Synthesis of benzofurans in ionic liquid by a PdCl2-catalyzed intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2004.06.110

PdCl₂-catalyzed intramolecular Heck reaction was conducted in ionic liquid, 1-n-butyl-3-methylimidazolium tetraborate ([BMIm] BF₄), substituted benzofurans were obtained in modest to satisfactory yields. The ionic liquid containing Pd catalyst can be used four times with a little loss of activity.

Full text of DOI:10.1016/j.tetlet.2004.06.110

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6235–6237
Synthesis of benzofurans in ionic liquid by a PdCl2-catalyzed
intramolecular Heck reaction
Xingang Xie, Bo Chen, Jiangping Lu, Junjie Han, Xuegong She* and Xinfu Pan*
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 12 March 2004; revised 16 June 2004; accepted 25 June 2004
Abstract—PdCl2-catalyzed intramolecular Heck reaction was conducted in ionic liquid, 1-n-butyl-3-methylimidazolium tetraborate
([BMIm] BF4), substituted benzofurans were obtained in modest to satisfactory yields. The ionic liquid containing Pd catalyst can be
used four times with a little loss of activity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
One of the prime principles of green chemistry is to de-
velop an alternative reaction medium, which is the basis
for the development of many cleaner chemical technolo-
gies. Particularly, ionic liquids have recently gained rec-
ognition as possible environmentally safe alternatives to
volatile organic solvents. Ionic liquids, especially those
based on the 1-n-alkyl-3-methyl imidazolium cation,
have shown great promise as novel reaction medium
for various catalytic processes.1 And these types of ionic
liquids have been demonstrated to be ideal immobilizing
agents for various ÔclassicalÕ transition-metal catalyst
precursors in reactions to enhance the reaction rate
and selectivity.2 In addition the products can be ex-
tracted by n-hexane or diethyl ether, or simply be dis-
tilled from the reaction mixture, and this made the
workup very easy to conduct. Moreover, the ionic liq-
uids with the metal catalyst can be recovered and recy-
cled without any loss of activity for several times. Due
to these advantages, ionic liquids have been recognized
as the optimal green reaction medium in laboratories
and factories.
needed to activate the catalyst Pd(OAc)2. However,
the yields of benzofurans were not very satisfactory.
Probably due to the low reaction efficiency, the reaction
was scarcely used in practice.
Considering the unique property of ionic liquids, the
reaction may proceed well in ionic liquid in the absence
of the additional (Bu)4NCl. This prompted us to have a
try. 1-n-Butyl-3-methyl imidazolium tetrafluoroborate
[BMIm] BF4 was a popular and available ionic liquid
and it has shown enhanced reactivity and selectivity in
several Pd-catalyzed reactions.5 But according to our
knowledge, it has not been applied to this type of reac-
tion, so it was chosen as reaction medium. ortho-Iodo
benzyl allyl ether was chosen as the first reactant and
a more available and economic Pd source, PdCl2 as cat-
alyst. When ortho-iodo benzyl allyl ether was treated
with 5mol% PdCl2, 1.5equiv (n-Bu)3N and 1equiv
NH4OOCH at 60ꢁC for 24h, it disappeared completely
and the product 3-methyl benzofuran was obtained in
71% isolated yields (Scheme 1). The yield was much
higher than its initial yield in DMF (47%).4 After the
reaction, the product was extracted by diethyl ether
and purified by column chromatography on silica gel
as usual. Since the catalyst remained completely in the
It remained a problem to construct the framework of
benzofuran in synthesizing of natural products and
pharmaceutical products.3 Pd-catalyzed intramolecular
Heck reaction of ortho-iodo aryl allyl ether is an attrac-
tive method to synthesize benzofurans.4 It is needed to
maintain the reaction mixture at 80 ꢁC for a compara-
tively long time (2 days), and additional (Bu)4NCl was
5% PdCl2, (n-Bu)3N
NH4O2CH
O
I
O
[BMIm] BF4, 60°C, 24 h.
Keywords: Intramolecular Heck reaction; Benzofurans; Ionic liquid.
*
Corresponding authors. Fax: +86-(0)931-8912582; e-mail: shexg@
lzu.edu.cn
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.110

6236
X. Xie et al. / Tetrahedron Letters 45 (2004) 6235–6237
Table 1. Recycle of the catalyst systema
5% PdCl , (n-Bu) N
R
3
O
O
2
3
Isolated yield (%)b
R
2
NH O CH
4
2
R
Run
1
R
1
R
2
R
°
4
[BMIm] BF , 60 C, 24 h.
4
1
2
3
4
71
66
60
57
I
R
4
R
3
Scheme 2.
a All the experiments were done according to Ref. 6.
b The products were identified by 200M 1H NMR and mass spectro-
metry.
results were summarized in Table 2. As exhibited in
Table 2, all the substrates proceeded well and modest
to satisfactory yields were obtained. And it seemed that
the less hindered the double bond (entry 1) or the better
the aryl leaving group (entry 5), the lower the yield of
benzofuran. This observation was in agreement with
the original paper.4 And the yields of the substrates with
a substituent on the aryl group were lower, respectively.
However, the character of the substituent did not have a
significant effect on the reaction yields (entries 6–8).
When it was concerned with entry 9, a mixture was
obtained in which the desired product was obtained only
ionic liquid, the catalyst system can be reused. Then an-
other partial of substrate, (n-Bu)3N and NH4OOCH
were added and the reaction was repeated. As shown
in Table 1, the catalyst system still kept high activity
after recycling four times. It proceeded in 66%, 60%
and 57% yields when it was used in the following three
runs.
To extend the scope of this methodology, we applied it
to other ortho-iodo aryl allyl ether (Scheme 2) and the
Table 2. Cyclization of other ortho-iodo aryl allyl ether
Entrya
Substrate
Productb
Isolated yield (%)
71
O
I
O
O
1
O
2
3
87
85
I
O
O
I
O
n-C7H15
O
n-C7H15
4
5
78
45
I
I
O
O
O
O
6
7
54
51
I
O
O
MeOOC
I
MeOOC
I
I
O
O
I
8
9
43
21
Cl
Cl
OMe
OMe
O
O
I
OHC
OHC
a All experiments were done according to Ref. 6.
b The products were identified by 200M 1H NMR and mass spectrometry.7

X. Xie et al. / Tetrahedron Letters 45 (2004) 6235–6237
6237
3. (a) McKittrick, A.; Steveson, R. J. Chem. Soc., Perkin
Trans. 1, 1983, 475–482; (b) Kraus, G. A.; Ning, Z.; John,
G. V.; Muthuka-man, N.; Philip, B. K. Org. Lett. 2000, 2,
2409–2410; (c) Sammelson, R. E.; Kurth, M. J. Chem. Rev
2001, 101, 137–202; (d) Yun, L.; Michael, R.; Yan, Z.;
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4. Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29,
4687–4690.
in 21% yields probably due to the affection of methoxy
group and aldehyde group on the aryl group.
In summary, we have developed an environmentally
friendly method to synthesize benzofurans. One major
advantage of our protocol is that the catalyst system
can be recycled and the green character of the ionic
liquid. This lowered the reaction temperature and
shortened the reaction time with satisfying yields. So
the reaction efficiency was greatly improved and it
may have great potential to construct the framework
of benzofuran in synthesizing of natural products and
pharmaceutical products.
5. Yogesh, R. J. Synlett 2004, 4, 746–747.
6. General procedure: 1mmol ortho-iodo aryl allyl ether,
1.5mmol (n-Bu)3N and 1mmol NH4OOCH and 0.05mmol
PdCl2 were added to 1.5mL [BMIm]BF4. The mixture was
heated to 60ꢁC and maintained for 24h. When the mixture
was cooled to room temperature, it was extracted by diethyl
ether (15mL·3). The Pd catalyst was kept and suspended
in the ionic liquid layer. The diethyl ether layers were
collected and concentrated in vacuum. Then the crude
mixture was purified by column chromatography on silica
gel to give the pure benzofurans.
Acknowledgements
7. The spectral data of some products. Product 1: 1H
NMR(200M, CDCl3): d=2.23(s, 3H), 7.18–7.53(m, 5H).
MS (EI): m/z(%)=132(70), 131(100), 103(43), 77(56). Prod-
This work was supported by the National Science foun-
dation (No. 20372026), NSFC (QT program), Gansu
Science foundation (No. YS031-A21-001) and Lanzhou
University foundation (No. 5715220101).
1
uct 4: H NMR(200M, CDCl3): d=0.85(t, J=4.3Hz, 3H),
1.27(m,10H), 1.67(t, J=3.0Hz, 2H) 2.63(s, 3H) 7.22–
7.52(m,4H). MS (EI): m/z(%)=358(100), 297(18), 233(22).
Product 6: 1H NMR(200M, CDCl3): d=1.29 (d, J=3.5Hz,
6H), 2.23(s, 3H), 3.02(m, 1H), 7.14–7.38(m, 3H). MS (EI):
m/z(%)=174(35), 159(100), 131(11). Product 7: 1H
NMR(200M, CDCl3): d=2.25(s, 3H), 3.91(s, 3H), 7.44–
8.01(m,3H), 8.26(s, 1H). MS (EI): m/z(%)=190(50),
159(100), 131(36), 103(14). Product 8: 1H NMR(200M,
CDCl3) d=2.19(s, 3H), 7.24–7.46(m, 2H), 7.62(s, 1H). MS
(EI): m/z(%)=292(100), 165(15), 137(14), 127(27).
References and notes
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Chem. Rev. 2002, 102, 3667–3692.