New chiral phosphinoimidazolidine ligand in palladium-catalyzed asymmetric allylic substitution

Article abstract of DOI:10.1016/S0040-4039(02)01676-3

Chiral phosphinoimidazolidine 3 was used as an excellent ligand in Pd-catalyzed asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate 5 with dimethyl malonate. Outstanding enantioselectivity of up to 99% and remarkable catalytic activity were observed. The ligand was also found to be effective in the asymmetric allylic amination of 5 with benzylamine.

Full text of DOI:10.1016/S0040-4039(02)01676-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7409–7411
New chiral phosphinoimidazolidine ligand in palladium-catalyzed
asymmetric allylic substitution
Myung-Jong Jin,* Sang-Han Kim, Sang-Joon Lee and Young-Mok Kim
School of Chemical Science & Engineering, Inha University, Inchon 402-751, Republic of Korea
Received 19 June 2002; revised 7 August 2002; accepted 9 August 2002
Abstract—Chiral phosphinoimidazolidine 3 was used as an excellent ligand in Pd-catalyzed asymmetric allylic alkylation of
racemic 1,3-diphenyl-2-propenyl acetate 5 with dimethyl malonate. Outstanding enantioselectivity of up to 99% and remarkable
catalytic activity were observed. The ligand was also found to be effective in the asymmetric allylic amination of 5 with
benzylamine. © 2002 Elsevier Science Ltd. All rights reserved.
Pd-catalyzed asymmetric allylic substitution has
received considerable attention as a useful asymmetric
carbonꢀcarbon and carbonꢀheteroatom forming pro-
cess, in which racemic or achiral allylic substrate can be
converted to an optically active product in the presence
of a palladium complex of chiral ligand.1,2 Develop-
ment of new chiral ligands is an important chapter of
current research in this area. Among numerous
reported ligands, phosphorus–nitrogen heterodonor lig-
ands are particularly effective in the asymmetric allylic
alkylation due to their different electronic properties
(trans effect).3,4 Phosphinooxazolines 1 represent one of
the most useful and versatile ligands in this area.3
Generally, most of the phosphorus–nitrogen ligands
possess an sp2 nitrogen donor. We were interested in
phosphorus–nitrogen ligands bearing an sp3 nitrogen
donor. Recently, we have found that phosphinooxazo-
lidines 2 can act as excellent chiral ligands for the
asymmetric catalysis.5 Introduction of the oxazolidine
moiety might open up a path to the development of
different kinds of chiral ligands. Encouraged by the
The phosphinoimidazolidine 36 was easily prepared
results, we have designed imidazolidine systems bearing
double sp3 nitrogens. We herein present semi-C2-sym-
metrical phosphinoimidazolidine 3 as a highly efficient
ligand which has the first application to the Pd-cata-
lyzed asymmetric allylic substitution.
through condensation of commercially available 2-
(diphenyl-phosphino)benzaldehyde and (1S,2S)-N,N%-
dimethylcyclo-hexane-1,2-diamine7 in refluxing benzene
over 12 h in nearly quantitative yield. Pyridinylimidazo-
lidine 4 was also prepared by the same method. The
catalytic properties of the palladium complexes formed
in situ from these ligands and [Pd(h3-C3H5)Cl]2 were
investigated in the asymmetric allylic alkylation of 1,3-
diphenyl-2-propenyl acetate 5 with dimethyl malonate.8
N,O-Bis-(trimethylsilyl) acetamide (BSA) combined
with a small amount of KOAc, NaOAc or LiOAc was
used as base. The data obtained are summarized in
Keywords: asymmetric catalysis; allylic substitution; imidazolidine
ligand; Pd catalyst.
* Corresponding author. Tel.: +82-32-860-7469; fax: +82-32-872-0959;
e-mail: mjjin@inha.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01676-3

7410
M.-J. Jin et al. / Tetrahedron Letters 43 (2002) 7409–7411
Table 1. Palladium-catalyzed asymmetric allylic alkylation of 5 with dimethyl malonatea
Entry
Ligand (mol%)b
Solvent
Additive
Temp. (°C)
Time (h)
Yield (%)c
Ee (%)d
1
3 (4.4)
3 (2.2)
3 (2.2)
3 (4.4)
3 (4.4)
3 (2.2)
3 (4.4)
3 (4.4)
3 (4.4)
3 (2.2)
3 (2.2)
3 (1.1)
3 (2.2)
3 (2.2)
4 (2.2)
4 (10)
THF
THF
THF
THF
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
THF
THF
THF
THF
CH2Cl2
THF
KOAc
KOAc
KOAc
KOAc
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
20
10
10
0
10
20
10
10
20
20
10
10
0
0.4
0.7
1.5
0.9
0.7
0.7
0.8
1
0.7
0.8
1
1
1.5
3
97
95
90
96
96
97
96
92
96
97
95
94
90
70
35
62
97
97
97
96
95
96
97
95
94
95
99
98
96
95
33
32
2
3e
4
5
6
7
8
9
10
11
12e
13
14
15
16
10
20
20
20
20
THF
a BSA (3 equiv.), dimethyl malonate (3 equiv.) and 4 mol% additive were used unless noted otherwise.
b Entries 1–15: ligand/[Pd(h3-C3H5)Cl]2=2.2, entry 16: ligand/[Pd(h3-C3H5)Cl]2=4.
c Isolated yield.
d Determined by HPLC with a chiralcel OD-H column. Absolute configuration was assigned by the sign of the optical rotation and the elution
order from a Daicel chiralcel column.
e BSA (2 equiv.) and dimethyl malonate (2 equiv.) were used.
Table 1. The reaction proceeded remarkably well both
in terms of enantioselectivity and reactivity. Optimum
results were obtained when the reaction was performed
at 10°C in THF. Use of THF is more desirable than
CH2Cl2 in this system. Additive source seems to have
little influence on the ee. BSA–LiOAc gave somewhat
better enantioselectivity. Under these conditions, ligand
3 afforded the substitution product (S)-6 with up to
99% ee (entry 11). The results are comparable to those
of phosphinooxazolines 1 and phosphinooxazolidines 2.
terminus trans to the phosphorus which is the better
p-acceptor. Therefore, the (S)-isomer is formed as the
It is noteworthy that nearly complete conversion and
major product, in accordance with the experimental
high ee were achieved with only 0.5 mol% Pd[(h3-
results.
C3H5)Cl]2 and 1.1 mol% 3 in 1 h (entry 12). In contrast,
chiral N,N-homodonor ligand 4 gave low asymmetric
induction and modest reactivity (entry 15 and 16).
Next, the asymmetric allylic amination9 of 1,3-
diphenyl-2-propenyl acetate 5 with benzylamine was
performed at 40°C in the presence of 2 mol% [Pd(h3-
C3H5)Cl]2 and 4.4 mol% 3. High enantioselectivity of
95% ee was observed for the generation of (S)-7. The
enantioselectivity was better than with phosphinooxa-
zolines 19b and phosphinooxazolidines 2.5 The asym-
metric induction by ligand 3 can be briefly explained as
follows. Presumably, the nucleophilic substitution pro-
ceeds through the less sterically-hindered endo-p-allyl-
palladium complex as a major intermediate (Scheme 1).
In the case of exo-p-allyl complex, severe repulsive
interaction would be generated between the imidazo-
lidine ring and the phenyl group in the substrate. The
nucleophilic attack occurs preferentially at the allyl
Scheme 1.

M.-J. Jin et al. / Tetrahedron Letters 43 (2002) 7409–7411
7411
In conclusion, we have demonstrated that chiral phos-
phinoimidazolidine could be used as a highly efficient
ligand in the asymmetric Pd-catalyzed allylic substitu-
tion. The results described above show the considerable
potential of such ligands in asymmetric catalysis. Fur-
ther synthesis of chiral imidazolidines and their applica-
tion are underway in our laboratory.
Synlett 2001, 12, 284–286; (j) Anderson, J. C.; Cubbon, R.
J.; Harling, J. D. Tetrahedron: Asymmetry 2001, 12, 923–
935.
5. Jin, M.-J.; Jung, J.-A.; Kim, S.-H. Tetrahedron Lett. 1999,
40, 5197–5198.
6. Synthesis of 3: To a solution of 2-(diphenylphosphino)-
benzaldehyde (290 mg, 1 mmol) in degassed benzene (5
mL), (1S,2S)-N,N%-dimethyl-cyclohexane-1,2-diamine (149
mg, 1.05 mmol) was added. The mixture was stirred at
75°C for 12 h, then concentrated under reduced pressure.
The crude product was purified by short flash chromato-
graphy on silica gel pretreated with triethylamine (5%
EtOAc–5% Et3N/hexane) to yield 3 (405 mg) as a colorless
glass: yield 96%; [h]D20=−59.3 (c 1.5, C6H6); MS (EI) m/e
415 (M+); 1H NMR l (CDCl3, 400 MHz) 7.64 (m, 1H),
Acknowledgements
This work was supported by the Center for Advanced
Bioseparation Technology, Inha University.
4
7.35–7.18 (m, 12H), 6.94 (m, 1H), 6.02 (d, JPH 4.5 Hz,
1H), 2.58 (m, 1H), 2.08 (s, 3H), 2.02 (m, 1H), 1.86 (m,
2H), 1.83 (s, 3H), 1.78 (m, 2H), 1.26 (br s, 4H). Anal. calcd
for C27H31N2P: C, 78.23; H, 7.54; N, 6.76. Found: C,
78.07; H, 7.61; N, 6.84%.
References
1. For recent reviews: (a) Togni, A.; Venanzi, L. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 497–526; (b) Trost, B. M.;
van Vranken, D. L. Chem. Rev. 1996, 96, 395–422; (c)
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1–45; (d) Helmchen, G.; Pfaltz, A.
Acc. Chem. Res. 2000, 33, 336–345.
2. Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Yamamoto, H., Eds.; Springer:
Heidelberg, 1999; Vol. 2, pp. 833–884.
3. (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1993, 32, 566–568; (b) Sprinz, J.; Helmchen, G. Tetra-
hedron Lett. 1993, 34, 1769–1772; (c) Dawson, G. J.; Frost,
C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett
1993, 34, 3149–3150; (d) Kudis, S.; Helmchen, G. Angew.
Chem., Int. Ed. Engl. 1998, 37, 3047–3050.
4. (a) Ahn, K. H.; Cho, C.-W.; Park, J.; Lee, S. Tetrahedron:
Asymmetry 1997, 8, 1179–1185; (b) Sudo, A.; Yoshida, H.;
Saigo, K. Tetrahedron: Asymmetry 1997, 8, 3205–3208; (c)
Pretot, R.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1998,
37, 323–325; (d) Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji,
Y.; Ikeda, I. Tetrahedron Lett. 1998, 39, 4343–4346; (e)
Hashimoto, Y.; Horie, Y.; Hayashi, M.; Saigo, K. Tetra-
hedron: Asymmetry 2000, 11, 2205; (f) Mino, T.; Tanaka,
Y.-i.; Akita, K.; Anada, K.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2001, 12, 1677–1682; (g) Saitoh,
A.; Achiwa, K.; Tanaka, K.; Morimoto, T. J. Org. Chem.
2000, 65, 4227–4240; (h) Fukuta, T.; Takehara, A.; Iwao,
M. Tetrahedron: Asymmetry 2001, 12, 2793–2799; (i) Ito,
K.; Kashiwagi, R.; Hayashi, S.; Uchida, T.; Katsuki, T.
7. Alexakis, A.; Mutti, S.; Mangeney, P. J. Org. Chem. 1992,
57, 1224–1237.
8. A representative procedure for allylic alkylation: In a
Schlenk tube the ligand 3 (4.6 mg, 0.011 mmol, 2.2 mol%)
and allylpalladium chloride dimer (1.9 mg, 0.0052 mmol,
1.0 mol%) were dissolved in THF (0.7 mL) and the
mixture was stirred at room temperature for 20 min. To
this solution 1,3-diphenyl-2-propenyl acetate (130 mg, 0.52
mmol) in THF (1.6 mL), dimethyl malonate (206 mg, 1.56
mmol), N,O-bis(trimethylsilyl)acetamide (317 mg, 1.56
mmol) and LiOAc (1.4 mg, 0.02 mmol) were successively
added. The mixture was stirred at a given temperature.
After the reaction was complete, the reaction mixture was
diluted with ether (15 mL), washed with cold saturated
aqueous ammonium chloride solution (10 mL). The
organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel (15% EtOAc/hexane). The
enantiomeric excess was determined by HPLC analysis
(chiralcel OD-H column; flow rate, 0.5 mL/min; hex-
ane:isopropanol=99:1, tr=23.4 min, ts=25.0 min).
9. (a) Hayashi, T.; Yamamodo, A.; Ito, Y.; Nishioka, E.;
Miura, H.; Yanagi, K. J. Am. Chem. Soc. 1989, 111,
6301–6311; (b) von Matt, P.; Loiseleur, O.; Koch, G.;
Pfaltz, A. Tetrahedron: Asymmetry 1994, 5, 573–584; (c)
Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uerura,
S. J. Org. Chem 1999, 64, 9374–9380.