Facile synthesis of indoles by K2CO3catalyzed cyclization reaction of 2-ethynylanilines in water

Article abstract of DOI:10.1016/j.cclet.2016.07.022

The cyclization reaction of 2-ethynyl-N-sulfonylanilides proceeded efficiently in water with the presence of a catalytic amount of K₂CO₃under transition metal-free condition to give indoles in high yields. The recovery and reusabilit

Full text of DOI:10.1016/j.cclet.2016.07.022

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CCLET 3797 1–4
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
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4
Facile synthesis of indoles by K2CO3 catalyzed cyclization
reaction of 2-ethynylanilines in water
5
6
Q1 Zhi Chen, Xiao-Xiao Shi, Dong-Qin Ge, Zhen-Zhen Jiang, Qi-Qi Jin, Hua-Jiang Jiang,
*
Jia-Shou Wu
7
School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The cyclization reaction of 2-ethynyl-N-sulfonylanilides proceeded efficiently in water with the
presence of a catalytic amount of K2CO3 under transition metal-free condition to give indoles in high
yields. The recovery and reusability of the present catalytic system were investigated.
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 12 June 2016
Received in revised form 8 July 2016
Accepted 12 July 2016
Available online xxx
Keywords:
2-Ethynylanilines
Cyclization reaction
Indoles
Water
Potassium carbonate
8
9
1. Introduction
conducted in water in the absence of any catalysts to give indoles 30
in moderate to good yields [6]. However, the use of microwave 31
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Indoles are particular interesting building units owing to their
frequent appearance in a vast number of biologically active
compounds [1]. After Fischer and Jourdan discovered the well-
known ‘‘Fischer indole synthesis’’ in 1883 [2], numerous synthetic
routes to indoles have been reported [3]. Among them, intramo-
lecular cyclization with 2-ethynylaniline derivatives is one of the
efficient strategies to assemble indole rings [3,4]. The presence of
transition metals greatly promoted the cyclization reaction of 2-
ethynylaniline derivatives [4]. On the other hand, water is the
cheapest and environmentally benign solvent. The use of water as
solvent in organic synthesis is of great interest [5]. In 2005, Hiroya
et al. reported the first example of synthesis of indoles from 2-
ethynylanilines via intramolecular cyclization reaction in water
catalyzed by a copper salt [4d]. Recently, Song et al. developed a
recyclable polystyrene-supported copper catalyst for the cycliza-
tion reaction of 2-ethynyl-N-sulfonylanilides in water [4e]. In view
of green chemistry, a transition metal-free version of this reaction
is more attractive and environment friendly. With the aid of
microwave irradiation, Carpita and Ribecai found that the
intramolecular cyclization reaction of 2-ethynylanilines could be
irradiation is unfavorable, especially in large-scale synthesis. 32
Therefore, developing more efficient and metal-free approach to 33
indoles is still desirable.
34
2. Experimental
35
2.1. General procedure for K2CO3 catalyzed cyclization reaction of 2- 36
ethynylanilines in water 37
To a solution of K2CO3 (0.15 equiv., 0.045 mmol) in water 38
(1.5 mL) was added substrate 1 (1 equiv., 0.3 mmol). The resulting 39
mixture was stirred vigorously at 130 8C in a sealed tube under an 40
argon atmosphere for 10 h. The reaction solution was cooled to 41
room temperature and extracted by CH2Cl2 (3 ꢀ 5 mL), and the 42
organic phase was collected, dried over anhydrous Na2SO4. Pure 43
product 2 was obtained by direct evaporation under reduced 44
pressure (2a, 2b, 2d, 2e, 2g–2j, 2m, 2n, 2p–2u, 2w or 2x) or by flash 45
chromatography on silica gel (2c, 2f, 2k, 2l, 2o or 2v).
46
2.2. General procedure for recycling experiment
47
To a solution of K2CO3 (0.15 equiv., 0.045 mmol) in water 48
(1.5 mL) was added 1j (1 equiv., 0.3 mmol). The resulting mixture 49
was stirred vigorously at 130 8C in a sealed tube under an argon 50
*
Corresponding author.
E-mail address: jsw79@sina.com (J.-S. Wu).
http://dx.doi.org/10.1016/j.cclet.2016.07.022
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z. Chen, et al., Facile synthesis of indoles by K2CO3 catalyzed cyclization reaction of 2-ethynylanilines
in water, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.07.022

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Z. Chen et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Table 1
Optimization of reaction conditions.a
O
Catalyst, Additive
H2O, 130 oC, 10 h
O
N
Ts
NHTs
1a
2a
Entry
Catalyst (mol %)
Additive (mol %)
Yieldb (%)
1
2c
3
Proline (10)
Proline (30)
Proline (30)
Proline (30)
Proline (30)
NaHCO3 (30)
Na2CO3 (30)
K2CO3 (30)
K2CO3 (30)
K2CO3 (15)
K2CO3 (10)
–
–
15
19
8
–
SDS (10)
4
CTAB (10)
35
37
65
93
99
99
99
95
0d
5
CTAB (20)
6
CTAB (10)
7
CTAB (10)
8
CTAB (10)
9
–
–
–
–
10
11
12
Scheme 1. Cyclization reaction promoted by proline.
a
Reaction conditions: 1a (0.3 mmol), additive and catalyst in water (1.5 mL) at
130 8C (oil bath) for 10 h. bIsolated yield. SDS: sodium dodecyl sulphate, CTAB:
cetyltrimethylammonium bromide. cReaction time 18 h. d1a was recovered.
51
52
53
54
55
atmosphere for 10 h. The reaction solution was cooled to room
temperature and extracted by CH2Cl2 (3 ꢀ 5 mL), and the organic
phase was collected, dried over anhydrous Na2SO4. Pure product 2j
was obtained by flash chromatography on silica gel. The aqueous
phase containing the catalyst was reused in the next cycle.
1-tosyl-1H-indole in 71% yield (Scheme 1). Unfortunately, when N-
tosylated 2-(4-ethoxyphenylethynyl)aniline 1a was used as the
substrate, the reaction was rather sluggish and the cyclization
product 2a was isolated in poor yield (15%; Table 1, entry 1) even
with prolonged reaction time and elevated catalyst loading (19%
yield; Table 1, entry 2). It is reported that reaction yield can be
enhanced by the addition of surfactants in water [8]. The addition
of sodium dodecyl sulphate (SDS) afforded declined yield (entry 3).
When cationic surfactant cetyltrimethylammonium bromide
(CTAB) was used, the yield was improved to 35% (Table 1,
entry 4). Attempt to further enhance the yield of 2a by increasing
63
64
65
66
67
68
69
70
71
72
73
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3. Results and discussion
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During our study on domino coupling reaction of 2-ethynyla-
nilines [7], we found that N-tosylated 2-ethynylaniline was
cyclized to 1-tosyl-1H-indole in 88% yield in water in the presence
of a catalytic amount of CuI and proline (Scheme 1). Interestingly,
the intramolecular cyclization reaction occurred even without
copper salt by adding 10 mol% proline in water at 130 8C giving
Table 2
Cyclization reaction of 2-alkynylanilines in water catalyzed by K2CO3.a,b
R
K2CO3 (15 mol%)
H2O, 130oC, 10 h
R
R'
R'
N
R''
NHR''
2
1
1
R
R0
R00
2
Yield (%)
1a
1b
1c
1d
1e
1f
4-OEt-Ph
H
Ts
2a
2b
2c
2d
2e
2f
99
99
4-OMe-Ph
H
Ts
4-Et-Ph
H
Ts
98
4-Me-Ph
H
Ts
99
Ph
H
Ts
98
4-Cl-Ph
H
Ts
97
1g
1h
1i
4-Br-Ph
H
Ts
2g
2h
2i
99
4-CN-Ph
H
Ts
100
100
98
n-Bu
H
Ts
1j
Cyclopropyl
H
Ts
2j
1k
1l
t-Bu
Ph
Ph
Ph
Ph
Ph
H
H
Ts
2k
2l
95
4-Me
4-F
4-Cl
4-CF3
5-CF3
H
Ts
92
1m
1n
1o
1p
1q
1r
Ts
2m
2n
2o
2p
2q
2r
99
Ts
100
96
Ts
Ts
99
Ts
100
99
H
4-Me
4-F
4-Cl
5-CF3
4-CF3
H
Ts
1s
1t
H
Ts
2s
2t
98
H
Ts
100
98
1u
1v
1w
1x
H
Ts
2u
2v
2w
2x
H
Ts
97
H
Benzenesulfonyl
Nos
97
H
H
98
a
Reaction conditions: 1 (0.3 mmol) and K2CO3 (15 mol%) in water (1.5 mL) at 130 8C (oil bath) for 10 h. bIsolated yield.
Please cite this article in press as: Z. Chen, et al., Facile synthesis of indoles by K2CO3 catalyzed cyclization reaction of 2-ethynylanilines
in water, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.07.022

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Z. Chen et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
3
Scheme 3. Possible reaction mechanism.
Scheme 2. Cyclization reactions with different N-substituted 2-alkynylanilines.
reaction still worked highly efficient with a sterically crowded 104
substrate, and 2k was formed in 95% yield under the optimal 105
reaction conditions. 2-Ethynylanilines with different substituent 106
groups on the aniline moiety were also investigated. 2-Pheny- 107
lethynyl-N-tosylanilines possessing F, Cl and CF3 substituents at 108
4 or 5-position reacted smoothly to afford 2m–2p in 96–100% 109
yields, while relatively lower yield was obtained with substrate 110
bearing electron-donating methyl group (2l, 92%). The intramo- 111
lecular cyclization proceeded smoothly to give the corresponding 112
indoles (2q–2v) in high yields irrespective of electronic variation 113
on the aniline part of 2-ethynyl-N-tosylanilides. Ethynylanilines 114
having phenylsulfonyl or 4-nitrophenylsulfonyl group on nitrogen 115
were also good substrates furnishing the corresponding cyclization 116
products in high yields (2w and 2x). When 2-(trimethylsilylethy- 117
nyl)aniline 1y was employed, only the desilylated cyclization 118
product 2q was obtained in quantitative yield (Scheme 2). It is 119
reported that the cyclization reaction is rather sensitive to the 120
acidity of the nitrogen-attached proton [12]. Indeed, no desired 121
product was isolated when 2-ethynylaniline 1aa, N-acetyl aniline 122
1ab or N-benzoyl derivative 1ac was used as the substrate (Scheme 123
2). In light of these results and based on the cyclization reaction of 124
2-ethynylanilines in literature [9,10], a plausible reaction pathway 125
is shown in Scheme 3. The reaction started with the deprotonation 126
of 1 leading to anion intermediate A. Subsequent intramolecular 127
nucleophilic addition gives alkene anion B. Protonolysis delivers 128
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87
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89
90
91
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93
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95
96
97
98
99
100
101
102
103
the amount of CTAB to 20 mol% failed (entry 5). It has been
demonstrated that the cyclization reaction of 2-ethynylanilines
can be achieved in organic solvents with excesses of strong bases
[9], such as EtONa [9a], t-BuOK or KH [9b-e]. More recently, Li et al.
found that a catalytic amount of t-BuOK was sufficient to affect the
cyclization reaction of 2-ethynylanilines in dry DMSO [10]. Inspired
by these reports and the fact that proline can act as a base [11], we
envisioned that simple inorganic base might be efficient catalyst
for the cyclization reaction of 2-ethynylanilines in water. Indeed,
with 30 mol% NaHCO3 as the catalyst, the cyclization product 2a
was isolated in 65% yield after 10 h in water (Table 1, entry 6). As
expected, the cyclization reaction was further improved when a
stronger base Na2CO3 was used as catalyst, and 2a was isolated in
excellent yield, 93% (entry 7). With the presence of 30 mol% K2CO3,
1a was cyclised to 2a in almost quantitative yield, 99% (Table 1,
entry 8). Notably, the addition of CTAB is not essential (entry 9),
and the cyclization reaction is still highly efficient with 15 mol%
K2CO3 (Table 1, entry 10). Further lower catalyst loading resulted in
inferior yield, 95% (entry 11). No desired product was isolated in
the absence of K2CO3 (entry 12).
The generality of this method was then tested with various
substituted 2-(arylethynyl)anilines, and the results were summa-
rized in Table 2. N-Tosylated 2-(arylethynyl)anilines with electron-
donating (1a–1d) or electron-withdrawing (1f–1h) substituents in
the aryl ring cyclised to the corresponding 2-arylindoles in high
yields. Notably, the nitrile group was found to be well tolerated
under the present reaction condition to afford 2h in quantitative
yield. Substrates bearing an alkyl substituent on the alkyne moiety
were also applicable (1i–1k). Unlike copper catalyzed cyclization
reaction of 2-ethynylanilines in organic solvent [4f], the cyclization
the final product 2.
129
The possibilities of recovery and reusability of the catalytic 130
system were also investigated using 1j by carrying out consecutive 131
cycles. 2j was extracted with CH2Cl2 after each catalytic reaction, 132
and the results are recorded in Table 3. The catalytic system can be 133
recycled at least six times with little loss in yield on the 6th run. 134
Table 3
Cyclization reaction of 2-alkynylanilines in water catalyzed by K2CO3.a
K2CO3 (15 mol%)
H2O, 130oC, 10 h
N
Ts
NHTs
2j
1j
Cycle
1
2
3
4
5
6
Yieldb (%)
99
99
99
99
97
95
a
Reaction conditions: 1j (0.3 mmol) and K2CO3 (15 mol%) in water (1.5 mL) at 130 8C (oil bath) for 10 h. bIsolated yield.
Please cite this article in press as: Z. Chen, et al., Facile synthesis of indoles by K2CO3 catalyzed cyclization reaction of 2-ethynylanilines
in water, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.07.022

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4. Conclusion
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In conclusion, we have developed a highly efficient method for
the synthesis of indoles via K2CO3 catalyzed cyclization reaction of
2-ethynyl-N-sulfonylanilides in water. It is noted that the present
procedure offers several advantages, including the absence of
transition metal, without the use of excess of strong base, green
solvent, the ease of product isolation and cleaner reactions.
Moreover, the recovery and reusability of the catalytic system
were also investigated, and it could be reused at least six times.
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Acknowledgments
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This work was supported by the National Natural Science
Foundation of China (No. 21402137) and Xinmiao Talents Program
of Zhejiang Province (No. 2016R430021).
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2016.07.022.
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Please cite this article in press as: Z. Chen, et al., Facile synthesis of indoles by K2CO3 catalyzed cyclization reaction of 2-ethynylanilines
in water, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.07.022