An efficient procedure for the synthesis of 3-aryl-4-methoxy-2(5H)-furanones by using the microwave-promoted Suzuki-Miyaura coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2006.08.052

The Suzuki-Miyaura coupling reactions of 3-bromo-2(5H)-furanones with a variety of arylboronic acids, promoted by microwave heating, efficiently generate 3-aryl-2(5H)-furanones. This remarkably rapid process serves as the foundation for a simple method to

Full text of DOI:10.1016/j.tetlet.2006.08.052

Tetrahedron Letters 47 (2006) 7427–7430
An efficient procedure for the synthesis of
-aryl-4-methoxy-2(5H)-furanones by using the
3
microwave-promoted Suzuki–Miyaura coupling reactions
Young Seob Song, Yun-Jeong Lee, Bum Tae Kim and Jung-Nyoung Heo*
Bioorganic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
Received 25 July 2006; revised 11 August 2006; accepted 17 August 2006
Abstract—The Suzuki–Miyaura coupling reactions of 3-bromo-2(5H)-furanones with a variety of arylboronic acids, promoted by
microwave heating, efficiently generate 3-aryl-2(5H)-furanones. This remarkably rapid process serves as the foundation for a simple
method to rapidly construct 3-aryl-2(5H)-furanone libraries.
Ó 2006 Elsevier Ltd. All rights reserved.
Molecules possessing the 2(5H)-furanone moiety, a
frequently found substructure in natural products and
biologically active compounds, have received consider-
Clearly, the search for 2(5H)-furanone containing sub-
stances that possess the same levels of COX-II inhibi-
tory activity as Vioxx, but have fewer side effects,
remains a significant challenge. The most common
among the limited number of methods available
for the preparation of 3-aryl-4-methoxy-2(5H)-fura-
nones 3 are thermal, photolytic, and oxidative ring
1
able attention in the contexts of plant protection, anti-
2
3
4
fungal, antibacterial, and anti-inflammatory agents.
Especially interesting in this regard are incrustoporin
(
5
6
Ò
1) and rofecoxib 2 (Vioxx ), which exhibit potent
7
fungicidal and selective COX-II inhibitory activity,
respectively. Even though Vioxx has been recently re-
called from the market, questions remain about whether
the net benefits of the drug outweigh its risks. It is has
been reported that some osteoarthritis and rheumatoid
arthritis sufferers claim that Vioxx is the only drug that
alleviates pain without causing severe ulcers.
expansion reactions of 4-hydroxy-2-cyclobutenones.
Another route for the synthesis of these compounds
involves the regioselective K-Selectride reduction of
8
substituted maleic anhydrides. Although both of these
procedures produce 3-aryl-4-methoxy-2(5H)-furanones
in high yields with high regioselectivities, a general,
efficient approach that enables the introduction of a
wide variety of substituents at the C-3 position is
desirable.
O
Me
CH3
S
R
O
9
OMe
The Suzuki–Miyaura coupling reaction appears to offer
O
the most direct approach for rapid construction of 3-
O
O
10,11
substituted-2(5H)-furanones.
Worthington and his
O
O
co-workers described the Suzuki–Miyaura reaction of
-bromo-5-methyl-2(5H)-furanone that affords 3-aryl-
O
Me
-)-Incrustoporin (1)
3
®
12
(
Rofecoxib (Vioxx , 2)
3
furanones. However, the yields of these processes were
unsatisfactory (36–56%) even when microwave heating
conditions were employed. Based on the results of our
recent investigations of the Suzuki–Miyaura coupling
1
3
14
reactions, we felt that the use of microwave heating
to accelerate the process would enhance reaction
efficiencies and lead to a functional group tolerant meth-
odology that would enable a high-speed construction of
3-substituted-2(5H)-furanones. In order to provide
Keywords: Suzuki reaction; Palladium; Boronic acids; Microwave;
Furanones; Tetronates; Butenolides.
*
Corresponding author. Tel.: +82 42 860 7085; fax: +82 42 861
307; e-mail: heojn@krict.re.kr
0
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.052

7428
Y. S. Song et al. / Tetrahedron Letters 47 (2006) 7427–7430
OMe
OMe
Br
that the use of H O as a co-solvent would positively
impact this process. Indeed, the reaction of 3-bromo-
2
Br , CH Cl
2
o
2
2
0
C, 3 h;
2
(5H)-furanone 5 with phenylboronic acid in 4:1 diox-
O
O
then Et N, rt, 3 h
3
ane/H O provided the coupling product 7a in 74% yield
2
O
4
O
5
80%
(
entry 7). When Pd(PPh ) and Na CO were employed
3 4 2 3
to promote the reaction in this solvent system, the yield
of 7a increased to 76% yield (entry 8). Finally, the opti-
mal yield of 85% was obtained when 2.4 equiv of
Na CO was used (entry 9); but it is important to note
Scheme 1.
2
3
that small changes in the amount of the base employed
lead to variations in reaction efficiencies in the range of
76–85%.
support for this proposal, we have investigated the
microwave-promoted Suzuki–Miyaura coupling reac-
tions of 3-bromo-4-methoxy-2(5H)-furanone (5) with
arylboronic acids.
With the optimized reaction conditions in hand, the
Suzuki–Miyaura reactions of 3-bromo-2(5H)-furanone
5 with a wide range of arylboronic acids were explored.
The results (Table 2) demonstrated that these processes
produced coupling products 7a–l in moderate to high
The starting 3-bromo-4-methoxy-2(5H)-furanone (5)
was prepared in a high yield via sequential bromination
and base-mediated elimination reactions of commer-
cially available 4-methoxy-2(5H)-furanone (4) (Scheme
1
6
yields. The coupling reactions took place with both
electron-deficient (entries 4–6) and electron-rich (entries
2 and 8) arylboronic acids. In addition, the Suzuki–
Miyaura coupling reactions of 5 with the sterically
demanding substrates (entries 9 and 10), such as the
ortho-methyl- and ortho-fluorophenylboronic acids, pro-
ceeded to afford the corresponding coupling products 7i
and 7j in respective yields of 67% and 65%. However,
the process was less effective with 2-thienylboronic
acid, giving the coupling product 7l in 52% yield
(entry 12).
1
5
1
). The Suzuki–Miyaura reactions of 3-bromo-2(5H)-
furanone 5 with phenylboronic acid (6a) in the presence
of several palladium catalysts were explored. The data
given in Table 1 illustrate that the use of Pd(PPh3)4
(
4 mol %) in combination with Cs CO (3.0 mol-equiv)
2 3
in 1,4-dioxane and microwave irradiation at 150 °C for
5
min (entry 1) led to the formation of 4-methoxy-3-
phenyl-2(5H)-furanone (7a) in 42% yield. We observed
that the use of aprotic polar solvents, such as CH CN
3
and DMF, gave lower reaction efficiencies (entries 2
and 3). When the reactions were carried out employing
a
palladium(II) precursor catalyst, such as
In summary, we have demonstrated that the Suzuki–
Miyaura reactions of 3-bromo-4-methoxy-2(5H)-
furanone with arylboronic acids, under microwave
irradiation conditions, serves as a general and highly
efficient method for the synthesis of 3-aryl-4-methoxy-
2(5H)-furanones. Further studies are underway in
our laboratory to evaluate the biological properties
of the 2(5H)-furanones produced in the current
effort.
Pd(PPh ) Cl , the yields increased (entries 4–7). Also,
changing the base from Cs CO to K CO caused a
3
2
2
2
3
2
3
small increase in the yield of the formation of 7a (entry
) and the use of K PO as a base led to a further
5
3
4
improvement in the yield to 66% (entry 6).
Previous observations made in our earlier studies of the
Suzuki–Miyaura reaction in aqueous media suggested
1
3
a
Table 1. Suzuki–Miyaura coupling of 3-bromo-4-methoxy-2(5H)-furanone with phenylboronic acid
OMe
Br
OMe
PhB(OH) (1.2 eq)
2
Pd catalyst (4 mol%)
base
O
O
o
MW, 150 C, 5 min
O
O
5
7a
b
Entry
Pd Source
Base
Solvents
Dioxane
CH CN
3
DMF
Dioxane
Dioxane
Dioxane
Dioxane/H
Dioxane/H
Dioxane/H
Dioxane/H
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
3
3
3
3
3
3
)
4
)
4
)
4
)
2
)
2
)
2
)
2
)
4
)
4
)
4
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
3
3
3
3
42
26
0
c
Cl
Cl
Cl
Cl
2
2
2
2
55
60
66
74
76
85
78
K
2
K
3
K
3
CO
PO
PO
3
4
4
2
O (4/1)
2
O (4/1)
2
O (4/1)
2
O (4/1)
Na
Na
Na
2
2
2
CO
CO
CO
3
3
3
(2.4 equiv)
(1.8 equiv)
10
a
b
c
2 3 4
Reaction conditions: 5 (1.0 mmol), PhB(OH) (1.2 mmol), Pd(PPh ) (4 mol %), base (3.0 mmol), microwave 150 °C, 5 min.
Isolated yields.
Furanone 5 was not recovered and biphenyl was obtained as a major product.

Y. S. Song et al. / Tetrahedron Letters 47 (2006) 7427–7430
7429
a
Table 2. Suzuki–Miyaura coupling of 3-bromo-4-methoxy-2(5H)-furanone with boronic acid
OMe
Br
Ar-B(OH) (1.2 eq)
OMe
Ar
2
Pd(PPh ) (4 mol%)
3
4
Na CO (2.4 eq)
O
2
3
O
dioxane/H O
2
O
5
o
O
7
MW, 150 C, 5 min
b
Entry
1
Boronic acid
HO) B
Product
Yield (%)
OMe
(
2
6a
7
a
85
O
O
OMe
2
3
(HO) B
OMe 6b
OMe 7b
76
70
2
O
O
OMe
(HO) B
Cl
6c
Cl
7c
2
O
O
OMe
4
5
6
7
8
9
(HO) B
CF3 6d
CF3 7d
67
68
60
70
77
2
O
O
OMe
(
(
(
(
HO) B
2
6e
6f
7e
7f
O
O
F
F
OMe
HO) B
2
O
O
CN
CN
OMe
HO) B
2
6g
7g
O
O
OBn
OBn
OMe
HO) B
O
2
6h
O
O
7h
O
O
O
OMe
(
(
HO) B
F
2
6i
F
7i
67
65
O
Me
F
O Me
OMe
HO) B
2
1
1
0
1
6j
7j
O
O
O
F
OMe
(
HO) B
2
6k
7k
69
O
(
continued on next page)

7430
Y. S. Song et al. / Tetrahedron Letters 47 (2006) 7427–7430
Table 2 (continued)
b
Entry
Boronic acid
Product
Yield (%)
OMe
S
12
6l
S
7l
52
(
HO) B
2
O
O
a
Reaction conditions: 5 (1.0 mmol), ArB(OH)
50 °C, 5 min.
Isolated yields.
2
(1.2 mmol), Pd(PPh
3
)
4
(4 mol %), Na
2
CO
3
(2.4 mmol), dioxane/H
2
O (4 mL/1 mL), microwave
1
b
Acknowledgments
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We thank the Korea Research Institute of Chemical
Technology (KK-0601-A2) and the Ministry of Com-
merce, Industry, and Energy (TS056-09) for financial
support of these studies.
(
d) Kotha, S.; Lahiri, S.; Kashinath, D. Tetrahedron 2002,
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1
0. Pd-catalyzed acylation of 4-methoxy-3-tributylstannyl-2-
furanone has been described, see: (a) Ley, S. V.; Wads-
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the direct alkylation and acylation of 3-lithiated 4-alkoxy-
2-triisopropylsilyloxyfuranes, see: (b) Paintner, F. F.;
Allmendinger, L.; Bauschke, G. Synlett 2005, 2735, and
references cited therein.
References and notes
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TM
1
639.
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Biotage Initiator EXP
microwave reactor. To a
5
6
thick-wall borosilicate glass vial (10 mL) were added 3-
4
bromo-2(5H)-furanone 5 (1 mmol), Pd(PPh ) (4 mol %),
3
4
. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson,
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arylboronic acid (1.2 mmol), and Na CO (2.4 mmol)
2 3
sequentially. The mixture was dissolved in dioxane/H O
2
(4 mL/1 mL) and degassed with argon for 5 min. Then, the
reaction vial was sealed and placed in the microwave
reactor and irradiated at 150 °C for 5 min. After cooling to
room temperature, the mixture was diluted with EtOAc,
dried over MgSO , and filtered through Celite. The filtrate
4
was concentrated in vacuo giving a residue which was
1
999, 9, 1773.
subjected to silica gel flash column chromatography
(EtOAc/hexanes). The spectral data for 7c: H NMR
1
7
. Verniest, G.; De Kimpe, N. Synlett 2005, 947, and
references cited therein.
. (a) Kayser, M. M.; Breau, L.; Eliev, S.; Morand, P.; Ip, H.
S. Can. J. Chem. 1986, 64, 104; (b) Knight, D. W.;
Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1979,
(300 MHz, CDCl ) d 7.84 (d, 2H, J = 8.7 Hz), 7.39 (d, 2H,
3
1
3
8
J = 8.7 Hz), 4.87 (s, 2H), 4.01 (s, 3H);
C NMR
(125 MHz, CDCl ) d 173.2, 172.2, 133.2, 128.7, 128.4,
3
+
127.7, 101.6, 64.4, 58.0; MS (EI) m/z [M] for C H ClO :
1
1
9
3
62.
calcd 224.02, found 224 (100), 195 (62), 152 (65), 123 (25).