Palladium-catalyzed one-pot synthesis of highly substituted furans by a three-component annulation reaction

Article abstract of DOI:10.1021/jo050908d

A new three-component cyclization-coupling reaction catalyzed by palladium was developed, producing polysubstituted furans in good yields from readily available substrates. The reaction conditions and the scope of the process were examined, and a possible mechanism is proposed.

Full text of DOI:10.1021/jo050908d

Several Pd-mediated strategies for the preparation of
furans have been developed.4 Among them, a one-pot
furan annelation reaction by a Pd-catalyzed reaction of
propargyl carbonates with â-keto esters was reported by
Tsuji,5 and Cacchi and Larock reported another pal-
ladium-catalyzed reaction of 2-propargyl-1,3-dicarbonyl
compounds with vinylic or aryl triflates or halides giving
2,3,5-trisubstituted furans.6 During the same period,
multicomponent condensations have gained considerable
interest in the field of heterocycle synthesis due to their
potential of generating molecular diversity in a single
synthetic step from simple, readily available starting
materials.7 In this area, methodologies based on pal-
ladium-catalyzed cascade reactions are of particular
importance owing to the diversity of bond-forming pro-
cesses available, the mildness of reaction conditions, the
high levels of chemo-, regio-, and stereoselectivities, and
the excellent functional group tolerance.8 There are some
methods have been devised for the synthesis of the
multiply substituted furans by multicomponent reaction.9
Herein, we wish to report a one-pot three-component
coupling-cyclization reaction based on palladium-medi-
ated that combines three readily available and inexpen-
sive materials, â-keto esters, propargyl carbonate, and
aryl iodide, to yield polysubstituted furans.
Palladium-Catalyzed One-Pot Synthesis of
Highly Substituted Furans by a
Three-Component Annulation Reaction
Xin-hua Duan,† Xue-yuan Liu,† Li-na Guo,†
Meng-chun Liao,† Wei-Min Liu,‡ and Yong-min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, P.R. China, and
State Key Laboratory of Solid Lubrication, Lanzhou
Institute of Physics, Chinese Academy of Science,
Lanzhou 730000, P.R. China
liangym@lzu.edu.cn
Received May 6, 2005
A new three-component cyclization-coupling reaction cata-
lyzed by palladium was developed, producing polysubstituted
furans in good yields from readily available substrates. The
reaction conditions and the scope of the process were
examined, and a possible mechanism is proposed.
Initially, we employed methyl acetoacetate 1a, prop-
argyl bromide 2a, and iodobenzene 3a as substrates to
afford trisubstituted furan 4a6 in 20% yield in the
presence of Pd2(dba)3‚CHCl3 (5 mol %) and KO-t-Bu (2.0
equiv) in DMF at 100 °C for 12 h (Table 1, entry 1).10
Then, we investigated the reaction under other pal-
ladium-catalyzed cyclization conditions. To our surprise,
in the presence of a catalytic amount of Pd(PPh3)4 in DMF
Highly substituted furans are structural features of
many natural products and important pharmaceuticals.1
They are also important reaction intermediates in organic
synthesis by virtue of their specific chemistry and latent
functionality.2 For these reasons, the efficient synthesis
of multiply substituted furans continues to attract the
interest of synthetic chemists.3 Thus, efficient and gen-
eral methodologies for the synthesis of furans with
substituents at some or all of the four positions are still
of current interest.
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Zhang, J. Chem. Commun. 2000, 117. (d) Ma, S.; Li, L. Org. Lett. 2000,
2, 941. (e) Aurrecoechea, J. M.; Pe´rez, E. Tetrahedron 2004, 60, 4139.
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Chem. 1998, 560, 163. (g) Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. J. Org. Chem. 1991, 56, 5816.
* To whom correspondence should be addressed. Tel: +86-931-
8912593. Fax: +86-931-8912582.
† Lanzhou University.
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J. J. Organomet. Chem. 1987, 334, 225. (c) Tsuji, J.; Mandai, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2589. (d) Tsuji, J.; Mandai, T. In Metal-
catalyzed cross coupling reaction; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinhein, 1998 (e) Greeves, N.; Torode, J. S. Synthesis
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‡ Chinese Academy of Science.
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Occurring Oxygen Ring Compounds; Butterworth: London, 1963. (d)
Natural Products Chemistry; Nakanishi, K., Goto, T., Ito, S., Natori,
S., Nozoe, S., Eds.; Kodansha: Tokyo, 1974; Vols. 1-3. (e) Dean, F.
M. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.,
Academic Press: New York, 1983; Vol. 31, pp 237-344. (f) Sargent,
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10.1021/jo050908d CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/19/2005
6980
J. Org. Chem. 2005, 70, 6980-6983

TABLE 1. Palladium-Catalyzed Synthesis of
2,3,5-Trisubstituted Furansa
and 3a as the reactants and Pd(PPh3)4 as the catalyst in
DMF. We found that K2CO3 was the most effective base.
Other bases such as K3PO4, Cs2CO3, NaOAc, and KO-t-
Bu were less effective, and Et3N was ineffective. We
sought to investigate various combinations of aryl ha-
lides, propargyl carbonates, and â-keto esters. The gen-
erality of the methodology was firmly demonstrated by
the variety of furans that could be produced. The results
are summarized in Table 2. Almost all aryl iodides gave
satisfactory results (entries 1-9). Importantly, the reac-
tions afforded the corresponding multiply substituted
furans products 5a-m in moderate to good yields with
excellent regioselectivities, except entry 5.
entry
1, R1 )
time (h)
product (yield, %)
1
2
CH3
C2H5
12
12
4a (20)b
4b (22)b
a The reaction was carried out at 100 °C using 2a (0.2 mmol),
nucleophile (0.2 mmol), aryl halide (0.2 mmol), KO-t-Bu (0.4 mmol),
and Pd2(dba)3‚CHCl3 (5 mol %) in DMF (2 mL). b Isolated yields.
SCHEME 1
Treatment of methyl acetoacetate, 2b, and iodobenzene
in a 1:1:1 ratio at 100 °C in DMF with 5 mol % of Pd-
(PPh3)4 and 2.0 equiv of K2CO3 for 12 h afford 5a in 40%
yield, but the Sonogashira-coupling product was isolated
in 5% yield. For 4-methyliodobenzene, a similar result
was observed. Fortunately, when the reaction was run
in the presence of 1.0 equiv of KI, only the desired
tetrasubstituted furan was formed (entry 1). However,
when 1-iodo-4-methoxybenzene was used, only a trace
amount of the desired product was isolated. We next
examined several aryl iodides to clarify the scope and
limitations of this reaction (entries 3-9). Electron-
deficient aryl halides performed much better than their
at 100 °C for 12 h, with K2CO3 as a base, the product
was identified as tetrasubstituted furan 5a by NMR and
MS, which was dramatically different from 4a (Scheme
1).
The reaction, when conducted with methyl propargyl
carbonate 2b, resulted in the obvious increase in the yield
to 40%. We then screened various bases using 1a, 2b,
TABLE 2. Palladium-Catalyzed Synthesis of Polysubstituted Furansa
a The reaction was carried out at 100 °C using 2b (0.2 mmol), nucleophile (0.2 mmol), aryl halide (0.2 mmol), K2CO3 (0.4 mmol), and
Pd(PPh3)4 (5 mol %) in DMF (2 mL). b Isolated yields of the major isomer. c The ratio was determined by 1H NMR analysis of the crude
reaction mixture. d Isolated yields of the two isomers. e Added 0.2 mmol of KI.
J. Org. Chem, Vol. 70, No. 17, 2005 6981

SCHEME 2
TABLE 3. Palladium-Catalyzed Synthesis of
2,3,4,5-Tetrasubstituted Furansa
SCHEME 3
a The reaction was carried out at 100 °C using 2c (0.2 mmol),
nucleophile (0.2 mmol), aryl halide (0.2 mmol), K2CO3 (0.4 mmol),
and Pd(PPh3)4 (5 mol %) in DMF (2 mL). b Isolated yields.
species 15. Complex 15 then undergoes decarboxylation
to give a methoxide anion,12 which picks up an acidic
hydrogen from the active methylene compound to give
the enolate complex 17. Then the enolate anion attacks
the sp carbon of the 1,2-propadienyl moiety to form the
palladium complex 18, which isomerizes to (π-allyl)-
palladium complex 19 by intramolecular proton transfer.
In the case of propargylic carbonates 2b, the π-allyl
complex 19 undergoes the intramolecular O-alkylation
with the carbonyl oxygen at the more substituted side of
the π-allyl system, leading predominantly to the regioi-
somer 5a-m (Table 2, entries 1-14).5 While, for the
propargylic carbonates 2c the attack occur on the less-
substituted side, the regioisomer 9a-c (Table 3, entries
1-3) being the predominant products.13
In conclusion, we have developed a palladium-cata-
lyzed novel three-component cyclization-coupling reaction
of propargyl carbonate, â-keto esters, and aryl iodide.
This three-component cyclization-coupling protocol pro-
vides an efficient access to a variety of polysubsituted
furans and shows some advantages in terms of its simple
operation, easily availability, and diversity of the starting
material.
electron-rich counterparts, and 4-chloroiodobenzene with
an electron-withdrawing group on the benzene ring
worked equally well to provide 5c in better yields than
4-methyliodobenzene (entry 3). In addition, 2-iodot-
hiophene also can give the furan 5j (entry 10). The use
of 2- bromothiophene instead of 2-iodothiophene produced
5j in a lower yield (entry 11). Another â-keto ester, ethyl
acetoacetate, also effected the three-component cycliza-
tion-coupling reaction, yielding the corresponding prod-
uct 5k-m (entries 12-14). Unfortunately, the use of
other â-keto esters and â-diketones afforded only a
minute amount of the desired product under the same
reaction conditions.
We then turned our attention to the cyclization reac-
tion using secondary carbonate 2c. However, substitution
of the hydrogen group by methyl gave a mixture of the
two annulated regioisomers 8 and 9, which can be
isolated on silica gel column (Table 3). In addition, we
established the structures of 5h and 9c by gHMBC
experiments.
Furthermore, condensation of propargylic tertiary
carbonate 2d, methyl acetoacetate and methyl 4- iodo-
benzoate 3h afforded none of the desired three- compo-
nent cyclization products and an identified product 10
was isolated (Scheme 2).
A tentative mechanism was proposed in Scheme 3.
Oxidative addition of the organic halide to the Pd0
catalyst generates a σ-arylPdIIX complex 12. The prop-
argyl carbonate reacts with palladium complex 12 to give
the π-palladium complex 14,11 upon coordination, the
C-H bond is weakened, and HX is removed from 14 in
the presence of a base to form arylalkynylpalladium
Experimental Section
Methyl 2,4-Dimethyl-5-phenylfuran-3-carboxylate 5a. To
a solution of Pd(PPh3)4 (11.5 mg, 0.01 mmol) in 2.0 mL of
anhydrous DMF under argon were added 2b (22.8 mg, 0.2
(11) (a) Cheng, J.; Sun, Y.; Wang, F.; Guo, M.; Xu, J.; Pan, Y.; Zhang,
Z. J. Org. Chem. 2004, 69, 5428. (b) Cacchi, S.; Fabrizi, G.; Moro, L. J.
Org. Chem. 1997, 62, 5327.
(12) (a) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem.
Soc. 2003, 125, 4874. (b) Yoshida, M.; Ihara, M. Angew. Chem., Int.
Ed. 2001, 40, 616. (c) Wang, F.; Tong, X.; Cheng, J.; Zhang, Z. Chem.
Eur. J. 2004, 10, 5338. (d) Labrosse, J. R.; Lhoste, P.; Sinou, D. J.
Org. Chem. 2001, 66, 6634.
(13) (a) Tsuji, J. Organic Syntheses with Palladium Compouds;
Springer-Verlag: Berlin, 1980; p 37. (b) Trost, B. M. Tetrahedron. 1977,
33, 2615. (c) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (d) Trost, B.
M. J. Organomet. Chem. 1986, 300, 263. (e) Tsuji, J. J. Organomet.
Chem. 1986, 300, 281. See also the references therein.
(10) For the detailed experimental procedure see the Supporting
Information.
6982 J. Org. Chem., Vol. 70, No. 17, 2005

mmol), iodobenzene (40.8 mg, 0.2 mmol), methyl acetoacetate
(23.2 mg, 0.2 mmol), and K2CO3 (55.2 mg, 0.4 mmol). The
mixture was stirred at 100 °C for 12 h.The reaction was
quenched with a saturated aqueous solution of ammonium
chloride, and the mixture was extracted with Et2O. The com-
bined organic extracts were washed with water and saturated
brine. The organic layer was dried (Na2SO4) and concentrated
in vacuo. The residue was purified by chromatography on silica
gel to afford 5a: oil; 1H NMR (300 MHz, CDCl3) δ 7.60-7.57 (d,
2H), 7.44-7.39 (t, 2H) 7.32-7.29 (t, 1H) 3.86 (s, 3H), 2.61 (s,
3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.2, 158.6,
147.7, 130.9, 128.5 (2C), 127.2, 126.1 (2C), 116.8, 115.1, 51.1,
14.5, 10.9; IR (KBr, cm-1) 2952, 2926, 1715, 1441, 1325, 1237,
1097, 765, 697; EI-MS m/z 230 (M+), 215, 198,170, 141, 128, 105,
77, 43. Anal. Calcd for C14H14O3: C, 73.03; H, 6.13. Found: C,
73.25; H, 6.38. For characterization data of other compounds
see the Supporting Information.
Acknowledgment. We thank the NSF (NSF-
20021001, NSF-20172024) and the “Hundred Scientist
Program” from the Chinese Academy of Sciences for
financial support.
Supporting Information Available: Typical experimen-
tal procedure and characterization for all products and gHMBC
experimental data of 5h and 9c. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO050908D
J. Org. Chem, Vol. 70, No. 17, 2005 6983