Facile synthesis of 3a,6a-dihydro-furo[2,3-b]furans and polysubstituted furans involving dearomatization of furan ring via electrocyclic ring-closure

Article abstract of DOI:10.1021/ol203232m

A facile and atom-economic method for the synthesis of 3a,6a-dihydro- furo[2,3-b]furan derivatives and polysubstituted furans starting from furylcarbionls has been developed. This protocol involved a domino Claisen rearrangement/dearomatizing electrocyclic ring-closure/aromatizing electrocyclic ring-opening sequence.

Full text of DOI:10.1021/ol203232m

ORGANIC
LETTERS
2012
Vol. 14, No. 2
616–619
Facile Synthesis of 3a,6a-Dihydro-
furo[2,3-b]furans and Polysubstituted
Furans Involving Dearomatization of
Furan Ring via Electrocyclic Ring-Closure
Biaolin Yin,* Guohui Zeng, Congbi Cai, Fanghua Ji, Li Huang, Zhengrong Li, and
Huanfeng Jiang
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou, Guangdong, 510640, China
blyin@scut.edu.cn
Received December 4, 2011
ABSTRACT
A facile and atom-economic method for the synthesis of 3a,6a-dihydro-furo[2,3-b]furan derivatives and polysubstituted furans starting from
furylcarbionls has been developed. This protocol involved a domino Claisen rearrangement/dearomatizing electrocyclic ring-closure/aromatizing
electrocyclic ring-opening sequence.
The transformation of readily available and stable
aromatic rings into functionalized alicyclic derivatives is
widely recognized as an attractive strategy for the con-
struction of valuable synthetic intermediates when the
conjugated π system is successfully broken up.1 Of partic-
ular interest is the dearomatization of furan ring due to
its lower Dewar resonance energy of 4.3 kcal mol and
because furan rings contain masked functionalities of
olefin, diene, enol ether, and 1,4-dicarbonyl. Accordingly,
the partial dearomatization of the furan ring allows the
reactivity of the remaining unsaturation to be intensively
exploited. To date, there are a number of different methods
that, with unequal scope, allow the dearomatization of the
furan ring and have been extensively used in the synthesis
of numerous bioactive molecules.2 For example, Birch
reduction of furan rings leads to 2,5-dihydrofurans.3
Furans have been widely used as dienes and less frequently
as dienophiles in cycloadditions for the construction
of different bicyclic or tricyclic skeletons.4 Oxidations of
furan derivatives produce 2,5-dialkoxy-2,5-dihydrofurans,5
6-hydroxy-6H-pyran-3-one,6 6-hydroxy-6H-pyran-3-one,7
(4) For selected recent examples of furan dearomatization through
DielsÀAlder cycloaddition, see: (a) Chen, C.-H.; Rao, P. D.; Liao, C.-C.
J. Am. Chem. Soc. 1998, 120, 13254. (b) Xiong, H.; Hsung, R. P.; Berry,
C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174. (c) Domingo,
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L. R.; Aurell, M. J. J. Org. Chem. 2002, 67, 959. (d) Toro, A.;
Deslongchamps, P. J. Org. Chem. 2003, 68, 6847. (e) Liu, L.; Gao, Y.;
Che,C.;Wu,N.;Wang,D.Z.;Li,C.-C.;Yang,Z.Chem. Commun. 2009,662.
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Trans. 1 2002, 1631. (b) Etchells, L. L.; Sardarian, A.; Whitehead, R. C.
Tetrahedron Lett. 2005, 46, 2803. (c) Mcdermott, P. J.; Stockman, R. A.
Org. Lett. 2005, 7, 27. (d) Etchells, L. L.; Helliwell, M.; Kershaw, N. M.;
Sardarian, A.; Whitehead, R. C. Tetrahedron 2006, 62, 10914. (e) Georgiou,
T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G. Org. Lett. 2006, 8,
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(b) Kallinen, A.; Tois, J.; Sjoeholm, R.; Franzen, R. Tetrahedron:
Asymmetry 2010, 21, 2367. (c) Hatano, M.; Mizuno, T.; Ishihara, K.
Chem. Commun. 2010, 46, 5443. (d) Noutsias, D.; Kouridaki, A.;
Vassilikogiannakis, G. Org. Lett. 2011, 13, 1166. (e) Egan, B. A.;
Paradowski, M.; Thomas, L. H.; Marquez, R. Org. Lett. 2011, 13, 2086.
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€
729. (b) Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem. Rev. 2000,
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(2) For reviews concerning the dearomatization of furan ring, see:
(a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Roche, S. P.; Porco, J
A., Jr. Angew. Chem., Int. Ed. Engl. 1996, 35, 729. (c) Bur, S. K.; Padwa,
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Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, p 603. (b) Donohoe, T. J.;
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r
10.1021/ol203232m
Published on Web 01/05/2012
2012 American Chemical Society

and buteno-lides.8 Other examples include acid-catalyzed
molecular rearrangement of 2-furylcarbinols into cyclo-
pentenones9 and nucleophilic addition to furanÀchromium
complexes.10 As a consequence, the development of a new
method for the dearomatization of furan rings continues to
be an active and rewarding research area.
Recently, we and other groups have disclosed accesses
to spiro-compounds 2 and other bioactive molecules
starting from furycarbinol 1 tethered to a side chain at the
R-position of its furan ring with a nucleophile (Scheme 1).11
We began by synthesizing 2-(furan-2-ylmethoxy)-
but-2-enedioic acid dimethyl ester (8a) via the addition reac-
tion of furfuryl alcohol (3a) with dimethyl 2-butynedioate
(7) in the presence of a catalytic amount (10 mol %)
of DABCO (Scheme 2).13 After completion of the addi-
tion reaction, 5 mol % of Pd(OAc)2 was added, and the
reaction mixture was then heated at 80 °C for 24 h to
undergo the Claisen rearrangement step.14 Unexpectedly,
no Claisen rearrangement-type product 4a was observed.
Scheme 2. Synthesis of 5a from 3a
Scheme 1. Synthetic Application of Furans Characterized by
Dearomatization
Instead, 3a,6a-dihydro-furo[2,3-b]furan 5a was formed
with a moderate yield (54%) over two steps. This un-
expected result is especially interesting and useful because
it provides a novel entry to 3a,6a-dihydro-furo[2,3-b]-
furans, key structural units in many important pharma-
ceuticals and bioactive natural products.15 Additionally,
5a is stable enough to store on the bench for several
months and can also be used as a versatile intermediate
for the construction of many other useful molecules.
Moreover, this transformation presented an unprece-
dented method for the dearomatization of five-membered
The key step involves the dearomatization of the
furan ring through an acid-catalyzed intramolecular
allylation-like reaction. These achievements encouraged
usto develop more novel strategies directed toward the
dearomatization of furan ring of 2-furylcarbinol and
expanding its synthetic applications. Electrocyclic
reaction of common conjugated poylenes (4π or 6π
electron system) is a well-known method for the pre-
paration of cyclic compounds.12 Nevertheless, to the
best of our knowledge, the dearomatizing electrocyclic
reaction involving π-electrons of the aromatic ring is
seldom reported. In this communication, we reported
the facile synthesis of 3a,6a-dihydro-furo[2,3-b]furan
derivatives 5 and polysubstituted furan 6 using
2-furylcarbinol as the starting material, which involved a
domino palladium-catalyzed Claisen rearrangement/
dearomatizing eletrocyclic ring-closure/aromatizing eletro-
cyclic ring-opening sequence.
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(14) Other Lewis acids such as CuSO4, ZnCl2, and CuCl2 were also
tested, but all resulted in a complicated reaction system. For related
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Org. Lett., Vol. 14, No. 2, 2012
617

aromatic rings via electrocyclic ring-closure. Hence, our
attention was piqued by the potential of this novel
transformation, and we decided to optimize the reaction
conditions for it.
Table 2. Synthesis of 5a
Table 1. Optimization of Reaction Conditionsa
entry
[Pd]
Pd(OAc)2
solvent
base
yieldb (%)
1
DCM
DMF
MeCN
THF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
54
trace
45
2
Pd(OAc)2
3
Pd(OAc)2
4
Pd(OAc)2
28
5
Pd(OAc)2
60
6
Pd(OAc)2
52
7
Pd(OAc)2
DIEA
60
8
Pd(OAc)2
TMEDA
pyridine
dppp
68
9
Pd(OAc)2
57
10
11
12
13
14
15
16
Pd(OAc)2
57
Pd(OAc)2
dppe
trace
ND
14
PdCl2
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
Pd(CF3COO)2
Pd(PPH3)4
Pd(MeCN)2Cl2
[Pd(MeCN)4][BF4]
42
82
10
a All reactions were performed on a 1 mmol scale. Yields of
isolated products are given. Unless otherwise noted, t = 80 °C. b t = 30 °C.
c t = 60 °C. d t = 140 °C.
a All reactions were carried out on a 1 mmol scale. b Yield determined
by 1H NMR using 1,3,5-trimehylbenzene as an internal standard.
As a model reaction, E-8a was treated with a variety
of bases and palladium sources in different solvents at
80 °C to optimize the reaction conditions. Initially, various
solvents were screened when Pd (OAc)2 was employed as
the catalyst and DABCO as the base (Table 1, entries
1À5). DCE was the best one and resulted in 5a in 60%
yield. Then, different bases were examined; TMEDA
was the best (Table 1, entry 8). Other nitrogen-containing
bases (e.g., DIEA, pyridine, DMAP) and two diphos-
phines of dppp and dppe were also capable of promoting
the transformation but provided lower yields than TMEDA
(Table 1, entries 5À11). Finally, palladium sources were
screened (Table 1, entries 12À16). The best result was
obtained when Pd(MeCN)2Cl2 was employed as the
catalyst (Table 1, entry 15). Thus, we concluded that
the optimized combination for this reaction was to use
DCE as the solvent, TMEDA (10 mol %) as the base, and
Pd(MeCN)2Cl2 (5 mol %) as the catalyst. It is worth
noting that under the same reaction conditions, Z-8a
can also be transformed into 5a with a yield comparable
to E-8a, but a longer reaction time is needed.
alkyl group, this transformation proceeded well, giving
5aÀl in moderate to good yields. Nevertheless, when R1
was an electron-withdrawing formyl or methoxycarbonyl
group, this transformation did not occur (5m and 5n).
These results imply that the electron-rich furan ring is
helpful for the cleavage of the C6ÀO bond, thus facilitat-
ing the transformation. Delightedly, when the aromatic
ring of E-8 was a benzofuran or thiophene, these were also
dearomatized and produced the furo[2,3-b]benzofuran
(5o, 5p) and dihydro-thieno[2,3-b]furan (5q, 5r) in mod-
erate to good yields.
Polysubstituted furan is a key structural unit in many
bioactive natural products and pharmaceuticals.16 It is
also a reactive species that can be engaged in complex
chemical transformations.2 In an attempt to highlight
the synthetic application of the obtained product 5, we
attempted to convert 5 into polysubstituted furan 6 via an
aromatizing electrocyclic ring-opening. Much to our
pleasure, 5c can be converted into 6c with almost a quan-
titative yield when heated in DCE at 100 °C for 24 h in the
To understand the generality of this transformation, we
subjected a variety of E-8 to provide 5 under the opti-
mized conditions. The results are summarized in Table 2.
When R1 (substitution at the 5-position of the furan ring)
was an electron-donating group such as H, TMS, or an
(16) (a) Dean, F. M.; Sargent, M. V. In Comprehensive Heterocyclic
Chemistry; Bird, C. W., Cheeseman, G. W. H., Eds.; Pergamon: New York,
1984; Vol. 4, p 531. (b) 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.
(c) Cacchi, S. J. Organomet. Chem. 1999, 576, 42.
618
Org. Lett., Vol. 14, No. 2, 2012

presence of TMEDA (10 mol %). Its structure was deter-
mined by single-crystal X-ray data analysis (6t, see the
Supporting Information). We also found that during the
transformation of E-8c into 5c, when the reaction tem-
perature was raised to 100 °C for 24 h, 6c was exclusively
obtained in 67% yield. Therefore, a series of polysubsti-
tuted furans 6 with diverse functionalities were synthe-
sized in moderate to good yields via an one-pot procedure
from E-8 (Scheme 3).
Scheme 4. Plausible Reaction Mechanism
Scheme 3. Synthesis of 6 from E-8 (All Reactions Were Per-
formed on a 1 mmol Scale)
protocol involves a palladium-catalyzed domino Claisen
rearrangement/dearomatizing electrocyclic ring-closure/
aromatizing ring-opening sequence. The unprecedented
dearomatization of five-membered aromatic rings
through electrocylic ring-closure would be helpful to
expand their synthetic application as building blocks in
organic synthesis. Further studies on the scope and
asymmetric aspect of these reactions, as well as their
application for the synthesis of natural bioactive pro-
ducts, are ongoing in our laboratory. The results will be
reported in due course.
a 80 °C. b 100 °C.
On the basis of the experimental results shown above,
a tentative mechanistic interpretation of the preceding
observations is proposed in Scheme 4. The coordination
of Pd(II) with the double bond of the furan ring of E-8
formed complex 9. The carbopalladation of the double
bond of the furan ring gave rise to intermediate 10, which
underwent a Pd(II) elimination step, producing 11 and
recycling the palladium catalyst. The aromatization of 11
provided 12. After deprotonation and dearomatizing
electrocyclic ring-closure steps, the carbanion 14 was
formed. The protonation of 14 at lower temperature formed
5, whereas at higher temperature, 14 was converted into 6
through two steps of aromatzing electrocyclic-opening
and protonation, subsequently.
Acknowledgment. ThisworkwassupportedbytheNSF
of China (21072062), the Fundamental Research Funds
for the Central Universities (2012ZZ0043), and the Nat-
ural Science Foundation of Guangdong Province, China
(10351064101000000).
In summary, employing a readily available furylcarbi-
nol as the starting material, we developed a facile and
atom-economic method for the synthesis of 3a,6a-dihydro-
furo[-2,3-b]furans and polysubstituted furans. These
two structural units are found in many bioactive prod-
ucts and might be used as synthetic building bolcks. This
Supporting Information Available. Details on general
experimental methods, crystal data and structure of 6t,
and copies of 1H NMR and 13C NMR spectra of all the
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
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