Highly efficient synthesis of 2,3,4-trisubstituted furans via silver-catalyzed sequential nucleophilic addition and cyclization reactions of haloalkynes

Article abstract of DOI:10.1016/j.tetlet.2013.05.140

A regioselective synthesis of 2,3,4-trisubstituted furans using AgNO ₃ catalyst from haloalkynes in a one-pot procedure has been reported. The transformation consists of a sequential silver-catalyzed nucleophilic addition and cyclization reaction of haloalkynes. A wide variety of haloalkynes can be used in this chemical process.

Full text of DOI:10.1016/j.tetlet.2013.05.140

Tetrahedron Letters 54 (2013) 4605–4609
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Tetrahedron Letters
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Highly efficient synthesis of 2,3,4-trisubstituted furans via
silver-catalyzed sequential nucleophilic addition and cyclization
reactions of haloalkynes q
⇑
Wei Zeng, Wanqing Wu, Huanfeng Jiang , Yadong Sun, Zhengwang Chen
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A regioselective synthesis of 2,3,4-trisubstituted furans using AgNO3 catalyst from haloalkynes in a one-
pot procedure has been reported. The transformation consists of a sequential silver-catalyzed nucleo-
philic addition and cyclization reaction of haloalkynes. A wide variety of haloalkynes can be used in this
chemical process.
Received 17 March 2013
Revised 23 May 2013
Accepted 30 May 2013
Available online 15 June 2013
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Furan
Silver
Haloalkynes
Nucleophilic addition
Cyclization
The haloalkynes are a pivotal class of compounds that have
been used widely in organic synthesis.1 Haloalkynes are generally
regarded as a dual functionalized molecule in reactions, which may
go through a metal–halogen exchange or be used as an electro-
philic alkyne.2 Due to these interesting characteristics of haloalky-
nes, many reactions of haloalkynes have been developed during
Table 1
Optimization of the reaction conditionsa
O
O
Br
N
O
Lewis acid, base
+
N
O
solvent, 100 °C
3a
1a
2a
Entry
Lewis acid
Base
Solvent
Yieldb (%)
1
2
3
4
5
Ag2O
AgSbF6
CuI
ZnCl2
AgNO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
45
50
30
21
60
(continued on next page)
q
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-
commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
⇑
Corresponding author. Tel./fax: +86 20 87112906.
E-mail address: jianghf@scut.edu.cn (H. Jiang).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.140

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W. Zeng et al. / Tetrahedron Letters 54 (2013) 4605–4609
Table 1 (continued)
Entry
Lewis acid
Base
Solvent
Yieldb (%)
6
7
8
In(OTf)2
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
Li2CO3
DABCO
Cs2CO3
DBU
t-BuOK
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
1,4-Dioxane
Toluene
NMP
41
88
54
70
50
71
21
15
51
41
70
9
10
11
12
13
14
15c
16d
DMSO
DMSO
a
Reactions were carried out using phenylethynyl bromide (1.0 mmol), ethyl 2-pyridylacetate (0.6 mmol), Lewis acid (0.2 equiv), base (1.0 equiv), 12 h.
b
c
Determined by GC.
Reaction at 60 °C.
Reaction at 120 °C.
d
Table 2
Substrate scope of 2,3,4-trisubstituted furansa,b
O
O
Br
O
N
O
AgNO3, DABCO
DMSO, 100 °C
+
R
N
O
R
1
2a
3
O
O
O
O
O
N
N
N
3b
, 85%
3c
, 84%
3a
, 88%
O
O
O
O
O
O
N
N
N
Br
F
Cl
3f
3e
, 80%
, 78%
3d
, 75%
O
O
O
O
O
Cl
O
N
N
N
O
3g
3h
3i
, 85%
, 75%
, 76%
O
O
O
O
N
N
3j
, 70%
3k
, 73%
a
Reactions were carried out using haloalkynes (1.0 mmol), ethyl 2-pyridylacetate (0.6 mmol), AgNO3 (0.2 equiv), DABCO (1.0 equiv), 100 °C, 12 h.
Isolated yields.
b
recent years, such as cycloaddition reactions,3 carbon–hydrogen
chemical transformations6 and also a very useful precursor to the
synthesis of heterocycles.7 Thus, the development of new reaction
systems to achieve efficient and selective nucleophilic addition for
heterocycle construction is still highly desirable.
functionalization reactions,4 and nucleophilic addition reactions.5
The vinyl halides generated by nucleophilic addition of haloalkynes
are very important intermediates that can undergo numerous

W. Zeng et al. / Tetrahedron Letters 54 (2013) 4605–4609
4607
Table 3
Substrate scope of 2,3,4-trisubstituted furansa,b
O
O
X
N
O
AgNO3, DABCO
DMSO, 100 °C
+
R
N
O
R
4
1
2b
X = Br, I
O
O
O
O
O
O
N
N
N
4c, X=Br 80%
4b, X=Br 86%
4a, X=Br 88%
X=I 64%
X=I 65%
X=I 70%
O
O
O
O
Cl
O
O
N
N
N
Br
Cl
4f, X=Br 73%
4d, X=Br 78%
X=I 61%
4e, X=Br 77%
X=I 55%
X=I 62%
O
O
N
4g, X=Br 79%
X=I 60%
a
Reactions were carried out using haloalkynes (1.0 mmol), methyl 2-pyridylacetate (0.6 mmol), AgNO3 (0.2 equiv), DABCO (1.0 equiv), 100 °C, 12 h.
Isolated yields.
b
Substituted furans are ubiquitous in biologically active mole-
with the above results, DMSO was found to be the most suitable
solvent. The temperature was then examined, and 100 °C was opti-
mal for this reaction (entries 15 and 16).
cules8 and have also been used as building blocks for both hetero-
cyclic and acyclic compounds.9 Consequently, the synthesis of
furans has attracted extensive interest.10 In particular, transition
metal-catalyzed nucleophilic addition of carbon–carbon triple
bond has proved to be a versatile method for the construction of
substituted heterocycles.11 In which, the transition metals usually
function as a Lewis acid to activate the carbon–carbon multiple
With the optimized conditions in hand [phenylethynyl bromide
(1.5 mmol), ethyl 2-pyridylacetate (1.0 mmol), AgNO3 (0.2 equiv),
and DABCO (1.0 equiv), 100 °C, 12 h], we then explored the sub-
strate scope of different arylethynyl bromides (Table 2). Aromatic
alkynylbromides with either electron-donating or electron-with-
drawing groups on the benzene ring were able to generate the cor-
responding products in excellent yields. The reaction conditions
were compatible with alkyl, alkoxy, and halogen groups on the
benzene ring, providing the corresponding products in good yields
(3a–3i). Fortunately, aryl- and cyclohexyl-substituted alkynyl bro-
mides were also suitable substrates for this transformation and
gave the desired furans 3j and 3k in 70% and 73% yields,
respectively.
To demonstrate the efficiency and generality of this process, we
have examined the transformation with haloalkynes (bromoalky-
nes and iodoalkynes) and methyl 2-pyridylacetate (2b) under the
optimized reaction conditions. As shown in Table 3, with 2b as
the starting material, aromatic alkynyl bromides and iodides with
either an electron-donating or electron-withdrawing group on the
benzene ring were able to transform into the corresponding prod-
ucts in moderate to good yields (55–88%). Generally, the alkynyl
bromides gave better results than those of alkynyl iodides, which
was due to the reason that the alkynyl iodides were likely to
bonds via
p-binding, thus facilitating the nucleophilic addition
process.12 As our continuing research programs on haloalkyne
chemistry and furan synthesis,5a,5b,13,14 herein, we report an effi-
cient method for the construction of 2,3,4-trisubstituted furans
via a sequential Ag-catalyzed nucleophilic addition and cyclization
reaction of haloalkynes.
We first studied the reaction of phenylethynyl bromide (1a) and
ethyl 2-pyridylacetate (2a) in DMSO using Ag2O as the Lewis acid
and Li2CO3 as the base. To our delight, the desired furan 3a was ob-
tained in 45% GC yield (Table 1, entry 1). This result prompted us to
screen suitable reaction conditions (Table 1). After Lewis acid eval-
uation, we found that AgNO3 was the best choice and afforded 3a
in 60% GC yield (entry 5), while other Lewis acids just led to mod-
erate or low yields (entries 1–6). Further investigation revealed
that the base played a critical role for this transformation (entries
7–10). Cs2CO3 and t-BuOK were less effective, and DBU just gave
moderate yields, while DABCO was the best choice. The effects of
different solvents were also studied (entries 11–14). Compared

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W. Zeng et al. / Tetrahedron Letters 54 (2013) 4605–4609
O
O
O
O
AgNO3 (15 mol %)
O
Cs2CO3 (2.0 equiv)
O
+
1
O
O
+
DMF, 80 oC, 8 h
O
5
5a
5a'
51%
5a:5a' = 10:1
Scheme 1. Reaction of ethyl benzoylacetate.
O
O
Br
N
O
AgNO3
+
(a)
N
DMSO, 100 o
C
O
3a, 31%
1a
2a
O
O
Br
N
O
DABCO
+
(b)
N
DMSO, 100 oC
O
3a, 0%
1a
2a
Scheme 2. Control experiments.
O
Br
O
N
1a
3a
O
-HBr
O
DABCO
[Ag]
DABCO
N
O
2a
N
OH
Br
O
N
O
Br
C
A
DABCO
O
N
OH
Br
B
Scheme 3. Proposed mechanism.
undergo the head-to-head dimerization coupling and generate the
1,4-diphenylbuta-1,3-diyne side products.15
We also examined the reaction of ethyl benzoylacetate with
phenylethynyl bromide, and the furan products 5a and 5a0 could
be obtained in 51% isolated yield. The ratio of 5a:5a0 is 10:1 (esti-
mated by the integral of 1H NMR, see Supplementary data for de-
tails). We suspected that the side product 5a0 might be generated
through the enol–ketone equilibrium in the ester carbonyl group
(Scheme 1).
To further gain a mechanistic insight into the process of this
reaction, several competition experiments were conducted. As
shown in Scheme 2, the reaction was less effective in the absence

W. Zeng et al. / Tetrahedron Letters 54 (2013) 4605–4609
4609
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AgNO3 (Scheme 2b).
16
On the basis of our experimental data and previous reports,11d
,
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a plausible reaction mechanism for the synthesis of furans is illus-
trated in Scheme 3. First, the vinyl bromide intermediate A was gen-
erated via an intermolecular nucleophilic addition of ethyl 2-
pyridylacetate to phenylethynyl bromide, promoted by DABCO
and AgNO3. Subsequently, B would undergo the enol–ketone equi-
librium to provide intermediate C. Finally, the carbon–oxygen bond
formation occurred with the loss of HBr to afford the corresponding
product 3a.
In summary, we have developed a highly efficient approach for
the synthesis of 2,3,4-trisubstituted furans via a sequential nucle-
ophilic addition and cyclization reaction of 2-pyridylacetic acid es-
ters and haloalkynes. This method exhibits a good aryl group
tolerance and provides the corresponding products in high yields
and regioselectivity. Furthermore, the readily available starting
materials and mild reaction conditions are some of the additional
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Acknowledgments
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We are grateful to the National Natural Science Foundation of
China (Nos. 21172076 and 20932002), the National Basic Research
Program of China (973 Program) (2011CB808600), the Guangdong
Natural
Science
Foundation
(10351064101000000,
S2012040007088), China Postdoctoral Science Foundation
(2012T50673), and the Fundamental Research Funds for the Cen-
tral Universities (2012ZP0003 and 2012ZB0011).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.140.
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