Further Application of an N-Ar Axially Chiral Mimetic-Type Ligand: Asymmetric Grignard Cross-Coupling Reaction

Article abstract of DOI:10.1055/s-2003-41485

A novel chiral ligand mimicking N-Ar axial chirality, (S)-N-[2- (diphenylphosphanyl)naphthalen-1-yl]-2-(piperidinylmethyl)piperidine, was found to exhibit good enantioselectivity (up to 80% ee) in the asymmetric cross-coupling reaction of 1-phenylethylmag

Full text of DOI:10.1055/s-2003-41485

LETTER
2047
Further Application of an N-Ar Axially Chiral Mimetic-Type Ligand:
Asymmetric Grignard Cross-Coupling Reaction
Application of
an
N
-A
r
A
d
xially Chiral
e
Mimetic-T
o
ype Ligand Horibe,a Kumiko Kazuta,b Minori Kotoku,a Kazuhiro Kondo,*b Hiroaki Okuno,a Yasuoki Murakami,a
Toyohiko Aoyama*b
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
b
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
E-mail: aoyama@phar.nagoya-cu.ac.jp; E-mail: kazuk@phar.nagoya-cu.ac.jp
Received 6 August 2003
give good enantioselectivity with b-bromostyrene. Herein
we would like to report our investigation of this reaction
using b-bromostyrene as a substrate with the ligand 1
mimicking N-Ar axial chirality.10 The results obtained
Abstract: A novel chiral ligand mimicking N-Ar axial chirality,
(S)-N-[2-(diphenylphosphanyl)naphthalen-1-yl]-2-(piperidinylmeth-
yl)piperidine, was found to exhibit good enantioselectivity (up to
80% ee) in the asymmetric cross-coupling reaction of 1-phenyl-
ethylmagnesium chloride with b-bromostyrene derivatives. with the ligand 1 are, to the best of our knowledge, the
Additionally, this type ligand is appealing, because it allows the
synthesis of a wide variety of analogues.
third best enantioselectivity in the reported literature.
Additionally, the ligand 1 is appealing, because it allows
Key words: N-Ar axis, chiral mimetics, optically active ligand,
Grignard cross-coupling, asymmetric Kumada–Corriu reaction
the synthesis of a wide variety of analogues.
n
n
X
X
N
N
Quite recently, we have developed a novel chiral ligand 1
mimicking N-Ar axial chirality based on the following
concept:1 the chiral ligand 1 may have the two
diasteromers due to the N-Ar axis and the chiral carbon in
solution (Figure 1). But, if the N-Ar axis in 1 is
configurationally flexible, and the complexation of 1 and
a metal is largely reflected by the asymmetric center of the
heterocyclic ring in 1, one of the two diastereomer
complexes due to the N-Ar axis, is expected to be selec-
tively formed (2a in Figure 2), leading to the creation of a
favorable asymmetric environment. The designed ligand
1i has been found to exhibit 99% ee with the use of (E)-
PAr2
PAr2
1
Figure 1
X
n
n
Stable Chiral
N-Ar Axis
X
M
M
N
N
PAr2
M = metal
Unstable complex 2b
PAr2
Stable complex 2a
1,3-diphenyl-2-propenyl acetate as the standard substrate, Figure 2
and has achieved better results than the representative
Pfaltz2 and Trost3 ligands with the use of (E)-1-phenyl-3-
We screened a variety of ligands 1 (>20) in the
asymmetric cross-coupling reaction of 1-phenylethyl-
magnesium chloride with b-bromostyrene. Selected
results are shown in Table 1. Reactions were carried out
with PdCl2(CH3CN)2 (5 mol%), the ligands 1a–n (5
mol%, Figure 3), and 1-phenylethylmagnesium chloride
(2 equiv, 0.5–0.7 mol/L in Et2O) in a,a,a-
trifluorotoluene11 at 0 °C.12 First, the effect of a pendant
substituent with the pyrrolidine-based ligands 1a–e was
examined.13 As shown in entries 1–5, the pendant
substituent played an important role. The ligands 1a–c
possessing a pendant oxygen group exhibited faster
reaction rate than 1d and 1e possessing a pendant nitrogen
group. Among the oxygen-containing ligands 1a–c, 1b
gave better results (entry 2, 66% yield, 66% ee). The ee of
5a was determined by HPLC analysis (Daicel Chiralcel
trimethylsilyl-2-propenyl acetate as the substrate, in the
palladium-catalyzed asymmetric allylic substitution with
dimethyl malonate as the pronucleophile.1 In order to
explore further application of the ligand 1, we planned to
search for a suitable asymmetric reaction. Our interest in
this ligand focused on its use in the asymmetric cross-
coupling reaction of 1-phenylethylmagnesium chloride
with alkenyl halides, which has met with success using
Kumada’s P,N-ligands.4,5 Many ligands have been
developed for the asymmetric cross-coupling reaction of
1-phenylethylmagnesium chloride with alkenyl halides,
but the best substrate showing more than 80% ee was
vinyl bromide.5a,5c–e,6,8,9 One type of substrate with which
it has been more difficult to achieve high selectivity is a
styrene derivative such as b-bromostyrene.5b,d,7 There are,
to date, only two examples by Knochel8 and Saigo9 that
OD, hexane/i-PrOH
=
100:1), and its absolute
configuration was determined by comparison with the re-
ported 5a.8 The inhibition of the reactivity observed with
the ligands 1d and 1e possessing the pendant nitrogen
substituent, a strong coordinating group, is considered to
SYNLETT 2003, No. 13, pp 2047–2051
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41485; Art ID: U16003ST
© Georg Thieme Verlag Stuttgart · New York

2048
H. Horibe et al.
LETTER
X
X
N
X
N
N
PPh2
R
PAr2
PAr2
1l: X=OBn, R=Me
1m: X=pyrrolidinyl, R=OMe
1a: X=OMOM, Ar=Ph
1b: X=OBn, Ar=Ph
1c: X=Ot-Bu, Ar=Ph
1d: X=pyrrolidinyl, Ar=Ph
1e: X=NBn2, Ar=Ph
1i: X=pyrrolidinyl, Ar=Ph
1j: X=piperidinyl, Ar=Ph
1k: X=piperidinyl, Ar=p-tolyl
N
1f: X=OBn, Ar=p-tolyl
1g: X=pyrrolidinyl, Ar=p-tolyl
1h: X=pyrrolidinyl, Ar=2-naphthyl
PPh2
MeO
1n
Figure 3
Table 1 Ligand Screeninga
n
n
Ph
X
PAr2
X
PdCl2(MeCN)2 (5 mol%)
*
N
N
Ph
ligand 1a–n (5 mol%)
MgCl
R
PAr2
+
*
CF3-C6H5, 0 °C
Br
Ph
Ph
3a
(E/Z = 6 : 1)
4 (2 equiv
0.5-0.7 M in Et2O)
5a
1a–k
1l–n
Entryb
Ligand
X
n
Ar
R
Time (h)
Yield (%) Ee (%)c
Absolute
configuration
1
2
1a
1b
1c
1d
1e
1i
OMOM
OBn
1
1
1
1
1
Ph
1
1
59
66
42
35
20
53
25
58
15
37
43
56
42
26
52
7
66
47
62
9
R
S
S
S
R
S
S
S
R
S
S
S
S
S
S
Ph
3
t-BuO
Ph
1
4
Pyrrolidinyl
NBn2
Ph
24
24
1
5
Ph
6
Pyrrolidinyl
Pyrrolidinyl
Piperidinyl
OBn
Ph
61
52
66
9
7d
8
1i
Ph
24
1
1j
Ph
9
1f
1
1
1
p-tolyl
p-tolyl
2-naphthyl
p-tolyl
Ph
24
24
24
1
10
11
12
13
14
15
1g
1h
1k
1l
Pyrrolidinyl
Pyrrolidinyl
Piperidinyl
OBn
65
56
55
63
69
7
1
1
Me
24
24
1
1m
1n
Pyrrolidinyl
H
Ph
MeO
MeO
Ph
a A mixture of (E)- and (Z)-b-bromostyrene (6:1) was used. The reactions were performed using 5 mol % of PdCl2(MeCN)2 and ligand 1a–n,
and 2 equiv of 4 in CF3-C6H5 at 0 °C.
b In all entries, a small amount of 6 was obtained with no enantioselectivity (for example, 1d afforded 2% yield and 0% ee).
Ph
Ph
6
c Determined by HPLC analysis.
d 1-Phenylethylmagnesium bromide was used.
Synlett 2003, No. 13, 2047–2051 © Thieme Stuttgart · New York

LETTER
Application of an N-Ar Axially Chiral Mimetic-Type Ligand
2049
be due to the internal coordination of the pendant nitrogen Table 2 Temperature Effect with Ligand 1b and 1ja
group to palladium. Molecular modeling studies
Entry Ligand Conditions
Yield
(%)
Ee
(%)
Absolute
configu-
ration
suggested that the piperidine based-ligand 1i avoids such
a problem, because coordination of the pendant nitrogen
group to the internal palladium seemed to be torsionally
unfavorable. As expected, replacement of the piperidine
ring on the naphthalene ring enhanced the reaction rate
while the chemical yield was increased to 53% from 35%
(entries 4 vs. 6). The use of 1-phenylethylmagnesium
bromide in place of the corresponding chloride decreased
both chemical yield and enantioselectivity (entries 6 vs.
7). Furthermore, employing the piperidine-based ligand
1j possessing the pendant piperidinyl group gave better
results (58% yield, 66% ee) than 1i (entries 6 vs. 8). The
effects of the diarylphosphino groups, the aromatic part
and so on, were also examined as shown in entries 9–15.
However, the ligands 1f–h and 1k–n gave less
satisfactory results. Thus, in terms of both chemical yield
and enantioselectivity, the two ligands 1b and 1j were
chosen as candidates for the next screening. The effect of
temperature on the reaction was examined (Table 2). In
the case of the ligand 1b, reduction of the temperature
from 0 to –10 °C resulted in no reaction (entry 1). On the
other hand, in the case of the ligand 1j, the
enantioselectivity was improved (entry 2: 71% ee).14
Furthermore, the use of (E)-b-bromostyrene (3a) in place
of a 6:1 mixture of (E)- and (Z)-isomers gave a slight
improvement of chemical yield and enantioselectivity
(entry 3: 69% yield, 72% ee).
1
1b
1j
1j
–10 °C, 24 h
–10 °C, 12 h
–10 °C, 6 h
NRb
66
–
–
S
S
2
71
72
3c,d
69
a A mixture of (E)- and (Z)-b-bromostyrene (6:1) was used except for
entry 3. The reactions were performed using 5 mol % of
PdCl2(MeCN)2 and ligand 1b or 1j, and 2 equiv of 4 in CF3-C6H5.
b No reaction occurred.
c When the reaction was performed at –20 °C, no reaction occurred.
d (E)-b-Bromostyrene was used.
isopropyl (3c) and p-chloro (3d) groups were found to be
employable, giving the corresponding products in good
enantioselectivities (entries 1–3, up to 80% ee), although,
unfortunately, the reaction with 3e bearing an electron-
donating group did not proceed (entry 4).16 The ee and
absolute configuration of 5b–d were determined by
HPLC analysis (Daicel Chiralpak AD, hexane/i-PrOH/
TFA=9:1:0.1) after conversion of 5b–d to the known car-
boxylic acid 7.17
In summary, we have shown that an N-Ar axially chiral
mimetic-type ligand is efficient in the asymmetric cross-
coupling reaction18–20 of 1-phenylethylmagnesium
chloride with b-bromostyrene derivatives. Analogues of
this ligand are being developed for use in other
asymmetric reactions.21,22
Using the ligand 1j, we examined the cross-coupling
reaction with several b-bromostyrenes as shown in
Table 3. Styrene derivatives15 bearing p-methyl (3b), p-
Table 3 Cross-Coupling Reaction of Several b-Bromostyrenes with Ligand 1ja
Ar
Pd-ligand 1j
Ar
MgCl
N
(5 mol%)
N
+
*
Ph
4 (2 equiv
0.5–0.7 M in Et2O)
PPh2
Br
CF3-C6H5, –10 °C
Ph
3b–e
5b–e
1j
Entry
1
Ar
Time (h)
Yield (%)
Ee (%)b
Absolute configuration
p-Me-C6H5 (3b)
p-i-Pr-C6H5 (3c)
p-Cl-C6H5 (3d)
p-MeO-C6H5 (3e)
3
4
50
49
51
NR
78
80
66
–
S
S
S
–
2
3c,d
4c
2
24
a (E)-b-Bromostyrene derivatives were used except for entry 3. The reactions were performed using 5 mol % of PdCl2(MeCN)2 and the ligand
1j, and 2 equiv of 4 in CF3-C6H5 at –10 °C.
b Determined by HPLC analysis of 7, which was obtained by the successive treatment of 5b–d with a catalytic amount of OsO4 (t-BuOH-H2O)
and RuO2 (NaIO4 in CCl4–MeCN–H2O at 0 °C, Sharpless conditions).
CO2H
7
Ph
*
c The reaction was performed at 0 °C.
d A 3.9:1 mixture of (E)- and (Z)-isomers was used.
Synlett 2003, No. 13, 2047–2051 © Thieme Stuttgart · New York

2050
H. Horibe et al.
LETTER
see: (a) Miyano, S.; Hattori, T.; Komuro, Y.; Kumobayashi,
H. Jpn. Kokai Tokkyo koho, H09241277, 1997; Chem.
Abstr. 1997, 127, 302486h. (b) Kondo, K.; Fujita, H.; Iida,
T.; Suzuki, T.; Murakami, Y. 30thCongress of Heterocyclic
Chemistry, November 24–26th; Hachioji: Japan, 1999.
(c) Mino, T.; Tanaka, Y.; Sakamoto, M.; Fujita, T.
Acknowledgment
Kazuhiro Kondo was financially supported by the Takeda Science
Foundation.
References
Heterocycles 2000, 53, 1485.
(14) The use of ligand 1i at ca.–20 °C afforded the coupling
product with 25% yield and 80% ee.
(1) Kondo, K.; Kazuta, K.; Fujita, H.; Sakamoto, Y.; Murakami,
Y. Tetrahedron 2002, 58, 5209.
(15) The physical data of 3a, 3b, 3d and 3e were comparable to
those reported: (a) Graven, A.; Jorgensen, K. A.; Dahl, S.;
Stanczak, A. J. Org. Chem. 1994, 59, 3543. (b) Ranu, B. C.;
Samanta, S.; Guchhait, S. K. J. Org. Chem. 2001, 66, 4102.
(c) The new styrene derivative 3c was characterized by IR,
1H- and 13C NMR, MS, and HRMS. The 1H NMR data of 3c
are shown below: 1H NMR (CDCl3): d = 1.24 (d, J = 6.9 Hz,
3 H × 2), 2.88 (sept, J = 6.9 Hz, 1 H), 6.70 (d, J = 13.8 Hz, 1
H), 7.07 (d, J = 13.8 Hz, 1 H), 7.13–7.29 (m, 4 H).
(2) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 566.
(3) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem.
Soc. 1992, 114, 9327.
(4) Grignard cross-coupling reaction is called the Kumada–
Corriu reaction: (a) Tamao, K.; Sumitani, K.; Kumada, M. J.
Am. Chem. Soc. 1972, 94, 4374. (b) Corriu, R. J. P.; Masse,
J. P. J. Chem. Soc., Chem. Commun. 1972, 144.
(5) (a) Hayashi, T.; Fukushima, M.; Konishi, M.; Kumada, M.
Tetrahedron Lett. 1980, 21, 79. (b) Hayashi, T.; Konishi,
M.; Fukushima, M.; Mise, T.; Kagotani, M.; Tajika, M.;
Kumada, M. J. Am. Chem. Soc. 1982, 104, 180.
(c) Hayashi, T.; Hagihara, T.; Katsuro, Y.; Kumada, M. Bull.
Chem. Soc. Jpn. 1983, 56, 363. (d) Hayashi, T.; Konishi,
M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J.
Org. Chem. 1983, 48, 2195. (e) Hayashi, T.; Yamamoto, A.;
Hojo, M.; Ito, Y. J. Chem. Soc., Chem. Commun. 1989, 495.
(6) (a) Vriesema, B. K.; Kellogg, R. M. Tetrahedron Lett. 1986,
27, 2049. (b) Cross, G.; Vriesema, B. K.; Boven, G.;
Kellogg, R. M.; van Bolhuis, F. J. Organomet. Chem. 1989,
370, 357. (c) Baker, K. V.; Brown, J. M.; Cooley, N. A.;
Hughes, G. D.; Taylar, R. J. J. Organomet. Chem. 1989, 370,
397. (d) Jedlicka, B.; Kratky, C.; Weissensteiner, W.;
Widhalm, M. J. Chem. Soc., Chem. Commun. 1993, 1329.
(e) Pellet-Rostaing, S.; Saluzzo, C.; Halle, R. T.; Breuzard,
J.; Vial, L.; Guyader, F. L.; Lemaire, M. Tetrahedron:
Asymmetry 2001, 12, 1983.
(7) (a) Kreuzfeld, H.-J.; Döbler, C.; Abicht, H.-P. J. Organomet.
Chem. 1987, 336, 287. (b) Döbler, C.; Kreuzfeld, H.-J. J.
Organomet. Chem. 1988, 344, 249. (c) Uemura, M.;
Miyake, R.; Nishimura, H.; Matsumoto, Y.; Hayashi, T.
Tetrahedron: Asymmetry 1992, 3, 213. (d) Yamago, S.;
Yanagawa, M.; Nakamura, E. J. Chem. Soc., Chem.
Commun. 1994, 52, 2093. (e) Richards, C. J.; Hibbs, D. E.;
Hursthouse, M. B. Tetrahedron Lett. 1995, 36, 3745.
(f) Yamago, S.; Yanagawa, M.; Mukai, H.; Nakamura, E.
Tetrahedron 1996, 52, 5091. (g) Lloyd-Jones, G. C.; Butts,
C. P. Tetrahedron 1998, 54, 901.
(16) The use of vinyl bromide and 1-propenyl bromide as
substrates resulted in no reaction.
(17) The racemic and optically active carboxylic acid 7 were
purchased from Aldrich Co., Ltd.
(18) The ligands 1b, 1d, 1e, and 1g–i were reported by us.1 The
new ligands 1a, 1c, 1f, 1j–l and 1n were characterized by IR,
1H- and 13C NMR, FABMS, and elemental analysis. All
ligands 1a–n were synthesized according to the typical
procedure described below.
(S)-N-[2-(Diphenylphosphanyl)naphthalen-1-yl]-2-
(piperidinylmethyl)piperidine (1j). To a stirred solution of
(S)-2-(piperidinylmethyl)piperidine (700 mg, 3.84 mmol) in
THF (4.0 mL) was gradually added BuLi (2.53 mL, 4.00
mmol, 1.58 M solution in hexane) at –30 °C, and the mixture
was stirred for 2 h at the same temperature. To this solution
was then added a solution of 1-methoxy-2-(diphenylphos-
phinoyl)naphthalene (680 mg, 1.90 mmol) in THF (2.0 mL)
at –30 °C. The whole mixture was stirred for 1 h at the same
temperature, quenched with H2O and extracted with EtOAc.
The organic extracts were successively washed with
saturated aq NH4Cl and brine, dried (Na2SO4) and
concentrated. Purification by silica gel column (Fuji Silysia
Chromatorex NH, EtOAc/hexane=1:5) gave a mixture (724
mg) of 1-(S)-N-[2-(diphenylphosphonyl)naphthalen-1-yl]-
2-(piperidinylmethyl)piperidine and small amounts of
impurities. This mixture was used for the next step without
further separation. IR (neat): n = 1308, 1254, 1192, 1161 cm–
1. 1H NMR (CDCl3): d = 0.75–1.15 (m, 8 H), 1.24–1.45 (m,
2 H), 1.60–1.94 (m, 8 H), 2.46 (dd, J = 13.3, 5.9 Hz, 1 H),
2.92 (br d, J = 11.1 Hz, 1 H), 3.36 (dd, J = 11.1, 11.1 Hz, 1
H), 3.51–3.62 (br, 1 H), 6.97 (dd, J = 12.1, 8.6 Hz, 1 H),
7.35–7.57 (m, 10 H), 7.65–7.87 (m, 4 H), 8.23 (d, J = 8.4 Hz,
1 H). 13C NMR (CDCl3): 24.29, 24.90, 25.47, 25.63, 31.38,
54.80, 56.09, 60.55, 62.23, 125.15, 125.42, 125.62, 126.21,
127.02, 127.95, 128.13, 128.65, 129.02, 129.22, 129.77,
130.74, 131.09, 131.23, 131.37, 131.94, 132.07, 134.15,
134.65, 135.09, 135.22, 135.66, 136.22, 136.63, 155.14.
FABMS: m/z = 509 (M+ + 1). The above mixture was
dissolved in p-xylene (7.0 mL), and Et3N (2.10 mL, 15.1
mmol) and HSiCl3 (1.4 mL, 14 mmol) were added at 0 °C.
The whole mixture was heated at 140 °C for 2 h. After being
cooled to r.t., the reaction mixture was carefully poured into
10% NaOH, and the whole mixture was extracted with
EtOAc. The organic extracts were successively washed with
water and brine, dried (Na2SO4), and concentrated.
Purification by silica gel column (Fuji Silysia Chromatorex
NH, hexane/EtOAc = 20:1) gave (S)-N-[2-(diphenylphos-
phanyl)naphthyl]-2-(piperidinylmethyl)piperidine (1j)
(505 mg, 54% in 2 steps) as a colorless amorphous.
(8) Schwink, L.; Knochel, P. Chem.–Eur. J. 1998, 4, 950.
(9) Hayashi, M.; Takaoki, K.; Hashimoto, Y.; Saigo, K.
Enantiomer 1997, 2, 293.
(10) For a planar chiral mimetic, see: Jones, G.; Butler, D. C. D.;
Richards, C. J. Tetrahedron Lett. 2000, 41, 9351.
(11) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(12) The use of other solvents such as THF, CH2Cl2 and toluene,
and the use of nickel salts in place of PdCl2(MeCN)2, gave
less satisfactory results.
(13) Use of the ligand 1o (Figure 4) possessing a pendant
methoxy group resulted in no reaction. For the ligand 1o,
OMe
N
PPh2
1o
Figure 4
Synlett 2003, No. 13, 2047–2051 © Thieme Stuttgart · New York

LETTER
Application of an N-Ar Axially Chiral Mimetic-Type Ligand
2051
[a]D28 +115 (c 1.60, dioxane). IR(nujol): n = 1300, 1275,
(19) For other catalytic asymmetric Grignard cross-couplings,
see: (a) Tamao, K.; Minato, A.; Miyake, N.; Matsuda, T.;
Kiso, Y.; Kumada, M. Chem. Lett. 1975, 133. (b) Tamao,
K.; Yamamoto, H.; Matsumoto, H.; Miyake, N.; Hayashi,
T.; Kumada, M. Tetrahedron Lett. 1977, 1389. (c) Hayashi,
T.; Konishi, M.; Okamoto, Y.; Kabeta, K.; Kumada, M. J.
Org. Chem. 1986, 51, 3772. (d) Iida, A.; Yamashita, M.
Bull. Chem. Soc. Jpn. 1988, 61, 2365. (e) Hayashi, T.;
Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988,
110, 8153. (f) Hayashi, T.; Hayashizaki, K.; Ito, Y.
Tetrahedron Lett. 1989, 30, 215. (g) Hayashi, T.; Niizuma,
S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc.
1995, 117, 9101. (h) Kamikawa, T.; Hayashi, T.
1206, 1159 cm–1. 1H NMR (CDCl3): d = 0.83–2.22 (m, 18
H), 2.66 (br d, J = 11.5 Hz, 1 H × 4/5), 3.01 (br d, J = 11.2
Hz, 1 H × 1/5), 3.30 (br dd, J = 11.5, 10.6 Hz, 1 H × 4/5),
3.45–3.53 (br, 1 H × 1/5), 3.55–3.73 (br, 1 H × 4/5), 4.13–
4.28 (br, 1 H × 1/5), 6.89 (dd, J = 8.6, 2.4 Hz, 1 H × 4/5), 7.09
(dd, J = 8.6, 3.8 Hz, 1 H × 1/5), 7.14–7.57 (m, 13 H), 7.72–
7.77 (m, 1 H × 1/5), 7.81 (dd, J = 6.3, 3.5 Hz, 1 H × 4/5), 8.05
(dd, J = 6.3, 3.5 Hz, 1 H × 4/5), 8.63 (dd, J = 6.3, 3.5 Hz,
1 H × 1/5). 13C NMR (CDCl3): 24.05, 24.29, 24.41, 25.27,
25.71, 25.93, 26.02, 27.47, 29.75, 31.59, 32.34, 54.10,
54.32, 54.93, 55.10, 57.17, 57.38, 59.20, 61.70, 62.50,
62.59, 124.80, 124.94, 125.49, 125.57, 125.78, 125.95,
126.02, 126.71, 127.44, 127.90, 127.97, 128.00, 128.13,
128.17, 128.27, 128.37, 128.63, 129.50, 131.91, 132.72,
133.00, 133.29, 133.54, 133.80, 133.95, 134.10, 134.26,
134.54, 134.66, 135.01, 135.19, 136.92, 137.40, 137.60,
138.35, 138.54, 138.81, 139.00, 139.63, 139.87, 150.99,
151.30, 153.92, 154.28. FABMS: m/z = 493 (M+ + 1). Anal.
Calcd for C33H37N2P: C, 80.46; H, 7.57; N, 5.69, Found: C,
80.27; H, 7.56; N, 5.85.
Tetrahedron 1999, 55, 3455. (i) Hölzer, B.; Hoffmann, R.
W. Chem. Commun. 2003, 732.
(20) Another type of catalytic asymmetric cross-coupling, the
Suzuki and Miyaura reaction, has been reported, see:
(a) Cho, S. Y.; Shibasaki, M. Tetrahedron: Asymmetry 1998,
9, 3751. (b) Cammidge, A. N.; Crépy, K. V. L. Chem.
Commun. 2000, 1723. (c) Yin, J.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 12051. (d) Castanet, A.-S.; Colobert,
F.; Broutin, P.-E.; Obringer, M. Tetrahedron: Asymmetry
2002, 13, 659.
Typical Procedure for Grignard Cross-Coupling
Reaction of (E)-b-Bromostyrene(3a) with Ligand 1j
(entry 3, Table 2). 1-Phenylethylmagnesium chloride (4)
(2.10 mL, 1.50 mmol, 0.70 mol/L in Et2O) was added to the
mixture of PdCl2(MeCN)2 (9.3 mg, 0.036 mmol) and the
ligand 1j (18.2 mg, 0.0369 mmol) in a,a,a-trifluorotoluene
(2.10 mL) at 0 °C, and the solution was stirred at the same
temperature for 30 min (CAUTION: stirring at 0 °C for 30
min for the favorable complexation of Pd and ligand 1j is
needed.). To the solution was added (E)-b-bromostyrene
(3a) (133 mg, 0.727 mmol) at –10 °C. The resulting solution
was stirred for 6 h at –10 °C. After usual work-up,
purification by silica gel column(hexane) afforded the
coupling product 5a (105 mg, 69%, 72% ee) as a colorless
oil. The ee was determined by HPLC analysis (Daicel
chiralcel OD, hexane/i-PrOH = 100:1, 0.3 mL/min, 254 nm):
tR/min = 34.9 (S), 37.1 (R).
(21) For recent chiral P,N(sp3)-ligands, see: (a) Mino, T.;
Tanaka, Y.; Akita, K.; Sakamoto, M.; Fujita, T.
Heterocycles 2003, 60, 9. (b) Shibatomi, K.; Uozumi, Y.
Tetrahedron: Asymmetry 2002, 13, 1769. (c) Jin, M.-J.;
Kim, S.-H.; Lee, S.-J.; Kim, Y.-M. Tetrahedron Lett. 2002,
43, 7409. (d) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc.
2001, 123, 2919. (e) Mino, T.; Hata, S.; Ohtaka, K.;
Sakamoto, M.; Fujita, T. Tetrahedron Lett. 2001, 42, 4837.
(f) Okuyama, Y.; Nakano, H.; Hongo, H. Tetrahedron:
Asymmetry 2000, 11, 1193. (g) Suzuki, Y.; Abe, I.; Hiroi, K.
Heterocycles 1999, 50, 89. (h) Cahill, J. P.; Cunneen, D.;
Guiry, P. J. Tetrahedron: Asymmetry 1999, 10, 4157.
(i) Bourghida, M.; Widhalm, M. Tetrahedron: Asymmetry
1998, 9, 1073. (j) Hattori, T.; Komuro, Y.; Hayashizaka, N.;
Takahashi, H.; Miyano, S. Enantiomer 1997, 2, 203; and
references cited therein.
(22) During the completion of this manuscript, we became aware
of a recent report by Mino, T. et al. of the Pd-catalyzed
asymmetric allylic alkylation with the ligand 1m: Mino, T.;
Tanaka, Y.; Sato, Y.; Saito, A.; Sakamoto, M.; Fujita, T.
Tetrahedron Lett. 2003, 44, 4677.
Synlett 2003, No. 13, 2047–2051 © Thieme Stuttgart · New York