Synthesis and Reactions of 3-Halogenated 2-CF3-Indoles

Halogenation of 2-trifluoromethylindole afforded 3-chloro-, 3-bromo- and 3-iodo derivatives in up to 98% yield. Methyl-, benzyl- and tosyl-groups can be installed at the nitrogen atom of prepared indoles in high yields by base catalyzed reaction with the corresponding alkylating (sulfonylating) reagents. A high synthetic utility of the prepared haloindoles in the reaction with various nucleophilies was shown. The reaction with 4-methylthiophenol and copper cyanide afforded the corresponding sulfides and nitriles in high yield. Palladium catalyzed cross-coupling with phenyl boronic acid and phenylacetylene gave the corresponding 3-phenyl-2-CF3-indoles and acetylenic derivatives in 72–98% yield.


Results
Thinking about further transformations of 2-CF 3 -indoles, we found surprisingly, that halogenation of these indoles has not been thoroughly and systematically investigated. To the best of our knowledge, only the iodination of 2-CF 3 -indole using N-iodosuccinimide was reported so far [60]. 3-Chloro-2-trifluromethylindole and its N-methyl derivative were reported but synthesized via the fluoroalkylation processes [61,62]. To fill this gap, we maintained the reaction of indole 2 with NCS, NBS, Br 2 and iodine. This approach afforded 3-chloro-, 3-bromo-and 3-iodoindoles 3a-3c in high yields (Scheme 1). In spite of the presence of electron-withdrawing trifluoromethyl group, 2-CF 3 -indole is a very reactive molecule towards electrophiles. All mentioned halogenation reactions were performed without the addition of Lewis acids. Moreover, 3-bromoindole 3b can be easily brominated in CH 2 Cl 2 at 5-position by the addition of second equivalent of bromine to give dibromoindole 4 in 75% yield in a few minutes. Bromination of 2 with two equivalents of Br 2 in AcOH proceeded very slowly (over a few hours) to give indole 4 in higher yield. Such a result can be explained by lower selectivity of bromination in CH 2 Cl 2 , leading for deeper bromination of the indole core. Alternatively, bromoindoles 3b and 4 were prepared by one-pot synthesis starting from enamine 1. For that purpose, a solution of bromine in AcOH was added to the reaction mixture obtained after the reduction step. Mono-and di-bromo derivatives were prepared in 58% and 56% yields calculating on two steps (Scheme 1). rated convenient approaches towards α-CF3-phenethylamines [48], CF3-enones [49][50][51], CF3-β-carbolines [52], 2-CF3-3-arylindoles [52], 2-CF3-3-benzylindoles [53] and unsubstituted 2-CF3-indoles [54,55]. We have also examined several electrophilic reagents for modification of 2-CF3-indoles at C-3 atom [55]. 2-CF3-Indoles are perspective compounds for drug design. Thus, derivatives of these indoles have demonstrated properties of selective COX-2 inhibitors [56], anti-inflammatory and neuroprotective actions [57], antiproliferative [58], antineoplastic properties [59] and antifungal properties [60]. In this article we continue investigation of synthetic potential of 2-CF3-indoles to study preparation of 3halogenated derivatives and their subsequent modification.

Results
Thinking about further transformations of 2-CF3-indoles, we found surprisingly, that halogenation of these indoles has not been thoroughly and systematically investigated. To the best of our knowledge, only the iodination of 2-CF3-indole using N-iodosuccinimide was reported so far [61]. 3-Chloro-2-trifluromethylindole and its N-methyl derivative were reported but synthesized via the fluoroalkylation processes [62,63]. To fill this gap, we maintained the reaction of indole 2 with NCS, NBS, Br2 and iodine. This approach afforded 3-chloro-, 3-bromo-and 3-iodoindoles 3a-3c in high yields (Scheme 1). In spite of the presence of electron-withdrawing trifluoromethyl group, 2-CF3-indole is a very reactive molecule towards electrophiles. All mentioned halogenation reactions were performed without the addition of Lewis acids. Moreover, 3-bromoindole 3b can be easily brominated in CH2Cl2 at 5-position by the addition of second equivalent of bromine to give dibromoindole 4 in 75% yield in a few minutes. Bromination of 2 with two equivalents of Br2 in AcOH proceeded very slowly (over a few hours) to give indole 4 in higher yield. Such a result can be explained by lower selectivity of bromination in CH2Cl2, leading for deeper bromination of the indole core. Alternatively, bromoindoles 3b and 4 were prepared by one-pot synthesis starting from enamine 1. For that purpose, a solution of bromine in AcOH was added to the reaction mixture obtained after the reduction step. Monoand di-bromo derivatives were prepared in 58% and 56% yields calculating on two steps (Scheme 1).

Scheme 1. Halogenation of 2-CF3-indoles.
Aryl halides are valuable starting materials for reactions with nucleophiles as well as for metal-catalyzed cross-coupling reactions. Having prepared a set of 3-halogenated 2-CF3-indoles, we decided to investigate their reactivity. In order to expand a set of substrates, N-methyl, N-benzyl and N-tosyl derivatives of indoles 5-7 were prepared as well. Aryl halides are valuable starting materials for reactions with nucleophiles as well as for metal-catalyzed cross-coupling reactions. Having prepared a set of 3-halogenated 2-CF 3 -indoles, we decided to investigate their reactivity. In order to expand a set of substrates, N-methyl, N-benzyl and N-tosyl derivatives of indoles 5-7 were prepared as well. Thus, treatment of indoles 2, 3a, 3b, 3c with NaH in DMF followed by the reaction with MeI, BnBr, TsCl afforded N-methyl, N-benzyl and N-tosyl indoles 5-7 in high yield (conditions A). Alternatively, K 2 CO 3 was used as a base for alkylation with MeI and BnBr (conditions B) (Scheme 2).

OR PEER REVIEW 3 of 16
Thus, treatment of indoles 2, 3a, 3b, 3c with NaH in DMF followed by the reaction with MeI, BnBr, TsCl afforded N-methyl, N-benzyl and N-tosyl indoles 5-7 in high yield (conditions A). Alternatively, K2CO3 was used as a base for alkylation with MeI and BnBr (conditions B) (Scheme 2).
Next, the reaction of prepared 3-halogeno-2-CF3-indoles with 4-methylthiophenol was investigated. It was found that reaction with this potent nucleophile is a very sensitive to the nature of both halogen and a base. Thus, reaction of bromo-and iodoindoles 3b,3c led to the mixture of desired substitution product 9 and indole 2, which is a result of the reduction. When K2CO3 was used as a base, the share of indole 9 was about 23-24%, while in the case of Cs2CO3, indole 9 became major product of the reaction (53-65%). Slightly better selectivity was observed for the reaction with N-tosylated bromoindole 7c (36% compared to 23%). It should be noted that the tosyl group did not survive in the reaction conditions to give deprotected NH-indoles. Dramatically better selectivity was observed for chloroindole 3a, giving substitution product 9 in 88:12 ratio with indole 2. Ultimate selectivity was achieved using chloroindole 7b. We found that reaction of 7b with 4-methylthiophenol at elevated temperatures led to thioether 9 in 72% yield. Substitution reaction with 7b was accompanied by detosylation to afford indole 9 without tosyl group at nitrogen atom. Eventually, the reaction of N-methyl-3-bromoindol 5c gave indole 10 in ratio 66:34 with indole 5a in 85% total yield (Scheme 3). It should be noted that chloroindoles 3a,7b are less reactive than bromo-and iodoindoles 3b,3c,7c. As a result, higher temperatures (150 °C instead of 80-100 °C) were used for full conversion. By the similar reason, reaction of N-methylbromoindole 5c was also performed at 150 °C. Next, the reaction of prepared 3-halogeno-2-CF 3 -indoles with 4-methylthiophenol was investigated. It was found that reaction with this potent nucleophile is a very sensitive to the nature of both halogen and a base. Thus, reaction of bromo-and iodoindoles 3b,3c led to the mixture of desired substitution product 9 and indole 2, which is a result of the reduction. When K 2 CO 3 was used as a base, the share of indole 9 was about 23-24%, while in the case of Cs 2 CO 3 , indole 9 became major product of the reaction (53-65%). Slightly better selectivity was observed for the reaction with N-tosylated bromoindole 7c (36% compared to 23%). It should be noted that the tosyl group did not survive in the reaction conditions to give deprotected NH-indoles. Dramatically better selectivity was observed for chloroindole 3a, giving substitution product 9 in 88:12 ratio with indole 2. Ultimate selectivity was achieved using chloroindole 7b. We found that reaction of 7b with 4-methylthiophenol at elevated temperatures led to thioether 9 in 72% yield. Substitution reaction with 7b was accompanied by detosylation to afford indole 9 without tosyl group at nitrogen atom. Eventually, the reaction of N-methyl-3-bromoindol 5c gave indole 10 in ratio 66:34 with indole 5a in 85% total yield (Scheme 3). It should be noted that chloroindoles 3a,7b are less reactive than bromoand iodoindoles 3b,3c,7c. As a result, higher temperatures (150 • C instead of 80-100 • C) were used for full conversion. By the similar reason, reaction of N-methylbromoindole 5c was also performed at 150 • C.
The formation of indoles 2 and 5a is a result of a two-step process which is initiated by a halophilic attack to bromo-and iodoindoles by a nucleophile to form anion 8. Subsequent protonation of carbanion 8 led to indoles 2 and 5a having a hydrogen atom at 3-position (Scheme 3). In contrast, chloroindoles are less prone to be objects for halophilic attack due to the higher energy of C-Cl bond and nucleophilic substitution is preferable. However, only very potent nucleophiles, like thiophenols, can participate in the reaction.
Less complicated results were obtained in the reactions with CuCN (Rosenmund von Braun reaction [63]). It is not surprising, because this reaction does not occur via the S N Ar mechanism [64,65]. The reaction of 3b with CuCN led to the mixture of nitrile 11 with indole 2 in 65:35 ratio. N-Tosylated bromoindole 7c afforded a 96:4 mixture of 11 and 2. One hundred percent chemoselectivity was achieved using iodoindole 3c. The corresponding nitrile 11 was isolated in 91% yield. Selectivity of the reaction of bromoindoles with CuCN raised dramatically after installation of methyl and benzyl groups at the nitrogen atom.
The formation of indoles 2 and 5a is a result of a two-step process which is initiated by a halophilic attack to bromo-and iodoindoles by a nucleophile to form anion 8. Subsequent protonation of carbanion 8 led to indoles 2 and 5a having a hydrogen atom at 3position (Scheme 3). In contrast, chloroindoles are less prone to be objects for halophilic attack due to the higher energy of C-Cl bond and nucleophilic substitution is preferable. However, only very potent nucleophiles, like thiophenols, can participate in the reaction.
Less complicated results were obtained in the reactions with CuCN (Rosenmund von Braun reaction [64]). It is not surprising, because this reaction does not occur via the SNAr mechanism [65,66]. The reaction of 3b with CuCN led to the mixture of nitrile 11 with indole 2 in 65:35 ratio. N-Tosylated bromoindole 7c afforded a 96:4 mixture of 11 and 2. One hundred percent chemoselectivity was achieved using iodoindole 3c. The corresponding nitrile 11 was isolated in 91% yield. Selectivity of the reaction of bromoindoles with CuCN raised dramatically after installation of methyl and benzyl groups at the nitrogen atom. Both N-methyl-and N-benzylindoles provided high yields of cyanation products (near 90%) 12 and 13. However, chloroindole 3a does not participate in the reaction (Scheme 4).  The formation of indoles 2 and 5a is a result of a two-step process which is initiated by a halophilic attack to bromo-and iodoindoles by a nucleophile to form anion 8. Subsequent protonation of carbanion 8 led to indoles 2 and 5a having a hydrogen atom at 3position (Scheme 3). In contrast, chloroindoles are less prone to be objects for halophilic attack due to the higher energy of C-Cl bond and nucleophilic substitution is preferable. However, only very potent nucleophiles, like thiophenols, can participate in the reaction.
Less complicated results were obtained in the reactions with CuCN (Rosenmund von Braun reaction [64]). It is not surprising, because this reaction does not occur via the SNAr mechanism [65,66]. The reaction of 3b with CuCN led to the mixture of nitrile 11 with indole 2 in 65:35 ratio. N-Tosylated bromoindole 7c afforded a 96:4 mixture of 11 and 2. One hundred percent chemoselectivity was achieved using iodoindole 3c. The corresponding nitrile 11 was isolated in 91% yield. Selectivity of the reaction of bromoindoles with CuCN raised dramatically after installation of methyl and benzyl groups at the nitrogen atom. Both N-methyl-and N-benzylindoles provided high yields of cyanation products (near 90%) 12 and 13. However, chloroindole 3a does not participate in the reaction (Scheme 4). Next, we investigated palladium-catalyzed cross-coupling reactions of bromo-and iodoindoles with phenyl boronic acid (Suzuki reaction) and phenylacetylene (Snogashira Next, we investigated palladium-catalyzed cross-coupling reactions of bromo-and iodoindoles with phenyl boronic acid (Suzuki reaction) and phenylacetylene (Snogashira reaction) in standard conditions for these reactions. We found that reactions of bromoindoles 3b,5c,6c with phenyl boronic acid proceeded very smoothly under catalysis with Pd(PPh 3 ) 4 in dioxane-water as a solvent using K 2 CO 3 as a base. The corresponding 3-phenylindoles 14-16 were isolated in high yield while the reduction products 2,5a,6a were formed in traces amounts (Scheme 5). reaction) in standard conditions for these reactions. We found that reaction doles 3b,5c,6c with phenyl boronic acid proceeded very smoothly under Pd(PPh3)4 in dioxane-water as a solvent using K2CO3 as a base. The corresp nylindoles 14-16 were isolated in high yield while the reduction product formed in traces amounts (Scheme 5). The Sonogashira reaction was carried out using (Pd(PPh3)2Cl2 and CuI Et3N as a solvent. We found that iodoindoles react easily with phenylacet temperature, but the result of the reaction depends on the substituent at the Thus, the reaction of N-unsubstituted iodoindole 3c only afforded the redu 2 in an 86% yield. The reaction of N-methyliodoindole afforded acetylen quantitative yield. In a similar manner, N-benzyliodoindole led to acetylen yield. In the case of N-tosyliodoindole, the desired indole 19 was isolated in the share of by-products 7a and 2 was about below 13% (Scheme 6).

Materials and Methods
General remarks. 1 H, 13 C and 19 F NMR spectra (see Supplementary Ma S1-S82) were recorded on a Bruker AVANCE 400 MHz spectrometer(Bru MA, USA) in CD3CN and CDCl3 at 400.1, 100.6 and 376.5 MHz, respectiv shifts (δ) in ppm are reported with the use of the residual CHD2CN and chlo (1.94, 7.25 for 1 H and 1.30, 77.0 for 13 C) as an internal reference. The 19 F c were referenced to C6F6 (−162.9 ppm). The coupling constants (J) are given HRMS spectra were measured at MicroTof Bruker Daltonics instrument. was performed on "Merck 60 F254" plates (Merck, Darmstadt, Germany). matography was performed on silica gel "Macherey-Nagel 0.063-0.2 nm were of reagent grade and were used as such or were distilled prior to use. E The Sonogashira reaction was carried out using (Pd(PPh 3 ) 2 Cl 2 and CuI as catalyst and Et 3 N as a solvent. We found that iodoindoles react easily with phenylacetylene at room temperature, but the result of the reaction depends on the substituent at the nitrogen atom. Thus, the reaction of N-unsubstituted iodoindole 3c only afforded the reduction product 2 in an 86% yield. The reaction of N-methyliodoindole afforded acetylene 17 in almost quantitative yield. In a similar manner, N-benzyliodoindole led to acetylene 18 in an 86% yield. In the case of N-tosyliodoindole, the desired indole 19 was isolated in 87% yield and the share of by-products 7a and 2 was about below 13% (Scheme 6).
Molecules 2022, 27, x FOR PEER REVIEW 5 of 16 reaction) in standard conditions for these reactions. We found that reactions of bromoindoles 3b,5c,6c with phenyl boronic acid proceeded very smoothly under catalysis with Pd(PPh3)4 in dioxane-water as a solvent using K2CO3 as a base. The corresponding 3-phenylindoles 14-16 were isolated in high yield while the reduction products 2,5a,6a were formed in traces amounts (Scheme 5).
The Sonogashira reaction was carried out using (Pd(PPh3)2Cl2 and CuI as catalyst and Et3N as a solvent. We found that iodoindoles react easily with phenylacetylene at room temperature, but the result of the reaction depends on the substituent at the nitrogen atom. Thus, the reaction of N-unsubstituted iodoindole 3c only afforded the reduction product 2 in an 86% yield. The reaction of N-methyliodoindole afforded acetylene 17 in almost quantitative yield. In a similar manner, N-benzyliodoindole led to acetylene 18 in an 86% yield. In the case of N-tosyliodoindole, the desired indole 19 was isolated in 87% yield and the share of by-products 7a and 2 was about below 13% (Scheme 6).

Materials and Methods
General remarks. 1  HRMS spectra were measured at MicroTof Bruker Daltonics instrument. TLC analysis was performed on "Merck 60 F254" plates (Merck, Darmstadt, Germany). Column chromatography was performed on silica gel "Macherey-Nagel 0.063-0.2 nm. All reagents were of reagent grade and were used as such or were distilled prior to use. Enamine 1 [45] and indole 2 [56] were prepared as reported previously. Melting points were determined on an Electrothermal 9100 apparatus.

Materials and Methods
General remarks. 1 19 F chemical shifts were referenced to C 6 F 6 (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). HRMS spectra were measured at MicroTof Bruker Daltonics instrument. TLC analysis was performed on "Merck 60 F 254 " plates (Merck, Darmstadt, Germany). Column chromatography was performed on silica gel "Macherey-Nagel 0.063-0.2 nm. All reagents were of reagent grade and were used as such or were distilled prior to use. Enamine 1 [44] and indole 2 [54] were prepared as reported previously. Melting points were determined on an Electrothermal 9100 apparatus. reaction. The reaction mixture was left at room temperature for 1 day. After the completion of the reaction ( 19 F NMR control), THF was evaporated in vacuo. The residue was dissolved in CH 2 Cl 2 (20 mL) and washed with a saturated solution of Na 2 SO 3 (5 mL) followed by water (20 mL). The organic phase was dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, and the residue formed was purified by passing it through a short silica gel pad using hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded 3-chloro-2-(trifluoromethyl)-1H-indole (3a) as beige crystals, m.p. 49-50 • C, yield 1.120 g (95%). 1  After the completion of the reaction ( 19 F NMR control) THF was evaporated in vacuo, the residue was dissolved in CH 2 Cl 2 (20 mL) and washed with a saturated solution of Na 2 SO 3 (5 mL), followed by water (20 mL). The organic phase was dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing it through a short silica gel pad using hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded 3-bromo-2-(trifluoromethyl)-1H-indole (3b) as a pale green-brown solid, m.p. 39-41 • C, yield 1.377 g (96%). 1  86 mmol), CH 2 Cl 2 (10 mL) and solution of Br 2 (0.950 g, 5.94 mmol) in CH 2 Cl 2 (1.5 mL) was added dropwise for 1 min. The reaction mixture was stirred for 1 min and washed with a saturated solution of Na 2 SO 3 (5 mL) followed by water (20 mL). The organic phase was dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing it through a short silica gel pad using hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded 3-bromo-2-(trifluoromethyl)-1H-indole (3b) as a pale green-brown solid, m.p. 39-41 • C, yield 1.51 g (98%).

Synthesis of 3-iodo-2-(trifluoromethyl)-1H-indole (3c)
. A 20 mL one-necked roundbottomed flask was charged with 2-(trifluoromethyl)-1H-indole (2) (0.555 g, 3.0 mmol), MeCN (6 mL), K 2 CO 3 (0.420 g, 3.043 mmol) and I 2 (1.230 g, 4.843 mmol). The reaction mixture was stirred at room temperature for 1 day. After the completion of the reaction ( 19 F NMR control), a saturated solution of Na 2 SO 3 (10 mL) was added to quench the reaction. The product was extracted by CH 2 Cl 2 (3 × 20 mL), the organic phase was washed by water (20 mL) and dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing it through a short silica gel pad using a hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded 3-iodo-2-(trifluoromethyl)-1H-indole (3c) as a pale yellow solid, m.p. 53-55 • C, yield 0.884 g (95%). 1  The reaction mixture was stirred for 5 min and then CH 2 Cl 2 (10 mL) was added. The solution formed was washed by saturated solution of Na 2 SO 3 (1 mL) followed by water (20 mL). The organic phase was dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing it through a short silica gel pad using a hexane-CH 2 Cl 2 mixture (3:1) as an eluent. The evaporation of the solvents afforded 3,5-dibromo-2-(trifluoromethyl)-1H-indole (4) as a pale yellow solid, m.p. 57-59 • C, yield 0.175 g (75%). 1  One-pot synthesis of 3-bromo-2-(trifluoromethyl)-1H-indole (3b) from enamine 1. A 50 mL one-necked round-bottomed flask was charged with enamine (1) (1.52 g, 5.31 mmol), acetic acid (25 mL) and water (5 mL). The reaction mixture was heated to 60 • C and Fe (1.19 g, 21.24 mmol) was added. The reaction mixture was stirred at 80 • C for 2 h. The reaction mixture was cooled to room temperature and 1M solution of Br 2 in acetic acid (8 mL, 8 mmol) was added. 19 F NMR analysis of the reaction mixture revealed the rest amounts of indole 2, which was converted into desired indole 3a by addition of 1M solution of Br 2 in acetic acid (1.72 mL). The reaction mixture was diluted with water (100 mL), the reaction product was extracted by CH 2 Cl 2 (3 × 20 mL), and the organic phase was washed by water (20 mL) and dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing through a short silica gel pad using hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded 3-bromo-2-(trifluoromethyl)-1H-indole (3b) as a pale green-brown solid, m.p. 39-41 • C, yield 0.814 g (58%). Modification of indoles at nitrogen atom using NaH and alkylating reagent (general procedure A). A 4 mL vial with a screw cap (for 1 mmol scale; 12 mL 2-3 mmol scale, 20 mL for 5-6 mmol scale) was charged with corresponding indole (1.0 mmol), DMF (1 mL) and NaH (0.090 g, 1.5 mmol, 60% suspension in mineral oil) was added at cooling with a cold-water bath. The reaction mixture was stirred at room temperature for 15 min and then corresponding alkylating reagent (MeI, BnBr, TsCl; 1.2 mmol) was added at cooling with a cold-water bath. The reaction mixture was stirred at room temperature overnight and then was broken by 0.1M HCl (5 mL). The product was extracted by CH 2 Cl 2 (3 × 10 mL), the organic phase was washed by water (2 × 10 mL) and brine (10 mL) and dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing through a short silica gel pad using hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded the corresponding indole.

Similary to the one pot synthesis of 3-bromo-2-(trifluoromethyl)-1H-indole
Modification of indoles at nitrogen atom using K 2 CO 3 and alkylating reagent (general procedure B). A 4 mL vial with a screw cap was charged with the corresponding indole (1.0 mmol), DMF (1 mL), K 2 CO 3 (0.207 g, 1.5 mmol) and corresponding alkylating reagent (MeI, BnBr, 1.2 mmol). The reaction mixture was stirred at room temperature overnight and then poured into 0.5 M HCl (10 mL). The product was extracted by CH 2 Cl 2 (3 × 10 mL), the organic phase was washed by water (2 × 10 mL), brine (10 mL) and dried over Na 2 SO 4 . Volatiles were evaporated in vacuo, the residue formed was purified by passing through a short silica gel pad using hexane-CH 2 Cl 2 mixture (3:1) as an eluent. Evaporation of the solvents afforded the corresponding indole.  19 F NMR (CDCl 3 , 376.5 MHz): δ −60.6 (s, 3F). NMR data of indole 5a are in agreement with those in the literature [66].

Conclusions
In conclusion, we investigated the modification of 2-CF 3 -indoles at the position C-3 and nitrogen atoms. A set of previously unknown 3-chloro-, 3-bromo-and 3-iodo-2-CF 3 -indoles was prepared in almost quantitative yields (93-98%). These indoles can be easily modified at the nitrogen atom by the reaction with MeI, BnBr and tosyl chloride in the presence of bases. The prepared trifluoromethylated indoles are valuable building blocks for the synthesis of 3-functionalized derivatives by the reactions with nucleophiles. However, the reaction path depends on the halogen's nature. Thus, the reaction of 3-chloro-2-CF 3indoles with 4-methylthiophenol afforded the corresponding sulfides in high yield. The Suzuki reaction of 3-bromo-2-CF 3 -indoles with phenyl boronic acid gave the corresponding 3-phenyl-2-CF 3 -indoles in 72-88% yield. 3-Cyano-2-CF 3 -indoles were synthesized in about 90% yields by the reaction of 3-iodo-2-CF 3 -indoles with CuCN. Sonogashira reactions of 3-iodo-2-CF 3 -indoles with phenylacetylene led smoothly to the corresponding acetylenic derivatives in high yield.