Rational tuning of the rigidity of a ligand scaffold: synthesis of diphenylsulfide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2010.01.015

The scaffold rigidity of bis(oxazoline) ligands was rationally tuned on the basis of literature information. Diphenylsulfide-linked bis(oxazoline) ligands with a flexible scaffold were efficiently synthesized to test our hypothesis. The improved enantioselectivity in palladium-catalyzed asymmetric allylic alkylation reaction was achieved as we expected.

Full text of DOI:10.1016/j.tetasy.2010.01.015

Tetrahedron: Asymmetry 21 (2010) 241–246
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Rational tuning of the rigidity of a ligand scaffold: synthesis of
diphenylsulfide-linked bis(oxazoline) ligands and their application
in asymmetric allylic alkylation
Xian Du a, Han Liu b, Da-Ming Du a,
*
a School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
b Beijing National Laboratory for Molecular Sciences (BNLMS), College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The scaffold rigidity of bis(oxazoline) ligands was rationally tuned on the basis of literature information.
Diphenylsulfide-linked bis(oxazoline) ligands with a flexible scaffold were efficiently synthesized to test
our hypothesis. The improved enantioselectivity in palladium-catalyzed asymmetric allylic alkylation
reaction was achieved as we expected.
Received 15 December 2009
Accepted 20 January 2010
Available online 2 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
efficient chiral ligands, including both monodentate and bidentate
ligands with P, N, S, Se, and C as coordinating atoms, have been
The development of asymmetric reactions catalyzed by transi-
tion metal complexes is a rapidly developing field in organic syn-
thesis, and the endeavor for rational design and preparation of
optically active ligands which coordinate to transition metals is
very important for obtaining excellent enantioselectivity.1 C2-Sym-
metric chiral bis(oxazoline) ligands have been extensively devel-
oped by chemists in the fields of coordination chemistry,
synthetic chemistry, and catalysis in recent years.2 Their great po-
tential was illustrated by the efficient preparation from commer-
cially available amino alcohols and carboxylic acids/aldehydes
through facile procedures with high scaffold diversity. Some ligand
scaffolds stand out from vast reports and have gained broad appli-
cations in different asymmetric transformations,3 while most li-
gand scaffolds give satisfying results only in specific cases.
Therefore, the design of novel ligands for designated reactions is
still difficult and unprofitable. In order to break through this bot-
tleneck, some groups have been dedicated to the research on the
relationship between ligand structure and enantioselectivity, espe-
cially the tuning of electronic effects and the rigidity of the ligand
scaffold. Over the past two decades, encouraging results have been
achieved in the former case.4 However, much less attention has
been paid with regards to the tuning of scaffold rigidity.5 Herein,
we report our recent progress on this subject.
synthesized and tested in this transformation. A variety of nucleo-
philes such as activated methylene compounds, enolates, enam-
ines, amines, phthalimides, phenols, sodium sulfinates, and
hydride generated in situ from formate, have been involved, with
good enantioselectivities and wide applications in the construction
of natural products or other bioactive molecules.7 In 2002, Gómez
et al. reported their pioneering investigation of how the scaffold
rigidity of C2-symmetric bis(oxazoline) ligands affected the enanti-
oselectivity in asymmetric allylic alkylation.8 A series of ligands
with different scaffold rigidity were tested in the reaction. The
DBFOX type ligand with a highly rigid skeleton that had many suc-
cessful applications gave only disappointing results; the much
more flexible diphenylether-linked ligand gave quantitative con-
version and 89% ee. Schulz et al. reported the synthesis of DBFOX
analogues with a dibenzothiophene scaffold9 and the moderate
enantioselectivity obtained in the same reaction. On the basis of
Gómez’s work and our experience in the application of ligands
with flexible diphenylamine scaffold,5b,10 we postulated that
X
X
As one of the most important enantioselective C–X (X = C, N, O,
S, and H) bond formation processes, the palladium-catalyzed
asymmetric allylic substitution which was first developed by Trost
and Strege in 1977,6 has attracted attention from synthetic chem-
ists all over the world over the past three decades. A plethora of
O
O
O
N
N
O
N
N
R
R
R
R
Rigid scaffold
Flexible scaffold
X = O enhanced enantioselectivity
X = S unknown enantioselectivity
* Corresponding author. Tel./fax: +86 10 68914985.
E-mail address: dudm@bit.edu.cn (D.-M. Du).
Figure 1. Rational tuning the rigidity of ligand scaffold.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.015

242
X. Du et al. / Tetrahedron: Asymmetry 21 (2010) 241–246
diphenylsulfide-linked bis(oxazoline) ligands11 should give high
catalytic activity and enantioselectivity (Fig. 1).
Table 1
Optimization of ligands and solvents for asymmetric allylic alkylationa
Entry
Ligand
Solvent
Conversionb (%)
eec (%)
2. Results and discussion
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1c
1c
1c
1d
1d
CH2Cl2
CH2Cl2
CH2Cl2
THF
Toluene
ClCH2CH2Cl
EtOH
>99
>99
>99
>99
>99
0
0
>99
>99
64
60
82
87
89
n.d.
n.d.
86
91
The diphenylsulfide-linked ligands 1a–d were synthesized from
thiosalicylic acid in six steps, via esterification,12 Ullmann cou-
pling, saponification, and oxazoline construction (Scheme 1). A di-
rect synthesis of acid 6 from 2-iodobenzoic acid and Na2S was
abandoned because of the high cost of anhydrous Na2S and the
harsh reaction conditions.13 Ligands 1a–d were all obtained in
good yields. With the desired ligands in hand, the effect of scaffold
CH2Cl2
Toluene
a
Unless noted otherwise, reactions were carried out with 1 equiv of (E)-1,3-
diphenylprop-2-en-1-yl acetate (0.5 mmol), 3 equiv of ethyl malonate (1.5 mmol),
6 mol % ligand, 2.5 mol % [Pd(
3-C3H5)Cl]2, 0.2 equiv of KOAc and 3.0 equiv of BSA
rigidity on enantioselectivity was tested with 2.5 mol % [Pd(g3
-
g
C3H5)Cl]2 and 6 mol % ligand, using (E)-1,3-diphenylprop-2-en-1-
yl acetate 9 as model substrate and diethyl malonate 10 as the
nucleophile (Scheme 2). The encouraging results are summarized
in Table 1. As we expected, our ligands with a flexible scaffold gave
good catalytic reactivity in the asymmetric allylic alkylation. Full
conversion can be achieved within 24 h at room temperature in
CH2Cl2. For further optimizing the reaction conditions, other sol-
vents were then screened. The enantioselectivity was improved
to 87% ee and 89% ee in THF and toluene, respectively (entries 4
and 5), while ClCH2CH2Cl with a chelating ability and the protic
solvent ethanol inhibit the reaction (entries 6 and 7). Considering
the relationship of the ligand steric effect and the enantioselectiv-
ity, the more bulky ligand 1d was tested. As expected, a further
improvement of enantioselectivity was observed (entries 8 and
9). Considering the smooth conversion of the starting material
in a mixture of 2 mL of solvent for 24 h at room temperature.
b
Conversion isolated after silica gel chromatography.
Determined by HPLC.
c
and good enantioselectivity of the product, further variation of
the catalyst loading was not examined.
Encouraged by the above-mentioned results, substrates (on a
0.5 mmol scale) and nucleophiles (1.5 mmol) scopes were investi-
gated in this reaction using 2.5 mol % [Pd(g
3-C3H5)Cl]2, 6 mol % li-
gand 1d, BSA (1.5 mmol) and anhydrous KOAc (0.10 mmol) in 2 mL
of toluene at room temperature. As illustrated in Figure 2, dimethyl
malonate gave the desired product 12 in 89% ee (whereas, 51% ee
was obtained in Schulz’s reports using the corresponding t-Bu
substituted DBT-Box, up to 77% ee was obtained with i-Pr substi-
I
CO2CH3
SH
SH
5% H2SO4
4
S
CH3OH, reflux
43%
0.5 equiv. Cu2O
pyridine,115 C, 22 h
CO2H
CO2CH3
CO2CH3
CO2CH3
º
3
2
5
88%
H2N
R
OH
S
SOCl2
reflux
NaOH
7a-d
S
Et3N, CH2Cl2
reflux
93%
HN
O
O
NH
CO2H
CO2H
OH HO
R
R
6
8a-d
R = Ph 95%
Bn 94%
i-Pr
92%
1) MeSO2Cl, Et3N
t-Bu
S
75%
2) NaOH/MeOH/H2O
reflux
R = Ph 92%
Bn 94%
O
N
N
O
i-Pr
73%
R
R
t-Bu
57%
1a d
-
Scheme 1. Synthesis of diphenylsulfide-linked bis(oxazoline) ligands.
1a-d 6 mol%
[Pd(η -C3H5)Cl]2 2.5 mol%
EtO2C
Ph
CO2Et
Ph
OAc
Ph
3
CH2(CO2Et)2
+
KOAc 0.2 equiv.
Ph
BSA 3.0 equiv.
10
9
11
rt, 24 h
Scheme 2. Asymmetric allylic alkylation of (E)-1,3-diphenylprop-2-en-1-yl acetate.

X. Du et al. / Tetrahedron: Asymmetry 21 (2010) 241–246
243
O
MeN
O
NMe
O
EtO2C
CO2Et
MeO2C
CO2Me
11
98% yield
91% ee
12
13
84% yield
73% yield
89% ee
85% ee
O
MeN
O
NMe
EtO2C
CO2Et
MeO2C
CO2Me
O
16
14
15
80% yield
98% yield
95% yield
42% ee
94% ee
94% ee
Figure 2. Substrate scope of the asymmetric allylic alkylation.
tuted DBT-Box.9). 1,3-Dimethylbarbituric acid also gave the de-
4. Experimental
sired product 13 in 85% ee. Slightly lower yields of 12 and 13 were
obtained in prolonged reaction times. The 1-naphthyl-substituted
substrate14 gave higher enantioselectivities (up to 94% ee) when
malonates were used, while only 42% ee was obtained using 1,3-
dimethylbarbituric acid. To the best of our knowledge, this was
the first time that 1,3-dimethylbarbituric acid was used as a nucle-
ophile in the asymmetric allylic alkylation reaction; this provides a
facile method to obtain chiral barbituric acid derivatives. Other sta-
bilized carbon nucleophiles such as nitromethane, indole deriva-
4.1. General remarks
Commercially available compounds were used without further
purification. Solvents were dried according to standard procedures.
Column chromatography was carried out using silica gel (200–300
mesh). Melting points were measured on a XT-4 melting point
apparatus without correction. The 1H NMR spectra were recorded
on a Mercury 300 MHz spectrometer, while 13C NMR spectra were
recorded at 75 MHz. Infrared spectra were obtained on a Nicolet
AVATAR 330 FTIR spectrometer. The ESIMS spectra were obtained
on Thermo Finnigan LCQ Deca XP Plus mass spectrometer. Optical
rotations were measured on Perkin–Elmer 341 or WZZ-3 spec-
trometer. The enantiomeric excesses of the products were deter-
mined by chiral HPLC using Agilent HP 1200 instrument on
Daicel Chiralpak AS-H and IA columns.
tives,
isopropylidene
malonate,
and
5,5-dimethyl-1,3-
cyclohexanedione did not give acceptable conversion. Amine
nucleophiles such as O-benzyl hydroxylamine, morpholine, and
phthalimide, were not suitable for our system, which may be
attributed to the competitive coordination of the nitrogen atom
to the palladium center. These results indicate that our tuning of
ligand scaffold rigidity is successful to some extent. Interestingly,
we noticed that the diphenylsulfide-linked bis(oxazoline) ligands
containing chiral moieties with an (S)-configuration led to the
alkylation product with an (S)-configuration as the major isomer.
This is in contrast with the result obtained when using DBT-Box,
where the (S)-configuration on the chiral ligand led to the (R)-
product as the major one. These N,S-chelating ligands act as a po-
tential tridentate ligand, but may also act as a bidentate or mono-
dentate ligand, which complicates the explanation of the exact
mechanism of asymmetric induction.9 Our results demonstrate
that a reversal in enantioselectivity can be achieved by tuning
the ligand scaffold from a rigid to a flexible one.
4.2. Synthesis of methyl thiosalicylate 312
To a 250 mL round bottom flask, thiosalicylic acid (15.4 g,
0.10 mol) and MeOH (100 mL) were added under argon, followed
by concentrated H2SO4 (0.49 g, 5 mmol). The mixture was refluxed
under argon for 24 h. Most of the solvent was removed in vacuo,
and the residue was extracted with EtOAc (3 ꢀ 100 mL). The com-
bined organic phase was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The desired product was obtained via distillation
under reduced pressure as a colorless liquid (7.20 g, 43% yield). 1H
NMR (300 MHz, CDCl3): d = 7.97 (d, J = 7.5 Hz, 1H), 7.27 (d,
J = 3.3 Hz, 2H), 7.10–7.13 (m, 1H), 4.71 (s, 1H), 3.88 (s, 3H). 13C
NMR (75 MHz, CDCl3): d = 166.7, 137.9, 132.1, 131.3, 130.6, 125.4,
124.3, 51.9.
3. Conclusion
A series of diphenylsulfide-linked bis(oxazoline) ligands with a
flexible ligand scaffold were designed on the basis of comparative
analysis of published results and synthesized with high efficiency
using commercially available, inexpensive starting materials. The
designed ligands gave good catalytic reactivity and enantioselec-
tivity in the asymmetric allylic alkylation as we predicted. The suc-
cess of our rational tuning may shed some light on ligand design
for similar transformations.
4.3. Synthesis of dimethyl 1,10-diphenylsulfide-2,20-
dicarboxylate 5
To a Schlenk tube were added methyl thiosalicylate (5.238 g,
31.2 mmol), methyl 2-iodobenzoate (8.994 g, 34.3 mmol), Cu2O
(2.246 g, 15.6 mmol), and pyridine (31.5 mL) under argon. The

244
X. Du et al. / Tetrahedron: Asymmetry 21 (2010) 241–246
mixture was heated under argon at 115 °C for 22 h. The mixture
was diluted with EtOAc (100 mL) and washed thoroughly with
water and brine. After being dried over anhydrous Na2SO4, the sol-
vent was removed in vacuo and the residue was purified by col-
umn chromatography using petroleum ether–EtOAc 20:1 as
126.5, 63.0, 53.2, 36.7. IR (neat): 3282, 3064, 2928, 1633, 1534,
1454, 1304, 1159, 1038, 739, 699 cmꢂ1. HR-ESIMS: m/z cacld for
C32H33N2O4S (M+H): 541.21610. Found: 541.21436.
4.5.3. 2,20-Bis[N-[(S)-1-hydroxymethyl-2-methylpropyl]carbam-
oyl]-1,10-diphenylsulfide 8c
Prepared according to the general procedure using 0.825 g
(3.01 mmol) acid 6 and 0.620 g (6.02 mmol) L-valinol. The product
eluent. The desired product was obtained as
a white solid
(8.292 g, 88% yield). Mp 76–78 °C (lit.15 78.0–78.5 °C). 1H NMR
(300 MHz, CDCl3): d = 7.90 (d, J = 7.5 Hz, 2H), 7.27–7.37 (m, 4H),
7.21 (d, J = 7.8 Hz, 2H), 3.85 (s, 6H). 13C NMR (75 MHz, CDCl3):
d = 167.1, 137.8, 132.7, 132.1, 131.8, 130.6, 126.7, 52.2.
was obtained as a pale yellow solid (1.220 g, 92% yield). Mp 79–
80 °C. ½a 2D0
ꢁ
¼ ꢂ55:4 (c 0.7, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d = 7.57 (d, J = 6.6 Hz, 2H), 7.27–7.30 (m, 4H), 7.19 (d, J = 7.8 Hz,
2H), 7.01 (d, J = 8.7 Hz, 2H), 3.75–3.82 (m, 4H), 3.58 (br, 4H),
1.81–1.92 (m, 2H), 0.91 (t, J = 6.3 Hz, 12H). 13C NMR (75 MHz,
CDCl3): 168.6, 137.3, 132.56, 132.55, 130.8, 129.2, 127.7, 62.6,
57.4, 29.0, 19.4, 19.0. IR (neat): 3282, 2961, 1636, 1537, 1464,
1320, 1067, 1053, 745 cmꢂ1. HR-ESIMS: m/z cacld for C24H33N2O4S
(M+H): 445.21610. Found: 445.21458.
4.4. Synthesis of 1,10-diphenylsulfide-2,20-dicarboxylic acid 6
To a 50 mL round bottom flask were added dimethyl 1,10-diphe-
nylsulfide-2,20-dicarboxylate (8.27 g, 27.4 mmol), NaOH (2.80 g,
70 mmol), MeOH (20 mL), and water (20 mL). The mixture was re-
fluxed for 3 h, and acidified with concentrated HCl (aq) after being
cooled to room temperature. The desired product was obtained
through filtration as a white solid (6.992 g, 93% yield). Mp 235–
238 °C (lit.16 227–230 °C). 1H NMR (300 MHz, DMSO-d6):
d = 13.14 (s, 2H), 7.84 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H),
7.38 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H). 13C NMR (75 MHz,
DMSO-d6): d = 167.7, 136.4, 132.9, 132.1, 132.0, 130.0, 126.9.
4.5.4. 2,20-Bis[N-[(S)-1-hydroxymethyl-2,2-dimethylpropyl]car-
bamoyl]-1,10-diphenylsulfide 8d
Prepared according to the general procedure using 0.503 g
(1.84 mmol) acid 6 and 0.431 g (3.68 mmol) L-tert-leucinol. The
product was obtained as a pale solid (0.647 g, 75% yield). Mp
211–212 °C ½a 2D0
ꢁ
¼ ꢂ16:7 (c 0.3, DMSO). 13H NMR (300 MHz,
4.5. General procedure for the preparation of bis(b-
hydroxyamide)s
DMSO): d = 7.96 (d, J = 9.6 Hz, 2H), 7.47–7.50 (m, 2H), 7.31 (dd,
J1 = 5.4 Hz, J2 = 3.3 Hz, 4H), 7.17–7.20 (m, 2H), 4.41 (t, J = 5.7 Hz,
2H), 3.78–3.85 (m, 2H), 3.61–3.67 (m, 2H), 3.39–3.48 (m, 2H),
0.91 (s, 18H). 13C NMR (75 MHz, DMSO-d6): d = 167.9, 139.9,
134.2, 132.7, 129.7, 127.9, 126.7, 60.6, 59.3, 33.8, 27.0. IR (neat):
3293, 2965, 2916, 1726, 1634, 1540, 1469, 1289, 1090, 728,
To a 50 mL round bottom flask, 1,10-diphenylsulfide-2,20-dicar-
boxylic acid (1 equiv) and SOCl2 (excess, as solvent) were added.
The mixture was refluxed at 80 °C for 4 h. The redundant SOCl2
was removed in vacuo to give a dark yellow oil. The oil was dis-
solved in CH2Cl2 (20 mL for 1 mmol substrate), and added drop-
wise to a solution of chiral amino alcohol (2 equiv) and Et3N
(5 equiv) at 0 °C. After the completion of addition, the mixture
was warmed to room temperature and stirred overnight. The reac-
tion was quenched by the addition of water, and the mixture was
extracted with CH2Cl2 (3 ꢀ 50 mL). The combined organic phase
was dried over anhydrous Na2SO4. The solvent was removed in va-
cuo and the crude product was purified by flash chromatography
using CH2Cl2–MeOH 50:1 (V/V) as eluent.
681 cmꢂ1
.
HR-ESIMS: m/z cacld for C26H37N2O4S (M+H):
473.24740. Found: 473.24801.
4.6. General procedure for the preparation of ligands
To a round bottom flask, the bis(hydroxyamide) (1 equiv) and
CH2Cl2 (20 mL for 1 mmol substrate) were added. To this mixture,
methanesulfonyl chloride (3.3 equiv) was added via syringe, fol-
lowed by Et3N (6.6 equiv). The mixture was stirred at room tem-
perature overnight. After being quenched by addition of water,
the organic phase was separated and dried with anhydrous Na2SO4.
Then the mixture was concentrated, and the residue was dissolved
in a 1:1 (V/V) mixture of MeOH and water, and refluxed in the pres-
ence of NaOH (4.0 equiv) for another 4 h. After removing the MeOH
in vacuo, the mixture was extracted with CH2Cl2 (3 ꢀ 50 mL). The
combined organic phase was washed with brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
purified by silica gel column chromatography using petroleum
ether–EtOAc 10:1 (V/V) as eluent.
4.5.1. 2,20-Bis[N-[(S)-2-hydroxy-1-phenylethyl] carbamoyl]-
1,10-diphenylsulfide 8a
Prepared according to the general procedure using 0.828 g
(3.02 mmol) acid 6 and 0.828 g (6.04 mmol) (S)-2-phenylglycinol.
The product was obtained as a white solid (1.476 g, 95% yield).
Mp 96–98 °C. ½a 2D0
ꢁ
¼ ꢂ12:9 (c 0.7 g/100 mL, CH2Cl2). 1H NMR
(300 MHz, CDCl3): d = 7.56 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 7.2 Hz,
2H), 7.15–7.31 (m, 16H), 5.06 (dd, J1 = 10.5 Hz, J2 = 6.0 Hz, 2H),
3.65–3.77 (m, 4H), 3.02 (br, 2H). 13C NMR (75 MHz, CDCl3):
d = 168.1, 138.8, 136.8, 132.9, 132.8, 131.1, 129.6, 128.7, 127.9,
127.5, 126.7, 65.7, 56.1. IR (neat): 3287, 2920, 1637, 1535, 1454,
1306, 1066, 754, 700 cmꢂ1. HR-ESIMS: m/z cacld for C30H29N2O4S
(M+H): 513.18480. Found: 513.18317.
4.6.1. 2,20-Bis[(S)-4-phenyloxazolin-2-yl]-1,10-diphenylsulfide 1a
Prepared according to the general procedure using 0.526 g
(1.03 mmol) 8a. The desired ligand was obtained as a colorless
oil (0.451 g, 92% yield). ½a D20
ꢁ
¼ ꢂ2:5 (c 0.7, CH2Cl2) 1H NMR
(300 MHz, CDCl3): d = 7.88 (d, J = 7.2 Hz, 2H), 7.19–7.38 (m, 16H),
5.36 (t, J = 9.3 Hz, 2H), 4.69 (t, J = 9.3 Hz, 2H), 4.12 (t, J = 8.4 Hz,
2H). 13C NMR (75 MHz, CDCl3): d = 164.3, 142.2, 137.2, 132.6,
131.2, 130.6, 129.2, 128.5, 127.3, 126.7, 126.6, 74.8, 70.4. IR (neat):
3062, 1646, 1586, 1559, 1494, 1474, 1454, 1435, 1354, 1312, 1238,
1140, 1096, 1032, 949, 910, 761, 733 cmꢂ1. HR-ESIMS: m/z cacld
for C30H25N2O2S (M+H): 477.16367. Found: 477.16200.
4.5.2. 2,20-Bis[N-[(S)-1-hydroxymethyl-2-phenylethyl]
carbamoyl]-1,10-diphenylsulfide 8b
Prepared according to the general procedure using 0.828 g
(3.02 mmol) acid 6 and 0.912 g (6.04 mmol)
L-phenylalaninol.
The product was obtained as a white solid (1.540 g, 94% yield).
Mp 89–91 °C. ½a 2D0
ꢁ
¼ ꢂ69:3 (c 0.6 g/100 mL, CH2Cl2). 1H NMR
(300 MHz, CDCl3): d = 7.41 (d, J = 6.9 Hz, 2H), 7.17–7.29 (m, 16H),
7.00 (d, J = 7.8 Hz, 2H), 4.22–4.25 (m, 2H), 3.59 (dd, J1 = 11.1 Hz,
J2 = 3.0 Hz, 2H), 3.48 (dd, J1 = 11.1 Hz, J2 = 4.2 Hz, 2H), 2.91 (br,
2H), 2.80–2.86 (m, 4H). 13C NMR (75 MHz, CDCl3): d = 168.2,
137.8, 136.9, 132.7, 132.6, 130.9, 129.3, 129.1, 128.5, 127.8,
4.6.2. 2,20-Bis[(S)-4-benzyloxazolin-2-yl]-1,10-diphenylsulfide 1b
Prepared according to the general procedure using 0.392 g
(1.01 mmol) 8b. The desired ligand was obtained as a colorless
oil (0.344 g, 94% yield). ½a D20
ꢁ
¼ ꢂ36:9 (c 0.6, CH2Cl2). 1H NMR

X. Du et al. / Tetrahedron: Asymmetry 21 (2010) 241–246
245
(300 MHz, CDCl3): d = 7.76 (d, J = 6.9 Hz, 2H), 7.21–7.33 (m, 16H),
4.49–4.59 (m, 2H), 4.24 (t, J = 9.0 Hz, 2H), 4.02 (t, J = 7.8 Hz, 2H),
3.14 (dd, J1 = 13.8 Hz, J2 = 5.4 Hz, 2H), 2.59 (dd, J1 = 13.8 Hz,
J2 = 8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): d = 163.4, 138.0, 137.2,
132.5, 131.0, 130.4, 129.3, 128.4, 126.6, 126.4, 71.7, 68.2, 41.7. IR
(neat): 3060, 2917, 2849, 1648, 1587, 1495, 1475, 1453, 1435,
J = 7.2 Hz, 2H), 3.96 (q, J = 7.2 Hz, 2H), 3.92 (d, J = 9.0 Hz, 1H),
1.20 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): d = 167.8, 167.3, 140.3, 136.8, 131.6, 129.3, 128.6, 128.4,
127.9, 127.4, 127.0, 126.3, 61.5, 61.3, 57.7, 49.2, 14.0, 13.7.
4.7.2. (S)-Dimethyl 2-[(E)-1,3-diphenylprop-2-en-1-yl]malonate
12
1355, 1286, 1245, 1139, 1093, 1030, 962, 910, 769, 732 cmꢂ1
.
HR-ESIMS: m/z cacld for C32H29N2O2S (M+H): 505.19497. Found:
505.19335.
Prepared according to the general procedure using (E)-1,3-
diphenylprop-2-en-1-yl acetate (0.126 g, 0.50 mmol), while the
reaction time was 48 h. The desired product was obtained as a col-
orless oil (149 mg, 84% yield). The ee was determined by chiral
HPLC on Daicel Chiralpak IA column (n-hexane–isopropanol
90:10 V/V, 0.5 mL/min, 254 nm, tminor = 15.7 min, tmajor = 19 min).
4.6.3. 2,20-Bis[(S)-4-isopropyloxazolin-2-yl]-1,10-diphenyl-
sulfide 1c
Prepared according to the general procedure using 0.713 g
(1.60 mmol) 8c. The desired ligand was obtained as a colorless
½
a 2D0
ꢁ
¼ ꢂ10:7 (c 0.7 g/100 mL, CH2Cl2, 89% ee). {Lit.18
oil (0.472 g, 73% yield). ½a D20
ꢁ
¼ ꢂ22:2 (c 0.6, CH2Cl2). 1H NMR
½
a 2D0
ꢁ
¼ ꢂ11:2 (c 1.04, CHCl3) 86% ee}, 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3): d = 7.74 (d, J = 6.9 Hz, 2H), 7.24–7.33 (m, 6H),
4.25–4.34 (m, 2H), 4.00–4.10 (m, 4H), 1.70–1.80 (m, 2H), 0.96 (d,
J = 6.3 Hz, 6H), 0.89 (d, J = 6.3 Hz, 6H). 13C NMR (75 MHz, CDCl3):
d = 162.8, 137.2, 132.5, 130.8, 130.2, 129.5, 126.5, 73.0, 70.1, 32.8,
18.7, 18.3. IR (neat): 2958, 2900, 2872, 1650, 1588, 1560, 1468,
d = 7.19–7.30 (m, 10H), 6.48 (d, J = 15.6 Hz, 1H), 6.33 (dd,
J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 4.27 (dd, J1 = 10.8 Hz, J2 = 8.4 Hz, 1H),
3.96 (d, J = 10.8 Hz, 1H), 3.69 (s, 3H), 3.51 (s, 3H). 13C NMR
(75 MHz, CDCl3): d = 168.1, 167.7, 140.1, 136.8, 131.8, 129.1,
128.7, 128.4, 127.8, 127.5, 127.1, 126.3, 57.6, 52.6, 52.4, 49.1.
1436, 1352, 1307, 1242, 1139, 1093, 1037, 963, 905, 767 cmꢂ1
.
HR-ESIMS: m/z cacld for C24H29N2O2S (M+H): 409.19497. Found:
409.19394.
4.7.3. (S)-1,3-Dimethyl-5-[(E)-1,3-diphenylprop-2-en-1-
yl]barbituric acid 13
Prepared according to the general procedure using (E)-1,3-
diphenylprop-2-en-1-yl acetate (0.126 g, 0.50 mmol), while the
reaction time was prolonged to 5 days; the desired product was
obtained as a light yellowish solid (127 mg, 73% yield). Mp 113–
114 °C. The ee was determined by chiral HPLC on Daicel Chiralpak
AS-H column (n-hexane–isopropanol 80:20 V/V, 1.0 mL/min,
4.6.4. 2,20-Bis[(S)-4-tert-butyloxazolin-2-yl]-1,10-
diphenylsulfide 1d
Prepared according to the general procedure using 0.523 g
(1.10 mmol) 8d. The desired ligand was obtained as a colorless
oil (0.274 g, 57% yield). ½a D20
ꢁ
¼ ꢂ108:6 (c 0.3, CH2Cl2). 1H NMR
(300 MHz, CDCl3): d = 7.74 (d, J = 6.9 Hz, 2H), 7.21–7.32 (m, 6H),
4.24 (t, J = 9.3 Hz, 2H), 4.13 (t, J = 8.1 Hz, 2H), 4.02 (dd,
J1 = 10.2 Hz, J2 = 8.1 Hz, 2H), 0.91 (s, 18H). 13C NMR (75 MHz,
CDCl3): d = 162.7, 137.4, 132.5, 130.7, 130.2, 129.5, 126.4, 76.7,
68.6, 33.8, 25.8. IR (neat): 2953, 2901, 2868, 1654, 1477, 1353,
1246, 1097, 1037, 1024, 964, 901, 764, 737 cmꢂ1. HR-ESIMS: m/z
cacld for C26H33N2O2S (M+H): 437.22627. Found: 437.22545.
254 nm, tmajor = 7.8 min, tminor = 9.6 min).
½
a 2D0
ꢁ
¼ þ67:8 (c 0.7,
CH2Cl2, 85% ee). 1H NMR (300 MHz, CDCl3): d = 7.41 (d, J = 7.5 Hz,
2H), 7.23–7.34 (m, 6H), 7.09–7.12 (m, 2H), 6.85 (dd, J1 = 15.9 Hz,
J2 = 8.7 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H), 4.41 (dd, J1 = 8.4 Hz,
J2 = 3.6 Hz, 1H), 3.87 (d, J = 3.6 Hz, 1H), 3.11 (s, 3H), 3.09 (s, 3H).
13C NMR (75 MHz, CDCl3): d = 167.9, 167.0, 150.9, 137.9, 136.6,
132.8, 128.64, 128.56, 128.2, 127.8, 127.5, 126.5, 56.1, 53.0, 28.1,
28.0. IR (neat): 2957, 1676, 1449, 1422, 1377, 1290, 1115, 970,
4.7. General procedure for catalytic asymmetric allylic
alkylation
747, 695 cmꢂ1
. HR-ESIMS: m/z cacld for C21H21N2O2 (M+H):
349.15522. Found: 349.15507.
To
a
flame dried Schlenk tube, [Pd(
g
3-C3H5)Cl]2 (4.6 mg,
4.7.4. (S)-Diethyl 2-[(E)-1,3-bis(naphth-1-yl)prop-2-en-1-
yl]malonate 14
0.0125 mmol) and ligand 1d (13.1 mg, 0.03 mmol) were added un-
der argon, followed by addition of toluene (2.0 mL). The solution
was stirred at room temperature for 0.5 h. Then allyl acetate sub-
strate (0.5 mmol) was added, and the mixture was stirred for
10 min before the addition of nucleophile (1.5 mmol), BSA
(0.37 mL, 1.5 mmol) and anhydrous KOAc (10 mg, 0.10 mmol).
After being stirred for 24–120 h, water was added and the mixture
was extracted with EtOAc (20 mL), and the combined organic
phase was dried over anhydrous Na2SO4. The solvent was removed
in vacuo, and the residue was purified by flash chromatography.
The ee was determined by chiral HPLC on Daicel Chiracel IA or
AS-H column. For details, see supporting information.
Prepared according to the general procedure using (E)-1,3-di(1-
naphthyl)prop-2-en-1-yl acetate (0.176 g, 0.50 mmol), while the
reaction time was 36 h. The desired product was obtained as a col-
orless oil (221 mg, 98% yield). The ee was determined by chiral
HPLC on Daicel Chiracel IA column (n-hexane–isopropanol 85:15
V/V, 0.8 mL/min, 254 nm, tminor = 7.9 min, tmajor = 10.3 min).
½
a 2D0
ꢁ
¼ þ33:6 (c 0.8, CH2Cl2, 94% ee). 1H NMR (300 MHz, CDCl3):
d = 8.42 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.82 (d,
J = 8.1 Hz, 1H), 7.71–7.75 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.29–
7.59 (m, 9H), 6.45 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 5.34 (t,
J = 9.6 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H), 4.21 (qd, J1 = 7.2 Hz,
J2 = 2.1 Hz, 2H), 3.85 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H),
0.80 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): d = 168.1,
167.3, 136.3, 134.5, 134.0, 133.4, 132.4, 131.4, 131.0, 129.5,
128.8, 128.3, 127.8, 127.6, 126.2, 125.9, 125.6, 125.4, 125.2,
124.4, 123.8, 123.6, 123.4, 61.6, 61.3, 57.6, 44.0, 14.0, 13.4. IR
(neat): 2986, 1753, 1730, 1394, 1368, 1280, 1250, 1177, 1154,
1031, 798, 777 cmꢂ1. HR-ESIMS: m/z cacld for C30H29O4 (M+H):
475.18853. Found: 475.18754.
4.7.1. (S)-Diethyl 2-[(E)-1,3-diphenylprop-2-en-1-yl]malonate
11
Prepared according to the general procedure using (E)-1,3-
diphenylprop-2-en-1-yl acetate (0.126 g, 0.50 mmol), while the
reaction time was 24 h. The desired product was obtained as color-
less oil (172 mg, 98% yield). The ee was determined by chiral HPLC
on Daicel Chiracel IA column (n-hexane–isopropanol 90:10 V/V,
0.5 mL/min,
254 nm,
tminor = 14.6 min,
tmajor = 17.7 min).
½
a 2D0
ꢁ
¼ ꢂ7:9 (c 2.3 g/100 mL, CH2Cl2, 91% ee). {Lit.17
½
a 2D5
ꢁ
¼ ꢂ17:2
4.7.5. (S)-Dimethyl 2-[(E)-1,3-bis(naphth-1-yl)prop-2-en-1-
yl]malonate 15
Prepared according to the general procedure using (E)-1,3-di(1-
naphthyl)prop-2-en-1-yl acetate (0.176 g, 0.50 mmol), while the
(c 1.02, CHCl3) 97% ee}. 1H NMR (300 MHz, CDCl3): d = 7.16–7.31
(m, 10H), 6.48 (d, J = 15.6 Hz, 1H), 6.34 (dd, J1 = 15.6 Hz,
J2 = 8.1 Hz, 1H), 4.27 (dd, J1 = 10.8 Hz, J2 = 8.7 Hz, 1H), 4.16 (q,

246
X. Du et al. / Tetrahedron: Asymmetry 21 (2010) 241–246
2. For reviews, see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1; (b) Gómez, M.; Muller, G.; Rocamora, M. Coord. Chem.
Rev. 1999, 193–195, 769; (c) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain,
H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605; (d) Rechavi, D.; Lemaire, M.
Chem. Rev. 2002, 102, 3467; (e) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004,
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702; (g) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505.
3. For reviews, see: (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325; (b)
Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119; (c) Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561; (d) Nishiyama, H.
Chem. Soc. Rev. 2007, 36, 1133.
4. For review, see: Flanagan, S. P.; Guiry, P. J. J. Organomet. Chem. 2006, 691, 2125;
For recent examples, see: (a) Jacobsen, E. N.; Zhang, W.; Guler, M. L. J. Am. Chem.
Soc. 1991, 113, 6703; (b) Nishiyama, H.; Yamaguchi, S.; Kondo, M.; Itoh, K. J.
Org. Chem. 1992, 57, 4306; (c) RajanBabu, T. V.; Ayers, T. A.; Casalnuovo, A. L. J.
Am. Chem. Soc. 1994, 116, 4101; (d) Park, S.-B.; Murata, K.; Matsumoto, H.;
Nishiyama, H. Tetrahedron: Asymmetry 1995, 6, 2487; (e) Belda, O.; Kaiser, N.-F.;
Bremberg, U.; Larhed, M.; Hallberg, A.; Moberg, C. J. Org. Chem. 2000, 65, 5868;
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A: Chem. 2001, 175, 27; (g) Jew, S.-S.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y. Org. Lett.
2002, 4, 4245; (h) McGarrigle, E. M.; Murphy, D. M.; Gilheany, D. G.
Tetrahedron: Asymmetry 2004, 15, 1343; (i) Fu, Y.; Hou, G.-H.; Xie, J.-H.; Xing,
L.; Wang, L.-X.; Zhou, Q.-L. J. Org. Chem. 2004, 69, 8157; (j) Okino, K.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119; (k) Liu, H.;
Xu, J. J. Mol. Catal. A: Chem. 2006, 244, 68; (l) Yan, X. X.; Peng, Q.; Zhang, Y.;
Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem. Int. Ed. 2006, 45, 1979;
(m) Yan, X. X.; Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.-L.; Wu, Y.-D. J. Am.
Chem. Soc. 2008, 130, 14362.
reaction time was 36 h. The desired product was obtained as yel-
lowish oil (170 mg, 80% yield). The ee was determined by chiral
HPLC on Daicel Chiralpak IA column (n-hexane–isopropanol
80:20 V/V, 1.0 mL/min, 254 nm, tminor = 8.1 min, tmajor = 12.3 min).
½
a 2D0
ꢁ
¼ þ46:9 (c 0.6 g/100 mL, CH2Cl2, 94% ee). 1H NMR (300 Hz,
CDCl3): d = 8.40 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.82 (d,
J = 8.1 Hz, 1H), 7.71–7.75 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.27–
7.58 (m, 9H), 6.42 (dd, J1 = 15.6 Hz, J2 = 8.7 Hz, 1H), 5.34 (t,
J = 9.6 Hz, 1H), 4.33 (d, J = 10.5 Hz, 1H), 3.71 (s, 3H), 3.40 (s, 3H).
13C NMR (75 MHz, CDCl3): d = 168.5, 167.7, 136.1, 134.5, 134.1,
133.3, 132.2, 131.3, 131.0, 129.8, 128.9, 128.3, 127.83, 127.77,
126.3, 125.9, 125.6, 125.4, 125.3, 124.2, 123.9, 123.6, 123.2, 57.2,
52.6, 52.4, 44.1.
4.7.6. (S)-1,3-Dimethyl-5-[(E)-1,3-bis(naphth-1-yl)prop-2-en-1-
yl]barbituric acid 16
Prepared according to the general procedure using (E)-1,3-di(1-
naphthyl)prop-2-en-1-yl acetate (0.176 g, 0.50 mmol), while the
reaction time was 3 days. The desired product was obtained as a
yellowish oil (213 mg, 95% yield). The ee was determined by chiral
HPLC on Daicel Chiralpak AS-H column (n-hexane–isopropanol
95:5, 1.0 mL/min, 254 nm, tminor = 17.2 min, tmajor = 19.0 min).
5. For recent examples, see: (a) Fang, T.; Xu, J.; Du, D.-M. Lett. Org. Chem. 2006, 3,
780; (b) Liu, H.; Li, W.; Du, D.-M. Sci. China, Ser. B 2009, 52, 1321.
6. Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977, 99, 1649.
½
a 2D0
ꢁ
¼ þ37:8 (c 0.67, CH2Cl2, 42% ee). 1H NMR (300 MHz, CDCl3):
d = 8.22 (d, J = 8.4 Hz, 1H), 8.00–8.03 (m, 1H), 7.89 (d, J = 8.1 Hz,
1H), 7.77–7.84 (m, 3H), 7.59–7.63 (m, 2H), 7.43–7.54 (m, 7H),
6.86 (dd, J1 = 15.3 Hz, J2 = 8.7 Hz, 1H), 5.46 (dd, J1 = 8.4 Hz,
J2 = 2.4 Hz, 1H), 4.13 (d, J = 2.7 Hz, 1H), 3.12 (s, 3H), 2.86 (s, 3H).
13C NMR (75 MHz, CDCl3): d = 167.7, 167.5, 151.0, 134.5, 134.3,
133.9, 133.5, 131.1, 131.0, 130.8, 129.9, 129.5, 128.7, 128.5,
128.3, 126.7, 126.2, 125.9, 125.6, 124.9, 124.2, 123.7, 122.3, 55.4,
47.5, 28.2, 28.1. IR (neat): 2960, 1678, 1449, 1422, 1377, 1291,
1066, 777 cmꢂ1. HR-ESIMS: m/z cacld for C29H25N2O3 (M+H):
471.16846. Found: 471.16770.
7. For recent reviews, see: (a) Trost, B. M.; van Vranken, D. M. Chem. Rev. 1996, 96,
395; (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (c) Lu, Z.; Ma, S.
Angew. Chem., Int. Ed. 2008, 47, 258; For selected reports, see: (d) Weix, D. J.;
Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7720; (e) Liu, D.; Xie, F.; Zhang, W.
Tetrahedron Lett. 2007, 48, 7591; (f) Zhao, X.; Liu, D.; Xie, F.; Zhang, W.
Tetrahedron 2009, 65, 512; (g) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129,
14548.
8. Gómez, M.; Jansat, S.; Muller, G.; Maestro, M. A.; Mahía, J. Organometallics 2002,
21, 1077.
9. (a) Voituriez, A.; Schulz, E. Tetrahedron: Asymmetry 2003, 14, 339; (b) Voituriez,
A.; Fiaud, J.-C.; Schulz, E. Tetrahedron Lett. 2002, 43, 4907.
10. (a) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron: Asymmetry 2004, 15,
3433; (b) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712; (c) Lu,
S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem. Soc. 2006, 128, 7418; (d) Lu, S.-
F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115; (e) Liu, H.; Xu, J.; Du, D.-M. Org. Lett.
2007, 9, 4725; (f) Liu, H.; Lu, S.-F.; Xu, J.; Du, D.-M. Chem. Asian J. 2008, 3, 1111.
11. The synthesis of 1c and the XRD structure of its complex with ZnCl2 has been
reported: Kooijman, H.; Spek, A. L.; Zondervan, C.; Feringa, B. L. Acta Crystallogr.,
Sect. E 2002, 58, m429.
Acknowledgments
We thank the National Natural Science Foundation of China
(Grant No. 20772006), the Development Program for Distinguished
Young and Middle-aged Teachers of Beijing Institute of Technology
and the Program for New Century Excellent Talents in University
(NCET-07-0011).
12. Eldin, S.; Jencks, W. P. J. Am. Chem. Soc. 1995, 117, 4851.
13. Rabai, J. Synthesis 1989, 523.
14. Kinoshita, N.; Kawabata, T.; Tsubaki, K.; Bando, M.; Fuji, K. Tetrahedron 2006,
62, 1756.
15. Nagy, P.; Csámpai, A.; Szabó, D.; Varga, J.; Harmat, V.; Ruff, F.; Kucsman, Á. J.
Chem. Soc., Perkin Trans. 2001, 339.
16. Dieter, H. Chem. Ber. 1987, 120, 1151.
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