Asian J. Research Chem. 2(4): Oct.-Dec.

2009

ISSN 0974-4169 RESEARCH ARTICLE

www.ajrconline.org

Facile and Efficient Oxidation of Sulfides to Sulfoxides Using Oxone and its Biological Evaluation
1

Department of Pharmaceutical Chemistry, Satara College of Pharmacy, Plot No. 1539, New Add MIDC, Degaon, Satara, Maharashtra 415 004 2 Parul College of Pharmacy, Vadodara, Gujarat *Corresponding Author E-mail: nsmahajan17@gmail.com

NS Mahajan1*, RL Jadhav1, KK Mali1, NV Pimpodkar1 and AM Manikrao2

ABSTRACT

A green highly sensitive oxidation of organic sulfides, N-substituted- - (4-phenyl-2-thiazolyl) thio-alkyl/aryl acetamides (I) to the corresponding sulfoxides (II) was developed employing solid-state condition by using Oxone. The synthesized compounds were confirmed by using elemental analysis and spectral data. These synthesized compounds were tested for their antibacterial and antifungal activities. None of them were found to possess any promising activity. This oxidation system is found clean, safe and operationally simple, environmental friendly and for these reasons meets the needs of contemporary green chemistry and is suitable for practical synthesis.

KEYWORDS: Antibacterial activity, antifungal activity, Oxone, oxidation.

The growth in the chemistry of organic sulfoxides during last decade was due to their importance as synthetic intermediates for the production of wide range of chemically and biologically active molecules. They often perform a major function as therapeutic agents such as antiulcer1 (proton pump inhibitor), antibacterial, antifungal, anti-atherosclerotic2, Antihypertensive3 and cardiotonic agents4, as well as psychotonics5 and vasodilators.6 The oxidation of sulfides to sulfoxides is the most straightforward synthetic route to the latter, and numerous reagents and oxidative procedures are available for this transformation. However, many of them cause overoxidation to the corresponding sulfones. Therefore, control of the reaction conditions, that is, time, temperature and the relative amount of oxidants, plays an important role in avoiding the formation of oxidation side products, but this is often hard to achieve and therefore there is still considerable interest in the development of selective oxidants for this transformation.7-12

INTRODUCTION:

A. R. Hajipour13 reported the solid-state oxidation method for the synthesis of sulfoxides by using Oxone (potassium peroxymonosulfate). This data instigated us to synthesize sulfoxides through solid-state synthesis and evaluate them for their antibacterial and antifungal activities. The final compounds obtained by said method were characterized by using elemental analysis and spectral data. All the melting points were determined by open capillary method in liquid paraffin bath. All the solvents were used after distillation. Oxone, aluminum chloride was purchased from S.D. Fine Chemicals, Mumbai. Silica gel G Plates (3x8cm) were used for TLC and spots were located by iodine vapors in a chamber. Column chromatography was performed on a neutral alumina column (2.5x45cm) using appropriate eluent. The IR spectra (KBr/nujol) were recorded on PERKINELMER FT-IR spectrometer and the values expressed in cm-1. 1H NMR spectra (in CDCl3) were taken on Brooker AC 200 MHz FT using TMS as an internal reference compound.

MATERIAL AND METHODS:

Received on 11.04.2009 Accepted on 09.07.2009

Asian J. Research Chem. 2(4):Oct.-Dec. 2009 page 407-410

Modified on 05.06.2009 AJRC All right reserved

407

Asian J. Research Chem. 2(4): Oct.-Dec. 2009

A. General Method of Preparation: A mixture of the appropriate sulfide (I) (1.72 mmoles), Oxone (2.4 g, 3.96 mmoles) and aluminum chloride (AlCl3) (0.22 g, 1.7 mmoles) was ground with pestle and mortar for 0.5 hr, and the product was taken up in dichloromethane (3 x 10 ml). The solution was washed with aqueous 20% sodium bicarbonate (NaHCO3) and water and then the solvent was evaporated. The product sulfoxide obtained (II) was >95% pure as found by TLC and 1H NMR analysis. The physicochemical characteristics and spectral data of various compounds II (a-f) are given in Table 1 and Table 2 respectively. B. Antibacterial and Antifungal Activities: The antibacterial and antifungal activities were performed by cup plate method.14-15 Base layer was obtained by pouring about 10-15 ml of the base layer medium into each previously sterilized petri dish and were allowed to attain room temperature. The overnight grown subculture was mixed with seed layer medium and about 10-15 ml of this medium was poured over the base layer and allowed to attain room temperature. The cups were made by scooping out agar with previously sterilized cork borer. The solutions of test compounds (concentrations 100 g/ml and 150 g/ml) were added in the cups by using pipettes. These plates were subsequently incubated at 370C for 48 hours. Inhibitory activity was measured (in mm) as the diameter of the observed inhibition zones for each organism. The tests were repeated to confirm the findings and average of the readings was taken into consideration. The figures obtained are reported as the mean of three readings.

of them found to have any promising activity. The data of antibacterial screening is given in Table 3 while data of antifungal screening is given in Table 4.

The purpose of this work was to synthesize various sulfoxides from the corresponding sulfides with great purity, high yields and environmental friendly way. This was achieved with good success by above described method. Much of the current work in the area of synthesis of sulfoxides from sulfides focuses on the use of transition metal catalyzed processes.16-20 However, a large number of such oxidation reactions often require the use of toxic metal reagents or catalysts. Consequently, from a Green Chemistry standpoint it is very important to develop a green oxidation system for chemical manufacturing. Oxone was proved as an ideal green oxidant due to its strength and lack of toxic by-products. The traditional reagents used in oxidation of sulfides to sulfoxides gave mixture of the corresponding sulfoxides and sulfones and also operating condition was difficult. These problems associated with the mostly used oxidants were successfully overcome by using this simple, effective and efficient solid-state oxidation method using Oxone. The procedure described above for the solid-state synthesis of the sulfides to sulfoxides by using Oxone proved extremely useful. The oxidations of the sulfides to the corresponding sulfoxides gave high and excellent yields of the products.

RESULTS AND DISCUSSION:

The synthesized compounds were evaluated for both antibacterial and antifungal activities. None of the above compounds showed any promising antibacterial and antifungal activities at 100 g/ml and 150 g/ml All the newly synthesized compounds II (a-f) were screened concentrations as compared with norfloxacin and for antibacterial activity against P.aeuroginose, E.coli and griseofulvin respectively. S. aureus and for antifungal activity against C. albicans and A. niger at 100 g/mL and 150 g/mL concentration using norfloxacin as reference standard for antibacterial activity. Griseofulvin was used as reference standard for antifungal activity and dimethylformamide (DMF) as a control for both the activities. Almost all the compounds II (a-f) exhibited moderate activity against said organisms but none

O xone
2 eq N SC H 2 -C O -N R R ' S 1 eq

A lC l 3

N S S

O C H 2 -C O -N R R '

Where, (a) R=H; R=C6H5, (b) R=H; R=C6H4Cl(p), (c) R=H; R=CH2C6H5, (d) R=H; R=n-C3H7, (e) R R= Pyrolidine-1-yl, (f) R R= Morpholine 1-yl.

II

408

Asian J. Research Chem. 2(4): Oct.-Dec. 2009 Table 1. Physicochemical data II (a-f)

N S S
Comp II a II b II c II d II e II f R H H H H R -C6H5 p-C1-C6H5 -CH2-C6H5 n-C3 H7
0

O CH2-CO-NRR'
Mol Formula C17 H14 N2 O2S2 C17 H13N2 O2S2 Cl C18 H16N2 O2S2 C14H16N2 O2S2 C15H16N2 O2S2 C15H16N2 O3S2 Elemental analysis Calc% Found % C H N 59.65 4.09 8.19 59.00 4.23 8.35 54.18 3.45 7.44 54.20 3.21 7.43 60.67 4.49 7.87 61.08 4.01 8.00 54.55 5.19 9.09 53.25 4.95 9.10 56.25 5.00 8.75 55.55 4.85 8.92 53.57 4.76 8.33 53.00 4.85 8.48

M.P. C 110-112 125-127

Yield % 97 96 97 98 95 95

Nature Off White needles Off White shining needles Off White shining needles Off White flakes Off White granules Off White granules

124-126 90-92 148-150 171-173

RR=Pyrolidine-1-yl RR=Morpholine-1-yl

Table 2. Spectral data II (a-f)

N S
IR Cm -1 KBr N=H C=O 3273 3278 3320 3542 & 3306 __ __ 1669 1670 1656

O CH2-CO-NRR'
SO 1036 1040 1038
1

S
C= N 1562 1560 1542 ArH

Comp II a II b II c

R H H H

R -C6H5 p-C1- C6H5 -CH2C6H5

HNMR (ppm) CDC13

699 & 759 730 & 750 715 & 735

II d II e II f

n-C3 H7

1649 1645 1649

1566 1565 1568

700 & 738 699 & 742 695 & 745

1041 1044 1045

RR= Pyrolidine-1-yl RR= Morpholine-1-yl

10.40(s, 1H,NH); 8.10 (d, 1H, 5-H); 7.70-7.39 (m, 10H, 2XC6H5); 4.10 (s, 2H,S-CH2). 10.40(br s, 1H,NH); 8.10 (d, 1H, 5-H); 7.70-7.35 (m, 9H,Ar-H); 4.1(s, 2H,S-CH2). 7.95(br s, 1H,NH); 7.80 (d, 1H, 5-H); 7.547.30(m, 10H, 2xC6-H5); 4.60 (d, 2CH2,of Benzyl); 4.10 (s, 2H,S-CH2). 8.00 (d, 1H, 5-H); 7.65-7.43 (m, 6H,C6-H5+ NH); 3.99 (s, 2H,S-CH2); 3.35 (q, 2H,NH-CH2); 1.55 (sext, 2H, -CH2-of n-propyl); 0.89 (t, 3H, -CH3 of n-propyl) __ __

Table 3. Antibacterial activity of compounds II (a-f) Zone of inhibition in millimeter (mm) Comp. R R P.aeuroginose S.aureus 100 g/ml 150 g/ml 100 g/ml II a H -C6 H5 15 19 29 II b H p-C1-C6 H5 15 19 28 II c H -CH2 - C6 H5 16 20 28 II d H n-C3H7 17 21 29 II e RR= Pyrolidine -1-yl 19 24 30 II f RR= Morpholine -1-yl 19 24 33 Standard Norfloxacin 20 25 35

150 g/ml 31 32 31 32 35 36 40

E.coli 100 g/ml 10 11 12 11 13 13 15

150 g/ml 14 15 16 13 17 18 20

409

Asian J. Research Chem. 2(4): Oct.-Dec. 2009 Table 4. Antifungal activity of compounds II (a-f) Comp. II a II b II c II d II e II f Standard R R

H -C6 H5 H p-C1-C6 H5 H -CH2 - C6 H5 H n-C3H7 RR= Pyrolidine - 1-yl RR= Morpholine - 1-yl Griseofulvin

Zone of inhibition in millimeter (mm) C.albicans A.niger 150 g/ml 100 g/ml 100 g/ml 23 25 22 25 27 23 26 29 24 28 31 23 30 33 27 31 34 31 35 38 33

150 g/ml 24 27 27 26 30 34 37

CONCLUSION:

9. 10.

As shown, the proposed synthetic scheme was found to be a selective method for the oxidation at room temperature of sulfides to the corresponding sulfoxides. This oxidation system is clean, safe and operationally simple and yields of the products are high. So, this solid state oxidation method meets the needs of contemporary green chemistry and is suitable for practical synthesis.

11.

REFERENCES:
1. 2. 3. 4.

5. 6.

7. 8.

Lai SKC, et al. Lansoprazole for the Prevention of Recurrences of Ulcer Complications from Long-Term LowDose Aspirin Use. New Eng J Med 2002; 346: 2033-38. Sovova M and Sova P. Pharmaceutical Significance of Allium sativum L. Antifungal effects. Ceska Slov Farm 2003; 52: 82-87. Kotelanski B, Grozmann RJ and Cohn JNC. Positive Inotropic Effect of Oral Esproquin in Normal Subjects. Pharmacol Ther 1973; 14: 427-433. Schmied R, Wang GX and Korth M. Intracellular Na+ Activity and Positive Inotropic Effect of Sulmazole in Guinea Pig Ventricular Myocardium: Comparison with a Cardioactive Steroid. Circ Res 1991; 68: 597-604. Nieves AV and Lang AE. Treatment of Excessive Daytime Sleepiness in Patient with Parkinsons disease with Modafinil. Clin Neuropharmacol 2002; 25: 111-114. Padmanabhan S, Lavin RC and Durant GJ. Asymmetric Synthesis of a Neuroprotective and Orally Active N-methylD-aspartate Receptor Ion-Channel Blocker: CNS 5788. Tetrahedron Asymmetr 2000; 11: 3455-3645. Kaczorowska K, et al. Oxidation of Sulfides to Sulfoxides. Part 2: Oxidation by Hydrogen Peroxide. Tetrahedron 2005; 61: 8315-8327. Wang SH, et al. Catalytic Sulfoxidation and Epoxidation with a Mn (III) triazacorrole: Evidence for a "Third oxidant" in Highvalent Porphyrinoid Oxidations. J Am Chem Soc 2004; 126: 18-19.

12. 13. 14. 15. 16.

17. 18. 19. 20.

Al-Hashimi M, et al. Selective Oxidations of Sulfides to Sulfoxides Using Immobilized Cerium Alkyl Phosphonate. Tetrahedron Lett 2005; 46: 4365-4398. Venkataramanan NS, Kuppuraj G and Rajagopal S. Metalsalen Complexes as Efficient Catalysts for the Oxygenation of Heteroatom Containing Organic Compounds: Synthetic and Mechanistic Aspects. Coord Chem Rev 2005; 249: 12491268. Du GD and Espenson JH. Oxidation of Triarylphosphines and Aryl Methyl Sulfides with Hydrogen Peroxide Catalyzed by Dioxovanadium (V) ion. Inorg Chem 2005; 44:24652471. Velusamy S, et al. Copper Catalyzed Oxidation of Sulfides to Sulfoxides with Aqueous Hydrogen Peroxide. Tetrahedron Lett 2005; 46: 3819-3822. Hajipour AR. Solid State Oxidations of Aromatic Sulfides to the Corresponding Phenyl and p-tolyl Sulfoxides and Sulfones Using Oxone. Ind J Chem 1997; 36B: 1069-1070. Seeley HW and Van Denmark PJ. Microbes in Action: A Laboratory Manual of Microbiology. 2nd ed. New York: Academic Press; 1975. p. 55. Kavangh FC. Analytical Microbiology. 1st ed. Academic Press, New York.1944; p.125. Shulpin GB, Suss-Fink G and Shulpina LS. Oxidations by the System, Hydrogen Peroxide Manganese (IV) ComplexCarboxylic Acid: Part 3. Oxygenation of Ethane, Higher Alkanes, Alcohols, Olefins and Sulfides. J Mol Catal A: Chem 2001; 170:17-34. Shabani A, Lee DG. Solvent Free Permanganate Oxidations. Tetrahedron Lett 2001; 42: 5833- 5838. Barker JE and Ren T. Facile Oxygenation of Organic Sulfides with Hydrogen Peroxide Catalyzed by Mn- Me (3) TACN Compounds. Tetrahedron Lett 2004; 45: 4681-4685. Mirkhani V, et al. Efficient Oxidation of Sulfides with Sodium Periodate Catalyzed by Manganese (III) Schiff Base Complexes. J Mol Catal A: Chem. 2005; 242: 251-255. Okun NM, et al. Highly Reactive Catalysts for Aerobic Thioether Oxidation - The Fe-substituted Polyoxometalate/ Hydrogen Dinitrate System. J Mol Catal A: Chem 2006; 246:11-17.

410