Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal-free and solvent-free conditions for minimizing waste generation

Brønsted acidic ionic liquid was found to be an efficient and recyclable catalyst for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones. The reactions proceeded smoothly with a broad scope of substrates providing the expected products in good to excellent yields under an atom-economical pathway. The low-cost recyclable catalyst, metal- and solvent-free conditions, and the ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination in synthesized pharmaceuticals.

replacing ZnCl 2 with ethylene glycol, oxalic acid or glucose (  Table 1, metal chlorides could be employed in the model reaction. However, these metal chlorides are moisture sensitive and easily decompose in the presence of a small amount of water. Furthermore, these metal chlorides could not be recovered and reused aer the aqueous workup. The prominent feature of [(4-SO 3 H)BMIM]HSO 4 is stability in water and in almost all cases, catalytic use, recovery, and reuse of [(4-SO 3 H)BMIM]HSO 4 are possible. In our study, we tested different ratios of [(4-SO 3 H)BMIM]HSO 4 with the aim of obtaining the desired product in high yield. The best yield was obtained in the presence of 10 mol% [(4-SO 3 H)BMIM]HSO 4 . When the amount of catalyst was increased to 15 mol%, the yield slightly improved. All attempts to reduce the amount of [(4-SO 3 H)BMIM]HSO 4 loading led to diminished yields.
With the optimized conditions in hand, we focused on using a variety of aromatic aldehydes. The results are presented in Scheme 1. A series of p-substituted benzaldehyde smoothly reacted with 2-aminobenzimidazole and ethyl acetoacetate to provide benzo [4,5]imidazo[1,2-a]pyrimidines in excellent yields. Electron-donating group on benzaldehyde, such as methoxybenzaldehyde, gave the expected products in excellent yield (90%), but longer reaction time was required (150 min). Electron-withdrawing groups on benzaldehyde, such as 2nitrobenzaldehyde and 4-nitrobenzaldehyde, were all effectively reactive and provided the corresponding products in excellent yields within shorter reaction times (75 min). Benzaldehyde bearing halogen substituents could also react smoothly to attain the expected products in high yields (88-92%), and the substituent position did not signicantly affect the reaction yield. In the interest of extending the scope of reaction, we examined acetonylacetone under the current method. To our delight, the reactions proceed smoothly to provide the desired products in high yields (88-93%) and shorter reaction times (60-90 min). Moreover, the method avoids the use of volatile organic solvents, harmful conditions, and additives making it greener than the previous reports. In addition, the pure products were obtained easily by recrystallization; thus, this method shows promise for application in industry.
The comparison of the present method with previously reported literature is shown in Table 2. The multicomponent reaction of 2-aminobenzimidazole, ethyl acetoacetate, and benzaldehyde in the presence of [(4-SO 3 H)BMIM]HSO 4 afforded the expected product in good yield within 2 h under metal-free and solvent-free conditions ( Table 2, entry 6). The previous studies reported that the same reaction also achieved the target products in moderate to good yields, but some methods required longer reaction time and/or high temperature ( Table 2, entries, 1-5). More importantly, the [(4-SO 3 H)BMIM]HSO 4 could be recovered and reused without any considerable loss in catalytic activity in a test of six cycles of reuse.
To get more information about the plausible mechanism, we performed three control experiments under the optimized conditions. 2-Benzylidene-3-oxobutanoate intermediate was detected as the major product (by GC-MS) when the model reaction was performed for 20 min. Thus, the reaction mainly followed Knoevenagel condensation between benzaldehyde and ethyl acetoacetate in the rst step, where the [(4-SO 3 H)BMIM] HSO 4 acted as a Brønsted acidic catalyst. The control experiments with only two components, i.e., the reaction of benzaldehyde with ethyl acetoacetate, also provided the desired product (2-benzylidene-3-oxobutanoate) in 70% yield, which was higher than the reaction yield of 2-aminobenzimidazole and benzaldehyde. The intermediate could completely convert into the desired product when 2-aminobenzimidazole was added. Based on the above control experiments and previous literature, the plausible mechanism is proposed, as presented in Scheme 2. The reaction rst followed Knoevenagel condensation between benzaldehyde and ethyl acetoacetate to produce 2-benzylidene-3-oxobutanoate as intermediate, which could further react with 2-aminobenzimidazole through Michael reaction. Finally, the desired product was obtained through cyclization and dehydration. The [(4-SO 3 H)BMIM]HSO 4 played a vital role in four steps of the reaction.

presence of [(4-SO 3 H)BMIM]HSO 4 (Scheme 3)
. The substituent on the benzene did not affect the reaction rate. In addition, pure products were obtained easily by recrystallization. Remarkably, the condensation between anthranilamide and benzaldehyde was successfully performed on a 50 mmol scale, and the expected yield was obtained equally with 1 mmol scale. This method avoids the use of volatile organic solvents, harmful conditions, and metal catalysts, thus showing promise for application in industrial processes. The comparison of the presented method with previously reported literature is shown in Table 3. The reaction of anthranilamide and benzaldehyde in the presence of [(4-SO 3 H) Table 2 Comparison of the present method with previous literature for the one-pot multicomponent synthesis of benzo [4,5] Table 3, entry 6). The previous studies reported that the same reaction also achieved the target products in good to excellent yields, but some methods required the use of a solvent, high temperature and/or longer reaction time (Table  3,  Recyclability of the catalyst is a necessary feature for theapplication in industrial processes. The recyclability of [(4-SO 3 H)BMIM]HSO 4 in this study was investigated in the model reactions with benzaldehyde under optimal conditions (Fig. 1). Aer completion of the reaction, the reaction mixture was diluted with ethanol, and the desired product was obtained by ltration. The catalyst was recovered, dried under vacuum for 6 h and reused for next cycles. The yields of the product slightly decreased aer the sixth cycle. The FT-IR spectra conrmed that there was no change in functional groups of [(4-SO 3 H)BMIM]HSO 4 (Fig. 2).
Scheme 3 Reaction scope with aldehydes.

Conclusions
We have developed a facile, efficient, and atom-economic method for preparing benzo [4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal-and solvent-free conditions. The presented method provides a straightforward and green approach for the preparation of biologically nitrogen-heterocyclic compounds from the readily available starting materials in good to excellent yields within short reaction time. Remarkably, [(4-SO 3 H)BMIM]HSO 4 Brønsted acidic ionic liquid showed to be particularly suitable for these transformations as highlighted by its environmental friendliness, low-cost, recyclability, and simplicity of operation.

Materials and instrumentation
All the reagents were purchased from Merck, Acros, and Sigma-Aldrich and used without further purication. Ultrasonic irradiation was performed in Elma sonic S30H. FT-IR spectra were analyzed using a Bruker Vertex 70 (KBr pellets). Thermogravimetric analysis was performed on Analyzer TGA Q5000. 1 H and 13 C NMR spectra were performed on a Bruker Advance 500.

Synthesis of [(4-SO 3 H)BMIM]HSO 4 under solvent-free sonication
[(4-SO 3 H)BMIM]HSO 4 was synthesized via a one-pot two-step procedure under solvent-free sonication according to our previous literature report. 22 General procedure for the synthesis of benzo [4,5]    Aer completion of the conversion, the reaction mixture was quenched with cold ethanol (10 mL). The crude product was ltered and washed with petroleum ether (10 mL), and then puried by recrystallization from ethanol to obtain the desired pure product.
General procedure for the synthesis 2,3-dihydroquinazolin-4(1H)-one A mixture of anthranilamide (136 mg, 1 mmol), benzaldehyde (106 mg, 1 mmol), and [(4-SO 3 H)BMIM]HSO 4 (31.6 mg, 0.1 mmol) was sonicated for 30 min at room temperature and the progress of the reaction was monitored by TLC or GC-MS. Aer completion of the conversion, the reaction mixture was quenched with ethanol (10 mL). The crude product was ltered and washed with petroleum ether (2 Â 5 mL), and then puried by recrystallization from ethanol to afford the desired pure product.

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