Fluoroalkyl substituted (Z)-dehydro α-amino ester as a building block for the fluorine-containing cyclopropyl α-amino esters and dihydrooxazole

Article abstract of DOI:10.1016/j.jfluchem.2008.03.008

Multi-functionalized β-trifluoromethyl and β-difluoromethyl substituted (Z)-α,β-dehydro α-amino esters have been successfully prepared from N-protected fluorinated threonine ester. Applications of this new fluorine-containing building block to the synthes

Full text of DOI:10.1016/j.jfluchem.2008.03.008

Journal of Fluorine Chemistry 129 (2008) 510–514
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Fluoroalkyl substituted (Z)-dehydro
a
-amino ester as a building block for the
fluorine-containing cyclopropyl
a
-amino esters and dihydrooxazole
Wen Wan a, Yinghong Gao a, Haizhen Jiang a, Jian Hao a,b,
*
a Department of Chemistry, Shanghai University, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Multi-functionalized
b-trifluoromethyl and b-difluoromethyl substituted (Z)-a,b-dehydro a-amino
Received 15 February 2008
Received in revised form 13 March 2008
Accepted 15 March 2008
Available online 22 March 2008
esters have been successfully prepared from N-protected fluorinated threonine ester. Applications of this
new fluorine-containing building block to the synthesis of biologically important fluorinated cylcopropyl
a
-amino esters and dihydrooxazole ester have also been reported.
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Dehydro amino acids
Fluorine-containing building blocks
Fluorine-containing cylcopropyl amino
acids
Cycloadditions
Dihydrooxazoles
1. Introduction
dibenzyl threonine ethyl ester 4, which were stereoselectively
synthesized according to the reported procedures for trifluor-
omethyl substituent (4a) [2]. Protection of hydroxyl group of 4a
with Tos group led to the formation of syn-8, which was further
Development of fluorine-containing building blocks for the
introduction of fluorine or a fluorinated moiety into organic
molecule is highly advantageous in pharmaceutical and agro-
chemical researches. The discovery of multi-functionalized fluor-
ine-containing building blocks still represents a great challenge in
organic synthesis [1].
transformed into N-dibenzyl protected (Z)-
a,b-dehydro amino
ester (9) in excellent yield via a -elimination of TsOH in the
b
presence of NaH. Other bases which were used for this elimination,
such as Et3N, K2CO3 and KOH either provided poor yields or
resulted in decomposition of product, and were not suitable for
this elimination (Path B, Scheme 1). The exchange of N-protection
group of 4 from benzyl group to benzoyl group was succeeded
through the deprotection of N-benzyl group of 4 and followed by
addition of benzoyl chloride under basic condition to afford the
Herein, we wish to report a facile and stereoselective route to
the preparation of multi-functionalized
dehydro amino ester which has been subjected to the pilot study
for the synthesis of biologically interested -fluoroalkyl sub-
stituted cyclopropyl -amino esters and trifluoroethyl substituted
b-fluoroalkyl (Z)-a,b-
b
a
dihydrooxazole ester. Preliminary evaluation of this newly
excogitated multi-functionalized fluorine-containing building
block reveals its potential synthetic value.
N,O-dibenzoyl protected 6 in excellent yields [3]. Subsequential b-
elimination of PhCO2H of 6a and 6b by using the bases of t-BuOK
and DBU resulted in the formations of desired N-benzoyl protected
trifluoromethyl and difluoromethyl substituted (Z)-
amino ester, respectively (Path A, Scheme 1). t-BuOK was once
employed as base for accomplishment of -elimination of both 6a
a,b-dehydro
2. Results and discussion
b
The route to the
amino ester (7 and 9) was started from fluorinated syn-N,N-
b
-fluoroalkyl substituted (Z)-
a
,
b
-dehydro
and 6b, however, good yield was only observed in the elimination
of 6a. The elimination of difluoromethyl substituent (6b) with t-
BuOK or NaH encountered partial decomposition of 6b (mainly due
to the a-elimination of HF of difluoromethyl group by strong base),
and significantly lowered the yield of 7b.
* Corresponding author at: Department of Chemistry, Shanghai University, 99
Shangda Road, Shanghai 200444, China. Tel.: +86 21 66133380;
fax: +86 21 66133380.
Other bases were also examined and as a result, DBU was
selected as an alternative base to minimize this unexpected side
reaction, and the moderate yield of 7b was obtained under this
E-mail address: jhao@shu.edu.cn (J. Hao).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.03.008

W. Wan et al. / Journal of Fluorine Chemistry 129 (2008) 510–514
511
Scheme 2. Synthesis of fluorinated cyclopropyl amino esters 11.
bulky N-benzyl groups of 9. This hypothesis was supported by the
successful cyclopropanation of less steric hindered with
7
diazomethane under same reaction condition. During the cyclo-
propanation process, the pyrazoline intermediate 10 was sched-
uled to be formed at initial step, the crude 10 (without purification)
was then subjected to photolysis by using a 125-W medium-
pressure mercury lamp as a photo source and afforded desired Z-
cylcopropyl
a-amino ester 11 in moderate yields (Scheme 2) [5].
The Z configuration of 11 was determined by NOE correlations.
It was pointed out that the hydrogen linked to nitrogen produced
NOE on one of the protons of the methylene group on the ring
instead of the proton neighbored to the fluoroalkyl group, which is
in agreement with the proposed configuration (Fig. 1). As
cycloaddition of diazomethane to a dehydroamino ester followed
by nitrogen extrusion has previously been proved to produce the
cyclopropane with the same configuration as the starting olefin,
therefore, the Z geometry of the double bond of 7 was established
according to the configuration of cyclopropyl amino esters.
Interesting result was observed while 7a was treated with
sulfoxonium ylide as an alkylidene transfer reagent in DMSO at RT
[6]. Reaction did not yield the desired cylcopropyl product 11a,
instead, the dihydrooxazole ester product 12 was formed as only
one product (Scheme 3). The X-ray crystallographic analysis
confirmed the structure of 12 (Fig. 2) [7].
The yield was not satisfied currently. Preliminary study showed
that the reaction which carried out at ambient temperature was
quite clean but more than 50% of 7a remained even with longer
reaction time. Increase of reaction temperature to 50 8C could help
the consumption of starting materials whereas the reaction
became much more complicated. A possible mechanism of its
formation was proposed in Scheme 4.
Scheme 1. Stereoselective route to fluorinated (Z)-a,b-dehydro a-amino esters.
reaction condition. The optimization of
b-elimination reaction of
6a by base was also performed. Results showed that elimination by
using organic base, such as t-BuOK, DBU, DABCO and Et3N provided
a good yield. Lower reaction temperature was propitious to better
stereoselectivity to form Z product 7a (Table 1).
It is known that cyclopropyl a-amino acids are of broad interest
as biological probes, enzyme inhibitors, and conformationally
constrained analogues of native amino acids [4]. However, the
bioactivity and its potential pharmaceutical value of fluoroalkyl
substituted cyclopropyl amino acids are less studied due to the lack
of efficient way to prepare. This encouraged us to explore the new
route to synthesize
acids through the fluorinated building block 9. However, the initial
assignment of cyclopropanation of (Z)- -dehydro amino ester 9
b-fluoroalkyl substituted cyclopropyl amino
a,b
with sulfoxonium ylide or diazomethane was failed. The reason for
this failure is possibly deduced to the steric hindrances of two
Table 1
Synthesis of trifluoromethyl
a,b-dehydroamino esters 7a by using different bases
Entry
Base
Solvent
Temperature
Time
Yielda
Z:Eb
1
2
3
4
5
6
7
8
9
Pyridine
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
RT
24 h
–
–
RT
24 h
24 h
78%c
Trace
Trace
80%c
84%c
70%
72%
87%
1.4:1
–
KOH
RT
K2CO3
DABCO
DBU
RT
24 h
–
RT
24 h
1.96:1
1.41:1
Z only
Z only
Z only
RT
1 h
DBU
À18 8C
À18 8C
À18 8C
1 h
NaH
45 min
30 min
t-BuOK
THF
a
The yields listed in this table are isolated yields.
b
c
The ratio of Z and E form was determined by 19F NMR.
Total yield for Z and E product.
Fig. 1. The NOE correlation of compound 11a.

512
W. Wan et al. / Journal of Fluorine Chemistry 129 (2008) 510–514
4. Experimental
4.1. General procedure for synthesis of fluorinated syn-3-benzamido-
4-ethoxy-4-oxobutan-2-yl benzoate (6)
To an ice-chilled mixture of fluorinated syn-ethyl 2-amino-3-
hydroxybutanoate (5) (2.49 mmol) and triethylamine (0.72 mL,
4.98 mmol) in dichloromethane (20 mL) was added benzoyl
chloride (0.58 mL, 4.98 mmol) in drop wise. The reaction was
completed after about 30 min. The solution was quenched with
saturated NH4Cl (aq) (5 mL), extracted with dichloromethane
(3 mL Â 15 mL), washed with saturated brine (5 mL). The collected
extraction was then dried over anhydrous magnesium sulfate and
evaporated to dryness. The crude product was purified by column
chromatography.
Scheme 3. Synthesis of dihydrooxazole ester 12.
4.1.1. syn-3-Benzamido-4-ethoxy-1,1,1-trifluoro-4-oxobutan-2-yl
benzoate (6a)
6a was obtained as a white solid in 90% yield. mp: 90–92 8C. 1H
NMR (500 MHz, CDCl3)
d = 1.31 (t, 3H, J = 7.0 Hz); 4.23–4.29 (m,
2H); 5.57 (dd, 1H, J = 9.0, 2.5 Hz); 6.13 (dq, 1H, J = 6.5, 2.5 Hz); 6.76
(d, 1H, J = 9.0 Hz); 7.46–8.07 (m, 10H). 19F NMR (470 MHz, CDCl3)
3
d
d
= À74.18 (d, 3F, JH–C–C–F = 6.5 Hz). 13C NMR (125 MHz, CDCl3)
= 14.13; 51.04; 63.10; 69.59 (q, 2JC–C–F = 32.5 Hz); 122.89 (q, 1JC–
F = 280.0 Hz); 127.41; 127.88; 128.90; 128.97; 130.31; 132.35;
133.59; 134.51; 164.28; 167.47; 168.28. IR (KBr) = 3294; 3068;
1747; 1642; 1259; 1186; 1144; 712; 692 cmÀ1
n
.
Fig. 2. X-ray crystallography of 12.
4.1.2. syn-3-Benzamido-4-ethoxy-1,1-difluoro-4-oxobutan-2-yl
benzoate (6b)
6b was obtained as a white solid in 91% yield. mp: 125–127 8C.
1H NMR (500 MHz, CDCl3)
d = 1.32 (t, 3H, J = 7.2 Hz); 4.25–4.32 (m,
2 H); 5.36 (dd, 1H, J = 8.5, 2.5 Hz); 5.79–5.85 (m, 1H); 6.14 (td, 1H,
J = 54.0, 5.0 Hz); 6.88 (d, 1H, J = 8.5 Hz); 7.45–7.81 (m, 10 H).
19F NMR (470 MHz, CDCl3)
d
= À126.75(ddd, 1F, 2JF–C–F = 294.2 Hz,
2JH–C–F = 54.0 Hz, 3JH–C–C–F = 10.3 Hz); À128.89 (ddd, 1F,
2
3
2JF–C–F = 294.2 Hz, JH–C–F = 54.0 Hz, JH–C–C–F = 10.8 Hz). 13C NMR
(125 MHz, CDCl3)
3JC–C–C–F = 3.8 Hz); 62.86; 71.80 (dd, JC–C–F = 29.4 Hz, JC–C–F
d
= 14.02; 51.48 (dd, 3JC–C–C–F = 3.8,
2
2
=
1
1
23.1 Hz); 112.96 (dd, JC–F = 245.0 Hz, JC–F = 242.5 Hz); 127.26;
128.36; 128.69; 128.76; 130.01; 132.24; 133.27; 134.00; 164.83;
167.63; 168.81. IR (KBr)
n = 3308; 3064; 1740; 1644; 1262; 1142;
1095; 1067; 707; 696 cmÀ1
.
4.2. Procedure for synthesis of (Z)-ethyl 2-benzamido-4,4,4-
trifluorobut-2-enoate (7a)
Scheme 4. . Proposed mechanism of the formation of 12.
The syn-3-benzamido-4-ethoxy-1,1,1-trifluoro-4-oxobutan-2-
yl benzoate (6a) (300 mg, 0.73 mmol) and potassium t-butoxide
(165 mg, 1.47 mmol) were dissolved in dry THF (20 mL) under
nitrogen. The mixture was stirred at À18 8C (under ice salt bath) for
30 min. The reaction was quenched with saturated brine (5 mL),
extracted with dichloromethane (3 mL Â 10 mL). The collected
extraction was dried over anhydrous magnesium sulfate and the
solvent was removed under reduced pressure to give a yellow
solid. The crude product was recrystallized from ethyl acetate to
afford a white solid; yield: 182 mg (87%). mp: 80–82 8C. 1H NMR
It is worth to point out that the
difluoromethyl substituted (Z)- -dehydro amino esters 7 and 9
could also be represented as an important precursor of
trifluoromethyl and -difluoromethyl substituted -amino acid
through a known reduction process [8]. The dihydrooxazole ester
b-trifluoromethyl and b-
a,b
b
-
b
a
12 could also be an important precursor of
a-fluoroalkyl
substituted serines or threonines [9].
3. Conclusions
(500 MHz, CDCl3) d = 1.35 (t, 3H, J = 7.2 Hz); 4.35 (q, 2H, J = 7.2 Hz);
6.07 (q, 1H, J = 8.0 Hz), 7.49–7.86 (m, 5H); 7.99 (s, 1H). 19F NMR
The multi-functionalized -trifluoromethyl and
methyl substituted (Z)-a,b-dehydro amino esters have been
successfully prepared as new fluorine-containing building block
from N-protected fluorinated threonine esters. Preliminary appli-
cation of this building block to the synthesis of biologically
b
b-difluoro-
3
(470 MHz, CDCl3)
d
d
= À59.44 (d, 3F, JH–C–C–F = 8.0 Hz). 13C NMR
2
(125 MHz, CDCl3)
= 14.08; 63.01; 111.79 (q, JC–C–F = 35.0 Hz);
1
122.68 (q, JC–F = 268.8 Hz); 127.78; 129.07; 132.30; 133.11;
3
135.25 (q, JC–C–C–F = 5.0 Hz); 163.16; 165.74. IR (KBr)
n = 3270;
3087; 1732; 1680; 1654; 1510; 1259; 1189; 1116; 712; 693 cmÀ1
.
important fluorinated Z-cylcopropyl
a-amino esters and dihy-
HRMS (ESI): m/z calcd for C13H13F3NO3 [M+H]+: 288.0842. Found:
drooxazole ester were also succeeded. The optimization of reaction
conditions is currently under investigation.
288.0838.

W. Wan et al. / Journal of Fluorine Chemistry 129 (2008) 510–514
513
4.3. Procedure for synthesis of (Z)-ethyl 2-benzamido-4,4-
698 cmÀ1. HRMS (ESI): m/z calcd for C20H21F3NO2 [M+H]+:
trifluorobut-2-enoate (7b)
364.1524. Found: 364.1527.
4.6. General procedure for the synthesis of fluorinated Z-ethyl 1-
To a solution of 3-benzamido-4-ethoxy-1,1-difluoro-4-oxobu-
tan-2-yl benzoate (6b) (300 mg, 0.77 mmol) in dichloromethane
(10 mL) was added DBU (0.23 ml, 1.54 mmol). The mixture was
stirred at À18 8C (under ice salt bath) for 1 h and then quenched
with saturated NH4Cl (aq) (3 mL), extracted with dichloromethane
(3 mL Â 8 mL) and washed with saturated brine (5 mL). The
collected dichloromethane extraction was evaporated to dryness
under vacuum after dried over anhydrous magnesium sulfate. The
crude product was purified by column chromatography to give a
white solid; yield: 139 mg (67%). mp: 62–64 8C. 1H NMR (500 MHz,
benzamido-2-methyl-cyclopropane carboxylate (11)
Excess ethereal solution of diazomethane was distilled into a
solution of fluorinated (Z)-ethyl 2-benzamido-4,4,4-trifluorobut-
2-enoate (7) (0.35 mmol) dissolved in ether (10 mL) at 0 8C. The
resulting solution was protected from light and stirred for another
3 h. Anhydrous CaCl2 was then added to destroy the excess
diazomethane and, after filtration, evaporated under vacuum to
give a yellow oil. The pyrazoline obtained was very unstable and
was used without further purification. It was then dissolved in
toluene (10 mL) and transferred into a quartz glass reactor under
nitrogen atmosphere, cooled at À18 8C (under ice salt bath) and
irradiated with a 125-W medium-pressure mercury lamp for 3 h.
The solvent was removed under vacuum and the crude was
purified by column chromatography.
CDCl3, ppm)
d = 1.38 (t, 3H, J = 7.0 Hz); 4.35 (q, 2H, J = 7.0 Hz); 6.49
(td, 1H, J = 10.8, 4.5 Hz); 6.79 (td, 1H, J = 55.0, 4.5 Hz,) 19F NMR
2
3
(470 MHz, CDCl3)
d
= À115.94 (dd, 2F, JH–C–F = 55.0 Hz, JH–C–C–
F = 10.8 Hz); 13C NMR (125 MHz, CDCl3)
d
=14.12; 63.18; 112.81 (t,
1JC–F = 232.5 Hz); 119.56 (t, JC–C–F = 28.8 Hz); 127.63; 129.01;
2
129.47; 132.84; 133.89; 163.97; 165.48. IR (KBr)
n = 3328, 3067;
1735; 1686; 1661; 1328; 1262; 1159; 1122; 1008; 709; 664 cmÀ1
.
HRMS (ESI): m/z calcd for C13H14F2NO3 [M+H]+: 270.0942. Found:
4.6.1. Z-Ethyl 1-benzamido-2-(trifluoromethyl)cyclopropane
carboxylate (11a)
270.0946.
11a was obtained as a white solid in 48% yield. mp: 119–21 8C.
1H NMR (500 MHz, CDCl3)
d = 1.27 (t, 3H, J = 7.2 Hz); 1.88 (t, 1H,
4.4. Procedure for synthesis of syn-ethyl 2-(dibenzyl-amino)-4,4,4-
J = 7.0 Hz); 2.15 (dd, 1H, J = 9.0 Hz, 7.0 Hz); 2.54–62 (m, 1 H); 4.22
trifluoro-3-(tosyloxy)butanoate (8)
(q, 2H, J = 7.2 Hz); 6.65 (s, 1H); 7.46–.78 (m, 5H). 19F NMR
3
(470 MHz, CDCl3)
(125 MHz, CDCl3)
d
d
= À61.24 (d, 3F, JH–C–C–F = 6.5 Hz). 13C NMR
syn-Ethyl 2-dibenzylamino-4,4,4-trifluoro-3-hydroxybutane
(4a) (394 mg, 1.03 mmol)and TsCl (197 mg, 1.03 mmol)was
dissolved in pyridine (10 mL) and the mixture was stirred at
room temperature for 18 h. It was quenched with saturated NH4Cl
(aq) (8 mL), extracted with dichloromethane (3 mL Â 10 mL) and
washed with saturated brine (5 mL). The collected extraction was
evaporated to dryness under vacuum after dried over anhydrous
magnesium sulfate and the crude product was purified by column
chromatography to afford 8 as a white solid; yield:393 mg (73%).
2
= 14.20; 19.17; 27.72 (q, JC–C–F = 36.3 Hz);
36.60; 62.66; 124.56 (q, 1JC–F = 271.3 Hz); 127.28; 128.89; 132.30;
133.83; 168.79; 169.71. IR (KBr)
1525; 1275; 1148; 1082; 726; 694 cmÀ1. HRMS (ESI): m/z calcd for
14H16F3NO3 [M+H]+: 303.1082. Found: 302.1085.
n = 3289; 3061; 1734; 1655;
C
4.6.2. Z-Ethyl 1-benzamido-2-(difluoromethyl)cyclopropane
carboxylate (11b)
mp: 66–68 8C. 1H NMR (500 MHz, CDCl3)
d = 1.37 (t, 3H, J = 7.2 Hz);
2.42 (s, 3H); 3.71 (d, 2H, J = 13.5 Hz); 3.87 (d, 1H, J = 5.5 Hz); 4.07
11b was obtained as a white solid in 46% yield. mp: 108–110 8C.
1H NMR (500 MHz, CDCl3)
d = 1.23 (t, 3H, J = 7.0 Hz); 1.64 (t, 1H,
J = 6.5 Hz); 1.95 (t, 1H, J = 6.5 Hz); 2.37–45 (m, 1H); 4.18 (q, 2H,
J = 7.0 Hz); 5.81 (td, 1H, J = 56.0, 4.5 Hz); 6.75 (s, 1H); 7.43–78 (m,
(d, 2H, J = 13.5 Hz); 4.30 (m, 2H); 5.55–5.60 (m, 1H); 7.20–7.74 (m,
3
14H). 19F NMR (470 MHz, CDCl3)
d
= À72.67 (d, 3F, JH–C–C–
2
5H). 19F NMR (470 MHz, CDCl3)
d
= À109.74 (ddd, 1F, JF–C–
F = 5.6 Hz). 13C NMR (125 MHz, CDCl3)
d = 14.14; 21.40; 55.78;
2
3
2
1
F = 290.5 Hz, JH–C–F = 56.0 Hz, JH–C–C–F = 8.5 Hz); À116.59 (ddd,
59.27; 61.58; 75.37 (q, JC–C–F = 31.3 Hz); 122.44 (q, JC–
1F, JF–C–F = 290.5 Hz, JH–C–F = 56.0 Hz, JH–C–C–F = 8.5 Hz). 13C
2
2
3
F = 281.3 Hz); 127.24; 127.66; 128.23; 129.07; 129.65; 133.50;
2
NMR (125 MHz, CDCl3)
d
= 14.18; 18.14; 28.43 (t, JC–C–
138.25; 145.30; 167.82 IR (KBr)
1151; 1027; 736; 698 cmÀ1
n = 3030; 1734; 1599; 1377; 1182;
3
1
F = 29.4 Hz); 36.71 (t, JC–C–C–F = 3.8 Hz); 62.29; 115.35 (t, JC–
.
F = 237.5 Hz); 127.29; 128.81; 132.27; 133.63; 169.18; 170.40. IR
(KBr)
n = 3280; 3031; 1740; 1652; 1524; 1340; 1265; 1187; 1035;
4.5. Procedure for synthesis of ethyl 2-(dibenzylamino)-4,4,4-
717; 693 cmÀ1. HRMS (ESI): m/z calcd for C14H17F2NO3 [M+H]+:
trifluoro-but-2-enoate (9)
285.1177. Found: 285.1180.
NaH (54 mg, 2.25 mmol, the mineral oil on the surface
was washed off with dry THF) was added to a solution of
4.7. Procedure for synthesis of ethyl 2-phenyl-4-(2,2,2-
trifluoroethyl)-4,5-dihydrooxazole-4-carboxylate (12)
syn-ethyl
2-(dibenzylamino)-4,4,4-trifluoro-3-(tosyloxy)bu-
tanoate (8) (393 mg, 0.75 mmol) in dry THF (15 mL). The mixture
was stirred at 0 8C for about 6 h. The reaction was monitored by
TLC and quenched with saturated NH4Cl (aq) (7 mL). The
suspension was extracted with ether (3 mL Â 10 mL) and washed
with saturated brine (5 mL). The collected organic layer was
dried over magnesium sulfate and then the solvent was removed
in vacuo to give 9 as a white solid; yield: 270 mg (98%). 1H NMR
Trimethylsulfoxonium iodide (462 mg, 2.1 mmol) was added to
a suspension of NaH (60% in mineral oil, 84 mg, 2.1 mmol) in dry
DMSO (15 mL), and the mixture was stirred under nitrogen at room
temperature for 30 min. A solution of (Z)-ethyl 2-benzamido-4,4,4-
trifluorobut-2-enoate (7a) (200 mg, 0.7 mmol) in DMSO (5 mL)
was then added, and the resulting mixture was stirred at room
temperature for 3 days. The suspension was quenched with
saturated brine (8 mL) and extracted with ether (3 mL Â 10 mL).
The collected extraction was evaporated to dryness under vacuum
after dried over anhydrous magnesium sulfate and the residue was
purified by column chromatography to afford compounds 12;
yield: 66 mg (31%); mp: 44–46 8C. 1H NMR (500 MHz, CDCl3)
(500 MHz, DMSO)
d = 1.22 (t, 3H, J = 7.0 Hz); 4.17 (s, 4H); 4.21 (q,
2H, J = 7.0 Hz); 5.32 (q, 1H, J = 9.0 Hz); 7.21–7.36 (m, 10H). 19F
3
NMR (470 MHz, DMSO, ppm)
d
= À52.83 (d, 3F, JH–C–C–
F = 9.0 Hz). 13C NMR (125 MHz, DMSO)
d
= 13.61; 54.82; 62.12;
2
1
98.10 (q, JC–C–F = 36.3 Hz); 123.78 (q, JC–F = 266.3 Hz); 127.51;
3
127.96; 128.44; 136.74; 148.33 (q, JC–C–C–F = 5.0 Hz); 164.76. IR
d
= 1.32 (t, 3H, J = 7.2 Hz); 2.60–2.70 (m, 1H); 3.17–3.27 (m,1H);
(KBr)
n = 3031; 1730; 1629; 1448; 1235; 1180; 1099; 737;

514
W. Wan et al. / Journal of Fluorine Chemistry 129 (2008) 510–514
References
4.23–4.37 (m, 2H); 4.46 (d, 1H, J = 9.5 Hz); 5.08 (d, 1H, J = 9.5 Hz);
7.41–7.97 (m, 5H). 19F NMR (470 MHz, CDCl3)
C–C–F = 10.6 Hz). 13C NMR (125 MHz, CDCl3)
d
= À61.21 (t, 3F, 3JH–
[1] (a) K. Mu¨ ller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886;
(b) K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 104 (2004) 1–16;
(c) M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 44 (2005) 214–231;
(d) X. Ren, W. Wan, H. Jiang, J. Hao, Mini-Rev. Org. Chem. 4 (2007) 330–337.
[2] C. Scolastico, E. Coonca, L. Prati, Synthesis 5 (1985) 850–855.
[3] E. White, Org. Synth. 5 (1973) 336–337.
[4] Z. Szakonyi, F. Fu, D. Tourwe, N.D. Kimpe, J. Org. Chem. 67 (2002) 2192–2196.
[5] J.T. Slama, R.K. Satsangi, A. Simmons, V. Lynch, R.E. Bolger, J. Sutties, J. Med. Chem.
33 (1990) 824–832.
d
= 14.05; 41.21 (q, 2JC–
C–F = 27.5 Hz); 62.61; 73.14 (q, 3JC–C–C–F = 2.5 Hz); 74.30; 125.32 (q,
1JC–F = 276.3 Hz); 126.66; 128.64; 128.87; 132.31; 166.12; 170.24.
IR (KBr)
n
.
= 2987; 1734; 1635; 1371; 1299; 1259; 1148; 726;
HRMS (ESI): m/z calcd for C14H15F3NO3 [M+H]+:
699 cmÀ1
302.1004. Found: 302.1005.
[6] (a) E.J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 87 (1965) 1353–1364;
(b) B.M. Trost, M.J. Bogdanowicz, J. Am. Chem. Soc. 95 (1973) 5298–5307;
(c) M. Mae, M. Matsuura, H. Amii, K. Uneyama, Tetrahedron Lett. 43 (2002) 2069–
2072.
[7] These data (CCDC 679604) can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] (a) G. Hattori, T. Hori, Y. Miyake, Y. Nishibayashi, J. Am. Chem. Soc. 129 (2007)
12930–12931;
(b) B. Jerome, H. Jens, S. Benjamin, A. Vasyl, V. Sergej, P. Angelika, B. Armin, Angew.
Chem. Int. Ed. 46 (2007) 5971–5974;
(c) B. Zhao, Z. Wang, K. Ding, Adv. Synth. Catal. 348 (2006) 1049–1057.
[9] J. Lee, Y. Lee, M. Kang, Y. Lee, B. Jeong, J. Lee, M. Kim, J. Choi, J. Ku, H. Park, S. Jew, J.
Org. Chem. 70 (2005) 4158–4161.
5. Acknowledgments
This work has been financially supported by National Natural
Science Foundation of China (20472049, 20772079) and
Shanghai Municipal Committee of Science and Technology
(07JC14020, 07ZR14040). We appreciate Professor Fengling
Qing in Shanghai Institute of Organic Chemistry, CAS, for his
kind help. We also thank Dr. H.M. Deng and the Instrumental
Analysis & Research Center of Shanghai University for NMR and
X-ray assistance.