Efficient synthetic method of β-fluorocinnamate by arylboronic acids and ethyl 3,3,3-trifluoropropionate under palladium-catalyzed conditions

Article abstract of DOI:10.1080/00397911.2020.1797813

A convenient and efficient method for synthesizing β-fluorocinnamate and derivatives is reported. Palladium (II) catalysis was employed in β-F elimination and coupling reaction of phenylboronic acid and ethyl 3,3,3-trifluoropropionate with a high yield and E-selectivity. The reaction was conducted under mild conditions and could be widely adapted to boronic acid substrates.

Full text of DOI:10.1080/00397911.2020.1797813

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Efficient synthetic method of β-fluorocinnamate
by arylboronic acids and ethyl 3,3,3-
trifluoropropionate under palladium-catalyzed
conditions
Wei-Hao Chen , Xiao-Jun Pei , Xiao-Xuan Li & Yi-Si Feng
To cite this article: Wei-Hao Chen , Xiao-Jun Pei , Xiao-Xuan Li & Yi-Si Feng (2020):
Efficient synthetic method of β-fluorocinnamate by arylboronic acids and ethyl 3,3,3-
trifluoropropionate under palladium-catalyzed conditions, Synthetic Communications, DOI:
10.1080/00397911.2020.1797813
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https://doi.org/10.1080/00397911.2020.1797813
Efficient synthetic method of b-fluorocinnamate by
arylboronic acids and ethyl 3,3,3-trifluoropropionate under
palladium-catalyzed conditions
Wei-Hao Chena, Xiao-Jun Peia, Xiao-Xuan Lia, and Yi-Si Fenga,b
aAnhui Province Key Laboratory of Advance Catalytic Materials and Reaction Engineering, School of
b
Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, P. R. China; Anhui
Provincial Laboratory of Heterocyclic Chemistry, Maanshan, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 23 February 2020
A convenient and efficient method for synthesizing b-fluorocinna-
mate and derivatives is reported. Palladium (II) catalysis was
employed in b-F elimination and coupling reaction of phenylboronic
acid and ethyl 3,3,3-trifluoropropionate with a high yield and E-
selectivity. The reaction was conducted under mild conditions and
could be widely adapted to boronic acid substrates.
KEYWORDS
Ethyl 333-
trifluoropropionate; b-fluo-
rocinnamate; one-step
synthesis; palladium
catalysis; phenylbor-
onic acid
GRAPHICAL ABSTRACT
Introduction
Monofluoroolefin compounds are highly important in medicinal and peptide chemistry
research[1–4] owing to the fact that the selective introduction of fluorine atoms can sig-
nificantly change the pharmacological properties of organic drug molecules.[5–8] As one
of the most important monofluorinated compounds, fluorocinnamates have attracted
much attention because cinnamate compounds are widely used in daily life, including
in perfumes and cosmetics,[9] research has shown that b-fluorocinnamate can slightly
improve the body’s resistance to drug-induced allergies.[10] Moreover, the fluorocin-
namic acid structure has superior chemical versatility and potential for further conver-
sion to fluorinated compounds with considerable application prospects.[9–13] Therefore,
the synthesis of b-fluorocinnamate is very valuable and provides an important tool for
synthetic and medicinal chemistry.
CONTACT Yi-Si Feng
fengyisi@hfut.edu.cn
Anhui Province Key Laboratory of Advance Catalytic Materials and
Reaction Engineering, School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, P.
R. China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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W.-H. CHEN ET AL.
Scheme 1. (a–c) Reported method for fluorocinnamates and method presented herein.
The use of fluorine-containing intermediates has become an important trend in the syn-
thesis of b-fluorocinnamate and other valuable fluorinated compounds in the last few dec-
ades.[14–17] For example, fluorinated organic zinc reagents (ZnBrCF2CH2CO2C2H5)[18]
were reported as fluorine sources for cross-coupling with halogenated aromatic hydrocar-
bons to obtain b-fluorocinnamate by Qing’s group; however, the reaction requires the syn-
thesis of ethyl 3-bromo-3-difluoropropionate via a two-step reaction, and the process is
relatively complex (Scheme 1a). Tetrabutyl ammonium fluoride (TBAF)[19] has also been
reported by Zhang et al. as a fluorine source to react with substituted ethyl a-bromocina-
mates to obtain b-fluorocinnamate (Scheme 1b). Jiang et al. found that AgF can be used
as a fluorinating agent to participate in the high chemo- and region-selectivity fluorination
of electron-deficient CꢀC triple bonds to access b-fluorocinnamate.[20] In 2016, Patrick’s
team[21] reported that ethyl (Z)-3-fluoropentenoate could be a fluorine source to react with
iodobenzene under palladium catalysis condition to obtain fluorocinnamate in medium
yield, but the raw materials are expensive and difficult to obtain. Although great progress
has been made in the synthesis of b-fluorocinnamate, the preparation of these fluorine
sources often needs a multi-step reaction, resulting in a complicated and expensive process.
Thus, the one-step synthesis of b-fluorocinnamate using cheap and convenient fluorine
sources must be developed.
3,3,3-trifluoropropionic acid and its esters are important synthetic intermediates of
bioactive compounds and functional materials[22–27] that have been commercialized.
Since our department has successfully realized the pioneering work on Pd-catalyzed
C–F activation of a-trifluoromethyl ketone and thus obtained
a variety of
a,b-unsaturated ketones.[28] We envisage using ethyl 3,3,3-trifluoropropionate as a fluor-
ine source to approach b-fluorocinnamate.
Inspired by our continuous efforts in fluorine chemistry,[28,29] we report here a
unique method of synthesizing b-fluorocinnamate in high yield and E-selectivity using
ethyl 3,3,3-trifluoropropionate as the fluorine source. The reaction has the following

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3
Table 1. Optimization of reaction conditions.
Selectivity
Entry
Catalysis
Base (1:1)
Solvent
Temperature (ꢁC)
Yieldb (%)
(E/Z)c
1
2
3
4
5
6
7
8
PdCl2
K3PO4
K3PO4
K3PO4
K2CO3
K3PO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
H2O
RTa
80
80
80
80
80
80
80
80
80
80
80
80
60
110
0
Trace
<5
11
43
40
46
62
75
64
52
<5
61
58
80
ND
ND
ND
PdCl2(dppf)
PdCl2(MeCN)2
Pd(OAc)2
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Na2CO3
Ag2CO3
K3PO4þNa2SiO3
K2CO3þNa2SiO3
Ag2CO3þNa2SiO3
K2CO3þNa2SiO3
K2CO3þNa2SiO3
K2CO3þNa2SiO3
K2CO3þNa2SiO3
K2CO3þNa2SiO3
9
10
11
12
13
14
15
THF
CH3CN
CH3CN
c
aRT: room temperature; bisolated yield shown in parentheses; selectivity detected by 1H NMR; ND: not detected.
advantages: (1) ethyl 3,3,3-trifluoropropionate is introduced as a new fluorine reagent to
obtain b-fluorocinnamate, (2) fluorocinnamate is synthesized through a one-step reac-
tion with simple reaction and mild conditions, and (3) stable and low-toxic arylboronic
acid is used as a coupling reagent, providing a wide range of substrates for the reaction.
Results and discussion
The initial research was targeted to evaluate the performance of different palladium cat-
alysts. Phenylboronic acid and ethyl 3,3,3-trifluoropropionate were used as model sub-
strates (Table 1). No product was observed when PdCl2 was used as a catalyst for the
reaction (Table 1, entry 1). Upon adding the ligand, the reaction began to produce a
trace of desired product. After comparison and screening, PPh3 was found to be the
most efficient ligand (Table 1, entries 2–5). Further research was performed to explore
the effect of different bases on the reaction. A series of bases (K3PO4, Na2CO3,
Ag2CO3) were studied to obtain the target product with CH3CN as the solvent at 80 ꢁC,
the yield could be increased to 46% (Table 1, entries 6 and 7). It is worth mentioning
that it was a pleasant surprise to find that the use of a mixed base significantly improves
the yield. Indeed, the yield of 3a increased to 75% when a mix of K3CO3/Na2SiO3 was
used. The reaction yield can still reach 64% under the same ratio of Ag2CO3 and
Na2SiO3 (Table 1, entries 8–10). The solvent of the reaction was then screened. When
CH3CN was changed to toluene, the yield dropped to 52%. Similarly, the conversion to
THF indicated that the yield of the target product was also reduced, only 61% can be
achieved; the experiment had also shown that water strongly inhibits the reaction
(Table 1, entries 11–13). In addition, the temperature has an effect on the yield of

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W.-H. CHEN ET AL.
Table 2. Substrate range of phenylboronic acid.
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Pd(PPh3)2Cl2 (5% mol), K2CO3/Na2SiO3 1:1 (3 equiv.), and
CH3CN (2 mL), at 110 ꢁC, 12 h.
the reaction. The yield would decrease slightly when the temperature was lowered to
60 ꢁC, but the reaction yield reached 80% at 110 ꢁC (Table 1, entries 14 and 15). In add-
ition, the structure of 3a detected was mainly E-configuration (E/Z ¼ 99%).
With the optimized reaction conditions in hand, the range of substrates was studied
next (Table 2). A series of aryl boronic acids with different substituents on the benzene
ring had good adaptability to this reaction. Substrates bearing electron-donating groups,
such as methyl/methoxy/tert-butyl on the para position of the benzene ring, were

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5
Scheme 2. Gram-scale experiment.
Scheme 3. Mechanism verification.
smoothly transformed into the corresponding E-configured fluorocinnamate ester 3b–d.
Halogen functional groups, that are sensitive to low-valence transition metals, can adapt
to the reaction and afford 3e–g in medium yields. Cyano groups that absorb electrons
have less effect on the reaction and can obtain 3h in moderate yields. 4-vinylphenylbor-
onic acid has good adaptability to the reaction and provides 4-vinyl-b-fluorocinnamate
3i in high yield. The ortho and meta substituents of the benzene ring were also well
adapted to the reaction, and 3j–m can be obtained in high yields. The poly-substituted
phenylboronic acids, such as 2,4-dimethylphenylboronic, 2,6-dimethylphenylboronic and
3,4-dimethylphenylboronic acid, can be converted into 3n, 3o, and 3p in high yields.
3,4-dichlorobenzeneboronic acid provides the corresponding fluorocinnamate 3q in
medium yield, it is worth mentioning that 3q is the only Z-type fluorocinnamate among
all substrates. The aryl boronic acid with benzene ring substituted by dihalogen only
gives the corresponding 3,5-difluoro-b-fluorocinnamate 3r in moderate yield. The
obtention of 3 s confirmed the suitability of tri-substituted phenylboronic acid for the
reaction. Thiophene boronic acid can produce 3t in high yields, which showed that the
proposed reaction is also very suitable for heterocyclic boronic acid. Moreover, the phe-
nylboronic acid substituted by 3,4-dimethyleneoxy can nicely adapt to the reaction, but
a small amount of Z configuration was detected (E/Z 9:1). However, no desired product
was obtained when a hydroxyl group was located on the benzene ring.
To prove the application prospect of the proposed fluorocinnamate synthesis method,
a gram-scale experiment was performed, and product 3a was obtained in 67% yield
(Scheme 2).
Further work was done mainly to study the reaction mechanism, Firstly, the fluorine
source 2a undergoes the first b-F elimination reaction in the presence of a base to generate
a difluoroolefin intermediate 2b,[30] we confirmed the existence of 2b through experiment
(Scheme 3). Intermediate 2b may subsequently participate in two different pathways. In the
first possible pathway (Scheme 4, Path I), aryl boronic acid transmetalated with Pd (II) to
generate palladium-aryl species B.[31,32] Subsequently, B is inserted by the difluoroolefin
intermediate 2b to form an alkyl-palladium species C. Finally, the target product 3 is
obtained by eliminating b-fluorine of C.[28] In the second possible pathway (Scheme 4,

6
W.-H. CHEN ET AL.
Scheme 4. Proposed mechanism.
path II), the palladium-aryl species B undergoes transmetalation and reductive elimination
to form Pd(0) complex D.[32,33] The Pd (0) complex D is then oxidatively inserted into the
difluoroalkene structure to produce Pd(II)-olefin species E, Pd(0) is oxidized to Pd(II) in
the process.[28] Transmetalation occurs from E to provide the key intermediate F. The tar-
get product 3 is obtained through a rapid reductive elimination of F,[28] and Pd (II) is
reduced to Pd (0). The specific path is shown in Scheme 4.
Conclusion
A unique and efficient method has been developed for the synthesis of b-fluorocinna-
mate in high yields with excellent E selectivity. The use of ethyl 3,3,3-trifluoropropio-
nate provides a convenient fluorine source for the synthesis of b-fluorocinnamate. The
one-step synthesis of b-fluorocinnamate was realized through the b-F elimination of
ethyl 3,3,3-propionate and coupling reaction with aryl boronic acids, which greatly
reduces the reaction cost. Moreover, this method has wide applicability and can be
adapted to most substrates with different substituents. Further research work will focus
on the derivatization and functionalization of b-fluorocinnamate.
Experimental
1H NMR (600 Hz) and 13C NMR (150 Hz) were recorded in CDCl3 or DMSO-d6 using
1
TMS as an internal standard. Data for H NMR are reported as follows: chemical shift
(ppm, scale), multiplicity, coupling constants (Hz), and integral. Data for 13C NMR are
reported in terms of chemical shift (ppm, scale), multiplicity, and coupling constants
(Hz). Data for 19F NMR are reported in terms of chemical shift (ppm, scale),

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SYNTHETIC COMMUNICATIONSV
7
multiplicity, and coupling constants (Hz). High-resolution mass spectra were obtained
by ESI on a TOF mass analyzer. HRMS (EI) was determined on a PerkinElmer
spectrometer.
General procedures for b-Fluorocinnamate (3a)
Phenylboronic acid 1a (0.2 mmol, 24.8 mg), Pd(PPh3)2Cl2 (5 mol%, 7.1 mg), K2CO3 (3
equiv., 41.4 mg) and Na2SiO3 (3 equiv., 85.2 mg) were sequentially added to a dry
Schlenk tube, then repeat the pumping and the vessel was degassed by three cycles of
nitrogen and vacuum, followed by addition of 3,3,3-trifluoropropionate 2a (0.6 mmol,
93.6 mg) and CH3CN (2 mL). The reaction mixture was stirred at 110 ꢁC for 12 hours,
chromatographic purification of the crude product on silica gel gave the desired product
b-fluorocinnamate 3a in 80% yield.
Spectral data for the selected compounds
Compound 3a18: Following the general procedure, the product was purified by flash
1
chromatography (PE/EA ¼ 20:1) as a yellow oil (30.1 mg, 80%). H NMR (600 MHz,
CDCl3) d 7.70 (d, J ¼ 7.2 Hz, 2H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.41 (t, J ¼ 7.8 Hz, 2H), 5.86
(d, J ¼ 20.6 Hz, 1H), 4.13 (q, J ¼ 7.1 Hz, 2H), 1.21 (t, J ¼ 7.1 Hz, 3H).13C NMR
(151 MHz, cdcl3) d 170.65, 168.89, 165.29, 131.21, 131.20, 129.01, 127.86, 101.70, 101.48,
77.00, 60.48, 14.04. 19F NMR (564 MHz, CDCl3) d ꢂ 67.81. HRMS (ES) m/z calcd. for
C11H11FO2: 194.1493; found: 194.1495.
Compound 3e18: Following the general procedure, the product was purified by flash
1
chromatography (PE/EA ¼ 20:1) as a yellow oil (26.7 mg, 63%). H NMR (600 MHz,
CDCl3) d 7.74 (dd, J ¼ 8.5, 5.4 Hz, 2H), 7.10 (t, J ¼ 8.5 Hz, 2H), 5.85 (d, J ¼ 20.9 Hz,
1H), 4.14 (q, J ¼ 7.1 Hz, 2H), 1.23 (t, J ¼ 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) d
169.58, 167.83, 165.08, 163.42, 131.39, 125.96, 115.20, 115.03, 101.41, 77.20, 60.55, 14.07.
19F NMR (564 MHz, CDCl3) d ꢂ 76.01, ꢂ107.53. HRMS (ES) m/z calcd. for
C11H11F2O2: 212.0649; found: 212.0651
1
Full experimental details, H, 13C NMR and 19F spectra. This material is found in the
“Supplementary Content” section of this article’s webpage.
Acknowledgments
We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of
this manuscript.
Funding
The present work was financially supported by Natural Science Foundation of China [21971050].
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