An Efficient Approach to 2-CF₃-Indoles Based on ortho-Nitrobenzaldehydes

Abstract

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF₃CCl₃ afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF₃-β-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H₂O system initiated intramolecular cyclization to afford 2-CF₃-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF₃-indole.

1. Introduction

Indole has been discovered in 1866 by Bayer [1]. This type of heterocycles became an object of intensive investigations [2,3,4,5,6,7,8] and recognized as a “privileged structure” in drug discovery [9]. Indole motif is an important structural unit of many pharmaceuticals and natural products [10]. Seven derivatives of indole can be found in the list of 200 best selling drugs in 2020. Tagrisso ($4.328 Bn), Trikafta ($3.864 Bn), Ofev ($2.448 Bn), Leuprorelin ($1.834 Bn), Alecensa ($1.292 Bn), Zoladex ($ 0.888 Bn) and Sutent ($0.819 Bn) were sold for more than $ 15 billion totally in 2020 worldwide [11].

Chemistry of fluorinated organic compounds is a booming area of modern organic chemistry, which is a result of unique physicochemical as well as biological properties of these compounds [12,13,14,15,16,17,18,19,20,21,22,23]. Thus, about 20% (more than 300 compounds) of currently used drugs [24,25,26,27,28,29,30,31] contain at least one fluorine atom [32]. In 2020, approximately 25% (14 out of 53) of all drugs and about 35% (14 out of 40) of “small-molecule drugs” approved by the FDA are fluorinated compounds [33]. At the same time, about 59% of all small-molecule drugs have a nitrogen heterocyclic motif [10]. Last year revealed, that three out of every four small-molecule drugs approved by the FDA in 2020 (28 out of 37) are representatives of that class [33]. Hence, elaboration of novel pathways to fluorinated nitrogen heterocycles are of great demand [34,35,36,37,38,39,40,41].

The brilliant example of such interest are 2-CF₃-indoles. According to the Reaxys database, this class of compounds enjoyed a boom of attention last decade. Thus, 107 out of 152 research articles dealing with 2-CF₃-indoles were published from 2011 to 2021. Previous decade revealed 19 articles, and 26 articles were published in period from 1977 to 2001 [42]. These massive investigations gained several promising bioactive 2-CF₃-indoles (Figure 1). The 2′-trifluoromethyl analogue of Indomethacin I was appeared to be a potent and selective COX-2 inhibitor [43]. Compound II having 2-CF₃-indole and cinnamic amide moieties possess anti-inflammatory and neuroprotective actions [44]. Indolyl-pyridinyl-propenone III was found to possess properties of antiproliferative [45] and antineoplastic agent [46]. 2-CF₃-indole IV revealed antifungal properties (Figure 1) [47].

Most synthetic approaches to such indoles can be divided to the methods of direct trifluoromethylation of indole core and cyclizations of various precursors having CF₃ group in appropriate position [38]. Both radical and electrophilic trifluoromethylations was performed using bis(perfluoroalkanoyl) peroxides [48], difluorodiiodomethane [49], hypervalent iodine reagents [50,51,52,53], CF₃I [54,55,56,57,58], Umemoto’s reagents [59,60], [(phen)CuCF₃] [61], and CF₃SO₂Na [62,63,64,65]. Cyclization approaches are based on formation of C2-C3 bond as a key step and deal with transformations of compounds having ortho-toluidine fragment [66,67,68,69,70,71,72,73,74,75,76]. One work reported transformation of 4- and 6-nitro-1-hydroxy indoles to NH indoles under treatment with bromoacetophenone (Figure 2) [77].

Several years ago, we have elaborated convenient approach to α-CF₃-β-aryl enamines on the base of the reaction of β-chloro-β-trifluromethylstyrenes with amines [78,79,80]. This potent CF₃-building blocks were successfully used as synthetic equivalents of trifluoromethyl benzyl ketones in the Fisher and Pictet–Spengler reaction to give 2-CF₃-3-arylindoles and CF₃-β-carbolines [81], synthesis of CF₃-enones [82,83,84] and α-CF₃-phenethylamines [85]. In continuation of the investigation of synthetic potential of α-CF₃-β-aryl enamines, we report in this article one pot two step synthesis of 2-CF₃-indoles (Figure 2).

2. Results

First, we investigated olefination of 2-nitrobenzaldehydes 1 to prepare the corresponding trifluoromethylated styrenes 2. The catalytic olefination reaction (COR) [15,86,87,88,89,90] and Wittig reaction were used for the synthesis of these alkenes. We performed screening of the reaction conditions for COR (see Supplementary Materials, Scheme S1). It was found, that ethylene glycol [89] is the solvent of choice for these substrates, in contrast to EtOH traditionally used for COR with CF₃CCl₃ [90]. It was also found, that the yield is very sensitive to the nature of the substituents (additional to ortho-nitro group) in aryl ring. The best yield in the whole series was obtained for unsubstituted 2-nitrobenzaldehyde, which was transformed by COR to styrene 2a in 88% yield. In the case of additional alkyl-, alkoxy- and halogen substituents in the aryl ring corresponding styrenes were isolated in good to high yields. However, in the case of aldehydes 1j,l,m having strong EWG substituents (nitro-, cyano- and carboxymethyl- groups) in 4-position the corresponding alkenes 2j,l,m were synthesized in lower yields using COR. Therefore, we tried also alternative synthesis based on Wittig olefination. As a result, some improvement was observed for these problematic aldehydes. It should be noted that olefination of 2-nitrobenzaldehydes using both methods proceeds stereoselectively to form mostly Z-isomer in up to 96:4 ratio with minor E-isomer. Assignment of the configuration of the isomers was maintained by comparison with the literature NMR data of similar styrenes without ortho-nitro-group [90] (Scheme 1).

Having in hand a series of trifluoromethylated ortho-nitrostyrenes, we investigated their transformation to 2-CF₃-indoles. The treatment of styrenes 2 with an access of pyrrolidine at room temperature led to α-CF₃-enamines 3 in high yield. We assumed, that reduction of ortho-nitro aryl derived α-CF₃-enamines 3 could led to 2-CF₃-indoles 4 through formation of intermediate anilines 3′ [91,92]. The reduction of model enamine 3a was studied in various conditions. It was found, that HCO₂H-Pd/C, Fe-AcOH-H₂O and Zn-AcOH-H₂O systems worked well to give 2-CF₃-indole 3a in 85, 86 and 85% yield correspondingly according to ¹⁹F NMR. Although all these systems showed almost equal results, we used Fe-AcOH-H₂O for our further transformations due to the lower price and toxicity of iron [93]. It should be noted, that crude enamine 3a can be used directly after evaporation of excessive pyrrolidine. So, the transformation of styrene 2 into indole 4 can be maintained as a one pot reaction without isolation of intermediate enamine 3. Moreover, this one pot conditions work for multigram scale reaction to afford 3.257 g (72%) of indole 4a in one run (Scheme 2).

Using these optimal conditions, we performed the synthesis of various 2-CF₃-indoles 4. It was found that the reaction has a general character allowing to prepare 2-CF₃-indoles having both electron-donating and electron-withdrawing groups in various positions of indole ring in good to high yield. 6-Amino-2-CF₃-indole 4j was synthesized in the case of styrene 2j having additional nitro-group. This indole is a perspective object for further modifications at amino group, which can provide compounds interesting for the medicinal chemistry.

One can notice that indoles 4 were mostly prepared in the yields higher than 50%, which is high enough taking into account the three step transformation. In contrast, indoles 4e and 4i were obtained in moderate yield (43% and 25%). The explanation of that fact is a side process taking place at the step of formation of enamine 3. Thus, monitoring of the reaction mixture in the reaction of 2c with pyrrolidine revealed the presence of compound 5c, which was isolated in 15% yield together with enamine 3c (80%). The structure of 5c was assigned by means of NMR and HRMS data. Thus, the key signals of 5c are the signals of carbonyl group (192.4 ppm), quaternary aminal carbon adjacent to CF₃-group (quadruplet at 86.4 ppm, J_CF = 28.1 Hz) in ¹³C NMR and N-OH group (7.74 ppm) in ¹H NMR. We have also observed formation of similar N-hydroxy indolin-3-ones 5 in several other reactions. Thus, in case of enamines 3e and 3i the admixture of compounds 5e and 5i were 28% and 39%, correspondingly (by ¹⁹F NMR; see Supplementary Materials for details). Even in the case of enamine 3a we observed formation of 5a in 4% yield (by ¹⁹F NMR). We did not investigate this side reaction thoroughly, but possible mechanism of this transformation was proposed using the literature data (Scheme 3) [94,95]. At first step dehydrochlorination of 2c leads to alkyne 6 [78]. Next, it is attacked by pyrrolidine to give zwitterion 7. Proton transfer in 7 affords enamine 3c. Alternatively, transformation of 7 leads to transfer of oxygen to form nitroso compound 8. This intermediate has in the structure a strong electron-donating fragment of “enoloenamine”. Intramolecular attack of this fragment to nitroso group led to indolin-1-olate derivative 9. Its protonation leads to N-hydroxy indolin-3-one 5c.

Interesting results were obtained in the case of styrenes 2n,o. These alkenes have halogens in para-position to nitro-group, which activates nucleophilic substitution of them. It was found that treatment of 4-fluorostyrene 2o with pyrrolidine led to substitution of both fluorine and chlorine during 1–2 h to give enamine 3n in 90% yield (Scheme 4). Similarly, substitution of both chlorine atoms in 4-chlorostyrene 2n afforded enamine 3n in 72% yield. However, in this case about 2–3 days were needed for full substitution of chlorine adjacent to aryl ring. It is not surprising, because fluorine is a better leaving group than chlorine. Next, we performed one pot synthesis of indole 10a from 4-fluorostyrene 2o. As a result, indole 10a was isolated in 45% yield (Scheme 4).

We proposed that using less nucleophilic amines would allow to perform selective synthesis of enamine without substitution of halogen in aryl ring. However, the reaction of 4-fluorostyrene 2o with piperidine afforded a mixture of enamine 11a and styrene 2p at room temperature. The heating of this reaction mixture at 90 °C for 3 h led to selective transformation of 2p into 11a (by ¹⁹F NMR), which was converted into indole 10b in 44% yield (one-pot). To our delight, the reaction of 4-chlorostyrene 2n with piperidine proceeded only at the double bond to form enamine 11b (observed in ¹⁹F NMR) after 1h at room temperature. One pot transformation of 11b under standard conditions afforded 5-chloro-2-CF₃-indole 4n in total 71% yield (Scheme 5).

To investigate the scope of the synthesis of 5-amino substituted indoles, we performed several reactions of styrene 2o with other primary and secondary amines. As a result, new family of 2-CF₃-indoles 10c–g having amine fragments of morpholine, azepane, diethylamine, methylamine and n-hexylamine was synthesized in good yields (Scheme 6).

Having prepared a set of 2-CF₃-indoles we found surprisingly that many typical reactions known for indoles are unknown for 2-CF₃-indoles. To fill this gap, we maintained reactions of indole 4a with several C-centered electrophiles. In our hands, formylation reaction by POCl₃-DMF afforded 3-formyl-2-CF₃-indole 17 in 53% yield. Friedel–Crafts acylation with AcCl-AlCl₃ led to corresponding ketone 18 in 64% yield. Reaction with ethoxy CF₃-enone 19 under catalysis with BF₃·Et₂O gave α,β-unsaturated CF₃ ketone 20, which is a valuable building block for the synthesis of complex fluorinated molecules. Very interesting results were observed in the reactions of 2-CF₃-indole with arylaldehydes in the media of alcohols under catalysis with MeSO₃H. The reaction with benzaldehyde, 4-chloro- and 4-methoxybenzaldehydes in methanol afforded methoxy-derivatives 21 in good yields. The reaction with 1.2 equivalents of benzaldehyde in ethanol led to ethoxy-derivative 22 in 74% yield, while the reaction with 0.5 equivalents of benzaldehyde in ethanol resulted in bisindolylmethane derivative 23 in moderate yield (Scheme 7). NMR monitoring of the reaction revealed, that after first few hours both indoles 22 and 23 can be found in the reaction mixture. Further heating led to decreasing of the amount of 22, while the amount of 23 showed increase. Based on that fact, we rationalized possible mechanism of formation of 23 as follows. At first step, 4a reacts with aldehyde to form 22, which is protonated by strong methanesulfonic acid to give oxonium salt 24. Friedel–Crafts alkylation of indole 4a by this oxonium salt afforded bisindolylmethane derivative 23.

It should be noted that a lot of attention has been paid to the elaboration of novel strategies for the synthesis of bisindolylmethane derivatives, because many of them exhibit a various kinds of physiological activity [96,97,98,99]. Thus, bisindolylmethanes revealed properties of antibacterial, antifungal, antimicrobial, anti-inflammatory and anti-cancer agents [100,101,102,103,104,105]. In addition, this structural unit can be found in the natural sources, for example in marine alkoloids [106,107,108]. To the best of our knowledge fluorinated bisindolylmethanes have not been reported to date. We believe that our approach to these compounds can be useful in design of potentially active physiologically active compounds.

3. Materials and Methods

General remarks.¹H, ¹³C and ¹⁹F NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer in CD₃CN, DMSO-d₆ and CDCl₃ at 400, 100 and 376 MHz, respectively. Chemical shifts (δ) in ppm are reported with the use of the residual CHD₂CN, DMSO-d₅ and chloroform signals (1.94, 2.54 and 7.25 for ¹H and 1.30, 39.5 77.0 for ¹³C) as internal reference. The ¹⁹F chemical shifts were referenced to C₆F₆, (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). ESI-MS spectra were measured at MicroTof Bruker Daltonics instrument. TLC analysis was performed on “Merck 60 F₂₅₄” plates. Column chromatography was performed on silica gel. All reagents were of reagent grade and were used as such or were distilled prior to use. β-Chloro-β-trifluoromethylstyrenes 1 were prepared as reported previously by catalytic olefination reaction [89,90] or by Wittig reaction [109]. Melting points were determined on an Electrothermal 9100 apparatus.

Synthesis of styrenes 2 by catalytic olefination reaction in EtOH or DMSO (general procedure I, 5 mmol scale) [90]. One neck 100 mL round bottomed flask was charged with N₂H₄·H₂O (0.265 g, 5.25 mmol), and solution of corresponding benzaldehyde (5 mmol in 25 mL of EtOH or DMSO) was added and stirred for 3 h until aldehyde disappeared (TLC control). Next, 1,2-ethylenediamine (0.65 mL, 7.5 mmol), CuCl (0.050 g, 0.5 mmol) were added and stirred for 1–2 min. After that CF₃CCl₃ (1.78 mL, 15 mmol) was added in one portion at cooling by cold water bath. Reaction mixture stirred overnight at room temperature, poured into water (100 mL) and extracted with CH₂Cl₂ (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na₂SO₄. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CH₂Cl₂ as an eluent.

Synthesis of styrenes 2 by catalytic olefination reaction in ethylene glycol (general procedure II) [89]. One neck 50 mL round bottomed flask was charged with 1 mmol of corresponding benzaldehyde, 10 mL of ethylene glycol, 0.25 mL (5 mmol) of N₂H₄·H₂O and stirred 0.5–1h until aldehyde disappeared (TLC control). Next, 0.38 mL (4.4 mmol) of 1,2-ethylenediamine, 0.0086 g (0.05 mmol) of CuCl₂·2H₂O was added and stirred for 1–2 min. After that CF₃CCl₃ (0.71 mL, 6 mmol) was added in one portion at cooling by cold water bath. Reaction mixture stirred overnight at room temperature, poured into water (50 mL) and extracted with CH₂Cl₂ (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na₂SO₄. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CH₂Cl₂ as an eluent.

Synthesis of styrene 2a by catalytic olefination reaction in EtOH (150 mmol scale). One neck 1000 mL round bottomed flask was charged with N₂H₄·H₂O (5.25 g, 105 mmol), and solution of 2-nitrobenzaldehyde (15.11 g, 100 mmol in 175 mL of EtOH) was added at vigorous stirring. The reaction mixture was stirred for 3 h until aldehyde disappeared (TLC control). Next, 1,2-ethylenediamine (10 mL, 150 mmol), CuCl (1 g, 10 mmol) were added and stirred for 1–2 min. After that CF₃CCl₃ (18 mL, 150 mmol) was added in one portion at cooling by cold water bath. The reaction mixture stirred overnight at room temperature, poured into HCl water solution (1000 mL, ~0.4–0.5 M) and extracted with CH₂Cl₂ (3 × 150 mL). Combined extract was washed with water (200 mL) and dried over Na₂SO₄. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad (~120–150 cm³ of silica gel) using 3:1 mixture of hexane as an eluent. Evaporation of the solvents afforded pure 2a as slightly yellow oil. Yield 17.1 g (68%).

Synthesis of styrenes 2 by Wittig reaction (general procedure III, 5 mmol scale) [109]. One neck 20 mL vial with a screw cap was charged with corresponding benzaldehyde (2 mmol), PPh₃ (1.258 g, 4.8 mmol), K₂CO₃ (0.028 g, 0.2 mmol), MeCN (2 mL) and CF₃CCl₃ (0.561 g, 3 mmol). The reaction mixture was stirred for 3–5 h at 80 °C and then poured into water (100 mL) and extracted with CH₂Cl₂ (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na₂SO₄. Solvents were evaporated in vacuo, the residue was purified by column chromatography on silica gel using 3:1 (2b,g,i,k,n) and 1:1 (2j,l,m) mixtures of hexane and CH₂Cl₂ as eluents.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene (2a). Obtained from 2-nitrobenzaldehyde. Obtained from 2-nitrobenzaldehyde 1a (0.151 g, 1 mmol) by procedure II. Сolorless oil, yield 0.223 g (88%). Mixture of Z/E isomers (82:18; by ¹⁹F NMR). NMR data of styrene 2a (see Supplementary Materials) are in agreement with those in the literature [110].

4-Chloro-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene (2b). Obtained from 4-chloro-2-nitrobenzaldehyde 1b (0.185g, 1 mmol) by procedure II. Light yellow oil, yield 0.223 g (78%). Mixture of Z/E isomers (90:10; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 8.21 (d, 1H, ⁴J = 2.1 Hz), 7.75–7.67 (m, 2H), 7.61 (d, 1H, ³J = 8.3 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 147.6, 136.4, 133.9, 132.4, 128.2 (q, ³J_CF = 4.8 Hz), 125.9, 125.4, 123.4 (q, ²J_CF = 38.0 Hz), 120.2 (q, ¹J_CF = 272.8 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.4 (d, 3F, ⁴J = 1.0 Hz). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.65 (dd, 1H, ³J = 8.3 Hz, ⁴J = 2.2 Hz), 7.46 (s, 1H), 7.32 (d, 1H, ³J = 8.3 Hz). Other signals are overlapped with those of major isomer. ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 136.2, 133.8, 132.1, 126.8, 125.2. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.2 (s, 3F). HRMS (ESI-TOF): m/z [M + Ag]⁺ Calcd for C₉H₄Cl₂F₃NO₂Ag⁺: 393.8610; found: 393.8619.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-methoxy-2-nitrobenzene(2c). Obtained from 3-methoxy-2-nitrobenzaldehyde 1c (0.188 g, 1.039 mmol) by procedure II. Yellow crystals, mp 42–44 °С, yield 0.211 g (75%). Mixture of Z/E isomers (76:24; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.50 (t, 1Н, ³J = 8.2 Hz), 7.34 (d, 1Н, ³J = 7.8 Hz), 7.24 (s, 1H), 7.13 (d, 1Н, ³J = 8.5 Hz), 3.91 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 151.26, 140.4, 131.43, 125.4, 125.0 (q, ³J_CF = 4.5 Hz), 124.9 (q, ²J_CF = 37.6 Hz), 121.0, 120.1 (q, ¹J_CF = 273.9 Hz), 114.0, 56.51. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.3 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.43 (t, 1Н, ³J = 8.2 Hz), 7.17 (s, 1H), 7.08 (d, 1Н, ³J = 8.5 Hz), 6.86 (d, 1Н, ³J = 7.8 Hz), 3.90 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 151.24, 139.2, 131.48, 130.0 (q, ³J_CF = 2.1 Hz), 126.8, 125.3 (q, ²J_CF = 37.6 Hz), 120.8 (q, ⁴J_CF = 2.5 Hz), 119.8 (q, ¹J_CF = 273.9 Hz), 113.4, 56.46. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.6 (s, 3F). HRMS (ESI-TOF): m/z [M + NH₄]⁺ Calcd for C₁₀H₁₁ClF₃N₂O₃⁺: 299.0405; found: 299.0404.

2-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methoxy-1-nitrobenzene(2d). Obtained from 5-methoxy-2-nitrobenzaldehyde 1d (0.183 g, 1.011 mmol) by procedure II. Yellow oil, yield 0.234 g (82%). Mixture of Z/E isomers (84:16; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 8.25–8.21 (m, 1H), 7.75 (s, 1H), 7.05–6.99 (m, 2H), 3.92 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 163.6, 140.0, 130.1 (q, ³J_CF = 4.8 Hz), 130.0, 127.7, 120.4 (q, ¹J_CF = 272.6 Hz), 121.9 (q, ²J_CF = 37.7 Hz), 116.2, 114.7, 56.1. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.2 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 8.20 (d, 1H, ³J = 6.6 Hz), 7.51 (s, 1H), 6.97 (d, 1H, ³J = 2.8 Hz), 6.77 (d, 1H, ³J = 2.7 Hz), 3.90 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 163.5, 139.2, 134.1 (q, ³J_CF = 2.3 Hz), 130.9, 127.5, 120.1 (q, ¹J_CF = 274.2 Hz), 121.2 (q, ²J_CF = 37.5 Hz), 115.9 (q, ³J_CF = 2.6 Hz), 114.5, 56.04. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.0 (s, 3F). HRMS (ESI-TOF): m/z [M + Na]⁺ Calcd for C₁₀H₇ClF₃NO₃Na⁺: 303.9959; found: 303.9957.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-3,5-dimethyl-2-nitrobenzene (2e). Obtained from 3,5-dimethyl-2-nitrobenzaldehyde 1e (0.174 g, 0.972 mmol) by procedure II. Yellow oil, yield 0.214 g (77%). Mixture of Z/E isomers (78:22; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.36 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 2.40 (s, 3H), 2.36 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 147.8, 141.5, 133.4, 131.4, 128.1, 126.8 (q, ³J_CF = 4.6 Hz), 124.9, 123.7 (q, ²J_CF = 37.5 Hz), 120.2 (q, ¹J_CF = 272.7 Hz), 21.1, 18.2. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.3 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.23 (s, 1H), 7.13 (s, 1H), 6.94 (s, 1H). Other signals are overlapped with those of major isomer. ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 146.6, 141.6, 133.1, 131.8 (q, ³J_CF = 2.3 Hz), 131.6, 127.9 (q, ⁴J_CF = 2.4 Hz), 126.4, 123.8 (q, ²J_CF = 37.4 Hz), 119.9 (q, ¹J_CF = 274.5 Hz), 20.9, 18.3. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.5 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₁H₁₀ClF₃NO₂⁺: 280.0347; found: 280.0641.

6-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxine (2f). Obtained from 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde 1f (0.212 g, 1.014 mmol) by procedure II. Pale yellow crystals, mp 104–106 °С, yield 0.241 g (78%). Mixture of Z/E isomers (80:20; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.81 (s, 1H), 7.68 (pseudo-d, 1H, ⁴J = 0.8 Hz), 7.10 (s, 1H), 4.45–4.28 (m, 4H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 148.2, 143.9, 129.2 (q, ³J_CF = 4.6 Hz), 121.5, 121.4 (q, ²J_CF = 37.5 Hz), 120.5 (q, ¹J_CF = 272.3 Hz), 119.3, 115.0, 64.7, 64.3. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.2 (d, 3F, ⁴J = 1.0 Hz). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.80 (s,1H), 7.43 (pseudo-d, 1H, ⁴J = 0.8 Hz), 6.79 (s, 1H). Other signals are overlapped with those of major isomer. ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 143.8, 140.5, 133.8 (q, ³J_CF = 2.3 Hz), 122.6, 121.5 (q, ²J_CF = 37.3 Hz), 120.2 (q, ¹J_CF = 274.1 Hz), 119.0 (q, ³J_CF = 2.5 Hz), 114.8, 64.2. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.1 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₁H₈ClF₃NO₄⁺: 310.0088; found: 310.0086.

2-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-1,4-dimethoxy-3-nitrobenzene(2g). Obtained from 1,4-dimethoxy-3-nitrobenzaldehyde 1g (0.222 g, 1.052 mmol) by procedure II. Pale yellow crystals, mp 72–73 °С, yield 0.254 g (78%). Mixture of Z/E isomers (91:9; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.18 (s, 1H), 7.07 (d, 1H, ³J = 9.3 Hz), 7.03 (d, 1H, ³J = 9.2 Hz), 3.87 (s, 3H), 3.83 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 150.2, 145.1, 126.8 (q, ²J_CF = 37.8 Hz), 124.0 (q, ³J_CF = 4.6 Hz), 119.9 (q, ¹J_CF = 272.9 Hz), 115.4, 114.4, 113.9, 57.0, 56.5. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.3 (d, 3F, ⁴J = 1.0 Hz). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 6.99 (d, 1H, ³J = 3.2 Hz), 6.98 (d, 1H, ³J = 3.2 Hz), 6.88 (s, 1H), 3.85 (s, 3H), 3.79 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 144.7, 140.4, 113.3, 56.9, 56.3. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −67.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₁H₁₀ClF₃NO₄⁺: 312.0245; found: 312.0251.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-4,5-dimethoxy-2-nitrobenzene(2h). Obtained from 2,5-dimethoxy-3-nitrobenzaldehyde 1h by procedure I (0.539 g, 2.55 mmol, DMSO) and by procedure II (0.245 g, 1.161 mmol). Pale yellow solid, mp 95–97 °С, yield 0.374 g (47%, I) yield 0.128 g (43%, II). Mixture of Z/E isomers (80:20; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.79–7.74 (m, 2H), 7.02 (s, 1H), 3.99 (s, 3H), 3.99 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 153.2, 149.4, 140.1, 129.9 (q, ³J_CF = 4.7 Hz), 121.6, 121.4 (q, ²J_CF = 37.3 Hz), 120.4 (q, ¹J_CF = 272.4 Hz), 112.1, 107.7, 56.6, 56.40. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.1 (d, 3F, ⁴J = 1.0 Hz). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.52 (pseudo-d, 1H, ⁴J = 0.6 Hz), 6.71 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). Other signals are overlapped with those of major isomer. ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 149.3, 138.9, 134.3 (q, ³J_CF = 2.3 Hz), 122.7, 120.2 (q, ¹J_CF = 274.3 Hz), 121.1 (q, ²J_CF = 37.2 Hz), 112.1, 107.5, 56.5, 56.38. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −62.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₁H₁₀ClF₃NO₄⁺: 312.0245; found: 312.0254.

5-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-6-nitrobenzo[d][1,3]dioxole (2i). Obtained from 4,5-ethylendioxy-2-nitrobenzaldehyde 1i (0.207 g, 1.062 mmol) by procedure II. Pale yellow solid, mp 100–103 °С, yield 0.155 g (52%). Mixture of Z/E isomers (79:21; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.68–7.66 (m, 2H), 6.99 (s, 1H). 6.19 (s, 2H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 152.22, 148.9, 141.8, 129.7 (q, ³J_CF = 4.8 Hz), 123.9, 121.8 (q, ²J_CF = 37.5 Hz), 120.4 (q, ¹J_CF = 272.5 Hz), 109.6, 105.7, 103.64. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.2 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.65 (s, 1H), 7.43 (d, 1Н, ⁴J = 0.6 Hz), 6.70 (s, 1H), 6.17 (s, 2H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 152.19, 148.8, 140.6, 134.0 (q, ³J_CF = 2.8 Hz), 124.9, 121.3 (q, ²J_CF = 37.4 Hz), 120.1 (q, ¹J_CF = 274.5 Hz), 109.5 (q, ⁴J_CF = 2.8 Hz), 105.4, 103.62. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.2 (s, 3F). HRMS (ESI-TOF): m/z [M + Na]⁺ Calcd for C₁₀H₅ClF₃NO₄Na⁺: 317.9751; found: 317.9752.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,4-dinitrobenzene (2j). Obtained from 2,4-dinitrobenzaldehyde by procedure (II, 0.196 g) and (III, 0.65 g). Yellow viscous oil, yield 0.014 g (5%, II), 0.248 (25%, (III). Mixture of Z/E isomers (96:4; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 9.03 (pseudo-d, 1H, ⁴J ~ 1.5 Hz), 8.58 (dd, 1H, ³J = 8.5 Hz, ⁴J = 2.3 Hz), 7.91 (d, 1H, ³J = 8.5 Hz), 7.78 (s, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 148.1, 147.4, 140.2, 133.0, 127.9, 127.6 (q, ³J_CF = 4.5 Hz), 125.0 (q, ²J_CF = 38.0 Hz), 120.6, 119.9 (q, ¹J_CF = 273.2 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −69.4 (d, 3F, ⁴J = 0.6 Hz). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.78 (br.s, 1H), 8.52 (dd, 1H, ³J = 8.5 Hz, ⁴J = 2.3 Hz), 7.64 (d, 1H, ³J = 8.5 Hz), 7.53 (s, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): 127.0. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. ^{19F NMR (CDCl}₃, 376.5 MHz): δ −62.2 (s, 3F). HRMS (ESI-TOF): m/z [M-H]^- Calcd for C₉H₃ClF₃N₂O₄⁻: 294.9739; found: 294.9732.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitro-4-(trifluoromethyl)benzene (2k). Obtained from 2-nitro-4-(trifluoromethyl)benzaldehyde 1k by procedure II (0.438 g, 2 mmol) and by procedure III (0.438 g, 2 mmol). Yellow oil, yield 0.395 g (62%, II), 0.365 g (57%, III). Mixture of Z/E isomers (92:8; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 8.49 (pseudo-d, 1H, ⁴J ~ 1.0 Hz), 7.99 (dd, 1H, ³J = 8.0 Hz, ⁴J = 0.7 Hz), 7.81 (d, 1H, ³J = 8.1 Hz), 7.77 (s, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 147.2, 132.8 (q, ²J_CF = 34.6 Hz), 132.4, 131.12, 130.3 (q, ³J_CF = 3.4 Hz), 128.2 (q, ³J_CF = 4.8 Hz), 124.3 (q, ²J_CF = 38.1 Hz), 122.53 (q, ³J_CF = 3.8 Hz), 122.46 (q, ¹J_CF = 273.1 Hz), 120.1 (q, ¹J_CF = 272.8 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −69.5 (s, 3F), −63.3 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.94 (dd, 1H, ³J = 8.0 Hz, ⁴J = 0.7 Hz), 7.56 (s, 1H), 7.53 (d, 1H, ³J = 8.2 Hz). Other signals are overlapped with those of major isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −62.3 (s, 3F). Other signals are overlapped with those of major isomer. HRMS (ESI-TOF): m/z [M + Ag]⁺ Calcd for C₁₀H₄ClF₆NO₂Ag⁺: 425.8880; found: 425.8874.

4-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-nitrobenzonitrile (2l). Obtained from 4-cyano-2-nitrobenzaldehyde 1l by procedure II (0.176 g, 1 mmol) and by procedure III (0.88 g, 5 mmol). Yellow oil, yield 0.070 g (25%) (II), 0.278 g (20%, III). Mixture of Z/E isomers (96:4; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ

δ 8.51 (d, 1H, ⁴J = 1.6 Hz), 8.01 (dd, 1H, ³J = 8.1 Hz, ⁴J = 1.6 Hz), 7.81 (d, 1H, ³J = 8.1 Hz), 7.75 (s, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 147.1, 136.6, 132.5, 131.7, 128.7, 127.9 (q, ³J_CF = 4.7 Hz), 124.3 (q, ²J_CF = 38.5 Hz), 119.8 (q, ¹J_CF = 273.0 Hz, CF₃), 115.9, 114.4. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.5 (s, 3F). E-isomer: ¹H NMR (CDCl₃, 400.1 MHz): δ 7.95 (dd, 1H, ³J = 8.0 Hz, ⁴J = 1.6 Hz), 7.50 (s, 1H). Other signals are overlapped with those of major isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.3 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₀H₅ClF₃N₂O₂⁺: 276.9986; found: 276.9986.

Methyl 4-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-nitrobenzoate (2m). Obtained from methyl 4-formyl-3-nitrobenzoate 1m by procedure II (0.209 g, 1 mmol) and by procedure III (0.209 g, 1 mmol). Beige crystals, yield 0.040 g (13%, II), 0.079 g (22%, III). Mixture of Z/E isomers (95:5; by ¹⁹F NMR). ¹H NMR (CDCl₃, 400.1 MHz):

δ 8.81 (d, 1H, ⁴J = 1.7 Hz), 8.35 (dd, 1H, ³J = 8.0 Hz, ⁴J = 1.7 Hz), 7.76 (s, 1H), 7.73 (d, 1H, ³J = 8.1 Hz), 3.99 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 164.3, 147.2, 134.2, 132.4, 131.7, 131.4, 128.6 (q, ³J_CF = 4.7 Hz), 126.1, 123.7 (q, ²J_CF = 38.0 Hz), 120.1 (q, ¹J_CF = 272.9 Hz), 53.0. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.4 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₁H₈ClF₃NO₄⁺: 310.0088; found: 310.0085.

4-Chloro-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-nitrobenzene (2n). Obtained from 5-chloro-2-nitrobenzaldehyde 1n (0.191g, 1.03 mmol) by procedure II. Yellow crystals, mp 46–48 °С, yield 0.221 g (75%). Mixture of Z/E isomers (91:9; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz):

δ 8.19 (d, 1Н, ³J = 8.8 Hz), 7.70 (s, 1H), 7.61 (d, 1Н, ⁴J = 2.1 Hz), 7.58–7.55 (m, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 145.3, 140.4, 131.1, 130.3, 129.2, 128.3 (q, ³J_CF = 4.8 Hz), 126.5, 123.4 (q, ²J_CF = 38.0 Hz), 120.1 (q, ¹J_CF = 272.9 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.5 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz):

δ 7.46 (s, 1H). Other signals are overlapped with those of major isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.3 (s, 3F). HRMS (ESI-TOF): m/z [M + Ag]⁺ Calcd for C₉H₄Cl₂F₃NO₂Ag⁺: 395.8583; found: 395.8587.

2-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-fluoro-1-nitrobenzene (2o). Obtained from 5-fluoro-2-nitrobenzaldehyde 1o (0.175g, 1.04 mmol) by procedure II. White crystals, mp 35–38 °С, yield 0.204 g (73%). Mixture of Z/E isomers (83:17; by ¹⁹F NMR). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz):

δ 8.28 (dd, 1Н, ³J = 9.1 Hz, ³J = 5.1 Hz), 7.73 (s, 1H), 7.34 (dd, 1Н, ³J = 8.5 Hz, ⁴J = 2.6 Hz), 7.31–7.25 (m, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 164.9 (d, ¹J_CF = 259.2 Hz), 143.3 (d, ⁴J_CF = 2.5 Hz), 130.6 (d, ³J_CF = 10.0 Hz), 128.5 (qd, ³J_CF = 4.5 Hz, ⁴J_CF = 0.9 Hz), 128.1 (d, ³J_CF = 10.2 Hz), 123.4 (q, ²J_CF = 37.9 Hz), 120.2 (q, ¹J_CF = 272.8 Hz), 118.4 (d, ²J_CF = 25.1 Hz), 117.3 (d, ²J_CF = 23.1 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −70.5 (s, 3F), −102.55–−102.71 (m, 1F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz):

δ 7.48 (s, 1H), 7.25–7.22 (m, 1H) 7.07 (dd, 1Н, ³J = 8.2 Hz, ⁴J = 2.7 Hz). Other signals are overlapped with those of major isomer. ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 164.7 (d, ¹J_CF = 259.8 Hz), 142.4, 132.3 (br.s), 131.4 (d, ³J_CF = 9.9 Hz), 127.9 (d, ³J_CF = 10.2 Hz), 122.6 (q, ²J_CF = 37.5 Hz), 120.0 (q, ¹J_CF = 274.4 Hz), 116.9, 118.0 (q, ⁴J_CF = 2.4 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −63.3 (s, 3F), −102.73–−102.88 (m, 1F). HRMS (ESI-TOF): m/z [M-F]⁺ Calcd for C₉H₄ClF₃NO₂⁺: 249.9877; found: 249.9873.

Synthesis of α-CF₃-β-(2-nitroaryl)enamines by the reaction with pyrrolidine in neat (general procedure) [78]. A one neck 25 mL round bottomed flask was charged with dry pyrrolidine (8.5 mL, 100 mmol), cooled down to −18 °C and corresponding styrene 2 (10 mmol) was added in one portion with vigorous stirring. The reaction mixture was stirred at room temperature for 1–3 h until all starting styrene was consumed (TLC or NMR monitoring). The excess of pyrrolidine was evaporated in vacuum, the viscous residue was dissolved in CH₂Cl₂ (50 mL), washed with water (3 × 50 mL) and dried over Na₂SO₄. CH₂Cl₂ was removed in vacuo, and the residue was filtered through a short silica gel pad using appropriate mixture 1:1 of hexane and CH₂Cl₂.

1-[(1Z)-2-(2-Nitrophenyl)-1-(trifluoromethyl)vinil]pyrrolidine (3a). Obtained from 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene 2a (6.04 g, 24 mmol). Yellow oil, yield 6.733 g (98%). Mixture of Z/E isomers (86:14; ¹⁹F NMR). NMR data of enamine 3a (see Supplementary Materials) are in agreement with those in the literature [78].

1-[(1Z)-2-(3-Methoxy-2-nitrophenyl)-1-(trifluoromethyl)vinil]pyrrolidine (3c). Obtained from 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-methoxy-2-nitrobenzene 2c (0.211 g, 0.75 mmol). Orange oil, yield 0.190 g (80%). Mixture of Z/E isomers (84:16; ¹⁹F NMR). NMR data of enamine 3с(see Supplementary Materials) are in agreement with those in the literature [84].

1-Hydroxy-7-methoxy-2-(pyrrolidin-1-yl)-2-(trifluoromethyl)indolin-3-one (5c). Obtained from 1-[2-chloro-3,3,3-trifluoro-1-propenyl]-3-methoxy-2-nitrobenzene 2c as an admixture in the synthesis of enamine 3c. Orange oil, yield 0.036 g (15%). ¹H NMR (CDCl₃, 400.1 MHz):

δ 7.74 (s, 1H), 7.24–7.28 (m, 1H), 7.01–7.15 (m, 2H), 3.90 (s, 3H), 3.11 (dd, 2Н, ³J = 7.2 Hz), 2.95 (q, 2Н, ³J = 6.9 Hz), 1.78 (t, 4Н, ³J = 6.2 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 192.4, 152.3, 149.3, 124.9, 122.6, 122.4 (q, ¹J_CF = 284.8 Hz), 118.9, 115.6, 86.4 (q, ²J_CF = 28.1 Hz), 55.9, 47.8, 24.4. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −73.6 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₄H₁₆F₃N₂O₃⁺: 317.1108; found: 317.1109.

1-[(1Z)-2-(5-methoxy-2-nitrophenyl)-1-(trifluoromethyl)vinil]pyrrolidine (3d). Obtained from 2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methoxy-1-nitrobenzene 2d (0.976 g, 3.465 mmol). Orange oil, yield 1.074 g (98%). Mixture of Z/E isomers (86:14; ¹⁹F NMR). NMR data of enamine 3d (see Supplementary Materials) are in agreement with those in the literature [84].

1-[(1Z)-(4-nitro-3-(3,3,3-trifluoro-2-(pyrrolidin-1-yl)prop-1-en-1-yl)phenyl]pyrrolidine (3n). Obtained from styrenes 2n (0.286 g, 1 mmol) or from styrene 2o (0.396 g, 1.469 mmol). Yellow orange solid, mp 145–147 °С, yield 0.255 g (72% from 2n), 0.468 g (90% from 2o). Mixture of Z/E isomers (84:16; ¹⁹F). For the mixture of isomers: Z-isomer: ¹H NMR (CDCl₃, 400.1 MHz):

δ 8.07 (d, 1Н, ³J = 9.3 Hz), 6.39–6.33 (m, 2Н), 6.20 (d, 1H, ⁴J = 2.4 Hz), 3.39–3.30 (m, 4Н), 3.02 (t, 4Н, ³J = 6.4 Hz), 2.11–2.02 (m, 4Н), 1.69–1.80 (m, 4Н). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 150.2, 135.8, 135.0, 133.9 (q, ²J_CF = 28.7 Hz), 127.7, 121.9 (q, ¹J_CF = 277.8 Hz), 112.9, 109.21, 104.1 (q, ³J_CF = 6.8 Hz), 50.4 (d, ⁴J_CF = 1.1 Hz), 47.7, 25.4, 25.3. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −65.8 (s, 3F). E- isomer: ¹H NMR (CDCl₃, 400.1 MHz):

δ 8.08 (d, 1Н, ³J = 9.3 Hz), 5.97 (s, 1Н), 6.27 (d, 1H, ⁴J = 2.4 Hz), 3.24 (t, 4Н, ³J = 6.5 Hz), 1.97–1.90 (m, 4Н). Other signals are overlapped with those of major isomer. ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 135.5 (q, ²J_CF = 27.3 Hz), 127.6, 113.8 (q, J = 3.4, CH = CCF₃), 109.24, 106.2 (q, ³J_CF = 3.4 Hz), 49.30 (d, ⁴J_CF = 1.1 Hz), 47.6, 24.6. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −59.2 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₇H₂₁F₃N₃O₂⁺: 356.1580; found: 356.1581.

Synthesis of indoles 4 by the reduction of nitro-substituted enamines 3 (general procedure IV). A one neck 25 mL round bottomed flask was charged with enamine 3 (0.5 mmol), glacial acetic acid (2 mL), water (0.2 mL) and Fe powder (0.112 g, 2 mmol). Reaction mixture was kept at 80 °С under stirring for 1–2 h until dissolving of Fe powder. Volatiles were evaporated in vacuo, the residue was suspended in CH₂Cl₂ (2–5 mL) and transferred on the short silica gel pad. The product was isolated using appropriate mixture of hexane and CH₂Cl₂ (3:1 for 4a, 4d); and mixture of CH₂Cl₂ and MeOH (100:1 for 4o) as eluents.

Multi-gram scale synthesis of indole 4a. A one neck 250 mL round bottomed flask was charged with enamine 3a (7.01 g, 24.5 mmol), glacial acetic acid (100 mL), water (20 mL) and Fe powder (5.49 g, 98 mmol). Reaction mixture was kept at 80–90 °С under stirring for 2 h until dissolving of Fe powder. The reaction mixture was poured into water (1000 mL), the precipitate formed was filtered off and washed by water (100 mL). Next, precipitate was washed with CH₂Cl₂ (2 × 50 mL), organic phase was dried over Na₂SO₄ and evaporated in vacuo to give pure indole 4a as colorless plates.

One pot synthesis of indoles 4 from styrenes 2 (general procedure V). A one neck 25 mL round bottomed flask was charged with pyrrolidine (1 mL, 11.8 mmol) and corresponding styrene 2 (0.5 mmol) was added in one portion with vigorous stirring. The reaction mixture was stirred at room temperature for 1–3 h until all starting styrene was consumed (TLC or NMR monitoring). The excess of pyrrolidine was evaporated in vacuum and the viscous residue was dissolved in glacial acetic acid (2 mL) and water (0.2 mL). After that Fe powder (0.112 g, 2 mmol) was added and the reaction mixture was kept at 80 °С under stirring for 1–2 h until dissolving of Fe powder. Volatiles were evaporated in vacuo, the residue was suspended in CH₂Cl₂ (2–5 mL) and transferred on the short silica gel pad. The product was isolated using appropriate mixtures of hexane and CH₂Cl₂ (3:1 for 4b,4c,4e,4k,4n; 1:1 for 4f,4g,4h,4i); CH₂Cl₂ (for 4l,4m) and mixture of CH₂Cl₂ and MeOH (100:1 for 4j,4o) as eluents.

2-(Trifluoromethyl)-1H-indole (4a). Obtained from enamine 3a (0.107 g, 0.374 mmol) by procedure IV. White crystals, m.p. 111–112 °C, yield 0.059 g (85%). NMR data of indole 4a (see Supplementary Materials) are in agreement with those in the literature [67].

6-Chloro-2-(trifluoromethyl)-1H-indole (4b). Obtained from styrene 2b (0.100 g, 0.35 mmol) by procedure V. Slightly yellow oil, yield 0.035 g (48%). NMR data of indole 4b (see Supplementary Materials) are in agreement with those in the literature [67].

7-Methoxy-2-(trifluoromethyl)-1H-indole (4c). Obtained from styrene 2c (0.149 g, 0.53 mmol) by procedure V. Colorless oil, yield 0.058 g (51%). NMR data of indole 4c (see SI) are in agreement with those in the literature [67].

5-Methoxy-2-(trifluoromethyl)-1H-indole (4d). Obtained from enamine 3d (0.088 g, 0.28 mmol) by procedure IV. Colorless crystals, m.p. 48–49 °C, yield 0.0382 g (64%). NMR data of indole 4d (see Supplementary Materials) are in agreement with those in the literature [67].

5,7-Dimethyl-2-(trifluoromethyl)-1H-indole (4e). Obtained from styrene 2e (0.109 g, 0.391 mmol) by procedure V. Slightly yellow oil, yield 0.036 g (43%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.16 (br.s, 1H), 7.30 (s, 1Н), 6.96 (s, 1Н), 6.88–6.82 (m, 1Н), 2.48 (s, 3H), 2.42 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 134.3, 130.7, 127.0, 126.5, 125.4 (q, ²J_CF = 38.9 Hz), 121.4 (q, ¹J_CF = 267.4 Hz), 120.6, 119.0, 104.3 (q, ³J_CF = 3.4 Hz), 21.3, 16.5. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.6 (d, 3F, ⁴J = 1.0 Hz). HRMS (ESI-TOF): m/z [M-H]^- Calcd for C₁₁H₉F₃N⁻: 212.0693; found: 212.0690.

7-(Trifluoromethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]-indole (4f). Obtained from styrene 2f (0.154 g, 0.497 mmol) by procedure V. White powder, m.p. 136–138 °C, yield 0.098 g (81%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.24 (br.s, 1H), 7.13 (s, 1Н), 6.87 (s, 1Н), 6.77 (s, 1Н), 4.28 (q, 4Н, ³J = 5.2 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 143.1, 140.1, 131.7, 125.5 (q, ²J_CF = 38.9 Hz), 121.2 (q, ¹J_CF = 267.3 Hz), 121.0, 107.9, 103.8 (q, ³J_CF = 3.4 Hz), 98.6, 64.5, 64.1. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.5 (s, 3F). HRMS (ESI-TOF): m/z [M-H]^- Calcd for C₁₁H₇F₃NO₂⁻: 242.0434; found: 242.0437.

4,7-Dimethoxy-2-(trifluoromethyl)-1H-indole (4g). Obtained from styrene 2g (0.107 g, 0.309 mmol) by procedure V. Light beige crystals, m.p. 74–76 °C, yield 0.053 g (70%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.73 (br.s, 1H), 7.05–7.01 (m, 1Н), 6.62 (d, 1Н, ³J = 8.3 Hz), 6.42 (d, 1Н, ³J = 8.3 Hz), 3.92 (s, 3H), 3.91 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 148.2, 140.9, 128.2, 124.3 (q, ²J_CF = 39.5 Hz), 121.2 (q, ¹J_CF = 267.5 Hz), 119.0, 103.9, 102.2 (q, ³J_CF = 3.3 Hz), 99.6, 55.7, 55.6. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.4 (d, 3F, ⁴J = 0.9 Hz). HRMS (ESI-TOF): m/z [M]⁺ Calcd for C₁₁H₁₀F₃NO₂⁺: 245.0658; found: 245.0667.

5,6-Dimethoxy-2-(trifluoromethyl)-1H-indole (4h). Obtained from styrene 2h (0.129 g, 0.416 mmol) by procedure V. White crystals, m.p. 89–90 °C, yield 0.055 g (54%). NMR data of indole 4h (see Supplementary Materials) are in agreement with those in the literature [67].

6-(Trifluoromethyl)-5H-[1,3]dioxolo[4.5-f]-indole (4i). Obtained from styrene 2i (0.125 g, 0.38 mmol) by procedure V. White crystals, m.p. 113–115 °C, yield 0.022 g (25%). NMR data of indole 4i (see Supplementary Materials) are in agreement with those in the literature [74].

2-(Trifluoromethyl)-1H-indole-6-amine (4j). Obtained from styrene 2j (0.293 g, 0.99 mmol) by procedure V. 8 Equivalents of Fe (0.448 g, 8 mmol) was used due to the presence of second nitro-group in the styrene 2j. Beige crystals, m.p. 124–126 °C, yield 0.119 g (60%). NMR data of indole 4j (see Supplementary Materials) are in agreement with those in the literature [67].

2,6-Bis(trifluoromethyl)-1H-indole (4k). Obtained from styrene 2k (0.240 g, 0.75 mmol) by procedure V. Yellow crystals, m.p. 46–47 °C, yield 0.0896 g (47%). NMR data of indole 4k (see Supplementary Materials) are in agreement with those in the literature [67].

2-(Trifluoromethyl)-1H-indole-6-carbonitril (4l). Obtained from styrene 2l (0.080 g, 0.291 mmol) by procedure V. Slightly brown solid, m.p. 112–114 °C, yield 0.0305 g (50%). ¹H NMR (CDCl₃, 400.1 MHz): δ 9.18 (br.s, 1H), 7.85 (pseudo-d, 1Н, ⁴J ~ 1.1 Hz), 7.77 (d, 1Н, ³J = 8.3 Hz), 7.43 (dd, 1Н, ³J = 8.3 Hz, ⁴J = 1.3 Hz), 6.99 (pseudo-dt, 1Н, ⁴J ~ 2.1 Hz, ⁴J ~ 1.0 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 134.9, 129.7, 129.5 (q, ²J_CF = 39.2 Hz), 123.7, 123.1, 120.6 (q, ¹J_CF = 268.6 Hz), 119.8, 117.0, 107.2, 104.4 (q, ³J_CF = 3.2 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −62.2 (d, 3F, ⁴J = 0.9 Hz). HRMS (ESI-TOF): m/z [M-H]^- Calcd for C₁₀H₄F₃N₂⁻: 209.0332; found: 209.0323.

Methyl 2-(trifluoromethyl)-1H-indole-6-carboxylate (4m). Obtained from styrene 2m (0.126 g, 0.408 mmol) by procedure V. Pale brown solid, yield 0.0525 g (53%). NMR data of indole 4m (see Supplementary Materials) are in agreement with those in the literature [67].

5-Cloro-2-(trifluoromethyl)-1H-indole (4n). Obtained from styrene 2n (0.083 g, 0.29 mmol) by procedure V (piperidine was used instead of pyrrolidine). Pale yellow crystals, m.p. 59–61 °C, yield 0.0327 g (71%). NMR data of indole 4n (see Supplementary Materials) are in agreement with those in the literature [64].

5-(Pyrrolidin-1-yl)-2-(trifluoromethyl)-1H-indole (10a). Obtained from enamine 3n (0.160 g, 0.45 mmol) by procedure V. Orange crystals, m.p. 130–131 °C, yield 0.052 g (45%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.11 (br.s, 1H), 7.26 (d, 1Н, ³J = 9.1 Hz), 6.86–6.70 (m, 3Н), 3.32 (t, 4Н, ³J = 6.6 Hz), 2.09–2.00 (m, 4H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 143.9, 129.4, 127.9, 125.6 (q, ²J_CF = 38.5 Hz), 121.4 (q, ¹J_CF = 267.5 Hz), 113.2, 112.1, 103.2 (q, ³J_CF = 3.3 Hz), 101.7, 48.6, 25.3. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.5 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₃H₁₄F₃N₂⁺: 255.1104; found: 255.1109.

One pot synthesis of indoles 10 from styrenes 2 (general procedure VI). A 4 mL vial with a screw cup was charged with corresponding amine (5 mmol) and styrene 2n (0.5 mmol). The reaction mixture was heated at appropriate temperature for several hours (see further) or at room temperature (for MeNH₂) until starting styrene was consumed (TLC or NMR monitoring). The excess of amine was evaporated in vacuo, the viscous residue was dissolved in glacial acetic acid (2 mL) and transferred into a one neck 25 mL round bottomed flask. Next, water (0.2 mL), Fe powder (0.112 g, 2 mmol) was added, and the reaction mixture was kept at 80 °С at stirring for 1–2 h until dissolving of Fe powder. Volatiles were evaporated in vacuo, the residue was suspended in CH₂Cl₂ (2–5 mL) and filtered through a short celite pad. The filtrate was evaporated, and the residue was purified by column chromatography on silica gel using appropriate mixtures of CH₂Cl₂ and MeOH (100:1 for 10b-e and 30:1 for 10f,g) as eluents.

5-(Piperidin-1-yl)-2-(trifluoromethyl)-1H-indole (10b). Obtained styrene 2n (0.109 g, 0.404 mmol) and piperidine (0.572 g) by heating at 90 °C for 3 h. Pale green-brown solid, m.p. 104–106 °C, yield 0.048 g (44%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.46 (br.s, 1H), 7.25 (d, 1Н, ³J = 8.9 Hz), 7.17 (pseudo-d, 1Н, ⁴J ~ 2.1 Hz), 7.12 (dd, 1Н, ³J = 8.9 Hz, ⁴J = 2.3 Hz), 6.82 (br.s, 1H), 3.14–3.07 (m, 4Н), 1.77 (dt, 4H, ³J = 11.3 Hz, ³J = 5.7 Hz), 1.62–1.54 (m, 2H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 147.9, 131.5, 127.2, 125.8 (q, ²J_CF = 38.8 Hz), 121.3 (q, ¹J_CF = 267.6 Hz), 119.5, 112.1, 108.4, 103.9 (q, ³J_CF = 3.4 Hz), 53.1, 26.2, 24.2. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.4 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₄H₁₆F₃N₂⁺: 269.1260; found: 269.1265.

4-(2-(Trifluoromethyl)-1H-indol-5yl)morpholine (10c). Obtained from styrene 2n (0.104 g, 0.385 mmol) and morpholine (0.530 g) by heating at 100 °C for 4 h. Pale green-brown solid, m.p. 167–169 °C, yield 0.061 g (59%). ¹H NMR (CDCl₃, 400.1 MHz):

δ 9.91 (br.s, 1Н), 7.42–7.36 (m, 1Н), 7.12–7.07 (m, 2Н), 6.84 (pseudo-dt, 1 H, ⁴J ~ 2.1 Hz, ⁴J ~ 1.0 Hz), 3.84–3.75 (m, 4H), 3.10–3.01 (m, 4H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 147.8, 133.0, 127.9, 126.3 (q, ²J_CF = 38.6 Hz), 122.6 (q, ¹J_CF = 266.5 Hz), 118.9, 113.5, 107.8, 104.1 (q, ³J_CF = 3.4 Hz), 67.6, 52.1. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −59.5 (d, 3F, ⁴J = 1.0 Hz). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₃H₁₄F₃N₂O⁺: 271.1053; found: 271.1057.

5-(Azepan-1-yl)-2-(trifluoromethyl)-1H-indole (10d). Obtained from styrene 2n (0.107 g, 0.396 mmol) and hexamethyleneimine (0.480 g) by heating at 100 °C for 4 h. Pale yellow-brown solid, m.p. 65–67 °C, yield 0.060 g (54%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.12 (br.s, 1Н), 7.23 (d, 1Н, ³J = 9.0 Hz), 6.92 (dd, 1Н, ³J = 9.0 Hz, ⁴J = 2.4 Hz), 6.88 (pseudo-d, 1 H, ⁴J ~ 2.2 Hz), 6.79 (br.s, 1H), 3.56–3.47 (m, 4H), 1.89–1.79 (m, 4H), 1.61–1.53 (m, 4H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 144.6, 129.1, 128.0, 125.6 (q, ²J_CF = 38.7 Hz), 121.4 (q, ¹J_CF = 267.4 Hz), 112.9, 112.2, 103.3 (q, ³J_CF = 3.1 Hz), 101.5, 50.0, 27.9, 27.1. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.5 (d, 3F, ⁴J = 0.9 Hz). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₅H₁₈F₃N₂⁺: 283.1417; found: 283.1424.

N,N-Diethyl-2-(trifluoromethyl)-1H-indole-5-amine (10e). Obtained from styrene 2n (0.101 g, 0.374 mmol) and diethylamine (0.480 g) by heating at 100 °C for 10 h. Pale brown oil, yield 0.041 g (43%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.29 (br.s, 1Н), 7.26 (d, 1Н, ³J = 8.7 Hz), 7.02–6.93 (m, 2Н), 6.79 (s, 1H), 3.33 (q, 4H, ³J = 7.1 Hz), 1.13 (t, 6H, ³J = 7.1 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 143.7, 130.3, 127.6, 125.7 (q, ²J_CF = 38.9 Hz), 121.4 (q, ¹J_CF = 267.4 Hz), 116.4, 112.2, 106.0, 103.5 (q, ³J_CF = 3.2 Hz), 45.9, 12.3. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.6 (d, 3F, ⁴J = 1.1 Hz). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₃H₁₆F₃N₂⁺: 257.1260; found: 257.1261.

N-Methyl-2-(trifluoromethyl)-1H-indole-5-amine (10f). Obtained from styrene 2n (0.116 g, 0.430 mmol) and n-methylamine (2 mL of 3.65 M solution in MeOH) by keeping the reaction mixture for 11 days. Pale green-brown solid, m.p. 133–135 °C, yield 0.040 g (44%). ¹H NMR (CD₃CN, 400.1 MHz): δ 9.74 (br.s, 1Н), 7.26 (d, 1Н, ³J = 8.7 Hz), 6.80–6.68 (m, 3Н), 2.77 (s, 3H). ¹³C{¹H} NMR (CD₃CN, 100.6 MHz): δ 145.9, 131.4, 128.5, 125.7 (q, ²J_CF = 38.5 Hz), 122.8 (q, ¹J_CF = 266.3 Hz), 116.2, 113.5, 103.4 (q, ³J_CF = 3.4 Hz), 101.0, 31.4. ¹⁹F NMR (CD₃CN, 376.5 MHz): δ −59.3 (d, 3F, ⁴J = 0.9 Hz). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₀H₁₀F₃N₂⁺: 215.0791; found: 215.0792.

N-Hexyl-2-(trifluoromethyl)-1H-indole-5-amine (10g). Obtained from styrene 2n (0.100 g, 0.370 mmol) and n-hexylamine (0.482 g) by heating at 100 °C for 4 h. Pale yellow-brown solid, m.p. 88–90 °C, yield 0.047 g (45%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.31 (br.s, 1Н), 7.17 (d, 1Н, ³J = 8.8 Hz), 6.82 (d, 1Н, ⁴J = 2.1 Hz), 6.77–6.69 (m, 2H), 3.16–3.10 (m, 2Н), 2.96 (br.s, 1H), 1.65 (dt, 2Н, ³J = 14.7 Hz, ³J = 7.2 Hz), 1.48–1.29 (m, 6H), 0.91 (t, 3H, ³J = 7.0 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 143.4, 130.3, 127.7, 125.6 (q, ²J_CF = 38.6 Hz), 121.4 (q, ¹J_CF = 267.4 Hz), 115.4, 112.3, 103.3 (q, ³J_CF = 3.3 Hz), 102.2, 45.1, 31.7, 29.5, 26.9, 22.6, 14.0. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −61.5 (d, 3F, ⁴J = 1.0 Hz). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₅H₂₀F₃N₂⁺: 285.1573; found: 285.1576.

Reactions of indole 4a with electrophiles.

Synthesis of 2-(trifluoromethyl)-1H-indol-3-carbaldehyde (17). A 4 mL vial with a screw cup was charged with DMF (0.5 mL), cooled to −18 °C (in the fridge) and then POCl₃ (0.210 g, 1.37 mmol) was added. The reaction mixture was kept at 5–7 °C (in the fridge) for 30 min and then indole 4a (0.108 g, 0.58 mmol). The reaction mixture was stirred for 6h at 80 °C, cooled down to room temperature and transferred to separating funnel with water (50 mL) using CH₂Cl₂ (30–40 mL). After shaking, organic phase was separated, water phase was extracted with CH₂Cl₂ (20 mL). Combined organic phase was washed with water (20 mL), and dried over Na₂SO₄. Volatiles were evaporated in vacuo, the residue formed was suspended in hexane-CH₂Cl₂ mixture (3:1, 2 mL). The precipitate was filtered off and dried in vacuo to give pure 17. Beige powder, m.p. 167–169 °C, yield 0.066 g (53%). NMR data of indole 17 (see Supplementary Materials) are in agreement with those in the literature [66].

1-(2-(Trifluoromethyl)-1H-indol-3-yl)ethanone (18). An 8 mL vial with a screw cup was charged with 1,2-dichloroethane (1.5 mL), AlCl₃ (0.124 g, 0.93 mmol), cooled to −18 °C (in the fridge) and then AcCl (0.047 g, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then indole 4a (0.089 g, 0.48 mmol) was added. The reaction mixture was stirred overnight and poured into water (50 mL). Water phase was extracted with CH₂Cl₂ (3 × 20 mL). Combined organic phase was washed with water (20 mL), and dried over Na₂SO₄. Volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel using CH₂Cl₂ followed by mixture of CH₂Cl₂ and MeOH (100:1) as eluents. Beige powder, m.p. 125–127 °C, yield 0.070 g (64%). ¹H NMR (CD₃CN, 400.1 MHz): δ 10.77 (br.s, 1Н), 8.11 (d, 1Н, ³J = 8.2 Hz), 7.60–7.56 (m, 1Н), 7.41–7.36 (m, 1Н), 7.35–7.30 (m, 1H), 2.66 (s, 3H). ¹³C{¹H} NMR (DMSO-d₆, 100.6 MHz): δ 192.7, 134.8, 126.9 (q, ²J_CF = 38.1 Hz), 125.4, 125.3, 124.8 (d, ⁴J_CF = 3.0 Hz), 123.0, 121.9, 121.1 (q, ¹J_CF = 269.6 Hz), 116.9 (q, ³J_CF = 1.5 Hz), 113.4 (d, ³J_CF = 6.2 Hz), 31.0. ¹⁹F NMR (CD₃CN, 376.5 MHz): δ −58.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₁H₉F₃NO⁺: 228.0631; found: 228.0635.

(E)-1,1,1-Trifluoro-4-(2-(trifluoromethyl)-1H-indol-3-yl)but-3-en-2-one (20). An 8 mL vial with a screw cup was charged with indole 4a (0.091 g, 0.49 mmol), (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one 19 (0.090 g, 0.54 mmol), 1,2-dichloroethane (1 mL), and BF₃·Et₂O (0.083 g, 0.059 mmol). The reaction mixture was stirred for 2h at 80 °C and poured into water (30 mL). Water phase was extracted with CH₂Cl₂ (3 × 20 mL). Combined organic phase was washed with water (20 mL), and dried over Na₂SO₄. Volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel using mixtures of hexane and CH₂Cl₂ (3:1 followed by 1:1) as eluents. Yellow powder, m.p. 125–127 °C, yield 0.0563 g (37%). ¹H NMR (CDCl₃, 400.1 MHz): δ 9.07 (br.s, 1Н), 8.30 (d, 1Н, ³J = 15.9 Hz), 7.98 (d, 1Н, ³J = 8.0 Hz), 7.53 (d, 1Н, ³J = 8.0 Hz), 7.50–7.43 (m, 1Н), 7.43–7.38 (m, 1H), 7.20 (d, 1Н, ³J = 15.9 Hz). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 180.1 (q, ²J_CF = 35.1 Hz), 139.7, 135.3, 128.9 (q, ²J_CF = 37.4 Hz), 126.2, 125.0, 123.7, 121.7, 120.7 (q, ¹J_CF = 270.5 Hz), 116.5 (q, ¹J_CF = 290.6 Hz), 116.6, 112.8, 112.7 (q, ³J_CF = 2.3 Hz). ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −59.0 (d, 3F, ⁴J = 0.8 Hz), −78.7 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₁₃H₈F₆NO⁺: 308.0505; found: 308.0509.

Reactions of indole 4a with benzaldehydes in alcohols under catalysis with MeSO₃H (general procedure VII). A 4 mL vial with a screw cup was charged with indole 4a (0.0925 g, 0.5 mmol), alcohol (MeOH or EtOH, 1 mL), corresponding benzaldehyde (0.6 mmol or 0.25 mmol for 23) and MeSO₃H (0.050g, 0.53 mmol). The reaction mixture was heated at 80 °C for appropriate time, volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel using mixtures of hexane and CH₂Cl₂ (3:1 followed by 1:1) as eluents.

3-(Methoxy(phenyl)methyl)-2-(trifluoromethyl)-1H-indole (21a). Obtained by the reaction of 4a (0.0925 g, 0.5 mmol) with benzaldehyde (0.065 g, 0.6 mmol) in MeOH by heating for 8h. White crystals, m.p. 86–88 °C, yield 0.100 g (68%). NMR data of indole 21a (see Supplementary Materials) are in agreement with those in the literature [84].

3-((4-Chlorophenyl)(methoxy)methyl)-2-(trifluoromethyl)-1H-indole (21b). Obtained by the reaction of 4a (0.0925 g, 0.5 mmol) with 4-chlorobenzaldehyde (0.084 g, 0.6 mmol) in MeOH by heating for 10h. White crystals, m.p. 112–113 °C, yield 0.112 g (66%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.44 (br.s, 1Н), 7.72 (d, 1Н, ³J = 8.1 Hz), 7.46–7.35 (m, 3Н), 7.35–7.25 (m, 3Н), 7.11 (ddd, 1Н, ³J = 8.1 Hz, ³J = 7.0 Hz, ⁴J = 1.0 Hz), 5.79 (s, 1H), 3.41 (s, 3Н). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 139.8, 135.4, 133.0, 128.3, 127.7, 125.2, 125.1, 123.2 (q, ²J_CF = 37.1 Hz), 122.7, 121.7 (q, ¹J_CF = 269.3 Hz), 121.2, 117.3 (q, ³J_CF = 2.4 Hz), 111.7, 56.9. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −58.2 (s, 3F). HRMS (ESI-TOF): m/z [M-MeO]^- Calcd for C₁₆H₁₀ClF₃N⁺: 308.0448; found: 308.0450.

3-(Methoxy(4-methoxyphenyl)methyl)-2-(trifluoromethyl)-1H-indole (21c). Obtained by the reaction of 4a (0.098 g, 0.53 mmol) with 4-methoxybenzaldehyde (0.087 g, 0.636 mmol) in MeOH by heating for 12h. Pale brown powder, m.p. 138-140 °С, yield 0.092 g (52%). NMR data of indole 21c (see Supplementary Materials) are in agreement with those in the literature [84].

3-(Ethoxy(phenyl)methyl)-2-(trifluoromethyl)-1H-indole (22). Obtained by the reaction of 4a (0.048 g, 0.259 mmol) with benzaldehyde (0.033 g, 0.306 mmol) in EtOH by heating for 8h. White crystals, m.p. 129–132 °C, yield 0.061 g (74%). NMR data of indole 22 (see Supplementary Materials) are in agreement with those in the literature [84].

3,3’-(Phenylmethylene)bis(2-(trifluoromethyl)-1H-indole) (23). Obtained by the reaction of 4a (0.087 g, 0.47 mmol) with benzaldehyde (0.026 g, 0.241 mmol) in EtOH by heating for 12h. Brown oil, yield 0.0486 g (45%). ¹H NMR (CDCl₃, 400.1 MHz): δ 8.41 (br.s, 2Н), 7.39 (d, 2Н, ³J = 8.3 Hz), 7.27 (d, 2Н, ⁴J = 2.2 Hz), 7.25–7.16 (m, 5H), 6.84 (ddd, 2Н, ³J = 8.1 Hz, ³J = 7.0 Hz, ⁴J = 1.0 Hz), 6.72 (d, 2Н, ³J = 8.1 Hz), 6.54 (s, 1H). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz): δ 142.0, 135.0, 128.8, 128.3, 127.2, 126.8, 124.3, 122.4 (q, ²J_CF = 37.5 Hz), 122.3, 121.7 (q, ¹J_CF = 269.6 Hz), 120.8, 118.8 (q, ³J_CF = 1.5 Hz), 111,7, 38,0. ¹⁹F NMR (CDCl₃, 376.5 MHz): δ −60.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]⁺ Calcd for C₂₅H₁₇F₆N₂⁺: 459.1290; found: 459.1290.

4. Conclusions

In conclusion, we elaborated a novel three-step pathway towards 2-CF₃-indoles starting from 2-nitrobenzaldehydes. Catalytic olefination reaction of 2-nitrobenzaldehydes with CF₃CCl₃ leads, efficiently, to the corresponding trifluoromethylated ortho-nitrostyrenes. The second step is a one pot formation of α-CF₃-β-(2-nitroaryl) enamines by the reaction with pyrrolidine. Finally, reduction of nitro group by Fe-AcOH-H₂O system initiated intramolecular cyclization to form 2-CF₃-indoles in up to 85% yields. A broad synthetic scope and simplicity of the procedures of all steps are the distinct advantages of the method. The prepared trifluoromethylated indoles are valuable staring materials to synthesize 3-functionalized derivatives using some reactions with C-electrophiles.