CuBr-catalyzed cascade reaction of 2-substituted-3-(1-alkynyl)chromones to synthesize functionalized 3-acylfurans

Article abstract of DOI:10.1016/j.tetlet.2013.04.070

A highly efficient CuBr-catalyzed domino reaction of 2-substituted-3-(1- alkynyl)chromones to synthesize functionalized 3-acylfurans has been developed. The reaction is mild, environmentally friendly and easily handled without the necessity for dry solvents and inert atmosphere.

Full text of DOI:10.1016/j.tetlet.2013.04.070

Tetrahedron Letters 54 (2013) 3410–3414
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuBr-catalyzed cascade reaction of 2-substituted-3-(1-alkynyl)chromones
to synthesize functionalized 3-acylfurans
⇑
Liping Huang, Feng Hu, Qingdong Ma, Youhong Hu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient CuBr-catalyzed domino reaction of 2-substituted-3-(1-alkynyl)chromones to synthesize
functionalized 3-acylfurans has been developed. The reaction is mild, environmentally friendly and easily
handled without the necessity for dry solvents and inert atmosphere.
Received 23 January 2013
Revised 12 April 2013
Accepted 17 April 2013
Available online 23 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
CuBr-catalyzed
Cascade reaction
3-Acylfuran
Highly efficient
Environment friendly
Introduction
nucleophile bond can be formed simultaneously. Based on these
intermediates, the synthesis of highly substituted furans through
Furans, which are naturally abundant,1 are widely used in
pharmaceuticals,2 fragrances,3 and flavors.4 As a class of impor-
tant heterocyclic compounds, they are also found useful as syn-
thetic intermediates or synthons in natural product syntheses5
and organic synthesis.1e,2e,6 Consequently, there has been contin-
ued interest in the development of efficient methods for the syn-
thesis of furans bearing multiple and diverse substitution
patterns.7 Since the general Friedel–Crafts acylation of furans oc-
curs exclusively at 2- and 5-positions in good yield,8 other ap-
proaches have been explored to construct 3-acylfurans.9 The
major reported synthetic protocols include photoreaction of fur-
an with aldehydes9a or arenecarbothioamides,9c cycloaddition of
1,3-dicarbonyl compounds with activated-olefins9b,9h and transi-
tion metal catalyzed transformation of 3-functionalized furan9e,9-
a transition metal, an acid catalyzed,10 or an electronphile-in-
duced11 cascade process has been reported recently. These tan-
dem processes, which use alcohol or water as O-based
nucleophile, could give highly substituted furans with an oxo-
substitutent in the 3-position.
Our research group has been focusing on functionalized 3-(1-
alkynl)chromones to synthesize highly substituted furans and
functionalized xanthones through acid-catalyzed10f,10g or base-
promoted cascade reactions respectively.10f,10g,12 In the acid-cata-
lyzed processes, we demonstrate that using CH3SO3H as the acid,
water as the nucleophile, and CuCl2 as the oxidant, a sequential
one-pot reaction of 3-(1-alkynyl)chromones through addition–
cyclization–oxidation, could construct the natural-product-like
scaffold furocoumarins in good yields.10f,10g Based on the current
plausible reaction mechanism, we hypothesized the transforma-
tion from 2-methyl-3-(1-alkynyl)chromone 1 could be promoted
by transition metal and water as the nucleophile through Michael
addition/cyclization to afford the corresponding product B (path
a).10b Alternatively, 1 could go through cyclization/nucleophilic at-
tack to give B (path b).10b Considering R3 was a nonhydrogen sub-
stitution, B might not be oxidized to undergo hydrolysis to give
functional 3-acylfurans 2 (Scheme 1).
f,9i,9j
or 1,3-dicarbonyl compounds.9k,9n,9 Considering reaction
conditions, synthetic steps, reagents with environmental concern
and synthetic utility, developing efficient methods for the syn-
thesis of functionalized 3-acylfurans remains to be necessary.
Herein, we reported CuBr-catalyzed cascade reaction of 2-substi-
tuted-3-(1-alkynyl)chromones to construct 3-acylfurans with
functionalized substitutions in good to excellent yields.
2-(1-Alkynyl)-2-alken-1-ones, which have
a
special
a,
b-unsaturated ketone skeleton with triple bond, are very
a
attractive units because a C–O bond and a remote carbon-
Results and discussion
To test the feasibility of this possible mechanism, we investi-
gated the reaction of 3-(4-methoxyphenyl)ethynyl)-2-methyl-
⇑
Corresponding author.
E-mail address: yhhu@mail.shcnc.ac.cn (Y. Hu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.070

L. Huang et al. / Tetrahedron Letters 54 (2013) 3410–3414
3411
OH
R1
R1
R3
O
H
R3
OH
R2
M
M
Michael
addition
R2
O
A
O
OH
B
Path a
M
R1
hydrolysis
-M
O
R2
OH
O
R2
O
R3
R1
1
H2O
R3
2
O
O
R1
-M
R1
hydrolysis
R2
M
Path b
R1
O
R3
O
H
1
M
O
R3
OH
R2
cylization
M
O
R2
B
O
R3
A'
H2O
Scheme 1. The proposed synthesis of 3-acylfurans.
Table 1
4H-chromen-4-one 1a with H2O under different reaction condi-
tions (Table 1). When the reaction was carried out under previ-
ous conditions, in which 0.2 equiv of CuCl was employed as
catalyst with 10 equiv of H2O in DMF at 90 °C, the desired prod-
uct 2a was isolated in 60% yield (Table 1, entry 1). When the
reaction was performed at 70 °C, it resulted in a satisfactory
yield of 77% (Table 1, entry 3). Among the Cu(I) salts (Table 1,
entries 3, 5, and 6), CuBr was most effective and gave 2a in
81% yield. CuBr2 could also catalyze the reaction albeit with infe-
rior yield (Table 1, entry 7). The yield of 2a was highest when
0.2 equiv of CuBr was employed (Table 1, entry 5). Examination
of different solvents revealed that DME afforded the best result
(Table 1, entries 11–14).
The observations described above showed that the optimized
conditions for production of 2a involved CuBr (0.2 equiv), H2O
(10 equiv) in DME at 70 °C for 10 h. The scope of this process
was explored (Table 2). Good to excellent yields were obtained
when R1 was an aromatic group on the acetylene moiety, and
there were no obvious electronic effects on the aromatic ring
(Table 2, entries 1–4). The reactions also proceeded smoothly
when R1 was a heterocycle or an aliphatic chain (Table 2, entries
5–8). It should be noted that when R1 had 5-pyrimidinyl substi-
tution, the desired product 2e could not be obtained due to the
poor solubility of 1e in DME. When replacing DME with DMF as
the solvent, 2e was generated in 89% yield. When the cyano
group of 1g existed, the reaction gave the low yield (Table 2, en-
try 7). The reason may be the coordination of copper with the
cyano13 to reduce the activity of alkyne. Reactions with different
substituents on the aryl ring of the 3-(1-alkynyl)chromones also
gave the good yields and exhibited the electronic effects obvi-
ously (Table 2, entries 9–10). Electron-withdrawing groups (1j)
in contrast to electron-donating groups (1i) on the arene ring
of chromone 1 (R2) at 4-position could facilitate the cascade
reaction and the final phenol product (2i) with electron-donating
group at 4-postion could be easily oxidized further.14 Finally,
Optimization of the reaction conditionsa
O
OMe
O
catalyst
O
solvent/H2O
HO
O
MeO
2a
1a
Entry
Catalyst (equiv)
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuBr (0.2)
CuI (0.2)
DMF
DMF
DMF
DMF
DMF
DMF
90
80
70
60 (24 h)
70
70
70
70
70
70
70
70
70
60
65
77
74
81
65
71
78
70
68
86
40
77
54
CuBr2 (0.2)
CuBr (0.1)
CuBr (0.5)
CuBr (1)
DMF
DMF
DMF
DMF
9
10
11
12
13
14
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
DME
MeCN
THF
1,4-Dioxane
70
a
The general reaction conditions: 1a (0.40 mmol), catalyst, and H2O (4 mmol) in
solvent (2 mL).
Isolated yield.
b
reactions took place well when R3 was ethyl, isopropyl or phenyl
(Table 2, entries 11–13). Notably, the steric effect of R3 had little
influence on the yield, so it was convenient to construct various
3-acylfurans by changing R3 substituent. Again, when R3 was
phenyl, the reaction was carried out in DMF for the same reason
of 1e.

3412
L. Huang et al. / Tetrahedron Letters 54 (2013) 3410–3414
Table 2
Synthesis of 3-acylfurans 2 from 2-alkyl-3-(1-alkynyl) chromones 1a
O
R1
R3
O
CuBr
R2
DME, H2O
70 oC
R2
R3
R1
O
O
HO
1
2
Entry
Substrate
Product
Yieldb (%)
OMe
O
O
1
86
O
1a
HO
2a
O
O
MeO
O
2
3
86
92
O
1b
HO
O
O
2b
O
1c
O
O
O
O
HO
2c
CF3
O
4
87
90
O
1d
HO
2d
F3C
N
O
O
N
5c
O
1e
N
N
2e
HO
O
O
O
S
6
7
8
76
61
80
O
1f
O
O
S
HO
O
2f
CN
1g
NC
O
O
O
O
2g
HO
1h
O
2h
O
HO
O
OMe
O
O
MeO
9
60
O
1i
2i
HO

L. Huang et al. / Tetrahedron Letters 54 (2013) 3410–3414
3413
Table 2 (continued)
Entry
Substrate
Product
Yieldb (%)
O
NO2
O
O
O2N
10
11
12
80
90
82
89
O
2j
1j
HO
O
O
O
1k
2k
2l
O
O
HO
O
O
1l
O
O
HO
Ph
O
13c
1m
O
O
Ph
HO
2m
a
The general reaction conditions: 1a (0.40 mmol), catalyst (0.02 mmol), and H2O (4 mmol) in solvent (2 mL).
Isolated yield.
The reactions were carried out in DMF.
b
c
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Conclusions
In conclusion, we have developed an efficient synthesis of mul-
ti-substituted 3-acylfurans through a CuBr-catalyzed cascade reac-
tion from simple 2-alkyl-3-(1-alkynyl)chromones. This cascade
process involves multiple reactions including 1,4-addition, cycliza-
tion and hydrolysis, which is mild, environmentally friendly and
easily handled without the necessity for dry solvents and inert
atmosphere. Further studies of this methodology and biological
evaluation of these compounds are under investigation.
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