Abstract
The chapter is devoted to the synthesis and application of indoles as well as some their azaanalogues bearing fluorine atoms, trifluoromethyl groups, and perfluorinated aryl fragments.
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1 Introduction
Indoles represent very important subunits of many natural products and pharmacologically active compounds [1]. Fluorinated indole derivatives are inhibitors of HIV-1 [2], CB2 cannabinoid receptor ligands found in the central nervous system [3], and factor Xa preventing thrombus [4]. Some fluorinated azaindoles, for example, fluorinated pyrrolopyrimidines are inhibitors of hepatitis C virus (HCV) RNA replication [5] and Y5 antagonists which are potential antiobesity agents [6]. Herein, we highlighted methods for the synthesis and application of fluoroindoles, trifluromethylpyrroles and some their azaanalogues.
2 Synthesis of Fluoroindoles and Deazapurines
2.1 Functionalization of the Pyrrole Ring
Several reagents were used for the electrophilic fluorination of indole. The first one used for this aim was trifluoromethyl hypofluorite (CF3OF). Treatment of N-acylindole 1 with trifluoromethyl hypofluorite in CF3Cl at −78 °C afforded a mixture of 2-fluoro-3-trifluoromethoxy- and 2,3-difluoroindoline derivatives 2–4 in high combined yield. Subsequent treatment of difluoride 4 with potassium hydroxide in methanol afforded quantitatively 3-fluoroindole 5. Similarly, starting from 1-formyl-2-methylindole reaction with trifluoromethyl hypofluorite resulted in formation of 2-methyl-3-fluoroindole 7 in low yield in mixture with 2-methyl-3-trifluormethoxyindole 8 [7].
Fluorination of indoles 9 and 11 using cesium fluoroxysulfate (CsOSO3F, CFS) or Selectfluor led to the corresponding 3-fluoroindolines, which are the products of conjugate addition of fluorine and methanol or water. Thus, fluorinated methoxyindolines 10, and 3-H-indoles 12 or hydroxyindolines 13 were obtained in methanolic or aqueous acetonitrile respectively [8a, b].
3-Fluoroindole 15 can be also prepared using Selectfluor. When acetonitrile was replaced by acetone and reaction was stopped before the starting N-methyl indole 14 was totally consumed, 3-fluoroindole derivative 15 was isolated in 45 % yield together with difluorohydroxyindoline derivative 16. This experiment led to claim that 3-fluoroindole derivative 15 was a reaction intermediate, subsequent fluorination resulted in the formation of difluoroindolines 12 and 13 [8b].
N-Fluoropyridinium triflates 18 are another useful type of fluorinating reagents applied for the preparation of fluorinated indoles. Using these reagents a series of 2-(3-fluoroindolyl)carboxylic acid derivatives 19 was prepared in good yields by treatment of indole-2-carboxylates or carboxamides 17 in dichloromethane [4, 9].
The problem of regioselective installation of fluorine into pyrrole ring of indole was resolved using tin substituted indoles as starting materials. Both 2- and 3-trimethylstannyl-1-(arylsulfonyl)indoles 20 and 22 can be used for fluorination with cesium fluoroxysulfate to afford 2-fluoro and 3-fluoroderivatives in 61 % and 72 % yields correspondingly. Using Selectfluor and xenon difluoride gave fluoroindoles in moderate yields. In addition, reaction of 2-trimethylstannylindole 20 with xenon difluoride afforded admixture of regioisomeric 3-fluoroindole 23 [8, 10].
Analogous transformation with cesium fluoroxysulfate in the case of more electron rich 1-methyl-2-(trimethylstannyl)-1H-indole 24 leads to 2-fluoro-1-methyl-1H-indole 25 in lower yield [8c].
A nucleophilic fluorination approach towards fluoroindoles was also elaborated. Using nucleophilic substitution of phenyliodonium group by fluoride under heating, 2-fluoroindole 25 and 3-fluoroindole 5 were prepared in good yields. The intermediate phenyl(indolyl)iodonium salts 26 and 28 were easily synthesized by treatment of (2-indolyl)trialkylstannane 24 [11] or indole 27a [12] with the corresponding polyvalent iodine compounds.
Similarly, 2-fluoroindole 30 derivative was obtained in 45 % yield by nucleophilic substitution of chloride in the 2-chloroindole 29 under heating with sodium fluoride in dimethyl sulfoxide [13]. The nucleophilic substitution proceeds in quite mild conditions for 29 due to the presence of activating nucleophilic substitution keto group in β-position of the indole.
An electrosynthesis of fluorinated indole derivatives was carried out by Fuchigami and co-workers. Anodic fluorination of various N-acetyl-3-substituted indole derivatives 31 was performed in acetonitrile to give a mixture of trans- and cis-2,3-difluoro-2,3-dihydroindoles 32, which afforded 3-fluoroindoles 35 and 34 after treatment with sodium methoxide [14].
An efficient pathway towards 3-fluoroindoles was proposed starting from isatines 35. Fluorinated 2-indolinones 36 were obtained in high yields by treatment of isatine derivatives 35 with diethylaminosulfur trifluoride in dichloromethane. In case of electron-donating substituents reduction of 36 with tetrahydrofuran-borane complex led smoothly to 3-fluoroindoles 37 in high yields.
The corresponding difluoroindolines 38 were mostly isolated in case of indoles with electron-withdrawing groups. It was mentioned, that 3-fluoroindoles 5 and 37a are quite unstable; the much more stable N-tosyl derivatives 23 and 39 can be prepared by treatment of 5 and 37a with tosyl chloride under basic catalysis [15].
7-Deazapurines (pyrrolo[2,3-d]pyrimidines) are shape mimics of the parent purines. Hence, one might expect the corresponding ribonucleosides can replace naturally occurring RNA-constituents as substrates or inhibitors. As a result, further modifications of the pyrrolo[2,3-d]pyrimidine moiety may provide novel pharmacologically active compounds against human immunodeficiency virus [16]. A great effort was devoted to investigations of 7-fluorinated 7-deazapurines. The fluorination of various 7H-pyrrolo[2,3-d]pyrimidines 40 with Selectfluor gave selectively 7-fluorinated 7-deazapurines 41 in moderate yields [17]. Alternatively, 7-fluorinated 7-deazapurines 41 were prepared by lithiation of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine 42, followed by subsequent treatment of the resulting intermediate with trimethylstannane chloride to give 5-trimethylstannane 43, which affords target 5-fluoroderivative 41 in 21 % yield after the reaction with Selectfluor [5].
The second step of new nucleoside preparation was the modification at the pyrrole nitrogen, using standard techniques of nucleoside synthesis such as the silyl-Hilbert-Johnson (or Vorbrüggen) reaction [17a, c, 18], alkylation under basic conditions [17d, 19] or Mitsunobu reaction [17f, 20]. By means of methods mentioned, a series of nucleosides 44–46 was prepared in moderate to good yields.
In the case of β-substituted pyrrolo[3,2-d]pyrimidines, the fluorine atom can be inserted into the molecule via metallation to α-position to pyrrole ring followed by fluorination. Thus, compound 47 reacted with n-butyllithium and N-fluorobenzenesulfonimide to produce fluoro derivative 48 in 52 % yield [21].
2.2 Heterocyclization
β,β-Difluorostyrenes 52 bearing a tosylamido group at the ortho-position underwent intramolecular nucleophilic substitution of the fluorine atom via a 5-endo trigonal process leading to 2-fluorinated indoles 53 [22, 23]. The cyclization is promoted by base, for example sodium hydride. The starting β,β-difluorostyrenes 52 were obtained accordingly to scheme below. Firstly, coupling of 2,2-difluorovinylboranes 50, generated in situ from 2,2,2-trifluoroethyl toluene-p-sulfonate 49, with N-butylmagnesio-o-iodoaniline were performed in the presence of copper(I) iodide and a palladium catalyst to give alkene 51. Next, alkene 51 was converted into 52 by the reaction with TsCl.
Another intramolecular cyclization of amine 58 is the last step in the pyrrolo[3,2-d]pyrimidine analogue 59 synthesis. Intermediate 58 formed in situ from nitro precursor 57 by reduction with tin(II) chloride is a key step of this version of Leimgruber–Batcho synthesis leading to formation of 59 finally. This simple three-step route to 59 started from the coupling of electron-poor dichloronitropyrimidine 54 with β-fluoroenamine 55 to form alkene 56. Regioselective nucleophilic substitution of chlorine with piperidine led to nitro precursor 57, which transforms into target pyrrolo[3,2-d]pyrimidine 59 by reduction in 6 % overall yield [5].
3 Synthesis of Trifluoromethylindoles
3.1 Direct Trifluoromethylation
Radical trifluoromethylation of N-trimethylsilylindole 27b with trifluoroiodomethane proceeded nonselectively into both 2- and 3-positions, with a preference for the 2-trifluoromethylindole formation [24]. Quench of the reaction mixture with methanol afforded the 2- and 3-trifluoromethylndoles 60a and 61 in 2/1 ratio. Similarly, the trifluoromethylation using difluorodiiodomethane [25] and bis(perfluoroalkanoyl)peroxide [26] led to a mixture of the same products. In all cases, the overall yield of isomeric indoles was moderate.
Perfect selectivity was achieved then hypervalent iodine reagent A [27] was used for electrophilic trifluoromethylation of indoles. Radical trifluoromethylation using CF3I-FeSO4-H2O2-DMSO system B [28] provided also excellent regioselectivity. However, yields of 2-trifluoromethylindoles 60a–c in both cases were moderate to good.
Another selective approach to 2-trifluoromethylindole is copper-mediated oxidative cross-coupling of 2-indolylboronic acid with TMSCF3. Reaction proceeds in mild conditions to give N-Boc-2-trifluoromethylindole 60d in 61 % yield [29].
The nucleophilic trifluoromethylation, which is based on the heating of N-methyl-2-iodoindole 63 with 10 equivalents of sodium trifluoroacetate and an equimolar amount of copper(I) iodide in N-methylpyrrolidinone, afforded N-methyl-2-trifluoromethylindole 60c in 65 % yield [30].
Formal N-trifluoromethylation of indole was performed in several steps, starting from indoline. At first step 3-cyanoindoline was treated with NaH, followed by CS2 and then MeI to form thioderivative 64. The latter was treated with tetrabutylammonium dihydrogen trifluoride, followed by NBS, to give N-CF3-indoline 65. Aromatization of 65 was carried out by reaction with NBS in CCl4 at reflux, leading to N-trifluoromethyl-3-bromoindole 66 [31].
3.2 Heterocyclizations
3.2.1 Formation of the C3-C4 Bond
Kobayashi et al. elaborated an unusual pathway for the synthesis of 2,3-bis(trifluoromethyl)indoles [32]. Photolysis of the 1-phenyl-4,5-bis(trifluoromethyl)-1H-1,2,3-triazole in hexane proceeded very slowly to afford the indole 68 in 44 % yield. It was proposed, that after homolytic nitrogen extrusion, the carbene 67 was formed. Intramolecular cyclization led to the indole 68.
Radical, photochemical and thermolytic generation of N-aryltrifluoroacetimidoyl radicals followed by intramolecular cyclization was successfully used to synthesize 2-trifluoromethylindoles [33]. The radical approach was based on treatment of imidoyl iodides 69a with tributyltin hydride in the presence of 2,2′-azabis(isobutyronitrile) (AIBN). The second method for the generation of N-aryltrifluoroacetimidoyl radicals 70 was based on the homolytic cleavage of carbon-iodine or carbon-tellurium bond in imidoyl iodides 69a and tellurides 69b under irradiation [34]. The third method involved the thermal homolysis of aza compounds 69c. All of these methods provided the indoles 71, 72 and 73, respectively, in high yields [33, 34].
The intramolecular Heck reaction of bromo- or iodoaryl enamines 74 is another versatile key step for the synthesis of indoles. Zero-valent palladium catalysis afforded a mixture of indoles 76 and reduced enamines 74 (X=H) via intermediate formation of 75 depending on the base used [35].
A variation of the intramolecular Heck coupling towards indoles bearing trifluoromethyl and aryl groups in the 2- and 3-positions was described by Chae and co-workers. First the C2-N bond was built, followed by ring closure that forms the C3-C4 bond. Accordingly, the palladium catalyzed addition of the trifluoromethyl(aryl) acetylenes 78 to the ortho-iodoanilines 77 afforded a mixture of the indoles 79 and 80 in high overall yield. Depending on the catalyst [20 mol% Pd(PPh)3 or 10 mol% Pd2(dba)3 · CHCl3, P(o-Tol)3], one isomeric indole of either 79 or 80 was formed predominantly [36].
Another versatile approach towards 3-trifluoromethylated indoles was elaborated by Rodrigues et al. Anilines 81 reacted with epoxy ethers 82 (prepared by epoxydation of the corresponding vinyl ethers) in hexafluoropropan-2-ol to form mixtures of diastereomeric indolines 83 in high yields. The ratio of the diastereomers varied between 96:4 and 79:21. These diastereomers can be separated easily by column chromatography. The reaction was general and allowed effective preparation of indolines with both electron-donating and electron-withdrawing substituents. Compounds with fused rings were also prepared by this method. Treatment of the major trans-diastereomer of 83 with thionyl chloride in pyridine afforded the 3-trifluoromethylindoles 84 in high yields [37].
3-Aryl-2-trifluoromethylindoles 88 were prepared regioselectively using trifluoromethyl-2-arylenamines as synthetic equivalents of trifluoromethylated carbonyl compounds in the Fischer indole synthesis. Accordingly, arylhydrazines 85 reacted smoothly with enamines 86 in acetic acid to give the α-trifluoromethylhydrazones 87. Fischer rearrangement of these hydrazones was performed in refluxing acetic acid the presence of methanesulfonic acid. As a result, a number of 3-aryl-2-trifluoromethylindoles were prepared in moderate to high yields [38]. This approach is first successful example of Fisher rearrangement for trifluoromethylated derivatives.
3.2.2 Formation of the C2-C3 Bond
Indole 90 was synthesized by a modified Madelung reaction from the amide 89 by treatment with potassium tert-butoxide. The presence of two strong electron-withdrawing groups (CN and CF3) in 89 facilitated both the deprotonation to the benzyl anion and its intramolecular cyclization under very mild conditions. Formation of 90 was completed in 10 min at room temperature in 81 % yield [39].
Miyashita and co-workers developed a novel 2-trifluoromethylindole synthesis based on thermolysis of 2-(N-acylamino)benzylmethyl ethers 91 in the presence of triphenylphosphine. However, this method has several disadvantages. The presence of a MeO-group in 5-position or 4-methoxyphenyl group at the benzyl carbon atom is necessary for the formation of 92, otherwise the yields tend to zero. An explanation invokes the necessity of resonance stabilization of the intermediate oxonium ion 93, which gives the key phosphonium salt 94 after attack by PPh3. Subsequent intramolecular Wittig reaction leads to 95 which affords the 3-H-indole 96. Isomerization of the latter leads to the target indole 92. Another significant disadvantage of the method is the four-steps synthetic sequence to reach the starting 2-(N-acylamino)benzyl methylethers 91 [40].
These disadvantages could be overcome by use of the phosphonium salts 98, which are prepared in two steps from amides 97. Bromination of 97 with NBS followed by reaction with triphenylphosphine permits to prepare 98 effectively. 2-Perfluoroalkylindoles 60a,d and 99 were obtained in high yields using this method [40, 41].
Okada and co-workers investigated the reactions of the quinoline and naphthalene bis(trifluoroacetyl) derivatives 100 with amino acid esters in acetonitrile [42]. Two COCF3 groups facilitate extremely nucleophilic substitution in 100 to make dimethylamino group good enough nucleophuge in this case. In the presence of equimolar amounts of sodium acetate (neutral media) the dimethylamino group was substituted with the amino acid ester moiety forming 101. Subsequent treatment with triethylamine resulted in cyclization of 101 into the condensed dihydropyrrole derivatives 102 as mixtures of diastereomers. Quinoline 101 (X=N) was not isolated, but spontaneously cyclized to give 1H-pyrrolo[3,2-h]quinoline 102 (X=N). In contrast, naphthalene 101 (X=СН) in basic media was stable enough to be isolated. Treatment of 102 (X=СН) with trifluoroacetic acid gave the 1H-benzo[g]indole 103 quantitatively.
Fürstner and co-workers used the McMurry reaction for the synthesis of 2-trifluoromethyl-3-phenylindole 105 from ketonamide 104. The reaction was performed either with two equivalents or substoichiometric amounts of titanium(III) chloride. In the latter case, large excesses of trimethylsilyl chloride and zinc were necessary [43].
Refluxing of N-trimethylsilyltoluidine 106 with n-butyllithium in hexane in the presence of TMEDA afforded the dianion 107, which on treatment with ethyl trifluoroacetate at −78 °C gave 2-trifluoromethylindole 60a in 47 % yield [30].
An interesting rearrangement was found by Frey et al. Heating the amino alcohol O-acetate 108 (R=Me) in acetonitrile led to the tricyclic indole derivative 110, while the trityl derivative 108 (R=Ph) afforded the dihydrocyclohepta[3,4]pyrrolo[1,2-a]indoles 111 in high yields. The authors suggested the carbene 109 as a key reaction intermediate, though the reaction mechanism is still a matter of discussion [44].
A convenient pathway to 2-fluoroalkyl-substituted indoles 114 was elaborated using the fluorinated N-[2-(haloalkyl)aryl]imidoyl chlorides 112 as key intermediates [45]. Treatment of the latter compounds with magnesium in tetrahydrofuran gave the Grignard compounds 113, which afforded the indoles 114 in high yields by intramolecular cyclization initiated by attack of the nucleophile on imidoyl fragment.
3.2.3 Formation of the C2-N Bond
A regioselective pathway to 2- and 3-trifluoromethylindoles based on the ring-opening reaction of compounds 115 was developed by Attanasi and co-workers. After treatment of 115 with HCl in methanol, the corresponding indoles 60a and 60a were obtained in good yields. The starting compounds 115 were prepared from trifluoroquinolines in three steps [46].
The synthesis of 3-trifluoromethyl-2-phenylindole 117 was accomplished by succeeding palladium catalyzed carbon−carbon cross-coupling of 116 with phenylboronic acid and carbon−nitrogen coupling in the presence of S-Phos [47].
Under similar conditions, 2-trifluoromethylindole 60a was prepared starting from 2-bromoaniline 118 and 2-bromo-3,3,3-trifluoroprop-1-ene 119 using palladium catalysis [48].
An efficient one-pot synthesis of substituted 2-trifluoromethylindoles was elaborated using copper(I)-catalyzed nucleophilic substitution of vinyl or aryl halogen atoms in styrenes 120 by primary amines. The resulting 2-trifluoromethylindoles 121 were prepared in moderate to good yields. The simplicity of the synthetic procedure and readily available starting materials are significant advantages of this method [49].
Another synthetic sequence for the preparation of 2-trifluoromehylindole 60a was developed. In the first step, the styrene 122 was converted into the enamine 123 in quantitative yield. Subsequent treatment of this enamine with zinc dust under the standard conditions of the Leimgruber-Batcho indole synthesis led to 2-trifluoromethylindole, also in almost quantitative yield. Moreover, a one-pot methodology without isolation of enamine was also applied. In that case, an overall 90 % yield was obtained [50].
A convenient method for the synthesis of 2-trifluoro-methyl-1H-indole-3-carboxylic acid esters 126 was elaborated using a cascade coupling, condensation and deacylation sequence. Starting from aryl trifluoacetamides 124 and ketoesters 125, the corresponding indoles 126 were prepared in good to excellent yields, using a catalytic system of copper(I) iodide and L-proline [51].
In conclusion, the synthesis of trifluoromethylated indoles is more difficult and less studied compared to synthesis of indoles bearing C-F bonds, therefore new effective strategies are very desirable to make these compounds to be more accessible building blocks for drug discovery.
4 Synthesis of Indoles with Fluorine Atoms in Carbocycle
The influence of the fluorine atom on the nature of indole system is lower when fluorine is located on the benzene ring. However, there is significant specificity for indoles having fully fluorinated benzene ring. This part of the chapter is focused on 4,5,6,7-tetrafluoroindole and derivatives.
A common approach to the 4,5,6,7-tetrafluoroindoles is based on the various heterocyclizations starting from pentafluorophenyl precursors. Thus, heating of 1-pentafluorophenyl-2-amino-ethanol 129 in dimethylformamide gives 4,5,6,7-tetrafluoroindole 132 in good yield. The reaction proceeds via intramolecular nucleophilic substitution of the o-fluorine atom, followed by dehydration [52].
Another possible route for the nucleophilic substitution of the ortho-fluorine atom includes intramolecular attack by the hydroxy group of 2-(hydroxyamino)-1-(pentafluorophenyl)ethanol 128. Heating of compound 128 in N,N-dimethylformamide in the presence of sodium fluoride led to cyclizations at the nitrogen to give 1,3-dihydroxy-4,5,6,7-tetrafluoro-indoline 130. The latter was readily reduced by zinc in acidic media into 4,5,6,7-tetrafluoroindole 132. The starting amino alcohols 128 and 129 were obtained by the potential-controlled electrochemical reduction of the nitroalcohol 127, which can be prepared directly from pentafluorobenzaldehyde and nitromethane.
Alternative method for the synthesis of tetrafluoroindole was described in 1968. Ketone 133 was heated under reflux with aniline in the presence of anhydrous zinc chloride in order to prepare the Schiff base 134. However, the only product isolated was N-phenyl-4,5,6,7-tetrafluoro-2-methylindole 136 (<10 %). The yield of 136 was increased up to 47 % by the addition of aniline hydrobromide to the reaction mixture. Thus, the improved synthesis of indole 136 includes heating of the ketone 133, aniline hydrobromide, anhydrous zinc chloride and aniline under reflux for 2 h [53].
A similar approach was realized by other authors starting from aldehyde 137. The reaction of the latter one with amines, followed by cyclization of intermediate 138 using lithium diisopropylamide as a base leads to tetrafluoroindole core. Finally, deprotection of 139 or 140 by a rhodium catalyst gave 3-methyl-4,5,6,7-tetrafluoroindole 141. Overall yield of 141 starting from 138 was 72 % [54].
Intramolecular nucleophilic substitution of fluorine led to the formation of the pyrrole ring in the above mentioned transformations. However, the C-arylation can precede the heterocyclization. For example, condensation of cyclic enamines 143 with perfluorobenzenes 142 gave fluorinated indoles 144 via formation of C-N and C-C bonds. The authors reported that initial C-arylation was in competition with an initial N-arylation producing N-dialkylaminopoly-fluoroarenes. The “C versus N” arylation ratio was found to be dependent upon the nature of the enamine [55].
Similar cyclizations based on N-arylation are also known. For instance, when pentafluorophenyl substituted aminofumarate 145 (prepared from pentafluoroaniline and diethyl acetylenedicarboxylate) was treated with sodium hydride in dimethylformamide under reflux the indole derivative 146 was isolated. However, the yield of the target indole was very low [56]. Subsequent hydrolysis and decarboxylation provided tetrafluoroindole 132 in 55 % yield.
An unusual formation of indoles via a formal Fischer cyclization of N-pentafluorophenyl hydrazones 147 was discovered by Brooke. Generally, the Fischer reaction demands the ortho-position be unoccupied. However, in refluxing tetraline, hydrazones 147 were transformed into polyfluoroindoles accompanying with the loss of one ortho-fluorine. Hydrazones of acetophenone and cyclohexanone afforded the corresponding indoles 148 and 149 in 12 and 18 % yields respectively. In case of acetaldehyde hydrazone, only a minor amount of parent tetrafluoroindole 132 were isolated. The mechanism of the reaction has not be clarified [57].
An efficient approach to polyfluoroindole was elaborated starting from hexafluorobenzene 142a [58] and pentafluoronitrobenzene 150 [59]. In the first step, perfluoroarylacetonitriles 152 were obtained by nucleophilic substitution of fluorine with cyanoacetate 151 followed by acid catalyzed decarboxylation. Alternatively, nitrile 152 could be prepared from pentafluorobenzyl bromide 153 by treatment with potassium cyanide. Next, nitriles 152 were reduced into β-polyfluoroarylethyl amine 154, which underwent facile cyclizations into fluorinated indolines 155. The latter were smoothly aromatized into the corresponding indoles 156 by treatment with manganese (IV) oxide or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
5 Properties
Fluorinated indoles reveal very similar properties in comparison to their non-fluorinated analogues. However, it should be noted that the chemistry of monofluorinated indoles (with fluorine atom attached to both 2 and 3 position) is scarcely studied. For example, 3-fluoroindole derivative 19a was debenzylated to give indole carboxylic acid ester 157 quantitatively; the latter one was converted into amide 159 by hydrolysis followed by reaction with the corresponding amine in the presence of BOP reagent [9a]. Nitrogen atom in case of 3-fluorosubstituted indole derivatives has usual nucleophilicity and can participate in standard indole reactions, for example reaction with tosyl chloride provided N-sulfonylation product in 61 % yield [15].
One more example of monofluoroindoles reactivity is hydrolysis of indole derivative 53a into oxindole 160, which was achieved under treatment with trifluoromethanesulfonic acid in hexafluoroisopropanol [60].
4,5,6,7-Tetrafluoroindoles were also shown to exhibit typical reactivity of indole. N-Substituted 4,5,6,7-tetrafluoroindole derivatives were obtained easily by the reaction of the parent indole with various electrophiles under basic conditions. Reaction of indoles 141 and 161 with acetic anhydride, benzoyl chloride, tosyl chloride and methanesulfonic acid ester afforded the corresponding N-substituted derivatives 162–165 in high yields [3, 54b].
Alternative approach to 4,5,6,7-tetrafluoroindole nitrogen modification was proposed by Trost et al. Reaction of 4,5,6,7-tetrafluoroindole 132 with vinyl azyridines 166 under Pd2(dba)3 catalysis proceeded with ring-opening to give, stereoselectively, allyl amine derivatives 167 in high yields [61].
In spite of electron withdrawing action of four fluorine atoms, 4,5,6,7-tetrafluoroindole 132 reacts with electrophiles under quite mild conditions to give products of substitution at the 3-position. For example, reaction of 132 with N-(carbobenzyloxy)piperidin-4-one 168 in the presence of trimethylsilyl triflate and triethylsilane afforded the corresponding piperidine derivative 169 [62]. Using sulfur trioxide-pyridine complex indolyl sulfonic acid 170 was obtained, which was further converted into sulfonyl amide 172 by reaction with phosphorus(V) oxychloride, followed by treatment with derivative of piperazine [2a].
Bromination was carried out using bromine in presence of catalytic amount of aluminum chloride or bromine-dioxane complex at 0–20 °C to form 3-bromoderivative 173 in high yield [63]. Electrophilic carbenoid species, generated at elevated temperature, reacted with polyfluoroindole to form indolyl carboxylic esters 174 after treatment with formic acid [58c].
Fluorinated 3-indolyl carbaldehyde 175 was obtained in yields up to 89 % by Vilsmeier-Haack reaction [58c, 63]. Aminomethylation afforded the corresponding fluorinated gramine derivatives 176 in good yields [58c, 63].
Reaction of chloroacetonitrile with 4,5,6,7-indolyl magnesium bromide, obtained by treatment of tetrafluoroindole with ethylmagnesium bromide, proceeded regioselectively at 3-position to afford the corresponding nitrile 177 in moderate yield [58c].
Oxidation of 3-methyltetrafluoroindoles 178 by selenium dioxide in presence of acetic anhydride can be stopped at the alcohol oxidation level step to give acetates 179. Fluorinated 3-indolylcarbaldehydes 180 were isolated in high yields when the oxidation was performed without addition of acetic anhydride [54]. Further oxidation of aldehyde was achieved by treatment with potassium permanganate to afford 3-indolylcarboxylic acid 181 in high yield [58c].
Reduction of the aldehyde 175 with lithium aluminum hydride [63] or zinc in hydrochloric acid [58c] gave fluorinated 3-methylindole 141 in good yield.
Fluorinated tryptamine 183 was prepared by Rh-catalyzed reduction of the corresponding nitrile 177 by hydrogen [58c]. Alternatively, the compound 183 was synthesized by lithium aluminum hydride reduction of nitroalkene 182, which was obtained by condensation of aldehyde 175 with nitromethane [54].
Through a similar reaction sequence, fluorinated tryptophan 187 was synthesized. Condensation of aldehyde 175 with N-benzoyl glycine afforded oxazolone 184, which was converted into unsaturated acid 185. Reduction of 185 by hydrogen and subsequent acid-catalyzed hydrolysis gave fluorinated tryptophan 187 in good total yield [54].
Fluorinated gramine analogue 188 was easily N-alkylated by reaction with methyliodide [58c] or dimethylsulfate [54, 63]. The tertiary amine salt 189 and the acetoxy derivative 179a are suitable substrates for various nucleophilic substitutions. For instance, treatment of 189 or 179a with potassium cyanide or sodium cyanide afforded the corresponding nitrile 177 [54, 58c] which was hydrolyzed into fluorinated indolyl acetic acid 193 [54]. Reaction of acetoxy compound 179a with secondary amines led to gramine 188. The corresponding tryptophan derivative 191 was obtained using the sodium salt of diethyl aminomalonate as a nucleophile [58c].
Trifluoromethylindoles undergo similar transformations in comparison to their non-fluorinated analogues as well. Thus, electrophilic substitution at the C-3 position takes place when the C-2 position is occupied by the trifluoromethyl group. The Mannich reaction provided dimethylaminomethyl derivatives in good yields under standard conditions [64].
Quaternization of the compounds 195b with methyl iodide and subsequent reactions with nucleophiles, e.g. potassium cyanide, thiophenol, and diethyl malonate, gave corresponding products 196–198 in 62–85 % yields [64].
Reduction of the nitrile group of the compound 199 and subsequent reaction with acetic anhydride led to 2-trifluoromethyltryptamine 200 [64]. For the reduction, Raney Ni was used, since hydrides, for example, lithium aluminium hydride, can reduce the trifluoromethyl group as well.
Hydrolysis of the nitrile 199 gave 2-trifluoromethylindole-3-acetic acid 201 in moderate yield [60]. A partial reduction of the nitrile group in 199 provided indole-3-acetaldehyde 202 in 51 % yield. The latter was used for the synthesis of the 2-trifluoromethylated analogue of oxypertine (an antipsychotic used in the treatment of schizophrenia) 203 upon treatment with N-phenylpiperazine and sodium cyanoborohydride [64].
2-Trifluoromethyltryptophan methyl ester 205 was synthesized from nitro derivative 204 obtained via direct reaction of 195a with methylnitroacetate. Chemoselective reduction of the nitro group was achieved by hydrogenation in the presence of Raney Ni in methanol [60].
N-Alkylation of indole 206 was achieved by treatment with NaH in DMF, followed by reaction with chloroacetonitrile [65]. Subsequent catalytic reduction of 207 with hydrogen under Raney-Ni followed by reaction with ethylcarbonate led to compound 208, which was investigated as melatonin receptor ligand.
Attanasi et al. investigated reactions of both 2-and 3-trifluoromethylindole involving trifluoromethyl group and leading to loss of fluorine. Treatment of trifluoromethylindoles with LiAlH4 gave methylindoles 210 and 213.
Reaction of 2-trifluoromethylindole with sodium ethoxide led to ortho-ether 209, while ethyl 3-indolylcarboxilate 212 was isolated in case 3-trifluoromethylindole. Reaction of 2-trifluoromethylindole with NaBH4 in ethanol led to ethyl 2-indolylcarboxilate 211. In contrast, reduction of trifluoromethyl group was observed to form 3-methylindole 213 in case of 3-isomer. Treatment of 3-trifluoromethylindol with sodium amide in liquid ammonia led to 3-cyanoindole 214, whereas 2-trifluoroindole did not reacted with sodium amide at all [46].
6 Pharmacological Properties of Fluorinated Indoles
Fluorinated indoles posses a broad scope of physiological activity and they are very prominent candidates for further biological testing and using as drugs. In this part of the chapter pharmacological properties of fluorinated indoles are collected (Table 1). One can see very broad spectrum of biological activity of such structures and synergism bringing both indole fragment and fluorine in a molecule.
7 Conclusions
Recent decades, fluorinated indoles and their analogues have enjoyed remarkable attention of chemists. However, one can definitely conclude that synthesis of these compounds is still challenging and attractive task.
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Financial support from the Russian Foundation for Basic Research (grants no. 12-03-00292-a and 13-03-01129) are gratefully acknowledged.
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Muzalevskiy, V.M., Serdyuk, O.V., Nenajdenko, V.G. (2014). Chemistry of Fluorinated Indoles. In: Nenajdenko, V. (eds) Fluorine in Heterocyclic Chemistry Volume 1. Springer, Cham. https://doi.org/10.1007/978-3-319-04346-3_3
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DOI: https://doi.org/10.1007/978-3-319-04346-3_3
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