Chiral aminophosphine phosphinite-palladium catalysts in asymmetric allylic alkylations

Article abstract of DOI:10.1016/S0957-4166(00)00412-2

Palladium complexes of chiral aminophosphine phosphinites were investigated for the asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. The chirality of the carbon bonded to O-PPh₂ in the ligands was found t

Full text of DOI:10.1016/S0957-4166(00)00412-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4297–4302
Chiral aminophosphine phosphinite–palladium catalysts in
asymmetric allylic alkylations
Liuzhu Gong,a Guoshu Chen,a Aiqiao Mi,a,* Yaozhong Jiang*,a Fangmin Fu,a Xin Cuia
and Albert S. C. Chanb
aUnion Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Academia Sinica,
Chengdu 610041, China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, China
Received 15 August 2000; accepted 10 October 2000
Abstract
Palladium complexes of chiral aminophosphine phosphinites were investigated for the asymmetric
allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. The chirality of the carbon
bonded to O-PPh2 in the ligands was found to be very important to the enantioselectivity of the catalysts.
Introduction of this stereogenic center has led to significantly improved enantioselectivities. © 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
The enantioselective palladium catalyzed nucleophilic substitution of allylic acetates with
carbon-based soft nucleophiles is among the most important methods for carbonꢀcarbon bond
formation in asymmetric catalysis. A large number of chiral ligands containing P,P-, P,N- and
N,N-chelating atoms have shown high enantioselectivity in this process.1 Chiral amino alcohols
can be easily prepared from natural or unnatural amino acids, and are very inexpensive chirality
sources for the design of chiral ligands. The chiral ligands with O-PPh2 or N-PPh2 groups, such
as diaminophosphines, diphosphinites and aminophosphine-phosphinites, have been synthesized
and studied.2 However, few chiral aminophosphine-phosphinites exhibit excellent enantioselec-
tivity for asymmetric allylic alkylations. In 1991, Cesarotti studied the nucleophilic addition to
the allyl complex of palladium containing N-diphenylphosphino-2-(diphenylphosphin-
oxymethyl)pyrroline ligand 1 and found very low enantioselectivities (20–30% e.e.). A detailed
mechanistic study on the basis of X-ray and NMR data suggested that the soft nucleophile
should attack the allyl terminus trans to N-PPh2.3 This indicates that site C-3 in complex 1 is
* Corresponding authors.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00412-2

4298
L. Gong et al. / Tetrahedron: Asymmetry 11 (2000) 4297–4302
more electrophilic than C-1. According to this transition state, we propose that the low
enantioselectivity might derive from the long distance between the stereogenic center and the
reaction site in 1. The distal relationship between the incoming nucleophile and the chiral
environment of the Pd complexes might make the chirality transfer rather inefficient.4 If the
carbon bonded to the O-PPh2 group is also stereogenic as shown in 2, it may provide more
stereocontrol for the reaction and lead to better enantioselectivity. In our previous work, we
have found that ligand 2a shows excellent enantioselective induction in asymmetric hydrogena-
tion of dehydroamino acid derivatives.5a,b Herein, our investigation on using this new type of
chiral aminophosphine-phosphinite ligand in the palladium catalyzed allylic alkylation will be
described.
2. Results and discussion
2.1. Synthesis of the chiral ligands
Ligands 2a–e were synthesized from the reaction of chlorodiphenylphosphine (Ph2PCl) with
the corresponding optically active aminoethanols5 (Scheme 1).
Scheme 1. Synthesis of chiral ligands
2.2. Asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl
malonate catalyzed by complexes of palladium and 2a
The reaction of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate was carried out
with bis-trimethylsilyl acetamide (BSA) as base at room temperature for 24 h in the presence of
1 mol% palladium complex of 2a (Scheme 2). A variety of reaction conditions have been
investigated and the results are summarized in Table 1.

L. Gong et al. / Tetrahedron: Asymmetry 11 (2000) 4297–4302
4299
Scheme 2. The enantioselective allylic alkylation of 3 with dimethyl malonate
Table 1
The enantioselective allylic alkylation of 3 with dimethyl malonate
Entry
Palladium
Pd:2a
Solvent
Additive
Yield (%)a
E.e.%b (config.)c
1
2
3
4
5
6
7
8
9
[Pd(allyl)Cl]2
Pd(OAc)2
Pd2(dba)3·CHCl3
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
1:1.25
1:1.25
1:1.25
1:1.25
1:1.25
1:1.25
1:1.25
1:1.25
1:1
Toluene
Toluene
Toluene
Toluene
THF
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
KOAc
Bu4NBr
93
67
86
95
96
98
96
97
84
96
96
79
56 (S)
56 (S)
46 (S)
58 (S)
52 (S)
52 (S)
51 (S)
24 (S)
45 (S)
60 (S)
43 (S)
42 (S)
CH2Cl2
DCE
Hexane
Toluene
Toluene
Toluene
Toluene
10
11
12
1:2
1:1.25
1:1.25
Pd(dba)2
Pd(dba)2
a Isolated yield.
b Measured by HPLC (Chiralcel OD, n-hexane:2-propanol=99:1).
c The absolute configuration was determined by comparing the specific rotation with the literature value.6
In this reaction, the palladium sources significantly affected the reactivity. The use of
[Pd(allyl)Cl]2, Pd2(dba)3·CHCl3 and Pd(dba)2 gave the product in high yield. The catalyst made
from Pd(dba)2 showed the best reactivity and enantioselectivity (entry 4). Toluene is the best
solvent for this reaction. Increasing the ratio of 2a to Pd from 1:1 to 1:2 (entries 9 and 10)
improved the e.e. from 45 to 60%. Changing the additive from LiOAc to other salts caused a
reduction in enantioselectivity (entries 4, 11 and 12).
2.3. The relationship between structures of ligands 2a–e and enantioselectivities
In the presence of 1 mol% of [Pd(allyl)Cl]2, ligands 2b–e were also examined for the reaction
of 3 with 4, and the results are shown in Table 2. All 2–palladium complexes exhibited high
catalytic activity and gave 100% conversion for the reactions. As we expected, the stereogenic
carbon bonded to the O-PPh2 in these ligands is very important for the improved enantioselec-
tivity from 2d to 2a. Without the second stereogenic center, ligand 2d gave very low enantiose-
lectivity (11% e.e.) (entry 4). The configuration of the product is also controlled by the carbon
bonded to O-PPh2. When the configuration of this carbon is inverted, but that of the carbon
bonded to N-PPh2 maintained, as shown from 2a to 2c, the configuration of the product 5 is
inverted from S to R (entries 1 and 3). When a methyl group replaced the phenyl group bonded
to C-1 (ligand 2e), the enantiomeric excess was reduced to 42% (entry 5).

4300
L. Gong et al. / Tetrahedron: Asymmetry 11 (2000) 4297–4302
Table 2
Enantioselective allylic alkylation catalyzed by the complexes of [Pd(allyl)Cl]2 and 2a–e
Entry
Ligand
Additive
Conversion (%)a
E.e.%b (config.)c
1
2
3
4
5
2a
2b
2c
2d
2e
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
100
100
100
100
100
56 (S)
56 (R)
52 (R)
11 (S)
42 (S)
a Measured by HPLC.
b Measured by HPLC (Chiralcel OD, n-hexane:isopropanol=99:1).
c The absolute configuration was determined by comparing the optical rotation with the literature value.6
3. Conclusion
In summary, we have demonstrated that the configuration of the carbon bonded to O-PPh2
in the aminophosphine-phosphinite ligands plays a very important role for the palladium
catalyzed enantioselective allylic alkylation. Introduction of this stereogenic center has led to
significantly improved enantioselectivities. This work indicates that further enhancement in
enantioselectivity could be achieved by further modification of the chiral environment at both of
the stereogenic centers in these ligands and particularly at the phosphinite site.
4. Experimental
4.1. General data
THF and toluene were distilled from sodium/benzophenone under nitrogen. Dichloro-
methane, hexane and 1,2-dichloroethane were distilled from CaH2. The palladium complexes
were gifts from Professor Yoshinori Yamamoto at Tohuko University in Japan.
Melting points were measured on a digital melting point apparatus and were uncorrected. IR
1
spectra were obtained on a Nicolet 200SXV spectrometer. H NMR spectra were recorded on
a Bruker AC-E 300 and Bruker AC-E 200 instruments. The e.e. and conversion were determined
by HPLC on a Beckman-110A chromatograph with a Beckman 165 variable wavelength
detector. Optical rotations were measured on a Perkin–Elmer 241 polarimeter. The Chiralcel
OD column was purchased from Daicel Chemical Industries, Ltd.
4.1.1. Preparation of (1R,2S)-2a
To a Schlenk flask charged with (1R,2S)-1,2-diphenyl-2-(N-methyl)aminoethanol (100 mg,
0.44 mmol) and benzene (5 mL) at 0°C was added Et3N (0.26 mL, 1.80 mmol) and Ph2PCl (0.24
mL, 1.45 mmol). The reaction mixture was warmed up to room temperature and stirred for 24
h. After flash chromatography (eluent: benzene), the solvent was removed in vacuo to yield
product as a white needle crystal (140 mg, yield: 53%). Mp 91–93°C; [h]2D0=−38.1 (c=0.278,
1
C6H6); IR (KBr): 3400, 3040, 2910, 1430 cm−1; H NMR (300 MHz, CDCl3) l: 2.21 (d, 3H,
J
J
P–H=2.5 Hz, CH3), 4.94 (dd, 1H, JH–H=10.4 Hz, JP–H=14.2 Hz, NCH), 5.57 (dd, 1H,
H–H=10.1 Hz, JP–H=8.3 Hz, OCH), 6.53–7.52 (m, 30H, ArꢀH). 13C NMR (50 MHz, CD2Cl2)

L. Gong et al. / Tetrahedron: Asymmetry 11 (2000) 4297–4302
4301
l 33.6, 75.13, 83.5, 128.0, 128.4, 128.6, 128.7, 128.8, 129.1, 129.2, 129.4, 129.5, 129.6, 130.8,
131.0, 131.2, 132.4, 132.6, 132.8, 139.3, 139.4, 140.5, 141.3, 142.3, 142.4, 142.9, 143.1; 31P NMR
(MeOH) l 64.8 (s, P(N)), 111.8 (s, P(O)).
4.1.2. Preparation of (1S,2R)-2b
Yield: 54%; mp 94–96°C; [h]2D0=+37.8 (c=0.218, C6H6); IR (KBr): 3410, 3050, 2920, 1430
cm−1; 1H NMR (300 MHz, CDCl3) l: 2.21 (d, 3H, JP–H=2.4 Hz, CH3), 4.94 (dd, 1H, JH–H=10.0
Hz, JP–H=14.4 Hz, NCH), 5.57 (dd, 1H, JH–H=10.4 Hz, JP–H=8.4 Hz, OCH), 6.53–7.74 (m,
30H, ArꢀH); 31P NMR (CDCl3) l 65.9 (s, P(N)), 113.3 (s, P(O)).
4.1.3. Preparation of (1S,2S)-2c
Yield: 66%; mp 148–150°C; [h]2D0=−46.5 (c=0.172, C6H6); IR (KBr): 3450, 3060, 2960, 1435
cm−1; 1H NMR (300 MHz, CDCl3) l: 2.42 (d, 3H, JP–H=2.4 Hz, CH3), 4.86 (dd, 1H, JH–H=10.0
Hz, JP–H=10.4 Hz, NCH), 5.39 (dd, 1H, JH–H=9.2 Hz, JP–H=6.8 Hz, OCH), 6.90–7.78 (m,
30H, ArꢀH); 31P NMR (CDCl3) l 63.7 (s, P(N)), 106.3 (s, P(O)).
4.1.4. General procedure for asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate
with dimethyl malonate
To a Schlenk flask charged with Pd(dba)2 (5.7 mg, 0.01 mmol) and 2a (7.2 mg, 0.012 mmol)
was added toluene (1 mL) under nitrogen. The resulting solution was stirred at room tempera-
ture for 1 h, and then was added a solution of 3 (252 mg, 1 mmol) in toluene (2 mL), BSA (0.74
mL, 3 mmol), 4 (0.34 mL, 3 mmol) and LiOAc (2.8 mg, 0.04 mmol) sequentially. The reaction
mixture was degassed with three freeze–thaw cycles, and finally warmed up to room temperature
for 20 h. The reaction was quenched by the addition of water (5 mL) and EtOAc (10 mL). The
aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine
and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by
flash chromatography on silica gel (eluent: EtOAc:hexane=1:9) to give 5 (308 mg, 95%) as a
colorless oil. Enantiomeric excess (S-major): 56% e.e., was determined on HPLC (Chiralcel OD
column, eluent: hexane:2-propanol=99:1, flow rate: 0.5 mL min−1, retention time: tR=26.24
min, tS=28.67 min).
Acknowledgements
We are grateful for the financial support from the National Science Foundation of China
(29790124, 29972040) and the Hong Kong Polytechnic University ASD6 Fund. We also thank
Professor Yoshinori Yamamoto at Tohoku University in Japan for his generous gifts of
palladium complexes.
References
1. (a) Trost, M. B.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395; (b) Cahill, J. P.; Guiry, P. J. Tetrahedron:
Asymmetry 1998, 9, 4301; (c) Chelucci, G.; Culeddu, N.; Saba, A.; Valenti, R. Tetrahedron: Asymmetry 1999, 10,
3537; (d) Jin, M. J. P.; Jung, J. A.; Kim, S. H. Tetrahedron 1999, 40, 5197; (e) Chelucci, G.; Deriu, S.; Saba, A.;
Valenti, R. Tetrahedron: Asymmetry 1999, 10, 1457; (f) Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg. A. J.

4302
L. Gong et al. / Tetrahedron: Asymmetry 11 (2000) 4297–4302
Org. Chem. 1999, 64, 1082; (g) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne´, M. R. J. Org.
Chem. 1999, 64, 2994; (h) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. Chem. Commun. 1999,
415; (i) Dierkes, P.; Ramdeehul, S.; Barloy, L.; De Cian, A.; Fischer, J.; Kamer, P. C.; Van Leeuwen, P. W. N.
M.; Osborn, J. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 3116; (j) Yan, Y. Y.; RajanBabu, T. V. Org. Lett. 2000,
2, 199.
2. (a) Fiorini, M.; Giongo, M. J. Mol. Catal. 1979, 5, 303; (b) Selke, R.; Pracejus, H. J. Mol. Catal. 1986, 37, 213;
(c) Cesarotti, E.; Chiesa, A.; D’Alfonso, D. Tetrahedron Lett. 1982, 23, 2995.
3. Cesarotti, E.; Grassi, M.; Prati, L.; Demartin, F. J. Chem. Soc., Dalton Trans. 1991, 2073.
4. (a) Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron Lett. 1986, 27, 191; (b) Hayashi, T. Pure Appl.
Chem. 1988, 60, 7; (c) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586.
5. (a) Mi, A. Q.; Lou, R. L.; Qin, Y.; Jiang, Y. Z.; Hu, W. H.; Chan, A. S. C. CN Appl. 97 1 076081.1; (b) Mi, A.
Q.; Lou, R. L.; Jiang, Y. Z.; Deng, J. G.; Qin, Y.; Fu, F. M.; Li, Z.; Hu, W. H.; Chan, A. S. C. Synlett 1998,
847; (c) Karim, A.; Mortreux, A.; Petit, F.; Buono, G.; Peiffer, G.; SIV, et C. J. Organomet. Chem. 1986, 317, 93;
(d) Suisse, I.; Bricout, H.; Mortreux, A. Tetrahedron Lett. 1994, 35, 413.
6. Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566.
.
.