ZnCl2 promoted efficient, one-pot synthesis of 3-arylmethyl and diarylmethyl indoles

Article abstract of DOI:10.1016/j.tetlet.2013.11.115

Anhydrous ZnCl₂ mediated convenient, one-pot synthesis of 3-arylmethyl and diarylmethyl indoles was accomplished in good yields. Under reaction condition, in situ formation of kinetically stable bis(indolyl)methane product was identified. Its s

Full text of DOI:10.1016/j.tetlet.2013.11.115

Tetrahedron Letters 55 (2014) 694–698
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Tetrahedron Letters
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ZnCl2 promoted efficient, one-pot synthesis of 3-arylmethyl
and diarylmethyl indoles
⇑
Subramaniapillai Selva Ganesan , Asaithampi Ganesan
School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Anhydrous ZnCl2 mediated convenient, one-pot synthesis of 3-arylmethyl and diarylmethyl indoles was
accomplished in good yields. Under reaction condition, in situ formation of kinetically stable bis(indo-
lyl)methane product was identified. Its subsequent conversion to the thermodynamically stable 3-dia-
rylmethyl indole at elevated temperature and pressure was confirmed by carrying out pressure tube
reaction with bis(indolyl)methane.
Received 12 September 2013
Revised 28 November 2013
Accepted 30 November 2013
Available online 5 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Zinc chloride
Friedel–Crafts reaction
3-Diarylmethyl indole
Pressure tube reaction
Multicomponent reactions offer a tangible way to access both
chemically and structurally diverse class of molecules.1 Moreover,
multicomponent organic transformations accomplished by readily
available, inexpensive catalysts/reagents are invariably attractive.
In continuation of our efforts to devise efficient multicomponent
reaction,2 herein we report anhydrous ZnCl2 mediated one-pot
synthesis of 3-arylmethyl and diarylmethyl indoles. Indole frame
work is present in plethora of bioactive molecules such as etodo-
lac,3 indometacin,4 and reserpine5 used for treating inflammation,
hypertension, and psychiatric disorders. The presence of indole
skeleton plays a vital role in determining anticancer activity of try-
prostatin A, an antimitotic agent used in the treatment of multi-
drug resistant tumours.6 3-Alkyl substituted indoles are useful in
the total synthesis of paraherquamide A,7 an anthelmintic agent;
clavicipitic acid,8 a derailment product of ergot alkaloid biosynthe-
sis; indolmycin,9 a novel antibiotic; veiutamine,10 a marine alka-
loid etc. Excellent reviews are available which provide significant
insight into the synthesis and applications of indole deriva-
tives.1a,11 Synthesis of 3-arylmethyl/diarylmethyl indole from in-
dole and aldehyde/ketone is difficult due to the high
nucleophilicity of indole toward azafulven intermediate leading
to the formation of bis(indolyl)methane.12 Steele and co-workers
utilized triethylsilane/trifluoroacetic acid reagent system to rapidly
donate hydride ion to the azafulven intermediate to form 3-aryl-
methyl indole. Campbell et al., employed TMSOTf/Et3SiH to
synthesize 3-arylmethyl indoles as selective COX-2 inhibitors.13
Trifluoroacetic acid,14a HClO4-SiO2,14b and ferric chloride15 were
useful in the synthesis of 3-arylmethyl/diarylmethyl indoles. Enan-
tioselective synthesis of 3-arylmethyl indoles using Zn(OTf)2-
axially chiral BINAM derived catalyst was reported by Shi and
co-workers.16 Jana et al., reported FeCl3 catalyzed C3-selective
Friedel–Crafts alkylation of indoles with allylic, benzylic, and prop-
argylic alcohols.17 Pei et al., reported chiral Brønsted acid catalyzed
enantioselective 3-arylmethyl indole synthesis.18 Damu et al., syn-
thesized 3-arylmethyl indole by DDQ mediated oxidative coupling
between indole and 1,3-diarylpropyne.19 Periasamy et al., success-
fully employed diimine-copper complexes20 and iron(III) oxide/
potassium tert-butoxide21 for the N-arylation of indole.
N,N-Dimethylaniline, bezaldehyde, and indole were chosen as
model substrates to find optimized reaction condition for ZnCl2
promoted 3-diarylmethyl indole 2 synthesis. Both methanesulfonic
acid and montmorillonite K10 in toluene solvent at 100 °C did not
yield the corresponding product 2, while anhydrous MgSO4 under
neat condition gave the product in 30% yield (Table 1, entries 1–3).
Interestingly, reaction with anhydrous ZnCl2 in ethanol gave prod-
uct 2 in 60% yield (entry 4). Encouraged by this result, anhydrous
ZnCl2 mediated Friedel–Crafts reaction was screened with different
solvents and reaction condition. The reaction carried out with one
equivalent of anhydrous ZnCl2 in methanol at room temperature
gave a marginal improvement in the yield to 64%, while in glycerol
indeed reduced the yield to 55% (Entries 5 and 6). By keeping the
reaction in methanol at 60 °C did not improve the yield (Footnote
f). Friedel–Crafts reaction in MeOH–H2O mixture (2 mL, 1:1 v/v)
⇑
Corresponding author. Tel.: +91 8973104963.
E-mail address: selva@biotech.sastra.edu (S.G. Subramaniapillai).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.115

S. G. Subramaniapillai, A. Ganesan / Tetrahedron Letters 55 (2014) 694–698
695
Table 1
Screening of reaction condition for 3-diarylmethyl indole synthesisa. Entry 9 gives the optimized condition for the reaction.
Entry
Catalyst/reagent (mmol)
Additive
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
CH3SO3H (0.4)
Montmorillonite-K10c
MgSO4 (1)
ZnCl2 (1)
ZnCl2 (1)
ZnCl2 (1)
ZnCl2 (1)
ZnCl2 (1)
ZnCl2 (1)
ZnCl2 (0.5)
ZnCl2 (0.2)
ZnSO4 (1)
Zn(OAc)2 (1)
Zn(NO3)2 (1)
ZnO (1)
ZnCl2 (1)
ZnCl2 (1)
ZnCl2 (1)
CH3SO3H (0.4)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Toluene
Toluene
Neat
C2H5OH
CH3OH
Glycerol
CH3OH:H2Oh
Neat
100
100
100
rt
5
7
3
Traces
NR
30
60
64
3d
4e
5e
6e
7g
8
12
12
12
12
12
5
10
12
5
5
5
5
10
7
rtf
rt
rt
rt
55
68 (46)i
40
9j
Toluenek
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
100
100
100
100
100
100
100
rt
76
61
57
NR
Traces
21
12
65
67
10
11
12
13
14
15
16
17
18
19
K10 (250 mg)
Silica (100 mg)l
HCl (1 mL)
—
100
100
100
5
5
40
Traces
a
b
c
d
e
f
All the reactions were carried out with 1 mmol of indole, 1.2 mmol of N,N-dimethylaniline and 1.2 mmol of benzaldehyde.
Yields are for the isolated products.
500 mg of catalyst was used.
Reaction carried out at room temperature for 12 h did not give the product.
2 mL of solvent was used.
Reaction carried out at 60 °C for 5 h gave 40% yield of the product.
Reaction carried out with only water (2 mL) did not give the product.
2 mL (1:1 v/v) of methanol and water was taken.
g
h
i
MeOH:H2O (2:2 mL v/v) at reflux for 12 h gave 46% yield.
Reaction carried out at room temperature for 12 h gave 60% yield of the product.
In toluene:MeOH (3.5:0.5 mL v/v) at 100 °C for 12 h gave 54% yield. In toluene: MeOH (3.5 mL:100 lL v/v) at 100 °C for 12 h gave 49% yield.
j
k
l
In the absence of ZnCl2, only trace quantity of product was formed.
gave 68% yield (Entry 7). Efforts to increase the yield by carrying
out the reaction in (a) MeOH–H2O mixture at reflux condition (b)
under neat condition (c) and in water medium were not successful
(Footnote i, Entry 8). Later, toluene was identified as suitable sol-
vent to carry out anhydrous ZnCl2 mediated 3-diarylmethyl indole
synthesis. Reaction carried out in toluene at room temperature for
12 h gave product 2 in 60% yield. The yield was increased to 76% by
carrying out the reaction at 100 °C for 5 h (Entry 9, Scheme 1).
One equivalent of anhydrous ZnCl2 was necessary to obtain
optimum yields. Reduction in the quantity of anhydrous ZnCl2 to
0.5 or 0.2 equiv increased the reaction time and reduced the prod-
uct yield to 61% or 57%, respectively (Entries 10 and 11). Addition
of methanol as co-solvent increased the solubility of ZnCl2 in tolu-
ene but did not improve the yield (Footnote k). We have also exam-
ined Zn(OAc)2, Zn(NO3)2, ZnO, and ZnSO4 promoted Friedel–Crafts
reaction of indole (Entries 12–15). However, none of the aforemen-
tioned reagents gave better yield than ZnCl2. It was previously re-
ported that the presence of additives substantially improved the
catalytic activity of ZnCl2.22 The role of montmorillonite K10, silica,
and HCl as additives was examined (Entries 16–18). However,
none of the additives enhanced the reaction yield. Anhydrous ZnCl2
mediated Friedel–Crafts reaction of indole, N,N-dimethylaniline,
and 37% formaldehyde solution in methanol gave product 3 in
76% yield (Scheme 2). Interestingly, in toluene solvent, formation
of product 3 was not observed.
This could be due to the poor solubility of aqueous formalde-
hyde (37%) solution in toluene. After optimization, 3-diarylmethyl
indole synthesis was screened for various aromatic aldehydes and
N,N-dialkylanilines (Scheme 3, Fig. 1). Anhydrous ZnCl2 mediated
Friedel–Crafts reaction was found to be general for both electron
donating and electron withdrawing aldehydes (Fig. 1, compounds
7 and 5).
N
N
anhyd. ZnCl2
MeOH
r.t., 12 h
CH2O
N
H
N
H
3
1
76% yield
Scheme 2. Synthesis of 3-arylmethyl indole.
R
N
Ar
R
ArCHO
anhyd. ZnCl2
Toluene
N
H
R
R
100 oC, 5 h
4-8
N
up to 68% yield
N
R
N
CHO
N
N
CH2O
anhyd. ZnCl2
H
1
R
anhyd. ZnCl2
Toluene
MeOH
r.t., 12 h
N
H
N
H
N
100 oC, 5 h
2
9
H
1
76% yield
65% yield
Scheme 1. Synthesis of 3-diarylmethyl indole.
Scheme 3. Synthesis of 3-diarylmethyl and 3-arylmethyl indole.

696
S. G. Subramaniapillai, A. Ganesan / Tetrahedron Letters 55 (2014) 694–698
Cl
Cl
Et
Et
N
N
N
4
N
H
5
N
H
66% yield
N
H
68% yield
6
MeO
58% yield
Cl
Et
N
Et
Et
N
Et
N
N
7
9
8
H
N
N
66% yield
51% yield
H
65% yield
H
Figure 1. 3-Diarylmethyl and 3-arylmethyl indole.
During the course of investigation on ZnCl2 mediated 3-dia-
However, only partial conversion of 11 to the corresponding prod-
uct 2 was observed. Successful conversion of the bis(indolyl)meth-
ane to the product 2 in 54% yield was achieved by carrying out the
reaction in a pressure tube (Scheme 5). Reactions carried out in tol-
uene at 60 °C and in DMF at 100 °C did not yield the desired prod-
uct. In benzene, product 2 was obtained in 52% yield. In addition to
appropriate solvent, both high temperature and pressure are vital
for this transformation. Previously, Mahadevan et al., employed tri-
fluoroacetic acid/Et3SiH to synthesize 3-arylmethyl indoles from
bis(indolyl)methane in 60% yield.26 To the best of our knowledge,
substitution of indole moiety in bis(indolyl)methane by N,N-
dimethylaniline in Friedel–Crafts reaction has not been reported
yet.
It was previously reported that bis(indolyl)methane deriva-
tives27a and dipyrromethane derivatives27b displayed good affinity
towards Zn2+ ions. Moreover, Zn2+ ions prefer to coordinate with
nitrogen atom of bis(tetrazole) ligands in a intermolecular fash-
ion.27c Bhuyan and co-workers reported the addition of indole
nucleophile to 3-alkylated indole to form diindolylmethane pro-
ceed via elimination-addition mechanism.28 Based on this, a plau-
sible mechanism for the formation of 3-diarylmethyl indole is
given in Scheme 6. Coordination of zinc chloride to nitrogen atom
of bis(indolyl)methane 11 could result in the elimination of indole
from 11 to form azafulven 10 intermediate. Subsequent addition
of N,N-dialkylaniline to azafulven followed by deprotonation
may result in the formation of product 2. N-methyl derivative
of bis(indolyl)methane (1-methyl-3-[(1-methyl-1H-indol-3-yl)
(phenyl)methyl]-1H-indole) was also synthesized and subjected
to pressure tube reaction condition. However, formation of corre-
sponding 3-diarylmethyl indole product was not observed. It
shows the presence of unsubstituted –NH in 11 is essential for
rylmethyl indole synthesis in toluene at room temperature, forma-
tion of bis(indolyl)methane 11 was observed in the reaction
medium which was later converted to the corresponding product
(Table 1, Footnote j). Initial formation of both 3-diarylmethyl in-
dole 2 and bis(indolyl)methane 11 in the reaction medium was fur-
ther confirmed by quenching the reaction within one hour at room
temperature. Due to the inhomogenity of the reaction medium, ef-
forts to periodically monitor the progress of reaction was unsuc-
cessful. Bhuyan and co-workers reported the formation of
bis(indolyl)methane as minor product along with 3-alkylated
indoles.23 Recently, Lubell and co-workers reported the in situ for-
mation of kinetically stable bis(indolyl)methane in the reaction
medium and its subsequent conversion to the 3-vinylindole in tri-
fluoroacetic acid mediated, microwave assisted 3-vinylindoles syn-
thesis.24 Based on this, we have proposed a plausible mechanism
for the formation of 3-diarylmethyl indole 2 from indole/bis(indo-
lyl)methane (1/11) (Scheme 4).
Reaction of indole 1 with benzaldehyde in the presence of ZnCl2
could result in the formation of azafulven 10.1a Addition of indole 1
to azafulven 10 may lead to the formation of kinetically stable
bis(indolyl)methane 11. In the presence of N,N-dimethylanilines
at higher temperature/elongated reaction time, bis(indolyl)meth-
ane could convert to the corresponding 3-diarylmethyl indole 2.
Moreover, bis(indolyl)methane 11 was completely soluble in tolu-
ene while 3-diarylmethyl indole 2 was sparingly soluble. This
could further facilitate the gradual transformation of bis(indo-
lyl)methane to 3-diarylmethyl indole 2 in toluene.
To further confirm this transformation, we have synthesized
bis(indolyl)methane 11 by closely following a literature report25
and subjected to test reaction condition (Table 1, Entry 9).
CHO
N
ZnCl2
N,N-Dimethylaniline
N
N
H
H
10
1
N
H
2
Azafulven
- Indole + Indole
NH
N
11
H
Scheme 4. Mechanism for the formation of 3-diarylmethyl indole.

S. G. Subramaniapillai, A. Ganesan / Tetrahedron Letters 55 (2014) 694–698
697
N
N,N-Dimethylaniline
anhyd. ZnCl2
Toluene
140 oC, 5 h
In pressure tube
54% yield
N
H
HN
bis(indolyl)methane
NH
2
11
Pressure tube reaction
Scheme 5. Synthesis of 3-diarylmethyl indole from bis(indolyl)methane.
N
NH
N
HN
N
-2 Indole
+2 Indole
ZnCl2
11
H
2
Toluene
N
H
H
H
N
N
H
Azafulven
Zn
Cl Cl
10
Scheme 6. Mechanism of formation of 2 from bis(indolyl)methane.
115. These data include MOL files and InChiKeys of the most
important compounds described in this article.
R
R
R
N
N
R
anhyd. AlCl3
References and notes
Toluene
140 oC, 5 h
HN
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Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486; (c) Nair, V.; Rajesh, C.;
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Res. 2003, 36, 899–907; (d) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev.
2012, 41, 3969–4009.
NH
N
H
11
In pressure tube
bis(indolyl)methane
R = Me, Et
R = Me (2) 71% yield
R = Et (4) 70% yield
2. Ganesan, S. S.; Rajendran, N.; Sundarakumar, S. I.; Ganesan, A.; Pemiah, B.
Synthesis 2013, 45, 1564–1568.
Scheme 7. Anhydrous AlCl3 mediated synthesis of 3-diarylmethyl indole
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Pace-Asciak, C. J. Med. Chem. 1983, 26, 1778–1780.
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the ZnCl2 mediated conversion of bis(indolyl)methane to 3-dia-
rylmethyl indole. Moreover, changing zinc chloride:bis(indo-
lyl)methane mole ratio to 0.5:1 did not affect the product 2 yield.
Further reducing zinc chloride to 0.1:1 reduced the product 2 yield
to 43%.
To improve the reaction yield, we have screened several Lewis
acids and anhydrous AlCl3 was found to be the suitable reagent
than anhydrous ZnCl2 for the efficient conversion of 11 to 2. In
presence of anhydrous AlCl3, reaction yield increased from 54% to
71% (Scheme 7). Anhydrous AlCl3 mediated Friedel–Crafts reaction
of unsymmetrical bis(indolyl)methane is underway in our
laboratory.
In summary, a convenient, one-pot methodology has been
established for 3-arylmethyl and diarylmethyl indole synthesis.29
The in situ formation of kinetically stable bis(indolyl)methane dur-
ing the reaction was identified and its conversion to the 3-diarylm-
ethyl indole was confirmed by carrying out the reaction under high
temperature and pressure.
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Acknowledgments
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S.S.G. thanks DST for DST-Fast Track Grant (No: SR/FT/CS-09/
2011). The authors thank the SASTRA University for providing lab
space and NMR facility. S.S.G. thanks Dr. Philip Anthony and Dr.
Elamparuthi for useful discussion.
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11.
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(160 lL, 2 mmol) in 10 mL of methanol, anhydrous zinc chloride (136 mg,
1 mmol) was added and the mixture was further stirred at room temperature
for 12 h. The reaction mixture was concentrated, quenched with water (10 mL)
and extracted with ethyl acetate (2 Â 10 mL). The combined organic extracts
were dried over anhydrous magnesium sulfate and the products were purified
by column chromatography on silica gel, using hexanes/EtOAc (95:5) as
eluent. 4-(1H-Indol-3-ylmethyl)-N,N-dimethylaniline (3): Off-white solid;
Yield = 190 mg (76%); m.p. 143 °C (143 °C);14b IR (KBr): 3408, 1610, 1517,
29. Representative procedure for 3-diarylmethyl indole synthesis: To
a stirred
homogeneous solution of indole (117 mg, 1 mmol), N,N-dimethylaniline
(152 L, 1.2 mmol) and benzaldehyde (122 L, 1.2 mmol) in 10 mL of
l
l
toluene, anhydrous ZnCl2 (136 mg, 1 mmol) was added and heated in an oil
bath at 100 °C for 5 h. The reaction mixture was quenched with 5 mL of cold
water and extracted with ethyl acetate (2 Â 10 mL). The organic extract was
separated, washed with brine, dried over anhydrous sodium sulphate and
solvents were evaporated under reduced pressure. The products were purified
by column chromatography on silica gel, using hexanes/EtOAc (95:5) as eluent.
4-((1H-Indol-3-yl) (phenyl)methyl)-N,N-dimethyl aniline (2): White Color
solid; Yield = 248 mg (76%); m.p. 161–162 °C (161–162 °C);15 IR (KBr): 3391,
1463, 1216, 1134, 750 cmÀ1 1H NMR (300 MHz, CDCl3) d (ppm): 2.91 (6H, s,
;
N(CH3)2), 4.03 (2H, s, Ar-CH2), 6.70 (2H, d, J = 8.4 Hz, ArH), 6.89–6.90 (1H, m,
ArH), 7.08 (1H, t, J = 7.2 Hz, ArH), 7.17 (3H, d, J = 8.4 Hz, ArH), 7.35 (1H, d,
J = 8.1 Hz, Ph), 7.55 (1H, d, J = 7.8 Hz, ArH), 7.93 (1H, s, NH); Procedure for the
synthesis of 4-((1H-Indol-3-yl) (phenyl)methyl)-N,N-dimethyl aniline (2) from
bis(indolyl)methane (11): To a homogeneous solution of bis(indolyl)methane
3090, 1615, 1451, 1358, 1336, 1517, 799, 739 cmÀ1
;
1H NMR (300 MHz, CDCl3)
(322 mg, 1 mmol) in 3 mL toluene in
a pressure reaction vessel, N,N-
d (ppm): 2.91 (6H, s, N(CH3)2), 5.59 (1H, s, Ar-CH), 6.58–6.59 (1H, m, ArH), 6.68
(2H, d, J = 8.7 Hz, ArH), 6.98 (1H, t, J = 7.8 Hz, ArH), 7.10 (2H, d, J = 8.7 Hz, ArH),
7.13–7.21(2H, m, ArH), 7.23–7.27 (5H, m, ArH), 7.35 (1H, d, J = 8.4 Hz, ArH),
7.94 (1H, s, NH). Representative procedure for 3-arylmethyl indole synthesis: To a
stirred homogeneous solution of indole (117 mg, 1 mmol), N,N-
dimethylaniline (254 L, 2 mmol) and (a) anhydrous ZnCl2 (136 mg, 1 mmol)
l
or (b) anhydrous aluminum chloride (133 mg, 1 mmol) were successively
added and heated in the oil bath at 140 °C for 5 h. The product was isolated
from the reaction mixture as stated in 3-diarylmethyl indole synthesis above.
(a) Yield = 176 mg (54%) (b) Yield = 232 mg (71%).
dimethylaniline (152 lL, 1.2 mmol) and formaldehyde (37%) solution