Cu(I)-catalyzed asymmetric chlorination of β-keto esters in the presence of chiral phosphine-schiff base type ligands

Article abstract of DOI:10.1002/chir.20913

Chiral phosphine-Schiff base type ligand L8 prepared from (R)-(-)-2-(diphenylphosphino)-1,1'-binaphthyl-2'-amine was found to be a fairly effective ligand for Cu(I)-promoted enantioselective chlorination of β-keto esters to give the corresponding products in high yields and with moderate enantioselectivities. Copyright

Full text of DOI:10.1002/chir.20913

CHIRALITY 23:272–276 (2011)
Cu(I)-Catalyzed Asymmetric Chlorination of b-Keto Esters in the
Presence of Chiral Phosphine-Schiff Base Type Ligands
JIA-JUN JIANG,1 JIAN HUANG,1 DE WANG,1 ZHI-LIANG YUAN,1 MEI-XIN ZHAO,1 FEI-JUN WANG,1 AND MIN SHI1,2
*
1Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering,
East China University of Science and Technology, Shanghai 200237, China
2State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
ABSTRACT
Chiral phosphine-Schiff base type ligand L8 prepared from (R)-(2)-2-(diphenyl-
phosphino)-1,1’-binaphthyl-2’-amine was found to be a fairly effective ligand for Cu(I)-promoted
enantioselective chlorination of b-keto esters to give the corresponding products in high yields
C
VV
and with moderate enantioselectivities. Chirality 23:272–276, 2011.
2010 Wiley-Liss, Inc.
KEY WORDS: enantioselective chlorination; b-keto esters; Cu(I)-catalyzed; phosphine-Schiff
base type ligands
Huanghai GF254 silica gel coated plates. Flash column chromatography
INTRODUCTION
was carried out using 300–400 mesh silica gel at increased pressure. All
reactions were performed under argon using standard Schlenk techni-
ques. Chiral HPLC was performed by using a SHIMADZU SPD-10A vp
series instrument with chiral columns (Chiralpak OJ-H, OD-H, and AD-H
columns, / 4.6 3 250 mm, Daicel Chemical) and the absolute configura-
tion of the major enantiomer was assigned according to the sign of the
specific rotation.33
Chiral phosphine-Schiff base type ligands L1-L6 were prepared
according to our previously reported procedure.32 Substrates 1a-1i were
prepared according to the literature.34 SI is available from the website or
from the authors.
The direct catalytic enantioselective functionalization of
carbon–hydrogen bonds to carbon-heteroatom bonds is an
important synthetic transformation.1 In particular, the enan-
tioselective electrophilic halogenation of dicarbonyl com-
pounds represents one of the best established strategies for
the construction of the chiral CÀÀX bonds in organic chemis-
try.2–5 The resulting chiral halogen-containing compounds
have attracted much attention in various research fields such
as biological and medicinal chemistry as well as material sci-
ence.6 The first enantioselective fluorination of b-keto esters
was reported by Togni and coworkers7–9 Following this pio-
neering work, Sodeoka and coworkers reported an efficient
enantioselective fluorination of various acyclic and cyclic
b-keto esters catalyzed by chiral BINAP-palladium com-
plexes.10–14 Other late transition metal complexes including
Cu(II), Ni(II), and Zn(II), which are complementary to the
palladium complexes, were also successfully applied to cata-
lyze asymmetric halogenation reactions.15–23 Moreover, or-
ganocatalytic asymmetric halogenation reactions have also
proven to be useful protocols for the asymmetric halogenation
of b-keto esters.24–31 However, in some cases, these methods
still suffer from some drawbacks including poor substrate-gen-
erality and low enantioselectivity. Thus, the development of
more general and practical methods is still highly challenging.
Previously, we reported the phosphine-Schiff base-Cu(I)-
catalyzed enantioselective Henry reaction.32 Herein, we will
demonstrate that these catalysts can also be used to effect
enantioselective chlorination of b-keto esters.
Typical Procedure of the Preparation of Chiral
Phosphine-Schiff Base Type Ligands L7 and L8
To
a solution of (R)-(2)-2-(diphenylphosphino)-1,1’-binaphthyl-2’-
amine (227 mg, 0.5 mmol) in absolute ethanol (4.0 mL) was added
salicylaldehydes (0.5 mmol) at room temperature and the reaction
mixture was stirred under reflux for 12 h. After cooling to room tempera-
ture, red precipitates settled out, which were filtered to give the corre-
sponding phosphine-Schiff base type ligands L7 and L8 as red solids.
(R,E)-3-((2’-(Diphenylphosphino)-1,1’-Binaphthyl-
2-ylimino)Methyl)Benzene-1,2-Diol L7
A red solid. Yield: 75%. Mp: 156–1588C; IR (CH2Cl2) m 3533, 3044,
2911, 1611, 1582, 1462, 1218, 745 cm21 1H NMR (CDCl3, TMS, 300
;
MHz) d 5.53 (s, 1H), 6.61-6.70 (m, 2H), 6.87-7.28 (m, 15H), 7.38-7.55
(m, 4H), 7.93-7.95 (m, 3H), 8.07 (d, J 5 9.0 Hz, 1H), 8.29 (s, 1H), 12.39
(s, 1H); 31P NMR (CDCl3, 121 MHz, 85% H3PO4) d -12.66; MS (ESI) m/z
574 (M111, 100); HRMS (ESI) Calcd. For C39H28NO2P (M1H1):
574.1936, found: 574.1920; [a]2D0 5 1108 (c 0.4, CHCl3).
(R,E)-3-((2’-(Diphenylphosphino)-1,1’-Binaphthyl-2-
ylimino)Methyl)-6-Nitrobenzene-1,2-Diol L8
EXPERIMENTAL
General Methods
A red solid. Yield: 55%. Mp: 165-167 8C; IR (CH2Cl2) m 3054, 2333,
1741, 1601, 1509, 1280, 1217, 1089, 818, 745, 694 cm21; 1H NMR (CDCl3,
TMS, 300 MHz) d 6.72 (d, J 5 8.7 Hz, 1H), 6.89-6.99 (m, 5H), 7.04-7.33
MP was obtained with a Yanagimoto micro melting point apparatus
and is uncorrected. Optical rotations were determined in a solution of
CHCl3 at 208C by using a Perkin–Elmer-241 MC polarimeter; [a]D-values
are given in units of 1021 deg cm2 g21. Infra-red spectra were measured
on a spectrometer. 1H NMR spectra and 31P NMR spectra were recorded
on a Bruker AM-400 spectrometer for solution in CDCl3 with tetrame-
thylsilane (TMS) as an internal standard. Mass spectra were recorded
with a HP-5989 instrument and HRMS was measured by a Finnigan
MA1 mass spectrometer. Organic solvents used were dried by standard
methods when necessary. Commercially obtained reagents were used
without further purification. All reactions were monitored by TLC with
Additional Supporting Information may be found in the online version of this
article.
*Correspondence to: Min Shi, Key Laboratory for Advanced Materials and
Institute of Fine Chemicals, School of Chemistry & Molecular Engineering,
East China University of Science and Technology, 130 Mei Long Lu, Shang-
hai 200237, China. E-mail: Mshi@mail.sioc.ac.cn
Received for publication 18 March 2010; Accepted 1 July 2010
DOI: 10.1002/chir.20913
Published online 11 October 2010 in Wiley Online Library
(wileyonlinelibrary.com).
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VV
2010 Wiley-Liss, Inc.

ASYMMETRIC CHLORINATION OF ꢀ-KETO ESTERS
273
(m, 9H), 7.44-7.54 (m, 4H), 7.67 (d, J 5 9.0 Hz, 1H), 7.97-8.03 (m, 3H),
8.15 (d, J 5 8.4 Hz, 1H), 9.17 (s, 1H), 15.22 (s, 1H); 31P NMR (CDCl3,
121 MHz, 85% H3PO4) d -13.11; MS (ESI) m/z 619 (M111, 100); HRMS
(ESI) Calcd. For C39H27N2O4P (M1H1): 619.1787, found: 619.1792;
[a]2D0 5 -221 (c 0.4, CHCl3).
1H NMR (400 MHz, CDCl3) d 3.54 (d, J 5 18.0 Hz, 1H), 3.82 (s, 3H),
4.10 (d, J 5 18.0 Hz, 1H), 7.62 (d, J 5 8.4 Hz, 1H), 7.68 (s, 1H), 7.72
(d, J 5 8.4 Hz, 1H).
(1)-5-Bromo-2-Chloro-1-Oxo-Indan-2-Carboxylic
Acid Tert-Butyl Ester (2f)
General Procedure for the Catalytic Enantioselective
A pale yellow solid. Yield 90%. A known product.33 [a]D20 5 116 (c
1.75, CHCl3, 52% ee). HPLC (DAICEL CHIRALPAK OJ-H, hexane/
iPrOH 5 90/10, 0.7 ml/min, 254 nm) tr (major) 5 11.21 min, tr (minor)
5 12.12 min.
Chlorination of b-Keto Esters
˚
To a Schlenk tube of ligand L8 (12.4 mg, 0.02 mmol) and 4 A molecu-
lar sieves (10 mg) in DCE (1.0 mL) was added CuOTfÁ1/2C6H6 (5.0 mg,
0.02 mmol), the resulting solution was stirred at room temperature for 30
minutes. Then the reaction tube was allowed to cool down to 08C followed
by the addition of the b-keto esters 1 (0.2 mmol) and the reaction mixture
was stirred for another 15 minutes. Finally, NCS (32 mg, 0.24 mmol) was
added to the solution and the resulting mixture was stirred for 2 h. After
completion of the reaction, saturated aqueous NH4Cl solution was added
for quenching the reaction. The aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with brine. After drying over
anhydrous Na2SO4, the solvent was removed under reduced pressure.
Further purification of the residue was performed by flash column chro-
matography on SiO2 (PE/EtOAc 5 10/1) to give the pure product 2. The
ee of the product 2 was determined by chiral HPLC analysis.
1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H), 3.51 (d, J 5 18.0 Hz, 1H),
4.00 (d, J 5 18.0 Hz, 1H), 7.61 (d, J 5 8.0 Hz, 1H), 7.66 (s, 1H), 7.71
(d, J 5 8.0 Hz, 1H).
(1)-2,5-Dichloro-1-Oxo-Indan-2-Carboxylic
Acid Methyl Ester (2g)
A white solid. Yield 99%. A known product.33 [a]D20 5 146 (c 1.35,
CHCl3, 82% ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/iPrOH 5
90/10, 0.65 ml/min, 254 nm) tr (minor) 5 14.44 min, tr (major) 5 16.25 min.
1H NMR (400 MHz, CDCl3) d 3.54 (d, J 5 18.0 Hz, 1H), 3.83 (s, 3H),
4.09 (d, J 5 18.0 Hz, 1H), 7.46 (d, J 5 8.0 Hz, 1H), 7.49 (s, 1H), 7.80
(d, J 5 8.0 Hz, 1H).
(1)-2-Chloro-1-Oxo-Indan-2-Carboxylic Acid
(1)-2,5-Dichloro-1-Oxo-Indan-2-Carboxylic
Methyl Ester (2a)
Acid Tert-Butyl Ester (2h)
A pale yellow oil. Yield 99%. A known product.33 [a]D20 5 151 (c 1.05,
CHCl3, 75% ee). HPLC (DAICEL CHIRALPAK AD-H, hexane/iPrOH 5
95/5, 0.75 ml/min, 230 nm) tr (major) 5 13.53 min, tr (minor) 5
14.57 min.
A pale yellow solid. Yield 99%. A known product.33 [a]D20 5 120
(c 1.70, CHCl3, 58% ee). HPLC (DAICEL CHIRALPAK OJ-H, hexane/
iPrOH 5 90/10, 0.7 ml/min, 254 nm) tr (major) 5 10.15 min, tr (minor)
5 11.54 min.
1H NMR (400 MHz, CDCl3) d 3.57 (d, J 5 17.6 Hz, 1H), 3.82 (s, 3H),
4.11 (d, J 5 17.6 Hz, 1H), 7.48 (t, J 5 8.0 Hz, 2H), 7.71 (t, J 5 7.2 Hz,
1H), 7.86 (d, J 5 8.0 Hz, 1H).
1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H), 3.51 (d, J 5 18.0 Hz, 1H),
4.00 (d, J 5 18.0 Hz, 1H), 7.45 (d, J 5 8.0 Hz, 1H), 7.48 (s, 1H), 7.79
(d, J 5 8.0 Hz, 1H).
(1)-2-Chloro-1-Oxo-Indan-2-Carboxylic
(1)-2-Chloro-5,6-Dimethoxy-1-Oxo-Indan-2-Carboxylic
Acid Isopropyl Ester (2b)
Acid Methyl Ester (2i)
A pale yellow oil. Yield 99%. A known product.33 [a]D20 5 136 (c 0.95,
CHCl3, 77% ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/iPrOH 5
95/5, 0.7 ml/min, 230 nm) tr (minor) 5 9.62 min, tr (major) 5 10.10 min.
1H NMR (300 MHz, CDCl3) d 1.23 (s, 3H), 1.26 (s, 3H), 3.56 (d, J 5
17.7 Hz, 1H), 4.07 (d, J 5 17.7 Hz, 1H), 5.04-5.16 (m, 1H), 7.48 (t, J 5
7.5 Hz, 2H), 7.71 (t, J 5 7.5 Hz, 1H), 7.86 (d, J 5 7.5 Hz, 1H).
A pale yellow solid. Yield 78%. A known product.33 [a]D20 5 130
(c 1.15, CHCl3, 67% ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/
iPrOH 5 80/20, 0.7 ml/min, 254 nm) tr (minor) 5 20.00 min, tr (major)
5 22.32 min.
1H NMR (400 MHz, CDCl3) d 3.48 (d, J 5 17.2 Hz, 1H), 3.82 (s, 3H),
3.93 (s, 3H), 4.00 (s, 3H), 4.03 (d, J 5 17.2 Hz, 1H), 6.88 (s, 1H), 7.24
(s, 1H).
(1)-2-Chloro-1-Oxo-Indan-2-Carboxylic
Acid Benzyl Ester (2c)
(1)-2-Chloro-5,6-Dimethoxy-1-Oxo-Indan-2-Carboxylic
A pale yellow oil. Yield 87%. A known product.33 [a]D20 5 133 (c 1.60,
CHCl3, 81% ee). HPLC (DAICEL CHIRALPAK AD-H, hexane/iPrOH 5
70/30, 0.6 ml/min, 230 nm) tr (minor) 5 11.88 min, tr (major) 5 12.67 min.
1H NMR (300 MHz, CDCl3) d 3.56 (d, J 5 18.0 Hz, 1H), 4.07 (d, J 5
18.0 Hz, 1H), 5.21 (d, J 5 12.6 Hz, 1H), 5.27 (d, J 5 12.6 Hz, 1H),
7.26-7.34 (m, 5H), 7.45-7.49 (m, 2H), 7.69 (t, J 5 7.5 Hz, 1H), 7.86 (d, J 5
8.1 Hz, 1H).
Acid Tert-Butyl Ester (2j)
A white solid. Yield 79%. A known product.33 [a]D20 5 111 (c 1.65,
CHCl3, 50% ee). HPLC (DAICEL CHIRALPAK OJ-H, hexane/iPrOH 5
80/20, 0.7 ml/min, 254 nm) tr (minor) 5 29.34 min, tr (major) 5 34.97 min.
1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H), 3.45 (d, J 5 17.6 Hz, 1H),
3.931 (s, 3H), 3.934 (d, J 5 17.6 Hz, 1H), 4.00 (s, 3H), 6.88 (s, 1H), 7.24
(s, 1H).
(1)-2-Chloro-1-Oxo-Indan-2-Carboxylic
(1)-2-Chloro-1-Oxo-1,2,3,4-Tetrahydro-Naphthalene-
Acid Tert-Butyl Ester (2d)
2-Carboxylic Acid Methyl Ester (2k)
A white solid. Yield 92%. A known product.33 [a]D20 5 125 (c 0.70,
CHCl3, 67% ee). HPLC (DAICEL CHIRALPAK OJ-H, hexane/iPrOH 5
70/30, 0.7 ml/min, 230 nm) tr (major) 5 8.90 min, tr (minor) 5 10.70 min.
1H NMR (300 MHz, CDCl3) d 1.43 (s, 9H), 3.54 (d, J 5 18.0 Hz, 1H),
4.02 (d, J 5 18.0 Hz, 1H), 7.47 (t, J 5 7.8 Hz, 2H), 7.70 (t, J 5 7.8 Hz,
1H), 7.86 (d, J 5 7.8 Hz, 1H).
A pale yellow oil. Yield 99%. A known product.33 [a]D20 5 112 (c 1.35,
CHCl3, 34% ee). HPLC (DAICEL CHIRALPAK IC-H, hexane/iPrOH 5
90/10, 0.8 ml/min, 230 nm) tr (major) 5 21.75 min, tr (minor) 5 26.85 min.
1H NMR (400 MHz, CDCl3) d 2.51-2.57 (m, 1H), 2.97-3.05 (m, 2H),
3.25-3.32 (m, 1H), 3.86 (s, 3H), 7.28 (d, J 5 7.2 Hz, 1H), 7.37 (t, J 5
7.6 Hz, 1H), 7.55 (t, J 5 7.6 Hz, 1H), 8.10 (d, J 5 8.0 Hz, 1H).
(1)-5-Bromo-2-Chloro-1-Oxo-Indan-2-Carboxylic
(1)-1-Chloro-2-Oxo-Cyclopentanecarboxylic
Acid Methyl Ester (2e)
Acid Tert-Butyl Ester (2l)
A white solid. Yield 99%. A known product.33 [a]D20 5 132 (c 1.35,
CHCl3, 71% ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/iPrOH 5
90/10, 0.7 ml/min, 254 nm) tr (minor) 5 17.34 min, tr (major) 5 20.54 min.
A pale yellow oil. Yield 63%. [a]2D0 5 10.6 (c 0.75, CHCl3, 12% ee).
HPLC (DAICEL CHIRALPAK OJ-H, hexane/iPrOH 5 90/10, 0.6 ml/min,
230 nm) tr (minor) 5 8.36 min, tr (major) 5 8.69 min.
Chirality DOI 10.1002/chir

274
JIANG ET AL.
1H NMR (300 MHz, CDCl3) d 1.49 (s, 9H), 2.06-2.17 (m, 2H), 2.33-2.45
TABLE 1. Optimization of the reaction conditions in the
asymmetric chlorination of b-keto ester 1a and electropjilic
chlorinating reagents 3
(m, 2H), 2.48-2.59 (m, 1H), 2.66-2.76 (m, 1H). 13C NMR (100 MHz,
CDCl3) d 19.1, 27.7, 35.4, 38.4, 70.3, 84.1, 166.0, 206.6. IR (CHCl3)
m 2981, 2936, 1748, 1719, 1591, 1459, 1396, 1371, 1256, 1143, 1003, 970
cm21. MS (EI) m/z 218.1 (M1, 4), 162.0 (67), 145.0 (45), 134.0 (60),
117.0 (39), 89.0 (27), 57.1 (100), 41.0 (18). HRMS (EI) Calcd. for
C10H15ClO3: 218.0710, Found: 218.0715.
Entrya
Lewis acid
3
Ligand Yield (%)b ee (%)c
(1)-Methyl 5-Chloro-2-Fluoro-1-Oxo-2,3-
Dihydro-1H-Indene-2-Carboxylate (2n)
A white solid. Yield 75%. [a]2D0 5 113 (c 0.25, CHCl3, 17% ee). HPLC
(DAICEL CHIRALPAK OD-H, hexane/iPrOH 5 95/5, 0.9 ml/min, 254
nm) tr (minor) 5 15.38 min, tr (major) 5 18.09 min.
1
2
3
4
5
6
7
8
9
CuOTfÁ1/2C6H6 NCS (3a)
L1
L2
L3
L4
L5
L6
L7
L8
L8
99
99
99
99
99
99
99
99
99
10 (2)
5 (2)
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
CuOTfÁ1/2C6H6
3a
3a
3a
3a
3a
3a
3a
18 (2)
33 (1)
16 (2)
30 (1)
35 (1)
68 (1)
3 (1)
1H NMR (400 MHz, CDCl3) d 3.42 (dd, J 5 22.8, 17.6 Hz, 1H), 3.78
(dd, J 5 17.6, 10.8 Hz, 1H), 3.82 (s, 3H), 7.46 (d, J 5 8.4 Hz, 1H), 7.51
(s, 1H), 7.78 (d, J 5 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 37.9 (d,
J 5 24.1 Hz), 53.4, 94.5 (d, J 5 200.7 Hz), 126.7, 126.9 (d, J 5 1.6 Hz),
129.6, 131.6, 143.5, 152.1 (d, J 5 3.4 Hz), 167.3 (d, J 5 27.6 Hz), 193.6
(d, J 5 18.3 Hz). 19F NMR (376 MHz, CDCl3, CF3COOH) d -164.0. IR
(CHCl3) m 2954, 2924, 2855, 1776, 1732, 1600, 1456, 1377, 1209 cm21
.
10
11
12
Cu(OTf)2
AgOAc
3a
3a
3a
L8
L8
L8
99
99
99
30 (1)
MS (ESI) m/z 265 (M11Na). HRMS (ESI) Calcd. for C11H8O3FClNa:
0
0
265.0044, Found: 265.0044.
Pd(OAc)2
aReaction conditions: 1a (0.2 mmol), 3 (0.24 mmol), Lewis acid (10 mol %),
Ligand (10 mol %), 4A MS (10 mg), CH2Cl2 (1.0 ml) and the reaction was car-
ried out 08C for 2 h.
RESULTS AND DISCUSSION
Synthesis of Chiral Phosphine-Schiff Base Type Ligands
bIsolated yield.
Chiral phosphine-Schiff base type ligands L1-L8 were syn-
thesized from the reaction of salicylaldehydes as well as its
analogues with (R)-(2)-2-(diphenylphosphino)-1,1’-binaphthyl-
2’-amine35,36 in absolute ethanol under reflux for 12 h, respec-
tively. After usual workup, these ligands can be obtained in
good yields (Scheme 1).
cDetermined by chiral HPLC analysis. The absolute configuration of the prod-
ucts was assigned by comparison with literature compounds.
˚
found that using CH2Cl2 as a solvent and 4 A MS (10 mg) as
an additive, the corresponding product 2a was obtained in
high yields at 08C and up to 68% ee was achieved using L8
as the ligand (Table 1, entries 1-8). Another electrophilic
chlorinating reagent 3b31 was also examined in this reaction,
giving the corresponding product 2a in very low ee (Table 1,
entry 9). By screening various Lewis acids such as AgOAc,
Cu(OTf)2, and Pd(OAc)2 in this asymmetric reaction, we
found that using CuOTf.1/2C6H6 as a Lewis acid gave the
best result, affording the product 2a in 68% ee and 99% yield
(Table 1, entries 9-12). It should be noted that chiral phos-
phine-salen type ligand L8, bearing a strong electron-with-
drawing such as NO2 substituent on the benzene ring, gave
the best result under identical conditions (Table 1, entry 8).
In addition, an electron-donating group or a weak electron-
withdrawing group on the benzene ring such as chiral phos-
phine-Schiff base type ligands L1-L7 gave the corresponding
product 2a in lower ees (5–35%) and good yields (Table 1,
entries 1-7). These results suggested that the substituent on
the benzene ring in the chiral phosphine-Schiff base type
ligands played a very important role in chiral induction in
this enantioselective chlorination of b-keto esters.
Cu(I)-catalyzed Asymmetric Chlorination of b-Keto
Esters in the Presence of Chiral
Phosphine-Schiff Base Type Ligands
Initial examinations using b-keto ester 1a and N-chloro-
succinimide (NCS) as the substrates in the presence of a
Lewis acid CuOTf.1/2C6H6 (10 mol %) combined with vari-
ous chiral phosphine-Schiff base type ligands L1-L8 (10 mol
%) were aimed at determining the optimal conditions; the
results of these experiments are summarized in Table 1. We
Using chiral phosphine-Schiff base type ligand L8 under
the standard conditions, we next examined the solvent and
temperature effects in this asymmetric reaction. The results
are summarized in Table 2. We found that DCE is the best
solvent, affording product 2a in 75% ee and 99% yield at 08C
(Table 2, entries 3 and 6-9). Lowering or elevating the reac-
tion temperature resulted in a decrease of the ee of the prod-
uct 2a (Table 2, entries 1-5). It should be noted that molecu-
˚
lar sieves 4 A are crucial for this enantioselective chlorination
˚
of b-keto esters because in the absence of MS 4 A, no ee
could be observed under identical conditions (Table 2,
˚
entries 10). Using 100 mg of MS 4 A as additives, no
Scheme 1. Preparation of phosphine-Schiff base type ligands L1-L8.
Chirality DOI 10.1002/chir

ASYMMETRIC CHLORINATION OF ꢀ-KETO ESTERS
TABLE 2. Optimization of the reaction conditions in the
275
asymmetric chlorination of b-keto ester 1a and
N-chlorosuccinimide (NCS)
Entrya
Solvent
T (8C)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Toluene
DCE
20
10
0
210
220
0
99
99
99
99
99
99
99
99
99
99
99
25 (1)
30 (1)
68 (1)
40 (1)
37 (1)
0
0
0
0
0
0
75 (1)
20 (1)
0
CHCl3
DCE
DCE
10d
11e
0
43 (1)
aReaction conditions: 1a (0.2 mmol), NCS (0.24 mmol), CuOTfÁ1/2C6H6 (10
mol %), L8 (10 mol %), 4A MS (10 mg), solvent (1.0 ml) and the reaction was
carried out for 2 h.
Scheme 2. Lewis acid catalyzed asymmetric halogenation of substrates
1k, 1l, 1m, and 1n.
bIsolated yield.
cDetermined by chiral HPLC analysis. The absolute configuration of the prod-
ucts was assigned by comparison with literature compounds.
dIn the absence of 4A MS.
e4A MS (100 mg) was added.
With these optimal reaction conditions in hand, a series of
b-keto esters 1a-1j with various substituents in the ester
group and on the aromatic scaffold were used to further
explore the substrate scope (Table 3). It was found that for
substrates 1a-1d with different ester groups, the correspond-
ing products 2a-2d were obtained in moderate enantiose-
lectivities (67–81% ee) and good yields (Table 3, entries 1-
4). Substrates 1e-1h bearing electron-withdrawing Cl or Br
atom and substrates 1i and 1j having electron-donating
such as MeO substituent on the benzene ring also pro-
duced the products 2e-2j in 78–99% yields and 50–82% ees
in this enantioselective chlorination of b-keto esters, indi-
cating a wide substrate scope in this reaction (Table 3,
entries 5-10). Furthermore, tetralone b-keto ester 1k and
cyclopentanone b-keto ester 1l were also used as sub-
strates in this enantioselective chlorination under the
standard conditions. However, it was found that the corre-
sponding products 2k and 2l were obtained in good yields
but with 34% ee and 12% ee, respectively (Scheme 2). In
the case of acyclic b-keto ester 1m, the product 2m was
formed in high yield without any enantioselectivity
(Scheme 2). On the other hand, the extension of the cata-
lytic system to the Lewis acid catalyzed asymmetric fluori-
nation of b-keto esters was also evaluated under the stand-
ard conditions. It was found that as for substrate 1n, the
corresponding product 2n was obtained in 75% yield and
17% ee using N-fluorodibenzenesulfonimide (NFSI) as the
fluorinating reagent. Further studies to improve the
efficiency of the present catalytic system in enantioselec-
tive fluorination of b-keto esters are undergoing in our lab-
oratories (Scheme 2).
significant improvement could be realized (Table 2, entry
11). The effect of MS 4 A is not clear at the present stage.
However, on the basis of previous investigation, it may be
attributed to the ability of molecular sieves to serve as a
Br/nsted base and to improve the catalyst stability.37
˚
Therefore, the best reaction conditions are to carry out the
reaction in DCE using CuOTf.1/2C6H6 (10 mol %) as a Lewis
˚
acid and 4 A MS (10 mg) as an additive, as well as N-chloro-
succinimide (NCS) as the halogen source in the presence of
phosphine-Schiff base type ligand L8 (10 mol %) at 08C.
TABLE 3. Asymmetric chlorination of b-keto esters 1 and
N-chlorosuccinimide (NCS) under the optimal conditions
Entrya
Substrate
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a, R1 5 Me, R2 5 R3 5 H
1b, R1 5 iPr, R2 5 R3 5 H
1c, R1 5 Bn, R2 5 R3 5 H
1d, R1 5 tBu, R2 5 R3 5 H
1e, R1 5 Me, R2 5 Br, R3 5 H
1f, R1 5 tBu, R2 5 Br, R3 5 H
1g, R1 5 Me, R2 5 Cl, R3 5 H
1h, R1 5 tBu, R2 5 Cl, R3 5 H
1i, R1 5 Me, R2 5 R3 5 OMe
1j, R1 5 tBu, R2 5 R3 5 OMe
2a, 99
2b, 99
2c, 87
2d, 92
2e, 99
2f, 90
2g, 99
2h, 99
2i, 78
2j, 79
75 (1)
77 (1)
81 (1)
67 (1)
71 (1)
52 (1)
82 (1)
58 (1)
67 (1)
50 (1)
9d
10d
Although the real active species has not yet been fully
understood, we believe that Cu(I) can be potentially coor-
dinated with the N, O, and P atoms in ligand L8 as we
proposed in our previous paper.32 A plausible reaction
mechanism for this asymmetric reaction is outlined in
Scheme 3. These interactions control the stereochemical
outcome of the reaction and subsequently accelerate the
reaction rate.
aReaction conditions: 1 (0.2 mmol), NCS (0.24 mmol), CuOTfÁ1/2C6H6 (10
mol %), L8 (10 mol %), 4A MS (10 mg), DCE (1.0 ml) and the reaction was
carried out 08C for 2 h.
bIsolated yield.
cDetermined by chiral HPLC analysis. The absolute configuration of the prod-
ucts was assigned by comparison with the literature compounds.
dThe reaction was performed for 24 h.
Chirality DOI 10.1002/chir

276
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Chirality DOI 10.1002/chir