Tetramethylguanidine-functionalized melamine as a multifunctional organocatalyst for the expeditious synthesis of 1,2,4-triazoloquinazolinones

Novel nano-ordered 1,1,3,3-tetramethylguanidine-functionalized melamine (Melamine@TMG) organocatalyst was prepared and adequately identified by various techniques including FTIR, EDX, XRD and SEM spectroscopic or microscopic methods as well as TGA and DTG analytical methods. The Melamine@TMG, as an effective multifunctional organocatalyst, was found to promote smoothly the three-component synthesis of 1,2,4-triazoloquinazolinone derivatives using cyclic dimedone, 3-amino-1,2,4-triazole and different benzaldehyde derivatives in EtOH at 40 °C. This practical method afforded the desired products in high to excellent yields (86–99%) and short reaction times (10–25 min). The main advantages of this new method are the use of heterogeneous multifunctional nanocatalyst, simple work-up procedure with no need for chromatographic purification, highly selective conversion of substrates and recyclability of the catalyst, which could be used in five consecutive runs with only a small decrease in its activity.

In this present work, we hereby report a green approach for the synthesis of 1,2,4-triazoloquinazolinones catalyzed by the 1,1,3,3-tetramethylguanidine superbase 79 anchored onto melamine (Melamine@TMG, 1) as a novel nano-ordered multifunctional and heterogeneous organocatalyst (Scheme 1). The Melamine@TMG catalyst was prepared in two definite steps: The melamine surface modification with 3-bromopropyl groups was the first step to afford Melamine@PrBr intermediate (I) 41 ; the second step was functionalization of the obtained Melamine@PrBr nanoparticles with the TMG base through bimolecular nucleophilic substitution (S N 2). The obtained nanocatalyst was characterized by different spectroscopic, microscopic, and analytical techniques. The efficiency of the Melamine@TMG nanocatalyst was examined in the synthesis of 1,2,4-triazoloquinazolinones. After completion of reactions, the Melamine@TMG nanocatalyst was separated from the crude products by washing in EtOH during crystallization of the desired products and exhibited the best catalytic performance in the first cycle (98% isolated product) and it's activity decreased slightly after four times of recycling (84% isolated product).  or local Companies and used as received, except for benzaldehyde which a fresh-distilled sample was used. X-ray diffraction (XRD) patterns were obtained using an X'Pert PRO MPD PANalytical Company. The infrared spectra of the catalyst and products were measured by a Bruker-Vector 33 Fourier transform infrared spectrometer (FTIR) using KBr discs. Scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) analysis were carried out on a TESCAN-Mira III. The thermogravimetric analysis (TGA) and derivative thermogravimetric (DTG) curves were determined on a TGA/DSC Mettler Toledo apparatus. 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AVANCE 500 in DMSO-d 6 at ambient temperature. The CHN analysis were measured by a Thermo Scientific Eager 800. All compounds, except 5c and 5i, are known and their structures were confirmed by comparison of their melting points as well as FTIR and 1 H NMR spectral data with the authentic samples (Supplementary Information).    and arylaldehyde (4, 1 mmol) in EtOH (3 mL), Melamine@TMG (1, 2.5 mol%, 15 mg) was added. The reaction mixture was stirred at 40 °C for times mentioned in Table 2 and the progress of the reaction was observed by TLC. After completion of the reaction, a precipitate was formed which was dissolved in additional EtOH (3 mL) by heating and filtered off to separate the catalyst 1. The filtrate was allowed to stand at room temperature to give pure products 5a-j. The separated catalyst was then washed with EtOAc and n-hexane (2 mL) for 10 min., respectively, and finally dried at 60 °C under vacuum for 0.5 h to be used for further next runs.
FTIR spectra of Melamine@TMG organocatalyst (1). In the FTIR spectrum of melamine (Fig. 1a, A), the bands at 3483 and 3411 cm −1 are related to the asymmetric and symmetric stretching vibrations of the N-H bonds of melamine 42,80, . The band at 1673 cm −1 is attributed to the bending vibrations of the NH 2 and the band   42,81 . For the Melamine@PrBr (Fig. 1a, B) and Melamine@TMG (Fig. 1a, C), new signals appeared at 1644, 1540, and 1014 cm −1 , which are associated with the stretching and scissoring vibrations of C=N, N-H, and C-N bonds of both TMG and melamine, respectively. Appearance of these characteristic bands confirm the existence of TMG moiety in the structure of the catalyst 1 79 . By considering this point that there are similar bands in the structure of melamine and TMG, it is not possible to determine clearly the signals of these two structures by FTIR analysis. Furthermore, the FTIR spectra of Melamine@TMG after five consecutive runs in the model reaction (Fig. 1b) demonstrated very good similarity with the fresh catalyst 1. This finding shows that the structure of Melamine@TMG organocatalyst (1) does not change during five consecutive runs.
XRD patterns of the Melamine@TMG organocatalyst (1). Comparative XRD patterns of the Melamine@TMG organocatalyst (1) and its components are presented in Fig. 2. As data in Fig. 2a  Energy dispersive X-ray spectroscopy of the nano-ordered Melamine@TMG (1). The chemical composition of the Melamine@PrBr (I) and Melamine@TMG organocatalyst (1) was determined by energy-dispersive X-ray (EDX) spectroscopy (Fig. 3). The EDX spectra of the Melamine@PrBr and nano-ordered Melamine@TMG showed the expected elements including Br, N and C. The obtained results confirm successful anchoring of 1,3-dibromopropane, as the linker, and TMG, as an organic base, to the melamine during depicted steps for preparation of the Melamine@TMG catalyst (1) in Scheme 1.
Scanning electron microscopy images of the Melamine@TMG organocatalyst (1). The scanning electron microscopy (SEM) images demonstrated that the nano-ordered Melamine@TMG (Fig. 4a,b) has a layered structure and the size of nanoparticles are mainly between 17 and 52 nm. On the other hand, the morphology of Mela-mine@TMG catalyst after five cycles in the model reaction was also preserved considerably (Fig. 4c,d).
Thermal gravimetric analysis and derivative thermogravimetry of the Melamine@TMG (1). The thermogravimetric analysis (TGA) of the Melamine@TMG organocatalyst (1) shows a two-step mass loss of the organic materials between 250-700 °C (Fig. 5a). The analysis represents that two distinct weight loss stages occur during the pyrolysis of the nanocatalyst. According to data presented in Fig. 5a, the residual mass percent of the www.nature.com/scientificreports/ Melamine@TMG at 700 °C is about 3.0%. Therefore, the weight loss of 82% from 250 to 406 °C can be attributed mostly to the loss and decomposition of organic TMG, its propylene linkage, and melamine's condensation on heating with the elimination of ammonia to form "melam", "melem", "melon" 82 , while the second weight loss peaks of 14.69% in the range of 406-694 °C can be assigned to complete decomposition of the melamine residue. These findings are also confirmed by the values reported in the derivative thermogravimetry (DTG) analysis (Fig. 5b). The most weight loss occurs at about 370 °C, which is related to the first stage of thermal decomposition. Although this catalyst decomposes mostly at 370 °C, it can be noted that the Melamine@TMG catalyst (1) demonstrated thermal stability up to 250 °C. Hence, it can easily be used in the range of room temperature to 250 °C without any significant change in its structure and catalytic activity.
In the next step, other carbocyclic aromatic aldehydes 5b-j with different substituents were used to develop the scope of the studied three-component reaction catalyzed by the multifunctional Melamine@TMG organocatalyst (1). The obtained results have been summarized in Table 2. As data in Table 2 show, all the studied aldehydes with both electron-withdrawing and electron-donating substituents were involved in the optimized conditions smoothly to produce the corresponding products in high to excellent yields. In general, the kind and position of functional groups on the aromatic ring of aldehyde exhibits an obvious impact on the required time for completion of the reaction. Indeed, aromatic aldehydes bearing electron-donating substituents (Entries 2-4 and 8) required longer reaction times compared to those ones containing electron-withdrawing groups (Entries 5-7 and 9,10).
According to the functional groups existing in the structure of catalyst 1 and reactivity of different aldehydes 4a-j, a reasonable mechanism for the synthesis of 1,2,4-tria-zoloquinazolinones 5a-j catalyzed by the multifunctional Melamine@TMG organocatalyst (1) is presented in Scheme 2. In the presence of the melamine-TMG nanocatalyst, the dimedone component 2 equilibrates with its corresponding enol form 2′ and reacts with the activated aldehydes 4 to form the intermediate III through the Knoevenagel condensation. After formation of the intermediate III, there are two possible paths for the reaction: Intermediate III at first takes part in the Michael addition with 3-amino-1,2,4-triazole 3 to form the intermediate IV and subsequent cyclization by imine formation. Then, the desired products 5a-j are formed after tautomerization of the obtained cyclic imine to its corresponding enamine as the last step (Path A). Simultaneously, one of the carbonyl groups in the intermediate III can be activated by the catalyst 1 to form the corresponding imine (intermediate V). Then, heteroannaulation occurs by the intramolecular Michael addition to afford the desired 1,2,4-triazoloquinazolinones 5a-j (Path B) 11,13,33,[86][87][88][89][90] . It should be noted that the only byproducts of the reaction are water molecules with no environmental impact and can be dissolved in EtOH, as a green solvent, to promote the reaction efficiently by the nano-ordered Melamine@TMG organocatalyst (1).
As a part of our study, the recyclability of Melamine@TMG organocatalyst (1) was also examined in the synthesis of model compound 5a. The results are reported in Fig. 6. Indeed, it was observed that the catalytic activity of catalyst 1 changed a little after four consecutive runs using the recycled samples .
To show the merits of the nano-ordered Melamine@TMG organocatalyst (1) for the multicomponent synthesis of 1,2,4-triazoloquinazolinones in comparison to the previously reported catalytic systems, Table 3 compares the obtained results for the synthesis of model compound 5a. It is obvious that the excellent yield of 1,2,4-triazoloquinazolinone 5a was achieved using a low loading of the present catalyst in a green solvent or at a lower temperature compared to the other reported systems.

Conclusion
In general, the novel nano-ordered 1,1,3,3-tetramethylguanidine-functionalized melamine (Melamine@TMG) organocatalyst was prepared and adequately characterized by various spectroscopic or microscopic methods as well as analytical techniques. The basic property of the catalyst was significantly increased by the incorporation of 1,1,3,3-tetramethylguanidine moiety while melamine itself acts as a bifunctional organocatalyst. The nanoordered multifunctional Melamine@TMG organocatalyst was successfully used, as an efficient recyclable catalyst, for the three-component synthesis of 1,2,4-triazoloquinazolinone scaffold from 3-amino-1,2,4-triazole, dimedone, and different aryl aldehydes under green and environmentally-benign conditions. This practical method afforded the corresponding products in high to excellent yields within short reaction times. Using a heterogeneous multifunctional nanocatalyst, simple work-up procedure with no need for chromatographic purification, affording highly selective conversion, and recyclability of the catalyst with only a small decrease in its activity are other main advantages of this new practical protocol for the synthesis of 1,2,4-triazoloquinazolinones.