C3-Symmetric chiral trisimidazoline: The role of a third imidazoline and its application to the nitro Michael reaction and the α-amination of β-ketoesters

Article abstract of DOI:10.1016/j.tet.2011.05.005

We describe the necessity of the C₃-symmetry and the role of a third imidazoline of trisimidazoline 3, which was recently developed by us as a new entry of organocatalyst. The utility of 3 as a Br?nsted base catalyst in the nitro Michael reaction and the α-amination of β-ketoesters was shown, and the recyclability of the catalyst was also demonstrated.

Full text of DOI:10.1016/j.tet.2011.05.005

Tetrahedron 67 (2011) 4862e4868
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C3-Symmetric chiral trisimidazoline: the role of a third imidazoline and its
application to the nitro Michael reaction and the
a
-amination of
b
-ketoesters
*
Kenichi Murai, Shunsuke Fukushima, Akira Nakamura, Masato Shimura, Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University 1-6, Yamadaeoka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the necessity of the C3-symmetry and the role of a third imidazoline of trisimidazoline 3,
which was recently developed by us as a new entry of organocatalyst. The utility of 3 as a Brønsted base
Received 10 March 2011
Received in revised form 2 May 2011
Accepted 3 May 2011
catalyst in the nitro Michael reaction and the
a
-amination of
b-ketoesters was shown, and the re-
cyclability of the catalyst was also demonstrated.
Available online 10 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
C3-Symmetry
Imidazoline
Organocatalyst
Asymmetric reaction
1. Introduction
organocatalysts. However, the necessity of the C3-symmetry and
the role of the third imidazoline still remained to be clarified,
though these points were very intriguing.
The design of a new catalyst for asymmetric reactions is one of
the key challenges and a highly important task in organic chem-
istry.1 In the design of a new catalyst scaffold, molecular symmetry
plays one of the powerful guidelines. It often simplifies the tran-
sition states and reduces the number of the diastereomeric reaction
sites to produce a favorable effect for enantioselectivity. Therefore,
C2-symmetric molecules have been widely found in both chiral li-
gands for metal catalyzed reactions and asymmetric organo-
catalysts.2 Compared to C2-symmetric molecules, the studies on
utilization of threefold symmetric molecules, C3-symmetric mole-
cules, are less commonly appeared, but various C3-symmetric
molecules were interestingly developed for chiral ligands in metal
catalyzed reactions.3,4 Their appealing structures have also been
applied to molecular recognitions and material sciences as well as
chiral ligands. However, there are very few reports on their utili-
zation as asymmetric organocatalysts.5
NO2
Ar
O
O
O
trisimidazoline 3
O
OMe
NO2
H
up to >20:1 dr
up to 96% ee
OMe
Ar
Ph
Ph
Ph
Ph
NH
N
NH
H
N
N
N
Ph
Ph
H
N
N
N
HN
Ph
Ph
Ph
Ph
N
HN
Ph
Ph
1
2
3
In this context, we have recently reported a C3-symmetric chiral
trisimidazoline 3 as a new entry of organocatalyst.6,7 We evaluated
monoimidazoline 1, bisimidazoline 2, and trisimidazoline 3 as
Brønsted base catalysts8 for the enantioselective conjugate addition
Fig. 1. Imidazoline catalysts 1e3 and nitro Michel reaction catalyzed by 3.
In this paper, we describe the necessity of the C3-symmetry of
trisimidazoline 3 based on the study comparing the reactivity and
the selectivity between trisimidazoline 3 and bisimidazoline 2. In
addition, to demonstrate the utility of 3 as a novel Brønsted base
of
a
-substituted
b
-ketoesters to nitroolefins and found that C3-
was the most effective
symmetric chiral trisimidazoline
3
(Fig. 1). The newly developed trisimidazoline 3 was regarded as
a pioneering successful example of C3-symmetric molecules for
catalyst, the substrate scope of the nitro Michael reaction of
ketoesters9,10 and the application to the asymmetric
-amination of
-ketoesters11 with di-tert-butyl azodicarboxylate are described.
The recyclability of catalyst 3 was also investigated. These detailed
b-
a
b
* Corresponding author. E-mail address: fujioka@phs.osaka-u.ac.jp (H. Fujioka).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.005

K. Murai et al. / Tetrahedron 67 (2011) 4862e4868
4863
studies about 3 are valuable because C3-symmetric trisimidazoline
3 possess a novel scaffold achieving the first highly enantioselective
reaction using imidazolines as organocatalysts.
2. Results and discussion
2.1. The study on the necessity of C3-symmetry
In our previous report, the three imidazoline catalysts, such as
monoimidazoline 1, bisimidazoline 2, and trisimidazoline 3, were
evaluated in the nitro Michael reaction of the methyl 2-oxocyclo-
pentanecarboxylate (4a) to the b-nitrostyrene (5a). The results are
again listed in Table 1. Thus, monoimidazoline 1 produced an al-
most racemic product in 29% yield (entry 1, 1% ee). In the case of C2-
symmetric bisimidazoline 2, the yield and the diastereoselectivity
of the product 6a were good, but the enantioselectivity was mod-
erate (entry 2, 61% ee). The C3-symmetric trisimidazoline 3 was
found to provide the best yield with good diastereo- and enantio-
selectivity (entry 3, 89% ee). Additionally, an increase in the loading
of 2 and a reduction of 3 did not have a significant influence on the
selectivity: 7.5 mol % of 2 afforded 6a in 67% ee (entry 4) and
2.5 mol % of 3 afforded 6a in 90% ee (entry 5). These results showed
that the number of imidazolines on the benzene ring has a signifi-
cant effect on the enantioselectivity and the superiority of C3-
symmetric structure was obvious in studied catalysts.
Fig. 2. Conversion of 4a versus reaction time using catalyst 3 (5 mol %), 2 (7.5 mol %),
and 1 (15 mol %).
We assumed that the lower selectivity of catalyst 2 was due to the
reaction proceeding on the outside of the discussed reaction site
caused by one of the two imidazolines. The slightly faster reaction
with 2 observed in Fig. 3 could be also because of the reaction by one
of the twoimidazolines. The proceedingof the twotypes of reactions
in bisimidazoline 2, especially the reaction outside of the site,
resulted in the decrease of the enantioselectivity of the product.
Table 1
Comparison of imidazoline catalysts 1e3a
Entry
Catalyst
Loading (mol %)
Yield (%) (dr)
ee (%)b
1c
2
3
4
5
1
2
3
2
3
5
5
5
7.5
2.5
29 (5:1)
1
61
89
67
90
91 (18:1)
94 (18:1)
90 (16:1)
97 (18:1)
a
Unless otherwise noted, the reaction was carried out with 4a (0.14 mmol), 5a
(0.21 mmol) and the catalyst (0.007 mmol) in toluene (0.47 mL) at room
temperature.
b
ee was determined by HPLC and ee of major diastereomer is shown.
The reaction did not completed and was stopped within 72 h.
c
It is intriguing where the necessity of C3-symmetric structure of
the catalyst is. Therefore, to investigate this point, reactions of 4a and
5a with catalyst 1e3 in CDCl3 were initially monitored using NMR
spectroscopy, respectively. The comparisonof conversionwith equal
amounts of imidazolines (trisimidazoline 3, 5 mol %; bisimidazoline
2, 7.5 mol %; monoimidazoline 1, 15 mol %) is shown in Fig. 2. Ap-
parently, the reaction rate of monoimidazoline 1 was very slow, and
those of bisimidazoline 2 and trisimidazoline 3 were comparable.
We assumed that at least two imidazolines should be involved in the
activation of the reaction, and the C3-symmetric structure had
a small contribution on the enhancement of the reaction.
Fig. 3. Conversion of 4a versus reaction time using catalyst 2 (7.5 mol %) and 3
(2.5 mol %).
The role of the C3-symmetric structure was then considered as
follows. Bisimidazoline structure could sufficiently enhance this
conjugateaddition,andtheintroductionof thethirdimidazolinering
on the 5-position of the bisimidazoline increased the enantiose-
lectivity. Due to the N]CeN structure, namely amidine moiety, the
imidazoline ring derived from chiral 1,2-diphenyl ethylenediamine
has C2-symmetric nature (Fig. 4). Therefore, three imidazolines can
The reactions could then be considered to occur mainly at the
site surrounded by two imidazolines. 3 has three sites surrounded
by two imidazolines and 2 has one site, then to investigate the
reaction with the same number of sites, an additional NMR study
was carried out using 2.5 mol % of 3 and 7.5 mol % of 2. As expected,
there was no significant difference in the reaction rate between the
reactions under the two reaction conditions, though the reaction
rate using 2 was slightly faster than the reaction rate using 3 (Fig. 3).
On the other hand, as for enantioselectivity, there was certainly
a difference between 2 and 3 as shown in entries 4 and 5 in Table 1.
C2-symmetr ic
Ph
Ph
Ph
Ph
N
NH
H2N
NH2
N
NH
R
C -symmetric
2
amidine
structure
R
chiral diamine
Fig. 4. C2-symmetric nature of imidazoline.

4864
K. Murai et al. / Tetrahedron 67 (2011) 4862e4868
make three equally-aligned reaction sites surrounded by two imi-
dazolines (Fig. 5). By depressing undesirable reactions catalyzed by
one imidazoline, the better chiral environment was provided.
enantioselectivity had been achieved. Therefore, from the view
point of an organocatalyst using imidazolines, the utility of trisi-
midazoline 3 was interesting. To investigate the further aspect of
trisimidazoline 3, following experiments were then performed.
The detail of the generality of the nitro Michael reaction of b-
undesirable reaction site
ketoesters to nitroolefins with trisimidazoline 3 was initially in-
(selectivity: low)
Ph
Ph
vestigated. The substrate scope coupled with previous results was
shown in Table 2. The reaction of cyclic b-ketoester 4a with various
N
NH
H
Ph
Ph
nitroolefins 5aej having electron-rich, electron-poor, bulky, and
hetero aromatics afforded the desired products in high yields with
good diastereo- and enantiostereoselectivity (entries 1e10). The
steric and electronic properties of the substituents on aromatic
rings have little effect on the stereoselectivities. Not only aromatic
nitroolefins but also aliphatic one, such as isobutyl substituted
nitroolefin 5k, were found to be applicable, though 10 mol % of the
catalyst loading and 3 equiv of the nitroolefin were necessary, due
to the low reactivity of 5k (entry 11). The indanone carboxylate 4b
and the tetralone carboxylate 4c were also applicable (entries 12
and 13) as previously reported. On the other hand, the reaction
N
NH
H
N
H
N
N
N
Ph
Ph Ph
Ph
N
HN
N
HN
Ph
Ph
Ph
Ph
desirable reaction site
(selectivity: high)
Fig. 5. Difference of reaction site.
From this consideration, to depress the reactions concerning
only one imidazoline, the introduction of a bulky substituent at the
5-position of bisimidazoline also seemed to be effective. Actually,
the reaction of 4a and 5a using bisimidazoline analogue 7,12a which
possesses a tert-butyl substituent, increased the enantioselectivity
of the product to 79% ee13 However, the selectivity with 7 was still
lower than that with trisimidazoline 3 (Fig. 6). Therefore, it is
concluded that the architecture of the C3-symmetric molecule
provides a superior approach to utilize the symmetric nature of the
imidazoline effectively.
using methyl acetoacetate (4d), acyclic b-ketoester, showed mod-
erate enantioselectivity compared to cyclic ones (entry 14). This
unexpectedly reduced selectivity could suggest the importance of
the structure of the
-ketoesters were more suitable substrates for high selectivity.
Our next interest was the recyclability of the trisimidazoline 3.
b-ketoesters in our reaction system: the cyclic
b
When the reaction of 4a (2.7 mmol) and 5a (4.1 mmol) with trisi-
midazoline 3 (2.5 mol %) was performed, 6a was obtained in the
high yield and the selectivity as well as the reaction of 0.14 mmol
scale (Scheme 1). In this reaction, we did not observe de-
composition of catalyst 3 (judged by TLC) and 97% of catalyst 3 was
recovered by SiO2 column chromatography. Recovered 3 also gave
a good result in the reaction of 4a and 5a (93%, 94% ee).
O
O
O
O
catalyst
OMe
NO2
NO2
Ph
OMe
toluene, rt
H
Ph
5a
4a
6a
O
O
O
trisimidazoline 3
O
OMe
NO2
H
(2.5 mol%)
H
NO2
Ph
toluene, -10 oC
OMe
(2.7 mmol)
Ph
5a (4.1 mmol)
H
4a
N
N
6a (95%, 95% ee)
Ph
Ph
N
HN
Ph
symmetric
steric
3
recovery of : 97%
with recovered 3: 6a (93%, 94% ee (0.18 mmol scale))
modification
Ph
modification
2: 61% ee
Scheme 1. A mmol scale reaction and recyclability of 3.
Ph
Ph
N
NH
As described above, trisimidazoline 3 effectively worked in con-
jugate addition of -ketoesters. Therefore, we assumed that another
type of asymmetric reaction using -ketoesters with an electrophile
should be possible with 3. The asymmetric -amination of
ketoesters was then applied, to explore the utility of 3 as an orga-
nocatalyst (Scheme 2). When trisimidazoline 3 was employed to the
b
H
N
N
Ph
H
b
N
N
Ph
Ph
Ph
a
b-
N
HN
N
HN
3: 89% ee
Fig. 6. Effect of the catalyst structure.
Ph
Ph
Ph
Ph
7: 79% ee
reaction of the
b-ketoester 4e and diethyl azodicarboxylate, the
aminated product 8a was expectedly produced in moderate selec-
tivity (78% ee). More bulky di-tert-butyl azodicarboxylate was found
to give the corresponding product 8b more selectively (82%, 92% ee).
This is promising result of trisimidazoline 3 as Brønsted base catalyst
2.2. The study on the utility of trisimidazoline 3
for the reaction using b-ketoesters. Interestingly, bisimidazoline 2
As described in introduction section, C3-symmetric trisimida-
zoline 3 had achieved the first highly enantioselective organo-
catalytic reaction using imidazolines as a chiral unit. This result was
valuable because despite attractive properties of imidazolines, such
as the basicity, nucleophilicity and the Brønsted acidity of their
salts, their utilizations as organocatalysts have not been signifi-
cantly explored:12 There are only a few asymmetric reactions using
imidazolines as an organocatalyst, such as the acid catalysts for the
DielseAlder reactions12a,b and the nucleophilic base catalysts for
the Morita BayliseHillman reaction,12c in which no high
gave the almost comparable selectivity with 4e. This is probably
because one imidazoline catalyzed reaction could have a relatively
small effect in the
a-amination with 4e. On the other hand, the re-
action with 2-acetyl-g-butyrolactone (4f) had again demonstrated
the significant efficiency of trisimidazoline 3 compared to bisimi-
dazoline 2; 3 gave 8c in moderate selectivity (53% ee),14 bycontrast, 2
gave an almost racemic product (4% ee). This difference could be
explained by the high reactivity of 4f: since the reaction with 4f
proceeded even in the absence of any catalyst (judged by TLC), one
imidazoline catalyzed reaction could have a much effect.

K. Murai et al. / Tetrahedron 67 (2011) 4862e4868
4865
Table 2
Generality of the conjugate addition of b
-ketoesters to nitroolefins with trisimidazoline 3a
Entry
1
4
R
6
Time (h)
48
Yield (%) (dr)
ee (%)f
Ph (5a)
95 (>20:1)
95
4a
6a
2b
3
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4-MeOC6H4 (5b)
4-MeC6H4 (5c)
4-ClC6H4 (5d)
4-FC6H4 (5e)
3-MeOC6H4 (5f)
2-MeC6H4 (5g)
2-BrC6H4 (5h)
2-ClC6H4 (5i)
2-thienyl (5j)
Isobutyl (5k)
6b
6c
6d
6e
6f
6g
6h
6i
85.5
47
24
28.5
31
70
45
75.5
48
94 (>20:1)
89 (>20:1)
91 (>20:1)
95 (>20:1)
98 (20:1)
93
93
96
94
93
94
93
93
90g
80
4
5b
6
7b
8
79 (16:1)
93 (>20:1)
96 (>20:1)
95 (>20:1)
73 (>20:1)
9
10
6j
6k
11b,d,e
139
12
Ph (5a)
42.5
99 (4:1)
74h
4b
4c
6l
13c,d
Ph (5a)
Ph (5a)
92
65
71 (>20:1)
89
65
6m
14e
75 (1:1)
6n
4d
a
Unless otherwise noted, the reaction was carried out with 4 (0.14 mmol), 5 (0.21 mmol) and 3 (0.007 mmol) in toluene (0.47 mL) at ꢀ10 ꢁC.
b
c
The reaction was carried out at 0 ꢁC.
The reaction was carried out at room temperature.
The reaction was carried out with 10 mol % of 3.
The reaction was carried out with 3 equiv of 5.
ee was determined by HPLC and ee of major diastereomer is shown.
Absolute and relative configurations were not determined.
Absolute configuration was not determined.
d
e
f
g
h
3. Conclusion
In summary, the necessity of the C3-symmetry and the role of
the third imidazoline of C3-symmetric trisimidazoline 3 were
revealed by the mechanistic study. Due to the presence of the third
imidazoline, the three equally-aligned reaction sites surrounded by
two imidazolines were created to give high enantioselectivity. In
addition, the utility of 3 as a novel Brønsted base catalyst was
RO2C
N
N
O
CO2R
O
O
O
catalyst (5 mol%)
OEt
8a: R= Et
OEt
toluene, -10 oC
: R= tBu
NCO2R
NHCO2R
8b
shown in the nitro Michael reaction and the
a-amination of b-
4e
ketoesters. The recyclability of the catalyst 3 was also demon-
strated. We think that this work demonstrated the efficiency of the
C3-symmetric molecules and imidazolines for the organocatalyst.
Future work will be dedicated to the development of novel asym-
metric reactions using trisimidazoline 3.15
with trisimidazoline 3
8a: 90%, 78% ee
: 82%, 92% ee
with bisimidazoline 2
8a: 89%, 74% ee
: 85%, 90% ee
8b
8b
tBuO2C
N
N
4. Experimental section
4.1. Materials
O
O
O
O
CO2tBu
catalyst (5 mol%)
toluene, -10 oC
O
O
8c
NCO2tBu
NHCO2tBu
4f
Unless otherwise noted, materials were purchased from com-
mercial suppliers and were used without purification. Preparations
of imidazoline catalysts 1e3 were reported previously.5 The nitro-
olefins 5bej16 and 5k10d were prepared according to the literature
procedure.
with trisimidazoline 3
8c: 99%, 53% ee
with bisimidazoline 2
8c: 92%, 4% ee
Scheme 2.
a
-Amination with azodicarboxylate.

4866
K. Murai et al. / Tetrahedron 67 (2011) 4862e4868
4.2. NMR experiments in Figs. 2 and 3
and washed with AcOEt. The filtrate was concentrated in vacuo, and
the residue was purified by SiO2 column chromatography (hexane/
To a solution of b-ketoester 4a (40.5 mg, 0.285 mmol) and imi-
AcOEt¼2/3) to give 7c (868.8 mg, 78%) as colorless solid. 1H NMR
dazoline catalyst (indicated in the following Table 3) in CDCl3
(0.95 mL) was added nitroolefin 5a (63.7 mg, 0.427 mmol) at room
temperature and stirred for 5 min. The resulting clear solution was
placed in NMR tube. The conversion of the reaction was monitored
with 1H NMR at the indicated reaction time (1, 3, 5, 7, and 9 h) by
(400 MHz CDCl3):
d
¼7.32 (s, 2H), 7.20 (s, 1H), 4.69 (d, J¼5.1 Hz, 4H),
1.79 (t, J¼5.1 Hz, 2H), 1.33 ppm (s, 9H).
4.3.3. 5-(tert-Butyl)isophthalaldehyde (7d)19. To a suspension of
MnO2 (2.76 g, 31.8 mmol) in 1,2-dichroloethane (11 mL) was added
(5-(tert-butyl)-1,3-phenylene)dimethanol (7c) (617.2 mg, 3.18
mmol). The reaction mixture was refluxed for 3 h. After being
cooled to room temperature, the reaction mixture was filtered
through Celite and washed with AcOEt. The filtrate was concen-
trated in vacuo, and the residue was purified by SiO2 column
chromatography (hexane/AcOEt¼3/1) to give 7d (470.0 mg, 78%) as
the integration of the following peaks:
5.29e5.10 ppm for 6a
d¼3.20e3.10 ppm for 4a and
colorless solid. 1H NMR (400 MHz CDCl3):
3H), 1.41 ppm (s, 9H).
d¼10.1 (s, 2H), 8.19 (s,
4.3.4. 5-tert-Butyl-bisimidazoline 712a. 5-(tert-Butyl)isophthalalyde
(7d) (50.3 mg, 0.264 mmol) and (S,S)-1,2-diphenyl ethylenedi-
amine (123.3 mg, 0.581 mmol) were dissolved in CH2Cl2 (6 mL) and
stirred for 2 h at 0 ꢁC under N2. The resulting solution was added
NBS (103.4 mg, 0.581 mmol) at 0 ꢁC and the mixture was stirred
overnight at room temperature. The reaction mixture was added to
Na2S2O5 aq and 5% NaOH aq, and extracted with CH2Cl2. Organic
layer was dried over Na2SO4 and evaporated in vacuo. The residue
was purified by SiO2 column chromatography (hexane/AcOEt/
triethylamine¼2/1/0.03) to give 7 (151.7 mg, 80%) as colorless solid.
Table 3
NMR experiments
Conversion (%)
Conditions
1 h
17
14
3 h
37
32
5 h
51
45
0
7 h
62
54
4.0
50
9 h
70
63
5.3
57
Trisimidazoline 3 (5 mol %)
Bisimidazoline 2 (7.5 mol %)
Monoimidazoline 1 (15 mol %)
Trisimidazoline 3 (2.5 mol %)
1H NMR (400 MHz CDCl3):
d
¼8.29 (t, J¼1.8 Hz, 1H), 8.15 (d,
0.2
13
1.8
30
39
J¼1.8 Hz, 2H), 7.39e7.29 (m, 20H), 5.49 (s, 2H), 5.14 (d, J¼8.1 Hz,
2H), 4.33 (dd, J¼1.8, 8.1 Hz, 2H), 1.42 ppm (s, 9H).
4.4. General procedure for asymmetric Michael addition of
substituted -ketoesters and nitroolefins
a-
4.3. Preparation of 5-tert-butyl-bisimidazoline 7
b
To a solution of b-ketoester 4 (1.0 equiv) and trisimidazoline 3
(0.05 equiv) in toluene (0.3 M) was added nitroolefin 5 (1.5 equiv)
at ꢀ10 ꢁC and the resulting solution was stirred at the same tem-
perature. After the reaction was completed (judged by TLC), the
reaction mixture was purified by SiO2 column chromatography to
give 6. Preparations of Michael adduct 6a, 6b, 6d, 6e, 6g, 6i, 6j, 6l,
and 6m according to the general procedure were reported
previously.6
4.4.1. Methyl 1-(2-nitro-1-p-tolylethyl)-2-oxocyclopentanecarbox-
ylate (6c)10d. Reaction was carried out according to the general
procedure with 4a (23.7 mg, 0.167 mmol), 3 (6.2 mg, 0.0083 mmol),
and (E)-1-methyl-4-(2-nitrovinyl)benzene (5c), (40.8 mg, 0.250
mmol) in toluene (0.56 mL) at ꢀ10 ꢁC to give 6c (45.4 mg, 89%, dr,
>20:1) as colorless oil. Reaction time: 47 h. Eluent of SiO2 column
4.3.1. Dimethyl 5-tert-butyl isophthalate (7b)17. A solution of 5-tert-
butyl isophthalic acid (7a) (2.17 g, 9.75 mmol) and sulfuric acid
(1 mL) in MeOH (20 mL) was refluxed for 2.5 h. After being cooled
to room temperature, the reaction mixture was diluted with AcOEt
and washed with 10% NaOH aq and brine. Organic layer was dried
over Na2SO4 and evaporated in vacuo to give 7b (2.33 g, 95%) as
chromatography: hexane/CH2Cl2¼1/4. [
a
]
ꢀ40.0 (c 1.69, CHCl3,
D28
93% ee); 1H NMR (400 MHz, CDCl3):
d
¼7.14e7.07 (m, 4H), 5.13 (dd,
J¼4.2, 13.7 Hz, 1H), 4.98 (dd, J¼11.0, 13.7 Hz, 1H), 4.05 (dd, J¼4.2,
11.0 Hz, 1H), 3.76 (s, 3H), 2.41e2.32 (m, 2H), 2.30 (s, 3H),
2.07e1.77 ppm (m, 4H). HPLC (DAICEL CHIRALPAK OD-H,
hexane/iPrOH¼97/3, flow rate¼1.0 mL/min, detection at 207 nm):
tminor¼16.7 min, tmajor¼21.3 min (major diastereomer); (minor di-
astereomer) 13.4, 17.7 min.
colorless solid. 1H NMR (400 MHz, CDCl3):
d
¼8.51 (t, J¼1.4 Hz, 1H),
8.27 (d, J¼1.4 Hz, 2H), 3.95 (s, 6H), 1.38 ppm (s, 9H).
4.3.2. (5-(tert-Butyl)-1,3-phenylene)dimethanol (7c)18. To a suspen-
sion of LiAlH4 (653.3 mg, 17.2 mmol) in THF (15 mL) was slowly
added dimethyl 5-tert-butyl isophthalate (7b) (1.47 g, 5.74 mmol)
in THF (15 mL) at 0 ꢁC and the resulting mixture was stirred over-
night at room temperature. The reaction was quenched with H2O
(1 mL) and 10% NaOH aq (1 mL) at 0 ꢁC. AcOEt (15 mL) and Celite
were added to the reaction mixture and resulting mixture was
stirred for 30 min. The resulting mixture was filtered through Celite
4.4.2. Methyl 1-(1-(3-methoxyphenyl)-2-nitroethyl)-2-oxocyclopent
anecarboxylate (6f)10d. Reaction was carried out according to the
general procedure with 4a (25.8 mg, 0.181 mmol), 3 (6.7 mg,
0.0091 mmol), and (E)-1-methoxy-3-(2-nitrovinyl)benzene (5f)
(48.8 mg, 0.272 mmol) in toluene (0.60 mL) at ꢀ10 ꢁC to give 6f
(57.1 mg, 98%, dr, 20:1) as colorless oil. Reaction time: 31 h. Eluent
of SiO2 column chromatography: hexane/CH2Cl2¼1/4. [
a]
ꢀ33.5
D28
(c 1.41, CHCl3, 93% ee); 1H NMR (400 MHz, CDCl3):
d¼7.24e7.20 (m,

K. Murai et al. / Tetrahedron 67 (2011) 4862e4868
4867
1H), 6.83e6.80 (m, 3H), 5.15 (dd, J¼4.0, 13.6 Hz, 1H), 5.00 (dd,
J¼11.0,13.6 Hz,1H), 4.04 (dd, J¼4.0,11.0 Hz,1H), 3.78 (s, 3H), 3.76 (s,
3H), 2.42e2.32 (m, 2H), 2.11e1.80 ppm (m, 4H). HPLC (DAICEL
CHIRALPAK OD-H, hexane/iPrOH¼99/1, flow rate¼1.0 mL/min, de-
tection at 207 nm): tminor¼50.9 min, tmajor¼60.2 min (major di-
astereomer); (minor diastereomer) 40.0, 48.0 min.
CHCl3, 78% ee). HPLC (DAICEL CHIRALPAK AD-H, hexane/iPrOH¼95/
5, flow rate¼1.0 mL/min, detection at 207 nm): tminor¼25.6 min,
tmajor¼22.1 min.
4.5.2. N0N-Bis(tert-butoxycarbonyl)-1-hydrazino-2-ox-
ocyclopentanecarboxylic acid ethyl ester (8b)11i. To a solution of
ethyl 2-oxocyclopentanecarboxylate (4e) (26.0 mg, 0.166 mmol)
and trisimidazoline 3 (6.2 mg, 0.0062 mmol) in toluene (0.55 mL)
was added di-tert-butyl azodicarboxylate (57.5 mg, 0.250 mmol)
at ꢀ10 ꢁC, and the mixture was stirred for 24 h at the same tem-
perature. After the reaction was completed (judged by TLC), the
reaction mixture was purified by SiO2 column chromatography
(AcOEt/CH2Cl2¼1/15) to give 8b (52.9 mg, 82%) as colorless oil.
4.4.3. Methyl 1-(1-(2-bromophenyl)-2-nitroethyl)-2-oxocyclopenta-
necarboxylate (6h)10d. Reaction was carried out according to the
general procedure with 4a (22.4 mg, 0.158 mmol), 3 (5.8 mg,
0.0079 mmol), and (E)-1-bromo-2-(2-nitrovinyl)benzene (5h)
(53.9 mg, 0.236 mmol) in toluene (0.52 mL) at ꢀ10 ꢁC to give 6h
(54.2 mg, 93%, dr, >20:1) as colorless oil. Reaction time: 45 h. Elu-
ent of SiO2 column chromatography: hexane/CH2Cl2¼1/4. [
a
]
[
d
a
]
ꢀ2.38 (c 1.23, CHCl3, 92% ee); 1H NMR (400 MHz, CDCl3):
D25
D26
þ18.1 (c 0.89, CHCl3, 95% ee); 1H NMR (400 MHz, CDCl3):
d
¼7.58
¼6.59 (br s, 1H), 4.23 (br s, 2H), 2.59e1.96 (m, 6H), 1.52e1.44 (m,
(dd, J¼1.2, 8.0 Hz, 1H), 7.52 (dd, J¼1.6, 8.0 Hz, 1H), 7.33e7.29 (m,
1H), 7.17e7.12 (m,1H), 5.48 (dd, J¼3.2,13.6 Hz,1H), 5.07 (dd, J¼10.8,
13.6 Hz, 1H), 4.51 (dd, J¼3.2, 10.8 Hz, 1H), 3.75 (s, 3H), 2.52e2.48
(m, 2H), 2.26e2.08 (m, 2H), 2.00e1.89 ppm (m, 2H). HPLC (DAICEL
CHIRALPAK AD-H, hexane/iPrOH¼90/10, flow rate¼1.0 mL/min,
detection at 207 nm): tminor¼9.3 min, tmajor¼10.7 min (major di-
astereomer); (minor diastereomer) 12.6, 13.0 min.
18H), 1.28 ppm (t, J¼7.2 Hz, 3H). HPLC (DAICEL CHIRALPAK AD-H,
hexane/EtOH¼95/5, flow rate¼1.0 mL/min, detection at 207 nm):
tminor¼4.9 min, tmajor¼6.0 min.
4.5.3. N0N-Bis(tert-butoxycarbonyl)-2-hydrazino-2-acetyl-
olactone (8c)11i. To a solution of 2-acetyl-
-butyrolactone (4f)
g-butyr-
g
(31.7 mg, 0.247 mmol) and trisimidazoline 3 (9.1 mg, 0.0091 mmol)
in toluene (0.82 mL) was added di-tert-butyl azodicarboxylate
(85.5 mg, 0.371 mmol) at ꢀ10 ꢁC, and the mixture was stirred for
21.5 h at the same temperature. After the reaction was completed
(judged by TLC), the reaction mixture was purified by SiO2 column
chromatography (hexane/AcOEt¼2.5/1) to give 8c (87.8 mg, 99%) as
4.4.4. Methyl 1-(4-methyl-1-nitropentan-2-yl)-2-oxocyclopentane-
carboxylate (6k)10d. Reaction was carried out according to the gen-
eral procedure with 4a (22.7 mg, 0.160 mmol),
3 (11.8 mg,
0.016 mmol), and (E)-4-methyl-1-nitropent-1-ene (5k) (61.9 mg,
0.480 mmol) in toluene (0.53 mL) at 0 ꢁC to give 6k (31.6 mg, 73%, dr,
>20:1) as colorless oil. Reaction time: 139 h. Eluent of SiO2 column
white solid. [
CDCl3):
a
]
þ1.36 (c 1.27, CHCl3, 53% ee); 1H NMR (400 MHz,
D27
d
¼6.80 (br s, 1H), 4.38 (m, 2H), 3.27e2.30 (m, 5H), 1.47 ppm
chromatography: hexane/CH2Cl2¼1/4. [
a
]
ꢀ66.1 (c 1.31, CHCl3,
(s, 18H). HPLC (DAICEL CHIRALPAK AD-H, hexane/EtOH¼95/5,
flow rate¼1.0 mL/min, detection at 207 nm): tminor¼7.0 min,
tmajor¼9.0 min.
D28
80% ee); 1H NMR (400 MHz, CDCl3):
d
¼4.89 (dd, J¼5.8, 14.6 Hz, 1H),
4.33 (dd, J¼4.2, 14.6 Hz, 1H), 3.71 (s, 3H), 2.95e2.90 (m, 1H),
2.64e2.58 (m, 1H), 2.49e2.26 (m, 2H), 2.07e1.92 (m, 3H), 1.61e1.42
(m, 2H),1.08e0.99 (m,1H), 0.91 ppm (d, J¼6.8 Hz, 6H). HPLC (DAICEL
CHIRALPAKOD-H, hexane/EtOH¼98/2,15 ꢁC, flow rate¼1.0 mL/min,
detection at 207 nm): tminor¼10.7 min, tmajor¼13.3 min (major di-
astereomer); (minor diastereomer) 11.7, 12.7 min.
Acknowledgements
This work was financially supported by Grant-in-Aid for Scien-
tific Research (B) and for Young Scientists (B) from JSPS.
4.4.5. Methyl-2-acetyl-4-nitro-3-phenylbutyrate
was carried out according to the general procedure with 4d
(30.7 mg, 0.213 mmol), 3 (7.9 mg, 0.0107 mmol), and trans-
nitrostylene (5a) (95.3 mg, 0.639 mmol) in toluene (0.71 mL)
at ꢀ10 ꢁC to give 6n (52.0 mg, 75%) as a white solid (1:1 diastereo
mixture). Reaction time: 65 h. Eluent of SiO2 column chromatog-
(6n)20. Reaction
Supplementary data
b
-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.005.
References and notes
raphy: hexane/AcOEt¼3/1. [
a
]
ꢀ31.3 (c 1.74, CHCl3, 65% ee); 1H
D27
NMR (400 MHz, CDCl3):
d
¼7.34e7.25 (m, 3H), 7.21e7.19 (m, 2H),
1. Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Heidelberg, 1999; Vols. 1e3.
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4. Interesting molecular recognitions and chiral ligands using C3-symmetric tri-
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Shin, S. K.; Ahn, K. H. J. Am. Chem. Soc. 2002, 124, 591; (b) Ahn, K. H.; Ku, H.-Y.;
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9. For selected reviews on asymmetric 1,4-addition, see: (a) Tsogoeva, S. B. Eur. J.
4.88e4.80 (m, 1H), 4.77 (d, J¼6.0 Hz, 1H), 4.29e4.18 (m, 1H), 4.12 (d,
J¼9.8 Hz, 0.5H), 4.05 (d, J¼9.8 Hz, 0.5H), 3.77 (s, 1.5H), 3.50 (s, 1.5H),
2.29 (s, 1.5H), 2.04 ppm (s, 1.5H). HPLC (DAICEL CHIRALPAK AD-H,
exane/EtOH¼95/5, 10 ꢁC, flow rate¼1.0 mL/min, detection at
207 nm): (first isomer) tminor¼23.7 min, tmajor¼45.7 min, (second
isomer) tminor¼40.3 min, tmajor¼36.2 min.
4.5.
a-Amination with azodicarboxylate
4 . 5 .1. N 0N - B i s ( e t h o x y c a r b o n y l ) - 1 - h y d r a z i n o - 2 - o x -
ocyclopentanecarboxylic acid ethyl ester (8a)21. To a solution of ethyl
2-oxocyclopentanecarboxylate (4e) (23.7 mg, 0.152 mmol) and tri-
simidazoline 3 (5.6 mg, 0.0076 mmol) in toluene (0.41 mL) was
added diethyl azodicarboxylate (2.2 M solution in toluene, 0.10 mL,
0.228 mmol) at ꢀ10 ꢁC, and the mixture was stirred for 1 h at the
same temperature. After the reaction was completed (judged by
TLC), the reaction mixture was purified by SiO2 column chroma-
tography (hexane/AcOEt¼2/1) to give 8a (45.0 mg, 90%) as colorless
€
€
ꢀ
oil. 1H NMR (400 MHz, CDCl3):
2.65e1.74 (m, 6H), 1.29e1.07 ppm (m, 9H). [
d
¼6.77 (br s, 1H), 4.35e4.16 (m, 6H),
€
Org. Chem. 2007, 1701; (b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M.
Synthesis 2007, 1279.
25
a]
D
þ1.92 (c 0.85,

4868
K. Murai et al. / Tetrahedron 67 (2011) 4862e4868
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Eur. J. 2008, 14, 8780; (e) Yu, Z.; Liu, X.; Zhou, L.; Lin, L.; Feng, X. Angew. Chem.,
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11, 437; (g) Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang, J.;
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€
€
12. (a) Tsogoeva, S. B.; Durner, G.; Bolte, M.; Gobel, M. W. Eur. J. Org. Chem. 2003,1661;
€
€
(b) Akalay, D.; Durner, G.; Bats, J. W.; Bolte, M.; Gobel, M. W. J. Org. Chem. 2007, 72,
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activity of 2.
14. The reaction at lower temperature (ꢀ40 ꢁC) did not improve the enantioselectivity.
15. Recently, we achieved the asymmetric bromolactonization of 5-substituted-5-
hexenoic acids based on the interesting molecular recognition of trisimidazoline
3 with carboxylic acids, see: Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima,
S.; Shimura, M.; Fujioka, H. Angew. Chem., Int. Ed. 2010, 49, 9174.
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a
-amination, see: (a) Janey, J. M. Angew.
-amination of b-
Chem. 2005, 117, 4364 and selected examples on asymmetric
a
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~
ꢀ
ꢀ
ribera, A. J. Org. Chem. 2004, 69, 6834.