Chiral diaminophosphine ligands with stable C(aryl)-N(amine) axial chirality derived from prolinol

Article abstract of DOI:10.1016/S0040-4039(03)01097-9

New type chiral ligands 3, which have a chiral carbon center and stable C(aryl)-N(amine) axial chirality, were prepared from chiral prolinol-derived aminophosphine oxide 4. Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (6)

Full text of DOI:10.1016/S0040-4039(03)01097-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4677–4679
Chiral diaminophosphine ligands with stable C(aryl)ꢀN(amine)
axial chirality derived from prolinol
Takashi Mino,* Youichi Tanaka, Yutaka Sato, Akio Saito, Masami Sakamoto and Tsutomu Fujita
Department of Materials Technology, Faculty of Engineering, Chiba University, Inage-ku, Chiba 263-8522, Japan
Received 13 March 2003; revised 16 April 2003; accepted 25 April 2003
Abstract—New type chiral ligands 3, which have a chiral carbon center and stable C(aryl)-N(amine) axial chirality, were prepared
from chiral prolinol-derived aminophosphine oxide 4. Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl
acetate (6) with a dimethyl malonate–BSA–LiOAc system was successfully carried out in the presence of 3d resulting in a good
yield with good enantioselectivity (up to 95% ee). © 2003 Elsevier Science Ltd. All rights reserved.
Pd-catalyzed allylic alkylation is a process that is widely
used in organic synthesis,1 and the development of
efficient enantioselective catalysis for this reaction is
awaited.2 It has been reported that chiral 2-(phosphi-
noaryl)oxazoline can induce high enantiomeric excesses
in this reaction.3 Following this pioneering study,
aminophosphines have been used as ligands, in particu-
lar, pyrrolidinyl-containing aminophosphines such as 14
and 25 have been found to be efficient chiral sources.6
The chiral diaminophosphine ligands 3 were easily pre-
Here, we report the preparation of new type chiral
pared from prolinol-derived aminophosphine oxide 45b
diaminophosphines 3, which have a chiral carbon cen-
in three steps (Scheme 1). Aminophosphine oxide 4 was
ter and C(aryl)ꢀN(amine) axial chirality, and discuss
converted into the corresponding bromide compound 5
using carbon tetrabromide–triphenylphosphine with a
91% yield. Using various amines such as diethylamine,
the amination of bromide compound 5 gave the corre-
sponding diaminophosphine oxide. This diaminophos-
their application to Pd-catalyzed asymmetric allylic
alkylation. We found that the C(aryl)ꢀN(amine) axial
chirality of ligands 3 is an important factor in the
reactivity and enantioselectivity of Pd-catalyzed allylic
alkylation.
Keywords: P,N-ligand; CꢀN axial chirality; palladium; asymmetric
allylic alkylation.
* Corresponding author. Tel.: +81 43 290 3385; fax: +81 43 290 3401;
e-mail: tmino@planet.tc.chiba-u.ac.jp
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01097-9

4678
T. Mino et al. / Tetrahedron Letters 44 (2003) 4677–4679
phine oxide was directly converted into the desired
chiral diaminophosphine ligand 3a using trichloro-
silane–triethylamine with a good yield. The other lig-
ands 3b–e were prepared in the same manner.
The diastereoisomer at chiral carbon center and
C(aryl)–N(amine) axial chirality were not observed with
diaminophosphine 1f, its related ligands4d and
aminophosphine 25. However, in the NMR spectra
of crude reaction mixtures of 3 diastereomeric atrop-
isomers were observed at room temperature.
Diaminophosphines 3a7 and 3b8 could not be separated
into atropisomers by chromatography. In the case of
3c,9 only the less polar atropisomer (aS,S)-3c was sepa-
rated. The more polar atropisomer (aR,S)-3c was
difficult to separate from the less polar atropisomer
(aS,S)-3c. Diaminophosphines 3d10 and 3e11 were suc-
cessfully obtained as stable single atropisomers after
purification by chromatography. Epimerization did not
occur in either atropisomer at room temperature for
over nine months. The stereochemistries of 3c–e were
determined on the basis of NOE experiments performed
on (aS,S)-3d and (aR,S)-3d (Fig. 1).
Figure 1. Selected NOE correlations of 3d.
Scheme 2.
These chiral diaminophosphines 3 were applied to the
chiral ligands for the Pd-catalyzed asymmetric allylic
alkylation of 1,3-diphenyl-2-propenyl acetate (6) with
dimethyl malonate (7) as a model reaction. This reac-
tion was carried out in the presence of 2 mol% of
[Pd(h3-C3H5)Cl]2, 4 mol% of 3, and a mixture of N,O-
bis(trimethylsilyl)acetamide (BSA) and 2 mol% of
LiOAc in toluene (Scheme 2, Table 1).12
tivity of 8 were decreased and the configuration of 8
was inverted (entry 2). This observation indicates that
C(aryl)ꢀN(amine) axial chirality is the more influential
factor determining the stereochemical outcome of
allylic alkylation than central chirality in pyrrolidine.
Next a reaction was carried out using (aS,S)-3d at
−10°C (Entry 3). Although the enantioselectivity was
improved to 91% ee, the reaction rate became slow.
Using ligand (aS,S)-3d, (S)-8 was obtained with a good
chemical yield, but the enantiomeric excess was moder-
ate at room temperature in toluene (entry 1). When the
reaction was carried out using the diastereomeric
atropisomer (aR,S)-3d, the reactivity and enantioselec-
We tried to change the similar solvent as toluene. When
the reaction was carried out in a,a,a-trifluorotoluene at
−10°C, reactivity was dramatically increased without
Table 1. Palladium-catalyzed asymmetric allylic alkylation using 3a
Entry
Ligand
M
Solv.
Temp. (°C)
Yield (%)b
Ee (%)c
Config.c
1
2
3
4
5
6
7
8
(aS,S)-3d
(aR,S)-3d
(aS,S)-3d
(aS,S)-3d
(aS,S)-3d
(S)-3d
(aR,S)-3d
(aS,S)-3e
(aR,S)-3e
(S)-3a
Li
Li
Li
Li
K
Li
Li
Li
Li
Li
Li
Li
Li
Li
Li
Li
PhMe
PhMe
PhMe
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
DCM
THF
Rt
Rt
93
65
15
95
89
91
NR
89
NR
92
84
94
97
97
96
99
82
15
91
91
86
91
–
S
R
S
S
S
S
–
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
90
–
S
–
9
10
11d
12
13
14
15
16
92
91
85
90
93
93
95
S
S
S
S
S
S
S
(S)-3b
(aS,S)-3c
(aS,S)-3d
(aS,S)-3d
(aS,S)-3d
(aS,S)-3d
CPMEe
Ether
a All reactions were 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 48 h.
e Cyclopentyl methyl ether.

T. Mino et al. / Tetrahedron Letters 44 (2003) 4677–4679
4679
decrease in enantioselectivity (entry 3 versus 4). When
the mixture of atropisomer (S)-3d13 was used as a
ligand instead of (aS,S)-3d, (S)-8 was obtained in good
yield without decrease of the enantioselectivity (entry
6). In this condition, we again carried out a reaction
using the atropisomeric ligand (aR,S)-3d (entry 7). But
the reaction did not occur after 24 h. This was also the
case for ligand 3e (entry 8 versus entry 9). (S)-8 with
good enantioselectivity was obtained only when the
reaction was carried out using (aS,S)-3e (entry 8).
These results mean that enantioselectivity in Pd-cata-
lyzed asymmetric allylic alkylation is not decreased by
using diastereomeric mixtures of ligands 3. When the
reactions were carried out using the diastereomeric
mixture of (S)-3a (entry 10) and (S)-3b (entry 11) at
−10°C, (S)-8 with good enantioselectivity was obtained,
but the reaction rate became slightly slow. In the case
of (aS,S)-3c, product 8 with moderate enantioselectivity
was obtained (entry 12). In order to improve the enan-
tioselectivity, we further examined the effect of reaction
solvents using the ligand (aS,S)-3d. A reaction carried
out in ether improved the enantioselectivity to 95% ee
(entry 16).
H.; Miyano, S. Enantiomer 1997, 2, 203; (b) Mino, T.;
Tanaka, Y.; Sakamoto, M.; Fujita, T. Heterocycles 2000,
53, 1485; (c) Mino, T.; Tanaka, Y.; Akita, K.; Anada, K.;
Sakamoto, M.; Fujita, T. Tetrahedron: Asymmetry 2001,
12, 1677; (d) Kondo, K.; Kazuta, K.; Fujita, H.;
Sakamoto, Y.; Murakami, Y. Tetrahedron 2002, 58, 5209.
5. (a) Mino, T.; Tanaka, Y.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2001, 12, 2435; (b) Mino, T.;
Tanaka, Y.; Akita, K.; Sakamoto, M.; Fujita, T. Hetero-
cycles 2003, 60, 9.
6. For other pyrrolidine-containing aminophosphine lig-
ands, see: (a) Farrell, A.; Goddard, R.; Guiry, P. J. J.
Org. Chem. 2002, 67, 4209; (b) Okuyama, Y.; Nakano,
H.; Hongo, H. Tetrahedron: Asymmetry 2000, 11, 1193;
(c) Suzuki, Y.; Abe, I.; Hiroi, K. Heterocycles 1999, 50,
89; (d) Hiroi, K.; Suzuki, Y.; Abe, I. Tetrahedron: Asym-
metry 1999, 10, 1173; (e) Cahill, J. P.; Cunneen, D.;
Guiry, P. J. Tetrahedron: Asymmetry 1999, 10, 4157.
7. Rate of (aS,S)-3a/(aR,S)-3a was ca. 2.3 determined by
NMR.
8. Rate of (aS,S)-3b/(aR,S)-3b was ca. 2.5 determined by
NMR.
9. Rate of (aS,S)-3c/(aR,S)-3c was ca. 2.0 determined by
NMR.
We successfully obtained chiral diaminophosphine with
stable C(aryl)ꢀN(amine) axial chirality such as that seen
for 3 and demonstrated the Pd-catalyzed asymmetric
allylic alkylation of 1,3-diphenyl-2-propenyl acetate (6)
with dimethyl malonate (7) using it with high enan-
tiomeric excess. Further studies on optimization of the
ligand and application to other asymmetric reactions
are underway in our group.
10. (aS,S)-3d (less polar): 41%; mp 112–113°C; [h]2D5=41.7°
1
(c 0.10, CHCl3): H NMR (CDCl3) l: 1.56–1.71 (m, 7H),
2.03–2.13 (m, 1H), 2.16–2.36 (m, 6H), 2.53–2.62 (m, 1H),
2.78 (dd, J=7.6 and 15.4 Hz, 1H), 3.66-3.75 (m, 1H),
3.79 (s, 3H), 6.40–6.43 (m, 1H), 6.40 (ddd, J=1.3, 2.8,
and 7.6 Hz, 1H), 6.86 (dd, J=0.6 and 8.0 Hz, 1H), 7.05
(ddd, J=0.8, 7.9, and 8.7 Hz, 1H), 7.25–7.35 (m, 10H);
13C NMR (CDCl3) l: 23.4, 24.2, 29.7, 31.5, 48.52, 51.9,
54.7, 55.0, 61.1, 61.7 (d, Jcp=3.3 Hz), 112.4, 124.9, 126.3,
128.1–128.2 (m), 134.0, 134.1, 134.3, 134.4, 138.7 (d,
Jcp=13.2 Hz), 139.2 (d, Jcp=14.6 Hz), 140.5, 142.7 (d,
Jcp=4.1 Hz), 158.3 (d, Jcp=3.6 Hz); 31P NMR (CDCl3)
l: −15.05; FAB-MS m/z (rel intensity): 445 (M++1, 100);
HRMS (FAB-MS) m/z calcd for C28H34N2OP+H
445.2409, found 445.2382. (aR,S)-3d (more polar): 29%;
mp 150–151°C; [h]D25=11.1° (c 0.10, CHCl3): 1H NMR
(CDCl3) l: 1.08–1.18 (m, 1H), 1.34–1.44 (m, 2H), 1.51–
1.55 (m, 1H), 1.56–1.65 (m, 4H), 1.89 (d, J=11.5 Hz,
1H), 2.19–2.31 (m, 4H), 2.68–2.76 (m 2H), 2.98–30.7 (m,
2H), 3.77 (s, 3H), 6.22 (ddd, J=1.2, 2.7, and 7.6 Hz, 1H),
6.85 (d, J=8.1 Hz, 1H), 7.03 (ddd, J=1.2, 7.6, and 8.1
Hz, 1H), 7.21–7.34 (m, 10H); 13C NMR (CDCl3) l: 23.0,
24.9, 30.5, 50.2, 51.3, 55.0, 55.1, 61.4, 122.4, 124.3, 124.3,
126.8, 128.1–128.3 (m), 133.8, 134.0, 134.1, 134.3, 138.9
(d, Jcp=9.7 Hz), 139.1 (d, Jcp=10.5 Hz), 140.9 (d, Jcp=
2.8 Hz), 142.4 (d, Jcp=18.6 Hz), 159.0 (d, Jcp=2.6 Hz);
31P NMR (CDCl3) l: −13.45; FAB-MS m/z (rel inten-
sity): 445 (M++1, 100); HRMS (FAB-MS) m/z calcd for
C28H34N2OP+H 445.2409, found 445.2369.
Acknowledgements
This work was partially supported by Saneyoshi Schol-
arship Foundation.
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