One-Pot Synthesis of Quinazoline Derivatives Using Copper Nanocatalyst Stabilized on Graphene Oxide Functionalized by N1,N2-bis((Pyridine-2-yl)Methyl)Benzene-1,2-Diamine

Having a biological property is just one of features of N -heterocycles. Another thing is to be dramatically well-designed. In other words, awe-inspiring combination of materials and the thing that really makes these materials just unique of its kind is nothing but its medical properties. That is why, majority of scientists are full of enthusiasm for synthesizing of these types of materials. ln this article, we have reported five effective methods for synthesizing quinazoline, which is a immensely important group of N heterocycles with using copper nanocatalyst stabilized on graphene oxide functionalized by N 1 , N 2 - bis ((pyridine-2-yl)methyl)benzene-1,2-diamine. Moreover, we have investigated the effects of substitutions connected to aldehydes, benzylamines and benzamides as a carbon source of quinazoline heterocyclic ring. Finally, we have assessed effects kinds of ammonium salts as a nitrogen source of quinazoline heterocyclic ring.


Introduction
Nowadays, majority of people of all around the world especially undeveloped countries are really suffering from a lack of drug, particularly bacterial medicines. Most of drugs that is used to treat bacterial diseases contain nitrogen-rich heterocyclic rings.This way, designing and discovering novel ways to synthesize these tipes of heterocycles is very essential.
Quinazolines are a category of nitrogen-containing heterocyclic compounds, using to treat bacterial illnesses. Quinazolines have unique properties. For example, if thiophene is in position 2 of quinazoline structure, which gives to quinazoline the antibacterial property.
Moreover, when benzene is in position of 4, that gives the inhibitory effect of modulating enzyme to quinazoline. But the most significant feature is here, in comparison with others, the simultaneous presence of thiophene and benzene, giving quinazoline both of mentioned properties ( Figure 1). The fact that presence of catalyst in chemical reaction is important is obvious to all. Not only does it play a crucial role in increasing reaction yield but it also comes with a multitude number of benefits. Such as, decreasing time of reaction, promoting speed and so on. To opt for a catalyst, there are three necessary factors that must be considered. They are simply: green, green and of course green. Because unfortunately nowadays not many people place a high value on environment. The massive burden of protecting the environment is on the shoulders of chemists. Indeed some other options are also worth mentioning such as, high operating speed, high thermal resistance and so on.Trying to accomplish this worthwhile goal has led us to using chemical materials with biological properties. Graphene oxide is a good example of chemical materials with biological property. In other words, it is a green material.
Actually, graphene oxide is a three-dimensional platform that destroy bacterias by covalent interaction with them in short time. The use graphene oxide in catalyst synthesis gives us hope that the catalyst's potential contact with the body will not cause any problems [17,28,38].
On the other hand, copper metal has attracted lots of attentions in the past few decades.
Probably, this is because of toxicity low or the extraordinary the activities it has shown itself.
Such as: the presence of copper in the body is essential to disable tyramine, anomalous diamagnetism behavior, high thermal resistance, biological properties and so on [32,33,35].
In this article, we have been able to produce a green catalyst with using a completely green method that have dealt with it in the following.

General Information and Methods
All commercially available chemicals were purchased from Merck (Kenilworth, NJ) and Fluka (Buchs, Switzerland) companies and used without further purification unless otherwise stated. Infrared (IR) spectroscopy was conducted on a Perkin Elmer GX FT-IR spectrometer.

Synthesis of N 1 ,N 2 -bis((pyridine-2-yl)methyl)benzene-1,2-diamine:
A mixture of benzene-1,2-diamine (6 mmol) and pyridine-2-carbaldehyde (12 mmol) was stirred in 25 mL of dry methanol under 60-80 °C for 12 h. Then, 24 mmol NaBH 4 was added to the reaction. After 12 h the reaction was completed then the reaction mixture was added 25 mL chloroform and 25 mL water. To purify, we created two phases of chloroform and water that product was dissolved in chloroform and impurities were dissolved in water. In this way they were separated each other.

Graphene oxide synthesis by Hummers method:
A mixture of natural graphite powder (5 g
The elements present in the catalyst were investigated using the EDX technique ( Figure 6).
In this spectrum, O, N, Cu, C peaks were observed corresponding to the compounds of graphene oxide, N 1 ,N 2 -bis((pyridine-2-yl)methyl)benzene-1,2-diamine, copper, graphene oxide and N 1 ,N 2 -bis((pyridine-2-yl)methyl)benzene-1,2-diamine. In XRD and SEM techniques, the size, shape and morphology of the catalyst were investigated. XRD relevant to graphene (spectrum a) and nanocatalyst (spectrum b) were investigated in Figure 7 and in the range of 2-90°. In spectrum, two peaks appear at 2θ=25°, 45° corresponding to 100 and 200 graphene oxide crystal plates. In spectrum b, five peak numbers with values of 25°, 35°, 43°, 55°, 72° are seen that 25° and 35° peak corresponds to the graphene oxide and the 43°, 55° and 72° peak, relevant to the copper metal. In addition, the intensity of the peaks is weaker than of GO, indicating connecting copper to graphene oxide but the crystalline structure of graphene oxide remains.  Derivative thermal gravimetric (DTG) and differential thermal (DTA) of GO@N-Ligand-Cu was also investigated ( Figure 9). Several degeneration stages observed for catalyst in the DTA pattern. The first weight loss is seen at 65 °C, which is estimated to be due to methanol solvent evaporation. The second weight loss occurs at temperatures of 90-100 °C, which may be related to the evaporation of ethanol and water solvents. The third weight loss is observed at 325 to 320 °C, which is related to the degradation of the N 1 ,N 2 -bis((pyridine-2yl)methyl)benzene-1,2-diamine compound and the graphene oxidized functional groups and the rest of the catalyst residues are degraded at the fourth weight loss at 410-500 °C. The obtained results indicate that the catalyst can be used up to 300 °C. After the synthesis and full characterization of GO@N-Ligand-Cu, the catalyst was used to synthesize N-heterocycles compounds such as quinazolines and bis-quinazoline which will be discussed in the following.

History
In 1869 Griess prepared the first quinazoline derivative, 2-cyano-3,4-dihydro-4oxoquinazoline, by the reaction of cyanogens with anthranilic acid. The bicyclic product was called bicyanoamido benzoyl and used this name until 1885 [13]. To determine the scope and generality of this protocol, we examined the types of ammonium salts as a nitrogen source and the types of aldehydes as a carbon source. Under a optimum condition, several ammonium halides were tested (NH 4 X, X= I, Br, Cl) which among them ammonium iodide had the best yield while the ammonium bromide had little yield. Seems to the larger volume of iodide causes crystal defect and makes it easier to break or since iodide has less electronegativity than bromide, it settles negative charge less quickly gains ammonium's protons. Then, ammonium acetate was used. The reaction yield was increased in the presence of ammonium acetate ( Table 2, entry 5). That may be related to the amount of energy needed to separate ammonia from the salt system or due to the production of stable acetic acid from ammonium acetate, the pH of the system decreases and the presence of H + in the reaction medium activates the carbonyl group.
The use of ammonium acetate in the reaction was prefered to other ones due to its high efficiency, low toxicity and easy separation. In another study, the effect and positions of electron releasing substituents and electronwithdrawing substituents attached to the aldehydes were investigated as carbon source. The highest yield was obtained as the electron releasing substituents were attached to the aldehyde in the para position (Table 4, entries 1 and 4, reaction 1). The reaction yield was relatively high in the ortho position (Table 4, entry12, reaction 1). Of course, the ortho positions may be due to spatial hindrance, that is less yield than the para position. As the substitutions were in the meta positions, it had no effect on reaction efficiency (Table 4, entries 5 and 13, reaction 1). However, substitutions of electron-withdrawing in para and ortho positions did not any affect on the efficiency of reaction (Table 4, entries 6 and 10).
The reaction yield is reduced if they are in the meta position (Table 4, entry 9, reaction 1). In scheme 3 we propose a mechanism for the conversion of 2-amino-5-chlorobenzophenone, ammonium acetate and aldehyde to quinazoline. Another advantage of this catalyst is to reuse. After completion of the reaction, by adding 10 mL of chloroform to the reaction mixture, the catalyst was separated from the product that it was used after washing and drying in the reaction model. Copper nanocatalyst can be used five times in a row without losing of activity ( Figure 10).   (Table 4, entry 2, reaction 2). It may be due to their resonance state at the ring formation stage that it helps protons exit radically. Furthermore, benzyls containing electronwithdrawing substituents were tested too. Electron-withdrawing substituents in the meta position results in lower reaction yield but other situations (para and ortho) had a little impact on reaction yield (Compare entry 9 with entries 10 and 16 in Table 4, reaction 2).  16 The proposed mechanism to the synthesis of quinazoline derivatives by the use of (2-  Table 5, entry 1).
Therefore, 0.006 g of nanocatalyst was sufficient to complete the reaction, of course a higher amount of catalyst does not increase yield (    After optimizing the condition, different amides were used. Although amides containing electron-withdrawing substituents at para and ortho positions increased the reaction yield (Table 4, entries 6, 10 and 16, reaction 3), electron releasing substituents reduced the reaction yields (Table 4, entries 1 and 2). The results are summarized in Table 4. Scheme 5 presents a proposed mechanism for quinazoline synthesis.  [38].
In addition to the strategies mentioned, we were able to synthesize quinazoline through another green method, that is a two-component reaction and one-pot of 2-amino-5cholorobenzophenone and benzylamine derivatives (Scheme 2, Reaction 4). During optimization of reaction condition, including temperature, the amount of catalyst and solvents, reaction of 2-amino-5-cholorobenzophenone with 2-(aminomethyl)-6methoxyphenol were used as the model substrate. As shown in Table 6, the reaction had the highest yield at 50 °C, 0.005 g of GO@N-Ligand-Cu in a solvent-free condition and a O 2 atmosphere (Entry 1). A bunch of benzylamines were tested that benzylamine containing electron releasing substituents exhibited the best activity (compare entries 3,10, 15 and 16 in Table 4). We observed to produce a trace amount of the product in the absence of copper nanocatalyst (Table 6, entry 21). We tested a solvent-free condition and many kinds of solvents. It turned out that a solvent-free condition had the highest yield (compare entries 1 and 14-19 in Table   6). The yield decreased when the temperature of reaction was lowered (compare entries 9 and 10 in Table 6). The results are summarized in Tables 4 and 6. A possible mechanism for the synthesis of quinazoline derivatives is proposed in Scheme 6 according to the results above. oxidation quinazoline is produced [39].
Part of our ongoing efforts in the lab for developing new chemical methods for quinazoline synthesis lead to the discovery of a new method was for quinazoline synthesis. To our knowledge, it is the first time that quinazoline is synthesized in this way. In this method, quinazoline was synthesized by the one-pot and two-component reaction of 2-(amino(phenyl)methyl)-4-chlorobenzeneamine and aldehyde derivatives in the presence of GO@N-Ligand-Cu nanocatalysts (Scheme 2, reaction 5). After checking the effects solvent, temperature, the amount of catalyst and a solvent-free condition in this reaction, we found that the reaction of furan-2-carbaldehyde and 2-(amino(phenyl)methyl)-4-chlorobenzenamine at 75 °C, a solvent-free condition and 0.005 g of catalyst has a yield 93% (Table 7, entry 1). After this reaction optimization, we studied the various aldehyde derivatives that its results are summarized in Table 4. The aldehydes containing the electron releasing substituents were most effective, especially if they were in the para position (compre entries 1,2,3 with 9 and 10, reaction 5 in the Table 4). Whereas the aldehydes containing the electron-withdrawing substituents were less yield. The mechanism proposed for this reaction is shown in Scheme 7.  Table 8.

Bis-Quinazoline
Nitrogen-rich heterocyclic compounds represent a unique class of chemicals with special properties and have been modified to design novel pharmaceutically active compounds. Bisquinazoline is considered a premium structure in pharmaceutical chemistry. Since they have several active centers, they have a high affinity to connect to pathogens. That is why, Their mechanism of action is extraordinary. Given this feature, the trend of using bis-quinazoline in the structure of drugs has been increasing in recent years. Figure 11 is an example of the structure of bis-quinazoline used in most sedatives. The proposed mechanism for the synthesis of bis-quinazoline is presented in Scheme 9.

Conclusion
There have been many attempts over the past few decades to synthesize N-heterocycles.
Every year, different ways of synthesizing them are offered around the world. In this article, we have synthesized a couple of green protocols for the synthesis of biological derivatives of quinazoline and bis-quinazoline. The main advantages of these methods are outlined as very simple, reliable, applicable, easy reaction workup, easy recyclability, and reusability of the catalyst. The synthesized catalyst and products were characterized by FE-SEM, MASS, H-NMR, C-NMR, TGA, XRD and FT-IR techniques. We have developed successfully a new approach toward the synthesis of quinazoline and bis-quinazoline.