INTRODUCTION:

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 anti-ulcer¹ (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

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.

MATERIAL AND METHODS:

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 PERKIN-ELMER 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.

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 μg/ml and 150 μg/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.

All the newly synthesized compounds II (a-f) were screened for antibacterial activity against P.aeuroginose, E.coli and S. aureus and for antifungal activity against C. albicans and A. niger at 100 μg/mL and 150 μg/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 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.

RESULTS AND DISCUSSION:

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.

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 μg/ml and 150 μg/ml concentrations as compared with norfloxacin and griseofulvin respectively.

Where, (a) R=H; R’=C₆H_5, (b) R=H; R’=C₆H₄Cl(p), (c) R=H; R’=CH₂C₆H_5,(d) R=H; R’=n-C₃H_7,(e) R R’= Pyrolidine-1-yl, (f) R R’= Morpholine –1-yl.

Table 1. Physicochemical data II (a-f)


Comp	R	R’	M.P. ⁰ C	Yield %	Nature	Mol Formula	Elemental analysis Calc% Found %
Comp	R	R’	M.P. ⁰ C	Yield %	Nature	Mol Formula	C	H	N
II a	H	-C₆H₅	110-112	97	Off White needles	C₁₇H₁₄ N₂ O₂S₂	59.65 59.00	4.09 4.23	8.19 8.35
II b	H	p-C1-C₆H₅	125-127	96	Off White shining needles	C₁₇H₁₃N₂ O₂S₂Cl	54.18 54.20	3.45 3.21	7.44 7.43
II c	H	-CH₂-C₆H₅	124-126	97	Off White shining needles	C₁₈H₁₆N₂ O₂S₂	60.67 61.08	4.49 4.01	7.87 8.00
II d	H	n-C₃ H₇	90-92	98	Off White flakes	C₁₄H₁₆N₂ O₂S₂	54.55 53.25	5.19 4.95	9.09 9.10
II e	RR’=Pyrolidine-1-yl		148-150	95	Off White granules	C₁₅H₁₆N₂ O₂S₂	56.25 55.55	5.00 4.85	8.75 8.92
II f	RR’=Morpholine-1-yl		171-173	95	Off White granules	C₁₅H₁₆N₂ O₃S₂	53.57 53.00	4.76 4.85	8.33 8.48

Table 2. Spectral data II (a-f)


Comp	R	R’	IR Cm ^-1 KBr					¹HNMR (ppm) CDC1₃
Comp	R	R’	νN=H	νC=O	νC= N	νArH	νSO	¹HNMR (ppm) CDC1₃
II a	H	-C₆H₅	3273	1669	1562	699 & 759	1036	10.40(s, 1H,NH); 8.10 (d, 1H, 5-H); 7.70-7.39 (m, 10H, 2XC6H5); 4.10 (s, 2H,S-CH₂).
II b	H	p-C1- C₆H₅	3278	1670	1560	730 & 750	1040	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).
II c	H	-CH₂C₆H₅	3320	1656	1542	715 & 735	1038	7.95(br s, 1H,NH); 7.80 (d, 1H, 5-H); 7.54-7.30(m, 10H, 2xC6-H₅); 4.60 (d, 2CH2,of Benzyl); 4.10 (s, 2H,S-CH₂).
II d	H	n-C₃ H₇	3542 & 3306	1649	1566	700 & 738	1041	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, -CH₃of n-propyl)
II e	RR’= Pyrolidine-1-yl		__	1645	1565	699 & 742	1044	__
II f	RR’= Morpholine-1-yl		__	1649	1568	695 & 745	1045	__

Table 3. Antibacterial activity of compounds II (a-f)

Comp.	R	R^’	Zone of inhibition in millimeter (mm)
			P.aeuroginose		S.aureus		E.coli
			100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml
II a	H	-C₆H₅	15	19	29	31	10	14
II b	H	p-C1-C₆ H₅	15	19	28	32	11	15
II c	H	-CH₂ - C₆ H₅	16	20	28	31	12	16
II d	H	n-C₃H₇	17	21	29	32	11	13
II e	RR’= Pyrolidine -1-yl		19	24	30	35	13	17
II f	RR’= Morpholine -1-yl		19	24	33	36	13	18
Standard	Norfloxacin		20	25	35	40	15	20

Table 4. Antifungal activity of compounds II (a-f)

Comp.	R	R’	Zone of inhibition in millimeter (mm)
			C.albicans		A.niger
			100 μg/ml	150 μg/ml	100 μg/ml	150 μg/ml
II a	H	-C₆H₅	23	25	22	24
II b	H	p-C1-C₆ H₅	25	27	23	27
II c	H	-CH₂ - C₆ H₅	26	29	24	27
II d	H	n-C₃H₇	28	31	23	26
II e	RR’= Pyrolidine - 1-yl		30	33	27	30
II f	RR’= Morpholine - 1-yl		31	34	31	34
Standard	Griseofulvin		35	38	33	37

CONCLUSION:

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.

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