Evaluation of Silica-H2SO4 as an Efficient Heterogeneous Catalyst for the Synthesis of Chalcones

We report an efficient silica-H2SO4 mediated synthesis of a variety of chalcones that afforded the targeted compounds in very good yield compared to base catalyzed solvent free conditions as well as acid or base catalyzed refluxing conditions.

Chemically chalcones are open chain flavonoids with two aromatic rings linked via a three carbon α,β-unsaturated enone system. These compounds are widely found in numerous species of plant, which are used as traditional folk medicines for treatment of a large number of diseases. Whether synthetic or OPEN ACCESS isolated from plants, chalcones have been found to be associated with diverse biological applications such as antiinflammatory [1], antipyretic, antimutagenic [2], antioxidant [3], cytotoxic, antitumor [4] and a large list yet to be mentioned.
With increasing concerns about environmental pollution, synthetic strategies are been developed that involve the use of less or no solvent. Similarly the heterogeneous catalysis is preferred over homogenous catalysis because of the work-up, economical and environmental advantages of the former. Silica-H 2 SO 4 (SSA) is a versatile, selective and a powerful catalyst that has been explored for various organic transformations, such as the synthesis of heterocyclic compounds [23][24][25][26][27], cross-aldol condensations [28], Michael additions [29], protection [30,31], deprotection [32] and oxidation reactions [33]. The major advantages of SSA include: ease of preparation, ease of removal from reaction mixtures, comparatively mild conditions as compared to H 2 SO 4 as well as NaOH. Since it requires no use of solvent, therefore it is economical as well as environmentally friendly and most important thing is that it can be recycled.
In this article, we wish to report an efficient and versatile procedure for the synthesis of chalcones in the presence of SSA and a comparison of the results of our synthesis to different methods in order to evaluate the effectiveness of the SSA-mediated synthesis of chalcones.

Results and Discussion
For the preparation of chalcones, four different reagents/reaction conditions were chosen: refluxing conditions using MeOH as a solvent in the presence of stoichiometric amount of H 2 SO 4 or NaOH, grinding the reactants with NaOH pallets under neat conditions (SF) and by heating the reactants with SSA in the absence of any solvent.
The SSA was prepared by two different reported methods. One method involves the addition of H 2 SO 4 to a suspension of silica gel in Et 2 O, followed by the evaporation of the solvent under reduced pressure and heating the resulting silica gel at 120 °C for 3 h [34]. The other method involves the addition of silica gel to HSO 3 Cl along with subsequent trapping of HCl produced during the reaction [35]. The SSA obtained by both methods was similar in form, i.e., a white solid, and showed similar results.
In order to determine the optimum amount of SSA required for a given transformation, the simplest chalcone 3a (obtained by condensing PhAc with PhCHO in the presence of varying amounts of SSA from 0.005 to 0.1 g) was synthesized (Scheme 1).
It is observed that best results are obtained with 0.02 g of SSA. If less than 0.02 g of SSA was employed the yield of the product was low or the transformation was incomplete. An increase in amount of SSA resulted in a slight increase in yield, but decomposition of the product and difficult isolation of the product was observed upon increasing (≥0.05 g) the amount of SSA (Table 1). In order to confirm the effectiveness of SSA three control experiments were performed, which include heating reactants with silica gel under solvent free conditions, using H 2 SO 4 (without silica gel) in MeOH (at 65 °C ) and by heating the aldehyde and ketone in the presence of silica gel and H 2 SO 4 at 65 °C both in the presence and absence of methanol (used as a solvent). No product formation was observed when only silica gel was used. When the reactants were heated together with silica and H 2 SO 4 in the absence of solvent, blackening of the contents of reaction flask was observed with no transformation occurred, even after 4 h. Heating the reactants with silica and H 2 SO 4 in MeOH yielded 1,3-diphenylprop-2-enone (3a) in less than 10% yield after 5 h. Heating the reactants in H 2 SO 4 using MeOH at 65 °C afforded the chalcone 3a in 28% yield after 4 h; however, refluxing the methanolic solution of reactants with H 2 SO 4 afforded chalcone 3a in 38% after 4 h.
The catalyst is not only removed easily, but can be recycled. The catalyst was recovered by simple filtration after the addition of CH 2 Cl 2 followed by partitioning between H 2 O and the organic layer. The residual catalyst was washed with acetone in order to extract any remaining product adsorbed on the catalyst surface, and it was then reactivated by placing in an oven for 30 min at 100 °C . The recovered catalyst was used three times for the synthesis of 1,3-diphenylprop-2-enone and almost the same yield was obtained as observed in the first run.

Synthesis of Open Chain Chalcones 3a-o
When substituted PhAc 1 and ArCHO 2 were condensed in the presence of different reagents, the capricious yield of the products 3 depends upon the nature of reagent used. In general, the base-catalyzed reaction under refluxing conditions gave the lowest yields in almost all cases. The effect was more pronounced when either substrate (i.e., 1 or 2) contains -I and +R groups (such as OH, NMe 2 ) or -I and -R groups (such as NO 2 ). The acid catalyzed reaction also suffered the problem of low yields. The low yield with base-catalyzed refluxing conditions was attributed to the oxidation of aldehydes to their corresponding carboxylic acids via the Cannizarro reaction, which results in an overall decrease in the active concentration of aldehyde 2. The oxidation of aldehydes to carboxylic acids was much pronounced with para-substituted 2. The solvent free (SF) conditions led to quite a high yield of the product; however, the yields were quite low when either or both of the reactants contains -I and +R/-R groups. The yields of such substrates under SSA conditions are quite higher (Scheme 2. Table 2). The formation of the chalcones 3a-o was confirmed by 1 H-NMR that indicated the presence of J trans (14.9-17.4 Hz). The mass spectra were also in agreement with the formation of the targeted chalcones.

Synthesis of Tetralone-and Indanone-Based Chalcones 5a-m
After the successful synthesis of various substituted chalcones 3a-o, the effect of reagent on the yield of tetralone-and indanone-based chalcones was studied. For this purpose the tetralone and/or indanone was allowed to condense with various aldehydes in the presence of acid, base, solvent free conditions and SSA. The trends were almost similar as observed in case of 3a-o. In most cases a molecular ion 6a or 6b was observed as a stable radical cation (Scheme 3, Table 3).  The change in ring size of tetralone and indanone didn't affect the yield of the product(s). The formation of arylidene indanone/tetralones was confirmed by 1 H-NMR that indicated the presence of an olefinic proton that appeared as a singlet (6.69-7.82 ppm) in most of the cases depending upon the -I and -R/+R effect of the locants at 2 (Figure 3). The XRD of a couple of products (5g and 5i, one from each case) confirmed the formation of a new C=C bond (1.337Å between C1 & C10 and 1.340Å between C10 & C11 respectively) ( Figure 1) [36].

Experimental
The TLC was carried out on pre-coated silica gel (0. 25

Preparation of SSA
Method A: The H 2 SO 4 was added to a stirred suspension of silica gel in Et 2 O. After stirring for 1 h, the solvent was evaporated under reduced pressure. The resulting SSA was placed in an oven at 120 °C for 3 h, which afforded SSA as a white solid.
Method B: The silica gel was added to HSO 3 Cl along with subsequent trapping of HCl produced during the reaction. The suspension thus formed was stirred at room temperature for 3 h and the resultant product was dried in fume-hood to remove any trapped HCl produced during the reaction. The SSA obtained in this manner was white sand like solid.

Representative Procedure for H 2 SO 4 Catalyzed Synthesis of Chalcones under Reflux
The PhAc (1 mL, 0.90 g, 7.53 mmol, 1 eq.) and PhCHO (0.84 g, 7.91 mmol, 1.05 eq.) were added to a stirred solution of H 2 SO 4 (0.5 mL, 0.86 g, 8.66 mmol, 1.15 eq.) in MeOH (15 mL) and the resulting reaction mixture was refluxed for 3 h. After the completion of reaction, the solvent was evaporated under a stream of N 2 . The resulting reaction mixture was neutralized with 10% aq. NaHCO 3 and partitioned between H 2 O (50 mL) and EtOAc (3 × 25 mL). The combined organic extract was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford product as white amorphous solid. Crystallization from CH 2 Cl 2 afforded product as colorless needles (0.89 g, 54%).

Representative Procedure for NaOH Catalyzed Synthesis of Chalcones under Reflux
The PhAc (1 mL, 0.90 g, 7.53 mmol, 1 eq.) and PhCHO (0.84 g, 7.91 mmol, 1.05 eq.) were added to a stirred solution of NaOH (0.35 g, 8.66 mmol, 1.15 eq.) in MeOH (15 mL) and the resulting reaction mixture was refluxed for 3 h. After the completion of reaction, the solvent was evaporated under a stream of N 2 . The resulting reaction mixture was acidified with dil. aq. HCl and partitioned between H 2 O (50 mL) and EtOAc (3 × 25 mL). The combined organic extract was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford product as white amorphous solid. Crystallization from CH 2 Cl 2 afforded product as colorless needles (0.74 g, 45%).

Representative Procedure for NaOH Catalyzed Synthesis of Chalcones under Solvent Free Conditions
The PhAc (1 mL, 0.90 g, 7.53 mmol, 1 eq) and PhCHO (0.84 g, 7.91 mmol, 1.05 eq) were ground together in a mortar and pestle in the presence of NaOH (0.30 g, 7.60 mmol, 1.01 eq) for 30 min. The reaction mixture was neutralized and extracted with Et 2 O (3 × 25 mL). The combined organic extract was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the enone as colourless solid (1.27 g, 77%).

Representative Procedure for the SSA Catalysed Synthesis of Chalcones
The SSA (0.02 g) was added to a well stirred suspension of PhAc (1 mL, 0.90 g, 7.53 mmol, 1 eq.) and PhCHO (0.84 g, 7.91 mmol, 1.05 eq.) and the resulting mixture was heated at 65 °C for 1.5 h. The reaction mixture was cooled to room temperature and partitioned between brine (25 mL) and CH 2 Cl 2 (3 × 15 mL) and solid SSA was filtered off. The SSA was washed with acetone (25 mL) to ensure desorption of product on SSA surface. The combined organic extract was washed with brine (3 × 25 mL) and the organic extract was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the chalcone as colorless solid (1.48 g, 91%).