Synthesis of benzo[c]phenanthridine alkaloids, using a novel palladium-phosphine combination system - Pd(OAc)2, DPPP, and Bu3P

Article abstract of DOI:10.1055/s-2002-19799

Total synthesis of several benzo[c]phenanthridine alkaloids was accomplished via an aryl-aryl coupling reaction using a novel Pd reagent prepared from Pd(OAc)₂ DPPP, and Bu₃P. This is a versatile method for the coupling reactions of not only aryl triflates and arenes but also aryl halides and arenes.

Full text of DOI:10.1055/s-2002-19799

PAPER
237
Synthesis of Benzo[c]Phenanthridine Alkaloids, Using a Novel Palladium–
Phosphine Combination System – Pd(OAc)2, DPPP, and Bu3P
S
ynthesisof Be
a
nzo[
c
]Phe
n
k
anthridine
A
a
lkaloids,
U
s
sing Pd(O 2
h
A
c)
,
D
PPP,iand Bu3
P
Harayama,* Toshihiko Akiyama, Yuichiro Nakano, Kentaro Shibaike, Hisashi Akamatsu, Akihiro Hori,
Hitoshi Abe, Yasuo Takeuchi
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Fax +81(86)2517963; E-mail: harayama@pharm.okayama-u.ac.jp
Received 20 September 2001; revised 16 November 2001
Recently, we succeeded in the total synthesis of several
benzo[c]phenanthridine alkaloids, chelerythrine (1),3a nit-
idine (2),3b norchelerythrine (3),3c and 12-methoxydihy-
drochelerythrine (4),3a using a biaryl coupling reaction of
halo amides with palladium as a catalyst. Subsequently,
we investigated a biaryl cyclization reaction of amides
possessing a triflate group as a leaving group (instead of a
halogen group) in order to examine the diversity of leav-
ing groups for a biaryl coupling reaction. We found a nov-
el palladium reagent system prepared from Pd(OAc)2, a
bidentate ligand {such as DPPP [1,3-bis-(diphenylphos-
phino)propane]} and Bu3P achieves this reaction.4 More-
over, this method was proven to be effective, not only for
triflate leaving groups, but also for halogen groups.4 Here,
we describe the total synthesis of several benzo[c]phenan-
thridine alkaloids using this novel method.
Abstract: Total synthesis of several benzo[c]phenanthridine alka-
loids was accomplished via an aryl-aryl coupling reaction using a
novel Pd reagent prepared from Pd(OAc)2, DPPP, and Bu3P. This is
a versatile method for the coupling reactions of not only aryl tri-
flates and arenes but also aryl halides and arenes.
Key words: intramolecular aryl-aryl coupling, ring closure, palla-
dium reagent, halo-amide, triflate-amide
Introduction
Fully aromatized benzo[c]phenanthridine alkaloids have a
broad range of potent pharmacological activities. They in-
clude anti-tumor and antiviral activities, inhibition of
DNA topoisomerase I, and so on.1 Therefore, attention is
focused on developing convenient and effective methods
for synthesizing these alkaloids and extensive efforts have
been directed toward developing a convenient method for
synthesizing benzo[c]phenanthridine alkaloids.2 Howev-
er, the reported methods have several disadvantages, such
as numerous steps, low yields, and absence of generality.
Synthesis of Starting Materials 9–12
We designed a common plan for synthesizing ben-
zo[c]phenanthridine alkaloids, as shown in Scheme 1.
O
R2
R = R1 = OMe, R2 = H
chelerythrine (1)
nitidine (2)
O
+
Me
R = H, R1 = R2 = OMe
N
MeO
R1
OMe
O
O
O
O
NMe
N
MeO
MeO
OMe
OMe
12-methoxydihydrochelerythrine (4)
norchelerythrine (3)
R3
R3
O
O
O
R1
MeO
R2
O
O
R2
OTf
X
O
+
N
N
CO2H
MeO
MeO
R
R
NHR
O
R
O
R1
R1
5 : R=Me, R1=OMe, R2=R3=H
6 : R=Me, R1=R3=H, R2=OMe
7 : R=CH2OMe, R1=OMe, R2=R3=H
8 : R=Me, R1=R3 =OMe, R2=H
13 : R=OMe, R1=H
14 : R=H, R1=OMe
9 : R=Me, R1=OMe, R2=R3=H
10 : R=Me, R1=R3=H, R2=OMe
11 : R=CH2OMe, R1=OMe, R2=R3=H
12 : R=Me, R1=R3 =OMe, R2=H
15 :R=H
16 : R=COCF3
17 : R=Me
a series X=OTf, b series X=I, c series X=Br
Scheme 1 Retrosynthetic plan for the synthesis of benzo[c]phenanthridine alkaloids
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2002,0,02,0237,0241,ftx,en;F07301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

238
T. Harayama et al.
PAPER
OH
OTf
OTf
1) MeI, K2CO3,
(87 %)
1) Tf2O, Et3N
(99 %)
CHO
OH
CO2H
OMe
1) (COCl)2
O
Me
9a
2) O3
3) Me2S
2) NaClO2,
35% H2O2
(91 %)
2) 16 , Et3N
OMe
OMe
OMe
(63 %)
18
4) c-HCl
19
13
(45 %)
Scheme 2 Synthesis of precursor 9a for the biaryl coupling reaction
Triflate-amides 9a and 10a, the starting materials for the tion of 9a proceeded quickly and in a higher yield to give
coupling reaction, were synthesized as follows. First, the oxychelerythrine (5)3a (see runs 1 and 2). Moreover, on
monomethylnaphthylamine 17 was synthesized from 6,7- applying the novel method to halo-amides 9b and 9c,3a
methylenedioxy-1-naphthylamine (15)3b via trifluoro- both amides gave 5 in excellent yields (see runs 3–6 in Ta-
acetylation, N-methylation, and hydrolysis. Thus, 15 was ble). Using this procedure, the coupling reaction of 10a
treated with trifluoroacetic anhydride to afford N-(6,7- provided oxynitidine (6)3b in excellent yield (see run 7 in
methylenedioxy-1-naphthyl)-2,2,2-trifluoroacetamide 16, Table) and 10b3b provided 6 in high yield (see runs 8 and
which was methylated with methyl iodide in the presence 9 in Table ).
of sodium hydride, and hydrolyzed with alkali to produce
17 in 76% total yield. Triflate-benzoic acid 13 for the syn-
The synthetic samples 5–8 were identical to authentic
samples, which had already been converted to the corre-
thesis of 9a was prepared as shown in Scheme 2. The re-
sponding natural products 1–4,3 by successive treatment
action of benzofuran 185 with triflic anhydride and
with LiAlH4 and HCl.
successive treatment with ozone, dimethyl sulfide, and
hydrochloric acid provided salicylaldehyde 19 in 45% to-
tal yield. Methylation of 19, followed by oxidation with
sodium chlorite and 35% hydrogen peroxide afforded 13
in 77% yield. Finally, reaction of the acid chloride of 13
with 17 provided triflate-amide 9a in 63% yield.
Consequently, the novel combination system consisting
of Pd(OAc)2, DPPP, Bu3P, and base is a very efficient and
powerful method for intramolecular aryl-aryl coupling re-
actions involving either a triflate or halogen as the leaving
group. We are now investigating the catalytic ability of
this method.
Next, triflate-benzoic acid 14 for synthesis of 10 was pre-
pared as shown in Scheme 3. The reaction of salicylalde-
hyde 206 with triflic anhydride followed by oxidation
Melting points were measured on a micro melting point hot-stage
apparatus (Yanagimoto) and are uncorrected. IR spectra were re-
corded in Nujol on a JASCO A-102 or JASCO FT/IR 350 spectro-
gave 14, which was treated with oxalyl chloride, followed
by 16, to afford triflate-amide 10a in 85% total yield.
Halo-amides 9b,3b 9c,3a 10b,3b 11b,3c and 12b3a were syn-
thesized using reported literature procedures.
photometer and 1H NMR spectra in CDCl3 on a Hitachi R-1500 (60
MHz) or Varian VXR-500 (500 MHz) spectrometer unless other-
wise stated. NMR data are reported in parts per million downfield
from tetramethylsilane as an internal standard ( = 0.0) and cou-
pling constants are given in Hertz. Mass spectra were obtained on a
VG-70SE spectrometer. Column chromatography was carried out
on silica gel (Wako gel C-200 or Merck, silica gel 60, No. 9385).
All experiments were carried out in an argon atmosphere and the ex-
tract was washed with brine, dried over anhyd MgSO4, then filtered,
and the filtrate was evaporated to dryness under reduced pressure,
unless otherwise noted. Pd(OAc)2 was treated with boiling benzene
and the mixture was filtered while hot. The hot filtrate was then con-
centrated to dryness to give purified Pd(OAc)2.
1) Tf2O, Et3N
(75%)
MeO
MeO
OH
MeO
MeO
OTf
1) SOCl2
10a
2) NaClO2,
35% H2O2
(97%)
2) 16 , Et3N
CHO
CO2H
(88%)
20
14
Scheme 3 Synthesis of precursor 10a for the biaryl coupling reaction
N-Methyl-6,7-methylenedioxy-1-naphthylamine (17)
To a solution of 15 (100 mg, 0.53 mmol) in anhyd pyridine (3 mL),
Tf2O (0.11 mL, 0.80 mmol) was added. The reaction mixture was
stirred at 0 °C for 30 min and poured into 10% HCl (10 mL) and
then extracted with Et2O. The residue was recrystallized from Et2O–
hexanes to afford 16 (140 mg, 93%) as colorless needles, mp 172–
174 °C.
Biaryl Coupling Reactions of Triflate-amides and
Halo-amides in the Presence of Palladium Reagent
The biaryl coupling reaction of 9–12 by our novel palladi-
um-phosphine combination system4 was examined. As
seen in the Table, small amounts of naphthobenzoazepi-
nones 21–24 were obtained with phenanthridones 5–8 in
IR (KBr): 3300, 1715 cm–1.
each reaction. The synthetic samples 233b and 243a were 1H NMR (60 MHz): = 6.07 (2 H, s, OCH2O), 7.03–7.74 (5 H, m,
ArH), 8.07 (1 H, br s, NH).
MS-FAB: m/z [M + H]+ calcd for C13H8F3NO3, 284; found, 284.
identical to the authentic sample. The structures of the
1
products 21 and 22 were elucidated on the basis of H
NMR spectral data, in which 21 showed only one singlet
signal due to an aromatic proton and 22 showed three sin-
glet signals due to aromatic protons in addition to signals
due to other aromatic protons (see Experimental). On us-
ing diisopropylethyl amine as the base, the coupling reac-
To a solution of 16 (105 mg, 0.37 mmol) prepared above and MeI
(205 mg, 1.48 mmol) in anhyd acetone (10 mL) was added solid
KOH (82.2 mg). The reaction mixture was refluxed for 20 min and
solvent removed under reduced pressure. The residue was dissolved
in EtOH (5 mL) and aq 5% NaOH solution (5 mL) and refluxed for
10 min. The reaction mixture was diluted with H2O (40 mL) and ex-
Synthesis 2002, No. 2, 237–241 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzo[c]Phenanthridine Alkaloids, Pd(OAc)2, DPPP, and Bu3P
239
Table Results of Coupling Reaction of Amides (9–12) to Benzo[c]phenanthridones (5–8) and naphthobenzoazepinones (21–24) in DMF un-
der Refluxa
R3
N
R3
N
O
R3
O
O
O
O
O
R2
R2
R2
X
+
N
MeO
MeO
MeO
R
R
R1
R
O
O
O
R1
R1
21 ~ 24
5 ~ 8
9 ~ 12
5 and 21 : R=Me, R1=OMe, R2=R3=H
6 and 22 : R=Me, R1=R3=H, R2=OMe
7 and 23 : R=CH2OMe, R1=OMe, R2=R3=H
8 and 24 : R=Me, R1=R3 =OMe, R2=H
9 : R=Me, R1=OMe, R2=R3=H
10 : R=Me, R1=R3=H, R2=OMe
11 : R=CH2OMe, R1=OMe, R2=R3=H
12 : R=Me, R1=R3 =OMe, R2=H
a series X=OTf, b series X=I, c series X=Br
Run
Starting
Material
Pd(OAc)2 Ligand
(eq)
Bu3P (eq) Base
Time
Products (Yield, %)
1
2
9a
9b
9c
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
iPr2Net
30 min
4 h
5
(81)
(62)
(85)
(95)
(79)
(89)
(93)
(94)
(88)
(83)
(90)
21
(~ 5)
(~ 3)
(~ 3)
(~ 3)
(~ 3)
(~ 2)
(~ 5)
(~ 2)
(~ 3)
(16)
Ag2CO3
iPr2Net
Ag2CO3
iPr2Net
Ag2CO3
iPr2NEt
iPr2Net
Ag2CO3
iPr2NEt
iPr2NEt
3
15 min
15 min
30 min
30 min
30 min
30 min
30 min
40 min
30 min
4
5
6
7
10a
10b
6
22
8
9
10
11
11b
12b
7
8
23
24
(9)
a All reactions were carried out using Pd(OAc)2 and ligand in a molar ratio of 1:1 and 2 equivalents of base.
tracted with Et2O (100 mL). The residue was recrystallized from
EtOH (10 mL) to afford 17 (60 mg, 82%) as pale yellow prisms, mp
105.5–106.5 °C.
1H NMR (60 MHz): = 2.50 (3 H, d, J = 0.9 Hz, CH3), 4.01 (3 H,
s, OCH3), 6.48 (1 H, q, J = 0.9 Hz, C3-H), 6.68 (1 H, d, J = 8.8 Hz,
C6-H), 7.07 (1 H, d, J = 8.8 Hz, C5-H).
IR (KBr): 3450 cm–1.
MS-FAB: m/z [M + H]+ calcd for C11H9F3O5S, 311; found, 311.
1H NMR (60 MHz): = 2.96 (3 H, s, NCH3), 3.33 (1 H, br s, NH),
5.99 (2 H, s, OCH2O), 6.52 (1 H, dd, J = 7.0, 2.1 Hz, C2-H), 7.02–
7.40 (5 H, m, ArH).
The triflate–benzofuran prepared above (3.46 g, 11.2 mmol) was
dissolved in anhyd CH2Cl2 (200 mL) and cooled to –78 °C. Ozone
was bubbled through the solution for 30 min with stirring. The pale–
blue reaction mixture was stirred at the same temperature further for
30 min. Excess ozone was removed by bubbling argon through the
solution for 15 min at –78 °C. DMS (2.0 mL, 27 mmol) was added
and the reaction mixture was stirred at r.t. for 1 h followed by con-
centration under reduced pressure. The residue was diluted with
H2O and extracted with EtOAc (300 mL). To the residue dissolved
in EtOH (60 mL) was added concd HCl (10 mL). The reaction mix-
ture was refluxed for 1 h, poured into H2O (100 mL), and extracted
with EtOAc (500 mL). The residue dissolved in hexanes–EtOAc
(5:1) and subjected to column chromatography on silica gel. Elution
with hexanes–EtOAc (5:1) afforded 19 (1.51 g, 45%) as colorless
plates (from hexanes) mp 75.5–76.5 °C.
Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C,
71.65; H, 5.37; N, 6.85.
6-[(Trifluoromethanesulfonyl)oxy]-2-hydroxy-3-
methoxybenzaldehyde (19)
To a mixture of 18 (2 g, 1.2 mmol) and anhyd NEt3 (3.13 mL, 22.4
mmol) in anhyd CH2Cl2 (40 mL) at 0 °C was added Tf2O (2.83 mL,
16.8 mmol) in CH2Cl2 (10 mL). The mixture was stirred for 20 min
at 0 °C. The mixture was diluted with CH2Cl2 (300 mL) and washed
with 1 N HCl (50 mL), sat. NaHCO3 (50 mL) and brine (80 mL).
The organic layer was dried over anhyd MgSO4. The residue dis-
solved in hexanes–EtOAc (2:1) and was subjected to column chro-
matography on silica gel. Elution with hexanes–EtOAc (2:1)
afforded 4-[(trifluoromethanesulfonyl)oxy]-7-methoxy-2-methyl-
benzo[b]furan (3.46 g, 99%) as colorless oil.
IR (KBr): 3150, 1680, 1140 cm–1.
1H NMR (60 MHz): = 3.94 (3 H, s, OCH3), 6.85 (1 H, d, J = 9.1
Hz, C4-H), 7.10 (1 H, d, J = 9.1 Hz, C5-H), 10.22 (1 H, s, CHO),
11.96 (1 H, s, OH).
IR (CHCl3): 1145 cm–1.
Synthesis 2002, No. 2, 237–241 ISSN 0039-7881 © Thieme Stuttgart · New York

240
T. Harayama et al.
PAPER
MS-FAB: m/z [M + H]+ calcd for C9H7F3O6S, 301; found, 301.
The organic layer was dried over anhyd MgSO4. The residue was
dissolved in CH2Cl2–hexanes (1:1) and was subjected to column
chromatography on silica gel. Elution with CH2Cl2–hexanes (1:1)
afforded 2-[(trifluoromethanesulfonyl)oxy]-4,5-dimethoxybenzal-
dehyde (1.29 g, 75%) as colorless needles (from hexanes) mp 76.5–
78 °C
IR (KBr): 1700, 1140 cm–1.
1H NMR (60 MHz): = 3.96 (3 H, s, OCH3), 3.99 (3 H, s, OCH3),
6.84 (1 H, s, C3-H), 7.42 (1 H, s, C6-H), 10.17 (1 H, s, CHO).
Anal. Calcd for C9H7F3O6S: C, 36.01; H, 2.35. Found: C, 36.31; H,
2.65.
6-[(Trifluoromethanesulfonyl)oxy]-2,3-dimethoxybenzoic Acid
(13)
To a mixture of 19 (1.43 g, 4.76 mmol) and K2CO3 (0.49 mg, 3.57
mmol) in anhyd DMF (50 mL) was added MeI (0.36 mL, 5.72
mmol) and the solution was stirred at r.t. for 2 h. The reaction mix-
ture was diluted with H2O (100 mL) and extracted with Et2O (300
mL). The residue dissolved in CHCl3 (20 mL) was subjected to col-
umn chromatography on silica gel. Elution with CHCl3 afforded 6-
[(trifluoromethanesulfonyl)oxy]-2,3-dimethoxybenzaldehyde (1.30
g, 87%) as colorless needles (from benzene–hexanes) mp 86–87 °C.
IR (KBr): 1700, 1145 cm–1.
1H NMR (60 MHz): = 3.94 (3 H, s, OCH3), 4.02 (3 H, s, OCH3),
7.08 (2 H, m, C4-H, C5-H), 10.42 (1 H, s, CHO).
Anal. Calcd for C10H9 F3O6S: C, 38.22; H, 2.89. Found: C, 38.30;
H, 2.88.
To a stirred mixture of triflate-benzaldehyde (934 mg, 2.97 mmol)
prepared above, monobasic sodium phosphate dihydrate (105 mg,
0.67 mmol) and 35% H2O2 (0.39 mL, 4.46 mmol) in CH3CN (30
mL) and H2O (3 mL) was added. A solution of NaClO2 (80%; 487
mg, 4.31 mmol) in H2O (3 mL) was added to the reaction mixture
and then solution was stirred at 10 °C for 3 h. After the decomposi-
tion of excess H2O2 with 10% aq NaHSO3 solution (20 mL), the
mixture was poured into H2O (100 mL) and extracted with EtOAc
(300 mL). The residue dissolved in hexanes–EtOAc (2:1) was sub-
jected to column chromatography on silica gel. Elution with hex-
anes–EtOAc (2:1) afforded 14 (954 mg, 97%) as colorless needles
(from benzene) mp 168–170 °C.
Anal. Calcd for C10H9 F3O6S: C, 38.22; H, 2.89. Found: C, 38.38;
H, 3.11.
To a stirred mixture of the benzaldehyde (500 mg, 1.59 mmol) pre-
pared above, monobasic NaHSO3 (62 mg, 0.40 mmol) and 35%
H2O2 (0.20 mL, 2.39 mmol) in CH3CN (20 mL) and H2O (1 mL)
were added. A solution of NaClO2 (80%; 270 mg, 2.39 mmol) in
H2O (1 mL) was added and the mixture was stirred at 10 °C for 6 h.
After the decomposition of excess H2O2 with 10% aq NaHSO3 so-
lution (20 mL), the mixture was poured into H2O (100 mL) and ex-
tracted with Et2O (300 mL). The crystalline residue was
recrystallized from Et2O–hexanes (20 mL) to afford 13 (480 mg,
91%) as colorless needles; mp 75–76.5 °C.
IR (KBr): 2950, 1700, 1140 cm–1.
1H NMR (60 MHz): = 3.97 (6 H, s, 2 OCH3), 6.74 (1 H, s, C3-
H), 7.62 (1 H, s, C6-H), 8.81 (1 H, s, COOH).
Anal. Calcd for C10H9 F3O7S: C, 36.37; H, 2.75. Found: C,36.53; H,
2.87.
IR (KBr): 2920, 1715, 1140 cm–1.
1H NMR (60 MHz): = 3.93 (3 H, s, OCH3), 3.98 (3 H, s, OCH3),
6.43 (1 H, bs, COOH), 7.07 (2 H, m, C4-H, C5-H).
2-[(Trifluoromethanesulfonyl)oxy]-4,5-dimethoxy-N-methyl-
N-(6,7-methylenedioxy-1-naphthyl)benzamide (10a)
A solution of 14 (420 mg, 127 mmol) and thionyl chloride (167 mg,
1.40 mmol) in anhyd CH2Cl2 (10 mL) and anhyd pyridine (0.2 mL)
was refluxed for 1.5 h. Then the reaction mixture was concentrated
to dryness under reduced pressure. To this residue was added a so-
lution of 16 (256 mg, 1.27 mmol) in anhyd CHCl3 (10 mL) and an-
hyd Et3N (0.2 mL, 1.53 mmol) and the mixture was stirred for 12 h
at r.t. The reaction mixture was concentrated to dryness and diluted
with CH2Cl2 (300 mL), then washed with 10% HCl (50 mL), sat.
NaHCO3 soln (50 mL) and brine (80 mL). The residue dissolved in
CHCl3 (10 mL) was subjected to column chromatography on silica
gel. Elution with CHCl3 afforded 10a (578 mg, 88%) as colorless
prisms (from benzene–hexanes) mp 184–185 °C.
Anal. Calcd for C10H9 F3O7S: C, 36.37; H, 2.75. Found: C, 36.43;
H, 2.92.
6-[(Trifluoromethanesulfonyl)oxy]-2,3-dimethoxy-N-methyl-
N-(6,7-methylenedioxy-1-naphthyl)benzamide (9a)
A few drops of anhyd DMF and oxalyl chloride (232 mg, 1.82
mmol) were added to a solution of 13 (300 mg, 0.91 mmol) in anhyd
CH2Cl2 (15 mL) under ice-cooling and the mixture was refluxed for
1.5 h. Then the reaction mixture was concentrated to dryness under
reduced pressure. To this residue was added a solution of 16 (210
mg, 1.0 mmol) in anhyd CH2Cl2 (2 mL) and anhyd Et3N (0.16 mL,
1.14 mmol) and this mixture was stirred for 30 min at r.t. The reac-
tion mixture was concentrated to dryness and diluted with CH2Cl2
(100 mL), then washed with 10% HCl (20 mL), sat. NaHCO3 solu-
tion (20 mL) and brine (50 mL). The residue was dissolved in
CHCl3 (10 mL) and subjected to column chromatography on silica
gel. Elution with CHCl3 afforded 9a (293 mg, 63%) as colorless
needles (from benzene–hexanes) mp 213–213.5 °C.
IR (KBr): 1655, 1140 cm–1.
1H NMR (500 MHz): = 3.29 (3 H, s, NCH3), 3.51 (3 H, s, OCH3),
3.74 (3 H, s, OCH3), 6.08 (2 H, s, OCH2O), 6.52 (1 H, s, ArH), 6.53
(1 H, s, ArH), 7.11–7.17 (3 H, m, ArH), 7.26 (1 H, s, ArH), 7.42 (1
H, dd, J = 6.5, 3.0 Hz, ArH).
Anal. Calcd for C22H18 F3 NO8S: C, 51.46; H, 3.53; N, 2.73. Found:
C, 51.74; H, 3.73; N, 2.66.
IR (KBr): 1660, 1145 cm–1.
1H NMR (500 MHz): = 3.27–4.10 (9 H, m, NCH3, 2 OCH3, rot-
amer), 6.06 (2 H, s, OCH2O), 6.63–7.68 (7 H, m, ArH, rotamer).
Coupling Reaction of Amides 9–12 by the Pd Reagent; General
Procedure
The reaction of amides 9–12 (0.3 mmol) in anhyd DMF (8 mL) was
carried out using Pd(OAc)2 and DPPP in a molar ratio of 1:1 and
one equiv of Bu3P, and 2 mol equiv of base under reflux. The reac-
tion mixture was diluted with Et2O (200 mL) and the precipitate was
removed by filtration. The filtrate was washed with 1 N HCl (20
mL), sat. NaHCO3 solution (20 mL) and brine (30 mL). The residue
was dissolved in hexanes–EtOAc (4:1) and subjected to column
chromatography on silica gel. Elution with hexanes–EtOAc (2:1)
gave naphthobenzoazepinones 21–24 and successive elution with
the same solvent afforded the phenanthridones 5–8.
Anal. Calcd for C22H18 F3 NO8S: C, 51.46; H, 3.53; N, 2.73. Found:
C, 51.30; H, 3.61; N, 2.85.
2-[(Trifluoromethanesulfonyl)oxy]-4,5-Dimethoxybenzoic Acid
(14)
To a mixture of 206 (1 g, 5.50 mmol) and anhyd Et3N (1.11 g, 11.0
mmol) in anhyd CH2Cl2 (40 mL) at 0 °C was added Tf2O (2.33 g,
8.25 mmol) in CH2Cl2 (10 mL). The mixture was stirred for 1 h at
0 °C. The mixture was diluted with CH2Cl2 (300 mL) and washed
with 1 N HCl (50 mL), sat. NaHCO3 (50 mL) and brine (80 mL).
Synthesis 2002, No. 2, 237–241 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzo[c]Phenanthridine Alkaloids, Pd(OAc)2, DPPP, and Bu3P
241
9,10-Dimethoxy-7-methyl-1,2-methylenedioxynaphtho[1,8-
cd][2]benzazepin-8(7H)-one (21)
Mp 202–204 °C, pale yellow needles (from hexanes–EtOAc).
IR (KBr): 1660 cm–1.
References
(1) (a) Simanek, V. The Alkaloids, Vol. 26; Brossi, A., Ed.;
Academic Press: New York, 1985, 185. (b) Dostal, J.;
Potacek, M. Collect. Czech. Chem. Commun. 1990, 55,
1H NMR (200 MHz): = 3.40 (3 H, s, NCH3), 3.87 (3 H, s, OCH3),
4.06 (3 H, s, OCH3), 6.11 (2 H, s, OCH2O), 6.92 (1 H, d, J = 9.0 Hz,
C11-H), 6.97 (1 H, s, C3-H), 7.16 (1 H, dd, J = 7.1, 1.6 Hz, C6-H),
7.27 (1 H, dd, J = 7.9, 7.1 Hz, C5-H), 7.34 (1 H, dd, J = 7.9, 1.61 Hz,
C4-H), 7.39 (1 H, d, J = 9.0 Hz, C12-H),
HRMS-FAB: m/z [M + H]+ calcd for C21H18NO5: 364.1185. Found:
364.1138.
2840. (c) Suffiness, M.; Cordell, G. The Alkaloids, Vol. 25;
Brossi, A., Ed.; Academic Press: New York, 1985, 178.
(d) MacKay, S. P.; Meth-Cohn, O.; Waigh, R. D. Adv.
Heterocycl. Chem. 1997, 67, 345. (e) Ishikawa, T.; Ishii, H.
Heterocycles 1999, 50, 627. (f) Herert, J. M.; Augereau, J.;
Gleye, J. P.; Maffrand, J. Biochem. Biophys. Res. Commun.
1990, 172, 993. (g) Fang, S.-D.; Wang, L.-K.; Hecht, S. M.
J. Org. Chem. 1993, 58, 5025. (h) Nakanishi, T.; Suzuki, M.
J. Nat. Prod. 1998, 61, 1263. (i) Vavreckova, C.; Gawlik, I.;
Müller, K. Planta Med. 1996, 62, 397. (j) Schmeller, T.;
Latz-Bruning, B.; Wink, M. Phytochemistry 1997, 44, 257.
(k) Nakanishi, T.; Suzuki, M.; Saimoto, A.; Kabasawa, T. J.
Nat. Prod. 1999, 62, 864; and references cited therein.
(l) Fleury, F.; Sukhanova, A.; Ianoul, A.; Devy, J.; Kudelina,
I.; Duval, O.; Alix, A.; Jardillier, J.; Nabiev, I. J. Biol. Chem.
2000, 275, 3501.
10,11-Dimethoxy-7-methyl-1,2-methylenedioxynaphtho[1,8-
cd][2]benzazepin-8(7H)-one (22)
Mp 232.5–236 °C, colorless needles (from hexanes–EtOAc).
IR (KBr): 1630 cm–1.
1H NMR (500 MHz): = 3.45 (3 H, s, NCH3), 3.87 (3 H, s, OCH3),
3.97 (3 H, s, OCH3), 6.12 (2 H, s, OCH2O), 7.02 (1 H, s, C3-H), 7.12
(1 H, dd, J = 7.5, 1.0 Hz, C6-H), 7.20 (1 H, s, C9-H or C12- H), 7.29
(1 H, dd, J = 7.5, 7.5 Hz, C5-H), 7.36 (1 H, d, J = 7.5 Hz, C4-H),
7.61 (1 H, s, C12-H or C9- H)
MS-FAB: m/z [M + H]+ calcd for C21H18NO5: 364.1185. Found:
364.1214.
(2) Recent papers for synthesis of benzo[c]phenanthridine
alkaloids: (a) Moreno, I.; Tellitu, I.; Etayo, J.; SanMartin,
R.; Domingueez, E. Tetrahedron 2001, 57, 5403; and
references cited therein. (b) Nakanishi, T.; Suzuki, M. Org.
Lett. 1999, 1, 985; and references cited therein. (c)Geen, G.
R.; Mann, I. S.; Mullane, V. M.; McKillop, A. Tetrahedron
1998, 54, 9875. (d) Ishikawa, T.; Saito, T.; Ishii, H.
Tetrahedron 1995, 51, 8447. (e) Minami, T.; Nishimoto, A.;
Hanaoka, M. Tetrahedron Lett. 1995, 36, 9505; and
references cited therein. (f) Seraphin, D.; Lynch, M. A.;
Duval, O. Tetrahedron Lett. 1995, 36, 5731. (g) Lynch, M.
A.; Duval, O.; Pochet, P.; Waigh, R. D. Bull. Soc. Chim. Fr.
1994, 131, 718.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific Rese-
arch (No. 09672144 and 11672103) from the Ministry of Education,
Science, Sports, and Culture. The authors are indebted to the SC-
1
NMR Laboratory of Okayama University for the H NMR experi-
ments.
(3) (a) Harayama, T.; Akiyama, T.; Akamatsu, H.; Kawano, K.;
Abe, H.; Takeuchi, Y. Synthesis 2001, 444. (b) Harayama,
T.; Shibaike, K. Heterocycles 1998, 49, 191. (c) Harayama,
T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.;
Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001,
523.
(4) Harayama, T.; Akiyama, T.; Nakano, Y. Chem. Pharm. Bull.
1997, 45, 1723.
(5) Ishii, H.; Kenmotsu, K.; Döpke, W.; Harayama, T. Chem.
Pharm. Bull. 1992, 40, 1770.
(6) Sihababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48,
1941.
Synthesis 2002, No. 2, 237–241 ISSN 0039-7881 © Thieme Stuttgart · New York