A new synthesis of indoles via intramolecular cyclization of ο-alkynyl N,N-dialkylanilines promoted by KOt-Bu/DMSO

Article abstract of DOI:10.1016/j.tetlet.2014.12.002

2-Aryl indoles could be prepared in excellent yields via the intramolecular cyclization of ο-alkynyl N,N-dialkylanilines. The reaction is efficiently promoted by the catalytic amount of KOt-Bu in DMSO at room temperature. A reaction mechanism involving α-

Full text of DOI:10.1016/j.tetlet.2014.12.002

Tetrahedron Letters 56 (2015) 478–481
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new synthesis of indoles via intramolecular cyclization of o-alkynyl
N,N-dialkylanilines promoted by KOt-Bu/DMSO
⇑
Yan-yan Chen, Jia-hua Chen, Niu-niu Zhang, Lin-miao Ye, Xue-Jing Zhang, Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Aryl indoles could be prepared in excellent yields via the intramolecular cyclization of o-alkynyl N,N-
dialkylanilines. The reaction is efficiently promoted by the catalytic amount of KOt-Bu in DMSO at room
Received 15 October 2014
Revised 24 November 2014
Accepted 1 December 2014
Available online 8 December 2014
temperature. A reaction mechanism involving
a-aminoalkyl radical intermediates is suggested.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Intramolecular cyclization
Amine
Alkyne
Free radical reaction
Indole derivatives possess a variety of interesting biological
activities.1 They are also the privileged structure motif of many nat-
ural products. The synthetic methods of indole derivatives have
been extensively studied.2 The classical methods include Fischer
indole synthesis, Larock heteroannulation, and reductive cycliza-
tion. In recent years, new approaches via the direct functionaliza-
tions of CAH bonds of amides, enamines, and acylhydrazines have
also been developed.3 Patel and Liang reported the synthesis of 3-
aryl indoles via transition-metal catalyzed oxidative coupling of
o-alkynyl N,N-dialkyl anilines.4,5 Zhou and co-workers reported vis-
ible-light promoted radical addition of o-alkynyl N,N-dialkylani-
lines. A series of indoles were prepared in good yields.6 Recently,
we reported the new synthesis of indole derivatives via the intra-
molecular coupling of tertiary amines and ketones in the presence
of KOt-Bu/DMF.7 We also found that KOt-Bu/DMF can promote
the intramolecular cyclization of o-alkenyl N,N-dialkyl anilines.8
was obtained in an excellent yield (Table 1, entry 1). The reaction
conditions were optimized and the results are summarized in
Table 1. The reaction also occurred at room temperature, but a
lower yield was obtained (Table 1, entry 2). The effect of reaction
solvents was also examined (Table 1, entries 3–7). DMSO was
found to be a better solvent than DMF. An excellent yield (95%)
could be obtained in DMSO at room temperature (Table 1, entry
3). Other solvents such as CH2Cl2, THF, toluene, and CH3CN are
incompatible with the reaction (Table 1, entries 4–7). The replace-
ment of KOt-Bu with KOMe led to a lower yield (Table 1, entry 8).
The application of other bases such as NaOMe, KOH, and K2CO3 did
not give product 2a (Table 1, entries 9–11). The effect of KOt-Bu
loading was also examined (Table 1, entries 12 and 13). Excellent
yields were kept with 0.3 and 0.1 equiv of KOt-Bu. The further
decrease of the KOt-Bu loading (0.05 equiv) resulted in a loss of
the yield.
In these transformations, the generation of
is proposed based on a series of experiment evidences. We specu-
lated that the intramolecular trapping of -aminoalkyl radicals
with alkynes can provide a new approach for the synthesis of
nitrogen heterocycles. In this Letter, we report the intramolecular
cyclization of o-alkynyl N,N-dialkylanilines promoted by KOt-Bu/
DMSO. The reaction provided 2-aryl indoles in excellent yields.
Initially, the reaction of 1a was examined in DMF with 1.5 equiv
of KOt-Bu at 90 °C. To our delight, the expected indole product 2a
a
-aminoalkyl radicals
With the optimal reaction conditions in hand, a range of N,N-
disubstituted-2-(phenylethynyl)anilines were examined and the
results are summarized in Table 2. The substrates 1b, 1d–1h with
electron-withdrawing groups including 2-chloro, 3-chloro, 4-flu-
oro, 4-chloro, 4-trifluoromethyl, 4-cyano provided the indoles 2b,
2d–2h in good yields (Table 2, entries 2, 4–8). The introduction
of 2-methoxy, 4-methoxy groups is also tolerable, however
1.5 equiv of KOt-Bu were required to achieve excellent yields
(Table 2, entries 3 and 9). The reaction of N-naphthyl and N-quin-
olinyl substrates 1j–1k provided the products in excellent yields
(Table 2, entries 10 and 11). N,N-Dibenzyl substrate 1l is also appli-
cable. Product 2l was obtained in a good yield (Table 2, entry 12).
a
⇑
Corresponding author.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
http://dx.doi.org/10.1016/j.tetlet.2014.12.002
0040-4039/Ó 2012 Elsevier Ltd. All rights reserved.

Y.-y. Chen et al. / Tetrahedron Letters 56 (2015) 478–481
479
Table 1
Table 3
Intramolecular cyclization of 1aa
Intramolecular cyclization of 2-(phenylethynyl)aniline derivativesa
R3
R3
KOt-Bu (0.1 equiv.)
base
DMSO, rt
N
N
solvent, rt
N
N
3a - 3h
4a 4h
-
Entry
Solvent
Base (equiv)
Yieldb/%
Entry
R3
Product
Yieldb/%
1c
2
3
4
5
6
7
8
9
10
11
12
13
DMF
DMF
DMSO
CH2Cl2
THF
Toluene
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
KOt-Bu (1.5)
KOt-Bu (1.5)
KOt-Bu (1.5)
KOt-Bu (1.5)
KOt-Bu (1.5)
KOt-Bu (1.5)
KOt-Bu (1.5)
KOMe (1.5)
NaOMe (1.5)
KOH (1.5)
96
83
95
0
0
0
0
71
0
0
0
1
2
3
4
5
6
7c
4-F-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-CF3-C6H4
1-Naphthyl
H
4a
4b
4c
4d
4e
4f
93
89
89
0
90
66
54
n-Butyl
4g
K2CO3 (1.5)
KOt-Bu (0.3)
KOt-Bu (0.1)
8d
4h
37
N
93
94
3h
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), base, solvent (1.5 mL), at rt,
a
under an argon atmosphere, 1 h.
Reaction conditions: 3a-3h (0.2 mmol, 1.0 equiv), KOt-Bu (0.02 mmol,
b
Isolated yields.
0.1 equiv), DMSO (1.5 mL), argon atmosphere, rt, 1 h.
c
b
Reaction was carried out at 90 °C.
Isolated yields.
KOt-Bu (0.04 mmol, 0.2 equiv) was used.
KOt-Bu (0.1 mmol, 0.5 equiv) was used.
c
d
Table 2
Intramolecular cyclization of substrates 1a-1oa
N
N
KOt-Bu (0.1 equiv.)
N
N
KOt-Bu (0.1 equiv.)
DMSO, rt
DMSO, rt
R1
4i
N
3i
N
R2
R1
R2
2a 2o
84% yield
1a - 1o
-
Entry
R1
R2
Product
Yieldb/%
KOt-Bu (0.1 equiv.)
N
1
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
benzyl
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
94
91
90
92
95
88
91
86
92
95
94
88
0
DMSO, rt
N
2
2-Cl-C6H4
2-MeO-C6H4
3-Cl-C6H4
4-F-C6H4
4-Cl-C6H4
4-CF3-C6H4
4-CN-C6H4
4-MeO-C6H4
2-Naphthyl
2-Quinolinyl
Ph
3c
4
3j
0% yield
5
6
7
8
Scheme 1. Intramolecular cyclization of 3i and 3j.
9c
10
11
12
13
2j
2k
2l
H
2m
KOt-Bu (0.1 equiv.)
Tempo (1.0 equiv.)
14
2n
2o
0
N
N
DMSO, Ar, rt
N
N
0% yield
1I
15d
77
KOt-Bu (0.1 equiv.)
N
N
DMSO, O2, rt
a
Reaction conditions: 1a–1o (0.2 mmol, 1.0 equiv), KOt-Bu (0.02 mmol,
0.1 equiv), DMSO (1.5 mL), argon atmosphere, rt, 1 h.
0% yield
b
Isolated yields.
KOt-Bu (0.3 mmol, 1.5 equiv) was used.
1l
c
d
KOt-Bu (0.1 mmol, 0.5 equiv) was used.
Scheme 2. Free radical inhibition experiments with Tempo and oxygen.

480
Y.-y. Chen et al. / Tetrahedron Letters 56 (2015) 478–481
O
S
O
S
KOt-Bu
O K
S
SET
DMSO
O
S
A
N
N
B
1a
O
S
O
S
N
N
2a
C
N
D
Scheme 3. Tentative reaction mechanism.
N,N-Dimethyl and pyrrolidinyl substrates (1m–1n) did not provide
the expected products (Table 2, entries 13 and 14). The activation
effect of a-aryl groups seems to be necessary for the reaction. Tet-
rahydroisoquinoline derived substrate 1o provided product 2o in a
In conclusion, we have developed a new intramolecular cycliza-
tion of o-alkynyl N,N-dialkylanilines. The reaction can be efficiently
promoted by the combination of KOt-Bu and DMSO. A number of
2-aryl indoles were prepared in good yields. A reaction mechanism
moderate yield (Table 2, entry 15).
via the a-aminoalkyl radical intermediate is suggested. The DMSO
Furthermore, we examined the influence of the substitution of
the alkyne moiety. The results are summarized in Table 3. The sub-
stitution of benzene ring with 4-fluoro, 4-chloro, and 4-methoxyl
group did not affect the yield substantially (Table 3, entries 1–3).
However, the substitution with trifluoromethyl group completely
inhibited the reaction (Table 3, entry 4). The similar results were also
observed in the reactions promoted by KOt-Bu/DMF.7,8 The exact
reason still remains elusive. When naphthyl alkyne 3e was exam-
ined, a good yield was obtained (Table 3, entry 5). The terminal
alkyne 3f is also applicable, however only a moderate yield was
obtained (Table 3, entry 6). Butyl alkyne 3g gave a lower yield
(Table 3, entry 7). The reaction of tetrahydroisoquinoline derived
alkyne 3h provided the expected product 4h in a low yield (Table 3,
entry 8). In this case, higher KOt-Bu loading(0.5 equiv) was required.
We prepared the substrate 3i with pyridine backbone. The reac-
tion of 3i occurred smoothly and gave the product 4i in a good
yield (Scheme 1). N-Methyl-N-(2-(phenylethynyl)benzyl)aniline
3j was also examined, but no reaction was observed (Scheme 1).
To probe the reaction mechanism, two controlling experiments
were carried out. The reaction was found to be inhibited
completely in the presence of Tempo (2,2,6,6-tetramethyl-piperi-
dine-1-oxyl) or oxygen (Scheme 2). Based on the results and our
previous studies, a reaction mechanism is proposed in Scheme 3.8
DMSO is deprotonated to give an anion. The anion transfers an
electron to another DMSO molecule and a DMSO radical A is
generated.9 A abstracts a hydrogen from the substrate 1a to give
radical generated in KOt-Bu/DMSO system probably works as the
crucial initiator. The reaction provides a practical synthesis of
2-aryl indoles from readily available 2-amino-phenylacetylene
derivatives.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21202208, 21172270, 21472248), Guangdong Engineering
Research Center of Chiral Drugs, and Guangdong Provincial Key
Laboratory of Construction Foundation (No. 2011A060901014)
for the financial supports of this study.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
12.002.
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excluded, the accumulated experiment evidences from a series of reactions
promoted by KOt-Bu/DMF and KOt-Bu/DMSO are more favorable with the
a-
amino alkyl radical mechanism. See Refs. 7,8 for the details.