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19 March 2019

Cu(II)-Catalyzed Oxidative Trifluoromethylation of Indoles with KF as the Base

,
,
and
1
Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
2
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266000, China
3
State Key Laboratory of Microbial Technology, Shandong University, No. 72 Binhai Road, Qingdao 266237, China
4
University of Chinese Academy of Sciences, Beijing 100049, China
Catalysts2019, 9(3), 278;https://doi.org/10.3390/catal9030278
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Abstract

This paper offers an efficient copper-catalyzed oxidative trifluoromethylation of indoles with low-cost CF3SO2Na via C–H activation. Notably, the use of a base is crucial for the trifluoromethylation of indoles. This reaction proceeds efficiently in good to excellent yields and is tolerance of a broad range of functional groups. Furthermore, melatonin, a medicine for sleep disorders, is converted to its 2-CF3 analogue in 68% yield. Studies of possible reaction pathways suggest that this reaction proceeds through a radical process.

1. Introduction

The trifluoromethyl group is a privileged motif of medicinal chemistry, as it can dramatically improve the binding selectivity, solubility, lipophilicity, and catabolic stability of drug candidates [1,2,3,4,5]. As a consequence, the development of new methods for the synthesis of trifluoromethylated arenes and heteroarenes has received substantial attention [6,7,8,9,10,11,12,13]. In 2010, Sodeoka reported a Cu(OAc)-catalyzed trifluoromethylation of indoles using expensive and sensitive Togni reagent as the trifluoromethyl source (Scheme 1a) [14]. However, this method is limited to dry solvents and expensive trifluoromethyl sources, and it requires long reaction times. Therefore, the identification of an alternative inexpensive and readily available trifluoromethylation agent is actively being pursued in current research [15,16,17,18,19,20,21]. A seminal advance in this area was developed by Langlois who reported a novel trifluoromethyl source, CF3SO2Na (Langlois reagent). Although the study was restricted to electron-rich subtrates, it greatly extended the field of trifluoromethylation chemistry [22]. Subsequently, Li et al. described the photoinduced trifluoromethylation of arenes with CF3SO2Na as the trifluoromethyl source (Scheme 1b) [23]. Very recently, the Baran group also extended the substrate scope to heterocycles with the trifluoromethyl salt in the absence of a metal catalyst; however, the reaction took 3–24 h (Scheme 1c) [24].
Scheme 1. Synthetic procedures for trifluoromethylation of arenes and heteroarenes.
Based on these procedures, we envisioned that CF3SO2Na is suitable for the trifluoromethylation of substituted indoles. Herein, we report an enhanced oxidative trifluoromethylation of unactivated indoles through a radical-mediated mechanism with commercially available CF3SO2Na as the trifluoromethyl source and KF as the base (Scheme 1d).

2. Results

At the start of our work, the experiment of 3-methyl-1H-indole (1a) with CF3SO2Na (2) under various conditions was investigated (Table 1). To our delight, the C2-trifluoromethylated indole was obtained in a 39% yield with CuI as a catalyst and tBuOOH (tert-butyl hydroperoxide, 70% solution in H2O) as the oxidant at 85 °C (Table 1, entry 1). Subsequently, we evaluated different catalyses, and Cu(II) appeared dramatically on the reaction, giving 3a in 55% yield (entries 1–5). The screening of other oxidants revealed that tBuOOH was the best oxidant (entries 6–8). The effects of different solvents were compared, and the desired trifluoromethylated product was obtained in a 62% total yield in DMA (dimethylacetamide) (entries 9–15). Moreover, we were pleased to find that the presence of a base slightly improved the yield of this reaction, and KF provided a satisfying yield (entries 16–18). Additionally, by carefully adjusting the amount of KF, the yield was further improved, and the reaction gave desired product 3a in 86% isolated yield (entry 19). Finally, performing the reaction at room temperature diminished the reaction rate and yield (entry 20).
Table 1. Optimization of the reaction conditions a.
With the optimized reaction conditions in hand, we explored the substrate scope. Our initial studies were focused on the reactions of 3-substituted and N-substituted indoles (Figure 1). To our satisfaction, a range of functional groups, such as linear alkyl groups, cyclic alkanes, esters, and amides, were tolerated in this reaction and provided the desired products in 47–86% (3a–3j). Notably, substrates with strong electron-withdrawing groups, such as halides and cyano, at the C3 position also reacted efficiently to give 3k and 3l in 45% and 58% yields respectively. Although the trifluoromethylation of N-benzyl indole required 12 h, it afforded the corresponding trifluoromethylated indole (3o) an excellent yield (70%).
Figure 1. Reaction scope of the 3-indoles and the N-indoles a. a Conditions: 1 (0.5 mmol), 2 (1.5 mmol), CuSO4 (10 mol %), tBuOOH (2.5 mmol), KF (50 mol%), DMA (3.0 mL), 85 °C, 1 h, under Ar. Isolated yield. b reaction time: 12 h.
Furthermore, a variety of substrates with functional groups on the benzene ring were also screened (Figure 2). Generally, a wide range of functional groups, such as fluoro, chloro, bromo, and methoxy, were compatible with this protocol (4a–4p). In particular, halides, such as F, Cl, and Br, were well-tolerated, affording the C2-trifluoromethylated indoles in good to excellent yields (53–83%). Moreover, the newly developed protocol was successfully applied to the late-stage trifluoromethylation of complex or bioactive substances (4q–4s). Notably, melatonin, a medicine for sleep disorders, was directly converted to its 2-CF3 analogue, 4s, in 68% yield using the optimized conditions.
Figure 2. Reaction scope of functional indoles a. a Conditions: 1 (0.5 mmol), 2 (1.5 mmol), CuSO4 (10 mol %), tBuOOH (2.5 mmol), KF (50 mol%), dimethylacetamide (DMA) (3.0 mL), 85 °C, 1 h, under Ar. Isolated yield. b Yield based on 1H NMR.
To elucidate the mechanism of this reaction, radical scavenger experiments were conducted (Scheme 2). When a radical inhibitor, including TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and BHT (butylated hydroxytoluene), was added, the reaction was dramatically suppressed, implying that a radical reaction pathway might be involved in the catalytic cycle.
Scheme 2. Mechanistic study. BHT: butylated hydroxytoluene; TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy.
Based on the above results and previous literature, a plausible mechanistic interpretation is depicted in Scheme 3 [22,24,25,26,27,28,29,30,31]. Initially, CF3SO2− reacts with tBuOOH to form •CF3 (A). Alternatively, A could also be derived from CF3SO2− and tBuO• (B). Subsequently, in situ-generated •CF3 species A adds to indole 1, affording radical intermediate C. Thereafter, intermediate D is formed by the oxidation of the Cu(II) catalyst, which regenerates the Cu(I) catalyst. Following deprotonation, D reacts with base to give the expected products 3 and 4. In addition, the Cu(I) catalyst is oxidized to Cu(II) by tBuOOH to complete the catalytic cycle.
Scheme 3. Proposed mechanism study.

3. Materials and Methods

1H NMR spectra were recorded on Bruker 500 MHz spectrometer and the chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; m, multiplet; q, quartet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were obtained at Bruker 125 MHz and referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3). The NMR yield was determined by 1H NMR using CH2Br2 as an internal standard. APEX II (Bruker Inc.) was used for ESI-HRMS. 19F NMR spectra were recorded on Bruker 470 MHz spectrometer (see Supplementary Materials). IR spectra were recorded by a Nicolet 5MX-S infrared spectrometer. Flash column chromatography was performed over silica gel 200–300. All reagents were weighed and handled in air at room temperature. All chemical reagents were purchased from Alfa, Acros, Aldrich, and TCI, J&K and used without further purification.
A dry Schlenk tube was charged with 1 (0.5 mmol), 2 (1.5 mmol), CuSO4 (12.5 mg, 10 mol%) and KF (14.7 mg, 50 mol%). DMA (dimethylacetamide, 3.0 mL) was added under argon, and the mixture was stirred at room temperature. tert-Butyl hydroperoxide (tBuOOH, 70% solution in H2O, 2.5 mmol) was dropped into the mixture under argon at room temperature. The resulting mixture was stirred at 85 °C for 1 h. Once the mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether) to give product 3 or 4.
3-Methyl-2-(trifluoromethyl)-1H-indole (3a) (86 mg, 86%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 3391, 2921, 2803, 1452, 1257, 1077, 1030, 754, 715 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.20 (t, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 135.2, 128.0, 124.7, 124.3 (q, JC-F = 262.5 Hz), 121.6 (q, J2 = 37.5 Hz), 120.4, 120.1, 114.0 (q, J3 = 3.0 Hz) 111.5, 8.3; 19F NMR (470 MHz, CDCl3) δ −58.6 (d, J = 1.1 Hz); HRMS (ESI) calcd. for C10H7NF3 [M − H]−, 198.0536; found: 198.0538.
Dimethyl 2-(2-(2-(trifluoromethyl)-1H-indol-3-yl)ethyl)malonate (3b). (117 mg, 68%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:40, Rf = 0.3); IR (neat): νmax 3394, 2923, 2843, 1724, 1260, 1111, 1078, 908, 730 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.60 Hz, 1H), 7.20 (t, 1H), 3.75 (s, 6H), 3.45 (t, J = 7.3 Hz, 1H), 2.30–2.95 (m, 2H), 2.35–2.25 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 169.6, 135.3, 127.1, 124.8, 122.0 (q, JC-F = 267.3 Hz), 121.7 (q, J2 = 36.8 Hz), 120.6, 120.1, 116.7 (q, J3 = 3.0 Hz), 111.8, 52.5, 51.1, 29.6, 21.5; 19F NMR (470 MHz, CDCl3) δ −58.3 (s); HRMS (ESI) calcd. for C16H15O4NF3 [M − H]−, 342.0959; found: 342.0956; HRMS (ESI) calcd. for C16H15O4NF3 [M − H]−, 342.0959; found: 342.0956.
Diethyl 2-(2-(2-(trifluoromethyl)-1H-indol-3-yl)ethyl)malonate (3c). (97 mg, 52%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:40, Rf = 0.3); IR (neat): νmax 3371, 2993, 2863, 1721, 1260, 1161, 1118, 908, 732 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.40 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.20 (t, 1H), 4.30–4.15 (m, 4H), 3.45 (t, J = 7.3 Hz, 1H), 3.00–2.90 (m, 2H), 2.35–2.20 (m, 2H), 1.30 (t, J = 7.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 169.28, 135.27, 127.16, 124.78, 121.9 (q, JC-F = 267.4 Hz), 121.6 (q, J2 = 36.8 Hz), 120.57, 120.17, 116.9 (q, J3 = 2.6 Hz), 111.73, 61.47, 51.57, 29.60, 21.57, 13.98; 19F NMR (470 MHz, CDCl3) δ −58.3 (s); HRMS (ESI) calcd. for C18H19O4NF3 [M − H]−, 370.1272; found: 370.1280.
Methyl 3-(2-(trifluoromethyl)-1H-indol-3-yl)propanoate (3d). (61 mg, 47%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 3386, 2943, 2822, 1324, 1261, 1106, 1076, 747, 725 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.35–7.25 (m, 2H), 7.25–7.20 (m, 1H), 3.95 (s, 2H), 3.70 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 135.1, 127.2, 124.9, 123.8 (q, JC-F = 267.4 Hz), 122.8 (q, J2 = 36.9 Hz), 121.0, 120.0, 111.8, 110.2 (q, J3 = 2.8 Hz), 52.2, 29.6; 19F NMR (470 MHz, CDCl3) δ −58.6 (s); HRMS (ESI) calcd. for C12H9O2NF3 [M − H]−, 256.0591; found: 256.0588.
Ethyl 3-(2-(trifluoromethyl)-1H-indol-3-yl)propanoate (3e). (93 mg, 72%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:40, Rf = 0.3); IR (neat): νmax 3321, 2823, 1323, 1146, 1097, 1052, 741, 726 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.20 (t, 1H), 3.70 (t, J = 7.7 Hz, 2H), 3.55 (q, J = 7.0 Hz, 2H), 3.25–3.15 (m, 2H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 135.2, 127.6, 124.7, 122.1 (q, J2 = 36.5 Hz), 122.0 (q, JC-F = 267.4 Hz), 120.5, 120.3, 114.9 (q, J3 = 3.0 Hz), 111.7, 70.6, 66.2, 24.6, 15.1; 19F NMR (470 MHz, CDCl3) δ −58.3 (s); HRMS (ESI) calcd. for C12H9O2NF3 [M − H]−, 256.0955; found: 256.0954.
3-Cyclohexyl-2-(trifluoromethyl)-1H-indole (3f). (72 mg, 54%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:40, Rf = 0.3); IR (neat): νmax 3387, 2922, 2823, 1318, 1249, 1115, 1082, 740, 705 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 3.00 (t, J = 12.1 Hz, 1H), 2.00–1.80 (m, 8H), 1.50–1.40 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 135.4, 126.3, 124.3, 123.9 (q, J3 = 3.0 Hz), 122.2, 122.1 (q, JC-F = 267.3 Hz), 120.5 (q, J2 = 36.0 Hz), 120.0, 111.9, 36.2, 32.8, 27.0, 26.2; 19F NMR (470 MHz, CDCl3) δ −57.5 (s); HRMS (ESI) calcd. for C15H15NF3 [M − H]−, 266.1162; found: 266.1163.
2-(2-(Trifluoromethyl)-1H-indol-3-yl)ethyl acetate (3g). (75 mg, 55%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:40, Rf = 0.3); IR (neat): νmax 3361, 2954, 1719, 1160, 1086, 1037, 907, 731 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3, 0.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.20 (t, 1H), 4.30 (t, J = 6.9 Hz, 2H), 3.25 (t, 2H), 2.00 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 135.2, 127.3, 124.8, 122.4 (q, J2 = 36.5 Hz), 121.9 (q, JC-F = 267.4 Hz), 120.7, 113.8 (q, J3 = 2.9 Hz), 111.8, 64.1, 23.4, 20.9; 19F NMR (470 MHz, CDCl3) δ −58.3 (s); HRMS (ESI) calcd. for C13H11O2NF3 [M − H]−, 270.0747; found: 270.0745.
1-(2-(Trifluoromethyl)-1H-indol-3-yl)propan-2-one (3h). (105 mg, 87%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:10, Rf = 0.3); IR (neat): νmax 3389, 2933, 2823, 1703, 1253, 1109, 1074, 740, 725 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.34–7.29 (m, 1H), 7.20–7.15 (m, 1H), 3.98 (s, 2H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 205.9, 135.3, 127.2, 126.0, 125.1, 124.0 (q, JC-F = 267.5 Hz), 123.1 (q, J3 = 3.4 Hz), 122.7 (q, J2 = 36.8 Hz), 121.1, 120.0, 112.0, 39.3, 28.9; 19F NMR (470 MHz, CDCl3) δ −58.3 (s); HRMS (ESI) calcd. for C12H9ONF3 [M − H]−, 240.0642; found: 240.0639.
Tert-butyl (2-(2-(trifluoromethyl)-1H-indol-3-yl)ethyl)carbamate (3i). (87 mg, 53%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:5, Rf = 0.3); IR (neat): νmax 3351, 2961, 2853, 1688, 1250, 1111, 1083, 732 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 6.6 Hz, 1H), 4.65 (s, 1H), 3.45 (s, 2H), 3.10 (s, 2H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.0, 135.4, 127.4, 124.7, 122.3 (q, J2 = 36.4 Hz), 122.0 (q, JC-F = 267.5 Hz), 120.5, 120.2, 115.0 (q, J3 = 3.0 Hz), 111.8, 79.3, 41.1, 28.3, 24.4; 19F NMR (470 MHz, CDCl3) δ −57.9 (s); HRMS (ESI) calcd. for C16H18O2N2F3 [M − H]−, 327.1326; found: 327.1322.
N-(2-(2-(trifluoromethyl)-1H-indol-3-yl)ethyl)acetamide (3j). (78 mg, 58%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:1, Rf = 0.3); IR (neat): νmax 3309, 2923, 2813, 1051, 1024, 1005, 820, 757 cm−1; 1H NMR (500 MHz, DMSO) δ 11.90 (s, 1H), 8.00 (t, J = 5.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 5.75 (s, 1H), 3.30–3.25 (m, 2H), 3.00 (t, J = 7.1 Hz, 2H), 1.75 (s, 3H); 13C NMR (125 MHz, DMSO) δ 169.2, 135.8, 126.9, 124.4, 122.4 (q, JC-F = 267.4 Hz), 121.2 (q, J2 = 36.0 Hz), 120.0, 117.9, 114.6 (q, J3 = 2.8 Hz), 112.4, 24.0, 22.7, 22.6; 19F NMR (470 MHz, DMSO) δ −56.5 (s); HRMS (ESI) calcd. for C13H14ON2F3 [M + H]+, 271.1053; found: 271.1057.
3-(2-Bromoethyl)-2-(trifluoromethyl)-1H-indole (3k). (66 mg, 45%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 3388, 2932, 2860, 1313, 1251, 1109, 1068, 741, 727 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.25–7.20 (m, 1H), 3.60–3.55 (m, 2H), 3.50–3.45 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 135.1, 126.9, 125.1, 122.2 (q, J2 = 36.9 Hz), 121.7 (q, JC-F = 267.5 Hz), 120.9, 119.9, 115.3 (q, J3 = 2.8 Hz), 111.8, 31.3, 27.7; 19F NMR (470 MHz, CDCl3) δ −58.3 (s); HRMS (ESI) calcd. for C11H8NBrF3 [M − H]−, 289.9798; found: 289.9792.
2-(2-(Trifluoromethyl)-1H-indol-3-yl)acetonitrile (3l). (65 mg, 58%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:10, Rf = 0.3); IR (neat): νmax 3396, 2995, 2873, 1328, 1161, 1133, 1073, 740, 618 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30–7.25 (m, 1H), 4.00 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 135.0, 125.9, 125.6, 122.8 (q, J2 = 37.5 Hz), 121.7, 121.2 (q, JC-F = 267.6 Hz),119.4, 116.8, 112.2, 105.5 (q, J3 = 2.5 Hz), 12.7; 19F NMR (470 MHz, CDCl3) δ −58.5 (s); HRMS (ESI) calcd. for C11H6N2F3 [M − H]−, 223.0489; found: 223.0489.
Tert-butyl 3-methyl-2-(trifluoromethyl)-1H-indole-1-carboxylate (3m). (117 mg, 78%). Isolated by flash column chromatography (petroleum ether, Rf = 0.3); IR (neat): νmax 2921, 2873, 1738, 1324, 1126, 1087, 743, 731 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.45–7.40 (m, 1H), 7.35–7.30 (m, 1H), 2.45 (q, J = 2.9 Hz, 3H), 1.65 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 149.0, 136.8, 128.6, 127.2, 123.0, 122.2 (q, J2 = 36.9 Hz), 121.9 (q, JC-F = 267.9 Hz), 119.9, 115.4, 111.5 (q, J3 = 3.0 Hz), 85.0, 29.7, 27.8; 19F NMR (470 MHz, CDCl3) δ −54.1 (d, J = 2.9 Hz); HRMS (ESI) calcd. for C15H16O2NF3K [M + K]+, 338.0770; found: 338.0773.
1-Benzyl-3-methyl-2-(trifluoromethyl)-1H-indole (3n). (78 mg, 54%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 2911, 1428, 1270, 1163, 1098, 1046, 737, 695 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 7.9 Hz, 1H), 7.30–7.25 (m, 3H), 7.25–7.20 (m, 3H), 7.00 (d, J = 7.2 Hz, 2H), 5.45 (s, 2H), 2.55–2.50 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 137.6, 137.4, 128.8, 128.6, 127.3, 125.8, 125.5, 124.9, 122.7 (q, JC-F = 268.3 Hz),122.7 (q, J2 = 34.9 Hz), 120.3, 114.9 (q, J3 = 2.9 Hz), 114.9, 110.5, 48.1, 29.7; 19F NMR (470 MHz, CDCl3) δ −55.1 (d, J = 1.6 Hz); HRMS (ESI) calcd. for C17H15NF3 [M + H]+, 290.1078; found: 290.1070.
(3-Methyl-2-(trifluoromethyl)-1H-indol-1-yl)(phenyl)methanone (3o). (106 mg, 70%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 2925, 2886, 1708, 1322, 1125, 1020, 711, 665 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.90–7.85 (m, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.25–7.20 (m, 1H), 7.15 (t, J = 7.7 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 2.55–2.50 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 168.5, 136.8, 134.1, 133.9, 130.3, 129.0, 128.8, 126.2, 124.3 (q, J2 = 37.0 Hz), 123.8 (q, JC-F = 271.1 Hz), 122.9 (q, J3 = 2.8 Hz), 122.7, 120.3, 113.7, 29.7; 19F NMR (470 MHz, CDCl3) δ −54.4 (d, J = 2.1 Hz); HRMS (ESI) calcd. for C17H11ONF3 [M − H]−, 302.0798; found: 302.0793.
4-Fluoro-3-methyl-2-(trifluoromethyl)-1H-indole (4a). (79 mg, 73%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 2204, 1165, 1118, 1054, 1027, 909, 731 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.20–7.15 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 11.0, 7.9 Hz, 1H), 2.55 (d, J = 1.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 159.2, 157.2, 137.5 (d, J = 10.9 Hz), 125.3 (d, J = 8.0 Hz), 121.7 (q, JC-F = 267.3 Hz), 121.6 (q, J2 = 36.5 Hz), 113.0 (q, J3 = 3.0 Hz), 107.6 (d, J = 4.0 Hz), 105.5 (d, J = 19.1 Hz), 9.9 (d, J = 2.9 Hz); 19F NMR (470 MHz, CDCl3) δ −58.8 (d, J = 1.3 Hz), -123.3 (dd, J = 11.1, 4.7 Hz); HRMS (ESI) calcd. for C10H6NF4 [M − H]−, 216.0442; found: 216.0443.
N-benzyl-N-methyl-3-phenylprop-2-yn-1-amine (4b). (81 mg, 58%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 1253, 1181, 1162, 1120, 1027, 908, 734 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.35–7.30 (m, 2H), 7.10 (t, J = 7.9 Hz, 1H), 2.70 (dd, J = 3.3, 1.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 136.2, 125.9, 125.3, 125.1, 122.9 (q, J2 = 36.1 Hz), 121.8 (q, JC-F = 267.5 Hz),115.9, 115.2 (q, J3 = 2.9 Hz), 111.0, 10.7; 19F NMR (470 MHz, CDCl3) δ −58.6 (d, J = 0.9 Hz); HRMS (ESI) calcd. for C10H6NBrF3 [M − H]−, 275.9641; found: 275.9644.
4-Methoxy-3-methyl-2-(trifluoromethyl)-1H-indole (4c). (62 mg, 54%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 3402, 2927, 2813, 1311, 1251, 1165, 1120 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 3.90 (s, 3H), 2.60 (dd, J = 3.6, 1.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 156.1, 136.7, 125.5, 121.1 (q, JC-F = 266.8 Hz), 120.1 (q, J2 = 36.4 Hz), 118.1, 114.9 (q, J3 = 3.1 Hz), 104.5, 100.1, 55.1, 10.5; 19F NMR (470 MHz, CDCl3) δ −58.4 (d, J = 1.3 Hz); HRMS (ESI) calcd. for C11H9ONF3 [M − H]−, 228.0642; found: 228.0641.
5-Chloro-3-methyl-2-(trifluoromethyl)-1H-indole (4d). (78 mg, 67%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 3396, 2995, 2874, 1445, 1251, 1094, 1025, 797, 720, 592 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.30–7.25 (m, 2H), 2.40 (dd, J = 3.4, 1.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 133.43, 129.06, 126.12, 125.17, 122.8 (q, J2 = 36.9 Hz), 121.7 (q, JC-F = 267.4 Hz), 119.57, 113.6 (q, J3 = 2.9 Hz), 112.69, 8.2; 19F NMR (470 MHz, CDCl3) δ −58.9 (d, J = 1.3 Hz); HRMS (ESI) calcd. for C10H6NClF3 [M − H]−, 232.0146; found: 232.0148.
5-Bromo-3-methyl-2-(trifluoromethyl)-1H-indole (4e). (113 mg, 81%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 3520, 2988, 2873, 1317, 1105, 1047, 1023, 793, 718 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.75 (s, 1H), 7.40 (dd, J = 8.7, 1.4 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 2.40 (d, J = 1.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 133.7, 129.7, 127.7, 122.8, 122.3 (q, J2 = 36.8 Hz), 121.7 (q, JC-F = 272.9 Hz), 113.6, 113.5 (q, J3 = 3.1 Hz), 113.1, 8.2; 19F NMR (470 MHz, CDCl3) δ −58.9 (d, J = 1.3 Hz); HRMS (ESI) calcd. for C10H6NBrF3 [M − H]−, 275.9641; found: 275.9645.
5-Methoxy-3-methyl-2-(trifluoromethyl)-1H-indole (4f). (66 mg, 58%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 3367, 2911, 2823, 1469, 1165, 1067, 1018, 840, 798, 725, 701, 624 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.30–7.25 (m, 1H), 7.00 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 3.90 (d, J = 0.9 Hz, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 154.5, 130.3, 128.4, 122.1 (q, J2 = 36.8 Hz), 122.0 (q, JC-F = 267.1 Hz), 115.6, 113.5 (q, J3 = 3.1 Hz), 112.5, 100.9, 55.8, 8.4; 19F NMR (470 MHz, CDCl3) δ −58.7 (d, J = 1.3 Hz); HRMS (ESI) calcd. for C11H9ONF3 [M − H]−, 228.0642; found: 228.0640.
6-Fluoro-3-methyl-2-(trifluoromethyl)-1H-indole (4g). (68 mg, 63%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 1318, 1258, 1118, 1027, 734 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.55 (dd, J = 8.7, 5.3 Hz, 1H), 7.05 (dd, J = 9.3, 2.1 Hz, 1H), 7.00–6.90 (m, 1H), 2.40 (dd, J = 3.6, 1.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.4 (d, J = 239.8 Hz), 135.2 (d, J = 13.3 Hz), 124.7, 121.9 (q, JC-F = 266.9 Hz), 121.8 (q, J2 = 36.6 Hz), 121.2 (d, J = 10.4 Hz), 114.3 (q, J3 = 2.8 Hz), 109.6 (d, J = 24.9 Hz), 97.7 (d, J = 26.4 Hz), 8.3; 19F NMR (470 MHz, CDCl3) δ −58.8 (d, J = 1.0 Hz), -117.1 (td, J = 9.4, 5.3 Hz); HRMS (ESI) calcd. for C10H6NF4 [M − H]−, 216.0442; found: 216.0441.
6-Chloro-3-methyl-2-(trifluoromethyl)-1H-indole (4h). (89 mg, 76%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 2223, 1052, 1025, 1007, 751, 726 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.5, 1.8 Hz, 1H), 2.40 (dd, J = 3.6, 1.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 135.4, 130.7, 126.6, 121.8 (q, JC-F = 267.1 Hz), 122.1 (q, J2 = 36.8 Hz), 121.3, 121.1, 114.2 (q, J3 = 3.0 Hz), 111.4, 8.2; 19F NMR (470 MHz, CDCl3) δ −58.9 (d, J = 1.3 Hz); HRMS (ESI) calcd. for C10H6NClF3 [M − H]−, 232.0146; found: 232.0146.
6-Methoxy-3-methyl-2-(trifluoromethyl)-1H-indole (4i). (74 mg, 65%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 2343, 1053, 1025, 1006, 819, 757, 727 cm−1; 1H NMR (500 MHz, DMSO) δ 11.60 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 6.85 (s, 1H), 6.75 (dd, J = 8.8, 1.9 Hz, 1H), 3.80 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz, DMSO) δ 157.7, 136.7, 122.7 (q, JC-F = 266.5 Hz), 121.6, 120.8, 119.2 (q, J2 = 35.8 Hz), 112.7 (q, J3 = 3.1 Hz), 110.9, 94.1, 55.3, 8.3; 19F NMR (470 MHz, DMSO) δ −56.4 (d, J = 1.5 Hz); HRMS (ESI) calcd. for C11H9ONF3 [M − H]−, 228.0642; found: 228.0641.
7-Fluoro-3-methyl-2-(trifluoromethyl)-1H-indole (4j). (74 mg, 68%). Isolated by flash column chromatography (petroleum ether, Rf = 0.3); IR (neat): νmax 2287, 1052, 1026, 1007, 908, 723 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.15–7.05 (m, 1H), 7.05 (dd, J = 10.8, 7.8 Hz, 1H), 2.45 (dd, J = 3.5, 1.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 149.5 (d, J = 244.4 Hz), 131.6 (d, J = 4.9 Hz), 123.9 (q, JC-F = 267.5 Hz), 122.4 (q, J2 = 36.6 Hz), 120.7 (d, J = 5.9 Hz), 115.8 (d, J = 3.6 Hz), 114.7 (q, J3 = 2.8 Hz), 109.3 (d, J = 15.6 Hz), 107.8 (d, J = 16.3 Hz), 8.5; 19F NMR (470 MHz, CDCl3) δ −59.0 (d, J = 1.0 Hz), -134.7 (dd, J = 11.0, 4.7 Hz); HRMS (ESI) calcd. for C10H6NF4 [M − H]−, 216.0442; found: 216.0442.
7-Chloro-3-methyl-2-(trifluoromethyl)-1H-indole (4k). (76 mg, 65%). Isolated by flash column chromatography (petroleum ether, Rf = 0.3); IR (neat): νmax 1313, 1164, 1119, 1027, 734 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 132.6, 129.3, 124.0, 122.3 (q, J2 = 37.0 Hz), 121.7 (q, JC-F = 267.4 Hz), 121.2, 118.7, 117.0, 115.1 (q, J3 = 2.9 Hz), 8.5; 19F NMR (470 MHz, CDCl3) δ −58.9 (d, J = 1.2 Hz); HRMS (ESI) calcd. for C10H6NClF3 [M − H]−, 232.0146; found: 232.0146.
7-Bromo-3-methyl-2-(trifluoromethyl)-1H-indole (4l). (99 mg, 71%). Isolated by flash column chromatography (petroleum ether, Rf = 0.3); IR (neat): νmax 3471, 2931, 2813, 1580, 1328, 1115, 908, 779, 731 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 2.45 (dd, J = 3.4, 1.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 134.0, 129.0, 127.0, 122.2 (q, J2 = 36.8 Hz), 121.7 (q, JC-F = 267.3 Hz), 121.5, 119.3, 115.2 (q, J3 = 3.0 Hz), 105.0, 8.6; 19F NMR (470 MHz, CDCl3) δ −58.8 (d, J = 1.1 Hz); HRMS (ESI) calcd. for C10H6NBrF3 [M − H]−, 275.9641; found: 275.9643.
7-Methoxy-3-methyl-2-(trifluoromethyl)-1H-indole (4m). (61 mg, 53%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 3411, 2918, 2806, 1265, 1161, 1109, 733 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.40 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 3.95 (s, 3H), 2.45–2.40 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 146.3, 129.3, 126.1, 122.1 (q, JC-F = 267.0 Hz), 121.3 (q, J2 = 36.8 Hz), 120.8, 114.3 (q, J3 = 2.9 Hz), 112.4, 103.9, 55.4, 8.5; 19F NMR (470 MHz, CDCl3) δ −58.7 (s); HRMS (ESI) calcd. for C11H9ONF3 [M − H]−, 228.0642; found: 228.0646.
5-Fluoro-3-methyl-2-(trifluoromethyl)-1H-indole (4n). (90 mg, 83%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 3393, 2921, 2863, 1325, 1169, 1109, 1026, 852, 796, 728 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.31 (dd, J = 8.9, 4.2 Hz, 1H), 7.27 (dd, J = 8.9, 2.5 Hz, 1H), 7.08 (td, J = 9.0, 2.4 Hz, 1H), 2.41–2.38 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 159.0, 157.1, 131.6, 128.5, 128.4, 123.2 (q, J2 = 36.8 Hz), 121.8 (q, JC-F = 267.4 Hz), 114.0 (q, J3 = 3.0 Hz), 113.7, 113.5, 112.6, 112.5, 104.9, 104.7, 8.3; 19F NMR (470 MHz, CDCl3) δ −58.96 (d, J = 1.4 Hz), -123.0 (td, J = 9.1, 4.2 Hz); HRMS (ESI) calcd. for C10H6NF4 [M − H]−, 216.0442; found: 216.0442.
6-Bromo-3-methyl-2-(trifluoromethyl)-1H-indole (4o). (39 mg, 28%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:100, Rf = 0.3); IR (neat): νmax 3390, 2901, 2862, 1325, 1172, 1109, 1022, 842, 728 cm−1; 1H NMR (500 MHz, CDCl3) 1H NMR (500 MHz, cdcl3) δ 8.18 (s, 1H), 7.53 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 1.6 Hz, 1H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) 13C NMR (126 MHz, cdcl3) δ 135.77, 126.94, 123.89, 122.0 (q, J2 = 36.9 Hz), 121.8 (q, JC-F = 267.3 Hz) 121.39, 118.39, 114.45, 114.2 (q, J3 = 2.9 Hz), 8.24; 19F NMR (470 MHz, CDCl3) δ −58.96 (d, J = 1.4 Hz), -123.0 (td, J = 9.1, 4.2 Hz); HRMS (ESI) calcd. for C10H6NF4 [M − H]−, 275.9641; found: 275.964.
2-(7-Ethyl-2-(trifluoromethyl)-1H-indol-3-yl)ethyl acetate (4q). (105 mg, 70%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:50, Rf = 0.3); IR (neat): νmax 3397, 2998, 2883, 1723, 1253, 1163, 1117, 908, 732 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.60–7.55 (m, 1H), 7.20–7.15 (m, 2H), 4.30 (dd, J = 9.1, 4.8 Hz, 2H), 3.25 (td, J = 6.9, 1.1 Hz, 2H), 2.90 (q, J = 7.6 Hz, 2H), 2.00 (s, 3H), 1.40 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 134.3, 129.8, 127.2, 123.2, 122.1 (q, J2 = 36.6 Hz), 122.0 (q, JC-F = 267.3 Hz), 121.1, 117.7, 114.4 (q, J3 = 2.8 Hz), 65.6, 64.1, 23.6, 20.9, 13.6; 19F NMR (470 MHz, CDCl3) δ −58.1 (s); HRMS (ESI) calcd. for C15H15O2NF3 [M − H]−, 298.1060; found: 298.1055.
2-(5-Methoxy-2-(trifluoromethyl)-1H-indol-3-yl)acetonitrile (4r). (54 mg, 42%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:10, Rf = 0.3); IR (neat): νmax 3389, 1052, 1024, 1005, 820, 757, 624, 558 cm−1; 1H NMR (500 MHz, DMSO) δ 12.30 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.00 (d, J = 8.9 Hz, 1H), 4.25 (s, 2H), 3.80 (s, 3H); 13C NMR (125 MHz, DMSO) δ 154.6, 130.7, 126.2, 122.2 (q, J2 = 36.8 Hz), 121.8 (q, JC-F = 267.5 Hz), 118.5, 116.3, 113.7, 105.4 (q, J3 = 2.3 Hz), 100.4, 55.6, 12.0; 19F NMR (470 MHz, DMSO) δ −56.9 (s); HRMS (ESI) calcd. for C12H8ON2F3 [M − H]−, 253.0594; found: 253.0591.
N-(2-(5-methoxy-2-(trifluoromethyl)-1H-indol-3-yl)ethyl)acetamide (4s) [24]. (102 mg, 68%). Isolated by flash column chromatography (ethyl acetate/petroleum ether = 1:10, Rf = 0.3); 1H NMR (500 MHz, DMSO) δ 12.30 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.00 (d, J = 8.9 Hz, 1H), 4.25 (s, 2H), 3.80 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 154.7, 130.6, 127.7, 122.7 (q, J2 = 36.4 Hz), 121.9 (q, JC-F = 267.3 Hz), 116.0, 114.3 (q, J3 = 2.8 Hz), 112.9, 100.5, 55.7, 40.0, 23.9, 23.2; 19F NMR (470 MHz, DMSO) δ −57.9 (s); HRMS (ESI) calcd. for C14H14O2N2F3 [M − H]−, 299.1013; found: 299.1009.

4. Conclusions

In conclusion, we have demonstrated a new application of KF as a base to promote the trifluoromethylation of electron-deficient and electron-rich indoles via C-H activation. Compared with previous works, this method features broad functional group tolerance, shorter reaction times, and a less expensive trifluoromethylating agent. This methodology allows the construction of a variety of bioactive molecules containing C2-trifluoromethylated indole moieties. The value of this strategy has been highlighted via the trifluoromethylation of melatonin in 68% yield. Preliminary mechanistic studies indicate that the reaction pathway may proceed through a radical process involving a Cu(II)/Cu(I) redox process.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/9/3/278/s1.

Author Contributions

X.S., X.L. and D.S. designed the project. X.S. performed the experiments. X.S., X.L. and L.M. analyzed the data. X.S. wrote the manuscript.

Funding

This work was supported by the Funded by National Natural Science Foundation of China (No. 81773586, 81703354), Key research and development project of Shandong province (2016GSF201193, 2016ZDJS07A13, 2016GSF115002, 2016GSF115009), Key Research Program of Frontier Sciences, CAS (QYZDB-SSW-DQC014), the Project of Discovery, Evaluation and Transformation of Active Natural Compounds, Strategic Biological Resources Service Network Program of Chinese Academy of Sciences (ZSTH-026), Shandong Provincial Natural Science Foundation for Distinguished Young Scholars (JQ201722), National Program for Support of Top-notch Young Professionals, and Taishan scholar Youth Project of Shandong province.

Conflicts of Interest

The authors declare no conflict of interest.

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