product in the reaction mixture is as low as 10% (path 3).

Scheme 69

The reaction of ethyl 2-methoxy-3,5-difluorobenzoate with morpholine when heated in DMSO proceeded with low substrate conversion, and the yields of ethyl 2-methoxy-3-(morpholin-4-yl)-5-fluorobenzoate and 3-fluorobenzoate were only 1.6 and 3.9%, respectively (Scheme 70)[217].

Scheme 70

From the studies presented in this Section, it can be concluded that the presence of a fluorine atom in the para position of the benzene ring with respect to the ester moiety is necessary for efficient nucleophilic substitution in polyfluorosalicylates.

The study of the biological properties of cycloalkylamine derivatives has shown that the introduction of heterocyclic amines into polyfluorosalicylic acids is an effective way of reducing their toxicity. At the same time, N-piperazine derivatives PTFA, PDFA (see Scheme 65), PMFA (see Scheme 68) have significant analgesic activity, and their morpholinecontaining analogues MTFA, MDFA (see Scheme 65) combine moderate anti-inflammatory and analgesic properties. In addition, MTFA and PTFA acids have shown the ability to inhibit the growth of M. tuberculosis H₃₇Rv strain at MIC = 6.25 mg ml^–1.

The substitution of the ortho-bromine atom in 2-bromopolyfluorobenzoic acids under the action of 2-methoxy-4-(trifluoromethoxy)phenols in the presence of a base (Cs₂CO₃) and a catalyst (CuI) on heating in toluene at 100 °C in a sealed ampoule has been described (Scheme 71)[218]. This gives o-phenyl-substituted acids. Difluoro-2-(3,5-dichlorophenoxy) benzoic acids were obtained in a similar way but using Cu(MeCN)₄PF₆ as the catalyst. Such acids have herbicidal activity against a number of weeds such as Alopecurus myosuroides, Avena fatua, Echinochloa crus-galli, Setaria faberi, Helianthus annuus and Ipomoea hederacea[219].

Scheme 71

Considering the data presented in this Section, it can be concluded that S_NAr^F reactions are a convenient tool for the synthesis of polyfluorobenzoic acids modified on the aromatic ring by various O- and N-containing units.

Recently, photocatalytic alkylation of polyfluoroarenes due to activation of the C – F bond have been widely studied[216], but similar transformations with polyfluorobenzoic acid derivatives are poorly described in the literature. For example, polyfluorobenzoic acid esters react with N-methylaniline under photocatalytic conditions in the presence of Ir(ppy)₂(dtbbpy)PF₆ (dtbbpy is 4,4'-di-tert-butyl-2,2'-dipyridyl) to give 4-(anilinomethyl)polyfluorobenzoic acid esters (Scheme 72)[220].

Scheme 72

Esters and amides of polyfluorobenzoic acids were found to react with alcohols at the para-position of the aryl ring to afford 4-substituted polyfluorobenzoates and polyfluorobenzamides (Scheme 73). This process is also carried out under photocatalytic conditions under visible light irradiation (blue LEDs) in the presence of the catalyst 4-CzIPN[221].

Scheme 73

Methyl pentafluorobenzoate reacts with alkenes under photocatalytic conditions in the presence of fac-Ir(ppy)₃ to give methyl esters of 4-alkyl-substituted tetrafluorobenzoic acids (Scheme 74a), with the methyl esters of 4-substituted 3,5,6-trifluorobenzoic acids characterized by substitution at the ortho-fluorine atom (see Scheme 74b)[222].

Scheme 74

The ability of polyfluorobenzoic acids and their derivatives to undergo S_NAr^F reactions is often exploited to construct heterocyclic cores, involving the carboxyl function and the adjacent ortho-fluorine atom in such transformations.

Polyfluorobenzoyl chlorides, which can be cyclized under the action of various dinucleophiles to form a diversity of heterocyclic structures, have proved to be highly reactive bifunctional building blocks[28, 223, 224]. It has been shown that cyclization of polyfluorobenzoyl chlorides with N,N-dinucleophiles such as alkylisothiourea[223, 224] and diphenylsubstituted guanidine[223] provides fluorine-containing 2-alkylthio-2-iminoquinazolin-4-ones (Scheme 75).

Scheme 75

The direction of cyclization of polyfluorobenzoyl chlorides with 2-aminoazaheterocycles depends on the process conditions[28, 223, 224]. Thus, [b]-annulated quinazolinones are obtained in dichloromethane at room temperature in the presence of DIPEA, whereas their [a]-annulated analogues are formed under more harsh conditions, e.g., in refluxing acetonitrile, toluene or DMF using 1,8-diazobicyclo[5.4.0]undec-7-en (DBU) as the base (Scheme 76).