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Pre
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C. R. Chimie 17 (2014) 305–309
A R
Artic
Rece
Acce
Avai
Keyw
Bis(
Arom
Vils
*
163
httpliminary communication/Communication
e-pot conversion of aromatic compounds to the
rresponding bis(indolyl)methanes by the Vilsmeier–Haack
action
jat Veisi a,*, Meral Ataee b, Pegah Darabi-Tabar a, Effat Amiri a, Ali Reza Faraji c
partment of Chemistry, Payame Noor University, 19395-4697 Tehran, Iran
partment of Chemistry, Islamic Azad University, Saveh Branch, Saveh, Iran
ulty of Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
ntroduction
In recent years, considerable attention has been focused
the development of efficient and operationally simple
tocols for carbon–carbon and carbon–heteroatom
ds formation for the construction of valuable mole-
es. The development of bis(indolyl)alkane synthesis has
n of considerable interest in organic synthesis because
their wide occurrence in various natural products
sessing biological activity and usefulness for drug
ign [1].
Bis(indolyl)alkane is known to promote estrogen
tabolism in both women and men, and is expected to
e an application in the prevention of breast cancer [2].
s, the development of facile and environmentally
ndly synthetic methods for the preparation of these
pounds constitutes an active area of investigation in
rmaceutical and organic synthesis [3–5].
Synthetically the reaction of 1H-indole with aldehydes
or ketones produces azafulvenium salts that react further
with a second 1H-indole molecule to form bis(indol-3-
yl)methanes [6]. In recent years, synthesis routes to this
class of molecules under mild conditions have been
reported, with promoters such as montmorillonite clay
K-10 [7], trichloro-1,3,5-triazine [8], AlPW12O40 [9],
sodium dodecyl sulfate (SDS) [10], ZrCl4 [11], H2NSO3H
[12], I2 [4], zeolites [13], bentonite [14], In(OTf)3/ionic
liquid [15], CuBr2 [16], Dy(OTf)3/ionic liquid [17], HClO4–
SiO2 [18], InCl3 [19], MW/Lewis acids (FeCl3, BiCl3, InCl3,
ZnCl2, CoCl2) [20], NaHSO4 and Amberlyst-15 [21], sulfated
zirconia [22], ZrOCl2/SiO2 [23], silica sulfuric acid (SSA)
[24], TiO2 [25], (NH4)2HPO4 [26], acidic ionic liquid [27],
NaBF4 [28], metal hydrogen sulfates [29], tetrabutylammo-
nium tribromide [30], superacid SO4
2/TiO2 [31], NaHSO4/
ionic liquid [32], NBS [33], Ph3CCl [34], H3PW12O40 [35],
LiClO4 [36], Zr(DS)4 [37], and Bi(NO3)3.5H2O [38]. However,
most of the existing methods involve toxic metal ions and
solvent, high cost and cumbersome work-up procedures.
Consequently, new procedures that address these draw-
backs are desirable.
 T I C L E I N F O
le history:
ived 11 April 2013
pted after revision 19 September 2013
lable online 21 February 2014
ords:
indolyl)methanes
atic compounds
meier–Haack reaction
A B S T R A C T
Various electron-rich aromatics could be smoothly converted into the corresponding
bis(indolyl)methanes in good to moderate yields by treatment of electron-rich aromatics
with POCl3 and DMF, followed by treatment with indole at room temperature. The present
article is the first report on a novel metal-free one-pot method for the preparation of
bis(indolyl)methanes from electron-rich aromatics.
 2013 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Corresponding author.
E-mail address: hojatveisi@yahoo.com (H. Veisi).
Contents lists available at ScienceDirect
Comptes Rendus Chimie
ww w.s c ien c edi r ec t . c om1-0748/$ – see front matter  2013 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
://dx.doi.org/10.1016/j.crci.2013.09.011
Table 1
One-pot conversion of aromatics into the corresponding bis(indolyl)methanes through aromatic N,N-dimethyliminium chlorides.
Entry Carbonyl compound Product Temperature (8C) Time
(min)
Yield
(%)a
Mp (8C) Mp (8C)
references
1 NHHN 40 5 h 55 124–125 124–125 [42]
2 Me NHHN
Me
40 3 h 65 94–95 93–94 [10]
3 OMe  NHHN
OMe
40 3 h 90 190–192 192–193 [39]
4 OMe
OMeMeO
NHHN
OMe
MeO OMe
40 2 h 90 225–227 226–227 [39]
5
Me2N
NHHN
NMe2
80 2 h 85 224–226 225–226 [10]
6
N
H
NHHN
NH
40 20 min 80 243–245 243–245 [10]
H. Veisi et al. / C. R. Chimie 17 (2014) 305–309306
2. E
from
furt
Tab
En
7
8
9
10
11
12
min
a
H. Veisi et al. / C. R. Chimie 17 (2014) 305–309 307xperimental
All commercially available chemicals were obtained
 Merck and Fluka companies, and used without
her purifications unless otherwise stated. 1H NMR
spectra were recorded on a Jeol 90 MHz FT NMR spectro-
meter using TMS as internal standard and chemical shifts d
are in ppm. Infrared (IR) measurements were conducted on
a PerkinElmer GX FT-IR spectrometer. All yields refer to
isolated products.
le 1 (Continued )
try Carbonyl compound Product Temperature (8C) Time
(min)
Yield
(%)a
Mp (8C) Mp (8C)
references
N
Me
NHHN
N
Me
40 2 h 90 253–254 251–253 [39]
NHHN 100 4 h 60 278–279 278–279 [36]
OMe NHHN
MeO
100 6 h 80 290–292 291–293 [10]
OMe
NHHN
OMe
100 2 h 82 282–284 280–282 [39]
S
NHHN
S
80 4 h 70 150–152 150–153 [39]
O
NHHN
O
80 15 min 75 322–324 320–322 [10]
: minute; h: hour.
Products were characterized by their physical properties, by comparison with authentic samples and by spectroscopic methods.
H. Veisi et al. / C. R. Chimie 17 (2014) 305–3093082.1. Typical experimental procedure
To a flask containing anisole (1 mmol) were added
POCl3 (1.1 mmol) and DMF (4 mmol) at 0 8C. After stirring
for 3 h at 40 8C, indole (2 mmol) was added to the reaction
mixture, which was then stirred for 1 h at r.t. After the
reaction, the mixture was poured into a NaHCO3 (10%)
solution and extracted with CHCl3 (3  20 mL). The organic
layer was dried over Na2SO4, filtered, and evaporated to
provide the corresponding bis(indolyl)methanes. The
resulting crude material was purified by recrystallization
from an ethanol/water mixture to afford the pure products.
2.2. Analytical data for the selected compounds
2.2.1. 3,30-Bisindolyl-4-methylphenylmethane (Table 1, entry
2)
Pinkish solid, m.p: 94–95 8C; IR (KBr): 3452, 3112, 3045,
2950, 1604, 1523, 1210, 1052, 765 cm1; 1H NMR (CDCl3,
90 MHz, d ppm): 2.38 (s, 3H), 5.85 (s, 1H), 6.70–7.55 (m,
ArH, 14H), 7.85 (br s, NH, 2H); 13C NMR (75 MHz, CDCl3): d
32.3, 55.0, 110.0, 110.9, 119.1, 119.2, 121.0, 121.9, 123.7,
127.6, 129.1, 132.5, 136.8, 156.2; MS: m/z 336; Anal. calcd.
for C24H20N2: C, 85.68; H, 5.99; N, 8.33. Found: C, 85.45; H,
5.88; N, 8.14.
2.2.2. 3,30-Bisindolyl-4-methoxylphenylmethane (Table 1,
entry 3)
Red solid; m.p: 190–192 8C; IR (KBr): 3408, 3056, 2932,
1597, 1486, 1450, 1335, 1102, 745 cm1; 1H NMR (90 MHz,
90 MHz, d ppm): 3.82 (s, 3H), 6.32 (s, 1H), 6.61 (s, 2H),
6.81–7.40 (m, ArH, 12H), 7.80 (br s, NH, 2H); 13C NMR
(75 MHz, CDCl3): d 32.3, 56.0, 110.0, 110.8, 119.2, 119.8,
120.6, 121.9, 123.7, 127.2, 129.9, 132.5, 136.9, 157.1; MS:
m/z 352; Anal. calcd. for C24H20N2O: C, 81.79; H, 5.72; N,
7.95. Found: C, 81.24; H, 5.45; N, 7.86.
2.2.3. Tri-(indolyl)methane (Table 1, entry 6)
Yellow solid, m.p: 243–245 8C; 1H NMR (DMSOd6,
90 MHz, d ppm): 9.67 (br s, 2H), 6.24 (s, 3H), 6.27–6.87
(m, 12H), 5.47 (s, 1H); IR (KBr) n: 3403, 3043, 2918 cm1;
MS: m/z 361; 13C NMR (75 MHz, CDCl3): d 31.6, 110.9,
111.9, 118.4, 119.5, 1121.2, 124.0, 126.3, 127.1, 128.5,
128.6, 137.0, 145.2; MS: m/z 361; Anal. calcd. for
C25H19N3: C, 83.08; H, 5.30; N, 11.63. Found: C, 83.41;
H, 5.48; N, 11.75.
2.2.4. 3,30-Bisindolyl-[2]thienylmethane (Table 1, entry 11)
Brown solid, m.p: 185–186 8C; IR (KBr): 3412, 1715,
1452, 1260, 1105 cm1; 1H NMR (CDCl3, 90 MHz, d ppm):
6.18 (s, 1H), 6.87 (s, 2H), 6.92–7.48 (m, ArH, 11H),
7.98 (br s, NH, 2H); 13C NMR (CDCl3): d 42.1, 102.1,
106.7, 110.6, 112.6, 119.3, 120.3, 121.5, 122.6, 131.1,
136.6, 142.1, 152.5; MS: m/z 328; Anal. calcd. for
C21H16N2S: C, 76.80; H, 4.91; N, 8.53. Found: C, 76.52;
H, 5.10; N, 8.35.
2.2.5. 3,30-Bisindolyl-2-furylmethane (Table 1, entry 12)
Pinkish solid, m.p: 322–324 8C; 1H NMR (CDCl3,
90 MHz, d ppm): 7.74 (br s, 2H), 7.32–7.63 (m, 9H), 7.09
(s, 2H), 6.21–6.35 (m, 2H), 5.82 (s, 1H); 13C NMR (CDCl3): d
42.2, 102.4, 106.2, 110.6, 112.6, 119.3, 120.3, 121.4, 122.6,
131.1, 136.3, 142.1, 152.5; MS: m/z 312; Anal. calcd. for
C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.67; H,
5.20; N, 8.85.
r.t.,  1 hAr- H
N
H
H
N
Ar1) POC l3 (1.1 mmol), DMF (4.0 mmol), temp., time
2) Ind ole  (2  mm ol),
Scheme 1.
Ar-H Ar-CH=N(CH3)2Cl
+
N
H
Ar
POCl3, DMF,  warm
N
H
N
H
(H3C)2N
ArH
N
H
(H3C)2HN
Ar
N
H
H
N
Ar HN
-HN(CH3)2
I
III
IIScheme 2.
3. R
het
on 
spo
sion
bis(
trea
wa
we
wa
dep
ind
for 
spo
Tab
lyl)
2. T
form
aro
sm
aza
the
4. C
dev
aro
goo
Thi
me
com
pot
bis(
elec
rea
and
bel
env
bis(
Ack
sup
H. Veisi et al. / C. R. Chimie 17 (2014) 305–309 309esult and discussion
Here, as part of our ongoing studies on the synthesis of
erocyclic compounds [39–42], we would like to report
the one-pot conversion of aromatics into the corre-
nding bis(indolyl)methanes (Scheme 1).
We planned to perform the metal-free one-pot conver-
 of aromatic compounds into the corresponding
indolyl)methanes using POCl3 and DMF, followed by
tment with indole at room temperature. The reaction
s carried out as follows: to a flask containing aromatics
re added POCl3 and DMF at 0 8C. Then, the mixture was
rmed at room temperature, 40 8C, 80 8C, or 100 8C,
ending on the substrate, for a few hours. Then, molecular
ole was added to the reaction mixture, which was stirred
one hour at room temperature to provide the corre-
nding bis(indolyl)methanes. The results are shown in
le 1. All the substrates gave the corresponding bis(indo-
methanes as a single isomer in good yields.
The plausible reaction mechanism is shown on Scheme
he initial step involves the Vilsmeier–Haack reaction to
 aromatic N,N-dimethyliminium salt I [43]. Once the
matic N,N-dimethyliminium salt I is formed, it reacts
oothly with indole to produce the corresponding
fulvene II, which further reacts with indole to generate
 corresponding bis(indolyl)methane III.
onclusion
In conclusion, a simple and convenient method has been
eloped for the direct conversion of various electron-rich
matics into the corresponding bis(indolyl)methanes in
d to moderate yields by the Vilsmeier–Haack reaction.
s is the first report on the synthesis of bis(indolyl)-
thanes from the corresponding electron-rich aromatic
pounds. The present reaction is a novel metal-free one-
 conversion of aromatics into the corresponding
indolyl)methanes, although the reaction is limited to
tron-rich aromatics. The advantages of the present
ction are operational simplicity, low cost, low toxicity,
 easy availability of reaction materials. Therefore, we
ieve that the present reactions are a useful and
ironmentally benign method for the preparation of
indolyl)methanes from aromatics directly.
nowledgment
We are thankful to Payame Noor University for partial
port of this work.
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