Pd-catalyzed asymmetric allylic aminations with aromatic amine nucleophiles using chiral diaminophosphine oxides: DIAPHOXs

Article abstract of DOI:10.1016/j.tetasy.2008.07.015

Asymmetric allylic aminations with aromatic amine nucleophiles using Pd-DIAPHOX catalyst systems are described. The asymmetric allylic aminations of various allylic carbonates proceeded using 2-5 mol % of the catalyst and BSA, providing the corresponding

Full text of DOI:10.1016/j.tetasy.2008.07.015

Tetrahedron: Asymmetry 19 (2008) 1751–1759
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Pd-catalyzed asymmetric allylic aminations with aromatic amine
nucleophiles using chiral diaminophosphine oxides: DIAPHOXs
*
Tetsuhiro Nemoto, Shinji Tamura, Tatsurou Sakamoto, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2008
Accepted 2 July 2008
Asymmetric allylic aminations with aromatic amine nucleophiles using Pd–DIAPHOX catalyst systems
are described. The asymmetric allylic aminations of various allylic carbonates proceeded using 2–
5 mol % of the catalyst and BSA, providing the corresponding N-aryl chiral allylic amines in up to 99%
ee for cyclic substrates, and in up to 97% ee for acyclic substrates.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
proceed using the Pd–DIAPHOX catalyst system (Scheme 1). This
is probably due to the lower nucleophilicities of the aromatic
Considerable effort has been directed toward the catalytic
asymmetric synthesis of -chiral amines because chiral amine
amines compared with those of aliphatic amines, or stabilized
anionic nitrogen nucleophiles derived from aromatic amines.8,9
We attempted to overcome this drawback by tuning the reaction
conditions. Herein, we describe a general and highly enantio-
selective allylic amination with aromatic amine nucleophiles using
Pd–DIAPHOX catalyst systems.
a
units are ubiquitous in biologically active compounds. Transition
metal-catalyzed asymmetric allylic amination is one of the most
useful methods for synthesizing chiral allylic amines.1 Several
transition metal-catalyzed asymmetric allylic aminations using
Pd,2 Ir,3 or other transition metal catalysts4 have been reported.
We recently developed aspartic acid-derived pentavalent chiral
phosphorus preligands: P-chirogenic diaminophosphine oxides
(DIAPHOXs) (Fig. 1).5 These preligands are activated in situ by
N,O-bis(trimethylsilyl)acetamide (BSA)-induced P(V) to P(III)
transformations to afford trivalent phosphorus ligands. DIAPHOXs
have been successfully applied to a Pd-catalyzed asymmetric
allylic amination of cyclic and acyclic allylic alcohol derivatives
using aliphatic amine nucleophiles, and various chiral allylic
amines were obtained in good yield with high enantiomeric
purity.6,7 In contrast to aliphatic amine nucleophiles, asymmetric
allylic amination with aromatic amine nucleophiles did not
[
η3-C H PdCl]
3 5 2
(1 mol %)
RP)-1a (4 mol %)
R
OCOOEt
Ph
HN
(S,
BSA (3 equiv)
Ph
Ph
Ph
Nucleophile (3 equiv)
CH Cl , rt, 24 h
benzylamine: 96%, 96% ee
-anisidine: No Reaction
2
2
p
[
η3-C H PdCl]
3 5 2
Ph
Ph
H
(1 mol %)
RP)-1a (4 mol %)
OCOOMe
(S,
N
R
BSA (3 equiv)
Nucleophile (3 equiv)
CH CN, rt, 17 h
benzylamine: 93%, 96% ee
-anisidine: trace
3
p
X
Scheme 1. Asymmetric allylic amination with p-anisidine under the previous
reaction conditions.
X
Y
H
1a: X = H, Y = H, R = phenyl
1b: X = H, Y = H, R = 1-naphthyl
1c: X = H, Y = H, R = 2-naphthyl
Y
1d: X = H, Y = H, R =
1e: X = H, Y = H, R = 3-biphenyl
1f: X = -Bu, Y = H, R = phenyl
1g: X = OMe, Y = OMe, R = phenyl
t-Bu
2. Results and discussion
HN
N
H
O
P
t
N
2.1. Asymmetric allylic amination of 2-substituted cycloalkenyl
carbonates using the Pd–DIAPHOX catalyst system
R
Figure 1. (S,RP)-DIAPHOX 1.
We previously reported that cyclic substrate 2, bearing a methyl
ester at the 2-position on the cyclohexenol framework, exhibits a
much higher reactivity toward aromatic amine nucleophiles in
comparison to other electrophiles.6b Therefore, the asymmetric
* Corresponding author. Tel./fax: +81 43 290 2987.
E-mail address: hamada@p.chiba-u.ac.jp (Y. Hamada).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.015

1752
T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
η3-C H PdCl]
3 5 2
allylic amination of 2 using p-anisidine was selected for the initial
optimization of the reaction conditions (Table 1). The effect of the
ligand structure was first examined using 2 mol % of Pd catalyst,
4 mol % of (S,RP)-DIAPHOX, and 3 equiv of BSA in CH3CN at 4 °C,
revealing that the catalyst prepared from 1a or 1g gave the product
(S)-3a in excellent yield with over 90% ee (entries 1–7). Although
[
Ph
Ph
(2.5 mol %)
RP)-1a (10 mol %)
BSA (3 equiv)
-anisidine (3 equiv)
solvent, rt
H
N
(S,
OCOOMe
p
OMe
(S)-5a
4
: 17 h, 8%, 95% ee
: 17 h, 99%, 97% ee
in CH CN
3
in DMF
Table 1
Optimization of the reaction conditions
Scheme 2. Asymmetric allylic amination of 4.
[
η3-C H PdCl]
3 5 2
(1 mol %)
S,RP)-DIAPHOX
(4 mol %)
MeO
O
MeO
O
(
H
the use of 1g as the preligand produced (S)-3a with slightly higher
enantioselectivity, the catalyst prepared from 1a exhibited higher
reactivity. Based on these results, 1a was used for further optimi-
zation. Examination of the solvent effect revealed that the best
reactivity was obtained when DMF was used as the solvent (entry
10). Although an enhanced reactivity in DMF was not observed at a
lower temperature, the reaction proceeded in 48 h to afford (S)-3a
in 99% yield with 95% ee (entry 12). These results led us to examine
the asymmetric allylic amination of 2-phenylcyclohexenyl alcohol
derivative 4 with p-anisidine using DMF as solvent (Scheme 2). The
reaction rate was remarkably enhanced when the reaction was
performed in DMF using 5 mol % of Pd catalyst and 10 mol % of
1a, and the corresponding product (S)-5a was obtained in 99% yield
with 97% ee.10,11
We next examined the scope and limitations of different cyclic
substrates (Table 2). Both CH3CN and DMF were used as solvents,
and the better results are listed in the Table. Using 2 mol % of Pd
catalyst and 4 mol % of 1a, the asymmetric allylic amination of 2
was performed using various aromatic amines as nucleophiles.
Primary aromatic amines with an electron-donating functional
group, as well as an electron-withdrawing functional group, and
N
OCOOMe
p
-anisidine (3 equiv)
BSA (3 equiv)
solvent (0.2 M)
OMe
a
(S)-3a
2
Entry DIAPHOX Solvent
Temperature Time (h) Yieldb (%) eec (% ee)
(°C)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1a
1a
1a
1a
1a
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
C2H5CN
CH2Cl2
DMF
4
4
4
4
4
4
4
4
4
7
48
50
51
64
65
24
16
24
4
99
42
78
55
99
99
99
99
98
99
99
99
90
42
71
48
88
89
91
73
78
90
94
95
10
11
12
4
CH3CN
DMF
ꢀ30
47
48
ꢀ30
a
b
c
For the determination of the absolute configuration, see Scheme 4.
Isolated yield.
Determined by HPLC analysis.
Table 2
Scope and limitations
[
(
η3-C H PdCl] (1 or 2.5 mol %)
S,RP)-1a (4 or 10 mol %)
3 5 2
R
R'
N
R
OCOOMe
Ar-NHR' (3 equiv), BSA (3 equiv)
Ar
solvent (0.2 M)
n
n
Entry
Substrates
Ar–NHR0
Pd cat. (mol %)
Solvent
Temperature (°C)
Product
Time (h)
Yielda (%)
eeb (% ee)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
17d
18
19
20
21
22
23
2
2
2
2
2
2
2
2
2
2
6
6
8
10
4
4
4
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 2)
R = COOMe (n = 1)
R = COOMe (n = 1)
R = CN (n = 2)
R = CONMe(OMe) (n = 2)
R = Ph (n = 2)
R = Ph (n = 2)
R = Ph (n = 2)
R = Ph (n = 1)
R = 4-MeO-C6H4 (n = 2)
R = 4-F–C6H4 (n = 2)
R = 2-naphthyl (n = 2)
R = CH2OTBS (n = 2)
R = H (n = 2)
4-MeO–C6H4NH2
C6H4NH2
2
2
2
2
2
2
2
2
2
2
2
2
2
5
5
5
5
2
5
5
5
5
5
DMF
ꢀ30
0
0
rt
0
rt
rt
rt
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
48
15
18
24
74
21
9
20
15
6
72
24
46
72
17
24
3
12
48
40
19
48
48
99
99
99
78
94
79
86
85
99
96
95
96
99
99
99
95 (S)c
93
91
87
91
87
90
94
96
94
78
84
91
CH3CN
CH3CN
DMF
CH3CN
DMF
CH3CN
CH3CN
DMF
4-t-Bu–C6H4NH2
4-Cl–C6H4NH2
3-MeO–C6H4NH2
3-Br–C6H4NH2
2-Cl–C6H4NH2
2-Br–C6H4NH2
Indoline
4-MeO–C6H4NHCH3
4-MeO–C6H4NH2
Indoline
4-MeO–C6H4NH2
4-MeO–C6H4NH2
4-MeO–C6H4NH2
4-Cl–C6H4NH2
Indoline
4-MeO–C6H4NH2
4-MeO–C6H4NH2
4-MeO–C6H4NH2
4-MeO–C6H4NH2
4-MeO–C6H4NH2
4-MeO–C6H4NH2
DMF
0
3j
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
CH3CN
ꢀ30
ꢀ30
0
0
rt
rt
rt
0
rt
rt
rt
rt
rt
7a
7b
9
11
5a
5b
5c
13
15
17
19
21
23
89
97 (S)c
98
73 (27)e
94
99
96
96
97
12
14
16
18
20
22
97
56 (43)e
99
93
79
91
99
78 (S)f
44
a
Isolated yield.
b
c
d
e
f
Determined by HPLC analysis.
For the determination of the absolute configuration, see Scheme 4.
Ten equivalents of amine were used as the nucleophile.
Recovery of the starting material.
The absolute configuration of 21 was determined by comparing the measured specific rotation of the authentic sample prepared from (S)-3a.

T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
1753
secondary aromatic amines were tolerant to this reaction, giving
Cl
the corresponding products 3a–j in good yield with 87–96% ee (en-
tries 1–10).12 Substrate 6, a cyclopentenol-type substrate with a
methyl ester, was also applicable to this reaction, affording the cor-
responding products with good enantioselectivities (entries 11 and
12). Similarly, a nitrile-type substrate 8, as well as a Weinreb
amide-type substrate 10, could be utilized for this reaction, provid-
ing the corresponding products 9 and 11 in excellent yield with
91% ee and 89% ee, respectively (entries 13 and 14). The asymmet-
ric allylic amination of 2-aryl-substituted cycloalkenyl alcohol
derivatives was also examined using DMF as the solvent. Asym-
metric allylic amination of 4 with primary and secondary aromatic
amines proceeded using 5 mol % of the catalyst to afford the corre-
sponding products in excellent enantioselectivity (entries 15–17).
Similarly, 2-phenyl-substituted cyclopentenol derivative 12 was
applicable to this reaction system, giving the product in 96% ee
using 2 mol % of the catalyst (entry 18). This reaction system was
also effective for cyclic allylic carbonates bearing a p-methoxy-
phenyl, p-fluorophenyl, or 2-naphthyl group, resulting in the for-
mation of chiral amines with up to 99% ee (entries 19–21). There
was a significant decrease in the reactivity, however, when 14, a
substrate with an electron-donating group on the aromatic ring,
was used as the electrophile (entry 19). Moreover, we examined
the asymmetric allylic amination of a 2-alkyl-substituted cyclo-
hexenol derivative 20 using p-anisidine, and the corresponding
product was produced in 79% yield with 78% ee (entry 22). A less
satisfactory result was obtained when a simple cyclohexenyl car-
bonate was used as an electrophile (entry 23).
26
p-chloroaniline (3 equiv)
HN
3
22 h, 99%, 96% ee
[η -C H PdCl] (1 mol %)
Ph
Ph
Ph
Ph
3
5
2
(S,R )-1a (4 mol %)
P
24
BSA (3 equiv)
DABCO (1 equiv), ether, rt
27
N
indoline (3 equiv)
21 h, 97%, 86% ee
OCOOMe
OMe
28
Ph
Ph
HN
3
[η -C H PdCl] (2.5 mol %)
3
5
2
Ph
Ph
(S,R )-1a (10 mol %)
P
29
BSA (3 equiv)
p-anisidine (3 equiv), DMF, rt
96 h, 84%, 38% ee
Scheme 3.
24 using p-anisidine (Table 3). When the reaction was performed
using 2 mol % of the catalyst in DMF, the desired product was ob-
tained in 74% ee, even though the yield was 30%. We hypothesized
that the reactivity of the aromatic amine nucleophiles could be in-
creased by the addition of amine bases through a hydrogen-bond-
ing interaction. Detailed examinations revealed that there was a
remarkable increase in the reactivity when 1 equiv of TMEDA or
DMP was added, providing (R)-25 in 99% yield with 90% ee, and
96% yield with 94% ee, respectively. DABCO was also an effective
additive to achieve high enantioselectivity (38% yield, 93% ee),
although the reactivity was low. We then examined the effect of
the solvent in detail using DMP or DABCO as the additive. The best
result was obtained when the reaction was performed in Et2O
using DABCO as the additive (99% yield, 97% ee).13 The optimized
conditions were applicable to other nucleophiles such as p-chloro-
aniline and indoline, affording the corresponding products in 99%
yield with 96% ee, and in 97% yield with 86% ee, respectively
(Scheme 3). The asymmetric allylic amination of 1,3-dialkylsubsti-
tuted allyl carbonate 28 was also examined using p-anisidine as
the nucleophile. Decarboxylative elimination occurred exclusively
when the reaction was performed in the presence of DABCO.14
The reaction proceeded very sluggishly in the absence of DABCO,
giving the corresponding product in 84% yield in 38% ee. There
was no improvement in enantioselectivity when other DIAPHOXs
were used as the preligands.
2.2. Asymmetric allylic amination of linear substrates using the
Pd–DIAPHOX catalyst system
Thus, the present catalytic asymmetric reaction had a broad
generality for both cyclic electrophiles and aromatic amine nucleo-
philes, affording N-aryl a-chiral allylic amines in up to 99% ee. The
satisfactory results in the reaction system using cyclic substrates
led us to turn our attention to the asymmetric allylic amination
of linear substrates. The reaction conditions were optimized for
the asymmetric allylic amination of 1,3-diphenylallyl carbonate
Table 3
Optimization of the reaction conditions
[
η 3-C H PdCl] (1 mol %)
3 5 2
(S,RP)-1a (4 mol %)
OMe
BSA (3 equiv)
additive (1 equiv)
OCOOEt
Ph
HN
2.3. Determination of the absolute configuration of 3a, 5a, and
25
Ph
p
-anisidine (3 equiv)
Ph
Ph
solvent (0.25 M), rt, 24 h
a
(R)-25
24
The absolute configuration of 3a, 5a, and 25 was determined by
transforming them into known chiral compounds (Scheme 4).
Hydrogenation of the conjugated olefin of 3a (90% ee, Table 1, entry
1) was performed using Pd(OH)2–C, to afford the cyclic anti-b-ami-
no acid derivative 30 in 85% yield. In this hydrogenation, the reac-
tion proceeded with complete diastereoselection, giving the anti
product exclusively. Oxidative cleavage of the p-methoxyphenyl
group of 30 using periodic acid,15 followed by the protection of
the resulting free amine with a carbobenzyloxy (Z) group, provided
the known compound 31.6b Comparison of the retention times of
chiral HPLC analysis of 31 with the literature data revealed that
the absolute stereochemistry of 3a was (S).16 Similarly, oxidative
cleavage of the p-methoxyphenyl group of 5a (97% ee, Scheme
2), followed by N-alkylation using ethyl bromoacetate, gave the
known compound 32,6a and the absolute configuration was deter-
mined to be (S).16 The absolute configuration of 25 (97% ee, Table 3,
entry 13) was determined using chiral HPLC analysis16 after
Entry
Solvent
Additive
Yieldb (%)
eec (% ee)
1
2
3
4
5
6
7
8
9
10
11
12
13
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Et2O
Et2O
Et2O
—
—
Trace
30
Trace
21
30
Trace
99
96
38
7
—
74
—
85
87
—
90
94
93
89
—
DBU
TMPd
Triethylamine
PMPd
TMEDA
DMPd
DABCO
Quinuclidine
—
Trace
88
99
DMP
DABCO
95
97
a
b
c
For the determination of the absolute configuration, see Scheme 4.
Isolated yield.
Determined by HPLC analysis.
d
TMP: 2,2,6,6-tetramethylpiperidine. PMP: 1,2,2,6,6-pentamethylpiperidine.
DMP: N,N-dimethylpiperazine.

1754
T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
formate, pyridine, CHCl3, rt]. For the spectroscopic data of these
compounds, see Ref. 6.
MeO
O
MeO
O
H
N
a
b,c
NHZ
3a
5a
85%
51%
4.2.1. General procedure for the asymmetric allylic amination
of cyclic substrates: (6S)-6-(4-ethoxyphenylamino)cyclohex-1-
enecarboxylic acid methyl ester (S)-3a
OMe
(2 steps)
30
(
S
,
S
)-31
(ref.6b)
To a stirred solution of 2 (47.9 mg, 0.22 mmol), [g
3-C3H5PdCl]2
Ph
H
b,d
N
COOEt
(0.82 mg, 0.0022 mmol), and (S,RP)-Ph-DIAPHOX 1a (3.5 mg,
0.0089 mmol) in CH3CN (1.1 mL) at room temperature was added
BSA (165 lL, 0.67 mmol), and the reaction mixture was stirred
24%
(2 steps)
(
S
)-32 (ref. 6a)
for 10 min at the same temperature. After the reaction was cooled
down to ꢀ30 °C, p-anisidine (82.7 mg, 0.67 mmol) was added, and
the resulting mixture was stirred for 47 h. After the reaction was
concentrated under reduced pressure, the crude residue was puri-
fied by flash column chromatography (hexane/AcOEt = 8:1) to give
3a (57.8 mg, 99% yield, 94% ee) as a pale brown solid. Mp 80–81 °C;
OMe
Ph
HN
Ph
N
e
f
25
Ph
Ph
98%
20%
Ph
Ph
)-33
(
R)-34 (ref. 6a)
(
R
IR (ATR):
m
;
3386, 2943, 1708, 1645, 1508, 1434, 1229, 1059, 817,
Scheme 4. Determination of the absolute configuration of 3a, 5a, and 25. Reagents
and conditions: (a) Pd(OH)2–C, H2, AcOEt, rt; (b) HIO4ꢃ2H2O, H2SO4, CH3CN–H2O, rt;
(c) benzyl chloroformate (ZCl), pyridine, CH2Cl2, rt; (d) ethyl bromoacetate, NEt3,
THF, rt; (e) benzyl bromide, K2CO3, DMF, rt; (f) Pd(dba)2 (5 mol %), t-Bu3P (4 mol %),
Cs2CO3, p-bromoanisole, toluene, 90 °C.
748 cmꢀ1
1H NMR (CDCl3): d 1.40–1.49 (m, 1H), 1.59–1.66 (m,
2H), 2.02–2.18 (m, 2H), 2.27–2.34 (m, 1H), 2.89 (broad peak
(NH), 1H), 3.72 (s, 3H), 3.74 (s, 3H), 4.35–4.39 (m, 1H), 6.64–6.68
(m, 2H), 6.76–6.80 (m, 2H), 7.11 (dd, J = 2.8 Hz, 4.8 Hz, 1H); 13C
NMR (CDCl3): d 16.1, 25.7, 26.5, 46.8, 51.7, 55.7, 114.8 (ꢁ2),
115.3 (ꢁ2), 131.5, 141.3, 142.5, 152.2, 167.3; EI-LRMS m/z 261
(M+); EI-HRMS calcd for C15H19NO3 (M+): 261.1365. Found:
converting into N-benzyl adducts 33, which could be prepared
from the known chiral amine (R)-346a using Pd-catalyzed amina-
tion of p-bromoanisole.17
261.1368; ½a 2D0
¼ ꢀ98:2 (c 0.62, CHCl3, 94% ee). The enantiomeric
ꢂ
excess was determined by chiral HPLC analysis (DAICEL CHIR-
ALPAK AD-H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR
24.7 min [(R)-isomer] and 26.8 min [(S)-isomer], detection at
254 nm).
3. Conclusion
In conclusion, we have succeeded in the general and highly
enantioselective allylic amination with aromatic amine nucleo-
philes using Pd–DIAPHOX catalyst systems. Using 2–5 mol % of
4.2.2. 6-Phenylaminocyclohex-1-enecarboxylic acid methyl
ester 3b
the catalyst, N-aryl a-chiral allylic amines were obtained in up to
White solid; Mp 98–99 °C; IR (ATR):
m 3382, 2946, 1698, 1597,
1435, 1244, 1060, 744 cmꢀ1; 1H NMR (CDCl3): d 1.44–1.65 (m, 4H),
2.07–2.35 (m, 2H), 3.63 (broad peak (NH), 1H), 3.71 (s, 3H), 4.46–
4.52 (m, 1H), 6.66–6.72 (m, 3H), 7.13 (dd, J = 2.8 Hz, 4.8 Hz, 1H)
7.15–7.19 (m, 2H); 13C NMR (CDCl3): d 16.1, 25.7, 26.6, 45.5,
51.8, 113.4 (ꢁ2), 117.3, 129.2 (ꢁ2), 131.3, 142.9, 147.0, 167.3; EI-
LRMS m/z 231 (M+); EI-HRMS calcd for C14H17NO2 (M+):
99% ee for cyclic substrates and in up to 97% ee for acyclic sub-
strates. Cyclic reaction adducts with a high enantiomeric purity
will be useful for the asymmetric synthesis of nitrogen-containing
natural products. Further studies are currently underway.
4. Experimental
4.1. General
231.1259. Found: 231.1256; ½a D25
¼ ꢀ80:4 (c 1.28, CHCl3, 93% ee).
ꢂ
The enantiomeric excess was determined by chiral HPLC analysis
(DAICEL CHIRALPAK AD-H, hexane/2-propanol = 95:5, flow rate:
0.5 mL/min, tR 16.8 min [minor isomer] and 20.5 min [major iso-
mer], detection at 254 nm).
Infrared (IR) spectra were recorded on a JASCO FT/IR 230 Fourier
transform infrared spectrophotometer, equipped with ATR (Smiths
Detection, DuraSample IR II). NMR spectra were recorded on a JEOL
ecp 400 spectrometer, operating at 400 MHz for 1H NMR, and
100 MHz for 13C NMR. Chemical shifts in CDCl3, were reported
downfield from TMS (=0 ppm) for 1H NMR. For 13C NMR, chemical
shifts were reported in the scale relative to the solvent signal
[CHCl3 (77.0 ppm)] as an internal reference. Optical rotations were
measured on a JASCO P-1020 polarimeter. EI mass spectra were
measured on JEOL GCmate. The enantiomeric excess (ee) was
determined by HPLC analysis. HPLC was performed on JASCO HPLC
systems consisting of the following: pump, PU-980; detector, UV-
970, measured at 254 nm; column, DAICEL CHIRALPAK AS-H, DAI-
CEL CHIRALPAK AD-H, DAICEL CHIRALPAK AD, DAICEL CHIRALCEL
OD-H, DAICEL CHIRALCEL OJ-H; mobile phase, hexane/2-propanol.
Reactions were carried out in dry solvent under argon atmosphere.
Other reagents were purified by the usual methods.
4.2.3. 6-(4-tert-Butylphenylamino)cyclohex-1-enecarboxylic
acid methyl ester 3c
White solid; Mp 84–85 °C; IR (ATR):
m 3382, 2944, 1704, 1613,
1517, 1306, 1242, 1059, 807, 754 cmꢀ1; 1H NMR (CDCl3): d 1.28 (s,
9H), 1.43–1.66 (m, 4H), 2.05–2.34 (m, 2H), 3.55 (broad peak (NH),
1H), 3.71 (s, 3H), 4.45–4.47 (m, 1H), 6.61–6.63 (m, 2H), 7.11 (dd,
J = 2.8 Hz, 4.8 Hz, 1H), 7.18–7.25 (m, 1H); 13C NMR (CDCl3): d
16.1, 25.7, 26.6, 31.5 (ꢁ3), 33.8, 45.6, 51.8, 113.1 (ꢁ2), 126.0
(ꢁ2), 131.5, 140.0, 142.7, 144.6, 167.4; EI-LRMS m/z 287 (M+); EI-
HRMS calcd for C18H25NO2 (M+): 287.1885. Found: 287.1884;
½
a 2D5
ꢂ
¼ ꢀ60:2 (c 1.23, CHCl3, 91% ee). The enantiomeric excess
was determined by chiral HPLC analysis (DAICEL CHIRALCEL OD-
H, hexane/2-propanol = 99:1, flow rate: 0.5 mL/min, tR 21.8 min
[minor isomer] and 26.8 min [major isomer], detection at 254 nm).
4.2. Experimental procedure of the Pd-catalyzed asymmetric
allylic amination and compound characterization
4.2.4. 6-(4-Chlorophenylamino)cyclohex-1-enecarboxylic acid
methyl ester 3d
White solid; Mp 113–114 °C; IR (ATR):
m
3378, 2949, 1700,
Reaction products were prepared according to the general pro-
cedure. Alkenyl carbonates were prepared from the corresponding
allylic alcohols using a usual procedure [methyl (or ethyl) chloro-
1595, 1509, 1438, 1268, 1065, 810 cmꢀ1
;
1H NMR (CDCl3): d
1.43–1.70 (m, 3H), 2.00–2.04 (m, 1H), 2.11–2.20 (m, 1H), 2.29–
2.35 (m, 1H), 3.65 (broad peak (NH), 1H), 3.70 (s, 3H), 4.39–4.43

T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
1755
(m, 1H), 6.56–6.60 (m, 2H), 7.08–7.12 (m, 2H), 7.14 (dd, J = 2.8 Hz,
4.8 Hz, 1H); 13C NMR (CDCl3): d 16.1, 25.6, 26.7, 45.8, 51.8, 114.4
(ꢁ2), 121.8, 129.0 (ꢁ2), 130.9, 143.1, 145.6, 167.1; EI-LRMS m/z
265 (M+); EI-HRMS calcd for C14H16ClNO2 (M+): 265.0870. Found:
(broad peak (NH), 1H), 4.49–4.57 (m, 1H), 6.54–6.58 (m, 1H),
6.85–6.87 (m, 1H), 7.17–7.26 (m, 1H), 7.19 (dd, J = 2.8 Hz, 4.8 Hz,
1H), 7.40–7.41 (m, 1H); 13C NMR (CDCl3): d 16.2, 25.7, 26.8, 45.7,
51.8, 110.3, 112.4, 117.9, 128.4, 130.7, 132.4, 143.4, 144.0, 167.0;
EI-LRMS m/z 309 (M+); EI-HRMS calcd for C14H16BrNO2 (M+):
265.0870; ½a 2D4
¼ ꢀ88:0 (c 1.41, CHCl3, 87% ee). The enantiomeric
ꢂ
excess was determined by chiral HPLC analysis (DAICEL CHIR-
ALPAK AD-H, hexane/2-propanol = 95:5, flow rate: 0.5 mL/min, tR
20.1 min [minor isomer] and 25.6 min [major isomer], detection
at 254 nm).
309.0364. Found: 309.0361; ½a D24
¼ ꢀ115:6 (c 1.61, CHCl3, 94%
ꢂ
ee). The enantiomeric excess was determined by chiral HPLC anal-
ysis (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 200:1, flow
rate: 0.5 mL/min, tR 25.1 min [major isomer] and 28.7 min [minor
isomer], detection at 254 nm).
4.2.5. 6-(3-Methoxyphenylamino)cyclohex-1-enecarboxylic
acid methyl ester 3e
4.2.9. 6-(2,3-Dihydroindol-1-yl)cyclohex-1-enecarboxylic acid
methyl ester 3i
White solid; Mp 82–83 °C; IR (ATR):
m 3391, 2944, 1712, 1610,
1494, 1242, 1209, 1158, 1060, 750 cmꢀ1; 1H NMR (CDCl3): d 1.42–
1.50 (m, 1H), 1.57–1.68 (m, 2H), 2.07–2.20 (m, 2H), 2.28–2.35 (m,
1H), 3.71 (s, 3H), 3.72 (broad peak (NH), 1H), 3.77 (s, 3H), 4.44–4.48
(m, 1H), 6.23 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 6.25–6.28 (m, 2H), 7.07
(dd, J = 8.0 Hz, 8.0 Hz, 1H), 7.13 (dd, J = 2.8 Hz, 4.8 Hz, 1H); 13C
NMR (CDCl3): d 16.1, 25.7, 26.6, 45.4, 51.8, 55.0, 99.3, 102.4,
106.5, 129.9, 131.1, 143.0, 148.3, 160.8, 167.2; EI-LRMS m/z 261
(M+); EI-HRMS calcd for C15H19NO3 (M+): 261.1365. Found:
Violet oil; IR (ATR): m 2945, 1715, 1646, 1605, 1488, 1434, 1394,
1242, 1065, 741 cmꢀ1; 1H NMR (CDCl3): d 1.64–1.77 (m, 3H), 1.96–
1.99 (m, 1H), 2.19–2.35 (m, 2H), 2.87–2.92 (m, 2H), 3.27–3.33 (m,
1H), 3.44–3.50 (m, 1H), 3.65 (s, 3H), 4.44–4.50 (m, 1H), 6.44 (d,
J = 8.0 Hz, 1H), 6.52–6.57 (m, 1H), 7.00–7.05 (m, 2H), 7.12–7.25
(m, 1H); 13C NMR (CDCl3): d 18.8, 25.6, 25.9, 28.3, 48.6, 49.8,
51.7, 105.7, 116.0, 124.2, 127.2, 129.4, 130.8, 142.8, 150.8, 167.8;
EI-LRMS m/z 257 (M+); EI-HRMS calcd for C16H19NO2 (M+):
261.1366; ½a 2D5
ꢂ
¼ ꢀ72:0 (c 1.43, CHCl3, 91% ee). The enantiomeric
257.1416. Found: 257.1418; ½a D25
¼ ꢀ105:2 (c 1.94, CHCl3, 96%
ꢂ
excess was determined by chiral HPLC analysis (DAICEL CHIRALCEL
OD-H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR 20.4 min
[major isomer] and 22.3 min [minor isomer], detection at
254 nm).
ee). The enantiomeric excess was determined by chiral HPLC anal-
ysis (DAICEL CHIRALCEL OJ-H, hexane/2-propanol = 92:8, flow
rate: 0.5 mL/min, tR 20.4 min [major isomer] and 28.0 min [minor
isomer], detection at 254 nm).
4.2.6. 6-(3-Bromophenylamino)cyclohex-1-enecarboxylic acid
methyl ester 3f
4.2.10. 6-[(4-Methoxyphenyl)-methylamino]-cyclohex-1-
enecarboxylic acid methyl ester 3j
Colorless oil; IR (ATR):
m
3394, 2947, 2088, 1716, 1507, 1262,
Yellow oil; IR (ATR):
m
2945, 1716, 1647, 1509, 1435, 1241,
1060, 984, 771, 669 cmꢀ1
;
1H NMR (CDCl3): d 1.46–1.67 (m, 3H),
1105, 1039, 812 cmꢀ1
;
1H NMR (CDCl3): d 1.59–1.72 (m, 3H),
2.02–2.19 (m, 2H), 2.31–2.36 (m, 1H), 3.68 (broad peak (NH),
1H), 3.72 (s, 3H), 4.40–4.45 (m, 1H), 6.55–6.57 (m, 1H), 6.79–
6.81 (m, 2H), 6.99–7.03 (m, 1H), 7.15–7.16 (dd, J = 2.8 Hz, 4.8 Hz,
1H); 13C NMR (CDCl3): d 16.2, 25.7, 26.7, 45.4, 51.8, 112.0, 115.8,
120.1, 123.3, 130.5, 130.8, 143.4, 148.3, 167.0; EI-LRMS m/z 309
(M+); EI-HRMS calcd for C14H16BrNO2 (M+): 309.0364. Found:
1.84–1.91 (m, 1H), 2.13–2.22 (m, 1H), 2.25–2.69 (m, 1H), 3.67 (s,
3H), 3.75 (s, 3H), 4.62–4.69 (m, 1H), 6.80–6.86 (m, 4H), 7.09 (dt,
J = 1.6 Hz, 4.0 Hz, 1H); 13C NMR (CDCl3): d 19.2, 25.6, 25.9, 33.8,
51.6, 53.9, 55.7, 114.5 (ꢁ2), 115.1 (ꢁ2), 132.2, 142.3, 144.3,
151.6, 167.9; EI-LRMS m/z 275 (M+); EI-HRMS calcd for
C
16H21NO3 (M+): 275.1521. Found: 275.1519; ½a 2D3
¼ ꢀ65:7 (c
ꢂ
309.0373; ½a 2D3
ꢂ
¼ ꢀ54:6 (c 0.48, CHCl3, 87% ee). The enantiomeric
1.58, CHCl3, 94% ee). The enantiomeric excess was determined by
chiral HPLC analysis (DAICEL CHIRALPAK OD-H, hexane/2-propa-
nol = 9:1, flow rate: 0.5 mL/min, tR 13.1 min [major isomer] and
14.7 min [minor isomer], detection at 254 nm).
excess was determined by chiral HPLC analysis (DAICEL CHIR-
ALPAK AD-H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR
13.5 min [minor isomer] and 14.9 min [major isomer], detection
at 254 nm).
4.2.11. (1S)-(4-Methoxyphenyl)-(2-phenylcyclohex-2-enyl)-
4.2.7. 6-(2-Chlorophenylamino)cyclohex-1-enecarboxylic acid
methyl ester 3g
amine 5a
Yellow oil; IR (ATR):
m
3403, 2935, 1716, 1540, 1508, 1457,
White solid; Mp 63–64 °C; IR (ATR):
m
3420, 2945, 1715, 1646,
1236, 1039, 818 cmꢀ1
;
1H NMR (CDCl3): d 1.60–1.74 (m, 3H),
1595, 1506, 1434, 1319, 1243, 1098, 1062, 1032, 739 cmꢀ1
;
1H
2.12–2.32 (m, 3H), 3.48 (broad peak (NH), 1H), 3.74 (s, 3H), 4.35–
4.43 (m, 1H), 6.31 (dd, J = 3.2 Hz, 4.4 Hz, 1H), 6.57–6.60 (m, 2H),
6.76–6.80 (m, 2H), 7.18–7.29 (m, 3H), 7.43–7.45 (m, 2H); 13C
NMR (CDCl3): d 17.0, 26.0, 27.4, 48.9, 55.8, 114.1 (ꢁ2), 115.0
(ꢁ2), 125.5 (ꢁ2), 126.9, 128.4 (ꢁ2), 128.5, 137.3, 140.3, 141.4,
151.7; EI-LRMS m/z 279 (M+); EI-HRMS calcd for C19H21NO (M+):
NMR (CDCl3): d 1.45–1.54 (m, 1H), 1.62–1.70 (m, 2H), 1.99–2.05
(m, 1H), 2.12–2.22 (m, 1H), 2.33–2.39 (m, 1H), 3.71 (s, 3H), 4.27
(broad peak (NH), 1H), 4.50–4.58 (m, 1H), 6.60–6.64 (m, 1H),
6.86–6.88 (m, 1H), 7.13–7.17 (m, 1H), 7.19 (dd, J = 2.8 Hz, 4.8 Hz,
1H), 7.22–7.26 (m, 1H); 13C NMR (CDCl3): d 16.1, 25.7, 26.8, 45.5,
51.8, 112.2, 117.2, 119.4, 127.7, 129.1, 130.7, 143.0, 143.4, 167.0;
EI-LRMS m/z 265 (M+); EI-HRMS calcd for C14H16ClNO2 (M+):
279.1623. Found: 279.1621; ½a D23
¼ ꢀ165:4 (c 0.14, CHCl3, 97%
ꢂ
ee). The enantiomeric excess was determined by chiral HPLC anal-
ysis (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 9:1, flow rate:
0.5 mL/min, tR 10.6 min [minor isomer] and 16.5 min [major iso-
mer], detection at 254 nm).
265.0870. Found: 265.0868; ½a D23
¼ ꢀ93:7 (c 2.14, CHCl3, 90% ee).
ꢂ
The enantiomeric excess was determined by chiral HPLC analysis
(DAICEL CHIRALCEL OD-H, hexane/2-propanol = 200:1, flow rate:
0.5 mL/min, tR 23.0 min [major isomer] and 25.7 min [minor iso-
mer], detection at 254 nm).
4.2.12. (4-Chlorophenyl)-(2-phenylcyclohex-2-enyl)amine 5b
White solid; Mp 88–89 °C; IR (ATR):
m
3414, 2930, 1596, 1495,
4.2.8. 6-(2-Bromophenylamino)cyclohex-1-enecarboxylic acid
methyl ester 3h
1399, 1308, 1247, 1091, 1003, 907, 814, 799, 756, 688 cmꢀ1
;
1H
NMR (CDCl3): d 1.64–1.71 (m, 3H), 2.08–2.29 (m, 3H), 3.76 (broad
peak (NH), 1H), 4.36–4.46 (m, 1H), 6.35 (dd, J = 3.2 Hz, 4.0 Hz, 1H),
6.50–6.54 (m, 2H), 7.08–7.12 (m, 2H), 7.18–7.29 (m, 3H), 7.39–7.41
(m, 2H); 13C NMR (CDCl3): d 17.0, 25.9, 27.3, 48.1, 113.8 (ꢁ2),
121.3, 125.3 (ꢁ2), 127.1, 128.4 (ꢁ2), 129.0, 129.1 (ꢁ2), 136.7,
White solid; Mp 42–43 °C; IR (ATR):
m
3402, 2945, 1715, 1646,
1595, 1506, 1455, 1434, 1316, 1260, 1244, 1061, 740 cmꢀ1
;
1H
NMR (CDCl3): d 1.46–1.53 (m, 1H), 1.63–1.70 (m, 2H), 1.98–2.02
(m, 1H), 2.15–2.22 (m, 1H), 2.33–2.40 (m, 1H), 3.72 (s, 3H), 4.28

1756
T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
139.9, 145.6; EI-LRMS m/z 283 (M+); EI-HRMS calcd for C18H18ClN
H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR 27.0 min
[minor isomer] and 28.9 min [major isomer], detection at 254 nm).
(M+): 283.1128. Found: 283.1131; ½a 1D8
ꢂ
¼ ꢀ49:0 (c 1.15, CHCl3, 98%
ee). The enantiomeric excess was determined by chiral HPLC anal-
ysis (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 9:1, flow rate:
0.5 mL/min, tR 10.3 min [minor isomer] and 20.3 min [major iso-
mer], detection at 254 nm).
4.2.17. 6-(4-Methoxyphenylamino)-cyclohex-1-enecarboxylic
acid methoxy-methyl-amide 11
Colorless oil; IR (ATR):
m 3343, 2933, 2830, 1625, 1508, 1463,
1440, 1379, 1289, 1230, 1179, 1115, 1036, 985, 820, 728 cmꢀ1
;
1H NMR (CDCl3): d 1.64–2.08 (m, 4H), 2.12–2.23 (m, 2H), 3.15 (s,
3H), 3.64 (s, 3H), 3.73 (s, 3H), 4.35–4.41 (m, 1H), 6.15–6.17 (m,
1H), 6.60–6.63 (m, 2H), 6.73–6.76 (m, 2H); 13C NMR (CDCl3): d
18.2, 24.9, 28.3, 33.2, 49.3, 55.7, 61.1, 114.7 (ꢁ2), 115.1 (ꢁ2),
131.5, 136.2, 141.2, 152.0, 171.3; EI-LRMS m/z 290 (M+); EI-HRMS
4.2.13. 1-(2,3-Dihydro-indol-1-yl)2-phenylcyclohex-2-ene 5c
Yellow oil; IR (ATR):
m
3023, 2930, 2856, 1605, 1489, 1459,
;
1392, 1264, 740, 695 cmꢀ1
1H NMR (CDCl3): d 1.70–1.97 (m,
4H), 2.25–2.28 (m, 2H), 2.63–2.69 (m, 1H), 2.76–2.79 (m, 1H),
3.06–3.12 (m, 1H), 3.37–3.44 (m, 1H), 4.63–4.66 (m, 1H), 6.31
(dt, J = 1.6 Hz, 4.0 Hz, 1H), 6.46–6.54 (m, 2H), 6.94–6.96 (m, 1H),
7.03–7.07 (m, 1H), 7.15–7.25 (m, 3H), 7.33–7.36 (m, 2H); 13C
NMR (CDCl3): d 20.3, 24.7, 26.0, 28.1, 48.3, 50.5, 105.4, 115.8,
124.2, 125.6 (ꢁ2), 126.6, 127.2, 128.0 (ꢁ2), 129.8, 129.8, 137.4,
calcd for
C
16H22N2O3 (M+): 290.1630. Found: 290.1635;
½
a 2D1
ꢂ
¼ ꢀ19:4 (c 0.34, CHCl3, 89% ee). The enantiomeric excess
was determined by chiral HPLC analysis (DAICEL CHIRALCEL OD-
H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR 19.7 min
[minor isomer] and 22.1 min [major isomer], detection at 254 nm).
140.8, 150.8; EI-LRMS m/z 275 (M+); EI-HRMS calcd for C20H21
N
(M+): 275.1674. Found: 275.1675; ½a 1D9
¼ ꢀ152:0 (c 0.31, CHCl3,
ꢂ
4.2.18. (4-Methoxyphenyl)-(2-phenylcyclopent-2-enyl)amine
13
99% ee). The enantiomeric excess was determined by chiral HPLC
analysis (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 92:8, flow
rate: 0.5 mL/min, tR 9.2 min [minor isomer] and 10.7 min [major
isomer], detection at 254 nm).
Yellow oil; IR (ATR):
m 3588, 2929, 1509, 1242, 1048, 832, 763,
693 cmꢀ1 1H NMR (CDCl3): d 1.99–2.05 (m, 1H), 2.29–2.38 (m,
;
1H), 2.47–2.54 (m, 1H), 3.52 (broad peak (NH), 1H), 3.76 (s, 3H),
4.77–4.85 (m, 1H), 6.38 (dd, J = 2.4 Hz, 3.2 Hz, 1H), 6.58–6.62 (m,
2 H), 6.79–6.82 (m, 2H), 7.21–7.32 (m, 3H), 7.49–7.51 (m, 2H);
13C NMR (CDCl3): d 31.0, 31.5, 55.9, 59.9, 114.3 (ꢁ2), 115.0 (ꢁ2),
126.2 (ꢁ2), 127.3, 128.5 (ꢁ2), 129.8, 134.7, 142.0, 143.0, 151.9;
EI-LRMS m/z 265 (M+); EI-HRMS calcd for C18H19NO (M+):
4.2.14. 5-(4-Methoxyphenylamino)cyclopent-1-enecarboxylic
acid methyl ester 7a
Yellow oil; IR (ATR):
m
3385, 2950, 2833, 1715, 1635, 1510,
1437, 1362, 1290, 1233, 1097, 1036, 821, 748 cmꢀ1
;
1H NMR
(CDCl3): d 1.94–2.01 (m, 1H), 2.27–2.36 (m, 1 H), 2.44–2.53 (m,
1H), 2.61–2.70 (m, 1H), 3.72 (broad peak (NH), 1H), 3.74 (s, 3H),
3.75 (s, 3H), 4.59–4.63 (m, 1H), 6.63–6.67 (m, 2H), 6.77–6.81 (m,
2H), 6.99–7.01 (m, 1H); 13C NMR (CDCl3): d 31.2, 31.5, 51.6, 55.7,
59.6, 114.7 (ꢁ2), 115.5 (ꢁ2), 136.8, 141.8, 147.5, 152.5, 165.1; EI-
LRMS m/z 247 (M+); EI-HRMS calcd for C14H17NO3 (M+):
265.1467. Found: 265.1465; ½a D23
¼ þ43:7 (c 0.14, CHCl3, 96% ee).
ꢂ
The enantiomeric excess was determined by chiral HPLC analysis
(DAICEL CHIRALCEL OD-H, hexane/2-propanol = 93:7, flow rate:
0.5 mL/min, tR 11.4 min [minor isomer] and 13.7 min [major iso-
mer], detection at 254 nm).
247.1208. Found: 247.1201; ½a D20
¼ þ50:6 (c 1.35, CHCl3, 78% ee).
ꢂ
4.2.19. (4-Methoxyphenyl)-[2-(4-methoxyphenyl)cyclohex-2-
enyl]amine 15
The enantiomeric excess was determined by chiral HPLC analysis
(DAICEL CHIRALPAK AD-H, hexane/2-propanol = 9:1, flow rate:
0.5 mL/min, tR 21.6 min [major isomer] and 26.3 min [minor iso-
mer], detection at 254 nm).
Yellow oil; IR (ATR):
m
3410, 2932, 2830, 1611, 1509, 1456,
1283, 1239, 1180, 1036, 817, 737 cmꢀ1
;
1H NMR (CDCl3): d 1.59–
1.72 (m, 3H), 2.11–2.30 (m, 3H), 3.50 (broad peak (NH), 1H), 3.75
(s, 3H), 3.77 (s, 3H), 4.32–4.36 (m, 1H), 6.22 (dd, J = 3.2 Hz,
4.4 Hz, 1H), 6.56–6.62 (m, 2H), 6.76–6.83 (m, 4H), 7.35–7.39 (m,
2H); 13C NMR (CDCl3): d 17.0, 25.9, 27.5, 48.9, 55.2, 55.8, 113.7
(ꢁ2), 114.0 (ꢁ2), 115.0 (ꢁ2), 126.5 (ꢁ2), 126.8, 132.8, 136.5,
141.5, 151.7, 158.6; EI-LRMS m/z 309 (M+); EI-HRMS calcd for
4.2.15. 6-(2,3-Dihydro-indol-1-yl)cyclopent-1-enecarboxylic
acid methyl ester 7b
Yellow oil; IR (ATR):
m
2949, 2841, 1717, 1606, 1541, 1507,
1489, 1473, 1288, 1265, 1100, 754 cmꢀ1
;
1H NMR (CDCl3): d
1.91–1.98 (m, 1H), 2.19–2.28 (m, 1H), 2.47–2.64 (m, 2H), 2.89–
2.93 (m, 2H), 3.18–3.29 (m, 2H), 3.69 (s, 3H), 5.00–5.07 (m, 1H),
6.52–6.61 (m, 2H), 7.00–7.06 (m, 3H); 13C NMR (CDCl3): d 26.6,
28.1, 32.1, 47.7, 51.5, 60.1, 107.0, 116.8, 124.3, 127.1, 130.0,
135.8, 146.8, 151.0, 165.1; EI-LRMS m/z 243 (M+); EI-HRMS calcd
C
20H23NO2 (M+): 309.1729. Found: 309.1715; ½a 2D0
¼ ꢀ88:9 (c
ꢂ
0.68, CHCl3, 96% ee). The enantiomeric excess was determined by
chiral HPLC analysis (DAICEL CHIRALCEL OD-H, hexane/2-propa-
nol = 9:1, flow rate: 0.5 mL/min, tR 14.0 min [minor isomer] and
17.4 min [major isomer], detection at 254 nm).
for C15H17NO2 (M+): 243.1259. Found: 243.1255; ½a 2D0
¼ ꢀ42:0 (c
ꢂ
0.59, CHCl3, 84% ee). The enantiomeric excess was determined by
chiral HPLC analysis (DAICEL CHIRALPAK AD-H, hexane/2-propa-
nol = 97:3, flow rate: 0.5 mL/min, tR 14.1 min [minor isomer] and
15.2 min [major isomer], detection at 254 nm).
4.2.20. [2-(4-Fluoro-phenyl)-cyclohex-2-enyl]-(4-methoxy-
phenyl)amine 17
Violet oil; IR (ATR):
m
3396, 2932, 1599, 1505, 1403, 1224, 1160,
1114, 1036, 812, 778, 737 cmꢀ1
;
1H NMR (CDCl3): d 1.60–1.72 (m,
3H), 2.10–2.31 (m, 3H), 3.47 (broad peak (NH), 1H), 3.74 (s, 3H),
4.31–4.35 (m, 1H), 6.24 (dd, J = 3.2 Hz, 4.4 Hz, 1H), 6.56–6.59 (m,
2H), 6.76–6.80 (m, 2H), 6.92–6.98 (m, 2H), 7.38–7.42 (m, 2H);
13C NMR (CDCl3): d 16.8, 25.9, 27.3, 49.0, 55.7, 114.1 (ꢁ2), 114.9
(ꢁ2), 115.0 (d, J = 20.6 Hz) (ꢁ2), 127.0 (d, J = 7.4 Hz) (ꢁ2), 128.3,
136.4, 136.5 (d, J = 3.3 Hz), 141.2, 151.8, 161.9 (d, J = 244 Hz); EI-
LRMS m/z 297 (M+); EI-HRMS calcd for C19H20FNO (M+):
4.2.16. 6-(4-Methoxy-phenylamino)cyclohex-1-enecarbonitrile
9
Yellow oil; IR (ATR):
m 3368, 2946, 2217, 1510, 1464, 1232,
1039, 822, 763 cmꢀ1 1H NMR (CDCl3): d 1.60–1.86 (m, 4H),
;
2.16–2.33 (m, 2H), 3.47 (broad peak (NH), 1H), 3.76 (s, 3H), 4.03–
4.08 (m, 1H), 6.68–6.70 (m, 2H), 6.77–6.80 (m, 3H); 13C NMR
(CDCl3): d 17.2, 25.9, 27.5, 49.7, 55.7, 114.9 (ꢁ2), 115.4 (ꢁ2),
115.6, 118.7, 140.3, 147.8, 152.7; EI-LRMS m/z 228 (M+); EI-HRMS
297.1529. Found: 297.1528; ½a D22
¼ ꢀ106:5 (c 0.50, CHCl3, 97%
ꢂ
ee). The enantiomeric excess was determined by chiral HPLC anal-
ysis (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 9:1, flow rate:
0.5 mL/min, tR 10.9 min [minor isomer] and 11.8 min [major iso-
mer], detection at 254 nm).
calcd for
¼ ꢀ65:1 (c 0.32, CHCl3, 91% ee). The enantiomeric excess
was determined by chiral HPLC analysis (DAICEL CHIRALPAK AD-
C
14H16N2O (M+): 228.1263. Found: 228.1254;
½ ꢂ
a 2D3

T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
1757
4.2.21. (4-Methoxyphenyl)-(2-naphthalen-2-yl-cyclohex-
2-enyl)amine 19
128.8 (ꢁ2), 130.9, 131.1, 136.7, 141.5, 142.3, 152.2; EI-LRMS m/z
315 (M+); EI-HRMS calcd for C22H21NO (M+): 315.1623. Found:
Yellow oil; IR (ATR):
m
3403, 3053, 2931, 2828, 1763, 1508,
315.1635; ½a 2D2
¼ ꢀ56:2 (c 0.80, CHCl3, 97% ee). The enantiomeric
ꢂ
1231, 1178, 1114, 1037, 815, 748 cmꢀ1
;
1H NMR (CDCl3): d 1.68–
excess was determined by chiral HPLC analysis (DAICEL CHIRALCEL
OD-H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR 48.0 min
[major isomer] and 63.9 min [minor isomer], detection at 254 nm).
1.79 (m, 3H), 2.17–2.39 (m, 3H), 3.57 (broad peak (NH), 1H), 3.76
(s, 3H), 4.51–4.56 (m, 1H), 6.46 (dd, J = 3.2 Hz, 4.8 Hz, 1H), 6.59–
6.63 (m, 2H), 6.78–6.80 (m, 2H), 7.38–7.42 (m, 2H), 7.59–7.62
(m, 1H), 7.71–7.78 (m, 3H), 7.82–7.88 (m, 1H); 13C NMR (CDCl3):
d 17.0, 26.1, 27.5, 49.0, 55.7, 114.1 (ꢁ2), 114.9 (ꢁ2), 124.0, 124.1,
125.5, 125.9, 127.3, 127.7, 128.1, 129.1, 132.5, 133.4, 137.2,
137.6, 141.4, 151.7; EI-LRMS m/z 329 (M+); EI-HRMS calcd for
4.2.25. (4-Chloro-phenyl)-(1,3-diphenylallyl)amine 26
Yellow oil; IR (ATR):
m 3385, 1596, 1494, 1313, 814, 746,
699 cmꢀ1 1H NMR (CDCl3): d 4.13 (broad peak (NH), 1H), 5.00
;
(d, J = 6.4 Hz, 1H), 6.35 (dd, J = 6.4 Hz, 16.0 Hz, 1H), 6.51–6.55 (m,
2H), 6.59 (d, J = 16.0 Hz, 1H), 7.05–7.09 (m, 2H), 7.20–7.41 (m,
10H); 13C NMR (CDCl3): d 60.7, 114.7 (ꢁ2), 122.3, 126.5 (ꢁ2),
127.1 (ꢁ2), 127.7, 127.8, 128.6 (ꢁ2), 128.9 (ꢁ2), 129.0 (ꢁ2),
130.2, 131.3, 136.5, 141.6, 145.7; EI-LRMS m/z 319 (M+); EI-HRMS
C
23H23NO (M+): 329.1780. Found: 329.1783; ½a 1D9
¼ ꢀ169:9 (c
ꢂ
3.10, CHCl3, 98% ee). The enantiomeric excess was determined by
chiral HPLC analysis (DAICEL CHIRALCEL OD-H, hexane/2-propa-
nol = 9:1, flow rate: 0.5 mL/min, tR 13.0 min [minor isomer] and
17.6 min [major isomer], detection at 254 nm).
calcd for
C
21H18ClN (M+): 319.1128. Found: 319.1132;
½
a 2D3
ꢂ
¼ ꢀ19:3 (c 1.60, CHCl3, 96% ee). The enantiomeric excess
4.2.22. (1S)-[2-(tert-Butyl-dimethylsilanyloxymethyl)cyclohex-
2-enyl]-(4-methoxy-phenyl)-amine 21
was determined by chiral HPLC analysis (DAICEL CHIRALCEL OD-
H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR 29.9 min
[minor isomer] and 42.8 min [major isomer], detection at 254 nm).
Yellow oil; IR (ATR):
m
3394, 2928, 2855, 1509, 1462, 1230,
1164, 1043, 1004, 835, 815, 775 cmꢀ1
;
1H NMR (CDCl3): d 0.04 (s,
6H), 0.90 (s, 9H), 1.53–1.61 (m, 3H), 1.89–2.08 (m, 3H), 3.55 (broad
peak (NH), 1H), 3.74 (s, 3H), 3.86–3.91 (m, 1H), 4.13 (dd, J = 1.6 Hz,
12.8 Hz, 1H), 4.19 (dd, J = 1.6 Hz, 12.8 Hz, 1H), 5.84–5.89 (m, 1H),
6.56–6.60 (m, 2H), 6.75–6.78 (m, 2H); 13C NMR (CDCl3): d ꢀ5.3
(ꢁ2), 17.8, 18.4, 25.0, 26.0 (ꢁ3), 27.5, 48.3, 55.9, 65.4, 114.4 (ꢁ2),
114.9 (ꢁ2), 125.9, 137.8, 141.9, 151.7; EI-LRMS m/z 347 (M+); EI-
HRMS calcd for C20H33NO2Si (M+): 347.2281. Found: 347.2274;
4.2.26. 1-(1,3-Diphenylallyl)-2,3-dihydro-1H-indole 27
Yellow oil; IR (ATR):
m
3023, 1603, 1483, 1387, 1246, 1156,
1072, 1025, 966, 916, 869, 740, 695 cmꢀ1
;
1H NMR (CDCl3): d
2.95 (t, J = 8.0 Hz, 2H), 3.37–3.42 (m, 2H), 5.10 (d, J = 7.6 Hz, 1H),
6.34–6.36 (m, 1H), 6.47 (dd, J = 7.6 Hz, 16.0 Hz, 1H), 6.60–6.64
(m, 1H), 6.64 (d, J = 16.0 Hz, 1H), 6.92–6.95 (m, 1H), 7.05–7.06
(m, 1H), 7.20–7.46 (m, 10H); 13C NMR (CDCl3): d 28.3, 50.6, 64.0,
108.4, 117.5, 124.4, 126.5 (ꢁ2), 127.0, 127.2, 127.6, 127.7 (ꢁ2),
127.8, 128.5 (ꢁ2), 128.5 (ꢁ2), 130.4, 132.7, 136.6, 140.7, 151.3;
½
a 2D3
ꢂ
¼ ꢀ14:7 (c 0.75, CHCl3, 78% ee). The enantiomeric excess
was determined by chiral HPLC analysis (DAICEL CHIRALPAK AD-
H, hexane/2-propanol = 200:1, flow rate: 0.5 mL/min, tR 10.8 min
[minor isomer] and 12.7 min [major isomer], detection at 254 nm).
EI-LRMS m/z 311 (M+); EI-HRMS calcd for C23H21
N
(M+):
311.1674. Found: 311.1664; ½a D25
¼ ꢀ10:8 (c 3.32, CHCl3, 86% ee).
ꢂ
The enantiomeric excess was determined by chiral HPLC analysis
(DAICEL CHIRALCEL OD-H, hexane/2-propanol = 200:1, flow rate:
0.3 mL/min, tR 31.6 min [minor isomer] and 35.0 min [major iso-
mer], detection at 254 nm).
4.2.23. Cyclohex-2-enyl-(4-methoxyphenyl)amine 23
Colorless oil; IR (ATR):
m
3394, 3022, 2929, 2830, 1509, 1463,
;
1230, 1179, 1038, 817 cmꢀ1
1H NMR (CDCl3): d 1.56–1.73 (m,
3H), 1.87–2.05 (m, 3H), 2.84 (broad peak (NH), 1H), 3.74 (s, 3H),
3.87–3.94 (m, 1H), 5.73–5.77 (m, 1H), 5.80–5.85 (m, 1H), 6.58–
6.62 (m, 2H), 6.76–6.80 (m, 2H); 13C NMR (CDCl3): d 19.7, 25.2,
29.0, 49.0, 55.8, 114.8 (ꢁ2), 114.9 (ꢁ2), 128.8, 129.8, 141.3,
152.0; EI-LRMS m/z 203 (M+); EI-HRMS calcd for C13H17NO (M+):
4.2.27. (4-Methoxy-phenyl)-(1-phenethyl-5-phenylpent-2-
enyl)amine 29
Yellow oil; IR (ATR):
m
3025, 2925, 2853, 1509, 1455, 1237,
1178, 1035, 970, 818, 747, 699 cmꢀ1
;
1H NMR (CDCl3): d 1.75–
203.1310. Found: 203.1302; ½a D23
ꢂ
¼ ꢀ30:4 (c 0.91, CHCl3, 44% ee).
1.93 (m, 2H), 2.32–2.37 (m, 2H), 2.60–2.68 (m, 4H), 3.65–3.70
(m, 1H), 3.74 (s, 3H), 3.75 (broad peak (NH), 1H), 5.33 (dd,
J = 6.8 Hz, 15.2 Hz, 1H), 5.63 (dt, J = 15.2 Hz, 6.8 Hz, 1H), 6.48–
6.52 (m, 2H), 6.72–6.76 (m, 2H), 7.12–7.29 (m, 10H); 13C NMR
(CDCl3): d 32.2, 34.0, 35.8, 37.6, 55.7, 55.8, 114.7 (ꢁ2), 114.8
(ꢁ2), 125.7, 125.8, 128.2 (ꢁ2), 128.3 (ꢁ2), 128.4 (ꢁ2), 128.5
(ꢁ2), 130.9, 132.6, 141.7, 141.9, 151.9; EI-LRMS m/z 371 (M+); EI-
HRMS calcd for C27H29NO (M+): 371.2249. Found: 371.2258;
The enantiomeric excess was determined by chiral HPLC analysis
(DAICEL CHIRALPAK AD-H, hexane/2-propanol = 95:5, flow rate:
0.5 mL/min, tR 15.8 min [minor isomer] and 17.2 min [major iso-
mer], detection at 254 nm).
4.2.24. General procedure for the asymmetric allylic amination
of linear substrates: (1R)-(1,3-diphenylallyl)-(4-methoxy-
phenyl)amine 25
½
a 2D5
ꢂ
¼ ꢀ0:3 (c 0.32, CHCl3, 40% ee). The enantiomeric excess was
To a stirred solution of 24 (67.3 mg, 0.24 mmol), [
(0.87 mg, 0.0024 mmol), (S,RP)-Ph-DIAPHOX
0.0096 mmol), and DABCO (26.7 mg 0.24 mmol) in Et2O
(0.95 mL) at room temperature was added BSA (175 L,
g
3-C3H5PdCl]2
1a (3.7 mg,
determined by chiral HPLC analysis (DAICEL CHIRALPAK AS-H, hex-
ane/2-propanol = 9:1, flow rate: 0.5 mL/min, tR 11.9 min [major
isomer] and 16.0 min [minor isomer], detection at 254 nm).
l
0.72 mmol), and the mixture was stirred at the same temperature.
After 10 min, p-anisidine (88.6 mg, 0.72 mmol) was added, and the
resulting mixture was stirred for 24 h. After the reaction was con-
centrated under reduced pressure, the crude residue was purified
by flash column chromatography (hexane/AcOEt = 30:1) to give
25 (75.2 mg, 99% yield, 97% ee) as a pale yellow solid. Mp 99–
4.3. Determination of the absolute configuration of 3a, 5a, and
25
4.3.1. (1S,2S)-2-(4-Methoxy-phenylamino)cyclohexane-
carboxylic acid methyl ester 30
A suspension of 3a (61.8 mg, 0.24 mmol) and 20 wt % Pd(OH)2–
C (6.2 mg) in AcOEt (2.4 mL) was stirred under H2 atmosphere at
room temperature. After 4 h, the reaction mixture was filtered
through a short pad of Celite, and the resulting solution was evap-
orated under reduced pressure. The obtained residue was purified
by flash column chromatography (SiO2, hexane/AcOEt = 5:1) to
100 °C; IR (ATR):
m 3385, 1509, 1239, 1178, 1035, 968, 819, 744,
698 cmꢀ1 1H NMR (CDCl3): d 3.72 (s, 3H), 3.89 (broad peak (NH),
;
1H), 5.00 (d, J = 6.4 Hz, 1H), 6.39 (dd, J = 6.4 Hz, 15.6 Hz, 1H),
6.59–6.62 (m, 2H), 6.62 (d, J = 15.6 Hz, 1H), 6.72–6.76 (m, 2H),
7.20–7.44 (m, 10H); 13C NMR (CDCl3): d 55.7, 61.5, 114.7 (ꢁ2),
114.9 (ꢁ2), 126.5 (ꢁ2), 127.2 (ꢁ2), 127.4, 127.6, 128.5 (ꢁ2),
give 30 (52.9 mg, 85% yield) as a white solid. IR:
m 3352, 2933,

1758
T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
2856, 1730, 1509, 1448, 1370, 1240, 1168, 1121, 1038, 822 cmꢀ1
;
J = 6.0 Hz, 1H), 6.45–6.48 (m, 2H), 6.69–6.72 (m, 2H), 6.75–6.78
(m, 2H), 7.14–7.39 (m, 15H); 13C NMR (CDCl3): d 53.2, 55.5, 66.9,
114.2 (ꢁ2), 118.5 (ꢁ2), 126.4, 126.4 (ꢁ2), 127.1, 127.2 (ꢁ2),
127.5, 127.9 (ꢁ2), 128.2 (ꢁ2), 128.4 (ꢁ2), 128.5 (ꢁ2), 128.9,
132.7, 136.8, 139.9, 141.0, 143.1, 152.7; EI-LRMS m/z 405 (M+);
1H NMR (CDCl3): d 1.00–1.04 (m, 1H), 1.21–1.39 (m, 2H), 1.57–
1.67 (m, 1H), 1.73–1.77 (m, 2H), 1.92–1.98 (m, 1H), 2.14–2.19
(m, 1H), 2.24–2.30 (m, 1H), 2.90 (broad peak (NH), 1H), 3.44 (dt,
J = 4.4 Hz, 10.4 Hz, 1H), 3.60 (s, 3H), 3.73 (s, 3H), 6.59–6.62 (m,
2H), 6.72–6.76 (m, 2H); 13C NMR (CDCl3): d 24.6, 24.7, 29.0, 32.9,
50.9, 51.6, 55.5, 55.7, 114.6 (ꢁ2), 115.6 (ꢁ2), 141.2, 152.2, 175.4;
½
a 2D6
ꢂ
¼ þ1:68 (c 0.25, CHCl3). Conditions of chiral HPLC analysis:
DAICEL CHIRALPAK AD-H, hexane/2-propanol = 93:7, flow rate:
0.5 mL/min, tR 9.9 min [(S)-isomer] and 10.2 min [(R)-isomer],
detection at 254 nm).
EI-LRMS m/z 263 (M+); ½a D25
¼ þ5:8 (c 2.30, CHCl3).
ꢂ
4.3.2. (1S,2S)-2-Benzyloxycarbonylaminocyclohexane-
carboxylic acid methyl ester 316b
Acknowledgments
To a stirred solution of 30 (100.1 mg, 0.38 mmol) in CH3CN/H2O
(7.6 mL, 1:1, v/v) were added HIO4ꢃ2H2O (140 mg, 0.57 mmol) and
1 M aqueous H2SO4 (0.38 mL). The mixture was stirred for 18 h at
room temperature, and then washed with CH2Cl2 (ꢁ3). After sepa-
ration of the organic phase, the aqueous phase was brought to pH
11 by the addition of 1 M aqueous NaOH, and extracted with AcOEt
(ꢁ3). The combined organic layers were evaporated under reduced
pressure, and the obtained crude residue was used directly for the
next reaction. To a stirred solution of crude sample and pyridine
This work was supported in part by a Grant-in Aid for Encour-
agement of Young Scientist (A) from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan, and the Daiichi-
Sankyo Award in Synthetic Organic Chemistry, Japan.
References
1. For reviews, see: (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1; (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921; (c) Lu, Z.; Ma, S. Angew. Chem., Int. Ed.
2008, 47, 258.
(40
lL, 0.54 mmol) in CH2Cl2 (1.1 mL) at 0 °C was added benzyl
chloroformate (60
l
L, 0.40 mmol) and the reaction mixture was
2. For representative examples, see: (a) Hayashi, T.; Yamamoto, A.; Ito, Y.;
Nishioka, E.; Miura, H.; Yanagi, K. J. Am. Chem. Soc. 1989, 111, 6301; (b) Trost, B.
M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089; (c) Evans, D. A.; Campos, K. R.;
Tedrow, J. S.; Michael, F. E.; Gagné, M. R. J. Org. Chem. 1999, 64, 2994; (d) Trost,
B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999, 121, 3057; (e) You, S.-L.; Zhu, X.-Z.; Lou,
Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471; (f) Zablocka, M.;
Koprowski, M.; Donnadieu, B.; Majoral, J.-P.; Achard, M.; Buono, G. Tetrahedron
Lett. 2003, 44, 2413; (g) Mori, M.; Nakanishi, M.; Kashijima, D.; Sato, Y. J. Am.
Chem. Soc. 2003, 125, 9801; (h) Uozumi, Y.; Tanaka, H.; Shibatomi, K. Org. Lett.
2004, 6, 281; (i) Faller, J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633; (j) Lyubimov, S. E.;
Davankov, V. A.; Gavrilov, K. N. Tetrahedron Lett. 2006, 47, 2721; (k) Kloetzing,
R. J.; Knochel, P. Tetrahedron: Asymmetry 2006, 17, 116; (l) Lam, F. L.; Au-Yeung,
T. T. L.; Cheung, H. Y.; Kok, S. H. L.; Lam, W. S.; Wong, K. Y.; Chen, A. S. C.
Tetrahedron: Asymmetry 2006, 17, 497; (m) Trost, B. M.; Fandrick, D. R.;
Brodmann, T.; Stiles, D. T. Angew. Chem., Int. Ed. 2007, 46, 6123; (n) Liu, D.; Xie,
F.; Zhang, W. J. Org. Chem. 2007, 72, 6992; (o) Imamoto, T.; Nishimura, M.;
Koide, A.; Yoshida, K. J. Org. Chem. 2007, 72, 7413; (p) Johannesen, S. A.; Glegola,
K.; Sinou, D.; Framery, E.; Skrydstrup, T. Tetrahedron Lett. 2007, 48, 3569; (q)
Shi, C.; Ojima, I. Tetrahedron 2007, 63, 8563; (r) Fukazawa, S.; Yamamoto, M.;
Hosaka, M.; Kikuchi, S. Eur. J. Org. Chem. 2007, 5540; (s) Birkholz, M.-N.;
Dubrovina, N. V.; Shuklov, I. A.; Holz, J.; Paciello, R.; Waloch, C.; Berit, B.;
Börner, A. Tetrahedron: Asymmetry 2007, 18, 2055; (t) Gavrilov, K. N.; Benetsky,
E. B.; Grishina, T. B.; Zheglov, S. V.; Rastorguev, E. A.; Petrovskii, P. V.; Macaev, F.
Z.; Davankov, V. A. Tetrahedron: Asymmetry 2007, 18, 2557; (u) Xie, F.; Liu, D.;
Zhang, W. Tetrahedron Lett. 2008, 49, 1012; (v) Gavrilov, K. N.; Zheglov, S. V.;
Vologzhanin, P. A.; Maksimova, M. G.; Safronov, A. S.; Lyubimov, S. E.;
Davankov, V. A.; Schäffner, B.; Börner, A. Tetrahedron Lett. 2008, 49,
3120.
stirred for 4 h at room temperature. The reaction mixture was di-
luted with AcOEt and washed with 1 M aqueous HCl and brine,
and then dried over Na2SO4. After concentration in vacuo, the ob-
tained residue was purified by flash column chromatography
(SiO2, hexane/AcOEt = 5:1) to give (S,S)-31 (56.3 mg, 2 steps 51%
yield) as a white solid. Conditions of chiral HPLC analysis: DAICEL
CHIRALPAK AD-H, hexane/2-propanol = 9:1, flow rate: 0.5 mL/min,
tR 33.2 min [(S,S)-isomer] and 35.2 min [(R,R)-isomer], detection at
254 nm).
4.3.3. (1S)-(2-Phenylcyclohex-2-enylamino)acetic acid ethyl
ester 326a
To a stirred solution of 5a (74.3 mg, 0.26 mmol) in CH3CN/H2O
(7.4 mL, 1:1, v/v) were added HIO4ꢃ2H2O (96.6 mg, 0.40 mmol)
and 1 M aqueous H2SO4 (0.26 mL). The mixture was stirred for
18 h at room temperature, and then washed with CH2Cl2 (ꢁ3).
After separation of the organic phase, the aqueous phase was
brought to pH 11 by the addition of 1 M aqueous NaOH, and was
extracted with AcOEt (ꢁ3). The combined organic layers were
evaporated under reduced pressure, and the obtained crude resi-
due was used directly for the next reaction. To a stirred solution
3. For representative examples, see: (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 15164; (b) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14272; (c) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew.
Chem., Int. Ed. 2004, 43, 2426; (d) Lipowsky, G.; Helmchen, G. Chem. Commun.
2004, 116; (e) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y. Org. Lett.
2004, 6, 4631; (f) Welter, C.; Dahnz, A.; Bruner, B.; Steiff, S.; Dübon, P.;
Helmchen, G. Org. Lett. 2005, 7, 1239; (g) Polet, D.; Alexakis, A. Org. Lett. 2005, 7,
1621; (h) Weihofen, R.; Tverskoy, O.; Helmuchen, G. Angew. Chem., Int. Ed.
2006, 45, 5546; (i) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Harwig, J. F. Org.
Lett. 2007, 9, 3949; (j) Lee, J. H.; Shin, S.; Kang, J.; Lee, S.-g. J. Org. Chem. 2007, 72,
7443.
4. Ru catalyst: (a) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi,
S. J. Am. Chem. Soc. 2001, 123, 10405; Ni catalyst: (b) Bekowitz, D. B.;
Maiti, G. Org. Lett. 2004, 6, 2661; Enantiospecific allylic amination using Rh
catalyst: (c) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761; (d) Evans, P. A.; Robinson, J. E.; Moffett, K. Org. Lett. 2001, 3,
3269.
of crude sample and triethylamine (20
(0.5 mL) at room temperature was added ethyl bromoacetate
(10 L, 0.10 mmol), and the reaction mixture was stirred for 3 h
at the same temperature. After concentration of the reaction mix-
ture in vacuo, the residue was purified by flash column chromatog-
raphy (SiO2, hexane/AcOEt = 10:1 to 7:1) to give (S)-32 (16.7 mg, 2
steps 24% yield) as yellow oil. Conditions of chiral HPLC analysis:
DAICEL CHIRALPAK AD, hexane/2-propanol = 98:2, flow rate:
0.4 mL/min, tR 19.0 min [(S)-isomer] and 22.8 min [(R)-isomer],
detection at 254 nm).
lL, 0.12 mmol) in THF
l
4.3.4. (1R)-Benzyl-(1,3-diphenylallyl)-(4-methoxyphenyl)amine
33
5. For reviews on phosphine oxide preligands in transition metal catalysis, see: (a)
Dubrovina, N. V.; Börner, A. Angew. Chem., Int. Ed. 2004, 43, 5883; (b)
Ackermann, L. Synthesis 2006, 1557; (c) Ackermann, L. Synlett 2007, 507; (d)
Nemoto, T.; Hamada, Y. Chem. Rec. 2007, 7, 150.
To a stirred solution of 25 (31.0 mg, 0.10 mmol) in DMF (0.5 mL)
at room temperature were added K2CO3 (20.4 mg, 0.15 mmol) and
benzyl bromide (20 lL, 0.15 mmol). After being stirred for 18 h, the
6. (a) Nemoto, T.; Masuda, T.; Akimoto, Y.; Fukuyama, T.; Hamada, Y. Org. Lett.
2005, 7, 4447; (b) Nemoto, T.; Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda,
T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9, 927.
7. For other asymmetric reactions using transition metal–DIAPHOX catalyst
systems, see: (a) Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.; Hatano, K.;
Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690; (b) Nemoto, T.; Masuda, T.;
Matsumoto, T.; Hamada, Y. J. Org. Chem. 2005, 70, 7172; (c) Nemoto, T.; Fukuda,
T.; Matsumoto, T.; Hitomi, T.; Hamada, Y. Adv. Synth. Catal. 2005, 347, 1504; (d)
Nemoto, T.; Jin, L.; Nakamura, H.; Hamada, Y. Tetrahedron Lett. 2006, 47, 6577;
reaction was diluted with Et2O, washed with water and brine, and
then dried over Na2SO4. After concentration in vacuo, the obtained
residue was purified by flash column chromatography (SiO2, hex-
ane/AcOEt = 20:1) to give (R)-33 (37.7 mg, 95% yield) as a colorless
oil. IR:
1158, 1043, 973, 805, 747, 696 cmꢀ1
3H), 4.43 (d, J = 16.8 Hz, 1H), 4.52 (d, J = 16.8 Hz, 1H), 5.45 (d,
m
3413, 3026, 2830, 1599, 1507, 1450, 1421, 1285, 1215,
;
1H NMR (CDCl3): d 3.68 (s,

T. Nemoto et al. / Tetrahedron: Asymmetry 19 (2008) 1751–1759
1759
(e) Nemoto, T.; Sakamoto, T.; Matsumoto, T.; Hamada, Y. Tetrahedron Lett. 2006,
47, 8737; (f) Nemoto, T.; Sakamoto, T.; Fukuyama, T.; Hamada, Y. Tetrahedron
Lett. 2007, 48, 4977; (g) Nemoto, T.; Harada, T.; Matsumoto, T.; Hamada, Y.
Tetrahedron Lett. 2007, 48, 6304; (h) Jin, L.; Nemoto, T.; Nakamura, H.; Hamada,
Y. Tetrahedron: Asymmetry 2008, 19, 1106.
compared with the case using 3 equiv of BSA to the electrophile (1 equiv to p-
anisidine).
11. For mechanistic studies on the catalyst structure of the Pd–DIAPHOX catalyst
system, see Ref. 7b.
12. When the asymmetric allylic amination of 2 was performed using N-tosyl-
protected p-anisidine as a nucleophile [conditions: Pd catalyst (2 mol %), (S,RP)-
1a (4 mol %), BSA (3 equiv), nucleophile (3 equiv), CH3CN, 0 °C], the product
was obtained with lower enantioselectivity (2 h, 92% yield, 61% ee.).
13. When the asymmetric allylic amination of 24 with p-anisidine was performed
using catalytic amount of DABCO, there was a decrease in reactivity without
significant loss of enantioselectivity [conditions: Pd catalyst (2 mol %), (S,RP)-
1a (4 mol %), BSA (3 equiv), p-anisidine (3 equiv), Et2O, rt]. DABCO = 100 mol %,
17 h, 99%, 97% ee. DABCO = 10 mol %, 24 h, 75%, 95% ee. DABCO = 5 mol %, 24 h,
29%, 92% ee. Although the role of DABCO is unknown at the present stage, these
data indicate that DABCO would interact with p-anisidine, rather than the Pd
catalyst, resulting in an increase in both reactivity and enantioselectivity.
14. Partial decarboxylative decomposition occurred when asymmetric allylic
amination of 2 or 4 with p-anisidine was performed in the presence of DABCO.
15. Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Alsters, P. L.; van
Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006, 47, 8109.
8. There are only a few examples of transition metal-catalyzed asymmetric allylic
amination using aromatic amine nucleophiles, see: Pd catalyst: (a) Dong, Y.;
Teesdale-Spittle, P.; Hoberg, J. O. Tetrahedron Lett. 2005, 46, 353; Ir catalyst: (b)
Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797; (c)
Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093; (d) Shashank, S.;
Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 11770; (e)
Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129,
7508.
9. For examples of non-asymmetric reactions, see: (a) Yang, S.-C.; Hung, C.-W. J.
Org. Chem. 1999, 64, 5000; (b) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.;
Shiga, N. J. Am. Chem. Soc. 2001, 123, 9525; (c) Ozawa, F.; Okamoto, H.;
Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002,
124, 10968; (d) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2007,
129, 14172; (e) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.; Ohshima, T.;
Mashima, K. Org. Lett. 2007, 9, 3371.
10. The ratio of p-anisidine and BSA affected the yield and enantioselectivity of the
reactions when using 2 and 4. Although both reactions proceeded using 0.5 or
1 equiv of BSA to the electrophile, there was a decrease in enantioselectivity
16. For the conditions of chiral HPLC analysis, see Section 4.
17. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman,
L. M. J. Org. Chem. 1999, 64, 5575.