Synthesis of novel chiral oxazoline-Schiff base ligands for the catalytic asymmetric chlorination of β-keto esters

Article abstract of DOI:10.1016/j.tetasy.2010.02.003

A series of novel monooxazoline-Schiff base ligands 1 has been successfully synthesized. The Cu(I)-1a complex showed excellent catalytic activities with up to 83% ee for the asymmetric α-chlorination of β-keto esters.

Full text of DOI:10.1016/j.tetasy.2010.02.003

Tetrahedron: Asymmetry 21 (2010) 247–253
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of novel chiral oxazoline-Schiff base ligands for the catalytic
asymmetric chlorination of b-keto esters
a,b,
Ming-Hui Qi a, Fei-Jun Wang a, , Min Shi
*
*
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130
MeiLong Road, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 December 2009
Accepted 1 February 2010
A series of novel monooxazoline-Schiff base ligands 1 has been successfully synthesized. The Cu(I)–1a
complex showed excellent catalytic activities with up to 83% ee for the asymmetric
a-chlorination of
b-keto esters.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
1a: R1 = R2 = H
1b: R1 = R2 = tBu
1c: R1 = R2 = Cl
N
Chiral halogen-containing compounds have attracted much
attention in various research fields such as biological and medicinal
chemistry as well as materials science.1 The effective construction of
carbon–halogen stereogenicity by electrophilic halogenation of car-
bonyl compounds has recently become the focus of intense research
efforts in synthetic organic chemistry.2
Ph
Ph
HO
R2
1d: R1 = OH, R2 = H
R1
O
N
O
Since the initial reports by Togni et al.,3 catalytic enantioselec-
tive halogenation reactions have attracted much attention.4 With
the development of Pd-catalyzed fluorination reactions of b-keto
esters with high enantioselectivities on the basis of palladium eno-
late chemistry,5 other late transition metal complexes including
Cu(II), Ni(II), and Zn(II) were also successfully applied to catalyze
asymmetric halogenation reactions.6 Moreover, organocatalyst-
catalyzed asymmetric halogenation reactions have also proven to
N
N
N
Cl
Ph
1e
HO
1f Cl
O
N
N
be useful protocols for the asymmetric
a-halogenation of b-keto
esters.7 However, in some cases, these methods still suffer from
some drawbacks including poor substrate-generality and low
enantioselectivity. Thus, the development of more general and
practical methods is still highly challenging. On the basis of a liter-
ature survey, we found that oxazoline ligands have been success-
fully applied in the Cu-catalyzed enantioselective aldol-type
addition of the enolate formed from keto esters with a variety of
electrophiles including a keto ester itself,6a,b,8 and has also recently
been used in the transition metal-catalyzed asymmetric halogena-
tion.9 Herein, we report the synthesis of a type of novel chiral oxaz-
oline-Schiff base ligands (Fig. 1) and their applications in the Cu-
HO
1g
Figure 1. Novel oxazoline-Schiff base ligands.
2. Results and discussion
Chiral oxazoline-Schiff base ligand 1a was synthesized accord-
ing to the procedure shown in Scheme 1. First, Fmoc-oxazoline
amine 2a was prepared in 92% yield from commercially available
catalyzed asymmetric
der mild conditions.
a-chlorination reaction of b-keto esters un-
N-Fmoc-L-valine with (S)-2-amino-2-phenylethanol under stan-
dard conditions. Then, removal of the Fmoc-protecting group affor-
ded oxazoline amine 3a in 95% yield.10 Finally, compound 3a was
converted into the desired oxazoline-Schiff base ligand 1a in mod-
erate yield by reaction with salicylaldehyde under basic conditions
(45% total yield for three steps).
* Corresponding authors.
E-mail address: Mshi@mail.sioc.ac.cn (M. Shi).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.003

248
M.-H. Qi et al. / Tetrahedron: Asymmetry 21 (2010) 247–253
Table 2
Optimization of the reaction conditions: ligand and temperaturea
O
N
a
NH2
Fmoc
OH
Ph
HO
N
H
+
ligand-CuOTf . 1/2C6H6 (5 mol%)
NCS (1.2 equiv)
O
O
92%
HN Fmoc
2a
Ph
Ph
O
O
O
CH2Cl2, 2 h
OMe
Cl OMe
O
4a
5a
O
N
b
c
N
N
Ph
95%
52%
Entry
Ligand
T (°C)
Yieldb (%)
% eec (config.)
NH2
3a
HO
1a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1a
1a
1a
rt
rt
rt
rt
rt
rt
rt
0
99
95
99
99
99
99
99
99
99
99
78 (R)
50 (R)
54 (R)
68 (R)
78 (R)
14 (R)
47 (R)
83 (R)
72 (R)
6 (R)
i
Scheme 1. Reagents and conditions: (a) PPh3 (3.0 equiv), Pr2NEt (3.0 equiv), CCl4
(5.0 equiv), CH2Cl2, 0 °C to rt, 12 h; (b) Et2NH/CH3OH = 1:1 (v/v), 0 °C to rt, 12 h; (c)
salicylaldehyde (1.0 equiv), anhydrous MgSO4, C2H5OH, reflux, 12 h.
To evaluate the chiral-inducing ability of ligand 1a in the Cu-
ꢁ20
catalyzed asymmetric
a-chlorination reaction of b-keto esters, 1a
10
ꢁ78
and various metal Lewis acids were initially used to catalyze the
asymmetric chlorination of methyl-1-indanone-2-carboxylate 4a
with N-chlorosuccinimide (NCS); the results of these experiments
are summarized in Table 1. As shown in Table 1, with the screening
of metal Lewis acids (Table 1, entries 1–8) and solvent effect (Ta-
ble 1, entries 9–13), it was found that using CuOTfꢀ1/2C6H6 as a Le-
wis acid in dichloromethane gave the best catalytic results,
affording methyl-2-chloro-1-indanone-2-carbonxylate 5a in quan-
titative yield and good enantioselectivity (78% ee) (Table 1, entry
8). We also attempted the slow addition of a DCM solution of
NCS within 15 min, but the addition procedure did not show any
significant effect on the enantioselectivity.
a
b
c
All reactions were carried out in the presence of 5 mol % of catalyst.
Isolated yield.
The ee values were determined by chiral HPLC analysis and the absolute con-
figuration was determined according to the literature.7j
electron-withdrawing groups on the benzene ring in this reaction
resulted in lower ee values (Table 2, entries 2 and 3). In addition,
using ligand 1g which has a bulky i-Pr substituent on the oxazoline
moiety in this reaction produced 5a in 99% yield with 47% ee
(Table 2, entry 7). It should also be noted that the use of ligand
1f, which has two chlorine atoms at the ortho-positions instead
of hydroxyl groups gave product 5a in poor enantioselectivity
(Table 2, entry 6). These results suggest that the hydroxyl group
at the ortho-positions of the benzene ring in ligands 1a–1e and
1g plays an important role in achieving higher enantioselectivity.
The influence of the reaction temperature was also investigated
using 1a as the ligand and it was found that at 0 °C, 5a could be
obtained in 83% ee and 99% yield (Table 2, entry 8). Lowering the
reaction temperatures further led to 5a in lower enantioselectivi-
ties under otherwise identical conditions, presumably due to the
inefficient coordination between the substrate and the catalytically
active species at such low temperatures (Table 2, entries 9 and 10).
With the optimal reaction conditions in hand, a series of b-keto
esters 4b–4j with varying substituents in the ester group and on
the aromatic scaffold was used to further explore the substrate
scope (Table 3). It was found that for substrates 4b–d with differ-
Table 1
Optimization of the reaction conditions: Lewis acid and solventa
O
O
1a
-Lewis acid (5 mol%)
NCS (1.2 equiv)
O
O
solvent, r.t., 2 h
OMe
Cl
OMe
5a
4a
Entry
Solvent
Lewis acid
Yieldb (%)
% eec (config.)
1
2
3
4
5
6
7
8
9
10
11
12
13
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
THF
Cu(OTf)2
Zn(OTf)2
99
99
91
99
99
87
99
99
99
99
99
99
99
53 (R)
2 (S)
5 (S)
Ni(CIO4)2 6H2O
Sc(OTf)3
Cu(CH3CN)4CIO4
Cu(OAc)2ꢀH2O
CuBr
CuOTf 1/2C6H6
CuOTf 1/2C6H6
CuOTf 1/2C6H6
CuOTf 1/2C6H6
CuOTf 1/2C6H6
CuOTf 1/2C6H6
0
39 (R)
72 (R)
28 (R)
78 (R)
53 (R)
50 (R)
64 (R)
16 (R)
54 (R)
Table 3
Lewis acid catalyzed asymmetric chlorination of substituted p-keto estersa
Et2O
MeOH
DMF
O
O
1a-CuOTf . 1/2C6H6 (5 mol%)
R3
R2
R3
R2
O
O
NCS (1.2 equiv)
CH2Cl2, 0 oC, 2 h
Toluene
OR1
Cl OR1
a
AII reactions were carried out at room temperature in the presence of 5 mol % of
cataIyst.
4b-j
5b-j
b
IsoIated yieId.
c
The ee vaIues were determined by chiraI HPLC anaIysis and the absoIute con-
Entry
Substrate
Yieldb (%)
% eec,d (config.)
figuration was determined according to the Iiterature.7j
1
2
3
4
5
6
7
8
9
4b, R1 = tPr, R2 = R3 = H
95
99
99
99
99
96
98
95
99
5b, 83 (ꢁ)
5c, 82 (ꢁ)
5d, 80 (ꢁ)
5e, 74 (ꢁ)
5f, 70 (ꢁ)
5g, 76 (ꢁ)
5h, 77 (ꢁ)
5i, 74 (ꢁ)
5j, 60 (ꢁ)
4c, R1 = tBu, R2 = R3 = H
4d, R1 = Bn, R2 = R3 = H
In order to further improve the enantioselectivity of this reac-
tion, the optimization of the structure of oxazoline-Schiff base li-
gand 1 was carried out and a series of oxazoline-Schiff base
ligands 1b–g (Fig. 1) was synthesized according to the same proce-
dure shown in Scheme 1 using the corresponding reagents. Next,
these ligands were also applied to catalyze the asymmetric chlori-
nation of methyl-1-indanone-2-carboxylate. The results are sum-
marized in Table 2. Ligands 1d and 1e showed high catalytic
activities to give 5a in higher enantioselectivities (Table 2, entries
1, 4, and 5). However, using either ligand 1b with sterically bulky/
electron-donating groups on the benzene ring or ligand 1c with
4e, R1 = Me, R2 = CI, R3 = H
4f, R1 = tBu, R2 = CI, R3 = H
4g, R1 = Me, R2 = Br, R3 = H
4h, R1 = tBu, R2 = Br, R3 = H
4i, R1 = Me, R2 = R3 = MeO
4j, R1 = tBu, R2 = R3 = MeO
a
b
c
All reactions were carried out at 0 °C in the presence of 5 mol % of catalyst.
Isolated yield.
The ee values were determined by chiral HPLC analysis.
The configurations were not determined, but the sign of optical rotation was
d
indicated in each case.

M.-H. Qi et al. / Tetrahedron: Asymmetry 21 (2010) 247–253
249
ent ester groups, the corresponding products 5b–5d were obtained
with similar enantioselectivities (80–83% ee) in high yields
(Table 3, entries 1–3). Substrates 4e–4h bearing an electron-with-
drawing Cl or Br atom and substrates 4i and 4j with electron-
donating groups such as an MeO substituent on the benzene ring
also produced the products 5i and 5j in 95–99% yields and 60–
77% ee’s in this enantioselective chlorination reaction, indicating
a wide substrate scope (Table 3, entries 4–9). Furthermore, tetra-
lone b-keto ester 4k and cyclopentanone b-keto ester 4l were also
used as substrates in this chlorination reaction under the standard
conditions; however, the corresponding products 5k and 5l were
obtained in 47% and 32% ee, respectively (Scheme 2). In the case
of acyclic b-keto ester 4m, product 5m was formed in high yield
but with no ee (Scheme 2).
reactions were monitored by TLC with Huanghai GF254 silica
gel-coated plates. Flash column chromatography was carried out
using 300–400 mesh silica gel at increased pressure.
4.2. General procedure for the synthesis of Fmoc protecting
oxazoline amine 2
At first, N-Fmoc-L-valine (6.79 g, 20 mmol), (S)-a-amino alcohol
(20 mmol) and PPh3 (15.74 g, 60 mmol) were weighed into a
flame-dried 250 mL three-neck bottle equipped with a constant
dropping funnel. The bottle was flushed with argon and 100 mL
of CH2Cl2 were added followed by the addition of DIPEA
(10.2 mL, 60 mmol). The bottle was cooled down to 0 °C with an
ice bath. Next, CCl4 (9.66 mL, 100 mmol) in another 50 mL of
CH2Cl2 was added through a funnel over one hour, during this per-
iod the bottle was allowed to warm up to ambient temperature.
The reaction was stirred for 12 h. The solvent was removed under
reduced pressure and then about 100 mL of EtOAc was added into
the residue. After 1–2 h of quiescence, colorless precipitates were
generated and the suspensions were subjected to filtration. The fil-
trate was concentrated in vacuo. Further purification was per-
formed by flash column chromatography on SiO2 (PE/EtOAc = 4/
1) to give product 2.
O
O
O
O
1a-CuOTf . 1/2C6H6 (5 mol%)
OMe
OMe
NCS (1.2 equiv)
Cl
CH2Cl2, 0 oC, 2 h
5k
4k
Yield = 99%, ee = 47%
O
O
1a-CuOTf . 1/2C6H6 (5 mol%)
O
O
NCS (1.2 equiv)
OtBu
Cl
5l
OtBu
CH2Cl2, 0 oC, 2 h
4.2.1. [(S)-2-Methyl-1-((S)-4-phenyl-4,5-dihydro-oxazol-2-yl)
propyl]carbamic acid 9H-fluoren-9-ylmethyl ester 2a
A white solid. Yield 92%. A known product:10 Mp: 119.2–
4l
Yield = 47%, ee = 32%
121.3 °C. ½a 2D0
ꢃ
¼ ꢁ38:2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d
O
O
O
O
1a-CuOTf . 1/2C6H6 (5 mol%)
1.00 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 2.16–2.24 (m, 1H),
4.16 (t, J = 8.4 Hz, 1H), 4.25 (t, J = 6.8 Hz, 1H), 4.41 (d, J = 6.8 Hz,
2H), 4.50 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 4.68 (t, J = 9.6 Hz, 1H), 5.22
(t, J = 9.6 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H), 7.23–7.41 (m, 9H), 7.60
(d, J = 6.8 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H).
NCS (1.2 equiv)
OtBu
OtBu
CH2Cl2, 0 oC, 2 h
Cl
5m
4m
Yield = 95%, ee = 0%
Scheme 2. Lewis acid catalyzed asymmetric chlorination of substrates 4k, 4l, and
4m.
4.2.2. [1-((S)-4-Isopropyl-4,5-dihydro-oxazol-2-yl)-(S)-2-methyl-
propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester 2b
A white solid. Yield 90%. A known product:10 Mp: 111.5–
3. Conclusion
112.5 °C. ½a 2D0
ꢃ
¼ ꢁ47:3 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) d
0.88–0.98 (m, 12H), 1.70–1.78 (m, 1H), 2.08–2.16 (m, 1H), 3.88–
3.94 (m, 1H), 4.02 (t, J = 8.0 Hz, 1H), 4.23–4.30 (m, 2H), 4.34–4.40
(m, 3H), 5.44 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.39 (t,
J = 7.6 Hz, 2H), 7.58–7.61 (m, 2H), 7.76 (d, J = 7.6 Hz, 2H).
In conclusion, a series of novel chiral oxazoline-Schiff base li-
gands 1a–g was synthesized and applied to the Cu(I)-catalyzed
asymmetric direct
a-chlorination of b-keto esters, leading to the
chlorination adducts in excellent yields with moderate to good
enantioselectivities under mild conditions. Further efforts to apply
the catalytic systems to other processes as well as to optimize the
structure of the catalysts are currently underway.
4.3. General procedure for the synthesis of oxazoline amine 3
Fmoc-protected oxazoline 2 (6.51 mmol) was dissolved in
15 mL of MeOH and cooled down to 0 °C with an ice bath. Then,
15 mL of Et2NH were added over 30 min. After completion of the
reaction, the solvent was removed under reduced pressure and
the residue was purified by a short path silica gel column chroma-
tography (EtOAc/EtOH = 10/1) to give product 3
4. Experimental
4.1. General
1H NMR spectra and 13C NMR spectra were recorded on a Bruker
AM-300 and AM-400 spectrometer for solution in CDCl3 with tet-
ramethylsilane (TMS) as an internal standard. Infrared spectra
were measured on a PERKIN-ELMER 983 spectrometer. Mass spec-
tra were recorded with a HP-5989 instrument. Commercially ob-
tained reagents were used without further purification. Melting
points were measured on a Yanagimoto micromelting apparatus
and are uncorrected. Optical rotations were determined at
589 nm (sodium D line) using a Perkin Elmer 341 MC Polarimeter
4.3.1. (S)-2-Methyl-1-((S)-4-phenyl-4,5-dihydro-oxazol-2-yl)
propylamine 3a
A yellow oil. Yield 90%. ½a D20
ꢃ
¼ ꢁ2:1 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.01 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H),
1.76 (br, 2H), 2.01–2.09 (m, 1H), 3.47 (d, J = 5.6 Hz, 1H), 4.14 (t,
J = 8.4 Hz, 1H), 4.66 (dd, J = 8.4 Hz, 10.0 Hz, 1H), 5.20 (t,
J = 10.0 Hz, 1H), 7.25–7.37 (m, 5H). 13C NMR (100 MHz, CDCl3) d
17.5, 19.2, 32.1, 55.4, 69.0, 74.7, 126.4, 127.4, 128.6, 142.0, 170.9.
and [a]
values are given with units of 10 cm2 degꢁ1 gꢁ1. Chiral
D
IR (CHCl3)
m 3350, 2962, 2872, 1755, 1660, 1495, 1454, 1365,
HPLC was performed by using a SHIMADZU SPD-10A vp series
instrument with chiral columns (Chiralpak OJ-H, OD-H, and AD-H
columns, u 4.6 ꢂ 250 mm, Daicel Chemical Co. Ltd). Organic sol-
vents used were dried by standard methods when necessary. All
1223, 1030, 988 cmꢁ1. MS (%) m/z 218.1 (M+, 1), 176.1 (11),
175.1 (100), 120.1 (15), 91.1 (50). HRMS calcd for C13H18N2O:
218.1419. Found: 218.1421.

250
M.-H. Qi et al. / Tetrahedron: Asymmetry 21 (2010) 247–253
4.3.2. 1-((S)-4-Isopropyl-4,5-dihydro-oxazol-2-yl)-(S)-2-methyl-
1H), 7.19–7.37 (m, 6H), 7.42 (s, 1H), 8.35 (s, 1H), 14.19 (br, 1H).
(Z- or E-isomer) 13C NMR (100 MHz, CDCl3) d 18.5, 19.4, 31.6,
69.3, 72.4, 74.7, 119.4, 122.7, 122.8, 126.4, 127.6, 128.7, 129.3,
132.4, 141.5, 156.2, 164.8, 166.3. (E- or Z-isomer) 13C NMR
(100 MHz, CDCl3) d 18.7, 19.4, 31.7, 69.3, 72.9, 74.9, 119.4, 122.7,
122.8, 126.5, 127.6, 128.7, 129.3, 132.4, 141.7, 156.3, 164.8,
propylamine 3b
A yellow oil. Yield 88%. ½a D20
ꢃ
¼ ꢁ77:2 (c 0.8, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.89 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H),
0.97 (d, J = 6.8 Hz, 6H), 1.65 (br, 2H), 1.71–1.79 (m, 1H), 1.91–
1.99 (m, 1H), 3.34 (d, J = 6.0 Hz, 1H), 3.87–3.93 (m, 1H), 3.98 (t,
J = 8.0 Hz, 1H), 4.25 (t, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 17.7, 18.2, 18.8, 19.4, 32.2, 32.6, 55.7, 70.1, 71.8, 169.4. IR (CHCl3)
166.3. IR (CHCl3)
m 2965, 1744, 1663, 1632, 1453, 1370, 1292,
1215, 1180, 976 cmꢁ1. MS (%) m/z 390.1 (M+, 51), 375.1 (30),
271.0 (50), 243.0 (56), 200.0 (57), 188.1 (100), 126.1 (37), 104.1
(42). HRMS calcd for C20H20Cl2N2O2: 390.0902. Found: 390.0904.
m
3327, 2959, 2926, 2872, 1750, 1664, 1467, 1386, 1368, 1241,
1088, 987 cmꢁ1. MS (%) m/z 184.2 (M+, 0.4), 142.1 (7), 141.1
(100), 69.1 (12), 55.0 (8). HRMS calcd for C10H20N2O: 184.1576.
Found: 184.1572.
4.4.4. 3-{[(S)-2-Methyl-1-((S)-4-phenyl-4,5-dihydrooxazol-2-yl)
propylimino]methyl}benzene-1,2-diol 1d12
4.4. General procedure for the synthesis of oxazoline-Schiff
base ligands 1
A yellow oil. Yield 46%. ½a D20
¼ ꢁ37:5 (c 1.05, CHCl3). (Z- or E-
ꢃ
isomer) 1H NMR (400 MHz, CDCl3) d 1.03 (d, J = 6.8 Hz, 3H), 1.08
(d, J = 6.8 Hz, 3H), 2.37–2.45 (m, 1H), 3.97 (d, J = 6.8 Hz, 1H), 4.18
(t, J = 9.2 Hz, 1H), 4.69 (t, J = 9.2 Hz, 1H), 5.25 (t, J = 9.2 Hz, 1H),
6.73 (t, J = 7.6 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz,
1H), 7.21–7.36 (m, 5H), 8.35 (d, J = 7.6 Hz, 1H). (E- or Z-isomer)
1H NMR (400 MHz, CDCl3) d 1.04 (d, J = 6.8 Hz, 3H), 1.08 (d,
J = 6.8 Hz, 3H), 2.37–2.45 (m, 1H), 3.97 (d, J = 6.8 Hz, 1H), 4.18 (t,
J = 9.2 Hz, 1H), 4.69 (t, J = 9.2 Hz, 1H), 5.25 (t, J = 9.2 Hz, 1H), 6.73
(t, J = 7.6 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H),
7.21–7.36 (m, 5H), 8.35 (d, J = 7.6 Hz, 1H). (Z- or E-isomer) 13C
NMR (100 MHz, CDCl3) d 18.6, 19.4, 31.7, 69.1, 72.0, 74.8, 117.2,
117.4, 118.2, 122.3, 126.5, 127.6, 128.7, 141.6, 145.4, 150.7,
166.2, 166.9. (E- or Z-isomer) 13C NMR (100 MHz, CDCl3) d 18.7,
19.4, 31.8, 69.2, 72.5, 75.0, 117.3, 117.5, 118.2, 122.3, 126.5,
To a solution of the oxazoline amine 3 (436.6 mg, 2.0 mmol) in
15 mL of EtOH was added the corresponding aldehyde (2.0 mmol),
then anhydrous MgSO4 (400 mg) was added into the resulting
solution. The reaction mixture was heated at reflux and stirred
for 12 h. Next, MgSO4 was removed by filtration, and the filtrate
was concentrated under vacuum and the residue was purified by
a short path silica gel column chromatography (PE/EtOAc = 10/1
with a few drops of Et3N) to give the pure product 1.
4.4.1. 2-{[(S)-2-Methyl-1-((S)-4-phenyl-4,5-dihydro-oxazol-2-
yl)propylimino]methyl}phenol 1a
A yellow solid. Yield 52%. Mp: 106.2–107.3 °C. ½a D20
¼ ꢁ34:8 (c
ꢃ
0.90, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.02 (d, J = 6.8 Hz, 3H),
1.08 (d, J = 6.8 Hz, 3H), 2.38–2.46 (m, 1H), 3.90 (d, J = 7.6 Hz, 1H),
4.16 (t, J = 8.4 Hz, 1H), 4.68 (t, J = 9.6 Hz, 1H), 5.21 (t, J = 9.6 Hz,
1H), 6.90 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.24–7.37 (m,
7H), 8.42 (s, 1H), 13.14 (s, 1H). 13C NMR (100 MHz, CDCl3) d 18.9,
19.6, 31.6, 69.3, 73.7, 74.9, 117.1, 118.6, 118.7, 126.5, 127.6,
127.6, 128.7, 141.8, 145.5, 150.9, 166.3, 167.0. IR (CHCl3) m 2965,
1743, 1659, 1630, 1466, 1364, 1273, 1233, 977 cmꢁ1. MS (%) m/z
338.2 (M+, 100), 323.1 (22), 234.1 (11), 219.1 (49), 190.1 (54),
148.0 (36). HRMS calcd for C20H22N2O3: 338.1630. Found:
338.1629.
128.8, 131.7, 132.7, 142.0, 161.1, 166.5, 167.2. IR (CHCl3)
m
2964,
4.4.5. 1-{[(S)-2-Methyl-1-((S)-4-phenyl-4,5-dihydro-oxazol-2-yl)
1743, 1662, 1630, 1494, 1460, 1279, 1206, 1151, 978 cmꢁ1. MS
(%) m/z 322.2 (M+, 83), 307.1 (21), 203.1 (28), 188.1 (100), 175.1
(56), 132.0 (37), 120.1 (17), 69.0 (12). HRMS calcd for
C20H22N2O2: 322.1681. Found: 322.1680.
propylimino]methyl}naphthalen-2-ol 1e12
A yellow oil. Yield 41%. ½a D20
¼ ꢁ26:4 (c 1.65, CHCl3). (Z- or E-
ꢃ
isomer) 1H NMR (400 MHz, CDCl3) d 1.10 (d, J = 6.8 Hz, 3H), 1.12
(d, J = 6.8 Hz, 3H), 2.40–2.48 (m, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.17
(t, J = 8.4 Hz, 1H), 4.70 (t, J = 9.6 Hz, 1H), 5.25 (t, J = 9.2 Hz, 1H),
7.03 (d, J = 9.2 Hz, 1H), 7.22–7.31 (m, 5H), 7.35 (t, J = 7.2 Hz, 1H),
7.46 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 9.2 Hz,
1H), 7.95 (d, J = 8.4 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 14.88 (s, 1H).
(E- or Z-isomer) 1H NMR (400 MHz, CDCl3) d 1.10 (d, J = 6.8 Hz,
3H), 1.12 (d, J = 6.8 Hz, 3H), 2.40–2.49 (m, 1H), 4.11 (d, J = 7.2 Hz,
1H), 4.19 (t, J = 8.4 Hz, 1H), 4.70 (t, J = 9.6 Hz, 1H), 5.26 (t,
J = 9.2 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 7.22–7.31 (m, 5H), 7.35 (t,
J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.74
(d, J = 9.2 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H),
14.88 (s, 1H). (Z- or E-isomer) 13C NMR (100 MHz, CDCl3) d 18.3,
19.2, 31.6, 69.2, 69.7, 74.7, 107.4, 118.3, 122.4, 122.8, 126.3,
126.6, 127.4, 128.5, 128.9, 133.0, 136.0, 141.5, 159.5, 166.2,
170.5, 170.9. (E- or Z-isomer) 13C NMR (100 MHz, CDCl3) d 18.4,
19.2, 31.6, 69.3, 69.7, 74.7, 107.5, 118.3, 122.6, 122.8, 126.3,
126.6, 127.6, 128.5, 128.9, 133.0, 136.1, 141.6, 159.8, 166.2,
4.4.2. 2,4-Di-tert-butyl-6-{[(S)-2-methyl-1-((S)-4-phenyl-4,5-
dihydrooxazol-2-yl)propylimino]methyl}phenol 1b
A yellow oil. Yield 47%. ½a D20
ꢃ
¼ ꢁ11:5 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.03 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H),
1.31 (s, 9H), 1.47 (s, 9H), 2.38–2.46 (m, 1H), 3.87 (d, J = 8.0 Hz,
1H), 4.10 (t, J = 8.4 Hz, 1H), 4.61 (t, J = 9.6 Hz, 1H), 5.17 (t,
J = 9.6 Hz, 1H), 7.13 (s, 1H), 7.23 (d, J = 7.6 Hz, 3H), 7.31 (t,
J = 7.6 Hz, 2H), 7.43 (s, 1H), 8.44 (s, 1H), 13.5 (s, 1H). 13C NMR
(100 MHz, CDCl3) d 19.0, 19.5, 29.4, 31.4, 31.5, 34.0, 34.9, 69.1,
73.6, 74.7, 117.6, 126.2, 126.4, 127.3, 127.4, 128.6, 136.7, 140.0,
142.0, 158.1, 167.3, 167.6; IR (CHCl3)
m 2961, 1743, 1659, 1629,
1467, 1362, 1273, 1250, 1173, 975 cmꢁ1; MS (%) m/z 434.3 (M+,
100), 419.3 (48), 315.2 (78), 287.2 (63), 188.1 (96), 175.1 (42),
120.1 (24), 91.1 (32); HRMS calcd for C28H38N2O2: 434.2933.
Found: 434.2934.
170.5, 171.0. IR (CHCl3)
m 2964, 1743, 1662, 1627, 1354, 1186,
4.4.3. 2,4-Dichloro-6-{[(S)-2-methyl-1-((S)-4-phenyl-4,5-
979 cmꢁ1. MS (%) m/z 372.2 (M+, 60), 253.1 (21), 225.1 (19),
188.1 (100), 182.1 (43), 127.1 (10). HRMS calcd for C24H24N2O2:
372.1838. Found: 372.1836.
dihydrooxazol-2-yl)propylimino]methyl}phenol 1c12
A yellow oil. Yield 41%. ½a D20
¼ ꢁ39:8 (c 1.05, CHCl3). (Z- or E-
ꢃ
isomer) 1H NMR (400 MHz, CDCl3) d 1.02 (d, J = 6.8 Hz, 3H), 1.07
(d, J = 6.8 Hz, 3H), 2.37–2.46 (m, 1H), 3.98 (d, J = 6.8 Hz, 1H), 4.14
(t, J = 8.4 Hz, 1H), 4.68 (t, J = 9.6 Hz, 1H), 5.21 (t, J = 9.6 Hz, 1H),
7.19–7.37 (m, 6H), 7.42 (s, 1H), 8.35 (s, 1H), 14.19 (br, 1H). (E- or
Z-isomer) 1H NMR (400 MHz, CDCl3) d 1.03 (d, J = 6.8 Hz, 3H),
1.07 (d, J = 6.8 Hz, 3H), 2.38–2.46 (m, 1H), 3.98 (d, J = 6.8 Hz, 1H),
4.16 (t, J = 8.4 Hz, 1H), 4.68 (t, J = 9.6 Hz, 1H), 5.24 (t, J = 9.6 Hz,
4.4.6. (2,6-Dichlorobenzylidene)-[(S)-2-methyl-1-((S)-4-phenyl-
4,5-dihydrooxazol-2-yl)propyl]amine 1f
A yellow oil. Yield 43%. ½a D20
ꢃ
¼ ꢁ61:2 (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3) d 1.08 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H),
2.45–2.54 (m, 1H), 3.98 (d, J = 8.0 Hz, 1H), 4.16 (t, J = 8.4 Hz, 1H),
4.69 (dd, J = 8.4 Hz, 10.4 Hz, 1H), 5.24 (dd, J = 8.4 Hz, 10.4 Hz, 1H),

M.-H. Qi et al. / Tetrahedron: Asymmetry 21 (2010) 247–253
251
7.19–7.36 (m, 8H), 8.52 (s, 1H). 13C NMR (100 MHz, CDCl3) d 19.1,
13C NMR (75 MHz, CDCl3) d 21.3, 21.4, 43.3, 68.1, 71.5, 125.9,
19.6, 31.3, 69.2, 74.8, 76.3, 126.5, 127.4, 128.4, 128.6, 130.3, 132.9,
126.3, 128.5, 132.5, 136.3, 150.6. IR (CHCl3) m 2925, 2856, 1758,
134.5, 142.1, 159.2, 167.3. IR (CHCl3)
m
2963, 2872, 1745, 1660,
1737, 1606, 1465, 1376, 1275, 1180, 1104, 1006, 922 cmꢁ1. MS
(%) m/z 217.1 (M+ꢁCl, 68), 175.0 (74), 165.0 (47), 157.0 (100),
147.0 (66), 131.0 (43), 102.0 (21), 101.0 (21). HRMS calcd for
C13H13O3 (M+ꢁCl): 217.0865. Found: 217.0865.
1580, 1559, 1431, 1192, 1094, 991, 957 cmꢁ1. MS (%) m/z 374.1
(M+, 0.3), 331.0 (6), 203.1 (23), 188.1 (100), 120.1 (5), 69.0 (7).
HRMS calcd for C20H20Cl2N2O: 374.0953. Found: 374.0934.
4.4.7. 2-(((S)-1-((S)-4-Isopropyl-4,5-dihydrooxazol-2-yl)-2-
4.5.3. 2-Chloro-1-oxo-indan-2-carboxylic acid tert-butyl ester
methylpropylimino)methyl)phenol 1g12
5c
A yellow solid. Yield 42%. Mp: 71.5–72.2 °C. ½a D20
ꢃ
¼ ꢁ54:1 (c
A white solid. Yield 99%. A known product:9b Mp: 62.9–64.5 °C.
¼ ꢁ38:4 (c 0.70, CHCl3, 82% ee). HPLC (DAICEL CHIRALPAK OJ-
1.05, CHCl3). (Z- or E-isomer) 1H NMR (400 MHz, CDCl3) d 0.85–
1.01 (m, 12H), 1.71–1.81 (m, 1H), 2.27–2.37 (m, 1H), 3.79 (d,
J = 7.6 Hz, 1H), 3.89–4.03 (m, 2H), 4.25–4.29 (m, 1H), 6.88 (t,
J = 7.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.26–7.29 (m, 1H), 7.32 (t,
J = 8.0 Hz, 1H), 8.37 (s, 1H), 13.18 (s, 1H). (E- or Z-isomer) 1H
NMR (400 MHz, CDCl3) d 0.85–1.01 (m, 12H), 1.71–1.81 (m, 1H),
2.27–2.37 (m, 1H), 3.80 (d, J = 7.6 Hz, 1H), 3.89–4.03 (m, 2H),
4.25–4.29 (m, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H),
7.26–7.29 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 8.37 (s, 1H), 13.20 (s,
1H). (Z- or E-isomer) 13C NMR (100 MHz, CDCl3) d 18.1, 18.3,
18.7, 18.9, 19.4, 31.6, 32.5, 70.1, 71.7, 73.4, 117.1, 118.6, 131.6,
132.6, 161.1, 165.7, 166.0. (E- or Z-isomer) 13C NMR (100 MHz,
CDCl3) d 18.1, 18.3, 18.8, 18.9, 19.4, 31.6, 32.5, 70.2, 71.7, 73.8,
½
a 2D0
ꢃ
H, hexane/IPA = 70/30, 0.7 mL/min, 230 nm) tr (minor) = 7.76 min,
tr (major) = 9.38 min. 1H NMR (300 MHz, CDCl3) d 1.43 (s, 9H),
3.54 (d, J = 18.0 Hz, 1H), 4.02 (d, J = 18.0 Hz, 1H), 7.47 (t,
J = 7.8 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H).
4.5.4. 2-Chloro-1-oxo-indan-2-carboxylic acid benzyl ester 5d
A pale yellow oil. Yield 99%. ½a D20
¼ ꢁ32:8 (c 1.60, CHCl3, 80%
ꢃ
ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/IPA = 70/30, 0.7 mL/
min, 230 nm) tr (major) = 9.88 min, tr (minor) = 10.55 min. 1H
NMR (300 MHz, CDCl3)
d 3.56 (d, J = 18.0 Hz, 1H), 4.07 (d,
J = 18.0 Hz, 1H), 5.21 (d, J = 12.6 Hz, 1H), 5.27 (d, J = 12.6 Hz, 1H),
7.26–7.34 (m, 5H), 7.45–7.49 (m, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.86
(d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 43.3, 68.0, 68.6,
125.9, 126.3, 127.9, 128.5, 128.6, 132.4, 134.6, 136.4, 150.4. IR
117.1, 118.6, 131.6, 132.6, 161.1, 165.8, 166.1. IR (CHCl3)
m 2962,
2930, 2873, 1665, 1630, 1580, 1497, 1461, 1279, 1151, 978 cmꢁ1
.
MS (%) m/z 288.2 (M+, 54), 273.2 (33), 245.1 (15), 175.1 (20),
154.1 (100), 132.0 (43). HRMS calcd for C17H24N2O2: 288.1838.
Found: 288.1837.
(CHCl3) m 2984, 2663, 1752, 1731, 1605, 1465, 1379, 1275, 1214,
1176, 1078, 1009, 940 cmꢁ1. MS (%) m/z 265.1 (M+ꢁCl, 4), 194.0
(13), 159.0 (24), 91.1 (100), 65.0 (6). HRMS calcd for C17H13O3
(M+ꢁCl): 265.0865. Found: 265.0860.
4.5. General procedure for the catalytic enantioselective
chlorination of b-keto esters
4.5.5. 2,5-Dichloro-1-oxo-indan-2-carboxylic acid methyl ester
5e
To a Schlenk tube with ligand 1a (3.2 mg, 0.01 mmol) in CH2Cl2
(1.0 mL) was added CuOTfꢀ1/2C6H6 (2.5 mg, 0.01 mmol). The
resulting solution was stirred at room temperature for 15 min.
Then the reaction tube was allowed to cool down to 0 °C followed
by the addition of the b-keto ester 4 (0.2 mmol) and the reaction
mixture was stirred for another 15 min. Finally, NCS (32 mg,
0.28 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 to quench the reaction. The
aqueous layer was extracted with Et2O. The combined organic lay-
ers were washed with water and brine. After drying over anhy-
drous Na2SO4, the solvent was removed under reduced pressure.
Further purification of the residue was performed by flash column
chromatography on SiO2 (PE/EtOAc = 10/1) to give the pure prod-
uct 5. The ee of the product 5 was determined by chiral HPLC
analysis.
A white solid. Yield 99%. A known product:11 Mp: 119.1–
120.0 °C. ½a 2D0
¼ ꢁ43:9 (c 1.35, CHCl3, 74% ee). HPLC (DAICEL CHIR-
ꢃ
ALPAK OD-H, hexane/IPA = 90/10, 0.65 mL/min, 230 nm) tr (ma-
jor) = 14.05 min, tr (minor) = 16.05 min. 1H NMR (400 MHz,
CDCl3) d 3.54 (d, J = 18.0 Hz, 1H), 3.83 (s, 3H), 4.09 (d, J = 18.0 Hz,
1H), 7.46 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H).
4.5.6. 2,5-Dichloro-1-oxo-indan-2-carboxylic acid tert-butyl
ester 5f
A
pale yellow solid. Yield 99%. Mp: 101.6–103.1 °C.
¼ ꢁ24:4 (c 1.70, CHCl3, 70% ee). HPLC (DAICEL CHIRALPAK
½ ꢃ
a 2D0
OJ-H, hexane/IPA = 90/10, 0.7 mL/min, 254 nm) tr (minor) = 10.16 -
min, tr (major) = 11.21 min. 1H NMR (400 MHz, CDCl3) d 1.44 (s,
9H), 3.51 (d, J = 18.0 Hz, 1H), 4.00 (d, J = 18.0 Hz, 1H), 7.45 (d,
J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 27.7, 43.1, 68.6, 84.7, 126.5, 126.8, 129.3,
131.2, 142.9, 152.0, 165.4, 194.1. IR (CHCl3)
m 2978, 2933, 1756,
4.5.1. (R)-2-Chloro-1-oxo-indan-2-carboxylic acid methyl ester
1732, 1599, 1416, 1370, 1261, 1151, 1070, 1005 cmꢁ1. MS (%) m/
z 300.0 (M+, 0.2), 244.0 (87), 227.0 (38), 216.0 (55), 209.0 (61),
199.0 (100), 181.0 (89), 165.0 (34), 136.0 (29), 57.1 (90), 41.0
(16). HRMS calcd for C14H14Cl2O3: 300.0320. Found: 300.0330.
5a
A pale yellow oil. Yield 99%. A known product:7j
½
a 2D0
ꢃ
¼ ꢁ55:7 (c
1.05, CHCl3, 83% ee). HPLC (DAICEL CHIRALPAK AD-H, hexane/
IPA = 95/5, 0.75 mL/min, 230 nm) tr (minor) = 13.44 min, tr (ma-
jor) = 14.61 min. 1H NMR (400 MHz, CDCl3) d 3.57 (d, J = 17.6 Hz,
1H), 3.82 (s, 3H), 4.11 (d, J = 17.6 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H),
7.71 (t, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H).
4.5.7. 5-Bromo-2-chloro-1-oxo-indan-2-carboxylic acid methyl
ester 5g
A white solid. Yield 96%. Mp: 121.6–122.5 °C. ½a D20
¼ ꢁ36:3 (c
ꢃ
1.35, CHCl3, 76% ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/
IPA = 90/10, 0.7 mL/min, 254 nm) tr (major) = 16.92 min, tr (min-
or) = 20.68 min. 1H NMR (400 MHz, CDCl3) d 3.54 (d, J = 18.0 Hz,
1H), 3.82 (s, 3H), 4.10 (d, J = 18.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H),
7.68 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d
42.9, 54.2, 67.6, 127.0, 129.6, 131.2, 132.1, 132.3, 151.9, 167.2,
4.5.2. 2-Chloro-1-oxo-indan-2-carboxylic acid isopropyl ester
5b
A pale yellow oil. Yield 95%. ½a D20
¼ ꢁ41:0 (c 0.95, CHCl3, 83%
ꢃ
ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/IPA = 95/5, 0.7 mL/
min, 230 nm) tr (major) = 11.24 min, tr (minor) = 11.86 min. 1H
NMR (300 MHz, CDCl3) d 1.23 (s, 3H), 1.26 (s, 3H), 3.56 (d,
J = 17.7 Hz, 1H), 4.07 (d, J = 17.7 Hz, 1H), 5.04–5.16 (m, 1H), 7.48
(t, J = 7.5 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H).
193.7. IR (CHCl3)
m 2955, 2844, 1765, 1741, 1593, 1435, 1317,
1263, 1210, 1178, 1058, 1030, 958 cmꢁ1. MS (%) m/z 301.9 (M+,
2), 269.0 (76), 267.0 (81), 236.9 (90), 234.9 (100), 208.9 (18),

252
M.-H. Qi et al. / Tetrahedron: Asymmetry 21 (2010) 247–253
206.9 (16), 136.0 (21). HRMS calcd for C11H8BrClO3: 301.9345.
Found: 301.9352.
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 cmꢁ1. MS (%) m/z 218.1 (M+, 4), 162.0 (67), 145.0 (45),
134.0 (60), 117.0 (39), 89.0 (27), 57.1 (100), 41.0 (18). HRMS calcd
for C10H15ClO3: 218.0710. Found: 218.0715.
4.5.8. 5-Bromo-2-chloro-1-oxo-indan-2-carboxylic acid tert-
butyl ester 5h
A pale yellow solid. Yield 98%. Mp: 99.9–100.4 °C. ½a D20
¼ ꢁ26:5
ꢃ
(c 1.75, CHCl3, 77% ee). HPLC (DAICEL CHIRALPAK OJ-H, hexane/
IPA = 90/10, 0.7 mL/min, 254 nm) tr (minor) = 11.35 min, tr (ma-
jor) = 12.18 min. 1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H), 3.51 (d,
J = 18.0 Hz, 1H), 4.00 (d, J = 18.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H),
7.66 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d
27.7, 43.0, 68.5, 84.7, 126.8, 129.5, 131.6, 131.8, 132.2, 152.1,
Acknowledgments
Financial support from the Shanghai Municipal Committee of
Science and Technology (06XD14005 and 08dj1400100-2), Na-
tional Basic Research Program of China (973)-2010CB833302, and
the National Natural Science Foundation of China (20902019,
20872162, 20672127, 20821002, 20732008 and 20702059) is
greatly acknowledged.
165.4, 194.3. IR (CHCl3)
m 2980, 2932, 1757, 1737, 1593, 1458,
1415, 1370, 1317, 1261, 1151, 1059, 1005 cmꢁ1. MS (%) m/z
344.0 (M+, 3), 289.9 (99), 287.9 (77), 261.9 (66), 259.9 (49), 244.9
(100), 242.9 (75), 227.0 (64), 225.0 (69), 211.0 (26), 209.0 (34),
136.0 (26), 57.1 (63). HRMS calcd for C14H14BrClO3: 343.9815.
Found: 343.9823.
References
1. (a) Filler, R.; Kobayashi, Y. Biomedical Aspects of Fluorine Chemistry; Elsevier
Biomedical Press and Kodansha Ltd: New York, Tokyo, 1982; (b) De Kimpe, N.;
Verhe, R. The Chemistry of
a-Haloketones, a-Haloaldehydes, and a-
4.5.9. 2-Chloro-5,6-dimethoxy-1-oxo-indan-2-carboxylic acid
methyl ester 5i
Haloimines; John Wiley & Sons: New York, 1988; (c) Ojima, I.; McCarthy, J.
R.; Welch, J. T.. Biomedical Frontiers of Fluorine Chemistry, ACS Symposium Series
639; American Chemical Society: Washington, DC, 1996; (d) Thomas, G.
Medicinal Chemistry: An Introduction; John Wiley & Sons: New York, 2000; (e)
Ramachandran, P. V.. Asymmetric Fluoroorganic Chemistry: Synthesis,
Applications, and Future Directions, ACS Symposium Series 746; American
Chemical Society: Washington, DC, 2000.
A pale yellow solid. Yield 95%. Mp: 136.9–138.2 °C. ½a D20
¼ ꢁ32:5
ꢃ
(c 1.15, CHCl3, 74% ee). HPLC (DAICEL CHIRALPAK OD-H, hexane/
IPA = 80/20, 0.7 mL/min, 254 nm) tr (major) = 18.32 min, tr (min-
or) = 20.73 min. 1H NMR (400 MHz, CDCl3) d 3.48 (d, J = 17.2 Hz,
1H), 3.82 (s, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 4.03 (d, J = 17.2 Hz, 1H),
6.88 (s, 1H), 7.24 (s, 1H). 13C NMR (100 MHz, CDCl3) d 43.1, 54.0,
56.2, 56.4, 68.4, 105.7, 107.0, 125.0, 146.4, 150.3, 157.0, 167.8,
2. (a) Muñiz, K. Angew. Chem. 2001, 113, 1701–1704. Angew. Chem., Int. Ed. 2001,
40, 1653–1656; (b) Ma, J. A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146; (c)
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147–1155; (d) France, S.;
Weatherwax, A.; Lectka, T. Eur. J. Org. Chem. 2005, 3, 475–479; (e) Oestreich,
M. Angew. Chem. 2005, 117, 2376–2379. Angew. Chem., Int. Ed. 2005, 44, 2324–
2327; (f) Pihko, P. M. Angew. Chem. 2006, 118, 558–561. Angew. Chem., Int. Ed.
2006, 45, 544–547; (g) Bobbio, C.; Gouverneur, V. Org. Biomol. Chem. 2006,
2065–2075; (h) Hamashima, Y.; Sodeoka, M. Synlett 2006, 1467–1478.
3. (a) Hintermann, L.; Togni, A. Angew. Chem. 2000, 112, 4530–4533. Angew.
Chem., Int. Ed. 2000, 39, 4359–4362; (b) Piana, S.; Devillers, I.; Togni, A.;
Rothisberger, U. Angew. Chem. 2002, 114, 1021–1024. Angew. Chem., Int. Ed.
2002, 41, 979–982; (c) Frantz, R.; Hintermann, L.; Perseghini, M.; Brogginio, D.;
Togni, A. Org. Lett. 2003, 5, 1709–1712; (d) Hintermann, L.; Togni, A. Helv. Chim.
Acta 2000, 83, 2425–2435; (e) Ibrahim, H.; Kleinbeck, F.; Togni, A. Helv. Chim.
Acta 2004, 87, 605–610.
193.4. IR (CHCl3)
m 2956, 2838, 1762, 1712, 1591, 1504, 1464,
1438, 1316, 1271, 1175, 1124, 1026 cmꢁ1. MS (%) m/z 284.0 (M+,
9), 248.1 (24), 225.0 (7), 217.0 (100), 190.1 (6), 175.0 (4), 147.0 (3),
119.1 (2). HRMS calcd for C13H13ClO5: 284.0452. Found: 284.0454.
4.5.10. 2-Chloro-5,6-dimethoxy-1-oxo-indan-2-carboxylic acid
tert-butyl ester 5j
A white solid. Yield 99%. Mp: 73.1–74.8 °C. ½a D20
¼ ꢁ15:0 (c 1.65,
ꢃ
CHCl3, 60% ee). HPLC (DAICEL CHIRALPAK OJ-H, hexane/IPA = 80/
20, 0.7 mL/min, 254 nm) tr (major) = 24.20 min, tr (minor) = 29.33 -
min. 1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H), 3.45 (d, J = 17.6 Hz,
1H), 3.931 (s, 3H), 3.934 (d, J = 17.6 Hz, 1H), 4.00 (s, 3H), 6.88 (s,
1H), 7.24 (s, 1H). 13C NMR (100 MHz, CDCl3) d 27.7, 43.2, 56.1,
56.4, 69.2, 84.2, 105.6, 106.9, 125.4, 146.5, 150.1, 156.7, 166.1,
4. Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru, T. J. Fluorine Chem. 2007, 128,
469–483.
5. (a) Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M. J. Am. Chem. Soc.
2002, 124, 14530–14531; (b) Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M.
Org. Lett. 2003, 5, 3225–3228; (c) Hamashima, Y.; Suzuki, T.; Shimura, Y.;
Shimizu, T.; Umebayashi, N.; Tamura, T.; Sasamoto, N.; Sodeoka, M. Tetrahedron
Lett. 2005, 46, 1447–1450; (d) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura,
Y.; Tsuchiya, Y.; Moriya, K.-i.; Goto, T.; Sodeoka, M. Tetrahedron 2006, 62, 7168–
7179; (e) Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005,
127, 10164–10165.
6. (a) Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007–1011; (b) Ma,
J.-A.; Cahard, D. J. Fluorine Chem. 2004, 125, 1357–1361; (c) Shibata, N.;
Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703–1706; (d) Shibata,
N.; Kohno, J.; Takai, K.; Ishimaru, T.; Nakamura, S.; Toru, T.; Kanemasa, S.
Angew. Chem. 2005, 117, 4276–4279. Angew. Chem., Int. Ed. 2005, 44, 4204–
4207; (e) Kim, H. R.; Kim, D. Y. Tetrahedron Lett. 2005, 46, 3115–3117; (f)
Bernardi, L.; Jørgensen, K. A. Chem. Commun. 2005, 1324–1326; (g) Kim, S. M.;
Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309–2311; (h) Kim, D. Y.; Park, E. J. Org.
Lett. 2002, 4, 545–547.
7. (a) Enders, D.; Hüttl, M. R. M. Synlett 2005, 991–993; (b) Marigo, M.;
Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem.
2005, 117, 3769–3772. Angew. Chem., Int. Ed. 2005, 44, 3703–3706; (c) Steiner,
D. D.; Mase, N.; Barbas, C. F., III Angew. Chem. 2005, 117, 3772–3776. Angew.
Chem., Int. Ed. 2005, 44, 3706–3710; (d) Beeson, T. D.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 8826–8828; (e) Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051–15053; (f) Shibata, N.;
Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728–10729; (g) Shibata,
N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001–7009; (h)
Shibata, N.; Yasui, H.; Nakamura, S.; Toru, T. Synlett 2007, 1153–1157; (i)
Suzuki, S.; Furuno, H.; Yokoyama, Y.; Inanaga, J. Tetrahedron: Asymmetry 2006,
17, 504–507; (j) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Angew. Chem. 2005, 117, 6375–6378. Angew. Chem., Int. Ed. 2005, 44,
6219–6222.
194.1. IR (CHCl3)
m 2978, 2931, 2874, 1754, 1713, 1591, 1504,
1463, 1370, 1315, 1271, 1153, 1123, 1009, 984 cmꢁ1. MS (%) m/z
326.1 (M+, 2), 270.0 (25), 252.0 (13), 234.1 (31), 217.0 (100),
191.1 (22), 175.0 (4), 147.0 (5), 119.1 (3). HRMS calcd for
C16H19ClO5: 326.0921. Found: 326.0923.
4.5.11. 2-Chloro-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-
carboxylic acid methyl ester 5k
A pale yellow oil. Yield 99%. A known product:11
½
a 2D0
ꢃ
¼ ꢁ13:9 (c
1.35, CHCl3, 47% ee). HPLC (DAICEL CHIRALPAK IC-H, hexane/
IPA = 90/10, 0.8 mL/min, 230 nm) tr (minor) = 20.46 min, tr (ma-
jor) = 24.69 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 = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 8.10
(d, J = 8.0 Hz, 1H).
4.5.12. 1-Chloro-2-oxo-cyclopentanecarboxylic acid tert-butyl
ester 5l
A pale yellow oil. Yield 47%. ½a D20
¼ ꢁ2:2 (c 0.55, CHCl3, 32% ee).
ꢃ
HPLC (DAICEL CHIRALPAK OJ-H, hexane/IPA = 90/10, 0.6 mL/min,
230 nm) tr (major) = 8.42 min, tr (minor) = 8.78 min. 1H NMR
(300 MHz, CDCl3) d 1.49 (s, 9H), 2.06–2.17 (m, 2H), 2.33–2.45 (m,
2H), 2.48–2.59 (m, 1H), 2.66–2.76 (m, 1H). 13C NMR (100 MHz,
8. (a) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Commun. 2000, 2211–2212;
(b) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem. 2001, 113, 3083–
3085. Angew. Chem., Int. Ed. 2001, 40, 2995–2997; (c) Juhl, K.; Jørgensen, K. A. J.
Am. Chem. Soc. 2002, 124, 2420–2421; (d) Marigo, M.; Kjærsgaard, A.; Juhl, K.;
Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359–2367; (e) Marigo,

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253
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11. Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S. Tetrahedron Lett. 2005,
46, 623–626.
9. (a) Marigo, M.; Kumaragurubaran, N.; Jorgensen, K. A. Chem. Eur. J. 2004, 10,
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12. Compounds 1c–1e and 1g were isolated as two isomeric mixtures (E- and Z-
isomer), which can be identified by NMR spectra, but we cannot separate them
from each other by column chromatography on SiO2.
10. Rajaram, S.; Sigman, M. S. Org. Lett. 2002, 4, 3399–3401.