Novel one-pot synthesis of 3-Phenylnaphtho[2,3-b]furan and 3-phenylbenzofurans under microwave irradiation and solvent-free conditions

Article abstract of DOI:10.1080/00397910902883702

A one-pot synthesis of functionalized benzofurans has been developed via O-alkylation, carbon-carbon coupling/cyclization, and dehydration/olefination tandem reactions from phenacyl bromide and phenols under microwave irradiation and solvent-free conditio

Full text of DOI:10.1080/00397910902883702

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Novel One-Pot Synthesis of 3-
Phenylnaphtho[2,3-b]furan and
3-Phenylbenzofurans Under
Microwave Irradiation and
Solvent-Free Conditions
Zhongxing Wang a , Jinzhong Gu a , Huanwang Jing a
& Yongmin Liang a
a State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu, China
Published online: 16 Oct 2009.
To cite this article: Zhongxing Wang , Jinzhong Gu , Huanwang Jing & Yongmin
Liang (2009) Novel One-Pot Synthesis of 3-Phenylnaphtho[2,3-b]furan and 3-
Phenylbenzofurans Under Microwave Irradiation and Solvent-Free Conditions,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:22, 4079-4087, DOI: 10.1080/00397910902883702
To link to this article: http://dx.doi.org/10.1080/00397910902883702
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Synthetic Communications1, 39: 4079–4087, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902883702
Novel One-Pot Synthesis
of 3-Phenylnaphtho[2,3-b]furan
and 3-Phenylbenzofurans Under Microwave
Irradiation and Solvent-Free Conditions
Zhongxing Wang, Jinzhong Gu, Huanwang Jing,
and Yongmin Liang
State Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University, Lanzhou, Gansu, China
Abstract: A one-pot synthesis of functionalized benzofurans has been developed
via O-alkylation, carbon–carbon coupling=cyclization, and dehydration=
olefination tandem reactions from phenacyl bromide and phenols under micro-
wave irradiation and solvent-free conditions in the presence of mineral-supported
reagent and inorganic base. The best selectivity for forming benzofuran product
has been achieved with Na2CO3 as a base. The order of activity of inorganic
base is as follows: K2CO3 > NaHCO3 > Na2CO3 > KHCO3 > Na2SO3 > KOH >
K3PO4 > NaOH > KH2PO4 > KOAc. This novel synthesis features three new
bonds and one ring system assembled in a single step.
Keywords: Benzofurans, microwave assisted, one pot, solid phase, tandem
reaction
INTRODUCTION
Benzofurans have attracted considerable interest in light of their biological
activity and their presence in a variety of significant natural products.[1,2]
Some of them were used as drugs. Consequently, a number of synthetic
Received December 1, 2008.
Address correspondence to Huanwang Jing, State Key Laboratory of Applied
Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, Gansu 730000, China. E-mail: hwjing@lzu.edu.cn
4079

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Z. Wang et al.
Scheme 1. Solid-state synthesis of phenyl ethers (I).
Scheme 2. MW-assisted solid-state synthesis of 3-phenylbenzofurans (II).
strategies have been developed.[3,4] However, the syntheses of benzofurans
generally taken place under harsh reaction conditions using hazardous
reagents and requiring a longer reaction time.
Microwave-assisted organic synthesis (MAOS) has been a powerful
technology in recently years since Gedye and co workers and the group
of Giguere and Majetich independently demonstrated its usefulness in
1986, and it has been applied in both academia and industry to develop
new methodologies and to discover new reactions including heterocyclic
ring-formation reactions.[5] In addition, the combination of microwave
irradiation with the use of mineral-supported reagents (MSR) under
solvent-free conditions provides more convenient pathways with advan-
tages such as enhanced reaction rates, greater yields, greater selectivity,
and ease of manipulation.[6–8]
We have reported a concise synthesis of phenyl ethers under
solvent-free conditions at room temperature by simply grinding the
mixture of phenols, alkyl bromides, and catalyst (Scheme 1).[9] We
describe herein a one-pot, microwave-assisted, solid-state synthesis of
3-phenylbenzofurans using an MSR on neutral Al2O3 (Scheme 2).
RESULTS AND DISCUSSION
The 2-naphthol was first chosen as a substrate in our investigations.
We found that it was able to react with phenacyl bromide using 1,4-
diazabicyclo[2,2,2]octane (DABCO) as catalyst and neutral Al2O3 as a
mineral-supported reagent to directly yield 3-phenylnaphtho[2,3-b]furan
with good yield along with little phenyl ether as a by-product under
microwave irradiation (Table 1, entry 1). Surprisingly, we also observed

Microwave-Assisted Synthesis of Benzofurans
4081
Table 1. Effect of inorganic base on the synthesis of 3-phenylnaphtho[2,3-b]furan
Entry
Base
Benzofuran yield (%)a
Phenyl ether yield (%)a
1
2
3
4
5
6
7
8
9
K2CO3=DABCO
K2CO3
77.3
80.4
70.4
58.7
10.7
75.9
68.1
39.1
32.6
38.0
27.5
10.5
9.9
<1
2.8
16.0
8.7
10.2
13.5
13.6
19.6
22.5
Na2CO3
Na2SO3
KOAC
NaHCO3
KHCO3
KOH
NaOH
K3PO4
KH2PO4
10
11
aIsolated yield.
Note. Reaction conditions: phenacyl bromide, 995 mg (5 mmol); naphthalene
(5 mmol); inorganic base (2.5 mmol); and Al2O3 (5.2 g).
that this reaction afforded benzofuran in better yields with the absence
of an organic base as catalyst (entry 2 vs. 1), which clearly indicates
the difference of the reaction outcomes between the simple grinding
method and the MAOS method. To select the best inorganic base for this
reaction, various inorganic bases were then tested for this microwave-
assisted reaction in the absence of organic base. The results revealed that
the Na2CO3 achieved the best selectivity for benzofuran formation,
and the order of the activity is as follows: K2CO3 > NaHCO3 >
Na2CO3 > KHCO3 > Na2SO3 > KOH > K3PO4 > NaOH > KH2PO4 >
KOAc (entries 3–11).
The various mineral-supported reagents were also applied to test
their catalytic ability for this reaction. The results in Table 2
Table 2. Effect of mineral-supported reagents on the synthesis of 3-phenyl-
naphtho[2,3-b]furan
Entry
MSR
Benzofuran yield (%)a
Phenyl ether yield (%)a
1
2
3
4
5
Neutral Al2O3
Basic Al2O3
Acid Al2O3
Silica gel
80.4
66.6
60.4
76.9
78.6
9.9
15.4
24.5
12.3
10.6
Molecular sieve
aIsolated yield.
Note. Reaction conditions: phenacyl bromide (5 mmol); naphthalene (5 mmol);
K2CO3; 350 mg (2.5 mmol); MSR (5.2 g).

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Z. Wang et al.
Table 3. Effect of base quantity on the synthesis of 3-phenylnaphtho[2,3-b]furan
Entry
K2CO3(mmol)
Benzofuran yield (%)a
Phenyl ether yield (%)a
1
2
3
4
5
6
7
2.0
2.5
4.0
5.0
7.5
10.0
15.0
71.3
80.4
45.7
38.2
15.6
7.1
4.5
9.9
38.5
47.2
61.9
75.9
81.0
—
aIsolated yield.
Note. Reaction conditions: phenacyl bromide (5 mmol); naphthalene (5 mmol);
Al2O3 (5.2 g).
demonstrate that neutral Al2O3 showed both the greatest selectivity and
greatest reactivity.
The quantity of inorganic base was next investigated for the synthesis
of 3-phenylnaphtho[2,3-b]furan and phenyl ethers. The results are sum-
marized in Table 3. Base quantity strongly affects the distribution of
these two products. For example, 2.5 equivalents of base is the best con-
dition for benzofuran formation (entry 2). On the other hand, less or
excess amount of base led to the decrease of benzofuran. The more excess
of base used, the more phenyl ether and the less benzofuran were
obtained (entries 1, 3–6). With the use of 15 equivalents of base, benzo-
furan formation was completely prohibited; instead, phenyl ether was
produced in the best yield (81%) (entry 7).
Furthermore, different microwave irradiation densities=powers were
also checked to select the best reaction condition, and the results are
Table 4. Effect of microwave power on the synthesis of 3-phenylnaphtho
[2,3-b]furan
Entry
Power (W)
Benzofuran yield (%)a
Phenyl ethers yield (%)a
1
2
3
4
5b
400
600
800
1000
30
54.5
65.5
80.4
63.5
63.8
23.9
19.1
9.9
17.5
17.8
aIsolated yield.
bCEM Discover instrument using an open vessel.
Note. Reaction conditions: phenacyl bromide, 995 mg (5 mmol); naphthalene
(5 mmol); Al2O3 (5.2 g); K2CO3, 350 mg (2.5 mmol).

Microwave-Assisted Synthesis of Benzofurans
4083
Table 5. One-pot synthesis of benzofurans via various phenols and phenacyl
bromide
Entry
1
Substrate
Benzofuran yield (%)a
80.4
Phenyl ether yield (%)a
9.9
2
77.7
7.2
3
4
41.3
38.7
43.3
36.9
5
6
7
20.6
21.6
21.2
52.0
49.6
35.3
42.6
8
9
45.5
32.0
50.5
—
10
11
88.3
Mixture
Mixture
aIsolated yield.
Note. Reaction conditions: phenacyl bromide, 995 mg (5 mmol); phenols
(5 mmol); Al2O3 (3 equivalents of substrate, w=w).

4084
Z. Wang et al.
listed in Table 4. When the microwave irradiation power was increased
from 400 W to 800 W, the yield of benzofuran was improved from 54%
to 80% (entries 1–3). However, when the microwave irradiation power
reached 1000 W, the yield of benzofuran decreased to 63.5% because of
the violent reaction condition that resulted in some decomposition
(entry 4). To better understand this reaction, a dedicated instrument
(CEM Discover) was used to carry out this one-pot reaction in an open
vessel. Unfortunately, even after more than 10 times of trial and error
with various microwave irradiation conditions, the yield of target product
was still low (entry 5). The reason might be the much higher density of
CEM, which caused the temperature of the reaction mixture to rise too
fast, compared with the domestic microwave oven. We observed that
when the temperature was increased to more than 150ꢀC, the reaction
mixture splashed out of the vessel. It was difficult to control the tempera-
ture and to keep it in a persistent range of 130–140ꢀC, the best reaction
temperature.
To further extend the scope of this reaction, several more substituted
phenols were screened with phenacyl bromide under optimum conditions.
The results are summarized in Table 5, and new compounds were fully
characterized. The result showed that the naphthols have more activity
and selectivity than other phenols (entries 1 and 2 vs. 3–11). In addi-
tion, the steric effect of substituents on the benzene ring is evident:
2-substituted phenols resulted in poor selectivity and reactivity (entries
6 and 7), and 3- and 4-substituted phenols have moderate selectivity
and reactivity (entries 3, 4, 8, and 9). The electron effect of benzene ring
was not a key factor in this reaction. The plain phenol has no reactivity
leading to benzofuran but only to phenol ether (entry 10). p-Nitrophenol
gave only a mass product that could not be isolated (entry 11).
EXPERIMENTAL
General Procedure for Preparation of Benzofurans
K2CO3 (2.5 mmol) and active Al2O3 were added to a solution of phenacyl
bromide (5 mmol) and corresponding phenol (5 mmol) in 1 ml of
dichloromethane. The resulting mixture was dried and placed in a flask
fitted with rubber plug, which had been punctured by a 12-gauge needle.
It was then placed in an unmodified household microwave oven and
irradiated for 5 min. The product was extracted with dichloromethane
and filtered. The solvent was evaporated under reduced pressure and
purified through column chromatography to give 3-phenylbenzofuran
and phenyl ether, respectively.

Microwave-Assisted Synthesis of Benzofurans
Data for New Compounds
4085
3-Phenylnaphtho[2,3-b]furan
1
White solid, mp 99–101ꢀC. H NMR (400 MHz, CDCl3): d ¼ 7.36 (t,
J ¼ 10.4 Hz, 1H), 7.45–7.53 (m, 4H), 7.60 (t, J ¼ 10.8 Hz, 1H), 7.68–7.76
(m, 2H), 7.92–7.97 (m, 3H), 8.19 (d, J ¼ 10.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d ¼ 100.42, 112.27, 123.43, 124.54, 124.61, 125.15,
126.24, 127.55, 128.24, 128.78, 128.82, 130.37, 130.58, 152.31, 155.32.
MS (EI) m=z: 94 (14), 122 (16), 215 (54), 244 (Mþ, 100). Anal. calcd.
for C18H12O: C, 88.50; H, 4.95. Found: C, 88.29; H, 4.99.
5-tert-Butyl-3-phenylbenzofunan
White solid, mp 77–80ꢀC. 1H NMR (400 MHz, CDCl3): d ¼ 1.39 (s, 9H),
6.99 (s, 1H), 7.34–7.36 (m, 2H), 7.42–7.46 (m, 3H), 7.58 (s, 1H), 7.85 (d,
J ¼ 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 31.84, 34.70, 101.48,
110.66, 117.07, 122.22, 123.66, 124.84, 126.68, 127.57, 128.97, 130.70,
141.50, 145.96, 153.15, 156.02. MS (EI) m=z: 77 (26), 103 (40), 165
(25), 220 (22), 235 (100), 250 (Mþ, 48). Anal. calcd. for C18H18O: C,
86.36; H, 7.25. Found: C, 86.45; H, 7.22.
CONCLUSION
In summary, we presented a reliable, rapid, and environmentally benign
method for synthesizing 3-phenylbenzofurans via a one-pot tandem reac-
tion combing O-alkylation, carbon–carbon coupling=cyclization, and
dehydration=olefination reactions of phenacyl bromide and phenols
under microwave irradiation and solvent-free conditions. This novel
methodology constructs three new bonds and one ring system in a single
step. It may also be useful for fabricating similar heterocycles such as
3-phenylbenzothiophins and 3-phenylindoles when the phenols are
replaced by thiols or amines, respectively. Further investigations to clar-
ify the mechanism of this reaction and its applications for synthesis of
other heterocycles are ongoing in our laboratory.
ACKNOWLEDGMENT
We are grateful for the financial support of the National Natural Science
Foundation of China (NSFC 20773055 and 20021001).

4086
Z. Wang et al.
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