Facile stereoselective syntheses of aryl substituted α,β-unsaturated esters containing a trifluoromethyl group

Article abstract of DOI:10.1002/hc.10032

Facile stereoselective synthesis of aryl substituted α,β-unsaturated esters containing a trifluoromethyl group was presented. The Suzuki-type cross-coupling reaction of arylboronic acids with ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate, which was generat

Full text of DOI:10.1002/hc.10032

Heteroatom Chemistry
Volume 13, Number 3, 2002
F
acile Stereoselective Syntheses of Aryl
Substituted �,�-Unsaturated Esters
Containing a Trifluoromethyl Group
1
1
2
Rui-Qi Pan, Ping-An Wang, and Min-Zhi Deng
1
Department of Chemistry, Northwest University, 710069 Xi’an, P. R. China
2
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Academy of Sciences, 200032 Shanghai, P. R. China
Received 14 November 2001; revised 29 September 2001
convenient strategy for the preparation and applica-
ABSTRACT: The Suzuki-type cross-coupling reac-
tion of arylboronic acids 3 with ethyl (Z)-3-iodo-
tion of trifluoromethylated building blocks [5], Qing
et al. reported a new method for the synthesis of
ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate 2 and its
alkynylation by the Sonogashira reaction [6]; Gildas
et al. [7] described a stereoselective access to func-
tional dienes containing the trifluoromethyl group
via the Stille coupling of the compound 2. Recently,
two papers contained a report of the stereoselective
syntheses of trifluoromethyl substituted retinoates
and their analogues [8,9] by use of the compound
4
,4,4-trifluoro-2-butenoate 2, which was generated by
hydroiodination of available ethyl 4,4,4-trifluoro-2-
butynoate 1, to afford ethyl (E)-3-aryl-4,4,4-trifluoro-
2
-butenoates 4, was studied for the first time. It was
found that under the optimum conditions the cross-
coupling reaction could readily give 4 as the sole
E-isomer in 76–91% yields. �C 2002 Wiley Periodicals,
Inc. Heteroatom Chem 13:287–290, 2002; Published on-
line in Wiley Interscience (www.interscience.wiley.com).
DOI 10.1002/hc.10032
2
as a key intermediate. However, the arylation of
compound 2 has not been reported. We also de-
scribed a novel and convenient method for produc-
ing ␣-(trifluoromethyl)styrenes by the arylation of
INTRODUCTION
2
-bromo-3,3,3-trifluoro-propene via the Suzuki-type
coupling [10]. As a continuous development of our
previous research on the methodology for prepar-
ing various derivatives bearing the trifluoromethyl
group, herein we wish to report a facile stereose-
lective synthesis of aryl substituted ␣,␤-unsaturated
esters containing the trifluoromethyl group by the
arylation of 2 via the Suzuki cross-coupling reaction.
Trifluoromethylated compounds, especially trifluo-
romethyl substituted ␣,␤-unsaturated esters, have at-
tracted the attention of synthetic chemists, because
of their unique physiologic and bioactivities [1] and
potential in synthetic organic chemistry [2]. Among
the approaches to trifluoromethylated organic com-
pounds, halogen exchange reaction [3] and trifluo-
romethylation [4] are possible methods, but these
suffer from low reactivity and selectivity. As a
RESULTS AND DISCUSSION
Synthesis of Ethyl
Correspondence to: Min-Zhi Deng; e-mail: dengmz@pub.sioc.
ac.cn.
(
Z)-3-iodo-4,4,4-trifluoro-2-butenoate 2
Contract grant sponsor: National Natural Science Foundation
of China.
�
c 2002 Wiley Periodicals, Inc.
According to either the Qing or Gildas procedures
[6,7], respectively, ethyl (Z)-3-iodo-4,4,4-trifluoro-
287

288 Pan, Wang, and Deng
SCHEME 1
SCHEME 3
The configurations of the cross-coupling reac-
2
-butenoate was prepared (Schemes 1 and 2). It
19
was found that both the methods provided the sole
tion products were characterized by F NMR and
19
1
stereoisomer, which was proved by the data of
NMR, HPLC, and GC to be the compound 2. The
single peak of the CF group in 2 (�
= � 10.2 for
CF CO H utilized as an external standard, upfield be-
ing positive) at � = � 10.0 demonstrated that the CF
and CO groups were trans oriented [11]. How-
F
H NMR spectrascopy. � Values of the products 4 at
F
� = � 10.0 revealed that the CF group and CO C H
3
2
2
5
3
F
group were trans oriented [11,12]. The chemical
3
2
shifts (beyond � = 6.50) of the olefinic H of all of
F
3
the products also proved that the CF group and the
3
2
C
2
H
5
proton of the vinyl group were present on the same
ever, Qing’s procedure required a relatively long re-
action time (72 h) and the yield was somewhat lower
than that obtained by the Gildas procedure.
side of the double bond in 4 [13]. Therefore, the con-
figuration of the compound 2 was retained in the
cross-coupling reaction, the same as that of other
Suzuki-type couplings [14,15].
In summary, we have provided a stereoselective
synthetic method for producing aryl substituted ␣,␤-
unsaturated esters 4 containing a trifluoromethyl
group from the arylboronic acids and 2 by the Suzuki
cross-coupling reaction. This method has many at-
tractive features: the easily availability of starting
materials, mild conditions, high yields, and effective
stereoselectivity.
Preparation of Ethyl
(
E)-3-aryl-4,4,4-trifluoro-2-butenoates 4
The arylboronic acids 3 are easily available and han-
dled, because of their stability to moisture and air.
The Suzuki-type coupling of the arylboronic acids
3
with compound 2 to obtain aryl substituted ␣,␤-
unsaturated esters 4 with a trifluoromethyl group
was investigated. Initially, o-methoxyphenylboronic
acid 3b was used as a starting material to optimize
the coupling conditions. It was found, that under
our previous conditions, the coupling reaction of 3b
with 2 could take place to produce the cross-coupling
product 4b in 55% yield (Scheme 3). Considering
EXPERIMENTAL
1
H NMR spectra were recorded on a Varian EM-360A
spectrometer using CCl
4
as the solvent with TMS as
an internal standard. F NMR spectra were obtained
on a Varian EM-360L spectrometer with CF CO
19
that Pd(PPh
because of its instability to air, Pd(PPh
used instead of Pd(PPh . From many experiments,
it was found that using Pd(PPh Cl as a catalyst and
PO O as a base in toluene, the cross-coupling
3
)
4
is difficult to prepare and preserve
3
2
H
3
)
2
2
Cl was
as an external standard and an upfield shift was des-
ignated as positive. Infrared spectra were taken on
a Shimadzu IR-440 spectrometer using films. Mass
spectra were taken on a HP5989A Mass spectrome-
ter using EI (70 eV). Elemental analyses were deter-
mined on a Foss-Heraeus Vario EL instrument. The
compound 2 was prepared according to the Qing and
Gildas methods, respectively [6,7].
)
3 4
3
)
2
2
K
3
4
�3H
2
of o-methoxyphenylboronic acid 3b with 2 readily
takes place at 100 C to produce, in 84% yield, the
�
product 4b (Scheme 4). Under these optimum con-
ditions, the cross-coupling of the various arylboronic
acids 3 with 2 were accomplished and the results are
shown in Table 1. The data of Table 1 demonstrates
that all the reaction of arylboronic acids 3 with 2
afforded the corresponding coupling products 4 in
high yields. Thus, the reaction procedure is a gener-
ally facile method for producing aryl substituted ␣,␤-
unsaturated esters bearing a trifluoromethyl group.
Typical Experimental Procedure
for Preparation of 4
To a solution of ethyl (Z)-3-iodo-4,4,4-trifluoro-
2-butenoate 2 (0.5 mmol) in toluene (3 ml), the
arylboronic acid 3 (0.6 mmol), Pd(PPh
3
)
2
2
Cl (11 mg,
SCHEME 2
SCHEME 4

Facile Stereoselective Syntheses of Aryl Substituted ␣,␤-Unsaturated Esters Containing a Trifluoromethyl Group 289
TABLE 1 The Synthesis of Ethyl (E )-3-Aryl-4,4,4-trifluoro-2-butenoates 4
a
Entry
Arylboronic Acids
Products
�F (ppm)
� 10.4
�H (ppm) (ole nic H)
Yields (%)
1
3a
3b
4a
4b
6.52
83
2
� 10.6
6.54
84
3
4
3c
3d
4c
4d
� 10.6
� 10.0
6.52
6.56
89
91
5
6
3e
3f
4e
4f
� 10.6
� 10.6
6.50
6.52
89
89
7
3g
3h
4g
4h
� 10.2
6.70
6.76
85
76
b
(
� 15.4 )
8
� 10.6
a
Isolated yields, based on the compound 2.
The shift of CF on the aryl circle.
3
b
1
9
0
.015 mmol), and K
3
PO
4
�3H
2
O (400 mg, 1.5 mmol)
4.06 (q, 2H), 6.52 (s, 1H), 7.10–7.60 (m, 5H);
F
+
were added under a nitrogen atmosphere. The
reaction mixture was stirred at 100 C for 6 h. The
NMR: � � 10.4 (s, CF ); MS (m/z): 244 (M , 75.5),
F
3
�
215 (78.1), 199 (100.0), 171 (25.3), 151 (57.1), 102
�
1
mixture was allowed to cool to room temperature,
water (10 ml) was added, and the mixture was ex-
tracted with ether (3 � 5 ml). The combined organic
layer was washed with brine (3 � 5 ml) and dried
(15.9); IR (cm ) 1730, 1280–1120, 700; Anal Calcd
for C H F O : C, 59.02; H, 4.54; Found: C, 59.21;
12
11
3
2
H, 4.63.
over MgSO . After removal of the solvent on a rotary
4
Ethyl (E)-3-(2-methoxyphenyl)-4,4,4-trifluoro-2-
evaporator, the residue was purified by flash silica
gel chromatography (petroluem ether : ethyl acetate
1
butenoate 4b. A light yellow oil; yield, 84%;
NMR: � 1.06 (t, 3H), 3.74 (s, 3H), 4.0 (q, 2H), 6.54 (s,
H), 6.70–7.50 (m, 4H); F NMR: �
H
H
=
15 : 1, v/v as the eluant) to yield 4a–h as light
19
1
F
� 10.6 (s, CF
3
);
yellow oils.
+
MS (m/z): 274 (M , 39.3), 229 (35.8), 215 (100.0), 151
�
1
(
10.3), 131 (25.6); IR (cm ) 1730, 1280–1120, 750;
Ethyl (E)-3-phenyl-4,4,4-trifluoro-2-butenoate 4a.
Anal Calcd for C13
C, 56.89; H, 4.61.
H
13
F
3
3
O : C, 56.94; H, 4.78; Found:
1
A light yellow oil; yield, 83%; H NMR: � 1.06 (t, 3H),
H

290 Pan, Wang, and Deng
Ethyl (E)-3-(4-methoxyphenyl)-4,4,4-trifluoro-2-
Ethyl (E)-3-(1-naphthyl)-4,4,4-trifluoro-2-buten-
oate 4h. A light yellow oil; yield, 76%; H NMR:
1
1
butenoate 4c. A light yellow oil; yield, 89%;
NMR: �
.52 (s, 1H), 6.70–7.25 (m, 4H); F NMR: �
H
H
1.10 (t, 3H), 3.75 (s, 3H), 4.04 (q, 2H),
H
� 0.65 (t, 3H), 3.70 (q, 2H), 6.76 (s, 1H), 7.10–7.90
19
19
6
(
(
F
� 10.6
(m, 7H); F NMR: �
F
� 10.6 (s, CF
3
); MS (m/z): 295
+
+
+
s, CF
3
); MS (m/z): 274 (M , 100.0), 245 (10.5), 229
(M + 1, 8.2), 294 (M , 37.0), 249 (15.0), 221 (28.5),
�
1
� 1
56.6), 201 (21.6), 181 (12.7), 133 (10.4); IR (cm )
201 (100.0), 152 (35.8); IR (cm ) 1725, 1280–1125,
1
5
730, 1280–1120, 830; Anal Calcd for C13
6.94; H, 4.78; Found: C, 57.15; H, 4.72.
H
13
F
3
O
3
: C,
795, 775; Anal Calcd for C16
Found: C, 65.75; H, 4.53.
H
13
F
3
2
O : C, 65.30; H, 4.45;
Ethyl (E)-3-(2-methylphenyl)-4,4,4-trifluoro-2-
1
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�
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1
1
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1
1
�
7
2
(
1
8
H
1
9
.15 (s, 4H); F NMR: �
F
� 10.6 (s, CF
3
); MS (m/z):
+
6
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[
H
13
F
3
O
2
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1
1
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.20–7.86 (m, 4H); F NMR: �
CF
), � 15.4 ( s, aryl CF
H
1.10 (t, 3H), 4.06 (q, 2H), 6.70 (s, 1H),
19
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F
� 10.2 (s, olefinic
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9
3.3), 283 (100.0), 263 (37.2), 235 (8.1), 169 (11.5),
4
�
1
1 (5.1); IR (cm ) 1730, 1310–1125, 800, 750; Anal
: C, 50.01; H, 3.23; Found: C,
[
Calcd for C13
H
10
F
6
O
2
2
5
0.34; H, 3.29