Bleaching Earth Catalyzed Synthesis of Bis (Indolyl) Methane’s Derivatives in (Polyethylene Glycol) PEG-400.

 

Bhaskar S. Dawane,* Santosh S. Chobe, Santosh N. Kinkar, Gajanan G. Mandawad, Omprakash S. Yemul, Rahul D. Kamble and Anil V. Shinde

School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Vishnupuri Nanded - 431606 (M.S.) India.

 

 

ABSTRACT:

Synthesis of bis(indolyl) methanes by the reaction of indoles with structurally diverse aldehydes and cyclohexanone in the presence of catalytic amount of bleaching earth in polyethylene glycol (PEG-400) as green solvent afforded the corresponding bis(indolyl) methanes in excellent yields. The effects of solvent, nature of substituents on the aromatic ring of aldehydes were investigated. The catalysts and solvent were reusable up to 4 times without significant loss of activity. The remarkable features of this procedure are high conversions, shorter reaction time and cleaner reaction profiles.

 

KEYWORDS: Bleaching earth clay, PEG-400, indole, aldehydes, bis (indolyl) methane.

 

1. INTRODUCTION:

Indoles and their derivatives such as Bis(indolyl) alkanes (BIMs) are important intermediates in organic synthesis because of their wide occurrences in various bio-active metabolites, marine origin and usefulness for drug design1. Various indole derivatives such as 3-substituted indoles are common components of drug and found to be of pharmaceutical interest in a variety of therapeutical areas2 For example, vibrindole A (3,30-diindolyl ethane) exhibits antibacterial activity, and 3,30-diindolyl methane has potent carcinogenic properties3. BIMs are known to promote estrogens metabolism in both women and men and in the presentation of breast cancer4. In addition, 1,1-bis(30-indolyl)-1-(p-substituted phenyl) methanes containing p-trifluoromethyl (DIM-C-p-CF3Ph), p-t-butyl (DIM-C-p-tBuPh), and p-phenyl (DIMC-p-C6H5Ph) substituent have been identified as belonging to a new class of peroxisome proliferators-activated receptors (PPAR) agonists that exhibit antitumorigenic activity5. Oxidized bis(indolyl) methanes containing a conjugated bis(indolyl) skeleton have acted as colorimetric sensors and chromogenic sensors6. Due to such pharmaceutical importance as well as other applications the synthesis of bis(indolyl)methane and its derivatives is receiving considerable attention these days7.

 

Synthesis of bis(indolyl)methane and its derivatives have been reported in literature without catalyst as well as using catalysts such as protic and Lewis acids8 LiClO4,9 In(OTf)3,10 I2,11 Dy(OTf)3,12 Sc(OTf)3,13 ceric ammonium nitrate (CAN),14 ZrOCl2,15 InCl3,8d and AlPW12O40,16 ionic liquids,17 trichloro-1,3,5-triazine,18 potassium hydrogen sulphate,19La(NO3)36H2O,20 and Fe(DS)3,21. However, there are still some drawbacks in these catalytic systems, such as the requirement for a large quantity of catalyst, long reaction times, poor yield of products, drastic conditions for catalyst preparation, or tedious workup that leads to the generation of large amounts of toxic waste.8–21 Synthesis without catalyst has longer reaction time, poor yields.22

In recent years the use of solid acidic catalysts such as clays, zeolite-HY23,24 have received considerable attention in different areas of organic synthesis. Several reports have been published on the use of solid acids as catalyst for BIM synthesis, but they need high temperatures for reactivation or CH3CN as solvent.4,17, 25-27 However, many of these reported methods suffer from one or more disadvantages such as harsh experimental procedure and reagents that are expensive, moisture sensitive, or highly toxic in nature. There is need of simple, efficient, environmentally benign, and economically viable chemical processes or methodologies for organic synthesis. A mild and efficient catalyst for the synthesis of bis(indolyl) methanes is highly desirable.

 

Naturally occurring bleaching earth is bentonite or montmorillonite clay which when acid activated using sulphuric acid increases absorption capacity of resultant clay. Bleaching earth has unique physical and chemical properties such as shape selectivity, acidic, basic nature and thermal stability. Bleaching earth is used in refining of vegetable oil 28 fats, greases and as a catalyst in reactions 29. Bleaching earth is fine powder with 5 micron particle size clay because of which it has more surface area than other solid supported catalysts. The comparative price of bleaching earth against the other available and used acids in BMI such as sulphated zirconia, 12-tungstosilicic acid, etc is very high. Moreover, bleaching earth is easily available in India/US with very low price (0.10 USD per Kg). Liquid polymers or low melting polymers have recently emerged as alternative green solvent systems with unique properties such as thermal stability, commercial availability, non-volatility, immiscibility with a number of organic solvents and recyclability30-31 Polyethylene glycols are among the one of green solvents.

 

We investigated the catalytic performance of commercially available bleaching earth in the one-pot synthesis of BIMs to overcome existing limitations. Hence, in this communication we wish to report a mild and highly efficient procedure for the synthesis of bis(indolyl)methane’s using an inexpensive reusable bleaching earth catalyst and PEG-400 as green solvent.

 

Scheme 1. Bleaching earth catalysed synthesis of bis (indolyl) methane.

 

2. MATERIALS AND METHODS:

2. (1) Experimental:

All the chemicals were purchased from MERCK and used as received. Bleaching earth (pH 2.7) was gifted sample from Supreme Silicones Pune. Reactions were monitored on TLC by comparison with the authentic samples. Yields refer to the isolated yields of the products. Melting points were obtained on a Mel-Temp Instruments USA. FTIR spectra were recorded on Shimatzu Co Japan., 1H NMR spectra were recorded on Varion Gemini 300 MHz spectrometer and GC-MS spectra were obtained on Agilent.

 

2. (2) General experimental procedure for synthesis of bis(indolyl)methanes:

A mixture of benzaldehyde (1 mmol), indole (2 mmol) and bleaching earth (10 mol %) in PEG-400 (15 ml) was stirred at 60ºC temperature for period of 25 mins. The progress of the reaction was followed by TLC, after completion of reaction as indicated by TLC the reaction mixture was quenched with water and extracted with ethyl acetate (3 X 10 ml) the clay was separated by filtration. The combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the crude compound. The crude compounds were purified by silica gel column chromatography using ethyl acetate/hexane as eluent to afford the desired compound in pure form. All the synthesised compounds were characterised by IR, NMR and MS. Similarly for other bis(indolyl)methanes derivatives we used the above procedure.

 

2. (3) Spectroscopic data of selected compounds:

2. (3-I) 2-[Bis-(1H-indol-3-yl)-methyl]-4-chlorophenol (7):

Yellow Crystal, M.P-(85-870C), IR (KBr): 1038,1339, 1421,3412(-NH) cm-1 NMR (DMSO-d6):  δ 5.42 (br,s, 1H, OH), δ 5.96(s,1H,Ar-CH), δ 6.92 (s, 3H), δ 7.05 (t, 2H, J=7.2Hz ) δ 7.12-7.16 (m,2H),7.24(t, 2H, J=7.2Hz),7.39 (d,4H, J=8.8 Hz), 8.06 (br,s,2H,-NH); M.S. (m/z): 372[M+]; Anal. Calcd for C23H17N2ClO: C, 74.O9; H,4.60 N,17.51%. Found: C, 73.98; H, 4.54; N, 17.42%.

 

2. (3-II) 2-[Bis-(1H-indol-3-yl)-methyl]-4-chlorophenol (8):

Light yellow Crystal, M.P-(96-980C), IR (KBr): 1041,1337, 1422,3415(-NH) cm-1 NMR (DMSO-d6):  δ 5.40 (br,s, 1H, OH), δ 5.92(s,1H,.Ar-CH), δ 6.94 (s, 3H), δ 7.1 (t, 2H, J=7.3Hz ) δ 7.14-7.20 (m,2H),7.26(t, 2H, J=7.3Hz),7.40(d,4H, J=8.8 Hz),8.10(br,s,2H,-NH); M.S. (m/z): 416[M+]; Anal. Calcd for C23H17N2BrO: C, 66.20; H,4.11 N,6.71%. Found: C, 66.08; H, 4.05; N, 6.56%.

 

Table 1: Data showing effect of different solvents on synthesis of bis(indolyl)methane:

Entry

Solvent

Catalyst

Time (min)

Yield (%)a

1

Ethanol

10% Bleaching earth

120

72

2

Acetic acid

10% Bleaching earth

100

68

3

DMF

10% Bleaching earth

45

65

4

Dioxane

10% Bleaching earth

50

78

5

MeCN

10% Bleaching earth

60

76

6

THF

10% Bleaching earth

75

64

7

PEG-400

10% Bleaching earth

25

94

a ) Isolated yields

 

Table 2: Bleaching earth-PEG 400 promoted synthesis of bis(indolyl)methane derivatives

a) Isolated yields

 

2. (3-III) 4-[Bis-(1H-indol-3-yl)-methyl]-2-Methoxyphenol (12):

Brown Crystal, M.P-(110-112ºC), IR (KBr): 1035,1342, 1426,3418(-NH) cm-1 NMR (DMSO-d6): δ 3.78 (s,1H, -OCH3),  δ 5.45 (br,s, 1H, OH), δ 5.84(s,1H,.Ar-CH), δ 6.84 (s, 2H), δ 6.92 (d,2H,J=8.2Hz), δ7.14(t,2H,J=7.2Hz), 7.18(t,2H,J=7.2Hz),7.16(s,2H), 7.36-7.40(m,4H),7.94 (br,s,2H,-NH); M.S. (m/z): 368[M+]; Anal. Calcd for C24H20N2O2: C, 78.24; H,5.47; N, 7.60%. Found: C, 78.15; H, 5.32; N, 7.48%.

 

3. RESULTS AND DISCUSSIONS:

Initially we attempted the electrophilic substitution reaction of benzaldehyde (1 mmol) with indole (2 mmol) using 10 mol % bleaching earth clay in PEG-400 as reaction solvent (Scheme 1). The reaction went to completion within 25 min and corresponding product (1) was obtained in 94 % yield. In order to optimise the reaction conditions, we carried out the above reaction in different solvents such as ethanol, acetic acid, dioxane, and DMF (Table 1). The reaction proceeded efficiently and smoothly at 60°C in the bleaching earth catalyst and PEG-400 solvent, and the products were obtained in excellent yields (94%). Furthermore, the reaction conditions are very mild, and no side-products were observed. The similar products formation reported in the literature without catalyst at 80°C with yields (92%).22 A wide variety of substituted carbonyl compounds were applied to prepare a wide range of bis(indolyl) methanes (Scheme 1). In all cases, the reaction proceeded efficiently in excellent yields. The results are summarized in Table 2.

 

Aromatic aldehydes (benzaldehyde Table 2, entry 1) reacted more rapidly than aliphatic aldehyde (cyclohexanone, Table 2, entry 13). The effect of electron deficiency and nature of the substituent on the aromatic ring showed some effect on this conversion. The nitro substituted aryl aldehydes required slightly longer reaction times than those of their simple and electron-rich counterparts to produce comparable yields (Table 2, entries 1–15). Electron-rich aldehydes such as anisaldehyde, and piperonal, reacted rapidly with indole to give corresponding products in excellent yields within 10 min (Table 2, entries 3, and 14).

 

Finally, the reuse of catalyst (bleaching earth) as well as solvent PEG-400 was studied and data has been presented in Table 3. The catalytic activity of bleaching earth gradually decreased in 3rd and 4th cycles. In the fifth cycle we didn't gain the desired product.

 

Table 3: Synthesis of bis(indolyl)methane derivatives

Cycle

Time (Hr)

Yield (%)a)

1

0.15

94

2

4

75

3

5

45

4

10

25

a) Isolated yields

 

Proposed mechanism of BIM formation using bleaching earth catalyst:

A proposed mechanism of the reaction the bleaching earth catalyses the reaction acts as a mild Lewis acid shown in Scheme 2. An aldehyde or ketone is first protonated by the solid acid catalyst and an electrophilic substitution reaction at the C-3 position of indole is carried out. After loss of water, an intermediate is generated, which is further activated by protons and serves as an electrophile to attack a second molecule of indole to form the corresponding BIM.

 

Scheme 2. A possible proposed reaction mechanism for formation of bis(indolyl) methanes in bleaching earth catalysed reactions with various aldehydes.

 

4. CONCLUSIONS:

In summary, we have developed a simple, convenient and efficient synthetic protocol, the electrophilic addition reaction of indole with carbonyl compound was successfully carried out in the presence of bleaching earth clay in PEG-400. Bleaching earth shows comparable catalytic activity in the synthesis of BIM. This method offers several significant advantage, such as eco-friendly, high conversion, easy handling, shorter reaction time and recyclable solvent as well as catalyst.

 

5. ACKNOWLEDGEMENT:

Authors are thankful to Prof B. P. Bandgar. BSD gratefully acknowledge to UGC New Delhi for postdoctoral research award (F.30-1/2009,SA-II). The authors are thankful to the Director School of Chemical Sciences, Swami Ramananad Teerth Marathwada University, Nanded and IICT Hyderabad for spectral analysis.

 

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Received on 14.04.2011

Modified on 15.07.2011

Accepted on 11.08.2011           

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Research J. Science and Tech.  3(5): Sept.-Oct. 2011: 251-256