342
Chemistry Letters Vol.37, No.3 (2008)
Asymmetric 1,3-Dipolar Cycloaddition Reaction of Azomethine Imines to Allyl Alcohol
Tomomitsu Kato, Shuhei Fujinami, Yutaka Ukaji,ꢀ and Katsuhiko Inomataꢀ
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa 920-1192
(Received December 4, 2007; CL-071345; E-mail: inomata@cacheibm.s.kanazawa-u.ac.jp)
Table 1. The asymmetric 1,3-dipolar cycloaddition of azomethine
imine 2a to allyl alcohol (1)
The asymmetric 1,3-dipolar cycloaddition of azomethine
imines to allyl alcohol was achieved by utilizing diisopropyl
(R,R)-tartrate as a chiral auxiliary to afford the corresponding
optically active trans-pyrazolidines with excellent regio-, dia-
stereo-, and enantioselectivities.
Entry
R12M1
R2M2X
Solvent
T/ꢁC Yield/%a ee/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Et2Zn
Et2Zn
Et2Zn
n-Bu2Mg n-BuMgBr
n-Bu2Mg n-BuMgCl
n-Bu2Mg n-BuMgI
n-Bu2Mg n-BuMgBr
EtZnCl
EtZnI
n-BuMgBr
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
25
25
25c
25
25
25
25
25
25
25
25
25
80
25
80
97
—
—
3
23
15
15
20
28
5
—
—
61
79
81
62
84
77
47
77
62
90
88
92
88
90
The development of 1,3-dipolar cycloaddition provided one
of the most powerful strategies for the enantioselective construc-
tion of 5-membered heterocycles.1 Considerable progress has
been made in the asymmetric 1,3-dipolar cycloaddition of nitro-
nes and nitrile oxides which contain oxygen, while the cycload-
dition of 1,3-dipoles with two nitrogen atoms were still limited.2
We have already reported asymmetric 1,3-dipolar cycloaddition
of nitrile oxides and nitrones utilizing tartaric acid ester as a
chiral auxiliary.3,4 Herein, we wish to describe an asymmetric
1,3-dipolar cycloaddition of azomethine imines to allyl alcohol
utilizing tartaric acid ester as a chiral auxiliary.
n-Bu2Mg n-BuMgBr Cl(CH2)2Cl
n-Bu2Mg n-BuMgBr
n-Bu2Mg n-BuMgBr
n-Bu2Mg n-BuMgBr
n-Bu2Mg n-BuMgBr
Et2O
THF
DME
CH3CN
10
5
15
66
23
64
53
n-Bu2Mg n-BuMgBr
C2H5CN
aIsolated yields. bEnantioselectivities were determined by HPLC analysis
(Daicel Chiralcel OD-H). cThe reaction time was 3 d.
First the 1,3-dipolar cycloaddition of 1-benzylidene-3-oxo-
pyrazolidin-1-ium-2-ide (2a) was examined in CH2Cl2 at rt.
When allyl alcohol (1) was treated with equimolar amount of di-
ethylzinc, diisopropyl (R,R)-tartrate [(R,R)-DIPT], and ethylzinc
halide, zinc-bridging intermediate 3 (M1 = M2 = Zn) would be
formed and the subsequent 1,3-dipolar cycloaddition was antici-
pated to proceed in a similar manner in the case of 1,3-dipolar
cycloaddition of nitrones.4a,4d In this case, however, such 1,3-di-
polar cycloaddition did not occur (Table 1, Entries 1 and 2). It
was found that a magnesium-mediated system instead of the
zinc-mediated system was effective to realize the 1,3-dipolar cy-
cloaddition; 1 was successively treated with dibutylmagnesium,
(R,R)-DIPT, butylmagnesium bromide, and 2a to give the corre-
sponding trans-pyrazolidine 4a in 23% yield with enantioselec-
tivity of 79% ee (Entry 4) with complete regio- and diastereose-
lectivities. Halogens in Grignard reagents did not influence so
much on the enantioselectivity (Entries 4–6). The effect of
solvent was next examined. In halogenated solvents, enantio-
selectivities were not altered much (Entries 4, 7, and 8). The fact
that rather polar THF showed higher enatioselectivity among
ethereal solvents (Entries 9–11) prompted us to use other polar
solvents. Product 4a was not obtained by using DMF and
DMSO, while nitriles were found to be solvent of choice to re-
alize excellent enantioselectivities (Entries 12 and 14). When
the reaction temperature was raised to accelerate the cycloaddi-
tion, the chemical yields were improved without remarkable de-
crease of enantioselectivities (Entries 12–16). In CH3CN, the cy-
cloadduct was obtained in 66% yield with the enantioselectivity
of 88% ee. The big difference was not observed in chemical
yields and enantioselectivities when the reaction was carried
out in CH3CN and C2H5CN.
The asymmetric cycloaddition of several azomethine imines
2 to allyl alcohol (1) was performed in CH3CN at 80 ꢁC (eq 2) as
shown in Table 2. Aryl-substituted azomethine imines 2a–2f re-
alized high enantioselectivities (Entries 1–6). The cycloaddition
of pentyl- and cyclohexyl-substituted azomethine imines 2g and
2h proceeded in moderate stereoselective manners (Entries 7 and
8), while t-butyl-substituted azomethine imine 2i resulted in high
enantioselectivity (Entry 9).
R
N
1) n-Bu Mg (1.0 equiv.)
O
2
N
O
H
4)
2) (R,R)-DIPT
(1.0 equiv.)
Ph
2
(2)
N N
(1.0 equiv.)
N
O
OH
N
H
4)
OH
1
1
1) R
M
(1.0 equiv.)
3) n-BuMgBr
80 °C, 2 d
in CH CN
3
2
R
2a
2) (R,R)-DIPT (1.0 equiv.)
(1.0 equiv.)
4
(1.0 equiv.)
1
OH
Ph
2
2
3) R M X (1.0 equiv.)
in solvent
T °C, 2 d
Next, in order to make the procedure simpler, only the
Grignard reagent was used as a magnesium source instead of di-
butylmagnesium. It is well known that dibutylmagnesium could
be generated from 2 equivalents of butylmagnesium bromide ac-
companied by generation of MgBr2. To a mixture of allyl alco-
hol (1) and (R,R)-DIPT were added 3 equivalents of butylmagne-
sium bromide and azomethine imine 2a successively (eq 3). Sur-
1
(1)
i
O
O Pr
X
O
N
2
O
M
N
H
N
N
O
1
OH
O
M
i
Ph
O
O Pr
4a
3
O
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