Facile synthesis of 2-substituted benzo[: B] furans and indoles by copper-catalyzed intramolecular cyclization of 2-alkynyl phenols and tosylanilines

Article abstract of DOI:10.1039/c9ra01260e

A catalytic amount of CuCl and Cs₂CO₃ was employed to synthesize a variety of 2-substituted benzo[b]furans and indoles by an intramolecular cyclization of 2-alkynyl phenols and tosylanilines. This protocol features mild conditions, h

Full text of DOI:10.1039/c9ra01260e

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Facile synthesis of 2-substituted benzo[b]furans
and indoles by copper-catalyzed intramolecular
cyclization of 2-alkynyl phenols and tosylanilines†
Cite this: RSC Adv., 2019, 9, 17975
*
*
*
Zhouting Rong,
Kexin Gao, Lei Zhou, Jianyuan Lin and Guoying Qian
Received 19th February 2019
Accepted 19th April 2019
A catalytic amount of CuCl and Cs2CO3 was employed to synthesize a variety of 2-substituted benzo[b]
furans and indoles by an intramolecular cyclization of 2-alkynyl phenols and tosylanilines. This protocol
features mild conditions, high yields and broad substrate scope, which makes it a practical method for
the synthesis of 2-substituted benzo[b]furans and indoles.
DOI: 10.1039/c9ra01260e
rsc.li/rsc-advances
synthesis of 2-substituted benzo[b]furans and indoles by
copper-catalyzed intramolecular cyclization of 2-alkynyl
Introduction
phenols and tosylanilines under mild conditions.
The skeletons of benzo[b]furans and indoles are widely spread
in many naturally occurring compounds1,2 and pharmaceutical
molecules.3,4 Many methods towards the synthesis of benzo[b]
furan and indole derivatives have been developed over the last
two decades.5,6
Results and discussion
Our studies started with the intramolecular cyclization of 2-
(phenylethynyl)phenol 1a as the substrate and the results were
summarized in Table 1. When exposing 1a to different
commercial available copper salts in dimethyl sulfoxide
(DMSO), no reaction took place aer 24 h at 23 ꢀC (entries 1–5).
Then 1 equivalent of triethylamine was added to each of these
To synthesize 2-substituted benzo[b]furans or indoles, the
most universal method seems to be the Sonogashira coupling of
2-halophenols or 2-haloanilines with alkynes, followed by het-
erocyclization of the hydroxyl or amino group with the triple
bond (Scheme 1, Pathway A).7 Some one-pot cascades have also
been developed according to this strategy (Scheme 1, Pathway
B).8 However, these transformations usually require the partic-
ipation of noble metals, ligands or harsh conditions to
complete the cyclizations.
Copper, in the merit of cost, is a superior choice in organic
catalysis.9 It has also been used in the construction of benzo[b]
furan and indole rings.10 For example, Venkataraman and co-
workers accomplished the synthesis of 2-arylbenzo[b]furans by
exposing aryl acetylenes and 2-iodophenols to 10 mol%
[Cu(phen) (PPh3)2]NO3 and 2 equivalents of Cs2CO3 in toluene
ꢀ
at 100 C for 24 h. Similar transformations were realized with
11
´
copper pincer complexes by Domınguez and with Cu(OTf)2-
BINAM by Sekar.12 2-Substituted indoles can also be obtained
aer the reaction of 2-ethynylaniline derivatives under reux in
Cu(OCOCF3)2 aqueous solution for 24 h.13 However, high reac-
tion temperature and the use of stoichiometric amount of base
are usually unavoidable to achieve high yields in these reac-
tions. Herein, we report a facile and inexpensive method for the
College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo
315100, People's Republic of China. E-mail: zrong@zwu.edu.cn; linjianyuan@zwu.
edu.cn; qiangy@zwu.edu.cn
† Electronic supplementary information (ESI) available: General methods and
experimental procedures, characterization and spectra of substrates and
products. See DOI: 10.1039/c9ra01260e
Scheme 1 Previous synthetic strategies for 2-substituted benzo[b]
furans or indoles and our optimal conditions.
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Table 1 Optimization of reaction conditionsa
furan synthesis,11–13,15 our optimized conditions featured lower
catalyst and base loading, ambient temperature and ligand free.
With the optimal conditions in hand, we started to explore
the substrate scope of this transformation and a variety of 2-
alkynyl phenols were employed. In general, this transformation
showed good functional group tolerance and the results were
listed in Table 2. 2-Arylethynyl phenols bearing either electron-
donating or electron-withdrawing substitutes on the alkynyl-
moiety proved to be suitable substrates to produce the corre-
sponding 2-aryl benzo[b]furans (2a–e) in good to excellent
yields. To our delight, the presence of hydroxyl group did not
interrupt the reaction, which afforded the desired benzo[b]
furans (2f–h) in excellent yields. 2-tert-Butylethynyl phenol and
2-phenylethynyl-3-hydroxyl pyridine also reacted smoothly to
give the corresponding products in 91% and 88% yield,
respectively.
Similar to 2-substituted benzo[b]furans, we proposed that 2-
substituted indoles could also be synthesized under our stan-
dard conditions. When 2-(phenylethynyl)aniline was used,
however, no reaction was observed, probably due to the low
acidity of the protons on the amino group. Hence, 2-(phenyl-
ethynyl)tosylaniline 3a was submitted to the standard condi-
tions and the reaction proceeded smoothly to afford N-tosyl-2-
phenyl indole 4a in 95% yield. Then various 2-alkynyl tosyla-
nilines were tested under the standard conditions and the
results were shown in Table 3. We found that in all cases, 2-
arylethynyl tosylanilines gave the desired products (4a–c) in
excellent yields. Similar results were obtained when different 2-
alkylethynyl tosylanilines (3d–f) were used as the substrates.
Hydroxyl group was still tolerated in this transformation and
tosylanilines with Me or Cl substitutes remained active to give
the corresponding tosylindoles 4i and 4j in 86% and 82% yield,
respectively.
Reaction
time (h)
Yieldb
(%)
Entry
[Cu]
Base
Solvent
1
2
3
4
5
6
7
8
CuCl
CuBr
CuCl2
CuBr2
Cu(OTf)2
CuCl
CuBr
CuCl2
CuBr2
Cu(OTf)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
—
—
—
—
—
—
Et3N
Et3N
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH2Cl2
THF
24
24
24
24
24
48
48
48
48
48
48
48
48
48
12
12
12
12
12
9
NRc
NR
NR
NR
NR
48
Trace
Trace
30
Trace
45
40
Trace
36
59
55
84
61
Trace
69
55
95
95
NR
9
Et3N
Et3N
Et3N
10
11
12
13
14
15
16
17
18
19
20
21
22
23f
24f
DIPEAd
Pyridine
DBUe
K2CO3
KOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
DMF
CH3CN
CH3CN
CH3CN
9
3
5
24
a
Unless otherwise noted, all reactions were performed with 1a (0.2
b
mmol), [Cu] (0.01 mmol), base (0.2 mmol) at 23 ꢀC. The yield of 2a
was determined by NMR with 1,3,5-trimethylbenzene as the internal
c
d
standard. NR ¼ no reaction. DIPEA ¼ N,N-diisopropylethylamine.
e
f
DBU ¼ 1,8-diazabicyclo[5.4.0]undec-7-ene. 0.01 mmol of Cs2CO3
Table 2 Substrate scope of benzo[b]furan synthesisa
was used.
reactions and we observed the slow formation of our desired
product 2a, with CuCl giving the best yield (48%) aer 48 h
(entry 6). This result pushed us to examine different commercial
available bases using CuCl as the catalyst and DMSO as the
solvent. Aer careful screening, Cs2CO3 stood out from a variety
of organic and inorganic bases to give the best yield (84%) aer
12 h at 23 ꢀC (entry 17). We then tested various commonly used
solvents and found out that acetonitrile dramatically acceler-
ated the reaction to produce 2-phenylbenzo[b]furan 2a with
ꢀ
95% yield aer 3 h at 23 C (entry 22).
To our surprise, adjusting the loading of Cs2CO3 to 5 mol%
did not cause any decrease in yield, although a slightly longer
reaction time was needed (entry 23). When the experiment was
carried out in the absence of CuCl, no reaction took place aer
24 h (entry 24), which suggested that copper catalyst was
essential for this conformation although recently Gao and co-
workers reported that this reaction could be completed at
a higher temperature without any transition metal catalyst.14
Compared with other copper-catalyzed methods for benzo[b]
a
All reactions were performed with 1 (0.5 mmol), CuCl (0.025 mmol),
Cs2CO3 (0.025 mmol) in CH3CN (2 mL) at 23 ꢀC for 5 h. Isolated
yields of 2 were listed. 2-Phenylethynyl-3-hydroxyl pyridine was used
as the substrate.
b
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Table 3 Substrate scope of copper-catalyzed indole synthesisa
offers a practical application for the facile synthesis of 2-
substituted benzo[b]furans and indoles.
A plausible mechanism of this reaction is then proposed
taking 1a as an example (Scheme 3). At the outset, 1a can be
deprotonated by Cs2CO3 to form A, which can be activated by
the solvated CuCl to afford intermediate B. Then B undergoes
an intramolecular cyclization to give intermediate C. The
subsequent protonolysis of C by 1a could afford our nal
product 2a accompanied with intermediate A for the next
catalytic cycle.
Conclusions
In conclusion, a practical copper-catalyzed method has been
developed for the facile synthesis of various 2-substituted benzo
[b]furans and indoles. The transformation can be accomplished
under mild conditions with low catalyst and base loading,
featuring broad substrate scope and high efficiency, which
shows great potential in the application for the large scale
production.
a
All reactions were performed with 3 (0.5 mmol), CuCl (0.025 mmol),
Cs2CO3 (0.025 mmol) in CH3CN (2 mL) at 23 ꢀC for 5 h. Isolated
yields of 4 were listed.
Experimental
General procedure for copper-catalyzed synthesis of 2-
substituted benzo[b]furans and indoles
CuCl (2.5 mg, 0.025 mmol) and Cs2CO3 (8.1 mg, 0.025 mmol)
were added to a solution of 2-alkynyl phenol 1 (or 2-alkynyl
tosylaniline 3, 0.5 mmol) in CH3CN (2 mL) and the mixture was
ꢀ
stirred at 23 C for 5 h. Then Et2O (10 mL) was added and the
Scheme 2 Gram scale preparation of 2a and 4a.
resulting mixture was washed sequentially with water (10 mL)
and brine (10 mL), dried over anhydrous Na2SO4. The solvent
was evaporated and the residue was puried by ash column
chromatography (hexane/EtOAc) to give 2-substituted benzo[b]
furans 2 (or 2-substituted indoles 4).
In order to demonstrate the utility and efficiency of this
transformation, we performed the gram scale reactions of 1a
and 3a in the presence of only 1 mol% of CuCl and Cs2CO3
(Scheme 2). Although the completion time was longer, both
reactions afforded the desired products in high yields.
Considering the low cost and high yield, this robust method
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by the Zhejiang Provincial Top Key
Discipline of Bioengineering (ZS2017014, ZS2018011 and
ZS2015005), the Scientic Research Development Foundation of
Zhejiang Wanli University and Zhejiang Provincial basic public
welfare research project (LGN18H300001).
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Scheme 3 Plausible reaction mechanism.
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