A novel and facile synthesis of 2,3-dihydrofuran derivatives containing trifluoromethyl group

Article abstract of DOI:10.1016/j.jfluchem.2006.12.006

A series of CF₃-containing 2,3-dihydrofuran derivatives were prepared via the reaction of arsonium bromides 1 with β,β-di(trifluoroacetyl)ethylene derivatives 2 in the presence of K₂CO₃, usually in a stereoselective manner

Full text of DOI:10.1016/j.jfluchem.2006.12.006

Journal of Fluorine Chemistry 128 (2007) 207–210
www.elsevier.com/locate/fluor
A novel and facile synthesis of 2,3-dihydrofuran derivatives
containing trifluoromethyl group
a
Jiaxian Qian , Weiguo Cao
a,b,c,*
a
, Hui Zhang , Jie Chen , Shizheng Zhu
a
b,**
a
Department of Chemistry, Shanghai University, Shanghai 200444, China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
b
c
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 31 October 2006; received in revised form 30 November 2006; accepted 12 December 2006
Available online 15 December 2006
Abstract
A series of CF
3
-containing 2,3-dihydrofuran derivatives were prepared via the reaction of arsonium bromides 1 with b,b-di(trifluoroace-
tyl)ethylene derivatives 2 in the presence of K CO , usually in a stereoselective manner with moderate yields. The structures of these compounds
2
3
1
13
were confirmed by H NMR, C NMR, IR, MS and HRMS as well.
2006 Elsevier B.V. All rights reserved.
#
Keywords: Arsenic ylides; 2,3-Dihydrofurans; Trifluoromethyl; Stereochemistry
1
. Introduction
2. Results and discussion
The synthesis of regio- and stereoselective poly- or
The reaction of excess arsonium bromides 1a–c [5] with
b,b-di(trifluoroacetyl)ethylene derivatives 2a–c proceeded
rapidly in the presence of K CO , in anhydrous THF at room
perfluoroalkylated molecules has become important in the field
of pharmaceutical research, owing to their unique physiological
and biological properties imparted by a fluoroalkyl group [1].
The importance of dihydrofuran derivatives is apparent as they
are present in a wide range of biologically active synthetic and
natural products [2]. Moreover, some dihydrofurans are also
potentially useful synthetic intermediates [3]. For example, they
are precursors offurans by oxidation [4]. Therefore, efficient and
general synthetic routes to these heterocycles are of strong
interest.
2
3
temperature to give trifluoromethyl containing 2,3-dihydro-
furan derivatives 3 in moderate yields (Scheme 1 and Table 1).
1
The structure of product 3 was confirmed by means of IR, H
1
3
and C NMR, MS and HRMS, and the configuration 3ab was
assigned via its 2D Proton NOESY spectrum. And 3ca was
1
1
assigned via its H- H COSYand 2D Proton NOESY spectrum.
According to the spectral analyses, it is believed that the
tetrasubstituted dihydrofuran ring bears trifluoromethyl. It is
noteworthy that in this reaction no similarly normal Wittig
reaction products were detected. It is significant that when R is
–CO CH or –CN, the reaction gave 2,3-dihydrofuran 3 with
The paper covers the reaction of arsenic ylides with b,b-
di(trifluoroacetyl)ethylene derivatives to afford trifluoromethyl
containing 2,3-dihydrofuran derivatives via Micheal addition in
moderate yields with high stereoselectivity.
2
3
high stereoselectivity and only one stereoisomer was isolated.
In product 3ab, two protons with chemical shifts d 4.54 and d
5.13 ppm attached to the two neighbouring carbon atoms in the
ring, respectively showed strong NOE effect. Accordingly, on
the basis of this evidence together with the coupling constants,
it may be concluded that the dihydrofuran is in cis
*
Corresponding author at: Department of Chemistry, Shanghai University,
Shanghai 200444, China. Tel.: +86 21 66134856; fax: +86 21 66134856.
1
1
configuration. However, the H- H COSY and 2D NOESY of
3ca is different from those of 3ab, showing two groups of
** Corresponding author.
E-mail address: wgcao@staff.shu.edu.cn (W. Cao).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.12.006

208
J. Qian et al. / Journal of Fluorine Chemistry 128 (2007) 207–210
Scheme 1.
peaks, which indicated a mixture of cis and trans isomers. And
we also proved the product 3c is a cis and trans mixture by
C- H COSY technique. For example, in product 3cb, the
Michael addition, forming intermediate 4, which could exist in
two conformations, A and B (Scheme 3). It was expected that
conformation B would be destabilized as the result of the steric
interaction of aryl and triphenylarsenylidene groups, and the
preferred conformation A then underwent anti-attacking
cyclization to form 5. A further question concerns the
stereoselectivity of 3c, the trans-isomer was also obtained
although the cis-isomer was the major product due to the
competing reaction pathway involving conformation B. At the
same time, we calculated the energy of conformation A and B
by the computer software. When R was –CO CH in arsonium
1
3
1
chemical shifts of C-2 and C-3 of the cis and trans isomers
appear as a pair of peaks, respectively, and the aryl-C of the cis
1
3
and trans isomers are no difference in C NMR, which
indicates the existence of a mixture of cis and trans isomers.
When one molar arsonium bromides 1 was used, the reaction
products were the mixture of 2,3-dihydrofuran 3 and 5. It is
hard to separate. Whereas an excess of arsonium bromides 1
was used in the reaction, 3 was the sole product, as Wittig
reaction occurred between arsenic ylide and 5 to form 3
2
3
bromides 1, the difference of the energy of conformation A and
3
(
Scheme 2).
The reaction mechanism shown in Scheme 2 would account
B is 9.50 ꢀ 10 kcal/mol, so cis-isomer was prepared.
However, when R was –COPh in arsonium bromides 1, the
difference of the energy of conformation A and B is
for the high stereoselectivity. The arsenic ylide attacked
nucleophilically the carbon carbon double bond, by way of a
2
7.75 ꢀ 10 kcal/mol, then both the cis and trans isomers were
formed.
In short, the facile and highly stereoselective synthesis of
trifluoromethyl-containing 2,3-dihydrofuran derivatives has
been developed via the reaction of arsenic ylide with a,b-
unsaturated ketones. The easy availability of the starting
materials, the reproducibility of triphenylarsine, the simplicity
of the procedure, the moderate yield and the high stereo-
selectivity of the products should offer a great promise for the
synthesis of physiological active dihydrofuranoid drugs.
Further studies are in progress.
Table 1
Preparation of compound 3
Substrate 1 Substrate 2 Product 3 State
Yield (%) Ratio of
isomers of
3
cis:trans
a
a
b
b
c
b
c
b
c
b
c
a
ab
ac
bb
bc
cb
cc
Yellow oil 63
Yellow oil 70
Yellow oil 50
Yellow oil 48
Yellow oil 56
Yellow oil 54
Yellow oil 61
100:0
100:0
100:0
100:0
64:36
77:23
67:33
c
c
3. Experimental
ca
Melting points were uncorrected. IR spectra were recorded
on an AVATAR370 FT spectrophotometer. NMR spectra were
determined with DRX 500 MHz spectrometer, using solutions
in deuterated chloroform with tetramethylsilane as the internal
1
13
19
standard for H and C nuclei, respectively. F NMR spectra
were recorded on DRX 500 MHz spectrometer with C F . J
6
6
values are given in Hz. LRMS spectra were run on a HP 5989A
spectrometer. HRMS spectra were run on Waters Micromass
GCT. The energy of conformation was calculated by HyPer
Chem 7.
3.1. General procedure for the preparation of 2 [6]
A
mixture of 1,1,1,5,5,5-hexafluoro-2,4-pentanedione
10 mmol, 2.08 g), 4-methoxy-benzaldehyde (10 mmol,
1.36 g) and acetic anhydride (10 ml) in a 25 flask, equipped
(
Scheme 2.

J. Qian et al. / Journal of Fluorine Chemistry 128 (2007) 207–210
209
Scheme 3.
with a reflux condenser, drying tube and magnetic stirring bar,
was heated at 80 8C for 8 h. Ac O and AcOH were removed by
distillation, the residue being distilled under vacuum to give 2b
5.34 (d, J = 7.5, 1H, furan-H), 6.23 (d, J = 3.5, 1H, furan-H),
6.31 (m, 1H, furan-H), 6.49 (s, 1H, CH), 7.73 (d, J = 1, 1H,
2
1
9
furan-H) ppm. F NMR (CDCl ): ꢁ68.5 (s, CF ), ꢁ67.0 (s,
3
3
1
3
(
85%).
CF ) ppm. C NMR (CDCl ): 169.3, 163.3, 149.3, 143.3 (q,
1
3 3
2
C, J = 37.5), 142.5 (q, 1C, J = 37.5), 128.5, 126.7,
2
C-F C-F
1
1
3
.2. Typical procedure for the preparation of 3
122.8, 119.3 (q, 1C, J = 240), 110.9 (q, 1C, J = 240),
C-F C-F
110.6, 108.8, 82.7, 53.3, 52.5, 50.3.
A mixture of 1 (2.5 mmol), 2b (1 mmol) and anhydrous THF
3 ml) was added K CO (4 mmol, 0.552 g) in a 10 ml flask, the
(
3.2.3. 3-[5-Benzoyl-4-(4-methoxy-phenyl)-2-
2
3
mixture was stirred at room temperature (monitored by TLC).
The solvent was removed by evaporation under the reduced
pressure and the residue was separated on a silica gel column
chromatography (GF254) with petroleum ether–ethyl acetate
mixture (v:v = 8:1) as eluent to give product 3.
trifluoromethyl-4,5-dihydrofuran-3-yl]-4,4,4-trifluoro-1-
phenyl-but-2-en-1-one (3cb)
Yellow oil; IR (film): n 2923, 1693, 1514, 1178, 833, 763,
ꢁ
1
+
690 cm . HRMS (EI) calcd for C H F O (M ) m/z
29
20 6 4
1
546.1266, found 546.1271. MS m/z 569.0 (M + Na).
NMR (CDCl ): cis 3.81 (s, 3H, OCH ), 5.26 (d, J = 4.5, 1H,
H
3
3
3
.2.1. 4-(2-Methoxycarbonyl-1-trifluoromethyl-vinyl)-3-(4-
furan-H), 5.62 (d, J = 4.5, 1H, furan-H), 6.16 (s, 1H, CH), 7.37–
7.80 (m, 14H, ArH) ppm. Trans 3.78 (s, 3H, OCH ), 5.10 (d,
J = 8, 1H, furan-H), 5.49 (d, J = 8, 1H, furan-H), 6.12 (s, 1H,
methoxy-phenyl)-5-trifluoromethyl-2,3-dihydrofuran-2-
carboxylic acid methyl ester (3ab)
Yellow oil; IR (film): n 3390, 2925, 1744, 1515, 1177,
3
1
CH), 7.30–7.78 (m, 14H, ArH) ppm. F NMR (CDCl ): cis
9
3
ꢁ
1
+
8
01 cm . HRMS (EI) calcd for C H F O (M ) m/z
4
ꢁ81.9 (s, CF ), ꢁ63.9 (s, CF ) ppm. Trans ꢁ84.6 (s, CF ),
1
9
16
6
3
3
3
1
13
ꢁ61.9 (s, CF ) ppm. C NMR (CDCl ): 193.7, 192.6, 154.7,
4
NMR (CDCl ): 3.69 (s, 3H, OCH ), 3.79 (s, 3H, OCH ),
54.0739, found 454.0743. MS m/z 477.1 (M + Na).
H
3
3
2
154.2, 138.4 (q, 1C, J = 37), 134.6, 134.1 (q, 1C, J
2
3
3
3
C-F C-
3
1
.85 (s, 3H, OCH ), 4.54 (d, J = 7, 1H, furan-H), 5.13 (d, J = 7,
3
= 36), 131.3, 130.9, 130.0, 129.8, 129.7, 128.9, 128.8, 128.6,
F
1
9
1
1
H, furan-H), 6.42 (s, 1H, CH), 6.83–7.20 (4H, ArH) ppm.
F
126.3, 124.4 (q, 1C, J = 245), 122.2 (q, 1C, J = 237),
C-F C-F
13
NMR (CDCl ): ꢁ68.6 (s, CF ), ꢁ66.3 (s, CF ) ppm. C NMR
114.3, 95.3 (trans, CH ), 94.4 (cis, CH ), 89.6 (trans, furan-
C), 88.7 (cis, furan-C), 55.4, 48.2 (trans, furan-C), 46.2 (cis,
furan-C).
3
3
3
2
(
(
CDCl ): 169.4, 163.3, 159.5, 142.0 (q, 1C, J = 37), 134.8
3 C-F
2
q, 1C, J = 37), 130.2, 129.2, 127.7, 125.2, 120.1 (q, 1C,
C-F
1
1
JC-F = 240), 118.5 (q, 1C, J = 237), 114.2, 86.1, 56.3, 55.2,
C-F
0 0 0 0
3.2.4. 3-(2 -Benzoyl-5 -trifluoromethyl-2 ,3 -dihydro-
5
2.9, 52.1.
0
0
[
2,3 ]bifuranyl-4 -yl)-4,4,4-trifluoro-1-phenyl-but-2-en-1-
one (3cc)
Yellow oil; IR (film): n 1684, 1592, 1175, 797, 766,
0
0
3.2.2. 4 -(2-Methoxycarbonyl-1-trifluoromethyl-vinyl)-5 -
0
trifluoromethyl-2 ,3 -dihydro-[2,3 ]bifuranyl-2 -carboxylic
0
0
0
ꢁ
687 cm . HRMS (EI) calcd for C H F O (M ) m/z
26 16 6 4
1
+
acid methyl ester (3ac)
Yellow oil; IR (film): n 3442, 2960, 1737, 1641, 1188 cm
ꢁ1
+
1
.
HRMS (EI) calcd for C H F O (M ) m/z 414.0538, found
506.0953, found 506.0953. MS m/z 507.0 (M + 1). H
NMR (CDCl ): cis 5.13 (d, J = 3, 1H, furan-H), 6.09 (d,
+
1
6
12
6
6
3
1
14.0538. MS m/z 436.9 (M + Na). H NMR (CDCl ): 3.73 (s,
4
J = 3, 1H, furan-H), 6.15 (s, 1H, CH), 6.27 (d, J = 3, 1H, furan-
H), 6.39 (m, 1H, furan-H), 7.44 (d, J = 1, 1H, furan-H), 7.45–
3
3
H, OCH ), 3.87 (s, 3H, OCH ), 4.80 (d, J = 7.5, 1H, furan-H),
3
3

210
J. Qian et al. / Journal of Fluorine Chemistry 128 (2007) 207–210
2
7
5
.77 (m, 10H, ArH) ppm. Trans 5.22 (d, J = 7, 1H, furan-H),
.67 (d, J = 7, 1H, furan-H), 6.17 (s, 1H, CH), 6.29 (m, 1H,
(CDCl ): 162.2, 150.2, 145.3 (q, 1C, J = 40), 138.6 (q, 1C,
3 C-F
2
1
JC-F = 40), 129.3, 125.2 (q, 1C, J = 240), 115.4 (q, 1C, J
1
C-F
C-
furan-H), 6.33 (m, J = 3, 1H, furan-H), 7.36 (d, J = 1, 1H,
= 240), 114.8, 114.3, 113.5, 110.8, 93.6, 75.9, 57.7, 55.5.
F
1
9
furan-H), 7.40–7.70 (m, 10H, ArH) ppm. F NMR (CDCl3):
cis ꢁ82.9 (s, CF ), ꢁ64.2 (s, CF ) ppm. Trans ꢁ84.9 (s, CF ),
3
3
3
0 0
.2.7. 4 -(2-Cyano-1-trifluoromethyl-vinyl)-5 -
3
trifluoromethyl-2 ,3-dihydro-[2,3 ]-bifluranyl-2 -
1
3
ꢁ
63.4 (s, CF ) ppm. C NMR (CDCl ): 193.1, 192.0, 155.2,
3 3
0
0
0
2
2
1
1
1
1
54.4, 147.2 (q, 1C, J = 38), 142.6 (q, 1C, J = 37),
C-F C-F
carbonitrile (3bc)
Yellow oil; IR (film): n 2925, 2233, 1198, 802 cm . HRMS
34.7, 134.3, 134.0, 129.7, 129.5, 129.0, 128.9, 128.8, 128.4,
1
26.5 (q, 1C, JC-F = 235), 126.3 (q, 1C, JC-F = 240),
10.9, 106.0, 95.0 (trans, CH ), 93.9 (cis, CH ), 85.1 (trans,
ꢁ
1
1
+
EI) calcd for C H F N O (M ) m/z 348.0333, found
(
1
4 6 6 2 2
+
1
48.0331. MS m/z 348.0 (M ). H NMR (CDCl ): 4.94 (d,
3
3
furan-C), 84.4 (cis, furan-C), 42.8 (trans, furan-C), 42.3 (cis,
furan-C).
J = 8, 1H, furan-H), 5.59 (d, J = 7.5, 1H, furan-H), 6.13 (d,
J = 1, 1H, furan-H), 6.35 (s, 1H, CH), 6.55 (m, 1H, furan-H),
1
9
6
.84 (d, J = 3.5, 1H, furan-H) ppm. F NMR (CDCl ): ꢁ67.8
3
3
.2.5. 3-(5-Benzoyl-4-p-tolyl-2-trifluoromethyl-4,5-
dihydro-furan-3-yl)-4,4,4-trifluoro-1-phenyl-but-2-en-1-one
3ca)
Yellow oil; IR (film): n 1693, 1595, 1177, 803, 763,
1
3
(
s, CF ), ꢁ66.0 (s, CF ) ppm. C NMR (CDCl ): 168.6, 146.9,
3 3 3
2
2
1
1
1
44.9 (q, 1C, J = 40), 131.5 (q, 1C, J = 40), 120.9 (q,
C-F C-F
(
1
C, J = 240), 115.0 (q, 1C, J = 240), 113.4, 111.5,
1
C-F
C-F
14.1, 110.6, 109.0, 105.7, 72.3, 51.6.
ꢁ
89 cm . HRMS (EI) calcd for C H F O (M ) m/z
29 20 6 3
1
+
6
5
+
1
30.1317, found 530.1310. MS m/z 531.0 (M + 1).
H
Acknowledgements
NMR (CDCl ): cis 2.35 (s, 3H, CH ), 5.31 (d, J = 4.5, 1H,
3
3
furan-H), 5.64 (d, J = 4.5, 1H, furan-H), 6.18 (s, 1H, CH), 7.25–
.80 (m, 10H, ArH) ppm. Trans 2.31 (s, 3H, CH ), 5.12 (d,
J = 8, 1H, furan-H), 5.50 (d, J = 8, 1H, furan-H), 6.16 (s, 1H,
Thanks are due to the National Natural Science Foundation
of China under the grant no. 20472047 and Natural Science
Foundation of Shanghai under the grant no. 04ZR14060 for
financial support. We also thank The Instrumental Analysis and
Research Center of Shanghai University for providing the
convenience in running all the NMR samples.
7
3
1
9
CH), 7.20–7.78 (m, 10H, ArH) ppm. F NMR (CDCl ): cis
3
ꢁ
ꢁ
81.9 (s, CF ), ꢁ63.9 (s, CF ) ppm. Trans ꢁ84.5 (s, CF ),
3
3
3
1
3
61.9 (s, CF ) ppm. C NMR (CDCl ): 193.7, 192.6, 154.7,
3 3
2
2
1
1
1
1
54.2, 136.4 (q, 1C, J = 37.5), 134.3 (q, 1C, J = 38),
C-F
C-F
34.1, 131.3, 131.2, 130.9, 129.8, 129.7, 129.6, 128.9, 128.7,
1
27.3, 126.4 (q, 1C, J = 240), 123.4 (q, 1C, J = 245),
References
1
C-F
C-F
05.9, 95.4 (trans, CH ), 94.4 (cis, CH ), 89.9 (trans, furan-
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.2.6. 4-(2-Cyano-1-trifluoromethyl-vinyl)-3-(4-methoxy-
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[
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HRMS (EI) calcd for C H F N O (M ) m/z 388.0646, found
7 10 6 2 2
1
+
1
M. Pohmakotr, A. Issaree, L. Sampaongoen, P. Tuchinda, V. Reutrakul,
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OCH ), 4.74 (d, J = 7, 1H, furan-H), 5.33 (d, J = 7, 1H, furan-
1
H), 6.05 (s, 1H, CH), 6.94–7.23 (4H, ArH) ppm. F NMR
88.0645. MS m/z 388.0 (M ). H NMR (CDCl ): 3.80 (s, 3H,
3
3
[
5] H.S. He, C.W.Y. Chung, T.Y.S. But, P.H. Toy, Tetrahedron 61 (2005) 1385–
9
1
405.
1
3
(
CDCl ): ꢁ67.8 (s, CF ), ꢁ66.7 (s, CF ) ppm. C NMR
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3
3
3