Asymmetrie 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohols

Article abstract of DOI:10.1246/cl.2010.1036

The asymmetric 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohols was achieved by utilizing diisopropyl (R,R)-tartrate as a chiral auxiliary to give the corresponding optically active trans-pyrazolidines with excellent regio-, diastere

Full text of DOI:10.1246/cl.2010.1036

doi:10.1246/cl.2010.1036
1036
Published on the web August 21, 2010
Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines to Homoallylic Alcohols
Katsuyoshi Tanaka, Tomomitsu Kato, Shuhei Fujinami, Yutaka Ukaji,* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192
(Received June 11, 2010; CL-100551; E-mail: inomata@se.kanazawa-u.ac.jp)
The asymmetric 1,3-dipolar cycloaddition of azomethine
imines to homoallylic alcohols was achieved by utilizing diiso-
propyl (R,R)-tartrate as a chiral auxiliary to give the correspond-
ing optically active trans-pyrazolidines with excellent regio-,
diastereo-, and enantioselectivities. The catalytic use of diiso-
propyl (R,R)-tartrate was also effective in the presence of MgBr2.
Table 1. The stoichiometric asymmetric 1,3-dipolar cyclo-
addition of azomethine imines 2 to homoallyl alcohol (1)
R
1) additive
N
(1.0 equiv)
2) (R,R)-DIPT
(1.0 equiv)
O
O
N
H
4)
2
N
N
(1.0 equiv)
OH
3) R'MgX
80 °C, 2 d
OH
R
in C H CN
(3.0 equiv)
1 (1.0 equiv)
3
2
5
1,3-Dipolar cycloaddition of azomethine imines to olefins is
a useful method for the synthesis of pyrazolidines, which have
biological activities1 and are versatile synthetic intermediates for
nitrogen containing chemicals such as 1,3-diamines.2 Compared
with progress of asymmetric 1,3-dipolar cycloaddition of
nitrones, that of azomethine imines is still limited.3 Recently
we have developed an asymmetric 1,3-dipolar cycloaddition of
azomethine imines to allyl alcohol utilizing a stoichiometric
and a catalytic amount of diisopropyl (R,R)-tartrate [(R,R)-
DIPT].4 In order to synthesize optically active nitrogen
containing chemicals with oxygen functionalities, it would be
ideal to employ various types of unsaturated alcohols as 1,3-
dipolarophiles. Herein, we wish to describe a stoichiometric and
a catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
imines to homoallylic alcohols utilizing (R,R)-DIPT as a chiral
auxiliary.
Entry Additive R¤MgX
R
3 Yield/% ee/%
1a
2
3
®
®
®
MeMgBr
MeMgBr
n-BuMgCl
Ph
a
80
90
82
65
76
76
85
24d
96
71
79
95b
93b
97b
93b
98b
99c
97b
95c
85b
91b
94b
4
MgBr2 MeMgBr
5
MgBr2 n-BuMgCl
6
7
8
9
10a
11e
®
®
®
®
®
®
n-BuMgCl p-MeOC6H4
n-BuMgCl p-ClC6H4
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
b
c
d
e
n-C5H11
c-C6H11
t-Bu
f
aSolvent was CH3CN instead of C2H5CN. Enantioselectivity
b
was determined by HPLC analysis (Daicel CHIRALCEL OD-
c
H). Enantioselectivity was deter-
mined by HPLC analysis (Daicel
CHIRALPAK IA). By-product 4,
First the 1,3-dipolar cycloaddition of 1-benzylidene-3-
oxopyrazolidin-1-ium-2-ide (2a) to homoallyl alcohol, 3-buten-
1-ol (1), was examined. To a mixture of 1.0 equiv of 1 and 1.0
equiv of (R,R)-DIPT were added 3.0 equiv of MeMgBr
and 1.0 equiv of azomethine imine 2a successively in CH3CN
and the reaction mixture was heated at 80 °C for 2 d.4a To our
surprise, the corresponding pyrazolidine 3a was obtained in an
excellent enantioselective manner with complete regio- and
diastereoselectivities (Table 1, Entry 1).5 By the use of C2H5CN
as a solvent, the chemical yield was enhanced (Entry 2).
Halogens in Grignard reagents slightly influenced the reaction.
When n-BuMgCl was used, the cycloadduct 3a was obtained in
97% ee (Entry 3). By addition of MgBr2, chemical yields tended
to decrease (Entries 4 and 5).
The asymmetric cycloaddition of several azomethine imines
2 to homoallyl alcohol (1) was performed in C2H5CN at 80 °C.
Aryl-substituted azomethine imines 2b and 2c realized excellent
enantioselectivities (Entries 6 and 7). The cycloaddition of a
pentyl-substituted azomethine imine 2d proceeded in an enan-
tioselective manner, while a by-product 4 was obtained in 52%
yield (Entry 8). The cycloaddition of a cyclohexyl-substituted
azomethine imine 2e afforded 3e with enantioselectivity over
90% ee by the use of CH3CN (Entry 10) instead of C2H5CN
(Entry 9) as a solvent. A t-butyl-substituted azomethine imine 2f
also resulted in excellent enantioselectivity (Entry 11).
O
d
N
N
produced via rearrangement of 2d
to an enamine intermediate, was
N
HN
e
obtained in 52% yield. The reac-
4
O
tion time was 4 d.
To a mixture of 1 and 0.2 equiv of (R,R)-DIPT were added 1.4
equiv of MeMgBr and azomethine imine 2a successively in
C2H5CN and the reaction mixture was heated at 80 °C for 2 d
(Table 2): Delightedly the corresponding pyrazolidine 3a was
obtained with high enantioselectivity (Entry 1). When n-
BuMgCl was used instead of MeMgBr, the enantioselectivity
was increased (Entry 2). As previously reported,4b the addition of
magnesium salt was expected to enhance the enantioselectivity.
By the addition of MgBr2, enantioselectivity went up to 93%
ee (Entry 3). When a slightly excess amount of homoallyl
alcohol (1) was employed, chemical yield was further improved
(Entry 4).
The catalytic asymmetric cycloaddition of several azo-
methine imines 2 to homoallyl alcohol (1) was performed in
C2H5CN at 80 °C. Aryl-substituted azomethine imines 2b and
2c realized excellent enantioselectivities (Entries 5 and 6). The
cycloaddition of pentyl- and cyclohexyl-substituted azomethine
imines 2d and 2e proceeded with moderate enantioselectivities
(Entries 7 and 8), while the t-butyl-substituted azomethine imine
2f still resulted in high enantioselection (Entry 9).
Next, in order to make the procedure more efficient, a
catalytic amount of (R,R)-DIPT was used as a chiral auxiliary.
Chem. Lett. 2010, 39, 1036-1038
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1037
Table 2. The catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine imines 2 to homoallyl alcohol (1)
R
1) MgBr
2
N
(1.0 equiv)
2) (R,R)-DIPT
(0.2 equiv)
O
1
O
N
H
4)
2
N
N
(1.0 equiv)
OH
3) R'MgX
(n + 0.4 equiv)
80 °C, t d
OH
R
5
7
1 (n equiv)
in C H CN
3
2
5
Entry R¤MgX
1a
MeMgBr 1.0
2a n-BuMgCl 1.0
n
R
3 t/d Yield/% ee/%
Ph
a
2
2
2
2
2
2
2
3
4
77
50
76
90
72
87
23d
93
80
83b
88b
93b
94b
93c
93b
65c
63b
83b
3
4
5
6
7
8
9
n-BuMgCl 1.0
n-BuMgCl 1.1
n-BuMgCl 1.1 p-MeOC6H4
n-BuMgCl 1.1 p-ClC6H4
n-BuMgCl 1.1
n-BuMgCl 1.1
n-BuMgCl 1.1
Figure 1.
b
c
d
e
f
n-C5H11
c-C6H11
t-Bu
b
aThe MgBr2 was not added as an additive in step 1. Enantio-
selectivity was determined by HPLC analysis (Daicel
c
CHIRALCEL OD-H). Enantioselectivity was determined by
Figure 2.
d
HPLC analysis (Daicel CHIRALPAK IA). By-product 4 was
obtained in 53% yield.
(Figure 2) and the azomethine imine moiety is located more
away from DIPT moiety than the case of other 1,3-dipoles such
as nitrile oxides or nitrones, in which allyl alcohol was suitable
as a 1,3-dipolarophile.5,8 Therefore, higher enantioselectivity
was realized especially in the catalytic reaction of aromatic
azomethine imines.4b
As described above, an attractive and unique asymmetric
cycloaddition of azomethine imines to homoallylic alcohols has
been developed. The present method would be useful for the
preparation of optically active nitrogen and oxygen containing
chemicals.
The 1,3-dipolar cycloaddition of 2a to other homoallylic
alcohols was examined. Although the reaction with (E)-3-
penten-1-ol did not proceed, 3-methyl-3-buten-1-ol (5) worked
as a dipolarophile to afford a cycloadduct 6 with excellent
enantioselectivity of 95% ee.
Ph
1) MgBr
2
N
(1.0 equiv)
2) (R,R)-DIPT
(0.2 equiv)
O
O
N
H
4)
N
N
2a
(1.0 equiv)
ð1Þ
OH
OH
Ph
78%, 95% ee
3) n-BuMgCl
(1.5 equiv)
80 °C, 3 d
in C H CN
6
5 (1.1 equiv)
2
5
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) and a Grant-in-Aid for Scientific Research
from Japan Society for the Promotion of Science (JSPS).
The absolute configuration of 3a was determined to be R,R
as follows: The enantiomerically rich 3a (94% ee) was treated
with (1S)-camphanic chloride and Et3N in the presence of a
catalytic amount of 4-(N,N-dimethylamino)pyridine in CH2Cl2
to give the corresponding ester 7 (98%). Recrystallization gave
the diastereomerically pure ester 7. The absolute stereochemistry
of pyrazolidine skeleton in 7 was determined to be R,R by X-ray
crystallographic analysis of a single crystal (Figure 1).6 Based
on the absolute configuration of 3a, the azomethine imine 2a
was revealed to attack from the re-face of olefinic moiety of
homoallyl alcohol (1), that is the same as that in the case of allyl
alcohol.4a,4b The absolute configurations of other products were
tentatively determined to be R,R for 3b, 3c, 3e, 3f, and 6, and
5S,7R (configurational arrangement of the substituents at the
5- and 7-positions is the same as other products) for 3d,
respectively.7
Although the precise mechanism is not yet clear, the
generation of chloromagnesium salt of homoallyl alcohol was
crucial because a 1,3-dipolar cycloaddition of 2a to the benzyl
homoallyl ether did not proceed at all in the presence of
bis(chloromagnesium) salt of (R,R)-DIPT in C2H5CN at 80 °C
for 2 d. At the transition state, not imine nitrogen but carbonyl
oxygen of 2 might coordinate to magnesium salt of DIPT
References and Notes
1
Examples of biologically active compounds containing a
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1976; B. Cross, C. P. Grasso, B. L. Walworth, U.S. Patent
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2
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Chem. Lett. 2010, 39, 1036-1038
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1038
A. Suárez, C. W. Downey, G. C. Fu, J. Am. Chem. Soc.
6
Single crystals of 7 were obtained by recrystallization from
Et2O/hexane. Crystal data: C24H30N2O5, Mr = 426.51,
monoclinic, P21, a = 6.749(1), b = 11.182(2), c =
14.898(2) ¡, V = 1101.4(3) ¡3, ¢ = 101.625(1)°, Z = 2.
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81, 1669.
D
calcd = 1.286 g cm¹3. R = 0.035 (Rw = 0.047) for 4154
reflections with I > 3.00·(I) and 281 variable parameters.
Crystallographic data for 7 have been deposited with
Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC-785029. Copies of the data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html.
25
4
5
a) T. Kato, S. Fujinami, Y. Ukaji, K. Inomata, Chem. Lett.
2008, 37, 342. b) K. Tanaka, T. Kato, Y. Ukaji, K. Inomata,
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Although the asymmetric 1,3-dipolar cycloaddition of a
nitrile oxide generated in situ to homoallyl alcohol (1) was
tried, no chiral induction was observed, that is different from
the case of a similar 1,3-dipolar cycloaddition to allyl
alcohol.8
7
8
Specific rotations (½¡ꢀD (EtOH)) of 3a, 3b, 3c, and 6 were
+54 (98% ee), +44 (99% ee), +61 (97% ee), and +34 (95%
ee), respectively, which support the presumed structure of
3b, 3c, and 6.
Y. Ukaji, K. Sada, K. Inomata, Chem. Lett. 1993, 22, 1847;
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OH
1) Et Zn
(1.0 equiv)
2) (R,R)-DIPT
2
N
4)
An
Cl
N
O
(1.0 equiv)
(1.1 equiv)
OH
3) Et Zn
2
(1.1 equiv)
0 °C, 24 h
OH
An
38%, 0% ee
1 (1.0 equiv)
in CHCl
3
(An = p-MeOC H )
6
4
Chem. Lett. 2010, 39, 1036-1038
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/