Palladium-catalyzed asymmetric allylic nucleophilic substitution reactions using chiral tert-butanesulfinylphosphine ligands

Article abstract of DOI:10.1016/j.tetasy.2009.07.041

The asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate 3 with dimethyl malonate proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂

Full text of DOI:10.1016/j.tetasy.2009.07.041

Tetrahedron: Asymmetry 20 (2009) 1953–1956
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Tetrahedron: Asymmetry
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Palladium-catalyzed asymmetric allylic nucleophilic substitution reactions
using chiral tert-butanesulfinylphosphine ligands
Junmin Chen a,b,c, Feng Lang a,b, Dong Li a,b, Linfeng Cun a, Jin Zhu a,b, Jingen Deng a,b, Jian Liao a,b,
*
a National Engineering Research Center of Chiral Drugs and Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
c College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2009
Revised 1 July 2009
Accepted 13 July 2009
Available online 14 September 2009
The asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate 3 with dimethyl malonate
proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(g3
-
C3H5)Cl]2, and chiral tert-butanesulfinylphosphine ligand 2c to give the allylic alkylation product in good
yield and high enantiomeric excess (up to 93% ee), while the enantioselectivities of allylic amination of 3
with various amines were moderate (up to 76% ee).
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
diethylzincadditiontoimines. Highactivitiesandenantioselectivities
(up to 94% ee) were achieved.8 Herein, we report the results of palla-
Palladium-catalyzed asymmetric allylic substitution has re-
ceived considerable attention as a useful asymmetric carbon–car-
bon and carbon–heteroatom bond-forming process. Racemic or
achiral allylic substrates can be converted into optically active
products in the presence of a palladium complex of a chiral ligand.1
In order to achieve high enantioselectivity, the development of no-
vel chiral ligands is an essential and challenging task.2 Some li-
gands have already been successfully produced and employed in
various allylic alkylation reactions. However, the use of a chiral
sulfoxide as a ligand is less common. Pioneered by Shibasaki in
1995,3 (S,S)-1,2-bis(p-tolylsulfinyl)benzene (BTSB) was first ap-
plied as a ligand in an asymmetric allylic alkylation (AAA) reaction,
which afforded moderate to good yields and moderate enantiose-
lectivities. Since then, many chiral sulfoxide bidentate ligands such
as other bis-sulfoxides,4 sulfoxide–oxazoline,5 sulfoxide–dialkyl
amine/sulfoxide–sulfonamide,6 and sulfoxide–phosphine,7 have
been applied to palladium-catalyzed asymmetric allylic substitu-
tion reaction without satisfactory results. In the case of sulfoxide
ligands, sulfoxide–phosphine 1 showed very good potential in
AAA reactions (Fig. 1), which generated up to 97% ee, but moderate
yield (49%) when using 12 mol % ligand 1.7a Encouraged by the
high enantioselectivity with phosphine–sulfoxide ligands and as
a part of our ongoing investigations of chiral ligands, we herein re-
port tert-butanesulfinylphosphine ligands 2 in AAA reactions.
Recently, we have synthesized a class of chiral tert-butanesulfinyl-
phosphine ligands 2a–c and applied them to catalytic asymmetric
dium-catalyzed enantioselective allylic substitutions of 1,3-diphe-
nyl-2-propenyl acetate 3 with dimethyl malonate and various
amines.
t-Bu
O
S
S
O
a: R = H
Ar
b: R = OCH3
PPh2 c: R = OCH2OCH3
NHPPh2
R
Ar=2-MeO-Napht
2
1
Figure 1.
2. Results and discussion
We first examined chiral ligands 2a–c under the standard con-
ditions reported by Mino et al.9 On a 0.5 mmol scale, rac-1,3-diphe-
nyl-2-propenyl acetate 3 reacted with 3.0 equiv dimethyl malonate
in the presence of 2.0 mol % [Pd(g
3-C3H5)Cl]2, 5.2 mol % ligand (S)-
2, 3.0 equiv N,O-bis(trimethylsilyl)acetamide (BSA), and a catalytic
amount of lithium acetate in 1.0 mL acetonitrile. The results are
summarized in Table 1. Under these conditions, the optically active
substitution product 4 was obtained in quantitative yield when
using ligands 2a–c, and 2c produced the best results (99% yield
and 81% ee, Table 1, entry 3). The absolute configuration of 4 was
determined to be (S) by comparing the specific rotation with the
* Corresponding author. Tel.: +86 28 85229250; fax: +86 28 85223978.
E-mail address: jliao10@cioc.ac.cn (J. Liao).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.041

1954
J. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 1953–1956
Table 1
The palladium-catalyzed asymmetric allylic alkylation reactiona
[Pa(η3-C3H5)Cl]2 (2.0 mol%)
Ligand 2 (5.2 mol%)
MeO2C
CO2Me
Ph
OAc
Ph
Ph
*
Ph
BSA, LiOAc, CH2(CO2Me)2
3
4
Entry
Ligand
Solvent
Temp. (°C)
Time (h)
Yieldb(%)
eec (%)
1
2
3
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
EtOAc
Toluene
Et2O
CH3CN
CH3CN
CH3CN
CH3CN
rt
rt
rt
rt
rt
rt
rt
rt
rt
16
16
16
16
16
16
16
10
10
24
36
48
48
98
99
99
99
93
98
91
94
94
99
89
79
68
62
73
81
78
77
77
62
68
64
89
90
91
93
4d
5e
6
7
8
9
10
11
12
13
0
ꢀ20
ꢀ40
ꢀ60
a
Reaction conditions: substrate (0.5 mmol), 2.0 mol % [Pd(g
3-C3H5)Cl]2, 5.2 mol % ligand, 1.5 mmol N,O-bis(trimethylsilyl)acetamide (BSA), 1.5 mmol dimethyl malonate,
1 mg LiOAc, and 1.0 mL of solvent.
b
Isolated yield.
Determined by HPLC with a Daicel chiral column.
NaOAc as salt.
KOAc as salt.
c
d
e
literature value.10 The effects of base and solvent on enantioselec-
tivity were also investigated. Sodium acetate and potassium ace-
tate led to a slight decrease in enantioselectivities (78% ee and
77% ee, respectively, Table 1, entries 4 and 5), and solvents such
as dichloromethane, ethyl acetate, toluene, and diethylether also
resulted in a decreased ee (Table 1, entries 6–9). To our delight,
decreasing the temperature enhanced the enantioselectivity,
although the reaction rate slowed (Table 1, entries 10–13). The
optimal reaction temperature was hence assigned as ꢀ60 °C, which
afforded the highest enantioselectivity (93% ee, Table 1, entry 13).
Having achieved enantioselective C–C bond formation, we also
evaluated the chiral tert-butanesulfinylphosphine ligands in a C–
N bond formation reaction. At room temperature, in the presence
of ligand 2, rac-1,3-diphenyl-2-propenyl acetate 3 was reacted
with benzylamine under conditions similar to those of alkylation
described above. We found that ligand 2c and acetonitrile were
also the best ligand and solvent, respectively. In addition, sodium
acetate was superior to lithium or potassium salt in this reaction
(Table 2, entries 1–3). Improved enantioselectivities (68% and
73% ee) were observed when the temperature was decreased to
Table 2
The palladium-catalyzed asymmetric allylic amination reactiona
[Pa(η3 -C3H5)Cl]2 (2.0 mol%)
Ligand 2c (5.2 mol%)
OAc
Ph
NR1R2
Ph
BSA, NaOAc, CH3CN, NR1R2
Ph
*
Ph
3
5
Entry
Amine
Temp.b(°C)
Time (h)
Yieldc(%)
eed(%)
1e
2f
3
4
5
6
7
8
9
10
11
12
13
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Morpholine
Pyrrolidine
Piperidine
Dibenzylamine
Cyclohexylamine
Phathalimide
Boc-piperazine
rt
rt
rt
12
12
12
16
24
24
10
16
16
16
16
24
24
99
99
99
99
99
75
99
98
98
98
98
56
93
53
62
63
68
73
67
76
52
56
<5
70
55
73
0
ꢀ20
ꢀ40
rt
rt
rt
rt
0
0
0
a
Reaction conditions: substrate (0.5 mmol), 2.0 mol % [Pd(
and 1.0 mL CH3CN.
g
3-C3H5)Cl]2, 5.2 mol % ligand, 1.5 mmol N,O-bis(trimethylsilyl)acetamide (BSA), 1.5 mmol amine, 1 mg NaOAc,
b
Three temperatures (ꢀ20 °C, 0 °C and rt) were screened for all substrates and the best results are presented in this table.
c
d
e
f
Isolated yield.
Determined by HPLC with a Daicel chiral column.
LiOAc as salt.
KOAc as salt.

J. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 1953–1956
1955
0 °C and ꢀ20 °C (Table 2, entries 4 and 5). However, decreasing the
temperature further (to ꢀ40 °C) was harmful to both enantioselec-
tivity and the yield (Table 2, entry 6). With the reaction conditions
optimized, other substrates were examined in this reaction. How-
ever, ꢀ20 °C was not the optimal temperature for several other
amines, which we screened at three temperatures (ꢀ20 °C, 0 °C,
and rt). As shown in Table 2, morpholine, pyrrolidine, piperidine,
and dibenzylamine demonstrated excellent activities and moder-
ate enantioselectivities (except dibenzylamine) at room tempera-
ture (Table 2, entries 7–10). Cyclohexylamine, phathalimide, and
Boc-piperazine showed moderate to high yields and moderate
enantioselectivities at 0 °C (Table 2, entries 11–13).
4.2. Typical procedure for the palladium-catalyzed asymmetric
allylic amination
Under an argon atmosphere, to a Schlenck flask containing ligand
2c(11.1 mg, 5.2 mol %) was added CH3CN (1 ml) followed by [Pd(g3
-
C3H5)Cl]2 (3.7 mg, 4.0 mol % Pd). The mixture was stirred at room
temperature for 45 min, and then rac-1,3-diphenyl-2-propenyl ace-
tate 3 (126 mg, 0.5 mmol) was added to the reaction via a syringe.
Themixture was cooledto ꢀ20 °C, benzylamine (0.16 mL, 1.5 mmol)
was added to the reaction, followed by N,O-bis(trimethylsilyl)acet-
amide (BSA, 0.37 mL, 1.5 mmol) and sodium acetate (1.0 mg). After
24 h, the reaction was diluted with Et2O, washed with saturated
NH4Cl(aq), saturated NaHCO3(aq), and brine. The combined aqueous
solutions were extracted with CH2Cl2. The combined organic solu-
tions were dried over MgSO4, filtered, concentrated in vacuo, and
purified by flash chromatography (85% hexane, 15% ethyl acetate)
3. Conclusion
to yield a yellow oil (99% yield); ½a D25
ꢁ
¼ ꢀ7:6 (c 0.48, CHCl3); 1H
In conclusion, we have demonstrated that palladium complex
derived from chiral tert-butanesulfinylphosphine ligand 2c was
an efficient catalyst for asymmetric allylic substitution of 1,3-
diphenylpropenyl acetate 3 with dimethyl malonate (up to 93%
ee) and nitrogen nucleophiles such as amines (up to 76% ee).
Further studies focusing on the modification of the ligands and
applications in other catalytic reactions are currently underway
in our laboratory.
NMR (CDCl3, 300 MHz): d 3.80 (s, 2H), 4.42 (d, J = 7.2 Hz, 1H), 6.36
(dd, J = 7.2 Hz, J = 15.9 Hz, 1H), 6.60 (d, J = 15.9 Hz, 1H), 7.22–7.47
(m, 15H). The enantiomeric excess was determined by chiral HPLC
using a Chiralcel AD-H column, hexane/propan-2-ol = 90/10 (V/V),
1.0 mL/min, 254 nm; 73% ee, (R)-isomer tr = 9.9 min, (S)-isomer
tr = 12.0 min. The absolute stereochemistry of the product [(R)-iso-
mer] was determined by comparison of the specific rotation to the
literature value.11
4. Experimental
4.2.1. (R)-N-[(E)-1,3-Diphenylallyl]cyclohexanamine
Colorless oil, 98% yield, ½a D25
ꢁ
¼ ꢀ8:5 (c 0.46, CHCl3); 1H NMR
All experiments were carried out under an argon atmosphere.
Commercial reagents were used as received without purification.
Commercial grade solvents were dried and purified by standard lit-
erature procedures. 1H NMR spectra were recorded at 300 MHz
and chemical shifts (d) are reported in ppm relative to CHCl3
(d = 7.27 ppm). Optical rotation data were recorded on Perkin–El-
mer Polarimeter-341. Enantiomeric excess was determined by
HPLC analysis on chiral columns in comparison with the authentic
racemates. Column chromatography was performed using silica gel
(200–300 mesh) eluting with ethyl acetate and petroleum ether.
The preparation of the chiral tert-butanesulfinylphosphine ligands
was carried out according to the reported method.8
(CDCl3, 300 MHz): d 0.87–1.27 (m, 6H), 1.69 (br, 1H), 2.00 (br,
2H), 1.89–1.97 (m, 2H), 2.44–2.48 (m, 1H), 4.58 (d, J = 7.4 Hz,
1H), 6.34 (dd, J = 8.1 Hz, J = 15.9 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H),
7.20–7.42 (m, 10H). The enantiomeric excess was determined by
chiral HPLC using a Chiralcel AD-H column, hexane/propan-2-
ol = 99/1 (V/V) (0.1% Et3N), 0.5 mL/min, 254 nm; 70% ee, (R)-isomer
tr = 7.9 min, (S)-isomer tr = 7.0 min. Absolute stereochemistry of
the product [(R)-isomer] was determined by comparison of the
specific rotation to the literature value.11
4.2.2. (R)-N-[(E)-1,3-Diphenylprop-2-enyl]morpholine
Pale solid, 99% yield, ½a D25
ꢁ
¼ ꢀ7:4 (c 0.34, CHCl3); 1H NMR
4.1. Typical procedure for the palladium-catalyzed asymmetric
allylic alkylation
(CDCl3, 300 MHz): d 2.36–2.57 (m, 4H), 3.70–3.73 (m, 4H), 3.79
(d, J = 9.0 Hz, 1H), 6.36 (dd, J = 8.6 Hz, J = 15.8 Hz, 1H), 6.58 (d,
J = 15.8 Hz, 1H), 7.21–7.42 (m, 10H). The enantiomeric excess
was determined by chiral HPLC using a Chiralcel OD-H column,
hexane/propan-2-ol = 90/10 (V/V), 1.0 mL/min, 254 nm; 76% ee,
(R)-isomer tr = 12.2 min, (S)-isomer tr = 6.3 min. The absolute ste-
reochemistry of the product [(R)-isomer] was determined by com-
parison of the specific rotation to the literature value.11
Under an argon atmosphere, to a Schlenck flask containing ligand
2c (11.1 mg, 5.2 mol %) was added CH3CN (1.0 ml) followed by
[Pd(g
3-C3H5)Cl]2 (3.7 mg, 4.0 mol % Pd). The mixture was stirred at
room temperature for 45 min, and then rac-1,3-diphenyl-2-prope-
nyl acetate 3 (126 mg, 0.5 mmol) was added to the reaction system
via a syringe. The mixture was then cooled to -60 °C, and dimethyl
malonate (0.17 ml, 1.5 mmol) was added to the mixture followed
by N,O-bis(trimethylsilyl)acetamide (BSA, 0.37 mL, 1.5 mmol) and
lithium acetate (1.0 mg). After 48 h, the reaction was diluted with
Et2O, washed with saturated NH4Cl(aq), saturated NaHCO3(aq),
and brine. The combined aqueous solutions were extracted with
CH2Cl2. The combined organic solutions were dried over MgSO4, fil-
tered, concentrated in vacuo, and purified by flash chromatography
(85% hexane, 15% ethyl acetate) to yield a yellow oil (68% yield);
4.2.3. (R)-N-[(E)-1,3-Diphenylprop-2-enyl]pyrrolidine
Pale solid, 98% yield, ½a D25
ꢁ
¼ ꢀ2:6 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz): d 1.79–1.84 (m, 4H), 2.43–2.58 (m, 4H), 3.76 (d,
J = 8.4 Hz, 1H), 6.36 (dd, J = 8.4 Hz, J = 15.8 Hz, 1H), 6.58 (d,
J = 15.8 Hz, 1H), 7.12–7.44 (m, 10H). The enantiomeric excess
was determined by chiral HPLC using a Chiralcel OD-H column,
hexane/propan-2-ol = 70/30 (V/V), 1.0 mL/min, 254 nm; 52% ee,
(R)-isomer tr = 7.5 min, (S)-isomer tr = 16.1 min. The absolute ste-
reochemistry of the product [(R)-isomer] was determined by com-
parison of the specific rotation to the literature value.12
½
a 2D5
ꢁ
¼ ꢀ21:4 (c 1.40, CHCl3); 1H NMR (CDCl3, 300 MHz): d 3.52 (s,
3H), 3.70 (s, 3H), 3.95 (d, J = 10.8 Hz, 1H), 4.27 (dd, J = 8.7 Hz,
J = 10.8 Hz, 1H), 6.34 (dd, J = 8.4 Hz, J = 15.9 Hz, 1H), 6.48 (d,
J = 15.6 Hz, 1H),7.20–7.34 (m, 10H). The enantiomeric excess was
determined by chiral HPLC using a Chiralcel AD-H column, hexane/
propan-2-ol = 95/5 (V/V), 1.0 mL/min, 254 nm; 93% ee, (S)-isomer
tr = 14.6 min, (R)-isomer tr = 19.8 min. The absolute stereochemistry
of the product [(S)-isomer] was determined by comparison of the
specific rotation to the literature value.10
4.2.4. (R)-N-[(E)-1,3-Diphenylprop-2-enyl]piperidine
Pale solid, 98% yield, ½a D25
ꢁ
¼ ꢀ11:7 (c 0.32, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.26–1.61 (m, 6H), 2.31–2.45 (m, 4H), 3.81
(d, J = 8.4 Hz, 1H), 6.36 (dd, J = 8.1 Hz, J = 15.8 Hz, 1H), 6.53 (d,
J = 15.8 Hz, 1H), 7.21–7.42 (m, 10H). The enantiomeric excess
was determined by chiral HPLC using a Chiralcel AD-H column,

1956
J. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 1953–1956
hexane/propan-2-ol = 70/30 (V/V), 0.5 mL/min, 254 nm; 56% ee,
(R)-isomer tr = 6.9 min, (S)-isomer tr = 7.3 min. The absolute
stereochemistry of the product [(R)-isomer] was determined by
comparison of the specific rotation to the literature value.11
determined by comparison of the specific rotation to the litera-
ture value.12
Acknowledgments
4.2.5. (2R,E)-N,N-Dibenzyl-1,4-diphenylbut-3-en-2-amine
Financial support from the National Natural Science Foundation
(Grant No. 20872139) and National Engineering Research Center of
China Drugs is greatly acknowledged by the authors.
Colorless oil, 98% yield, ½a D25
ꢁ
¼ ꢀ2:9 (c 0.50, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 3.62 (d, J = 13.8 Hz, 2H), 3.74 (d, J = 13.8 Hz,
2H), 4.44 (d, J = 6.9 Hz, 1H), 6.50–6.52 (m, 2H), 7.21–7.57 (m,
20H). The enantiomeric excess was determined by chiral HPLC
using a Chiralcel AD-H column, hexane/propan-2-ol = 70/30 (V/
V), 0.5 mL/min, 254 nm; 3% ee, (R)-isomer tr = 6.7 min, (S)-isomer
tr = 7.0 min. The absolute stereochemistry of the product [(R)-iso-
mer] was determined by comparison of the specific rotation to
the literature value.13
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White solid, 93% yield, ½a D25
ꢁ
¼ ꢀ16:0 (c 0.50, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.45 (s, 9H), 2.36–2.54 (m, 4H), 3.43 (br,
4H), 3.82 (d, J = 9.0 Hz, 1H), 6.26 (dd, J = 8.1 Hz, J = 15.9 Hz,
1H), 6.55 (d, J = 15.9 Hz, 1H), 7.19–7.41 (m, 10H). The enantio-
meric excess was determined by chiral HPLC using a Chiralcel
AD-H column, hexane/propan-2-ol = 90/10 (V/V), 1.0 mL/min,
254 nm; 73% ee, (R)-isomer tr = 5.9 min, (S)-isomer tr = 5.4 min.
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