[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

Article abstract of DOI:10.1016/j.tet.2008.03.030

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.

Full text of DOI:10.1016/j.tet.2008.03.030

Tetrahedron 64 (2008) 5291–5297
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[4þ2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones
with electron-deficient dienophiles
*
Shang-Shing P. Chou , Hui-Chen Wang, Pong-Won Chen, Chun-Han Yang
Department of Chemistry, Fu Jen Catholic University, Taipei 24205, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
[4þ2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-
2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and
methyl acrylate) gave new isoquinuclidine products 8–10. The N-tosyl group of 6a and 6b was also
efficiently converted to N-alkyl derivatives 6c–f, which showed different stereoselectivity toward
reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl
vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to
the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-
O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the
cycloaddition reactions were also compared with semi-empirical calculations.
Received 22 January 2008
Received in revised form 5 March 2008
Accepted 11 March 2008
Available online 14 March 2008
Keywords:
2-Pyridones
[4þ2] Cycloaddition reactions
Diels–Alder reactions
Isoquinuclidines
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
4-thio-substituted 2-pyridones,39,40 and have studied some of their
synthetic applications.41–45 Since the only two literature reports
The synthesisof 2-pyridoneringis anareaof continuinginterest1
because many compounds of this structure (such as camptothecin,
Fredericamycin A, pyridoxatin, huperzine A, etc.) posses important
biological activities.2–7 2-Pyridones can also be used as starting
materials for synthesizing more complex molecules. For example, 2-
pyridones (1) are often used as dienes in the Diels–Alder reaction.8
The isoquinuclidine products (2) are valuable intermediates for the
synthesis of alkaloids9–11 and in medicinal chemistry.12
with C-4 substituents (1, X¼Ph, CO2Me, COMe; R¼Me)27,30 gave
good yields of cycloaddition products with dienophiles, we would
also like to study the cycloaddition reactions of 4-sulfide- and
sulfone-substituted 2-pyridones (1, X¼PhS, PhSO2; R¼Ts, alkyl)
with some electron-deficient dienophiles. The reactivity, regiose-
lectivity, and stereoselectivity of the cycloaddition reactions will be
compared with semi-empirical calculations.
From literature survey of the use of 2-pyridones as dienes in
the Diels–Alder reaction, we find several generalizations: (1)
N-Unsubstituted 2-pyridones usually undergo Michael-type addi-
tion to the dienophile, instead of cycloaddition reactions.13–15 (2)
Most studies have used N-alkyl-substituted 2-pyridones as the di-
ene,16–23 and the reaction yields are in general quite low. (3) N-Acyl
groups cannot be used for the Diels–Alder reaction because of facile
acyl migration to yield 2-acyloxypyridines.24,25 (4) Substituents on
the 2-pyridone ring can affect significantly the reactivity, regiose-
lectivity, and stereoselectivity of the cycloaddition.23,26–34 (5)
N-Sulfonylated 2-pyridones show greater reactivity and regiocon-
trol over N-alkyl analogues.35–37 (6) High pressure can sometimes
increase the yields of the cycloaddition reactions, but may also
decrease the stereoselectivity.38
X
X
W
O
N
+
W
N
R
1
O
R
2
2. Results and discussion
Reaction of 3-(phenylthio)-3-sulfolene (3)46,47 with p-toluene-
sulfonyl isocyanate (PTSI) in tolune at 110 ꢀC in the presence of
1 equiv of sodium bicarbonate and a catalytic amount of hydro-
quinone (HQ) gave the [4þ2] cyclization product 4, which was
directly treated with N-bromosuccinimide (NBS). The bromo in-
termediate 5 upon further reaction with pyrrolidine in DMF
resulted in the formation of 2-pyridone 6a.43 The overall yield of
this three-step sequence was 43%. Oxidation of 6a with mCPBA gave
the corresponding sulfone 6b in excellent yield.40
We recently reported the first aza-Diels–Alder reactions of thio-
substituted 1,3-butadienes with arylsulfonyl isocyanates to give
* Corresponding author. Tel.: þ886 2 29052474; fax: þ886 2 29023209.
E-mail address: chem1004@mails.fju.edu.tw (S.-S.P. Chou).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.030

5292
S.-S.P. Chou et al. / Tetrahedron 64 (2008) 5291–5297
SPh
SPh
NBS (1.1 eq)
(3 eq)
N C O
Ts
Tol, 110 °C, 2 h
HQ (cat.), NaHCO3 (1 eq)
Tol, 110 °C, 4.5 h
S
N
Ts
O
O2
3
4
SO2Ph
SPh
SPh
Br
N
(2 eq)
H
mCPBA (2.5 eq)
DMF, 0 °C, 1 h
CH2Cl2, rt, 1.5 h
N
Ts
O
N
Ts
O
N
Ts
5
O
6a (43%)
6b (98%)
Using Parson’s method of cleaving the N-tosyl group of amides
with Bu3SnH/AIBN,48 followed by treatment with t-BuOK/RX,40
2-pyridones 6a and 6b were converted to the alkyl-substituted
derivatives 6c–f in very good yields.
R1
R1
1. Bu3SnH (2.2 eq)
AIBN (cat.)
Tol, reflux, 1 h
t
2. BuOK (4 eq)
N
Ts
O
N
O
R2X (4 eq)
rt, 1 d
R2
6c, R1 = SPh, R2 = CH3
6d, R1 = SPh, R2 = Bn
6e, R1 = SO2Ph, R2 = CH3
6f, R1 = SO2Ph, R2 = Bn
6a, R1 = SPh
(100%)
(89%)
(95%)
(100%)
6b, R1 = SO2Ph
Figure 1. X-ray structure of compound 9a.
Having prepared the 2-pyridones 6a–f efficiently, we then
studied their cycloaddition reactions with some electron-deficient
dienophiles: N-methylmaleimide (7a), N-phenylmaleimide (7b),
and methyl acrylate (7c). The cycloaddition reactions were carried
out in sealed tubes using toluene as the solvent, and the results are
shown in Table 1. After a few trials of the reaction conditions, it was
found that thermolysis of sulfide-substituted 2-pyridone 6a with
dienophiles 7a and 7b proceeded well at 150 ꢀC for 2 d (entries 1
and 2) to give cycloaddition products 8a and 9a, respectively, in
good yields. The X-ray structure of 9a (Fig. 1)49 clearly showed that
it is the endo addition product (C]O of the imide group cis to the
C]C) and has the cis ring junction. Since compounds 8a and 9a
have similar splitting patterns in their 1H NMR spectra, compound
8a is also assumed to be the endo addition product. The reactions of
sulfone-substituted 2-pyridone 6b with dienophiles 7a and 7b also
proceeded at 150 ꢀC (entries 4 and 5) to give the corresponding
products 8b and 9b. The X-ray structure of compound 8b (Fig. 2)49
also shows that it is the endo addition product. The reaction yields
for 8b and 9b were about 20% lower than those for 8a and 9a. This
might be due to the reactivity difference of 6a and 6b; the sulfide
substituent in 6a is an electron-donating group, whereas the
sulfone substituent in 6b is an electron-withdrawing group. On the
other hand, the lower reactivity of 6b may not necessarily lead to
a lower yield of the cycloaddition products than 6a, as we shall see
in their reactions with methyl acrylate (7c).
The reaction of 6a with 7c in toluene at 150 ꢀC for 2 d in the
presence of a small amount of butylated hydroxytoluene (BHT) to
retard the polymerization of methyl acrylate (entry 3) gave the
cycloaddition product 10a regio- and stereospecifically, albeit in
low yield. Similar reaction of 6b with 7c (entry 6) gave a good yield
of endo product 10b and a small amount of exo product 10c,
Table 1
Cycloaddition reactions of 2-pyridones 6a–f with dienophiles 7
Entry
Pyridone
Dienophilea
Conditionsb
Product (% yield)
1
2
3
4
5
6
7
8
9
10
6a
6a
6a
6b
6b
6b
6c
6d
6e
6f
7a
7b
7c
7a
7b
7c
7b
7b
7b
7b
150 ꢀC, 2 d
8a (69)
9a (66)
10a (28)
8b (50)
150 ꢀC, 2 d
BHT (cat.), 150 ꢀC, 2 d
150 ꢀC, 2 d
100 ꢀC, 1 d; 150 ꢀC, 1.5 d
BHT (cat.), 150 ꢀC, 44 h
150 ꢀC, 2 d
9b (44)
10b (53), 10c (7)c
11a (52), 11b (23)
12a (55), 12b (14)
13 (20)d
150 ꢀC, 2 d
150 ꢀC, 2 d
150 ꢀC, 2 d
14a (21), 14b (33)
a
Dienophiles 7a and 7b were used in 10 equiv, and 7c was used in 20 equiv.
All reactions were carried out in a sealed tube, using toluene as the solvent.
4-(Phenylsulfonyl)-O-tosyl-2-pyridone (16b) was also obtained in 33%.
The unreacted 6e was also obtained in 29%.
b
c
d
Figure 2. X-ray structure of compound 8b.

S.-S.P. Chou et al. / Tetrahedron 64 (2008) 5291–5297
5293
Reaction of N-methylated 2-pyridone 6c with 7b at 150 ꢀC for
2 d (entry 7) gave good yields of the cycloaddition products 11a and
11b, which were separated by flash chromatography. The ste-
reochemistry of 11a and 11b was established by comparing the
coupling constant between H-6 and H-7 (J6,7¼4.2 Hz for 11a,
J6,7¼2.7 Hz for 11b). Thus, in agreement with the literature
observations18,29 as well as the coupling constants for endo and
exo products 10b and 10c, the major product 11a was assigned
the endo isomer, and the minor product 11b the exo isomer.
Reaction of N-benzylated 2-pyridone 6d with 7b at 150 ꢀC for
2 d (entry 8) also gave a mixture of the cycloaddition products
12a and 12b. Stereochemical assignment is similar to that for
11a and 11b. The reaction of 6e with 7b (entry 9) gave a low
yield of the endo product 13 together with some unreacted 6e,
whereas a similar reaction of 6f with 7b (entry 10) led to
a mixture of the endo product 14a and the exo product 14b. It is
rather surprising to find that the major product is 14b. Pre-
sumably, the steric repulsion between the N-phenyl group with
the phenylsulfonyl group in forming the endo product 14a out-
weighs the electronic effect. From the reactions of 2-pyridones
6c–f with 7b (entries 7–10) it is quite obvious that substitution
of the N-tosyl group of 2-pyridones 6a and 6b for an alkyl group
(methyl or benzyl) led to the formation of both endo and exo
cycloaddition products. This complements with the literature
findings that N-sulfonylated 2-pyridones show greater reactivity
and regiocontrol over their N-alkyl analogues.35–37 We can fur-
ther add that N-sulfonylated 2-pyridones also increase the
preference for endo addition products over their N-alkyl
analogues.
Figure 3. X-ray structure of compound 10b.
together with some tosyl migration product 16b. The X-ray struc-
ture of compound 10b is shown in Figure 3,49 which clearly shows
its regiochemistry and endo configuration. Some important 1H NMR
data for compounds 10a, 10b, and 10c are shown in Figure 4. Since
compounds 10b and 10c have similar chemical shifts for H-4 and
H-5, we propose that they are stereoisomers, not regioisomers. The
most significant spectral difference between the endo and exo
products 10b and 10c is the coupling constant between H-3 and
H-5 (J3,5¼3.3 Hz for 10b, J3,5¼1.8 Hz for 10c). Compound 10a also
has J3,5¼3.3 Hz, indicating its endo structure. Similar observations
that the endo isomer has larger coupling constant than the exo
isomer have been made in the literature.18,29 As compared to the
literature results (1, R¼Ts, X¼H: 10% yield of two endo isomeric
products, 0.6:1),37 the presence of 4-phenylthio group in 6a or
4-phenylsulfonyl group in 6b significantly increases the yields
and regioselectivity of the cycloaddition reaction with methyl
acrylate (7c).
O
O
N
Ph
N Me
CO2Me
O
7b
O
7a
7c
R
R
R
SO2Ph
O
O
O
N
O
N
O
N
O
N
N
N
CO2CH3
Ph
Me
Ts
Ts
Ts
Ts
O
O
CO2CH3
8a, R = SPh
8b, R = SO2Ph
10a, R = SPh
10b, R = SO2Ph
9a, R =SPh
9b, R = SO2Ph
10c
SPh
SPh
SPh
O
SPh
O
N
O
O
N
O
O
H
6 O
O
N
N
Ph
Ph
N
N
H7
H7
Me
Bn
N
Ph
N
O
Bn
O
Me
H6
11a
O
O
Ph
12a
12b
11b
SO2Ph
N
SO2Ph
SO2Ph
O
O
O
N
O
N
O
N
O
N
N
Ph
Ph
Bn
O
O
Me
Bn
O
Ph
13
14a
14b

5294
S.-S.P. Chou et al. / Tetrahedron 64 (2008) 5291–5297
J
4, 6 = 2.1 Hz
J
4, 6 = 2.7 Hz
J
4, 6 = 2.6 Hz
SPh
SO2Ph
SO2Ph
J
1, 4 = 2.7 Hz
H6
H6
J
1, 4 = 4.8 Hz
H6
J
1, 4 = 3.0 Hz
H4
H4
H4
H3
O
H1
O
H1
O
H1
J
1,
3 = 1.7 Hz
J
2, 4 = 2.4 Hz
CO2Me
H2
J
2, 4 = 2.4 Hz
H2
CO2Me
H2
TsN
TsN
TsN
H3
J
1, 3 = 10.8 Hz
H5
J1, 3 = 3.0 Hz
H3
H5
H5
CO2Me
2, 3 = 4.2 Hz
J2, 3 = 6.6 Hz
J2, 3 = 9.9 Hz
J
10c
10a
10b
J
3, 5 = 1.8 Hz
J
3, 5 = 3.3 Hz
J
3, 5 = 3.3 Hz
J5, 6 = 6.0 Hz
J5, 6 = 6.0 Hz
J5, 6 = 6.0 Hz
Figure 4. Some 1H NMR coupling constants for compounds 10a, 10b, and 10c.
We have also carried out thermolysis of 2-pyridones 6a and 6b
with other dienophiles: dimethyl acetylenedicarboxylate (15a),
methyl vinyl ketone (15b), ethyl vinyl ether (15c), and methyl
methacrylate (15d), but have only obtained quantitatively the
corresponding tosyl migration products 16a and 16b. Apparently
these dienophiles 15 are less reactive (or more easily decomposed
under the reaction conditions) than compounds 7, so that the tosyl
migration reaction dominates.
In order to explain the regioselectivity of the cycloaddition
reactions of 2-pyridones 6a and 6b with dienophile 7c, we have
calculated the LUMO-coefficients of dienophile 7c and the HOMO-
coefficients of dienes 6a and 6b (Table 3). The C-2 of methyl acrylate
(7c) has a larger LUMO-coefficient than that at C-1, and the C-3 of
6a and 6b has a larger HOMO-coefficient than that at C-6. Thus, we
expect that the C-2 of 7c would be connected with the C-3 of 6a and
6b in the cycloaddition reaction. Indeed, the formation of 10a from
6a, as well as the formation of 10b and 10c from 6b, agrees with this
prediction.
R
R
To explain the stereoselectivity of the cycloaddition reaction, we
have calculated the heat of formation (DHf) for endo and exo
products (Table 4). It can be seen that the endo products 10b, 11a,
12a, and 14a are all more stable than the corresponding exo
products 10c, 11b, 12b, and 14b. Except for the formation of
products 14, the endo isomer is the major product in all the other
cases. Shusherina and co-workers showed that for the reactions of
1-alkyl-3-methyl-2-pyridone with N-phenylmaleimide, the endo
cycloadduct obtained at lower temperature was the kinetic prod-
uct, and the exo cycloadduct obtained at higher temperature was
the thermodynamic product.50 It was also emphasized that the
dienophile 15 (10 eq)
Tol, BHT (cat.)
150 °C, 2 d
N
Ts
O
N
OTs
16a, R = SPh (100%)
16b, R = SO2Ph (100%)
6a, R = SPh
6b, R = SO2Ph
O
MeO2C
CO2Me
CO2Me
15d
O
15a
15b
15c
Table 3
In order to explain the reactivity of dienes 6a–f as well as the
regioselectivity and stereoselectivity of the cycloaddition reactions,
we have used a semi-empirical PM3 method of HyperChem to
calculate the HOMO–LUMO energy differences and coefficients. As
expected, the more favorable interaction is between HOMO of the
diene and LUMO of the dienophile. The HOMOdiene–LUMOdienophile
energy difference DE for different pairs of dienes and dienophiles is
listed in Table 2. Using N-phenylmaleimide (7b) as the dienophile, it
is predicted from the DE values that the reactivity of the dienes
would follow the order: 6c, 6d>6a>6e, 6f>6b. It is quite
understandable that N-alkyl groups in 6c and 6d, as compared to
N-tosyl group in 6a, would increase the electron density and thus
the reactivity of 2-pyridones. On the other hand, 4-phenylthio
group in 6a would be a much better electron-donating group than
4-phenylsulfonyl group in 6b so that the reactivity of 6a would be
greater than that of 6b. The reactivity of the dienophiles would be:
7b>7a>7c.
HOMO-coefficients of dienes 6a, 6b, and LUMO-coefficients of dienophile 7c
SPh
SO2Ph
3
CO2Me
3
2
1
6
6
N
Ts
O
N
O
Ts
7c
6a
6b
Diene
HOMO-coefficients
C-3
C-6
6a
6b
0.1913
0.1358
0.0348
0.1284
Dienophile
LUMO-coefficients
C-1
C-2
7c
0.1657
0.2171
Table 2
Favorable HOMOdiene–LUMOdienophile energy difference DE calculated by HyperChem
PM3 method
Table 4
Entry
Diene
Dienophile
DE (eV)
Calculated heat of formation (DHf) for cycloaddition products
1
2
3
4
5
6
7
8
9
10
6a
6a
6a
6b
6b
6b
6c
6d
6e
6f
7a
7b
7c
7a
7b
7c
7b
7b
7b
7b
7.66
7.53
8.76
8.27
7.92
9.36
7.37
7.38
7.78
7.84
Compound
DHf (kcal/mol)
10b
10c
11a
11b
12a
12b
14a
14b
ꢁ96.062
ꢁ95.452
ꢁ3.932
ꢁ3.520
17.506
20.523
ꢁ44.513
ꢁ38.597

S.-S.P. Chou et al. / Tetrahedron 64 (2008) 5291–5297
5295
presence of a substituent at the ends of the conjugated system of
2-pyridone (the 3-methyl group in this case) was essential for
obtaining the exo product. In our present studies, although there
are no substituents at the ends of the conjugated system of
2-pyridones 6, we still obtained both the endo and exo products for
the reactions of N-phenylmaleimide with N-alkyl derivatives 6c,d,f.
On the other hand, only the endo products 9a and 9b were obtained
from the N-tosyl analogues 6a and 6b.
4.2.2. N-Benzyl-4-(phenylthio)-2-pyridone (6d)
Light yellow liquid; IR (neat) 3061, 1652, 1592, 1513, 1495, 1474,
1455, 1440, 1360, 1305, 1244, 1160, 1118, 1073, 1047, 1025, 957, 929,
847, 750, 735, 693 cmꢁ1; 1H NMR d 5.04 (2H, s), 5.94 (1H, dd, J¼2.0,
7.2 Hz), 6.06 (1H, d, J¼2.0 Hz), 7.07 (1H, d, J¼7.2 Hz), 7.24–7.44 (8H,
m), 7.51–7.54 (2H, m); 13C NMR d 51.3, 105.3, 114.1, 128.0, 128.1,
128.6, 128.9, 129.9, 130.0, 135.6, 136.1, 136.4, 154.1, 161.5; HRMS m/z
293.0867 (calcd for C18H15NOS: 293.0874).
4.2.3. N-Methyl-4-(phenylsulfonyl)-2-pyridone (6e)
3. Conclusion
Yellow solid, mp 133–135 ꢀC; IR (KBr) 3071, 2926, 1656, 1591,
1536, 1477, 1448, 1408, 1320, 1164, 1138, 1087, 1062, 997, 866, 782,
756, 731, 685, 647 cmꢁ1; 1H NMR d 3.53 (3H, s), 6.50 (1H, dd, J¼2.1,
7.2 Hz), 7.08 (1H, d, J¼2.1 Hz), 7.40 (1H, d, J¼7.2 Hz), 7.56–7.66 (3H,
m), 7.93–7.96 (2H, m); 13C NMR d 37.9, 101.6, 119.9, 128.3, 129.6,
134.3, 139.0, 140.4, 152.4, 161.7; HRMS m/z 249.0462 (calcd for
We have studied the [4þ2] cycloaddition reactions of
4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-
tosyl-2-pyridone (6b) with electron-deficient dienophiles
7
(N-methylmaleimide, N-phenylmaleimide, and methyl acrylate)
to give new isoquinuclidine products 8–10. The yields obtained
from 6a were higher than those from 6b, indicating the activating
ability of the sulfide group as compared to the sulfone group. The
N-tosyl group of 6a and 6b was also efficiently converted to the
N-alkyl derivatives 6c–f, which showed different stereoselectivity
in their reactions with dienophiles 7. Several other dienophiles 15
(dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl
ether, and methyl methacrylate) were found not to react with 6a
or 6b, but led to the formation of tosyl migration products
4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-
O-tosyl-2-pyridinol (16b), respectively. The reactivity, regiose-
lectivity, and stereoselectivity of the cycloaddition reactions were
compared with semi-empirical calculations.
C12H11NO3S: 249.0460).
4.2.4. N-Benzyl-4-(phenylsulfonyl)-2-pyridone (6f)
Yellow solid, mp 155–157 ꢀC; IR (KBr) 3070, 2930, 1661, 1593,
1536, 1446, 1323, 1163, 1085, 727, 688, 645 cmꢁ1 1H NMR d 5.09
;
(2H, s), 6.47 (1H, dd, J¼1.8, 7.2 Hz), 7.10 (1H, d, J¼1.8 Hz), 7.25–7.35
(3H, m), 7.37 (1H, d, J¼7.2 Hz), 7.53–7.66 (5H, m), 7.92–7.96 (2H, m);
13C NMR d 52.4, 101.9, 120.4, 128.36, 128.40, 128.5, 129.1, 129.6,
134.4, 135.1, 139.3,152.2,161.3, 170.2; HRMS m/z 325.0772 (calcd for
C18H15NO3S: 325.0773).
4.3. General procedure for cycloaddition reactions
of 2-pyridones 6 with dienophiles 7 or 15
A mixture of 2-pyridone 6 (0.28 mmol) and dienophile 7 or 15
(2.8 mmol for 7a or 7b; 5.6 mmol for 7c together with 20 mg of
BHT; 2.8 mmol for 15 together with 20 mg of BHT) in dried toluene
(5 mL) was heated in a sealed tube at an appropriate temperature
for a period of time (Table 1). The solvent was then removed under
vacuum, and the crude product was purified by flash chromatog-
raphy using ethyl acetate/hexane as eluent to give the product.
4. Experimental
4.1. General
Melting points were determined with a SMP3 melting appara-
tus. Infrared spectra were recorded with a Perkin Elmer 1600 FTIR
spectrometer. 1H and 13C NMR spectra were recorded on a Bruker
Avance 300 spectrometer operating at 300 and 75 MHz, re-
spectively, using CDCl3 as solvent. Chemical shifts (d) are reported
in parts per million (ppm) and the coupling constants (J) are given
in hertz. High resolution mass spectra (HRMS) were measured with
a mass spectrometer JEOL JMS-SX102A. Flash column chromato-
graphic purifications were performed using Merck 60H silica gel.
4.3.1. endo-4-Methyl-10-(phenylthio)-8-tosyl-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (8a)
White solid, mp 150–151 ꢀC (decomp.); IR (KBr) 3072, 2947,
1782, 1732, 1705, 1597, 1435, 1359, 1280, 1244, 1171, 1092, 1023, 990,
968, 904, 813, 754, 691, 661 cmꢁ1; 1H NMR d 2.46 (3H, s), 2.95–3.00
(4H, m), 3.32 (1H, dd, J¼3.3, 8.1 Hz), 3.55 (1H, dd, J¼3.3, 8.1 Hz),
3.77 (1H, dd, J¼0.8, 3.3 Hz), 5.62–5.65 (2H, m), 7.15 (2H, d,
J¼8.1 Hz), 7.31–7.40 (5H, m), 7.84 (2H, d, J¼8.1 Hz); 13C NMR d 21.7,
25.1, 39.6, 47.6, 51.0, 54.3, 120.5, 128.0, 128.3, 128.5, 129.7, 129.8,
134.1, 134.9, 141.3, 145.6, 167.1, 173.4, 173.8; HRMS m/z 468.0814
(calcd for C23H20N2O5S2: 468.0814).
4.2. General procedure for preparation of 6c–f from 6a and 6b
To a solution of compound 6a or 6b (0.28 mmol) and AIBN
(0.06 mmol) in degassed toluene (5 mL) was added Bu3SnH
(0.17 mL, 0.62 mmol). The mixture was heated at reflux under
nitrogen for 2 h. During this period another two portions of AIBN
(0.06 mmol each) in toluene (5 mL) were added in 30 min interval.
The reaction mixture is cooled to room temperature. Then alkyl
halide (1.12 mmol) and t-BuOK (1.12 mmol) were added sequen-
tially. After stirring at room temperature for 1.5 h (checked by TLC),
the solvent was removed under vacuum and the crude product was
purified by flash chromatography using ethyl acetate/hexane (1:2
to 1:1) with 5–10% of Et3N as eluent to give the product 6c–f.
4.3.2. endo-4-Methyl-10-(phenylsulfonyl)-8-tosyl-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (8b)
White solid, mp 230–232 ꢀC (decomp.); IR (KBr) 3065, 2906,
1783, 1704, 1596, 1440, 1383, 1308, 1156, 1089, 1017, 970, 900, 814,
733, 688, 662 cmꢁ1; 1H NMR d 2.47 (3H, s), 2.73 (3H, s), 3.30 (1H, dd,
J¼2.7, 8.1 Hz), 3.69 (1H, dd, J¼4.5, 8.1 Hz), 4.08 (1H, dd, J¼2.7,
4.8 Hz), 5.96 (1H, dd, J¼4.5, 5.7 Hz), 7.30–7.80 (10H, m); 13C NMR
d 21.8, 25.3, 39.2, 46.6, 46.9, 53.1, 128.2, 128.5, 129.8, 130.0, 134.5,
134.8, 137.1, 137.6, 145.2, 146.2, 165.4, 172.0, 172.8; HRMS m/z
500.0711 (calcd for C23H20N2O7S2: 500.0712).
4.2.1. N-Methyl-4-(phenylthio)-2-pyridone (6c)
Light yellow solid, mp 126–127 ꢀC; IR (KBr) 3071, 1650, 1589,
1511, 1474, 1440, 1409, 1330, 1305, 1244, 1182, 1038, 934, 845, 752,
4.3.3. endo-4-Phenyl-10-(phenylthio)-8-tosyl-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (9a)
White solid, mp 206–207 ꢀC; IR (KBr) 3030, 2930, 1716, 1596,
1498, 1379, 1172, 1090, 984, 906, 752, 691, 661, 635 cmꢁ1; 1H NMR
d 2.47 (3H, s), 3.43 (1H, dd, J¼3.3, 8.1 Hz), 3.69 (1H, dd, J¼3.9,
707, 692 cmꢁ1
;
1H NMR d 3.54 (3H, s), 5.98 (1H, dd, J¼1.8, 7.2 Hz),
6.03 (1H, d, J¼1.8 Hz), 7.13 (1H, d, J¼7.2 Hz), 7.42–7.54 (5H, m); 13
C
NMR d 37.0, 105.1, 113.8, 128.7, 129.88, 129.91, 135.4, 137.2, 154.2,
162.0; HRMS m/z 217.0556 (calcd for C12H11NOS: 217.0561).

5296
S.-S.P. Chou et al. / Tetrahedron 64 (2008) 5291–5297
8.1 Hz), 3.88 (1H, dd, J¼2.0, 3.3 Hz), 5.72–5.80 (2H, m), 7.17–7.53
(12H, m), 7.78 (2H, d, J¼8.4 Hz); 13C NMR d 21.8, 39.6, 47.8, 51.3,
54.6,120.4,126.2, 128.2, 128.4, 129.2, 129.4, 129.8, 130.0, 130.1, 131.2,
134.5, 135.2, 141.7, 145.7, 167.2, 172.6, 172.8; HRMS m/z 530.0969
(calcd for C28H22N2O5S2: 530.0970).
J¼2.7, 8.4 Hz), 3.32 (1H, dd, J¼3.0, 8.4 Hz), 3.92 (1H, dd, J¼2.1,
3.0 Hz), 4.61 (1H, dd, J¼2.7, 6.0 Hz), 6.04 (1H, dd, J¼2.1, 6.0 Hz),
7.15–7.58 (10H, m); 13C NMR d 33.1, 43.6, 48.9, 51.0, 58.3, 124.8,
126.6, 129.2, 129.3, 129.4, 129.8, 130.1, 131.4, 133.6, 143.3, 168.6,
173.8,174.0; HRMS m/z 390.1040 (calcd for C22H18N2O3S: 390.1038).
4.3.4. endo-4-Phenyl-10-(phenylsulfonyl)-8-tosyl-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (9b)
4.3.10. endo-8-Benzyl-4-phenyl-10-(phenylthio)-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (12a)
White solid, mp 266–267 ꢀC; IR (KBr) 3052, 2930, 1719, 1596,
1498, 1380, 1308, 1173, 1090, 906, 747, 688, 662, 640 cmꢁ1; 1H NMR
d 2.49 (3H, s), 3.42 (1H, dd, J¼3.0, 8.4 Hz), 3.85 (1H, dd, J¼4.7,
8.4 Hz), 4.12 (1H, dd, J¼2.1, 3.0 Hz), 6.05 (1H, dd, J¼4.7, 5.7 Hz),
7.19–7.60 (13H, m), 7.80 (2H, d, J¼8.4 Hz); 13C NMR d 21.9, 39.1, 46.6,
47.2, 53.4, 126.2, 128.2, 128.4, 129.4, 129.5, 129.8, 129.9, 130.0, 130.4,
133.9, 134.5, 134.8, 137.4, 146.2, 165.4, 171.1, 171.9; HRMS m/z
562.0863 (calcd for C28H22N2O7S2: 562.0868).
Light yellow solid, mp 83–85 ꢀC; IR (KBr) 3062, 2926, 1778, 1714,
1682, 1593, 1497, 1476, 1447, 1424, 1381, 1320, 1234, 1186, 1069,
1023, 965, 938, 801, 770, 750, 691 cmꢁ1 1H NMR d 3.25 (1H, dd,
;
J¼4.2, 8.1 Hz), 3.38 (1H, dd, J¼3.3, 8.1 Hz), 3.94 (1H, dd, J¼2.1,
3.3 Hz), 4.40–4.44 (3H, m), 5.61 (1H, dd, J¼2.1, 5.7 Hz), 7.10–7.14
(4H, m), 7.23–7.38 (11H, m); 13C NMR 40.6, 47.4, 47.9, 50.0, 54.5,
121.1,125.7,127.6,127.7,128.4 (ꢂ2),128.5,128.6,129.0,129.2,131.68,
131.74, 135.5, 140.6, 169.3, 172.8, 173.2; HRMS m/z 466.1352 (calcd
for C28H22N2O3S: 466.1351).
4.3.5. endo-Methyl 3-oxo-8-(phenylthio)-2-tosyl-2-aza-
bicyclo[2.2.2]oct-7-ene-6-carboxylate (10a)
4.3.11. exo-8-Benzyl-4-phenyl-10-(phenylthio)-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (12b)
White solid, mp 136–138 ꢀC; IR (KBr) 3106, 2942, 2868, 2810,
1631, 1615, 1510, 1474, 1456, 1437, 1243, 1120, 1067, 1025, 988, 916,
856, 777, 748, 706, 687 cmꢁ1; 1H NMR d 2.09–2.13 (2H, m), 2.44 (3H,
s), 3.25 (1H, ddd, J¼1.7, 3.3, 6.6 Hz), 3.30 (1H, dd, J¼2.1, 2.7 Hz), 3.70
(3H, s), 5.61 (1H, dd, J¼3.3, 6.0 Hz), 5.93 (1H, dd, J¼2.1, 6.0 Hz),
7.20–7.33 (7H, m), 7.85 (2H, d, J¼8.4 Hz); 13C NMR d 21.7, 25.0, 45.6,
50.4, 52.5, 55.5, 124.0, 128.1, 129.0, 129.55, 129.63, 130.4, 133.3,
135.6, 142.3, 145.2, 169.8, 171.2; HRMS m/z 443.0855 (calcd for
Light yellow solid, mp 205–207 ꢀC; IR (KBr) 3058, 2924, 1716,
1682, 1595, 1497, 1455, 1382, 1189, 742, 691 cmꢁ1 1H NMR d 3.15
;
(1H, dd, J¼2.7, 8.7 Hz), 3.28 (1H, dd, J¼3.0, 8.7 Hz), 3.68 (1H, d,
J¼15 Hz), 3.94 (1H, dd, J¼2.1, 3.0 Hz), 4.47 (1H, dd, J¼2.7, 6.0 Hz),
5.10 (1H, d, J¼15 Hz), 5.81 (1H, dd, J¼2.1, 6.0 Hz), 7.04–7.13 (4H, m),
7.19–7.23 (3H, m), 7.31–7.42 (8H, m); 13C NMR d 43.8, 48.6, 48.8,
51.5, 55.6, 126.7 (ꢂ2), 128.0, 128.5, 128.9, 129.2, 129.3, 129.5, 129.9,
130.7, 131.7, 133.5, 135.9, 142.5, 168.6, 173.9, 174.1; HRMS m/z
466.1351 (calcd for C28H22N2O3S: 466.1351).
C
22H21NO5S2: 443.0861).
4.3.6. endo-Methyl 3-oxo-8-(phenylsulfonyl)-2-tosyl-2-aza-
bicyclo[2.2.2]oct-7-ene-6-carboxylate (10b)
4.3.12. endo-8-Methyl-4-phenyl-10-(phenylsulfonyl)-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (13)
White solid, mp 180–181 ꢀC; IR (KBr) 3046, 2954, 2919,1732,1362,
1322, 1172, 1086, 719 cmꢁ1
;
1H NMR d 1.70 (1H, ddd, J¼3.0, 4.8,
White solid, mp 243–244 ꢀC; IR (KBr) 3093, 2949, 1719, 1694,
1497, 1447, 1382, 1308, 1179, 1155, 1089, 1002, 807, 749, 728, 688,
629 cmꢁ1; 1H NMR d 2.92 (3H, s), 3.40 (1H, dd, J¼3.0, 8.4 Hz), 3.75
(1H, dd, J¼4.5, 8.4 Hz), 4.22 (1H, dd, J¼2.1, 3.0 Hz), 4.84 (1H, dd,
J¼4.5, 5.7 Hz), 7.20–7.23 (2H, m), 7.39–7.48 (6H, m), 7.56–7.62 (1H,
m), 7.82–7.85 (2H, m); 13C NMR d 32.6, 40.7, 46.1, 46.6, 56.6, 126.4,
128.7, 129.1, 129.3,129.8,131.4, 134.7, 137.6, 137.9, 146.5, 168.9, 172.0,
173.0; HRMS m/z 422.0941 (calcd for C22H18N2O5S: 422.0936).
13.5 Hz), 2.22 (1H, ddd, J¼2.7, 9.9,13.5 Hz), 2.46 (3H, s), 3.33 (1H, ddd,
J¼2.7, 3.3,9.9 Hz), 3.64(1H, dd, J¼2.7, 4.8 Hz), 3.71(3H, s), 5.84(1H, dd,
J¼3.3,6.0 Hz), 7.29–7.79(10H, m);13CNMRd21.8,25.8, 45.1, 45.3,52.9,
54.4, 128.1, 128.2, 129.6, 129.8, 134.3, 135.0, 138.1, 138.2, 145.7, 145.9,
167.6, 170.7; HRMS m/z 475.0757 (calcd for C22H21NO5S2: 475.0759).
4.3.7. exo-Methyl 3-oxo-8-(phenylsulfonyl)-2-tosyl-2-aza-
bicyclo[2.2.2]oct-7-ene-6-carboxylate (10c)
White solid, mp 167–169 ꢀC; IR (KBr) 3047, 2924, 1732, 1596,
1447, 1354, 1323, 1249, 1221, 1172, 1157, 1124, 1090, 1038, 1012, 881,
854, 815, 792, 760, 741, 718, 680, 635 cmꢁ1; 1H NMR d 1.84 (1H, ddd,
J¼3.0, 10.8, 13.8 Hz), 2.46 (3H, s), 2.50 (1H, ddd, J¼2.4, 4.2, 13.8 Hz),
2.81 (1H, ddd, J¼1.8, 4.2, 10.8 Hz), 3.62–3.66 (1H, m), 3.77 (3H, s),
5.86 (1H, dd, J¼1.8, 6.0 Hz), 7.28–7.65 (8H, m), 7.73 (2H, d,
J¼8.4 Hz); 13C NMR d 21.8, 25.8, 45.1, 45.3, 52.9, 54.4, 128.1, 128.18,
129.6, 129.8, 134.3, 135.0, 138.1, 138.2, 145.7, 145.9, 167.6, 170.7;
HRMS m/z 475.0751 (calcd for C22H21NO5S2: 475.0759).
4.3.13. endo-8-Benzyl-4-phenyl-10-(phenylsulfonyl)-4,8-diaza-
tricyclo[5.2.2.02,6]-undec-10-ene-3,5,9-trione (14a)
White solid, mp 187–188 ꢀC; IR (KBr) 3064, 2925, 1782, 1715,
1690, 1597, 1497, 1447, 1421, 1384, 1321, 1309, 1237, 1195, 1155, 1098,
1085, 1069, 1028, 998, 961, 937, 799, 744, 730, 688, 662 cmꢁ1 1H
;
NMR d 3.43 (1H, dd, J¼3.0, 8.1 Hz), 3.51 (1H, dd, J¼4.2, 8.1 Hz), 4.26–
4.32 (2H, m), 4.60 (1H, d, J¼15 Hz), 4.78 (1H, dd, J¼4.2, 5.7 Hz), 7.04–
7.08 (2H, m), 7.17–7.20 (3H, m), 7.32–7.63 (9H, m), 7.80–7.83 (2H, m);
13C NMR d 40.6, 46.4, 46.7, 48.7, 54.1,126.3,128.2,128.5,128.6,129.0,
129.2 (ꢂ2), 129.7, 131.2, 134.5, 135.5, 137.8, 138.4, 145.6, 168.4, 172.0,
172.9; HRMS m/z 498.1259 (calcd for C28H22N2O5S: 498.1249).
4.3.8. endo-8-Methyl-4-phenyl-10-(phenylthio)-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (11a)
Yellow solid, mp 90–92 ꢀC; IR (KBr) 3070, 2926,1778,1715, 1682,
4.3.14. exo-8-Benzyl-4-phenyl-10-(phenylsulfonyl)-4,8-diaza-
tricyclo[5.2.2.02,6]-undec-10-ene-3,5,9-trione (14b)
1593, 1496, 1440, 1384, 1185, 1040, 998, 803, 748, 692 cmꢁ1 1H
;
NMR d 2.94 (3H, s), 3.45 (1H, dd, J¼3.0, 8.1 Hz), 3.61 (1H, dd, J¼4.2,
8.1 Hz), 3.93 (1H, dd, J¼2.1, 3.0 Hz), 4.51 (1H, dd, J¼4.2, 5.7 Hz), 5.81
(1H, dd, J¼2.1, 5.7 Hz), 7.23–7.52 (10H, m); 13C NMR d 32.2, 41.2,
47.7, 51.1, 57.5, 120.3, 126.5, 129.0, 129.2, 129.4, 129.6, 129.8, 130.0,
134.4, 141.8, 170.1, 173.4, 173.9; HRMS m/z 390.1036 (calcd for
Light brown solid, mp 248–250 ꢀC; IR (KBr) 3070, 2925, 1717,
1665, 1599, 1497, 1448, 1424, 1388, 1320, 1233, 1201, 1152, 1099,
1082, 947, 868, 793, 743, 722, 688, 657 cmꢁ1 1H NMR (DMSO-d6)
;
d 3.12 (1H, dd, J¼3.3, 8.4 Hz), 3.49 (1H, dd, J¼2.4, 8.4 Hz), 3.79 (1H,
d, J¼15 Hz), 3.93 (1H, dd, J¼1.8, 3.3 Hz), 4.77 (1H, d, J¼15 Hz), 4.89
(1H, dd, J¼2.4, 5.7 Hz), 6.91–6.94 (2H, m), 7.03–7.06 (2H, m),
7.27–7.29 (3H, m), 7.41–7.50 (4H, m), 7.70–7.90 (5H, m); 13C NMR
(DMSO-d6) d 43.5, 45.6, 46.4, 48.3, 55.9,126.6,127.48,127.58,127.64,
128.5, 128.7, 129.0, 130.0, 131.6, 134.6, 135.9, 138.0, 143.0, 143.9,
167.0, 173.5, 173.7; HRMS m/z 498.1244 (calcd for C28H22N2O5S:
498.1249).
C
22H18N2O3S: 390.1038).
4.3.9. exo-8-Methyl-4-phenyl-10-(phenylthio)-4,8-diaza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,9-trione (11b)
Yellow solid, mp 210–212 ꢀC; IR (KBr) 3047, 2895, 1716, 1497,
1386, 1191, 745, 692 cmꢁ1 1H NMR d 2.88 (3H, s), 3.26 (1H, dd,
;

S.-S.P. Chou et al. / Tetrahedron 64 (2008) 5291–5297
5297
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4.3.15. 4-(Phenylthio)-O-tosyl-pyridinol (16a)
White solid, mp 164–165 ꢀC; IR (KBr) 3047, 2923, 1625, 1123,
1033, 1009, 682 cmꢁ1; 1H NMR d 2.44 (3H, s), 6.62 (1H, d, J¼1.5 Hz),
6.84 (1H, dd, J¼1.5, 5.1 Hz), 7.31 (2H, d, J¼8.1 Hz), 7.46–7.54 (5H,
m), 7.85 (2H, d, J¼8.1 Hz), 7.97 (1H, d, J¼5.1 Hz); 13C NMR d 21.4,
109.4, 111.84, 126.0, 126.5, 129.0, 129.7, 130.5, 131.1, 134.8, 135.6,
140.9, 160.5, 163.7; HRMS m/z 357.0498 (calcd for C18H15NO3S2:
357.0493).
20. Tomisawa, H.; Hongo, H.; Kato, H.; Haraki, T.; Fujita, R. Chem. Pharm. Bull. 1979,
27, 670–675.
4.3.16. 4-(Phenylsulfonyl)-O-tosyl-2-pyridinol (16b)
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White solid, mp 200 ꢀC (decomp.); IR (KBr) 3070, 2680, 1823,
1643, 1527,1495, 1448, 1360, 1333,1315, 1246,1216,1159, 1131, 1105,
1074, 1031, 1007, 940, 891, 189, 804, 761, 703, 681, 636 cmꢁ1 1H
;
NMR d 2.46 (3H, s), 7.35 (2H, d, J¼8.2 Hz), 7.50 (1H, s), 7.58–7.68
(4H, m), 7.89 (2H, d, J¼8.2 Hz), 7.94 (2H, d, J¼7.2 Hz), 8.43 (1H, d,
J¼5.1 Hz); 13C NMR d 21.8, 113.3, 119.4, 128.4, 128.8, 129.86, 129.90,
130.1, 133.4, 134.6, 145.9, 149.9, 154.0, 157.9; HRMS m/z 389.0388
(calcd for C18H15NO5S2: 389.0392).
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Acknowledgements
Financial support of this work by the National Science Council of
the Republic of China is gratefully acknowledged (NSC 92-213-
M-030-003 and 95-2113-M-030-002).
References and notes
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