Enantioselective Synthesis of CF3S-Containing Compounds via Ir-Catalyzed Allylic Alkylations of CF3S-Substituted Functionalized Methylene Derivatives

Article abstract of DOI:10.1021/acs.joc.9b02123

Enantioselective Ir-catalyzed allylic alkylations of CF₃S-substituted functionalized methylene derivatives are established under mild conditions. This method provides the CF₃S-containing branched products in good to high yields with high regio- and enantioselectivities.

Full text of DOI:10.1021/acs.joc.9b02123

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Note
Enantioselective synthesis of CF3S-containing compounds via Ir-catalyzed
allylic alkylations of CF3S-substituted functionalized methylene derivatives
Tao Song, Xiaoming Zhao, and Xiaolin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02123 • Publication Date (Web): 28 Oct 2019
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Enantioselective synthesis of CF3S-containing compounds via
Ir-catalyzed allylic alkylations of CF3S-substituted functionalized
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methylene derivatives
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Tao Song, Xiaoming Zhao*, Xiaolin Wang
School of Chemical Technology and Engineering, Tongji University, 1239 Siping Road, 200092
Shanghai, P. R. China
E-mail: xmzhao08@mail.tongji.edu.cn
R2
R1
R
SCF3
[Ir(COD)Cl]2/L1
SCF3

+
R
OCO2Me
R1 R2
Cs2CO3, DCM, 20 oC
13 examples

R1 = CO2Et, H
R2 = CO2Et, PhCO
up to 90% yield 95% ee
R = alkyl, aryl
ABSTRACT: Enantioselective Ir-catalyzed allylic alkylations of CF3S-substituted functionalized
methylene derivatives are established under the mild conditions. This method provides the
CF3S-containing branched products in good to high yields with high regioselective and
enantioselectivities.
T
rifluoromethylthio (CF3S)-containing compounds are of great importance to pharmaceutical
industry.1 The incorporation of a CF3S group into organic molecules can greatly enhance their
membrane permeability and metabolic stability owing to its high lipophilicity and high
electronegativity.2
There are four bioactive compounds and drugs such as Cefazaflur,3
3,4-dihydro-2H-benzo[e][1,2]oxaborinene acid,4 (1H-1,2,4-triazol-1-yl) phenylether,5 and
TFMTA,6 which all contain a CF3S moiety (Figure 1). More significantly, there is a chiral center
bearing a CF3SCH2 group in TFMTA (Figure 1). Therefore, new method for the enantioselective
synthesis of compounds with a CF3S group is highly desirable.
O
N
OH
HO
O
N
N
N
O
OH
O
N
S
B
O
O
SCF3
S
N
H
N
H
F3CS
H
Cefazaflur
H-Benzo[e][1,2]oxaborinine acid
Cl
O
F3CS
HO
N
N
O
SCF3
NH2
N
N
OH
N
N
O
N
1H-1,2,4-Triazol-1-yl) ether
TFMTA
Figure 1. Bioactive Compounds and Drugs with a CF3S Group
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The synthesis of CF3S-containing compounds by transition-metal-catalyzed allylic
substitution includes (1) the use of trifluoromethylthiolating reagent as a nucleophile or (2)
the use of CF3S-substituted building block as a nucleophile. In general, sulfur-containing
nucleophiles may poison transition-metal catalyst,7 therefore, CF3S ion as a nucleophile in
such a reaction is less reported,8 for example, the use of CsSCF3 as a nucleophile in
Ru-catalyzed allylic trifluoromethylthiolation was described and it gave the linear
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CF3S-containing products by a double allylic trifluoromethylthiolation (eq-1 in Scheme 1) 8a
.
Recently, a pioneer study on enantioselective synthesis of CF3S-containing allylic products
was developed by Rh-catalyzed [2,3]-sigmatropic rearrangement of a sulfonium ylide (eq-2 in
Scheme 1).9 Iridium-catalyzed asymmetric allylic substitution has been become a useful
tool for the synthesis of optically active compounds.10
In fact, the synthesis of
CF3S-containing compounds by Ir-catalyzed allylic alkylation is uncultivated area in
fluorine chemistry (eq-3 in Scheme 1). In this paper, we describe an iridium-catalyzed
allylic substitution of CF3S-substituted functionalized methylene derivatives, producing the
branched allylic products bearing a CF3S group.
Previous work
OCO2Me
Ru complex
MeCN, 50 oC
CsSCF3
R
SCF3
eq-1
eq-2
+
R
up to 91% yield
R = alkyl, aryl
R1
EtO2C 
N2
SCF3
Rh2(S-DOSP)4
DCM, -10 oC
+
SCF3
R
R1 CO2Et

R
up to 99% yield,
98% ee and 40/60 dr
R = H, Ph
R1 = aryl, alkene
This work
R
R2
R1 SCF3
[Ir(COD)Cl]2/L
SCF3
+

eq-3
OCO2Me
R1 R2
R

R1 = CO2Et, H
R2 = CO2Et, PhCO
R = alkyl, aryl
up to 90% yield 95% ee
Scheme 1. Synthesis of CF3S-containing Compounds
Table 1. Optimization Studies for Ir-catalyzed Allylic Alkylation of Diethyl
2-((trifluoromethyl)thio)malonate 2aa
F3CS
CO2Et
2
CO2Et
CO2Et
SCF3
Ir/L
EtO2C
H
CO2Et
SCF3
Ph
+
Ph
OCO Me
+
2
Sovlent, rt
Ph
1a
4a
2a
3a
yield of 3a
entry
Ir salt
L
base
sol
temp (oC)
3a/4ac
ee (%)d
(%)b
1
2
3
5
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
L1
L1
L1
L1
K3PO4
K3PO4
K3PO4
K3PO4
THF
toluene
MeCN
DCM
20
20
20
20
82
99/1
99/1
99/1
99/1
81
75
64
85
50
55
85
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[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(Cp*)Cl2]2
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
CsF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
20
20
20
20
20
20
20
20
10
30
20
20
70
70
75
5
99/1
99/1
99/1
-
73
70
94
-
7
K2CO3
Cs2CO3
LiOH
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9
10
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17
TDB
5
-
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
47
20
10
51
77
-
99/1
99/1
-
82
22
-
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99/1
99/1
-
95
91
-
Ir(COD)(acac) L1
-
-
-
aReaction conditions: [Ir(COD)Cl]2 (0.002 mmol), L (0.004 mmol), 1a (0.10 mmol), 2a (0.12 mmol), and base (0.20
mmol) in solvent (2 mL) at 0-40 °C for 12 h. Isolated yield. 3a/4a was determined by 1H NMR. Determined by a
b
c
d
chiral HPLC analysis.
O
O
O
O
O
N
O
O
P
N
P
N
P
N
PPh2
L4, PHOX
L1
(S.S,Sa)-
L3
(S)-
L2
(S.S,Sa)-
Figure 2. Ligands Used in Enantioselective Ir-catalyzed Allylic Alkylations
We initially examined a model reaction between (E)-cinnamyl methyl carbonate (1a) and
diethyl 2-((trifluoromethyl)thio)malonate (2a)11 in the presence of K3PO4 and iridium complex11
generated from [Ir(COD)Cl]2 (COD = 1,5-cyclooctadiene) and Feringa’s ligand L112 at 20 °C.
To our delight, the formation of diethyl 2-(1-phenylallyl)-2-((trifluoromethyl)thio)malonate (3a)
and diethyl 2-cinnamyl-2-((trifluoromethyl)thio)malonate (4a) was observed (Table 1).
Encouraged by these results, we examined a range of solvents such as THF, toluene,
dichloromethane (DCM) and acetonitrile (MeCN). The reaction outcomes revealed that DCM
gave the superior results (87% yield, 3a/4a 99/1 and 85% ee); the remaining solvents including
THF, toluene and MeCN led to acceptable to good results (Table 1, entries 1-4). After screening
bases
including
K3PO4,
CsF,
K2CO3,
Cs2CO3,
LiOH
and
2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (TDB), we found that the enantioselectivity
was improved from 85% to 94% when Cs2CO3 was used. The use of K3PO4, CsF and K2CO3
resulted in 3a in 69-80% yield with 70-85% ee; LiOH and TDB are ineffective for this reaction
(Table 1, entries 5-10). Ligand plays a significant role in Ir-catalyzed asymmetric substitutions;7
therefore, a set of ligands such as (S,S,Sa)-Feringa’s L1, L2,12 (S)-Carreira’s L313 and PHOX L414
(Figure 2) was tested.
The structural change of the ligands has a great influence on the
enantioselectivity. For instance, the steric demand of L2 is larger than that of L1; however, L2
gave a lower ee value than that of L1; both L3 and L4 were employed and they gave the poor
results (Table 1, entries 8, 11-13). The reaction was performed at either 30 °C or 10 °C; and
45% yield or 78% yield was obtained, respectively; maintaining the high level of regio- and
selectivities (entry 8, 14 and 15). The different iridium complexes such as [Ir(Cp*)Cl2]2 and
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Ir(COD)(acac) were also examined and they failed to catalyze this reaction (Table 1, entries 16
and 17).
Thus, we chose entry 8 of Table 1 as the standard conditions for the further
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investigation.
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Table 2. Scope of the Allylic Carbonates 1 and CF3S-containing Functionalized Methylene
Derivatives 2a,b,c,d,e
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R2
R1
R2
SCF3
F3CS
R
R1
L1
[Ir(COD)Cl]2/
R1
H
R2

R
+
R
OCO Me
2
+
SCF3
Cs2CO3, DCM
20 oC
2
1
3
4
F3CS
(CO2Et)2
F3CS
(CO2Et)2
F3CS
(CO2Et)2
F3CS
(CO2Et)2
F
Cl
Br
3a,
75% yield
94% ee
3a/4a
3d
3b
, 84% yield
90% ee
3d/4d
,84% yield
90% ee
3b/4b
3c
, 78% yield
93% ee
3b/4b
= 99/1
= 99/1
= 99/1
= 99/1
F3CS
(CO2Et)2
F3CS
(CO2Et)2
F3CS
(CO2Et)2
F3CS
(CO2Et)2
MeO
O
Ph
Br
3h
, 65% yield
88% ee
3g
, 62% yield
91% ee
3f
3e
, 90% yield
95% ee
3f/4f
,70% yield
93% ee
3h/4h
= 99/1
3g/4g
= 99/1
3e/4e
= 99/1
= 99/1
SCF3
PhOC


SCF3
PhOC
SCF3
PhOC




F3CS
(CO2Et)2
Cl
Br
3j
, 68% yield
92%, 96% ee
53/47 dr
3k
, 78% yield
78%, 67% ee
53/47 dr
3i
3l
, 61% yield
45% ee
3i/4i
, 70% yield
98%, 81% ee
53/47 dr
= 99/1
3j/4j
= 99/1
3k/4k
= 99/1
3l/4l
= 99/1
O
Ph
F3CS
(CO2Et)2


SCF3
S
3m
, 88% yield
3n
, 55% yield
88% ee
3n/4n
91%, 87% ee
55/45 dr
3m/4m
= 99/1
= 99/1
aReaction conditions: [Ir(COD)Cl]2 (0.002 mmol), L1 (0.004 mmol), 1 (0.10 mmol), 2 (0.12 mmol), and Cs2CO3
(0.20 mmol) in DCM (2 mL) at 20 °C for 12 h. b Isolated yield. c3/4 was determined by NMR. dThe diastereomeric
ratio was determined by 19F NMR spectroscopic analysis. eDetermined by chiral HPLC analysis.
With the optimized conditions in hand, we examined the scope of various allylic carbonates
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(1) with a range of CF3S-substituted functionalized methylene derivatives (2). For diethyl
2-((trifluoromethyl)thio)malonate (2a), 1a and the substituted allyl carbonates (1b-e) with an
electron-attracting group (e.g., 3-F, 3-Cl, 3-Br, and 4-Br) on the phenyl ring afforded the
corresponding CF3S-containing products (3a-e) in good to high yields (70-84%) with excellent
regioselectivities (99/1) and high enantioselectivities (90-94% ee) (Table 2).
Notably, the
CF3S-containg products 3d and 3e contain a bromine group on the phenyl ring which can undergo
useful transformation. The substrates 1f-g with an electron-donating group (e.g., 4-Ph and
3-MeO) on the phenyl ring gave the branched 3f-g in fair to high yields (62-90% yield) with
excellent regioselectivities (99/1) and high enantioselectivities (91-95% ee) (Table 2). The
heterocyclic allylic substrates such as (E)-3-(furan-2-yl)allyl methyl carbonate 1h and (E)-methyl
(3-(thiophen-2-yl)allyl) carbonate 1n gave the CF3S-containing product 3h and 3n in a 62% yield
with 3h/4h in 99/1 and 88% ee and a 55% yield with 3n/4n in 99/1 and 88% ee, respectively
(Table 2). The aliphatic substrate such as (E)-but-2-en-1-yl methyl carbonate (1i) also worded
well (Table 2). For 1-phenyl-2-((trifluoromethyl)thio)ethan-1-one (2b), the substrates 1a, 1c and
1e were examined and they afforded the corresponding products 3j, 3k and 3l in good yields
(68-78% yields) with high regioselectivities (99/1) and good to excellent enantioselectivities
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(67-98% ee) but with the poor dr value (Table 2).
For
a
racemic
2-((trifluoromethyl)thio)-3,4-dihydronaphthalen-1(2H)-one (2c), the substrate 1a gave 3m in a
88% yield with 3m/4m (99/1) and 87-91% ee but with poor diastereoselectivity (Table 2). The
absolute configuration of compound 3f was determined as S by the transmitted circular dichroism
(TCD) method.15
CO2Et
CO2Et
F3CS
OCO2Me
[Ir(COD)Cl]2/L1
EtO2C
H
CO2Et
SCF3
+
Cs2CO3, DCM
20 oC
1f
2a
3f
858 mg
3.20 mmol
1.00 g
3.84 mmol
1.23 g
85% yield
95% ee
3f/4f
= 99/1
Scheme 2 Large-Scale Synthesis of 3f.
A large-scale synthesis of CF3S-bearing compound 3 was also tested, for example, the
reaction of (E)-3-([1,1'-biphenyl]-4-yl)allyl methyl carbonate 1f (3.20 mmol, 858 mg) and diethyl
2-((trifluoromethyl)thio)malonate 2a (3.84 mmol, 1.00 g) in the presene of Cs2CO3 (6.40 mmol,
2.10 g) and DCM (50 mL) was conducted under the idendical contitions. After the completion of
the reaction (12h), the CF3S-substituted product 3f (1.23 g, 85% yield, 3f/4f = 99/1, 95% ee) was
obtained (Scheme 2).
In summary, we developed an enantioselective Ir-catalyzed allylic alkylation of the linear
allylic carbonates with CF3S-substituted functionalized methylene derivatives, which afforded the
CF3S-containing allylic compounds in moderate to high yields with a high level of regio- and
enantioselectivities. This is the first example for the synthesis of chiral CF3S-containing
allylproducts derived from diethyl 2-((trifluoromethyl)thio)malonate.
EXPERIMENTAL SECTION
All manipulations were carried out under argon atmosphere using standard Schlenk techniques. All glassware was
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oven or flame-dried immediately prior to use. All reagents were obtained from commercial sources, most of them
from Adamas-beta and used without further purification, unless stated otherwise. AgSCF3 and
N-trifluoromethylthiosaccharin were obtained from Zhongke Bangqi (Shenzhen) Fluoro-biomedical Materials Co.,
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1
Ltd. H NMR spectra were obtained at 600 MHz and recorded relative to the tetramethylsilane signal (0 ppm) or
residual protio-solvent. 13C NMR spectra were obtained at 151 MHz, and chemical shifts were recorded relative to
the solvent resonance (CDCl3, 77.0 ppm). 19F NMR spectra were obtained at 565 MHz. Infrared (IR) spectra were
recorded on an IR spectrometer with KBr wafers or a film on KBr plate. High resolution mass spectra (HRMS)
were recorded on a micro TOF II mass spectrometer using electrospray ionization (ESI). Melting point
temperatures were measured at a heating rate of 5 °C/min and are uncorrected. TCD (transmitted circular
dichroism) spectra were recorded as ethyl acetate solution on a JASCO J-1500 spectropolarimeter at room
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temperature. Data for H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet or unresolved, br = broad singlet, coupling constant(s) in Hz, integration). Data
for 13C NMR and 19F NMR are reported in terms of chemical shift (δ, ppm). Reactions were monitored by thin
layer chromatography (TLC) using silicycle precoated silica gel plates. Flash column chromatography was
performed on silica gel 60 (particle size 200-300 mesh ASTM purchased from Yantai of China) and eluted with
petroleum ether/ethyl acetate. The allylic carbonates 1 were prepared according to the known procedures.16
The synthesis of diethyl 2-((trifluoromethyl)thio)malonate (2a). 11b To a reaction tube were added AgSCF3 (2.0
equiv., 1.68 mmol, 351 mg), KI (2.0 equiv., 1.68 mmol, 279 mg), diethyl 2-bromomalonate (1.0 equiv., 0.84 mmol,
200 mg) and acetone (2 mL). The mixture was stirred at room temperature for 15 min. The solvent was removed
under reduced pressure and the residue was treated with Et2O (10 mL). The precipitate was removed by filtration
and the filtrate was concentrated to give the crude product. The crude residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 20/1) to give the desired product 2a. 1H NMR (400 MHz,
Chloroform-d) δ 4.70 (s, 1H), 4.31 (q, J = 7.2 Hz, 4H), 1.32 (t, J = 7.2 Hz, 6H). 19F NMR (377 MHz,
Chloroform-d) δ -41.09 (s).
The synthesis of diethyl 2-((trifluoromethyl)thio)malonate (2b). 11b To a reaction tube were added AgSCF3 (2.0
equiv., 2.0 mmol, 418 mg), KI (2.0 equiv., 2.0 mmol, 332 mg), 2-bromo-1-phenylethanone (1.0 equiv., 1.0 mmol,
200 mg) and acetone (2 mL). The mixture was stirred at room temperature for 15 min. The solvent was removed
under reduced pressure and the residue was treated with Et2O (10 mL). The precipitate was removed by filtration
and the filtrate was concentrated to give the desired product 2b. 1H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J =
7.6 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 4.53 (s, 2H). 19F NMR (376 MHz, Chloroform-d) δ
-41.43 (s).
The synthesis of diethyl 2-((trifluoromethyl)thio)malonate (2c).11c A Shlenk tube (25 mL) charged with
3,4-dihydronaphthalen-1(2H)-one (0.3 mmol, 43.80 mg), and morpholinium chloride (0.09 mmol, 11.00 mg),
N-trifluoromethylthiosaccharin (0.45 mmol, 127 mg) was vacuumed and filled with argon, repeating three times.
Me3SiCl (54 μL, 0.45 mmol) and CH3CN (6.0 mL) were then added under argon atmosphere. The mixture was
o
heated by an oil bath at 80 C for 12 h. The solvent was removed under vacuum and the residue was purified by
flask column chromatography (Eluent: petroleum ether/ethyl ether = 20/1) to give trifluoromethylthiolated ketone
2c. 1H NMR (600 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.38–7.32
(m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 4.37 (dd, J = 10.9, 4.4 Hz, 1H), 3.16–3.10 (m, 2H), 2.73-2.68 (m, 1H), 2.40 (m,
1H). 19F NMR (565 MHz, Chloroform-d) δ -38.72 (s).
General procedure for the synthesis of 3a-3m. [Ir(COD)Cl]2 (0.001 mmol, 2 mol %) and phosphoramidite ligand
L1 (0.002 mmol, 4 mol %) were dissolved in THF (0.5 mL) and propylamine (0.2 mL) in a dry Schlenk tube filled
with argon. The reaction mixture was heated by an oil bath at 50 °C for 30 min, and then the volatile solvents were
removed under vacuum to give
a yellow solid. After that, allylic carbonate 1 (0.05 mmol),
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(trifluoromethyl)thio-methylene derivatives 2 (0.06 mmol, 120 mol %), cesium carbonate (0.10 mmol, 200 mol %),
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and DCM (1.0 mL) were added. The reaction was stirred at 20 C until the carbonate was fully consumed and
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monitored by TLC or H NMR. Then the crude reaction mixture was filtrated with celite, and the solvent was
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removed under reduced pressure. The ratio of regioisomers (branched to linear b/l) was determined by 1H NMR of
the crude reaction mixture. The crude residue was purified by flash column chromatography (petroleum ether/ethyl
acetate:100/1-80/1) to give the allylic products 3a-m.
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Diethyl (S)-2-(1-phenylallyl)-2-((trifluoromethyl)thio)malonate (3a). Colorless oil; yield 75% (28.3 mg); [α]D
=
28.2 (c 1.0, EtOAc); 94% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 95/5; flow
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rate = 0.4 mL/min; detection wavelength = 214 nm; tR = 11.6, 12.9 min]. H NMR (600 MHz, Chloroform-d) δ
7.29 (m, 2H), 7.26 (m, 2H), 6.41 (dt, J = 17.8, 9.3 Hz, 1H), 5.21 (d, J = 10.2 Hz, 1H), 5.12 (d, J = 16.9 Hz, 1H),
4.39 (d, J = 8.3 Hz, 1H), 4.33 – 4.23 (m, 2H), 4.20 – 4.16 (m, 2H), 1.27 (m, 6H). 19F NMR (565 MHz,
Chloroform-d) δ -37.0 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 165.2 (2c), 136.2, 134.6, 128.6, 128.2 (q, J
= 310.1 Hz), 127.3, 126.9, 118.0, 66.0, 61.9 (2c), 53.92, 12.6 (2c). HRMS (ESI-TOF): calcd for C17H20F3O4S [M +
H]+: 377.1034; Found: 377.1032. IR (KBr): ν max (cm-1) = 2959, 2924, 2853, 1732, 1455, 1368, 1259, 1155, 1130,
1097, 1016, 802, 742, 701.
Diethyl (S)-2-(1-(3-fluorophenyl)allyl)-2-((trifluoromethyl)thio)malonate (3b). Colorless oil; yield 84% (33.1 mg);
[α]D20 = 24.8 (c 1.0, EtOAc); 90% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 100/1;
flow rate = 0.4 mL/min; detection wavelength = 214 nm; tR = 12.4 min, 14.4 min]. 1H NMR (600 MHz,
Chloroform-d) δ 7.30 – 7.24 (m, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.01 – 6.95 (m, 2H), 6.36 (ddd, J = 17.2, 10.0, 8.6
Hz, 2H), 5.23 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 16.9 Hz, 1H), 4.39 (d, J = 8.4 Hz, 1H), 4.33 – 4.14 (m, 4H), 1.29 (t,
J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H). 19F NMR (565 MHz, Chloroform-d) δ -36.9 (s, 3F), -112.6 (s, 1F).
13C{1H} NMR (150 MHz, Chloroform-d) δ 166.1(2C), 162.5 (d, J = 246.0 Hz), 139.8 (d, J = 7.2 Hz), 135.1, 129.7
(d, J = 8.2 Hz), 129.1 (q, J = 310.1 Hz), 125.4 (d, J = 2.8 Hz), 119.5, 116.6 (d, J = 22.3 Hz), 114.9 (d, J = 21.0 Hz),
66.7, 63.1 (2C), 54.4, 13.6 (2C). HRMS (ESI-TOF): calcd for C17H19F4O4S [M + H]+: 395.0940; Found: 395.0943.
IR (KBr): ν max (cm-1) = 2986, 1732, 1613, 1589, 1488, 1447, 1244, 1209, 1130, 1098, 929, 857, 757, 699.
Diethyl (S)-2-(1-(3-chlorophenyl)allyl)-2-((trifluoromethyl)thio)malonate (3c). Colorless oil; yield 78% (32.0 mg);
[α]D20 = 39.9 (c 1.0, EtOAc); 93% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 100/1;
flow rate = 0.4 mL/min; detection wavelength = 214 nm; tR = 13.2 min, 14.7 min]. 1H NMR (600 MHz,
Chloroform-d) δ 7.28 – 7.21 (m, 3H), 7.18 (m, 1H), 6.35 (ddd, J = 17.0, 10.1, 8.5 Hz, 1H), 5.24 (d, J = 10.2 Hz,
1H), 5.13 (d, J = 16.9 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 4.34 – 4.13 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J =
7.2 Hz, 3H). 19F NMR (565 MHz, Chloroform-d) δ -37.0 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 166.0
(2C), 139.5, 135.0, 134.0, 129.7, 129.5, 129.1 (q, J = 310.0 Hz), 128.1, 128.0, 119.6, 66.7, 63.1 (2C), 54.4, 13.7
(2C). HRMS (ESI-TOF): calcd for C17H19ClF3O4S [M + H]+: 411.0645; Found: 411.0652. IR (KBr): ν max (cm-1) =
2985, 1731, 1594, 1573, 1475, 1445, 1368, 1247, 1129, 1094, 1032, 999, 928, 781, 757, 696.
Diethyl (S)-2-(1-(3-bromophenyl)allyl)-2-((trifluoromethyl)thio)malonate (3d). Colorless oil; yield 84% (38.2 mg);
[α]D20 = 43.6 (c 1.0, EtOAc); 90% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 100/1;
flow rate = 0.2 mL/min; detection wavelength = 214 nm; tR = 24.3 min, 26.3 min]. 1H NMR (600 MHz,
Chloroform-d) δ 7.50 – 7.36 (m, 2H), 7.23 (m, 1H), 7.18 (m, 1H), 6.34 (dt, J = 17.8, 9.3 Hz, 1H), 5.24 (d, J = 10.2
Hz, 1H), 5.14 (d, J = 16.9 Hz, 1H), 4.36 (d, J = 8.5 Hz, 1H), 4.33 – 4.15 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H), 1.23 (t,
J = 7.2 Hz, 3H). 19F NMR (565 MHz, Chloroform-d) δ -37.0 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 166.0
(2C), 139.8, 135.0, 132.6, 131.0, 129.8, 129.1 (q, J = 310.2 Hz), 128.5, 122.3, 119.7, 66.7, 63.2 (2C), 54.3, 13.7
(2C). HRMS (ESI-TOF): calcd for C17H19BrF3O4S [M + H]+: 455.0140; Found: 455.0140. IR (KBr): ν max (cm-1) =
2984, 1731, 1567, 1474, 1445, 1368, 1246, 1129, 1095, 1032, 997, 928, 861, 778, 757, 694.
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Diethyl (S)-2-(1-(4-bromophenyl)allyl)-2-((trifluoromethyl)thio)malonate (3e). Colorless oil; yield 70% (31.7 mg);
[α]D20 = 48.8 (c 1.0, EtOAc); 93% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 100/1;
flow rate = 0.4 mL/min; detection wavelength = 214 nm; tR = 15.0 min, 18.9 min]. 1H NMR (600 MHz,
Chloroform-d) δ 7.45 – 7.41 (m, 2H), 7.16 – 7.13 (m, 2H), 6.35 (ddd, J = 16.9, 10.2, 8.3 Hz, 1H), 5.22 (dt, J = 10.3,
1.1 Hz, 1H), 5.10 (dt, J = 16.9, 1.2 Hz, 1H), 4.36 (d, J = 8.3 Hz, 1H), 4.33 – 4.13 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H),
1.23 (t, J = 7.2 Hz, 3H). 19F NMR (565 MHz, Chloroform-d) δ -36.9 (s). 13C{1H} NMR (151 MHz, Chloroform-d)
δ 166.1, 136.4, 135.2, 131.5, 131.4, 129.1 (q, J = 310.1 Hz), 122.1, 119.4, 66.7, 63.1 (2C), 54.2, 13.7 (2C). HRMS
(ESI-TOF): calcd for C17H19BrF3O4S [M + H]+: 455.0140; Found: 455.0140. IR (KBr): ν max (cm-1) = 2984, 2927,
1731, 1488, 1465, 1445, 1368, 1247, 1154, 1130, 1095, 1010, 927, 861, 821, 757, 741.
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Diethyl (S)-2-(1-([1,1'-biphenyl]-4-yl)allyl)-2-((trifluoromethyl)thio)malonate (3f). Colorless oil; yield 90% (40.5
mg); [α]D20 = 40.0 (c 1.0, EtOAc); 95% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol =
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100/1; flow rate = 0.6 mL/min; detection wavelength = 214 nm; tR =26.6 min, 46.2 min]. H NMR (600 MHz,
Chloroform-d) δ 7.57 (d, J = 7.7 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.38 – 7.28 (m, 3H),
6.44 (dt, J = 17.8, 9.4 Hz, 1H), 5.24 (d, J = 10.2 Hz, 1H), 5.17 (dd, J = 16.9, 1.3 Hz, 1H), 4.44 (d, J = 8.4 Hz, 1H),
4.36 – 4.24 (m, 2H), 4.20 (p, J = 7.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). 19F NMR (565
MHz, Chloroform-d) δ -36.9 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 166.3 (2C), 140.8, 140.5, 136.3,
135.6, 130.0, 129.2 (q, J = 310.1 Hz), 128.8, 127.4, 127.1, 127.0, 119.2, 66.9, 63.0 (2C), 54.7, 13.7 (2C). HRMS
(ESI-TOF): calcd for C23H24F3O4S [M + H]+: 453.1347; Found: 453.1343. IR (KBr): ν
(cm-1) = 2983, 1732,
max
1487, 1446, 1367, 1306, 1274, 1257, 1128, 1097, 1008, 926, 844, 763, 698.
Diethyl (S)-2-(1-(3-methoxyphenyl)allyl)-2-((trifluoromethyl)thio)malonate (3g). Pale yellow oil; yield 62% (25.1
mg); [α]D20 = 23.6 (c 1.0, EtOAc); 91% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol =
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100/1; flow rate = 0.2 mL/min; detection wavelength = 214 nm; tR =34.9 min, 37.9 min]. H NMR (600 MHz,
Chloroform-d) δ 7.22 (t, J = 8.2 Hz, 1H), 6.82 (m, 3H), 6.39 (dt, J = 18.0, 9.3 Hz, 1H), 5.20 (d, J = 10.2 Hz, 1H),
5.14 (d, J = 16.9 Hz, 1H), 4.35 (d, J = 8.4 Hz, 1H), 4.33 – 4.24 (m, 2H), 4.19 (qd, J = 7.2, 4.0 Hz, 2H), 3.79 (s, 3H),
1.29 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). 19F NMR (565 MHz, Chloroform-d) δ -37.0 (s). 13C{1H} NMR
(151 MHz, Chloroform-d) δ 166.3 (2C), 159.4, 138.6, 135.5, 129.3, 129.2 (q, J = 310.1 Hz), 121.8, 119.0, 115.6,
113.2, 66.9, 63.0 (2C), 55.2, 55.0, 13.7 (2C). HRMS (ESI-TOF): calcd for C18H22F3O5S [M + H]+: 407.1140;
Found: 407.1144. IR (KBr): ν
(cm-1) = 2983, 2927, 1737, 1599, 1584, 1490, 1465, 1367, 1302, 1247, 1156,
max
1129, 1100, 1050, 1000, 927, 858, 777, 757, 702.
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Diethyl (S)-2-(1-(furan-2-yl)allyl)-2-((trifluoromethyl)thio)malonate (3h). Yellow oil; yield 65% (23.8 mg); [α]D
= 32.4 (c 1.0, EtOAc); 88% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 95/5; flow
rate = 0.4 mL/min; detection wavelength = 214 nm; tR = 11.0 min, 12.4 min]. 1H NMR (600 MHz, Chloroform-d)
δ 7.27 (s, 1H), 6.25 (s, 1H), 6.18 (s, 1H), 6.12 (dt, J = 17.9, 9.2 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 5.10 (d, J =
17.0 Hz, 1H), 4.49 (d, J = 8.4 Hz, 1H), 4.20 (m, 4H), 1.27 – 1.20 (m, 6H). 19F NMR (565 MHz, Chloroform-d) δ
-37.3 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 164.9 (2C), 149.5, 141.1, 131.9, 128.2 (q, J = 309.7 Hz),
118.7, 109.4, 108.6, 64.8, 62.0 (2C), 47.6, 12.7 (2C). HRMS (ESI-TOF): calcd for C15H18F3O5S [M + H]+:
367.0827 ; Found: 367.0827. IR (KBr): ν max (cm-1) = 2918, 2849, 1732, 1646, 1456, 1275, 1260, 1104, 764, 749.
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Diethyl (R)-2-(but-3-en-2-yl)-2-((trifluoromethyl)thio)malonate (3i). Colorless oil; yield 61% (19.2 mg); [α]D
=
-3.2 (c 1.0, EtOAc); 45% ee [ChiralPark IA column; n-hexane/2-propanol = 95.5; flow rate = 0.8 mL/min;
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detection wavelength = 214 nm; tR = 3.8 min, 4.2 min]. H NMR (600 MHz, Chloroform-d) δ 5.88 (dt, J = 17.7,
9.2 Hz, 1H), 5.20 – 5.10 (m, 2H), 4.28 (q, J = 7.1 Hz, 4H), 3.22 (p, J = 7.2 Hz, 1H), 1.31 (t, J = 7.1 Hz, 6H), 1.25
(d, J = 6.9 Hz, 3H). 19F NMR (565 MHz, Chloroform-d) δ -37.1 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ
166.3 (2C), 137.1, 129.3 (q, J = 309.6 Hz), 117.8, 62.8 (2C), 43.1, 31.6, 16.6, 13.8 (2C). HRMS (ESI-TOF): calcd
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for C12H18F3O4S [M + H]+: 315.0878; Found: 315.0877. IR (KBr): ν
(cm-1) = 2984, 1730, 1447, 1368, 1246,
max
1096, 1033, 924, 861, 844, 757, 657.
1,3-Diphenyl-2-((trifluoromethyl)thio)pent-4-en-1-one (3j). Colorless oil; yield 68% (22.7 mg); [α]D20 = 55.2 (c 1.0,
EtOAc); 92%, 96% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 90/10; flow rate =
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0.5 mL/min; detection wavelength = 214 nm; tR = 11.6 min, 14.4 min, 16.5 min, 24.2 min]. H NMR (600 MHz,
Chloroform-d) δ 7.89 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 (m, 3H), 7.34 (m,
5H), 7.27 – 7.23 (m, 1H), 7.17 (d, J = 6.4 Hz, 5H), 7.09 (t, J = 7.2 Hz, 1H), 6.16 (dt, J = 17.8, 9.3 Hz, 1H), 6.04 (dt,
J = 17.2, 9.1 Hz, 1H), 5.28 (d, J = 10.1 Hz, 1H), 5.21 (d, J = 16.9 Hz, 1H), 5.15 – 5.03 (m, 4H), 4.06 – 3.85 (m,
2H). 19F NMR (565 MHz, Chloroform-d) δ -39.2 (s), -39.6 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 196.7,
196.5, 139.7, 139.1, 136.7, 136.5, 136.1, 135.8, 135.6, 133.8, 133.6, 130.3 (q, J = 307.5 Hz), 130.2 (q, J = 307.8
Hz), 123.0, 129.6, 129.2, 128.94, 128.90, 128.9, 128.83, 128.77, 128.58, 128.56, 128.29, 128.27, 128.2, 128.1,
128.0, 127.7, 127.4, 119.0, 118.8, 52.4, 52.0, 51.4, 51.3. HRMS (ESI-TOF): calcd for C18H16F3OS [M + H]+:
337.0874; Found: 337.0871. IR (KBr): ν max (cm-1) = 3030, 1682, 1595, 1448, 1325, 1276, 1202, 1151, 1101, 984,
925, 756, 698, 687, 652, 518.
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3-(3-Chlorophenyl)-1-phenyl-2-((trifluoromethyl)thio)pent-4-en-1-one (3k). Colorless oil; yield 78% (28.8 mg);
[α]D20 = 105.2 (c 1.0, EtOAc); 78%, 67% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol
= 95/5; flow rate = 0.3 mL/min; detection wavelength = 214 nm; tR = 18.1 min, 20.4 min, 21.3 min, 22.8 min] 1H
NMR (600 MHz, Chloroform-d) δ 7.90 (d, J = 7.9 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.53
(t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.28 – 7.22 (m, 2H), 7.21 – 7.04 (m, 6H), 6.11
(dt, J = 18.0, 9.5 Hz, 1H), 5.98 (dt, J = 17.9, 9.3 Hz, 1H), 5.31 (d, J = 10.1 Hz, 1H), 5.21 (d, J = 16.9 Hz, 1H), 5.15
– 5.00 (m, 4H), 3.96 (m, 2H). 19F NMR (565 MHz, Chloroform-d) δ -39.09 (s), -39.47 (s). 13C{1H} NMR (151
MHz, Chloroform-d) δ 195.1, 195.0, 140.6, 140.0, 134.9, 134.8, 134.42, 134.39, 133.6, 133.5, 133.0, 132.8, 129.1
(q, J = 307.7 Hz), 129.0 (q, J = 308.0 Hz), 128.99, 128.95, 127.9, 127.7, 127.5, 127.4, 127.2, 127.2, 126.8, 126.6,
125.6, 125.2, 118.5, 118.3, 50.9, 50.5, 49.98, 49.95. HRMS (ESI-TOF): calcd for C18H15ClF3OS [M + H]+:
371.0484; Found: 371.0486. IR (KBr): ν max (cm-1) = 2925, 1682, 1595, 1575, 1476, 1448, 1431, 1271, 1200, 1153,
1105, 927, 783, 757, 693, 654.
3-(4-Bromophenyl)-1-phenyl-2-((trifluoromethyl)thio)pent-4-en-1-one (3l). Colorless solid; yield 70% (29.2 mg);
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m.p. 59-61 °C; [α]D = 78.4 (c 1.0, EtOAc); 98%, 81% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm);
n-hexane/2-propanol = 95/5; flow rate = 0.3 mL/min; detection wavelength = 214 nm; tR = 20.4 min, 28.6 min,
30.2 min, 51.8 min]. 1H NMR (600 MHz, Chloroform-d) δ 7.90 (d, J = 7.8 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.50
(t, J = 7.4 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 5.98 (dt, J = 17.6, 9.2 Hz, 1H), 5.10 (d, J =
5.8 Hz, 1H), 5.08 (s, 1H), 5.05 (d, J = 9.5 Hz, 1H), 3.97 (t, J = 8.9 Hz, 1H). 19F NMR (565 MHz, Chloroform-d) δ
-39.48 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 196.2, 138.0, 135.8, 135.7, 134.0, 131.9, 130.03, 130.00 (q,
J = 307.8 Hz), 128.9, 128.5, 121.6, 119.1, 51.6, 51.0. HRMS (ESI-TOF): calcd for C18H15BrF3OS [M + H]+:
414.9979; Found: 414.9970. IR (KBr): ν max (cm-1) = 2921, 2851, 1682, 1589, 1488, 1402, 1275, 1261, 1156, 1110,
1011, 926, 812, 764, 750, 688, 519.
2-(1-Phenylallyl)-2-((trifluoromethyl)thio)-3,4-dihydronaphthalen-1(2H)-one (3m). Colorless oil; yield 88% (31.9
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mg); [α]D = 3.5 (c 1.0, EtOAc); 91%, 87% ee [Daicel CHIRALCEL AD-H (0.46 cm × 25 cm);
n-hexane/2-propanol = 100/1; flow rate = 0.1 mL/min; detection wavelength = 214 nm; tR = 57.9 min, 61.8 min,
64.3 min, 71.3 min]. 1H NMR (600 MHz, Chloroform-d) δ 8.13 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.52
(t, J = 7.5 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.40 – 7.21 (m, 12H), 7.18 (t, J = 7.6 Hz, 2H), 6.30 (m, 2H), 5.31 (d, J
= 10.2 Hz, 1H), 5.25 – 5.12 (m, 3H), 4.73 (d, J = 9.3 Hz, 1H), 4.55 (d, J = 8.1 Hz, 1H), 3.17 (m, 2H), 3.06 – 2.89
(m, 2H), 2.69 (t, J = 12.2 Hz, 1H), 2.50 (t, J = 14.4 Hz, 1H), 2.38 (dt, J = 14.5, 4.5 Hz, 2H). 19F NMR (565 MHz,
Chloroform-d) δ -34.29 (s), -34.73 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 190.4, 189.6, 141.1, 140.5,
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138.0, 137.3, 134.9, 134.3, 132.9, 132.6, 130.4, 128.7 (q, J = 309.5 Hz) 128.6 (q, J = 309.6 Hz), 129.9, 129.6,
129.4, 128.0, 127.9, 127.6, 127.5, 127.4, 127.14, 127.11, 126.4, 126.2, 126.1, 126.0, 118.7, 118.5, 62.6, 62.0,
52.74, 50.73, 28.6, 28.2, 24.4, 24.2. HRMS (ESI-TOF): calcd for C20H18F3OS [M + H]+: 363.1030; Found:
363.1024. IR (KBr): ν max (cm-1) = 2922, 1686, 1599, 1453, 1284, 1251, 1124, 1099, 922, 774, 755, 744, 713, 673,
486.
Diethyl (S)-2-(1-(thiophen-2-yl)allyl)-2-((trifluoromethyl)thio)malonate (3n). Brown oil; yield 55% (21.1 mg);
[α]D20 = 16.3 (c 1.0, EtOAc); 88% ee [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); n-hexane/2-propanol = 100/1;
flow rate = 0.4 mL/min; detection wavelength = 214 nm; tR = 17.2 min, 19.0 min]. 1H NMR (600 MHz,
Chloroform-d) δ 7.23 (d, J = 5.1 Hz, 1H), 6.98 – 6.90 (m, 2H), 6.31 (dt, J = 18.0, 9.4 Hz, 1H), 5.23 – 5.15 (m, 2H),
4.66 (d, J = 8.6 Hz, 1H), 4.37 – 4.10 (m, 4H), 1.25 (dt, J = 36.2, 7.1 Hz, 6H). 19F NMR (565 MHz, Chloroform-d)
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δ -36.8 (s). 13C{1H} NMR (151 MHz, Chloroform-d) δ 166.1, 139.3, 135.3, 129.2 (q, J = 310.2 Hz), 127.8, 126.4,
125.8, 119.3, 77.2, 77.0, 76.8, 67.1, 63.1, 63.1, 50.7, 13.7, 13.6. HRMS (ESI-TOF): calcd for C15H17F3NaO4S2 [M
+ H]+: 405.0418; Found: 405.0413. IR (KBr): ν max (cm-1) = 1738, 1271, 1249, 1099, 993, 933, 855, 779, 736, 700,
420, 406.
ASSOCIATED CONTENT
Supporting Information
1H, 13C, 19F NMR spectra and HPLC chromatograms for all isolated products found in the SI.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xmzhao08@mail.tongji.edu.cn.
ORCID
Xiaoming Zhao: 0000-0002-1447-128X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful acknowledge the NSFC (21971193) and the Fundamental Research Funds for the Central
Universities for financial support of this research.
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