A facile and mild approach for stereoselective synthesis of α-fluoro-α,β-unsaturated esters from α-fluoro-β-keto esters via deacylation

Article abstract of DOI:10.1055/s-0034-1378917

The highly stereoselective olefination reaction of α-fluoro-β-keto esters for the synthesis of α-fluoro-α,β-unsaturated esters has been developed. The olefination combines nucleophilic addition, intramolecular nucleophilic addition, and elimination in one step, as well as provides a facile synthetic approach to α-fluoro-α,β-unsaturated esters which are important units in many biologically active compounds and useful precursors in a variety of functional-group transformations.

Full text of DOI:10.1055/s-0034-1378917

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 127–132
letter
127
J. Qian et al.
Letter
Synlett
A Facile and Mild Approach for Stereoselective Synthesis of
α-Fluoro-α,β-unsaturated Esters from α-Fluoro-β-keto Esters
via Deacylation
α-Fluoro-α,β-unsaturated Esters
Jinlong Qian
Wenbin Yi*
Meifang Lv
Chun Cai
School of Chemical Engineering, Nanjing University of Science
& Technology, Nanjing, Jiangsu 210094, P. R. of China
+
8
6
2
(
5
8
)
4
3
1
5
0
3
0
yiwenbin@mail.njust.edu.cn
Witting reaction:3b
Received: 02.08.2014
Accepted after revision: 09.10.2014
Published online: 05.11.2014
O
H
O
Et2Zn (4equiv)
CH2Cl2, r.t., 3 h
O
DOI: 10.1055/s-0034-1378917; Art ID: st-2014-w0647-l
Br
OEt
+
Ph
OEt
F
Ph
H
Abstract The highly stereoselective olefination reaction of α-fluoro-β-
keto esters for the synthesis of α-fluoro-α,β-unsaturated esters has
been developed. The olefination combines nucleophilic addition, intra-
molecular nucleophilic addition, and elimination in one step, as well as
provides a facile synthetic approach to α-fluoro-α,β-unsaturated esters
which are important units in many biologically active compounds and
useful precursors in a variety of functional-group transformations.
Br
F
63%
Z/E = 99:1
thia-Wittig reaction:4a
O
H
O
O
i) LDA
F
OEt
Ph
OEt
+
ii) MCPBA, CH2Cl2
iii) SO2Cl2, CH2Cl2
Ph
H
S
F
Key words olefination, highly stereoselective, deacylation, fluoro-
olefins, carbon–carbon bond cleavage
t-Bu
O
53%
Z/E = 99:1
Horner-Wadsworth-Emmons reaction:5g
Organofluorine compounds have experienced consider-
able growth in academic interest in recent years due to
their growing importance in drug development purposes
and crop protection.1 In particular, α-fluoro-α,β-unsaturat-
ed esters are well known as precursors to biologically active
compounds and have been successfully used to prepare a
new generation of modified pheromones, herbicides, and
medicines2 (selected bioactive structures are shown in Fig-
ure 1). The traditional approaches for the preparation of
these compounds are based on the Wittig,3 thia-Wittig,4
Horner–Wadsworth–Emmons (HWE),5 Peterson,6 or fluo-
rous Julia7 olefination reactions (Scheme 1). Most of these
procedures generally suffer from several major drawbacks
including the requirement of metal catalysts,3 harsh reac-
tion conditions,4,5 low selectivity,6 and the use of expensive
or complex starting materials.5–8
O
P
O
H
O
i) n-BuLi, THF,
EtO
EtO
O
0 °C, 1 h
OEt
+
Ph
OEt
ii) r.t., 20 h
H
Ph
F
F
59%
Z/E = 100:0
Peterson reaction:6a
H
O
O
O
LDA
F
Ph
OEt
+
OEt
Si(CH3)3
Ph
H
F
82%
Z/E = 1.3:1
Julia olefination reaction:7c
F
H
O
O
K2CO3,
TBAB, DMF
OMe
O
F3C
S
Ph
OMe
+
O
O
r.t., 18 h
H
Ph
F
63%
Z/E = 92:8
CF3
Scheme 1 Traditional approach for the preparation of α-fluoro-α,β-
unsaturated esters
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 127–132

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J. Qian et al.
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O
H
N
N
N
OEt
N
O
F
S
OEt
MeO
F
respiratory system agents2h
antitumor agents2i
F
O
O
O
Me
Ph
O
Ph
N
O
OEt
O
F
Me
nervous system agents2j
anti-inflammatory agents2k
O
OEt
F
O
OEt
OH
Et
F
N
F
AcHN
O
O
anti-infective agents2l
antidiabetic agents2m
Figure 1 Selected bioactive structures
Owing to the stability of carbon–carbon bonds, their
cleavage has long remained a great challenge for organic
chemists.9 Decarboxylation10b,c and deacylation10a,d are two
types of the most prevailing methods to fulfill this purpose
because of their efficiency informing reactive intermediates
that successively promote the bond cleavage under mild
conditions.10 The descriptions of this potentially useful and
versatile molecule for the synthesis of α-functionalized α,β-
unsaturated carbonyl compounds date back to 1978, in
which Tsuboi’s group reported the synthesis of 5,5,5-tri-
chloro-3-penten-2-one by the reaction of chloral with
2,4-pentanedione via deacylation process.11 In 2004, they
continuously developed this method for the synthesis of
α-chloro-α,β-unsaturated esters by the reaction of chlori-
nated ethyl acetoacetates with aldehydes.12
cleophilic addition, intramolecular nucleophilic addition,
and elimination in one step. This protocol also provides a
practical, simple, and mild synthetic approach to α-fluoro-
α,β-unsaturated carbonyl compounds.
The starting material ethyl 2-fluoro-3-oxo-3-phenyl-
propanoate (1a) was easily prepared by stirring the corre-
sponding β-keto ester with 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Select-
fluorTM) according to the literature procedure.13 Our initial
study on olefination study started with the reaction of 1a
and benzaldehyde (2a). A variety of parameters was sum-
marized in Table 1. With regard to the influence of reaction
temperature, it was found that the yield of the product 3aa
increased from 56% at room temperature (Table 1, entry 1)
to 80% at 40 °C (Table 1, entry 4) by using cesium carbonate
as the base, whereas the yield had a significant reduction
when the reaction conducted at 60 °C and 80 °C (Table 1,
entries 2 and 3). Beside the cesium carbonate, other cesium
salts (CsF and CsOAc) were tested, but only low efficiency
were obtained (Table 1, entries 5 and 6). The reaction did
not work in the presence of Na2CO3, NaOH, KOH, or KOt-Bu
(Table 1, entries 7–13). Further studies indicated that the
superior result was available by using acetonitrile com-
pared with other solvents (Table 1, entries 4, 14–19). Based
on the 1H NMR data and comparison with the reported ex-
perimental data,3b,e it was to our delight that a high ratio
(up to 99:1) of Z stereoisomer was identified.
Along this line, we herein reported the first example of
the synthesis of α-fluoro-α,β-unsaturated esters from α-
fluoro-β-keto esters and aldehydes through deacylation
process (Scheme 2). This process successfully combines nu-
Scheme 2 Reaction of α-fluoro-β-keto esters with aldehydes
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 127–132

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J. Qian et al.
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Table 1 Optimization of Reaction Conditionsa
derivates 1b–d produced the corresponding α-fluoro-
α,β-unsaturated esters in moderate to high yields (Table 2,
entries 17–20), and indicated that electron-withdrawing
substituents make deacylation proceed slightly more effi-
ciently [NO2/H/OMe = 87:80:63 (%)]. More economical α-
fluoro-β-keto ester 1e gave poor yields in the reaction (Ta-
ble 2, entries 21, 22). It should be noteworthy that the Z/E
ratios of this transformation are extremely high. X-ray crys-
tal-structure analysis confirmed the structure and selectiv-
ity of product 3ag (Figure 2).
O
O
O
O
base
Ph
OEt
+
Ph
OEt
Ph
H
solvent, 8 h
F
F
2a
3aa
1a
Entry Base
Solvent
Temp (°C) Yield (%)b
Z/Ec
97:3
1d
2
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
r.t.
60
80
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
56
64
39
80
24
5e
7e
20
0
95:5
95:5
96:4
95:5
–
3
Cs2CO3
Cs2CO3
CsF
Table 2 High Stereoselective Olefination Reactions of Different α-Flu-
oro-β-keto Esters 1 with Different Aldehydes 2a
4
5
O
O
O
O
6
CsOAc
Na2CO3
K2CO3
NaOH
KOH
Cs2CO3
R1
OR2
+
R3
OR2
7
–
R3
H
MeCN, 40 °C, 8 h
F
F
8
91:9
–
1
2
3
9
En- R1
try
R2
R3
Yield (%)b Z/Ec
10
11
12
13
14
15
16
17
18
19
0
–
Et3N
0
–
1
2
3
4
5
6
7
8
9
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
Et
2a Ph
3aa 80
3ab 50
3ac 54
3ad 87
3ae 86
3af 89
3ag 94
3ah 92
3ai 88
3aj 85
3ak 77
3al 81
3am 75
3an 93
3ao 95
3ap 87
3aa 63
3aa 87
3dh 82
3dg 84
3aa 21
3ag 34
96:4
93:7
pyridine
KOt-Bu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
–
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
2b 4-MeC6H4
2c 4-Me3OC6H4
2d 4-ClC6H4
2e 4-BrC6H4
2f 4-FC6H4
0
–
94:6
97:3
98:2
98:2
99:1
99:1
97:3
99:1
94:6
96:4
94:6
96:4
95:5
93:7
94:6
99:1
99:1
99:1
93:7
95:5
62
45
56
31
25
60
96:4
99:1
96:4
97:3
99:1
99:1
dioxane
CHCl3
DMF
2g 4-F3CC6H4
2h 4-O2NC6H4
2i 2-O2NC6H4
2j 3-O2NC6H4
2k 2-furfuryl
2l 1-naphthyl
2m 2-thienyl
2n 2-pyridyl
2o PhCH2CH2
2p cyclohexyl
2a Ph
DMSO
toluene
a Reaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), base (1 mmol).
b Isolated yields.
10 1a Ph
11 1a Ph
12 1a Ph
13 1a Ph
14 1a Ph
15 1a Ph
16 1a Ph
c Relative ratio of the crude determined by 1H NMR spectroscopy.
d Reaction for 48 h.
e GC yield based on 2a.
With a set of optimized conditions in hand, the scope of
α-fluoro-β-keto esters 1 and aldehydes 2 were investigated
(Table 2).14 The reactions of α-fluoro-β-keto esters with aryl
aldehydes bearing electron-withdrawing substituents (Ta-
ble 2, entries 4–10) was more effective than electron-
donating ones (Table 2, entries 2 and 3), and could be
smoothly transformed into the desired products in excel-
lent yields. Aromatic aldehydes with substituents at differ-
ent positions of the aryl ring (para, meta, and ortho
position) reacted well under the standard conditions (Table
2, entries 8–10). In addition, 1-naphthaldehyde, furfural,
2-thienaldehyde, and 2-pyridinecarboxaldehyde had good
yields in this transformation, generating 3am, 3ak, 3ao and
3ap in 81%, 77%, 75%, and 93% yield, respectively (Table 2,
entries 11–14). Alkyl aldehydes also worked well in high
yields (Table 2, entries 15 and 16). α-Fluoro-β-keto esters
17 1b 4-C6H4
18 1c 4-O2NC6H4
19 1d 4-FC6H4
20 1d 4-FC6H4
21 1e Me
2a Ph
Me
Me
Et
2h 4-O2NC6H4
2g 4-F3CC6H4
2a Ph
22 1e Me
Et
2g 4-F3CC6H4
a Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), Cs2CO3 (1.0 mmol).
b Isolated yields.
c Relative ratio of the crude determined by 1H NMR spectroscopy.
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These olefination reactions can be conducted without
using Schlenk technique on a larger scale. The olefination of
fluorous benzoylacetate 1a with benzaldehyde (2a) on a
two-gram scale occurred in a high yield (81%) similar to
that of the reaction conducted on a smaller scale (Scheme
4). The benzoic acid was collected for experimental use.
Thus, these reactions should be practical for a number of
applications in medicinal chemistry.
Figure 2 X-ray structure of compound 3ag (CCDC 970020)
According to the reported literature11 and experimental
points a possible mechanism for this transformation is pro-
posed in Scheme 5, in which Cs2CO3 plays an important role
as a promoter of nucleophilic addition. Weak bases could
not make nucleophilic addition happen. Strong base make
the product decompose into (Z)-2-fluoro-3-phenylacrylic
acid (see the Supporting Information). An intramolecular
nucleophilic addition of intermediates ii preferentially
adopts an antiperiplanar conformation, which is much
more thermodynamicly and kineticly stable than its other
conformation, and forms a four-membered-ring transition
We thought it could be possible to perform deacylation
to produce α-fluoro-α,β-unsaturated ketones and amides. It
was found that deacylation could be easily achieved by the
same method using 2-fluoro-1,3-dione and α-fluoro-β-keto
amide compounds (Scheme 3). Thus, reactions of 2-fluoro-
1,3-diphenylpropane-1,3-dione (4a) or 2-fluoro-3-oxo-N,3-
diphenylpropanamide (4b) with benzaldehydes 2 gave ole-
fination products in 61–88% yields with extremely high Z/E
ratios.
O
O
O
Cs2CO3
O
+
R2
R1
Ph
R1
R2
H
MeCN, 40 °C, 12 h
F
F
5
4
2
ketone product
O
CF3
O
O
F3C
Ph
Ph
Ph
Ph
F
F
F
F3C
5ag, 72%b (Z/Ec= 99:1)
5aq, 74%b (Z/Ec = 99:1)
5ar, 84%b (Z/Ec = 99:1)
O
O
O
Ph
Ph
N
F
S
F
F
5an, 78%b (Z/Ec = 96:4)
5am, 88%b (Z/Ec = 99:1)
5al, 82%b (Z/Ec = 99:1)
amide product
O
O
Ph
Ph
N
N
H
H
F
F
F3C
5bg, 76%b (Z/Ec = 99:1)
5bl, 61%b (Z/Ec = 99:1)
Scheme 3 Highly stereoselective olefination reaction of α-fluoro-α,β-unsaturated ketone and amide with different aldehydes 2.a a 4 (0.55 mmol), 2
(0.5 mmol), Cs2CO3 (1 mmol). b Isolated yields. c Determined by 1H NMR spectroscopy.
O
O
O
1) Cs2CO3, MeCN,
40 °C, 8 h
COOH
O
OEt
Ph
OEt
+
+
2) H+
Ph
H
F
F
1a
2a
3aa
81%, Z/E = 96:4
Scheme 4 Highly stereoselective olefination on gram scale
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 127–132

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O
base
O
O
O
O
R3
H
–
2
R1
R2
R1
R2
F
F
[base+H]+
1 or 4
i
O–
R2
O
R1
O–
R3
R1
O
H
O
H
F
F
R3
O
R3
O
H
O
F
R2
R2
R1
O–
3 or 5
ii
iii
H
O
O
R1
R2
R3
ii antiperiplanar conformation
–
O
F
Scheme 5 Proposed mechanism
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state iii. The final elimination of unstable transition state iii
produces the designed product 3.
In conclusion, a highly stereoselective olefination reac-
tion of α-fluoro-β-keto esters for the synthesis of α-fluoro-
α,β-unsaturated esters has been developed. This method
provides a practical, simple, and mild synthetic approach to
α-fluoro-α,β-unsaturated esters, which are important units
in biologically active molecules. The protocol was also used
to prepare α-fluoro-α,β-unsaturated ketones and amides.
The high stereoselectivity and excellent yields makes this
transformation very efficient and practical. Further studies
to extend the synthetic applications for fluorinated com-
pound are ongoing in our group.
Acknowledgment
We thank the Fundamental Research Funds for the Central Universi-
ties (30920130111002), National Natural Science Foundation of China
(21476116), and Natural Science Foundation of Jiangsu
(BK20141394). We also thank the Center for Advanced Materials and
Technology for financial support.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378917.
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p
p
ortioInfgrmoaitn
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ortiInfogrmoaitn
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Wiley: New York, 1993. (b) Crabtree, R. H. Nature (London, U.K.)
2000, 408, 415.
(10) (a) Cai, S. J.; Wang, F.; Xi, C. J. J. Org. Chem. 2012, 77, 2331.
(b) Yin, L.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
9610. (c) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2008,
130, 11852. (d) Chen, Y.; Wang, Y. J.; Sun, Z. M.; Ma, D. W. Org.
Lett. 2008, 10, 625.
(11) (a) Tsuboi, S.; Uno, T.; Takeda, A. Chem. Lett. 1978, 1325.
(b) Ueno, Y.; Setoi, H.; Okawara, M. Tetrahedron Lett. 1978, 39,
3753.
(12) Nakatsu, S.; Gubaidullin, A. T.; Mamedov, V. A.; Tsuboi, S. Tetra-
hedron 2004, 60, 2337.
Ethyl (Z)-2-Fluoro-3-phenylacrylate (3aa)
Colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 6.8 Hz, 2
H), 7.43–7.35 (m, 3 H), 6.92 (d, J = 35.2 Hz, 1 H), 4.35 (q, J = 7.1
Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H). 19F NMR (470 MHz, CDCl3): δ =
–125.31 (s). 13C NMR (126 MHz, CDCl3): δ = 160.45 (d, J = 34.3
Hz), 146.07 (d, J = 267.5 Hz), 130.20 (s), 129.30 (d, J = 7.2 Hz),
128.68 (s), 127.82 (s), 116.48 (s), 60.89 (s), 13.23 (s). MS (EI):
m/z = 194.12 [M+].
(Z)-2-Fluoro-1-phenyl-3-[2-(trifluoromethyl)phenyl]prop-
2-en-1-one (5ar)
Colorless solid. 1H NMR (500 MHz, CDCl3): δ = 8.03 (d, J = 7.9 Hz,
1 H), 7.90 (d, J = 7.6 Hz, 2 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.63 (t, J =
7.5 Hz, 2 H), 7.56–7.47 (m, 3 H), 7.19 (d, J = 33.6 Hz, 1 H). 19F
NMR (470 MHz, CDCl3): δ = –59.57 (s), –118.61 (s). 13C NMR
(126 MHz, CDCl3): δ = 187.69 (d, J = 28.3 Hz), 154.69 (d, J = 276.2
Hz), 135.67 (s), 133.32 (s), 132.07 (s), 131.51 (d, J = 12.1 Hz),
129.47 (d, J = 3.6 Hz), 129.32 (s), 129.11 (s), 128.59 (s), 126.22
(q, J = 5.5 Hz), 124.96 (s), 122.79 (s), 115.25 (s). MS (EI): m/z =
294.15 [M+].
(13) Hornung, C. H.; Hallmark, B.; Baumann, M.; Baxendale, I. R.; Ley,
S. V.; Hester, P.; Clayton, P.; Mackley, M. R. Ind. Eng. Chem. Res.
2010, 49, 4576.
(14) Typical Experimental Procedure for the Fluoroolefins
The reaction mixture of fluorinated substrates (0.55 mmol),
aldehyde (0.5 mmol), Cs2CO3 (1 mmol) and MeCN (1.5 mL) was
stirred at 40 °C for the indicated time until complete consump-
tion of the starting material, which was monitored by TLC anal-
ysis (6–12 h). The solvents were removed by rotary evaporation
to provide raw products. The residue was then chromato-
graphed on silica gel (eluent: hexane–EtOAc), affording the
desired fluoroolefins.
(Z)-2-Fluoro-N-phenyl-3-[4-(trifluoromethyl)phenyl]acryl-
amide (5bg)
Colorless solid. 1H NMR (500 MHz, DMSO): δ = 10.47 (s, 1 H),
7.90 (d, J = 8.2 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.74 (d, J = 7.7
Hz, 2 H), 7.35 (t, J = 7.9 Hz, 2 H), 7.20–7.07 (m, 2 H). 19F NMR
(470 MHz, DMSO): δ = –61.30 (s), –121.52 (s). 13C NMR (126
MHz, DMSO): δ = 157.26 (d, J = 29.8 Hz), 50.89 (d, J = 281.5 Hz),
137.26 (s), 134.70 (s), 129.89 (d, J = 6.0 Hz), 128.52 (d, J = 32.1
Hz), 128.18 (s), 125.22 (s), 24.04 (s), 120.38 (s), 111.49 (s). MS
(EI): m/z = 309.10 [M+].
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 127–132

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