Copper-catalyzed Di- and trifluoromethylation of α,β-unsaturated carboxylic acids: A protocol for vinylic fluoroalkylations

Article abstract of DOI:10.1002/anie.201200140

Dual action: The Lewis acid CuF₂·2 H₂O efficiently catalyzes the reaction between electrophilic fluoroalkylating agents and α,β-unsaturated carboxylic acids by dually activating both reactants, thus affording di- and trifluoromethyl alkenes in high yields with excellent E/Z selectivity. Copyright

Full text of DOI:10.1002/anie.201200140

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DOI: 10.1002/anie.201200140
Synthetic Methods
Copper-Catalyzed Di- and Trifluoromethylation of a,b-Unsaturated
Carboxylic Acids: A Protocol for Vinylic Fluoroalkylations**
Zhengbiao He, Tao Luo, Mingyou Hu, Yanjing Cao, and Jinbo Hu*
The incorporation of fluorinated moieties into organic
molecules can often result in profound and useful changes
in their physical, chemical, and biological properties.[1] In
medicinal chemistry, for example, the selective incorporation
of a trifluoromethyl (CF3) or difluoromethyl (CF2H) group
into drug candidates often dramatically alters their stability,
lipophilicity, bioavailability, and biopotency.[2] Hence, it has
been of great synthetic interest to develop efficient methods
for the incorporation of the CF3 or CF2H group into organic
molecules. However, although a variety of processes for the
Carboxylic acids are ubiquitous compounds in organic
chemistry, which are commercially available in a large
variety.[9] Recently, carboxylic acids have been frequently
used as attractive reactants for metal-catalyzed decarboxyla-
tive C C cross-coupling reactions.[9–11] However, to the best of
ꢀ
our knowledge, selective fluoroalkylation (such as di- and
trifluoromethylation) of nonfluorinated carboxylic acids with
fluoroalkylating agents through a decarboxylative fluoro-
alkylation protocol has never been reported [Eq. (3)]. Herein,
we disclose our success in developing a new powerful protocol
for vinylic di- and trifluoromethylation through the copper-
catalyzed decarboxylative fluoroalkylation of a,b-unsatu-
rated carboxylic acids with a Togni-type electrophilic fluoro-
alkylating agent[12,13] [Eq. (3)].
ꢀ
ꢀ
construction of Csp3 CF3 (or Csp3 CF2H) bonds have been
developed,[3] there are fewer processes for the construction of
ꢀ
ꢀ
Csp2 CF3 (or Csp2 CF2H) bonds. Currently, the reaction
between an aryl (or vinyl) halide and a stoichiometric
amount of a CF3Cu reagent represents the most widely used
method for the construction of Csp2 CF3 bonds,[4] yet a similar
ꢀ
ꢀ
process for Csp2 CF2H bond formation has been challenging
owing to the thermal instability of (CF2H)Cu species.[5] In
addition, the past three years has witnessed rapid advances in
copper- and palladium-catalyzed trifluoromethylation reac-
[4,6,7]
ꢀ
tions for the construction of Caryl CF3 bonds.
transition-metal-catalyzed trifluoromethylations for the
However,
ꢀ
direct construction of Cvinyl CF3 bonds have not been well
developed. Recently, the groups of Liu and Shen reported
copper(I)-catalyzed reaction of vinylboronic acids with elec-
trophilic trifluoromethylation reagents [Eq. (1)],[6f,g] and Cho
and Buchwald reported a palladium(0)-catalyzed trifluoro-
methylation of cyclohexenyl sulfonates with nucleophilic
trifluoromethylation reagents [Eq. (2)].[8] However, the pro-
cess by Liu and Shen produces a mixture of trifluoromethy-
lated alkene stereoisomers,[6f,g] and the process by Cho and
Buchwald was shown to be effective only with six-memberd
cyclohexenyl sulfonates.[8] Furthermore, to the best of our
At the onset of our investigation, we chose the reaction
between the IIII-CF2SO2Ph reagent (1a) and 3,3-diphenyl-
acrylic acid (2a) as a model reaction to survey the reaction
conditions, thus taking advantage of the ready availability of
1a in our group.[13] As shown in Table 1, when CuF2·2H2O was
used as the catalyst, it was found that both solvent and
temperature were crucial for the reaction. It is particularly
interesting that the addition of water as a cosolvent and
tetramethylethylenediamine (TMEDA) as an additive can
significantly increase the yield of the product, and the ratio of
the mixed solvents also influences the yield (entries 1–4 and
11–15). Lowering the amount of the catalyst and the reaction
temperature decreases the yield (entries 9, 10, 12, and 16).
Finally, the optimal yield of product 3a (73%) was obtained
when 1a and 2a (molar ratio 1:3.0) were stirred in H2O/DCE
(4:3) in the presence of CuF2·2H2O (20 mol%) and TMEDA
(25 mol%) at 808C for 12 hours (entry 12).
ꢀ
knowledge, the metal-catalyzed construction of Cvinyl CF2R
(R ¼ F) bonds has never been reported. Therefore, an
efficient and general protocol for the catalytic di- and
trifluoromethylations of vinylic carbon atoms is highly
desired.
[*] Z. He, T. Luo, M. Hu, Y. Cao, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai, 200032 (China)
E-mail: jinbohu@sioc.ac.cn
[**] Support of our work by the National Natural Science Foundation of
China (20825209, 20832008) and the National Basic Research
Program of China (2012CB215500) is gratefully acknowledged.
By using the optimized reaction conditions (Table 1,
entry 12), we next examined the substrate scope of the
present copper-catalyzed decarboxylative fluoroalkylation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200140.
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Table 1: Survey of reaction conditions.
Table 2: (Phenylsulfonyl)difluoromethylation of a,b-unsaturated carbox-
ylic acids 2 with reagent 1a.[a,b]
Entry Equiv Solvent[a]
Equiv
Equiv
T
Yield
2a
CuF2·2H2O TMEDA [8C] [%][b]
1
2
3
4
2.0
2.0
2.0
2.0
1,4-dioxane
DME
H2O/DME (1:4)
H2O/1,4-dioxane
(1:4)
0.20
0.20
0.20
0.20
–
–
–
–
80
80
80
80
10
15
20
25
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
H2O/CH3CN (1:4)
H2O/DMF (1:4)
H2O/CCl4 (2:3)
H2O/DCE (2:3)
H2O/DCE (2:3)
H2O/DCE (2:3)
H2O/DCE (2:3)
H2O/DCE (4:3)
H2O/DCE (4:1)
H2O/DCE (1:4)
DCE
0.20
0.20
0.20
0.20
0.20
0.05
0.20
0.20
0.20
0.20
0.20
0.20
0.30
0.20
–
–
–
–
80
31
80 trace
80
80
80
80
80
80
80
80
80
50
80
80
35
43
61
52
65
73
61
57
52
51
60
62
9
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.40
10
11
12
13
14
15
16
17
18
H2O/DCE (4:3)
H2O/DCE (4:3)
H2O/DCE (4:3)
[a] The data in the parentheses refer to the volume ratio. [b] Determined
by 19F NMR spectroscopy using PhCF3 as an internal standard.
DCE=1,2-dichloromethane, DME=1,2-dimethoxyethane, DMF=N,N’-
dimethylformamide, TMEDA=N,N,N’,N’-tetramethylethylendiamine.
reaction. The results are summarized in Table 2. The reaction
proved to be general and amenable to a range of structurally
diverse substrates (2a–t, all with an E configuration), and the
desired products 3a–t were produced in satisfactory yields.
We found that both electron-rich and electron-deficient aryl-
substituted acids reacted with 1a to give products such as 3b–j
in excellent yields. Furthermore, heteroaryl-substituted a,b-
unsaturated carboxylic acids are also viable substrates in the
current reaction, thus giving the corresponding heteroaryl-
substituted alkenes (3k, 3l, 3m, and 3r). It is worthwhile
mentioning that the alkyl-substituted a,b-unsaturated car-
boxylic acid 2t was also found to react smoothly with 1a to
give the corresponding product 3t in good yield. Notably, the
reactions were found to be highly stereoselective, with only
the E isomer of the product being observed in each case
(Table 2). Since the (phenylsulfonyl)difluoromethyl group is
a versatile functionality that can be readily transformed into
the difluoromethyl (CF2H) group,[14] the present synthetic
[a] A mixture of 1a (0.6 mmol), 2 (1.8 mmol), CuF2·2H2O (0.12 mmol,
ca. 20 mol%), TMEDA (0.15 mmol, ca. 25 mol%), DCE (3 mL), H2O
(4 mL) was stirred at 808C for 12 h. [b] Yield of isolated product.
Table 3. It was found that, the trifluoromethylation of a,b-
unsaturated carboxylic acids 4 (all with an E configuration)
bearing electron-rich aryl substituents proceeded smoothly to
afford the corresponding CF3-containing products 5 in
moderate to good yields. The reactions with electron-deficient
substrates, however, gave lower yields of product (Table 3).
Notably, the trifluoromethylation reaction was also found to
be stereoselective, with the CF3-functionalized alkenes 5a–k
being formed with an E/Z ratio ranging from 92:8 to greater
than 99:1 (Table 3). The major E isomers of the products 5a–
k could be purified by silica gel chromatography.
To gain some mechanistic insights into the current
decarboxylative fluoroalkylation reaction, two sets of com-
parative experiments were designed (Scheme 1). Firstly, while
the reaction between 1a and carboxylic acid 2s gave the
desired product 3s in 65% yield, a similar reaction between
1a and (E)-trimethyl(styryl)silane (6) did not furnish the
ꢀ
method opens up a new avenue for the construction of Cvinyl
CF2H bonds.
Encouraged by the aforementioned (phenysulfonyl)-
difluoromethylation reactions, we extended the reaction to
trifluoromethylation by using Togniꢀs reagent 1b.[12] After
a quick scanning of the reaction conditions (see Table S-1 in
the Supporting Information), we found that under similar
reaction conditions, the reactivity of reagent 1b was some-
what different from that of 1a. Consequently, we modified the
reactant ratio to 4/1b = 4:1. The data are summarized in
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Table 3: Trifluoromethylation of a,b-unsaturated carboxylic acids 4 with
reagent 1b.[a,b,c]
Scheme 1. The importance of both the carboxylic acid functionality and
Togni-type reagents for the reaction.
[a] A mixture of 1b (0.8 mmol), 4 (3.2 mmol), CuF2·2H2O (0.16 mmol,
ca. 20 mol%), 1,4-dioxane (4 mL), H2O (1 mL) was stirred at 808C for
12 h. [b] Yield of isolated E isomer of the product. [c] E/Z ratio was
determined by 19F NMR spectroscopy of the crude product mixture.
and the iodonium ion to afford the intermediate C. The
intermediate C then undergoes decarboxylation[16] to give the
thermodynamically stable E-alkene intermediate D, which
undergoes reductive elimination to generate the species E
product 3s. In contrast, the reaction between 1a and styrene
did not deliver the fluoroalkylated product 8. These results
indicate that the presence of a carboxylic acid
group in substrates plays an important role for
F
the success of the efficient C R (RF = fluori-
ꢀ
nated alkyl groups) formation reaction. Sec-
ondly, as mentioned shown Table 3, carboxylic
acid 4e readily reacted with Togniꢀs reagent 1b
to give the corresponding CF3-containing prod-
uct 5e in 70% yield. However, when we replaced
the Togniꢀs reagent 1b with another electrophilic
trifluoromethylating agent,
9
(Umemoto
reagent),[15] the formation of the desired product
5e was not observed, which suggests that the use
of Togni-type reagents 1a,b is important to the
success of current decarboxylative fluoroalkyla-
tion reaction.
Based on the experimental results, we pro-
pose a plausible reaction mechanism for the
current copper-catalyzed decarboxylative fluoro-
alkylations (Scheme 2). The hypervalent iodine
reagent 1a should undergo a copper-catalyzed
bond cleavage to generate the highly electro-
philic iodonium salt A, which then coordinates to
the carboxylic acid functionality to generate the
intermediate B. B then undergoes an intramo-
lecular reaction between the alkene functionality Scheme 2. Proposed reaction mechanism.
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In summary, we have developed a new strategy for the
F
ꢀ
vinylic C R bond formation, that is, Lewis acid catalyzed di-
and trifluoromethylation of a,b-unsaturated carboxylic acids
through decarboxylative fluoroalkylation. A wide range of
a,b-unsaturated carboxylic acids (including alkyl- and aryl-
substituted ones) were subjected to the present reaction
conditions and furnished the corresponding di- and trifluor-
omethylated alkenes in high yields and with excellent E/Z
selectivity. The Lewis acid (CuF2·2H2O) was found to play an
important role in the reaction by both enhancing the electro-
philicity of Togni-type reagents and promoting the decarbox-
ylation of a,b-unsaturated carboxylic acids.
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Keywords: carboxylic acids · copper · fluorine · stereoselectivity ·
synthetic methods
.
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