International Conference On Emerging Green Technologies(ICEGT 2011) July 27-30,2011
Synthesis of Novel Bis(indolyl)methanes(BIMs) via Green Methodology
G. S. Suresh Kumarand S. Kumaresan*
Department of Chemistry, Manonmaniam Sundaranar University, Tirunelveli, Tamilnadu, India
Abstract
An efficient and environmentally benign pathway for selective synthesis of aryl-3,3’-bis(indolyl)methanes (BIMs) from 2-methylindole and formylphenoxyalkyl esters is described here.These electrophilic aromatic substitution reactions are achieved in good yield using potash alum in water.
Keywords: Bis(indolyl)methanes (BIMs), formylphenoxyalkyl esters, alum, catalyst reusability, green methodology.
Introduction
Bis(indolyl)methanes (BIMs) and their derivatives have received more attention due to their bioactivities against human pathogens [1]. BIMs exhibit antimicrobial, antifungal, antibiotic, antibacterial, antiangiogenic, cytotoxic, antimetastatic, analgesic, anti-inflammatory etc. activity [2]. There has been a vast interest to developing newer synthetic methods for various BIMs. Syntheses of BIMs have been reviewed by Morteza Shiri et. al [3].
Hence, the development of more efficient and green methods for the preparation of these kinds of compounds is still an active on-going research area. This prompted us to initiate a systematic investigation to look into the feasibility of synthesizing BIMs applying green methodology.We have synthesized phenoxyalkyl esters of 3,3’-bis(indolyl)methane derivatives from 2-methylindole and formylphenoxyalkyl estersusing potash alum in water.
Results and discussion
Ethyl 2-(4-formylphenoxy)acetate (1a) and 2-methylindole were chosen as model substrates for the synthesis of ethyl 2-[2-{bis(2-methyl-1H-indol-3-yl)methyl}phenoxy]acetate (2a).We have compared the efficiency of different catalysts (TBATB [4a], anhydrous ZnCl2[4b], FeCl3·6H2O [4c], montmorillonite clay K-10 [4d], CAN [4e], Meldrum’s acid [4f], and potash alum [4g]) employed in the synthesis of 2a.
The results indicate that TBATB, anhydrous ZnCl2, FeCl3·6H2O, montmorillonite clay K-10, CAN, Meldrum’s acid, and potash alumcatalysts afforded better yields(76, 82, 78, 80, 63, 68, and 82% for 0.5-3.5h) of the desired product. But we observed that the above catalysts suffer demerits such as their hygroscopic nature and difficulty in recovering after reaction.Montmorillonite clay K-10 and CAN require heating under solvent-free conditions. It is difficult to recoverMeldrum’s acid after the reaction because it affords some by products. Potash alum in water is an efficient catalyst for the synthesis of phenoxyalkyl ester derivatives of BIMs due to its nonhygroscopic nature, and the ability to catalyze the reaction in water without the formation of any side product.Condensation of 2-methylindole with ethyl 2-(4-formylphenoxy)acetate(1a) using potash alumwas systematically investigated by studying the effects of the various process-parameters on the yield of BIM 2a.
The effect of water on the synthesis of 2ausing potash alum (10 mol% for 5 mmol scale) at 80 oC was studied. Volume of water was varied from 1 mL to 10 mL. The yield of 2a was 48% with 1 mL, 65% with 3 mL, 82% with 5 mL, 82% with 7 mL, and 78% with 10 mL. Lower volume of water is insufficient to dissolve the starting materials whereas an increase in water quantity increases the solubility of product leading to lesser recovery of the solid product.
We checked the effect of temperature on the synthesis of 2ausing potash alum (10 mol% for 5 mmol scale) in water (5 mL)at 30, 40, 60, 80, and 100 oC. It is obvious that at 30 oC, reaction did not proceed even after 24 h andat 40 oC, 28 % conversion was observed after 24h. The reactions proceeded slow affording lower yields, this may be due to the immiscibility of the starting materials in water. At 60, 80 and 100 oC, the yield of 2a is 68, 82 and 82 %. From this, we fixed 80 oCas the optimum temperature for these reactions.
Our attention was then focused on the possibility of catalyst reusability which was highly preferable for greener processes.After completion of the reaction, the product 2a was filtered. The effluent was washed with diethyl ether followed by ethyl acetate. Then the aqueous layer was concentrated under vacuum at 60 oC and the solid (alum) obtained was washed with acetone and dried in calcium chloride desicator. This recovered alum was used again for the same synthesis of 2a. The recovered alum gave nearly the same yield.
A wide range of formylphenoxyalkyl esters was subjected to solvent-free conditions. The results are summarized in Table 2.
Table 1 Alum catalyzed synthesis of BIMsa
Entry / Aldehyde / Reaction time (min) / Isolated Yieldb (%)2a / o-OCH2COOCH2CH3 / 2.00 / 80
2b / o-OCH2CH2COOCH2CH3 / 1.75 / 82
2c / m-OCH3, p-OCH2COOCH2CH3 / 1.00 / 88
2d / m-OCH3, p-OCH2CH2COOCH2CH3 / 0.75 / 88
2e / p-OCH2COOCH2CH3 / 1.00 / 84
2f / p-OCH2CH2COOCH2CH3 / 1.00 / 86
aThe formylphenoxyacetic/propionic acid ester (5.0 mmol) was treated with 2-methylindole (10.0 mmol) in the presence of alum (10 mol%) in water (5 mL) at 80oC.
bYield of the corresponding bis(indolyl)methanes obtained after purification.
A series of o- and p-substituted formylphenoxyalkyl esters were found to undergo electrophilic substitution reaction with 2-methylindole smoothly to afford a wide range of substituted bis(indolyl)methanes in good to excellent yields. It is interesting to note that the para- isomers of ethyl formylphenoxyacetate/propionate undergo a facile reaction leading to higher yields in short duration of time. But the corresponding ortho- esters involve higher reaction time and moderate yields of products. Steric inhibition by the ortho- substituent in the transition state may be attributed for the lower yield and prolonged reaction time.
Conclusion
In conclusion, a simple, convenient and efficient protocol for the synthesis of novel phenoxyalkyl ester of BIMs from formylphenoxyalkyl esters and 2-methylindole, using alum in water at 80 oChas been formulated. The catalytic use of alum is quite feasible because of its easy handling, easy recovery, reusability, and environmentally friendly nature.
Experiment
Synthesis of BIMs from 2-methylindole and formylphenoxyalkyl ester:
2-Methylindole (10 mmol, 2 equiv.), formylphenoxyalkyl ester (5 mmol, 1 equiv.) and alum (10 mol%) were taken in a RBF containing water (5 mL/ 5 mmol). The reaction mixture was heated at 80oC.The progress of the reaction was monitored by TLC (hexane: ethyl acetate, 4:1). After completion of the reaction, the solid formed was filtered and purified by column chromatography (hexane: ethyl acetate).
The spectral data of Ethyl 2-[2-{bis(2-methyl-1H-indol-3-yl)methyl}phenoxy] acetate (2a). Pale pink solid, 80% yield, 1H NMR (300MHz, CDCl3): 1.20 (t,3H), 2.05 (s, 6H), 4.12 (q, 2H), 4.38 (s, 2H), 6.33 (s, 1H), 6.76-7.25 (m, 12H), 7.68 (s, 2H), 13C NMR (75 MHz, CDCl3): 12.2, 14.1, 33.4, 60.9, 66.4, 109.8, 112.3, 113.3, 118.9,119.3, 120.3, 121.5, 127.2, 129.3, 130.6, 131.7, 133.3, 135.0, 156.3, 169.3, FT-IR (KBr): 3406, 3369, 1733 cm-1, ESI-MS: m/z 452.2 (M+, 10%), 451.2 (M+-H, 32%), 322.1 (M+– Indole, 100%),
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