Eco-friendly and efficient synthesis of bis(indolyl)methanes under microwave irradiation

Treatment of 2-arylindole derivatives with structurally diverse aldehydes in the presence of glacial acetic acid as an efficient, mild, and inexpensive catalyst under microwave irradiation condition compared with the conventional method afforded excellent yields of biologically important bis(indolyl)methane and tetraindolyl(terephthalyl)dimethane derivatives.


Introduction
The indole moiety is featured in a variety of pharmacologically and biologically active compounds. 1Among various indole derivatives, di (1-H-indolyl-3-yl)methanes (DIM) and 1,4bis[di(1H-indol-3-yl)methyl]benzenes display diverse pharmacological activities and are useful in the treatment of fibromyalgia, chronic fatigue and irritable bowel syndrome. 2These compounds also inhibit the proliferation of both estrogen dependent and independent cultured breast tumor cells. 3,4Thus, the development of high-throughput methods for the synthesis of bis(indolyl)methanes remains a topic of paramount importance in view of their versatile biological and pharmacological activities.Numerous methods describing the synthesis of bis(indolyl)methanes were reported in the literature employing protic acids 5 and Lewis acids. 6,7owever, there are still some drawbacks in these catalytic systems including the requirement of large, 8,9 or stoichiometric amount of catalysts, 10,11 long reaction times, 8,9 low yields of products 11 and drastic condition for catalyst preparation. 12Recently, metal triflate in ionic liquid, 13 Fe(III) salts in ionic liquids 14 and ionic liquids 15 were reported to be efficient for this transformation.Although ionic liquids are reusable they are very expensive.
During the past two decades many publications have described the successful combination of microwave irradiation as a nonclassical energy source with alternative reaction media.Microwave irradiation is well known to promote the synthesis of a variety of compounds, 16,17 where chemical reactions are accelerated because of selective absorption of microwaves by polar molecules.
Recently, the coupling of microwave irradiation with polar organic molecules under solventfree conditions has received notable attention. 17A literature survey reveals examples of specific reactions, which do not occur under conventional heating, but could be possible by microwave irradiation. 18n continuation of our interest on indole derivatives 19 as well as the utility of microwave synthesis under solvent-free conditions, 20 we focus in this article on an efficient and facile microwave irradiation synthesis of pharmacologically interesting di(1H-indol-3-yl)methane and  1,4-bis[di(1H-indol-3-yl)methyl]benzene derivatives.

Results and Discussion
In the present article, a facile route using glacial acetic acid as a mild and highly efficient catalyst for a comparative synthesis of di(1H-indol-3-yl)methanes 3 by conventional heating and under microwave irradiation condition were described (Scheme 1).Attempts to synthesize some known di(1H-indol-3-yl)methane derivatives using catalysts such as I 2 , 21 silica sulfuric acid, 22 HClO 4 -SiO 2 23 under thermal conditions, revealed that the reactions took very long, required a huge amount of catalyst more than the reported, afforded low to moderate yields, and in some cases many by-products were formed.
In comparison with the reported methods, glacial acetic acid turned out to be an efficient medium in terms of handling, yields, and reaction times when carrying out the reactions under microwave irradiation.Thus, a mixture of 2-arylindole derivative 1a-d and aldehyde 2a-g (2:1 mmol) in glacial acetic acid was subjected to microwave irradiation with successive 30 sec periods to avoid overheating of the catalyst.The resulting di(1H-indol-3-yl)methanes 3 were obtained in excellent yields especially with aromatic and heteroaromatic aldehydes, but in the case of aliphatic aldehydes the yields were moderate to good (Table 1).
The work-up of these reactions is easy because some of the products either crystallized directly from the acetic acid, or upon pouring the reaction mixture onto water the solid product precipitated and was obtained by filtration and recrystallization.
All products 3 and 5 were obtained both by the microwave irradiation and conventional heating.Irrespective of these reaction conditions the IR spectra of each product are identical.

Experimental Section
General Procedures.All melting points were taken on a Stuart scientific melting point apparatus (Stuart Scientific, Stone, Staffordshire, UK).1H NMR spectra of DMSO-d 6 solutions were recorded on a Varian Germini-2000 (300 MHz) spectrometer (Varian Inc., Palo Alto, CA, USA).IR spectra were recorded (KBr) on a Pye-Unicam Sp-883 spectrophotometer, Microanalytical Laboratory, Faculty of Science, Cairo University.Elemental analyses (C, H, N) were conducted using the Elemental Analyzer Yanaca CHN Corder MT-3.MS spectra were run on GC MS-QP 1000 EX Mass Spectrometer (Shimadzu).The microwave-induced reactions were carried out in an open Pyrex-glass vessel by using a domestic microwave oven (WhirlPool-TALENT).The synthesized products and each reaction carried out under conventionally or microwave (MW) irradiation condition were monitored by thinlayer chromatography (TLC) on Merck silica gel 60 F254 plates (type E; Merck) using UV light (254 and 360 nm) for detection.