An efficient one-pot synthesis of bis-indolylmethanes containing pyrazolyl catalyzed by Bronsted acidic ionic liquid under solvent-free conditions

Article abstract of DOI:10.1002/jhet.650

Figure represented. Bronsted acidic ionic liquid [PyNCH ₂CO₂H][HSO₄] was found to be an effective catalyst for the condensation reactions of indoles with various 4-formylpyrazoles to afford the corresponding bis-indolylmet

Full text of DOI:10.1002/jhet.650

July 2011
An Efficient One-Pot Synthesis of Bis-Indolylmethanes
Containing Pyrazolyl Catalyzed by Brønsted Acidic Ionic Liquid
Under Solvent-Free Conditions
845
Chenjiang Liu* and Chuanji Yu
Key Laboratory of Oil and Gas Fine Chemicals, School of Chemistry and Chemical Engineering,
Xinjiang University, Ministry of Education, Urumqi 830046, People’s Republic of China
*E-mail: pxylcj@126.com
Received March 19, 2010
DOI 10.1002/jhet.650
Published online 12 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
Brønsted acidic ionic liquid [PyNCH2CO2H][HSO4] was found to be an effective catalyst for the con-
densation reactions of indoles with various 4-formylpyrazoles to afford the corresponding bis-indolylme-
thanes containing pyrazole under solvent-free conditions. The satisfactory results were obtained with
excellent yields, short reaction time, and simplicity in the experimental procedure.
J. Heterocyclic Chem., 48, 845 (2011).
INTRODUCTION
solvent-free conditions. Here, an efficient and practical
method for the synthesis of target compounds is
described and none of them has yet been reported in the
literature (Scheme 1).
In recent years, bis-indolylmethanes have received
much attention due to their potential applications in the
pharmaceutical and agrochemical industries [1]. Conse-
quently, numerous methods describing the preparation
of bis-indolylmethanes have been reported in the litera-
ture using protic acids or Lewis acids as catalyst includ-
ing AlPW12O40 [2], LiClO4 [3], Zeokarb-225 [4], oxone
[5], HClO4-SiO2 [6], oxalic acid [7], HTP or supported
HTP [8] and so on. However, some of the previously
reported methods suffer from several setbacks, such as
expensive and highly toxic catalysts, long reaction time,
and low yield. To avoid these limitations, there is a
need for simple environmentally friendly procedures for
the preparation of bis-indolylmethanes.
RESULTS AND DISCUSSION
Various reaction parameters, such as reaction time,
temperature, and the molar ratio of ionic liquid to the
substrate were studied using the reaction of indole with
5-chloro-4-formyl-3-methyl-1-phenylpyrazole as a model
and the results were presented in Table 1. The influence
of the molar ratio of ionic liquid to the substrate was
examined for the model reaction first. Raising the molar
ratio of ionic liquid/substrate from 0 to 12.5 resulted in
increasing in yield from 0 to 99% (entries 1–5), while
the molar ratio of ionic liquid to the substrate over 12.5
resulted in decreasing in yield (entry 6). Then the effect
of reaction time on yield was investigated (entries 5 and
7–10). The results showed the reaction nearly tend to
equilibrium after 30 min. Excessively prolonged time
did not change the yield significantly. At last, the influ-
ence of the reaction temperature on the yield was also
investigated (entries 10–13). It was clear that the highest
yield was provided when the reaction temperature was
Recently, ionic liquids (ILs) have attracted increasing
interest in the context of Green Chemistry owing to
their advantageous properties [9,10]. Due to their unique
biological properties, pyrazole derivatives have attracted
much attention [11]. In continuation of our interest in
ILs applications for green chemistry [12], we studied
the possibility to synthesize bis-indolylmethanes con-
taining pyrazolyl using 4-formylpyrazole instead of ordi-
nary aldehydes as substrates and using Brønsted acidic
ionic liquid [PyNCH2CO2H][HSO4] as catalyst under
C
V
2011 HeteroCorporation

846
C. Liu and C. Yu
Vol 48
Scheme 1
80ꢀC. Therefore, the best condition uses 0.125:2:1 mole
ratio of ionic liquid, indole, and 4-formylpyrazole at
80ꢀC for 30 min.
and Brønsted acidic ionic liquid [PyNCH2CO2H][HSO4]
(0.125 mmol) was reacted at 80ꢀC for 0.5 h under solvent-free
conditions. After cooling, the reaction mixture was poured
onto crushed ice (30 g). The resulting precipitate was filtered
under suction, and then recrystallized from ethanol to afford
the pure product 3a. The same procedure was used for the syn-
thesis of products 3b–j. The physicochemical data for the syn-
thesized compounds are as shown below.
To examine the scope and generality of this procedure,
we extended the methodology to different indoles and 4-
formylpyrazoles. The results were presented in Table 2. In
general, the reaction proceeded easily and the correspond-
ing adducts were isolated in excellent yields. A proposed
reaction mechanism for the condensation reactions of
indoles with 5-chloro-4-formyl-3-methyl-1-phenylpyrazole
was presented in Scheme 2. The 5-chloro-4-formyl-3-
methyl-1-phenylpyrazole was first activated by proton and
then carried out electron rich b-position of indole ring.
After loss of water, an intermediate 4 was generated.
Then the intermediate 4 was served as an electrophile to
attack a second molecule of indole to form the product.
In conclusion, we described an efficient and simple
method for the synthesis of a series of novel bis-indolyl-
methanes containing pyrazole using 4-formylpyrazole
instead of ordinary aldehydes as substrate and using
Brønsted acidic ionic liquid [PyNCH2CO2H][HSO4] as
catalyst under solvent-free conditions. Hence, a clean
and environmentally friendly strategy for the synthesis
of bis-indolylmethanes is developed. At the same time,
it is an important supplement to the existing methods
for the synthesis of bis-indolylmethanes.
Bis-(indol-3-yl)(5-chloro-3-methyl-1-phenylpyrazol-4-yl)
methane (3a). Mp 196–198ꢀC. IR (KBr): 3372, 2921, 1610,
1
1512, 1479, 1366, 738 cm–1; H-NMR (400 MHz, DMSO-d6):
d ¼ 1.99 (s, 3H, CH3), 5.83 (s, 1H), 6.87–7.58 (m, 15H, ArH),
10.87 (brs, 2H, NH); Anal Calcd for C27H21N4Cl: C, 74.22; H,
4.84; N, 12.82. Found: C, 74.36; H, 4.89; N, 12.74.
Bis-(indol-3-yl)(3-methyl-5-phenoxyl-1-phenylpyrazol-4-yl)
methane (3b). Mp 209–210ꢀC; IR (KBr): 3365, 2911, 1609,
1
1552, 1454, 1362, 737 cm–1; H-NMR (400 MHz, DMSO-d6):
d ¼ 1.99 (s, 3H, CH3), 5.58 (s, 1H), 6.76–7.59 (m, 20H, ArH),
10.75 (brs, 2H, NH) Anal Calcd for C33H26N4O: C, 80.14; H,
5.30; N, 11.33. Found: C, 80.26; H, 5.39; N, 11.24.
Bis-(2-methylindol-3-yl)(5-chloro-3-methyl-1-phenylpyrazol-4-
yl)methane (3c). Mp 196–198ꢀC; IR (KBr): 3385, 2921, 1599,
1
1502, 1459, 1356, 742 cm-1; H-NMR (400 MHz, DMSO-d6):
Table 1
Effect of different reaction conditions for condensation of 3a.a
Temperture
(ꢀC)
Time
(min)
Catalyst
(mol%)
Yield
(%)b
Entry
1
2
100
100
100
100
100
100
100
100
100
100
35
120
120
120
120
120
120
10
0
2.5
0
32
58
89
99
94
68
87
99
98
43
81
98
3
4
5
10
EXPERIMENTAL
Melting points were determined using a Bu¨chi B-540 instru-
ment and are uncorrected. The IR spectra were obtained as po-
tassium bromide pellets with a FTS-40 spectrometer (BIO-
RAD). The 1H-NMR spectra were measured on a Varian
Inova-400 spectrometer using TMS as an internal standard in
CDCl3 or DMSO-d6. Elemental analysis (C, H, N) was per-
formed on a Perkin-Elmer Analyzer 2400. The Brønsted acidic
ionic liquid [PyNCH2CO2H][HSO4] was synthesized according
to previous literature [13].
5
6
12.5
15
7
12.5
12.5
12.5
12.5
12.5
12.5
12.5
8
9
20
60
10
11
12
13
30
30
55
80
30
30
a Reaction conditions: indole (2 mmol), 5-chloro-4-formyl-3-methyl-1-
phenylpyrazole (1 mmol) and catalyst.
b Isolated yields.
General procedure for the synthesis of bis-indolyl-
methane containing pyrazolyl. A mixture of 5-chloro-4-
formyl-3-methyl-1-phenylpyrazole (1 mmol), indole (2 mmol),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
An Efficient One-Pot Synthesis of Bis-Indolylmethanes Containing Pyrazolyl
Catalyzed by Brønsted Acidic Ionic Liquid Under Solvent-Free Conditions
847
Table 2
[PyNCH2CO2H][HSO4]-catalyzed one-pot synthesis of the bis-indolylmethanes containing pyrazole 3.a
Product
R
R1
R2
R3
Yields (%)b
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
Cl
C6H5O
Cl
C6H5O
p-Cl-C6H4O
Cl
C6H5O
Cl
C6H5O
p-Cl-C6H4O
98
94
92
91
87
94
85
98
93
89
H
H
CH3
CH3
CH3
H
H
H
H
H
H
H
CH3O
Br
H
H
CH3
CH3
CH3
H
H
H
3j
H
H
a Reaction conditions: 4-formylpyrazoles (1mmol), indole or substituted indoles (2 mmol), catalyst (12.5 mol%), 0.5 h, 80 ꢀC.
b Isolated yields.
d ¼ 1.88 (s, 3H, CH3), 2.03 (s, 6H, 2ꢁCH3), 5.56 (s, 1H),
6.89–7.73 (m, 13H, ArH), 10.51 (brs, 2H, NH); Anal Calcd for
C29H25N4Cl: C, 74.91; H, 5.42; N, 12.05. Found: C, 74.76; H,
5.49; N, 12.16.
DMSO-d6): d ¼ 1.96 (s, 3H, CH3), 3.63 (s, 6H, 2ꢁOCH3),
5.73 (s, 1H), 6.73–7.56 (m, 13H, ArH), 10.72 (brs, 2H, NH);
Anal Calcd for C29H25N4O2Cl: C, 70.08; H, 5.07; N, 11.27.
Found: C, 70.22; H, 4.98; N, 11.14.
Bis-(2-methylindol-3-yl)(3-methyl-5-phenoxyl-1-phenylpyra-
zol-4-yl)methane (3d). Mp 280–281ꢀC; IR (KBr): 3377, 2910,
1597, 1503, 1455, 1363, 744 cm-1; 1H-NMR (400 MHz,
DMSO-d6): d ¼ 1.80 (s, 3H, CH3), 1.94 (s, 6H, 2ꢁCH3), 5.56
(s, 1H), 6.32–7.55 (m, 18H, ArH), 10.51 (brs, 2H, NH); Anal
Calcd for C35H30N4O: C, 80.43; H, 5.79; N, 10.72. Found: C,
80.26; H, 5.69; N, 10.84.
Bis-(5-bromoindol-3-yl)(3-methyl-5-phenoxyl-1-phenyl pyr-
azol-4-yl)methane (3g). Mp 175–177ꢀC; IR (KBr): 3424,
1
2923, 1594, 1503, 1454, 1380, 751 cm-1; H-NMR (400 MHz,
DMSO-d6): d ¼ 1.99 (s, 3H, CH3), 5.57 (s, 1H), 6.64–7.75 (m,
16H, ArH), 11.00 (brs, 2H, NH); Anal Calcd for
C33H24N4OBr2: C, 60.76; H, 3.71; N, 8.59. Found: C, 60.88;
H, 3.78; N, 8.74.
Bis-(2-methylindol-3-yl)(5-(4-chlorophenoxyl)-3-methyl-1-phe-
nylpyrazol-4-yl)methane (3e). Mp 269–272ꢀC; IR (KBr): 3375,
Bis-(1-methylindol-3-yl)(5-chloro-3-methyl-1-phenylpyra-
zol-4yl)methane (3h). Mp 190–193ꢀC;IR (KBr): 2930, 1595,
1
1
2912, 1594, 1503, 1484, 1380, 735 cm-1; H-NMR (400 MHz,
1492, 1462, 1371, 740 cm-1; H-NMR (400 MHz, DMSO-d6):
DMSO-d6): d ¼ 2.00 (s, 3H, CH3), 2.12 (s, 6H, 2ꢁCH3), 5.71
(s, 1H), 6.07–7.55 (m, 17H, ArH), 10.51 (brs, 2H, NH); Anal
Calcd for C35H29N4OCl: C, 75.46; H, 5.25; N, 10.06. Found:
C, 75.36; H, 5.19; N, 10.24.
Bis-(5-methoxylindol-3-yl)(5-chloro-3-methyl-1-phenyl pyr-
azol-4yl)methane (3f). Mp 125–127ꢀC; IR (KBr): 3386, 2968,
1578, 1502, 1484, 1365, 783 cm-1; 1H-NMR (400 MHz,
d ¼ 1.99 (s, 3H, CH3), 3.78 (s, 6H, 2ꢁCH3), 5.83 (s, 1H),
6.96–7.58 (m, 15H, ArH); Anal. Calcd for C29H25N4Cl: C,
74.91; H, 5.42; N, 12.05. Found: C, 74.76; H, 5.49; N, 12.21.
Bis-(1-methylindol-3-yl)(3-methyl-5-phenoxyl-1-phenylpyra-
zol-4yl)methane (3i). Mp 184–186ꢀC; IR (KBr): 2929, 1596,
1
1579, 1470, 1368, 739 cm-1; H-NMR (400 MHz, DMSO-d6):
d ¼ 2.11 (s, 3H, CH3), 3.61 (s, 6H, 2ꢁCH3), 5.62 (s, 1H),
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

848
C. Liu and C. Yu
Vol 48
[3] Yadav, J. S.; Reddy, B. V. S.; Murthy, Ch. V. S. R.;
Kumar, G. M.; Madan, Ch. Synthesis 2001, 783.
[4] Magesh, C. J.; Nagarajan, R.; Karthik, M.; Perumal, P. T.
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6.57–7.58 (m, 20H, ArH); Anal Calcd for C35H30N4O: C,
80.43; H, 5.79; N, 10.72. Found: C, 80.56; H, 5.71; N, 10.84.
Bis-(1-methylindol3-yl)(5-(4-chlorophenoxyl)-3-methyl-1-phe-
nylpyrazol-4-yl)methane (3j). Mp 172–174ꢀC.IR (KBr): 2915,
1584, 1563, 1494, 1378, 735 cm-1; 1H-NMR (400 MHz,
DMSO-d6): d ¼ 2.17 (s, 3H, CH3), 3.60 (s, 6H, 2ꢁCH3), 5.62
(s, 1H), 6.40–7.56 (m, 19H, ArH); Anal. Calcd for
C35H29N4OCl: C, 75.46; H, 5.25; N, 10.06. Found: C, 75.28;
H, 5.18; N, 10.24.
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Acknowledgment. We gratefully acknowledge support from the
National Natural Science Foundation of China (No. 20862016)
ˆ
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet