Ionic liquid 3-methyl-1-sulfonic acid imidazolium chloride as a novel and highly efficient catalyst for the very rapid synthesis of bis(indolyl)methanes under solvent-free conditions

Full text of DOI:10.1080/00304940903585495

This article was downloaded by: [University of Tennessee, Knoxville]
On: 20 November 2012, At: 05:38
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
Ionic Liquid 3-Methyl-1-sulfonic Acid
Imidazolium Chloride as a Novel and
Highly Efficient Catalyst for the Very
Rapid Synthesis of bis(Indolyl)methanes
under Solvent-free Conditions
Mohammad Ali Zolfigol a , Ardeshir Khazaei a , Ahmad Reza Moosavi-
Zare a & Abdolkarim Zare b
a Faculty of Chemistry, Bu-Ali Sina University, Hamadan, Iran
b Department of Chemistry, Payame Noor University (PNU), Iran
Version of record first published: 03 Feb 2010.
To cite this article: Mohammad Ali Zolfigol, Ardeshir Khazaei, Ahmad Reza Moosavi-Zare &
Abdolkarim Zare (2010): Ionic Liquid 3-Methyl-1-sulfonic Acid Imidazolium Chloride as a Novel
and Highly Efficient Catalyst for the Very Rapid Synthesis of bis(Indolyl)methanes under Solvent-
free Conditions, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 42:1, 95-102
To link to this article: http://dx.doi.org/10.1080/00304940903585495
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Organic Preparations and Procedures International, 42:95–102, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903585495
Ionic Liquid 3-Methyl-1-sulfonic Acid Imidazolium
Chloride as a Novel and Highly Efficient Catalyst for
the Very Rapid Synthesis of bis(Indolyl)methanes
under Solvent-free Conditions
Mohammad Ali Zolfigol,1 Ardeshir Khazaei,1 Ahmad Reza
Moosavi-Zare,1 and Abdolkarim Zare2
1Faculty of Chemistry, Bu-Ali Sina University Hamadan, Iran
2Department of Chemistry, Payame Noor University (PNU), Iran
The exploitation of ionic liquids as solvents in organic transformations has been reported ex-
tensively during the past decade.1–5 The most useful properties of ionic liquids are the ability
to dissolve a wide range of substances, very low vapor pressure, high thermal stability, recy-
clability, non-flammability, safety and the fact that they can be stored for long times without
decomposition.1–5 Moreover, it is often possible to achieve reactions in ionic liquids that
otherwise proceed with great difficulty, or even not at all.1,2 These green solvents have been
also extensively used as catalysts in various organic reactions.6–17 As part of our ongoing
program to extend applications of acidic catalysts and reagents in organic synthesis,18,19
we have prepared 3-methyl-1-sulfonic acid imidazolium chloride {[Msim]Cl} as a new
Brønsted acidic ionic liquid, from the simple reaction of 1-methylimidazole with chloro-
sulfonic acid at room temperature (Scheme 1). We believe that this novel ionic liquid
can be applied as catalyst in different organic transformations. Herein, we report that
bis(indolyl)methane derivatives can be very rapidly (nearly immediately) synthesized from
indoles and carbonyl compounds in the presence of catalytic amount of [Msim]Cl under
solvent-free conditions at room temperature.
Scheme 1
Solvent-free organic reactions have been used as useful technique in organic
synthesis.20,21 Solid-state protocol often leads to shorter reaction times, higher yields,
Received September 18, 2009; in final form November 27, 2009.
Address correspondence to either Mohammad Ali Zolfigol, Faculty of Chemistry, Bu-Ali
Sina University, Hamadan, 6517838683, Iran. E-mail: mzolfigol@yahoo.com or Ardeshir Khazaei,
Faculty of Chemistry, Bu-Ali Sina University, Hamadan, 6517838683, Iran. E-mail: Khazaei 1326@
yahoo.com
95

96
Zolfigol et al.
easier work-up, compliance with green chemistry protocols, and may enhance the regio-
and stereoselectivity of reactions.20,21 bis(Indolyl)methane derivatives are very important
compounds as they display various biological and pharmaceuticals activities.22–27 Synthe-
sis of bis(indolyl)methanes via the condensation of indoles with carbonyl compounds is
one of the important and well-known transformations in organic synthesis.28–43 In general,
this transformation requires a protic acid28–32 or a Lewis acid33–43 to activate carbonyl
compounds. For this purpose, several reagents and catalysts such as acetic acid,28 sil-
ica sulfuric acid,29 H3PMo12O40.xH2O,30 HY-Zeolite,31 Zn(HSO4)2,32 ZrOCl2.8H2O,33
AlPW12O40,34 In(OTf)3,35 Dy(OTf)3,36 La(PFO)3,37 Zeokarb-225,38 MgSO4,39 trityl
chloride,40 P2O5/SiO2,41 Zr(DS)4 and silica chloride43 have been employed. Moreover,
42
the preparation of bis(indolyl)methanes using ionic liquids 1-butyl-3-methylimidazolium
bromide (MW, 400 W, 150◦C, 6–21 min)7 and 1-methylimidazolium hydrogen sulfate (or
trifluoroacetate) (more than 100 mol% of ionic liquid, r.t., 10–40 min)8 has been reported.
Although various methods on the preparation of bis(indolyl)methanes are known, to the
best of our knowledge there is no report on the synthesis of these attractive compounds in
few seconds. This paper describes the first application of our novel ionic liquid [Msim]Cl
as catalyst for the preparation of bis(indolyl)methanes via the condensation of indoles with
aldehydes as well as ketones under solvent-free conditions at room temperature (Scheme 2).
It is worth noting that this is the first report on the rapid preparation of bis(indoly)methanes
under extremely mild reaction conditions.
Scheme 2
To optimize the reaction conditions, the synthesis of compound 1a was selected as a
model reaction (Scheme 2). Thus to a mixture of benzaldehyde (2 mmol) and 3-methyl-
1-sulfonic acid imidazolium chloride (0.5 mmol, 25 mol%) in a mortar was added indole
(4.1 mmol), and the resulting mixture was ground vigorously at room temperature; the
product was obtained in 96% yield after 10 seconds. Increasing the amount of [Msim]Cl
to more than 25 mol% showed no substantial improvement in the reaction results, whereas
the yield decreased and the reaction times increased by reducing the amount of the catalyst.
To assess the efficiency and the usefulness of [Msim]Cl with respect to known Brønsted
acidic ionic liquids, the model reaction was also examined using some of these ionic
liquids including [Hmim]HSO4, [Hmim]Tfa, [Hmim]OTs, [Hmim]BF4 and [Bmim]HSO4
as catalysts; the results summarized in Table 1 show that [Msim]Cl afforded 1a in higher
yield and remarkably shorter reaction time.
Indole and 2-methylindole were then treated with structurally diverse aldehydes as
well as ketones in the presence of ionic liquid [Msim]Cl under solvent-free conditions
at room temperature in order to evaluate the applicability and scope of the catalyst

Very Rapid Synthesis of bis(Indolyl)methanes
97
Table 1
Comparative Condensation of Indole with Benzaldehyde in the Presence of Various
Brønsted Acidic Ionic Liquids at Room Temperature
Entry
Ionic Liquid (mol%)
Time
Yielda (%)
1
2
3
4
5
6
7
8
[Msim]Cl (25)
10 sec.
15 min.
1 hour
10 min.
50 min.
5 hrs
96
90
78
90
75
65
58
71
[Hmim]HSO4 (111)8
[Hmim]HSO4 (25)
[Hmim]Tfa (102)8
[Hmim]Tfa (25)
[Hmim]OTS (25)
[Hmim]BF4 (25)
[Bmim]HSO4 (25)
5 hrs.
2.5 hrs.
aIsolated pure product.
(Table 2). The data in Table 2 indicate that indoles were efficiently condensed with all types
of aldehydes including aromatic aldehydes bearing electron-withdrawing and electron-
releasing substituents, halogens, aliphatic aldehydes as well as ketones, and the desired
bis(indolyl)methanes were produced in excellent yields within 10–90 seconds.
The condensation of indole with terephthaldehyde was also successfully completed
very rapidly in [Msim]Cl. When 2.05 equivalents of indole was treated with terephtha-
laldehyde, bis(indolyl)methane 2 was obtained as the major product while the use of 4.2
equivalents of indole afforded di-bis(indolyl)methane 3 as the main product (Scheme 3).
Scheme 3
In summary, we have introduced ionic liquid, 3-methyl-1-sulfonic acid imidazolium
chloride, as a novel, highly efficient, easily prepared and relatively cheap catalyst in organic
synthesis. In this work, this acidic ionic liquid has been used successfully as catalyst for the
very rapid synthesis of bis(indolyl)methanes via the condensation of indoles with aldehydes
as well as ketones under solvent-free conditions at room temperature.

98
Zolfigol et al.
Table 2
Synthesis of bis(Indolyl)methanes from Indoles and Carbonyl Compounds using [Msim]Cl
at Room Temperature
Entry
1
X
H
Carbonyl Compound Producta Time (s) Yieldb (%)
mp. ◦C (lit.)
1a
1b
1c
1d
1e
1f
10
10
10
10
10
10
96
95
93
92
95
90
139–141
(140–142)39
2
3
4
5
6
H
H
H
H
H
119–121
(119–121)41
95–97
(97–99)29
185–187
(178–181)29
217–219
(217–219)39
219–221
(218–220)39
7
8
H
H
1g
1h
10
15
95
93
77–79
(78–80)41
74–76
(69–71)40
9
H
1i
10
94
146–148
(147–149)41
10
11
12
H
H
H
1j
1k
1l
15
15
20
89
87
91
71–73
(71–73)39
127–129
(123–126)44
161, dec.
(162, dec.)41
13c
H
1m
90
76
161–164
(165–167)45
(Continued on next page)

Very Rapid Synthesis of bis(Indolyl)methanes
99
Table 2
Synthesis of bis(Indolyl)methanes from Indoles and Carbonyl Compounds using [Msim]Cl
at Room Temperature (Continued)
Entry
14c
X
H
Carbonyl Compound Producta Time (s) Yieldb (%)
mp. ◦C (lit.)
1n
1o
1p
1q
80
15
15
15
81
94
92
94
163–165
(162–164)46
15
16
17
Me
Me
Me
245–247
(247–248)44
175–177
(174–175)44
239–241
(240–242)31
aAll compounds were identified by comparison of their melting points and NMR data with those
in the authentic samples.
bIsolated pure product.
cThis reaction was carried out using 40 mol% of [Msim]Cl.
Experimental Section
All chemicals were purchased from Merck or Fluka Chemical Companies. The progress of
the reactions was monitored by thin-layer-chromatography (TLC) using silica gel SILG/UV
254 plates. The 1H NMR (250 MHz) and 13C NMR (62.5 MHz) were run on a Bruker Avance
DPX-250, FT-NMR spectrometer (δ) using TMS as an internal standard. Microanalyses
were performed on a Perkin-Elmer 240-B microanalyzer. Melting points were recorded on
a Stuart Scientific Apparatus SMP3 (UK) in open capillary tubes.
Procedure for the Preparation of Ionic Liquid [Msim]Cl
A 100 mL round-bottomed flask was charged with 1-methylimidazole (0.410 g, 5 mmol) in
dry CH2Cl2 (50 mL), and then chlorosulfonic acid (0.605 g, 5.2 mmol) was added dropwise
over a period of 5 min at room temperature. Afterward, the reaction mixture was stirred
for 20 min, stand for 5 min, and the CH2Cl2 was decanted. The residue was washed with
dry CH2Cl2 (3 × 20 mL) and dried under vacuum to give [Msim]Cl (0.912 g) as a viscous
colorless oil.
1H NMR (DMSO-d6): δ 3.77 (s, 3H, CH3), 7.46 (t, J = 1.8 Hz, 1H), 8.84 (t, J = 1.8 Hz,
1H), 12.20 (s, 1H), 13.91 (s, 1H); 13C NMR (DMSO-d6): δ 36.5, 120.6, 124.2, 138.6.
Anal. Calcd for C4H7ClN2O3S: C, 24.19; H, 3.55; N, 14.10. Found: C, 24.41; H, 3.69;
N, 13.92.

100
Zolfigol et al.
General Procedure for the Synthesis of bis(Indolyl)methanes
To a mixture of carbonyl compound (2 mmol) and [Msim]Cl (0.1 g, 0.5 mmol, 25 mol%)
in a mortar was added indole (4.1 mmol), and the resulting mixture was ground at room
temperature for 10–90 seconds (Table 2). After completion of the reaction, as monitored
by TLC, the reaction mixture was extracted with Et2O (2 × 40 mL). The organic extracts
were then combined and washed with saturated solution of NaHSO3 (2 × 30 mL) to
remove unreacted aldehyde and then with saturated solution of NaHCO3 (2 × 30 mL). The
organic layer was separated and dried over Na2SO4. The solvent was evaporated and the
crude product was purified by recrystallization from EtOAc/petroleum ether (1:2) or plate
chromatography on silica gel eluted with EtOAc/petroleum ether (1:2).
Selected Spectral Data of the Products
3-[(1H-Indol-3-yl)(phenyl)methyl]-1H-indole (1a): Pink solid, mp. 139–141◦C
(lit.39 140–142◦C); 1H NMR (CDCl3): δ 5.86 (s, 1H, ArCH), 6.66 (s, 2H), 7.11 (t, J =
6.9 Hz, 2H), 7.14–7.22 (m, 3H), 7.28–7.31 (m, 2H), 7.35–7.42 (m, 6H), 7.93 (br, 2H, NH);
13C NMR (CDCl3): δ 31.6, 110.9, 111.9, 118.4, 119.5, 121.2, 124.0, 126.3, 127.1, 128.5,
128.6, 137.0, 145.2.
Anal. Calcd for C23H18N2: C, 85.68; H, 5.63; N, 8.69. Found: C, 85.94; H, 5.82; N,
8.52.
3-[(2-Chlorophenyl)(1H-indol-3-yl)methyl]-1H-indole (1h): Pink solid, mp.
1
74–76◦C (lit.40 69–71◦C); H NMR (CDCl3): δ 6.32 (s, 1H, ArCH), 6.67 (s, 2H), 7.02
(t, J = 7.8 Hz, 2H), 7.10–7.22 (m, 6H), 7.38–7.43 (m, 4H), 7.98 (br, 2H, NH); 13C NMR
(CDCl3): δ 37.1, 110.4, 111.6, 119.2, 120.0, 122.4, 123.9, 126.8, 127.3, 128.5, 130.5, 131.4,
135.6, 136.8, 141.5.
Anal. Calcd for C23H17ClN2: C, 77.41; H, 4.80; N, 7.85. Found: C, 77.64; H, 4.94; N,
7.69.
4-[Di(1H-indol-3-yl)methyl]benzaldehyde (2): Pink solid, mp. 256◦C (dec.) [lit.41
257◦C (dec.)]; 1H NMR (CDCl3): δ 6.08 (s, 1H, ArCH), 6.67 (s, 2H), 6.94–7.01 (m, 4H),
7.21 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.60 (d, J =
7.8 Hz, 2H), 8.02 (br, 2H, NH), 9.68 (s, 1H, O = CH); 13C NMR (CDCl3): δ 36.1, 110.8,
112.4, 119.6, 120.0, 121.5, 124.7, 127.6, 130.0, 130.9, 134.8, 137.9, 146.7, 191.5.
Anal. Calcd for C24H18N2O: C, 82.26; H, 5.18; N, 7.99. Found: C, 82.45; H, 5.06; N,
7.83.
Acknowledgements
The authors gratefully acknowledge partial support of this work by the Research Affairs
Office of Bu-Ali Sina University (Grant number 32-1716 entitled development of chemical
methods, reagent and molecules.), and Center of Excellence in Development of Chemical
Method (CEDCM) Hamadan, I.R Iran.
References
1. K. Mikami, “Green Reaction Media in Organic Synthesis”, Blackwell Publishing, Oxford, UK,
2005.

Very Rapid Synthesis of bis(Indolyl)methanes
101
2. R. D. Rogers, “Ionic Liquids As Green Solvents: Progress and Prospects”, American Chemical
Society Publication, Washington, 2005.
3. A. Zare, A. Hasaninejad, R. Safinejad, A. R. Moosavi- Zare, A. Khalafi-Nezhad, M. H. Beyzavi,
M. Miralai-Moredi, E. Dehghani and P. Kazerooni-Mojarrad, ARKIVOC, xvi, 51 (2008).
4. A. Zare, A. Hasaninejad, A. R. Moosavi Zare, A. Parhami, H. Sharghi and A. Khalafi-Nezhad,
Can. J. Chem., 85, 438 (2007).
5. A. Zare, A. Hasaninejad, A. Khalafi-Nezhad, A. R. Moosavi Zare and A. Parhami, ARKIVOC,
xiii, 105 (2007).
6. A. Zare, A. R. Moosavi-Zare, A. Hasaninejad, A. Parhami, A. Khalafi-Nezhad and M. H. Beyzavi,
Synth. Commun., 39, 3156 (2009).
7. A. Zare, A. Parhami, A. R. Moosavi-Zare, A. Hasaninejad, A. Khalafi-Nezhad and M. H. Beyzavi,
Can. J. Chem., 87, 416 (2009).
8. M. Dabiri, P. Salehi, M. Baghbanzadeh, M. Shakouri, S. Otokesh, T. Ekrami and R. Doosti, J.
Iran. Chem. Soc., 4, 393 (2007); Chem. Abstr., 150, 77605 (2009).
9. G. Zhao, T. Jiang, H. Gao, B. Han, J. Huang and D. Sun, Green Chem., 6, 75 (2004).
10. J. R. Harjani, S. J. Nara and M. M. Salunkhe, Tetrahedron Lett., 43, 1127 (2002).
11. V. V. Namboodiri and R. S. Varma, Chem. Commun., 342 (2002).
12. V. R. Koch, L. L. Miller and R. A. Osteryoung, J. Am. Chem. Soc., 98, 5277 (1976).
13. D. S. Kim and W. S. Ahn, Korean J. Chem. Eng., 20, 39 (2003); Chem. Abstr., 139, 86942 (2003).
14. D. S. Newman, R. E. Winans and R. L. McBeth, J. Electrochem. Soc., 131, 1079 (1984).
15. C. J. Adams, M. J. Earle, G. Roberts and K. R. Seddon, Chem. Commun., 2097 (1998).
16. P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. de Souza and J. Dupont, Polyhedron, 15, 1217
(1996).
17. H.-P. Zhu, F. Yang, J. Tang, M.-Y. He, Green Chem., 5, 38 (2003).
18. P. Salehi, M. A. Zolfigol, F. Shirini and M. Baghbanzadeh, Curr. Org. Chem., 10, 2171 (2006).
19. F. Shirini, M. A. Zolfigol, P. Salehi and M. Abedini, Curr. Org. Chem., 12, 183 (2008).
20. K. Tanaka, “Solvent-free Organic Synthesis”, Wiley-VCH, GmbH and KGaA, Weinheim, 2004.
21. A. Loupy, “Microwave in Organic Synthesis”, Wiley-VCH, Weinheim, 2004.
22. J. J. Michnovicz, H. L. Bradlow, M. J. Huang, T. Osawa, C. T. Ho and R. T. Rosen (editors)
“Food Phytochemicals for Cancer Prevention 1: Fruits and Vegetables”, American Chemical
Society, Washington, D.C., 1994.
23. T. Osawa and M. Namiki, Tetrahedron Lett., 24, 4719 (1983).
24. R. Bell, S. Carmell and N. Sar, J. Nat. Prod., 57, 1587 (1994).
25. G. Bifulco, I. Bruno, R. Riccio, J. Lavayre and G. Bourdy, J. Nat. Prod., 58, 1254 (1995).
26. A. Ramirez and S. Garcia-Rubio, Curr. Med. Chem., 10, 1891 (2003).
27. S. Zhao, X. Liao and J. M. Cook, Org. Lett., 4, 687 (2002).
28. A. Kamal and A. A. Qureshi, Tetrahedron, 19, 513 (1963).
29. D. M. Pore, U. V. Desai, T. S. Thopate and P. P. Wadgaonkar, ARKIVOC, xii, 75 (2006).

102
Zolfigol et al.
30. M. A. Zolfigol, P. Salehi and M. Shiri, Phosphorus, Sulfur, and Silicon, 179, 2273 (2004).
31. A. V. Reddy, K. Ravinder, V. L. N. Reddy, T. V. Goud, V. Ravikanth and Y. Venkateswarlu,
Synth. Commun., 33, 3687 (2003).
32. K. Niknam, M. A. Zolfigol, T. Sadabadi and A. Nejati, J. Iran. Chem. Soc., 3, 318 (2006); Chem.
Abstr., 147, 118094 (2009).
33. H. Firouzabadi, N. Iranpoor, M. Jafarpour and A. Ghadiri, J. Mol. Cat. A: Chem., 253, 249
(2006).
34. H. Firouzabadi, N. Iranpoor and A. A. Jafari, J. Mol. Catal. A: Chem., 244, 168 (2006).
35. R. Nagarajan and P. T. Perumal, Tetrahedron, 58, 1229 (2002).
36. X. Mi, S. Luo, J. He and J. P. Cheng, Tetrahedron Lett., 45, 4567 (2004).
37. L. Wang, J. H. Han, T. Sheng, J. Z. Fan and X. Tang, Synlett, 337 (2005).
38. C. J. Magesh, R. Nagarajan, M. Karthik and P. T. Perumal, Applied Catal. A: General, 266, 1
(2004).
39. A. Hasaninejad, A. Parhami, A. Zare, A. Khalafi-Nezhad, A. Nasrolahi Shirazi and A. R. Moosavi
Zare, Polish J. Chem., 82, 565 (2008); Chem. Abstr., 150, 168107 (2009).
40. A. Khalafi-Nezhad, A. Parhami, A. Zare, A. R. Moosavi Zare, A. Hasaninejad and F. Panahi,
Synthesis, 617 (2008).
41. A. Hasaninejad, A. Zare, H. Sharghi, K. Niknam and M. Shekouhy, ARKIVOC, xiv, 39 (2007).
42. M. A. Zolfigol, P. Salehi, M. Shiri and Z. Tanbakouchian, Catal. Commun., 8, 173 (2007).
43. A. Hasaninejad, A. Zare, H. Sharghi, M. Shekouhy, R. Khalifeh, A. Salimi Beni and A. R.
Moosavi Zare, Can. J. Chem., 85, 416 (2007).
44. M. L. Deb and P. J. Bhuyan, Tetrahedron Lett., 47, 1441 (2006).
45. X. Zeng, S. Ji and S. Wang, Tetrahedron, 61, 10235 (2005).
46. J.-T. Li, H.-G. Dai, W.-Z. Xu and T.-S. Li, Ultrason. Sonochem., 13, 24 (2006).