Facile synthesis of benzofurans via copper-catalyzed aerobic oxidative cyclization of phenols and alkynes

Article abstract of DOI:10.1039/c3cc42326c

Regioselective synthesis of polysubstituted benzofurans using a copper catalyst and molecular oxygen from phenols and alkynes in a one-pot procedure has been reported. The transformation consists of a sequential nucleophilic addition of phenols to alkynes and oxidative cyclization. A wide variety of phenols and alkynes can be used in the same manner.

Full text of DOI:10.1039/c3cc42326c

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Facile synthesis of benzofurans via copper-catalyzed
aerobic oxidative cyclization of phenols and alkynes†
Cite this: Chem. Commun., 2013,
49, 6611
Wei Zeng, Wanqing Wu, Huanfeng Jiang,* Liangbin Huang, Yadong Sun,
Zhengwang Chen and Xianwei Li
Received 30th March 2013,
Accepted 3rd June 2013
DOI: 10.1039/c3cc42326c
www.rsc.org/chemcomm
Regioselective synthesis of polysubstituted benzofurans using a reports on copper-catalyzed oxidative C–H bond functionaliza-
copper catalyst and molecular oxygen from phenols and alkynes in tion or nucleophilic/cyclization reactions for the synthesis of
a one-pot procedure has been reported. The transformation con- heterocycles.10 Herein, we report a novel and efficient copper-
sists of a sequential nucleophilic addition of phenols to alkynes catalyzed sequential nucleophilic addition and oxidative cycli-
and oxidative cyclization. A wide variety of phenols and alkynes zation of easily available phenols and alkynes using O2 as the
can be used in the same manner.
oxidant, which provides polysubstituted benzofuran derivatives
in moderate to good yields.
Benzofurans are ubiquitous in biologically active molecules1
Based on our continuing efforts to achieve copper-catalyzed
and have also been used as building blocks for both hetero- bond formation reactions, nucleophilic additions and homo-
cyclic and acyclic compounds.2 Many efforts have been made to coupling reactions of alkynes,11 we first studied the reaction of
achieve efficient synthesis of these motifs.3 In the past decades, phenols and 1,2-diphenylethyne in PhNO2 using CuCl2Á2H2O as
transition metal-catalyzed reactions have emerged as powerful a catalyst, ZnCl2 as a Lewis acid, and O2 as an oxidant. The
methods for the synthesis of benzofurans,4 but simple phenols reaction was chosen as a model system to investigate the
have rarely been used as starting materials to directly construct proposed transformation (Table 1).
these scaffolds.5 As common precursors and core structures of
chemicals ranging from pharmaceuticals to polymers, phenols
are versatile synthetic intermediates and useful reagents for
Table 1 Optimization of the reaction conditionsa
C–H functionalization in organic synthesis.6 However, under
oxidative conditions, dearomatization of phenols is likely to
occur and generate quinol/quinone-derived products.7 Such a
drawback restricts the application of phenols in the synthesis of
heterocyclic compounds via transition metal-catalyzed oxidative
Entry
Lewis acid
[Cu]
Solvent
Yieldb (%)
cyclizations.
From an economical and environmental viewpoint, catalytic
1
2
3
4
5
6
7
8
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
AgNO3
In(OTf)2
Zn(OTf)2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
—
CuCl2Á2H2O
CuBr2
CuI
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
DMSO
DMF
45
50
54
60
80
43
40
60
84
—
—
—
—
93
35
—
11
oxidation processes employing molecular oxygen (O2) or air as a
terminal oxidant are extremely valuable and will be more
applicable to industrial catalysis. The direct oxidative coupling
between two C–H bonds provides a highly attractive strategy for
ideal chemical synthesis.8 Compared with the methods based
on noble-metals, copper–oxygen based methods are obviously
economically attractive. The development of copper-catalyzed
aerobic oxidative C–H functionalizations leads to new types
of synthetic transformations.9 Collectively, there are many
Cu(acac)2
Cu(OTf)2
Cu(BF4)2Á6H2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
9
10
11
12
13
14c
15c,d
16
17
NMP
Xylene
PhNO2
PhNO2
PhNO2
PhNO2
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn;
Fax: +8620-87112906; Tel: +8620-87112906
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra of selected compounds. See DOI: 10.1039/c3cc42326c
Cu(OTf)2
a
Reactions were carried out using 1a (1.5 mmol), 2a (1.0 mmol), Lewis
b
acid (1.5 eq.), cat. (10% mol), solvent (2 mL), O2, 24 h. Determined by
c
d
GC. Reaction at 120 1C. Reaction in air.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 6611--6613 6611

View Article Online
Communication
ChemComm
To our delight, the desired benzofuran 3a was obtained
With the optimized conditions in hand [phenol (1.5 mmol),
in 45% GC yield (Table 1, entry 1). Initial screening revealed 1,2-diphenylethyne (1.0 mmol), O2, ZnCl2 (1.5 eq.), Cu(OTf)2
that Cu(OTf)2 was the best choice for this transformation, and (10% mol), 120 1C, 24 h], we focused on the scope of this
other copper salts such as CuBr2 and CuI were also effective, transformation. A variety of phenol derivatives were examined
albeit affording the products with slightly diminished yields and the results are summarized in Table 2. The reaction could
(entries 2–5). Use of other conventional Lewis acids as catalysts be successfully applied to a range of different substituted
resulted in far less effectiveness (entries 7 and 8). Though phenols and gave the corresponding products in moderate to
Zn(OTf)2 gave a better yield (entry 9), we chose ZnCl2 as the excellent yields. Phenols with either an electron-donating or an
Lewis acid because it is economically attractive. After solvent electron-withdrawing group on the benzene ring generated the
evaluation we found that PhNO2 was the only effective solvent, corresponding products in moderate to good yields. Clearly,
while no reaction occurred in other solvents (entries 10–13). electronic effects play an important role, as electron-rich sub-
The temperature was then examined, and it was found that a stituents (3a–d, 3l, 3m) on the benzene ring favored the
higher temperature was suitable for this reaction (entry 14). The transformation. It should be noted that reaction conditions
reaction was less effective when proceeding in air (entry 15). were also compatible with the sulfide group (3n), fluoro, chloro,
Several control experiments were conducted. Under the standard bromo and iodo substituent groups (3e–3k), which could be
reaction conditions, no product could be detected in the absence used for further reactions. Fortunately, 2-naphthol and aryl-
of a copper catalyst (entry 16). Moreover, the transformation substituted phenols could be successfully generated in this
was less effective when proceeding without the addition of the reaction system (3o, 3p).
Lewis acid (entry 17).
To further demonstrate the efficiency and generality of this
process, we then examined the transformation with a range of
1,2-diphenylethyne derivatives under the optimized reaction
conditions. As shown in Table 3, with 1,2-diphenylethyne
derivatives as starting materials, all the tested reactions pro-
ceeded smoothly and afforded the corresponding benzofurans
(4a–4f) under the standard conditions. To our delight, when
phenylethyne with one alkyl at one side and an aryl group at the
other side is used, the desired unsymmetrical products 4g–4i
could also be synthesized in this way and showed high regio-
selectivity. The structure of compound 4i was further confirmed
by NOESY analysis (see ESI† for details).
Table 2 Substrate scope of 2,3-disubstituted benzofuransa,b
On the basis of our experimental data and previous reports,12
a plausible reaction mechanism for this copper-catalyzed synthesis
Table 3 Substrate scope of 2,3-disubstituted benzofuransa,b
a
a
Reactions were carried out using phenols (1.5 mmol), 2a (1.0 mmol),
Reactions were carried out using 1a (1.5 mmol), alkynes (1.0 mmol),
b
b
ZnCl2 (1.5 eq.), Cu(OTf)2 (10% mol), PhNO2 (2 mL), O2, 24 h. Isolated ZnCl2 (1.5 eq.), Cu(OTf)2 (10% mol), PhNO2 (2 mL), 24 h. Isolated
yields obtained using flash chromatography.
yields obtained using flash chromatography.
c
6612 Chem. Commun., 2013, 49, 6611--6613
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
D. Engelmeier, S. Vajrodaya, O. Hofer and H. Greger, J. Nat. Prod.,
2002, 65, 820.
2 (a) T. Kitamura and K. Otsubo, J. Org. Chem., 2012, 77, 2978;
(b) J. Zhang, L. Li, Y. Wang, W. Wang, J. Xue and Y. Li, Org. Lett.,
2012, 14, 4528.
3 For reviews, see: (a) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008,
108, 3395; (b) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004,
104, 2127; (c) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644;
(d) F. Alonso, I. P. Beletskaya and M. Yus, Chem. Rev., 2004,
104, 3079.
4 For selected examples, see: (a) K. Tsuchikama, Y. Hashimoto,
K. Endo and T. Shibata, Adv. Synth. Catal., 2009, 351, 2850;
(b) B. Lu, B. Wang, Y. Zhang and D. Ma, J. Org. Chem., 2007,
72, 5337; (c) Y. Liu, J. Qian, S. Lou and Z. Xu, J. Org. Chem., 2010,
75, 6300; (d) N. Matsuda, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2012, 77, 617; (e) B. Gabriele, R. Mancuso and G. Salerno,
J. Org. Chem., 2008, 73, 7336; ( f ) L. Zhou, Y. Shi, Q. Xiao, Y. Liu,
F. Ye, Y. Zhang and J. Wang, Org. Lett., 2011, 13, 968–971; (g) S. Ye,
G. Liu, S. Pu and J. Wu, Org. Lett., 2012, 14, 70; (h) Y. Komlne,
A. Kamlsawa and K. Tanaka, Org. Lett., 2009, 11, 2361;
Scheme 1 Proposed mechanism.
´
´
(i) C. Martınez, R. Alvarez and J. M. Aurrecoechea, Org. Lett., 2009,
11, 1083.
of benzofurans is illustrated in Scheme 1. First, (E)-(1-phenoxy-
ethene-1,2-diyl)-dibenzene A was generated from an intermolecular
nucleophilic addition of phenol 1a to 1,2-diphenylethyne 2a,
promoted by Cu(II) and Lewis acid. Subsequently, A undergoes
an intramolecular electrophilic substitution via C–H function-
alization of the aromatic hydrogen in the presence of the Cu
catalyst to give an intermediate B, followed by the oxidative
cyclization to form a new carbon–carbon bond and afford the
final product 3a.
In summary, we have developed a highly efficient approach
for the synthesis of polysubstituted benzofurans via copper-
catalyzed nucleophilic addition and aerobic oxidative cyclization
of phenols and alkynes. It is noteworthy that this method
exhibits good functional group tolerance and provides an attractive
synthetic strategy for the benzofuran derivatives. Furthermore, the
use of readily available starting materials and molecular oxygen as
the oxidant makes the overall chemical transformation sustainable
and practical. Detailed investigations to understand the reac-
tion mechanism and expansion of the synthetic applications
are ongoing in our laboratory.
5 (a) D. Lee, K. Kwon and C. S. Yi, J. Am. Chem. Soc., 2012, 134, 7325;
(b) X. Guo, R. Yu, H. Li and Z. Li, J. Am. Chem. Soc., 2009, 131, 17387;
(c) W. Zhou, Y. Zhang, P. Li and L. Wang, Org. Biomol. Chem., 2012,
10, 7184; (d) L. M. Geary and P. G. Hultin, Eur. J. Org. Chem., 2010,
5563.
6 For selected examples, see: (a) C. Huang, B. Chattopadhyay and
V. Gevorgyan, J. Am. Chem. Soc., 2011, 133, 12406; (b) A. Kirste,
B. Elsler, G. Schnakenburg and S. R. Waldvogel, J. Am. Chem. Soc.,
2012, 134, 3571; (c) T. Imahori, T. Tokuda, T. Taguchi and
H. Takahata, Org. Lett., 2012, 14, 1172.
7 (a) D. Magdziak, S. J. Meek and T. R. R. Pettus, Chem. Rev., 2004,
104, 1383; (b) N. T. Vo, R. D. M. Pace, F. O’Hara and M. J. Gaunt,
J. Am. Chem. Soc., 2008, 130, 404; (c) S. Dong, J. Zhu and J. A. Porco.
Jr, J. Am. Chem. Soc., 2008, 130, 2738; (d) M. O. Ratnikov, L. E. Farkas
and M. P. Doyle, J. Org. Chem., 2012, 77, 10294; (e) M. O. Ratnikov,
L. E. Farkas, E. C. McLaughlin, G. Chiou, H. Choi, S. H. El-Khalafy
and M. P. Doyle, J. Org. Chem., 2011, 76, 2585; ( f ) J. K. Boppisetti
and V. B. Birman, Org. Lett., 2009, 11, 1221.
8 (a) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev., 2009,
38, 2447; (b) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39, 540;
(c) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev.,
2011, 40, 5068; (d) J. Muzart and J. L. Bras, Chem. Rev., 2011,
111, 1170; (e) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev.,
2011, 111, 1780; ( f ) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,
111, 1215.
9 A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem., Int. Ed.,
2011, 50, 11062.
We are grateful to the National Natural Science Foundation of
China (20932002, 21172076 and 21202046), the National Basic
Research Program of China (973 Program) (2011CB808600), the
Guangdong Natural Science Foundation (10351064101000000
and S2012040007088), China Postdoctoral Science Foundation
(2012T50673) and the Fundamental Research Funds for the
Central Universities (2012ZP0003 and 2012ZB0011).
10 (a) G. Zhang, J. Miao, Y. Zhao and H. Ge, Angew. Chem., Int. Ed.,
2012, 51, 8318; (b) L. Zhang, J. Cheng, T. Ohishi and Z. Hou, Angew.
Chem., Int. Ed., 2010, 49, 8670; (c) S. Ueda and H. Nagasawa, Angew.
Chem., Int. Ed., 2008, 47, 6411; (d) C. Wan, J. Zhang, S. Wang, J. Fan
and Z. Wang, Org. Lett., 2010, 12, 2338; (e) H. Jiang, W. Zeng, Y. Li,
W. Wu, L. Huang and W. Fu, J. Org. Chem., 2012, 77, 5179.
11 (a) L. Huang, H. Jiang, C. Qi and X. Liu, J. Am. Chem. Soc., 2010,
132, 17652; (b) X. Li, L. Huang, H. Chen, W. Wu, H. Huang and H. Jiang,
Chem. Sci., 2012, 3, 3463; (c) H. Cao, H. Jiang, W. Yao and X. Liu,
Org. Lett., 2009, 11, 1931; (d) W. Liu, H. Jiang, M. Zhang and C. Qi,
J. Org. Chem., 2010, 75, 966; (e) H. Jiang, W. Yao, H. Cao, H. Huang
and D. Cao, J. Org. Chem., 2010, 75, 5347; ( f ) Y. Wen, S. Zhu,
H. Jiang, A. Wang and Z. Chen, Synlett, 2011, 1023.
Notes and references
1 (a) K. Song and I. Raskin, J. Nat. Prod., 2002, 65, 76; (b) B. Sritularak,
K. Likhitwitayawuid, J. Conrad, B. Vogler, S. Reeb, I. Klaiber and
W. Kraus, J. Nat. Prod., 2002, 65, 589; (c) T. Pacher, C. Seger, 12 Y. Yamamoto, J. Org. Chem., 2007, 72, 7817.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 6611--6613 6613