Efficient Knoevenagel Condensation Reactions Catalyzed by Activated Gel Zirconium ( IV ) Oxide

In past decades, several carbon-carbon bond-forming reactions have been discovered, and their applications in organic chemistry have also been well documented in the literature [1–6]. Base-catalyzed transformations are frequently used both on small scale as well as large scale in organic synthesis, for example, in Aldol [7], Knoevenagel [8], Henry [9], and Michael [10] reactions. To catalyze these processes, organic amines, alkali alkoxides, and alkali hydroxides are commonly used as a homogeneous phase with the reagents. Although effective, these reagents are difficult to separate and, in many cases, are not recycled. To alleviate this problem, solid basic catalysts have been developed utilizing either inorganic solid materials, such as base metal oxides and carbonates, or by supporting organic bases, for example, amines, on inorganic or polymeric supports. is approach has attracted intense interest and has been reviewed extensively [11, 12]. Effective heterogeneous base catalysis have been found for Aldol [13– 15], Knoevenagel [16–18], Henry [19, 20], and Michael [21] reactions, and, inmany, cases the solid base is recyclable [22]. Chalcones are the main precursors for the biosynthesis of �avonoids, which are frequent components of the human diet [23]. Recently, studies on biological evaluation of chalcones revealed some to be anticancer [24, 25], anti-in�ammatory [26, 27], antimitotic [28], antitubercular [29], cardiovascular [30], cell differentiation inducing [31], nitric oxide regulation modulatory [32], and antihyperglycemic agents [33]. Of the many methods available for the synthesis of chalcones, the most widely used is the base-catalyzed Claisen-Schmidt reaction in which the condensation of a ketone with an aldehyde is carried out in the presence of aq. NaOH [34], KOH [35], Ba(OH)2 [36, 37], hydrotalcites [38], LiHDMS [39], and calcined NaNO3/natural phosphates [40].e acidcatalyzed methodologies include the use of AlCl3 [40], dry HCl [41], Zn(bpy)(OAC)2 [42], TiCl4 [43], CpZrH2/NiCl2 [44], Zeolites [45], RuCl3 [46], and Select�uor [47].


Experimental
Aldehydes were distilled before use.Melting points were determined using a Linkman HF591 heating stage, used in conjunction with a TC92 controller, and reuncorrected.NMR spectra were recorded using a Bruker DRX500 machine at room temperature. 1H and 13 C NMR spectra were measured using deuterochloroform as solvent, and chemical shis were measured relatives to residual solvent as an internal standard and are expressed in parts per million ().Mass spectra were obtained using a Micro Mass LCT machine in ES or EI mode.Infrared spectra were measured on a Perkin Elmer Paragon 100 FT-IR spectrometer.

Results and Discussion
In our continued interest, in the Knoevenagel condensations and its application in the synthesis of bioactive molecules, we report here a very simple and highly efficient method for the condensation of various aromatic (1) with active methylene compound (2), for example, dimedone, in the presence of ZrOCl 2 /NaNH 2 as catalysis in THF at room temperature with stirring (Scheme 1).It was exciting to observe that all the reactions occurred rapidly and were complete in just a few minutes giving excellent yields of the Knoevenagel products (3) (Table 1).
To determine the appropriate concentration of the catalyst zirconium oxychloride/sodium amide, we investigated the model reaction at different concentration of zirconium oxychloride/sodium amide such as 5, 10, 15, and 20 mol%.e product was found in 35%, 65%, 88%, and 88% yield, respectively.is indicates that 15 mol% of zirconium oxychloride/sodium amide is sufficient to carry out the reaction smoothly (Table 2).e temperature of 25 ∘ C was chosen as optimum temperature.Any further increase in the temperature failed to enhance the reaction rate substantially, while lowering the temperature below 25 ∘ C did show down the reaction rate (Table 3).
In order to evaluate the effect of solvent, various solvents such as dichloromethane, chloroform, ethyl acetate, methanol, water, and tetrahydrofurane were used for the model reaction in the presence of zirconium oxychloride/sodium amide.Surprisingly, use of dichloromethane stopped the reaction at the Knoevenagel condensation step and no further reaction took place (TLC).Reaction in chloroform, ethyl acetate, methanol, and water resulted in moderate yields trace, whereas water brought the reaction to completion efficiently to furnish the product in excellent 88% yield (Table 4, entry 6).

Conclusion
In summary, we have developed an expedient and clean protocol for the synthesis of substituted 2,2 � -(arylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) derivatives.is method has the advantages of a wide scope of substrates, operational simplicity, easy work-up procedures, shorter reaction times, and high yields.

T 1 :
Reaction time, yields, and melting points of the products (3a-j).