Transition-metal-catalyzed domino reactions: Efficient one-pot regiospecific synthesis of highly functionalized polysubstituted furans from electron-deficient alkynes and 2-Yn-1-ols

Article abstract of DOI:10.1055/s-0030-1258461

Based on the reactive behavior of different transition-metal catalysts, three methods for the synthesis of highly functionalized polysubstituted furan derivatives are presented: (i) copper(I) iodide catalyzed regiospecific synthesis of furan aldehydes/ketones from alkynols and diethyl but-2-ynedioate under atmospheric pressure; (ii) nano-Cu-catalyzed domino process for the regioselective synthesis of -carbonylfurans from readily accessible starting materials; (iii) silver-catalyzed one-pot cyclization in toluene at 50 C for the synthesis of furan derivatives. It was notably that all the domino reactions were smooth under mild conditions with commercially available catalysts, and afforded highly functionalized furans in moderate to good yields. As we know, furans derivatives are extremely useful organic molecules used as synthetic building blocks for the synthesis of more elaborate heterocyclic compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258461

FEATURE ARTICLE
1019
Transition-Metal-Catalyzed Domino Reactions: Efficient One-Pot
Regiospecific Synthesis of Highly Functionalized Polysubstituted Furans from
Electron-Deficient Alkynes and 2-Yn-1-ols
O
ne-Pot Regiospec
u
ific Synthes
a
is of
P
olysubstitut
C
ed Furans ao,a,b Huanfeng Jiang,*a Huawen Huanga
a
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. of China
Fax +86(20)87112906; E-mail: jianghf@scut.edu.cn
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. of China
b
Received 14 December 2010; revised 28 January 2011
tion-metal-catalyzed domino reactions have dramatically
improved and expanded, providing an indispensable, sim-
ple methodology for synthetic organic chemistry. There-
fore, new strategies and methodologies for the
Abstract: Based on the reactive behavior of different transition-
metal catalysts, three methods for the synthesis of highly function-
alized polysubstituted furan derivatives are presented: (i) copper(I)
iodide catalyzed regiospecific synthesis of furan aldehydes/ketones
from alkynols and diethyl but-2-ynedioate under atmospheric pres- construction of heterocyclic skeletons are required to
sure; (ii) nano-Cu2O-catalyzed domino process for the regioselec-
make the already known domino reactions simpler, less
expensive, and greener.4
tive synthesis of a-carbonylfurans from readily accessible starting
materials; (iii) silver-catalyzed one-pot cyclization in toluene at 50
Moreover, copper and silver were among the first metals
identified by early humans and they are also important
transition-metal catalysts. They are widely used to synthe-
size various functionalized molecules in organic chemis-
try. In this paper, we would like to design copper- and
silver-catalyzed reactions for the construction of function-
alized furan skeletons.
°C for the synthesis of furan derivatives. It was notably that all the
domino reactions were smooth under mild conditions with commer-
cially available catalysts, and afforded highly functionalized furans
in moderate to good yields. As we know, furans derivatives are ex-
tremely useful organic molecules used as synthetic building blocks
for the synthesis of more elaborate heterocyclic compounds.
Key words: transition-metal-catalyzed domino reaction, function-
alized polysubstituted furan, copper(I) iodide, nano-Cu2O, silver(I)
acetate
Furans are one of the most important heterocyclic
compounds5 and worthy of our attention as functionalized
furan exhibit extensively biological activity6 and many
naturally occurring compounds contain the furan skeleton
as a key structural unit.7 Therefore, organic chemists have
been making extensive efforts to construct furan deriva-
tives by developing new and efficient synthetic methodol-
ogies.8 Transition-metal-catalyzed domino reactions are
one of the most attractive methodologies for the synthesis
of furans,9 since transition-metal-catalyzed domino reac-
tions can directly construct polysubstituted furans from
readily accessible starting materials under mild
conditions10 (Scheme 1). Although several useful proce-
dures have been developed that allow the preparation of
functionalized furan molecule, there is still an intrinsic
need to design transition-metal-catalyzed domino reac-
tions for the synthesis of furans under mild conditions and
using simple catalytic systems.
Introduction
Synthetic organic transformations are at the heart of syn-
thetic chemistry and have been developed in a fascinating
way over the past few decades.1 Insofar as one of the fun-
damental aims of organic synthesis is the preparation of
complex and diverse compounds from readily accessible
starting materials, the importance of synthetic efficiency
becomes immediately apparent and has been well-recog-
nized by organic synthetic chemists. Domino reactions
have received attention and have been extensively used as
powerful tools in modern organic synthesis for the syn-
thetically efficient construction of various heterocyclic
molecules in one sequence without the isolation of inter-
mediates.2 It was obvious that this type of reaction would
allow the minimization of waste and, thus, make waste
management unnecessary, since they use dramatically de-
creased amounts of solvents, reagents, and energy when
compared to stepwise reactions.3 In the past few years, or-
ganic chemists have been expected not only to design new
chemical reactions but also to improve catalyst systems to
maximize resource utilization and decrease waste, espe-
cially in terms of environmental health and safety. Transi-
R1
Ph
R3
Ph
X
Nu
PdCl2(MeCN)2
R3
+
NuH
Ph
+
R2
Ph
base, r.t., MeCN
R1
R2
O
O
R2
R2
R2
R3
Rh or Ag or Pd or Au
or
R3 R1
R1
R3
R1
O
O
O
R1
SYNTHESIS 2011, No. 7, pp 1019–1036
Advanced online publication: 03.03.2011
DOI: 10.1055/s-0030-1258461; Art ID: Z53310SS
x
x
.
x
x
.2
0
1
1
Cu
Ru
R1
R2OH
R1
R1
R1
+
OR2
O
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Transition-metal-catalyzed synthesis of furans

1020
H. Cao et al.
FEATURE ARTICLE
Herein, we reported two convenient copper(I)-11 and sil- lo[2.2.2]octane13 (DABCO, 10 mol%), with 2.5 mol% of
ver(I)-catalyzed12 protocols for the synthesis of highly silver(I) tetrafluoroborate or copper(I) iodide in N,N-di-
functionalized polysubstituted furans 3 and 4 by a one-pot methylformamide at 80 °C. Interestingly, different poly-
cyclization reaction from electron-deficient alkynes 1 and substituted furan rings, 3aa and 4aa, were obtained with
alkynols 2 (Scheme 2 and Figure 1).
high regiospecificity (Scheme 2). Subsequently, our ef-
forts focused on searching for potential catalysts and suit-
able reaction conditions to synthesize a-carbonyl
polysubstituted furans 3aa, since few general procedures
are available for the synthesis of a-carbonyl polysubstitut-
ed furans.
Results and Discussion
Copper(I)-Catalyzed Synthesis of a-Carbonyl
Polysubstituted Furans
Encouraged by the copper(I) iodide catalyzed synthesis of
furan derivatives, the effect of several commercially
available copper salts, solvents, and various temperatures
on the reactivity and selectivity in the domino reaction of
Initially, 1,5-enyne 3a, the adduct of diethyl but-2-ynedio-
ate (1a) with prop-2-yn-1-ol (2a) was treated, in the
presence of a catalytic amount of 1,4-diazabicyc-
EtO2C
AgBF4, DMF
COOEt
80 °C, Ph3P
EtO2C
O
EtO2C
DABCO
+
4aa
CH2Cl2, r.t.
EtO2C
O
COOEt
OH
2a
EtO2C
O2, CuI
A
1a
H
DMF, 80 °C
EtO2C
O
O
3aa
Scheme 2 Silver(I)- or copper(I)-catalyzed one-pot synthesis of furan derivatives
Biographical Sketches
Dr. Hua Cao was born in He achieved his Ph.D. in Jiang. He was awarded the
Hunan, China, in 1981. Af- 2010 from the South China Research Award in 2008.
ter receiving his B.S. degree University of Technology, His current research inter-
in chemistry at the Hunan working on domino reaction ests are focused on develop-
Normal University in 2004, for the synthesis of pyrim- ing new metal-catalyzed
he obtained his M.S. degree idines, oxazines, and furans system and methodologies
under the supervision of from
electron-deficient for the construction of sev-
Prof. Baoan Song in 2007 alkynes under the supervi- eral functionalized hetero-
from Guizhou University. sion of Prof. Huanfeng cyclic compounds.
Prof. Dr. Huanfeng Jiang my of Sciences. In 2003, he Engineering, SCUT. His re-
was born in Hubei, China, in joined South China Univer- search interests include syn-
1961. He obtained his Ph.D. sity of Technology (SCUT). thetic methodology, green
at SIOC in 1993, and then He is currently the leading chemistry, and carbon diox-
became a research fellow at Professor of Chemistry and ide conversion.
Guangzhou Institute of Deputy Dean of School of
Chemistry, Chinese Acade- Chemistry and Chemical
Huawen Huang was raised of Professor Fan Daidi. He Technology (Guangzhou,
in Hunan, China. He re- is currently a Ph.D. candi- China). His current research
ceived a B.S. degree from date in the laboratory of is focused on novel methods
the School of Chemical Professor Huanfeng Jiang in for the synthesis of hetero-
Engineering at Northwest the School of Chemistry and cyclic compounds.
University (Xi’an, China) in Chemical Engineering, at
2009 under the mentorship South China University of
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1021
1a with 2a were surveyed. In a typical procedure, 1a (0.5
mmol), 2a (0.5 mmol) and DABCO in dichloromethane
were stirred for 10 minutes at room temperature; the solu-
tion was evaporated to dryness under reduced pressure.
Subsequently, 2.5 mol% of the copper salt in N,N-dimeth-
ylformamide were added at 50 °C. It was found that the
desired product 3aa was formed in the presence of cop-
per(I) catalysts (Table 1), such as copper(I) chloride (en-
try 1), copper(I) iodide (entry 2), copper(I) bromide (entry
3), and copper(I) oxide (entry 4). On the other hand, it was
also confirmed that little reaction took place in the pres-
ence of copper(II), such as copper(II) oxide (entry 5) and
copper(II) bromide (entry 6), even for prolonged reaction
times. With regard to the solvent, only N,N-dimethyl-
formamide was proven to be suitable in the presence of
copper(I) iodide and 3aa was obtained in 71% yield, while
other solvents, such as dichloromethane (entry 7), toluene
(entry 8), tetrahydrofuran (entry 9), and 1,4-dioxane (en-
try 10), led to lower yields. Finally, different temperatures
were also examined (entries 11–14), and the results
showed that the optimal temperature in N,N-dimethyl-
formamide was 80 °C.
Table 1 Screening of Copper Salts in the Synthesis of a-Carbonyl
Polysubstituted Furans
CO2Et
EtO2C
cat.
DABCO
+
CH2Cl2, r.t.
H
r.t. to 100 °C
EtO2C
O
CO2Et
HO
2a
O
1a
3aa
Entry
1
Catalyst
CuCl
CuI
Solvent
DMF
Temp (°C) Yielda (%)
50
50
50
50
50
50
50
50
50
50
r.t.
80
30
100
53
71
62
59
19
23
45
44
19
27
8
2
DMF
3
CuBr
Cu2O
CuO
CuBr2
CuI
DMF
4
DMF
5
DMF
6
DMF
7
CH2Cl2
toluene
THF
8
CuI
9
CuI
To explore the scope of the reaction with diethyl but-2-
ynedioate (1a), the effects of various 2-yn-1-ols 2
(Figure 1) were examined. First, prop-2-yn-1-ol (2a) was
tested and the corresponding furan 3aa was obtained in
10
11
12
13
14
CuI
1,4-dioxane
DMF
CuI
CuI
DMF
78
31
74
R3
COR1
CuI
DMF
CuI
DMF
R2
a Isolated yields.
HO
1a R1 = OEt, R2 = CO2Et
1b R1 = Ph, R2 = CO2Et
1c R1 = R2 = 4-Tol
2a R3 = H
78% isolated yield (Scheme 3). Other 3-substituted 2-yn-
1-ols 2c,d,h–p were also employed and the corresponding
furans 3ac,ad,ah–ap were formed in 45–71% isolated
yields. From Scheme 3, these results indicated that ali-
phatic groups could work well as aryl groups. The pres-
ence of either electron-donating aryl groups (e.g., 2i, 2l)
or electron-withdrawing groups (e.g., 2j, 2k) on the aro-
matic ring of the alkynols resulted in the formation of
furans (e.g., 3ai, 3al or 3aj, 3ak, respectively) in good
yields in this transformation. It was also obvious that sub-
stituents presented in the p- and m-positions of the aro-
matic group of alkynols, such as 2d and 2l had no negative
effects on the reaction and the respective furans 3ad and
3al were formed in good yield. However, if more sterical-
ly hindered o-substituted aromatic groups, such as 2i and
2m, were employed in the alkynol, the corresponding
products 3ai and 3am were obtained in lower yields. Sub-
sequently, the effect of 1,3-disubstituted 2-yn-ols were
examined and the desired furans 3ap–ar were obtained in
54–59% yields (Scheme 3). Unfortunately, when 1a was
exchanged by other alkynoates, such as ethyl propynoate
or ethyl but-2-ynoate (1d), the desired products were not
detected.
2b R3 = Me
2c R3 = Ph
1d R1 = OEt, R2 = Me
1e R1 = R2 = Ph
2d R3 = 3-Tol
2e R3 = 4-MeOC6H4
2f R3 = 4-O2NC6H4
2g R3 = pyridin-2-yl
2h R3 = thiophen-2-yl
2i R3 = 2-MeOC6H4
2j R3 = 4-MeO2CC6H4
2k R3 = 2-FC6H4
2i R3 = 2-MeOC6H4
2j R3 = 4-MeO2CC6H4
2k R3 = 4-FC6H4
2l R3 = 4-EtC6H4
2m R3 = 2-Tol
1f R1 = thiophen-2-yl, R2 = Ph
1g R1 = 4-Tol, R2 = Ph
1h R1 = OMe R2 = CO2Me
2n R3 = 2-EtC6H4
2o R3 = Et
R3
R3
OH
HO
R4
2s R3 = Ph
2p R3 = Me, R4 = Et
2q R3 = R4 = Et
2t R3 = 4-Tol
2r R3 = Ph, R4 = Pr
Figure 1 Electron-deficient alkynes 1 and alkynols 2 utilized
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1022
H. Cao et al.
FEATURE ARTICLE
R1
Table 2 Optimization of the Reaction Conditions
CO2Et
R1
CO2Et
EtO2C
1) DABCO, CH2Cl2
2) O2/CuI, DMF, 80 °C
EtO2C
Ph
Bu3P
cat.
+
R2
+
CH2Cl2, r.t.
EtO2C
HO
R2
CHO
CO2Et
O
O
HO
Ph
O
1a
2a,c,d,h–p
3aa,ac,ad,ah–am,ap–ar
1b
2a
3ba
Entry Catalyst
Air or O2
(atm)
Temp
(°C)
Yielda
(%)
EtO2C
EtO2C
Ph
EtO2C
1
2
5 mol% CuI
5 mol% Cu2O
air
80
80
120
80
80
80
80
80
80
80
80
80
80
80
80
100
50
r.t.
–
EtO2C
CHO
O
EtO2C
3ac 71%
CHO
CHO
EtO2C
3ad 67%
O
O
air
<5
<5
–
3aa 78%
3
5 mol% Cu2O
air
CO2Me
S
4
5 mol% Ru3(CO)12
5 mol% PdCl2
air
EtO2C
EtO2C
EtO2C
OMe
EtO2C
5
air
–
EtO2C
CHO
CHO
O
6
5 mol% Pd(OAc)2
5 mol% Pd(dba)2
5 mol% NiSO4
air
–
O
CHO
EtO2C
O
7
air
–
3ah 68%
3ai 45%
3aj 69%
8
air
trace
62
67
46
41
58
69
68
65
75
–
EtO2C
EtO2C
9
5 mol% nano-Cu2O
5 mol% nano-Cu2O
5 mol% nano-Cu2O
5 mol% nano-Cu2O
10 mol% nano-Cu2O
10 mol% nano-Cu2O
10 mol% nano-Cu2O
10 mol% nano-Cu2O
10 mol% nano-Cu2O
10 mol% nano-Cu2O
air
EtO2C
F
O
O
10
11
12
13
14
15
16
17
18
O2 (1)
O2 (3)
O2 (5)
O2 (5)
O2 (1)
air
EtO2C
EtO2C
EtO2C
CHO
O
O
O
3aq 54%
3ak 61%
3ap 57%
Et
EtO2C
EtO2C
Ph
EtO2C
O
EtO2C
CHO
EtO2C
O
O
EtO2C
CHO
O
3am 52%
3ar 59%
3al 64%
air
Scheme 3 Copper(I) iodide catalyzed domino reactions for the syn-
thesis of furans
air
air
a GC yields.
Nano-Cu2O-Catalyzed Domino Reaction Synthesis
of Furans
per(I) oxide (entry 2). We assumed that an increase in
temperature might influence the formation of 3ba. How-
ever, it was observed that the yield of 3ba did not change
markedly even at 120 °C (entry 3). Other late-transition-
metal catalysts, such as Ru3(CO)12, PdCl2, Pd(OAc)2, and
Pd(dba)2 (entries 4–7), were also employed; however, no
conversion was observed in these cases. Nickel(II) sulfate
was also used as the catalyst, and trace of 3ba was detect-
ed by GC-MS (entry 8).
This domino process could not take place when ethyl phe-
nylpropynoate (1b) was employed as the substrate, replac-
ing diethyl but-2-ynedioate (1a), in the presence of
copper(I) iodide catalyst (Table 2, entry 1). Therefore, it
was essential to design and develop a new method for the
synthesis of a-carbonyl furans.
Initially, we chose ethyl phenylpropynoate (1b) and prop-
2-yn-1-ol (2a) as the standard substrates to search for po-
tential catalysts and suitable reaction conditions, and the
results are summarized in Table 2. In a typical procedure,
1b (0.5 mmol), 2a (0.5 mmol) and tributylphosphine14
were added and the mixture was stirred for 30 minutes in
dichloromethane at room temperature. The solution was
then evaporated to dryness under reduced pressure. Sub-
sequently, the catalyst was added in N,N-dimethylform-
amide at 50 °C.
Inspired by the result that copper(I) oxide could catalyze
the reaction, we attempted to prepare nano-Cu2O. Accord-
ing to previous reports,15 copper(I) oxide microcrystals
were prepared by a simple hydrothermal method. Cop-
per(II) acetate monohydrate and acetic acid (AR grade)
were employed as starting materials. First, Cu(OAc)2·H2O
(1.548 g) was dissolved in deionized water (50 mL) to
form a clear solution. Then, acetic acid (1 mL) was added
into the solution under continuous stirring to form the pre-
cursor solution. The precursor solution was transferred
As shown in Table 2, the corresponding product 3ba was
detected when copper(I) iodide was substituted by cop-
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1023
into Teflon-lined stainless steel autoclave, which was then the above results, we tried to change the amount of cata-
maintained at 200 °C for 27 hours. The red product col- lyst to improve the yield of 3ba. The results indicated that
lected from the bottom of the container was washed with the corresponding furan 3ba was formed in moderate to
deionized water several times and dried in a vacuum oven good yield by using 10 mol% nano-Cu2O (entries 13–17).
at 60 °C for five hours. The formation of the nano-Cu2O Next, we examined the effect of solvents and tempera-
was confirmed by XRD (Figure 2) and SEM analysis tures and found that N,N-dimethylformamide and 50 °C
(Figure 3).
were optimum conditions for this transformation. Balanc-
ing all results it was concluded that the optimal conditions
for this domino reaction involved the use of 10 mol%
nano-Cu2O in N,N-dimethylformamide at 50 °C.
With the optimal reaction conditions in hand, we next ex-
plored the scope of this domino reaction. The results are
summarized in Scheme 4. It was shown that the reaction
conditions are useful for a range of electron-deficient
alkynes 1b–e and 3-substituted 2-yn-ols. It was obvious
that the reaction between ethyl phenylpropynoate (1b)
and differently 3-substituted 2-yn-1-ols 2a–h (R3 = H,
Me, Ph, 3-Tol, 4-MeOC6H4, 4-O2NC6H4, pyridin-2-yl,
thiophen-2-yl) had a beneficial effect on the reaction
products, and in most cases the corresponding products
3aa–ah were obtained in moderate to good yields. These
results indicated that the substituted 2-yn-1-ol with differ-
ent substituent groups presented on the aromatic ring
could react smoothly, and the corresponding products
were obtained in good yields. It was also shown that both
electron-rich and electron-withdrawing groups at the aro-
matic ring had no effect on this domino reaction.
Figure 2 XRD pattern of copper(I) oxide particles
To further expand the scope of this transformation, other
electron-deficient alkynes, such as 1,3-bis(4-tolyl)prop-2-
yn-1-one (1c), ethyl but-2-ynoate (1d), and 1,3-diphenyl-
prop-2-yn-1-one (1e), were employed. The results
showed that ethyl but-2-ynoate (1d) and aryl alkynyl ke-
tones 1c,e were also well tolerated under the optimum
conditions and afforded the corresponding products in
good yields (60–73%). It was noteworthy that no other
regioisomers were detected in this transformation, which
indicated that this cyclization was regioselective and
chemoselective. Finally, the molecular structure of repre-
sentative product 3cc was determined by X-ray crystal-
lography (Figure 4).
Figure 3 SEM Images of nano-Cu2O
As we expected, the reaction yield of 3ba dramatically in-
creased to 62% (entry 9), when 5 mol% nano-Cu2O was
employed in N,N-dimethylformamide under atmospheric
pressure. We attempted to improve the yields by substitut-
ing air by oxygen and even increasing oxygen pressure
(entries 10–12). It was noteworthy that the use of pure
oxygen instead of atmospheric oxygen had no significant
influence on the yields. However, when a higher pressure of
oxygen was used (entries 11 and 12), the yield decreased
gradually, which indicated that nano-Cu2O was oxidized
to copper(II) oxide at high oxygen pressures. Inspired by
Figure 4 X-ray crystal structure of compound 3cc
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1024
H. Cao et al.
FEATURE ARTICLE
R3
R3
COR1
R2
O
+
R3
R1OC
R2
O
1. DABCO or Bu3P
nano-Cu2O
DMF, 50 °C
Bu3P
R2
OH
CH2Cl2, r.t.
+
R3
CH2Cl2, r.t.
CHO
2. O2, nano-Cu2O
50 °C
O
R2
HO
2a–h
R1
3bs,es,at,hs
Ph
CHO
R1
1a,b,e,h
O
1b–e
3ba–bh,ca–cc,db,ea,ef,eh
2s,t
EtO2C
Ph
Ph
EtO2C
Ph
EtO2C
Ph
Ph
Ph
O
CHO
EtO2C
CHO
3bc 63%
CHO
3bb 67%
O
O
O
3ba 71%
CHO
Ph
O
CHO
Ph
O
NO2
OMe
3bs 42%
3es 45%
EtO2C
Ph
EtO2C
EtO2C
Ph
Ph
CHO
3bf 66%
Ph
CHO
CHO
O
O
O
MeO2C
EtO2C
3bd 68%
3be 65%
O
CHO
MeO2C
3hs 51%
CHO
EtO2C
O
S
O
EtO2C
Ph
EtO2C
Ph
N
3at 49%
CHO
O
Scheme 5 The formation of 2-ynylfurans; isolated yields
CHO
CHO
O
O
3bg 69%
3bh 62%
3ca 67%
EtO2C
corresponding products were obtained (Scheme 6). Nota-
bly, it was found that a pair of isomer furans was observed
and gave high yields of products under the optimized con-
ditions. This result demonstrated that since two carbonyl
groups in complex D (Scheme 12) were both active in the
following cyclization reaction, regioisomers would be
produced.
O
O
CHO
CHO
O
O
3db 60%
O
CHO
3cb 73%
3cc 70%
Ph
Ph
Ph
O
Ph
O
Silver(I) Acetate Catalyzed Domino Reaction Syn-
thesis of Furans
O
CHO
3ec 71%
Ph
O
CHO
Ph
CHO
Ph
O
From above investigation, two efficient domino reactions
were developed for the synthesis of a-carbonyl furans by
copper(I) catalysis. Next, we report a convenient silver-
catalyzed domino reaction for the synthesis of polysubsti-
tuted furans.
O
3ea 68%
3eb 73%
NO2
OMe
S
Ph
O
Ph
O
Ph
O
Initially, the reaction of 1a with 2a was investigated as a
model system to explore potential catalysts and suitable
reaction conditions and the results are shown in Table 3.
Based on the experience of our previous work, it was ob-
vious that 4aa was obtained in the presence of silver(I)
tetrafluoroborate and triphenylphosphine in N,N-dimeth-
ylformamide at 80 °C (Scheme 1 and Table 3, entry 1).
We next examined the reaction using 5 mol% of silver(I)
acetate and 10 mol% triphenylphoshine and the yield of
4aa dramatically increased to 68% (entry 2). Other cata-
lysts, such as 5 mol% AgNO3, 5 mol% Ag2CO3, 5 mol%
PdCl2, 5 mol% Pd(OAc)2, 5 mol% Pd(dba)2, 5 mol%
Ru3(CO)12, and 3 mol% AuCl3, were employed (entries 3–
10). The results indicated that silver(I) acetate was an ef-
ficient catalyst for the synthesis of polysubstituted furans.
Subsequently, the effects of solvents were examined for
this domino reaction. To our surprise, when toluene was
used as the solvent, it was found that the yield of 3aa in-
CHO
Ph
CHO
O
Ph
CHO
Ph
O
O
3ee 71%
3ef 67%
3eh 61%
Scheme 4 Nano-Cu2O-catalyzed synthesis of furans
Furthermore, 5-phenylpenta-2,4-diyn-1-ol (2s) and 5-(4-
tolyl)penta-2,4-diyn-1-ol (2t) (Scheme 5) were also sur-
veyed and the desired products 3bs, 3es, 3at, 3hs were ob-
tained in 42–51% yield. It was especially noteworthy that
novel 2,4,5-trisubstituted 3-ynylfurans were obtained in
an extremely direct manner without tedious stepwise syn-
thesis.16
Finally, the substrates 3-phenyl-1-(thiophen-2-yl)prop-2-
yn-1-one (1f) and 3-phenyl-1-(4-tolyl)prop-2-yn-1-one
(1g) were also examined as replacements for 1a–e and the
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1025
O
Table 3 Optimization of the Synthesis of 4aa
O
R2
Ph
R2
R2 Ph
+
R1
Ph
CO2Et
Bu3P
nano-Cu2O
DMF, 50 °C
EtO2C
+
EtO2C
EtO2C
DABCO
CH2Cl2, r.t.
cat.
R1
+
O
CH2Cl2, r.t.
O
O
R1
EtO2C
OH
O
O
CO2Et
OH
2a
1f,g
2a,c
3fa,fc,ga
4fa,fc,ga
1a
3a
4aa
O
O
Entry Catalyst
Solvent
Temp Yielda
(°C) (%)
Ph
S
CHO
O
1
2
5 mol% AgBF4/10% Ph3P
5 mol% AgOAc/10% Ph3P
5 mol% AgNO3/10% Ph3P
5 mol% AgCO3/10% Ph3P
5 mol% PdCl2/10% Ph3P
5 mol% Pd(OAc)2/10% Ph3P
5 mol% Pd(dba)2
DMF
DMF
DMF
DMF
CH2Cl2
DMF
DMF
DMF
DMF
DMF
100
100
100
100
50
37
68
32
trace
–
CHO
Ph
3fa
O
S
4fa
53% (1:1)
3
O
O
4
Ph
Ph
S
Ph
5
S
CHO
O
CHO
Ph
O
6
100
100
100
100
100
100
100
–
3fc
4fc
7
–
50% (3:1)
8
5 mol% Ru3(CO)12
–
O
O
9
3 mol% AuCl3
11
13
76
40
46
79
–
Ph
10
11
12
13
14
15
3 mol% AuCl3/5 mol% Ph3P
CHO
Ph
CHO
O
O
5 mol% AgOAc/10 mol% Ph3P toluene
5 mol% AgOAc/10 mol% Ph3P DCE
3ga
4ga
54% (3:2)
Scheme 6 The formation of regioisomeric furans (ratio determined
5 mol% AgOAc/10 mol% Ph3P 1,4-dioxane 100
by 1H NMR)
5 mol% AgOAc/10 mol% Ph3P toluene
5 mol% AgOAc/10 mol% Ph3P toluene
50
r.t.
creased to 76% (entry 11). Other solvents, such as 1,2-
dichloroethane and 1,4-dioxane, were also employed and
led to moderate yields (entries 12 and 13). Finally, differ-
ent temperatures were also tested (entries 7–14), and it
was found that 50 °C was the optimum for this transform-
ation.
a Yield determined by GC.
estingly, the desired products 4cs, 4es, 4hs, and 4ht were
formed in 68–75% yields. No formation of other regioiso-
mers was observed by GC/MS. It was especially notewor-
thy that novel 2,3,5-trisubstituted 4-ynylfurans were
formerly formed in an extremely direct manner without
tedious stepwise synthesis.
On the basis of the above optimization of the reaction con-
ditions, it provided possible to synthesize a series of
polysubstituted furans by silver(I) acetate catalysis
(Scheme 7). The typical results indicated that the reaction
was quite general, forming polysubstituted furans with
very high regio- and stereoselectivity; In the electron-de-
ficient alkyne 1, R1 may be aryl, OEt, or OMe; R2 may be
CO2Et, aryl, or CO2Me. Differently 3-substituted 2-yn-1-
ols 2 (R3 = H, Me, Ph, 3-Tol, 4-MeOC6H4, 2-MeOC6H4,
2-FC6H4, thiophen-2-yl, 4-EtC6H4, 2-EtC6H4) had a bene-
ficial effect on the reaction products, and in most cases the
corresponding products 4aa–ht were obtained in moder-
ate to good yields. These results showed that aliphatic
groups could work well as aryl groups. Both electron-rich
aryl groups and electron-withdrawing groups were ob-
tained good yields in this transformation. Subsequently,
ethyl 3-phenylpropynoate (1b) and 1,3-diphenylprop-2-
yn-1-one (1e) were also examined and the desired prod-
ucts 4be, 4ea, and 4ec were obtained in 70–79% yields.
Furthermore, 5-phenylpenta-2,4-diyn-1-ol (2s) and 5-(4-
tolyl)penta-2,4-diyn-1-ol (2t) were also employed. Inter-
These promising results encouraged us to extend the
scope of the reaction using other electron-deficient
alkynes (R1 ≠ R2). Interestingly, substrates bearing differ-
ent substituents gave a pair of regio-isomers. As shown in
Scheme 8, electron-deficient alkynes 1f, 1g, 1i were ex-
amined and the desired products 4ia–gc and their regio-
isomers 5ia–gc were obtained in reasonable yields. To our
knowledge, this transformation has not been previously
reported. The molecular structure of representative prod-
uct 5ic was confirmed by an X-ray diffraction study
(Figure 5).
Mechanism
To gain further insight into the mechanism of this novel
transformation, we envisioned the possibility to trap the
intermediates of the domino reaction. Recently,
Hofmann17 has reported the formation of a carbene dimer
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1026
H. Cao et al.
FEATURE ARTICLE
R3
O
O
R2
Ph
R3
R2
R2
Ph
COR1
R1
Ph
1. Bu3P
CH2Cl2, r.t.
R3
R1OC
R2
R1OC
R2
AgOAc
Ph3P
+
+
DABCO
+
2. AgOAc
toluene, 50 °C
OH
toluene
50 °C
CH2Cl2
r.t.
OH
R1
O
O
R2
O
O
R1
O
1
2
4
5
1a–c,e,h 2a–e,h–o,s,t
4aa–ht
A
O
EtO2C
EtO2C
EtO2C
Ph
Cl
Ph
O
EtO2C
O
EtO2C
EtO2C
O
O
O
4aa 71%
4ab 70%
4ac 68%
Ph
O
OMe
Cl
4ia
5ia
73% (50:50)a
S
O
EtO2C
EtO2C
EtO2C
Cl
Ph
Ph
O
Ph
EtO2C
EtO2C
EtO2C
O
O
O
O
4ad 68%
4ae 66%
4ah 64%
Ph
O
CO2Me
Cl
4ic
5ic
64% (45:55)a
O
EtO2C
EtO2C
OMe
EtO2C
O
Ph
F
S
EtO2C
EtO2C
EtO2C
O
O
O
O
5fa
O
Ph
4ai 55%
4aj 69%
4ak 62%
O
S
4fa
Et
72% (50:50)a
O
Ph
EtO2C
EtO2C
EtO2C
Et
EtO2C
EtO2C
EtO2C
O
O
O
O
Ph
O
O
4al 67%
4am 59%
4an 53%
5ga
4ga
83% (57:43)b
Ph
OMe
O
O
O
Ph
Ph
EtO2C
Ph
EtO2C
Ph
O
Ph
EtO2C
Ph
O
O
O
4ao 64%
4be 79%a
4ea 70%a
4gc
5gc
40% (50:50)b
Ph
O
Ph
Scheme 8 Cyclization of alkynyl ketones with 2-yn-1-ols (a ratio
O
O
determined by HPLC; b ratio determined by 1H NMR)
Ph
Ph
Ph
Ph
O
CO2Et
nano-Cu2O,
DMF, 50 °C
Ph
EtO2C
O
O
DABCO
O
4ec 78%a
4cs 75%a
4es 72%a
+
O
CH2Cl2, r.t.
OH
EtO2C
OEt
O
N2
CO2Et
OEt
1a
2a
6
32%
Ph
Scheme 9 The formation of compound 6
MeO2C
MeO2C
O
EtO2C
MeO2C
MeO2C
EtO2C
N2
O
O
X OEt
O
4hs 70%
4ht 68%
CHO
EtO2C
nano-Cu2O,
DMF, 50 °C
EtO2C
O
O
Scheme 7 Silver(I)-catalyzed formation of polysubstituted furans
OEt
(a Bu3P-substituted DABCO as catalyst)
3aa
6
Scheme 10 The reaction of 3aa with ethyl 2-diazoacetate
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1027
via reaction of a copper(I) carbene with nucleophilic diazo
compounds. Stimulated by this novel result, we tried to
trap a copper carbene in our reactions by using ethyl 2-di-
azoacetate (Scheme 9). Compounds 1a (0.5 mmol) and 2a
(0.5 mmol) with DABCO (0.05 mmol) in dichlo-
romethane were stirred for 10 minutes at room tempera-
ture. The solution was evaporated and N,N-
dimethylformamide (3 mL) and nano-Cu2O (0.3 mmol)
were added at 50 °C. Subsequently, ethyl 2-diazoacetate
(0.8 mmol) was added; interestingly, the vinylfuran 6 was
observed. Compound 6 was not formed (Scheme 10)
when 3aa reacted with ethyl 2-diazoacetate under the op-
timal conditions. These results indicated that a copper car-
bene complex was likely to be formed during this domino
reaction.
To investigate a possible H-migration in the reaction, an
experiment was performed using deuterium-labeled prop-
2-yn-1-ol (2aD) at 50 °C by nano-Cu2O catalysis
(Scheme 11). Compounds 3aaD and 4aaD were not ob-
served as the products, which indicated that the deuterium
was eliminated during the rearrangement and cyclization
processes.
Figure 5 X-ray crystal structure of compound 5ic
CO2Et
EtO2C
D
4
EtO2C
2
3
EtO2C
EtO2C
D
O
nano-Cu2O
X
DABCO
+
+
CH2Cl2, r.t.
CDO
EtO2C
DMF, 50 °C
CHO
6
EtO2C
5
O
O
OD
CO2Et
3aaD
4aaD
2aD
1a
Scheme 11 Deuterium-labeling experiment
O
O
R2
O
O
R4
O
R4
R2
R1
R4
R1
R4
R4
R2
R1
1. DABCO, Bu3P
1. DABCO, Bu3P
2. AgOAc, 80 °C
+
+
+
O
O
2. O2, nano-Cu2O, 80 °C
R3
R2
R1
R2
O
O
O
O
R1
R3
R3
HO
R3
R3
DABCO, Bu3P
CuL
O2
R4
AgL
O
R2
O
O
R4
R2
R1
R4
R1
R2
path II
AgL
H
O
R4
R1
O
R3
CuL
R3
CuL
R3
E'
R2
•
A
O
O
ML
R1
O
R3
E
path I
path II
O2
D'
path I
R4
O
path II
R4
ML
O
R2
CuL
H
O
R4
O
R2
•
R1
O
R3
AgL
R3
R2
O
R4
O
R1
O
R3
B
CuL
R3
path I
R2
R1
D
R1
M = Ag, Cu
C'
C
Scheme 12 Proposed mechanism
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1028
H. Cao et al.
FEATURE ARTICLE
was added. The aq soln was extracted with Et2O (3 × 8 mL) and the
combined extracts were dried (anhyd MgSO4). The solvent was re-
moved and the crude product was separated by column chromatog-
raphy to give a pure sample of 3aa.
On the basis of the above experimental results, a plausible
reaction mechanism is shown in Scheme 12. DABCO- or
tributylphosphine-promoted nucleophilic addition of pro-
pargyl alcohol to electron-deficient alkynes formed enyne
adduct A. A 6-endo-dig addition of the enol ether onto
copper(I)-alkyne complex B resulted in the formation of
intermediates C or C¢, which collapsed to give the b-allen-
ic ketones D or D¢.18 Complex D underwent cyclization,
1,3-H shift, and oxidation to form E and E¢.19 Since two
carbonyl groups in complex D were both active in the fol-
lowing cyclization reaction, carbene complexes E and E¢
would be produced by different attack direction (paths I
and II) in the presence of a copper catalyst and air. Subse-
Ethyl 5-Formyl-2-phenylfuran-3-carboxylate (3ba); Typical
Procedure
Ethyl phenylpropynoate (1b, 0.5 mmol), prop-2-yn-1-ol (2a, 0.5
mmol), and Bu3P (0.05 mmol) in CH2Cl2 were stirred at r.t. for 30
min. The soln was evaporated to dryness under reduced pressure.
Subsequently, DMF and nano-Cu2O were added at 50 °C. After
completion of the reaction (TLC monitoring), H2O (8 mL) was add-
ed. The aq soln was extracted with Et2O (3 × 8 mL) and the com-
bined extracts were dried (anhyd MgSO4). The solvent was
removed and the crude product was separated by column chroma-
quently, carbene complexes E and E¢ underwent carbene tography to give a pure sample of 3ba.
oxidation20 with an oxygen metathesis to give the desired
products a-carbonyl furans. While complex D¢ underwent
cyclization, the desired products were formed by H shift
directly.
Diethyl 5-Methylfuran-2,3-dicarboxylate (4aa); Typical Proce-
dure
Diethyl acetylenedicarboxylate (1a, 0.5 mmol), prop-2-yn-1-ol (2a,
0.5 mmol), and DABCO (0.05 mmol) in CH2Cl2 were stirred at r.t.
for 10 min. The soln was evaporated to dryness under reduced pres-
sure. Subsequently, AgOAc/Ph3P and toluene were added at 50 °C.
After completion of the reaction (TLC monitoring), the soln was
evaporated to dryness under reduced pressure and then H2O (8 mL)
was added. The aq soln was extracted with Et2O (3 × 8 mL) and the
combined extracts were dried (anhyd MgSO4). The solvent was re-
moved and the crude product was separated by column chromatog-
raphy to give a pure sample of 4aa.
Conclusion
In summary, we have reported an unprecedented cop-
per(I)-catalyzed synthesize of a-carbonyl furans via a
cyclization/rearrangement/oxidation sequence of 1,5-
enynes and also described silver(I) acetate catalyzed, one-
pot domino reactions for the synthesis of polysubstituted
furan under mild conditions. All the catalytic systems
were environmentally benign and effective for the forma-
tion C–C and C–O bonds. In addition, our findings opened
a convenient synthetic route to a variety of a-carbonyl
furans which are useful synthetic intermediates for bioac-
tive and natural compounds. It was noteworthy that these
synthesis methods are also attractive because furans are
extremely useful organic molecules that are used as syn-
thetic building blocks for the synthesis of more elaborate
heterocyclic compounds.
Diethyl 5-Formylfuran-2,3-dicarboxylate (3aa)
IR (KBr): 2978, 1732, 1667, 1574, 1028 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.75 (s, 1 H), 7.45 (s, 1 H), 4.32–
4.44 (m, 4 H), 1.22–1.40 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 178.3, 160.9, 157.1, 151.6, 147.0,
124.4, 119.2, 62.4, 61.9, 14.0.
MS (EI): m/z = 240, 213, 195, 167, 140.
Anal. Calcd for C11H12O6: C, 55.00; H, 5.04. Found: C, 55.08; H,
5.02.
Diethyl 5-Formyl-4-phenylfuran-2,3-dicarboxylate (3ac)
IR (KBr): 3069, 2977, 1734, 1680, 1546 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.70 (s, 1 H), 7.47 (s, 5 H), 4.43
(q, J = 8.0 Hz, 2 H), 4.28 (q, J = 8.0 Hz, 2 H), 1.40 (t, J = 8.0 Hz, 3
H), 1.22 (q, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 162.0, 157.1, 147.5, 144.3,
136.1, 129.7, 129.5, 128.7, 127.5, 126.3, 62.3, 62.1, 14.0, 13.7.
All reactions were performed under an air atmosphere in a round-
bottom flask equipped with a magnetic stirrer bar; yields are isolat-
ed yields unless otherwise stated. 1H and 13C NMR spectra were re-
corded using a Bruker Avance 400 MHz NMR spectrometer and
referenced to d = 7.26 and 77.0 for CDCl3 solvent, respectively,
with TMS as internal standard. IR spectra were obtained as KBr pel-
lets or as liquid films between two KBr pellets with a Bruker Vector
22 spectrometer. Mass spectra were recorded on a Shimadzu
GCMS–QP5050A at an ionization voltage of 70 eV equipped with
a DB–WAX capillary column (i.d. = 0.25 mm, length = 30 m). El-
emental analysis was performed on a Vario EL elemental analyzer.
TLC was performed using commercially prepared 100–400 mesh
silica gel plates (GF254), and visualization was effected at 254 nm.
All the other chemicals were purchased from Aldrich Chemicals.
MS (EI): m/z = 316, 288, 225, 213, 170, 115, 77.
Anal. Calcd for C17H16O6: C, 64.55; H, 5.10. Found: C, 64.67; H,
5.08.
Diethyl 5-Formyl-4-(3-tolyl)furan-2,3-dicarboxylate (3ad)
IR (KBr): 3052, 2984, 1739, 1580, 1538, 788 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.69 (s, 1 H), 7.26–7.35 (m, 4 H),
4.43 (q, J = 8.0 Hz, 2 H), 4.31 (q, J = 8.0 Hz, 2 H), 2.40 (s, 3 H),
1.40 (t, J = 8.0 Hz, 3 H), 1.26 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 162.0, 157.1, 147.5, 144.2,
138.5, 136.4, 130.5, 128.6, 127.4, 126.3, 62.3, 62.1, 21.3, 14.0,
13.8.
Diethyl 5-Formylfuran-2,3-dicarboxylate (3aa); Typical Proce-
dure
Diethyl acetylenedicarboxylate (1a, 0.5 mmol), prop-2-yn-1-ol (2a,
0.5 mmol), and DABCO (0.05 mmol) in CH2Cl2 were stirred at r.t.
for 10 min. The soln was evaporated to dryness under reduced pres-
sure. Subsequently, 2.5% mmol CuI and DMF were added at 80 °C.
After completion of the reaction (TLC monitoring), the soln was
evaporated to dryness under reduced pressure and then H2O (8 mL)
MS (EI): m/z = 330, 302, 284, 227, 184, 143, 128, 115, 91, 77.
Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.58; H,
5.44.
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1029
Diethyl 5-Formyl-4-(thiophen-2-yl)furan-2,3-dicarboxylate
(3ah)
13C NMR (100 MHz, CDCl3): d = 178.2, 162.2, 157.2, 147.5, 146.2,
144.2, 136.4, 129.5, 128.3, 126.4, 124.7, 62.4, 62.2, 28.6, 15.2,
14.1, 13.8.
IR (KBr): 3067, 2983, 1733, 1717, 1698, 1653, 1558 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.91 (s, 1 H), 7.53 (d, J = 5.2 Hz,
1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.15–7.17 (m, 1 H), 4.37–4.47 (m, 4
H), 1.41 (t, J = 7.2 Hz, 3 H), 1.34 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 162.2, 157.1, 147.5, 144.3,
132.4, 130.5, 129.1, 128.5, 128.0, 127.6, 127.0, 126.3, 62.6, 14.1,
13.9.
MS (EI): m/z = 344, 241, 213, 169, 141, 128, 115, 91, 77.
Anal. Calcd for C19H20O6: C, 66.27; H, 5.85. Found: C, 66.02; H,
5.90.
Diethyl 5-Formyl-4-(2-tolyl)furan-2,3-dicarboxylate (3am)
IR (KBr): 3110, 2984, 1732, 1587, 1444, 718 cm–1.
MS (EI): m/z = 322, 294, 220, 148, 121.
1H NMR (400 MHz, CDCl3): d = 9.54 (s, 1 H), 7.25–7.40 (m, 4 H),
4.45 (q, J = 7.2 Hz, 2 H), 4.21 (q, J = 7.2 Hz, 2 H), 2.23 (s, 3 H),
1.44 (t, J = 7.2 Hz, 3 H), 1.11 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 161.5, 157.4, 147.9, 145.1,
137.2, 136.0, 130.3, 129.7, 127.3, 125.8, 62.5, 61.9, 20.0, 14.2,
13.7.
Anal. Calcd for C15H14O6S: C, 55.89; H, 4.38. Found: C, 55.97; H,
4.36.
Diethyl 5-Formyl-4-(2-methoxyphenyl)furan-2,3-dicarboxy-
late (3ai)
IR (KBr): 3054, 2985, 1735, 1718, 1651, 1618, 1057 cm–1.
MS (EI): m/z = 330, 301, 257, 211, 155, 127, 115, 77.
1H NMR (400 MHz, CDCl3): d = 9.62 (s, 1 H), 7.42–7.44 (m, 1 H),
7.32–7.34 (m, 1 H), 6.97–7.06 (m, 2 H), 4.42 (q, J = 7.2 Hz, 2 H),
4.22 (q, J = 7.2 Hz, 2 H), 3.77 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.18
(t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.3, 161.9, 157.4, 156.8, 147.8,
144.8, 133.1 131.6, 131.4, 126.6, 120.8, 116.8, 111.0, 62.3, 61.7,
55.3, 14.2, 13.9.
Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.34; H,
5.52.
Diethyl 4-Methyl-5-propanoylfuran-2,3-dicarboxylate (3ap)
IR (KBr): 2984, 1731, 1684, 1586, 1539, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.38–4.44 (m, 4 H), 2.98 (q,
J = 7.2 Hz, 2 H), 2.44 (s, 3 H), 1.37–1.41 (m, 6 H), 1.20 (t, J = 7.2
Hz, 3 H).
MS (EI): m/z = 346, 315, 271, 227, 215, 199, 171, 115, 77.
Anal. Calcd for C18H18O7: C, 62.42; H, 5.24. Found: C, 62.30; H,
5.26.
13C NMR (100 MHz, CDCl3): d = 192.5, 162.5, 157.4, 142.2, 128.7,
126.6, 62.0, 61.7, 28.7, 14.0, 13.77, 9.28, 7.23.
MS (EI): m/z = 282, 253, 236, 209, 153, 136.
Diethyl 5-Formyl-4-[4-(methoxycarbonyl)phenyl]furan-2,3-di-
carboxylate (3aj)
Anal. Calcd for C14H18O6: C, 59.57; H, 6.43. Found: C, 59.68; H,
6.37.
IR (KBr): 3052, 2983, 1734, 1714, 1650, 1609, 1033 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.73 (s, 1 H), 8.12 (d, J = 8.0 Hz,
2 H), 7.55 (d, J = 8.0 Hz, 2 H), 4.46 (q, J = 8.0 Hz, 2 H), 4.30 (q,
J = 8.0 Hz, 2 H), 3.96 (s, 3 H), 1.39 (t, J = 8.0 Hz, 3 H), 1.21 (t,
J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 166.3, 161.8, 157.1, 147.7,
144.7, 134.4, 132.2, 131.4, 129.9, 129.7, 126.2, 62.6, 62.4, 52.4,
14.1, 13.9.
Diethyl 4-Ethyl-5-propanoylfuran-2,3-dicarboxylate (3aq)
IR (KBr): 2985, 1728. 1684, 1523, 1136 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.40 (q, J = 8.0 Hz, 4 H), 2.96 (q,
J = 7.6 Hz, 2 H), 2.87 (q, J = 7.6 Hz, 2 H), 1.36–1.40 (m, 6 H),
1.15–1.21 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 192.5, 162.9, 157.6, 148.1, 142.2,
135.0, 126.5, 62.0, 60.4, 32.8, 21.1, 14.2, 14.1, 7.39.
MS (EI): m/z = 374, 347, 315, 271, 213, 129, 59.
MS (EI): m/z = 296, 250, 221, 192, 178, 91, 57, 43.
Anal. Calcd for C19H18O8: C, 60.96; H, 4.85. Found: C, 61.04; H,
4.83.
Anal. Calcd for C15H20O6: C, 60.80; H, 6.80. Found: C, 60.95; H,
6.74.
Diethyl 4-(2-Fluorophenyl)-5-formylfuran-2,3-dicarboxylate
(3ak)
Diethyl 5-Butanoyl-4-phenylfuran-2,3-dicarboxylate (3ar)
IR (KBr): 3059, 2965, 1733, 1695, 1592 cm–1.
IR (KBr): 3071, 2986, 1696, 1621, 1593 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40 (s, 5 H), 4.41 (q, J = 7.2 Hz,
2 H), 4.22 (q, J = 7.2 Hz, 2 H), 2.84 (q, J = 7.2 Hz, 2 H), 1.63–1.72
(m, 2 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H), 0.96 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.6, 162.5, 157.4, 147.7, 141.7,
131.7, 131.4, 129.5, 129.0, 128.3, 127.1, 122.8, 62.8, 62.0, 41.7,
17.0, 14.2, 13.9, 13.7.
1H NMR (400 MHz, CDCl3): d = 9.67 (s, 1 H), 7.37–7.45 (m, 2 H),
7.14–7.23 (m, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.25 (q, J = 7.2 Hz, 2
H), 1.38 (t, J = 7.2 Hz, 3 H), 1.17 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 161.5, 161.1, 158.6, 157.2,
147.9, 145.4, 131.9, 131.7, 129.1, 126.0, 124.5, 116.0, 62.6, 62.1,
14.1, 13.8.
MS (EI): m/z = 344, 241, 213, 169, 141, 128, 115, 91, 77.
MS (EI): m/z = 358, 330, 284, 241, 184, 129, 43.
Anal. Calcd for C17H15FO6: C, 61.08; H, 4.52. Found: C, 61.21; H,
4.49.
Anal. Calcd for C20H22O6: C, 67.03; H, 6.19. Found: C, 66.89; H,
6.23.
Diethyl 4-(4-Ethylphenyl)-5-formylfuran-2,3-dicarboxylate
(3al)
Ethyl 5-Formyl-2-phenylfuran-3-carboxylate (3ba)
IR (KBr): 2921, 2853, 1683, 1216, 766 cm–1.
IR (KBr): 3064, 2971, 1738, 1665, 1602, 1477 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.66 (s, 1 H), 8.06–8.08 (m, 2 H),
7.64 (s, 1 H), 7.45–7.47 (m, 3 H), 4.31 (q, J = 7.2 Hz, 2 H), 1.33 (t,
J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 9.63 (s, 1 H), 7.30 (d, J = 8.0 Hz,
2 H), 7.21 (t, J = 8.0 Hz, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 4.22 (q,
J = 7.2 Hz, 2 H), 2.64 (q, J = 7.6 Hz, 2 H), 1.33 (t, J = 7.2 Hz, 3 H),
1.15–1.22 (m, 6 H).
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1030
H. Cao et al.
FEATURE ARTICLE
13C NMR (100 MHz, CDCl3): d = 177.4, 162.2, 161.5, 150.2, 131.0,
Ethyl 5-Formyl-2-phenyl-4-(pyridin-2-yl)furan-3-carboxylate
(3bg)
129.1, 128.3, 128.2, 123.8, 116.1, 61.2, 14.1.
IR (KBr): 2912, 2847, 1763, 1725, 1236, 626 cm–1.
HRMS (EI): m/z [M]+ calcd for C14H12O4: 244.0736; found:
244.0732.
1H NMR (400 MHz, CDCl3): d = 9.75 (s, 1 H), 8.70–8.72 (m, 1 H),
7.35–7.97 (m, 8 H), 4.19 (q, J = 7.2 Hz, 2 H), 1.03 (t, J = 7.2 Hz, 3
Ethyl 5-Formyl-4-methyl-2-phenylfuran-3-carboxylate (3bb)
H).
IR (KBr): 2927, 1771, 1722, 1599, 1238, 698 cm–1.
13C NMR (100 MHz, CDCl3): d = 178.3, 163.2, 158.8, 149.5, 149.2,
147.4, 137.3, 136.2, 130.7, 128.4, 128.3, 124.9, 123.4, 116.3, 61.2,
13.6.
HRMS (EI): m/z [M]+ calcd for C19H15NO4: 321.1001; found:
321.006.
1H NMR (400 MHz, CDCl3): d = 9.81 (s, 1 H), 7.81–7.83 (m, 2 H),
7.41–7.43 (m, 3 H), 4.27 (q, J = 7.2 Hz, 2 H), 2.55 (s, 3 H), 1.28 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.7, 163.1, 160.8, 147.4, 135.2,
130.5, 128.9, 128.6, 128.1, 116.6, 60.9, 13.9, 10.1.
Ethyl 5-Formyl-2-phenyl-4-(thiophen-2-yl)furan-3-carboxylate
(3bh)
HRMS (EI): m/z [M]+ calcd for C15H14O4: 258.0892; found:
258.0889.
IR (KBr): 2925, 1765, 1722, 1675, 1236, 704 cm–1.
Ethyl 5-Formyl-2,4-diphenylfuran-3-carboxylate (3bc)
1H NMR (400 MHz, CDCl3): d = 9.67 (s, 1 H), 7.86–7.89 (m, 2 H),
7.12–7.50 (m, 6 H), 4.21 (q, J = 7.2 Hz, 2 H), 1.11 (t, J = 7.2 Hz, 3
IR (KBr): 2983, 1772, 1724, 1677, 1228, 695 cm–1.
H).
1H NMR (400 MHz, CDCl3): d = 9.47 (s, 1 H), 7.93–7.95 (m, 2 H),
7.44 (s, 8 H), 4.11 (q, J = 7.2 Hz, 2 H), 1.00 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.2, 163.1, 158.9, 147.9, 135.3,
133.5, 130.8, 130.2, 128.5, 128.4, 128.3, 127.4, 126.9, 125.8, 116.5,
61.5, 13.6.
HRMS (EI): m/z [M]+ calcd for C18H14O4S: 326.0613; found:
326.0605.
13C NMR (100 MHz, CDCl3): d = 177.4, 163.1, 159.3, 146.9, 140.1,
130.8, 129.8, 129.1, 128.5, 128.4, 128.2, 116.4, 61.2, 13.5.
HRMS (EI): m/z [M]+ calcd for C20H16O4: 320.1049; found:
320.1044.
4-(4-Methylbenzoyl)-5-(4-tolyl)furan-2-carbaldehyde (3ca)
Ethyl 5-Formyl-2-phenyl-4-(3-tolyl)furan-3-carboxylate (3bd)
IR (KBr): 3054, 2973, 2855, 1773, 1724, 1674, 1577, 1276, 782,
693 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.50 (s, 1 H), 7.94–7.97 (m, 2 H),
7.27–7.48 (m, 7 H), 4.13 (q, J = 7.2 Hz, 2 H), 2.42 (s, 3 H), 1.01 (t,
J = 7.2 Hz, 3 H).
IR (KBr): 2985, 1772, 1666, 1604, 1145, 830 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.70 (s, 1 H), 7.72–7.77 (m, 4 H),
7.43 (s, 1 H), 7.16–7.27 (m, 4 H), 2.42 (s, 3 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.1, 177.3, 159.7, 150.1, 144.5,
141.2, 134.7, 129.9, 129.3, 128.0, 125.5, 123.7, 122.5, 21.6, 21.4.
13C NMR (100 MHz, CDCl3): d = 176.9, 162.7, 158.6, 146.5, 139.7,
137.4, 130.2, 130.0, 129.3, 128.6, 128.2, 128.1, 128.0, 127.9, 127.7,
126.6, 116.1, 60.7, 20.8, 13.0.
HRMS (EI): m/z [M]+ calcd for C20H16O3: 304.1099; found:
304.1095.
3-Methyl-4-(4-methylbenzoyl)-5-(4-tolyl)furan-2-carbalde-
hyde (3cb)
HRMS (EI): m/z [M]+ calcd for C21H18O4: 334.1205; found:
334.1201.
IR (KBr): 3050, 2929, 1770, 1660, 1603, 1245, 1179, 962, 826
cm–1.
Ethyl 5-Formyl-4-(4-methoxyphenyl)-2-phenylfuran-3-carbox-
ylate (3be)
1H NMR (400 MHz, CDCl3): d = 9.83 (s, 1 H), 7.71–7.73 (m, 2 H),
7.45–7.47 (m, 2 H), 7.05–7.18 (m, 4 H), 2.35 (s, 3 H), 2.27 (s, 6 H).
IR (KBr): 3053, 2923, 2847, 1724, 1674, 1245, 844 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.50 (s, 1 H), 7.91–7.93 (m, 2 H),
7.39–7.48 (m, 5 H), 6.98–7.00 (m, 2 H), 4.14 (q, J = 7.2 Hz, 2 H),
3.87 (s, 3 H), 1.05 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.8, 177.6, 156.5, 147.3, 145.1,
140.5, 134.6, 129.8, 129.5, 129.4, 129.3, 129.0, 127.3, 127.1, 125.6,
123.7, 21.7, 21.3, 9.33.
13C NMR (100 MHz, CDCl3): d = 177.5, 163.4, 160.5, 147.0, 139.8,
131.5, 131.2, 130.7, 130.3, 128.8, 128.5, 128.4, 121.2, 113.8, 61.2,
55.3, 13.6.
HRMS (EI): m/z [M]+ calcd for C21H18O3: 318.1256; found:
318.1253.
4-(4-Methylbenzoyl)-3-phenyl-5-(4-tolyl)furan-2-carbaldehyde
(3cc)
HRMS (EI): m/z [M]+ calcd for C21H18O5: 350.1154; found:
350.1150.
IR (KBr): 3054, 2920, 1768, 1659, 1607, 1238, 957 cm–1.
Ethyl5-Formyl-4-(4-nitrophenyl)-2-phenylfuran-3-carboxylate
(3bf)
1H NMR (400 MHz, CDCl3): d = 9.60 (s, 1 H), 7.59–7.70 (m, 4 H),
7.08–7.37 (m, 9 H), 2.30 (s, 6 H).
IR (KBr): 3060, 2977, 2854, 2229, 1773, 1722, 1680, 1227, 695
13C NMR (100 MHz, CDCl3): d = 191.6, 177.2, 156.0, 146.3, 144.9,
140.7, 140.0, 134.4, 129.8, 129.6, 129.4, 129.3, 129.0, 128.8, 128.5,
127.2, 125.3, 122.5, 21.6, 21.3.
HRMS (EI): m/z [M]+ calcd for C26H20O3: 380.1412; found:
380.1409.
cm–1.
1H NMR (400 MHz, CDCl3): d = 9.52 (s, 1 H), 7.93–7.95 (m, 2 H),
7.75–7.77 (m, 2 H), 7.48–7.60 (m, 5 H), 4.11 (q, J = 7.2 Hz, 2 H),
1.00 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 176.4, 161.9, 159.7, 146.4, 136.3,
133.9, 131.4, 130.6, 130.2, 128.3, 128.0, 127.5, 117.7, 115.6, 112.5,
60.9, 13.1.
Ethyl 5-Formyl-2,4-dimethylfuran-3-carboxylate (3db)
IR (KBr): 2971, 1744, 1715, 1678, 1559 cm–1.
HRMS (EI): m/z [M]+ calcd for C20H15NO6: 365.0899; found:
365.0904.
1H NMR (400 MHz, CDCl3): d = 9.69 (s, 1 H), 4.28 (q, J = 7.2 Hz,
2 H), 2.62 (s, 3 H), 2.50 (s, 3 H), 1.33 (t, J = 7.2 Hz, 3 H).
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1031
13C NMR (100 MHz, CDCl3): d = 176.9, 164.5, 163.3, 147.3, 134.9,
13C NMR (100 MHz, CDCl3): d = 190.4, 177.1, 155.9, 146.7, 134.1,
116.4, 60.5, 14.7, 14.2, 9.98.
133.1, 132.1, 130.4, 130.2, 129.7, 129.1, 128.8, 128.7, 128.6, 128.5,
128.4, 128.3, 127.8, 127.3, 122.7.
HRMS (EI): m/z [M]+ calcd for C10H12O4: 196.0736; found:
196.0729.
HRMS (EI): m/z [M]+ calcd for C22H14O3S: 358.0664; found:
358.0660.
4-Benzoyl-5-phenylfuran-2-carbaldehyde (3ea)
1H NMR (400 MHz, CDCl3): d = 9.70 (s, 1 H), 7.78–7.82 (m, 4 H),
7.53–7.57 (m, 1 H), 7.32–7.44 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 190.4, 177.5, 159.8, 150.3, 137.0,
133.5, 130.7, 129.6, 128.6, 128.4, 128.2, 123.7, 122.7.
HRMS (EI): m/z [M]+ calcd for C18H12O3: 276.0786; found:
276.0780.
Ethyl 5-Formyl-2-phenyl-4-(phenylethynyl)furan-3-carboxy-
late (3bs)
IR (KBr): 3067, 2983, 1733, 1717, 1698, 1653, 1558 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.91 (s, 1 H), 7.93–7.95 (m, 2 H),
7.38–7.58 (m, 8 H), 4.37 (q, 2 H), 1.34 (t, 3 H).
13C NMR (100 MHz, CDCl3): d = 176.0, 161.9, 161.0, 151.2, 131.8,
131.1, 129.5, 129.1, 128.6, 128.3, 127.8, 121.9, 121.0, 99.7, 61.4,
14.1.
HRMS (EI): m/z [M]+ calcd for C22H16O4: 344.1049; found:
344.1045.
4-Benzoyl-3-methyl-5-phenylfuran-2-carbaldehyde (3eb)
IR (KBr): 3027, 2864, 1705, 1663, 1598, 658 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.86 (s, 1 H), 7.79–7.81 (m, 2 H),
7.23–7.55 (m, 8 H), 2.31 (s, 3 H).
4-Benzoyl-5-phenyl-3-(phenylethynyl)furan-2-carbaldehyde
(3es)
13C NMR (100 MHz, CDCl3): d = 192.0, 177.7, 156.8, 147.4, 136.8,
133.9, 132.4, 130.1, 129.6, 128.7, 128.6, 128.3, 127.5, 127.1, 123.8,
9.37.
HRMS (EI): m/z [M]+ calcd for C19H14O3: 290.0943; found:
290.0933.
IR (KBr): 3067, 2983, 1733, 1717, 1698, 1653, 1558 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.89 (s, 1 H), 7.94–7.95 (m, 2 H),
7.75–7.77 (m, 2 H), 7.57–7.61 (m, 1 H), 7.22–7.48 (m, 8 H), 7.09–
7.11 (m, 2 H).
4-Benzoyl-3,5-diphenylfuran-2-carbaldehyde (3ec)
13C NMR (100 MHz, CDCl3): d = 190.3, 175.8, 158.0, 150.5, 136.7,
134.0, 132.4, 131.7, 130.9, 130.0, 129.5, 128.7, 128.6, 128.3, 127.7,
127.5, 127.1, 124.7, 123.6, 121.2, 121.0, 100.6.
IR (KBr): 3034, 2968, 2923, 1660, 1593, 1051, 695 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.61 (s, 1 H), 7.69–7.77 (m, 4 H),
7.26–7.45 (m, 11 H).
HRMS (EI): m/z [M]+ calcd for C26H16O3: 376.1099; found:
376.1054.
13C NMR (100 MHz, CDCl3): d = 191.9, 177.4, 156.2, 146.5, 140.1,
136.6, 133.9, 130.4, 129.6, 129.4, 129.2, 128.7, 128.6, 127.9, 127.4,
122.8.
HRMS (EI): m/z [M]+ calcd for C24H16O3: 352.1099; found:
352.1093.
Diethyl 5-Formyl-4-(4-tolylethynyl)furan-2,3-dicarboxylate
(3at)
IR (KBr): 2977, 1748, 1720, 1609 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.94 (s, 1 H), 7.44–7.45 (m, 2 H),
7.19–7.20 (m, 2 H), 4.22–4.46 (m, 4 H), 2.39 (s, 3 H), 1.39–1.41 (m,
6 H).
13C NMR (100 MHz, CDCl3): d = 176.6, 160.6, 156.8, 151.6, 145.6,
140.3, 131.9, 129.3, 126.1, 118.3, 118.1, 100.5, 62.6, 62.5, 21.6,
14.1, 14.0.
4-Benzoyl-3-(4-methoxyphenyl)-5-phenylfuran-2-carbalde-
hyde (3ee)
IR (KBr): 3028, 2966, 1754, 1719, 1661 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.61 (s, 1 H), 7.26–7.78 (m, 14 H),
3.73 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 192.1, 177.3, 160.4, 156.0, 146.5,
139.7, 136.8, 133.9, 131.0, 130.3, 129.7, 128.7, 128.6, 128.1, 127.4,
122.9, 120.8, 114.2, 55.2.
HRMS (EI): m/z [M]+ calcd for C25H18O3: 382.1205; found:
382.1199.
HRMS (EI): m/z [M]+ calcd for C20H18O6: 354.1103; found:
354.1107.
Dimethyl 5-Formyl-4-(phenylethynyl)furan-2,3-dicarboxylate
(3hs)
IR (KBr): 2983, 2874, 1763, 1724, 1642 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.93 (s, 1 H), 7.53–7.55 (m, 2 H),
4-Benzoyl-3-(4-nitrophenyl)-5-phenylfuran-2-carbaldehyde
(3ef)
7.37–7.39 (m, 3 H), 3.97 (s, 3 H), 3.96 (s, 3 H).
IR (KBr): 3029, 2950, 1761, 1720, 1624 cm–1.
13C NMR (100 MHz, CDCl3): d = 176.5, 160.9, 157.2, 151.7, 145.5,
132.0, 129.9, 128.5, 125.9, 121.2, 117.8, 100.3, 53.2, 53.0.
HRMS (EI): m/z [M]+ calcd for C17H12O6: 312.0634; found:
1H NMR (400 MHz, CDCl3): d = 9.66 (s, 1 H), 7.65–7.98 (m, 6 H),
7.29–7.49 (m, 8 H).
312.0627.
13C NMR (100 MHz, CDCl3): d = 191.2, 177.1, 156.8, 146.5, 136.3,
134.3, 132.4, 132.2, 132.1, 130.7, 130.3, 129.6, 128.9, 128.8, 128.6,
127.5, 127.1, 122.6.
HRMS (EI): m/z [M]+ calcd for C24H15NO5: 397.0950; found:
397.0946.
5-Phenyl-4-(thiophen-2-ylcarbonyl)furan-2-carbaldehyde (3fa)
1H NMR (400 MHz, CDCl3): d = 9.74 (s, 1 H), 7.87–7.89 (m, 2 H),
7.72–7.74 (m, 1 H), 7.56–7.59 (m, 2 H), 7.40–7.41 (m, 3 H), 7.08–
7.11 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.9, 177.4, 159.1, 150.4, 143.9,
4-Benzoyl-5-phenyl-3-(thiophen-2-yl)furan-2-carbaldehyde
(3eh)
135.3, 134.8, 130.8, 128.7, 128.3, 128.1, 122.8.
IR (KBr): 3026, 2937, 1769, 1726, 1650 cm–1.
4-Benzoyl-5-(thiophen-2-yl)furan-2-carbaldehyde (4fa)
1H NMR (400 MHz, CDCl3): d = 9.66 (s, 1 H), 8.08–8.09 (m, 1 H),
7.82–7.84 (m, 2 H), 7.42–7.62 (m, 5 H), 7.12–7.14 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 9.84 (s, 1 H), 7.81–7.83 (m, 2 H),
7.66–7.69 (m, 2 H), 7.32–7.48 (m, 8 H), 7.17–7.18 (m, 1 H).
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1032
H. Cao et al.
FEATURE ARTICLE
IR (KBr): 3059, 2984, 1732, 1558, 1177, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.22–7.34 (m, 5 H), 4.29 (q,
J = 7.2 Hz, 2 H), 4.21 (q, J = 7.2 Hz, 2 H), 2.34 (s, 3 H), 1.31 (t,
J = 7.2 Hz, 3 H), 1.14 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.9, 157.8, 152.6, 139.5, 131.7,
130.7, 128.8, 128.3, 127.7, 126.6, 122.6, 111.4, 61.6, 61.2, 14.2,
13.9, 12.6.
13C NMR (100 MHz, CDCl3): d = 189.5, 177.2, 155.9, 149.2, 137.8,
133.2, 131.3, 130.9, 129.3, 128.7, 128.0, 123.8, 120.8.
3,5-Diphenyl-4-(thiophen-2-ylcarbonyl)furan-2-carbaldehyde
(3fc) and 4-Benzoyl-3-phenyl-5-(thiophen-2-yl)furan-2-carbal-
dehyde (4fc)
1H NMR (400 MHz, CDCl3): d = 9.62 (s, 1 H), 9.58 (s, 0.33 H),
7.75–7.78 (m, 2 H), 7.71–7.74 (m, 0.68 H), 7.60–7.61 (m, 0.35 H),
7.57–7.58 (m, 1 H), 7.41–7.43 (m, 2.62 H), 7.34–7.36 (m, 6.20 H),
7.01–7.03 (m, 0.32 H), 7.34–7.36 (m, 6.20 H), 7.25–7.32 (m, 1.32
H), 7.01–7.03 (m, 0.32 H), 6.88–6.90 (m, 1 H).
MS (EI): m/z = 302, 257, 229, 202, 185, 128, 77.
Anal. Calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.30; H,
6.14.
13C NMR (100 MHz, CDCl3): d = 183.8, 182.8, 177.4, 177.1, 158.6,
158.5, 155.6, 154.9, 146.4, 144.1, 142.4, 140.5, 139.6, 135.8, 135.4,
133.7, 130.4, 129.7, 129.3, 128.8, 128.7, 128.4, 128.3, 127.4, 123.4,
122.9.
Diethyl 5-Methyl-4-(3-tolyl)furan-2,3-dicarboxylate (4ad)
Yellowish viscous oil.
IR (KBr): 3052, 2984, 2935, 1733, 1610, 1557, 1096, 789 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.19–7.21 (m, 1 H), 7.02–7.09 (m,
3 H), 4.31 (q, J = 7.2 Hz, 2 H), 4.21 (q, J = 7.2 Hz, 2 H), 2.34 (s, 3
H), 2.30 (s, 3 H), 1.29 (t, J = 6.8 Hz, 3 H), 1.16 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.0, 157.8, 152.6, 139.4, 138.1,
130.6, 129.4, 128.5, 128.4, 126.7, 125.8, 122.7, 61.6, 61.2, 21.3,
14.1, 13.9, 12.6.
4-(4-Methylbenzoyl)-5-phenylfuran-2-carbaldehyde (3ga) and
4-Benzoyl-5-(4-tolyl)furan-2-carbaldehyde (4ga)
1H NMR (400 MHz, CDCl3): d = 9.73 (s, 1 H), 9.71 (s, 0.67 H),
7.82–7.86 (m, 3.37 H), 7.73–7.78 (m, 3.32 H), 7.57–7.60 (m, 0.68
H), 7.60–7.61 (m, 0.35 H), 7.57–7.58 (m, 1 H), 7.41–7.43 (m, 2.62
H), 7.34–7.36 (m, 0.86 H), 7.17–7.47 (m, 9.70 H), 2.42 (s, 3 H),
2.37 (s, 2 H).
MS (EI): m/z = 316, 271, 243, 199, 91.
13C NMR (100 MHz, CDCl3): d = 190.4, 190.0, 177.4, 177.3, 160.1,
159.2, 150.4, 150.2, 144.6, 141.3, 137.3, 134.0, 133.4, 130.6, 130.1,
129.9, 129.6, 129.3, 128.9, 128.6, 128.4, 128.3, 128.2, 128.1, 126.5,
123.7, 123.4, 123.0, 122.3, 21.6, 21.4.
Anal. Calcd for C18H20O5: C, 68.34; H, 6.37. Found: C, 68.13; H,
6.45.
Diethyl 4-(4-Methoxyphenyl)-5-methylfuran-2,3-dicarboxylate
(4ae)
Diethyl (E)-5-(3-Ethoxy-3-oxoprop-1-enyl)furan-2,3-dicarbox-
ylate (6)
Yellowish viscous oil.
IR (KBr): 3041, 2983, 1737, 1606, 1560, 773 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.22 (d, J = 8.0 Hz, 2 H), 6.94 (t,
J = 9.6 Hz, 2 H), 4.39 (q, J = 8.0 Hz, 2 H), 4.27 (q, J = 8.0 Hz, 2 H),
3.82 (s, 3 H), 2.39 (s, 3 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.24 (t, J = 7.2
Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.34–7.38 (m, 1 H), 6.86 (s, 1 H),
6.51–6.55 (m, 1 H), 4.20–4.40 (m, 6 H), 1.27–1.38 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 165.9, 161.7, 157.4, 151.7, 144.3,
129.1, 125.2, 120.9, 115.0, 61.8, 61.6, 60.8, 14.0.
HRMS (EI): m/z [M]+ calcd for C15H18O7: 310.1053; found:
310.1049.
13C NMR (100 MHz, CDCl3): d = 164.0, 159.1, 157.8, 152.4, 139.3,
130.0, 126.7, 122.9, 122.2, 114.0, 61.6, 61.2, 55.2, 14.1, 13.9, 12.5.
Diethyl 5-Methylfuran-2,3-dicarboxylate (4aa)
Yellowish viscous oil.
MS (EI): m/z = 332, 304, 287, 259, 232, 187, 115.
Anal. Calcd for C18H20O6: C, 65.05; H, 6.07. Found: C, 65.22; H,
5.93.
IR (KBr): 2980, 1725, 1603, 1581, 1138 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.30 (s, 1 H), 4.25–4.31 (m, 4 H),
2.30 (s, 3 H), 1.26–1.32 (m, 6 H).
Diethyl 5-Methyl-4-(thiophen-2-yl)furan-2,3-dicarboxylate
13C NMR (100 MHz, CDCl3): d = 162.7, 157.8, 155.4, 142.0, 125.1,
(4ah)
Yellowish viscous oil.
IR (KBr): 3057, 2986, 1732, 1612, 1575, 1027 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.34 (m, 1 H), 7.05–7.06 (m,
2 H), 4.30–4.39 (m, 4 H), 2.49 (s, 3 H), 1.28–1.37 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 163.7, 157.6, 153.2, 139.5, 132.9,
127.3 126.9, 125.9, 116.1, 111.6, 61.9, 61.4, 14.2, 13.9, 13.0.
109.2, 61.2, 14.1, 14.0, 13.5.
MS (EI): m/z = 226, 198, 181, 153, 126, 109.
Anal. Calcd for C11H14O5: C, 58.40; H, 6.24. Found: C, 58.26; H,
6.32.
Diethyl 4,5-Dimethylfuran-2,3-dicarboxylate (4ab)
Yellowish viscous oil.
IR (KBr): 2983, 1722, 1556, 1092 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.27–4.35 (m, 4 H), 2.25 (s, 3 H),
1.96 (s, 3 H), 1.29–1.35 (m, 6 H).
MS (EI): m/z = 308, 263, 235, 208, 163, 135, 91.
Anal. Calcd for C15H16O5S: C, 58.43; H, 5.23. Found: C, 58.26; H,
5.17.
13C NMR (100 MHz, CDCl3): d = 163.9, 157.9, 152.0, 140.0, 126.5,
Diethyl 4-(2-Methoxyphenyl)-5-methylfuran-2,3-dicarboxylate
(4ai)
Yellowish viscous oil.
IR (KBr): 3044, 2971, 1731, 1609, 1561, 1156 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.97 (d, J = 8.0 Hz, 1 H), 7.49 (t,
J = 7.6 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H),
4.36 (q, J = 6.8 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 2 H), 3.72 (s, 3 H),
2.20 (s, 3 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.03 (t, J = 7.2 Hz, 3 H).
116.57, 61.3, 61.0, 14.2, 14.1, 11.7, 8.50.
MS (EI): m/z = 240, 229, 194, 166, 137.
Anal. Calcd for C12H16O5: C, 59.99; H, 6.71. Found: C, 60.24; H,
6.63.
Diethyl 5-Methyl-4-phenylfuran-2,3-dicarboxylate (4ac)
Yellowish viscous oil.
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
MS (EI): m/z = 316, 270, 242, 198, 170, 115, 91.
1033
13C NMR (100 MHz, CDCl3): d = 167.1, 162.8, 158.0, 152.2, 140.4,
131.9, 131.6, 131.1, 130.5, 128.2, 126.1, 122.7, 61.2, 61.1, 52.1,
14.1, 13.6, 12.2.
Anal. Calcd for C18H20O5: C, 68.34; H, 6.37. Found: C, 68.25; H,
6.44.
MS (EI): m/z = 332, 314, 242, 226.
Diethyl 4-(2-Ethylphenyl)-5-methylfuran-2,3-dicarboxylate
(4an)
Yellowish viscous oil.
Anal. Calcd for C18H20O6: C, 65.05; H, 6.07. Found: C, 65.20; H,
5.95.
Diethyl 4-[4-(Methoxycarbonyl)phenyl]-5-methylfuran-2,3-di-
carboxylate (4aj)
Yellowish viscous oil.
IR (KBr): 3046, 2983, 1729, 1612, 1573, 1046 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.05 (d, J = 8.0 Hz, 2 H), 7.34 (t,
J = 8.0 Hz, 2 H), 4.37 (q, J = 8.0 Hz, 2 H), 4.26 (q, J = 8.0 Hz, 2 H),
3.90 (s, 3 H), 2.39 (s, 3 H), 1.33 (t, J = 8.0 Hz, 3 H), 1.19 (t, J = 8.0
Hz, 3 H).
IR (KBr): 3042, 2985, 1727, 1608, 1562, 763 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25–7.33 (m, 2 H), 7.06–7.15 (m,
2 H), 4.35 (q, J = 8.0 Hz, 2 H), 4.18 (q, J = 8.0 Hz, 2 H), 2.50 (q,
J = 7.6 Hz, 2 H), 2.30 (s, 3 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.14 (t,
J = 7.2 Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.1, 157.7, 153.6, 140.5, 131.3,
129.9, 126.3, 124.0, 118.6, 116.8, 115.8, 61.4, 61.3, 46.2, 14.1,
13.7, 12.6, 11.5.
13C NMR (100 MHz, CDCl3): d = 166.6, 163.6, 157.6, 153.0, 152.9,
140.0, 135.5, 129.8, 128.8, 126.1, 121.8, 61.8, 61.4, 52.1, 14.1,
13.9, 12.7.
MS (EI): m/z = 330, 315, 285, 257, 77.
Anal. Calcd for C19H22O5: C, 69.07; H, 6.71. Found: C, 70.42; H,
6.65.
MS (EI): m/z = 360, 329, 315, 288, 211, 143, 128, 58.
Diethyl 4-Ethyl-5-methylfuran-2,3-dicarboxylate (4ao)
Yellowish viscous oil.
IR (KBr): 2981, 1730, 1603, 1528, 1105 cm–1.
Anal. Calcd for C19H20O7: C, 63.33; H, 5.59. Found: C, 63.02; H,
5.63.
Diethyl 4-(2-Fluorophenyl)-5-methylfuran-2,3-dicarboxylate
(4ak)
Yellowish viscous oil.
IR (KBr): 3057, 2986, 1732, 1612, 1575, 1027 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.33 (m, 2 H), 7.07–7.15 (m,
2 H), 4.36 (q, J = 7.2 Hz, 2 H), 4.21 (q, J = 8.0 Hz, 2 H), 2.31 (s, 3
H), 1.32 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.1, 157.7, 153.6, 140.5, 131.3,
129.9, 129.8 126.3, 124.1, 118.6, 115.8, 115.6, 61.4, 61.3, 14.1,
13.8, 12.7.
1H NMR (400 MHz, CDCl3): d = 4.28–4.36 (m, 4 H), 2.39 (d,
J = 7.6 Hz, 2 H), 2.27 (s, 3 H), 1.29–1.36 (m, 6 H), 1.07 (t, J = 7.6
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.1, 157.9, 151.8, 139.7, 122.8,
110.8, 61.4, 61.0, 16.9, 14.7, 14.1, 14.0, 11.7.
MS (EI): m/z = 254, 208, 179, 162, 135, 108.
Anal. Calcd for C13H18O5: C, 61.40; H, 7.14. Found: C, 61.16; H,
7.20.
Ethyl 4-(4-Methoxyphenyl)-5-methyl-2-phenylfuran-3-carbox-
ylate (3be)
MS (EI): m/z = 320, 275, 247, 220, 203, 116.
White solid; mp 100.8–102.7 °C.
IR (KBr): 3057, 2986, 1732, 1612, 1575, 1027 cm–1.
Anal. Calcd for C17H17FO5: C, 63.74; H, 5.35. Found: C, 63.56; H,
5.42.
1H NMR (400 MHz, CDCl3): d = 7.83 (d, J = 7.2 Hz, 2 H), 7.36–
7.44 (m, 3 H), 7.26 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 7.6 Hz, 2 H),
4.13 (q, J = 6.8 Hz, 2 H), 3.85 (s, 3 H), 2.32 (s, 3 H), 1.05 (t, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.6, 158.7, 153.7, 148.2, 130.7,
130.2, 128.5, 128.0, 127.5, 125.2, 122.5, 115.0, 113.4, 60.3, 55.2,
13.6, 11.9.
Diethyl 4-(4-Ethylphenyl)-5-methylfuran-2,3-dicarboxylate
(4al)
Yellowish viscous oil.
IR (KBr): 3039, 2975, 1728, 1600, 1577, 765 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.19 (s, 4 H), 4.35 (q, J = 7.2 Hz,
2 H), 4.25 (q, J = 7.2 Hz, 2 H), 2.63 (q, J = 7.6 Hz, 2 H), 2.38 (s, 3
H), 1.33 (t, J = 6.8 Hz, 3 H), 1.18–1.25 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 164.0, 157.8, 152.5, 143.8, 139.4,
128.7, 128.0, 127.9, 126.7, 122.6, 61.6, 61.2, 28.5, 15.3, 14.2, 13.9,
12.6.
MS (EI): m/z = 336, 308, 291, 105, 77.
Anal. Calcd for C21H20O4: C, 74.98; H, 5.99. Found: C, 74.76; H,
6.02.
MS (EI): m/z = 330, 315, 285, 258, 77.
(5-Methyl-2-phenylfuran-3-yl)(phenyl)methanone (4ea)
Yellowish viscous oil.
IR (KBr): 3037, 1746, 1612, 1582, 1031 cm–1.
Anal. Calcd for C19H22O5: C, 69.07; H, 6.71. Found: C, 69.29; H,
6.57.
1H NMR (400 MHz, CDCl3): d = 7.81 (d, J = 9.6 Hz, 2 H), 7.64–
Diethyl 5-Methyl-4-(2-tolyl)furan-2,3-dicarboxylate (4am)
Yellowish viscous oil.
IR (KBr): 3048, 2983, 1732, 1560, 1450, 1177, 758 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.11–7.26 (m, 4 H), 4.39 (q,
J = 8.0 Hz, 2 H), 4.14 (q, J = 8.0 Hz, 2 H), 2.21 (s, 3 H), 2.15 (s, 3
H), 1.37 (t, J = 8.0 Hz, 3 H), 1.08 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.3, 157.9, 152.7, 140.0, 137.4,
130.4, 129.9, 128.3, 126.9, 125.5, 122.4, 111.3, 61.2, 60.6, 19.7,
14.2, 13.7, 12.3.
7.66 (m, 2 H), 7.25–7.49 (m, 6 H), 6.28 (s, 1 H), 2.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.9, 154.4, 151.1, 138.2, 132.6,
130.0, 129.6, 128.9, 128.6, 128.5, 128.4, 128.2, 127.2, 121.7, 109.7,
13.3.
MS (EI): m/z = 262, 185, 105, 77.
Anal. Calcd for C18H14O2: C, 82.42; H, 5.38. Found: C, 82.03; H,
5.42.
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1034
H. Cao et al.
FEATURE ARTICLE
(5-Methyl-2,4-diphenylfuran-3-yl)(phenyl)methanone (4ec)
Yellowish viscous oil.
13C NMR (100 MHz, CDCl3): d = 162.0, 158.5, 157.2, 140.0, 138.3,
130.9, 128.6, 125.9, 119.1, 106.0, 94.5, 52.0, 51.8, 20.9, 12.5.
IR (KBr): 3032, 1749, 1604, 1576 cm–1.
MS (EI): m/z = 312, 297, 281, 167, 59.
1H NMR (400 MHz, CDCl3): d = 7.81 (d, J = 9.6 Hz, 2 H), 7.55–
7.57 (d, J = 8.4 Hz, 2 H), 7.35–7.39 (m, 1 H), 7.14–7.27 (m, 10 H),
2.45 (s, 3 H).
Anal. Calcd for C18H16O5: C, 69.22; H, 5.16. Found: C, 69.43; H,
5.19.
(2-Chlorophenyl)(5-methyl-2-phenylfuran-3-yl)methanone
13C NMR (100 MHz, CDCl3): d = 193.7, 150.8, 148.1, 137.5, 133.1,
132.2, 130.0, 129.8, 129.7, 129.3, 129.0, 128.9, 128.7, 128.6, 128.4,
128.2, 128.0, 126.8, 126.2, 123.5, 121.7, 12.2.
(4ia)
IR (KBr): 3027, 1723, 1608, 1542 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.76–7.78 (m, 2 H), 7.20–7.36 (m,
7 H), 6.23 (s, 1 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 189.8, 156.9, 151.5, 139.7, 131.3,
130.9, 130.0, 129.7, 129.2, 129.1, 128.9, 128.0, 127.9, 126.3, 122.5,
109.0, 13.3.
MS (EI): m/z = 262, 141, 105, 77.
Anal. Calcd for C24H18O2: C, 85.18; H, 5.36. Found: C, 84.92; H,
5.43.
[5-Methyl-4-(phenylethynyl)-2-(4-tolyl)furan-3-yl](4-tol-
yl)methanone (4cs)
MS (EI): m/z = 296, 185, 139, 77.
White solid; mp 142.5–144.3 °C.
IR (KBr): 3035, 2950, 1742, 1645 cm–1.
Anal. Calcd for C18H13ClO2: C, 72.85; H, 4.42. Found: C, 72.73; H,
4.49.
1H NMR (400 MHz, CDCl3): d = 7.84 (d, J = 8.0 Hz, 2 H), 7.53 (d,
J = 8.0 Hz, 2 H), 7.06–7.22 (m, 9 H), 2.53 (s, 3 H), 2.38 (s, 3 H),
2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.1, 154.4, 151.8, 143.4, 138.2,
134.8, 130.6, 129.8, 128.6, 128.5, 127.5, 127.4, 126.2, 126.0, 122.7,
121.2, 105.6, 94.5, 79.6, 21.4, 20.7, 12.3.
[5-Methyl-2-(2-chlorophenyl)furan-3-yl](phenyl)methanone
(5ia)
Yellowish viscous oil.
IR (KBr): 3029, 1720, 1600, 1537 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 8.0 Hz, 2 H), 7.37–
7.43 (m, 2 H), 7.22–7.33 (m, 3 H), 7.16–7.20 (m, 2 H), 6.46 (s, 1 H),
2.43 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.0, 152.4, 138.0, 133.5, 132.2,
131.9, 130.1, 129.8, 129.7, 129.3, 127.8, 126.3, 124.3, 108.2, 13.4.
MS (EI): m/z = 390, 223, 207, 119, 105, 91, 77.
Anal. Calcd for C28H22O2: C, 86.13; H, 5.68. Found: C, 85.90; H,
5.70.
[5-Methyl-2-phenyl-4-(phenylethynyl)furan-3-yl](phe-
nyl)methanone (4es)
Yellowish viscous oil.
IR (KBr): 3029 1738, 1632 cm–1.
MS (EI): m/z = 296, 261, 130, 77.
Anal. Calcd for C18H13ClO2: C, 72.85; H, 4.42. Found: C, 72.42; H,
4.46.
(2-Chlorophenyl)(5-methyl-2,4-diphenylfuran-3-yl)methanone
(4ic)
Yellowish viscous oil.
IR (KBr): 3018, 1732 1609, 1561 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.71–7.73 (m, 2 H), 7.42–7.44 (m,
1 H), 7.14–7.32 (m, 11 H), 2.47 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.9, 150.7, 149.1, 137.6, 133.4,
132.5, 132.1, 132.0, 130.1, 129.8, 129.6, 129.4, 129.3, 128.1, 127.7,
126.8, 126.4, 124.2, 122.8, 12.3.
1H NMR (400 MHz, CDCl3): d = 7.94 (d, J = 7.2 Hz, 2 H), 7.08–
7.65 (m, 13 H), 2.54 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.3, 154.8, 151.9, 137.2, 132.7,
130.7, 129.6, 128.8, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.6,
127.5, 126.7, 126.1, 122.5, 121.7, 105.7, 94.7, 79.4, 12.3.
MS (EI): m/z = 390, 223, 207, 119, 105, 91, 77.
Anal. Calcd for C26H18O2: C, 86.16; H, 5.01. Found: C, 86.41; H,
4.97.
Dimethyl 5-Methyl-4-(2-phenylethynyl)furan-2,3-dicarboxy-
late (4hs)
MS (EI): m/z = 372, 261, 139, 111, 105, 77.
Anal. Calcd for C24H17ClO2: C, 77.31; H, 4.60. Found: C, 77.13; H,
4.68.
IR (KBr): 3051 2969, 1730, 1647, 1582, 1027 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.45–7.47 (m, 2 H), 7.31–7.33 (m,
3 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 2.49 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.6, 159.4, 157.8, 140.6, 131.6,
128.7, 128.5, 126.4, 122.7, 106.5, 94.9, 52.7, 52.5, 13.2.
[2-(2-Chlorophenyl)-5-methyl-4-phenylfuran-3-yl](phe-
nyl)methanone (5ic)
White solid; mp 121–123 °C.
IR (KBr): 3021, 1730 1613, 1570 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.70–7.73 (m, 2 H), 7.29–7.35 (m,
5 H), 7.16–7.25 (m, 7 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.0, 154.5, 148.4, 138.4, 132.6,
132.0, 131.7, 131.0, 129.6, 129.3, 128.9, 128.5, 128.1, 127.9, 127.7,
127.5, 126.8, 125.9, 123.3, 12.0.
MS (EI): m/z = 298, 267, 211, 152, 59.
Anal. Calcd for C17H14O5: C, 68.45; H, 4.73. Found: C, 68.59; H,
4.69.
Dimethyl 5-Methyl-4-(4-tolylethynyl)furan-2,3-dicarboxylate
(4ht)
White solid; mp 123.9–125.4 °C.
IR (KBr): 3055 2973, 1728, 1650 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J = 8.0 Hz, 2 H), 7.13 (d,
J = 7.2 Hz, 2 H), 3.95 (s, 3 H), 3.91 (s, 3 H), 2.50 (s, 3 H), 2.36 (s,
3 H).
MS (EI): m/z = 372, 337, 105, 77.
Anal. Calcd for C24H17ClO2: C, 77.31; H, 4.60. Found: C, 77.54; H,
4.51.
(5-Methyl-2-phenylfuran-3-yl)(thiophen-2-yl)methanone (4fa)
Yellowish viscous oil.
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Regiospecific Synthesis of Polysubstituted Furans
1035
IR (KBr): 3020, 1728 1610, 1540 cm–1.
References
1H NMR (400 MHz, CDCl3): d = 7.78–7.80 (m, 2 H), 7.63–7.66 (m,
2 H), 7.30–7.39 (m, 3 H), 7.06–7.08 (m, 1 H), 6.44 (s, 1 H), 2.45 (s,
3 H).
(1) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127. (b) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem.
Rev. 2005, 105, 2329. (c) Bellina, F.; Rossi, R. Chem. Rev.
2010, 110, 1082.
13C NMR (100 MHz, CDCl3): d = 183.4, 153.6, 151.3, 144.8,
134.2, 133.9, 133.0, 130.8, 130.0, 128.6, 128.3, 127.8, 127.0, 121.6,
109.3, 13.4.
(2) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Enders, D.;
Grondal, C.; Hüttl, M. R. Angew. Chem. Int. Ed. 2007, 46,
1570. (c) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem.
Int. Ed. 2008, 47, 7539. (d) Ikeda, S. Acc. Chem. Res. 2000,
33, 511. (e) de Meijere, A.; von Zezschwitz, P.; Bräse, S.
Acc. Chem. Res. 2005, 38, 413. (f) Stragies, R.; Blechert, S.
J. Am. Chem. Soc. 2000, 122, 9584. (g) Nordmann, G.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
(h) Cárdenas, D. J.; Martín-Matute, B.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 5033. (i) Marigo, M.; Schulte,
T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 15710. (j) Schreiber, S. L. Science 2000, 287, 1964.
(k) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(3) Tietze, L. F.; Beifuss, U. Angew. Chem, Int. Ed. 1993, 32,
131.
MS (EI): m/z = 268, 235, 165, 111, 77.
Anal. Calcd for C16H12O2S: C, 71.62; H, 4.51. Found: C, 71.84; H,
4.14.
[5-Methyl-2-(thiophen-2-yl)furan-3-yl](phenyl)methanone
(5fa)
IR (KBr): 3025, 1726, 1602, 1530 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.88–7.90 (m, 3 H), 7.48–7.60 (m,
3 H), 7.38–7.40 (m, 1 H), 7.08–7.10 (m, 1 H), 6.29 (s, 1 H), 2.41 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 190.5, 150.4, 138.9, 132.2,
132.0, 129.3, 128.2, 127.6, 127.3, 127.1, 120.3, 109.7, 13.3.
MS (EI): m/z = 268, 191, 105, 77.
(4) (a) Lia, L.; Shi, J. Adv. Synth. Catal. 2008, 350, 667.
(b) Zhan, B. Z.; White, M. A.; Sham, T.; Pincock, J. A.;
Doucet, R. J.; Rao, K. V. R.; Robertson, K. N.; Cameron, T.
S. J. Am. Chem. Soc. 2003, 125, 2195. (c) Polshettiwar, V.;
Varma, R. S. Acc. Chem. Res. 2008, 41, 629. (d) Leitner,
W. Acc. Chem. Res. 2002, 35, 746. (e) Anastas, P. T.;
Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686. (f) Li, C.
J. Acc. Chem. Res. 2009, 42, 335.
(5) (a) Han, X.; Widenhoefer, R. A. J. Org. Chem. 2003, 69,
1738. (b) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2,
297. (c) Duan, X.; Liu, X.; Guo, L.; Liao, M.; Liu, W.;
Liang, Y. J. Org. Chem. 2005, 70, 6980.
(6) (a) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun,
J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. J. Med.
Chem. 2001, 44, 3838. (b) Bolognesi, M. L.; Budriesi, R.;
Chiarini, A.; Poggesi, E.; Leonardi, A.; Melchiorre, C.
J. Med. Chem. 1998, 41, 4484. (c) Hopkins, K. T.; Wilson,
W. D.; Bender, B. C.; McCurdy, D. R.; Hall, J. E.; Tidwell,
R. R.; Kumar, A.; Bajic, M.; Boykin, D. W. J. Med. Chem.
1998, 41, 3872. (d) Rahmathullah, S. M.; Hall, J. E.; Bender,
B. C.; McCurdy, D. R.; Tidwell, R. R.; Boykin, D. W.
J. Med. Chem. 1999, 42, 3994. (e) Francesconi, I.; Wilson,
W. D.; Tanious, F. A.; Hall, J. E.; Bender, B. C.; Tidwell, R.
R.; McCurdy, D.; Boykin, D. W. J. Med. Chem. 1999, 42,
2260. (f) Mullican, M. D.; Sorenson, R. J.; Connor, D. T.;
Thueson, D. O.; Kennedy, J. A.; Conroy, M. C. J. Med.
Chem. 1991, 34, 2186.
(7) (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42.
(b) Bandurraga, M. M.; William, F.; Donovan, S. F.; Clardy,
J. J. Am. Chem. Soc. 1982, 104, 6463. (c) Marshall, J. A.;
McNulty, L. M.; Zou, D. J. Org. Chem. 1999, 64, 5193.
(d) Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962.
(e) Marshall, J. A.; Wallace, E. M. J. Org. Chem. 1995, 60,
796. (f) 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.
Anal. Calcd for C16H12O2S: C, 71.62; H, 4.51. Found: C, 71.76; H,
4.15.
(5-Methyl-2-phenylfuran-3-yl)(4-tolyl)methanone (4ga) and
[5-Methyl-2-(4-tolyl)furan-3-yl](phenyl)methanone (5ga)
1H NMR (400 MHz, CDCl3): d = 7.87 (d, J = 8.0 Hz, 2 H), 7.82 (d,
J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 8.0 Hz, 2 H),
7.38–7.43 (m, 3 H), 7.30–7.32 (m, 3 H), 7.21 (d, J = 8.0 Hz, 2 H),
7.14 (d, J = 8.0 Hz, 2 H), 6.31 (s, 2 H), 2.42 (s, 3 H), 2.41 (s, 3 H),
2.39 (s, 3 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.9, 191.7, 154.9, 153.9, 151.0,
150.8, 143.5, 138.7, 138.4, 135.8, 132.5, 132.3, 130.1, 129.9, 129.6,
129.4, 129.0, 128.9, 128.6, 128.4, 128.3, 128.2, 128.1, 127.3, 127.2,
127.1, 127.1, 121.9, 121.1, 109.8, 109.7, 21.6, 21.3, 13.5, 13.4.
MS (EI): m/z = 276, 105, 91, 55.
Anal. Calcd for C19H16O2: C, 82.58; H, 5.84. Found: C, 82.15; H,
5.90.
(5-Methyl-2,4-diphenylfuran-3-yl)(4-tolyl)methanone (4gc)and
[5-Methyl-4-phenyl-2-(4-tolyl)furan-3-yl](phenyl)methanone
(5gc)
1H NMR (400 MHz, CDCl3): d = 7.80 (d, J = 8.0 Hz, 2 H), 7.62 (d,
J = 7.2 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 2 H),
7.25–7.32 (m, 16 H), 7.08–9.10 (m, 4 H), 2.50 (s, 3 H), 2.49 (s, 3
H), 2.32 (s, 3 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 194.0, 193, 8, 148.3, 144.4, 138.3,
133.3, 132.6, 132.5, 130.2, 130.0, 129.4, 129.3, 128.7, 128.5, 128.4,
128.2, 127.1, 126.4, 126.2, 123.7, 21.8, 21.4, 12.6, 12.5.
MS (EI): m/z = 352, 105, 91, 77, 55.
Anal. Calcd for C25H20O2: C, 85.20; H, 5.72. Found: C, 85.77; H,
5.68.
(8) (a) Zhang, M.; Jiang, H.; Neumann, H.; Beller, M.; Dixneuf,
P. H. Angew. Chem. Int. Ed. 2009, 48, 1681. (b) Ma, S. M.;
Zhang, J. L. J. Am. Chem. Soc. 2003, 125, 12386. (c) Jung,
C.; Wang, J. C.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
4118. (d) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem.
Soc. 2004, 126, 11164.
(9) (a) Wei, H.; Zhai, H.; Xu, P. J. Org. Chem. 2009, 74, 2224.
(b) Xiao, Y.; Zhang, J. Angew. Chem. Int. Ed. 2008, 47,
1903. (c) Liu, R.; Zhang, J. Chem. Eur. J. 2009, 15, 9303.
(d) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed.
Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
20625205, 20772034, and 20932002), National Basic Research
Program of China (973 Program) (No. 2011CB808600), the Docto-
ral Fund of the Ministry of Education of China (No.
20090172110014) and Guangdong Natural Science Foundation
(No. 10351064101000000) for financial support.
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York

1036
H. Cao et al.
FEATURE ARTICLE
2007, 46, 5195. (e) Kima, S.; Leea, P. Adv. Synth. Catal.
2008, 350, 547. (f) Bates, C. G.; Saejueng, P.; Murphy, J.
M.; Venkataraman, D. Org. Lett. 2002, 4, 4727. (g) Kel’in,
A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95.
(h) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew.
Chem. Int. Ed. 2004, 43, 2280.
(16) (a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo,
Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720.
(b) Sagar, P.; Fröhlich, R.; Würthwein, E. Angew. Chem. Int.
Ed. 2004, 43, 5694; Angew. Chem. 2004, 116, 5812.
(17) Hofmann, P.; Shishkov, I. V.; Rominger, F. Inorg. Chem.
2008, 47, 11755.
(18) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
15978. (b) Grissom, J. W.; Kilingberg, D.; Huang, D.;
Slattery, B. J. J. Org. Chem. 1997, 62, 603. (c) Nevado, C.;
Cárdenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2003, 9,
2627.
(19) (a) Gómez-Gallego, M.; Mancheño, M. J.; Sierra, M. A. Acc.
Chem. Res. 2005, 38, 44. (b) Harvey, D. F.; Sigano, D. M.
Chem. Rev. 1996, 96, 271. (c) Sierra, M. A. Chem. Rev.
2000, 100, 3591.
(20) (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121,
11680. (b) Perdicchia, D.; Licandro, E.; Maiorana, S.;
Vandoni, B.; Baldoli, C. Org. Lett. 2002, 4, 827.
(c) Barluenga, J.; Andina, F.; Fernández-Rodríguez, M. A.;
García-García, P.; Merino, I.; Aguilar, E. J. Org. Chem.
2004, 69, 7352. (d) Witham, C. A.; Mauleón, P.; Shapiro, N.
D.; Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129,
5838. (e) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
Chem. Rev. 2010, 110, 704.
(10) (a) Xiao, Y.; Zhang, J. Adv. Synth. Catal. 2009, 351, 617.
(b) Donohoe, T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou,
P. A. Org. Lett. 2007, 9, 963. (c) Nanayakkara, P.; Alper, H.
Adv. Synth. Catal. 2006, 348, 545. (d) Cadierno, V.; Díez,
J.; Gimeno, J.; Nebra, N. J. Org. Chem. 2008, 73, 5852.
(e) Cadierno, V.; Gimeno, J.; Nebraa, N. Adv. Synth. Catal.
2007, 349, 382.
(11) (a) Cao, H.; Jiang, H. F.; Yao, W. J.; Liu, X. H. Org. Lett.
2009, 11, 1931. (b) Cao, H.; Jiang, H. F.; Yuan, G. Q.; Chen,
Z. W.; Qi, C. R.; Huang, H. W. Chem. Eur. J. 2010, 16,
10553.
(12) Cao, H.; Jiang, H.; Mai, R.; Zhu, S.; Qi, C. Adv. Synth. Catal.
2010, 352, 143.
(13) Fan, M. J.; Li, G. Q.; Liang, Y. M. Tetrahedron 2006, 62,
6782.
(14) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
(15) (a) Xu, H. L.; Wang, W. Z.; Zhu, W. J. Phys. Chem. B 2006,
110, 13829. (b) Tan, Y.; Xue, X.; Peng, Q.; Zhao, H.; Wang,
T.; Li, Y. Nano Lett. 2007, 7, 3723. (c) Liang, X.; Gao, L.;
Yang, S.; Sun, J. Adv. Mater. 2009, 21, 1. (d) Zheng, Z.;
Huang, B.; Wang, Z.; Guo, M.; Qin, X.; Zhang, X.; Wang,
P.; Dai, Y. J. Phys. Chem. C 2009, 113, 14448.
Synthesis 2011, No. 7, 1019–1036 © Thieme Stuttgart · New York