Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their Catalytic Activity for Asymmetric Diels Alder Reaction

Article abstract of DOI:10.1002/jhet.5570400505

3-Aryl-l-menthopyrazoles 1 and 2 and related compounds were prepared from l-menthone, and their enantioselective activities were discussed as chiral ligands. In this series of compounds, 2,6-bis(2-methyl-l-menthopyrazol-3-yl)pyridine (8a), which had both

Full text of DOI:10.1002/jhet.5570400505

Sep-Oct 2003
Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their
Catalytic Activity for Asymmetric Diels Alder Reaction
Choji Kashima,* Saori Shibata, Hiroyo Yokoyama, and Takehiko Nishio
773
Department of Chemistry, University of Tsukuba,
Ten-nodai, Tsukuba, Ibaraki 305-8571, Japan
Received April 10, 2003
3-Aryl-l-menthopyrazoles 1 and 2 and related compounds were prepared from l-menthone, and their enan-
tioselective activities were discussed as chiral ligands. In this series of compounds, 2,6-bis(2-methyl-l-men-
thopyrazol-3-yl)pyridine (8a), which had both structural features of 3-phenyl-l-menthopyrazole (1b) and C2
symmetric ligand in the molecule, should form the C2 symmetric complex in situ with Zn(OTf)2 or
Ni(ClO4)2•6H2O. The subsequent complex catalyzed the Diels Alder reaction of 1-acryloyl-3,5-
dimethylpyrazole (11a) with cyclopentadiene (12) enantioselectively up to 75 % ee.
J. Heterocyclic Chem., 40, 773(2003).
Introduction.
Pyrazoles are good ligands for various Lewis acids [21],
and the optically active pyrazoles are expected to show
effective chiral catalytic activities for various enantiose-
lective syntheses. These optically active pyrazoles have
already exhibited chiral catalytic activity in the borane
reduction and the dialkylzinc addition on the prochiral car-
bonyl compounds [22]. Furthermore, bis(pyrazolyl)-
methanes, which were regarded as bidentate pyrazole lig-
Recently we designed and prepared 3-phenyl-l-men-
thopyrazole (1b) and related compounds as chiral pyra-
zoles [1]. Moreover, we have investigated the excellent
properties of these chiral pyrazoles as a new chiral auxil-
iary [2,3], which has unique structure and properties differ-
ent from the conventional chiral auxiliaries [4]. The most
important characteristics of this auxiliary are that the acyl
substrate terminates to nitrogen atom of heteroaryl pyra-
zole ring, and that the chiral atmosphere surrounds the sub-
strate. That is, the (4R)-methyl group of 1b is located
close to the 3-phenyl group and steric hindrance is relaxed
by twisting of the benzene ring, which overlaps one side of
the terminal nitrogen atom. These structural features cause
the transmission of the chirality of the (4R)-methyl group
into the terminal nitrogen atom through torsional asymme-
try of phenyl group, and cause the diastereofacial effect in
the reactions of the substrate moiety with alkyl halides [5],
phenyldisulfide [6], acyl chloride [7], aldehydes [8], and
compounds containing C=N bond [9]. The asymmetric
addition of Grignard reagents [10], dienes [11] and 1,3-
dipolar compounds [12] on N-(a,b -unsaturated)-acyl sub-
stituted pyrazoles have been reported as well. Otherwise,
N-acylheteroaromatics such as N-acylimidazoles are uti-
lized as the activated acyl moiety in a wide variety of
organic syntheses [13]. As an analogue of these N-acyl-
heteroaromatics, N-acylpyrazoles are easily converted into
acyl derivatives by the action of nucleophiles such as alco-
hols [14], amines [15], Grignard reagents [16], and
organozinc compounds [17] under basic or acidic condi-
tions [18].
and with C symmetry, showed chiral catalytic activity for
2
Diels Alder reaction by the formation of magnesium com-
plex [23]. However, we have strongly desired to develop
more effective catalyst of optically active pyrazole deriva-
tives for a wide variety of synthetic reactions. Therefore,
we designed the optically active 2,6-bis(l-menthopyrazol-
3-yl)pyridine (2a), which had both structural features of 3-
aryl-l-menthopyrazole (1) and tridentate ligand with C
2
symmetry in the molecule. Here we will report the prepa-
ration of 2a and the related pyrazoles. Also, their chiral
catalytic activities in the Diels Alder reaction will be dis-
cussed as the extension of the stereoselective Diels Alder
reaction using menthopyrazoles [10,23].
Results and Discussion.
Since the coordination abilities depend on the properties
of heteroaromatics, we undertook the preparation of 3-het-
eroaryl-l-menthopyrazoles (1a) as a structural analogue of
1b summarized in Scheme 1. By the reaction of het-
eroaroyl chlorides (3) on l-menthone in the presence of
lithium diisopropylamide, the corresponding 2-hetaroyl-l-
menthones (4) were prepared. The subsequent diketones 4
were treated with hydrazine hydrate under the acidic con-
ditions, 3-heteroaryl-l-menthopyrazoles (1) were prepared
in good yields (Table 1). Similarly 3-heteroaryl-2-methyl-
l-menthopyrazoles (5) were obtained by the treatment of 4
with methylhydrazine together with small portions of
regioisomeric 3-hetrayl-1-methyl-l-menthopyrazoles (6).
Otherwise, 6 can be synthesized by methylation of 1 with
methyl iodide.
Since Evans reported the enantioselective Diels Alder
reactions using the C symmetric chiral catalyst such as
2
2,2-bis[2-(4-(S)-phenyl-1,3-oxazolyl)]propane [(S,S)-Ph-
box] [19], many papers concerning the analogous box
derivatives have appeared in the literature [20].
Particularly the tridentate ligands in the box-series exhib-
ited high stereoselective catalytic effects in various organic
syntheses.
1,3-Bis(l-menthopyrazol-3-yl)benzene (2b) as a C
2
symmetric bidentate ligand was prepared from isoph-

774
C. Kashima, S. Shibata, H. Yokoyama, and T. Nishio
Vol. 40
Alternatively, a regioisomer of 8b, 1,3-bis(1-methyl-l-
menthopyrazol-3-yl)benzene (9b) was regioselectively
prepared by direct methylation of 2b using methyl iodide
and butyllithium. Although 1,4-bis(l-menthopyrazol-3-
yl)benzene (2c) was obtained in good yield by similar
reaction conditions, 1,2-analogue could not be prepared
due to their steric hindrance and phthalic diester (10) of
menthone enolate was afforded.
Table 1
Preparation of 3-Heteroaryl-l-menthopyrazoles and their N-Methyl
Derivatives from 4
Run
Aroyl-l-menthone[a] Hydrazine
Product (Yield, %)
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
Py
Py
Ph
Ph
Fura
Fura
Thio
Thio
Pyra
Pyra
NH NH
1a (27)
5a (65) + 6a (17)
1b (96)
5b (83) + 6b (12)
1c (100)
5c (78) + 6c (10)
1d (80)
5d (82) + 6d (trace)
1e (51)
5e (36) + 6e (16)
2
2
MeNHNH
2
2
2
2
2
NH NH
2 2
MeNHNH
NH NH
Analogously, C symmetric tridentate ligands were pre-
2
2
2
MeNHNH
NH NH
pared from pyridine-2,6-dicarbonyl chloride and l-men-
thone through the corresponding tetraketone intermediate
(7a). Finally, 7a was treated with hydrazine hydrate to
give 2,6-bis(l-menthopyrazol-3-yl)pyridine (2a). Two
regioisomeric derivatives 1,3-bis(2-methyl-l-menthopyra-
zol-3-yl)pyridine (8a) and 1,3-bis(1-methyl-l-menthopyra-
zol-3-yl)pyridine (9a) were prepared by treatment of 7a
with methylhydrazine and by the direct methylation of 2a,
respectively.
In order to reveal the capability of ligands as chiral cata-
lysts, the asymmetric Diels Alder reaction of 1-acryloyl-
3,5-dimethylpyrazoles (11a) with cyclopentadiene (12)
was performed by using 3-heteroaryl-l-menthopyrazoles
2
2
MeNHNH
NH NH
2
2
10
MeNHNH
[a] 2-Pyridinyl, 2-furyl, 2-thienyl and 5-methyl-1-phenylpyrazol-3-yl
groups were abbreviated as Py, Fura, Thio, and Pyra, respectively.
thaloyl chloride and l-menthone. By the action of lithium
diisopropylamide, the corresponding tetraketone interme-
diate 7b was afforded in moderate yield, then 7b was
treated with hydrazine hydrate to give 2b. The treatment
of 7b with methylhydrazine afforded predominantly 1,3-
bis(2-methyl-l-menthopyrazol-3-yl)benzene ( 8b).
(1, 5 and 6) in the presence of Zn(OTf) as a catalyst. The
2

Sep-Oct 2003
Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their Catalytic Activity
775
main product was found to be 1-(endo-bicyclo[2.2.1]hept-
5-ene-2-carbonyl)-3,5-dimethylpyrazole (13a) accompa-
nied with small portions of exo-isomer 14a. The enan-
tiomeric mixture of 13a was converted into methyl endo-
bicyclo[2.2.1]hept-5-ene-2-carboxylate (15) by treatment
with sodium methoxide in methanol, and the stereostruc-
ture and ratio of the predominant enantiomer was deduced
by chiral gas chromatography.
Compared with the cases of 3-phenyl-l-menthopyrazoles
(1b, 5b and 6b), similar enantioselectivities in the Diels
Alder reactions were observed by the catalyst of l-men-
thopyrazoles having various heteroaryl groups other than
pyridine as shown in Table 2. Methyl group on either N-1
or N-2 atom in compounds 5 and 6 did not affect the enan-
tioselectivity in these reactions. In the cases of pyridine
substituted analogues (1a), some enantioselective promo-
tion under the neutral conditions were observed, while the
deprotonation from 1a by the addition of butyllithium set
back to the similar activity to that of 1b.
mainly coordinate with the nitrogen atom of pyridine ring
in 1a, 5a and 6a, while the other ligands should be coordi-
nated on the nitrogen atom of menthopyrazole ring. Thus
the enantioselectivity by these ligands was mainly depen-
dent on the coordination site of the zinc atom.
Although 1,3-bis(l-menthopyrazol-3-yl)benzenes (2b,
8b, and 9b) seemed to be a bidentate ligand having C sym-
2
metry, distinguishable enantioselectivity did not appear in
the Diels Alder reaction using Zn(OTf) , as listed in
Table 2
2
Table 3. If nitrogen atom of one pyrazole on 2b or 9b
approached to the other side of pyrazole nitrogen in the
appropriate distance as a bidentate ligand, 2-H hydrogen
atom on benzene ring should move to the hindered position
for the complex formation. When these ligands were
Catalytic Effect of 3-Heteroaryl-l-menthopyrazoles for Diels Alder Reaction
Run
Ligand
Ar[b]
Lewis
Acid[a]
Additive Yield Endo %ee %
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1b
1b
5b
6b
1a
1a
5a
6a
Ph
Ph
Ph
Ph
Py
Py
Py
Py
H
H
Zn(OTf)
Zn(OTf)
79
76
89
84
92
79
90
91
63
72
77
82
72
80
98
76
79
79
98
73
92
94
93
92
93
95
94
92
93
91
91
93
93
94
93
93
86
95
89
92
24
25
40
28
32
25
26
23
23
21
21
30
21
20
27
25
24
18
23
26
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
BuLi
BuLi
BuLi
BuLi
BuLi
treated with equimolar amount of Zn(OTf) , one of two
2
2-Me Zn(OTf)
1-Me Zn(OTf)
H
H
2-Me Zn(OTf)
1-Me Zn(OTf)
H
H
pyrazole moieties should chelate independently to the zinc
atom to form a partially coordinated complex. These
assumptions reasonably explained that these compounds
exhibited similar enantioselectivities in the asymmetric
Diels Alder reaction. Even though these ligands were
Zn(OTf)
Zn(OTf)
1c Fura
1c Fura
5c Fura 2-Me Zn(OTf)
6c Fura 1-Me Zn(OTf)
1d Thio
1d Thio
5d Thio 2-Me Zn(OTf)
6d Thio 1-Me Zn(OTf)
1e Pyra
1e Pyra
5e Pyra 2-Me Zn(OTf)
6e Pyra 1-Me Zn(OTf)
Zn(OTf)
Zn(OTf)
Table 3
Catalytic Effect of Bis(l-menthopyrazol-3-yl)arenes
for Diels Alder Reaction
H
H
Zn(OTf)
Zn(OTf)
Run
Ligand
Ar[a] R
Lewis
Acid
Mole Additive Yield Endo % ee %
Ratio
H
H
Zn(OTf)
Zn(OTf)
1
2
3
4
5
6
7
8
9
2a Py
H
H
H
H
H
H
H
H
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
95
95
98
93
62
77
92
85
84
95
98
94
85
97
89
89
92
92
95
93
92
94
93
94
92
91
95
93
92
91
96
95
27
23
43
22
20
18
27
20
67
43
33
30
21
21
31
34
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2a Py
2a Py
2a Py
2b Ph
2b Ph
2b Ph
2b Ph
BuLi
BuLi
[a] The molar ratio between ligand and Zn(OTf) was 1:1; [b]2-Pyridinyl,
2
2-furyl, 2-thienyl and 5-methyl-1-phenylpyrazol-3-yl groups were abbrevi-
ated as Py, Fura, Thio, and Pyra, respectively.
BuLi
BuLi
8a Py 2-Me Zn(OTf)
10 8a Py 2-Me Zn(OTf)
11 8b Ph 2-Me Zn(OTf)
12 8b Ph 2-Me Zn(OTf)
13 9a Py 1-Me Zn(OTf)
14 9a Py 1-Me Zn(OTf)
15 9b Ph 1-Me Zn(OTf)
16 9b Ph 1-Me Zn(OTf)
Since the complex formation of the heteroatoms was
generally proportional to their basicity, the coordination
abilities of heteroaryl group should be the order of pyrazo-
lato anion > pyridine > pyrazole > thiophen or furan. By
addition of strong base such as butyllithium, N-unsubsti-
tuted pyrazoles should be deprotonated to form the corre-
sponding pyrazolato anion, and should perform as good
ligands toward Lewis acid. Therefore, zinc atom should
[a] 2,6-Disubstituted pyridine and 1,3-disubstituted benzene groups were
abbreviated as Py and Ph, respectively.

776
C. Kashima, S. Shibata, H. Yokoyama, and T. Nishio
Vol. 40
treated with 2 molar amounts of Zn(OTf) for the complete
2
complex formation with all pyrazole moieties,any remark-
able change was not observed in these Diels Alder reaction.
2,6-Bis(l-menthopyrazol-3-yl)pyridines (2a, 8a and 9a)
had a 2,6-disubstituted pyridine ring, which strongly pre-
ferred the complex formation rather than pyrazole moiety.
Moreover, the absence of 1-H hydrogen atom on pyridine
ring should avoid the steric inhibition of the complex for-
mation differently from the cases of 1,3-bis(l-menthopyra-
zol-3-yl)benzenes. Particularly the structures of 2a and 9a
were expected to be suitable for tridentate complex forma-
tion with the effective chiral surrounding.
The X-ray structural analysis gave the molecular structure
of 1c, in which the furan and pyrazole rings were bonded in
syn-form and the heteroatoms of both rings were located in
sufficiently near position for the bidentate chelation, as
shown in Figure 1. On the contrary in structure 1a and 9a,
pyridine ring and pyrazole rings were bonded in twisted
anti-form, as shown in the ORTEP drawing in Figure 2 and
Figure 3, respectively. Namely in crystal state, the Lewis
basic nitrogen atoms of pyridine and pyrazoles were unfa-
vorably located at far position, in spite of the expectation of
the good tridentate ligand. In order to take a role of the
bidentate or tridentate ligand, the bond rotation from the
most stable conformer was required along the restricted
bond between pyridine and pyrazole ring.
Figure 3. ORTEP of 2,6-Bis(1-methyl-l-menthopyrazol-3-yl)pyridine (9a).
Zn(OTf) , and the enantioselectivity increased up to 43 %
2
ee under the forced conditions for tridentate complex for-
mation by the deprotonation from the pyrazole ring of 2a
using butyllithium.
By the use of 8a as a chiral ligand, the asymmetric Diels
Alder reaction was observed with the good enantioselec-
tivity up to 67 % ee, and the enantioselectivity fell down
into 43 % ee when 8a was used together with 2 molar
equivalents of Zn(OTf) . These results can reasonably be
2
explained by the following speculations. The central pyri-
dine ring of 8a should be surrounded by 4 methyl groups
on 2-, 2’-, 4- and 4’-position, and the steric hindrance was
relaxed by the twisted anti-form as an analogy of 9a.
Accordingly it was speculated that the basic nitrogen
atoms of pyridine and pyrazoles are located far away from
each other with their lone pairs of electrons directed in
opposite directions. Thus the complex with Zn(OTf)
2
should be formed on the pyridine nitrogen keeping their C
2
symmetry. By the use of 2 molar amounts of Lewis acid,
one Lewis acid should coordinate to pyridine and the other
on the pyrazole nitrogen, and the subsequent complex
should loose its C symmetry.
2
For giving full play to the catalytic ability of these lig-
ands, the reaction of various 3,5-disubstituted 1-acryl-
oylpyrazoles (11b, 11c, and 11d) were carried out as listed
in Table 4, and 11a was the most preferable substrate for
the asymmetric catalytic Diels Alder reaction.
Figure 1. ORTEP of 3-(2-Furyl)-l-menthopyrazole (1c).
Generally the catalytic activity of the complex molecule
was affected by the stability, which depends on either the
structure of ligand or the property of the Lewis acid. After
attempting complex formation of these ligands with various
Lewis acids, Zn(OTf) was regarded as the most preferable
2
activator for these Diels Alder reactions as listed in Table 5.
Although the complex with Ni(ClO ) •6H O did not show
4 2
2
Table 4
The Substituent Effect of Pyrazole in Diels Alder Reaction
Catalyzed by 8b and Zn(OTf)
Figure 2. ORTEP of 3-(Pyridin-2’-yl)-l-menthopyrazole (1a).
2
Run
Substrate
Yield
Endo %
ee %
1
R
When the Diels Alder reaction of 11a was carried out in
1
2
3
4
11a
11b
11c
11d
Me
H
t-Bu
Ph
84
60
44
62
92
95
91
85
67
48
33
23
the presence of 9a and Zn(OTf) , the enantioselectivity
2
was found to be less than that of 9b. Also the reaction pro-
ceeded with similar selectivity by the use of 2a and

Sep-Oct 2003
Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their Catalytic Activity
777
Table
5
chromatography on SHIMADZU GC-14A gas chromatograph
using Chrompack Chirasil DEX-CB capillary column (0.25 mm
x 25 m). The yields of the Diels Alder adducts 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.
The X-ray structural analyses of the crystals were performed by
the Rigaku R-AXIS RAPID-F X-Ray diffraction camera con-
trolled with Rigaku R-AXIS RAPID AUTO program, and their
data were analyzed by Rigaku Crystal Structure MFC
Application (Ver. 1.0.0.1).
Catalytic Effect of Bis(l-menthopyrazol-3-yl)pyridine and Various Lewis
Acid on Diels Alder Reaction
Run
Ligand
Ar[a] R
Lewis
Acid
Mole Additive Yield Endo ee
Ratio
%
%
1
2
3
4
5
6
7
8
9
2a Py
H
H
H
H
H
H
H
H
Cu(OTf)
1:1
63
69
59
95
51
86
69
98
53
84
58
76
82
68
84
79
43
74
89
85
89
6
2
2a Py
2a Py
2a Py
2a Py
2a Py
2a Py
2a Py
Mg(ClO ) 1:1
95 19
94 17
92 27
94 22
95 40
94 38
95 43
98 45
83 27
92 13
86 11
94 75
93 21
92 67
91 28
92 12
95 12
4 2
Ni(ClO )
1:1
1:1
1:1
4 2
Zn(OTf)
2
Cu(OTf)
BuLi
BuLi
BuLi
BuLi
2
Materials.
Mg(ClO ) 1:1
4 2
Ni(ClO )
1:1
1:1
1:1
1:1
3,5-Disubstituted 1-acryloylpyrazoles (11) were prepared from
the corresponding pyrazoles and acryloyl chloride in the presence
of triethylamine according to the method of the previous paper
[9,13a], purified by silica gel column chromatography and distil-
lation, and was stored in the refrigerator. During this protocol,
the addition of hydroquinone was required to inhibit polymeriza-
tion which could be effective during the concentration and the
distillation procedure. Tetrahydrofuran was dried over sodium
benzophenone ketyl radical and distilled just before use.
Diisopropylamine and dichloromethane were distilled over cal-
cium hydride under argon atmosphere. Anhydrous methanol was
obtained by the distillation from the suspension of magnesium
methoxide in methanol. Cyclopentadiene (12) was prepared by
the pyrolysis of dicyclopentadiene at 160°, distilled and stored in
the freezer. Molecular Sieves 4 Å were freshly dried at 250°
under reduced pressure for 3 h.
4 2
Zn(OTf)
2
8a Py 2-Me
Cu(OTf)
2
3
10 8a Py 2-Me
La(OTf)
11 8a Py 2-Me Mg(ClO ) 1:1
4 2
12 8a Py 2-Me Ni(ClO )
1:1
1:1
1:1
1:1
1:1
1:1
4 2
13 8a Py 2-Me Ni(ClO )
BuLi
4 2
3
14 8a Py 2-Me
15 8a Py 2-Me
RuCl
Zn(OTf)
2
16 8a Py 2-Me Zn(SCN)
2
2
17 9a Py 1-Me
Cu(OTf)
18 9a Py 1-Me Mg(ClO ) 1:1
4 2
19 9a Py 1-Me Ni(ClO )
1:1
1:1
94
92 21
8
4 2
20 9a Py 1-Me
Zn(OTf)
2
[a] 2,6-Disubstituted pyridine was abbreviated as Py.
any remarkable enantioselectivity, the Diels Alder reaction
of 11 with 12 succeeded with an enantioselectivity of 75 %
ee using the complex catalyst which was formed in situ
from 8a and Ni(ClO ) •6H O in the presence of equimolar
Ethyl 5-Methyl-1-phenylpyrazole-3-carboxylate.
To the toluene (10 ml) solution of ethyl 2,4-dioxovalerate (6.6
mmol, 1.05 g), phenylhydrazine (11 mmol, 1.2 g) in toluene (2
ml) was added drop by drop under refluxing. After continuous
refluxing for 3.5 h, the reaction mixture was washed with dilute
hydrochloric acid, aqueous sodium hydrogencarbonate and brine.
The organic layer was dried over anhydrous magnesium sulfate,
and concentrated to give the crude product. By silica gel column
chromatography with hexane-ethyl acetate (3:1 v/v) mixture as
eluent, ethyl 5-methyl-1-phenylpyrazole-3-carboxylate was
4 2
2
amount of butyllithium.
Conclusion.
3-Heteroaryl-l-menthopyrazoles 1 and 2 and related
compounds were prepared from l-menthone, and their
enantioselective activities were discussed as chiral ligands.
In this series of compounds, 2,6-bis(2-methyl-l-menthopy-
razol-3-yl)pyridine (8a), which had both structural fea-
1
obtained in 74 % yield; H nmr: d 1.40 (3H, t, J=6.9 Hz), 2.33
(3H, d, J=0.7 Hz), 4.42 (2H, q, J=6.9 Hz), 6.74 (1H, d, J=0.7 Hz),
7.41-7.49 (5H, m).
tures of 3-phenyl-l-menthopyrazole (1b) and C symmet-
2
5-Methyl-1-phenylpyrazole-3-carboxylic Acid.
ric ligand in the molecule, should form the C symmetric
2
The mixture of ethyl 5-methyl-1-phenylpyrazole-2-carboxy-
late (4.8 mmol, 1.1 g), sodium hydroxide (1.2 g), ethanol (3 ml)
and water (27 ml) was heated for 2.5 h at 90°. After acidified
with dilute hydrochloric acid, the reaction mixture was extracted
with ether. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated. By recrystal-
lization of the residue, 5-methyl-1-phenylpyrazole-3-carboxylic
acid was obtained in 79 % yield; H nmr: d 2.35 (3H, d, J=0.7
Hz), 6.59 (1H, broad s), 6.80 (1H, d, J=0.7 Hz), 7.41-7.53 (5H,
m); ir (chloroform): n 3482, 1688, 1256 cm-1.
complex in situ with Zn(OTf) or Ni(ClO ) •6H O. The
2
4 2
2
catalytic amount of subsequent complex promoted the
Diels Alder reaction of 1-acryloyl-3,5-dimethylpyrazole
(11a) with cyclopentadiene (12) enantioselectively up to
75 % ee. From these facts, the utilities of chiral pyrazoles
for asymmetric synthesis increased by the use as a catalyst
rather than an auxiliary.
1
EXPERIMENTAL
Preparation of 2-Furoyl Chloride (3c) and 5-Methyl-1-
phenylpyrazole-3-carbonyl Chloride (3e).
Melting points are uncorrected. 1H nmr and 13C nmr spectra
were obtained on JEOL JNM-EX270 (270 MHz) spectrometer in
deuterochloroform with tetramethylsilane as an internal standard.
The ir spectra were measured by Shimadzu IR-460 spectrometer.
The enantiomer ratios were given from the peak ratios of gas
2-Furoyl chloride (3c) and 5-methyl-1-phenylpyrazole-3-car-
bonyl chloride (3e) were prepared from the corresponding car-
boxylic acid by refluxing with excess amount of thionyl chloride.
After removal of the excess thionyl chloride under reduced pres-

778
C. Kashima, S. Shibata, H. Yokoyama, and T. Nishio
Vol. 40
sure, the residue was directly used for the acylation of l-men-
Anal. Calcd. for C15H20O2S: C, 68.14; H, 7.63; S, 12.13.
thone without purification.
Found: C, 68.24; H, 7.57; S, 11.72.
5-Methyl-1-Phenylpyrazole-3-carbonyl Chloride (3e).
(3R,6S)-6-Isopropyl-3-methyl-2-(5-methyl-1-phenylpyrazole-3-
carbonyl)cyclohexanone (4e).
The title compound was obtained; bp 150°/ 10 mm Hg; 1H
nmr: d 2.35 (3H, d, J=0.7 Hz), 6.84 (1H, d, J=0.7 Hz), 7.44-7.54
(5H, m); 13C nmr: d 12.4 (CH3), 110.4 (CH), 125.3 (CH), 129.2
(CH), 129.4 (CH), 138.7 (C), 141.9 (C), 145.9 (C), 162.3 (C); ir
(chloroform): n 1762, 836 cm-1.
Compound 4e was obtained in 66 % yield; 1H nmr: d 0.84 (3H,
d, J=6.6 Hz), 0.89 (3H, d, J=6.9 Hz), 1.00 (3H, d, J=6.3 Hz),
1.40-1.60 (1H, m), 1.62 (1H, s), 1.96-2.15 (2H, m), 2.25-2.33
(1H, m), 2.32 (3H, d, J=0.7 Hz), 2.40-2.60 (1H, m), 4.41 (1H, d,
J=12.9 Hz), 6.77 (1H, d, J=0.7 Hz), 7.40-7.54 (5H, m); 13C nmr:
d 12.4 (CH3), 18.5 (CH3), 21.0 (CH3), 21.1 (CH3), 26.0 (CH2),
28.0 (CH2), 33.4 (CH), 36.9 (CH), 56.5 (CH), 65.8 (CH), 107.0
(CH), 125.2 (CH), 128.5 (CH), 129.2 (CH), 139.1 (C), 141.1 (C),
151.9 (C), 193.8 (C), 209.2 (C).
(3R,6S)-2-Heteroaroyl-3-methyl-6-isopropylcyclohexanone (4).
According to the previously reported method [5], l-menthone
(1.2 g, 7.9 mmol) in tetrahydrofuran (2 ml) was added at -5°
under argon atmosphere to a tetrahydrofuran (10 ml) solution of
lithium diisopropylamide, which was prepared from diisopropy-
lamine (1 ml) and butyllithium in hexane solution (1.55 M, 5 ml,
7.75 mmol). After stirring for 30 min, heteroaroyl chloride (3)
(8.5 mmol) in tetrahydrofuran (2 ml) was added at -5° and stirred
for 5 h at room temperature. The reaction mixture was quenched
with water, acidified with dilute hydrochloric acid and extracted
with ether. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and the solvent was removed.
The product (4) was purified by silica gel column chromatogra-
phy with hexane-ethyl acetate mixture as eluent.
Anal. Calcd. for C21H26N2O2: C, 74.53; H, 7.74; N, 8.28.
Found: C, 74.20; H, 7.53; N, 8.14.
Preparation of 3-Heteroaryl-l-menthopyrazole (1).
The mixture of4 (2.0 mmol), hydrazine hydrate (16 mmol, 800
mg) and hydrazine hydrochloride (0.5 mmol, 34 mg) in methanol
(15 ml) was refluxed for 7 h. The reaction mixture was diluted
with water and extracted with ether. The organic layer was
washed with dilute hydrochloric acid and brine, and dried over
anhydrous magnesium sulfate. After removal of the solvent, the
residue was chromatographed on silica gel column with benzene-
ethyl acetate mixture as eluent.
(3R,6S)-6-Isopropyl-3-methyl-2-(2-pyridinecarbonyl)cyclohexa-
none (4a).
3-(2-Pyridyl)-l-menthopyrazole (1a).
Compound 4a was obtained in 37% yield; bp 130°/14mm Hg;
1H nmr: d 0.85 (3H, d, J=6.6 Hz), 0.91 (3H, d, J=6.6 Hz), 1.00
(3H, d, J=6.3 Hz), 1.23-1.46 (2H, m), 1.87-2.18 (4H, m), 2.31-
2.38 (1H, m), 4.77 (1H, d, J=8.2 Hz), 7.40-7.45 (1H, m), 7.79-
7.86 (1H, m), 8.06-8.10 (1H, m), 8.58-8.60 (1H, m); 13C nmr: d
18.5 (CH3), 20.9 (CH3), 22.1 (CH3), 35.7 (CH), 27.7 (CH2), 35.3
(CH), 50.7 (CH2), 55.7 (CH), 64.0 (CH), 121.6 (CH), 126.9
(CH), 136.8 (CH), 148.5 (CH), 153.1 (C), 199.2 (C), 209.4 (C).
Anal. Calcd. for C16H21NO2: C, 74.10; H, 8.16; N, 5.4.
Found: C, 73.82; H, 8.07; N, 5.44.
Compound 1a was obtained in 27% yield; mp 96-101° (from
Hexane); 1H nmr: d 0.89 (3H, d, J=6.9 Hz), 1.06 (3H, d, J=6.9
Hz), 1.14 (3H, d, J=6.6 Hz), 1.37-1.48 (1H, m), 1.64-1.73 (1H,
m), 1.82-1.93 (1H, m), 2.64 (1H, q, J=5.9 Hz), 3.27 (1H, d-d,
J=12.8, 6.3 Hz), 7.16-7.21 (1H, m), 7.65-7.76 (2H, m), 8.60-8.63
(1H,m); 13C nmr: d 19.0 (CH3), 21.0 (CH3), 21.2 (CH3), 21.4
(CH3), 26.8 (CH), 30.3 (CH2), 30.8 (CH), 39.7 (CH), 120.0 (C),
121.1 (CH), 122.0 (CH), 136.4 (CH), 149.3 (CH), 151.1 (C).
Anal. Calcd. for C16H21N3•1/4H2O : C, 73.95; H, 8.34; N,
16.17. Found: C, 73.70 H, 8.12; N, 16.03.
(3R,6S)-2-(2-Furancarbonyl)-6-isopropyl-3-methylcyclohexa-
none (4c).
3-(2-Furyl)-l-menthopyrazole (1c).
Compound 4c was obtained in 37 % yield; mp 148-149°
(hexane); H nmr: d 0.85 (3H, d, J=6.9 Hz), 0.92 (3H, d, J=6.9
Compound 1c was obtained in 100 % yield; mp 129.5-130.5°
(H2O-MeOH); H nmr: d 0.86 (3H, d, J=6.6 Hz), 1.00 (3H, d,
1
1
J=6.6 Hz), 1.14 (3H, d, J=6.9 Hz), 1.36-1.46 (1H, m), 1.60-1.71
(1H, m), 1.79-1.91 (1H, m), 1.95-2.10 (2H, m), 2.54-2.62 (1H,
m), 3.02-3.10 (1H, m), 6.47 (1H, d-d, J=3.3, 2.0 Hz), 6.57 (1H, d-
d, J=3.3, 0.7 Hz), 7.46 (1H, d-d, J=2.0, 0.7 Hz); 13C nmr: d 19.2
(CH3), 20.7 (CH3), 21.0 (CH3), 21.2 (CH2), 26.2 (CH2), 29.9
(CH), 30.9 (CH), 39.0 (CH), 106.7 (CH), 111.2 (CH), 113.7 (C),
128.2 (C), 141.5 (CH).
Hz), 0.99 (3H, d, J=6.3 Hz), 1.46-1.59 (2H, m), 1.99-2.29 (4H,
m), 2.45-2.55 (1H, m), 3.86 (1H, d, J=12.5 Hz), 6.53 (1H, d-d,
J=3.6, 1.7 Hz), 7.19 (1H, d-d, J=3.6, 0.7 Hz), 7.53 (1H, d-d,
J=1.7, 0.7 Hz); 13C nmr: d 18.5 (CH3), 21.1 (CH3), 26.0 (CH2),
27.5 (CH2), 33.4 (CH), 36.8 (CH), 26.6 (CH), 66.4 (CH), 112.5
(CH), 116.8 (CH), 146.1 (CH), 153.7 (C), 186.8 (C), 208.2 (C).
Anal. Calcd. for C15H20O3: C, 72.55; H, 8.12. Found: C,
72.24; H, 8.06.
Anal. Calcd. for C15H20N2O: C, 73.74; H, 8.25; N, 11.47.
Found: C, 73.77; H, 8.03; N, 11.55.
(3R,6S)-6-Isopropyl-3-methyl-2-(2-thiophenecarbonyl)cyclo-
hexanone (4d).
3-(2-Thienyl)-l-menthopyrazole (1d).
Compound 4d was obtained in 35 % yield; mp 139-140°
(hexane); 1H nmr: d 0.86 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6
Hz), 1.01 (3H, d, J=6.3 Hz), 1.48-1.65 (3H, m), 2.00-2.26 (3H, m),
2.50-2.55 (1H, m), 3.84 (1H, d, J=12.5 Hz), 7.11 (1H, d-d, J=5.0,
4.0 Hz), 7.58 (1H, d-d, J=3.6, 1.0 Hz), 7.63 (1H, d-d, J=5.0, 1.3
Hz); 13C nmr: d 18.5 (CH3), 21.1 (CH3), 21.2 (CH3), 26.0 (CH2),
27.7 (CH2), 33.4 (CH), 37.6 (CH), 56.8 (CH), 67.6 (CH), 128.1
(CH), 131.8 (CH), 133.8 (CH), 145.3 (C), 190.1 (C), 208.1 (C).
Compound 1d was obtained in 80 % yield; mp 118-119° (sub-
limation); H nmr: d 0.85 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.9
1
Hz), 1.13 (3H, d, J=6.6 Hz), 1.38-1.46 (1H, m), 1.62-1.71 (1H,
m), 1.80-1.86 (1H, m), 1.95-2.08 (2H, m), 2.52-2.60 (1H, m),
3.05-3.13 (1H, m), 7.06 (1H, d-d, J=4.9, 4.0 Hz), 7.24-7.27 (2H,
m); 13C nmr: d 19.2 (CH3), 20.4 (CH2), 21.0 (CH3), 26.2 (CH2),
29.8 (CH), 30.8 (CH), 38.8 (CH), 118.5 (C), 124.3 (CH), 124.6
(CH), 127.2 (CH), 136.5 (C).

Sep-Oct 2003
Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their Catalytic Activity
779
Anal. Calcd. for C15H20N2S: C, 69.19; H, 7.74; N, 10.76; S,
Anal. Calcd. for C16H22N2S: C, 70.03; H, 8.08; N, 10.21; S,
12.31. Found: C, 68.50; H, 7.76; N, 10.68; S, 11.21.
11.68. Found: C, 69.90; H, 8.12; N, 10.09; S, 11.06.
3-(5-Methyl-1-phenylpyrazol-3-yl)-l-menthopyrazole (1e).
2-Methyl-3-(5-methyl-1-phenylpyrazol-3-yll-)m- enthopyrazole (5e).
Compound 1e was obtained in 51 % yield; 1H nmr: d 0.87 (3H,
d, J=6.9 Hz), 1.04 (3H, d, J=6.6 Hz), 1.24 (3H, d, J=6.9 Hz),
1.37-1.43 (1H, m), 1.62-1.71 (1H, m), 1.84-1.88 (1H, m), 1.98-
2.07 (1H, m), 2.11-2.17 (1H, m), 2.38 (3H, d, J=0.7 Hz), 2.58-
2.64 (1H, m), 3.11-3.17 (1H, sex, J=6.3 Hz), 6.49 (1H, s), 7.44-
7.53 (5H, m); 13C nmr: d 12.5 (CH3), 19.0 (CH3), 21.0 (CH3),
21.5 (CH2), 26.4 (CH2), 30.3 (C), 30.7 (CH), 39.6 (CH), 105.6
(CH), 119.3 (C), 124.8 (CH), 127.5 (C), 128.3 (C), 129.0 (CH),
139.6 (C).
Compound 5e was obtained in 36 % yield; 1H nmr: d 0.84 (3H,
d, J=6.6 Hz), 1.03 (3H, d, J=6.9 Hz), 1.05 (3H, d, J=7.3 Hz),
1.49-1.59 (1H, m), 1.67-1.87 (2H, m), 1.95-2.01 (1H, m), 2.32-
2.40 (1H, m), 2.42 (3H, s), 2.59-2.65 (1H, m), 2.96-3.00 (1H, m),
3.93 (3H, s), 6.33 (1H, d, J=0.7 Hz), 7.35-7.51 (5H, m); 13C nmr:
d 12.6 (CH3), 18.2 (CH3), 20.9 (CH3), 21.0 (CH3), 22.0 (CH2),
27.2 (CH2), 30.2 (CH), 31.8 (CH), 37.8 (CH), 40.4 (C), 107.9
(CH), 121.4 (C), 124.5 (C), 124.7 (CH), 127.7 (C), 129.1 (CH),
139.3 (C), 139.7 (C), 143.3 (C), 150.5 (C).
Anal. Calcd. for C21H26N4: C, 75.41; H, 7.84; N, 16.75.
Found: C, 74.71; H, 7.63; N, 16.53.
Anal. Calcd. for C22H28N4: C, 75.82; H, 8.10; N, 16.08.
Found: C, 75.58; H, 7.56; N, 16.26.
Preparation of 3-Heteroaryl-2-methyl-l-menthopyrazole (5).
Preparation of 3-Heteroaryl-1-methyl-l-menthopyrazole (6).
Butyllithium in hexane solution (1.55 M, 0.56 ml, 0.87 mmol)
was added to a tetrahydrofuran solution of 1 (0.8 mmol) at -5°
and kept for 30 min with stirring under argon atmosphere. To the
reaction mixture was added methyl iodide (6.7 mmol, 958 mg) in
tetrahydrofuran (1 ml) at -5°, and then stirred for 6 h at room tem-
perature. The reaction mixture was quenched with water, acidi-
fied with dilute hydrochloric acid, and extracted with ether. The
organic layer was washed with dilute hydrochloric acid, aqueous
sodium hydrogencarbonate and brine. It was dried over anhy-
drous magnesium sulfate, and the solvent was removed to obtain
the product mixture. From the nmr spectrum of the mixture, the
regioisomer ratio was estimated, summarized in Table 1. The
product mixture was chromatographed on silica gel column with
benzene-ethyl acetate mixture as eluent to obtained 6.
The mixture of 4 (1.0 mmol), methylhydrazine (6.8 mmol, 313
mg) and hydrochloric acid (6 M, 60 mg) in methanol (7 ml) was
refluxed for 7 h. The reaction mixture was diluted with water and
extracted with ether. The organic layer was washed with dilute
hydrochloric acid, aqueous sodium hydrogencarbonate and brine.
It was dried over anhydrous magnesium sulfate, and the solvent
was removed to obtain the product mixture. From the nmr spec-
trum of the mixture, the regioisomer ratio was estimated, summa-
rized in Table 1. The product mixture was chromatographed on
silica gel column with benzene-ethyl acetate mixture as eluent.
2-Methyl-3-(2-pyridyl)-l-menthopyrazole (5a).
Compound 5a was obtained in 65% yield; bp 80°/14mm Hg;
1H nmr: d 0.79 (3H, d, J=6.6 Hz), 0.86 (3H, d, J=6.6 Hz), 1.07
(3H, d, J=6.6 Hz), 1.23-1.28 (1H, m), 1.52-1.56 (1H, m), 1.82-
1.86 (1H, m), 1.99-2.01 (1H, m), 2.40-2.47 (1H, m), 2.61-2.69
(1H, m), 2.94-2.97 (1H, m), 3.86 (3H, s), 7.24-7.29 (1H, m), 7.45
(1H, d, J=7.9 Hz), 7.73-7.79 (1H, m), 8.73 (1H, d, J=5.5 Hz).
Anal. Calcd. for C17H23N3: C, 75.80; H, 8.61; N, 15.6. Found:
C, 75.39; H, 8.23; N, 15.34.
1-Methyl-3-(2-pyridyl)-l-menthopyrazole (6a).
Compound 6a was obtained in 67% yield; 80°/14mm Hg; 1H
nmr: d 0.84 (3H, d, J=6.6 Hz), 1.04 (3H, d, J=6.6 Hz), 1.19 (3H,
d, J=6.6 Hz), 1.57-1.88 (4H, m), 2.26-2.33 (1H, m), 2.71 (1H, q,
J=6.3 Hz), 3.40-3.46 (1H, m), 3.85 (3H, s), 7.10-7.15 (1H, m),
7.63-7.69 (1H, m), 7.80-7.84 (1H, m), 8.60-8.63 (1H, m), 13C
nmr: d 17.6 (CH3), 20.5 (CH2), 20.7 (CH3), 21.2 (CH3), 26.4
(CH), 29.2 (CH2), 29.8 (CH), 37.8 (CH3), 38.1 (CH), 121.0
(CH), 121.3 (CH), 121.8 (C), 135.9 (CH), 142.6 (C), 146.3 (C),
149.0 (CH), 154.1 (C).
3-(2-Furyl)-2-methyl-l-menthopyrazole (5c).
Compound 5c was obtained in 78 % yield; 1H nmr: d 0.85 (3H,
d, J=6.6 Hz), 0.94 (3H, d, J=6.9 Hz), 1.05 (3H, d, J=6.9 Hz),
1.25-1.36 (1H, m), 1.52-1.58 (1H, m), 1.81-1.87 (1H, m), 1.92-
2.00 (1H, m), 2.29-2.37 (1H, m), 2.58-2.64 (1H, m), 2.86-2.92
(1H, m), 3.85 (3H, s), 6.46 (1H, d-d, J=3.3, 0.7 Hz), 6.51 (1H, d-
d, J=3.3, 1.7 Hz), 7.53 (1H, d-d, J=2.0, 1.0 Hz); 13C nmr: d 18.2
(CH3), 20.6 (CH3), 20.8 (CH3), 22.0 (CH2), 27.1 (CH2), 30.2
(CH), 31.5 (CH), 37.7 (CH), 40.3 (CH3), 110.0 (CH), 111.1 (CH),
122.0 (C), 129.9 (C), 142.4 (CH), 144.9 (C), 150.7 (C).
Anal. Calcd. for C17H23N3: C, 75.8; H, 8.61; N, 15.6. Found:
C, 75.30; H, 8.58; N,15.23.
3-(2-Furyl)-1-methyl-l-menthopyrazole (6c).
Compound 6c was obtained in 76 % yield; 1H nmr: d 0.90 (3H,
d, J=6.9 Hz), 1.01 (3H, d, J=6.9 Hz), 1.11 (3H, d, J=6.6 Hz),
1.43-1.52 (1H, m), 1.76-1.91 (2H, m), 1.93-2.08 (2H, m), 2.53-
2.59 (1H, m), 3.10-3.17 (1H, m), 3.79 (3H, s), 6.46 (1H, d-d,
J=3.3, 2.0 Hz), 6.57 (1H, d-d, J=3.3, 0.7 Hz), 7.45 (1H, d-d,
J=2.0, 0.7 Hz); 13C nmr: d 19.8 (CH3), 19.9 (CH3), 21.1 (CH3),
21.4 (CH2), 25.4 (CH2), 27.0 (CH), 31.5 (CH), 37.0 (CH), 37.0
(CH3), 105.8 (CH), 110.9 (CH), 119.0 (C), 139.5 (C), 141.1
(CH), 141.7 (C), 149.3 (C).
Anal. Calcd. for C 16H22N2O: C, 74.38; H, 8.58; N,
10.84.?Found: C, 73.89; H, 8.51; N, 10.25.
2-Methyl-3-(2-thienyl)-l-menthopyrazole (5d).
Compound 5d was obtained in 82 % yield; 1H nmr: d 0.86 (3H,
d, J=6.6 Hz), 0.86 (3H, d, J=6.6 Hz), 1.07 (3H, d, J=6.9 Hz),
1.23-1.33 (1H, m), 1.50-1.55 (1H, m), 1.81-1.98 (2H, m), 2.34-
2.42 (1H, m), 2.59-2.67 (1H, m), 2.80-2.87 (1H, m), 3.74 (3H, s),
7.04 (1H, d-d, J=3.6, 1.3 Hz), 7.12 (1H, d-d, J=5.3, 3.6 Hz), 7.45
(1H, d-d, J=5.0, 1.0 Hz); 13C nmr: d 18.0 (CH3), 20.6 (CH3), 20.8
(CH3), 22.4 (CH2), 27.3 (CH2), 30.0 (CH), 32.1 (CH), 36.8 (CH),
40.6 (CH3), 122.1 (C), 127.1 (CH), 127.2 (CH), 128.5 (CH),
131.8 (C), 132.2 (C), 150.7 (C).
Anal. Calcd. for C16H22N2O: C, 74.38; H, 8.58; N, 10.84.
Found: C, 73.85; H, 8.43; N, 10.54.
1-Methyl-3-(2-thienyl)-l-menthopyrazole (6d).
Compound 6d was obtained in 61 % yield; 1H nmr: d 0.91 (3H,
d, J=6.9 Hz), 1.01 (3H, d, J=6.9 Hz), 1.11 (3H, d, J=6.9 Hz),

780
C. Kashima, S. Shibata, H. Yokoyama, and T. Nishio
Vol. 40
1.45-1.52 (1H, m), 1.76-1.87 (2H, m), 1.97-2.08 (2H, m), 2.52-
2.58 (1H, m), 3.15-3.21 (1H, m), 3.77 (3H, s), 7.05 (1H, d-d,
J=5.3, 3.6 Hz), 7.21 (1H, d-d, J=5.3, 1.0 Hz), 7.28 (1H, d-d,
J=3.6, 1.0 Hz); 13C nmr: d 19.8 (CH3), 19.9 (CH3), 20.8 (CH3),
21.4 (CH2), 25.5 (CH2), 27.0 (CH), 31.5 (CH), 37.0 (CH), 37.1
(CH3), 118.8 (C), 123.4 (CH), 123.6 (CH), 127.2 (CH), 137.3
(C), 142.1 (C), 142.3 (C).
Hz), 0.86 (3H, d, J=6.9 Hz), 0.92 (3H, d, J=6.6 Hz), 0.98 (3H, d,
J=6.3 Hz), 0.99 (3H, d, J=6.6 Hz), 1.41-2.00 (6H, m), 2.03-2.34
(6H, m), 2.53-2.60 (2H, m), 4.00 (1H, d, J=11.6 Hz), 4.63 (1H, d,
J=4.6 Hz), 7.88 (2H, d, J=8.6 Hz), 8.06 (2H, d, J=8.6 Hz); 13C
nmr: d 18.5 (CH3), 18.7 (CH3), 20.9 (CH3), 21.1 (CH3), 21.2
(CH3), 26.0 (CH2), 27.8 (CH2), 28.0 (CH2), 29.1 (CH), 33.4
(CH), 37.4 (CH), 39.5 (CH), 53.1 (CH), 57.0 (CH), 66.1 (CH),
66.5 (CH), 128.2 (CH), 128.9 (CH), 141.1 (C), 196.2 (C), 197.9
(C), 208.3 (C), 209.2 (C).
Anal. Calcd. for C16H22N2S: C, 70.03; H, 8.08; N, 10.21; S,
11.68. Found: C, 70.23; H, 7.97; N, 10.21; S, 11.82.
1-Methyl-3-(5-methyl-1-phenylpyrazol-3-yl)-l-menthopyrazole
(6e).
Di[(3S,6R)-6-isopropyl-3-methyl]cyclohex-1-enyl Phthalate
(10).
Compound 6e was obtained in 87% yield; 1H nmr: d 0.89 (3H,
d, J=6.9 Hz), 1.00 (3H, d, J=6.9 Hz), 1.19 (3H, d, J=6.9 Hz),
1.43-1.49 (1H, m), 1.78-1.86 (2H, m), 1.96-2.09 (2H, m), 2.39
(3H, s), 2.54-2.60 (1H, m), 3.30-3.35 (1H, m), 3.80 (3H, s), 6.57
(1H, s), 7.31-7.55 (5H, m); 13C nmr: d 12.7 (CH3), 19.9 (CH3),
20.2 (CH2), 21.4 (CH3), 25.7 (CH2), 27.4 (CH), 31.5 (CH), 37.0
(CH), 37.3 (CH3), 105.5 (CH), 120.0 (C), 124.6 (CH), 127.0
(CH), 128.8 (CH), 139.0 (C), 140.3 (C), 141.7 (C), 141.8 (C),
147.1 (C).
Compound 10 was obtained in 56 % yield; mp 106-107°
(methanol); 1H nmr: d 0.81 (6H, d, J=6.6 Hz), 0.90 (6H, d, J=6.9
Hz), 1.04 (6H, d, J=7.3 Hz), 1.16-1.30 (2H, m), 1.35-1.49 (2H,
m), 1.74-1.85 (4H, m), 1.95-2.05 (2H, m), 2.28-2.34 (2H, m),
2.58-2.64 (2H, m), 5.49 (2H, s), 7.56 (2H, d-d, J=5.9, 3.3 Hz),
7.78 (2H, d-d, J=5.6, 3.3 Hz);13C nmr: d 16.8 (CH3), 20.1 (CH3),
21.7 (CH3), 22.3 (CH2), 27.4 (CH2), 30.2 (CH), 30.7 (CH), 41.7
(CH), 122.4 (CH), 129.1 (CH), 131.1 (CH), 132.1 (C), 150.3 (C),
165.4 (C); ir (chloroform): n 3019, 1735, 1286, 1271 cm-1.
Anal. Calcd. for C28H38O4: C, 76.68; H, 8.73. Found: C,
75.92; H, 8.69.
Anal. Calcd. for C22H28N4: C, 75.82; H, 8.1; N, 16.08. Found:
C, 75.29; H, 7.81; N, 15.59.
2,6-Bis[(3S,6R)-3-isopropyl-6-methyl-2-oxocyclohexanecar-
bonyl]pyridine (7a).
Reaction of Phthaloyl Chlorides with l-Menthone.
According to the previously reported method [5], l-menthone
(620 mg, 4.0 mmol) in tetrahydrofuran (2 ml) was added at -5°
under argon atmosphere to a tetrahydrofuran (5 ml) solution of
lithium diisopropylamide, which was prepared from diisopropy-
lamine (0.6 ml) and butyllithium in hexane solution (1.55 M, 2.6
ml, 4.0 mmol). After stirring for 30 min, isophthaloyl, tereph-
thaloyl or phthaloyl chloride (406 mg, 2.0 mmol) in tetrahydrofu-
ran (2 ml) was added at -5° and stirred for 3 h at room tempera-
ture. The reaction mixture was quenched with water, acidified
with dilute hydrochloric acid and extracted with ether. The
organic layer was washed with brine, dried over anhydrous mag-
nesium sulfate, and the solvent was removed. The product (7b or
7c) was roughly purified by silica gel column chromatography
with hexane-ethyl acetate mixture as eluent, and was provided to
the preparation of 2 and 8. In the case of phthaloyl chloride,
tetraketone 7 could not be obtained and di[(3S,6R)-6-isopropyl-
3-methyl]cyclohex-1-enyl phthalate (10) was isolated by recryl-
stallization from methanol.
According to the previously reported method [5], l-menthone
(620 mg, 4.0 mmol) in tetrahydrofuran (2 ml) was added at -5°
under argon atmosphere to the tetrahydrofuran (5 ml) solution of
lithium diisopropylamide, which was prepared from diisopropy-
lamine (0.6 ml) and butyllithium in hexane solution (1.55 M, 2.6
ml, 4.0 mmol). After stirring for 30 min, powder of pyridine-
2,6-dicarbonyl chloride hydrochloride (480 mg, 2.0 mmol) was
directly added at -5° and stirred for 3 h at room temperature. The
reaction mixture was quenched with water, acidified with dilute
hydrochloric acid and extracted with ether. The organic layer
was washed with brine, dried over anhydrous magnesium sul-
fate, and the solvent was removed. The product (7a) was puri-
fied by silica gel column chromatography with hexane-ethyl
1
acetate (7:1 v/v) mixture in 55 % yield; H nmr: d 0.92 (6H, d,
J=6.9 Hz), 0.95 (6H, d, J=6.3 Hz), 0.99 (6H, d, J=6.6 Hz), 1.47-
1.64 (4H, m), 2.02-2.14 (4H, m), 2.19-2.36 (4H, m), 2.48-2.54
(2H, m), 4.58 (2H, d, J=11.9 Hz), 8.01 (1H, q, J=7.9 Hz), 8.25
(2H, d, J=7.9 Hz); 13C nmr: d 19.0 (CH3), 21.0 (CH3), 21.9
(CH3), 27.1 (CH), 29.3 (CH2), 33.7 (CH2), 36.7 (CH), 57.8
(CH), 64.3 (CH), 125.0 (CH), 138.2 (CH), 152.1 (C), 197.6 (C),
209.3 (C).
1,3-Bis-[(3S,6R)-3-isopropyl-6-methyl-2-oxocyclohexanecar-
bonyl]benzene (7b).
Compound 7b was obtained in 41% yield; 105-107°
(methanol) 1H nmr: d 0.87 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6
Hz), 0.98 (3H, d, J=6.3 Hz), 1.50-1.66 (3H, m), 2.04-2.20 (2H,
m), 2.25-2.33 (1H, m), 2.51-2.57 (1H, m), 4.04 (1H, d, J=11.5
Hz), 7.55 (1H, t, J=7.8 Hz), 7.99 (2H, d, J=7.8 Hz), 8.27 (1H, s);
13C nmr: d 18.5 (CH3), 21.1 (CH3), 21.2 (CH3), 26.0 (CH), 27.8
(CH2), 33.4 (CH2), 37.6 (CH), 57.0 (CH), 66.3 (CH), 127.5
(CH), 129.1 (CH), 132.2 (CH), 138.3 (C), 197.6 (C), 208.8 (C).
Anal. Calcd. for C22H28N4: C, 76.68; H, 8.73. Found: C,
76.32; H, 8.27.
Anal. Calcd. for C27H37NO4: C, 73.77; H, 8.48; N, 3.19.
Found: C, 73.86; H, 8.50; N, 3.08.
2,6-Bis(l-menthopyrazol-3-yl)pyridine (2a) and 1,3-Bis(l-men-
thopyrazol-3-yl)benzene (2b).
The mixture of 7 (14.0 mmol), hydrazine hydrate (160 mmol,
8.0 g) and hydrazine hydrochloride (8.2 mmol, 562 mg) in
methanol (20 ml) was refluxed for 19 h. The reaction mixture
was diluted with water and extracted with ether. The organic
layer was washed with dilute hydrochloric acid and brine, dried
over anhydrous magnesium sulfate. After removal of the solvent,
the residue was chromatographed on silica gel column with ben-
zene-ethyl acetate mixture or recrystallized from aqueous
methanol.
1,4-Bis-[(3S,6R)-3-isopropyl-6-methyl-2-oxocyclohexanecar-
bonyl]benzene (7c).
Compound 7c was obtained in 44 % yield; mp 172-173°
(methanol); 1H nmr: d 0.83 (3H, d, J=6.6 Hz), 0.85 (3H, d, J=6.6

Sep-Oct 2003
Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their Catalytic Activity
781
2,6-Bis(l-menthopyrazol-3-yl)pyridine (2a).
J=6.9 Hz), 1.08 (6H, d, J=6.9 Hz), 1.20-30 (2H, q, J=12.5 Hz),
1.44-58 (2H, q, J=12.2 Hz), 1.82-98 (4H, m), 2.40-46 (2H, m),
2.62-67 (2H, m), 2.76-86 (2H, m), 3.70 (6H, s), 7.29-37 (3H, m),
7.49 (1H, t, J=6.9 Hz); 13C nmr: d 17.9 (CH3), 20.8 (CH3), 22.7
(CH2), 27.4 (CH), 29.9 (CH), 32.6 (CH2), 36.8 (CH3), 40.9 (CH),
120.6 (C), 128.6 (CH), 129.5 (CH), 130.8 (CH), 132.5 (C), 138.8
(C), 150.9 (C).
1
Compound 2a was obtained in 62% yield; mp 124-134°; H
nmr: d 0.92 (6H, d, J=5.9 Hz), 1.06 (6H, d, J=6.9 Hz), 1.45-1.50
(1H, m), 1.69-1.76 (1H, m), 1.86-1.96 (1H, m), 2.03-2.18 (2H,
m), 2.63 (1H, q, J=5.6 Hz), 3.33 (1H, d-d, J=12.2, 5.6 Hz), 7.59
(2H, d, J=7.6 Hz), 7.76 (1H, d-d, J=8.6, 7.3 Hz); 13C nmr: d 19.2
(CH3), 21.0 (CH2), 21.1 (CH3), 26.8 (CH), 29.7 (CH2), 30.9
(CH), 39.5 (CH), 118.9 (CH), 120.0 (C), 136.9 (CH), 141.1 (C),
149.3 (C), 150.2 (C).
Anal. Calcd. for C30H42N4: C, 78.56; H, 9.23; N, 12.21.
Found: C, 78.56; H, 9.26; N, 11.81.
Anal. Calcd. for C27H37N5: C, 75.13; H, 8.64; N, 16.23.
Found: C, 75.78; H, 8.55; N, 15.43
2,6-Bis(1-methyl-l-menthopyrazol-3-yl)pyridine (9a) and 1,3-
Bis(1-methyl-l-menthopyrazol-3-yl)benzene (9b).
1,3-Bis(l-menthopyrazol-3-yl)benzene (2b).
Under argon atmosphere, butyllithium in hexane solution (1.55
M, 1.28 ml, 2.0 mmol) was added to the tetrahydrofuran (5 ml)
solution of 2 (1.1 mmol) at -5° and kept for 30 min with stirring.
To the reaction mixture was added methyl iodide (2.2 mmol, 318
mg) in tetrahydrofuran (3 ml) at -5°, and then stirred for 2 h at
room temperature. The reaction mixture was quenched with
water, acidified with dilute hydrochloric acid, and extracted with
ether. The organic layer was washed with brine, dried over anhy-
drous magnesium sulfate, and concentrated. The product (9) was
purified from the residual mixture by recrystallization or by silica
gel column chromatography with benzene-ethyl acetate mixture
as eluent.
Compound 2b was obtained in 39% yield; 1H nmr: d 0.84 (3H,
d, J=6.6 Hz), 0.90 (3H, d, J=6.9 Hz), 1.00 (3H, d, J=6.6 Hz), 1.25
(2H,m, 1.54 (2H, m), 1.79 (2H, m), 2.00 (2H,m), 2.21 (2H, m),
2.62 (2H, m), 2.99 (2H, m), 7.22 (1H,t, J=7.8 Hz), 7.38 (2H, d
J=7.6 Hz), 7.64 (1H, s); 13C nmr: d 18.2 (CH3), 20.7 (CH3), 20.8
(CH3), 21.9 (CH2), 26.9 (CH), 30.0 (CH), 31.7 (CH2), 39.9 (CH),
118.4 (C), 126.7 (CH), 128.1 (CH), 133.5 (CH), 144.8 (C), 146.8
(C).
Anal. Calcd. for C28H38N4: C, 78.09; H, 8.89; N, 13.01.
Found: C, 78.31; H, 9.22; N, 12.82.
1,4-Bis(l-menthopyrazol-3-yl)benzene (2c).
2,6-Bis(1-methyl-l-menthopyrazol-3-yl)pyridine (9a).
Compound 2c was obtained in 54 % yield; mp 268-269°
(methanol); 1H nmr: d 0.89 (6H, d, J=6.8 Hz), 1.01 (6H, d, J=6.7
Hz), 1.06 (6H, d, J=6.8 Hz), 1.25-1.36 (2H, m), 1.56-1.62 (2H,
m), 1.83-1.89 (2H, m), 2.02-2.08 (2H, m), 2.17-2.24 (2H, m),
2.64-2.68 (2H, m), 3.07-3.11 (2H, m), 7.61 (4H, s); 13C nmr: d
18.6 (CH3), 20.8 (CH3), 20.9 (CH3), 22.1 (CH2), 27.2 (CH2),
30.4 (CH), 31.7 (CH), 39.9 (CH), 118.9 (C), 127.5 (CH).
Anal. Calcd. for C28H38N4: C28H38N4•CH3OH: C, 75.28; H,
9.15; N, 12.11. Found: C, 75.46; H, 8.96; N, 12.50.
Compound 9a was obtained in 81% yield; mp 260-270°
(MeOH-AcOEt); 1H nmr: d 0.92 (6H, d, J=6.6 Hz), 1.04 (6H, d,
J=6.9 Hz), 1.04 (6H, d, J=6.6 Hz), 1.40-1.47 (2H, m), 1.77-1.85
(4H, m), 1.99-2.15 (4H, m), 2.57-2.62 (2H, m), 3.52-3.58 (2H,
m), 3.83 (6H, s), 7.66 (1H, dd, J=8.6, 7.3 Hz), 7.81 (2H, d, J=7.3
Hz); 13C nmr: d 19.7 (CH3), 20.4 (CH2), 21.5 (CH3), 22.0 (CH3),
25.8 (CH), 27.7 (CH2), 31.4 (CH), 37.3 (CH3), 37.5 (CH), 119.1
(CH), 121.3 (C), 136.1 (CH), 142.1 (C), 147.4 (C), 153.4 (C).
Anal. Calcd. for C29H41N5: C, 75.77; H, 8.99; N, 15.24.
Found: C, 75.71; H, 8.57; N, 15.07.
2,6-Bis(2-methyl-l-menthopyrazol-3-yl)pyridine (8a) and 1,3-
Bis(2-methyl-l-menthopyrazol-3-yl)benzene (8b).
1,3-Bis(1-methyl-l-menthopyrazol-3-yl)benzene (9b).
The mixture of 7 (2.3 mmol), methylhydrazine (9.6 mmol, 440
mg) and p-toluenesulfonic acid (2.0 mmol, 387 mg) in methanol
(50 ml) was refluxed for 9 h. The reaction mixture was diluted
with water and extracted with toluene. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate, and
concentrated. The product mixture was chromatographed on sil-
ica gel column with benzene-ethyl acetate mixture as eluent.
Compound 9b was obtained in 7% yield; mp 217-219°
(methanol); 1H nmr: d 0.93 (3H, d, J=6.3 Hz), 0.94 (3H, d, J=6.3
Hz), 1.02 (3H, d, J=6.9 Hz), 1.36-1.42 (1H, m), 1.74-1.81 (2H,
m), 2.01-2.16 (2H, m), 2.57 (1H, dd, J=5.6, 4.3 Hz), 3.21-3.26
(1H, m), 3.81 (3H, s), 7.38 (1H, t, J=7.6 Hz), 7.62 (2H, d, J=7.6
Hz), 8.02 (1H, s); 13C nmr: d 19.6 (CH3), 20.6 (CH2), 21.4
(CH3), 21.5 (CH3), 26.0 (CH), 27.9 (CH2), 31.1 (CH), 37.1
(CH3), 37.7 (CH), 119.1 (C), 126.0 (CH), 128.3 (CH), 135.1 (C),
142.0 (C), 147.8 (C).
2,6-Bis(2-methyl-l-menthopyrazol-3-yl)pyridine (8a).
Compound 8a was obtained in 25% yield; mp 68-71°; 1H nmr:
d 0.85 (3H, d, J=6.6 Hz), 0.87 (6H, d, J=6.6 Hz), 1.08 (6H, d,
J=6.9 Hz), 1.25-1.30 (2H, m), 1.53-1.57 (2H, m), 1.83-1.88 (2H,
m), 1.98-2.03 (2H, m), 2.38-2.45 (2H, m), 2.61-2.67 (2H, m),
2.96-2.99 (2H, m), 3.86 (6H, s), 7.40 (2H, d, J=7.6 Hz), 7.81 (1H,
t, J=7.6 Hz); 13C nmr: d 28.0 (CH3), 20.8 (CH3), 21.2 (CH3),
22.4 (CH2), 27.4 (CH), 29.9 (CH), 32.2 (CH2), 37.8 (CH3), 40.7
(CH), 121.3 (C), 123.3 (CH), 136.3 (CH), 137.7 (C), 150.5 (C),
151.0 (C).
Anal. Calcd. for C30H42N4: C, 78.56; H, 9.23; N, 12.21.
Found: C, 78.16; H, 8.82; N, 11.98.
Diels Alder Reaction of 3,5-Disubstituted-1-acryloylpyrazole
(11) with Cyclopentadiene (12).
Under argon atmosphere, the mixture of 3-heteroaryl-l-men-
thopyrazole ligand (1, 2, 5, 6, 8, or 9) (0.03 mmol), Lewis acid
(0.025 mmol) and Molecular Sieves 4 Å (ca. 100 mg) in
dichloromethane (0.5 ml) was stirred for 30 min at 0°. In some
cases, 0.03 mmol of Lewis acid was used toward the ligand (2, 8,
or 9) (0.015 mmol). 3,5-Disubstituted-1-acryloylpyrazole (11)
(0.25 mmol) in dichloromethane (1 ml) was added to the reaction
mixture, and stirred for another 30 min at 0°. Cyclopentadiene
(12) (2.4 mmol, 0.2 ml) was added and the mixture was kept stir-
Anal. Calcd. for C29H41N5: C, 75.77; H, 8.99; N, 15.24.
Found: C, 75.37; H, 8.59; N, 14.85.
1,3-Bis(2-methyl-l-menthopyrazol-3-yl)benzene (8b).
Compound 8b was obtained in 7 % yield; mp 202-203° (ben-
1
zene-hexane); H nmr: d 0.75 (6H, d, J=6.9 Hz), 0.87 (6H, d,

782
C. Kashima, S. Shibata, H. Yokoyama, and T. Nishio
Vol. 40
7821 (1994).
[6] C. Kashima, K. Takahashi, and A. Hosomi, Heterocycles,
42, 241 (1996).
[7] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Tetrahedron, 52, 10335 (1996).
ring for 5 h at 0°. The reaction mixture was washed with dilute
hydrochloric acid, saturated sodium hydrogencarbonate, aqueous
NaCl, dried over anhydrous magnesium sulfate, and concen-
trated. After addition of appropriate amount of phenanthrene as
an internal standard, the reaction residue was injected to the gas
chromatography to determine the product yields.
[8] C. Kashima, I. Fukuchi, K. Takahashi, K. Fukusaka, and A.
Hosomi, Heterocycles, 47, 357 (1998).
Further the reaction residue was dissolved in methanol solu-
tion of sodium methoxide, which was prepared from sodium (5
mg) and methanol (1 ml). The subsequent methanol solution was
stirred for 45 min at room temperature, diluted with water, and
extracted with ether. After washing with dilute hydrochloric
acid, the ether extract was directly injected to the chiral column
gas chromatography to evaluate the endo-exo isomer ratio and
the enantiomer ratio of endo-adduct (13). The results are sum-
marized in Table 2 and Table 3.
[9] C. Kashima, K. Fukusaka, and K. Takahashi, J.
Heterocyclic Chem., 34, 1559 (1997).
[10] C. Kashima, K. Takahashi, K. Fukusaka, and A. Hosomi, J.
Heterocyclic Chem., 35, 503 (1998).
[11] C. Kashima, K. Fukusaka, K. Takahashi, and Y. Yokoyama,
J. Org. Chem., 64, 1108 (1999).
[12] C. Kashima, K. Takahashi, I. Fukuchi, and K. Fukusaka,
Heterocycles, 44, 289 (1997).
[13a] H. A. Staab, Angew. Chem., 74, 407 (1962); [b] T. Kamijo,
H. Harada, and K. Iizuka, Chem. Pharm. Bull., 32, 5044 (1984); [c]
T. Kitagawa, M. Kawaguchi, S. Inoue, and S. Katayama, Chem.
Pharm. Bull., 39, 3030 (1991).
[14a] C. Kashima, H. Harada, I. Kita, I. Fukuchi, and A. Hosomi,
Synthesis, 61 (1994); [b] C. Kashima, S. Mizuhara, Y. Miwa, and Y.
Yokoyama, Tetrahedron Asymm., 13, 1713 (2002).
[15] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Heterocycles, 38, 1407 (1994).
[16] C. Kashima, I. Kita, K. Takahashi, and A. Hosomi, J.
Heterocyclic Chem., 32, 25 (1995).
Formation of 2a under Forced Conditions.
Under argon atmosphere, butyllithium in hexane solution (1.55
M, 0.03 mmol) was added to the mixture of 2,6-bis(l-menthopy-
razol-3-yl)pyridine (2a) (0.03 mmol), Lewis acid (0.025 mmol)
and Molecular Sieves 4 Å (ca. 100 mg) in dichloromethane (0.5
ml), and stirred for 30 min at 0°. The reaction mixture was
applied for the Diels Alder reaction catalyst described as above,
and the results were summarized in Table 2 and Table 3.
[17] C. Kashima, I. Kita, K. Takahashi, and A. Hosomi, J.
Heterocyclic Chem., 32, 723 (1995).
Acknowledgements.
The authors are grateful to the Chemical Analysis Center,
University of Tsukuba, for the measurement of various kinds of
spectra, X-ray structural analyses and the elemental analyses.
[18] C. Kashima, Heterocycles, 60, 437 (2003).
[19a] D. A. Evans, K. A. Woerpel, M. M. Hinman, and M. M.
Faul, J. Am. Chem. Soc., 113, 726 (1991); [b] D. A. Evans, S. J.
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Am. Chem. Soc., 121, 7559 (1999); [d] D. A. Evans, D. M. Barnes, J.
S. Johnson, T. Lectka, P. von Matt, S. J. Miller, J. A. Murry, R. D.
Norcross, E. A.. Shaughuessy, and K. R. Campos, J. Am. Chem. Soc.,
121, 7582 (1999).
REFERENCES AND NOTES
*
E-Mail: Choji.kashima@nifty.ne.jp
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[3a] C. Kashima, Y. Miwa, S. Shibata, and H. Nakazono, J.
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