Alum as a Catalyst for the Synthesis of Bispyrazole Derivatives

Compounds with pyrazolemoieties as nitrogen-containing heterocyclic systems have received attention owing to their diverse biological activities. Alum (KAl(SO4)2 ̈12H2O) is an inexpensive, reusable and nontoxic catalyst used to synthesize 1H-pyrazole derivatives via the reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and carbonyl compound under solvent-free conditions at 60  ̋C. The proposed method has been used for the preparation of 1H-pyrazole derivatives to yield green products for cleaning-in-place and to avoid toxic catalysts and hazardous solvents in accordance with the philosophy of sustainable chemistry.

The significant role of compounds with pyrazole moieties in medicinal chemistry and interest in the use of heterogeneous catalysts has encouraged the use of alum for organic synthesis.This study reports on the preparation of a range of bispyrazole derivatives by means of the reaction of two equivalent 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one compounds with one equivalent carbonyl compound.

Chemicals
All chemicals were purchased from Merck or Fluka Chemical (Darmstadt, Germany).The known products were identified by comparison of their melting points and spectral data with those reported in the literature.

General Procedure for Preparation of Bispyrazol Derivatives
A mixture of 1 mmol substituted aryl aldehyde or N-alkyl substituted isatin derivative, 2 mmol 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (350 mg) and 0.1 g KAl(SO 4 ) 2 ¨12H 2 O (20 mol%) was stirred at 60 ˝C.After completion of the reaction as indicated by thin-layer chromatography (TLC) (Merck, Darmstadt, Germany), the reaction mixture was poured into water and stirred for 5 min.The products were collected by filtration, washed with water, and then recrystallized using ethanol (EtOH) to provide the desired products.

General Procedure for Catalyst Recovery
To recover the catalyst, the reaction mixture was poured into water, the products were filtered and then the water was removed under vacuum.The catalyst was then washed with acetone and dried at room temperature.1.The preparation of 1-alkyl-3,3-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)indolin-2-ones using alumas catalyst at 60 ˝C under solvent free condition.

Entry
The reaction was monitored by TLC.After completion of the reaction, the reaction mixture was poured into water and stirred for 5 min.The solid product was collected by simple filtration and washed with water.The crude solid was then recrystallized using EtOH to provide pure products.Different solvents were used to estimate the effect of the solvent (Table 2).The reaction were carried out in the presence 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol), In a typical experiment, a solvent-free mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2.00 mmol) and 2-hydroxybenzaldehyde (1.00 mmol) was heated at 60 ˝C in the presence of a catalytic amount of alum (20% mol).
The reaction was monitored by TLC.After completion of the reaction, the reaction mixture was poured into water and stirred for 5 min.The solid product was collected by simple filtration and washed with water.The crude solid was then recrystallized using EtOH to provide pure products.Different solvents were used to estimate the effect of the solvent (Table 2).As shown, the reaction could be carried out in the absence of solvent to produce an excellent yield.To determine the best molar ratio of the catalyst, the reaction was tested for 10%, 20% and 25% mol.Table 1 indicates that 20% mol alum produced the best results in terms of reaction time and yield.No product was observed in the absence of catalyst (Table 2, entry 1) which further requires the use of alum in this transformation (Table 2, entry 8).The activity of the recycled alum was examined in 5 successive runs (Table 2, entry 5).
To evaluate the generality and versatility of this method, optimized conditions were employed and substituted aromatic aldehydes bearing either electron-donating or electron-withdrawing substituents with 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one in the presence of alum to achieve the corresponding 4,4-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s.Table 3 indicates that the method is suitable and efficient for different aromatic aldehydes.The activation of the carbonyl compound by binding to alum with carbonyl oxygen enhanced the electrophilicity of the carbonyl carbon and improved the reaction rate.The efficiency of alum was compared with the results of other catalysts (Table 4) using a condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with 2-hydroxybenzaldehyde under the test conditions described above.
To compare the efficiency of our catalyst with the reported catalysts for the synthesis of 4,4 1 -(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s, we have tabulated the results of these catalysts to perform the condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with 4-chlorobenzaldehyde, in Table 5.As Table 5 indicates, the reaction times were shorter and the yields were higher when our catalysts were utilized.

Reaction Condition Time (min) Yield b (%) Reference
Silica-bonded S-sulfonic acid (sBSSA) (0.  Isatins are starting materials used for drug synthesis and have shown a wide range of biological effects.To further expand the scope of the reaction in the present study [25], the aromatic aldehydes were replaced with N-alkyl isatin derivatives (Figure 2).Isatins are starting materials used for drug synthesis and have shown a wide range of biological effects.To further expand the scope of the reaction in the present study [25], the aromatic aldehydes were replaced with N-alkyl isatin derivatives (Figure 2).The first step was preparation of the prerequisite N-alkyl isatin derivatives.Perillo et al. [26] undertook a comprehensive reinvestigation of this protocol and examined a range of bases (Na2CO3, K2CO3, Cs2CO3, CaH2, TEA, LiOH, NMM, NaOEt) in different solvents (DMF, DMA, HMPT, MeCN, DMSO, NMP) and found that optimal conditions consisted of K2CO3 or Cs2CO3 and a few drops of DMF or N-methyl-2-pyrrolidinone (Figure 3).The first step was preparation of the prerequisite N-alkyl isatin derivatives.Perillo et al. [26] undertook a comprehensive reinvestigation of this protocol and examined a range of bases (Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , CaH 2 , TEA, LiOH, NMM, NaOEt) in different solvents (DMF, DMA, HMPT, MeCN, DMSO, NMP) and found that optimal conditions consisted of K 2 CO 3 or Cs 2 CO 3 and a few drops of DMF or N-methyl-2-pyrrolidinone (Figure 3).Isatins are starting materials used for drug synthesis and have shown a wide range of biological effects.To further expand the scope of the reaction in the present study [25], the aromatic aldehydes were replaced with N-alkyl isatin derivatives (Figure 2).The first step was preparation of the prerequisite N-alkyl isatin derivatives.Perillo et al. [26] undertook a comprehensive reinvestigation of this protocol and examined a range of bases (Na2CO3, K2CO3, Cs2CO3, CaH2, TEA, LiOH, NMM, NaOEt) in different solvents (DMF, DMA, HMPT, MeCN, DMSO, NMP) and found that optimal conditions consisted of K2CO3 or Cs2CO3 and a few drops of DMF or N-methyl-2-pyrrolidinone (Figure 3).Using this method, the reactions of 2a-d with alkyl halides and isatin produced the corresponding N-alkyl substituted isatin derivatives (Table 6).Under these optimal conditions, the scope and generality of the protocol was next examined by employing N-alkyl substituted isatins derivatives (1 mmol) and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol).
As seen in Table 1, N-alkyl isatin derivatives easily transformed into the desired products with good yields.All products were fully characterized and their structures were confirmed by IR, 1 H and 13 C-NMR spectra.
a Yield of isolated product.