Enantioselective fluorination of β-ketoesters catalysed by complexes of new mono-oxazoline ligands

Article abstract of DOI:10.1016/j.jfluchem.2015.02.017

A new kind of mono-oxazoline ligands which combined diaryl methyl units and chiral oxazoline units together using pyridine as linker was prepared. Their applications in enantioselective electrophilic fluorination of β-ketoesters by NFSI were investigated, and the corresponding products were obtained in excellent yield (up to 90%) and good enantioselectivity (78%) in CH₂Cl₂ at -60 °C.

Full text of DOI:10.1016/j.jfluchem.2015.02.017

Accepted Manuscript
Title: Enantioselective fluorination of β-ketoesters catalyzed
by complexes of new mono-oxazoline ligands
Author: Teng Niu Xiping Han Danfeng Huang Ke-Hu Wang
Yingpeng Su Yulai Hu Ying Fu
PII:
S0022-1139(15)00072-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.02.017
FLUOR 8523
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Received date:
Revised date:
Accepted date:
22-12-2014
25-2-2015
26-2-2015
Please cite this article as: T. Niu, X. Han, D. Huang, K.-H. Wang, Y. Su,
Y. Hu, Y. Fu, Enantioselective fluorination of rmbeta-ketoesters catalyzed by
complexes of new mono-oxazoline ligands, Journal of Fluorine Chemistry (2015),
http://dx.doi.org/10.1016/j.jfluchem.2015.02.017
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Enantioselective fluorination of β-ketoesters catalyzed by
complexes of new mono-oxazoline ligands
Teng Niu, Xiping Han, Danfeng Huang,* Ke-Hu Wang, Yingpeng Su, Yulai Hu,*
Ying Fu
College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning Road (E.), Lanzhou,
Gansu 730070, P. R. China.
Tel.: +86-931-7971989; fax: +86-931-7971989.
E-mail: huyl@nwnu.edu.cn (Y. Hu).
ABSTRACT
A new kind of mono-oxazoline ligands which combined diaryl methyl units and chiral oxazoline units together
using pyridine as linker was prepared. Their applications in enantioselective electrophilic fluorination of β-
ketoesters by NFSI were investigated, and the corresponding products were obtained in excellent yield (up to 90%)
and good enantioselectivity (78%) in CH2Cl2 at -60oC.
Keywords: Enantioselective synthesis, Catalysis, Electrophilic fluorination; Mono-oxazoline ligands
1. Introduction
Wide applications of fluorine containing compounds in pharmaceuticals and agrochemicals have led to
increasing attention to the development of efficient methods to install fluorine atom into organic molecules [1].
Among the fluorine-containing drugs, many of them contain fluorine-attached chiral centers [1e,2]. Thus,
enantioselective installation of fluorine atom into organic molecules becomes more and more important. Despite
recent progress in asymmetric fluorination [3], enantioselective construction of fluorine-containing stereocenter is
still challenging. The commonly used strategies such as chiral transition metal complexes catalyzed reaction [4]
and organocatalysis [5] have been successfully applied in asymmetric fluorinations. However, new methods are
still needed for enantioselective fluorination. As for the enantioselective transition metal complexes catalyzed
fluorination, some of the traditional chiral oxazoline ligands proved to be effective [6], and some mono-oxazoline
ligands also show excellent enantioselective fluorination using NFSI or Selectfluor as fluorination reagents [7]. In
our research group, a new kind of mono-oxazoline ligands which combined diphenyl methyl units and chiral
oxazoline ring together with pyridine ring as the linker were prepared recently (Figure 1). The ligands were tested
in the enantioselective fluorination of β-ketoesters with NFSI as fluorine source, and moderate ee value was
Page 1 of 21

obtained. Herein, we wish to report the results of enantioselective fluorination of β-ketoesters using mono-
oxazoline compounds L1-6 (Figure 1) as chiral ligands.
R1
R1
R1
R1
O
O
N
N
OH
OH
N
N
CH3
Ph
L3: R1 = Phenyl
L4: R1 = 2-Naphthyl
L1: R1 = Phenyl
L2: R1 =2-Naphthyl
R1
R1
O
N
OH
N
Ph
L5: R1 = Phenyl
L6: R1 = 2-Naphthyl
Figure 1. Designed mono-oxazoline ligands L1-6
2. Results and Discussion
The ligands L1-6 were prepared according to the procedure showed in Scheme 1. The dimethyl
pyridine-2,6-dicarboxylate 2 was obtained from the corresponding diacid 1. Mono-amidation of the
ester 2 with amino alcohols gave amides 3, which was cyclized in the presence of TsCl / Et3N in DCM
to give the compounds 4. After the reaction of compounds 4 with Grignard reagents, the final ligands 5
(L1-6) were obtained.
HO
R2
H2SO4
CH3OH
HO
OH
O
O
NH2
N
N
O
O
O
O
O
O
Toluene
reflux
1
2
H
N
O
TsCl, Et3N
CH2Cl2
O
O
N
OH
N
R2
O
N
3
R2
4
R1
R1
R1MgBr
THF
O
N
OH
N
R2
R1 = Phenyl, 2-Naphthyl; R2 = Methyl, Phenyl, Benzyl
5
Scheme 1. Synthetic route of ligands L1-6 from pyridine-2,6-dicarboxylic acid
With ligands L1-6 in hands, the enantioselective fluorination of β-ketoesters was investigated. At the beginning,
the enantioselective fluorination of methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate 6a was carried out in the
Page 2 of 21

presence of ligand L5 (12 mol %) and Ni(ClO4)2•6H2O (10 mol% ) in DCM at room temperature using NFSI as
fluorinating reagent. After 5 hours, the corresponding product 7a was obtained in 90% yield, but it was racemic
(Table 1, entry 1). The same reaction was next conducted at 0oC, and the product 7a was obtained in 92% yield
and 11% ee after 10 hours reaction (Table 1, entry 2). It seemed that the reaction temperature had great influence
on the ee value. Thus, the influence of temperature on the ee value was investigated. The results in Table 1 clearly
showed that the ee value of 7a was increased with the decrease of reaction temperature. When the temperature was
lowered to -60oC, the ee value of 7a was increased up to 75%. In order to further improve the ee value of 7a, the
effects of the solvents were checked again (Table 1, entries 5-11). The results showed that DCM was the most
suitable solvent. The reactions in other solvents, such as ethanol, methanol, chloroform and diethyl ether, gave 7a
in high yield but in low ee value. The reactions in toluene or THF gave the racemic product in high yield.
Table 1 Influence of temperature and solvents on the enantioselective fluorination reactiona
Ligand 5 (12 mol%)
O
O
.
Ni(ClO4)26H2O (10 mol%)
O
F
O
NFSI (1.2 equiv)
4Å MS, Solvent, -60oC
OMe
OMe
6a
7a
Entry
1
2
3
4
5
6
7
8
9
10
11
T (oC)
rt
Time (h) Solvents
Yield (%)b ee (%)c
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
90
92
90
88
90
88
88
85
87
83
87
0
0
10
12
14
14
14
14
14
14
14
14
11
23
43
75
11
17
16
67
0
-20
-45
-60
-60
-60
-60
-60
-60
-60
MeOH
CHCl3
Et2O
Toluene
THF
0
a Reaction conditions: Ni(ClO4)2•6H2O (10 mol%), ligand 5 (12 mol%), 4Å molecular sieves (50 mg) and 6a (0.25 mmol) were
dissolved in dry solvent (2 mL), and NFSI (0.3 mmol) was then added directly to the mixture. b Isolate yield; c The ee value of 7a
was determined by HPLC analysis with a Chiralcel AD-H column, 2-propanol-hexane (10 : 90), 1.0 mL/min, λ = 254 nm.
Under the optimized reaction temperature and solvent, the effects of ligands L1-6 were tested in the presence of
Ni(ClO4)2•6H2O. The results in Table 2 proved that the substituents on the oxazoline ring of the ligands had great
influence on the ee value of 7a (Table 2). When methyl or benzyl group was attached to the oxazoline ring of the
Page 3 of 21

ligands such as L1-4, the ee value of 7a was very low. When phenyl ring was connected to the oxazoline ring of
the ligands, the ee value of 7a was much better. The phenyl ring on the oxazoline can adjust their conformation by
π effect. Substrate will match better with the ligands in transition states of the reaction. For example, ligand L5
gave product 7a in 90% yield and 75% ee, and ligand L6 gave product 7a in 86% yield and 63% ee.
Next, we checked the influence of other metal catalysts on the ee value of 7a under the optimized reaction
temperature and solvent using L5 as the chiral ligand. It was found that all of the other metal catalysts except
-
Ni(ClO4)2•6H2O gave low ee value (Table 3). This due to the anion ClO4 is a very weak coordination ligand.
Thus, when Ni(ClO4)2•6H2O was used as catalyst, the β-ketoester can coordinated to the central metal better. A
more tight transition state can be formed in the reaction to give better enantioselectivty.
Table 2 Influence of different ligands L1-6 on the ee value of 7aa
O
Ligands (12 mol%)
Ni(ClO4)2.6H2O (10 mol%)
NFSI (1.2 equiv)
O
O
F
O
4Å MS, CH2Cl2, -60oC
OMe
OMe
6a
7a
O
N
O
N
N
OH
OH
N
L2
L1
CH3
CH3
Yieldb = 87%
Yieldb = 88%
eec
=
5%
eec
0%
=
O
O
N
N
OH
OH
N
N
L3
L4
Ph
Ph
Yieldb = 85%
eec
9%
Yieldb = 87%
eec = 13%
=
O
O
N
N
OH
N
OH
N
L6
L5
Ph
Ph
Yieldb = 86%
eec = 63%
Yieldb = 90%
eec = 75%
a
Reaction conditions: Ni(ClO4)2•6H2O (10 mol%), ligands (12 mol%), 4Å molecular sieves (50 mg) and 6a (0.25 mmol) were
b
dissolved in dry CH2Cl2 (2 mL) at room temperature, and NFSI (0.3 mmol) was then added directly to the mixture at -60°C.
c
Isolate yield; The ee value of 7a was determined by HPLC analysis with a Chiralcel AD-H column, 2-propanol-hexane (10 :
90), 1.0 mL/min, λ = 254 nm.
Page 4 of 21

Table 3 Influence of different metal catalysts on the enantioselective fluorination reactiona
Ligand 5 (12 mol%)
Cat. (10 mol%)
NFSI (1.2 equiv)
O
O
O
F
O
4Å MS, CH2Cl2, -60oC
OMe
OMe
6a
7a
Entry Lewis acid
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
Mg(OTf)2
Ni(ClO4)2•6H2O
Sc(OTf)3
Ni(acac)2
Ni(PPh3)2Cl2
Cu(OTf)2
81
90
85
83
87
84
81
86
15
75
17
5
13
11
11
0
Pd(OAc)2
Mg(ClO4)2
a Reaction conditions: Lewis acid (10 mol%), ligand 5 (12 mol%), 4Å molecular sieves (50 mg) and 6a (0.25 mmol) were mixed
b
in a flask at room temperature in dry CH2Cl2 (2 mL), and then NFSI (0.3 mmol) was added directly to the mixture at -60°C.
Isolate yield; c The ee value of of 7a was determined by HPLC analysis with a Chiralcel AD-H column, 2-propanol-hexane (10 :
90), 1.0 mL/min, λ = 254 nm.
Finally, the substrates scope was investigated under the optimized reaction conditions (Table 4). It was showed
that the alkoxy groups on β-ketoesters have great influence on ee value of the products. When sterically hindered
6d such as t-butoxyl group was used as substrate, the reaction gave racemic product 7d. The substrates with other
alkoxy groups such as methoxyl, ethoxyl, i-propoxyl and benzyloxyl groups gave the products in good ee values
and high yields. The substituents on phenyl ring of β-ketoesters had little influence on ee values of the products,
but phenyl ring itself had big influence on the ee values of the products. For example, when methyl 2-oxocyclo-
pentanecarboxylate (6l) was used, racemic product (7l) was obtained. Tetralone derivatives such as 6m and 6n
gave very low enantioselectivity (7m and 7n). The acyclic β-ketoester 6p gave 7p in 25% ee and 41% yield. The
acyclic product 7o was obtained in racemic.
Table 4 Scope of substrates investigated in the enantioselective fluorination reactiona
L5 (12 mol%)
Ni(ClO4)2.6H2O (10 mol%)
O
O
)
R1
R2
R1
R2
O
F
NFSI (1.2 equiv)
O
4Å MS, CH2Cl2, -60oC
)
OR3
(
(
OR3
n
n
n = 1,2
n = 1,2
7a-n
6a-n
Page 5 of 21

O
O
O
F
O
F
F
O
O
OPri
OEt
OMe
7c, 90% yieldb
78% eec
7b, 85% yieldb
77% eec
7a, 90% yieldb
75% eec
O
F
O
O
F
O
F
O
O
OBut
OBn
OMe
Cl
7d, 89% yieldb
0% eec
7e, 83% yieldb
78% eec
7f, 84% yieldb
77% eec
O
O
O
F
F
O
F
O
O
OBn
OBn
OMe
Br
Br
O
Cl
7g, 88% yieldb
77% eec
7h, 85% yieldb
71% eec
7i, 87%yieldb
71% eec
O
O
O
F
H3C
O
H3C
F
O
F
OMe
OBn
OMe
7k, 85% yieldb
78% eec
7j, 87% yieldb
71% eec
7l, 30% yieldb
0% eec
O
O
O
O
O
O
O
H
O
F
OMe
F
OBn
Ph
OEt
Ph
OEt
F
F
H3C
7p, 41% yieldb
25% eec
7n, 89% yieldb
0% eec
7m, 86% yieldb
13% eec
7o, 40% yieldb
0% eec
a
Reaction conditions: Ni(ClO4)2·6H2O (10 mol%), ligand 5 (12 mol%), 4Å molecular sieves (50 mg) and 6 (0.25 mmol) were
mixed in a flask at room temperature in dry CH2Cl2 (2 mL), and then NFSI (0.3 mmol) was added directly to the mixture at -
60°C. b Isolate yield; c The ee value of 7 was determined by HPLC analysis with a Chiralcel AD-H or OD-H column, 2-propanol-
hexane (10 : 90), 1.0 mL/min, λ = 254 nm.
3. Conclusions
A new type of mono-oxazoline ligands have been prepared and applied in the enantioselective electrophilic
fluorination of β-ketoesters. The results showed that good enantioselectivity can be reached when the ligand L5
was applied in enantioselective fluorination of β-ketoesters using NFSI as fluorination reagent. Further application
of the ligands will be investigated in other reactions.
4. Experimental
4.1. General
All the reactions were performed in flame-dried glassware under argon atmosphere. The solvents were distilled
by standard methods. Reagents were obtained from commercial suppliers and used without further purification
unless otherwise noted. Flash column chromatography was carried out using Qingdao silica Gel (230-400 mesh).
Page 6 of 21

Analytical thin layer chromatography (TLC) was done using Qingdao silica Gel (silica gel GF254). TLC plates
were analyzed by an exposure to ultraviolet (UV) light and/or submersion in phosphomolybdic acid solution or in
I2. 1HNMR, 13CNMR and 19F NMR spectra were recorded at 400 MHz and 100 MHz on Varian Mercury 400 plus
instrument, respectively. Chemical shifts are reported as δ values (ppm) relative to tetramethylsilane (TMS) for 1H
NMR and chloroform for 13C NMR. The following abbreviations are used for the multiplicities: s: singlet, d:
doublet, dd: doublet of doublet, t: triplet, q: quadruplet, m: multiplet, br: broad signal for proton spectra; Coupling
constants (J) are reported in Hertz (Hz). Melting points were uncorrected. Infrared spectra were recorded on an IR
spectrometer (Perkin Elmer BX FT-IR), and absorption frequencies were reported in reciprocal centimetres (cm-1).
The HRMS data were measured on MALDI-TOF type of instrument for the high resolution mass spectra. The
enantio- and diastereomeric excesses of products were determined by chiral HPLC analysis at 254 nm using the
indicated chiral column. The substrates 6a-6k, 6m were prepared according to literature procedures [8,9], 6l was
purchased from Alfa Aesar.
4.2 Preparation of Ligands L1-L6
4.2.1 General procedure for the synthesis of dimethyl pyridine-2,6-dicarboxylate 2
Pyridine-2,6-dicarboxylic acid (0.50 g, 2.9 mmol), 40 mL of methanol and four drops of concentrated sulfuric
acid were added in a flam-dried flask under Ar atmosphere. The mixture was refluxed for 9 hours, and then cooled
to room temperature. Saturated aqueous sodium carbonate (10 mL) and ethyl ether (10 mL) were then added to the
reaction mixture and stirred for 10 minutes. Organic layer was separated, and the aqueous phase was extracted
with ethyl ether (10 mL×3). The organic layer were combined, dried over anhydrous MgSO4 and then concentrated
under reduced pressure. The residue was purified by recrystallization from mixed solvent of ethyl acetate and
petroleum ether to afford product 2 in white solid (0.52 g, 91%); Mp: 127-128°C.
4.2.2 General procedure for the synthesis of monoamides 3
Page 7 of 21

A mixture of dimethyl pyridine-2,6-dicarboxylate 2 (0.04 mol) and chiral amino alcohols (0.04 mol ) in toluene
(200 mL) was stirred in a dried flask at 110°C for 24 hours. After cooled to room temperature, the mixture was
concentrated under reduced pressure, purified by flash column chromatography using petroleum ether : ethyl
acetate = 1 : 1 as eluent to give the desired product monoamides 3.
4.2.3 General procedure for the synthesis of mono-oxazolines 4
A solution of monoamide 3 (11.0 g, 0.036 mol), TsCl (10.0 g, 0.04 mol) and triethylamine (108.0 g, 1.1 mol) in
dry dichloromethane (60 mL) was stirred overnight at room temperature and then refluxed for 18 hours. After
cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was
purified by flash column chromatography using petroleum ether : ethyl acetate = 1 : 2 as eluent to obtain the
desired product mono-oxazolines 4.
4.2.4 General procedure for the synthesis of Ligands L1-L6
In an oven dried two neck 50 mL round-bottom flask equipped with magnetic stirrer and nitrogen inlet, the
mono-oxazoline 4 (2.1 mmol) dissolved in 10 mL of THF was added. The mixture was cooled to 0°C and a
solution of RMgBr (8 mmol) in THF was added dropwise under nitrogen atmosphere. The reaction mixture was
stirred for 1 hour at 0°C. After the reaction was completed (detected by TLC), it was quenched with saturated
NH4Cl (15 mL) and extracted with ethyl acetate (3×10 mL). The organic layer were combined, dried over
anhydrous MgSO4, and then concentrated under reduced pressure. The residue was purified by flash column
chromatography using petroleum ether : ethyl acetate = 1 : 2 as eluent to obtain the ligands L1-L6.
(S)-(6-(4-methyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl)diphenylmethanol (L1): White solid (yield 50%). mp: 64–65
1
oC; HNMR (CDCl3, 400 MHz): δ 8.14 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H),
7.36–7.22 (m, 10H), 5.30 (s, 1H), 4.27–4.21 (m, 1H), 3.77–3.60 (m, 2H) 1.27 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 163.2, 154.8, 144.9, 137.6, 136.9, 129.2, 128.6, 128.1, 124.7, 122.7, 80.8, 72.3, 68.1, 41.6;
Page 8 of 21

HRMS (ESI ) m/z calcd for C22H21N2O2 [M+H]+ = 345.1598, found 345.1593.
(S)-(6-(4-methyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl)di(naphthalen-2-yl)methanol (L2): White solid (yield 60%).
mp: 168-170 oC; 1HNMR (CDCl3, 400 MHz): δ 8.35 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0
Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.41–7.38 (m, 2H), 7.28–7.24 (m, 3H), 7.19–7.15 (m,
3H), 6.97 (d, J = 8.0 Hz, 1H), 6.63 (br, 1H), 4.60 (t, J = 8.8 Hz, 1H), 4.49–4.43 (m, 1H), 4.04 (t, J = 8.0 Hz, 1H),
1.41 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.9, 162.5, 145.6, 137.0, 134.9, 129.1, 128.4, 125.4,
125.3, 124.2, 122.9, 84.1, 74.5, 62.3, 21.3; HRMS (ESI) m/z calcd for C30H25N2O2 [M+H]+ = 445.1911, found
445.1914.
(S)-(6-(4-benzyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl)diphenylmethanol (L3): White solid (yield 50%). mp: 44–
48oC; IR (KBr): 3389, 1642, 1575, 1448, 1043; 1H NMR (CDCl3, 400 MHz): δ 8.00 (d, J = 7.6 Hz, 1H), 7.75–7.70
(m, 1H), 7.33–7.20 (m, 16H), 6.34 (s, 1H), 4.66–4.62 (m, 1H), 4.42 (t, J = 4.8 Hz, 1H), 4.22 (t, J = 7.6 Hz, 1H),
3.29–3.24 (m, 1H), 2.77–2.72 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 163.2, 162.8, 145.8, 144.9, 137.7, 136.9,
129.2, 128.6, 128.1, 127.9, 127.4, 126.6, 124.9, 122.7, 80.8, 72.3, 68.1, 41.7; HRMS ( ESI) m/z calcd for
C28H25N2O2 [M+H]+ = 421.1911, found 421.1906.
(S)-(6-(4-benzyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl)di(naphthalen-2-yl)methanol (L4): White solid (yield 47%).
o
mp: 56–58 C; IR (KBr): 3407, 1642, 1573, 1455, 1365, 1059, 803, 780, 704; 1H NMR (CDCl3, 400 MHz): δ
8.36–8.29 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.85–7.74 (m, 4H), 7.65–7.61 (m, 1H), 7.43–7.19 (m, 13H), 6.98 (d, J
= 8.0 Hz, 1H), 6.62 (s, 1H), 4.69–4.65 (m, 1H), 4.44 (t, J = 8.8 Hz, 1H ), 4.24 (t, J = 8.0 Hz, 1H), 3.33–3.20 (m,
1H), 2.83–2.77 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 163.9, 163.0, 145.5, 137.7, 137.1, 134.9, 129.2, 128.6,
128.4, 126.6, 125.4, 125.3, 124.1, 122.9, 84.1, 72.4, 68.1, 41.6; HRMS (ESI) m/z calcd for C36H29N2O2 [M+H]+ =
521.2224, found 521.2225.
(S)-diphenyl(6-(4-phenyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl)methanol (L5): White solid (yield 73%). mp: 56–58
Page 9 of 21

oC; 1H NMR (CDCl3, 400 MHz): δ 8.10 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.40–7.23 (m, 16H), 6.36 (s,
1H), 5.44 (t, J = 9.6 Hz, 1H), 4.87 (t, J = 8.4 Hz, 1H), 4.36 (t, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
163.7, 162.7, 145.8, 137.0, 128.8, 128.2, 128.1, 128.0, 127.9, 127.8, 127.4, 126.8, 125.2, 123.0, 81.0, 75.3, 70.3.
HRMS (ESI) m/z calcd for C27H23N2O2 [M+H]+ = 407.1754, found 407.1761.
(S)-di(naphthalen-2-yl)(6-(4-phenyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl)methanol (L6): White solid (yield 55%).
1
mp: 121–123 oC; H NMR (CDCl3, 400 MHz): δ 8.36 (t, J = 8.0 Hz, 2H), 8.15(d, J = 8.0 Hz, 1H), 7.85–7.78 (m,
4H), 7.63 (t, J = 8.0 Hz, 1H), 7.42–7.35 (m, 7H), 7.32–7.20 (m, 4H), 7.19–7.17 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H),
6.66 (s, 1H), 5.50–5.46 (m, 1H), 4.92–4.87 (m, 1H), 4.40–4.35(m, 1H); 13C NMR (CDCl3, 100 MHz) δ 164.0,
163.8, 145.3, 141.6, 137.1, 135.0, 132.0, 129.2, 129.1, 128.8, 128.4, 127.7, 127.5, 126.8, 125.9, 125.6, 125.3,
124.2, 123.1, 84.1, 75.2, 70.3; HRMS (ESI, pos. ) m/z calcd for C35H27N2O2 [M+H]+ = 507.2067, found 507.2072.
4.3 General Procedure for fluorination of β-ketoesters
Ni(ClO4)2•6H2O ( 10 mol%) and ligand 5 (12 mol%) were stirred in a dried flask under vacuum for 2 hours at
room temperature, and then 4Å molecular sieves (50 mg) and dry CH2Cl2 (2 mL) were added under argon
atmosphere and stirred for 1 hour. Substrate 6 (0.25 mmol) was added to the flask. After stirring for 30 minutes at -
60°C, N-fluorobenzenesulfonimide (NFSI; 1.2 equiv) was added directly to the mixture at -60°C. The reaction
mixture was stirred at -60°C for 14 hours, and then warmed to room temperature. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by flash column chromatography using
petroleum ether : ethyl acetate = 6 : 1 as eluent to obtain the desired products 7a-p.
Methyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7a): White solid (75% ee), mp 78–80°C , Rf = 0.3,
20
hexane/EtOAc = 6:1; [α]D = –19.6 (c = 0.13, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.7 Hz, 1H),
7.74–7.70 (m, 1H), 7.52–7.46 (m, 2H), 3.85–3.77 (m, 4H), 3.50–3.40 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
195.10 (d, J = 18.0 Hz), 167.76 (d, J = 28.0 Hz), 150.80 (d, J = 4.0 Hz), 136.76, 133.13, 128.63, 126.57, 125.63,
Page 10 of 21

94.56 (d, J = 200.0 Hz), 53.23, 38.18 (d, J = 24.0 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –165.77 (dd, J = 23.3,
11.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 10.8 min (major), t2 = 12.7
min (minor).
Ethyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7b): colourless oil (77% ee), Rf = 0.4, hexane/EtOAc
20
= 6:1; [α]D = –14.9 (c = 0.14, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 7.7 Hz, 1H), 7.73–7.69 (m,
1H), 7.52–7.45 (m, 2H), 4.28 (q, J = 21.4 Hz, 2H), 3.81 (dd, J = 17.6, 11.5 Hz, 1H), 3.46 (dd, J = 23.3, 17.6 Hz,
1H), 1.26 (t, J = 4.0 Hz, 3H ); 13C NMR (100 MHz, CDCl3): δ 195.24 (d, J = 18.1 Hz), 167.26 (d, J = 27.7 Hz),
150.86 (d, J = 3.6 Hz), 136.67, 133.25, 128.60, 126.56, 125.62, 94.46 (d, J = 201.6 Hz), 62.58, 38.22 (d, J = 23.9
Hz), 13.99; 19F-NMR (CDCl3, 376.5 MHz): δ –163.12 (dd, J = 23.3, 11.3 Hz); HPLC (Chiralcel AD-H, i-
PrOH/hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 13.1 min (major), t2 = 15.2min (minor).
Isopropyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7c): White solid (78% ee), mp 49–51°C , Rf
=
20
1
0.5, hexane/EtOAc = 6:1; [α]D = –10.8 (c = 0.12, CHCl3); H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.7 Hz,
1H), 7.73–7.69 (m, 1H), 7.52–7.45 (m, 2H), 5.14 (m, 1H), 3.78 (dd, J = 17.6, 11.7 Hz, 1H), 3.45 (dd, J = 23.3,
17.6 Hz, 1H), 1.25 (dd, J = 9.8, 6.4 Hz, 6H ); 13C NMR (100 MHz, CDCl3): δ 195.32 (d, J = 18.0 Hz), 166.8 (d, J
= 27.4 Hz), 150.90 (d, J = 3.6 Hz), 136.58, 133.27, 128.52, 126.52, 125.63, 94.36 (d, J = 201.5 Hz), 70.65, 38.19
(d, J = 24.0 Hz), 21.52, 21.40; 19F-NMR (CDCl3, 376.5 MHz): δ –163.00 (dd, J = 23.3, 11.7 Hz); HPLC (Chiralcel
AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 25.3 min (minor), t2 = 27.0min (major).
Tert-butyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7d): colourless oil (giving racemic 7d), Rf = 0.4,
hexane/EtOAc = 8:1; 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.7 Hz, 1H), 7.70–7.67 (m, 1H), 7.51–7.44 (m,
2H), 3.74 (dd, J = 17.5, 10.7 Hz, 1H), 3.42 (dd, J = 22.8, 17.5 Hz, 1H), 1.43 (s, 9H ); 13C NMR (100 MHz,
CDCl3): δ 195.30 (d, J = 18.0 Hz), 166.2 (d, J = 27.6 Hz), 150.94 (d, J = 3.7 Hz), 136.42, 133.56, 128.44, 126.43,
125.45, 94.32 (d, J = 199.3 Hz), 84.13, 38.30 (d, J = 24.1 Hz), 27.81; 19F NMR (CDCl3, 376.5 MHz): δ –162.68
Page 11 of 21

(dd, J = 23.0, 10.5 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 9.2 min, t2 =
10.5 min.
Benzyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7e): White solid (78% ee), mp 71–74 °C, Rf = 0.4,
20
1
hexane/EtOAc = 8:1; [α]D = –3.5 (c = 0.10, CHCl3); H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.7 Hz, 1H),
7.71–7.66 (m, 1H), 7.48–7.43 (m, 2H), 7.32–7.23 (m, 5H), 5.27 (d, J = 12.3 Hz, 1H), 5.20 (d, J = 12.3 Hz, 1H),
3.78 (dd, J = 16.9, 11.4 Hz, 1H), 3.44 (dd, J = 23.2, 17.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 194.96 (d, J =
18.4 Hz), 167.04 (d, J = 28.1 Hz), 150.71 (d, J = 3.6 Hz), 136.67, 134.58, 133.17, 128.58, 128.54, 128.47, 127.91,
126.53, 125.56, 94.52 (d, J = 201.9 Hz), 67.73, 38.13 (d, J = 23.8 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –163.14
(dd, J = 23.3, 11.7 Hz); HPLC (Chiralcel OD-H, i-PrOH/hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 15.02min
(major), t2 = 17.8 min (minor).
Methyl 5-chloro-2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7f): White solid (77% ee), mp 89–92°C ,
20
Rf = 0.4, hexane/EtOAc = 5:1; [α]D = –35.3 (c = 0.12, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0
Hz, 1H), 7.52 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 3.83–3.76 (m, 4H), 3.47 (dd, J = 23.3, 17.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 193.62 (d, J = 16.7 Hz), 167.25 (d, J = 27.4 Hz), 152.11 (d, J = 4.3 Hz), 143.41, 131.52,
129.49, 126.82, 126.62, 94.41 (d, J = 201.2 Hz), 53.23, 37.82 (d, J = 23.6 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –
166.93 (dd, J = 23.0, 11.0 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 15.8
min (minor), t2 = 17.7 min (major).
Benzyl 5-chloro-2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7g): White solid (77% ee), mp 86–89°C ,
Rf = 0.4, hexane/EtOAc = 5:1; [α]D20 = –12.4 (c = 0.12, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.2
Hz, 1H), 7.48–7.43 (m, 2H), 7.36–7.31 (m, 3H), 7.27–7.25 (m, 2H), 5.28 (d, J = 12.3 Hz, 1H), 5.21 (d, J = 12.3
Hz, 1H), 3.75 (dd, J = 17.9 11.3 Hz, 1H), 3.43 (dd, J = 22.8, 17.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 193.56
(d, J = 18.5 Hz), 167.73 (d, J = 28.1 Hz), 152.09 (d, J = 3.7 Hz), 143.45, 134.46, 131.67, 129.55, 128.64, 128.09,
Page 12 of 21

126.84, 126.71, 94.40 (d, J = 203.1 Hz), 68.00, 37.85 (d, J = 24.1 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –162.59
(dd, J = 23.0, 11.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 27.2 min
(minor), t2 = 28.9 min (major).
Methyl 5-bromo-2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7h): White solid (71% ee), mp 87–80°C,
20
Rf = 0.4, hexane/EtOAc = 5:1; [α]D = –19.8. (c = 0.16, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.71–7.69 (m,
2H), 7.63–7.61 (m, 1H), 3.82–3.76 (m, 4H), 3.47 (dd, J = 22.7, 18.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
193.89 (d, J = 18.2 Hz), 167.22 (d, J = 27.8 Hz), 152.13 (d, J = 3.8 Hz), 135.84, 132.42, 129.91, 128.43, 126.66,
94.33 (d, J = 202.6 Hz), 53.36, 37.76 (d, J = 24.2 Hz); 19 F-NMR (CDCl3, 376.5 MHz): δ –164.36 (dd, J = 23.0,
11.0 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 18.0 min (minor), t2 = 18.9
min (major).
Benzyl 5-bromo-2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7i): White solid (71% ee), mp 90–93°C ,
Rf = 0.4, hexane/EtOAc = 5:1; [α]D20 = –7.1 (c = 0.12, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.69–7.66 (m, 2H),
7.61–7.58 (m, 1H), 7.34–7.32 (m, 3H), 7.27–7.24 (m, 2H), 5.27 (d, J = 12.3 Hz, 1H), 5.21 (d, J = 12.3 Hz, 1H),
3.75 (dd, J = 17.8, 11.2 Hz, 1H), 3.42 (dd, J = 22.8, 17.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 193.79 (d, J =
18.2 Hz), 167.67 (d, J = 28.1 Hz), 152.11 (d, J = 3.7 Hz), 134.45, 132.38, 132.02, 129.90, 128.63, 128.07, 126.67,
94.31 (d, J = 203.2 Hz), 67.99, 37.75 (d, J = 24.3 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –166.15 (dd, J = 23.0,
11.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 24.3 min (minor), t2 = 26.1
min (major).
Methyl 2-fluoro-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7j): White solid (71% ee), mp 102–104°C
, Rf = 0.4, hexane/EtOAc = 8:1; [α]D20 = -18.3 (c = 0.12, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.53
(d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 3.80–3.72 (m, 4H), 3.41 (dd, J = 23.3, 17.5 Hz, 1H), 2.43 (s, 3H); 13
C
NMR (100 MHz, CDCl3): δ 195.11 (d, J = 18.2 Hz), 167.72 (d, J = 28.2 Hz), 148.21 (d, J = 3.8 Hz), 138.79,
Page 13 of 21

138.04, 133.24, 126.20, 125.38, 94.89 (d, J = 201.3 Hz), 53.14, 37.83 (d, J = 23.7 Hz), 21.02; 19F-NMR (CDCl3,
376.5 MHz): δ –163.10 (dd, J = 23.7, 11.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254
nm) t1 = 13.5 min (major), t2 = 14.8 min (minor).
Benzyl 2-fluoro-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7k): White solid (78% ee), mp 95–97°C,
Rf = 0.4, hexane/EtOAc = 8:1; [α]D20 = –9.7 (c = 0.13, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.61 (s, 1H) 7.49
(d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.32–7.23 (m, 5H), 5.26 (d, J = 12.3 Hz, 1H), 5.19 (d, J = 12.4 Hz,
1H), 3.72 (dd, J = 17.5, 11.4 Hz, 1H), 3.38 (dd, J = 23.1, 17.5 Hz, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 195.04 (d, J = 18.1 Hz), 167.16 (d, J = 28.2 Hz), 148.17 (d, J = 3.7 Hz), 138.76, 137.99, 134.62, 133.31, 128.54,
128.31, 127.93, 126.19, 125.40, 94.88 (d, J = 201.7 Hz), 67.68, 37.82 (d, J = 23.8 Hz), 24.80; 19F-NMR (CDCl3,
376.5 MHz): δ –162.95 (dd, J = 23.3, 11.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254
nm) t1 = 20.0 min (major), t2 = 22.7min (minor).
Methyl 1-fluoro-2-oxocyclopentanecarboxylate (7l): colourless oil (racemic 7l), Rf = 0.3, hexane/EtOAc = 4:1; 1H
NMR (400 MHz, CDCl3): δ 3.83 (s, 3H), 2.62–2.53 (m, 1H), 2.52–2.48 (m, 2H), 2.39–2.27 (m, 1H), 2.18–2.12 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 207.38 (d, J = 16.8 Hz), 167.81 (d, J = 27.7 Hz), 94.71 (d, J = 200.1 Hz)
52.98, 35.64, 33.84 (d, J = 20.8 Hz), 18.00 (d, J = 3.2 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –165.95 (t, J = 21.1
Hz); HPLC (Chiralcel OB-H, i-PrOH/hexane = 10/90, 1.0 mL/min, 220 nm) t1 = 23.7 min, t2 = 28.0 min.
Methyl 2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (7m): colourless oil (13% ee), Rf = 0.4,
1
hexane/EtOAc = 8:1; H NMR (400 MHz, CDCl3): δ 8.08–8.06 (m, 1H), 7.58–7.54 (m, 1H), 7.39–7.35 (m, 1H),
7.29 (d, J = 7.7 Hz, 1H), 3.83 (s, 3H), 3.23–3.05 (m, 2H), 2.79–2.67 (m, 1H), 2.60–2.50 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 188.44 (d, J = 19.0 Hz), 167.80 (d, J = 26.0 Hz), 143.11, 134.60, 130.40, 128.75, 128.47, 127.26,
93.26 (d, J = 192.8 Hz), 53.04, 31.82 (d, J = 22.1 Hz), 24.80 (d, J = 7.7 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –
166.63 (dd, J = 22.6, 11.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 10.3
Page 14 of 21

min (minor), t2 = 11.2 min (minor).
Benzyl 2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (7n): colourless oil (racemic 7n), Rf = 0.4,
1
hexane/EtOAc = 10:1; H NMR (400 MHz, CDCl3): δ 8.08–8.06 (m, 1H), 7.56–7.51 (m, 1H), 7.37–7.29 (m, 4H),
7.26–7.22 (m, 3H), 5.29 (d, J = 12.3 Hz, 1H), 5.21 (d, J = 12.3 Hz, 1H), 3.18–3.10 (m, 1H), 3.02–2.95 (m, 1H),
2.77–2.65 (m, 1H), 2.58–2.48 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 188.40 (d, J = 18.7 Hz), 167.12 (d, J =
26.3 Hz), 142.98, 134.62, 134.50, 129.50, 128.70, 128.51, 128.43, 128.35, 127.93, 127.19, 93.20 (d, J = 194.2 Hz),
67.63, 31.75 (d, J = 22.1 Hz), 24.73 (d, J = 7.3 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –166.99 (dd, J = 22.6, 11.0
Hz); HPLC (Chiralcel OD-H, i-PrOH/hexane = 10/90, 1.0 mL/min, 254 nm) t1 = 13.6 min, t2 = 16.2 min.
1
Ethyl 2-fluoro-3-oxo-3-phenylpropanoate (7o): colourless oil (racemic 7o), Rf = 0.3, hexane/EtOAc = 10:1; H
NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.67–7.62 (m, 1H), 7.53–7.49 (m, 2H), 5.88 (d, J = 48.8 Hz, 1H),
4.34–4.27 (m, 2H), 1.26 (t, J = 14.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 189.48 (d, J = 20.3 Hz), 167.85 (d, J
= 24.1 Hz), 134.51, 133.28, 129.50, 128.79, 90.00 (d, J = 197.5 Hz), 62.69, 13.91; 19F-NMR (CDCl3, 376.5 MHz):
δ –189.05 (d, J = 48.6 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane = 02/98, 1.0 mL/min, 254 nm) t1 = 10.2 min,
t2 = 11.6 min.
Ethyl 2-fluoro-2-methyl-3-oxo-3-phenylpropanoate (7p): colourless oil (25% ee ), Rf = 0.4, hexane/EtOAc = 20:1;
1H NMR (400 MHz, CDCl3): δ 7.68–7.27 (m, 5H), 4.29–4.22 (m, 2H), 1.90–1.85 (m, 3H), 1.20–1.17 (m, 3H); 13
C
NMR (100 MHz, CDCl3): δ 191.75 (d, J = 24.3 Hz), 168.55 (d, J = 24.1 Hz), 133.88, 130.94, 129.69, 128.93,
97.90 (d, J = 193.5 Hz), 62.55, 21.03 (d, J = 22.9 Hz), 13.83 (d, J = 6.8 Hz); 19F-NMR (CDCl3, 376.5 MHz): δ –
148.29; HPLC (Chiralcel OB-H, i-PrOH/hexane = 10/90, 0.5 mL/min, 254 nm) t1 = 14.0 min (major), t2 = 16.4 min
(minor).
Acknowledgements
We are thankful for financial support from the National Natural Science Foundation of China (Grant No.
Page 15 of 21

21262031); Key Laboratory Polymer Materials of Gansu Province (Northwest Normal University); Bioactive
Product Engineering Research Center for Gansu Distinctive Plants; and State Key Laboratory of Applied Organic
Chemistry, Lanzhou University.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
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5 For organocatalyzed asymmetric fluorination, see:
(a) X. Yang, R.J. Phipps, F.D. Toste, J. Am. Chem. Soc. 136(2014) 5225-5228;
(b) W.-T. Meng, Y. Zheng, J. Nie, H.-Y. Xiong, J.-A. Ma, J. Org. Chem. 78(2013) 559-567;
Page 17 of 21

(c) R.J. Phipps, K. Hiramatsu, F.D. Toste, J. Am. Chem. Soc. 134(2012) 8376-8379;
(d) P. Kwiatkowski, T.D. Beeson, J.C. Conrad, D.W.C. MacMillan, J. Am. Chem. Soc. 133(2011) 1738-1741;
(e) D.D. Steiner, N. Mase, C.F. Barbas III, Angew. Chem. Int. Ed. 44(2005) 3706-3710;
(f) T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura, T. Toru, M. Shiro, Angew. Chem. Int. Ed. 47(2008) 4157-
4161;
(g) O. Lozano, G. Blessley, T.M. del Campo, A.L. Thompson, G.T. Giuffredi, M. Bettati, M. Walker, R. Borman, V.
Gouverneur, Angew. Chem. Int. Ed. 50(2011) 8105-8109;
(h) T.D. Beeson, D.W.C. MacMillan, J. Am. Chem. Soc. 127(2005) 8826-8828;
(i) H. Cui, P. Li, Z. Chai, C. Zheng, G. Zhao, S. Zhu, J. Org. Chem. 74(2009) 1400-1402;
(j) V. Rauniyar, A.D. Lackner, G.L. Hamilton, F.D. Toste, Science 334(2011) 1681-1684.
6 (a) Q.-H. Deng, H. Wadepohl, L.H. Gade, Chem. Eur. J. 17(2011) 14922-14928;
(b) D.S. Reddy, N. Shibata, T. Horikawa, S. Suzuki, S. Nakamura, T. Toru, M. Shiro, Chem. Asian J. 4(2009) 1411-1415;
(c) J. Nie, H-W. Zhu, H.-F. Cui, M.-Q. Hua, J.-A. Ma, Org Lett. 9(2007) 3053-3056;
(d) J-A. Ma, D. Cahard, Tetrahedron: Asymmetry (2004)15 1007-1011;
(e) D.S. Reddy, N. Shibata, J. Nagai, S. Nakamura, T. Toru, S. Kanemasa, Angew. Chem. Int. Ed. 47(2008) 164-168.
7 (a) K. Shibatomi, A. Narayama, Y. Soga, T. Muto, S. Iwasa, Org. Lett. 13(2011) 2944-2947;
(b) K. Shibatomi, Y. Tsuzuki, S.-I. Nakata, Y. Sumikawa, S. Iwasa, Synlett 2007 551-554.
8 A.M. R. Smith, D. Billen, K.K. (Mimi)Hii, Chem. Commun. 2009 3925–3927.
9 A.M.R. Smith, H.S. Rzepa, A.J.P. White, K.K. (Mimi) Hii, J. Org. Chem. 75(2010) 3085–3096.
Page 18 of 21

Graphical Content
Enantioselective fluorination of β-ketoesters catalyzed
by complexes of new mono-oxazoline ligands
Teng Niu, Xiping Han, Danfeng Huang,* Ke-Hu Wang, Yingpeng
Su, Yulai Hu,* Ying Fu
L5 (12 mol%)
O
.
O
Ni(ClO4)2 6H2O (10 mol%)
R1
R2
R1
R2
O
NFSI (1.2 equiv)
F
O
4Å MS
CH2Cl2, -60oC
OR3
(
(
)
)
OR3
n
n
n = 1,2
n = 1,2
R1 = H, Me; R2 = H, Cl, Br;
R3 = Me, Et, Pri, But, Bn
Yield: up to 90%
Ee: up to 78%
Page 19 of 21

Graphical Content
Enantioselective fluorination of β-ketoesters catalyzed
by complexes of new mono-oxazoline ligands
Teng Niu, Xiping Han, Danfeng Huang,* Ke-Hu Wang, Yingpeng
Su, Yulai Hu,* Ying Fu
Enantioselective electrophilic fluorination of β-ketoesters by NFSI was investigated by using
new kind of chiral mono-oxazoline ligands(L1-L6), and moderate to good ee value were
obtained.
Page 20 of 21

Highlights
1. A new kind of mono-oxazoline ligands was prepared.
2. The ligands combined diaryl methyl units and chiral oxazoline ring
together.
3. Pyridine ring was used as the linker of the two units.
4. The ligands were applied in the enantioselective electrophilic
fluorination of β-ketoesters.
5. Moderate ee values were obtained.
Page 21 of 21