Synthesis of Diindolylmethanes ( DIMs ) Catalyzed by Silicotungstic Acid by Grinding Method

The synthesis of diindolylmethanes (DIMs) via the condensation of indole and aromatic aldehydes catalyzed by silicotungstic acid was carried out in 68%~98% yields at room temperature within 1~5 min by grinding. This method provides several advantages such as operational simplicity, higher yield and environment friendly.


Introduction
The reactions of indoles have received much attention as a number of their derivatives, which found applications in the field of pharmaceuticals, agrochemicals and material sciences 1 .Among the indole derivatives, the diindolylmethanes (DIMs) have potential uses in biological activities such as antibacterial and antitumor properties 2 .The principal synthetic avenues to the DIMs comprise the protic acid, Lewis acid or solid acid-catalysed reaction of indole with aldehydes (or ketones).In view of that, several synthetic methods for the preparation of DIMs have been reported by using catalysts such as: InCl 3  , trichloro-1,3,5-triazine 3f , zeolite 3g,,3h , sulphamic 3i , polyindole salt 3j , RE(PFO) 3 3k , ultrasound/CAN 3l , montmorillonite K10 3m , ultrasound/aminosulfonic acid 3n , iodine 4 , p-toluenesulfonic acid 5 , fluoroboric acid adsorbed on silica gel 6 , phosphorus pentoxide/silica gel (P 2 O 5 /SiO 2 ) 7 , diammonium hydrogen phosphate 8 , ammonium chloride 2 , ZnO 9a , Montmorillonite K10-ZnCl 2 9b , Zr-OPO 3 H 10 and H 6 P 2 W 18 O 62 11 .However, in spite of their potential utility, some of the reported methods suffer from drawbacks such as long reaction times, expensive catalysts, low yields and cumbersome product isolation procedures.
Grinding method often leads to shorter reaction time, increased yields, easier workup, matches with green chemistry protocols, has been considered as an useful protocol in organic synthesis 7,18,19 .Recently, our laboratory has used the grinding method for the synthesis of 5-arylidene barbituric acid catalyzed by anhydrous zinc chloride 18b or aminosulfonic acid 18c and the synthesis of α,β-unsaturated ketone catalyzed by KF-Al 2 O 3 20 , 10-arylmethylene anthrone catalyzed by KF-Al 2 O 3 19 and di(indolyl)methanes (DIMs) catalyzed by montmorillonite K10-ZnCl 2 9b .In this paper, we report an efficient preparation of diindolylmethanes (DIMs) catalyzed by silicotungstic acid (SiO

Experimental
Liquid aldehydes or ketones were purified by distillation before using.Melting points were uncorrected. 1H NMR spectra were measured on a Bruker AVANCE III-600 (600 MHz) spectrometer using TMS as internal standard and CDCl 3 as solvent.Mass spectra were determined on a Agilent Technologies 6310 Lon Trap LC/MS.

General procedure of condensation of indole with aldehydes or ketones
Aldehydes or ketones (1, 0.5 mmol), indole (2, 1 mmol) and silicotungstic acid (SiO 2 .12WO 3 .24H 2 O) (33 mg, 0.01 mmol) were mixed in a mortar and ground at room temperature for the period of time as indicated in Table 2.The reaction was followed by TLC.After the completion of the reaction, the mixture was extracted with EtOAc (3×15 mL), washed with water (3×10 mL) and then dried with anhydrous magnesium sulfate over night and filtered.The solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel eluted with petroleum ether or the mixture of EtOAc and petroleum ether.The authenticity of the known compounds 3a~3e, 3h~3m and 3o~3q was established by comparing their melting points with that reported in literatures 4,21~23 , the rests (3f, 3g and 3n) were established by 1 H NMR and mass spectra.

Results and Discussion
The influence of the amount of catalyst on the reaction was examined.As shown in Table 1, the amount of silicotungstic acid had a significant effect on the reaction yield.When using 0.005 mmol, 0.01 mmol, 0.02 mmol catalysts, the yield of 3a was 57% (Entry 2), 95% (Entry 3), 96% (Entry 4) respectively.In the absence of silicotungstic acid, the yield of 3a was only 11% (Entry 1).It seems that changing the amount of molar ratio of silicotungstic acid (Entries 3, 4) had not a significant effect on the yield of 3a.So we chose 0.01 mmol silicotungstic acid as the optimum amount.A series of experiments for the synthesis of diindoylmenthanes were performed via the condensation of indole (1, 1 mmol) and aldehydes or ketones (2, 0.5 mmol) catalyzed by silicotungstic acid (33 mg, 0.01 mmol).The results were summarized in Table 2.
As shown in the Table 2, the method presented here represented an efficient procedure in terms of high yield, mild reaction conditions, and easy workup.For example, 3-((1H-Indol-3-yl)(2-nitrophenyl)methyl)-1H-indole (3f) was previously prepared in 84% yield catalyzed by ZnO with stirring at 80 o C for 45 min 9a , whereas present procedure offered 3f in 98% yield at r.t.within 1 min.
In the present procedure, the reaction was very tolerant of aromatic aldehydes carrying either electron-withdrawing or electron-donating substituent groups.However, the condensation of indole and ketones (Entries 12~15) or aliphatic aldehydes (Entries 16, 17) was carried out in lower yields.This indicates that the method has some limitations with respect to ketones or aliphatic aldehydes.

Conclusion
In summary, we have developed an efficient, environment friendly route to the synthesis of diindolylmethanes via the condensation of indole with aromatic aldehydes catalyzed with silicotungstic acid by grinding.But the method has some limitations with respect to ketones or aliphatic aldehydes.

Table 1 .
The effect of amount of silicotungstic acid on the yield of 3a by grinding.* *Substrate benzaldehyde 0.5 mmol, indole 1.0 mmol.

Table 2 .
Synthesis of di(indolyl)methanes from aldehydes (or ketones) and indole catalyzed by silicotungstic acid by grinding.