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Article

An Efficient Synthesis of 2-CF3-3-Benzylindoles

by
Vasiliy M. Muzalevskiy
,
Zoia A. Sizova
and
Valentine G. Nenajdenko
*
Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(16), 5084; https://doi.org/10.3390/molecules26165084
Submission received: 22 July 2021 / Revised: 20 August 2021 / Accepted: 20 August 2021 / Published: 22 August 2021
(This article belongs to the Special Issue The Chemistry of Nitrocompounds)
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Abstract

:
The reaction of α-CF3-β-(2-nitroaryl) enamines with benzaldehydes afforded effectively α,β-diaryl-CF3-enones having nitro group. Subsequent reduction of nitro group by NH4HCO2-Pd/C system initiated intramolecular cyclization to give 2-CF3-3-benzylindoles. Target products can be prepared in up to quantitative yields. Broad synthetic scope of the reaction was shown. Probable mechanism of indole formation is proposed.

1. Introduction

Organofluorine chemistry is now hot topic area of modern organic chemistry. A lot of attention has been paid to elaboration of novel synthetic approaches towards fluorine-containing compounds as well as investigation of their chemical properties. Such concern of the chemists about these compounds is a result of their unique physicochemical and biological properties [1,2,3,4,5]. Fluorinated compounds are widely used as construction materials, components of liquid crystalline compositions, agrochemicals [6,7,8,9] and pharmaceuticals [10,11,12]. It was reported recently, that about 20% (more than 300 compounds) of currently used drugs [13,14,15,16,17,18,19,20] contain at least one fluorine atom [21]. Moreover, last years revealed the tendency of increasing of these values. Thus, share of fluoropharmaceuticals among new small-molecule drugs was 45% in 2018 [22], and 41% in 2019 [23]. On the other hand, about 59% of small-molecule drugs are the derivatives of nitrogen heterocyclic compounds [24]. As a result, novel approaches to fluorinated heterocycles are highly attractive [25,26,27,28,29,30,31].
Indole [32,33,34,35,36,37,38] is a “privileged structure” in drug discovery [39] and can be frequently found in pharmaceuticals and natural products [24]. The derivatives of 2-arylindoles exhibit antibacterial, anticancer, anti-oxidant, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis and antiparkinsonian activities [40]. The amino acid tryptophan is an essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. The biogenic amines tryptamine and serotonin as well as the mammalian hormone melatonin are important regulators of psychiatric health [41]. Indole derived marketed drugs include the nonsteroidal anti-inflammatory drug Indomethacin [42,43], anti-HIV drug Delavirdine [44,45], beta-blocker Pindolol [46,47], antintineoplastic drugs Panobinostat [48,49] and Apaziquone [50,51] (Figure 1).
One of the most reliable strategies for the synthesis of fluorinated heterocycles is using of fluorinated building blocks, highly reactive small-molecules. For example, α,β-unsaturated CF3-ketones were shown to possess a great potential in the synthesis of various organofluorine compounds, including carbo- and heterocycles [52,53,54,55,56,57,58,59,60,61]. Our group has been deeply involved in this chemistry. Recently, we have reported an efficient approach towards α,β-diaryl-CF3-enones—a new type of fluorinated building block. The reaction of arylaldehydes with α-CF3-β-aryl enamines gave the corresponding α,β-diaryl-CF3-enones in good to high yields at heating in acetic acid. Based on the reactions with hydrazines a convenient pathway to exhaustingly substituted fluorinated pyrazolines and pyrazoles were elaborated, including derivatives of Celecoxib, Mavocoxib (nonsteroidal anti-inflammatory drugs) and SC-560 (anti-cancer drug) [62]. Using reduction of α-aryl-β-(2-nitroaryl)-CF3-enones a novel synthetic approach towards 2-CF3-3-arylquinolines was developed [63]. Shifting nitro group to α-aryl ring-opened a pathway to various functionalized 2-CF3-indoles by the reduction with ammonium formate followed by reactions with various nucleophiles [64].
In continuation of the investigation of α,β-diaryl-CF3-enones chemistry, in this article, we report synthesis of 2-CF3-3-benzylindoles by reduction of nitro group in α-(2-nitroaryl)-β-aryl-CF3-enones followed by intramolecular cyclization (Figure 2).
It should be noted, that 2-CF3-3-benzylindoles are quite a rare type of indoles. The approaches to the synthesis of these indoles were not studied systematically and have been not in the main focus of the publications. As a result, syntheses of only few 2-CF3-3-benzylindoles were reported. Thus, prepared in three steps, N-[2-(1-alkynyl)phenyl]trifluoroacetimidoyl iodides were transformed into desired indoles by the tin-radical promoted cyclization of N-[2-(1-alkynyl)phenyl]trifluoroacetimidoyl iodides as reported by Uneyama [65]. The copper-catalyzed C(sp2)-H trifluoromethylation of N,N-disubstituted hydrazones using the Togni’s reagent followed by Fischer indole cyclization of CF3-hydrazones formed was described by Monteiro and Bouyssi [66]). N-Methylmorpholine mediated direct trifluoromethylation of 3-benzylindole with Umemoto’s reagent was reported by Ma and Yu [67]. In spite of the mentioned methods allowed to prepare 2-CF3-indoles in good yields (59–64%), low atom efficiency and high price of some used reagent should be taken into account (Figure 2).

2. Results

To start our investigation, we prepared a set of α-(2-nitroaryl)-β-aryl-CF3-enones using recently elaborated by us synthetic protocol [64]. Condensation of α-CF3-β-(2-nitroaryl)enamines 1 with arylaldehydes 2 in acetic acid at 80–90 °C led to the corresponding α-(2-nitroaryl)-β-aryl-CF3-enones 3 in good to high yields. The reaction is very general, almost no limitations were found to give variety of such enones with a possibility to have different substituents in both aromatic rings. Moreover, some heterocyclic derivatives can be prepared as well (Scheme 1).
Next, we investigated the reductive cyclization of ketone 3a in various conditions (Scheme 2). Firstly, we employed standard conditions of Leimgruber–Batcho [68] and Reissert [69] synthesis of indoles, which involve the reduction of nitro group followed by intramolecular cyclization of aniline formed. Thus, heating of ketone 3a using Fe-AcOH-H2O, Zn-EtOH-HCl and SnCl2•2H2O-EtOH systems led to the formation of a variety of hardly identifiable products, in which we were able to identify only 2-CF3-3-benzylindole 4a and its acetoxy-derivative 5a (by 19F NMR, Scheme 2). Better results were achieved when Zn-AcOH system was used. In this case, indoles 4a and 5a were isolated in 20% and 47% yield correspondingly (Table 1, entry 1). Further heating of this reaction mixture with additional amount of Zn led to a partial transformation of acetoxy indole 5a into indole 4a (Table 1, entry 2). In Zn-AcOH-MeOH system methoxy-indol 6a became the main product, which was isolated in 77% yield (Table 1, entry 3). Further improvements in terms of chemoselectivity were made using catalytic hydrogenation on Pd/C in MeOH. Thus, reduction using H2 at room temperature or NH4HCO2 (hydrogen surrogate) at 65 °C afforded 2-CF3-3-benzylindole 4a in about 90% yield. In both cases methoxy-substituted indole 6a was formed as a byproduct in less than 1% yield (Table 1, entries 4,5). Ultimate selectivity of the reaction was achieved by the reduction with 5 equivalents of NH4HCO2 on Pd/C in MeOH at room temperature. In this conditions 2-CF3-3-benzylindole 4a was isolated in almost quantitative yield while byproduct 6a was not formed at all (Table 1, entry 6). It is worth noting that the reaction with NH4HCO2 (Table 1, entries 5,6) leads to a mixture of indole 4a and indolinol D, which structure is proved by NMR spectra of the reaction mixture. However, indolinol D eliminates water instantly followed by aromatization after addition of an acid (Scheme 2 and Scheme 3).
Careful analysis of results of experiments (Table 1) forced us to propose that the reaction can proceed via the formation of cyclic hemiaminal B (Scheme 3). To confirm our preposition, we performed the reduction of 3a with 3.3 equivalents of NH4HCO2 (the precise amount needed for NO2 reduction only). Heating of the reaction mixture for 1h at 60 °C led highly selectively to assembling of methoxy-substituted indole 6a in 86% yield (Table 1, entry 7). We have also found, that using THF as a solvent instead of methanol allowed to stop the reaction at the step of intermediate unsaturated indolinol B. Compound B is stable enough to be isolated in crude form (by evaporation of the solvent). The structure of B was confirmed by NMR and HRMS spectra (Scheme 3). It was also found that compound B eliminates water slowly at standing in CDCl3 solution (directly in NMR tube). Thus, NMR spectra of this solution measured after about a month (36 days) showed the complete transformation of B into C (Scheme 3). An attempt to perform acid catalyzed elimination of water from B in THF the solution and isolate C was failed. Thus, the addition of pTSA to the THF solution of B followed by evaporation of the solvent led to severe tarring immediately. However, the addition of pTSA to solution of B in methanol led to desired elimination of water followed by the conjugated addition of methanol to form methoxy-indole 5a (Table 1, entry 8). Similarly, the addition of methanol to CDCl3 solution of C (obtained by standing in NMR tube, see above) led to the transformation of C into 5a (by 19F NMR). So, we have successfully confirmed the mechanism of the reaction. Thus, reduction of the nitro group in indole 3a led to aniline A, which cyclizes to unsaturated indolinol B. Elimination of water from B afforded conjugated imine C, which is a strong Michael acceptor due to aromatization facilitating addition of nucleophiles. Hydrogenation of the double bond of B leads to saturated indolinol D. Elimination of water from D finalizes the process to afford indole 4a.
Next, we investigated the synthetic scope of the synthesis of CF3-indoles 4. Using the optimal reaction conditions, we performed a reduction of a number of ketones 3 to afford corresponding indoles 4 in high to quantitative yields (Scheme 4.).
The reaction has a wide synthetic scope, allowing preparing indoles having both electron-donating and electron-withdrawing groups as well as bulky ortho-substituents and naphthyl fragment. It should be noted, that ketones 3j–l bearing the additional nitro groups were transformed into amino-substituted indoles 4j–l. These indoles are interesting objects for the further modifications at NH2-group to give promising derivatives in terms of drug design. In the case of bulky ketone 3o having 1-naphthyl substituent reduction in standard conditions (5 equivalents of NH4HCO2) led to the formation of admixture of methoxy-indole 6b (about 28%). Probably, the rate of hydrogenation of the double bond of unsaturated indolinol B is lower due to its steric hindrance and the reaction cannot be completed because of full decomposition of NH4HCO2 on Pd/C during the reaction course. Nevertheless, using of 8 equivalents of NH4HCO2 allowed to overcome this obstacle to give selectively indole 4o in 87% yield. The reduction of ketones 3p and 3q having additional methoxy group in nitro-aryl fragment led to 5- and 8-methoxyindoles correspondingly.
Ketones 3r,s having heterocyclic substituents were also involved in the transformation. It should be noted that reduction of thiophene derivative 3r proceeded much more slowly compared to other substrates, which can be explained by poisoning of palladium by thiophene moiety [70]. Thus, attempt to perform the reaction in standard conditions led mostly to methoxy-indole 6c. However, increasing of the amount of NH4HCO2 to 15 equivalents and prolongation of the reaction time to 5 days allowed to prepare desired indole 4r in good yield. Separation of admixture of 6c from target indole 4r was carried out by column chromatography. It should be noted, that it is one of few cases, then column chromatography was used for purification of the products (4l,r,s). All other indoles were isolated in pure form just after separation from the inorganic admixtures (Pd/C and NH4Cl). Due to the low stability of pyridine derived ketone 3s the reduction of this compound was performed without its isolation. An attempt to use NH4HCO2 in AcOH afforded a complex mixture of products. However, using HCO2H instead of NH4HCO2 showed much better results. Indole 4s having pyridine substituent was isolated in 21% yield from enamine 1a. Taking into account moderate yield at first step of the reaction sequence (30% for the formation of 3v) the yield at the reduction step can be estimated as 70% (Scheme 5).

3. Materials and Methods

General Remarks

1H, 13C and 19F NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer (Bruker Corp., Carlsruhe, Germany) in CD3CN and CDCl3 at 400, 100 and 376 MHz respectively. Chemical shifts (δ) in ppm are reported with the use of the residual CHD2CN and chloroform signals (1.94 and 7.25 for 1H and 1.30, 77.0 for 13C) as internal reference. The 19F chemical shifts were referenced to C6F6, (−162.9 ppm). ESI-MS spectra were measured with an Orbitrap Elite instrument (Thermo Fisher Scientific, Waltham, MA USA). TLC analysis was performed on “Merck 60 F254” plates (Merck, Darmstadt, Germany). Column chromatography was performed on silica gel. Melting points were determined on an Electrothermal 9100 apparatus (Electrothermal, Stone, Staffordshire, UK). All reagents were of reagent grade and were used as such or were distilled prior to use. Starting α-CF3-β-aryl enamines 1 were synthesized using previously reported procedures by the reaction with 10 equivalents of pyrrolidine in neat [71].
Synthesis of α-CF3-β-(2-nitroaryl)enamines 1 by the Reaction with Pyrrolidine in Neat (General Procedure). One neck 25 mL round-bottomed flask was charged with dry pyrrolidine (8.5 mL, 100 mmol), cooled down to −18 °C and the corresponding styrene (10 mmol) was added in one portion with vigorous stirring. The reaction mixture was stirred at room temperature for 1-3 h until starting styrene was consumed (TLC or NMR monitoring). The excess of pyrrolidine was evaporated in a vacuum, the viscous residue was dissolved in CH2Cl2 (50 mL), washed with 10% K2CO3 solution (2 × 50 mL) and dried over Na2SO4. CH2Cl2 was removed in vacuo to give crude enamine, which was used without further purification. For characterization data of enamines 1 see [64].
Synthesis of ketones 3 by the reactions of α-(trifluoromethyl)enamines with aromatic aldehydes (general procedure). One-necked 50-mL round bottom flask (or 12 mL vial) was charged with enamine 1 (5 mmol), aromatic aldehyde 2 (5.75 mmol) and glacial acetic acid (15 mL or 5 mL for reaction in the vial). Reaction mixture was kept at 80–90 °C (hotplate stirrer) under stirring for 6-10 h until consumption of aldehyde and corresponding benzyl ketone formed by the hydrolysis of enamine (1H NMR control). Volatiles were evaporated in vacuo, the residue was dissolved in CH2Cl2 (50 mL), washed with water (2 × 20 mL) and dried over Na2SO4. Volatiles were evaporated in vacuo, the residue was purified by column chromatography, using mixtures of hexane and CH2Cl2 (3:1, 1:1), CH2Cl2, mixture of CH2Cl2 and MeOH (100:1) as eluents. For characterization data of ketones 3 see [64].
Reductive cyclization of nitro-ketones 3 to 2-CF3-indoles 4. 12 mL vial with a screw cap was charged with ketone 4 (0.2 mmol), NH4HCO2 (0.063 g, 1.00 mmol, 5 equiv.), Pd/C (10%, 0.0108 g, 0.01 mmol, 5 mol%) and methanol (1.2 mL). Next, the reaction mixture was kept under stirring at 60 °C for 0.5-1 h (conditions a) or at room temperature for 1 day (conditions b). After that, 6M HCl (0.25 mL, 1.5 mmol) was added in 4-5 portions (evolution of CO2!). The reaction mixture was filtered through a short celite pad and dispersed between water (10 mL) and CH2Cl2 (20 mL). Aqueous layer was separated and extracted with CH2Cl2 (3 × 10 mL). Combined organic phases were dried over Na2SO4, volatiles were evaporated in vacuo, to give pure indole 4. In the case of indoles 4l, 4n, 4r, 4s additional purification by column chromatography on silica gel was performed. Reduction of ketones 3j–l, having additional nitro group, was performed using 8 equivalents of NH4HCO2 at room temperature (conditions c).
3-Benzyl-2-(trifluoromethyl)-1H-indole (4a). Obtained using conditions a (0.108 g, 0.34 mmol of 3a) or conditions b (0.055 g, 0.171 mmol of 3a). Pale brown crystals, m.p. 103–104 °C, yield 0.084 g (91%, A) 0.0465 g (99%, B). 1H NMR (CDCl3, 400.1 MHz): δ 8.25 (br.s, 1H), 7.57 (d, 1H, 3J = 8.1 Hz), 7.39 (d, 1H, 3J = 8.2 Hz), 7.27–7.37 (m, 5H), 7.20–7.26 (m, 1H), 7.13–7.19 (m, 1H), 4.32 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 139.9, 135.3, 128.4, 128.3, 127.4, 126.1, 124.8, 122.03 (q, 2JCF = 36.5 Hz), 122.01 (q, 1JCF = 269.0 Hz), 120.8, 120.7, 116.8 (q, 3JCF = 2.8 Hz), 111.7, 29.8. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F). NMR data are in agreement with those in the literature [67].
3-(4-Methylbenzyl)-2-(trifluoromethyl)-1H-indole (4b). Obtained using conditions a (0.109 g, 0.325 mmol of 3b). Pale brown solid, m.p. 88–90 °C, yield 0.090 g (96%). 1H NMR (CDCl3, 400.1 MHz): δ 8.24 (br.s, 1H), 7.63 (d, 1H, 3J = 8.1 Hz), 7.35–7.44 (m, 2H), 7.25 (d, 2H, 3J = 8.0 Hz), 7.19–7.23 (m, 1H), 7.17 (d, 2H, 3J = 7.9 Hz), 4.33 (s, 2H), 2.39 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 136.9, 135.6, 135.3, 129.1, 128.1, 127.4, 124.7, 122.1(q, 1JCF = 269.0 Hz), 121.9 (q, 2JCF = 36.5 Hz), 120.8, 120.6, 117.0 (q, 3JCF = 2.8 Hz), 111.6, 29.3, 20.9. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H13F3N−: 288.1006; found: 288.1009.
3-(4-(tert-Butyl)benzyl)-2-(trifluoromethyl)-1H-indole (4c). Obtained using conditions b (0.120 g, 0.318 mmol of 3c). Pale brown solid, m.p. 85–87 °C, yield 0.100 g (95%). 1H NMR (CDCl3, 400.1 MHz): δ 8.23 (br.s, 1H), 7.64 (d, 1H, 3J = 8.1 Hz), 7.33–7.42 (m, 4H), 7.25–7.32 (m, 2H), 7.19 (ddd, 1H, 3J = 8.0 Hz, 3J = 6.6 Hz, 4J = 1.4 Hz), 4.32 (s, 2H), 1.36 (s, 9H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 148.9, 136.9, 135.3, 127.9, 127.5, 125.3, 124.8, 122.0 (q, 1JCF = 269.1 Hz), 121.9 (q, 2JCF = 36.7 Hz), 120.9, 120.6, 117.1 (q, 3JCF = 2.6 Hz), 111.6, 34.3, 31.3, 29.2. 19F NMR (CDCl3, 376.5 MHz): δ −59.0 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C20H19F3N−: 330.1475; found: 330.1472.
3-(4-Fluorobenzyl)-2-(trifluoromethyl)-1H-indole (4d). Obtained using conditions a (0.126 g, 0.372 mmol of 3d). Brown viscous oil, yield 0.105 g (96%). 1H NMR (CDCl3, 400.1 MHz): δ 8.30 (br.s, 1H), 7.56 (d, 1H, 3J = 8.1 Hz), 7.33–7.45 (m, 2H), 7.16–7.28 (m, 3H), 6.94–7.05 (m, 2H), 4.29 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 161.3 (d, 1JCF = 243.8 Hz), 135.6 (d, 4JCF = 2.8 Hz), 135.3, 129.6 (d, 3JCF = 7.9 Hz), 127.3, 124.9, 122.0 (q, 2JCF = 36.4 Hz), 121.9 (q, 1JCF = 269.0 Hz), 120.8, 120.6, 116.6 (q, 3JCF = 2.6 Hz), 115.1 (d, 2JCF = 21.3 Hz), 111.7, 28.9. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F), −118.19 – −118.55 (m, 1F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C16H10F4N−: 292.0755; found: 292.0749.
2-(Trifluoromethyl)-3-(4-(trifluoromethyl)benzyl)-1H-indole (4e). Obtained using conditions b (0.147 g, 0.378 mmol of 3e). Pale brown solid, m.p. 54–56 °C, yield 0.129 g (>99%). 1H NMR (CDCl3, 400.1 MHz): δ 8.36 (br.s, 1H), 7.50–7.66 (m, 3H), 7.40–7.49(m, 1H), 7.39-7.40 (m, 3H), 7.19 (t, 1H, 3J = 7.5 Hz),4.35 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 144.0, 135.3, 128.49 (q, 2JCF = 32.3 Hz), 128.51, 127.2, 125.4 (q, 3JCF = 3.7 Hz), 124.3 (q, 1JCF = 271.9 Hz), 122.4 (q, 2JCF = 36.8 Hz), 121.9 (q, 1JCF = 269.1 Hz), 121.0, 120.4, 115.6 (q, 3JCF = 2.6 Hz), 111.9, 29.5. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F), −63.4 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H10F6N−: 342.0723; found: 342.0714.
Methyl 4-((2-(trifluoromethyl)-1H-indol-3-yl)methyl)benzoate (4f). Obtained using conditions b (0.085 g, 0.224 mmol of 3f). Pale yellow solid, m.p. 109–111 °C, yield 0.074 g (>99%). 1H NMR (CDCl3, 400.1 MHz): δ 8.69 (br.s, 1H), 7.95 (d, 2H, 3J = 8.3 Hz), 7.48 (d, 2H, 3J = 8.1 Hz), 7.41 (d, 1H, 3J = 8.3 Hz), 7.27–7.35 (m, 3H), 7.10–7.16 (m, 1H), 4.32 (s, 2H), 3.90 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 167.2, 145.5, 135.4, 129.8, 128.3, 128.0, 127.2, 124.9, 122.3 (q, 2JCF = 36.8 Hz), 121.9 (q, 1JCF = 269.0 Hz), 120.8, 120.4, 115.5 (q, 3JCF = 2.9 Hz), 111.8, 52.0, 29.8. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C18H13F3NO2−: 332.0904; found: 332.0904.
3-(4-Methoxybenzyl)-2-(trifluoromethyl)-1H-indole (4g). Obtained using conditions b (0.057 g, 0.161 mmol of 3g). White powder, m.p. 116–118 °C, yield 0.047 g (95%). 1H NMR (CDCl3, 400.1 MHz): δ 8.34 (br.s, 1H), 7.56 (d, 1H, 3J = 8.1 Hz), 7.37 (d, 1H, 3J = 8.2 Hz), 7.32 (t, 1H, 3J = 7.5 Hz), 7.20 (d, 2H, 3J = 8.5 Hz), 7.11–7.17 (m, 1H), 6.84 (d, 2H, 3J = 8.6 Hz), 4.24 (s, 2H), 3.79 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 157.8, 135.3, 132.1, 129.2, 127.4, 124.8, 122.0 (q, 1JCF = 268.9 Hz), 121.9 (q, 2JCF = 36.7 Hz), 120.8, 120.6, 117.2 (q, 3JCF = 2.8 Hz), 113.8, 111.7, 55.2, 28.9. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H13F3NO−: 304.0955; found: 304.0945.
3-(3-Methoxybenzyl)-2-(trifluoromethyl)-1H-indole (4h). Obtained using conditions b (0.104 g, 0.296 mmol of 3h). Pale brown solid, m.p. 55–57 °C, yield 0.080 g (89%). 1H NMR (CDCl3, 400.1 MHz): δ 8.35 (br.s, 1H), 7.57 (d, 1H, 3J = 8.1 Hz), 7.28–7.38 (m, 2H), 7.21 (d, 1H, 3J = 7.9 Hz), 7.12–7.17 (m, 1H), 6.90 (d, 1H, 3J = 7.7 Hz), 6.85 (pseudo-s, 1H), 6.77 (dd, 1H, 3J = 8.2 Hz, 4J = 2.3 Hz), 4.28 (s, 2H), 3.77 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.6, 141.6, 135.3, 129.3, 127.4, 124.8, 122.01 (q, 2JCF = 36.5 Hz), 121.99 (q, 1JCF = 269.1 Hz), 120.8, 120.70, 120.65, 116.5 (q, 3JCF = 2.9 Hz), 114.3, 111.7, 111.2, 55.0, 29.7. 19F NMR (CDCl3, 376.5 MHz): δ −59.0 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H13F3NO−: 304.0955; found: 304.0953.
3-(2-Methoxybenzyl)-2-(trifluoromethyl)-1H-indole (4i). Obtained using conditions b (0.116 g, 0.330 mmol of 3i). Pale yellow solid, m.p. 67–69 °C, yield 0.099 g (98%). 1H NMR (CDCl3, 400.1 MHz): δ 8.28 (br.s, 1H), 7.58 (d, 1H, 3J = 8.1 Hz), 7.31–7.41 (m, 2H), 7.20–7.25 (m, 1H), 7.15 (ddd, 1H, 3J = 8.0 Hz, 3J = 6.8 Hz, 4J = 1.2 Hz), 6.96–7.02 (m, 1H), 6.94 (dd, 1H, 3J = 8.2 Hz, 4J = 0.7 Hz), 6.85 (td, 1H, 3J = 7.5 Hz, 4J = 1.0 Hz), 4.34 (s, 2H), 3.94 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 157.0, 135.3, 129.2, 128.2, 127.7, 127.2, 124.7 122.3 (q, 2JCF = 36.7 Hz), 122.1 (q, 1JCF = 269.0 Hz), 121.0, 120.5, 120.4, 116.5 (q, 3JCF = 2.7 Hz), 111.5, 109.9, 55.2, 23.3. 19F NMR (CDCl3, 376.5 MHz): δ −59.3 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H13F3NO−: 304.0955; found: 304.0951.
4-((2-(Trifluoromethyl)-1H-indol-3-yl)methyl)aniline (4j). Obtained using conditions c (0.112 g, 0.306 mmol of 3j). Pale brown solid, m.p. 175–177 °C, yield 0.087 g (98%). 1H NMR (CDCl3, 400.1 MHz): δ 9.87 (br.s, 1H), 7.55 (d, 1H, 3J = 8.1 Hz), 7.46 (d, 1H, 3J = 8.3 Hz), 7.28 (t, 1H, 3J = 7.6 Hz), 7.09 (ddd, 1H, 3J = 8.0 Hz, 3J = 7.1 Hz, 4J = 0.9 Hz), 6.95 (d, 2H, 3J = 8.4 Hz), 6.54 (d, 2H, 3J = 8.5 Hz), 4.11 (s, 2H), 3.98 (br.s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 146.9, 136.8, 130.0, 129.7, 127.9, 125.4, 123.4 (q, 1JCF = 268.1 Hz), 122.1 (q, 2JCF = 36.6 Hz), 121.4, 121.0, 115.4, 112.9, 29.2. 19F NMR (CDCl3, 376.5 MHz): δ −56.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H14F3N2+: 291.1104; found: 291.1110.
3-((2-(Trifluoromethyl)-1H-indol-3-yl)methyl)aniline (4k). Obtained using conditions c (0.120 g, 0.328 mmol of 3k). Pale yellow solid, m.p. 138–140 °C, yield 0.086 g (90%). 1H NMR (CDCl3, 400.1 MHz): δ 8.56 (br.s, 1H), 7.56 (d, 1H, 3J = 8.1 Hz), 7.26–7.35 (m, 2H), 7.05–7.15 (m, 2H), 6.72 (d, 2H, 3J = 7.6 Hz), 6.57 (br.s, 1H), 6.53 (dd, 1H, 3J = 7.9 Hz, 3J = 1.7 Hz), 4.20 (s, 2H), 3.54 (br.s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 146.2, 141.3, 135.3, 129.2, 127.5, 124.7, 121.97 (q, 2JCF = 36.5 Hz), 122.02 (q, 1JCF = 268.7 Hz), 120.8, 120.5,118.9, 116.6 (q, 3JCF = 2.4 Hz), 115.2, 113.2, 111.6, 29.65. 19F NMR (CDCl3, 376.5 MHz): δ −58.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H14F3N2+: 291.1104; found: 291.1111.
2-((2-(Trifluoromethyl)-1H-indol-3-yl)methyl)aniline (4l). Obtained using conditions c (0.160 g, 0.437 mmol of 3l). Purified by column chromatography, using gradient elution by CH2Cl2 followed by mixture CH2Cl2-MeOH (100:1, 30:1). Pale yellow solid, m.p. 136–138 °C, yield 0.097 g (76%). 1H NMR (CDCl3, 400.1 MHz): δ 8.50 (br.s, 1H), 7.40 (d, 1H, 3J = 8.1 Hz), 7.35 (d, 1H, 3J = 8.2 Hz), 7.29 (t, 1H, 3J = 7.5 Hz), 7.08–7.12 (m, 1H), 7.04–7.08 (m, 1H), 6.93 (d, 1H, 3J = 7.5 Hz), 6.67–6.75 (m, 2H), 4.13 (s, 2H), 3.53 (br.s, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 144.2, 135.3, 129.5, 127.5, 127.4, 124.9, 123.9, 122.4 (q, 2JCF = 36.8 Hz), 121.9 (q, 1JCF = 269.0 Hz), 120.9, 120.7, 118.8, 115.7, 115.0 (q, 3JCF = 2.9 Hz), 111.7, 25.9. 19F NMR (CDCl3, 376.5 MHz): δ −59.3 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H14F3N2+: 291.1104; found: 291.1104.
3-(3-Phenoxybenzyl)-2-(trifluoromethyl)-1H-indole (4m). Obtained using conditions b (0.126 g, 0.305 mmol of 3m). Pale yellow solid, m.p. 71–73 °C, yield 0.107 g (96%). 1H NMR (CDCl3, 400.1 MHz): δ 8.33 (br.s, 1H), 7.56 (d, 1H, 3J = 8.1 Hz), 7.31–7.41 (m, 4H), 7.22-7.27 (m, 1H), 7.10–7.20 (m, 2H), 6.97-7.07 (m, 4H), 6.86 (dd, 1H, 3J = 8.1 Hz, 4J = 1.7 Hz), 4.29 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 157.14, 157.11, 142.1, 135.3, 129.6, 127.3, 124.8, 123.3, 123.1, 122.1 (q, 2JCF = 36.7 Hz), 121.9 (q, 1JCF = 269.0 Hz), 120.69, 120.65, 119.1, 118.7, 116.5, 116.3 (q, 3JCF = 2.5 Hz), 111.7, 29.6. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C22H15F3NO−: 366.1111; found: 366.1107.
3-((Perfluorophenyl)methyl)-2-(trifluoromethyl)-1H-indole (4n). Obtained using conditions b (0.117 g, 0.285 mmol of 3n). Purified by column chromatography, using gradient elution by mixture hexane-CH2Cl2 (4:1) followed by mixture hexane-CH2Cl2 (2:1). Pale brown solid, m.p. 131–133 °C, yield 0.082 g (79%). 1H NMR (CDCl3, 400.1 MHz): δ 8.32 (br.s, 1H), 7.56 (d, 1H, 3J = 8.1 Hz), 7.37–7.42 (m, 1H), 7.29–7.36 (m, 1H), 7.19 (ddd, 1H, 3J = 8.1 Hz, 3J = 6.9 Hz, 4J = 1.1 Hz), 4.32 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 145.3 (dddt, 1JCF = 246.8 Hz, 3JCF = 11.8 Hz, 4JCF = 7.8 Hz, 5JCF = 3.8 Hz, CF), 140.04 (dm, 1JCF = 258.6 Hz, m1 141.5-141.1, m2 138.9-138.6, CF), 137.5 (dm, 1JCF = 257.8 Hz, m1 138.9–138.6, m2 136.5–136.1, CF), 135.0, 126.6, 125.1, 122.3 (q, 2JCF = 37.4 Hz), 121.7 (q, 1JCF = 269.1 Hz), 121.1, 119.7, 113.1, 112.9, 111.9, 29.8 (d, 3JCF = 20.6 Hz, CF). 19F NMR (CDCl3, 376.5 MHz): δ −59.7 (s, 3F), −142.98 – −143.23 (m, 2F), −157.9 (t, 1F, J = 20.8 Hz), −163.47 – −163.67 (m, 2F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C16H6F8N−: 364.0378; found: 364.0373.
3-(Naphthalen-1-ylmethyl)-2-(trifluoromethyl)-1H-indole (4o). Obtained using conditions b (0.043 g, 0.116 mmol of 3o) and 8 equivalents of NH4HCO2 (0.059 g, 0.94 mmol, 8 equiv.). White solid, m.p. 69–71 °C, yield 0.0328 g (87%). 1H NMR (CDCl3, 400.1 MHz): δ 8.37 (br.s, 1H), 8.29 (d, 1H, 3J = 8.4 Hz), 7.90–7.98 (m, 1H), 7.76 (d, 1H, 3J = 8.2 Hz), 7.59–7.66 (m, 1H), 7.53-7.59(m, 1H), 7.43 (d, 1H, 3J = 8.3 Hz), 07.29-7.39 (m, 3H), 7.08 (ddd, 1H, 3J = 8.0 Hz, 3J = 7.1 Hz, 4J = 0.9 Hz), 7.04 (dd, 1H, 3J = 7.1 Hz, 4J = 0.9 Hz), 4.78 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 135.4, 135.3, 133.6, 131.9, 128.8, 127.7, 126.9, 126.1, 125.6, 125.5, 125.4, 124.9, 123.2, 122.7 (q, 2JCF = 36.7 Hz), 122.0 (q, 1JCF = 269.3 Hz), 120.9, 120.7, 115.7 (q, 3JCF = 2.9 Hz), 111.7, 26.6. 19F NMR (CDCl3, 376.5 MHz): δ −59.7 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C20H13F3N−: 324.1006; found: 324.1002.
3-(Methoxy(naphthalen-1-yl)methyl)-2-(trifluoromethyl)-1H-indole (6b). Obtained using conditions b (0.153 g, 0.412 mmol of 3o) as a mixture with indole 4o (yield 0.069 g (51%) for 4o). Purified by column chromatography, using mixture of hexane and CH2Cl2 (1:1) as an eluent. Yellow powder, m.p. 65–67 °C, yield 0.041 g (28%). 1H NMR (CDCl3, 400.1 MHz): δ 8.53 (br.s, 1H), 8.17 (d, 1H, 3J = 8.5 Hz), 7.88 (dd, 1H, 3J = 8.3 Hz, 4J = 0.9 Hz), 7.81 (d, 1H, 3J = 8.0 Hz), 7.74 (d, 1H, 3J = 8.2 Hz), 7.53–7.60 (m, 1H), 7.47–7.53 (m, 1H), 7.40 (d, 2H, 3J = 8.2 Hz), 7.36 (d, 1H, 3J = 7.9 Hz), 7.28–7.34 (m, 1H), 7.06-7.13 (m, 1H), 6.51 (s, 1H), 3.54 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 135.6, 135.3, 134.0, 131.6, 128.9, 128.7, 126.5, 126.3, 125.6, 125.3, 124.98, 124.94, 123.8, 123.3 (q, 2JCF = 37.4 Hz), 123.0, 121.7 (q, 1JCF = 269.5 Hz), 121.2, 116.5 (q, 3JCF = 2.6 Hz), 111.7, 75.5, 57.2. 19F NMR (CDCl3, 376.5 MHz): δ −59.0 (s, 3F). HRMS (ESI-TOF): m/z [M − OMe]− Calcd for C20H14F3N−: 324.1002; found: 324.1006.
3-Benzyl-7-methoxy-2-(trifluoromethyl)-1H-indole (4p). Obtained using conditions b (0.053 g, 0.151 mmol of 3p). Green-yellowish viscous oil, yield 0.044 g (96%). 1H NMR (CDCl3, 400.1 MHz): δ 8.57 (br.s, 1H), 7.23–7.30 (m, 4H), 7.15–7.22 (m,1H), 7.11 (d, 1H, 3J = 8.1 Hz), 7.04 (t, 1H, 3J = 7.6 Hz), 6.72 (d, 1H, 3J = 7.6 Hz), 4.26 (s, 2H), 3.97 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 146.3, 140.0, 128.7, 128.4, 128.3, 126.3, 126.0, 122.0 (q, 1JCF = 268.9 Hz), 121.8 (q, 2JCF = 36.8 Hz), 121.2, 117.1 (q, 3JCF = 2.8 Hz), 113.1, 103.9, 55.4, 30.0. 19F NMR (CDCl3, 376.5 MHz): δ −59.1 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H13F3NO−: 304.0955; found: 304.0960.
3-Benzyl-5-methoxy-2-(trifluoromethyl)-1H-indole (4q). Obtained using conditions b (0.098 g, 0.279 mmol of 3q). Pale brown solid, m.p. 102–104 °C, yield 0.0826 g (97%). 1H NMR (CDCl3, 400.1 MHz): δ 8.29 (br.s, 1H), 7.24–7.33 (m, 5H), 7.19–7.24 (m,1H), 6.99 (dd, 1H, 3J = 8.9 Hz, 4J = 2.4 Hz), 6.92 (d, 1H, 4J = 2.4 Hz), 4.27 (s, 2H), 3.78 (s,3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 154.5, 139.9, 130.5, 128.4, 128.3, 127.9, 126.1, 122.6 (q, 2JCF = 36.7 Hz), 121.9 (q, 1JCF = 269.0 Hz), 116.2 (q, 3JCF = 2.4 Hz), 115.6, 112.6, 101.6, 55.7, 29.8. 19F NMR (CDCl3, 376.5 MHz): δ −59.2 (s, 3F). HRMS (ESI-TOF): m/z [M − H]− Calcd for C17H13F3NO−: 304.0955; found: 304.0946.
Reduction of ketone 3r. Using conditions a: 12 mL vial with a screw cap was charged with ketone 3r (0.072 g, 0.220 mmol), NH4HCO2 (0.069 g, 1.10 mmol, 5 equiv.), Pd/C (10%, 0.012 g, 0.011 mmol, 5 mol%) and methanol (1.5 mL). Next, the reaction mixture was kept under stirring at 60 °C for 1 h. After that, 6M HCl (0.25 mL, 1.5 mmol) was added in 4-5 portions (evolution of CO2!). The reaction mixture was filtered through a short celite pad and dispersed between water (10 mL) and CH2Cl2 (20 mL). Aqueous layer was separated and extracted with CH2Cl2 (3 × 10 mL). Combined organic phases were dried over Na2SO4, volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel, using gradient elution by mixture hexane-CH2Cl2 (4:1) followed by mixture hexane-CH2Cl2 (2:1) to give 3-(thiophen-2-ylmethyl)-2-(trifluoromethyl)-1H-indole (4r), yield 0.0048 g, (8%) and 3-(methoxy(thiophen-2-yl)methyl)-2-(trifluoromethyl)-1H-indole (5a), yield 0.035 g, (51%).
Using conditions d: 12 mL vial with a screw cap was charged with ketone 3r (0.068 g, 0.208 mmol), NH4HCO2 (0.188 g, 2.98 mmol, ~15 equiv.), Pd/C (10%, 0.011 g, 0.0104 mmol, 5 mol%) and methanol (3 mL). Next, the reaction mixture was kept under stirring for 1 day. After that, 6M HCl (0.5 mL, 3 mmol) was added in 4-5 portions (evolution of CO2!). The reaction mixture was filtered through a short celite pad and dispersed between water (10 mL) and CH2Cl2 (20 mL). Aqueous layer was separated and extracted with CH2Cl2 (3 × 10 mL). Combined organic phases were dried over Na2SO4, volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel, using gradient elution by mixture hexane-CH2Cl2 (4:1) followed by mixture hexane-CH2Cl2 (2:1) to give 3-(thiophen-2-ylmethyl)-2-(trifluoromethyl)-1H-indole (4r), yield 0.031 g, (53%) and 3-(methoxy(thiophen-2-yl)methyl)-2-(trifluoromethyl)-1H-indole (5a), yield 0.0038 g, (6%).
3-(Thiophen-2-ylmethyl)-2-(trifluoromethyl)-1H-indole (4r). White powder, m.p. 88–90 °C. 1H NMR (CDCl3, 400.1 MHz): δ 8.26 (br.s, 1H), 7.63 (d, 1H, 3J = 8.1 Hz), 7.37–7.42 (m, 1H), 7.29-7.35 (m, 1H), 7.17 (ddd, 1H, 3J = 8.0 Hz, 3J = 7.0 Hz, 4J = 1.0 Hz), 7.10 (dd, 1H, 3J = 5.1 Hz, 4J = 1.2 Hz), 6.89 (dd, 1H, 3J = 5.1 Hz, 4J = 3.5 Hz), 6.80-6.86 (m,1H), 4.44 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 143.0, 135.2, 127.0, 126.7, 125.0, 124.8, 123.6, 121.8 (q, 1JCF = 269.0 Hz), 121.7 (q, 2JCF = 36.8 Hz), 120.8, 120.5, 116.4 (q, 3JCF = 2.7 Hz), 111.7, 24.2. 19F NMR (CDCl3, 376.5 MHz): δ −59.3 (s, 3F). HRMS (ESI-TOF): m/z [M − H]+ Calcd for C14H9F3NOS+: 280.0402; found: 280.0404.
3-(Methoxy(thiophen-2-yl)methyl)-2-(trifluoromethyl)-1H-indole (6a). Grey solid, m.p. 110–112 °C. 1H NMR (CDCl3, 400.1 MHz): δ 8.43 (br.s, 1H), 7.90 (d, 1H, 3J = 8.1 Hz), 7.39 (d, 1H, 3J = 8.3 Hz), 7.32 (t, 1H, 3J = 7.6 Hz), 7.23 (d, 1H, 3J = 5.0 Hz), 7.15 (t, 1H, 3J = 7.5 Hz), 6.86–6.92 (m, 1H), 6.83 (d, 1H, 4J = 3.4 Hz), 6.03 (s, 1H), 3.41 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 145.1, 135.3, 126.4, 125.2, 125.1, 125.0, 124.7, 123.0, 122.9 (q, 2JCF = 37.3 Hz), 121.6 (q, 1JCF = 269.4 Hz), 121.1, 117.3 (q, 3JCF = 2.6 Hz), 111.7, 74.3, 56.8. 19F NMR (CDCl3, 376.5 MHz): δ −58.5 (s, 3F). HRMS (ESI-TOF): m/z [M + Na]+ Calcd for C15H12F3NOS+: 334.0484; found: 334.0475.
Synthesis of 3-(pyridin-4-ylmethyl)-2-(trifluoromethyl)-1H-indole (4s). 12 mL vial was charged with enamine 1a (0.5 mmol), isonicotinaldehyde 2s (0.0669 g, 0.625 mmol) and glacial acetic acid (1 mL). Reaction mixture was kept at 80–90 °C (hotplate stirrer) under stirring for 10 h. The reaction mixture was cooled down to room temperature. Next, Pd/C (10%, 0.027 g, 0.025 mmol, 5 mol%) and formic acid (0.115 g, 2.5 mmol) was added and the reaction mixture was heated at 75 °C under stirring for 3 h. The reaction mixture was filtered through a short celite pad and dispersed between water (10 mL) and CH2Cl2 (20 mL). Aqueous layer was separated and extracted with CH2Cl2 (3×10 mL). Combined organic phases were dried over Na2SO4, volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel, using gradient elution by mixture hexane-CH2Cl2 (1:1) followed by CH2Cl2 and CH2Cl2-MeOH (100:1) as eluents. Pale yellow-brown powder, m.p. 185–187 °C, yield 0.029 g (21%). 1H NMR (CDCl3, 400.1 MHz): δ 9.03 (br.s, 1H), 8.42–8.50 (m, 2H),7.46 (d, 1H, 3J = 8.1 Hz), 7.43 (d, 2H, 3J = 8.3 Hz), 7.32 (t, 1H, 3J = 7.6 Hz), 7.11–7.18 (m, 3H), 4.26 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 150.5, 136.8, 127.8, 125.7, 124.4, 123.2 (q, 1JCF = 268.2 Hz), 123.1 (q, 2JCF = 36.5 Hz), 121.5, 121.0, 115.1 (q, 3JCF = 2.7 Hz), 113.1, 29.5. 19F NMR (CDCl3, 376.5 MHz): δ −59.3 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C15H12F3N2+: 277.0947; found: 277.0950. See Supplementary Materials.

4. Conclusions

In conclusion, we elaborated a novel two-step pathway towards 2-CF3-3-benzylindoles. Based on condensation of α-CF3-β-(2-nitroaryl) enamines with benzaldehydes the first step leads effectively to nitro-substituted α,β-diaryl-CF3-enones. The second one is a reduction of nitro group by NH4HCO2-Pd/C system followed by intramolecular cyclization to 2-CF3-3-benzylindoles in up to quantitative yields. High selectivity and the reaction yield of all steps are the distinct advantages of the method. Combining the experimental observations and the data of the NMR monitoring of the reaction mixtures, possible scheme of the transformation is evaluated and discussed.

Supplementary Materials

Copy of all 1H, 13C and 19F NMR spectra are available online.

Author Contributions

Conceptualization, V.M.M. and V.G.N.; methodology, V.M.M.; validation, V.M.M.; formal analysis, V.M.M.; investigation, V.M.M. and Z.A.S.; writing—original draft preparation, V.M.M.; writing—review and editing, V.M.M., Z.A.S.; and V.G.N.; visualization, V.M.M.; supervision, V.M.M.; project administration, V.G.N.; funding acquisition, V.G.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by RUSSIAN SCIENCE FOUNDATION, grant number 18-13-00136.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in Supplementary Materials.

Acknowledgments

The authors acknowledge partial support from M.V. Lomonosov Moscow State University Program of Development.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3 and 4 are available from the authors.

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Molecules 26 05084 g001 550
Figure 1. Indole based marketed drugs.
Figure 1. Indole based marketed drugs.
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Molecules 26 05084 g002 550
Figure 2. Approaches to 2-CF3-3-benzylindoles.
Figure 2. Approaches to 2-CF3-3-benzylindoles.
Molecules 26 05084 g002
Molecules 26 05084 sch001 550
Scheme 1. Synthesis of α-(2-nitroaryl)-β-aryl-CF3-enones 3.
Scheme 1. Synthesis of α-(2-nitroaryl)-β-aryl-CF3-enones 3.
Molecules 26 05084 sch001
Molecules 26 05084 sch002 550
Scheme 2. Reduction of ketone 3a in various conditions.
Scheme 2. Reduction of ketone 3a in various conditions.
Molecules 26 05084 sch002
Molecules 26 05084 sch003 550
Scheme 3. Mechanism of transformation of 3a into indoles 4a and 6a.
Scheme 3. Mechanism of transformation of 3a into indoles 4a and 6a.
Molecules 26 05084 sch003
Molecules 26 05084 sch004 550
Scheme 4. Synthesis of 2-CF3-3-benzylindoles 4.
Scheme 4. Synthesis of 2-CF3-3-benzylindoles 4.
Molecules 26 05084 sch004
Molecules 26 05084 sch005 550
Scheme 5. Reduction of ketones 3, having heterocyclic substituents.
Scheme 5. Reduction of ketones 3, having heterocyclic substituents.
Molecules 26 05084 sch005
Table
Table 1. Reduction of ketone 3a in various conditions.
Table 1. Reduction of ketone 3a in various conditions.
Title 1Reaction ConditionsYield of 4a, %Yield of 5a, %Yield of 6a, %
entry 16 eq. Zn, AcOH, 80 °C, 4h2047-
entry 212 eq. Zn, AcOH, 80 °C, 14h433-
entry 36 eq. Zn, AcOH-MeOH, 65 °C, 8h8277
entry 4H2, MeOH, 5 mol% Pd/C, r.t., 1 day89-<1
entry 55 eq. NH4HCO2, MeOH,
5 mol% Pd/C, r.t., 60 °C, 1 h		91-<1
entry 65 eq. NH4HCO2, MeOH,
5 mol% Pd/C, r.t., 1 day		99--
entry 73.3 equiv. NH4HCO2, MeOH,
5 mol% Pd/C, 60 °C, 1 h		<1-86
entry 83.3 equiv. NH4HCO2, THF,
5 mol% Pd/C, r.t., 1 day; then pTSA, MeOH		traces-81
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Muzalevskiy, V.M.; Sizova, Z.A.; Nenajdenko, V.G. An Efficient Synthesis of 2-CF3-3-Benzylindoles. Molecules 2021, 26, 5084. https://doi.org/10.3390/molecules26165084

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Muzalevskiy VM, Sizova ZA, Nenajdenko VG. An Efficient Synthesis of 2-CF3-3-Benzylindoles. Molecules. 2021; 26(16):5084. https://doi.org/10.3390/molecules26165084

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Muzalevskiy, Vasiliy M., Zoia A. Sizova, and Valentine G. Nenajdenko. 2021. "An Efficient Synthesis of 2-CF3-3-Benzylindoles" Molecules 26, no. 16: 5084. https://doi.org/10.3390/molecules26165084

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