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Article

HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation

by
Guangkai Yao
1,2,
Zhi-Xiang Zhang
1,2,
Cheng-Bei Zhang
1,2,
Han-Hong Xu
1,2,* and
Ri-Yuan Tang
1,3,*
1
Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China
2
State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou 510642, China
3
Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(12), 3317; https://doi.org/10.3390/molecules23123317
Submission received: 27 November 2018 / Revised: 10 December 2018 / Accepted: 11 December 2018 / Published: 14 December 2018
(This article belongs to the Collection Heterocyclic Compounds)
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Abstract

:
1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was found to be effective for the Bischler indole synthesis under microwave irradiation in the absence of a metal catalyst. Under the catalysis of HFIP, a wide range of α-amino arylacetones were successfully transformed into indole derivatives with moderate to good yields.

Graphical Abstract

1. Introduction

Indole is an important structural unit that is present in many natural alkaloids [1,2,3]. Indole derivatives, such as indole-3-acetic acid (IAA) [4], physostigmine [5], amisulbrom [6], and fluvastatin [7], possess a large range of biological activities (Scheme 1A). The development of efficient and simple synthetic methods for indoles is highly desired [8,9,10]. The classical name reactions, such as Bischler indole synthesis [11,12], Fischer indole synthesis [13,14], Bartoli indole synthesis [15,16], have been widely used for indole synthesis. In recent years, efforts have been devoted to improve the Bischler indole synthesis [17,18,19,20,21,22,23]. Metal catalysts, including Rh [17], Ir [18], Ru [19], and Zn [20], have been applied to such transformations. However, most of these metal reagents are expensive, and the metal pollution is an inevitable problem in the preparation of indoles. α-Amino arylacetone, being used for indole synthesis, has multiple reactive sites [24,25,26]. In the presence of a metal catalyst, α-amino arylacetone was transformed into indolone [24] or a-ketoamide [25], and even underwent the cleavage of the C-N bond [26]. Thus, the development of metal-free and mild conditions for the selective transformation of α-amino arylacetone is highly desired. Chen and co-workers reported that NH4PF6 could promote the Bischler indole synthesis under metal-free conditions [27]. However, the preparation of NH4PF6 requires the use of corrosive NH4F and PCl5, which are harmful to the environment. We envision that a protic solvent would be able to promote the cyclodehydration of α-amino carbonyl compounds at the assistance of microwave irradiation. Because microwave synthetic technology often greatly improves the reaction efficiency and shortens the reaction time [28,29,30]. Herein we report a HFIP-promoted Bischler indole synthesis under microwave irradiation in the absence of any additive (Scheme 1B).

2. Results and Discussion

Our study began with the reaction of 2-(methylphenylamino)-1-phenyl-ethanone (1a) with different protic solvents under microwave irradiation (Table 1, entries 1–4). The reaction proceeded well in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) at 120 °C under microwave irradiation for 30 min, giving the desired product 2 in 76% yield (entry 1). CF3CH2OH was also effective for the cyclodehydration reaction, albeit with a 45% yield (entry 2). The reaction with i-PrOH or EtOH gave product 2 only 21% and 23% yield, respectively (entries 3 and 4). The reaction temperature significantly influenced the product yield. The product yield decreased when the reaction was conducted at a lower temperature (e.g., 51% yield at 80 °C and 72% yield at 100 °C (entries 5 and 6)). Next, the reaction time was examined. The product yield was increased to 88% by prolonging the reaction time to 40 min (entry 8). Whereas the reaction at 20 min reduced the product yield to 58% (entry 7). The product 2 was also obtained with 86% yield when the reaction was conducted under oil bath heating conditions for 16 h (entry 9). It is worth noting that the compound 2 is an excellent inhibitor of tubulin polymerization [31,32].
With the optimized reaction conditions in hand, the reaction scope was investigated (Table 2). Initially, substituents, including methyl, phenyl, methoxy, nitro, trifluoromethyl, cyano, bromo, chloro, and fluoro, on the benzene ring of arylethanone were investigated. All of these groups were well accepted to provide their corresponding products (3–14) in moderate to good yields. Most of these functional groups are readily modified to provide a wide range of indole derivatives. To our delight, substrates bearing a naphthalene, benzodioxepin, or benzofuran motif still performed well to provide their corresponding products (15–17) in moderate to good yields.
It is worth noting that products 18 and 19, with an ester group, were also successfully prepared. The further modification of the ester group is able to provide diverse interesting indole derivatives. Subsequently, substituents on the benzene ring of aniline were evaluated. The results show that methoxy, bromo, and chloro groups were compatible with the reaction conditions, providing their corresponding products (20–22) in good yields. The reaction with 1-phenyl-2-(phenylamino)ethanone did not occur, suggesting that the N-methyl protecting group is essential for such a transformation (product 23). To our delight, the benzyl protecting substrate also underwent the reaction well to give product 24 in 82% yield; whereas the reaction of N-Boc protecting substrate did not occur. Interestingly, the pharmaceutically important pyrrolo[3,2,1-ij]quinoline derivatives were also successfully synthesized by this simple protocol [33,34,35]. Numerous useful functional groups, such as methoxy, trifluoromethyl, bromo, chloro, and fluoro groups, were well tolerated (products 25–29). For example, halo-substituted compounds 27 and 28 were synthetically useful for further modifications by cross-coupling reactions. Both naphthalene and benzofuran moieties were also accepted to afford products 31 and 32 in good yields. The ester group of product 33 is attractive to the medicinal community. 1-[Methyl(phenyl)amino]butan-2-one still underwent the reaction smoothly to provide the desired product 34 in 90% yield.
According to the Bischler reaction mechanism [11,12] and the present results, a possible reaction pathway was illustrated, as shown in Scheme 2. HFIP may play the role of an acid that activates the carbonyl for the Friedel-Crafts cyclization to produce an intermediate A. The HFIP anion facilitates the elimination of the hydrogen atom to produce an intermediate B. The hydroxyl of the intermediate B accepts a proton from HFIP to form an intermediate C, followed by a dehydration process to provide an intermediate D. Finally, the intermediate D undergoes a deprotonation process to afford the desired product. In the reaction, microwave irradiation may promote the electron flow of α-amino arylacetone, and greatly improve the reaction efficiency.

3. Materials and Methods

3.1. General Information

NMR spectroscopy were performed on a Bruker Avance 500 instrument (Bruker, Billerica, MA, USA) (500 MHz for 1H, 126 MHz for 13C-NMR spectroscopy), using CDCl3 and DMSO-d6 as the solvent, and calibrated using residual deuterated solvents as an internal reference (CDCl3: δ 7.26 ppm for 1H-NMR, δ 77.16 ppm for 13C-NMR; DMSO-d6: δ 2.50 ppm for 1H-NMR, δ = 39.52 ppm for 13C-NMR). The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Mass spectra were measured on an Agilent GC-MS-5975C Plus spectrometer (EI) (Agilent, Santa Clara, CA, USA). LC-MS (ESI) analysis was measured on an AB Sciex API3200 (AB SCIEX, Framingham, MA, USA). HRMS (ESI) analyses was measured on a Thermo Scientific LTQ Orbitrap XL instrument (Thermo Scientific, Waltham, MA, USA). Microwave experiments were conducted in a CEM Discover single-mode instrument (CEM Corporation, Matthews, NC, USA) using the internal probe.

3.2. General Procedure for the Synthesis of Indoles and Pyrrolo[3,2,1-ij]quinolones

A mixture of α-amino arylethanone (1a) (0.6 mmol) in HFIP (3 mL) was sealed in a pressure vessel tube, and was stirred at 120 °C under microwave irradiation for 40 min. After the reaction finished, the crude reaction mixture was diluted with EtOAc (5 mL), and filtered through a short pad of celite. The sealed tube and celite pad were washed with an additional 20 mL of EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography using hexanes and EtOAc as the eluent (NMR spectra for all compounds shown in Supplementary Materials).
1-Methyl-3-phenyl-1H-indole (2). Yellow solid. 87% yield (108 mg). M.P.: 65–67 °C. 1H-NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.3, 1.3 Hz, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.28–7.22 (m, 2H), 7.22–7.13 (m, 2H), 3.79 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 137.5, 135.6, 128.7, 127.3, 126.5, 126.1, 125.7, 121.9, 119.9, 119.8, 116.7, 109.5, 32.8; LRMS (EI, 70 Ev) m/z (%): 207 (M+, 100).
1-Methyl-3-(p-tolyl)-1H-indole (3). Yellow solid. 83% yield (110 mg). M.P.: 66–68 °C. 1H-NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.35–7.27 (m, 4H), 7.25–7.18 (m, 3H), 3.84 (s, 3H), 2.44 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 137.4, 135.2, 132.7, 129.4, 127.2, 126.2, 121.9, 119.9, 119.7, 116.6, 109.4, 32.8, 21.1; LRMS (EI, 70 Ev) m/z (%): 221 (M+, 100).
3-([1,1′-Biphenyl]-4-yl)-1-methyl-1H-indole (4). Pale yellow soild. 66% yield (112 mg). M.P.: 131–132 °C. 1H-NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.79–7.72 (m, 4H), 7.54 (t, J = 7.7 Hz, 2H), 7.47–7.40 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.34–7.27 (m, 2H), 3.88 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 141.0, 138.3, 137.5, 134.7, 128.7, 127.5, 127.4, 127.0, 126.9, 126.6, 126.1, 122.0, 119.9, 116.2, 109.5, 32.8; HRMS (ESI) for C21H18N (M + H+): calcd. 284.1434, found 284.1436.
3-(4-Methoxyphenyl)-1-methyl-1H-indole (5). Yellow solid. 77% yield (109 mg). M.P.: 97–99 °C. 1H-NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.63–7.56 (m, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.33–7.27 (m, 1H), 7.21 (td, J = 7.5, 7.1, 1.0 Hz, 1H), 7.17 (s, 1H), 7.07–6.98 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H).13C-NMR (126 MHz, CDCl3) δ 157.9, 137.3, 128.4, 128.2, 126.2, 125.9, 121.8, 119.8, 119.6, 116.4, 114.2, 109.4, 55.3, 32.7; LRMS (EI, 70 Ev) m/z (%): 237 (M+, 100).
1-Methyl-3-(4-nitrophenyl)-1H-indole (6) [36]. Light yellow solid. 72% yield (109 mg). M.P.: 139–140 °C. 1H-NMR (500 MHz, CDCl3) δ 8.38–8.16 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.84–7.71 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.31–7.24 (m, 1H), 3.88 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 145.2, 142.8, 137.8, 128.3, 126.6, 125.6, 124.3, 122.7, 121.0, 119.6, 114.6, 110.0, 33.1; LRMS (EI, 70 Ev) m/z (%): 252 (M+, 100).
1-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-indole (7) [27]. White solid. 65% yield (107 mg). M.P.: 81–82 °C. 1H-NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.35–7.28 (m, 2H), 7.27–7.17 (m, 1H), 3.86 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 139.4, 137.6, 127.6, 127.3, 127.0, 125.9, 125.7 (q, J = 3.8 Hz), 124.6 (q, J = 270.1 Hz), 122.4, 120.4, 119.7, 115.4, 109.8, 33.0; LRMS (EI, 70 Ev) m/z (%): 275 (M+, 100).
4-(1-Methyl-1H-indol-3-yl)benzonitrile (8). Light yellow solid. 73% yield (102 mg). M.P.: 146–148 °C. 1H-NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.40–7.32 (m, 2H), 7.29 (t, J = 7.5 Hz, 1H), 3.88 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 140.6, 137.6, 132.5, 127.8, 126.9, 125.5, 122.5, 120.7, 119.5, 119.4, 114.8, 109.9, 108.3, 33.0; LRMS (EI, 70 Ev) m/z (%): 232 (M+, 100).
3-(4-Bromophenyl)-1-methyl-1H-indole (9) [36]. Yellow solid. 82% yield (140 mg). M.P.: 108–109 °C. 1H-NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.62–7.49 (m, 4H), 7.38 (d, J = 8.2 Hz, 1H), 7.35–7.28 (m, 1H), 7.25–7.17 (m, 2H), 3.84 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 137.5, 134.6, 131.8, 128.7, 126.6, 125.9, 122.1, 120.1, 119.6, 119.2, 115.5, 109.6, 32.8; LRMS (EI, 70 Ev) m/z (%): 287 (M+, 100), 285 (M+, 100).
3-(4-Chlorophenyl)-1-methyl-1H-indole (10). Light brown solid. 76% yield (110 mg). M.P.: 97–99 °C. 1H-NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.67–7.53 (m, 2H), 7.45–7.35 (m, 3H), 7.33–7.29 (m, 1H), 7.25–7.19 (m, 2H), 3.84 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 137.5, 134.1, 131.2, 128.8, 128.4, 126.6, 125.9, 122.1, 120.1, 119.6, 115.5, 109.6, 32.9; LRMS (EI, 70 Ev) m/z (%): 241 (M+, 100).
1-Methyl-3-(3-nitrophenyl)-1H-indole (11). Orange solid. 56% yield (85 mg). M.P.: 108–109 °C. 1H-NMR (500 MHz, CDCl3) δ 8.49 (t, J = 2.0 Hz, 1H), 8.08 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.38–7.30 (m, 2H), 7.26 (t, J = 7.5 Hz, 2H), 3.87 (s, 2H). 13C-NMR (126 MHz, CDCl3) δ 148.7, 137.5, 137.5, 132.6, 129.5, 127.4, 125.6, 122.5, 121.4, 120.6, 120.1, 119.3, 114.3, 109.8, 33.0; LRMS (EI, 70 Ev) m/z (%): 252 (M+, 100); HRMS (ESI) for C15H13N2O2 (M + H+): calcd. 253.0899, found 253.0894.
3-(1-Methyl-1H-indol-3-yl)benzonitrile (12). Yellow solid. 61% yield (85 mg). M.P.: 121–124 °C. 1H-NMR (500 MHz, CDCl3) δ 7.98–7.80 (m, 3H), 7.58–7.46 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.36–7.30 (m, 1H), 7.29–7.18 (m, 2H), 3.86 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 137.5, 137.0, 131.2, 130.3, 129.5, 128.8, 127.1, 125.6, 122.4, 120.5, 119.3, 119.1, 114.4, 112.8, 109.8, 33.0; LRMS (EI, 70 Ev) m/z (%): 232 (M+, 100); HRMS (ESI) for C16H13N2 (M + H+): calcd. 232.2860, found 232.2868.
3-(3,4-Dimethoxyphenyl)-1-methyl-1H-indole (13). Yellow oil. 76% yield (122 mg). 1H-NMR (500 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.26–7.15 (m, 3H), 7.15–7.10 (m, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). 13C-NMR (126 MHz, DMSO-d6) δ 149.5, 147.4, 137.6, 128.8, 127.5, 125.9, 121.8, 120.0, 119.7, 119.0, 115.4, 113.0, 111.1, 110.5, 56.1, 55.9, 32.9; LRMS (EI, 70 Ev) m/z (%): 267 (M+, 100); HRMS (ESI) for C18H18NO2 (M + H+): calcd. 268.1332, found 268.1335.
3-(3,4-Difluorophenyl)-1-methyl-1H-indole (14) [27]. Yellow oil. 73% yield (106 mg).1H-NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 1H), 7.48–7.40 (m, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.36–7.28 (m, 2H), 7.25–7.17 (m, 3H), 3.85 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ151.5 (d, J = 12.8 Hz), 149.6 (t, J = 13.0 Hz), 147.7 (d, J = 12.8 Hz), 137.4, 132.8 (dd, J = 6.6, 3.8 Hz), 126.7, 125.8, 122.9 (dd, J = 5.8, 3.3 Hz), 122.3, 120.2, 119.4, 117.4 (d, J = 17.4 Hz), 115.8 (d, J = 17.4 Hz), 114.9, 109.7, 32.9; LRMS (EI, 70 Ev) m/z (%): 243 (M+, 100).
1-Methyl-3-(naphthalen-2-yl)-1H-indole (15). Colorless oil. 82% yield (126 mg). 1H-NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 8.00–7.90 (m, 3H), 7.87 (dd, J = 8.5, 1.7 Hz, 1H), 7.60–7.49 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.42–7.37 (m, 1H), 7.36 (s, 1H), 7.35–7.31 (m, 1H), 3.85 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 137.5, 134.0, 133.1, 131.9, 128.2, 127.7, 127.6, 126.9, 126.4, 126.2, 126.0, 125.0, 124.8, 122.0, 120.0, 120.0, 116.5, 109.6, 32.8; LRMS (EI, 70 Ev) m/z (%): 257 (M+, 100).
3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-methyl-1H-indole (16). Yellow oil. 55% yield (92 mg). 1H-NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 8.0, 1.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.34–7.30 (m, 1H), 7.28 (dd, J = 8.5, 1.8 Hz, 1H), 7.27–7.20 (m, 1H), 7.21 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 4.31 (dt, J = 10.9, 5.6 Hz, 4H), 3.84 (s, 3H), 2.34–2.17 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 151.3, 149.3, 137.3, 131.2, 126.2, 126.0, 122.1, 121.8, 121.8, 120.1, 119.8, 119.7, 115.8, 109.4, 70.6, 70.5, 32.7, 32.0; LRMS (EI, 70 Ev) m/z (%): 279 (M+, 100); HRMS (ESI) for C18H18NO2 (M + H+): calcd. 280.1259, found 280.1263.
3-(Benzofuran-2-yl)-1-methyl-1H-indole (17) [27]. Yellow oil. 47% yield (70 mg). 1H-NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.60–7.55 (m, 1H), 7.54–7.49 (m, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.37–7.27 (m, 2H), 7.27–7.20 (m, 2H), 6.91 (s, 1H), 3.85 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 153.8, 152.9, 137.4, 129.9, 127.5, 125.0, 123.0, 122.6, 122.5, 120.6, 120.3, 120.0, 110.5, 109.7, 106.9, 99.0, 33.0; LRMS (EI, 70 Ev) m/z (%): 247 (M+, 100).
Ethyl 1-methyl-1H-indole-3-carboxylate (18) [37]. Yellow oil. 45% yield (55 mg). 1H-NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 8.02 (dd, J = 7.1, 1.3 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.30–7.20 (m, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C-NMR (126 MHz, DMSO-d6) δ 164.5, 137.4, 136.5, 126.5, 122.8, 121.9, 121.0, 111.2, 105.9, 59.4, 33.4, 14.9; LRMS (EI, 70 Ev) m/z (%): 203 (M+, 100).
Ethyl 2-(1-methyl-1H-indol-3-yl)acetate (19) [27]. Yellow oil. 72% yield (94 mg). 1H-NMR (500 MHz, CDCl3) δ 7.64 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.28–7.22 (m, 1H), 7.18–7.12 (m, 1H), 7.06 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.78 (s, 2H), 3.77 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C-NMR (126 MHz, CDCl3) δ 172.1, 136.8, 127.7, 127.6, 121.7, 119.0, 118.9, 109.2, 106.9, 60.7, 32.6, 31.3, 14.2; LRMS (EI, 70 Ev) m/z (%): 217 (M+, 100).
5-Methoxy-1-methyl-3-phenyl-1H-indole (20). Light yellow solid. 78% yield (111 mg). M.P.: 80–81 °C. 1H-NMR (500 MHz, CDCl3) δ 7.65 (d, J = 7.1 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.41 (d, J = 2.4 Hz, 1H), 7.32–7.24 (m, 1H), 7.21 (s, 1H), 6.96 (dd, J = 8.8, 2.4 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 3H).13C-NMR (126 MHz, CDCl3) δ 154.6, 135.8, 132.9, 128.7, 127.2, 127.1, 126.4, 125.6, 116.3, 112.2, 110.2, 101.8, 56.0, 33.0; LRMS (EI, 70 Ev) m/z (%): 237 (M+, 100).
5-Bromo-1-methyl-3-phenyl-1H-indole (21) [36]. Yellow oil. 65% yield (111 mg). 1H-NMR (500 MHz, CDCl3) δ 8.06 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.36 (dd, J = 8.7, 1.7 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 136.1, 134.8, 128.8, 127.8, 127.5, 127.3, 126.0, 124.8, 122.4, 116.4, 113.4, 111.0, 33.0; LRMS (EI, 70 Ev) m/z (%): 287 (M+, 100), 285 (M+, 100).
5-Chloro-1-methyl-3-phenyl-1H-indole (22) [27]. Yellow soild. 77% yield (111 mg). M.P.: 87–89 °C. 1H-NMR (500 MHz, CDCl3) δ 7.90 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.2, 1.2 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.33–7.27 (m, 2H), 7.25–7.20 (m, 2H), 3.82 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 135.8, 134.9, 128.8, 127.7, 127.2, 127.1, 126.0, 125.8, 122.2, 119.3, 116.5, 110.5, 33.0; LRMS (EI, 70 Ev) m/z (%): 241 (M+, 100).
1-benzyl-3-phenyl-1H-indole (24). Yellow oil. 82% yield (146 mg). 1H-NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.3 Hz, 1H), 7.71 (dd, J = 8.2, 1.1 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.39–7.28 (m, 6H), 7.28–7.23 (m, 2H), 7.21 (d, J = 6.8 Hz, 2H), 5.39 (s, 2H). 13C-NMR (126 MHz, CDCl3) δ 137.3, 137.2, 135.6, 128.9, 128.8, 127.8, 127.4, 127.0, 126.5, 126.0, 125.9, 122.2, 120.2, 120.1, 117.4, 110.1, 50.2; LRMS (EI, 70 Ev) m/z (%): 283 (M+, 100).
1-(4-Methoxyphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (25) [27]. Yellow solid. 82% yield (129 mg). M.P.: 127–129 °C. 1H-NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.68–7.52 (m, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.0, 7.1 Hz, 1H), 7.04–6.87 (m, 3H), 4.99–3.96 (m, 2H), 3.87 (s, 3H), 3.04 (t, J = 6.1 Hz, 2H), 2.46–2.03 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 157.7, 134.8, 128.8, 127.9, 123.7, 123.0, 121.9, 120.1, 118.8, 117.4, 116.2, 114.2, 55.3, 44.1, 24.7, 22.8; LRMS (EI, 70 Ev) m/z (%): 263 (M+, 100).
1-[4-(Trifluoromethyl)phenyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (26) [27]. Yellow oil. 81% yield (146 mg). 1H-NMR (500 MHz, CDCl3) δ 7.84–7.74 (m, 3H), 7.68 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 7.16 (dd, J = 8.0, 7.1 Hz, 1H), 7.02 (dd, J = 7.1, 1.1 Hz, 1H), 4.50–3.87 (m, 2H), 3.05 (t, J = 6.1 Hz, 2H), 2.58–2.10 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 139.9, 135.0, 127.8, 127.1 (q, J = 32.4 Hz), 126.5, 125.6 (q, J = 3.8 Hz), 124.5, 124.4 (q, J = 269.9 Hz), 123.5, 122.3, 120.9, 119.4, 117.3, 115.1, 44.3, 24.6, 22.7; LRMS (EI, 70 Ev) m/z (%): 301 (M+, 100).
1-(4-Bromophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (27) [27]. Yellow solid. 83% yield (155 mg). M.P.: 156–158 °C.1H-NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.60–7.44 (m, 4H), 7.29 (s, 1H), 7.12 (dd, J = 8.0, 7.1 Hz, 1H), 7.04–6.92 (m, 1H), 4.29–4.13 (m, 2H), 3.03 (t, J = 6.1 Hz, 2H), 2.42–2.12 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 135.1, 134.9, 131.7, 128.2, 123.8, 123.4, 122.2, 120.6, 119.1, 118.8, 117.2, 115.3, 44.2, 24.6, 22.7; LRMS (EI, 70 Ev) m/z (%): 313 (M+, 100), 311 (M+, 100).
1-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (28) [27]. Yellow solid. 85% yield (136 mg). M.P.: 126–128 °C. 1H-NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.65–7.57 (m, 2H), 7.45–7.35 (m, 2H), 7.28 (s, 1H), 7.17–7.10 (m, 1H), 7.00 (dd, J = 7.0, 1.0 Hz, 1H), 4.33–4.04 (m, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.55–1.99 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 134.9, 134.7, 130.9, 128.8, 127.9, 123.8, 123.5, 122.1, 120.6, 119.1, 117.2, 115.3, 44.2, 24.7, 22.7; LRMS (EI, 70 Ev) m/z (%): 267 (M+, 100).
1-(4-Fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (29) [27]. Yellow oil. 87% yield (131 mg). 1H-NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 1H), 7.67–7.60 (m, 2H), 7.24 (s, 1H), 7.17–7.08 (m, 3H), 6.99 (d, J = 7.0 Hz, 1H), 4.33–3.95 (m, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.51–2.08 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ161.14 (d, J = 243.9 Hz), 134.87, 132.19 (d, J = 3.2 Hz), 128.19 (d, J = 7.7 Hz), 123.60, 123.49, 122.07, 120.42, 119.03, 117.19, 115.60 (d, J = 3.8 Hz), 115.42, 44.17, 24.68, 22.77; LRMS (EI, 70 Ev) m/z (%): 251 (M+, 100).
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (30). Yellow oil. 71% yield (110 mg). 1H-NMR (500 MHz, CDCl3) δ 7.95 (d, J = 1.2 Hz, 1H), 7.93–7.88 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54–7.43 (m, 2H), 7.33 (s, 1H), 7.16 (dd, J = 8.1, 7.0 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 4.59–3.87 (m, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.42–2.13 (m, 2H).13C-NMR (126 MHz, CDCl3) δ 137.5, 134.9, 130.6, 129.7, 129.4, 128.5, 124.3, 123.2, 122.3, 121.0, 119.4, 119.2, 116.9, 114.2, 112.7, 44.3, 24.6, 22.6; HRMS (ESI) for C18H16N2 (M + H+): calcd. 259.1230, found 259.1231.
1-(Naphthalen-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (31) [27]. White solid. 78% yield (132 mg). M.P.: 126–128 °C. 1H-NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.92–7.84 (m, 3H), 7.86–7.78 (m, 2H), 7.47 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.45–7.38 (m, 2H), 7.15 (dd, J = 7.9, 7.1 Hz, 1H), 7.00 (dd, J = 7.0, 1.0 Hz, 1H), 4.35–4.05 (m, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.39–2.14 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 135.1, 134.1, 133.7, 131.8, 128.1, 127.7, 127.6, 126.0, 126.0, 124.9, 124.3, 124.2, 123.8, 122.1, 120.5, 119.1, 117.6, 116.4, 44.2, 24.7, 22.8; LRMS (EI, 70 Ev) m/z (%): 283 (M+, 100).
1-(Benzofuran-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (32) [27]. Yellow solid. 71% yield (116 mg). M.P.: 141–143 °C.1H-NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.60–7.54 (m, 1H), 7.53–7.46 (m, 1H), 7.27–7.16 (m, 3H), 7.03 (dd, J = 7.1, 1.1 Hz, 1H), 6.89 (d, J = 0.9 Hz, 1H), 4.45–3.88 (m, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.50–2.14 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 153.8, 153.5, 134.8, 130.0, 124.6, 122.8, 122.8, 122.6, 122.3, 121.0, 119.9, 119.5, 117.8, 110.5, 106.9, 98.7, 44.4, 24.6, 22.8; LRMS (EI, 70 Ev) m/z (%): 273 (M+, 100).
Ethyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylate (33) [27]. Yellow oil. 66% yield (96 mg). 1H-NMR (500 MHz, CDCl3) δ 7.49–7.36 (m, 1H), 7.13–7.00 (m, 2H), 6.93 (dd, J = 7.1, 1.1 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.17–4.08 (m, 2H), 3.78 (d, J = 0.8 Hz, 2H), 3.00 (t, J = 6.1 Hz, 2H), 2.33–2.05 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C-NMR (126 MHz, CDCl3) δ 172.2, 134.3, 125.2, 124.9, 121.6, 119.5, 118.5, 116.5, 106.8, 60.6, 43.9, 31.7, 24.6, 22.8, 14.2; LRMS (EI, 70 Ev) m/z (%): 243 (M+, 100).
1-Ethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (34) [27]. Yellow oil. 90% yield (100 mg). 1H-NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.9 Hz, 1H), 7.11–6.95 (m, 1H), 6.91 (dd, J = 7.0, 1.2 Hz, 1H), 6.87 (s, 1H), 4.28–3.89 (m, 2H), 2.99 (t, J = 6.1 Hz, 2H), 2.87–2.65 (m, 2H), 2.45–2.05 (m, 2H), 1.37–1.31 (m, 3H). 13C-NMR (126 MHz, CDCl3) δ 134.6, 125.1, 122.6, 121.5, 118.9, 118.2, 117.4, 116.6, 43.8, 24.7, 23.0, 18.7, 14.9; LRMS (EI, 70 Ev) m/z (%): 185 (M+, 100).

4. Conclusions

In summary, HFIP was found to be effective for Bischler indole synthesis under microwave irradiation in the absence of metal catalyst and additive. A variety of α-amino arylacetones were transformed into indole derivatives under the catalysis of HFIP. Interestingly, the pharmaceutically important pyrrolo[3,2,1-ij]quinoline derivatives were also successfully prepared by this simple protocol. This practical synthetic method has several advantages: Metal-free and additive-free conditions, H2O is the only by-product, and HFIP is readily recovered by rotary distillation.

Supplementary Materials

The following are available online. The 1H and 13C-NMR spectra of 2–22 and 24–34 can be found in the supplementary materials.

Author Contributions

G.Y. and C.-B.Z. performed the experiments and developed the reactions. G.Y. and Z.X.Z. prepared the data, H.-H.X. and R.-Y.T. had the idea for this work and prepared this manuscript with feedback.

Funding

We gratefully thank the Science Technology Program Project of Guangdong Province (No. 2016B020204005) and the Natural Science Foundation of Guangdong Province (Grant 2016A030313387) for the financial support.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 2–22, 24–34 are available from the authors.
Molecules 23 03317 sch001 550
Scheme 1. Indole drugs and a novel synthetic method.
Scheme 1. Indole drugs and a novel synthetic method.
Molecules 23 03317 sch001
Molecules 23 03317 sch002 550
Scheme 2. A possible reaction pathway.
Scheme 2. A possible reaction pathway.
Molecules 23 03317 sch002
Table
Table 1. Screening of optimal conditions a.
Table 1. Screening of optimal conditions a.
Molecules 23 03317 i001
EntrySolventTime/(min)T/°CYield (%) b
1HFIP3012076
2CF3CH2OH3012045
3i-PrOH3012021
4EtOH3012023
5HFIP308051
6HFIP3010072
7HFIP2012058
8HFIP4012088
9 cHFIP96012086
a Reaction conditions: 1a (0.6 mmol), solvent (3 mL), under microwave irradiation. b Isolated yields. c Under oil bath heating conditions.
Table
Table 2. HFIP-promoted synthesis of indoles under microwave irradiation a.
Table 2. HFIP-promoted synthesis of indoles under microwave irradiation a.
Molecules 23 03317 i002
Molecules 23 03317 i003
a Reaction conditions: 1 (0.6 mmol), in HFIP (3 mL) at 120 °C, under microwave irradiation for 40 min.

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Yao, G.; Zhang, Z.-X.; Zhang, C.-B.; Xu, H.-H.; Tang, R.-Y. HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation. Molecules 2018, 23, 3317. https://doi.org/10.3390/molecules23123317

AMA Style

Yao G, Zhang Z-X, Zhang C-B, Xu H-H, Tang R-Y. HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation. Molecules. 2018; 23(12):3317. https://doi.org/10.3390/molecules23123317

Chicago/Turabian Style

Yao, Guangkai, Zhi-Xiang Zhang, Cheng-Bei Zhang, Han-Hong Xu, and Ri-Yuan Tang. 2018. "HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation" Molecules 23, no. 12: 3317. https://doi.org/10.3390/molecules23123317

APA Style

Yao, G., Zhang, Z. -X., Zhang, C. -B., Xu, H. -H., & Tang, R. -Y. (2018). HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation. Molecules, 23(12), 3317. https://doi.org/10.3390/molecules23123317

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