Catalytic Enantioselective Protonation of Monofluorinated Silyl Enol Ethers towards Chiral α-Fluoroketones

Article abstract of DOI:10.1002/cjoc.201900198

Described herein is an organocatalytic enantioselective protonation of monofluorinated silyl enol ethers, affording an array of optically active α-secondary α-fluoroketones in good to high yields and enantioselectivities, under the catalysis of bifunction

Full text of DOI:10.1002/cjoc.201900198

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Catalytic Enantioselective Protonation of Monofluorinated Silyl Enol Ethers
towards Chiral α-Fluoroketones
Authors: Kui Liao, Xiao-Si Hu, Ren-Yi Zhu, Ruo-Han Rao, Jin-Sheng Yu,* Feng Zhou,
and Jian Zhou*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2019, 37, 10.1002/cjoc.201900198.
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Catalytic Enantioselective Protonation of Monofluorinated Silyl Enol
Ethers towards Chiral α-Fluoroketones
Kui Liao, a Xiao-Si Hu, a Ren-Yi Zhu, a Ruo-Han Rao,b Jin-Sheng Yu,*,a Feng Zhou, a and Jian Zhou*, a, c
a Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development; Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, East China Normal University, Shanghai 200062 China
b Chengdu Shude High School Foreign Language Campus, 398N Bairihong West Road, Chengdu, Sichuan 610066, China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032 China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
ABSTRACT Described herein is an organocatalytic enantioselective protonation of monofluorinated silyl enol ethers, affording an array of optically active
α-secondary α-fluoroketones in good to high yields and enantioselectivities, under the catalysis of bifunctional cinchonidine derived squaramide C4. It
represents a rare example of facile synthesis of enantioenriched α-secondary α-fluoroketones. With D2O as the deuterium source and MeOD as the solvent,
the first highly enantioselective preparation of chiral α-deuterated α-fluoroketones in >92 % deuteration is developed.
KEY WORDS Enantioselective Protonation, Monofluorinated Silyl Enol Ethers, Chiral α-Fluoroketone, Organocatalysis
while enantioselective protonation of prochiral enolate
Introduction
The selective incorporation of a fluorine or fluorinated moiety into
derivatives allows facile synthesis of chiral α-monosubstituted
carbonyl compounds,[7] few attention is paid to the application of
organic molecules has been identified as a fruitful tool to improve
this strategy to access α-fluoroketones. In 2003, Hénin et al tried a
the pharmacological properties in drug discovery,[1] because the
decarboxylative protonation of benzyl 2-fluoro-1-tetralone-2-
carboxylate 1a, with 66% ee obtained.[8a] In 2006, Stoltz et al
presence of a fluorine moiety often brings about beneficial effects
such as the enhancement in bioavailability, lipophilicity, and
achieved up to 88% ee in the synthesis (S)-2-fluoro-1-tetralone via
metabolic stability.[2] Consequently, efficient and selective
introduction of fluorine atoms or fluoroalkyl groups is much
sought after in medicinal research.[3] Among various fluorinated
motifs, optically active α-fluorocarbonyl compounds represent a
type of privileged scaffolds, owing to their occurrence in bioactive
molecules (fluasterone,[4a] and 12-fIuoroforskolin[4b] for example)
and chiral catalyst[4c] (Figure 1). In addition, they can serve as
versatile fluorinated synthons.[4d]
the decarboxylative protonation.[8b] Later, Levacher and Oudeyer
attempted organocatalytic protonation of monofluorinated silyl
enol ether (m-FSEE) 2d, and found chiral amine (DHQ)2AQN could
afford 3d in 75% ee.[8c,d] Nevertheless, all the three reports only
disclosed the synthesis of α-fluoro tetralone 3d, and the catalytic
asymmetric protonation to structurally diverse α-fluoroketones
waits for further exploration in terms of enantioselectivity and
substrate scope.
F
O
O
F
O
HO
F
O
H
F
O
O
OH
OH
H
H
F
OAc
OTBDPS
H
Precursor of
2'-fluoronucleosides
Fluasterone
12-FIuoroforskolin
Chiral catalyst
Figure 1 Selected compounds featuring α-fluorocarbonyl unit.
In the past decade, much attention has gone to the catalytic
enantioselective synthesis of α-fluorocarbonyl compounds. Some
synthetic strategies are developed, including electrophilic
fluorination[5a-e], nucleophilic fluorination[5f-g], functionalization of
α-fluoroenolate equivalents[5h-l] or other α-fluorinated
substrates[5m-n] (Scheme 1A).[3b] However, despite ongoing
progress, catalytic asymmetric synthesis of α-secondary α-fluoro
carbonyl compounds is largely undeveloped.[6] On the other hand,
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Liao et al.
Report
Scheme 1 Known synthetic strategies and this work
bifunctional catalyst C1 that we developed for Michael reaction
involving m-FSEEs afforded product 3a in 90% yield with only 6%
ee after 1 day (entry 1). Our phosphoramide-tertiary amine
catalyst C2 exhibited much lower reactivity, but the ee value was
improved to 47% (entry 2). Cinchona alkaloid derived bifunctional
catalyst C3 further increased the enantioselectivity to 53% (entry
3). To our pleasure, cinchonidine derived squaramide catalyst C4
enabled the reaction to furnish 3a in up to 76% ee with 69% yield,
albeit with prolong reaction time (entry 4). Then we examined
solvent effects to improve the reactivity and enantioselectivity
(entries 5-12). While the use of toluene, CH2Cl2, THF, EtOAc, and
MeCN all led to low ee values, alcoholic solvents proved to be
capable of enhancing the enantioselectivity, and trifluoroethanol
(TFE) turned out to be the best in terms of enantioselectivity and
reactivity, as the reaction could finish within 1 day to afford the
desired product 3a in up to 77% yield and 86% ee (entry 12).
Considering that alcoholic solvents might act as the proton source,
so we conducted the reaction in the absence of H2O. However, a
diminished 75% ee for product 3a was detected, indicating the
indispensable role of H2O in achieving high enantioselectivity
(entry 13 vs 12).[17] Besides, lowering the reaction temperature to
0 oC, the enantioselectivity of 3a was increased to 89% (entry 14).
Furthermore, decreasing the usage of catalyst C4 from 10 mol% to
5 mol% furnished the α-fluoroindanone 3a in 81% yield and 90%
ee (entry 15).
a
access
strategy to
-fluoro carbonyl
compounds
A) Synthetic
Functionalization of
-fluoroenolate
equivalents
Electrophilic
fluorination
O
O
a
R1
R1
+
R
R
F
R2
F
R2
R1
O
R
Functionalization of
a
O
O
Nucleophilic
fluorination
-fluorinated
substrates
R1
F
FG
+
R
R
F
R1
R2
F
a
a
-fluoroketones
-secondary
Known methods toward
B)
mol%)
Quinine
O
(30
mol%), H , MeCN
CO2Bn
Pd/C
(2.5
2
F
ee)
66%
(95%,
1a
O
S
tBu-Phox
mol%)
O
CO2allyl
(
)-
(12.5
mol%)
F
F
Pd(OAc)2 (2.5
HCO
Dioxane,
MS
2H,
4Å
1b
ee)
one
only
example
88%
(79%,
OTMS
F
AQN
(DHQ)2
mol%)
(10
PhCOF, EtOH, DMF
ee)
75%
(83%,
2d
work
This
C)
O
OTMS
H
Organocatalysis
R1
F
F
∗
R1
+
H2O
R2
R2
Based on these optimizations, we determined to run the catalytic
enantioselective protonation of m-FSEEs in CF3CH2OH (0.1 M) at 0 °C,
in the presence of 5 mol% catalyst C4. We studied the substrate scope
with respect to differently substituted monofluorinated silyl enol
ethers, and all the reactions were run on a 0.3 mmol scale. As shown in
Table 2, five-membered cyclic monofluorinated silyl enol ethers were
first examined. It was found that α-fluoroindanones derived m-FSEEs
2a and 2b worked well to afford the corresponding product 3a and 3b
in 76% and 92% yield, 88% and 81% ee, respectively. The α-fluoro
benzofuranone 3c could be obtained in 81% ee, albeit with 36% yield,
due to the formation of side aldol byproduct.[18]
2
3
Monofluorinated silyl enol ethers 2, as readily available
α-fluorinated enolate precursors, have received growing attention
for the diversity-oriented synthesis of chiral α-fluoroketones.[9]
The past decade has witnessed a variety of elegant protocols
based on m-FSEEs, including allylation,[10] arylation,[11] aldol,[12]
Michael[13] and Mannich reaction,[14] as well as olefination.[15]
Since the Paquin group pioneered a Pd-catalyzed enantioselective
allylation reaction of m-FSEEs 2 in 2007,[10a] m-FSEEs have found
increasing application in asymmetric catalysis. As a continuation in
exploring diversity-oriented synthesis using fluorinated silyl enol
ethers,[12-16] we have found chiral bifunctional amine catalysts
were able to efficiently activate m-FSEEs for the aldol reaction
with isatins,[12a] Mannich reaction with cyclic N-sulfonyl ketimines,
Table 1 Condition optimizationa
O
OTMS
F
Cat.
mol%)
(10
∗
and Michael addition to isatylidene malononitriles.[13a] Based
[14a]
+
H2O
F
Solvent
M) 25 o Time
,
C,
(0.1
on these results, we wonder whether it is possible to extend
bifunctional amine catalysis to enantioselective protonation of
m-FSEEs, providing a facile entry to structurally diverse chiral
α-fluoroketones. Herein, we wish to report a cinchona alkaloid
derived bifunctional squaramide catalyzed highly enantioselective
protonation of m-FSEEs to chiral α-secondary α-fluoroketones.
mmol)
2a
3a
equiv)
(1.0
(0.1
Ph
OMe
N
N
NH
N
N
H
N
H
H
N
P
OR
N
P
H
N
Ar
N
OH
OR
N
OEt
O
O
O
OEt
Results and Discussion
C4
O
=
C1
C2
C3
=
3,5-(CF3
(Ar
2C6H3
(R 3-pentyl)
)
)
Our study commenced with the investigation of different
bifunctional chiral amine catalysts for the enantioselective
hydrolysis of indanone derived m-FSEE 2a. All the reactions were
performed in anhydrous acetone at room temperature (Table 1).
The use of 10 mol% chiral phosphoramide-secondary amine
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Running title
Chin. J. Chem.
We next turned our attention to investigate the performance of
Entry
1
Cat.
C1
C2
C3
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
Solvent
Acetone
Acetone
Acetone
Acetone
Toluene
CH2Cl2
H2O
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
Time (d) Yield (%)
Ee (%)
6
six-membered
cyclic
m-FSEEs.
Differently
substituted
α-fluorotetralone derived silyl enol ethers all proceeded well to
produce the target products 3d-h with 72-97% yields and 88-90% ee.
However, the use of 10 mol% or 20 mol% catalyst was required to
ensure satisfactory yields. Additionally, seven-membered α-fluoro
1-benzosuberone 3i was also obtained in 61% yield with 80% ee. And
optically enriched 6-fluoro cyclohexenones 3j-k could also be
produced with 68-91% yield and 81-91% ee values, from the simply
cyclohexenone derived m-FSEEs. Notably, 2-fluorobutyrophenone
derived acyclic fluorinated silyl enol ether 2l (E/Z >20:1) also turned
out to be a viable substrate, providing the desired optically active
acyclic α-fluoroketones 3l in 83% yield and 72% ee.[19]
1
5
5
7
7
7
7
7
7
3
7
1
1
4
6
90
88
97
69
31
61
37
49
49
82
47
77
87
83
81
2
47
53b
76
47
64
49
64
67
87
79
86
75
89
90
3
4
5
6
7
THF
Table 2 Substrate scope a
8
EtOAc
O
OTMS
H
C4
mol%)
(5-20
F
R1
F
R1
∗
+
9
MeCN
H
2O
R2
R2
CF CH OH
M) 0 o
C
,
(0.1
3
2
mmol)
2
3
10
11
12
13
14c
15c,d
MeOH
equiv)
(1.0
(0.3
O
O
iPrOH
O
O
F
F
F
F
O
Cl
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
3a
3b
3c
3d
ee
ee
ee
ee
F
76%
88%
92%
MeO
81%
O
36%
81%
72%
90%
O
yield,
yield,
yield,
yield,
O
O
F
1.0
1.0
Br
F
F
MeO
OMe
3g
3e
yield,
O
3f
3h
a
Unless noted, all reactions were run on a 0.1 mmol scale at room
ee
ee
ee
ee
88%
83%
88%
97%
90%
95%
88%
86%
yield,
yield,
O
yield,
O
temperature, with 10 mol% chiral catalyst ; isolated yield was reported; ee
was determined by chiral HPLC analysis. b Opposite enantiomer. At 0 C.
c
o
d
F
O
F
F
∗ Et
5 mol% C4 used.
Ph
F
Et
Et
Me Me
Scheme 2 Synthetic elaborations.
3i
3j
3k
3l
eeb
eeb
91%
81%
68%
83%
72%
ee
ee
91%
yield,
yield,
61%
80%
yield,
yield,
OH
LiBH
TiCl
4 (2.0 equivs)
equivs)
a
Unless otherwise noted, all reactions were run on a 0.3 mmol scale in
4 (1.5
CF3CH2OH (0.1 M) at 0 oC; 5 mol% C4 for 3a-c, 10 mol% C4 for 3i, 20 mol%
C4 for 3d-h, 3j-n; b At 25 oC.
F
Et2 -78 o 4 h
O
>
,
C,
4
ee
dr, 90%
97%, 20:1
O
The synthetic utility of this method was illustrated by the synthesis
of optically active β-fluoroalcohols (Scheme 2). For example, the
product 3a could be readily reduced by LiBH4 to produce
anti-β-fluoroalcohol 4 in 97% yield, >20:1 dr with 90% ee, in the
presence of TiCl4.[20] Treatment of 3a with ethynylmagnesium
bromide in THF at -20 oC delivered β-fluoro propargyl alcohol 5 in
91% yield and >20:1 dr, without any loss of ee value. The relative
and absolute configuration of 5 was assigned to be (1S, 2R) by single
crystal X-ray analysis of its O-Ac protected derivative 6.[21] The absolute
configuration of the product 3a-c was tentatively assigned to be R
based on the absolute configuration of 6. And absolute configuration
of products 3d-k was determined by comparing optical rotation values
with the literature data.[22]
F
HO
3a
MgBr
(2.0 equivs)
(R) F
ee)
(S)
(90%
THF -20 o 4 h
,
C,
>
ee
dr, 90%
5
91%, 20:1
AcO
(R) F
(S)
6
X-ray of 6
Given the replacement of hydrogen with deuterium in the
bioactive molecules emerges as a promising strategy to improve
Chin. J. Chem. 2019, 37, XXX－XXX
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Liao et al.
Report
the pharmacological properties in medicinal research. Since FDA
approved the first deuterated drug, Austedo, in 2017,[23] many
deuterated compounds have become clinical drugs, such as
DRX-065[24] and DRX-164.[25] In this light, the development of
efficient synthetic approaches for the preparation of deuterated
compounds is very much in demand. Accordingly, we tried to
incorporate deuterium into α-fluoroketone to access deuterated
α-fluoroketones[26] a type of molecules of important potential value in
drug discovery. To our delight, with D2O as the deuterium source, the
reaction of α-fluoro indanone or tetralone derived m-FSEEs
proceeded smoothly under the catalysis of C4 in MeOD, delivering
α-deuterated α-fluoroindanone 3m and α-fluorotetralone 3n in 90%
ee, 98% yield with 95% D, and 90% ee, 57% yield with 92% D,
respectively (Scheme 3). Notably, this represents the first highly
enantioselective catalytic synthesis of enantioenriched α-deuterated
α-fluoroketones.
Scheme 4 Fluorine effects and proposed transition state.
O
OTMS
or
C4
mol%)
20
(5
+
H2O
equiv)
X
X
TFE
M) 0 o
C
,
(0.1
(1.0
:
=
=
2a
X
X
F
=
=
:
ee
3a
(
X
X
5 mol% C4 76%
88%
F,
yield,
)
:
2o
Cl
:
ee
3o
(
Cl, 20 mol% C4 81%
0%
yield,
)
transition state
Proposed
N
CF3
O
O
N
H
F3C
N
N
H
Si
O
H
H
O
F
R1
R2
Scheme 3 Synthesis of chiral α-deuterated α-fluoroketones.
O
OTMS
Conclusions
C4
mol%)
or
(5-10
F
+
D2O
F
D
n
CD OD
M) 0 25 oC
n
In conclusion, we have developed a highly enantioselective
protonation of m-FSEEs by using a bifunctional cinchonidine
derived squaramide C4 and water as the proton source. This
provides a facile synthesis of structurally diverse enantioenriched
α-secondary α-fluoroketones. The resulting chiral α-fluoroketones
can be readily elaborated into the corresponding β-fluoroalcohols
without the loss of enantioselectivity. Notably, chiral α-deuterated
α-fluoroketones of important potential applications in medicinal
research, could be achieved with excellent enantioselectivity by this
protocol. The study of the detailed reaction mechanism and the
extension of scope toward other diversified chiral α-fluorinated
ketones are now ongoing in our laboratory.
,
(0.1
3
3
mmol)
(0.3
equiv)
(1.0
n =
ee,
ee,
1: 98%
2: 57%
90%
90%
95% D 3m
yield,
yield,
(
)
n =
n =
2a
2d
1
2
(
)
)
n =
92% D 3n
(
)
(
Interestingly, obvious fluorine effect was observed in the current
enantioselective protonation reaction, as the use of chlorinated silyl
enol ether 2o only produced the corresponding product 3o in 0% ee
and 81% yield, in sharp contrast to 88% ee with 76% yield for 3a.
Although the origin of this strong fluorine effect is not clear by
now, we speculated that it might be related to the possible
C-F…H-X interactions in the transition state, which have been found to
strongly influence of organic reaction by us and other groups.[27] Based
on this speculation, together with our results in the activation of FSEEs
by amine catalysis for reaction development,[12a,13a,14a,16ab] we proposed
a transition state in which the tertiary amine part of catalyst C4
activated silyl enol ethers 2 via the n-σ* interaction between the
silicon and nitrogen atom, whilst the squaramide moiety
interacted with proton source. The C-F…H-X interaction between
the water bonded to the two N-H bonds of squaramide[28] and the
C-F bond of the m-FSEE activated by tertiary amine moiety of C4
organized a favorable transition, allowing the proton to attack the
Si face. Without such a subtle interaction, it is difficult to realize
face discrimination to achieve high to excellent enantioselectivity,
as supported by the result obtained by using chlorinated silyl
ether 2o. Subsequently, the silyl enol ethers attached the proton
to provide the optically pure α-fluoroketones.
Experimental
General information
Reactions were monitored by thin layer chromatography using
UV light to visualize the course of reaction. Purification of reaction
products was carried out by flash chromatography on silica gel.
Chemical yields refer to pure isolated substances. Infrared (IR)
spectra were obtained using SHIMADZU TRT racer-100. The [α]D
was recorded using PolAAr 3005 High Accuracy Polarimeter and
Anton Paar MCP 5500. H, 19F, 13C NMR spectra were obtained
1
using a Bruker DPX-400 and 300 MHz spectrometers. Chemical
shifts are reported in ppm from CDCl3 with the solvent resonance
or (CH3)4Si as the internal standard. The following abbreviations
were used to designate chemical shift multiplicities: s = singlet, d
= doublet, t = triplet, q = quartet, h = heptet, m = multiplet, br =
broad. Coupling constants (J) are reported in Hertz.
All
reactions were run in air except noted. Anhydrous THF and
toluene were prepared by distillation over sodium-benzophenone
ketyl prior to use. Anhydrous CH2Cl2 and CH3CN were prepared by
first distillation over P2O5 and then from CaH2. Anhydrous EtOAc
and acetone was prepared by first distillation over activated
CaSO4 and then stored in 5Å molecular sieves. The
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Running title
Chin. J. Chem.
monofluorinated enol silyl ethers 2a-2c, 2m and 2p were
prepared according to literature reports,[14a,15a] 2d-2l were
prepared according to literature reports.[10a,11b] PE and TFE are the
abbreviation of petroleum ether and 2,2,2-trifluoroethanol,
respectively.
14.35 min, tr (major) = 16.56 min) gave the isomeric composition
of the product: 84% ee, [α]27D = -4.3 (c = 0.5, CHCl3); 1H NMR (400
MHz, CDCl3): δ 7.70-7.67 (m, 2H), 7.20-7.14 (m, 2H), 5.79 (d, J =
58.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 192.99 (d, J = 14.0 Hz,
1C), 171.41 (d, J = 3.0 Hz, 1C), 139.47, 124.59 (d, J = 157.0 Hz, 1C),
118.31, 113.49, 104.23 (d, J = 4.0 Hz, 1C), 101.87 (d, J = 3.0 Hz, 1C);
19F NMR (376 MHz, CDCl3): -139.84 (s, 1F). GC-MS: 152 (M+, 94),
151 (7), 124 (17), 104 (69), 96 (11), 76 (100), 63 (8), 50 (35); HRMS
(EI): Exact mass calcd for C8H5FO2 [M]+: 152.0274, Found:
152.0270.
General procedure
To a 5.0 mL vial were added chiral squaramides C4 (5-20 mol%)
and monofluorinated silyl enol ethers 2 (0.3 mmol, the structure
and numbering of 2 was shown in the supporting information),
followed by the addition of TFE (3.0 mL). The resulting mixture
was stirred at the indicated temperature (0 or 25 oC) for about 30
min before distilled water H2O (0.30 mmol, 1.0 equiv) was added.
After full conversion of 2 by TLC analysis, the reaction mixture was
directly subjected to flash column chromatography to afford the
desired chiral α-fluoroketones 3, using the indicated eluent. (Note:
the reaction for synthesis of deuterated products 3m-n was
performed under N2 atmosphere)
(2'S)-2,2'-Difluoro-3'-hydroxy-2',3'-dihydro-[2,3'-bibenzofuran]
-3(2H)-one (A): during the protonation reaction of
monofluorinated silyl enol ether 2c, a byproduct A generated
from the aldol reaction of 2c with product 3c was observed, and
isolated (PE/CH2Cl2 = 10:1) as a white solid in 54% yield, m. p.
116-118 oC. HPLC analysis revealed that the dr vlues is 1.5:1, HPLC
i
analysis (Chiralpak AS-H, PrOH/hexane = 15/85, 1.0 mL/min, 205
nm; major diastereomer: tr (minor) = 12.55 min, tr (major) = 17.97
min, minor diastereomer: tr (major) = 15.10 min, tr (minor) = 20.54
min) gave the isomeric composition of the major diastereomer: 81%
ee and the minor diastereomer: 83% ee, [α]27D = -108.1 (c = 1.0,
(R)-2-Fluoro-2,3-dihydro-1H-inden-1-one (3a): Prepared by the
general procedure from 2a (65.4 mg, 0.3 mmol) and H2O (5.5 uL,
0.3 mmol, 1.0 equiv) with C4 (9.0 mg, 0.015 mmol, 5 mol%),
1
o
CHCl3); H NMR for the major diastereomer (400 MHz, CDCl3): δ
stirred at 0 C for 7 d and column chromatography (PE/CH2Cl2 =
7.76-7.69 (m, 2H), 7.65 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.41 (td, J =
8.0 Hz, J = 1.2 Hz, 1H), 7.23-7.20 (m, 2H), 7.14 (td, J = 7.6 Hz, J =
0.8 Hz, 1H), 7.02-7.00 (m, 1H), 6.93 (dd, J = 62.4 Hz, J = 1.6 Hz, 1H),
3.03 (br, 1H); 13C NMR for the major diastereomer (100 MHz,
CDCl3): δ 192.85 (d, J = 18.0 Hz, 1C), 170.96 (d, J = 2.0 Hz, 1C),
158.32, 139.51, 132.27, 126.76, 125.47, 123.98, 123.22, 122.56,
119.11, 113.29, 111.15, 108.49 (d, J = 236.0 Hz, 1C), 107.50 (dd, J
= 239.0 Hz, J = 6.0 Hz, 1C), 82.39 (dd, J = 35.0 Hz, J = 9.0 Hz, 1C);
19F NMR for the major diastereomer (376 MHz, CDCl3): -127.99 (s,
1F), -137.99 (s, 1F). IR (neat): 3447, 1715, 1617, 1473, 1457, 1091,
753, 505; HRMS (ESI): Exact mass calcd for C16H10F2NaO4 [M+Na]+:
327.0439, Found: 327.0442.
20:1) afforded the product 3a in 76% yield as white solid.[29] HPLC
i
analysis (Chiralpak AS-H, PrOH/hexane = 15/85, 1.0 mL/min, 205
nm; tr (minor) = 9.57 min, tr (major) = 11.48 min) gave the isomeric
composition of the product: 87% ee, [α]27D = -3.0 (c = 0.5, CHCl3);
1H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 7.5 Hz, 1H), 7.70-7.65 (m,
1H), 7.48-7.41 (m, 2H), 5.27 (ddd, J = 51.0 Hz, J = 7.8 Hz, J = 4.5 Hz,
1H), 3.69-3.58 (m, 1H), 3.31-3.16 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 199.96 (d, J = 15.0 Hz, 1C), 149.69 (d, J = 5.0 Hz, 1C),
136.39, 133.91, 128.46, 126.84 (d, J = 2.0 Hz, 1C), 124.75, 90.51
(dd, J = 186.0 Hz, J = 3.0 Hz, 1C), 33.46 (d, J = 21.0 Hz, 1C); 19F
NMR (376 MHz, CDCl3): -193.98 (s, 1F).
(R)-5-Chloro-2-fluoro-2,3-dihydro-1H-inden-1-one (3b): Prepared
by the general procedure from 2b (76.8 mg, 0.3 mmol) and H2O
(5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (9.0 mg, 0.015 mmol, 5
mol%), stirred at 0 oC for 7 d and column chromatography
(PE/CH2Cl2 = 20:1) afforded the product 3b in 81% yield as white
(R)-2-Fluoro-3,4-dihydronaphthalen-1(2H)-one (3d): Prepared
by the general procedure from 2d (70.8 mg, 0.3 mmol) and H2O
(5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06 mmol, 20
mol%), stirred at 0 oC for 4 d and column chromatography
(PE/CH2Cl2 = 20:1) afforded the product 3d in 72% yield as white
solid.[29] HPLC analysis (Chiralpak AS-H, iPrOH/hexane = 15/85, 1.0
mL/min, 205 nm; tr (minor) = 9.20 min, tr (major) = 12.31 min)
i
solid.[30] HPLC analysis (Chiralpak AS-H, PrOH/hexane = 15/85, 1.0
mL/min, 205 nm; tr (minor) = 11.53 min, tr (major) = 15.79 min)
gave the isomeric composition of the product: 80% ee, [α]27
=
D
1
gave the isomeric composition of the product: 91% ee, [α]27
=
D
1
-2.7 (c = 1.00, CHCl3); H NMR (300 MHz, CDCl3): δ 7.72 (d, J = 8.1
Hz, 1H), 7.46-7.39 (m, 2H), 5.26 (ddd, J = 51.0 Hz, J = 7.8 Hz, J = 4.2
Hz, 1H), 3.66-3.55 (m, 1H), 3.28-3.13 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 198.40 (d, J = 15.0 Hz, 1C), 151.16 (d, J = 6.0 Hz, 1C),
142.94, 132.34, 129.32, 127.06, 125.93 (d, J = 1.0 Hz, 1C), 90.18 (d,
J = 193.0 Hz, 1C), 33.22 (d, J = 22.0 Hz, 1C); 19F NMR (282 MHz,
CDCl3): -193.01~-193.22 (m, 1F).
+53.1 (c = 1.00, CHCl3) or [α]20D = +40.4 (c = 1.00, p-dioxane); H
NMR (300 MHz, CDCl3): δ 8.08-8.06 (m, 1H), 7.55-7.50 (m, 1H),
7.38-7.33 (m, 1H), 7.28-7.26 (m, 1H), 5.15 (ddd, J = 48.0 Hz, J =
12.6 Hz, J = 5.1 Hz, 1H), 3.16-3.11 (m, 2H), 2.61-2.53 (m, 1H),
2.40-2.32 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 193.36 (d, J =
15.0 Hz, 1C), 143.03, 134.19, 131.23, 128.67, 127.83 (d, J = 1.0 Hz,
1C), 127.15, 91.21 (d, J = 187.0 Hz, 1C), 30.14 (d, J = 19.0 Hz, 1C),
27.01 (d, J = 11.0 Hz, 1C); 19F NMR (282 MHz, CDCl3): -190.33~
-190.36 (m, 1F). Its absolute configuration was determined to be R
by comparing the optical rotation value with the literature data[8a]
[α]25D = +64.9 (c = 0.43, p-dioxane) for (R)-configurated 3d in the
reported literature. Based on this, the absolute configuration of
products 3e-k were tentatively deduced by analogy.
(S)-2-Fluorobenzofuran-3(2H)-one (3c): Prepared by the general
procedure from 2c (67.2 mg, 0.3 mmol) and H2O (5.5 uL, 0.3 mmol,
o
1.0 equiv) with C4 (9.0 mg, 0.015 mmol, 5 mol%), stirred at 0 C
:
for 2 d and column chromatography (PE/CH2Cl2 = 20:1) afforded
the product 3c in 36% yield as yellow oil. HPLC analysis (Chiralpak
i
OJ-H, PrOH/hexane = 3/97, 1.0 mL/min, 205 nm; tr (minor) =
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Liao et al.
Report
i
B
O
F
(R)-7-Bromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (3e):
PrOH/hexane = 15/85, 1.0 mL/min, 205 nm; tr (minor) = 21.53 min,
Prepared by the general procedure from 2e (94.2 mg, 0.3 mmol)
and H2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06
mmol, 20 mol%), stirred at 0 oC for 6 d and column
tr (major) = 33.65 min) gave the isomeric composition of the
1
product: 88% ee, [α]26D = +29.0 (c = 1.00, CHCl3); H NMR (300
MHz, CDCl3): δ 8.04 (d, J = 8.7 Hz, 1H), 6.89-6.85 (m, 1H), 6.70 (d, J
chromatography (PE/CH2Cl2 = 20:1) afforded the product 3e in 97% = 2.4 Hz, 1H), 5.09 (ddd, J = 48.0 Hz, J = 12.3 Hz, J = 5.1 Hz, 1H),
yield as yellow solid.[31] HPLC analysis (Chiralpak AS-H,
3.87 (s, 3H), 3.10-3.07 (m, 2H), 2.59-2.50 (m, 1H), 2.41-2.29 (m,
iPrOH/hexane = 15/85, 1.0 mL/min, 205 nm; tr (minor) = 10.24 min, 1H); 13C NMR (100 MHz, CDCl3): δ 191.94 (d, J = 14.0 Hz, 1C),
tr (major) = 15.39 min) gave the isomeric composition of the
164.25, 145.59 (d, J = 1.0 Hz, 1C), 130.31 (d, J = 2.0 Hz, 1C), 124.67,
113.82, 112.51, 90.94 (d, J = 185.0 Hz, 1C), 55.55 (d, J = 4.0 Hz, 1C),
30.13 (d, J = 19.0 Hz, 1C), 27.23 (d, J = 11.0 Hz, 1C); 19F NMR (282
MHz, CDCl3): -190.33~ -190.40 (m, 1F).
(R)-6-Fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (3i):
Prepared by the general procedure from 2i (75.0 mg, 0.3 mmol)
and H2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06
mmol, 20 mol%), stirred at 0 oC to rt for 10 d and column
chromatography (PE/CH2Cl2 = 20:1) afforded the product 3i in 61%
yield as yellow oil.[33] HPLC analysis (Chiralpak AS-H, iPrOH/hexane
= 15/85, 1.0 mL/min, 205 nm; tr (minor) = 7.20 min, tr (major) =
8.01 min) gave the isomeric composition of the product: 80% ee,
[α]20D = -5.1 (c = 0.80, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.75 (d,
1
product: 90% ee, [α]26D = +28.6 (c = 1.00, CHCl3); H NMR (300
MHz, CDCl3): δ 8.17 (d, J = 2.8 Hz, 1H), 7.64-7.61 (m, 1H), 7.16 (d, J
= 11.2 Hz, 1H), 5.13 (ddd, J = 47.7 Hz, J = 12.6 Hz, J = 5.1 Hz, 1H),
3.10-3.05 (m, 2H), 2.58-2.53 (m, 1H), 2.41-2.31 (m, 1 H); 13C NMR
(100 MHz, CDCl3): δ 192.09 (d, J = 15.0 Hz, 1C), 141.78, 136.98 (d,
J = 7.0 Hz, 1C), 132.73, 130.54, 130.45, 121.20, 90.88 (d, J = 184.0
Hz, 1C), 29.88 (d, J = 19.0 Hz, 1C), 26.55 (d, J = 5.0 Hz, 1C); 19F
NMR (282 MHz, CDCl3): -190.75~ -190.79 (m, 1F).
(R)-2-Fluoro-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (3f):
Prepared by the general procedure from 2f (79.8 mg, 0.3 mmol)
and H2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06
mmol, 20 mol%), stirred at 0 oC for 6 d and column
chromatography (PE/CH2Cl2 = 20:1) afforded the product 3f in 95% J = 7.6 Hz, 1H), 7.45-7.41 (m, 1H), 7.34-7.30 (m, 1H), 7.22 (d, J =
yield as white solid.[32] HPLC analysis (Chiralpak AS-H,
7.6 Hz, 1H), 5.24 (ddd, J = 56.4 Hz, J = 12.8 Hz, J = 7.6 Hz, 1H),
iPrOH/hexane = 15/85, 1.0 mL/min, 205 nm; tr (minor) = 10.25 min, 3.02-2.94 (m, 2H), 2.38-2.30 (m, 1H), 2.15-1.92 (m, 3H); 13C NMR
tr (major) = 13.92 min) gave the isomeric composition of the
(100 MHz, CDCl3): δ 200.31 (d, J = 19.0 Hz, 1C), 141.89, 135.93,
132.38, 130.17, 129.26 (d, J = 1.0 Hz, 1C), 126.79, 94.81 (d, J =
183.0 Hz, 1C), 34.30, 30.61 (d, J = 21.0 Hz, 1C), 23.00 (d, J = 8.0 Hz,
1C); 19F NMR (376 MHz, CDCl3): -182.63 (s, 1F).
1
product: 88% ee, [α]20D = +78.4 (c = 1.00, CHCl3); H NMR (400
MHz, CDCl3): δ 7.50 (d, J = 2.4 Hz, 1H), 7.18-7.16 (m, 1H),
7.10-7.08 (m, 1H), 5.12 (ddd, J = 48.0 Hz, J = 12.8 Hz, J = 5.2 Hz,
1H), 3.83 (d, J = 0.8 Hz, 3H), 3.07-3.04 (m, 2H), 2.58-2.52 (m, 1H),
2.36-2.29 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 193.35 (d, J = 15.0
Hz, 1C), 158.67, 135.68, 132.06, 129.94, 122.72, 109.37, 91.33 (d,
J = 186.0 Hz, 1C), 55.59, 30.37 (d, J = 19.0 Hz, 1C), 26.26 (d, J =
12.0 Hz, 1C); 19F NMR (376 MHz, CDCl3): -190.37 (s, 1F).
(R)-2-Fluoro-5-methoxy-3,4-dihydronaphthalen-1(2H)-one (3g):
Prepared by the general procedure from 2g (79.8 mg, 0.3 mmol)
and H2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06
mmol, 20 mol%), stirred at 0 oC for 7 d and column
(R)-4,4-Diethyl-6-fluorocyclohex-2-en-1-one (3j): Prepared by
the general procedure from 2j (72.6 mg, 0.3 mmol) and H2O (5.5
uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06 mmol, 20 mol%),
o
stirred at 0 C for 7 d and column chromatography (PE/CH2Cl2 =
20:1) afforded the product 3j in 91% yield as yellow solid. HPLC
i
analysis (Chiralpak OD-H, PrOH/hexane = 3/97, 1.0 mL/min, 205
nm; tr (minor) = 10.85 min, tr (major) = 11.58 min) gave the
isomeric composition of the product: 81% ee, [α]20D = +50.8 (c =
1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.67 (d, J = 10.0 Hz, 1H),
chromatography (PE/CH2Cl2 = 20:1) afforded the product 3g in 86% 5.94 (dd, J = 10.4 Hz, J = 4.4 Hz, 1H), 5.08 (ddd, J = 48.4 Hz, J = 13.2
yield as white solid.[33] HPLC analysis (Chiralpak AS-H,
Hz, J = 6.0 Hz, 1H), 2.24-2.18 (m, 1H), 2.06-1.97 (m, 1H), 1.66-1.46
iPrOH/hexane = 15/85, 1.0 mL/min, 205 nm; tr (minor) = 10.34 min, (m, 4H), 0.95 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.6 Hz, 3H); 13C NMR
tr (major) = 12.75 min) gave the isomeric composition of the
(100 MHz, CDCl3): δ 194.71 (d, J = 14.0 Hz, 1C), 158.69, 126.08,
88.10 (d, J = 185.0 Hz, 1C), 41.79 (d, J = 10.0 Hz, 1C), 36.69 (d, J =
17.0 Hz, 1C), 31.48, 30.04, 8.82, 7.95; 19F NMR (376 MHz, CDCl3):
-194.38 (s, 1F); IR (neat): 3302, 2970, 2854, 2168, 1728, 1493,
1463, 752; HRMS (ESI): Exact mass calcd for C10H15FNaO [M+Na]+:
193.0999, Found: 193.0999.
(R)-6-Fluoro-4,4-dimethylcyclohex-2-en-1-one (3k): Prepared
by the general procedure from 2k (64.2 mg, 0.3 mmol) and H2O
(5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06 mmol, 20
mol%), stirred at 0 oC for 7 d and column chromatography
1
product: 88% ee, [α]20D = +60.8 (c = 1.00, CHCl3); H NMR (400
MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.05
(d, J = 8.0 Hz, 1H), 5.12 (ddd, J = 48.4 Hz, J = 13.2 Hz, J = 5.2 Hz,
1H), 3.87 (s, 3H), 3.28-3.22 (m, 1H), 2.84-2.75 (m, 1 H), 2.59-2.53
(m, 1 H), 2.29-2.23 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 193.75
(d, J = 15.0 Hz, 1C), 156.70, 132.26, 131.96 (d, J = 2.0 Hz, 1C),
127.79, 119.07 (d, J = 2.0 Hz, 1C), 114.89, 91.12 (d, J = 187.0 Hz,
1C), 55.73 (d, J = 2.0 Hz, 1C), 29.23 (d, J = 18.0 Hz, 1C), 21.02 (d, J
= 11.0 Hz, 1C); 19F NMR (376 MHz, CDCl3): -191.00 (s, 1F).
(R)-2-Fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (3h): (PE/CH2Cl2 = 20:1) afforded the product 3k in 68% yield as white
Prepared by the general procedure from 2h (79.8 mg, 0.3 mmol)
and H2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (18.0 mg, 0.03
mmol, 10 mol%), stirred at 0 oC for 5 d and column
solid.[10a] HPLC analysis (Chiralpak AS-H, iPrOH/hexane = 15/85, 1.0
mL/min, 205 nm; tr (major) = 11.60 min, tr (minor) = 13.52 min)
gave the isomeric composition of the product: 91% ee, [α]20
=
D
1
chromatography (PE/CH2Cl2 = 20:1) afforded the product 3h in 83% +1.7 (c = 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 6.64 (d, J =
yield as white solid.[11b] HPLC analysis (Chiralpak AS-H,
10.0 Hz, 1H), 5.84-5.80 (m, 1H), 5.04 (ddd, J = 47.6 Hz, J = 13.2 Hz,
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
J = 5.6 Hz, 1H), 2.25-2.19 (m, 1H), 2.06-1.98 (m, 1H), 1.23 (s, 3H),
1.18 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.40 (d, J = 14.0 Hz,
1C), 159.71, 124.36, 87.98 (d, J = 185.0 Hz, 1C), 42.26 (d, J = 16.0
90 (98), 77 (5), 63 (22), 51 (11); HRMS (EI): Exact mass calcd for
C10H8DFO [M]+: 165.0700, Found: 165.0699.
2-Chloro-2,3-dihydro-1H-inden-1-one (3o): Prepared by the
Hz, 1C), 35.47 (d, J = 11.0 Hz, 1C), 30.47, 26.11; 19F NMR (376 MHz, general procedure from 2o (71.4 mg, 0.3 mmol) and H2O (5.5 uL,
CDCl3): -195.74 (s, 1F).
0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06 mmol, 20 mol%),
o
2-Fluoro-1-phenylbutan-1-one (3l): Prepared by the general
procedure from 2l (71.4 mg, 0.3 mmol, E/Z > 20:1)[34] and H2O (5.5
uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06 mmol, 20 mol%),
stirred at 0 C for 3 d and column chromatography (PE/CH2Cl2 =
20:1) afforded the product 3o in 81% yield as yellow oil.[36] HPLC
i
analysis (Chiralpak AS-H, PrOH/hexane = 20/80, 1.0 mL/min, 205
o
stirred at 25 C for 5 d and column chromatography (PE/CH2Cl2 =
nm; tr = 8.51 min, tr = 12.30 min) gave the isomeric composition of
the product: 0% ee; 1H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 7.8 Hz,
1H), 7.68-7.63 (m, 1H), 7.46-7.39 (m, 2H), 4.55 (dd, J = 7.8 Hz, J =
4.2 Hz, 1H), 3.81-3.73 (m, 1H), 3.31-3.24 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 199.27, 150.79, 136.11, 133.82, 128.35, 126.44,
124.99, 55.76, 37.55.
20:1) afforded the product 3l in 83% yield as yellow oil.[35] HPLC
i
analysis (Chiralpak AS-H, PrOH/hexane = 20/80, 1.0 mL/min, 205
nm; tr (minor) = 4.52 min, tr (major) = 5.70 min) gave the isomeric
composition of the product: 72% ee, [α]20D = -7.5 (c = 0.80, CHCl3);
1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.6 Hz, 2H), 7.62-7.58 (m,
1H), 7.50-7.46 (m, 2H), 5.52 (ddd, J = 49.2 Hz, J = 7.6 Hz, J = 4.4 Hz,
1H), 2.11-1.93 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 196.87 (d, J = 19.0 Hz, 1C), 134.43, 133.76, 128.86 (d, J =
4.0 Hz, 1C), 128.75, 94.80 (d, J = 182.0 Hz, 1C), 26.13 (d, J = 22.0
Hz, 1C), 9.08; 19F NMR (376 MHz, CDCl3): -191.12 (s, 1F).
2-(Trifluoromethyl)-3,4-dihydronaphthalen-1(2H)-one
(3p):
Prepared by the general procedure from 2p (85.8 mg, 0.3 mmol)
and H2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (36.0 mg, 0.06
mmol, 20 mol%), stirred at 0 oC for 3 d and column
chromatography (PE/CH2Cl2 = 20:1 to 10:1) afforded the product
3p in 99% yield as yellow oil.[37] HPLC analysis (Chiralpak AS-H,
iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm; tr = 5.19 min, tr = 6.70
(R)-2-Fluoro-2,3-dihydro-1H-inden-1-one-2-d (3m): Prepared
by the general procedure from 2a (65.4 mg, 0.3 mmol) and D2O
(5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (9.0 mg, 0.015 mmol, 5
1
min) gave the isomeric composition of the product: 0% ee; H
o
mol%) in MeOD (3 mL), stirred at 25 C for 1.5 d and column
NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz,
chromatography (PE/CH2Cl2 = 20:1) afforded the product 3m in 98% 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 3.32-3.22 (m,
o
yield with 95% D at α-atom as a white solid (m.p. 50-51 C). HPLC
1H), 3.14-3.03 (m, 2H), 2.53-2.47 (m, 1H), 2.32-2.22 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 190.23, 143.11, 134.20, 131.94, 128.80,
127.83, 127.10, 125.11 (q, J = 278.0 Hz, 1C), 50.90 (q, J = 26.0 Hz,
1C), 27.53, 23.44; 19F NMR (376 MHz, CDCl3): -67.54 (s, 1F).
i
analysis (Chiralpak AS-H, PrOH/hexane = 10/90, 1.0 mL/min, 230
nm; tr (minor) = 11.04 min, tr (major) =13.41 min) gave the
isomeric composition of the product: 90% ee, [α]20D = -8.6 (c = 0.5,
1
CHCl3); H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.6 Hz, 1H),
7.68-7.64 (m, 1H), 7.47-7.41 (m, 2H), 5.26 (ddd, J = 50.8 Hz, J = 7.6
Hz, J = 4.4 Hz, 0.06H), 3.62 (dd, J = 17.2 Hz, J = 7.2 Hz, 1H), 3.22
(dd, J = 23.2 Hz, J =17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
199.95 (d, J = 15.0 Hz, 1C), 149.74 (d, J = 5.0 Hz, 1C), 136.38,
133.95, 128.45, 126.84 (d, J = 2.0 Hz, 1C), 124.76 (d, J = 2.0 Hz, 1C),
90.29-88.94 (m, 1C), 33.36 (d, J = 21.0 Hz, 1C); 19F NMR (376 MHz,
CDCl3): -194.58 (t, 1F). GC-MS: 152 (M+, 10), 151 (100), 123 (60),
102 (23), 97 (13), 76 (31), 63 (6), 50 (12); HRMS (EI): Exact mass
calcd for C9H6DFO [M]+: 151.0544, Found: 151.0546.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We thank the financial support from the National Natural Science
Foundation of China (No. 21725203).
(R)-2-Fluoro-3,4-dihydronaphthalen-1(2H)-one-2-d
(3n):
Prepared by the general procedure from 2d (70.8 mg, 0.3 mmol)
References
and D2O (5.5 uL, 0.3 mmol, 1.0 equiv) with C4 (9.0 mg, 0.015
o
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3n in 57% yield with 92% D at α-atom as brown oil. HPLC analysis
i
(Chiralpak AD-H, PrOH/hexane = 5/95, 1.0 mL/min, 205 nm; tr
(minor) = 9.28 min, tr (major) = 9.84 min) gave the isomeric
composition of the product: 90% ee, [α]20D = +55.5 (c = 0.5, CHCl3);
1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6
Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 5.16 (ddd, J
= 48.4 Hz, J = 12.8 Hz, J = 5.2 Hz, 0.11H), 3.15-3.12 (m, 2H),
2.61-2.54 (m, 1H), 2.40-2.33 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
193.39 (d, J = 15.0 Hz, 1C), 143.05, 134.19, 131.25, 128.67, 127.83
(d, J = 2.0 Hz, 1C), 127.15, 91.93-89.62 (m, 1C), 30.03 (d, J = 19.0
Hz, 1C), 26.97 (d, J = 11.0 Hz, 1C); 19F NMR (376 MHz, CDCl3):
-191.10 (t, 1F). GC-MS: 165 (M+, 89), 134 (8), 118 (100), 109 (3),
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Liao et al.
Report
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Liao et al.
Report
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other proton sources all gave inferior outcomes in CF3CH2OH
under other same condition. Typical results for the investigation
of proton sources as illustrated below: H2O (89% ee); PhOH (72%
ee); citric acid (9% ee); PhCO2H (3% ee); AcOH (14% ee).
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enol ether 2c with product 3c, would be take place in this case,
which afforded a byproduct A with 54% yield, 1.5:1 dr and 81%
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O
OH
∗
∗
1.5:1 dr
(major)
54%,
ee
O
81%
F
F
O
A
[19] We would like to thank one reviewer for suggesting us to test
the performance of substrates bearing α-CF3 substitution.
However, when α-trifluoromethyl substituted enol silyl ether 2p
was prepared and subjected to the standard condition, we found
to our regret that only racemic desired product 3p was obtained,
as shown below.
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OTMS
O
∗
CF3
CF3
C4
mol%)
(20
H2O
equiv)
+
CF CH O 0 o 3 d
H,
C,
2
3
(1.0
,
ee
3p
99%, 0%
2p
Standard condition
[20] Mohanta, P. K.; Davis, T. A.; Gooch, J. R.; Flowers, II, R. A.
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[21] Supplementary crystallographic data have been deposited at the
Cambridge Crystallographic Data Center (CCDC: 1904673).
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Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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Entry for the Table of Contents
Page No.
Cinchonidine derived
Catalytic Enantioselective Protonation of
Monofluorinated Silyl Enol Ethers toward Chiral
α-Fluoroketones
O
OTMS
H D
F
C4
squaramide
( )
or
H
D
2O
2O
F
R1
+
∗
R1
R2
or
H
MeOD
CF3CH2O
R2
equiv)
(1.0
0 oC~rt
examples
14
to
ee
91%
97%,
up
We report a highly organocatalytic enantioselective protonation of monofluorinated silyl enol
ethers with water as proton source, which represents a rare example of facile synthesis of optically
active α-secondary α-fluoroketones. Moreover, with D2O as the deuterium source and MeOD as
the solvent, the first highly enantioselective catalytic synthesis of enantioenriched α-deuterated
α-fluoroketones is developed.
Kui Liao,a Xiao-Si Hu,a Ren-Yi Zhu,a Ruo-Han Rao,b
Jin-Sheng Yu,*,a Feng Zhou, a and Jian Zhou*, a, c
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.