Eu₂O₃ modified CeO₂ nanoparticles as a heterogeneous catalyst for an efficient green multicomponent synthesis of novel phenyldiazenyl-acridinedione-carboxylic acid derivatives in aqueous medium

Abstract

A green and highly efficient protocol has been developed for the synthesis of phenyldiazenyl-acridinedione-carboxylic acids by a one-pot multicomponent coupling of 1,3-dicarbonyl compounds, 4-hydroxy-3-methoxy-5-(substituted-phenyl-diazenyl)-benzaldehydes and glycine using europium modified ceria nanoparticles as the catalyst in aqueous medium. An environmentally benign reaction procedure, a wide diversity of products, excellent yields and reusability of the catalyst make the present method extremely advantageous for the synthesis of phenyldiazenyl-acridinedione-carboxylic acids. The formation, size and oxidation state of the metal ions present in the nano-europium modified ceria is confirmed by powdered-XRD, TEM and XPS techniques.

---

Introduction

Multicomponent reactions (MCRs) have been typically employed to quickly launch structurally varied and/or complex compounds from a number of simple starting materials in a one-pot approach.¹ These reactions are useful for a broad range of functional groups and provide an opportunity for performing a diversity of post-multicomponent reaction transformations, such as re-functionalization and cyclization.² MCRs in aqueous media are highly advantageous since water is environmental friendly and it has exceptional physical and chemical properties which may lead to certain reactivities and selectivities usually unachievable by organic solvents.³

Nano metal oxide catalysis is a green chemistry approach to chemical conversions because of its mild reaction conditions, high selectivity, formation of few by-products and low energy requirements. Therefore, the search for promising new nano metal oxides to reach eco-friendly reactions continue to avoid the use of hazardous Lewis acids, bases and other harsh reaction conditions and produce the diverse nature of chemical substances with higher yields.⁴

Acridines represent a significant class of biologically active compounds, which have important attention from many medicinal and pharmaceutical chemists, because of their antibacterial,⁵ myorelaxant,⁶ antimalarial⁷ and anticancer activities.⁸ In recent years, diazo compounds have become significant due to their activities such as tyrosinase inhibition,⁹ anticancer,¹⁰ antifungal¹¹ and vesicular glutamate transporter inhibition.¹² Hence, synthesis of diazo group containing acridine derivatives using green protocols has become a significant consideration for us.

In continuation of our efforts towards the development of green synthetic methods to novel heterocyclic molecules¹³ herein, we report a facile synthesis of 4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)-dihydropyridine-acetic acid derivatives. To the best of our knowledge, for the first time, an ecofriendly process was developed for the synthesis of novel 4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)-dihydropyridine-acetic acid scaffold from 1,3-dicarbonyl compounds, 4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)benzaldehydes and glycine using europium modified ceria nanoparticles (CeO₂–Eu₂O₃) as catalyst in aqueous medium. The catalyst was prepared by coprecipitation method and characterized using powdered-XRD, TEM and XPS techniques.

Results and discussions

Nanosized Ce_0.8Eu_0.2O_2−δ (CE 8 : 2 mole ratio based on oxides) solid solutions were prepared by a modified co-precipitation method using appropriate amounts of the corresponding cerium(III) nitrate hexahydrate [Ce(NO₃)₃·6H₂O, 99.99%, Aldrich] and europium(III) nitrate pentahydrate [Eu(NO₃)₃·5H₂O, 99.9%, Aldrich] precursors respectively. The desired amounts of precursors were dissolved separately in double-distilled water under mild stirring conditions and mixed together. Dilute aqueous ammonia solution was added drop-wise over a period until the pH of the solution reached ∼8.5 and CE hydroxide formed. The obtained light yellow colored precipitate was decanted, filtered, and washed with distilled water multiple times followed by oven drying at 393 K for 12 h. The oven dried samples were crushed using an agate mortar and calcined in air at 773 K for 5 h at a heating rate of 5 K min⁻¹. Finally, the CE material was obtained, which was thoroughly investigated by XRD, TEM and XPS techniques. For comparative purpose, pure cerium oxide (CeO₂, labelled as C) was also prepared in a similar way.

Fig. 1 Shows the XRD patterns of CE and C material. The planes are observed at 2θ = 28.4°, 32.8°, 47.3°, 55.7°. From the analysis of XRD, it is understood that only one type of crystalline phases is present in the prepared sample. Absence of any peaks corresponding to dopant oxide (Eu₂O₃) confirms the formation of solid solutions. The average crystallite size was calculated by the Debye–Scherrer equation using most intense peaks (111), (200), (220), and (311), which is 8.4 nm and the surface area of the material was measured using nitrogen adsorption–desorption method at 90 m² gm⁻¹. These values for pure ceria are 8.9 nm and 40 m² gm⁻¹. From this, it is clear that the crystallite size of ceria material decreases and surface area increases upon introduction of europium oxide into the ceria lattice. This is one of the significant factors to determine the activity of the catalysts.

Fig. 1 Powder X-ray diffraction patterns of europium modified ceria (CE) and pure ceria (C) nanoparticles.

Fig. 2 shows the TEM images of the CE and pure C material. From the figure, it is clear that, the average particle size was in the range of 8–10 nm, which is well in agreement with XRD data.

Fig. 2 Transmission electron microscopy image of pure ceria (a) and europium modified ceria (b) nanoparticles.

XP spectra are used to know the oxidation states of the metal ions present on the surface of the solid solution. Fig. 3(a) and (b) represent the Ce 3d and O 1s spectra of CE and C material. Ce 3d spectra were deconvoluted into eight peaks corresponding to four pairs of spin–orbit doublets and the peaks were labeled as u and v referred to the 3d_3/2 and 3d_5/2 spin–orbit components, respectively. The peaks designated as u, u′′, u′′′ and v, v′′, v′′′ can be assigned to Ce⁴⁺ while the peaks u′ and v′ belong to Ce³⁺ suggesting the coexistence of Ce³⁺ and Ce⁴⁺ in the CE material. From the figure, it is clear that the position of the Ce 3d peaks of CE material shifted to lower binding energy compared to pure ceria indicates the formation of vacancy defects in the doped sample contrast to pure ceria.¹⁴

Fig. 3 (a) Ce 3d XP spectra of CE and C, (b) O 1s XP spectra of CE and C and (c) Eu 3d XP spectrum of europium modified ceria nanoparticles.

O 1s spectra of CE and C material calcined at 773 K are presented in Fig. 3(b). From the figure two peaks were observed, one is at 529.3 eV and other one is at 531.7 eV. The former can be related to lattice oxygen (O_I) and the latter to the adsorbed oxygen (O_II). It indicates that two types of oxygens are present in the CE material. The binding energy of the above two peaks (O_I and O_II) of CE is lower than pure ceria. It signifies that the environment present around the oxygen atoms is different i.e., Ce–O–Ce versus Ce–O–Eu, which influence the catalytic properties of ceria significantly.

Eu 3d XP spectrum of prepared material is shown in Fig. 3(c). The peak observed at 1134 eV corresponds to Eu³⁺ and shows that the dopant is present in the trivalent state only.¹⁵

From the characterization studies (XRD, TEM and XPS), it is apparent that the properties of CE material like surface area and oxygen defects are significantly improved with respect to pure ceria.

A green multicomponent synthesis of 4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)-dihydropyridine-acetic acid derivatives was achieved by a reaction among 1,3-dicarbonyl compounds (1a–b, 2 mmol), 4-hydroxy-3-methoxy-5-(substituted-phenyl-diazenyl)-benzaldehydes (2a–f, 1 mmol) and glycine (3, 1 mmol) in the presence of CeO₂–Eu₂O₃ nanoparticles (NPs) acting as catalyst in aqueous medium at 80 °C. A model reaction was conducted using 5,5-dimethylcyclohexane-1,3-dione 1a and 4-hydroxy-3-methoxy-5-((4-nitrophenyl)-diazenyl)-benzaldehyde 2c along with glycine 3 employing different solvents, catalysts at different temperatures for optimizing the reaction conditions.

Initially the reaction was performed with a variety of solvents like methanol, ethanol, water, acetonitrile (Table 1, entries 1–4) and it was observed that aqueous medium afforded better yields than other solvents. Further, we focused on the evaluation of different catalysts for the model reaction in water at 80 °C. A wide range of catalysts like sodium hydroxide, piperidine, triethylamine, acetic acid, ferric chloride (Table 1, entries 5–9) including nano catalysts like Fe₃O₄, TiO₂, CeO₂ (C), CeO₂–Eu₂O₃ (CE) (Table 1, entries 10–13) were employed to test their efficacy for the specific synthesis of compound 4c. Amongst, CeO₂ and CeO₂–Eu₂O₃ exhibiting better results. In these, CeO₂–Eu₂O₃, showing improved performance than pure ceria, which can be supported from the characterization studies. The results showed that in the presence of CeO₂–Eu₂O₃ (europium modified ceria nanoparticles), the desired product 4c was obtained in 90% yield and the yield of the desired product was tested using different mol ratios (10, 20, 30 mol%). The maximum yield was found with the 20 mol% catalyst (Table 1, entry 14). Lower than this, catalyst did not yield any promising result and when the reaction was tried using 30 mol% (Table 1, entry 15), no improvement was observed in the yields of 4c. The results were similar with the reaction when 20 mol% catalyst was used. As an extension of the above, we also studied the effect of temperature on the above reaction at different temperatures like room temperature, 40 °C, 60 °C and reflux temperature (Table 1, entries 16–19). Among these results, we found that 80 °C temperature enhanced the reaction yields.

Table 1 Effect of solvent and catalysts in the synthesis of 4c

Entry^a	Catalyst (mol%)	Solvent	Temperature (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 5,5-dimethylcyclohexane-1,3-dione (2 mmol), 4-hydroxy-3-methoxy-5-((4-nitrophenyl)-diazenyl)-benzaldehyde (1 mmol) and glycine (1 mmol), solvent (1 mL) and catalyst.b Yields of isolated products.
1	—	Methanol	80	24	5
2	—	Ethanol	80	24	12
3	—	Water	80	24	27
4	—	Acetonitrile	80	24	15
5	NaOH (10%)	Water	80	15	36
6	Piperidine (10%)	Water	80	8	31
7	Triethylamine (10%)	Water	80	8	29
8	Acetic acid (10%)	Water	80	8	63
9	FeCl3(10%)	Water	80	8	51
10	Fe3O4 (10%)	Water	80	8	57
11	TiO2 (10%)	Water	80	8	44
12	CeO2 (10%)	Water	80	8	75
13	CeO2–Eu2O3 (10%)	Water	80	4	82
14	CeO2–Eu2O3 (20%)	Water	80	2	90
15	CeO2–Eu2O3 (30%)	Water	80	2	90
16	CeO2–Eu2O3 (20%)	Water	rt	2	55
17	CeO2–Eu2O3 (20%)	Water	40	2	71
18	CeO2–Eu2O3 (20%)	Water	60	2	79
19	CeO2–Eu2O3 (20%)	Water	Reflux	2	83

---

The well optimized one-step reaction protocol was adopted to create a diverse series of (4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)-dihydropyridine-acetic acids 4a–l in good to excellent yields (69–91%) with 1,3-dicarbonyl compounds 1a–b, 4-hydroxy-3-methoxy-5-(substituted-phenyl-diazenyl)-benzaldehydes 2a–f and glycine 3 in the presence of CeO₂–Eu₂O₃ nanoparticles (NPs) as a catalyst in aqueous medium at 80 °C. To estimate the scope and generality of the procedure, 4-hydroxy-3-methoxy-5-(substituted-phenyl)diazenyl)-benzaldehydes like 4-hydroxy-3-methoxy-5-(phenyldiazenyl)-benzaldehyde (2a), 4-hydroxy-3-methoxy-5-(p-tolyldiazenyl)-benzaldehyde (2b), 4-hydroxy-3-methoxy-5-((4-nitrophenyl)diazenyl)-benzaldehyde (2c), 4-hydroxy-3-methoxy-5-((3-nitrophenyl)diazenyl)-benzaldehyde (2d), 4-hydroxy-3-methoxy-5-((2-nitrophenyl)diazenyl)-benzaldehyde (2e) and 3-((3-fluoro-4-morpholinophenyl)diazenyl)-4-hydroxy-5-methoxybenzaldehyde (2f) having both electron-donating and electron-withdrawing groups were reacted with 1,3-dicarbonyl compounds like 5,5-dimethyl-1,3-cyclohexanedione (1a) and 1,3-cyclohexanedione (1b); along with glycine (3) under optimized conditions, and results are summarized in Table 2.

Table 2 Synthesis of 4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)-dihydropyridine-acetic acids 4a–l^a

a Reaction conditions: 1,3-dicarbonyl compounds (2 mmol), 4-hydroxy-3-methoxy-5-((4-substituted-phenyl)-diazenyl)-benzaldehyde (1 mmol) and glycine (1 mmol), water (1 mL) and nano-CeO₂–Eu₂O₃.b Yields of isolated products.

---

The recyclability is of excessive significance of applying a catalytic system in industrial processes. Therefore, the recyclability of the catalyst was investigated in the synthesis of compound 4c with 5,5-dimethylcyclohexane-1,3-dione 1a, 4-hydroxy-3-methoxy-5-((4-nitrophenyl)-diazenyl)-benzaldehyde 2c and glycine 3. After completion of the reaction, the reaction mixture was cooled to room temperature and the product was extracted with ethyl acetate. The catalyst was separated by filtration, washed with acetone, dried and used for the next run. The catalytic activity of the CeO₂–Eu₂O₃ was restored within the limits of the experimental errors for the four successive recycled runs (Fig. 4). A plausible reaction mechanism for the formation of acridines involves the activation of aldehyde 2 by CeO₂–Eu₂O₃ nanoparticles followed the attack of enol form of 1,3-dicarbonyl compound 1 to give the intermediate A. The formation of intermediate (B) takes place by a condensation between 1,3-dicarbonyl compound 1 and glycine 3. Subsequently a Michael type addition occurs between intermediate A and B producing intermediate (C). Intermediate C undergoes intermolecular cyclization to afford the final product 5 as depicted in the Scheme 1. The structures of the synthesized compounds were well characterized by IR, ¹H-NMR, ¹³C-NMR spectroscopy, mass spectrometry and elemental analysis.

Fig. 4 Reusability studies of the nano-sized CeO₂–Eu₂O₃ catalyst for the synthesis of compound.

Scheme 1 : Proposed mechanism for the formation of phenyldiazenyl-acridinedione-carboxylic acid derivatives (4).

Experimental results

Materials and method

All reagents were procured from commercial sources and used without further purification. A Bruker WM-4 (X) spectrophotometer (577 model) was used for recording IR spectra (KBr). NMR spectra were recorded on a Bruker WM-500 spectrophotometer at 400 MHz (¹H), Bruker WM-400 spectrophotometer at 400 MHz (¹H) and 100 MHz (¹³C) respectively, in DMSO-d₆ with TMS as an internal standard. Elemental analysis was performed on a Carlo Erba EA 1108 automatic elemental analyzer. Mass spectra (ESI) were recorded on a jeo1 JMSD-300 spectrometer. XRD data was acquired in the 2θ range of 12–80° on a Rigaku Multiflex instrument using Cu Kα (λ = 1.5418 Å) radiation and a scintillation counter detector. XRD phases present in the samples were identified with the help of the Powder Diffraction File-International Centre for Diffraction Data (PDF-ICDD). The average size of the crystalline domain (D) of CE was estimated with the help of the Scherrer eqn (1) using the XRD data of all prominent lines.

D = Kλ/β cos θ (1)

where D denotes the crystallite size, λ the X-ray wavelength (1.541 Å), K the particle shape factor taken as 1, β the peak width (FWHM, full width at half maximum) in radians, and θ the Bragg diffraction angle. The BET surface areas were measured by nitrogen adsorption–desorption isotherms at liquid nitrogen temperature using a Micromeritics ASAP 2020 instrument.

HRTEM studies were made on a JEM-2010 (JEOL) instrument equipped with a slow-scan CCD camera at an accelerating voltage of 200 kV.

The XPS measurements were performed on a Shimadzu (ESCA 3400) spectrometer by using Al Kα (1486.7 eV) radiation as the excitation source. Charging effects of catalyst samples were corrected by using the binding energy of the adventitious carbon (C 1s) at 284.6 eV as internal reference. The XPS analysis was done at ambient temperature and pressures usually in the order of less than 10⁻⁸ Pa.

Synthesis of 2-(9-(4-hydroxy-3-methoxy-5-(substituted-phenyldiazenyl)phenyl)-1,8-dioxo-octahydroacridin-10(9H)-yl)acetic acid derivatives (4a–l)

A mixture of 1,3-dicarbonyl compound (2 mmol), 4-hydroxy-3-methoxy-5-(substituted-phenyl diazenyl)-benzaldehyde (1 mmol) and glycine (1 mmol) in water (1 mL) was taken in a 50 mL round bottom flask and the catalyst of europium modified ceria nanoparticles (20 mol%, 104.8 mg) was added. The resulting mixture was kept at 80 °C for 2–2.5 hours until the full conversion was achieved (monitored by TLC). After completion of the reaction the product was separated from the catalyst by extraction with ethyl acetate, which was evaporated under vacuum. The product was purified by column chromatography using silica gel [3.9 : 6.0 : 0.1 hexane : ethyl acetate : methanol] to afford the pure compounds (4a–l).

2-(9-(4-Hydroxy-3-methoxy-5-(phenyldiazenyl)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4a). Dark red solid; mp 251–253 °C; IR (KBr, cm⁻¹) ν_max: 3426, 2950, 1728, 1669; ¹H NMR (400 MHz, DMSO-d₆): δ 1.02 (s, 6H, –CH₃), 1.06 (s, 6H, –CH₃), 2.32–2.44 (m, 10H), 3.86 (s, 3H, –OCH₃), 4.18 (s, 1H), 6.97 (s, 1H, ArH), 7.17 (s, 1H, ArH), 7.45–7.52 (m, 3H, ArH), 7.93 (d, 2H, J = 8.0 Hz, ArH), 12.12 (s, 1H, –OH), 13.08 (s, 1H, –COOH); ¹³C NMR (100 MHz, DMSO-d₆): δ 198.17, 195.57, 162.73, 159.55, 151.45, 148.63, 143.62, 137.44, 135.19, 132.70, 128.97, 124.17, 121.12, 115.77, 113.65, 55.78, 52.34, 49.46, 36.38, 32.99, 28.31, 25.73; ESI-MS (m/z): 558 (M + 1); anal. calcd for C₃₂H₃₅N₃O₆: C, 68.92; H, 6.33; N, 7.54; found: C, 68.72; H, 6.44; N, 7.38.

2-(9-(4-Hydroxy-3-methoxy-5-(p-tolyldiazenyl)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4b). Dark red solid; mp 247–248 °C; IR (KBr, cm⁻¹) ν_max: 3425, 2949, 1732, 1667; ¹H NMR (400 MHz, CDCl₃): δ 1.16 (s, 6H, –CH₃), 1.31 (s, 6H, –CH₃), 2.26–2.54 (m, 13H), 3.86 (s, 3H, –OCH₃), 5.59 (s, 1H), 6.75 (s, 1H, ArH), 7.30 (s, 1H, ArH), 7.33 (d, 2H, J = 8.0 Hz, ArH), 7.75 (d, 2H, J = 8.0 Hz, ArH), 12.09 (s, 1H, –OH), 13.19 (s, 1H, –COOH); ¹³C NMR (100 MHz, DMSO-d₆): δ 198.32, 195.74, 162.36, 157.71, 148.05, 144.91, 140.78, 137.43, 135.60, 134.87, 122.00, 119.90, 114.14, 112.56, 112.01, 55.62, 50.86, 50.13, 34.55, 31.25, 29.55, 27.13, 21.62; ESI-MS (m/z): 572 (M + 1); anal. calcd for C₃₃H₃₇N₃O₆: C, 69.33; H, 6.52; N, 7.35; found: C, 69.42; H, 6.39; N, 7.21.

2-(9-(4-Hydroxy-3-methoxy-5-((4-nitrophenyl)diazenyl)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4c). Dark red solid; mp 262–263 °C; IR (KBr, cm⁻¹) ν_max: 3426, 2948, 1729, 1670; ¹H NMR (400 MHz, CDCl₃-d₆): δ 1.14 (s, 6H, –CH₃), 1.29 (s, 6H, –CH₃), 2.35–2.52 (m, 10H), 3.85 (s, 3H, –OCH₃), 5.55 (s, 1H), 6.78 (s, 1H, ArH), 7.28 (s, 1H, ArH), 7.94 (d, 2H, J = 8.0 Hz, ArH), 8.38 (d, 2H, J = 8.0 Hz, ArH), 12.04 (s, 1H, –OH), 12.87 (s, 1H, –COOH); ¹³C NMR (100 MHz, CDCl₃): δ 190.86, 189.56, 153.51, 148.84, 148.40, 143.31, 137.34, 129.59, 125.02, 122.73, 122.52, 115.31, 115.23, 56.32, 47.10, 46.43, 32.33, 31.40, 29.78, 27.19; ESI-MS (m/z): 603 (M + 1); anal. calcd for C₃₂H₃₄N₄O₈: C, 63.78; H, 5.69; N, 9.30; found: C, 63.91; H, 5.89; N, 9.18.

2-(9-(4-Hydroxy-3-methoxy-5-((3-nitrophenyl)diazenyl)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4d). Dark red solid; mp 269–270 °C; IR (KBr, cm⁻¹) ν_max: 3425, 2949, 1730, 1670; ¹H NMR (400 MHz, CDCl₃): δ 1.14 (s, 6H, –CH₃), 1.30 (s, 6H, –CH₃), 2.35–2.54 (m, 10H), 3.85 (s, 3H, –OCH₃), 5.56 (s, 1H), 6.80 (s, 1H, ArH), 7.32 (s, 1H, ArH), 7.71 (t, 1H, J = 8.0 Hz, ArH), 8.15 (d, 1H, J = 8.0 Hz, ArH), 8.32 (d, 1H, J = 8.0 Hz, ArH), 8.66 (s, 1H, ArH), 12.04 (s, 1H, –OH), 12.47 (s, 1H, –COOH); ¹³C NMR (100 MHz, CDCl₃): δ 190.86, 189.59, 151.08, 149.17, 148.63, 141.68, 136.99, 130.27, 129.47, 128.96, 124.88, 122.71, 115.91, 115.27, 115.14, 56.35, 47.12, 46.45, 32.31, 31.49, 29.68, 27.26; ESI-MS (m/z): 603 (M + 1); anal. calcd for C₃₂H₃₄N₄O₈: C, 63.78; H, 5.69; N, 9.30; found: C, 63.99; H, 5.49; N, 9.55.

2-(9-(4-Hydroxy-3-methoxy-5-((2-nitrophenyl)diazenyl)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4e). Dark red solid; mp 255–256 °C; IR (KBr, cm⁻¹) ν_max: 3426, 2947, 1725, 1669; ¹H NMR (400 MHz, CDCl₃): δ 1.13 (s, 6H, –CH₃), 1.28 (s, 6H, –CH₃), 2.34–2.52 (m, 10H), 3.83 (s, 3H, –OCH₃), 5.51 (s, 1H), 6.68 (s, 1H, ArH), 7.13 (s, 1H, ArH), 7.53 (t, 1H, J = 8.0 Hz, ArH), 7.72 (t, 1H, J = 8.0 Hz, ArH), 7.97 (d, 1H, J = 8.0 Hz, ArH), 8.11 (d, 1H, J = 8.0 Hz, ArH), 12.05 (s, 1H, –OH), 13.18 (s, 1H, –COOH); ¹³C NMR (100 MHz, CDCl₃): δ 190.77, 189.54, 149.61, 148.04, 143.81, 142.32, 137.73, 134.03, 129.47, 125.37, 122.14, 118.17, 115.17, 114.85, 56.25, 47.07, 46.43, 31.39, 30.97, 29.76, 27.21; ESI-MS (m/z): 603 (M + 1); anal. calcd for C₃₂H₃₄N₄O₈: C, 63.78; H, 5.69; N, 9.30; found: C, 63.90; H, 5.42; N, 9.51.

2-(9-(3-((3-Fluoro-4-morpholinophenyl)diazenyl)-4-hydroxy-5-methoxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4f). Dark red solid; mp 244–245 °C; IR (KBr, cm⁻¹) ν_max: 3425, 2953, 1750, 1670; ¹H NMR (400 MHz, CDCl₃): δ 1.14 (s, 6H, –CH₃), 1.30 (s, 6H, –CH₃), 2.35–2.54 (m, 10H), 3.20–3.24 (m, 4H), 3.83 (s, 3H, –OCH₃), 3.88–3.91 (m, 4H), 5.55 (s, 1H), 6.72 (s, 1H, ArH), 6.99 (d, 1H, J = 8.0 Hz, ArH), 7.24 (s, 1H, ArH), 7.74 (d, 1H, J = 8.0 Hz, ArH), 8.17 (s, 1H, ArH), 12.04 (s, 1H, –OH), 12.81 (s, 1H, –COOH); ¹³C NMR (100 MHz, CDCl₃): δ 190.67, 189.51, 156.79, 154.32, 148.44, 146.24, 145.19, 142.48, 140.96, 136.83, 128.77, 123.32, 122.36, 122.24, 122.05, 117.93, 113.64, 107.61, 107.38, 66.81, 56.28, 50.38, 47.11, 46.44, 32.28, 31.42, 30.97, 29.75, 27.24; ESI-MS (m/z): 661 (M + 1); anal. calcd for C₃₆H₄₁FN₄O₇: C, 65.44; H, 6.25; N, 8.48; found: C, 65.31; H, 6.33; N, 8.62.

2-(9-(4-Hydroxy-3-methoxy-5-(phenyldiazenyl)phenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4g). Dark red solid; mp 254–255 °C; IR (KBr, cm⁻¹) ν_max: 3425, 2949, 1749, 1669; ¹H NMR (400 MHz, CDCl₃): δ 2.01–2.08 (m, 4H), 2.34–2.43 (m, 6H), 2.64–2.73 (m, 4H), 3.99 (s, 3H, –OCH₃), 4.82 (s, 1H), 7.24 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.46–7.53 (m, 3H, ArH), 7.83 (d, 2H, ArH), 11.64 (s, 1H, –OH), 13.22 (s, 1H, –COOH); ¹³C NMR (100 MHz, DMSO-d₆): δ 198.74, 195.83, 164.81, 162.49, 158.77, 151.52, 148.98, 144.08, 138.13, 135.70, 131.47, 129.66, 123.22, 122.32, 119.98, 114.78, 113.83, 112.79, 55.81, 47.06, 36.71, 34.87, 26.16, 23.48; ESI-MS (m/z): 502 (M + 1); anal. calcd for C₂₈H₂₇N₃O₆: C, 67.05; H, 5.43; N, 8.38; found: C, 67.22; H, 5.21; N, 8.59.

2-(9-(4-Hydroxy-3-methoxy-5-(p-tolyldiazenyl)phenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4h). Dark red solid; mp 232–233 °C; IR (KBr, cm⁻¹) ν_max: 3426, 2948, 1748, 1670; ¹H NMR (400 MHz, DMSO-d₆): δ 1.90–2.00 (m, 4H), 2.29–2.33 (m, 6H), 2.41 (s, 3H, –CH₃), 2.60–2.69 (m, 4H), 3.83 (s, 3H, –OCH₃), 4.23 (s, 1H), 6.90 (s, 1H, ArH), 7.13 (s, 1H, ArH), 7.39 (d, 2H, J = 8.0 Hz, ArH), 7.90 (d, 2H, ArH), 10.98 (s, 1H, –OH), 12.88 (s, 1H, –COOH); ¹³C NMR (100 MHz, DMSO-d₆): δ 198.41, 196.23, 164.75, 158.38, 149.54, 148.33, 143.38, 141.37, 137.62, 135.29, 129.59, 122.15, 119.33, 114.59, 113.87, 112.71, 55.47, 49.80, 36.71, 34.43, 26.10, 21.43, 19.31; ESI-MS (m/z): 516 (M + 1); anal. calcd for C₂₉H₂₉N₃O₆: C, 67.56; H, 5.67; N, 8.15; found: C, 67.39; H, 5.43; N, 8.33.

2-(9-(4-Hydroxy-3-methoxy-5-((4-nitrophenyl)diazenyl)phenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4i). Dark red solid; mp 245–246 °C; IR (KBr, cm⁻¹) ν_max: 3426, 2950, 1749, 1671; ¹H NMR (400 MHz, CDCl₃): δ 2.04–2.11 (m, 4H), 2.37–2.44 (m, 6H), 2.67–2.73 (m, 4H), 3.99 (s, 3H, –OCH₃), 4.81 (s, 1H), 7.24 (s, 1H, ArH), 7.29 (s, 1H, ArH), 7.96 (d, 2H, J = 8.0 Hz, ArH), 8.37 (d, 2H, ArH), 12.51 (s, 1H, –OH), 13.04 (s, 1H, –COOH); ¹³C NMR (100 MHz, CDCl₃): δ 191.05, 189.86, 152.88, 150.27, 149.04, 145.34, 140.38, 138.20, 136.52, 135.36, 133.00, 130.79, 129.07, 126.75, 125.21, 122.92, 111.68, 56.65, 49.34, 37.01, 35.97, 27.32, 21.23; ESI-MS (m/z): 547 (M + 1); anal. calcd for C₂₈H₂₆N₄O₈: C, 61.53; H, 4.80; N, 10.25; found: C, 61.72; H, 4.93; N, 10.50.

2-(9-(4-Hydroxy-3-methoxy-5-((3-nitrophenyl)diazenyl)phenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4j). Dark red solid; mp 229–230 °C; IR (KBr, cm⁻¹) ν_max: 3427, 2951, 1743, 1669; ¹H NMR (400 MHz, DMSO-d₆): δ 1.94–2.02 (m, 4H), 2.27–2.34 (m, 6H), 2.64–2.74 (m, 4H), 3.83 (s, 3H, –OCH₃), 4.59 (s, 1H), 6.98 (s, 1H, ArH), 7.16 (s, 1H, ArH), 7.83 (t, 1H, J = 8.0 Hz, ArH), 8.22 (d, 1H, J = 8.0 Hz, ArH), 8.42 (d, 1H, J = 8.0 Hz, ArH), 8.74 (s, 1H, ArH), 11.72 (s, 1H, –OH), 12.44 (s, 1H, –COOH); ¹³C NMR (100 MHz, DMSO-d₆): δ 197.02, 195.80, 155.43, 154.50, 149.43, 148.56, 145.31, 141.98, 138.60, 135.55, 132.25, 130.28, 125.40, 124.19, 56.48, 48.72, 36.91, 30.87, 26.96, 20.40; ESI-MS (m/z): 547 (M + 1); anal. calcd for C₂₈H₂₆N₄O₈: C, 61.53; H, 4.80; N, 10.25; found: C, 61.38; H, 4.62; N, 10.49.

2-(9-(4-Hydroxy-3-methoxy-5-((2-nitrophenyl)diazenyl)phenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4k). Dark red solid; mp 276–277 °C; IR (KBr, cm⁻¹) ν_max: 3425, 2950, 1750, 1634; ¹H NMR (400 MHz, CDCl₃): δ 2.03–2.11 (m, 4H), 2.36–2.46 (m, 6H), 2.56–2.69 (m, 4H), 3.99 (s, 3H, –OCH₃), 4.82 (s, 1H), 7.21 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.51 (t, 2H, J = 8.0 Hz, ArH), 7.83 (d, 2H, J = 8.0 Hz, ArH), 11.61 (s, 1H, –OH), 13.22 (s, 1H, –COOH); ¹³C NMR (100 MHz, DMSO-d₆): δ 198.45, 196.28, 164.57, 158.45, 152.30, 150.34, 148.71, 145.72, 139.65, 136.68, 132.24, 129.85, 124.95, 119.48, 117.25, 115.03, 113.25, 108.87, 56.09, 49.63, 37.36, 34.87, 26.36, 19.57; ESI-MS (m/z): 547 (M + 1); anal. calcd for C₂₈H₂₆N₄O₈: C, 61.53; H, 4.80; N, 10.25; found: C, 61.76; H, 4.94; N, 10.41.

2-(9-(3-((3-Fluoro-4-morpholinophenyl)diazenyl)-4-hydroxy-5-methoxyphenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (4l). Dark red solid; mp 233–234 °C; IR (KBr, cm⁻¹) ν_max: 3425, 2950, 1748, 1670; ¹H NMR (400 MHz, CDCl₃): δ 2.02–2.08 (m, 4H), 2.36–2.41 (m, 6H), 2.68–2.74 (m, 4H), 3.20–3.25 (m, 4H), 3.88–3.91 (m, 4H), 3.98 (s, 3H, –OCH₃), 4.81 (s, 1H), 6.98 (d, 2H, J = 8.0 Hz, ArH), 7.18 (s, 1H, ArH), 7.22 (s, 1H, ArH), 7.62 (s, 1H, ArH), 11.78 (s, 1H, –OH), 12.98 (s, 1H, –COOH); ¹³C NMR (100 MHz, CDCl₃): δ 198.50, 196.97, 164.19, 148.06, 145.24, 141.54, 138.04, 136.91, 135.83, 134.96, 132.13, 122.66, 122.17, 117.95, 116.68, 116.14, 66.81, 56.54, 50.39, 48.03, 36.96, 27.20, 21.27, 20.32; ESI-MS (m/z): 605 (M + 1); anal. calcd for C₃₂H₃₃FN₄O₇: C, 63.57; H, 5.50; N, 9.27; found: C, 63.78; H, 5.38; N, 9.10.

Conclusion

In summary, we have developed an efficient and eco-friendly procedure for the one-pot synthesis of phenyldiazenyl-acridinedione-carboxylic acids by a multicomponent reaction of 1,3-dicarbonyl compounds, 4-hydroxy-3-methoxy-5-(substituted-phenyl-diazenyl)-benzaldehydes and glycine using europium modified ceria nanoparticles as a powerful catalyst under aqueous medium. This protocol has the advantages of a wide scope of operational simplicity, short reaction times, high yields, avoiding the use of toxic solvents and reusability of catalyst.

Acknowledgements

The authors are thankful to the Director, National Institute of Technology, Warangal, for providing facilities. One of the authors PSVK also grateful to council of scientific & industrial research (CSIR), New Delhi [File no. 09/922 (0005)2012/EMR-I], India, for the award of senior research fellowship.

References

1. (a) M. M. Khan, R. Yousuf, S. Khan and Shafiullah, RSC Adv., 2015, 5, 57883–57905; (b) M. N. Elinson, E. O. Dorofeeva, A. N. Vereshchagin, R. F. Nasybullin and M. P. Egorov, Catal.: Sci. Technol., 2015, 5, 2384–2387; (c) M. J. Climent, A. Corma and S. Iborra, RSC Adv., 2012, 2, 16–58; (d) P. S. V. Kumar, L. Suresh, G. Bhargavi, S. Basavoju and G. V. P. Chandramouli, ACS Sustainable Chem. Eng., 2015, 3, 2944–2950.
2. (a) S. Pal, M. N. Khan, S. Karamthulla and L. H. Choudhury, RSC Adv., 2013, 3, 15705–15711; (b) Z. Chen and J. Wu, Org. Lett., 2010, 12, 4856–4859; (c) P. Slobbe, E. Ruijter and R. V. A. Orru, Med. Chem. Commun., 2012, 3, 1189–1218; (d) L. Levi and T. J. J. Muller, Chem. Soc. Rev., 2016, 45, 2825–2846; (e) R. C. Cioc, E. Ruijter and R. V. A. Orru, Green Chem., 2014, 16, 2958–2975; (f) H. G. O. Alvim, E. N. da Silva Juniorb and B. A. D. Neto, RSC Adv., 2014, 4, 54282–54299.
3. (a) S. R. Kale, S. S. Kahandal, A. S. Burange, M. B. Gawande and R. V. Jayaram, Catal.: Sci. Technol., 2013, 3, 2050–2056; (b) S. Takale, S. Parab, K. Phatangare, R. Pisal and A. Chaskar, Catal.: Sci. Technol., 2011, 1, 1128–1132.
4. (a) U. C. Rajesh, Divya and D. S. Rawat, RSC Adv., 2014, 4, 41323–41330; (b) X. Marset, J. M. Pérez and D. J. Ramon, Green Chem., 2016, 18, 826–833; (c) S. Lingala, P. S. V. Kumar, T. Vinodkumar and C. Garimella, RSC Adv., 2016, 6, 68788–68797.
5. N. K. Ladani, D. C. Mungra, M. P. Patel and R. G. Patel, Chin. Chem. Lett., 2011, 22, 1407–1410.
6. M. G. Gunduz, F. Isli, A. El-Khouly, S. Yıldırım, G. S. O. Fincan, R. Şimşek, C. Şafak, Y. Sarıoglu, S. O. Yıldırım and R. J. Butcher, Eur. J. Med. Chem., 2014, 75, 258–266.
7. C. W. Muth, H. L. Minigh, S. Chookruvong, L. A. Hall and H. Chao, J. Med. Chem., 1981, 24, 1016–1018.
8. K. B. Ramesh and M. A. Pasha, Bioorg. Med. Chem. Lett., 2014, 24, 3907–3913.
9. H. Xu and X. Zeng, Bioorg. Med. Chem. Lett., 2010, 20, 4193–4195.
10. M. Tonelli, I. Vazzana, B. Tasso, V. Boido, F. Sparatore, M. Fermeglia, M. S. Paneni, P. Posocco, S. Pricl, P. L. Colla, C. Ibba, G. Collu and R. Loddo, Bioorg. Med. Chem., 2009, 17, 4425–4440.
11. H. Hamidiana, R. Tagizadeha, S. Fozoonib, V. Abbasalipoura, A. Taheric and M. Namjoud, Bioorg. Med. Chem., 2013, 21, 2088–2092.
12. F. Favre-Besse, O. Poirel, T. Bersot, E. Kim-Grellier, S. Daumas, S. E. Mestikawy, F. C. Acher and N. Pietrancosta, Eur. J. Med. Chem., 2014, 78, 236–247.
13. (a) P. Sagar Vijay Kumar, L. Suresh, T. Vinodkumar, B. M. Reddy and G. V. P. Chandramouli, ACS Sustainable Chem. Eng., 2016, 4, 2376–2386; (b) L. Suresh, Y. Poornachandra, S. Kanakaraju, C. Ganesh Kumar and G. V. P. Chandramouli, Org. Biomol. Chem., 2015, 13, 7294–7306.
14. Z. Wang, Q. Wang, Y. Liao, G. Shen, X. Gong, N. Han, H. Liu and Y. Chen, ChemPhysChem, 2011, 12, 2763–2770.
15. T. Vinodkumar, D. Naga Durgasri, B. M. Reddy and I. Alxneit, Catal. Lett., 2014, 144, 2033–2042.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra17990h

---