An efficient and green approach for the synthesis of 2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates using Bi2O3/ZrO2 as a reusable catalyst

A novel material of bismuth loaded on zirconia (Bi2O3/ZrO2) is synthesized by simple wet-impregnation method and characterized by several techniques (P-XRD, TEM, SEM, BET, etc.). Bi2O3/ZrO2 proved to be a good catalyst for the four-component, one-pot reaction to produce a new series of 2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate derivatives with excellent yields (91 to 98%) under mild conditions at RT with short reaction times (≈20 min). The structures of the target molecules were confirmed by 1H NMR, 13C NMR, 15N NMR, HRMS and FT-IR. The catalyst is easily separable and can be reused for six cycles without ostensible loss of activity. This method is inexpensive, atom-efficient and no chromatographic separations are needed.


Introduction
In pharmaceutical research, methods for the synthesis of medicinally important scaffolds in high yields under moderate conditions fascinate all. 1 Multicomponent reactions (MCRs) are one-step reactions, in which three or more starting materials are integrated together to obtain the target molecule with no need for separation of intermediates. 2 In MCRs, the product formation takes place through reaction of multiple reactive components present in the reaction media in sequence. The main characteristics are high atom economy, eco-compatibility, and efficient forming of multiple-bonds, which are the near ideal targets in the modern organic synthesis. 3,4 Heterogeneous catalysts play a key role in the development of cost-effective and eco-friendly protocols in organic synthesis. 5 The main benets are the recyclability and reusability of the catalytic material, which are not observed in other organic or inorganic homogenous catalysts. 6 The principal assets of heterogeneous catalysts are their high surface area, simple handling, low toxicity, short reaction times, easy separation, and thermal and mechanical stability, relative to many homogenous catalysts. 7 To vary the surface characteristics of heterogeneous catalysts, the use of mixed oxides is an attractive option. 8,9 The recent literature reveals that zirconium oxide has been used either as an active material or a support in catalysts in the design of various organic transformations, with good product selectivity. 10-12 ZrO 2 even shows potential catalyst activity in water. Its redox properties, high surface area, and acidic and basic sites make it superior to other catalytic ESI. † 12 Furthermore, ZrO 2 is less-expensive, stable, non-hazardous, reusable and viably available. 3,13 Bismuth is a green grade element and its related compounds play a prominent role in many organic transformations, such as oxidation, reduction, and C-C bond formation reactions, 14 owing to the presence of Lewis acidic character. Moreover, it is non-toxic and highly stable. 15 Hence, the use of bismuth oxide-loaded zirconia catalysts is an elective choice for the present synthetic scheme.
Heterocyclic molecules have become important in the elds of pharmaceutical, agro, industrial and combinatorial chemistry. 16 Accomplishing facile and easy methods for the design of new composite heterocyclic moieties is a key aspect and ongoing challenge in the eld of heterocyclic chemistry. Pyrano [2,3-c]pyrazoles and their derivatives are signicant nitrogencontaining heterocyclic molecules with interesting biological and pharmaceutical properties, such as anti-inammatory, 17 anticancer, 18 antioxidant, 19 anti-bacterial 20 and anti-tubercular agents. 21 Subsequently, the preparation of several substituted pyrano [2,3-c]pyrazole derivatives has been explored by different methods, using silica-supported tetramethylguanidine, 22 BS-2G-Ti, 23 Ba(OH) 2 , 24 g-alumina, 25 Amberlyst A21, 26 acetic acid, 27 visible light-assisted synthesis 28 etc. as catalysts. All these reactions reported have low yields, with many demanding expensive chemicals, harsh reaction conditions and long reaction times. Therefore, an improvement over existing procedures with a greener approach with enhanced yields under milder conditions is necessary and vital.
With consistent interest in development of improved methods for the synthesis of different biologically active scaffolds, we have previously reported varied enriched protocols for the synthesis of novel heterocycles. [29][30][31][32] In this communication, we report a new catalyst material Bi 2 O 3 /ZrO 2 for MCRs for the synthesis of new functionalized pyrano [2,3-c] pyrazole derivatives by using a one-pot four-component reaction.

Catalyst preparation
A series of bismuth oxide-loaded zirconia (Bi 2 O 3 /ZrO 2 ) catalyst materials with different weight percentages were prepared (1, 2.5, & 5 wt%) by employing wet impregnation method. [31][32][33][34][35] A mixture of zirconium oxide (ZrO 2 , 2 g, Alfa Aesar) and an appropriate amount (wt%) of bismuth chloride (BiCl 3 , Alfa Aesar) in deionised water (60 mL) was agitated with vigorous stirring at room temperature (RT) for 7 h. The resultant slurry was heated to and preserved at 75 C for 1.5 h and then allowed to cool to RT. Then, the slurry was ltered under vacuum and dried in an oven at 120-140 C for 8 h, and further calcined at 450 C for 6 h in the presence of air to afford different wt% of Bi 2 O 3 /ZrO 2 . Instrumentation details are included in the (ESI-I †).

General procedure for the synthesis of pyranopyrazole derivatives (5a-k)
In order to examine the efficiency of the prepared Bi 2 O 3 /ZrO 2 catalyst, in a 25 mL reaction ask at RT, an equi-molar mixture of the chosen aromatic aldehyde (1 mmol), malononitrile (1 mmol), hydrazine hydrate (1 mmol), diethyl acetylenedicarboxylate (1 mmol) and Bi 2 O 3 /ZrO 2 (30 mg) catalyst were added under stirring using ethanol as the solvent (5 mL) for 15 minutes (Scheme 1). The progression of the reaction was observed by TLC. Aer completion of the reaction, the catalyst material was recovered by simple ltration and the organic compound was separated by addition of an appropriate amount of ethanol. Then, the pure target products were obtained aer evaporation of ethanol under vacuum. All the reaction products were characterised using various spectral techniques ( 1 H-NMR, 15 N NMR, 13 C-NMR, HRMS and FT-IR). The related details and spectra are included in the (ESI-II †).

TEM analysis
The TEM image of 2.5 wt% bismuth loaded on zirconia is shown in Fig. 2a. It shows that bismuth particles settled as irregular black particles on the spherical shaped zirconia particles. The highly dispersed bismuth particles occur due to ne interaction between bismuth and the zirconia oxides. In order to analyse the particle size distribution ( Fig. 2b) quantitatively, the histogram was tted with the Gaussian function and the mean particle size was calculated to be 8.54 nm.  (Fig. 3b), with minor but prominent quantities of surface improvement of bismuth. Fig. 4 illustrates the nitrogen adsorption-desorption isotherm of the Bi 2 O 3 /ZrO 2 catalyst material. The N 2 isotherm was associated to type IV, a typical H2-hysteresis loop, which describes characteristic mesoporous material lying within the p/p o range of 0.59-0.97. The BET surface area of the 2.5% Bi 2 O 3 /ZrO 2 catalyst material was shown to be 80.40 m 2 g À1 , pore volume 0.320 cm 3 g À1 and pore size 106.4Å. For the 1% Bi 2 O 3 /ZrO 2 catalyst loading, the particles are small and have a high surface area, but had less active sites relative to the 2.5% Bi 2 O 3 /ZrO 2 . With the 5% Bi 2 O 3 /ZrO 2 loading, the bismuth particles are   visibly larger, and hence have a smaller surface area, when compared to the 2.5% loading and thus slightly lower yield. Hence, Bi 2 O 3 on ZrO 2 acts as a good promoter for the present transformation. These results suggest that bismuth on zirconia could act as a good promoter for the growth of additional crystalline faces, which cooperate to enhance the catalytic activity.

Pyridine IR analysis
The ex situ pyridine 36 adsorbed FT-IR spectrum in the range of 1600-1400 cm À1 for the prepared Bi 2 O 3 /ZrO 2 is displayed in Fig. 5. The bands at 1449 cm À1 , 1487 cm À1 and 1530 cm À1 were attributed to Lewis, Brønsted, and Lewis and Brønsted acidic sites respectively. Upon careful examination, the prepared catalyst material reveals strong Lewis acidic and weak Brønsted acidic sites.

Reaction optimization
The   most reactive acidic sites owing to its nature and exhibited better catalytic activity compared to the other mixed catalysts. Furthermore, these catalysts have higher surface area, smaller particle sizes and more catalytic active sites than the related oxide homologues. Therefore, 2.5% Bi 2 O 3 /ZrO 2 catalyst was preferred for all further reactions to attain excellent product yields. The model reaction with 2.5% Bi 2 O 3 /ZrO 2 was conducted using varied non-polar and polar (protic and aprotic) solvents, such as n-hexane, toluene, THF, DMF, H 2 O, MeOH and EtOH, at RT (Table 2). No reaction was observed with non-polar solvents (n-hexane and toluene; Table 2, entries 1 and 2). However, polar aprotic solvents (THF and DMF) revealed a very low yield ( Table  2, entries 3 and 4). Further, the reaction occurred efficiently with polar solvents (H 2 O, MeOH and EtOH) and with excellent yields in short reaction times except with H 2 O ( Table 2, entries 5-7). When using H 2 O, as a polar green solvent, the reaction time increased and the yield was decreased. Based on these results, ethanol was chosen as the ideal solvent, which is also environmentally friendly and cost-effective. Next, the model reaction was evaluated by employing different amounts of 2.5% Bi 2 O 3 /ZrO 2 catalyst. The summarized outcomes (Table 3, entries 1-3) show that the increase in amount of catalyst from 10 mg to 30 mg leads to an increase in the product yield from 58% to 98% plus decreased reaction time. No signicant change was observed in the yield of product with further increase in the amount of catalyst from 30 mg to 60 mg. Therefore, 30 mg of Bi 2 O 3 /ZrO 2 catalyst was used for the further reactions.
For the optimised reaction conditions, to establish the wider scope of the protocol, the method was applied for the synthesis of different pyranopyrazoles using various substituted aromatic aldehydes (Table S4 †) and the results are summarized in Table  4. The 2.5% Bi 2 O 3 /ZrO 2 catalyst material catalysed the facile one-pot synthesis of pyranopyrazole derivatives with excellent yields in short reaction times (<20 min). Remarkably, the aldehydes with both electron donating and electron withdrawing (ortho, meta and para) substituents worked efficiently under the reaction conditions, producing the corresponding target products (5a-k).

Reusability of catalyst
The reusability and recyclability of a solid catalyst material is an important parameter as per green chemistry principles. Several recycling experiments were conducted to examine the stability and sustainability of the catalyst material. Aer completion of every run, ltration was employed to separate the catalyst from the crude product.
Then the catalyst was washed with ethanol and dried at 120 C for 3 h for up to seven runs. Marginal loss of less than 5% of the catalyst was observed in the recovery procedure. Then it was washed with ethanol and dried at 120 C for 3 h. The loss was supplemented to 30 mg by adding the minute amount required. Activity was retained with no loss in the rst six runs, then the material's catalytic activity weakened by 4% in the 7th cycle. No loss of catalytic activity could be observed up to the 6th run owing to the minor losses in the recovery process and nonleaching of the active material.

Mechanism
In agreement with experimental results, a plausible mechanism is suggested in Scheme 2. The presence of Lewis acidity on the catalyst surface would facilitate the reaction. It may be assumed that in the rst step Knoevenagel condensation 37 is achieved by the coordination of Lewis acidic sites with the oxygen of the carbonyl group, forming a carbocation intermediate (a). In the    next step, the active methylene group reacts with the carbocation intermediate giving (b); next it will dissociate from the catalyst surface taking a proton from the protic solvent (EtOH) and giving (c). It will further undergo dehydration giving (3). In the next step, ethyl 5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (6) is possibly formed by the reaction between hydrazine hydrate (5) with diethyl acetylenedicarboxylate (4). Finally, a Michael addition between (3) and (6) occurs, yielding the desired product selectively through 6-exo-dig cyclization. The catalytic efficiency of the Bi 2 O 3 /ZrO 2 on the title reaction in comparison with other reported catalysts is summarized in the Table 5.

Conclusion
In summary, we designed a highly efficient and cost-effective method for the synthesis of pyranopyrazole derivatives via a one-pot, four-component reaction in ethanol as a green solvent, using environmentally benign Bi 2 O 3 /ZrO 2 as a selective catalyst. Of the 11 derivatives synthesised, eight are new molecules. The operational simplicity, short reaction times, high yields, eco-friendly solvent, and mild reaction conditions make this method attractive. Additionally, the catalyst can be easily recovered and recycled for at least six runs without loss of efficiency. Moreover, expansion of the reaction scope and synthetic and medicinal applications of this methodology are in progress in our laboratory.

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