Cu(II)/polyimide linked COF: An effective mesoporous catalyst for solvent-free 1,5-benzodiazepine synthesis

1 Introduction

The application of COFs as a heterogeneous ligand for immobilizing transition metal ions to support a variety of organic reactions has been shown to be promising (Chen, Chen et al. 2021, Zhang, Lu et al. 2021, Chen, Zhang et al. 2022, Chen, Zhang et al. 2022). Lately, PI-COFs (covalent organic polyimide frameworks) with high thermal resistance, extraordinary mechanical quality, big pore sizes and predominant chemical stability have been created and prepared by incorporating linear and tetrahedral building blocks through the imidization response. While many studies have demonstrated the potential of PI-COFs to be excellent functional materials for drug delivery (Fang, Wang et al. 2015), chemo and biosensors (Wang, Guo et al. 2022) and organic dye depollution (Wang, Xue et al. 2017), the study of PI-COFs as transition metal carriers has received relatively little attention.

Among the heterocyclic compounds that are widely used in medicinal chemistry, benzodiazepines are one of the compounds that have been studied; On the other hand, the synthesis of these compounds has been noticed by organic chemists in recent years through their many biological and medicinal characteristics and industrial uses (Mishra, Sharma et al. 2022). Benzodiazepines are one of the most important sedative-hypnotic drugs. Due to the double effectiveness of these compounds in the treatment of convulsions, anxiety, and insomnia, they have been successful in therapeutic issues and have been able to take the place of barbiturates, and at the same time, they are more reliable. The most famous drugs in this category are alprazolam, diazepam, clonazepam, oxazepam, lorazepam and chlordiazepoxide (Sanabria, Cuenca et al. 2021).

Many methods of synthesizing 1,5-benzodiazepines have one or more restrictions, such as prolonged reaction times, incidence of side reactions, harsh reaction conditions, low yields, use of corruptive chemicals (viz. trifluoroacetic acid, gaseous hydrogen chloride) and hazardous reagents (viz. chloroform, piperidine, pyridine), high-boiling-point solvent (viz. dimethylformamide), and cumbersome processing (Nasir, Ali et al. 2017). Catalysts such as boron trifluoride etherate (Herbert and Suschitzky 1974), sodium borohydride (Morales, Bulbarela et al. 1986), ceric ammonium nitrate (Varala, Enugala et al. 2006), acetic acid under microwave conditions (Pozarentzi, Stephanidou-Stephanatou et al. 2002), magnesium oxide/phosphoryl chloride (Balakrishna and Kaboudin 2001), ytterbium(III) trifluoromethanesulfonate (Curini, Epifano et al. 2003), ferrocene anchored activated carbon (Kusuma, Patil et al. 2022), cerium-enriched magnetic nano-catalyst (Wen, Wang et al. 2022), MIL-101 metal–organic framework (Sarkar, Gupta et al. 2021) and Cu(II)-clay nano-catalyst (Shaikh, Baseer et al. 2020) were used to improve the efficiency of the reaction. The most impediments of these catalysts are that they are misplaced within the work-up strategy, cannot be recuperated or reutilized, and are exceedingly poisonous and costly (Singh, Sharda et al. 2020). Hence, an improved catalyst for the synthesis of 1,5-benzadiazepines is required to attain gentle reaction conditions, simple operation, economy, and selectivity.

As part of our investigation plan in the context of nano-catalysts (Moeinpour and Khojastehnezhad 2012, Moeinpour, Dorostkar-Ahmadi et al. 2014, Khojastehnezhad, Moeinpou et al. 2015, Rahimizadeh, Seyedi et al. 2015, Khodsetan and Moeinpour 2020, Monajjemifar, Moeinpour et al. 2021, Moeinpour, Khalifeh et al. 2022) we report herein polyimide linked covalent organic frameworks (PI-COFs) used as nano-catalysts for the preparation of benzodiazepine derivatives. The generic procedure is given in Scheme 1.

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Scheme 1

Cu@PI-COF catalyst-mediated synthesis of 1,5-benzadiazepines.

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2 Experimental

3 Results and discussion

The preparation route of Cu@PI-COF is shown in Schemes 2 and 3.

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Scheme 2

Synthesis of PI-COF.

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Scheme 3

Cu@PI-COF catalysis platform illustration.

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Characterization of the PI-COF structure has been done by FT-IR, XRD, and FESEM and TEM techniques. Figures and related interpretations are given in the Electronic Supporting Material (ESM), Figs S1-S3.

The stabilization of the catalyst is a significant factor for its practicable applications. TGA showed that Cu@PI-COF was intact up to 380 °C, implying good thermostability (Fig. 1).

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Fig. 1

TGA plot of Cu@PI-COF.

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The Fig. S4 illustrates N₂ adsorption and desorption isotherms for the PI-COF and Cu@PI-COF composites. Pure PI-COFs have a specific surface area (SSA) of 43.90 m²/g and pore volumes of 0.035 cm³/g. Adsorption quantities of nitrogen gradually decrease after loading the active ingredient. Cu@PI-COF has SSA and pore volume of 30.73 m²/g and 0.029 cm³/g, respectively. Moreover, the pore sizes measured for PI-COF and Cu@PI-COF were 3.7 nm and 3.3 nm respectively (Fig. S5). Therefore, based on the above, a pore-blocking effect may occur because Cu(II) occupies the PI-COF pores (Xu and Prodanović 2018, Moeinpour, Soofivand et al. 2019).

After the characterization of Cu@PI-COF, its catalytic function in the multicomponent preparation of 1,5-benzodiazepines was evaluated. Optimizing the reaction conditions was the next step in synthesis of 1,5-benzodiazepines. Therefore, the catalytic efficiency was examined during the 1,5-benzodiazepines synthesis as model under different reaction conditions (microwave strength, catalyst dosage and time). To achieve this goal, reaction with three components in one pot consisting of 1,2-diaminobenzene (1 mmol,0.108 g), dimedone (1 mmol, 0.140 g) and benzaldehyde (1 mmol, 0.106 g) was chosen as the sample under solvent-free conditions (Scheme 1). The findings were tabulated in Table 1. The findings indicated that without the Cu@PI-COF the reaction did not go forward even after 30 min (Table 1, entry 1). The results showed that the optimal conditions were reached when the reaction was accomplished in the presence of 0.2 g Cu@PI-COF under solvent-free conditions and under microwave irradiation leading to corresponding benzodiazepine (3,3-dimethyl-11-phenyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one) in 5 min and 96 % yield (Table 1, entry 5). Remarkably, the yield of the reaction did not show a significant change with respect to conversion by increasing the Cu@PI-COF dosage up to 0.5 g (Table 1, entries 6–7). If we reduce the Cu@PI-COF dose to 0.01 g, the yield also decreases (Table 1, entry 8). To show the performance of Cu(II) during the reaction, the performance of PI-COF in the reaction under optimal conditions was also studied. The findings represented that when PI-COF was used, no progression in the sample reaction was observed due to the absence of Cu(II), affirming that its presence is required for the catalysis of the reaction (Table 1, entry 12). Additionally, the sample reaction was performed with Cu(CH₃COO)₂ for 5 min under optimal conditions, yielding corresponding benzodiazepine (3,3-dimethyl-11-phenyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one) with 33 % yield (Table 1, entry 13). The results demonstrate that Cu(CH₃COO)₂ exhibits negligible performance compared to Cu@PI-COF under optimized conditions. Solvents are not considered here due to the green chemistry design.

Table 2 Benzodiazepine derivatives synthesis in the presence of Cu@PI-COF.

Entry	Ar	Product	Yield (%)a	Mp (°C)
				Observed	Literature
1	C6H5		96	246–248	250–252 (Naeimi and Foroughi 2016)
2	4-Cl-C6H4		98	232–234	235–237 (Nasir, Ali et al. 2017)
3	4-NO2-C6H4		96	273–274	274–275 (Naeimi and Foroughi 2016)
4	4-OCH3-C6H4		97	225–227	229–231 (Nasir, Ali et al. 2017)
5	4-CH3-C6H4		98	227–229	224–226 (Nasir, Ali et al. 2017)
6	2-OH-C6H4		96	197–199	201–202 (Nasir, Ali et al. 2017)
7	2-OH-3-OCH3-C6H4		93	271–273	269–270 (Nasir, Ali et al. 2017)
8	2-Thienyl		96	226–227	227–229 (Naeimi and Foroughi 2016)
9	3-NO2-C6H4		93	145–146	144–146 (Maleki and Kamalzare 2014)
10	2-NO2-C6H4		95	230–232	230–232 (Naeimi and Foroughi 2015)
11	2-Cl-C6H4		96	232–234	233–235 (Maleki and Kamalzare 2014)
12	2,4-Dichloro-C6H3		98	251–252	250–252 (Maleki and Kamalzare 2014)
13	4-OH-C6H4		98	225–226	225–226 (Maleki and Kamalzare 2014)
14	4-Dimethylamino-C6H4		98	230–231	228–230 (Kolos, Yurchenko et al. 2004)
15	2-Furyl		94	216–217	216–218 (Maleki and Kamalzare 2014)
16	C6H5		95	268–270	267–269 (Indalkar, Patil et al. 2017)
17	C6H5		94	270–272	270–272 (Esfandiari, Kareem Abbas et al. 2022)

After identifying the most suitable reaction conditions, we needed to assess the scope and efficacy of the reaction. In this respect, 1,2-diaminobenzene, dimedone and aromatic aldehydes were selected to carry out the reaction to give the related benzodiazepine derivatives and the outcomes are depicted in Table 2. Regarding the aromatic aldehydes comprising both electron-withdrawing and electron-donating substituents, they can be effectively transformed to benzodiazepines in high yields, as indicated in Table 2. Further, the optimized reaction protocol was also extendable to substituted o-phenylenediamines (Table 2, entries 16 and 17), resulted in good yields of the corresponding 4,7-disubstituted-1,5-benzodiazepines. As can be seen from the data in Table 2, this procedure can be carried out for all aromatic aldehydes. It can be stated that the reaction time was significantly shortened by microwave irradiation and the products were synthesized with the best efficiency, without producing by-products and requiring purification by column or flash chromatography. By comparing melting points and ¹H NMR spectra with authentic samples, the products were identified.

A possible mechanism for the reaction is outlined in Scheme 4. The reaction undergoes a primary nucleophilic addition followed by water elimination to give intermediate A. The intermediate A is then condensed with aromatic aldehydes to yield B, which is then transformed into the benzodiazepine 4 by intramolecular [6 + 1] cyclization (Bennamane, Kaoua et al. 2008, Zohreh, Alizadeh et al. 2010).

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Scheme 4

Plausible mechanism for Cu@PI-COF catalyzed synthesis of benzodiazepines.

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The stability and recyclability of the Cu@PI-COF was confirmed in the sample reaction for the production of benzodiazepine 3,3-dimethyl-11-phenyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one. After the reaction was complete, ethanol was added and the Cu@PI-COF was isolated by filtration, washed with acetone, then desiccated and reused for the next experiment without appreciable loss of its catalytic performance. As shown in Fig. 2, the catalyst can still be used after 5 cycles of continuous power. ICP-AES analysis indicated that the extent of Cu(II) leached into the reaction media is very small (0.5 ppm).

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Fig. 2

Recyclability of Cu@PI-COF in the sample reaction.

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The TEM and SEM pictures of the fresh and reused catalysts showed that only minor morphological changes happened (Fig. 3a and 3b).

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Fig. 3

SEM (a) and TEM (b) images of recycled Cu@PI-COF catalyst.

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Table 3 compares the efficiency of the present method for the production 1,5-benzodiazepine derivatives is compared with other published papers. As illustrated in Table 3, the Cu@PI-COF catalyst has the best efficiency in the shortest time compared to the reported processes in the presence of different catalysts.

4 Conclusion

Briefly, the use of a Cu@PI-COF catalyst under microwave irradiation facilitates the preparation of 1,5-benzodiazepines through condensation between 1,2-diaminobenzene, dimedone, and various aromatic aldehydes. It should be noted that this method is very simple and effective and is used to synthesize derivatives of this group of compounds. This new and effective one-pot three-component procedure not only features the use of microwaves and a substantial product yield, but also offers mild reaction conditions, high purity, shorter reaction times, ease of operation, reutilization of heterogeneous nano catalysts, easy workup and high atom economy. The association of microwave irradiation and heterogeneous catalysis has enabled the future improvement of effective, rapid, and eco-friendly synthetic methods. The reutilization of Cu@PI-COF was high and it could be reutilized 5 times without significantly decreasing its first activity. We expect that this synthetic manner will provide better scope for the preparation of benzodiazepine analogs and will be a more viable replacement for the other available protocols.