Optically active palladium-catalyzed asymmetric amination of aryl halide

Article abstract of DOI:10.1016/j.tetasy.2005.06.002

The asymmetric amination of aryl halides with racemic amines was examined in the presence of a transition metal complex having a chiral ligand. The yield and enantioselectivity of the products were strongly influenced by the kind of base, reaction temperature, solvent, and the additive. The best result was obtained from the reaction of 2-iodoanisole with 1-(1-naphthyl)ethylamine in the presence of sodium methoxide and 18-crown-6 by Pd-Tol-BINAP to afford the product in 70% yield with 80% ee.

Full text of DOI:10.1016/j.tetasy.2005.06.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2307–2314
Optically active palladium-catalyzed asymmetric
amination of aryl halide
Junya Tagashira, Daisuke Imao, Tetsuya Yamamoto, Tetsuo Ohta,*
Isao Furukawa and Yoshihiko Ito
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
Received 12 May 2005; accepted 2 June 2005
Available online 29 June 2005
Abstract—The asymmetric amination of aryl halides with racemic amines was examined in the presence of a transition metal com-
plex having a chiral ligand. The yield and enantioselectivity of the products were strongly influenced by the kind of base, reaction
temperature, solvent, and the additive. The best result was obtained from the reaction of 2-iodoanisole with 1-(1-naphthyl)ethyl-
amine in the presence of sodium methoxide and 18-crown-6 by Pd–Tol–BINAP to afford the product in 70% yield with 80% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and (S)-Tol–BINAP in 86% yield with 21% ee.
Pd(OAc)2 was not a good catalyst precursor for this
reaction, while the Pt, Ni, and Cu precursors gave no
reaction product. Various chiral ligands were then tested
in combination with Pd2(dba)3ÆCHCl3. No reaction
product was obtained using (R,R)-CHIRAPHOS and
(S,S)-BPPM, while a racemic product was yielded by
(S,R)-BPPFA and (S)-iPr-MOP. An optically active
product was produced when (R,R)-MOD-DIOP, (S,S)-
BDPP, (R)-MOP, and (S)-BINAP were used. Conse-
quently, Tol–BINAP was the best ligand among those
tested (see Scheme 1).
Substitution reactions of aryl halides using transition
metal catalyst have been extensively developed in vari-
ous fields.1 Recently, palladium-catalyzed coupling of
aryl halides with amines has been demonstrated to be
a mild and efficient method for the synthesis of a variety
of aniline derivatives.2–5 Although this method is good
for the preparation of such compounds, there is only
one report of its application for the synthesis of optically
active compounds, in which chiral amines were still
used.6 Such optically active aniline derivatives, such as
BL-V8, hexahydro-carbazoles and Dynamics A, are
known to have biological activities.7 Herein, we report
their preparation using a racemic amine by kinetic reso-
lution catalyzed by palladium complex with chiral
ligand.8
Even though no reaction product was obtained in ace-
tonitrile and chloroform, the reaction proceeded
smoothly in various solvents with yields over 80%
(Table 2). Furthermore, the enantiomeric excesses of
the products were about 20% in every solvent except
cyclohexane. When 1-phenylethylamine was used as
the solvent, a 30% enantiomeric excess of product was
achieved.
2. Results and discussion
First, the catalysts were examined for a reaction of
4-bromobiphenyl and racemic 1-phenylethylamine in
the presence of sodium tert-butoxide in toluene at
70 °C (Table 1). The product, 4-phenyl-N-(1-phenyl-
ethyl)aniline 3a, was obtained using Pd2(dba)3ÆCHCl3
Concerning the base that was added, little effect on
selectivity was observed in different cations, while reac-
tivity significantly changed when using potassium
instead of sodium (Table 3, entries 1 and 4). On the
other hand, the anion caused a difference in the reactiv-
ity and selectivity, that is, ethoxide and methoxide
showed better selectivities than tert-butoxide. A reaction
with carbonate, Na2CO3, K2CO3, or Cs2CO3, as a base
yielded no product at all.
*
Corresponding author. Tel.: +81 774 65 6548; fax: +81 774 65
6789; e-mail: tota@mail.doshisha.ac.jp
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.002

2308
J. Tagashira et al. / Tetrahedron: Asymmetry 16 (2005) 2307–2314
Table 1. Effect of liganda
Entry
Metal source
Ligand
Yieldb (%)
eec (%)
1
2
3
4
5
Pd2(dba)3ÆCHCl3
Pd(OAc)2
Pt(dba)2
86
14
Nr
5
21
27
(S)-Tol–BINAP
—
Racemate
—
Ni(cod)2
CuI
Nr
6
(R,R)-CHIRAPHOS
(S,S)-BPPM
Nr
Nr
27
85
12
63
71
83
—
—
7
8
(S,R)-BPPFA
(S)-iPr–MOP
R,R)-MOD–DIOP
(S,S)-BDPP
Racemate
Racemate
9
Pd2(dba)3ÆCHCl3
10(
11
12
13
7
7
(R)-MOP
(S)-BINAP
7
13
a Reaction condition: 4-bromobiphenyl 0.5 mmol, 1-phenylethylamine 1.2 mmol, metal source 4.0 mol % as a metal atom, ligand 0.02 mmol, NaOtBu
0.7 mmol, toluene 1 mL, 24 h, 70 °C, under Ar.
b Isolated yield.
c Determined by HPLC analysis using a Daicel Chiralcel OD-H column (eluent, hexane/2-propanol = 90/10, flow rate: 0.5 mL/min; detector UV
254 nm).
Table 3. Effect of basea
X
Yieldb (%)
eec (%)
NH2
catalyst
Entry
Base
R2
N
H
+
R1
R2
*
1
2
3
4
5
6
7
NaOtBu
NaOMe
NaOEt
KOtBu
Cs2CO3
K2CO3
Na2CO3
86
82
28
27
Nr
Nr
Nr
21
26
25
18
—
—
—
base, solvent
R1
3a-o
1
2
Scheme 1.
Table 2. Effect of solventa
a Reaction condition: 4-bromobiphenyl 0.5 mmol, 1-phenylethylamine
1.2 mmol, Pd2(dba)3ÆCHCl3 0.01 mmol (4.0 mol %), (R)-Tol–BINAP
0.02 mmol, base 0.7 mmol, toluene 1 mL, 24 h, 70 °C, under Ar.
b Isolated yield.
c Determined by HPLC analysis using a Daicel Chiralcel OD-H col-
umn (eluent, hexane/2-propanol = 90/10, flow rate: 0.5 mL/min;
detector UV 254 nm).
Entry
Solvent
Yieldb (%)
eec (%)
21
1
Toluene
Cyclohexane
CH3CN
CHCl3
1,4-Dioxane
HMPA
DMSO
DMA
86
2
906
Nr
Nr
83
3
—
—
18
15
19
22
26
4
5
6
93
7
86
8
80d
57d
24
.
X
Pd2(dba)3 CHCl3
9
10Pyridine
DMF
NH2
R2
(R)-Tol-BINAP
R2
N
H
+
91
R1
*
NaOtBu, Toluene
70 oC, 24 h
11
12
Et3N
Nonee
90
87
25
30
R1
3a-m
1
2
a Reaction condition: 4-bromobiphenyl 0.5 mmol, 1-phenylethylamine
1.2 mmol, Pd2(dba)3ÆCHCl3 0.01 mmol (4.0 mol %), (R)-Tol–BINAP
0.02 mmol, NaOtBu 0.7 mmol, solvent 1 mL, 24 h, 70 °C, under Ar.
b Isolated yield.
Scheme 2.
The structure of the amine affected the selectivity but
not the reactivity. When the substituent on 1-C of ethyl-
amine was changed to ethyl, phenyl, and 1-naphthyl,
the yields of the products were almost the same but
the stereoselectivity of the products increased using the
substrates with a larger steric hindrance (Table 4, entries
1, 12, and 13).
c Determined by HPLC analysis using a Daicel Chiralcel OD-H col-
umn (eluent, hexane/2-propanol = 90/10, flow rate: 0.5 mL/min;
detector UV 254 nm).
d By-product was observed.
e 1-Phenylethylamine (1.2 mL) was used as the reaction solvent.
Various aryl halides were subjected to this reaction
(Scheme 2, Table 4). The yields of the products were
slightly affected by the substituent on the bromobenz-
ene. On the other hand, the stereoselectivities varied
by changing the substrate. Substrates with an electron-
donating substituent (–CH3, –OCH3) showed better
enantioselectivities than those with an electron-with-
drawing substituent (–CN).
The reaction temperature strongly affected the yield and
enantiomeric excess of the product. At 70 °C, the reac-
tion proceeded smoothly, and a higher enantioselectivity
was obtained at room temperature, even though the
yield was quite low (Table 4, entries 2 and 14). A pro-
longed reaction time did not improve the yield (Table
4, entries 15 and 16).

J. Tagashira et al. / Tetrahedron: Asymmetry 16 (2005) 2307–2314
Table 4. Asymmetric amination of aryl halidesa
2309
Entry
Aryl halide 1
R1 =
Amine 2
R2 =
Product 3
X =
Br
Yieldb (%)
eec (%)
1
2d
4-Ph
Ph
3a
86
31
21
39
3
4
5
Br
Br
Br
4-CH3
3-CH3
2-CH3
Ph
Ph
Ph
3b
3c
3d
73
79
75
20
16
25
6
7
8
4-OCH3
3-OCH3
2-OCH3
3e
3f
4021
68
19
30
3g
71
9
4-CN
3h
3i
3j
86
10
103-CN
11
8016
82
2-CN
4-Ph
4-Ph
5
8
12
Br
Br
Et
3k
3l
87
13
14d
1-Np
84
3058
37
15d,e
16d,e,f
Br
I
2-CH3
1-Np
3m
Trace
4
72
72
a Reaction condition: aryl halide 0.5 mmol, amine 1.2 mmol, Pd2(dba)3ÆCHCl3 0.01 mmol (4.0 mol %), (R)-Tol–BINAP 0.02 mmol, NaOtBu
0.7 mmol, toluene 1 mL, 24 h, 70 °C, under Ar.
b Determined by 1H NMR of the reaction mixture using an internal standard method.
c Determined by chiral HPLC analysis (see Section 4).
d At room temperature.
e NaOMe was used as the base, and amine (1.2 mL) was used as the reaction solvent.
f Reaction was performed for 72 h.
Good enantioselectivity (72% ee) was achieved from the
reaction of 2-bromotoluene and 1-(1-naphthyl)ethyl-
amine at room temperature in the presence of a base
of sodium methoxide, but the yield was quite low.
Therefore, 2-iodotoluene was employed for this reac-
tion. However, the yield did not improve. The effect of
additives was then studied to obtain the product in high
yield, because the addition of crown ether or ammonium
salt reportedly accelerates the reaction.9 The addition of
ammonium salts effectively yielded product 3a in higher
yields without any loss of enantioselectivity (Table 5).
Use of tetrabutylammonium bromide increased the yield
to 53%. Obtaining a higher yield by adding ammonium
salt was difficult because of its low solubility. Crown
ether (1.4 equiv) was then added to the reaction to pro-
vide a product in 27% yield. Interestingly, using
4.2 equiv of sodium methoxide and 4.2 equiv of crown
ether increased the yield to 85% in 74% ee, although
no improvement in the yield was observed using
4.2 equiv of sodium methoxide without crown ether.
Although Buchwald et al. demonstrated a zero-order
reaction in base,10 our results indicate otherwise, when
Table 5. Asymmetric amination of aryl halides using 1-(1-naphthyl)ethylaminea
Entry
Aryl halide 1
R1 =
Additiveb (equiv)
Product 3
Yieldc (%)
eed (%)
1
2-CH3
Me4NCl (1.0)
Bu4NBr (1.0)
Bu4NI (1.0)
3m
29
53
6
74
72
71
71
74
2
3
4
5e
18-Crown-6 (1.4)
18-Crown-6 (4.2)
27
85
6e
H
18-Crown-6 (4.2)
3n
3o
6071
7e
8f
2-OCH3
18-Crown-6 (4.2)
18-Crown-6 (8.4)
26
7080
79
a All reactions were performed using an aryl halide (0.5 mmol), 19 equiv of 1-(1-naphthyl)ethylamine, 1.4 equiv of NaOCH3, 2 mol %
Pd2(dba)3ÆCHCl3/4 mol % (R)-Tol–BINAP, and an additive at room temperature for 24 h.
b Equivalent to halide.
c Determined by 1H NMR of the reaction mixture using an internal standard method.
d Determined by chiral HPLC analysis (see Section 4).
e 4.2 equiv of NaOCH3 was used.
f 8.4 equiv of NaOCH3 was used.

2310
J. Tagashira et al. / Tetrahedron: Asymmetry 16 (2005) 2307–2314
100
90
80
70
60
I
NH2
1-naphthyl
+
R1
1
2
.
Pd2(dba)3 CHCl3
(R)-Tol-BINAP
R
S
1-naphthyl
N
H
R1
*
50
40
30
20
10
0
NaOtBu, Toluene
additive, 70 oC, 24 h
3m-o
Scheme 3.
using a combination of base and 18-crown-6. 2-Iodoani-
sole, using 8.4 equiv of sodium methoxide and the same
amount of crown ether, gave a satisfactory yield of 70%,
while 4.2 equiv of them afforded product 3c in only 26%
yield (see Scheme 3).
0
5
10 15 20 25 30 35 40 45 50 55
Time (h)
Figure 1. Comparison of the reaction yields of 4-bromobiphenyl with
(R)- or (S)-1-(1-naphthyl)ethylamine in the presence of (R)-Tol–
BINAP–Pd catalyst.
As described above, better stereoselectivity was obtained
from the reaction using a large amount of amine (Table
2, entry 12), suggesting that the reaction proceeded via a
kinetic resolution of the amine. If the reaction proceeds
in a kinetic resolution fashion, the remaining amine
should also be optically active. Therefore, the remaining
amine from the reaction of 4-bromobiphenyl and
2 equiv of 1-(1-naphthyl)ethylamine at 70 °C for 24 h
was investigated. From this reaction, the product was
obtained in 85% yield with 37% ee, while the remaining
amine was isolated with 35% yield and 29% ee.
Although the yield was low by column chromatography,
stereoselectivity was close to the calculated value of
27% ee.
methoxide as a base did not affect the yield of the
product.
To investigate the reaction sequence, bromoaryl–palla-
dium species, prepared in situ by the reaction of
Pd2(dba)3ÆCHCl3, (S)-BINAP, and 4-bromobiphenyl
in toluene, was allowed to react with 1-phenylethyl-
amine. Reaction at 70 °C and at 100 °C did not
proceed at all. These results indicate that, without
crown ether, the reaction proceeds through the coordi-
nation of the amine to the palladium center, and
then this intermediate reacts with the aryl halide, as
already demonstrated by Buchwald et al. This mecha-
nism explains the effect on the stereoselectivity of the
structures of aryl halide, amine, and base. That is,
the intermediates coordinated with the amine are dia-
stereomeric, and that these diastereomers should
show a different reactivity to the aryl halide and to
the base. Therefore, a different enantioselectivity was
detected.
The optically active amines were then used for this reac-
tion. When an equivalent of (R)-1-(1-naphthyl)ethyl-
amine was employed using (R)-Tol–BINAP, the reac-
tion at 55 °C proceeded in 90% yield after 5 h. On the
other hand, the reaction of (S)-1-(1-naphthyl)ethyl-
amine using (R)-Tol–BINAP resulted in a 68% yield
after 5 h under the same reaction conditions. These
results indicate that the reaction of (R)-1-(1-naphthyl)-
ethylamine using (R)-Tol–BINAP is faster than (S)-iso-
mer using (R)-Tol–BINAP, while the reaction of
racemic amine proceeds with kinetic resolution (see
Fig. 1).
On the other hand, the reaction was accelerated using
crown ether. This phenomenon could be explained as
follows: the same intermediate from the palladium
and amine reacted with a strong base, a cation-free
methoxide, which is prepared using sodium methoxide
with crown ether, to give the anionic palladium species.
This anionic species might have reacted with an aryl
halide faster than the intermediate coordinated by the
amine. At the same time, the steric energies (MM2 cal-
culation) of both anionic diastereomers of (S)-Tol–BI-
NAP–Pd having (R)- or (S)-1-phenylethylamine and
(R)- or (S)-1-(1-naphthyl)ethylamine as the covalent
bond between the palladium atom and nitrogen atom
were conferred. Modeling results correlated with the
conclusion that the (S)-isomer of the aniline derivatives
are dominant when using (S)-Tol–BINAP as a ligand,
and that 1-(1-naphthyl)ethylamine shows better stereo-
selectivity than 1-phenylethylamine. These results might
demonstrate the role of crown ether on catalytic cycles
(see Fig. 2).
The mechanism of the coupling of aryl halides and
amines catalyzed by a palladium complex has been
extensively studied. Buchwald et al. demonstrated that
the coordination of an amine to a palladium center
accelerates the oxidative addition of aryl halides to a
metal center.10 They also showed that the reaction rate
depended on the concentration of the aryl halide and
amine instead of the concentration of the additive
base. Hartwig suggested that the reaction rate depends
on the concentration of the catalyst.11 In our reac-
tion system, the enantioselectivity was influenced
either by the kind of aryl halide, amine, or base. Fur-
thermore, the yield of the product depended on the
amount of a combination of crown ether and
sodium methoxide as base; while the amount of sodium

J. Tagashira et al. / Tetrahedron: Asymmetry 16 (2005) 2307–2314
2311
4.2. Pd-catalyzed coupling of a-substituted amines with
aryl bromides
Ar
P
P
Pd
NRR'
The aryl bromide (0.5 mmol), amine (1.2 mmol),
Pd2(dba)3ÆCHCl3 (11 mg, 0.01 mmol, 4 mol % Pd),
NaOtBu (67 mg, 0.7 mmol, 1.4 equiv) and toluene
(1 mL) were added to a dried sealable Schlenk tube
which was capped with a septum, purged with argon,
and then heated to 70 °C for 24 h. The reaction mixture
was then allowed to cool to room temperature, diluted
with Et2O (10mL), and filtered through Celite. The Cel-
ite was then rinsed with Et2O. The filtrate was concen-
trated to give the crude product. Purification by
column chromatography (10% EtOAc/hexane) afforded
the pure product.
NRR'
Ar
P
X
P
Pd
Pd
ArNRR'
NHRR'
P
P
Pd
ArX
P
P
NRR'
OCH3
P
P
NHRR'
HOCH3
Pd
4.3. (S)-4-Phenyl-N-(1-phenylethyl)aniline 3a6
Figure 2. Plausible mechanism.
25
D
25
D
½aŠ ¼ À11.9 (c 0.5, CHCl3) {lit.6 ½aŠ ¼ þ54 for
(R)-4-phenyl-1-phenylethylaniline in >99% ee}, 21% ee
[(R)-Tol–BINAP] by HPLC (Chiralcel OD, hexane/
2-propanol = 1:9, 0.5 mL/min, tR = 16.3 min (major),
tR = 19.5 min (minor)); 1H NMR (CDCl3): d 1.54
(d, 3H, J = 6.7 Hz), 4.13 (s, 1H), 4.52 (q, J = 6.7 Hz,
1H), 6.56–6.60(m, 2H), 7.2–07.25 (m, 2H), 7.31–
7.40(m, 8H), 7.48 (d, 2H, J = 5.2 Hz); GC–MS (m/z)
273.
3. Conclusion
In conclusion, asymmetric amination was examined
using aryl halides and racemic amines in the presence
of a transition metal complex with a chiral ligand.
Pd2(dba)3ÆCHCl3 combined with Tol–BINAP was dem-
onstrated to be the best catalyst. The best results (70%
yield, 80% enantiomeric excess of the product) were
obtained from the reaction of 2-iodoanisole with excess
and racemic 1-(1-naphthyl)ethylamine without solvent
at room temperature for 24 h in the presence of 18-
crown-6 as the additive, NaOCH3 as the base, and
LnPd (Ln = (R) or (S)-Tol–BINAP) as the catalyst.
Obtaining optically active aniline derivatives from race-
mic amines increases the utility of aryl amination
reactions.
4.4. 4-Methyl-N-(1-phenylethyl)aniline 3b12
25
½aŠ ¼ þ26 (c 0.5, CHCl3); 20% ee [(R)-Tol–BINAP] by
D
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
2-propanol = 9/1, 0.5 mL/min, tR = 11.1 min (major),
tR = 12.2 min (minor)); H NMR (CDCl3, 400 MHz):
1
d 1.52 (d, 3H, J = 6.7 Hz), 2.18 (s, 3H), 4.45 (q, 1H,
J = 6.7 Hz), 6.46 (d, J = 8.4 Hz, 2H, Ar), 6.90(d,
J = 8.4, 2H, Ar), 7.20–737 (5H, m, Ar); GC–MS (m/z)
211.
4. Experimental
4.1. General
4.5. 3-Methyl-N-(1-phenylethyl)aniline 3c13
25
½aŠ ¼ þ16 (c 0.5, CHCl3); 16% ee [(R)-Tol–BINAP] by
Nuclear magnetic resonance spectra were measured
using a JEOL JNM A-400 (1H NMR: 400 MHz, 13C
NMR: 100 MHz) spectrometer with tetramethylsilane
D
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
2-propanol = 9/1, 0.5 mL/min, tR = 10.1 min (minor),
1
1
as the internal standard for the H NMR and CDCl3
tR = 12.8 min (major)); H NMR (CDCl3, 400 MHz): d
at 77 ppm for the 13C NMR. IR spectra were measured
on a Shimadzu IR-408 spectrometer. Mass spectral
1.51 (d, J = 6.8, 3H, CHCH3), 2.20(s, 3H, C H4CH3),
6
4.47 (q, J = 6.8, 1H, CHNH), 6.30–6.32 (m, 1H, Ar),
6.37 (m, 1H, Ar), 6.47 (d, J = 7.2, 1H, Ar), 6.95–6.99
(m, 1H, Ar), 7.20–7.24 (m, 1H, Ar), 7.29–7.39 (m, 4H,
Ar); GC–MS (m/z) 211.
(GC–MS) data were recorded on
a
Shimadzu
GP2000A instrument. High resolution mass spectra
(FAB) were measured using a JEOL JMS-700 with
meta-nitrobenzyl alcohol as the matrix and PEG-200
as the calibration standard. The enantiomeric
excesses were determined by HPLC analyses using a
Hitachi series L-7100 HPLC with a detection sys-
tem using a Chiralcel OD or OJ column. Optical rota-
4.6. 2-Methyl-N-(1-phenylethyl)aniline 3d12
25
½aŠ ¼ þ14 (c 0.5, CHCl3), 25% ee [(R)-Tol–BINAP] by
D
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
2-propanol = 9/1, 0.5 mL/min, tR = 10.3 min (minor),
tions were measured using
spectrometer.
a
Horiba SEPA-200
1
tR = 18.8 min (major)); H NMR (CDCl3, 400 MHz): d
1.55 (d, J = 6.8 Hz, 3H, CHCH3), 2.21 (s, 3H,
C6H4CH3), 3.85 (s, 1H, NH), 4.52 (q, J = 6.8 Hz, 1H,
CHNH), 6.36 (d, J = 6.8 Hz, 1H, Ar), 6.59 (t,
J = 7.2 Hz, 1H, Ar), 6.94 (t, J = 7.6 Hz, 1H, Ar), 7.04
(d, J = 7.6 Hz, 1H, Ar), 7.19–7.23 (m, 1H, Ar), 7.28–
7.36 (m, 4H, Ar); GC–MS (m/z) 211.
All reactions were performed under an argon atmo-
sphere using standard Schlenk techniques. All solvents
were dried by standard methods and distilled under
argon. Commercially available compounds were used
without further purification.

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J. Tagashira et al. / Tetrahedron: Asymmetry 16 (2005) 2307–2314
4.7. 4-Methoxy-N-(1-phenylethyl)aniline 3e14
GC–MS (m/z) 222. HR-MS (FAB, PEG-200) calcd for
C15H14N2 222.1157. Found 222.1166.
25
D
20
365
½aŠ ¼ þ6.0( c 0.3, CHCl3) {lit.14 ½aŠ ¼ þ27.1 (c 1.21,
EtOH) 59% ee, (R)}; 21% ee [(S)-Tol–BINAP] by HPLC
(column: Daicel Chiralcel OD-H; eluent: hexane/2-pro-
panol = 99/1, 0.5 mL/min, tR = 24.4 min (major), tR =
25.6 min (minor)); 1H NMR (CDCl3, 400 MHz): d
1.49 (d, J = 6.8, 3H, CHCH3), 3.68 (s, 3H, OCH3),
4.40(q, J = 6.8, 1H, CHNH), 6.46 (d, J = 9.2, 2H, Ar),
6.68 (d, J = 9.2, 2H, Ar), 7.19–7.37 (m, 5H, Ar); GC–
MS (m/z) 227.
4.12. 2-(1-Phenylethylamino)benzonitrile 3j18
25
½aŠ ¼ À6.0( c 0.5, CHCl3); 5% ee [(R)-Tol–BINAP] by
D
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
2-propanol = 8/2, 0.5 mL/min, tR = 8.7 min (minor),
1
tR = 11.5 min (major)); H NMR (CDCl3, 400 MHz): d
1.58 (d, J = 6.8, 3H, CHCH3), 4.57 (quintet,
J = 6.8 Hz, 1H, CHNH), 4.90(br, 1H, N H), 6.42 (d,
J = 8.4, 1H, Ar), 6.62 (t, J = 7.6, 1H, Ar), 7.16–7.28
(m, 2H, Ar), 7.32–7.35 (m, 4H, Ar), 7.36–7.40(m, 1H,
Ar); GC–MS (m/z) 222.
4.8. 3-Methoxy-N-(1-phenylethyl)aniline 3f15
25
½aŠ ¼ þ8.0( c 0.5, CHCl3); 19% ee [(S)-Tol–BINAP] by
D
HPLC (column: Daicel Chiralcel OJ; eluent: hexane/
2-propanol = 9/1, 0.5 mL/min, tR = 36.9 min (minor),
4.13. N-(2-Butyl)-4-phenylaniline 3k
25
D
1
tR = 19.5 min (major)); H NMR (CDCl3, 400 MHz): d
½aŠ ¼ þ10( c 0.5, CHCl3); 8% ee [(S)-Tol–BINAP] by
1.48 (d, J = 6.4, 3H, CHCH3), 3.66 (s, 3H, OCH3),
4.06 (br, 1H, NH), 4.46 (q, J = 6.4 Hz, 1H, CHNH),
6.05 (t, J = 4.8, 1H, Ar), 6.13 (dd, J = 2.0, 7.6 Hz, 1H,
Ar), 6.20(dd, J = 2.0, 7.6, 1H, Ar), 6.98 (t, J = 8.4 Hz,
1H, Ar), 7.18–7.22 (m, 1H, Ar), 7.28–7.36 (m, 4H, Ar);
GC–MS (m/z) 227.
HPLC (column: Daicel Chiralcel OD-H; eluent: hex-
ane/2-propanol = 99/1, 0.5 mL/min), tR = 26.2 min (ma-
jor), tR = 28.7 min (minor); IR (NaCl) m 3400, 3000,
2950, 1600, 1520, 1480, 1450, 1400, 1370, 1320, 1290,
1
1270, 1240, 1190, 1160, 820, 760, 690 cmÀ1; H NMR
(CDCl3, 400 MHz): d 0.97 (t, J = 7.4 Hz, 3H, CH2CH3),
1.20(d, J = 6.4 Hz, 3H, CHCH3), 1.45–1.66 (m, 2H,
CHCH2CH3), 3.44 (sextet, J = 6.4, 1H, CHNH), 6.65
(d, J = 8.8, 2H, Ar), 7.22–7.26 (m, 1H, Ar), 7.36–7.44
(m, 4H, Ar), 7.52–7.54 (m, 2H, Ar); 13C NMR
(100 MHz): d 10.4, 20.2, 29.5, 49.7, 113.1, 125.8, 126.1,
127.9, 128.6, 129.4, 141.2, 147.0; GC–MS (m/z) 225.
HR-MS (FAB, PEG-200) calcd for C16H19N 225.1518.
Found 225.1539.
4.9. (S)-2-Methoxy-N-(1-phenylethyl)aniline 3g16
25
D
25
D
½aŠ ¼ þ14 (c 0.5, CHCl3) {lit.16 ½aŠ ¼ þ38.5 (c 10.3,
CHCl3) for 88% ee of (S)-3g}; 30% ee ((S)-Tol–BINAP)
by HPLC (column: Daicel Chiralcel OD-H; eluent: hex-
ane/2-propanol = 9/1, 0.5 mL/min, tR = 9.3 min (major),
1
tR = 11.8 min (minor)); H NMR (CDCl3, 400 MHz): d
1.54 (d, J = 6.8 Hz, 3H, CHCH3), 3.87 (s, 3H, OCH3),
4.46 (q, J = 6.8 Hz, 1H, CHNH), 4.63 (br, 1H, NH),
6.30–6.35 (m, 1H, Ar), 6.59–6.62 (m, 1H, Ar), 6.67–
6.89 (m, 2H, Ar), 7.18–7.37 (m, 5H, Ar); GC–MS (m/z)
227.
4.14. N-(1-(1-Naphthyl)ethyl)-4-phenylaniline 3l
25
D
½aŠ ¼ þ86 (c 0.5, CHCl3); 37% ee [(S)-Tol–BINAP] by
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
2-propanol = 9/1, 0.5 mL/min) tR = 27.0min (minor),
tR = 32.9 min (major); IR (KBr) m 3400, 3020, 1620,
1600, 1520, 1480, 1440, 1370, 1320, 1300, 1270, 1250,
4.10. 4-(1-Phenylethylamino)benzonitrile 3h17
25
½aŠ ¼ þ6.1 (c 0.5, CHCl3); 10% ee [(R)-Tol–BINAP] by
1230, 1190, 1140, 820, 800, 770, 760, 690 cmÀ1 1H
.
D
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
NMR (CDCl3, 400 MHz): d 1.70(d, J = 6.8 Hz, 3H,
CHCH3), 5.33 (q, J = 6.8 Hz, 1H, CHNH), 6.57 (d,
J = 8.8 Hz, 2H, Ar), 7.19–7.59 (m, 10H, Ar), 7.68 (d,
J = 6.8 Hz, 1H, Ar), 7.76 (d, J = 8.4 Hz, 1H, Ar), 7.91
(d, J = 8.0Hz, 1H, Ar), 8.17 (d, J = 8.0Hz, 1H, Ar);
13C NMR (100 MHz): d 23.6, 49.5, 113.3, 122.2, 122.5,
125.5, 125.9, 125.9, 126.1, 126.2, 127.5, 127.8, 128.6,
129.1, 130.0, 130.6, 134.0, 139.7, 141.1, 146.4; GC–MS
(m/z) 323. HR-MS (FAB, PEG-200) calcd for
C24H21N 323.1674. Found 323.1686.
2-propanol = 8/2, 0.5 mL/min, tR = 10.7 min (major),
tR = 12.5 min (minor)); H NMR (CDCl3, 400 MHz):
1
d 1.54 (d, J = 6.4, 3H, CHCH3), 4.51 (quintet, J = 6.4,
1H, CHNH), 4.68 (br, 1H, NH), 6.47 (d, J = 8.8, 2H,
Ar), 7.22–7.27 (m, 2H, Ar), 7.29–7.35 (m, 5H, Ar).
GC–MS (m/z) 222.
4.11. 3-(1-Phenylethylamino)benzonitrile 3i
25
D
½aŠ ¼ À5.9 (c 0.5, CHCl3); 16% ee ((R)-Tol–BINAP) by
HPLC (column: Daicel Chiralcel OD-H; eluent: hexane/
2-propanol = 8/2, 0.5 mL/min, tR = 10.2 min (minor),
tR = 13.3 min (major); IR (KBr) m 3368, 2966, 2228,
1603, 1522, 1479, 1433, 1335, 1299, 1269, 1200, 1165,
4.15. 2-Methyl-N-(1-(1-naphthyl)ethyl)aniline 3m
25
D
½aŠ ¼ þ226 (c 0.5, CHCl3); 100% ee (product from
the reaction using enantiomerically pure amine) by
HPLC (column: Daicel Chiralcel OD-H; eluent:
hexane/2-propanol = 9/1, 0.5 mL/min, tR = 11.5 min
(major), tR = 12.4 min (minor)); IR (KBr) m 3400,
2950, 1600, 1580, 1500, 1470, 1460, 1380, 1310, 1300,
1
843, 781, 765, 704, 677, 548 cmÀ1; H NMR (CDCl3,
400 MHz): d 1.53 (d, J = 6.8, 3H, CHCH3), 4.31 (br,
1H, NH), 4.46 (q, J = 6.8, 1H, CHNH), 6.68–6.71 (m,
2H, Ar), 6.87–6.90(m, 1H, Ar), 7.10–7.14 (m, 1H, Ar),
7.22–7.28 (m, 1H, Ar), 7.30–7.34 (m, 4H, Ar); 13C
NMR (100 MHz): d 24.9, 53.3, 112.6, 115.5, 117.6,
119.5, 120.7, 125.6, 127.3, 128.9, 129.7, 143.8, 147.3;
1250, 1220, 1170, 800, 770, 750 cmÀ1
(CDCl3, 400 MHz):
CHCH3), 2.28 (s, 3H, PhCH3), 5.33 (q, J = 6.4 Hz,
;
1H NMR
d
1.72 (d, J = 6.4 Hz, 3H,

J. Tagashira et al. / Tetrahedron: Asymmetry 16 (2005) 2307–2314
2313
1H, CHNH), 6.26 (s, 1H, Ar), 6.60(t, J = 7.6 Hz, 1H,
Ar), 6.87 (t, J = 8.0Hz, 1H, Ar), 7.07 (d, J = 7.6 Hz,
1H, Ar), 7.40(t, J = 7.6 Hz, 1H, Ar), 7.50–7.62 (m,
3H, Ar), 7.75 (d, J = 7.6, 1H, Ar), 7.91 (d,
J = 8.0Hz, 1H, Ar), 8.17 (d, J = 8.0Hz, 1H, Ar); 13C
NMR (100 MHz): d 17.7, 23.8, 49.3, 110.8, 116.7,
121.5, 122.1, 122.5, 125.4, 125.9, 126.0, 127.0, 127.4,
129.1, 129.9, 130.6, 134.0, 139.8, 144.8; GC–MS (m/z)
261. HR-MS (FAB, PEG-200) calcd for C19H19N
261.1517. Found 261.1533.
at Doshisha University from the Ministry of Education,
Japan.
References
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4.16. (R)-N-(1-(1-Naphthyl)ethyl)aniline 3n19
25
D
25
D
½aŠ ¼ þ142 (c 0.5, CHCl3) {lit.19 ½aŠ ¼ þ249 (c 1.9,
CH3OH) for (R)-3n}; 75% ee [(S)-Tol–BINAP] by
HPLC (column: Daicel Chiralcel OD-H; eluent: hex-
ane/2-propanol = 9/1, 0.5 mL/min, tR = 30.8 min (min-
or), tR = 67.7 min (major)); 1H NMR (CDCl3,
400 MHz): d 1.66 (d, J = 6.8 Hz, 3H, CHCH3), 4.26
(br, 1H, NH), 5.28 (t, 1H, J = 6.8 Hz, CHNH), 6.49
(d, 2H, J = 8.0Hz, Ar), 6.64 (t, 1H, J =7.2 Hz, Ar),
7.04–7.08 (m, 2H, Ar), 7.41 (t, 1H, J = 7.8 Hz, Ar),
7.50–7.58 (m, 2H, Ar), 7.66 (d, 1H, J = 6.8 Hz, Ar),
7.75 (d, 1H, J = 8.0Hz, Ar), 7.91 (d, 1H, J = 7.6 Hz,
Ar), 8.16 (d, 1H, J = 8.4 Hz, Ar); GC–MS (m/z) 224.
4.17. (S)-2-Methoxy-N-(1-(1-naphthyl)ethyl)aniline 3o19
25
D
25
D
½aŠ ¼ þ170( c 0.3, CHCl3) {lit.19 ½aŠ ¼ À249 (c 1.9,
CH3OH) for (R)-3o}; 80% ee [(S)-Tol–BINAP] by
HPLC (column: Daicel Chiralcel OD-H; eluent: hex-
ane/2-propanol = 9/1, 0.5 mL/min, tR = 11.3 min (min-
or), tR = 20.4 min (major)); 1H NMR (CDCl3,
400 MHz): d 1.65 (d, 3H, J = 6.8 Hz, CHCH3), 3.85 (s,
3H, OCH3), 4.76 (br, 1H, NH), 5.25 (q, 1H,
J = 6.8 Hz, CHNH), 6.19–6.21 (m, 1H, Ar), 6.55–6.61
(m, 2H, Ar), 6.72–6.76 (m, 1H, Ar), 7.35 (t, 1H,
J = 8.0Hz, Ar), 7.44–7.54 (m, 2H, Ar), 7.61 (d, 1H,
J = 7.6 Hz, Ar), 7.69 (d, 1H, J = 8.4 Hz, Ar), 7.86 (d,
1H, J = 8.0Hz, Ar), 8.14 (d, 1H, J = 8.4 Hz, Ar); GC–
MS (m/z) 277.
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BINAP–Pd having (R)-1-phenylethylamine or (S)-1-
phenylethylamine as the covalent bond between the
palladium atom and nitrogen atom were conferred.
(S)-Tol–BINAP–Pd–(S)-1-phenylethylamine
(À71.22
kcal/mol) is more stable than (S)-Tol–BINAP–Pd–(R)-
1-phenylethylamine (À70.72 kcal/mol). In the case of
1-(1-naphthyl)ethylamine, (S)-Tol–BINAP–Pd–(S)-1-
(1-naphthyl)ethylamine (À80.71 kcal/mol) is more stable
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Acknowledgements
This work was partially supported by Doshisha Univer-
sityꢀs Research Promotion Fund and a grant to RCAST

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`
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