Co3O4/NiO@GQD@SO3H nanocomposite as a superior catalyst for the synthesis of chromenpyrimidines

A three-component reaction involving aromatic aldehydes, 6-amino-1,3-dimethyluracil and 4-hydroxycoumarin was achieved in the presence of the Co3O4/NiO@GQD@SO3H nanocomposite as a highly effective heterogeneous catalyst to produce chromenpyrimidines. The catalyst was characterized via FT-IR, SEM, XRD, EDS, TGA, BET and VSM. This new catalyst was demonstrated to be highly effective in the preparation of chromenpyrimidines. Atom economy, low catalyst loading, reusable catalyst, applicability to a wide range of substrates and high product yields are some of the important features of this protocol.


Introduction
Chromenpyrimidines are a common scaffold in multiple bioactive compounds and possess several pharmacological properties. 1 These compounds are used as analgesic, antipyretic, 2 anti-microbial, 3,4 anti-biolm, 5 anti-inammatory, 6 anticancer, 7 antitubercular agents. 8 Some other examples of pyrimidines as prominent drug molecules include uramustine, piritrexim isetionate, tegafur, oxuridine, methotrexate, trimethoprim, piromidic acid, tetroxoprim and dipyridamole, which have high bioavailability, slow onset and prolonged effect. 9 Chromenpyrimidines have been regarded as signicant targets of organic synthesis. Therefore, the development of effective methods for the preparation of chromenpyrimidines is an attractive challenge. Several methods have been reported for the preparation of chromenpyrimidines in the presence of diverse catalysts including L-proline-derived secondary aminothiourea, 10 sulfamic acid, 11 Zr(HSO 4 ) 4 , 12 L-proline, 13 and bifunctional thiourea-based organocatalyst. 14 However, some of the reported procedures have disadvantages including long reaction times, use of toxic and non-reusable catalysts and undesirable reaction conditions. Therefore, to avoid these drawbacks, the search for effective methods for the preparation of chromenpyrimidines is still desirable. Nanoparticles exhibit good catalytic activity owing to their large surface area and active sites. Metal oxides are a broad class of materials that have been researched extensively due to their unique attributes and potential applications in various elds. Graphene quantum dots (GQDs) are a new member of the carbon nanostructure family, which have quasi-spherical structures. GQDs have gained intensive attention due to their signicant features, biological, 15 biomedical, 16 and therapeutic applications, 17 as a new class of photocatalysts 18 and surfactants, 19 and electrochemical biosensing, 20 electrocatalytic, 21 lithium battery, 22 optical and photovoltaic, 23 photoluminescence, 24,25 bioimaging, 26 and catalytic applications. 27 The potential applications of N-graphene quantum dots were recently reviewed based on experimental and theoretical studies. [28][29][30][31] The synthesis of highly efficient nanocomposite catalysts for the synthesis of organic compounds is still a big challenge. To obtain a larger surface area and more active sites, nanocatalysts are functionalized with active groups. [32][33][34] It has been demonstrated that the decoration of nanocatalysts with GQDs prevents the aggregation of ne particles, and thus increases the effective surface area and number of reactive sites for efficient catalytic reactions. The chemical groups on GQD can catalyze chemical reactions, and their -COOH and -SO 3 H groups can serve as acid catalysts for many reactions. [27][28][29][30][31][32][33][34][35][36] Herein, we report the use of a Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite as a new efficient catalyst for the preparation of chromenpyrimidines through a three-component reaction involving aromatic aldehydes, 6amino-1,3-dimethyluracil and 4-hydroxycoumarin (Scheme 1).

Results and discussion
Initially, we prepared Co 3 O 4 /NiO nanoparticles via simple techniques. A facile hydrothermal method was used for the preparation of N-GQDs. 37 Sulfonated graphene quantum dots were prepared using chlorosulfonic acid. 38 The XRD patterns of  Fig. 5b. The peak at approximately 1475-1580 cm À1 is attributed to the C]C bonds. The presence of the sulfonyl group is also veried by the peaks at 1215 and 1120 cm À1 . The broad peak at 3350 cm À1 is related to the stretching vibrational absorptions of OH (SO 3 H) (Fig. 5c).
The BET specic surface area of the Co 3 O 4 /NiO and Co 3 O 4 / NiO@GQD@SO 3 H nanocomposites was measured by nitrogen gas adsorption-desorption isotherms (Fig. 6). The results indicate that the BET specic surface area of Co 3 O 4 /NiO improved from 12.25 to 32.43 m 2 g À1 aer modication with the GQDs; therefore, more active sites were introduced on the surface of Co 3 O 4 /NiO@GQD@SO 3 H.
TGA (thermogravimetric analysis) was used to evaluate the thermal stability of the Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite. The nanocomposite displayed suitable thermal stability without a signicant decrease in weight (Fig. 7). The weight loss at temperatures below 210 C is owing to the removal of physically adsorbed solvent and surface hydroxyl   Initially, we carried out a three-component reaction with 4nitrobenzaldehyde, 6-amino-1,3-dimethyluracil and 4-hydroxycoumarin as a model reaction. The model reactions were performed in the presence of NaHSO 4 , ZrO 2 , p-TSA, Co 3 O 4 , NiO, Co 3 O 4 /NiO, Co 3 O 4 /NiO@GQDs and Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite as catalysts. The reactions were tested using diverse solvents including ethanol, acetonitrile, water and dimethylformamide. The best results were obtained in EtOH and we found that the reaction gave convincing results in the presence of the Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite (5 mg) under reux conditions (Table 1).
A series of aromatic aldehydes were studied under the optimum conditions (Table 2). Good yields were obtained using aromatic aldehydes either bearing electron-withdrawing substituents or electron-donating substituents.
We also investigated the recyclability of the Co 3 O 4 / NiO@GQD@SO 3 H nanocomposite as a catalyst for the model reaction under reux conditions in ethanol. The results showed that nanocomposite can be reused several times without noticeable loss in its catalytic activity (yield in the range of 93% to 91%) (Fig. 9).
The plausible mechanism for the preparation of chromenpyrimidines using the Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite is shown in Scheme 2. Firstly, we assumed that the reaction occurs via condensation between 6-amino-1,3dimethyluracil and aldehyde to form intermediate I on the active sites of the Co 3 O 4 /NiO@GQD@SO 3 H nanocatalyst. Then, 4-hydroxycoumarin is added to intermediate I to give intermediate II. Then, migration of the hydrogen atom provides the nal product (Scheme 2).
To study the applicability of this method for large-scale synthesis, we performed selected reactions at the 10 mmol scale. As can be seen, the reactions on a large scale gave the product with a gradual decrease in reaction yield (Table 3).
To compare the efficiency of the Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite with the reported catalysts for the synthesis of chromenpyrimidines, we tabulated the results in Table 4. As indicated in Table 4, the Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite is superior to the reported catalysts. As expected, the increased surface area due to the small particle size increased the reactivity of the catalyst, which is responsible for the accessibility of the substrate molecules on the catalyst surface.
The activity of catalysts is inuenced by their acid-base properties and many other factors such as surface area, geometric structure (particularly pore structure), distribution of sites and polarity of the surface sites. 41,42 The SO 3 H groups distributed on the surface of Co 3 O 4 /NiO@GQDs activate the groups of the substrates. In this mechanism, the surface atoms of Co 3 O 4 /NiO@GQD@SO 3 H activate the C]O and C]N groups for better reaction with nucleophiles. The Co 3 O 4 / NiO@GQD@SO 3 H nanocomposite has Lewis and Brønsted acid properties, which increase the activity of the catalyst.

Preparation of Co 3 O 4 /NiO nanoparticles
Co(NO 3 ) 3 and NiCl 2 with a 3 : 1 molar ratio were dissolved in ethylene glycol. Aerward, the appropriate amount of aqueous ammonia solution (28 wt%) was added to the above solution until the pH reached 10. Then, the transparent solution was placed in an autoclave at 150 C for 4 h. The obtained precipitate was washed twice with methanol and dried at 60 C for 8 h. Finally, the product was calcined at 500 C for 2 h.

Preparation of Co 3 O 4 /NiO@N-GQD nanocomposite
1 g citric acid and was dissolved in 20 mL deionized water, and stirred to form a clear solution. Subsequently, 0.3 mL ethylenediamine was added to the above solution and mixed to obtain a clear solution. Then, 0.1 g Co 3 O 4 /NiO nanoparticles was added to the mixture. The mixture was stirred at room temperature for 5 min. Then the solution was transferred to a 50 mL Teon-lined stainless autoclave, which was sealed and heated to 180 C for 12 h in an electric oven. Finally, the asprepared nanostructured Co 3 O 4 /NiO@GQDs was obtained, which was washed several times with deionized water and ethanol, and then dried in an oven until a constant weight was achieved.

Preparation of Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite
1 g of Co 3 O 4 /NiO@N-GQD nanocomposite was dispersed in dry CH 2 Cl 2 (10 mL) and sonicated for 5 min. Then, chlorosulfonic acid (0.8 mL in dry CH 2 Cl 2 ) was added dropwise to a cooled (icebath) mixture of Co 3 O 4 /NiO@N-GQDs for 30 min under N 2 with vigorous stirring. The mixture was stirred for 120 min, while the residual HCl was removed by suction. The resulted Co 3 O 4 / NiO@GQD@SO 3 H nanocomposite was separated, washed several times with dried CH 2 Cl 2 before drying under vacuum at 60 C.   NiO@GQD@SO 3 H nanocomposite was stirred in 5 mL ethanol under reux. The reaction was monitored by TLC. Aer completion of the reaction, the solution was ltered, and the heterogeneous catalyst was recovered. Water was added, and the precipitate was collected by ltration and washed with water. The crude product was recrystallized or washed with ethanol to give the pure product.

Conclusions
In conclusion, we reported an efficient method for the synthesis of chromenpyrimidines using the Co 3 O 4 /NiO@GQD@SO 3 H nanocomposite as a superior catalyst under reux conditions. The new catalyst was characterized via FT-IR, SEM, XRD, EDS, TGA, BET and VSM. The current method provides obvious advantages, including environmental friendliness, short reaction time, reusability of the catalyst, low catalyst loading and simple workup procedure.

Conflicts of interest
There are no conicts to declare.