Catalytic asymmetric intramolecular hydroamination of aminoalkenes

Article abstract of DOI:10.1016/j.tetlet.2007.07.117

Asymmetric intramolecular cyclization of aminoalkenes was catalyzed by a catalytic amount of n-butyllithium, diisopropylamine, and a newly designed chiral bisoxazoline in toluene to produce kinetically controlled exo-cyclized amines with up to 91% ee quan

Full text of DOI:10.1016/j.tetlet.2007.07.117

Tetrahedron Letters 48 (2007) 6648–6650
Catalytic asymmetric intramolecular hydroamination
of aminoalkenes
Tokutaro Ogata, Atsushi Ujihara, Susumu Tsuchida, Tomoko Shimizu,
Atsunori Kaneshige and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 26 June 2007; revised 12 July 2007; accepted 19 July 2007
Available online 27 July 2007
Abstract—Asymmetric intramolecular cyclization of aminoalkenes was catalyzed by a catalytic amount of n-butyllithium, diisopro-
pylamine, and a newly designed chiral bisoxazoline in toluene to produce kinetically controlled exo-cyclized amines with up to 91%
ee quantitatively.
Ó 2007 Elsevier Ltd. All rights reserved.
Nitrogen containing chiral compounds are of impor-
tance and interest from the view points of biological
R
R
R
R
(
)n
N
H
( )n
N
H
( )n
N
N
1
2
+
+
activity as well as utility in synthetic chemistry. Asym-
metric synthesis of these compounds has been the target
of considerable enthusiastic efforts. Although brilliant
successes have been reported by using the methodologies
of asymmetric alkylation and hydrogenation of C–N
1
5
6
H
Li
Bu-Li
X-Li
Bu-H
X-H
R
3
,4
R
double bonds, approaches toward catalytic asymmet-
ric amination of C–C double bonds has just been started
recently. Of these approaches, asymmetric conjugate
amination of C–C double bonds that are activated by
an electron-withdrawing group has met some successes
as has been shown by the reaction of lithium amide as
(
)n
N
Li
( )n
N
( )n
Li
2
3
4
Scheme 1. Intramolecular hydroamination via lithium amide.
5
,6
a nitrogen nucleophile. On the other hand, direct ami-
7
,8
nation of simple C–C double bonds that are not acti-
asymmetric conversion of 2 to 3 and 4. This scheme,
however, involves some problems in that stoichiometric
conversion of 1 to 2 suggests no agents present for pro-
tonation of 3 and 4. Another problem is difficulty in the
conversion of N–Li 2 to C–Li 3 and 4 due to unfavor-
able acid–base equilibrium.
9
vated and extension to an asymmetric reaction have
remained in relatively undeveloped stage. We have
already reported the chiral ligand-controlled asymmetric
conjugate amination reaction of lithium amides with
1
0
enoates. As a next generation of the studies, we
describe the lithium-catalyzed asymmetric intramole-
cular amination of aminoalkenes.
We began our studies by treating 1a with 1.2 equiv of
n-butyllithium in the presence of 1.5 equiv of established
i-PrBox ligand 7a in toluene at À60 °C for 5 h (Scheme
2, Fig. 1, Table 1, entry 1). The product 5a was obtained
in 6% yield along with recovery of 1a unchanged.
Although the yield was poor as we had expected, the
enantioselectivity was as fair as 54% ee. This low conver-
sion problem was partially solved by using catalytic
amounts of butyllithium and 7a to give 5a with 74%
ee in 22% yield at À60 °C, and with 63% ee quantita-
tively at room temperature (entries 2 and 3). Then, we
The reaction of lithium amide 2 derived from aminoalk-
ene 1 by lithiation gives 3 and 4 via exo-and endo-cycli-
zation, respectively (Scheme 1). Protonation of 3 and 4
completes the hydroamination of 1 to give 5 and 6. A
chiral ligand for lithium offers a chance to realize the
*
Corresponding author. Tel.: +81 75 753 4553; fax: +81 75 753
604; e-mail: tomioka@pharm.kyoto-u.ac.jp
4
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.117

T. Ogata et al. / Tetrahedron Letters 48 (2007) 6648–6650
6649
bulkier t-Bu group, in place of i-Pr, on the oxazoline
ring worst effected the amination to need higher temper-
ature to complete the reaction, giving 5a with poor 31%
i
-PrBox 7a
NHMe
NMe
n
-BuLi
DIA
2
ee (entry 1). Replacement of dimethyl group (R ) with
toluene
temp, 5 h
diethyl group, 7c, did not realize higher selectivity as
well as reactivity (entry 2). It is interesting to find that
one methylene interval between oxazoline skeleton and
bulky appendage (7d,e) is important to effect higher
enantioselectivity of 84% and 78% ee (entries 3 and 4).
New chiral Box 7f bearing a neopentyl group on the
oxazoline, however, gave 5a with decreased 75% ee
1
a
5a
Scheme 2. Intramolecular hydroamination of 1a via lithium amide.
R2 R2
O
O
O
O
O
O
(entry 5).
N
N
N
N
N
N
H
H
H
H
R1
R1
2
Further approach toward the better Box ligand was the
modification of i-Pr group of 7a. Among two new Box
ligands prepared, 7g was better than 7h to give 5a with
81% ee (entries 6 and 7). New ligand 7i of much more
rigid skeleton gave 5a with 62% ee (entry 8). The stereo-
chemistry of 7 and the absolute configurations of 5a pro-
duced by the action of the corresponding 7 are in good
relationships without any exception.
7g
7h
1
7a: R = i-Pr, R = Me
1
2
b: R = t-Bu, R = Me
c: R = i-Pr, R = Et
d: R = i-PrCH , R = Me
e: R = c-HexCH , R = Me
O
O
1
2
1
2
N
N
2
1
2
2
1
2
f: R = t-BuCH , R = Me
7i
2
Figure 1. Chiral bisoxazolines (Box) 7.
Under the established conditions of 0.2 equiv each of
butyllithium and DIA, and 0.4 equiv of 7, the catalytic
asymmetric amination of 1b was examined (Table 3).
exo-Cyclized five-membered 5b was obtained regioselec-
tively and % ee reached to 91% by using newly designed
Table 1. Intramolecular amination of 1a giving (S)-5a
Entry BuLi DIA 7a Temperature Yield ee
equiv) (equiv) (equiv) (°C) (%)
(
(%)
1
2
3
4
5
1.2
0.2
0.1
0.2
0.2
0
0
0
0.2
0.2
1.5
0.4
0.2
0
À60
À60
rt
6
22
99
0
54
74
63
7h (entry 8). It is noteworthy that the reaction was
catalyzed by 0.05 equiv each of butyllithium, DIA, and
0.1 equiv of 7h to give (R)-5b with 91% ee quantitatively
(entry 9). It is also important to note that only exo-cyc-
lized five-membered 5b was obtained without any detec-
tion of endo-cyclized six-membered 6b.
À60
0.4
À60
99
71
examined effect of diisopropylamine (DIA) as an exter-
nal protonating agent. The reaction with 0.2 equiv of
butyllithium and 0.2 equiv of DIA did not proceed at
À60 °C for 5 h, resulting in recovery of 1a (entry 4).
However, further addition of 0.4 equiv of 7a promoted
the reaction to give (S)-5a with 71% ee quantitatively
Contrary to the selective formation of exo-product 5b
under asymmetric reaction conditions in toluene, a mix-
ture of 5b and endo-cyclized 6b was obtained in 94% and
5% isolated yields, respectively, when the reaction was
conducted in THF for 15 min (Scheme 3). The same
reaction gave 5b and 6b in 64% and 34% yields after
(
entry 5). This indicates that protonation of 3 or 4 is
required to proceed the reaction, and a coordinating
agent for lithium activates lithium amide 2 to afford 3
or 4. Regioselective production of exo-cyclized six-mem-
bered 5a suggests the kinetically controlled exo-cycliza-
tion to give 3 in preference to endo-attack.
5
h. The reaction for 24 h gave 5b and 6b in the reversed
Table 3. Catalytic asymmetric intramolecular amination of 1b
Box 7 (0.4 equiv)
NHMe
n
-BuLi (0.2 equiv)
DIA (0.2 equiv)
NMe
Ph
Asymmetric amination of 1a was further examined
under the catalysis of known chiral bisoxazolines 7a–e
(
Fig. 1, Table 2). It became apparent that 7b bearing a
toluene
1
b
Ph
5b
–
60 °C, 5 h
a
Table 2. Catalytic asymmetric amination of 1a giving 5a
Entry
7
Yield (%)
ee (%)
R/S
Entry
7
Temperature
Time
(h)
Yield
(%)
ee
(%)
R/S
1
2
3
4
5
6
7
8
a
b
c
d
e
f
99
89
99
99
99
99
99
98
99
98
84
19
84
79
76
71
66
91
91
86
S
S
S
S
S
S
S
R
R
R
(
°C)
1
2
3
4
5
6
7
8
b
c
d
e
f
rt
5
27
5
5
5
5
15
22
99
99
97
92
90
25
91
54
31
62
84
78
75
81
60
62
S
S
S
S
S
S
R
R
À60
À60
À60
À60
À60
À60
À60
g
h
h
i
g
h
i
a
9
10
a
a
The reaction was conducted with 0.4 equiv of 7, 0.2–0.4 equiv of
The reaction was carried out using 0.1 equiv of 7h, 0.05 equiv each of
butyllithium and 0.2 equiv of DIA at À60 °C.
butyllithium and DIA.

6
650
T. Ogata et al. / Tetrahedron Letters 48 (2007) 6648–6650
4. (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.;
n
-BuLi (0.1 equiv)
NMe
DIA (0.15 equiv)
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1b
5b
+
THF
–
78 °C to rt
5 min
6
5%
b
1
94%
65%
32%
5
h
34%
67%
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n
-BuLi (0.4 equiv)
DIA (0.6 equiv)
6
b
b
5b
9%
+
+
6b
87%
THF
78 °C to rt, 15 h
–
n
-BuLi (0.4 equiv)
DIA (0.2 equiv)
5
5b
racemic-6b
9
1% ee
THF
11%, 25% ee
80%
–
78 °C to 50 °C, 3 h
Scheme 3. Hydroamination of 1b and equilibrium in THF.
7
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fact, treatment of 6b under the amination conditions
in THF gave 5b in 9% yield along with recovery of 6b.
Similarly, treatment of 5b with 91% ee gave 5b with
decreased 25% ee in 11% yield and racemic-6b in 80%
yield. Attempted isomerization of racemic 5b under the
asymmetric conditions in toluene gave back 5b
unchanged probably because of difficulty in lithiation.
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in the catalytic asymmetric reaction in toluene.
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In conclusion, we have developed lithium-catalyzed
asymmetric hydroamination of aminoalkenes by using
a chiral external Box ligand. Kinetically controlled reac-
tion is operative in preference to thermodynamic equi-
librium. Since the present procedure is simple, further
application is promisingly broad.
8
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1
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This research was supported by the 21st Century COE
Program ‘Knowledge Information Infrastructure for
Genome Science’ and a Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular
Transformations’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. T.O.
thanks JSPS for fellowship.
1
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