Synthesis of novel benzimidazole-diindolylmethane hybrid compounds within the green chemistry context

The syntheses of novel hybrid 2-(3,3 ' -diindolylmethylphenyl)-1 H -benzimidazole regioisomers under eco-friendly, solvent-less, catalyst-free conditions and using microwave energy with good to excellent yields in short reaction times were achieved.


Introduction
3,3'-Diindolylmethane (DIM, Figure 1A), the major acid condensation product of indole-3-carbinol (I3C, Figure 1B), is a promising antitumor agent derived from Brassica (Cruciferous) vegetables. 1 The anticarcinogenic effects of DIM have been shown in animal models of spontaneous, carcinogen-induced or transplanted tumors. 2,3Because of their effectiveness and low toxicity, I3C and DIM have become widely used in adjunct therapies for recurrent respiratory papillomatosis (RRP), caused by some types of human papilloma viruses (HPVs). 4,5he benzimidazole pharmacophore is known to be an important structural core in medicinal chemistry that shows a broad spectrum of pharmacological activities.Several compounds containing the benzimidazole scaffold have been used as antiparasitic, 6 antimicrobial, 7 antitumor, 8 and antihistaminic agents. 9he main methodology to synthesize DIM and its derivatives is by a condensation reaction between an indole with either aliphatic or aromatic aldehydes or ketones employing Broensted-Lowry acids 10 or Lewis acids. 11Some of these reactions have long reaction times 12 or low yields of products. 13Benzimidazole derivatives have usually been synthesized by classical cyclocondensation of o-phenylenediamines with the corresponding carboxylic acids under harsh dehydrating reaction conditions 14 or from aldehydes under oxidative conditions.Some reagents such as nitrobenzene 15 and sodium metabisulfite, 16,17 have been employed for this last purpose.
On the other hand, microwave irradiation is well known to promote the syntheses of a great variety of compounds, [18][19][20] where chemical reactions are accelerated because of selective absorption of microwaves by polar molecules and the coupling of these two factors under solvent-free conditions has received notable attention. 21A literature survey reveals examples of specific reactions, which do not occur under conventional heating, but could be possible by microwave irradiation. 22he synthesis of some DIM derivatives using catalysts such as silica sulfuric acid 23 under thermal conditions involved reactions that took a long time and provided low to moderate yields.In some cases, many byproducts were formed when the reactions were carried out in aqueous medium and under controlled conditions at pH values of 1.0, 1.5, 2.5 and 7.2, respectively. 24In recent years, diindolylmethane synthesis has taken a greener direction, such as: using infrared energy in solvent-less conditions and in presence of a bentonitic clay, 25 with ultrasound energy and aminosulfonic acid as catalyst, 26 under microwave solvent-free irradiation with Lewis acid-catalysis, 27 in ionic liquids, [28][29][30] with SBA-15-supported poly [4styrenesulfonyl(perfluorobutylsulfonyl)imide] as heterogeneous Broensted-Lowry acid catalyst, 31 using Montmorillonite K-10 clay, 32,33 with nickel nanoparticles as a reusable catalyst under solvent-free conditions, 34 employing ion exchange resins, 35,36 with eutectic salts, 37 synthesis mediated by Zeokarb-225, 38 and with zeolites, 14,39 amongst others.
As a continuation of our interest in the syntheses of diindolylmethane derivatives, herein we report the synthesis of novel hybrid benzimidazole-diindolylmethane compounds using some principles of green chemistry such as the use of microwave energy source for the activation of reactions under solvent-free and catalyst-free conditions.

Results and Discussion
Following two previously established possible routes by us to synthesize 2-(4-(bis(1H-indol-3yl)methyl)phenyl)-1H-benzimidazole, we started with o-phenylenediamine and terephthalaldehyde to obtain 1 (Scheme 1), in order to generate compound 4a by microwave irradiation but the main obtained product was 2 in 80% yield.
A second synthetic route, which used 1H-indole and terephthalaldehyde, was successful and we obtained the diindolylmethane 3a in 96% yield in 8 min of reaction time by microwave irradiation (Scheme 2).Then, a mixture of o-phenylenediamine and 1 eq of 3a were irradiated with microwave energy for 3 min and the product 4a was generated in 88% reaction yield.

Scheme 1. Synthetic route A for 4a.
Encouraged by this result, we realized the synthesis of 4a-4l compounds, Table 1, using different indole derivatives and the 3 regioisomers of formylbenzaldehyde, according with the Scheme 3.
a 8 min at 850W.b : Yield of isolated products.C : 3 min at 850W.
The structures of all the synthesized compounds were established on the basis of IR, 1 HNMR, 13 C-NMR spectral data, and molecular weights were confirmed by high resolution mass spectrometry or elemental analysis.
As an example, the 1 H-NMR of compound 3b showed a singlet at δ 3.69 integrating for 6 protons for the two methyl groups attached to nitrogen atoms; two singlets appeared at δ 5.95, integrating for one proton, and δ 6.54, integrating for two protons, are due to H10 and for hydrogens at position 2 of the indole structure, respectively.Two triplets appeared around δ 7.00 (J 7 Hz) and 7.24 (J 7 Hz) each integrating for two protons attached at H5 and H6, respectively.A multiplet around δ 7.29-7.37integrating for 4 protons is assigned to aromatic protons H4 and H7.Two doublets at 7.53 (J 9 Hz) and 7.80 (J 9 Hz) are due to H12 and H13 respectively.Finally, a singlet at δ 9.98 integrating for one proton is assigned to C 15 -H.Its 13 C-NMR spectra showed 15 signals which corresponds to all magnetically inequivalent carbons.At δ 32.8 and δ 40.4 assigned to C1 and C10 respectively.The carbonyl carbon signal appeared at δ 192.2 and the aromatic carbons appeared between δ 109.3 and δ 151.9.
On the other hand, the 1 H-NMR of compound 4b showed equivalent shifts, multiplicity and number of protons on each one signal for protons of methyl groups, H2, H10, H12 and H13 than compound 3b and the signal for proton the aldehyde is not observed.A singlet at δ 5.31 is assigned to proton attached to nitrogen of the benzimidazole moiety and two multiplets around δ 6.70-7.40 are assigned for the other aromatic protons.Its 13 C-NMR spectra showed 18 signals which corresponds to all magnetically inequivalent carbons.

Conclusions
We present straightforward synthetic methodology to generate novel hybrid diindolylmethylphenylbenzimidazole compounds.Because these reactions are conducted in the absence of solvents and catalysts and using microwave energy for the activation of the reactions, they provide the desired products under conditions that are within the context of green chemistry.

Experimental Section
General.Melting points were determined on a Buchi B-450 device and are uncorrected.The microwave monomode oven used was a Microwave Synthesis Reactor, Monowave 300, Anton Paar, employing sealed reaction vessels and the monitoring of the reaction mixture temperature was determined with an internal probe.The 1 H and 13 C NMR spectra were obtained from a Varian EM-390 (300 MHz) apparatus.Chemical shifts are given in ppm relative to TMS for CDCl3 or ppm relative to DMSO-d6 (Sigma-Aldrich) as mentioned in the corresponding spectral data (According to Gottlieb et al., the signals for DMSO and H2O present in DMSO-d6 appear at 2.55 and 3.33 ppm, respectively). 43The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; m, multiplet.Mass spectrometry (MS) was performed on a JEOL JMS-SX102A spectrometer by EI + at an ionization potential of 70 eV and with FAB + techniques.IR spectra were © ARKAT USA, Inc obtained with a Perkin-Elmer 283B spectrophotometer, using either KBr tablet or film techniques.The following starting materials were commercially available: 1H-indole, N-methylindole, 2-methylindole, 2-phenylindole, terephthalaldehyde, isophthalaldehyde, phthalaldehyde, o-phenylenediamine (all Sigma-Aldrich).
Typical procedures (Formylphenyl)diindolylmethanes derivatives 3a-3l.In a microwave tube indole (5.7141 mmol) and the dialdehyde (2.8570 mmol) were added; this mixture was mixed well and irradiated with microwave energy (195 °C at 850 W) for 8 min.Then, once the mixture reaction cooled at room temperature, the corresponding reaction products were extracted with acetone and the solvent was removed at reduced pressure.All products were purified by recrystallization with a mixture of ethanol/water.(Benzimidazol-2-yl)-3,3′-diindolylmethanes 4a-4l.In a microwave tube were added a (formylphenyl) diindolylmethane (3) (1.4251 mmol) and o-phenylenediamine (1.4251 mmol).The reagents were well blended and then irradiate with microwave energy for 3 min (195 °C at 850 W).Microwave irradiation was performed at 1 minute intervals.The solids formed were dissolved in acetone and purified by preparative chromatography on silica gel using an eluting system of hexane/ethyl acetate (7:3).The products were scraped from the chromatographic plate and the solids were placed in a funnel.The silica gel was washed with hot ethanol, which was collected in a beaker in an ice bath; cold water was added for crystallization.In some cases, it was necessary to add a little cold acetone with water to achieve precipitation and the pure product was obtained as a sticky semisolid substance.

Table 1 .
Synthesis of compounds 3 and 4 by microwave irradiationCompound