Sustainable construction: admicellar catalysed synthesis of pyrimido[4,5-b]quinolines in an aqueous system

Abstract

A simple and highly efficient strategy has been documented for the rapid and convenient synthesis of 1-methyl-5-phenylbenzo[g]pyrimido[4,5-b]quinoline-2,4,6,11(1H,3H)-tetraone from aldehydes, 2-hydroxynaphthalene1,4dione and 6-aminouracil in the presence of nano ZnO under an aqueous admicellar system at 80 °C. Results show that nano ZnO is a potential catalyst for the synthesis of pyrimido[4,5-b]quinoline. Nano ZnO was recovered and reused efficiently several times for the synthesis of the desired product which is an essential parameter of green synthesis. The reported method represents an eco-friendly alternative to classical protocols. Nano size of ZnO was confirmed by EDS, transmission electron microscopy (TEM) and XRD techniques.

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Introduction

In recent years, with the vogue of green chemistry, eco-friendly chemical processes or strategies have attracted tremendous attention.¹ Taking into consideration that organic solvents are the main source of hazardous waste, the development of methods with diminished use of organic solvents is of high priority. Therefore, the use of water as a green solvent for organic synthesis is economical and environmentally benign. But in some cases, due to low solubility of the organic substrates in aqueous medium, surfactants were efficiently used to facilitate the organic reactions through the formation of micelles.² Recently, research has been conducted toward the synthesis and use of metal oxide nanoparticles due to their distinctive properties in comparison to the bulk metals.

Another foremost reaction template in aqueous medium called ‘admicelle’ is a relatively new aspect in science. At a lower surfactant concentration, admicelles are formed in water by the adsorption of surfactant on solid–liquid interfaces of nano particles.³ In aqueous condition, nanoparticles are accumulated to form big particles having low catalytic activity and in these cases, use of a surfactant forms admicelles. The hydrophobic core present within admicelles furnishes a region which dissolves the water-insoluble organic compounds. This phenomenon is termed as ‘adsolubilization’. A reaction template is thus formed on the surface of the nanoparticles where the organic syntheses can be promoted by the nano catalyst under admicellar system. Formation of admicelles plays vital role in many practical applications, including ore flotation, petroleum recovery, food science, agriculture etc. and can notably improve the result of many reactions.

Furthermore, several studies have focused on findings water-compatible and reusable catalysts.⁴ Among various metal oxide ZnO nanoparticles, have received considerable attention because of their unique properties and remarkable applications in various fields. It is well known that nano ZnO as a catalyst plays an important role in synthetic organic chemistry because of its high catalytic activity, reusability, easy handling and nontoxicity.^5a

Molecules which contain more than one nucleus recently gain attention due to their remarkable chemical and biological properties. Composite molecules are chemical units composed of two (or more) structural units in which characteristics of several components have been altered to give rise to altogether new set of properties. Using the concept of molecular hybridization, pyrimidine and quinoline have been combined to access a hybrid molecule-pyrimido[4,5-b]quinoline which possess broad range of biological profiles. Their importance is certified by the fact that a number of workers have documented their synthesis.^5b–d Although many publications have already reported synthesis of pyrimido[4,5-b]quinoline but these protocols suffers from various drawbacks such as use of expensive catalysts, high amount of promoter, toxic or volatile organic solvents, harsh reaction conditions or release of hazardous wastes etc.

Pyrimido[4,5-b]quinoline derivatives have attracted considerable interest because they exhibit promising biological activities such as antimalarial, anticancer, antimicrobial and anti-inflammatory.⁶ These advantages encouraged us towards the development of a new environmentally benign synthetic method, of pyrimido[4,5-b]quinoline system by using equimolecular amounts of 2-hydroxynaphthalene1,4dione (1), 4-chlorobenzaldehyde (2) and 6-aminouracil (3) in CTAB–water system in the presence of nano ZnO. The general synthetic protocol of the present investigation is shown in Scheme 1.

Scheme 1 Synthesis of 1-methyl-5-phenylbenzo[g]pyrimido[4,5-b]quinoline-2,4,6,11(1H,3H)-tetraone.

Result and discussion

ZnO nano particle was synthesised by using the reported methodology⁷ with little modification. For a typical synthesis of ZnO nano particle, appropriate amount of Zinc acetate was taken in 100 ml of methanol and continuously stirred for 0.5 hours at room temperature. Simultaneously, KOH solution was prepared in 100 ml of methanol. Now, both the solutions were mixed with constant stirring for 10 hours. The final solution was allowed to cool at room temperature and aged overnight. This solution was centrifuged and washed several times with absolute ethanol and water in order to remove unnecessary impurities. The desired product was placed in a vacuum oven for 10 h at 50 °C to get powders of ZnO nanoparticles.

ZnO nano particles are characterized by EDS pattern which displays the peak of oxygen and zinc showing the elemental composition (Fig. 1). Fig. 2 shows the XRD pattern of ZnO nano particles (red line). XRD spectra show broad peaks at the positions of 31.59°, 34.22°, 36.09°, 47.53°, 56.55°, 62.70°, 67.81° and 79.87°, which are in good agreement with the standard JCPDS file for ZnO (JCPDS 36-1451, a = b = 3.249 Å, c = 5.206 Å) and can be indexed as the hexagonal wurtzite structure of ZnO having space group P6₃mc. All the available reflections of the XRD phases have been fitted with Gaussian distribution. The broadening of XRD peaks (i.e. Scherrer's broadening) indicating the formation of nano particles of ZnO. The particle size, d, of ZnO nano particles were calculated by Debye–Scherrer's equation and observed around ∼15 nm in size. The morphology of ZnO was noticed and found to be spherical in nature having diameters ranging from 15 to 25 nm. On further investigation (Fig. 3) the size and morphology of nano ZnO was analyzed by TEM images and the inset of the fig shows the representative selected area electron diffraction (SAED) pattern which display that the prepared ZnO nanoparticles were polycrystalline in nature. The increased catalytic activity of the synthesized nano ZnO over commercial bulk catalysts due to the higher surface to volume ratio, thus resulting in higher surface concentrations of the reactive sites.

Fig. 1 Shows the EDS pattern of the ZnO nano particle.

Fig. 2 XRD pattern of fresh nano ZnO (red line), reused ZnO (black line) nano particle.

Fig. 3 Shows the representative TEM image of the prepared nano ZnO.

In our preliminary experiment, we have investigated the optimization reaction condition regarding with both the catalyst and the solvent. For this purpose, 2-hydroxynaphthalene1,4-dione (1), 4-chlorobenzaldehyde (2) and 6-aminouracil (3) were chosen as model substrates for the synthesis of representative compound (4a). Initially we have performed the reaction employing nano ZnO as a catalyst and water as a solvent because cyclization reactions occur more easily in polar solvents⁸ and also from green synthesis point of view water has been proved to be best for solution-phase chemistry.⁹ The reaction occurs but the product was obtained in traces (Table 1, entry 1).

Table 1 Effect of surfactant on the yield of the product in water^a

Entry	Surfactant	Temp. (°C)	Concentration	Yield^b (%)
a Reaction condition: all reaction were carried out using 2-hydroxynaphthalene1,4-dione, (1 mmol), 4-chloroaldehyde (1 mmol), 6-aminouracil (1 mmol), in surfactant, H2O (50 ml) at 80 °C.b Yield of isolated product.
1	—	80	—	Trace
2	CTAB	80	20	27
3	CTAB	80	50	42
4	CTAB	80	60	47
5	CTAB	80	70	51
6	CTAB	80	80	65
7	CTAB	80	90	65
8	CTAB	r.t.	80	—
9	CTAB	Reflux	80	65
10	CTAB	80	100	23
11	SDS	80	80	25
12	TTAB	80	80	33

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To avoid this problem we turned our attention to use cetryltrimethyl ammonium bromide (CTAB: cmc value 0.92 mM) as a surfactant. It is the best to utilize CTAB because it acts as emulsifying agent when mixed with organic substrate to form colloidal dispersion, which facilitate our model reactions.¹⁰ Powdered activated carbon method¹¹ or the potassium ferrate method¹² used for the removal of surfactant. We carried out the reaction with 20 mM of CTAB in water, the reaction occurs but again the yield was not good but improved as compared to the previous observation. Inspired by this success, the reaction was run with 50 mM of CTAB in 50 ml water. This gave only 42% yield of the product (Table 1, entry 3). Delightfully, the reaction afforded maximum yield 65% (Table 1, entry 6) when the reaction was carried out with 80 mM of CTAB. No improvement in yield was observed when concentration of CTAB was further increased. Different types of other surface active reagents like sodium dodecylsulfate (SDS: cmc value 8.1 mM) and tetradecyltrimethylammonium bromide (TTAB: cmc value 3.8 mM) have been evaluated (Table 1, entries 11 and 12), but they did not give satisfactory results in comparison to CTAB.

Thus 80 mM CTAB was sufficient to push the reaction forward. To increase the yield of the product, we performed a series of reactions by changing the concentration of the catalyst i.e. nano ZnO, from 5 mol% to 20 mol%. Thus, 15 mol% of catalyst was chosen as suitable quantity of the catalyst for the reaction.

Numerous parameters like solvent, catalyst and temperature provide dramatic improvement in reaction. In order to show that nano ZnO was vital for this conversion in micellar system we have performed this reaction in the presence of other catalyst like InCl₃, SiO₂, Alumina and AcOH. The results are listed in Table 2, which clearly indicate that nano ZnO is the suitable catalyst for the proposed transformation. The most attractive feature of this strategy is that this methodology involves nano ZnO in a small amount. Only 15% nano ZnO is sufficient and the amount of the product dramatically increases from 65% to 95%. When the reaction was performed with the decreased amount from 15 mol% to 10 mol% and 5 mol%, the yield of the product 4a was reduced (Table 2, entries 5 and 6), but the use of 20 mol% of nano ZnO did not affect the yield (Table 2, entry 8). At last, we investigate the effect of other organic solvents (Table 3), but the result was not as good as it was in water (Table 4).

Table 2 Optimization of catalyst on the yield of product in aqueous solution of CTAB^a

Entry	Catalyst	Amount (mol%)	Time (h)	Yield^b (%)
a Reaction condition: all reaction were carried out using 2-hydroxynaphthalene1,4-dione, (1 mmol), aldehydes (1 mmol), 6-aminouracil (1 mmol), in CTAB–H2O (50 ml), at 80 °C.b Yield of isolated product.
1	InCl3	15	10	30
2	SiO2	15	10	32
3	Alumina	15	10	25
4	AcOH	15	10	22
5	Nano ZnO	5	10	54
6	Nano ZnO	10	6	73
7	Nano ZnO	15	4	95
8	Nano ZnO	20	4	95

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Table 3 Optimization table for solvent for the synthesis of compound 4^a

Entry	Solvent	Time (h)	Yield^b (%)
a Reaction condition: all reaction were carried out using 2-hydroxynaphthalene1,4-dione, (1 mmol), 4-chlorobenzaldehyde (1 mmol), 1-methyl 6-aminouracil (1 mmol), ZnO (15 mol%), in CTAB–H2O (50 ml), at 80 °C.b Yield of isolated product.
1	CH3CN	6	54
2	Toluene	6	73
3	EtOH	4	82
4	H2O	4	95

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Table 4 Scope of substrate for the synthesis of compound 4^a

Entry	2-hydroxynaphthalene1,4dione	Aldehydes (R1)	6-aminouracil (R)	Product 4	Yield^b (%)
a Reaction condition: all reaction were carried out using 2-hydroxynaphthalene1,4-dione, (1 mmol), aldehydes (1 mmol), 6-aminouracil (1 mmol), nano ZnO, in CTAB–H2O (50 ml), at 80 °C.b Yield of isolated product.
1	1a	4-Cl	–H	4a	95
2	1a	4-Br	–H	4b	95
3	1a	4-NO2	–H	4c	93
4	1a	–C6H5	–H	4d	89
5	1a	3-Me	–H	4e	93
6	1a	2-Me	–H	4f	93
7	1a	4-Me	–H	4g	94
8	1a	4-OMe	–H	4h	95
9	1a	4-Cl	–Me	4i	95
10	1a	4-Br	–Me	4j	95
11	1a	4-Me	–Me	4k	95
12	1a	3-Me	–Me	4l	92

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It was also noticed that the reaction temperature also play important role in this synthesis. Reaction did not take place at room temperature. When the temperature was increased the yield of product also increased and 80 °C was found optimum temperature for maximum conversion. At increased concentration of CTAB (just above CMC), we observed that there is no improvement in the yield of the product. But, at very high concentration of CTAB yield of the obtained product was very low. The reason behind this problem is that at a high concentration of CTAB (CMC), formation of micelles solubilizes the organic compounds within its hydrophobic core.

With the optimized conditions in hand, we explore the scope and limitation of this synthetic procedure by using variety of reactants. A variety of aldehydes and aminouracil were used. Interestingly, a wide range of aldehydes (containing electron withdrawing and electron donating group) were undergoing smooth transformation in this conversion.

The electronic effect and the nature of the substituent on the aldehyde do not show any obvious effects in terms of yield and reaction time.

Based on previously documented reactions and our experiment plausible mechanism for the nano-ZnO catalysed formation of compounds 4 is depicted in Scheme 2. Organic reagents come closer to each other in the hydrophobic area of admicelles and the reaction between them is catalyzed by ZnO nano particle. Use of ZnO nano-particles promote the formation of admicelles in aqueous medium and improved this reaction procedure.

Scheme 2 Plausible mechanism for the synthesis of compound 4a–4l.

We speculated that the first reaction is, probably involves the reaction between starting material naphtha and aldehyde to generate an intermediate. Then 6-aminouracil attacks to intermediate I in Michael type fashion to generate another intermediate which undergoes intramolecular cyclisation by the reaction of nucleophilic amino function to lead to the desired product in excellent yield. Compounds 4 and its derivatives are stable solids whose structures were confirmed by IR, ¹H, ¹³C NMR spectroscopy and elemental analysis.

In terms of green chemistry, efficient recovery and reusability of the catalyst is very important, thus the recovery and recyclability of nano ZnO were also examined. After the reaction was completed, ethyl acetate was added to the reaction mixture. The reaction mixture was stirred until complete dissolution of desired product in ethyl acetate was observed. The two layers were then separated. The aqueous layer was reused for the same experiment for next cycles. There was no appreciable change was observed in yield of desired product (shown in Fig. 4). This was also confirmed by comparison of XRD pattern of the fresh nano ZnO and the reused one after fifth cycle. As displayed in Fig. 2 XRD spectra of reused catalyst was found to be almost similar to the fresh one. The almost similar broadening in XRD pattern of recovered ZnO nanoparticles do not aggregate during the reaction.

Fig. 4 Reusability of ZnO nano particles for the synthesis of compound 4.

Conclusion

In conclusion, the present work disclose environmentally benign multicomponent protocols for the synthesis of 1-methyl-5-phenylbenzo[g]pyrimido[4,5-b]quinoline-2,4,6,11(1H,3H)-tetraone, employing CTAB–H₂O as the reaction medium and nano ZnO as the catalyst. This strategy is endowed with several advantages such as use of aqueous medium, catalytic reaction, excellent yield and ease of operation. The mild reaction conditions and eco-friendly practicability made this methodology an attractive approach to prepare pyrimido[4,5-b]quinoline derivatives in good amount.

Experimental

Material and methods

All chemical were reagent grade purchased from Aldrich and Alfa Aesar and were used without purification. NMR spectra were recorded on a BRUKER AVANCE II-400FT Spectrometer (400 for ¹H NMR, 100 MHz for ¹³C) using DMSO as solvent and TMS as an internal reference. ESI-MS were recorded on a Quattro II (ESI) spectrometer.

Characterization techniques used

The prepared nanoparticles of ZnO were thoroughly characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM) in order to elaborate structural properties in precise 75 manner. XRD was performed on Rigaku D/max-2200 PC diffractometer operated at 40 kV per 40 mA, using CuKα1 radiation with wavelength of 1.54 Å in the wide angle region from 20° to 80° on 2θ scale. The size and morphology of prepared nanoparticles were found using a transmission electron 80 microscope (model Tecnai 30 G2S-Twin electron microscope) operated at 300 kV accelerating voltage by dissolving the as synthesized powder sample in ethanol and then placing a drop of this dilute ethanolic solution on the surface of a carbon coated 200 mess copper grid.

General procedure for the synthesis of 2,4,6-substituted pyrimidine-5-carbonitriles

Aldehydes (1 mmol), 6-aminouracil (1.0 mmol) and the 2-hydroxynaphthalene1,4dione were added in the mixture of CTAB (80 mM)–H₂O (50 ml) and nano ZnO (15 mol%) at 80 °C. After completion of reaction the reaction mixture was being cooled and solid product was separated.

Reusability of ZnO nano particle

After completion of the reaction, 10 ml of ethyl acetate were added to the reaction mixture. The reaction mixture was stirred until complete dissolution of desired product in ethyl acetate was observed. The two layers were then separated. The aqueous layer was reused for the same experiment for next cycles.

5-(4-Chlorophenyl)benzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4a). Orange powder; mp 294 °C. IR (KBr) (ν_max/cm⁻¹): 3313, 3244, 1724, 1650, 1595, 1542. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 5.08 (s, 1H, CH), 7.26 (d, ³J_HH = 8.4 Hz, 2H), 7.35 (d, ³J_HH = 8.5 Hz, 2H), 7.78–8.06 (m, 4H, H-Ar), 9.36 (s, 1H, NH), 10.20 (s, 1H, NH), 10.94 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 34.9, 89.0, 118.7, 126.7, 126.8, 128.8 (2 CH), 130.8 (2 CH), 130.9, 131.9, 132.5, 134.3, 135.8, 138.8, 144.4, 148.7, 150.2, 163.4, 179.7, 182.5. MS (EI, 70 eV): m/z (%): 405 (M⁺, 10), 371 (10), 325 (45), 234 (28), 156 (26), 77 (78), 57 (80), 43 (100). For C₂₁H₁₂ClN₃O₄ (405.79): C, 62.16; H, 2.98; N, 10.36; found: C, 62.24; H, 2.86; N, 10.50.

5-(4-Bromophenyl)benzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4b). Orange powder; mp 299 °C. IR (KBr) (ν_max/cm⁻¹): 3403, 3246, 3054, 1734, 1664, 1603, 1575. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 5.12 (s, 1H, CH), 6.92–7.98 (m, 8H, H-Ar), 9.31 (s, 1H, NH), 10.16 (s, 1H, NH), 10.84 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 35.5, 87.0, 119.7, 124.3, 126.5, 126.9, 129.8 (2 CH), 131.4 (2 CH), 132.2, 134.5, 135.8, 138.7, 149.0, 154.7, 159.2, 163.3, 181.5, 184.5. MS (EI, 70 eV): m/z (%): 449 (M⁺, 8), 371 (12), 373 (50), 278 (30), 156 (22), 76 (80), 57 (80), 43 (100). For C₂₁H₁₂BrN₃O₄ (450.24): C, 56.02; H, 2.69; N, 9.33; found: C, 56.18; H, 2.58; N, 14.35.

5-(4-Nitrophenyl)benzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4c). Red powder; mp 297 °C. IR (KBr) (ν_max/cm⁻¹): 3359, 3241, 3074, 1720, 1684, 1632, 1578. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 5.23 (s, 1H, CH), 7.35 (d, ³J_HH = 8.5 Hz, 2H), 7.46 (d, ³J_HH = 8.5 Hz, 2H), 7.75–8.12 (m, 4H, H-Ar), 9.30 (s, 1H, NH), 10.20 (s, 1H, NH), 10.84 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 37.1, 87.9, 119.2, 126.8, 126.9, 128.8 (2 CH), 130.9 (2 CH), 131.1, 132.0, 132.7, 134.5, 136.0, 138.9, 144.9, 151.2, 160.0, 163.4, 181.7, 183.5. MS (EI, 70 eV): m/z (%): 416 (M⁺, 15), 371 (16), 340 (54), 245 (34), 156 (18), 76 (84), 57 (76), 43 (100). For C₂₁H₁₂N₄O₆ (416.34): C, 60.58; H, 2.91; N, 13.46; found: C, 60.74; H, 2.86; N, 13.50.

5-Phenylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4d). Red powder; mp 300 °C. IR (KBr) (ν_max/cm⁻¹): 3410, 3249, 3065, 1715, 1645, 1603, 1560. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 5.22 (s, 1H, CH), 7.12–8.01 (m, 9H, H-Ar), 9.28 (s, 1H, NH), 10.10 (s, 1H, NH), 10.81 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 35.5, 86.6, 119.7, 124.3, 126.5, 126.9, 127.8 (2 CH), 128.9 (2 CH), 131.5, 132.5, 134.2, 135.3, 139.8, 151.1, 155.7, 159.2, 163.5, 181.8, 185.5. MS (EI, 70 eV): m/z (%): 371 (M⁺, 5), 328 (12), 295 (42), 200 (30), 156 (22), 76 (80), 43 (100). For C₂₁H₁₃N₃O₄ (371.35): C, 67.92; H, 3.53; N, 11.32; found: C, 68.05; H, 3.50; N, 11.45.

5-o-Tolylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4e). Red powder; mp 277 °C. IR (KBr) (ν_max/cm⁻¹): 3415, 3246, 3056, 1713, 1656, 1603, 1532. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 2.76 (s, 3H, Me), 5.16 (s, 1H, CH), 7.00–8.03 (m, 8H, H-Ar), 9.30 (s, 1H, NH), 10.19 (s, 1H, NH), 10.85 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 21.2, 35.4, 86.7, 116.9, 123.9, 126.3, 126.8, 127.3, 127.9, 128.6, 131.2, 132.5, 134.1, 135.1, 135.3, 137.9, 139.1, 151.0, 158.2, 163.5, 181.4, 183.3. MS (EI, 70 eV): m/z (%): 385 (M⁺, 10), 309 (44), 214 (26), 156 (20), 91 (74), 57 (82), 43 (100). For C₂₂H₁₅N₃O₄ (385.37): C, 68.57; H, 3.92; N, 10.90; O, 16.61; found: C, 68.81; H, 3.75; N, 10.91.

5-m-Tolylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4f). Red powder; mp 282 °C. IR (KBr) (ν_max/cm⁻¹): 3327, 3266, 3051, 1723, 1655, 1612, 1525. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 2.70 (s, 3H, Me), 5.21 (s, 1H, CH), 7.01–8.12 (m, 8H, H-Ar), 9.25 (s, 1H, NH), 10.15 (s, 1H, NH), 10.83 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 23.5, 35.5, 86.4, 117.5, 124.1, 126.4, 126.9, 127.3, 128.0, 128.6, 131.5, 132.5, 134.3, 135.3, 135.6, 138.0, 139.4, 151.5, 160.2, 163.3, 181.9, 183.5. MS (EI, 70 eV): m/z (%): 385 (M⁺, 8), 294 (40), 214 (22), 156 (28), 91 (70), 57 (78), 43 (100). For C₂₂H₁₅N₃O₄ (385.37): C, 68.57; H, 3.92; N, 10.90; found: C, 68.70; H, 3.85; N, 10.86.

5-p-Tolylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4g). Red powder; mp 311 °C. IR (KBr) (ν_max/cm⁻¹): 3401, 3254, 3059, 1713, 1655, 1608, 1515. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 2.18 (s, 3H, Me), 5.05 (s, 1H, CH), 7.01 (d, ³J_HH = 7.7 Hz, 2H), 7.19 (d, ³J_HH = 7.7 Hz, 2H), 7.79–8.05 (m, 4H, H-Ar), 9.20 (s, 1H, NH), 10.13 (s, 1H, NH), 10.88 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 21.0, 35.3, 86.5, 114.9, 126.7, 126.8, 129.0 (2 CH), 130.5 (2 CH), 130.8, 131.3, 132.5, 134.3, 135.8, 138.8, 144.4, 148.7, 159.2, 163.4, 179.8, 183.1. MS (EI, 70 eV): m/z (%): 385 (M⁺, 5), 294 (45), 214 (30), 156 (20), 76 (78), 57 (82), 43 (100). For C₂₂H₁₅N₃O₄ (385.37): C, 68.57; H, 3.92; N, 10.90; found: C, 68.50; H, 3.87; N, 10.81.

5-(4-Methoxyphenyl)benzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4h). Orange powder; mp 301 °C. IR (KBr) (ν_max/cm⁻¹): 3429, 3176, 3054, 1704, 1679, 1609, 1532. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 3.64 (s, 3H, OMe), 5.01 (s, 1H, CH), 6.75 (d, ³J_HH = 7.7 Hz, 2H, H-Ar), 7.20 (d, ³J_HH = 7.6 Hz, 2H, H-Ar), 7.80–8.02 (m, 4H, H-Ar), 9.30 (s, 1H, NH), 10.16 (s, 1H, NH), 10.90 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 32.5, 55.7, 86.5, 114.3 (2 CH), 124.4, 126.2, 126.7, 129.7, 130.1, 130.5, 133.1, 133.2, 133.7, 135.3, 137.9 (2 CH), 144.7, 159.2, 163.4, 179.8, 183.0. MS (EI, 70 eV): m/z (%): 401 (M⁺, 15), 358 (14), 325 (30), 230 (26), 156 (22), 57 (76), 43 (100). For C₂₂H₁₅N₃O₅ (401.37): C, 65.83; H, 3.77; N, 10.47; found: C, 65.87; H, 3.75; N, 10.59.

5-(4-Chlorophenyl)-1,3-dimethylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4i). Orange powder; mp 251 °C. IR (KBr) (ν_max/cm⁻¹): 3401, 1715, 1653, 1580, 1516. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 3.18 (s, 3H, NMe), 3.35 (s, 3H, NMe), 5.64 (s, 1H, CH), 7.11–7.89 (m, 8H, H-Ar), 13.10 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 29.0, 31.3, 35.3, 86.1, 118.9, 124.1, 126.7, 126.9, 130.3 (2CH), 131.4, 131.5 (2CH), 132.6, 134.3, 135.2, 138.9, 151.1, 155.2, 156.4, 164.3, 181.6, 186.6. MS (EI, 70 eV): m/z (%): 433 (M⁺, 5), 322 (8), 271 (30), 235 (100), 156 (72), 76 (82), 57 (26). For C₂₃H₁₆ClN₃O₄ (433.84): C, 63.67; H, 3.72; Cl, 8.17; N, 9.69; found: C, 63.84; H, 3.55; N, 8.28.

5-(4-Bromophenyl)-1,3-dimethylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4j). Orange powder; mp 229 °C. IR (KBr) (ν_max/cm⁻¹): 3395, 1700, 1656, 1573, 1512. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 3.12 (s, 3H, NMe), 3.36 (s, 3H, NMe), 5.79 (s, 1H, CH), 7.19–7.9 (m, 8H, H-Ar), 13.16 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 29.1, 31.3, 35.3, 86.1, 119.5, 124.0, 126.5, 126.9, 130.0 (2CH), 131.4, 131.6 (2CH), 132.5, 134.3, 135.2, 139.0, 151.0, 155.2, 156.3, 164.3, 181.8, 186.6. MS (EI, 70 eV): m/z (%): 477 (M⁺, 5), 338 (22), 321 (32), 235 (100), 156 (76), 76 (80). For C₂₃H₁₆BrN₃O₄ (478.29): C, 57.76; H, 3.37; N, 8.79; found: C, 57.86; H, 3.35; N, 8.83.

1,3-Dimethyl-5-m-tolylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4k). Red powder; mp 195 °C. IR (KBr) (ν_max/cm⁻¹): 3325, 1705, 1656, 1570, 1520. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 2.22 (s, 3H, Me), 3.14 (s, 3H, NMe), 3.36 (s, 3H, NMe), 5.80 (s, 1H, CH), 6.94–8.02 (m, 8H, H-Ar), 13.06 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 22.0, 29.0, 31.2, 35.5, 86.7, 111.8, 124.6, 126.5, 126.9, 127.2, 128.0, 128.8, 131.4, 132.6, 134.3, 135.3, 135.4, 137.9, 139.1, 151.0, 155.2, 164.5, 181.9, 184.3. MS (EI, 70 eV): m/z (%): 413 (M⁺, 8), 275 (16), 257 (22), 235 (100). For C₂₄H₁₉N₃O₄ (413.43): C, 69.72; H, 4.63; N, 10.16; found: C, 69.86; H, 4.53; N, 10.05.

1,3-Dimethyl-5-p-tolylbenzo[G]pyrimido[4,5-b]quinoline-2,4,6,11(1h,3h,5h,12h)-tetraone (4l). Red powder; mp 263 °C. IR (KBr) (ν_max/cm⁻¹): 3356, 1721, 1655, 1565. ¹H NMR (400 MHz, DMSO-d₆): δ_H (ppm) 2.26 (s, 3H, Me), 3.10 (s, 3H, NMe), 3.32 (s, 3H, NMe), 5.51 (s, 1H, CH), 6.98 (d, ³J_HH = 7.8 Hz, H-Ar), 7.20 (d, ³J_HH = 7.9 Hz, H-Ar), 7.75–8.04 (m, 4H, H-Ar), 9.03 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C (ppm) 22.2, 28.9, 31.5, 36.5, 88.7, 116.0, 124.3, 126.5, 126.9, 128.8 (2CH), 130.7 (2CH), 131.6, 134.5, 135.3, 135.4, 136.9, 139.4, 151.0, 158.2, 163.5, 180.7, 184.1. MS (EI, 70 eV): m/z (%): 413 (M⁺, 10), 322 (6), 275 (20), 235 (100), 156 (72), 76 (80). For C₂₄H₁₉N₃O₄ (413.43): C, 69.72; H, 4.63; N, 10.16; found: C, 69.78; H, 4.45; N, 10.21.

Acknowledgements

P. Rai and Rahila thanks to CSIR for their Senior Research Fellowship. H. Sagir thanks to UGC for her Junior Research Fellowship. Authors gratefully acknowledge the SAIF, Punjab University, Chandigarh, for providing all the spectroscopic data and Nanotechnology Application Centre, University of Allahabad for powder XRD and EDS.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra00791g

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