Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines to allyl alcohol utilizing tartaric acid ester as a chiral auxiliary

Article abstract of DOI:10.3987/COM-09-S(S)116

The catalytic regio- and enantioselective 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 enan

Full text of DOI:10.3987/COM-09-S(S)116

HETEROCYCLES, Vol. 80, No. 2, 2010
887
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 887 - 893. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd August, 2009, Accepted, 22nd October, 2009, Published online, 22nd October, 2009
DOI: 10.3987/COM-09-S(S)116
CATALYTIC ASYMMETRIC 1,3-DIPOLAR CYCLOADDITION OF
AZOMETHINE IMINES TO ALLYL ALCOHOL UTILIZING TARTARIC
ACID ESTER AS A CHIRAL AUXILIARY
Katsuyoshi Tanaka, Tomomitsu Kato, Yutaka Ukaji,* and Katsuhiko
Inomata*
Division of Material Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan;
E-mail: inomata@cacheibm.s.kanazawa-u.ac.jp
Abstract – The catalytic regio- and enantioselective 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 enantioselectivities up to 93% ee. Addition of MgBr2
was crucial to realize reproducible high enantioselectivity.
The 1,3-dipolar cycloaddition is one of the most important methods for the construction of heterocyclic
5-membered rings in organic chemistry.1 The current challenge for 1,3-dipolar cycloaddition is to
control the absolute configuration because the multiple chiral centers can be formed in a single step.2
Although a lot of cycloadditions of nitrone possessing nitrogen and oxygen atoms have been developed,
the cycloaddition of azomethine imine which contains two nitrogen atoms was still limited.3 We have
previously reported asymmetric 1,3-dipolar cycloadditions of nitrile oxides and nitrones utilizing tartaric
acid ester as a chiral auxiliary.4,5 Recently we also developed an asymmetric 1,3-dipolar cycloaddition
of azomethine imines to allyl alcohol utilizing a stoichiometric amount of diisopropyl (R,R)-tartrate
[(R,R)-DIPT] as a chiral auxiliary.6 Toward improvement of this method, we made efforts to establish
the catalytic reaction system. Herein, we describe the regio- and enantioselective 1,3-dipolar
cycloaddition of azomethine imines using a catalytic amount of (R,R)-DIPT as a chiral auxiliary.
First, the 1,3-dipolar cycloaddition of an azomethine imine, 1-benzylidene-3-oxopyrazolidin-1-ium-2-ide
(2a), was examined using 0.2 equivalent of (R,R)-DIPT in MeCN at 80 °C: To a mixed solution of allyl
alcohol (1) and 0.2 equivalent of (R,R)-DIPT in MeCN were added 1.4 equivalents of MeMgBr and
Dedicated to Professor Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 2, 2010
azomethine imine 2a successively at 0 °C.6 After heating at 80 °C for 2 d, the corresponding
trans-pyrazolidine 3a was obtained with moderate enantioselectivity (Table 1, Entry 1). Production of
regioisomer and/or diastereomer was not confirmed. When the azomethine imine 2a was slowly added
into the reaction mixture, no enhancement of the enantioselectivity was observed (Entry 2). The
solubility of azomethine imine 2a is low in less polar solvent. Thus, the azomethine imine 2a might
gradually dissolve in the less polar organic solvent to be supplied into the reaction system with progress
of the reaction, that is, 0.2 equivalent of bis(bromomagnesium)salt of (R,R)-DIPT could act just like a
stoichiometric catalyst toward slightly dissolved 2a. Actually, when benzene was used as a cosolvent,
the reaction mixture was heterogeneous, but enantioselectivity was slightly enhanced (Entry 3). The use
c
of toluene or C5H9OMe as a cosolvent did not improve the enantioselectivity (Entries 4 and 5). The
pyrazolidine 3a was obtained in 75% ee in MeCN/ClCH2CH2Cl even the reaction mixture was
homogeneous (Entry 6). Though other cosolvents were widely examined, improvement of the
enantioselectivity was not observed any more (for example, Entry 7). These results indicated that slow
loading of the azomethine imine into the reaction mixture was not so effective as we initially expected.
Table 1. The effect of the cosolvent for the catalytic 1,3-dipolar cycloaddition of 2aa
Ph
N
O
O
N
3)H
1) (R,R)-DIPT (0.2 equiv.)
N N
OH
2) MeMgBr (1.4 equiv.)
2a (1.0 equiv.)
OH
Ph
80 °C, 2 d
1 (1.0 equiv.)
3a
Entry
Solvent
MeCN
Yield/%
ee/%b
56
1
2c
3
4
5
6
7
60
58
59
79
74
53
71
MeCN
42
MeCN / benzene (1/1)
MeCN / toluene (1/1)
MeCN / cC5H9OMe (1/1)
MeCN / ClCH2CH2Cl (1/1)
MeCN / THF (1/1)
64
42
53
75
39
aMeMgBr (1.04 M in THF) was used. bEnantiomer ratios were determined
by HPLC analysis (Daicel Chiralcel OD-H). cThe azomethine imine 2a
was slowly added into the reaction mixture over a period of 5 h.
Next, the effect of Lewis acid was investigated, since it was expected to work as an activator of the
asymmetric 1,3-dipolar cycloaddition under chiral reaction field derived from magnesium salt of
(R,R)-DIPT or a promoter of the exchange of the magnesium salt of the produced pyrazolidine for the
magnesium salt of allyl alcohol.7 The reaction was carried out by an alternative procedure: Azomethine

HETEROCYCLES, Vol. 80, No. 2, 2010
889
imine 2a was treated with Lewis acid, followed by subsequent addition of allyl alcohol (1), (R,R)-DIPT,
and Grignard reagent as shown in Table 2. The reproducible higher enantioselectivity was realized
8
when the 1,3-dipolar cycloaddition was performed in the presence of an equimolar amount of MgBr2 in
EtCN (Entry 2). The enantioselectivity was rather fluctuated in the absence of MgBr2 even by this
addition procedure.9 Pre-treatment of azomethine imine 2a with MgBr2 made 2a soluble in the solvent
by formation of MgBr2 complex to realize the reproducible results. When the amount of MgBr2 was
reduced to half, enantioselectivity decreased (Entry 3). Furthermore, the use of alkylmagnesium
chloride as a Grignard reagent to generate magnesium alkoxides improved the enantioselectivity
remarkably (Entry 4).
The concentration of the Grignard reagent scarcely influenced the
enantioselectivity (Entries 4 and 5). Influence of anion in the magnesium salt was next investigated.
MgCl2 was found to be also effective, though it did not dissolve completely in the reaction mixture (Entry
Table 2. The effect of the magnesium salts for the catalytic 1,3-dipolar cycloaddition of 2a
1) MgX (1.0 equiv.)
2
O
Ph
OH
2)
1 (1.0 equiv.) 4) RMgX' (1.4 equiv.)
N
N N
O
N
H
OH
3) (R,R)-DIPT (0.2 equiv.)
80 °C, 2 d
Ph
2a (1.0 equiv.)
3a
Entry
RMgX’
MeMgBrc
MgX2
MgBr2
MgBr2
Solvent
MeCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
Yield/%
65
ee/%a
60
67
49
82
82
83
87
78
83
80
76
59
17
1b
2b
3b
4b
5b
6g
7h
8i
9b
10b
11b
12b
13b
MeMgBrc
MeMgBrc
nBuMgCle
MeMgClf
MeMgClf
MeMgClf
MeMgClf
MeMgClf
MeMgBrc
MeMgClf
nBuMgCle
nBuMgCle
72
d
MgBr2
MgBr2
75
75
MgBr2
75
MgBr2
69
MgBr2
70
MgBr2
87
MgCl2
77
MgCl2
71
MgI2
41
Mg(OTf)2
56
Mg(ClO4)2
8
aEnantiomer ratios were determined by HPLC analysis (Daicel Chiralcel OD-H).
bReaction was carried out on 0.5 mmol scale of 2a in 6 ml EtCN. cMeMgBr (1.04 M in
THF) was used. d0.5 equivalent of MgBr2 was used. e nBuMgCl (1.04 M in THF) was
used. fMeMgCl (3.0 M in THF) was used. gReaction was carried out on 0.5 mmol
scale of 2a in 12 ml EtCN. hReaction was carried out on 1.0 mmol scale of 2a in 6 ml
EtCN. iReaction was carried out on 1.5 mmol scale of 2a in 6 ml EtCN.

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HETEROCYCLES, Vol. 80, No. 2, 2010
9). MgCl2 worked well even when MeMgBr was used to generate magnesium alkoxides (Entry 10).
MgI2 and Mg(OTf)2 were not so effective compared with MgBr2 (Entries 11 and 12). Mg(ClO4)2
showed poor enantioselectivity (Entry 13). Furthermore, the enantioselectivity was slightly influenced
by the concentration of the reactants (Entries 5–8). The cycloaddition under much concentrated
conditions afforded 3a with lower enantioselectivity (Entry 8).
Due to simplicity and reproducibility of
the procedure, the following reactions were carried out by the use of MgBr2 as a Lewis acid.10
The catalytic asymmetric cycloaddition of several azomethine imines 2 to allyl alcohol (1) was performed
in the presence of MgBr2 as shown in Table 3.11 Aryl-substituted azomethine imines 2b and 2c realized
high enantioselectivities (Entries 2 and 3). The cycloaddition of pentyl- and cyclohexyl-substituted
azomethine imines 2d and 2e also proceeded in an enantioselective manner (Entries 4 and 5).
t-Butyl-substituted azomethine imine 2f resulted in the highest enantioselectivity of 93% ee (Entry 6).
The absolute configuration of 3a was previously determined to be R,R by chemical correlation.6 The
absolute configurations of other products were tentatively determined to be R,R for 3b, 3c, 3e, and 3f and
5S,7R (configurational arrangement of the substituents at 5- and 7-positions is same as other products) for
3d, respectively.
Table 3. The asymmetric 1,3-dipolar cycloaddition of azomethine imines 2a
1) MgBr (1.0 equiv.)
2
O
R
OH
2)
1 (1.0 equiv.) 4) MeMgCl (1.4 equiv.)
N
N N
O
N
H
OH
3) (R,R)-DIPT (0.2 equiv.)
80 °C, t d
R
2a-f (1.0 equiv.)
in EtCN
3a-f
Entry
1b
2d
3d
4b
5d
6d
R
Ph
2
a
b
c
d
e
f
t/d
2
Yield/%
ee/%
70
63
74
54e
71
65
87c
89c
84c
81f
84c
93c
pMeOC6H4
pClC6H4
nC5H11
cC6H11
tBu
2
2
2
4
4
aMeMgCl (3.0 M in THF) was used. bReaction was carried out on 1.0 mmol
scale of 2 in 6 ml EtCN. cEnantiomer ratio was determined by HPLC analysis
(Daicel Chiralcel OD-H). dReaction was carried out on 0.5 mmol scale of 2 in
1
6 ml EtCN. eYield was determined by H NMR analysis due to difficulty
separating from a by-product 4 (22% yield) (see ref. 12). fEnantiomer ratio
was determined by HPLC analysis (Daicel Chiralpak IA).
O
O
N N
N N
OH
N
(5S) (7R)
3d
HN
4
O

HETEROCYCLES, Vol. 80, No. 2, 2010
891
Although the precise reaction mechanism is not yet clear, a plausible mechanism of the catalytic cycle is
shown in Scheme 1. In this system, the dramatic rate enhancement was not observed by the addition of
magnesium salt. The salt might promote the replacement of the produced magnesium-bridging chiral
salt (E) by the magnesium salt of 1 (B)13 and azomethine imine complex with magnesium salt (C) to
release a magnesium bridging salt (F) from the catalytic cycle smoothly. Furthermore, there might be
another possibility that magnesium salt diminishes the direct uncatalyzed racemic reaction between B and
C into F through the tight complexation of the azomethine imine with magnesium salt by reducing the
dipolar nature of the azomethine imine. However, the present reaction was found not to be the case,
because the reaction without the magnesium tartrate proceeded as well.14
X
2
Mg
i
R
X'MgO
X'MgO
CO Pr
2
OMgX'
N
O
N
H
i
CO Pr
2
B
C
A
Initiation of Reaction
(X, X' = Cl or Br)
X
X
X'
Mg
O
i
Mg
O Pr
O
R
N
N
O
O
MgX
H
2
N N
Mg
i
O Pr
O
O
O
MgX'
R
Mg
O
D
F
X'
2
X'
O
i
O Pr
X
Mg
X
Mg
Mg
2
2
O
R
O
OMgX'
N
O Mg
i
O
O Pr
N
N
H
O
N
R
Mg
O
B
Scheme 1.
C
X'
2
E
As described above, an attractive catalytic asymmetric cycloaddition of azomethine imines to allyl
alcohol has been developed. Because of easy availability of (R,R)- and (S,S)-DIPT, this method
provides the useful way to prepare both enantiomers of trans-pyrazolidines.
ACKNOWLEDGEMENTS
The present work was financially supported in part by a Grant-in-Aid for Scientific Research on Priority
Areas “Advanced Molecular Transformations of Carbon Resources” from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT) and a Grant-in-Aid for Scientific Research (C) from
Japan Society for the Promotion of Science (JSPS).

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HETEROCYCLES, Vol. 80, No. 2, 2010
REFERENCES AND NOTES
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7. It was reported that magnesium salts accelerated 1,3-dipolar cycloaddition of nitrile oxides and
nitrones to allylic alcohols: S. Kanemasa, T. Tsuruoka, and E. Wada, Tetrahedron Lett., 1993, 34,
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8. Magnesium bromide was generated in situ by the treatment of magnesium metal with
1,2-dibromoethane in THF.
9. The cycloaddition in the absence of MgBr2 in MeCN once gave 3a in 52% yield with 63% ee.

HETEROCYCLES, Vol. 80, No. 2, 2010
893
However, in the worst case, 3a was produced in 66% yield with 35% ee.
10. Not only magnesium salts but also other metal salts were examined. However, the chemical yields
and/or the enantioselectivity of the product 3a were not satisfactory as follows. Chemical yield/ee;
Zn(OTf)2: 41%/15% ee, CuCl2: 9%/80% ee, Cu(OTf)2: 4%/57% ee, NiCl2: 52%/66% ee, Cp2TiCl2:
17%/93% ee, Cp2ZrCl2: 17%/85% ee.
11. By comparison of the results between from the reaction of 1.0 mmol scale of 2 in 6 ml EtCN and
from the reaction of 0.5 mmol scale of 2 in 6 ml EtCN, the better results are listed in Table 3.
12. By-product 4 might be produced by 1,3-dipolar cycloaddition of 2d to an enamine-type tautomer of
2d generated in situ.
13. The 1,3-dipolar cycloaddition of 2a to ally benzyl ether did not proceed at all under similar reaction
conditions. The generation of chloromagnesium salt of allyl alcohol (1) (B) was crucial for the
present reaction.
1) MgBr (1.0 equiv.)
2
O
Ph
OBn
2) (R,R)-DIPT (0.2 equiv.) 4)
(1.0 equiv.)
N
N N
O
N
H
OBn
3) MeMgCl (0.4 equiv.)
80 °C, 2 d
Ph
2a (1.0 equiv.)
in EtCN
14. A background reaction in the absence of chloromagnesium salt of (R,R)-DIPT gave racemic 3a in
65% yield under the similar conditions.
1) MgBr (1.0 equiv.)
2
O
Ph
OH
2)
1 (1.0 equiv.) 3) MeMgCl (1.0 equiv.)
N
N N
O
N
H
OH
80 °C, 2 d
in EtCN
Ph
2a (1.0 equiv.)
rac-3a
65%