A simple and efficient approach to 2-alkynylbenzofurans under mild copper(i)-catalyzed conditions

Article abstract of DOI:10.1039/c3ra00093a

The copper(i)-catalyzed synthetic method for the preparation of 2-alkynylbenzofurans from gem-dihaloolefins has been established using DABCO and TBAF·3H₂O as a cocatalyst. This methodology relies on a simple reaction system and inexpensive Cu s

Full text of DOI:10.1039/c3ra00093a

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
A simple and efficient approach to
2-alkynylbenzofurans under mild copper(I)-catalyzed
Cite this: RSC Advances, 2013, 3, 3865
conditions3
Received 8th January 2013,
Accepted 10th January 2013
Jianming Liu,a Ningfei Zhang,a Yuanyuan Yue,a Dong Wang,b Yuanli Zhang,a
Xin Zhanga and Kelei Zhuo*a
DOI: 10.1039/c3ra00093a
www.rsc.org/advances
The copper(I)-catalyzed synthetic method for the preparation of
The gem-dihaloolefins, owing to their simple and readily
available starting materials,7 broad functional group tolerance,
mild reaction conditions, facile operation, and high regioselec-
tivity, could be used for the construction of heterocyclic
compounds. Following the pioneering efforts, this strategy has
been applied to the preparation of a variety of heterocycles, such
as indoles,8 benzothiophenes,9 benzofurans,5 and isocoumarins10
through tandem reactions. Therefore, the transition metal-
catalyzed tandem reaction serves as an atom-economical and
environmentally benign alternative for C–C and C–heteroatom
bond formation.11 In the reactions mentioned above, Pd is used
extensively because of its tolerance of many functional groups, its
low toxicity and regioselectivity. However, in recent years copper-
catalyzed reactions have received considerable attention because
of their high efficiency and low costs.12 Inspired by recently
reported advantages of the Cu-catalyzed tandem reaction, we
hypothesized that inexpensive Cu catalysts should be capable of
promoting intramolecular cross-coupling reactions and
Sonogashira reactions of gem-dihaloolefins. Herein, we describe
a novel catalytic system which is not dependent phosphine ligand
or precious metal to mediate this reaction with an efficient
performance. This methodology relies on a simple reaction system
and inexpensive Cu salts as catalysts.
2-alkynylbenzofurans from gem-dihaloolefins has been estab-
lished using DABCO and TBAF?3H2O as
a cocatalyst. This
methodology relies on a simple reaction system and inexpensive
Cu salts as catalysts. It is generally applicable to gem-dihaloolefins
and phenylacetylenes.
2-Alkynylbenzofuran derivatives have attracted much attention in
biological and material sciences as ubiquitous building blocks
with wide-ranging pharmaceutical and pharmacological proper-
ties.1 Thus, a number of synthetic strategies have been reported
for the construction of these privileged molecular entities.
Previously developed approaches for the preparation of members
of this family include a Pd-catalyzed intramolecular coupling
reaction with 2-(4-trimethylsilyl-1,3-butadiyn-1-yl)-tert-butyldi-
methylsilylphenol,2 Pd- and Cu-catalyzed cascade reaction of
2-ethynylphenols with (E)-1,2-diiodoalkenes and the one-pot
Suzuki coupling/direct arylation of (E)-1,2-dichlorovinyl ethers
and alkynyl trifluoroborates.3 An alternative procedure includes a
transition metal-catalyzed sequential Suzuki–Miyaura coupling/
intra-molecular direct arylation between dichlorovinyl ethers and
organoboronic acids.4 Despite the existence of several methods for
the synthesis of 2-alkynylbenzofuran derivatives, versatile and
flexible methods to construct the target compounds are still
desired. Recently, Lautens et al. described a novel and practical
method of alkynyl benzofuran synthesis via tandem CuI and Pd-
catalyzed cross-couplings.5 Meanwhile, Wang et al. reported a
similar Pd-catalyzed process involving 2-bromobenzofuran and
phenylacetylene to generate the corresponding cross-coupling
products in high yields under the Sonogashira reaction condi-
tions.6 These approaches to prepare 2-alkynylbenzofuran are
summarized in Scheme 1.
aKey Laboratory of Green Chemical Media and Reactions, Ministry of Education,
School of Chemistry nd Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China. E-mail: klzhuo@263.net; Fax: (+86)-373-3326336
bDepartment of Bio-Health Technology, College of Biomedical Science, Kangwon
National University, Chuncheon, Gangwon-Do, 200-701, Korea
Scheme 1 Direct approaches to 2-alkynylbenzofuran.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra00093a
3
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 3865–3868 | 3865

View Article Online
Communication
RSC Advances
Table 1 Influence of the base, catalyst, and solvent on the cross-coupling
between 2-(2, 2-dibromovinyl)phenol and phenylacetylenea
Entry Catalyst
Base
Solvent
T/uC Yield (%)b
1
2
3
4
5
6
7
8
CuIc
CuId
CuIe
CuI
CuI
CuBr
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
140
140
140
140
140
140
140
140
140
140
140
140
140
73
trace
80
94(86)c
73
82
59
74
53
92
48
86
31
66
88
trace
87
67
Cu(OAc)2?H2O Cs2CO3
Cu(acac)2
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3
Cs2CO3
K2CO3
KOH
Na2CO3
K3PO4?3H2O DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
17
18
Dioxane 140
THF 140
Toluene 140
DMF
DMF
CuI
CuI
120
100
a
Reaction conditions: CuI (0.15 mmol), DABCO (0.30 mmol), gem-
dihaloolefin (1.0 mmol), phenylacetylene (1.5 mmol), TBAF?3H2O
Scheme 2 Ligands screened in the tandem reaction.
b
(1.0 mmol), base (2.0 mmol), solvent (5.0 mL). Yields were
c
determined by GC with n-dodecane as an internal standard. Yield
d
of isolated product. DABCO and TBAF?3H2O were not added.
We initially tested the tandem reaction of 2-(2,2-dibromovinyl)-
phenol with phenylacetylene using 15 mol% CuI in N,N-dimethyl
formamide at 140 uC in a N2 atmosphere. The reaction parameters
including various ligands, copper catalysts, solvents and bases
were investigated. The ligands screened are shown in Scheme 2.
Ligand L1 was prepared in 89% yield by a catalytic tandem
reaction, while Ligand L2 was prepared in 36% yield. We believe
that the most promising preliminary results were obtained using
L5, L6, L8, and L9 as the supporting ligand. We observed that the
latter provided a superior yield (91%). We postulated that the key
point to achieve this transformation is the excellent coordination
of L3 to the Cu catalyst and its high solubility in the DMF system.
The development of an applicable tandem reaction procedure
requires further assessment of the catalyst activity. These studies
revealed that the reactions conducted with Cu(I) catalysts could
result in high reactivities in DMF. It was found that CuI was the
most efficient catalyst, producing the corresponding alkynyl
benzofuran in 94% yield (Table 1, entry 4). Bases have an
insignificant influence on the catalyst activity (Table 1, entries 10
and 13), while solvents play an important role in the chemical
process (Table 1, entries 14–16). DMF turns out to be the most
efficient solvent amongst the solvents DMF, THF, dioxane, and
toluene. A low reaction temperature leads to a low yield in forming
the tandem coupling reaction product (Table 1, entries 17 and 18).
Under optimized conditions, various electron-rich and elec-
tron-poor phenylacetylenes were investigated in their reaction with
gem-dibromovinylphenol (3aa–3af, Table 2). The results indicated
that the scope of the reaction was quite broad given that alkyl,
methoxyl, fluoro and halo substituents were tolerated. The desired
products were obtained in high yields up to 86% and the reactions
were highly regioselective. To our delight, the p-tert-butyl
substituted compounds were formed in excellent yields.
e
TBAF?3H2O was not added.
Furthermore, various functional groups can be tolerated both in
the gem-dibromovinylphenol and the phenyl fragment, including a
large range of methyl, methoxyl, and halo substituents (3ba–3ef). It
was found that both electron-rich groups and electron-poor groups
at the para- and meta- positions of the gem-dibromovinylphenol
gave higher yields from 50% to 88%. Meanwhile, the tandem
coupling reaction of 1-(2, 2-dibromovinyl)naphthalen-2-ol and
phenylacetylenes with various electron releasing and withdrawing
groups also proceeded smoothly to give the corresponding alkynyl
benzofurans in high yields.
Under similar conditions, we were able to extend this copper-
catalytic protocol to the coupling of 4-chloro-2-(2, 2-dibromovinyl)-
phenol with 1-(tert-butyl)-4-ethynylbenzene. We found that the
electronic and steric effects of the groups attached to 4-chloro-2-(2,
2-dibromovinyl)phenol can not be ignored for either the initial
tandem coupling reaction or the sequential Sonogashira reaction.
The target product was obtained in moderate yield up to 64%
(Scheme 3). In addition, benzyl derivatives which are valuable
compounds, are found as a substructure of natural products, and
are utilized as corrosion inhibitors of mild steel and photo-
sensitive agents in photocurable coatings. Under similar condi-
tions to those reported by Sajiki,13 we have established a Pd/C-
catalyzed environmentally benign process for the oxidation of
2-alkynylbenzofuran to corresponding benzil derivatives using
DMSO and oxygen as dual oxidizing agents. The 2-(phenylethy-
nyl)benzofuran underwent the oxidation to give 1-(benzofuran-2-
yl)-2-phenylethane-1,2-dione in good yield to 70% (Scheme 4).
3866 | RSC Adv., 2013, 3, 3865–3868
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
Table 2 Tandem coupling products from gem-dibromovinylphenols and phe-
nylacetylenesa,b
Scheme 4 Pd/C-catalyzed environmentally benign process for the oxidation of
2-alkynylbenzofuran.
Scheme 5 Control experiment confirming the CuI-catalyzed tandem reactions of
gem-dihaloolefins.
2-bromobenzofuran, followed by reductive elimination of the
copper(III) intermediate (in neutral or cationic type), giving the
tandem coupling product and regenerating the active copper(I)
complex.
In conclusion, we have explored the convenient and efficient
synthesis of 2-alkynylbenzofurans from gem-dihaloolefins via a
sequential cyclization and Sonogashira reaction. By applying this
elegant protocol, a wide range of electron-rich and electron-poor
2-alkynylbenzofurans were obtained. We believe that such a
simple and effective catalyst system could provide good insight
into the synthesis of related 2-alkynylbenzofurans.
a
Reaction conditions: CuI (0.15 mmol), DABCO (0.30 mmol), gem-
dihaloolefin (1.0 mmol), phenylacetylene (1.5 mmol), TBAF?3H2O
(1.0 mmol), Cs2CO3 (2.0 mmol), DMF (5.0 mL). Yield of isolated
product.
b
To explore the mechanism for this reaction, control experi-
ments were conducted under the standard reaction conditions
(Scheme 5). The tandem cross coupling of 2-(2, 2-dibromovinyl)-
phenol, 2-bromobenzofuran with (phenylethynyl)copper was also
carried out smoothly in a good yield (up to 86%). A working
mechanism was proposed as an outline in Fig. 1 for the Cu-
catalyzed tandem cross coupling reaction.14 The reaction of
intermediate Cu complexes (a four-center transition state pro-
posed by Castro and Stephens) with phenylacetylene afforded a
copper(I)-complex intermediate. The latter occurs to form a four-
coordinated copper(III) complex by oxidative addition with
Scheme 3 Cu(I)-catalyzed tandem coupling products from 4-chloro-2-(2, 2-dibro-
movinyl)phenol with 1-(tert-butyl)-4-ethynylbenzene.
Fig. 1 Possible mechanism for the CuI-catalyzed tandem reactions of 2-(2,2-
dibromovinyl)phenol.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 3865–3868 | 3867

View Article Online
Communication
RSC Advances
2007, 72, 5152; (c) Y. Q. Fang and M. Lautens, J. Org. Chem.,
2008, 73, 538; (d) D. I. Chai and M. Lautens, J. Org. Chem., 2009,
74, 3054; (e) Y. Q. Fang and M. Lautens, Org. Lett., 2005, 7, 3549;
(f) J. Yuen, Y. Q. Fang and M. Lautens, Org. Lett., 2006, 8, 653; (g)
A. Fayol, Y. Q. Fang and M. Lautens, Org. Lett., 2006, 8, 4203; (h)
M. Nagamochi, Y. Q. Fang and M. Lautens, Org. Lett., 2007, 9,
2955; (i) C. S. Bryan and M. Lautens, Org. Lett., 2008, 10, 4633;
(j) T. O. Viera, L. A. Meaney, Y. L. Shi and H. Alper, Org. Lett.,
2008, 10, 4899; (k) M. Arthuls, R. Pontikis and J. C. Florent, Org.
Lett., 2009, 11, 4608.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (No. 21103044, 21173070, 21205029),
Ph.D. Programs Foundation of Ministry of Education of China
(No. 20114104120003), and Foundation of Henan Educational
Committee (12B150013) for generous financial support.
Notes and references
1 (a) I. Muhammad, X. C. Li, M. R. Jacob, B. L. Tekwani, D.
C. Dunbar and D. Ferreira, J. Nat. Prod., 2003, 66, 804; (b)
M. Lounasmaa and A. Tolvanen, Nat. Prod. Rep., 2000, 17, 175;
(c) R. S. Ward, Nat. Prod. Rep., 1997, 14, 43; (d) A. Gangjee,
R. Devrai, J. J. Mc Guire and R. L. Kisliuk, J. Med. Chem., 1995,
38, 3798.
2 V. Fiandanese, D. Bottalico, G. Marchese and A. Punzi,
Tetrahedron, 2008, 64, 7301.
3 Y. Liang, L. M. Tao, Y. H. Zhang and J. H. Li, Synthesis, 2008, 24,
3988.
4 L. M. Geary and P. G. Hultin, Eur. J. Org. Chem., 2010, 5563.
5 M. Nagamochi, Y. Q. Fang and M. Lautens, Org. Lett., 2007, 9,
2955.
6 W. Chen, Y. C. Zhang, L. Zhang, M. Wang and L. Wang, Chem.
Commun., 2011, 47, 10476.
7 (a) W. Shen and S. A. Thomas, Org. Lett., 2000, 2, 2857; (b)
M. Lera and C. J. Hayes, Org. Lett., 2000, 2, 3873; (c) M. L.
N. Rao, D. N. Jadhav and P. Dasgupta, Org. Lett., 2010, 12, 2048;
9 (a) C. S. Bryan, J. A. Braunger and M. Lautens, Angew. Chem.,
Int. Ed., 2009, 48, 7064; (b) S. G. Newman, V. Aureggi, C.
S. Bryan and M. Lautens, Chem. Commun., 2009, 5236.
10 W. Shen and L. Wang, Tetrahedron Lett., 1998, 39, 7625.
11 (a) X.-Y. Liu and C. M. Che, Angew. Chem., Int. Ed., 2008, 47,
3805. For recent reviews, see: (b) L. F. Tietze, Chem. Rev., 1996,
96, 115; (c) J. M. Lee, Y. Na, H. Han and S. Chang, Chem. Soc.
Rev., 2004, 33, 302; (d) A. Ajamian and J. L. Gleason, Angew.
Chem., Int. Ed., 2004, 43, 3754; (e) J. C. Wasilke, S. J. Obrey, R.
T. Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001; (f) A. de
Meijere, P. von Zezschwitz and S. Brase, Acc. Chem. Res., 2005,
38, 413.
12 (a) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev.,
2004, 248, 2337; (b) C. Koradin, K. Polborn and P. Knochel,
Angew. Chem., Int. Ed., 2002, 41, 2535; (c) F. Himo, T. Lovell,
R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless and
V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210; (d) A. Kondoh,
H. Yorimitsu and K. Oshima, J. Am. Chem. Soc., 2007, 129, 4099;
(e) H. Isobe, K. Cho, N. Solin, D. B. Werz, P. H. Seeberger and
E. Nakamura, Org. Lett., 2007, 9, 4611.
`
(d) B. P. Berciano, S. Lebrequier, F. Besselievre and S. Pigue,
Org. Lett., 2010, 12, 4038; (e) A. Coste, G. Karthikeyan, F. Couty
and G. Evano, Angew. Chem., Int. Ed., 2009, 48, 4381; (f) A. Coste,
F. Couty and G. Evano, Org. Lett., 2009, 11, 4454; (g) S. Ye,
G. Liu, S. Z. Pu and J. Wu, Org. Lett., 2012, 14, 70; (h)
L. Ackermann, C. Kornhaass and Y. J. Zhu, Org. Lett., 2012, 14,
1824; (i) X. R. Qin, X. F. Cong, D. B. Zhao, J. S. You and J. B. Lan,
Chem. Commun., 2011, 47, 5611.
13 S. Mori, M. Takubo, T. Yanase, T. Maegawa, Y. Monguchi and
H. Sajiki, Adv. Synth. Catal., 2010, 352, 1630.
14 (a) R. D. Stephens and C. E. Castro, J. Org. Chem., 1963, 28,
2163; (b) J. H. Li, J. L. Li, D. P. Wang, S. F. Pi, Y. X. Xie, M.
B. Zhang and X. C. Hu, J. Org. Chem., 2007, 72, 2053; (c)
F. Monnier, F. Turtaut, L. Duroure and M. Taillefer, Org. Lett.,
2008, 10, 3203.
8 (a) Y. Q. Fang, R. Karisch and M. Lautens, J. Org. Chem., 2007,
72, 1341; (b) Y. Q. Fang, Y. Yuen and M. Lautens, J. Org. Chem.,
3868 | RSC Adv., 2013, 3, 3865–3868
This journal is ß The Royal Society of Chemistry 2013