A new catalytic application of a keggin acid in the synthesis of symmetrical bis(indolyl)alkanes

Article abstract of DOI:10.3987/COM-05-10587

Silicotungstic acid, H₄SiW₁₂O₄₀, an important Keggin heteropoly acid, efficiently catalysed the reaction of indoles with aryl aldehydes in ethyl acetate solution at room temperature to furnish symmetrical bis(indolyl)alkanes expeditiously.

Full text of DOI:10.3987/COM-05-10587

HETEROCYCLES, Vol. 68, No.2, 2006
331
HETEROCYCLES, Vol. 68, No. 2, 2006, pp. 331 - 338. © The Japan Institute of Heterocyclic Chemistry
Received, 11th October, 2005, Accepted, 14th December, 2005, Published online, 16th December, 2005. COM-05-10587
A NEW CATALYTIC APPLICATION OF A KEGGIN ACID IN THE
SYNTHESIS OF SYMMETRICAL BIS(INDOLYL)ALKANES
a∗
a
a
b
Manas Chakrabarty, Ajanta Mukherji, Sulakshana Karmakar, Shiho Arima,
b
and Yoshihiro Harigaya
a
Department of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700009,
India
E-mail:chakmanas@yahoo.co.in
b
School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108,
Japan
4
Abstract- Silicotungstic acid, H SiW12O40, an important Keggin heteropoly acid,
efficiently catalysed the reaction of indoles with aryl aldehydes in ethyl acetate
solution at room temperature to furnish symmetrical bis(indolyl)alkanes
expeditiously.
INTRODUCTION
4
+
5+
The Keggin heteropoly acids (HPAs), H8-nXM12
O
40 (where X is Si , P , etc., n is the oxidation state of
6
+
6+
1
X, and M is Mo or W ), are exceptionally strong Brönsted acids, which are mainly due to their
2
possessing a pseudoliquid phase which allows both the bulk protons and the surface protons to
participate in catalytic activity. Moreover, these HPAs are environmentally benign. As a result, the major
Keggin acids, viz. phosphotungstic, silicotungstic, phosphomolybdic and siliocomolybdic acids are being
3
increasingly applied as catalysts in homogeneous, heterogeneous and biphasic reactions.
Indolic, bisindolic, and trisindolic substances as well as annulated indoles have been our major synthetic
4
5
targets in recent years. The well-documented anti-cancer property of bis(indol-3-yl)methane and
6
bis(5-methoxyindol-3-yl)methane have brought to fore the importance of the symmetrical
bis(indolyl)alkanes (BIAs). The BIAs, though of synthetic origin, have also been reported from fungi,
7
bacteria, tunicates and sponges and display significant biological activities. These are mainly prepared by
the reaction of indoles or indolyl Grignard reagents with aldehydes or ketones or their masked forms
8
using protic or Lewis acids and even solid acids, sometimes applying alternative sources of energy.
9
Nevertheless, the increasing importance of green chemistry and the various disadvantages (like the use of

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HETEROCYCLES, Vol. 68, No.2, 2006
stoichiometric or larger amounts of acids, creation of toxic wastes, very long reaction periods, very low or
widely varying yields, etc.) of the extant synthetic routes warrant newer applications of particularly
eco-friendly catalysts for the synthesis of the symmetrical BIAs. In response to this need and in
10
continuation of our ongoing interest in this field, we have now successfully employed the Keggin HPA,
silicotungstic acid (STA), H 40 , as an efficient homogeneous catalyst for the solution phase
4
SiW12O
synthesis of the symmetrical BIAs from indoles and aryl aldehydes at room temperature. Our findings,
since important, are presented herein.
RESULTS AND DISCUSSION
Five assorted indoles (1a-e) were treated separately at room temperature with several aryl aldehydes
11
(
2a-m; 0.75-2.0 equiv ) in ethyl acetate solution using 2.0-3.5 mol% of STA (i.e. 50% w/w with respect
to the indoles). Indole (1a) failed completely to react with 2i, 2l and 2m. In all other cases, the
corresponding symmetrical BIAs (3aa-ah, aj, ak, bd, bf, cd, cf, dd, df, ea) were obtained as the sole
products, isolated in 63-97% yields (Scheme 1, Table 1). The known BIAs were identified either from
1
their H NMR spectroscopic data or by direct comparisons (mp, mixed mp, co-TLC) and the new BIAs by
1
13
IR, H and C NMR spectra, including DEPT 135, LR and HR EI/FAB-MS spectral and micro-analytical
data.
Ar
X
X
X
STA (2-3.5 mol%)
+
ArCHO
EtOAc
rt, 1 min - 2 h
N
N
N
H
H
H
6
3-97%
3
aa-ah, aj-ak, bd, bf, cd, cf, dd, df
2
a-m
1
1
1
1
1
a: X = H
b: X = OMe
c: X = NO
d: X = Br
CH3
2
e: 3-Methylindole
)2
N
H
ea
CHPh
3
Scheme 1
The results unveiled the influence of the electronic nature of the substituents of both indoles and aryl
aldehydes on the time of the reactions. Thus, except for the 2/3-formyl heteroarenes (2j-m), the reaction
of indole (1a), 5-methoxyindole (1b) and 5-bromoindole (1d) with benzaldehyde (2a) and its 2/3/4-nitro,
4-trifluoromethoxy and 4-methoxy derivatives (2b-f) were quite expeditious (1-5 min), except for the
reaction of 1b with 2f, which inexplicably required 45 min for the completion of the reaction. In contrast,

HETEROCYCLES, Vol. 68, No.2, 2006
333
Table 1. Application of STA as catalyst in the synthesis of symmetrical BIAs
a
Entry Indoles
1) X=
ArCHO
Equiv Time BIA (3) Yield (%)
of (2)
(
(2)
1
2
3
4
5
6
7
8
9
a: H
a: Ph
2 6 4
b: 2-NO C H
0.75
1.5
5 min
5 min
5 min
5 min
1 min
5 min
2 h
aa
ab
ac
ad
ae
af
ag
ah
−
95
95
82
74
88
90
63
93
−
a
a
c: 3-NO
2
C
6
H
4
0.75
0.75
0.75
1.5
a
d: 4-NO
2
C
6
H
4
a
e: 4-CF
f: 4-MeOC
g: 2-HOC
h: 4-HOC
i: 4-Me NC
3
OC
6
H
4
a
6 4
H
a
6
H
4
1.0
a
6
H
4
0.75
1.0
1.5 h
b
a
2
6
H
4
6 h
c
1
0
1
2
3
4
5
6
7
8
9
0
a
j: 2-Thienyl
2.0
7 min
aj
ak
−
90
73
−
c
1
1
1
1
1
1
1
1
1
2
a
k: 2-Furyl
2.0
30 min
b
a
l: 2-Pyrrolyl
2.0
6 h
b
a
m: 3-Indolyl
1.0
6 h
−
−
b: OMe
d
f
0.75
1.0
1 min
45 min
2 h
bd
bf
cd
cf
73
78
97
82
89
89
94
b
c: NO
2
d
f
0.75
1.0
c
1 h
d: Br
d
d
f
0.75
1.0
5 min
5 min
2 h
dd
df
ea
e: 3-Me
a
0.75
a
b
c
Refer to isolated pure products; Carried out under reflux; For 2j and 2k (Entries 10 and
11), a solution of STA in EtOAc added dropwise.
the reaction of 1a with 2/4-hydroxybenzaldehydes (2g/h) required considerably longer periods (2/1.5 h),
while that with 4-dimethylaminobenzaldehyde (2i) led to acomplete failure of the reaction. Among the four
2
/3-formylheteroarenes (2j-m) reacting with 1a, the aldehydes (2j) and (2k) required 7 min and 30 min,
respectively for the completion of their reactions, whereas 2l and 2m did not react at all. These observations
are compatible with the decreasing electrophilic character of the formyl carbon in these substrates. As
anticipated, 5-nitroindole (1c), with its reduced nucleophilicity, took longer periods (2/1 h) in its reactions
with two aryl aldehydes (2d/f). In the case of the reaction of 3-methylindole (1e) with 2a, the expected
symmetrical BIA, bis(3-methylindol-2-yl)phenylmethane (3ea) was formed in a comparable yield but

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HETEROCYCLES, Vol. 68, No.2, 2006
requiring a much longer period, which is due to the well known nucleophilicity at C-2, as compared to
that at C-3, of the indole nucleus.
When applied to the reaction of indole (1a) with acetaldehyde, propionaldehyde and (±)-glyceraldehyde as
well as with acetone, 2-butanone and acetophenone separately but under similar conditions, STA (2mol%)
proved to be less effective for the first two alkanals (furnishing the respective BIAs in 30% and 35%yields,
respectively) but failed for glyceraldehyde and the ketones. Pertinently, the recyclability of STA could not
be checked because of its high solubility in both ethyl acetate and water.
To conclude, the eco-friendly Keggin HPA, silicotungstic acid, has been demonstrated to be highly
efficacious even at low catalytic concentrations (2-3.5 mol%) for the solution-phase synthesis of
symmetrical BIAs and remarkably rapid for those BIAs (e.g. entry 14), which stem from both indoles
bearing electron-donating substituents (e.g. 5-MeO-indole, 1b) and benzaldehydes bearing electron-
2 6 4
withdrawing groups (e.g. 4-NO C H CHO, 2d).
EXPERIMENTAL
Mps were determined on aToshniwal apparatus and are uncorrected. IR spectra were recorded on aNicolet
Impact 410 or a Perkin-Elmer RX 1FT-IR spectrophotometer, LR EI/FAB-MS in JEOL JMS-AX505HA
1
13
and HR EI/FAB-MS in JEOL JMS-700 MStation mass spectrometers, H (500 MHz) and C (125 MHz)
NMR spectra, both 1D and 2D, including DEPT 135, HMQC and HMBC spectra, in a Bruker DRX 500
NMR spectrometer. In FAB-MS spectrum, m-nitrobenzyl alcohol was used as the liquid matrix. Individual
1
13
H and C NMR spectral assignments of 3bf, 3cf and 3df were based on HMQC and HMBC spectral
analyses. TLCs were carried out on silica gel G (Merck, India) plates. PE refers to petroleum ether, bp
0-80 °C.
6
General Experimental Procedure. STA, procured commercially (from Speer Laboratories, Kolkata,
India) as a polyhydrate, was heated at ca. 110 °C for 1hand then cooled to rt in adesiccator before use. To
a solution of the indole (0.25 mmol) and aldehyde (0.75-2.0 equiv.) in EtOAc (4 mL) was added with
stirring asolution of STA (2.0-3.5 mol%) in EtOAc (3mL) at rt. The stirring was continued until the indole
was consumed (TLC). The mixture was diluted alittle with EtOAc, filtered through abed of celite to free it
from a small amount of precipitate and washed with EtOAc (2 × 5 mL). The pooled filtrates were washed
2 4
with water (2 × 15 mL), the organic phase separated and dried (Na SO ) and the solvent removed. The
resulting residue was purified either by crystallisation or by preparative TLC using PE-EtOAc, followed by
recrystallisation, to afford pure BIAs. Unless stated otherwise, the BIAs were crystallised from PE-EtOAc.
The following BIAs were identified by direct comparison (for samples available in the laboratory) or by
1
comparing their mps with the reported mps along with H NMR spectroscopic data. 3aa: mp 148 ºC (PE-

HETEROCYCLES, Vol. 68, No.2, 2006
335
1
2
13
14
CCl
4
) (lit., 150-152 ºC); 3ab: mp 140 ºC (lit., 141-143 ºC); 3ac: mp 218-220 ºC (lit., 218-220 ºC);
13
15
3
ad: mp 240 ºC (lit., 220-222 ºC); 3af: mp 194-195 ºC (PE-CH
2
Cl
2
) (lit., 191-193 ºC); 3ag: mp 198 ºC
1
6
15
17
(
PE-CH
2
Cl
2
) (lit., 199-200 ºC); 3ah: mp 134-136 ºC (lit., 130-132 ºC); 3aj: mp 160 ºC (lit., 163-165
18
18
ºC); 3ak: mp >325 ºC (lit., 325 ºC); 3ea: mp 162 ºC (lit., 160 ºC).
Bis(indol-3-yl)(4′-trifluoromethoxyphenyl)methane (3ae): mp 272-274 °C (decomp); IR (KBr): 3424,
-1 1
1
605, 1508, 1455, 1245, 1174, 1097, 1028, 794 cm ; H NMR (CDCl
3
): δ 5.88 (1H, s), 6.62 (2H, s), 7.0
(
(
2H, t, J=7.5 Hz), 7.10 (2H, d, J=8 Hz), 7.17 (2H, t, J=7.5 Hz), 7.34 (4H, m), 7.35 (2H, d, J=7.5 Hz), 7.92
13
2H, br s); C NMR: δ 30.1 (OCF ), 39.9 (Ar CH), 111.5, 119.7, 120.1, 121.0, 122.5, 124.0, 130.3 (all
3
3
+
Ar-CH), 119.6, 127.3, 137.1, 143.1, 148.0 (all Ar-C); EI-MS: m/z (%) 406 (M , 100), 405 (41), 305 (20),
2
4
90 (14), 289 (19), 288 (12), 245 (52), 243 (13); HRMS (EI): calcd for C24
17 2 3
H N OF , 406.1293; found
06.1290; Anal. Calcd for C24 OF : C, 70.93; H, 4.19; N, 6.89. Found: C, 70.92; H, 4.18; N, 6.87.
H
17
N
2
3
Bis(5-methoxyindol-3-yl)(4′-nitrophenyl)methane (3bd): mp 142 °C; IR (KBr): 3410, 1590, 1515, 1481,
-
1 1
1
6
343, 1209, 1171, 1032, 1036, 797, 720 cm ; H NMR (CDCl
3
): δ 3.69 (6H, s), 5.86 (1H, s), 6.65 (2H, s),
.74 (2H, d,J=2 Hz), 6.85 (2H, dd, J =8.5 Hz, J =2 Hz), 7.26 and 7.48 (2H, deach, J=8.5 Hz), 7.95 (2H,br
1
2
1
3
s), 8.12 (2H, d, J=8.5 Hz); C NMR: δ 40.6 (Ar
3
CH), 56.3 (OCH
3
), 102.1, 112.3, 112.5, 124.0, 124.9,
+
1
29.9 (all Ar-CH), 118.0, 127.5, 132.2, 146.9, 152.2, 154.3 (all Ar-C); EI-MS: m/z (%) 427 (M , 100), 426
(
26), 396 (13), 305 (56), 281 (5), 280 (5), 234 (8), 147 (7); HRMS (EI): calcd for C25
21 3 4
H N O , 427.1532;
found 427.1535; Anal. Calcd for C25 : C, 70.25; H, 4.92; N, 9.83. Found: C,70.32; H,4.94; N,9.81.
21 3 4
H N O
Bis(5-methoxyindol-3-yl)(4′-methoxyphenyl)methane (3bf): mp 198-200 °C; IR (nujol): 3316, 1626,
-
1 1
1
4
580, 1245, 1205, 1170, 1037, 800 cm ; H NMR (DMSO-d ): δ 3.52 (6H, s, 2×5-OCH ), 3.63 (3H, s,
6
3
3 3 1 2
′-OCH ), 5.61 (1H, s,Ar CH), 6.63 (2H, dd, J =9 Hz, J =2 Hz, 2×H-6), 6.66 (2H, d,J=2 Hz, 2×H-4), 6.72
(2H, d, J=1.5 Hz, 2×H-2), 6.77 (2H, d,J=8.5 Hz, H-3′,5′), 7.17 (2H, d,J=9 Hz, 2×H-7), 7.19 (2H, d,J=9 Hz,
1
3
H-2′,6′), 10.54 (2H, br s, 2×NH); C NMR: δ 39.6 (Ar
3
CH), 55.8 (4′-OCH
3
3
), 56.1 (2×5-OCH ), 102.4
(
(
2×CH-4), 111.3 (2×CH-6), 112.8 (2×CH-7), 114.2 (CH-3′, 5′), 118.9 (2×C-3), 125.0 (2×CH-2), 127.8
2×C-3a), 130.0 (CH-2′, 6′), 132.7 (2×C-7a), 137.8 (C-1′), 153.4 (2×C-5), 158.1 (C-4′); EI-MS: m/z (%)
+
4
12 (M , 100), 397 (7), 381 (10), 305 (36), 265 (20), 250 (8); HRMS (EI): calcd for C26
H
24
N
2
O
3
, 412.1787;
found 412.1782; Anal. Calcd for C H N O : C, 75.73; H, 5.82; N,6.79. Found: C,75.78; H, 5.83; N,6.77.
2
6
24
2
3
Bis(5-nitroindol-3-yl)(4′-nitrophenyl)methane (3cd): mp 293 °C (PE-C
6
H
6
); IR (nujol): 3384, 1622,
): δ6.41 (1H, s), 7.15 (2H, d, J=1.5
=2 Hz), 8.13 (2H,d,J=8.5 Hz), 8.32 (2H,
3
CH), 113.1, 116.9, 117.6, 124.6, 128.8, 130.2 (all
-
1 1
1
596, 1507, 1465, 1324, 1086, 811, 739, 678 cm ; H NMR (DMSO-d
6
Hz), 7.49 and 7.59 (2H, deach, J=9 Hz), 7.92 (2H, dd, J =9 Hz, J
1
2
1
3
d, J=2 Hz), 11.70 (2H, br s); C NMR: δ 38.8 (Ar

336
HETEROCYCLES, Vol. 68, No.2, 2006
Ar-CH), 120.1, 126.4, 140.6, 141.2, 147.0, 152.6 (all Ar-C); FAB-MS: m/z (%) 480 (M+Na), 458 (M+H),
+
4
4
3
57 (M , 100), 441 (37), 412 (16), 335 (16), 296 (35); HRMS (FAB+): calcd for C23
H
16
N
5
O
6
(M+H),
58.1101; found 458.1105; Anal. Calcd for C23
.27; N, 15.35.
15 5 6
H N O : C, 60.39; H, 3.28; N, 15.32. Found: C, 60.46; H,
Bis(5-nitroindol-3-yl)(4′-methoxyphenyl)methane (3cf): mp 294-295 °C (decomp); IR (KBr): 3291,
-
1
1
1
620, 1511, 1465, 1324, 1242, 1088, 1029, 801, 736, 669 cm ; H NMR (DMSO-d
′-OCH ), 6.11 (1H, s, Ar CH), 6.87 (2H, d, J=8.5 Hz, H-3′,5′), 7.09 (2H, d, J=1 Hz, 2×H-2), 7.28 (2H, d,
=9 Hz, J =2 Hz, 2×H-6), 8.29 (2H, d,J=2
CH), 55.8 (4′-OCH ), 112.9 (2×CH-7), 114.6
CH-3′, 5′), 117.0 (2×CH-4), 117.4 (2×CH-6), 121.7 (2×C-3), 126.6 (2×C-3a), 128.3 (2×CH-2), 130.0
6
): δ 3.70 (3H, s,
4
3
3
J=8.5 Hz, H-2′,6′), 7.53 (2H, d, J=9 Hz, 2×H-7), 7.96 (2H, dd, J
1
2
1
3
Hz, 2×H-4), 11.62 (2H, s, 2×NH); C NMR: δ 38.5 (Ar
3
3
(
+
(
CH-2′, 6′), 136.5 (C-1′), 140.6 (2×C-7a), 141.0 (2×C-5), 158.5 (C-4′); EI-MS: m/z (%)442 (M , 100), 441
(
22), 425 (15), 411 (10), 395 (11), 335 (18), 280 (19); HRMS (EI): calcd for C H N O , 442.1278; found
2
4
18
4
5
4
18 4 5
42.1276; Anal. Calcd for C24H N O : C, 65.16; H, 4.07; N, 12.67. Found: C, 65.22; H, 4.06; N, 12.69.
Bis(5-bromoindol-3-yl)(4′-nitrophenyl)methane (3dd): mp 189-190 °C(decomp); IR (KBr): 3417, 1595,
-1 1
1
510, 1454, 1343, 1213, 1100, 860, 789 cm ; H NMR (CDCl
3
): δ 5.58 (1H, s), 6.65 (2H, d, J=2 Hz),
7
.26-7.27 (4H, m), 7.42 (2H, d, J=1.5 Hz), 7.44 (2H, d, J=8.5 Hz), 8.10 (2H, br s), 8.15 (2H, d, J=8.5 Hz);
1
3
C NMR: δ40.2 (Ar
3
CH), 113.2, 122.3, 124.2, 125.2, 125.8, 129.8 (all Ar-CH), 113.4, 117.8, 128.6, 135.7,
+
1
47.2, 151.2 (all Ar-C); EI-MS: m/z (%)527 (M+4, 74), 525 (M+2, 100), 523 (M , 79), 446 (16), 444 (18),
7
9
4
05 (28), 403 (57), 401 (34); HRMS (EI): calcd for C H N O Br , 522.9531; found 522.9533; Anal.
23 15 3 2 2
7
9+81
Calcd for C23
H
15
N
3
O
2
2
Br : C, 52.57; H, 2.85; N, 8.00. Found: C, 52.61; H, 2.84; N, 7.98.
Bis(5-bromoindol-3yl)(4′-methoxyphenyl)methane (3df): mp 250 °C (decomp) (PE-CH
2
Cl
): δ 3.51 (3H, s,
CH), 6.65 (2H,d,J=8.5 Hz, H-3′,5′), 6.65 (2H, d,J=2.5 Hz, 2×H-2), 6.94 (2H, dd,
=1.5 Hz, 2×H-6), 7.02 (2H, d, J=8.5 Hz, H-2′,6′), 7.13 (2H, d, J=8.5 Hz, 2×H-7), 7.20 (2H, d,
2
); IR (KBr):
-
1 1
3
411, 1611, 1506, 1458, 1419, 1262, 1217, 1164, 1014, 743 cm ; H NMR (DMSO-d
′-OCH ), 5.58 (1H, s,Ar
=8.5 Hz, J
J=1.5 Hz, 2×H-4), 10.83 (2H, br s, 2×NH); C NMR: δ 38.9 (Ar
14.4 (2×CH-7; CH-3′,5′), 118.8 (2×C-3), 122.0 (2×CH-4), 124.2 (2×CH-6), 125.9 (2×CH-2), 129.2
6
4
3
3
J
1
2
1
3
3
CH), 55.8 (4′-OCH ), 111.7 (2×C-5),
3
1
(
2×C-3a), 129.9 (CH-2′, 6′), 136.1 (2×C-7a), 137.1 (C-1′), 158.3 (C-4′); EI-MS: m/z (%) 512 (M+4, 49),
+
5
10 (M+2, 100), 508 (M , 55), 431 (7), 429 (11), 405 (12), 403 (26), 401 (18), 315 (20), 313 (22); HRMS
7
9
79+81
(
EI): calcd for C24
H
18
N
2
O Br
2
, 507.9786; found 507.9801; Anal. Calcd for C24
H
18
N
2
O
2
Br : C, 56.47;
H, 3.53; N, 5.49. Found: 56.52; H, 3.54; N, 5.47.

HETEROCYCLES, Vol. 68, No.2, 2006
337
ACKNOWLEDGEMENTS
The authors express their sincere thanks to the Director, Bose Institute for providing laboratory facilities,
the C.S.I.R., Govt. of India for providing fellowships (A.M. and S.K.), Mr. B. Majumder, NMR Facilities
and Mr. P. Dey, Microanalytical Laboratory, both of Bose Institute, for recording the spectra.
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