Manganese(III) Acetate Mediated Synthesis of 3-arylsulfenylindoles and Evaluation of Their Antibacterial Activity

The present work reports a simple and efficient method for the sulfenylation of a wide variety of indoles with aryl, benzothiazolethiols using manganese(III) acetate promoted free radical reaction. This method is selective at the C3 position of indoles and offers several advantages such as broad substrate scope, functional group tolerance (bromo, carboxylic acid, methoxy, difluoromethoxy, ester groups) and gives the required products in good to excellent yields. The experimental simplicity makes it a useful and attractive approach for the synthesis of 3-arylsulfenylindoles. The compounds 1-12 are evaluated for the anti-bacterial agents. Most of them exhibited promising activities.


INTRODUCTION
Among the most important heterocyclic units indole nucleus has received major attention as a key structural building block due to their medicinal and pharmaceutical applications. 1urther 3-thioindole motifs are very common in various drugs for the treatment of heart disease, 2 allergies, 3 these are also utilized in the field of organic nonlinear optical materials. 4The following compounds such as MK-886 (III) is having antitumor activity, 5 L-737,126 (VII) is identified as a potent anti-HIV agent, 6 the 3-(arylsulfenyl)indole is able to inhibit human breast cancer cell growth, 7 vasoconstrictor tinazoline (I) is 4,5-dihydro-2-(3-indolyl) mercaptoimidazole known as a nasal decongestant 8 and acting as an alpha-adrenergic blocking drug (Figure 1).
It is planned to synthesize analogues of tinazoline by replacing the imidazole moiety with benzimidazole because compounds containing benzimidazole have numerous biological activities, for example antitumor 9 and antiparasitic 10 .Although compounds containing both indole-benzimidazoles are known to show diuretic acitivity 11 but their complete study is unexplored and hence this work targets to synthesize compounds containing both indole-benzimidazoles (or benzothiazole ) through C-S bond.
Recently, various methods are reported for the 3-arylthiolation of indoles using the various sulfenylating agents such as buntesalts, 12 disulfides, 13 sulfenyl halides, 14 and N-thioarylphthalimides. 15 Reagents such as Vanadium oxyacetylacetonate, 16 AlCl 3 17 , Selectfluor 18 , NCS 19 , oxone 20 , FeF 3 21 , (bis(trifluoroacetoxy)iodo benzene) 22 , Cu 23 and Iodine 24 , and CeCl 3 30 have been reported under different conditions.Particularly substrates substituted benzimidazolethiol and benzothiazolethiol were unexplored in the 3-arylthiolation.Therefore, the development of a simple, convenient and general methodology for the sulfenylation of indoles utilizing a stable and readily available reagent would extend the scope of this reaction and further applications of 3-arylsulfenyl indole products.
Although Mn(OAc) 3 is a good singleelectron oxidant, selective, mild oxidant and commercially available.Use of Mn(III)acetate in C-C bond construction between carbon centered radical with olefins 25 and arenes 26 was well investigated.But its applications are limited mostly in the field of sulfur-centered free radicals generating from thiols. 27The main advantage in the selection of this reagent is its moderate reactivity thereby is envisioned higher selectivity in the thioarylation.

MATERIAL AND METHODS
Initially we conducted reaction between 1H-indole and 1H-benzoimidazole thiol using Mn(OAc) 3 and tried to optimize the reaction conditions (Table 1).In the beginning, this reaction is conducted under solvent free conditions followed by preferred solvents such as water and ethanol.But good results were not observed in the reaction.Then reaction is examined with toluene, acetonitrile, THF, DMF and acetic acid 28 .Among the different solvents surveyed, better yield was observed with acetic acid and moderate yield in DMF.Acetic acid is the solvent of choice, because it has a good solubility for Mn(OAc) 3 and also giving higher yields in addition to that it degrades rapidly to harmless substances in the environment.

EXPERIMENTAL Chemistry
Melting points were determined in open capillaries and are uncorrected.IR spectra (KBr) were recorded on a Jasco, FT/IR-4100 spectrophotometer.Mass spectras were recorded on Shimadzu, LC-2010EV. 1 H NMR and 13 C NMR spectra were recorded on JEOL 400MHz and Brukar Avance 300 MHz spectrometer.TMS was used as internal reference.All the analysis data obtained at Sapala Organics Private Limited, Hyderabad.

MATERIALS AND METHODS
Manganese(III) acetate mono hydrate used for these reactions was purchased from Aldrich & Company.All the other solvents and raw materials were purchased from common suppliers.Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (60A°; Aldrich & Company), visualized under 254 nm ultraviolet Light.Column chromatography separations were performed using silica gel (70-230 mesh) obtained from the Aldrich Company.The solvents used for elution varied depending on the compound and included either one or a combination of hexane and ethylacetate.All reactions were conducted under a nitrogen atmosphere unless otherwise noted.

Typical experimental procedure for the synthesis of Compounds 1-14.
Manganese triacetate (2 mmol) is added portion wise to a pre dissolved solution of Indole (1mmol) and benzimidazolethiol (1mmol) in acetic acid (10mL) at room temperature under Nitrogen atmosphere.The reaction mixture is stirred at 80 °C for 2 hours.After completion of reaction, as monitored by T.L.C analysis, the reaction mixture was quenched by the addition of water 20 ml.The organic compounds are extracted with ethyl acetate (3x20ml).The combined layers are dried over anh.Na 2 SO 4 .The required product is purified by column chromatography, eluted with 8% methanol in DCM to get the product.The product is confirmed by 1 H, 13 C, NMR, IR and mass.

Anti-bacterial activity
The newly synthesized compounds 1 to 12 are screened for antibacterial activity against gram-positive bacterium (B.subtilis and S. aureus) and Gram-negative bacteria (P.aeruginosa, E. coli and S. typhi).Dimethyl formamide is used as solvent control.The bacterial culture was inoculated on nutrient agar (Merck & Co.) (20 mL) and poured into sterilized Petri dishes (99 mm).Media plates were inoculated with liquid cultures homogeneously by spread plate method.All the test compounds were dissolved in dimethyl formamide(DMF) to get different concentration of 100 µL and loaded into the wells of agar plates directly.Plates inoculated with the bacteria were incubated at 37 o C for 24 hours.All determinations were done in triplicates.Amoxicillin (1mg/mL) were used as standard drugs for antibacterial.
The results for antibacterial activities depicted in Table 3.It reveals most of the compounds (1, 2, 4, 6, 8, 10, 11, and 12) showing good anti-bacterial activity against E.coli.Incorporation of the ester group in the fourth position of the indole nucleus is favorable to anti-bacterial activity.Whereas the incorporation of Bromo or Methyl group on the indole nucleus is unfavorable to anti-bacterial activity.

CONCLUSION
A simple, convenient and inventive protocol for the sulfenylation of indoles using Mn(OAc) 3 reagent was developed.This method offers several advantages such as broad substrate scope, high yields and regioselectivity.The experimental simplicity makes it a valuable and elegant strategy for the synthesis of 3-sulfenyl indoles.