Synthesis of chiral fluorine-containing compounds via Pd-catalyzed asymmetrical allylations of dimethyl 2-fluoromalonate using sulfonamide-pyridine ligands

Article abstract of DOI:10.1016/j.jfluchem.2016.07.010

Chiral o-aniline sulfoxides serving as chiral sulfurous source were synthesized, from which new sulfonamide-pyridine ligands were made in three-steps. These compounds proved to be efficient S,N-ligands for enantiocontrol of palladium-catalyzed allylic sub

Full text of DOI:10.1016/j.jfluchem.2016.07.010

Journal of Fluorine Chemistry 189 (2016) 13–21
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short Communication
Synthesis of chiral fluorine-containing compounds via Pd-catalyzed
asymmetrical allylations of dimethyl 2-fluoromalonate using
sulfonamide-pyridine ligands
*
Min Zhang, Mingzhu Zhao, Purui Zheng, Hongbo Zhang, Xiaoming Zhao
Shanghai Key Lab of Chemical Assessment and Sustainability, Department of Chemistry, Tongji University, 11239 Siping Road, Shanghai 200092, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
Chiral o-aniline sulfoxides serving as chiral sulfurous source were synthesized, from which new
sulfonamide-pyridine ligands were made in three-steps. These compounds proved to be efficient S,N-
ligands for enantiocontrol of palladium-catalyzed allylic substitutions of dimethyl 2-fluoromalonate. The
induced effect of the Pd/S,N-ligand catalyst on the enantioselectivity depends on the steric demand of the
substituent on the sulfoxide moiety. This method provided the fluorine-containing allylic products with
up to 94% ee.
Received 28 March 2016
Received in revised form 22 June 2016
Accepted 20 July 2016
Available online 25 July 2016
Keywords:
Fluorine-containing compound
Dimethyl 2-fluoromalonate
Allylation
ã 2016 Elsevier B.V. All rights reserved.
Sulfonamide-pyridine ligand
Enantioselectivity
1. Introduction
Difluprednate are popular drugs [6d,7]. There are several methods
reported for the synthesis of monofluorinated compounds [6a]
Asymmetric catalysis with transition metal complexes has been
rapidly developing in synthetic chemistry. Chiral ligands play an
essential role for the achievement of excellent stereoselectivity. In
this regard, design and synthesis of novel effective ligands remain a
big challenge [1]. Chiral sulfoxides were used as an auxiliary in
asymmetric synthesis [2]. More recently, chiral sulfoxide ligands
have attracted considerable attention for their utilization in
asymmetric synthesis [3]. The sulfinyl group of such ligands is
featured with both an intrinsic stereogenic center and binding site
to transition metals. Therefore, it is reasoned that a structurally
proper sulfoxide could possibly act as a sulfur ligand [4], which
may offer sulfurous source for asymmetric catalysis. There were
several examples focused on palladium (Pd)-catalyzed asymmetric
allylations with using chiral sulfoxide ligands [5], which made
from tert-butylsulfinyl group. [5g–j] To expand the chiral sources of
sulfoxide ligands, a structural diversity of o-aniline sulfoxides has
been envisioned, which may be synthesized according to our
previous works (Scheme 1).
however, transition metal-catalyzed asymmetrical allylic substi-
tutions of fluorinated methylene derivatives are less disclosed [8],
which could afford the monofluorinated allylic products. Herein
we report the synthesis of new chiral sulfonamide-pyridine ligands
stemmed from o-aniline sulfoxides and their application in Pd-
catalyzed asymmetric allylic substitutions of dimethyl 2-fluoro-
malonate.
2. Results and discussion
We initially aimed at developing a method for the preparation
of enantioenriched 2-allylthio-substituted aniline 3 on a large-
scale (Scheme 1). This allylation reaction was carried out on a
4 mmol scale; and we found that the presence of a little water led
to the reduction of the yield; and that the amount of iridium
catalyst has an influence on this reaction. After avoiding the
presence of water and reducing iridium catalyst from 2 mmol% to
1 mmol%, a large-scale synthetic method for 3 was developed on
the basis of our previous work [9] (see: SI). The key intermediate 5
was prepared by a reduction of 3 with o-nitro benzenesulfonylhy-
drazide (NBSH) [10], following by an oxidation with mCPBA
without loss of ee value (Scheme 1, see: SI).
Fluorine-containing compounds are of great importance to
pharmaceutical industry [6]. In particular, optically active mono-
fluorinated compounds such as Pharmacia, Clofarabin, and
As a result, two isomers (50 and 5) were obtained and they can
be separated by flash column chromatography. Among these
isomers, the absolute configuration of 5b' (R1 = 3,5-di-MeOC6H3)
* Corresponding author.
E-mail address: xmzhao08@mail.tongji.edu.cn (X. Zhao).
http://dx.doi.org/10.1016/j.jfluchem.2016.07.010
0022-1139/ã 2016 Elsevier B.V. All rights reserved.

14
M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
2-methylpropan-2-olate (tBuOK), K3PO4, LiCl, 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU), CsF and tetra-butylammonium fluoride
(TBAF) was further investigated, we found that Cs2CO3 led to a
t
superior result, whereas K3PO4, BuOK and CsF gave moderate to
good ee (entries 2, 3 and 6). Both LiCl and DBU were unsuitable for
the reaction (entries 4 and 5). TBAF led to the highest yield but with
an acceptable ee (entry 7). Variation of solvents has a significant
impact on this reaction (entries 8 ꢀ 10). Chiral ligands are essential
for the enantiocontrol of palladium-catalyzed allylic substitutions
[5]. Consequently, a variety of the chiral sulfonamide-pyridine
ligands was further explored. For instance, (Ss,R)-6a containing a
phenyl group gave a somewhat lower ee than that of (Rs,S)-6b,
which contains a 3,5-di-methoxy group on the phenyl ring (entry
8). The different configuration of ligand (Ss,R)-6a and (Rs,S)-6b
resulted in the opposite configuration of 9a (entry 8 vs entry 11).
(Rs,S)-6c bearing a furanyl group gave a little lower ee than that of
(Ss,R)-6a although it is structurally similar to (Ss,R)-6a (entry 12).
Interestingly, (Rs,R)-6d with the least steric substituent such as a
methyl group gave rise to good ee (entry 13). (Rs,R)-6f bearing a
pyridine ring was also examined and it led to a poor outcome
(entry 14). These results suggested that both the steric demand and
nature of the substituent in 6 have a great influence on the
enantioselectivity of this reaction. Furthermore, both Josiphos [16]
and Trost ligands [17] were examined under the optimized
conditions; Josiphos ligand gave 9a in racemic form with a 83%
yield (entry 15). Trost ligand led to a moderate result (entry16). It is
noted that only trace amount of 9a was formed when the reaction
was carried out at 0 ꢁC. Change of the ratio of reactants has a
considerable influence, for example, 9a was obtained in an
improved yield (80%) albeit with a lowering ee (70%) when the
ratio of 7a/8a in 3/1 was employed at room temperature.
Analysis of 7a which was recovered upon the completion of the
reaction by HPLC on a chiral stationary phase illustrated that it was
racemic.
Scheme 1. Synthesis of new chiral sulfonamide-pyridine ligands 6.
was established as (Rs,S) by its X-ray diffraction analysis (Fig. 1)
[11]. Finally, the treatment of 5, either (Rs,S)-5 or (Ss,R)-50, with
potassium hydride (KH) at ꢀ40 ꢁC, following by a reaction with
methyl 6-((allyloxy)methyl)picolinate, gave the corresponding
ligand 6 (Scheme 1 and Fig. 2) [12]. The 6-(allyloxymethyl)
picolinamide, a substituent at 6-position of pyridine moiety, is
optimal for these N,S-ligands, which were reported in our previous
work [13]. We found that the N,S-ligands generated from tert-
butylsulfinyl group are unsuitable for Pd-catalyzed asymmetrical
allylations of 2-napthyl-substituted allylic acetate with dimethyl
2-fluoromalonate [13].
To evaluate the catalytic potential of the S,N-ligand 6, a Pd-
catalyzed reaction of (E)-1,3-bis(3-fluorophenyl)allyl acetate 7a
with dimethyl 2-fluoromalonate 8a [14] was carried out (Table 1).
In the presence of a catalyst [15] made from [Pd(C3H5)Cl2] and
(Rs,S)-6b, the reaction was performed in THF at room temperature
without base and no allylic products were observed. When sodium
hydride (NaH) was used as an additive, to our delight, the allylic
product 9a was formed in a 35% yield with 80% ee; a little amount
of (E)-1,3-bis(3-fluorophenyl)prop-2-en-1-ol was observed as
well (entry 1). Thus, a number of bases including potassium
Having established the optimized reaction conditions pre-
sented in entry 8 of Table 1, the scope of a series of (E)-1,3-
disubstituted allyl acetates
7 was examined (Table 2). The
substrates 7a and b with the 3-substituted group, which is an
Fig. 1. X-ray structure of (Rs,S)-5b'.

M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
15
O
O
O
O
N
N
O
O
HN
N
HN
HN
O
O
S
S
O
R1
S
Et
Et
O
6d
(Rs,R)-
R1
(Rs,S)-6c
(Rs,S)-6a: R1 = H
(Rs,S)- : R1 = OMe
6b
Me
PCy2
PPh2
Fe
O
O
NH HN
O
O
N
PPh2 Ph2P
HN
S
O
Josiphos
(R)-6e
Trost Ligand
O
N
HN
O
S
Et
(Rs, S)-6f
Fig. 2. Sulfonamide-pyridine ligands 6, Josiphos, and Trost ligand.
Table 1
indicated that either substituted position or electron-withdrawing
nature of the substituent on the phenyl ring has a significant
impact on the enantioselectivity of this reaction [18]. Both 3-
bromo- and 4-bromo substituted substrates (7c and f) led to the
similar results (Table 2).
Screening the reaction conditions for a Pd-catalyzed allyic substitution using
sulfoxide-pyridine ligands 6.a
Entry
L
Add.
Sol.
Yield of 9a (%)b
ee (%)c
1
2
3
4
5
6
7
8
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6a
6c
6d
6f
Josiphos
Trost
NaH
THF
THF
THF
THF
THF
THF
THF
THF
DCM
Tol.
THF
THF
THF
THF
THF
THF
35
24
15
NR
11
15
76
73
11
10
51
25
41
18
83
75
80
69
82
–
tBuOK
K3PO4
LiCl
With using (E)-1,3-diphenylallyl acetate 7g as a substrate, 9g
was obtained in a 73% yield and 88% ee (Table 2). Significantly,
substrate with a bulky group such as 2-napthyl-substituted allylic
acetate 7h provided 9h in a moderate yield and a high ee value
(Table 2). This method could be used for the synthesis of the 6-
methoxy-2-napthyl-substituted allylic product, an analogue of 9h,
which could be transformed into fluorinated Naproxen [8c]. In
contrast with our previous work [13], the ligand (R)-6e [13] (Fig. 2)
other than 6b was employed for the substrate 7h under the similar
conditions and it gave 9h in a 82% yield and 65% ee. These results
revealed that the sulfonamide moiety has a significant effect on the
enantiocontrol. In this regard, the ligand 6b in the induced effect
on the enantioselectivity is supplementary to that of (R)-6e. The
substrates 7i with the 3-substituted group, which is an electron-
donating group (e.g., 3-Me), on the phenyl ring gave the allylic
products 9i in a 75% yield and 77% ee (Table 2). However, (E)-pent-
3-en-2-yl acetate 7j was tested and the desired allylic product was
not obtained. The racemic fluorinated ethyl 3-oxobutanoate 8b was
used and it gave the corresponding allylic product 9j in a 74% yield
with 94% ee but 1/1.2 dr (Table 2).
DBU
CsF
TBAF
rac
66
54
94
47
80
ꢀ80
72
70
15
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
rac.
65
a
Reaction conditions: [Pd(C3H5)Cl]2 (4 mol%),
L (8 mol%), 7a (0.1 mmol), 8
(0.30 mmol) and additive (0.3 mmol) in solvent (2 mL) at room temperature.
b
Isolated yield.
Determined by a chiral HPLC analysis.
c
electron-withdrawing group (e.g., 3-F and 3-Cl), on the phenyl ring
offered the allylic products 9a and b in good yields with high
enantioselectivities (87–94% ee, Table 2). In contrast, replacing the
same group, either –F or –Cl, from 3-position to 4-position
respectively gave rise to the corresponding products 9d–e with
somewhat lower ees than that of 9a and b (Table 2). The results
The transformation of 9 made in this method was explored, for
example, the treatment of (E)-dimethyl 2-(1,3-bis(4-chlorophenyl)
allyl)-2-fluoromalona 9e with lithium hydroxide monohydrate in

16
M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
Table 2
Scope of Pd-catalyzed allylic substitutions using the ligand (Rs,S)-6ba–c
.
aReaction conditions: [Pd(C3H5)Cl]2 (4 mol%), 6 (8 mol%), 7 (0.1 mmol), 8 (0.30 mmol) and Cs2CO3 (0.3 mmol) in THF (2 mL) at room temperature.
bIsolated yield.
cee was determined by a chiral HPLC analysis.
THF/H2O at room temperature gave (E)-2-(1,3-bis(4-chlorophenyl)
allyl)-2-fluoromalonic acid in 95% yield with [a D
20 = +45.2ꢁ.
M-type and W-type, in this allylation process (Fig. 3). M-type of
p-allyl-Pd complex, in which the allyl phenyl group would assume
]
In order to determine their absolute configuration, 9c was
established as R by comparing with the known chiral compound
[13].
a position remote from the pyridine- and sulfoxides moiety, is
intended to bias allyl intermediate since the steric demand of both
substituent at the 6-position of pyridine and sulfoxides moiety. The
nucleophilic attack is more favoured at allyl carbon, which is trans
On the basis of our observation in this reaction and other works
[19], there are two presumed types of
p
-allyl-Pd intermidiates,
O
HN
O
O
HN
S
S
OMe
OMe
O
N
N
O
MeO
MeO
O
M-type
W-type
disfavored
favored
Fig. 3. Transition states in catalytic process.

M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
17
to sulfur of M-type intermediate; and it thus gives the allylic
(400 MHz, CDCl3) d= 7.18–7.14 (m, 3H), 7.09 (dt, J = 6.8, 1.6 Hz, 1H),
product with R configuration [19b].
7.00–6.93 (m, 2H), 6.59 (d, J = 8.0 Hz, 1H), 6.42 (dd, J = 8.0, 1.2 Hz,
1H), 6.35 (dt, J = 8.0, 0.8 Hz, 1H), 5.01 (br, 2H), 4.49 (dd, J = 12.0,
12.0 Hz, 1H), 2.58-2.48 (m, 1H), 2.16–2.04 (m, 1H), 0.95 (t, J = 7.2 Hz,
3. Conclusion
3H). 13C NMR (100 MHz, CDCl3)
d= 147.9, 133.9, 131.8, 128.7, 128.1,
In conclusion, we have developed a new entrance to chiral o-
aniline sulfoxides, which are used for the synthesis of chiral
sulfoamide pyridine ligands. These ligands are effective for Pd-
catalyzed allylic substitutions of dimethyl 2-fluoromalonate,
which furnished monofluorinated allylic compounds in moderate
yields with up to excellent enantioselectivity. This is the first
example for the synthesis of multiple chiral o-aniline sulfoxides,
which can serve as a new chiral sulfurous source for the synthesis
of various S-ligands.
127.8, 119.8, 116.8, 116.2, 116.2, 67.4, 22.2, 11.4 ppm. IR (KBr): nmax
(cmꢀ1) = 3365, 3200, 3006, 2969, 2922, 2852,1276,1253,1001, 773,
726. HRMS (ESI+) calcd for C15H17NNaOS [M+Na]+: 282.0923,
Found: 282.0921.
4.2.3. 2-((S)-((S)-1-(3, 5-Dimethoxyphenyl)propyl)sulfinyl)aniline
(5b)
Thickness oil; 24% yield; 94% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL OD-H (0.46 cm ꢂ
25 cm); hexane/2-propanol = 80/20; flow rate = 1.0 mL/min; detec-
tion wavelength = 214 nm; tR = 13.402 (minor),17.541 (major) min];
4. Experimental
[
a
]
20 = ꢀ284.1ꢁ (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d= 7.18
D
4.1. General
(dt, J = 8.0, 1.2 Hz, 1H), 7.02 (dd, J = 7.6, 1.2 Hz, 1H), 6.67 (dt, J = 7.6,
0.8 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 6.33-6.32 (m, 2H),
4.52 (br, 2H), 4.12 (dd, J = 10.0, 10.0 Hz, 1H), 3.71 (s, 6H), 1.94-1.85
All manipulations were carried out under the argon atmosphere
using standard Schlenk techniques. All glassware was oven or
flame dried immediately prior to use. All solvents were purified
and dried according to standard methods prior to use, unless stated
otherwise.
All reagents were obtained from commercial sources and used
without further purification. 1H NMR spectra were obtained at
400 MHz and recorded relative to tetramethylsilane signal (0 ppm)
or residual protio-solvent. 13C NMR spectra were obtained at
100 MHz and chemical shifts were recorded relative to the solvent
resonance (CDCl3, 77.0 ppm). Data for 1H NMR are recorded as
(m, 2H), 0.87 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d= 160.5,
147.7, 136.0, 132.0, 127.7, 120.9, 117.1, 117.0, 107.3, 100.3, 68.6, 55.1,
22.0, 11.5 ppm. IR (KBr): nmax (cmꢀ1) = 3445, 3322, 3220, 2969,
2938, 2857,1470,1205,1150,1061,1009, 840, 758, 722. HRMS (ESI+)
calcd for C17H21NNaO3S [M+Na]+: 342.1134, Found: 342.1131.
4.2.4. 2-((R)-((S)-1-(3, 5-Dimethoxyphenyl)propyl)sulfinyl)aniline
(5b’)
Thickness oil; 60% yield; 99.9% ee (after crystallization). The ee
of the product was determined by chiral HPLC [Daicel CHIRALCEL
OD-H (0.46 cm ꢂ 25 cm); hexane/2-propanol = 80/20; flow rate =
1.0 mL/min; detection wavelength = 214 nm; tR = 7.785 (minor),
follows: chemical shift (d, 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 are
19.836 (major) min]; [a D
(400 MHz, CDCl3) d= 7.11 (dt, J = 8.0, 1.2 Hz, 1H), 6.62 (d, J = 8.4 Hz,
]
20 = ꢀ255.3ꢁ (c 1.0, CHCl3). 1H NMR
reported in terms of chemical shift (
d
, ppm).
1H), 6.52 (dd, J = 8.0, 1.2 Hz, 1H), 6.42 (dt, J = 7.6, 1.2 Hz, 1H), 6.28 (s,
1H), 6.10–6.09 (m, 2H), 4.67 (br, 2H), 4.41 (dd, J = 12.0, 12.0 Hz, 1H),
3.62 (s, 6H), 2.54–2.45 (m, 1H), 2.12–2.00 (m, 1H), 0.98 (t, J = 7.2 Hz,
4.2. General procedure for the synthesis of sulfoxide 5 and 50
To a solution of 4 (2.0 mmol) in DCM (10 mL) were added 3-
chlorobenzoperoxoic acid (2.0 mmol) at 30 ꢁC. The reaction was
carried out 30 min with TLC-followed. Then the mixture was
quenched by 10% Na2S2O4 and sat. NaHCO3 and extracted by DCM.
The organic layer was washed with brine, dried by Na2SO4 and then
concentrated. The crude residue was purified by flash column
chromatography to give the desired products 5 and 50.
3H). 13C NMR (100 MHz, CDCl3)
d= 160.5, 147.8, 136.3, 132.0, 128.5,
120.6, 117.0, 116.8, 106.8, 100.3, 67.8, 55.2, 22.3, 11.5 ppm. IR (KBr):
nmax (cmꢀ1) = 3440, 3323, 3220, 2996, 2965, 2938, 2871, 2835,
1470, 1206, 1147, 1067, 1009, 839, 758, 722. HRMS (ESI+) calcd for
C
17H21NNaO3S [M+Na]+: 342.1134, Found: 342.1132.
4.2.5. 2-((S)-((S)-1-(Furan-3-yl)propyl)sulfinyl)aniline (5c)
Thickness oil; 16% yield; 94% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL AD-H (0.46 cm ꢂ 25
cm); hexane/2-propanol = 90/10; flow rate = 1.2 mL/min; detection
wavelength = 214 nm; tR = 21.742 (major), 25.416 (minor) min];
4.2.1. 2-((R)-((R)-1-Phenylpropyl)sulfinyl)aniline (5a)
White solid; mp: 95.1–95.9 ꢁC; 26% yield; 96% ee. The ee of the
product was determined by chiral HPLC [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10; flow rate = 1.2 mL/
min; detection wavelength = 214 nm; tR = 20.215 (minor), 31.227
[a
]
20 = ꢀ27.5ꢁ (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d= 7.40 (s,
D
1H), 7.27 (s, 1H), 7.21 (dt, J = 8.4, 1.2 Hz, 1H), 7.04 (dd, J = 8.0, 1.2 Hz,
1H), 6.71 (dt, J = 7.6, 0.8 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H),
4.40 (dd, J = 9.2, 9.2 Hz, 1H), 3.65 (br, 2H), 1.97–1.79 (m, 2H), 0.96 (t,
(major) min]; [a D
CDCl3) = 7.33–7.25 (m, 3H), 7.18–7.10 (m, 3H), 7.00-6.95 (d,
]
20 = +320.1ꢁ (c 1.0, CHCl3). 1H NMR (400 MHz,
d
J = 7.6 Hz, 1H), 6.63 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 4.74 (br,
2H), 4.17 (dd, J = 5.6, 5.6 Hz,1H), 2.02–1.93 (m, 2H), 0.87 (t, J = 7.2 Hz,
J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d= 147.8, 143.1, 142.2,
132.1, 127.7, 121.0, 118.2, 117.3, 117.2, 110.2, 60.7, 22.2, 11.8 ppm. IR
(KBr): nmax (cmꢀ1) = 3426, 3333, 3221, 3062, 2969, 2876, 1323,
1267, 1160, 1020, 870, 759, 605, 521. HRMS (ESI+) calcd for
3H). 13C NMR (100 MHz, CDCl3)
d= 147.5, 133.5, 131.9, 129.4, 128.2,
128.0, 127.4, 120.8, 117.0, 117.0, 68.3, 22.0, 11.6 ppm. IR (KBr): nmax
(cmꢀ1) = 3360, 3205, 3006, 2969, 2922, 2882, 1296,1273, 1001, 743,
656. HRMS (ESI+) calcd for C15H17NNaOS [M+Na]+: 282.0923,
Found: 282.0919
C
13H15NNaO2S [M+Na]+: 272.0716, Found: 272.0712.
4.2.6. 2-((R)-((S)-1-(Furan-3-yl)propyl)sulfinyl)aniline (5c’)
Thickness oil; 62% yield; [a D
(400 MHz, CDCl3) d= 7.28 (s, 1H), 7.16 (dt, J = 8.4, 1.2 Hz, 1H), 6.96 (s,
]
20 = ꢀ27.4ꢁ (c 1.0, CHCl3). 1H NMR
4.2.2. 2-((S)-((R)-1-Phenylpropyl)sulfinyl)aniline (5a’)
White solid; mp: 111.2–112.1 ꢁC; 58% yield; 96% ee. The ee of
the product was determined by chiral HPLC [Daicel CHIRALCEL
AD-H (0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10; flow rate =
1.0 mL/min; detection wavelength = 214 nm; tR = 15.449 (major),
2H), 6.71 (dd, J = 8.0, 1.6 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.52 (t,
J = 7.6 Hz, 1H), 6.09 (s, 1H), 5.08 (br, 2H), 4.44 (dd, J = 12.0, 12.0 Hz,
1H), 2.50–2.40 (m, 1H), 1.96–1.85 (m, 1H), 1.2 (t, J = 7.2 Hz, 3H). 13
C
NMR (100 MHz, CDCl3)
d= 148.0, 143.1, 141.9, 132.2, 128.9, 120.4,
17.066 (minor) min]; [a]D
20 = +303.3ꢁ (c 1.0, CHCl3). 1H NMR
118.6, 117.1, 116.6, 109.6, 58.7, 22.4, 11.5 ppm. IR (KBr): nmax

18
M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
(cmꢀ1) = 3421, 3319, 3197, 3067, 2964, 2936, 2871, 1258, 1010, 866,
796, 749, 605, 530. HRMS (ESI+) calcd for C13H15NNaO2S [M+Na]+:
272.0716, Found: 272.0715.
cm); hexane/2-propanol = 80/20; flow rate = 1.0 mL/min; detection
wavelength = 214 nm; tR = 7.395 (minor), 9.060 (major) min];
[
a]D
20 = ꢀ105.0ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d= 11.6
(br, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.92 (t,
J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.15 (d,
J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.14 (t, J = 2.4 Hz, 1H), 6.03 (ddt,
J = 16.0, 10.4, 5.2 Hz, 1H), 6.00 (d, J = 2.4 Hz, 2H), 5.37 (d, J = 17.2 Hz,
1H), 5.26 (d, J = 10.4 Hz, 1H), 4.84–4.76 (m, 2H), 4.20 (dt, J = 5.2,
1.6 Hz, 2H), 4.02 (dd, J = 11.2, 11.6 Hz, 1H), 3.46 (s, 6H), 2.56–2.46
(m, 1H), 2.13–1.97 (m, 1H), 0.93 (t, J = 7.6 Hz, 1H). 13C NMR
4.2.7. 2-((R)-sec-Butylsulfinyl)aniline (5d)
Light yellow oil; 48% yield; 88% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL AD-H (0.46 cm
ꢂ 25 cm); hexane/2-propanol = 90/10; flow rate = 1.2 mL/min; de-
tection wavelength = 214 nm; tR = 13.208 (minor), 15.979 (major)
min]; [
a
]
20 = ꢀ83.1ꢁ (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
D
d
= 7.25–7.18 (m, 2H), 6.76 (dt, J = 7.6, 1.2 Hz, 1H), 6.66 (d, J = 8.0 Hz,
(100 MHz, CDCl3) d= 162.6, 160.5, 158.1, 148.8, 139.1, 138.0, 134.9,
1H), 4.86 (br, 2H), 3.29–3.21 (m, 1H), 1.68-1.55 (m, 1H), 1.47–1.38
134.4, 132.1, 127.8, 127.2, 123.8, 123.2, 121.6, 120.9, 117.3, 107.0,
100.2, 72.6, 72.2, 71.9, 22.3, 11.6 ppm. IR (KBr): nmax (cmꢀ1) = 3448,
3090, 3002, 2969, 2918, 2852,1514,1150,1211,1066,1020, 926, 824,
749. HRMS (ESI+) calcd for C27H30NaN2O3 [M+Na]+: 517.1768,
Found: 517.1765.
(m, 1H), 1.36 (d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d= 147.9, 132.1, 128.0, 120.8, 117.4, 117.2, 57.3,
23.6, 12.3, 11.0 ppm. IR (KBr): nmax (cmꢀ1) = 3431, 3324, 3207, 3022,
2969, 2922, 2875,1155, 1062, 1001, 759, 717, 525. HRMS (ESI+)
calcd for C10H15NNaOS [M+Na]+: 220.0767, Found: 220.0768.
4.3.3. 6-(Allyloxymethyl)-N-(2-((R)-((S)-1-(furan-3-yl)propyl)
sulfinyl)phenyl)picolinamide (6c)
4.2.8. 2-((S)-sec-Butylsulfinyl)aniline (5d’)
Light yellow oil; 25% yield; 93% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL AD-H (0.46 cm ꢂ 25
cm); hexane/2-propanol = 90/10; flow rate = 1.2 mL/min; detection
wavelength = 214 nm; tR = 12.301 (major), 13.549 (minor) min];
Thickness oil; 82% yield; [
a
]
20 = ꢀ47.8ꢁ (c 0.5, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
= 11.8 (br, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.15 (d,
J = 8.0 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.50 (t,
J = 8.4 Hz, 1H), 7.17–7.15 (m, 2H), 7.07 (t, J = 8.4 Hz, 1H), 7.00 (s, 1H),
6.03 (ddt, J = 16.0, 10.8, 5.6 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 5.38 (d,
J = 17.2 Hz, 1H), 5.26 (dd, J = 10.4, 1.2 Hz, 1H), 4.82–4.75 (m, 2H),
4.19 (dt, J = 5.6, 1.6 Hz, 2H), 4.00 (dd, J = 11.2, 11.2 Hz, 1H), 2.48–2.38
(m, 1H), 1.92–1.84 (m, 1H), 0.96 (t, J = 7.2 Hz, 1H). 13C NMR
[a] d= 7.24
20 = +107.3ꢁ (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
D
(dt, J = 1.2, 8.0 Hz, 1H), 6.76 (dd, J = 7.6, 1.2 Hz, 1H), 6.72 (dt, J = 7.6,
0.8 Hz, 1H), 6.67 (dd, J = 8.0, 0.8 Hz, 1H), 5.02 (br, 2H), 3.52–3.44 (m,
1H), 2.15–2.04 (m,1H),1.67–1.60 (m,1H),1.07 (t, J = 7.2 Hz, 3H), 0.99
(d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d= 148.3, 132.3, 128.8,
(100 MHz, CDCl3)
d= 162.8, 157.8, 148.9, 143.3, 142.0, 139.1, 138.0,
1120.4, 117.4, 117.0, 56.0, 23.0, 13.0, 10.4 ppm. IR (KBr): nmax
(cmꢀ1) = 3421, 3309, 3197, 2969, 2922, 2857, 1309, 1001, 749, 721,
530. HRMS (ESI+) calcd for C10H15NNaOS [M+Na]+: 220.0767,
Found: 220.0769.
134.2, 132.4, 127.7, 127.2, 124.0, 123.1, 122.0, 121.0, 117.6, 117.3,
109.5, 72.6, 71.9, 62.5, 22.3, 11.5 ppm. IR (KBr): nmax (cmꢀ1) = 3560,
3058, 2974, 2918, 2852, 1687, 1514, 1051, 1015, 870, 749. HRMS
(ESI + ) calcd for C23H24NaN2O4 [M + Na]+: 447.1349, Found:
447.1346.
4.3. General procedure for the synthesis of new chiral sulfonamide-
pyridine ligands 6
4.3.4. 6-(Allyloxymethyl)-N-(2-((R)-sec-butylsulfinyl)phenyl)
picolinamide (6d)
An oven-dried round-bottomed flask equipped with a magnetic
stir bar was charged with KH (0.5 mmol, 30% in mineral oil) and
3 mL of THF under argon atmosphere, the mixture was cool at
ꢀ40 ꢁC for 10 min, and 50 (0.5 mmol) was added; and the mixture
was stirred at ꢀ40 ꢁC for 1 h. Then methyl 6-((allyloxy)methyl)
picolinate (0.51 mmol) was added and stirred for another 1 h. The
crude residue was concentrated in vacuo and purified by flash
column chromatography (hexane/ethyl acetate) to provide the
desired products 6.
Thickness oil; 88% yield; [a D
]
20 = ꢀ8.3ꢁ (c 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3)
d
= 12.0 (br, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.16 (d,
J = 7.6 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.56 (t,
J = 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 6.00
(ddt, J = 16.0, 10.8, 5.6 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 5.37 (d,
J = 17.2 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 4.80–4.72 (m, 2H), 4.16 (d,
J = 5.6 Hz, 2H), 3.28–3.19 (m, 1H), 2.12–2.02 (m, 1H), 1.72–1.61 (m,
1H), 1.03–0.99 (m, 6H). 13C NMR (100 MHz, CDCl3)
d= 163.0, 158.0,
148.8, 139.1, 138.1, 134.2, 132.4, 127.9, 127.3, 124.0, 123.4, 122.3,
121.1, 117.3, 72.6, 71.9, 58.8, 22.8, 12.7, 10.5 ppm. IR (KBr): nmax
(cmꢀ1) = 3557, 3193, 2978, 2848, 2922, 1533, 1034, 917, 824, 754.
HRMS (ESI+) calcd for C20H24NaN2O3 [M+Na]+: 395.1400, Found:
395.1403.
4.3.1. 6-(Allyloxymethyl)-N-(2-((S)-((R)-1-phenylpropyl)sulfinyl)
phenyl)picolinamide (6a)
Thickness oil; 81% yield; [
a
]
20 = ꢀ55.7ꢁ (c 0.5, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
= 11.7 (br, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.13 (d,
J = 7.6 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.44 (t,
J = 8.0 Hz, 1H), 7.10–6.91 (m, 5H), 6.86 (d, J = 7.6 Hz, 1H), 6.02 (ddt,
J = 16.0, 10.4, 6.4 Hz, 1H), 5.40 (d, J = 17.2 Hz, 1H), 5.27 (d, J = 10.4 Hz,
1H), 4.84–4.76 (m, 2H), 4.20 (d, J = 5.6 Hz, 2H), 4.13 (dd, J = 11.2,
11.2 Hz, 1H), 2.59–2.47 (m, 1H), 2.13–2.03 (m, 1H), 0.89 (t, J = 7.6 Hz,
4.3.5. N-(2-((R-((S)-1-Phenylpropyl)sulfinyl) phenyl)picolinamide
(6f)
Thickness oil; 86% yield. [
(400 MHz, CDCl3) = 11.58 (br, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.56 (d,
a]
20 = +43.9ꢁ (c 0.5, CHCl3). 1H NMR
D
d
1H). 13C NMR (100 MHz, CDCl3)
d= 162.77, 157.8, 148.9, 138.9, 138.0,
J = 8.4 Hz, 1H), 8.23 (d, J = 6.8 Hz, 1H), 7.91 (dt, J = 8.0, 1.6 Hz, 1H),
7.50 (t, J = 6.8 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H),
7.03–6.96 (m, 4H), 6.88 (d, J = 7.6 Hz, 1H), 4.12 (dd, J = 11.2, 11.2 Hz,
1H), 2.56–2.51 (m, 1H), 2.13–2.04 (m, 1H), 0.90 (t, J = 7.6 Hz, 1H).
134.2, 132.9, 132.2, 128.9, 128.3, 127.3, 123.9, 123.0, 121.7, 121.0,
117.3, 72.6, 71.9, 71.4, 22.3, 11.6 ppm. IR (KBr): nmax (cmꢀ1) = 3450,
3053, 2964, 2932, 2880, 2848, 1682, 1575, 1318, 1020, 754, 698.
HRMS (ESI+) calcd for C25H26NaN2O3 [M+Na]+: 457.1556, Found:
457.1558.
13C NMR (100 MHz, CDCl3)
d
= 162.8, 149.8, 148.3, 138.9, 137.2,
132.9, 132.1, 129.4, 128.9, 128.3, 127.7, 127.2, 126.4, 123.2, 124.5,
122.0, 71.6, 22.4, 11.6 ppm. IR(KBr):
(cmꢀ1) = 3420, 3022,
max
4.3.2. 6-(Allyloxymethyl)-N-(2-((R)-((S)-1-(3, 5-dimethoxyphenyl)
propyl)sulfinyl)phenyl)picolinamide (6b)
Thickness oil; 87% yield; 97% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL AD-H (0.46 cm ꢂ 25
2964, 2928, 2898, 2882, 2848, 1674, 1562, 1311, 1020, 755, 674.
HRMS (ESI+) calcd for C21H20NaN2O2S [M+Na]+: 387.1138, Found:
387.1132.

M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
19
4.4. General procedure for the Pd-catalyzed enantioselective allylic
alkylations
8.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, CDCl3)
d
= ꢀ175.5. 13C NMR (100 MHz, CDCl3)
d= 165.2 (d, J = 25.3 Hz),
164.8 (d, J = 25.6 Hz), 138.6, 138.3, 133.4, 132.1 (d, J = 2.3 Hz), 131.1,
131.0, 130.3, 130.1, 129.3, 127.7 (d, J = 2.5 Hz), 125.5 (d, J = 5.4 Hz),
125.2, 122.8, 122.6, 97.0 (d, J = 209.0 Hz), 53.7, 53.4, 53.2 (d,
J = 18.3 Hz) ppm. IR (KBr): nmax (cmꢀ1) = 3053, 2997, 2969, 2927,
2848, 1766, 1593, 1561, 1477, 1467, 1435, 1248, 1141, 1043, 973, 777,
703, 614. HRMS (ESI+) calcd for C20H17Br2FNaO4 [M+Na]+:
520.9370, Found: 520.9369.
[Pd(C3H5)Cl]2 (0.004 mmol, 4 mol%), [6-(allyloxymethyl)-N-(2-
((R)-((S)-1-(3,5-dimethoxyphenyl)propyl)sulfinyl)phenyl)picoli-
namide] (6b, 0.008 mmol, 8 mol%), and (E)-1,3-disubstituted allyl
acetates 7 (0.1 mmol) were dissolved in THF (2.0 mL) in a dry
Schlenk tube filled with argon. The reaction mixture was stirred for
30 min at room temperature. Then Cs2CO3 (3.0 equiv) and dimethyl
2-fluoromalonate 8 (0.3 mmol, 3.0 equiv) were added. After the
completion of the reaction monitoring by TLC, the crude reaction
mixture was filtrated with celite and the solvent was removed
under reduced pressure. The crude residue was purified by flash
column chromatography (petroleum ether/ethyl acetate) to give
the desired products 9.
4.4.4. (E)-Dimethyl 2-(1, 3-bis(4-fluorophenyl)allyl)-2-
fluoromalonate (9d)
White solid; mp: 91.4–92.3 ꢁC; 70% yield; 80% ee. The ee of the
product was determined by chiral HPLC [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min; detection wavelength = 214 nm; tR = 16.966 (major), 18.703
4.4.1. (E)-Dimethyl 2-(1, 3-bis(3-fluorophenyl)allyl)-2-
fluoromalonate (9a)
(minor) min]; [
CDCl3) = 7.37–7.26 (m, 4H), 7.04–6.96 (m, 4H), 6.51 (d, J = 15.6 Hz,
1H), 6.33 (dd, J = 15.6, 9.2 Hz, 1H), 4.51 (dd, J = 30.8, 9.2 Hz, 1H), 3.83
a]
20 = +59.3ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz,
D
d
White solid; mp: 93.1–94.2 ꢁC, 73% yield; 94% ee. The ee of the
product was determined by chiral HPLC [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min; detection wavelength = 214 nm; tR = 11.056 (minor), 11.827
(s, 3H), 3.62 (s, 3H). 19F NMR (376 MHz, CDCl3)
d
= ꢀ113.6, ꢀ114.2,
ꢀ176.1. 13C NMR (100 MHz, CDCl3)
d= 165.4 (d, J = 25.1 Hz), 165.1 (d,
J = 25.7 Hz), 162.5 (d, J = 246.1 Hz), 162.3 (d, J = 245.3 Hz), 133.2,
132.4 (d, J = 3.3 Hz), 130.8, 130.7, 128.1, 128.0, 124.2, 115.6 (d,
J = 8.5 Hz), 115.4 (d, J = 9.1 Hz), 97.0 (d, J = 208.4 Hz), 53.5, 53.2, 52.9
(d, J = 18.4 Hz) ppm. IR (KBr): nmax (cmꢀ1) = 3048, 3006, 2960, 2908,
2843, 1770, 1598, 1509, 1439, 1230, 1169, 1057, 978, 838, 740, 521,
507. HRMS (ESI+) calcd for C20H17F3NaO4 [M+Na]+: 401.0971,
Found: 401.0774.
(major) min]; [a D
CDCl3) = 7.33–7.23 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.12–7.10 (m,
]
20 = +21.7ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz,
d
2H), 7.05 (d, J = 8.0 Hz, 1H), 7.01–6.91 (m, 2H), 6.54 (d, J = 16.0 Hz,
1H), 6.42 (dd, J = 16.0, 8.8 Hz, 1H), 4.53 (dd, J = 30.4, 8.8 Hz, 1H), 3.83
(s, 3H), 3.64 (s, 3H). 19F NMR (376 MHz, CDCl3)
d
= ꢀ112.2, ꢀ113.3,
ꢀ175.6. 13C NMR (100 MHz, CDCl3)
d= 165.3 (d, J = 25.3 Hz), 164.9
(d, J = 25.8 Hz),163.0 (d, J = 244.3 Hz),162.7 (d, J = 245.1 Hz),138.8 (d,
J = 7.1 Hz), 138.5 (d, J = 7.6 Hz), 133.6 (d, J = 2.5 Hz), 130.1 (dd, J = 8.2,
8.4 Hz), 125.4 (d, J = 4.5 Hz), 124.5 (dd, J = 2.5, 2.5 Hz), 122.4 (d,
J = 2.7 Hz), 116.2 (d, J = 2.5 Hz), 116.0 (d, J = 2.6 Hz), 115.0 (d,
J = 3.4 Hz), 114.8 (d, J = 4.1 Hz), 113.0 (d, J = 21.7 Hz), 97.1 (d,
J = 208.9 Hz), 53.7, 53.3, 53.1 (d, J = 19.6 Hz) ppm. IR (KBr): nnmax
(cmꢀ1) = 3057, 2956, 2910, 2833, 1759, 1438, 1280, 1270, 1148, 1051,
970, 904, 746. HRMS (ESI+) calcd for C20H17F3NaO4 [M+Na]+:
401.0971, Found: 401.0775.
4.4.5. (E)-Dimethyl 2-(1, 3-bis(4-chlorophenyl)allyl)-2-
fluoromalonate (9e)
White solid; mp: 102.1–102.5 ꢁC; 71% yield; 81% ee. The ee of the
product was determined by chiral HPLC [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min; detection wavelength = 214 nm; tR = 14.625 (major), 16.354
(minor) min]; [
CDCl3) = 7.34–7.31 (m, 4H), 7.29–7.25 (m, 4H), 6.51 (d, J = 16.4 Hz,
a]
20 = +65.6ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz,
D
d
1H), 6.39 (dd, J = 16.0, 8.8 Hz, 1H), 4.52 (dd, J = 30.8, 8.8 Hz, 1H), 3.83
4.4.2. (E)-Dimethyl 2-(1, 3-bis(3-chlorophenyl)allyl)-2-
fluoromalonate (9b)
(s, 3H), 3.63 (s, 3H). 19F NMR (376 MHz, CDCl3)
(100 MHz, CDCl3)
d
= ꢀ175.7. 13C NMR
d
= 165.2 (d, J = 25.4 Hz), 164.8 (d, J = 25.7 Hz),
Thickness oil; 82% yield; 87% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL AD-H (0.46 cm ꢂ 25
cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/min; detection
wavelength = 214 nm; tR = 11.409 (minor), 12.319 (major) min];
134.9, 134.7, 133.8, 133.6, 133.3, 130.4, 130.3, 128.8, 128.6, 127.7,
124.8 (d, J = 4.3 Hz), 97.0 (d, J = 208.9 Hz), 53.5, 53.2, 52.9 (d,
J = 18.4 Hz) ppm. IR (KBr): nmax (cmꢀ1) = 3025, 3002, 2950, 2922,
2852, 1756, 1281, 1481, 1262, 1099, 978, 833, 763, 754, 511. HRMS
(ESI+) calcd for C20H17Cl2FNaO4 [M+Na]+: 433.0380, Found:
433.0385.
[a]D d= 7.37 (s,
20 = +61.2ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
1H), 7.33 (s, 1H), 7.27–7.26 (m, 3H), 7.23–7.21 (m, 3H), 6.51 (d,
J = 15.6 Hz, 1H), 6.41 (dd, J = 15.6, 8.8 Hz, 1H), 4.50 (dd, J = 30.8,
8.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, CDCl3)
4.4.6. (E)-Dimethyl 2-(1, 3-bis(4-bromophenyl)allyl)-2-
fluoromalonate (9f)
d
= ꢀ175.5. 13C NMR (100 MHz, CDCl3)
d= 165.3 (d, J = 25.3 Hz),
164.9 (d, J = 25.6 Hz), 138.4, 138.0, 134.6, 134.5, 133.5, 129.9, 129.8,
129.3 (d, J = 2.4 Hz), 128.2, 128.1, 127.2 (d, J = 2.4 Hz), 126.4, 125.5 (d,
J = 5.5 Hz), 124.8, 97.0 (d, J = 208.9 Hz), 53.7, 53.4, 53.4 (d, J = 18.4
Hz) ppm. IR (KBr): nmax (cmꢀ1) = 3062, 3016, 2960, 2927, 1756,
1598,1561, 1435,1262, 1141, 1048, 959, 787, 703. HRMS (ESI+) calcd
for C20H17Cl2FNaO4 [M+Na]+: 433.0380, Found: 433.0381.
White solid; mp: 71.5–72.6 ꢁC; 78% yield; 83% ee. The ee of the
product was determined by chiral HPLC [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 80/20, flow rate = 1.0 mL/
min; detection wavelength = 214 nm; tR = 17.997 (major), 21.487
(minor) min]; [a D
CDCl3) = 7.46 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.25 (d,
]
20 = +27.3ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz,
d
J = 6.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 15.6 Hz, 1H), 6.38
(dd, J = 15.6, 8.8 Hz, 1H), 4.49 (dd, J = 31.2, 8.8 Hz, 1H), 3.82 (s, 3H),
4.4.3. (E)-Dimethyl 2-(1, 3-bis(3-bromophenyl)allyl)-2-
fluoromalonate (9c)
3.64 (s, 3H). 19F NMR (376 MHz, CDCl3)
d
= ꢀ175.8. 13C NMR
White solid; mp: 93.1–93.9 ꢁC; 74% yield; 81% ee. The ee of the
product was determined by chiral HPLC [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min; detection wavelength = 214 nm; tR = 11.602 (minor), 12.944
(100 MHz, CDCl3) d= 165.3 (d, J = 25.1 Hz), 164.9 (d, J = 25.7 Hz),
135.5, 135.1, 133.5, 131.9, 131.7, 130.8, 130.7, 128.0, 124.9 (d,
J = 4.5 Hz), 122.1, 121.9, 97.0 (d, J = 208.7 Hz), 53.7, 53.4, 53.1 (d,
J = 18.5 Hz) ppm. IR (KBr): nmax (cmꢀ1) = 3039, 2964, 2927, 2843,
176, 1486, 1258, 1155, 1076, 1048, 1015, 964, 768, 563, 511. HRMS
(ESI+) calcd for C20H17Br2FNaO4 [M+Na]+: 520.9370, Found:
520.9374.
(major) min]; [
CDCl3) = 7.54–7.49 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (d,
a]
20 = +61.2ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz,
D
d
J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.25–7.15 (m, 3H), 6.50 (d,
J = 15.6 Hz, 1H), 6.40 (dd, J = 16.0, 8.8 Hz, 1H), 4.49 (dd, J = 30.8,

20
M. Zhang et al. / Journal of Fluorine Chemistry 189 (2016) 13–21
4.4.7. (E)-Dimethyl 2-(1, 3-diphenylallyl)-2-fluoromalonate (9g) [4]
White solid; 73% yield; 88% ee. The ee of the product was
determined by chiral HPLC [Daicel CHIRALCEL AD-H (0.46 cm ꢂ 25
cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/min; detection
wavelength = 214 nm; tR = 13.931 (major), 16.480 (minor) min];
(d, J = 2.3 Hz), 130.2(d, J = 2.7 Hz), 128.9, 128.8, 128.7, 128.7, 127.6,
127.6,124.9 (d, J = 3.8 Hz),124.8 (d, J = 5.0 Hz),102.7 (d, J = 202.4 Hz),
102.6 (d, J = 206.1 Hz), 62.9, 62.7, 52.6(d, J = 18.1 Hz), 52.5 (d,
J = 18.1 Hz), 26.8, 26.8, 14.1, 13.7 ppm. IR(KBr): nmax (cmꢀ1) = 3063,
3022, 3006, 2950, 2928, 2855, 1731, 1756, 1280, 1262, 1181, 1090,
987, 863, 763, 754, 611. HRMS (ESI+) calcd for C21H19Cl2FNaO3 [M
+Na]+: 431.0587, Found: 431.0584.
[a] d= 7.40–
20 = +24.4ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
D
7.38 (m, 2H), 7.36–7.32 (m, 4H), 7.30–7.27 (m, 3H), 7.24–7.21 (m,
1H), 6.58 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.8 Hz, 1H), 4.53 (dd,
J = 31.6, 8.8 Hz, 1H), 3.82 (s, 3H), 3.61 (s, 3H). 19F NMR (376 MHz,
4.4.11. Synthesis of the allylic dicarboxylic acids (10)
CDCl3)
d
= ꢀ175.9. 13C NMR (100 MHz, CDCl3)
d
= 165.6 (d,
To a solution of 9e (0.2 mmol) in the binary solvent composed of
J = 25.5 Hz), 165.1 (d, J = 25.8 Hz), 136.9, 136.5, 134.3, 129.1, 129.0,
128.5, 127.8, 127.8, 126.5, 124.6 (d, J = 3.5 Hz), 97.5 (d, J = 208.5 Hz),
53.8 (d, J = 18.3 Hz), 53.5, 53.2 ppm.
THF (3.0 mL) and H2O (1.0 mL) was added LiOH H2O lithium
ꢃ
hydroxide monohydrate (0.5 mmol). The mixture was stirred at
25 ꢁC for 5 h and then poured into water (10 mL). After acidifying
with diluted aqueous HCl solution, the precipitate was collected by
filtration and washed with H2O to give 10 (72.6 mg) as a light
4.4.8. (E)-Dimethyl 2-(1, 3-bis(3-fluorophenyl)allyl)-2-
fluoromalonate (9h)
yellow solid. (E)-2-(1,3-Bis(4-chlorophenyl)allyl)-2-fluoromalonic
20
White solid; mp: 102.2–103.4 ꢁC; 70% yield; 91% ee. The ee of
the product was determined by chiral HPLC [Daicel CHIRALCEL
AD-H (0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10, flow rate =
1.0 mL/min; detection wavelength = 214 nm; tR = 29.258 (major),
acid (10): White solid; mp: 153.4 ꢀ154.3 ꢁC; 95% yield. [
a
]
=
D
+45.2ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz, (CD3)2SO)
d= 13.95 (br,
2H), 7.46–7.35 (m, 8H), 6.62–6.52 (m, 2H), 4.49 (dd, J = 30.8, 7.6 Hz,
1H). 19F NMR (376 MHz, (CD3)2SO)
(CD3)2SO) d= 166.3 (d, J = 25.8 Hz),166.0 (d, J = 25.8 Hz),136.7,135.2,
d
= ꢀ172.9. 13C NMR (100 MHz,
35.442 (minor) min]; [a D
]
20 = +45.0ꢁ (c 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3) = 7.90 (s, 1H), 7.86–7.80 (m, 3H), 7.78–7.74 (m,
d
132.2, 132.1, 131.1, 128.6, 128.3, 128.1, 126.4, 126.3, 96.5 (d,
J = 202.6 Hz), 51.7 (d, J = 18.4 Hz) ppm. IR(KBr): nmax (cmꢀ1) = 3650,
3062, 3022, 2960, 2852,1710,1655,1281,1120, 987, 833, 754. HRMS
(ESI+) calcd for C18H12Cl2FO4Na [M+Na]+: 405.0067, Found:
405.0061.
3H), 7.69 (s, 1H), 7.59–7.55 (m, 2H), 7.48–7.41 (m, 4H), 6.77 (d,
J = 15.6 Hz, 1H), 6.68 (dd, J = 16.0, 8.8 Hz, 1H), 4.77 (dd, J = 31.6,
8.8 Hz, 1H), 3.85 (s, 3H), 3.57 (s, 3H). 19F NMR (376 MHz, CDCl3)
d
= ꢀ175.4. 13C NMR (100 MHz, CDCl3)
d= 165.7 (d, J = 25.4 Hz),
165.2 (d, J = 25.7 Hz), 134.6, 134.2, 133.9, 133.4, 133.3, 133.1, 132.8,
128.4, 128.2, 128.0, 127.9, 127.6, 127.5, 126.9, 126.9, 126.6, 126.3,
126.1, 126.1, 126.0, 124.9 (d, J = 4.4 Hz), 123.5, 97.9 (d, J = 208.5 Hz),
54.0 (d, J = 18.3 Hz), 53.6, 53.3 (d, J = 18.5 Hz) ppm. IR (KBr): nmax
(cmꢀ1) = 3057, 2951, 2925, 2844, 1759, 1265, 1133, 1036, 970, 919,
827, 751, 481. HRMS (ESI+) calcd for C28H23FNaO4 [M+Na]+:
465.1473, Found: 465.1470.
Acknowledgments
We thank the NSFC (No. 21272175) and Shanghai science and
technology commission (14DZ2261100) for generous financial
support.
Appendix A. Supplementary data
4.4.9. (E)-Dimethyl 2-(1,3-di-m-tolylallyl)-2-fluoromalonate (9i)
White solid; mp: 97.5–98.6 ꢁC; 75% yield; 77% ee. The ee of the
product was determined by chiral HPLC. [Daicel CHIRALCEL AD-H
(0.46 cm ꢂ 25 cm); hexane/2-propanol = 90/10, flow rate = 1.0 mL/
min; detection wavelength = 214 nm; tR = 7.983 (major), 8.740
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
jfluchem.2016.07.010.
(minor) min]; [a D
CDCl3) = 7.18–7.14 (m, 6H), 7.07–7.03 (m, 2H), 6.54 (d, J = 15.6 Hz,
]
20 = +45.3ꢁ (c 0.5, CHCl3). 1H NMR (400 MHz,
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