The synthesis of heterocycles has always been an essential and growing area of organic chemistry as heterocycle compounds show a various range of biological activities [1-5]. Phenazines exhibit important biological properties such as anti-tumor , antibacterial , anti-proliferative , antifungal , and anti-inflammatory . These attributes make phenazines notable targets in organic preparation for future consideration. A number of procedures have been developed for the preparation of phenazines using p-TSA , glacial acetic acid , 1,4-diazabicyclo[2.2.2]octane (DABCO) [13,14], thiourea-based organocatalysts , caffeine , theophylline , L-proline , 1-butyl-3-methylimidazolium hydroxide ([Bmim]OH) , and Et3N . Each of these procedures may have its own advantages but also suffer from such apparent drawbacks as prolonged reaction times, complicated work-up, non-reusable catalyst, low yield, or hazardous reaction conditions. To elude these restrictions, discovery of an efficient, easily accessible catalyst with high catalytic activity for the preparation of phenazines is still favored. In recent years, synthesis and immobilization of nanoparticles in ionic liquids (ILs) have been widely investigated [21,22]. Ionic liquids can be considered as valuable key precursor compounds for catalysts [23, 24]. The nature of cation-anion interactions in ambient temperature ionic liquids is an issue of increasing interest [25,26]. The structures of 1-ethyl-3-methylimidazolium (Emim) and 1-butyl-3-methylimidazolium (Bmim) with transition metal chloride anions including NiCl42-, CoCl42-, and PdCl42- were investigated [27,28]. Ideally, introducing neat processes and utilizing eco-friendly and green nanocatalysts which can be simply recycled at the end of reactions have received considerable attention in recent years [29-31]. Herein, we reported the preparation of bis (1(3-trimethoxysilylpropyl)3-methyl-imidazolium)nickel tetrachloride tethered to colloidal silica nanoparticles as a resuable catalyst  and investigated its catalytic activity for one-pot multicomponent synthesis of phenazines under ultrasonic irradiations (Scheme 1).
Preparation of 1-(3-trimethoxysilylpropyl) -3-methyl-imidazolium chloride
Ionic liquid was prepared according to the procedure reported in the literature .
Preparation of bis (1(3-trimethoxysilylpropyl)-3-methyl-imidazolium) nickel tetrachloride tethered to colloidal nano-silica (ionic liquid/ colloidal nano-silica)
0.098 mL of colloidal silica nanoparticles (LUDOX SM colloidal silica 30 wt. % suspension in H2O) was diluted in 3 mL of deionized water, and 1.5 mmol of 1-(3-trimethoxysilylpropyl) -3-methyl-imidazolium chloride IL was added slowly with continuous stirring during one hour. Then, 0.18 g of NiCl2.6H2O was added and refluxed for 24 h. After 24 h, ionic liquid functionalized colloidal nano-silica was separated by centrifugation and washed with acetone and methanol for four times, then, ionic liquid-tethered colloidal silica nanoparticles was dried by lyophilization/freeze-drying .
The purity of the resultant ionic liquid-tethered colloidal silica nanoparticles was confirmed using 1H NMR spectrum. The Ni loading was measured using XRF to be 3.3 wt%.
General procedure for the preparation of phenazines
A mixture of hydroxynaphthoquinone (1 mmol), o-phenylenediamine (1 mmol) aldehydes (1mmol) and malononitrile (1.5 mmol) and ionic liquid-tethered colloidal silica nanoparticles (8 mg) in EtOH (15 mL) was sonicated at 40 W power in appropriate times. The progress of the reaction was monitored by TLC (EtOAc/n-hexane 2:1). After completion of the reaction, the mixture was cooled to room temperature and nanocatalyst was easily separated by centrifuging. The solvent was evaporated and the solid obtained was ﬁltered and then washed with EtOH and water (ratio: 5:5) to afford the pure desired product.
3-Amino-1-(4-cyano-phenyl)-1H-benzo[a]pyrano[2,3-c]phenazine-2-carbonitrile (5h): Yellow solid, m.p.: 288-290 ºC; IR (KBr, ν, cm-1): 3324, 3175, 3045, 2832, 2182, 2138, 1646, 1623, 1482, 1456, 1445, 1394, 1382, 1358, 1339, 1295; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 5.43 (s, 1H, CH), 7.25 (s, 2H, NH2), 7.39 (d, J = 8.0 Hz, 2H, Ar-H), 7.43 (d, J = 8.0 Hz, 2H, Ar-H), 7.83-8.08 (m, 4H, Ar-H), 8.14-8.17 (m, 1H, Ar-H), 8.18-8.23 (m, 1H, Ar-H), 8.45 (d, 1H, J = 7.6 Hz, Ar-H), 9.18 (d, 1H, J = 7.2 Hz, Ar-H); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 37.4, 57.8, 113.8, 115.2, 118.3, 122.2, 124.4, 125.6, 126.3, 127.7, 128.2, 128.8, 129.0, 129.2, 130.2, 130.3, 130.6, 130.8, 139.9, 140.2, 140.7, 141.3, 145.6, 146.4, 159.5; Anal. Calcd. for C27H15N5O: C, 76.22; H, 3.55; N, 16.46; Found: C, 76.17; H, 3.42; N, 16.34.
3-Amino-1-(4-methoxy-phenyl)-1H-benzo[a]pyrano[2,3-c]phenazine-2-carbonitrile (5m): Yellow solid, m.p.: 268-269 ºC; IR (KBr, ν, cm-1): 3316, 3174, 3047, 2828, 2180, 1653, 1622, 1585, 1486, 1465, 1452, 1394, 1354, 1330, 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 3.85 (s, 3H, OCH3), 5.86 (s, 1H, CH), 6.67 (d, 2H, J = 7.6 Hz, Ar–H), 6.92 (d, 2H, J = 7.6 Hz, Ar–H), 7.35 (s, 2H, NH2), 7.86-7.94 (m, 4H, Ar–H), 7.99-8.42 (m, 3H), 9.10 (d, 1H, J = 8.0 Hz, Ar–H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 37.5, 55.3, 58.3, 112.2, 115.3, 115.5, 120.2, 120.5, 121.4, 125.2, 127.2, 129.1, 129.4, 129.7, 130.1, 130.6, 130.8, 130.8, 140.3, 141.3, 141.9, 146.5, 147.3, 159.6, 160.7; Anal. Calcd. for C27H18N4O2: C, 75.34; H, 4.21; N, 13.02; Found C, 75.23; H, 4.15; N, 12.95.
RESULTS AND DISCUSSION
Characterization of the nanocatalyst
Figs. 1a and 1b indicate the 1H NMR spectra for the 1(3-trimethoxysilylpropyl)-3-methyl-imidazolium chloride and bis (1(3-trimethoxysilylpropyl)-3-methyl-imidazolium) nickel tetrachloride tethered to colloidal silica nanoparticles in dimethyl sulfoxide (DMSO), respectively. The NMR spectra of both materials are consistent with expected results for untethered and silica-tethered ionic liquids.
Fig. 2 displays FE-SEM (Field emission- scanning electron microscopy) image of bis (1(3-trimethoxysilylpropyl)-3-methyl-imidazolium) nickel tetrachloride tethered to colloidal nano-silica (nanocatalyst). The SEM images show particles with diameters in the nanometer range.
In order to study the size distribution of nanocatalysts, DLS (dynamic light scattering) measurements of the nanoparticles were exhibited in Fig. 3. This size distribution is centered at a value of 15.9 nm.
The elemental compositions of the nanocatalyst were studied by EDS (energy dispersive spectroscopy). EDS confirmed the presence of Si, O, N, Cl, and Ni in the compound (Fig. 4).
Thermogravimetric analysis (TGA) evaluates the thermal stability of the ionic liquid of untethered to SiO2 (pure ionic liquid) and silica-tethered ionic liquids (ionic liquid/colloidal nano-silica with molar ratio 2.5 and 5.5). The curve shows a weight loss about 46.62% and 31.73% for ionic liquid/colloidal nano-silica with molar ratio 5.5 and 2.5, respectively, from 240 to 610 ºC, resulting from the decomposition of organic spacer attaching to the nanoparticles. Hence, the nanocatalyst was stable up to 240 °C, confirming that it could be stably utilized in organic reactions at temperatures between the ranges of 90–140 °C (Fig. 5).
Investigation of catalytic activity for synthesis of phenazines
Initially, we focused on the systematic evaluation of diverse catalysts for the model reaction of hydroxynaphthoquinone, o-phenylenediamine, 4-chlorobenzaldehyde, and malononitrile under different conditions. To obtain the ideal reaction conditions for the synthesis of compound 5b, we studied some other catalysts and solvents which are shown in Table 1. Screening of different catalysts containing NiCl2, imidazole, ZrOCl2, P-TSA, CuCl2 and nanocatalyst (ionic liquid/colloidal nano-silica) revealed ionic liquid/colloidal nano-silica (with molar ratio 2.5) as the most effective catalyst to perform this reaction under ultrasonic irradiations (40 W) in ethanol. The results illustrated that the sonication certainly affected the reaction system. It could reduce the reaction time and increase the yield of the products. Accordingly, it should be noted that electron-withdrawing groups increased the rate of reaction and gave better yields than thoset with electron-donating groups. Several functional groups, such as Cl, OMe, CN, and CH3, are compatible under the reaction conditions. Interestingly, a variety of aromatic aldehydes, including ortho, meta and para-substituted aryl aldehydes, participated well in this reaction and gave the corresponding products in a good to excellent yield (Table 2).
We investigated reusability of the ionic liquid/colloidal nano-silica as acatalyst for the synthesis of product 5b, and it was found that product yields reduced to a small extent on each reuse (run 1, 96%; run 2, 96%; run 3, 95%; run 4, 95%; run 5, 94%, run 6, 94%). After completion of the reaction, the mixture was cooled to room temperature and nanocatalyst was easily separated by centrifuging. The nanoparticles were then washed four times with dichloromethane and dried at room temperature for 24 h.
To determine the degree of leaching of the metal from the heterogeneous nanocatalyst, the catalyst was removed by filtration and the Ni amount in reaction medium after each reaction cycle was measured using inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The analysis of the reaction mixture by the ICP technique displayed that the leaching of Ni was negligible (the leaching of Ni in five continuous runs was found to be ≤0.5 ppm). We believe that this could be a reason for the extreme stability of the catalyst presented herein.
A proposed mechanism for the synthesis of benzopyranophenazines using nanocatalyst is shown in Scheme 2. (i) The initial condensation of hydroxynaphthoquinone with o-phenylenediamine affords intermediate I; (ii) Knoevenagel condensation of malononitrile and benzaldehydes to form the intermediate II; (iii) The Michael addition of intermediate I with intermediate II formed intermediate III, which in subsequent cyclization and tautomerism affords the corresponding products. In this mechanism, the surface atoms of nanocatalyst activate the C=O and C≡N groups for better reaction with nucleophiles.
In conclusion, we have reported an efficient method for the synthesis of benzopyranophenazines using ionic liquid/colloidal nano-silica as a superior catalyst under ultrasonic irradiations. The new catalyst is characterized by 1H NMR, FE-SEM, EDS, DLS and TGA. The current method provides obvious positive points containing environmental friendliness, reusability of the catalyst, low catalyst loading and use of ultrasonic irradiation as a valuable and powerful technology.
The authors are grateful to University of Kashan for supporting this work by Grant NO: 159196/XXX.
CONFLICT OF INTEREST
The author declares that there is no conflict of interest.