Synthesis of multisubstituted furans via copper-catalyzed intramolecular O-vinylation of ketones with vinyl bromides

Article abstract of DOI:10.1016/j.tetlet.2010.05.040

With the catalysis of CuI/3,4,7,8-tetramethyl-1,10-phenanthroline, various ketones smoothly underwent the intramolecular O-vinylation with vinyl bromides leading to the efficient synthesis of the corresponding multisubstituted furans.

Full text of DOI:10.1016/j.tetlet.2010.05.040

Tetrahedron Letters 51 (2010) 3678–3681
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Synthesis of multisubstituted furans via copper-catalyzed intramolecular
O-vinylation of ketones with vinyl bromides
Liqun Chen a, Yewen Fang b, Qiwu Zhao b, Min Shi a,b, Chaozhong Li b,
*
a School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
With the catalysis of CuI/3,4,7,8-tetramethyl-1,10-phenanthroline, various ketones smoothly underwent
the intramolecular O-vinylation with vinyl bromides leading to the efficient synthesis of the correspond-
ing multisubstituted furans.
Received 30 March 2010
Revised 10 May 2010
Accepted 11 May 2010
Available online 15 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Furans are important structural motifs in a number of biologi-
cally active natural products and medicinal agents such as naka-
domarin A1 and Sumiki’s acid.2 They are also versatile building
blocks in organic synthesis.3 Preparations of furans have long been
an important topic in organic chemistry and continue to be actively
pursued.4 Conventional methods include the Feist–Bénary reac-
tions and the Paal–Knorr furan synthesis.3 The recently developed
transition metal (Pd, Ru, and Au)-catalyzed cycloisomerization4b of
allenyl ketones,5 alkynones,6 alkynyl epoxides7, or (Z)-2-en-4-yn-
1-ols8 provides atom-economic entries to the corresponding fur-
ans. However, these methods suffer from either the limited scope
of application or the use of expensive catalysts. Hence, the devel-
opment of mild and general synthesis of furans is still highly desir-
able especially in view of industrial applications. Herein, we report
that the Cu(I)-catalyzed intramolecular O-vinylation of ketones
with vinyl bromides or even chlorides serves as a simple and effi-
cient method to the corresponding multisubstituted furans.
In the past decade, we have witnessed a rapid progress in the
formation of aryl C–O bonds via copper-catalyzed Ullmann cou-
pling between aryl halides and O-centered nucleophiles.9 The high
stability and low costs of the copper catalysts make these transfor-
mations attractive for industrial applications. By the appropriate
choice of copper source, ligand, base, and solvent, these reactions
have been developed to include a wide range of substrates under
mild conditions. Ketone enolates, alcohols, and even carboxylates
can be employed as the nucleophiles. This method has also been
extended to the inter-10 and intramolecular11,12 O-vinylation reac-
tions. Nevertheless, compared to O-arylation, the O-vinylation reac-
tions are much less explored. We recently reported the
intramolecular O-vinylation of b-ketoesters with vinyl bromides
leading to the efficient formation of five-, six-, and even seven-mem-
bered cyclic alkenyl ethers.12a When an ordinary ketone enolate was
used as the nucleophile, the corresponding furan was obtained via
the in-situ isomerization of the O-vinylation product. However,
the yield was very low (22%). This could be attributed to the much
more difficult enolization of simple ketones than b-ketoesters. Such
a phenomenon was also observed in the intramolecular O-arylation
reactions.13 Driven by our interest in copper-catalyzed intramolec-
ular vinylation reactions,12,14 we set out to further investigate the
O-vinylation reactions of ordinary ketones in order to develop these
coupling processes into a useful method for furan synthesis.
6-Bromo-1-phenylhept-6-en-3-one (1a) was thus chosen as the
model substrate for the optimization of reaction conditions
(Table 1). Compound 1a was first subjected to the following typical
conditions for Ullmann coupling: 10 mol % of CuI, 40 mol % of N,N0-
dimethylethylenediamine (L-1),15 3 equiv of Cs2CO3 in refluxing
dioxane. The expected furan 2a was obtained in only 5% yield while
most of the starting material remained unchanged (Table 1, entry
1). Changing the ligand to 2-isobutyrylcyclohexanone (L-2)16 or
L
-proline (L-3)17 did not help (Table 1, entries 2 and 3). With the
use of 1,10-phenanthroline (L-4),18 the yield of 2a was slightly
increased (Table 1, entry 4). When the ligand was switched to
3,4,7,8-tetramethyl-1,10-phenanthroline (L-5),10a we were de-
lighted to find that 2a was isolated in 57% yield (Table 1, entry
5). Extending the reaction time from 10 to 20 h led to the quanti-
tative formation of 2a (Table 1, entry 8). Furthermore, when the
amount of L-5 was reduced to 20 mol %, the same result was
achieved (Table 1, entry 9). The effect of bases was also screened
and Cs2CO3 turned out to be superior over K2CO3 and K3PO4 (Table
1, entries 5–7). Again, without the ligand or base, no reaction
occurred (Table 1, entries 10 and 11).
With the optimized conditions (Table 1, entry 9) in hand, we
then examined the generality of this method. The results are sum-
marized in Tables 2 and 3.19 In addition to 2,5-dialkyl-substituted
furans (2a, 2e, 2f, and 2j), 2-aryl-substituted furans 2b–d could
also be achieved in excellent yields. The reactions showed an excel-
lent tolerance toward functional groups such as NO2 (1f), Ac (1e),
* Corresponding author. Tel.: +86 21 5492 5160; fax: +86 21 5492 5099.
E-mail address: clig@mail.sioc.ac.cn (C. Li).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.040

L. Chen et al. / Tetrahedron Letters 51 (2010) 3678–3681
3679
Table 1
or CO2Me (1j). Substrates 1g and 1h having a 3-alkyl substituent
furnished the corresponding 2,3,5-trisubstituted furans 2g and
2h, respectively. However, the reactions were relatively slow, pre-
sumably because of the increased steric hindrance in the enoliza-
tion of ketones. As a comparison, the reaction of cyclohexanone
1i proceeded smoothly to give the bicyclic product 2i in a high
yield.
Optimization of reaction conditions
O
O
Conditions
Bn
Bn
Br
2a
1a
O
O
Compared to ketones 1, substrates 3 bearing a 3-aryl group
were much more reactive and the coupling proceeded at a much
lower temperature (THF, reflux), as illustrated in Table 3. The en-
hanced reactivity of 3 should be attributed to the fact that the
aryl-substitution makes the enolization of ketones 3 much easier.
3-Aryl-2,5-dialkyl-substituted furans 4a–d were thus isolated in
high yields under milder conditions. With cyclohexenyl bromide
3e as the substrate, the tetrasubstituted furan 4e was generated
in almost quantitative yield, demonstrating the high potential of
the intramolecular O-vinylation in the synthesis of multisubsti-
tuted furans.
MeHN
NHMe
CO2H
N
H
L-1
L-3
L-2
N
N
N
N
L-5
L-4
Entrya
Ligand (mol %)
Base
Time (h)
Yield (%)b
Besides ketones, aldehydes could also be utilized in the O-
vinylation reactions. As an example, the treatment of aldehyde
5 under the above-mentioned optimized conditions (Table 3)
afforded the corresponding 2,4-disubstituted furan 6 in 97% yield
(Eq. 1). Furthermore, vinyl chloride 7 also underwent intramolec-
ular O-vinylation to give the expected furan such 4a in high yield
(Eq. 2).
1
2
3
4
5
6
7
8
L-1 (40)
L-2 (40)
L-3 (40)
L-4 (40)
L-5 (40)
L-5 (40)
L-5 (40)
L-5 (40)
L-5 (20)
None
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
None
10
10
10
10
10
10
10
20
24
24
24
5
5
Trace
10
57
Trace
10
99
99
0
CuI (10 mol %)
L-5 (20 mol %)
O
O
9
10
11
Me
H
ð1Þ
L-5 (20)
0
Cs2CO3 (3 equiv)
THF, reflux, 12 h
Ph Br
5
Ph
a
6 (97%)
Conditions: 1a (0.3 mmol), CuI (0.03 mmol), ligand, base (0.6 mmol), dioxane
(10 mL), reflux.
b
Isolated yield of 2a based on 1a.
Table 2
O-Vinylation of ketones in refluxing dioxane
Entrya
Substrate
Product
Time (h)
Yieldb (%)
O
O
Me
R
R
Br
1
2
3
1a (R = BnCH2)
2a
2b
2c
2d
2e
2f
24
5
7
3
12
10
99
99
99
82
59
87
1b (R = Ph)
1c (R = 4-Me-C6H4)
1d (R = 4-Cl–C6H4)
1e (R = 4-Ac-C6H4CH2CH2)
1f (R = 4-NO2–C6H4CH2CH2)
4
5c
6c
O
O
Me
Ph
7
8
22
20
58
55
Ph
Me
Me
Bn
Me Br
2g
1g
O
O
Me
Me
Me
Bn Br
2h
2i
1h
O
O
9
12
20
85
98
Br
1i
O
Bn
Me
O
Me
Bn
10
MeO2C
Me CO2Me
Br
2j
1j
a
b
c
Reaction conditions: 1 (0.3 mmol), CuI (0.03 mmol), L-5 (0.06 mmol), Cs2CO3 (0.6 mmol), dioxane (10 mL), reflux.
Isolated yield based on 1.
20 mol % of CuI and 40 mol % of L-5 were used.

3680
L. Chen et al. / Tetrahedron Letters 51 (2010) 3678–3681
Table 3
O-Vinylation of ketones in refluxing THF
Entrya
Substrate
Product
Time (h)
15
Yieldb (%)
99
O
O
O
O
Me
Me
1
Ph
Me
4a
Bn
3a
Ph Br
Ph Br
Ph Br
O
2
3
24
15
99
99
Ph
3b
Ph
Me
Ph
4b
O
3c
4c
O
O
Me
Me
Br
4
11
10
70
99
4d
3d
3e
MeO
OMe
O
O
Me
Ph
5
Ph Br
4e
a
Reaction conditions: 3 (0.3 mmol), CuI (0.03 mmol), L-5 (0.06 mmol), Cs2CO3 (0.6 mmol), THF (10 mL), reflux.
Isolated yield based on 3.
b
5. For selected examples, see: (a) Alcaide, B.; Almendros, P.; Campo, T. M. Eur. J.
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A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kelin, A. V.; Gevorgyan, V. J. Am.
Chem. Soc. 2008, 130, 1440.
CuI (20 mol %)
O
O
Me
L-5 (40 mol %)
Me
Ph
ð2Þ
Cs2CO3 (2 equiv)
dioxane, reflux, 20 h
Ph Cl
7
4a (97%)
The above-described reactions dealt with the O-vinylation in a
5-exo-like mode. As an extension, the vinylation of ketone 8 in a
6-endo-like mode also proceeded smoothly to give the correspond-
ing pyran 9 in 94% yield (Eq. 3).
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Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450; (i) Evano, G.; Toumi, M.; Coste, A.
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O
Br
CuI (20 mol %)
L-5 (40 mol %)
Me
Ph
O
ð3Þ
Cs2CO3 (2 equiv)
dioxane, reflux, 43 h
Ph
8
9 (94%)
In conclusion, the chemistry detailed above has clearly demon-
strated that the Cu(I)-catalyzed intramolecular O-vinylation reac-
tions of ordinary ketones with vinyl halides offer a convenient
and efficient entry to multisubstituted furans. This should be of
important application in organic synthesis.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (Grant Nos. 20702060 and 20832006) and by the
Shanghai Municipal Committee of Science and Technology (Grant
No. 07XD14038).
12. (a) Fang, Y.; Li, C. Chem. Commun. 2005, 3574; (b) Fang, Y.; Li, C. J. Am. Chem.
Soc. 2007, 129, 8092; (c) Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.; Zhu, S.; Li, C.
Org. Lett. 2009, 11, 4084.
13. Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
14. (a) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035; (b) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365;
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Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 297.
4. (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955; (b) Brown, R. C. D. Angew. Chem., Int. Ed.
2005, 44, 850.
18. Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
19. Typical procedure for the Cu(I)-catalyzed intramolecular O-vinylation reactions:
The mixture of ketone 1j (102 mg, 0.30 mmol), CuI (6 mg, 0.030 mmol), L-5
(14 mg, 0.060 mmol), and Cs2CO3 (0.19 g, 0.60 mmol) in dioxane (10 mL) was
stirred at reflux for 20 h under nitrogen atmosphere. The resulting mixture was

L. Chen et al. / Tetrahedron Letters 51 (2010) 3678–3681
3681
cooled down to room temperature and filtered. The filtrate was then
concentrated in vacuo and the crude product was purified by flash
chromatography on silica gel with hexane/EtOAc (10:1, v:v) as the eluent to
give the pure product 2j as a colorless oil. Yield: 76 mg (98%). 1H NMR
(400 MHz, CDCl3) d 1.30 (3H, s), 2.23 (3H, s), 3.21 (2H, s), 3.62 (3H, s), 5.79–5.80
(1H, m), 5.85 (1H, d, J = 3.6 Hz), 6.81–6.83 (2H, m), 7.09–7.12 (3H, m). 13C NMR
(100 MHz, CDCl3) d 13.7, 20.6, 43.1, 48.3, 52.3, 106.2, 107.3, 126.5, 127.9, 130.3,
136.9, 151.3, 154.0, 174.6. IR (film):
(cmꢀ1) 3209, 2951, 1737, 1605, 1562,
1496, 1454, 1377, 1238, 1219, 1101, 1024, 786. EIMS: m/z (rel intensity) 258
(M+, 9), 199 (14), 181 (6), 167 (100), 139 (6), 118 (6), 107 (42), 91 (26), 65 (7),
43 (8). HRMS calcd for C16H18O3 (M): 258.1256. Found: 258.1255.
m