Skip to main content
Organic and Medicinal Chemistry Letters
Download PDF

Silver triflate catalyzed synthesis of 3-aminoalkylated indoles and evaluation of their antibacterial activities

Organic and Medicinal Chemistry Letters volume 1, Article number: 10 (2011) Cite this article

Abstract

An efficient, one-pot synthesis was developed for 3-aminoalkylated indoles by three-component coupling reaction of aldehydes, N-methylanilines, and indoles using AgOTf as a catalyst. A series of twenty 3-aminoalkylated indoles was evaluated for their antibacterial activities against both Gram negative and Gram positive bacteria. Compounds 4b and 4r showed good antibacterial activity against both Gram positive and Gram negative strains. However, inversing the property of substituent (from 4r to 4q) resulted in the significant fall in the magnitude of antibacterial activity against Escherichia coli.

Introduction

Antimicrobial resistance continues to grow quickly among key microbial pathogens and has become a severe global problem in recent years. Bacterial resistance to almost all available antibacterial agents has been reported [1]. Because of this many infectious diseases, such as HIV infection, staphylococcal infection, tuberculosis, influenza, gonorrhea, candida infection, and malaria, are becoming difficult to treat. Thus, along with trying to control bacterial resistance there is an urgent need for new potent classes of antibiotics with novel modes of action.

The indole scaffold is a prominent and privileged structural motif which is embodied in a myriad of natural products and molecules of pharmaceutical interest in a variety of therapeutic areas [2, 3]. They possess a wide spectrum of biological activities such as antibacterial [4], anticonvulsant, and antihypertensive activity. bis-Indole-based compounds have been reported to have broad-spectrum antibacterial activities against antibiotic-resistant strains and are currently being pursued as topical agents (Figure 1) [5–7]. 1,2,3,4-Tetrahydropyrazino [1, 2] indoles [8] and triazino [[8],6-b] indoles [9] have been reported to have antifungal properties. Hapalindole A isolated from the blue green algae Hapalosiphon fontinalis is a 3-substituted indole derivative. It exhibits potent antibacterial and antimycotic activities [10]. The antibacterial activity of 3-substituted indole derivatives has not been much studied. Owing to interesting chemical and biological properties of indole molecules, development of efficient methods that allow rapid access to functionalized indoles with different substitution patterns constitutes an emerging area in organic synthesis.

Figure 1
figure 1

Chemical structure of bis -indole derivatives used as antibacterial agents.

Full size image

Multicomponent reactions have received a great attention of organic chemists as they can provide drug-like molecules with several degrees of structural diversity in a one-pot operation and offer significant advantages over conventional linear-type syntheses such as high atom economy and E-factors, low cost, reduction in overall reaction time, and operational simplicity. There are only a few methods available for the synthesis of 3-aminoalkylated indoles which have been found in many natural products. Recently, a one-pot multicomponent method was developed for the synthesis of 3-aminoalkylated indoles by the reaction of aldehyde, amine, and indole [11–14]. The reaction requires longer time, high temperature, and is generally accompanied by formation of bis-indolyl compound. Thus, there is still high need for the development of an efficient and straightforward method for the synthesis of 3-substituted indole derivatives. In continuation to our interest in novel reaction methodologies under environmentally friendly conditions [15, 16], we herein report an efficient silver triflate catalyzed synthesis of 3-aminoalkylated indoles and their antibacterial activities.

Experimental

General

Melting points were determined in open capillary tubes on a MPA120-Automated Melting Point apparatus and are uncorrected. The1H and13C NMR spectra were recorded on a Bruker Heaven 11400 (400 MHz) spectrometer using TMS as internal standard and the chemical shifts are expressed in ppm. All the metal triflates, indole, N-methylaniline, and aldehydes were purchased from Sigma-Aldrich. The products were purified by column chromatography using silica gel (60-120 mesh, S. D. Fine, India). The bacterial cultures (Bacillus subtilis MTCC 121, Staphylococcus aureus MTCC 96 and Escherichia coli MTCC 1652) were procured from Microbial Type Culture Collection, Institute of Microbial Technology, Chandigarh, India. Dimethyl sulfoxide (DMSO) and chloramphenicol (standard broad spectrum antibiotic) were used as negative and positive controls, respectively. The experiments were carried out in triplicates.

General procedure for preparation of 3-aminoalkylated indoles (4)

To a solution of N-methylaniline (114 mg, 1.2 mmol) and a benzaldehyde (1.0 mmol) in acetonitrile (10 mL), AgOTf (30 mg) was added. The reaction mixture was stirred at room temperature. After 30 min, indole or N-methylindole (0.71 mmol) was added to the reaction and the mixture was allowed it to stir for an additional 90 min. The progress of reaction was monitored by TLC. After completion of the reaction, solvent was removed under reduced pressure. To the residue, diethyl ether was added and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography on silica gel (100-200 mesh) using ethyl acetate/hexane as eluents to yield a pure product (4a-4r). All the compounds were characterized by ESI-MS,1H NMR, and13C NMR spectroscopic data.

N-((4-Chlorophenyl)(1H-indol-3-yl)methyl)-N-methylbenzenamine (4a)

Brown solid, m.p. 183-185°C;1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.37 (d, J = 4.0 Hz, 2H), 7.27-7.16 (m 5H), 7.03 (d, J = 8.0 Hz, 3H), 6.57 (d, J = 8.0 Hz, 3H), 5.55 (s, 1H), 2.83 (s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 147.5, 141.6, 137.0, 135.5, 132.9, 129.8, 129.1, 129.0, 127.3, 124.2, 121.9, 120.8, 120.2, 119.3, 113.1, 111.2, 47.6, 31.0, 21.1; ESI-MS (m/z): 346.9975 [M + H]+.

N-((1H-Indol-3-yl)(p-tolyl)methyl)-N-methylbenzenamine (4b)

Brown solid, m.p. 136-138°C;1H NMR (400 MHz, DMSO-d 6): δ 10.62 (s, 1H), 7.31 (d, J = 8.0 Hz 1H), 7.07-6.98 (m, 7H), 6.92-6.90 (m, 1H), 6.62-6.61 (m, 1H), 6.43 (d, J = 8.4 Hz, 2H), 5.46 (s, 1H), 5.40 (s, 1H), 2.49-2.48 (m, 3H), 2.24 (s, 1H);13C NMR (100 MHz, DMSO-d 6): δ 147.6, 141.7, 136.7, 135.4, 133.2, 129.7, 128.9, 128.8, 127.2, 123.9, 121.9, 120.9, 120.1, 119.3, 112.4, 111.0, 47.6, 31.0, 21.1; ESI-MS (m/z): 327.0665 [M + H]+.

N-((1H-Indol-3-yl)(4-methoxyphenyl)methyl)-N-methylbenzenamine (4c)

Brown solid, m.p. 177-179°C;1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 7.42-7. 26 (m, 3H), 7.16 (d, J = 7.6 Hz, 3H), 7.06-6.98 (m, 3H), 6.83 (d, J = 7.6, 2H), 6.56 (d, J = 8.0 Hz, 3H), 5.54 (s, 1H), 3.80 (s, 3H), 2.83 (s, 3H);13C NMR (100 MHz, CDCl3): δ 168.98, 157.90, 147.56, 136.99, 133.29, 129.85, 129.65, 127.13, 123.90, 121.97, 120.16, 119.27, 113.56, 112.40, 110.97, 55.21, 47.13, 30.95; ESI-MS (m/z): 343.0446 [M + H]+.

N-((1H-Indol-3-yl)(phenyl)methyl)-N-methylbenzenamine (4d)

Brown solid, mp 189-191°C;1H NMR (400 MHz, DMSO-d 6): δ 10.01 (s, 1H), 7.57 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26-7.20 (m, 4H), 7.17-7.14 (m, 2H), 7.09-6.86 (m, 3H), 6.60 (d, J = 2.0 Hz, 3H), 5.53 (s, 1H), 2.79 (s, 3H);13C NMR (100 MHz, CDCl3): δ 147.7, 144.9, 133.0, 130.1, 129.8, 129.0, 128.2, 127.2, 124.0, 122.0, 120.7, 120.1, 119.3, 112.4, 111.0, 48.0, 31.0; ESI-MS (m/z): 313.0450 [M + H]+.

N-((1H-Indol-3-yl)(4-hydroxy phenyl)methyl)-N-methylbenzenamine (4e)

Brown solid, m.p. 139-140°C;1H NMR (400 MHz, CDCl3): δ 7.929 (s, 3H), 7.41-7.01 (m, 7H), 6.75-6.57 (m, 4H), 5.84 (s, 1H), 5.31 (s, 1H), 2.83 (s, 3H);13C NMR (100 MHz, CDCl3): δ 153.8, 136.8, 133.5, 130.5, 130.1, 129.9, 127.1, 123.9, 123.6, 122.0, 120.0, 119.3, 115.1, 112.3, 111.1, 47.1, 39.5, 31.0; ESI-MS (m/z): 329.0347 [M + H]+.

N-((4-Hydroxy-3-bromophenyl)(1H-indol-3-yl)methyl)-N-methylbenzenamine (4f)

Brown solid, m.p. 187-189°C;1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 7.38-7.19 (m, 4H), 7.08-6.93 (m, 5H), 6.59 (s, 3H), 5.50 (s, 1H), 2.84 (s, 3H);13C NMR (100 MHz, CDCl3): δ 150.3, 147.6, 138.5, 136.9, 132.0, 129.7, 129.6, 127.0, 123.9, 123.6, 122.6, 122.1, 119.9, 119.4, 115.7, 112.6, 111.1, 110.1, 46.9, 31.0; ESI-MS (m/z): 406.9101 [M + H]+.

N-((1H-Indol-3-yl)(3-methoxyphenyl)methyl)-N-methylbenzenamine (4g)

Brown solid, m.p. 136-139°C;1H NMR (400 MHz, CDCl3): δ 7.939 (s, 2H), 7.43-7.22 (m, 3H), 7.20-7.17 (m, 3H), 7.08-6.86 (m, 2H), 6.84-6.81 (m, 2H), 6.57 (d, J = 7.6 Hz, 2H), 5.56 (s, 1H), 3.75 (s, 3H), 2.83 (s, 3H);13C NMR (100 MHz, CDCl3): δ 159.5, 148.5, 147.6, 146.5, 145.8, 136.7, 132.9, 129.7, 127.1, 123.9, 123.6, 122.0, 121.6, 120.1, 120.0, 115.0, 112.5, 111.2, 110.1, 55.5, 48.0, 31.0; ESI-MS (m/z): 343.0968 [M + H]+.

N-((1H-Indol-3-yl)(2,4-dimethoxyphenyl)methyl)-N-methylbenzenaminen (4h)

Brown solid, m.p. 123-126°C;1H NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.34-7.27 (m, 2H), 7.16-6.92 (m, 4H), 6.57-6.37 (m, 4H), 5.59 (s, 1H), 3.79 (s, 6H), 2.83 (s, 3H);13C NMR (100 MHz, CDCl3): δ 159.9, 157.9, 147.3, 136.8, 130.2, 130.0, 129.7, 125.7, 125.0, 123.9, 121.8, 120.2, 119.1, 112.4, 112.3, 110.9, 103.8, 95.6, 55.7, 55.3, 39.1, 31.1; ESI-MS (m/z): 373.0427 [M + H]+.

N-Methyl-N-((1-methyl-1H-indol-3-yl)(phenyl)methyl)benzenamine (4i)

Brown solid, mp 189-191°C;1H NMR (400 MHz, CDCl3): δ 7.28-7.22 (m, 8H), 7.04 (d, J = 8.0 Hz, 4H), 6.58-6.45 (m, 3H), 5.59 (s, 1H), 3.71 (s, 3H), 2.84 (s,3H);13C NMR (100 MHz, CDCl3): δ 129.73, 128.97, 128.71, 128.35, 128.18, 125.94, 124.55, 122.32, 121.67, 121.52, 121.52, 120.18, 119.04, 118.72, 112.37, 109.06, 94.27, 47.90, 32.68, 30.93. ESI-MS (m/z): 327.055 [M + H]+.

N-((4-Chlorophenyl)(1-methyl-1H-indol-3-yl)methyl)-N-methylbenzenamine (4j)

Brown solid, m.p. 208-210°C;1H NMR (400 MHz, CDCl3): δ 7.29-7.18 (m, 7H), 7.03 (d, J = 8.0 Hz, 3H), 6.57 (d, J = 4.0 Hz, 4H), 6.42 (s, 1H), 5.54 (s, 1H), 3.71 (s, 3H), 2.84 (s, 3H);13C NMR (100 MHz, CDCl3): δ 147.8, 143.5, 137.5, 132.5, 131.6, 130.9, 130.3, 130.2, 129.7, 129. 6, 128.7, 128.5, 128.3, 121.7, 120.5, 118.9, 118.6, 112.6, 112.4, 109.2, 47.3, 32.7, 30.9. ESI-MS (m/z): 361.002 [M + H]+.

N-Methyl-N-((1-methyl-1H-indol-3-yl)(p-tolyl)methyl)benzenamine (4k)

Brown solid, m.p. 202-204°C;1H NMR (400 MHz, CDCl3): δ 7.31-7.26 (m, 3H), 7.19-7.01 (m, 8H), 6.57 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H), 5.56 (s, 1H), 3.71 (s, 3H), 2.84 (s, 3H), 2.35 (s, 3H);13C NMR (100 MHz, CDCl3): δ 147.6, 142.0, 137.5, 135.3, 133.9, 129.7, 128.9, 128.8, 128.7, 127.5, 121.5, 120.2,119.2, 118.7, 112.4, 109.0, 47.5, 32.7, 31.0, 21.1; ESI-MS (m/z): 341.066 [M + H]+.

N-((1H-indol-3-yl)(3-nitrophenyl)methyl)-N-methylbenzenamine (4l)

Brown solid, m.p. 193-194°C;1H NMR (400 MHz, CDCl3): δ 8.13-8.07 (m, 3H), 7.59 (d, J = 8.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.06-7.02 (m, 3H), 6.66-6.57 (m, 3H), 5.68 (s, 1H), 2.84 (s, 3H);13C (100 MHz, CDCl3): δ 148.1, 147.8, 146.8, 136.5, 134.9, 130.9, 129.4, 128.8, 126.4, 123.8, 123.5, 122.1, 121.1, 119.4, 119.4, 119.1, 112.3, 112.2, 111.0, 47.5, 30.6; ESI-MS (m/z): 358.007 [M + H]+.

N-((5-Bromo-1H-indol-3-yl)(phenyl)methyl)-N-methylbenzenamine (4m)

Brown solid, m.p. 207-209°C;1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.39 (s, 1H), 7.27-7.23 (m, 7H), 7.02 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.0 Hz, 3H), 5.52 (s, 1H), 2.83 (s, 3H);13C NMR (100 MHz, CDCl3): δ 147.5, 144.3, 135.4, 132.7, 129.7, 128.9, 128.3, 126.2, 125.2, 125.0, 122.5, 120.4, 112.7, 112.5, 47.7, 31.1; ESI-MS (m/z): 390.9823 [M + H]+ and 392.9105 [M + 2 + H]+.

N-((5-Methoxy-1H-indol-3-yl)(4-methoxyphenyl)methyl)-N-methylbenzenamine (4n)

Brown solid, m.p. 203-205°C;1H NMR (400 MHz, DMSO-d 6): δ 10.62 (s, 1H), 7.24-7.20 (m, 3H), 7.09 (d, J = 4.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 6.70-6.66 (m, 3H), 6.60-6.53 (m, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.68 (s, 3H), 3.44 (s, 3H), 2.48 (s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 157.8, 153.1, 137.7, 132.3, 129.9, 129.7, 129.4, 127.4, 124.7, 118.5, 113.8, 112.5, 111.9, 111.0, 102.0, 55.7, 55.4, 47.0, 30.4; ESI-MS (m/z): 373.1681 [M + H]+.

N-((5-Methoxy-1H-indol-3-yl)(p-tolyl)methyl)-N-methylbenzenamine (4o)

Brown solid m.p. 197-199°C;1H NMR (400 MHz, DMSO-d 6): δ 10.60 (s, 1H), 7.21 (d, J = 4.0 Hz, 3H), 7.06 (d, J = 8.0 Hz, 3H), 6.91 (d, J = 4.0 Hz, 1H), 6.77 (s, 1H), 6.69-6.66 (m, 3H), 6.59-6.52 (m, 1H), 6.42 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.57 (s, 3H), 2.48 (s, 3H), 2.23 (s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 153.1, 148.9, 142.5, 135.0, 132.3, 129.5, 129.1, 128.9, 128.7, 127.5, 124.7, 118.3, 112.4, 111.9, 110.9, 102.0, 55.7, 47.4, 30.4, 21.1; ESI-MS (m/z): 357.1747 [M + H]+.

N-((5-Bromo-1H-indol-3-yl)(p-tolyl)methyl)-N-methylbenzenamine (4p)

Brown solid, m.p. 195-197°C;1H NMR (400 MHz, DMSO-d 6): δ 11.02 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 7.08-7.00 (m, 4H), 6.89 (d, J = 4.0 Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 2H), 5.39 (s, 1H), 2.48 (s, 3H), 2.22 (s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 148.7, 142.4, 135.7, 135.3, 131.7, 129.4, 129.2, 128.7, 126.0, 123.9, 121.7, 119.4, 114.0, 112.0, 111.3, 47.0, 30.4, 21.1; ESI-MS (m/z): 405.0683 [M + H]+ and 407.072 [M + 2 + H]+.

4-Chloro-N-((4-chlorophenyl)(5-methoxy-1H-indol-3-yl)methyl)benzenamine (4q)

Brown solid, m.p. 190-191°C;1H NMR (400 MHz, DMSO-d 6): δ 11.02 (s,1H), 7.29 (d, J = 4.0 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 4.0 Hz, 2H), 6.89 (d, J = 4.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 3H), 6.67 (s, 1H), 6.43 (d, J = 4.0 Hz, 2H), 5.39 (s, 1H), 3.69 (s, 3H), 2.47(s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 157.8, 148.6, 137.4, 135.8, 131.7, 129.8, 129.4, 128.9, 126.0, 123.9, 121.8, 119.3, 114.0, 112.0, 111.1, 55.4, 46.6, 30.4; ESI-MS (m/z): 421.0695 [M + H]+.

N-((4-Chlorophenyl)(5-methoxy-1H-indol-3-yl)methyl)-N-methylbenzenamine (4r)

Brown solid, m.p. 201-203°C;1H NMR (400 MHz, DMSO-d 6): δ 10.60 (s, 1H), 7.31-7.28 (m, 5H), 7.22-7.17 (m, 2H), 6.91 (s, 1H), 6.79 (s, 1H), 6.69 (s, 2H), 6.52 (s, 1H), 6.43 (d, J = 4.0 Hz, 2H), 5.73 (s, 1H), 3.30 (s, 3H), 2.47(s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 153.2, 148.9, 144.6, 132.3, 131.2, 130.8, 130.6, 129.5, 128.4, 127.3, 125.3, 125.2, 124.8, 117.7, 112.6, 112.0, 111.1, 55.7, 47.3, 30.3; ESI-MS (m/z): 377.1223 [M + H]+.

N-((4-chlorophenyl)(5-methoxy-1H-indol-3-yl)methyl)benzenamine (4s)

Brown solid, m.p. 198-201°C;1H NMR (400 MHz, MeOH) δ 7.258-7.164 (m, 6H), 6.95 (d, J = 8.0 Hz, 2H), 6.73-6.55 (m, 3H), 6.53 (d, J = 10.0 Hz, 2H), 5.47 (s, 1H), 3.61 (s, 3H);13C NMR (100 MHz, DMSO-d 6): δ 154.7, 148.3, 141.3, 132.3, 130.9, 129.3, 128.9, 128.7, 128.2, 123.4, 117.5, 112.5, 112.3, 112.1, 110.7, 109.5, 55.3; ESI-MS (m/z): 363.21 [M + H]+, 365.20 [M + H +2]+.

Anti-bacterial assay

Zone of inhibition assay was performed at 128 μg mL-1 concentration for all the compounds (4a-s) using disk diffusion method [17]. For this purpose, Mueller-Hilton (HiMedia, India) agar medium was prepared and sterilized by autoclaving at 121°C at 15 psi for 15 min. The medium was poured into sterile Petri dishes under aseptic conditions using laminar air flow chamber. After the solidification of medium, the suspension of the test organism (106 cfu mL-1) was swabbed onto the individual media plates using a sterile glass spreader. A sterile disk (9-mm diameter) impregnated with compound was placed over media surface and the plates were incubated at 37°C for 18-24 h under dark conditions. The determination as to whether the organism is susceptible, intermediate, or resistant was made by measuring the size of zone of inhibition in comparison with standard antibiotic.

MIC assay was performed to determine the lowest concentration of compound necessary to inhibit a test organism. MIC values were evaluated for all the compounds (4a-t) using broth microdilution method as per the standard guidelines [18]. Assay was carried out for the compounds at 0.5, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, 64.0, 128.0 μg mL-1 concentrations. A set of tubes containing Muller Hilton broth medium with different concentrations of compounds were prepared. The tubes were inoculated with bacterial cultures (106 cfu mL-1) and incubated on a rotary shaker (180 rpm) at 37°C for 18-24 h under dark conditions. MIC values were defined as lowest concentration of compound that prevented the visible growth of bacteria after the incubation period. All the experiments were performed in three replicates.

Results and discussion

Chemistry

Initially, we investigated reaction of indole benzaldehyde, and N-methylaniline to give 4a in acetonitrile using different Lewis acid catalysts (Table 1). Among different catalysts studied AgOTf gave highest yield of 4a (Table 1, entry 2). Among other catalysts, Ce(OTf)3, Yb(OTf)3 and pTSA gave good yield of 4a (Table 1, entries 7, 10, and 12). Formation of bis(indolyl)methane (5-32%) as side product was observed with most of the catalyst studied except with AgOTf, Ce(OTf)3, and Yb(OTf)3.

Table 1 Optimization of reaction condition for model reaction generating 4a
Full size table

Subsequently, we investigated different solvents such as DCM, DMSO, DMF, THF, acetonitrile, and ionic liquid [bmim][BF4] for the model reaction. Acetonitrile was found to give highest yield of 4a among all the screened solvent. In case of ionic liquid [bmim][BF4] imine was major product. In other solvents substrate did not consume completely and there was mixture of starting material, imine, and 4a. For further studies we selected AgOTf (10 mol%) as catalyst and acetonitrile as reaction medium of choice.

After determining the optimized reaction conditions, we next studied the substrate scope by taking indoles, aldehydes, and N-methyl anilines bearing different substituent for the synthesis of 3-aminoalkylated indoles (4). The results are summarized in Table 2. The structure of the synthesized compounds was confirmed by1H NMR,13C NMR, and mass spectroscopic data. A wide range of structurally diverse aldehydes gave the corresponding product 4 in good to excellent yields. Aromatic aldehyde having an electron-donating group gave higher yield as compared to aromatic aldehydes with electron withdrawing group (entry 12, Table 2). The reaction was equally effective for N-methylindole and 5-unsubstituted indoles affording the desired 3-aminoalkylated indoles in almost equally high yields (entries 13-18, Table 2). However, poor yield of corresponding 3-substituted indole was obtained from aniline (entry 19, Table 1). When aliphatic amines were used it did not result in 3-substituted indole under these conditions.

Table 2 Synthesis of 3-aminoalkylated indoles (4a-t) catalyzed by AgOTf
Full size table

Then, we investigated the possibility of recycling of the catalyst. After the first cycle for model reaction, the solvent was concentrated under vacuum. Diethyl ether was added to the residue obtained and filtered leaving behind AgOTf. The recovered AgOTf was again taken in a round bottom flask and charged with 4-chlorobenzaldehyde (1a), N-methylaniline (3), and acetonitrile and allowed to react for 30 min followed by the addition of indole and reaction was allowed to continue for additional 90 min. The above sequence was repeated four times to give 4a in good yields (88, 85, 83, and 80%) without much loss in catalytic activity of catalyst.

The reaction is assumed to proceed through two-step domino sequence. The first step is believed to be formation of iminium ion after reaction of the benzaldehyde and N-methylaniline. The next step is nucleophilic attack of indole on iminium ion followed by proton loss to give a 3-substituted indole. The structure of product is consistent with the synthesis of 3-aminoalkylated indoles via multicomponent condensation reaction of indoles, aldehyde, and amines [11–14].

Anti-bacterial activity

An array of 20 diversely substituted indoles was evaluated for in vitro antibacterial activity against both Gram positive and Gram negative bacteria. The results of antibacterial activity of compounds (4a-r) are shown in Table 2. The compounds indicating notable antibacterial activity are indicated in bold (Table 2). Compounds 4q, 4r, 4i, and 4b showed significant antibacterial activity against Gram positive bacteria and 4r, 4b, 4o, and 4l against Gram negative bacteria. These results suggest that analog 4b and 4r can be used as potential broad spectrum antibacterial agents as they are potent against both Gram positive and Gram negative bacteria.

Compound 4d (without functional groups) was not showing any antibacterial activity, however, substitution of electron withdrawing groups at phenyl ring (4l, 4f) exhibited increase in antibacterial activity against Gram negative organisms. Interestingly, introduction of electron-releasing group at phenyl ring (4b) showed good activity against both the Gram positive and Gram negative bacterial strains.

Among the compounds 4i-k, the compound 4i showed antibacterial activity against only B. subtilis but substituting the R'' position with an electron withdrawing group (4j, chloro) results in relatively less activity. In contrast, introducing an electron-releasing group at R'' position (4k, methoxy) made it further ineffective toward B. subtilis but found to be active against other two bacterial strains (Table 3).

Table 3 Zone of inhibition and MIC values of compounds against Gram positive and Gram negative bacteria
Full size table

Conclusion

In conclusion, we have developed an efficient and straightforward synthesis of 3-aminoalkylated indoles by one-pot three-component coupling reaction of a benzaldehyde, N-methylaniline, and indole or N-methylindole using AgOTf as catalyst. Simplicity, easy work up, short reaction time, environment friendly catalyst, and excellent yield are the advantages which will make this a practical method for synthesis of 3-aminoalkylated indoles over existing methods. All the synthesized compounds were evaluated for their antibacterial activities against both Gram negative and Gram positive bacteria. Compounds 4b and 4r showed good antibacterial activity against both Gram positive and Gram negative strains. However, inversing the property of substituent (from 4r to 4q) resulted in the significant fall in the magnitude of antibacterial activity against E. coli. This study provides insights for further optimizing of substituted indoles for the discovery of potent antibacterial agents.

References

  1. Raghunath D: Emerging antibiotic resistance in bacteria with special reference to India. J Biosci 2008, 33: 593–603. 10.1007/s12038-008-0077-9

    Article  CAS  Google Scholar 

  2. Lounasmaa M, Tolvanen A: Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat Prod Rep 2000, 17: 175–191. 10.1039/a809402k

    Article  CAS  Google Scholar 

  3. Hibino S, Choshi T: Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat Prod Rep 2002, 19: 148–180. 10.1039/b007740m

    Article  CAS  Google Scholar 

  4. Collinus JF: Antibiotics, proteins and nucleic acids. Br Med Bull 1965, 21: 223–228.

    Google Scholar 

  5. Panchal RG, Ulrich RL, Lane D, Butler MM, Houseweart C, Opperman T, Williams JD, Peet NP, Moir DT, Nguyen T, Gussio R, Bowlin T, Bavari S: Novel broad-spectrum bis-(imidazolinylindole) derivatives with potent antibacterial activities against antibiotic-resistant strains. Antimicrob Agents Chemother 2009, 53: 4283–4291. 10.1128/AAC.01709-08

    Article  CAS  Google Scholar 

  6. Opperman TJ, Williams JD, Houseweart C, Panchal RG, Bavari S, Peet NP, Moir DT, Bowlin TL: Efflux-mediated bis-indole resistance in Staphylococcus aureus reveals differential substrate specificities for MepA and MepR. Bioorg Med Chem 2010, 18: 2123–2130. 10.1016/j.bmc.2010.02.005

    Article  CAS  Google Scholar 

  7. Butler MM, Williams JD, Peet NP, Moir DT, Panchal RG, Bavari S, Shinabarger DL, Bowlin TL: Comparative in vitro activity profiles of novel bis-indole antibacterials against gram-positive and gram-negative clinical isolates. Antimicrob Agents Chemother 2010, 54: 3974–3977. 10.1128/AAC.00484-10

    Article  CAS  Google Scholar 

  8. Tiwari RK, Singh D, Singh J, Yadav V, Pathak AK, Dabur R, Chhillar AK, Singh R, Sharma GL, Chandra R, Verma AK: Synthesis and antibacterial activity of substituted 1,2,3,4-tetrahydropyrazino [1,2-a]indoles. Bioorg Med Chem Lett 2006, 16: 413–416. 10.1016/j.bmcl.2005.09.066

    Article  CAS  Google Scholar 

  9. Speirs RJ, Welch JT, Cynamon MH: Activity of n -propyl pyrazinoate against pyrazinamide-resistant mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide. Antimicrob Agents Chemother 1995, 39: 1269–1271.

    Article  CAS  Google Scholar 

  10. Moore RE, Cheuk C, Patterson GML: Hapalindoles: new alkaloids from the blue-green alga Hapalosiphon fontinalis. J Am Chem Soc 1984, 106: 6456–6457. 10.1021/ja00333a079

    Article  CAS  Google Scholar 

  11. Yadav DK, Patel R, Srivastava VP, Watel G, Yadav LDS: Bromodimethylsulfonium bromide (BDMS)-catalyzed multicomponent synthesis of 3-aminoalkylated indoles. Tetrahedron Lett 2010, 51: 5701–5703. 10.1016/j.tetlet.2010.08.065

    Article  CAS  Google Scholar 

  12. Srihari P, Sing VK, Bhunia DC, Yadav JS: One-pot three-component coupling reaction: solvent-free synthesis of novel 3-substituted indoles catalyzed by PMA-SiO 2 . Tetrahedron Lett 2009, 50: 3763–3766. 10.1016/j.tetlet.2009.02.176

    Article  CAS  Google Scholar 

  13. Das B, Kumar JN, Kumar AS, Damodar KA: Facile synthesis of 3-[(n-alkylanilino)(aryl)methyl]indoles using TCT. Synthesis 2010, 914–916.

    Google Scholar 

  14. Rao VK, Chhikara BS, Shirazi AN, Tiwari R, Parang K, Kumar A: 3-Substitued indoles: one-pot synthesis and evaluation of anticancer and Src kinase inhibitory activities. Bioorg Med Chem Lett 2011, 21: 3511–3514. 10.1016/j.bmcl.2011.05.010

    Article  CAS  Google Scholar 

  15. Kumar A, Rao MS, Rao VK: Sodium dodecyl sulfate-assisted synthesis of 1-(benzothiazolylamino)-methyl-2-naphthols in water. Aust J Chem 2010, 63: 1538–1540. 10.1071/CH10209

    Article  CAS  Google Scholar 

  16. Kumar A, Rao MS, Rao VK: Cerium triflate: an efficient and recyclable catalyst for chemoselective thioacetalization of carbonyl compounds under solvent-free conditions. Aust J Chem 2010, 63: 135–140. 10.1071/CH09296

    Article  CAS  Google Scholar 

  17. Clinical and Laboratory Standards Institute (NCCLS): Performance standards for antimicrobial disk susceptibility tests: approved standard, 9th edn. (M2-A9). Clinical and Laboratory Standards Institute, Wayne, PA;

  18. Clinical and Laboratory Standards Institute (NCCLS): Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard, 7th edn. (M7-A7). Clinical and Laboratory Standards Institute, Wayne, PA; 2006.

    Google Scholar 

Download references

Acknowledgements

The financial support in the form of research project No. 39-733/2010 (SR) from University Grant Commission (UGC), New Delhi is highly acknowledged. VKR thanks BITS Pilani for research fellowship.

Author information

Authors and Affiliations

  1. Department of Chemistry, Birla Institute of Technology and Science, Pilani, 333 031, Rajasthan, India

    Vagicherla Kameshwara Rao, Madharam Sudershan Rao & Anil Kumar

  2. Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, 333 031, Rajasthan, India

    Navin Jain & Jitendra Panwar

Authors
  1. Vagicherla Kameshwara Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Madharam Sudershan Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Navin Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jitendra Panwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anil Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anil Kumar.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Rao, V.K., Rao, M.S., Jain, N. et al. Silver triflate catalyzed synthesis of 3-aminoalkylated indoles and evaluation of their antibacterial activities. Org Med Chem Lett 1, 10 (2011). https://doi.org/10.1186/2191-2858-1-10

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/2191-2858-1-10

Keywords