A simple and efficient preparation of bis(indolyl)methanes catalyzed by HCl/silica gel under solvent-free conditions

A rapid, simple and efficient method for the synthesis of bis(indolyl)methanes (BIMs) via the electrophilic substitution reaction of indoles with benzaldehydes promoted by hydrochloric acid supported on silica gel was developed. The advantages of the present method entail short reaction times, high yields, ease of experimental method and product isolation, benign reaction conditions and low cost


Figure 1. Selected examples of biologically active bis(indolyl)methanes (BIMs).
Due to the importance of BIMs in various areas, synthetic methodologies toward the synthesis of BIMs received enormous attention and were continuously developed.Among numerous methods, the Friedel-Crafts acylation reaction or electrophilic substitution reaction of indoles with aldehydes or ketones under a variety of reaction conditions is a classical strategy.Numerous reagents and reaction conditions were developed and reported to access BIMs including Brønsted or Lewis acid, [22][23][24][25][26][27][28][29][30] iodine, 31 methanol, 32 cyclodextrin/electrolysis, 33 metal salts, 22,[34][35][36][37] ionic liquids, 22,[38][39][40] visible light, [41][42] surfactants, 43 vitamin B1 44 and enzymes. 457][48][49][50][51][52][53] Although, literature synthetic methodologies are useful and satisfactory, there are some limitations and some of the methods suffer from particular drawbacks such as the use of organic solvents, expensive catalysts, toxic reagents, high catalyst loading, the formation of toxic by-products, long reaction time and elevated reaction temperature.Thus, the development of an efficient, simple and eco-friendly methods for accessing bis(indolyl)methanes (BIMs) is still a challenging task.In this work, we describe our findings toward the synthesis of BIMs mediated by HCl supported SiO2 as an acid catalyst under mechano-chemical activation and solvent-free reaction conditions.

Results and Discussion
We started our study with the reaction between indole (1a) and benzaldehyde (2a) as the model substrates to screen for optimization reaction conditions.Thus, a mixture of indole (1a) and benzaldehyde (2a) in the presence of HCl which is supported on various type of supporting materials (such as silica gel, alumina and zeolite) was ground in mortar at room temperature for 20 minutes and the results are summarized in Table 1.
In the presence of HCl (0.6 equiv.),among various supports screened including silica gel, neutral alumina, basic alumina, and zeolite, silica gel (SiO2) gave the best results providing the desired 3,3'-(phenylmethylene)bis(1Hindole) (3a) in 94% yield (Table 1, entries 1-4).Lower yields were observed with lower HCl loadings (Table 1, entries 5 & 6) while no further improvement in the yield of bisindole 3a upon increasing HCl loading (Table 1, entry 7).Control experiments were carried out by carrying out the reactions in the absence of either silica support or HCl.The reaction readily proceeded when silica support was excluded from the reaction yielding the bisindole 3a in 69% yield (Table 1, entry 8) but in the absence of HCl, the bisindole 3a was not formed (Table 1, entry 9).To highlight the efficiency of the present method, the reactions of indole (1a) with benzaldehyde (2a) under some selected literature methodologies to access 3,3'-(phenylmethylene)bis(1H-indole) (3a) were carried out (Table 2).It was found that the present method is comparable to the existing methods and is one of the optimum procedures.a The present method.
Worthy of note was that gram scale experiment, examined under the optimized condition reactions, gave 3,3'-(phenylmethylene)bis(1H-indole) (3a) in a comparable 89% yield.Finally, a synthetic application of the present work was demonstrated for the synthesis of a bioactive trisindoline. 13Under the optimized reaction conditions, the indole (1a) (2 mmol) and isatin (1 mmol) delivered trisindoline in a good 77% yield (Scheme 1).

Conclusions
In summary, we have developed a rapid, simple, solvent-free, and efficient method for the synthesis of bis(indolyl)methanes (BIMs) in good to excellent yields via electrophilic substitution reaction of indoles with benzaldehydes using hydrochloric acid as an inexpensive catalyst and silica gel as the support.The present method offers ease of operation, broad functional group compatibility and the scalability of the reaction.The synthetic application of the present method to access bioactive trisindoline alkaloid is also highlighted.

Experimental Section
General.All isolated compounds were characterized on the basis of 1 H and 13 C NMR spectroscopic data, IR spectra, and HRMS data. 1 H and 13 C NMR spectra were recorded on a Bruker Ascend™ spectrometer. 1 H and 13 C NMR chemical shifts are reported in ppm using residual non-deuterated solvent peak as an internal standard.Infrared spectra were recorded with a Bruker TENSOR27 spectrometer.High-Resolution Mass Spectra (HRMS) were recorded with a Bruker micro TOF spectrometer in the ESI mode.Melting points were recorded with a Sanyo Gallenkamp apparatus.Reactions were monitored by thin-layer chromatography (TLC) and visualized by UV and a solution of KMnO4.Reagents and solvents were obtained from commercial sources and used without further purification.Purification of the reaction products was carried out by column chromatography on silica gel (0.063-0.200 mm).After column chromatography, analytically pure solids were obtained by recrystallization from CH2Cl2-hexanes.
General procedure for the synthesis of bis(indolyl)methanes 3. A mixture of 1.2 M HCl (0.5 mL, 0.6 mmol) and silica gel (500 mg) was ground together in a mortar with a pestle before indoles (2.0 mmol), benzaldehydes (1.0 mmol) were added in a mortar, and a mixture was ground further for 20 minutes at room temperature.After completion of the reaction monitored by using TLC, the reaction mixture was suspended in EtOAc (25 mL), filtered, and the filtrate was quenched with saturated NaHCO3 (2×20 mL) and water (20 mL).The organic layer was separated and dried with anhydrous Na2SO4, then the organic solvent was evaporated.The crude reaction mixture was purified by column chromatography using EtOAc/hexanes as eluent to afford the corresponding product.

Table 3 .
Substrate scope of the synthesis of bis(indolyl)methanes 3 a