1 Introduction

The main feature of the catalysis science in this century is protection of environment and human health by omission of hazardous materials and use safe non-volatile ionic liquids [1]. Ionic liquids are interesting due to high polarity [2], negligible volatility [3], high thermal stability [4], and tunable structures which have been extensively developed to promote of various organic reactions [5]. The properties of ionic liquids differ by change in their cation/anion parts and despite the influence of the anion constituent on the properties of ionic liquids, their cationic parts are mainly based on guanidine [6], amines [7], and heterocyclic salts of pyridinium [8], thiazolium [9], imidazolium [10], or triazolium rings (Fig. 1) [11]. Bronsted acid and protic Ionic liquids (PILs) are among the best green alternatives for corrosive acid catalysts/solvents in chemical transformations [12].

Fig. 1
figure 1

Samples of various ionic liquids

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In order to make possible economic savings and pollution prevention, multi-component domino reactions (MDRs), have considerable potential for the synthesis of complex heterocyclic molecules and for drug design and drug discovery, arising from minimization of time, waste, energy, and cost [13]. Phenazine based compounds are nitrogen-containing heterocycles that are present in natural products and synthetic materials showing a variety of biological functions [14], including antibiotic [15], antimicrobial [16], antimalarial [17] and antiparasitic activities [18]. By virtue of their DNA intercalating ability, they exhibit anticancer activity in leukemia and solid tumors [19]. For example, pyridophenazinediones [20] and pyridazinophenazinedione [21] derivatives are known for their antitumor activities (Fig. 2).

Fig. 2
figure 2

Some biologically active derivatives of Phenazines

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In continuation of our research on the synthesis and applications of homogenous and heterogeneous catalysts in organic chemistry [22, 23], here, we use the [(EtO)3Si(CH2)3N+H3][CH3COO−] as basic ionic liquid, and reusable catalyst for the one-pot synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives by four-component condensation of 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, malononitrile and arylaldehydes at 90 °C under solvent-free conditions (Scheme 1).

Scheme 1
scheme 1

Preparation of benzo[a]pyrano[2,3-c]phenazine derivatives in the presence of [(EtO)3Si(CH2)3N+H3][CH3COO−] as a basic ionic liquid catalyst

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2 Experimental

2.1 Materials and methods

All reagents were purchased from Merck or Aldrich and used without any further purification. The purities of the starting materials used in the our research were 2-hydroxy-1,4-naphthoquinone (98%), benzene-1,2-diamine (98%), malononitrile (99%), (3-aminopropyl)triethoxysilane (98%), and aromatic aldehydes (98–99%). All yields refer to isolated products after purification. Nuclear magnetic resonance (1HNMR) and Carbon-13 nuclear magnetic resonance (13CNMR) spectra were recorded using a Bruker Advance DPX 300 MHz instrument. The spectra were provided in DMSO-d6 as deuterated solvent. Fourier Transform Infrared (FT-IR) spectra were recorded using a JASCO FT-IR 460 Plus spectrophotometer. Melting points were determined in open capillaries using a BUCHI 510 melting point apparatus. Thin layer chromatography (TLC) was performed on silica‐gel Poly Gram SIL G/UV 254 plates.

2.2 Preparation of [(EtO)3Si(CH2)3N+H3][CH3COO−]

According to the literature [22], APTES ((3-aminopropyl)triethoxysilane) (10 mmol) was placed in a two necked flask equipped with a reflux condenser and a dropping funnel. The flask was placed in an ice bath. Under vigorous stirring with a magnetic stirring bar, acetic acid (10 mmol) was added dropwise to the flask in about 60 min. Stirring was continued for 24 h at room temperature, to obtain a viscous yellow liquid. The ionic liquid was prepared. The stable ionic liquid sample could be stored at room temperature for over 6 month. The ionic liquid was identified by FT-IR, 1HNMR and 13CNMR spectra [22].

2.3 General Procedure for the Direct Synthesis of Benzo[a]pyrano[2,3-c]phenazine (5A–O) Derivatives Using [(EtO)3Si(CH2)3N+H3][CH3COO−] as Basic Ionic Liquid Catalyst

[(EtO)3Si(CH2)3N+H3][CH3COO−] (30 mol%) was added to a mixture of 2-hydroxynaphthalene-1,4-dione (1 mmol) and benzene-1,2-diamine (1 mmol) at 90 °C. After 5 min an orange solid of benzo[a]phenazine was formed. Then, aryl aldehydes (1 mmol), and malononitrile (1 mmol), were added to this obtained mixture. The progress of the reaction was monitored by TLC (petroleum benzene/ethyl acetate: 1/3). After completion of the reaction, ethanol (3 mL) was added to the reaction mixture and warmed mixture. Then, mixture was cooled, the ionic liquid as catalyst is dissolved in ethanol. The ethanol containing the catalyst is separated and then the resulting solid product was subsequently recrystallized from hot ethanol to give the pure solid. The synthesis of all the known products were approved by the comparison of their melting point, FT-IR, 1HNMR and 13CNMR spectra with those of authentic literature samples. The new products were identified by FT-IR, 1HNMR and 13CNMR spectra. The new unknown products are characterized as follows:

2.4 Experimental Characterization Data and Spectra of the New Compounds

3-Amino-1-(2-hydroxy-3-methoxyphenyl)-1H-benzo[a]pyrano[2,3-c]phenazine-2-carbonitrile (5E): Time: 55 min, Yield (%): 89%, M.p. (°C) (Observed): 267–269; IR (KBr) (νmax/cm−1): 3440, 3374, 3316, 3199, 3069, 2169, 1663, 1630, 1594, 1513, 1461, 1386, 1346, 1293, 1248, 1221, 1174, 1159, 1140, 1110, 1052, 953, 855, 826, 794, 771, 749, 735, 724, 656, 640, 621, 583, 554, 527, 476, 448, 413; 1HNMR (300 MHz, DMSO-d6): δH (ppm) 3.69 (3H, s, CH3), 5.69 (1H, s, CH), 6.62 (1H, t, J = 7.2 Hz, Ar–H), 6.69 (1H, d, J = 6.3 Hz, Ar–H), 6.80 (1H, d, J = 6.3 Hz, Ar–H), 7.22 (2H, s, NH2), 7.87–7.98 (4H, m, Ar–H), 8.04–8.07 (1H, m, Ar–H), 8.18–8.21 (1H, m, Ar–H), 8.40 (1H, d, J = 7.8 Hz, Ar–H), 8.88 (1H, s, OH), 9.13 (1H, d, J = 7.5 Hz, Ar–H), 13CNMR (75 MHz, DMSO-d6): δC (ppm) 33.0, 56.0, 57.5, 110.4, 113.8, 119.0, 120.9, 121.9, 122.5, 125.2, 126.1, 128.9, 129.2, 130.1, 130.4, 130.8, 131.1, 131.7, 140.1, 140.3, 141.3, 141.6, 144.5, 147.1, 148.2, 160.6.

figure a

3-Amino-1-(2,5-dihydroxyphenyl)-1H-benzo[a]pyrano[2,3-c]phenazine-2-carbonitrile (5H): Time: 95 min, Yield (%): 92%, M.p. (°C) (Observed): > 280; IR (KBr) (νmax/cm−1): 3425, 3338, 3059, 2940, 2821, 2750, 2719, 2598, 2191, 1662, 1631, 1594, 1526, 1484, 1461, 1404, 1348, 1325, 1292, 1222, 1139, 1084, 1052, 1004, 916, 854, 762, 723, 698, 641, 618, 583, 554, 528, 503, 450; 1HNMR (300 MHz, DMSO-d6): δH (ppm) 6.07 (1H, s, CH), 6.37 (1H, s, Ar–H), 7.22 (2H, s, NH2), 7.37 (1H, d, J = 6.6 Hz, Ar–H), 8.16 (3H, s, Ar–H), 8.33 (6H, s, Ar–H), 8.87 (1H, s, OH), 9.08 (1H, s, OH); 13CNMR (75 MHz, DMSO-d6): δC (ppm) 33.0, 57.5, 110.4, 113.8, 119.0, 120.9, 121.9, 122.5, 125.2, 126.1, 128.9, 129.5, 129.2, 130.1, 130.4, 130.8, 131.1, 131.7, 140.1, 140.3, 141.3, 141.6, 144.5, 147.1, 148.2, 160.6.

figure b

3-Amino-1-(naphthalen-1-yl)-1H-benzo[a]pyrano[2,3-c]phenazine-2-carbonitrile (5L): Time: 35 min, Yield (%): 95%, M.p. (°C) (Observed): > 280; IR (KBr) (νmax/cm−1): 3465, 3356, 3171, 3087, 3054, 3039, 2184, 1659, 1621, 1590, 1495, 1471, 1398, 1383, 1328, 1291, 1262, 1222, 1162, 1106, 1053, 1022, 950, 860, 779, 754, 667, 637, 610, 545, 449, 424, 404; 1HNMR (300 MHz, DMSO-d6): δH (ppm) 6.33 (1H, s, CH), 7.22–7.30 (2H, t, m, Ar–H), 7.34 (2H, s, NH2), 7.55–7.69 (3H, m, Ar–H), 7.77–7.83 (2H, s, Ar–H), 7.85–7.95 (2H, m, Ar–H), 7.97–8.02 (1H, m, Ar–H), 8.05–8.07 (1H, m, Ar–H), 8.22 (1H, d, J = 8.1 Hz, Ar–H), 8.49 (1H, d, J = 7.2, Ar–H), 8.89 (1H, d, J = 8.84 Hz, Ar–H), 9.22 (1H, d, J = 7.8 Hz, Ar–H); 13CNMR (75 MHz, DMSO-d6): δC (ppm) 35.6, 55.9, 82.8, 112.1, 114.5, 122.5, 122.7, 125.2, 125.4, 126.1, 126.2, 128.9, 129.0, 129.2, 129.5, 130.2, 130.4, 130.9, 131.0, 132.3, 136.1, 140.1, 140.2, 141.4, 142.0, 144.0, 146.6, 148.2, 152.6, 158.1.

figure c

2.5 Optimization of the Reaction Conditions for Prepation of Phenazine Derivatives

To evaluate the activity of the [(EtO)3Si(CH2)3N+H3][CH3COO−] as ionic liquid, at first, the one-pot and four-component reaction of 2-hydroxynaphthalene-1,4-dione (1 mmol), benzene-1,2-diamine (1 mmol), benzaldehyde (1 mmol), and malononitrile (1 mmol) as a model reaction was selected. The model was examined in different solvents such as H2O, EtOH, DMF, toluene, and solvent-free under various temperatures conditions in the presence of [(EtO)3Si(CH2)3N+H3][CH3COO−] (30 mol%) as catalyst (Table 1). The best result was obtained at 90 °C under solvent-free conditions (Table 1, Entry 12).

Table 1 Optimization of reaction conditions for preparation of 3-amino-1-phenyl-1H-benzo[a]pyrano[2,3-c]phenazine-2-carbonitrilea (5A) in the presence of [(EtO)3Si(CH2)3N+H3][CH3COO−] as catalyst in different solvents and various amount of the catalyst under several temperature
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Next, the model reaction was tested at different amount of [(EtO)3Si(CH2)3N+H3][CH3COO−] (10, 20, 30, 40, 50 mol%) at 90 °C under solvent-free conditions. The best results were obtained at 90 °C under solvent-free conditions in the presence of 30 mol% of [(EtO)3Si(CH2)3N+H3][CH3COO−] as catalyst (Fig. 3).

Fig. 3
figure 3

The study of reaction model in the presence of different amounts of [(EtO)3Si(CH2)3N+H3][CH3COO−] as ionic liquid

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After optimization of the reaction conditions, to investigate the efficiency and the scope of the procedure, numerous benzo[a]pyrano[2,3-c]phenazine derivatives were produced by the one-pot four-component condensation reaction between aromatic aldehydes with 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, and malononitrile using basic ionic liquid [(EtO)3Si(CH2)3N+H3][CH3COO−] at 90 °C under solvent-free reaction conditions. The results are displayed in Table 2. The effect of substituents on the aromatic ring was assessed strong in terms of yields under these reaction conditions. Both categories of aromatic aldehydes counting electron-releasing and electron-withdrawing substituents on their aromatic ring gained the appropriate products in high to excellent yields in short reaction time. The reaction times of aromatic aldehydes having electron withdrawing groups was rather faster than that of electron donating groups.

Table 2 Synthesis of benzo[a]pyrano[2,3-c]phenazinea in the precence of [(EtO)3Si(CH2)3N+H3][CH3COO−] as catalyst
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According to the literature [23,24,25], The proposed mechanism for product formation is shown in Scheme 2. First, benzene-1,2-diamine (1) condenses with 2-hydroxynaphthalene-1,4-dione (2) and provides 6H-benzo[a]phenazin-5-one (A) [26]. The reaction of intermediate (A) with aryl aldehydes (3) in the presence of basic ionic liquids as catalysts under Knoevenagel condensation cause to form intermediate (B), which reacts in the presence of ionic liquids as catalysts with malononitrile (4) to form Michael adduct intermediate (C), then the intermediate (C) undergo the cyclization, and 1,3-hydrogen shift cause to prepare finally the desired products (Scheme 2).

Scheme 2.
scheme 2

Mechanism for the synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives in the presence of [(EtO)3Si(CH2)3N+H3][CH3COO−] as basic ionic liquid as catalyst

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Reusability of the catalysts is important in green environmental chemistry. For this purpose, we studied, the reaction of 2-hydroxynaphthalene-1,4-dione (1 mmol) and benzene-1,2-diamine (1 mmol), benzaldehyde (1 mmol) and malononitrile (1 mmol) as a model under solvent-free conditions at 90 °C. After completion of reactions, ionic liquid as catalyst was soluble in EtOH and could be recovered and reused conveniently after removing ethanol under vacuum at 70 °C for 2 h. The recovered catalyst was reused for at least five runs without any loss of its activity (Fig. 4).

Fig. 4
figure 4

The recycling of the [(EtO)3Si(CH2)3N+H3][CH3COO−] as new catalyst

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We also compared this method for preparation of benzo[a]pyrano[2,3-c]phenazine derivatives with various catalysts in literature (Table 3). We observed that our reported method, using [(EtO)3Si(CH2)3N+H3][CH3COO−] as the catalyst, is simple, effective, applicable and comparable with many catalytic systems for the synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives (Table 3, Entry 10).

Table 3 Comparison result of [(EtO)3Si(CH2)3N+H3][CH3COO−] with other reported catalysts in the literature for preparation of benzo[a]pyrano-[2,3-c]phenazine
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3 Conclusions

The four-component and one-pot synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives was achieved in a simple, and green manner conditions in the presence of ionic liquid, [(EtO)3Si(CH2)3N+H3][CH3COO−], as catalyst. The phenazine derivatives were obtained in excellent yields. Recyclability of ionic liquid, easy work-up, and uses environment-friendly reaction conditions are advantages of this effective MCR protocol.