Diastereoselective Diels-Alder reaction of 2-(α,β-unsaturated)acyl-3- phenyl-1-menthopyrazoles

Article abstract of DOI:10.1021/jo981255m

The reaction of 2-(α,β-unsaturated)acyl-3-phenyl-1-menthopyrazoles (9) with dienes gave Diels-Alder adducts in good yield. The addition of MgBr₂ · OEt₂ or ZnCl₂ accelerated these reactions through the formation of chelating bonds such as N ··· Mg ··· O=C or N ··· Zn ··· O=C. The structural fixation by these catalysts also promoted the endo and diastereoselectivities of the Diels-Alder addition on the Re-face of the dienophiles. These results were supported by PM3 calculations, in which the heats of formation of the transition states anticipated the remarkable differences between the Re- and Si-facial attacks of the dienes.

Full text of DOI:10.1021/jo981255m

1108
J . Org. Chem. 1999, 64, 1108-1114
Dia ster eoselective Diels-Ald er Rea ction of
2-(r,â-Un sa tu r a ted )a cyl-3-p h en yl-l-m en th op yr a zoles
Choji Kashima,* Kiyoshi Fukusaka, Katsumi Takahashi, and Yukihiro Yokoyama
Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571, J apan
Received J une 29, 1998
The reaction of 2-(R,â-unsaturated)acyl-3-phenyl-l-menthopyrazoles (9) with dienes gave Diels-
Alder adducts in good yield. The addition of MgBr2‚OEt2 or ZnCl2 accelerated these reactions through
the formation of chelating bonds such as N‚‚‚Mg‚‚‚OdC or N‚‚‚Zn‚‚‚OdC. The structural fixation
by these catalysts also promoted the endo and diastereoselectivities of the Diels-Alder addition
on the Re-face of the dienophiles. These results were supported by PM3 calculations, in which the
heats of formation of the transition states anticipated the remarkable differences between the Re-
and Si-facial attacks of the dienes.
We have recently developed a method of preparation
idazoles are utilized as the activated acyl moiety in a wide
variety of organic syntheses.11 As analogues of these
N-acylheteroaromatics, N-acylpyrazoles are easily con-
verted into acyl derivatives by the action of nucleophiles
such as alcohols,12 amines,13 Grignard reagents,14 and
organozinc compounds15 under basic or acidic conditions.
Since the reaction proceeds by the facial attacks of
dienes, asymmetric Diels-Alder reactions using chiral
auxiliaries or catalysts have been widely reported.16 For
the further extended utility of 1 as a new chiral auxiliary,
we report here the diastereofacial Diels-Alder reaction
of 2-(R,â-unsaturated)acyl-3-phenyl-l-menthopyrazoles (9)
and determine the steric properties of 1.
for 3-phenyl-l-menthopyrazole (1) as a new chiral auxil-
iary,1 which has unique structure and properties that are
different from the conventional chiral auxiliaries.2 The
most important characteristics of this auxiliary are that
the substrate terminates in the nitrogen atom of a
heteroaromatic pyrazole ring in a chiral environment.
The steric hindrance of 1 is especially relaxed by the
twisting of the benzene ring, which overlaps one side of
the terminal nitrogen atom.1 This structural feature
causes a diastereofacial effect in the reactions on the
substrate moiety. Moreover, the lone pair of electrons on
the adjacent nitrogen play the role of a Lewis base,
causing the chelation of N‚‚‚Li-O in the lithium enolate
derived from N-acylpyrazoles. These chelations freeze the
bond rotation of the acyl group so that it is fixed in a syn
configuration. As a result, the chirality of the (4R)-methyl
group of 1 causes a highly asymmetric induction on the
acyl group of 2-acyl-3-phenyl-l-menthopyrazoles in the
reactions with alkyl halides,3 diphenyl disulfide,4 acyl
chloride,5 aldehydes,6 and CdN compounds.7 A similar
chelation of N‚‚‚Mg‚‚‚OdC, which is observed in the
mixture of N-acylpyrazoles and MgBr2‚OEt2,8 induces the
asymmetric addition of Grignard reagents9 and 1,3-
dipolar compounds10 on N-(R,â-unsaturated)acylpyra-
zoles. Otherwise, N-acylheteroaromatics such as N-acylim-
Resu lts a n d Discu ssion
To optimize conditions for the Diels-Alder reactions
of N-(R,â-unsaturated)acylpyrazoles, the reaction of 1-acry-
loyl-3,5-dimethylpyrazole (2a ) and cyclopentadiene (3)
was first studied as the simplest and most convenient
dienophile and diene (Scheme 1). When 2a was treated
with 3 in chloroform at room temperature, the reaction
was complete in 2 h, giving a mixture of endo- and exo-
(11) (a) Staab, H. A. Angew. Chem. 1962, 74, 407. (b) Kamijo, T.;
Harada, H.; Iizuka, K. Chem. Pharm. Bull. 1984, 32, 5044. (c)
Kitagawa, T.; Kawaguchi, M.; Inoue, S.; Katayama, S. Chem. Pharm.
Bull. 1991, 39, 3030.
* To whom correspondence should be addressed. E-mail: kashima@
chac.tsukuba.ac.jp.
(1) Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A. Tetrahedron
Lett. 1993, 34, 8305.
(12) Kashima, C.; Harada, H.; Kita, I.; Fukuchi, I.; Hosomi, A.
Synthesis 1994, 61.
(13) Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A. Hetero-
cycles 1994, 38, 1407.
(2) For recent reviews, see: (a) Asymmetric Synthesis; Morrison, J .
D., Ed.; Academic Press, Inc.: New York, 1983-1985; Vols. 1-5. (b)
Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 298. (c) Gant, T. G.;
Meyers, A. I. Tetrahedron 1994, 50, 2297.
(3) Kashima, C.; Fukuchi, I.; Hosomi, A. J . Org. Chem. 1994, 59,
7821.
(4) Kashima, C.; Takahashi, K.; Hosomi, A. Heterocycles 1996, 42,
241.
(5) Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A. Tetrahedron
1996, 52, 10335.
(6) Kashima, C.; Fukuchi, I.; Takahashi, K.; Fukusaka, K.; Hosomi,
A. Heterocycles 1998, 47, 357
(7) Kashima, C.; Fukusaka, K.; Takahashi, K. J . Heterocycl. Chem.
1997, 34, 1559.
(8) Kashima, C.; Takahashi, K.; Fukusaka, K. J . Heterocycl. Chem.
1995, 32, 1775.
(9) Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A. J . Hetero-
cycl. Chem. 1998, 35, 503.
(14) Kashima, C.; Kita, I.; Takahashi, K.; Hosomi, A. J . Heterocycl.
Chem. 1995, 32, 25.
(15) Kashima, C.; Kita, I.; Takahashi, K.; Hosomi, A. J . Heterocycl.
Chem. 1995, 32, 723.
(16) (a) Paquette, L. A. In Asymmetric Synthesis; Morrison, J . D.,
Ed; Academic: New York, 1984; Vol. 3, Chapter 4. (b) Oppolzer, W.
Angew. Chem., Int. Ed. Engl. 1984, 23, 876. (c) Masamune, S.; Choy,
W.; Petersen, J . S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24,
1. (d) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta
1984, 67, 1397. (e) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am.
Chem. Soc. 1984, 106, 4261. (f) Sibi, M. P.; Deshpande, P. K.; J i, J .
Tetrahedron Lett. 1995, 36, 8965. (g) Chapuis, C.; de Saint Laumer, J .
Y.; Marty, M. Helv. Chim. Acta 1997, 80, 146. (h) Narasaka, K.;
Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J . J .
Am. Chem. Soc. 1989, 111, 5340. (i) Corey, E. J .; Matsumura, Y.
Tetrahedron Lett. 1991, 32, 6289. (j) Haase, C.; Sarko, C. R.; DiMare,
M. J . Org. Chem. 1995, 60, 1777. (k) Seebach, D.; Dahinden, R.; Marti,
R. E.; Beck, A. K.; Plattner, D. A.; Kuhnle, F. N. M. J . Org. Chem.
1995, 60, 1788. (l) Gothelf, K. V.; J orgensen, K. A. J . Org. Chem. 1995,
60, 6847.
(10) Kashima, C.; Takahashi, K.; Fukuchi, I.; Fukusaka, K. Hetero-
cycles 1997, 44, 289.
10.1021/jo981255m CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

Diels-Alder Reaction of L-Menthopyrazoles
J . Org. Chem., Vol. 64, No. 4, 1999 1109
Sch em e 1
the Diels-Alder reaction of 1-cinnamoyl-3,5-dimeth-
ylpyrazole (2c) is very slow (runs 11 and 12) and that
high-pressure conditions are necessary to produce the
adduct in moderate yield (run 13). The addition of MgBr2‚
OEt2 was less effective under high-pressure conditions
(run 14). Similarly, the reaction of 1-crotonoyl-3,5-di-
methylpyrazoles (2b) was accelerated when using either
the MgBr2‚OEt2 catalyst (run 10) or high-pressure condi-
tions (run 9). Further, 2a gave the Diels-Alder adducts
with 1,3-butadiene (5) and 2,3-dimethyl-1,3-butadiene (6)
in high yield at room temperature in the presence of
MgBr2‚OEt2 (run 16 and 17). In the case of 2-methyl-1,3-
butadiene (7), 1-(4′-methyl-3′-cyclohexene)carbonyl-3,5-
dimethylpyrazole (8f) was obtained without any regioi-
somer (run 18). On the basis of these results, the Diels-
Alder reaction of N-(R,â-unsaturated)acylpyrazoles (2)
was carried out in toluene under mild conditions and was
accelerated with high stereoselectivity of endo isomers
by the addition of Lewis acids such as BF3‚OEt2, MgBr2‚
OEt2, and ZnCl2. Even when the reaction was forced
under high pressure and temperature, no adduct was
obtained with anthracene, furan, or ethyl vinyl ether.
When 2-acryloyl-3-phenyl-l-menthopyrazole (9a ) was
treated with 3 for 17 h, the mixture of four stereoisomers
was afforded in high yield, as listed in Table 3 and shown
in Scheme 2. The diastereomer ratio was evaluated from
the olefinic and 4-Me peak intensities of the 1H NMR
spectrum. The major product was found to be the endo
cycloadduct having a 2′R- conformation ((1′S,2′R,4′R)-
10a ). On the basis of the HPLC and 1H NMR peak
intensities of the δ 5.7-6.3 ppm region, the endo-exo
ratio was found to be 96:4, and the amount of the endo
isomer was 15% that of the 2′R diastereomer excess (run
1). The formation of 10a was catalyzed 10 times faster
through the use of BF3‚OEt2 without any promotion of
diastereoselectivity (run 2). The MgBr2‚OEt2 catalyst
exhibited the reversed diastereoselectivity of an endo
cycloadduct ((1′R,2′S,4′S)-10a ) with high 2′S-preference
(run 3). By the addition of ZnCl2 (run 4), the endo
cycloadduct was formed exclusively with high diastereo-
selectivity. The structure of (1′R,2′S,4′S)-10a was identi-
fied by conversion into benzyl bicyclo[2.2.1]hept-5-ene-
2-carboxylate and the comparison of its optical rotation
with the literature value.17
Ta ble 1. Diels-Ald er Rea ction Ra tes of
1-Acr yloyl-3,5-d im eth ylp yr a zole (2a ) w ith
Cyclop en ta d ien e (3)
reaction rate
run T (°C) solvent
Lewis acid
(L/mol‚s)
relative rate
1
2
0
0
Toluene none
3.5 × 10-5
2.5 × 10-5
4.3 × 10-5
3.3 × 10-4
2.5 × 10-4
4.5 × 10-4
3.4 × 10-5
1.8 × 10-3
8.8 × 10-4
3.3 × 10-3
1.0
0.7
1.2
9.4
7.1
13
1.0
51
25
THF
none
none
Toluene none
none
none
Toluene LiBr
Toluene BF3‚OEt2
Toluene MgBr2‚OEt2
Toluene ZnCl2
3
0
CHCl3
4
5
6
7
32
32
32
0
THF
CHCl3
8
0
9
0
10
0
94
Diels-Alder adducts (4a ). The endo-exo isomer ratios
were evaluated by HPLC. The structure of 4a was
determined by derivatization into authentic benzyl bicyclo-
[2.2.1]hept-5-ene-2-carboxylate. By monitoring 2a using
HPLC, toluene and chloroform were found to be the
favorable solvents under ordinary pressure, and the
reaction rate at 0 °C was evaluated to be about 4 × 10-5
L/mol‚s, as summarized in Table 1 (runs 1 and 3). An
acceleration of the reaction rates was observed with the
addition of Lewis acids such as BF3‚OEt2 (run 8), MgBr2‚
OEt2 (run 9), and ZnCl2 (run 10), but LiBr was not
effective (run 7). A preference for the endo isomer was
observed with BF3‚OEt2 (run 3), MgBr2‚OEt2 (run 4), and
ZnCl2 (run 5), as summarized in Table 2. Strong Lewis
acids such as TiCl4 (run 6) and AlCl3 (run 7) depressed
the formation of Diels-Alder adducts due to the C-N
bond cleavage of N-acylpyrazoles. Table 2 also shows that
Ta ble 2. Diels-Ald er Rea ction of 1-(r,â-Un sa tu r a ted )Acyl-3,5-d im eth ylp yr a zole (2) w ith 1,3-Dien es (3, 5, 6, a n d 7) in
Tolu en e
substrate
pressure
(bar)
ratio
endo:exo
run
R1
diene
T (°C)
Lewis acid
product
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2c
2d
2a
2a
2a
H
H
H
H
H
H
H
Me
Me
Me
Ph
Ph
Ph
Ph
CO2Et
H
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
6
7
50
32
32
32
32
32
32
80
25
32
32
32
25
25
32
32
32
32
1
1
1
1
1
1
1
1
none
LiBr
BF3‚OEt2
MgBr2‚OEt2
ZnCl2
TiCl4
AlCl3
none
none
MgBr2‚OEt2
none
MgBr2‚OEt2
none
MgBr2‚OEt2
MgBr2‚OEt2
MgBr2‚OEt2
MgBr2‚OEt2
MgBr2‚OEt2
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
4c
4c
4c
4d
8a
8e
8f
99
90
88
90
95
42
52
28
85
93
17
33
56
60
91
83
90
88
87:13
80:20
93: 7
90:10
97:3
72:28
89:11
75:25
80:20
89:11
67:33
78:22
67:33
74:26
67:33
8000
1
1
1
8000
8000
1
1
1
1
H
H
100:0a
a
Regioisomer ratio of 4-methyl and 3-methyl derivatives of 1-(3-cyclohexene)carbonyl-3,5-dimethylpyrazoles.

1110 J . Org. Chem., Vol. 64, No. 4, 1999
Kashima et al.
Ta ble 3. Diels-Ald er Rea ction of 2-(r,â-Un sa tu r a ted )Acyl-3-p h en yl-l-m en th op yr a zole (9) w ith Cyclop en ta d ien e (3)
substrate
ratio
endo:exo
% de (endo)
(conf)
% de (exo)
(conf)
run
R1
Lewis acid
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
9a
9a
9a
9a
9b
9b
9b
9c
9c
9c
9d
9d
9d
H
H
H
H
Me
Me
Me
Ph
Ph
Ph
none
17
1.5
2
1
17
8
98
90
98
98
56
90
91
75
50
65
99
95
96
96:4
94:6
96:4
15 (2′R)
12 (2′R)
84 (2′S)
85 (2′S)
12 (2′S)
86 (2′S)
83 (2′S)
25 (2′R)
8 (2′R)
11
BF3‚OEt2
MgBr2‚OEt2
ZnCl2
none
MgBr2‚OEt2
ZnCl2
none
MgBr2‚OEt2
ZnCl2
none
MgBr2‚OEt2
ZnCl2
>99:1
60:40
79:21
96:4
63:37
20:80
20:80
76:24
60:40
88:12
27 (2′S)
27 (2′S)
4
17
17
17
2
1.5
1
8 (2′R)
9 (1,R)
1
CO2Et
CO2Et
CO2Et
20
80
81 (2′R)
47 (2′R)
Sch em e 2
Ta ble 4. Rea ction of 2-(r,â-Un sa tu r a ted )a cyl-3-p h en yl-l-m en th op yr a zoles (9) w ith 1,3-Dien es (5-7)
dienophile
R1
1,3-diene
R2
run
R3
Lewis acid
time (h)
product
yield (%)
% de (conf)
1
2
3
4
5
6
7
8
9
9a
9a
9a
9a
9a
9a
9a
9a
9d
9d
9d
H
H
H
H
H
H
H
H
5
5
5
7
6
6
6
6
5
6
6
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
Me
H
None
MgBr2‚OEt2
ZnCl2
ZnCl2
None
BF3‚OEt2
MgBr2‚OEt2
ZnCl2
42
17
4
10
80
12
15
7
11a
11a
11a
11f
11e
11e
11e
11e
11d
11g
11g
2
98
97
95a
17
67
99
90
90
97
98
20(1′R)
80(1′S)
90(1′S)
>95(1′S)
28(1′R)
3(1′S)
>95(1′S)
>95(1′S)
75(1′R)
33(1′S)
72(1′R)
CO2Et
CO2Et
CO2Et
ZnCl2
MgBr2‚OEt2
ZnCl2
20
3
2
10
11
Me
Me
Me
Me
a
The regioisomer ratio was found to be 100:0.
The Diels-Alder reaction of 2-(â-substituted R,â-un-
saturated)acyl-3-phenyl-l-menthopyrazoles (9b-c) re-
quired reaction conditions of higher pressure and/or
temperature, and the formation of exo isomers (10) was
increased, as summarized in Table 3. When the ethoxy-
carbonyl group at the â-position was introduced as an
electron-withdrawing group, the reaction of 9d was
accelerated (runs 11-13). Similar reaction propensities
were observed in the Diels-Alder reaction of 9 with 5
and 6. Table 4 shows that either MgBr2‚OEt2 or ZnCl2
can catalyze the diastereoselective Diels-Alder reaction
of 9 with 1,3-butadienes with 1′S preference (runs 2, 3,
7, and 8), while the alternate diastereoisomers are formed
in the reactions without a catalyst (runs 1 and 5). In the
case of 9d , the stereocontrol effects of MgBr2‚OEt2 and
ZnCl2 were rather small (runs 9-11). The stereostructure
of the cycloadduct (11) was determined by the conversion
into methyl 3-cyclohexene-1-carboxylate as well as the
comparison of its optical rotation with authentic data.18
In the case of 7, the ZnCl2-catalyzed reaction of 9a
afforded only one diastereoisomer of 2-(4′-methyl-3′-
cyclohexene-1′-carbonyl)-3-phenyl-l-menthopyrazole ((1′S)-
11f) in 95% yield (run 4).
To reveal the diastereofacial properties of 1 in more
detail, a rational explanation of the diastereoselection in
the Diels-Alder reaction of 9 was attempted through the
use of PM3 calculations. From previous NMR studies,9
the preferable structure of N-(R,â-unsaturated)acylpyra-
zoles was proposed to be the anti-s-cis form, in which the
R-proton is deshielded by the anisotropic effect of the
pyrazole ring. When N-acylpyrazoles were treated with
MgBr2‚OEt2, the structure changed into the syn-s-cis
form, and the bond rotation between the acyl group and
the pyrazole ring was fixed by the chelation of N‚‚‚Mg‚
(17) Evans, A.; Chapman, T. K.; Bisaha, J . J . Am. Chem. Soc. 1988,
110, 1238.
(18) Schwartz, H. M.; Wu, W.-S.; Marr, W. P.; J ones, J . B. J . Am.
Chem. Soc. 1978, 100, 5199.

Diels-Alder Reaction of L-Menthopyrazoles
J . Org. Chem., Vol. 64, No. 4, 1999 1111
F igu r e 1. Reaction profile of 9a with 5.
Ch a r t 1
Ta ble 5. Ch a r ges a n d Electr on Den sities of th e Acr ylic
Moiety a n d th e Hea t of F or m a tion (∆Hfa ) on
2-Acr yloyl-3-p h en yl-l-m en th op yr a zoles (9a )
were calculated dependent on two facial attacks of 5,
which included two transition state geometries of endo
and exo approach due to the orientation of 1,3-butadiene,
as summarized in Table 6 and Chart 1. The energy
differences among these four transition states suggest
that the diastereoselection is ineffective, and the reaction
profile is shown in Figure 1i. These calculations antici-
pated the actual experimental fact that the reaction of
9a and 5 in the absence of catalyst afforded (1′R)-2-(3′-
cyclohexene-1′-carbonyl)-3-phenyl-l-menthopyrazole (1′R-
11a ) with low diastereoselectivity (Table 4, run 1).
density
charge
2′-C
a
∆Hf
2′-C
3′-C
3′-C
(kcal/mol)
9a
3.945
3.930
3.938
3.950
3.926
3.938
-0.213
-0.357
-0.384
0.023
0.098
0.053
55.43
-49.18
2.15
9a + MgBr2
9a + ZnCl2
a
∆Hf presented the heat of formation of the starting mixture
of 9a and 5 with catalyst.
‚‚OdC. A similar structural change was anticipated with
the addition of ZnCl2. These structural aspects based on
NMR spectra were supported by the PM3 calculation of
9a . The electron densities of the 2′- and 3′-carbon atoms
were decreased, and the double bond of the acrylic moiety
was more polarized by Mg or Zn chelation, as sum-
marized in Table 5. The bond features of the acrylic
moiety also confirm previous results showing that the
reaction rate is accelerated by the addition of MgBr2‚OEt2
or ZnCl2.
Similarly, the reaction profile of 9a with 5 was obtained
by calculations based on the starting mixture, the transi-
tion state, and the product, including the chelating bond
of N‚‚‚Mg‚‚‚OdC and N‚‚‚Zn‚‚‚OdC. The case of MgBr2
shown in Figure 1ii indicates that the transition barrier
of the Re-face attack was 4.2 kcal/mol lower than that of
the Si-face attack. The difference of the transition bar-
riers supported a diastereoselective reaction. Moreover,
this reaction profile suggested that the diastereoselective
reaction of 9a with 5 is governed by kinetic control rather
than thermodynamic control. Compared with the A and
B transition states, the lower reaction barrier of transi-
tion state D could explain the acceleration of the reaction
The calculation of the heats of formation (∆Hf) was
performed for the mixture of 5 and the anti-s-cis form of
9a . The ∆Hf of the product (11a ) was also obtained by
the PM3 calculation. Moreover, four transition states
a
Ta ble 6. ∆Hf (k ca l/m ol) of th e Tr a n sition Sta tes of 2-Acr yloyl-3-p h en yl-l-m en th op yr a zoles (9a ) a n d 1,3-Bu ta d ien e (5)
none
MgBr2
ZnCl2
a
a
a
transition state
∆Hf
∆Ea
∆Hf
∆Ea
30.05
23.76 (D)
28.89
∆Hf
∆Ea
Re-face/endo
Re-face/exo
Si-face/endo
Si-face/exo
83.35
83.42
83.92
83.15
27.91 (B)
27.98
28.48
-19.13
-25.42
-20.29
-21.22
29.61
27.17
29.68
28.66
27.46
25.02
27.53
26.51
27.71 (A)
27.97 (C)
a
∆Hf and ∆E refer to the heats of formation of the transition state and their differences from those of the starting mixture, respectively.
The transition states of the reaction profiles are presented in the parentheses.
b

1112 J . Org. Chem., Vol. 64, No. 4, 1999
Kashima et al.
(3H, s), 2.48 (3H, d, J ) 0.7 Hz), 2.96 (1H, s), 3.41 (1H, s),
4.08-4.14 (1H, m), 5.87-5.93 (1H, m), 5.93 (1H, s), 6.25-6.28
(1H, m); 13C NMR δ 13.3 (CH3), 14.1 (CH3), 29.2 (CH2), 42.5
(CH), 43.0 (CH), 47.0 (CH), 49.8 (CH2), 110.3 (CH), 131.3 (CH),
137.5 (CH), 143.6 (C), 151.1 (C), 174.8 (C).
Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95.
Found: C, 71.82; H, 7.44; N, 12.99.
1-(3′-Meth ylbicyclo[2.2.1]h ep t-5′-en e-2′-ca r bon yl)-3,5-
d im eth ylp yr a zole (4b): IR (CHCl3) 3026, 1717, 1582, 1380,
1333.
by the addition of MgBr2‚OEt2 (Table 4, run 2). The
reaction profile of 9a and 5 in the presence of ZnCl2
(Table 4, run 3) was supported by the corresponding
results of the PM3 transition-state calculations.
In conclusion, the reaction of 2-(R,â-unsaturated)acyl-
3-phenyl-l-menthopyrazoles (9) with dienes gave Diels-
Alder adducts in good yield. The addition of MgBr2‚OEt2
or ZnCl2 accelerated these reactions by the formation of
chelate bonds such as N‚‚‚Mg‚‚‚OdC or N‚‚‚Zn‚‚‚OdC.
The structural fixation by these catalysts also promoted
the endo and diastereoselectivities of the Diels-Alder
addition on the Re-face of the dienophile. These results
were supported by PM3 transition-state calculations.
Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16.
Found: C, 72.77; H, 7.98; N, 12.29.
2′-En d o-3′-exo-isom er : 1H NMR δ 1.20 (3H, d, J ) 6.8 Hz),
1.44-1.49 (1H, m), 1.71-1.81 (1H, m), 2.01-2.11 (1H, m), 2.26
(3H, s), 2.48 (3H, d, J ) 0.7 Hz), 2.54-2.55 (1H, m), 3.35 (1H,
s), 3.62-3.65 (1H, m), 5.86-5.93 (1H, m), 5.94 (1H, s), 6.35-
6.38 (1H, m); 13C NMR δ 13.3 (CH3), 14.1 (CH3), 20.0 (CH3),
36.5 (CH2), 46.6 (CH), 47.9 (CH), 49.1 (CH), 51.5 (CH), 110.3
(CH), 131.6 (CH), 138.6 (CH), 143.6 (C), 151.0 (C), 174.6 (C).
2′-Exo-3′-en d o-isom er : 1H NMR δ 0.97 (3H, d, J ) 6.8 Hz),
1.42-1.46 (1H, m), 1.75-1.87 (1H, m), 2.22 (3H, s), 2.47-2.55
(1H, m), 2.54 (3H, d, J ) 0.7 Hz), 2.76 (1H, s), 2.98-3.04 (2H,
m), 5.95 (1H, s), 6.18-6.21 (1H, m), 6.30-6.34 (1H, m).
1-(3′-P h en ylbicyclo[2.2.1]h ep t-5′-en e-2′-ca r bon yl)-3,5-
d im eth ylp yr a zole (4c): mp 82-83 °C (from hexane); IR
(CHCl3) 3063, 3029, 1714, 1601, 1584, 1383, 1335.
Anal. Calcd for C19H20N2O: C, 78.05; H, 6.9; N, 9.58.
Found: C, 77.95; H, 6.93; N, 9.64.
Exp er im en ta l Section
1H NMR data were collected on a Varian NMR Gemini-200
(200 MHz) spectrometer in deuteriochloroform with tetram-
ethylsilane used as an internal standard. Optical rotations
were observed using a J ASCO DIP-370 digital polarimeter.
The HPLC analysis was carried out using an SIL-C18 column
on a J ASCO BIP-I chromatograph using an aqueous methanol
solvent. The reactions under high pressure were carried out
in a Hikari-Kouatu-Kiki high-pressure reactor. The melting
points are uncorrected. When the isomers of the products were
hardly separated by chromatography, the elemental analyses
of the isomer mixtures were performed.
Ma ter ia ls. Cyclopentadiene (3), which was freshly prepared
from dicyclopentadiene by thermolysis, was used in this
experiment. N-(R,â-Unsaturated)acylpyrazoles (2 and 9) were
prepared by the method described previously.9,10 2-(2′-Ethoxy-
carbonyl)acryloyl-3-phenyl-l-menthopyrazole (2d ) was pre-
pared from 1 (2.54 g, 9.99 mmol) and fumaric acid monoethyl
ester (1.58 g, 11.0 mmol) in the action of thionyl chloride (0.81
mL, 11.1 mmol): yield 55%; IR (CHCl3) 3027, 1709, 1359, 1351,
1304; 1H NMR δ 0.72 (3H, d, J ) 6.8 Hz), 0.93 (3H, d, J ) 6.6
Hz), 1.10 (3H, d, J ) 7.0 Hz), 1.33 (3H, t, J ) 7.1 Hz), 1.18-
1.37 (1H, m), 1.44-1.59 (1H, m), 1.87-2.00 (2H, m), 2.45-
2.54 (1H, m), 2.61-2.79 (2H, m), 4.28 (2H, q, J ) 7.1 Hz), 6.90
(1H, d, J ) 15.6 Hz), 7.26-7.44 (5H, m), 8.30 (1H, d, J ) 15.8
Hz); 13C NMR δ 13.6 (CH3), 17.9 (CH3), 19.6 (CH3), 19.9 (CH3),
22.2 (CH2), 27.1 (CH), 29.3 (CH), 31.6 (CH2), 40.9 (CH), 60.8
(CH2), 127.6 (CH), 127.9 (CH), 128.9 (CH), 133.4 (CH), 133.6
(CH), 156.7 (C).
2′-En d o-3′-exo-isom er : 1H NMR δ 1.48-1.65 (2H, m),
1.99-2.03 (1H, m), 2.21 (3H, s), 2.50 (3H, s), 3.06 (1H, s), 3.56
(1H, s), 4.24-4.28 (1H, m), 5.93 (1H, s), 5.95-5.99 (1H, m),
6.51-6.55 (1H, m), 7.14-7.33 (5H, m); 13C NMR δ 13.3 (CH3),
14.1 (CH3), 46.3 (CH2), 47.8 (CH), 48.3 (CH), 48.9 (CH), 51.0
(CH), 110.5 (CH), 125.6 (CH), 127.3 (CH), 128.1 (CH), 132.6
(CH), 135.8 (C), 139.3 (CH), 143.8 (C), 151.3 (C), 174.0 (C).
2′-Exo-3′-en d o-isom er : 1H NMR δ 1.48-1.53 (1H, m),
1.92-1.99 (1H, m), 2.17 (3H, s), 2.53 (3H, s), 3.18 (1H, s), 3.34-
3.37 (2H, m), 3.92-3.95 (1H, m), 5.93 (1H, s), 6.05-6.08 (1H,
m), 6.45-6.53 (1H, m), 7.14-7.33 (5H, m).
1-(3′-Eth oxyca r bon ylbicyclo[2.2.1]h ep t-5′-en e-2′-ca r bo-
n yl)-3,5-d im eth ylp yr a zole (4d ): IR (CHCl3) 3027, 1720,
1583, 1379, 1335, 1271, 1183.
Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72.
Found: C, 66.50; H, 7.02; N, 9.66.
2′-En d o-3′-exo-isom er : 1H NMR δ 1.27 (3H, t, J ) 7.2 Hz),
1.41-1.51 (1H, m), 1.84-1.89 (1H, m), 2.22 (3H, s), 2.47 (3H,
d, J ) 0.6 Hz), 2.76-2.79 (1H, m), 3.14 (1H, d, J ) 1.4 Hz),
3.49 (1H, d, J ) 5 Hz), 4.08-4.24 (2H, m), 4.36-4.40 (1H, m),
5.93 (1H, d, J ) 0.6 Hz), 6.07-6.11 (1H, m), 6.29-6.33 (1H,
m); 13C NMR δ 13.3 (CH3), 13.8 (CH3), 13.9 (CH3), 45.2 (CH),
46.5 (CH), 47.0 (CH), 47.2 (CH2), 60.2 (CH2), 110.5 (CH), 134.6
(CH), 136.9 (CH), 143.6 (C), 151.4 (C), 173.1 (C), 174.3 (C).
2′-Exo-3′-en d o-isom er : 1H NMR δ 1.23 (3H, t, J ) 7.2 Hz),
1.41-1.51 (1H, m), 1.65-1.70 (1H, m), 2.35 (3H, s), 2.53 (3H,
d, J ) 0.8 Hz), 3.20 (1H, s), 3.21 (1H, s), 3.48-3.55 (1H, m),
3.83-3.86 (1H, m), 4.05-4.24 (2H, m), 5.94 (1H, s), 6.13-6.17
(1H, m), 6.39-6.43 (1H, m).
Anal. Calcd for C23H28N2O3: C, 72.60; H, 7.42; N, 7.36.
Found: C, 72.30; H, 7.58; N, 7.29.
Op tim iza tion of th e Rea ction Con d ition s. To the mix-
ture of 2a (150 mg, 1.0 mmol), Lewis acid (1.1 mmol), and
benzophenone (ca. 40 mg, as an internal standard) in various
solvents (8 mL) was added 3 (0.83 mL, 10 mmol), and the
mixture was kept at the observed temperature under nitrogen
atmosphere. A part of the mixture was quenched with triethy-
lamine at the indicated times and was monitored by HPLC.
The results are summarized in Table 1.
Gen er a l P r oced u r e for th e Diels-Ald er Rea ction . A
mixture of N-(R,â-unsaturated)acylpyrazole (2 or 9) (0.55
mmol) and MgBr2‚OEt2 (157 mg, 0.61 mmol) in toluene (4.4
mL) was kept for 15 min at 32 °C. 1,3-Diene (1.1 mmol) was
added to the mixture and the resulting mixture kept at 32 °C
for another 3 h with stirring. The reaction mixture was
quenched with water and extracted with CH2Cl2. The organic
layer was washed with dilute hydrochloric acid, water, aqueous
NaHCO3, and aqueous NaCl and dried over anhydrous MgSO4.
The solvent was removed. From the olefinic peak intensities
in the 1H NMR spectrum and/or the HPLC peaks, the dias-
tereomer ratio was evaluated. The residue was then chro-
matographed on a silica gel column with a benzene-hexane
mixture. In the case of a high-pressure reaction, the mixture
was pressed for 17 h and then concentrated. The residue was
worked up as described above.
1-(3′-Cycloh exen eca r bon yl)-3,5-d im eth ylp yr a zole (8a ):
1
IR (CHCl3) 3030, 1721, 1384, 1344, 1335; H NMR: δ 1.66-
1.87 (1H, m), 1.99-2.20 (3H, m), 2.23 (3H, s), 2.31-2.35 (2H,
m), 2.54 (3H, d, J ) 1.0 Hz), 3.83-3.96 (1H, m), 5.73 (2H, s),
5.96 (1H, d, J ) 0.4 Hz); 13C NMR δ 13.3 (CH3), 14.1 (CH3),
24.0 (CH2), 24.7 (CH2), 27.3 (CH2), 38.1 (CH), 110.7 (CH), 124.9
(CH), 126.1 (CH), 143.7 (C), 151.4 (C), 176.7 (C).
Anal. Calcd for C12H16N2O: C, 70.56; H, 7.9; N, 13.71.
Found: C, 70.61; H, 7.91; N, 13.77.
1-(3′,4′-Dim eth yl-3′-cycloh exen eca r bon yl)-3,5-d im eth -
ylp yr a zole (8e): IR (CHCl3) 3029, 1720, 1386, 1342; 1H NMR
δ 1.61 (6H, s), 1.67-1.82 (1H, m), 1.89-2.04 (3H, m), 2.21 (3H,
s), 2.21-2.26 (1H, m), 2.51 (3H, m), 3.76-3.94 (1H, m), 5.92
(1H, s); 13C NMR δ 13.3 (CH3), 14.1 (CH3), 18.3 (CH3), 18.4
(CH3), 25.4 (CH2), 30.5 (CH2), 33.7 (CH2), 39.0 (CH), 110.6
(CH), 127.9 (C), 131.2 (C), 143.6 (C), 151.3 (C), 176.8 (C).
Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N, 12.06.
Found: C, 72.33; H, 8.47; N, 12.07.
E n d o-1-(b icyclo[2.2.1]h ep t -5′-en e-2′-ca r b on yl)-3,5-d i-
m eth ylp yr a zole (4a ): IR (CHCl3) 3029, 1720, 1582, 1378,
1
1361; H NMR δ 1.46-1.56 (3H, m), 1.83-2.03 (1H, m), 2.25

Diels-Alder Reaction of L-Menthopyrazoles
J . Org. Chem., Vol. 64, No. 4, 1999 1113
1-(4′-Meth yl-3′-cycloh exen ecar bon yl)-3.5-dim eth ylpyr a-
zole (8f): IR (CHCl3) 3030, 1721, 1385, 1338, 1221, 1210; H
29.4 (CH), 31.7 (CH2), 40.8 (CH), 46.1 (CH), 47.6 (CH), 48.6
(CH), 48.7 (CH2), 51.6 (CH), 125.5 (C), 127.3 (CH), 127.3 (CH),
127.5 (CH), 127.5 (CH), 127.7 (CH), 128.0 (CH), 128.7 (C),
128.9 (CH), 132.6 (C), 139.1 (CH), 144.1 (C), 155.2 (C), 172.7
(C).
1
NMR δ 1.68 (3H, s), 1.73-1.91 (2H, m), 1.94-2.40 (4H, m),
2.23 (3H, s), 2.53 (3H, d, J ) 1.0 Hz), 3.75-3.90 (1H, m), 5.41-
5.43 (1H, m), 5.95 (1H, s); 13C NMR δ 13.3 (CH3), 14.1 (CH3),
22.9 (CH3), 25.1 (CH2), 27.6 (CH2), 28.9 (CH2), 38.1 (CH), 110.6
(CH), 119.0 (CH), 133.2 (C), 143.6 (C), 151.3 (C), 176.9 (C).
Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83.
Found: C, 71.62; H, 8.41; N, 12.79.
2-(Bicyclo[2.2.1]h ept-5′-en e-2′-car bon yl)-3-ph en yl-l-m en -
th op yr a zole (10a ): IR (CHCl3) 3063, 2960, 1723, 1572, 1360,
1280.
1
(1′S,2′S,3′R,4′S)-Isom er : H NMR δ 0.68 (3H, d, J ) 6.6
Hz), 0.95 (3H, d, J ) 6.8 Hz), 1.09 (3H, d, J ) 7.0 Hz), 1.19-
1.31 (1H, m), 1.40-1.68 (2H, m), 1.76-2.00 (3H, m), 2.31-
2.52 (1H, m), 2.55-2.65 (1H, m), 2.69-2.79 (1H, m) 3.02 (1H,
s), 3.25-3.30 (1H, m), 3.63 (1H, s), 4.35-4.39 (1H, m), 6.05-
6.10 (1H, m), 6.44-6.48 (1H, m), 7.11-7.38 (10H, m).
1
(1′S,2′R,3′S,4′R)-Isom er : H NMR δ 0.66 (3H, d, J ) 6.6
Anal. Calcd for C25H30N2O: C, 80.17; H, 8.07; N, 7.48.
Found: C, 79.78; H, 8.0; N, 7.45.
Hz), 1.00 (3H, d, J ) 6.8 Hz), 1.09 (3H, d, J ) 6.8 Hz), 1.14-
1.29 (1H, m), 1.38-1.59 (2H, m), 1.76-1.97 (2H, m), 2.17-
2.36 (1H, m), 2.51-2.58 (1H, m), 2.61-2.77 (1H, m), 3.10 (1H,
s), 3.15 (1H, s), 3.90 (1H, br s), 6.03-6.07 (1H, m), 6.41-6.45
(1H, m), 7.15-7.39 (10H, m).
1
(1′R,2′S,4′S)-Isom er : H NMR δ 0.67 (3H, d, J ) 6.6 Hz),
0.94 (3H, d, J ) 7.2 Hz), 1.09 (3H, d, J ) 6.8 Hz), 1.18-1.32
(1H, m), 1.43-1.61 (4H, m), 1.85-1.97 (3H, m), 2.30-2.52 (1H,
m), 2.59-2.79 (2H, m), 2.90 (1H, s), 3.43 (1H, s), 4.06-4.17
(1H, m), 5.95-5.99 (1H, m), 6.16-6.19 (1H, m), 7.11-7.40 (5H,
m); 13C NMR δ 18.2 (CH3), 19.7 (CH3), 19.9 (CH3), 22.7 (CH2),
26.9 (CH), 29.5 (CH2), 29.5 (CH), 31.9 (CH2), 41.0 (CH), 42.5
(CH), 43.8 (CH), 46.7 (CH), 49.6 (CH2), 125.2 (C), 127.5 (CH),
127.6 (CH), 128.8 (CH), 131.7 (CH), 132.5 (C), 137.3 (CH),
140.5 (C), 154.9 (C), 173.6 (C).
2-(3′-Eth oxyca r bon ylbicyclo[2.2.1]h ep t-5′-en e-2′-ca r bo-
n yl)-3-p h en yl-l-m en t h op yr a zole (10d ): IR (CHCl3) 3064,
1720, 1581, 1332, 1321.
Anal. Calcd for C28H34N2O3: C, 75.31; H, 7.67; N, 6.27.
Found: C, 75.16; H, 7.55; N, 6.22.
1
(1′R,2′R,3′S,4′R)-Isom er : H NMR δ 0.67 (3H, d, J ) 6.8
Hz), 0.91 (3H, d, J ) 6.8 Hz), 1.09 (3H, d, J ) 6.8 Hz), 1.23
(3H, t, J ) 7.1 Hz), 1.16-1.31 (1H, m), 1.39-1.67 (2H, m),
1.76-2.01 (3H, m), 2.37-2.53 (1H, m), 2.61-2.82 (3H, m), 3.12
(1H, s), 3.56 (1H, s), 4.01-4.25 (2H, m), 4.45-4.49 (1H, m),
1
(1′S,2′S,4′S)-Isom er : H NMR δ 0.67 (3H, d, J ) 6.6 Hz),
0.98 (3H, d, J ) 6.8 Hz), 1.12 (3H, d, J ) 5.8 Hz), 1.18-1.32
(1H, m), 1.43-1.61 (4H, m), 1.85-1.97 (3H, m), 2.30-2.52 (1H,
m), 2.59-2.79 (2H, m), 2.90 (1H, s), 3.43 (1H, s), 4.06-4.17
(1H, m), 5.74-5.78 (1H, m), 6.12-6.16 (1H, m), 7.11-7.40 (5H,
m).
6.08-6.12 (1H, m), 6.26-6.30 (1H, m), 7.18-7.39 (5H, m); 13
C
NMR δ 13.8 (CH3), 17.6 (CH3), 19.6 (CH3), 20.1 (CH3), 21.9
(CH2), 26.9 (CH), 29.2 (CH), 31.7 (CH2), 40.9 (CH), 46.5 (CH),
46.8 (CH), 47.0 (CH), 47.4 (CH), 49.0 (CH2), 60.2 (CH2), 125.4
(C), 127.5 (CH), 127.7 (CH), 128.7 (C), 128.8 (CH), 134.7 (CH),
136.8 (C), 137.3 (CH), 155.4 (C), 171.9 (C), 174.4 (C).
2-(3′-Met h ylb icyclo[2.2.1]h ep t -5′-en e-2′-ca r b on yl)-3-
p h en yl-l-m en th op yr a zole (10b): IR (CHCl3) 3063, 1721,
1571, 1369, 1324.
1
Anal. Calcd for C26H32N2O: C, 80.37; H, 8.3; N, 7.21.
Found: C, 80.54; H, 8.46; N, 7.17.
(1′S,2′R,3′S,4′R)-Isom er : H NMR δ 0.69 (3H, d, J ) 6.6
Hz), 0.91 (3H, d, J ) 6.8 Hz), 1.09 (3H, d, J ) 6.8 Hz), 1.27
(3H, t, J ) 7.2 Hz), 1.21-1.32 (1H, m), 1.40-1.67 (2H, m),
1.77-2.01 (3H, m), 2.34-2.52 (1H, m), 2.59-2.82 (3H, m), 3.22
(1H, s), 3.30 (1H, s), 3.44-3.52 (1H, m), 3.89-3.98 (1H, m),
3.99-4.24 (2H, m), 6.09-6.14 (1H, m), 6.36-6.40 (1H, m),
7.19-7.41 (5H, m).
1
(1′R,2′S,3′R,4′S)-Isom er : H NMR δ 0.67 (3H, d, J ) 6.6
Hz), 0.93 (3H, d, J ) 6.8 Hz), 1.10 (3H, d, J ) 7.0 Hz), 1.16
(3H, d, J ) 7.0 Hz), 1.28-1.32 (2H, m), 1.42-1.61 (2H, m),
1.70-1.74 (1H, m), 1.82-2.01 (3H, m), 2.48 (1H, s), 2.59-2.80
(2H, m), 3.39 (1H, s), 3.59-3.68 (1H, m), 5.94-5.98 (1H, m),
6.26-6.31 (1H, m), 7.20-7.40 (5H, m); 13C NMR δ 18.0 (CH3),
19.6 (CH3), 20.0 (CH3), 22.6 (CH2), 26.9 (CH), 29.4 (CH), 31.9
(CH2), 36.4 (CH), 41.0 (CH), 46.5 (CH), 47.9 (CH), 49.1 (CH2),
51.8 (CH), 127.1 (C), 127.5 (CH), 128.7 (CH), 131.8 (CH), 132.6
(C), 138.4 (CH), 155.0 (C), 173.6 (C).
(1′S)-2-(3′-Cycloh exen eca r b on yl)-3-p h en yl-l-m en t h o-
p yr a zole (11a ): IR (CHCl3) 3029, 1713, 1556, 1459; 1H NMR
δ 0.69 (3H, d, J ) 6.6 Hz), 0.95 (3H, d, J ) 6.8 Hz), 1.08 (3H,
d, J ) 7.0 Hz), 1.14-1.33 (1H, m), 1.43-1.73 (2H, m), 1.82-
2.23 (5H, m), 2.30-2.47 (3H, m), 2.57-2.81 (2H, m), 3.83-
3.98 (1H, m), 5.75 (2H, AB, J ) 4.0 Hz), 7.24-7.44 (5H, m);
13C NMR δ 17.7 (CH3), 19.3 (CH3), 20.2 (CH3), 20.3 (CH2), 24.0
(CH2), 24.7 (CH2), 26.6 (CH), 27.0 (CH), 29.7 (CH2), 31.2 (CH2),
38.9 (CH), 39.3 (CH), 125.0 (C), 126.3 (CH), 127.1 (CH), 127.2
(CH), 127.2 (CH), 128.1 (CH), 128.8 (C), 132.5 (C), 146.0 (C),
180.3 (C).
1
(1′S,2′R,3′S,4′R)-Isom er : H NMR δ 0.67 (3H, d, J ) 6.6
Hz), 0.86 (3H, d, J ) 6.6 Hz), 1.08 (3H, d, J ) 6.8 Hz), 1.16
(3H, d, J ) 7.0 Hz), 1.28-1.32 (2H, m), 1.42-1.61 (2H, m),
1.70-1.74 (1H, m), 1.82-2.01 (3H, m), 2.48 (1H, s), 2.59-2.80
(2H, m), 3.39 (1H, s), 3.59-3.68 (1H, m), 5.73-5.76 (1H, m),
6.15-6.19 (1H, m), 7.20-7.40 (5H, m).
1
(1′S,2′S,3′R,4′S)-Isom er : H NMR δ 0.68 (3H, d, J ) 6.8
Anal. Calcd for C24H30N2O: C, 79.52; H, 8.34; N, 7.73.
Found: C, 79.54; H, 8.29; N, 7.48.
Hz), 0.94 (3H, d, J ) 7.0 Hz), 1.00 (3H, d, J ) 6.8 Hz), 1.09
(3H, d, J ) 7.0 Hz), 1.15-1.36 (2H, m), 1.40-1.70 (1H, m),
1.76-2.01 (2H, m), 2.26-2.48 (2H, m), 2.50-2.82 (3H, m), 2.69
(1H, s), 2.95 (1H, s), 2.95-3.07 (1H, m), 6.15-6.19 (1H, m),
6.28-6.33 (1H, m), 7.03-7.42 (5H, m).
(1′R,2′R)-2-(6′-Eth oxycar bon yl-3′-cycloh exen ecar bon yl)-
3-p h en yl-l-m en th op yr a zole (11d ): IR (CHCl3) 3030, 1724,
1581, 1368, 1321; 1H NMR δ 0.70 (3H, d, J ) 6.6 Hz), 0.95
(3H, d, J ) 6.6 Hz), 1.05-1.12 (6H, m), 1.16-1.33 (2H, m),
1.43-1.60 (1H, m), 1.79-2.00 (2H, m), 2.13-2.33 (2H, m),
2.39-2.56 (1H, m), 2.59-2.80 (3H, m), 2.88-3.02 (1H, m),
3.90-4.32 (3H, m), 5.71 (2H, AB, J ) 1.6 Hz), 7.09-7.38 (5H,
m); 13C NMR δ 13.5 (CH3), 18.0 (CH3), 19.7 (CH3), 20.0 (CH3),
22.5 (CH2), 26.9 (CH), 27.6 (CH2), 28.5 (CH2), 29.4 (CH), 31.7
(CH2), 40.2 (CH), 40.5 (CH), 40.9 (CH), 59.9 (CH2), 124.5 (CH),
125.0 (C), 125.7 (C), 127.4 (CH), 127.6 (CH), 128.8 (CH), 132.3
(C), 140.4 (C), 155.5 (C), 174.3 (C), 174.6 (C).
1
(1′R,2′R,3′S,4′R)-Isom er : H NMR δ 0.67 (3H, d, J ) 6.8
Hz), 0.89 (3H, d, J ) 6.8 Hz), 0.97 (3H, d, J ) 6.8 Hz), 1.08
(3H, d, J ) 6.8 Hz), 1.15-1.36 (2H, m), 1.40-1.70 (1H, m),
1.76-2.01 (2H, m), 2.26-2.48 (2H, m), 2.50-2.82 (3H, m), 2.69
(1H, s), 2.95 (1H, s), 2.95-3.07 (1H, m), 6.15-6.19 (1H, m),
6.27-6.31 (1H, m), 7.03-7.42 (5H, m).
2-(3′-P h en ylb icyclo[2.2.1]h ep t -5′-en e-2′-ca r b on yl)-3-
p h en yl-l-m en th op yr a zole (10c): IR (CHCl3) 3063, 1719,
1602, 1581, 1368, 1334.
Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45.
Found: C, 74.60; H, 7.92; N, 6.51.
Anal. Calcd for C31H34N2O: C, 82.63; H, 7.61; N, 6.22.
Found: C, 82.56; H, 7.56; N, 6.19.
(1′S)-2-(3′,4′-Dim eth yl-3′-cycloh exen ecar bon yl)-3-ph en yl-
l-m en th op yr a zole (11e): IR (CHCl3) 1709, 1458, 1560, 1458;
1H NMR: δ 0.68 (3H, d, J ) 6.8 Hz), 0.94 (3H, d, J ) 6.8 Hz),
1.07 (3H, d, J ) 7.0 Hz), 1.21-1.43 (1H, m), 1.48-1.69 (2H,
m), 1.62 (6H, s), 1.82-2.47 (8H, m), 2.57-2.81 (2H, m), 3.80-
3.96 (1H, m), 7.26-7.41 (5H, m); 13C NMR δ 18.4 (CH3), 18.5
(CH3), 18.6 (CH2), 19.3 (CH3), 20.3 (CH3), 20.7 (CH3), 25.4 (CH),
26.7 (CH2), 30.7 (CH), 30.8 (CH2), 33.6 (CH2), 33.9 (CH2), 37.6
1
(1′R,2′R,3′S,4′R)-Isom er : H NMR δ 0.68 (3H, d, J ) 6.6
Hz), 0.95 (3H, d, J ) 6.8 Hz), 1.09 (3H, d, J ) 7.0 Hz), 1.19-
1.31 (1H, m), 1.40-1.68 (2H, m), 1.76-2.00 (3H, m), 2.31-
2.52 (1H, m), 2.55-2.65 (1H, m), 2.69-2.79 (1H, m) 3.02 (1H,
s), 3.25-3.30 (1H, m), 3.57 (1H, s), 4.22-4.27 (1H, m), 5.86-
5.90 (1H, m), 6.36-6.40 (1H, m), 7.11-7.38 (10H, m); 13C NMR
δ 17.9 (CH3), 19.8 (CH3), 20.0 (CH3), 22.3 (CH2), 26.9 (CH),

1114 J . Org. Chem., Vol. 64, No. 4, 1999
Kashima et al.
(CH), 39.4 (CH), 123.8 (C), 124.2 (C), 124.8 (C), 127.2 (CH),
128.1 (CH), 128.1 (CH), 133.2 (C), 145.4 (C), 151.5 (C), 176.9
(C).
Anal. Calcd for C26H34N2O: C, 79.96; H, 8.77; N, 7.17.
Found: C, 79.84; H, 8.79; N, 6.99.
(1′S)-2-(4′-Meth yl-3′-cycloh exen eca r bon yl)-3-p h en yl-l-
m en th op yr a zole (11f): IR (CHCl3) 3022, 1716, 1560, 1210;
1H NMR δ 0.69 (3H, d, J ) 6.8 Hz), 0.95 (3H, d, J ) 6.8 Hz),
1.08 (3H, d, J ) 6.8 Hz), 1.16-1.33 (1H, m), 1.43-1.76 (2H,
m), 1.67 (3H, m), 1.82-2.15 (5H, m), 2.32-2.48 (3H, m), 2.60-
2.81 (2H, m), 3.77-3.91 (1H, m), 5.42 (1H, s), 7.24-7.39 (5H,
m); 13C NMR δ 17.7 (CH3), 19.3 (CH3), 20.2 (CH3), 20.4 (CH2),
21.4 (CH3), 23.0 (CH2), 25.0 (CH2), 26.6 (CH), 28.8 (CH), 29.7
(CH2), 31.2 (CH2), 38.8 (CH), 39.3 (CH), 119.0 (C), 127.1 (CH),
127.2 (CH), 127.4 (CH), 128.1 (CH), 133.4 (C), 144.0 (C), 146.0
(C), 80.5 (C).
benzyl alcohol (0.33 mL, 3.1 mmol), and BF3‚OEt2 (0.27 mL,
2.1 mmol) in THF (4 mL) was heated for 18 h at 60 °C, and
the reaction mixture was worked up as usual. Benzyl
(1R,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carboxylate was purified
by silica gel column chromatography with hexanes-ethyl
acetate mixture: yield 75%; 1H NMR δ 1.23-1.28 (1H, m),
1.38-1.51 (2H, m), 1.84-1.97 (1H, m), 2.89-2.90 (1H, m),
2.95-3.04 (1H, m), 3.22-3.23 (1H, m), 5.06 (2H, AB-q, J )
12.6 Hz), 5.87 (1H, d-d, J ) 5.6, 2.8 Hz), 6.18 (1H, d-d, J )
5.6, 3.0 Hz), 7.34 (5H, s); [R]19 -106.1° (c 1.79, CHCl3) [ref17
D
[R]D -129° (c 1.39, CHCl3)].
Met h yl (1S)-3-Cycloh exen eca r b oxyla t e. The Diels-
Alder adduct ((S)-11a ) (530 mg, 1.7 mmol) was treated with
BF3‚OEt2 (0.43 mL, 3.4 mmol) in methanol (3.4 mL) at 60 °C
for 17 h with stirring. Methyl (1S)-3-cyclohexenecarboxylate
was purified by silica gel column chromatography with ben-
zene: yield 70%; 1H NMR δ 1.60-1.78 (1H, m), 1.96-2.00 (1H,
m), 2.00-2.12 (2H, m), 2.23-2.26 (2H, m), 2.49-2.60 (1H, m),
Anal. Calcd for C25H32N2O: C, 79.74; H, 8.57; N, 7.44.
Found: C, 79.41; H, 8.28; N, 7.12.
(1′R,6′R)-2-(3′,4′-Dim eth yl-6′-eth oxyca r bon yl-3′-cyclo-
h exen eca r bon yl)-3-p h en yl-l-m en th op yr a zole (11g): IR
(CHCl3) 3029, 1724, 1210; 1H NMR δ 0.70 (3H, d, J ) 6.8 Hz),
0.94 (3H, d, J ) 6.8 Hz), 1.09 (3H, d, J ) 6.8 Hz), 1.09 (3H, t,
J ) 7.2 Hz), 1.19-1.33 (2H, m), 1.64 (6H, s), 1.84-2.03 (2H,
m), 2.03-2.35 (3H, m), 2.37-2.52 (2H, m), 2.57-2.98 (3H, m),
3.90-4.30 (3H, m), 7.24-7.39 (5H, m); 13C NMR δ 13.5 (CH3),
18.0 (CH3), 18.2 (CH3), 19.7 (CH3), 20.0 (CH3), 22.4 (CH2), 26.8
(CH2), 29.3 (CH2), 31.7 (CH2), 33.7 (CH), 34.6 (CH), 40.9 (CH),
41.2 (CH), 59.8 (CH2), 123.5 (C), 123.9 (C), 125.6 (C), 127.4
(CH), 127.6 (CH), 128.0 (C), 128.7 (C), 132.4 (C), 155.4 (C),
174.3 (C), 174.8 (C).
3.69 (3H, s), 5.68 (2H, s), 7.38 (5H, s); [R]19 -68.4° (c 1.60,
D
CHCl3) [ref18 [R]25 -86.3°(c 1.0, CHCl3)].
D
P M3 Ca lcu la tion of th e Str u ctu r es a n d th e Tr a n sition
Sta tes. All geometries of starting mixture and the products
were optimized with use of the PM3 method by Spartan v.4.1.1.
software package on an SGI indigo2 computer. The temporary
geometries of the transition states were set by the extension
of the bond length of the products and then calculated by
gradient norm minimization.
Ack n ow led gm en t. The authors are grateful to the
Chemical Analysis Center, University of Tsukuba, for
the measurement of the NMR spectra and the elemental
analyses.
Anal. Calcd for C29H38N2O3: C, 75.29; H, 8.28; N, 6.06.
Found: C, 75.07; H, 8.48; N, 5.88.
Ben zyl (1′R,2′S,4′S)-Bicyclo[2.2.1]h ep t-5-en e-2-ca r box-
yla te. The mixture of (1′R,2′S,4′S)-10a (395 mg, 1.0 mmol),
J O981255M