Total synthesis of benzo[c]phenanthridine alkaloids, chelerythrine and 12-methoxydihydrochelerythrine, by a palladium-assisted internal biaryl coupling reaction

Article abstract of DOI:10.1055/s-2001-11424

A covenient and versatile synthesis of benzo[c]phenanthridine alkaloids, chelerythrine (1) and 12-methoxydihydrochelerythrine (5), was accomplished via an internal aryl-aryl coupling reaction of haloamides 8 and 9 by a palladium-assisted cyclization reaction.

Full text of DOI:10.1055/s-2001-11424

444
PAPER
Total Synthesis of Benzo[c]phenanthridine Alkaloids, Chelerythrine and
12-Methoxydihydrochelerythrine, by a Palladium-Assisted Internal Biaryl
Coupling Reaction
Takashi Harayama,* Toshihiko Akiyama, Hisashi Akamatsu, Kazuko Kawano, 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 25 September 2000; revised 25 October 2000
a convenient and versatile method for synthesizing these
Abstract: A covenient and versatile synthesis of benzo[c]phenan-
alkaloids.
thridine alkaloids, chelerythrine (1) and 12-methoxydihydrochel-
erythrine (5), was accomplished via an internal aryl-aryl coupling
reaction of haloamides 8 and 9 by a palladium-assisted cyclization
reaction.
Recently, we accomplished the total synthesis of 1 by an
internal biaryl coupling reaction of haloamides 8 using a
palladium reagent as shown in Scheme 1.3 Subsequently,
in order to examine the generality of this method, we ap-
plied it to the synthesis of 12-methoxydihydrocheleryth-
rine (5), which was isolated from Bocconia integrifolia
Humb. & Bonpl. in 1991,4 and succeeded in the total syn-
thesis of 5. The details of these results are the subject of
this paper.
Key words: alkaloids, internal aryl-aryl coupling, ring closure,
Heck-type reaction, palladium, haloamides
Introduction
Fully aromatized benzo[c]phenanthridine alkaloids have
attracted much attention because of their potent pharma-
cological activities.1 It was recently found that, among
these alkaloids, chelerythrine (1)1f and fagaridine (2)1g,1h
inhibited protein kinase C and DNA topoisomerase 1, re-
spectively, and sanguinarine (3)1i,1j showed inhibition of
lipoxygenase and mediated chemical defense against mi-
croorganisms, virus and herbivores in plants. Moreover,
nitidine (4) and related compounds1k including
ethoxidine1l possessing 12-alkoxy group showed strong
antileukemic activity including the inhibition of DNA to-
poisomerases. Although many reports on the total synthe-
sis of fully aromatized benzo[c]phenanthridine alkaloids
have been published,2 the methods had some disadvantag-
es such as excessive number of steps, low yield, and/or ab-
sence of generality. Therefore, we endeavored to develop
Internal Coupling Reaction of N-Methylbenzanalide
Derivatives 13
The cross-coupling reaction with a palladium catalyst has
been an extremely useful tool in organic synthesis.5 We
designed a synthetic plan for 1 and 5 involving an internal
biaryl cyclization by palladium as the key reaction,6 as
shown in Scheme 1. Since the coupling product, oxychel-
erythrine (6), has already been converted into cheleryth-
rine (1),7 the synthesis of 6 indicates a formal synthesis of
1. It was reported that an internal coupling reaction of
bromoamide 13b with a Pd reagent proceeded in 50%
yield. 6a In order to improve the yield, the cyclization re-
action including iodoamide 13a7 was re-examined using
purified Pd(OAc)2,9 a phosphine ligand and a base. The
OMe
R3
12
R = R1 = OMe, R2 =R3= H
R = OMe, R1 = OH, R2 =R3= H
R, R1 = OCH2O, R2 =R3= H
R = R3= H, R1 = R2 = OMe
R = R1 = R3= OMe, R2 = H
chelerythrine (1)
fagaridine (2)
O
12
O
O
O
sanguinarine (3)
R2
R1
N
MeO
nitidine (4)
+
Me
N
MeO
12-methoxychelerythrine (19)
Me
R
12-methoxydihydrochelerythrine (5)
R
R
R
O
O
O
O
O
X
X
O
+
N
MeO
CO2H
N
MeO
MeO
Me
MeO
Me
NH2
O
MeO
O
MeO
11 : R = H
12 : R = OMe
8 : R = H
10
oxychelerythrine (6) R = H
7 : R = OMe
9 : R = OMe
a series : X = I, b series : X = Br
Synthesis 2001, No. 3, 444–450 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Benzo[c]phenanthridine Alkaloids, Chelerythrine and 12-Methoxydihydrochelerythrine
445
results are summarized in Table 1. By using Pd(OAc)2 doamide 8a was more reactive than the bromoamide 8b.
(0.2 equivalent) Ph3P and Ag2CO3, the solvent had no cru- Since the coupling product 6 had already been converted
cial effect on the internal coupling reaction of iodoamide into chelerythrine (1),7 the synthesis of 6 indicates a for-
13a, although Ag2CO3 was superior to diisopropylethy- mal synthesis of 1.
lamine. Interestingly, good results were obtained when no
phosphine ligand was employed (see runs 10 and 11 in Ta-
ble 1).5c,5d On the other hand, the coupling reaction of bro-
OH
OH
1) i-AmONO
O
moamide 13b proceeded slowly even when using a
O
O
2) Pd/C, H2
3) CH3COCl
63%
stoichiometric amount of Pd(OAc)2 in the presence of
PPh3 as a ligand in DMF (see run12 in Table 1). However,
on using tri(o-tolyl)phosphine [(o-Tol)3P] as a ligand, the
reaction proceeded smoothly with 0.2 equivalent of
Pd(OAc)2 and gave phenanthridone 146a,8b in an excellent
yield (see run 13 in Table 1).
O
NHAc
15
16
OMe
O
O
MeI
1N HCl
72%
.
12 HCl
86%
NHAc
17
Synthesis of Oxychelerythrine (6)
Scheme 2
Since the palladium-mediated coupling reaction of benza-
nilide derivatives 13 was successful as shown in Table 1,
we investigated the total synthesis of 1 utilizing this meth-
od. Our concise synthetic route is outlined in Scheme 1.
Starting materials 8 for the cyclization reaction were pre-
pared from the iodoacid 10a10 or bromoacid 10b11 and
naphthylamine 11.12 Thus, successive treatment of 10
with oxalyl chloride and 11 in the presence of triethy-
lamine afforded secondary amides, which were methylat-
ed with methyl iodide in the presence of sodium hydride
in DMF to give iodoamide 8a and bromoamide 8b in 56%
and 72% yields, respectively. The coupling reaction of
both haloamides 8 with Pd(OAc)2, PPh3 or (o-Tol)3P and
Ag2CO3 in DMF under reflux afforded oxychelerythrine
(6)7 in excellent yield as shown in Table 2, although io-
Synthesis of 12-Methoxydihydrochelerythrine (5)
We subsequently investigated the total synthesis of 5 uti-
lizing the method according to the synthetic route outlined
in Scheme 1. The preparation of the key compound 9a
was realized by condensation between the carboxylic acid
1010 and naphthylamine 12, which was derived from 6,7-
methylenedioxy-1-naphthol (15)13 via several steps as
shown in Scheme 2. Thus, the basic nitrosation of 15 fol-
lowed by hydrogenation14 and acetylation afforded acetyl
amide 16 in 63% yield. The methylation of 16 gave 17 in
X
N
N
Me
Me
O
O
13a X=I
13b X=Br
14
Table 1 Results of Cyclization Reaction of 2-Halo-N-methyl-N-phenylbenzamide (13)a
Substrate
Run
Pd(OAc)2
(equiv)
Ligand
Base
Solvent
Temp.
Time
Yield (%)
14
S.M.
13a
1
2
3
4
5
6
7
8
9
0.05
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
PPh3
PPh3
P(o-Tol)3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
i-Pr2NEt
i-Pr2NEt
Ag2CO3
AcONa
DMF
DMF
DMF
DMF
xylene
benzene
CH3CN
DMF
benzene
DMF
Refl.
Refl.
Refl.
30 35ºC
30 35ºC
Refl.
Refl.
Refl.
40 min
15 min
15 min
35 h
79
93
93
85
93
98
95
21
45
90
96
23 h
10 min
15 min
4.5 h
6 h
20 min
25 min
7
14
Refl.
Refl.
Refl.
10
11
DMF
13b
12
13
1.0
0.2
PPh3
P(o-Tol)3
Ag2CO3
Ag2CO3
DMF
DMF
Refl.
Refl.
60 h
1.5 h
75
99
7
a All reactions were carried out using Pd(OAc)2 and ligand in a ratio of 1:2 and 2 mol equivalent of base.
Synthesis 2001, No. 3, 444–450 ISSN 0039-7881 © Thieme Stuttgart · New York

446
T. Harayama et al.
PAPER
Table 2 Results of Cyclization Reaction of 6-Halo-2,3-dimethoxy-
N-methyl-N-(6,7-methylenedioxy-1-naphthyl)benzamide (8) to Oxy-
chelerythrine (6) in DMF under Refluxa
In conclusion, the biaryl coupling reaction using the Pd re-
agent is very convenient and effective for preparing ben-
zo[c]phenanthridine alkaloids. We are presently
investigating the generality of this method.
Sub- Run Pd(OAc)2 Ligand
Base
Time
Yield
(%)
6
strate
(equiv)
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-
photometer and 1H and 13C NMR spectra in CDCl3 on a Hitachi R-
1500 (60 MHz) or Varian VXR-200 (200 MHz) or 500 (500 MHz)
spectrometer unless otherwise stated. NMR data are reported in
parts per million downfield from TMS as an internal standard ( =
0.0) and coupling 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 atmo-
sphere and the extract was washed with brine, dried over anhyd
MgSO4, then filtered, and the filtrate was evaporated to dryness un-
der reduced pressure, unless otherwise noted. Pd(OAc)2 was treated
with boiling benzene and the mixture was filtered while hot. The hot
filrate was then concentrated to dryness to give purified Pd(OAc)2.9
8a
1
2
0.2
0.2
PPh3
Ag2CO3 20 min 85
P(o-Tol)3 Ag2CO3 20 min 94
8b
3
4
0.2
0.2
PPh3
Ag2CO3 2 h
79
96
P(o-Tol)3 Ag2CO3 3 h
a All reactions were carried out in the presence of ligand (0.4 equiv)
and base (2 equiv).
86% yield, which was hydrolyzed with hydrochloric acid
to give naphthylamine 12 as its hydrochloride in 72%
yield. Successive treatment of 10 with oxalyl chloride and
12 in the presence of triethylamine afforded a secondary
amide, which was methylated with methyl iodide in the
presence of sodium hydride in DMF to give the amide 9a
in 76% yield. The coupling reaction of amide 9a with
Pd(OAc)2, a phosphine ligand and Ag2CO3 in DMF under
reflux afforded 12-methoxyoxychelerythrine (7) in excel-
lent yield along with a small amount of benzoazepinone
1815 as shown in Table 3 (see runs 2 4 in Table 3). The
structures of both the products 7 and 18 were elucidated
Cyclization Reaction of N-Methylbenzanilides 13 by Palladium
Reagent; General Procedure
The reaction of 13 (30.8 mg, 62.7 mmol) with Pd(OAc)2, a phos-
phine ligand, and Ag2CO3 (36.4 mg, 125 mmol) in anhyd DMF (3
mL) was carried out under the reaction conditions indicated in Ta-
ble 1. The reaction mixture was diluted with Et2O and the precipi-
tate was removed by filtration. The filtrate was washed with brine
and the solvent evaporated. The residue was dissolved in CHCl3 and
subjected to column chromatography on silica gel. Elution with
hexane/EtOAc (4:1) gave phenanthridone (14) as colorless needles
(from hexane); mp 110 111°C (Lit.,6a mp 105 108 °C; Lit.,8b mp
108.5 °C).
1
on the basis of spectral data, especially H NMR of 7
which showed three singlet signals due to aromatic
protons, whereas 18 showed only one singlet signal
for an aromatic proton (see Experimental). Reduction
of 7 with LiAlH4 followed by treatment with HCl gave
12-methoxychelerythrine (19) in 82% yield, which was
reduced with NaBH4 to afford 12-methoxydihydrochel-
erythrine (5) (mp 173 175 °C)16 in 77% yield. Spectral
data of the synthetic material were in good agreement
with the reported data of the authentic sample as shown in
Table 4.
6-Iodo-2,3-dimethoxy-N-methyl-N-(6,7-methylenedioxy-1-
naphthyl)benzamide (8a)
Oxalyl chloride (840 mg, 6.49 mmol) was added to a solution of 10a
(1.02 g, 3.25 mmol) in anhyd CH2Cl2 (30 mL) and the stirred mix-
ture was refluxed for 90 min. Then, the mixture was concentrated to
dryness under reduced pressure. To this residue was added a solu-
tion of 11 (495 mg, 2.60 mmol) in anhyd CH2Cl2 (15 mL) and anhyd
Table 3 Results of Cyclization Reaction of 6–Iodo–2,3–dimethoxy–N–(4–methoxy–6,7–methylenedioxy–1–naphthyl)–N–methylbenzamide
(9a) to 7,8,12–Trimethoxy–5–methyl–2,3–methylenedioxy–6(5H)–benzo[c]phenanthridinone (7) in DMF under Reflux
O
MeO
OMe
O
O
O
I
+
7
N
N
MeO
MeO
Me
Me
MeO
O
MeO
O
9a
18
Run
Pd(OAc)2
Ligand
L/Pda
Base
Time (min)
Yield (%)
(equiv)
7
18
1
2
3
4
5
0.2
0.2
0.2
0.2
0.2
P(o-Tol)3
PPh3
2
2
1
2
2
Na2CO3
Ag2CO3
Ag2CO3
Ag2CO3
NaOAc
180
30
30
30
120
51
91
86
95
20
-
9
6
5
-
DPPPb
P(o-Tol)3
P(o-Tol)3
a Molar ratio between ligand and Pd(OAc)2.
b DPPP:1,3-Bis(diphenylphosphino)propane.
Synthesis 2001, No. 3, 444–450 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Benzo[c]phenanthridine Alkaloids, Chelerythrine and 12-Methoxydihydrochelerythrine
447
Table 4 Comparison of 13C and 1H NMR Spectral Data Derived from 12–Methoxydihydrochelerythrine (5)a and Synthetic Sample
Carbon
12–Methoxydihydrochelerythrine (5)
Synthetic Sample
1Hb
13Cc
1Hd
13Ce
mult; (J, Hz)
mult; (J, Hz)
C–1
C–2
C–3
C–4
C–4a
C–4b
C–6
7.55 s
7.67 s
4.27 s
99.5
148.5
147.2
100.7
127.5
136.3
49.0
7.55 s
99.5
148.4
147.2
100.7
127.4
135.9
49.0
7.65 s
4.27 s
C–6a
C–7 ·
C–8
C–9
C–10
C–10a
C–10b
C–11
126.6
146.3
152.4
110.9
118.5
126.5
124.2
98.7
126.4
146.2
152.3
110.8
118.5
126.4
123.9
98.7
6.94 d (8.5)
7.48 d (8.5)
6.94 d (8.5)
7.48 d (8.5)
7.05 s
7.05 s
C–12
152.4
122.4
101.0
41.3
61.0
55.9
152.3
122.4
101.0
41.3
61.1
55.8
C–12a
–OCH2O– (2,3)
N–Me
7–OMe
8–OMe
12–OMe
6.05 s
2.53 s
3.87 s
3.93 s
4.03 s
6.05 s
2.53 s
3.87 s
3.93 s
4.03 s
55.7
55.7
a See reference 4.
b 1H NMR recorded in CDCl3 at 300 MHz; shifts in ppm.
c 13C NMR recorded in CDCl3 at 75.5 MHz; shifts in ppm.
d 1H NMR recorded in CDCl3 at 500 MHz; shifts in ppm.
e 13C NMR recorded in CDCl3 at 125 MHz; shifts in ppm.
Et3N (394 mg, 3.90 mmol) and the mixture was stirred for 50 min
at r.t. The mixture was concentrated to dryness and diluted with
CH2Cl2, then washed with 10% HCl, aq sat. NaHCO3 solution and
brine. The residue was dissolved in CHCl3 and the solution was sub-
jected to column chromatography on silica gel. Elution with hex-
ane/EtOAc (3:1) gave 6-iodo-2,3-dimethoxy-N-(6,7-methylene-
dioxy-1-naphthyl)benzamide (891 mg, 58%) as colorless needles
(from benzene); mp 268 268.5 °C.
Anal. calcd for C21H18INO5: C, 51.34; H, 3.69; N, 2.85. Found : C,
51.55; H, 3.82; N, 2.88.
6-Bromo-2,3-dimethoxy-N-methyl-N-(6,7-methylenedioxy-1-
naphthyl)benzamide (8b)
A few drops of anhyd DMF and oxalyl chloride (788 mg,
6.13 mmol) were added to a solution of 10b (1.02 g, 3.25 mmol) in
anhyd CH2Cl2 (30 mL) and the stirred mixture was refluxed for 80
min. Then the mixture was concentrated to dryness under reduced
pressure. To this residue was added a solution of 11 (458 mg,
2.45 mmol) in anhyd CH2Cl2 (15 mL) and anhyd Et3N (372 mg,
3.67 mmol) and the mixture was stirred for 1 h at r.t. The mixture
was concentrated to dryness and diluted with CH2Cl2, then washed
with 10% HCl, aq sat. NaHCO3 solution and brine. The residue was
dissolved in CHCl3 and the solution was subjected to column chro-
matography on silica gel. Elution with hexane/EtOAc (3:1) gave
6-bromo-2,3-dimethoxy-N-(6,7-methylenedioxy-1-naphthyl)benz-
amide (1.01 g, 77%) as colorless needles (from benzene/hexane),
mp 237.5 239 °C.
1
IR (KBr): = 3250, 1660 cm .
1H NMR (60 MHz): = 3.86 (6 H, s, 2 × OCH3), 6.15 (2 H, s,
OCH2O), 6.98 (1 H, d, J = 8.8 Hz, C4- or C5’-H), 7.35 (1 H, s, C5-
H), 7.45 7.67 (5 H, m, aromatic protons), 10.29 (1 H, br s, NH).
FAB-MS (positive ion mode): m/z = 478 [M+ + 1].
Anal. calcd for C20H16INO5: C, 50.33; H, 3.38; N, 2.93. Found : C,
50.58; H, 3.50; N, 2.80.
To a suspension of iodobenzamide prepared as above (500 mg,
1.05 mmol) and NaH (121 mg 63% dispersion in mineral oil, 3.14
mmol) in anhyd DMF (30 mL) was added MeI (164 mg, 1.15
mmol). After stirring for 90 min at r.t., the reaction mixture was di-
luted with Et2O and washed with 10% HCl and brine. The residue
dissolved in EtOAc/hexane was subjected to column chromatogra-
phy on silica gel. Elution with hexane/EtOAc (2:1) gave 8a (496
mg, 96%) as colorless needles (from EtOAc); mp 176 177 °C.
1
IR (KBr): = 3250, 1660 cm .
1H NMR (60 MHz, DMSO-d6): = 3.87 (6 H, s, 2 × OCH3), 6.15 (2
H, s, OCH2O), 6.97 (1 H, d, J = 8.8 Hz, C4- or C5-H), 7.35 (1 H, s,
C5’-H), 7.45 7.67 (5 H, m, aromatic protons), 10.28 (1 H, br s, NH).
Anal. calcd for C20H16BrNO5: C, 55.83; H, 3.75; N, 3.26. Found : C,
55.89; H, 3.79; N, 3.12.
1
IR (KBr): = 1650 cm .
1H NMR (60 MHz): = 3.19 (3 H, s, NCH3), 3.56 4.02 (6 H, m,
2 × OCH3), 6.05 (2 H, s, OCH2O), 6.68 7.73 (7 H, m, aromatic pro-
tons).
To a suspension of bromobenzamide prepared as above (500 mg,
1.16 mmol) and NaH (134 mg, 63% dispersion in mineral oil,
3.49 mmol) in anhyd DMF (30 mL) was added MeI (165 mg,
1.16 mmol). The reaction mixture was stirred for 5 h at r.t., diluted
with Et2O and then washed with 10% HCl and brine. The residue
FAB-MS (positive ion mode): m/z = 492 [M+ + 1].
Synthesis 2001, No. 3, 444–450 ISSN 0039-7881 © Thieme Stuttgart · New York

448
T. Harayama et al.
PAPER
was dissolved in CHCl3 and subjected to column chromatography
on silica gel. Elution with EtOAc gave 8b (478 mg, 93%) as color-
less needles (from benzene/hexane), mp 178 179 °C.
4-Methoxy-6,7-methylenedioxy-1-naphthylamine (12) Hydro-
chloride
A solution of 17 (101 mg, 0.39 mmol) in 1 N HCl (5 mL) and
MeOH (5 mL) was refluxed for 7.5 h and evaporated to dryness un-
der reduced pressure. The residue was recrystallized from MeOH/
Et2O to give 12·HCl (71 mg, 72%) as colorless prisms; mp 201 205
°C.
1
IR (KBr): = 1650 cm .
1H NMR (60 MHz, DMSO-d6): = 3.13 3.98 (9 H, m, NCH3 and
2 × OCH3), 6.18 (2 H, s, OCH2O), 6.82 7.85 (7 H, m, aromatic pro-
tons).
1
IR (KBr): = 2900 (br), 2560 cm .
Anal. calcd for C21H18BrNO5: C, 56.77; H, 4.08; N, 3.15. Found : C,
57.01; H, 4.15; N, 3.20.
1H NMR (60 MHz): = 3.91 (3 H, s, OCH3), 6.04 (2 H, s, OCH2O),
6.60 (2 H, C2 and C3-H), 7.14 (1 H, s, C5-H), 7.55 (1 H, s, C8-H).
FAB-MS (positive ion mode): m/z = 218 [M + 1]+.
Oxychelerythrine (6) from Haloamides 8 Catalyzed by Palladi-
um Reagent; General Procedure
Anal. calcd for C12H12NO3•1/9H2O : C, 56.37; H, 4.82; N, 5.48.
Found : C, 56.30; H, 4.77; N, 5.40.
Reaction of 8 (62.7 mmol) with Pd(OAc)2, a phosphine ligand, and
Ag2CO3 (36.4 mg, 125 mmol) in anhyd DMF (3 mL) was carried
out under the reaction conditions indicated in Table 2. The reaction
mixture was diluted with Et2O and the precipitate was removed by
filtration. The filtrate was washed with brine and the solvent was
evaporated. The residue was dissolved in CHCl3 and subjected to
column chromatography on silica gel. Elution with hexane/EtOAc
(2:1) gave oxychelerythrine (6) as colorless needles (from ben-
zene); mp 209 211°C (Lit.7b mp 199 203 °C). This compound was
identical with an authentic sample of oxychelerythrine (6).7
6-Iodo-2,3-dimethoxy-N-(4-methoxy-6,7-methylenedioxy-1-
naphthyl)-N-methylbenzamide (9a)
A few drops of anhyd DMF and oxalyl chloride (951 mg,
7.49 mmol) were added to a solution of 10a (961 mg, 3.12 mmol)
in anhyd CH2Cl2 (40 mL) under ice-cooling and the mixture was re-
fluxed for 3 h. Then the mixture was concentrated to dryness under
reduced pressure. To this residue was added a solution of 12
(660 mg, 2.60 mmol) in anhyd CH2Cl2 (20 mL) and anhyd Et3N
(757 mg, 7.49 mmol) and the mixture was stirred for 30 min at r.t.
The mixture was concentrated to dryness and diluted with CH2Cl2,
then washed with 10% HCl, aq sat. NaHCO3 solution and brine. The
residue was recrystallized from CHCl3/hexane to give 6-iodo-2,3-
dimethoxy-N-(4-methoxy-6,7-methylenedioxy-1-naphthyl)benza-
mide (1.11 g, 84%) as colorless needles; mp 284 285.5 °C.
N-(4-Hydroxy-6,7-methylenedioxy-1-naphthyl)acetamide (16)
To a suspension of 15 (1.73 g, 9.21mmol) and K2CO3(12.7 g,
11.1 mmol) in DMF (30 mL) was added isoamyl nitrite (1.49 mL)
under ice-cooling and the mixture was stirred for 30 min at 0 °C. Af-
ter stirring for an additional 90 min at r.t., the mixture was poured
into H2O and extracted with EtOAc. A solution of the residue in
THF (50 mL) was hydrogenated at r.t. and at atmospheric pressure
in the presence of 10% Pd/C (220 mg). After disappearance of the
starting material on TLC, the mixture was filtered. To the filtrate
were added pyridine (10 mL) and acetyl chloride (1 mL). The mix-
ture was stirred for 20 min at r.t. and poured into 5% HCl and then
extracted with Et2O. The residue was recrystallized from acetone/
hexane to afford 16 (1.43 g, 63%) as colorless needles; mp 254 256
°C.
1
IR (KBr): = 3240, 1655 cm .
1H NMR (200 MHz, DMSO-d6): = 3.86 (3 H, s, OCH3), 3.87 (3
H, s, OCH3), 3.95 (3 H, s, OCH3), 6.16 (2 H, s, OCH2O), 6.90 (1 H,
d, J = 8.3 Hz, C9-H), 6.98 (1 H, d, J = 8.6 Hz, C4-H), 7.33 (1 H, d,
J = 8.3 Hz, C8-H), 7.45 (1 H, s, C11 or C14-H), 7.59 (1 H, d, J = 8.6
Hz, C5-H), 10.13 (1 H, br s, NH).
FAB-MS (positive ion mode): m/z = 507 [M+ + 1].
Anal. calcd for C21H18INO6: C, 49.72; H, 3.58; N, 2.76. Found: C,
49.31; H, 3.78; N, 2.94.
1
IR (KBr): = 3240, 1620 cm .
1H NMR (500 MHz, DMSO-d6): = 2.09 (3 H, s, COCH3), 6.12 (2
H, s, OCH2O), 6.69 (1 H, d, J = 8.6 Hz, C3-H), 7.11 (1 H, d, J = 8.5
Hz, C2-H), 7.19 (1 H, s, C5-H), 7.39 (1 H, s, C8-H), 9.47 (1 H, s,
NH), 9.89 (1 H, s, OH).
To a suspension of the iodobenzamide prepared as above (122 mg,
0.24 mmol) and NaH (48 mg 63% dispersion in mineral oil,
1.2 mmol) in anhyd DMF (10 mL) was added MeI (102 mg,
0.72 mmol). After stirring for 20 h at r.t., the reaction mixture was
diluted with EtOAc and washed with 10% HCl and brine. The resi-
due was dissolved in EtOAc/hexane and subjected to column chro-
matography on silica gel. Elution with CHCl3 gave 9a (115 mg,
91%) as colorless prisms; mp 186 187 °C.
Anal. calcd for C13H11NO4: C, 63.67; H, 4.52; N, 5.17. Found :
C,63.41; H, 4.79; N, 5.59.
N-(4-Methoxy-6,7-methylenedioxy-1-naphthyl)acetamide (17)
To a suspension of 16 (34.3 mg, 0.14 mmol) and K2CO3 (14.5 mg,
0.105 mmol) in anhyd DMF (2 mL) was added MeI (0.013 mL).
The reaction mixture was stirred for 20 min at r.t. and poured into
5% HCl and then extracted with EtOAc. The residue was recrystal-
lized from CHCl3/hexane to afford 17 (31.3 mg, 86%) as colorless
needles; mp 254 255 °C.
1
IR (KBr): = 1645 cm .
1H NMR (200 MHz): = 3.17 4.01 (12 H, m, 3 × OCH3 and NCH3
rotamer), 6.05 (2 H, m, OCH2O, rotamer), 6.36 7.67 (6 H, m, aro-
matic protons, rotamer).
Anal. calcd for C22H20INO6: C, 50.69 H, 3.87; N, 2.69. Found: C,
50.89; H, 4.08; N, 2.58.
1
IR (KBr): = 3260, 1680 cm .
1H NMR (200 MHz, DMSO-d6): = 2.11 (3 H, s, COCH3), 3.92 (3
H, s, OCH3), 6.14 (2 H, s, OCH2O), 6.82 (1 H, d, J = 8.2 Hz, C3-H),
7.27 (1 H, d, J = 8.2 Hz, C2-H), 7.27 (1 H, s, C5-H), 7.42 (1 H, s, C8-
H), 9.56 (1 H, s, NH).
Cyclization of Iodoamide (9a) by Palladium Reagent; General
Procedure
Reaction of 9a (52.1 mg, 0.10 mmol) with Pd(OAc)2 (4.5 mg,
0.02mmol), a phosphine ligand, and a base in anhyd DMF (3 mL)
was carried out under the reaction conditions indicated in Table 3.
The reaction mixture was diluted with Et2O and the precipitate was
removed by filtering. The filtrate was washed with brine and the sol-
vent was evaporated. The residue was dissolved in CHCl3 and sub-
jected to column chromatography on silica gel. Elution with CHCl3
gave 4,9,10-trimethoxy-7-methyl-1,2-methylenedioxy-8(7H)ben-
ACPI-MS (positive ion mode): m/z = 260 [M + 1]+.
Anal. calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found : C,
64.22; H, 5.04; N, 5.40.
Synthesis 2001, No. 3, 444–450 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Benzo[c]phenanthridine Alkaloids, Chelerythrine and 12-Methoxydihydrochelerythrine
449
zo[e]naphth[1,8-bc]azepinone (18) and successive elution with the
same solvent gave 7,8,12-trimethoxy-5-methyl-2,3-methylene-
dioxy-6(5H)-benzo[c]phenenthridone (12-methoxyoxycheleryth-
rine) (7).
thoxydihydrochelerythrine and to the SC-NMR Laboratory of Oka-
yama University for the NMR experiments.
References
18
Mp 251 253°C; colorless prisms (from EtOAc).
(1) (a) Simanek, V. The Alkaloids, Vol. 26; Brossi A., Ed.;
Academic Press: New York, 1983, pp. 185 240.
(b) Dostal, J.; Potacek, M. Coll. Czech. Chem. Commun. 1990,
55, 2840.
1
IR (KBr): = 1645 cm .
1H NMR (200 MHz): = 3.36 (3 H, s, NCH3), 3.87 (3 H, s, OCH3),
3.94 (3 H, s, OCH3), 4.06 (3 H, s, OCH3), 6.12 (2 H, s, OCH2O),
6.66 (1 H, d, J = 8.4 Hz, C5-H), 6.91 (1 H, d, J = 9.0 Hz, C11-H),
7.09 (1 H, d, J = 8.4 Hz, C6-H), 7.37 (1 H, d, J = 9.0 Hz, C12-H),
7.42 (1 H, s, C3-H).
(c) Suffiness, W. M.; Gordell, G. A. The Alkaloids, Vol. 25;
Brossi A.,Ed.; Academic Press: New York, 1983, pp 178 188
(d) MacKay, S. P.; Meth-Cohn, O.; Waigh, R. D. Adv.
Heterocyclic Chem. 1997, 67, 345
(e) Ishikawa,T.; Ishii, H. Heterocycles 1999, 50, 627.
(f) Herert, J. M.; Augereau, J. M.; 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 Medica
1996, 62, 397.
Anal. calcd for C22H19NO6: C, 67.17; H, 4.87; N, 3.56. Found: C,
67.15; H, 5.09; N, 3.54.
7
Mp 168 170°C; colorless needles (from EtOH) (Lit.17 mp 108
110°C).
IR (KBr): = 1645 cm-1.
1H NMR (60 MHz): = 3.86 (3 H, s, NCH3), 3.98 (3 H, s, OCH3),
4.08 (6 H, s, 2 × OCH3), 6.08 (2 H, s, OCH2O), 7.28 (1 H, s, C11-H),
7.35 (1 H, d, J = 9.1 Hz, C9-H), 7.49 (1 H, s, C1-H), 7.61 (1 H, s, C4-
H), 7.91 (1 H, d, J = 9.1 Hz, C10-H).
(j) Schmeller, T.; Latz-Bruning, B.; Wink, M. Phytochemistry
1997, 44, 257.
(k) Nakanishi, T.; Suzuki, M.; Saimoto, A.; Kawabata,T. J.
Nat. Prod. 1999, 62, 864, and references cited therein.
(l) Fleury, F.; Sukhanova, a.; Ianoul, A.; Devy, J.; Kudelina,
I.; Duva, O.; Alix, A. J. P.; Jardillier, J. C.; Nabiev, I. J. Biol.
Chem. 2000, 275, 3501.
High Resolution FAB-MS: Calcd for C22H19NO6: 393.1212. Found:
393.1270.
12-Methoxychelerythrine Chloride (19)
(2) Review related to Refs, including 1a-e:
(a) Ninomiya, I.; Naito, T. Recent Dev. Chem. Nat. Carbon
Comp. 1984, 10, 9.
LiAlH4 (6.8 mg, 0.3 mmol) was added to a solution of 7 (39.4 mg,
0.10 mmol) in anhyd THF (2 mL) and the mixture was stirred for
20 min at r.t. Excess hydride was decomposed with wet Et2O and
the organic layer was decanted. The residue was treated with 10%
HCl (2 mL) at r.t. to produce 19 (20.4 mg, 82%) as yellow needles
(from EtOH/Et2O), mp 175 °C.
For recent papers for synthesis of benzo[c]phenanthridine
alkaloids, see:
(b) Nakanishi,T.; Suzuki, M. Org. Lett. 1999, 1, 985, and
references cited therein.
1H NMR (200 MHz, CD3OD): = 4.12 (3 H, s, OCH3), 4.25 (3 H,
s, OCH3), 4.26 (3 H, s, OCH3), 4.91 (3 H, s, NCH3), 6.26 (2 H, s,
OCH2O), 7.73 (1 H, s, C11-H), 7.79 (1 H, C1-H), 8.06 (1 H, C4-H),
8.12 (1 H, d, J = 9.5 Hz, C9-H), 8.62 (1 H, d, J = 9.1 Hz, C10-H),
9.72 (1 H, s, C6-H).
(c) Geen, G. R.; Mann, I. S.; Mullane, 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.
Anal. calcd for C22H20ClNO5 H2O: C, 61.19; H, 5.14; N, 3.24.
Found: C, 61.42; H, 4.85; N, 3.22.
(g) Lynch, M. A.; Duval, O.; Pochet, P.; Waigh, R. D. Bull.
Soc. Chim. Fr. 1994, 131, 718.
(3) Harayama, T.; Akiyama, T.; Kawano, K. Chem. Pharm. Bull.
1996, 44, 1643.
(4) Oechslin, S. M.; Konig, G. M.; Oechslin-Merkel, K.; Wright,
A. D.; Kinghorn, A. D.; Stiche, O. J. Nat. Prod. 1991, 54, 519.
(5) (a) Tsuji, J. Palladium Reagents and Catalysts, John Wiley &
Sons Inc. New York, 1995; pp 125-252.
12-Methoxydihydrochelerythrine (5)
A solution of 19 (26.6 mg, 0.07 mmol) and NaBH4 (19.0 mg,
0.50 mmol) in absolute MeOH (2.5 mL) was stirred at r.t. for 30
min. The mixture was diluted with H2O and extracted with CHCl3.
The residue was subjected to column chromatography on Al2O3
with benzene to afford 5 (18.7 mg, 77%) as pale yellow needles
(from benzene/MeOH); mp 173 174.5°C.
1H NMR (500 MHz) and 13C NMR (125 MHz) data are given in Ta-
ble 4.
(b) Knight, D.W. Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M., Fleming I., Eds.; Pergamon: Oxford, 1991; pp
481 520.
(c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
(d) Beletskaya, I. P.; Cheorakov, A. V. Chem. Rev. 2000, 100,
3009.
Anal. calcd for C22H21NO5: C, 69.64; H, 5.58; N, 3.69. Found: C,
69.62; H, 5.79; N, 3.61.
The NMR data of the synthetic sample were identical with the re-
ported data of the authentic sample.4
(6) (a) Ames D. E.; Opaeko A. Tetrahedron 1984, 40, 1919.
(b) Bringmann G.; Walter R.; Weirich R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 977, and references cited therein.
(c) Hosoya T.; Takashiro E.; Matsumoto T.; Suzuki K. J. Am.
Chem. Soc. 1994, 116, 1004, and references cited therein.
(d) Deshpande P.; Martin O. R. Tetrahedron Lett. 1990, 31,
6313.
Acknowledgement
This research was supported by a Grant-in-Aid for Scientific Rese-
arch (No. 11672103) from the Ministry of Education, Science,
Sports, and Culture. The authors are indebted to Professor O. Sti-
cher, Swiss Federal Institute of Technology Zurich, Department of
Pharmacy, for providing us with copies of spectral data of 12-me-
(e) Hosoya T.; Takashiro E.; Matsumoto T.; Suzuki K.
Tetrahedron Lett. 1994, 35, 4591.
(f) Miyaura N.; Suzuki A., Chem. Rev. 1995, 95, 2457.
Synthesis 2001, No. 3, 444–450 ISSN 0039-7881 © Thieme Stuttgart · New York

450
T. Harayama et al.
PAPER
(7) (a) Hanaoka, M.; Motonishi, T.; Mukai, C. J. Chem. Soc.,
Perkin Trans.1 1986, 2253.
(13) Harayama, T.; Yasuda, H.; Akiyama, T.; Takeuchi, Y.; Abe,
H. Chem. Pharm. Bull. 2000, 48, 861.
(b) Ishii, H.; Ishikawa, T.; Ichikawa, Y.; Sakamoto, M.;
Ishikawa, M.; Takahashi, T. Chem. Pharm. Bull. 1984,32,
2984.
(14) (a) Ishikawa, T.; Watanabe, T.;Tanigawa, H.; Saito, T.;
Kotake, K.; Ohashi, Y.; Ishii H. J. Org. Chem. 1996, 61, 2774.
(b) Ishikawa, T.; Saito, T.; Ishii, H. Tetrahedron 1995, 51,
8447.
(15) In synthetic studies on oxychelerythrine (6) mentioned above,
cyclization reaction of 8 by Pd reagent afforded a trace of a
byproduct, which was presumed to be benzazepinone,
corresponding to a 4-demethoxy compound of 18. However,
we could not fully characterize this byproduct.
(16) There is no report on mp of 5 in the literature.4
(17) Yamaguchi, H.; Harigaya, Y.; Onda, M. Chem. Pharm. Bull.
1983, 31, 1601.
(8) (a) Hey, D. H.; Jones, G. H.; Perkins, M. J. J. Chem. Soc. (C)
1971, 116.
(b) Bowman, W. R.; Heaney, H.; Jordan, B. H. Tetrahedron
1991, 47, 10119.
(9) Ohrai K.; Kondo K.; Sodeoka M.; Shibasaki M. J. Am. Chem.
Soc. 1994, 116, 11737.
(10) Dyke, S. F.; Tiley, E. P. Tetrahedron 1975, 31, 561.
(11) (a) Auerbach, J.; Weisman, S. A.; Blacklock, T. J.; Angeles,
M. R.; Hoogsteen, K. Tetrahedron Lett. 1993, 34, 931.
(b) Nimgirawath, S.; Ponghusabun, O.-A. Aust. J. Chem.
1994, 47, 951.
(12) Harayama, T.; Shibaike, K. Heterocycles 1998, 49, 191.
Article Identifier:
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