General and efficient synthesis of 2,3-unsubstituted indoles catalyzed by acidic mesoporous molecular sieves

Article abstract of DOI:10.1016/j.tet.2013.03.026

A general and efficient method for the synthesis of 2,3-unsubstituted indoles has been established by the intramolecular cyclization of N-benzyl 2-anilinoacetals. Acidic mesoporous molecular sieve (MCM-41-SO₃H) has shown excellent catalytic activity on this transformation, and the 2,3-unsubstituted indoles bearing 7-substituent or strong electron-withdrawing substituents also could be achieved by this protocol. Moreover, the heterogeneous catalyst, MCM-41-SO₃H, could be conveniently recovered and reused without obvious loss of the catalytic activity. This work will provide an economic and environmental-benign method for the construction of various indole derivatives.

Full text of DOI:10.1016/j.tet.2013.03.026

Tetrahedron 69 (2013) 3927e3933
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
General and efficient synthesis of 2,3-unsubstituted indoles
catalyzed by acidic mesoporous molecular sieves
Nan Sun a, Lingfen Hong a, Fang Huang a, Hong Ren a, Weimin Mo a, Baoxiang Hu a,
,b,
Zhenlu Shen a, Xinquan Hu a
*
a College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, PR China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient method for the synthesis of 2,3-unsubstituted indoles has been established by the
intramolecular cyclization of N-benzyl 2-anilinoacetals. Acidic mesoporous molecular sieve (MCM-41-
SO3H) has shown excellent catalytic activity on this transformation, and the 2,3-unsubstituted indoles
bearing 7-substituent or strong electron-withdrawing substituents also could be achieved by this pro-
tocol. Moreover, the heterogeneous catalyst, MCM-41-SO3H, could be conveniently recovered and reused
without obvious loss of the catalytic activity. This work will provide an economic and environmental-
benign method for the construction of various indole derivatives.
Received 15 January 2013
Received in revised form 28 February 2013
Accepted 8 March 2013
Available online 14 March 2013
Keywords:
2,3-Unsubstituted indoles
N-Benzyl 2-anilinoacetals
Heterogeneous catalysis
MCM-41-SO3H mesoporous molecular sieve
Shape/size selectivity
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
first reported in the early 1880s (Scheme 1).10 However, this method
remains unpractical for the synthesis of 2,3-unsubstituted indole due
Indole is one of the most common structural scaffolds in natural
products.1 As most of its derivatives exhibit more or less bio-
activities, indole has been one of the most common heterocyclic
motifs presented in the top selling pharmaceuticals.2 2,3-
Unsubstituted indoles have been employed as the basic skeletons
and important building blocks for the synthesis of more compli-
cated indole derivatives by selective functionalization.3 Although
numerous methods are reported for the construction of indole
nucleus,4 most of them are limited to 2- or/and 3-substituted indole
derivatives. Although unsubstituted indole has been industrially
prepared from aniline and ethylene glycol under vapor phase re-
action conditions (453e623 K), this method is unsuitable for the
synthesis of functionalized 2,3-unsubstituted indoles.5 Most
existing methods such as LeimgrubereBatcho indole synthesis,6
Bartoli indole synthesis,7 and also transition-metal-catalyzed cy-
clization processes from o-ethynyl anilines8 or o-vinylanilines9 still
suffer from the requirement of the specific ortho-substituted sub-
strates, harsh reaction conditions or unsatisfied yields.
to these unsolved problems: (1) Selectivity. 2,3-Unsubstituted indoles
are sensitive to acids and thus complicated side reactions are in-
evitable as soon as they are formed under acidic reaction conditions;
(2) Reactivity and substrate scope limitation. As a variant of a Frie-
deleCrafts reaction (electrophilic attack) on the phenyl ring, this
strategy is difficult for the synthesis of indoles with the electron-
withdrawing groups (such as CF3, CN, NO2, etc.) under conventional
conditions. Moreover, the reactions are normally unsuccessful for
substrates with ortho-substituents;12 (3) Non-catalytic process and
environmental issues. Large excess amount of acids (such as BF3,
(CF3CO)2O, CF3COOH, TiCl4, etc.) are essentially required to promote
In addition to the above-mentioned methods for 2,3-unsubstituted
indole, the acid-promoted cyclization of 2-anilinoacetals to indole was
Scheme 1. Synthesis of 2,3-unsubstituted indoles by cyclization of 2-anilinoacetals.
* Corresponding author. E-mail address: xinquan@zjut.edu.cn (X. Hu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.026

3928
N. Sun et al. / Tetrahedron 69 (2013) 3927e3933
the transformation with limited successful examples. Due to the more
strict environmental regulations, both the academic and industrial
researchers are currently focusing on replacing stoichiometric pro-
cesses with catalytic ones.13 Therefore, the development of a selective,
general, and catalytic process that can overcome those problems is
highly demanded.
With these challenges in mind, we envisioned that the em-
ployment of solid acids, especially molecular sieves, as the catalyst
would be an ideal approach to overcome these intractable prob-
lems, as they have the following special properties:14 (1) These
materials have ordered pores in molecular dimensions. Each pore is
considered as a typical catalytic microreactor and only the substrate
with suitable size could access into the pores and allow the re-
actions to occur; (2) Molecular sieves naturely have large surface
area and high adsorption capacity, which can be varied from hy-
drophobic to hydrophilic. In this respect, they can absorb the sub-
different pore dimensions (Table 1).17 The results showed that the
microporous acidic zeolites (H-ZSM-5 and HY) could not efficiently
promote the cyclization, probably due to the inaccessibility of the
substrate 1 into their pores (entries 1 and 2, Table 1). To our delight,
the propylsulfonic acid-functionalized mesoporous silica, MCM-41-
SO3H, with a relative large pore diameter, exhibited extraordinary
activity for this cyclization reaction. Using MCM-41-SO3H as cata-
lyst, complete conversion of the substrate 1 was observed within
1 h and the desired indole product 2 was afforded in 82% isolated
yield (entry 3, Table 1). Besides pore dimension, the acidity of the
molecular sieves is also critical for the transformation, as no re-
action occurred when the unmodified parent, mesoporous MCM-41
silica with a pore diameter of 3.0 nm, was applied as the catalyst.
We reckoned that the success of MCM-41-SO3H on this trans-
formation was attributed to the combination of its strong acidity
and its proper pore dimension.
Table 1
The cyclization of N-substituted 2-anilinoacetals under the catalysis of different types of acidic molecular sievesa
Entry
Cat.b
Dpc (nm)
R
T (h)
Conv.d (%)
Yielde (%)
2/3f
1
2
3
4
H-ZSM-5
H-Y
MCM-41-SO3H
MCM-41-SO3H
MCM-41-SO3H
MCM-41-SO3H
0.5
0.7
1.9
1.9
1.9
1.9
Me
Me
Me
i-Bu
Bn
8
8
1
1
1
6
<5
d
d
d
<10
>99
>99
>99
70
d
86(82)
89(87)
96(93)
22
85:15
90:10
100:0
d
5
6g
DPM
a
All reactions were carried out with 2 mmol of substrate, 0.10 g of catalyst, and 10 mL solvent at refluxing temperature.
H-ZSM-5: SiO2/Al2O3¼25; H-Y: SiO2/Al2O3¼5.6; MCM-41-SO3H: 0.6 mmol Hþ/g.
b
c
Pore diameters (Dp) of H-ZSM-5 and HY were estimated from their crystallographic data and pore diameter of MCM-41-SO3H was calculated from the adsorption branch of
N2 adsorption/desorption isotherms by the BJH method.
d
Determined by GC with area normalization method.
Determined by GC with diisobutyl phthalate (DIBP) as the internal standard. The data in parentheses were isolated yields.
Determined by HPLC.
DPM: diphenylmethyl.
e
f
g
strate for further transformation and subsequently release the
product. Thus, the acid-promoted side reactions of the formed
products could be avoided; (3) Strong electric fields exist in the pore
structures of molecular sieves. This property together with molec-
ular confinement might result in pre-activation of the reactants and
lead to the superior catalytic ability of molecular sieves in many
chemical transformations, including FriedeleCrafts type re-
actions.15 Based on these unique properties of molecular sieves, we
are confident that a suitable material might solve the problems in
the strategy shown in Scheme 1 and serve as catalyst for the po-
tential cyclization for the construction of 2,3-unsubstituted indoles.
During the last decade, the application of molecular sieves and
relative materials, especially these with regular mesoporous
structures, in the acid-catalyzed reactions has become an attractive
research area in the heterogeneous catalysis and green chemistry.16
Herein, we reported the first acidic mesoporous molecular sieves-
catalyzed synthesis of 2,3-unsubstituted indoles, including
electron-deficient indoles and 7-substituted indoles.
Although a complete conversion of the substrate 1(R¼Me) was
observed under the catalysis of MCM-41-SO3H and an 82% yield of
N-methyl indole was isolated, a significant amount of by-product 3
(about 15%, HPLC area) was also detected (entry 3, Table 1). It was
strongly hinted that the molecule size of N-methyl indole is much
smaller than the pore dimension, and thus the by-product 3 could
be formed by the subsequent competing alkylation of the produced
N-methyl indole with the uncyclized starting substrate 1. Although
MCM-41-SO3H demonstrated its catalytic ability in the cyclization
of N-methyl-N-(2,2-diethoxyethyl)aniline, efforts in further opti-
mization of reaction conditions were difficult to improve the se-
lectivity between N-methyl indole and the side product 3.
Considering that the shape/size selectivity is a distinguished
property of molecular sieves,18 we assumed that there are two
potential routes to meet the requirement of this selectivity. One is to
narrow the pore dimension of the catalyst MCM-41-SO3H,19 the
other is to enlarge the molecular size of the starting materials to
inhibit forming even large-size by-product. Relative to the modifi-
cation of pore dimension, the increase of the molecular size of the
starting material is more convenient and practical. A direct ap-
proach is to change the original N-methyl group with other larger
alkyl groups such as iso-butyl or benzyl group, etc. Thus, the N-iso-
butyl and N-benzyl substituted N-(2,2-diethoxyethyl)anilines (1,
R¼i-Bu and Bn) were examined in the MCM-41-SO3H catalyzed
2. Results and discussion
We started our investigation by studying the cyclization of N-
methyl-N-(2,2-diethoxyethyl)aniline (1, R¼Me) to form N-methyl
indole (2) in the presence of various acidic molecular sieves with

N. Sun et al. / Tetrahedron 69 (2013) 3927e3933
3929
cyclization to form the corresponding N-substituted indoles 2. To
our delight, both i-Bu and Bn substituted substrates afforded a full
conversion under the same reaction conditions (entries 4 and 5,
Table 1). When i-Bu group was applied, the ratio of indole 2 (R¼i-
Bu) and by-product 3 (R¼i-Bu) was increased to 90:10 (entry 4,
Table 1). By using a larger Bn group, no by-product 3 (R¼Bn) was
observed (entry 5, Table 1) and the isolated yield of the desired N-
Bn indole was improved to 93%. An incomplete conversion (70%)
was observed when CHPh2 (DPM) was employed as the R group,
even after elongating the reaction time to 6 h and the cyclization
product N-DPM indole was obtained with only 22% yield (entry 6,
Table 1). This result might be attributed to the large molecular size
of both the substrate 1 (R¼DPM) and the product N-DPM indole,
which restricted their diffusion in the pores of the catalyst MCM-
41-SO3H. The substrate or product might be detained in the pores of
the catalyst, which deactivated the catalyst. The above results
showed that benzyl group provided the ideal molecular size for the
selective 2,3-unsubstituted indole synthesis with MCM-41-SO3H as
the catalyst. Moreover, under the present reaction conditions, the
TOF was achieved more than 33 hꢀ1 based on the number of acidic
sites in MCM-41-SO3H. Therefore, a highly efficient catalytic process
for the construction of 2,3-unsubstituted indole ring was success-
fully established via the cyclization of N-benzyl 2-anilinoacetal.
Next, we tried to demonstrate the generality of this catalytic
process for the synthesis of various N-benzyl 2,3-unsubstituted
indoles. As shown in Table 2, a wide range of N-benzyl N-(2,2-
Table 2
Preparation of various N-benzyl 2,3-unsubstituted indoles from N-benzyl N-(2,2-diethoxyethyl)anilinesa
Entry
1
1b (R)
1a (H)
Product
2
Yieldc (%)
93
2a
2
3
1b (4-OMe)
1c (4-SMe)
2b
2c
97
97
4
5
1d (4-Me)
1e (4-Cl)
2d
2e
95
90
6
7
8
9
1f (4-Br)
1g (4-F)
2f
89
93
80
65
2g
2h
2i
1h (4-CF3)
1i (4-CN)
10d
1j (4-CONMe2)
2j
68
(continued on next page)

3930
N. Sun et al. / Tetrahedron 69 (2013) 3927e3933
Table 2 (continued )
Entry
1b (R)
Product
2
Yieldc (%)
61
11d
1k (4-NO2)
2k
12
13
1l (3,5-diMe)
1m (2-Me)
1n (2-Cl)
2l
97
75
51
2m
2n
14
a
Reaction conditions: 2 mmol of substrates and 0.10 g of MCM-41-SO3H were refluxed in 10 mL of toluene.
The procedure for the synthesis of substrates 1 was presented in Supplementary data.
Isolated yield based on substrates.
b
c
d
MCM-41-SO3H of 0.30 g was used.
diethoxyethyl)anilines 1ae1n were smoothly converted to their
might be rationalized that the molecular size in vertical direction of
6-substituted N-benzyl indoles was smaller than that of 4-
substituted isomers. Therefore, the 6-substituted isomers were
formed preferentially in the pores of MCM-41-SO3H. The obtained
results were also consistent with the shape/size selectivity prop-
erty of molecular sieves.
The conveniently recovering and recycling property is one of the
most important advantages of heterogeneous catalysts. We further
tested the potential recycling ability of MCM-41-SO3H in this 2,3-
unsubstituted indole synthesis. With the cyclization of N-benzyl-
N-(2,2-diethoxyethyl) aniline (1a) to form N-benzyl 2,3-
unsubstituted indole (2a) as model reaction, we are pleased to
find that the recovered MCM-41-SO3H by simple filtration main-
tained its catalytic activity. No obvious loss of the catalytic activity
was observed even after five cycles (Table 3).
corresponding N-benzyl 2,3-unsubstituted indoles 2ae2n in the
presence of MCM-41-SO3H as the catalyst. Under similar reaction
conditions, the substrates bearing various para-substituents, in-
cluding electron-donating and electron-withdrawing groups were
all converted to the desired 5-substituted N-benzyl indoles in good
to excellent yields (1be1k, Table 2). It is specially noted that the
substrates with strong electron-withdrawing groups, such as CF3,
CN, CON(CH3)2, NO2, could also afford the desired 2,3-
unsubstituted indoles in moderate to good yields (1he1k, Table
2), while these substrates were almost inert in the previously re-
ported protocols.11 ortho-Substituted substrates are long consid-
ered to be challenging to form the indole product.11 However,
utilizing MCM-41-SO3H as the catalyst, the 7-substituted indoles
were conveniently formed in reasonable to good yields (1m and 1n,
Table 2). The activity of MCM-41-SO3H on the cyclization of these
electron-deficient and ortho-substituted substrates could be at-
tributed to both the strong electric fields and the confinement of
these guest substrates in its pores.14 The C(sp2)eBr bond was
usually incompatible in transition-metal-catalyzed indole synthe-
sis,8,9 while it was well tolerated in this transformation and the
product indole was obtained with an isolated yield of 89% (2f).
Moreover, the indole with multiple substituents on phenyl ring
could also be constructed in high yield (2l, Table 2). It is noteworthy
that no formation of side products 3 was observed in all these
transformations.
Table 3
Recycling test of MCM-41-SO3Ha
Entry
Recycles
T
b (h)
Conv. (%)
Yieldc (%)
1
2
3
4
5
Fresh
1.0
1.0
1.0
1.5
1.5
>99
>99
>99
>99
>99
96
97
95
95
95
1
2
3
4
Furthermore, by employing substrates with meta-substituents
(1o and 1p, Scheme 2), both 4- and 6-substituted N-benzyl indole
isomers were obtained (2o and 2p, Scheme 2). The reactions
showed that the selectivity of 6-substituted isomers was slightly
higher than that of 4-substituted isomers (Scheme 2),20 which
a
Scale: 2 mmol.
b
c
Time for the complete conversion of 1a.
Yields determined by GC with diisobutyl phthalate (DIBP) as the internal
standard.
In summary, we have successfully developed a heterogeneous
catalytic strategy for the synthesis of 2,3-unsubstituted indoles.
Under the catalysis of propylsulfonic acid-functionalized meso-
porous silica (MCM-41-SO3H), a wide range of N-benzyl 2-
anilinoacetals were smoothly converted to their corresponding N-
benzyl 2,3-unsubstituted indoles in good to excellent yields. This
Scheme 2. Reaction of meta-substituted N-benzyl 2-anilinoacetals.

N. Sun et al. / Tetrahedron 69 (2013) 3927e3933
3931
protocol solved the problems existed in the cyclization of 2-
anilinoacetals bearing ortho-substituent or strong electron-
withdrawing substituents. The heterogeneous catalyst MCM-41-
SO3H could be conveniently recovered and reused without obvi-
ous loss of the catalytic activity. Therefore, this work provides an
economic and environmental-benign method for the construction
of various indole derivatives.
d
¼50.2, 101.9, 109.9, 119.7, 121.2, 121.9, 126.9, 127.7, 128.4, 128.9,
136.5, 137.7; EI-HRMS m/z calcd for C15H13N [M]þ 207.1048, found
207.1038.
3.2.2. 1-Benzyl-5-methoxy-1H-indole 2b. Yield 97%, white solid, mp
69.5e69.9 ꢂC, (lit.23 mp 66e68 ꢂC); 1H NMR (500 MHz, CDCl3)
d
¼3.86 (s, 3H), 5.31 (s, 2H), 6.48 (d, J¼3.0 Hz, 1H), 6.83e7.32 (m,
9H); 13C NMR (125 MHz, CDCl3)
d
¼50.3, 55.8, 101.2, 102.6, 110.4,
3. Experimental section
3.1. General
112.0, 126.7, 127.6, 128.74, 128.82, 129.11, 131.7, 137.6, 154.1; EI-
HRMS m/z calcd for C16H15NO [M]þ 237.1154, found 237.1160.
3.2.3. 1-Benzyl-5-methylthio-1H-indole 2c. Yield 97%, colorless liq-
Heterogeneous catalyst H-ZSM-5 (SiO2/Al2O3¼25, Dp¼0.5 nm,
SBET¼320 m2/g), H-Y (SiO2/Al2O3¼5.6, Dp¼0.7 nm, SBET¼600 m2/g)
and MCM-41 (Dp¼3.0 nm, SBET¼1050 m2/g) were purchased from
Nankai University Catalyst Co., Ltd, Tianjin, China. MCM-41-SO3H
was prepared from MCM-41 by grafting method in our lab.21 The
ordered mesoporous structure of the catalyst MCM-41-SO3H was
confirmed by XRD analysis on a PANalytical X’Pert PRO diffrac-
uid; 1H NMR (500 MHz, CDCl3)
d
¼2.51 (s, 3H), 5.30 (s, 2H), 6.50 (d,
J¼3.0 Hz, 1H), 7.09e7.66 (m, 9H); 13C NMR (125 MHz, CDCl3)
d
¼18.6, 50.1, 101.2, 110.2, 121.5, 123.6, 126.7, 127.6, 127.7, 128.71,
128.91, 129.4, 135.0, 137.2; EI-HRMS m/z calcd for C16H15NS [M]þ
253.0925, found 253.0931.
3.2.4. 1-Benzyl-5-methyl-1H-indole 2d. Yield 95%, white solid, mp
tometer using Cu K
a
radiation. The specific surface area (SBET) of the
39.0e41.3 ꢂC; 1H NMR (500 MHz, CDCl3)
d¼2.51 (s, 3H), 5.34 (s, 2H),
catalyst MCM-41-SO3H was 560 m2/g by recording nitrogen ad-
sorption/desorption isotherms at liquid N2 temperature on
a Thermo Micromeritics ASAP 2021C apparatus, and the pore di-
ameter (Dp) of the catalyst MCM-41-SO3H was 1.9 nm from ad-
sorption branch of the N2 adsorption/desorption isotherm by the
BJH (BarretteJoynereHalenda) method using the Halsey equation.
The acid capacity of the prepared catalyst MCM-41-SO3H was about
0.6 mmol/g by the potentiometric titration method on a Mettler
Toledo T50 automatic titrator equipped with a Mettler Teledo
DGi111-SC combined glass electrode. All proton and 13C NMR
spectra were recorded on Bruker AVANCE III 500 MHz spectrometer
in deuterium solvents with tetramethylsilane (TMS) as internal
standard. High-resolution mass spectra were recorded in the EI
mode on Waters GCT Premier TOF mass spectrometer with an
6.53 (d, J¼3.0 Hz,1H), 7.05e7.51 (m, 9H); 13C NMR (125 MHz, CDCl3)
d
¼21.5, 50.2, 101.2, 109.5, 120.7, 123.4, 126.8, 127.6, 128.4, 128.8,
129.1, 134.8, 137.8; EI-HRMS m/z calcd for C16H15N [M]þ 221.1204,
found 221.1201.
3.2.5. 1-Benzyl-5-chloro-1H-indole 2e. Yield 90%, white solid, mp
61.1e62.1 ꢂC (lit.23 mp 58e60 ꢂC); 1H NMR (500 MHz, CDCl3)
d
¼5.32 (s, 2H), 6.51 (d, J¼3.0 Hz, 1H), 7.09e7.63 (m, 9H); 13C NMR
(125 MHz, CDCl3)
127.8, 128.9, 129.6, 129.8, 134.7, 137.1; EI-HRMS calcd for C15H12ClN
[M]þ 241.0658, found 241.0664.
d
¼50.3, 101.4, 110.8, 120.4, 122.0, 125.4, 126.7,
3.2.6. 1-Benzyl-5-bromo-1H-indole 2f. Yield 89%, white solid, mp
90.6e91.4 ꢂC (lit.23 mp 85e86 ꢂC); 1H NMR (500 MHz, CDCl3)
Agilent 6890 gas chromatography using
a
DB-XLB column
d
¼5.32 (s, 2H), 6.51 (d, J¼3.0 Hz, 1H), 7.09e7.79 (m, 9H); 13C NMR
(30 mꢁ0.25 mm (i.d.), 0.25
m
) or ESI mode on an Agilent 6210 LC/
(125 MHz, CDCl3)
d
¼50.3, 101.3, 111.2, 112.9, 123.5, 124.6, 126.7,
TOF mass spectrometer. GC analyses were performed on Thermo
TRACE GC Ultra instrument with FID detector using an HP-5 cap-
127.8, 128.9, 129.5, 130.5, 135.0, 137.1; EI-HRMS m/z calcd for
C15H12BrN [M]þ 285.0153, found 285.0143.
illary column (30 mꢁ0.25 mm (i.d.), 0.25
performed on Waters 1525 instrument with UV detector (230 nm)
) at room
temperature and mobile phase (90:10 CH3CN/H2O) with a flow rate
of 0.8 mL/min. Flash column chromatography was performed with
basic Al2O3 (200e300 mesh) with ethyl acetate/petroleum as elu-
ent. Melting points (uncorrected) were determined on BUCHI M-
565 apparatus. Toluene was fresh distilled before use. Other sol-
vents and reagents were directly used without further purification.
m). HPLC analyses were
3.2.7. 1-Benzyl-5-fluoro-1H-indole 2g. Yield 93%, white solid; mp
using a Atlantis ODS column (150ꢁ4.6 mm (i.d.), 3.5
m
61.4e61.8 ꢂC; 1H NMR (500 MHz, CDCl3)
d
¼5.33 (s, 2H), 6.53 (d,
J¼3.0 Hz,1H), 6.91e7.35(m, 9H); 13C NMR (125 MHz, CDCl3)
¼50.4,
d
101.6 (d, J¼4.7 Hz),105.7(d, J¼23.0 Hz),110.1 (d, J¼26.4 Hz),110.4 (d,
J¼10.1 Hz), 126.7, 127.8, 128.8, 129.0 (d, J¼10.3 Hz), 129.9, 133.0,
137.3, 158.0 (d, J¼232.4 Hz); EI-HRMS m/z calcd for C15H12FN [M]þ
225.0954, found 225.0948.
3.2.8. 1-Benzyl-5-trifluoromethyl-1H-indole 2h. Yield 80%, white
3.2. General procedure for the synthesis of N-benzyl 2,3-
unsubstituted indoles
solid, mp 61.7e62.1 ꢂC; 1H NMR (500 MHz, CDCl3)
d
¼5.38 (s, 2H),
6.66 (d, J¼3.0 Hz, 1H), 7.11e7.97 (m, 9H); 13C NMR (125 MHz, CDCl3)
d
¼50.3, 102.8, 109.9, 118.5 (q, J¼3.4 Hz), 118.8 (q, J¼4.5 Hz), 122.0 (q,
A 25 mL round-bottomed flask was charged with N-benzyl N-
(2,2-diethoxyethyl)anilines (2 mmol), MCM-41-SO3H (0.10 g), and
toluene (10 mL). The mixture was stirred under refluxing condition
for several hours until the reaction was completed based on GC
determination. After the reaction was finished, the mixture was
cooled to room temperature. Then the catalyst MCM-41-SO3H was
filtered off, and washed with toluene (10 mLꢁ3). The combined
filtrate was concentrated in vacuo to remove the solvent. The
resulting residue was purified by flash column chromatography on
basic Al2O3 (petroleum ether/ethyl acetate) to afford the desired N-
benzyl 2,3-unsubstituted indoles.
J¼31.8 Hz), 125.4 (q, J¼269.6 Hz), 126.74, 127.91, 128.05, 128.91,
130.0, 136.8, 137.6; EI-HRMS m/z calcd for C16H12F3N [M]þ
275.0922, found 275.0914.
3.2.9. 1-Benzyl-1H-indole-5-carbonitrile 2i. Yield 65%, white solid;
mp 103.2e104.3 ꢂC; 1H NMR (500 MHz, CDCl3)
d
¼5.37 (s, 2H), 6.65
(d, J¼3.0 Hz, 1H), 7.10e8.01 (m, 9H); 13C NMR (125 MHz, CDCl3)
d
¼50.4, 102.76, 102.80, 110.6, 120.7, 124.7, 126.60, 126.74, 128.1,
128.5, 129.0, 130.6, 136.4, 137.8; EI-HRMS m/z calcd for C16H12N2
[M]þ 232.1000, found 232.0992.
3.2.10. 1-Benzyl-N,N-dimethyl-1H-indole-5-carboxamide 2j. Yield
3.2.1. 1-Benzyl-1H-indole 2a. Yield 93%, white solid, mp
42.0e42.1 ꢂC (lit.22 mp 38.5e40 ꢂC); 1H NMR (500 MHz, CDCl3)
d
68%, colorless liquid; 1H NMR (500 MHz, CDCl3)
d
¼3.09 (br s, 6H),
5.32 (s, 2H), 6.59 (d, J¼3.0 Hz, 1H), 7.09e7.76 (m, 9H); 13C NMR
¼5.38 (s, 2H), 6.64e7.75 (m, 11H); 13C NMR (125 MHz, CDCl3)
(125 MHz, CDCl3)
d
¼35.7, 40.1, 50.2, 102.4, 109.5, 120.6, 121.3, 126.8,

3932
N. Sun et al. / Tetrahedron 69 (2013) 3927e3933
127.57, 127.73, 128.09, 128.8, 129.4, 136.8, 137.2, 173.0; EI-HRMS m/z
at 100 ꢂC for 2 h. The recovered catalyst was then reused directly in
the next reaction.
calcd for C18H18N2O [M]þ 278.1419, found 278.1415.
3.2.11. 1-Benzyl-5-nitro-1H-indole 2k. Yield 61%, white solid, mp
96.5e96.8 ꢂC (lit.24 mp 85e90 ꢂC); 1H NMR (500 MHz, CDCl3)
d
Acknowledgements
¼5.39 (s, 2H), 6.75 (d, J¼3.0 Hz, 1H), 7.12e8.63 (m, 9H); 13C NMR
We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (No. 20772111, 20876149) and
the Key Innovation Team Project of Zhejiang Province, China (No.
2009R50002).
(125 MHz, CDCl3)
d
¼50.6, 104.4, 109.6, 117.5, 118.3, 126.8, 127.95,
128.16, 129.0, 131.4, 136.2, 139.1, 141.8; EI-HRMS m/z calcd for
C15H12N2O2 [M]þ 252.0899, found 252.0917.
3.2.12. 1-Benzyl-3,5-dimethyl-1H-indole 2l. Yield 97%, colorless
Supplementary data
liquid; 1H NMR (500 MHz, CDCl3)
d
¼2.53 (s, 3H), 2.66 (s, 3H), 5.36
(s, 2H), 6.63 (d, J¼3.0 Hz, 1H), 6.89e7.41(m, 8H); 13C NMR
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.026.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
(125 MHz, CDCl3)
d
¼18.7, 21.9, 50.1, 100.1, 107.3, 121.8, 126.5, 126.8,
127.1, 127.5, 128.8, 130.1, 131.7, 136.6, 137.9; EI-HRMS m/z calcd for
C17H17N [M]þ 235.1361, found 235.1332.
3.2.13. 1-Benzyl-7-methyl-1H-indole 2m. Yield 75%, white solid, mp
References and notes
54.3e55.1 ꢂC; 1H NMR (500 MHz, CDCl3)
d
¼2.59 (s, 3H), 5.63 (s, 2H),
6.62 (d, J¼3.0 Hz, 1H), 6.94e7.59 (m, 9H); 13C NMR (125 MHz,
1. (a) Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod. Rep. 2010, 27, 1630e1680; (b)
Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489e4497.
2. (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem.
2011, 7, 442e495; (b) Patil, S. A.; Patil, R.; Miller, D. D. Curr. Med. Chem. 2011, 18,
615e637; (c) de Sa Alves, F. R.; Barreiro, E. J.; Manssour Fraga, C. A. Mini-Rev.
Med. Chem. 2009, 9, 782e793.
CDCl3)
d
¼19.6, 52.3, 102.1, 119.2, 119.9, 121.1, 124.7, 125.5, 127.3,
128.9, 129.9, 130.2, 135.1, 139.8; EI-HRMS m/z calcd for C16H15
N
[M]þ 221.1204, found 221.1199.
3. (a) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39,
4449e4465; (b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608e9644; (c) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673e714.
4. For very recent papers on indole synthesis, see: (a) Yang, Q.-Q.; Xiao, C.; Lu,
L.-Q.; An, J.; Tan, F.; Li, B.-J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51,
9137e9140; (b) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134,
9098e9101; (c) Maity, S.; Zheng, N. Angew. Chem., Int. Ed. 2012, 51, 9562e9566;
(d) Shi, Z.; Glorius, F. Angew. Chem., Int. Ed. 2012, 9220e9222; For selected
reviews on indole synthesis, see: (e) Taber, D. F.; Tirunahari, P. K. Tetrahedron
2011, 67, 7195e7210; (f) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469e6480; (g)
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875e2911; (h) Gribble, G.
W. J. Chem. Soc., Perkin Trans. 1 2000, 1045e1075.
3.2.14. 1-Benzyl-7-chloro-1H-indole 2n. Yield 51%, white solid, mp
59.9e61.3 ꢂC (lit.25 mp 58e59 ꢂC); 1H NMR (500 MHz, CDCl3)
d
¼5.80 (s, 2H), 6.58 (d, J¼3.0 Hz, 1H), 7.01e7.56 (m, 9H); 13C NMR
(125 MHz, CDCl3)
d
¼51.8, 102.5, 116.8, 119.9, 120.4, 123.6, 126.2,
127.4, 128.7, 131.0, 131.6, 131.9, 139.1; EI-HRMS m/z calcd for
C15H12ClN [M]þ 241.0658, found 241.0672.
3.2.15. 1-Benzyl-4-methyl-1H-indole and 1-benzyl-6-methyl-1H-in-
dole 2o. Yield 92%, white solid, mp 44.2e45.5 ꢂC; 1H NMR
(500 MHz, CDCl3)
5.35(s, 0.68H), 6.54 (d, J¼3.0 Hz, 0.63H), 6.61 (d, J¼3.0 Hz, 0.37H),
6.95e7.58 (m, 9H); 13C NMR (125 MHz, CDCl3)
d
¼2.48 (s, 1.88H), 2.62 (s, 1.12H), 5.33(s, 1.32H),
5. Lucarelli, C.; Vaccari, A. Green Chem. 2011, 13, 1941e1949.
6. (a) Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160e167; (b)
Clark, R. D.; Repke, D. H. Heterocycles 1984, 22, 195e221.
7. Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163e178.
8. (a) Varela-Fernandez, A.; Varela, J. A.; Saa, C. Adv. Synth. Catal. 2011, 353,
1933e1937; (b) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46,
2074e2077.
9. Yamaguchi, M.; Arisawa, M.; Hirama, M. Chem. Commun. 1998, 1399e1400.
10. (a) Berlinerblau, J.; Polikiev, H. Monatsh. Chem. 1887, 8, 187e191; (b)
Berlinerblau, J. Monatsh. Chem. 1887, 8, 180e186.
11. (a) Ty, N.; Dupeyre, G.; Chabot, G. G.; Seguin, J.; Tillequin, F.; Scherman, D.;
Michel, S.; Cachet, X. Bioorg. Med. Chem. 2008, 16, 7494e7503; (b) Cherif, M.;
Cotelle, P.; Catteau, J.-P. Heterocycles 1992, 34, 1749e1758; (c) Bobbitt, J. M.;
Bourque, A. J. Heterocycles 1987, 25, 601e616; (d) Sundberg, R. J.; Laurino, J. P. J.
Org. Chem. 1984, 49, 249e254; (e) Nordlander, J. E.; Catalane, D. B.; Kotian, K. D.;
Stevens, R. M.; Haky, J. E. J. Org. Chem. 1981, 46, 778e782; (f) Hewlins, M. J. E.;
Jackson, A. H.; Oliveira-Campos, A.-M.; Shannon, P. V. R. J. Chem. Soc., Perkin
Trans. 1 1981, 2906e2911; (g) Jackson, A. H.; Jenkins, P. R.; Shannon, P. V. R. J.
Chem. Soc., Perkin Trans. 1 1977, 1698e1704; (h) Bevis, M. J.; Forbes, E. J.; Naik, N.
N.; Uff, B. C. Tetrahedron 1971, 27, 1253e1259.
12. Sundberg reported that the substituents at the ortho-position and the nitrogen
atom of ortho-position substituted 2-anilinoacetals sterically resisted the
molecules to form a coplanar geometry and thus resulted the unsuccessful
cyclization of these subatrates (see Ref. 11d). Yin very recently reported that
some 2,3-unsubstituted indoles containing nitro group or 7-substituted group
could be synthesized in excess CF3COOH, however, the cyclization was strongly
depended on the existing of amino group on the phenyl ring (to form 5-
aminoindoles) and thus the potential application of this method was very
narrow ( Liu, K.; Yin, D. Org. Lett. 2008, 11, 637e639 ).
d¼18.8, 21.9, 49.9,
50.2, 100.2, 101.5, 107.4, 109.6, 119.8, 120.6, 121.38, 121.87, 126.54,
126.74, 126.81, 127.53, 127.57, 127.62, 127.65, 128.62, 128.76, 130.4,
131.5, 136.1, 136.8, 137.67, 137.76; EI-HRMS (EI) m/z calcd for
C16H15N 221.1204, found 221.1203. 1-Benzyl-4-methyl-1H-indole:
white solid, mp 49.0e49.3 ꢂC; 1H NMR (500 MHz, CDCl3)
d
¼2.71 (s,
3H), 5.39 (s, 2H), 6.71 (d, J¼3.0 Hz, 1H), 7.05e7.41 (m, 9H); 13C NMR
(125 MHz, CDCl3)
127.65, 127.73, 128.70, 128.84, 130.5, 136.2, 137.8; EI-HRMS m/z
d
¼18.9, 50.3, 100.3, 107.5, 119.9, 122.0, 126.9,
calcd for C16H15N [M]þ 221.1204, found 221.1213.
3.2.16. 1-Benzyl-4-chloro-1H-indole and 1-benzyl-6-chloro-1H-in-
dole 2p. Yield 90%, white solid, mp 44.0e45.7 ꢂC; 1H NMR
(500 MHz, CDCl3)
d
¼5.30 (s, 1.13H), 5.34(s, 0.87H), 6.55 (d, J¼3.0 Hz,
0.57H), 6.68 (d, J¼3.0 Hz, 0.43H), 7.08e7.58 (m, 9H); 13C NMR
(125 MHz, CDCl3)
d
¼50.1, 50.4,100.3,101.9,108.4,109.7,119.3,120.3,
121.8, 122.3, 126.2, 126.7, 127.23, 127.45, 127.69, 127.75, 128.79,
128.82, 128.96, 136.69, 136.92, 136.98, 137.0; EI-HRMS m/z calcd for
C15H12ClN [M]þ 241.0658, found 241.0670. 1-Benzyl-4-chloro-1H-
indole: white solid; mp 58.2e58.5 ꢂC (lit. mp 57e58 ꢂC); 1H NMR
(500 MHz, CDCl3)
d
¼5.34 (s, 2H), 6.75 (d, J¼3.0 Hz, 1H), 7.13e7.37
13. Clark, J. H. Green Chem. 2006, 8, 17e21.
14. (a) Corma, A. J. Catal. 2003, 216, 298e312; (b) Corma, A. Chem. Rev. 1997, 97,
(m, 9H); 13C NMR (125 MHz, CDCl3)
d
¼50.5, 100.4, 108.5, 119.4,
2373e2420.
122.4, 126.8, 127.9, 128.91, 128.96, 137.09, 137.10; EI-HRMS m/z calcd
15. Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077e1104.
for C15H12ClN [M]þ 241.0658, found 241.0661.
16. (a) Chen, F.; Meng, X.; Xiao, F.-S. Catal. Surv. Asia 2011, 15, 37e48; (b)
ꢀ
Martín-Aranda, R.; Cejka, J. Top. Catal. 2010, 53, 141e153; (c) Melero, J. A.; van
Grieken, R.; Morales, G. Chem. Rev. 2006, 106, 3790e3812; (d) Clark, J. H.;
Macquarrie, D. J.; Tavener, S. J. Dalton Trans. 2006, 4297e4309.
3.3. Procedure for recovering of the catalyst MCM-41-SO3H
17. The cyclization of N-methyl-N-(2,2-diethoxyethyl)aniline to form N-methyl
indole under the homogeneous acidic conditions has been reported by Uff. In
this report, 3 equiv of BF3 and 2 equiv of (CF3CO)2O in CH3COOH was required to
promote the cyclization reaction and the yield of N-methyl indole was 60%. See:
Ref. 11h.
After the reaction of N-Benzyl-N-(2,2-diethoxyethyl)anilines
was complete, the reaction mixture was cooled to room tempera-
ture. The catalyst MCM-41-SO3H was filtered off and successively
washed with toluene (10 mLꢁ3) and ethanol (5 mLꢁ3), then dried
18. Weisz, P. B.; Frilette, V. J.; Maatman, R. W.; Mower, E. B. J. Catal. 1962, 1, 307e312.

N. Sun et al. / Tetrahedron 69 (2013) 3927e3933
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ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
19. Rac, B.; Nagy, M.; Palinko, I.; Molnar, A. Appl. Catal., A: Gen. 2007, 316, 152e159.
20. The ratios of two isomers were determined by 1H NMR, see Supplementary data.
21. MCM-41-SO3H was prepared from the commercially available mesoporous
MCM-41 silica in our lab, see: Sun, N.; Wang, S.; Mo, W.; Hu, B.; Shen, Z.; Hu, X.
Tetrahedron 2010, 66, 7142e7148.
23. Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc.
2003, 125, 10780e10781.
24. Gasparotto, V.; Castagliuolo, I.; Ferlin, M. G. J. Med. Chem. 2007, 50,
5509e5513.
25. Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L.
Science 2010, 328, 1679e1681.
22. Harayama, T.; Hori, A.; Abe, H.; Takeuchi, Y. Tetrahedron Lett. 2004, 60, 1611e1616.