Unexpected regioselective Heck arylation of ethyl (E)-4,4,4-trifluorocrotonate

Article abstract of DOI:10.1016/S0022-1139(00)00305-5

Palladium-catalyzed Heck reactions of ethyl (E)-4,4,4-trifluorocrotonate 1 with aryl bromides 2a-f gave an unexpected α-arylated compound 4, ethyl (Z)-2-aryl-4,4,4-trifluorocrotonate, mainly rather than normal β-arylated compound 3, ethyl (Z)-3-aryl-4,4,4-trifluorocrotonate.

Full text of DOI:10.1016/S0022-1139(00)00305-5

Journal of Fluorine Chemistry 105 (2000) 169±173
Unexpected regioselective Heck arylation of ethyl
(E)-4,4,4-tri¯uorocrotonate
Yuefa Gong*, Katsuya Kato, Hiroshi Kimoto
National Industrial Research Institute of Nagoya, Hirate-cho, Kita-ku, Nagoya 462-8510, Japan
Received 23 February 2000; received in revised form 15 April 2000; accepted 23 May 2000
Abstract
Palladium-catalyzed Heck reactions of ethyl (E)-4,4,4-tri¯uorocrotonate 1 with aryl bromides 2a±f gave an unexpected a-arylated
compound 4, ethyl (Z)-2-aryl-4,4,4-tri¯uorocrotonate, mainly rather than normal b-arylated compound 3, ethyl (Z)-3-aryl-4,4,4-
tri¯uorocrotonate. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Heck reaction; Regioselective; Arylation; 4,4,4-tri¯uorocrotonate
1. Introduction
2. Results and discussion
The palladium-catalyzed arylation (Heck reaction) is
widely used to synthesize a variety of organic compounds
[1,9±12]. This reaction produces regioselective arylation at
the terminal b-position of electron-de®cient ole®ns, such as
a,b-unsaturated carbonyl compounds and at the a- or b-
position of electron-rich ole®ns, such as enol ethers, depend-
ing on the chelate control [2,13±16]. b-Arylation of ethyl
acrylate with bromobenzene affords ethyl trans-3-phenyl-
propenoate, which on further arylation forms ethyl 3,3-
diphenyl propenoate in the presence of an excess amount
of bromobenzene [3,17].
Recently, we have studied the effect of ¯uorine atoms on
the bioactivity of indole-3-acetic acid (IAA), a famous plant
hormone. A number of ¯uorinated derivatives of IAA have
been prepared, of which 4,4,4-tri¯uoro-3-(indol-3-yl)buta-
noic acid is superior to IAA in the promotion of plant root
growth [4,18]. This ®nding stimulated us to extend our
research to a variety of plant growth regulators. As a part
of our study, we undertook preparation of a tri¯uoromethy-
lated analogue of cinnamic acid, a well-known bioactive
compound [5], by the Heck reaction of ethyl (E)-4,4,4-
tri¯uorocrotonate 1 with bromoarenes. The unexpected a-
arylated product 4 was obtained mainly instead of the b-
arylated product 3. We here report the palladium-catalyzed
reaction of 1 with a number of aryl bromides 2a±f.
The reaction of ethyl (E)-4,4,4-tri¯uorocrotonate 1 and
bromobenzene 2a with a catalytic amount of palladium
acetate as the pre-catalyst and triphenylphosphine as the
ligand produced b-arylated product 3a and a-arylated pro-
duct 4a (Scheme 1). The reaction was conducted in DMF at
1008C with N,N-diisopropylethylamine as the base. Some
amounts of diarylation products 5 and 6, characterized by
their GC±MS and 1H NMR spectra, also were produced, but
the attempt to separate them was failed by silica gel column
chromatography. For this reason, here the regioselective and
stereospeci®c formation of monoarylated products are
mainly discussed.
Palladium-catalyzed arylation of 1 with various aryl
bromides 2b±e was also performed under the above condi-
tions. Only a trace amount of the arylation product was
detected by GC±MS for 1-bromonaphthalene 2c, and none
for 2-bromothiophene 2e. In contrast, arylation products 3b,
3d and 4b, 4d were produced in moderate yields. Details of
the reactions are given in Table 1 (runs 1±5). Furthermore,
higher yields of 3 and 4 were obtained when a less sterically
hindered bidentate ligand, 1,3-bis(diphenylphosphino)pro-
pane (DPPP), was used as the supporting ligand (Table 1,
runs 6±11). On the other hand, the yields of 3a and 4a
decreased when the molar ratio 2:1 changed from 2:1 to 1:1
(runs 7 and 6). The decreases in the yields of the mono-
arylated products also occurred when a large excess of aryl
bromide was used owing to severe diarylation (run 8). In all
cases, the formation of a-arylated compounds 4 was favored
clearly much more than that of b-arylated compounds 3.
* Corresponding author. Tel.: ‡81-52-911-3296; fax: ‡81-52-911-2428.
E-mail address: gong@nirin.go.jp (Y. Gong).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 0 5 - 5

170
Y. Gong et al. / Journal of Fluorine Chemistry 105 (2000) 169±173
Scheme 1
Table 1
Palladium-catalyzed arylation of ethyl 4,4,4-trifluorocrotonatea
Run
ArBrb
2:1
Ligand
Conditions
3/4c
4 (yields %)d
1
2
2a
2b
2c
2d
2e
2a
2a
2a
2b
2d
2f
2:1
2:1
2:1
2:1
2:1
1:1
2:1
5:1
2:1
2:1
2:1
Ph3P
1008C, 24 h
1208C, 36 h
1208C, 24 h
1208C, 24 h
1208C, 24 h
1208C, 24 h
1208C, 24 h
1208C, 24 h
1208C, 30 h
1208C, 30 h
1208C, 24 h
29/71
43/57
±
20
Ph3P
26
3
Ph3P
Trace
30
4
Ph3P
Ph3P
41/59
±
5
None
26
6
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
32/68
30/70
33/67
34/66
33/67
43/57
7
47
23
8
9
48
10
11
43
22
a A mixture of 1 (1.0 mmol), 2 (2.0 mmol), i-Pr2NEt (2.0 mmol), Pd(OAc)2 (0.05 mmol), and ligand (0.12 mmol) was heated in DMF (4.5 ml) under
argon.
b 2a: bromobenzene; 2b: 4-bromoanisole; 2c: 1-bromonaphthalene; 2d: 2-bromonaphthalene; 2e: 2-bromothiophene; 2f: 4-bromochlorobenzene.
c Calculated by 1H NMR integration.
d Isolated yields.
Products 3 and 4 were easily distinguished by the different
splitting pattern of their ole®nic protons. The peak of a-
proton of 1 is split into doublet by one b-proton, and that of
b-proton into doublet-quartet by one a-proton and three
¯uorine atoms1. b-Arylation led to the removal of b-proton,
thus, the a-proton of 3 shows singlet. Similarly, the b-proton
of a-arylated product 4 shows a simple quartet (Jˆ7.9 Hz).
In order to con®rm the structure of a-arylated compound
4, compound 4a has been prepared according to the follow-
ing way (Scheme 2). Firstly, ethyl 2-phenyl-4,4,4-tri¯uor-
oacetoacetate 7a, prepared by the condensation of ethyl
phenylacetate and ethyl tri¯uoroacetate, was reduced into
the corresponding alcohol 8a. The latter was then dehy-
drated to form (Z)-4a and (E)-4a in the ratio of about 1:9 as
determined by 19F NMR. The b-protons of both (Z)-4a and
(E)-4a are split into quartets with the same splitting constant
(JHFˆ7.9 Hz), but their chemical shifts (d) are greatly
different. The b-proton of (E)-4a has a higher d value
(6.87) compared with that of (Z)-4a (6.02) because of the
strong deshielding effect of the ethoxycarbonyl group. Based
on this spectroscopic analysis, we can believe (Z)-4a was
formed stereospeci®cally in the palladium-catalyzed reac-
tion via a syn-b-hydride elimination (Scheme 3). This result
is in agreement with experimental observations by Heck [6].
On the other hand, the geometric isomers of b-arylated
product 3a have been prepared via the Reformatsky reaction
and the subsequent dehydration. Ethyl 3-hydroxy-3-phenyl-
4,4,4-tri¯uorobutyrate (9a), obtained from the reaction of
2,2,2-tri¯uoroacetophenone, ethyl bromoacetate and zinc
powder in toluene, was dehydrated to form (E)-3a and
(Z)-3a in the ratio of about 5:1 (Scheme 4). They are easily
distinguished by comparing the chemical shift of the ¯uorine
atoms. The higher d value (101.72) belongs to (Z)-3a, and
the lower d value (94.36) to (E)-3a owing to the obvious
deshielding effect of the ethoxycarbonyl group. In addition,
the a-ole®nic protons of (E)-3a and (Z)-3a show singlet, but
(E)-3a has a higher d value (6.59) than (Z)-3a (6.33).
Apparently, it is (Z)-3a that was formed in the palladium-
catalyzed reaction (Scheme 3).
The regioselectivity of palladium-catalyzed arylation of
the ole®ns was related only to the coordination-insertion
pathway. Migration of the aryl group in the complex was
markedly affected by the steric and electronic factors of the
substituents. Usually migration favored the less substituted
carbon with lower electron density, therefore only b-aryla-
tion occurred in the palladium-catalyzed arylation of ethyl
acrylate, including ethyl cinnamate [3].
1
1 1: H NMR (CDCl3) d: 6.85 (b-H, dq, Jˆ16.0, 5.9 Hz), 6.47 (a-H,
d, Jˆ16.0 Hz), 4.28 (OCH2, q, Jˆ7.0 Hz), 1.33 (CH3, t, Jˆ7.0 Hz). 19
NMR (CDCl3) d: 96.27 (CF3, d, Jˆ5.9 Hz).
F
However, a-arylation (path b, Scheme 3) was greatly
favored in the case of 1, though only the b-addition took

Y. Gong et al. / Journal of Fluorine Chemistry 105 (2000) 169±173
171
Scheme 2
Scheme 3
place in its reactions with various nucleophiles [7,19]. In
fact, we realized that the tri¯uoromethyl group is much
bulkier and stronger electron-inductive than the ethoxycar-
bonyl group from their Hammett substituent constant sp
(0.53 for CF3, 0.44 for COOEt), but its resonance contribu-
tion sR (0.08) is smaller (0.16 for CO2Et) [8]. Therefore, we
can consider that the steric hindrance and/or the inductive
contribution of the substituent, play an important rule on
regioselective migration of the aryl group in the palladium-
catalyzed reactions, although the conjugative contribution
usually acts as the main factor in other nucleophilic addi-
tions.
promoting plant growth. In fact, the biological test was done
using Chinese cabbage seeds by comparing their ability to
enhance the root growth [18]. The parallel tests demonstrate
that all of the four compounds are biologically active. Of the
four compounds, (Z)-3d shows the best activity in root
growth promotion, which is about 1.4 times higher com-
pared to blank test. The activity of (Z)-4d is a little lower
than that of (Z)-3d, but much higher than that of (Z)-3a and
(Z)-4a. In addition, no detectable effect was observed on
hypocotyls for the four compounds. The bioactivities are
under further investigations using other plants and in the
®eld.
The biological activity of the above compounds (Z)-3a,
(Z)-4a, (Z)-3d and (Z)-4d has been simply investigated in
3. Experimental details
3.1. General
1H NMR spectra were recorded with tetramethylsilane
(TMS) as an internal standard at 90 MHz on a Hitachi R-
90H FT spectrometer. 19F NMR spectra were recorded with
hexa¯uorobenzene as an internal standard at 84.7 MHz on
the same spectrometer. Mass spectra (70 eV) were measured
on a Hitachi M-80 instrument. High-resolution mass spectra
were measured on a JEOL JMS-SX102A MS spectrometer.
Scheme 4

172
Y. Gong et al. / Journal of Fluorine Chemistry 105 (2000) 169±173
3.2. Ethyl (Z)-3-phenyl-4,4,4-trifluorocrotonate (Z)-3a and
ethyl (Z)-2-phenyl-4,4,4-trifluorocrotonate (Z)-4a
0.0494 g) in anhydrous N,N-DMF (4.5 ml) was degassed
under a argon ¯ow for 5 min, and then heated with con-
tinuous stirring at 1208C for 30 h. The residue was puri®ed
on a silica gel column to afford 0.062 g of (Z)-3d (21.1%)
and 0.126 g of (Z)-4d (42.9%).
A
mixture of ethyl (E)-4,4,4-tri¯uorocrotonate
(1.0 mmol, 0.168 g), bromobenzene (2.0 mmol, 0.314 g),
diisopropylethylamine (2.0 mmol, 0.258 g), palladium acet-
ate (0.05 mmol, 0.0112 g), triphenylphophine (0.12 mmol,
0.0314 g) in anhydrous N,N-dimethylformamide (DMF,
4.5 ml) was degassed under a argon ¯ow for 5 min, and
then heated with continuous stirring at 1008C for 24 h. After
cooled, the reaction mixture was poured into a saturated
NH4Cl aqueous solution (20 ml). The aqueous layer was
extracted with ether (3Â20 ml), and the combined organic
phases were washed with saturated NH4Cl (aq), dried over
MgSO4, ®ltered, and concentrated at reduced pressure. The
residue was puri®ed on a silica gel column with hexane/ethyl
acetate (20:1, v/v) as the elution, to give 0.020 g of (Z)-3a
(8.0%) and 0.048 g of (Z)-4a (19.7%).
For (Z)-3d: 1H NMR (CDCl3) d: 7.84 (4H, m), 7.54 (3H,
m), 6.46 (1H, s), 4.33 (2H, q, Jˆ7.3 Hz), 1.36 (3H, t, Jˆ
7.3 Hz). 19F NMR (CDCl3) d: 102.07 (3F, s). MS (m/e): 294
‡
(M , 81.3), 266 (15.4), 249 (41.6), 248 (100.0). HRMS Calc.
294.0868, Found: 294.0857.
For (Z)-4d: 1H NMR (CDCl3) d: 7.85 (4H, m), 7.53 (3H,
m), 6.15 (1H, q, Jˆ7.9 Hz), 4.42 (2H, q, Jˆ7.3 Hz), 1.37
(3H, t, Jˆ7.3 Hz). 19F NMR (CDCl3) d: 101.92 (3F, d, Jˆz
‡
7.9 Hz). MS (m/e): 294 (M , 100.0), 265 (12.1), 249 (18.6),
221 (23.8), 201 (33.5). HRMS Calc. 294.0868, Found:
294.0870.
3.5. Ethyl (Z)-3-(4-chlorophenyl)-4,4,4-trifluorocrotonate
(Z)-3f and ethyl (Z)-2-(4-chlorophenyl)-4,4,4-
trifluorocrotonate (Z)-4f
For (Z)-3a: 1H NMR (CDCl3) d: 7.41 (5H, s), 6.33 (1H, s),
4.31 (2H, q, Jˆ7.2 Hz), 1.35 (3H, t, Jˆ7.2 Hz). 19F NMR
‡
(CDCl3) d: 101.72 (3F, s). MS (m/e): 244 (M , 60.2), 215
(49.6), 199 (100.0), 171 (15.0). HRMS Calc. 244.0711,
4-Bromochlorobenzene (2.0 mmol, 0.383 g) was used
instead, and the reaction was done at 1208C for 24 h
according to the above procedure. The residue was puri®ed
on a silica gel column to give 0.047 g of (Z)-3f (16.9%) and
0.062 g of (Z)-4f (22.3%).
Found: 244.0713.
For (Z)-4a: 1H NMR (CDCl3) d: 7.42 (5H, s), 6.02 (1H, q,
Jˆ7.9 Hz), 4.37 (2H, q, Jˆ7.1 Hz), 1.35 (3H, t, Jˆ7.1 Hz).
19F NMR (CDCl3) d: 101.73 (3F, d, Jˆ7.9 Hz). MS (m/e):
244 (M , 100.0), 216 (24.9), 199 (31.3), 171 (95.8). HRMS
For (Z)-3f: 1H NMR (CDCl3) d: 7.36 (4H, s), 6.32 (1H, s),
4.32 (2H, q, Jˆ7.0 Hz), 1.35 (3H, t, Jˆ7.0 Hz). 19F NMR
‡
Calc. 244.0711, Found: 244.0693.
‡
(CDCl3) d: 101.65 (3F, s). MS (m/e): 278 (M , 46.8), 260
(92.5), 232 (100.0), 205 (78.3). HRMS Calc. 278.0321,
3.3. Ethyl (Z)-3-(4-anisyl)-4,4,4-trifluorocrotonate (Z)-3b
and ethyl (Z)-2-(4-anisyl)-4,4,4-trifluorocrotonate (Z)-4b
Found: 278.0309.
For (Z)-4f: 1H NMR (CDCl3) d: 7.38 (4H, s), 6.01 (1H, q,
Jˆ7.7 Hz), 4.36 (2H, q, Jˆ7.3 Hz), 1.35 (3H, t, Jˆ7.3 Hz).
19F NMR (CDCl3) d: 101.61 (3F, d, Jˆ7.7 Hz). MS (m/e):
4-Bromoanisole (2.0 mmol, 0.374 g) was used instead of
bromobenzene. The reaction was carried out at 1208C for
36 h, and worked-up similarly to give 0.054 g of (Z)-3b
(19.6%) and 0.072 g of (Z)-4b (26.2%).
‡
278 (M , 95.4), 250 (41.9), 205 (100.0). HRMS Calc.
278.0321, Found: 278.0323.
For (Z)-3b: 1H NMR (CDCl3) d: 7.34 (2H, d, Jˆ8.8), 6.90
(2H, d, Jˆ8.8), 6.28 (1H, s), 4.29 (2H, q, Jˆ7.0 Hz), 3.83
(3H, s), 1.34 (3H, t, Jˆ7.0 Hz). 19F NMR (CDCl3) d: 101.72
3.6. Preparation of (E)-4a and (Z)-4a
‡
(3F, s). MS (m/e): 274 (M , 100.0), 229 (61.5), 201 (9.7).
In a ¯ask, 20 ml of toluene and 1.2 g of clean sodium was
placed. The sodium is melted by means of an oil bath and the
stirrer is used to powder the sodium. After cooled, the
toluene is decanted. To the sodium 8.2 g (50 mmol) of ethyl
phenylacetate and 7.1 g (50 mmol) of ethyl tri¯uoroacetate
are slowly added at 0±58C. The mixture is heated with
vigorous stirring at 60±708C for 1 h, then chilled, acidi®ed
with 1 N HCl, extracted with ethyl acetate. The organic layer
is dried over calcium chloride, ®ltered, the solvent removed,
and the residue is distilled under reduced pressure to yield
2.9 g (22%) of ethyl 2-phenyl-4,4,4-tri¯uoroacetoacetate 7a,
bp 78±828C/10 mmHg.
HRMS Calc. 274.0817, Found: 274.0818.
For (Z)-4b: 1H NMR (CDCl3) d: 7.38 (2H, d, Jˆ8.8), 6.90
(2H, d, Jˆ8.8), 5.94 (1H, q, Jˆ7.9 Hz), 4.36 (2H, q, Jˆ
7.3 Hz), 3.82 (3H, s), 1.35 (3H, t, Jˆ7.3 Hz). 19F NMR
‡
(CDCl3) d: 102.14 (3F, d, Jˆ7.9 Hz). MS (m/e): 274 (M ,
100.0), 229 (14.9), 201 (81.3). HRMS Calc. 274.0817,
Found: 274.0828.
3.4. Ethyl (Z)-3-(2-naphthyl)-4,4,4-trifluorocrotonate (Z)-
3d and ethyl (Z)-2-(2-naphthyl)-4,4,4-trifluorocrotonate
(Z)-4d
To a solution of 0.52 g of compound 7a (2.0 mmol) in
10 ml ethanol, 0.11 g of sodium borohydride (2.9 mmol)
is added in portion at room temperature. The mixture is
stirred for 2 h, then acidi®ed with 1 N HCl, extracted with
ethyl acetate. The crude product is puri®ed by silica gel
A
mixture of ethyl (E)-4,4,4-tri¯uorocrotonate
(1.0 mmol, 0.168 g), 2-bromonaphthalene (2.0 mmol,
0.414 g), diisopropylethylamine (2.0 mmol, 0.258 g), palla-
dium acetate (0.05 mmol, 0.0112 g), DPPP (0.12 mmol,

Y. Gong et al. / Journal of Fluorine Chemistry 105 (2000) 169±173
173
column chromatography (hexane/EtOAc 7:1) to give 0.48 g
(92%) of ethyl 2-phenyl-3-hydroxy-4,4,4-tri¯uorobutyrate
8a.
A mixture of compound 8a (0.26 g, 1.0 mmol), sodium
acetate (0.08 g) and acetic anhydride (0.20 g) in 2.0 ml
tributylamine is re¯uxed with stirring for 4 h. The work-
up is done as mentioned above. The residue is passed
through a silica gel column (hexane/EtOAc 15:1), and
0.16 g (66%) of the target compounds (E)-4a and (Z)-4a
are collected.
Acknowledgements
Y. Gong thanks for the Science and Technology Agency
of Japan (STA) for the award of Fellowship Program, which
is managed by the Research Development Corporation of
Japan (JRDC) in cooperation with Japan International
Science and Technology Exchange Center (JISTEC).
References
For (E)-4a: 1H NMR (CDCl3) d: 7.35 (5H, m), 6.87 (1H,
q, Jˆ7.9 Hz), 4.26 (2H, q, Jˆ7.1 Hz), 1.27 (3H, t, Jˆ
7.1 Hz). 19F NMR (CDCl3) d: 104.10 (3F, d, Jˆ7.9 Hz).
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‡
MS (m/e): 244 (M , 58.6), 216 (8.9), 199 (8.3), 171 (100.0),
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To a ¯ask containing a nitrogen atmosphere are added
0.65 g of fresh zinc powder, and 10 ml of dry toluene. The
mixture is re¯uxed while a solution of 1.74 g (10 mmol) of
2,2,2-tri¯uoroacetophenone and 3.34 g (20 mmol) of ethyl
bromoacetate in 10 ml of dry toluene is added dropwise with
vigorous stirring. The addition is completed in about 15 min,
and the mixture then re¯uxed for 2 h. When the solution has
cooled to room temperature, 5 ml of 4 N HCl is added and
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through a silica gel column (hexane/EtOAc 7:1) to give
0.45 g (17%) of ethyl 3-hydroxy-3-phenyl-4,4,4-tri¯uoro-
butyrate 9a.
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Dehydration of compound 9a is carried out according to
the same procedure with 8a, and gives the target compounds
(E)-3a and (Z)-3a.
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s), 4.10 (2H, q, Jˆ7.2 Hz), 1.15 (3H, t, Jˆ7.2 Hz). 19F NMR
‡
(CDCl3) d: 94.36 (3F, s). MS (m/e): 244 (M , 81.6), 215
(28.3), 199 (100.0), 171 (16.2), 151 (78.9).
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