Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

Natural dolomitic limestone (NDL) is employed as a heterogeneous green catalyst for the synthesis of medicinally valuable benzimidazoles, dihydropyrimidinones, and highly functionalized pyridines via C–N, C–C, and C–S bond formations in a mixture of ethanol and H2O under ultrasound irradiation. The catalyst is characterized by XRD, FTIR, Raman spectroscopy, SEM, and EDAX analysis. The main advantages of this methodology include the wide substrate scope, cleaner reaction profile, short reaction times, and excellent isolated yields. The products do not require chromatographic purification, and the catalyst can be reused seven times. Therefore, the catalyst is a greener alternative for the synthesis of the above N-heterocycles compared to the existing reported catalysts.


Introduction
Nitrogen heterocycles are recognized as "privileged medicinal scaffolds" because these compounds are found in a wide variety of bioactive natural products and pharmaceuticals [1][2][3]. Among them, benzimidazoles, dihydropyrimidinones, and pyridines have emerged as promising and valuable structural units in many pharmaceutical lead compounds ( Figure 1) [4][5][6][7][8][9]. Hence, there is a great need for the development of a green and sustainable synthetic route to the aforesaid nitrogen-containing heterocycles.

Results and Discussion
Geological background of the NDL catalyst

Catalyst characterization
The NDL catalyst was ground into a fine powder and then sieved in a 200-mesh sieve. The chemical composition of the catalyst was determined by standard quantitative analysis. The basic strength of the catalyst was analyzed by using Hammett indicators. The catalyst was characterized by XRD, IR, Raman, SEM, and EDAX analysis.
The chemical composition of the NDL was determined by adopting a standard quantitative analysis [75]. The obtained results are summarized in Table 1.
The Raman spectrum of the NDL catalyst is shown in Figure 4. The band at 1092 cm −1 was attributed to the symmetric stretching vibration (ν 1 ) of the carbonate group. The peaks at 714 and 1435 cm −1 were assigned to a symmetric bending (ν 4 ) and an asymmetric stretching vibration (ν 3 ) of carbonate. The weak peak at 1750 cm −1 was due to the combined band ν 1 + ν 4 . The bands at 152 and 278 cm −1 were ascribed to the external vibrations of the carbonate group [76,77]. The presence of aluminium silicates and iron oxides present in the sample were confirmed by Raman spectroscopy. The bands at 418, 578, 753, and 985 cm −1 were assigned to Al-O bending, Si-O rocking, Al-O stretching, and Si-OH stretching vibrations, respectively [85]. Further, a very weak peak at 618 cm −1 was attributed to iron oxide, and a very broad peak at 1312 cm −1 (magnon) indi-cated the presence of magnetically ordered ferromagnetic or antiferromagnetic iron oxides [86]. The observed Raman and infrared vibrational bands of the NDL were in good agreement with the reported values. The minor shift in the band positions might be due to the presence of trace metal contents and impurities.
The morphology of the NDL catalyst was analyzed by scanning electron microscopy ( Figure 5). The SEM images revealed that the morphology of the NDL catalyst consists of irregular shapes and sizes with a random dispersion. Further, the elemental composition of the NDL catalyst was determined by EDAX analysis ( Figure 6).

NDL-catalyzed synthesis of 1,2-disubtituted benzimidazoles 3
To check the catalytic activity of the NDL, initially, o-phenylenediamine (1) and benzaldehyde (2a) were chosen as model substrates to optimize the reaction conditions for the syn-        Table 2, entries 2-4 and 6-8). From the above observations, it was concluded that the ultrasound irradi-ation method is better than the conventional method in giving the maximum yield of 3a.
Next, the amount of catalyst was varied (using 2.5, 5.0, 7.5, 10.0, and 12.5 wt %, respectively,) to improve the yield of 3a ( Table 3). The study revealed that 5.0 wt % of the NDL was the best option to get the highest yield of the product 3a (98%) in a short reaction time (10 min, Table 3, entry 3). It was also noticed that the same yield was obtained with an increasing amount of the catalyst, i.e., 7.5, 10.0, and 12.5 wt % (Table 3, entries 4-6).
In order to demonstrate the effect of the temperature on the course of the model reaction, the control experiment was performed at different temperature ranges (30-35, 35-40, 40-45, and 45-50 °C) by using the model substrates 1 and 2a in the presence of 5.0 wt % of the NDL in a mixture of ethanol and water 1:1 for 10 min under both conventional stirring and ultrasound irradiation. The obtained results are presented in Table 4. It was observed that the reaction proceeded with an improved yield of 3a (70-98%) by increasing the temperature range from 30-35 to 45-50 °C with an ultrasound irradiation method ( Table 4, entries 1-4). Under conventional stirring, the yield of the product 3a increased from low to moderate when the reaction temperature was raised from 30-35 °C to reflux (Table 4, entries 1-5). From the results, it was concluded that a temperature of 45-50 °C is the optimum temperature to obtain the maximum yield of the desired product 3a within a short reaction time (10 min) under ultrasound irradiation (Table 4, entry 4).
To demonstrate the generality and substrate scope of the present method, a variety of (hetero)aromatic aldehydes was investigated. The obtained results are presented in Table 5. o-Phenylenediamine (1) reacted well with benzaldehyde (2a) to obtain the corresponding product 3a with 98% yield (  Table 5, entries 2-7, 10 and 11), a deactivating group (4-NO 2 : 2l, Table 5, entry 12), or a halo group (4-F: 2m, 4-Cl: 2n, and 4-Br: 2o, Table 5, entries 13-15) in different positions provided good to excellent isolated yields of the corresponding products 3b-g and 3j-o that ranged from 94 to 98% in a stipulated period of time, as specified in Table 5. Further, heteroaromatic aldehydes, such as furan-2-aldehyde (2p) and thiophene-2-aldehyde (2q) produced the corresponding products 3p and 3q in good isolated yields within a short period of time (15 min and 13 min, respectively, Table 5, entries 16 and 17).
However, salicylaldehyde (2h) afforded the unexpected product 2,2'-((1E,1'E)-(1,2-phenylenebis(azanylylidene))bis(methan-ylylidene))diphenol (3h, bisimine I) within 10 min (Table 5, entry 8). The reaction was expected to proceed through the activation of the carbonyl group of 2h (of which 2.0 mmol were used) by the cations (Ca 2+ and Mg 2+ , respectively) of the NDL. This was followed by a nucleophilic attack of the NH 2 groups of o-phenylenediamine (1, of which 1.0 mmol was used), which are activated by the carbonate part of the NDL, followed by dehydration to obtain 3h (Scheme 2). Due to the mild basic nature of the NDL catalyst, it acts as a dual activator of the electrophilic carbonyl and the nucleophilic NH 2 groups. The formation of the bisimine I was confirmed by 1 H NMR spectral studies (Figure 7). In the 1 H NMR spectrum (DMSO-d 6 ), the two hydroxy protons of the bisimine I appeared as a broad, strongly downfield-shifted singlet at δ 13.19. The sharp singlet at δ 8.66 indicated the two imine protons (-N=CH) of the bisimine I. From this result, it was confirmed that the reaction stopped at the bisimine I stage. This was due to the intramolecular hydrogen bonding between the hydrogen atom of the orthohydroxy group and the nitrogen atom of the imine group in a six-membered ring transition state [87]. Similarly, the reaction between 3-ethoxysalicylaldehyde (2i) and o-phenylenediamine (1) also ended with the intermediate 6,6'-((1E,1'E)-(1,2phenylenebis(azanylylidene))bis(methanylylidene))bis(2ethoxyphenol) (3i) stage (Table 4, entry 9 and Supporting Information File 1, Figure S13). Most of the synthesized compounds are known and were identified easily by comparison of the melting point and spectroscopic data with those reported.
Evaluation of the green chemistry metrics for the synthesis of benzimidazoles 3, dihydropyrimidinones 7, and highly functionalized pyridines 11 In order to evaluate the "greenness" of the proposed methodologies, the green chemistry metrics, such as the atom economy (AE), E-factor, process mass intensity (PMI), Curzon's reac-  tion mass efficiency (RME), and generalized or global reaction mass efficiency (gRME) were evaluated by adopting established standard empirical formulae [88,89]. The obtained results are summarized in Tables 8-10. This study revealed that the reactions displayed a good to excellent AE (88-95%) and Curzon's RME (78-93%) as well as a low to moderate E-factor (26.202-50.760) and PMI (27.202-51.760). The detailed calculations of the green chemistry metrics (AE, E-factor, PMI, Curzon's RME, and gRME) for the synthesis of the compounds 3a, 7a, and 11a (Table 8, entry 1, Table 9, entry 1, and Table 10, entry 1) are presented in Supporting Information File 1 (see Reaction-S1-Reaction-S3).

Catalyst reusability experiments
Catalyst reusability tests were performed showcasing the synthesis of the compounds 3k, 7a, and 11e under the optimized reaction conditions.
Catalyst reusability experiments in the synthesis of compounds 3k, 7a, and 11e The catalyst was tested for reusability in the preparation of 3k using o-phenylenediamine (1) and 3-ethoxy-4-hydroxybenzaldehyde (2k) under USI for 10 min. After completion of the first reaction cycle, the reaction mass was allowed to cool to rt, and ethyl acetate (4.0 mL) was added. Then, the catalyst was

Effect of ultrasonication on the structure of the catalyst
The recovered catalyst after the 7th cycle of each synthesis was characterized by XRD to study the structural changes due to ultrasonication. As can be seen in Figure 8, the diffraction peak positions of the catalyst recovered after the synthesis of the compounds 3k, 7a, and 11e (Figure 8b-d), respectively, remained the same as compared to the fresh catalyst ( Figure 8a). It was also noticed that the broadening in the XRD pattern of the recovered catalyst had increased with an increase a E-factor = m inputs f − mass of the target product ( m 11) − mass of the recovered materials/ m 11. b PMI = ( m inputs − mass of the recovered materials)/ m 11 or 1 + E-factor. c Curzon's RME = m 11/ m 2 + m 8 + m 9/10 or yield × AE × 1/SF; SF = 1. d gRME = 100⋅( m 11/( m inputs − mass of the recovered materials)) or 100⋅(1/(1 + E-factor)). em inputs = m 2 + m 8 + m 9/10 + m S + m C + m WPM + m PM.
of the ultrasonication time. This clearly indicated that the amorphization of the recovered catalyst was enhanced by increasing the ultrasonication time.

Conclusion
An environmentally benign NDL catalyst was characterized and utilized as a heterogeneous catalyst for the synthesis of 2-aryl-1-arylmethyl-1H-benzo[d]imidazoles, dihydropyrimidinones/ -thiones, and 2-amino-4-(hetero)aryl-3,5-dicarbonitrile-6sulfanylpyridines in a mixture of ethanol and H 2 O 1:1 under ultrasound irradiation. Notable advantages of this methodology include the clean reaction profile, broad substrate scope, simplicity of the process and handling, low catalyst loading, and the easy and quick isolation of the products in good to excellent yield. Besides, the products obtained were in an adequate purity without the need for chromatographic separation, and the catalyst was reused 7 times without a significant loss of the catalytic activity. Hence, the catalyst is a greener alternative for the synthesis of 1,2-disubstituted benzimidazoles, dihydropyrimidinones/-thiones, and highly substituted pyridines when compared to the existing reported catalysts. Further, the expansion of the catalyst scope and the generality for the synthesis of other privileged nitrogen-and sulfur-based heterocycles is under progress in our laboratory.

Experimental
See Supporting Information File 1 for full experimental data of compounds 3, 7, and 11.