A facile approach to polysubstituted 2-pyridones. Application to the synthesis of 3,4-disubstituted isoquinolinone and total synthesis of oxyisoterihanine

Article abstract of DOI:10.1016/j.tet.2007.06.101

A facile approach to polysubstituted 2-pyridones from 1-benzyl-5,6-dialkyl-3-(4-toluenesulfonyl)pyridin-2-one was described. A new approach to 3,4-disubstituted isoquinolinone and total synthesis of oxyisoterihanine will also be reported.

Full text of DOI:10.1016/j.tet.2007.06.101

Tetrahedron 63 (2007) 9825–9835
A facile approach to polysubstituted 2-pyridones. Application
to the synthesis of 3,4-disubstituted isoquinolinone
and total synthesis of oxyisoterihanine
Tsung-Hsiu Tsai,a Wen-Hsuan Chung,a Jung-Kai Chang,a Ru-Ting Hsub and Nein-Chen Changa,
*
aDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
bDepartment of Nursing, Shu-Zen College of Medicine and Management, Kaohsiung County 821, Taiwan
Received 5 June 2007; revised 27 June 2007; accepted 29 June 2007
Available online 10 July 2007
Abstract—A facile approach to polysubstituted 2-pyridones from 1-benzyl-5,6-dialkyl-3-(4-toluenesulfonyl)pyridin-2-one was described. A
new approach to 3,4-disubstituted isoquinolinone and total synthesis of oxyisoterihanine will also be reported.
Ó 2007 Elsevier Ltd. All rights reserved.
CF3
1. Introduction
R3
R4
Ts
O
R3
O
O
Ts
O
The 2-pyridone core is an important framework that can be
found in numerous biologically active compounds.1 It is
a common template utilized for the synthesis of a wide vari-
ety of nitrogen heterocycles such as pyridine, piperidine,
quinolizidine, and indolizidine alkaloids.2 Although a great
number of methods have been reported for the synthesis of
2-pyridones,3 the development of new and flexible
approach to polysubstituted 2-pyridones is still required.
During the course of our study of regioselective introduction
of substituent at C-6 carbonyl in 3-sulfonyl glutarimides 1,4
the resulting exo or endo enlactams 2 have been successfully
converted to L-733,060 3, CP-99,994 4, and cassine 55
(Fig. 1). We envisioned that this result can be further applied
to the synthesis of polysubstituted 2-pyridones.
CF3
N
H
Ph
N
N
R1
R1
3. L-733,060
1
2
OH
H
O
N
N
CH3
10
OCH3
H
N
H
Ph
5. Cassine
4. CP-99,994
Figure 1. The application of exo or endo enlactams to L-733,060 3, CP-
99,994 4 and cassine 5.
2. Results and discussion
Table 1. Synthesis of 3,6-disubstituted and 3,5,6-trisubstituted 2-pyridones
7 from 2
2.1. Synthesis of polysubstituted 2-pyridones
R1
Ts
O
R3
R4
3
5
Ts
O
R3
R4
R1
O
R3
R4
NaOMe
1) NaH
2) R1X
We first examined the synthesis of 3,6-disubstituted and
3,5,6-trisubstituted 2-pyridones. Alkylation of enlactam 2
at C-3 position followed by dehydrosulfonation with sodium
methoxide furnished the desired 2-pyridones 7. Some repre-
sentative examples are listed in Table 1.
6
N
N
N
Bn
Bn
Bn
6
7
2
Entry
R1
R3
R4
Yield (%)
7a
7b
7c
7d
Me
Bn
Me
Me
H
H
Me
Me
Et
Et
Me
Et
86
80
85
81
Keywords: 2-Pyridones; Isoquinolinone; Benzo[c]phenanthridine; Oxyiso-
terihanine.
* Corresponding author. Tel.: +886 7 525 2000 3914; fax: +886 7 525 3913;
e-mail: ncchang@mail.nsysu.edu.tw
All yields are based on compound 2.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.101

9826
T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
We next investigated the synthesis of 4,5,6-trisubstituted
10 and tetrasubstituted 2-pyridone 11. We envisioned that
3-sulfonyl-2-pyridone 8 might be a reasonable precursor
for the synthesis of these compounds. 2-Pyridones 8 was
easily accomplished by oxidation of enlactam 2 with DDQ
(Table 2).
C-6 position might promote the proton migration and elim-
ination (Scheme 2). The synthesis of 4,5,6-trisubstituted
2-pyridone was demonstrated by the conversion of 9a to
10a. Removing the tosyl group on 9a with sodium amalgam
followed by oxidation of the resulting enlactam with DDQ
yielded 10a in 80%. Alkylation of 9 followed by dehydrosul-
fonation with DBU provided the corresponding tetrasubsti-
tuted 2-pyridones 11.7 Some examples are listed in Table
4. It is noteworthy that 2-pyridones 11c contained four
different substituents.
Table 2. Synthesis of 5,6-disubstituted 2-pyridone 8 from 2
R3
R4
Ts
R3
Ts
DDQ
toluene, reflux
O
N
O
N
R4
Bn
8
Bn
2
H
H
Ts
O
Ts
EtMgBr
70%
8c
Entry
R3
R4
Yield (%)
N
Bn
Ph
O
N
Bn
Ph
O
N
Bn
Ph
8a
8b
8c
8d
Me
Me
Me
Bn
Me
Et
Ph
Me
85
90
81
88
10e
Scheme 2. Proposed mechanism for the formation of 8c to 10e.
Table 4. Synthesis of tetrasubstituted 2-pyridones 11 from 9
R2
R2
R3
R4
R1
O
R3
R4
R1
R2
R3
R4
Yield (%)
Ts
O
R3
R4
Entry
11a
11b
11c
11d
Me
Me
Allyl
Me
Me
Me
Ph
Et
Me
Me
Me
Bn
Me
Et
Et
Me
95
93
90
92
O
N
Bn
10
N
Bn
11
N
Bn
8
All yields are based on compound 9.
With desired 2-pyridone 8 in hand, we investigated the intro-
duction of substituent at C-4 position. Treatment of 8 with
3 equiv of Grignard reagents furnished 1,4-addition product
2.2. A new approach to isoquinolinone skeleton 14
9
6b in all substrates except 8c (Scheme 1 and Table 3).
To demonstrate the synthetic potential of these results, a new
approach to isoquinolinone skeleton was tested. As shown in
Scheme 3, 1,4-addition of an allylmagnesium bromide to 8b
followed by allylation furnished diallyl enlactam 12. Per-
forming ring-closing metathesis reaction on 12 with first
generation Grubbs catalyst followed by dehydrosulfonation
produced isoquinolinone 14. Presumably, after dehydrosul-
fonation of 12, the resulting 13 oxidized spontaneously to
form isoquinolinone 14.
R2
R2
R2MgBr
Ts
O
R3
R4
R3
R4
8
+
N
Bn
9
O
N
Bn
10
1) NaH / R1X
2) DBU
1) Na/Hg
2) DDQ
R2
R1
O
R3
R4
N
Ts
1)
MgBr
1) RCM, CH2Cl2
Bn
11
Ts
2) t-BnOK, t-BuOH
2) NaH/
O
N
Bn
O
N
Bn
Br
reflux, 81%
67%
Scheme 1. Synthesis of 4,5,6-trisubstituted 2-pyridones 10 and tetrasubsti-
tuted 2-pyridones 11 from 8.
8b
12
We were slightly surprised to obtain 10e as the major product
during the reaction. It indicated that proton exchange oc-
curred after 1,4-addition. The presence of phenyl group at
O
N
O
N
Bn
Bn
14
Table 3. Ratio of compounds 9 and 10
13
Entry R2
R3
R4
Reaction time (h) Yield (%) 9:10
Scheme 3. Synthesis of isoquinolinone 14.
a
b
c
d
e
Me
Me
Ph
Me Me 24
70
75
70
73
81
70:0
75:0
70:0
73:0
30:70
Me Et
Me Et
24
24
24
24
2.3. Synthesis of benzo[c]phenanthridine nucleus
Vinyl Me Et
Et Me Ph
Encouraged by the successful construction of isoquinolinone
skeleton, we further investigated the possibility of building
All yields are based on compound 8.

T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
9827
up the core structure of benzo[c]phenanthridine alkaloids
distributed in Papaveraceous and Rutaceous plants.8 The al-
kaloids have attracted considerable attention from synthetic
organic chemists and biochemists over the last two decades
due to their unique structure and biological activity.9 Oxy-
terihanine 15a, a phenolic benzo[c]phenanthridine, was
isolated from Xanthoxylum nitidum (Roxb.) D. C. (Fagara
nitida Roxb.) in 1984.9c The structures of 15a and 15b
were further confirmed by Ishii et al. (Fig. 2).10b Our strategy
for the synthesis of 15 was shown in Scheme 4. The core
structure of 15b was envisaged to arise from tricyclic pyri-
done derivative 16 via the procedures developed above. Pyri-
done 16 was predicted to derive from enlactam 17 through
Friedel–Crafts reaction. Enlactam 17 was anticipated to
arise from [3+3] cycloaddition adduct 18.
trifluoride yielded Friedel–Crafts reaction and aromatization
product 22. Oxidation of 22 with DDQ furnished the desired
tricyclic pyridone 16.
O
O
O
O
Ts
O
Ts
O
H2 , Ra/Ni
[3+3]
OAc
+
THF, r.t.
(95%)
NaH, THF
(78%)
NH
CH3
19
N
CH3
O
O
MeO
O
20
18
1) NaH
2)
Br
O
O
O
O
O
3) Ac2O
4) Et3N, MeOH
Ts
Ts
O
, Mg
BF
3 OEt2
CH2Cl2
(93%)
6
To test the strategy toward 15b, we first set out to synthesize
tricyclic pyridone derivative 16 (Scheme 5). Following the
method developed in our laboratory,4 reaction of a-sulfonyl
acetamide 19 with Baylis–Hillman adduct 20 furnished
[3+3] annulation product glutarimide 18 in 78% yield. Hy-
drogenation of 18 in the presence of Ra/Ni gave 21 in 95%
yield. Regioselective addition of aryl group at C-6 position
in 21 followed by dehydration of the resulting hydroxylac-
tam produced enlactam 17.5 Exposure of 17 to boron
O
N
CH3
N
O
CH3
)
(65%
O
O
17
21
Ts
O
Ts
O
DDQ
N
CH3
N
CH3
Toluene, reflux.
(83%)
O
O
O
O
22
16
OR2
Scheme 5. Synthesis of tricyclic pyridone 16.
9
R1O
8
7
10
A
11
C
With required 16 in hand, the next task was to build the
fourth ring on 16. Following the procedures described in
Scheme 6, tetracyclic enlactam 256a was prepared in 84%
from 16. To accomplish the synthesis of the core skeleton
of benzo[c]phenanthridine, enlactam 25 was dehydrosulfo-
nated with DBU, and the resulting 26 was oxidized with
DDQ, which afforded the desired 27 in 92% yield for two
steps sequence.
12
B
6
1
N
5
O
N
D
2
4
O
3
O
oxyterihanine 15a R1=H, R2=Me
benzo[c]phenanthridine
oxyisoterihanine 15b R1=Me, R2=H
Figure 2. The core structure of benzo[c]phenanthridine alkaloids.
2.4. Total synthesis of oxyisoterihanine 15b
OH
O
The synthesis of oxyisoterihanine 15b was carried out as de-
picted in Scheme 7. Oxidation of 25 with m-CPBA furnished
epoxide 286c in 94% yield. Exposure of 28 in methanol and
dichloromethane in the presence of boron trifluoride af-
forded 29 in 85% yield. The structure of 29 was unequivo-
cally established by single-crystal X-ray analysis (Diagram
1).6a Finally, Swern oxidation of 29 furnished ketone 30,
which was further dehydrosulfonated with DBU to afford
15b in 65% yield. The spectral data of 15b were in agree-
ment with those reported in the literature.10
Ts
O
N
O
N
CH3
CH3
O
O
O
Oxyisoterihanine 15b
O
16
O
O
O
O
Ts
O
Ts
[3+3]
N
O
N
CH3
O
3. Conclusion
CH3
O
17
18
O
In conclusion, we have disclosed an efficient and regiocon-
trolled synthesis of polysubstituted 2-pyridones. Starting
from readily available glutarimides, the substituents can be
introduced to glutarimides or the corresponding 2-pyridones
in different stages at desired positions to form substituted
2-pyridones. Synthesis of isoquinolinone 14 was accom-
plished, which provided a potential new approach to isoqui-
nolinone derivatives with different substituents at C-3 and
C-4 positions. New approach to the core skeleton of
O
O
Ts
O
+
OAc
NH
MeO
O
CH3
20
19
Scheme 4. Retrosynthesis of oxyisoterihanine 15b.

9828
T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
Ts
O
Ts
MgBr
Br
Ts
O
RCM
N
CH3
N
CH3
O
N
CH3
THF
NaH, THF
(94%)
CH2Cl2 , r.t.
(96%)
(98%)
O
O
O
O
H
O
O
16
23
24
DBU
DDQ
THF, reflux.
(99%)
Ts
O
THF, 60 °C
O
N
CH3
O
N
N
CH3
(93%
)
CH3
O
O
O
O
O
O
25
26
27
Scheme 6. Synthesis of benzo[c]phenanthridine 27.
OH
O
MeO
H
H
H
m-CPBA
CH2Cl2, r.t.
BF3 OEt2
CH2Cl2, MeOH
(85%)
Ts
O
Ts
O
Ts
O
N
CH3
N
CH3
N
CH3
(94%)
O
O
O
O
O
25
28
O
29
OH
O
MeO
MeO
H
DBU
Swern ox.
Ts
O
THF, reflux.
(65%, 2 steps)
O
N
CH3
N
CH3
30
Scheme 7. Completion of the total synthesis of oxyisoterihanine 15b.
O
O
O
Oxyisoterihanine 15b
O
benzo[c]phenanthridine was developed. Total synthesis of
oxyisoterihanine 15b was accomplished. Further application
of these results to the synthesis of polysubstituted pyridines,
tri and tetracyclicquinoline and isoquinoline alkaloids are
underway in our laboratory.
4. Experimental
4.1. General
Melting points were determined with melting point appara-
tus and were uncorrected. 1H NMR and 13C NMR were re-
corded on Varian VRX 500 spectrometer. NMR spectra
were recorded in CDCl3 (1H NMR at 500 MHz and 13C
NMR at 125 MHz), and chemical shifts are expressed in
parts per million (d) relative to internal Me4Si.
OH
MeO
Ts
O
N
CH3
Tetrahydrofuran was distilled prior to use. All other reagents
and solvents were obtained from commercial sources and
were used without any further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen
with magnetic stirring. Solutions of products in organic sol-
vents were dried with anhydrous magnesium sulfate before
concentration under vacuum.
O
O
29
4.2. Synthesis of polysubstituted 2-pyridones
4.2.1. General procedure for the preparation of 5,6-di-
substituted-D-enlactams (2). A solution of glutarimide 1
(387 mg, 1 mmol) in dry THF (5 mL) was added to a rapidly
stirred suspension of sodium hydride (60 mg, 1.5 mmol,
Diagram 1. X-ray crystallography of 29.

T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
9829
60%) in tetrahydrofuran (20 mL). The reaction mixture
was stirred at room temperature for 15 min, methylmagne-
sium bromide (1.3 mmol) was added in one portion and
further stirred at room temperature for 30 min, then
quenched with acetic anhydride (122.4 mg, 1.2 mmol) and
the reaction mixture was stirred for an additional 30 min.
After the reaction was completed, the reaction mixture was
quenched with a saturated ammonium chloride solution
(1 mL), filtered through Celite. The organic layer was
extracted with ethyl acetate (3ꢀ20 mL), dried, filtered, and
concentrated. The crude product was purified by silica gel
chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to
afford 2.
4.2.2.4. 1-Benzyl-6-ethyl-3,5-dimethylpyridin-2-one
(7d). Yield 89%; yellow oil; H NMR (500 MHz, CDCl3)
1
d 7.29–7.22 (m, 5H), 7.10 (s, 1H), 7.09 (d, J¼6.0 Hz, 2H),
5.41 (br s, 2H), 2.56 (q, J¼7.5 Hz, 2H), 2.16 (s, 3H), 2.07 (s,
3H), 1.09 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 163.4, 144.8, 140.8, 137.5, 128.6 (2C), 127.0, 126.2 (2C),
126.1, 112.0, 76.8, 47.1, 23.0, 17.2, 12.6; HRMS (ESI,
M++1) calcd for C16H20NO 242.1545, found 242.1546.
4.2.3. General procedure for the preparation of 5,6-di-
substituted pyridin-2-one (8). DDQ (1.2 mmol) was added
to a solution of 5,6-disubstituted-D-enlactams 2 (1 mmol) in
toluene (20 mL). After the reaction mixture was stirred at re-
fluxing temperature for 10 h, 10% NaOH (1 mL) was added
to destroy the remaining DDQ and filtered through Celite.
The organic layer was extracted with dichloromethane
(3ꢀ20 mL), dried, filtered, and concentrated. The crude
product was purified by silica gel chromatography (dichloro-
methane/methanol¼100:1) to afford 8.
4.2.2. General procedure for the preparation of 3,6-di-
substituted pyridin-2-one and 3,5,6-trisubstituted pyr-
idin-2-one (7). A solution of enlactam 2 (1 mmol) in dry
THF (5 mL) was added to a rapidly stirred suspension of
sodium hydride (1.5 mmol, 60%) in tetrahydrofuran
(20 mL). After the reaction mixture was stirred at room
temperature for 15 min, alkyl halide (1.1 mmol) was added.
The reaction was completed, the reaction mixture was
quenched with a saturated ammonium chloride solution
(1 mL) and filtered through Celite. The organic layer was
extracted with ethyl acetate (3ꢀ20 mL), dried, filtered, and
concentrated. The crude product was purified by silica gel
chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to
afford 6. Sodium methoxide (1.1 mmol) was added to a rap-
idly stirred solution of 6 in THF (20 mL) at room tempera-
ture. After the reaction was accomplished (monitored by
TLC), the reaction mixture was quenched with water
(2 mL) and filtered through Celite. The organic layer was
extracted with ethyl acetate (3ꢀ20 mL), dried, filtered, and
concentrated. The crude product was purified by silica gel
chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to
afford 7.
4.2.3.1. 1-Benzyl-5,6-dimethyl-3-(4-toluenesulfonyl)-
pyridin-2-one (8a). Yield 85%; yellow oil; 1H NMR
(500 MHz, CDCl3) d 8.25 (s, 1H), 8.00 (d, J¼7.5 Hz, 2H),
7.3 (d, J¼8.0 Hz, 2H), 7.27–7.23 (m, 3H), 7.02 (d, J¼
7.5 Hz, 2H), 5.32 (br s, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.16
(s, 3H); 13C NMR (125 MHz, CDCl3) d 157.7, 151.5, 144.5,
144.0, 137.1, 135.3, 129.2 (2C), 128.9 (4C), 127.6, 126.6,
126.4 (2C), 112.5, 47.8, 21.6, 18.2, 17.6; HRMS (ESI,
M++1) calcd for C21H22NO3S 368.1320, found 368.1318.
4.2.3.2. 1-Benzyl-6-ethyl-5-methyl-3-(4-toluenesulfon-
yl)pyridin-2-one (8b). Yield 90%; yellow oil; H NMR
1
(500 MHz, CDCl3) d 8.24 (s, 1H), 8.09 (d, J¼7.5 Hz, 2H),
7.30 (d, J¼7.5 Hz, 2H), 7.26–7.20 (m, 3H), 6.98 (d,
J¼6.5 Hz, 2H), 5.32 (br s, 2H), 2.61 (q, J¼8.0 Hz, 2H),
2.41 (s, 3H), 2.19 (s, 3H), 1.089 (t, J¼8.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 157.7, 156.4, 145.0, 144.0,
137.0, 135.8, 129.2 (2C), 129.0 (2C), 128.9 (2C), 127.5,
126.8, 126.2 (2C), 112.0, 47.2, 24.0, 21.6, 17.2, 11.8;
HRMS (ESI, M++1) calcd for C22H24NO3S 382.1477, found
382.1477.
4.2.2.1. 1-Benzyl-6-ethyl-3-methylpyridin-2-one (7a).
Yield 77%; yellow oil; H NMR (500 MHz, CDCl3) 7.31–
1
7.20 (m, 6H), 7.11 (d, J¼8.0 Hz, 2H), 5.99 (d, J¼7.0 Hz,
1H), 5.39 (br s, 2H), 2.55 (q, J¼8.0 Hz, 2H), 2.17 (s, 3H),
1.17 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
164.1, 148.5, 137.0, 136.5, 128.7 (2C), 127.1, 126.4, 126.3
(2C), 104.0, 46.6, 25.7, 17.3, 12.5; HRMS (ESI, M++1)
calcd for C15H18NO 228.1388, found 228.1390.
4.2.3.3. 1-Benzyl-5-methyl-6-phenyl-3-(4-toluenesul-
fonyl)pyridin-2-one (8c). Yield 81%; yellow oil; 1H NMR
(500 MHz, CDCl3) d 8.36 (s, 1H), 8.07 (d, J¼8.5 Hz, 2H),
7.42–7.07 (m, 8H), 6.85 (d, J¼7.0 Hz, 2H), 6.63 (d,
J¼7.0 Hz, 2H), 5.01 (br s, 2H), 2.44 (s, 3H), 1.81 (s, 3H);
13C NMR (125 MHz, CDCl3) d 157.2, 153.6, 144.7, 144.2,
136.9, 136.2 (2C), 133.0, 129.6, 129.2 (2C), 129.1 (2C),
128.9 (2C), 128.3 (2C), 128.0 (2C), 127.2, 126.9 (2C),
113.4, 49.2, 21.7, 17.9; HRMS (ESI, M++1) calcd for
C26H24NO3S 430.1477, found 430.1479.
4.2.2.2. 1,3-Dibenzyl-6-ethylpyridin-2-one (7b). Yield
68%; yellow oil; H NMR (500 MHz, CDCl3) d 7.31–7.20
1
(m, 8H), 7.10 (d, J¼7.0 Hz, 2H), 6.99 (d, J¼8.0 Hz, 1H),
5.98 (d, J¼7.0 Hz, 1H), 5.39 (br s, 2H), 3.89 (s, 2H), 2.55
(q, J¼7.5 Hz, 2H), 1.15 (t, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 163.5, 149.0, 140.0, 136.9, 136.4,
129.9, 128.4 (2C), 128.7 (2C), 128.4 (2C), 127.1, 126.2
(2C), 126.1, 104.0, 46.7, 36.7, 25.7, 12.4; HRMS (ESI,
M++1) calcd for C21H22NO 304.1701, found 304.1699.
4.2.3.4. 1,5-Dibenzyl-6-methyl-3-(4-toluenesulfonyl)-
pyridin-2-one (8d). Yield 88%; yellow oil; 1H NMR
(500 MHz, CDCl3) d 8.30 (s, 1H), 8.01 (d, J¼9.0 Hz, 2H),
7.32–7.25 (m, 8H), 7.07 (d, J¼7.5 Hz, 2H), 7.01 (d,
J¼8.0 Hz, 2H), 5.32 (br s, 2H), 3.87 (s, 2H), 2.42 (s, 3H),
2.21 (s, 3H); 13C NMR (125 MHz, CDCl3) d 157.7, 152.6,
144.6, 144.1, 138.5, 136.9, 135.1, 129.2 (2C), 129.0 (2C),
128.9 (2C), 18.9 (2C), 127.9 (2C), 127.6, 127.0, 126.8,
126.3 (2C), 115.7, 47.9, 37.8, 21.6, 17.7; HRMS (ESI,
M++1) calcd for C27H26NO3S 444.1633, found 444.1635.
4.2.2.3. 1-Benzyl-3,5,6-trimethylpyridin-2-one (7c).
Yield 87%; yellow oil; 1H NMR (500 MHz, CDCl3)
d 7.31–7.10 (m, 6H), 5.41 (br s, 2H), 2.18 (s, 2H), 2.17 (s,
3H), 2.05 (s, 3H); 13C NMR (125 MHz, CDCl3) d 163.5,
140.5, 139.7, 137.0, 128.7 (2C), 128.5, 127.1, 126.4 (2C),
112.4, 47.7, 18.0, 17.2, 16.4; FAB C15H17NO, m/z (%)¼91
(100.0), 228 (M++1, 15.3).

9830
T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
4.2.4. General procedure for the preparation of 4,5,6-tri-
substituted pyridin-2-one (9). Grignard reagent (1.3 mmol)
was added to a solution of compound 8 (1 mmol) in dry THF
(5 mL) at room temperature. After the reaction was accom-
plished (monitored by TLC), the reaction mixture was
quenched with water (2 mL) and filtered through Celite.
The organic layer was extracted with ethyl acetate (3ꢀ
20 mL), dried, filtered, and concentrated. The crude product
was purified by silica gel chromatography (n-hexane/ethyl
acetate¼4:1 to 2:1) to afford 9.
yellow oil; 1H NMR (500 MHz, CDCl3) d 7.83 (d,
J¼8.0 Hz, 2H), 7.38–6.92 (m, 12H), 5.05 (d, J¼15.0 Hz,
1H), 3.99 (d, J¼15.0 Hz, 1H), 3.95 (s, 1H), 2.89 (t,
J¼7.5 Hz, 1H), 2.47 (s, 3H), 1.66 (s, 3H), 1.59–1.52 (m,
1H), 1.40–1.34 (m, 1H), 0.93 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 161.8, 145.0, 137.4, 136.6, 134.4,
134.2, 129.8 (3C), 128.6 (3C), 128.2, 128.1 (3C), 128.0
(3C), 127.1, 117.6, 70.7, 47.1, 40.0, 25.0, 21.7, 19.3, 11.4;
HRMS (ESI, M++1) calcd for C28H30NO3S 460.1946, found
460.1950.
4.2.4.1.
1-Benzyl-4,5,6-trimethyl-3-(4-toluenesul-
4.2.5. General procedure for the preparation of 4,5,6-tri-
substituted pyridin-2-one (10). Sodium amalgam (Na/Hg,
3.0 g) and sodium phosphate (40 mg) were added to a stirred
solution of 9 (1 mmol) in methanol (20 mL) and vigorously
stirred for 2 h at room temperature. The residue was filtered
and washed with methanol (2ꢀ10 mL). The combined or-
ganic layers were concentrated to obtain the crude product.
After the crude product was purified by silica gel chromato-
graphy (n-hexane/ethyl acetate¼4:1 to 2:1), to afford the
desulfonation product, which then dissolved in toluene
(10 mL), DDQ (2 equiv) was added and stirred at refluxing
temperature for 10 h. After the reaction was accomplished
(monitored by TLC), the reaction mixture was quenched
with water (2 mL) and filtered through Celite. The organic
layer was extracted with ethyl acetate (3ꢀ20 mL), dried,
filtered, and concentrated. The crude product was purified
by silica gel chromatography (n-hexane/ethyl acetate¼4:1
to 2:1) to afford 10.
fonyl)-3,4-dihydropyridin-2-one (9a). Yield 70%; yellow
oil; 1H NMR (500 MHz, CDCl3) d 7.73 (d, J¼8.5 Hz, 2H),
7.32–7.22 (m, 7H), 5.13 (d, J¼16.0 Hz, 1H), 4.49 (d, J¼
16.0 Hz, 1H), 3.85–3.84 (m, 1H), 2.96 (dd, J¼6.5,
14.0 Hz, 1H), 2.43 (s, 3H), 1.73 (s, 3H), 1.60 (s, 3H), 1.05
(d, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 161.4,
144.9, 137.7, 136.1, 129.4 (2C), 128.8 (2C), 128.7 (2C),
128.3, 127.2, 126.9 (2C), 115.1, 72.9, 45.8, 33.4, 21.7,
17.6, 17.5, 14.5; HRMS (ESI, M++1) calcd for
C22H26NO3S 384.1633, found 384.1636.
4.2.4.2. 1-Benzyl-6-ethyl-4,5-dimethyl-3-(4-toluene-
sulfonyl)-3,4-dihydropyridin-2-one (9b). Yield 75%; yel-
1
low oil; H NMR (500 MHz, CDCl3) d 7.75 (d, J¼8.5 Hz,
2H), 7.33–7.23 (m, 7H), 5.20 (d, J¼15.5 Hz, 1H), 4.53 (d,
J¼15.5 Hz, 2H), 3.80 (s, 1H), 2.95 (q, J¼7.5 Hz, 1H), 2.42
(s, 3H), 2.32–2.24 (m, 1H), 2.18–2.11 (m, 1H), 1.04–0.98 (m,
6H); 13C NMR (125 MHz, CDCl3) d 161.8, 144.9, 137.8,
136.4, 133.4, 129.7 (2C), 128.6 (2C), 128.5 (2C), 127.1,
127.0 (2C), 115.4, 72.4, 45.5, 32.9, 21.7, 21.0, 17.5, 17.3,
12.3; HRMS (ESI, M++1) calcd for C23H28NO3S 398.1790,
found 398.1792.
4.2.5.1. 1-Benzyl-4-ethyl-5-methyl-6-phenylpyridin-2-
one (10e). Yield 70%; yellow oil; 1H NMR (500 MHz,
CDCl3) d 7.37–7.30 (m, 3H), 7.16–7.14 (m, 4H), 6.95 (d,
J¼7.0 Hz, 2H), 6.82–6.80 (m, 2H), 5.08 (br s, 2H), 2.67
(q, J¼7.5 Hz, 2H), 1.75 (s, 3H), 1.27 (t, J¼7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 162.4, 143.3, 138.1, 137.7,
134.5, 133.7, 129.3 (2C), 128.7, 128.5 (2C), 128.1 (2C),
126.9 (2C), 126.7, 113.4, 49.1, 23.8, 17.9, 12.7; HRMS
(ESI, M++1) calcd for C21H21NO 304.1701, found
304.1698.
4.2.4.3. 1-Benzyl-6-ethyl-5-methyl-4-phenyl-3-(4-tolu-
enesulfonyl)-3,4-dihydropyridin-2-one (9c). Yield 70%;
yellow oil; 1H NMR (500 MHz, CDCl3) d 7.80 (d, J¼
8.5 Hz, 2H), 7.34–7.18 (m, 10H), 7.01–7.00 (m, 2H), 5.22
(d, J¼15.5 Hz, 1H), 4.58 (d, J¼15.5 Hz, 1H), 4.21 (s, 1H),
4.09 (s, 1H), 2.48–2.42 (m, 1H), 2.44 (s, 3H), 2.38–2.33
(m, 1H), 1.82 (s, 3H), 1.11 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 161.3, 145.1, 137.9, 137.4, 136.0,
129.9 (2C), 129.0 (2C), 128.7 (2C), 128.5, 128.4 (2C), 127.6
(2C), 127.5 (2C), 127.3, 126.5, 112.1, 73.1, 45.7, 43.2, 21.7,
21.3, 17.9, 12.5; HRMS (ESI, M++1) calcd for C28H30NO3S
460.1946, found 460.1948.
4.2.6. General procedure for the preparation of 3,4,5,6-
tetrasubstituted pyridin-2-one (11). A solution of com-
pound 9 (1 mmol) in dry THF (5 mL) was added to a rapidly
stirred suspension of sodium hydride (60 mg, 1.2 mmol,
60%) in THF (20 mL). The resulting mixture was stirred at
room temperature for 15 min, iodide methane (1.3 mmol)
was added. After the reaction was completed (monitored
by TLC), the reaction mixture was quenched with water
(2 mL) and filtered through Celite. The organic layer was
extracted with ethyl acetate (3ꢀ20 mL) and dried with anhy-
drous MgSO4, filtered and concentrated. After the crude al-
kylated product was purified by silica gel chromatography
(n-hexane/ethyl acetate¼4:1 to 2:1), t-BuOH (15 mL) and
t-BuOK (1.1 mmol) were added to a solution of alkylated
product in THF (20 mL) at room temperature and stirred
for 10 h. After the reaction was accomplished (monitored
by TLC), the reaction mixture was quenched with water
(2 mL) and filtered through Celite. The organic layer was
extracted with ethyl acetate (3ꢀ20 mL), dried, filtered, and
concentrated. The crude product was purified by silica gel
chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to
afford 11.
4.2.4.4.
1-Benzyl-6-ethyl-5-methyl-3-(4-toluenesul-
fonyl)-4-vinyl-3,4-dihydropyridin-2-one (9d). Yield 73%;
yellow oil; 1H NMR (500 MHz, CDCl3) d 7.77 (d, J¼8.0 Hz,
2H), 7.34 (d, J¼8.0 Hz, 2H), 7.29–7.20 (m, 5H), 5.61–5.55
(m, 1H), 5.22 (d, J¼15.5 Hz, 1H), 5.09–5.02 (m, 2H), 4.50
(d, J¼15.5 Hz, 1H), 4.95 (s, 1H), 3.54 (d, J¼5.5 Hz, 1H),
2.44 (s, 3H), 2.36–2.28 (m, 1H), 2.24–2.14 (m, 1H), 1.83
(s, 3H), 1.03 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 161.8, 145.0, 137.6, 136.4, 135.3, 133.5, 129.7
(2C), 128.6 (2C), 128.4 (2C), 127.14, 127.05 (2C), 116.9,
111.7, 70.3, 45.5, 41.6, 21.7, 21.1, 17.4, 12.4; HRMS (ESI,
M++1) calcd for C24H28NO3S 410.1790, found 410.1788.
4.2.4.5. 1-Benzyl-4-ethyl-5-methyl-6-phenyl-3-(4-tolu-
enesulfonyl)-3,4-dihydropyridin-2-one (9e). Yield 30%;

T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
9831
4.2.6.1.
1-Benzyl-3,4,5,6-tetramethylpyridin-2-one
7.34–7.23 (m, 7H), 5.82–5.74 (m, 1H), 5.72–5.63 (m, 1H),
5.12 (d, J¼15.0 Hz, 1H), 5.06–4.84 (m, 4H), 4.53 (d,
J¼15.0 Hz, 1H), 2.97–2.93 (m, 1H), 2.80 (dd, J¼5.0,
10.0 Hz, 1H), 2.64–2.42 (m, 3H), 2.44 (s, 3H), 2.32–2.15
(m, 2H), 1.76 (s, 3H), 0.90 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 166.8, 144.6, 137.7, 136.5, 135.8,
134.3, 131.3 (2C), 131.2 (2C), 129.1 (2C), 128.6 (2C),
127.3 (2C), 124.5, 119.6, 116.7, 115.0, 74.9, 45.1, 37.2,
29.7, 21.6 (2C), 20.9, 12.4; HRMS (ESI, M++1) calcd for
C28H34NO3S 464.2259, found 464.2256.
1
(11a). Yield 95%; yellow oil; H NMR (500 MHz, CDCl3)
d 7.30–7.19 (m, 3H), 7.11 (d, J¼7.0 Hz, 2H), 5.43 (br s,
2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H);
13C NMR (125 MHz, CDCl3) d 162.8, 146.3, 138.0, 137.2,
128.6 (2C), 126.9, 126.2 (2C), 123.0, 113.2, 48.0, 17.2,
16.6, 15.1, 13.5; HRMS (ESI, M++1) calcd for C16H20NO
242.1545, found 242.1547.
4.2.6.2. 1-Benzyl-6-ethyl-3,4,5-trimethylpyridin-2-one
(11b). Yield 93%; yellow oil; 1H NMR (500 MHz, CDCl3)
d 7.29–7.20 (m, 3H), 7.09 (d, J¼7.5 Hz, 2H), 5.43 (br s,
2H), 2.61 (q, J¼7.5 Hz, 2H), 2.19 (s, 3H), 2.17 (s, 3H),
2.06 (s, 3H), 1.09 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 162.8, 146.7, 143.2, 137.7, 128.7 (2C), 126.9,
126.1 (2C), 123.5, 112.8, 47.5, 23.2, 17.1, 14.5, 13.5, 12.9;
HRMS (ESI, M++1) calcd for C17H22NO 256.1701, found
256.1699.
4.3.2. 2-Benzyl-3-ethyl-4-methylisoquinolin-1-one (14).
Diallyl compound 12 (165 mg, 0.36 mmol) in dry dichloro-
methane (40 mL) was added to first generation Grubbs cat-
alyst [(C6H11)3P]2Cl2RuC2H3Ph (29.6 mg, 0.036 mmol,
10 mol %), and the mixture was allowed to react for 12 h
at room temperature. After the reaction was completed
(monitored by TLC), the mixture was quenched with water
(20 mL) and extracted with dichloromethane (2ꢀ30 mL)
and dried with anhydrous MgSO4, filtered and concentrated.
To the solution of the residue in t-BuOH (15 mL) was added
t-BuOK (44 mg, 1.1 mmol) and then heated to reflux for
24 h. The organic solvent was evaporated under reduced
pressure and the residue was extracted with water (15 mL)
and ethyl acetate (3ꢀ20 mL). The combined organic layer
was dried with anhydrous MgSO4, filtered and concentrated.
The crude product was purified by silica gel chromatography
(n-hexane/ethyl acetate¼4:1 to 2:1) to afford isoquinolinone
4.2.6.3. 1-Benzyl-6-ethyl-5-methyl-4-phenyl-3-propen-
ylpyridin-2-one (11c). Yield 90%; yellow oil; H NMR
1
(500 MHz, CDCl3) d 7.47–7.11 (m, 10H), 7.05–6.98 (m,
1H), 5.87 (d, J¼14.0 Hz, 1H), 5.50 (br s, 2H), 2.83 (q,
J¼7.5 Hz, 2H), 1.74 (s, 3H), 1.66 (d, J¼1.5 Hz, 3H), 1.15
(t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 161.7,
150.9, 144.9, 139.3, 137.4, 131.1, 128.7 (2C), 128.5 (2C),
128.4 (2C), 127.2, 127.1, 126.2 (2C), 126.0, 122.8, 112.1,
47.4, 23.7, 19.9, 15.6, 12.7; HRMS (ESI, M++1) calcd for
C24H26NO 344.2014, found 344.2017.
1
derivative 14 (78 mg, 81%) as a colorless oil. H NMR
(500 MHz, CDCl3) d 8.52 (d, J¼10.0 Hz, 1H), 7.71–7.69
(m, 2H), 7.50–7.46 (m, 1H), 7.31–7.21 (m, 3H), 7.14 (d,
J¼7.5 Hz, 2H), 5.51 (br s, 2H), 2.73 (q, J¼7.5 Hz, 2H),
2.34 (s, 3H), 1.18 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 163.0, 141.0, 137.8, 137.5, 132.3, 128.7 (2C),
128.5, 127.0, 126.0 (2C), 125.9, 124.6, 122.6, 109.1, 47.1,
23.1, 13.5, 13.3; HRMS (ESI, M++1) calcd for C19H20NO
278.1545, found 278.1547.
4.2.6.4. 1,5-Dibenzyl-4-ethyl-3,6-dimethylpyridin-2-
one (11d). Yield 92%; yellow oil; H NMR (500 MHz,
1
CDCl3) d 7.31–7.02 (m, 10H), 5.45 (br s, 2H), 3.88 (s,
2H), 2.50 (q, J¼7.5 Hz, 2H), 2.23 (s, 3H), 2.16 (s, 3H),
1.06 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 163.4, 151.9, 140.7, 139.8, 137.1, 128.7 (2C), 128.6
(2C), 127.5 (2C), 127.1, 126.3, 126.2 (2C), 123.3, 114.7,
48.1, 33.9, 23.8, 16.8, 13.3, 13.0; HRMS (ESI, M++1) calcd
for C23H26NO 332.2014, found 332.2012.
4.4. Synthesis of benzo[c]phenanthridine nucleus
4.3. Synthesis of isoquinolinone skeleton 14
4.4.1. 3-(2,2-Dimethoxyethylidene)-1-methyl-5-(4-tolu-
enesulfonyl)piperidine-2,6-dione (18). A solution of a-
sulfonyl methylacetamide 19 (3.0 g, 13.2 mmol) in dry
THF (30 mL) was added to a rapidly stirred suspension of
sodium hydride (1.6 g, 39.6 mmol, 60%) in dry THF
(20 mL). After the reaction mixture was stirred at room tem-
perature for 30 min, a solution of a,b-unsaturated ester 20
(3.7 g, 15.8 mmol) in dry THF (70 mL) was added. The
resulting mixture was stirred for 15 min, quenched with
saturated ammonium chloride solution (25 mL) in an ice
bath, and concentrated under reduced pressure. The residue
was diluted with water (10 mL) and extracted with ethyl ace-
tate (3ꢀ50 mL). The combined organic layers were washed
with brine (2ꢀ40 mL), dried over anhydrous MgSO4, fil-
tered and evaporated. Purification on silica gel (n-hexane/
ethyl acetate/triethyl amine¼4:1:0.01 to 2:1:0.01) produced
glutarimide 18 (3.8 g, 78%) as a white solid; 1H NMR
(500 MHz, CDCl3) d 7.76–7.72 (m, 2H), 7.39–7.37 (m,
2H), 6.99 (dd, J¼2.5, 5.5 Hz, 0.8 H), 5.77 (d, J¼7.0 Hz,
0.2H), 5.29 (dd, J¼1.0, 5.5 Hz, 0.8 H), 4.17 (m, 1H),
3.78–3.74 (m, 1H), 3.48 (s, 0.6H), 3.44 (s, 0.6H), 3.42 (s,
2.4H), 3.35 (s, 2.4H), 3.21 (s, 2.4H), 3.19 (s, 0.6H), 2.99–
2.93 (m, 1H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3)
4.3.1. 3,4-Diallyl-1-benzyl-6-ethyl-5-methyl-3-(4-tolu-
enesulfonyl)-3,4-dihydropyridin-2-one (12). Allylmagne-
sium bromide (2.0 mL, 1.3 mmol) was added to a solution
of compound 8b (570 mg, 1.5 mmol) in dry THF (15 mL).
After the reaction was accomplished (monitored by TLC),
the reaction mixture was quenched with water (5 mL) and
filtered through Celite. The organic layer was extracted
with ethyl acetate (3ꢀ20 mL), dried, filtered, and concen-
trated. Without purification, the residue in dry THF (5 mL)
was added to a suspension of sodium hydride (72 mg,
1.2 mmol, 60%) in THF (10 mL) and stirred at room temper-
ature for 15 min. Allyl bromide (270 mg, 1.5 mmol) was
added to the solution. After the reaction was completed
(monitored by TLC), the reaction mixturewas quenched with
water (5 mL) and the organic solvent was evaporated under
reduced pressure. The residue was extracted with ethyl ace-
tate (3ꢀ20 mL) and dried with anhydrous MgSO4, filtered
and concentrated. The crude product was purified by silica
gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to
afford single diallyl compound 12 (450 mg, 67%) as a yellow
oil. 1H NMR (500 MHz, CDCl3) d 8.14 (d, J¼8.0 Hz, 2H),

9832
T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
d 164.5, 164.4 (0.2C), 164.3 (0.8C), 146.0 (0.8C), 145.9
(0.2C), 142.5 (0.2C), 140.1 (0.8C), 134.6 (0.2C), 134.3
(0.8C), 123.0 (1.6C), 129.9 (0.4C), 129.2 (0.4C), 129.1
(1.6C), 127.0 (0.8C), 124.9 (0.2C), 99.1 (0.8C), 98.9
(0.2C), 66.0 (0.2C), 65.8 (0.8C), 54.7 (0.2C), 53.9 (0.2C),
53.0 (0.8C), 52.2 (0.8C), 28.4 (0.2C), 27.8 (0.8C), 27.4
(0.2C), 22.0 (0.8C), 21.8; HRMS (ESI, M++1) calcd for
C17H21O6NSNa 390.0987, found 390.0985. Mp: 118.6–
119.7 ꢁC.
(n-hexane/ethyl acetate/triethyl amine¼6:1:0.01 to
4:1:0.01) to afford 17 (733 mg, 65%) as a pale yellow oil;
1H NMR (500 MHz, CDCl3) d 7.81 (d, J¼8.0 Hz, 2H),
7.34 (d, J¼8.0 Hz, 1H), 6.84–6.77 (m, 1H), 6.70–6.66 (m,
1H), 6.58–6.55 (m, 1H), 5.98 (dd, J¼1.5, 3.0 Hz, 2H),
4.40 (t, J¼5.5 Hz, 1H), 4.00 (dd, J¼4.0, 7.0 Hz, 1H), 3.30
(s, 3H), 3.26 (s, 3H), 3.15 (dd, J¼3.5, 17.5 Hz, 1H), 2.95
(dd, J¼7.0, 17.5 Hz, 1H), 2.75 (s, 3H), 2.44 (s, 3H), 2.37–
2.25 (m, 2H); HRMS (ESI, M++1) calcd for C24H28NO7S
474.1578, found 474.1585.
4.4.2. 3-(2,2-Dimethoxyethyl)-1-methyl-5-(4-toluenesul-
fonyl)piperidine-2,6-dione (21). To a solution of glutar-
imide 18 (3.2 g, 8.7 mmol) in dry THF (60 mL) was added
2.1 g of Raney nickel 2800 (H2O). The reaction slurry was
stirred at room temperature for 12 h under 40 psi H2. The re-
action mixture was filtered over Celite and the solution was
concentrated under reduced pressure. Purification on silica
gel (hexane/ethyl acetate/triethyl amine¼4:1:0.01 to
4.4.4. 1-Methyl-8,9-methylenedioxy-3-(4-toluenesul-
fonyl)-3,4-dihydro-1H-benzo[h]quinoline-2-one (22). To
a solution of lactam 17 (1.8 g, 3.3 mmol) and anhydrous
MgSO4 (2.0 g) in dichloromethane was added boron trifluo-
ride diethyl ether complex (0.75 mL, 8.1 mmol) at ꢂ30 ꢁC.
The mixture was stirred for 20 h at that temperature. The re-
action mixture was filtered and was added saturated sodium
bicarbonate solution to neutralize. The mixture was ex-
tracted with dichloromethane (3ꢀ50 mL). The combined
organic layers were washed with brine (2ꢀ40 mL), dried
over anhydrous MgSO4, filtered and evaporated. The crude
product was purified by silica gel chromatography (n-
hexane/ethyl acetate¼4:1 to 2:1) to afford 22 (1.5 g, 93%)
1
2:1:0.01) produced 21 (3.1 g, 95%) as a white solid; H
NMR (500 MHz, CDCl3) d 7.88 (d, J¼8.0 Hz, 0.4H), 7.76
(d, J¼8.0 Hz, 1.6H), 7.39–7.37 (m, 2H), 4.65 (t, J¼5.5 Hz,
0.2H), 4.61 (t, J¼5.5 Hz, 0.8H), 4.20 (dd, J¼5.5, 13.0 Hz,
0.2H), 4.14 (dd, J¼3.0, 6.0 Hz, 0.8H), 3.40–3.32 (m, 7H),
3.17 (s, 2.4H), 3.08 (s, 0.6H), 2.91–2.87 (m, 0.8H), 2.78–
2.73 (m, 0.2H), 2.47 (s, 2.4H), 2.46 (s, 0.6H), 2.37–2.32
(m, 1H), 2.19–2.13 (m, 1H), 1.80–1.75 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 173.4 (0.8C), 173.0 (0.2C), 165.2
(0.2C), 164.7 (0.8C), 145.7 (0.8C), 145.4 (0.2C), 135.6
(0.2C), 135.1 (0.8C), 129.9 (1.6C), 129.6 (0.4C), 129.5
(0.4C), 129.0 (1.6C), 103.0 (0.8C), 102.5 (0.2C), 65.8
(0.8C), 65.6 (0.2C), 53.9, 53.5 (0.8C), 53.2 (0.2C), 37.1
(0.2C), 34.9 (0.8C), 34.0 (0.8C), 33.4 (0.2C), 27.5 (0.8C),
27.5 (0.2C), 24.0 (0.8C), 23.7 (0.2C), 21.7 (0.8C), 21.7
(0.2C). Anal. Calcd for C17H23NO6S: C, 55.27; H, 6.28;
N, 3.79. Found: C, 55.11; H, 6.43; N, 3.58.
1
as a white solid; H NMR (500 MHz, CDCl3) d 7.49 (d,
J¼8.0 Hz, 2H), 7.42 (d, J¼8.5 Hz, 1H), 7.18 (d, J¼8.5 Hz,
1H), 7.06 (s, 1H), 6.97 (d, J¼8.0 Hz, 2H), 6.75 (s, 1H),
6.05 (d, J¼6.0 Hz, 2H), 4.28 (t, J¼5.5 Hz, 1H), 3.55–3.54
(m, 2H), 3.44 (s, 3H), 2.20 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 165.3, 147.4, 147.2, 144.5, 136.6, 135.4, 131.9,
129.0 (2C), 128.7 (2C), 124.8, 124.0, 121.8, 121.1, 104.5,
101.4, 99.9, 67.0, 38.4, 28.0, 21.3; HRMS (ESI, M++1) calcd
for C22H20NO5S 410.1062, found 410.1059. Anal. Calcd for
C22H19NO5S: C, 64.53; H, 4.68; N, 3.42. Found C, 64.23; H,
4.39; N, 3.45. Mp: 209.4–211.3 ꢁC.
4.4.3. 6-(Benzo[1,3]dioxol-5-yl)-5-(2,2-dimethoxyethyl)-
1-methyl-3-(4-toluenesulfonyl)-3,4-dihydro-1H-pyridin-
2-one (17). A solution of glutarimide 21 (890 mg, 2.4 mmol)
in dry THF (40 mL) was added to a rapidly stirred suspen-
sion of sodium hydride (140 mg, 3.6 mmol, 60%) in THF
(10 mL). After the reaction mixture was stirred at room tem-
perature for 15 min, the Grignard reagent, which was pre-
pared by 4-bromo-1,2-(methylenedioxy)benzene (1.5 mL,
12.0 mmol) with magnesium (410 mg, 16.8 mmol) in dry
THF (30 mL) at reflux temperature for 1 h, was added at
room temperature in one portion by syringe. The resulting
mixture was stirred at room temperature for 60 min. After
the reaction was accomplished (monitored by TLC), acetic
anhydride (2.3 mL, 24.1 mmol) was added at room temper-
ature for 30 min. After the reaction was accomplished (moni-
tored by TLC), the reaction mixture was quenched with
water (3 mL) and filtered through Celite. The organic layer
was extracted with ethyl acetate (3ꢀ30 mL) and dried with
anhydrous MgSO4, filtered, and concentrated. The residue
was diluted with methanol (20 mL), and was added triethyl
amine (0.5 mL). After the reaction mixture was stirred at
room temperature for 36 h, then concentrated under reduced
pressure. The residue was diluted with water (10 mL) and
extracted with ethyl acetate (3ꢀ30 mL). The combined
organic layers were washed with brine (2ꢀ40 mL), dried
over anhydrous MgSO4, filtered and evaporated. The
crude product was purified by silica gel chromatography
4.4.5. 1-Methyl-8,9-methylenedioxy-3-(4-toluenesul-
fonyl)-1H-benzo[h]quinoline-2-one (16). To a solution of
22 (610 mg, 1.5 mmol) in toluene (35 mL) was added
DDQ (1.0 g, 4.5 mmol). The resulting mixture was refluxed
for 1 day. After removal of the precipitates by filtration,
a large amount of 5% NaOH was added to the filtrate and
the mixture was extracted with dichloromethane (3ꢀ
30 mL). The combined organic layers were washed with
5% NaOH, dried over anhydrous MgSO4, filtered and evap-
orated. Purification on silica gel (dichloromethane/meth-
anol¼200:1 to 100:1) produced 16 (500 mg, 83%) as
1
a white solid; H NMR (500 MHz, CDCl3) d 8.78 (s, 1H),
8.06 (d, J¼8.5 Hz, 2H), 7.70 (s, 1H), 7.53 (d, J¼8.5 Hz,
1H), 7.50 (d, J¼8.5 Hz, 1H), 7.33 (d, J¼8.5 Hz, 2H), 7.21
(s, 1H), 3.95 (s, 3H), 2.42 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 159.3, 149.6, 147.5, 144.5, 142.9, 142.3, 136.6,
135.3, 129.4 (2C), 129.3 (2C), 129.2, 125.1, 124.2, 119.2,
116.1, 105.5, 103.2, 102.1, 40.5, 21.7; HRMS (ESI, M++1)
calcd for C22H18NO5S 408.0906, found 408.0903. Anal.
Calcd for C22H17NO5S: C, 64.85; H, 4.21; N, 3.44. Found
C, 64.84; H, 4.10; N, 3.51. Mp: 329.5–331.8 ꢁC.
4.4.6. 4-Allyl-1-methyl-8,9-methylenedioxy-3-(4-toluene-
sulfonyl)-3,4-dihydro-1H-benzo[h]quinoline-2-one (23).
To a solution of 16 (100 mg, 0.25 mmol) in dry THF
(10 mL) was added allylmagnesium bromide (1.0 mmol)
in one portion by syringe. The resulting mixture was stirred

T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
9833
at room temperature for 1.5 h. After the reaction was accom-
plished (monitored by TLC), the reaction mixture was
quenched with water (2 mL) and filtered through Celite.
The organic layer was extracted with ethyl acetate (3ꢀ
20 mL) and dried with anhydrous MgSO4, filtered, and con-
centrated. The crude product was purified by silica gel chro-
matography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 23
(108 mg, 98%), which was crystallized from n-hexane/ethyl
4.4.8. 5-Methyl-2,3-methylenedioxy-6a-(4-toluenesul-
fonyl)-6a,7,10,10a-tetrahydrobenzo[c]phenanthridin-
6(5H)-one (25). First generation Grubbs catalyst (22 mg,
0.02 mmol) was added to a solution of 24 (100 mg,
0.2 mmol) in dichloromethane (10 mL) at room tempera-
ture for 7.5 h. The mixture was concentrated and purified
by flash column chromatography (n-hexane/ethyl acetate¼
4:1 to 2:1) to yield 25 (91 mg, 96%), which was crystal-
1
1
acetate as a colorless solid; H NMR (500 MHz, CDCl3)
lized from n-hexane/ethyl acetate as colorless crystals; H
d 7.41 (d, J¼8.5 Hz, 1H), 7.24 (d, J¼8.5 Hz, 2H), 7.13 (d, J¼
8.5 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J¼8.5 Hz, 2H), 6.63 (s,
1H), 6.05–6.04 (m, 2H), 5.77–5.69 (m, 1H), 5.15 (d, J¼
10.5 Hz, 1H), 5.07 (d, J¼17.0 Hz, 1H), 4.30 (s, 1H), 3.67
(t, J¼7.0 Hz, 1H), 3.41 (s, 3H), 2.45–2.40 (m, 1H), 2.28–
2.22 (m, 1H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 164.3, 147.2, 147.1, 144.3, 136.1, 134.8, 133.0, 131.9,
128.8 (2C), 128.2 (2C), 124.9, 124.4, 123.9, 121.8, 119.4,
104.4, 101.4, 100.2, 72.1, 39.2, 39.1, 38.8, 21.1; HRMS (ESI,
M++1) calcd for C25H24NO5S 450.1375, found 450.1373.
Anal. Calcd for C25H23NO5S: C, 66.80; H, 5.16; N, 3.12.
Found C, 66.88; H, 5.24; N, 3.20. Mp: 227.1–228.7 ꢁC.
NMR (500 MHz, CDCl3) d 7.52 (d, J¼8.5 Hz, 1H), 7.29
(d, J¼8.5 Hz, 1H), 7.12 (d, J¼8.0 Hz, 2H), 7.07 (s, 1H),
6.78 (d, J¼8.0 Hz, 2H), 6.62 (s, 1H), 6.05 (dd, J¼1.0,
3.5 Hz, 2H), 6.02–5.97 (m, 1H), 5.86–5.82 (m, 1H),
3.66 (dd, J¼6.5, 11.5 Hz, 1H), 3.48–3.43 (m, 1H), 3.41
(s, 3H), 3.31–3.23 (m, 1H), 2.82–2.72 (m, 2H), 2.15
(s, 3H); 13C NMR (125 MHz, CDCl3) d 166.7, 144.6,
144.6, 141.3, 134.05, 133.8, 129.3, 126.0 (2C), 126.0
(2C), 123.1, 122.27, 122.25, 120.5, 118.8, 117.9, 101.8,
98.7, 97.8, 66.7, 36.4, 35.3, 28.3, 23.6, 18.6; HRMS
(ESI, M++1) calcd for C26H23NO5S 462.1375, found
462.1377. Anal. Calcd for C26H22NO5S: C, 67.66; H,
5.02; N, 3.03. Found C, 66.25; H, 4.63; N, 2.88. Mp:
203.2–205.1 ꢁC.
4.4.7. 3,4-Diallyl-1-methyl-8,9-methylenedioxy-3-(4-tolu-
enesulfonyl)-3,4-dihydro-1H-benzo[h]quinoline-2-one
(24). A solution of 23 (108 mg, 0.24 mmol) in dry THF
(10 mL) was added to a rapidly stirred suspension of sodium
hydride (13 mg, 0.31 mmol, 60%) in dry THF (2 mL). After
the reaction mixture was stirred at room temperature for
30 min, the allyl bromide (0.04 mL, 0.48 mmol) was added.
The resulting mixture was stirred for 30 h, quenched with
water (3 mL), and concentrated under reduced pressure.
The residue was diluted with water (3 mL) and extracted
with ethyl acetate (3ꢀ20 mL). The combined organic layers
were washed with brine (2ꢀ30 mL), dried over anhydrous
MgSO4, filtered and evaporated. Purification on silica gel
(n-hexane/ethyl acetate¼4:1 to 2:1) produced 24 (111 mg,
4.4.9. 7,10-Dihydro-5-methyl-2,3-methylenedioxyben-
zo[c]phenanthridin-6(5H)-one (26). To a solution of 25
(70 mg, 0.15 mmol) in dry THF (10 mL) was added DBU
(0.05 mL, 0.3 mmol). The resulting mixture was heated
to 60 ꢁC for 20 h. After the reaction was accomplished
(monitored by TLC), the resulting mixture was concen-
trated under reduced pressure. The residue was diluted
with water (10 mL) and extracted with dichloromethane
(3ꢀ30 mL). The combined organic layers were washed
with brine (2ꢀ40 mL), dried over anhydrous MgSO4, fil-
tered and evaporated. Purification on silica gel (n-hexane/
ethyl acetate¼2:1 to 1:1) to yield 26 (45 mg, 93%) as
a white solid; 1H NMR (500 MHz, CDCl3) d 7.71 (s,
1H), 7.52 (d, J¼8.5 Hz, 1H), 7.49 (d, J¼8.5 Hz, 1H),
7.18 (s, 1H), 6.11 (s, 2H), 6.05–6.00 (m, 1H), 6.94–6.90
(m, 1H), 3.98 (s, 3H), 3.58–3.54 (m, 2H), 3.34–3.30 (m,
2H); 13C NMR (125 MHz, CDCl3) d 164.3, 147.7, 146.8,
139.3, 137.5, 132.2, 124.5, 124.1, 122.8, 121.8, 119.9,
119.2, 117.8, 104.8, 102.8, 101.5, 40.5, 27.0, 25.5;
HRMS (ESI, M++1) calcd for C19H16NO3 306.1130, found
306.1129. Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95;
N, 4.59. Found C, 74.29; H, 5.24; N, 4.46. Mp: 232.6–
233.9 ꢁC.
1
94%) as a white solid; H NMR (500 MHz, CDCl3) d 8.24
(d, J¼8.0 Hz, 1.2H), 7.45–7.35 (m, 2.8H), 7.12–7.01 (m,
3H), 6.71 (d, J¼7.5 Hz, 0.6H), 6.64 (s, 0.4H), 6.07–6.03
(m, 2H), 5.98–5.90 (m, 0.4H), 5.78–5.67 (m, 1H), 5.39 (d,
J¼17.0 Hz, 0.4H), 5.32–5.26 (m, 1.4H), 5.17 (d,
J¼10.0 Hz, 0.4H), 4.95 (d, J¼10.0 Hz, 0.6H), 4.87 (d, J¼
17.0 Hz, 0.6H), 4.73 (d, J¼10.0 Hz, 0.6H), 4.10 (d,
J¼17.0 Hz, 0.6H), 3.73–3.70 (m, 0.4H), 3.61–3.58 (m,
0.6H), 3.49–3.44 (m, 3.4H), 3.24–3.14 (m, 1H), 3.04–2.96
(m, 0.8H), 2.74–2.68 (m, 0.6H), 2.44 (s, 1.8H), 2.29 (dd,
J¼7.5, 16.0 Hz, 0.6H), 2.16 (dd, J¼7.5, 16.0 Hz, 0.6H),
2.06 (s, 1.2H); 13C NMR (125 MHz, CDCl3) d 168.6 (0.6C),
167.2 (0.4C), 147.8 (0.6C), 147.4 (0.6C), 147.1 (0.4C), 146.9
(0.4C), 144.9 (0.6C), 143.6 (0.4C), 137.4 (0.4C), 136.0
(1.2C), 135.3 (0.8C), 134.5 (0.6C), 131.8 (0.4C), 131.7
(0.4C), 131.6 (0.6C), 131.3 (1.2C), 130.3 (0.6C), 129.3
(1.2C), 128.5 (0.8C), 128.3 (0.8C), 125.7 (0.6C), 124.9
(0.4C), 124.7, 124.4 (0.6C), 122.3 (0.4C), 121.7 (0.6C),
121.1 (0.4C), 121.1 (0.4C), 119.9 (0.6C), 117.6 (0.6C), 116.5
(0.4C), 104.8 (0.6C), 104.2 (0.4C), 101.4 (0.6C), 101.3
(0.4C), 100.3 (0.4C), 99.8 (0.6C), 75.0 (0.6C), 74.7 (0.4C),
44.6 (0.6C), 39.7 (0.4C), 39.3 (0.4C), 38.5 (0.6C), 36.5
(0.6C), 36.1 (0.6C), 34.0 (0.4C), 29.5 (0.4C), 21.6 (0.6C),
21.1 (0.4C); HRMS (ESI, M++1) calcd for C28H28NO5S
490.1688, found 490.1690. Anal. Calcd for C28H27NO5S:
C, 68.69; H, 5.56; N, 2.86. Found C, 68.50; H, 5.40; N,
2.93. Mp: 213.5–214.6 ꢁC.
4.4.10. 5-Methyl-2,3-methylenedioxybenzo[c]phenan-
thridin-6(5H)-one (27). To a solution of 26 (36 mg,
0.1 mmol) in dry THF (10 mL) was added DDQ (79 mg,
0.35 mmol), and the resulting mixture was refluxed for 2 h.
The mixture was concentrated and purified by column chro-
matography (dichloromethane/methanol¼1:0 to 100:1)) to
yield 27 (38 mg, 99%) as a pale yellow oil; 1H NMR
(500 MHz, CDCl3) d 8.55 (dd, J¼1.0, 8.0 Hz, 1H), 8.27
(d, J¼8.0 Hz, 1H), 8.12 (d, J¼8.5 Hz, 1H), 7.79–7.76 (m,
1H), 7.64 (s, 1H), 7.60–7.57 (m, 2H), 7.19 (s, 1H), 6.11 (s,
2H), 3.99 (s, 3H); 13C NMR (125 MHz, CDCl3) d 164.8,
147.7, 147.1, 136.5, 134.0, 132.6, 132.4, 128.5, 127.7,
125.1, 123.4, 121.9, 121.0, 118.6, 116.9, 104.8, 102.7,
101.6, 41.2; HRMS (ESI, M++1) calcd for C19H13NO3
304.0974, found 304.0975.

9834
T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
4.5. Total synthesis of oxyisoterihanine 15b
accomplished and allowed to warm to room temperature,
then quenched with water (3 mL), and concentrated under
reduced pressure. The residue was diluted with water (3 mL)
and extracted with ethyl acetate (3ꢀ20 mL). The combined
organic layers were washed with brine (2ꢀ30 mL), dried
over anhydrous MgSO4, filtered and evaporated. The residue
was dissolved in THF (5 mL) and added DBU (0.02 mL,
0.13 mmol). The resulting mixture was refluxed for 1 h. Af-
ter the reaction was accomplished (monitored by TLC), the
resulting mixture was concentrated under reduced pressure.
The residue was diluted with water (5 mL) and extracted
with dichloromethane (5ꢀ30 mL). The combined organic
layers were washed with brine (2ꢀ40 mL), dried over anhy-
drous MgSO4, filtered and evaporated. Purification on silica
gel (dichloromethane/methanol¼100:1) to yield 15b
(11.7 mg, 65%) as a white solid; 1H NMR (300 MHz,
CDCl3) d 7.97 (d, J¼8.4 Hz, 1H), 7.94 (s, 1H), 7.74 (s,
1H), 7.64 (s, 1H), 7.56 (d, J¼8.4 Hz, 1H), 7.19 (s, 1H),
6.18 (s, 1H), 6.10 (s, 2H), 4.08 (s, 3H), 3.98 (s, 3H);
HRMS (FAB, M++1) C20H16NO5 350.1028, found
350.1037. Mp: 299.8–302.0 ꢁC.
4.5.1. 5-Benzyl-8,9-epoxy-8,9-dihydroxy-2,3-methylene-
dioxy-6a-(4-toluenesulfonyl)-6a,7,8,9,10,10a-hexahydro-
benzo[c]phenanthridin-6(5H)-one (28). To a solution of 25
(30 mg, 0.065 mmol) in dichloromethane (2.0 mL) was
added m-CPBA (28 mg, 0.16 mmol) at room temperature
for 2 days. After the reaction was accomplished (monitored
by TLC), quenched with saturated sodium bicarbonate aque-
ous solution, and extracted with dichloromethane (3ꢀ
20 mL). The combined organic layers were washed with
brine (2ꢀ40 mL), dried over anhydrous MgSO4, filtered
and evaporated. Purification on silica gel (n-hexane/ethyl
acetate¼4:1 to 2:1) produced 28 (29 mg, 94%) as a white
1
solid; H NMR (500 MHz, CDCl3) d 7.46 (d, J¼8.5 Hz,
1H), 7.25 (d, J¼8.5 Hz, 1H), 7.18 (d, J¼8.0 Hz, 2H), 7.03 (s,
1H), 6.80 (d, J¼8.0 Hz, 2H), 6.72 (s, 1H), 6.06 (d, J¼9.5 Hz,
2H), 3.64–3.53 (m, 3H), 3.49–3.45 (m, 1H), 3.39 (s, 3H),
2.98–2.86 (m, 2H), 2.54 (d, J¼17.5 Hz, 1H), 2.10 (s, 3H);
13C NMR (125 MHz, CDCl3) d 168.0, 147.2, 147.2, 144.0,
136.2, 135.4, 131.8, 128.8 (2C), 128.5 (2C), 124.9, 124.1,
121.2, 120.2, 104.3, 101.4, 100.3, 67.2, 53.3, 50.5, 39.3, 34.0,
29.6, 25.2, 21.2; HRMS (ESI, M++1) calcd for C26H24NO6S
478.1324, found 478.1321. Mp: 202.6 ꢁC (dec).
Acknowledgements
4.5.2. 9-Hydroxy-8-methoxy-5-methyl-2,3-methylene-
dioxy-6a-(4-toluenesulfonyl)-6a,7,8,9,10,10a-hexahydro-
benzo[c]phenanthridin-6(5H)-one (29). To a solution of 28
(109 mg, 0.23 mmol) in methanol (9 mL) and dichlorome-
thane (3 mL) was added boron trifluoride diethyl ether com-
plex (0.09 mL, 0.68 mmol) in an ice bath for 1 h and allowed
to warm to room temperature for 35 h. After the reaction was
accomplished (monitored by TLC), quenched with saturated
sodium bicarbonate aqueous solution, and extracted with di-
chloromethane (3ꢀ30 mL). The combined organic layers
were washed with brine (2ꢀ40 mL), dried over anhydrous
MgSO4, filtered and evaporated. Purification on silica gel
(dichloromethane/methanol¼40:1) produced 29 (98 mg,
85%), which was crystallized from n-hexane/ethyl acetate
The authors would like to thank the National Science Coun-
cil of the Republic of China for financial support.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.06.101.
References and notes
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P. G., Ed.; Pergamon: Oxford, 1979; Vol. 4, p 3; (b) Bailey,
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G. R., Ed.; Wiley: New York, NY, 1984; Vol. 144, p 1, Part
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1
as colorless crystals; H NMR (500 MHz, CDCl3) d 7.53
(d, J¼8.0 Hz, 1H), 7.29 (d, J¼8.0 Hz, 1H), 7.07 (s, 1H),
6.81 (d, J¼7.5 Hz, 2H), 6.55 (d, J¼7.5 Hz, 2H), 6.25 (s,
1H), 6.02 (dd, J¼1.0, 4.5 Hz, 2H), 4.34–4.32 (m, 1H),
3.80 (dd, J¼4.0, 13.0 Hz, 1H), 3.57–3.55 (m, 1H), 3.54 (s,
3H), 3.37 (dd, J¼3.5, 16.0 Hz, 1H), 3.34 (s, 3H), 3.21 (dt,
J¼3.5, 13.5 Hz, 1H), 2.39 (dd, J¼3.5, 16.0 Hz, 1H), 2.21
(td, J¼3.5, 13.5 Hz, 1H), 2.12 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 170.4, 147.0, 146.9, 143.5, 138.6,
136.6, 131.7, 128.4 (2C), 127.9 (2C), 125.0, 124.9, 121.7,
120.3, 104.4, 101.2, 100.1, 78.0, 70.2, 67.8, 57.3, 38.8,
35.0, 27.7, 26.8, 21.0; HRMS (ESI, M++1) calcd for
C27H28NO7S 510.1586, found 510.1587. Anal. Calcd for
C27H27NO7S: C, 63.64; H, 5.34; N, 2.75. Found C, 63.34;
H, 5.21; N, 2.75. Mp: 188.6 ꢁC (dec).
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dioxybenzo[c]phenanthridin-6(5H)-one (15b). To a solu-
tion of oxalyl chloride (0.02 mL, 0.16 mmol) in
dichloromethane (2 mL) was added dimethyl sulfoxide
(0.02 mL, 0.27 mmol) at ꢂ78 ꢁC for 10 min. Then to added
the solution, which have 29 (26.3 mg, 0.05 mmol) in di-
chloromethane (2 mL) for 1 h, and then to added triethyl
amine (0.5 mL) for 30 min. After the reaction was

T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835
9835
Chapman and Hall: London, 1989; (g) Daly, J. W. J. Nat. Prod.
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