Selective synthesis of 3-methylene-2,3-dihydrofurans or 1,2,4-trisubstituted furans via tandem reactions of allenic ketones with α-chloro β-keto esters or ketones

Article abstract of DOI:10.1055/s-0033-1340671

Novel and efficient synthesis of functionalized furan derivatives have been developed in this paper. Promoted by K₂CO₃, allenic ketones underwent tandem reactions with 2-chloroacetoacetate or 3-chloropentane-2,4-dione to afford 3-met

Full text of DOI:10.1055/s-0033-1340671

LETTER
▌687
lSeteterlective Synthesis of 3-Methylene-2,3-dihydrofurans or 1,2,4-Trisubstituted
Furans via Tandem Reactions of Allenic Ketones with α-Chloro β-Keto Esters
or Ketones
Selective Synthesis of 3-Methylene-2,3-dihydrofurans
Qiang Wang,a,b Lei Yang,b Xuesen Fan*a
a
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key
Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang 453007, P. R. of China
Fax +86(373)3326336; E-mail: xuesen.fan@htu.cn
b
School of Physics-Chemistry, Henan Polytechnic University, Jiaozuo 454003, P. R. of China
Received: 02.12.2013; Accepted after revision: 05.01.2014
ity and form the basic structure of many natural products,
Abstract: Novel and efficient synthesis of functionalized furan de-
such as aflatoxins and others.3 Notwithstanding their im-
rivatives have been developed in this paper. Promoted by K2CO3,
portance, simple and efficient synthetic methods toward
2,3-dihydrofurans without using transition-metal catalysts
allenic ketones underwent tandem reactions with 2-chloroacetoace-
tate or 3-chloropentane-2,4-dione to afford 3-methylene-2,3-dihy-
drofurans with high efficiency under remarkably mild conditions. are still highly desirable.4
When the same substrates were treated with potassium carbonate
and triphenylphosphine, on the other hand, 1,2,4-trisubstituted fu-
rans could be obtained in good yields.
O
CO2Et
COMe
CO2Et
O
Cl
O
Key words: allenic ketones, furan derivatives, phosphine catalysis,
tandem reactions
A
base
CO2Et
Cl
O
Ph
Cl
•
R
2
1
B
The development of efficient and novel synthetic strate-
gies by employing functionalized allenes as versatile syn-
thetic intermediates has become a hot topic in organic
synthesis.1 As a continuation of our study in this field, we
have recently developed a selective synthesis of oxepin-
3(2H)-ones via base-promoted tandem reaction of 1,2-al-
lenic ketone with 4-chloroacetoacetate (Scheme 1).2
CO2Et
Cl
COMe
COMe
CO2Et
O
Ph
O
Ph
C
3
Scheme 2 Proposed synthesis of 3-methylene-3-dihydrofuran via a
cascade reaction of 1,2-allenic ketone with 2-chloroacetoacetate
O
O
O
To check the feasibility of our proposed preparation of 3,
1-phenylbuta-2,3-dien-1-one (1a) and ethyl 2-chloroace-
toacetate (2a) were treated with K2CO3 in THF at room
temperature for two hours. To our delight, ethyl 2-acetyl-
3-methylene-5-phenyl-2,3-dihydronpuran-2-carboxylate
(3aa) was obtained in a yield of 75%.
CO2Et
O
Cl
base
Ph
OEt
O
O
O
Cl
OEt
•
Cl
Ph
Ph
CO2Et
O
CO2Et
O
CO2Et
O
Then, a number of solvents (CH2Cl2, EtOAc, toluene,
DMSO, and MeCN), different bases (Na2CO3, NaHCO3,
LiOH, and NaOH) were tested. It was found that the high-
est yield could be obtained when the reaction was run in
MeCN at room temperature for one hour in the presence
of one equivalent of K2CO3. With the optimized reaction
conditions, the scope of the synthesis of 3 was then stud-
ied with a series of substituted 1,2-allenic ketones 1a–e
and α-halogenated active methylene compounds 2a,b.
Representative results are shown in Table 1.5 It turned out
that both 1-aryl- (Table 1, entries 1–3, 5) and 1-phenyl-
ethyl-substituted (Table 1, entry 4) 1,2-allenic ketones un-
derwent this tandem reaction smoothly to afford the
corresponding 3-methylene-2,3-dihydrofurans 3 in good
yields. It was noted that the electronic nature of substitu-
ents does not show an obvious effect on the yield of 3 (Ta-
ble 1, entries1–3). On the other hand, the retarding effect
of sterics on this reaction is illustrated in Table 1, entry 6
O
– Cl
O
O
Ph
Ph
Cl
Scheme 1 Synthesis of oxepin-3(2H)-one via tandem reaction of
1,2-allenic ketone with 4-chloroacetoacetate
Inspired by the above results, we envisioned a new syn-
thetic pathway toward 3-methylene-2,3-dihydrofuran (3)
via a cascade reaction of 1,2-allenic ketone 1 with 2-chlo-
roacetoacetate (2) as shown in Scheme 2. It is well known
that 2,3-dihydrofurans belong to an important class of
compounds which show a wide range of biological activ-
SYNLETT 2014, 25, 0687–0692
Advanced online publication: 10.02.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340671; Art ID: ST-2013-W1097-L
© Georg Thieme Verlag Stuttgart · New York

688
Q. Wang et al.
LETTER
where 1,2-allenic ketone bearing a substituent on the ter- reaction are summarized in Table 2. Firstly, it showed that
minal position of the allenic unit gave the corresponding the amount of Ph3P has a remarkable effect on this reac-
product in lower yield.
tion (Table 2, entries 1–4). In the absence of Ph3P, no for-
mation of 4aa was observed. With 0.1 or 0.2 equivalents
of Ph3P, the yield of 4aa was very low. With 0.5 equiva-
lents of Ph3P, a yield of 65% could be obtained (Table 2,
entry 4). Further increase in the dosage of Ph3P did not
improve the reaction obviously (Table 2, entry 5). It was also
demonstrated that 1,4-diazabicyclo[2,2,2]-octane (DABCO)
and Me3P did not perform as well in terms of catalytic ac-
tivity as Ph3P for this reaction (Table 2, entries 7 and 8).
Subsequently, the effect of different solvents was also ex-
amined. Among the solvents studied, toluene turned out to
be the most efficient (Table 2 entries 9–11). With toluene
as solvent, other bases, such as Na2CO3, KOH, LiOH, or
NaHCO3, were also tried. They gave lower yields of 4aa
than K2CO3 (Table 2, entries 12–15).
Table 1 Synthesis of Substituted 2,3-Dihydrofurans 3a
R2
O
O
K2CO3
COR3
R2
•
COMe
COR3
R1
+
MeCN, r.t.
R1
O
Cl
2a,b
1a–e
3aa–3da, 3na, 3ab
Entry
R1, R2
R3
Yield of 3 (%)b
1
2
3
4
5
6
1a Ph, H
2a OEt
2a OEt
2a OEt
2a OEt
2b Me
2a OEt
3aa 85
3ba 82
3ca 86
3da 81
3ab 83
3na 54
1b 4-BrC6H4, H
1c 4-MeC6H4, H
1d PhCH2CH2, H
1a Ph, H
Table 2 Optimization Studies for the Formations of 4aaa
CO2Et
O
1n Ph, Me
O
O
CO2Et
•
conditions
a Reaction conditions: 1 (1.5 mmol), 2 (1.65 mmol), K2CO3 (1.5
mmol), MeCN (5 mL), r.t., 1 h.
+
Ph
Ph
O
Cl
2a
b Isolated yield.
1a
4aa
Entry
Base
Catalyst (equiv) Solvent
Yield (%)b
Recently, phosphine-catalyzed cycloaddition reactions of
allenoates or their surrogates as a nucleophile with various
electrophiles have emerged as a versatile platform for the
synthesis of valuable five- and six-membered cyclic struc-
tures.1k,m,6 We noticed that in the formation of 3-methy-
lene-2,3-dihydrofurans 3, allenic ketones 1 were actually
acting as an electrophile while 2-chloroacetoacetate (2)
was acting as a nucleophile. If treated with phosphine, on
the other hand, allenic ketones are expected to be trans-
formed into a nucleophilic intermediate6 to undergo a nu-
cleophilic reaction with 2-chloroacetoacetate (2). To
explore the possible reactivity of allenic ketones with 2-
chloroacetoacetate under the promotion of phosphine, the
mixture of 1a (1 mmol), 2a (1.1 mmol), Ph3P (0.1 mmol),
and K2CO3 (1 mmol) in toluene was stirred at room tem-
perature for 0.5 hours. It turned out that the reaction gave
a yellow solid product, which was identified as a polysub-
stituted furan 4aa based on its NMR and HRMS spectra.
1
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3Cl
THF
trace
15
20
65
66
25
27
24
26
14
10
40
34
30
15
Ph3P (0.1)
Ph3P (0.2)
Ph3P (0.5)
Ph3P (1.0)
Ph3P (0.5)
DABCO(0.5)
Me3P(0.5)
Ph3P (0.5)
Ph3P (0.5)
Ph3P (0.5)
Ph3P (0.5)
Ph3P (0.5)
Ph3P (0.5)
Ph3P (0.5)
3
4
5
6
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KOH
8
9
10
11
12
13
14
15
MeCN
toluene
toluene
toluene
toluene
Furans represent an important class of heterocycles since
they occur in a multitude of natural products7 and possess
a broad spectrum of biological and pharmaceutical prop-
erties.8 Furthermore, they are also versatile building
blocks in synthetic organic chemistry.9 Although many
synthetic routes for their preparation have been devel-
oped, this field is still far from being solved and the devel-
opment of efficient ways to construct furan molecules
from readily available starting materials under mild con-
ditions remains an important goal.10 This urged us to opti-
mize the above process to develop it into an efficient and
general protocol for the preparation of functionalized fu-
rans.
LiOH
NaHCO3
a Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), base (1.0
mmol), solvent (5 mL), r.t., 1.5 h.
b Isolated yield.
With the optimized conditions in hands, the scope and
generality for the synthesis of 1,2,4-trisubstituted furans
was investigated.11 It turned out that both 1-aryl (Table 3,
entries 1–10, 13, and 14) and 1-benzyl- (Table 3, entries
11 and 15) or 1-phenylethyl-substituted (Table 3, entries
12 and 16) 1,2-allenic ketones underwent this tandem re-
For this purpose, the amount of phosphine, different
bases, and solvents were screened and their effects on this
Synlett 2014, 25, 687–692
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Synthesis of 3-Methylene-2,3-dihydrofurans
689
action smoothly to afford the desired furan in moderate to
good yields. Functional groups such as F, Cl, Br, CH3O,
and CF3 are well tolerated. Clearly, the electronic nature
of substituents on the aromatic ring shows an obvious ef-
fect on the yield of 4aa. Substrates with an electron-donat-
ing group gave better yields (Table 3, entries 6, 7, 9, and
10) than that with an electron-withdrawing group (Table
3, entries 2–5, 8). Promisingly, this transformation could
be extended to 3-chloropentane-2,4-dione (2b), though
the yields of the corresponding products were lower (Ta-
ble 3, entries 14–16).
O
PPh3
COMe
COR
O
Ph3P
+
Cl
2a,b
•
Ph
Ph
1
A
– Cl
O
PPh3 COR
O
PPh3 COR
base
Ph
Ph
O
C
B
O
O
PPh3 COR
O
COR
– Ph3P
Ph3P
O
Table 3 Synthesis of Substituted Furans 4a
Ph
4
O
Ph
COR2
O
O
K2CO3 (1 equiv)
Ph3P (0.5 equiv)
D
E
COR2
O
•
R1
+
R1
Scheme 3 Plausible pathway for the formation of 4
toluene, r.t.
Cl
O
1a–m
2a,b
4aa–4ma, 4jb–4kb
In summary, we have established a highly selective, con-
venient, and practical method to synthesize 2,3-dihydro-
furans or 1,2,4-trisubstituted furans from the tandem
reaction of 1,2-allenic ketones with α-chloro β-keto esters
or ketones under the promotion of potassium carbonate or
a combination of triphenylphosphine and potassium car-
bonate at room temperature. With advantages such as
readily available acyclic substrates, free of expensive cat-
alysts/reagents, and extremely mild reaction conditions,
the methods developed herein should be important appli-
cations in heterocyclic chemistry and related areas.
Entry
R1
R2
Yield of 4 (%)b
1
2
1a Ph
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2a OEt
2b Me
2b Me
2b Me
4aa 65
4ba 58
4ca 52
4da 53
4ea 40
4fa 82
4ga 80
4ha 45
4ia 74
4ja 72
4ka 83
4la 88
4ma 42
4jb 40
4kb 42
4lb 44
1b 4-FC6H4
3
1c 4-ClC6H4
1d 4-BrC6H4
1e 4-CNC6H4
1f 4-MeC6H4
1g 4-MeOC6H4
1h 3-BrC6H4
1i 3-MeC6H4
1j 2-MeOC6H4
1k Bn
4
5
6
7
Acknowledgment
8
We thank the National Natural Science Foundation of China
(21172057, 21272058 and 21307028), Postdoctoral Science Foun-
dation of Henan Province (2012058), STRPHP (14A150048),
RFDP (20114104110005), PCSIRT (IRT 1061) and BCTRP
(132300410293) for financial support.
9
10
11
12
13
14
15
16
1l PhCH2CH2
1m furan-2-yl
1j 2-MeOC6H4
1k Bn
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
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1l PhCH2CH2
a Reaction conditions: 1 (1.5 mmol), 2 (1.65 mmol), Ph3P (0.75
mmol), K2CO3 (1.5 mmol), toluene (5 mL), r.t., 1.5 h.
b Isolated yield.
Based on the above observations, a plausible mechanistic
pathway for the formation of 4 is proposed in Scheme 3.
Firstly, nucleophilic addition of triphenylphosphine onto
allenic ketone 1 results in a phosphonium intermediate A.
Then, A undergoes an intermolecular C-nucleophilic sub-
stitution with 2 to afford B, which is then deprotonated to
give a zwitterionic intermediate C. Intermediate C can
readily isomerize to its tautomer D. Compound D under-
goes a 5-exo-trig process to produce the furan intermedi-
ate E. Subsequent expulsion of the phosphine catalyst
from E furnishes 4.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 687–692

690
Q. Wang et al.
LETTER
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1,1′-(3-Methylene-5-phenyl-2,3-dihydrofuran-2,2-
diyl)diethanone (3ab, Table 1, Entry 5)
Eluent: EtOAc–PE (1:15); yellow oil; yield: 83%. 1H NMR
(400 MHz, CDCl3): δ = 7.71–7.69 (m, 2 H), 7.44–7.42 (m, 3
H), 6.08 (s, 1 H), 5.13 (s, 1 H), 5.03 (s, 1 H), 2.31 (s, 3 H).
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(5) Typical Procedure for the Preparation of Compounds
3aa–da,na,ab – Exemplified with 3aa (Table 1, Entry 1)
To a flask containing 1-phenylbuta-2,3-dien-1-one (1a, 1
mmol) and ethyl 2-chloroacetoacetate (2, 1.1 mmol) in
MeCN (3 mL) were added anhydrous K2CO3 (1.0 mmol).
The solution was stirred at r.t. for 1 h. The reaction then was
quenched with aq NH4Cl and extracted with EtOAc (3 × 5
mL). The combined organic phases were dried, filtered, and
concentrated under vacuum. The residue was purified by
column chromatography over silica gel using EtOAc–PE
(1:15, v/v) as eluent to give 3aa (68%).
1,1′-(3-Ethylidene-5-phenyl-2,3-dihydrofuran-2,2-
diyl)diethanone (3na, Table 1, Entry 6)
Eluent: EtOAc–PE (1:15); yellow oil; yield: 54%. 1H NMR
(400 MHz, CDCl3): δ = 7.71–7.69 (m, 2 H), 7.42–7.36 (m, 3
H), 6.18 (s, 1 H), 5.51 (q, J = 7.6 Hz, 1 H), 4.31–4.23 (m, 2
H), 2.29 (s, 3 H), 1.85 (d, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.6
Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 200.8, 166.7,
159.6, 136.9, 129.5, 128.6, 125.4, 116.2, 98.6, 93.8, 62.4,
25.1, 15.4, 14.0. ESI-HRMS: m/z calcd for C16H17O3 [M +
H]+: 257.1178; found: 257.1183.
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2-Acetyl-3-methylene-5-phenyl-2,3-dihydrofuran-2-
carboxylate (3aa, Table 1, Entry 1)
Eluent: EtOAc–PE (1:15), yellow oil; yield: 85%. 1H NMR
(400 MHz, CDCl3): δ = 7.71–7.68 (m, 2 H), 7.42–7.38 (m, 3
H), 6.07 (s, 1 H), 5.18 (s, 1 H), 5.12 (s, 1 H), 4.29 (q, J = 6.8
Hz, 2 H), 2.31 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 200.0, 166.1, 161.1, 144.7, 129.9,
129.1, 128.8, 128.6, 125.6, 104.9, 101.9, 94.1, 62.5, 25.1,
14.013. ESI-HRMS: m/z calcd for C16H17O4 [M + H]+:
273.1127; found: 273.1137.
Ethyl 2-Acetyl-5-(4-bromophenyl)-3-methylene-2,3-
dihydrofuran-2-carboxylate (3ba, Table 1, Entry 2)
Eluent: EtOAc–PE (1:15); yellow oil; yield: 82%. 1H NMR
(400 MHz, CDCl3): δ = 7.54–7.53 (m, 4 H), 6.06 (s, 1 H),
5.20 (s, 1 H), 5.14 (s, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 2.30 (s,
3 H), 1.30 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 199.7, 166.0, 160.0, 144.3, 131.9, 128.0, 127.1, 124.0,
105.7, 102.5, 94.1, 62.7, 25.1, 14.0. ESI-HRMS: m/z calcd
for C16H16BrO4 [M + H]+: 351.0232; found: 351.0237.
Ethyl 2-Acetyl-3-methylene-5-p-tolyl-2,3-dihydrofuran-
2-carboxylate (3ca, Table 1, Entry 3)
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K. J. Med. Chem. 2002, 45, 2670. (d) Helder, L.; Hemerly,
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(e) Reichstein, A.; Vortherms, S.; Bannwitz, S.; Tentrop, J.;
Prinz, H.; Müller, K. J. Med. Chem. 2012, 55, 7273.
(9) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Katritzky,
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Cen, J.; Lin, J.; Zhu, Q.; Fu, M.; Jiang, H. Org. Lett. 2013,
15, 1080.
Eluent: EtOAc–PE (1:15); yellow oil; yield: 86%. 1H NMR
(400 MHz, CDCl3): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.21 (d,
J = 8.0 Hz, 2 H), 6.02 (s, 1 H), 5.51 (s, 1 H), 5.08 (s, 1 H),
4.29 (t, J = 6.8 Hz, 2 H), 2.38 (s, 3 H), 2.31 (s, 3 H), 1.30 (t,
J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 200.2,
166.2, 161.4, 144.8, 140.2, 129.3, 126.4, 125.6, 104.3,
101.1, 94.0, 62.5, 25.1, 25.5, 14.0. ESI-HRMS: m/z calcd for
C17H19O4 [M + H]+: 287.1283; found: 287.1280.
Ethyl 2-Acetyl-3-methylene-5-(3-oxo-3-phenylpropyl)-
2,3-dihydrofuran-2-carboxylate (3da, Table 1, Entry 4)
Eluent: EtOAc–PE (1:15); yellow oil; yield: 81%. 1H NMR
(400 MHz, CDCl3): δ = 7.31–7.27 (m, 2 H), 7.22–7.20 (m, 3
H), 5.38 (s, 1 H), 4.99 (s, 1 H), 4.95 (s, 1 H), 4.31–4.25 (m,
2 H), 2.96–2.91 (m, 2 H), 2.70–2.66 (m, 2 H), 2.23 (s, 3 H),
1.38 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ =
199.6, 166.2, 165.1, 144.6, 140.4, 128.5, 128.4, 128.3,
126.4, 103.1, 102.9, 94.1, 62.5, 32.6, 30.0, 24.9, 14.0. ESI-
HRMS: m/z calcd for C19H21O5 [M + H]+: 329.1389; found:
Synlett 2014, 25, 687–692
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Synthesis of 3-Methylene-2,3-dihydrofurans
691
(11) Typical Procedure for the Preparation of Compounds
4aa–ma,jb–kb – Exemplified with 4aa (Table 3, Entry 1)
To a flask containing 1-phenylbuta-2,3-dien-1-one (1a, 1
mmol) and triphenylphosphine (0.5 mmol) in toluene (5 mL)
were added ethyl 2-chloroacetoacetate (2, 1.1 mmol) and
anhydrous K2CO3 (1.0 mmol). The solution was stirred at r.t.
for 1.5 h. The reaction then was quenched with aq NH4Cl
and extracted with EtOAc (3 × 5 mL). The combined organic
phases were dried, filtered, and concentrated under vacuum.
The residue was purified by column chromatography over
silica gel using EtOAc–PE (1:30, v/v) as eluent to give 4aa
(65%).
J = 8.0 Hz, 2 H), 6.47 (s, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.20
(s, 2 H), 2.51 (s, 3 H), 2.38 (s, 3 H), 1.29 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.3, 164.1, 158.8, 146.4,
144.5, 133.5, 129.4, 128.7, 114.4, 109.2, 60.0, 37.9, 21.7,
14.4, 13.8. ESI-HRMS: m/z calcd for C17H19O4 [M + H]+:
287.1283; found: 287.1289.
Ethyl 5-[2-(4-Methoxyphenyl)-2-oxoethyl]-2-
methylfuran-3-carboxylate (4ga, Table 3, Entry 7)
Eluent: EtOAc–PE (1:10); white solid; yield: 80%. 1H NMR
(400 MHz, CD3OD and DMSO-d6): δ = 8.07 (d, J = 8.8 Hz,
2 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.53 (s, 1 H), 4.38 (s, 2 H),
4.28 (q, J = 6.8 Hz, 2 H), 3.92 (s, 3 H), 2.55 (s, 3 H), 1.35 (t,
J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 193.8,
164.1, 163.8, 158.4, 148.0, 130.9, 129.1, 114.2, 114.0,
108.9, 60.0, 55.2, 37.3, 13.8, 12.3. ESI-HRMS: m/z calcd for
C17H19O5 [M + H]+: 303.1232; found: 303.1236.
Ethyl 2-Methyl-5-(2-oxo-2-phenylethyl)furan-3-
carboxylate (4aa, Table 3, Entry 1)
Eluent: EtOAc–PE (1:30); yellow syrup; yield: 65%. 1H
NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.0 Hz, 2 H), 7.57
(t, J = 7.2 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 6.49 (s, 1 H),
4.24 (s, 2 H), 4.24 (q, J = 7.6 Hz, 2 H), 2.52 (s, 3 H), 1.30 (t,
J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 194.6,
164.0, 158.8, 146.2, 136.0, 133.6, 128.8, 128.5, 114.5,
109.3, 60.1, 38.0, 14.4, 13.8. ESI-HRMS: m/z calcd for
C16H17O4 [M + H]+: 273.1127; found: 273.1130.
Ethyl 5-[2-(3-Bromophenyl)-2-oxoethyl]-2-methylfuran-
3-carboxylate (4ha, Table 3, Entry 8)
Eluent: EtOAc–PE (1:30); white solid; yield: 40%. 1H NMR
(400 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.91 (d, J = 7.6 Hz, 1
H), 7.71 (d, J = 8.4 Hz, 1 H), 7.36 (t, J = 8.4 Hz, 1 H), 6.50
(s, 1 H), 4.26 (q, J = 7.6 Hz, 2 H), 4.23 (s, 2 H), 2.54 (s, 3 H),
1.32 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ =
193.3, 164.0, 159.0, 145.5, 137.7, 136.4, 131.6, 130.4,
127.1, 123.1, 114.5, 109.6, 60.1, 38.1, 14.4, 13.8. ESI-
HRMS: m/z calcd for C16H16BrO4 [M + H]+: 351.0232;
found: 351.0237.
Ethyl 5-[2-(4-Fluorophenyl)-2-oxoethyl]-2-methylfuran-
3-carboxylate (4ba, Table 3, Entry 2)
Eluent: EtOAc–PE (1:30); yellow solid; yield: 58%. 1H
NMR (400 MHz, CDCl3): δ = 8.03–8.00 (m, 2 H), 7.313–
7.308 (m, 1 H), 7.15–7.11 (m, 2 H), 6.49 (s, 1 H), 4.24 (q,
J = 7.6 Hz, 2 H), 4.21 (s, 2 H), 2.52 (s, 3 H), 1.30 (t, J = 7.2
Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 193.1, 167.2,
164.7, 164.0, 158.9, 146.0, 133.8, 133.6, 132.4, 132.4,
132.1, 131.3, 131.2, 128.8, 128.6, 128.6, 128.5, 116.0,
115.8, 114.5, 109.4, 60.1, 38.0, 14.4, 13.8. ESI-HRMS: m/z
calcd for C16H16FO4 [M + H]+: 291.1033; found: 291.1037.
Ethyl 5-[2-(4-Chlorophenyl)-2-oxoethyl]-2-methylfuran-
3-carboxylate (4ca, Table 3, Entry 3)
Ethyl 2-Methyl-5-(2-oxo-2-m-tolylethyl)furan-3-
carboxylate (4ia, Table 3, Entry 9)
Eluent: EtOAc–PE (1:15); yellow oil; yield: 74%. 1H NMR
(400 MHz, CDCl3): δ = 7.79–7.77 (m, 2 H), 7.37–7.26 (m, 2
H), 6.48 (s, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 4.22 (s, 2 H), 2.53
(s, 3 H), 2.40 (s, 3 H), 1.31 (t, J = 7.6 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 194.7, 164.0, 158.7, 146.3, 138.6,
136.2, 134.3, 129.0, 128.6, 125.8, 114.5, 109.3, 60.0, 38.0,
21.3, 14.3, 13.7. ESI-HRMS: m/z calcd for C17H19O4 [M +
H]+: 287.1283; found: 287.1289.
Eluent: EtOAc–PE (1:30); yellow solid; yield: 52%. 1H
NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 2 H), 7.44
(d, J = 8.8 Hz, 2 H), 6.49 (s, 1 H), 4.24 (q, J = 7.2 Hz, 2 H),
Ethyl 5-[2-(2-Methoxyphenyl)-2-oxoethyl]-2-
4.22 (s, 2 H), 2.52 (s, 3 H), 1.31 (t, J = 6.8 Hz, 3 H). 13
C
methylfuran-3-carboxylate (4ja, Table 3, Entry 10)
Eluent: EtOAc–PE (1:10); white solid, yield 72%. 1H NMR
(400 MHz, CDCl3): δ = 7.73–7.71 (m, 1 H), 7.47–7.42 (m, 1
H), 6.99–6.93 (m, 2 H), 6.43 (s, 1 H), 4.26 (s, 2 H), 4.23 (q,
J = 6.8 Hz, 2 H), 3.89 (s, 3 H), 2.51 (s, 3 H), 1.29 (t, J = 6.8
Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 196.5, 164.1,
158.7, 158.4, 147.3, 134.1, 130.8, 127.2, 120.8, 114.3,
111.6, 108.8, 59.9, 55.5, 42.6, 14.3, 13.7. ESI-HRMS: m/z
calcd for C17H19O5: [M + H]+: 303.1232; found: 303.1236.
Ethyl 2-Methyl-5-(2-oxo-3-phenylpropyl)furan-3-
carboxylate (4ka, Table 3, Entry 11)
NMR (100 MHz, CDCl3): δ = 193.5, 164.0, 159.0, 145.8,
140.1, 134.3, 123.0, 129.1, 114.5, 109.5, 60.1, 38.1, 14.4,
13.8. ESI-HRMS: m/z calcd for C16H16ClO4 [M + H]+:
307.0737; found: 307.0742.
Ethyl 5-[2-(4-Bromophenyl)-2-oxoethyl]-2-methylfuran-
3-carboxylate (4da, Table 3, Entry 4)
Eluent: EtOAc–PE (1:30); yellow solid; yield: 53%. 1H
NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.4 Hz, 2 H), 7.58
(d, J = 8.4 Hz, 2 H), 6.47 (s, 1 H), 4.23 (q, J = 6.8 Hz, 2 H),
4.20 (s, 2 H), 2.51 (s, 3 H), 1.29 (t, J = 6.8 Hz, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 193.6, 163.9, 158.9, 145.8,
134.7, 132.1, 130.1, 128.8, 114.5, 109.5, 60.1, 38.0, 14.4,
13.8. ESI-HRMS: m/z calcd for C16H16BrO4 [M + H]+:
351.0232; found: 351.0237.
Ethyl 5-[2-(4-Cyanophenyl)-2-oxoethyl]-2-methylfuran-
3-carboxylate (4ea, Table 3, Entry 5)
Eluent: EtOAc–PE (1:15); white solid; yield: 83%. 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.25 (m, 3 H), 7.17–7.15 (m, 2
H), 6.43 (s, 1 H), 4.25 (q, J = 6.8 Hz, 2 H), 3.73 (s, 2 H), 3.67
(s, 2 H), 2.51 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 202.8, 163.9, 158.8, 145.9, 133.6,
129.4, 128.8, 127.2, 114.5, 109.4, 60.0, 49.1, 41.2, 14.3,
13.7. ESI-HRMS: m/z calcd for C17H19O4 [M + H]+:
287.1283; found: 287.1288.
Eluent: EtOAc–PE (1:10); white solid; yield: 40%. 1H NMR
(400 MHz, CDCl3): δ = 8.08 (d, J = 8.4 Hz, 2 H), 7.79 (d,
J = 8.4 Hz, 2 H), 6.51 (s, 1 H), 4.27 (s, 2 H), 4.25 (q, J = 7.2
Hz, 2 H), 2.53 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 193.3, 163.9, 159.1, 145.0, 138.9,
132.7, 129.0, 117.8, 116.8, 114.6, 109.8, 60.2, 38.4, 14.4,
13.8. ESI-HRMS: m/z calcd for C17H16NO4 [M + H]+:
298.1079; found: 298.1083.
Ethyl 2-Methyl-5-(2-oxo-4-phenylbutyl)furan-3-
carboxylate (4la, Table 3, Entry 12)
Eluent: EtOAc–PE (1:15); colorless oil; yield: 88%. 1H
NMR (400 MHz, CDCl3): δ = 7.29–7.25 (m, 2 H), 7.20–7.15
(m, 3 H), 6.43 (s, 1 H), 4.26 (q, J = 7.2 Hz, 2 H), 2.89 (t,
J = 7.2 Hz, 2 H), 2.79 (t, J = 7.2 Hz, 2 H), 2.53 (s, 3 H), 1.33
(t, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 204.8,
164.0, 158.9, 146.0, 140.7, 133.9, 133.7, 128.5, 128.4,
126.2, 114.5, 109.3, 60.1, 43.5, 42.2, 29.6, 14.4, 13.8. ESI-
HRMS: m/z calcd for C18H21O4 [M + H]+: 301.1440; found:
Ethyl 2-Methyl-5-(2-oxo-2-p-tolylethyl)furan-3-
carboxylate (4fa, Table 3, Entry 6)
Eluent: EtOAc–PE (1:15); white solid; yield: 82%. 1H NMR
(400 MHz, CDCl3): δ = 7.87 (d, J = 8.2 Hz, 2 H), 7.24 (d,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 687–692

692
Q. Wang et al.
301.1446.
LETTER
273.1127; found: 273.1125.
Ethyl 5-[2-(Furan-2-yl)-2-oxoethyl]-2-methylfuran-3-
carboxylate (4ma, Table 3, Entry 13)
1-(4-Acetyl-5-methylfuran-2-yl)-3-phenylpropan-2-one
(4kb, Table 3, Entry 15)
Eluent: EtOAc–PE (1:10); yellow solid; yield: 42%. 1H
NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 1.2 Hz, 1 H),
7.26–7.25 (m, 1 H), 6.56–6.55 (m, 1 H), 6.50 (s, 1 H), 4.25
(q, J = 6.8 Hz, 2 H), 4.10 (s, 2 H), 2.52 (s, 3 H), 1.31 (t,
J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 183.5,
164.1, 158.9, 151.9, 147.0, 145.6, 118.3, 114.5, 112.6,
109.4, 60.1, 37.8, 14.4, 13.8. ESI-HRMS: m/z calcd for
C14H15O5 [M + H]+: 263.0919; found: 263.0915.
Eluent: EtOAc–PE (1:10) yellow oil; yield: 42%. 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.26 (m, 3 H), 7.18–7.17 (m, 2
H), 6.39 (s, 1 H), 3.76 (s, 2 H), 3.70 (s, 2 H), 2.52 (s, 3 H),
2.36 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 203.0, 194.1,
158.1, 145.8, 133.4, 129.5, 128.9, 127.3, 122.3, 109.2, 49.4,
41.0, 29.2, 14.4. ESI-HRMS: m/z calcd for C16H17O3 [M +
H]+: 257.1178; found: 257.1184.
1-(4-Acetyl-5-methylfuran-2-yl)-4-phenylbutan-2-one
(4lb, Table 3, Entry 16)
2-(4-Acetyl-5-methylfuran-2-yl)-1-(2-methoxyphenyl)-
ethanone (4jb, Table 3, Entry 14)
Eluent: EtOAc–PE (1:10); yellow oil; yield: 44%. 1H NMR
(400 MHz, CDCl3): δ = 7.29–7.25 (m, 2 H), 7.21–7.15 (m, 3
H), 6.38 (s, 1 H), 3.64 (s, 2 H), 2.90 (t, J = 7.6 Hz, 2 H), 2.81
(t, J = 8.0 Hz, 2 H), 2.53 (s, 3 H), 2.36 (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 204.7, 194.1, 158.1, 145.9, 140.7,
128.6, 128.4, 126.3, 122.3, 109.1, 43.7, 42.1, 29.6, 29.2,
14.4. ESI-HRMS: m/z calcd for C17H19O3 [M + H]+:
271.1334; found: 271.1341.
Eluent: EtOAc–PE (1:30); white solid; yield: 40%. 1H NMR
(400 MHz, CDCl3): δ = 7.78–7.76 (m, 1 H), 7.51–7.47 (m, 1
H), 7.03–6.97 (m, 2 H), 6.43 (s, 1 H), 4.30 (s, 2 H), 3.93 (s,
3 H), 2.54 (s, 3 H), 2.36 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 196.6, 194.4, 158.8, 157.8, 147.3, 134.3, 130.9,
126.9, 122.2, 120.9, 111.6, 108.7, 59.9, 55.6, 42.6, 29.2,
14.5. ESI-HRMS: m/z calcd for C16H17O4 [M + H]+:
Synlett 2014, 25, 687–692
© Georg Thieme Verlag Stuttgart · New York

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