Polyvinylsulfonic acid: An Efficient and Recyclable

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coumarins. This method involves the reaction between phenol with β-keto ester in the presence of an acidic catalysts as well as chloroaluminate ionic liquids.

International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

_________________________________________Research Article

Polyvinylsulfonic acid: An Efficient and Recyclable Bronsted Acid Catalyst for Pechmann Condensation B. Suresh Kuarm1, Peter. A. Crooks2 and B. Rajitha1* 1Department

of Chemistry, National Institute of Technology, Warangal, Andhra Pradesh,

India. 2Department

of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for

Medical Sciences, Little Rock, AR, USA. __________________________________________________________________________________ ABSTRACT An efficient, mild and environmentally friendly method has been developed for the Pechmann condensation to synthesize coumarins in the presence of Polyvinylsulfonic acid as a catalyst. The one-pot condensation of phenols and ethyl acetoacetates proceeded smoothly under solvent free conditions to afford the corresponding product in high yield with short reaction times. The catalyst could be easily recycled. Key Words: Polyvinyl sulfonic acid(PVSA), Pechmann condensation, coumarins. INTRODUCTION Coumarins have been extensively investigated and widely used but still generate much interest. Coumarins are structural units of several natural products and feature widely in pharmacologically and biologically active compounds 1. Many coumarins and its derivatives exhibit high level of biological activity 2. Besides functionalized coumarins 3, polycyclic coumarins such as calanolides 4, isolated from Calophyllum genus, others have shown potent anticancer, 5 and antiHIV (NNRTI) activity 6. Coumarins have been synthesised by several methods, including Pechmann, Perkin, Knoevenagel, and Wittig reactions. The Pechmann reaction is the most widely applied method for synthesising coumarins as it involves the condensation of phenols with βketonic esters in the presence of a variety of acidic condensing agents and gives good yields of coumarins. This method involves the reaction between phenol with β-keto ester in the presence of an acidic catalysts as well as chloroaluminate ionic liquids. The main disadvantages of the processes using these catalysts are, longer reaction time, large amount of the catalyst, tedious purification process after completion of the reaction and some of the catalysts are highly expensive, some of the existing methods are that the catalysts are destroyed in the work-up procedure and cannot be recovered or re-used. These shortcomings surely insist for a safe, eco-friendly and efficient method. Hence it is highly essential to develop, ecofriendly, green synthesis of coumarins.

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Recently, the direction of science and technology has been shifting more towards eco-friendly, and reusable catalysts. Polyvinylsulfonic acid is known since several decades; however its catalytic activities were not studied so far. Polyvinylsulfonic acid (PVSA) is an excellent candidate for exploration of Brønsted acid based organic transformations. We herein report PVSA as a novel Brønsted acid catalyst for the synthesis of coumarins (Scheme 1). Polyvinylsulfonic acid (PVSA) is a strong aliphatic polymeric sulfonic acid and has high solubility in water and lower alcohols 7-9. EXPERIMENTAL The progress of the reaction was monitored by TLC and visualized with UV light. IR spectra (KBr) were recorded on Shimadzu FTIR model 8010 spectrometer and the 1H NMR spectra was measured on a Varian Gemini 200-MHz spectrometer using TMS as internal standard. The C, H, and N analysis of the compound was done on a Carlo Erba model EA1108. Mass spectra were recorded on a Jeol JMS D-300 spectrometer. PVSA was prepared according to the reported procedure. 10

Preparation and characterization of PVSA PVSA was prepared in two steps using Breslow’s method 11. In the first step, sodium vinylsulfonate was polymerized to sodium salt of polyvinylsulfonic acid (Na-PVSA), average molecular weight was found to be ~55,000 by specific viscosity measurement. Free acid (PVSA) was prepared by ion exchange technique. The pH

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ISSN: 2229-3701

International Journal of Research in Pharmaceutical and Biomedical Sciences

of 0.01 N PVSA solution was checked and found to be 2.83. Na-PVSA a precursor of PVSA was characterized by XRD, DSC and FT-IR techniques. XRD profile showed absence of sharp peaks, conforming amorphous nature of Na-PVSA. DSC thermograph showed thermal stability of Na-PVSA up to 350 oC, however peak at 92.6 oC was observed due to removal of water molecule from hydrated Na-PVSA. FT-IR spectrum of Na-PVSA showed a medium band at 724 cm-1 which is assigned to polymeric methylene group (–CH2–). The intense peak at 1189 cm-1 is attributed to sulphonate group. The band at 1448 cm-1 is assigned to CH2 bond deformation. The intense peak at 1673 cm-1 is attributed to in-plane deformation of water molecule. The band at 2924 cm-1 is due to CH2 stretching vibration. Stretching vibration of –OH group of water molecule is a broad band and observed at about 3441 cm-1. Thus from the above spectra formation of Na salt of polyvinylsulfonic acid is confirmed. General procedure for synthesis of coumarins A mixture of the phenol 1 (1 mmol), β-ketoester 2 (1 mmol) and polyvinylsulfonic acid (10 mol%) was stirred at room temperature under solvent free condition for the appropriate time according to (Table 1). Completion of the reaction was confirmed by TLC. After completion of reaction, water (5 ml) was added to the reaction mixture and stirred for 2 min, filtered and recrystallized from ethanol to afford corresponding products in good yields. After filtration, the filtrate (water) containing the catalyst could be evaporated under reduced pressure and the recovered catalyst was reused directly for the next run. The recovered catalyst can be reused at least three additional times in subsequent reactions without significant decrease in product yield (Table 2). Spectral data (Table-3, entry-1) IR (KBr, cm-1): 3400, 1725, 1530; (CDCl3) d 2.39 (s, 3 H), 3.28 (br s, 1H), 6.06 (s, 1H), 6.8 (s, 1H), 6.82 (d, 1H), 7.44 (d, 1H) 13C

OH R

EtO

NMR (CDCl3): δ = 161.7, 159.6, 152.6, 151.80, 128.9, 113.9, 112.5, 111.5, 109.7, 22.0; EIMS (m/z) 176 (M+); Anal. Calcd for C10H8O3: C, 68.10 4.71. Found 68.18 4.55. (Table-3, entry-6): IR (KBr, cm-1): 3417, 1676, 1620, 1585, 1443, 1156, 811; 1H NMR (300 MHz, CDCl3): δ 2.37 (3H, s), 6.12 (1H, s), 6.86 (1H, d, J = 8.6 Hz), 7.11 (1H, d, J= 8.6 Hz); 13C NMR (DMSO-d6): δ161.7, 155.5, 153.3, 149.6, 145.21, 122.3, 114.2, 112.5, 110.3, 22.5; EIMS (m/z) 192 (M+); Anal. Calcd for C10H8O4: C, 62.50; H, 4.20. Found: C, 62.54; H, 4.15. RESULTS AND DISCUSSION In continuation to our quest on synthesis of coumarins by employing various catalysts. A very simple methodology has been followed in our protocol. In this synthesis, mixture of phenols and ethylacetoacetates was stirred at r.t in the presence of PVSA under solvent free conditions. The progress of the reaction was checked by TLC and after work-up the corresponding coumarins were obtained in excellent yields. The reaction between phenols with ethylacetoacetates was chosen as a probe to evaluate the catalytic activity of PVSA. An increase in the quantity of the catalyst up to 10 mol % not only increased the yield but also reduced the reaction time. Considerably, our studies clearly indicate that even 10 mol % of PVSA was sufficient to catalyze the reaction efficiently to produce high yield (95%) within very short reaction time (Table-3). Therefore, the catalyst loading was optimized to 10 mol % for further reactions. It seems noteworthy to mention that the reaction was not successful in the absence of the catalyst. A screening of the solvents was also carried out under similar reaction conditions. Solvents such as dichloromethane, toluene, THF, acetonitrile, ethanol and water were used to study the reaction as well as under solvent free conditions. The results have been summarized in Table 4. The yields of the reactions under solvent free conditions were comparable to that in water but under solvent free conditions the reaction was much faster.

O Polyvinyl sulfonic acid

O

O

neat, R.T R1

1

O

R R1

2

3 Scheme-1

Scheme 1: Synthesis of coumarins using Polyvinyl sulfonic acid

Vol. 3 (1) Jan – Mar 2012

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

Table-1: Polyvinyl sulfonic acid catalyzed synthesis of coumarins Entry

Phenol

HO

1

Ester

O

OH

Coumarin

O

HO

O

O

OEt

Time (hr)

Yield (%)a

20

95

25

93

25

91

35

93

30

92

30

94

25

93

30

94

25

93

30

90

M. P(oC)

185

CH3 HO

2

OH

O

HO

O

Cl

O

O

180

OEt CH2Cl

HO

3

O

OH

O

HO

Ph

O

O

OEt

257

Ph HO

4

OH

O

HO

O

O

O

OEt

HO

5

HO

OH

O

OEt

O

187

OH CH2Cl

OH

OH

OH HO

O

O

Cl

6

280

OH CH3

OH

O

OH

HO

O

O

O

OEt

242

CH3 OH HO

7

OH

O

OH

O

Cl

HO

O

O

OEt

134

CH2Cl HO

8

O

OH

HO

O

O

264

O

OEt CH3 O

OH O

9

O

O OEt

153

OH O

10

O

O

O

OEt CH3

81

a

Yields refer to pure products and all products were characterized by comparison of their physical data and in 1H NMR, IR, and mass spectral data with those authentic samples.

Table 2: Results of recyclability of the Polyvinyl sulfonic acida Run 1 2 3 4

Cycle 0 1 2 3

Time (min) 20 20 20 20

Yield (%) 95 93 89 81

a

Reaction conditions: Resorcinol (1 mmol), EAA (1 mmol), Polyvinyl sulfonic acid (10 mol %) stirred at room temperature under solvent free conditions.

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

Table 3: Influence of the catalytic amounts of Polyvinyl sulfonic acida Entry 1 2 3 4 5 6

Catalyst (mol %) None 1 5 10 10 15

Time (min) 90 20 20 20 40 20

Yield (%)b Trace 25 66 95 95 95

a

Reaction conditions: Resorcinol (1 mmol), EAA (1 mmol), Polyvinyl sulfonic acid (10 mol %) stirred at room temperature under solvent free conditions. b Isolated yields.

Table 4: Effect of various solvents a Entry 1 2 3 4 5 6

Solvent Neat Dichloroethane Toluene Acetonitrile Ethanol Water

Yieldb (%) 95 65 76 55 85 91

a

Reaction conditions: Resorcinol (1 mmol), EAA (1 mmol), Polyvinyl sulfonic acid (10 mol %) stirred at room temperature under solvent free conditions. b Isolated yields.

CONCLUSION In summary, we have developed a clean and environmentally friendly method for the one-pot synthesis of coumarins via Pechmann condensation of Phenols with Ethylacetoacetates using Polyvinyl sulfonic acid as an efficient and recyclable catalyst in good to excellent yields with relatively short reaction times at room temperature. ACKNOWLEDGMENT B.S.K is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for providing financial support in the form of a CSIRSRF award. REFERENCES 1. O’Kennedy R and Thornes RD. Coumarins: Biology, Applications and Mode of Action, Wiley and Sons, Chichester, 1997. 2. Murray RDH, Mendez J and Brown SA. The Natural Coumarins, Occurrence, Chemistry and Biochemistry, Wiley, New York, 1982. 3. Singer LA and Long NP. Vinyl Radicals. Stereoselectivity in Hydrogen Atom Transfer to Equilibrated Isomeric Vinyl Radicals J Am Chem Soc 1996; 88: 5213. 4. Kashman Y, Gustafson KR, Fuller R, Cardellina JH, McMahon JB, Currens MJ, Buckheit RW, Hughes SH, Cragg GM and Boyd MR. HIV inhibitory natural products. Part 7. The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest

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tree, Calophyllum lanigerum. J Med Chem. 1992;35:2735. 5. Wang CJ, Hsieh YJ, Chu CY, Lin YL and Tseng TH. Inhibition of cell cycle progression in human leukemia HL-60 cells by esculetin. Cancer Lett. 2002;183:163. 6. Kirkiacharian S, Thuy DT, Sicsic S, Bakhchinian R, Kurkjian R and Tonnaire T. Structure–activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors. II Farmaco. 2002;57:703. 7. Esenberg H and Mohan GR. Aqueous Solutions of Polyvinylsulfonic Acid: Phase Separation and Specific. Interactions with Ions, Viscosity, Conductance and Potentiometry. J Phys Chem. 1959;63:671. 8. Distler H. The Chemistry of Vinylsulfonic Acid. Angew Chem Int Ed. 1965;4:300. 9. Kutner A and Breslow DS. Encyclopedia of Polymer Science and Technology, EPST, second ed., John Wiley and sons, New York, 1986. 10. Sunil SE, Anil GP, Malhari DB and Bhalchandra MB. Polyvinylsulfonic Acid as a novel Brønsted acid catalyst for Michael addition of indoles to a,bUnsaturated ketones. Catal Commun. 2009;10:1569. 11. Breslow DS and Kutner A. Use of the second virial coefficient to estimate chain Branching. J Polym Sci. 1958;17:295.

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