Tetramethyl guanidinium chlorosulfonate as a highly efficient and recyclable organocatalyst for the preparation of bis(indolyl)methane derivatives

Article abstract of DOI:10.1016/j.catcom.2014.08.003

The synthesis and characterization of a novel superbase ionic liquid, tetramethylguanidinium chlorosulfonate, are described. The guanidine ionic liquid (GIL) was characterized by FT-IR and NMR spectroscopies, and wide-angle X-ray scattering techniques, as

Full text of DOI:10.1016/j.catcom.2014.08.003

Tetramethyl guanidinium chlorosulfonate as a highly efficient and recyclable
organocatalyst for the preparation of bis(indolyl)methane derivatives
Reddi Mohan Naidu Kalla, Johnson V. John, Huiju Park, Il Kim
PII:
DOI:
Reference:
S1566-7367(14)00307-0
doi: 10.1016/j.catcom.2014.08.003
CATCOM 4002
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Catalysis Communications
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Revised date:
Accepted date:
3 June 2014
1 August 2014
2 August 2014
Please cite this article as: Reddi Mohan Naidu Kalla, Johnson V. John, Huiju Park,
Il Kim, Tetramethyl guanidinium chlorosulfonate as a highly efficient and recyclable
organocatalyst for the preparation of bis(indolyl)methane derivatives, Catalysis Commu-
nications (2014), doi: 10.1016/j.catcom.2014.08.003
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ACCEPTED MANUSCRIPT
Tetramethyl guanidinium chlorosulfonate as a highly efficient and recyclable
organocatalyst for the preparation of bis(indolyl)methane derivatives
Reddi Mohan Naidu Kalla, Johnson V. John, Huiju Park, and Il Kim*
BK21 PLUS Centre for Advanced Chemical Technology, Department of Polymer Science and
Engineering, Pusan National University, Busan 609-735, Republic of Korea.
Abstract
The synthesis and characterization of a novel superbase ionic liquid, tetramethylguanidinium
chlorosulfonate, is described. The guanidine ionic liquid (GIL) was characterized by FT-IR and
NMR spectroscopies, and wide-angle X-ray scattering techniques, as well as thermogravimetric
analysis. The GIL functions as an effective, environmentally benign, and recyclable catalyst for
the synthesis of various bis(indolyl)methanes in outstanding yields (90–96%), within short
reaction times; further, no chromatographic purification step for the product is required.
Keywords: Bis(indolyl)methanes; Organocatalysis; Chlorosulfonic acid; Ionic liquid;
Tetramethylguanidine
*Corresponding author
E-mail: ilkim@pusan.ac.kr
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1. Introduction
Currently, many researchers are focusing on the development of green chemical methods to
reduce waste, environmental hazards, cost, and energy consumption by using eco-friendly
reagents and reaction conditions, which are of great importance in chemical synthesis and
engineering. In addition, the realization of multiple transformations in a single operation is
highly compatible with the goals of green and sustainable chemistry. In terms of public concern,
the use of environmentally benign solvents such as water or the deployment of solvent-free
conditions represents a highly potent and green chemical protocol from the viewpoints of both
cost-effectiveness and ease of synthesis.
Synthetic heterocyclic compounds play an important role in organic and medicinal chemistry.
Indole is an important nitrogen heterocyclic compound (NHC), with a variety of natural and
synthetic derivatives displaying various biological properties [1]. Among them,
bis(indolyl)methanes (BIMs) are an important class of NHCs possessing diverse
pharmacological activities such as antimicrobial [2,3], anti-inflammatory [4], anti-oxidant [5],
and anticancer [6] activities; further, BIMs can aid the inhibition cancer cell growth through the
induction of apoptosis and metastasis [7]. In addition, indole–carbazole derivatives act as triplet
energy materials [8], while oxidized BIMs are used as dyes [9] and colorimetric sensors [10,11].
In view of these important applications, there is increasing interest in the preparation of BIMs.
An important approach for the direct synthesis of BIMs is based on the electrophilic
substitution of indole with carbonyl compounds in the presence of Brønsted or Lewis acids [12–
14], heteropolyacids [15], and ionic liquids (ILs) such as FeCl3-basedILs [16], [bmim][BF4],
[bmim][PF6] [17], [bmim][MeSO4] (bmim = 1-butyl-3-methylimidazolium) [18], guanidinium
ILs [19], and secondary amine-based ILs [20]. The majority of the Lewis acids are highly
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moisture sensitive and may form stable complexes with the lone pair of electrons at nitrogen,
sometimes decomposing in the presence of certain ligands in the reaction media. Accordingly, an
excess of Lewis acid is required, which often results in poor reaction progress and by-product
formation. To solve the abovementioned problems, it is necessary to identify mild reaction
conditions using stable and reusable catalysts for the preparation of BIMs.
Advances in ILs and the related methodologies are centered on improving the efficiency of
ILs, which is necessary for application in both sustainable and environmentally friendly
methods; such protocols are the most important objectives of the renewable chemical industry
[21]. Various GILs can be prepared by simply neutralizing tetramethylguanidine (TMG) with an
equimolar amount of carboxylic acid, fluorinated carboxylic acid, nitric acid, or sulfuric acid
[22]. These TMG-based ILs have recently drawn much attention because they behave as green
solvents and show outstanding performance in catalysis and eco-friendly synthesis. Akbari et al.
synthesized four GILs and used them for the Boc protection of amines [22]. Li et al. also
prepared three GILs and used them in the Heck reaction with a palladium support [23]. Recently,
Carrera et al. demonstrated a different approach by neutralizing TMG with amino acids such as
L-alanine, L-phenylalanine, and DL-tryptophan [24]. Very recently, Lei et al. [25] prepared
1,1,3,3-tetramethylguanidinium imidazole ([TMG][IM]) and employed it for the absorption and
desorption of CO2. Numerous GILs have been prepared, mostly by the neutralization of TMG
with acids, and employed as catalysts as well as solvents. The reaction time for GIL formation is
typically 2 h; however, only a few GILs are formed as solids, while the others appear as liquids
or semisolids, which makes their separation from the reaction mixture more difficult.
Nonetheless, while GILs are conceptually eco-friendly, nontoxic, and recyclable solvents and/or
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catalysts, there is a need for alternatives that are easily separable from the reaction mixture and
can be used as catalysts in organic reactions.
As a continuation of our ongoing research on the development of green methodologies [26],
we describe a new TMG IL that can be used as a catalyst for the electrophilic substitution of
substituted indoles with various substituted aromatic aldehydes (Scheme 1). The reactions
proceeded to completion within a few minutes, with high yields (90–96%) of BIMs. The IL
could be reused up to three times without any apparent decrease in catalytic activity. The reused
catalyst did not affect the product selectivity. To the best of our knowledge, there are no reports
on the synthesis of new TMG IL species and their applicability for the electrophilic substitution
reaction of indoles with aldehydes.
2. Experimental
2.1. General
Indole, 2-methylindole (both purchased from Sigma-Aldrich Co., USA), 5-bromoindole, TMG
(both purchased from Alfa Aesar), and various substituted aldehydes (Sigma-Aldrich Co., USA)
were used without further purifications. All the experiments were carried out under neat
conditions; pre-coated silica gel plates (Merck, Germany) developed with iodine were used for
1
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analytical thin-layer chromatography (TLC). H NMR (400 MHz) and C NMR (100 MHz)
spectra were recorded on a Varian INOVA 400 NMR spectrometer. Chemical shift values were
relative to tetramethylsilane (TMS; Me4Si). The data are presented as follows: chemical shift
(ppm), multiplicity (s = singlet, d = doublet, m = multiplet, brs = broad singlet), coupling
constant J(Hz). FTIR spectra were recorded on a Shimadzu IR Prestige 21 spectrometer at r.t.
The samples were analyzed as KBr discs in the range 3500–500 cm−1.
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2.2. Synthesis of TMG IL
A 50-mL reaction flask was charged with a solution of TMG (2 mmol) in CH2Cl2 (15 mL). To
the resulting solution was added chlorosulfonic acid (2 mmol) in CH2Cl2 (10 mL) over a period
of 5 min at 0 °C. After the addition was complete, the reaction mixture was stirred at room
temperature for 40 min. At this point, the reaction mixture was concentrated by rotary
evaporation; the concentrated mixture was then washed with CH2Cl2 (30 mL) and dried by rotary
evaporation at 70 °C to afford TMG IL as a colorless solid (Scheme 1).
TMG IL: white solid, mp 40–42 °C and decomposition point (by thermogravimetric analysis
(TGA)) 287.2 °C. IR (KBr): ν (cm−1) 3284, 3115, 1650, 1608, 1558, 1415, 1162, 1070, 885, 733,
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657, 598; H NMR (400 MHz, D2O): δ (ppm) 2.81 (s, 12H, –CH3 × 4); C NMR (100 MHz,
D2O): δ (ppm) 161.5, 38.8; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.74 (s, 2H, –NH2) 2.85 (s,
12H, –CH3 × 4); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 161.3, 39.3. Anal. cacld for
C5H14N3O3SCl: C, 25.92; H, 6.09; N, 18.14. Found: C, 26.96; H, 6.01; N, 19.57.
2.3. General procedure for synthesis of BIMs
To a mixture of indole, 2-methylindole, or 5-bromoindole (2 mmol) and aldehyde (1 mmol) in a
50-mL reaction flask equipped with a magnetic stirring bar was added the IL (3 mol %); the
resulting reaction mixture was stirred at r.t. After completion of the reaction (monitored by
TLC), the product was extracted with 20 mL of ethyl acetate (EA). The solvent was evaporated
under reduced pressure, and the obtained solid was washed with hexane and recrystallized from
ethanol to afford the product. The insoluble IL was separated by simple filtration, washed twice
with EA, and then dried under vacuum before reuse. All the previously known products afforded
spectral and physical data consistent with those reported in the literature for samples prepared
using previously reported methods. The new products were characterized by their melting points,
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as well as IR, H NMR, and C NMR spectra. Detailed descriptions of reaction times, yields,
melting points, and spectral data for all compounds 1–36 are given in Supporting Information.
3. Results and Discussion
3.1. Characterization of the new TMG IL
A simple stoichiometric reaction of TMG with chlorosulfonic acid under mild conditions
afforded a colorless solid after evaporation of the solvents, without using any specific
purification procedures. The spectrum (see Fig. S1 in Supporting Information) showed O=S=O
asymmetric and symmetric stretching peaks at 1162 and 1070 cm−1, respectively, and an S–O
stretching peak at 733 cm−1, which precisely confirmed the SO3 group linkage. Further, the C=N
vibrations at 1650 cm−1indicated the presence of an imine. The abovementioned peaks confirmed
the IL identity, and were in good agreement with the reported data [27].
The 1H and 13C NMR spectra of TMG IL were also recorded (Fig. 1). The 1H NMR spectrum
(Fig. 1(a)) of the TMG IL shows a single peak at 2.81 ppm, assigned to methyl protons. Note that
the guanidinium protons are observed in D2O as HDO at 4.5 ppm, because of H-D exchange.
1
However, when recording the H NMR spectrum in DMSO-d6 (Fig. 1(c)), the guanidinium
protons are observed at 7.47 ppm, together with the methyl protons at 2.85 ppm, indicating that
the ClSO3H proton migrated to TMG. The absence of observable peaks between 11 ppm and 14
ppm further confirms this migration. In addition, no peaks indicating the existence of unreacted
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ClSO3H are observed. In the C NMR spectra (Figs. 1(b) and 1(d)), two peaks are observed at
161.5 and 38.8 ppm in D2O, and at 161.3 and 39.7 ppm in DMSO-d6, which are attributed to
C=N and –N–CH3 carbons, respectively. Gao et al. [27] reported a TMG IL structure with the
13
positive charge on the carbon atom; if this were true, the carbon peak in the C NMR would
appear at 44–45 ppm. However, in Figs. 1(b) and 1(d), no peaks at 44–45 ppm were observed,
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indicating that the positive charge is located on the nitrogen atom; this was confirmed by the
presence of the imine carbon peak at 161.5 ppm in Fig. 1(b) and at 161.3 ppm in Fig. 1(d). The
TMG IL was also characterized by powder X-ray diffraction (XRD) (Fig. 2(a)). The XRD
pattern showed characteristic diffraction peaks of the IL, indicating a crystalline structure.
Moreover, the characteristic peaks at 2θ = 25°–80° indicate a SO3 group, confirming that this IL
contains an SO3 functionality [28]. The thermal stability of the TMG IL, as measured by
thermogravimetric analysis (TGA), is shown in Fig. 2(b). Complete degradation occurred
between 265 and 365 °C, indicating that the IL is stable up to 250 °C.
3.3. Application of TMG IL for the synthesis of BIMs
The synthesis of BIMs can be classified as a pseudo three-component reaction (TCR), i.e., two
molecules of indole react with one molecule of aldehyde. In general, TCRs usually require high
reaction temperatures, long reaction times, high catalyst loadings, and exotic reagents to promote
the formation of the desired product. To avoid these problems, TCRs can be carried out with
suitable promoters, which are inexpensive, easily available, and recyclable. Initially, BIMs were
prepared in the presence of an inexpensive superbase TMG, in which case the product yield was
low. The reaction was carried out with ClSO3H, but this resulted in charring; as a result, we
could not identify the products. We next proposed that the low yields could be improved if TMG
and ClSO3H were combined to form the new ionic liquid TMG IL, which could be applied to the
synthesis of BIMs. Gratifyingly, the reactions proceeded smoothly in high yields. The synergetic
effect of the TMG IL reactions results in better yields as compared to those obtained with
individual TMG or ClSO3H. First, the reactions were carried out in different organic solvents
such as CH3CN, CH2Cl2, and THF. While these solvents smoothly facilitated the reaction with
acceptable yields (85%), long reaction times (2–3 h) were required. Subsequently, we decided to
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carry out the reaction under neat conditions; in this case, the reaction proceeded to completion
within 40 min, affording the product in quantitative yield (96%).
To determine the appropriate concentration of TMG IL, we investigated the model reaction at
different catalyst loadings of 1.0, 2.0, 3.0, and 4.0 mol%, which afforded product yields of 65%,
72%, 96%, and 96%, respectively. The product yield remained constant at 96% when the catalyst
was increased from 3.0 to 4.0 mol%, indicating that a 3.0 mol% loading was sufficient for
optimal results considering the reaction time and product yield (Fig. 3(a)).
After optimization of the reaction conditions, additional reactions of indole and its derivatives
with various substituted aromatic aldehydes were carried out in the presence of 3 mol% TMG IL
under neat conditions to establish the generality of this methodology; the results are summarized
in the Experimental section. All the reactions proceeded smoothly to afford the products in good
yields. Both electron-donating and electron-withdrawing substituents on the indole moiety were
suitable for the reaction, and the corresponding substituted products were successfully isolated
.2-Methylindole afforded a lower product yield as compared to 5-bromoindole and indole
because of the methyl substituent at the 2-position. Aromatic aldehydes containing electron-
donating, electron-withdrawing, and halogen substituents on the aromatic ring were utilized
successfully in the reaction, and the desired products were obtained in high yields within a very
short time. The reaction did not proceed with ketones because of their lower reactivity and higher
stability as compared to aldehydes.
The merits of TMG IL were compared with those of other reported ILs for the synthesis of
BIMs. Very recently, Das et al. [20] reported the use of secondary amine-based ILs for the
synthesis of BIMs using microwave irradiation, an additional energy source for product
formation, as well as column chromatography for product isolation. In 2009, Rad-Moghadam
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[19] demonstrated the synthesis of BIMs promoted by [TMGT] and [TMGTf] ILs (TMGT:
N,N,N,N-tetra methyl guanidinium trifluoroacetate; TMGTf: N,N,N,N-tetra methyl guanidinium
triflate). In that study, [TMGT] was found to be superior to [TMGTf]. For [TMGT], the TMG is
neutralized with trifluoroacetic acid (TFA), which is a good chemical reagent for organic
transformations. The synthesis of BIMs was possible only under drastic conditions in the case of
using [TMGTf]. In addition, Yadav et al. [17] reported the synthesis of BIMs using [bmim]BF4
or [bmim]PF6 over a reaction time of almost 270 min, and with 92% yield. Chakraborti et al. [18]
also reported the synthesis of BIMs in 95% yield using a [bmim][MeSO4] IL, which required a
tedious work-up procedure. Compared to the abovementioned ILs, the new TMG IL described
here is superior for the synthesis of BIMs; this is because of the high yields and the non-
requirement of drastic reaction conditions, additional energy sources (i.e., microwave,
ultrasonication), and laborious work-up procedures. The full comparison is summarized in
Table1.
The reusability of the TMG IL was also examined for the preparation of compound 1 from the
reaction of indole with benzaldehyde. The catalyst was easily recovered by the addition of EA to
the reaction mixture; the insoluble TMG IL could be separated by simple filtration, washing
twice with EA (30 mL), and drying in vacuum. The catalyst displayed good reusability after
three runs (Fig. 3(b)).
The structures of all the compounds were confirmed using IR, 1H, and 13C NMR spectroscopy.
In the 1H NMR spectra, the –NH proton signal appeared as a singlet at 10.37–7.68 ppm. The Ar–
CH proton signal also appeared as a singlet at 6.27–5.28 ppm, confirming product formation; the
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remaining proton signals were observed in the expected regions. In the C NMR spectrum, the
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Ar–CH carbon signal was observed at 54.1–36.8 ppm, confirming the formation of BIMs [29]
(see Supporting Information).
4. Conclusions
A simple, highly efficient, and green procedure for the synthesis of BIMs in the presence of a
novel TMG IL catalyst, under solvent-free conditions, has been described. This low-cost
protocol has several advantages, including a clean reaction medium (solvent-free), use of easily
available chemicals, high yields, and easy work-up procedures. This protocol provides the
synthetic chemists with a rapid and efficient method for preparing nitrogen-containing
heterocycles. In addition, the structure of the novel TMG IL is confirmed by FTIR and NMR
spectroscopic analyses, XRD techniques, and TGA.
Acknowledgements
This work was supported by the Basic Science Research Program through the National Research
Foundation of Korea funded by the Ministry of Education (2012R1A1A2041315) and the Fusion
Research Program for Green Technologies through the National Research Foundation of Korea
funded by the Ministry of Education (2012M3C1A1054502). The authors would also like to
thank the BK21 PLUS Program for the partial financial support.
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Captions
Scheme caption
Scheme 1. Preparation of BIMs by the reaction of indoles and aldehydes in the presence of a
TMG IL catalyst.
Figure captions
Fig. 1.1H and 13CNMR spectra of TMG IL measured in D2O [(a) and (b)] and DMSO-d6 [(c) and
(d)].
Fig. 2. (a) XRD pattern and (b) thermogram of TMG IL.
Fig. 3. Effect of the amount (a) and recycle (TMG IL = 3.0 mol%) (b) of TMG IL on the yield of
compound 1. Conditions: indole = 2 mmol and benzaldehyde= 1 mmol.
Table caption
Table 1. Comparison of various ILs and normal catalyst for the synthesis of BIMs.
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Figure 1
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Figure
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Figure
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Scheme 1
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Table 1. Comparison of various ILs and normal catalyst for the synthesis of BIMs.
Entry
IL (amount)
Condition Time Yield
Ref.
(min)
3
(%)
99
93
87
92
96
97
96
1
2
3
4
5
6
7
Secondary amine based ILs (10mol %)
[TMGT][TMGTf] (1 mL)
Microwave
Neat
20
19
15
[bmim]BF4or [bmim]PF6 (2 mL)
[bmim][MeSO4] (5 mol %)
Neat
270
20
17
Neat
18
Pyridinium tribromide (2 mol %)
Dodecylbenzenesulfonic Acid (30 mol %)
TMG IL (3mol %)
CH3CN
H2O
20
30
18
31
Neat
40
This
work
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Graphical Abstract
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Highlights
▶Novel tetramethylguanidineionic liquid (TMG IL) is synthesized and well characterized.
▶The TMG IL is an excellent organocatalyst for the synthesis of bisindolylmethanes.
▶Bisindolylmethanes are obtained in quantitative yields at environmentally benign conditions.
▶ The TMG IL catalyst is recyclable without losing its catalytic activity.
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