A mild, efficient and improved protocol for the synthesis of novel indolyl crown ethers, di(indolyl)pyrazolyl methanes and 3-alkylated indoles using H 4[Si(W3O10)3]

Article abstract of DOI:10.1016/j.tet.2005.09.108

Efficient electrophilic substitution reactions of indoles with various aldehydes proceed smoothly in acetonitrile using heteropoly acid (H ₄[Si(W₃O₁₀)₃]) to afford the corresponding new indolyl crown ethers and

Full text of DOI:10.1016/j.tet.2005.09.108

Tetrahedron 61 (2005) 12275–12281
A mild, efficient and improved protocol for the synthesis of novel
indolyl crown ethers, di(indolyl)pyrazolyl methanes and
3
-alkylated indoles using H [Si(W O ) ]
4 3 10 3
a
Rajendran Murugan, Murugesan Karthikeyan, Paramasivam T. Perumal
a
b
a,
and Boreddy S. R. Reddy
*
a
Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India
b
Organic Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India
Received 18 July 2005; revised 30 August 2005; accepted 22 September 2005
Available online 27 October 2005
Abstract—Efficient electrophilic substitution reactions of indoles with various aldehydes proceed smoothly in acetonitrile using heteropoly
acid (H [Si(W ]) to afford the corresponding new indolyl crown ethers and di(indolyl)pyrazolyl methanes. H [Si(W ] is also
4
3
O
10
)
3
4
3 10 3
O )
found to catalyze the Michael addition of indoles to a,b-unsaturated compounds for the synthesis of 3-alkylated indoles.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
reactions proceed, more than stoichiometric amounts of
Lewis acids are required because the acids are trapped by
nitrogen.
1
6
The synthesis and the reactions of indoles have received
much interest for over a century because a number of their
derivatives occur in nature and possess a variety of
The 3-position of indole is the preferred site for the
electrophilic substitution reactions, 3-alkyl or acyl indoles
are versatile intermediates for the synthesis of a wide range
1
biological activities. Pyrazole derivatives have been
2
found to have anticancer, antiviral and antihyperglycemic
3
4
activity. Our efforts here are to synthesize the di(indolyl)-
pyrazolyl methanes which might exert high antimicrobial
17
of indole derivatives. A simple and direct method for the
synthesis of 3-alkylated indoles involves the conjugate
addition of indoles to a,b-unsaturated compounds in the
5
activity. Crown ethers are heteromacrocycles in which the
1
8
19
framework is typically comprised of repeating ethylene
oxy[–(CH CH O)–] units. Nitrogen and sulfur commonly
presence of either protic or Lewis acids. However, the
acid catalyzed conjugate addition of indoles requires careful
control of acidity to prevent side reactions such as
dimerization or polymerization. Many of these procedures
involve strongly acidic conditions, expensive reagents and
long reaction times, give low yields of the products and
involve cumbersome experimental product isolation pro-
2
2
replace oxygen in this framework leading to a great variety
of compounds that have been used in molecular recognition
6
studies and supramolecular chemistry. Alkali metal
cation–p interactions have recently received considerable
attention due to their biological importance.
7
2
0
cedures. The lanthanide triflates and gold catalysts though
less acidic are rather expensive which limits their use in
large scale synthesis. For this reason, cheaper acid catalysts
that secure catalytic activity, low toxicity, moisture and air
tolerance are desirable. In this paper, we wish to introduce
H [Si(W O ) ] as mild, highly efficient moisture tolerant
The electrophilic substitution reactions of indoles with
aromatic aldehydes afford corresponding bis(indolyl)-
8
methanes. Lewis acids, protic acids, ionic liquids,
9
10
1
1
12
13
14
iodine, clays, LPDE, amberlyst-15 and RE(PFO)3
15
are known to promote these reactions. However, many
Lewis acids are deactivated or sometimes decomposed by
nitrogen containing reactants. Even when the desired
4
3 10 3
catalyst for the preparation of indole derivatives under mild
conditions.
Heteropolyacids are remarkable catalysts that are used in
both homogenous and heterogeneous conditions. Their
Keywords: Indolyl crown ether; Di(indolyl)pyrazolyl methanes; Michael
addition; 3-Alkylated indoles.
2
1
*
Corresponding author. Tel.: C91 44 24 4404 427; fax: C91 44 2491
589; e-mail: induchem2000@yahoo.com
application as acid catalysts has been already reviewed.
H [Si(W O ) ] is a solid heteropolyacid that has been used
1
4
3 10 3
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.108

12276
R. Murugan et al. / Tetrahedron 61 (2005) 12275–12281
2
2
for the synthesis of trioxanes, polymerization and for
estimating nicotine and radioactive cesium in some
2
3
derivatives. Its efficiency as an acid catalyst in conden-
sation and Michael addition in indoles is explored in this
report.
Scheme 2.
2
. Results and discussion
Di(indolyl)pyrazolylmethanes have been synthesized via
H [Si(W O ) ] catalyzed condensation of indole (2 equiv)
4
3 10 3
and pyrazolyl aldehydes (1 equiv). The reaction is facile and
is complete within 30 min at room temperature. The method
reported is favorable as good yields (89–95%) are obtained
(Scheme 1). The procedure finds easy applicability because
of the solubility of H [Si(W O ) ] in acetonitrile.
4
3 10 3
Figure 1. X-ray crystal structure of 3a.
Scheme 1.
H [Si(W O ) ] was found to be an excellent acid catalyst
4
3 10 3
in terms of conversion and reaction time (Table 2).
The catalytic activity of H [Si(W O ) ] is found to vary
4
3 10 3
with different solvents (Table 1). The reaction of indole 1
with pyrazolyl aldehyde 4a using H [Si(W O ) ]
The maximum yield was 95% for 5a. In fact, all
the pyrazolyl aldehyde condensed with indoles giving
di(indolyl)pyrazolylmethanes 5a–h in high yields (89–
4
3
10 3
(
20 mol%) as a catalyst was chosen as a model for
optimization. Acetonitrile was found to give maximum
yield followed by THF. The catalyst was found to be only
mildly effective in dichloromethane. The effect of different
ionic liquids on the H [Si(W O ) ] (20 mol%) catalyzed
9
5%). The catalytic activity of H [Si(W O ) ] was
4 3 10 3
explored for the Michael addition of indole with a,b-
unsaturated carbonyl compounds (Scheme 3). Methyl vinyl
ketone reacted with indole and 2-methyl indole in the
presence of a catalytic amount of H [Si(W O ) ] to give
4
3 10 3
reaction was also examined. Butyl methyl imidazolium
chloride [bmim][Cl] was found to be better than the other
ionic liquids, but it could not compete with the effectiveness
of the catalyst in acetonitrile.
4
3 10 3
the 3-alkylated indoles (7a, 7c) in excellent yields (Table 3).
The reaction was found to proceed smoothly at ambient
temperature with high selectivity. Other electron deficient
olefins like phenyl vinyl ketone 6b afforded the product in
good yield (87%). The same reaction was attempted with
b-nitro styrene 6d with indole in the presence of
H [Si(W O ) ]. The corresponding 3-alkylated indole 7f
Table 1. Effect of solvent on the conversion to di(indolyl)pyrazolyl
methane (5a)
a
Entry
Solvents
Time (min)
Yield (%)
a
b
c
d
e
f
EtOH
THF
60
60
60
25
60
60
60
75
87
20
95
56
41
72
4
3 10 3
was obtained in 90% yield without any side reactions
thereby emphasizing the mild catalytic activity of
H [Si(W O ) ].
CH
CH
2
Cl
CN
2
3
[pmim][Br]
[ppy][Br]
[bmim][Cl]
4
3 10 3
g
The reactions were clean and the products were obtained in
high yields (85–93%) without the formation of any side
products such as dimers or trimers, which are normally
observed under the influence of strong acids. Furthermore,
no aqueous work-up was required after completion of the
reaction. The reaction mixture was directly charged into a
column after removing the solvent under vacuum.
a
Isolated yields.
New indolyl crown ethers have been synthesized (Scheme 2)
via H [Si(W O ) ] (20 mol%) catalyzed condensation of
indole 2 (1 equiv) and aldehyde (1 equiv) under mild
4
3 10 3
conditions. The reaction is facile and complete within
2
4
4
5 min at room temperature. The structure of 3a was
further confirmed by single crystal X-ray crystallography
Fig. 1).
(
3. Conclusions
The efficacy of Lewis acids, such as CuI, ZnCl , FeCl ,
2
In conclusion, we report H [Si(W O ) ] as a highly
4
3
3 10 3
CeCl and InCl in acetonitrile was studied for the synthesis
3
of di(indolyl)pyrazolylmethane 5a. In comparison,
efficient catalyst for the synthesis of new indolyl crown
ethers, di(indolyl)pyrazolylmethanes and Michael addition
3

R. Murugan et al. / Tetrahedron 61 (2005) 12275–12281
12277
a
4 3 10 3
Table 2. H [Si(W O ) ] catalyzed synthesis of di(indolyl)pyrazolyl methanes
b
Entry
Substituents
Time (min)
Yield (%)
1
2
3
4
6
R
R
R
R
C
a
b
c
d
e
f
H
H
H
H
5
5a
25
30
30
25
30
30
30
30
95
94
91
90
93
89
94
91
H
H
H
H
H
Me
Me
H
H
H
Me
H
H
H
H
H
OMe
H
H
m-OMeC
p-OMeC
p-ClC
6
H
H
6 4
5d
4
5b
5c
6
H
4
C
C
C
6
H
6
H
6
H
5
5
5
5e
5f
5g
g
h
H
H
6 5
p-ClC H
5h
a
All products were characterized by IR, NMR and mass spectra.
Isolated yields after purification.
b
spectrometer. IR spectra were recorded on a Perkin–Elmer
FTIR spectrometer. NMR spectra were obtained on a JEOL
ECA-500 MHz spectrometer. NMR was recorded at
500 MHz in CDCl and DMSO-d and the chemical shifts
3 6
are given in d. X-ray diffraction data were made on a Bruker
SMART CCD area detector with monochromated Mo Ka
radiation.
Scheme 3.
a
Table 3. H
4
[Si(W
3
O
10
)
3
] catalyzed synthesis of 3-alkylated indoles
b
Entry
Substituents
Product
Time (min)
Yield (%)
1
R
2
R
3
R
5
R
6
R
a
b
c
d
e
f
g
h
i
H
H
H
H
Me
H
n-Pr
n-Bu
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
COMe 6a
COPh 6b
COMe 6a
COPh 6c
COPh 6c
NO 6d
2
COPh 6c
COPh 6c
7a
7b
7c
7d
7e
7f
7g
7h
7i
15
15
10
25
15
15
20
15
25
20
85
87
91
89
93
90
92
90
90
93
p-OMeC
p-OMeC
Ph
p-OMeC
p-OMeC
Ph
6
H
H
4
4
6
6
H
H
4
4
6
NO
NO
2
6d
6e
j
H
CO Me
2
2
7j
a
All products were characterized by IR, NMR and mass spectra.
Isolated yields after purification.
b
of indoles with a,b-unsaturated carbonyl compounds.
The reactions were successfully carried out in the
presence of a catalytic amount of H [Si(W O ) ] in
4.1.1. 1-[2-(2-{2-[2-(1H-Indol-1-yl)ethoxy]ethoxy}ethoxy)-
ethyl]-1H-indole (2). Indole 1a (500 mg, 4.27 mmol) was
added to a suspension of NaH (60% in oil, 256 mg, 6.41 mmol
washed with dry n-hexane [3!10 mL] by syringe) in dry
DMF (30 mL), was stirred at 0 8C under nitrogen atmosphere.
After the evolution of hydrogen gas had ceased, a dry DMF
4
3 10 3
acetonitrile. H [Si(W O ) ] offers several advantages
4
3 10 3
including mild reaction conditions, cleaner reactions,
shorter reaction times, and high yields of products.
This simple experimental procedure, offers an alternative
route to the synthesis of biologically active indole
derivatives.
(10 mL) solution of tetraethylene glycol ditosylate (1.07 g,
2.14 mmol) was added dropwise to the suspension with
stirring for 50 min at room temperature. After the reaction was
complete, the organic solution was filtered and evaporated in
vacuum, extracted with EtOAc (3!20 mL) washed with
4
. Experimental
water, the brine then dried over anhydrous Na SO and
2 4
purified by column chromatography (Merck, 100–200 mesh,
EtOAc–hexane, 2:8) to afford the pure product 2 in 85% yield
4
.1. General
(1.42 g) as a light yellow oil; [Found: C, 73.41; H, 7.15; N,
7
(
.12. C H N O requires C, 73.44; H, 7.19; N, 7.14%]; n
3
2
4
28
2
max
Melting points were recorded on a CONCORD melting
point apparatus and are uncorrected. Analytical TLC was
performed on precoated sheets of silica gel G of 0.25 mm
thickness containing PF254 indicator (Merck, Darmstadt).
H [Si(W O ) ] was purchased from Sisco Research Lab,
K1
neat) 3301, 1610, 1464, 1101, 754 cm ; dH (500 MHz,
CDCl ) 7.70 (2H, d, JZ8.0 Hz, ind H), 7.40 (2H, d, JZ
9
3
3
.1 Hz, ind H), 7.27 (2H, t, JZ7.4 Hz, ind H), 7.21 (2H, t, JZ
.4 Hz, ind H), 7.17 (2H, t, JZ7.4 Hz, C]CHN), 6.55 (2H, d,
4
3 10 3
India and used as such. Column chromatography was
performed with silica gel (100–200 mesh, s.d fine). Mass
spectra were recorded on JEOL-JMS DX 303HF mass
JZ2.9 Hz, CH]CHN), 4.30 (4H, t, JZ5.7 Hz, CH
(4H, t, JZ5.7 Hz, OCH CH N), 3.53–3.49 (8H, m, OCH
CH O); d (125 MHz, CDCl ) 136.2, 128.8, 128.7, 121.6,
2
N), 3.79
-
2
2
2
2
C
3

12278
R. Murugan et al. / Tetrahedron 61 (2005) 12275–12281
1
(
21.1, 119.5, 109.5, 101.3, 70.9, 70.7, 70.3, 46.3; m/z 392
M ).
4.3.1. 3-[1H-Indol-3-yl(3-phenyl-1H-pyrazol-4-yl)methyl]-
1H-indole (5a). Light orange solid (630 mg, 95%), mp
C
2
C H N C, 80.39; H, 5.19; N, 14.42%]; n (KBr) 3410,
3
06 8C; [Found: C, 80.38; H, 5.16; N, 14.40. requires
2
6
20
4
max
4
.2. Typical experimental procedure 3
K1
048, 1627, 1462, 1420, 1339, 1095, 745 cm ; dH
(
(
500 MHz, DMSO-d ) 12.52 (1H, br s, pyr NH), 10.78
6
2H, s, ind NH), 7.56 (2H, d, JZ7.6 Hz), 7.44 (1H, s, pyr
A mixture of indole 2 (510 mg, 1.30 mmol), 4-(dimethyl-
amino)benzaldehyde (194 mg, 1.30 mmol) and
H [Si(W O ) ] (20 mol%) in acetonitrile (10 mL) was
stirred at room temperature for 45 min. After complete
conversion, as indicated by TLC, the reaction mixture was
concentrated in vacuum, and purified by column chroma-
tography on silica gel (Merck, 100–200 mesh, EtOAc–
hexane, 3:7) to afford the pure product 3b in 52% yield
C]CHN), 7.35–7.27 (5H, m, Ph), 7.17 (2H, d, JZ7.6 Hz,
ind H), 6.99 (2H, t, JZ7.6 Hz, ind H), 6.86 (2H, s, ind
C]CHN), 6.81 (2H, t, JZ7.7 Hz, ind H), 5.83 (1H, s,
Ar CH); d (125 MHz, DMSO-d ) 170.9, 137.2, 134.3,
1
1
4
3 10 3
3
C
6
32.4, 129.2, 127.9, 126.8, 123.9, 121.4, 119.3, 118.8,
14.3, 112.1, 111.2, 56.6, 30.2; m/z 388 (M ).
C
(
354 mg).
4
.3.2. 3-[1H-Indol-3-yl(3-(3-methoxyphenyl)-1H-pyra-
zol-4-yl)methyl]-1H-indole (5b). Orange solid (672 mg,
94%), mp 202–204 8C; [Found: C, 77.45; H, 5.32; N, 13.36.
4
.2.1. 3-[1-[2-(2-{2-[2-(1H-Indolyl-1-yl)ethoxy]ethoxy}-
ethoxy)ethyl](4-methoxyphenyl)methyl]-1H-indole (3a).
Orange crystal (280 mg, 43%), mp 140–142 8C; [Found: C,
C
27
H
22
N
4
O requires C, 77.49; H, 5.30; N, 13.39%]; nmax
(KBr) 3418, 3037, 1620, 1462, 1431, 1250, 1088, 1037,
K1
7
6
7
5.25; H, 6.68; N, 5.51. C H N O requires C, 75.27; H,
2 34 2 4
745 cm ; d (500 MHz, DMSO-d ) 12.80 (1H, br s, pyr
H 6
3
.71; N, 5.49%]; n
(KBr) 2865, 1609, 1465, 1350, 1103,
NH), 10.76 (2H, s, ind NH), 7.31 (2H, d, JZ8.4 Hz, Ph),
7.27 (1H, s, pyr C]CHN), 7.24–7.17 (4H, m, Ph and ind
H), 7.03 (1H, s, Ph), 7.00 (3H, t, JZ7.6 Hz, ind H), 6.85
(2H, s, ind C]CHN), 6.81 (2H, t, JZ7.7 Hz, ind H), 5.83
(1H, s, Ar
d ) 159.7, 137.2, 130.1, 129.4, 126.9, 125.3, 123.9, 122.0,
6
max
K1
40 cm ; d (500 MHz, CDCl ) 7.42 (2H, d, JZ8.4 Hz,
H
3
ind H), 7.31 (2H, d, JZ7.6 Hz, ind H), 7.28 (2H, d, JZ
8
.4 Hz, Ph), 7.19 (2H, t, JZ7.6 Hz, ind H), 7.01 (2H, t, JZ
.6 Hz, ind H), 6.85 (2H, d, JZ8.4 Hz, Ph), 6.75 (2H, s,
7
C]CHN), 5.87 (1H, s, Ar CH), 4.27–4.23 (2H, m, CH N),
3
CH), 3.37 (3H, s, OCH ); d (125 MHz, DMSO-
3 C
3
2
4
.15–4.12 (2H, m, CH N), 3.81 (3H, s, OCH ), 3.74–3.66
2
121.4, 119.9, 119.4, 119.1, 118.7, 116.2, 114.0, 112.6,
112.0, 55.0, 30.4; m/z 418 (M ).
3
C
(4H, m, OCH ), 3.46–3.43 (2H, m, OCH ), 3.37–3.30 (6H,
m, OCH CH O); d (125 MHz, CDCl ) 157.9, 136.8, 136.7,
2
2
2
2
C
3
1
1
29.8, 129.7, 128.6, 127.7, 121.3, 120.1, 118.8, 113.6,
09.1, 72.0, 71.1, 70.0, 55.3, 46.3, 39.1; m/z 510 (M ); lmax
4.3.3. 3-[1H-Indol-3-yl(3-(4-methoxyphenyl)-1H-pyra-
zol-4-yl)methyl]-1H-indole (5c). Brown solid (650 mg,
91%), mp 207–209 8C; [Found: C, 77.46; H, 5.28; N, 13.41.
C H N O requires C, 77.49; H, 5.30; N, 13.39%]; n
max
C
(
UV, MeOH) 309.6 nm.
2
7
22
4
(
1
KBr) 3414, 3034, 1612, 1427, 1415, 1338, 1238, 1088,
018, 745 cm ; d (500 MHz, DMSO-d ) 12.83 (1H, br s,
H 6
4
.2.2. 3-[1-[2-(2-{2-[2-(1H-Indolyl-1-yl)ethoxy]ethoxy}-
K1
ethoxy)ethyl](4-N,N-dimethylaminophenyl)methyl]-1H-
indole (3b). Pink crystal (354 mg, 52%), mp 162–164 8C;
pyr NH), 10.80 (2H, s, ind NH), 7.50 (2H, d, JZ8.0 Hz, Ph),
7
7
.42 (1H, s, pyr C]CHN), 7.32 (2H, t, JZ7.6 Hz, ind H),
.20 (2H, d, JZ7.7 Hz, ind H), 7.02 (2H, t, JZ7.6 Hz, Ph),
[
Found: C, 75.65; H, 7.11; N, 7.99. C H N O requires C,
33 37 3 3
7
1
5.69; H, 7.12; N, 8.02%]; n
466, 1350, 1123, 729 cm ; d (500 MHz, CDCl ) 7.41
(KBr) 2865, 1611, 1517,
max
K1
6.91 (2H, t, JZ7.6 Hz, ind H), 6.88 (2H, s, ind C]CHN),
.85 (2H, t, JZ7.7 Hz, ind H), 5.83 (1H, s, Ar CH), 3.73
H
3
6
(
1
1
3
(
2H, d, JZ8.0 Hz, ind H), 7.29 (2H, d, JZ8.6 Hz, Ph),
3H, s, OCH ); d (125 MHz, DMSO-d ) 162.8, 159.1,
3 C 6
7
6
.21–7.14 (4H, m, ind H), 6.98 (2H, t, JZ7.4 Hz, ind H),
.74 (2H, s, C]CHN), 6.70 (2H, d, JZ8.6 Hz, ind H), 5.81
37.2, 130.2, 128.9, 126.9, 123.8, 121.3, 119.4, 119.2,
18.6, 114.5, 112.5, 111.9, 110.0, 55.5, 30.2; m/z 418 (M ).
C
(1H, s, Ar CH), 4.27–4.20 (2H, m, CH N), 4.15–4.09 (2H,
m, CH N), 3.73–3.64 (4H, m, OCH CH N), 3.45–3.40 (2H,
m, OCH ), 3.35–3.25 (6H, m, OCH CH O), 2.92 (6H, s,
2
N(CH ) ); d (125 MHz, CDCl ) 156.3. 136.6, 129.4, 128.5,
3
1
7
3
2
2
2
2
4
4
9
.3.4. 3-[1H-Indol-3-yl(3-(4-chlorophenyl)-1H-pyrazol-
-yl)methyl]-1H-indole (5d). Orange solid (649 mg,
0%), mp 227–228 8C; [Found: C, 73.80; H, 4.53; N,
2
2
2
C
3
27.8, 121.1, 120.3, 119.2, 118.6, 112.9, 109.0, 105.4, 72.0,
1.1, 70.0, 55.7, 46.3, 41.0; m/z 523 (M ); lmax (UV,
C
13.19. C26
nmax (KBr) 3417, 1623, 1454, 1416, 1099, 737 cm ; dH
500 MHz, DMSO-d ) 12.85 (1H, br s, pyr NH), 10.80 (2H,
H19ClN requires C, 73.84; H, 4.53; N, 13.25%];
4
K1
MeOH) 309.0 nm.
(
6
s, ind NH), 7.61 (2H, d, JZ8.2 Hz, Ph), 7.39 (3H, t, JZ
7.6 Hz, Ph), 7.35 (1H, t, JZ7.6 Hz, ind H), 7.34 (1H, s, pyr
C]CHN), 7.22 (2H, d, JZ8.0 Hz, ind H), 7.03 (2H, t, JZ
7.7 Hz, ind H), 6.88 (2H, s, ind C]CHN), 6.85 (2H, t, JZ
4
.3. Typical experimental procedure 5
A mixture of indole 1a (200 mg, 1.71 mmol), 3-phenyl-1H-
pyrazole-4-carbaldehyde 4a (147 mg, 0.85 mmol) and
H [Si(W O ) ] (20 mol%) in acetonitrile (10 mL) was
stirred at room temperature for 25 min. After complete
conversion, as indicated by TLC, the solvent was
evaporated under vacuum and the product purified by
column chromatography on silica gel (100–200 mesh,
EtOAc–hexane, 3:7). The product obtained was analyzed
and the yield was found to be (630 mg, 95%). The same
procedure was followed for all the reactions (Table 2).
7.6 Hz, ind H), 5.86 (1H, s, Ar
CH); d (125 MHz, DMSO-
3
C
d
119.5, 118.5, 116.6, 116.1, 115.9, 111.8, 109.2, 33.5; m/z
) 160.1, 137.2, 134.4, 128.7, 126.6, 126.2, 124.0, 121.1,
6
4
3 10 3
C
422 (M ).
4.3.5. 2-Methyl-3-[(2-methyl-1H-indol-3-yl)(3-phenyl-
1H-pyrazol-4-yl)methyl]-1H-indole (5e). Brownish
orange solid (591 mg, 93%), mp 194–196 8C; [Found: C,
80.71; H, 5.80; N, 13.42. C H N requires C, 80.74; H,
2
8 24 4

R. Murugan et al. / Tetrahedron 61 (2005) 12275–12281
12279
5
1
.81; N, 13.45%]; n (KBr) 3422, 3298, 1656, 1472, 1113,
042, 756 cm ; d (500 MHz, DMSO-d ) 12.75 (1H, br s,
conversion, as indicated by TLC, the solvent was
evaporated under vacuum and the product purified by
column chromatography on silica gel (100–200 mesh,
EtOAc–hexane, 2:8) and the product was obtained
(458 mg, 92% yield, Table 3).
max
K1
H
6
pyr NH), 10.64 (2H, s, ind NH), 7.50 (2H, d, JZ7.6 Hz, Ph),
7
7
6
.23 (3H, t, JZ6.9 Hz, Ph), 7.17 (2H, d, JZ7.6 Hz, ind H),
.14 (1H, s, pyr C]CHN), 6.92 (2H, d, JZ7.6 Hz, ind H),
.86 (2H, t, JZ7.6 Hz, ind H), 6.68 (2H, t, JZ7.6 Hz, ind
1
9a
H), 5.78 (1H, s, Ar CH), 2.04 (6H, s, CH ); d (125 MHz,
DMSO-d ) 170.8, 160.9, 135.5, 131.9, 128.9, 128.6, 127.3,
1
3
4.4.1. 4-(1H-Indol-3-yl)butan-2-one (7a). Light brown
solid (272 mg, 85%), mp 70–72 8C; [Found: 76.95; H, 7.02;
N, 7.45. C H NO requires C, 76.98; H, 7.00; N, 7.48%];
3
3
C
6
21.5, 120.1, 118.7, 118.5, 113.4, 112.5, 111.8, 110.9, 60.3,
0.3; m/z 416 (M ).
1
2 13
C
K1
nmax (KBr) 3409, 2928, 1709, 1165, 1067, 745 cm ; dH
500 MHz, CDCl ) 8.01 (1H, s, ind NH), 7.38 (1H, d, JZ
(
3
4
.3.6.
5-Methoxy-3-[(5-methoxy-1H-indol-3-yl)(3-
7.6 Hz, ind H), 7.28 (1H, d, JZ7.6 Hz, ind H), 7.17 (1H, t,
JZ7.1 Hz, ind H), 7.10 (1H, t, JZ7.0 Hz, ind H), 7.02 (1H,
phenyl-1H-pyrazol-4-yl)methyl]-1H-indole (5f). Orange
solid (615 mg, 90%), mp 118–120 8C; [Found: C, 74.94; H,
s, C]CHN), 3.05 (2H, t, JZ6.8 Hz, ind CH ), 2.80 (2H, t,
2
5
1
7
.33; N, 12.48. C H N O requires C, 74.98; H, 5.39; N,
4
JZ6.8 Hz, CH C]O), 2.13 (3H, s, CH ); d (125 MHz,
2
8
24
2
2
3
C
2.49%]; n
72 cm ; d (500 MHz, DMSO-d ) 12.70 (1H, br s, pyr
(KBr) 3417, 3300, 1620, 1482, 1211, 1054,
CDCl ) 201.9, 136.7, 128.7, 126.4, 122.1, 121.5, 119.4,
max
3
K1
C
118.5, 111.4, 110.8, 39.5, 8.9; m/z 187 (M ).
H
6
NH), 10.59 (2H, s, ind NH), 7.54 (2H, d, JZ7.6 Hz, Ph),
.34 (2H, t, JZ6.9 Hz, Ph), 7.27 (1H, t, JZ7.6 Hz, Ph), 7.21
1H, s, pyr C]CHN), 7.19 (2H, s, ind H), 6.85 (2H, s, ind
1
9a
7
(
4.4.2. 3-(1H-Indol-3-yl)-1-phenylpropan-1-one (7b).
Brown solid (370 mg, 87%), mp 126–127 8C; [Found: C,
C]CHN), 6.65 (2H, dd, JZ2.3, 8.4 Hz, ind H), 6.57 (2H, s,
ind H), 5.67 (1H, s, Ar CH), 3.51 (6H, s, OCH ); d
82.94; H, 6.03; N, 5.59. C H NO requires C, 82.90; H,
7 15
1
3
3
C
6.06; N, 5.62%]; nmax (KBr) 3410, 3055, 2928, 1683, 1335,
1205, 1097, 742 cm ; d (500 MHz, CDCl ) 8.05 (1H, s,
K1
(
125 MHz, DMSO-d ) 170.5, 153.1, 135.6, 130.6, 130.0,
6
H
3
1
1
29.4, 129.1, 127.9, 127.3, 124.5, 121.6, 118.7, 112.6,
11.0, 101.6, 55.7, 30.3; m/z 448 (M ).
ind NH), 7.64–7.53 (2H, m, ind H), 7.48–7.32 (5H, m, Ph),
7.19–7.05 (3H, m, ind H), 3.51 (2H, t, JZ7.6 Hz, ind CH2),
C
3
.26 (2H, t, JZ7.6 Hz, CH C]O); d (125 MHz, CDCl )
2 C 3
4
1
.3.7. 1-Methyl-3-[(1-methyl-1H-indol-3-yl)(3-phenyl-
H-pyrazol-4-yl)methyl]-1H-indole (5g). Brown solid
201.0, 138.2, 136.2, 132.9, 128.6, 128.1, 126.8, 121.9,
121.5, 118.9, 118.4, 111.7, 110.8, 39.5, 19.9; m/z 249 (M ).
C
(
1
561 mg, 94%), mp 142 8C; [Found: C, 80.72; H, 5.78; N,
3.44. C H N requires C, 80.74; H, 5.81; N, 13.45%];
nmax (KBr) 3432, 3059, 2926, 1616, 1473, 1329, 1097, 1013,
1
9a
4.4.3. 4-(2-Methyl-1H-indol-3-yl)butan-2-one (7c).
Colorless oil (313 mg, 91%); [Found: C, 77.55; H, 5.57;
2
8 24 4
K1
7
40 cm ; d (500 MHz, DMSO-d ) 12.84 (1H, br s, pyr
6
N, 6.92. C H NO requires C, 77.58; H, 7.51; N, 6.96%];
13 15
H
NH), 7.55 (2H, d, JZ8.4 Hz, Ph), 7.35 (2H, d, JZ8.5 Hz,
Ph), 7.33 (3H, d, JZ3.9 Hz, Ph and ind H), 7.31 (1H, s, pyr
C]CHN), 7.18 (2H, d, JZ7.6 Hz, ind H), 7.05 (2H, t, JZ
nmax (neat) 3415, 3028, 1714, 1457, 1371, 1226, 1035,
748 cm ; d (500 MHz, CDCl ) 8.01 (1H, s, ind NH), 7.35
K1
H
3
(1H, d, JZ7.1 Hz, ind H), 7.15 (1H, t, JZ7.1 Hz, ind H),
7.10 (1H, t, JZ7.0 Hz, ind H), 6.95 (1H, d, JZ2.1 Hz, ind
H), 3.05 (2H, t, JZ6.8 Hz), 2.80 (2H, t, JZ6.8 Hz,
CH C]O), 2.41 (3H, s, CH C]O), 2.13 (3H, s, ind
7
.6 Hz, ind H), 6.85 (2H, t, JZ7.6 Hz, ind H), 6.83 (2H, s,
C]CHN), 5.80 (1H, s, Ar CH), 3.64 (6H, s, CH ); d
C
3
3
(
125 MHz, DMSO-d ) 164.2, 149.4, 137.6, 132.2, 129.4,
6
2
3
1
1
29.1, 128.3, 127.1, 122.1, 121.5, 119.5, 118.9, 118.2,
16.5, 110.2, 32.8, 29.9; m/z 416 (M ).
CH ); d (125 MHz, CDCl ) 201.8, 136.2, 128.5, 126.4,
3 C 3
C
123.9, 121.6, 119.7, 118.9, 110.4, 78.3, 38.5, 19.7, 12.4; m/z
2
C
01 (M ).
4
.3.8. 1-Methyl-3-[(1-methyl-1H-indol-3-yl)(3-(4-chloro
phenyl)-1H-pyrazol-4-yl)methyl]-1H-indole (5h). Orange
solid (625 mg, 91%), mp 138 8C; [Found: C, 74.56; H, 5.11;
N, 12.39. C H ClN requires C, 74.57; H, 5.14; N,
4.4.4. 3-(1H-Indol-3-yl)-3-(4-methoxy phenyl)-1-phenyl
propan-1-one (7d). Brown solid (540 mg, 89%), mp 128–
130 8C; [Found: C, 81.07; H, 5.93; N, 3.95. C H NO
2
2
8
23
4
24 21
1
1
2.42%]; nmax (KBr) 3431, 3056, 2928, 1617, 1470, 1326,
097, 745 cm ; d (500 MHz, DMSO-d ) 12.85 (1H, br s,
requires C, 81.10; H, 5.96; N, 3.94%]; nmax (KBr) 3425,
3300, 2925, 1675, 1508, 1465, 1035, 739 cm ; dH
K1
K1
H
6
pyr NH), 7.54 (2H, d, JZ8.4 Hz, Ph), 7.35 (2H, d, JZ
.5 Hz, Ph), 7.33 (2H, d, JZ7.6 Hz, ind H), 7.31 (1H, s, pyr
C]CHN), 7.18 (2H, d, JZ8.5 Hz, ind H), 7.05 (2H, t, JZ
.7 Hz, ind H), 6.85 (2H, t, JZ7.6 Hz, ind H), 6.82 (2H, s,
ind C]CHN), 5.79 (1H, s, Ar CH), 3.64 (6H, s, CH ); d
C
(500 MHz, CDCl ) 8.09 (1H, s, ind NH), 7.95 (2H, d, JZ
3
8
7.5 Hz, Ph), 7.55 (1H, t, JZ7.5 Hz, Ph), 7.45–7.41 (3H, m,
Ph), 7.28 (3H, dd, JZ2.3, 10.9 Hz, Ph), 7.16 (1H, t, JZ
8.0 Hz, ind H), 7.05 (1H, t, JZ6.9 Hz, ind H), 6.93 (1H, s,
C]CHN), 6.82 (2H, d, JZ11.4 Hz, Ph), 5.06 (1H, t, JZ
6.9 Hz, Ar CH), 3.79–3.74 (2H, m, CH ), 3.73 (3H, s,
7
3
3
(
125 MHz, DMSO-d ) 161.5, 152.1, 129.4, 129.1, 128.3,
6
2
2
1
1
27.1, 122.1, 121.5, 119.5, 118.9, 118.2, 117.1, 115.2,
11.1, 110.2, 89.7, 32.1; m/z 450 (M ).
OCH ); d (125 MHz, CDCl ) 199.9, 158.1, 137.3, 136.8,
3 C 3
C
136.5, 133.2, 128.9, 128.7, 128.3, 126.7, 122.2, 121.5,
19.7, 119.6, 119.5, 113.9, 111.4, 55.3, 45.5, 37.6; m/z 355
(M ).
1
C
4
.4. Typical experimental procedure 7
To a mixture of 1-propyl indole (200 mg, 1.26 mmol) and
4.4.5. 3-(1-Methyl-1H-indol-3-yl)-3-(4-methoxyphenyl)-
1-phenylpropan-1-one (7e). Brown solid (523 mg, 93%),
mp 112 8C; [Found: C, 81.25; H, 6.24; N, 3.81. C H NO
2
(
(
2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one 4g
299 mg, 1.26 mmol) in acetonitrile (10 mL),
2
5
23
H [Si(W O ) ] (20 mol%) was added and the reaction
4
stirred for 20 min at room temperature. After complete
requires C, 81.27; H, 6.27; N, 3.79%]; n
3302, 2925, 1505, 1035, 745 cm ; d (500 MHz, CDCl )
H 3
(KBr) 3420,
max
3
10 3
K1

12280
R. Murugan et al. / Tetrahedron 61 (2005) 12275–12281
7
7
.95 (2H, d, JZ7.6 Hz, Ph), 7.54 (1H, t, JZ6.9 Hz, Ph),
.47–7.42 (3H, m, Ph), 7.28 (3H, t, JZ8.6 Hz, Ph), 7.20
127.4, 124.8, 124.1, 117.1, 108.1, 104.8, 102.3, 85.0, 37.5;
m/z 282 (M ).
C
(
2H, t, JZ7.4 Hz, ind H), 7.03 (1H, s, C]CHN), 6.83 (2H,
t, JZ8.5 Hz, ind H), 5.04 (1H, t, JZ6.9 Hz, Ar CH), 3.82–
2
4.4.10. Methyl-2-(1H-indol-3-yl)-3-nitropropanoate (7j).
Light yellow oil (335 mg, 90%); [Found: C, 58.00; H, 4.85;
N, 11.27. C H N O requires C, 58.06; H, 4.87; N,
3
3
1
1
4
.78 (2H, dd, JZ6.3, 16.6 Hz, CH ), 3.75 (3H, s, OCH ),
2 3
.72 (3H, s, NCH ); d (125 MHz, CDCl ) 198.9, 158.0,
3
C
3
1
2 12 2 4
K1
37.5, 137.3, 136.6, 133.1, 128.9, 128.7, 128.2, 127.1,
26.3, 121.8, 120.4, 119.7, 118.9, 118.3, 113.9, 109.3, 55.3,
5.5, 37.6; m/z 369 (M ).
1
1.29%]; nmax (neat) 3409, 3035, 1747, 1374, 745 cm ; dH
(
500 MHz, CDCl ) 8.02 (1H, s, ind NH), 7.64 (1H, d, JZ
3
C
8
(
.4 Hz), 7.40–7.35 (1H, m), 7.32–7.13 (3H, m), 5.28–5.19
1H, m), 4.81–4.60 (2H, m, CH ), 3.73 (3H, s, CH ); d
C
2
3
19a
.4.6. 3-(2-Nitro-1-phenylethyl)-1H-indole (7f). Color-
4
less oil (409 mg, 90%); [Found: C, 72.11; H, 5.27; N, 10.54.
(125 MHz, CDCl ) 172.0, 136.4, 125.9, 123.3, 123.1, 120.6,
3
C
118.7, 111.9, 76.3, 53.0, 39.1; m/z 248 (M ).
C H N O requires C, 72.17; H, 5.30; N, 10.58%]; n
max
1
6
14
2
2
K1
neat): 3417, 3030, 2925, 1456, 1223, 1015, 745 cm ; dH
(
(
500 MHz, CDCl ) 8.01 (1H, s, ind NH), 7.42 (1H, d, JZ
3
Acknowledgements
7
.6 Hz, Ph), 7.33–7.24 (6H, m, Ph and ind H), 7.21 (1H, t,
JZ7.6 Hz, ind H), 7.08 (1H, t, JZ7.6 Hz, ind H), 6.97 (1H,
R.M. thanks Dr. R. Sridhar-National University of
Singapore and E. Ramesh—University of Madras for their
help.
d, JZ2.5 Hz, ind H), 5.20 (1H, t, JZ7.6 Hz, Ar CH), 4.81
2
(
2H, m, CH ); d (125 MHz, CDCl ) 139.2, 136.5, 128.9,
2 C 3
1
1
27.6, 127.4, 125.9, 123.4, 121.6, 119.8, 118.8, 114.1,
11.4, 79.4, 40.9; m/z 266 (M ).
C
4
1
.4.7. 3-(1-Propyl-1H-indol-3-yl)-3-(4-methoxyphenyl)-
-phenylpropan-1-one (7g). Brown oil (459 mg, 92%);
References and notes
[
Found: C, 81.53; H, 6.84; N, 3.50. C H NO requires C,
27 27 2
8
1
1.58; H, 6.85; N, 3.52%]; nmax (neat) 3425, 3300, 2925,
504, 1463, 1035, 742 cm ; d (500 MHz, CDCl ) 8.13
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New
York, 1996; p 113. (b) Marugan, J. J.; Manthey, C.; Anaclerio,
B.; Lafrance, L.; Lu, T.; Leonard, K. A.; Crysler, C.;
Eisennagel, S.; Dasgupta, M.; Tomczuk, B. J. Med. Chem.
2005, 48, 926–934.
K1
H
3
(
(
2H, d, JZ8.0 Hz, Ph), 8.11 (1H, d, JZ8.1 Hz, Ph), 7.74
1H, d, JZ8.1 Hz, Ph), 7.61–7.45 (5H, m, Ph), 7.38 (1H, t,
JZ7.4 Hz, ind H), 7.24 (1H, t, JZ7.4 Hz, ind H), 7.15 (1H,
s, C]CHN), 7.00 (2H, d, JZ8.5 Hz, ind H), 5.34 (1H, s,
Ar CH), 4.06 (2H, t, JZ6.9 Hz, CH N), 3.99 (2H, dd, JZ
2. Manfredini, S.; Bazzanini, R.; Baraldi, P. G.; Guarneri, M.;
Bonora, M.; Marangoni, M.; Simoni, D.; Pani, A.; Scintu, F.;
Pinna, E.; Pisano, L.; Colla, P. L. Anti-Cancer Drug Des. 1996,
11, 193–204.
2
2
6
.3, 20.6 Hz, CH C]O), 3.80 (3H, s, OCH ), 1.95–1.88
2 3
(2H, m, CH ), 1.02 (3H, t, JZ7.4 Hz, CH ); d (125 MHz,
CDCl ) 199.0, 158.4, 137.6, 137.1, 137.0, 133.3, 129.2,
2 3 C
3
3. Ugarkar, B. G.; Cottam, H. B.; McKernan, P. A.; Robins,
R. K.; Revankar, G. R. J. Med. Chem. 1984, 27, 1026–1030.
4. Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.;
Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med.
Chem. 1996, 39, 3920–3928.
1
1
28.9, 128.4, 127.6, 125.7, 121.9, 120.1, 118.3, 119.1,
14.2, 109.9, 55.3, 48.1, 45.8, 37.9, 23.8, 11.8; m/z 397
C
(
M ).
4.4.8. 3-(1-Butyl-1H-indol-3-yl)-3-(4-methoxyphenyl)-1-
phenylpropan-1-one (7h). Brown oil (442 mg, 93%);
5. (a) Baraldi, P. G.; Chiarini, A.; Budriesi, R.; Roberti, M.;
Casolari, A.; Manfredini, S.; Simony, D.; Zanirato, V.; Varani,
K.; Borrea, P. A. Drug Des. Deliv. 1989, 5, 13–29. (b) Sridhar,
R.; Perumal, P. T.; Etti, S.; Shanmugam, G.; Ponnuswamy,
M. N.; Prabavathy, V. R.; Mathivanan, N. Bioorg. Med. Chem.
Lett. 2004, 14, 6035–6040.
[
C, 81.72; H, 7.10; N, 3.40%]; n
Found: C, 81.69; H, 7.12; N, 3.41. C H NO requires
28 29 2
(neat) 3420, 3307, 2922,
max
H
K1
1
675, 1465, 1037, 740 cm ; d (500 MHz, CDCl ) 8.08
3
(
7
2H, d, JZ8.0 Hz, Ph), 7.76 (2H, d, JZ8.0 Hz, Ph), 7.64–
.47 (5H, m, Ph), 7.39 (1H, d, JZ7.6 Hz, ind H), 7.25 (2H, t,
6. (a) Lehn, J. M. Angew. Chem., Int. Ed. 1988, 27, 89–112. (b)
Cram, D. J. Angew. Chem., Int. Ed. 1988, 27, 1009–1020. (c)
Gokel, G. W.; Leevy, W. M.; Weber, M. E. Chem. Rev. 2004,
104, 2723–2750.
JZ7.4 Hz, Ph), 7.17 (1H, d, JZ6.9 Hz, ind H), 7.03 (1H, s,
C]CHN), 5.05 (1H, s, Ar CH), 4.07 (2H, t, JZ7.6 Hz,
2
NCH ), 4.01–3.95 (2H, m, CH C]O), 3.82 (3H, s, OCH ),
1
2
2
3
.97–1.85 (4H, m, CH ), 0.89 (3H, t, JZ7.6 Hz, CH ); d
7. (a) Dougherty, D. A. Science 1996, 271, 163–168. (b) Ma,
J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303–1324.
8. Chatterjee, A.; Manna, S.; Banerji, J.; Pracard, C.; Prange, T.;
Shoolery, J. J. Chem. Soc., Perkin Trans. 1 1980, 553–555.
9. (a) Kamal, A.; Qureshi, A. A. Tetrahedron 1963, 19, 513–520.
2
3
C
(
125 MHz, CDCl ) 199.9, 159.0, 137.2, 136.6, 133.2, 129.2,
3
1
1
28.7, 128.2, 127.6, 126.3, 121.8, 120.4, 119.7, 119.5,
19.1, 118.3, 113.7, 110.4, 55.3, 48.1, 45.8, 38.0, 24.0, 11.8;
C
m/z 411 (M ).
(b) Noland, W. E.; Venkiteswaran, M. R.; Lovald, R. A.
J. Org. Chem. 1961, 26, 4249–4254.
4.4.9. 3-(2-Nitro-1-phenylethyl)-1H-indol-5-ol (7i).
Brown solid (319 mg, 90%), mp 124 8C; [Found: C,
10. (a) Ji, S.-J.; Zhou, M.-F.; Wang, S.-Y.; Loh, T.-P. Synlett 2003,
2077–2079. (b) Gu, D.-G.; Ji, S.-J.; Jiang, Z.-Q.; Zhou, M.-F.;
Loh, T.-P. Synlett 2005, 959–962.
6
5
7
7
2
8.01; H, 4.95; N, 9.88. C H N O requires C, 68.07; H,
16 14 2 3
.00; N, 9.92%]; n
(KBr) 3406, 3030, 1745, 1376, 1035,
42 cm ; dH (500 MHz, CDCl ) 8.05 (1H, s, ind NH),
max
K1
11. Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Tetrahedron
2004, 60, 2051–2055.
3
.32–7.20 (5H, m), 7.18 (1H, d, JZ8.4 Hz), 6.98 (1H, d, JZ
.6 Hz), 6.83–6.73 (2H, m), 5.11–4.80 (4H, m); dC
12. Yadav, J. S.; Reddy, B. V. S.; Satheesh, G. Tetrahedron Lett.
2004, 45, 3673–3676.
(
125 MHz, CDCl ) 155.6, 148.7, 134.4, 132.9, 132.5,
3

R. Murugan et al. / Tetrahedron 61 (2005) 12275–12281
12281
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1
1
1
1
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2
004, 45, 5099–5102.
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2
3
21. (a) Okuhara, T.; Mizuno, N.; Misono, M. Adv. Catal. 1996, 41,
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2
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24. Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre,
CCDC Nos. 278106 for compound 3a. Structural parameters
for 3a: data collection: Bruker SMART CCD area detector;
1
1
(
1
˚
radiation: Mo Ka wavelength: 0.71073 A; crystal size: 0.22!
3
0.20!0.18 A ; crystal system: triclinic; space group: P ¯ı (#4);
˚
2
˚
˚
Tetrahedron 2004, 60, 6679–6684. (c) Bartoli, G.; Bartolacci,
M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L.;
Torregiani, E. J. Org. Chem. 2003, 68, 4594–4597.
unit cell: aZ10.4646(9) A, bZ15.3530(13) A, cZ
˚
18.8220(16) A, aZ101.008(1)8, bZ106.060(1)8, gZ
98.345(1)8.