Cycloaddition reactions of 4-sulfur-substituted dihydro-2-pyridones and 2-pyridones with conjugated dienes

Article abstract of DOI:10.1016/j.tet.2007.11.090

Cycloaddition reactions of sulfoxide- and sulfone-substituted dihydro-2-pyridones and 2-pyridones with electron-rich dienes gave new bicyclic and tricyclic products in good to fair yields. The reactivity, regioselectivity, and stereoselectivity of these r

Full text of DOI:10.1016/j.tet.2007.11.090

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1879e1887
www.elsevier.com/locate/tet
Cycloaddition reactions of 4-sulfur-substituted dihydro-2-pyridones
and 2-pyridones with conjugated dienes
*
Shang-Shing P. Chou , Pong-Won Chen
Department of Chemistry, Fu Jen Catholic University, Taipei 24205, Taiwan, ROC
Received 20 September 2007; received in revised form 22 November 2007; accepted 28 November 2007
Available online 20 December 2007
Abstract
Cycloaddition reactions of sulfoxide- and sulfone-substituted dihydro-2-pyridones and 2-pyridones with electron-rich dienes gave new
bicyclic and tricyclic products in good to fair yields. The reactivity, regioselectivity, and stereoselectivity of these reactions were compared
with semi-empirical theoretical calculations. Evidence is provided for rather unusual two parallel reaction pathways for the cross-DielseAlder
reaction of a sulfone-substituted 2-pyridone with cyclopentadiene.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Cycloaddition reactions; 2-Pyridones; Dihydro-2-pyridones; Conjugated dienes
1. Introduction
rich dienes have been little studied.18,19 Only alkyl and ester
substituents at C-3 of compounds 2 have been reported for
such reactions.
2-Pyridones are often used as dienes in the DielseAlder
reaction.1 The isoquinuclidine products are valuable interme-
diates in the synthesis of alkaloids2e4 and in medicinal chemi-
stry.5 In contrast, the use of 2-pyridones as dienophiles is less
common. Only 2-pyridones (1) with electron-withdrawing
group(s) attached to the ring can react as dienophiles with
electron-rich dienes to give isoquinolone derivatives,6e14
which can be used for the synthesis of isoquinoline alka-
loids.15e17 The electron-withdrawing groups that have been
studied include CN, CO2Me, COR, and NO2, and the substit-
uent on the nitrogen can be methyl, hydrogen, or arylsulfonyl.
High temperature and long reaction time, or extra-high pres-
sure is usually required. Often times the reaction yields are
low, and the cycloaddition products are sometimes further
decomposed. In contrast to the many studies directed toward
2-pyridones, the corresponding cycloaddition reactions of
electron-deficient 5,6-dihydro-2-pyridones (2) with electron-
The synthesis of 2-pyridone ring is an area of continuing
interest20 because many compounds of this structure (such
as camptothecin, Fredericamycin A, pyridoxatin, huperzine
A, etc.) posses important biological activities.21e26 We re-
cently reported the first aza-DielseAlder reactions of thio-
substituted 1,3-butadienes with arylsulfonyl isocyanates to
give 4-thio-substituted 2-pyridones,27,28 and have studied
some of their synthetic applications.29e32 In this paper we de-
scribe the synthesis of several sulfoxide- or sulfone-substituted
dihydro-2-pyridones and 2-pyridones, as well as their cycload-
dition reactions with some electron-rich dienes. Unlike previ-
ous derivatives as shown in 1 and 2, the sulfoxide and sulfone
substituents can be more easily eliminated from the initial
cycloaddition products. In the present study we have synthe-
sized several interesting new isoquinolone derivatives, and
have identified two parallel reaction pathways for the cross-
DielseAlder reaction of a sulfone-substituted 2-pyridone
with cyclopentadiene. The reactivity, regioselectivity, and
stereoselectivity of these reactions are also compared with
semi-empirical theoretical calculations.
* 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 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.090

1880
S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
Table 1
Oxidation of sulfides 4a, 5a, and 7aa
X
X
Entry
Reactant
m-CPBA (equiv)
Product (yield, %)
N
R
O
N
R
1
O
1
2
3
4
a
4a
5a
5a
7a
3
4b (99)
2
1.1
3
5b (24), 5c (58)
5b (99)
7b (97)
X = alkyl, CO2Me
X = CN, CO2Me, COR, NO2
R = Me, H, ArSO2
3
R = CO2Me, ArSO2
All reactions were carried out in CH2Cl2 at room temperature for 2 h.
2. Results and discussion
SO2Ph SO2Ph
SO2Ph
SOPh
2.1. Preparation of sulfur-substituted dihydro-
2-pyridones and 2-pyridones
N
Ts
O
N
Ts
O
N
Ts
O
N
Ts
O
Reaction of 3-(phenylthio)-3-sulfolene (3)33,34 with p-toluene-
sulfonyl isocyanate (PTSI) in toluene at 110 ꢀC in the presence
of 1 equiv of sodium bicarbonate and a catalytic amount of
hydroquinone (HQ) gave the cyclization product 4a, which
upon treatment with acid or base yielded the conjugated
dihydro-2-pyridone 5a (Eq. 1).28 If 4a was directly treated
with N-bromosuccinimide (NBS), the bromo intermediate 6
upon further reaction with triethylamine or pyrrolidine resulted
in the formation of 2-pyridone 7a (Eq. 2).31 Oxidation of
sulfides 4a, 5a, and 7a with suitable equivalents of m-CPBA
(Table 1) gave the corresponding sulfoxide 5c and sulfones
4b, 5b,28 and 7b31 in fair to excellent yields.
4b
5b
5c
7b
are shown in Figures 1 and 2.35 We suspected that the minor
product 10 might have derived from the reaction of 8a with
5b, which was isomerized from 4b in the reaction process.
We then subjected compound 4b to the same thermolysis con-
dition without diene 8a. Indeed, we obtained a mixture of 4b
and 5b in a ratio of 93:7 (Eq. 3). We also carried out a similar
thermolysis of 5b, and found that the mixture of 4b and 5b
was obtained in 23:77 (Eq. 4). It is interesting to note that
heating 5b with 8a at 140 ꢀC for 24 h (entry 2) gave only prod-
uct 10 in good yield. Judging from the reaction temperatures
needed for the thermolysis, it is apparent that compound 5b
is more reactive than 4b, probably because the C]C double
bond of 5b is activated by two electron-withdrawing groups
whereas that of 4b is activated by only one group. In agree-
ment with this observation, although only a small amount of
5b was generated from 4b (Eq. 3), the ratio of product 10 to
9 (0.65) far exceeded that of 5b to 4b (0.08). On the other
hand, despite the fact that during the thermolysis of 5b with
diene 8a a significant amount of 4b was also generated
SPh
SPh
SPh
(5 eq)
N C O
acid
Ts
or base
HQ (cat.), NaHCO3 (1 eq)
Tol, 110 °C, 4.5 h
S
N
Ts
O
N
Ts
O
O2
5a (71%)
3
4a
ð1Þ
SPh
SPh
Table 2
Cycloaddition reactions of 2-pyridones 4b, 5b, 5c, and 7b with dienes 8
Br
Et3N (2 eq)
NBS (1.1 eq)
Tol, 110 °C, 2 h
4a
CH2Cl2, rt, 2 h
Entry
Pyridone
Dienea
Conditionsb
Product (yield %)
N
Ts
7a (43%)
O
N
Ts
6
O
1
4b
5b
5b
5b
5b
5c
5c
7b
7b
7b
7b
7b
7b
7b
8a
8a
8a
8b
8c
8a
8a
8a
8a
8b
8c
8c
8c
8c
160 ꢀC, 48 h
140 ꢀC, 24 h
140 ꢀC, 24 hc
160 ꢀC, 48 h
140 ꢀC, 24 h
140 ꢀC, 24 h
140 ꢀC, 24 hc
140 ꢀC, 24 h
140 ꢀC, 24 hc
160 ꢀC, 48 h
140 ꢀC, 24 h
80 ꢀC, 48 h
50 ꢀC, 96 h
rt, 1 weeke
9 (40), 10 (26)
10 (78)
10 (75)
2
3
ð2Þ
4
11 (75)
12 (80)
5
2.2. Cycloaddition reactions of sulfur-substituted
dihydro-2-pyridones and 2-pyridones
6
10 (83)
10 (82)
7
8
13 (70)
13 (68)
14 (71)
9
We have studied the cycloaddition reactions of dihydro-
2-pyridones 4b, 5b, 5c, and 2-pyridone 7b with some
electron-rich dienes 8, which include 1-methoxy-3-trimethyl-
silyloxy-1,3-butadiene (8a), 2,3-dimethyl-1,3-butadiene (8b),
and cyclopentadiene (8c). Most of the cycloaddition reactions
were carried out in a sealed tube using toluene as the solvent,
and the results are shown in Table 2. After a few trials of
reaction conditions, it was found that thermolysis of vinyl sul-
fone 4b with Danishefsky’s diene (8a) proceeded well at
160 ꢀC for 48 h (entry 1) to give a separable mixture of cyclo-
addition products 9 and 10. The X-ray structures of 9 and 10
10
11
12
13
14
a
15a (36), 15b (37)
15a (30), 15b (32)d
15a (19), 15b (22), 16 (29)
N.R.
Diene 8a was used in 3 equiv, and dienes 8bec were used in large excess.
All reactions were carried out in a sealed tube, using toluene as the solvent
b
unless stated otherwise.
c
After thermolysis, the reaction mixture was also treated with camphorsul-
fonic acid (CSA, 0.1 equiv) in THF at 80 ꢀC for 4.5 h.
d
Compound 7b (15%) was also recovered.
Neat 8c was used.
e

S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
1881
(Eq. 4), the higher reactivity of 5b together with lower reaction
C12
temperature (140 ꢀC in entry 2 instead of 160 ꢀC in entry 1)
led only to the formation of cycloaddition product 10 (entry
2). It is also worthwhile mentioning that cycloaddition reac-
tions of Danishefsky’s diene (8a) with dienophiles usually
require an acidic treatment (for example, camphorsulfonic
acid) to obtain the final product. However, in our studies we
found that this treatment was not necessary (compare entries
2 with 3, 6 with 7, and 8 with 9 in Table 2). To explain this
rather unusual result, using 5b as an example, we propose
that the initial cycloaddition product A could eliminate benz-
enesulfinic acid under thermolysis condition to form an inter-
mediate B. The sulfinic acid generated could further catalyze
the formation of intermediate C, which is then tautomerized
to product 10 (Scheme 1).
C11
C10
O4
C13
C9
N1
C8
S1
C15
O3
C14
O2
C16
O1
C1
C7
C2
C6
Me3SiO
OMe
8a
C4
8c
8b
C3
C5
SO2Ph
SO2Ph
SO2Ph
Figure 1. X-ray structure of 9.
Tol, sealed tube
160 °C, 48 h
+
ð3Þ
ð4Þ
N
Ts
4b
O
N
Ts
O
N
Ts
O
of the phenylsulfonyl group with the C-3 hydrogen, and did
not eliminate benzenesulfinic acid during the thermolysis.
Product 12 has the C]C double bond endo to the C]O
group. Vinyl sulfoxide 5c underwent the cycloaddition reac-
tion with Danishefsky’s diene (8a) under condition (entries 6
and 7) similar to sulfone 5b, and gave the same product 10
even in slightly higher yields. Apparently, in this reaction
benzenesulfinic acid was eliminated, which probably also cata-
lyzed the hydrolysis of cycloaddition intermediates to the
product 10 (similar to Scheme 1). Reactions of sulfone-
substituted 2-pyridone 7b with dienes 8a and 8b gave the
cycloaddition products 13 and 14, respectively, in good yields
(entries 8e10). The X-ray structures of compounds 13 and 14
are provided in Supplementary data.35 It is apparent that in
these two reactions 2-pyridone 7b, though bearing a diene
moiety, acted as a dienophile with the electron-rich dienes
5b (93 : 7)
4b
SO2Ph
SO2Ph
SO2Ph
Tol, sealed tube
160 °C, 48 h
+
N
Ts
O
N
Ts
O
N
Ts
O
5b
5b (23 : 77)
4b
The reaction of dihydro-2-pyridone 5b with dienes 8b and
8c (entries 4 and 5) gave the cycloaddition products 11 and 12,
respectively, in good yields. The X-ray structures of com-
pounds 11 and 12 are provided in Supplementary data.35 It
is interesting to note that product 11 retains the cis relationship
OH
O
PhO2S
PhO2S
N
Ts
O
N
Ts
O
N
Ts
O
N
Ts
O
9
10
12
11
OH
SO2Ph
SO2Ph
PhO2S
N
N
Ts
Ts
N
Ts
O
N
Ts
O
N
Ts
O
O
O
15a
16
15b
13
14

1882
S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
C15
C14
O1
S1
C16
N1
C2
C3
C13
C4
O4
C7
C9
C1
C6
O2
C12
C8
C10
C5
C11
O3
O5
C31
C18
C32
N2
C19
S2
C20
C22
C29
C30
C21
C17
O8
O6
C25
C26
C23
C24
C28
O7
C27
Figure 2. X-ray structure of 10.
The formation of 15a and 15b was quite surprising, because
we had expected that cyclopentadiene would react as a diene.
However, there are a few reports in the literature that cyclo-
pentadiene reacts as a dienophile with other dienes.14,36e38
The separated 15a and 15b, upon subjecting to the reaction
condition shown in entry 11, did not interconvert or decom-
pose. This means that compounds 15a and 15b were stable,
kinetic products. We also found that heating compound 16
in toluene at 140 ꢀC for 24 h gave a quantitative conversion
to a mixture of 15a and 7b (Eq. 5). Apparently, under this
reaction condition, compound 16 underwent a Cope rearrange-
ment to give compound 15a, as well as a cycloreversion to
give 2-pyridone 7b. The fact that compound 15b was not
obtained from Eq. 5 indicates that compound 7b did not react
with the small amount of cyclopentadiene generated from the
reaction (only 1 equiv, as opposed to large excess used in entry
11). Thus we propose the pathways for the reaction of com-
pound 7b with cyclopentadiene as shown in Scheme 2. At
low reaction temperature such as 50 ꢀC, cyclopentadiene can
react as a diene (path A) to form the cycloaddition product
16, which can undergo a Cope rearrangement at higher tem-
perature to give product 15a (not 15b), or revert back to the
starting material 7b. However, at higher reaction temperature,
cyclopentadiene preferentially reacts as a dienophile (path B)
to generate products 15a and 15b directly.
OSiMe3
SO2Ph
Me3SiO
OSiMe3
PhO2S
+
OMe
OMe
H
O
N
O
N
Ts
Ts
8a
5b
A
O
OH
H+
-PhSO2H
OMe
N
O
N
Ts
C
O
N
Ts
O
Ts
B
10
Scheme 1. Proposed mechanism for the formation of compound 10
from 5b.
8a and 8b. The reaction of 7b with cyclopentadiene (6c) at
140 ꢀC for 24 h (entry 11) gave a mixture of two regioisomeric
cycloaddition products 15a and 15b, which could be separated
by column chromatography. Carrying out the reaction of 7b
with 6c at 80 ꢀC for 48 h (entry 12) again led to the mixture
of 15a and 15b, together with some unreacted starting material
7b. However, if the reaction of 7b with 6c was performed at
50 ꢀC for 96 h (entry 13), a new product 16 was obtained
besides 15a and 15b. The X-ray structures of compounds
15a, 15b, and 16 are provided in Supplementary data.35
Both 15a and 15b have the C]C double bond endo to the
vinyl sulfone, but they differ in regiochemistry. If 7b was
stirred with neat cyclopentadiene at room temperature for 1
week (entry 14), no reaction was observed.
2.3. Semi-empirical calculations
In order to explain the reactivity of dienophiles 4b, 5b, 5c,
and 7b as well as the regioselectivity and stereoselectivity of
the cycloaddition reactions, we have used a semi-empirical

S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
1883
PhO2S
SO2Ph
Cope
rearr.
path A
(low T)
N
N
Ts
O
Ts
O
SO2Ph
16
15a
+
N
O
SO2Ph
SO2Ph
Ts
6c
path B
7b
+
N
(high T)
N
Ts
Ts
O
O
15a
15b
Scheme 2. Proposed pathways for the reaction of 7b with 6c.
LUMO of the dienophile. The HOMOdieneeLUMOdienophile
energy difference DE for different pairs of dienes and dieno-
philes is listed in Table 3. From the calculated DE values,
the reactivity order of dienophiles is predicted: 7b>5b>4b,
5c; the reactivity order of dienes would be: 8a>8b, 8c. Experi-
mentally, we found that compound 4b was significantly less
reactive than the other three dienophiles, and also that diene
8b was less reactive than 8a and 8c. To explain the regioselec-
tivity of the cycloaddition reaction, the LUMO-coefficients of
dienophiles 4b, 5b, 5c, and 7b and HOMO-coefficients of di-
enes 8a and 8c are calculated (Table 4). It can be seen that the
HOMO-coefficient of diene 8a at C-4 is much larger than that at
C-1. The LUMO-coefficients of compounds 5b, 5c, and 7b at
C-4 are larger than those at C-3. This indicates that the elec-
tron-withdrawing ability of the (TsN)C]O group attached to
C-3 is greater than that of the sulfur-substituent at C-4. Exper-
imentally, the regiospecific formation of cycloadducts 10 and
13 agrees with the theoretical calculation. For compound 4b,
the LUMO-coefficient at C-5 is much larger than that at C-4,
and the structure of cycloaddition product 9 is also in agree-
ment with this prediction. For the direct formation of
cycloaddition products 15a and 15b from compound 7b and
cyclopentadiene (path B in Scheme 2), the more favorable
SO2Ph
PhO2S
SO2Ph
Tol, sealed tube
140 °C, 24 h
+
N
Ts
N
O
N
Ts
O
Ts
O
16
7b (29 : 71)
15a
ð5Þ
PM3 method of HyperChem to calculate the HOMOeLUMO
energy differences and coefficients. As expected, the more
favorable interaction is between HOMO of the diene and
Table 3
Favorable HOMOdieneeLUMOdienophile energy difference DE calculated by
HyperChem PM3 method
Entry
Diene
Dienophile
DE (eV)
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8b
8b
8c
8c
4b
5b
5c
7b
5b
7b
5b
7b
7.40
7.33
7.40
7.23
8.23
8.13
8.23
8.14
Table 4
LUMO-coefficients of dienophiles 4b, 5b, 5c, and 7b and HOMO-coefficients of dienes 8a and 8c
Dienophile
LUMO-coefficients
C-3
C-4
C-5
C-6
4b
5b
5c
7b
0.0096
0.1886
0.2271
0.1889
0.0243
0.1524
0.2004
0.1869
0.1261
Diene
HOMO-coefficients
C-1
C-2
C-4
8a
8c
0.3825
0.1913
0.6454
0.1913
0.1372
SO2Ph
SO2Ph
SOPh
SO2Ph
3
4
4
4
4
1
4
OSiM3
5
1
2
3
3
4
N
O
N
O
N
O
6
N
O
Ts
Ts
Ts
Ts
OMe
8a
8c
4b
5b
5c
7b

1884
S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
Table 5
Calculated heat of formation (DHf) for cycloaddition products 12, 15a, 15b,
and 16
measured with a mass spectrometer Finnigan/Thermo Quest
MAT 95XL. X-ray crystal structures were obtained with an
Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD).
Elemental analyses were carried out with Heraeus Vario
III-NCSH, Heraeus CHN-O-S-Rapid Analyzer or Elementar
Vario EL III. Flash column chromatographic purifications
were performed using Merck 60H silica gel.
Compound
DHf (kcal/mol)
endo-12
exo-12
ꢁ67.895
ꢁ60.181
ꢁ74.366
ꢁ73.859
ꢁ74.430
ꢁ74.021
ꢁ46.222
ꢁ38.982
endo-15a
exo-15a
endo-15b
exo-15b
endo-16
exo-16
4.2. General procedure for the oxidation of sulfides
4a and 5a
To a solution of sulfide 4a or 5a (1.4 mmol) in CH2Cl2
(10 mL) in an ice bath was added slowly another solution of
m-CPBA (50%, 1.5 mmol for the preparation of 5c, or
5.2 mmol for the preparation of 4b) in CH2Cl2 (10 mL). The
mixture was then stirred at room temperature for 1.5 h, and
was washed sequentially with 5% Na2S2O3 and 5% NaHCO3,
dried (MgSO4), and evaporated. The crude product was purified
by flash chromatography using ethyl acetate/hexane (1:2) as el-
uent to give purified product 4b and 5c. Sufones 5b28 and 7b31
were prepared similarly.
interaction of the HOMO of cyclopentadiene at C-1 with the
LUMO of compound 7b at C-3 predicts that the major
regioisomer would be 15a. However, the amounts of 15a and
15b obtained experimentally (entries 11e13 in Table 2) were
about equal. We have also calculated the coefficients for
LUMO of cyclopentadiene and HOMO of 7b (not shown
in Table 4), which would again favor the formation of
product 15a.
We have also calculated the heat of formation (DHf) for
cycloaddition products 12, 15a, 15b, and 16 (Table 5) in order
to compare the relative stability of the endo and exo stereoiso-
mers. It can be seen that the endo isomers are all more stable
than the exo isomers. Experimentally, we have only obtained
the endo isomer for products 12, 15a, 15b, and 16. This means
that these endo isomers are either thermodynamic products or
formed faster.
4.2.1. 3,6-Dihydro-4-(phenylsulfonyl)-1-tosylpyridin-2(1H)-
one (4b)
White solid (CH2Cl2/hexane), mp 186e188 ꢀC; IR (film)
3055, 2920, 2855, 1702, 1447, 1355, 1308, 1283, 1253,
1
1169, 1146, 1089, 812, 724, 705, 686, 654 cmꢁ1; H NMR
(CDCl3, 300 MHz) d 7.90 (2H, d, J¼8.3 Hz), 7.84 (2H, d,
J¼7.4 Hz), 7.69e7.54 (3H, m), 7.31 (2H, d, J¼8.3 Hz),
7.07e7.05 (1H, m), 4.73e4.70 (2H, m), 3.14e3.11 (2H, m),
2.42 (3H, s); 13C NMR (CDCl3, 75 MHz) d 164.2, 145.7,
137.2, 135.4, 134.8, 134.3, 129.6, 129.4, 129.0, 128.8,
128.3, 47.2, 31.7, 21.6; FABMS (relative intensity) m/z 392
(MþþH, 58), 155 (76), 102 (95), 91 (100), 83 (28), 81 (31),
77 (34), 71 (31), 69 (49), 67 (34), 57 (64), 55 (73), 43 (63),
41 (53); FABHRMS m/z 392.0658 (MþþH, calcd for
C18H18NO5S2: 392.0626).
3. Conclusion
We have synthesized sulfoxide- and sulfone-substituted di-
hydro-2-pyridones 4b, 5b, 5c, and 2-pyridone 7b, and have
studied their cycloaddition reactions with electron-rich dienes
8. Several new bicyclic and tricyclic products 9e16 have been
obtained in good to fair yields. The sulfoxide or sulfone sub-
stituent not only increases the reactivity of the dienophiles, but
can also be readily eliminated when reacting with Danishef-
sky’s diene. Rather unusual two parallel reaction pathways
have been established for the cycloaddition reaction of 2-pyri-
done 7b with cyclopentadiene: cyclopentadiene reacts as
a diene at low temperature, but as a dienophile at high temper-
ature. The reactivity, regioselectivity, and stereoselectivity of
these cycloaddition reactions agree quite well with semi-
empirical theoretical calculations.
4.2.2. 5,6-Dihydro-4-(phenylsulfinyl)-1-tosylpyridin-2(1H)-
one (5c)
White solid (EtOAc/hexane), mp 175e176 ꢀC; IR (film)
3063, 2915, 2878, 1683, 1366, 1292, 1163, 1082, 688 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) d 7.90 (2H, d, J¼8.2 Hz), 7.64e
7.55 (5H, m), 7.33 (2H, d, J¼8.2 Hz), 6.54 (1H, s), 4.09e3.99
(2H, m), 2.44e2.38 (5H, m); 13C NMR (CDCl3, 75 MHz)
d 162.0, 160.9, 145.1, 140.2, 135.1, 132.3, 129.8, 129.4, 128.4,
125.1, 122.2, 44.0, 22.1, 21.5; EIMS (relative intensity) m/z
375 (Mþ, 0.1), 311 (51), 294 (16), 186 (30), 155 (31), 125
(12), 120 (30), 91 (100), 77 (13), 67 (18), 65 (19); HRMS
m/z 375.0604 (calcd for C18H17NO4S2: 375.0599). Anal.
Calcd for C18H17NO4S2: C, 57.58; H, 4.56; N, 3.73; S, 17.08.
Found: C, 57.26; H, 4.57; N, 3.88; S, 17.02.
4. Experimental
4.1. General
Melting points were determined with a SMP3 melting ap-
paratus. Infrared spectra were recorded with a Perkin Elmer
1
1600 FTIR spectrometer. H and 13C NMR spectra were re-
corded on a Bruker Avance 300 spectrometer operating at
300 and 75 MHz, respectively. 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
4.3. General procedure for the cycloaddition reaction
To a mixture of 2-pyridone 4b, 5b, 5c, or 7b (0.26 mmol) in
dried toluene (3 mL) was added diene 8a (0.78 mmol), 8b, or

S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
1885
8c (1 mL). The mixture was heated in a sealed tube (see Table
4.3.4. endo-4-Aza-7-benzensulfonyl-4-tosyl-tricyclo-
2 for the reaction condition). After cooling to room tempera-
ture, the solvent was removed under vacuum and the crude
product was purified by flash chromatography using ethyl
acetate/hexane as eluent.
[6.2.1.02,7]undec-9-en-3-one (12)
White solid (EtOAc/hexane), mp 154e156 ꢀC; IR (film)
3062, 2988, 2915, 1687, 1594, 1480, 1447, 1354, 1285,
;
1218, 1171, 1145, 901, 817, 728 cmꢁ1 1H NMR (CDCl3,
300 MHz) d 7.93e7.90 (2H, m), 7.80 (2H, d, J¼8.2 Hz),
7.78e7.61 (3H, m), 7.32 (2H, d, J¼8.2 Hz), 6.28 (1H, dd,
J¼5.2, 3.0 Hz), 6.11 (1H, dd, J¼5.2, 3.3 Hz), 4.19 (1H, ddd,
J¼13.2, 4.5, 3.0 Hz), 3.97 (1H, td, J¼12.6, 2.7 Hz), 3.63
(1H, d, J¼3.9 Hz), 3.50 (1H, br s), 2.97 (1H, d, J¼1.5 Hz),
2.45e2.35 (5H, m), 1.73 (1H, ddd, J¼16.8, 12.3, 4.8 Hz),
1.43 (1H, d, J¼6.2 Hz); 13C NMR (CDCl3, 75 MHz) d 169.4,
145.0, 140.6, 137.1, 136.1, 135.6, 134.4, 130.0, 129.5, 129.4,
128.5, 73.1, 51.1, 48.0, 47.3, 46.2, 43.3, 29.4, 21.7; EIMS (rel-
ative intensity) m/z 457 (Mþ, 0.1), 393 (81), 327 (44), 316
(63), 252 (94), 185 (58), 155 (61), 133 (49), 105 (44), 91
(100), 77 (62), 66 (60); HRMS m/z 457.1023 (calcd for
C23H23NO5S2 m/z 457.1018). Anal. Calcd for C23H23NO5S2:
C, 60.37; H, 5.07; N, 3.06. Found: C, 60.28; H, 5.04; N, 2.90.
4.3.1. 8,8a-Dihydro-2-tosylisoquinoline-3,7(1H,2H)-
dione (9)
Yellow solid (EtOAc), mp 192e194 ꢀC; IR (film) 3055,
2923, 2886, 1679, 1351, 1325, 1171, 1134, 905, 710,
665 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 7.95 (2H, d,
;
J¼8.2 Hz), 7.34 (2H, d, J¼8.2 Hz), 7.13 (1H, d, J¼9.8 Hz),
6.29 (1H, d, J¼9.8 Hz), 6.02 (1H, s), 4.67 (1H, dd, J¼11.4,
4.8 Hz), 3.42e3.28 (2H, m), 2.81 (1H, dd, J¼16.0, 5.7 Hz),
2.44 (3H, s), 2.28 (1H, dd, J¼16.0, 12.6 Hz); 13C NMR
(CDCl3, 75 MHz) d 195.2, 162.6, 148.1, 145.2, 141.6, 135.3,
133.3, 129.5, 128.6, 124.5, 48.6, 39.3, 32.9, 21.6; FABMS
(relative intensity) m/z 318 (MþþH, 100), 307 (101), 154
(55), 107 (24), 91 (56), 77 (31), 57 (25); FABHRMS m/z
318.0800 (MþþH, calcd for C16H16NO4S: 318.0800).
4.3.5. 6-Hydroxy-2-tosylisoquinolin-1(2H)-one (13)
White solid (CH2Cl2/EtOAc), mp 222e224 ꢀC; IR (film)
3446, 1646, 1359, 1171, 673 cmꢁ1 1H NMR (acetone-d6,
;
4.3.2. 3,4-Dihydro-6-hydroxy-2-tosylisoquinolin-1(2H)-
one (10)
300 MHz) d 9.12 (1H, s), 8.02 (2H, d, J¼8.2 Hz), 7.80 (1H,
d, J¼8.1 Hz), 7.59 (1H, d, J¼2.7 Hz), 7.56 (1H, d, J¼8.1 Hz),
7.46 (2H, d, J¼8.2 Hz), 7.29 (1H, dd, J¼8.7, 2.7 Hz), 6.69
(1H, d, J¼8.1 Hz), 2.44 (3H, s); 13C NMR (acetone-d6,
75 MHz) d 160.5, 158.4, 146.8, 135.8, 130.5, 130.4, 130.3,
129.4, 128.8, 124.3, 123.5, 112.5, 108.0, 21.6; FABMS (rela-
tive intensity) m/z 316 (MþþH, 100), 307 (18), 251 (59), 161
(48), 154 (82), 136 (76), 107 (30), 91 (53), 77 (34), 57 (20);
HRMS m/z 316.0652 (MþþH) (calcd for C16H14NO4S:
316.0644). Anal. Calcd for C16H13NO4S: C, 60.94; H, 4.16;
N, 4.44; S, 10.17. Found: C, 61.14; H, 4.04; N, 4.36; S, 9.81.
Yellow solid (CH2Cl2/EtOAc), mp 160e162 ꢀC; IR (film)
3439, 1661, 1609, 1340, 1281, 1244, 1163, 1119, 1086, 706,
1
662 cmꢁ1; H NMR (CDCl3, 300 MHz) d 7.95 (2H, d, J¼
8.4 Hz), 7.84 (1H, d, J¼8.7 Hz), 7.31 (2H, d, J¼8.4 Hz), 6.72
(1H, dd, J¼8.7, 2.1 Hz), 6.66 (1H, s), 6.22 (1H, br s), 4.19
(2H, t, J¼6.3 Hz), 3.04 (2H, t, J¼6.3 Hz), 2.41 (3H, s); 13C
NMR (CDCl3, 75 MHz) d 163.7, 161.0, 144.8, 142.0, 136.2,
131.7, 129.4, 128.4, 120.3, 115.1, 113.8, 44.8, 29.0, 21.6;
FABMS (relative intensity) m/z 318 (MþþH, 100), 307 (66),
289 (42), 253 (35), 219 (19), 186 (17), 154 (100), 136 (99),
107 (63), 91 (72), 89 (52), 77 (57), 57 (31); FABHRMS m/z
318.0796 (MþþH) (calcd for C16H16NO4S: 318.0800). Anal.
Calcd for C16H15NO4S: C, 60.55; H, 4.76; N, 4.41; S, 10.10.
Found: C, 60.60; H, 4.85; N, 4.43; S, 10.11.
4.3.6. 5,8-Dihydro-6,7-dimethyl-2-tosylisoquinolin-1(2H)-
one (14)
White solid (EtOAc/hexane), mp 210e211 ꢀC; IR (film)
3054, 2987, 1664, 1422, 1366, 1256, 1176, 896 cmꢁ1; 1H NMR
(CDCl3, 300 MHz) d 7.98 (2H, d, J¼8.2 Hz), 7.91 (1H, d,
J¼7.8 Hz), 7.33 (2H, d, J¼8.2 Hz), 6.04 (1H, d, J¼7.8 Hz),
3.08 (2H, t, J¼6.3 Hz), 2.93 (2H, t, J¼6.3 Hz), 2.43 (3H, s),
1.67 (6H, s); 13C NMR (CDCl3, 75 MHz) d 159.6, 146.6,
145.7, 133.9, 129.7, 129.4, 127.6, 126.9, 123.5, 120.6, 107.7,
36.6, 30.9, 21.7, 18.2, 17.9; FABMS (relative intensity) m/z
330 (MþþH, 100), 264 (25), 174 (55), 154 (63), 136 (58),
107 (30), 91 (50), 69 (49), 55 (42); FABHRMS m/z 330.1158
(MþþH) (calcd for C18H20NO3S: 330.1164).
4.3.3. 3,4,4a,5,8,8a-Hexahydro-6,7-dimethyl-4a-
(phenylsulfonyl)-2-tosylisoquinolin-1(2H)-one (11)
White solid (EtOAc/hexane), mp 137e138 ꢀC; IR (film)
3115, 3032, 1702, 1549, 1422, 1265, 896, 734 cmꢁ1; 1H NMR
(CDCl3, 300 MHz) d 7.94 (2H, d, J¼8.3 Hz), 7.76 (2H, d,
J¼8.4 Hz), 7.67e7.63 (1H, m), 7.54 (2H, t, J¼7.8 Hz), 7.32
(2H, d, J¼8.3 Hz), 4.21e4.13 (2H, m), 2.84 (1H, t, J¼
7.5 Hz), 2.45 (3H, s), 2.48e2.25 (5H, m), 1.94 (1H, d,
J¼16.8 Hz), 1.52 (3H, s), 1.47 (3H, s); 13C NMR (CDCl3,
75 MHz) d 170.9, 144.6, 135.4, 134.6, 134.3, 130.3, 129.1,
129.0, 128.6, 122.9, 121.2, 64.0, 43.6, 42.0, 35.9, 33.2, 24.9,
21.6, 18.7, 18.0; FABMS (relative intensity) m/z 474 (MþþH,
51), 332 (100), 176 (32), 155 (25), 133 (45), 91 (54), 77 (20);
FABHRMS m/z 474.1399 (MþþH) (calcd for C24H28NO5S2:
474.1409). Anal. Calcd for C24H27NO5S2: C, 60.86; H,
5.75; N, 2.96; S, 13.54. Found: C, 60.75; H, 5.48; N, 2.95; S,
13.25.
4.3.7. endo-8-Aza-10-benzenesulfonyl-8-tosyl-tricyclo-
[5.2.2.02,6]undec-4,10-dien-9-one (15a)
White solid (CH2Cl2/EtOAc), mp 200e202 ꢀC; IR (film)
3063, 2930, 2856, 1731, 1594, 1451, 1362, 1351, 1317,
1
1307, 1171, 1156, 1093, 747, 673 cmꢁ1; H NMR (CDCl3,
300 MHz) d 7.74 (2H, d, J¼8.1 Hz), 7.62e7.57 (3H, m),
7.41 (2H, t, J¼7.8 Hz), 7.27 (2H, d, J¼8.1 Hz), 7.21 (1H,
dd, J¼6.3, 2.1 Hz), 5.53 (1H, dd, J¼6.0, 3.6 Hz), 5.45 (1H,

1886
S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
dd, J¼5.4, 2.1 Hz), 3.62e3.59 (2H, m), 2.90e2.81 (1H, m),
2.58e2.46 (4H, m), 2.16e2.10 (1H, m); 13C NMR (CDCl3,
75 MHz) d 167.8, 145.1, 142.9, 139.9, 138.1, 136.7, 135.2,
134.0, 129.6, 129.4, 127.9, 127.8, 127.1, 55.8, 54.4, 50.7, 36.8,
35.3, 21.7; FABMS (relative intensity) m/z 456 (MþþH, 46),
447 (23), 391 (18), 327 (17), 299 (38), 289 (25), 265 (24),
207 (23), 154 (94), 149 (100), 105 (58), 57 (84); FABHRMS
m/z 456.0941 (MþþH) (calcd for C23H22NO5S2: 456.0939).
Anal. Calcd for C23H21NO5S2: C, 60.64; H, 4.65; N, 3.07;
S, 14.08. Found: C, 60.69; H, 4.44; N, 2.88; S, 14.28.
with this article can be found, in the online version, at
doi:10.1016/j.tet.2007.11.090.
References and notes
1. For a review, see: Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H.
Tetrahedron 1992, 48, 9111e9171.
2. For the synthesis of vinblastine-type alkaloids, see: Kuehne, M. E.;
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thus roseus (L.); Brossi, A., Suffness, M., Eds.; Academic: San Diego,
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3. For the synthesis of ibogaine-type alkaloids, see: Popik, P.; Skolnick, P.
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6124e6134.
4.3.8. endo-8-Aza-10-benzenesulfonyl-8-tosyl-tricyclo-
[5.2.2.02,6]undec-3,10-dien-9-one (15b)
White solid (CH2Cl2/EtOAc), mp 186e187 ꢀC; IR (film)
3063, 2923, 2849, 1727, 1359, 1322, 1171, 1156, 1089, 909,
1
735, 669 cmꢁ1; H NMR (CDCl3, 300 MHz) d 7.77 (2H, d,
5. Krow, G. R.; Cheung, O. H.; Hu, Z.; Huang, Q.; Hutchinson, J.; Liu, N.;
Nguyen, K. T.; Ulrich, S.; Yuan, J.; Xiao, Y.; Wypij, D. M.; Zuo, F.;
Carroll, P. J. Tetrahedron 1999, 55, 7747e7756.
J¼8.4 Hz), 7.67e7.58 (3H, m), 7.44 (2H, dt, J¼7.8, 1.5 Hz),
7.27 (2H, d, J¼8.4 Hz), 7.22 (1H, dd, J¼6.0, 2.4 Hz), 5.54e
5.49 (2H, m), 5.10 (1H, dd, J¼5.5, 2.2 Hz), 3.66 (1H, dd,
J¼2.7, 2.4 Hz), 3.33e3.29 (1H, m), 3.16e3.08 (1H, m),
2.57e2.46 (4H, m), 1.93e1.84 (1H, m); 13C NMR (CDCl3,
75 MHz) d 167.9, 145.9, 145.2, 138.1, 136.9, 135.3, 134.0,
133.0, 129.6, 129.3, 129.1, 128.2, 127.9, 56.2, 49.5, 48.2, 42.0,
35.5, 21.7; FABMS (relative intensity) m/z 456 (MþþH, 82),
447 (34), 425 (22), 390 (92), 383 (25), 327 (34), 307 (69), 299
(66), 289 (62), 265 (29), 219 (35), 205 (28), 183 (46), 165
(64), 154 (100), 149 (100), 137 (100); FABHRMS m/z
456.0947 (MþþH) (calcd for C23H22NO5S2: 456.0939).
6. Kato, H.; Fujita, R.; Hongo, H.; Tomisawa, H. Heterocycles 1979, 12,
1e4.
7. Tomisawa, H.; Kato, H.; Fujita, R.; Hongo, H. Chem. Pharm. Bull. 1979,
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12. Fujita, R.; Watanabe, K.; Nishiuchi, Y.; Honda, R.; Matsuzaki, H.; Hongo,
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4.3.9. endo-4-Aza-7-benzensulfonyl-4-tosyl-tricyclo-
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[6.2.1.02,7]undec-5,9-dien-3-one (16)
White solid (CH2Cl2/EtOAc), mp 145e146 ꢀC; IR (film)
3070, 2952, 1705, 1362, 1285, 1174, 1148, 1085, 735,
665 cmꢁ1; 1H NMR (CDCl3, 300 MHz) d 7.76e7.73 (2H, m),
7.57e7.38 (3H, m), 7.41 (2H, t, J¼7.8 Hz), 7.27 (2H, d, J¼
8.4 Hz), 6.72 (1H, d, J¼8.7 Hz), 6.20 (1H, dd, J¼5.5,
3.3 Hz), 6.08 (1H, dd, J¼5.5, 2.7 Hz), 5.20 (1H, d, J¼8.7 Hz),
3.77 (1H, d, J¼1.5 Hz), 3.55 (1H, d, J¼3.3 Hz), 3.49 (1H, br
s), 2.46 (3H, s), 2.39 (1H, d, J¼9.3 Hz), 1.87 (1H, d, J¼
9.3 Hz); 13C NMR (CDCl3, 75 MHz) d 166.5, 145.4, 138.8,
137.1, 136.7, 134.5, 133.8, 129.5, 129.4, 128.8, 128.4, 125.6,
104.4, 73.6, 51.2, 50.5, 49.5, 46.1, 21.7; FABMS (relative in-
tensity) m/z 456 (MþþH, 82), 390 (37), 314 (100), 155 (29),
91 (28), 77 (11); FABHRMS m/z 456.0931 (MþþH) (calcd
for C23H22NO5S2: 456.0939).
15. Vicario, J. L.; Badia, D.; Carrillo, L.; Etxebarria, J. Curr. Org. Chem.
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Acknowledgements
Financial support of this work by the National Science
Council of the Republic of China is gratefully acknowledged
(NSC 94-2113-M-030-005 and 95-2113-M-030-002).
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Supplementary data
A PDF file containing the X-ray crystal structures of com-
pounds 11e16 is provided. Supplementary data associated
32. Chou, S. S. P.; Liang, C. F.; Lee, T. M.; Liu, C. F. Tetrahedron 2007, 63,
8267e8273.

S.-S.P. Chou, P.-W. Chen / Tetrahedron 64 (2008) 1879e1887
1887
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CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
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35. Crystallographic data (excluding structure factors) for compounds 9e16
in this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication CCDC 668437-668445, respec-
tively. Copies of the data can be obtained, free of charge, on application to