Asymmetric 1,3-Dipolar cycloaddition reactions of azomethine imines with acrolein catalyzed by L-proline and its derivatives

Article abstract of DOI:10.3987/COM-10-11967

1,3-Dipolar cycloadditions between acrolein and various N,N'-cyclic azomethine imines in the presence of L-proline and its derivatives as organocatalysts were investigated. Reactions that were catalyzed by (S)-indline-2-carboxylic acid (30 mol%) in CHCl

Full text of DOI:10.3987/COM-10-11967

HETEROCYCLES, Vol. 81, No. 7, 2010
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HETEROCYCLES, Vol. 81, No. 7, 2010, pp. 1669 - 1688. © The Japan Institute of Heterocyclic Chemistry
Received, 30th April, 2010, Accepted, 8th June, 2010, Published online, 9th June, 2010
DOI: 10.3987/COM-10-11967
ASYMMETRIC 1,3-DIPOLAR CYCLOADDITION REACTIONS OF
AZOMETHINE IMINES WITH ACROLEIN CATALYZED BY
L-PROLINE AND ITS DERIVATIVES
Hiroyuki Suga,†* Tadashi Arikawa,† Kennosuke Itoh,† Yukihisa Okumura,†
Akikazu Kakehi,† and Motoo Shiro‡
Department of Chemistry and Material Engineering, Faculty of Engineering,
Shinshu University, Wakasato, Nagano 380-8553, Japan and Rigaku Corporation,
3-9-12 Matsubaracho, Akishima, Tokyo 196-8666, Japan, E-mail:
sugahio@shinshu-u.ac.jp
Abstract – 1,3-Dipolar cycloadditions between acrolein and various N,N’-cyclic
azomethine imines in the presence of L-proline and its derivatives as
organocatalysts were investigated.
Reactions that were catalyzed by
(S)-indline-2-carboxylic acid (30 mol%) in CHCl3/MeOH 97:3 (v/v) showed high
exo-selectivities (exo/endo 91:9 ~ 99:1) and enantioselectivities (75 ~ 98% ee).
In contrast, reactions catalyzed by L-proline (30 mol%) under similar conditions
favored the endo-cycloadduct (83:27 ~ 99:1) with modest to good
enantioselectivities (31 ~ 83% ee). Based on our studies, the diastereoselective
mechanism of the L-proline-catalyzed reaction was found to involve the
isomerization of the exo- to the endo-cycloadduct in the presence of L-proline.
INTRODUCTION
1,3-Dipolar cycloadditions have served as powerful and effective reactions in the construction of
five-membered heterocyclic compounds, commonly found within the fundamental frameworks of
numerous biologically important natural products.1, 2c During the past two decades, various catalytic
asymmetric 1,3-dipolar cycloadditions that are catalyzed by chiral Lewis acids and organocatalysts have
been developed.2 For the contribution of such asymmetric dipolar cycloaddition chemistry, we have
recently reported on chiral Ni(II) complexes of binaphthyldiimine (BINIM) as highly effective catalysts
for providing high levels of asymmetric induction for the cycloadditions of nitrones,3 azomethine imines,4

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HETEROCYCLES, Vol. 81, No. 7, 2010
nitrile oxides,5 and carbonyl ylides.6 For the reactions between N,N’-cyclic azomethine imines and
3-acryloyl-2-oxazolidinone, the catalytic effects of the BINIM-Ni(II) complexes were also evident in
terms of rate acceleration with high endo- and enantioselectivity of the cycloadducts.4 Upon further
1
investigations using H NMR, the BINIM-Ni(II) complex was found to be predominantly coordinated to
the azomethine imine rather than 3-acryloyl-2-oxazolidinone during the reaction. In contrast to the
BINIM-Ni(II)-catalyzed reactions, the use of aminoindanol-derived bis(oxazoline)-Cu(OTf)2 as the
catalyst resulted in high exo- and enantioselectivities for similar cycloadditions involving N,N’-cyclic
azomethine imines and 2-acryloyl-3-pyrazolidinones.7 However, for such chiral Lewis acid-catalyzed
reactions, good reactivities with high enantioselectivities were limited to acrylic acid derivatives as the
dipolarophiles, presumably due to the relatively basic nature of the N,N’-cyclic azomethine imines.8
High levels of asymmetric induction have been reported for the organocatalytic [3+2] cycloadditions of
N,N’-cyclic azomethine imines catalyzed by ,-bis-[3,5-di(trifluoromethyl)phenyl]prolinol9
(exo-selectivity) and 9-amino-9-deoxyepiquinine derivatives10 (endo-selectivity). For these reactions,
the disubstituted alkenes, which possess an aldehyde or ketone moiety, were effectively activated as the
dipolarophiles – specifically, the above organocatalytic cycloadditions involve -substituted-,-
unsaturated aldehydes and cyclohexenone, respectively. Acrolein, however, remained to be employed
as a dipolarophile for these organocatalytic cycloadditions of N,N’-cyclic azomethine imines. In this
paper, we describe the cycloadditions between acrolein and N,N’-cyclic azomethine imines that are
catalyzed by either L-proline to selectively give the corresponding endo-cycloadducts with good
enantioselectivity, or by (S)-indoline-2-carboxylic acid to give the exo-cycloadducts with extremely high
diastereo- and enantioselectivities.
RESULTS AND DISCUSSION
Cycloadditions of azomethine imines catalyzed by L-proline
O
O
O
O
O
CO2H
N
H
N
N
N
N
NaBH4
N
30 mol%
N
N
N
N
N
CHO
in CHCl3-
EtOH
in CHCl3
2
OH
OH
H
Ph
1aa
CHO
endo-3aa
CHO
exo-3aa
Ph
endo-3aa'
Ph
exo-3aa'
Ph
Ph
Scheme 1
Initially, the cycloaddition between azomethine imine 1aa and acrolein (2) was carried out in the presence

HETEROCYCLES, Vol. 81, No. 7, 2010
1671
Table 1. L-proline-catalyzed cycloaddition reaction of azomethine imine 1aa with acrolein (2)a
Entry Purification of
Additive (%, v/v)c Time (h) Yield (%)d endo/exoe
% eef
endo
b
CHCl3
exo
74
58
64
69
74
68
68
ND
77
84
88
84
88
1
2
No
None
17
5
93
66
90
94
53
81
84
85
93
87
83
86
90
88 : 12
57: 43
80 : 20
86 : 14
85 : 15
76 : 24
92 : 8
78
48
73
75
76
73
73
77
79
83
83
76
79
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
None
3
EtOH (0.1)
EtOH (1.0)
i-PrOH (1.0)
MeOH (0.1)
MeOH (0.5)
MeOH (1.0)
MeOH (2.0)
MeOH (3.0)
MeOH (4.0)
MeOH (5.0)
MeOH (3.0)
17
20
21
15
28
19
28
24
24
19
34
4
5
6
7
8
91 : 9
9
95 : 5
10
11
12
13g
94 : 6
89 : 11
78 : 22
73 : 27
a
o
b
The reaction was carried out in CHCl3 in the presence of L-proline (30 mol%) at 25 C.
No:
commercial grade CHCl3 (stabilized with EtOH, 0.3 ~ 1.0%, v/v; Kanto Kagaku) was used without
c
further purifications, Yes: CHCl3 purified by drying with CaCl2 then distilled over P2O5.
Percent
d
values (v/v) are based on the volume of CHCl3.
The yield of the corresponding alcohols after
e
1
f
reduction with NaBH4.
Determined using H NMR analysis.
Determined using chiral HPLC
g
(Daicel Chiralpak AD-H) analysis after conversion to the corresponding alcohol via NaBH4 reduction.
10 mol% of L-proline was used.
of L-proline (30 mol%) as the catalyst (Scheme 1, Table 1). Although the reaction in CH2Cl2 was
unsuccessful,11 presumably due to the insolubility of L-proline, the reaction in CHCl3 (commercial grade)
o
at 25 C for 17 h gave the cycloadducts in high yield with an endo/exo ratio of 88:12 (entry 1).12 The
cycloadducts were isolated, after reduction with NaBH4, as the corresponding alcohols. Enantiomeric
excesses of the endo- (78% ee) and exo-cycloadducts (74% ee) were determined using HPLC analysis of
the corresponding alcohols. Interestingly, under similar conditions, the use of purified CHCl3 (dried
over CaCl2, followed by distillation over P2O5) resulted in a lower yield with decreased diastereo- and
enantioselectivity (entry 2). Because commercial grade CHCl3 contains 0.3 ~ 1.0% (v/v) EtOH as a

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HETEROCYCLES, Vol. 81, No. 7, 2010
stabilizer, we decided to examine the inclusion of alcohols such as EtOH, i-PrOH, and MeOH as
additives of dried and purified CHCl3. Among the three alcohols (entries 4, 5, and 8), the addition of
MeOH was found to give the highest diastereo- and enantioselectivity of the endo-cycloadduct (entry 8),
in which an amount of 3.0% (v/v) MeOH gave the optimal diastereo- (endo/exo 94:6) and enantio-
selectivity (83% ee) (entry 10). Finally, a lower catalyst loading (10 mol%) resulted in slightly lower
diastereo- (endo/exo 73:27) and enantioselectivity (79% ee) of the endo-cycloadduct (entry 13).
Although a precise role of MeOH is not clear, an addition of MeOH presumably increases solubility of
L-proline and accelerates the formation of an active iminium ion. An amount of the solvent
(CHCl3/MeOH 97:3 (v/v), 42 mL for 0.5 mmol scale) is also important factor for the reaction rate
probably because of solubility of L-proline.
Table 2. L-proline-catalyzed reactions of azomethine imines with acrolein (2)a
R1
R1
R1
R1
R1
O
N
O
O
CO2H
R1
N
H
R2
R2
R2
R2
N
N
30 mol%
R2
R2
N
N
N
CHO
in CHCl3-MeOH
(97 : 3 v/v%)
R3
2
R3
H
R3
CHO
exo-3
CHO
1
endo-3
Entry R1
R2
H
R3
Ph
1
1aa
Time (h)
24
3
3aa
Yield (%)b endo/exoc
% eed, endo
1
2
3
4
5
6
7
8
9
H
Me
H
87
89
50
68
81
88
85
78
54
94 : 6
87 : 13
90 : 10
99 : 1
83 (84)e
H
Me
H
Ph
Ph
1ba
1ca
1ab
1af
1ag
1ai
14
39
24
48
24
24
52
52
3ba
3ca
3ab
3af
3ag
3ai
78 (83)e
79 (69)e
74
H
p-ClC6H4
o-ClC6H4
p-MeC6H4
2-Naphthyl
Cyclohexyl
Isobutyl
H
H
88 : 12
99 : 1
50
H
H
74
H
H
99 : 1
82
H
H
1aj
1ak
3aj
3ak
> 99 : 1
83 : 27
31
H
H
32
a
The reactions were carried out in purified CHCl3/MeOH 97:3 (v/v) in the presence of L-proline (30
b
c
mol%) at 25 oC.
The yield of the corresponding alcohols after reduction with NaBH4.
Determined
1
d
using H NMR analysis.
Determined using chiral HPLC (Daicel Chiralpak AD-H or OD-H) analysis
e
after conversion to the corresponding alcohol via NaBH4 reduction.
Enantioselectivity of the
exo-cycloadduct.

HETEROCYCLES, Vol. 81, No. 7, 2010
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Next, the cycloadditions were carried out under the optimized conditions using azomethine imines 1ba
and 1ca, which possess dimethyl substituents at their pyrazolidinone ring (Table 2, entries 2 and 3,
respectively), to afford the corresponding endo-cycloadducts with relatively good enantioselectivities.
The scope of the R3-substituent was investigated using azomethine imines with p- and o-substituted
phenyl, 2-naphthyl, and alkyl substituents. As shown in entries 4 – 9, the reactions exhibited good to
high endo-selectivities. Although the imines with p-substituted phenyl and 2-naphthyl substituents
showed relatively good enantioselectivities, the o-chlorophenyl- and alkyl-substituted imines resulted in
merely moderate enantioselectivities.
Cycloaddition of azomethine imine 1aa catalyzed by other L-proline derivatives
In attempts to improve the enantioselectivity, several other L-proline derivatives were evaluated as
organocatalysts, as shown in Table 3 (Scheme 1). The use of L-proline derivative 4 (entry 2), which
possesses a bulky TBDMSO-substituent at the 4-position of the pyrrolidine ring, failed to improve the
enantioselectivity of the endo-cycloadduct. The use of L-proline methyl ester hydrochloride (5) resulted
in a reversal of the facial selectivity, albeit with only slight asymmetric induction (entry 3). Although
the combination of L-prolinol 6 and p-nitrobenzoic acid as catalysts resulted in a low-yielding reaction
with only slight exo- and enantioselectivity (entry 4), the combination of TMS ether 7 and p-nitrobenzoic
acid gave the endo-cycloadduct selectively in a high yield (entry 5), thus providing a complimentary
enantioselectivity of the endo-cycloadduct to that of L-proline with the opposite facial selectivity.
Surprisingly, the reaction catalyzed by (S)-indoline-2-carboxylic acid selectively gave the
exo-cycloadduct in a high yield with good enantioselectivity (entry 6). Finally, although a longer
o
reaction time was necessary, lowering the reaction temperature to 0 C helped improve the exo/endo-
(91:1) and enantioselectivity (94% ee) (entry 7).
Cycloadditions of azomethine imines catalyzed by (S)-indoline-2-carboxylic acid
The reaction of azomethine imine 1aa with acrolein (2) in the presence of 10 mol%
(S)-indoline-2-carboxylic acid under similar conditions resulted in decreased yield and exo-selectivity
with good enantioselectivity of exo-adduct (Table 4, entry 2). The cycloadditions between acrolein (2)
and dimethyl-substituted azomethine imines 1ba and 1ca proceeded smoothly in the presence of
o
(S)-indoline-2-carboxylic acid (30 mol%) in CHCl3/MeOH 97:3 (v/v) at 0 C to selectively give the
corresponding exo-cycloadducts in high yields with high enantioselectivities (entries 3 and 4,
respectively). In particular, the highest exo- (> 99:1) and enantioselectivy (96% ee) were obtained using
azomethine imine 1ca. Subsequently, dimethyl-substituted azomethine imines 1cb – 1ce and 1cg – 1ch,

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HETEROCYCLES, Vol. 81, No. 7, 2010
Table 3.
Cycloadditions of azomethine imine 1aa with acrolein (2) catalyzed by several
organocatalystsa
Entry
1
Organocatalyst
Time (h)
24
Yield (%)b
87
endo:exoc
% eed
endo
exo
94 : 6
83
78
-14
1
84
CO2H
CO2H
N
H
TBDMSO
2
3
4
5
40
6
75
67
94 : 6
88 : 12
44 : 56
95 : 5
NDe
17
0
4
N
H
CO2Me
HCl
5
N
H
Ph
Ph
6
2
< 18
87
N
H
OH
(p-NO2C6H4CO2H (30 mol%))
Ph
6
-84
57
Ph
7
N
H
OTMS
(p-NO2C6H4CO2H (30 mol%))
6
20
70
91
94
15 : 85
9 : 91
19
20
86
94
7f
CO2H
8
N
H
a The reactions were carried out in purified CHCl3/MeOH 97:3 (v/v) in the presence of an organocatalyst
o
b
c
(30 mol%) at 25 C.
The yield of the corresponding alcohols after reduction with NaBH4.
1
d
Determined using H NMR analysis.
Determined using chiral HPLC (Daicel Chiralpak AD-H)
e
f
analysis after conversion to the corresponding alcohol via NaBH4 reduction.
reaction was carried out at 0 oC.
Not determined.
The
which possess p-substituted phenyl groups as the R3–substituent, were examined under similar conditions.
As shown in entries 5 – 10, relatively good to excellent enantioselectivies (98 ~ 75% ee) along with
extremely high exo-selectivities (> 99:1) were observed, regardless of the electronic character of the
p-susbstituents. However, in the case of o-chlorophenyl derivative 1cf (R1 = H, R2 = Me, R3 =
o-ClC6H4), the reaction did not give cycloadducts under similar conditions. The use of 2-naphthyl
derivative 1ci (R1 = H, R2 = Me, R3 = 2-naphthyl) also gave the exo-cycloadduct as the sole product with

HETEROCYCLES, Vol. 81, No. 7, 2010
1675
high enantioselectivity (entry 11). Although the reaction of cyclohexyl derivative 1cj (R1 = H, R2 = Me,
R3 = cyclohecyl) also showed good enantioselectivity with high exo-selectivity, the yield was
unsatisfactory (entry 12).
Table 4. (S)-Indoline-2-carboxylic acid-catalyzed cycloadditions of azomethine imines with acrolein
(2)a
R1
R1
R1
R1
R2
R2
R1
R1
O
N
O
N
O
CO2H
N
H
R2
R2
R2
30 mol%
N
R2
N
N
N
CHO
in CHCl3-MeOH
(97 : 3 v/v%)
R3
2
R3
H
R3
CHO
exo-3
CHO
1
endo-3
Entry R1
R2
R3
1
Time (h)
3
Yield (%)b exo:endoc
% eed, exo
1
2f
3
H
H
H
Ph
Ph
Ph
Ph
1aa
70
3aa
3aa
3ba
3ca
3cb
3cc
3cd
3ce
3cg
3ch
3ci
94
55
91 : 9
94 (20)e
90 (30)e
93 (6)e
96
H
1aa 163
88 : 12
92 : 8
Me
H
H
1ba
1ca
1cb
1cc
1cd
1ce
1cg
72
36
95
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
82
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
5
H
p-ClC6H4
p-BrC6H4
p-CNC6H4
p-NO2C6H4
p-MeC6H4
42
72
94
6
H
56
76
93
7
H
60
73
96
8
H
124
42
75
75
9
H
66
97
10
11
12
H
p-MeOC6H4 1ch
56
77
98
H
2-Naphthyl
Cyclohexyl
1ci
1cj
60
83
95
H
149
3cj
< 29
88
a
The reactions were carried out in purified CHCl3/MeOH 97:3 (v/v) in the presence of
o
b
(S)-indoline-2-carboxylic acid (30 mol%) at 0 C.
The yield of the corresponding alcohols after
c
1
d
reduction with NaBH4.
Determined using H NMR analysis.
Determined using chiral HPLC
(Daicel Chiralpak AD-H or IA) analysis after conversion to the corresponding alcohol via NaBH4
f
reduction. e Enantioselectivity of the endo-cycloadduct.
The reaction was carried out with 10 mol%
of the catalyst.

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HETEROCYCLES, Vol. 81, No. 7, 2010
Isomerization of the exo- to the endo-cycloadduct
O
O
CO2H
N
H
N
N
(30 mol%)
N
N
in CHCl3-MeOH
(97/3 v/v)
Ph
CHO
Ph
CHO
exo-3aa
endo-3aa
65 h
exo : endo = 92 : 8
exo : endo = 6 : 94
Scheme 2
Table 5. Relationship between reaction time and the endo/exo ratio for L-proline-catalyzed cycloadditions
between azomethine imine 1aa and acrolein (2)a
Entry
Time (h)
Yield (%)b
endo:exoc
47 : 53
60 : 40
81 : 19
92 : 8
% ee,d endo
exo
88
82
88
88
84
1
2
3
4
1
3
27
73
87
92
87
82
73
72
79
83
6
12
24
5
94 : 6
a
The reactions were carried out in purified CHCl3/MeOH 97:3 (v/v) in the presence of L-proline (30
b
c
mol%) at 25 oC.
The yield of the corresponding alcohols after reduction with NaBH4.
Determined
1
d
using H NMR analysis.
Determined using chiral HPLC (Daicel Chiralpak AD-H or OD-H) analysis
after conversion to the corresponding alcohol via NaBH4 reduction.
To gain insight into the reaction mechanisms causing opposite diastereoselectivities exhibited by the
L-proline and the (S)-indoline-2-carboxylic acid catalyts, an exo-enriched (exo/endo 92:8) mixture of
diastereomers 3aa was treated with L-proline (30 mol%) in CHCl3/MeOH 97:3 (v/v) at 25 oC (Scheme 2).
Surprisingly, after stirring for 65 h, the exo/endo ratio indicated an endo-enriched (exo:endo 6:94) mixture,
which strongly suggests that the exo-cycloadduct isomerizes to the endo-cycloadduct under our reaction
conditions. To further investigate the endo-selectivity of the L-proline-catalyzed reactions, the rate of
the endo/exo–isomerization was determined, under a catalyst loading of 30 mol% (Table 5, Scheme 1).
After a reaction time of 1 h, the cycloadducts were obtained with an endo/exo ratio of 47:53 (27% yield,
entry 1). Longer reaction times resulted in higher endo/exo ratios (entries 2 – 5), ending with an
endo/exo ratio of 94:4 after 24 h (87% yield, entry 5). The enantioselectivities of the endo- and

HETEROCYCLES, Vol. 81, No. 7, 2010
1677
exo-cycloadducts were 83% ee and 84% ee, respectively.
These results indicate that the
exo-cycloadduct isomerizes to the endo-cycloadduct in the presence of L-proline as the catalyst.
Absolute configuration of exo-3cc with reaction mechanism for the asymmetric induction
To gain insight into the mechanism behind the asymmetric induction, X-ray crystal analysis was carried
out using the corresponding alcohol derived from exo-3cc via NaBH4 reduction.
For the
(S)-indoline-2-carboxylic acid-catalyzed reaction, the resulting alcohol obtained via NaBH4 reduction
possesses a (5S,6R)-configuration (Figure 1). As shown in Scheme 3, the high exo-selectivity can be
attributable to the selective formation of a sterically-favorable Z-iminium ion that is susceptible to the
cycloaddition by the azomethine imine via an exo-approach. The selectivity is further assisted by
favorable interactions between the negative charge of the carboxylate ion and the positive charge of the
azomethine imine from the upper side of the olefin moiety. The configuration obtained from this facial
selectivity (upper side approach) is consistent with that observed by X-ray analysis, as shown in Figure 1.
O
N
N
(5S)
(6R)
OH
Br
Figure 1. ORTEP drawing of the corresponding alcohol obtained from exo-3cc
On the other hand, for the L-proline-catalyzed reactions, although the initial diastereoselectivity remains
unclear, the exo-cycloadduct readily epimerizes at the aldehyde-substituted stereogenic center, under the
reaction conditions, to the more thermodynamically stable endo-cycloadduct. The facial selectivity
during the asymmetric induction would be similar to that of the (S)-indoline-2-carboxylic acid-catalyzed
reactions.
In contrast to these organocatalysts that possess a carboxylic acid moiety, the
L-prolininol-derived TMS ether catalyst 7 exhibited the opposite facial selectivity (Table 3, entry 4),
which can be attributed to the effective shielding of the upper side by the sterically hindered TMS ether
moiety thus blocking the interactions of the positive charge of azomethine imine.

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CO2H
CHO
CO2
CO2
N
N
H
N
H
E
Z
O
O
O
C
CO2
R
N
N
H
O
N
N
N
N
N
R
R
R
O2C
N
CHO
N
N
N
O
O
Scheme 3
CONCLUSION
We have demonstrated that (S)-indoline-2-carboxylic acid (30 mol%) can serve as an efficient
organocatalyst for the asymmetric cycloadditions between N,N’-cyclic azomethine imines and acrolein to
afford the corresponding exo-cycloadducts with high diastereo- (91:1 ~ > 99:1) and enantioselectivities
(75 ~ 98% ee). In contrast, the L-proline catalyst (30 mol%) afforded the endo-cycloadducts selectively
(83:27 ~ > 99:1) with modest to good enantioselectivities (31 ~ 83% ee). The contrasting
diastereoselectivites can be explained based on our studies that showed the isomerization of the
exo-cycloadduc into the endo-cycloadduct in the presence of L-proline. The solvent system of
CHCl3/MeOH 97:3 (v/v) was also essential for optimizing the cycloadditions.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were taken with FT/IR spectrophotometer. 1H NMR
spectra were run at 400 MHz. Chemical shifts are expressed in parts per million downfield from
13
tetramethylsilane as an internal standard. C NMR spectra were recorded at 100 MHz using broadband
proton decoupling. Chemical shifts are expressed in parts per million downfield from tetramethylsilane,
using the middle resonance of CDCl3 (77.0 ppm) as an internal standard. For preparative column
chromatography, Wakogel C-300HG was employed. All reactions were carried out under an argon
atmosphere in dried glassware.
L-Proline, L-proline methyl ester hydrochloride (5),
(S)-indoline-2-carboxylic acid (8), and acrolein (2) are commercially available and used without further
purification. (4R)-4-(t-Butyldimethylsilyloxy)-L-proline (4),13 L-prolinol 6,14 and TMS ether 715 were
prepared according to the procedure reported previously. Azomethine imines were prepared according
to the procedure reported by Fu.16 CHCl3 was purified by distillation first from CaCl2 and then P2O5

HETEROCYCLES, Vol. 81, No. 7, 2010
1679
under argon. CH2Cl2 was purified by distillation first from CaCl2 and then CaH2 under argon. MeOH
and ethanol were purified by distillation from the corresponding magnesium alkoxide.
General procedure for the asymmetric cycloaddition reaction of azomethine imine with acrolein
was exemplified by the reaction of azomethine imine 1ca in the presence of
(S)-indoline-2-carboxylic acid.
Azomethine imine 1ca (101.1 mg, 0.50 mmol) was added to a solution of acrolein (66.7 l, 1.0 mmol)
and (S)-indoline-2-carboxylic acid (24.5 mg, 0.15 mmol) in CHCl3 (40.7 mL) and MeOH (1.3 mL) at 0
oC. After stirring the mixture for 36 h at the same temperature, a solution of NaBH4 (75.7 mg, 2.0
mmol) in EtOH (5.0 mL) was added, and then the stirring was continued for 1 h. The reaction was
quenched with saturated aqueous NH4Cl solution (5.0 mL) and water (10.0 mL), and then the mixture
was extracted with CHCl3 (10.0 mL x 3). The combined extracts were dried over Na2SO4 and
evaporated in vacuo. The residue was chromatographed on silica gel with EtOAc and EtOAc-MeOH
(30 : 1 v/v) as an eluent to give the corresponding alcohol derived from exo-3ca’ (exo : endo = >99 : 1,
106.4 mg, 82%). The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H,
o
hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 C, tmajor = 47.0 min
(exo), tminor = 62.4 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one
o
26
o
(exo-3ca’): Colorless plates; mp 223-224 C (MeOH-Et2O); []D -60.5 (c 1.0, MeOH, exo : endo =
>99 : 1, 96% ee).; IR (KBr) 3367, 2964, 2926, 2879, 2359, 1678, 1601, 1473, 1432, 1398, 1370, 1296,
1222, 1177, 1113, 1047, 970, 912, 868, 758, 707, 683, 625, 507 cm-1; 1H NMR (CDCl3)  = 1.06 (3H, s),
1.26 (3H, s), 1.60 (1H, brs), 2.46 (1H, d, J = 16.1 Hz), 2.68 (1H, d, J = 16.1 Hz), 2.83 (1H, m), 3.30 (1H,
ddd, J = 1.2 Hz, 3.9 Hz, 11.7 Hz), 3.35-3.47 (2H, m), 4.00 (1H, dd, J = 8.5, 11.7 Hz), 4.17 (1H, d, J = 7.3
13
Hz), 7.30-7.45 (5H, m); C NMR (CDCl3)  = 22.5 (CH3), 29.1 (CH3), 43.2 (CH2), 47.7 (CH2), 48.2
(CH), 60.2 (C), 62.6 (CH2), 64.5 (CH), 127.7 (CH), 127.9 (CH), 128.5 (CH), 136.7 (C), 168.7 (C); Mass
(EI) m/z 260 (M+), 201, 91, 77, 56. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%.
Found: C, 69.17; H, 7.82; N, 10.72%.
(5R,6R)-6-Hydroxymethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3aa’): Colorless
o
26
o
plates; mp 111.5-112.5 C (benzene); []D -147.3 (c 1.0, CHCl3, exo : endo = 94 : 6, 94% ee (exo),
20% ee (endo)).; IR (KBr) 3424, 2947, 2847, 2360, 1664, 1470, 1426, 1213, 1139, 1041, 990, 749, 704,
1
601, 551 cm-1; H NMR (CDCl3)  = 1.79 (1H, brs), 2.69 (1H, ddd, J = 6.3 Hz, 9.3 Hz, 16.6 Hz), 2.80
(1H, m), 2.85-2.95 (2H, m), 3.33 (1H, m), 3.37-3.43 (2H, m), 3.63 (1H, ddd, J = 6.3 Hz, 9.3 Hz, 11.0 Hz),
13
3.79 (1H, d, J = 7.1 Hz), 4.05 (1H, dd, J = 8.5 Hz, 11.7 Hz), 7.29-7.55 (5H, m); C NMR (CDCl3)  =

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HETEROCYCLES, Vol. 81, No. 7, 2010
32.8 (CH2), 43.9 (CH2), 47.7 (CH), 48.0 (CH2), 62.2 (CH2), 71.6 (CH), 127.1 (CH), 127.9 (CH), 128.7
(CH), 134.7 (C), 170.5 (C).; MS (EI) m/z 232 (M+), 173, 117, 91, 78, 49; HRMS (EI) Calcd for
C13H16N2O2: (M+), 232.1236. Found: 232.1236. Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N,
12.04%. Found: C, 67.46; H, 6.95; N, 11.82%. The enantiomeric excess was determined by HPLC
analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5
mL/min, 35 °C, tminor = 36.8 min (endo), tmajor = 44.1 min (endo), tmajor = 88.6 min (exo), tminor = 136.5
min (exo)).
(5R,6R)-6-Hydroxymethyl-2,2-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one
(exo-3ba’): Colorless prisms; mp 57.5-59.0 oC (CH2Cl2-hexane); []D26 -117.7 o (c 1.0, CHCl3, exo : endo
= 92 : 8, 93% ee (exo), 6% ee (endo)); IR (KBr) 3423, 2965, 2362, 1670, 1457, 136,5 1047, 757, 705, 498
cm-1; 1H NMR (CDCl3)  = 1.21 (3H, s), 1.34 (3H, s), 2.04 (1H, brs), 2.55 (1H, d, J = 9.5 Hz), 2.94 (1H,
m), 3.31-3.42 (3H, m), 3.45 (1H, dd, J = 2.7 Hz, 11.6 Hz), 3.66 (1H, d, J = 6.6 Hz), 4.00 (1H, dd, J = 8.3
13
Hz, 11.6 Hz), 7.28-7.48 (5H, m); C NMR (CDCl3)  = 23.7 (CH3), 24.1 (CH3), 42.9 (CH2), 46.0 (C),
47.7 (CH), 61.8 (CH2), 64.9 (CH2), 72.7 (CH), 126.9 (CH), 127.7 (CH), 128.4 (CH), 134.5 (C), 170.7 (C);
Mass (EI) m/z 260 (M+), 201, 117, 92, 78. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%.
Found: C, 69.21; H, 7.78; N, 10.72%. The enantiomeric excess was determined by HPLC analysis
(Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min,
35 °C, tminor = 16.3 min (endo), tmajor = 19.0 min (endo), tmajor = 29.1 min (exo), tminor = 39.1 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-chlorophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one
o
25
o
(exo-3cb’): Colorless prisms.; mp. 184-184.5 C (benzene); []D -67.6 (c 1.0, MeOH, exo : endo =
>99 : 1, 94% ee (exo)).; IR (KBr) 3396, 2974, 2927, 2854, 1670, 1488, 1469, 1411, 1399, 1382, 1372,
1325, 1289, 1250, 1225, 1198, 1173, 1123, 1104, 1086 cm-1; 1H NMR (CDCl3)  = 1.05 (3H, s), 1.23 (3H,
s), 1.68 (1H, brs), 2.47 (1H, d, J = 16.3 Hz), 2.67 (1H, d, J = 16.3 Hz), 2.80 (1H, m), 3.26-3.36 (2H, m),
3.41 (1H, dd, J = 6.6, 11.0 Hz), 4.00 (1H, dd, J = 8.2, 11.0 Hz), 4.14 (1H, d, J = 7.6 Hz), 7.30-7.43 (4H,
13
m); C NMR (CDCl3)  = 22.3 (CH3), 28.9 (CH3), 43.3 (CH2), 47.7 (CH2), 47.8 (CH), 60.3 (C), 62.2
(CH2), 63.3 (CH), 128.6 (CH), 129.0 (CH), 133.5 (C), 135.4 (C), 168.4 (C); Mass (EI) m/z 294 (M+), 151,
126, 111, 92, 83, 56. Anal. Calcd for C15H19ClN2O2: C, 61.12; H, 6.50; N, 9.72%. Found: C, 60.83; H,
6.57; N, 9.72%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA,
o
hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 1.0 mL/min, 35 C, tminor = 24.7 min
(endo), tmajor = 27.5 min (endo), tmajor = 52.0 min (exo), tminor = 67.3 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-bromophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one
(exo-3cc’): Colorless plates; mp 202-203 oC (benzene); []D23 -63.6 o (c 0.80, MeOH, exo : endo = >99 :
1, 93% ee (exo)); IR (KBr) 3370, 2967, 2941, 2910, 2876, 1665, 1486, 1449, 1427, 1407, 1387, 1370,

HETEROCYCLES, Vol. 81, No. 7, 2010
1681
1351, 1294, 1220, 1205, 1177, 1162, 1122, 1111, 1072, 1049, 1010 cm-1; 1H NMR (CDCl3)  = 1.05 (3H,
s), 1.24 (3H, s), 1.58 (1H, brs), 2.45 (1H, d, J = 16.3 Hz), 2.66 (1H, d, J = 16.3 Hz), 2.80 (1H, m), 3.29
(1H, ddd, J = 1.5 Hz, 4.4 Hz, 11.7 Hz), 3.31-3.47 (2H, m), 4.01 (1H, dd, J = 8.5, 11.7 Hz), 4.13 (1H, d, J
13
= 7.3 Hz), 7.27-7.33 (2H, m), 7.46-7.54 (2H, m); C NMR (CDCl3)  = 22.5 (CH3), 29.0 (CH3), 43.3
(CH2), 47.6 (CH2), 47.8 (CH), 60.4 (C), 62.4 (CH2), 63.6 (CH), 121.7 (C), 129.4 (CH), 131.5 (CH), 136.0
(C), 168.7 (C); Mass (EI) m/z 338 (M+), 138, 126, 111, 83, 56. Anal. Calcd for C15H19BrN2O2: C,
53.11; H, 5.65; N, 8.26%. Found: C, 53.03; H, 5.65; N, 8.26%.; The enantiomeric excess was
determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV
254 nm, flow rate = 1.0 mL/min, 35 oC, tminor = 9.1 min (endo), tmajor = 11.4 min (endo), tmajor = 20.3 min
(exo), tminor = 26.9 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-cyanophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one
o
23
o
(exo-3cd’): Colorless needles; mp 163-164.5 C (benzene); []D -98.4 (c 1.0, MeOH, exo : endo =
>99 : 1, 96% ee (exo)); IR (KBr) 3379, 2976, 2953, 2934, 2911, 2892, 2225, 1671, 1605, 1504, 1474,
1443, 1421, 1371, 1294, 1252, 1229, 1181, 1157, 1122, 1111, 1075, 1051, 1018 cm-1; 1H NMR (CDCl3) 
= 1.04 (3H, s), 1.25 (3H, s), 1.68 (1H, brs), 2.46 (1H, d, J = 16.4 Hz), 2.66 (1H, d, J = 16.4 Hz), 2.87 (1H,
m), 3.24 (1H, m), 3.28 (1H, ddd, J = 1.2, 4.6, 11.7 Hz), 3.36 (1H, dd, J = 7.5 Hz, 10.7 Hz), 4.05 (1H, dd,
13
J = 8.5 Hz, 11.7 Hz), 4.21 (1H, d, J = 7.8 Hz), 7.50 – 7.61 (2H, m), 7.63 – 7.73 (2H, m); C NMR
(CDCl3)  = 22.3 (CH3), 28.7 (CH3), 43.4 (CH2), 47.2 (CH2), 47.5 (CH), 60.4 (C), 61.7 (CH2), 63.0 (CH),
111.3 (C), 118.2 (C), 128.4 (CH), 131.8 (CH), 142.9 (C), 168.7 (C).; Mass (EI) m/z 285 (M+), 111, 83, 56.
Anal. Calcd for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73%. Found: C, 67.15; H, 6.89; N, 14.75%. The
enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 5 : 1
o
v/v%, detector: UV 254 nm, flow rate = 0.4 mL/min, 35 C, tminor = 22.4 min (endo), tmajor = 25.0 min
(endo), tmajor = 37.0 min (exo), tminor = 46.0 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-nitrophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one
(exo-3ce’): Pale yellow leaflets; mp 161.5-163 oC (benzene); []D23 -55.3 o (c 0.80, MeOH, exo : endo =
>99 : 1, 75% ee (exo)).; IR (KBr) 3384, 2976, 2963, 2944, 2897, 1646, 1597, 1525, 1465, 1421, 1385,
1370, 1345, 1314, 1296, 1228, 1108, 1074, 1053, 1035 cm-1; 1H NMR (CDCl3)  = 1.05 (3H, s), 1.25 (3H,
s), 2.20 (1H, brs), 2.46 (1H, d, J = 16.8 Hz), 2.67 (1H, d, J = 16.3 Hz), 2.90 (1H, m), 3.20 (1H, dd, J = 5.4,
10.5 Hz), 3.29 (1H, ddd, J = 1.2, 4.6, 12.0 Hz), 3.37 (1H, dd, J = 7.8, 10.5 Hz), 4.04 (1H, dd, J = 8.3, 12.0
13
Hz), 4.27 (1H, d, J = 8.1 Hz), 7.56-7.71 (2H, m), 8.14-8.34 (2H, m); C NMR (CDCl3)  = 22.8 (CH3),
29.1 (CH3), 43.5 (CH2), 47.1 (CH2), 47.8 (CH), 60.4 (C), 62.1 (CH2), 63.4 (CH), 123.5 (CH), 128.7
(CH), 145.1 (C), 147.3 (C), 169.6 (C); Mass (EI) m/z 305 (M+), 111, 78. Anal. Calcd for C15H19N3O4: C,
59.01; H, 6.27; N, 13.76%. Found: C, 59.21; H, 6.17; N, 13.66%.; The enantiomeric excess was

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HETEROCYCLES, Vol. 81, No. 7, 2010
determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV
254 nm, flow rate = 1.0 mL/min, 35 oC, tminor = 18.1 min (endo), tmajor = 24.8 min (endo), tmajor = 37.3 min
(exo), tminor = 64.1 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-p-toyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3cg’):
Colorless needles; mp 187-187.5 oC (benzene); []D23 -67.7 o (c 0.80, MeOH, exo : endo = >99 : 1, 97%
ee (exo)); IR (KBr) 3368, 3094, 3060, 3028, 3010, 2963, 2926, 2875, 1685, 1632, 1515, 1474, 1449, 1431,
1398, 1371, 1297, 1256, 1222, 1205, 1182, 1167, 1125, 1078, 1053 cm-1; 1H NMR (CDCl3)  = 1.06 (3H,
s), 1.23 (3H, s), 1.71 (1H, brs), 2.35 (3H, s), 2.46 (1H, d, J = 16.3 Hz), 2.68 (1H, d, J = 16.3 Hz), 2.79
(1H, m), 3.28 (1H, dd, J = 3.7 Hz, 11.7 Hz), 3.38 – 3.46 (2H, m), 3.97 (1H, dd, J = 8.5 Hz, 11.7 Hz), 4.14
13
(1H, d, J = 7.3 Hz), 7.14 – 7.20 (2H, m), 7.27 – 7.34 (2H, m); C NMR (CDCl3)  = 21.2 (CH3), 22.1
(CH3), 28.7 (CH3), 42.9 (CH2), 47.9 (CH2), 47.9 (CH), 60.3 (C), 62.5 (CH2), 64.1 (CH), 127.5 (CH),
129.0 (CH), 133.3 (C), 137.4 (C), 167.9 (C); Mass (EI) m/z 274 (M+), 131, 111, 83, 56; Anal. Calcd for
C16H22N2O2: C, 70.04; H, 8.08; N, 10.21%. Found: C, 70.04; H, 8.07; N, 10.23%.; The enantiomeric
excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector:
UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tminor = 21.5 min (endo), tmajor = 23.7 min (endo), tmajor = 39.6
min (exo), tminor = 47.3 min (exo)).
(5R,6R)-6-Hydroxymethyl-5-(4-methoxyphenyl)-3,3-dimethyltetrahydropyrazolo[1,2-a]pyrazol-1-
o
26
o
one (exo-3ch’): Colorless needles; mp 192 C (benzene); []D -70.5 (c 0.80, MeOH, exo : endo =
>99 : 1, 98% ee (exo)).; IR (KBr) 3344, 2989, 2972, 2951, 2892, 2878, 2834, 1683, 1632, 1615, 1583,
1516, 1473, 1465, 1443, 1431, 1402, 1369, 1296, 1256, 1221, 1204, 1170, 1126, 1109, 1078, 1053, 1036,
cm-1; 1H NMR (CDCl3)  = 1.07 (3H, s), 1.21 (3H, s), 1.77 (1H, brs), 2.44 (1H, d, J = 16.3 Hz), 2.68 (1H,
d, J = 16.3 Hz), 2.77 (1H, m), 3.29 (1H, dd, J = 3.7 Hz, 11.7 Hz), 3.39 – 3.50 (2H, m), 3.82 (3H, s), 3.97
(1H, dd, J = 8.5 Hz, 11.7 Hz), 4.13 (1H, d, J = 7.3 Hz), 6.84 – 6.96 (2H, m), 7.28–7.38 (2H, m); 13C NMR
(CDCl3)  = 22.0 (CH3), 28.7 (CH3), 43.0 (CH2), 48.0 (CH2), 47.8 (CH), 55.1 (CH3), 60.2 (C), 62.2
(CH2), 63.3 (CH), 113.6 (CH), 128.0 (C), 128.7 (CH), 158.8 (C), 167.5 (C); Mass (EI) m/z 290 (M+), 147,
111, 83, 56. Anal. Calcd for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65%. Found: C, 66.07; H, 7.99; N,
9.41%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane :
o
2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 C, tminor = 30.8 min (endo),
tmajor = 33.5 min (endo), tmajor = 60.4 min (exo), tminor = 70.6 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(2-naphthyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one
(exo-3ci’): Pale red prisms; mp 260-261 oC (MeOH); []D26 -43.7 o (c 0.40, MeOH, exo : endo = >99 : 1,
95% ee (exo)).; IR (KBr) 3351, 2990, 2970, 2925, 2877, 1671, 1632, 1599, 1507, 1473, 1446, 1428, 1402,
1
1388, 1365, 1306, 1294, 1252, 1221, 1202, 1174, 1124, 1109, 1079, 1050 cm-1; H NMR (CDCl3)  =

HETEROCYCLES, Vol. 81, No. 7, 2010
1683
1.09 (3H, s), 1.27 (3H, s), 1.60 (1H, brs), 2.49 (1H, d, J = 16.4 Hz), 2.71 (1H, d, J = 16.4 Hz), 2.90 (1H,
m), 3.36 (1H, m), 3.39 (1H, dd, J = 5.6 Hz, 11.2 Hz), 3.46 (1H, dd, J = 6.3 Hz, 11.2 Hz), 4.05 (1H, dd, J
= 8.1 Hz, 11.2 Hz), 4.35 (1H, d, J = 7.3 Hz), 7.46 – 7.61 (3H, m), 7.77 – 7.96 (4H, m); 13C NMR (CDCl3)
 = 22.8 (CH3), 29.2 (CH3), 43.2 (CH2), 47.7 (CH2), 48.3 (CH), 60.3 (C), 62.7 (CH2), 64.7 (CH), 125.3
(CH), 126.2 (CH), 126.4 (CH), 126.8 (CH), 127.6 (CH), 127.7 (CH), 128.2 (CH), 132.9 (C), 133.0 (C),
134.3 (C); Mass (EI) m/z 310 (M+), 167, 111, 83, 56. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N,
9.03%. Found: C, 73.39; H, 7.33; N, 8.97%. The enantiomeric excess was determined by HPLC
analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5
mL/min, 35 oC, tminor = 26.2 min (endo), tmajor = 31.1 min (endo), tmajor = 55.2 min (exo), tminor = 74.1 min
(exo)).
(5R,6R)-5-Cyclohexyl-6-hydroxymethyl-3,3-dimethyltetrahydropyrazolo[1,2-a]pyrazol-1-one
(exo-3cj’): Pale yellow oil; []D23 +40.6 o (c 0.60, MeOH, exo : endo = >99 : 1, 88% ee (exo)).; IR (neat)
2984, 2932, 2856, 2361, 1680, 1452, 1371, 1113 cm-1; 1H NMR (CDCl3)  = 1.15 – 1.70 (11H, m), 1.26
(6H, s), 2.17 (1H, d, J = 14.9 Hz), 2.62 (1H, m), 2.79 (1H, d, J = 14.9 Hz), 2.99 – 3.09 (2H, m), 3.81-3.84
(2H, m), 3.99 (1H, dd, J = 8.3 Hz, 11.2 Hz), The signal of OH could not be identified; Mass (EI) m/z 266
(M+), 141; HRMS (EI) Found: m/z 266.1950. Calcd for C15H26N2O2 (M+): 266.1994. Anal. Calcd for
C15H26N2O2: C, 67.63; H, 9.84; N, 10.52%. Found: C, 68.21; H, 9.85; N, 9.93% (Satisfactory elemental
analysis was not obtained). The enantiomeric excess was determined by HPLC analysis (Daicel
Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tminor
= 19.6 min (endo), tmajor = 20.1 min (endo), tmajor = 31.2 min (exo), tminor = 34.0 min (exo)).
(5R,6S)-6-Hydroxymethyl-5-phenyl-tetrahydropyrazolo[1,2-a]pyrazol-1-one
(endo-3aa’):
Pale
orange leaflets; mp 142-143 oC (benzene-hexane); []D26 -14.1 o (c 1.0, CHCl3, endo : exo = 94 : 6, 83%
ee (endo), 84% ee (exo)).; IR (KBr) 3387, 3028, 2935, 2852, 2356, 1680, 1471, 1411, 1306, 1251, 1200,
1
1160, 1129, 1060, 1019, 837, 797, 754, 699, 610, 581 cm-1; H NMR (CDCl3)  = 2.52 (1H, brs),
2.69–2.77 (3H, m), 2.93 (1H, dt, J = 11.2 Hz, 8.8 Hz), 3.41 (1H, d, J = 9.3 Hz), 3.45 (1H, dt, J = 11.2 Hz,
7.8 Hz), 3.52 (1H, dd, J = 9.8 Hz, 11.2 Hz), 3.61 (1H, dd, J = 5.0 Hz, 11.5 Hz), 3.71 (1H, dd, J = 3.8 Hz,
11.5 Hz), 3.82 (1H, dd, J = 6.6 Hz, 11.2 Hz), 7.32-7.41 (5H, m); 13C NMR (CDCl3)  = 32.8 (CH2), 43.2
(CH2), 47.5 (CH2), 52.7 (CH), 60.0 (CH2), 71.0 (CH), 127.6 (CH), 128.0 (CH), 128.8 (CH), 137.1 (C),
170.3 (C); MS (EI) m/z 232 (M+), 173, 117, 91, 78, 56; HRMS (EI) Calcd for C13H16N2O2: (M+),
232.1212. Found: 232.1236. Anal. Calcd for C19H20N4O4: C, 67.22; H, 6.94; N, 12.04%. Found: C,
67.99; H, 7.39; N, 10.61% (Satisfactory elemental analysis was not obtained). The enantiomeric excess
was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector:
UV 254 nm, Flow rate = 0.5 mL/min, 35 oC, tminor = 35.0 min (endo), tmajor = 41.9 min (endo), tmajor = 84.3

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HETEROCYCLES, Vol. 81, No. 7, 2010
min (exo), tminor = 130.0 min (exo)).
(5R,6S)-6-Hydroxymethyl-2,2-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one
o
26
o
(endo-3ba’): Colorless prisms; mp 129-130.5 C (CH2Cl2-hexane); []D -27.6 (c 0.80, CHCl3, endo :
exo = 87 : 13, 78% ee (endo), 83% ee (exo)).; IR (KBr) 3440, 3031, 2971, 2927, 2838, 2360, 1694, 1469,
1
1405, 1367, 1345, 1306, 1254, 1191, 1127, 1074, 1038, 995, 949, 839, 775, 744, 697, 602, 556 cm-1; H
NMR (CDCl3)  = 1.21 (3H, s), 1.29 (3H, s), 2.59 (1H, brs), 2.62 (1H, d, J = 9.5 Hz), 2.75 (1H, m), 3.21
(1H, d, J = 9.5 Hz), 3.37 (1H, d, J = 9.3 Hz), 3.53-3.65 (2H, m), 3.72 (1H, dd, J = 3.6 Hz, 11.2 Hz), 3.83
13
(1H, dd, J = 8.0 Hz, 11.2 Hz), 7.23-7.45 (5H, m); C NMR (CDCl3)  = 23.8 (CH3), 24.1 (CH3), 42.4
(CH2), 52.6 (CH), 59.8 (CH2), 64.5 (CH2), 72.4 (CH), 127.6 (CH), 128.0 (CH), 128.5 (CH), 137.0 (C),
170.7 (C); Mass (EI) m/z 260 (M+), 201, 117, 91, 56. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N,
10.76%. Found: C, 68.88; H, 7.97; N, 10.86%. The enantiomeric excess was determined by HPLC
analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5
mL/min, 35 oC, tminor = 16.4 min (endo), tmajor = 18.9 min (endo), tmajor = 29.1 min (exo), tminor = 39.2 min
(exo).
(5R,6S)-6-Hydroxymethyl-3,3-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one
(endo-3ca’): Colorless leaflets; mp 142-143 oC (CH2Cl2-hexane); []D26 +23.6 o (c 1.0, CHCl3, endo : exo
= 90 : 10, 79% ee (endo), 69% ee (exo)); IR (KBr) 3437, 3029, 2970, 2935, 2872, 2360, 1687, 1461, 1379,
1292, 1252, 1229, 1177, 1060, 817, 753, 701, 594, 543 cm-1; 1H NMR (CDCl3)  = 1.01 (6H, s), 1.97 (1H,
brs), 2.47 (1H, d, J = 16.6 Hz), 2.63 (1H, d, J = 16.6 Hz), 2.67 (1H, m), 3.50-3.63 (2H, m), 3.64-3.76 (2H,
13
m), 3.78 (1H, d, J = 9.3 Hz), 7.27-7.44 (5H, m); C NMR (CDCl3)  = 22.7 (CH3), 28.6 (CH3), 42.5
(CH2), 47.8 (CH2), 53.7 (CH), 59.9 (CH2), 63.2 (CH), 127.6 (CH), 127.7 (CH), 128.4 (CH), 139.4 (C),
168.1 (C); Mass (EI) m/z 260 (M+), 201, 138, 117, 91, 56. Anal. Calcd for C15H20N2O2: C, 69.20; H,
7.74; N, 10.76%. Found: C, 69.17; H, 7.82; N, 10.72%. The enantiomeric excess was determined by
HPLC analysis (Daicel Chiralpak IA, CH2Cl2 : hexane : 2-PrOH = 20 : 10 : 1 v/v%, detector: UV 254 nm,
flow rate = 0.3 mL/min, 25 oC, tmajor and tminor = 40.5 min (exo), tmajor = 44.0 min (endo), tminor = 47.4 min
(endo)).
(5R,6S)-5-(4-Chlorophenyl)-6-hydroxymethyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ab’):
Colorless needles; mp 200.5-201 oC (benzene); []D26 -17.5 o (c 0.80, MeOH, endo : exo = 99 : 1, 74% ee
(endo)); IR (KBr) 3289, 3041, 2972, 2945, 2928, 2888, 2865, 1645, 1498, 1460, 1419, 1380, 1347, 1303,
1204, 1182, 1119, 1090 cm-1; 1H NMR (CDCl3)  = 2.22 (1H, brs), 2.60-2.79 (3H, m), 2.92 (1H, dt, J =
11.2, 8.4 Hz), 3.40 (1H, d, J = 8.8 Hz), 3.43-3.56 (2H, m), 3.60 (1H, dd, J = 5.4, 11.2 Hz), 3.70 (1H, dd, J
= 3.9, 11.2 Hz), 3.81 (1H, dd, J = 6.1, 11.2 Hz), 7.35 (5H, brs); 13C NMR (CDCl3)  = 32.8 (CH2), 43.2
(CH2), 47.4 (CH2), 53.0 (CH), 59.9 (CH2), 70.3 (CH), 128.8 (CH), 129.0 (CH), 133.9 (C), 135.9 (C),

HETEROCYCLES, Vol. 81, No. 7, 2010
1685
170.9 (C); Mass (EI) m/z 266 (M+), 151, 115, 98, 56. Anal. Calcd for C13H15ClN2O2: C, 58.54; H, 5.67;
N, 10.50%. Found: C, 58.61; H, 5.63; N, 10.47%. The enantiomeric excess was determined by HPLC
analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5
mL/min, 35 °C, tminor = 65.0 min (endo), tmajor = 70.2 min (endo)).
(5R,6S)-5-(2-Chlorophenyl)-6-hydroxymethyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3af’):
Pale yellow oil; []D24 +1.1 o (c 0.80, MeOH, endo : exo = 88 : 12, 50% ee (endo)).; IR (KBr) 3354, 2990,
2943, 2916, 2884, 1653, 1569, 1471, 1422, 1373, 1312, 1272, 1200, 1161, 1139, 1115, 1091, 1053, 1033
cm-1; 1H NMR (CDCl3)  = 2.17 (1H, brs), 2.63-2.83 (3H, m), 3.00 (1H, ddd, J = 7.8. 9.0, 11.2 Hz), 3.43
(1H, ddd, J = 7.3, 9.3, 11.2 Hz), 3.54 (1H, m), 3.68 (1H, dd, J = 5.4, 11.2 Hz), 3.74 (1H, dd, J = 4.4, 11.2
Hz), 3.85 (1H, dd, J = 6.1, 11.2 Hz), 4.02 (1H, d, J = 9.0 Hz), 7.20-7.40 (3H, m), 7.63-7.71 (1H, m); 13C
NMR (CDCl3)  = 32.5 (CH2), 44.0 (CH2), 47.3 (CH2), 53.4 (CH), 60.9 (CH2), 66.4 (CH), 127.2 (CH),
128.9 (CH), 129.0 (CH), 129.3 (CH), 133.9 (C), 135.0 (C), 171.3 (C); Mass (EI) m/z 266 (M+), 151, 125,
84, 77, 56. Anal. Calcd for C13H15ClN2O2: C, 58.54; H, 5.67; N, 10.50%. Found: C, 58.66; H, 5.76; N,
10.30%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane :
o
2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 C, tminor = 20.4 min (endo),
tmajor = 35.4 min (endo)).
(5R,6S)-6-Hydroxymethyl-5-p-tolyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ag’): Colorless
needles; mp 189-190 oC (benzene); []D27 -6.6 o (c 0.80, MeOH, endo : exo = 99 : 1, 74% ee (endo)); IR
(KBr) 3343, 3026, 2949, 2926, 2889, 2868, 1661, 1518, 1458, 1418, 1381, 1303, 1256, 1215, 1205, 1186,
1108, 1086, 1024 cm-1; 1H NMR (CDCl3)  = 1.90 (1H, brs), 2.36 (3H, s), 2.65-2.79 (3H, m), 2.93 (1H, dt,
J = 11.2, 8.4 Hz), 3.33 (1H, d, J = 9.5 Hz), 3.43 (1H, dt, J = 11.2, 7.7 Hz), 3.53 (1H, m), 3.61 (1H, m),
3.70 (1H, m), 3.78 (1H, dd, J = 6.8, 9.0 Hz), 7.16-7.21 (2H, m), 7.26-7.32 (2H, m); 13C NMR (CDCl3)  =
21.2 (CH3), 32.8 (CH2), 43.2 (CH2), 47.5 (CH2), 52.7 (CH), 60.0 (CH2), 70.9 (CH), 127.5 (CH), 129.2
(CH), 133.9 (C), 137.7 (C), 170.3 (C); Mass (EI) m/z 246 (M+), 131, 98, 56. Anal. Calcd for
C14H18N2O2: C, 68.27; H, 7.37; N, 11.37%. Found: C, 68.35; H, 7.41; N, 11.25%. The enantiomeric
excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 20 : 1 v/v%,
detector: UV 254 nm, Flow rate = 0.5 mL/min, 35 oC, tminor = 51.3 min (endo), tmajor = 55.9 min (endo)).
(5R,6S)-6-Hydroxymethyl-5-(2-naphthyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ai’): Pale
yellow prisms; mp 196-197 oC (benzene-MeOH); []D24 -13.7 o (c 0.80, MeOH, endo : exo = 99 : 1, 82%
ee (endo)).; IR (KBr) 3463, 3402, 3384, 2932, 2888, 2853, 2811, 1671, 1598, 1509, 1472, 1408, 1380,
1
1349, 1247, 1205, 1127, 1097, 1085, 1064, 1041, 1019 cm-1; H NMR (CDCl3)  = 1.96 (1H, brs),
2.70-2.83 (2H, m), 2.85 (1H, m), 2.99 (1H, dt, J = 11.2, 8.5 Hz), 3.47 (1H, ddd, J = 7.3, 8.5, 11.2 Hz),
3.59 (1H, m), 3.65 (1H, m), 3.75 (1H, m), 3.85 (1H, dd, J = 6.6, 11.2 Hz), 7.43-7.63 (3H, m), 7.78-7.92

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HETEROCYCLES, Vol. 81, No. 7, 2010
13
(4H, m); C NMR (CDCl3)  = 32.8 (CH2), 43.4 (CH2), 47.5 (CH2), 52.8 (CH), 60.2 (CH2), 71.3 (CH),
124.9 (CH), 126.1 (CH), 126.2 (CH), 127.3 (CH), 127.5 (CH), 127.6 (CH), 128.5 (CH), 133.0 (C), 133.1
(C), 134.6 (C), 171.0 (C); Mass (EI) m/z 282 (M+), 167, 78, 56. Anal. Calcd for C17H18N2O2: C, 72.32;
H, 6.43; N, 9.92%. Found: C, 72.52; H, 6.20; N, 9.95%. The enantiomeric excess was determined by
HPLC analysis (Daicel Chiralpak OD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate
= 1.0 mL/min, 35 oC, tminor = 72.9 min (endo), tmajor = 85.7 min (endo)).
(5R,6S)-5-Cyclohexyl-6-hydroxymethyltetrahydropyrazolo[1,2-a]pyrazol-1-one
(endo-3aj’):
23
o
Colorless oil; []D -12.4 (c 0.60, MeOH, endo : exo = 99 : 1, 31% ee (endo)); IR (neat) 3374, 3018,
2930, 2856, 2401, 2361, 2339, 1669, 1451, 1426, 1215, 1045 cm-1; 1H NMR (CDCl3)  = 0.87-1.82 (11H,
m), 1.86 (1H, brs), 2.18 (1H, m), 2.51 (1H, m), 2.65 (1H, ddd, J = 4.9, 9.5, 14.4 Hz), 2.77 (1H, m), 2.94
(1H, m), 3.15 (1H, m), 3.46 (1H, dd, J = 7.8, 10.7 Hz), 3.56-3.70 (2H, m), 3.84 (1H, m); 13C NMR
(CDCl3)  = 26.2 (CH2), 26.4 (CH2), 29.79 (CH2), 29.85 (CH2), 34.0 (CH2), 41.2 (CH), 42.5 (CH2), 46.9
(CH), 52.0 (CH2), 63.6 (CH2), 73.4 (CH), 167.6 (C); Mass (EI) m/z 238 (M+), 156, 55. Anal. Calcd for
C13H22N2O2: C, 65.51; H, 9.30; N, 11.75%. Found: C, 65.27; H, 9.52; N, 11.71%. The enantiomeric
excess was determined by HPLC analysis (Daicel Chiralpak OD-H, hexane : 2-PrOH = 20 : 1 v/v%,
detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 oC, tmajor = 22.2 min (endo), tminor = 27.6 min (endo)).
(5R,6S)-6-hydroxymethyl-5-Isobutyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ak’): Colorless
oil; []D23 -18.4 o (c 0.80, MeOH, endo : exo = 83 : 17, 32% ee (endo)); IR (KBr) 3282, 3000, 2954, 2913,
2905, 2866, 1671, 1470, 1426, 1377, 1366, 1328, 1319, 1253, 1226, 1191, 1165, 1150, 1109, 1091 cm-1;
1H NMR (CDCl3)  = 0.94 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 1.33-1.58 (2H, m), 1.61-1.83 (2H,
m), 2.43 (1H, m), 2.50 (1H, m), 2.66 (1H, ddd, J = 5.1, 9.3, 14.4 Hz), 2.77 (1H, m), 2.99 (1H, q, J = 9.3
Hz), 3.32 (1H, m), 3.54-3.65 (2H, m), 3.66-3.77 (2H, m); 13C NMR (CDCl3)  = 22.7 (CH3), 23.4 (CH3),
25.4 (CH), 33.9 (CH2), 34.0 (CH2), 42.5 (CH2), 42.5 (CH2), 50.4 (CH), 62.2 (CH2), 65.4 (CH), 167.9 (C).;
Mass (EI) m/z 212 (M+), 156, 125, 81, 55; HRMS (EI) Calcd for C11H20N2O2: (M+), 212.1215. Found:
212.1551. Anal. Calcd for C11H20N2O2: C, 62.23; H, 9.50; N, 13.20%. Found: C, 61.92; H, 9.90; N,
13.11%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane :
o
2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 C, tmajor = 17.3 min (endo),
tminor = 21.2 min (endo), tmimor = 36.2 min (exo), tmajor = 41.0 min (exo)).
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (nos. 17550097, 20550094,
and 20200052) from the Ministry of Education, Science and Culture, Japan.

HETEROCYCLES, Vol. 81, No. 7, 2010
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REFERENCES AND NOTES
† Shinshu University
‡ Rigaku Corporation
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For representative examples of reactions using
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11. The reactions in the other solvent systems examined in the presence of L-proline (30 mol%) at room
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endo:exo = 98:2, -3% ee (endo); EtOH: 72 h, 34% yield, endo:exo = 91:9, -8% ee (endo); DMF: 186
h, No reaction; CHCl3/H2O 99:1 (v/v): 324 h, No reaction.
12. The reaction without L-proline was sluggish but slowly proceeded at room temperature for 231 h in
CHCl3/EtOH 88:22 (v/v) to give the cycloadducts (endo: exo = 56:44) in 22% yield (With L-proline
(30 mol%) under same conditions: 53 h, 63% yield, endo: exo = 98:2, 66% ee (endo)).
13. H. Ohtake, Y. Imada, and S. Murahashi, Bull. Chem. Soc. Jpn., 1999, 72, 2737.
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