Asymmetric diels alder reaction using pyrazole derivatives as a chiral catalyst

Article abstract of DOI:10.1002/jhet.5570400420

N-Acylpyrazoles (1) were promising as good dienophiles, which were easily converted into the desired carboxylic derivatives. Bis(pyrazolyl)methanes, which were derived from chiral pyrazoles, showed the activity of chiral catalyst. Particularly 10 mol% of bis(isomenthopyrazol-1,1′-yl)methane (8a) catalyzed enantioselectively the Diels Alder reaction up to 40 % ee by the formation of complex with Mg(ClO₄)₂.

Full text of DOI:10.1002/jhet.5570400420

Jul-Aug 2003
Asymmetric Diels Alder Reaction using Pyrazole
Derivatives as a Chiral Catalyst
681
Choji Kashima,* Yohei Miwa, Saori Shibata, and Hiroyuki Nakazono
Department of Chemistry, University of Tsukuba,
Ten-nodai, Tsukuba, Ibaraki 305-8571, Japan
(E-Mail: kashima@chac.tsukuba.ac.jp)
Received December 30, 2002
N-Acylpyrazoles (1) were promising as good dienophiles, which were easily converted into the desired
carboxylic derivatives. Bis(pyrazolyl)methanes, which were derived from chiral pyrazoles, showed the
activity of chiral catalyst. Particularly 10 mol% of bis(isomenthopyrazol-1,1'-yl)methane (8a) catalyzed
enantioselectively the Diels Alder reaction up to 40 % ee by the formation of complex with Mg(ClO4)2.
J. Heterocyclic Chem., 40, 681(2003).
Recently we have reported the preparation and the utili-
ties of the optically active pyrazoles as a new chiral auxil-
iary [1,2], which has unique structure and properties differ-
ent from the conventional chiral auxiliaries [3]. Since
Evans reported the enantioselective Diels Alder reactions
using the chiral catalyst such as 2,2-bis[2-[4-(S)-phenyl-
1,3-oxazolyl]]propane [(S,S)-Ph-box] [4], many papers
concerning the analogous box derivatives have appeared in
the literature [5]. From the fact that pyrazoles are good lig-
ands for various Lewis acids [6], optically active pyrazoles
are expected to show effective chiral catalytic activities for
various enantioselective syntheses. These optically active
pyrazoles have already exhibited chiral catalytic activities
in borane mediated reductions and dialkylzinc addition on
the prochiral carbonyl compounds [7]. As an extension of
the diastereoselective Diels Alder reaction using 3-phenyl-
l-menthopyrazole [10], we will report here the utilities of
optically active pyrazole derivatives for either a conve-
nient dienophile or a chiral catalyst in enantioselective
Diels Alder reactions.
From these results, N-(a,b -unsaturated) acyl substituted
pyrazoles were concluded to be convenient dienophiles for
the asymmetric Diels Alder reactions.
Results and Discussion.
Firstly, N-(a,b -unsaturated) acyl substituted pyrazoles
were inspected using optically active box derivative as a
chiral catalyst. When 1-acryloyl-3,5-dimethylpyrazole
(1a) was treated with cyclopentadiene in the presence of
Mg[(R,R)-Ph-box] complex, 1-(bicyclo[2.2.1]hept-5-ene-
2-carbonyl)-3,5-dimethylpyrazole (2a) was afforded in 80
% yield with 86 % of Endo isomer ratio and 60 % ee of
Endo isomer (Scheme 1). Under the same conditions from
3-acryloyloxazolidine-2-one (4a), 3-(bicyclo[2.2.1]hept-5-
ene-2-carbonyl)oxazolidine-2-one (3a) was obtained in 80
% yield with 90 % of Endo isomer ratio and 30 % ee of
Endo isomer. Moreover, the functionalization of 2a into
various carboxylic derivatives was easy to realize by the
action of appropriate nucleophiles under acidic or basic
conditions. By the action of sodium alkoxide, 2a was con-
verted into the corresponding bicyclo[2.2.1]hept-5-ene-2-
carboxylic acid esters (5a) in 80 % ee. Alcoholysis of 2a
was also successful in the presence of boron trifluoride in
75 % yield with complete retention of its configuration.
As part of a series of studies concerning optically active
3-phenyl-l-menthopyrazole, l-menthopyrazole, isomen-
thopyrazole, carvomenthopyrazole and carvoisomen-
thopyrazole were previously prepared by the formylation
of menthone or carvomenthone using LDA [2]. The utility
of these optically active pyrazoles as chiral catalyst was
studied secondly. Many papers concerning poly(pyra-
zolyl)alkanes and their metal complexes were reported in
the literature [8]. Some optically active bis(pyrazolyl)-
methanes and borane analogues have already been pre-
pared from terpenoids such as camphor and menthone [9].
Particularly the metal complexes of these optically active
pyrazole compounds were applied as chiral Lewis acid cat-
alysts for cyclopropanation and allylic alkylation [10].
However, the steric effects of substituent groups in the
complex formation were still obscure. Accordingly the
NMR spectra of various bis(pyrazolyl)methanes were
studied in the presence of Lewis acid. When Zn(OTf) was
2
gradually added to bis(pyrazol-1,1'-yl)methane (6a) solu-

682
Vol. 40
C. Kashima, Y. Miwa, S. Shibata, and H. Nakazono
1
13
Ratio of Zn/OTf) /6a
Figure 1. H NMR Shifts of 6a
tion (Scheme 2), the sharp H- and C-NMR signals were
all shifted and saturated at the equimolar mixture, as
shown in Figures 1 and 2. In the case of bis(3,5-
dimethylpyrazol-1,1'-yl)methane (6b), similar shifts were
observed in all signals, which were however broadened at
room temperature. These signals were split at –40 °C,
while sharp signals were observed at 60 °C. These remark-
able peak shifts of bis(3,5-di-t-butylpyrazol-1,1'-
yl)methane (6c) and bis(3-p-tolylpyrazol-1,1'-yl)methane
2
1
(6d) were not observed by the addition of Zn(OTf) , even
2
after the prolonged period of standing. These NMR obser-
vations suggested that the bulky substituent groups on the
pyrazole ring of 6 retarded or prohibited the formation of
zinc complexes. Furthermore, the catalytic activities of
Mg and Zn complexes of 6b were evaluated by the reac-
tion rates of the Diels Alder reaction, as summarized in
Table 1. The reaction of 1crotonoyl-3,5-dimethylpyrazole
(1b) with cyclopentadiene was accelerated 6.2 times by
the catalytic amounts of Mg complex of 6b. From these
facts, bis(menthopyrazolyl)methane and their analogues
Ratio of Zn/OTf) /6a
Figure 2. C NMR Shifts of 6a
2
13
seemed to be promising as a chiral catalysts for the asym-
metric Diels Alder reaction.
Therefore bis(pyrazolyl)alkane derived from various
optically active pyrazoles was designed as the ligand for
Table 1
Catalytic Effects of Metal Complex of 6b in Diels Alder Reaction with Cyclopentadiene
Run
Dienophile
6b
Lewis Acid
k /k
cat 0
mol %
mol %
____
1
2
3
4
5
6
4b
4b
4b
1b
1b
1b
3-Crotonoyl-2-oxazolidinone
3-Crotonoyl-2-oxazolidinone
3-Crotonoyl-2-oxazolidinone
1-Crotonoyl-3,5-dimethylpyrazole
1-Crotonoyl-3,5-dimethylpyrazole
1-Crotonoyl-3,5-dimethylpyrazole
0
0
12
0
12
12
0
1
Zn(OTf)
Zn(OTf)
____
10
10
0
10
10
1.7
2.7
1
1.9
6.2
2
2
Zn(OTf)
Mg(ClO )
2
4 2
Table 2
Preparation of Chiral Bis(pyrazolyl)alkane using Diiodomethane and NaH
Run
Pyrazole
R
Product
Yield
1
2
3
R
R
a
b
c
1
2
3
4
5
6
7
8
7
10
12
14
16
18
7
(R)-Me
(R)-Me
(R)-Me
(S)-i-Pr
(S)-i-Pr
Bornyl
(R)-Me
(R)-Me
(R)-i-Pr
(R)-i-Pr
(S)-i-Pr
(S)-Me
(R)-Me
H
Ph
Ph
H
8
19
23
32
10
[a]
9
36
43
35
33
[a]
32
0
36
13
23
32
53
40
26
33
11
13
15
17
19
20
21
H
(R)-i-Pr
(S)-i-Pr
H
H
0
0
9
0
[a] Failed to be isolated because of poor yields.

Jul-Aug 2003
Asymmetric Diels Alder Reaction using Pyrazole Derivatives as a Chiral Catalyst
683
chiral Lewis acid. Due to the different regioisomeric
nitrogen atoms on menthopyrazole ring, 3 regioisomers,
the pyrazol-1,1'-yl - (a), the pyrazol-1,2'-yl - (b) and the
bis(pyrazol-2,2'-yl)methanes (c) were anticipated.
Actually, the regioisomers of bis(isomenthopyrazolyl)-
methanes (8) were prepared from isomenthopyrazole (7)
by the action of dibromomethane under phase transfer
conditions [23c]. Similarly optically active bis-
(pyrazolyl)methanes (11, 13, 15, 17, and 19) were
prepared from the corresponding pyrazoles (10, 12, 14,
16, and 18) [2a,4] under modified conditions using
diiodomethane and NaH (Scheme 3), as listed in Table 2.
According to the preparative method of 2,2-bis(pyrazol-
1,1'-yl)propane [22], 2,2-bis(isomenthopyrazol-2,2'-
yl)propane (20c) and 2,2-bis(l-menthopyrazol-2,2'-
yl)propane (21c) were prepared from 2,2-dimethoxy-
propane and the corresponding pyrazoles in the presence
of p-toluenesulfonic acid.
Finally asymmetric Diels Alder reaction of 1-(a,b -
unsaturated) acyl substituted pyrazoles with cyclopentadi-
ene was performed in the presence of Mg(ClO ) and
4 2
bis(pyrazolyl)alkanes (8, 11, 13, 15, 17, 20 and 21) derived
from optically active pyrazoles (Scheme 4). By the use of
Mg(ClO ) and bis(isomenthopyrazol-1,1'-yl)methane
4 2
(8a), the Diels Alder Reaction with cyclopentadiene was
optimized and summarized in Table 3. The sufficient cat-
alytic amount was estimated to be about 10 mol%. The
reaction temperature was optimized to be 0 °C, as lower
temperature retarded the reaction without any progression
in enantioselectivity. The b-substituent group of (a,b -
unsaturated) acyl pyrazoles retarded the Diels Alder reac-
tion and required drastic reaction conditions. Substituent

684
Vol. 40
C. Kashima, Y. Miwa, S. Shibata, and H. Nakazono
Table 3
Optimization of Diels Alder Reaction of 1 Catalyzed by 8a and Mg(ClO )
4 2
Run[a]
Mg(ClO )
mol%
8a
mol%
Dienophile
R
Temp
°C
Product
Endo%
4 2
1
2
3
R
R
Yield%
%Ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
17
18
19
10
10
10
10
30
50
10
10
10
10
10
10
10
10
10
10
10
12
12
5
1b
1b
1b
1b
1b
1b
1b
1a
1a
1a
1a
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
Ph
COOEt
Me
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
30
30
30
30
30
30
0
30
0
-5
-27
0
0
30
0
0
0
2b
9
42
5
32
58
60
2
92
81
62
57
7
85
62
40
51
77
78
76
74
75
88
80
91
76
84
84
94
85
71
73
91
87
97
26
25
15
33
28
2b
2b
2b
2b
2b
2b
2a
2a
2a
2a
2c
2d
2e
2f
15
36
60
12
12
12
12
12
12
12
12
12
12
12
29
___
29
40
39
39
15
___
12
21
35
34
t-Bu
Ph
COOEt
t-Bu
Ph
Me
1g
1h
2g
2h
[a] All data were obtained in the presence of MS4A, except run 1.
Table 4
Asymmetric Diels Alder Reaction of 1a with Cyclopentadiene Catalyzed by Mg(ClO ) and Chiral Bis(pyrazolyl)alkanes
4 2
Run
Bis(pyrazolyl)methanes
Product (2a)
1
2
3
R
R
R
Yield %
Endo %
% Ee
Conf.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
8a
8b
8c
(R)-Me
(R)-Me
(R)-Me
(R)-Me
(R)-Me
(R)-Me
(R)-Me
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
Bornyl
Bornyl
Bornyl
(R)-i-Pr
(R)-i-Pr
(R)-i-Pr
(R)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-Me
(S)-Me
(S)-Me
(R)-Me
(R)-Me
(S)-Me
54
H
H
H
81
75
91
63
85
86
98
75
75
74
93
95
87
18
20
22
84
91
92
94
83
82
79
87
92
93
87
83
95
S
40
23
17
18
1
S
S
S
S
R
R
S
S
S
S
S
S
S
20c
13a
13b
13c
15a
15b
15c
17b
17c
21c
19a
19b
19c
H
Ph
Ph
Ph
H
H
H
H
H
H
2
11
15
30
19
17
1
23
95
84
94
59
47
S
S
[a] The Diels Alder reactions of 1a were carried out at 0 °C in the presence of 10 mol% of Mg(ClO ) , 12 mol% of bis(pyrazolyl)alkane, and MS4A.
4 2
groups on pyrazole ring were less effective sterically
and/or electronically.
chiral catalysts in this series of bis(pyrazolyl)methanes
need to be found.
Under optimal conditions using 1a, the catalytic effects
In conclusion, N-acylpyrazoles (1) were promising as
good dienophiles, which were easily converted into the
desired carboxylic derivatives by the action of nucleophiles.
Bis(pyrazolyl)methanes, which were derived from the chiral
pyrazoles, showed the activity of chiral catalyst. Particularly
10 mol% of bis(isomenthopyrazol-1,1'-yl)methane (8a) cat-
alyzed enantioselectively the Diels Alder reaction up to 40 %
of bis(pyrazolyl)methanes and Mg(ClO ) were revealed
4 2
as summarized in Table 4. The bulky group substituted
bis(pyrazolyl)methanes, which were hard to form the Mg-
complex as discussed above, showed to be less effective
for the enantioselective reaction. At this moment, bis(iso-
menthopyrazol-1,1'-yl)methane (8a) seemed to be the
highest enantioselectivity of 40 % ee, but more effective
ee by the formation of complex with Mg(ClO ) .
4 2

Jul-Aug 2003
Asymmetric Diels Alder Reaction using Pyrazole Derivatives as a Chiral Catalyst
685
EXPERIMENTAL
h. The resulting mixture was quenched with water and extracted
with Et2O. The organic layer was washed with water and aqueous
NaCl, dried over anhydrous MgSO 4, and concentrated.
Compounds 8 and 19 were identical with the authentic data
[24c,23c].
Melting points are uncorrected. 1H NMR and 13C NMR spec-
tra were obtained on JEOL JNM-EX270 (270 MHz) spectrome-
ter in deuterochloroform with tetramethylsilane as an internal
standard. The enantiomer ratios were evaluated from the peak
ratios of gas chromatography on SHIMADZU GC-14A gas chro-
matograph using Chrompack Chirasil DEX-CB capillary column
(0.25 mm x 25 m). The yields of the products were evaluated by
GL Science GC-353 gas chromatograph using dimethylsiloxane
type capillary column (0.25 mm x 30 m) of GL Science TC-1.
Bis(3-phenylisomenthopyrazol-1,1'-yl)methane (11a).
Compound 11a was obtained in 14 % yield; mp 71-72 °C
1
(Sublimation); H NMR: d 0.82 (6H, d, J=6.9 Hz), 0.99 (6H, d,
J=6.9 Hz), 1.16 (6H, d, J=6.6 Hz), 1.50-1.80 (8H, m), 2.43-2.51
(2H, m), 2.55-2.68 (2H, m), 3.01-3.12 (2H, m), 6.49 (2H, s),
7.29-7.41 (6H, m), 7.36 (4H, dd, J=8.4, 1.3 Hz); 13C NMR: d
17.4 (CH3), 19.3 (CH2), 20.5 (CH3), 21.0 (CH3), 26.2 (CH), 29.3
(CH), 29.7 (CH2), 36.9 (CH), 65.4 (CH2), 121.8 (C), 127.0 (CH),
127.2 (CH), 128.3 (CH), 134.5 (C), 143.1 (C), 147.5 (C).
Anal. Calcd. for C35H44N4: C, 80.72; H, 8.52; N, 10.76.
Found: C, 80.81; H, 8.46; N, 10.24.
Materials.
(R,R)-Ph-box was commercially available from Aldrich
Chemical Co. N-(a,b -Unsaturated) acylpyrazoles (1) were pre-
pared from the corresponding pyrazoles and (a,b -unsaturated)
acyl chlorides in the presence of triethylamine according to the
method of the previous paper [9,13a], and purified by silica gel
column chromatography and distillation. In the cases of N-acry-
loylpyrazoles, the addition of hydroquinone was required to
inhibit the polymerization in the procedures of concentration and
the distillation. Moreover N-acryloylpyrazoles were stored in the
refrigerator.
Bis(3-phenylisomenthopyrazol-1,2'-yl)methane (11b).
Compound 11b was obtained in 23 % yield; mp 49-50 °C
1
(Sublimation); H NMR: d 0.80 (3H, d, J=6.9 Hz), 0.83 (3H, d,
J=6.9 Hz), 0.85 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.9 Hz), 1.04
(3H, d, J=6.8 Hz), 1.15 (3H, d, J=6.8 Hz), 1.26-1.30 (1H, m),
1.54-1.67 (4H, m), 1.72-1.77 (2H, m), 1.80-1.86 (1H, m), 2.27-
2.31 (1H, m), 2.35-2.38 (1H, m), 2.59-2.62 (1H, m), 2.79-2.81
(1H, m), 3.07-3.12 (1H, m), 3.15-3.18 (1H, m), 6.07 (2H, d,
J=14.1 Hz), 6.17 (2H, d, J=14.1 Hz), 7.25-7.42 (6H, m), 7.50
(2H, d, J=6.8 Hz), 7.69 (2H, d, J=7.4 Hz); 13C NMR: d 18.1
(CH3), 18.6 (CH3), 20.1 (CH3), 20.4 (CH3), 20.5 (CH3), 20.7
(CH3), 20.8 (CH2), 21.1 (CH2), 21.5 (CH), 25.3 (CH), 26.5 (CH),
29.3 (CH), 30.2 (CH2), 36.9 (CH2), 40.7 (CH), 61.8 (CH2), 120.7
(C), 121.5 (C), 126.9 (CH), 127.0 (CH), 128.13 (CH), 128.19
(CH), 128.28 (CH), 128.31 (C), 130.5 (CH), 134.9 (C), 140.0
(C), 143.8 (C), 147.7 (C), 151.6 (C).
The optically active pyrazoles (7, 9, 10, 12, 14, and 16) were
prepared from l-menthone and carvone according to the previous
paper [2a], and 18 was prepared by the method of House [23c].
1-Acryloyl-3,5-di(t-butyl)pyrazole (1f).
1
Compound 1f was obtained in 72 %; H NMR: d 1.30 (9H, s),
1.44 (9H, s), 5.89 (1H, d, J=10.4 Hz), 6.15 (1H, s), 6.57 (1H, d,
J=17.3 Hz), 7.64-75 (1H, dd, J=17.3, 10.4 Hz); 13C NMR: d 29.3
(CH3), 29.7 (CH3), 32.3 (C), 33.2 (C), 106.7 (CH2), 130.3 (CH),
130.3 (CH), 157.4 (C), 163.1 (C), 164.7 (C).
Anal. Calcd. for C14H22N2O: C, 71.76; H, 9.46; N, 11.95.
Found: C, 71.35; H, 9.02; N, 11.99.
Anal. Calcd. for C35H44N4: C, 80.72; H, 8.52; N, 10.76.
Found: C, 80.71; H, 8.36; N, 10.11.
1-Acryloyl-3,5-diphenylpyrazole (1g).
Bis(3-phenylisomenthopyrazol-2,2'-yl)methane (11c).
1
Compound 1g was obtained in 49 % yield; H NMR: d 6.01
Compound 11c was obtained in 43 % yield; mp 69-70 °C
(Sublimation); H NMR: d 0.80 (6H, d, J=6.6 Hz), 0.88 (6H, d,
(1H, d, J=10.2 Hz), 6.62 (1H, d, J=17.2 Hz), 6.75 (1H, s), 7.40-
50 (8H, m), 7.71-7.81 (1H, dd, J=17.2, 10.2 Hz), 7.91 (2H, d,
J=7.9 Hz); 13C NMR: d 110.1 (CH2), 126.2 (CH), 127.9 (CH),
128.2 (CH), 128.8 (CH), 128.9 (CH), 129.2 (CH), 131.1 (C),
131.6 (C), 132.5 (CH), 147.7 (C), 153.6 (C), 164.1 (C).
Anal. Calcd. for C18H14N2O: C, 78.81; H, 5.14; N, 10.21.
Found: C, 78.41; H, 5.26; N, 10.20.
1
J=6.9 Hz), 0.95 (6H, d, J=6.9 Hz), 1.52-1.74 (8H, m), 2.23-2.30
(2H, m), 2.55-2.61 (2H, m), 2.74-2.80 (2H, m), 5.82 (2H, s),
7.37-7.46 (6H, m), 7.63 (4H, dd, J=7.6, 1.3 Hz); 13C NMR: d
18.3 (CH3), 20.0 (CH2), 20.1 (CH3), 22.0 (CH3), 25.2 (CH), 30.2
(CH), 30.4 (CH2), 40.8 (CH), 59.4 (CH2), 121.3 (C), 128.18
(CH), 128.23 (CH), 130.6 (CH), 131.0 (C), 140.6 (C), 151.7 (C).
Anal. Calcd. for C35H44N4: C, 80.72; H, 8.52; N, 10.76.
Found: C, 80.67; H, 8.41; N, 10.63.
1-Acryloyl-3-ethoxycarbonyl-5-methylpyrazole (1h).
Compound 1h was obtained in 93 % yield; bp 140 °C/5 mm
1
Hg; H NMR: d 1.40 (3H, t, J=7.2 Hz), 2.65 (3H, d, J=1 Hz),
Bis(3-phenyl-l-menthopyrazol-1,1'-yl)methane (13a).
4.42 (2H, q, J=7.1 Hz), 6.05-6.11 (1H, m), 6.65-6.75 (2H, m),
7.62-7.75 (1.H, m); 13C NMR: d 14.2 (CH3), 14.6 (CH3), 61.5
(CH2), 111.7 (CH), 127.5 (CH2), 133.6 (CH), 145.2 (C), 145.8
(C), 161.7 (C), 165.3 (C).
Anal. Calcd. for C10H12N2O3: C, 57.69; H, 5.81; N, 13.45.
Found: C, 57.59; H, 5.85; N, 13.48.
Compound 13a was obtained in 32 % yield; mp 62 °C (from
1
MeOH); H NMR: d 0.90 (6H, d, J=6.9 Hz), 0.94 (6H, d, J=6.9
Hz), 1.09 (6H, d, J=6.9 Hz), 1.30-38 (2H, m), 1.63-80 (4H, m),
1.98-2.10 (2H, m), 2.16-28 (2H, m), 2.51-55 (2H, m), 3.17-21
(2H, m), 6.45 (2H, s), 7.28-41 (6H, m), 7.71 (4H, d, J=7.3 Hz);
13C NMR: d 19.5 (CH3), 20.4 (CH3), 21.4 (CH3), 21.5 (CH2),
26.3 (CH), 27.7 (CH), 31.0 (CH2), 36.7 (CH), 64.7 (CH2), 120.8
(C), 127.1 (CH), 127.3 (CH), 128.4 (CH), 134.7 (C), 143.5 (C),
148.5 (C).
General Preparation of Bis(pyrazolyl)methanes.
The corresponding pyrazole (50 mmol) in DMF (20 ml) was
added to a suspension of NaH (60 % in oil, 1.5 g, 37.5 mmol) in
DMF (10 ml). After stirring for 15 min at room temperature,
diiodomethane (8.3 ml, 31 mmol) was added and refluxed for 12
Anal. Calcd. for C35H44N4: C, 80.72; H, 8.52; N, 10.76.
Found: C, 80.81; H, 8.59; N, 10.68.

686
Vol. 40
C. Kashima, Y. Miwa, S. Shibata, and H. Nakazono
2.57 (2H, m), 2.68-2.73 (2H, m), 6.15 (2H, s), 7.25 (2H, s); 13
NMR: d 18.6 (CH3), 20.5 (CH3), 21.1 (CH3), 21.2 (CH2), 28.1
(CH), 29.7 (CH2), 31.5 (CH2), 38.5 (CH), 65.5 (CH2), 120.6 (C),
126.5 (CH), 155.4 (C).
Anal. Calcd. for C23H36N4: C, 74.95; H, 9.85; N, 15.2. Found:
C, 74.51; H, 9.32; N, 15.14.
C
Bis(3-phenyl-l-menthopyrazol-1,2'-yl)methane (13b).
Compound 13b was obtained in 35 % yield; mp 144 °C (from
MeOH); 1H NMR: d 0.72 (3H, d, J=6.7 Hz), 0.81 (3H, d,
J=6.8Hz), 0.90 (3H, d, J=6.9 Hz), 0.92 (3H, d, J=6.8 Hz), 0.98
(3H, d, J=6.9 Hz), 1.03 (3H, d, J=6.9 Hz), 1.19-21 (1H, m), 1.35-
38 (1H, m), 1.45-47 (1H, m), 1.70-74 (1H, m), 1.77-83 (2H, m),
1.89-92 (1H, m), 2.02-04 (1H, m), 2.13-17 (1H, m), 2.31-34 (1H,
m), 2.62-65 (1H, m), 2.73-76 (1H, m), 3.00-03 (1H, m), 3.14-17
(1H, m), 6.18 (2H, s), 7.22-46 (8H, m), 7.10 (2H, d, J=7.5 Hz);
13C NMR: d 18.7 (CH3), 19.8 (CH3), 20.2 (CH3), 20.3 (CH3),
20.7 (CH3), 21.3 (CH3), 21.4 (CH2), 23.2 (CH2), 26.2 (CH), 27.4
(CH), 27.5 (CH), 30.2 (CH), 31.3 (CH2), 32.7 (CH2), 36.6 (CH),
40.9 (CH), 61.7 (CH2), 119.7 (C), 121.6 (C), 126.9 (CH), 126.9
(CH), 128.0 (CH), 128.3 (CH), 128.3 (CH), 130.0 (CH), 131.4
(C), 134.7 (C), 140.4 (C), 143.0 (C), 147.9 (C), 152.0 (C).
Anal. Calcd. for C35H44N4: C, 80.72; H, 8.52; N, 10.76.
Found: C, 80.71; H, 8.55; N, 10.76.
Bis(carvomenthopyrazol-2,2'-yl)methane (17c).
Compound 17c was obtained in 53 % yield; mp 106-107 °C
(from MeOH-H2O); 1H NMR: d 0.77 (6H, d, J=6.9 Hz), 0.94
(6H, d, J=6.6 Hz), 1.30 (6H, d, J=6.6 Hz), 1.75-1.80 (2H, m),
1.88-2.02 (4H, m), 1.88-2.01 (2H, m), 2.53-2.57 (2H, m), 2.68-
2.73 (2H, m), 6.15 (2H, s), 7.25 (2H, s); 13C NMR: d 17.9 (CH3),
19.9 (CH3), 20.1 (CH3), 24.0 (CH2), 29.9 (CH), 31.4 (CH2), 32.5
(CH2), 39.2 (CH), 65.6 (CH2), 121.1 (C), 125.9 (CH), 155.3 (C).
Anal. Calcd. for C23H36N4: C, 74.95; H, 9.85; N, 15.2. Found:
C, 74.20; H, 9.21; N, 15.13.
The General Preparation of 2,2-Bis(pyrazolyl)propanes.
Bis(3-phenyl-l-menthopyrazol-2,2'-yl)methane (13c).
A toluene (4 ml) solution of pyrazole (7 or 9, 356 mg, 2.0
mmol) and 2,2-dimethoxypropane (129 mg, 1.24 mmol) was
refluxed for 20 h in the presence of p-toluenesulfonic acid (15.5
mg, 0.08 mmol) under argon atmosphere. The mixture was
quenched with water and extracted with Et2O. The organic layer
was washed with dilute hydrochloric acid, saturated NaHCO3
and saturated NaCl solutions. After dried over anhydrous
MgSO4, the solvent was removed. The residue was purified by
silica gel chromatography with hexane-ethyl acetate mixture.
Compound 13c was obtained in 23 % yield; mp 153 °C (from
MeOH); H NMR: d 0.72 (6H, d, J=6.9 Hz), 0.87 (6H, d, J=6.9
1
Hz), 1.04 (6H, d, J=6.9 Hz), 1.18 (2H, q, J=12.5 Hz), 1.44 (2H, q,
J=12.5 Hz), 1.76-86 (2H, m), 1.89-99 (2H, m), 2.28-43 (2H, m),
2.52-2.63 (2H, m), 2.77-89 (2H, m), 5.76 (2H, s), 7.31-45 (6H,
m), 7.66 (4H, d, J=7.9 Hz); 13C NMR: d 18.4 (CH3), 20.4 (CH3),
20.6 (CH3), 23.5 (CH2), 27.5 (CH), 29.9 (CH), 32.8 (CH2), 41.2
(CH), 59.5 (CH2), 120.5 (C), 128.1 (CH), 128.14 (CH), 130.5
(CH), 131.5 (C), 141.2 (C), 152.7 (C).
Anal. Calcd. for C35H44N4: C, 80.72; H, 8.52; N, 10.76.
Found: C, 80.57; H, 8.63; N, 10.69.
2,2-Bis(isomenthopyrazol-2,2'-yl)propane (20c).
Compound 20c was obtained in 26 % yield; mp 95 °C; 1H
NMR: d 0.83 (6H, d, J=6.9 Hz), 0.97 (6H, d, J=6.9 Hz), 1.09 (6H,
d, J=6.9 Hz), 1.39-1.46 (2H, m), 1.62-1.82 (6H, m), 2.11 (2H,
oct, J=6.6 Hz), 2.20 (6H, s), 2.55 (2H, q, J=5.9 Hz), 2.70 (2H,
sext, J=5.9 Hz), 7.06 (2H, s); 13C NMR: d 19.0 (CH3), 20.7
(CH3), 22.2 (CH3), 22.4 (CH3), 26.5 (CH2), 27.6 (CH), 29.7
(CH2), 31.0 (CH), 39.6 (CH), 76.2 (C), 122.7 (C), 123.6 (CH),
151.4 (C).
Bis(isocarvomenthopyrazol-1,1'-yl)methane (15a).
Compound 15a was obtained in 10 % yield; mp 82-83 °C
1
(Sublimation); H NMR: d 0.80 (6H, d, J=6.9 Hz), 0.97 (6H, d,
J=6.9 Hz), 1.12 (6H, d, J=6.9 Hz), 1.43-1.80 (8H, m), 2.02-2.11
(2H, m), 2.51-2.61 (2H, m), 3.29-3.26 (2H, m), 6.19 (2H, s), 7.29
(2H, s); 13C NMR: d 17.6 (CH3), 18.7 (CH3), 20.0 (CH3), 25.0
(CH2), 30.1 (CH), 30.8 (CH2), 38.7 (CH2), 61.5 (CH2), 119.8
(C), 137.4 (CH), 144.4 (C).
Anal. Calcd. for C25H40N4: C, 75.71; H, 10.17; N, 14.13.
Found: C, 75.52; H, 9.75; N, 14.12.
Anal. Calcd. for C23H36N4: C, 74.95; H, 9.85; N, 15.2. Found:
C, 74.77; H, 9.58; N, 15.05.
2,2-Bis(l-menthopyrazol-2,2'-yl)propane (21c).
Bis(isocarvomenthopyrazole-1,2'-yl)methane (15b).
Compound 21c was obtained in 33 % yield; mp 74 °C; 1H
NMR: d 0.79 (6H, d, J=6.9 Hz), 0.98 (6H, d, J=6.9 Hz), 1.10 (6H,
d, J=6.9 Hz), 1.16 (2H, q, J=12.2 Hz), 1.40 (2H, q, J=12.9 Hz),
1.82-1.89 (4H, m), 2.17 (6H, s), 2.34-2.42 (2H, m), 2.52-2.58
(2H, m), 2.61-2.72 (2H, m), 6.92 (2H, d, J=1.0 Hz); 13C NMR: d
18.7 (CH3), 20.9 (CH3), 22.5 (CH3), 24.8 (CH3), 28.8 (CH2),
29.0 (CH), 31.2 (CH2), 33.7 (CH), 41.5 (CH), 77.7 (C), 124.3
(CH), 124.6 (C), 152.4 (C).
1
Compound 15b was obtained in 33 % yield; H NMR: d 0.81
(3H, d, J=6.9 Hz), 0.81 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.9 Hz),
0.98 (3H, d, J=6.9 Hz), 1.17 (3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9
Hz), 1.55-1.63 (5H, m), 1.70-1.83 (4H, m), 2.00-2.12 (1H, m),
2.41-2.48 (1H, m), 2.55-2.60 (1H, m), 2.84-2.92 (2H, m), 3.04-
3.15 (2H, m), 6.14 (2H, s), 7.22 (1H, s), 7.35 (1H, s); 13C NMR:
d 17.7 (CH3), 18.7 (CH3), 18.8 (CH3), 20.1 (CH3), 20.2 (CH3),
20.7 (CH3), 21.1 (CH2), 21.5 (CH2), 25.2 (CH), 28.1 (CH), 29.6
(CH), 30.1 (CH), 30.8 (CH2), 31.4 (CH2), 38.6 (CH), 38.7 (CH),
63.1 (CH2), 119.8 (C), 120.5 (C), 125.9 (CH), 137.9 (CH), 144.1
(C), 154.6 (C).
Anal. Calcd. for C25H40N4: C, 75.71; H, 10.17; N, 14.13.
Found: C, 75.59; H, 9.47; N, 14.16.
Detection of Zn-Complexation of 6 by NMR Spectroscopy.
Appropriate amounts of Zn(OTf)2 were added to the solution
of 6 in CDCl3-CD3OD mixture (1:1 v/v), and 1H and 13C NMR
spectra were measured. The complexation of 6 with Zn(OTf)2
was observed by the shifts of all signals. When more than
equimolar amounts of Zn(OTf)2 were added, the shifts of signals
were saturated. The result of 6a was plotted in Figure 1 and 2,
where the down field shifts were defined to be positive Ddvalues.
Anal. Calcd. for C23H36N4: C, 74.95; H, 9.85; N, 15.2. Found:
C, 74.52; H, 9.43; N, 14.13.
Bis(isocarvomenthopyrazol-2,2'-yl)methane (15c).
Compound 15c was obtained in 32 % yield; 1H NMR: d 0.77
(6H, d, J=6.9 Hz), 0.94 (6H, d, J=6.6 Hz), 1.30 (6H, d, J=6.6 Hz),
1.24-1.40 (4H, m), 1.75-2.01 (2H, m), 1.88-2.01 (2H, m), 2.53-

Jul-Aug 2003
Asymmetric Diels Alder Reaction using Pyrazole Derivatives as a Chiral Catalyst
687
General Procedure of Asymmetric Diels Alder Reaction
Catalyzed by (R,R)-Ph-box or Bis(pyrazolyl)alkanes.
(CH), 50.3 (CH2), 109.3 (CH), 126.2 (CH), 127.9 (CH2), 128.6
(CH), 128.77 (CH), 128.84 (CH), 129.0 (CH), 131.4 (C), 131.7
(CH), 132.1 (C), 138.0 (CH), 147.3 (C), 153.0 (C), 174.0 (C).
Anal. Calcd. for C23H20N2O: C, 81.15; H, 5.92; N, 8.23.
Found: C, 80.94; H, 5,95; N, 8.20.
A mixture of chiral ligand (0.03 mmol) of (S,S)-Ph-box or
bis(pyrazolyl)alkanes, Lewis acid (0.025 mmol) and MS4A (ca.
80 mg) in CH2Cl2 (0.5 ml) was stirred for 30 min at room tem-
perature under an argon atmosphere. Subsequently dienophile
(4b or 1, 0.25 mmol) in CH2Cl2 (1 ml) was added and stirred for
another half an hour. Cyclopentadiene (0.2 ml, 2.43 mmol) was
then added and stirred for 5 h at appropriate temperature. The
reaction was monitored from time to time by GC and HPLC
using phenanthrene as an internal standard. After the reaction
was complete, the reaction mixture was quenched with water and
extracted with CH2Cl2. The organic layer was washed with dilute
hydrochloric acid, saturated NaHCO3 and saturated NaCl solu-
tion. After drying over anhydrous MgSO4, the solvent was
removed. The separation of Endo and Exo isomers was per-
formed by silica gel column chromatography with benzene-
hexane mixture. The products 2a, 2b, 2c and 2d were identified
with authentic samples [10].
Endo-1-(Bicyclo[2.2.1]hept-5-ene-2-carbonyl)-3-ethoxycar-
bonyl-5-methylpyrazole (2h).
1
Compound 2h was obtained; H NMR: d 1.41 (3H, t, J=7.3
Hz), 1.50 (2H, br s), 1.49-57 (2H, m), 2.04 (1H, t-d, J=10.4, 3.6
Hz), 2.54 (3H, s), 2.99 (1H, broad s), 3.42 (1H, broad s), 4.22-28
(1H, m), 4.41 (2H, q, J=7.3 Hz), 5.86-89 (1H, m), 6.27-30 (1H,
m), 6.59 (1H, s); 13C NMR: d 14.3 (CH3), 14.5 (CH3), 29.8
(CH2), 43.0 (CH), 43.7 (CH), 47.5 (CH), 50.3 (CH2), 61.3 (CH2),
111.0 (CH), 131.5 (CH), 138.2 (CH), 144.5 (C), 145.3 (C), 162.0
(C), 175.7 (C).
Anal. Calcd. for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.37; H, 6.65; N, 10.03.
Acknowledgement.
The Endo isomer (0.06 mmol) dissolved in MeOH solution (1
ml) of sodium methoxide (0.2 mmol), and stirred for 1 h at room
temperature. The resulting mixture was quenched with water and
extracted with Et2O. The organic layer was washed with dilute
hydrochloric acid, saturated NaHCO3 and saturated NaCl solu-
tions. After drying over anhydrous MgSO4, the solvent was
removed. From the GC measurement on the chiral phase column,
the enantiomer excess of the residual methyl ester of the
cycloadduct was evaluated.
The authors are grateful to the Chemical Analysis Center,
University of Tsukuba, for the measurement of various kinds of
spectra and the elemental analyses.
REFERENCES AND NOTES
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Endo-1-(3-Methylbicyclo[2.2.1]hept-5-en-2-ylcarbonyl)-pyra-
zole (2e).
1
Compound 2e was obtained; H NMR: d 1.23 (3H, d, J=6.9
Hz), 1.51 (1H, d, J=8.6 Hz), 1.78 (1H, d, J=8.9 Hz), 2.12 (1H,
sext, J=6.6 Hz), 2.59 (1H, s), 3.37 (1H, s), 3.63 (1H, t, J=3.9 Hz),
5.88 (1H, m), 6.39 (1H, m), 6.43 (1H, s), 7.73 (1H, s), 8.22 (1H,
d, J=2.9 Hz); 13C NMR: d 20.4 (CH3), 37.2 (CH2), 47.0 (CH),
48.6 (CH), 49.6 (CH), 51.1 (CH), 109.0 (CH), 128.3 (CH), 131.7
(CH), 139.2 (CH), 143.5 (CH), 173.0 (C).
Anal. Calcd. for C12H14N2O: C, 71.26; H, 6.98; N, 13.85.
Found: C, 70.19; H, 7.11; N, 13.74.
Endo-1-(Bicyclo[2.2.1]heptene-4-carbonyl)-3,5-di(t-butyl)pyra-
zole (2f).
Compound 2f was obtained; 1H NMR: d 1.31 (9H, s), 1.36
(9H, s), 1.45 (2H, s), 1.52-1.57 (1H, m), 1.98 (1H, t-d, J=10.4,
3.6 Hz), 2.94 (1H, broad s), 3.36 (1H, broad s), 4.20-4.27 (1H,
m), 5.86-5.89 (1H, m), 6.08 (1H, s), 6.22-6.25 (1H, m); 13C
NMR: d 29.3 (CH3), 29.7 (CH2), 29.9 (CH3), 32.3 (C), 33.1 (C),
43.0 (CH), 45.3 (CH), 47.4 (CH), 50.1 (CH2), 105.6 (CH), 132.0
(C), 137.5 (CH), 156.7 (C), 162.3 (C), 174.9 (C).
[5] S. Kanemasa, Y. Oderaotoshi, S. Sakaguchi, H.
Yamamoto, J. Tanaka, E. Wada, and D. P. Curran, J. Am. Chem. Soc.,
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Tsukamoto, Y. Miwa, and K. Higashide, J. Heterocyclic Chem., 38,
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Y. Tsukamoto, J. Heterocyclic Chem., 39, 917 (2002).
[8a] S. Trofimenko, Progr.Inorg.Chem., 34, 115 (1986); [b] D.
L. Jameson and R. K. Castellano, Inorg. Synth., 32, 51 (1998).
[9a] M. H. Chisholm, N. W. Eilerts, J. C. Huffman, S. S. Iyer,
M. Pacold, and K. Phomphrai, J. Am. Chem. Soc., 122, 11845 (2000);
[b] M. H. Chisholm, S. S. Iyer, and W. E. Streib, New J. Chem., 24
393 (2000); [c] D. A. House, P. J. Steel, and A. A. Watson, Aus. J.
Chem., 39, 1525 (1986); [d] M. C. Keyes, V. G. Young, Jr., and W. B.
Tolman, Organomatallics, 15, 4133 (1996).
Anal. Calcd. for C19H28N2O: C, 75.96; H, 9.39; N, 9.32.
Found: C, 75.63; H, 9.41; N, 9.14.
Endo-1-(Bicyclo[2.2.1]heptene-4-carbonyl)-3,5-diphenylpyra-
zole (2g).
Compound2g was obtained; 1H NMR:d 1.52 (1H, s), 1.52 (1H,
s), 1.59 (1H, dd, J=10.4 ,3.6 Hz), 2.05 (1H, t-d, J=10.4, 3.6 Hz),
2.98 (1H, broad s), 3.57 (1H, broad s), 4.25-34 (1H, m), 5.94-97
(1H, m), 6.23-26 (1H, m), 6.69 (1H, s), 7.39-49 (8H, m), 7.93 (2H,
d, J=8.1 Hz);13C NMR: d 29.8 (CH2), 43.0 (CH), 44.3 (CH), 47.6
[10a] M. C. Keyes, B. M. Chamberlain, S. A. Caltagirone, J. A.

688
Vol. 40
C. Kashima, Y. Miwa, S. Shibata, and H. Nakazono
Halfen, and W. B. Tolman, Organometallics, 17, 1984 (1998); [b]
D. L. Christenson, C. J. Tokar, and W. B. Tolman, Organometallics,
14, 2148 (1995); [c] M. Bovens, A. Togni, and L. M. Venanzi,
J. Organomet. Chem., 451, C28 (1993).