Novel chiral phosphine-oxazinane ligands in palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1016/S0040-4039(01)00860-7

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (8a) with a dimethyl malonate-BSA-LiOAc system has been successfully carried out in the presence of novel chiral phosphine-oxazinane ligands such as 5b in good yields with good enantioselectivities (up to 95% ee).

Full text of DOI:10.1016/S0040-4039(01)00860-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4837–4839
Novel chiral phosphine–oxazinane ligands in palladium-catalyzed
asymmetric allylic alkylation
Takashi Mino,* Sosuke Hata, Kouji Ohtaka, Masami Sakamoto and Tsutomu Fujita
Department of Materials Technology, Faculty of Engineering, Chiba University, Inage-ku, Chiba 263-8522, Japan
Received 2 March 2001; revised 8 May 2001; accepted 18 May 2001
Abstract—Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (8a) with a dimethyl malonate–
BSA–LiOAc system has been successfully carried out in the presence of novel chiral phosphine–oxazinane ligands such as 5b in
good yields with good enantioselectivities (up to 95% ee). © 2001 Elsevier Science Ltd. All rights reserved.
Palladium-catalyzed asymmetric allylic alkylation is a
useful process for asymmetric CꢀC bond forming reac-
tions. To achieve high enantioselectivity in the catalytic
reaction, a variety of chiral ligands have been studied.1
Among the ligands, chiral oxazolines have proved to be
extremely efficient ligands in some catalytic reactions.2
Recently, chiral phosphine–oxazine ligand 13 and chiral
phosphine–oxazolidine ligands 24 and 35 were shown to
be effective ligands in palladium-catalyzed asymmetric
allylic alkylation similarly to phosphine–oxazolines. On
the other hand, palladium-catalyzed asymmetric allylic
alkylation using phosphine–oxathiane ligand 4 has been
reported.6 To the best of our knowledge, the oxazinane
type ligands have never been involved in this area. With
the aim of exploiting the less popular oxazinanes, we
synthesized chiral phosphine–oxazinane, starting from
(S)-ketopinic acid.7 Herein, we wish to describe the first
application of the oxazinanes as ligands to the palla-
dium-catalyzed asymmetric allylic alkylation.
prepared by the corresponding amines with (S)-
ketopinic acid followed by the reduction of 6, and the
condensation of aminoalcohols 7 with 2-(diphenyl-
phosphino)benzaldehyde.
The ligands 5 were obtained the diasteromerically pure
within NMR spectra. The stereochemistry of 5b was
1
determined by NOE measurement of H NMR spectra.
Thus, the NOE experiment for 5b confirmed interac-
tions between the Ha and Hb and between Hb and Hc
(Fig. 1).
We applied the chiral phosphine–oxazinane ligands 5 to
the palladium-catalyzed asymmetric allylic alkylation of
1,3-diphenyl-2-propenyl acetate (8a) with a dimethyl
malonate (9a) (Scheme 2). This reaction was carried out
in the presence of 2 mol% of [Pd(h3-C3H5)Cl]2, 4 mol%
of chiral ligand, and a mixture of N,O-bis(trimethyl-
silyl)acetamide (BSA) and 2 mol% of LiOAc at room
temperature (entries 1–4, Table 2). These ligands 5
showed similar reactivity and enantioselectivity except
5d. Using ligand 5b, the product (R)-10a was obtained
the best enantioselectivity (79% ee) in these ligands 5
(entry 2). We investigated the effect of solvents on this
reaction using 5b (entries 2 and 5, 6, 8). When the
reaction was carried out in toluene, the enantioselectiv-
ity was higher than for the other solvents (entry 6). On
The synthesis of phosphine–oxazinane ligands 5 is
shown in Scheme 1 and Table 1. These ligands 58 were
Keywords: asymmetric synthesis; phosphine; oxazinane; palladium.
* Corresponding author. Tel.: +81 43 290 3385; fax: +81 43 290 3401;
e-mail: tmino@planet.tc.chiba-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00860-7

4838
T. Mino et al. / Tetrahedron Letters 42 (2001) 4837–4839
the other hand, with diethyl methylmalonate (9c), the
reaction gave the corresponding product 10c9 in moder-
ate enantioselectivity (entry 7). The reaction at 0°C
further improved the enantioselectivity to 88% ee (entry
9). Although the reaction rate became slow by further
depressing the temperature (−20°C), the enantioselectiv-
ity was improved to 95% ee (entry 10). When 1,3-
diphenyl-2-propenyl pivalate (8b) was used instead of
1,3-diphenyl-2-propenyl acetate (8a), the reaction with
a dimethyl malonate (9a) gave the product 10a in good
enantioselectivity (entry 11). When diethyl malonate
(9b) was used instead of 9a, the reaction gave the
corresponding product 10b10 in good enantioselectivity
(entry 12).
Scheme 1.
Table 1. Synthesis of phosphine–oxazinane ligands 5
Entry
R
Yield of 6 (%) Yield of 7 (%) Yield of 5 (%)
1
2
3
4
Et
36
58
65
52
59
90
65
6
55
47
64
38
n-Pr
n-Bu
Bn
Figure 1. Selected NOE correlations of 5b.
Scheme 2.
Table 2. Asymmetric allylic alkylation using chiral ligands 5a
Entry
Ligand
R
R1
R2
Solv.
Temp. (°C)
Yield of 10 (%)b
Ee of 10 (%)c
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5b
5b
5b
5b
5b
5b
5b
5b
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Et
H
H
H
H
H
H
Me
H
H
H
H
H
THF
THF
THF
THF
Ether
PhMe
PhMe
MeCN
PhMe
PhMe
PhMe
PhMe
rt
rt
rt
rt
rt
rt
rt
rt
85
98
82
13
87
81
59
47
90
50
20
73
64
79
74
22
80
85
60
65
88
95
95
92f
9d
10d
11e
12e
0
−20
−20
−20
a The reaction was carried out for 24 h.
b Isolated yields.
c Determined by HPLC analysis using a chiral column (Chiralcel OD-H).
d This reaction was carried out for 100 h.
e This reaction was carried out for 120 h.
f Determined by HPLC analysis using a chiral column (Chiralcel OJ).

T. Mino et al. / Tetrahedron Letters 42 (2001) 4837–4839
4839
In conclusion, we have prepared novel chiral phos-
NMR (300 MHz, CDCl3) l 0.68 (t, 6.9 Hz, 3H), 0.83–
0.87 (m, 1H), 0.90 (s, 3H), 0.94–0.98 (m, 1H), 1.21–1.34
(m, 3H), 1.36–1.42 (m, 1H), 1.41 (s, 3H), 1.50 (dd, 7.9
and 13.3 Hz, 1H), 1.60–1.72 (m, 2H), 1.77–1.84 (m, 1H),
1.98–2.03 (m, 1H), 2.05 (d, 12.2 Hz, 1H), 3.10 (d, 12.2
Hz, 1H), 3.32 (dd, 2.8 and 7.8 Hz, 1H), 5.23 (d, 7.1 Hz,
1H), 6.84–6.85 (m, 1H), 7.17–7.19 (m, 1H), 7.26–7.38 (m,
11H), 7.73–7.76 (m, 1H); 13C NMR (75 MHz, CDCl3) l
11.52, 20.05, 20.54, 22.69, 26.96, 31.16, 37.39, 45.59,
46.08, 46.20, 52.27, 53.84, 83.13, 92.00 (d, 26.9 Hz),
128.21–128.54 (Ar, m), 128.83, 129.41, 132.83, 133.77 (d,
19.7 Hz), 134.70 (d, 20.7 Hz), 135.86 (d, 14.5 Hz), 136.45
(d, 10.5 Hz), 136.90 (d, 10.3 Hz), 144.98 (d, 20.7 Hz); 31P
NMR (122 MHz, CDCl3) l −16.0; FAB-MS (m/z) 482
(M+−H, 27); HRMS (FAB) calcd for C32H38NOP+H
484.2768, found 484.2735.
phine–oxazinane such as 5b and demonstrated the pal-
ladium-catalyzed
asymmetric
allylic
alkylation
proceeded using these ligands with a good enantiomeric
excess of up to 95% ee. Further application and modifi-
cation of the ligand 5 are in progress.
References
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Selected data for 5c: [h]2D0=−41.5° (c 0.11, CHCl3); 1H
NMR (300 MHz, CDCl3) l 0.72 (t, 7.3 Hz, 3H), 0.90 (s,
3H), 0.94–1.68 (m, 8H), 1.41 (s, 3H), 1.78–1.84 (m, 1H),
2.01–2.09 (m, 1H), 2.04 (d, 12.1 Hz, 1H), 2.17 (br, 3H),
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1
Selected data for 5d: [h]2D0=−156.0° (c 0.03, CHCl3); H
NMR (300 MHz, CDCl3) l 0.85 (s, 3H), 0.86–0.92 (m,
2H), 1.23–1.28 (m, 4H), 1.52 (s, 3H), 1.57–1.59 (m, 1H),
2.52–2.57 (m, 1H), 3.02 (d, 14.3 Hz, 1H), 3.10 (d, 12.3
Hz, 1H), 3.68 (d, 14.3 Hz, 1H), 3.79 (d, 12.3 Hz, 1H),
5.19 (d, 6.9 Hz, 1H), 6.74–6.75 (m, 1H), 7.07–7.10 (m,
6H), 7.23–7.36 (m, 11H), 7.75–7.82 (m, 1H); 31P NMR
(122 MHz, CDCl3) l −14.4; FAB-MS (m/z) 530 (M+−H,
18); HRMS (FAB) calcd for C36H38NOP+H 532.2769,
found 532.2747.
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8. Selected data for 5a: [h]2D0=−39.0° (c 0.10, CHCl3); 1H
NMR (300 MHz, CDCl3) l 0.83 (t, 7.1 Hz, 3H), 0.83–
1.02 (m, 2H), 0.90 (s, 3H), 1.34–1.69 (m, 5H), 1.39 (s,
3H), 1.76–1.84 (m, 1H), 2.09 (d, 12.2 Hz, 1H), 2.13–2.22
(m, 1H), 3.12 (d, 12.2 Hz, 1H), 3.28 (dd, 2.9 and 7.8 Hz,
1H), 5.22 (d, 7.1 Hz, 1H), 6.83–6.85 (m, 1H), 7.17–7.18
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(M+−H, 70); HRMS (FAB) calcd for C31H36NOP+H
470.2613, found 470.2595
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.