Novel multiple-acidic ionic liquids: Green and efficient catalysts for the synthesis of bis-indolylmethanes under solvent-free conditions

Accepted Manuscript Title: Novel multiple-acidic ionic liquids: Green and efficient catalysts for the synthesis of bis-indolylmethanes under solvent-free conditions Author: Anguo Ying Zhifeng Li Yuxiang Ni Songlin Xu Hailiang Hou Huanan Hu PII: DOI: Reference:

S1226-086X(14)00462-6 http://dx.doi.org/doi:10.1016/j.jiec.2014.09.019 JIEC 2214

To appear in: Received date: Revised date: Accepted date:

24-6-2014 5-9-2014 13-9-2014

Please cite this article as: A. Ying, Z. Li, Y. Ni, S. Xu, H. Hou, H. Hu, Novel multiple-acidic ionic liquids: Green and efficient catalysts for the synthesis of bisindolylmethanes under solvent-free conditions, Journal of Industrial and Engineering Chemistry (2014), http://dx.doi.org/10.1016/j.jiec.2014.09.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Highlights 1. Design and synthesis of four novel multiple-acidic ionic liquids

catalyzed by the novel triethanolamine (TEA) based ILs

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3. Fully discussed the proposed mechanism and verified it with experiment.

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2. Development of protocol for the efficient and green preparation of bis-indolylmethanes

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

Novel multiple-acidic ionic liquids: green and efficient

catalysts for the synthesis of bis-indolylmethanes under solvent-free conditions

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Anguo Ying a *, Zhifeng Li b, Yuxiang Ni b, Songlin Xu b *, Hailiang Hou b, Huanan Hu a a

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School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, People’s Republic of China b School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China

ABSTRACT: Four novel multiple-acidic ionic liquids based on triethanolamine (TEA) were

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prepared and used as efficient catalysts to synthesize bis-indolylmethanes at room temperature without any organic solvent. [TEOA][HSO4] showed the best catalytic performance. The optimal

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amount of catalyst was 10 mol%. Various aldehydes/ketones reacted with indole/substituted indole smoothly and afforded to corresponding products in 70%-99% yields within minutes. Additionally,

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the ionic liquid could be reused up to five times with only a slight decrease in catalytic activity. Finally, a possible reaction mechanism was given. Techniques of acidity test and NMR were

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introduced to verify the proposed mechanism. Keywords: Bis-indolylmethanes; Ionic liquids; Indoles; Aldehydes; Ketones; Green chemistry



* Corresponding authors. Tel/fax: +86 576 88660359. E-mail address: [email protected] or [email protected] (A. Ying), [email protected] (S. Xu). Electronic supplementary information (ESI) available: detailed NMR spectra of novel acidic ionic liquids and condensation products. 2

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1. Introduction

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The bis-indolylmethanes(BIMs) are a valuable class of compounds, which have versatile biological activities and are widely present in various biologically active natural products[1-3].

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Studies have shown that the BIMs can promote beneficial estrogen metabolism and induce

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apoptosis in human cancer cell[4,5]. In view of their significant position in medicinal chemistry, the preparation of BIMs has always been a hot in pharmaceutical and organic synthesis[6]. In

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general, the BIMs are prepared by the condensation of carbonyl compounds with indoles in the presence of catalysts. So far, many catalysts have been reported, such as ABS[7], FeIII[8], LiClO4[10],

HPA/TPI-Fe3O4[11],

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NaHSO4/SiO2[9],

ZrOCl2·8H2O–silica

gel[12],

p-toluenesulfonic acid[13], palladium nanoparticles (PdNPs) [14] and so on. Although these

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catalysts have achieved a lot of success, most of the reported procedures suffer from some disadvantages such as tedious work-up procedure, long reaction time, use of a larger

Ac ce p

stoichiometric amount of catalyst and hazardous solvents which is not suited for practical use and incompatible with “green chemistry”. With the rapid development in the field of catalytic and synthetic chemistry, developing a more practical, green and efficient catalytic system for the synthesis of BIMs is, therefore, highly desirable. Ionic liquids (ILs) are low melting salts that have attracted steady attention[15]. Compared with

traditional organic solvents, ILs present many advantages including low vapor pressure, excellent solvation ability, good thermal stability and recyclability. Furthermore, the properties of ILs can be changed by appropriate modification of their cation or anion, which has earned them the sobriquet of “designer solvents” [16,17]. Thus, ILs have been successfully used as green solvents,

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as well as catalysts or promoters in Mannich reaction[18], Friedel-Crafts reaction [19], Michael addition[20], Knoevenagel condensation[21] and so on. Without exception, ILs also have been

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used in the synthesis of BIMs[22-24]. In recent years, it was reported that the strongly acidic SO3H-functionalized ILs have been developed as efficient catalysts for many organic reactions

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affording outstanding performances[25,26]. Owing to the existence of SO3H functional groups, it

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is very likely to be used for the synthesis of BIMs. However, what we have learned is that this is rarely reported.

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Triethanolamine (TEA) is an amino alcohol that mostly used in cosmetic formulations as emulsifiers, wetting agents, thickeners, detergents, and alkalizing agents[27]. Both the properties

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of amines and alcohols, TEA is also used in chemical field. Recently, our group prepared a series of functionalized ionic liquids based on 2-aminoethanol and successfully used as catalysts for the

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Henry reaction[28]. Encouraged by the exciting performances, herein we report the development of a series of novel multiple-acidic SO3H-functionalized ionic liquids based on TEA and their use

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as catalysts for the synthesis of BIMs.

2. Experimental

General. All the materials in reactions were commercially available and were used without

further purification. 1H NMR spectra was acquired at 400 MHz, and

13

C NMR was acquired at

100 MHz on a Bruker Avance DPX 400 spectrometer in CDCl3, D2O or DMSO. Chemical shifts were reported in parts per million (δ), relative to the internal standard of tetramethylsilane (TMS). All reactions were monitored by thin layer chromatography (TLC) performed on 0.25 mm silica gel 60-F plates. Flash chromatography separation was performed on silica gel (100-200 mesh).

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Preparation

of

the

catalysts

[TEOA][X].

Triethanolamine(TEA)

(0.1

mol)

and

dichloromethane (DCM; 30 mL) were added into a 100 mL three-neck flask and cooled in an ice

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bath. Then, with an intensive mixing, chlorosulfonic acid (0.3 mol) was added dropwise at a temperature of not higher than 5 ℃. After addition, the reaction mixture was removed from the

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ice bath and stirred for 3 h at room temperature. Upon completion of the reaction, the reaction

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solution was filtered. The resulting solid cake was washed with DCM, and dried for 3 hours. The resulting solid was dissolved in 50 ml of water and different acids were added dropwise with

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vigorous stirring. The reaction mixture was heated at 60 °C for 5 h. The water was evaporated at vacuum distillation and the product was then dried under vacuum at 70 ℃ for another 8 h to

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afford the desired ILs.

General procedure for the synthesis of Bis-indolylmethanes. In a typical experiment, a

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mixture of aldehydes/ketones (1.0 mmol), indole/substituted indole compounds (2.0 mmol) and catalyst (10 mol%) was stirred at room temperature for the appropriate time. The progress of the

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reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The solvent was purified by silica gel column chromatography to afford the corresponding products. The products were characterized by 1H NMR and 13C NMR. The residue ionic liquid was dried at 80 ℃ under vacuum for 6 h and reused several times without further purification.

3. Results and discussion Scheme 1. Synthesis of the [TEOA][X] ionic liquids

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Four kinds of TEA based ionic liquids were synthesized (Scheme 1) and used to the reaction of aldehydes/ketones and indole/substituted indole. At the beginning, the reaction of benzaldehyde

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and indole was selected as a model reaction to explore the optimal conditions. Moreover, two kind of conventional ionic liquids [BmIm][BF4] and [BmIm][PF6] were also tested. The results were

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shown in Table 1. Notably, the reaction could not proceed at all in the absence of any

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catalyst(Table 1, Entry 1). Unfortunately, as shown, [BmIm][BF4] and [BmIm][PF6] also had no catalytic effect even the time was prolonged to 60 min (Table 1, Entries 2,3). To our delight, the

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four TEA based ionic liquids showed very good catalytic performances (Table 1, Entries 4-7). In view of the reaction time and yield, the catalytic effect order was as follows: [TEOA][HSO4] >

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[TEOA][CH3SO3] > [TEOA][CF3COO] > [TEOA][NO3]. The [TEOA][HSO4] catalyzed the reaction successfully and the yield up to 90%. With the best catalyst in hand, we carried out

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the reaction in the presence of 5, 10, 15, and 20 mol % [TEOA][HSO4] to optimize the amount of catalyst(Table 1, Entries 7-10). From Table 1, it was found that when the amount of

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[TEOA][HSO4] increase to 10 mol%, the best performance was obtained. Whereas continue to increase the amount of catalyst, the yield of reaction would decrease slightly. Thus, the 10 mol% [TEOA][HSO4] was the optimal amount of catalyst and was subjected to further examination. Table 1. Effect of ionic liquids on the reaction of benzaldehyde and indole[a]

With the optimal conditions in hand, we extended our studies to the reaction of indole with a variety of aldehydes/ketones to evaluate the scope and limitations of this methodology and the results were presented in Table 2. It was apparent from that all reactions proceeded smoothly with functionality-substituted aromatic aldehydes to afford the corresponding BIMs in good to

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excellent yields. Among these cases, electronic effects had some influence on the reaction course that aromatic aldehydes bearing electron-withdrawing groups (CF3 and F) reacted generally faster

(Table 2,

Entries 2-6). The reactions of

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than aldehydes bearing electron-donating (CH3 and OCH3) substituents and obtained higher yields indole and aromatic aldehydes bearing

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electron-withdrawing groups (CF3 and F) were almost quantitative transformation and the yields

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were up to 98% and 99% (Table 2, Entries 5, 6). Some hetero aromatic aldehydes (thiophene-2-carbaldehyde, furan-2-carbaldehyde) were also employed in this reaction and the

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reaction time was relatively longer with a lower yield (Table 2, Entries 9, 10). Unfortunately, 3-pyridinecarboxaldehyde could not react well with indole only achieved a trace yield (Table 2,

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Entry 11). Aliphatic aldehydes were also efficient substrates in this reaction system, to give the corresponding products within 5 min in 90%-91% yields (Table 2, Entries 7, 8). Encouraged by

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these satisfying results, we attempted to use acetone react with indole. Probably due to the steric effects of acetone, only 70% of yield was received even the reaction time was prolonged to 30 min

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(Table 2, Entry 12).

Subsequently, the substituted indoles were introduced to this methodology to react with

benzaldehyde (Table 2, Entries 13-15). Compared with indole, the substituted indoles reacted faster to give the corresponding BIMs in outstanding yields. The methyl-substituted indoles obtained higher yield, however, the yield of nitro-substituted indole was relatively lower. In short, the methodology was efficiently applicable to substituted indoles.

Table 2. Reactions of aldehydes/ketones and indole/substituted indole catalyzed by [TEOA][HSO4][a]

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To evaluate the industrial applicability of this methodology, a large scale reaction was

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attempted with 50 mmol benzaldehyde and 100 mmol indole under the optimal conditions. 91% yield of the desired product was gained and this result revealed this protocol had the prospects for

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industrial applications.

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From the above, we have known this methodology has applicability for aldehydes and ketones, but what would happen if a mixture of aldehydes and ketones was added to the reaction system.

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To explore the substrate selectivity of this methodology, we implemented an experiment of a mixture of 1 mmol benzaldehyde and 1mmol acetone reacted with 2 mmol indole (Scheme 2). To

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our satisfaction, 98% of product was the synthetic product of benzaldehyde reacted with indole

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proving this method was also highly chemoselective for aldehydes.

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Scheme 2. Chemoselectivity of the reaction system

The recyclability of catalyst is an important factor affecting the economics of practical

applications of ionic liquids. The model reaction of benzaldehyde and indole was chosen to investigate this issue under the optimal conditions. Because of ionic liquid is insoluble in ethyl acetate, so, upon completion of the reaction, the product was extracted by several cycles of ethyl acetate, and the residue ionic liquid was dried at 80 °C under a vacuum for 6h. After that the ionic liquid was reused to next run. As demonstrated in Figure 1, the ionic liquid ([TEOA][HSO4]) could be recycled and reused up to five time with only a slight decrease in catalytic activity.

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Fig. 1. Recycling of [TEOA][ HSO4] in reaction of benzaldehyde with indole To show the merit of the present work, the result regarding the reaction of benzaldehyde and indole was compared with the reported results in the literatures. As shown in Table 3, all of the

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results demonstrated that the [TEOA][HSO4] could be an excellent catalyst for the reaction in view of the reaction conditions, the reaction time and yield of the product. Consequently, this protocol provided a practical and green surrogate for the synthesis of BIMs.

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Table 3. Comparison results with different catalysts and conditions in the reaction of

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benzaldehyde and indole

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The high activity of [TEOA][HSO4] catalyzing synthesis of BIMs could be rationalized by the proposed mechanism(Scheme 3). We hold that hydrogen-bonding interactions play a crucial role

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in the reaction from two aspects. On one hand, the quadruple hydrogen-bonding interactions could

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activate the carbonyl group and increase the electrophilicity of the C atom of carbonyl group. On

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the other hand, after the formation of the intermediate A, the quadruple hydrogen-bonding interactions could accelerate the departure of water molecules to form the intermediate B.

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Therefore, [TEOA][HSO4] showed a high catalytic activity.

Scheme 3. Proposed mechanism for the synthesis of bis-indolylmethanes promoted by [TEOA][HSO4]

To verify this plausible mechanism, we commenced from two roles. Firstly, the hydrogen-bonding interactions were so important that we had reason to believe the acidity of the ILs could decide the catalytic performances. In 2003, Bernard Gilbert and his co-workers reported a new method to determine the acidity of the ILs based on Hammett function[32]. In our previous 9

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works, this method was introduced to determine the acidity of ILs successfully[28]. As a continuation of our works, we conducted the acidity test of the four ILs on a Shimadzu model

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UV2401-PC spectrometer with 4-nitroaniline as the indicator in dichloromethane (DCM). The UV absorption values of 4-nitroaniline in four ionic liquids in DCM were shown in Figure 2. It was

calculated by the Hammett function H0, equally,

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H0 = pK(I)aq + log([I]s /[IH+]s)

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easy to distinguish that the maximum absorbance was observed at 348 nm. The acidity was

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where pK(I)aq was the pKa value of 4-nitroaniline(a constant value, 0.99 ), [IH]s and [I]s represented the mole concentrations of the protonated and unprotonated forms of 4-nitroaniline,

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which could be drew by comparing the absorbances of curves between the blank sample (no ILs addition) and samples dissolving the acidic ILs. It was easily inferred from the function that the

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acidity of ILs was negative correlation with the UV absorption, namely, the smaller of UV absorption, the greater acidity. The detailed results were given in Table 4. As shown, the order of

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acidity was [TEOA][HSO4] > [TEOA][CH3SO3] > [TEOA][CF3COO] > [TEOA][NO3]. The

results were consistent with the catalytic performance of ILs precisely making this plausible mechanism more credible.

Table 4. Results of the Hammett function for determining the acidity of ILs in DCM at room temperature

Fig. 2. Absorption spectra of 4-nitroaniline dissolving four ionic liquids in DCM: Samples from top to bottom are blank, [TEOA][NO3], [TEOA][CF3COO], [TEOA][CH3SO3], [TEOA][HSO4]

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respectively.

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Secondly, the strong hydrogen-bonding interactions could probably make the chemical shift value of the carbonyl carbon atom shift from the original position. Take benzaldehyde as an we

compared

the

13

C

NMR spectrums

of

benzaldehyde

and

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example,

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benzaldehyde-[TEOA][HSO4] mixture. As we guessed, Table 5 showed that the chemical shift of carbonyl carbon atom in benzaldehyde was 193.28 while it was 193.43 in mixture. The offset of

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0.15 indicated the possibility of the mechanism from another point.

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4. Conclusions

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Table 5. 13C NMR data of benzaldehyde and benzaldehyde-[TEOA][HSO4] mixture

In conclusion, we developed four novel multiple-acidic ionic liquids based on TEA. Amongst

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the four ILs, [TEOA][HSO4] showed the best catalytic performance. The catalytic reactions were carried out at room temperature without any organic solvent, which was compatible with the concept of green chemistry. Reaction system only used 10 mmol% [TEOA][HSO4] and was

applicable to a series of aldehydes/ketones react with indole/substituted indole. The reactions proceeded smoothly and afforded the desired products in good to excellent yields. It was noteworthy that the ionic liquid could be reused up to five times with only a slight decrease in catalytic activity. This protocol provided a practical and green surrogate for the synthesis of BIMs.

Acknowledgments 11

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We are very grateful for the financial support for this research from the National Natural Science Foundation of China (Grant 21106090 and 21176170), Foundation of Low Carbon Fatty

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Amine Engineering Research Center of Zhejiang Province (2012E10033), and Zhejiang Provincial

Ac ce p

te

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M

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Natural Science Foundation of China (No.LY12B02004).

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References

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[1] F. Lingens, W. Goebel, Biochim. Biophys. Acta, Gen. Subj. 148 (1967) 70-83. [2] E. Fahy, B.C.M. Potts, D.J. Faulkner, K. Smith, J. Nat. Prod. 54 (1991) 564-569.

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[3] B. Bao, Q. Sun, X. Yao, J. Hong, C.O. Lee, C.J. Sim, K.S. Im, J.H. Jung, J. Nat. Prod. 68

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(2005) 711-715.

[4] P. Diana, A. Carbone, P. Barraja, A. Montalbano, A. Martorana, G. Dattolo, O. Gia, L.D. Via,

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G. Cirrincione, Bioorg. Med. Chem. Lett. 17 (2007) 2342-2346.

[5] N. Ichite, M.B. Chougule, T. Jackson, S.V. Fulzele, S. Safe, M. Singh, Clin. Cancer Res. 15

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(2009) 543-552.

[6] H. Gong, Z.F. Jie, Chin. J. Org. Chem. 32 (2012) 1195-1207.

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d

[7] J.T. Li, M.X. Sun, G.Y. He, X.Y. Xu, Ultrason. Sonochem. 18 (2011) 412-414. [8] S.J. Ji, M.F. Zhou, D.G. Gu, Z.Q. Jiang, T.P. Loh, Eur. J. Org. Chem. 2004 (2004) 1584-1587.

Ac ce p

[9] C. Ramesh, J. Banerjee, R. Pal, B. Das, Adv. Synth. Catal. 345 (2003) 557-559. [10] J.S. Yadav, B.V. Subba Reddy, C.V.S.R. Murthy, G.M. Kumar, C. Madan, Synthesis, 2001 (2001) 783-787.

[11] R. Tayebee, M.M. Amini, N. Abdollahi, A. Aliakbari, S. Rabiei, H. Ramshini, Appl Catal A-Gen. 468 (2013) 75-87.

[12] H. Firouzabadi, N. Iranpoor, M. Jafarpour, A. Ghaderi, J. Mol. Catal. 253 (2006) 249-251. [13] M.A. Pasha,; V.P. Jayashankara, J. Pharmacol. Toxicol. 1 (2006) 585-590. [14]

N.

Edayadulla,

N.

Basavegowda,

Y.R.

Lee,

J.

Ind.

Eng.

Chem.

(2014),

http://dx.doi.org/10.1016/j.jiec.2014.06.007.

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[15] H. Olivier-Bourbigou, L. Magna, D. Morvan, Appl. Catal. A-Gen. 373 (2010) 1-56. [16] Š. Toma, M. Mečiarová, R. Šebesta, Eur. J. Org. Chem. 2009 (2009) 321-327.

[18] X. Zheng, Y.B Qian, Y. Wang, Eur. J. Org. Chem. 2010 (2010) 515-522.

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[19] P.H. Tran, F. Duus. T.N. Le, Tetrahedron Lett. 53 (2012) 222-224.

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[17] S. Lee, Chem. Commun. 10 (2006) 1049-1063.

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[20] Z.F. Li, H.L. Hou, A.G. Ying, S.L. Xu, Chin. J. Org. Chem. 34 (2014) 1074-1091. [21] D.Z. Xu, Y. Liu, S. Shi, Y.M. Wang, Green Chem. 12 (2010) 514-517.

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[22] S.A.R. Mulla, A. Sudalai, M.Y. Pathan, S.A. Siddique, S.M. Inamdar, S.S. Chavan, R.S. Reddy, RSC Adv. 2 (2012) 3525-3529.

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[23] C. Liu, C.J. Yu, Heterocyclic Chem. 48 (2011) 845-848.

[24] A.K. Chakraborti, S.R. Roy, D. Kumar, P. Chopra, Green Chem. 10 (2008) 1111-1118.

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d

[25] D. Fang, X.L. Zhou, Z.W. Ye, Z.L. Liu, Ind. Eng. Chem. Res. 45 (2006) 7982-7984. [26] Q. Zhang, J. Luo, Y. Wei, Green Chem. 12 (2010) 2246-2254.

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[27] K.H. Beyer, W.F. Bergfeld, W.O. Berndt, R.K. Boutwell, W.W. Carlton, D.K. Hoffmann, A.L. Schroeter, J. Am. Coll. Toxicol. 2 (1983) 183-235. [28] A.G. Ying, S.L. Xu, S. Liu, Y.X. Ni, J.G. Yang, C.L. Wu, Ind. Eng. Chem. Res. 53 (2014) 547-552.

[29] M. Karthik, C.J. Magesh, P.T. Perumal, M. Palanichamy, B. Arabindoo, V. Murugesan, Appl. Catal., A 286 (2005) 137-141. [30] T.J. Gibbs, N.C. Tomkinson. Org. Biomol. Chem. 3 (2005) 4043-4045. [31] J.R. Satam, K.D. Parghi, R.V. Jayaram. Catal. Commun. 9 (2008) 1071-1078. [32] C. Thomazeau, H. Olivier-Bourbigou, L. Magna, S. Luts, B. Gilbert, J. Am. Chem. Soc. 125

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te

d

M

an

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cr

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(2003) 5264-5265.

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R1 O H O O S O O S O O S O O S O O O O O H

H

H

R1 R

N H

14 examples Yields: 70-99 %

OH

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Graphical abstract

OSO3H

M

N

NH Cl

rt, DCM HO3 SO

60℃, 5h

NH

X

-

HO 3SO

OSO3 H

OSO3H X=HSO 4, CF3 COO, NO3 , CH3 SO3

te

d

OH

OSO3 H

HX

3ClSO3 H HO

N H

cr

N H

R

N H

R

R2

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R2

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Scheme 1 Synthesis of the [TEOA][X] ionic liquids

Table 1 Effect of ionic liquids on the reaction of benzaldehyde and indole[a]

N H

CHO

catalyst rt, solvent-free N H

N H

Entry

Catalyst (mol %)

Time (min)

Yield (%)[b]

1

Blank

60

Trace

2

[BmIm][BF4] (30)

60

Trace

16

Page 16 of 21

3

[BmIm][PF6] (30)

60

Trace

4

[TEOA][NO3] (20)

20

82

5

[TEOA][CF3COO] (20)

20

86

6

[TEOA][CH3SO3] (20)

15

7

[TEOA][HSO4] (20)

10

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8

[TEOA][ HSO4] (5)

25

9

[TEOA][ HSO4] (10)

10

[TEOA][ HSO4] (15)

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88

cr

90

85

92

10

89

an

10

[a] Reaction conditions: benzaldehyde (1.0mmol), indole (2.0mmol), room temperature,

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solvent-free.

te

d

[b] Isolated yield.

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Table 2 Reactions of aldehydes/ketones and indole/substituted indole catalyzed by

O

R

N H

Entry

R

R1

[TEOA][HSO4][a] R1 10 % [TEOA][ HSO 4]

R2

rt, solvent-free

R1

R2

R2

R

R N H

N H

Time Product[b]

Yield (%)[c] (min)

1

H

C6H5

H

2a

10

92

2

H

4-CH3C6H4

H

2b

12

90

3

H

4-OCH3C6H4

H

2c

20

88

17

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H

3-OCH3C6H4

H

2d

15

90

5

H

4-CF3C6H4

H

2e

3

98

6

H

4-FC6H4

H

2f

2

99

7

H

CH3CH2

H

2g

5

91

8

H

2-CH3CH3CH

H

2h

5

90

9

H

Thienyl

H

2i

10

H

Furyl

H

11

H

Pyridyl

H

12

H

CH3

13

1-CH3

C6H5

14

2-CH3

C6H5

15

5-NO2

C6H5

80

us

cr 25 20

85

--

30

Trace

an

2j

2k

30

70

H

2l

2

93

H

2m

2

93

H

2n

7

88

M

CH3

te

d

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4

[a] Reaction conditions: benzaldehyde (1.0mmol), indole (2.0mmol), room temperature,

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[TEOA][ HSO4](10 mol%), solvent-free.

[b] Isolated yield.

[c] Products were ascertained by 1H and 13C NMR spectroscopy

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Page 18 of 21

CHO

98%

N H

rt, solvent-free

N H 2 mmol

O N H

cr

N H

1 mmol

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N H

10 % [TEOA][ HSO 4]

1 mmol

2%

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M

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Scheme 2 Chemoselectivity of the reaction system

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Fig. 1 Recycling of [TEOA][ HSO4] in reaction of benzaldehyde with indole

Table 3 Comparison results with different catalysts and conditions in the reaction of benzaldehyde and indole

Entry

Catalyst

Conditions

Time

Yield(%)

1

Zeolite

CH2Cl2, rt

2h

82[29]

MeOH, rt

32 h

84 [30] 90[31]

2

N”-Isopropylbenzohydrazide hydrochloride

3

TPA-ZrO2

Solvent-free, 60℃

30min

4

[TEOA][HSO4]

Solvent-free, rt

10min

92 (present work)

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O

H

R2

R N A

N H

N

B

R R1

N H

R2

R

an

N

R2 R

N H

N H

M

H

R1

R

R

N H

H O O S O O S O O S O O S O O O O O H

H

us

R1 R2

- H2O

cr

R

N H

R

HO R 1 R2

ip t

R1 H H H H O O S O O S O O S O O S O O O O O

d

N H

te

Scheme 3 Proposed mechanism for the synthesis of bis-indolylmethanes promoted by

Ac ce p

[TEOA][HSO4]

Table 4 Results of the Hammett function for determining the acidity of ILs in DCM at room temperature

ionic liquid

absorbance

[I]s (%)

[IH+]s(%)

[I]s /[IH+]s

H0

Blank

1.659

100

0

--

--

[TEOA][NO3]

0.323

19.5

80.5

0.242

0.374

[TEOA][CF3COO]

0.125

7.5

92.5

0.081

-0.102

[TEOA][CH3SO3]

0.060

3.6

96.4

0.037

-0.442

20

Page 20 of 21

0.030

1.8

98.2

0.018

-0.755

M

an

us

cr

ip t

[TEOA][HSO4]

Fig. 2 Absorption spectra of 4-nitroaniline dissolving four ionic liquids in DCM: Samples from top

te

d

to bottom are blank, [TEOA][NO3], [TEOA][CF3COO], [TEOA][CH3SO3], [TEOA][HSO4] respectively.

Ac ce p

Table 5 13C NMR data of benzaldehyde and benzaldehyde-[TEOA][HSO4] mixture

Structure

O

2

5

1 H

3

4

Carbon number

δ benzaldehyde

mixture

C1

193.28

193.43

C2

136.64

136.67

C3

129.87

129.89

C4

129.44

129.47

C5

134.82

134.89

21

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