Palladium-catalyzed asymmetric allylic substitution using novel phosphino-ester (PHEST) ligands with 1,1'-binaphthyl skeleton

Article abstract of DOI:10.1016/S0957-4166(00)00370-0

The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a 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/S0957-4166(00)00370-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4009–4015
Palladium-catalyzed asymmetric allylic substitution using
novel phosphino-ester (PHEST) ligands with 1,1%-binaphthyl
skeleton
Hidehiko Kodama, Toshiji Taiji, Tetsuo Ohta* and Isao Furukawa
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha University, Kyotanabe,
Kyoto 610-0394, Japan
Received 31 August 2000; accepted 14 September 2000
Abstract
The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a
proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(h3-
C3H5)Cl]2, and the chiral ligand (R)-i-Pr2N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in
89% yield with 99% ee. Furthermore, the asymmetric allylic amination of 1 with potassium phthalimide
2c has been carried out using the same ligand to give the allylic amination product (S)-3c in 10% yield
with 66% ee. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The palladium-catalyzed asymmetric allylic substitution reactions,1 alkylation and amination,
have been attracting considerable attention due to their potential for the enantioselective
formation of new covalent bonds such as carbonꢀcarbon and carbonꢀnitrogen bonds. These
reactions have been extensively studied2 for the palladium-catalyzed substitution on racemic
1,3-diphenyl-2-propenyl acetate 1 with carbon or nitrogen nucleophiles and are excellent models
for testing the design principles of asymmetric ligands.
The design and synthesis of ligands have mainly focused on chiral phosphorus-containing
ligands as chiral phosphines are excellent ligands in asymmetric catalysis, and among them, the
prime role is played by those possessing the binaphthyl scaffold.3 Both C2-symmetrical (e.g.
BINAP4) and unsymmetrical (e.g. MOP,5 MAP6 and NOBIN7) representatives often give levels
of asymmetric induction previously reserved to enzymes. Although many palladium complexes
of bidentate ligands are excellent catalysts for allylic substitution reactions, the palladium
complexes of conventional chiral monophosphines are normally not effective.8 Therefore, we
* Corresponding author.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00370-0

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H. Kodama et al. / Tetrahedron: Asymmetry 11 (2000) 4009–4015
synthesized novel chiral phosphino-ester (PHEST) ligands with a 1,1%-binaphthyl skeleton and
performed the palladium-catalyzed allylic substitution with carbon or nitrogen nucleophiles.
2. Results and discussion
Novel phosphino-ester (PHEST) ligands, (R)-5a and (R)-5b, were obtained from (R)-2-
diphenylphosphino-2%-hydroxy-1,1%-binaphthyl (R)-49 and the corresponding acid chlorides in
the presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine (DMAP) in 92
and 95% yields, respectively (Scheme 1). These PHEST ligands were characterized using
1
infrared, H and 31P NMR spectra, and elemental analysis.
Scheme 1.
The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 was performed at
room temperature in the presence of the Pd–PHEST complex generated in situ from 2 mol% of
bis[(p-allyl)palladium chloride] and 6 mol% of (R)-5a or (R)-5b. The nucleophile was generated
from dimethyl malonate in the presence of BSA (N,O-bis(trimethylsilyl)acetamide) and a
catalytic amount of lithium acetate.
As shown in Table 1, the allylic alkylation catalyzed by 6 mol% (R)-5a and 2 mol%
bis[(p-allyl)palladium chloride] in dichloromethane as the solvent at room temperature for 24 h
smoothly proceeded to afford the product (R)-3a in 89% yield with 99% ee (Table 1, entry 1).
The effect of solvent on this reaction was examined using (R)-5a as the ligand (Table 1, entries

H. Kodama et al. / Tetrahedron: Asymmetry 11 (2000) 4009–4015
4011
Table 1
Palladium-catalyzed asymmetric allylic alkylationa
Entry
Ligand
Solvent
Yield (%)b
Ee (%)c
1
2
3
4
5
6e
7
8
9
(R)-5a
(R)-5a
(R)-5a
(R)-5a
(R)-5a
(R)-5a
(R)-5b
(R)-5b
CH2Cl2
THF
PhCH3
Et2O
CH3CN
CH2Cl2
CH2Cl2
THF
89
55
21
44
80
71
86
38
59
99d
90
95
88
85
94
96
96
85
(R)-MeO-MOP
CH2Cl2
a Reaction conditions: The catalyst [Pd(h3-C3H5)Cl]2 (0.01 mmol) and PHEST ligand ((R)-5a,b) (0.03 mmol) were
stirred in solvent (1.0 mL) for 0.5 h, and 1 (0.50 mmol) in solvent (2 mL), dimethyl malonate (2) (1.5 mmol), lithium
acetate (0.01 mmol) and BSA (1.5 mmol) were added to the catalyst solution, and then the mixture was stirred for
24 h at room temperature.
b Isolated yield.
c Determined by HPLC analysis using a Daicel Chiralcel OD-H column.
d [h]D23=+18.0 (c 1.1, EtOH) (lit.10 [h]2D3=+18.4 (c 1.1, EtOH)).
e The catalyst, 0.67 mol% [Pd(h3-C3H5)Cl]2, and 2.0 mol% PHEST ligand were used.
2–5). The reaction proceeded faster in dichloromethane and acetonitrile as the solvent (Table 1,
entries 1 and 5), and slower in tetrahydrofuran, toluene and diethyl ether (Table 1, entries 2–4).
Moreover, the effect of the amount of catalyst was also examined. The allylic alkylation
catalyzed by 2 mol% (R)-5a and 0.67 mol% [Pd(h3-C3H5)Cl]2 at room temperature smoothly
proceeded to give (R)-3a in 71% yield with 94% ee (Table 1, entry 6). The effect of the ligand
was next examined. There were few differences in the yields and enantiomeric excesses of the
product between the reaction using (R)-5a and (R)-5b as the ligand (Table 1, entries 7 and 8).
However, using the (R)-MeO-MOP ligand led to a lower enantiomeric excess of (R)-3a (Table
1, entry 9). Interestingly, in this reaction, the absolute configuration of allylic product was
changed in comparison with the results of bidentate ligands, such as BINAP11 or MAP.6
Next, the effect of base on the reaction with (R)-5a and (R)-5b was evaluated (Table 2). The
allylic alkylation catalyzed by (R)-5a using sodium acetate or potassium acetate, instead of
lithium acetate, proceeded to give (R)-3a in 85 and 72% yields with 65 and 64% ee, respectively
(Table 2, entries 2 and 3). Using (R)-5b as the ligand also led to low enantiomeric excesses of
(R)-3a (Table 2, entries 5 and 6).

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H. Kodama et al. / Tetrahedron: Asymmetry 11 (2000) 4009–4015
Table 2
Effect of base on palladium-catalyzed asymmetric allylic alkylationa
Entry
Ligand
Base
Yield (%)b
Ee (%)c
1
2
3
4
5
6
(R)-5a
(R)-5a
(R)-5a
(R)-5b
(R)-5b
(R)-5b
LiOAc+BSA
NaOAc+BSA
KOAc+BSA
LiOAc+BSA
NaOAc+BSA
KOAc+BSA
89
85
72
86
94
62
99
65
64
96
50
47
a See Table 1. CH2Cl2 was used as the solvent.
b Isolated yield.
c Determined by HPLC analysis using a Daicel Chiralcel OD-H column.
Clearly, these results demonstrated the superiority of lithium acetate and BSA as the base in
dichloromethane as the solvent (Table 2). If lithium acetate is taken into account, we can
envisage the chelation of the lithium cation by the carbonyl moiety including the PHEST ligand
and oxygen atom of the dimethyl malonate anion, thus this chelation stabilizes the transition
state even further.
Moreover, the asymmetric allylic amination of rac-1,3-diphenyl-2-propenyl acetate 1 was
performed at 50°C in the presence of the Pd(0)–ligand complex generated in situ from 2.5 mol%
of Pd2(dba)3 and 5 mol% of (R)-5a. Benzylamine 2b and potassium phthalimide 2c as the
nucleophile were used. The reaction using benzylamine proceeded to give (S)-3b in 15% yield
with 44% ee. Using potassium phthalimide as the nucleophile instead of benzylamine led to a
66% ee.
3. Conclusion
In conclusion, the palladium-catalyzed asymmetric allylic alkylation of rac-1,3-diphenyl-2-
propenyl acetate 1 with dimethyl malonate 2a smoothly proceeded in the presence of lithium
acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(h3-C3H5)Cl]2, and the chiral ligand (R)-i-
Pr2N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in 89% yield with 99% ee. We
found that the choice of the metal acetate was very important in this reaction.

H. Kodama et al. / Tetrahedron: Asymmetry 11 (2000) 4009–4015
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4. Experimental
All experiments were carried out under an argon atmosphere. Commercial reagents were used
as received without further purification. All solvents were dried using standard procedures. The
1H NMR (400 MHz) spectra were recorded on a Jeol JNM A-400 spectrometer with TMS as the
internal standard. The 31P NMR (161 MHz) spectra were recorded using a Jeol JNM A-400
spectrometer with 85% phosphoric acid as the external standard. Optical rotations were
recorded using a Horiba SEPA-200 polarimeter. Enantiomeric excesses (% ees) were determined
by HPLC analyses. The preparation of (R)-2-diphenylphosphino-2%-hydroxy-1,1%-binaphthyl
(R)-4 was carried out according to the reported method.9
4.1. Preparation of phosphino-ester (PHEST) ligands
(R)-2-(N,N-Diisopropylcarbamoyloxy)-2%-diphenylphosphino-1,1%-binaphthyl (R)-5a: To a
solution of (R)-2-diphenylphospino-2%-hydroxy-1,1%-binaphthyl (R)-4 (0.52 g, 1.14 mmol) in
dichloromethane (15 mL) were added N,N-diisopropylcarbamoyl chloride (0.22 g, 1.32 mmol),
triethylamine (0.19 g, 1.39 mmol), and 4-dimethylaminopyridine (0.036 g, 0.29 mmol). The
reaction mixture was stirred for 48 h at room temperature. The resulting mixture was quenched
with water, and then extracted with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate and evaporated to dryness, and the residue was chromatographed on
silica gel (dichloromethane) to give (R)-2-(N,N-diisopropylcarbamoyloxy)-2%-diphenylphos-
phino-1,1%-binaphthyl (R)-5a as a white solid (0.61g, 92%); mp 158–161°C; MS m/z 582 (M+);
1
[h]2D5 +50.0 (c 1, CHCl3); H NMR (CDCl3): l 0.18 (d, J=5.6 Hz, 3H), 0.66 (d, J=6.0 Hz, 3H),
0.74 (d, J=5.2 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), 3.34 (m, 2H), 6.96–7.50 (m, 17H), 7.55 (d,
J=8.8 Hz, 1H), 7.83 (t, J=8.0 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H); 31P
NMR (CDCl3): l −14.79; IR (KBr): 3050, 2900, 1715, 1425, 1310, 1220, 1150, 1045, 1005 cm−1.
Found: C, 80.53; H, 6.24; N, 2.41. Calcd for C39H36NO2P: C, 80.25; H, 6.17; N, 2.22.
In a similar method, compound (R)-5b was prepared from (R)-2-diphenylphospino-2%-
hydroxy-1,1%-binaphthyl (R)-4 and tert-butylacetyl chloride.
(R)-2-(tert-Butylacetyloxy)-2%-diphenylphosphino-1,1%-binaphthyl (R)-5b: Yield 95%; mp 136–
1
138°C; MS m/z 553 (M+); [h]D25 +14.0 (c 1, CHCl3); H NMR (CDCl3): l 0.48 (s, 9H), 1.85 (s,
2H), 6.93–6.95 (m, 2H), 7.04–7.47 (m, 16H), 7.84 (t, J=8.8 Hz, 2H), 7.90 (d, J=8.0 Hz, 1H),
8.00 (d, J=8.8 Hz, 1H); 31P NMR (CDCl3): l −14.02; IR (KBr): 3030, 2940, 1750, 1470, 1430,
1320, 1210, 1190, 1110, 970 cm−1. Found: C, 82.40; H, 6.01. Calcd for C38H33O2P: C, 82.59; H,
6.02.
4.2. A typical procedure for palladium-catalyzed asymmetric allylic alkylation of rac-1,3-
diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a
A solution of the PHEST ligand (0.03 mmol) and [Pd(h3-C3H5)Cl]2 (0.004 g, 0.01 mmol) in
dichloromethane (1 mL) was stirred at room temperature for 30 min. This solution was
successively treated with a solution of rac-1,3-diphenyl-2-propenyl acetate (1) (0.13 g, 0.50
mmol) in dichloromethane (2 mL), dimethyl malonate (2a) (0.17 mL, 1.5 mmol), N,O-
bis(trimethylsilyl)acetamide (0.37 mL, 1.5 mmol) and metal acetate (0.01 mmol). The reaction
mixture was then stirred for 24 h at room temperature. The reaction mixture was quenched with
saturated aqueous ammonium chloride, and then extracted with diethyl ether. The organic layer

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H. Kodama et al. / Tetrahedron: Asymmetry 11 (2000) 4009–4015
was dried over anhydrous sodium sulfate and evaporated to dryness, and the residue was
chromatographed on silica gel (ethyl acetate:hexane=1:4) to give dimethyl (1,3-diphenyl-2-prop-
enyl)malonate (R)-3a. The enantiomeric excess was determined by HPLC analysis using a Daicel
Chiralcel OD-H column (eluent, 1:99 2-propanol:hexane; flow rate 0.3 mL/min; detection, UV
254 nm; retention times, 27.9 (R):29.2 min (S)).
4.3. A typical procedure for palladium-catalyzed asymmetric allylic amination of rac-1,3-
diphenyl-2-propenyl acetate 1 with benzylamine 2b
A solution of the PHEST ligand (0.025 mmol) and Pd2(dba)3 (0.017 g, 0.013 mmol) in
tetrahydrofuran (2 mL) was stirred at room temperature for 30 min. This solution was then
successively treated with a solution of rac-1,3-diphenyl-2-propenyl acetate 1 (0.13 g, 0.50 mmol)
in tetrahydrofuran (1 mL) and benzylamine 2b (0.13 g, 1.2 mmol). The reaction mixture was
stirred for 48 h at 50°C. The reaction mixture was quenched with saturated aqueous ammonium
chloride, and then extracted with diethyl ether. The organic layer was dried over anhydrous
sodium sulfate and evaporated to dryness, and the residue was chromatographed on silica gel
(ethyl acetate:hexane=1:4) to give N-((E)-1,3-diphenyl-2-propenyl)benzylamine (S)-3b. The
enantiomeric excess was determined by HPLC analysis using a Daicel Chiralcel OD-H column
(eluent, 1:99 2-propanol:hexane; flow rate 0.5 mL/min; detection, UV 254 nm; retention times,
15.4 (R):16.2 min (S)). [h]D23=+12 (c 1.76, CHCl3) (lit.12 [h]2D3=+25 (c 1.76, CHCl3); 96% ee).
In a similar method, N-((E)-1,3-diphenyl-2-propenyl)phthalimide (S)-3c was prepared from
rac-1,3-diphenyl-2-propenyl acetate 1 and potassium phthalimide 2c as the nitrogen nucleophile.
The work up and determination of the enantiomeric excesses and the absolute configurations
were performed in the same way as described above. The enantiomeric excess was determined
using a Daicel Chiralcel OD-H column (eluent, 1:99 2-propanol:hexane; flow rate 0.5 mL/min;
detection, UV 254 nm; retention times, 22.3 min (S):30.8 min (R)). [h]2D3=+11 (c 1.70, CHCl3)
(lit.12 [h]D23=−17 (c 1.70, CHCl3); 99% ee R).
Acknowledgements
We thank Dr. Takayuki Yamashita for helpful discussions during the course of this work. We
also thank an undergraduate project student, Atsushi Shimotsuji. This work was partially
supported by Doshisha University’s Research Promotion Fund and a grant to RCAST at
Doshisha University from the Ministry of Education, Japan.
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