F--Free Deoxyhydrotrifluoromethylation of α-Keto Esters with Ph3P+CF2CO2-: Synthesis of α-CF3-Substituted Esters

Article abstract of DOI:10.1021/acs.joc.0c01518

Trifluoromethylated compounds are usually obtained via trifluoromethylation reaction by the use of CF3SiMe3 and NaSO2CF3, Umemoto's and Togni's reagents. Here, an external fluorine anion-free direct deoxyhydrotrifluoromethylation of α-keto esters with a d

Full text of DOI:10.1021/acs.joc.0c01518

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Article
F-Free Deoxyhydrotrifluoromethylation of #-Keto Esters
with Ph3P+CF2CO2-: Synthesis of #-CF3-Substituted Esters
Ying Zheng, Yimin Jia, Yuan Yuan, Zhong-Xing Jiang, and Zhigang Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01518 • Publication Date (Web): 21 Jul 2020
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The Journal of Organic Chemistry
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F--Free Deoxyhydrotrifluoromethylation of α-Keto Esters
-
with Ph3P+CF2CO2 : Synthesis of α-CF3-Substituted Esters
Ying Zheng, Yimin Jia, Yuan Yuan, Zhong-Xing Jiang,* and Zhigang Yang*
Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, School
of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
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Prof. Zhong-Xing Jiang, E-mail: zxjiang@whu.edu.cn.
Prof. Zhigang Yang, E-mail: zgyang@whu.edu.cn.
Table of Contents Graphic
CF3
R1
CO2R2
O
H2O
Ph3P+CF2COO-
R1
CO2R2
+
DMSO
60 oC
R1 = Ar, Alkyl, Alkenyl
-

no external F

late-stage functionalization
ABSTRACT
Trifluoromethylated compounds are usually obtained via trifluoromethylation reaction by use of
CF3SiMe3, NaSO2CF3, Umemoto’s and Togni’s reagent. Here, an external fluorine anion-free direct
deoxyhydrotrifluoromethylation of α-keto esters with a difluoromethylating reagent has been achieved
in which the employment of water can promote the dissociation of CF2 group to form CF3 moiety, which
provides the successful transformation. The current protocol demonstrates one of the most practical
approaches to generate α-trifluoromethyl esters with a broad substrate scope and high functional group
compatibility, in which it is applicable to late-stage modification of biologically active compounds and
can be readily scaled up. Mechanistic investigation reveals that an in situ generated gem-difluoroalkene
intermediate is decomposed by water, giving rise to acid fluoride and HF.
INTRODUCTION
Trifluoromethyl (CF3) containing organic compounds do not exist in natural products.1 The
development of efficient synthetic methodologies for the incorporation of CF3 group into organic
molecules has received more attention in recent years.2 Owing to its unique physical, chemical and
biological properties, CF3 group can substantially alter an organic molecule’s lipophilicity, metabolic
stability and ability to cross the blood-brain barrier, trifluoromethylated compounds have found wide
application in the medicinal, pharmaceutical, agricultural, and material sciences.3
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Although significant advancements in this field have been made in the direct introduction of CF3
group into organic moieties, such as nucleophilic, electrophilic, and free radical reactions,2 the methods
for the synthesis of functionalized α-trifluoromethylated carboxylic acid esters is still relatively
limited.6-11 In addition, α-trifluoromethylated carboxylic acids, which have been identified as bioactive
compounds4 and versatile intermediates5 in synthetic chemistry. To this end, a few elegant work showed
that the synthesis of α-CF3 esters could be achieved by the reaction of ester derivatives,6 α-diazo esters7
and sensitive ketene silyl acetals8 with Togni’s reagent,9 Umemoto’s reagent,6a,10 CF3I and TMSCF3
(Scheme 1a). Most of these methods required highly activated substrates such as β-keto esters, α-nitro
esters or silyl enol ethers, catalyst and/or excess base. Consequently, the substrate scope and practicality
of such methodologies are limited.
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Scheme 1. Direct Trifluoromethylation for the Synthesis of α-CF3 Esters
CF
3 reagent
(a) Traditional routes: from
O
R1
[CF ]
Electrophilic
3
OR
H/Cl
N2
CF3
CO2R
TMSCF
CuI,
3
R1
R1
R1
CO2R
OSi
Togni reagent
OR
(b) This work:
CF
2 reagent
from
H2O (1.0 equiv)
CF3
CO2R
CF3
CO2R
O
Ph3P+CF2COO-
or
R1
CO2R
Ar
R2
DMSO, 60 oC
More recently, Kobayashi and co-workers11 have developed an alternative approach to access α-
trifluoromethyl esters or acids through fluorocarboxylation of gem-difluoroalkenes. However, this
version requires stoichiometric quantities of CsF for constructing CF3 group from difluoroalkene and
the use of high pressure CO2 as starting materials, which impedes its wide applications. Therefore, it is
still of great demand to develop a practical, more convenient and suitable method for large-scale
preparation procedure for the synthesis of α-CF3 esters with wide functional group compatibility. Given
the widespread availability of difluoromethylating reagents, we wondered whether the formation of α-
CF3 esters from a difluoromethylating reagent should proceed in a practical and sustainable fashion
under neutral conditions without the presence of a catalyst. There are many methods that have reported
gem-difluoroalkene which can be served as an alternative CF3 precursor. However, an additional
fluoride anion reagent, such as Et3N.HF, KF, CsF, AgF, or Bu4NF is necessary in order to construct a
trifluoromethyl moiety.11-12 Currently, various types of difluoromethylating reagents, especially that
serve as the difluorocarbene precursors, have been developed and their reactivity towards different
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nucleophiles and electrophiles studied.13 It is step- and atom-economy if a CF3 group is formed directly
from a difluoromethylating reagent without an extra fluoride anion reagent. Herein, we describe a novel
and catalyst-free process for the synthesis of functionalized α-trifluoromethyl esters through
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3
4
5
6
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deoxyhydrotrifluoromethylation of α-keto esters, in which a difluoromethylating reagent Ph3P+CF2CO2
14 is the sole CF3 source (Scheme 1b).
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Scheme 2. Initial Trials with Different Difluoromethy-lating Reagent
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F
F
CF3
R
CO2Me
O
[CF2]
+
R
CO2Me
R
CO2Me
DMSO, 60 oC, 1 h
1a
2a
3a
R = styryl
[CF2]
2a
3a
(%)
(%)
0
0
0
0
HCF2Cl/PPh3
ClCF2CO2Na/PPh3
Ph3P+CF2CO2
trace
17
-
With our continued interests on the development of fluoroalkylation based on difunctionalization
strategy,15 we began our investigation of this transformation by attempting the
deoxyhydrotrifluoromethylation of trans-methyl 2-oxo-4-phenylbut-3-enoate 1a. According to previous
reports, the treatment of aldehydes and ketones with typical difluorocarbene precursors, such as
-
ClCF2H, ClCF2COONa, Ph3P+CF2CO2 , etc, gem-difluoroalkenes could be readily formed in the
absence of an additional fluoride anion reagent.14a,14b,16 Obviously, a key challenge for such process is to
avoid the reaction progress terminated at gem-difluoroalkene. Initially, when ClCF2H /PPh3,
-
ClCF2COONa/PPh3 or Ph3P+CF2CO2 were employed as difluoromethylating reagent and react with 1a
in dimethyl sulfoxide (DMSO) at 60 oC under an argon atmosphere for 1 h (Scheme 2). Surprisingly, no
gem-difluoroalkene could be detected by 19F NMR spectroscopy. The desired trifluoromethylated
product 3a was observed in 17% yield from Ph3P+CF2CO2 . Encouraged by these preliminary results,
-
several other commonly difluoromethylating reagents such as BrCF2PO(OEt)2/tBuOK, BrCF2COOK,
BrCF2COOEt and TMSCF2Br were also investigated, however, no fluorinated products were observed
except for the complex reaction system.
Interestingly, when 1.0 equiv of water was added, the yield of the expected product 3a was
increased significantly to 98% (85% yield was isolated, Table 1, entry 1). Decreasing or increasing the
amount of water reduced the yields of product to 78% and 86%, respectively (Table 1, entries 2-3).
When the other protonic additives such as MeOH, EtOH, and iPrOH were employed instead of water,
the expected reaction could also take place, albeit in lower yields (Table 1, entries 4-6). The product 3a
almost could not be obtained when relatively strong acidic additive AcOH was used (Table 1, entry 7).
The results indicate that the efficiency of trifluoromethylation depends on the additive, with an
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appropriate acidity. Then, several other solvents such as toluene, MeCN, THF, CH2Cl2, EtOAc, and
DMF were screened (Table 1, entries 8-13), but the yield of 3a was less than 63%. Finally, when the
reaction was carried out at room temperature, 3a was observed in less than 5% yield (Table 1, entry 14).
It is noteworthy that the gem-difluoroalkene 2a was not observed in all these conditions.
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Table 1. Investigation of the Reaction Conditionsa
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CF3
CO2Me
O
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60
H2O (1.0 equiv)
DMSO, 60 oC, 1 h
+ Ph3P+CF2COO-
Ph
CO2Me
Ph
1a
3a
entry
yield (%)b
deviation from the standard conditions
1
none
98 (85)c
78
2
0.5 equiv H2O
3
3.0 equiv H2O
86
4
MeOH instead of H2O
EtOH instead of H2O
iPrOH instead of H2O
AcOH instead of H2O
toluene as the solvent
MeCN as the solvent
THF as the solvent
CH2Cl2 as the solvent
EtOAc as the solvent
DMF as the solvent
the reaction was carried out at rt
56
5
73
6
82
7
12
8
<5
51
9
10
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27
18
44
62
<5
aReaction conditions: 1a (0.1 mmol), Ph3P+CF2CO2 (2.0 equiv) and H2O (1.0
equiv) in DMSO (1.0 mL) at 60 oC (oil bath) for 1 h. bYields determined by 19
-
F
c
NMR spectroscopy using trifluorotoluene as an internal standard. The yield is
for the isolated and purified product 3a.
With the optimized conditions in hand (Table 1, entry 1), the generality of the transformation was
examined with respect to different alkenyl-substituted α-keto esters (Scheme 3). This reaction system
was not sensitive to the steric hindrance of the ester group adjacent to the ketone carbon, and changing
from the methyl to ethyl and even functional polyethylene glycol (PEG) esters caused no drop in the
yields of the corresponding products (3a-d, 77-84%). Subsequently, α-keto esters substrates bearing
aromatic rings substituted with an electron-donating (OMe) or electron-withdrawing group (Cl, Br) on
the ortho-, para-, or meta-position were investigated, leading to the expected pruducts 3e-i in good
yields. Substrate with a fused ring (1j, R = 2-naphthyl) worked smoothly, providing product 3j in 78%
yield. For furan and thiophene-derived α-keto esters, desired products 3k-l were obtained in 65% yields.
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It is worth noting that substrate containing a diene moiety was compatible with the current reaction
protocol (3m). Substrate bearing two substituents at the aromatic ring of the styrene (1n) was also
converted into α-CF3 ester efficiently. Significantly, when an aliphatic alkene was combined in the α-
keto ester and subjected to the standard reaction conditions, a high yield was provided (3o).
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Scheme 3. Substrate Scope of Alkenyl-substituted α-Keto Estersa
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CF3
CO2R'
O
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H2O (1.0 equiv)
DMSO, 60 oC, 1 h
+ Ph3P+CF2COO-
R
CO2R'
R
1
3
3a
, R' = Me, 79%
3b
, R' = Et, 78%
3c
, R' = (CH2CH2O)2Me, 84%
3d
, R' = (CH2CH2O)4Bn, 77%
CF3
CO2Me
R
CF3
CO2R'
Ph
3e
3f
, R = Cl, 72%
, R = Br, 58%
CF3
CO2Me
CF3
3g
3h
, R = OMe, 79%
, R = Br, 69%
O
CO2Me
R
R
3i
, 78%
CF3
CO2Me
CF3
CF3
CO2Me
CO2Me
Ph
x
3k
3m
, 69%
3j
, x = O, 65%
, R = 2-naphthyl, 78%
3l
, x = S, 65%
CF3
CF3
O
CO2Me
CO2Me
O
3n
, 79%
3o
, 71%
aReaction conditions: 1 (0.5 mmol), Ph3P+CF2CO2 (2.0 equiv) and H2O (1.0
-
o
equiv) in DMSO (5.0 mL) at 60 C (oil bath) for 1 h. Yields are for the
isolated products 3. Yield of the isolated and purified product
Inspired by the above results, we turned our attention to the unique reactivity of α-keto esters and
performed some further experiments by utilizing different aryl-substituted α-keto esters (Scheme 4). The
electronic property, positional change (para- or meta-) of the aromatic ring, and steric bulk of the esters
did not have much impact on reaction efficiency, the products 5a-h were afforded in good yields. It
should be noted that substrates 4i-j bearing fused ring moiety were tolerable with the reaction
procedure. Heteroaryl α-keto ester 4k is tolerated under the similar reaction conditions, albeit in a lower
yield (36%). When an alkyl α-keto ester methyl 2-oxopropanoate was examined, the corresponding
product was observed in 47% yield by 19F NMR spectroscopy. Unfortunately, the product is difficult to
isolate from relatively complicated reaction system, even purification of it 4 times through the silica gel
column. The synthetic utility of this protocol was further investigated by late-stage
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Scheme 4. Substrate Scope of Aryl-substituted α-Keto Estersa
1
2
3
4
5
CF3
O
H2O (1.0 equiv)
DMSO, 60 oC, 12 h
+
Ph3P+CF2COO-
Ar
CO2R
Ar
CO2R
4
5
6
7
8
9
CF3
CF3
CF3
CO2Ph
CO2Ph
CO2Ph
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Me
MeO
5a
, 75%
5b
, 78%
5c
, 73%
CF3
CF3
CF3
CO2Ph
CO2Ph
CO2Ph
F
Cl
Br
5d
5g
5f
, 68%
, 67%
, 76%
, 82%
5e
5h
, 68%
CF3
CF3
CF3
CO2Bn
CO2Ph
CO2Ph
5i
, 76%
, 74%
CF3
CF3
CO2Me
CO2Ph
S
5k
, 36%
5j
Late-stage deoxyhydrotrifluoromethylation of complex molecules
CF3
CF3
iPr
R
O
O
O
n
O
O
iPr
5l
, n = 2 , R = Me, 67%
5m
, n = 4 , R = Bn, 72%
(from polyethylene glycol)
5n
, 75%
(from propofol)
CF3
CF3
O
CO2Me
O
CO2Me
O
Ph
O
CO2Me
, 59%, d.r. = 1:1
5o
, 71%, d.r. = 1:1
5p
(from malic acid)
(from mandelic acid)
O
OAc
OAc
O
O
O
AcO
AcO
CF3
CF3
O
O
O
O
O
O
5q
, 52%, d.r. = 1:1
5r
, 72%, d.r. = 56:44
(from glucose)
(from mannose)
aReaction conditions: 4 (0.5 mmol), Ph3P+CF2CO2 (3.0 equiv) and H2O (1.0
-
o
equiv) in DMSO (5.0 mL) at 60 C (oil bath) for 12 h. Yields are for the
isolated products 5. Diastereomeric ratio was determined by 1H NMR and 19
F
NMR analysis of the crude product.
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deoxyhydrotrifluoromethylation of complex molecules. Polyethylene glycols (PEGs),17 which are
water-soluble, nontoxic, and biocompatible polymers with widely applications, were included to
subsrates and subjected to the deoxyhydrotrifluoromethylation, the reactions proceeded smoothly to
generate desired products 5l-m in 67-72% yields. Substrate 4n derivatived from propofol,18 a widely
used intravenous anesthetic in clinical practice, gave the resulting product 5n in 75% yield. Mandelic
acid19 and malic acid20 derivatives 4o-p were readily transformed to the corresponding functionalized α-
CF3 ester 5o-p in moderate to good yields. Lastly, glycosyl containing α-keto esters 4q-r prepared from
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glucose21 and mannose,22 respectively, could successfully react with Ph3P+CF2CO2 , led to the
glycosylated products 5q-r in 52-72% yields and approximate 1:1 dr. However, probably because of
high volatility of some products, relatively low yields were obtained in these cases.
To further demonstrate the practical advantage of the current deoxyhydrotrifluoromethylation, a
gram-scale reaction for the preparation of 5a was conducted. The reaction proceeded smoothly under
the optimal reaction conditions, the resulting product was achieved without significant drop in the yield
(69%, Scheme 5a). Encouraged by this result, we intended to apply this methodology to construct the
trifluorinated analogue of Naproxen, which is a regularly used drug for the treatment of joint swelling,
pain, and inflammation through inhibiting the action of cyclooxygenase involved in the production of
prostaglandins. With this impression in mind, conducting the deoxyhydrotrifluoromethylation of α-keto
ester 4s on larger scale, 1.02 g of the desired α-CF3 ester 5s was furnished. Subsequently, the
trifluorinated Naproxen 6 was formed in 87% yield by reduction of 5s with Pd/C (Scheme 5b).
Scheme 5. Gram-scale Synthesis and Construction of Trifluoromethylated Naproxen
(a) Gram-scale experiment
CF3
CO2Ph
O
H2O (1.0 equiv)
DMSO, 60 oC, 12 h
+ Ph3P+CF2COO-
CO2Ph
5a
4a
, 4.4 mmol, 1.00 g
, 0.86 g, 69%
(b) Practical construction of Naproxen analogue
CF3
O
H2O (1.0 equiv)
Ph3P+CF2COO-
CO2Bn
CO2Bn
DMSO, 60 oC, 12 h
MeO
MeO
58%
4s
, 4.7 mmol, 1.50 g
5s
, 1.02 g
CF3
CO2H
Pd/C, H2
THF
87%
MeO
6
, 0.67 g
trifluorinated Naproxen
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A series of additional experiments were conducted to gain insights into the reaction mechanism
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3
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(Scheme 6). Interestingly, we analysed the reaction of 4a with Ph3P+CF2CO2 under standard reaction
conditions and found that a large amount of Ph3PO was observed (Scheme 6a). It indicates that a Wittig
reaction may be occuring during the trifluoromethylation process and produced a gem-difluoroalkene as
the key intermediate. Then, a gem-difluoroalkene 7 was synthesized and subjected to standard
conditions, providing the corresponding α-CF3 ester 8 in 82% yield, which confirms our speculation. In
the meantime, the resulting α-CF3 ester 8 was also detected in 62% yield in the absence of
4
5
6
7
8
9
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60
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Ph3P+CF2CO2 (Scheme 6b). These results clearly show that the CF3 group on the products may come
from the hydrolysis of gem-difluoroalkenes. Treatment of gem-difluoroalkene 7 with NaOH in methanol
at room temperature, malonate 9 was detected in the reaction mixture by HRMS (Scheme 6c). A similar
malonate 10 was also afforded when the product 5a was used under the same conditions, demonstrating
that the CF3 group of alkyl is unstable under strongly basic conditions (Scheme 6d).
Scheme 6. Preliminary Mechanistic Exploration
H2O (1.0 equiv)
CF3
CO2Ph
O
Ph3P+CF2COO-
(a)
(b)
Ph3PO
(83%)
+
Ph
CO2Ph
Ph
DMSO, 60 oC, 12 h
4a
5a
, 81%
with or without
Ph3P+CF2COO-
CF3
CO2Me
F
F
Ph
DMSO, 60 oC, 12 h
H2O (1.0 equiv)
Ph
CO2Me
7
8
with Ph3P+CF2COO-, 82%
without Ph3P+CF2COO-, 62%
F
F
COOMe
NaOH
(c)
(d)
Ph
CO2Me
Ph
COOMe
MeOH, rt, 3 h
H2O (1.0 equiv)
7
9
(determined by HRMS)
CF3
CO2Ph
COOMe
NaOH
Ph
Ph
COOPh
10
, 48%
MeOH, rt, 3 h
H2O (1.0 equiv)
5a
In light of above experimental results and literature reports,14 a possible mechanism is described
-
(Scheme 7). Initially, Ph3P+CF2CO2 can easily undergo a thermal decarboxylation to furnish the
phosphonium ylide (Ph3P=CF2), which further reacts with α-keto ester 4t results in the formation of
gem-difluoroalkene 7 via a Wittig reaction. The species A could be obtained after the hydrolysis of gem-
difluoroalkene. Subsequently, the elimination of HF from species A generated the enolate intermediate
B, which could be further converted to the species C through the equilibrium between ketone and enol.
Alternatively, a side product malonate 9 was furnished in the presence of methanol. Finally, the
nucleophilic addition of gem-difluoroalkene 7 or intermediate C with HF delivered the α-CF3 ester 8.
Moreover, the difluorocarbene intermediate (:CF2), which could be easily formed by dissociation of the
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phosphonium ylide, was captured by dimethyl sulfoxide, followed by thermal decomposition of the
difluoromethylated intermediate in the presence of water, gives rise to CO and HF.2d,14d The gem-
difluoroalkene was not detected in the reaction system owing to a rapid reaction process in which the
fluoride ion (F−) nucleophilic attacked the double bond (C=CF2).
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8
CONCLUSION
9
In summary, a facile procedure for the efficient deoxyhydrotrifluoromethylation of a wide range of
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α-keto esters has been demonstrated, using Ph3P+CF2CO2 as the powerful trifluoromethylating reagent
without an extra fluoride anion reagent. Water acts as essential role in promotion of the reaction to
generate the trifluoromethyl moiety by decomposing the difluoromethylated intermediate. The
employment of this protocol as a late-stage functionalization tool has also been developed through the
successful deoxyhydrotrifluoromethylation of bioactive compounds. Owing to readily available and
bench-stable starting materials as well as step-economy, this transformation is efficient and easy to scale
up. Further development of other kinds of trifluoromethylation reactions using difluoromethylating
reagents are currently underway in our laboratory.
Scheme 7. Suggested Mechanism
O
4t
F
F
Ph
CO2Me
-CO2
Ph3P+CF2COO-
Ph3P
CF2
Ph
CO2Me
O

-Ph3PO
7
F
F
F
F
OH
CO2Me
-HF
H2O
OH

-H2O
Ph
CO2Me
Ph
Ph
CO2Me
A
B
C
COOMe
MeOH
Ph
COOMe
9
CF3
CO2Me
F
F
F
O
HF
or
Ph
Ph
CO2Me
Ph
CO2Me
7
C
8
HF from the reaction of DMSO and Ph3P=CF2
O
CFH
CF H
O
O
S
2
-F-
S
-PPh3
S
CF2
CF2
Ph3P
D
E
OH
O
H
O
S
-HF
H2O
O
S
O
S
H
F
+
CO
F
G
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EXPERIMENTAL SECTION
General
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Unless otherwise noted, proton (1H), proton-decoupled carbon [13C{1H}] and proton-decoupled
fluorine [19F{1H}] NMR spectra were recorded on Bruker Avance 400 MHz spectrometers. 1H NMR
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spectra were referenced to tetramethylsilane (s, 0.00 ppm) using CDCl3 as solvent, C NMR spectra
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were referenced to solvent carbons (77.16 ppm for CDCl3). F NMR spectra were referenced to 2%
perfluorobenzene (s, -164.90 ppm) in CDCl3. THF, Et2O, toluene, EtOAc, DMF, MeCN and DMSO
were dried and freshly distilled prior to use. Flash chromatography was performed on silica gel (200 -
o
300 mesh) with either EtOAc/petroleum ether (PE, 60 - 90 C). High-resolution mass spectrometry
(HRMS) were recorded on a LTQ Orbitrap Elite or Agilent 1100-MSD spectrometers.
The known compounds 1a-1b23, 1e24, 1f-1n23, 1o24, 4a28, 4e29, 4g28, 4j25a, 4k25b and 4s30 were
prepared according to reported procedures, and all the spectra data are in agreement with the reports.
Synthesis of substrates
Preparation of compound 1c, 1d.26
To a solution of potassium (E)-2-oxo-4-phenylbut-3-enoate (2.1 g, 10.0 mmol, 1.0 equiv) in water
(10 mL), 1 N HCl (15 mL) was added dropwise under magnetic stirring. The reaction mixture was
stirred at rt for 12 h. A precipitate was generally formed and ethyl acetate (20 mL) was added to the
mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 20
mL). Organic layers were combined and dried on sodium sulfate. After filtration, solvent was removed
under reduced pressure. The resulting residue was used for the next reaction without further purification.
To a solution of above residue in CH2Cl2 (20 mL) at 0 °C, were added successively DMAP (0.1 g,
12.0 mmol, 0.2 equiv), phenol or alcohol (5.9 mmol, 1.0 equiv), and DCC (1.8 g, 8.8 mmol, 1.5 equiv).
The reaction mixture was stirred at rt for 15 h, filtered through a short pad of celite and concentrated
under reduced pressure. The crude material was purified by flash chromatography to afford the desired
product.
2-(2-Methoxyethoxy)ethyl (E)-2-oxo-4-phenylbut-3-enoate (1c). The product (1.33 g, 81% yield)
1
was purified with silica gel chromatography (petroleum ether/ethyl acetate = 5/1) as a yellow oil; H
NMR (400 MHz, CDCl3) δ 7.86 (d, J = 16.2 Hz, 1H), 7.63 (dd, J = 7.6, 1.5 Hz, 2H), 7.48 – 7.40 (m,
3H), 7.33 (d, J = 16.2 Hz, 1H), 4.50 (dd, J = 5.5, 4.2 Hz, 2H), 3.84 (dd, J = 5.5, 4.2 Hz, 2H), 3.69 (dd, J
= 5.6, 3.6 Hz, 2H), 3.56 (dd, J = 5.6, 3.6 Hz, 2H), 3.38 (s, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3)
δ 182.7, 162.2, 148.6, 134.0, 131.6, 129.1, 129.0, 120.7, 71.8, 70.5, 68.6, 65.2, 59.0 ppm; HRMS-ESI
m/z : [M+Na]+ calcd for C15H18NaO5 301.1046, found 301.1052.
+
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Phenyl-2,5,8,11-tetraoxatridecan-13-yl (E)-2-oxo-4-phenylbut-3-enoate (1d). The product (2.14 g,
82% yield) was purified with silica gel chromatography (dichloromethane/methanol = 50/1) as a yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 16.2 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.43 – 7.25 (m,
9H), 4.54 (s, 2H), 4.47 – 4.45 (m, 2H), 3.82 – 3.80 (m, 2H), 3.69 – 3.60 (m, 12H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 182.6, 162.1, 148.5, 138.2, 133.9, 131.6 128.99, 128.94, 128.2, 127.6, 127.5,
120.6, 73.1, 70.54, 70.50, 70.49, 70.47, 69.3 68.4, 65.1 ppm; HRMS-ESI m/z : [M+Na]+ calcd for
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C25H30NaO7 465.1884, found 465.1894.
Preparation of compound 4b-4d, 4f, 4h-4i26, 27
To a solution of functionalized acetophenone (10 mmol, 1.0 equiv) in pyridine (15 mL) was added
selenium dioxide (1.3 g, 12 mmol, 1.2 equiv.) at room temperature and the mixture was stirred at 110 oC
(oil bath) for 20 h. After filtration of the reaction mixture, the residue was washed with CH2Cl2 and the
filtrate was concentrated in vacuo. The resulting residue was used for the next reaction without further
purification.
To a solution of above residue in CH2Cl2 (20 mL), at 0 °C, were added successively DMAP (0.1 g,
12 mmol, 0.2 equiv), phenol or alcohol (5.9 mmol, 1.0 equiv), and DCC (1.8 g, 8.8 mmol, 1.5 equiv).
The reaction mixture was stirred at rt for 15 h, filtered through a short pad of celite and concentrated
under reduced pressure. The crude material was purified by flash chromatography to afford the desired
product.
Phenyl 2-oxo-2-(p-tolyl)acetate (4b). The product (1.06 g, 75% yield) was purified with silica gel
chromatography (petroleum ether/ethyl acetate = 50/1) as a white solid, mp = 80–83 °C;. 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 8.2 Hz, 2H), 7.46 (dd, J = 10.8, 5.0 Hz, 2H), 7.37 – 7.26 (m, 5H), 2.47 (s,
13
3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 185.0, 162.1, 150.0, 146.8, 130.4, 130.0, 129.9, 129.8,
+
126.8, 121.4, 22.1 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C15H12NaO3 263.0679, found 263.0683.
Phenyl 2-(4-methoxyphenyl)-2-oxoacetate (4c). The product (0.95 g, 63% yield) was purified with
1
silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as a white solid, mp = 56–59 °C; H
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.9 Hz, 2H), 7.46 (t, J = 7.9 Hz, 2H), 7.34 – 7.26 (m, 3H), 7.02
(d, J = 8.9 Hz, 2H), 3.92 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 183.7, 165.4, 162.2, 150.1,
13
132.9, 129.8, 126.8, 125.4, 121.4, 114.5, 55.8 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C15H12NaO4
+
279.0628, found 279.0634.
Phenyl 2-(4-fluorophenyl)-2-oxoacetate (4d). The product (1.28 g, 89% yield) was purified with
silica gel chromatography (petroleum ether/ethyl acetate = 50/1) as a white solid, mp = 41–43 oC;. H
1
NMR (400 MHz, CDCl3) δ 8.19 – 8.16 (m, 2H), 7.44 (dd, J = 11.2, 4.4 Hz, 2H), 7.33 – 7.20 (m, 5H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 183.5, 167.1 (d, J = 258.9 Hz), 161.5, 150.0, 133.2 (d, J = 9.9
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Hz), 129.8, 128.9 (d, J = 2.8 Hz), 126.9, 121.3, 116.5 (d, J = 22.3 Hz) ppm; 19F{1H} NMR (376 MHz,
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2
3
4
+
CDCl3) δ -103.6 (s, 1F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C14H9FNaO3 267.0428, found
267.0433.
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6
Phenyl 2-(4-bromophenyl)-2-oxoacetate (4f). The product (1.31 g, 73% yield) was purified with
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1
silica gel chromatography (petroleum ether/ethyl acetate = 50/1) as a white solid, mp = 62–65 oC;. H
9
NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.46 (t, J = 7.9 Hz, 2H),
7.34 – 7.25 (m, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 184.0, 161.2, 149.9, 132.6 131.7, 131.2,
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131.0, 129.9, 126.9, 121.3 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C14H9BrNaO3 326.9627, found
326.9647.
Phenyl 2-oxo-2-(m-tolyl)acetate (4h). The product (1.01 g, 71% yield) was purified with silica gel
chromatography (petroleum ether/ethyl acetate = 30/1) as a white solid, mp = 46–49 oC;. 1H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 6.2 Hz, 2H), 7.51 – 7.41 (m, 4H), 7.33 – 7.25 (m, 3H), 2.43 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 185.6, 162.1, 150.0, 139.1, 136.2, 132.3, 130.5, 129.8, 129.0,
+
127.6, 126.8, 121.3, 21.4 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C15H12NaO3 263.0679, found
263.0685.
Phenyl 2-(naphthalen-2-yl)-2-oxoacetate (4i). The product (1.35 g, 83% yield) was purified with
silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as a yellow solid, mp = 65–67 oC;. 1H
NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.09 (dd, J = 8.6, 1.7 Hz, 1H), 7.95 – 7.84 (m, 3H), 7.64 – 7.60
(m, 1H), 7.56 – 7.52 (m, 1H), 7.47 – 7.43 (m, 2H), 7.30 (dd, J = 10.7, 4.1 Hz, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 185.2, 162.0, 150.1, 136.5, 133.8, 132.3, 130.2, 129.9, 129.8, 129.7, 129.2, 128.0,
+
127.4, 126.8, 124.0, 121.4 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C18H12NaO3 299.0679, found
299.0685.
Preparation of compound 4l-4r.26
A solution of 2.5 N NaOH (0.8 g, 20.0 mmol, 2.0 equiv) was added to methyl 2-oxo-2-
phenylacetate (1.6 g, 10.0 mmol, 1.0 equiv.) and the mixture was stirred for 2 hours at room
temperature. After the reaction was finished, 1 N HCl (20 mL) was added to the mixture until the pH
was lower than 7.0, which was then extracted with ethyl acetate (3 x 30 mL). Organic phases were
combined and dried over sodium sulfate. The solvent was then removed under vacuum to afford the α-
keto acids without further purification.
To a solution of above residue in CH2Cl2 (20 mL), at 0 °C, were added successively DMAP (0.1 g,
12 mmol, 0.2 equiv), phenol or alcohol (5.9 mmol, 1.0 equiv), and DCC (1.8 g, 8.8 mmol, 1.5 equiv).
The reaction mixture was stirred at rt for 15 h, filtered through a short pad of celite and concentrated
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under reduced pressure. The crude material was purified by flash chromatography to afford the desired
product.
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2-(2-Methoxyethoxy)ethyl 2-oxo-2-phenylacetate (4l). The product (1.27 g, 85% yield) was purified
with silica gel chromatography (petroleum ether/ethyl acetate = 5/1) as a pale yellow oil; 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 7.3 Hz, 2H), 7.65 (dd, J = 9.3, 5.5 Hz, 1H), 7.50 (dd, J = 10.1, 5.4 Hz, 2H),
4.58 – 4.55 (m, 2H), 3.85 – 3.82 (m, 2H), 3.68 – 3.66 (m, 2H), 3.57 – 3.54 (m, 2H), 3.36 (d, J = 4.0 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 186.1, 163.6, 134.8, 132.1, 129.9, 128.7, 71.6, 70.3, 68.4,
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64.7, 58.8 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C13H16NaO5 275.0890, found 275.0893.
Phenyl-2,5,8,11-tetraoxatridecan-13-yl 2-oxo-2-phenylacetate (4m). The product (2.11 g, 86%
yield) was purified with silica gel chromatography (dichloromethane/methanol = 50/1) as a pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz,
2H), 7.34 – 7.26 (m, 5H), 4.55 – 4.52 (m, 4H), 3.83 – 3.81 (m, 2H), 3.69 – 3.61 (m, 12H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 186.3, 163.8, 138.3, 135.0, 132.4, 130.1, 128.9, 128.4, 127.8, 127.6, 73.2,
+
70.7, 70.6, 69.4, 68.6, 65.0 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C23H28NaO7 439.1727, found
439.1735.
2,6-Diisopropylphenyl 2-oxo-2-phenylacetate (4n). The product (1.36 g, 74% yield) was purified
1
with silica gel chromatography (petroleum ether/ethyl acetate = 100/1) as a yellow oil; H NMR (400
MHz, CDCl3) δ 8.15 – 8.13 (m, 2H), 7.72 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.32 – 7.22 (m,
3H), 3.14 – 3.05 (m, 2H), 1.26 (d, J = 6.8 Hz, 12H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 185.7,
13
162.5, 144.8, 140.5, 135.4, 132.5, 130.2, 129.3, 127.4, 124.4, 27.6, 22.9 ppm; HRMS-ESI m/z : [M+H]+
+
calcd for C20H23O3 311.1642, found 311.1649.
(R)-2-Methoxy-2-oxo-1-phenylethyl 2-oxo-2-phenylacetate (4o). The product (1.30 g, 74% yield)
was purified with silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as a pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 8.16 – 8.14 (m, 2H), 7.71 – 7.66 (m, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.50 –
7.40 (m, 5H), 6.16 (s, 1H), 3.81 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 185.8, 168.6, 163.4,
135.3, 132.6, 132.4, 130.4 129.8, 129.12, 129.07, 127.9, 75.9, 53.2 ppm; HRMS-ESI m/z : [M+K]+
+
calcd for C17H14KO5 337.0473, found 337.0477.
Dimethyl (S)-2-(2-oxo-2-phenylacetoxy)succinate (4p). The product (1.67 g, 96% yield) was
1
purified with silica gel chromatography (petroleum ether/ethyl acetate = 5/1) as a pale yellow oil; H
NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H),
5.78 (dd, J = 7.1, 5.0 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 3H), 3.05 – 3.03 (m, 2H) ppm; 13C{1H} NMR (101
MHz, CDCl3) δ 185.6, 169.3, 168.4, 162.9, 135.3, 132.3, 130.4, 129.1, 69.5, 53.2, 52.5, 35.7 ppm;
HRMS-ESI m/z : [M+Br]- calcd for C14H14BrO7 372.9923, found 372.9914.
-
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(3aR,5R,6S,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-
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2
3
4
5
6
7
8
9
d][1,3]dioxol-6-yl 2-oxo-2-phenylacetate (4q). The product (1.83 g, 79% yield) was purified with silica
gel chromatography (petroleum ether/ethyl acetate = 5/1) as a colorless oil; 1H NMR (400 MHz, CDCl3)
δ 8.05 (d, J = 7.5 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 5.95 (d, J = 3.7 Hz, 1H),
5.67 (d, J = 3.0 Hz, 1H), 4.66 (d, J = 3.7 Hz, 1H), 4.28 (dd, J = 8.6, 3.0 Hz, 1H), 4.20 – 4.16 (m, 1H),
4.11 (dt, J = 8.7, 5.0 Hz, 1H), 4.02 (dd, J = 8.8, 4.4 Hz, 1H), 1.56 (s, 3H), 1.47 (s, 3H), 1.34 (s, 6H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 185.8, 162.6, 135.3, 132.3, 130.2, 129.0, 112.7, 109.6, 105.4,
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+
83.3, 80.2, 77.3, 72.4, 67.6, 27.0, 26.8, 26.3, 25.3 ppm; HRMS-ESI m/z : [M+H]+ calcd for C20H25O8
393.1544, found 393.1551.
(2R,3R,4S,5S,6R)-2-(Acetoxymethyl)-6-(2-oxo-2-phenylacetoxy)tetrahydro-2H-pyran-3,4,5-triyl
triacetate (4r). The product (2.72 g, 96% yield) was purified with silica gel chromatography
o
1
(dichloromethane/methanol = 50/1) as a white solid, mp = 93–96 C;. H NMR (400 MHz, CDCl3) δ
8.03 (d, J = 7.5 Hz, 2H), 7.72 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 6.36 (d, J = 1.6 Hz, 1H), 5.43
– 5.35 (m, 3H), 4.32 (dd, J = 12.4, 5.0 Hz, 1H), 4.19 – 4.11 (m, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 2.05 (s,
3H), 2.01 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 184.6, 170.6, 169.9, 169.8, 169.6, 160.9,
13
135.6, 131.9, 130.2, 129.3, 92.2, 71.3, 68.6, 68.0, 65.3, 62.0, 20.82, 20.77, 20.7, 20.6 ppm; HRMS-ESI
m/z : [M+K]+ calcd for C22H24KO12+ 519.0899, found 519.0924.
General procedure for deoxyhydrotrifluoromethylation of alkenyl-substituted α-keto esters with
Ph3P+CF2 COO-
In an argon-filled glovebox, a dry reaction tube was charged with methyl (E)-2-oxo-4-phenyl- but-3-
enoate 1a (0.5 mmol, 1.0 equiv), 2,2-difluoro-2-(triphenylphosphonio)acetate (1.0 mmol, 2.0 equiv),
and DMSO (5.0 mL). H2O (0.5 mmol, 1.0 equiv) was added to the reaction mixture at the room
temperature in the end. The mixture kept stirring at 60 oC (oil bath) for 1 hour. The residue was directly
subjected to silica gel flash chromatography to afford the desired product 3a in 79% yield.
Methyl (E)-4-phenyl-2-(trifluoromethyl)but-3-enoate (3a).11 The product (96.0 mg, 79% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.42 – 7.28 (m, 5H), 6.70 (d, J = 15.8 Hz, 1H), 6.22 (dd, J = 15.8 Hz,
9.4Hz, 1H), 3.99 – 3.89 (m, 1H), 3.80 (s, 3H) ppm; F{1H} NMR (376 MHz, CDCl3) δ -71.4 (s, 3F)
19
ppm.
Ethyl (E)-4-phenyl-2-(trifluoromethyl)but-3-enoate (3b). The product (106.2 mg, 78% yield) was
1
purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a colorless oil; H
NMR (400 MHz, CDCl3) δ 7.42 – 7.27 (m, 5H), 6.70 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 9.3 Hz,
1H), 4.26 (qd, J = 7.1, 1.3 Hz, 2H), 3.91 (p, J = 8.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H) ppm; C{1H}
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NMR (101 MHz, CDCl3) δ 166.2 (q, J = 2.8 Hz), 138.2, 135.6, 128.8, 126.9, 123.9 (q, J = 280.2 Hz),
116.9 (d, J = 2.5 Hz), 62.3, 54.3 (q, J = 29.0 Hz), 14.1 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -71.3
1
2
3
4
+
(s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C13H13F3NaO2 281.0760, found 281.0759.
5
6
7
8
2-(2-Methoxyethoxy)ethyl (E)-4-phenyl-2-(trifluoromethyl)but-3-enoate (3c). The product (139.1
mg, 84% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 5/1) as a
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.28 (m, 5H), 6.71 (d, J = 15.9 Hz, 1H), 6.23 (dd, J =
15.9, 9.2 Hz, 1H), 4.36 (dd, J = 5.5, 3.8 Hz, 2H), 3.98 (p, J = 8.4 Hz, 1H), 3.73 – 3.70 (m, 2H), 3.61 (dd,
J = 5.6, 3.5 Hz, 2H), 3.49 (dd, J = 5.5, 3.6 Hz, 2H), 3.33 (s, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3) δ 166.0 (d, J = 2.6 Hz), 138.2, 135.4, 128.7, 126.8, 123.8 (q, J = 280.3 Hz), 116.5 (d, J = 2.3
9
10
11
12
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54
55
56
57
58
59
60
19
Hz), 71.8, 70.5, 68.7, 65.0, 58.9, 53.9 (q, J = 29.0 Hz) ppm; F{1H} NMR (376 MHz, CDCl3) δ -71.2
-
(s, 3F) ppm; HRMS-ESI m/z : [M-H]- calcd for C16H18F3O4 331.1163, found 331.1160.
Phenyl-2,5,8,11-tetraoxatridecan-13-yl(E)-4-phenyl-2-(trifluoromethyl)but-3-enoate (3d). The
product (191.2 mg, 77% yield) was purified with silica gel chromatography (petroleum ether/ethyl
acetate = 3/1) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.25 (m, 10H), 6.70 (d, J = 15.9 Hz,
1H), 6.22 (dd, J = 15.9, 9.2 Hz, 1H), 4.55 (s, 2H), 4.33 (dd, J = 5.4, 3.3 Hz, 2H), 3.97 (p, J = 8.4 Hz,
13
1H), 3.71 – 3.61 (m, 14H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 165.8 (d, J = 2.6 Hz), 138.13,
138.07, 135.2, 128.5, 128.2, 127.5, 127.4, 126.6, 123.7 (q, J = 280.3 Hz), 116.4 (d, J = 2.3 Hz), 73.0,
19
70.43, 70.40, 70.35, 69.3, 68.5, 64.9, 53.7 (q, J = 28.9 Hz) ppm; F{1H} NMR (376 MHz, CDCl3) δ -
+
71.2 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C26H31F3NaO6 519.1965, found 519.1963.
Methyl (E)-4-(2-chlorophenyl)-2-(trifluoromethyl)but-3-enoate (3e). The product (100.0 mg, 72%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.54 (m, 1H), 7.36 (dt, J = 6.3, 2.9 Hz, 1H), 7.26 –
7.21 (m, 2H), 7.12 (d, J = 15.8 Hz, 1H), 6.23 (dd, J = 15.8, 9.4 Hz, 1H), 4.01 (p, J = 8.4 Hz, 1H), 3.82
13
(s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 166.4 (q, J = 2.6 Hz), 134.5, 133.6, 133.5, 129.90,
129.83, 127.2, 127.1, 123.7 (q, J = 280.4 Hz), 119.5 (d, J = 2.4 Hz), 54.1 (q, J = 29.2 Hz), 53.1 ppm;
19F{1H} NMR (376 MHz, CDCl3) δ -71.1 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for
+
C12H10ClF3NaO2 301.0214, found 301.0207.
Methyl (E)-4-(2-bromophenyl)-2-(trifluoromethyl)but-3-enoate (3f). The product (86.8 mg, 58%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.1 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.7 Hz,
1H), 7.07 (d, J = 15.8 Hz, 1H), 6.18 (dd, J = 15.8, 9.3 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.83 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 166.3 (d, J = 2.8 Hz), 137.1, 135.4, 133.1, 130.1, 127.8, 127.4,
19
123.9, 123.7 (q, J = 280.3 Hz), 119.7 (d, J = 2.5 Hz), 54.0 (q, J = 29.2 Hz), 53.1 ppm; F{1H} NMR
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+
(376 MHz, CDCl3) δ -71.2 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C12H10BrF3NaO2
1
2
3
344.9708, found 344.9701.
4
5
6
7
8
9
Methyl (E)-4-(4-methoxyphenyl)-2-(trifluoromethyl)but-3-enoate (3g). The product (108.7 mg,
79% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as a pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.64 (d, J =
15.8 Hz, 1H), 6.07 (dd, J = 15.8, 9.3 Hz, 1H), 3.90 (dt, J = 16.9, 8.4 Hz, 1H), 3.80 (d, J = 4.5 Hz, 6H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 166.8 (d, J = 2.8 Hz), 160.2, 137.8, 128.3, 128.2, 123.9 (q, J
10
11
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45
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54
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56
57
58
59
60
19
= 280.2 Hz), 114.3 (d, J = 2.5 Hz), 114.2, 55.4, 54.2 (q, J = 29.2 Hz), 53.0 ppm; F{1H} NMR (376
+
MHz, CDCl3) δ -71.3 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C13H13F3NaO3 297.0709,
found 297.0707.
Methyl (E)-4-(4-bromophenyl)-2-(trifluoromethyl)but-3-enoate (3h). The product (111.8 mg, 69%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 7/1) as a white
solid, mp = 38–40 oC;. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H),
6.64 (d, J = 15.9 Hz, 1H), 6.21 (dd, J = 15.9, 9.3 Hz, 1H), 3.99 – 3.86 (m, 1H), 3.80 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 166.3 (d, J = 2.6 Hz), 137.1, 134.4, 131.9, 128.4, 123.7 (q, J =
280.2 Hz), 122.8, 117.5 (d, J = 2.4 Hz), 53.9 (q, J = 29.2 Hz), 53.1 ppm; F{1H} NMR (376 MHz,
19
+
CDCl3) δ -71.2 (s, 3F) ppm; HRMS-ESI m/z : [M+K]+ calcd for C12H10BrF3KO2 360.9448, found
360.9439.
Methyl (E)-4-(3-methoxyphenyl)-2-(trifluoromethyl)but-3-enoate (3i). The product (107.4 mg,
78% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as a
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.25 (t, J = 7.9 Hz, 1H), 6.96 (dd, J = 22.2Hz, 4.8 Hz 2H),
6.85 (dd, J = 8.2, 2.0 Hz, 1H), 6.67 (d, J = 15.8 Hz, 1H), 6.21 (dd, J = 15.8, 9.3 Hz, 1H), 3.98 – 3.89 (m,
1H), 3.80 (d, J = 3.7 Hz, 6H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 166.54 (q, J = 2.7 Hz), 160.0,
13
138.3, 136.8, 129.8, 123.8 (q, J = 280.2 Hz), 119.5, 116.9 (d, J = 2.5 Hz), 114.6, 112.0, 55.3, 54.0 (q, J
= 29.1 Hz), 53.0 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -71.1 (s, 3F) ppm; HRMS-ESI m/z :
+
[M+Na]+ calcd for C13H13F3NaO3 297.0709, found 297.0707.
Methyl (E)-4-(naphthalen-2-yl)-2-(trifluoromethyl)but-3-enoate (3j). The product (115.4 mg, 78%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 4/1) as a white
solid, mp = 83–86 oC;. 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 12.5, 7.8 Hz, 1H), 7.60 (dd, J = 8.6,
1.5 Hz, 1H), 7.50 – 7.45 (m, 2H), 6.86 (d, J = 15.8 Hz, 1H), 6.34 (dd, J = 15.8, 9.3 Hz, 1H), 4.03 – 3.95
(m, 1H), 3.83 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 166.6 (d, J = 2.7 Hz), 138.4, 133.5,
13
133.4, 132.9, 128.5, 128.2, 127.8, 127.5, 126.6, 126.5, 123.9 (q, J = 280.3 Hz), 123.3, 116.9 (d, J = 2.4
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Hz), 54.1 (q, J = 29.1 Hz), 53.0 ppm; F{1H} NMR (376 MHz, CDCl3) δ -71.0 (s, 3F) ppm; HRMS-
19
1
2
3
+
ESI m/z : [M+Na]+ calcd for C16H13F3NaO2 317.0760, found 317.0756.
4
5
6
7
8
9
Methyl (E)-4-(furan-2-yl)-2-(trifluoromethyl)but-3-enoate (3k). The product (75.6 mg, 65% yield)
was purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a yellow oil; 1H
NMR (400 MHz, CDCl3) δ 7.39 (d, J = 1.3 Hz, 1H), 6.51 (d, J = 15.8 Hz, 1H), 6.40 – 6.34 (m, 2H),
13
6.14 (dd, J = 15.8, 9.4 Hz, 1H), 3.87 (dt, J = 11.2, 8.5 Hz, 1H), 3.80 (s, 3H) ppm; C{1H} NMR (101
10
11
12
13
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42
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48
49
50
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53
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58
59
60
MHz, CDCl3) δ 166.5 (q, J = 3.1 Hz), 151.1, 143.1, 126.0, 123.8 (q, J = 280.3 Hz), 114.9 (d, J = 2.9
19
Hz), 111.6, 110.3, 53.8 (q, J = 29.3 Hz), 53.1 ppm; F{1H} NMR (376 MHz, CDCl3) δ -71.3 (s, 3F)
+
ppm; HRMS-ESI m/z : [M+Na]+ calcd for C10H9F3NaO3 257.0396, found 257.0395.
Methyl (E)-4-(thiophen-2-yl)-2-(trifluoromethyl)but-3-enoate (3l). The product (81.6 mg, 65%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a pale
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 5.0 Hz, 1H), 7.04 – 6.96 (m, 2H), 6.82 (d, J =
13
15.7 Hz, 1H), 6.02 (dd, J = 15.7, 9.3 Hz, 1H), 3.92 – 3.84 (m, 1H), 3.80 (s, 3H) ppm; C{1H} NMR
(101 MHz, CDCl3) δ 166.4 (d, J = 2.7 Hz), 140.2, 131.2, 127.61, 127.56, 125.9, 123.8 (q, J = 280.2 Hz),
115.7 (d, J = 2.4 Hz), 53.9 (q, J = 29.3 Hz), 53.1 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -71.3 (s, 3F)
ppm; HRMS-ESI m/z : [M+Na]+ calcd for C10H9F3NaO2S+ 273.0168, found 273.0174.
Methyl (3E,5E)-6-phenyl-2-(trifluoromethyl)hexa-3,5-dienoate (3m). The product (93.8 mg, 69%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 5/1) as a white
o
1
solid, mp = 44–48 C;. H NMR (400 MHz, CDCl3) δ 7.82 – 7.77 (m, 4H), 7.61 (dd, J = 8.6, 1.5 Hz,
1H), 7.51 – 7.46 (m, 2H), 6.87 (d, J = 15.8 Hz, 1H), 6.34 (dd, J = 15.8, 9.3 Hz, 1H), 3.99 (p, J = 8.3 Hz,
1H), 3.83 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 166.5 (d, J = 2.6 Hz), 138.4, 136.6, 135.4,
128.8, 128.3, 127.0, 126.7, 123.8 (q, J = 280.1 Hz), 119.8 (d, J = 2.5 Hz), 53.8 (q, J = 29.2 Hz), 53.0
ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -71.3 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for
+
C14H13F3NaO2 293.0760, found 293.0757.
Methyl (E)-4-(3,4-dimethoxyphenyl)-2-(trifluoromethyl)but-3-enoate (3n). The product (120.1 mg,
79% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 5/1) as a
colorless oil; 1H NMR (400 MHz, CDCl3) δ 6.96 – 6.93 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.64 (d, J =
13
15.8 Hz, 1H), 6.07 (dd, J = 15.8, 9.3 Hz, 1H), 3.94 – 3.89 (m, 7H), 3.81 (s, 3H) ppm; C{1H} NMR
(101 MHz, CDCl3) δ 166.8 (d, J = 2.8 Hz), 149.8, 149.2, 138.0, 128.5, 123.9 (q, J = 280.2 Hz), 120.5,
19
114.4 (d, J = 2.4 Hz), 111.1, 108.9, 55.96, 55.94, 54.0 (q, J = 29.1 Hz), 53.0 ppm; F{1H} NMR (376
+
MHz, CDCl3) δ -71.4 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C14H15F3NaO4 327.0815,
found 327.0813.
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Methyl (E)-4-cyclohexyl-2-(trifluoromethyl)but-3-enoate (3o). The product (89.1 mg, 71% yield)
was purified with silica gel chromatography (petroleum ether/dichloromethane = 30/1) as a colorless oil;
1H NMR (400 MHz, CDCl3) δ 5.78 (dd, J = 15.5, 6.6 Hz, 1H), 5.47 (dd, J = 15.5, 9.2 Hz, 1H), 3.77 (s,
3H), 3.70 (p, J = 8.5 Hz, 1H), 2.02 (dt, J = 10.3, 6.8 Hz, 1H), 1.75 – 1.64 (m, 5H) , 1.32 – 1.05 (m, 5H)
1
2
3
4
5
6
13
ppm; C{1H} NMR (101 MHz, CDCl3) δ 167.1 (d, J = 2.8 Hz), 146.1, 124.0 (q, J = 279.9 Hz), 115.4
7
8
9
(d, J = 2.3 Hz), 54.0 (q, J = 28.8 Hz), 52.8, 40.7, 32.3, 26.1, 25.9 ppm; 19F{1H} NMR (376 MHz,
10
11
12
13
14
15
16
17
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19
20
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25
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29
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34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
CDCl3) δ -71.8 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C12H17F3NaO2 273.1073, found
273.1072.
General procedure for deoxyhydrotrifluoromethylation of aryl-substituted α-keto esters with
Ph3P+CF2 COO-
In an argon-filled glovebox, a dry reaction tube was charged with phenyl 2-oxo-2-phenyl- acetate 4a
(0.5 mmol, 1.0 equiv), 2,2-difluoro-2-(triphenylphosphonio)acetate (1.5 mmol, 3.0 equiv), and DMSO
(5.0 mL). H2O (0.5 mmol, 1.0 equiv) was added to the reaction mixture at the room temperature in the
o
end. The mixture kept stirring at 60 C (oil bath) for 12 hours. The residue was directly subjected to
silica gel flash chromatography (petroleum ether/dichloromethane = 10/1) to afford the desired product
5a in 75% yield.
Phenyl 3,3,3-trifluoro-2-phenylpropanoate (5a). The product (104.8 mg, 75% yield) was purified
with silica gel chromatography (petroleum ether/dichloromethane = 10/1) as a pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.53 (d, J = 2.9 Hz, 2H), 7.44 – 7.43 (m, 3H), 7.35 (t, J = 7.9 Hz, 2H), 7.23 (t, J =
7.4 Hz, 1H), 7.05 – 7.03 (m, 2H), 4.57 (q, J = 8.4 Hz, 1H) ppm; C{1H} NMR (101 MHz, CDCl3) δ
13
164.8 (q, J = 2.7 Hz), 150.2, 129.64, 129.60, 129.2, 129.0 (d, J = 1.6 Hz), 126.6, 123.8 (q, J = 279.8
Hz), 121.2, 55.6 (q, J = 29.1 Hz) ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.6 (s, 3F) ppm; HRMS-
+
ESI m/z : [M+Na]+ calcd for C15H11F3NaO2 303.0603, found 303.0600.
Phenyl 3,3,3-trifluoro-2-(p-tolyl)propanoate (5b). The product (115.2 mg, 78% yield) was purified
with silica gel chromatography (petroleum ether/dichloromethane = 10/1) as a pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.40 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.19 (dd, J = 12.1, 7.7 Hz, 3H),
7.02 (d, J = 8.0 Hz, 2H), 4.52 (q, J = 8.3 Hz, 1H), 2.33 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3)
δ 165.0 (q, J = 2.7 Hz), 150.3, 139.6, 130.0, 129.6, 129.5, 126.5, 126.0 (d, J = 1.5 Hz), 123.8 (q, J =
279.8 Hz), 121.2, 55.3 (q, J = 29.1 Hz), 21.2 ppm; F{1H} NMR (376 MHz, CDCl3) δ -70.8 (s, 3F)
19
ppm; HRMS-ESI m/z : [M+Na]+ calcd for C16H13F3NaO2 317.0760, found 317.0757.
+
Phenyl 3,3,3-trifluoro-2-(4-methoxyphenyl)propanoate (5c). The product (113.0 mg, 73% yield)
was purified with silica gel chromatography (petroleum ether/ethyl acetate = 50/1) as a yellow solid, mp
= 46–48 oC;. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.22 (t, J
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= 7.4 Hz, 1H), 7.04 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 4.51 (q, J = 8.4 Hz, 1H), 3.79 (s, 3H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 165.1 (d, J = 2.7 Hz), 160.6, 150.2, 130.8, 129.6, 126.5, 123.8
1
2
3
4
19
(q, J = 279.7 Hz), 121.2, 120.9 (d, J = 1.6 Hz), 114.6, 55.3, 54.8 (q, J = 29.5 Hz) ppm; F{1H} NMR
5
6
+
(376 MHz, CDCl3) δ -71.0 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C16H13F3NaO3 333.0709,
7
8
found 333.0705.
9
Phenyl 3,3,3-trifluoro-2-(4-fluorophenyl)propanoate (5d). The product (100.6 mg, 67% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 15/1) as a pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.5, 5.2 Hz, 2H), 7.38 – 7.34 (m, 2H), 7.26 – 7.22 (m, 1H),
7.15 – 7.03 (m, 4H), 4.56 (q, J = 8.3 Hz, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 164.7 (d, J = 2.4
Hz), 163.6 (d, J = 249.3 Hz), 150.2, 131.5 (d, J = 8.4 Hz), 129.7, 126.7, 124.9 (q, J = 1.7 Hz), 123.6 (qd,
10
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44
45
46
47
48
49
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54
55
56
57
58
59
60
19
J = 279.8 Hz), 121.2, 116.4 (d, J = 21.9 Hz), 54.9 (q, J = 29.4 Hz) ppm; F{1H} NMR (376 MHz,
+
CDCl3) δ -70.9 (s, 3F), -114.7 (s, 1F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C15H10F4NaO2
321.0509, found 321.0517.
Phenyl 2-(4-chlorophenyl)-3,3,3-trifluoropropanoate (5e). The product (107.7 mg, 68% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 15/1) as a pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.50 – 7.36 (m, 6H), 7.26 (dd, J = 8.4, 6.4 Hz, 1H), 7.06 – 7.03 (m, 2H),
4.55 (q, J = 8.3 Hz, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 164.5 (d, J = 2.9 Hz), 150.1, 136.0,
131.0, 129.7, 129.6, 127.5 (d, J = 1.4 Hz), 126.7, 123.5 (q, J = 280.0 Hz), 121.2, 55.0 (q, J = 29.5 Hz)
ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.8 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for
+
C15H10ClF3NaO2 337.0214, found 337.0220.
Phenyl 2-(4-bromophenyl)-3,3,3-trifluoropropanoate (5f). The product (122.6 mg, 68% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 15/1) as a white solid, mp
= 51–53 oC;. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.5 Hz, 2H), 7.41 – 7.34 (m, 4H), 7.23 (dd, J =
13
10.6, 4.2 Hz, 1H), 7.04 (d, J = 7.7 Hz, 2H), 4.53 (q, J = 8.3 Hz, 1H) ppm; C{1H} NMR (101 MHz,
CDCl3) δ 164.4 (d, J = 2.7 Hz), 150.1, 132.5, 131.3, 129.7, 128.0 (d, J = 1.5 Hz), 126.7, 124.2, 123.4 (q,
J = 280.0 Hz), 121.1, 55.1(q, J = 29.5 Hz) ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.7 (s, 3F) ppm;
+
HRMS-ESI m/z : [M+Na]+ calcd for C15H10BrF3NaO2 380.9708, found 380.9718.
Benzyl 3,3,3-trifluoro-2-phenylpropanoate (5g). The product (112.1 mg, 76% yield) was purified
with silica gel chromatography (petroleum ether/dichloromethane = 10/1) as a pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.40 – 7.22 (m, 10H), 5.16 (dd, J = 33.0, 12.3 Hz, 2H), 4.36 (q, J = 7.6 Hz, 1H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 166.1 (q, J = 2.6 Hz), 135.0, 129.6, 129.3, 129.0, 128.7,
128.6, 128.2, 123.8 (q, J = 279.8 Hz), 67.7, 55.6 (q, J = 28.9 Hz) ppm; 19F{1H} NMR (376 MHz,
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CDCl3) δ -70.4 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C16H13F3NaO2 317.0760, found
+
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317.0757.
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Phenyl 3,3,3-trifluoro-2-(m-tolyl)propanoate (5h). The product (109.3 mg, 74% yield) was purified
with silica gel chromatography (petroleum ether/dichloromethane = 15/1) as a pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.36 – 7.19 (m, 7H), 7.04 – 7.02 (m, 2H), 4.52 (q, J = 8.4 Hz, 1H), 2.37 (s, 3H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 164.9 (d, J = 2.7 Hz), 150.2, 139.1, 130.4, 130.3, 129.7,
129.1, 128.9 (d, J = 1.5 Hz), 126.6, 126.5, 123.8 (q, J = 279.9 Hz), 121.3, 55.6 (q, J = 29.1 Hz), 21.5
ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.7 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for
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+
C16H13F3NaO2 317.0760, found 317.0758.
Phenyl 3,3,3-trifluoro-2-(naphthalen-2-yl)propanoate (5i). The product (124.7 mg, 76% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 15/1) as a pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.89 – 7.82 (m, 3H), 7.61 (d, J = 8.5 Hz, 1H), 7.52 – 7.48
(m, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.18 (dd, J = 12.8, 5.3 Hz, 1H), 7.03 (d, J = 7.8 Hz, 2H), 4.73 (q, J =
8.3 Hz, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 164.9 (d, J = 2.5 Hz), 150.2, 133.6, 133.3, 129.7,
129.6, 129.2, 128.3, 127.8, 127.2, 126.9, 126.6, 126.4 (d, J = 1.2 Hz), 126.2, 123.9 (q, J = 280.0 Hz),
19
121.2, 55.7 (q, J = 29.2 Hz) ppm; F{1H} NMR (376 MHz, CDCl3) δ -70.3 (s, 3F) ppm; HRMS-ESI
+
m/z : [M+Na]+ calcd for C19H13F3NaO2 353.0760, found 353.0755.
Methyl 3,3,3-trifluoro-2-(naphthalen-2-yl)propanoate (5j). The product (110.0 mg, 82% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 15/1) as a white solid, mp
= 56–59 oC;. 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.83 – 7.78 (m, 3H), 7.53 – 7.45 (m, 3H), 4.50
(q, J = 8.5 Hz, 1H), 3.72 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 166.8 (q, J = 2.6 Hz), 133.5,
133.2, 129.5, 128.9, 128.2, 127.8, 127.0, 126.8, 126.3, 124.0 (q, J = 279.8 Hz), 55.5 (q, J = 28.9 Hz),
53.0 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.5 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for
+
C14H11F3NaO2 291.0603, found 291.0600.
Phenyl 3,3,3-trifluoro-2-(thiophen-2-yl)propanoate (5k). The product (51.5 mg, 36% yield) was
purified with silica gel chromatography (petroleum ether/ dichloromethane = 15/1) as a colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.41 – 7.24 (m, 5H), 7.10 – 7.06 (m, 3H), 4.86 (q, J = 8.0 Hz, 1H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 164.0 (d, J = 2.6 Hz), 150.2, 129.7, 128.9 (d, J = 1.9 Hz), 127.8,
19
127.4, 126.7, 123.1 (q, J = 280.6 Hz), 121.2, 51.3 (q, J = 30.8 Hz) ppm; F{1H} NMR (376 MHz,
CDCl3) δ -71.5 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C13H9F3NaO2S+ 309.0168, found
309.0172.
2-(2-Methoxyethoxy)ethyl 3,3,3-trifluoro-2-phenylpropanoate (5l). The product (102.3 mg, 67%
yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 5/1) as a pale yellow
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The Journal of Organic Chemistry
oil; 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.38 (m, 5H), 4.41 – 4.34 (m, 2H), 4.32 – 4.27 (m, 1H),3.68 –
3.66 (m, 2H), 3.55 (dd, J = 5.5, 2.9 Hz, 2H), 3.47 (td, J = 6.1, 3.2 Hz, 2H), 3.35 (d, J = 2.3 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 166.1 (q, J = 2.6 Hz), 129.5, 129.3 (d, J = 1.5 Hz), 129.2, 128.9,
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123.7 (q, J = 279.7 Hz), 71.8, 70.5, 68.7, 65.0, 59.0, 55.4 (q, J = 28.8 Hz) ppm; F{1H} NMR (376
+
MHz, CDCl3) δ -70.7 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C14H17F3NaO4 329.0971,
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found 329.0967.
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Phenyl-2,5,8,11-tetraoxatridecan-13-yl 3,3,3-trifluoro-2-phenylpropanoate (5m). The product
(168.1 mg, 72% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 4/1)
as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.24 (m, 10H), 4.56 (s, 2H), 4.40 – 4.33 (m,
2H), 4.29 – 4.23 (m, 1H), 3.68 – 3.53 (m, 14H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 166.2 (q, J =
2.9 Hz), 138.3, 129.6, 129.32 (d, J = 1.7 Hz), 129.27, 129.0, 128.4, 127.8, 127.7, 123.7 (q, J = 279.8
Hz), 73.3, 70.69, 70.68, 70.64, 70.60, 69.5, 68.7, 65.0, 55.4 (q, J = 28.9 Hz) ppm; F{1H} NMR (376
19
+
MHz, CDCl3) δ -70.8 (s, 3F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C24H29F3NaO6 493.1808,
found 493.1801.
2,6-Diisopropylphenyl 3,3,3-trifluoro-2-phenylpropanoate (5n). The product (116.3 mg, 75%
yield) was purified with silica gel chromatography (petroleum ether/dichloromethane = 100/1) as a
o
1
white solid, mp = 80–82 C;. H NMR (400 MHz, CDCl3) δ 7.59 – 7.41 (m, 5H), 7.18 (dd, J = 24.3,
16.7 Hz, 3H), 4.64 (q, J = 8.5 Hz, 1H), 2.86 (s, 1H), 2.40 (s, 1H), 1.27 – 0.86 (m, 12H) ppm; C{1H}
13
NMR (101 MHz, CDCl3) δ 164.9 (q, J = 2.5 Hz), 145.0, 140.5, 129.74, 129.71, 129.2, 128.9 (d, J = 1.4
Hz), 127.2, 124.1, 123.9 (q, J = 279.6 Hz), 55.7 (q, J = 29.4 Hz), 27.5, 22.9 ppm; F{1H} NMR (376
19
-
MHz, CDCl3) δ -70.5 (s, 3F) ppm; HRMS-ESI m/z : [M-H]- calcd for C21H22F3O2 363.1577, found
363.1577.
(R)-2-Methoxy-2-oxo-1-phenylethyl 3,3,3-trifluoro-2-phenylpropanoate (5o). The product (106.1
mg, 71% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 30/1) as a
1
pale yellow oil and as an inseparable mixture of diastereoisomers (d. r. = 1:1); H NMR (400 MHz,
CDCl3) δ 7.48 – 7.35 (m, 10H), 6.00 (s, 1H), 4.49 (dq, J = 16.8, 8.4 Hz, 1H), 3.72 (s, 1.5H), 3.64 (s,
1.5H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 168.4, 168.3, 165.60 (d, J = 2.5 Hz), 165.57 (d, J = 2.5
Hz), 133.0, 132.9, 129.8, 129.7, 129.6, 129.5, 129.4, 129.02, 128.95, 128.9, 128.8 (d, J = 1.2 Hz), 127.7,
127.5, 123.7 (q, J = 280.1 Hz), 123.7 (q, J = 280.1 Hz), 75.7, 75.6, 55.4 (q, J = 29.3 Hz), 55.3 (q, J =
28.9 Hz), 52.8, 52.7 ppm; F{1H} NMR (376 MHz, CDCl3) δ -70.62 (s, 1.5F), -70.63 (s, 1.5F) ppm;
19
HRMS-ESI m/z : [M+K]+ calcd for C18H15F3KO4 391.0554, found 391.0557.
+
Dimethyl (2S)-2-((3,3,3-trifluoro-2-phenylpropanoyl)oxy)succinate (5p). The product (102.9 mg,
59% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate = 7/1) as a pale
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yellow oil and as an inseparable mixture of diastereoisomers (d. r. = 1:1); 1H NMR (400 MHz, CDCl3) δ
7.45 – 7.39 (m, 5H), 5.59 (ddd, J = 12.7, 7.9, 4.6 Hz, 1H), 4.42 (qd, J = 8.4, 6.2 Hz, 1H), 3.77 (s, 1.5H),
3.67 (d, J = 12.5 Hz, 3H), 3.53 (s, 1.5H), 2.98 – 2.81 (m, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ
169.3, 169.0, 168.5, 168.4, 165.2 (d, J = 3.0 Hz), 165.1 (d, J = 2.8 Hz), 129.7, 129.6, 129.4, 129.0,
128.9, 128.7 (d, J = 0.9 Hz), 123.6 (q, J = 279.5 Hz), 123.5 (q, J = 279.7 Hz), 69.5, 69.4, 55.3 (q, J =
29.3 Hz), 55.2 (q, J = 29.2 Hz), 52.9, 52.8, 52.3, 52.1, 35.7 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -
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-
70.7 (s, 1.5F), -70.8 (s, 1.5F) ppm; HRMS-ESI m/z : [M-H]- calcd for C15H14F3O6 347.0748, found
347.0749.
(3aR,5R,6S,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-6-yl 3,3,3-trifluoro-2-phenylpropanoate (5q). The product (115.5 mg, 52% yield) was
purified with silica gel chromatography (petroleum ether/dichloromethane = 1/1) as a colorless oil and
1
as an inseparable mixture of diastereoisomers (d. r. = 1:1); H NMR (400 MHz, CDCl3) δ 7.46 – 7.40
(m, 5H), 5.88 (d, J = 3.5 Hz, 0.5H), 5.74 (d, J = 3.6 Hz, 0.5H), 5.40 – 5.39 (m, 1H), 4.50 (d, J = 3.6 Hz,
0.5H), 4.40 – 4.32 (m, 1.5H), 4.19 (s, 1H), 4.13 (dd, J = 8.2, 2.7 Hz, 1H), 3.99 – 3.96 (m, 0.5H), 3.91 –
3.82 (m, 1H), 3.78 (dt, J = 8.2, 5.5 Hz, 0.5H), 1.51 (s, 3H), 1.41 (s, 1.5H), 1.31 (dd, J = 14.2, 10.2 Hz,
13
6H), 1.10 (s, 1.5H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 164.9 (d, J = 2.8 Hz), 164.7 (d, J = 2.6
Hz), 129.6, 129.53, 129.50, 129.14, 129.09, 128.9 (d, J = 1.0 Hz), 123.6 (q, J = 280.0 Hz), 112.7, 109.6,
109.4, 105.21, 105.18, 83.2, 83.0, 80.1, 77.6, 77.3, 72.3, 71.9, 67.7, 67.4, 55.7 (q, J = 29.3 Hz), 55.6 (q,
19
J = 28.9 Hz) 26.9, 26.83, 26.78, 26.3, 25.1, 24.9 ppm; F{1H} NMR (376 MHz, CDCl3) δ -70.6 (s,
-
1.5F), -70.7 (s, 1.5F) ppm; HRMS-ESI m/z : [M+Cl]- calcd for C21H25ClF3O7 481.1246, found
481.1240.
(2R,3R,4S,5S,6R)-2-(Acetoxymethyl)-6-((3,3,3-trifluoro-2-phenylpropanoyl)oxy)tetrahydro-2H-
pyran-3,4,5-triyl triacetate (5r). The product (192.1 mg, 72% yield) was purified with silica gel
chromatography (petroleum ether/ethyl acetate = 4/1) as a yellow oil and as an inseparable mixture of
diastereoisomers (d. r. = 56:44); 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.43 (m, 5H), 6.15 (dd, J = 13.7,
1.5 Hz, 1H), 5.32 – 5.13 (m, 3H), 4.45 (qd, J = 8.3, 4.0 Hz, 1H), 4.25 (dd, J = 12.4, 5.7 Hz, 0.44H), 4.11
(ddd, J = 17.4, 12.4, 3.5 Hz, 1H), 4.00 (ddd, J = 9.8, 5.6, 2.0 Hz, 0.44H), 3.85 (dd, J = 12.5, 2.1 Hz,
0.56H), 3.34 (ddd, J = 10.1, 4.7, 2.1 Hz, 0.56H), 2.07 (ddd, J = 26.4, 20.7, 2.9 Hz, 12H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 170.4, 170.3, 169.7, 169.6, 169.51, 169.47, 169.3, 163.5 (d, J = 2.7 Hz),
163.3 (d, J = 2.5 Hz), 129.54, 129.50, 129.4, 129.3, 129.2, 129.1, 128.7, 128.3, 123.4 (q, J = 280.3 Hz),
123.3 (q, J = 279.7 Hz), 91.9, 91.2, 71.2, 70.7, 68.5, 68.4, 67.7, 65.2, 64.7, 61.9, 61.5, 55.1 (q, J = 29.2
Hz), 55.0 (q, J = 29.4 Hz), 20.50, 20.45, 20.4 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.0 (s, 1.32F),
-70.5 (s, 1.68F) ppm; HRMS-ESI m/z : [M+Na]+ calcd for C23H25F3NaO11+ 557.1241, found 557.1248.
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The Journal of Organic Chemistry
Benzyl 3,3,3-trifluoro-2-(6-methoxynaphthalen-2-yl)propanoate (5s). In an argon-filled glovebox,
a dry flask was charged with phenyl benzyl 2-(6-methoxynaphthalen-2-yl)-2-oxoacetate 4s (1.50 g, 4.7
mmol, 1.0 equiv), 2,2-difluoro- 2-(triphenylphosphonio)acetate (5.00 g, 14.1 mmol, 3.0 equiv), and
DMSO (40 mL). H2O (0.08 g, 4.7 mmol, 1.0 equiv) was added to the reaction mixture at the room
o
7
8
temperature in the end. The mixture kept stirring at 60 C (oil bath) for 12 hours. Water (50 mL) was
9
added, and the mixture was extracted with ethyl acetate (3 x 30 mL). Organic layers were combined and
concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum
ether/ethyl acetate = 5/1) to afford the desired product 5s (1.02 g, 2.7 mmol) in 58% yield as a yellow
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o
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solid, mp = 84–87 C;. H NMR (400 MHz, CDCl3) δ 7.79 – 7.69 (m, 3H), 7.46 (d, J = 8.5 Hz, 1H),
7.32 – 7.25 (m, 5H), 7.19 – 7.13 (m, 2H), 5.26 (d, J = 12.3 Hz, 1H), 5.17 (d, J = 12.3 Hz, 1H), 4.50 (q, J
= 8.5 Hz, 1H), 3.92 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 166.3 (q, J =2.3 Hz), 158.6 135.0,
134.8, 129.8, 129.2, 128.72, 128.65, 128.3, 127.7, 127.0, 124.3 (d, J = 1.5 Hz), 124.0 (q, J = 280.0 Hz),
119.7, 105.6, 67.8, 55.54 (q, J = 28.9 Hz), 55.47 ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.6 (s, 3F)
+
ppm; HRMS-ESI m/z : [M+H]+ calcd for C21H18F3O3 375.1203, found 375.1218.
3,3,3-Trifluoro-2-(6-methoxynaphthalen-2-yl)propanoic acid (6).11 To a solution of 5s in THF (20
mL) were added Pd/C (10% on carbon, 0.85 g, 0.8 mmol, 0.3 equiv). The reaction mixture was stirred
under H2 atmosphere (balloon) at rt for 3 h, filtered through a short pad of celite and concentrated under
reduced pressure. The crude material was purified by flash chromatography (dichloromethane/methanol
= 10/1) to afford the desired product 6 (0.67 g, 2.4 mmol) in 87% yield as a yellow solid, mp = 131–133
1
oC;. H NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.74 (dd, J = 15.5, 8.8 Hz, 2H), 7.51 (d, J = 8.5 Hz,
1H), 7.19 – 7.11 (m, 2H), 4.67 (q, J = 8.9 Hz, 1H), 3.86 (s, 3H) ppm; 19F{1H} NMR (376 MHz, CDCl3)
δ -70.6 (s, 3F) ppm.
Methyl 3,3,3-trifluoro-2-phenylpropanoate (8).7b In an argon-filled glovebox, a dry reaction tube
was charged with phenyl methyl 3,3-difluoro -2-phenylacrylate 7 (0.1 mmol, 1.0 equiv), 2,2-difluoro-2-
(triphenylphosphonio)acetate (0.3 mmol, 3.0 equiv), and DMSO (1 mL). H2O (0.1 mmol, 1.0 equiv) was
added to the reaction mixture at the room temperature in the end. The mixture kept stirring at 60 oC (oil
bath) for 12 hours. Yields of product 8 were determined by 19F NMR spectroscopy using
trifluorotoluene as an internal standard. 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.37 (m, 5H), 4.33 (q, J =
8.6 Hz, 1H), 3.74 (s, 3H) ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -70.8 (s, 3F) ppm.
Methyl 3-phenyl 2-phenylmalonate (10). A dry reaction tube was charged with phenyl 3,3,3-
trifluoro-2-phenylpropanoate 5a (0.3 mmol, 1.0 equiv), NaOH (0.6 mmol, 2.0 equiv), and MeOH (2
mL). H2O (0.3 mmol, 1.0 equiv) was added to the reaction mixture at the room temperature in the end.
The mixture kept stirring at rt for 3 hours. The resulting mixture was directly subjected to silica gel flash
chromatography (petroleum ether/dichloromethane = 10/1) to afford the desired product 10 (38.9 mg,
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0.14 mmol) in 48% yield as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 7.8, 1.3 Hz,
2H), 7.43 – 7.35 (m, 5H), 7.24 (dd, J = 12.2, 4.7 Hz, 1H), 7.08 (d, J = 7.8 Hz, 2H), 4.88 (s, 1H), 3.82 (s,
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4
13
3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 168.5, 166.8, 150.7, 132.3, 129.6, 129.5, 129.0, 128.7,
5
6
+
126.3, 121.4, 57.9, 53.2 ppm; HRMS-ESI m/z : [M+Na]+ calcd for C16H14NaO4 293.0784, found
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293.0788.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Screening of reaction conditions and copies of 1H, 13C, 19F NMR (PDF)
AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are thankful for financial support from the National Key Research and Development Program of
China (grant No. 2016YFC1304704 and 2018YFA0704000), and the Key Research Program of Frontier
Sciences, CAS (QYZDY-SSWSLH018). We are grateful to Dr. Guofu Qiu and Dr. Jianli Duan in
School of Pharmaceutical Sciences at Wuhan University for the NMR and HRMS analysis ，
respectively.
REFERENCES
(1) (a) Harper, D. B.; O’Hagan, D. The Fluorinated Natural Products. Nat. Prod. Rep. 1994, 11, 123-
133. (b) O’Hagan, D.; Harper, D. B. Fluorine-containing Natural Products. J. Fluorine Chem. 1999,
100, 127-133.
(2) (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Catalysis for Fluorination and Trifluoromethylation.
Nature 2011, 473, 470-477. (b) Charpentier, J.; Früh, N.; Togni, A. Electrophilic Trifluoromethylation
by Use of Hypervalent Iodine Reagents. Chem. Rev. 2015, 115, 650-682. (c) Yang, C.; Hassanpour, A.;
Ghorbanpour, K.; Abdolmohammadi, S.; Vessally, E. Recent Advances in Direct Trifluoromethylation
of Olefinic C–H Bonds. RSC Adv. 2019, 9, 27625-27639 and references cited therein.
(3) (a) Hiyama, T. Organo-fluorine Compounds, Chemistry and Applications, Springer-Verlag:
Berlin Heidelberg, 2000. (b) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking
24
ACS Paragon Plus Environment

Page 25 of 29
The Journal of Organic Chemistry
Beyond Intuition. Science 2007, 317, 1881-1886. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320-330. (d) Ojima, I. Fluorine in
Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Chichester, 2009. (e) Fujiwara, T.;
O’Hagan, D. Successful Fluorine-containing Herbicide Agrochemicals. J. Fluorine Chem. 2014, 167,
16-29. (f) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.;
Liu, H. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II−III
Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas.
Chem. Rev. 2016, 116, 422-518. (g) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and
Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822-5880. (h) Mei, H.; Han, J.;
Fustero, S.; Medio-Simon, M.; Sedgwick, D. M.; Santi, C.; Ruzziconi, R.; Soloshonok, V. A. Fluorine-
Containing Drugs Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25, 11797-11819. (i) Moschner,
J.; Stulberg, V.; Fernandes, R.; Huhmann, S.; Leppkes, J.; Koksch, B. Approaches to Obtaining
Fluorinated α‑Amino Acids. Chem. Rev. 2019, 119, 10718-10801.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) (a) Middleton, W. J.; Bingham, E. M. The Synthesis of Antiinflammatory α-(trifluoromethyl)
Arylacetic Acids. J. Fluorine Chem. 1983, 22, 561-574. (b) Butovich, I. A.; Soloshonok, V. A.; Kukhar,
V. P. The Unusual Action of (R,S)-2-Hydroxy-2-trifluoromethyl-trans-n-octadec-4-enoic Acid on 5-
Lipoxygenase from Potato Tubers. Eur. J. Biochem. 1991, 199, 153-155. (c) Sculptoreanu, A.;
Yoshimura, N.; de Groat, W. C. KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-
trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K+ Currents in
Neurons of the Dorsal Root Ganglion of the Adult Rat. J. Pharmacol. Exp. Ther. 2004, 310, 159-168.
(d) Parker, J. S.; Bower, J. F.; Murray, P. M.; Patel, B.; Talavera, P. Kepner-Tregoe Decision Analysis
as a Tool To Aid Route Selection. Part 3. Application to a Back-Up Series of Compounds in the PDK
Project. Org. Process Res. Dev. 2008, 12, 1060-1077. (e) Combs, A. P. Recent Advances in the
Discovery of Competitive Protein Tyrosine Phosphatase 1B Inhibitors for the Treatment of Diabetes,
Obesity, and Cancer. J. Med. Chem. 2010, 53, 2333-2344. (f) Vorobyeva, D. V.; Peregudov, A. S.;
Röschenthaler, G.-V.; Osipov, S. N. Synthesis of α-CF3-Containing Triazolyl Amino Acids as Potential
Neurotransmitters via Click-reaction. J. Fluorine Chem. 2015, 175, 60-67.
(5) (a) Carnell, A. J.; Hale, I.; Denis, S.; Wanders, R. J. A.; Isaacs, W. B.; Wilson, B. A.;
Ferdinandusse, S. Design, Synthesis, and In Vitro Testing of α-Methylacyl-CoA Racemase Inhibitors. J.
Med. Chem. 2007, 50, 2700-2707. (b) Wang, X.; Buchwald, S. L. Synthesis of Optically Pure 2 ‑
Trifluoromethyl Lactic Acid by Asymmetric Hydroformylation. J. Org. Chem. 2013, 78, 3429-3433. (c)
Dong, K.; Li, Y.; Wang, Z.; Ding, K. Catalytic Asymmetric Hydrogenation of α-CF3- or β-CF3-
Substituted Acrylic Acids using Rhodium(I) Complexes with a Combination of Chiral and Achiral
Ligands. Angew. Chem. Int. Ed. 2013, 52, 14191-14195. (d) Han, X.; Wu, H.; Wang, W.; Dong, C.;
25
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The Journal of Organic Chemistry
Page 26 of 29
Tien, P.; Wu, S.; Zhou, H.-B. Synthesis and SARs of Indole-based α-Amino Acids as Potent HIV-1
Non-nucleoside Reverse Transcriptase Inhibitors. Org. Biomol. Chem. 2014, 12, 8308-8317. (e) Chen,
M. Z.; Sach, N. W.; Nuhant, P.; Fadeyi, O. O.; Trujillo, J.; Lombardo, V.; Bernier, L.; Unwalla, R.;
Flick, A. C. Synthesis of (R)- and (S)-α-Trifluoromethyl Propanoic Acids via Asymmetric
Hydrogenation followed by Salt Resolution. Tetrahedron: Asymmetry 2016, 27, 882-887. (f) Banerjee,
S.; Schmidt, J.; Talmon, Y.; Hori, H.; Asaid, T.; Ameduri, B. A Degradable Fluorinated Surfactant for
Emulsion Polymerization of Vinylidene Fluoride. Chem. Commun. 2018, 54, 11399-11402. (g) Bhakta,
U.; Kattamuri, P. V.; Siitonen, J. H.; Alemany, L. B.; Kürti, L. Enantioselective Catalytic Allylation of
Acyclic Ketiminoesters: Synthesis of α ‑Fully-Substituted Amino Esters. Org. Lett. 2019, 21, 9208-
9211.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Umemoto, T.; Ishihara, S. Power-Variable Electrophilic Trifluoromethylating Agents. S-, Se-,
and Te-(Trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium Salt System. J. Am. Chem. Soc.
1993, 115, 2156-2164. (b) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. Highly Enantioselective Copper-
Catalyzed Electrophilic Trifluoromethylation of β-Ketoesters. J. Am. Chem. Soc. 2012, 134, 10769-
10772. (c) Gelat, F.; Patra, A.; Pannecoucke, X.; Biju, A. T.; Poisson, T.; Besset, T. N ‑Heterocyclic
Carbene-Catalyzed Synthesis of α ‑ Trifluoromethyl Esters. Org. Lett. 2018, 20, 3897-3901 and
references cited therein.
(7) (a) Hu, M.; Ni, C.; Hu, J. Copper-Mediated Trifluoromethylation of α ‑ Diazo Esters with
TMSCF3: The Important Role of Water as a Promoter. J. Am. Chem. Soc. 2012, 134, 15257-15260. (b)
Hu, X.-Q.; Han, J.-B.; Zhang, C.-P. Cu-Mediated Trifluoromethylation of Aromatic α-Diazo Esters with
the Yagupolskii–Umemoto Reagent. Eur. J. Org. Chem. 2017, 324-331.
(8) (a) Miura, K.; Takeyama, Y.; Oshima, K.; Utimoto, K. Triethylborane Induced
Perfluoroalkylation of Silyl Enol Ethers and Ketene Silyl Acetals with Perfluoroalkyl Iodides. Bull.
Chem. Soc. Jpn. 1991, 64, 1542-1553. (b) Sato, K.; Yuki, T.; Yamaguchi, R.; Hamano, T.; Tarui, A.;
Omote, M.; Kumadaki, I.; Ando, A. Mechanistic Studies on α-Trifluoromethylation of Ketones via Silyl
Enol Ethers and Its Application to Other Carbonyl Compounds. J. Org. Chem. 2009, 74, 3815-3819. (c)
Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Photoredox Catalysis: A Mild, Operationally Simple
Approach to the Synthesis of α-Trifluoromethyl Carbonyl Compounds. Angew. Chem. Int. Ed. 2011, 50,
6119-6122. (d) Katayev, D.; Matoušek, V.; Koller, R.; Togni, A. Lewis Acid Catalyzed Synthesis of α‑
Trifluoromethyl Esters and Lactones by Electrophilic Trifluoromethylation. Org. Lett. 2015, 17, 5898-
5901. (e) Katayev, D.; Václavík, J.; Brüning, F.; Commare, B.; Togni, A. Synthesis of Quaternary α-
Perfluoroalkyl Lactams via Electrophilic Perfluoroalkylation. Chem. Commun. 2016, 52, 4049-4052.
26
ACS Paragon Plus Environment

Page 27 of 29
1
The Journal of Organic Chemistry
(9) Eisenberger, P.; Gischig, S.; Togni, A. Novel 10-I-3 Hypervalent Iodine-Based Compounds for
2
3
Electrophilic Trifluoromethylation. Chem. - Eur. J. 2006, 12, 2579-2586.
4
5
6
(10) Umemoto, T.; Ishihara, S. Power-variable Trifluoromethylating Agents, (Trifluoromethyl)
dibenzothio- and -Selenophenium Salt System. Tetrahedron Lett. 1990, 31, 3579-3582.
7
8
9
(11) Yoo, W.-J.; Kondo, J.; Rodríguez-Santamaría, J. A.; Nguyen, T. V. Q.; Kobayashi, S. Efficient
Synthesis of a-Trifluoromethyl Carboxylic Acids and Esters through Fluorocarboxylation of gem-
Difluoroalkenes. Angew. Chem. Int. Ed. 2019, 58, 6772-6775.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) (a) Nguyen, B. V.; Burton, D. J. A New Route for the Preparation of Substituted 2,2-
Difluorostyrenes and a Convenient Route to Substituted (2,2,2-Trifluoroethyl)benzenes. J. Org. Chem.
1997, 62, 7758-7764. (b) Qiao, Y.; Si, T.; Yang, M.-H.; Altman, R. A. Metal-Free Trifluoromethylation
of Aromatic and Heteroaromatic Aldehydes and Ketones. J. Org. Chem. 2014, 79, 7122-7131. (c) Deng,
X.; Lin, J.; Zheng, J.; Xiao, J. Cu-Promoted Oxidative Trifluoromethylation of Terminal Alkynes with
Difluoromethylene Phosphobetaine. Chin. J. Chem. 2014, 32, 689-693. (d) Gao, B.; Zhao, Y.; Ni, C.;
Hu, J. AgF-Mediated Fluorinative Homocoupling of gem-Difluoroalkenes. Org. Lett. 2014, 16, 102-
105. (e) Gao, B.; Zhao, Y.; Hu, J. AgF-Mediated Fluorinative Cross-Coupling of Two Olefins: Facile
Access to α-CF3 Alkenes and β-CF3 Ketones. Angew. Chem. Int. Ed. 2015, 54, 638-642. (f) Tian, P.;
Wang, C.-Q.; Cai, S.-H.; Song, S.; Ye, L.; Feng, C.; Loh, T.-P. F- Nucleophilic-Addition-Induced
Allylic Alkylation. J. Am. Chem. Soc. 2016, 138, 15869-15872. (g) Tang, H.-J.; Lin, L.-Z.; Feng, C.;
Loh, T.-P. Palladium-Catalyzed Fluoroarylation of gem-Difluoroalkenes. Angew. Chem. Int. Ed. 2017,
56, 9872-9876. (h) Tang, H.-J.; Zhang, Y.-F.; Jiang, Y.-W.; Feng, C. F− Nucleophilic-Addition-Induced
[3+2] Annulation: Direct Access to CF3 ‑Substituted Indenes. Org. Lett. 2018, 20, 5190-5193. (i) Liu,
H.; Ge, L.; Wang, D.-X.; Chen, N.; Feng, C. Photoredox-Coupled F-Nucleophilic Addition: Allylation
of gem-Difluoroalkenes. Angew. Chem. Int. Ed. 2019, 58, 3918-3922.
(13) (a) Hu, J.; Zhang, W.; Wang, F. Selective Difluoromethylation and Monofluoromethylation
Reactions. Chem. Commun. 2009, 7465-7478. (b) Zhang, C.-P.; Chen, Q.-Y. Guo, Y.; Xiao, J.-C.; Gu,
Y.-C. Progress in Fluoroalkylation of Organic Compounds via Sulfinatodehalogenation Initiation
System. Chem. Soc. Rev. 2012, 41, 4536-4559. (c) Ni, C.; Hu, J. Recent Advances in the Synthetic
Application of Difluorocarbene. Synthesis 2014, 46, 842-863. (d) Ni, C.; Hu, M.; Hu, J. Good
Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for
Organic Synthesis. Chem. Rev. 2015, 115, 765-825. (e) Pan, X.; Xia, H.; Wu, J. Recent Advances in
Photoinduced Trifluoromethylation and Difluoroalkylation. Org. Chem. Front. 2016, 3, 1163-1185. (f)
Dilman, A. D.; Levin, V. V. Difluorocarbene as a Building Block for Consecutive Bond-Forming
Reactions. Acc. Chem. Res. 2018, 51, 1272-1280. (g) Feng, Z.; Xiao, Y.-L.; Zhang, X. Transition-Metal
27
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The Journal of Organic Chemistry
Page 28 of 29
(Cu, Pd, Ni)-Catalyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides. Acc. Chem.
Res. 2018, 51, 2264-2278.
1
2
3
4
5
6
7
8
9
(14) (a) Zheng, J.; Cai, J.; Lin, J.-H.; Guo, Y.; Xiao, J.-C. Synthesis and Decarboxylative Wittig
Reaction of Difluoromethylene Phosphobetaine. Chem. Commun. 2013, 49, 7513-7515. (b) Zheng, J.;
Lin, J.-H.; Cai, J.; Xiao, J.-C. Conversion between Difluorocarbene and Difluoromethylene Ylide.
Chem. - Eur. J. 2013, 19, 15261-15266. (c) Zheng, J.; Lin, J.-H.; Yu, L.-Y.; Wei, Y.; Zheng, X.; Xiao,
J.-C. Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from
Diazocompounds for the Synthesis of gem-Difluoroolefins. Org. Lett. 2015, 17, 6150-6153. (d) Zheng,
J.; Lin, J.-H.; Deng, X.-Y.; Xiao, J.-C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-Promoted
Decomposition of Difluorocarbene and the Subsequent Trifluoromethylation. Org. Lett. 2015, 17, 532-
535. (e) Liu, Y.; Zhang, K.; Huang, Y.; Pan, S.; Liu, X.-Q.; Yang, Y.; Jiang ,Y.; Xu, X.-H. Synthesis of
3-Fluoroalkenyl-3-trifluoromethyl-2-oxindoles by the Reaction of Indoline-2,3-diones with
Difluoromethylene Phosphabetaine. Chem. Commun. 2016, 52, 5969-5972. (f) Zheng, J.; Cheng, R.;
Lin, J.-H.; Yu, D.-H.; Ma, L.; Jia, L.; Zhang, L.; Wang, L.; Xiao, J.-C.; Liang, S. H. An Unconventional
Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18F-Labeled α-SCF3
Carbonyl Compounds. Angew. Chem. Int. Ed. 2017, 56, 3196-3200. (g) Yu, J.; Lin, J.-H.; Xiao, J.-C.
Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines. Angew. Chem. Int.
Ed. 2017, 56, 16669-16673.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) (a) Fu, M.; Chen, L.; Jiang, Y.; Jiang, Z.-X.; Yang, Z. Copper-Catalyzed Intermolecular
Chloro- and Bromotrifluoromethylation of Alkenes. Org. Lett. 2016, 18, 348-351. (b) Jia, Y.; Qin, H.;
Wang, N.; Jiang, Z.-X.; Yang, Z. Fe2O3 ‑Promoted Intermolecular Chlorotrifluoromethylthiolation of
Alkenes. J. Org. Chem. 2018, 83, 2808-2817.
(16) Fuqua, S. A.; Duncan, W. G.; Silverstein, R. M. A One-Step Synthesis of 1,1-Difluoro Olefins
from Aldehydes. J. Org. Chem. 1965, 30, 1027-1029.
(17) Harris, J. M.; Chess, R. B. Effect of Pegylation on Pharmaceuticals. Nat. Rev. Drug Discovery
2003, 2, 214-221.
(18) Baker, M. T.; Naguib, M. Propofol: The Challenges of Formulation. Anesthesiology 2005, 103,
860-876.
(19) Van Patten, P. L. Mandelic Acid and Urinary Tract Infections. Antonie van Leeuwenhoek 1979,
45, 622-623.
(20) Goldberg, I.; Rokem, J. S.; Pines, O. Organic Acids: Old Metabolites, New Themes. J. Chem.
Technol. Biotechnol. 2006, 81, 1601-1611.
28
ACS Paragon Plus Environment

Page 29 of 29
1
The Journal of Organic Chemistry
(21) Adeva-Andany, M. M.; Pérez-Felpete, N.; Fernández-Fernández, C.; Donapetry-García, C.;
2
3
Pazos-García, C. Liver Glucose Metabolism in Humans. Biosci. Rep. 2016, 36, e00416.
4
5
6
7
8
9
(22) Hu, X.; Shi, Y.; Zhang, P.; Miao, M.; Zhang, T.; Jiang, B. D-Mannose: Properties, Production,
and Applications: An Overview. Comp. Rev. Food Sci. Food Safety, 2016 15, 773-785.
(23) Tang, X.-Z.; Tong, L.; Liang, H.-J.; Liang, J.; Zou, Y.; Zhang, X.-J.; Yan, M.; Chan, A. S. C.
Facile Synthesis of Substituted Diaryl sulfones via a [3 + 3] Benzannulation Strategy. Org. Biomol.
Chem. 2018, 16, 3560-3563.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24) Feng, J.; Fu, X.; Chen, Z.; Lin, L.; Liu, X.; Feng, X. Efficient Enantioselective Synthesis of
Dihydropyrans Using a Chiral N,N′-Dioxide as Organocatalyst. Org. Lett. 2013, 15, 2640-2643.
(25) (a) Zhuang, J.; Wang, C.; Xie, F.; Zhang, W. One-pot Efficient Synthesis of Aryl α-Keto Esters
from Aryl-ketones. Tetrahedron. 2009, 65, 9797-9800. (b) Harada, K.; Imbe, Y.; Nishihira, K.; Tanaka,
S.; Fujitsu, S.; Sugise, R.; Kashiwagi, K.; Sumida, T.; Doi, T.; Nishio, M. Phosphorus Catalysts for
Decarbonylation Reaction. US Patent US005892091A, 1999.
(26) Hameury, T.; Guillemont, J.; Hijfte, L. V.; Bellosta, V.; Cossy, J. Diastereodivergent Addition
of Allenylzincs to Aryl Glyoxylates. Org. Lett. 2009, 11, 2397-2400.
(27) Karasawa, T.; Oriez, R.; Kumagai, N.; Shibasaki, M. anti-Selective Catalytic Asymmetric
Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active
Pharmaceutical Ingredients. J. Am. Chem. Soc. 2018, 140, 12290-12295.
(28) Jin, Z.; Jiang, K.; Fu, Z.; Torres, J.; Zheng, P.; Yang, S.; Song, B.-A.; Chi, Y. R. Nucleophilic
β-Carbon Activation of Propionic Acid as a 3-Carbon Synthon by Carbene Organocatalysis. Chem. -
Eur. J. 2015, 21, 9360-9363.
(29) Duan, H.-F.; Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L. Enantioselective Rhodium-
Catalyzed Addition of Arylboronic Acids to α-Ketoesters. Angew. Chem. Int. Ed. 2008, 47, 4351-4353.
(30) Chen, J.; Li, F.; Wang, F.; Hu, Y.; Zhang, Z.; Zhao, M.; Zhang, W. Pd(OAc)2-Catalyzed
Asymmetric Hydrogenation of α-Iminoesters. Org. Lett. 2019, 21, 9060-9065.
29
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