INTRODUCTION

The development of new methods for the synthesis of biologically active compounds is an important prob­lem in current synthetic chemistry from both environ­mental and economic points of view. Chromene has emerged as a privileged scaffold for drug design and discovery and attracted great attention since many natural and synthetic chromene derivatives possess important biological properties such as antimicrobial [l], antiviral [2], antitumor [3], antivascular [4], and anticonvulsant activities [5]. They are also utilized in cosmetics, pigments, biodegradable agrochemicals, as well as photoactive materials [6]. Generally, the syn­thesis of 2-amino-4H-chromene involves cyclization of an aromatic aldehyde, malononitrile (or ethyl cyano­acetate), and enolizable CH-acidic compounds, e.g., phenol [7], resorcinol [8], 4-hydroxycoumarin [9], or dimedone [10].

A common method for the synthesis of chromenes is based on the condensation of aldehyde, phenol, and malononitrile in the presence of an organic base such as piperidine [11]. Several other reagents, such as Mg/Al hydrotalcite [12], KF or NaOAc [13], and basic ionic liquid [14] have been reported to effectively catalyze the one-pot synthesis of 2-aminochromenes. Most of these methods are characterized by long reac­tion times, harsh reaction conditions, low yields, and use of organic solvents.

RESULTS AND DISCUSSION

We initially focused on optimization of the reaction conditions. A mixture of resorcinol, malononitrile, and benzaldehyde in ethanol was refluxed in the presence of indium(III) chloride (15 mol %) as a model reaction (Scheme 1). Different polar and nonpolar solvent were tried, and ethanol was found to be the best solvent due to high reaction rate and high yield (Table 1, entry no. 6). The other polar protic solvents gave moderate yield (Table 1, entry no. 5), while the reaction in aprotic solvent like acetonitrile, DMF, THF, and methy­lene chloride was slower, which lead to lower yields (Table 1, entry nos. 1–4). The model reaction was also carried out using different amounts of the catalyst (Table 2). Excellent yield was achieved by using 15 mol % of InCl3 (Table 2, entry no. 6).

Scheme
scheme 1

1.

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Table 1. Optimization of the reaction conditions using different solventsa
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Table 2. Optimization of the amount of InCl3a
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Under the optimized conditions (15 mol % InCl3, ethanol, reflux, 5 h), different substituted benzalde­hydes 2a–2e were reacted with resorcinol (1) and malononitrile (3). Regardless of the substituent nature, either electron-withdrawing or electron-donating, the corresponding 2-amino-4H-chromene derivatives 4a–4e were obtained in good to excellent yields. The prod­ucts were characterized by IR, 1H and 13C NMR, and mass spectra and elemental analyses.

The synthesized compounds were evaluated for their antimicrobial activity using the agar well diffusion method (Muller–Hinton agar medium). The results are collected in Table 3. Compounds 4a, 4c, and 4e showed good antibacterial activity against Staphylococcus aureus as compared to the standard drugs penicillin and streptomycin. Compounds 4a, 4b, and 4d showed good antibacterial activity against Escherichia coli, and compounds 4b, 4d, and 4e were active against Proteus vulgaris. Compounds 4c, 4d, and 4e showed good zones of inhibition against Aspergillus fumigatus, and 4b, 4d, and 4e showed good activity against Aspergillus niger. Nystatin was used as the standard antifungal drug.

Table 3. Antimicrobial activity (diameter of inhibition zone,a mm) of compounds 4a–4e
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All chemicals (analytical grade) were obtained from Sigma–Aldrich and Thomas Baker and were used without further purification. The reactions were carried out in dried glassware. The melting points were meas­ured in open capillary tubes and are uncorrected. The IR spectra were recorded in KBr on a Perkin Elmer FTIR spectrometer. The mass spectra (electron impact) were run on a Shimadzu LCMS-2010EV instrument. The 1H and 13C NMR spectra were recorded on a Bruker Avance III HD spectrometer at 400 MHz for 1H using DMSO-d6 as a solvent and tetra­methylsilane as an internal standard.

General procedure for the synthesis of 2-amino-4H-chromene derivatives 4a–4e. A mixture of resor­cinol (10 mmol), malononitrile (10 mmol), aromatic aldehyde (10 mmol), and InCl3 (15 mol %) in ethanol was refluxed for 5 h. After completion of the reaction (TLC), the mixture was cooled to room temperature and poured into ice water, and the solid product was filtered off, washed with 50 mL of water, and recrys­tallized from ethanol. The spectral and analytical data for newly synthesized compounds 4b–4d are given below.

2-Amino-7-hydroxy-4-(4-methoxyphenyl)-4H-chromene-3-carbonitrile (4b). Yield 85%, mp 115–117°C. IR spectrum, ν, cm–1: 3420, 3350, 2192, 1660, 1580. 1H NMR spectrum, δ, ppm: 3.60 s (3H, OCH3), 4.66 s (1H, 4-H), 6.50–6.90 m (3H, Harom), 6.90 d (2H, Harom), 7.20 d (2H, Harom), 7.96 s (2H, NH2), 8.90 s (1H, OH). 13C NMR spectrum, δC, ppm: 161.4, 157.2, 152.5, 147.9, 143.1, 139.8, 135.5, 130.2, 126.0, 120.5, 114.3, 111.9, 102.5, 56.5, 51.2, 22.0. Mass spectrum: m/z 294 (Irel 100%) [M]+. Found, %: C 69.40; H 4.80; N 9.50. C17H14N2O3. Calculated, %: C 69.38; H 4.79; N 9.52.

2-Amino-4-(4-chlorophenyl)-7-hydroxy-4H-chromene-3-carbonitrile (4c). Yield 84%, mp 225–227°C. IR spectrum, ν, cm–1: 3450, 3340, 2196, 1650, 1566. 1H NMR spectrum, δ, ppm: 4.72 s (1H, 4-H), 6.40–6.95 m (3H, Harom), 7.20 d (2H, Harom), 7.50 d (2H, Harom), 7.90 s (2H, NH2), 8.92 s (1H, OH). 13C NMR spectrum, δC, ppm: 160.9, 156.8, 152.2, 148.0, 144.1, 139.0, 135.6, 130.2, 126.5, 120.5, 114.6, 112.0, 102.5, 56.2, 48.2. Mass spectrum: m/z 298 (Irel 100%) [M]+. Found, %: C 64.30; H 3.70; N 9.40. C16H11ClN2O2. Calculated, %: C 64.33; H 3.71; N 9.38.

2-Amino-4-(4-bromophenyl)-7-hydroxy-4H-chromene-3-carbonitrile (4d). Yield 88%, mp 230–232°C. IR spectrum, ν, cm–1: 3470, 3350, 2190, 1655, 1548. 1H NMR spectrum, δ, ppm: 4.70 s (1H, CH), 6.45–6.90 m (3H, Harom), 7.22 d (2H, Harom), 7.65 d (2H, Harom), 7.90 s (2H, NH2), 8.90 s (1H, OH). 13C NMR spectrum, δC, ppm: 160.5, 156.9, 152.0, 148.0, 144.5, 140.0, 135.4, 130.2, 126.5, 120.6, 114.0, 112.0, 102.0, 56.5, 48.2. Mass spectrum: m/z 342 (Irel 100%) [M]+. Found, %: C 56.00; H 3.25; N 8.15. C16H11BrN2O2. Calculated, %: C 56.00; H 3.23; N 8.16.

CONCLUSIONS

An operationally simple, inexpensive, efficient, and eco-friendly synthesis of 2-amino-4H-chromene deriv­a­tives by one-pot three-component condensation has been developed. The procedure offers several advan­tages, including improved yields, cleaner reactions, and low cost, which makes it a useful and attractive strategy in view of economic and environmental aspects. Some of the synthesized compounds showed a good activity against gram-positive and gram-nega­tive bacterial strains.