Transition metal-catalyzed formation of CF3-substituted α,β-unsaturated alkene and the synthesis of α-trifluoromethyl substituted β-amino ester

Article abstract of DOI:10.1016/j.tet.2006.09.041

A new transition metal-catalyzed formation of CF₃-substituted α,β-unsaturated alkenes through the ylide intermediate from the reaction between methyl 3,3,3-trifluoro-2-diazopropionate 1 and aryl aldehydes has been developed. Further transformation of the alkene affords the α-trifluoromethyl substituted β-amino ester, a valuable intermediate in the synthesis of fluorine-containing amino acids with potential biological application.

Full text of DOI:10.1016/j.tet.2006.09.041

Tetrahedron 62 (2006) 11760–11765
Transition metal-catalyzed formation of CF3-substituted
a,b-unsaturated alkene and the synthesis of a-trifluoromethyl
substituted b-amino ester
b,
Wan Pang,a,b Shifa Zhu,b Huanfeng jianga, and Shizheng Zhu
*
*
aCollege of Chemistry, South China University of Technology, Guangzhou 510640, China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 12 July 2006; revised 11 September 2006; accepted 12 September 2006
Abstract—A new transition metal-catalyzed formation of CF3-substituted a,b-unsaturated alkenes through the ylide intermediate from the
reaction between methyl 3,3,3-trifluoro-2-diazopropionate 1 and aryl aldehydes has been developed. Further transformation of the alkene
affords the a-trifluoromethyl substituted b-amino ester, a valuable intermediate in the synthesis of fluorine-containing amino acids with
potential biological application.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Fluorinated amino acids also play an important role in the
field of biological tracers, mechanistic probes, enzyme in-
hibitors, and medical applications including control of blood
pressure, treatment of allergies, and inhibition of tumor
growth.7 Additionally, fluorinated b-amino acids are now
recognized as potentially exciting building blocks for the
synthesis of b-peptides, antibiotics, and enzyme inhibitors.8
It is well documented that the replacement of hydrogen with
fluorine in organic molecules can make a profound and un-
expected influence on the physical and biological properties
of organic compounds.1 Much attention has been directed to-
ward the fluoro substitution during the last decade.2 What is
more, due to the unique physical and biological properties
impacted by the CF3 group, trifluoromethylation is an ongo-
ing area of research. Thus, the preparation of trifluoromethyl
containing molecules has been of great interest not only to
biochemists and medicinal chemists, but also to the synthetic
organic fluorine chemists.3
Usually, b-amino acid can be synthesized from the a,b-unsat-
urated carboxylic ester. Michael addition of hydrazoic acid
(HN3) produces the azide compound, which can be easily
converted to the corresponding b-amino ester using well
established chemistry (Scheme 1).9 In this paper, in order to
avoid the explosive hydrazoic acid, we chose the readily
available andrelativelystablesodiumazideas thedirectazide
source. Advantages of the protocol include high-yielding
reaction and mild reaction condition.
Amino acids are the basic units of proteins. More than 200
different amino acids are found in living organisms.4 Hence,
synthesis of novel amino acids has always been one of the
research focuses of organic chemists. Among them, fluo-
rine-containing amino acids have attracted considerable at-
tention and enjoyed widespread bioorganic applications.5
The strong carbon–fluorine bond is particularly resistant to
metabolic transformations, and the electronegativity of fluo-
rine can have a significant effect on the basicity or acidity of
neighboring groups and on the electron distribution, and can
change the overall reactivity and stability of the molecules.6
R2 CO2R1
HN3
R3
H
H
H
R2
R3
CO2R1
N3
R2
R3
CO2R1
NH2
Reduction
H
Scheme 1.
In our previous work, we have developed several methods to
synthesize fluorinated alkene from fluorinated diazo com-
pounds and aldehydes through the ylide intermediate.10a
Therefore, we wondered whether methyl 3,3,3-trifluoro-
2-diazopropionate 1 could react with aldehydes to give the
Keywords: Catalysis; CF3-substituted; Ylide; a,b-Unsaturated alkenes;
b-Amino ester.
* Corresponding authors. Tel.: +86 21 54925184; fax: +86 21 64166128;
e-mail: zhusz@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.041

W. Pang et al. / Tetrahedron 62 (2006) 11760–11765
11761
H
H
CF3 CO2Me
CF3 CO2Me
CF3
CO2Me
CF3
Ar
CO2Me
NH2
HN3
ArCHO
aza-Michael addition
N2 Wittig-type Reaction
N3 Reduction
Ar
Ar
H
H
4
1
2
3
Scheme 2.
corresponding CF3-containing a,b-unsaturated alkenes 2
through the ylide intermediate, which could be easily trans-
formed into the corresponding trifluoromethyl containing
b-amino esters (Scheme 2).
As indicated in Table 1, the reaction yields, through arso-
nium ylide intermediate, are unsatisfied even using refluxing
toluene. It is known that antimony ylide is more reactive than
the arsonium ylide. We envisioned that antimony ylide could
give better reaction results. When SbBu3 was used instead
of Ph3As, under the same reaction conditions, however, no
alkene product was detected (Table 1, entries 4 and 5). It
may be explained that the rhodium catalyst was poisoned
by the strong reductive SbBu3. When cuprous bromide
(CuBr) was used as the catalyst, alkene 2c was isolated in
moderate yield in refluxing benzene (Table 1, entry 6). The
yield of product 2c was not improved at higher temperature
(refluxing in toluene) (Table 1, entry 7). Inorganic or organic
copper catalyst such as CuBr, Cu(acac)2, and Cu(hfacac)2
Herein, we wish to report a successful synthesis of trifluoro-
methylated b-amino esters from diazo compound 1.
2. Results and discussion
Initially, arsonium ylide intermediate was used to prepare
alkene 2. 4-Nitrobenzaldehyde was used as the substrate,
1 mol % Rh2(OAc)4 was used as the catalyst, and refluxing
THF as the solvent. The expected alkene 2b was isolated
in only 9% yield. In the meantime, trace amount of 1,3-
dioxolane 5 (3%) was isolated (Table 1, entry1). It should
come from the 1,3-dipolar addition of the carbonyl ylide
intermediate and the aldehyde (Scheme 3).3a
Ar
N2
ArCHO
CF3
LnM
Ph3As
CF3
CO2Me
CO2Me
F3C
CO2Me
N2
1
2
Ph3As=O
Ph3As or SbBu3
The proposed reaction mechanism is depicted in Scheme 4.
Due to the electron-withdrawing properties of the flanking
trifluoromethyl and methoxyl carbonyl groups, the ylide in-
termediate could be too stable to react with the aldehyde to
give alkene 2. To improve the yield, more severe reaction
conditions were employed. Increasing the reaction tempera-
ture to 80 ꢀC (refluxing in benzene), improved the yields of
alkene 2b and 1,3-dioxolane 5 to 19 and 14%, respectively
(Table 1, entry 2). Further increasing the reaction tempera-
ture to 110 ꢀC (refluxing in toluene), improved the yield of
2b to 36%. But the yield of 5 fell to 7% (Table 1, entry 3).
CF3
CO2Me
LnM
Ar
H
O
Ar
N2
CF3
O
LnM
O
F3C
CO2Me
N2
CO2Me
H
Ar
CO2Me
CF3
1
ArCHO
H
ArCHO
CF3
LnM
CO2Me
Scheme 4.
Table 1. The optimization of reaction condition
Entry
ArCHO (Ar¼)
Lewis base
Catalyst
Solvent
Product yield (%)a
2
5
1
2
3
4
5
6
7
8
9
p-NO2C6H4-
p-NO2C6H4-
p-NO2C6H4-
p-BrC6H4-
p-BrC6H4-
p-BrC6H4-
p-BrC6H4-
p-BrC6H4-
p-BrC6H4-
Ph3As
Ph3As
Ph3As
SbBu3
SbBu3
SbBu3
SbBu3
SbBu3
SbBu3
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
CuBr
CuBr
Cu(acac)2
Cu(hfacac)2
THF
9 (2b)
3
14
7
—
—
—
—
—
—
Benzene
Toluene
Benzene
Toluene
Benzene
Toluene
Benzene
Toluene
19 (2b)
36 (2b)
—
—
55 (2c)
59 (2c)
57 (2c)
54 (2c)
a
Isolated yields based on aldehyde.
C6H4O2N-p
CF3
CO2Me
+
CF3
CO2Me
+
Rh2(OAc)4
O
p-NO2C6H4CHO
+
AsPh3
1.1
O
CF3
N2
1.2
THF
reflux
p-NO2C6H4
MeO2C
1.0
C6H4O2N-p
1
2b
5
9%
3%
Scheme 3.

11762
W. Pang et al. / Tetrahedron 62 (2006) 11760–11765
H
H
H
gave the corresponding alkenes in similar yields (Table 1,
entries 6–9).
CF3
CO2Me
NH2
CF3
CO2Me
N3
.
SnCl2 2H2O
MeOH
N2
p-BrC6H4
p-BrC6H4
H
3
Then under the optimized reaction conditions (Table 1, entry
8), (Scheme 5), a series of aromatic aldehydes were used
to prepare various alkene 2. The results are summarized in
Table 2.
4 32%
Scheme 7.
H
H
CF3
CO2Me
N3
CF3
p-BrC6H4
CO2Me
PdC/H(1atm)
CF3
CO2Me
+
O
CF3
R
CO2Me
Cu(acac)2
SbBu3
1.1
+
MeOH
N2
R
H
toluene
reflux
p-BrC6H4
NH2
74%
N2
1.2
1
H
3
H
4
1.0
2
Scheme 8.
Scheme 5.
a
The structure of 4 was further confirmed by the X-ray crystal
diffraction (Fig. 1).
Table 2. Reaction results of 1 with aryl aldehydes and SbBu3
Entry
ArCHO (Ar¼)
Ph-
p-NO2C6H4-
p-BrC6H4-
o-ClC6H4-
p-CH3OC6H4-
MeO
Product
Yield (%)b
1
2
3
4
5
2a
2bc
2c
2d
2e
46
36
57
69
62
6
7
8
a
2f
62
85
77
OMe
Br
trans-PhCH]CH-
2g
2h
O
Cu(acac)2 (10 mol %), diazo compound:aldehyde:SbBu3¼1.2:1.0:1.1 are
used for all reactions.
Isolated yields based on aldehyde.
b
c
Rh2(OAc)4 and Ph3As system was used.
It shows that all of the aromatic aldehydes employed afford
the corresponding alkene 2 in satisfying yields.
Figure 1. Crystal structure of 4.
With the a,b-unsaturated alkenes in hand, we then explored
its reaction with the hydrazoic acid (HN3) to produce the
azide compound. It is necessary to generate the HN3 in
situ, because it is explosive and poisonous. Based on the lit-
erature,12 methyl 3-(4-bromophenyl)-2-(trifluoromethyl)-
acrylate 2c was chosen as the substrate. In aqueous THF,
2c reacted with the hydrazoic acid, which was generated in
situ from NaN3 and HOAc, for 48 h at room temperature
to give the corresponding azide 3 in quantitative yield. The
product was essentially pure after general work-up and could
be used directly in the next step (Scheme 6).
3. Conclusion
In summary, we successfully synthesize a series of CF3-
substituted a,b-unsaturated alkenes from the transition
metal-catalyzed reaction between methyl 3,3,3-trifluoro-2-
diazopropionate 1 and aryl aldehydes. CF3-Substituted a,b-
unsaturated alkenes can be further transferred into b-amino
ester through a two-step procedure. This paper provides a
good choice for the synthesis of CF3-substituted b-amino
acid.
H
CF3
CO2Me
CF3
CO2Me
NaN3, HOAc
4. Experimental
4.1. General
H2O, THF
rt, 48h
N3
p-BrC6H4
p-BrC6H
4 H
2c
3 100%
Scheme 6.
Melting points were measured in a SGWÒ X-4 micro-melt-
ing point apparatus and were uncorrected. 1H and 19F NMR
spectra were recorded on a Bruker AM-300 spectrometer
with Me4Si and CFCl3 (with upfield negative) as the internal
and external standards, respectively. IR spectra were ob-
tained with a Nicolet AV-360 spectrophotometer. Low-reso-
lution mass spectra or high-resolution mass spectra (HRMS)
were obtained on a Finnigan GC–MS 4021 or a Finnigan
MAR-8430 instrument using the electron impact ionization
technique (70 eV), respectively. The X-ray structural analy-
sis was performed with a Rigaku/AFC 7R Diffractometer.
Elemental analyses were performed by this institute.
It is well known that azide can be easily reduced to give the
corresponding amine product.11 Initially, SnCl2$2H2O was
used to reduce the azide 3 to give only 32% of the desired
a-trifluoromethyl substituted b-amino ester 4 (Scheme 7).
Pd–C/H2 is the most popular catalytic system for the reduc-
tion of the azide. Furthermore, it is an atom economical and
environmental benign reaction. The reaction results showed
that the azide can be easily transformed into the desired
amino ester 4 in 74% yield using Pd–C/H2 (1 atm) (Scheme 8).

W. Pang et al. / Tetrahedron 62 (2006) 11760–11765
11763
4.2. General method for the reaction of methyl 3,3,3-
trifluoro-2-diazopropionate 1 with aldehydes
(CDCl3, 300 MHz): d 8.33 (2H, d, J¼9.0 Hz), 8.28 (2H, d,
J¼9.0 Hz), 7.78 (2H, d, J¼9.0 Hz), 7.60 (2H, d,
J¼9.0 Hz), 6.87 (1H, s), 5.65 (1H, s), 3.43 (3H, s) ppm.
19F NMR (CDCl3, 282 MHz): d ꢁ73.8 (CF3, s) ppm. MS
(70 eV, EI): 443 ([M+1]+, 1), 291 (13), 275 (42), 258 (16),
166 (100), 150 (19), 89 (30), 59 (30). Anal. Calcd for
C18H13F3O8N2: C, 48.88; H, 2.96; N, 6.33%. Found: C,
49.01; H, 3.01; N, 6.23%.
A mixture of 2 (1 mmol), AsPh3 or SbBu3 (1.5 mmol),
and Rh2(OAc)4 (5 mg, 1 mol %) or Cu(acac)2 (78.6 mg,
20 mmol %) in anhydrous toluene (1.5 ml) in a schrock tube
was heated to reflux and a solution of 1a (252 mg, 1.5 mmol)
in toluene (2 ml) was added dropwise. The resulting mixture
was stirred for 15 h under N2 atmosphere. Upon completion
of the reaction (monitored by TLC), the reaction mixture
was cooled to room temperature and the crude product
was filtered. The residue was purified by column chromato-
graphy on silica gel using ethyl ester–hexane as eluent to
give 3a (106 mg, 46%).
4.2.4. Methyl 3-(4-bromophenyl)-2-(trifluoromethyl)-
acrylate (3c).
CF3
CO2Me
Br
4.2.1. Methyl 3-phenyl-2-(trifluoromethyl)acrylate (3a).
Colorless solid with mp: 43–45 ꢀC, Z/E¼1:3.3. IR (KBr),
cmꢁ1: 2996, 2959, 1917, 1724, 1649, 1490, 1440, 1384,
1312, 1278, 1133, 1021. 1H NMR (CDCl3, 300 MHz):
d 7.56–7.51 (2H, m), 7.27–7.24 (2H, m), 379 (3H, s) ppm.
19F NMR (CDCl3, 282 MHz): d ꢁ58.5 (CF3, s, Z), ꢁ64.4
(CF3, s, E) ppm. MS (70 eV, EI): 310 (M+, 100), 308 (95),
291 (M+ꢁF, 2.7), 279 (63), 277 (67), 250 (40), 248 (40),
198 (48), 189 (25), 187 (23), 170 (50), 169 (49), 151 (37),
101 (29), 75 (47), 69 (39). Anal. Calcd for C11H8BrF3O2:
C, 42.75; H, 2.61%. Found: C, 42.86; H, 2.65%.
CF3
CO2Me
Ph
Colorless liquid, Z/E¼1:3.6. IR (KBr), cmꢁ1: 2956, 2929,
1958, 1736, 1638, 1578, 1496, 1450, 1438, 1391, 1280, 1167,
1136, 1043. H NMR (CDCl3, 300 MHz): d 8.10 (1H, s),
1
7.42–7.37 (5H, m, Ar), 3.90 (3H, s, Z), 3.78 (3H, s, E) ppm.
19F NMR (CDCl3, 282 MHz): d ꢁ58.0 (CF3, s, Z), ꢁ63.8
(CF3, s, E) ppm. 13C NMR (CDCl3, 75.44 MHz): d 163.8,
140.4 (t, JCF¼5.8 Hz), 132.2, 130.4, 130.2, 129.3, 128.8,
128.3, 52.3 ppm. MS (70 eV, EI): 230 (M+, 54), 229
(M+ꢁ1, 52), 211 (M+ꢁF, 1.6), 199 (57), 151 (40), 109
(100), 77 (25), 69 (8.0). HRMS for C11H9O2F3 calcd:
230.0555. Found: 230.0556.
4.2.5. Methyl 3-(2-chlorophenyl)-2-(trifluoromethyl)-
acrylate (3d).
CF3
CO2Me
4.2.2. Methyl 3-(4-nitrophenyl)-2-(trifluoromethyl)acry-
late (3b).
Cl
CF3
CO2Me
Colorless liquid, Z/E¼1:5.3. IR (KBr), cmꢁ1: 2957, 1739,
1647, 1471, 1439, 1387, 1290, 1269, 1171, 1141, 1045. 1H
NMR (CDCl3, 300 MHz): d 8.18 (1H, s), 7.44–7.25 (4H,
m, Ar), 3.91 (3H, s, Z), 3.70 (3H, s, E) ppm. 19F NMR
(CDCl3, 282 MHz): d ꢁ58.5 (CF3, s, Z), ꢁ64.1 (CF3, s,
E) ppm. 13C NMR (CDCl3, 75.44 MHz): d 163.0, 145.5 (t,
JCF¼3.0 Hz), 133.3, 131.8, 131.0, 130.9, 129.3, 129.2,
126.5, 126.4, 53.0 ppm. MS (70 eV, EI): 264 (M+, 1.4),
245 (M+ꢁF, 1.0), 233 (12), 230 (13), 229 (100), 195 (14),
161 (17), 101 (12), 75 (20), 69 (6.6). HRMS for
C11H8O2F2Cl calcd: 245.0181. Found 245.0182 (M+ꢁF).
NO2
Colorless solid with mp: 54–56 ꢀC. IR (KBr), cmꢁ1: 2998,
2964, 1941, 1733, 1655, 1602, 1523, 1443, 1384, 1354, 1312,
1237, 1217, 1164, 1143, 1019. 1H NMR (CDCl3, 300 MHz):
d 8.26 (d, 2H, J¼9.0 Hz), 7.54 (d, 2H, J¼9.0 Hz), 3.79
(s, 3H) ppm. 19F NMR (CDCl3, 282 MHz): d ꢁ64.7
(s, E) ppm. MS (70 eV, EI): 275 (M+, 90), 274 (70), 258
(58), 244 (100), 243 (52), 228 (27), 206 (M+ꢁF, 13), 198
(67), 169 (55). Anal. Calcd for C11H8F3O4N: C, 48.01; H,
2.93; N, 5.09%. Found: C, 48.26; H, 3.06; N, 5.00%.
4.2.6. Methyl 3-(2-methyloxyphenyl)-2-(trifluoromethyl)-
acrylate (3e).
CF3
CO2Me
4.2.3. Methyl 2,5-bis(4-nitrophenyl)-4-(trifluoromethyl)-
1,3-dioxolane-4-carboxylate (5).
CO2Me
CF3
O
MeO
O
O
N
O
Colorless liquid, Z/E¼1:1.4. IR (KBr), cmꢁ1: 2957, 2843,
1732, 1634, 1514, 1463, 1439, 1393, 1264, 1175, 1129,
1032. H NMR (CDCl3, 300 MHz): d 8.00 (1H, s, Z), 7.40
1
N
O
O
(2H, m, Ar), 6.93–6.88 (2H, m, Ar), 3.87 (3H, s, Z), 3.84
(3H, s) 3.82 (3H, s, E) ppm. 19F NMR (CDCl3, 282 MHz):
d ꢁ58.0 (CF3, s, Z), ꢁ63.3 (CF3, s, E) ppm. 13C NMR
(CDCl3, 75.44 MHz): d 164.2, 148.3 (t, JCF¼2.8 Hz, Z),
Colorless solid with mp: 171–173 ꢀC. IR (KBr), cmꢁ1: 3089,
2958, 1752, 1608, 1521, 1351, 1302, 1200, 1117. 1H NMR

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W. Pang et al. / Tetrahedron 62 (2006) 11760–11765
140.1 (t, JCF¼5.6 Hz, E), 132.3, 131.6, 124.6, 124.5, 114.1,
113.9, 55.3, 52.3 ppm. MS (70 eV, EI): 260 (M+, 100), 241
(M+ꢁF, 3.9), 229 (55), 200 (52), 139 (83), 75 (8.5), 69
(7.9). HRMS for C12H11O3F3 calcd: 260.0660. Found:
260.0660.
128.0 (t, JCF¼3.0 Hz), 119.6, 119.5, 113.0, 112.9,
52.4 ppm. MS (70 eV, EI): 220 (M+, 34), 201 (M+ꢁF, 3.9),
189 (48), 160 (18), 113 (32), 99 (100), 83 (23), 69 (9.1),
68 (2.9), 63 (52), 59 (43). HRMS for C9H7O3F3 calcd:
220.0347. Found: 220.0351.
4.2.7. Methyl 3-(2,5-dimethyloxy-4-bromophenyl)-2-(tri-
fluoromethyl)acrylate (3f).
4.3. General method for the synthesis of a-trifluoro-
methyl substituted b-amino ester (4)
F
O
In a 25 ml flask containing alkene 2c (352 mg, 1 mmol) was
added 5 ml of THF and cooled in an ice-water bath, then a so-
lution of NaN3 (260 mg, 4 mmol) in H2O (1 ml) was added.
The temperature of the mixture is adjusted to 0 ꢀC, and a so-
lution of HOAc (240 mg, 4 mmol) was added dropwise with
vigorous stirring over 20–30 min. The yellow reaction mix-
ture was allowed to stir for 48 h at room temperature. After
the reaction was completed (monitored by TLC), the reac-
tion mixture was diluted with CH2Cl2, which was washed
with saturated NaHCO3 and water, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure
using a rotary evaporator. The yield was almost quantitative.
The product was essentially pure after general work-up and
could be used directly in the next step. A mixture of the
crude azide and 10% palladium-on-carbon (20 mg) in abso-
lute ethanol (6 ml) was stirred at 25 ꢀC under 1 atm of hydro-
gen for 24 h. The catalyst was filtered and washed with
CH2Cl2. The filtrates were concentrated under reduced pres-
sure using a rotary evaporator, and the crude reaction prod-
uct was purified by column chromatography on silica gel
using ethyl acetate–hexane as eluent to give 4 (243 mg,
74%).
F
F
O
OCH3
Br
H3CO
Colorless solid with mp: 127–129 ꢀC, Z/E¼3.2:1. IR (KBr),
cmꢁ1: 2969, 2857, 1732, 1632, 1603, 1488, 1465, 1441,
1432, 1394, 1296, 1258, 1214, 1179, 1127, 1054, 1040,
1
1025. H NMR (CDCl3, 300 MHz): d 8.12 (1H, s), 7.12
(1H, s, Ar), 6086 (1H, s, Ar), 3.90 (3H, s, Z), 3.85 (3H, s),
3.83 (3H, s, E) ppm. 19F NMR (CDCl3, 282 MHz):
d ꢁ58.6 (CF3, s, Z), ꢁ63.7 (CF3, s, E) ppm. MS (70 eV,
EI): 370 (M++1, 56), 369 (M+, 9.3), 368 (55), 339 (54),
337 (61), 246 (23), 231 (44), 69 (14), 59 (100). Anal. Calcd
for C13H12BrF3O4: C, 42.30; H, 3.28%. Found: C, 42.41; H,
3.36%.
4.2.8. Methyl 3-phenylvinyl-2-(trifluoromethyl)acrylate
(3g).
CF3
CO2Me
4.3.1. Methyl 2-(amino(4-bromophenyl)methyl)-3,3,3-
trifluoropropanoate (4).
Colorless liquid, Z/E¼1:1.8. IR (KBr), cmꢁ1: 3027, 2956,
1724, 1624, 1595, 1438, 1384, 1293, 1245, 1129. 1H NMR
(CDCl3, 300 MHz): d 7.96 (1H, dd, J¼15, 11 Hz), 7.57–
7.54 (2H, m, Ar), 7.40–7.37 (3H, m, Ar), 7.31 (1H, d,
J¼11 Hz), 7.08 (1H, d, J¼15 Hz), 3.86 (3H, s, Z), 3.89
(3H, s, E) ppm. 19F NMR (CDCl3, 282 MHz): d ꢁ57.9
(CF3, s, Z), ꢁ63.0 (CF3, s, E) ppm. 13C NMR (CDCl3,
75.44 MHz): d 163.1, 146.0 (t, JCF¼5.3 Hz), 147.2, 135.5,
130.4, 129.0, 128.1, 124.6, 123.0, 121.0, 52.1 ppm. MS
(70 eV, EI): 256 (M+, 38), 237 (M+ꢁF, 2.9), 177 (100),
128 (52), 102 (32), 77 (47), 69 (23), 51 (49). HRMS for
C13H11O2F3 calcd: 256.0711. Found: 256.0711.
H
CF3
H2N
CO2Me
H
Br
Colorless solid with mp: 72–74 ꢀC. IR (KBr), cmꢁ1: 2957,
2930, 1908, 1751, 1641, 1489, 1438, 1409, 1354, 1163,
1119, 1074, 1012. H NMR (300 MHz, CDCl3): d 7.48–
7.43 (2H, m), 7.23–7.19 (2H, m), 4.51–4.47 (1H, m),
3.76 (3H, s), 3.44 (1H, s), 1.73 (2H, s) ppm. 19F NMR
(CDCl3, 282 MHz): d ꢁ65.1 (d, J¼7.9 Hz), ꢁ64.32 (d,
J¼8.4 Hz) ppm. EIMS (m/z, %): 327/325 (M+2/M+, 3/3),
186 (98), 184 (100), 159 (9), 157 (9), 77 (27), 59 (16).
Anal. Calcd for C11H11F3BrO2N: C, 40.51; H, 3.40; N,
4.30%. Found: C, 40.69; H, 3.52; N, 4.19%.
1
4.2.9. Methyl 3-furan-2-(trifluoromethyl)acrylate (3h).
CF3
CO2Me
O
4.3.1.1. X-ray data of 4. C11H11BrF3NO2: MW¼326.12,
CCDC no. 614315, monoclinic, space group: C2/c, a¼
Colorless liquid, Z/E¼1:4.5. IR (KBr), cmꢁ1: 2959, 2928,
21.606(3) A, b¼5.4235(7) A, c¼24.378(3) A; a¼90.00 ,
ꢀ
˚
˚
˚
3
˚
2856, 1731, 1633, 1468, 1438, 1377, 1285, 1224, 1134,
1044, 1025. H NMR (CDCl3, 300 MHz): d 7.81 (1H, s,
b¼2599.4(6)ꢀ,
g¼90.00ꢀ;
V¼2599.4(6) A ,
Z¼8,
Dc¼1.667 g/cm3, F(000)¼1296. Radiation, Mo Ka (l¼
1
˚
Z), 7.58 (1H, s, E), 7.67 (1H, d, J¼1 Hz, Z), 7.30 (1H, d,
J¼3 Hz, E), 7.08 (1H, d, J¼3 Hz, Z), 7.24 (1H, d, J¼1 Hz,
E), 6.59 (1H, dd, J¼1, 3 Hz, Z), 6.56 (1H, dd, J¼1, 3 Hz,
E), 3.92 (3H, s, Z), 3.88 (3H, s, E) ppm. 19F NMR (CDCl3,
282 MHz): d ꢁ59.5 (CF3, s, Z), ꢁ63.0 (CF3, s, E) ppm.
13C NMR (CDCl3, 75.44 MHz): d 163.3, 152.2, 146.3,
0.71073 A). Crystal dimension, 0.467ꢂ0.89ꢂ0.329 mm.
Intensity data were collected at 293(2) K with a Bruker P4
four-circle diffractometer with graphite monochromator
˚
and Mo Ka radiation (l¼0.71073 A). A total of 2815 inde-
pendent reflection was measured in the range 1.84<q<27.00ꢀ.

W. Pang et al. / Tetrahedron 62 (2006) 11760–11765
11765
5. (a) Osipov, S. N.; Sewald, N.; Kolomiets, A. F.; Fokin, A. V.;
Burger, K. Tetrahedron Lett. 1996, 37, 615–618; (b) Iseki, K.
Tetrahedron 1998, 54, 13887–13914; (c) Yoder, N. C.;
Kumar, K. Chem. Soc. Rev. 2002, 31, 335–341; (d) Katagiri,
T.; Uneyama, K. Chirality 2003, 15, 4–9; (e) Dave, R.;
Badet, B.; Meffre, P. Amino Acids 2003, 24, 245–261.
6. Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17, 621–
631.
The structure was solved by directed methods and expanded
using Fourier techniques. The nonhydrogen atoms were
refined anisotropically; hydrogen atoms were included but
not refined. The final cycle of full matrix least-square refine-
ment was based on F2. The final R and wR value were 0.0457
and 0.0889, respectively. All calculations were performed
using the SHELX-97 program.
7. (a) Qiu, X. L.; Meng, W. D.; Qing, F. L. Tetrahedron 2004, 60,
6711–6745; (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58,
7991–8035; (c) Schirlin, D.; Baltzer, S.; Altenburger, J. M.;
Tarnus, C.; Remy, J. M. Tetrahedron 1996, 52, 305–318; (d)
Nakayama, K.; Kawato, H. C.; Inagaki, H.; Nakajima, R.;
Kitamura, A.; Someya, K.; Ohta, T. Org. Lett. 2000, 2, 977–980.
8. (a) Hart, D. J.; Ha, D. C. Chem. Rev. 1989, 89, 1447–1465; (b)
van der Steen, F. H.; van Koten, G. Tetrahedron 1991, 47,
7503–7524; (c) Soloshonok, V. A.; Soloshonok, I. V.;
Kukhar, V. P.; Svedas, V. D. J. Org. Chem. 1998, 63, 1878–
1884; (d) Uneyama, K.; Hao, J.; Amii, H. Tetrahedron Lett.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (NNSFC) (Nos. 20472106 and 20532040) for
financial support.
References and notes
1. (a) Goldman, P. Science 1969, 164, 1123–1130; (b) Welch, J. T.
Tetrahedron 1987, 43, 3123–3197.
ꢀ
ꢀ
1998, 39, 4079–4082; (e) Abouabdellah, A.; Begue, J.-P.;
Binnet-Delpon, D.; Thanh Nga, T. T. J. Org. Chem. 1997, 62,
8826–8833.
2. (a) Asymmetric Fluoroorganic Chemistry; Ramachandran,
P. V., Ed.; ACS symposium Series 746; American Chemical
Society: Washington, DC, 1999; (b) Kitazume, T.; Yamazaki,
T. Experimental Methods in Organic Fluorine Chemistry;
Gordon and Breach Science: Amsterdam, 1998; (c)
Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series
639; American Chemical Society: Washington, DC, 1996;
(d) Synthesis and Chemistry of Agrochemical III; Baker,
D. R., Fenyes, J. G., Steffens, J. J., Eds.; ACS Symposium
Series 504; American Chemical Society: Washington, DC,
1992; (e) Welch, J. T. Selective Fluorination in Organic and
Bioorganic Chemistry; ACS Symposium Series; American
Chemical Society: Washington, DC, 1991.
3. (a) Jiang, B.; Zhang, X. B.; Luo, Z. H. Org. Lett. 2002, 4, 2453–
2455; (b) Shi, G. Q.; Xu, Y. Y. J. Chem. Soc., Chem. Commun.
1987, 607–608; (c) Shi, G. Q.; Xu, Y. Y. Tetrahedron 1991, 47,
1629–1648; (d) Shi, G. Q.; Xu, Y. Y.; Xu, M. J. Fluorine Chem.
1991, 52, 149–157; (e) Shi, G. Q.; Xu, Y. Y. J. Org. Chem. 1990,
55, 3383–3386; (f) Shi, G. Q.; Cao, Z. Y.; Cai, W. L.
Tetrahedron 1995, 51, 5011–5018; (g) Mloston, G. Helv.
Chim. Acta 1996, 79, 1537–1545; (h) Hoffmann, M. G.;
Wenkert, E. Tetrahedron 1993, 49, 1057–1067; (i) Guillaume,
M.; Janousek, Z.; Viehe, H. G.; Wynants, C.; Declercq, J.-P.;
Tinant, B. J. Fluorine Chem. 1994, 69, 253–256; (j)
Guillaume, M.; Janousek, Z.; Viehe, H. G. Synthesis 1995,
921–923.
9. (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002,
4, 1319–1322; (b) Wabnitz, T. C.; Spencer, J. B. Org. Lett.
2003, 5, 2141–2144; (c) Wabnitz, T. C.; Spencer, J. B.
Tetrahedron Lett. 2002, 43, 3891–3894; (d) Srivastava, N.;
Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114; (e)
Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.; Hulme, C.
J. Am. Chem. Soc. 1996, 118, 3406–3418; (f) Lakshmipathi,
P.; Rao, A. V. R. Tetrahedron Lett. 1997, 38, 2551–2552;
(g) Cuerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett.
1999, 1, 1107–1109; (h) Myers, J. K.; Jacobsen, E. N. J. Am.
Chem. Soc. 1999, 121, 8959–8960; (i) Horstmann, T. E.;
Cuerin, D. J.; Miller, S. J. Angew. Chem., Int. Ed. 2000, 39,
3635–3638.
10. (a) Zhu, S. F.; Liao, Y. X.; Zhu, S. Z. Org. Lett. 2004, 6, 377–
380; (b) Zhu, S. F.; Liao, Y. X.; Zhu, S. Z. Synlett 2005, 1429–
1432; (c) Zhu, S. F.; Xing, C. H.; Zhu, S. Z. Tetrahedron 2006,
62, 829–832; (d) Zhu, S. Z.; Zhu, S. F.; Liao, Y. X. J. Fluorine
Chem. 2004, 125, 1071–1076; (e) Zhu, S. F.; Xing, C. H.; Pang,
W.; Zhu, S. Z. Tetrahedron Lett. 2006, 47, 5897–5900.
11. (a) Xu, L. W.; Xia, C. G.; Li, J. W.; Zhou, S. L. Synlett 2003,
2246–2248; (b) Xu, L. W.; Xia, C. G.; Zhou, S. L.; Li, J. W.
Tetrahedron Lett. 2004, 45, 1219–1221.
12. (a) Zou, Y.; Fahmi, N. E.; Vialas, C.; Miller, G. M.; Hecht,
S. M. J. Am. Chem. Soc. 2002, 124, 9476–9488; (b) Belleau,
B.; Cooper, P. J. Med. Chem. 1963, 6, 579–583; (c)
Walborsky, H. M.; Baum, M. E. J. Org. Chem. 1956, 21,
538–539.
4. Horton, H. R.; Moran, L. A.; Ochs, R. S.; Rawn, J. D.;
Scrimgeous, K. G. Principle of Biochemistry, 3rd ed.;
2003; p 59.