Microwave-assisted synthesis of novel 1-{[(diindolyl)methyl]benzyl}-2- {[(diindolyl)methyl]phenyl}-1 H -benzimidazole scaffold via two-consecutive multicomponent reactions

An efficient microwave synthesis of 1-{3-or 4-[bis(1 H -indol-3-yl)methyl]benzyl}-2-{3-or 4-[bis(1 H -indol-3- yl)methyl]phenyl}-1 H -benzimidazole derivatives was achieved. This novel azaheterocyclic hybrid scaffold was assembled in excellent overall yield through two-consecutive ABB-type 3CR design by the reaction of (3-or 4-formylphenyl)diindolylmethanes, synthesized from a mixture of isophthalaldehyde or terephthalaldehyde, respectively, 1 H -indole or derivatives, and ortho -phenylenediamine. The use of microwave technology, catalyst-free, and solvent-free conditions, as well as the avoidance of time-consuming and tedious workup procedure, make it an appealing method to access a novel (1DIMB-2DIMP)BZ scaffold endowed with potential biological activity.

Among the various structural classes highlight Hamacanthin 5, isolated from marine sponges Spongosorites sp, which is a 5,6-dihydropyrazin-2(1H)-one with two-indolyl molecular units. 8But more importantly, it has been noted that replacement of functionals groups or structural contraction of the azaheterocyclic ring, as in Tulongicin 6, the biological activity significatively is affected.In this regard, the 4,5dihydro-1H-imidazole core attached to the bis(indolyl)methane structural unit specifically acts as an antimicrobial agent that inhibits the growth of S. aureus (Figure 1). 9 In the same way, synthetic compounds such as indolo [2,3-b]quinoline derivatives 7 and chromeno [2,3-b]indole derivatives 8 highly promising as anti-MRSA agents. 10egarding the DIM core, it has been proposed as a relevant building block in the pursuit of highly functionalized indole derivatives.
Despite this important breakthrough, significant synthetic challenges remain to be solved in the synthesis of structurally elaborated and diverse heterocyclic-DIM molecules.][13][14] Benzimidazole is an important structural core in pharmaceutical chemistry, where it has been used in antitumor, 15 antiparasitic, 16 antimicrobial, 17 and antihistaminic agents. 18Benzimidazole derivatives with short peptide sequences have antidiabetic, antibiofilm, and antioxidant activities. 19dditionally, some complexes with metals such as cobalt(II) and zinc(II) and coordinated to benzimidazole bearing 1-benzyl and 2-phenyl moieties have shown effective anticancer activity, 20 and some organophosphorus-benzimidazole compounds have potential pesticidal activity. 21enzimidazole derivatives have been usually synthesized by classical cyclocondensation of ophenylenediamines with the corresponding carboxylic acids 22 or from aldehydes under oxidative conditions with some reagents such as sodium metabisulfite 23,24 or nitrobenzene 25 .

Results and Discussion
To assembling the more elaborated and sterically congested scaffold 15a-h it was devised from a twoconsecutive ABB-type 3CR design based on the incorporation of 4-(bis(1H-indol-3-yl)methyl)benzaldehyde derivatives 12a-h as key reactants in a subsequent post-multicomponent step.These target building blocks were selectively prepared by reacting 2 mmol of 1H-indole 10a or its derivatives 10b-d with 1 mmol of either isophthalaldehyde or terephthalaldehyde 9a-b under microwave irradiation following the conditions outlined in Scheme 1-MCR 1.In our hands, all eight synthesized 3,3´-DIMs 12a-h was obtained in excellent yield (91-96 %).
For the syntheses of the target molecules 15a-h, in a first instance, it is important to mention that the ortho isomers of 12a-h did not react with 13 at the used reaction conditions to give the corresponding target molecules, what is attributed to the great steric effect presented.So, taking into account that the pattern of substitution of the starting reagents 12a-h (that is 1,3 or 1,4) may exert a notable influence on the efficiency of transformation of the reaction, we initially re-explored the synthesis of the sterically least hindered substrate with para substitution 12a and o-phenylenediamine 13 in 1:1 molar ratio.Such findings assume the transitory formation of a double Schiff base as the key intermediate from which evolve the formation of the 2substituted benzimidazole 14a as the thermodynamic more stable product after undertaking a 5-exo-trig ring closure and subsequent aromatization, as we reported previously.So, when the experiment was conducted in a 2:1 molar ratio, product 15a was successfully obtained in 85 % yield by an intramolecular 1,3-hydride migration as the final step in the proposed reaction mechanism, Scheme 2, whereas the 2-substituted benzimidazole 14a was isolated in only 8 % yield as a byproduct (Table 1, entry 1).Scheme 2. Proposed mechanism for the formation of 1,2-disubstituted benzimidazoles.
][31][32] IR, 1 H, 13 C NMR spectroscopy, and HRMS analysis confirmed the structural attributes of compound 15a.Briefly, the key methylene moiety deduced from the intramolecular 1,3-hydride migration tethered to N-1 of the imidazole skeleton appears as singlet signal at 6.43 ppm in the 1 H NMR spectra, whereas the two signals occurring at 52.4 and 153.6 ppm in the 13 C NMR spectra were attributed to NCH2-and C-2 of the imidazole ring, respectively.
Inspired by the above findings, we set out to explore the scope and efficiency of the reaction by using several 1,4-and 1,3-diindolylmethanearenecarbaldehydes 12b-h.Table 1 shows the results obtained by the microwave effect, highlighting that neither substituent effects (H, Me, Ph on N-1 and C-2) nor the steric factors derived from the pattern of substitution of the bis(indolyl)methane motif and the arenecarbaldehyde moiety noticeably affect the selectivity and overall yield of all synthesized target products 15b-h.In this regard, we found that the more sterically demanding 1-{3-[bis(2-phenyl-1H-indol-3-yl)methyl]benzyl}-2-{3-[bis(2-phenyl-1H-indol-3-yl)methyl]phenyl}-1H-benzimidazole 15h is obtained in excellent yield (Table 1, entry 8), comparable with the outcomes delivered in the synthesis of the least sterically demanding azaheterocycle compound 15a (Table 1, entry 1).
Therefore, the logical inference from these findings suggests that the structural complexity level of the arenecarbaldehyde derivative used as starting reactive has no significant detrimental effect on the efficiency and rate of reaction.
[a] No determined

Conclusions
It was shown that the synthesis of (1DIMB-2DIMP)BZ from a two-consecutive multicomponent 3CR approach can be selectively promoted by the microwave effect, in short reaction times.Its operational simplicity and low environmental load combined with its excellent yields, broad substrate scope, and high efficiency of reaction achieved under catalyst-free and solvent-free conditions open a new way to synthesize bis(1,2-indolyl derivatives)benzimidazole molecules with potential biological interest.The use of microwave technology, catalyst-free and solvent-free conditions, as well as avoiding tedious workup procedure, make it an appealing method to access novel (1DIMB-2DIMP)BZ scaffold endowed with potential biological activity.

Experimental Section
General.All microwave-assisted organic reactions were carried out using a monowave 300 Microwave Synthesis Reactor by Anton Paar.The reaction temperature was monitored with an immersing ruby thermometer.Melting points were determined on a Buchi B-450 apparatus. 1H and 13 C NMR spectra were recorded on a Varian EM-390 (300 MHz) instrument in CDCl3 or DMSO-d6, and chemical shifts (δ) are given in ppm relative to TMS.Mass spectrometry (FAB + ) was measured on a JEOL JMS-SX102A mass spectrometer.IR spectra were recorded on a Perkin-Elmer 283B spectrophotometer using ATR techniques.All reagents, as well as solvents, were acquired from Aldrich without any treatment from its commercial presentation.
Typical procedures.The syntheses of 14a-h were reported previously. 23The experimental procedure for 14a was: A mixture of (formylphenyl) diindolylmethane 12a (1.4251 mmol, 0.4987 g) and o-phenylenediamine 13 (1.4251 mmol, 0.1539 g), were thoroughly blended in a 20 mL microwave vial, pressure sealing and exposed to irradiation in a monowave 300 microwave reactor at 195 °C for 3 min.The solids formed were purified by preparative chromatography on silica gel using an eluting system of hexane/ethyl acetate (7:3) and recrystallized from ethanol-water. 15eneral procedure for the synthesis of (1DIMB-2DIMP)BZ (15a-h).A mixture of 3(or 4)-formylphenyl)diindol-3-ylmethane 12a-h (2.00 mmol, 0.7000 g for 1H-indole, 0.7560 g for 1H-methylindole, 0.7560 g for 2-methyl-1H-indole and 1.004 g for 2-phenyl-1H-indole) and o-phenylenediamine 13 (1.00 mmol, 0.2160 g) were thoroughly blended in a 20 mL microwave vial, pressure sealing and exposed to irradiation in a monowave 300 microwave reactor at 195 °C for 3 min (the progress of the reaction was monitored by TLC).After cooled at room temperature, the crude reaction was poured into ice-water and it was left stirring for 5 minutes.The resulting suspension was filtered, dried, and eventually purified by preparative chromatography using an eluting system a mixture of Hex/AcOEt (6:4).After carefully scraping the spots on the silica plate, the main detected product was extracted with hot ethanol, filtered, and dried to afford the spectroscopy pure compounds 15a-h.

Table 1 .
Assembling of 15a-h by catalysis-free ABB-type three multicompound reaction.