Gold(I)-catalyzed sequential cycloisomerization/bis-addition of o-ethynylanilines: an efficient access to bis(indolyl)methanes and di(indolyl)indolin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2008.11.086

An efficient synthesis of bis(indolyl)methanes and di(indolyl)indolin-2-ones has been developed by a sequential approach involving gold(I)-catalyzed cycloisomerization/bis-addition of o-ethynylanilines with various aldehydes and isatins, respectively. This methodology opens clean and synthetically competitive alternative to the already established procedures of the synthesis of bis(indolyl)methanes and di(indolyl)indolin-2-ones.

Full text of DOI:10.1016/j.tetlet.2008.11.086

Tetrahedron Letters 50 (2009) 644–647
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold(I) catalyzed sequential cycloisomerization/bis-addition
of o-ethynylanilines: an efficient access to bis(indolyl)methanes
and di(indolyl)indolin-2-ones
*
C. Praveen, Y. Wilson Sagayaraj, P. T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of bis(indolyl)methanes and di(indolyl)indolin-2-ones have been developed by a
sequential approach involving gold(I) catalyzed cycloisomerization/bis-addition of o-ethynylanilines
with various aldehydes and isatins respectively. This methodology opens clean and synthetically compet-
itive alternative to the already established procedures of the synthesis of bis(indolyl)methanes and
di(indolyl)indolin-2-ones.
Received 8 October 2008
Revised 10 November 2008
Accepted 22 November 2008
Available online 27 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Bis(indolyl)methanes constitute an important class of heterocy-
clic compounds that display diverse pharmacological activities and
are useful in the treatment of fibromyalgia, chronic fatigue and irri-
table bowel syndrome.1 They are known to promote beneficial
estrogen metabolism2 and induce apoptosis in human cancer cells.
Thus the development of high-throughput methods for the synthe-
sis of bis(indolyl)methanes remains a topic of paramount impor-
tance in view of their versatile biological and pharmacological
properties. Bis(indolyl)methanes have been prepared mainly by
the reaction of indole with carbonyl compounds in the presence of
Lewis acids such as LiClO4,3 InCl3,4 I2,5 CuBr2,6 [RE(PFO)3],7 ZrCl4,8
and Bronsted acids such as sulphamic acid,9,10 PTSA,11 KHSO4.12
All the synthetic avenues to bis(indolyl)methanes comprise reac-
tion between pre-constructed indole skeletons with aldehydes (or
zation of o-ethynylanilines followed by C3 functionalization leading
to 3-substituted indoles have been developed with remarkable
improvements in terms of efficiency and scope of application.19
However there is no report for the construction of bis(indolyl)meth-
anes and di(indolyl)indolin-2-ones via one-pot cycloisomerization/
bis-addition process. More recently it has been shown that the
alkynophilic Lewis acidity of Au(I) and Au(III) present new opportu-
nities for the cycloisomerization of wide array of alkynes-tethered
nucleophiles.20 The unique reactivity of Au(I) and Au(III) with
allenes and alkynes opened the doors to the discovery and invention
of new reactions.21 But, participation of Au(I) and Au(III) in intramo-
lecular cyclization/C3 functionalization of o-ethynylanilines to
3-substituted indoles were less explored.22 In our ongoing efforts
on intramolecular cyclization reactions23 and stimulated by the
growing interest in the development of gold catalysis,24 we became
interested in the development of gold-catalyzed synthesis of
3-substituted indoles. In particular we focussed our attention to
the preparation of bis(indolyl)methanes and di(indolyl)indolin-2-
ones through an integrated process involving two basic steps, cyclo-
isomerization of o-ethynylanilines followed by bis-addition with
aldehydes and isatins (Scheme 1).
We initiated our studies by reacting o-(phenylethynyl) aniline
(6) and biphenyl-4-carbaldehyde (2d) with 5 mol % AuCl in aceto-
nitrile at room temperature. Under this condition only the cyclo-
isomerized product that is, 2-phenyl indole was obtained as the
sole product (85% isolated yield). Bis-addition, under these condi-
tions proved to be ineffective, even when the reaction was carried
out for 24 h. By elevating the temperature to 80 °C, we were able to
obtain the bis-addition product (7d) in high yield in a short reac-
tion time (Table 1, entry 4). When the same reaction was
performed using 2 mol % of AuCl, only 40% of the product (7d)
was formed, and 35% of the starting material, that is, 2-(phenyleth-
their acetals), ketones, a-ketoacids, imines, iminium salts or nitro-
nes.13 On the otherhand 3,3-diaryloxindoles, a basic framework
widely found in clinical drugs and biologically active substances
have been shown to possess antiproliferative, antibacterial, antipro-
tozoal and antiinflammatory activities.14 These compounds have
also been used as laxatives15 and lead molecules for Ca2+ depletion
mediated inhibition of translation initiation.16 The 3,3-di(indol-
y)indolin-2-ones can be formed by the reaction of isatin and indoles
under acidic conditions for long reaction times or catalyzed by KAl
(SO4)2 under microwave conditions.17 Only a few methodologies
has been accommodated for the synthesis of di(indolyl)indolin-2-
ones.15,18 As a result of the increased interest, new efficient methods
are needed to synthesise these compounds and generate structur-
ally diverse bis(indolyl)methanes and di(indolyl)indolin-2-ones
with a variety of substituents. In recent years, intramolecular cycli-
* Corresponding author. Tel.: +91 44 24911329; fax: +91 44 24911539.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.086

C. Praveen et al. / Tetrahedron Letters 50 (2009) 644–647
645
R
H
O
H
N
O
N
Ar
R1
R1
R
O
NH
N
R
3
ArCHO 2
R
H
R
HN
N
NH2
H
1
4
5
Scheme 1.
ynyl)aniline (6) was recovered. So we inferred that 2 mol % of AuCl
was ineffective for the complete cycloisomerization of o-(phenyl-
ethynyl)aniline. Toluene, methanol and dichloromethane gave only
38%, 20%, and 50% of the product respectively. Based on these
observations, we used a procedure, that utilizes 5 mol % of AuCl
in acetonitrile under reflux, followed by the addition of 0.5 equiv
of aldehyde, for the synthesis of bis(indolyl)methanes. (Scheme
2).25
Under these conditions, the reaction proceeded smoothly with a
wide range of functionalized aldehydes, including those containing
ether, phenol, carboxylic acid, polyaromatic and heteroaromatic
groups. The results are summarized in Table 1. The results revealed
that electron deficiency and the nature of the araldehyde had
marked effect on this conversion. Aldehydes with electron
withdrawing groups gave lower yields of the products (entry 3)
than those with electron releasing counterparts (entries 1–2). This
observation was in good agreement with other bis-addition proto-
cols.3,26 Moreover this method is chemoselective. For example,
when a 1:1 mixture of biphenyl-4-carbaldehyde (2d) and aceto-
phenone (2l) was allowed to react with 2-(phenylethynyl)aniline
(6) and AuCl in acetonitrile, it was found that only 3,30-(biphe-
nyl-4-ylmethylene)bis(2-phenyl-1H-indole) (7d) was obtained,
while acetophenone did not give the corresponding product (7l).
On the basis of the above results we extended our methodology
for the synthesis of bis(indolyl)methanes derived from aldehydes
with structural diversity including polycyclic and heteroaromatic.
All these aldehydes gave good yields of products (7a–7k). However
the low yields in the case of (7e) and (7g) may be attributed to the
lower reactivity of their corresponding aldehydes (2e and 2g)
towards bis-addition. The 1H NMR spectra of compounds (7a–7k)
in DMSO-d6 consisted of a characteristic singlet due to the methine
proton (–CH-Ar) in the region of 5.8–6.7 ppm. Another characteris-
tic feature of the 1H NMR spectra was the appearance of a singlet at
dH 11.3–11.5 ppm, which corresponds to two indole-NH protons.
These observations confirm the formation of bis(indolyl)methanes.
A tentative mechanistic interpretation (Scheme 3) to explain
the formation of the observed bis(indolyl)methanes (7) might
Table 1
Gold(I) catalyzed synthesis of bis(indolyl)methanes from 2-(phenylethynyl)aniline 6
and aldehyde 2
Entry
ArCHO 2
CHO
Producta
Time (h)
Yieldb
R1
R2
R4
R3
1
2
3
4
R1 = H, R2 = OMe, R3 = OH, R4 = Br
R
R
R
2a
2b
2c
2d
7a
7b
7c
7d
2.0
2.0
1.5
1.5
76
79
65
80
1 = Br, R2 = H, R3 = OMe, R4 = OMe
1 = H, R2 = H, R3 = COOH, R4 = H
1 = H, R2 = H, R3 = Ph, R4 = H
reasonably assume a reaction path that implies an initial
nation of Lewis acidic AuCl with the alkyne residue (6) to form a
-complex (8). Subsequent nucleophilic attack of the tethered ami-
p-coordi-
p
CHO
2e
5
6
7e
7f
4.0
1.0
53
85
N
Me
no group leads to ring closure to afford cyclized intermediate (9),
followed by Proto-deauration affording indole (10) and AuCl. The
later activates the carbonyl oxygen of the aldehyde and carries
out an electrophilic addition reaction at C3 of the indole (10) giving
intermediate (11). After loss of water, an azafulvene derivative (12)
is generated, which reacts further with a second molecule of indole
to form the bis(indolyl)methane (7).
With an efficient protocol for the gold catalyzed synthesis of
bis(indolyl)methanes in hand, we next set out to apply the same
reaction conditions for the synthesis of di(indolyl)indolin-2-ones
from various 2-ethynylanilines and isatins (Scheme 4).27 The
results of which are summarized in Table 2.
The substituents on the aniline moiety play a significant role in
the cycloisomerization/bis-addition process. The presence of elec-
tron-releasing group, such as methyl in para position to the amino
group enhances the product formation as indicated by a short reac-
tion time and higher yield (entry 4). Similarly, for a strong elec-
tron-withdrawing group, such as cyano, para to amino group,
CHO
O
2f
O
Br
CHO
7
8
2g
7g
7h
3.5
0.5
59
83
N
Cl
CHO
2h
Et
N
9
7i
7j
7k
7l
0.5
0.5
0.5
1.5
77
76
82
—
2i
2j
CHO
CHO
10
11
Cl
N
H
Ph
Ph
N
N
2k
Ar
OHC
Me
Ph
1) 5 mol % AuCl, MeCN/N2, reflux, 1h
Ph
12
O
2) 0.5 eq ArCHO 2, reflux
2l
N
NH2
H
7
6
a
Isolated yield.
b
The products were characterized by IR, 1H NMR, 13C NMR and mass spectra.
Scheme 2.

646
C. Praveen et al. / Tetrahedron Letters 50 (2009) 644–647
AuCl
_
AuCl
Ph
Ph
AuCl
..
NH2
Ph
..
NH2
Ph
N
H
NH2
+
8
10
9
6
Ph
H
N
Ar
Ar
Ar
H
H
AuCl
OH
10
O
10
Ph
Ph
Ph
+
-H2O
-AuCl
N
N
H
Ar
H
N
AuCl
12
11
7
Scheme 3.
R2
compatibility and no additional solvent extraction steps are the
noteworthy advantages of this method. Further studies to
delineate the scope and limitations of the present methodology
are underway.
R3
N
R1
O
R2
1) 5 mol% AuCl, MeCN/N2, reflux, 1h
R4
R2
NH
R3
N
R1
R1
NH2
2)
Acknowledgement
O
N
R4
H
O
13
14
15
The authors thank the Council of Scientific and Industrial
Research, New Delhi, India for the research fellowship.
Scheme 4.
References and notes
Table 2
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Entry
R1
R2
R3
R4
Time (h)
Productb
Yieldc (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
nBu
H
H
Cl
Me
CN
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H
Me
H
H
H
H
H
Me
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H
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In summary, an efficient and one-pot synthesis of structurally
diverse bis(indolyl)methanes and di(indolyl)indolin-2-ones via
Au(I) catalyzed cycloisomerization/bis-addition of o-ethynylani-
lines with aldehydes and isatins has been developed. This method-
ology affords the products in good yields and could be extended to
a wide range of aldehydes/isatins. Significantly this procedure
affords indoles with a free –NH group without requiring the use
of nitrogen protecting group. One-pot synthesis, functional group

C. Praveen et al. / Tetrahedron Letters 50 (2009) 644–647
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1042, 746, 698 cmꢀ1 1H NMR (500 MHz, DMSO-d6) dH 3.47 (s, 3H, –OCH3), 5.87
.
(s, 1H, –CH-Ar), 6.66–6.71 (m, 3H, Ar-H), 6.78 (s, 1H, Ar-H), 6.91 (d, 2H,
J = 7.6 Hz, Ar-H), 6.98 (t, 2H, J = 7.6 Hz, Ar-H), 7.19–7.21 (m, 6H, Ar-H), 7.28–
7.29 (m, 4H, Ar-H), 7.34 (d, 2H, J = 8.4 Hz, Ar-H), 9.30 (s, 1H, –OH), 11.3 (s, 2H, –
NH). 13C NMR (75 MHz, DMSO-d6) dC 56.1, 64.8, 109.0, 111.3, 112.1, 113.8,
118.6, 120.5, 120.9, 124.1, 127.2, 128.0, 128.2, 132.7, 135.3, 136.1, 137.4, 141.9,
148.4 (2C). MS (EI): m/z = 597 [M+], 599[M+2]. Anal. Calcd for C36H27BrN2O2: C,
72.14; H, 4.54; N, 4.67. Found: C, 72.22; H, 4.50; N, 4.71.
26. Yadav, J. S.; Reddy, B. V. S.; Sunitha, S. Adv. Synth. Catal. 2003, 345.
27. General procedure for the synthesis of di(indolyl)indolin-2-ones 15a–15f.
Representative procedure for 3,3-Bis(2-butyl-1H-indol-3-yl)indolin-2-one 15f
(Table 2, entry 6): To
a solution of o-hexynylaniline (1.0 mmol) in
acetonitrile (1 mL) under N2 was added AuCl (5 mol %) in acetonitrile (1 mL)
and stirred the mixture under reflux for 1 h. To this reaction mixture 0.5 mmol
of isatin was added and the mixture was refluxed for the specified time (Table
2). After completion of the reaction as indicated by TLC, the reaction mixture
was concentrated under reduced pressure and purified by column
chromatography over silica gel (100–200 mesh) to afford pure product 15f
(70%) as a brown solid; mp 199–201 °C; Rf = 0.50 (AcOEt/petroleum ether 25%).
IR (KBr): 749, 1459, 1713, 2925, 3385 cmꢀ1 1H NMR (500 MHz, DMSO-d6) dH
.
0.59 (t, 3H, J = 6.8 Hz, –CH3), 0.67 (t, 3H, J = 6.8 Hz, –CH3), 0.91–1.42 (m, 8H, –
CH2–CH2–CH3), 2.29–2.35 (m, 4H, Ar-CH2–), 6.39 (d, 1H, J = 7.6 Hz, Ar-H), 6.50
(t, 1H, J = 6.9 Hz, Ar-H), 6.58 (t, 1H, J = 7.6 Hz, Ar-H), 6.79–6.90 (m, 5H, Ar-H),
7.12–7.18 (m, 4H, Ar-H), 10.47 (s, 1H, –NH–CO–), 10.70 (s, 1H, –NH), 10.75 (s,
1H, –NH). 13C NMR (125 MHz, DMSO-d6) dC 13.9, 14.0, 22.6 (2C), 26.9, 27.0,
31.4, 31.8, 53.1, 109.6, 109.7, 110.6, 110.7, 111.0, 117.9, 118.0, 120.0, 120.2,
120.5, 120.9, 121.5, 125.6, 127.6, 128.0, 128.1, 135.7, 135.8, 136.2, 136.3, 138.5,
141.5, 179.6. MS (EI): m/z = 973 [dimer+Na+]. Anal. Calcd for C32H33N3O: C,
80.81; H, 6.99; N, 8.83. Found: C, 80.97; H, 7.05; N, 8.76.
25. General procedure for the synthesis of bis(indolyl)methanes 7a–7k. Representative
procedure for 4-[bis(2-phenyl-1H-indol-3-yl)methyl]-2-bromo-6-methoxyphenol