Organocatalyzed Sulfa-Michael Addition of Thiophenols on Trisubstituted α-Fluoroacrylates, a Straightforward Access to Chiral Fluorinated Compounds

Article abstract of DOI:10.1021/acs.joc.0c02081

In this manuscript, a simple and efficient sulfa-Michael addition reaction of aryl thiols to trisubstituted α-fluoro-α,β-unsaturated esters both in racemic and, for the first time, in enantioselective version is reported. The commercially available dimer of cinchona derivatives (DHQ)2PYR was used as a catalyst. This strategy showed a great tolerance for various substrates and substituents, providing fair to excellent yields, moderate to excellent diastereoselectivities (2:1 to >99:1), and low to good enantioselectivities (2 to 87%). The reaction has been applied to the synthesis of fluorinated analogues of diltiazem and tiazesim, both therapeutic agents.

Full text of DOI:10.1021/acs.joc.0c02081

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Article
Organocatalyzed Sulfa-Michael Addition of Thiophenols on
Trisubstituted α‑Fluoroacrylates, a Straightforward Access to Chiral
Fluorinated Compounds
Xin Huang, Emilie David, Philippe Jubault, Tatiana Besset, and Samuel Couve-Bonnaire*
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ABSTRACT: In this manuscript, a simple and efficient sulfa-Michael
addition reaction of aryl thiols to trisubstituted α-fluoro-α,β-unsaturated
esters both in racemic and, for the first time, in enantioselective version is
reported. The commercially available dimer of cinchona derivatives
(DHQ)2PYR was used as a catalyst. This strategy showed a great tolerance
for various substrates and substituents, providing fair to excellent yields,
moderate to excellent diastereoselectivities (2:1 to >99:1), and low to good
enantioselectivities (2 to 87%). The reaction has been applied to the
synthesis of fluorinated analogues of diltiazem and tiazesim, both therapeutic
agents.
asymmetric reaction and no conjugate addition on trisub-
stituted fluoroalkene substrates have been reported. Indeed, to
the best of our knowledge, the asymmetric 1,4-addition of
nucleophiles with β-substituted-α-fluoroacrylates has not been
developed yet and only very few examples have been reported
in the racemic version to date. In an early report, Normant et
al. studied the addition of lithium dimethylcuprate on α-fluoro-
α,β-unsaturated ketones, aldehydes, and esters.9 Both 1,2- and
1,4-adducts were formed and the ratios depend on the steric
hindrance at the β-position of the substrate. Although the
cuprates are well-known to be 1,4-regioselective,10 the fluorine
atom increased the electrophilicity of the geminal carbonyl
moiety allowing the 1,2-adduct formation in non-negligible
amount and pointing out the unusual reactivity of fluorinated
Michael acceptors. Even more surprisingly, in the case of β-
substituted-α-fluoroacrylates, no 1,4-adduct was isolated
because the enolate from 1,4-addition underwent a Claisen
reaction to form a dimeric product with concomitant loss of
the fluorine atom (Scheme 1, eq a). Later on, in their quest to
fluorinated heterocycles, Schlosser et al. reported two examples
of 1,4-addition of thiophenols on 2-fluoro-3-methoxyacrylate, a
specially designed Michael acceptor, using a catalytic amount
of t-BuOK or 1 equiv of n-BuLi as a base, affording the
corresponding 1,4-adduct as a mixture of diastereoisomers in
3:1 to 3:2 ratios and in good yields (Scheme 1, eq b).11
INTRODUCTION
■
Fluorine-containing compounds are widely used in various
fields including polymers, pharmaceuticals, and agrochemi-
cals.1 Indeed, because of the highest electronegativity and the
small size of the fluorine atom, the incorporation of one or
several fluorine atoms into organic compounds often brings
unique physical, chemical, and biological properties. Consid-
ering the importance of chirality as well as the introduction of a
fluorinated moiety into organic compounds, the quest for
methods to create stereogenic fluorinated carbon centers with
high enantioselectivity and catalytic efficiency is highly
valuable.2 The asymmetric construction of stereogenic
fluorinated carbon centers can be achieved by asymmetric
direct fluorination or starting from already fluorinated
molecules as prochiral sp2 substrates. In this context,
organocatalysis emerged as a powerful tool in asymmetric
synthesis3 and had a large impact on the development of
asymmetric and catalytic conjugate additions of various
nucleophiles to Michael acceptors for the construction of
carbon−carbon and carbon−heteroatom bonds.4 In the past
few years, part of our research program was dedicated to easy
and efficient accesses to 2-fluoroacrylates,5 which could serve
as a Michael acceptor. Surprisingly, although the Michael
addition is a well-known strategy to obtain highly function-
alized products, only sporadic examples have been reported
with fluoroalkene-type Michael acceptors, while the latter
could be a suitable source of fine-fluorinated chemicals. For
example, alkyl 2-fluoroacrylates have been used as Michael
acceptors since the sixties to the specific synthesis of relevant γ-
fluoroglutamic acid.6 Other gem-fluoro-carbonyl7 or -sulfonyl
derivatives8 have also been submitted to Michael addition in
the presence of various nucleophiles but, to our knowledge, no
Received: August 28, 2020
https://dx.doi.org/10.1021/acs.joc.0c02081
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

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Scheme 1. Conjugate Addition on β-Substituted-α-
fluoroacrylates: State of the Art and This Work
Table 1. Optimization of SMA Reactions in the Racemic
Version
a
conv. (%) ;
b
a
entry
1
2
x
y
solvent
T °C
(yield (%))
dr
1.1
1.1
1.1
1.1
1.1
2
2
3
5
10
0.14
0.14
0.14
0.14
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
22
reflux
22
80
80
80
80
80
80
Traces
Traces
50
75 (37)
0
98 (84)
94 (81)
91 (77)
100 (89)
100 (91)
d
3
4
d
73:27
5
6
7
8
9
10
0.14
0.1
0.1
0.1
0.1
77:23
76:24
74:26
76:24
77:23
80
a
b
Determined by 19F NMR. Isolated yield of the mixture of
c
diastereoisomers. dr determined by 19F NMR of the crude mixture.
d
24 h reaction.
Considering the dearth of examples for the racemic and
asymmetric conjugate addition of nucleophiles with fluoroa-
crylates, herein, we report the sulfa-Michael addition
(SMA)4c,12 of thiophenol derivatives with α-fluoroacrylates
both in racemic and enantioselective ways (Scheme 1, eq c).
Two more general points highlighted the relevance of our
study: (i) sulfur-containing compounds13 are very important as
biochemical reagents as well as pharmaceutical agents and the
one-pot formation of products bearing both sulfur and fluorine
atoms could lead to interesting new structures toward
biorelevant molecules; (ii) although the asymmetric SMA
reaction is known from a long time and has been studied with a
large variety of Michael acceptors,4c,12a only few organo-
catalytic studies have been reported with α,β-unsaturated
esters substituted in the α14 or β position15 and even less with
acrylates substituted in both α and β positions,16 whereas in
the latter, two stereogenic centers could be concomitantly
formed.
isolated in moderate 37% yield because of difficulties to
separate product 3 from the remaining starting material and
disulfide byproducts (Table 1, entry 4). The structure of 1,4-
1
adduct was approved by H, 13C, and 19F NMR experiments
and also by mass spectrometry. Diastereoisomers were
obtained in a 73/27 ratio according to 19F NMR of the
crude. The SMA reaction did not proceed in the absence of
triethylamine (Table 1, entry 5). It is noteworthy that the use
of sodium thiophenolate instead of the couple thiophenol/
triethylamine was totally inefficient.17 Increasing the amount of
thiophenol to 2 equiv led to an improved 84% yield in 16 h
(Table 1, entry 6). With 2 equiv of thiophenol, the amount of
NEt3 could be reduced to 0.1 equiv giving almost the same
isolated yield and dr (Table 1, entry 7). We finally found that
this reaction could be performed in neat thiophenol (Table 1,
entries 8−10). Comparing different equivalents of thiophenol,
5 equiv of thiophenol gave full conversion and 1,4-adducts
were isolated in 89% and 76:24 dr (Table 1, entry 9). No real
improvement was observed with 10 equiv of thiophenol (Table
1, entry 10). The use of other tertiary amines such as N,N-
diisopropylethylamine or 1,8-diazabicyclo-[5.4.0]undec-7-ene
led to lower isolated yields of the reaction, while slightly
improving the dr.17
Having identified suitable conditions for racemic SMA
reactions on α-fluoroacrylates, we rapidly turned our attention
to the development of the corresponding asymmetric 1,4-
additions screening chiral catalysts and temperatures (Table
2). All the reactions were performed in neat thiophenol
according to the previous study. The use of natural cinchona
alkaloids18 as the cinchonine led to good conversion but no
stereodifferentiation (Table 2, entry 1). The use of quinine as a
catalyst allowed us to obtain an enantioselectivity but with a
low 15% value. Enhancing the catalyst loading to 20 mol %
increased the conversion without positive influence on the
enantioselectivity. Quinidine gave reverse enantioselectivity
compared to quinine, albeit with lower conversion (Table 2,
entry 4). The use of aryl ethers of bis-cinchona alkaloids19
(DHQ)2PYR gave full conversion, good diastereoisomeric
RESULTS AND DISCUSSION
■
We chose (Z)-ethyl 2-fluoro-5-phenylpent-2-enoate (1a) as a
model Michael acceptor and the thiophenol as a nucleophile to
begin our study on the SMA reaction. First investigations were
carried out in a racemic version. SMA being usually efficiently
carried out under basic conditions,4c we decided to consider
the low pKa of thiophenol and use the weak base NEt3 as a
catalyst. Worthy of note is that whatever the precaution taken,
during the SMA reactions, the oxidation of thiophenol
occurred as a side reaction making the isolation of 1,4-adducts
difficult. To minimize the production of disulfide byproducts,
all the tests were performed in degassed solvents under argon.
Traces of 1,4-adducts were identified by 19F NMR (character-
istic doublet of doublet corresponding to two diastereoisomers
at −195.0 and −197.0 ppm) when using triethylamine as a
catalytic base in dichloromethane; the conversion was not
improved when the reaction mixture was heated to reflux for a
longer time (Table 1, entries 1−2). Among other solvents
tested, acetonitrile appeared as the most suitable one, leading
to 50 and 75% conversion at 22 °C (room temperature) and
80 °C, respectively (Table 1, entries 3−4). 1,4-adduct 3 was
B
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Table 2. Optimization of the Asymmetric SMA Reaction
a
b
c
d
entry
catalyst
x
conv. (%) ; (yield (%))
dr
ee (%)
1
2
3
4
5
6
7
cinchonine
quinine
quinine
10
10
20
10
10
10
5
10
10
10
10
98
90
96
85
100
63
98
100
89 (73)
42
86:14
83:17
80:20
85:15
89:11
88:12
87:13
85:15
85:15
81:19
84:16
0
15
15
−13
66
−72
60
37
70
73
71
quinidine
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2PYR
(DHQ)2PYR
(DHQ)2PYR
(DHQ)2PYR
e
8
9
f
g
10
11 ,
fh
(DHQ)2PYR
100 (82)
a
b
c
d
Determined by 19F NMR. Isolated yield of the mixture of diastereoisomers. dr determined by 19F NMR of the crude mixture. Determined for
e
f
g
major diastereoisomer by HPLC. Reaction carried out at 80 °C, 16 h of reaction. Reaction carried out at 0 °C. Reaction carried out at −20 °C.
h
5 days of reaction.
ratio, and allowed us to significantly enhance the ee value to
66% (Table 2, entry 5).
as iso-propyl or tert-butyl group led to lower yields and ee
values.17 (DHQ)2PYR, giving the best result in terms of
conversion, diastereoisomeric and enantiomeric excesses, was
selected to study the scope of the reaction with thiophenol
acting both as a reagent and solvent. With the optimized
conditions in hand, the scope of the SMA reaction of a variety
of thiols on some α-fluoroacrylates was investigated in both
racemic and enantioselective ways (Scheme 2). We will first
comment briefly about the racemic process before discussing
more in detail the asymmetric SMA reaction.
Mostly, the racemic way furnished good-to-excellent yield
(61 to 98% yield) whatever the substituent contained in thiol
or fluoroacrylate, except for compounds 17, 21, and 27, for
which the yield is below 50% (40 to 46%). Diastereomeric
ratios were obtained in a range from 71:29 to 92:8 with a
major diastereoisomer in favor of the syn-configuration. This
stereoselectivity was ascertained by X-ray analysis of crystals
obtained from racemic product 13 (Figure 1a).21a
The use of (DHQD)2PYR gave 72% ee but incomplete
conversion (Table 2, entry 6). Lowering the catalyst loading to
5 mol % decreased both the conversion and the enantiomeric
excess (Table 2, entry 7). The reaction carried out at 80 °C
was complete after 16 h but gave a low 37% ee value (Table 2,
entry 8). Decreasing the temperature allowed us to increase
the ee value to 70 and 73%, at 0 and −20 °C, respectively.
Nevertheless, the conversion was lower in these conditions
(Table 2, entries 9−10). Finally, carrying out the reaction at 0
°C for 5 days furnished full conversion with 71% of
enantiomeric excess. It is noteworthy that we tested more
than 15 catalysts, including other natural or modified cinchona
alkaloids, chiral amines, and also urea derivatives,20 including
the Takemoto’s urea,20a which was already used successfully in
the SMA reaction, but the best results were obtained with
(DHQ)2PYR as a catalyst.17 Other dimers were also tested
such as (DHQ)2PHAL and (DHQ)2AQN but these catalysts
gave lower ee values. It is important to note that, in order to
increase the enantiomeric excess, we studied the influence of
about 15 solvents on the reaction. None of them was more
efficient that the reaction carried out in neat thiophenol.17
Finally, the use of bulkier ester than methyl or ethyl group such
For the asymmetric reaction, with the (Z)-ethyl 2-fluoro-5-
phenylpent-2-enoate 1a, aryl thiols bearing electron-donating
groups, such as methyl (in ortho-, meta-, and para-position),
methoxy, or amino, successfully furnished the desired products
5−9 in good-to-excellent yields (74−95%) and good-to-very
good diastereoselectivities (81:19 to 95:5). For unsubstituted 3
C
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Scheme 2. Scope of the SMA Reaction on α-Fluoroacrylates
a
d
g
b
c
Isolated yield of diastereoisomers. Determined by 19F NMR of the crude mixture. Determined for the major diastereoisomer by HPLC.
e
f
Reaction performed on the 1.5 mmol scale of α-fluoroacrylate 1a. Reaction carried out at 22 °C (room temperature). Toluene as a solvent.
Absolute configuration of 18 was determined using a single-crystal X-ray diffractometer; the two stereogenic centers are both in the S absolute
h
configuration. Reaction performed on the 1 mmol scale of α-fluoroacrylate 1c.
and ortho- or meta-substituted thioaryl 6−8, good ee values
were obtained (71 to 84%). However, thioaryl bearing a
substituent in para-position 4 (p-Br), 5 (p-OMe), and 9 (p-
Me) was obtained in low-to-fair ee values: 23, 38, and 54%,
respectively. Unfortunately, 2-thionaphthol, which proved to
be the best aryl thiol in the asymmetric 1,4-addition to cyclic
enones,19b furnished the product 11 with only 29% of ee. The
substrate scope could be extended to thiophene thiol to give
1,4-adduct 10 in good 73% yields, 88:12 dr ratio, and 67% of
ee. Additions of 4-bromothiophenol and naphthyl thiol to a
fluorinated Michael acceptor bearing a nitro-aryl substituent
also occurred in good yields and diastereoselectivities but
without enantioselectivities for products 12 and 13. Usually,
diastereomeric ratios were better in the enantioselective
version of the reaction than in the racemic one, except for
compounds 4 and 11. Cyclohexyl α-fluoroacrylate 1c was also
used in the SMA reaction, giving moderate-to-good yields (32
to 77%) and good-to-complete diastereoselectivities, from
69:31 for 15, bearing a bromine atom in the para-position, to
100:0 leading to the formation of a single diastereoisomer for
D
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Table 3. Influence of the Double-Bond Geometry
b
c
d
entry
substrate
cond.
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
(Z)-1a
(E)-1a
(Z)-1d
A
A
A
A
B
B
B
B
91
93
61
74
82
86
54
56
76:24
26:74
87:13
33:67
84:16
14:86
88:12
24:76
Figure 1. (a) X-ray of major diastereoisomers of 13 obtained in the
racemic way (mixture of syn-enantiomers). (b) X-ray of major
enantiomer of 18.
e
(E)-1d
(Z)-1a
(E)-1a
(Z)-1d
71
74
63
51
the products 14 and 17, obtained from thiophenol and
thiophene thiol, respectively. As for substrate 1a, substitution
in the para-position was detrimental for ee giving a low value
for products 15 and 16. Substitution in the meta-position also
led, in this case, to low 26% of ee. Product 18 obtained from 2-
aminothiophenol gave the best enantiomeric excess 87%. The
X-ray analysis of 18 crystals confirmed the syn-configuration
and revealed that the two stereogenic centers are both in S
absolute configurations (Figure 1b).21b
e
(E)-1d
a
Conditions A = NEt3 (10 mol %), 80 °C, overnight: conditions B =
b
(DHQ)2PYR (10 mol %), 0 °C, 5 or 8 days. Isolated yield of the
c
mixture of diastereoisomers. dr determined by 19F NMR of the crude
d
mixture. Determined for the major diastereoisomer by HPLC.
Contaminated with 10% of (Z)-1d.
e
furnishing the desired products 3 and 18 in 73% of isolated
yield, 87:13 of dr, and 72% of ee and 51% of isolated yield,
91:9 of dr, and 85% of ee, respectively.
Then, we studied SMA addition on different aryl α-
fluoroacrylates (1d−i). Generally, with aryl α-fluoroacrylates,
lower yields, compared to alkyl-fluoroacrylates 1a−c, were
obtained in 1,4-adducts 20−27 (22 to 78%), albeit with very
good-to-excellent diastereoselectivities (87:13 to 100:0). Fair-
to-good ee values were obtained for these aryl substrates in a
range from 51 to 73%. α-Fluorocinnamates bearing a cyano
group at the ortho-, meta-, and para-position of the phenyl
moiety gave the desired products 24−26 in similar results
showing no significant substituent effects. Although the
electronic feature of fluoroacrylates or aryl thiol does not
seem to have an impact on the reaction, having a substituent in
para-position of the aryl thiol implied a lack of stereoselectivity
meaning that the approach of the thiol is important in the
enantioselective process. A kinetic study showed that the dr
and ee did not evolve from the beginning to the completion of
the reaction.17 To get insight in the influence of the double-
bond geometry, we synthesized substrates 1a and 1d in the E
configuration and submitted them to the SMA reaction.
Interestingly, although similar yields and enantiomeric excesses
for the major diastereoisomer were achieved, reversed
diastereoisomer ratios were obtained starting with (E)-
fluoroacrylates in place of its (Z)-congener, meaning that the
face attack does not vary with the geometry of the double bond
(Table 3). It has to be noted that for the reaction of (E)-1d,
there was a little amount of (Z)-isomer in (E)-substrate (E/Z
ratio: 90:10, (Z)-1d coming from the synthesis of starting
material) explaining the lower dr obtained (Table 3, entries 4
and 8). Ninomiya’s research group reported the same kind of
reversal dr depending on the double-bond configuration with
the SMA reaction between thiophenol and α,β-trisubstituted
acrylates in the presence of a catalytic amount of the base and
proposed a concerted process to explain their results.22 In our
case, we probably also have a concerted mechanism with the
thiol addition preferentially on the Si face of the β-position of
the alkene and the concomitant protonation on the opposite
Re face of the α-position. A substituent in para-position of the
aryl thiol should prevent the stereodifferentiation by steric
hindrance. Two reactions on a larger scale were carried out
with success starting from 1a (1.5 mmol) and 1c (1 mmol),
Finally, we applied our methodology to the synthesis of
fluorinated analogues of biomolecules from both 21 and 27
compounds as starting materials. A two-step synthesis,23
a
cyclization under acid catalysis followed by an alkylation
reaction, allowed us to obtain, without variation of ee values,
fluoroanalogues of both diltiazem, a calcium channel blocker,
clinically used since 1974 as an antianginal and antihyperten-
sive agent, and tiazesim, an antidepressant agent (Scheme 3).24
CONCLUSIONS
■
In summary, we developed a simple and efficient SMA reaction
on β-substituted-α-fluoroacrylates in both racemic and, for the
first time, in enantioselective version. This strategy shows great
tolerance of various substrates and substituents, providing
modest-to-excellent yields and moderate-to-good diastereose-
lectivities in a racemic way (40−98%, dr = 3:1 to 12:1).
In an enantioselective way, good levels of reactivity, fair-to-
excellent diastereoselectivities, and moderate-to-good enantio-
selectivities were achieved using commercially available
(DHQ)2PYR as a catalyst (22−95%, dr = 2:1 to >99:1, ee
up to 87%). Two fluorinated analogues of therapeutic agents
were successfully synthesized using this SMA strategy. Other
Michael addition reactions with fluorinated Michael acceptors
are presently under study in our laboratory.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise mentioned, all the
reagents were purchased from commercial sources and used without
further purification. All reactions were carried out in an oven-dried
sealed tube under argon. Reaction temperatures were reported as the
temperature of the bath surrounding the vessel. The dry solvents used
were purified by distillation over the dry agents indicated in brackets
and were transferred under argon: THF (Na, benzophenone),
CH2Cl2 (CaH2), and toluene (Na, benzophenone). Anhydrous
DMF, CH3CN, 1,4-dioxane, Et2O, and DME were purchased from
Acros Organics (Solvents Extra Dry over Molecular Sieve, Acroseal).
Flash chromatography was carried out using Silicaflash P60 silica gel
(40−60 mm); solvents used were PE = petroleum ether and EA =
E
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Scheme 3. Synthesis of Fluorinated Analogues of Biomolecules
ethyl acetate. Melting points (mp) were determined on a Fisher
Enantioselective Pathway. In an over-dried sealed tube, α-
fluoroacrylate (0.3 mmol, 1 equiv) and thiol (1.5 mmol, 5 equiv),
followed by (DHQ)2PYR (0.03 mmol, 10 mol %) were introduced,
the tube was sealed and then freezed by liquid nitrogen, the air was
removed under high vacuum, and argon was introduced. The reaction
mixture was stirred at 0 °C or at 22 °C (room temperature) for 5 to 8
days. Then, the reaction mixture was purified by silica gel column
chromatography (eluent: PE/EtOAc or PE/CH2Cl2).
1
Scientific hot-stage melting-point apparatus and are uncorrected. H,
13C, and 19F NMR spectra were recorded using a Bruker AVANCE-
300 spectrometer operating at 300 MHz (1H), 75 MHz (13C), and
282 MHz (19F), using CDCl3 as an NMR solvent. The chemical shifts
(δ) were calibrated on residual proton and carbon resonances of
CDCl3 (1H, δ = 7.26 ppm and 13C, δ = 77.2 ppm) or relative to
external CFCl3 (19F, δ = 0.0 ppm). The multiplicity signals were
indicated with the common abbreviations: s (singlet), d (doublet), t
(triplet), q (quadruplet), m (multiplet), and br (broad) and the
combinations thereof. IR spectra were recorded on a PerkinElmer
Spectrum 100 FT IR spectrometer. High-resolution mass spectra
(HRMS) were recorded on a JEOL AccuTof 4G spectrometer
coupled to a GC HP Agilent 7890. Enantiomeric excesses (ee) were
determined using a SpectraSYSTEM HPLC equipped with a
P1000XR pump, a UV1000 detector, and a Rheodyne injector. See
specific conditions detailed for each compound.
Characterization Data for Products. (2S,3S)-Ethyl 2-Fluoro-5-
phenyl-3-(phenylthio)pentanoate (3). (Z)-Ethyl 2-fluoro-5-phenyl-
pent-2-enoate (0.3 mmol, 66.6 mg) and (DHQ)2PYR (0.03 mmol,
26.4 mg) were stirred in neat thiophenol (1.5 mmol, 165 mg) at 0 °C
for 5 days according to the general procedure b. 19F NMR of the
crude product showed dr = 84:16. The crude was purified by silica gel
column chromatography (PE/EtOAc, from 20/1 to 15/1, v/v)
affording two diastereoisomers in 82% yield (major: 67 mg as a
colorless oil; minor: 14 mg as a colorless oil). 71% ee was obtained for
the major diastereoisomer [determined by HPLC, IC column, Hept/
i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.810
min, t (major) = 7.507 min]. The reaction performed on 1.5 mmol
(Z)-ethyl 2-fluoro-5-phenylpent-2-enoate led to 73% of isolated yield
(major: 304 mg, major and minor mixture: 59 mg), dr: 87:13, and ee:
72% (major diastereoisomer). The racemic product has been obtained
following the procedure a (the same scale) in 91% yield (major: 80
mg as a colorless oil; minor: 11 mg as a colorless oil) with dr = 76:24.
General Procedure for Synthesis of Fluoroacrylates. Syn-
thesis of Aliphatic Fluoroacrylates.5a To an anhydrous CH2Cl2
solution (10 mL/mmol of aldehyde) of the appropriate aldehyde (1.0
equiv) and ethyl dibromofluoroacetate (2.0 equiv) was added
diethylzinc (1 M in hexane, 4.0 equiv) dropwise under argon. The
reaction mixture was stirred during 3 h at 22 °C (room temperature)
(until antialcohol was not detected by 19F NMR). The resulting
solution was then poured into saturated NH4Cl, CH2Cl2 was
evaporated under vacuum, EtOAc was added, and the mixture was
stirred for 15 min. The remaining zinc salts were filtered off through a
[α]2D0 −18.0 (c 1.23, CDCl3); H NMR (300 MHz, CDCl3): δ
1
2
7.37−7.34 (m, 2H), 7.22−7.05 (m, 8H), 4.97 (dd, 1H, JH−F = 48.0
Hz, JH−H = 3.0 Hz), 4.13−3.89 (m, 2H), 3.49−3.33 (m, 1H), 2.92−
2.68 (m, 2H), 2.09−1.91 (m, 2H), 1.12 (t, 3H, JH−H = 9.0 Hz). 19F
2
3
NMR (282 MHz, CDCl3): δ −197.0 (dd, JF−H = 48.0 Hz, JF−H
=
28.2 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 167.9 (d, 2JC−F = 22.5
Hz), 140.7, 133.8, 132.9, 129.0, 128.5, 128.5, 127.6, 126.2, 90.5 (d,
2
1JC−F = 195.0 Hz), 61.7, 50.5 (d, JC−F = 22.5 Hz), 33.4, 33.2, 14.0.
Buchner funnel. The heterogeneous resulting solution was extracted
̈
twice with Et2O (2 × 20 mL/mmol of aldehyde), dried over MgSO4,
and concentrated under reduced pressure and then purified by flash
silica gel column chromatography.
IR: 2980, 1761, 1737, 1475, 1266, 1212, 1103, 1024, 745, 692, 557,
491 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C19H22FO2S,
333.1325; found, 333.1319.
Synthesis of Aromatic Fluoroacrylates.5b In a vial were added
iodoarene (1.0 equiv), fluoroacrylate (1.5 equiv), Ag2CO3 (2.0 equiv),
(2S,3R)-Ethyl 2-Fluoro-5-phenyl-3(phenylthio)pentanoate (anti-
3). (E)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol, 66.6 mg)
and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
thiophenol (1.5 mmol, 165 mg) at 0 °C for 5 days according to the
general procedure b. 19F NMR of the crude product showed dr =
14:86. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 20/1 to 15/1, v/v) affording two diastereoisomers
in 86% yield (major: 39 mg as a colorless oil; major and minor
mixture: 47 mg). About 74% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 230 nm, t (minor) = 5.340 min, t
(major) = 5.803 min]. The racemic product has been obtained
following the procedure a (the same scale) in 93% yield (major: 72
mg as a colorless oil; minor: 21 mg as a colorless oil) with dr = 26:74.
1H NMR (300 MHz, CDCl3): δ 7.40−7.37 (m, 2H), 7.25−7.09
(m, 8H), 4.80 (dd, 1H, 2JH−F = 48.0 Hz, JH−H = 6.0 Hz), 4.07 (q, 2H,
JH−H = 6.0 Hz), 3.42−3.31 (m, 1H), 2.94−2.70 (m, 2H), 1.94−1.87
(m, 2H), 1.13 (t, 3H, JH−H = 9.0 Hz). 19F NMR (282 MHz, CDCl3):
δ −195.7 (dd, 2JF−H = 48.0 Hz, 3JF−H = 22.6 Hz). 13C{1H} NMR (75
and Pd(TFA)2 (10 mol %). The vial was then filled with 1,4-dioxane
(5 mL/mmol of iodoarene) and then was heated to 90 °C (oil bath)
for 4 h. The crude was filtered over celite and washed with EA (3 ×
30 mL/mmol of iodoarene) and then the solvent was evaporated. The
crude was then purified by flash silica gel column chromatography.
General Procedure for SMA of Fluoroacrylates. Racemic
Pathway. In an over-dried sealed tube, α-fluoroacrylate 1 (0.3 mmol,
1 equiv) and thiol 2 (1.5 mmol, 5 equiv), followed by NEt3 (0.03
mmol, 10 mol %) were introduced, and the tube was sealed and then
freezed by liquid nitrogen, the air was removed under high vacuum,
and argon was introduced. The reaction mixture was stirred at 80 °C
(oil bath) for 16 h and then was cooled to room temperature. The
reaction mixture was purified by silica gel column chromatography
(eluent: PE/EtOAc or PE/CH2Cl2).
2
MHz, CDCl3): δ 168.1 (d, JC−F = 22.5 Hz), 140.8, 133.2, 132.9,
1
129.2, 128.5, 127.9, 126.2, 90.3 (d, JC−F = 195.0 Hz), 61.8, 49.5 (d,
2JC−F = 15.0 Hz), 32.8, 30.6, 14.1.
F
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The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(2S,3S)-Ethyl 3-((4-Bromophenyl)thio)-2-fluoro-5-phenylpenta-
noate (4). (Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol,
66.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in
neat 4-bromobenzenethiol (1.5 mmol, 281 mg) at 0 °C for 5 days
according to the general procedure b. 19F NMR of the crude product
showed dr = 67:33. The crude was purified by silica gel column
chromatography (PE/EtOAc, from 15/1 to 10/1, v/v) affording two
diastereoisomers in 38% yield (major: 38 mg as a white solid; minor:
9 mg as a white solid). About 23% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
98/2, flow = 1 mL/min, λ = 254 nm, t (minor) = 9.810 min, t (major)
= 11.183 min]. The racemic product has been obtained following the
procedure a (the same scale) in 98% yield (major: 107 mg as a white
solid; minor: 13 mg as a white solid) with dr = 73:27.
25.4 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 168.1 (d, 2JC−F = 22.5
Hz), 149.2, 140.7, 137.3, 130.5, 128.5, 128.4, 126.2, 118.4, 115.1,
1
2
114.9, 89.8 (d, JC−F = 187.5 Hz), 61.8, 49.6 (d, JC−F = 15.0 Hz),
33.2, 32.9, 14.0. IR: 3468, 3371, 2925, 1754, 1607, 1479, 1216, 1103,
1022, 857, 747, 699, 454 cm−1. HRMS (API+) m/z: [M + H]+ calcd
for C19H23FNO2S, 348.1434; found, 348.1426.
(2S,3S)-Ethyl 2-Fluoro-5-phenyl-3-(o-tolylthio)pentanoate (7).
(Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol, 66.6 mg) and
(DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat 2-
methylbenzenethiol (1.5 mmol, 186 mg) at 0 °C for 5 days according
to the general procedure b. 19F NMR of the crude product showed dr
= 95:5. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 91% yield (major: 78 mg as a colorless oil; major and minor
mixture: 16 mg). About 78% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 5.793 min, t
(major) = 6.470 min]. The racemic product has been obtained
following the procedure a (the same scale) in 91% yield (major: 68
mg as a colorless oil; major and minor mixture: 26 mg) with dr =
73:27.
1
[α]2D0 −6.1 (c 1.09, CDCl3); mp 54−56 °C; H NMR (300 MHz,
CDCl3): δ 7.34−7.31 (m, 2H), 7.22−7.06 (m, 7H), 4.97 (dd, 1H,
2JH−F = 51.0 Hz, JH−H = 3.0 Hz), 4.13−4.02 (m, 2H), 3.41−3.29 (m,
1H), 2.85−2.73 (m, 2H), 2.07−1.93 (m, 2H), 1.17 (t, 3H, JH−H = 6.0
2
Hz). 19F NMR (282 MHz, CDCl3): δ −197.2 (dd, JF−H = 51.0 Hz,
3JF−H = 31.0 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 167.8 (d, 2JC−F
= 22.5 Hz), 140.4, 134.5, 132.8, 132.0, 128.6, 128.5, 126.3, 122.0, 90.6
(d, 1JC−F = 187.5 Hz), 61.8, 50.4 (d, 2JC−F = 15.0 Hz), 33.3, 33.1, 14.1.
IR: 2920, 1757, 1474, 1209, 1091, 815, 695, 585, 478 cm−1. HRMS
(API+) m/z: [M + H]+ calcd for C19H21BrFO2S, 411.0430; found,
411.0429.
1
[α]2D0 +29.4 (c 0.68, CDCl3); H NMR (300 MHz, CDCl3): δ
2
7.24−7.06 (m, 9H), 4.98 (d, 1H, JH−F = 48.0 Hz), 4.08−3.83 (m,
2H), 3.57−3.45 (m, 1H), 2.84−2.75 (m, 2H), 2.34 (S, 3H), 2.15−
1.97 (m, 2H), 1.10 (t, 3H, JH−H = 9.0 Hz). 19F NMR (282 MHz,
2
3
CDCl3): δ −196.5 (dd, JF−H = 48.0 Hz, JF−H = 28.2 Hz). 13C{1H}
(2S,3S)-Ethyl 2-Fluoro-3-((4-methoxyphenyl)thio)-5-phenylpen-
tanoate (5). (Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol,
66.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
4-methoxybenzenethiol (1.5 mmol, 210 mg) at 0 °C for 5 days
according to the general procedure b. 19F NMR of the crude product
showed dr = 81:19. The crude was purified by silica gel column
chromatography (PE/EtOAc, from 49/1 to 19/1, v/v) affording two
diastereoisomers in 74% yield (major: 71 mg as a colorless oil; minor:
9 mg as a colorless oil; major and minor mixture: 12 mg). About 38%
ee was obtained for the major diastereoisomer [determined by HPLC,
IC column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 8.783 min, t (major) = 9.857 min]. The racemic product
has been obtained following the procedure a (the same scale) in 87%
yield (major: 78 mg as a colorless oil; minor: 19 mg as a colorless oil)
with dr = 84:16.
NMR (75 MHz, CDCl3): δ 167.8 (d, 2JC−F = 22.5 Hz), 140.6, 140.1,
133.3, 132.3, 130.4, 128.5, 128.5, 127.4, 126.5, 126.2, 90.0 (d, 1JC−F
=
187.5 Hz), 61.7, 49.7 (d, 2JC−F = 22.5 Hz), 33.5, 33.2, 20.9, 13.9. IR:
2935, 1761, 1736, 1454, 1299, 1212, 1025, 747, 699, 558, 438 cm−1.
HRMS (API+) m/z: [M + H]+ calcd for C20H24FO2S, 347.1481;
found, 347.1480.
(2S,3S)-Ethyl 2-Fluoro-5-phenyl-3-(m-tolylthio)pentanoate (8).
(Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol, 66.6 mg) and
(DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat 3-
methylbenzenethiol (1.5 mmol, 186 mg) at 0 °C for 5 days according
to the general procedure b. 19F NMR of the crude product showed dr
= 94:6. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 95% yield (major: 86 mg as a colorless oil; major and minor
mixture: 13 mg). About 80% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.873 min, t
(major) = 7.530 min]. The racemic product has been obtained
following the procedure a (the same scale) in 84% yield (major: 66
mg as a colorless oil; major and minor mixture: 21 mg) with dr =
72:28.
[α]2D0 −10.4 (c 0.57, CDCl3); H NMR (300 MHz, CDCl3): δ
1
7.36−7.33 (m, 2H), 7.19−7.06 (m, 5H), 6.75−6.73 (m, 2H), 4.92 (d,
2
1H, JH−F = 48.0 Hz), 4.16−4.01 (m, 2H), 3.71 (S, 3H), 3.27−3.17
(m, 1H), 2.89−2.70 (m, 2H), 1.99−1.88 (m, 2H), 1.17 (t, 3H, JH−H
=
2
6.0 Hz). 19F NMR (282 MHz, CDCl3): δ −197.1 (dd, JF−H = 48.0
Hz, 3JF−H = 28.2 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 168.1 (d,
2JC−F = 30.0 Hz), 159.9, 140.9, 136.2, 128.6, 128.5, 126.2, 123.4,
[α]2D0 −18.8 (c 0.89, CDCl3); H NMR (300 MHz, CDCl3): δ
1
1
1
114.5, 90.8 (d, JC−F = 187.5 Hz), 61.7, 55.4, 51.1 (d, JC−F = 22.5
Hz), 33.2, 33.0, 14.1. IR: 2940, 1760, 1455, 1494, 1245, 1026, 829,
699, 525, 493 cm−1. HRMS (API+) m/z: [M + H]+ calcd for
C20H24FO3S, 363.1430; found, 363.1426.
2
7.23−6.97 (m, 9H), 4.97 (d, 1H, JH−F = 48.0 Hz, JH−H 3.0 Hz),
4.12−3.93 (m, 2H), 3.47−3.34 (m, 1H), 2.91−2.69 (m, 2H), 2.23 (S,
3H), 2.06−1.89 (m, 2H), 1.13 (t, 3H, JH−H = 9.0 Hz). 19F NMR (282
2
3
MHz, CDCl3): δ −196.8 (dd, JF−H = 48.0 Hz, JF−H = 28.2 Hz).
(2S,3S)-Ethyl 3-((2-Aminophenyl)thio)-2-fluoro-5-phenylpenta-
noate (6). (Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol,
66.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in
neat 2-aminobenzenethiol (1.5 mmol, 188 mg) at 0 °C for 5 days
according to the general procedure b. 19F NMR of the crude product
showed dr = 90:10. The crude was purified by silica gel column
chromatography (PE/EtOAc, from 10/1 to 8/1, v/v) affording two
diastereoisomers in 95% yield (major: 89 mg as a yellow oil; major
and minor mixture: 11 mg). About 84% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 230 nm, t (minor) = 11.380 min, t
(major) = 15.850 min]. The racemic product has been obtained
following the procedure a (the same scale) in 91% yield (major: 61
mg as a yellow oil; major and minor mixture: 34 mg) with dr = 80:20.
13C{1H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC−F = 22.5 Hz),
2
140.7, 138.7, 133.5, 133.3, 129.7, 128.8, 128.5, 128.4, 126.2, 90.5 (d,
2
1JC−F = 187.5 Hz), 61.7, 50.4 (d, JC−F = 22.5 Hz), 33.4, 33.1, 21.3,
14.0. IR: 2933, 1762, 1737, 1454, 1299, 1212, 1025, 749, 698, 557,
432 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C20H24FO2S,
347.1481; found, 347.1479.
(2S,3S)-Ethyl 2-Fluoro-5-phenyl-3-(p-tolylthio)pentanoate (9).
(Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol, 66.6 mg) and
(DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat 4-
methylbenzenethiol (1.5 mmol, 186 mg) at 0 °C for 5 days according
to the general procedure b. 19F NMR of the crude product showed dr
= 85:15. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 82% yield (major: 77 mg as a colorless oil; minor: 8 mg as a
colorless oil). About 54% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 7.347 min, t
(major) = 8.143 min]. The racemic product has been obtained
[α]2D0 +13.4 (c 1.08, CDCl3); H NMR (300 MHz, CDCl3): δ
1
2
7.30−7.02 (m, 7H), 6.63−6.56 (m, 2H), 4.92 (d, 1H, JH−F = 48.0
Hz), 4.32 (S, 2H), 4.10−3.95 (m, 2H), 3.36 (d, 1H, J = 27 Hz),
2.85−2.75 (m, 2H), 2.07−1.91 (m, 2H), 1.15 (t, 3H, JH−H = 6.0 Hz).
19F NMR (282 MHz, CDCl3): δ −196.0 (dd, 2JF−H = 48.0 Hz, 3JF−H
=
G
https://dx.doi.org/10.1021/acs.joc.0c02081
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
following the procedure a (the same scale) in 67% yield (major: 31
mg as a colorless oil; minor: 9 mg as a colorless oil; major and minor
mixture: 30 mg) with dr = 74:26.
NMR of the crude product showed dr = 80:20. The crude was
purified by silica gel column chromatography (PE/EtOAc, from 15/1
to 10/1, v/v) affording two diastereoisomers in 77% yield (major: 72
mg as a yellow oil; major and minor mixture: 33 mg). About 2% ee
was obtained for the major diastereoisomer [determined by HPLC,
IC column, Hept/i-PrOH: 99/1, flow = 1 mL/min, λ = 254 nm, t
(minor) = 125.503 min, t (major) = 115.393 min]. The racemic
product has been obtained following the procedure a (the same scale)
in 73% yield (major: 75 mg as a yellow oil; major and minor mixture:
24 mg) with dr = 82:18.
1
[α]2D0 −14.0 (c 0.84, CDCl3); H NMR (300 MHz, CDCl3): δ
2
7.28−7.00 (m, 9H), 4.94 (d, 1H, JH−F = 48.0 Hz), 4.13−3.97 (m,
2H), 3.40−3.25 (m, 1H), 2.92−2.68 (m, 2H), 2.24 (S, 3H), 2.03−
1.91 (m, 2H), 1.15 (t, 3H, JH−H = 6.0 Hz). 19F NMR (282 MHz,
2
3
CDCl3): δ −196.8 (dd, JF−H = 48.0 Hz, JF−H = 28.2 Hz). 13C{1H}
NMR (75 MHz, CDCl3): δ 168.0 (d, 2JC−F = 22.5 Hz), 140.8, 137.9,
1
133.5, 129.7, 129.7, 128.5, 128.5, 126.2, 90.6 (d, JC−F = 187.5 Hz),
[α]2D0 −0.34 (c 0.87, CDCl3); 1H NMR (300 MHz, CDCl3): δ 8.07
(d, 2H, JH−H = 9.0 Hz), 7.37−7.34 (m, 2H), 7.27−7.19 (m, 4H), 4.98
(dd, 1H, 2JH−F = 48.0 Hz, JH−H = 3.0 Hz), 4.21−4.01 (m, 2H), 3.43−
3.28 (m, 1H), 3.03−2.77 (m, 2H), 2.14−1.91 (m, 2H), 1.19 (t, 3H,
61.7, 50.7 (d, 2JC−F = 15.0 Hz), 33.2, 33.2, 21.1, 14.0. IR: 2920, 1762,
1737, 1493, 1300, 1211, 1104, 1020, 811, 749, 699, 556, 496 cm−1.
HRMS (API+) m/z: [M + H]+ calcd for C20H24FO2S, 347.1481;
found, 347.1481.
J
H−H = 6.0 Hz). 19F NMR (282 MHz, CDCl3): δ −196.4 (dd, 2JF−H
=
(2S,3S)-Ethyl 2-Fluoro-5-phenyl-3-(thiophen-2-ylthio)-
pentanoate (10). (Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3
mmol, 66.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were
stirred in neat thiophene-2-thiol (1.5 mmol, 174 mg) at 0 °C for 5
days according to the general procedure b. 19F NMR of the crude
product showed dr = 88:12. The crude was purified by silica gel
column chromatography (PE/EtOAc, from 15/1 to 10/1, v/v)
affording two diastereoisomers in 73% yield (major: 41 mg as a yellow
oil; major and minor mixture: 33 mg). About 67% ee was obtained for
the major diastereoisomer [determined by HPLC, IC column, Hept/
i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.183
min, t (major) = 7.050 min]. The racemic product has been obtained
following the procedure a (the same scale) in 83% yield (major: 60
mg as a yellow oil; major and minor mixture: 24 mg) with dr = 83:17.
48.0 Hz, 3JF−H = 28.2 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 167.6
2
(d, JC−F = 30.0 Hz), 148.3, 146.7, 134.7, 132.3, 132.2, 129.2, 123.9,
2
122.4, 90.5 (d, C−F, = 187.5 Hz), 62.0, 50.6 (d, JC−F = 22.5 Hz),
33.0, 32.9, 14.1. IR: 2940, 1759, 1737, 1599, 1516, 1343, 1068, 852,
817, 698, 479 cm−1. HRMS (API−) m/z: [M]+ calcd for
C19H19BrFNO4S, 455.0202; found, 455.0193.
(2S,3S)-Ethyl 2-Fluoro-3-(naphthalen-2-ylthio)-5-(4-
nitrophenyl)pentanoate (13). (Z)-Ethyl 2-fluoro-5-(4-nitrophenyl)-
pent-2-enoate (0.3 mmol, 80.1 mg), naphthalene-2-thiol (1.5 mmol,
240 mg), and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in
toluene at 0 °C for 8 days according to the general procedure b. 19F
NMR of the crude product showed dr = 84:16. The crude was
purified by silica gel column chromatography (PE/EtOAc, from 10/1
to 8/1, v/v) affording two diastereoisomers in 55% yield (major: 47
mg as a yellow solid; major and minor mixture: 23 mg). About 8% ee
was obtained for the major diastereoisomer [determined by HPLC,
IC column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 35.240 min, t (major) = 45.267 min]. The racemic product
has been obtained following the procedure a (the same scale) in 75%
yield (major: 71 mg as a yellow solid; major and minor mixture: 25
mg) with dr = 87:13.
[α]2D0 −15.7 (c 0.69, CDCl3); H NMR (300 MHz, CDCl3): δ
1
7.33−7.31 (m, 1H), 7.24−7.10 (m, 6H), 6.92−6.89 (m, 1H), 4.91
(dd, 1H, 2JH−F = 48.0 Hz, JH−H = 6.0 Hz), 4.20−4.08 (m, 2H), 3.21−
3.14 (m, 1H), 2.95−2.73 (m, 2H), 1.99−1.91 (m, 2H), 1.21 (t, 3H,
J
H−H = 6.0 Hz). 19F NMR (282 MHz, CDCl3): δ −196.5 (dd, 2JF−H
=
48.0 Hz, 3JF−H = 25.4 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 167.9
2
(d, JC−F = 22.5 Hz), 140.7, 136.5, 130.8, 130.6, 128.6, 128.5, 127.6,
1
2
126.2, 90.4 (d, JC−F = 195.0 Hz), 61.8, 52.4 (d, JC−F = 15.0 Hz),
33.1, 32.5, 32.4, 14.1. IR: 2940, 1760, 1737, 1216, 1023, 847, 749,
698, 493 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C17H20FO2S2,
339.0889; found, 339.0899.
[α]2D0 −2.2 (c 0.68, CDCl3); mp 86−88 °C; H NMR (300 MHz,
1
CDCl3): δ 8.00 (d, 2H, JH−H = 9.0 Hz), 7.84 (s, 1H), 7.76−7.65 (m,
2
3H), 7.45−7.40 (m, 3H), 7.20−7.18 (m, 2H), 5.02 (dd, 1H, JH−F
=
48.0 Hz, JH−H = 3.0 Hz), 4.16−3.93 (m, 2H), 3.59−3.44 (m, 1H),
3.07−2.82 (m, 2H), 2.19−1.97 (m, 2H), 1.13 (t, 3H, JH−H = 6.0 Hz).
(2S,3S)-Ethyl 2-Fluoro-3-(naphthalen-2-ylthio)-5-phenylpenta-
noate (11). (Z)-Ethyl 2-fluoro-5-phenylpent-2-enoate (0.3 mmol,
66.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
naphthalene-2-thiol (1.5 mmol, 240 mg) at 0 °C for 8 days according
to the general procedure b. 19F NMR of the crude product showed dr
= 73:27. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 31% yield (major: 27 mg as a colorless oil; major and minor
mixture: 8 mg). About 29% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 7.777 min, t
(major) = 8.900 min]. The racemic product has been obtained
following the procedure a (the same scale) in 84% yield (major: 80
mg as a colorless oil; major and minor mixture: 16 mg) with dr =
80:20.
19F NMR (282 MHz, CDCl3): δ −196.0 (dd, 2JF−H = 48.0 Hz, 3JF−H
=
28.2 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 167.7 (d, 2JC−F = 30.0
Hz), 148.5, 146.6, 133.5, 132.6, 131.9, 130.6, 129.8, 129.8, 129.3,
1
128.8, 127.7, 127.4, 126.9, 126.7, 123.8, 90.5 (d, JC−F = 187.5 Hz),
61.9, 50.4 (d, 2JC−F = 22.5 Hz), 33.1, 33.0, 14.0. IR: 2925, 1764, 1490,
1222, 1109, 1027, 830, 523, 468 cm−1. HRMS (API−) m/z: [M]+
calcd for C23H22FNO4S, 427.1254; found, 427.1254.
(2S,3S)-Ethyl 3-Cyclohexyl-2-fluoro-3-(phenylthio)propanoate
(14). (Z)-Ethyl 3-cyclohexyl-2-fluoroacrylate (0.3 mmol, 60.0 mg)
and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
benzenethiol (1.5 mmol, 165 mg) at 0 °C for 5 days according to the
general procedure b. 19F NMR of the crude product showed dr =
100:0. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording only one
diastereoisomer in 34% yield (32 mg as a colorless oil). About 65%
ee was obtained for it [determined by HPLC, IC column, Hept/i-
PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 6.607 min,
t (major) = 7.450 min]. The racemic product has been obtained
following the procedure a (the same scale) in 86% yield (major: 61
mg as a colorless oil; major and minor mixture: 19 mg) with dr =
82:18.
[α]2D0 −7.7 (c 0.57, CDCl3); 1H NMR (300 MHz, CDCl3): δ 7.80−
7.65 (m, 4H), 7.41−7.38 (m, 3H), 7.21−7.06 (m, 5H), 5.01 (d, 1H,
2JH−F = 48.0 Hz), 4.06−3.86 (m, 2H), 3.60−3.46 (m, 1H), 2.95−2.72
(m, 2H), 2.12−2.00 (m, 2H), 1.07 (t, 3H, JH−H = 6.0 Hz). 19F NMR
(282 MHz, CDCl3): δ −196.8 (dd, 2JF−H = 48.0 Hz, 3JF−H = 28.2 Hz).
2
13C{1H} NMR (75 MHz, CDCl3): δ 167.9 (d, JC−F = 22.5 Hz),
140.8, 133.5, 132.4, 131.6, 131.1, 129.8, 128.6, 128.5, 127.7, 127.4,
126.6, 126.4, 126.3, 90.5 (d, 1JC−F = 187.5 Hz), 61.7, 50.3 (d, 2JC−F
=
[α]2D0 −5.6 (c 0.32, CDCl3); 1H NMR (300 MHz, CDCl3): δ 7.39−
22.5 Hz), 33.4, 33.2, 14.0. IR: 2933, 1760, 1736, 1497, 1454, 1212,
1103, 1023, 858, 814, 744, 699, 475 cm−1. HRMS (API+) m/z: [M +
H]+ calcd for C23H24FO2S, 383.1481; found, 383.1477.
2
7.36 (m, 2H), 7.22−7.13 (m, 3H), 5.20 (dd, 1H, JH−F = 48.0 Hz,
J
H−H = 3.0 Hz), 4.10−3.81 (m, 2H), 3.34−3.19 (m, 1H), 2.14 (d, 1H,
JH−H = 15.0 Hz), 1.84−1.53 (m, 5H), 1.21−1.13 (m, 5H), 1.07 (t,
3H, JH−H = 6.0 Hz). 19F NMR (282 MHz, CDCl3): δ −197.9 (dd,
2JF−H = 48.0 Hz, 3JF−H = 36.7 Hz). 13C{1H} NMR (75 MHz, CDCl3):
δ 168.6 (d, 2JC−F = 30.0 Hz), 135.7, 132.0, 128.9, 127.1, 89.3 (d, 1JC−F
(2S,3S)-Ethyl 3-((4-Bromophenyl)thio)-2-fluoro-5-(4-
nitrophenyl)pentanoate (12). (Z)-Ethyl 2-fluoro-5-(4-nitrophenyl)-
pent-2-enoate (0.3 mmol, 80.1 mg), 4-bromobenzenethiol (1.5 mmol,
283.5 mg), and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in
toluene at 0 °C for 8 days according to the general procedure b. 19F
2
= 187.5 Hz), 61.6, 57.9 (d, JC−F = 15.0 Hz), 40.7, 31.1, 30.8, 26.2,
H
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26.1, 13.9. IR: 2925, 1763, 1735, 1440, 1214, 1102, 1024, 746, 691,
537, 481 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C17H24FO2S,
311.1481; found, 311.1491.
2JH−F = 48.0 Hz, JH−H = 3.0 Hz), 4.26−4.02 (m, 2H), 3.11−2.96 (m,
1H), 2.19 (d, 1H, JH−H = 12.0 Hz), 1.83−1.63 (m, 5H), 1.22−1.05
2
(m, 8H). 19F NMR (282 MHz, CDCl3): δ −198.3 (dd, JF−H = 48.0
Hz, 3JF−H = 33.8 Hz). 13C{1H} NMR (75 MHz, CDCl31): δ 168.5 (d,
(2S,3S)-Ethyl 3-((4-Bromophenyl)thio)-3-cyclohexyl-2-fluoropro-
panoate (15). (Z)-Ethyl 3-cyclohexyl-2-fluoroacrylate (0.3 mmol,
60.0 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
4-bromobenzenethiol (1.5 mmol, 283.5 mg) at 0 °C for 8 days
according to the general procedure b. 19F NMR of the crude product
showed dr = 69:31. The crude was purified by silica gel column
chromatography (PE/EtOAc, from 10/1 to 8/1, v/v) affording two
diastereoisomers in 38% yield (major: 24 mg as a white solid; major
and minor mixture: 20 mg). About 11% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 5.987 min, t
(major) = 6.587 min]. The racemic product has been obtained
following the procedure a (the same scale) in 76% yield (major: 62
mg as a white solid; major and minor mixture: 24 mg) with dr =
71:29.
2JC−F = 22.5 Hz), 135.4, 133.2, 130.0, 127.3, 89.1 (d, JC−F = 195.0
Hz), 61.7, 60.4 (d, 2JC−F = 15.0 Hz), 39.8, 31.1, 30.5, 26.2, 26.1, 14.1.
IR: 2925, 1762, 1736, 1448, 1216, 1024, 847, 700, 533, 495 cm−1.
HRMS (API+) m/z: [M + H]+ calcd for C15H22FO2S2, 317.1045;
found, 317.1051.
(2S,3S)-Ethyl 3-((2-Aminophenyl)thio)-3-cyclohexyl-2-fluoropro-
panoate (18). (Z)-Ethyl 3-cyclohexyl-2-fluoroacrylate (0.3 mmol,
60.0 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
2-aminobenzenethiol (1.5 mmol, 188.0 mg) at room temperature for
8 days according to the general procedure b. 19F NMR of the crude
product showed dr = 90:10. The crude was purified by silica gel
column chromatography (PE/EtOAc, from 10/1 to 8/1, v/v)
affording two diastereoisomers in 55% yield (major: 45 mg as a
yellow solid, major and minor mixture: 9 mg). About 87% ee was
obtained for the major diastereoisomer [determined by HPLC, IC
column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 16.160 min, t (major) = 22.437 min]. The reaction
performed on 1 mmol of (Z)-ethyl 3-cyclohexyl-2-fluoroacrylate led
to 51% of isolated yield (major: 132 mg, major and minor mixture: 34
mg), dr: 91:9 and ee: 85% (major diastereoisomer). The racemic
product has been obtained following the procedure a (the same scale)
in 75% yield (major: 38 mg as a yellow solid; minor: 11 mg as a
yellow solid; major and minor mixture: 19 mg) with dr = 80:20.
[α]2D0 +2.5 (c 1.02, CDCl3); mp 31−33 °C; H NMR (300 MHz,
1
CDCl3): δ 7.33−7.23 (m, 4H), 5.20 (dd, 1H, 2JH−F = 48.0 Hz, JH−H
3.0 Hz), 4.15−3.90 (m, 2H), 3.28−3.13 (m, 1H), 2.09 (d, 1H, JH−H
=
=
12.0 Hz), 1.82−1.59 (m, 5H), 1.18−0.98 (m, 8H). 19F NMR (282
2
3
MHz, CDCl3): δ −197.7 (dd, JF−H = 48.0 Hz, JF−H = 33.8 Hz).
13C{1H} NMR (75 MHz, CDCl3): δ 168.6 (d, JC−F = 30.0 Hz),
2
134.7, 133.7, 121.3, 89.3 (d, 1JC−F = 195.0 Hz), 61.8, 58.0 (d, 2JC−F
=
22.5 Hz), 40.5, 31.0, 30.7, 26.1, 26.1, 14.0. IR: 2920, 1753, 1472,
1299, 1216, 817, 595, 466, 483 cm−1. HRMS (API+) m/z: [M + H]+
calcd for C17H23BrFO2S, 389.0586; found, 389.0596.
[α]2D0 +24.1 (c 0.22, CDCl3); mp 112−113 °C; H NMR (300
1
(2S,3S)-Ethyl 3-Cyclohexyl-2-fluoro-3-((4-methoxyphenyl)thio)-
propanoate (16). (Z)-Ethyl 3-cyclohexyl-2-fluoroacrylate (0.3
mmol, 60.0 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were
stirred in neat 4-methoxybenzenethiol (1.5 mmol, 210 mg) at 0 °C for
5 days according to the general procedure b. 19F NMR of the crude
product showed dr = 80:20. The crude was purified by silica gel
column chromatography (PE/EtOAc, from 20/1 to 15/1, v/v)
affording two diastereoisomers in 77% yield (major: 60 mg as a white
solid; major and minor mixture: 19 mg). About 32% ee was obtained
for the major diastereoisomer [determined by HPLC, IC column,
Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) =
8.557 min, t (major) = 10.183 min]. The racemic product has been
obtained following the procedure a (the same scale) in 65% yield
(major: 47 mg as a white solid; major and minor mixture: 19 mg)
with dr = 78:22.
MHz, CDCl3): δ 7.28 (d, 1H, JH−H = 6.0 Hz), 7.03−6.98 (m, 1H),
2
6.61−6.56 (m, 2H), 5.09 (dd, 1H, JH−F = 48.0 Hz, JH−H = 3.0 Hz),
4.29 (s, 2H), 4.05−3.94 (m, 1H), 3.80−3.69 (m, 1H), 3.35−3.21 (m,
1H), 2.02−1.88 (m, 2H), 1.74−1.61 (m, 4H), 1.26−1.04 (m, 8H).
19F NMR (282 MHz, CDCl3): δ −196.1 (dd, 2JF−H = 48.0 Hz, 3JF−H
=
33.8 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 168.7 (d, 2JC−F = 30.0
1
Hz), 148.7, 136.5, 129.8, 118.4, 116.7, 115.0, 88.7 (d, JC−F = 187.5
Hz), 61.6, 56.7 (d, 2JC−F = 15.0 Hz), 40.9, 31.0, 30.5, 30.5, 26.4, 26.3,
26.2, 13.9. IR: 3445, 3351, 2925, 1748, 1613, 1480, 1233, 737, 602,
454 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C17H25FNO2S,
326.1590; found, 326.1594.
(2S,3S)-Ethyl 3-Cyclohexyl-2-fluoro-3-(m-tolylthio)propanoate
(19). (Z)-Ethyl 3-cyclohexyl-2-fluoroacrylate (0.3 mmol, 60.0 mg)
and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat 3-
methylbenzenethiol (1.5 mmol, 186.3 mg) at 0 °C for 5 days
according to the general procedure b. 19F NMR of the crude product
showed dr = 81:19. The crude was purified by silica gel column
chromatography (PE/EtOAc, from 15/1 to 10/1, v/v) affording two
diastereoisomers in 44% yield (major: 35 mg as a colorless oil, major
and minor mixture: 8 mg). About 26% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 7.013 min, t
(major) = 7.820 min]. The racemic product has been obtained
following the procedure a (the same scale) in 67% yield (major: 54
mg as a colorless oil; major and minor mixture: 11 mg) with dr =
80:20.
[α]2D0 −5.4 (c 0.61, CDCl3); mp 57−58 °C; H NMR (300 MHz,
1
CDCl3): δ 7.35−7.33 (m, 2H), 6.76−6.73 (m, 2H), 5.17 (dd, 1H,
2JH−F = 48.0 Hz, JH−H = 2.4 Hz), 4.17−3.91 (m, 2H), 3.72 (s, 3H),
3.14−3.00 (m, 1H), 2.15 (d, 1H, JH−H = 6.0 Hz), 1.81−1.58 (m, 5H),
1.18−1.01 (m, 8H). 19F NMR (282 MHz, CDCl3): δ −197.9 (dd,
2JF−H = 48.0 Hz, 3JF−H = 36.7 Hz). 13C{1H} NMR (75 MHz, CDCl3):
δ 168.8 (d, 2JC−F = 22.5 Hz), 159.4, 135.2, 125.5, 114.4, 89.4 (d, 1JC−F
2
= 187.5 Hz), 61.6, 58.7 (d, JC−F = 15.0 Hz), 55.3, 40.2, 31.1, 30.7,
26.2, 26.2, 14.0. IR: 2926, 1763, 1590, 1490, 1222, 1026, 830, 594,
522, 473 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C18H26FO3S,
341.1587; found, 341.1581.
[α]2D0 −20.3 (c 0.10, CDCl3); H NMR (300 MHz, CDCl3): δ
1
(2S,3S)-Ethyl 3-Cyclohexyl-2-fluoro-3-(thiophen-2-ylthio)-
propanoate (17). (Z)-Ethyl 3-cyclohexyl-2-fluoroacrylate (0.3
mmol, 60.0 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were
stirred in neat thiophene-2-thiol (1.5 mmol, 174 mg) at 0 °C for 5
days according to the general procedure b. 19F NMR of the crude
product showed dr = 100:0. The crude was purified by silica gel
column chromatography (PE/EtOAc, from 15/1 to 10/1, v/v)
affording only one diastereoisomer in 32% yield (30 mg as a yellow
oil). About 59% ee was obtained for it [determined by HPLC, IC
column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 6.583 min, t (major) = 8.433 min]. The racemic product
has been obtained following the procedure a (the same scale) in 43%
yield (major: 30 mg as a yellow oil; major and minor mixture: 11 mg)
with dr = 82:18.
7.19−7.15 (m, 2H), 7.11−7.05 (m, 1H), 6.96−6.93 (m, 1H), 5.19
(dd, 1H, 2JH−F = 51.0 Hz, JH−H = 3.0 Hz), 4.11−3.81 (m, 2H), 3.34−
3.19 (m, 1H), 2.24 (s, 3H), 2.13 (d, 1H, JH−H = 12.0 Hz), 1.71−1.60
(m, 5H), 1.20−1.01 (m, 8H). 19F NMR (282 MHz, CDCl3): δ
2
3
−197.7 (dd, JF−H = 51.0 Hz, JF−H = 33.8 Hz). 13C{1H} NMR (75
2
MHz, CDCl3): δ 168.6 (d, JC−F = 22.5 Hz), 138.6, 135.5, 132.4,
128.9, 128.7, 127.9, 89.3 (d, 1JC−F = 187.5 Hz), 61.6, 57.8 (d, 2JC−F
=
22.5 Hz), 40.8, 31.1, 30.8, 26.2, 26.1, 21.3, 13.9. IR: 2925, 1764, 1735,
1600, 1449, 1213, 1102, 1025, 856, 776, 690, 541, 436 cm−1. HRMS
(API+) m/z: [M + H]+ calcd for C18H26FO2S, 325.1638; found,
325.1647.
(2S,3S)-Methyl 2-Fluoro-3-phenyl-3-(phenylthio)propanoate
(20). (Z)-Methyl 2-fluoro-3-phenylacrylate (0.3 mmol, 54.4 mg)
and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
benzenethiol (1.5 mmol, 165.0 mg) at 0 °C for 8 days according to
[α]2D0 −8.3 (c 0.06, CDCl3); 1H NMR (300 MHz, CDCl3): δ 7.29−
7.26 (m, 1H), 7.09−7.08 (m, 1H), 6.89−6.86 (m, 1H), 5.17 (dd, 1H,
I
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the general procedure b. 19F NMR of the crude product showed dr =
88:12. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 54% yield (major: 40 mg as a white solid, major and minor mixture:
7 mg). About 63% ee was obtained for the major diastereoisomer
[determined by HPLC, IC column, Hept/i-PrOH: 90/10, flow = 1
mL/min, λ = 254 nm, t (minor) = 6.530 min, t (major) = 7.053 min].
The racemic product has been obtained following the procedure a
(the same scale) in 61% yield (major: 42 mg as a white solid, major
and minor mixture: 11 mg) with dr = 83:17.
days according to the general procedure b. 19F NMR of the crude
product showed dr = 87:13. The crude was purified by silica gel
column chromatography (PE/EtOAc, from 15/1 to 10/1, v/v)
affording two diastereoisomers in 72% yield (major: 50 mg as a
colorless oil, major and minor mixture: 16 mg). About 62% ee was
obtained for the major diastereoisomer [determined by HPLC, IC
column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 6.750 min, t (major) = 7.183 min]. The racemic product
has been obtained following the procedure a (the same scale) in 89%
yield (major: 45 mg as a colorless oil, major and minor mixture: 37
mg) with dr = 85:15.
[α]2D0 +101.4 (c 0.67, CDCl3); mp 52−53 °C; 1H NMR (300 MHz,
CDCl3): δ 7.31−7.22 (m, 7H), 7.18−7.14 (m, 3H), 5.16 (dd, 1H,
2JH−F = 48.0 Hz, JH−H = 3.0 Hz), 4.60 (dd, 1H, 3JH−F = 28.0 Hz, JH−H
= 3.0 Hz), 3.61 (s, 3H). 19F NMR (282 MHz, CDCl3): δ −194.2 (dd,
2JF−H = 48.0 Hz, 3JF−H = 28.0 Hz). 13C{1H} NMR (75 MHz, CDCl3):
δ 167.9 (d, 2JC−F = 30.0 Hz), 137.8, 133.6, 132.9, 128.9, 128.7, 128.4,
[α]2D0 +113.0 (c 0.70, CDCl3); H NMR (300 MHz, CDCl3): δ
1
2
7.31−7.20 (m, 5H), 7.07−6.94 (m, 4H), 5.15 (dd, 1H, JH−F = 48.0
3
Hz, JH−H = 3.0 Hz), 4.59 (dd, 1H, JH−F = 28.0 Hz, JH−H = 3.0 Hz),
3.60 (s, 3H), 2.18 (s, 3H). 19F NMR (282 MHz, CDCl3): δ −194.1
2
3
(dd, JF−H = 48.0 Hz, JF−H = 28.0 Hz). 13C{1H} NMR (75 MHz,
1
128.4, 126.2, 127.7, 91.3 (d, JC−F = 187.5 Hz), 55.8 (d, 2JC−F = 22.5
2
CDCl3): δ 168.0 (d, JC−F = 22.5 Hz), 138.7, 138.0, 133.5, 133.3,
129.8, 128.8, 128.7, 128.6, 128.4, 128.4, 128.1, 91.3 (d, 1JC−F = 187.5
Hz), 52.6. IR: 2947, 1755, 1438, 1225, 1087, 1001, 736, 701, 688,
540, 467 cm−1. HRMS (API+) m/z: [M + H]+ calcd for C16H16FO2S,
291.0855; found, 291.0859.
2
Hz), 55.7 (d, JC−F = 22.5 Hz), 52.5, 21.2. IR: 2960, 1765, 1741,
1437, 1219, 1101, 774, 692, 544, 436 cm−1. HRMS (API+) m/z: [M +
H]+ calcd for C17H18FO2S, 305.1012; found, 305.1024.
(2S,3R)-Methyl 2-Fluoro-3-phenyl-3-(phenylthio)propanoate
(anti-20). (E)-Methyl 2-fluoro-3-phenylacrylate (0.3 mmol, 54.4
mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
benzenethiol (1.5 mmol, 165.0 mg) at 0 °C for 8 days according to
the general procedure b. 19F NMR of the crude product showed dr =
24:76. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 56% yield (major and minor mixture: 49 mg as a white solid).
About 51% ee was obtained for the major diastereoisomer
[determined by HPLC, IC column, Hept/i-PrOH: 95/5, flow = 1
mL/min, λ = 230 nm, t (minor) = 6.773 min, t (major) = 7.453 min].
The racemic product has been obtained following the procedure a
(the same scale) in 74% yield (major: 30 mg as a white solid; major
and minor mixture: 34 mg) with dr = 33:67.
(2S,3S)-Methyl 2-Fluoro-3-(phenylthio)-3-(p-tolyl)propanoate
(23). (Z)-Methyl 2-fluoro-3-(p-tolyl)acrylate (0.3 mmol, 58.3 mg)
and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat
benzenethiol (1.5 mmol, 151.5 mg) at 0 °C for 8 days according to
the general procedure b. 19F NMR of the crude product showed dr =
88:12. The crude was purified by silica gel column chromatography
(PE/EtOAc, from 15/1 to 10/1, v/v) affording two diastereoisomers
in 36% yield (major: 29 mg as a white solid, major and minor mixture:
4 mg). About 69% ee was obtained for the major diastereoisomer
[determined by HPLC, IC column, Hept/i-PrOH: 90/10, flow = 1
mL/min, λ = 254 nm, t (minor) = 6.490 min, t (major) = 7.410 min].
The racemic product has been obtained following the procedure a
(the same scale) in 75% yield (major: 51 mg as a white solid; major
and minor mixture: 17 mg) with dr = 77:23.
1H NMR (300 MHz, CDCl3): δ 7.38−7.34 (m, 2H), 7.25−7.19
2
(m, 8H), 5.09 (dd, 1H, JH−F = 48.0 Hz, JH−H = 3.0 Hz), 4.56 (dd,
[α]2D0 +129.6 (c 0.57, CDCl3); mp 82−84 °C; 1H NMR (300 MHz,
CDCl3): δ 7.27−7.24 (m, 2H), 7.17−7.13 (m, 4H), 7.05−7.03 (m,
3
1H, JH−F = 28.0 Hz, JH−H = 6.0 Hz), 3.54 (s, 3H). 19F NMR (282
2
3
MHz, CDCl3): δ −195.0 (dd, JF−H = 48.0 Hz, JF−H = 26.0 Hz).
2
2H), 5.12 (dd, 1H, JH−F = 48.0 Hz, JH−H = 6.0 Hz), 4.57 (dd, 1H,
13C{1H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC−F = 22.5 Hz),
2
3JH−F = 28.0 Hz, JH−H = 6.0 Hz), 3.60 (s, 3H), 2.24 (s, 3H). 19F NMR
(282 MHz, CDCl3): δ −194.0 (dd, 2JF−H = 48.0 Hz, 3JF−H = 28.0 Hz).
135.5, 133.5, 132.9, 129.2, 128.9, 128.8, 128.6, 128.4, 128.4, 89.2 (d,
2
1JC−F = 195.0 Hz), 54.6 (d, JC−F = 15.0 Hz), 52.4.
2
13C{1H} NMR (75 MHz, CDCl3): δ 168.0 (d, JC−F = 22.5 Hz),
(2S,3S)-Methyl 3-((2-Aminophenyl)thio)-2-fluoro-3-phenylpro-
panoate (21). (Z)-Methyl 2-fluoro-3-phenylacrylate (0.3 mmol,
54.4 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in
neat 2-aminobenzenethiol (1.5 mmol, 188.0 mg) at room temperature
for 4 days according to the general procedure b. 19F NMR of the
crude product showed dr = 91:9. The crude was purified by silica gel
column chromatography (DCM/PE, from 5/1 to 2/1, v/v) affording
two diastereoisomers in 22% yield (major: 16 mg as a yellow solid,
major and minor mixture: 4 mg). About 51% ee was obtained for the
major diastereoisomer [determined by HPLC, IC column, Hept/i-
PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 11.947 min,
t (major) = 14.737 min]. The racemic product has been obtained
following the procedure a (the same scale) in 46% yield (major: 34
mg as a yellow solid, major and minor mixture: 8 mg) with dr = 87:13.
[α]2D0 +111.2 (c 1.02, CDCl3); mp 77−79 °C; 1H NMR (300 MHz,
CDCl3): δ 7.24−7.21 (m, 5H), 7.10−7.00 (m, 2H), 6.62−6.47 (m,
2H), 5.13 (dd, 1H, 2JH−F = 48.0, JH−H = 3.0 Hz), 4.48 (dd, 1H, 3JH−F
= 28.0 Hz, JH−H = 3.0 Hz), 4.23 (s, 2H), 3.56 (s, 3H). 19F NMR (282
138.0, 134.8, 133.8, 132.8, 129.4, 128.9, 128.3, 128.2, 127.8, 91.5 (d,
2
1JC−F = 195.0 Hz), 55.5 (d, JC−F = 22.5 Hz), 52.6, 21.2. IR: 2927,
1739, 1434, 1269, 1085, 1008, 741, 570, 413 cm−1. HRMS (API+) m/
z: [M + H]+ calcd for C17H18FO2S, 305.1012; found, 305.1009.
(2S,3S)-Methyl 3-(2-Cyanophenyl)-2-fluoro-3-(phenylthio)-
propanoate (24). (Z)-Methyl 3-(2-cyanophenyl)-2-fluoroacrylate
(0.3 mmol, 61.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were
stirred in neat benzenethiol (1.5 mmol, 151.5 mg) at room
temperature for 5 days according to the general procedure b. 19F
NMR of the crude product showed dr = 87:13. The crude was
purified by silica gel column chromatography (PE/EtOAc, from 15/1
to 10/1, v/v) affording two diastereoisomers in 78% yield (major: 56
mg as a white solid, major and minor mixture: 14 mg). About 52% ee
was obtained for the major diastereoisomer [determined by HPLC,
IC column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 12.513 min, t (major) = 13.350 min]. The racemic product
has been obtained following the procedure a (the same scale) in 62%
yield (major: 43 mg as a white solid; major and minor mixture: 16
mg) with dr = 89:11.
2
3
MHz, CDCl3): δ −194.2 (dd, JF−H = 48.0 Hz, JF−H = 28.0 Hz).
2
13C{1H} NMR (75 MHz, CDCl3): δ 168.1 (d, JC−F = 30.0 Hz),
[α]2D0 +3.0 (c 1.03, CDCl3); mp 71−72 °C; H NMR (300 MHz,
1
149.2, 138.1, 137.5, 130.8, 128.6, 128.3, 128.3, 128.1, 118.3, 115.0,
89.5 (d, 1JC−F = 195.0 Hz), 54.0 (d, 2JC−F = 22.5 Hz), 52.5. IR: 3432,
3327, 2951, 1755, 1609, 1217, 1101, 751, 698, 530, 457 cm−1. HRMS
(API+) m/z: [M + H]+ calcd for C16H17FNO2S, 306.0964; found,
306.0964.
(2S,3S)-Methyl 2-Fluoro-3-phenyl-3-(m-tolylthio)propanoate
(22). (Z)-Methyl 2-fluoro-3-phenylacrylate (0.3 mmol, 54.4 mg)
and (DHQ)2PYR (0.03 mmol, 26.4 mg) were stirred in neat 3-
methylbenzenethiol (1.5 mmol, 186.3 mg) at room temperature for 5
CDCl3): δ 7.74−7.71 (m, 1H), 7.56−7.51 (m, 2H), 7.35−7.29 (m,
2
3H), 7.20−7.18 (m, 3H), 5.20 (dd, 1H, JH−F = 48.0 Hz, JH−H = 3.0
Hz), 5.12 (dd, 1H, 3JH−F = 28.0 Hz, JH−H = 3.0 Hz), 3.64 (s, 3H). 19
F
=
2
3
NMR (282 MHz, CDCl3): δ −195.8 (dd, JF−H = 48.0 Hz, JF−H
28.0 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 167.0 (d, 2JC−F = 22.5
Hz), 141.4, 133.4, 133.2, 132.8, 132.1, 130.0, 129.9, 129.2, 128.6,
1
2
128.5, 117.0, 112.1, 89.9 (d, JC−F = 195.0 Hz), 53.0 (d, JC−F = 15.0
Hz), 52.8. IR: 2947, 2224, 1732, 1438, 1283, 1106, 1016, 743, 692,
J
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3
555, 491 cm−1. HRMS (API+) m/z: [M + H]+ calcd for
C17H15FNO2S, 316.0808; found, 316.0814.
Hz), 4.44 (dd, 1H, JH−F = 28.0 Hz, JH−H = 3.0 Hz), 4.25 (s, 2H),
3.71 (s, 3H), 3.54 (s, 3H). 19F NMR (282 MHz, CDCl3): δ −193.9
(dd, JF−H = 48.0 Hz, JF−H = 28.0 Hz). 13C{1H} NMR (75 MHz,
2
3
(2S,3S)-Methyl 3-(3-Cyanophenyl)-2-fluoro-3-(phenylthio)-
propanoate (25). (Z)-Methyl 3-(3-cyanophenyl)-2-fluoroacrylate
(0.3 mmol, 61.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were
stirred in neat benzenethiol (1.5 mmol, 151.5 mg) at room
temperature for 5 days according to the general procedure b. 19F
NMR of the crude product showed dr = 92:8. The crude was purified
by silica gel column chromatography (PE/EtOAc, from 15/1 to 10/1,
v/v) affording two diastereoisomers in 76% yield (major: 60 mg as a
colorless oil, major and minor mixture: 8 mg). About 52% ee was
obtained for the major diastereoisomer [determined by HPLC, IC
column, Hept/i-PrOH: 90/10, flow = 1 mL/min, λ = 254 nm, t
(minor) = 50.573 min, t (major) = 54.183 min]. The racemic product
has been obtained following the procedure a (the same scale) in 62%
yield (major: 54 mg as a colorless oil; major and minor mixture: 5
mg) with dr = 92:8.
2
CDCl3): δ 168.1 (d, JC−F = 22.5 Hz), 159.3, 149.2, 137.5, 130.8,
130.1, 129.5, 129.5, 118.3, 115.2, 115.0, 113.9, 91.0 (d, 1JC−F = 195.0
2
Hz), 55.3, 53.4 (d, JC−F = 22.5 Hz), 52.5. IR: 3354, 2953, 1754,
1605, 1511, 1480, 1243, 1102, 1023, 827, 743, 534, 435 cm−1. HRMS
(ESI+) m/z: [M + H]+ calcd for C17H19FNO3S, 336.1070; found,
336.1062.
(2S,3S)-3-Fluoro-2-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-
4(5H)-one (28). Compound 21 (0.35 mmol, 106.8 mg) and p-TsOH
(0.07 mmol, 6.9 mg) were added into 2 mL of xylene and the
resulting mixture was heated to reflux overnight. After completion of
the reaction, the solvent was removed in vacuo and the crude mixture
was purified by column chromatography (PE/EtOAc, from 5/1 to 4/
1, v/v) to give the desired product (28) in 85% yield (81 mg, white
solid). 51% ee [determined by HPLC, AD-H column, Hept/i-PrOH:
80/20, flow = 1 mL/min, λ = 254 nm, t (minor) = 10.467 min, t
(major) = 14.543 min].
[α]2D0 +85.8 (c 1.15, CDCl3); H NMR (300 MHz, CDCl3): δ
1
7.56−7.48 (m, 3H), 7.37−7.32 (m, 1H), 7.23−7.16 (m, 5H), 5.16
(dd, 1H, 2JH−F = 48.0 Hz, JH−H = 3.0 Hz), 4.60 (dd, 1H, 3JH−F = 28.0
Hz, JH−H = 3.0 Hz), 3.69 (s, 3H). 19F NMR (282 MHz, CDCl3): δ
[α]2D3 +126.1 (c 0.80, CDCl3); mp 161−163 °C; H NMR (300
1
MHz, CDCl3): δ 9.39 (s, 1H), 7.74 (d, 1H, JH−H = 6.0 Hz), 7.59−
7.58 (m, 2H), 7.45−7.35 (m, 4H), 7.27−7.21 (m, 2H), 5.36−5.18
2
3
−195.4 (dd, JF−H = 48.0 Hz, JF−H = 28.0 Hz). 13C{1H} NMR (75
2
(m, 2H). 19F NMR (282 MHz, CDCl3): δ −190.5 (dd, JF−H = 47.9
2
MHz, CDCl3): δ 167.5 (d, JC−F = 22.5 Hz), 139.7, 133.4, 133.0,
Hz, JF−H = 8.5 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 169.6 (d,
3
132.9, 132.4, 132.0, 131.8, 129.5, 129.2, 128.5, 118.4, 112.8, 90.7 (d,
2
1JC−F = 195.0 Hz), 55.2 (d, JC−F = 15.0 Hz), 52.8. IR: 2953, 2231,
2JC−F = 22.5 Hz), 140.3, 135.3, 135.3, 134.8, 130.6, 129.3, 128.8,
1763, 1438, 1221, 1102, 1008, 801, 739, 690, 528, 479 cm−1. HRMS
(API+) m/z: [M + H]+ calcd for C17H15FNO2S, 316.0808; found,
316.0808.
128.5, 126.7, 126.5, 123.1, 88.8 (d, 1JC−F = 195.0 Hz), 56.3 (d, 2JC−F
=
15.0 Hz). IR: 3188, 3072, 2961, 2903, 1687, 1474, 1306, 1075, 768,
736, 717, 696, 524, 463 cm−1. HRMS (API+) m/z: [M + H]+ calcd for
C15H13FNOS, 274.0702; found, 274.0707.
(2S,3S)-Methyl 3-(4-Cyanophenyl)-2-fluoro-3-(phenylthio)-
propanoate (26). (Z)-Methyl 3-(4-cyanophenyl)-2-fluoroacrylate
(0.3 mmol, 61.6 mg) and (DHQ)2PYR (0.03 mmol, 26.4 mg) were
stirred in neat benzenethiol (1.5 mmol, 151.5 mg) at room
temperature for 5 days according to the general procedure b. 19F
NMR of the crude product showed dr = 100:0. The crude was
purified by silica gel column chromatography (PE/EtOAc, from 15/1
to 10/1, v/v) affording an only diastereoisomer in 70% yield (66 mg
as a white solid). About 68% ee was obtained for the major
diastereoisomer [determined by HPLC, IC column, Hept/i-PrOH:
90/10, flow = 1 mL/min, λ = 254 nm, t (minor) = 21.380 min, t
(major) = 23.313 min]. The racemic product has been obtained
following the procedure a (the same scale) in 64% yield (major: 51
mg as a white solid; major and minor mixture: 9 mg) with dr = 81:19.
[α]2D0 +168.8 (c 0.32, CDCl3); mp 79−80 °C; 1H NMR (300 MHz,
CDCl3): δ 7.54−7.38 (m, 4H), 7.23−7.16 (m, 5H), 5.17 (dd, 1H,
2JH−F = 48.0 Hz, JH−H = 3.0 Hz), 4.61 (dd, 1H, 3JH−F = 28.0 Hz, JH−H
(2S,3S)-3-Fluoro-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]-
thiazepin-4(5H)-one (29). Compound 27 (0.2 mmol, 67.0 mg) and
p-TsOH (0.04 mmol, 3.9 mg) were added into 1.2 mL of xylene and
the resulting mixture was heated to reflux overnight. After completion
of the reaction, the solvent was removed in vacuo and the crude
mixture was purified by column chromatography (PE/EtOAc, from
5/1 to 3/1, v/v) to give the desired product 29 in 76% yield (46 mg,
white solid). 73% ee [determined by HPLC, AD-H column, Hept/i-
PrOH: 80/20, flow = 1 mL/min, λ = 254 nm, t (minor) = 13.940 min,
t (major) = 21.507 min].
[α]2D3 +122.2 (c 0.54, CDCl3); mp 165−166 °C; H NMR (300
1
MHz, CDCl3): δ 9.00 (s, 1H), 7.63 (d, 1H, JH−H = 9.0 Hz), 7.41−
7.30 (m, 3H), 7.18−7.11 (m, 2H), 6.81−6.75 (m, 2H), 5.22−5.04
(m, 2H), 3.71 (s, 3H). 19F NMR (282 MHz, CDCl3): δ −190.4 (ddd,
2JF−H = 47.9 Hz, 3JF−H = 8.5 Hz, 4JF−H = 2.8 Hz). 13C{1H} NMR (75
2
MHz, CDCl3): δ 169.3 (d, JC−F = 22.5 Hz), 160.0, 140.3, 134.8,
= 3.0 Hz), 3.70 (s, 3H). 19F NMR (282 MHz, CDCl3): δ −195.3 (dd,
2JF−H = 48.0 Hz, 3JF−H = 28.0 Hz). 13C{1H} NMR (75 MHz, CDCl3):
δ 167.5 (d, 2JC−F = 30.0 Hz), 143.3, 133.4, 132.4, 132.4, 129.3, 129.3,
130.5, 130.5, 126.8, 123.1, 113.9, 88.4 (d, 1JC−F = 195.0 Hz), 55.6 (d,
2JC−F = 22.5 Hz), 55.3. IR: 3189, 3076, 2923, 2856, 1684, 1513, 1475,
1306, 1250, 1083, 1027, 785, 764, 652, 490, 410 cm−1. HRMS (API+)
m/z: [M + H]+ calcd for C16H15FNO2S, 304.0808; found, 304.0812.
(2S,3S)-5-(2-(Dimethylamino)ethyl)-3-fluoro-2-phenyl-2,3-
dihydrobenzo[b][1,4]thiazepin-4(5H)-one (30). To a solution of
compound 28 (0.25 mmol, 68.5 mg) in EA (1.5 mL) were added 2-
dimethylaminoethyl chloride hydrochloride (72.0 mg, 0.50 mmol),
followed by potassium carbonate (138.0 mg, 1.0 mmol) and H2O (15
μL). After the mixture was stirred for 24 h under reflux, it was cooled
to room temperature. The mixture was dried over Na2SO4 and then
the crude mixture was purified by column chromatography (DCM/
MeOH, 10/1 to 8/1, v/v) to give the desired product 30 in 41% yield
(35 mg, white solid). 51% ee, [determined by HPLC, luxcell 2
column, Hept/i-PrOH: 80/20, flow = 1 mL/min, λ = 254 nm, t
(minor) = 16.503 min, t (major) = 19.920 min].
129.2, 126.5, 118.4, 112.1, 90.6 (d, 1JC−F = 195.0 Hz), 55.6 (d, 2JC−F
=
15.0 Hz), 52.9. IR: 2967, 2237, 1767, 1441, 1214, 1096, 1003, 836,
745, 570, 437 cm−1. HRMS (API+) m/z: [M + H]+ calcd for
C17H15FNO2S, 316.0808; found, 316.0790.
(2S,3S)-Methyl 3-((2-Aminophenyl)thio)-2-fluoro-3-(4-
methoxyphenyl)propanoate (27). (Z)-Methyl 2-fluoro-3-(4-
methoxyphenyl)acrylate (0.3 mmol, 63.1 mg) and (DHQ)2PYR
(0.03 mmol, 26.4 mg) were stirred in neat 2-aminobenzenethiol (1.5
mmol, 188.0 mg) at room temperature for 3 days according to the
general procedure b. 19F NMR of the crude product showed dr =
94:6. The crude was purified by silica gel column chromatography
(DCM/PE, from 5/1 to 2/1, v/v) affording two diastereoisomers in
37% yield (major: 30 mg as a yellow solid, major and minor mixture:
7 mg). About 73% ee was obtained for the major diastereoisomer
[determined by HPLC, IC column, Hept/i-PrOH: 90/10, flow = 1
mL/min, λ = 254 nm, t (minor) = 16.977 min, t (major) = 23.033
min]. The racemic product has been obtained following the
procedure a (the same scale) in 40% yield (major: 35 mg as a
yellow solid, major and minor mixture: 5 mg) with dr = 87:13.
[α]2D0 +183.2 (c 2.20, CDCl3); mp 80−82 °C; 1H NMR (300 MHz,
CDCl3): δ 7.18−6.99 (m, 4H), 6.76−6.73 (m, 2H), 6.62−6.59 (m,
[α]2D0 +144.9 (c 0.31, CDCl3); mp 165−166 °C; H NMR (300
1
MHz, CDCl3): δ 7.84−7.73 (m, 1H), 7.59−7.28 (m, 8H), 5.43−4.90
(m, 2H), 4.53−4.26 (m, 1H), 3.85−3.71 (m, 1H), 2.79−2.45 (m,
2H), 2.29 (s, 6H). 19F NMR (282 MHz, CDCl3): δ −189.3 (d, 2JF−H
= 47.9 Hz). 13C{1H} NMR (75 MHz, CDCl3): δ 166.5 (d, JC−F
=
2
22.5 Hz), 145.1, 135.5, 131.1, 129.9, 128.9, 128.5, 128.4, 128.2, 128.1,
127.6, 124.7, 86.2 (d, JC−F = 187.5 Hz), 56.7, 55.0 (d, JC−F = 22.5
Hz), 47.8, 45.6. IR: 3064, 2939, 2765, 1681, 1441, 1179, 1088, 856,
1
2
2
1H), 6.52−6.47 (m, 1H), 5.09 (dd, 1H, JH−F = 48.0 Hz, JH−H = 3.0
K
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766, 602, 591, 428 cm−1. HRMS (ESI+) m/z: [M + H]+ calcd for
C19H22FN2OS, 345.1437; found, 345.1449.
ACKNOWLEDGMENTS
■
́
This work was partially supported by Normandie Universite
(2S,3S)-5-(2-(Dimethylamino)ethyl)-3-fluoro-2-(4-Methoxyphen-
yl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (31). To a solution
of compound 29 (0.15 mmol, 45.0 mg) in EA (1.0 mL) were added 2-
dimethylaminoethyl chloride hydrochloride (43.2 mg, 0.30 mmol),
followed by potassium carbonate (82.8 mg, 0.6 mmol) and H2O (10
μL). After the mixture was stirred for 24 h under reflux, it was cooled
to room temperature. The mixture was dried over Na2SO4 and then
the crude mixture was purified by column chromatography (DCM/
MeOH, 9/1 to 8/1, v/v) to give the desired product 31 in 32% yield
(18 mg, colorless oil). 73% ee, [determined by HPLC, luxcell 2
column, Hept/i-PrOH: 80/20, flow = 1.2 mL/min, λ = 254 nm, t
(minor) = 18.370 min, t (major) = 23.353 min].
́
(NU), the Region Normandie, the Centre National de la
́
Recherche Scientifique (CNRS), Universite de Rouen
Normandie (URN), INSA Rouen Normandie, Labex SynOrg
(ANR-11-LABX-0029), and Innovation Chimie Carnot (I2C).
X.H. thanks the CSC (China Scholarship Council) for a
doctoral fellowship. E. D. thanks the European Fund for
Regional Development for postdoctoral fellowship (FEDER
BIOFLUORG 32819).
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[α]2D0 +126.4 (c 0.47, CDCl3); H NMR (300 MHz, CDCl3): δ
1
■
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7.72−7.64 (m, 1H), 7.43−7.35 (m, 3H), 7.23−7.19 (m, 2H), 6.86−
6.75 (m, 2H), 5.28−4.78 (m, 2H), 4.45−4.17 (m, 1H), 3.74 (s, 3H),
3.71−3.62 (m, 1H), 2.71−2.32 (m, 2H), 2.21 (s, 6H). 19F NMR (282
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MHz, CDCl3): δ −189.2 (d, JF−H = 47.9 Hz). 13C{1H} NMR (75
2
MHz, CDCl3): δ 166.6 (d, JC−F = 22.5 Hz), 160.0, 145.0, 135.4,
1
131.0, 129.4, 128.2, 127.6, 124.6, 113.9, 86.1 (d, JC−F = 187.5 Hz),
56.6, 55.3, 54.5 (d, 2JC−F = 22.5 Hz), 47.7, 45.5. IR: 3058, 2938, 2770,
1676, 1609, 1511, 1251, 1178, 1092, 1029, 732, 602, 407 cm−1.
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found, 375.1532.
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(d) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02081.
■
sı
(2) (a) Qiu, X.-L.; Yue, X.; Qing, F.-L. In Chiral Drugs: Chemistry
and Biological Action; Lin, G.-Q., You, Q.-D., Cheng, J.-F., Eds.; John
Wiley & Sons, Inc.: Hoboken, NJ, 2011; pp 195−251. (b) Cahard, D.;
Xu, X.; Couve-Bonnaire, S.; Pannecoucke, X. Fluorine & chirality:
how to create a nonracemic stereogenic carbon−fluorine centre?
Chem. Soc. Rev. 2010, 39, 558−568. (c) Shibata, N.; Ishimaru, T.;
Nakamura, S.; Toru, T. New approaches to enantioselective
fluorination: Cinchona alkaloids combinations and chiral ligands/
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Cahard, D. Asymmetric fluorination, trifluoromethylation, and
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(3) (a) Asymmetric Organocatalysis 1; List, B., Ed.; Science of
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Optimization tables; kinetic studies; crystallographic
data for products 13 and 18; copies of NMR (1H, 19F,
and 13C{1H}) spectra for all new compounds; and
HPLC chromatograms (PDF)
Crystallographic data for product 13 (CIF)
Crystallographic data for product 18 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
Samuel Couve-Bonnaire − Normandie Universite, COBRA,
UMR 6014 et FR 3038, Universite de Rouen, INSA Rouen,
́
́
CNRS, 76821 Mont Saint-Aignan Cedex, France;
orcid.org/0000-0003-2149-0849; Email: samuel.couve-
bonnaire@insa-rouen.fr
́
Stuttgart, 2012. (c) Aleman, J.; Cabrera, S. Applications of asymmetric
organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42,
774−793.
Authors
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heteroatom bond forming by asymmetric Michael addition. Mol.
Diversity 2014, 18, 411−439. (b) Vicario, J.; Badía, D.; Carrillo, L.
Organocatalytic enantioselective Michael and hetero-Michael reac-
́
Xin Huang − Normandie Universite, COBRA, UMR 6014 et FR
3038, Universite de Rouen, INSA Rouen, CNRS, 76821 Mont
Saint-Aignan Cedex, France
́
tions. Synthesis 2007, 2007, 2065−2092. (c) Enders, D.; Luttgen, K.;
̈
́
Emilie David − Normandie Universite, COBRA, UMR 6014 et
Narine, A. Asymmetric sulfa-Michael additions. Synthesis 2007, 2007,
959−980. (d) Enders, D.; Wang, C.; Liebich, J. X. Organocatalytic
asymmetric aza-Michael additions. Chem.Eur. J. 2009, 15, 11058−
́
FR 3038, Universite de Rouen, INSA Rouen, CNRS, 76821
Mont Saint-Aignan Cedex, France
́
Philippe Jubault − Normandie Universite, COBRA, UMR 6014
̈
11076. (e) Nising, C. F.; Brase, S. Recent developments in the field of
́
et FR 3038, Universite de Rouen, INSA Rouen, CNRS, 76821
oxa-Michael reactions. Chem. Soc. Rev. 2012, 41, 988−999.
(f) Tsogoeva, S. B. Recent Advances in Asymmetric organocatalytic
1,4-conjugate additions. Eur. J. Org. Chem. 2007, 2007, 1701−1716.
(5) (a) Lemonnier, G.; Zoute, L.; Dupas, G.; Quirion, J.-C.; Jubault,
P. Diethylzinc-mediated one-step stereoselective synthesis of α-
fluoroacrylates from aldehydes and ketones. two different pathways
depending on the carbonyl partner. J. Org. Chem. 2009, 74, 4124−
Mont Saint-Aignan Cedex, France; orcid.org/0000-0002-
3295-9326
́
Tatiana Besset − Normandie Universite, COBRA, UMR 6014
et FR 3038, Universite de Rouen, INSA Rouen, CNRS, 76821
Mont Saint-Aignan Cedex, France; orcid.org/0000-0003-
́
4877-5270
́
4131. (b) Rousee, K.; Bouillon, J.-P.; Couve-Bonnaire, S.;
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02081
Pannecoucke, X. Stereospecific synthesis of tri- and tetrasubstituted
α-fluoroacrylates by Mizoroki−Heck reaction. Org. Lett. 2016, 18,
540−543.
Notes
́
(6) (a) Hudlicky, M. The synthesis of γ-fluoroglutamic acid.
The authors declare no competing financial interest.
Tetrahedron Lett. 1960, 1, 21−22. (b) Tsushima, T.; Kawada, K.;
L
https://dx.doi.org/10.1021/acs.joc.0c02081
J. Org. Chem. XXXX, XXX, XXX−XXX

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