Rh2(OAc)4 catalyzed formation of fluorine-containing polysubstituted furans from diazocompounds and aromatic alkynes

Article abstract of DOI:10.1016/j.tet.2009.12.015

A new building block strategy for the synthesis of fluorine-containing 1,2,4-trisubstituted furan was reported. The 1,2,4-trisubstituted furan was constructed through [3+2] cycloaddition reaction of fluoroacetyl-containing diazocompound and aromatic alkyne, catalyzed by Rh₂(OAc)₄.

Full text of DOI:10.1016/j.tet.2009.12.015

Tetrahedron 66 (2010) 1261–1266
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rh2(OAc)4 catalyzed formation of fluorine-containing polysubstituted furans
from diazocompounds and aromatic alkynes
,
,
,
a,
*
Wan Pang a b, Shifa Zhu a b, Yong Xin a, Huanfeng Jiang b , Shizheng Zhu
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, South China University of Technology, Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 October 2009
Received in revised form 30 November 2009
Accepted 4 December 2009
Available online 23 December 2009
A new building block strategy for the synthesis of fluorine-containing 1,2,4-trisubstituted furan was
reported. The 1,2,4-trisubstituted furan was constructed through [3þ2] cycloaddition reaction of
fluoroacetyl-containing diazocompound and aromatic alkyne, catalyzed by Rh2(OAc)4.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Fluorinated diazocompounds
Polysubstituted furans
X-ray crystallographic analysis
1. Introduction
reaction of fluoroacetyl-containing diazocompound and aromatic
alkyne to form 1,2,4-trisubstituted fluoro-containing furan.
Polysubstituted furan derivatives are a class of compounds with
fundamentally important heterocyclic molecules as well as having
practical utility as recurring unit in many natural molecules and
medicinal molecules.1 As well known, the introduction of fluorine
atoms into a medicinal molecule can often bring some unpredict-
able huge influence on its bioactivity.2 Due to the importance and
increasing concern of polysubstituted furan in pharmaceutical and
biological field, fluorine-containing polysubstituted furans also
attracted the great interests of chemists and biochemists. However,
how to efficiently and selectively introduce the fluorine atom into
the furan structure is an often met problem.3
2. Results and discussions
Considering the special diazocompound structure of ethyl 2-
diazo-4,4,4-trifluoro-3-oxobutanoate 2a, the reaction of phenyl-
acetylene 1a with equimolar of 2a was firstly investigated in
anhydrous DCM at refluxing temperature. After stirring for 4 h, to
our delight, the reaction was found to occur very smoothly, and the
followed 19F NMR spectra of crude product revealed that there were
two main products in a ratio of w1:1.5. Finally, the two products
were obtained after general work-up and purification. The major
product 4aa, obtained in 38% yield, was readily identified as 1-tri-
Of all kinds of methods to synthesize polysubstituted furans,
transitional metal-catalyzed [3þ2] cycloaddition of
a-carbonyl
diazocompounds with alkynes was considered one of the most
versatile and efficient methods for chemical selective construction
of the five-membered ring structures.4 Among known catalytic
systems, Rh-complex was proved to be the most successful and
reliable catalyst for this reaction.5
fluoromethyl substituted furan and a typical singlet at
d
ꢀ60.9 ppm
for trifluorometyl group in 19F NMR spectrum also confirmed the
existence of CF3 functional group. Another product 3aa with
a strong fluorescence property was also isolated successfully in 25%
yield. During the identification process, except for the similar 1H
NMR spectrum, the same molecular ion peaks (m/z 284) were ob-
served evidently in the corresponding mass spectra, which in-
dicated that 3aa and 4aa are isomeric compounds, even though the
intensities of the other fragmental ion peaks were different. This
point was further substantiated by the high-resolution mass
spectra (HRMS) of 3aa and 4aa. Comparing the 19F NMR spectra of
3aa and 4aa, the product 3aa showed a single strong peak at
As one continued research project to study the reaction of
fluorine-containing diazocompounds, we herein reported a build-
ing block strategy for the synthesis of fluorine-containing 1,2,4-
trisubstituted furan: Rh2(OAc)4 can catalyze [3þ2] cycloaddition
d
ꢀ75.5 ppm, corresponding to the trifluoroacetyl group, which is
* Corresponding authors. Tel.: þ86 21 54925184; fax: þ86 21 64166128.
E-mail address: zhusz@mail.sioc.ac.cn (S. Zhu).
similar to the chemical shift of CF3C(O) in substrate 2a.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.015

1262
W. Pang et al. / Tetrahedron 66 (2010) 1261–1266
However, despite the above spectral data, it was still difficult
important to be aware of that the reaction between diazo-
compound 2b and EDG substituted ethynylbenzene could only
afford the furan structure 3. The reason was under study in our
laboratory. The structures of all compounds could be figured out
from the spectral data. Consider 3aa, for example, the 13C signal
of trifluoroacetyl carbons at 173.4 ppm and 116.5 ppm together
with the 19F signal at ꢀ75.5 ppm for trifluoroacethyl group ex-
cluded furan structure 4. The 13C signal at 145.0, 104.4, 96.8 and
164.2 ppm for the C-1, C-2, C-3 and C-4 furan carbon atoms, re-
spectively, establish the structure of 3. For 4aa, the 13C signal of
ester carbonyl group at 160.9 ppm and absence of 13C signal of
fluoroacetyl carbons at 170–175 ppm as well as 19F signal at
ꢀ60.9 ppm for trifluoromethyl group proved the furan structure
4. The 13C signal at 154.9, 106.9, 121.4 and 142.2 ppm for the C-5,
C-6, C-7 and C-8 furan carbon atoms, respectively, establish the
structure of 4 (Scheme 1).
to determine the concrete structure of 3aa. Finally, the similar
structure of 3ca was further elucidated by a single crystal X-ray
diffraction analysis. The molecular structure of 3ca is shown in
Figure 1. It is an unexpected 2-trifluoroacethyl substituted furan
product. Several interesting features could be seen from Figure 1:
the distance of C1–O2 (1.309(2)Å) and C1–O1 (1.326(2)Å) is
considerably shorter than the standard single bond of C–O
(1.43 Å), but longer than the standard double bond of C]O
(1.22 Å). Meanwhile, the distance of C1–C2 (1.373(3) Å) and C2–C5
(1.429(3) Å) is considerably longer than the standard double bond
of C]C (1.34 Å), but shorter than the standard single bond of C–C
(1.53 Å). These data indicated that the double-bond character for
the C1–C2 bond was weakened and the electron density between
C1, O2, O1, C2 and C5 was shared. From analyzing the structural
data of 3ca, we were delighted to find that product 3 was a good
1,3-electrophilic reagent. From Figure 1, it can be seen that
product 3 has a push–pull alkene group in its right side. Com-
pared to its hydrocarbon analogues, the reaction activity of 3 was
greatly increased by the strong electron-withdrawing property of
tri- or difluoroacetyl, which could react with various nucleophiles,
such as carbonous, phosphorous, sulfide and nitrous nucleophiles.
In addition, 1,3-dipolar cycloaddition reactions and other un-
saturated ketones with electron-rich alkene, nitrile oxides and
azides were also extensively researched.6 Therefore, it is quite
worthy of a well-study to use product 3 as a good 1,3-electrophilic
reagent.
Table 1
The reaction results of 1 with 2
Entry
1(R)
2(Rf)
3 (yield, %)a
4 (yield, %)a
1
2
3
4
5
6
7
8
H
H
CF3
BrCF2
CF3
BrCF2
CF3
BrCF2
CF3
BrCF2
CF3
BrCF2
3aa (25)
3ab (27)
3ba (26)
3bb (14)
3ca (21)
3cb (14)
3da (26)
3db (15)
3ea (20)
3eb (13)
db
4aa (38)
db
C4H9
C4H9
Me
Me
OMe
OMe
F
4ba (26)
db
4ca (36)
db
4da (38)
db
9
10
11
4ea (35)
db
F
4fa (12)
CF3
Ph
a
Isolated yield based on diazocompound.
No corresponding product was isolated.
b
Based on the experimental results and product structures, the
proposed reaction mechanism is depicted in Scheme 2. Due to the
electron-withdrawing properties of the flanking carbonyl groups,
the intermediate A was stable. Moreover, the carbon anion was
stable by the electron-withdrawing effect of the neighbouring
acetyl groups. So the intermediate A readily reacted with alkynes in
two paths to form two furan isomers.
Inspired by the above results, we speculated that the diazo-
compound with only one carbonyl group could give one furan
product exclusively. Fortunately, the reaction result was consis-
tent with what we thought. When methyl 2-diazo-3,3,3-tri-
Figure 1. The molecular structure of 3ca.
fluoropropanoate
5 reacted with phenylacetylene, only one
Under the same reaction conditions, we further examined the
scope of the reaction with a variety of differently substituted 1 or
2. As can be seen from the data in Table 1, the isolated yields were
not quite high, probably due to the lost during purification and
the generally high purities of the library compounds. It is
product was isolated. From the spectral data, the structure of 6a is
depicted as shown in Scheme 3. But the isolated yield was not so
good, the next studies of the reaction was under taken in our
laboratory.
R
O
O
R
O
OEt
O
Rh2(OAc)4
OEt
(1mol%)
CH2Cl2, reflux
Rf
O
+
Rf
4
1
2
+
R
8
5
N2
2(a-b)
3
6
7
1(a-f)
CO2Et
Rf
3(aa-fa)
a: Rf=CF3
b: Rf=BrCF2
4(aa-eb)
Scheme 1.

W. Pang et al. / Tetrahedron 66 (2010) 1261–1266
1263
a
4.2.1. 1-(2-Ethoxy-5-phenylfuran-3-yl)-2,2,2-trifluoroethanone
(3aa).
O
O
O
Ar
Rf
O
Rf
Ar
Path a
RhLn
a
b
Rf
OEt
CO2Et
4
N2
2
OEt
b
P
a
+
O
C
t
h
b
A
O
OEt
O
O
Ar
OEt
O
N2
Ar
C
H
O
O
Rf
OEt
F3C
Rf
mp: 45-47
.
3
RhLn
Scheme 2.
Mp: 45–47 ꢁC. IR (KBr):
1442, 1390, 1361, 1308, 1285, 1257, 1141, 1009, 877, 759, 723,
691 cmꢀ1. 1H NMR (300 MHz, CDCl3):
n
¼2988, 1737, 1702, 1617, 1564, 1462,
O
d¼7.56–7.42 (m, 2H, Ph–H),
F3C
Rh2(OAc)4
(0.5mol%)
7.40–7.37 (m, 2H, Ph–H), 7.32–7.30 (m, 1H, Ph–H), 6.91 (s, 1H, CH),
O
OMe
CF3
OMe
+
4.67 (q, 2H, J¼7.2 Hz, CH2), 1.57 (t, 3H, J¼7.2 Hz, CH3). 13C NMR
CH2Cl2, reflux
N2
(100 MHz, CDCl3):
d
¼14.7, 68.6, 96.8, 104.4, 116.5 (q, J¼288.4 Hz),
123.2, 128.0, 128.8, 144.9, 164.2, 173.2 (q, J¼36.5 Hz). 19F NMR
1a
5
6a (17%)
(282 MHz, CDCl3):
d
¼ꢀ75.5 (s, 3F). MS: m/z (%)¼284 (Mþ, 41), 256
Scheme 3.
(98), 227 (12), 186 (82), 177 (12), 159 (30), 131 (34), 105 (100), 77
(99), 51 (33). HRMS (EI) Calcd for C14H11O3F3: 284.0660; found:
284.0655.
3. Conclusions
In summary, [3þ2] cycloaddition reaction of aromatic alkyne
1 with fluoroacetyl-containing diazocompound 2 in the presence
of rhodium(II) acetate was investigated. When the diazo-
compounds have two strong electron-withdrawing groups (such
as acetyl group) besides the C]N2 bond, the reaction tends to
proceed through a polar transition state towards the formation
of furan products and the cycloaddition products of fluorine-
containing 1,2,4-trisubstituted furans 3 and 4 are important
structural units in natural products with remarkable biological
activities and useful building blocks in organic synthesis. The
further synthetic application of these compounds is carrying on
in our laboratory.
4.2.2. Ethyl 5-phenyl-2-(trifluoromethyl)furan-3-carboxylate (4aa).
O
CF3
CO2Et
mp: 37-39
.
Mp: 37–39 ꢁC. IR (KBr):
1488, 1452, 1400, 1387, 1324, 1250, 1174, 1134, 1052, 1034, 930, 835,
778, 762, 747 cmꢀ1. 1H NMR (300 MHz, CDCl3):
n
¼2986, 1738, 1619, 1603, 1585, 1556,
d
¼7.61–7.60 (m, 2H,
Ph–H), 7.35–7.28 (m, 3H, Ph–H), 6.94 (s, 1H, CH), 4.28 (q, 2H,
4. Experimental section
4.1. General
J¼7.2 Hz, CH2), 1.29 (t, 3H, J¼7.2 Hz, CH3). 13C NMR (100 MHz,
CDCl3):
d
¼13.9, 61.5, 106.9, 118.7 (q, J¼267.5 Hz), 121.4, 128.4, 128.9,
129.3, 142.2 (q, J¼42.3 Hz), 154.9, 160.9. 19F NMR (282 MHz, CDCl3):
d
¼ꢀ60.9(s, 3F). MS: m/z (%)¼284 (Mþ, 100), 256 (42), 239 (46), 211
Uncorrected melting points were measured by an SGWX-4 mi-
cro-melting point apparatus. 1H and 19F NMR spectra were recor-
ded in CDCl3 (unless mentioned in text), Bruker AM-300
spectrometer with Me4Si and CFCl3 (with up field negative) as the
internal and external standards, respectively. IR spectra were car-
ried on a Nicolet AV-360 spectrophotometer. Lower resolution
mass or high-resolution mass spectra (HRMS) were obtained from
a Finnigan GC–MS 4021 or a Finnigan MAR-8430 instrument using
the electron impact ionization technique (70 eV), respectively. The
X-ray structural analysis was performed on a Rigaku/AFC 7R
Diffractometer. Elemental analyses were performed by Shanghai
Institute of Organic Chemistry.
(28), 183 (17), 159 (6), 133 (15), 114 (16), 105 (48), 77 (29). HRMS (EI)
calcd for C14H11O3F3: 284.0660; found: 284.0662.
4.2.3. 2-Bromo-1-(2-ethoxy-5-phenylfuran-3-yl)-2,2-difluoro-
ethanone (3ab).
O
OEt
O
BrF2C
mp: 64-66
.
4.2. Typical procedure of the cycloaddition reaction of
fluoroacetyl-containing diazocompounds and aromatic
alkynes
Mp: 64–66 ꢁC. IR (KBr):
1434, 1390, 1361, 1307, 1293, 1256, 1169, 1124, 1020, 961, 918, 883,
854, 766, 727, 691 cmꢀ1 1H NMR (300 MHz, CDCl3):
n
¼2985, 1684, 1617, 1560, 1474, 1457,
Under nitrogen atmosphere, to a dry schlenk tube containing
Rh2(OAc)4 (4 mg, 1 mol %), phenylacetylenes 1 (1.2 equiv) and
CH2Cl2 (2 mL), a solution of diazocompound 2 (210 mg, 1 mmol) in
2 mL CH2Cl2 was added over 4 h by a syringe pump. After addition,
the reaction mixture was stirred at reflux temperature for about
8 h, until the starting material of diazocompound disappeared
while monitoring by TLC. The solvent was removed in vacuum and
the residue was purified on silica gel using ethyl acetate–hexane as
eluent to afford the corresponding products.
.
d¼7.57–7.54
(m, 2H, Ph–H), 7.42–7.37 (m, 2H, Ph–H), 7.32–7.29 (m, 1H, Ph–H),
6.93 (s, 1H, CH), 4.68 (q, 2H, J¼7.2 Hz, CH2), 1.58 (t, 3H, J¼7.2 Hz,
CH3). 13C NMR (100 MHz, CDCl3):
d
¼14.8, 68.5, 95.1, 104.9, 113.8 (t,
J¼317.9 Hz), 123.2, 128.0, 128.9, 144.5, 164.5, 174.9 (t, J¼27.1 Hz). 19F
NMR (282 MHz, CDCl3):
d
¼ꢀ60.4 (s, 3F). MS: m/z (%)¼344 (Mþ, 14),
316 (17), 237 (100), 215 (31), 209 (55), 187 (33), 159 (42), 131 (13),
115 (13), 105 (85), 77 (63), 51 (20). HRMS (EI) calcd for
C14H11O3F2Br: 343.9860; found: 343.9871.

1264
W. Pang et al. / Tetrahedron 66 (2010) 1261–1266
4.2.4. 1-(5-(4-Butylphenyl)-2-ethoxyfuran-3-yl)-2,2,2-tri-
4.2.7. 1-(2-Ethoxy-5-p-tolylfuran-3-yl)-2,2,2-trifluoroethanone
fluoroethanone (3ba).
(3ca).
C4H9
Me
O
O
OEt
O
OEt
O
F3C
F3C
mp: .94-96
.
IR (KBr):
1361, 1308, 1290, 1257, 1200, 1154, 1013, 938, 911, 877, 835, 812, 769,
722 cmꢀ1. 1H NMR (300 MHz, CDCl3):
n
¼2960, 2932, 2861, 1701, 1585, 1509, 1458, 1414, 1390,
Mp: 94–96 ꢁC. IR (KBr):
1284, 1193, 1135, 1020, 937, 910, 813, 770, 722, 692 cmꢀ1
NMR (300 MHz, CDCl3):
n
¼3007, 1683, 1562, 1443, 1389, 1359,
.
1H
d
¼7.50 (d, 2H, J¼8.7 Hz, Ph–
H), 7.21 (d, 2H, J¼8.4 Hz, Ph–H), 6.85 (s, 1H, CH), 4.57 (q, 2H,
J¼7.2 Hz, CH2), 2.63 (t, 2H, J¼7.8 Hz, C2H4), 1.66–1.58 (m, 2H, C2H4),
1.56 (t, 3H, J¼7.2 Hz, CH3), 1.43–1.27 (m, 2H, C2H4), 0.94 (t, 3H,
d
¼7.43 (d, 2H, J¼7.8 Hz, Ph–H), 7.22 (d,
2H, J¼8.7 Hz, Ph–H), 6.83 (s, 1H, CH), 4.65 (q, 2H, J¼7.2 Hz, CH2),
2.36 (s, 3H, Me), 1.55 (t, 3H, J¼7.2 Hz, CH3). 13C NMR (100 MHz,
J¼7.8 Hz, C2H4). 13C NMR (100 MHz, CDCl3):
¼13.8, 14.6, 22.2, 33.4,
d
CDCl3):
d
¼14.6, 21.2, 68.5, 96.7, 103.4, 116.5 (q, J¼288.1 Hz),
123.2, 126.1, 129.5, 138.0, 145.2, 164.1, 173.1 (q, J¼36.5 Hz). 19F
35.3, 68.4, 96.7, 103.4, 116.5 (q, J¼288.3 Hz), 123.1, 126.2, 128.8,
143.1, 145.3, 164.0, 173.0 (q, J¼36.3 Hz). 19F NMR (282 MHz, CDCl3):
NMR (282 MHz, CDCl3):
d
¼ꢀ75.5 (s, 3F). MS: m/z (%)¼298 (Mþ,
d
¼ꢀ75.5 (s, 3F). MS: m/z (%)¼340 (Mþ, 38), 312 (100), 285 (16), 269
34), 270 (100), 241 (16), 201 (44), 200 (62), 191 (11), 173 (20),
145 (26), 119 (68), 91 (60). HRMS (EI) calcd for C15H13O3F3:
298.0817; found: 298.0821.
(92), 255 (25), 242 (30), 227 (17),199 (52),161 (74),115 (24), 91 (45),
57 (30). HRMS (EI) calcd for C18H19O3F3: 340.1286; found: 340.1290.
X-ray data of 3ca. C15H13F3O3: Mw¼298.25, CCDC no. 654747,
4.2.5. Ethyl 5-(4-butylphenyl)-2-(trifluoromethyl)furan-3-carboxyl-
ate (4ba).
monoclinic, space group: P2(1)/n, a¼7.2318(9) Å, b¼13.0877(15) Å,
c¼15.2582(18) Å;
a
¼90.00ꢁ,
b
¼103.244(2)ꢁ,
g
¼90.00ꢁ; V¼1405.7
(3) Å3, Z¼4, Dc¼1.409 g/cm3, F(000)¼616. Radiation, Mo
Ka
C4H9
(l
¼0.71073 Å). Crystal dimension, 0.502ꢂ0.450ꢂ0.357 mm.
O
CF3
Intensity data were collected at 293(2) K with a Bruker P4 four-
circle diffractometer with graphite monochromator and Mo K
radiation (
¼0.71073 Å). A total of 2755 independent reflection was
measured in range 5.486<
<44.948ꢁ. The structure was solved by
a
CO2Et
l
mp: 42-44
.
q
directed methods and expanded using Fourier techniques. The
nonhydrogen atoms were refined anisotropically, hydrogen atoms
were included but not refined. The final cycle of fullmatrix least-
square refinement was based on F2. The final R and wR values were
0.0560 and 0.1469, respectively. All calculations were performed
using the SHELX-97 program.
Mp: 42–44 ꢁC. IR (KBr):
1557, 1499, 1467, 1423, 1385, 1323, 1247, 1173, 1136, 1117, 1050, 1032,
1018, 931, 829, 776, 746 cmꢀ1. 1H NMR (300 MHz, CDCl3):
n
¼2960, 2932, 2874, 1736, 1610, 1579,
d
¼7.50 (d,
2H, J¼8.1 Hz, Ph–H), 7.12 (d, 2H, J¼7.8 Hz, Ph–H), 6.88 (s, 1H, CH),
4.26 (q, 2H, J¼7.2 Hz, CH2), 2.52 (t, 2H, J¼7.8 Hz, C2H4),1.55–1.45 (m,
2H, C2H4), 1.32–1.22 (m, 2H, C2H4), 1.28 (t, 3H, J¼7.2 Hz, CH3), 0.83
(t, 3H, J¼7.5 Hz, C2H4). 13C NMR (100 MHz, CDCl3):
¼13.8, 13.9,
d
4.2.8. Ethyl 5-p-tolyl-2-(trifluoromethyl)furan-3-carboxylate (4ca).
22.3, 33.4, 35.5, 61.5, 106.2, 118.8 (q, J¼267.7 Hz), 121.4, 124.6, 125.9,
129.0, 141.8 (q, J¼42.6 Hz), 144.6, 155.2, 160.9. MS: m/z (%)¼340
(Mþ, 61), 297 (100), 269 (49), 225 (2), 196 (4), 155 (3), 128 (4), 115
(4), 91 (3). HRMS (EI) calcd for C14H11O3F3: 340.1286; found:
340.1290.
Me
O
CF3
CO2Et
mp: 72-74
.
4.2.6. 2-Bromo-1-(5-(4-butylphenyl)-2-ethoxyfuran-3-yl)-2,2-di-
fluoroethanone (3bb).
Mp: 72–74 ꢁC. IR (KBr):
1446,1325,1248,1147,1051,1031, 929, 858, 836, 820, 779, 749 cmꢀ1
1H NMR (300 MHz, CDCl3):
n
¼2995, 1731, 1606, 1579, 1556, 1499,
.
C4H9
d¼7.57 (d, 2H, J¼8.4 Hz, Ph–H), 7.22 (d,
O
OEt
O
2H, J¼7.8 Hz, Ph–H), 6.97 (s, 1H, CH), 4.36 (q, 2H, J¼7.2 Hz, CH2),
2.37 (s, 3H, Me), 1.38 (t, 3H, J¼7.2 Hz, CH3). 13C NMR (100 MHz,
CDCl3):
d
¼13.9, 21.3, 61.5, 106.2, 118.8 (q, J¼267.9 Hz), 121.3, 124.5,
BrF2C
125.7, 129.6, 139.5, 141.8 (q, J¼42.3 Hz), 155.2, 160.9. 19F NMR
(282 MHz, CDCl3):
(38), 253 (26), 225 (20), 197 (15), 119 (42), 91 (12). HRMS (EI) calcd
for C15H13O3F3: 298.0817; found: 298.0818.
d
¼ꢀ61.3(s, 3F). MS: m/z (%)¼298 (Mþ, 100), 270
IR (KBr):
1389, 1261, 1159, 1095, 1015, 966, 882, 852, 801 cmꢀ1
(300 MHz, CDCl3):
n
¼2961, 2931, 2859, 1737, 1693, 1604, 1582, 1559, 1443,
.
1H NMR
d
¼7.47 (d, 2H, J¼8.1 Hz, Ph–H), 7.21 (d, 2H,
4.2.9. 2-Bromo-1-(2-ethoxy-5-p-tolylfuran-3-yl)-2,2-difluoro-
ethanone (3cb).
J¼8.4 Hz, Ph–H), 6.87 (s, 1H, CH), 4.67 (q, 2H, J¼7.2 Hz, CH2), 2.62 (t,
2H, J¼7.5 Hz, C2H4), 1.61–1.55 (m, 2H, C2H4), 1.57 (t, 3H, J¼7.2 Hz,
CH3), 1.40–1.32 (m, 2H, C2H4), 0.93 (t, 3H, J¼7.5 Hz, C2H4). 13C NMR
(100 MHz, CDCl3):
d
¼13.9, 14.8, 22.3, 33.4, 35.4, 68.5, 95.0, 109.6,
Me
113.8 (t, J¼318.1 Hz), 123.2, 126.4, 128.9, 143.1, 144.9, 164.4, 174.9 (t,
O
OEt
O
J¼27.4 Hz). 19F NMR (282 MHz, CDCl3):
¼ꢀ60.5 (s, 3F). MS: m/z
d
(%)¼400 (Mþ, 14), 371 (12), 293 (100), 271 (15), 243 (14), 215 (18),
161 (30), 115 (25), 91 (24), 57 (46). HRMS (EI) calcd for
C18H19O3F2Br: 400.0486; found: 400.0486.
BrF2C

W. Pang et al. / Tetrahedron 66 (2010) 1261–1266
1265
IR (KBr):
1013, 965, 884, 852, 817, 726 cmꢀ1
¼7.45 (d, 2H, J¼8.7 Hz, Ph–H), 7.20 (d, 2H, J¼7.8 Hz, Ph–H), 6.87 (s,
n
¼2984, 1738, 1693, 1560, 1444, 1390, 1360, 1267, 1160,
Mp: 76–77 ꢁC. IR (KBr):
n
¼3438, 2967, 2842, 1763, 1743, 1678,
.
1H NMR (300 MHz, CDCl3):
1599, 1579, 1513, 1493, 1465, 1259, 1175, 1027, 974, 834, 778, 759,
d
738 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
¼7.47 (d, 2H, J¼8.7 Hz, Ph–
1H, CH), 4.66 (q, 2H, J¼7.2 Hz, CH2), 2.37 (s, 3H, Me), 1.57 (t, 3H,
H), 6.92 (d, 2H, J¼9.3 Hz, Ph–H), 6.76 (s, 1H, CH), 4.64 (q, 2H,
J¼7.2 Hz, CH3). 13C NMR (100 MHz, CDCl3):
¼14.8, 21.3, 68.5, 95.0,
d
J¼6.6 Hz, CH2), 3.82 (s, 3H, OMe), 1.56 (t, 3H, J¼6.6 Hz, CH3). 13C
104.0, 109.6 (t, J¼316.8 Hz), 123.2, 126.1, 129.6, 138.0, 164.4, 174.9 (t,
NMR (100 MHz, CDCl3):
d
¼14.8, 55.4, 68.5, 96.0, 103.0, 113.9 (t,
J¼28.1 Hz). 19F NMR (282 MHz, CDCl3):
d
¼ꢀ60.8 (s, 3F). MS: m/z
J¼319.0 Hz), 114.4, 121.7, 124.8, 144.7, 159.5, 164.3, 174.9 (t,
(%)¼358 (Mþ,17), 330 (14), 251 (74), 223 (25), 201 (22),173 (29),119
(100), 91 (55), 65 (24). HRMS (EI) calcd for C15H13O3F2Br: 358.0016;
found: 358.0022.
J¼26.6 Hz). 19F NMR (282 MHz, CDCl3):
¼ꢀ60.4 (s, 3F). MS: m/z
d
(%)¼374 (Mþ, 12), 347 (18), 317 (3), 267 (50), 239 (12), 216 (16), 135
(100), 107 (15), 92 (17), 77 (26). HRMS (EI) calcd for C15H13O3F2Br:
373.9965; found: 373.9977.
4.2.10. 1-(2-Ethoxy-5-(4-methoxyphenyl)furan-3-yl)-2,2,2-tri-
fluoroethanone (3da).
4.2.13. 1-(2-Ethoxy-5-(4-fluorophenyl)furan-3-yl)-2,2,2-tri-
fluoroethanone (3ea).
MeO
F
O
OEt
O
O
OEt
O
F3C
mp: 79-81
.
F3C
mp: 82-84
.
Mp: 82–84 ꢁC. IR (KBr):
1392, 1362, 1318, 1285, 1255, 1233, 1193, 1183, 1168, 1148, 1007, 947,
909, 878, 810, 768, 722, 694 cmꢀ1 1H NMR (300 MHz, CDCl3):
¼7.53 (dd, 2H, JHH¼8.4 Hz, JHF¼5.1 Hz, Ph–H), 7.10 (dd, 2H,
n
¼3118, 3001, 1663, 1576, 1508, 1467,
Mp: 79–81 ꢁC. IR (KBr):
1361, 1298, 1251, 1141, 1021, 938, 910, 876, 832, 768, 722 cmꢀ1. 1H
NMR (300 MHz, CDCl3):
n
¼2939, 1697, 1586, 1509, 1459, 1389,
.
d
¼7.47 (d, 2H, J¼7.8 Hz, Ph–H), 6.92 (d,
d
2H, J¼7.5 Hz, Ph–H), 6.74 (s, 1H, CH), 4.64 (q, 2H, J¼6.6 Hz, CH2),
JHH¼JHF¼8.4 Hz, Ph–H), 6.84 (s, 1H, CH), 4.67 (q, 2H, J¼7.2 Hz, CH2),
3.83 (s, 3H, OMe), 1.55 (t, 3H, J¼6.6 Hz, CH3). 13C NMR (100 MHz,
1.56 (t, 3H, J¼7.2 Hz, CH3). 13C NMR (100 MHz, CDCl3):
¼14.7, 68.7,
d
CDCl3):
d
¼14.6, 55.3, 68.5, 96.8, 102.4, 114.4, 116.6 (q, J¼288.4 Hz),
96.8, 104.0, 116.0 (d, J¼22.1 Hz), 116.5 (q, J¼290.0 Hz), 125.1 (d,
J¼8.0 Hz), 125.2, 144.1, 162.4 (d, J¼248.1 Hz), 164.2, 173.1 (q,
121.7, 124.8, 145.1, 159.6, 164.0, 172.7 (q, J¼36.5 Hz). 19F NMR
(282 MHz, CDCl3):
d
¼ꢀ75.9 (s, 3F). MS: m/z (%)¼314 (Mþ, 56), 286
J¼36.5 Hz). 19F NMR (282 MHz, CDCl3):
¼ꢀ76.0 (s, 3F), ꢀ113.2 (s,
d
(100), 257 (38), 216 (42), 207 (27), 161 (13), 135 (60), 107 (14), 92
(16), 77 (24). HRMS (EI) calcd for C15H13O4F3: 314.0766; found:
314.0777.
1F). MS: m/z (%)¼302 (Mþ, 27), 274 (86), 245 (13), 204 (77),195 (17),
177 (31), 149 (33), 123 (100), 95 (60). HRMS (EI) calcd for
C14H10O3F4: 302.0566; found: 302.0555.
4.2.11. Ethyl 5-(4-methoxyphenyl)-2-(trifluoromethyl)furan-3-car-
boxylate (4da).
4.2.14. Ethyl 5-(4-fluorophenyl)-2-(trifluoromethyl)furan-3-carbox-
ylate (4ea).
F
MeO
O
CF3
O
CF3
CO2Et
mp: 84-86
.
CO2Et
mp: 73-75
.
Mp: 84–86 ꢁC. IR (KBr):
n
¼3127, 2982, 1727, 1606, 1597, 1560,
1497, 1459, 1431, 1325, 1296, 1251, 1194, 1163, 1133, 1054, 1031, 1013,
930, 838, 809, 778, 748, 619 cmꢀ1 1H NMR (300 MHz, CDCl3):
¼7.68 (dd, 2H, JHH¼JHF¼6.9 Hz, Ph–H), 7.16 (dd, 2H,
Mp: 73–75 ꢁC. IR (KBr):
1327, 1248, 1179, 1134, 1029, 930, 835, 770 cmꢀ1. 1H NMR (300 MHz,
CDCl3):
¼7.62 (d, 2H, J¼9.0 Hz, Ph–H), 6.94 (d, 2H, J¼9.0 Hz, Ph–H),
n
¼2991, 1721, 1606, 1582, 1500, 1457,
.
d
d
JHH¼JHF¼8.1 Hz, Ph–H), 6.99 (s, 1H, CH), 4.37 (q, 2H, J¼6.9 Hz, CH2),
6.90 (s, 1H, CH), 4.36 (q, 2H, J¼6.9 Hz, CH2), 3.84 (s, 3H, OMe), 1.38
1.38 (t, 3H, J¼6.6 Hz, CH3). 13C NMR (100 MHz, CDCl3):
¼13.9, 61.6,
d
(t, 3H, J¼6.9 Hz, CH3). 13C NMR (100 MHz, CDCl3):
¼13.9, 55.3, 61.5,
d
106.7, 116.1 (d, J¼21.9 Hz), 118.6 (q, J¼266.8 Hz), 121.4, 124.8 (d,
J¼2.9 Hz), 126.6 (d, J¼8.1 Hz), 142.2 (q, J¼42.9 Hz), 154.0, 160.8,
105.4, 114.4, 118.8 (q, J¼267.3 Hz), 121.3, 121.4, 126.2, 141.5 (q,
J¼42.3 Hz), 155.1, 160.5, 161.0. 19F NMR (282 MHz, CDCl3):
163.3 (d, J¼250.5 Hz). 19F NMR (282 MHz, CDCl3):
¼ꢀ61.8 (s, 3F),
d
d
¼ꢀ61.7(s, 3F). MS: m/z (%)¼314 (Mþ, 100), 286 (34), 269 (15), 257
ꢀ111.2 (s, 1F). MS: m/z (%)¼302 (Mþ, 100), 274 (45), 257 (46), 229
(31), 229 (31), 201 (22), 177 (8), 151 (23), 132 (19), 123 (61), 95 (19).
HRMS (EI) calcd for C14H10O3F4: 302.0566; found: 302.0571.
(7), 214 (11), 216 (15), 135 (33). HRMS (EI) calcd for C15H13O4F3:
314.0766; found: 314.0780.
4.2.12. 2-Bromo-1-(2-ethoxy-5-(4-methoxyphenyl)furan-3-yl)-2,2-
difluoroethanone (3db).
4.2.15. 2-Bromo-1-(2-ethoxy-5-(4-fluorophenyl)furan-3-yl)-2,2-di-
fluoroethanone (3eb).
MeO
F
O
O
OEt
O
OEt
O
BrF2C
BrF2C
mp: 76-77
.
mp: 59-63 .

1266
W. Pang et al. / Tetrahedron 66 (2010) 1261–1266
(10), 195 (100), 167 (18), 159 (7), 139 (55), 131 (17), 115 (15), 103
(13), 77 (12). HRMS (EI) calcd for C16H13O3F3: 310.0817; found:
310.0825.
Mp: 59–63 ꢁC. IR (KBr):
n
¼3425, 2986, 1696, 1585, 1561, 1506, 1443,
1359, 1235, 1158, 1134, 1010, 965, 852, 837, 726 cmꢀ1
.
1H NMR
(300 MHz, CDCl3):
d
¼7.53 (dd, 2H, JHH¼8.4 Hz, JHF¼6.9 Hz, Ph–H),
7.09 (dd, 2H, JHH¼JHF¼8.4 Hz, Ph–H), 6.87 (s, 1H, CH), 4.67 (q, 2H,
4.2.17. 2-Methoxy-5-phenyl-3-(trifluoromethyl)furan (5a).
J¼7.2 Hz, CH2), 1.58 (t, 3H, J¼7.2 Hz, CH3). 13C NMR (100 MHz,
CDCl3):
d
¼14.7, 68.6, 95.0, 104.6, 113.7 (t, J¼317.2 Hz), 116.0 (q,
J¼22.0 Hz), 125.1 (d, J¼8.7 Hz), 125.2, 143.7, 162.4 (d, J¼246.7 Hz),
164.4, 174.9 (t, J¼28.1 Hz). 19F NMR (282 MHz, CDCl3):
d¼ꢀ60.4 (s,
O
OMe
CF3
3F), ꢀ113.3 (s, 1F). MS: m/z (%)¼362 (Mþ, 8), 334 (9), 255 (72), 227
(40), 205 (24), 177 (41), 149 (9), 133 (13), 123 (100), 95 (46). HRMS
(EI) calcd for C14H10O3F3Br: 361.9765; found: 361.9779.
X-ray data of 3eb. C14H10BrF3O3: Mw¼363.13, CCDC no. 674746,
IR (KBr):
1019, 934, 908, 814, 790, 767, 721, 698 cmꢀ1
CDCl3):
¼7.54–7.50 (m, 2H, Ph–H), 7.40–7.38 (m, 3H, Ph–H), 6.74 (s,
n
¼3155, 2957, 1739, 1490, 1448, 1438, 1317, 1145, 1040,
1H NMR (300 MHz,
triclinic, space group: Pꢀ1, a¼9.1062(3) Å, b¼10.9613(4) Å,
.
c¼15.6322(6) Å;
a
¼73.452(2)ꢁ,
b
¼77.710(2)ꢁ,
g
¼84.341(2)ꢁ;
d
V¼1460.23(9) Å3, Z¼4, Dc¼1.652 g/cm3, F(000)¼720. Radiation, Mo
1H, CH), 3.66 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d¼52.5, 93.0,
111.1, 123.3, 124.6 (q, J¼274.5 Hz), 129.1, 130.3, 131.1, 169.6. 19F NMR
Ka
(l¼0.71073 Å). Crystal dimension, 0.30ꢂ0.28ꢂ0.20 mm.
(282 MHz, CDCl3):
d
¼ꢀ65.0 (s, 3F). MS: m/z (%)¼242 (Mþ, 17), 227
Intensity data were collected at 298(2) K with a Bruker P4 four-
circle diffractometer with graphite monochromator and Mo K
radiation (
¼0.71073 Å). A total of 6733 independent reflection was
measured in range 2.29<
<20.69ꢁ. The structure was solved by
a
(100), 183 (77), 179 (49), 164 (10), 151 (18), 133 (80), 109 (23), 105
(62), 77 (18), 69 (8). HRMS (EI) calcd for C12H9O2F3: 242.0555;
found: 242.0563.
l
q
directed methods and expanded using Fourier techniques. The
nonhydrogen atoms were refined anisotropically, hydrogen atoms
were included but not refined. The final cycle of fullmatrix least-
square refinement was based on F2. The final R and wR values were
0.0936 and 0.2295, respectively. All calculations were performed
using the SHELX-97 program.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (NNSFC) (Nos. 20625205 and 20532040) for financial support.
References and notes
4.2.16. Ethyl 5-phenyl-2-(trifluoromethyl)furan-3-carboxylate (4fa).
1. (a) Lipshut, B. H. Chem. Rev. 1986, 86, 795; (b) Sammond, D. M.; Sammakia, T.
Tetrahedron Lett. 1996, 37, 6065; (c) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P.
L.; Lo, T. H.; Tong, S. Y.; Wong, G. N. Tetrahedron 1998, 54, 1955; (d) Keay, B. A.
Chem. Soc. Rev. 1999, 28, 209; (e) Onitsuka, S.; Nishino, H.; Kurosawa, K. Tetra-
hedron Lett. 2000, 41, 3149; (f) Alagoz, O.; Yilmaz, M.; Pekel, A. T. Synth. Commun.
2006, 36, 1005.
EtO2C
F3C
O
2. (a) Jiang, B.; Zhang, X. B.; Luo, Z. H. Org. Lett. 2002, 4, 2453; (b) Shi, G. Q.; Xu,
Y. Y. J. Chem. Soc., Chem. Commun. 1987, 607; (c). Shi, G. Q.; Xu, Y. Y. Tetrahe-
dron 1991, 47, 1629; (d). Shi, G. Q.; Xu, Y. Y.; Xu, M. J. Fluorine Chem. 1991, 52,
149; (e) Shi, G. Q.; Xu, Y. Y. J. Org. Chem. 1990, 55, 3383; (f) Shi, G. Q.; Cao, Z. Y.;
Cai, W. L. Tetrahedron 1995, 51, 5011; (g). Mloston, G. Helv. Chim. Acta 1996, 79,
1537; (h) Hoffmann, M. G.; Wenkert, E. Tetrahedron 1993, 49, 1057; (i) Guil-
laume, M.; Janousek, Z.; Viehe, H. G.; Wynants, C.; Declercq, J.-P.; Tinant, B. J.
J. Fluorine Chem. 1994, 69, 253; (j) Guillaume, M.; Janousek, Z.; Viehe, H. G.
Synthesis 1995, 921.
mp: 56-57
.
Mp: 56–57 ꢁC. IR (KBr):
1448, 1422, 1404, 1389, 1322, 1288, 1254, 1232, 1174, 1108, 1035,
959, 838, 776, 751, 740, 695 cmꢀ1 1H NMR (300 MHz, CDCl3):
n
¼2984, 2962, 2933, 1739, 1602, 1536,
.
d
¼7.51–7.48 (m, 2H, Ph–H), 7.41–7.32 (m, 3H, Ph–H), 7.20 (d,
3. (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Kodansha:
Tokyo, 1982; (b) Welch, J. T.; Eswarakrishnan, S. Fluorine in bioorganic Chemistry;
J¼15.9 Hz, 1H, CH), 6.84 (d, J¼16.5 Hz, 1H, CH), 6.76 (s, 1H, CH),
4.32 (q, 2H, J¼7.2 Hz, CH2), 1.38 (t, 3H, J¼7.2 Hz, CH3). 13C NMR
´
´
Wiley: New York, NY, 1991; (c) Begue, J.-P.; Bonnet-Delpon, D.; Dogbeavou, R.;
Oure´vitch, M. J. Chem. Soc., Perkin Trans. 11993, 2787 and literatures cited therein.
4. Davies, H. M. L.; Romines, K. R. Tetrahedron 1988, 44, 3343.
(100 MHz, CDCl3):
d
¼14.0, 61.6, 109.4, 114.3, 118.7 (q,
J¼269.8 Hz), 121.2, 123.9, 126.9, 128.8, 128.9, 132.0, 135.7, 141.9
5. Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley: New York, NY, 1998.
6. Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753.
(q, J¼36.4 Hz), 154.0, 160.9. 19F NMR (282 MHz, CDCl3):
d
¼ꢀ61.3(s, 3F). MS: m/z (%)¼310 (Mþ, 90), 282 (5), 265 (13), 241