Diels-Alder reaction of 2(1H)-pyridones acting as dienes

Article abstract of DOI:10.1248/cpb.56.480

Diels-Alder reactions between N-phenylmaleimide, acting as the dienophile, and 2(1H)-pyridones having a methoxy or a chloro substituent, were carried out, under atmospheric and high pressure conditions, to give the corresponding isoquinuclidine derivatives. Stereoselectivity of the Diels-Alder reactions was studied using molecular orbital calculations.

Full text of DOI:10.1248/cpb.56.480

480
Chem. Pharm. Bull. 56(4) 480—484 (2008)
Vol. 56, No. 4
Diels–Alder Reaction of 2(1H)-Pyridones Acting as Dienes
Masato HOSHINO, Hisao MATSUZAKI, and Reiko FUJITA*
Tohoku Pharmaceutical University; 4–4–1 Komatsushima, Aoba-ku, Sendai 981–8558, Japan.
Received October 31, 2007; accepted January 21, 2008; published online January 23, 2008
Diels–Alder reactions between N-phenylmaleimide, acting as the dienophile, and 2(1H)-pyridones having a
methoxy or a chloro substituent, were carried out, under atmospheric and high pressure conditions, to give the
corresponding isoquinuclidine derivatives. Stereoselectivity of the Diels–Alder reactions was studied using molec-
ular orbital calculations.
Key words Diels–Alder reaction; isoquinuclidine; methoxy-2(1H)-pyridone; chloro-2(1H)-pyridone; N-phenylmaleimide; mo-
lecular orbital calculation
Preparation of isoquinuclidines via Diels–Alder (DA) 93% and 4c, 44%), respectively. For the 1-unsubstituted 3-
reaction between a dienophile and 2(1H)-pyridone, acting methoxypyridone (2a) and 4-methoxypyridone (2b) afforded
as the diene, would be highly useful towards possible inter- endo-DA-adducts (5a, 89% and 8, 51%), in contrast, the re-
mediates in the synthesis of iboga alkaloids.1) Accordingly, action between 2c and 3 did not afford any DA-adducts, and
we have developed the synthesis of isoquinuclidines bearing 2c was recovered.
various substituents such as Me, COOMe, COMe, and
Next, as listed in Table 2, DA reactions were carried out
Ph.2—8) As an extension of our synthetic methodology, we using chloropyridones (9a—d, 10a—d)14—18) and a large ex-
present the DA reactions between N-phenylmaleimide (as the cess 3. In the cases of 3-chloropyridone (9a) and 4-chloropy-
dienophile), and 1-substituted or 1-unsubstituted 2(1H)-pyri- ridone (9b), the DA reactions with 3 gave endo-DA-adducts
dones having a methoxy or chloro substituent at 3—6 posi- (11a, 73% and 11b, 77%), and exo-DA-adducts (13a, 10%
tions (as the diene). In addition to atmospheric (AP) condi- and 13b, 19%), respectively. In contrast, the reaction using 5-
tions, the reactions were also performed under high pressure chloropyridone (9c) gave only endo-DA-adduct (11c, 88%),
(HP), which has proven to be effective in overcoming the en- whereas 6-chloropyridone (9d) did not afford any DA-
ergy barriers imposed by steric and electronic effects of DA adducts, and 9d was recovered. For the 1-unsubstituted pyri-
reactions.9) Furthermore, the stereoselectivities of the DA re- dones (10a—d), only the reactions of 4-chloropyridone
actions of the 2(1H)-pyridones and Michael addition reac- (10b) and 5-chloropyridone (10c) were successful the former
tions of 1-unsubstituted 2(1H)-pyridones were determined afforded endo-DA–Michael-adduct (15, 84%), whereas the
using molecular orbital (MO) calculations.
latter gave endo-DA-adduct (12c, 79%). The configurations
DA Reactions between 2(1H)-Pyridones and N-Phenyl- of the two substituents at the 5- and 6-positions for endo-DA-
maleimide As listed in Table 1, the DA reactions were ini- adducts (4a—c, 5a, 8, 11a—c, 12c, 15), and exo-DA-adducts
tially investigated using methoxypyridones (1a—c, 2a— (6a, 13a—c) were determined based on the coupling con-
1
c)10—13) and a large excess N-phenylmaleimide (3) under AP stants of their H-NMR spectra. For isoquinuclidine deriva-
at 110 °C for 3 d. For the 1-substituted methoxypyridones, tives, the coupling constant between the bridge-head protons
the DA reaction of 3-methoxypyridone (1a) afforded endo- and Hexo is generally 3.5—4.5 Hz, and for Hendo, less than
DA-adduct (4a, 36%) and exo-DA-adduct (6a, 23%), 3.5 Hz.2—8)
whereas the DA reactions of 4-methoxypyridone (1b) and 6-
Finally, as listed in Table 3, HP DA reactions between a
methoxypyridone (1c) gave only the endo-DA-adducts (4b, excess 3 and 1a—c, 2a—c, 9a—d, and 10a—d were carried
Table 1. DA Reaction of 1, 2 with 3 in Sealed Tube
Temp.
(°C)
Time
(d)
Yield (%)
endo
Yield (%)
Entry
Pyridone
R
R1
R2
R3
Adduct
Adduct
exo
1
2
3
4
5
6
1a
1b
1c
2a
2b
2c
Me
Me
Me
H
H
H
OMe
H
H
OMe
H
H
H
OMe
H
H
OMe
H
H
H
OMe
H
H
OMe
110
110
110
110
110
110
3
3
3
3
3
3
4a
4b
4c
5a
8
36
93
44
89
51
0
6a
6b
6c
7a
7b
7c
23
0
0
0
0
5c
0
∗ To whom correspondence should be addressed. e-mail: refujita@tohoku-pharm.ac.jp
© 2008 Pharmaceutical Society of Japan

April 2008
481
Table 2. DA Reaction of 9, 10 with 3 in Sealed Tube
Temp.
(°C)
Time
(d)
Yield (%)
endo
Yield (%)
Entry
Pyridone
R
R1
R2
R3
R4
Adduct
Adduct
exo
1
2
3
4
5
6
7
8
9a
9b
9c
Me
Me
Me
Me
H
H
H
H
Cl
H
H
H
Cl
H
H
H
H
Cl
H
H
H
Cl
H
H
H
H
Cl
H
H
H
Cl
H
H
H
H
Cl
H
H
H
Cl
110
110
110
110
110
110
110
110
3
3
3
3
3
3
3
3
11a
11b
11c
11d
12a
15
73
77
88
0
13a
13b
13c
13d
14a
14b
14c
14d
10
19
0
0
0
0
0
0
9d
10a
10b
10c
10d
0
84
79
0
12c
12d
Table 3. DA Reaction of 1, 2, 9 and 10 with 3 under 10 kbar in CH2Cl2
Yield
(%)
endo
Yield
(%)
exo
Temp. Time
Entry Pyridone
Adduct
Adduct
(°C)
(d)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
2a
2b
2c
9a
9b
9c
90
90
90
90
90
90
90
90
90
90
90
90
90
90
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4a
4b
4c
5a
5d
31
35
21
63
33
0
80
60
81
0
6a
6b
6c
7a
7b
0
0
0
0
0
0
0
0
5
0
0
0
0
0
Fig. 1. Structures of endo- and exo-Type TS’s for the Reaction of 1b with
3 Optimized Using PM5 Method
5c
7c
11a
11b
11c
11d
12a
15
13a
13b
13c
13d
14a
14b
14c
14d
Calculated interatomic distances are: C3–C1ꢀꢁ1.994 Å, C6–C2ꢀꢁ2.333 Å (left);
C3–C1ꢀꢁ1.969 Å, C6–C2ꢀꢁ2.441 Å (right).
9d
10a
10b
10c
10d
0
and exo-adducts, were selected; upon optimization of the se-
lected structures, the activation energies (Ea) were calculated
using PM5 method.19) The optimized TS structures are
shown in Fig. 1, and the calculated Ea values are listed in
Table 4, together with the experimental yields of the adducts.
As shown in Table 4, the Ea values of TS that lead to the
endo-adducts are lower than those leading to the exo-adducts,
which is consistent with the experimental results showing
that the main products are the endo-adducts. The retro-DA
reactions are not thought to occur, because calculated Ea val-
ues of the retro-DA reactions are about 30 kcal/mol greater
than those of the forward reactions. For example, the Ea val-
ues of the retro-DA reactions (Entry 1 of Table 4) are 54.51
18
75
0
12c
12d
out under 10 kbar at 90 °C for 2 d in CH2Cl2. In the case of kcal/mol (endo) and 55.45 kcal/mol (exo).
9c, the HP DA reaction resulted in both endo-adduct 11c and
In the cases of the 4-substituted pyridones 2b and 10b, the
exo-adduct 13c; in contrast, 13c was not obtained under AP sole formation of DA–Michael adducts 8 and 15 can be ex-
conditions. For the HP DA reaction of 2b, Michael-adduct 5d plained by the tautomerization of 2(1H)-pyridone in these
was the sole product, which implies that endo-DA–Michael- cases, the Michael addition reaction occurs between 3 and
adducts 8 and 15 are derived from the Michael-adducts of 3 presumably the enol tautomer of 2(1H)-pyridone. For the
with 2b or 10b, respectively. Based on the yields of the Michael addition reactions of 2a—d and 10a—d with 3, Ea
adducts produced under AP conditions and those formed values were calculated using Gaussian 03 at the HF/6-31G(d)
under HP conditions, the HP DA reactions did not exhibit level.20) As shown in Table 5, the lowest calculated Ea values
significant increases in the yields of the adducts.
correlate to the Michael reactions involving 4-substituted
Theoretical Studies Using MO Method Theoretical pyridones, which would also explain the sole formation of
studies were carried out for the DA reaction of pyridones the DA–Michael adducts.
1a—c, 2a—c, 9a—d, and 10a—d with 3. For each reaction,
In summary, DA reactions between dienophile 3 and
two transition states (TS), which were related to the endo- 2(1H)-pyridones bearing a methoxy or a chloro group were

482
Vol. 56, No. 4
Table 4. Calculated Activation Energies (Ea) and Experimental Yields of Adducts for DA Reaction of 2-Pyridones with N-Phenylmaleimide (PM5
Method)
endo-Addition
exo-Addition
Ea (exo)ꢂEa (endo)
Entry
NR
Pyridone
Ea
(kcal/mol)
Adduct (yield)
(%)
Ea
(kcal/mol)
Adduct (yield)
(%)
(kcal/mol)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
NMe
NMe
NMe
NH
NH
NH
NMe
NMe
NMe
NMe
NH
3-OMe
4-OMe
6-OMe
3-OMe
4-OMe
6-OMe
3-Cl
4-Cl
5-Cl
6-Cl
3-Cl
20.23
21.08
17.18
20.85
19.54a)
19.04
23.25
22.26
22.25
22.10
23.97
22.09a)
23.03
23.25
36
93
44
89
61a)
0
73
77
88
0
21.62
22.37
20.36
22.04
25.81a)
22.21
24.93
22.77
22.87
24.52
25.46
28.54a)
23.46
25.50
23
0
0
0
0
1.39
1.29
3.19
1.19
6.27a)
3.15
1.68
0.51
0.62
2.42
1.49
6.45a)
0.43
2.25
0
10
19
0
0
0
0
0
0
0
NH
NH
NH
4-Cl
5-Cl
6-Cl
84a)
79
0
a) For Michael adducts.
as described above to give 4b, c, 5a, c, d, 6a—c, 7a—c, 8, 11a—d, 12a—d,
13a—d, 14a—d, and 15, respectively, as summarized in Table 3.
Table 5. Caluculated Activation Energies (Ea) for Michael Addition of 2-
Pyridones with N-Phenylmaleimide Calculated at HF/6-31(d) Level
4-Methoxy-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
endo-dicarboximide (4a) Colorless plates (benzene–acetone), mp 180—
Ea
(kcal/mol)
Ea
(kcal/mol)
Pyridone
Pyridone
1
181 °C. IR (KBr) cmꢂ1: 1779, 1619, 736, 699. H-NMR (CDCl3) d: 3.00
(3H, s, NMe), 3.52 (1H, dd, Jꢁ1.1, 8.3 Hz, H-5), 3.68 (1H, dd, Jꢁ4.0,
8.3 Hz, H-6), 3.85 (3H, s, OMe), 4.59 (1H, ddd, Jꢁ1.1, 4.0, 6.2 Hz, H-1),
6.50 (1H, dd, Jꢁ6.2, 8.1 Hz, H-7), 6.55 (1H, dd, Jꢁ1.1, 8.1 Hz, H-8), 6.49—
7.19 (2H, m, H-aromatic), 7.36—7.47 (3H, m, H-aromatic). 13C-NMR
(CDCl3) d: 32.73, 41.86, 47.14, 54.62, 55.27, 82.73, 126.07 (C2), 128.85,
129.06 (C2), 129.23, 131.15, 135.16, 170.55, 171.86, 173.40. LMS m/z: 313
(Mꢃꢃ1), 256, 173, 139, 119. HR-MS m/z: Calcd for C17H17N2O4: 313.1188.
Found: 313.1229.
3-OMe
4-OMe
5-OMe
6-OMe
36.19
33.50
34.92
41.66
3-Cl
4-Cl
5-Cl
6-Cl
37.34
36.54
37.55
45.72
successfully carried out under the AP and HP conditions to
stereoselectively afford endo-DA-adducts. The experimental
8-Methoxy-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
endo-dicarboximide (4b) Colorless columns (acetone), mp 218—221 °C.
results were supported by calculated Ea values of the corre- IR (KBr) cmꢂ1: 1779, 1689, 1593, 752, 714, 693. 1H-NMR (CDCl3) d: 2.97
(3H, s, NMe), 3.44 (1H, dd, Jꢁ3.7, 8.1 Hz, H-5), 3.55 (3H, s, OMe), 3.61
(1H, dd, Jꢁ4.0, 8.1 Hz, H-6), 3.90 (1H, dd, Jꢁ2.6, 3.7 Hz, H-4), 4.57 (1H,
sponding reactions.
Experimental
dd, Jꢁ4.0, 6.2 Hz, H-1), 5.15 (1H, dd, Jꢁ2.6, 6.2 Hz, H-7), 7.13—7.15 (2H,
The following instruments were used to obtain physical data: melting m, H-aromatic), 7.37—7.48 (3H, m, H-aromatic). 13C-NMR (CDCl3) d:
points, Yanaco micro-melting point apparatus (values are uncorrected); IR 32.04, 41.05, 47.75, 49.59, 56.32, 56.65, 93.00, 125.88, 128.90 (C2),
spectra, Perkin Elmer FT-IR 1725X spectrophotometer; MS spectra, JEOL 129.14, 131.27 (C2), 160.18, 169.96, 173.67, 173.87. LMS m/z: 312 (Mꢃ),
JMN-DX 303/JMA-DA 5000 spectrometer; NMR spectra, JEOL JNM-GSX 173, 139, 108. HR-MS m/z: Calcd for C17H16N2O4: 312.1110. Found:
400 (1H-NMR, 400 MHz; 13C-NMR, 100 MHz), JEOL JNM-EX270 (1H-
NMR, 270 MHz; 13C-NMR, 67.8 MHz), and JEOL JNM-PMX 60SI spec-
312.1122.
1-Methoxy-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
trometers with tetramethylsilane (TMS) as an internal standard; elemental endo-dicarboximide (4c) Colorless plates (acetone), mp 165—166 °C. IR
analyses, Perkin Elmer 2400 CHN Elemental Analyzer. For column chro- (KBr) cmꢂ1: 1781, 1619, 714, 699. 1H-NMR (CDCl3) d: 2.93 (3H, s, NMe),
matography, Merck Kieselgel silica gel 60 (230—400 mesh) was used.
3.40 (1H, dd, Jꢁ3.6, 8.3 Hz, H-5), 3.53 (1H, d, Jꢁ8.3 Hz, H-6), 3.74 (3H, s,
General Procedures for Diels–Alder Reactions of 1a—c, 2a—c, 9a—d, OMe), 4.02 (1H, ddd, Jꢁ1.6, 3.6, 5.9 Hz, H-4), 6.49 (1H, dd, Jꢁ5.9, 8.3 Hz,
and 10a—d with 3 a) A mixture of 1a (0.695 g, 5 mmol) and 3 (6.92 g,
H-8), 6.65 (1H, dd, Jꢁ1.6, 8.3 Hz, H-7), 7.15—7.19 (2H, m, H-aromatic),
40 mmol) was heated at 110 °C for 3 d. The resulting reaction mixture was 7.39—7.49 (3H, m, H-aromatic). 13C-NMR (CDCl3) d: 26.15, 42.08, 45.21,
purified by column chromatography (silica gel). The first fraction, which 49.01, 55.11, 91.66, 126.17 (C2), 128.96, 129.17 (C2), 129.81, 131.25,
was eluted with hexane–acetone (1 : 2), was evaporated to afford 3. The sec-
ond and third fractions were evaporated to give exo-DA-adduct (6a, 0.352 g, m/z: Calcd for C17H16N2O4: 312.1111. Found: 312.1147.
132.96, 170.87, 171.96, 174.01. LMS m/z: 312 (Mꢃ), 297, 255, 173. HR-MS
23%) and endo-DA-adduct (4a, 0.560 g, 36%), respectively. b) The reactions
of 1b, c, 2a—c, 9a—d, and 10a—d with 3 were carried out under the condi-
4-Methoxy-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
exo-dicarboximide (6a) Colorless plates (MeOH–acetone), mp 239—
1
tions listed in Tables 1 and 2, and the resulting reaction mixtures were 240 °C. IR (KBr) cmꢂ1: 1780, 1619, 714, 699. H-NMR (CDCl3) d: 2.91
treated in the same manner as described above to give 4b, c, 5a—c, 6a—c,
7a—c, 8, 11a—d, 12a—d, 13a—d, 14a—d, and 15, respectively, as sum- 8.4 Hz, H-5), 3.78 (3H, s, OMe), 4.59 (1H, ddd, Jꢁ1.1, 2.5, 5.5 Hz, H-1),
marized in Tables 1 and 2.
6.64 (1H, dd, Jꢁ5.5, 8.0 Hz, H-7), 6.71 (1H, dd, Jꢁ1.1, 8.0 Hz, H-8), 7.15—
General Procedures for High Pressure Diels–Alder Reactions of 1a— 7.19 (2H, m, H-aromatic), 7.37—7.47 (3H, m, H-aromatic). 13C-NMR
c, 2a—c, 9a—d, and 10a—d with 3 a) A solution of 1a (56 mg,
(CDCl3) d: 33.51, 45.78, 48.45, 54.66, 56.23, 83.39, 126.65 (C2), 129.01,
(3H, s, NMe), 3.32 (1H, dd, Jꢁ2.5, 8.4 Hz, H-6), 3.35 (1H, dd, Jꢁ1.1,
0.4 mmol) and 3 (138 mg, 0.8 mmol) in CH2Cl2 (1 ml) in a Teflon tube, was 129.26 (C2), 131.34, 131.96, 135.67, 135.62, 168.64, 171.53, 173.69. LMS
placed in a high-pressure reactor and pressurized to 10 kbar, followed by m/z: 313 (Mꢃꢃ1), 255, 173, 125, 108. HR-MS m/z: Calcd for C17H17N2O4:
heating to 90 °C. After 2 d, the pressure was released, and the reaction mix- 313.1188. Found: 313.1276.
ture was purified using column chromatography (silica gel) with hexane–
acetone (1 : 2) as the eluent to afford 4a (35 mg, 31%). b) The reactions of
1b, c, 2a—c, 9a—d, and 10a—d with 3 were carried out under the condi-
4-Methoxy-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-endo-di-
carboximide (5a) Colorless crystalline powder (CHCl3), mp 250—253 °C.
1
IR (KBr) cmꢂ1: 1779, 1713, 1659, 753, 693. H-NMR (DMSO-d6) d: 3.65
tions listed in Table 3; the reaction mixtures were treated in the same manner (3H, s, OMe), 3.65—3.67 (1H, br d, H-5), 3.71 (1H, d, Jꢁ4.0, 8.0 Hz, H-6),

April 2008
483
IR (KBr) cmꢂ1: 1782, 1713, 1684, 1594, 742. 1H-NMR (DMSO-d6) d: 3.34
(3H, s, NMe), 3.50—3.57 (2H, m, H-5,6), 4.83 (1H, ddd, Jꢁ1.7, 3.0, 5.6 Hz,
H-1), 4.45 (1H, dd, Jꢁ1.7, 8.0 Hz, H-8), 6.77 (1H, dd, Jꢁ5.6, 8.0 Hz, H-7),
7.07—7.19 (2H, m, H-aromatic), 7.42—7.56 (3H, m, H-aromatic). 13C-
NMR (DMSO-d6) d: 33.23, 48.23, 48.84, 55.89, 69.04, 126.32 (C2), 128.32,
128.69 (C2), 131.18, 133.70, 137.28, 164.91, 171.22, 173.14. LMS m/z: 318
(Mꢃꢃ2), 316 (Mꢃ), 261, 173, 119. HR-MS m/z: Calcd for C16H13ClN2O3:
316.0615. Found: 316.0633.
4.53 (1H, ddd, Jꢁ1.0, 4.0, 5.3 Hz, H-1), 6.44 (1H, dd, Jꢁ1.0, 8.3 Hz, H-8),
6.56 (1H, dd, Jꢁ5.3, 8.3 Hz, H-7), 7.11—7.18 (2H, m, H-aromatic), 7.41—
7.51 (3H, m, H-aromatic), 8.70 (1H, br s, NH). 13C-NMR (DMSO-d6) d:
40.62, 47.01, 48.11, 52.93, 81.74, 126.29 (C2), 128.05, 128.44 (C2), 130.87,
131.38, 133.62, 171.97, 172.39, 173.68. LMS m/z: 298 (Mꢃ), 255, 173. HR-
MS m/z: Calcd for C16H14N2O4: 298.0954. Found: 298.0971.
8-Methoxy-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-endo-di-
carboximide (8) Colorless crystalline powder (acetone), mp 160—162 °C.
1
IR (KBr) cmꢂ1: 1780, 1619, 736, 714. H-NMR (CDCl3) d: 2.75 (1H, dd,
8-Chloro-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
exo-dicarboximide (13b) Colorless needles (acetone), mp 245—246 °C.
Jꢁ6.6, 18 Hz, H-10), 3.19 (1H, dd, Jꢁ9.4, 18 Hz, H-10), 3.57 (1H, dd,
Jꢁ3.3, 8.2 Hz, H-5), 3.58 (3H, s, OMe), 3.90 (1H, dd, Jꢁ4.0, 8.2 Hz, H-6),
4.01 (1H, dd, Jꢁ2.5, 3.3 Hz, H-4), 4.30 (1H, dd, Jꢁ4.0, 6.3 Hz, H-1), 5.20
(1H, dd, Jꢁ2.6, 6.3 Hz, H-7), 5.10 (1H, dd, Jꢁ6.6, 9.4 Hz, H-9), 7.11—7.15
(2H, m, H-aromatic), 7.33—7.55 (8H, m, H-aromatic). 13C-NMR (CDCl3)
d: 29.71, 33.40, 40.54, 48.43, 49.63, 52.75, 53.51, 56.57, 93.44, 125.99,
126.29 (C2), 129.03, 129.10, 129.33 (C2), 129.36, 131.28, 131.31, 136.56,
160.31, 170.29, 172.15, 173.06, 173.49, 173.77. LMS m/z: 471 (Mꢃ), 298,
205, 173. HR-MS m/z: Calcd for C26H21N3O6: 471.1430. Found: 471.1460.
4-Chloro-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
endo-dicarboximide (11a) Colorless columns (acetone), mp 202—
203 °C. IR (KBr) cmꢂ1: 1781, 1718, 1697, 1598, 758, 689. 1H-NMR
(CDCl3) d: 3.07 (3H, s, NMe), 3.42 (1H, dd, Jꢁ1.0, 8.0 Hz, H-5), 3.73 (1H,
dd, Jꢁ4.4, 8.0 Hz, H-6), 4.65 (1H, ddd, Jꢁ1.0, 3.3, 4.4 Hz, H-1), 6.49—6.58
(2H, m, H-7,8), 7.17—7.27 (2H, m, H-aromatic), 7.40—7.49 (3H, m, H-aro-
matic). 13C-NMR (CDCl3) d: 33.74, 46.73, 47.80, 55.49, 68.91, 126.15
(C2), 129.13, 129.23 (C2), 130.33, 131.06, 137.23, 166.96, 171.22, 172.70.
LMS m/z: 318 (Mꢃꢃ2), 316 (Mꢃ), 262, 173. HR-MS m/z: Calcd for
C16H13ClN2O3: 316.0615. Found: 316.0587.
1
IR (KBr) cmꢂ1: 1780, 1710, 1596, 742. H-NMR (CDCl3) d: 2.90 (3H, s,
NMe), 3.33 (1H, dd, Jꢁ2.7, 8.5 Hz, H-6), 3.46 (1H, dd, Jꢁ3.3, 8.5 Hz, H-5),
4.05 (1H, dd, Jꢁ2.3, 3.3 Hz, H-4), 4.73 (1H, dd, Jꢁ2.7, 6.1 Hz, H-1), 6.52
(1H, dd, Jꢁ2.3, 6.1 Hz, H-7), 7.13—7.23 (2H, m, H-aromatic), 7.40—7.50
(3H, m, H-aromatic). 13C-NMR (DMSO-d6) d: 33.02, 43.28, 48.12, 53.80,
58.13, 126.48 (C2), 127.77, 129.23, 129.39 (C2), 131.12, 136.89, 17.66,
171.84, 173.03, 173.52. LMS m/z: 318 (Mꢃꢃ2), 316 (Mꢃ), 259, 173, 119.
HR-MS m/z: Calcd for C16H13ClN2O3: 316.0615. Found: 316.0669.
7-Chloro-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
exo-dicarboximide (13c) Colorless needles (CHCl3), mp ꢄ300 °C. IR
(KBr) cmꢂ1: 1780, 1713, 1600, 740. 1H-NMR (CDCl3) d: 2.94 (3H, s,
NMe), 3.30 (1H, dd, Jꢁ3.5, 8.6 Hz, H-5), 3.49 (1H, dd, Jꢁ2.8, 8.6 Hz, H-6),
4.04 (1H, dd, Jꢁ3.5, 6.8 Hz, H-4), 4.62 (1H, dd, Jꢁ2.3, 2.8 Hz, H-1), 6.45
(1H, dd, Jꢁ2.3, 6.8 Hz, H-8), 7.15—7.19 (2H, m, H-aromatic), 7.40—7.50
(3H, m, H-aromatic). 13C-NMR (CDCl3) d: 33.34, 43.79, 47.12, 47.57,
64.16, 126.48 (C2), 127.11, 129.24, 129.41 (C2), 131.14, 135.94, 168.59,
173.28, 173.43. LMS m/z: 318 (Mꢃꢃ2), 316 (Mꢃ), 259, 173, 119. HR-MS
m/z: Calcd for C16H13ClN2O3: 316.0615. Found: 316.0669.
3-[4-Methoxy-2(1H)-pyridinyl]-N-phenylmaleimide (5d) Polorless
8-Chloro-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
endo-dicarboximide (11b) Colorless needles (acetone), mp 233—235 °C.
IR (KBr) cmꢂ1: 1779, 1710, 1680, 1600, 742. 1H-NMR (CDCl3) d: 2.97
(3H, s, NMe), 3.50 (1H, dd, Jꢁ3.5, 8.3 Hz, H-5), 3.65 (1H, dd, Jꢁ4.1,
8.3 Hz, H-6), 4.10 (1H, dd, Jꢁ2.3, 3.5 Hz, H-4), 4.66 (1H, dd, Jꢁ4.1,
6.1 Hz, H-1), 6.45 (1H, dd, Jꢁ2.3, 6.1 Hz, H-7), 7.15—7.18 (2H, m, H-aro-
matic), 7.43—7.47 (3H, m, H-aromatic). 13C-NMR (CDCl3) d: 33.02, 43.28,
48.12, 53.80, 58.13, 126.48 (C2), 127.77, 129.23, 129.39 (C2), 131.12,
136.89, 167.66, 173.03, 173.51. LMS m/z: 318 (Mꢃꢃ2), 316 (Mꢃ), 259,
173, 119. HR-MS m/z: Calcd for C16H13ClN2O3: 316.0615. Found:
316.0565.
7-Chloro-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
endo-dicarboximide (11c) Colorless needles (acetone), mp 227—228 °C.
IR (KBr) cmꢂ1: 1778, 1713, 1687, 1672, 1595, 752, 692. 1H-NMR (CDCl3)
d: 3.03 (3H, s, NMe), 3.47 (1H, dd, Jꢁ3.7, 8.0 Hz, H-5), 3.69 (1H, Jꢁ4.4,
8.0 Hz, H-6), 4.05 (1H, dd, Jꢁ3.7, 6.6 Hz, H-4), 4.61 (1H, dd, Jꢁ2.5,
4.4 Hz, H-1), 6.37 (1H, dd, Jꢁ2.5, 6.6 Hz, H-8), 7.16—7.18 (3H, m, H-aro-
matic), 7.36—7.50 (2H, m, H-aromatic). 13C-NMR (CDCl3) d: 32.65, 41.67,
46.69, 46.83, 63.55, 125.67, 126.18 (C2), 129.09, 129.25 (C2), 131.01,
133.38, 169.83, 172.28, 173.77. LMS m/z: 318, 316 (Mꢃ), 261, 173, 143.
HR-MS m/z: Calcd for C16H13ClN2O3: 316.0615. Found: 316.0576.
1
needles (acetone), mp 237—240 °C. IR (KBr) cmꢂ1: 1775, 1660, 1596. H-
NMR (CDCl3) d: 3.22 (2H, d, Jꢁ7.3 Hz, CH2), 3.77 (3H, s, OMe), 4.68
(1H, dd, Jꢁ7.3, 7.3 Hz, CH), 5.77 (1H, d, Jꢁ2.8 Hz, H-3), 5.99 (1H, dd,
Jꢁ2.8, 7.6 Hz, H-5), 7.16 (1H, d, Jꢁ7.6 Hz, H-6), 7.32—7.65 (5H, m, H-
aromatic). 13C-NMR (CDCl3) d: 34.52, 55.74, 59.94, 97.29, 102.16, 126.79
(C2) 128.85, 129.23 (C2), 132.05, 137.79, 163.47, 169.14, 171.15, 172.93.
LMS m/z: 298 (Mꢃ), 178, 150. HR-MS m/z: Calcd for C16H14N2O4:
298.0954. Found: 298.0931.
Calculation of Activation Energy We assumed that the reactants were
far apart at the initial state. The structure of each state in the reactions was
optimized using the semi-empirical molecular orbital PM5 method.19) The
solvent effect was not considered. After optimizing the TS structure, the vi-
brational calculation was carried out to confirm that the TS had only one
imaginary vibrational frequency. The intrinsic reaction coordinate calcula-
tion was also performed to ensure that the TS connected the initial and the
intended final state. The activation energy Ea was calculated by the differ-
ence in energy between the TS and the initial state. The values of Ea of
Michael reactions were calculated essentially in the same way as DA reac-
tion but using ab initio molecular orbital Gaussian 03 method at HF/6-
31G(d) level.20)
8-Chloro-N-phenyl-2-(3-N-phenyl-2,3-dioxopyrrolyl)-3-oxo-2-azabicy-
clo[2.2.2]oct-7-ene-5,6-exo-dicarboximide (15) Colorless plates (ace-
References
1
tone), mp 163—165 °C. IR (KBr) cmꢂ1: 1778, 1600. H-NMR (CDCl3) d:
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1950 (1981).
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Amsterdam, 1988.
3.09 (1H, dd, Jꢁ6.4, 18.0 Hz, H-10), 3.20 (1H, dd, Jꢁ9.0, 18.0 Hz, H-10),
3.55 (1H, dd, Jꢁ3.5, 7.9 Hz, H-5), 4.10 (1H, dd, Jꢁ1.5, 3.5 Hz, H-4), 4.19
(1H, dd, Jꢁ4.1, 7.9 Hz, H-6), 4.30 (1H, dd, Jꢁ6.4, 9.0 Hz, H-9), 4.79 (1H,
dd, Jꢁ4.1, 6.2 Hz, H-1), 6.53 (1H, dd, Jꢁ1.5, 6.2 Hz, H-7), 7.15—7.19 (2H,
m, H-aromatic), 7.26—7.32 (2H, m, H-aromatic), 7.41—7.52 (6H, m, H-
aromatic). 13C-NMR (CDCl3) d: 34.51, 41.20, 47.30, 53.39, 57.99, 59.30,
126.23 (C2), 126.37 (C2), 126.44, 18.97, 129.13, 129.20 (C2), 129.26 (C2),
130.96, 131.38, 134.03, 169.76, 172.31, 172.47, 173.14, 173.43. LMS m/z:
477 (Mꢃꢃ2), 475 (Mꢃ), 316, 318, 261, 259, 173. HR-MS m/z: Calcd for
C25H18ClN3O5: 475.0935. Found: 475.0917.
7-Chloro-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-endo-dicar-
boximide (12c) Colorless columns (acetone), mp 290 °C. IR (KBr) cmꢂ1
:
1
1780, 1703, 1618, 759, 694. H-NMR (DMSO-d6) d: 3.57 (1H, dd, Jꢁ3.3,
7.9 Hz, H-5), 3.64 (1H, dd, Jꢁ3.3, 4.3 Hz, H-4), 3.80 (1H, dd, Jꢁ4.3,
7.9 Hz, H-6), 4.55 (1H, dd, Jꢁ2.0, 4.3 Hz, H-1), 6.60 (1H, dd, Jꢁ2.0,
4.3 Hz, H-8), 7.10—7.16 (2H, m, H-aromatic), 7.43—7.53 (3H, m, H-aro-
matic), 8.75 (1H, br s, NH). 13C-NMR (CDCl3) d: 39.67, 40.59, 47.45,
55.49, 125.53, 126.16 (C2), 128.21, 128.60 (C2), 131.26, 133.32, 171.9,
172.87, 174.41. LMS m/z: 304 (Mꢃꢃ2), 302 (Mꢃ), 259, 173, 119. HR-MS
m/z: Calcd for C15H11ClN2O3: 302.0458. Found: 302.0453.
11) Fujita R., Okuyama Y., Hongo H., Tohoku Yakka Daigaku Kenkyu
Nempo, 40, 115—122 (1993) [Chem. Abstr., 121, 280523 (1994)].
12) Katrityky A. R., Popp F. D., Rowe J. D., J. Chem. Soc. B, 1966, 562—
564 (1966).
4-Chloro-2-methyl-N-phenyl-3-oxo-2-azabicyclo[2.2.2]oct-7-ene-5,6-
exo-dicarboximide (13a) Colorless columns (acetone), mp 288—290 °C.

484
Vol. 56, No. 4
13) Hertog H. J., Bunrman D. J., Rec. Trav. Chim., 75, 257—264 (1956).
14) Fujita R., Hongo H., Tohoku Yakka Daigaku Kenkyu Nempo, 42,
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