Tetrahedron Letters 55 (2014) 2612–2617

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Tetrahedron Letters

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TsOH-SiO2 as an efficient and eco-friendly catalyst for Knoevenagelcondensation

http://dx.doi.org/10.1016/j.tetlet.2014.02.1220040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +91 9412653054.E-mail address: siddiqui_zeba@yahoo.co.in (Z.N. Siddiqui).

Zeba N. Siddiqui ⇑, Saima TarannumDepartment of Chemistry, Aligarh Muslim University, Aligarh 202002, India

a r t i c l e i n f o

Article history:Received 7 December 2013Revised 25 February 2014Accepted 27 February 2014Available online 13 March 2014

Keywords:TsOH-SiO2

Heterogeneous catalystAlkenyl pyrazolesSolvent-free reaction

a b s t r a c t

Tosic acid on silica gel (TsOH-SiO2) was synthesized and characterized using microscopic andspectroscopic techniques such as powder X-ray diffraction (XRD), scanning electron microscopy (SEM)and FT-IR spectroscopy. Thermal behaviour of the catalyst was investigated by differential scanningcalorimetry (DSC) and thermogravimetric (TG) analysis. TsOH-SiO2 showed excellent catalytic activityfor the Knoevenagel condensation and was recyclable for six cycles.

� 2014 Elsevier Ltd. All rights reserved.

The Knoevenagel reaction provides one of the most importantpotential alternatives in the synthesis of electrophilic olefinderivatives utilizing active methylene and carbonyl compounds.1

Knoevenagel reactions are classically performed under homoge-neous conditions using ammonia, amines, pyridine, piperidineand their salts as basic catalysts which cause complications inproduct separation, catalyst regeneration, etc.2,3 To overcome theseproblems, several reaction conditions were tried which includedthe use of microwaves,4 surfactants,5 zeolites,6 ionic liquids7 andheterogeneous catalysts.8 With regard to efficient methods forthe synthesis of alkene derivatives by heterogeneous catalysis, afew reports are available in the literature including silica–HClO4,9

KF/NP and NaNO3/NP,10 hydrotalcite in ionic liquid medium,11

CeCl3/7H2O–NaI,12 ZnO,13 silica-supported piperazine,14 nickelnanoparticles,15 borate zirconia,16 silica–NH4OAc17 and silica–ZrCl4.18 Unfortunately, some of these methods have disadvantagessuch as use of expensive reagents and toxic solvents, low yields,prolonged reaction time, tedious procedure etc.

Knoevenagel reaction under heterogeneous conditions is achallenging task due to its high reaction rate, recyclability ofcatalytic system, formation of clean products and suppression ofside product formation. Straightforward syntheses of heteroge-neous catalysts were performed by supporting homogeneousmineral and organic acids on porous solids. Among the varioussupports, silica presents many advantages such as stability,reusability, no swelling and ease of handling.19 In this context,

perchloric,20 sulfuric,21 sulfamic,22 phosphoric23 acids and phos-phorus pentoxide24 are normally supported on silica by simplepore filling and/or by interacting with the surface of the solid.Although there are numerous reports on different acid catalystssupported on silica, relatively less work is available on tosic acidsupported on silica gel as heterogeneous catalyst.25–29 Thus, thereis a lot of scope to further evaluate the catalyst for its application invarious organic reactions.

Pyrazoles occupy a special role in the realm of synthetic organicchemistry. Members of this group display a broad range of phar-macological activities such as antimicrobial, anti-inflammatory,anticonvulsant, analgesic, herbicidal, antioxidant, cytotoxic andanticancer activities.30 Numerous synthetic pyrazole derivativeshave been used as valuable leads in photographic,31 ultravioletstabilizers32 and energetic materials.33 Such important pyrazolederivatives include natural products (S)-pyrazolylalanine, pyrazo-mycin and synthetic compounds sildenafil, ionazolac, difenamiz-ole, mepirizole etc.

In the present investigation, the characterization of TsOH-SiO2

using microscopic and spectroscopic methods has been described(Figs. 1, 2, 3, 4, 5 and 6, Supplementary data). The number of H+ siteson the TsOH-SiO2 was determined by acid–base titration and wasfound to be 0.54 meq/g. The catalytic activity of TsOH-SiO2 wasinvestigated for Knoevenagel condensation between different 5-aryl-oxy-3-methyl-1-phenylpyrazole-4-carbaldehydes and various cyclicactive methylene compounds.34

To determine the best reaction conditions, we studied the influ-ence of varying parameters such as catalysts, solvents, supportingmaterials, different amounts of loaded TsOH on supporting material

Table 1The influence of different catalysts on the model reaction under thermal solvent-freecondition

Entrya Catalyst Timeb Yieldc (%)

1 TsOH-SiO2 5 min 942 TsOH 15 min 723 Silica sulfamic acid 10 min Trace4 Silica sulfuric acid 20 min 645 NaHSO4–SiO2 10 min 686 Cellulose sulfuric acid 1.2 h Trace7 Xanthan sulfuric acid 40 min 488 Sulfamic acid 15 min 449 Camphor sulfonic acid 25 min 44

10 Chlorosulfonic acid 1.5 h 3811 Sulfanilic acid 2 h 3212 Silica gel 3 h 42

a Reaction of 3-methyl-5-phenoxy-1-phenylpyrazole-4-carbaldehyde (1 mmol)with 1,3-dimethyl-2,4,6-pyrimidinetrione (1 mmol) in the presence of 30 mg ofcatalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 2Effect of various solvents for the synthesis of 5a using solution conditions versus thesolvent-free method in the presence of TsOH-SiO2

Entrya Solvent Temperature Timeb Yieldc (%)

1 —/Grinding rt 5 min 622 — 70 �C 5 min 943 CH3OH Reflux 4 h 624 CH3CH2OH Reflux 3.5 h 685 (CH3)2CHOH Reflux 7 h 566 CHCl3 Reflux 16 h Trace7 CH3CN Reflux 17.5 h Trace8 PEG-200 Reflux 3 h Mixture9 PEG-400 Reflux 3.5 h Mixture

10 CH3COOH Reflux 4 h Mixture

a Reaction of 3-methyl-5-phenoxy-1-phenylpyrazole-4-carbaldehyde (1 mmol)with 1,3-dimethyl-2,4,6-pyrimidinetrione (1 mmol) in the presence of 30 mg ofcatalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 3Effect of different supports on the synthesis of 5a under thermal solvent-freecondition

Entrya Supports Timeb (min) Yieldc (%)

1 Silica gel 5 942 Zirconia 15 Trace3 Acidic alumina 30 724 Basic alumina 35 645 Neutral alumina 35 606 Titania 40 45

a Reaction of 3-methyl-5-phenoxy-1-phenylpyrazole-4-carbaldehyde (1 mmol)with 1,3-dimethyl-2,4,6-pyrimidinetrione (1 mmol) in the presence of 30 mg ofcatalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 4Effect of TsOH loading on the support for the synthesis of 5a under thermal solvent-free condition

Entrya TsOH-SiO2 (%w/w) Timeb (min) Yieldc (%)

1 10 35 642 12 20 763 15 15 824 20 5 945 25 5 94

a Reaction of 3-methyl-5-phenoxy-1-phenylpyrazole-4-carbaldehyde (1 mmol)with 1,3-dimethyl-2,4,6-pyrimidinetrione (1 mmol) in the presence of 30 mg ofcatalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 5Effect of amount of catalyst on the synthesis of 5a under thermal solvent-freecondition

Entry TsOH-SiO2 (mg) Timea (min) Yieldb

1 10 50 542 20 35 683 30 5 944 40 5 94

a Reaction progress monitored by TLC.b Isolated yield.

Z. N. Siddiqui, S. Tarannum / Tetrahedron Letters 55 (2014) 2612–2617 2613

and amount of catalyst. The reaction of 3-methyl-5-phenoxy-1-phenylpyrazole-4-carbaldehyde (1 mmol) with 1,3-dimethyl-2,4,6-pyrimidinetrione (1 mmol) was selected as a model reactionfor all catalytic studies.

In order to evaluate the superiority of TsOH-SiO2, the modelreaction was performed with various sulfur containing catalysts.The order of reactivity of various catalysts was TsOH-SiO2 >TsOH > NaHSO4–SiO2 > silica sulfuric acid > xanthan sulfuricacid > sulfamic acid > camphor sulfonic acid > chlorosulfonicacid > sulfanilic acid > silica sulfamic acid > cellulose sulfuric acid(Table 1). The results revealed that TsOH-SiO2 was the most effec-tive for the said reaction as it catalysed the reaction at a much fas-ter rate (5 min) with excellent yield of the product (94%) (entry 1).Adsorption of TsOH on solid surface (silica) increases surface areaof the catalyst. The increased surface area provides more activesites for the interaction of reactants enhancing rate of the reaction.TsOH is also moisture sensitive and may affect rate of the reaction(entry 2) giving product in 72% yield only as compared to TsOH-SiO2 (product yield 94%). Knoevenagel condensation using freshlysynthesized TsOH-SiO2 and TsOH-SiO2 after keeping it in ambientatmosphere for 5 days produced same results. This showed thatthere was no obvious deteriorating effect of atmospheric oxygenor moisture towards the activity of the supported catalyst. Afterdoing the controlled experiments it was found that the supportedcatalyst was more efficient and less moisture sensitive than theunsupported catalyst. In a comparative study, the model reactionwas also performed in the presence of silica gel under same reac-tion condition, it was observed that the reaction was completedin 3 h but only 42% product could be isolated (entry 12).

In order to evaluate the influence of various solvents, the modelreaction was carried out in different organic solvents such asCH3OH, CH3CH2OH, (CH3)2CHOH, CH3COOH, CHCl3, CH3CN andpolyethylene glycols (Table 2). When CH3OH, CH3CH2OH and(CH3)2CHOH were employed as solvents, moderate yield of theproduct was obtained after a long period of time (entries 3–5). Rel-atively less polar solvents like CHCl3 and CH3CN gave only traceamount of the product (entries 6 and 7). When the reaction wasperformed in PEG-200, PEG-400 and CH3COOH, the reaction wentto completion in a relatively shorter time period giving a mixtureof products (entries 8–10). In order to examine the specific effectof temperature on product formation, the model reaction was alsocarried out at room temperature under grinding condition. It wasobserved that the reaction was completed in same time period asthat of thermal solvent-free condition but product yield was mod-erate (entry 1).

The effect of different supports over the catalytic performancewas also examined using the model reaction (Table 3). Amongthe various supports the maximum conversion was obtained whentosic acid was supported on silica (entry 1). When zirconia (ZrO2)was used as support, the product was obtained in trace amount

NNPh

+

O

O

Q

O

O

Q

NNPh

H

(3a-d) (4a-e)

TsOH-SiO2

70 °CSolvent-free

(5a-t)

H3C

O

CHO

O

H3C

X X

NNPh

(2a-d)

H3C

Cl

CHO

+

(1)

DMF, KOH120 °C

X

OH

X = Q =

3a 3b 3c 3d

H NO2 OCH3 Cl

4a 4b 4c 4d 4e

CH3 N C

O

N CH3 HN C

O

NH HN C

S

NH O C O

H3C CH3

Scheme 1. Synthesis of alkenyl pyrazoles (5a–t) using TsOH-SiO2 under thermal solvent-free conditions.

Table 6The reaction of 5-aryloxy-3-methyl-1-phenylpyrazole-4-carbaldehydes and cyclicactive methylene compounds in presence of TsOH-SiO2 under thermal solvent-freeconditions

Entry Product Timea (min) Yieldb (%)

1 N

N

O

ON

NOO

H3C

Ph

CH3

CH3

5a

5 94

2 NH

NH

O

ON

NO O

H3C

Ph

5b

5 92

3 NH

NH

O

SN

NO O

H3C

Ph

5c

10 92

4 O

O

O

NN OO

H3C

Ph

CH3

CH3

5d

7 89

Table 6 (continued)

Entry Product Timea (min) Yieldb (%)

5N

N

H3C

Ph

O

O

O

5e

7 92

6N

N

O

ON

N O

NO2

O

H3C

Ph

CH3

CH3

5f

5 94

7NH

NH

O

ON

NO

NO2

O

H3C

Ph

5g

7 92

8NH

NH

O

SN

N O

NO2

O

H3C

Ph

5h

7 90

2614 Z. N. Siddiqui, S. Tarannum / Tetrahedron Letters 55 (2014) 2612–2617

Table 6 (continued)

Entry Product Timea (min) Yieldb (%)

9O

O

O

NN O

NO2

O

H3C

Ph

CH3

CH3

5i

5 90

10

NN

H3C

Ph

O

O

O

NO25j

8 93

11N

N

O

ON

NO

OCH3

O

H3C

Ph

CH3

CH3

5k

7 92

12NH

NH

O

ON

NO

OCH3

O

H3C

Ph

5l

10 90

13NH

NH

O

SN

NO

OCH3

O

H3C

Ph

5m

10 88

14O

O

O

NN

O

OCH3

O

H3C

Ph

CH3CH3

5n

7 88

Table 6 (continued)

Entry Product Timea (min) Yieldb (%)

15

NN

H3C

Ph

O

O

O

OCH35o

5 90

16N

N

O

ON

N O

Cl

O

H3C

Ph

CH3

CH3

5p

8 92

17

NH

NH

O

ON

N O

Cl

O

H3C

Ph

5q

10 90

18NH

NH

O

SN

N O

Cl

O

H3C

Ph

5r

10 88

19O

O

O

NN O

Cl

O

H3C

Ph

CH3

CH3

5s

10 90

20

NN

H3C

Ph

O

O

O

Cl

5t

7 92

a Reaction progress monitored by TLC.b Isolated yield.

Z. N. Siddiqui, S. Tarannum / Tetrahedron Letters 55 (2014) 2612–2617 2615

5 5 5 5 5 5

94 94 93 91 90 88

0

20

40

60

80

100

1 2 3 4 5 6

Yiel

d %

No. of Cycles

Time (min) Yield (%)

Figure 1. Recyclability of the catalytic system.

2616 Z. N. Siddiqui, S. Tarannum / Tetrahedron Letters 55 (2014) 2612–2617

(entry 2). Employing acidic, basic and neutral alumina as supportsthe product yield was moderate to good and reaction proceededsluggishly (entries 3–5). Using titania (TiO2), the yield of productwas again unsatisfactory (entry 6).

Different loadings of TsOH on silica support (10%, 12%, 15%, 20%and 25% w/w of TsOH supported on SiO2) were also investigated forthe model reaction (Table 4). The data revealed that with 20% w/wTsOH-SiO2 maximum yield of the product (94%) was obtained in ashorter time period (entry 4). Further, increase in the loading ofTsOH had no effect on the yield of the product (entry 5).

Different amounts of the TsOH-SiO2 catalyst were also exam-ined (10, 20, 30, and 40 mg) to get optimum reaction condition(Table 5). The results showed 30 mg as the optimal quantity of cat-alyst to obtain the best yield (entry 3).

Considering the above optimistic results, in the present investi-gation, the catalytic activity of TsOH-SiO2 was evaluated for thesynthesis of novel alkenyl pyrazole derivatives via Knoevenagelcondensation. For Knoevenagel condensation, aldehydes (3a–d)were obtained by reaction of 5-chloro-3-methyl-1-phenylpyra-zole-4- carbaldehyde (1) and phenols (2a–d) in DMF/KOH. All pyr-azole-4-carbaldehydes (3a–d) underwent smooth condensationwith cyclic active methylene compounds (4a–e) to afford alkenederivatives (5a–t) in excellent yields (Scheme 1).

This general methodology allowed convenient synthesis of al-kenes. The influence of the electronic nature of the aryl substitu-ents in the aldehydes was explored by the use of differentaryloxy substituted aldehydes. It was found that all the reactionsproceeded smoothly with both electron-withdrawing and elec-tron-releasing substituents (Table 6). The structural assignmentof all novel compounds (5a–t) was done by elemental and spectro-scopic data (IR, NMR and MS). The IR spectrum of the newly syn-thesized compound (5a) exhibited a strong absorption band at1646 cm�1 for the carbonyl group of 1,3-dimethyl pyrimidinetri-one. The proton nuclear magnetic resonance spectroscopy exhib-ited sharp singlets at d 2.28, 3.14 and 3.19 for the methyl groupof the pyrazole moiety and two methyl groups of 1,3-dimethyl pyr-imidinetrione respectively. The olefinic proton was discernible as asinglet at d 8.22. Ten aromatic protons (phenyl groups of pyrazolemoiety) were discernible as multiplets in the aromatic region d6.90–7.93. The 13C NMR spectrum showed signals at d 161.20and 28.13 for carbonyl and methyl group of 1,3-dimethyl pyrimi-dinetrione respectively. Other carbon signals appeared at theirappropriate positions and are discussed in Supplementary infor-mation. Further, evidence for the formation of 5a was obtainedby mass spectrum which showed a molecular ion peak at m/z416 (M+).

In order to investigate the reusable properties of TsOH-SiO2 forthe synthesis of 5a, recycling experiments were conducted usingthe model reaction and the results are shown in Fig. 1. After com-pletion of the reaction, the catalyst was washed with ethyl acetate(3 � 5 mL), dried under vacuum at 70 �C for 4 h and then reused.After the recyclability experiment, the catalyst was analysed byX-ray diffraction and SEM analyses (Figs. 2b and 4, Supplementarydata). The SEM image and XRD indicated that there was only a

negligible change in the morphology of the catalyst up to six con-secutive cycles.

In conclusion, a library of novel alkenyl pyrazole derivatives hasbeen synthesized employing tosic acid supported on silica gel asgreen catalyst in Knoevenagel condensation. This method offersseveral advantages including enhanced reaction rates, ease ofhandling, easy availability of the reagents at low cost, simplicityof work-up procedure and recyclability of catalyst which make ita beneficial and attractive synthetic strategy.

Acknowledgements

UGC, New Delhi, is gratefully acknowledged for awardingresearch fellowship to S.T., Special Assistance ProgrammeScheme (Departmental Research Support Phase 1) and DST (FIST,PURSE). The authors are thankful to the Centre of Nanotechnology,Department of Applied Physics and University SophisticatedInstrument Facility (USIF), AMU, Aligarh for providing powderX-Ray diffractometer and SEM–EDX facilities. The authors wouldalso like to thank SAIF, Punjab University, Chandigarh for providingspectral data.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.122.

References and notes

1. Jones, G. In Organic Reactions; Wiley: New York, 1967; Vol. XV,; p 2042. Tietze, L. F.; Beifuss, U. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,

I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 341.3. Tietze, L. F. Chem. Rev. 1996, 96, 115.4. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2007, 48, 785.5. Bose, D. S.; Narsaiah, A. V. J. Chem. Res. (S) 2001, 36.6. Reddy, T. I.; Verma, R. S. Tetrahedron Lett. 1997, 38, 1721.7. Zhao, S.; Wang, X.; Zhang, L. RSC Adv. 2013, 3, 11691.8. Bennazha, J.; Zahouilly, M.; Boukhari, A.; Holt, E. M. J. Mol. Catal. A: Chem. 2003,

202, 247.9. Bharate, S. B.; Mudududdla, R.; Bharate, J. B.; Battini, N.; Battula, S.; Yadav, R. R.;

Singh, B.; Vishwakarma, R. A. Org. Biomol. Chem. 2012, 10, 5143.10. Sebti, S.; Smahi, A.; Solhy, A. Tetrahedron Lett. 2002, 43, 1813.11. Khan, F. A.; Dash, J.; Satapathy, R.; Upadhyaya, S. K. Tetrahedron Lett. 2004, 45,

3055.12. Bartoli, G.; Beleggia, R.; Giuli, S.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.;

Paoletti, M. Tetrahedron Lett. 2006, 47, 6501.13. Kiamehr, M.; Moghaddam, F. M. Tetrahedron Lett. 2009, 50, 6723.14. Shanmuganathan, S.; Greiner, L.; de Maria, P. D. Tetrahedron Lett. 2010, 51,

6670.15. Khurana, J. M.; Vij, K. Tetrahedron Lett. 2011, 52, 3666.16. Shindalkar, S. S.; Madje, B. R.; Hangarge, R. V.; Patil, P. T.; Dongare, M. K.;

Shingare, M. S. J. Korean Chem. Soc. 2005, 49, 377.17. Gupta, R.; Gupta, M.; Paul, S.; Rajive, G. Bull. Korean Chem. Soc. 2009, 30, 2419.18. Vijender, M.; Kishore, P.; Satyanarayana, B. Arkivoc 2008, xiii, 122.19. Polshettiwar, V.; Len, C.; Fihri, A. Coord. Chem. Rev. 2009, 253, 2599.20. Ansari, M. I.; Hussain, M. K.; Yadav, N.; Gupta, P. K.; Hajela, K. Tetrahedron Lett.

2012, 53, 2063.21. Veisi, H. Tetrahedron Lett. 2010, 51, 2109.22. Siddiqui, Z. N.; Ahmed, N. Appl. Organometal. Chem. 2013, 27, 553.23. Rostamizadeh, S.; Amani, A. M.; Shadjou, N. Phosphorus, Sulfur Silicon 2012, 187,

238.24. Siddiqui, Z. N.; Khan, T. Catal. Sci. Technol. 2013, 3, 2032.25. Chakrabarty, M.; Mukherjee, R.; Karmakar, S.; Harigaya, Y. Monatsh. Chem.

2007, 138, 1279.26. Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2007, 48, 5181.27. Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. J. Org. Chem.

2009, 74, 4009.28. Borah, K. J.; Phukan, M.; Borah, R. Synth. Commun. 2008, 38, 3082.29. Kumar, D.; Sonawane, M.; Pujala, B.; Jain, V. K.; Bhagat, S.; Chakraborti, A. K.

Green Chem. 2013, 15, 2872.30. Dewangan, D.; Kumar, T.; Alexander, A.; Nagori, K.; Tripathi, D. K. CPR 2011, 1,

369.31. Cavero, E.; Uriel, S.; Romero, P.; Serrano, J. L.; Gimenez, R. J. Am. Chem. Soc.

2007, 129, 11608.32. Catalan, J.; Fabero, F.; Claramunt, R. M.; Maria, M. D. S.; Foces-Foces, M. C.;

Cano, F. H.; Martinez-Ripoll, M.; Elguero, J.; Sastre, R. J. Am. Chem. Soc. 1992,114, 5039.

Z. N. Siddiqui, S. Tarannum / Tetrahedron Letters 55 (2014) 2612–2617 2617

33. Ye, C.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley, B.; Shreeve, J. M. Org.Lett. 2007, 9, 3841.

34. General procedure for the preparation of products 5a–t. A mixture of 5-aryloxy-3-methyl-1-phenylpyrazole-4-carbaldehydes 3a–d (10 mmol), activemethylene compounds 4a–e (10 mmol), and 0.3 g of TsOH-SiO2 (20% w/w)

was heated at 70 �C. Upon completion of the reaction (as confirmed by TLC) thereaction mixture was cooled to room temperature and ethyl acetate (5 mL) wasadded. The reaction mixture was filtered to remove the catalyst andconcentrated to furnish products 5a–t which was further purified byrecrystallization with suitable solvents.