Next Article in Journal
Internalization of Titanium Dioxide Nanoparticles Is Cytotoxic for H9c2 Rat Cardiomyoblasts
Next Article in Special Issue
Synthesis of Spirooxindole-O-Naphthoquinone-Tetrazolo[1,5-a]Pyrimidine Hybrids as Potential Anticancer Agents
Previous Article in Journal
A Simple, Sensitive, and Reliable Method for the Simultaneous Determination of Multiple Antibiotics in Vegetables through SPE-HPLC-MS/MS
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)3 in Solvent-Free Conditions

1
College of Chemistry and Chemical Engineering, Xinxiang University, Xinxiang 453003, Henan, China
2
School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, Henan, China
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(8), 1954; https://doi.org/10.3390/molecules23081954
Submission received: 11 July 2018 / Revised: 28 July 2018 / Accepted: 31 July 2018 / Published: 6 August 2018
(This article belongs to the Special Issue Multicomponent Reactions)

Abstract

:
Novel 1,4-naphthoquinones possessing indole scaffolds were prepared by the reaction of 2-hydroxy-1,4-naphthoquinone-substituted salicylic aldehydes and indoles using In(OTf)3 as a catalyst. The method has the advantages of simple operation, mild reaction conditions, and friendly environment.

Graphical Abstract

1. Introduction

Multi-component reactions, in which multiple reactants are combined to form a single, more complex system, have been used extensively to synthesize chemically and biologically important compounds [1]. This reaction provides a wide range of possibilities to efficiently construct highly complex molecules in one process, thus avoiding complex purification operations and saving solvents and reagents. In the past decade, the three component and four component reactions have undergone tremendous development [2].
Quinone skeletons are present in a broad range of natural products and synthetic molecules with important biological activities [3]. Among them, 1,4-naphthoquinone scaffolds have received considerable attention because of the synthetic challenges associated with their changeable molecular architecture and their interesting biological properties, such as their anticancer [4], antifungal [5], antiviral [6], and anti-inflammatory activities [7]. 1,4-Naphthoquinone skeleton can be found in a wide range of natural products, such as α-lapachone [8], rhinacanthin C [9], and avicequinone C [10] (Figure 1). In this context, the development of facile methods to access these new targets with structural diversity is very desirable and valuable for drug discovery.
Bioactive indole compounds are widely distributed in nature [11] and presented in the market [12] as active pharmaceutical ingredients [13,14]. Moreover, in modern times, indole derivatives are significant players in a diverse array of markets such as dyes, plastics, agriculture, vitamin supplements, over-the-counter drugs, flavor enhancers, and perfumery.
Herein, we describe a simple and efficient method for rapid preparation of 1,4-naphthoquinones possessing indole scaffolds using a catalytic amount of In(OTf)3 under solvent-free conditions (Scheme 1). As far as we know, it is probably the first example of synthesis 1,4-naphthoquinones possessing indole scaffolds using In(OTf)3 as catalyst under solvent-free conditions. As a result, 1,4-naphthoquinones-fused indoles, which combine two kinds of bioactive heterocyclic nuclei, are expected to become a research hotspot in pharmacology. Further studies to delineate the activities of the novel compounds are underway.

2. Results and Discussion

Initially, we began our studies by evaluating the reaction between 2-hydroxy-1,4-naphthoquinone, salicylic aldehyde, and 2-phenylindole using In(OTf)3 (20 mol %) as the catalyst in toluene as the solvent at 110 °C for 8 h, which provided the desired product 4a in a 35% yield. Encouraged by this preliminary result, the screening of solvents and catalysts, as well as the in fluence of temperature and catalyst loading, was investigated to establish the optimized reaction conditions (Table 1). Solvent effects were first investigated (Table 1, compare entries 1–6). The neat reaction provided higher yields than those using other organic solvents (entries 2–6). To improve the yields, we then examined this reaction using different catalysts; the In(OTf)3 catalyst showed the best performance (entry 6). When this reaction was carried out without In(OTf)3 or in the presence of p-TsOH, H2SO4, FeCl3, Sc(OTf)3, or InCl3, the product was obtained in low yield (Table 1, entries 7–12). The effect of the reaction temperature was investigated; it was observed that the reaction performed at 110 °C provided the best results (entries 6, 13–15). We also evaluated the amount of In(OTf)3 required for the reaction; the results from Table 1 (entries 6, 16–18) show that 10 mol % In(OTf)3 at 110 °C under solvent-free conditions is optimal for the reaction.
Under optimal conditions, we then developed the design and diversity-oriented synthesis of novel 1,4-naphthoquinones possessing indole scaffolds. Different substituted salicylic aldehydes and indoles were applied to this reaction to access structural diversity of target molecules. As illustrated in Table 2, the method is suitable for a wide scope of substituted salicylic aldehydes and indoles. In all cases, the three component reactions are regioselective to 1,4-naphthoquinone derivatives 4, and their structures were characterized by analytical and spectroscopic methods. For example, the infrared spectra of 4a exhibited that the absorption of two C=O bonds existed at 1650 and 1632 cm−1; the high resolution mass spectrum of 4a showed the quasi ion peak ([M + Na]+) at m/z = 476.1262, which agreed with the 1:1:1 adduct of 2-phenylindole, salicylic aldehyde, and 2-hydroxy-1,4-naphthoquinone with the loss of two water molecules. The 1H NMR spectrum of 4a displayed two singlets at δ = 5.82 ppm and δ = 11.39 ppm, which belong to CH group of C-12 position and NH protons, respectively. 13C NMR spectrum of 4a exhibited 29 distinct resonances. Among them, three characteristic signals at δ = 29.5 ppm (arising from the Ar–CH group), 183.9, and 178.2 ppm (due to the two nonequivalent carbonyl groups) were shown.
In Scheme 2, we show the suggested ways to form the hybrid. It is possible that lawone initially reacts with substituted salicylic aldehyde 2 to form olefin 5, which goes through a nucleophilic addition of indole to form the Mannich-type intermediate 6. This step is then followed by an intramolecular dehydration to yield to product 4.

3. Materials and Methods

3.1. General Information

Melting points were determined on a XT-4 binocular microscope and were uncorrected. NMR spectra were determined on Bruker AV-400 spectrometer at room temperature using TMS as internal standard. IR spectra were determined on FTS-40 infrared spectrometer. High resolution mass spectra were recorded on a bruker micrOTOF-QIII mass spectrometer. Commercially available reagents were used throughout without further purification, unless otherwise stated.

3.2. General Procedure for the Synthesis of Compounds 4

To a mixture of indole (1 mmol), substituted salicylic aldehyde (1 mmol) and 2-hydroxy-1,4-naphthoquinone (1 mmol), In(OTf)3 (0.1 mmol) was added. The mixture was stirred at 110 °C for 5–7 h. After completion of the reaction (TLC), the reaction mixture is cooled to room temperature, treated with water (10 mL), extracted with CH2Cl2 (2 × 10 mL), and filtered, and the solvent is evaporated in vacuo. Solvent was evaporated and the crude product purified by silica gel column chromatography using petroleum ether: dichloromethane (v:v = 1:3) as eluent to afford the pure product 4 (the copy of IR, 1H NMR, 13C NMR, and HMRS of compounds 4 see Supplementary Materials).
12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4a): Reddish-brown powder, m.p. 260–262 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.39 (s, 1H), 8.07–8.00 (m, 3H), 7.90–7.80 (m, 3H), 7.59 (t, 2H, J = 7.6 Hz), 7.49 (t, 1H, J = 7.2 Hz), 7.31–7.28 (m, 4H), 7.23–7.21 (m, 2H), 7.19 (t, 2H, J = 1.2 Hz), 5.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.9, 178.2, 150.9, 148.2, 136.3, 135.3, 135.2, 134.4, 133.4, 131.8, 130.7, 129.8, 129.6 (2C), 129.2 (2C), 128.7, 128.6, 126.9, 126.5, 126.3, 126.1, 124.1, 121.8, 121.3, 119.8, 118.1, 117.2, 115.2, 112.0, 29.5; IR (KBr): v 3360, 1632, 1650 cm−1; HRMS-ESI (m/z): calcd for C31H19NNaO3 [M + Na]+: 476.1263, found: 476.1262.
2-Bromo-12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4b): Red powder, m.p. 279–280 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.46 (s, 1H), 8.04–8.02 (m, 1H), 7.93–7.78 (m, 5H), 7.58 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.37–7.32 (m, 3H), 7.24 (d, J = 8.8 Hz ,1H), 7.04 (t, J = 7.6 Hz ,1H), 6.92–6.89 (m, 2H), 5.79 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.6, 177.8, 150.5, 147.3, 136.2, 135.6, 135.2, 134.5, 133.2, 132.0, 131.6 (2C), 130.6, 129.5 (2C), 129.3 (2C), 128.7, 126.8, 126.6, 126.5, 126.3, 122.0, 120.9, 120.0, 119.6, 118.0, 117.4, 114.8, 112.2, 19.4; IR (KBr): v 3379, 1671, 1634 cm−1; HRMS-ESI (m/z): calcd for C31H18BrNNaO3 [M + Na]+: 554.0368, found: 554.0362.
2-Chloro-12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4c): Red powder, m.p. 275-276 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.46 (s, 1H), 8.05–8.03 (m, 1H), 7.93–7.80 (m, 5H), 7.58 (t, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.34–7.32 (m, 3H), 7.27–7.24 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz ,1H), 6.77 (d, J = 2.0 Hz ,1H), 6.92–6.89 (m, 2H), 5.81 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.6, 177.9, 150.6, 146.9, 136.2, 135.6, 135.2, 134.5, 133.2, 131.7, 130.7, 129.5 (2C), 129.4 (2C), 129.3, 129.0, 128.8, 128.7, 126.8, 126.5, 126.3, 126.2, 122.0, 120.8, 120.0, 119.3, 118.0, 114.8, 112.2, 29.6; IR (KBr): v 3377, 1675, 1634 cm−1; HRMS-ESI (m/z): calcd for C31H18ClNNaO3 [M + Na]+: 510.0873, found: 510.0858.
4-Bromo-2-chloro-12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4d): Red powder, m.p. 243–244 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.49 (s, 1H), 8.07–8.04 (m, 1H), 7.90–7.80 (m, 5H), 7.67 (d, J = 2.4 Hz, 1H), 7.57–7.46 (m, 3H), 7.39–7.32 (m, 2H), 7.08–7.04 (m, 1H), 6.97–6.93 (m, 1H), 6.78 (d, J = 2.4 Hz ,1H), 5.85 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.5, 177.4, 150.3, 144.2, 136.1, 136.0, 135.2, 134.6, 133.0, 131.6, 130.7, 129.6, 129.5 (2C), 129.2 (2C), 128.8, 128.5, 127.7, 127.4, 126.8, 126.5, 126.4, 122.1, 121.3, 120.1, 118.0, 114.6, 112.2, 112.0, 30.0; IR (KBr): v 3288, 1685, 1637 cm−1; HRMS-ESI (m/z): calcd for C31H17BrClNNaO3 [M + Na]+: 587.9978, found: 587.9968.
2-Methyl-12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4e): Orange-red powder, m.p. 244–245 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.38 (s, 1H), 8.03–7.99 (m, 3H), 7.86–776 (m, 3H), 7.60 (t, J = 7.6 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.32–7.26 (m, 2H), 7.13 (d, J = 8.0 Hz ,1H), 7.03–6.96 (m, 2H), 6.86 (t, J = 7.2 Hz, 2H), 6.63 (s, 3H), 5.72 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.7, 178.2, 150.9, 146.2, 136.3, 135.3, 135.1, 134.3, 133.5, 131.8, 130.7, 129.8, 129.5 (2C), 129.4 (2C), 129.2, 128.5, 126.9, 126.4, 126.3, 123.7, 121.8, 121.1, 119.7, 118.1, 117.0, 115.2, 112.0, 29.5, 20.8; IR (KBr): v 3372, 1677, 1631 cm−1; HRMS-ESI (m/z): calcd for C32H21NNaO3 [M + Na]+: 490.1419, found: 490.1410.
2-Nitro-12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4f): Yellow powder, m.p. 245–246 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.07–8.04 (m, 1H), 7.90–7.80 (m, 5H), 7.67 (d, J = 2.4 Hz, 1H), 7.57–7.46 (m, 3H), 7.39–7.32 (m, 2H), 7.08–7.04 (m, 1H), 6.97–6.93 (m, 1H), 6.78 (d J = 2.4 Hz, 1H), 5.85 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.6, 177.6, 152.3, 150.2, 144.7, 136.2, 136.0, 135.3, 134.7, 133.0, 131.6, 130.7, 129.5 (2C), 129.3 (2C), 128.9, 126.8, 126.6, 126.4, 125.7, 125.5, 124.4, 122.1, 121.3, 120.1, 118.7, 118.1, 114.9, 112.2, 29.6; IR (KBr): v 3358, 1680, 1665, 1644 cm−1; HRMS-ESI (m/z): calcd for C31H18N2NaO5 [M + Na]+: 521.113, found: 521.1106.
2-Methoxy-12-(2-Phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4g): Yellow powder, m.p. 211–212 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.35 (s, 1H), 8.06–7.98 (m, 3H), 7.88–7.78 (m, 3H), 7.59 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.31–7.26 (m, 2H), 7.02–6.98 (m, 1H), 6.88–6.83 (m, 2H), 6.73 (d J = 7.4 Hz, 1H), 6.60–6.58 (m, 1H), 5.72 (s, 1H), 3.71 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 183.8, 178.2, 159.4, 150.9, 148.7, 136.3, 135.2, 135.1, 134.4, 133.5, 131.8, 130.7, 130.3, 129.5 (2C), 129.2 (2C), 128.5, 126.9, 126.4, 126.3, 121.8, 121.6, 119.7, 118.2, 115.9, 115.4, 113.2, 112.0, 101.7, 55.9, 29.0; IR (KBr): v 3326, 1682, 1638 cm−1; HRMS-ESI (m/z): calcd for C32H21NNaO4 [M + Na]+: 506.1368, found: 506.1358.
2,4-Dibromo-12-(2-phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4h): Red powder, m.p. 252–253 °C, 1H NMR (400 MHz,DMSO-d6) δ: 11.50 (s, 1H), 8.06 (dd, J = 2.0, 7.6 Hz, 1H), 7.88–7.82 (m, 5H), 7.77 (d, J = 2.4 Hz, 1H), 7.57–7.47 (m, 3H), 7.39–7.33 (m, 2H), 7.08–7.04 (m, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.0 Hz, 1H), 5.85 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.5, 177.4, 150.3, 144.6, 136.1, 136.0, 135.2, 134.6, 134.2, 133.0, 131.6, 131.5, 130.7, 129.5 (2C), 129.3 (2C), 128.8, 128.1, 126.8, 126.5, 126.4, 122.1, 121.4, 120.1, 118.0, 117.3, 114.7, 112.2, 112.1, 29.9; IR (KBr): v 3289, 1683, 1635 cm−1; HRMS-ESI (m/z): calcd for C31H17Br2NNaO3 [M + Na]+: 631.9473, found: 631.9462.
3-Methoxy-12-(2-phenyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4i): Orange-red powder, m.p. 244–245 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.40 (s, 1H), 8.05–8.00 (m, 3H), 7.88–7.78 (m, 3H), 7.61 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.32–7.20 (m, 3H), 7.03–6.99 (m, 1H), 6.88–6.84 (m, 1H), 6.77 (dd, J = 2.8, 8.8 Hz, 1H), 5.75 (s, 1H), 3.51 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.8, 178.2, 156.8, 151.2, 142.1, 136.3, 135.3, 135.1, 134.3, 133.4, 131.8, 130.7, 129.6 (2C), 129.3 (2C), 128.6, 126.8, 126.4, 126.3, 125.1, 121.8, 120.2, 119.7, 118.3, 118.1, 115.0, 114.1, 114.0, 112.1, 55.5, 29.9; IR (KBr): v 3304, 1683, 1638 cm−1; HRMS-ESI (m/z): calcd for C32H21NNaO4 [M + Na]+: 506.1368, found: 506.1357.
4-Bromo-2-chloro-12-(1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4j): Yellow-brown powder, m.p. 248–250 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.08 (s, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.92–7.84 (m, 3H), 7.73 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.33–7.31 (d, J = 7.6 Hz, 1H), 7.08–7.00 (m, 2H), 5.71 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.2, 177.7, 150.5, 144.9, 136.7, 135.0, 134.6, 131.7, 131.3, 131.2, 129.6, 129.0, 128.6, 126.6, 126.2, 125.5, 124.9, 122.1, 121.8, 119.7, 118.5, 118.2, 112.3, 111.8, 29.9; IR (KBr): v 3403, 1633, 1680 cm−1; HRMS-ESI (m/z): calcd for C25H13BrClNNaO3 [M + Na]+: 511.9665, found: 511.9664.
2-chloro-12-(1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4k): Brown powder, m.p. 343–345 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.04 (s, 1H), 7.91–7.89 (m, 1H), 7.85–7.82 (m, 3H), 7.61 (d, J = 8.0 Hz, 1H), 7.46–7.30 (m, 5H), 7.06–6.96 (m, 2H), 5.67 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.4, 178.2, 150.5, 147.6, 136.7, 135.0, 134.4, 131.8, 131.1, 129.5, 129.4, 128.5, 127.1, 126.5, 126.2, 125.6, 124.6, 121.7, 119.5, 119.3, 118.5 (2C), 112.3, 29.5; IR (KBr): v 3410, 1634, 1685 cm−1; HRMS-ESI (m/z): calcd for C25H14ClNNaO3 [M + Na]+: 434.0560, found: 434.0559.
2-Bromo-12-(1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4l): Reddish-brown powder, m.p. 262–264 °C, 1H NMR (400 MHz, DMSO-d6) δ: 8.10–8.07 (m, 1H), 7.91–7.82 (m, 3H), 7.61–7.58 (m, 2H), 7.46–7.43 (m, 1H), 7.36–7.30 (m, 3H), 7.04 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.3, 178.2, 150.5, 148.1, 136.7, 135.0, 134.4, 132.5, 131.8, 131.4, 131.1, 127.5, 126.5, 126.2, 125.6, 124.6, 121.8, 121.7, 119.7, 119.5 (2C), 118.5, 117.4, 112.3, 29.4; IR (KBr): v 3410, 1633, 1683 cm−1; HRMS-ESI (m/z): calcd for C25H14BrNNaO3 [M + Na]+: 478.0055, found: 478.0056.
2-Fluoro-12-(1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4m): Reddish-brown powder, m.p. 330–332 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.02 (s, 1H), 8.10–8.08 (m, 1H), 7.92–7.82 (m, 3H), 7.61 (d, J = 8.8 Hz, 1H), 7.43–7.40 (m, 1H), 7.35–7.22 (m, 3H), 7.15–7.10 (m, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 6.8 Hz, 1H), 5.66 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.4, 178.4, 160.6, 150.7, 145.2, 136.8, 135.0, 134.4, 131.8, 131.1, 126.5, 126.2, 125.6, 124.5, 121.6, 121.2, 119.5, 119.2, 119.1, 118.5, 118.4, 115.8, 115.7, 112.2, 29.8; IR (KBr): v 3416, 1650, 1638 cm−1; HRMS-ESI (m/z): calcd for C25H14FNNaO3 [M + Na]+: 418.0855, found: 418.0858.
2-Chloro-12-(2-methyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4n): Reddish-brown powder, m.p. 264–265 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 8.05–7.79 (m, 4H), 7.41 (d, J = 8.8 Hz, 1H), 7.33–7.30 (m, 1H), 7.19 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 5.57 (s, 1H), 2.63 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 183.4, 178.2, 149.9, 147.8, 135.5, 135.1, 134.5, 133.4, 131.7, 130.8, 129.9, 129.6, 128.7, 126.7, 126.5, 126.2, 121.1, 120.5, 119.3, 119.0, 116.9, 113.5, 111.4, 29.1, 12.1; IR (KBr): v 3379, 1679, 1660, 1635 cm−1; HRMS-ESI (m/z): calcd for C26H16ClNNaO3 [M + Na]+: 448.0716, found: 448.0707.
2-Methyl-12-(2-methyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4o): Reddish-brown powder, m.p. 269–270 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.92 (s, 1H), 8.01 (dd, J = 4.0, 7.2 Hz, 1H), 7.85–7.75 (m, 3H), 7.20–7.17 (m, 2H), 7.09–7.02 (m, 2H), 6.90–6.85 (m, 2H), 6.77 (t, J = 7.6 Hz, 1H), 5.44 (s, 1H), 2.59 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 183.5, 178.5, 150.2, 146.9, 135.4, 135.3, 135.0, 134.3, 132.9, 131.7, 130.8, 130.4, 129.3, 126.8, 126.4, 126.1, 123.6, 121.4, 120.4, 119.1, 117.1, 116.8, 114.1, 111.2, 29.1, 20.7, 12.1; IR (KBr): v 3375, 1673, 1632 cm−1; HRMS-ESI (m/z): calcd for C27H19NNaO3 [M + Na]+: 428.1263, found: 428.1263.
12-(2-Methyl-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4p): Yellow-brown powder, m.p. 350–352 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.94 (s, 1H), 8.05 (d, J = 4.4Hz, 1H), 7.86–7.80 (m, 3H), 7.35–7.24 (m, 2H), 7.18–7.07 (m, 4H), 6.87 (t, J = 7.2 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H) 5.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.5, 178.5, 150.2, 148.9, 135.5, 135.1, 134.4, 132.9, 131.7, 130.8, 130.5, 128.6, 126.8, 126.5, 126.2, 126.1, 124.0, 121.6, 120.4, 119.1, 117.1, 117.0, 114.1, 111.2, 29.0, 12.1; IR (KBr): v 3401, 2919, 1631, 1649 cm−1; HRMS-ESI (m/z): calcd for C26H17NNaO3 [M + Na]+: 414.1106, found: 414.1102.
12-(5-Methoxy-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4q): Yellow-brown powder, m.p. 260–261 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 8.10–8.08 (m, 1H), 7.93–7.83 (m, 3H), 7.42 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.6Hz, 1H), 7.30–7.24 (m, 2H), 7.19–7.12 (m, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.70–6.67 (m, 1H), 5.61 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 183.5, 178.5, 153.7, 150.7, 149.0, 135.0, 134.4, 131.9, 131.1, 130.2, 128.6, 126.8, 126.5, 126.2, 126.0, 125.0, 124.9, 122.2, 118.7, 117.2, 112.8, 111.3, 100.7, 55.7, 29.5; IR (KBr): v 3442, 2926, 1631, 1654 cm−1; HRMS-ESI (m/z): calcd for C26H17NNaO4 [M + Na]+: 430.1055, found: 430.1062.
12-(4-Methoxy-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4r): Yellow-brown powder, m.p. 190–192 °C, 1H NMR (400 MHz, DMSO-d6) δ: 8.12–8.10 (m, 1H), 7.87–7.81 (m, 3H), 7.47 (d, J = 7.6 Hz, 1H), 7.27–7.16 (m, 3H), 7.09 (t, J = 6.4 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.0Hz, 1H), 6.51 (d, J = 7.6Hz, 1H), 5.91 (s, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 183.6, 178.7, 154.2, 151.0, 148.4, 138.3, 135.0 (2C), 133.7, 132.4, 131.1, 130.1, 128.0, 126.4, 125.9, 123.4, 122.7, 120.1, 117.2, 115.7, 111.5, 105.5, 99.9, 55.4, 29.8; IR(KBr): v 3441, 2930, 1633, 1644 cm−1; HRMS-ESI (m/z): calcd for C26H17NNaO4 [M + Na]+: 430.1055, found: 430.1054.
12-(5-Chloro-1H-indol-3-yl)-12H-benzo[b]xanthene-6,11-dione (4s): Yellow-brown powder, m.p. 256–257 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.19 (s, 1H), 8.10–8.08 (m, 1H), 7.93–7.83 (m, 3H), 7.72 (d, J = 1.6 Hz, 1H), 7.16–7.12 (m, 5H), 7.06 (t, J = 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 5.66 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 183.5, 178.4, 150.8, 148.8, 135.1, 134.9, 134.4, 131.8, 131.2, 130.2, 128.7, 126.9, 126.5, 126.3, 126.2, 126.1, 124.9, 124.1, 122.1, 121.6, 119.3, 118.1, 117.3, 113.7, 29.1; IR(KBr): 3407, 2922, 1633, 1685 cm−1; HRMS-ESI (m/z): calcd for C25H14ClNNaO3 [M + Na]+: 434.0560, found: 434.0557.

4. Conclusions

A green and efficient procedure for the synthesis of 1,4-naphthoquinones possessing indole scaffolds was investigated via the three-component reaction of 2-hydroxy-1,4-naphthoquinone, substituted salicylic aldehydes, and indoles using In(OTf)3 as a catalyst. The method has the advantages of simple operation, mild reaction conditions, and a hospitable environment.

Supplementary Materials

The following are available online: IR, 1H NMR, 13C NMR, and HMRS of compounds 4.

Author Contributions

L.W. conceived and designed the experiments; X.Y. performed the synthesis.

Funding

This research was funded by NSFC-Henan Joint Fund (No. U1604164) and Key Scientific Research Projects in Universities of Henan Province (No. 16A350010).

Acknowledgments

We are grateful for financial support from the Natural Science Foundation of China and Key Scientific Research Projects from the Universities of Henan Province.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ruijter, E.; Orru, R.V.A. Multicomponent reactions—Opportunities for the pharmaceutical industry. Drug Discov. Today Technol. 2013, 10, e10–e15. [Google Scholar] [CrossRef] [PubMed]
  2. Bora, U.; Saikia, A.; Boruah, R.C. A novel microwave-mediated one-pot synthesis of Indolizines via a three-component reaction. Org. Lett. 2003, 5, 435–438. [Google Scholar] [CrossRef] [PubMed]
  3. Thompson, R.H. Naturally Occurring Quinones IV: Recents Advances; Champman & Hall: London, UK, 1997. [Google Scholar]
  4. Benites, J.; Valderrama, J.A.; Bettega, K.; Pedrosa, R.C.; Calderon, P.B.; Verrax, J. Biological evaluation of donor-acceptor aminonaphthoquinones as antitumor agents. Eur. J. Med. Chem. 2010, 45, 6052–6057. [Google Scholar] [CrossRef] [PubMed]
  5. Leyva, E.; López, L.; Cruz, R.; Espinosa-González, C.G. Synthesis and studies of the antifungal activity of 2-anilino-/2,3-dianilino-/2-phenoxy- and 2,3-diphenoxy-1,4-naphthoquinones. Res. Chem. Intermediat. 2016, 1–15. [Google Scholar] [CrossRef]
  6. Jin, Y.R.; Ryu, C.K.; Moon, C.K.; Cho, M.R.; Yun, Y.P. Inhibitory effects of J78, a newly synthesized 1,4-naphthoquinone derivative, on experimental thrombosis and platelet aggregation. Pharmacology 2004, 70, 195–200. [Google Scholar] [CrossRef] [PubMed]
  7. Sasaki, K.; Abe, H.; Yoshizaki, F. In vitro antifungal activity of naphthoquinone derivatives. Biol. Pharm. Bull. 2002, 25, 669–670. [Google Scholar] [CrossRef] [PubMed]
  8. Shetgiri, N.P.; Kokitkar, S.V.; Sawant, S.N. Radermachera xylocarpa: The highły efficient source of lapachol and synthesis of its derivatives. Acta. Pol. Pharm. 2001, 58, 133–135. [Google Scholar] [PubMed]
  9. Siripong, P.; Yahuafai, J.; Shimizu, K.; Ichikawa, K.; Yonezawa, S.; Asai, T.; Kanokmedakul, K.; Ruchirawat, S.; Oku, N. Antitumor activity of liposomal naphthoquinone esters isolated from thai medicinal plant: Rhinacanthus nasutus KURZ. Biol. Pharm. Bull. 2006, 29, 2279–2283. [Google Scholar] [CrossRef] [PubMed]
  10. Han, L.; Huang, X.; Dahse, H.M.; Moellmann, U.; Fu, H.; Grabley, S.; Sattler, I.; Lin, W. Unusual naphthoquinone derivatives from the twigs of Avicennia marina. J. Nat. Prod. 2007, 70, 923–927. [Google Scholar] [CrossRef] [PubMed]
  11. Bialonska, D.; Zjawiony, J.K. Aplysinopsins-marine indole alkaloids: Chemistry, bioactivity and ecological significance. Mar. Drugs 2009, 7, 66–183. [Google Scholar] [CrossRef] [PubMed]
  12. Biswal, S.; Sahoo, U.; Sethy, S.; Kumar, H.K.S.; Banerjee, M. Indole: The molecule of diverse biological activities. Asian J. Pharm. Clin. Res. 2012, 5, 1–6. [Google Scholar]
  13. Freidonk-Mueschenborn, E.; Fox, A. Resolution of concentration–response differences in onset of effect between subcutaneous and oral sumatriptan. Headach. J. Head Face Pain 2005, 45, 632–637. [Google Scholar] [CrossRef] [PubMed]
  14. Generali, J.A.; Cada, D.J. Off-label drug uses-ondansetron: Postanesthetic shivering. Hosp. Pharm. 2009, 44, 670–671. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds 4 are available from the authors.
Figure 1. Structure of some natural 1,4-naphthoquinones.
Figure 1. Structure of some natural 1,4-naphthoquinones.
Molecules 23 01954 g001
Scheme 1. Synthesis of 1,4-naphthoquinones possessing indole scaffolds.
Scheme 1. Synthesis of 1,4-naphthoquinones possessing indole scaffolds.
Molecules 23 01954 sch001
Scheme 2. A suggested pathway for the formation of 1,4-naphthoquinones-possessing indole scaffolds.
Scheme 2. A suggested pathway for the formation of 1,4-naphthoquinones-possessing indole scaffolds.
Molecules 23 01954 sch002
Table 1. Reaction conditions optimization for the synthesis 4a.
Table 1. Reaction conditions optimization for the synthesis 4a.
EntrySolventCatalystTemperature/°CTime/hYield/% 1
1TolueneIn(OTf)3 (10 mol %)110835
2DMFIn(OTf)3 (10 mol %)110839
3EtOHIn(OTf)3 (10 mol %)reflux128
4CH3CNIn(OTf)3 (10 mol %)reflux127
5H2OIn(OTf)3 (10 mol %)11012trace
6-In(OTf)3 (10 mol %)110653
7--1101011
8-p-TsOH (10 mol %)110825
9-H2SO4 (10 mol %)11088
10-FeCl3 (10 mol %)110829
11-Sc(OTf)3 (10 mol %)110836
12 InCl3 (10 mol %)110842
13-In(OTf)3 (10 mol %)2512trace
14-In(OTf)3 (10 mol %)100643
15 In(OTf)3 (10 mol %)120651
16-In(OTf)3 (5 mol %)110640
17-In(OTf)3 (15 mol %)110649
18-In(OTf)3 (20 mol %)110653
1 Isolated yield.
Table 2. Preparation of 1,4-naphthoquinones possessing indole scaffolds.
Table 2. Preparation of 1,4-naphthoquinones possessing indole scaffolds.
EntryR1R2Time/hProductYield/%
1H2-Ph64a53
25-Br2-Ph54b57
35-Cl2-Ph64c50
43-Br-5-Cl2-Ph54d53
55-Me2-Ph74e48
65-NO22-Ph74f46
75-MeO2-Ph74g42
83,5-Br22-Ph54h63
94-MeO2-Ph64i55
103-Br-5-ClH74j41
105-ClH74k42
125-BrH74l44
135-FH74m47
145-Cl2-Me54n59
155-Me2-Me54o48
16H2-Me54p50
17H5-MeO74q40
18H4-MeO74r42
19H5-Cl74s43

Share and Cite

MDPI and ACS Style

Yang, X.; Wu, L. Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)3 in Solvent-Free Conditions. Molecules 2018, 23, 1954. https://doi.org/10.3390/molecules23081954

AMA Style

Yang X, Wu L. Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)3 in Solvent-Free Conditions. Molecules. 2018; 23(8):1954. https://doi.org/10.3390/molecules23081954

Chicago/Turabian Style

Yang, Xiaojuan, and Liqiang Wu. 2018. "Synthesis of Novel 1,4-Naphthoquinones Possessing Indole Scaffolds Using In(OTf)3 in Solvent-Free Conditions" Molecules 23, no. 8: 1954. https://doi.org/10.3390/molecules23081954

Article Metrics

Back to TopTop