Copper-catalyzed decarboxylative trifluoroethylation of cinnamic acids

Article abstract of DOI:10.1016/j.tetlet.2017.01.060

An efficient Cu-catalyzed stereoselective trifluoroethylation through the decarboxylative cross-coupling of cinnamic acid derivatives with CF₃CH₂I is described. The ready availability of the starting materials, the high level of functional group tolerance, and excellent E selectivity make this protocol a safe and operationally convenient strategy for the efficient synthesis of trifluoroethyl derivatives.

Full text of DOI:10.1016/j.tetlet.2017.01.060

Accepted Manuscript
Copper-Catalyzed Decarboxylative Trifluoroethylation of Cinnamic acids
Yun Zhang, Hongli Du, Mingxiang Zhu, Jingya Li, Dapeng Zou, Yangjie Wu,
Yusheng Wu
PII:
S0040-4039(17)30091-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.060
TETL 48563
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 November 2016
16 January 2017
18 January 2017
Please cite this article as: Zhang, Y., Du, H., Zhu, M., Li, J., Zou, D., Wu, Y., Wu, Y., Copper-Catalyzed
Decarboxylative Trifluoroethylation of Cinnamic acids, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.01.060
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Copper-Catalyzed Decarboxylative
Trifluoroethylation of Cinnamic acids
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Yun Zhang, Hongli Du, Mingxiang Zhu, Jingya Li, Dapeng Zou*, Yangjie Wu*, Yusheng Wu*

1
Tetrahedron Letters
Copper-Catalyzed Decarboxylative Trifluoroethylation of Cinnamic acids
Yun Zhanga, Hongli Dua, Mingxiang Zhua, Jingya Lib,c, Dapeng Zoua,b, Yangjie Wua, Yusheng Wub,d
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, PR China.
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China.
c Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou, 450052, PR China.
d Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient Cu-catalyzed stereoselective trifluoroethylation through the decarboxylative cross-
coupling of cinnamic acid derivatives with CF3CH2I is described. The ready availability of the
starting materials, the high level of functional group tolerance, and excellent E selectivity make
this protocol a safe and operationally convenient strategy for the efficient synthesis of
trifluoroethyl derivatives.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoroethylation
Decarboxylative cross-coupling
Stereoselectivity
trifluoroethylation through copper-catalyzed decarboxylative
fluoroalkylation of cinnamic acids with CF3CH2I. To our delight,
it is the first report about decarboxylative cross-coupling reaction
between cinnamic acids and CF3CH2I.
Introduction
The incorporation of fluorinated moieties into organic molecules
can often result in profound and useful changes in their physical,
chemical, and biological properties.1 For example, the selective
incorporation of
a trifluoromethyl(CF3) group into drug
candidates often dramatically alters their stability, lipophilicity,
bioavailability and biopotency.2 Compounds containing the Csp2-
CF3 moiety have been shown to be useful fluorinated substituents
in the medicinal chemistry over the years(Figure 1).3 Hence, it
has been of great synthetic interest to develop efficient methods
for the incorporation of the CF3 group into organic molecules.
However, the amount of researches on trifluoroethylation has
been far less than that on trifluoromethylation. Currently, only a
limited number of methods are available.4 The first direct 2, 2, 2-
trifluoroethylation on iodobenzene, despite the low yield, was
reported in 1969.5 To date, the direct 2, 2, 2-trifluoroethylation
has been categorized into C(sp2-vinyl)-CH2CF36, C(sp2-aryl)-
CH2CF37, C(sp)-CH2CF38, and C(sp3)-CH2CF39 formations
through CF3CH2 radical or metal-mediated cross-coupling
processes.
Meanwhile, transition metal-catalyzed decarboxylative
trifluoromethylation is an attractive protocol for the synthesis of
Cvinyl-CF3. Hu,14 Liu,15 Maiti16 and Duan17 have reported
chronologically and independently the transition-metal-catalyzed
trifluoromethylation of α, β-unsaturated carboxylic acids. We
were interested in the synthesis of trifluoroethyl compounds7a,18
and trifluoroethyl aryl ethers19, as well as the fields of
decarboxylation coupling.20 Herein, we disclose our success in
Figure 1. Molecules containning the Cvinyl-CF3 moiety.
Results and Discussion
In the initial investigation, the reaction between CF3CH2I and
cinnamic acid (1a) was chosen as the model reaction to survey
the reaction conditions. Optimization with respect to bases,
solvents, catalysts and several additives were explored. The
results are summarized in Table 1.
Table 1. Copper-Catalyzed Decarboxylative Trifluoroethylation
of Cinnamic acid: Variation of Reaction Conditionsa
COOH
CH2CF3
[Cu] cat, additive, ligand
base, solvent, heat, time
ICH2CF3
+
developing
a
new powerful protocol for vinylic
 Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, zdp@zzu.edu.cn,
wyj@zzu.edu.cn

2
Tetrahedron
(entries 14-16). To find the matched cases of copper source and
Liga
nd
Additiv
e
Yield
(%) b
solvent, other solvents were tested. In the presence of Cu(OTf)2,
the tested solvents, including DMA, DMF, toluene, CH3CN and
1,4-dioxane, gave unsatisfactory results (entries 17-21).
Interestingly, the reaction could be carried out under air
atmosphere with a slightly lower yield (entry 22). Then, the
influence of reaction time and temperature was also studied
(entries 23, 28). Increasing temperature to 120 oC, the yields were
decreased. Moreover, the influence of the catalyst loading on the
reaction was studied (entries 24-25). Thus, the optimized
conditions was achieved through the combination of 0.4 mmol
cinnamic acid, 2 equiv CF3CH2I, 40 mol% Cu(OTf)2, 2 equiv
Ag2CO3, and 3 mL DMSO in the presence of Et3N at 80 °C under
Ar atmosphere for 24 h.
Entry
Base
Catalyst
Solvent
1
2
iPr2NH
Py
CuCl2
CuCl2
---
---
---
---
---
---
---
---
---
---
---
---
---
L1
L2
L3
---
---
---
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
---
trace
---
---
30
16
28
23
73
47
---
trace
---
40
41
49
9
3
Cs2CO3
NaOAc
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CuCl2
4
CuCl2
5
CuCl2
6
CuCO3
7
CuSO4
8
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
9
10
11
12
13
14
15
16
17
18
19
20
AgNO3
AgTFA
AgOTs
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Figure 2. The structure of bidentate nitrgen ligands.
With the optimized reaction conditions in hand, we turned our
attention to the substrate scope evaluation of the copper-
catalyzed decarboxylative trifluoroethylation of cinnamic acids
(Table 2). This catalytic strategy has good substrate
compatibility and show excellent chemoselectivity. A series of
substituted cinnamic acids readily underwent decarboxylative
coupling with CF3CH2I to get the corresponding products in
moderate yields. For examples, halogen-containing cinnamic acid
derivatives afforded the desired products with yields ranging
from 55% to 61% (entries 2-6). It is noteworthy that cinnamic
acid carrying chloride atom at different positions on the phenyl
ring had little influence on the efficiency of the reaction (entries
3-5). While cinnamic acid derivatives with electron-donating
substituents (Me, MeO, OH, Me2N) provided the desired
products with yields ranging from 41% to 44% (entries 7-10).
Electron-poor cinnamic acids (entries 11-13) underwent the
decarboxylation to afford uncomfortable yields. Di-chloro
cinnamic acids and tri-methoxy cinnamic acids could also
successfully participate in the coupling reaction (entries 15-16).
3-(1-Naphthyl)acrylic acid reacted with CF3CH2I efficiently to
give the desired product in 40% yield. All the above used
cinnamic acids were trans type. When cis-2-methoxycinnamic
acid was used under these reaction conditions, the trans-isomer
was obtained in 37% yield (entry 18).
DMF
8
Toluene
9
1,4-
Dioxane
Et3N
Cu(OTf)2
---
Ag2CO3
10
21
22c
23d
24e
25f
26
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
---
---
---
---
---
---
---
---
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
---
42
57
58
29
7
27
---
60
28g
a
Reactions were performed with 0.4 mmol of cinnamic acid, 2 equiv of
CF3CH2I, 40 mol% of catalyst, 2 equiv of base, 2 equiv of additive, 20 mol%
ligand, 3 mL of solvent at 80 °C for 24 h under Ar atmosphere. b Yield was
determined by GC-MS using Di-N-pentyl phthalate as the internal standard. c
The reaction was performed under air. d The reaction was performed for 12 h
under Ar. e The reaction was conducted on a 20 mol% catalyst. f The reaction
Plausible catalytic cycle
Based on previous literature reports and our studied results,21
we proposed a plausible catalytic cycle (Figure 3). With the help
of silver salt, CF3CH2I produced the CF3CH2+ (A). The acrylic
acid reacted with copper salts to form the cupric cinnamate B. A
attacked the α-position of the double bond in cupric cinnamate B
to give a steady intermediate C. After elimination of carbon
dioxide and Cu(I) from C, the desired product was obtained.
Then Cu(I) was oxidized by Ag(I) in the presence of cinnamid
acid to get the cupric cinnamate B and complete the catalytic
cycle.
g
was conducted on a 50 mol% catalyst. The reaction was performed at
100 °C.
Initial studies in the presence of 40 mol% CuCl2, Ag2CO3 (2
equiv) and DMSO (3 mL) (entries 1-5) showed that Et3N
effectively facilitated the reaction and 30% of the desired product
was obtained. To our delight, it is no Z-isomer was detected
under these reaction conditions. Next, the influence of different
copper sources on the reaction was examined (Table 1, entries 5-
9) and Cu(OTf)2 was found to be the most effective one to afford
the desired product in 73% yield (entry 9). According to the
above conditions, a series of silver salts were also investigated.
Compared with Ag2O, AgNO3, AgTFA and AgOTs, Ag2CO3 was
the most effective additive for the cross-coupling reaction
(entries 9-13). The effect of ligands on the cross-coupling
reaction were then investigated. The combination of Cu(OTf)2
with different ligands (Figure 2) gave inferior yields.
Table 2. Scope of Cinnamic acids with CF3CH2Ia

3
a Reactions were performed with cinnamic acids (0.4 mmol), CF3CH2I (2
equiv), Cu(OTf)2 (40 mol%), Ag2CO3 (2 equiv), Et3N (2 equiv), DMSO (3
mL) at 80 °C for 24 h under Ar atmosphere. b Isolated yields.
Figure 3. Proposed Cu-Catalyzed Reaction
Conclusion
In conclusion, we provides a new, stereoselective strategy for the
incorporation of trifluoroethyl into α, β-unsaturated carboxylic
acids containing structures by using decarboxylative cross-
coupling reaction of various cinnamic acid derivatives with
CF3CH2I. From a synthetic standpoint, this transformation is
simple and efficient for incorporating the trifluoroethyl moiety
into target structures. Moreover, this new and unusual simple
strategy for the simultaneous incorporation of CH2CF3
functionalities is also of important due to increasing interest in
fluoroorganic compounds.
Acknowledgments
We are grateful to the Natural Science Foundation of China
(21172200), Research Program of Fundamental and Advanced
Technology of Henan Province (122300413203), and
Technology Research and Development Funds of Zhengzhou
(141PRCYY516) for financial support.
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5
Highlights
. Copper catalysized decarboxylative cross-
coupling
. One step to make trifluoroethyl alkenes
. Mild reaction conditions with modest to good
yields