Cent. Eur. J. Chem. • 6(4) • 2008 • 622–626
DOI: 10.2478/s11532-008-0069-5
Central European Journal of Chemistry
Ionic Liquid Promoted Synthesis of Bis(indolyl)
methanes
Research Article
Sandip A. Sadaphal, Kiran F. Shelke, Swapnil S.Sonar, Murlidhar S. Shingare*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad (M.S.) 431004, India
Received 20 June 2008; Accepted 29 August 2008
Abstract: 1 -benzyl-3-methyl imidazolium hydrogen sulphate [bnmim][HSO4] was found to be an effective catalyst for the condensation reaction
of indoles and derivatives with benzaldehydes in microwave irradiation with lower reaction time and higher yields to give bis(indolyl)
methanes.
Keywords: 1-benzyl-3-methyl imidazolium hydrogen sulphate [bnmim][HSO4] • Bis(indolyl) methanes • Microwave irradiation
© Versita Warsaw and Springer-Verlag Berlin Heidelberg.
1. Introduction
Ionic Liquids [ILs] are green alternatives; the search
for non-volatile and a recyclable alternative is holding
a key role in this field of research. A proper choice of
cations and anions is required to achieve ionic salts that
are liquids at room temperature and are appropriately
termed as room temperature ionic liquids [RTILs]. Ionic
liquids [ILs] are emerging as effective promoters and
solvents for green chemical reaction. Over the past
few years, a variety of catalytic reactions have been
successfully conducted using ILs as solvents. One of
the most important advantages of ILs is the behavior
of solvophobic interactions that generate an internal
pressure which promote the association of the reagents
in a solvent cavity during the activation process and show
an acceleration of the various reactions in comparison
to conventional solvents [1-4].
ILs are green alternatives for traditional organic
solvents in chemistry and ILs have generated
considerable interest as environmentally benign
reaction media due to their unique properties such
as ease of recyclability, ability to dissolve a variety of
organic ,inorganic and metal complexes materials,
non- flammable nature and high thermal stability [5]. A
growing number of chemical reactions in these media,
such as Kabachnik-Fields reaction [6], polymerization
[7], hydrogenation [8], Diels-Alder reactions [9], have
been reported. The ionic liquids based on the 1,3-dialkyl
imidazolium are becoming more important for synthetic
applications. The preparation of the 1,3-dialkylimdazolium
halides via conventional as well as non conventional
methods is well documented in literature [10].
ILs with acidic counterions like 1-hexyl-3methyl-imidazolium
hydrogen
sulphate
([hmim]
[HSO4]) [11], 1-butyl-3-methyl-imidazoliumdihydogen
phosphate([bmim][H2PO4])
[11],
1-[2-(2-hydroxyethoxy)ethyl]-3-methyl-imidazolium hydrogen sulphate
([heemim][HSO4]) [11] and 1-butyl-3-methyl-imidazolium
chloroaluminate ([bmim]Cl.2AlCl3) [12] can be used as
good acid catalysts. Moreover their polar nature makes
them ideal for use in a microwave oven.
In an effort to develop clean alternative methods for
the synthesis of different bioactive compounds, we get
interested in the synthesis of bis(indolyl) methanes using
Ionic liquids. Bis(indolyl) methanes and their derivatives
has attracted much attention due to their synthetic as
well as biological applications [13]. The most ubiquitous
of the known bioactive alkaloids are based on the indole
moiety [14]. Vibrindole A has been demonstrated for
the first time to exhibit antibacterial activity against S.
aureus, S.albus, and B. subtilis; gentamycin is in use
as a standard drug [15]. Bis(indolyl)methanes are
very active cruciferous substances used for promoting
beneficial estrogen metabolism and inducing apoptosis
in human cancer cells [16]. Synthetically the reaction of
* E-mail: [email protected]
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S.A. Sadaphal et al.
HSO4
Figure 1.
N+
2.1. General Procedure for the Synthesis of
Bis(indolyl) methanes
N
1-benzyl-3-methyl imidazolium hydrogen sulphate [bnmim] [HSO4].
Ar
Ar-CHO
1
Z
N
H
R
2
Scheme 1.
[bnmim][HSO4]
MW, 450W
R
N Z
H
3
Z N
H
R
Synthesis of Bis(indolyl) methanes by reacting benzaldehydes and indoles.
1H-indole with aldehydes produces azafulvenium salts
that react further with a second 1H-indole molecule to
form bis(indolyl) methanes [17] and these reactions
are inherently green owing to the total atom efficiency
[18] due to itheir solvent free condition. Solvent free
reactions have been demonstrated to be an efficient
technique for various organic reactions instead of using
harmful solvents. Bis(indolyl)methanes are prepared
by several reported methods. Recently rare earth
perfluorooctanoate [RE(PFO)3] [19], trichloro-1,3,5triazine [20], hexamethylenetetramine-bromine [21],
ion-exchange resin [22], Ionic liquids in conjugation
with In(OTf)3 or FeCl3•6H2O [23], ZrOCl4 [24], ZrCl4
[25], antimony(III) Sulphate [26], Ph3CCl [27], More
recently ZrOCl2•8H2O/silica gel [28], heteropoly acid
[29], protic solvent [30], [acmim]Cl [31], [hmim] [HSO4]
[31], ILIS-SO2Cl [32] were also found to promote and
this reactions. In this paper we report the use of ionic
liquid 1-benzyl-3-methyl imidazolium hydrogen sulphate
[bnmim] [HSO4] (Fig. 1).
Using [bnmim] [HSO4] the reaction goes through
very simply and rapidly under microwave irradiation
(Scheme 1).
2. Experimental Procedures
The catalyst [bnmim] [HSO4] was prepared according
to literature methods [11]. The completion of reactions
was monitored by TLC and products were identified by
comparing melting points with those found in literature
and spectral analysis [23-27]. Melting points were
recorded in open capillaries and are uncorrected.
IR spectra were recorded on a matrix of KBr with
Perkin-Elmer 1430 spectrometer.1HNMR spectra were
recorded on Varian NMR spectrometer, Model Mercury
Plus (400MHz), Mass spectra [ES-MS] were recorded
on a Water-Micro mass Quattro-II spectrophotometer.
For the microwave irradiation experiments described
below, a microwave oven equipped with a turntable was
used (LG Smart Chef MS-255R operating at 2450 MHz
having maximum output of 900 W) for reaction.
(0.5 mmole) [bnmim] [HSO4] was added to a mixture
of (2.0 mmol) indole and (1.0 mmol) aldehyde in a
beaker. The reaction mixture was irradiated at 450 W
in microwave oven for an appropriate amount of time.
The completion of the reaction was monitored by TLC.
The resultant reaction mixture was cooled and the
product was separated by simple extraction with CH2Cl2.
The crude product was obtained by concentrating the
reaction mixture under vacuum. The crude product was
recrystalised using ethanol.
2.2. Characterisation of the products
3,3’ bis(indolyl) phenylmethane 3a. IR (KBr): 3478,
3019, 1601, 1522, 1456, 1419, 1215, 1093, 1017,
757, 669 cm-1; PMR (CDCl3): δH 5.89(1H, s), 6.67(2H,
s), 7.09-7.58(13H, m), 7.94(2H, bs, NH); ES-MS E/Z
322(M+).
3,3’ bis(indolyl)-4-methylphenylmethane 3b. IR
(KBr): 3480, 3020, 1602, 1512, 1456, 1417, 1215,
1091, 1021,759, 669 cm-1; PMR (CDCl3):δH 2.31(3H, s
), 5.84(1H, s), 6.64(2H, s), 6.85-7.40(12H, m), 7.94(2H,
bs, NH); ES-MS E/Z 336(M+).
3,3’ bis(indolyl)-4-methoxyphenylmethane 3c. IR
(KBr): 3480, 3019, 2838, 1610, 1509, 1455, 1456,
1417, 1336, 1216, 1091, 1033, 759 cm-1; PMR (CDCl3):
δH 3.77(3H, s), 5.84(1H, s), 6.64(2H, d), 6.83(2H d),
7.03(2H t),7.2(2H, t); 7.26-7.40(6H, m), 7.89(2H, bs,
NH); ES-MS E/Z 352(M+).
3,3’ bis(indolyl)-3,4-dimethoxyphenylmethane 3d.
IR (KBr): 3480, 3020, 1604, 1512, 1456, 1418, 1336,
1216, 1091, 1033, 759 cm-1; PMR (CDCl3): δH 3.76(3H,
s ), 3.85(3H, s ), 5.83(1H, s), 6.65(2H, d), 6.78(2H, d),
7.0(3H, t), 7.17(2H, t), 7.29-7.43(4H, m), 7.91(2H, bs,
NH); ES-MS E/Z 382(M+).
3,3’ bis(indolyl)-4-chlorophenylmethane 3e. IR (KBr):
3478, 3020, 2927, 1600, 1523, 1456, 1417, 1216, 1091,
1015, 759 670 cm-1; PMR. (CDCl3): δH 5.88 (1H, s), 6.63
(2H, brs), 7.00-7.70(12H, m), 7.92(2H, bs, NH); ES-MS
E/Z 322(M+).
3,3’ bisindolyl(2-furfuryl)methane 3j. IR (KBr): 3477,
3019, 2399, 1600, 1456, 1419, 1216, 1093, 1021, 757,
670 cm-1; PMR (CDCl3): δH 5.94 (1H, s), 6.06 (1H, d),
6.30(1H, d), 6.87(1H, d), 7.08(2H, t), 7.17(2H, t), 7.29
-7.48(5H, m),7.95(2H, bs, NH). ES-MS E/Z 312(M+).
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Ionic Liquid Promoted Synthesis of Bis(indolyl)
methanes
Table 1.
Comparison of data in the synthesis of 3,3’bis(indolyl)phenylmethane (3a) under various reaction conditions.
Entry
Reaction condition
time (min)
yield (%)
1.
[bnmim] [HSO4] / MW
5
93
2.
[bnmim] [HSO4] / R.T.
30
55
3.
Microwave Irradiation without [bnmim]
[HSO4]
15
50
4.
Without [bnmim] [HSO4] / MW
60
40
3. Results and Discussion
During the initial study, the reaction of benzaldehyde
with indole (1:2 molar ratios) using a catalytic amount
(0.5 mmole) of [bnmim] [HSO4] was performed. The
reaction was carried out using a microwave oven as
an energy source. To evaluate the effect of microwave
energy, model reaction was performed at 180 W (40°C),
270 W (60°C), 360 W (90°C), 450 W (120°C) and 600 W
(150°C). We found that with the increase in power from
180 W to 450 W, an increase in the yield and a decrease
in reaction time was observed. Beyond 450 W resulted
in an increase in reaction time. Hence the reaction could
be performed most efficiently at 450W. A similar effect is
observed in Table 1.
Table 2.
Entry
Under these optimized reaction conditions the
desired bis(indolyl)methane (3a, Table 2) was obtained
with 93% yield within 5 min. Hence all the derivatives
of bis(indolyl) methanes were prepared at 450 W using
(0.5 mmole) [bnmim] [HSO4] as a catalyst. This protocol
is superior as compared with the literature data (Table 3)
with respect to reaction time and ecofriendliness. We
also performed the reaction of benzaldehyde with
substituted indoles using [bnmim] [HSO4] which gives
satishfactory results with respect to reaction time and
yield (Table 4).
Next we investigated the reusability and recycling
of [bnmim] [HSO4]. At first, we put (0.5 mmole)
[bnmim] [HSO4] to a mixture of (2.0 mmol) indole and
(1.0 mmol) benzaldehyde in a beaker. The reaction
mixture was irradiated at 450 W in microwave oven for
appropriate time. After the usual workup procedure (see
Experimental) of the reaction, the insoluble [bnmim]
[HSO4] can be directly recycled in subsequent runs.
The activity of the catalyst did not show any significant
decrease in activity even after 3 runs (Table 5).
Characterization of bis(indolyl)methanes 3a-3l (R = Z = H).
Ar
Time (min.)
Yield (%)
M.P. (oC)a
3a
C6H5
5
93
124-126
3b
4-Me C6H4
14
90
97-99
3c
4-MeO C6H4
15
89
191-193
3d
3,4-MeO C6H3
17
88
220-222
3e
4-Cl C6H4
6
95
104-105
3f
4-OH C6H4
18
88
123-125
3g
4-NO2 C6H4
5
96
221-223
3h
3-MeO, 4-OH C6H3
10
88
111-113
3i
2-pyridyl
11
91
137-139
3j
2-furyl
19
85
319-321
3k
2-thiophyl
16
86
278-280
2-Piperanyl
17
90
98-99
3l
a
melting points compared with physical data in [23-27]
Table 3.
Comparison of data in the synthesis of compound 3a using [bnmim][HSO4] with those found in literature.
Entry
Catalyst
Condition
Time (min)
Yield (%)
1
ZrCl4
CH3CN/RT
35
91
2
ZrOCl4
CH3CN/RT
35
89
3
Sb2(SO4)3
MeOH/RT
90
96
4
Ph3CCl
Grinding/RT
20
90
5
La(PFO)3
EtOH/RT
30
90
6
[hmim] [HSO4]
EtOH/RT
60
97
7
ILIS-SO2Cl
MeCN/RT
330
97
8
[bnmim] [HSO4]
Neat/MW
5
93
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S.A. Sadaphal et al.
Table 4.
Entry
Reaction of benzaldehyde with substituted indoles.
Substituted indole
Time (min)
1
R = H, Z = Me
2
R = 5-Me, Z = H
a
Yield (%)
M.P. (oC)a
10
81
246-248
13
85
196-198
melting points compared with physical data in [30]
Table 5.
The The recycling of [bnmim][HSO4] in the synthesis of
compound 3a.
Entry
Time (min)
Yield (%)a
0
5
93
1
7
91
2
9
90
3
12
89
a
isolated yields
4. Conclusions
Novelty of this procedure is introduction of [bnmim] [HSO4]
as an efficient catalyst for the synthesis of bis(indolyl)
methanes. This methodology is environmentally benign
and gives better results for synthesis of bis(indolyl)
methanes.
Acknowledgements
The authors are thankful to The Head, Department of
Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, for providing laboratory
facilities.
References
[1] T. Welton, Chem.Rev. 99, 2071 (1999)
[2] P. Wasserscheid and W. Keim, Angew. Chem. Int.
Ed. 39, 3772 (2000)
[3] R. Sheldon, Chem.Commun. 2399 (2001)
[4] C.O. Kappe, Tetrahedron 49, 6937 (1993) and
references cited therein
[5] J. G. Huddleston, A. E Visser, W. M. Reichert, H.
D. Willauer, G. A. Broker and R. D. Rogers, Green
Chem. 3, 156 (2001)
[6] S. Lee, J. H. Park, J. Kang and J. K Lee, Chem.
Commun. 1698 (2001)
[7] S. Csihony, C. Fischmeister, C. Bruneau, I. T.
Horvath and P. H. Dixneuf, New J. Chem. 11, 1667
(2002)
[8] (a) T. Fischer, A. Sethi, T. Welton, J. Woolf,
Tetrahedron Lett. 40, 793 (1999); (b) Z. Baan, Z. Finta,
G. Keglevich and I. Hermecz, Tetrahedron Lett. 46,
6203 (2005)
[9] A. Agarwal, N. L. Lancaster, A. R. Sethi and T.
Welton, Green Chem. 5, 517 (2002)
[10] R.S. Varma and V.V. Namboodiri, Pure Appl.Chem.
73, 1309 (2001)
[11] J. Fraga-Dubreuil, J. K. Bourahla, M. Rahmouni,
J. P. Bazureau and J. Hamelin, Catal. Commun. 3,
185 (2002)
[12] M.K. Potdar, S.S. Mohile and M.M. Salunkhe,
Tetrahedron Lett. 42, 9285 (2001)
[13] (a) T. Osawa and M. Namiki, Tetrahedron Lett.
24, 4719 (1983); (b) J.K. Porter, C.W. Bacon, J.D.
Robbin, D.S. Himmelsbach and H.C. Higman, J
Agric Food Chem. 25, 88 (1977); (c) T.R. Garbe,
M. Kobayashi, N. Shimizu, N. Takesue, M. Ozawa
and H. Yukawa, J Nat Prod. 63, 596 (2000)
[14] (a) G.W. Gribble, In comprehensive Heterocyclic Chemistry, 2nd ed. (Pergamon Pres: New
York, 1996) 202; (b) V. Snieckus, In The Alkaloids
(Academic Press: New York, 1998) 11
[15] C. Hong, G.L. Firestone, L.F. Bjeldanes, Biochem.
Pharmaco 63, 1085 (2002)
[16] X. Ge, S. Yannai, G. Rennert, N. Gruener and F. A.
Fares, Biochem. Biophys. Res. Commun. 228, 153
(1996)
[17] (a) C. Lin, J. Hsu, M.N.V. Sastry, H. Fang, Z. Tu, J.
Liu and Y. Ching-Fa, Tetrahedron, 61, 11751 (2005);
(b) G. Bartoli, M. Bartolacci, M. Bosco, G. Foglia, A.
Giuliani, E. Mareantoni, L. Sambri and E. Torregiani,
J. Org. Chem. 68, 4594 (2003)
[18] P. Anastas and J. C. Warner, Green chemistry,
theory and practice (Oxford, UK, 1998)
[19] L. M. Wang, J. W. Han, H. Tian, J. Sheng, Z. Y. Fan
and X. P. Tang, Synlett 337 (2005)
[20] G. V. M. Sharma, J. J. Reddy, P. S. Lakshmi and P.
R. Krishna, Tetrahedron Lett. 45, 7729 (2004)
[21] B. P. Bandgar, S. V. Bettigeri and N. S. Joshi,
Monatsh. Chem. 135, 1265 (2004)
[22] X. L. Feng, C. J. Guan and C. X. Zhao, Synth.
Commun. 34, 487 (2004)
[23] (a) S. J. Ji, M. F. Zhou, D. G. Gu, S. Y. Wang and
T. P. Loh, Synlett 2077 (2003); (b) S. J. Ji, M. F.
Zhou, D. G. Gu, Z. Q. Jiang and T. P. Loh, Eur. J.
Org. Chem. 1584 (2004)
[24] R. R. Nagawade and D. B. Shinde, Acta Chim.
Slov. 53, 210 (2006)
[25] R. R. Nagawade, D. B. Shinde, Bull. Korean Chem.
Soc. 26, 12 (2005)
[26] A. Srinivasa, P.P. Varma, V. Hulikal and K. M.
Mahadevan, Monatsh. Chem., 39, 111 (2008)
[27] A. Khallafi-Nezhad et. al., Synthesis 617 (2008)
[28] H. Firouzabadi, N. Iranpoor, M. Jafarpour, A.
Ghaderi, J. Mol. Catal. A: Chem., 253, 249 (2006)
625
Unauthenticated
Download Date | 6/15/17 11:02 AM
Ionic Liquid Promoted Synthesis of Bis(indolyl)
methanes
[29] N. Azizi , L. Torkian, M. R. Saidi, J. Mol. Catal. A:
Chem. 275, 109 (2007)
[30] M. L. Deb, P. J. Bhuyan, Tetrahedron Lett. 47, 1441
(2006)
[31] G. D. Gong, JI Shun-Jun, J. Zhao-Qin, Z.
Min-Feng, L. Teck-Peng, Synlett 959 (2005)
[32] H. Hagiwara, M. Sekifuji, T. Hoshi, K. Qiao, C.
Yokoyamac, Synlett 1320 (2007)
626
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