Asymmetric 1,3-dipolar cycloaddition reaction of azomethine imines to allyl alcohol

Article abstract of DOI:10.1246/cl.2008.342

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. Copyright

Full text of DOI:10.1246/cl.2008.342

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
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.3 (2008)
343
Table 2. The asymmetric 1,3-dipolar cycloaddition of azomethine
imines 2
O
N
N
Entry
R
Yield/%a
ee/%
88b
92b
92b
91b
88b
82c
72c
54b
89b
N
HN
1
2
3
4
5
6
7
8
9
Ph
a
b
c
d
e
f
g
h
i
66
57
49
67
53
42
7d
p-EtC6H4
p-MeOC6H4
p-ClC6H4
p-O2NC6H4
2-Furyl
n-C5H11
c-C6H11
t-Bu
5
O
O
O
H
N
N
N
N
R
17
36
R
O
N
O
H
aIsolated yields. bEnantioselectivity was determined by HPLC analysis
(Daicel Chiralcel OD-H). cEnantioselectivity was determined by HPLC
analysis (Daicel Chiralcel IA). dYield was determined by 1H NMR analy-
sis due to difficulty separating from a by-product 5.
O
O
6
HN
S
H
CH3
prisingly, the pyrazolidine 4a was obtained in an enhanced
chemical yield with the excellent enantioselectivity (Table 3,
Entry 1).5 In this procedure, it is not yet clear whether the inter-
mediate 3 was produced along with the generation of MgBr2 or a
different intermediate was formed.6 When the reaction was car-
ried out longer time, the chemical yield was slightly enhanced
(Entry 2). The 1,3-dipolar cycloaddition of several other azo-
methine imines 2 also realized excellent enantioselectivities as
listed in Table 3, even in the case of pentyl- and cyclohexyl-
substituted ones 2g and 2h (Entries 8 and 9).7
Figure 1.
As described above, an attractive asymmetric cycloaddition
of azomethine imines to allyl alcohol has been developed.
The present work was financially supported in part by a
Grant-in-Aid for Scientific Research on Priority Areas ‘‘Ad-
vanced Molecular Transformations of Carbon Resources’’
from The Ministry of Education, Culture, Sports, Science and
Technology (MEXT).
R
N
References and Notes
1
O
N
O
H
3)
a) K. V. Gothelf, K. A. Jørgensen, Chem. Commun. 2000, 1449. b) K. V.
Gothelf, in Cycloaddition Reactions in Organic Synthesis, ed. by S.
Kobayashi, K. A. Jørgensen, Wiley-VCH, Weinheim, 2002, Chap. 6. c) S.
Kanemasa, in Cycloaddition Reactions in Organic Synthesis, ed. by S.
Kobayashi, K. A. Jørgensen, Wiley-VCH, Weinheim, 2002, Chap. 7.
Azomethine imines and related species: S. Kobayashi, H. Shimizu, Y.
Yamashita, H. Ishitani, J. Kobayashi, J. Am. Chem. Soc. 2002, 124, 13678; R.
Shintani, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 10778; Y. Yamashita, S.
Kobayashi, J. Am. Chem. Soc. 2004, 126, 11279; S. Shirakawa, P. J.
1) (R,R)-DIPT
(1.0 equiv.)
2
(3)
OH
N N
(1.0 equiv.)
OH
2) n-BuMgBr
80 °C, t d
R
(3.0 equiv.)
in CH CN
1
4
3
2
Table 3. The asymmetric 1,3-dipolar cycloaddition of azomethine
imines 2 by the use of only the Grignard reagent as a magnesium
source
´
Lombardi, J. L. Leighton, J. Am. Chem. Soc. 2005, 127, 9974; A. Suarez,
C. W. Downey, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11244; W. Chen,
X.-H. Yuan, R. Li, W. Du, Y. Wu, L.-S. Ding, Y.-C. Chen, Adv. Synth. Catal.
2006, 348, 1818; H. Suga, A. Funyu, A. Kakehi, Org. Lett. 2007, 9, 97; W. Chen,
W. Du, Y.-Z. Duan, Y. Wu, S.-Y. Yang, Y.-C. Chen, Angew. Chem., Int. Ed.
2007, 46, 7667. Nitrile imines; M. P. Sibi, L. M. Stanley, C. P.
Jasperse, J. Am. Chem. Soc. 2005, 127, 8276; M. P. Sibi, L. M. Stanley, T.
Soeta, Adv. Synth. Catal. 2006, 348, 2371. Diazoalkanes; S. Kanemasa, T.
Kanai, J. Am. Chem. Soc. 2000, 122, 10710; T. Kano, T. Hashimoto, K.
Maruoka, J. Am. Chem. Soc. 2006, 128, 2174; M. P. Sibi, L. M. Stanley, T. Soeta,
Org. Lett. 2007, 9, 1553.
Y. Ukaji, K. Sada, K. Inomata, Chem. Lett. 1993, 1847; M. Shimizu, Y. Ukaji, K.
Inomata, Chem. Lett. 1996, 455; Y. Yoshida, Y. Ukaji, S. Fujinami, K.
Inomata, Chem. Lett. 1998, 1023; Y. Ukaji, M. Ima, T. Yamada, K. Inomata,
Heterocycles 2000, 52, 563; M. Tsuji, Y. Ukaji, K. Inomata, Chem. Lett.
2002, 1112; Y. Ukaji, K. Inomata, Synlett 2003, 1075.
a) Y. Ukaji, K. Taniguchi, K. Sada, K. Inomata, Chem. Lett. 1997, 547. b)
D. Xia, K. Taniguchi, Y. Ukaji, K. Inomata, Chem. Lett. 2001, 468. c) D. Xia,
Y. Ukaji, S. Fujinami, K. Inomata, Chem. Lett. 2002, 302. d) D. Xia,
K. Taniguchi, Y. Hamamoto, K. Sada, S. Fujinami, Y. Ukaji, K. Inomata, Bull.
Chem. Soc. Jpn. 2006, 79, 1069.
Enantioselectivity also increased in other solvents than CH3CN by this proce-
dure: Solvent/temperature/reaction time/yield of 4a/ee; THF/66 ꢁC/2
d/53%/84% ee; Cl(CH2)2Cl/80 ꢁC/2 d/57%/90% ee.
Entry
R
t=d
Yield/%a
ee/%
1
2
Ph
a
2
4
4
2
2
4
2
3
4
4
74
81
57
75
75
66
60
51e
78
50
95b
94b
96b
94b
94b
94b
88d
96d
94b
96b
3c
4
p-EtC6H4
p-MeOC6H4
p-ClC6H4
p-O2NC6H4
2-Furyl
n-C5H11
c-C6H11
t-Bu
b
c
d
e
f
g
h
i
5
6c
7c
8c
9c
10c
3
4
5
aIsolated yields. bEnantioselectivity was determined by HPLC analysis
(Daicel Chiralcel OD-H). cMeMgBr was used instead of n-BuMgBr.
dEnantioselectivity was determined by HPLC analysis (Daicel Chiralcel
IA). eYield was determined by 1H NMR analysis due to difficulty separat-
ing from the by-product 5.
The absolute configuration of 4a was determined to be R,R
as follows: The enantiomerically rich 4a (80% ee) was treated
with (S)-1-phenylethyl isocyanate in the presence of a catalytic
amount of 4-(N,N-dimethylamino)pyridine in CH2Cl2 to give
the corresponding urethane 6 (79%). Twice recrystallization
from hexane gave diastereomerically pure 6. The absolute
stereochemistry of pyrazolidine skeleton in 6 was determined
to be R,R by X-ray crystallographic analysis of its single crystal
(Figure 1).8 The absolute configurations of other products
4b–4i were tentatively determined to be also R,R.
6
7
When MgBr2 was added in the reaction in Table 2, Entry 1, 4a was obtained
in 78% yield with 84% ee.
Although the 1,3-dipolar cycloaddition of 2a to (E)-2-buten-1-ol was carried out
under similar conditions in Table 3, Entry
cycloadduct was not obtained.
1 for 7 d, the corresponding
8
Single crystals of 6, obtained by recrystallization from toluene/hexane,
contain hexane (hexane/6 = 1/4) in disorder. Crystal data: C23:5H28:5N3O3,
˚
fw 401.00, monoclinic, P21, a ¼ 12:713ð8Þ, b ¼ 6:994ð4Þ, c ¼ 13:958ð9Þ A,
3
ꢁ
V ¼ 1154ð1Þ A , ꢀ ¼ 111:469ð5Þ , Z ¼ 2. Dcalcd ¼ 1:153 g/cm3. R ¼ 0:070
(Rw ¼ 0:105) for 4539 reflections with I > 3:00ꢁðIÞ and 265 variable parame-
ters. Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett.
˚
Published on the web (Advance View) February 23, 2008; doi:10.1246/cl.2008.342