Synthetic approach to polysubstituted furans: An efficient addition/oxidative cyclization of alkynoates and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo902375k

(Chemical Equation Presented) A novel and reliable method for the direct construction of polysubstituted furans is reported. The key transformation involves Sn(II)- and Cu(I)-involved addition/ oxidative cyclization of alkynoates and 1,3-dicarbonyl compounds in the presence of 2,3-dichloro-5,6- dicyano-benzoquinone.

Full text of DOI:10.1021/jo902375k

pubs.acs.org/joc
applied as pharmaceuticals and organic materials.1 Many of
Synthetic Approach to Polysubstituted Furans: An
Efficient Addition/Oxidative Cyclization of
Alkynoates and 1,3-Dicarbonyl Compounds
the naturally occurring furans have shown interesting biolo-
gical activities, such as antiallergic and antiasthamatic,2 as
well as cytotoxic and antitumor properties,3 antidiabetic
activity,4 and several other potentially useful activities.5 In
addition, furans are also present in important commercial
products such as dyes, essential oils, cosmetics, flavor, and
fragrance compounds.6
Our group recently focused on developing hydroalkyla-
tion and hydroamination of alkynes to construct heterocyc-
lic molecules catalyzed by palladium, copper, or base, but
these methodologies were never mentioned as oxidative
processes.7 Recently, Li and Zhang reported a new type of
cross-dehydrogenative-coupling (CDC) reaction under mild
conditions to construct diester ethers catalyzed by a combi-
nation of indium and copper catalysts in the presence of 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ).8 In view of the
convergent and modular nature of the transformation, we
were drawn to the prospect of utilizing of this methodology
to heterocycles construction. Herein, we apply this metho-
dology to construct furans in a way which has never been
reported in the literature. To the best of our knowledge,
reports about the synthesis of furan derivatives through an
oxidative process are rather rare, although there are many
strategies for their synthesis.9
Weibing Liu, Huanfeng Jiang,* Min Zhang, and
Chaorong Qi
School of Chemistry and Chemical Engineering, South China
University of Technology, 381 Wushan Road,
Guangzhou 510640, China
jianghf@scut.edu.cn
Received November 9, 2009
Our preliminary investigations were focused on the sys-
tematic evaluation of different catalysts for the desired
addition/oxidative cyclization of diethyl but-2-ynedioate
(1a) and 1-phenylbutane-1,3-dione (2a) (Table 1). As shown
in Table 1, the combination of SnCl2 and CuI afforded the
best result in 1,2-dichloroethane (DCE) (entries 1-4). Chan-
ging the counterion of copper salt or replacing Cu(I) with
Cu(II) led to inferior results (entries 5-8). We also investi-
gated the reactivity of some other oxidants, such as benzoyl
peroxide, PIDA, benzoquinone, etc., but the results were not
inspiring (entries 10-14). Among the various solvents ex-
amined, toluene, 1,2-dichloroethane (DCE), and dioxane
(entries 4, 15, and 16) were practical for this transformation.
When the reaction was carried out without oxidant (entry 9)
as well as with a decreased the dosage of DDQ (entry 22),
A novel and reliable method for the direct construction
of polysubstituted furans is reported. The key transfor-
mation involves Sn(II)- and Cu(I)-involved addition/
oxidative cyclization of alkynoates and 1,3-dicarbonyl
compounds in the presence of 2,3-dichloro-5,6-dicyano-
benzoquinone.
Furan derivatives widely occur as important structural
units in a variety of synthetic and natural sources that can be
(1) (a) Shevchenko, N. E. Chem. Heterocycl. Compd. 1999, 35, 164–166.
(b) Lipshutz, B. H. Chem. Rev. 1986, 86, 795–819. (c) Chakraborty, T. K.;
Arora, A.; Roy, S.; Kumar, N.; Maiti, S. J. Med. Chem. 2007, 50, 5539–5542.
(d) Corma, A.; Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411–2502. (e)
Gandini, A.; Belgacem, M. N. Prog. Polym. Sci. 1997, 22, 1203–1379. (f)
Lasseuguette, E.; Gandini, A.; Belgacem, M. N.; Timpe, H. J. Polymer 2005,
46, 5476–5483. (g) Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. J. Med.
(6) (a) Wong, H. N. C.; Yang, Y. Tetrahedron 1994, 50, 9583–9608.
(b) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687–7692.
(7) (a) Liu, W. B.; Jiang, H. F.; Zhu, S. F.; Wang, W. Tetrahedron 2009,
65, 7985–7988. (b) Liu, W. B.; Jiang, H. F.; Qiao, C. L. Tetrahedron 2009, 65,
2110–2115. (c) Liu, W. B.; Jiang, H. F.; Zhou, P.; Zhu, S. F. Synlett 2009, No.
20, 3295–3298. (d) Cao, H.; Wang, X. J.; Jiang, H. F. Chem.;Eur. J. 2008,
14, 11623–11633. (e) Cao, H.; Jiang, H. F.; Qi, C. R. Tetrahedron Lett. 2009,
50, 1209–1204. (f) Cao, H.; Jiang, H. F.; Yao, W. J. Org. Lett. 2009, 11, 1931–
1933. (g) Jiang, H. F.; Mai, R. H.; Cao, H. Org. Biomol.Chem. 2009, 7, 4943–
4953. (h) Zhu, Q. H.; Jiang, H. F.; Li, J. H. J. Comb. Chem. 2009, 11, 685–696.
(i) Zhu, Q. H.; Jiang, H. F.; Li, J. H. Tetrahedron 2009, 65, 4604–4613. (j)
Zhang, M.; Jiang, H. F.; Liu, H. L. Org. Lett. 2007, 9, 4111–4113. (k) Zhang,
M.; Jiang, H. F.; Wang, A. Z. Synlett 2007, No. 20, 3241–3218.
(8) Zhang, Y. H.; Li, C. J. Angew. Chem., Int. Ed. 2006, 45, 1949–1952.
(9) (a) Gu, Z. H.; Wang, X. K.; Shu, W.; Ma, S. M. J. Am. Chem. Soc.
2007, 129, 10948–10956. (b) Dudnik, A. S.; Sromek, A. W.; Rubina, M.;
Kim, J. T.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440–1452. (c) Xia,
Y. Z.; Dundnik, A. S.; Govorgyan, V.; Li, Y. H. J. Am. Chem. Soc. 2008, 130,
6940–6941. (d) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2005, 127, 10500–10501. (e) Dyker, G. Angew. Chem. 2000, 112, 4407–
4409. (f) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. 2006, 118, 8064–
8105. (g) Zhang, M.; Jiang, H. F.; Neumann, H.; Beller, M.; Dixneuf, P. H.
Angew. Chem., Int. Ed. 2009, 48, 1681–1684.
ꢀ
Chem. 1971, 111, 1147–1152. (h) Benahmed-Gasmi, A.; Frere, P.; Roncali, J.
J. Electroanal. Chem. 1996, 406, 231–234. (i) Frere, P.; Skabara, P. Chem.
ꢀ
Soc. Rev. 2005, 34, 69–98.
(2) Summers, J. B.; Moore, J. L. U. S. Patent 4,769,387, 1988; Chem.
Abstr. 1989, 110, 23717t.
(3) Bandurraga, M. M.; Fenical, W.; Donovan, S. F.; Clardy, J. J. Am.
Chem. Soc. 1982, 104, 6463–6465.
(4) Sum, F. W.; Wong, V. S.; Largis, H. E.; Malvey, R. Bioorg. Med.
Chem. Lett. 2003, 13, 2191–2193.
(5) (a) Kobayashi, J.; Ohizumi, Y.; Nakamura, H. Tetrahedron Lett.
1986, 27, 2113–2116. (b) Hofnung, M.; Quillardet, V. M.; Touati, E. Res.
Microbiol. 2002, 153, 427–430. (c) Khan, M. W.; Alam, M. J.; Rashid, M. A.;
Chowdhury, R. Bioorg. Med. Chem. 2005, 13, 4796–4805. (d) Yang, Z.; Hon,
M. P.; Chui, K. Y. Tetrahedron Lett. 1991, 32, 2061–2064. (e) Helder, L.;
Hemerly, J. P.; Pauletti, P. M. Nat. Prod. Res. 2005, 19, 319–323. (f) Tsai, I.
L.; Hsieh, C. F.; Duh, C. Y. Phytochemistry 1998, 48, 1371–1375. (g) Kao, C.
L.; Chern, J. W. J. Org. Chem. 2002, 67, 6772–6787. (h) Yang, Z.; Liu, H. B.;
Lee, C. M.; Chang, H. M.; Wong, H. N. C. J. Org. Chem. 1992, 57, 7248–
7251. (i) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670–
2673. (j) Kerr, D. J.; Hamel, E.; Jung, M. K.; Flynn, B. L. Bioorg. Med. Chem.
2007, 15, 3290–3298. (k) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org.
Lett. 2001, 3, 651–654.
966 J. Org. Chem. 2010, 75, 966–968
Published on Web 01/07/2010
DOI: 10.1021/jo902375k
r
2010 American Chemical Society

Liu et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
SCHEME 1. Synthesis of Polyfunctional Furans from Alkyno-
ates and 1.3-Dicarbonyl Compoundsa
oxidant
(1.2 equiv)
yieldb
solvent (%)
entry
catalyst (equiv)
CuI (0.1)
CuCl2 (0.1)
SnCl2 (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuCl2 (0.1)
1
2
3
4
5
6
7
8
9
DDQ
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
DDQ
DDQ
DDQ
DDQ
75
71
68
9
SnCl2 (0.1)/Cu(OAc)2 (0.1) DDQ
SnCl2 (0.1)/CuBr (0.1)
SnCl2 (0.1)/Cu2O (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
SnCl2 (0.1)/CuI (0.1)
DDQ
DDQ
none
66
10
benzoyl peroxide DCE
H2O2
PIDA
benzoquinone
O2 (1 atm)
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
21
11
12
13
14
15
16
17
18
DCE
DCE
DCE
DCE
38
trace
toluene 77
dioxane 50
CH3CN 28
DMF 23
toluene 80
toluene 86
toluene 86
toluene 25
toluene 83
c
19[c, dd] SnCl2 (0.1)/CuI (0.1)
c
e
20[c, e ] SnCl2(0.1)/CuI(0.1)
21[cc]
SnCl2 (0.1)/CuI (0.1)
22[c, e, ff ] SnCl2 (0.1)/CuI (0.1)
c
e
c
e
23[c, e, gg] SnCl2 (0.1)/CuI (0.1)
aReaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), in 2 mL
of solvent at 80 °C for 5 h. bIsolated yields. cReaction temperature:
f
100 °C. dReaction time: 3 h. eReaction time: 4 h. DDQ (0.5 equiv).
gDDQ (2.0 equiv).
a significant decrease of the yield was observed. However,
there was no obvious influence on the reaction when the
reaction time was decreased (entries 19-21) or the dosage of
DDQ was increased (entry 23).
Under the optimized conditions, the reaction was applied
to a range of different substrates. Different 1,3-dicarbonyl
compounds could successfully react with alkynoates to
afford the corresponding furan derivatives (Scheme 1). As
revealed in Scheme 1, the electronic contribution of the
substituents on the alkynes has a significant influence on
the reaction. This transformation proceeded smoothly and
afforded the desired product in good to excellent yields for
those alkynes substituted with two electron-withdrawing
groups. For example, the reaction of diethyl but-2-ynedioate
with benzoylacetone led to 3aa in 86% isolated yield, and the
reaction on a larger scale (2.0 mmol) could also lead to 84%
isolated yields, while methyl propiolate ethyl only gave 3ca in
80% isolated yield. In addition, when ethyl 3-phenylpropio-
late was used in the reaction with pentane-2,4-dione, only
3bd was obtained in 51% yield.
aThe yields of isolated products are listed. Conditions: (a) 1 (0.5 mmol),
2 (0.5 mmol); (b) 1a (2.0 mmol), 2a (2.0 mmol).
SCHEME 2. Plausible Reaction Mechanism
A plausible mechanism of this transformation is shown in
Scheme 2. The reaction starts with a double metal-activating
process:10 (1) 1,3-dicarbonyl compound is activated by Cu(I)
to form 5; (2) Sn(II) is used as the Lewis acid to activate
the C-C triple bond of alkynoate and lead to 4. Subse-
quently, the coupling of the two intermediates results in the
Michael additional product 6 and regenerates the catalysts.
1,3-Hydrogen shift in 6 forms intermediate 7 due to the
(10) Christoffers, J. Eur. J. Org. Chem. 1998, 1259–1266.
J. Org. Chem. Vol. 75, No. 3, 2010 967

Liu et al.
JOCNote
resonance phenomenon of keto-enol tautomerism in 1,3-
dicarbonyl compounds.7b The following step involves a
hydride abstraction from the tautomers 8 and 9 to generate
a cationic species 8.8,11 Finally, the ultimate product 3 results
from the dehydrocyclization process in the intermediate 8.
In conclusion, we have established a facile and efficient
method to synthesize polysubstituted furans via tin(II)- and
copper(I)-involved addition/oxidative cyclization of alkyno-
ates and 1,3-dicarbonyl compounds using DDQ as the
oxidant. This methodology not only provides a simple way
to construct polysubstituted furan derivatives but also opens
a brand new way to build oxygen-containing vinyl ether
compounds through oxidation. The readily accessible start-
ing materials, relatively cheap oxidant DDQ and tin/copper
catalyst, as well as the mild reaction conditions and good to
excellent yields make the present reaction potentially useful
in organic synthesis.
analyzed by GC and GC-MS. Volatiles were removed under
reduced pressure, and the crude product was subjected to
isolation by PTLC (GF254) and eluted with a 10:2 petroleum
ether-diethyl ether mixture to give 142.3 mg (86%) of diethyl 4-
acetyl-5-phenylfuran-2,3-dicarboxylate (3aa)12 as a pale yellow
viscous oil. IR νmax (KBr): 3065, 2996, 2938, 1724, 1659, 1597,
1410, 1252, 1171, 1060, 942, 910, 864, 772, 697 cm-1. 1H NMR
(400 MHz, CDCl3): δ 7.72-7.70 (m, 2H), 7.57-7.53 (m, 1H),
7.45-7.41 (m, 2H), 4.36 (q, 2H, J = 7.2 Hz), 3.94 (q, 2H, J =
7.2 Hz), 2.41 (s, 3H), 1.34 (t, 3H, J = 7.2 Hz), 1.05 (t, 3H, J =
7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 189.8, 262.2, 159.3,
157.4, 140.4, 137.8, 133.2, 128.8, 128.5, 125.5, 122.1, 67.8, 61.7,
14.0, 13.9, 13.5. GC-MS m/z (rel intens): 330.07 (Mþ, 69.67),
240.92 (100).
Synthesis of Ethyl 4-Benzoyl-3,5-diphenylfuran-2-carboxylate
(3bb). The product was synthesized in the same manner as 3aa
starting from ethyl 3-phenylpropiolate (87 mg, 0.5 mmol), 1,3-
diphenylpropane-1,3-dione (112 mg, 0.5 mmol), 2 mL of to-
luene, SnCl2 (9.5 mg, 0.05 mmol), CuI (9.5 mg, 0.05 mmol), and
DDQ (135.6 mg, 0.6 mmol). Compound 3bb was obtained as a
yellow solid in 55% yield (110.1 mg). Mp: 109-110 °C. IR νmax
(KBr): 2961, 2896, 1815, 1710, 1659, 1401, 1270, 1236, 1173,
Experimental Section
Typical Procedure for the Synthesis of Diethyl 4-Acetyl-5-
phenylfuran-2,3-dicarboxylate (3aa). To a stirring mixture of
diethyl but-2-ynedioate (1a, 85 mg, 0.50 mmol) and 1-phenyl-
butane-1,3-dione (2a, 81 mg, 0.5 mmol) were added successively
2 mL of toluene, SnCl2 (9.5 mg, 0.05 mmol), CuI (9.5 mg,
0.05 mmol), and DDQ (135.6 mg, 0.6 mmol). The mixture was
stirred at 100 °C for 4 h in a round-bottom flask. After cooling,
the solvent was diluted with water and extracted with diethyl
ether. The ether layer was washed with saturated salt water and
dried with anhydrous MgSO4. The resulting mixture was then
1029, 973, 900, 863, 765, 688 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.74-7.72 (m, 1H), 7.66-7.65 (m, 1H), 7.30-7.28
(m, 1H), 7.24-7.18 (m, 7H), 4.27 (q, 2H, J = 7.2 Hz), 1.23
(t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 192.4, 158.7,
154.1, 138.6, 136.9, 135.3, 133.6, 130.2, 129.7, 128.6, 128.5,
128.4, 128.3, 128.2, 127.6, 127.0, 123.4, 61.0, 14.0. GC-MS m/z
(rel intens): 396.14 (Mþ, 73.45), 104.98 (100). Anal. Calcd for
C26H20O4: C, 78.77; H, 5.09. Found: C, 78.60; H, 4.89.
Acknowledgment. We thank the National Natural
Foundation of China (Nos. 20625205, 20772034, and
20932002) and Guangdong Natural Science Foundation
(No. 07118070) for financial support.
(11) (a) Ying, B. P.; Trogden, B. G.; Kohlman, D. T.; Liang, S. X.; Xu, Y.
C. Org. Lett. 2004, 6, 1523–1526. (b) Dinh, T. Q.; Du, X.; Armstrong, R. W.
J. Org. Chem. 1996, 61, 6606–6616. (c) Hirschmann, R.; Ducry, L.; Smith, A.
B. III. J. Org. Chem. 2000, 65, 8307–8316. (d) Sawada, D.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521–10532. (e) Gurjar, M. K.;
Maheshwar, K. J. Org. Chem. 2001, 66, 7552–7554. (f) Cheng, D. P.; Bao, W.
L. Adv. Synth. Catal. 2008, 350, 1263–1266.
(12) (a) Yoshiyuki, H.; Kobayasi, M.; Hitosi, N. Tetrahedron 1970, 26,
4353–4360. (b) Masaaki, T.; Yoshiyuki, H.; Hitosi., N. Tetrahedron Lett.
1969, 25, 2053–2056.
Supporting Information Available: Full experimental details
and copies of NMR spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
968 J. Org. Chem. Vol. 75, No. 3, 2010