Synthesis of new dimeric-PEG-supported cinchona ammonium salts as chiral phase transfer catalysts for the alkylation of Schiff bases with water as the solvent

Article abstract of DOI:10.1016/j.tetasy.2006.12.024

The water-soluble PEG-supported cinchona ammonium salts were successfully synthesized and used as chiral phase transfer catalysts for the asymmetric alkylation of tert-butyl benzophenone Schiff base derivatives with high chemical yields (up to 98%) and en

Full text of DOI:10.1016/j.tetasy.2006.12.024

Tetrahedron: Asymmetry 18 (2007) 108–114
Synthesis of new dimeric-PEG-supported cinchona
ammonium salts as chiral phase transfer catalysts for the
alkylation of Schiff bases with water as the solvent
Xin Wang, Liang Yin, Ting Yang and Yongmei Wang*
Department of Chemistry, NanKai University, 300071 Tianjin, China
Received 23 October 2006; accepted 21 December 2006
Abstract—The water-soluble PEG-supported cinchona ammonium salts were successfully synthesized and used as chiral phase transfer
catalysts for the asymmetric alkylation of tert-butyl benzophenone Schiff base derivatives with high chemical yields (up to 98%) and
enantioselectivities (up to 97%) in aqueous media. The recycling results showed that the polymers were stable and rarely lost activities.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1
. Introduction
of the cinchona alkaloids could catalyze the process, typi-
cally leading to enantioselectivities in the range of 42–
66% ee. Later, the same group demonstrated that N-benz-
5
Chiral phase transfer catalysis (CPTC) is a very useful
approach that typically involves simple experimental oper-
ations, mild reaction conditions, inexpensive, environmen-
tally benign reagents and large-scale reactions. The CPTC
methodology has been applied to the Michael addition,
yl-O-alkyl cinchona alkaloids derivatives generated in the
reactions could lead to remarkably higher enantiomeric ex-
1
6
cess. Finally, the third generation of catalysts, cinchona
2
a,b
alkaloids with the bulky group N-anthracenylmethyl in-
stead of the benzyl group, was reported in 1997 indepen-
2
c–h
2i
Darzen reaction,
tion,
cyclopropanation, aldol condensa-
2
j–l
2m–o
2p–r
6a
6b
7
fluorination,
epoxidation,
and alkylation,
dently by Lygo and Corey. Recently, dimeric and
8
9
0
reactions amongst others.
trimeric cinchona alkaloid derivatives, guanidinium salts,
C -symmetric ammonium salts derived from BINOL,
phosphonium salts, TADDOL, tartaric derivatives,
and other metal catalysts have emerged as powerful
variants.
1
2
1
1
12
13
Among these, asymmetric alkylation of tert-butyl benzo-
phenone Schiff base derivatives 1 has received much atten-
tion and been successfully applied to the enantioselective
synthesis of natural and unnatural amino acids (Scheme
1
4
3
4
1
). In 1989, O’Donnell reported that N-benzyl derivatives
With the aim of improving the efficiency of these catalytic
processes and making the ligands and catalysts readily
1
5
recoverable and recyclable, considerable effort has been
devoted to the immobilization of cinchona alkaloids on
polymers.
Ph
N
CO2t-Bu
CPTC
Ph
N
CO2t-Bu
*
RX
Ph CO
alkylation
2
Ph
Ph
R
1
2
3
H+
Our group is one of the pioneers in this research field. We
have anchored cinchona alkaloids to cross-linked polysty-
rene and used them for the asymmetric alkylation of tert-
butyl benzophenone Schiff base derivative, although the
enantioselectivity was not satisfactory. Subsequently, many
scientists had synthesized multifarious polymer-supported
chiral phase-transfer catalysts, and investigated their appli-
cations for the alkylation of tert-butyl benzophenone
Schiff’s base. For these systems, the catalytic reactions
O
H N
2
*
Ot-Bu
1
6
R
Scheme 1.
*
Corresponding author. Tel./fax: +86 22 2350 2654; e-mail: wangxinadv@
yahoo.com.cn
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.024

X. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 108–114
109
could not proceed in aqueous media. Neither the yield nor
the ee were very satisfactory, and furthermore, the recycled
polymers lost activities due to saponification. Moreover,
stringent reaction condition and the instability of the PS-
ation of tert-butyl benzophenone Schiff base derivative cat-
alyzed by the PEG supported cinchona alkaloids in
aqueous media.
1
7
PTC were difficult problems to overcome.
2
. Results and discussion
For the purpose of increasing the enantiomeric excess and
carrying out the reaction in aqueous media without any
organic solvent, we successfully synthesized the dimeric
cinchonine, which had been N-anchored to a long linear
PEG chain, and investigated asymmetric epoxidation of
chalcones catalyzed by this novel PS-PTC (the highest ee
was 86%). Unfortunately, since the reaction cannot pro-
ceed in water, the advantage of this catalyst could not be
revealed. Therefore, herein we report the asymmetric alkyl-
The polymers were prepared by the following method: re-
sin-supported ammonium salts 4a and 4b (Fig. 1) were ob-
tained by the reactions of diacetamido-PEG2000 chloride
19
with an excess (2 equiv) of cinchonidine and quinine,
respectively, in refluxing chloroform. After filtration and
washing thoroughly with diethyl ether, polymer-supported
quaternary ammonium chlorides 4a and 4b were obtained.
Moreover, the cinchonine-derived PEG-supported ammo-
nium salt 4c (Fig. 1) was also obtained. As cinchonine
has been considered as a pseudoenantiomer of cinchoni-
dine, its use offers a simple way of achieving opposite
enantioselection.
1
8
H
N
N
O
HO
+
The polymer supported dimeric CPTCs were tested as
water-soluble catalysts in the asymmetric alkylation of
the tert-butyl benzophenone Schiff base 1 with PEG-sup-
ported quinine 4b. Various factors that may affect the reac-
tion were examined, such as the temperature, the solvent,
the concentration and species of the inorganic base, the
amounts of the benzyl bromide and CPTC. It was found
that the reaction proceeded best in 1 M aqueous solution
of KOH (10 equiv, 2 mL) at room temperature, with benzyl
bromide (2.4 equiv) and PS-PTC (10 mol %). We also at-
tempted to perform the reaction at 0 ꢁC (Table 1, entry
9). However, the result was unsatisfactory since the PS-
PTC was deposited when the temperature was low. As
shown in Table 1, both the chemical and enantiomeric ex-
cesses are higher when the solvent is water rather than clas-
sical organic solvents. The amount of benzophenone 3 is
_
_
N
NH
O
Cl
R
R
Cl
+
N
H
HO
N
H
4
a, R=H
4
b, R=OMe
N
N
H
Cl
O
OH
+
H
N
_
_
R
N
Cl
R
H
H
+
OH
O
N
N
4
c, R=H
Figure 1.
Table 1. Asymmetric alkylation of 1 in the presence of catalyst 4b with different solvents
CH Br
2
Ph
Ph
Ph
PS-PTC 4b 10% mol
CO2t-Bu
CO2
t
-Bu
N
*
N
RT
Ph
1
2
c
d
e
Entry
Solvent
Toluene
BnBr (equiv)
Yield (%)
ee (%) Config
a
1
2.4
2.4
2.4
2.4
1.2
2.4
5.0
10.0
2.4
2.4
2.4
73
54
59
74
86
98
97
95
78
93
89
65(S)
48(S)
54(S)
71(S)
79(S)
83(S)
81(S)
82(S)
55(S)
72(S)
72(S)
a
2
2 2
CH Cl
a
3
Toluene/CH
2
Cl
2
7:3
7:3
a
4
Toluene/CHCl
1 M KOH
1 M KOH
1 M KOH
1 M KOH
1 M KOH
1 M NaOH
10 M KOH
3
5
6
7
8
b
9
1
1
0
1
a
b
c
The reaction was carried out in organic solvent (2 mL) and 13 equiv 9 M aqueous solution of KOH (0.3 mL).
The reaction was performed at 0 ꢁC.
Isolated yield.
d
e
Enantiomeric excess was determined by HPLC analysis using a chiral column (DAICEL Chiralcel OD-H) with hexane–isopropanol as an eluent.
The absolute configuration was confirmed by comparison of the HPLC retention time of an authentic sample, which was synthesized independently by
6
b
reported procedures.

110
X. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 108–114
also decreased in aqueous media. It indicated that the best
the acetamido-group, which connected cinchona and
PEG, is hardly disintegrated under the mild reaction
conditions.
way to prevent the decomposition of 2 was to use water as
2
0a
the solvent.
After optimizing the reaction condition with PS-PTC 4b,
we were also interested in the effects of other CPTCs
Encouraged by these preliminary results, different benzyl
bromides and other alkyl halides were tested as electro-
philes (Table 3). Satisfactory ees and yields were obtained
under the conditions above by alkylation with a substituted
benzyl bromide, allylic bromide, and alkyl iodide. The solid
or liquid state, and amounts of the electrophiles, which
have been reported to affect the result substantially,
showed no significant influence on the enantioselectivity
and yield in this current system. The difference may be re-
lated to the structure of our catalyst. The linking PEG
group is a high-powered surfactant, which can mix the or-
ganic compound with water, resulting in a homogeneous
reaction system, and therefore no obvious difference was
observed between solid and liquid halides. The alkylated
product could be obtained in good yields and ee with a
small quantity of electrophiles.
including PEG-supported cinchonine 4c and cinchonidine
7d
4
a, CPTC 5 reported by Thierry,1 and catalysts 6a, 6b
4
prepared by O’Donnell’s method (Fig. 2). As shown in
Table 2, the reaction afforded the best results with PS-
PTC 4b. The desired product 2 was obtained in 98% yield
and 83% ee. Under the same reaction condition, the
polymer 5 and catalysts 6a, 6b seemed to give a notable
decrease in both the chemical yield and enantioselectivity.
We were also interested in the recovery and recycling of
the polymers. Fortunately, satisfactory ee and yields were
obtained using the recovered catalysts 4b (Table 2, entries
2
0
4
–6). This reproducibility showed that the catalyst is
much more stable than other PEG-supported cinchona
1
7e
alkaloids that had been reported previously,
since
Table 2. Asymmetric alkylation of 1 with different catalysts in aqueous media
CH2Br
Ph
Ph
Ph
CPTCs 10% mol
M KOH, RT
CO2t-Bu
CO2
t
-Bu
N
*
N
1
Ph
1
2
e
f
g
Entry
Catalyst
Catalyst (equiv)
Yield (%)
ee (%) Config.
1
2
3
4b
4b
4b
4b
4b
4b
4c
4c
4c
4a
5
0.1
0.05
0.01
0.1
0.1
0.1
0.1
0.05
0.1
0.1
0.1
0.1
0.1
98
90
73
94
92
88
97
92
76
95
76
81
85
83(S)
73(S)
57(S)
82(S)
80(S)
80(S)
80(R)
69(R)
74(R)
75(S)
38(S)
61(S)
68(S)
a
4
b
5
c
6
7
8
9
d
1
1
1
1
0
1
2
3
6a
6b
a
b
c
d
e
f
Recycled catalyst for the first run.
Recycled catalyst for the second run.
Recycled catalyst for the third run.
The reaction was performed with toluene/CHCl
Isolated yield.
3
7:3 as the solvent.
Enantiomeric excess was determined by HPLC analysis using a chiral column (DAICEL Chiralcel OD-H) with hexane–isopropanol as an eluent.
g
The absolute configuration was confirmed by comparison of the HPLC retention time of an authentic sample, which was synthesized independently by
6
b
reported procedures.
O
-
MeO-PEG5
000
O
Cl
_
N
O
Br
+
N
+
OR
N
N
6
a R=H
5
6b R=allyl
Figure 2.

X. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 108–114
111
Table 3. Asymmetric alkylation of 1 in the presence of catalyst 4b with various electrophiles in aqueous media
Ph
Ph
Ph
PS-PTC 4b 10% mol
M KOH, RT
CO2t-Bu
CO2
t
-Bu
N
*
N
RX
1
Ph
R
1
2
a
b
c
Entry
RX
No.
Yield (%)
ee (%) Config.
1
2
3
4
5
6
7
8
9
PhCH
2
Br
PhCH
PhCH
PhCH
o-ClPhCH Br
m-ClPhCH Br
p-ClPhCH Br
CH @CHCH
2a
2b
2c
2d
2e
2f
98
84
86
91
94
83
82
77
82
79
83(S)
82(S)
90(S)
85(S)
97(S)
92(S)
91(S)
86(S)
90(S)
83(S)
o-CH
m-CH
p-CH
3
2
Br
Br
Br
3
2
3
2
2
2
2
2g
2h
2i
2
2
Br
C
2
H
5
I
1
0
CH
3
I
2j
a
b
c
Isolated yield.
Enantiomeric excess was determined by HPLC analysis using a chiral column (DAICEL Chiralcel OD-H) with hexane–isopropanol as an eluent.
The absolute configuration was confirmed by comparison of the HPLC retention time of an authentic sample, which was synthesized independently by
reported procedures.
3
a,6a,b,11a,8
3
. Conclusion
days at 20 ꢁC); IR (KBr) m: 3422, 3218, 3068, 2885, 1678,
590, 1510, 1467, 1360, 1344, 1281, 1242, 1112, 1061,
1
ꢁ1 1
In summary, we have successfully synthesized the water-
soluble PS-PTC, which can catalyze the asymmetric alkyl-
ation of tert-butyl benzophenone Schiff base derivatives
with high chemical yields and enantioselectivities in aque-
ous media. In addition, due to the stability of the catalyst,
we obtained steady yield and ee with the recycled PS-PTC.
Further research focusing on the application of PS-PTC is
under investigation in our laboratory.
963, 842, 779 cm ; H NMR (300 MHz, CDCl ): d 9.37–
3
9.34 (m, 2H), 8.92 (d, 2H, J = 4.5 Hz), 8.10 (d, 2H,
J = 8.4 Hz), 7.97 (d, 2H, J = 7.5 Hz), 7.83 (d, 2H, J =
4.5 Hz), 7.66 (d, 2H, J = 8.1 Hz), 7.59 (d, 2H,
J = 6.9 Hz), 5.58–5.44 (m, 2H), 5.24 (d, 2H, J = 17.1 Hz),
5.00 (d, 2H, J = 10.2 Hz), 4.92–4.89 (m, 2H), 4.79–4.71
(m, 2H), 4.42–4.27 (m, 4H), 3.89–3.71 (m, 2H, PEG),
3.66–3.53 (m, PEG), 3.41–3.37 (m, 2H, PEG), 2.77–2.76
(
0
m, 2H), 2.26–1.92 (m, 16H), 1.15–1.07 (m, 2H), 0.81–
.76 (m, 2H); C NMR: d 164.6, 139.1, 136.9, 136.8,
1
3
4. Experimental
130.3, 128.1, 124.8, 123.6, 123.1, 117.4, 110.0, 106.4, 70.7,
9.0, 65.7, 65.0, 61.8, 59.8, 56.4, 38.0, 26.3, 25.7, 21.9.
6
All the reagents and solvents employed the best grade
available and were used without further purification. The
H NMR and C NMR spectra were recorded on a Bruker
4.1.2. Characterization of PS-PTC ammonium salts 4b.
A
1
13
20
light brown solid, mp 45–46 ꢁC; ½aꢀ ¼ ꢁ20:2 (c 0.4,
D
AC-P300 instrument in CDCl . Melting points were deter-
CH Cl ); solubility in water: 245 mg/mL (stable for several
3
2
2
mined using an electrothermal apparatus and are uncor-
rected. Optical rotations were measured on a Perkin–
Elmer 341 Polarimeter at 20 ꢁC. Enantiomeric excesses
were determined by HPLC using Daicel Chiralcel OD-H
columns with racemic products as standards.
days at 20 ꢁC); IR (KBr) m: 3421, 3210, 3077, 2884, 1677,
1621, 1588, 1560, 1508, 1467, 1359, 1344, 1280, 1241,
ꢁ
1 1
1112, 963, 841, 779 cm ; H NMR (300 MHz, CDCl ): d
3
9.26–9.20 (m, 2H), 8.77 (d, 2H, J = 4.8 Hz), 8.09 (d, 2H,
J = 9 Hz), 7.96–7.87 (m, 4H), 7.41–7.37 (m, 2H), 5.62–
5.52 (m, 2H), 5.29 (d, 2H, J = 17 Hz), 5.07 (d, 2H,
4
.1. General procedure for the synthesis of PEG-supported
ammonium salts 4a, 4b, and 4c
J = 12 Hz), 4.95–4.84 (m, 2H), 4.57–4.51 (m, 2H), 4.09–
4.06 (m, 4H), 3.89–3.80 (m, 4H, PEG), 3.66–3.51 (m,
PEG), 3.47 (s, 6H), 2.80–2.70 (m, 4H), 2.18–1.81 (m,
14H), 1.11–0.95 (m, 4H); C NMR: d 164.8, 158.6,
137.4, 137.3, 137.0, 131.2, 126.2, 122.9, 120.5, 117.1,
110.0, 101.4, 70.7, 69.0, 66.2, 63.6, 61.7, 59.7, 57.5, 56.9,
37.9, 26.4, 25.8, 22.3.
1
3
To a suspension of cinchonine, cinchonidine, or quinine
(
2 mmol) in chloroform (20 mL) was added diacetamido-
PEG2000 chloride (0.5 equiv), and the mixture was stirred
at reflux for 100 h. The reaction mixture was cooled to room
temperature and the solid was filtered, evaporated in vacuo.
Diethyl ether (25 mL) was added to the residue, frozen, and
the solid was filtered. The crude product thus obtained was
crystallized from dichloromethane–diethyl ether mixture to
afford the polymer-supported ammonium salts.
4.1.3. Characterization of PS-PTC ammonium salts 4c.
A
2
0
red solid, mp 44–46 ꢁC; ½aꢀ ¼ þ45:3 (c 0.4, CH Cl ); Sol-
D
2
2
ubility in water: 180 mg/mL (stable for several days at
20 ꢁC); IR (KBr) m: 3404, 3210, 3040, 2956, 1690, 1637,
ꢁ
1
1
590, 1510, 1462, 1425, 1386, 1310, 931, 855, 779 cm ;
1
4
.1.1. Characterization of PS-PTC ammonium salts 4a.
A
H NMR (300 MHz, CDCl ): d 9.39–9.36 (m, 2H), 8.92
3
20
light yellow solid, mp 48–50 ꢁC; ½aꢀ ¼ ꢁ15:6 (c 0.4,
(d, 2H, J = 4.5 Hz), 8.07–7.92 (m, 4H), 7.85 (d, 2H,
J = 4.5 Hz), 7.63–7.50 (m, 4H), 6.01–5.82 (m, 2H), 5.57
D
CH Cl ); solubility in water: 175 mg/mL (stable for several
2
2

112
X. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 108–114
(
4
d, 2H, J = 14.7 Hz), 5.31–5.25 (m, 4H), 4.77–4.64 (m, 4H),
.46–4.41 (m, 2H), 4.17–4.06 (m, 4H), 3.90–3.86 (m, 2H,
PEG), 3.65–3.54 (m, PEG), 3.45–3.39 (m, 2H, PEG),
(300 MHz, CDCl ): d 7.72–7.69 (m, 3H, Ph–H), 7.58–7.50
3
(m, 5H, Ph–H), 7.30–7.26 (m, 2H, Ph–H), 7.06–7.03 (m,
2H, Ph–H), 6.61–6.56 (m, 2H, Ph–H), 4.24–4.09 (dd, 1H,
J = 9.2, 4.4 Hz, CHC@O), 3.18–3.13 (dd, 2H, J = 13.6,
9.2 Hz, PhCH ), 2.28 (s, 3H, CH ), 1.44 (s, 9H, t-Bu)
2
0
1
1
2
.78–2.46 (m, 6H), 2.27–2.19 (m, 2H), 1.97–1.77 (m, 6H),
1
3
.96–0.85 (m, 4H); C NMR: d 163.9, 139.4, 138.6,
35.1, 131.8, 128.7, 124.8, 123.9, 123.8, 118.7, 110.0,
03.0, 70.8, 70.0, 65.9, 61.9, 59.6, 55.7, 38.3, 27.1, 24.1,
1.2.
2
3
ppm; IR (neat) 2972, 2927, 1732, 1621, 1511, 1444, 1367,
ꢁ1
1286, 1151, 894, 840, 762 cm ; HPLC analysis: DAICEL
Chiralcel OD-H, hexane/isopropanol = 99.5:0.5, flow
rate = 0.5 mL/min, retention time: 20.6 min (R) and
24.5 min (S).
4
.2. General procedure for asymmetric alkylation of tert-
butyl benzophenone Schiff base derivatives with PS-PTC 4a,
b, and 4c
4
4.2.4. (S)-tert-Butyl-3-(4-methylphenyl)-2-diphenylmethyl-
ene amino propanoate 2d (Table 3, entry 4). Yield: 91%;
2
0
1
Poly(ethylene glycol)-2000 supported cinchona alkaloid
0.02 mmol) and N-(diphenylmethylene)-glycine tert-butyl
½aꢀ ¼ ꢁ15:7 (c 0.2, CHCl3); ee = 85%;
H NMR
D
(
(300MHz, CDCl ) d: 7.72–7.69 (m, 1H, Ph–H), 7.60–7.50
3
ester (59 mg, 0.2 mmol) dissolved in 2 mL of 1 M aqueous
potassium hydroxide solution at room temperature. After
the dropwise addition of benzyl bromide (0.48 mmol), the
reaction mixture was further stirred for 6 h at room tem-
perature (determined by TLC). Then 10 mL water was
added, and the resulting mixture was extracted by CH Cl
(m, 3H, Ph–H), 7.32–7.29 (m, 4H, Ph–H), 7.05–7.03 (m,
4H, Ph–H), 6.64–6.62 (m, 2H, Ph–H), 4.13–4.07 (m, 1H,
CHC@O), 3.19–3.18 (m, 2H, PhCH ), 2.26 (s, 3H,
2
CH ),1.44 (s, 9H, t-Bu) ppm; IR (neat) 2978, 2928, 1735,
3
1624, 1516, 1447, 1367, 1286, 1151, 910, 845, 779,
ꢁ1
696 cm ; HPLC analysis: DAICEL Chiralcel OD-H, hex-
ane/isopropanol = 99.5:0.5, flow rate = 0.5 mL/min, reten-
tion time: 12.8 min (S) and 21.2 min (R).
2
2
(
10 mL · 3). The combined organic phase was washed with
water (10 mL · 2), dried over anhydrous sodium sulfate,
filtered off, and evaporated in vacuo. Diethyl ether
(
15 mL) was added in the residue, shaken, and then stilled.
4.2.5. (S)-tert-Butyl-3-(2-chlorophenyl)-2-diphenylmethylene
amino propanoate 2e (Table 3, entry 5). Yield: 94%;
The polymeric catalyst was filtered and reclaimed. The
solution was concentrated under reduced pressure to give
the crude product 2. Further purification by column chro-
matography on silica gel (petroleum/ethyl acetate 30:1 as
2
0
1
½aꢀ ¼ ꢁ16:3 (c 0.2, CHCl3); ee = 97%;
H NMR
D
(300 MHz, CDCl ): d 7.62–7.61 (m, 2H, Ph–H), 7.41–7.39
3
(m, 2H, Ph–H), 7.38–7.27 (m, 6H, Ph–H), 7.17–7.12 (t,
the eluent, neutralized with 1% Et N) afforded 2 as a color-
1H, J = 7.2 Hz, Ph–H), 7.06–7.04 (m, 3H, Ph–H), 4.39–
3
less oil.
4.38 (m, 1H, CHC@O), 3.48–3.47 (m, 2H, PhCH ), 1.47
2
(
s, 9H, t-Bu) ppm; IR (neat) 2978, 2928, 1728, 1626,
ꢁ1
4
.2.1. (S)-tert-Butyl-3-phenyl-2-diphenylmethylene amino
¼
1508, 1447, 1369, 1285, 1221, 1148, 841, 781, 698 cm ;
2
D
0
propanoate 2a (Table 3, entry 1). Yield: 98%; ½aꢀ
HPLC analysis: DAICEL Chiralcel OD-H, hexane/isopro-
panol = 99.5:0.5, flow rate = 0.5 mL/min, retention time:
15.6 min (R) and 17.8 min (S).
1
ꢁ
12:6 (c 0.2, CHCl ); ee = 83%; HNMR (300 MHz,
3
CDCl ): d 7.56–7.58 (m, 2H, Ph–H), 7.26–7.38 (m, 6H,
3
Ph–H), 7.13–7.21 (m, 3H, Ph–H), 7.04–7.06 (m, 2H, Ph–
H), 6.60 (br d, 2H, J = 6.0 Hz, Ph–H), 4.10 (dd, 1H,
J = 4.4, 9.6 Hz, CHC@O), 3.23 (dd, 1H, J = 4.4, 13.6 Hz,
PhCH ), 3.15 (dd, 1H, J = 9.6, 13.6 Hz, PhCH ), 1.44 (s,
4.2.6. (S)-tert-Butyl-3-(3-chlorophenyl)-2-diphenylmethylene
amino propanoate 2f (Table 3, entry 6). Yield: 83%;
2
0
1
½aꢀ ¼ ꢁ16:6 (c 0.2, CHCl3); ee = 92%;
H NMR
2
2
D
9
1
H, t-Bu) ppm; IR (neat): 2978, 1732, 1624, 1576, 1495,
(300 MHz, CDCl ): d 7.60–7.57 (m, 2H, Ph–H), 7.57–7.36
3
ꢁ
1
447, 1367, 1286, 1150, 1082, 1030, 849, 756, 696 cm
;
(m, 6H, Ph–H), 7.14–7.12 (m, 2H, Ph–H), 7.07–6.91 (m,
HPLC analysis: DAICEL Chiralcel OD-H, hexane/isopro-
panol = 99.5:0.5, flow rate = 0.5 mL/min, retention time:
2H, Ph–H), 6.68–6.66 (m, 2H, Ph–H), 4.13–4.11 (m, 1H,
CHC@O), 3.21–3.19 (m, 2H, PhCH ), 1.46 (s, 9H, t-Bu)
2
1
6.9 min (R) and 24.1 min (S).
ppm; IR (neat) 2974, 2921, 1726, 1624, 1506, 1447, 1369,
ꢁ1
1
286, 1148, 865, 787, 742 cm ; HPLC analysis: DAICEL
4
.2.2. (S)-tert-Butyl-3-(2-methylphenyl)-2-diphenylmethyl-
Chiralcel OD-H, hexane/isopropanol = 99.5:0.5, flow
rate = 0.5 mL/min, retention time: 14.8 min (S) and
21.8 min (R).
ene amino propanoate 2b (Table 3, entry 2). Yield: 84%;
2
D
0
1
½
aꢀ ¼ ꢁ14:1 (c 0.2, CHCl3); ee = 82%;
H NMR
(
(
300 MHz, CDCl ): d 7.72–7.69 (m, 3H, Ph–H), 7.59–7.50
3
m, 3H, Ph–H), 7.32–7.29 (m, 4H, Ph–H), 7.08–6.63 (m,
4.2.7. (S)-tert-Butyl-3-(4-chlorophenyl)-2-diphenylmethylene
amino propanoate 2g (Table 3, entry 7). Yield: 82%;
4
3
1
1
H, Ph–H), 4.08–3.19 (dd, 1H, J = 9.2, 4.4 Hz, CHC@O),
2
D
0
1
.17 (dd, 2H, J = 13.6, 9.2 Hz, PhCH ), 2.26 (s, 3H, CH ),
½aꢀ ¼ ꢁ15:8 (c 0.2, CHCl3); ee = 91%;
H NMR
2
3
.44 (s, 9H, t-Bu) ppm; IR (neat) 2972, 2927, 1732, 1621,
511, 1444, 1367, 1286, 1151, 894, 840, 762 cm ; HPLC
(300 MHz, CDCl ): d 7.62–7.60 (m, 2H, Ph–H), 7.36–7.25
3
ꢁ
1
(m, 6H, Ph–H), 7.16 (d, 2H, J = 8.0 Hz, Ph–H), 7.04 (d,
analysis: DAICEL Chiralcel OD-H, hexane/isopropa-
nol = 99.5:0.5, flow rate = 0.5 mL/min, retention time:
1H, J = 8.0 Hz, Ph–H), 6.63 (m, 3H, Ph–H), 4.48 (m,
1H, CHC@O), 3.69–3.48 (m, 2H, PhCH ), 1.45 (s, 9H, t-
2
2
0.7 min (R) and 29.6 min (S).
Bu) ppm; IR (neat) 2978, 1732, 1661, 1622, 1560, 1437,
ꢁ
1
1
369, 1286, 1148, 841, 787, 698 cm ; HPLC analysis:
4
.2.3. (S)-tert-Butyl-3-(3-methylphenyl)-2-diphenylmethyl-
DAICEL Chiralcel OD-H, hexane/isopropanol = 99.5:0.5,
flow rate = 0.5 mL/min, retention time: 12.1 min (S) and
21.1 min (R).
ene amino propanoate 2c (Table 3, entry 3). Yield: 86%;
2
0
1
½
aꢀ ¼ ꢁ13:7 (c 0.2, CHCl3); ee = 90%;
H NMR
D

X. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 108–114
113
4
.2.8. (S)-tert-Butyl-3-(2-allyl)-2-diphenylmethylene amino
¼
T. Tetrahedron Lett. 1998, 39, 8299–8302; (g) Arai, S.; Shioiri,
T. Tetrahedron 2002, 58, 1407–1413; (h) Arai, S.; Tokumaru,
K.; Aoyama, T. Tetrahedron Lett. 2004, 45, 1845–1848; (i)
Arai, S.; Nakayama, K.; Ishida, T.; Shioiri, T. Tetrahedron
Lett. 1999, 40, 4215–4218; (j) Horikawa, M.; Buch-Petersen,
J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843–3846; (k)
Ooi, T.; Doda, K.; Maruoka, K. Org. Lett. 2001, 3, 1273–
2
D
0
propanoate 2h (Table 3, entry 8). Yield: 77%; ½aꢀ
1
ꢁ
11:4 (c 0.2, CHCl ); ee = 86%; H NMR (300 MHz,
3
CDCl ): d 7.65–7.62 (m, 2H, Ph–H), 7.47–7.29 (m, 6H,
3
Ph–H), 7.20–7.16 (m, 2H, Ph–H), 5.62–5.60 (m, 1H,
CH@CH ), 5.03 (dd, 1H, J = 17.2, 1.5 Hz, CH@CH ),
5
2
2
.01 (dd, 1H, J = 10.2, 1.5 Hz, CH@CH ), 4.00 (dd, 1H,
2
1
276; (l) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed.
J = 7.6, 5.6 Hz, CHC@O), 2.57–2.69 (m, 2H, CH2–
1999, 38, 1931–1934; (m) Kim, D. Y.; Park, E. J. Org. Lett.
2002, 4, 545–547; (n) Shibata, N.; Suzuki, E.; Takeuchi, Y. J.
Am. Chem. Soc. 2000, 122, 10728–10729; (o) Mohar, B.;
Baudoux, J.; Plaquevent, J.-C.; Cahard, D. Angew. Chem.,
Int. Ed. 2001, 40, 4214–4216; (p) Brown, R. C. D.; Keily, J. F.
Angew. Chem., Int. Ed. 2001, 40, 4496–4498; (q) Arai, S.;
Tsuge, H.; Oku, M.; Miura, M.; Shioiri, T. Tetrahedron 2002,
CH@CH ), 1.44 (s, 9H, t-Bu) ppm; IR (neat) 2978, 1735,
1
HPLC analysis: DAICEL Chiralcel OD-H, hexane/isopro-
panol = 99.5:0.5, flow rate = 0.5 mL/min, retention time:
9
2
ꢁ
1
624, 1447, 1367, 1286, 1151, 916, 847, 781, 696 cm ;
.3 min (S) and 10.9 min (R).
5
8, 1623–1630; (r) Lygo, B.; To, D. C. M. Tetrahedron Lett.
4
.2.9. (S)-tert-Butyl-3-ethyl-2-diphenylmethylene amino pro-
20
2001, 42, 1343–1346.
panoate 2i (Table 3, entry 9). Yield: 82%; ½aꢀ ¼ ꢁ12:2 (c
D
3. (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998,
39, 5347–5350; (b) Lygo, B. Tetrahedron Lett. 1999, 40, 1389–
1
0
7
7
.2, CHCl ); ee = 90%; H NMR (300 MHz, CDCl ): d
3
3
.62–7.65 (br m, 2H, Ph–H), 7.30–7.50 (m, 6H, Ph–H),
.17–7.20 (m, 2H, Ph–H), 3.85 (dd, 1H, J = 5.7, 3.9 Hz,
1
392; (c) Lygo, B.; Andrews, B. I.; Slack, D. Tetrahedron
Lett. 2003, 44, 9039–9041; (d) Ooi, T.; Tayama, E.; Maruoka,
K. Angew. Chem., Int. Ed. 2003, 42, 579–582.
CHC@O), 1.86–1.95 (m, 2H, CH CH ), 1.44 (s, 9H, t-
Bu), 0.87 (t, 3H, J = 5.4 Hz, CH ) ppm; IR (neat) 2978,
1
ysis: DAICEL Chiralcel OD-H, hexane/isopropa-
nol = 99.5:0.5, flow rate = 0.5 mL/min, retention time:
1
2
3
4. O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
3
ꢁ
1
1
989, 111, 2353–2355.
. O’Donnell, M. J.; Wu, S.; Hoffman, J. C. Tetrahedron 1994,
0, 4507–4518.
. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
595–8598; (b) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem.
735, 1624, 1447, 1367, 1279, 1153, 696 cm ; HPLC anal-
5
6
5
1.6 min (S) and 13.3 min (R).
8
Soc. 1997, 119, 12414–12415; (c) Park, H.-g.; Jeong, B.-S.;
Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.;
Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036–3038; (d)
Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-g.
Org. Lett. 2002, 4, 4245–4248.
. Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-g.
Chem. Commun. 2001, 1244–1245.
. Park, H.-g.; Jeong, B.-s.; Yoo, M.-s.; Park, M.-k.; Huh, H.;
Jew, S.-s. Tetrahedron Lett. 2001, 42, 4645–4648.
. Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Naga-
sawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832–2834.
4
.2.10. (S)-tert-Butyl-3-methyl-2-diphenylmethylene amino
¼
2
D
0
propanoate 2j (Table 3, entry 10). Yield: 79%; ½aꢀ
1
ꢁ
10:8 (c 0.2, CHCl ); ee = 83%; H NMR (300 MHz,
3
CDCl ): d 7.62–7.65 (m, 2H, Ph–H), 7.51–7.30 (m, 6H,
3
7
8
9
Ph–H), 7.20–7.17 (m, 2H, Ph–H), 4.03 (q, 1H,
J = 6.8 Hz, CHC@O), 1.46 (d, 3H, J = 6.8 Hz, CH3),
1
1
.44 (s, 9H, t-Bu) ppm; IR (neat) 2978, 1735, 1624, 1447,
367, 1286, 1153, 1030, 849, 781, 696 cm ; HPLC analy-
ꢁ1
sis: DAICEL Chiralcel OD-H, hexane/isopropa-
nol = 99.5:0.5, flow rate = 0.5 mL/min, retention time:
1
0. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
999, 121, 6519–6520; (b) Ooi, T.; Uematsu, Y.; Kameda, M.;
1
0.7 min (S) and 12.0 min (R).
1
Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551–1554; (c)
Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 5139–5151.
Acknowledgements
1
1
1. (a) Manabe, K. Tetrahedron Lett. 1998, 39, 5807–5810; (b)
Manabe, K. Tetrahedron 1998, 54, 14465–14476.
The authors thank the National Natural Science Founda-
tion of China (20472032) and the State Key Laboratory
of Elemento-Organic Chemistry for financial support.
2. (a) Belokon, Y. N.; Kotchetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.;
Parmar, V. S.; Kumar, R.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 851–857; (b) Belokon, Y. N.; Kotchet-
kov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov,
A. A.; Larionov, O. V.; Singh, I.; Parmar, V. S.; Vyskocil, S.;
Kagan, H. B. J. Org. Chem. 2000, 65, 7041–7048.
References
1
. (a) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer
Catalysis, 3rd ed.; VCH: Weinheim, 1993; (b) Starks, C.
M.; Liotta, C. L.; Halpern, M. Phase Transfer Catalysis—
Fundamentals, Applications and Industrial Perspectives; Chap-
man and Hall: New York, 1994; (c) Phase Transfer Catalysis
Symposium Series; Halpern, M. E., Ed.; American Chemical
Society, ACS: Washington, DC, 1995; Vol. 659; (d) Maruoka,
K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028.
13. Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43,
9535–9537.
14. (a) Belokon, Y. N.; Davies, R. G.; North, M. Tetrahedron
Lett. 2000, 41, 7245–7248; (b) Belokon, Y. N.; Kochetkov, K.
A.; Churkina, T. D.; Ikonnikov, N. S.; Vyskocil, S.; Kagan,
H. B. Tetrahedron: Asymmetry 1999, 10, 1723–1728; (c)
Belokon, Y. N.; North, M.; Churkina, T. D.; Ikonnikov, N.
S.; Maleev, V. I. Tetrahedron 2001, 57, 2491–2498; (d) Tzalis,
D.; Knochel, P. Tetrahedron Lett. 1999, 40, 3685–3688; (e)
Belokon, Y. N.; Bhave, D.; D’Addario, D.; Groaz, E.;
Maleev, V.; North, M.; Pertrosyan, A. Tetrahedron Lett.
2003, 44, 2045–2048.
2
. (a) Ma, D.; Cheng, K. Tetrahedron: Asymmetry 1999, 10,
7
13–719; (b) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Isobe,
T.; Seki, H.; Fukuda, K. Chem. Commun. 2001, 245–246; (c)
Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145–2148; (d)
Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999,
15. Chiral Catalyst Immobilization and Recycling; De Vos, D. E.,
Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH:
Weinheim, 2000.
5
5, 6375–6386; (e) Arai, S.; Shirai, Y.; Shioiri, T.; Ishida, T.
Chem. Commun. 1999, 49–50; (f) Arai, S.; Ishida, T.; Shioiri,

114
X. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 108–114
1
1
6. (a) Wang, Y.; Zhang, Zh.; Wang, Zh.; Meng, J.; Hodge, P.
Adv. Synth. Catal. 2004, 346, 1186–1194; (g) Chinchilla, R.;
Maz o´ n, P.; N a´ jera, C. Molecules 2004, 9, 349–364.
18. Lv, J.; Wang, X.; Liu, J.; Zhang, L.; Wang, Y. Tetrahedron:
Asymmetry 2006, 17, 330–335.
19. (a) Neumann, M.; Geckeler, K. E. React. Funct. Polym. 1997,
33, 173–184; (b) Smith, P. A. S.; Hall, J. H.; Kan, R. O. J.
Am. Chem. Soc. 1962, 84, 485–489; (c) Speziale, A. J.; Hamm,
P. C. J. Am. Chem. Soc. 1956, 78, 2556–2559.
20. (a) Mase, N.; Ohno, T.; Morimoto, H.; Nitta, F.; Yoda, H.;
Takabe, K. Tetrahedron Lett. 2005, 46, 3213–3216; (b) Li, L.;
Zhang, Zh.; Zhu, X.; Popa, A.; Wang, Sh. Synlett 2005, 12,
1873–1876.
Chin. J. Polym. Sci. 1998, 16, 356–361; (b) Zhang, Zh.; Wang,
Y.; Wang, Zh.; Hodge, P. React. Funct. Polym. 1999, 41, 37–43.
7. (a) Chichilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asym-
metry 2000, 11, 3277–3281; (b) Baptiste, T.; Thierry, P.;
Christophe, A.; Jean-Christophe, P.; Dominique, C. Synthesis
2
001, 11, 1742–1746; (c) Thierry, B.; Plaquevent, J.-C.;
Cahard, D. Tetrahedron: Asymmetry 2001, 12, 983–986; (d)
Thierry, B.; Plaquevent, J.-C.; Cahard, D. Tetrahedron:
Asymmetry 2003, 14, 1671–1677; (e) Danelli, T.; Annunziata,
R.; Benaglia, M.; Cinquini, M. Tetrahedron: Asymmetry
2
003, 14, 461–467; (f) Chinchilla, R.; Maz o´ n, P.; N a´ jera, C.