Abstract
The chapter is devoted to the synthesis and application of thiophenes (selenophenes) and benzothiophenes bearing fluorine atoms, CF3 groups, and perfluorinated aryl fragments.
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1 Introduction
Fluorinated thiophene derivatives are widely used as soluble semiconductors [1], polymers [2], blue light emitting materials [3], and liquid crystals [4]. Some of them represent potent selective class II histone deacetylase (HDAC) inhibitors [5], agonists of sphingosine-1-phosphate (S1P) receptors [6], and some reveal fungicidal properties [7], anti-inflammatory, and immunoregulatory activity [8]. In addition, thiophene-substituted perfluorocyclopentenes are being investigated as thermally irreversible photochromic compounds having a high resistance to fatigue [9]. Herein, we describe methods for the preparation of thiophenes with a fluorine atom in the 2- and 3-position, and polyfluorothiophenes. These methods are classified into functionalization of the thiophene ring and heterocyclizations. This principle of classification is also applied for thiophenes with a perfluoroalkyl group, their benzoanalogues, and benzothiophenes with four fluorine atoms on the carbocycle.
2 Synthesis of Fluorothiophenes
2.1 Functionalization of the Thiophene Ring
Direct fluorination of thiophene with molecular fluorine (F2) is inconvenient as it is not selective process, owing to the extreme reactivity of molecular fluorine. For example, the reaction of thiophene 1 with fluorine at −63 °C (5 % F2 in He) gave a mixture of 2- and 3-fluorothiophene 2 and 3 in a 2:1 ratio [10]. The synthesis of 3-fluorothiophene 3 is challenging due to the higher reactivity of the 2-position of thiophene. When a tenfold excess of fluorine was used, the 3-substituted isomer 3 (68 %) was three times more abundant then the 2-substituted product 2.
The treatment of 2-(thiophene-2-yl)acetonitrile 4 with perchloryl fluoride (FClO3) in N,N-dimethylformamide in the presence of sodium ethoxide was also not selective. The formation of 2-(5-fluorothiophen-2-yl)acetonitrile 5 was accompanied by fluorination of the methylene group to give 2-fluoro-(2-thiophen-2-yl)acetonitrile 6 [11].
Gaseous SF3 + is a gentle and effective electrophilic monofluorinating reagent for five-membered heterocyclic compounds. The reaction of thiophenes 1,7 with gaseous SF3 +, generated by electron ionization of sulfur hexafluoride and acting as a source of fluorine cation (F+), is one more example of a direct fluorination process [12].
1-(Chloromethyl)-4-fluoro-1,4-diazobicyclo[2.2.2]octane tetrafluoroborate (SelectfluorTM) can also serve as selective fluorinating reagent. Thus 3-acetamidothiophene 9 was fluorinated in the 2-position exclusively on treatment with SelectfluorTM, but the yield of 11 was 5 % [13]. Fluorination of the isomeric 2-acetamidothiophene 10 gave the 3-fluorinated product 12 in low yield.
However, the 60 % conversion was achieved using Selectfluor for the overnight performed fluorination reaction of methyl thiophene-2-carboxylate derivative 13 [14].
Thiophene 1 was fluorinated with potassium tetrafluorocobaltate(III) (KCoF4) to give a mixture of hexafluorotetrahydrothiophene 15 and 2,2,5,5-tetrafluoro-2,5-dihydrothiophene 17 as major products. When hexafluorotetrahydrothiophene 15 was bubbled through molten potassium hydroxide, tetrafluorothiophene 19 was formed in low yield. When sodium methoxide was used, substitution of fluoride took place [15]. 2,5-Difluorothiophene 18 was obtained in 50 % yield by heating of 2,2,5,5-tetrafluoro-2,5-dihydrothiophene 17 with sodium fluoride at 530 °C. These conditions were found to be optimal, since the reaction did not occur at moderate temperatures (<480 °C). However, at 530 °C side reactions also took place, thus accounting for the only moderate yield of 2,5-difluorothiophene 18 [16].
A more convenient approach to the synthesis of fluorothiophenes was based on the reaction of their organolithiums (easily prepared by metallation or halogen-metal exchange) with electrophilic fluorinating reagents such as perchloryl fluoride [17] or N-fluorodibenzenesulfonimide [18]. The yields of target fluorinated thiophenes 2, 8 and 23, 25 were moderate. This approach was proposed by Gronowitz and Rosén [19] for the preparation of various substituted 2-fluorothiophenes and 3-fluorothiophenes. Complications can arise in the case of halogen-metal exchange: rearrangement can occur if the thienyllithium is thermodynamically unstable. The metallation of 2- and 3-fluorothiophenes followed by reaction with electrophiles was found to provide substituted 2-fluorothiophenes and 3-fluorothiophenes, since fluorine does not interfere in the metallation or in the halogen-metal exchange.
Fluorination of 2-selenophenyllithium 25 with perchloryl fluoride gave a mixture of 2-selenophene 26 and 2,5-difluoroselenophene 27 [20].
3-Fluorothiophene derivatives were easily obtained starting from the corresponding 3-bromothiophenes (Br-Li exchange). For example, the reactions of 3-thienyllithium obtained from 28 with N-fluorodibenzenesulfonimide as electrophilic fluorinating reagent led to the 3-fluorosubsituted thiophene 29 [18, 21].
In some cases, the direct metallation was also applied for the synthesis of 3-fluorothiophenes. Thus, 3-fluorothiophene-2-carboxylic acid 30 was prepared in two steps from the corresponding thiophene-2-carboxylic acid 22 by treatment with n-butyllithium followed by reaction with N-fluorodibenzenesulfonimide [22]. This approach was applied to the synthesis of monomer 32 for thieno[3,4-b]thiophene polymers 33 used in organic solar cells [23].
Another convenient approach is based on the use of N-fluorodibenzenesulfonimide. 2,3-Difluoro-, 2,4-difluoro- [18], 3,4-difluoro-, and 2,3,4-trifluorothiophenes can be prepared by this method. Thus, lithiation of 2,5-di(trimethylsilyl)-3,4-dibromothiophene 34 with n-BuLi followed by treatment with N-fluorodibenzenesulfonimide provides 3,4-difluoro-2,5-bis(trimethylsilyl)-thiophene 35. The latter was transformed into 2,5-dibromo-3,4-difluorothiophene 36. 1-Bromo-2,3,4-trifluorothiophene 37 was prepared similarly [24].
The first reported method for the preparation of 2-fluorothiophene 2 was the reaction of 2-iodothiophene 38 with SbF3 in nitromethane. However, the method was inconvenient since it gave the target 2-fluorothiophene 2 in less than 10 % yield [25].
A more useful approach to fluorothiophenes was based on transformations of iodonium salts. 2-Thienyliodoniym salts, for example dithiophen-2-yliodonium hexafluorophosphate 39, afford 2-fluorothiophene 2 (37 %) and thiophene 1 (20 %) after treatment with potassium fluoride and heating at 172–175 °C [26].
It is known that nitro group is a good leaving group for aromatic nucleophilic substitution and can be substituted by fluoride. For example, 5-nitrothiophene-2-carbonitrile 40 reacted with potassium fluoride in the presence of tetraphenylphosphonium bromide and phthaloyl dichloride in sulfolane at 180 °C providing 5-fluoro-2-cyanothiophene-2-carbonitrile 41 in 76 % yield [14, 27]. The reaction of 2-cyano-3-chlorothiophene 42 with CsF in dimethylsulfoxide gave 2-cyano-3-fluorothiophene 43 in 86 % yield. Subsequent hydrolysis by sodium hydroxide and decarboxylation gave 3-fluorothiophene 3 in 93 % yield [28].
One more method for the synthesis of 3-fluorothiophene is based on the thermal decomposition of a diazonium tetrafluoroborate (Schiemann reaction), which has been successfully used in the synthesis of a variety of fluorobenzenes. The reaction was carried out by heating of thiophene diazonium salt 45 in dry xylene (48 %) [29] or in a mixture with silica gel under vacuum (67 %) [13, 30].
The straightforward synthetic route to 3-chloro-4-fluorothiophene-1,1-dioxide 50 involved chlorofluorination of 3-sulfolene 47, photochemical chlorination, and dehydrochlorination of 3,3,4-trichloro-4-fluorosulfolane 49 [31].
2.2 Heterocyclization
The transformation of 4,4-difluoro-3-trifluoromethylbut-3-ene-1-ones 53, easily prepared from hexafluoroacetone (HFA), into 2-fluoro-3-trifluoromethylthiophenes 54 proceeded on heating with phosphorus pentasulfide [32]. Yields of 2-fluoro-3-trifluoromethylthiophenes 54 depend on the reaction conditions and the progress of the transformation should be monitored by 19F NMR spectroscopy. The starting compounds were formed by elimination of water from hexafluoroacetone aldols 51 obtained by reaction of HFA with enol silyl ethers in the presence of Lewis acid such as SnCl4. The unsaturated ketones 52 were reduced with SnCl2 and 53 were cyclized to the desired thiophenes 54 with phosphorus pentasulfide [33].
The reaction of (Z)-α-fluoro-β-(phehylthio)butanones 55 with methyl or ethyl thioglycolate in dimethylsulfoxide led to substituted 3-fluorothiophenes 56 in moderate to high yields. The authors proposed nonclassical nucleophilic vinylic substitution mechanism, occurring through an enolate intermediate. The first step of the sequence is the Michael addition that gives enolate; subsequent cyclization and aromatization leads to the target 3-fluorothiophenes 56 [34].
3 Synthesis of Fluorobenzothiophenes
Methods for the synthesis of fluorobenzothiophenes are rare. A lithiation-fluorination sequence by treatment of benzothiophenes 57 with n-BuLi followed by fluorination with perchloryl fluoride [35], N2F2 [36], or N-fluorodibenzenesulfonimide afforded 2-fluorobenzo[b]thiophenes 58 in good yields [37].
3-Fluorobenzo[b]thiophenes 60 and 62 were synthesized from the lithiated precursors by treatment with perchloryl fluoride [35] or N-fluorodibenzenesulfonimide in good yields [38]. The lithium derivatives were obtained from 3-bromobenzo[b]thiophene derivatives 59 and 61 and n-butyllithium.
Fluorobenzo[b]thiophenes synthesis was also accomplished through a 5-endo-trig cyclization. Successive reaction of β,β-difluoro-o-methylsulfinylstyrene 63 first with trifluoroacetic anhydride and triethylamine in dichloromethane and then with potassium carbonate provided 2-fluorobenzo[b]thiophene 64 in 82 % yield [39].
3-Fluorobenzothiophene derivative 68 was prepared in 44 % yield starting from 4-(methylthio)-l-(trifluoromethyl)benzene 65 by double metallation with n-BuLi and subsequent reaction with CO2. The primary intramolecular cyclization of 66 was anchimerically assisted by the carboxylate anion in ortho position and gave rise to a nucleophilic substitution of the fluorine atom by the SCH− anion. The resulting intermediate 67 aromatized after acidification into 3-fluorobenzo[b]thiophene 68 [40].
Fluorinated benzo[b]thiophene derivative 70 was synthesized in 93 % yield by the intramolecular cyclization of anodically fluorinated open-chain sulfide 69 containing the 2-cyanophenyl group [41].
4 Synthesis of Perfluoroalkylthiophenes
4.1 Functionalization of the Thiophene Ring
A perfluoroalkyl group can be incorporated onto the thiophene ring directly, or a haloalkyl substituent can be transformed into a perfluoroalkyl moiety. For example, treatment of 2,5-bis(trichloromethyl)-3,4-dichlorothiophene 71 with AgF resulted in exchange of chlorine by fluorine in the CCl3-groups. It should be noted that no exchange took place for the chlorine atoms attached directly to the thiophene ring. In a similar way, brominated 2,5-dimethylthiophene 73 gave a 2,5-bis(difluoromethyl)thiophene derivative 74 under the same conditions [42].
A very useful method for the introduction of a CF3 group onto the thiophene ring is the transformation of a carboxylic group with SF4. Depending on the conditions, thiophene-2,5-dicarboxylic acid 75 reacted with SF4 and HF to produce 5-(trifluoromethyl)thiophene-2-carboxylic acid 76 and 2,5-bis(trifluoromethyl)-thiophene 77. At lower temperature, the compound 76 was the major product, while 77 was obtained at 130 °C with five equivalents of SF4 [43].
The direct trifluoromethylation of thiophene can be performed under electrophilic and radical conditions. The electrophilic reaction proceeded in the gas phase using trifluoromethyl cations obtained from CF4 under radiolysis (60Co γ-rays) [44]. The selectivity trend for thiophene in the gas phase follows the order C2 > C3 > S1. The major products of this transformation were found to be monosubstituted trifluoromethylthiophenes 78 and 79 (<20 % yield) [45]. It has been proposed that the trifluoromethylation proceeds through electrophilic substitution and single-electron transfer mechanisms.
Electrophilic perfluoroalkylation has been performed with the use of iodonium salts RfI(Ar)X, where the perfluoroalkyl group is bonded with a positively charged heteroatom. The trifluoromethylation of thiophene 1 with C8F17I(Ph)OSO2CF3 in dichloromethane at room temperature proceeds in 73 % yield in the presence of 2,6-di-tert-butyl-4-methylpyridine as a base [46].
Radical perfluoroalkylation is more versatile because it can be performed under thermal, photolytic, oxidative, and reductive conditions. For example, the photochemical reaction of thiophene 1 with bis(trifluoromethyl)tellurium or trifluoromethyliodide yields 2-trifluoromethylthiophene 78 as the major product. The most suitable reagent in this case was found to be bis(trifluoromethyl)tellurium. Similarly, perfluoroalkylation of thiophene with perfluorodecyl iodide under thermal conditions (175 °C, 24 h, steel bomb) provided predominantly the 2-substituted isomer 82. The latter was the sole product when the reaction was carried out at higher temperature [47].
2-Nonylthiophene 84 was trifluoromethylated with trifluoromethyliodide in acetonitrile under irradiation to produce 2-nonyl-5-trifluoromethylthiophene 85. A trace amount of 3,5-bis(trifluoromethyl)-2-nonylthiophene was also formed in this reaction. However, the conversion was not complete and starting thiophene (25 %) was recovered [48].
Nonafluoro-4-iodobutane can serve as a source of nonafluorbutyl radical under oxidative conditions. The reaction with thiophene 1 was carried out under reflux in AcOH in the presence of hydrogen peroxide and benzoyl peroxide. Other solvents appeared to be less effective, probably because hydrogen abstraction from the solvent by nonafluorbutyl radical competes with the attack of thiophene [49].
Perfluoroalkylation is often performed with bis(perfluoralkanoyl)peroxides, e.g. bis(trifluoroacetyl)peroxide and bis(heptafluorobutyryl)peroxide, which are thermally stable, convenient to use, and can be obtained from the corresponding anhydrides and hydrogen peroxide in Freon 113 (CFCl2CF2Cl) as a solvent. Perfluorooxaalkanoylperoxides provide the same reactivity. The mechanism of the transformation includes oxidation of thiophene to radical cation, followed by reaction with perfluoro radical to produce 2-perfluoroalkylthiophenes [50].
Interestingly, the perfluoroalkyl group can be incorporated onto the thiophene ring even if the corresponding peroxide cannot be synthesized. For example, when thiophene was treated with bis(perfluoralkanoyl)peroxide in the presence of pyridinium perfluoroalkanoate, not only the perfluoroalkyl group of the peroxide, but also the perfluoroalkyl group of perfluoroalkanoate was incorporated [51].
It is well known that xenon fluoride trifluoroacetate, obtained from XeF2 and trifluoroacetic acid, is able to generate trifluoromethyl radicals which allow introduction of the trifluoromethyl group onto the aromatic ring at room temperature. The trifluoromethylation of thiophene-2-carbaldehyde bistrifluoro-acetate 91 gave 5-trifluoromethyl-thiophene-2-carbaldehyde 92 in 24 % yield [7].
Fluoroalkylation reaction can also be performed using transition-metals catalysis. In the presence of a catalytic amount of tetrakis(triphenylphosphine)nickel, polyfluoroalkyl iodide reacted with thiophene to produce the 2-substituted isomer 93 as the sole product. To complete the reaction, addition of sodium hydride was required to absorb hydroiodic acid by-product [52].
The silver-mediated trifluoromethylation of thiopene with TMSCF3 gave 2- and 3-trifluoroderivatives 78 and 79 in 72 % total yield. The authors proposed that the reaction proceeds via AgCF3 intermediates [53].
The copper-promoted substitution of halogen atoms on the thiophene ring provides another method for perfluoroalkylation. For example, 2-perfluorohexylthiophene 96 and 2,5-bis(perfluorohexyl)-thiophene 97 were obtained from the corresponding bromothiophenes 94 and 95 and perfluorohexyl iodide in dimethylsulfoxide (isolated yields are given in parentheses) trough reaction with the organocopper intermediate, perfluorohexyl copper(I) [54]. More detailed information about fluorinated organometallics and their use in organic synthesis was presented in a review [55], and some examples of copper promoted perfluoroalkylation of halothiophenes are also described in papers [2b, 8, 56].
Another method of trifluoromethylation was based on the electrochemical reaction (copper anode) of 2-bromothiophene 94 with bromotrifluoromethane in DMF. In comparison to usual methods leading to trifluoromethylcopper, this one offered an advantage because it allowed the use of CF3Br instead of the more expensive CF3I. However, the reaction was not selective and gave a mixture of 2- and 3-isomers 78 and 79. The use of 2-iodothiophene 38 as a starting material was found to be more effective: 2-trifluoromethylthiophene 78 was obtained in 60 % yield [57].
Sodium trifluoroacetate, in the presence of copper(I) iodide, was also used as trifluoromethyl source to replace halogen by trifluoromethyl group in the thiophene system. Sodium trifluoroacetate was decarboxylated, forming fluoroform, when heated alone in aqueous N-methylpyrrolidin-2-one. The addition of copper(I) iodide increased the rate of decarboxylation dramatically. The mechanism of this process was explored and an intermediate [CF3CuI]− was proposed. Introduction of higher perfluoroalkyl groups from their corresponding sodium perfluoroalkane carboxylates was also shown to be possible [58].
The reaction of 2-thienyllithium with perfluoroalkyliodides and bromides gave 2-halothiophenes 38, 94 rather than corresponding perfluoroalkylated thiophene [59].
The copper-catalyzed substitution of a halogen atom was used for the preparation of 3-perfluoroalkylthiophenes. Usually, the reaction involves the heating of 3-iodothiophene 98 with perfluoroalkyliodide in N,N-dimethylformamide or dimethylsulfoxide [54]. In some cases, however, it was not possible to obtain useful quantities of the three-substituted products. When the perfluoroalkyl group was not trifluoromethyl, two isomers were formed due to the addition of the perfluoroalkyl anion to the C(2)–C(3) double bond. The ratio of isomers was also influenced by the nature of halogen: iodine, which is better leaving group than bromine, gave a lower percentage of rearrangement [60].
An improved method of 3-trifluoromethylthiophene 79 synthesis was the reaction of methyl-2-chloro-2,2-difluoroacetate with 3-iodothiophene 98 in the presence of copper(I) iodide and potassium fluoride in N,N-dimethylformamide. The reaction was carried out at 125 °C and gave 3-trifluoromethylthiophene 79 in 46 % as the sole product [61]. The proposed mechanism includes the formation of the copper(I) iodide salt or a complex, followed by its decarboxylation to yield difluorocarbene; the latter then reacts with fluoride to establish an equilibrium with trifluoromethyl anion. In the presence of copper(I) iodide, the equilibrium was readily shifted to give trifluoromethyl copper species CF3CuI−, which reacted with halides to afford the final products [62].
The reaction of direct cupration of fluoroform provides a source for the introduction of the trifluoromethyl group into organic molecules, including thiophene [63].
Recently, it was demonstrated that a small amount of copper(I) iodide-phenanthroline complex efficiently catalyzes aromatic trifluoromethylation of 2-iodothiophenes 38 and 102 leading to 2-trifluoromethylated products 78 and 103 in 75–85 % yields [64].
Dithioacetales 104 have been transformed into difluoromethyl derivatives 105: a one-pot desulfurative fluorination of dithiolane led to the synthesis of difluoroalkylthiophene. Treatment of the dithioacetales 104a, b with pyridinium polyhydrogen fluoride (PPHF) and nitrosyl tetrafluoroborate at 0 °C led to 3-(1,1-difluoroheptyl) thiophene 105a (40 %) or 3-(1,1-difluorononyl)thiophene 105b (30 %) [65].
Fluorination of a carboxylic group with sulfur tetrafluoride was applied to the incorporation of the trifluoromethyl and difluoromethyl group onto the thiophene ring [43, 66]. As it was mentioned, 2,5-bis(trifluoromethyl)thiophene 77 was obtained by the reaction of thiophene-2,5-dicarboxylic 75 acid with five equivalents of sulfur tetrafluoride at 130 °C. This approach can also be used for the synthesis of oligothiophenes annelated with hexafluorocyclopentene 110. The latter have good electron-donating properties and inherently low electron affinities, and have widespread applications as hole-transporting materials to various electronics such as organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs), and organic solar cells. The synthesis of such thiophenes includes three steps.
The first is fluorination of cyclopenta[c]thiophene-4,6-dione 106 by treatment with N-fluoro-6-(trifluoromethyl)pyridinium-2-sulfonate (MEC-04B) in ethyl acetate to give 1,3-dibromo-5,5-difluorocyclopenta[c]thiophene-4,6-dione 107 in 84 % yield. Then, conversion of the two carbonyl groups to difluoromethylene groups was accomplished via formation of the bis-1,3-dithiolane derivative 108 followed by desulfurative fluorination with hydrofluoric acid-pyridine complex and dibromatin (1,3-dibromo-5,5-dimethylhydantoin) in dichloromethane to afford 1,3-dibromohexafluorocyclopenta[c]thiophene 109 in a two-step yield of 73 % [1d, 67].
2-Substituted thiophenes were found to react with tetrafluoroethylene (TFE) at high temperatures to produce 4,4,5,5,6,6-hexafluorocyclopenta[b]thiophene 112. In such a reaction, 3-thiophenethiol 111 gave rise to the major product 112, along with 4,4,5,5,6,6,7,7-octafluorocyclohexa[b]thiophene 113. Yields of the products were low [68].
4.2 Heterocyclization and Cycloaddition
The most versatile method for synthesis of 2-trifluoromethylthiophenes is based on heterocyclizations with the participation of methyl thioglycolate (HSCH2COOMe). For example, 2-trifluoromethylthiophene 116 was formed as a result of condensation of trifluoromethyl-substituted α,β-unsaturated ester 115 and methyl thioglycolate in the presence of a base. 2-Trifluoromethyl- and (perfluoroalkyl)thiophenes were prepared by reaction with α-fluoroalkylacetates in good yields [69]. A similar transformation took place when fluoroalkylpropynoates 117 were treated with methyl thioglycolate under basic conditions [70].
6-Trifluoromethylpyranopyrazole 121 reacted at C(6) atom with excess of methyl mercaptoacetate in the presence of triethylamine to form a derivative 122 of trifluoromethyl thiophene bonded with a pyrazole fragment. The reaction took place via pyran ring opening and intramolecular aldol-type condensation [71].
Ethyl mercaptopyruvate 124 was also transformed into 2-trifluoromethylthiophene 125 in 54 % yield by reaction with 2,3-dibromo-4,4,4-trifluorobutanenitrile 123 in the presence of triethylamine at 50 °C [72]. The condensation of a trifluoromethylethylene 126 derivative with ethyl thioglycolate in ethanol proceeded analogously [73].
Additionally, sulfur and perfluoroalkyl functionalities can both be present in the same starting molecule. For example, nucleophilic attack of trifluoromethylated thiolate 128 on phenacyl bromides 129 followed by spontaneous aldol cyclization gave 5-substituted 2-trifluoromethylthiophene 130 in yields of 20–60 % [74]. 4,4,4-Trifluoro-3-(4-nitrobenzylthio)-2-phenylbut-2-enal 132 obtained from trifluorosubstituted β-chlorovinylaldehyde 131 afforded the trifluoromethylthiophene product 133 in 66 % yield on heating in N,N-dimethylformamide [75].
Some heterocyclizations have been used for the preparation of 3-perfluoroalkylthiophenes. As an illustration, treatment of 1,1,6,6-tetrakis(ethylsulfanyl)-2,5-bis(trifluoromethyl)-hexa-1,5-dien-3-yne 135 with a mixture of trifluoroacetic acid and water for 2 h at 75 °C led to the thiophene derivative 136 in high yield. The starting compound 135 was obtained by reaction of perfluoroketene dithioacetal 134 with bis(trimethylsilyl)acetylene [76].
2,3,5-Trisubstituted thiophene 138 was synthesized in good yields using a tandem Michael addition and intramolecular Knoevenagel condensation strategy starting from readily available acetylenic ketone 137 in the presence of cesium carbonate and magnesium sulfate as a base to initiate the reaction [77].
1,3,3,3-Tetrafluoro-2-(methoxycarbonyl)propenyl methoxycarbonylmethyl sulfide 139, with its activated α-methylene group, underwent intramolecular cyclocondensation in the presence of sodium methoxide as a catalyst to form 3-trifluoromethylthiophene 140 in 37 % yield. The fluorine atom at the 2-position was substituted by a methoxy group when an excess of sodium methoxide was used [78].
The reaction of mercaptomethyleniminium salts 141 with trifluoroacetic anhydride in the presence of triethylamine yielded substituted 2-aminothiophenes, including 3-trifluoromethyl heterocycle 143. The starting mercaptomethyleniminium salts were prepared by S-alkylation of thioacetamides. When triethylamine was not used in the reaction, it was possible to isolate the intermediate ketene-S,N-aminals 142 and cyclize them under basic conditions [79].
Ethyl-2-(4,4,4-trifluoro-3-oxo-1-phenylbut-1-enylthio)acetate 144 gave 3-trifluoromethylthiophene derivative 145 in moderate yield upon treatment with sodium hydride in benzene in the presence dimethylsulfoxide. The same reaction in tetrahydrofuran yielded a mixture of 2- and 3-trifluoromethylthiophene 146 and 145 with a predominance of the 2-isomer 146 [80].
Triaryl-ß-trifluoromethylthiophenes 148, 149 were synthesized from 1,3-dithiolium-4-olates 147 and various 1-aryl-3,3,3-trifluoro-1-propynes. The 1,3-dipolar cycloaddition was carried out by heating in xylene at 120 °C. Interestingly, when the substituents Ar1 and Ar2 in the mesoionic 1,3-dithiolium-4-olates were swapped, the isomer ratio was completely reversed. The observed regioselectivity was explained by HOMO-LUMO interactions of the reacting species [81].
1,2,3,4-Tetrakis(trifluoromethyl)buta-1,3-diene 151 was employed for the preparation of 2,3,4,5-tetrakis(trifluoromethyl)thiophene 152. The transformation can be performed by treatment of the diene with potassium sulfide in N,N-dimethylformamide at room temperature [82] or by heating at reflux with thiourea in acetonitrile [83]. The starting diene 151 was obtained from perfluoro-3,4-bis(trifluoromethyl)hex-3-ene 150.
2,3,4,5-Tetrakis(trifluoromethyl)thiophene 152 was also obtained by addition of sulfur to hexafluoro-2-butyne at 110–200 °C [84]. The process is supposed to involve reaction of an intermediate dithietene 153 with starting hexafluoro-2-butyne at high temperature. This mechanism was supported by the preparation of 2,3-bis(trifluoromethyl)thiophene 154 and tetrakis(trifluoromethyl)thiophene 152 from dithietene 153 and the corresponding alkynes [85].
The reaction with dimethyltrisulfide 155 as sulfur source occurred at 110 °C in sulfolane giving tetrakis(trifluoromethyl)thiophene 152. No other sulfur heterocycles were detected and the authors presumed that a different process was taking place under these conditions. They concluded that a nucleophilic cyclisation process operates with the cis-addition occurring because sulfur is both a bulky and a neutral nucleophile [84].
Photolysis or heating of bistrifluoromethylthioacetylene 156 with sulfur afforded 2,3,4,5-tetrakis(trifluoromethylthio)thiophene 157 in low yield. The transformation was determined to proceed via an intermediate 1,2-dithiin derivative 159; this was supported by the reaction of 3,6-bis(perfluoroalkyl)-1,2-dithiins 160 that produced 2,5-bis(perfluoroalkyl)thiophenes 77, 161 under irradiation [86].
The photolysis of bis(trifluoromethyl)thiophenes 154 and 77 and tristrifluoromethylated thiophene provides a simple way to produce isomeric structures, but usually these procedures are not synthetically useful for the preparation of thiophene derivatives [87].
A convenient synthesis of 2,5-bis(trifluoromethyl)thiophene 167 involved the [4 + 2]-cycloaddition reaction of acetylenes to 2,5-bis(trifluoromethyl)-1,3,4-thiadiazole 165 and subsequent elimination of nitrogen. The reaction proceeded under sufficiently mild conditions and led to 2,5-bis(trifluoromethyl)thiophene 167 in high yield [88].
Another type of cycloaddition used to produce, in this case, 3,4-bis(trifluoromethyl)thiophene 170 was the reaction of hexafluoro-2-butyne with mesoionic thiazolium system 168. Phenyl isocyanate was eliminated from the initial adduct, giving the substituted thiophene in more than 90 % yield [89].
The reaction of bis(dithiobenzyl)nickel 171 with alkynes yielded thiophene derivative 172. In view of the improved method of preparation of the complexes, this reaction has been applied to the synthesis of difficult-to-access substituted thiophene derivatives. Complexes are air-stable and easily available from benzoin and phosphorus pentasulfide [90].
5 Synthesis of Perfluoroalkylbenzothiophenes
Direct trifluoromethylation of benzo[b]thiophene is not selective. For instance, photochemical reaction with bromotrifluoromethane yielded a mixture of 3-, 4- and 7-trifluoromethylbenzo[b]thiophenes (173, 174 and 175), which correlates with the values of electron density in the molecule [91].
Oxidative trifluoromethylation with bis(trifluoroacetyl)peroxide provided a similar result, while the reaction with bis(heptafluorobutyryl)peroxide afforded 3-heptafluoropropylbenzo[b]thiophene 176 as a major product (54 %) with some 7-substituted isomer 177 [50].
A more effective method for the preparation of 2-trifluoromethylbenzo[b]thiophene 173 involved the treatment of orthothioester 178 with 1,3-dibromo-5,5-dimethylhydantoin (DBH) or N-bromosuccinimide (NBS) followed by hydrofluoric acid-pyridine complex. The target compound was obtained by this method in 40 % yield [92].
Through direct trifluoromethylation, 7-methyl-3-trifluoromethyl-benzo[b]thiophene 179 was prepared in 54 % yield from 7-methyl-3-bromobenzo[b]thiophene 59. The reaction took place with sodium trifluoroacetate and copper(I) iodide in N-methylpyrrolidone at 180 °C [35].
Recently, simple copper-catalyzed trifluoromethylation of aryl boronic acids under mild conditions was developed. Using (trifluoromethyl)trimethylsilane (Me3SiCF3) [93], trifluoromethyldibenzothiophenium triflate [94], or Togni’s reagent [95], 2-trifluoromethylbenzo[b]thiophene 173 was prepared in 45–73 % yields.
A straightforward method for the synthesis of 5- or 6-substituted 2-trifluoromethylbenzo[b]thiophenes involved the reaction of ortho-fluorinated trifluoroacetophenones 181 with methyl thioglycolate [96]. The starting trifluoroacetophenones 181 were prepared from fluorobenzenes and ethyl trifluoroacetate. The key transformation proceeded in the presence of triethylamine at room temperature in acetonitrile and produced methyl 3-trifluoromethylbenzo[b]thiophene-2-carboxylates 182 in good yields. The products 182 were easily transformed into their corresponding 3-trifluoromethylbenzo[b]thiophenes 183.
A similar approach was used for the preparation of the thienothiophene derivative 185: the treatment of the trifluoroacetyl-substituted thiophene 184 with ethyl thioglycolate gave the condensed thiophene [97] bearing a trifluoromethyl group [98].
An alternative approach to benzo[b]thiophene derivatives includes treatment of an aryl-substituted ketene dithioacetal monoxide 188 with trifluoromethanesulfonic anhydride [99] (Tf2O) in the presence of K2CO3 in toluene at 25 °C, followed by addition of ethanolamine to the reaction mixture, provided benzo[b]thiophenes, including 3-trifluoromethylbenzo[b]thiophene 189, in good yields. The cyclization proceeded through formation of reactive sulfonium electrophile [100]. The synthesis of the starting material 188 was also facile and scalable, starting from aryl ketone 186 and formaldehyde dimethyl dithioacetal S-oxide (FAMSO) [101].
In 2011 a copper-catalyzed thiolation annulation reaction of 2-bromo alkynylbenzenes 190 with sodium sulfide has been developed. This approach provided 2-substituted benzo[b]thiophenes in moderate to good yields [102]. Also, synthesis of the 2-trifluoromethyl benzothiophene 192 was carried out in high yield using the thiophenol equivalent of the phenolic phosphonium bromide salt 191 [103].
6 Synthesis of Perfluoroarylthiophenes
Usually, methods used for the synthesis of 2-perfluoroarylthiophenes synthesis are also applicable for the preparation of 3-perfluoroarylthiophenes. Although not numerous, they include reactions with organometallic reagents, cross-coupling reactions, and heterocyclization.
6.1 Organometallic Synthesis
Perfluoroaryl thiophene derivatives 195–197 were obtained by nucleophilic aromatic substitution via thienyllithium intermediates 194. The reaction is quite simple and is widely used for the preparation of various fluoroaromatics [59].
Lithiated bithiophene also gave rise to pentafluorophenyl derivative 199 in moderate yield. The SNAr-type reaction proceeded with hexafluorobenzene in 8 h. The starting compound was obtained from the corresponding thiophene on treatment with n-butyllithium [104].
2-Thienyllitium and 4-hexyl-2-thienyllithium reacted with hexafluorobenzene to give the triaryl derivatives 201 (65 %) and 202 (66 %), respectively. The procedure is noteworthy since the lithiation of 3-hexylthiophene was regiospecific and resulted in the isolation of a single isomer. The compounds 201, 202 have been used as precursors for oligothiophene 203 synthesis and preparation of polymeric materials [105].
Similarly, lithiated chlorothiophenes reacted with hexafluorobenzene to produce fluoroaryl derivatives. Addition of hexafluorobenzene to trichloro-2-thienyl-lithium 204 in tetrahydrofuran at −78 °C gave 1,2,4,5-tetrakis(trichloro-2-thienyl)difluorobenzene 205 and 1,4-bis(trichloro-2-thienyl)tetrafluorobenzene 206. A similar reaction in diethyl ether at −15 to −20 °C also gave both 205 (44 %) and 206 (20 %) products [106].
2,7-Disubstituted hexafluoro-9-heterofluorenes 208 were synthesized via nucleophilic aromatic substitution (SNAr) reactions of 2-thienyllithium with various octafluoroheterofluorenes 207. These compounds are of interest as possible building blocks for materials with useful electron-transport properties, since they possess relatively low LUMO energy levels [107].
6.2 Cross-Coupling
More often, cross-coupling reactions are applied for the preparation of perfluoroarylthiophenes. Cupper and palladium catalysts are common for arylation. For example, palladium-catalyzed Stille coupling with iodo- and bromosubstituted fluoroarenes gave the fluoroarene-modified thiophenes which can act as organic semiconductors [108]. The palladium-catalyzed reaction was performed with the corresponding stannylated thiophenes (e.g. 209, 211) in toluene under reflux. Numerous thiophene derivatives have been obtained by this method. Product yields for these transformations ranged from moderate to good (45–80 %) [109].
2-(Pentafluorophenyl)thiophene 210 and its derivatives were also synthesized by a palladium catalyzed Suzuki reaction between pentafluoroiodobenzene and thiophene boronic acid derivative. However, considering the ready accessibility of 2-halothiophenes by electrophilic substitutions of thiophenes, commercially available pentafluorophenylboronic acid is the counterpart of choice for the Suzuki coupling. The use of DMF as a solvent and potassium phosphate as a base in the presence of palladium catalyst allowed for the synthesis of a wide range of compounds, including thiophene-fused system and oligothiophenes with various chain lengths, such as 216, as well as several selenophene homologues, for example 217 [110].
The palladium-catalyzed decarboxylative coupling of potassium pentafluorobenzoate with aryl chlorides, bromides and triflates was shown to be a useful method for the synthesis of polyfluorobiaryls from readily accessible polyfluorobenzoate salts. For instance, 2- and 3-chlorothiophens 218, 219 reacted with potassium pentafluorobenzoate to produce pentafluorophenyl derivatives 210 and 220. The reaction proceeded in refluxed diglyme in the presence palladium acetate(II) [111].
A similar coupling proceeded with 2-iodo-5-nitrothiophenene 221 in the presence of a copper catalyst. A possible explanation for the outstanding performance of diglyme is that it can coordinate to K+, thereby facilitating the complexation between CuI and pentafluorobenzoate.
This protocol was applicable to aryl iodides but not to less reactive aryl bromides. This problem was solved by using 1,10-phenanthroline as a ligand: 2- and 3-bromothiophenes 94 and 101 formed the corresponding pentafluorophenyl derivatives in good yields in the presence of a copper-phenanthroline catalytic system [112].
All of the methods presented above are based on cross-couplings of halogenated thiophenes and different pentafluorophenyl derivatives. However, the arylation of polyfluorobenzene C-H bonds can also be used for the synthesis of perfluoroarylthiophenes. For example, 2-bromothiophene 94 and pentafluorobenzene gave 2-(perfluorophenyl)thiophene 210 in 92 % yield in the presence of phenanthroline [113].
A similar monoarylation was performed with 2- and 3-bromothiophenes 94 and 101 under palladium-catalyzed conditions in good yields. The use of a more effective palladium catalyst with the phosphine ligand S-Phos allowed for the temperature of this transformation to be reduced to 80 °C [114].
2,5-Bisperfluorophenylthiophene 195 was obtained by a one-pot sequential iodination and copper-catalyzed cross-coupling of arene C–H bonds. The first step was the electrophilic halogenations with incorporation of the iodine atom. Then, copper-catalyzed arylation allowed for a highly regioselective heterocoupling, thereby leading to the diarylated product 195 [115].
The previous three examples involved the couplings of halogenated thiophenes with different substrates. However, it is also possible to perform coupling between thiophene and halogen-substituted arenes. The reaction of thiophene derivatives 223, 224 with pentafluoroiodobenzene proceeded in the presence of bis(triphenylphosphine)palladium(II) dichloride and silver nitrate [116].
The transition-metal-free carbon-carbon bond formation by fluoride activation of silicon-carbon bonds has been used for coupling of perfluoroarenes and trimethylsilylthiophene derivative 227. In the case of 2,5-bis(trimethylsilyl)thiophenes, the ratio of isolated products indicated that the first and second attacks on perfluorobenzene proceeded with the same rate, or that conversion of the second TMS group can be more rapid than that of the first [117].
6.3 Heterocyclization
The heterocyclization of substituted alkynes with sulfur was also shown to be applicable for the preparation of perfluoroarylthiophenes. When a mixture of 1,2-bis(perfluorophenyl)ethyne 230 and sulfur was heated in benzene at 220–230 °C the tetrakis(perfluorophenyl)thiophene 231 was formed in 30 % yield [118].
Another pathway to perfluoroalkylthiophenes involved the cyclization of zirconocene obtained from pentafluorophenyl-substituted alkynes. The fluorophenyl-substituted alkynes was synthesized by coupling of the appropriate fluoroaryl iodide with a terminal alkyne catalyzed by tetrakis(triphenylphosphine)-palladium(0) and CuI. Reaction of the resulting alkyne 232 with Negishi’s zirconocene synthon at low temperature followed by warming to room temperature afforded zirconacyclopentadienes 233 in high yields. The reaction of the latter with S2Cl2 gave thiophene 234 in high yield [119].
7 Synthesis of Perfluoroarylbenzothiophenes
The known approaches to perfluoroarylbenzothiophenes are generally based on the cross-couplings and reactions with organometallic reagents. For example, benzo[1,2-b:4,5-b′]dithiophene 235 and -diselenophene 236, which are known p-channel semiconducting materials, were modified via palladium-catalyzed Suzuki-Miyaura coupling reaction. The reaction proceeded in moderate yields and gave compounds 237, 238 which can act as n-semiconductors [120].
Another method for the synthesis of 2,6-diphenylbenzo[1,2-b:4,5-b′]dithiophene 241 and diselenophene fluorinated derivatives 242 was based on the reaction of their bismetalates with perfluoroarenes. The same transformation was also performed with trimethylsilyl derivatives using a catalytic amount of cesium fluoride in the presence of 18-crown-6 [121].
The synthesis of functionalized anthradithiophenes was achieved through condensation of thiophenes derivatives with cyclohexane-1,4-dione. The starting 5-perfluorophenyl-2,3-thiophenedicarboxaldehyde was prepared in 45 % yield by Stille coupling of 5-(tributylstannyl)-2,3-bis(1,3-dioxolan-2-yl)thiophene with bromopentafluorobenzene. The reaction of thiophenedicarboxaldehyde with cyclohexane-1,4-dione gave intermediate quinone 244 that produced dipentafluorophenylanthradithiophene 245 on reduction. The latter is a semiconductor for organic thin-film transistors (OTFTs) [109]. A similar reaction with a 5,6,7,8-tetrafluoroanthracene derivative leads to 7,8,9,10-tetrafluoro-2-pentafluorophenyltetraceno[2,3-b]thiophene 247.
8 Benzothiophenes with Perfluorinated Carbocycle
Benzothiophenes with a fully fluorinated carbocycle are usually prepared by way of cyclization reactions. For example, when pentafluorophenyl prop-2-ynyl sulfide 248 in Freon 113 was heated at 180 °C 4,5,6,7-tetrafluoro-2-fluoromethylbenzo[b]thiophene 249 was obtained in low yield. A similar isomerisation of the naphthalene compound 250 was more efficient and gave the 2-fluoromethyl derivative 251 in 41 % yield. Distillation of the starting compound under vacuum through silica-filled tube led to the target compound 251 in 81 % yield [122].
More often, such compounds are synthesized via cyclization induced by organometallics. For example, 2,3,4,5,6-pentafluorobenzyl methyl sulfoxide 252 gave 4,5,6,7-tetrafluorobenzo[c]thiophene 253 on treatment with BuLi in THF at −70 °C. The mechanism invokes the nucleophilic replacement of ortho -fluorine by CH2Li and aromatization. Treatment of the naphthalene sulphoxide 254 with BuLi gave 4,5,6,7,8,9-hexafluoronaphtho[1,2-c]thiophene 256 in inseparable mixture of the 7- and 8-butyl derivatives 257 and 258, as well as the aldehyde 255 in 50 % yield [123].
In 1967, the formation of diethyl 4,5,6,7-tetrafluoro-benzo[b]thiophen-2,3-dicarboxylate 259 in 49 % yield, by the reaction of lithium pentafluorobenzenethiolate with diethyl acetylenedicarboxylate in THF under reflux, was reported [124]. Later, the cyclization reaction was shown to occur under very mild conditions (−70 to −58 °C) in 74 % yield [125]. A similar reaction of lithium 1,3,4,5,6,7,8-heptafluoro-2-naphthalenethiolate and its isoquinoline derivative with dimethyl acetylenedicarboxylate was reported to give polyfluorinated condensed products 261 and 262 [126].
9 Conclusion
Fluorinated thiophene derivatives have found a broad application as biologically intriguing molecules and especially as modern organic materials. However, methods for their synthesis are still limited. The direct fluorination or trifluoromethylation of thiophene is either not selective or proceeds in low yields. The most convenient approach to fluorothiophenes and their benzoanalogues involves lithiation-fluorination reactions. Other common methods are based on heterocyclizations with participation of methyl thioglycolate, or cycloaddition reactions. The scarce methods for fluorinated thiophenes synthesis give a chance for synthetic chemists to elaborate new, better pathways to these intriguing and useful compounds.
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Serdyuk, O.V., Abaev, V.T., Butin, A.V., Nenajdenko, V.G. (2014). Fluorinated Thiophenes and Their Analogues. In: Nenajdenko, V. (eds) Fluorine in Heterocyclic Chemistry Volume 1. Springer, Cham. https://doi.org/10.1007/978-3-319-04346-3_6
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