Next Article in Journal
Development and Validation of a Method for Determination of 43 Antimicrobial Drugs in Western-Style Pork Products by UPLC-MS/MS with the Aid of Experimental Design
Previous Article in Journal
Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
Previous Article in Special Issue
Synthetic Optimizations for Gram-Scale Preparation of 1-O-Methyl d-Glycero-α-d-gluco-heptoside 7-Phosphate from d-Glucose
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 23
10.3390/molecules27238281
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Boron Trifluoride Etherate Promoted Regioselective 3-Acylation of Indoles with Anhydrides

by
Yunyun Zheng
,
Jiuling Li
* and
Kai Wei
*
Henan Engineering Research Center of Funiu Mountain’s Medical Resources Utilization and Molecular Medicine, School of Medical Sciences, Pingdingshan University, Pingdingshan 467000, China
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(23), 8281; https://doi.org/10.3390/molecules27238281
Submission received: 5 November 2022 / Revised: 22 November 2022 / Accepted: 23 November 2022 / Published: 28 November 2022
(This article belongs to the Special Issue New Synthetic Methods towards Biologically Relevant Compounds)
Browse Figures
Review Reports Versions Notes

Abstract

:
An efficient, high-yielding and scalable procedure for the regioselective 3-acylation of indoles with anhydrides promoted by boron trifluoride etherate under mild conditions was reported. This novel protocol provided a simple way to prepare 3-(benzofuran-2-yl) indole in three steps.

Graphical Abstract

1. Introduction

The indole and its derivatives are versatile structural motifs in organic and medicinal chemistry [1,2,3,4,5,6,7,8,9], which have been regarded as “privileged fragments” in biologically active natural products and pharmaceutical compounds. Among them, 3-acylindole moiety has not only been found to act as a proven pharmacophore element in bioactive molecules such as Analogue, Bruceolline and so on [10,11,12,13,14,15,16,17,18,19] (Figure 1), but has also served as a versatile intermediate in the synthesis of indole derivatives [20,21,22,23,24,25,26,27,28,29,30]. For examples, an analogue of deoxytopsentin displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity [14]. Oxi8006 is one of the first indole-based, colchicine-site-binding inhibitors of tubulin assembly into microtubules. OXi8006 is a potent inhibitor of tubulin polymerization (IC50 = 1.1 μM) and competes with radiolabeled colchicine at the colchicine binding site of tubulin. OXi8006 was shown to be cytotoxic against three evaluated human cancer cell lines, NCI-H460, DU-145 and SK-OV-3, with an average GI50 of 25.7 nM [18,19]. Consequently, developing a more efficient and practical protocol for the synthesis of 3-acylindoles has gained considerable attention [31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46].
Regioselective functionalization of indoles is one of the most important challenges in the field of indole chemistry, especially in the acylation of free (N-H) indoles. Though many strategies, such as the metal-catalyzed intramolecular oxidative coupling reaction for the preparation of 3-acylindoles, have been developed in recent decades [31,32,33,34,35,36,37], the requirement for expensive and complex ligands and mental catalysts in this novel protocol make few of them suitable for lab or industrial preparation today. The Friedel–Crafts reaction was still regarded as the most promising, practical and convenient protocol [38,39,40,41,42]. AlCl3 [38,39,40], SnCl4 [40], TiCl4 [40], ZrCl4 [41] dialkylaluminum chloride [43,44,45,46] were the most commonly used reagents to promote acylation due to their easy availability and high reactivity. However, these common Lewis acids suffered from some limitations. Some of them required additional protection and deprotection steps to eliminate 1-acylation and 1,3-diacylation [41]. In the above developed methods, most of the reagents were poor-moisture-tolerant and air-sensitive, and the presence of a metal ion resulted in a laborious and frustrated workup. In addition, most of the metal ions are toxic and must be carefully removed from the products, especially for the drug and pharmaceutical industry. Additionally, environmental awareness has also made them not preferred in this transformation, especially in the large-scale processes. The application of more environmentally benign solid Lewis acids or Brønsted acidic ionic liquids such as modified zeolites or bisulfate in this acylation process have also been reported [47,48], but only very limited substrates have been used, and the preparation of the Brønsted acidic ionic liquid was more complex than the commercial reagents. Accordingly, a metal-free, more environmentally benign regioselective acylation procedure to prepare 3-acylindoles under mild reaction conditions and simple workup is highly desirable.
Herein, we report a high regioselective and scalable protocol (Scheme 1) for the 3-acylatation of indoles with anhydrides in the presence of boron trifluoride etherate, a very common and easy-to-handle Lewis acid that has been widely used in organic reactions [49].

2. Results and Discussion

At the beginning of our studies, acylation of indole 1a with acetic anhydride 2a in different solvents in the presence of BF3·Et2O was explored (Table 1, entries 1–6). We found that the acylation reaction could occur in DCM, DCE, CHCl3, MeCN or 1,4-dioxane, and that DCM gave the best results (Table 1, entry 1). Then, the amount of BF3·Et2O (Table 1, entries 7–10) and anhydride (Table 1, entries 11–13) were investigated, which revealed that when the ratio of indole, anhydride and BF3·Et2O was 1:1.2:1, the yield of 3-acylindole 3aa achieved 83% (Table 1, entry 12). Another important point is that in the absence of BF3·Et2O (entry 7), no desired product was achieved. Further screening of the reaction temperature showed that room temperature was the best choice (Table 1, entries 14–15).
With the optimal reaction conditions, the aliphatic, alicyclic and aryl anhydrides were subjected to investigate the scope of anhydrides in the acylation reaction. The results are summarized in Table 2. The aliphatic, alicyclic and aryl anhydrides could react with indole 1a smoothly to furnish the desired products 3 in good-to-excellent yields (Table 2, entries 1–6). However, no desired products were observed for 4-chloro and 4-nitro benzoic anhydrides, perhaps due to the solubility of anhydrides in DCM (Table 2, entries 7–8).
To test the scope of the present protocols, various substituents at different positions of indole ring, including the 1- and 2-substitued indoles, were investigated. As shown in Table 3, both electron-donating and electron-withdrawing substituents in indoles gave the corresponding 3-acylindoles in good-to-excellent yields (from 53% to 93%). The position of the substituents and the electronic nature on the indole ring did not play important roles; only the indoles with electron-withdrawing groups afforded a slightly better yield. The 1-methylindole (1b entry1–4) and 2-phenyl-1H-indole (1d entry9–12) needed a longer time to finish the reaction. From Table 3, we can see the aliphatic anhydrides usually gave higher yields than the aryl ones. Furthermore, the structure of the 3-acylation products 3ec was further confirmed by X-ray diffraction analysis (see Supplementary Materials).
Compared with the aforementioned protocols promoted by the common Lewis acids or dialkylaluminum chloride, the more moisture-tolerant, air-stable and easy-to-handle BF3·Et2O provided an efficient entry to 3-acylindoles. It is also worth noting that when the acylation of indole 1a with acetic anhydride was carried out on more than a 10 g (0.1 mol, 11.7 g) scale, the 3-acylation reaction still provided 80% yield (Scheme 2), which would lead these compounds to be applied more easily.
3-Benzofuranyl indoles are one of the most important scaffolds in heterocycle chemistry [50,51,52]. The popular methods to synthesize these compounds are the transition-metal catalyzed cross-coupling reaction, which suffered from limited substrates, requirement of complex ligands, and trace amounts of metals in the products [50,51], and preparation via the Sc(OTf)3-mediated Meinwald epoxide rearrangement of benzofuran-2-yl oxirane with aryl-hydrazine [52]. During the studies of O-arylation and [3,3]-rearrangement with diaryliodonium salts in our group [53,54], we surmised that 3-benzofuran-2-yl indole could be synthesized easily from 3aa (Scheme 3). Firstly, 3aa was converted to the oxime 4, which further underwent a C-O formation with diphenyliodonium triflate to give the O-phenyl-oxime 5 which could undergo a [3,3]-rearrangement in acid condition [55] to accomplish the 3-benzofuranyl indoles 6 with 67% yield.

3. Experimental Section

Unless otherwise noted, all reactions were performed under air atmosphere, and commercial materials and solvents were used directly without further purification. All reagents were weighed and handled in air at room temperature. 1H-NMR and 13C-NMR spectra were recorded on Bruker Avance 400 and 600 spectrometers. Chemical shifts are reported in parts per million (δ) referenced to tetramethylsilane (0.0 ppm), chloroform (7.26 ppm or 77.0 ppm) and DMSO (2.5 ppm or 39.5 ppm), respectively. Data for 1H-NMR and 13C-NMR spectroscopy are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant (Hz), integration. X-ray single crystal diffraction data were recorded on Bruker D8 QUEST and Bruker APEX DUO. High Resolution Mass spectra were taken on an AB QSTAR Pulsar mass spectrometer or Aglient LC/MSD TOF mass spectrometer. Melting points were measured on a Hanon MP 430 auto melting-point system and are uncorrected. Silica gel (200–300 mesh) for column chromatography and silica GF254 for TLC were obtained from Merck Chemicals Co. Ltd. (Shanghai, China). Petroleum ether with the boiling range of 60–90 °C was used for column chromatography. All reactions were conducted in dried glassware under a positive pressure of dry nitrogen or argon. Reagents and starting materials were accordingly transferred via syringe or cannula. Reaction temperatures refer to the external oil bath temperature and are uncorrected. Conditional optimization and copies of spectroscopic characterization of all new compounds are available in the Supplementary Materials.

3.1. General Procedure for the Synthesis of Product (3aa–3jd)

A mixture of indole 1 (0.5 mmol), anhydride 2 (0.6 mmol), and BF3·Et2O (BF3 46.5%) (0.5 mmol, 64 μL) in DCM was stirred at room temperature for the desired time. After the reaction was completed, saturated sodium bicarbonate (10 mL) was added. The reaction mixture was stirred for 5 min and then extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and, after evaporation of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel using petroleum ether/EtOAc (6:1 to 2:1) as the eluents to give product 3.
1-(1H-Indol-3-yl)ethanone (3aa). Pale yellow solid; 66 mg, 83% yield, m.p. 195–196 °C (lit. 192–193 °C); [41] 1H NMR (500 MHz, DMSO-d6) δ = 11.94 (s, 1H), 8.31 (s, 1H), 8.21–8.14 (m, 1H), 7.50–7.42 (m, 1H), 7.23–7.15 (m, 2H), 2.45 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.1, 137.1, 134.7, 125.7, 123.1, 122.1, 121.82, 117.3, 112.5, 27.7. HRMS (ESI): m/z [M+H]+ calcd for C10H10NO: 160.0757; found: 160.0761.
1-(1H-Indol-3-yl)propan-1-one (3ab). White solid; 79 mg, 91% yield, m.p. 161–162 °C (lit. 162–163 °C) [39]; 1H NMR (500 MHz, DMSO-d6) δ = 11.91 (s, 1H), 8.31 (d, J = 3.1 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.23–7.13 (m, 2H), 2.88 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.3, 137.1, 133.9, 125.9, 123.1, 122.0, 121.8, 116.5, 112.5, 32.3, 9.6. HRMS (ESI): m/z [M+H]+ calcd for C11H12NO: 174.0913; found: 174.0915.
1-(1H-Indol-3-yl)butan-1-one (3ac). White solid; 80 mg, 85% yield, m.p. 176–177 °C (lit. 181–182 °C) [56]; 1H NMR (500 MHz, DMSO-d6) δ = 11.91 (s, 1H), 8.33 (d, J = 3.1 Hz, 1H), 8.20 (d, J = 7.1 Hz, 1H), 7.51–7.43 (m, 1H), 7.22–7.15 (m, 2H), 2.82 (t, J = 7.3 Hz, 2H), 1.71–1.63 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 195.8, 137.1, 134.2, 125.9, 123.1, 122.0, 121.9, 117.0, 112.5, 41.2, 18.8, 14.4. HRMS (ESI): m/z [M+H]+ calcd for C12H14NO: 188.1070; found: 188.1068.
Cyclohexyl(1H-indol-3-yl)methanone (3ad). White solid; 82 mg, 72% yield, m.p. 194–195 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.92 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.48–7.46 (m, 1H), 7.22–7.16 (m, 2H), 3.21–3.16 (m, 1H), 1.80–1.76 (m, 4H), 1.69 (d, J = 12.8 Hz, 1H), 1.50–1.37 (m, 4H), 1.25–1.16 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 199.3, 137.3, 133.9, 126.2, 123.1, 122.0, 121.9, 115.6, 112.5, 46.6, 30.2, 26.2, 25.8. HRMS (ESI): m/z [M+H]+ calcd for C15H18NO: 228.1383; found: 228.1385.
(1H-Indol-3-yl)(phenyl)methanone (3ae). Pale yellow solid; 84 mg, 76% yield, m.p. 223–224 °C (lit. 243–245 °C) [41]; 1H NMR (500 MHz, DMSO-d6) δ = 12.10 (s, 1H), 8.26 (d, J = 7.3 Hz, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7.80–7.70 (m, 2H), 7.63–7.60 (m, 1H), 7.57–7.52 (m, 3H), 7.29–7.22 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ = 190.5, 140.9, 137.2, 136.3, 131.6, 128.9, 128.8, 126.7, 123.6, 122.4, 121.9, 115.5, 112.7. HRMS (ESI): m/z [M+H]+ calcd for C15H12NO: 222.0913; found: 222.0911.
(1H-Indol-3-yl)(4-methoxyphenyl)methanone (3af). Pale yellow solid; 100 mg, 80% yield, m.p. 205–206 °C (lit. 208 °C) [57]; 1H NMR (500 MHz, DMSO-d6) δ = 12.01 (s, 1H), 8.23 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7.83–7.80 (m, 2H), 7.53–7.51 (m, 1H), 7.26–7.21 (m, 2H), 7.09–7.06 (m, 2H), 3.86 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 189.2, 162.2, 137.1, 135.3, 133.45, 131.1, 126.9, 123.4, 122.1, 121.9, 115.6, 114.1, 112.6, 55.9. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO2: 252.1019; found: 252.1018.
(1H-Indol-3-yl)(m-tolyl)methanone (3ag). Pale yellow solid; 83 mg, 71% yield, m.p. 234–236 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.05 (s, 1H), 8.27 (d, J = 7.1 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.62–7.57 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.44–7.40 (m, 2H), 7.29–7.22 (m, 2H), 2.41 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ = 190.6, 141.1, 138.2, 137.2, 136.1, 132.1, 129.3, 128.7, 126.7, 126.1, 123.6, 122.3, 122.0, 115.6, 112.7, 21.5. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO: 236.1070; found: 236.1071.
1-(1-Methyl-1H-indol-3-yl)ethanone (3ba). White solid; 75 mg, 87% yield, m.p. 102–103 °C (lit. 105–107 °C) [58]; 1H NMR (500 MHz, DMSO-d6) δ = 8.32 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.30–7.26 (m, 1H), 7.25–7.21 (m, 1H), 3.86 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 192.5, 138.4, 138.4, 137.7, 126.2, 123.2, 122.4, 121.9, 116.1, 110.9, 33.5, 27.7. HRMS (ESI): m/z [M+H]+ calcd for C11H12NO: 174.0913; found: 174.0919.
1-(1-Methyl-1H-indol-3-yl)propan-1-one (3bb). White solid; 77 mg, 82% yield, m.p. 72–73 °C; 1H NMR (500 MHz, DMSO-d6) δ = 8.33 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.30–7.25 (m, 1H), 7.25–7.21 (m, 1H), 3.86 (s, 3H), 2.84 (q, J = 7.4 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 195.7, 137.7, 137.6, 126.3, 123.1, 122.4, 121.9, 115.3, 110.9, 33.5, 32.4, 9.6. HRMS (ESI): m/z [M+H]+ calcd for C12H14NO: 188.1070; found: 188.1073.
1-(1-Methyl-1H-indol-3-yl)butan-1-one (3bc). Brown oil; 71 mg, 71% yield; 1H NMR (500 MHz, DMSO-d6) δ = 8.30 (d, J = 2.4 Hz, 1H), 8.28–8.24 (m, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.29–7.20 (m, 2H), 3.84 (d, J = 2.6 Hz, 3H), 2.80–2.75 (m, 2H), 1.72–1.64 (m, 2H), 0.97–0.91 (m, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 195.5, 137.9, 137.7, 126.3, 123.2, 122.4, 122.0, 115.8, 110.9, 41.3, 33.5, 18.8, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C13H16NO: 202.1226; found: 202.1228.
(1-Methyl-1H-indol-3-yl)(phenyl)methanone (3bd). White solid; 62 mg, 53% yield, m.p. 110–111 °C (lit. 116–118 °C) [41]; 1H NMR (500 MHz, DMSO-d6) δ = 8.29 (d, J = 7.5 Hz, 1H), 8.02 (s, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.79–7.78 (m, 1H), 7.64–7.56 (m, 3H), 7.56–7.53 (m, 1H), 7.36–7.33 (m, 1H), 7.32–7.28 (m, 1H), 3.89 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 189.9, 141.0, 139.9, 137.8, 131.5, 128.9, 128.8, 127.1, 123.7, 122.8, 122.1, 114.3, 111.1, 33.6. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO: 236.1070; found: 236.1074.
1-(2-Methyl-1H-indol-3-yl)ethanone (3ca). White solid; 59 mg, 68% yield, m.p. 203–204 °C (lit. 201–202 °C) [59]; 1H NMR (500 MHz, DMSO-d6) δ = 11.84 (s, 1H), 8.04–7.99 (m, 1H), 7.39–7.34 (m, 1H), 7.16–7.11 (m, 2H), 2.68 (s, 3H), 2.51 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.4, 144.6, 135.1, 127.4, 122.2, 121.7, 121.0, 113.9, 111.6, 31.4, 15.4. HRMS (ESI): m/z [M+H]+ calcd for C11H12NO: 174.0913; found: 174.0915.
1-(2-Methyl-1H-indol-3-yl)propan-1-one (3cb). Yellow solid; 66 mg, 71% yield, m.p. 140–141 °C (lit. 150 °C) [60]; 1H NMR (500 MHz, DMSO-d6) δ = 11.82 (s, 1H), 8.03–7.99 (m, 1H), 7.39–7.35 (m, 1H), 7.16–7.11 (m, 2H), 2.90 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.5, 144.3, 135.2, 127.2, 122.1, 121.7, 121.1, 113.4, 111.6, 35.4, 15.6, 8.8. HRMS (ESI): m/z [M+H]+ calcd for C12H14NO: 188.7070; found: 188.1076.
1-(2-Methyl-1H-indol-3-yl)butan-1-one (3cc). White solid; 75 mg, 74% yield, m.p. 143–144 °C (lit. 157–158 °C) [60]; 1H NMR (500 MHz, DMSO-d6) δ = 11.82 (s, 1H), 8.02–7.97 (m, 1H), 7.39–7.34 (m, 1H), 7.17–7.09 (m, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.67 (h, J = 7.3 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 195.9, 144.3, 135.2, 127.1, 122.1, 121.7, 121.0, 113.6, 111.6, 44.3, 17.7, 15.6, 14.4. HRMS (ESI): m/z [M+H]+ calcd for C13H16NO: 202.1226; found: 202.1232.
(2-Methyl-1H-indol-3-yl)(phenyl)methanone (3cd). Pale yellow solid; 66,mg, 56% yield, m.p. 180–181 °C (lit. 183–185 °C) [57]; 1H NMR (500 MHz, DMSO-d6) δ = 11.96 (s, 1H), 7.61–7.57 (m, 3H), 7.53–7.48 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.15–7.09 (m, 1H), 7.04–6.98 (m, 1H), 2.38 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 192.2, 145.0, 142.1, 135.4, 131.5, 128.8, 128.5, 127.7, 122.3, 121.4, 120.5, 112.9, 111.7, 14.7. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO: 236.1070; found: 236.1077.
1-(2-Phenyl-1H-indol-3-yl)ethanone (3da). White solid; 74 mg, 62% yield, m.p. 231–232 °C (lit. 220–222 °C) [61]; 1H NMR (500 MHz, DMSO-d6) δ = 12.11 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 3.6 Hz, 2H), 7.56 (d, J = 3.6 Hz, 3H), 7.42 (d, J = 7.7 Hz, 1H), 7.25–7.18 (m, 2H), 2.07 (s, 3H); 13CNMR (125 MHz, DMSO-d6)δ = 194.0, 145.4, 135.9, 133.2, 130.5, 129.8, 128.9, 127.5, 123.3, 122.20, 122.0, 114.7, 112.0, 30.6. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO: 236.1070; found: 236.1068.
1-(2-Phenyl-1H-indol-3-yl)propan-1-one (3db). White solid; 80 mg, 65% yield, m.p. 192–193 °C (lit. 189 °C) [62]; 1H NMR (500 MHz, DMSO-d6) δ = 12.07 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.65–7.61 (m, 2H), 7.59–7.54 (m, 3H), 7.42 (dd, J = 7.1, 1.2 Hz, 1H), 7.25–7.17 (m, 2H), 2.42 (q, J = 7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 197.5, 144.6, 135.9, 133.4, 130.28, 129.7, 128.9, 127.5, 123.2, 122.1, 122.0, 114.2, 112.0, 34.8, 9.3. HRMS (ESI): m/z [M+H]+ calcd for C17H16NO: 250.1226; found: 250.1232.
1-(2-Phenyl-1H-indol-3-yl)butan-1-one (3dc). White solid; 92 mg, 70% yield, m.p. 168–169 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.08 (s, 1H), 8.18 (dd, J = 7.0, 1.4 Hz, 1H), 7.65–7.61 (m, 2H), 7.58–7.55 (m, 3H), 7.43 (dd, J = 7.0, 1.0 Hz, 1H), 7.21 (ddd, J = 9.1, 7.5, 1.3 Hz, 2H), 2.38 (t, J = 7.3 Hz, 2H), 1.48 (h, J = 7.4 Hz, 2H), 0.69 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 197.2, 144.7, 135.9, 133.4, 130.3, 129.7, 128.9, 127.5, 123.2, 122.1, 122.0, 114.6, 112.1, 43.6, 18.5, 14.1. HRMS (ESI): m/z [M+H]+ calcd for C18H18NO: 264.1383; found: 264.1381.
Phenyl(2-phenyl-1H-indol-3-yl)methanone (3dd). White solid; 88 mg, 59% yield, m.p. 231–232 °C (lit. 223–224 °C) [63]; 1H NMR (500 MHz, DMSO-d6) δ = 12.22 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.54–7.50 (m, 3H), 7.40–7.37 (m, 2H), 7.37–7.34 (m, 1H), 7.27–7.23 (m, 4H), 7.23–7.19 (m, 2H), 7.18–7.14 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 192.6, 144.5, 140.3, 136.3, 132.0, 131.8, 130.0, 129.5, 128.9, 128.7, 128.5, 128.2, 123.3, 121.9, 121.0, 112.6, 112.3. HRMS (ESI): m/z [M+H]+ calcd for C21H16NO: 298.1226; found: 298.1224.
1-(5-Bromo-1H-indol-3-yl)ethanone (3ea). White solid; 103 mg, 87% yield, m.p. 220–221 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.13 (s, 1H), 8.38 (d, J = 3.1 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 8.6, 2.0 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.2, 136.0, 135.9, 127.5, 125.8, 123.9, 116.7, 114.9, 114.7, 27.6. HRMS (ESI): m/z [M+H]+ calcd for C10H9BrNO: 237.9862; found: 237.9860.
1-(5-Bromo-1H-indol-3-yl)propan-1-one (3eb). White solid; 117 mg, 93% yield, m.p. 230–231 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.10 (s, 1H), 8.38 (d, J = 2.9 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 8.6, 2.0 Hz, 1H), 2.88 (q, J = 7.4 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.4, 135.8, 135.2, 127.7, 125.7, 123.9, 115.92, 114.9, 114.6, 32.3, 9.4. HRMS (ESI): m/z [M+H]+ calcd for C11H11BrNO: 22.0019; found: 252.0020.
1-(5-Bromo-1H-indol-3-yl)butan-1-one (3ec). White solid; 111 mg, 84% yield, m.p. 232–233 °C (lit. 160–161 °C) [64]; 1H NMR (500 MHz, DMSO-d6) δ = 12.12 (s, 1H), 8.40 (d, J = 3.1 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.6, 2.0 Hz, 1H), 2.82 (t, J = 7.3 Hz, 2H), 1.66 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13CNMR (125 MHz, DMSO-d6) δ = 195.9, 135.8, 135.4, 127.6, 125.7, 124.0, 116.4, 114.9, 114.6, 41.1, 18.7, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C12H13BrNO: 266.0715; found: 266.0720.
(5-Bromo-1H-indol-3-yl)(phenyl)methanone (3ed). White solid; 105 mg, 79% yield, m.p. 272–273 °C (lit. 265–267 °C) [41]; 1H NMR (500 MHz, DMSO-d6) δ = 12.26 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 8.6, 1.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 190.3, 140.5, 137.3, 136.0, 131.8, 129.0, 128.9, 128.5, 126.2, 124.1, 115.2, 114.9, 114.8. HRMS (ESI): m/z [M+H]+ calcd for C15H11BrNO: 300.0019; found: 300.0021.
3-Acetyl-1H-indole-5-carbonitrile (3fa). White solid; 86 mg, 93% yield, m.p. 271–272 °C (lit. 295–296 °C) [39]; 1H NMR (500 MHz, DMSO-d6) δ = 12.43 (s, 1H), 8.54 (s, 1H), 8.53 (d, J = 0.9 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 2.49 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.3, 138.9, 136.9, 126.8, 126.1, 125.5, 120.6, 117.4, 114.0, 104.4, 27.7. HRMS (ESI): m/z [M+H]+ calcd for C11H9N2O: 185.0709; found: 185.0714.
3-Propionyl-1H-indole-5-carbonitrile (3fb). White solid; 90 mg, 91% yield, m.p. 259–260 °C (lit. 252–254 °C) [39]; 1H NMR (500 MHz, DMSO-d6) δ = 12.41 (s, 1H), 8.55 (d, J = 0.9 Hz, 1H), 8.54 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 2.92 (q, J = 7.3 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.5, 138.9, 136.2, 126.8, 126.0, 125.6, 120.7, 116.6, 114.0, 104.3, 32.4, 9.2. HRMS (ESI): m/z [M+H]+ calcd for C12H11N2O: 199.0866; found: 199.0861.
3-Butyryl-1H-indole-5-carbonitrile (3fc). White solid; 93 mg, 88% yield, m.p. 209–210 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.42 (s, 1H), 8.56 (d, J = 2.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.4, 1.5 Hz, 1H), 2.86 (t, J = 7.3 Hz, 2H), 1.71–1.63(m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.1, 138.9, 136.5, 126.9, 126.1, 125.6, 120.7, 117.1, 114.1, 104.3, 41.2, 18.5, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C13H13N2O: 213.1022; found: 213.1020.
3-Benzoyl-1H-indole-5-carbonitrile (3fd). White solid; 65 mg, 53% yield, m.p. 202–204 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.56 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.74–7.69 (m, 1H), 7.67–7.62 (m, 2H), 7.59–7.54 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ = 190.3, 140.2, 139.1, 138.4, 132.1, 129.0, 128.9, 126.0, 127.58, 126.6, 120.6, 115.6, 114.3, 104.6. HRMS (ESI): m/z [M+H]+ calcd for C16H11N2O: 247.0866; found: 247.0870.
1-(5-Methyl-1H-indol-3-yl)ethanone (3ga). Pale yellow solid; 76 mg, 88% yield, m.p. 190–191 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.82 (s, 1H), 8.25 (d, J = 3.1 Hz, 1H), 7.99 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.03 (dd, J = 8.2, 1.4 Hz, 1H), 2.43 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.0, 135.5, 134.8, 130.8, 126.0, 124.6, 121.5, 116.8, 112.2, 27.7, 21.8. HRMS (ESI): m/z [M+H]+ calcd for C11H12NO: 174.0913; found: 174.0920.
1-(5-Methyl-1H-indol-3-yl)propan-1-one (3gb). Pale yellow solid; 78 mg, 83% yield, m.p. 225–226 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.78 (s, 1H), 8.25 (d, J = 3.1 Hz, 1H), 8.00 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.3, 1.4 Hz, 1H), 2.85 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.3, 135.4, 133.9, 130.8, 126.2, 124.6, 121.6, 116.1, 112.1, 32.3, 21.8, 9.7. HRMS (ESI): m/z [M+H]+ calcd for C12H14NO: 188.1070; found: 188.1076.
1-(5-Methyl-1H-indol-3-yl)butan-1-one (3gc). Yellow solid; 76 mg, 76% yield, m.p. 195–196 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.79 (s, 1H), 8.26 (d, J = 3.1 Hz, 1H), 8.01 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.02 (dd, J = 8.3, 1.2 Hz, 1H), 2.79 (t, J = 7.3 Hz, 2H), 2.40 (s, 3H), 1.70–1.62 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13CNMR (125 MHz, DMSO-d6) δ = 195.8, 135.4, 134.1, 130.8, 126.2, 124.6, 121.1, 116.6, 112.1, 41.1, 21.8, 18.9, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C13H16NO: 202.1226; found: 202.1225.
(5-Methyl-1H-indol-3-yl)(phenyl)methanone (3gd). White solid; 79 mg, 67% yield, m.p. 227–228 °C (lit. 228 °C) [56]; 1H NMR (500 MHz, DMSO-d6) δ = 11.97 (s, 1H), 8.09 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.79–7.78 (m, 1H), 7.77–7.76 (m, 1H), 7.62–7.58 (m, 1H), 7.56–7.52 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.10 (dd, J = 8.3, 1.5 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 190.4, 141.1, 136.2, 135.5, 131.4, 131.2, 128.8, 128.8, 127.0, 125.1, 121.7, 115.1, 112.3, 21.8. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO: 236.1070; found: 236.1074.
1-(5-Methoxy-1H-indol-3-yl)ethanone (3ha). Pale yellow solid; 76 mg, 80% yield, m.p. 209–210 °C (lit. 170 °C) [65]; 1H NMR (500 MHz, DMSO-d6) δ = 11.81 (s, 1H), 8.25 (d, J = 3.1 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.6 Hz, 1H), 3.77 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 193.0, 155.8, 135.0, 132.0, 126.5, 117.1, 113.2, 113.0, 103.5, 55.7, 27.6. HRMS (ESI): m/z [M+H]+ calcd for C11H12NO2: 190.0863; found: 190.0860.
1-(5-Methoxy-1H-indol-3-yl)propan-1-one (3hb). Yellow solid; 76 mg, 75% yield, m.p. 202–203 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.78 (s, 1H), 8.25 (d, J = 3.2 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.5 Hz, 1H), 3.78 (s, 3H), 2.85 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.3, 155.8, 134.1, 131.9, 126.7, 116.3, 113.2, 113.0, 103.6, 55.7, 32.2, 9.6. HRMS (ESI): m/z [M+H]+ calcd for C12H14NO2: 204.1019; found: 204.1022.
1-(5-Methoxy-1H-indol-3-yl)butan-1-one (3hc). Yellow solid; 74 mg, 68% yield, m.p. 151–152 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.80 (s, 1H), 8.26 (d, J = 3.1 Hz, 1H), 7.72 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.6 Hz, 1H), 3.78 (s, 3H), 2.79 (t, J = 7.3 Hz, 2H), 1.69–1.63 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 195.8, 155.8, 134.3, 131.9, 126.6, 116.8, 113.2, 113.1, 103.5, 55.7, 41.1, 18.8, 14.4. HRMS (ESI): m/z [M+H]+ calcd for C13H16NO2: 218.1176; found: 218.1180.
(5-Methoxy-1H-indol-3-yl)(phenyl)methanone (3hd). Pale yellow solid; 80 mg, 64% yield, m.p. 213–215 °C (lit. 169–170 °C) [66]; 1H NMR (500 MHz, DMSO-d6) δ = 11.97 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 1.0 Hz, 1H), 7.77–7.62 (m, 1H), 7.62–7.58 (m, 1H), 7.57–7.52 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.6 Hz, 1H), 3.81 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 190.4, 156.0, 141.1, 136.4, 132.0, 131.4, 128.9, 128.8, 127.5, 115.3, 113.5, 113.5, 103.7, 55.8. HRMS (ESI): m/z [M+H]+ calcd for C16H14NO2: 252.1019; found: 252.1020.
1-(6-Fluoro-1H-indol-3-yl)ethanone (3ia). Pale yellow solid; 81 mg, 92% yield, m.p. 227–228 °C (lit. 236 °C) [67]; 1H NMR (500 MHz, DMSO-d6) δ = 11.98 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 8.15 (dd, J = 8.7, 5.7 Hz, 1H), 7.26 (dd, J = 9.7, 2.4 Hz, 1H), 7.06–7.02 (m, 1H), 2.44 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.09, 159.68 (d, J = 235.0 Hz), 137.16 (d, J = 12.5 Hz), 135.5, 122.9 (d, J = 10.0 Hz), 122.4, 117.2, 110.4 (d, J = 23.8 Hz), 98.8 (d, J = 25.0 Hz), 27.6. HRMS (ESI): m/z [M+H]+ calcd for C10H9FNO: 178.0663; found: 178.0666.
1-(6-Fluoro-1H-indol-3-yl)propan-1-one (3ib). Pale yellow solid; 84 mg, 88% yield, m.p. 215–216 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.95 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 8.17 (dd, J = 8.7, 5.7 Hz, 1H), 7.25 (dd, J = 9.7, 2.3 Hz, 1H), 7.07–7.01 (m, 1H), 2.87 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.3, 159.7 (d, J = 235.0 Hz), 137.1 (d, J = 12.5 Hz), 134.6 (d, J = 1.3 Hz), 122.9 (d, J = 10.0 Hz), 122.6, 116.4, 110.3, (d, J = 23.7 Hz), 98.7 (d, J = 25.0 Hz), 32.2, 9.5. HRMS (ESI): m/z [M+H]+ calcd for C11H11FNO: 192.0819; found: 192.0823.
1-(6-Fluoro-1H-indol-3-yl)butan-1-one (3ic). White solid; 83 mg, 81% yield, m.p. 190–191 °C; 1H NMR (500 MHz, DMSO-d6) δ = 11.97 (s, 1H), 8.34 (s, 1H), 8.17 (dd, J = 8.7, 5.7 Hz, 1H), 7.25 (dd, J = 9.7, 2.3 Hz, 1H), 7.06–7.01 (m, 1H), 2.81 (t, J = 7.3 Hz, 2H), 1.71–1.59 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 195.8, 159.7 (d, J = 235.0 Hz), 137.2 (d, J = 12.5 Hz), 134.8 (d, J = 1.3 Hz), 123.0 (d, J = 10.0 Hz), 122.6, 116.9, 110.3 (d, J = 23.8 Hz), 98.7 (d, J = 26.3 Hz), 41.0, 18.7, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C12H13FNO: 206.0976; found: 206.0972.
(6-Fluoro-1H-indol-3-yl)(phenyl)methanone (3id). White solid; 80 mg, 67% yield, m.p. 268–269 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.12 (s, 1H), 8.25 (dd, J = 8.7, 5.7 Hz, 1H), 7.96 (d, J = 2.7 Hz, 1H), 7.83–7.77 (m, 2H), 7.64–7.60 (m, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.32 (dd, J = 9.6, 2.3 Hz, 1H), 7.14–7.09 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 190.3, 159.9 (d, J = 236.3 Hz), 140.7, 1373 (d, J = 12.5 Hz), 136.9, 131.6, 128.9 (d, J = 3.8 Hz), 123.1 (d, J = 10.0 Hz), 123.1, 115.4, 110.7 (d, J = 23.8 Hz), 99.0 (d, J = 26.3 Hz). HRMS (ESI): m/z [M+H]+ calcd for C15H11FNO: 240.0819; found: 240.0825.
1-(7-Bromo-1H-indol-3-yl)ethanone (3ja). White solid; 108 mg, 91% yield, m.p. 184–185 °C (lit. 190–191 °C) [67]; 1H NMR (500 MHz, DMSO-d6) δ = 12.19 (s, 1H), 8.37 (s, 1H), 8.19 (dd, J = 7.9, 0.8 Hz, 1H), 7.45 (dd, J = 7.6, 0.8 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 2.48 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 193.4, 135.6, 135.5, 127.4, 125.9, 123.6, 121.2, 118.1, 105.1, 27.9. HRMS (ESI): m/z [M+H]+ calcd for C10H9BrNO: 237.9862; found: 237.9868.
1-(7-Bromo-1H-indol-3-yl)propan-1-one (3jb). White solid; 112 mg, 89% yield, m.p. 148–149 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.16 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.44 (dd, J = 7.6, 0.9 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 2.92 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.6, 135.5, 134.8, 127.6, 125.8, 123.6, 121.3, 117.4, 105.1, 32.4, 9.3. HRMS (ESI): m/z [M+H]+ calcd for C11H11BrNO: 22.0019; found: 252.0016.
1-(7-Bromo-1H-indol-3-yl)butan-1-one (3jc). White solid; 117 mg, 88% yield, m.p. 158–159 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.17 (s, 1H), 8.38 (s, 1H), 8.21 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 2.86 (t, J = 7.3 Hz, 2H), 1.70–1.62 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 196.2, 135.5, 135.0, 127.6, 125.9, 123.6, 121.3, 117.8, 105.1, 41.2, 18.6, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C12H13BrNO: 266.0715; found: 266.0717.
(7-Bromo-1H-indol-3-yl)(phenyl)methanone (3jd). White solid; 123mg, 82% yield, m.p. 204–205 °C; 1H NMR (500 MHz, DMSO-d6) δ = 12.38 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.59–7.54 (m, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 190.5, 140.5, 136.6, 135.6, 131.9, 129.0, 128.9, 128.4, 126.3, 123.9, 121.4, 116.4, 105.2. HRMS (ESI): m/z [M+H]+ calcd for C15H11BrNO: 300.0019; found: 300.0018.

3.2. Up to Ten Scale Synthesis of Selected (3aa)

A total of 11.7 g (0.1 mol) of indole 1 was dissolved in 200 mL of DCM and 12.6 g (12.0 mL, 0.12 mol) of acetic anhydride 2a was added. Then, 14.6 g (0.1 mol) of BF3.Et2O was added dropwise to the stirred mixture at room temperature. After finishing the addition, the reaction mixture was stirred continuously at room temperature until completed. Then, 100 mL of saturated sodium bicarbonate was added and stirred at room temperature for about 0.5 h. The organic layer was separated and the water phase was extracted with DCM (2 × 100 mL). The organic layer was combined, washed with saturated sodium bicarbonate (2 × 100 mL) and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel or recrystallized from MeOH/H2O (5:1) to give 3aa 12.7 g in 80% yield.

3.3. Procedure for Synthesis of 4

A solution of synthesized 3aa (10.0 mmol, 1.59 g), NH2OH·HCl (20.0 mmol, 1.39 g) and pyridine (30.0 mmol, 2.4 mL) in MeOH (30 mL) was stirred at room temperature for about 18~24 h. The reaction mixture was evaporated to remove MeOH in vacuo, and to the residue was then added to water (50 mL). After extraction with DCM (2 × 50 mL), the combined organic layers were washed with brine, dried over Na2SO4, and filtered. Volatiles were removed under vacuum to give the oxime 4 as a white solid without any purification to the next step (1.2 g, 69% yield, m.p. 144–146 °C (lit. 147–148 °C)) [68].

3.4. Procedure for Synthesis of 5

A Schlenk tube was charged with 4 (0.5 mmol, 87 mg), and DCE (5 mL). t-BuOK (0.75 mmol, 1.5 equiv) was added in one portion at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 min. Then, Ph2IOTf (0.75 mmol, 220 mg, 1.5 equiv) was added in one portion. The reaction was stirred at room temperature for 4 h. At this time, the DCE was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 1/6 to 1/3 to provide product 5.
(E)-1-(1H-indol-3-yl)ethanone O-phenyl oxime (5). Yellow oil; 106 mg, yield 85%; 1H NMR (400 MHz, CDCl3) δ = 8.50–8.46 (m, 1H), 8.27 (s, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.42 (s, 2H), 7.41 (s, 2H), 7.37–7.34 (m, 1H), 7.32–7.28 (m, 2H), 7.10–7.04 (m, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 159.9, 155.4, 137.5, 136.8, 130.3, 129.4, 127.5, 126.2, 124.5, 123.4, 121.7, 121.5, 114.7, 113.9, 111.2, 13.6; HRMS (ESI): m/z [M+H]+ calcd for C16H15N2O: 251.1179; found: 251.1171.

3.5. Procedure for Synthesis of 6

A Schlenk tube, open to air, was charged with 5 (0.5 mmol, 125 mg) and 1,4-dioxane (5 mL). A total of 4 M HCl (0.75 mL, 6 equiv) and H2O (0.054 mL, 6 equiv) was added in one portion at room temperature. The mixture was stirred at 80 °C. The reaction was monitored by TLC until 5 was consumed completely (8−12 h). At this time, the solvent was removed under reduced pressure, and the residue was washed with saturated sodium bicarbonate (10 mL). Then, after extraction with DCM (3 × 10 mL), the combined organic layers were dried over Na2SO4 and filtered. DCM was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 1/10 to 1/8 to provide product 6.
3-(Benzofuran-2-yl)-1H-indole (6). White solid; 72 mg, 62% yield, m.p. 147–148 °C (lit. 162–163 °C) [69]; 1H NMR (500 MHz, CDCl3) δ = 8.33 (s, 1H), 8.14–8.08 (m, 1H), 7.71 (s, 1H), 7.63 (dd, J = 5.9, 2.3 Hz, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.45–7.41 (m, 1H), 7.36–7.31 (m, 2H), 7.31–7.27 (m, 2H), 6.97 (s, 1H); 13C NMR (125 MHz, CDCl3) δ = 154.0, 153.0, 136.6, 129.9, 124.6, 123.3, 123.15, 123.06, 122.8, 121.1, 120.34, 120.29, 111.7, 110.8, 108.7, 99.7; HRMS (ESI): m/z [M+H]+ calcd for C16H12NO: 234.0913; found: 234.0916.

4. Conclusions

In conclusion, we have developed a mild and efficient synthetic method for the BF3·Et2O-promoted acylation of free (N-H) indoles with anhydrides. This protocol afforded a variety of 3-acylindoles in good-to-excellent yields with high regioselectivity and was easily up to 10 g scale. 3-Benzofuran-2-yl indole can be synthesized in good yield in three steps. This protocol accomplished the challenging acylation of free (N-H) indoles successfully. Further studies on their synthetic applications are currently underway in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238281/s1, Conditional optimization and copies of spectroscopic characterization of all new compounds, X-ray Single Crystal Diffraction Data of 3ec.

Author Contributions

Data curation, K.W.; formal analysis, Y.Z.; investigation, Y.Z. and K.W.; methodology, Y.Z.; writing—original draft, J.L. and K.W.; writing—review and editing, J.L. and K.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Key Scientific Research Projects in Colleges and Universities of Henan Province (No. 22A150019), the grants from the PhD Research Program of Pingdingshan University (Grant No. PXY-BSDQ-2022038).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

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

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Shiri, M. Indoles in Multicomponent Processes (MCPs). Chem. Rev. 2012, 112, 3508–3549. [Google Scholar] [CrossRef] [PubMed]
  2. Kochanowska, K.; Anna, J.; Hamann, M.T. Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010, 110, 4489–4497. [Google Scholar] [CrossRef] [Green Version]
  3. Humphrey, G.R.; Kuethe, J.T. Practical Methodologies for the Synthesis of Indoles. Chem. Rev. 2006, 106, 2875–2911. [Google Scholar] [CrossRef]
  4. Cacchi, S.; Fabrizi, G. Synthesis and Functionalization of Indoles through Palladium-catalyzed Reactions. Chem. Rev. 2005, 105, 2873. [Google Scholar] [CrossRef] [PubMed]
  5. Horton, D.A.; Bourne, G.T.; Smythe, M.L. The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893–930. [Google Scholar] [CrossRef]
  6. Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J.C. Progress in Palladium-based Catalytic Systems for the Sustainable Synthesis of Annulated Heterocycles: A Focus on Indole Backbones. Chem. Soc. Rev. 2012, 41, 3929–3968. [Google Scholar] [CrossRef] [PubMed]
  7. Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Organocatalytic strategies for the asymmetric functionalization of indoles. Chem. Soc. Rev. 2010, 39, 4449–4465. [Google Scholar] [CrossRef]
  8. Miller, K.A.; Williams, R.M. Synthetic Approaches to the Bicyclo[2.2.2]diazaoctane Ring System Common to the Paraherquamides, Stephacidins and Related Prenylated Indole Alkaloids. Chem. Soc. Rev. 2009, 38, 3160–3174. [Google Scholar] [CrossRef] [Green Version]
  9. Jiang, P.; Chen, S.; Huang, H.; Hu, K.; Xia, Y.; Deng, G.J. Metal-free Synthesis of Indolo[2,3-b]indoles through Aerobic Cascade Dehydrogenative Aromatization/Oxidative Annulation. Green Synth. Catal. 2021, 2, 78–81. [Google Scholar] [CrossRef]
  10. Patil, S.A.; Patil, R.; Miller, D.D. Solid Phase Synthesis of Biologically Important Indoles. Curr. Med. Chem. 2009, 16, 2531–2565. [Google Scholar] [CrossRef]
  11. Golantsov, N.E.; Festa, A.A.; Karchava, A.V.; Yurovskaya, M.A. Marine Indole Alkaloids Containing an 1-(indol-3-yl)ethane-1,2-diamine Fragment (Review). Chem. Heterocycl. Compd. 2013, 49, 203–225. [Google Scholar] [CrossRef]
  12. Ruiz-Sanchis, P.; Savina, S.A.; Albericio, F.; Alvarez, M. Structure, Bioactivity and Synthesis of Natural Products with Hexahydropyrrolo[2,3-b]indole. Chem. Eur. J. 2011, 17, 1388–1408. [Google Scholar] [CrossRef]
  13. Fontana, G. Current Bioactive Azole-Containing Natural Products. Curr. Bioact. Compd. 2010, 6, 284–308. [Google Scholar] [CrossRef]
  14. Veale, C.J.L.; Zoraghi, R.; Young, R.M.; Morrison, J.P.; Pretheeban, M.; Lobb, K.A.; Reiner, N.E.; Anderson, R.J.; Davies-Coleman, M.T. Synthetic Analogues of the Marine Bisindole Deoxytopsentin: Potent Selective Inhibitors of MRSA Pyruvate Kinase. J. Nat. Prod. 2015, 78, 355–362. [Google Scholar] [CrossRef]
  15. Hadimani, M.B.; Macdonough, M.T.; Ghatak, A.; Strecker, T.E.; Lopez, R.; Sriram, M.; Nguyen, B.L.; Hall, J.J.; Kessler, R.J.; Shirali, A.R.; et al. Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent. J. Nat. Prod. 2013, 76, 1668–1678. [Google Scholar] [CrossRef] [Green Version]
  16. Pinney, K.G.; Wang, F.; Del Pilar Mejia, M. Indole-Containing and Combretastatin-Related Anti-Mitotic and Anti-Tubulin Polymerization Agents. WIPO (PCT) Patents WO 2001019794, 22 March 2001. [Google Scholar]
  17. Chen, H.; Bai, J.; Fang, Z.F.; Yu, S.S.; Ma, S.G.; Xu, S.; Li, Y.; Qu, J.; Ren, J.S.; Li, L.; et al. Indole Alkaloids and Quassinoids from the Stems of Brucea mollis. J. Nat. Prod. 2011, 74, 2438–2445. [Google Scholar] [CrossRef]
  18. Rago, A.J.; Dong, G.B. Synthesis of Indoles, Indolines, and Carbazoles via Palladium-Catalyzed C–H Activation. Green Synth. Catal. 2021, 2, 216–227. [Google Scholar] [CrossRef]
  19. Strecker, T.E.; Odutola, S.O.; Lopez, R.; Cooper, M.S.; Tidmore, J.K.; Charlton-Sevcik, A.K.; Li, L.; MacDonough, M.T.; Hadimani, M.B.; Ghatak, A.; et al. The Vascular Disrupting Activity of OXi8006 in Endothelial Cells and its Phosphate Prodrug OXi8007 in Breast Tumor Xenografts. Cancer Lett. 2015, 369, 229–241. [Google Scholar] [CrossRef] [Green Version]
  20. Barresi, E.; Bruno, A.; Taliani, S.; Cosconati, S.; Da Pozzo, E.; Salerno, S.; Simorini, F.; Daniele, S.; Giacomelli, C.; Marini, A.M.; et al. Deepening the Topology of the Translocator Protein Binding Site by Novel N,N-Dialkyl-2-arylindol-3-ylglyoxylamides. J. Med. Chem. 2015, 58, 6081–6092. [Google Scholar] [CrossRef]
  21. Kathirvelan, D.; Haribabu, J.; Reddy, B.S.R.; Balachandran, C.; Duraipandiyan, V. Facile and Diastereoselective Synthesis of 3,2′-Spiropyrrolidine-oxindoles Derivatives, their Molecular Docking and Antiproliferative Activities. Bioorg. Med. Chem. Lett. 2015, 25, 389–399. [Google Scholar] [CrossRef]
  22. Horbert, R.; Pinchuk, B.; Johannes, E.; Schlosser, J.; Schmidt, D.; Cappel, D.; Totzke, F.; Schaechtele, C.; Peifer, C. Optimization of Potent DFG-in Inhibitors of Platelet Derived Growth Factor Receptorβ (PDGF-Rβ) Guided by Water Thermodynamics. J. Med. Chem. 2015, 58, 170–182. [Google Scholar] [CrossRef]
  23. Singh, P.; Prasher, P.; Dhillon, P.; Bhatti, R. Indole Based Peptidomimetics as Anti-inflammatory and Anti-hyperalgesic Agents: Dual Inhibition of 5-LOX and COX-2 Enzymes. Eur. J. Med. Chem. 2015, 97, 104–123. [Google Scholar] [CrossRef]
  24. Mielczarek, M.; Thomas, R.V.; Ma, C.; Kandemir, H.; Yang, X.; Bhadbhade, M.; Black, D.S.C.; Griffith, R.; Lewis, P.J.; Kumar, N. Synthesis and Biological Activity of Novel Mono-indole and Mono-benzofuran Inhibitors of Bacterial Transcription Initiation Complex Formation. Bioorg. Med. Chem. 2015, 23, 1763–1775. [Google Scholar] [CrossRef]
  25. Khan, A.H.; Chen, J.S. Synthesis of Breitfussin B by Late-Stage Bromination. Org. Lett. 2015, 17, 3718–3721. [Google Scholar] [CrossRef] [Green Version]
  26. Ye, Q.; Mao, W.L.; Zhou, Y.B.; Xu, L.; Li, Q.; Gao, Y.X.; Wang, J.; Li, C.H.; Xu, Y.Z.; Xu, Y. Synthesis and Biological Evaluation of 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides as Potent, Selective GSK-3β Inhibitors and Neuroprotective Agents. Bioorg. Med. Chem. 2015, 23, 1179–1188. [Google Scholar] [CrossRef]
  27. Yoo, E.; Salunke, D.B.; Sil, D.; Guo, X.Q.; Salyer, A.C.D.; Hermanson, A.R.; Kumar, M.; Malladi, S.S.; Balakrishna, R.; Thompson, W.H.; et al. Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure–Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds. J. Med. Chem. 2014, 57, 7955–7970. [Google Scholar] [CrossRef] [Green Version]
  28. Kamalraja, J.; Sowndarya, R.; Perumal, P.T. A Greener Approach for the Regioselective Synthesis of Multifunctionalized Indolylpyrrole and Indolyltriazolylpyrrole Hybrids via Michael Addition of α-Azido Ketones. Synlett 2014, 25, 2208–2212. [Google Scholar] [CrossRef]
  29. Muscia, G.C.; Hautmann, S.; Buldain, G.Y.; Asis, S.E.; Gutschow, M. Synthesis and Evaluation of 2-(1H-indol-3-yl)-4-Phenylquinolines as Inhibitors of Cholesterol Esterase. Bioorg. Med. Chem. Lett. 2014, 24, 1545–1549. [Google Scholar] [CrossRef]
  30. Kumar, D.; Maruthi Kumar, N.; Tantak, M.P.; Ogura, M.; Kusaka, E.; Ito, T. Synthesis and Identification of α-Cyano Bis(indolyl)chalcones as Novel Anticancer Agents. Bioorg. Med. Chem. Lett. 2014, 24, 5170–5174. [Google Scholar] [CrossRef]
  31. Wu, W.L.; Su, W.P. Mild and Selective Ru-Catalyzed Formylation and Fe-Catalyzed Acylation of Free (N–H) Indoles Using Anilines as the Carbonyl Source. J. Am. Chem. Soc. 2011, 133, 11924–11927. [Google Scholar] [CrossRef]
  32. Gu, L.J.; Liu, J.Y.; Zhang, L.Z.; Xiong, Y.; Wang, R. Synthesis of 3-Acylindoles via Decarboxylative Cross-coupling Reaction of Free (N-H) Indoles with α-Oxocarboxylic Acids. Chin. Chem. Lett. 2014, 25, 90–92. [Google Scholar] [CrossRef]
  33. Xia, X.F.; Zhang, L.L.; Song, X.R.; Niu, Y.N.; Liu, X.Y.; Liang, Y.M. Palladium–copper-cocatalyzed Intramolecular Oxidative Coupling: An Efficient and Atom-economical Strategy for the Synthesis of 3-Acylindoles. Chem. Commun. 2013, 49, 1410–1412. [Google Scholar] [CrossRef] [PubMed]
  34. Yu, L.; Li, P.H.; Wang, L. Copper-promoted Decarboxylative Direct C3-acylation of N-substituted Indoles with α-Oxocarboxylic Acids. Chem. Commun. 2013, 49, 2368–2370. [Google Scholar] [CrossRef] [Green Version]
  35. Ma, Y.H.; You, J.S.; Song, F.J. Facile Access to 3-Acylindoles through Palladium-Catalyzed Addition of Indoles to Nitriles: The One-Pot Synthesis of Indenoindolones. Chem. Eur. J. 2013, 19, 1189–1193. [Google Scholar] [CrossRef]
  36. Jiang, T.S.; Wang, G.W. Synthesis of 3-Acylindoles by Palladium-Catalyzed Acylation of Free (N–H) Indoles with Nitriles. Org. Lett. 2013, 15, 788–791. [Google Scholar] [CrossRef] [PubMed]
  37. Tang, R.Y.; Guo, X.K.; Xiang, J.N.; Li, J.H. Palladium-Catalyzed Synthesis of 3-Acylated Indoles Involving Oxidative Cross-Coupling of Indoles with α-Amino Carbonyl Compounds. J. Org. Chem. 2013, 78, 11163–11171. [Google Scholar] [CrossRef] [PubMed]
  38. Yeung, K.S.; Farkas, M.E.; Qiu, Z.L.; Yang, Z. Friedel–Crafts Acylation of Indoles in Acidic Imidazolium Chloroaluminate Ionic Liquid at Room Temperature. Tetrahedron Lett. 2002, 43, 5793–5795. [Google Scholar] [CrossRef]
  39. Xu, H.; Yang, W.-B.; Wang, Q. Antifungal Agents. Part 3: Synthesis and Antifungal Activities of 3-Acylindole Analogs against Phytopathogenic Fungi In Vitro. Chem. Biol. Drug. Des. 2011, 78, 864–868. [Google Scholar] [CrossRef]
  40. Ottoni, O.; Neder, A.D.F.; Dias, A.K.B.; Cruz, R.P.A.; Aquino, L.B. Acylation of Indole under Friedel−Crafts ConditionsAn Improved Method to Obtain 3-Acylindoles Regioselectively. Org. Lett. 2001, 3, 1005–1007. [Google Scholar] [CrossRef]
  41. Guchhait, S.K.; Kashyap, M.; Kamble, H. ZrCl4-Mediated Regio- and Chemoselective Friedel–Crafts Acylation of Indole. J. Org. Chem. 2011, 76, 4753–4758. [Google Scholar] [CrossRef]
  42. Zhang, Z.W.; Xue, H.; Li, H.L.; Kang, H.P.; Feng, J.; Lin, A.J.; Liu, S.X. Collective Synthesis of 3-Acylindoles, Indole-3-carboxylic Esters, Indole-3-sulfinic Acids, and 3-(Methylsulfonyl)indoles from Free (N–H) Indoles via Common N-Indolyl Triethylborate. Org. Lett. 2016, 18, 3918–3921. [Google Scholar] [CrossRef] [PubMed]
  43. Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. A General Method for Acylation of Indoles at the 3-Position with Acyl Chlorides in the Presence of Dialkylaluminum Chloride. Org. Lett. 2000, 2, 1485–1487. [Google Scholar] [CrossRef] [PubMed]
  44. Katritzky, A.R.; Suzuki, K.; Singh, S.K.; He, H.Y. Regiospecific C-Acylation of Pyrroles and Indoles Using N-Acylbenzotriazoles. J. Org. Chem. 2003, 68, 5720–5723. [Google Scholar] [CrossRef] [PubMed]
  45. Wynne, J.H.; Lloyd, C.T.; Jensen, S.D.; Boson, S.; Stalick, W.M. 3-Acylindoles via a One-Pot, Regioselective Friedel-Crafts Reaction. Synthesis 2004, 14, 2277–2282. [Google Scholar] [CrossRef]
  46. Yao, S.J.; Ren, Z.H.; Guan, Z.H. Recent Advances on the Synthesis of Acylindoles. Tetrahedron Lett. 2016, 57, 3892–3901. [Google Scholar] [CrossRef]
  47. Bohstroem, Z.; Holmberg, K. Friedel–Crafts Acylation of 2-methylindole with Acetic Anhydride Using Mesoporous HZSM-5. J. Mol. Catal. A-CHEM 2013, 366, 64–73. [Google Scholar] [CrossRef]
  48. Tran, P.H.; Nguyen, A.T.D.; Nguyen, H.T.; Le, T.N. Brønsted Acidic Ionic Liquid-Promoted Direct C3-acylation of N-unsubstituted Indoles with Acid Anhydrides under Microwave Irradiation. RSC Adv. 2017, 7, 54399–54406. [Google Scholar] [CrossRef] [Green Version]
  49. Cornel, V.; Lovely, C.J. Boron Trifluoride Etherate, e-EROS Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons: Hoboken, NJ, USA, 2007. [Google Scholar] [CrossRef]
  50. Kuhl, N.; Hopkinson, M.N.; Glorius, F. Selective Rhodium(III)-Catalyzed Cross-Dehydrogenative Coupling of Furan and Thiophene Derivatives. Angew. Chem. Int. Ed. 2012, 51, 8230–8234. [Google Scholar] [CrossRef]
  51. Zou, Y.J.; Yue, G.Z.; Xu, J.W.; Zhou, J.R. General Suzuki Coupling of Heteroaryl Bromides by Using Tri-tert-butylphosphine as a Supporting Ligand. Eur. J. Org. Chem. 2014, 5901–5905. [Google Scholar] [CrossRef]
  52. Donald, J.R.; Taylor, R.J.K. Tandem Meinwald Rearrangement-Fischer Indolisation: A One-Pot Conversion of Epoxides into Indoles. Synlett 2009, 1, 59–62. [Google Scholar] [CrossRef]
  53. Shi, W.M.; Ma, X.P.; Pan, C.X.; Su, G.F.; Mo, D.L. Tandem C–O and C–N Bonds Formation Through O-Arylation and [3,3]-Rearrangement by Diaryliodonium Salts: Synthesis of N-Aryl Benzo[1,2,3]triazin-4(1H)-one Derivatives. J. Org. Chem. 2015, 80, 11175–11183. [Google Scholar] [CrossRef] [PubMed]
  54. Ma, X.P.; Shi, W.M.; Mo, X.L.; Li, X.H.; Li, L.G.; Pan, C.X.; Chen, B.; Su, G.F.; Mo, D.L. Synthesis of α,β-Unsaturated N-Aryl Ketonitrones from Oximes and Diaryliodonium Salts: Observation of a Metal-Free N-Arylation Process. J. Org. Chem. 2015, 80, 10098–10107. [Google Scholar] [CrossRef] [PubMed]
  55. Gao, H.Y.; Xu, Q.L.; Keene, C.; Kurti, L. Scalable, Transition-Metal-Free Direct Oxime O-Arylation: Rapid Access to O-Arylhydroxylamines and Substituted Benzo[b]furans. Chem. Eur. J. 2014, 20, 8883–8887. [Google Scholar] [CrossRef]
  56. Ito, Y.; Kobayashi, K.; Saegusa, T. Indole Syntheses with o-Tolyl Isocyanide. 3-Acylindoles and 2-substituted Indoles. J. Org. Chem. 1979, 44, 2030–2032. [Google Scholar] [CrossRef]
  57. Yu, J.B.; Zhang, C.; Yang, X.J.; Su, W.K. Decarboxylative Acylation of N-free Indoles Enabled by a Catalytic Amount of Copper Catalyst and liquid-assisted grinding. Org. Biomol. Chem. 2019, 17, 4446–4451. [Google Scholar] [CrossRef]
  58. Davies, J.R.; Kane, P.D.; Moddy, C.J.; Slawin, A.M.Z. Control of Competing N−H Insertion and Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions of 3-Indolyl Diazoketoesters. Synthesis of a Potential Precursor to the Marine 5-(3-Indolyl)oxazole Martefragin A. J. Org. Chem. 2005, 70, 5840–5851. [Google Scholar] [CrossRef]
  59. Ali, M.A.; Punniyamurthy, T. Domino Ligand-Free Copper-Catalyzed Synthesis of Polysubstituted Indoles. Synlett 2011, 5, 623–626. [Google Scholar] [CrossRef] [Green Version]
  60. Kamenov, L.; Yudin, L.G.; Budylin, V.A.; Kost, A.N. The Chemistry of Indole. Chem. Heterocycl. Compd. 1970, 6, 856–859. [Google Scholar] [CrossRef]
  61. Qu, J.; Kumar, N.; Alamgir, M.; Black, D. StC. A Versatile Dynthetic Route to 11H-indolo[3,2-c]isoquinolines. Tetrahedron Lett. 2009, 50, 5628–5630. [Google Scholar] [CrossRef]
  62. Buchmann, G.; Rossner, D. Beitrag zur Chemie des 2-Phenyl-indols. II. Über acylierte 2-Phenyl-indole und ihre Reaktivität. J. Fuer Prakt. Chem. 1964, 25, 117–134. [Google Scholar] [CrossRef]
  63. Na, Y.M.; Borgne, M.L.; Pagniez, F.; Baut, G.L.; Pape, P.L. Synthesis and Antifungal Activity of New 1-Halogenobenzyl-3-imidazolylmethylindole Derivatives. Eur. J. Med. Chem. 2003, 38, 75–87. [Google Scholar] [CrossRef]
  64. Barreca, M.L.; Ferro, S.; Rao, A.; De Luca, L.; Zappala, M.; Monforte, A.M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. Pharmacophore-Based Design of HIV-1 Integrase Strand-Transfer Inhibitors. J. Med. Chem. 2005, 48, 7084–7088. [Google Scholar] [CrossRef] [PubMed]
  65. Bartoli, G.; Palmieri, G.; Petrini, M. A New Approach to the Synthesis of 2-Substituted Indoles: Reaction of Dimetallated Ortho-trimethylsilylmethylanilides with Esters. Tetrahedron 1990, 46, 1379–1384. [Google Scholar] [CrossRef]
  66. Zhang, F.; Zhao, Y.F.; Sun, L.; Ding, L.; Gu, Y.C.; Gong, P. Synthesis and Anti-tumor Activity of 2-Amino-3-Cyano-6-(1H-indol-3-yl)-4-Phenylpyridine. Eur. J. Med. Chem. 2011, 46, 3149–3157. [Google Scholar] [CrossRef]
  67. Giraud, F.; Alves, G.; Debiton, E.; Nauton, L.; Thery, V.; Durieu, E.; Ferandin, Y.; Lozach, O.; Meijer, L.; Anizon, F.; et al. Synthesis, Protein Kinase Inhibitory Potencies, and in Vitro Antiproliferative Activities of Meridianin Derivatives. J. Med. Chem. 2011, 54, 4474–4489. [Google Scholar] [CrossRef]
  68. Yurovskaya, M.A.; Druzhinina, V.V.; Budylin, V.A.; Bundel, Y.G.; Yufit, D.S.; Struchkov, Y.T. Structure of 3-acylindole oximes. Chem. Heterocycl. Compd. 1983, 19, 184–187. [Google Scholar] [CrossRef]
  69. Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E.; Sferrazza, A. 3-Aroylindoles via Copper-Catalyzed Cyclization of N-(2-Iodoaryl)enaminones. Synlett 2009, 9, 1480–1484. [Google Scholar] [CrossRef]
Molecules 27 08281 g001 550
Figure 1. Bioactive products containing acylindole.
Figure 1. Bioactive products containing acylindole.
Molecules 27 08281 g001
Molecules 27 08281 sch001 550
Scheme 1. Boron-trifluoride-etherate-promoted 3-acylation.
Scheme 1. Boron-trifluoride-etherate-promoted 3-acylation.
Molecules 27 08281 sch001
Molecules 27 08281 sch002 550
Scheme 2. Up to ten grams scale preparation for 3aa.
Scheme 2. Up to ten grams scale preparation for 3aa.
Molecules 27 08281 sch002
Molecules 27 08281 sch003 550
Scheme 3. Synthesis of 3-benzofuran-2-yl indole 6.
Scheme 3. Synthesis of 3-benzofuran-2-yl indole 6.
Molecules 27 08281 sch003
Table
Table 1. Optimization of reaction conditions.
Table 1. Optimization of reaction conditions.
Molecules 27 08281 i001
Entry2a (Eq.)BF3·Et2O (Eq.)SolventTemp. (°C)Time (h)Yield (%)
11.01.0DCMrt1.270
21.01.0DCErt1.040
31.01.0CHCl3rt1.041
41.01.0THFrt8.0trace
51.01.0CH3CNrt3.055
61.01.01,4-dioxanert1.562
71.00DCMrt1.0nr
81.00.5DCMrt1.560
91.01.2DCMrt1.066
101.01.5 mL―rt0.530
111.11.0DCMrt1.078
121.21.0DCMrt1.083
131.31.0DCMrt1.082
141.21.0DCM02.580
151.21.0DCM500.340
Reaction conditions unless noted otherwise: 1a (0.5 mmol), solvent (1.5 mL), BF3·Et2O (BF3, 46.5%). nr: no reaction.
Table
Table 2. Scope of anhydrides.
Table 2. Scope of anhydrides.
Molecules 27 08281 i002
Entry2R3Yield (%)
12bEt3ab91
22cn-Pr3ac85
32dcyclohexyl3ad72
42ePh3ae76
52f4-CH3O-C6H43af80
62g3-CH3-C6H43ag71
72h4-Cl-C6H43ahnp
82j4-NO2-C6H43ajnp
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), BF3·Et2O (BF3 46.5%, 1 equiv), DCM (1.5 mL), rt, 2–3 h, np: no product.
Table
Table 3. Acylation of substituted indoles with anhydrides.
Table 3. Acylation of substituted indoles with anhydrides.
Molecules 27 08281 i003
EntryRR1R2X3Yield (%)
1MeMeHH3ba87
2EtMeHH3bb82
3 n-PrMeHH3bc71
4PhMeHH3bd53
5MeHMeH3ca68
6EtHMeH3cb71
7n-PrHMeH3cc74
8PhHMeH3cd56
9MeHPhH3da62
10EtHPhH3db65
11n-PrHPhH3dc70
12PhHPhH3dd59
13MeHH5-Br3ea87
14EtHH5-Br3eb93
15n-PrHH5-Br3ec84
16PhHH5-Br3ed70
17MeHH5-CN3fa93
18EtHH5-CN3fb91
19n-PrHH5-CN3fc88
20PhHH5-CN3fd53
21MeHH5-CH33ga88
22EtHH5-CH33gb83
23n-PrHH5-CH33gc76
24PhHH5-CH33gd67
25MeHH5-OCH33ha80
26EtHH5-OCH33hb75
27n-PrHH5-OCH33hc68
28PhHH5-OCH33hd64
29MeHH6-F3ia92
30EtHH6-F3ib88
31n-PrHH6-F3ic81
32PhHH6-F3id67
33MeHH7-Br3ja91
34EtHH7-Br3jb89
35n-PrHH7-Br3jc88
36PhHH7-Br3jd82
Reaction conditions a: 1 (0.5 mmol), anhydrides (0.6 mmol), BF3·Et2O (0.5 mmol), DCM (1.5 mL), rt, stirred 1.5~2 h. (Entries 5~12) b, rt, stirred 12 h.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Zheng, Y.; Li, J.; Wei, K. Boron Trifluoride Etherate Promoted Regioselective 3-Acylation of Indoles with Anhydrides. Molecules 2022, 27, 8281. https://doi.org/10.3390/molecules27238281

AMA Style

Zheng Y, Li J, Wei K. Boron Trifluoride Etherate Promoted Regioselective 3-Acylation of Indoles with Anhydrides. Molecules. 2022; 27(23):8281. https://doi.org/10.3390/molecules27238281

Chicago/Turabian Style

Zheng, Yunyun, Jiuling Li, and Kai Wei. 2022. "Boron Trifluoride Etherate Promoted Regioselective 3-Acylation of Indoles with Anhydrides" Molecules 27, no. 23: 8281. https://doi.org/10.3390/molecules27238281

APA Style

Zheng, Y., Li, J., & Wei, K. (2022). Boron Trifluoride Etherate Promoted Regioselective 3-Acylation of Indoles with Anhydrides. Molecules, 27(23), 8281. https://doi.org/10.3390/molecules27238281

Article Metrics

Back to TopTop