New chiral ligands, pyrrolidinyl- and 2-azanorbornyl- phosphinooxazolidines for palladium-catalyzed asymmetric allylation

Article abstract of DOI:10.1016/S0957-4166(00)00049-5

Pyrrolidinyl- 2 and 2-azanorbornylphosphinooxazolidines 3, a new type of optically active ligands, were synthesized easily and their abilities as ligands were examined in Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. Enantiomeric excesses of up to 96% have been obtained using 1 mol% of [PdCl(η³-C₃H₅)]₂ and 2.1 mol% of 2. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00049-5

Tetrahedron: Asymmetry 11 (2000) 1193±1198
New chiral ligands, pyrrolidinyl- and 2-azanorbornyl-
phosphinooxazolidines for palladium-catalyzed
asymmetric allylation
Yuko Okuyama, Hiroto Nakano* and Hiroshi Hongo*
Tohoku Pharmaceutical University, Aoba-ku, Sendai 981, Japan
Received 27 December 1999; accepted 31 January 2000
Abstract
Pyrrolidinyl- 2 and 2-azanorbornylphosphinooxazolidines 3, a new type of optically active ligands, were
synthesized easily and their abilities as ligands were examined in Pd-catalyzed asymmetric allylic alkylation
of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. Enantiomeric excesses of up to 96% have been
3
obtained using 1 mol% of [PdCl(Z -C H )] and 2.1 mol% of 2. # 2000 Elsevier Science Ltd. All rights
3
5 2
reserved.
1
. Introduction
Catalytic asymmetric synthesis has been a challenging subject in organic synthesis. The devel-
opment of ecient enantioselective catalysts applicable to a wide range of carbon±carbon bond
forming reactions represents a pivotal challenge to the synthetic community. Among the ligands,
1
chiral oxazolines have proved to be extremely ecient ligands in some catalytic reactions.
Recently, chiral phosphinooxazolidine 1 has been shown to be an e€ective ligand in Pd-catalyzed
2
asymmetric allylic substitutions similarly to phosphinooxazolines. To the best of our knowledge,
there is only one system 1. We wish to report the synthesis of two kinds of new chiral ligands,
pyrrolidine-based phosphinooxazolidine 2 and 2-azanorbornane-based phosphinooxazolidine 3,
3
followed by the application to Pd-catalyzed allylic alkylation. This allylation has been widely
employed as an ecient and convenient tool for carbon±carbon and carbon±heteroatom bond
formation in the ®eld of organic synthesis.
*
Corresponding authors. E-mail: hnakano@tohoku-pharm.ac.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00049-5

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Y. Okuyama et al. / Tetrahedron: Asymmetry 11 (2000) 1193±1198
2
. Results and discussion
Preparations of the chiral ligands 2 and 3 are described in Scheme 1. The chiral pyrrolidinyl-
phosphinooxazolidine 2 was readily synthesized by the condensation of commercially available
R)-pyrrolidinylmethanol 4 with 2-(diphenylphosphino)benzaldehyde 5 in re¯uxing benzene using
(
a Dean±Stark apparatus. More sterically constrained 2-azanorbornylphosphinooxazolidine 3 was
4
obtained from 6, reported by our group, with 5 in re¯uxing toluene. The stereochemistries of the
newly created stereogenic center at the 2-position of the 1,3-oxazolidine ring for 2 and 3 were
1
determined by the NOE measurement of H NMR spectra, respectively. Thus, the NOE exper-
iments for 2 and 3 con®rmed an interaction between the hydrogen at the 2-position and at the 4-
position, respectively.
Scheme 1.
In order to examine the e€ectiveness of the ligands, the enantioselective allylic alkylation of
1,3-diphenyl-2-propenyl acetate 7 with dimethyl malonate was tried in the presence of p-allyl-
palladium chloride dimer. The results are summarized in Table 1. The reaction was tried under
3
the BSA standard conditions (entries 1±7). Using 2.5 mol% [PdCl(Z -C H )] and 10 mol%
3
5 2
2
ligands (2 and 3), similarly to Jin's report, good results were not obtained, although both ligands
2
and 3 worked to give the alkylation product 8 (entries 1 and 2). The excellent result (98 and
5
3
9
However, 2-azanorbornane-based phosphinooxazolidine 3 was also less e€ective (53%, 43% ee)
6% ee) (entry 3) was achieved by using 1 mol% [PdCl(Z -C H )] and 2.1 mol% ligand 2.
3
5 2
under these reaction conditions (entry 4). Furthermore, this reaction was carried out under other
ꢀ
reaction conditions using ligand 2 (entries 5±10). The reduction of the temperature to 0 or 10 C
decreased the enantiomeric excesses (entries 5 and 6). When THF was used as a solvent, high
enantiomeric excess (95% ee) was con®rmed similarly to the case of entry 3 (entry 7). The reaction
in acetonitrile did not give a good result (entry 8). The conditions using tetrabutylammonium
¯uoride (TBAF) gave 85 and 87% ee (entry 9). However, reduction of the temperature decreased
the enantiomeric excess (73% ee) (entry 10).

Y. Okuyama et al. / Tetrahedron: Asymmetry 11 (2000) 1193±1198
1195
Table 1
Asymmetric Pd-catalyzed allylation of 1,3-diphenyl-2-propenyl acetate
Unfortunately, better results were not found under these conditions. From the above results,
phosphinooxazoline 2 is an excellent ligand in this allylation under the reaction conditions of
entry 3.
It is considered that the enantioselective step in Pd-catalyzed allylation is the substitution of
p-allyl complexes with nucleophiles and nucleophilic attack occurs predominantly at the allyl
6
terminus from trans to the better p-acceptor (PꢁN). Since the (S)-product was obtained as the
major enantiomer, the reaction probably proceeds through an M-type 10 rather than a W-type 9
6
intermediate. In addition, the di€erentiation of chemical yields and enantiomeric excesses for the
ligands 2 and 3 may be explained by steric inferences. Thus, the 2-azanorbornane skeleton, which

1
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Y. Okuyama et al. / Tetrahedron: Asymmetry 11 (2000) 1193±1198
is more bulky than the pyrrolidine skeleton, obstructs the construction of the p-allyl palladium
complex 11 (Scheme 2).
Scheme 2.
3
. Conclusions
We have prepared two kinds of new chiral ligands 2 and 3. These worked as ligands for allylic
substitution reactions. In particular 2 was a good and e€ective ligand and gave an excellent chemical
yield and enantiomeric excess. It is expected that 2 and 3 would act as good ligands in other catalytic
asymmetric reactions. Further applications and modi®cations of the ligand 2 are in progress.
4
. Experimental
4
.1. General
1
IR spectra were measured with a Perkin±Elmer 1725X spectrophotometer. H NMR spectra
were recorded on a JEOL JNM-GSX 270 and a JEOL JNM-LA 400 spectrometer with TMS
as an internal standard. MS were taken on Hitachi RMG-6MG and JEOL-JNM-DX 303
spectrometers. Optical rotations were measured with a JASCO-DIP-370 digital polarimeter. Thin
layer chromatography was performed with Merck F-254 silica gel plates. Preparative thin layer
chromatography was carried out on Merck PSC-Fertirplatten Kieselgel 60 F254 plates.
4
.2. (2R,5R)-1-Aza-2-(2-diphenylphosphino)phenyl-3-oxa-4,4-diphenylbicyclo[3.3.0]octane 2
(R)-(+)-a,a-Diphenyl-2-pyrrolidinemethanol 4 (100 mg, 0.4 mmol), 2-(diphenylphosphino)-
benzaldehyde 5 (128 mg, 0.44 mmol), p-toluenesulfonic acid monohydrate (30 mg, 0.16 mmol)

Y. Okuyama et al. / Tetrahedron: Asymmetry 11 (2000) 1193±1198
1197
and benzene (8 ml) were placed in a ¯ask equipped with a Dean±Stark trap. The mixture was
re¯uxed overnight. The solvent was evaporated under reduced pressure and the residue was pur-
ꢀ
i®ed by preparative TLC (hexane:ether=6:1) to give pure 2 (112 mg) in 54% yield. Mp 52±54 C,
� 1
23
1
‰
ꢀŠ =+95.0 (c 1.0, CHCl ). IR (®lm) cm : 746, 697. H NMR (CDCl ) ꢁ 7.62 (m, 1H), 7.11±
D
.38 (m, 22H), 6.88 (m, 1H), 6.36 (d, J=6.3 Hz, 1H), 4.31 (t, J=7.0 Hz, 1H), 2.93 (m, 1H), 2.75
3
3
7
(
m, 1H), 1.43±1.70 (m, 4H). 13C NMR (CDCl ) ꢁ 137.18, 133.99, 133.81, 133.70, 133.52, 133.28,
3
1
1
6
28.83, 128.26, 128.21, 128.15, 128.10, 128.00, 127.77, 127.69, 127.63, 127.50, 126.47, 126.39,
26.18, 126.04, 94.78, 94.45, 73.34, 50.52, 27.82, 24.43. Anal. calcd for C H NOP: C, 82.26; H,
.14; N, 2.66. Found: C, 81.98; H, 6.10; N, 2.46. MS m/z: 525 (M ).
36
32
+
2,6
4
.3. (1R,3S,6S,7S)-2-Aza-3-(2-diphenylphosphino)phenyl-4-oxa-5,5-diphenyltricyclo[5.2.1.0 ]-
decane 3
Compound 6 (200 mg, 0.72 mmol), 2-(diphenylphosphino)benzaldehyde 5 (240 mg, 0.81 mmol)
and toluene (20 ml) were placed in a ¯ask equipped with a Dean±Stark trap. The mixture was
re¯uxed for 48 h. The solvent was evaporated under reduced pressure and the residue was
puri®ed by preparative TLC (hexane:ether=5:1) to give pure 3 (230 mg) in 65% yield. Mp 230±
ꢀ
23
D
� 1
1
2
1
1
32 C, ‰ꢀŠ =� 45.3 (c 1.7, CHCl ). IR (®lm) cm : 748, 697. H NMR (CDCl ) ꢁ 8.14 (m,
3
3
H), 7.05±7.69 (m, 23H), 6.06 (d, J=5.3 Hz, 1H), 4.11 (s, 1H), 2.56 (s, 1H), 1.89 (br s, 1H),
.51 (d, J=9.5 Hz), 1.16±1.26 (m, 2H), 0.82 (m, 1H), 0.65 (m, 1H), 0.53 (d, J=9.5 Hz, 1H).
C NMR (CDCl ) ꢁ 138.40, 138.32, 137.62, 137.55, 135.88, 135.65, 134.90, 134.89, 134.43,
1
3
3
1
1
34.23, 133.43, 133.24, 129.06, 128.86, 128.52, 128.50, 128.43, 128.01, 127.99, 127.94, 127.60,
25.90, 125.85, 115.95, 112.12, 81.41, 81.58, 60.39, 53.01, 51.54, 51.51, 27.92, 23.75. Anal. calcd
for C H NOP: C, 82.73; H, 6.21; N, 2.54. Found: C, 82.84; H, 6.18; N, 2.45. MS m/z: 551
34
38
+
(
M ).
4.4. General procedure [method A (entries 1±8), method B (entries 9±10)] for the Pd-catalyzed
allylic substitutions of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate using 2 and 3 as
chiral ligands
Method A: a mixture of ligand 2 (entries 1±2: 0.04 mmol; entries 3±8: 0.008 mmol) and
3
[
PdCl(Z -C H )] (entries 1±2: 0.01 mmol; entries 3±8: 0.004 mmol) in dry solvent (1 ml) indicated
3
5 2
in Table 1 was stirred at room temperature for 1 h and the resulting yellow solution was added to
a mixture of acetate 7 (0.4 mmol) and base [entries 1±8: potassium acetate (entries 1±2: 0.012
mmol; entries 3±8: 0.008 mmol)] in dry solvent (1 ml) using a syringe followed by the addition of
dimethyl malonate (1.2 mmol) and BSA (1.2 mmol). Method B: a mixture of ligand 2 (0.008
3
mmol) and [PdCl(Z -C H )] (0.004 mmol) in dry solvent (1 ml) was stirred at room temperature
3
5 2
for 1 h and the resulting yellow solution was added to a solution of acetate 7 (0.4 mmol) in dry
solvent (1 ml) using a syringe followed by the addition of a mixture of dimethyl malonate (1.2
mmol), TBAF (1.2 mmol) and BSA (1.2 mmol). The reactions of methods A and B were carried
out at ambient temperature and the reaction mixtures were diluted with ether and were quenched
with satd NH Cl. The organic layer was washed with brine and dried over MgSO . The solvent
4
4
was evaporated under reduced pressure and the residue was puri®ed by preparative TLC
(hexane:ether=5:1) to give a pure product 8. The enantiomeric excess was determined by HPLC
(Chiralcel OD-H, 0.5 ml/min, hexane:2-propanol=98:2). The absolute con®guration was deter-
mined by speci®c rotation.
3a,b

1
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Y. Okuyama et al. / Tetrahedron: Asymmetry 11 (2000) 1193±1198
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