Synthesis of trisphaeridine and norchelerythrine through palladium-catalyzed aryl-aryl coupling reactions

Article abstract of DOI:10.1039/b008683p

The synthesis of triphaeridine and norchelerythrine through palladium-catalyzed aryl-aryl coupling reactions was studied. The secondary amides were synthesized from 6-bromopiperonylicacid and aniline, and from piperonylic acid and 2-iodoaniline respectively, and were methoxymethylated for the preparation of starting materials for the cyclization reaction. All experiments were carried out in an argon atmosphere and the extract was washed with brine. The nuclear magnetic resonance (NMR) spectral data showed the presence of singlet signals due to aromatic proton in the products.

Full text of DOI:10.1039/b008683p

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Synthesis of trisphaeridine and norchelerythrine through
palladium-catalyzed aryl–aryl coupling reactions
Takashi Harayama,* Hisashi Akamatsu, Kana Okamura, Taeko Miyagoe, Toshihiko Akiyama,
Hitoshi Abe and Yasuo Takeuchi
1
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama,
700-8530, Japan. E-mail: harayama@pharm.okayama-u.ac.jp; Fax: +81(86)2517963
Received (in Cambridge, UK) 27th October 2000, Accepted 11th January 2001
First published as an Advance Article on the web 7th February 2001
Total syntheses of trisphaeridine (3) and norchelerythrine (4), fully aromatized phenanthridine and
benzo[c]phenanthridine alkaloids, were accomplished via the internal aryl–aryl coupling reaction of halo amides
protected by a methoxymethyl group with the palladium reagent, followed by reduction with lithium aluminium
hydride and treatment with hydrochloric acid.
Introduction
Fully aromatized benzo[c]phenanthridine alkaloids have a
broad range of potent pharmacological activities such as
antitumour and antiviral activities, and inhibition of DNA
topoisomerase I.1–12 Therefore, attention is still focused on the
development of convenient and effective methods for syn-
thesizing these alkaloids.1–5,13,14 However, the reported methods
have several disadvantages such as numerous steps, low total
yield and/or lack of generalizability. We have been studying the
development of more rapid and versatile synthetic methods for
these alkaloids and recently developed a convenient method
for the synthesis of chelerythrine (1)15 and nitidine (2),16
quaternary benzo[c]phenanthridine alkaloids, using an internal
aryl–aryl coupling reaction assisted by palladium. To examine
the general applicability of this method for synthesizing benzo-
[c]phenanthridine alkaloids, we attempted to apply this method
to the synthesis of trisphaeridine (3)17,18 and norchelerythrine
(4),1 tertiary phenanthridine and benzo[c]phenanthridine
alkaloids. For the synthesis of these alkaloids, ring closure of
secondary amides such as 5a and 6a is expected to be a more
direct and convenient method. Ames and Opalko reported in
1984 that 5a possessing a halogen atom on the benzoyl ring did
not give rise to a cyclized product, whereas 6a possessing a
halogen atom on the aniline ring provided the expected product
(7a) in poor to moderate yield.19 However, we speculated that a
tertiary amide (5b), which was protected by the methoxymethyl
(MOM) group, could be converted to an N-MOM lactam (7b)
with the assistance of a Pd reagent, because the cyclization
reaction of a tertiary N-methylamide (5c) proceeded smoothly
and gave the desired product in high yield.15 Moreover, we
supposed that 7b could be transformed to a fully aromatized
tertiary base (8) by successive treatment with LiAlH4 and
HCl.
Results and discussion
We began our studies with the biaryl coupling reaction of
amides 5b and 6b by means of a Pd reagent as a preliminary
experiment. These amides were prepared by reaction of sec-
ondary amides 5a20 and 6a21 with dimethoxymethane in the
presence of P2O5 in yields of 62 and 85%, respectively, and then
the cyclization reaction using the Pd reagent was examined. The
results are summarized in Table 1. The reaction generally gave
the desired product in good to excellent yield, and in the pres-
ence or absence of a bidentate ligand provided 7b in high yield.
Reduction of 7b with LiAlH4 followed by treatment with HCl
gave phenanthridine (8)22 in a yield of 54%.
DOI: 10.1039/b008683p
J. Chem. Soc., Perkin Trans. 1, 2001, 523–528
This journal is © The Royal Society of Chemistry 2001
523

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Table 1 Results of the cyclization reaction of 2-iodo-N-methoxymethyl-N-phenylbenzamide (5b) or N-(2-iodophenyl)-N-
methoxymethylbenzamide (6b) to 5-methoxymethylphenanthridin-6(5H)-one (7b) in DMF under refluxa
Run
Pd(OAc)2 (eq.)
Ligand
Base
Time/min
Yield of 7b (%)
5b
1
2b
3
4
5
6
7
8
9
10
11
12
13
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
—
—
—
Na2CO3
Na2CO3
Ag2CO3
Na2CO3
Ag2CO3
AcONa
Na2CO3
Na2CO3
Ag2CO3
Na2CO3
Na2CO3
Ag2CO3
Na2CO3
60
180
40
40
60
20
90
30
40
60
40
40
60
97
88
84
94
91
97
97
94
91
89
83
82
87
PPh3 (2)
PPh3 (2)
PPh3 (2)
P(o-Tol)3 (2)
DPPPc (1)
DPPPc (1)
—
PPh3 (2)
PPh3 (2)
DPPPc (1)
6b
a All reactions were carried out using Pd(OAc)2 and ligand in a ratio of 1 : 2 and 2 mol equivalents of base. b Reaction temperature: 130 ЊC. c DPPP:
1,3-bis(diphenylphosphino)propane.
Table 2 Results of cyclization reactions of 2-bromo-N-methoxymethyl-4,5-methylenedioxy-N-phenylbenzamide (12a) to 5-methoxymethyl-8,9-
methylenedioxyphenanthridin-6(5H)-one (13) in DMF under refluxa
Yield (%)
Run
Pd(OAc)2 (eq.)
Ligand
Base
Time/h
13
S.M.b
1
2
3
4
5
0.1
0.1
0.1
0.2
1.0
PPh3
Ag2CO3
Na2CO3
Ag2CO3
Ag2CO3
Ag2CO3
3
6.5
2
1.5
0.5
59
73
75
81
89
27
—
—
—
—
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
a All reactions were carried out using Pd(OAc)2 and ligand in a ratio of 1 : 2 and 2 mol equivalents of base. b S.M. = starting material.
Scheme 1
Next, we applied this methodology to the synthesis of tri-
sphaeridine (3),23 a tertiary phenanthridine alkaloid, which has
been isolated from a few plants of Amaryllidaceae.17,18 We
planned the synthetic route for 3 as shown in Scheme 1.
Starting materials (12) for the cyclization reaction were pre-
pared by methoxymethylation of the corresponding secondary
amides (11), which were synthesized from 6-bromopiperonylic
acid (9a)24 and aniline (10a), and from piperonylic acid (9b)
and 2-iodoaniline (10b), respectively (Scheme 1). Thus, succes-
sive treatment of the acids with oxalyl chloride and anilines
in the presence of triethylamine afforded 11, which was meth-
oxymethylated with chloromethyl methyl ether in the presence
of sodium hydride in DMF to give bromo amide (12a) and iodo
amide (12b) in yields of 62 and 67%, respectively. Subsequently,
the cyclization reaction of 12a and 12b using the Pd reagent was
examined and the results are summarized in Tables 2 and 3,
respectively. The reaction of 12a provided the expected product
13 in good to excellent yield, especially with the use of P(o-Tol)3
as a phosphine ligand. On the other hand, 12b, which possesses
an iodo group as a leaving group on the aniline part, gave 14,
which was formed by connection to a more hindered carbon, as
a major product along with 13 as a minor product. The influ-
ence of oxygen substituent(s) on the cyclization position is now
under investigation in our laboratory. Reduction of 13 with
LiAlH4 followed by treatment with HCl gave trisphaeridine
(3)17,18 in a yield of 54%. The spectral data of the synthetic
material were in good agreement with the reported data of an
authentic sample.18,23e
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Table 3 Results of cyclization reactions of N-(2-iodophenyl)-N-methoxymethyl-3,4-methylenedioxybenzamide (12b) in DMF under refluxa
Run
Pd(OAc)2 (eq.)
Ligand
Base
Time/h
Yield (%) of 13 + 14
13 : 14
1
2
0.1
0.1
PPh3
PPh3
Na2CO3
Ag2CO3
2
2
73
72
1 : 4
1 : 4.9
a All reactions were carried out using Pd(OAc)2 and ligand in a ratio of 1 : 2 and 2 mol equivalents of base.
Table 4 Results of cyclization reactions of 6-iodo-2,3-dimethoxy-N-methoxymethyl-N-(6,7-methoxydioxy-1-naphthyl)benzamide (18) in DMF
under refluxa
Yield (%)
Run
Pd(OAc)2 (eq.)
Ligand (L : Pd)
Base
Time/min
19
20
1
2
3
4
5
6
7
0.2
0.2
1.0
0.2
0.2
0.2
0.2
—
Na2CO3
Na2CO3
Na2CO3
Ag2CO3
Na2CO3
Ag2CO3
Na2CO3
300
40
30
30
60
40
60
10
51
76
70
74
96
61
—
13
20
18
16
1
PPh3 (2)
PPh3 (2)
PPh3 (2)
P(o-Tol)3 (2)
P(o-Tol)3 (2)
DPPP (1)
14
a All reactions were carried out using Pd(OAc)2 and ligand in a ratio of 1 : 2 and 2 mol equivalents of base.
Scheme 2
Subsequently, total synthesis of norchelerythrine (4)23b,25 was
investigated by applying the synthetic strategy described above.
Since o-halobenzoic acid is likely to be more accessible than
o-haloaniline and cyclization reaction of 12b with a halo group
on the aniline part using a Pd reagent yielded two products, we
designed a route for the synthesis of 4 through an amide (18)
that is protected by the MOM group and possesses a halo group
on the benzoyl part, as shown in Scheme 2. Methoxymethyl-
ation of the amide 17,15 which was synthesized from the acid
(15)26 and the amine (16),15 with chloromethyl methyl ether
in the presence of NaH gave the protected amide 18 in a yield
of 87%. The coupling reaction of amide 18 with Pd(OAc)2,
a phosphine ligand and a base in DMF under reflux afforded
19 in good to excellent yield, accompanied by a small amount
of benzazepinone (20)27 as shown in Table 4 (see runs 3–6).
A combination of P(o-Tol)3 and Ag2CO3 was the most effective
combination of additives. The structures of the products
19 and 20 were elucidated on the basis of spectral data,
especially 1H-NMR data in which 20 showed two singlet
signals due to aromatic protons, whereas 19 showed only one
singlet signal due to an aromatic proton (see Experimental).
Moreover, in the 1H-NMR spectra the signals attributable
to the methylene protons of the MOM group appeared
extraordinarily broad in CDCl3 solution, whereas the signal
appeared as a broad singlet at δ 5.00 in d6-DMSO solution at
80 ЊC. Reduction of 19 with LiAlH4 and subsequent treatment
with HCl provided 4 (92%), which was identical with an
authentic sample.
Experimental
Melting points were measured on a micro melting point hot-
stage apparatus (Yanagimoto) and are quoted as uncorrected
values. IR spectra were recorded for samples in KBr pellets with
a JASCO A-102 or JASCO FT/IR 350 spectrophotometer, and
1H- and 13C-NMR spectra were recorded in deuteriochloroform
on a Hitachi R-1500 (60 MHz), Varian VXR-200 (200 MHz) or
-500 (500 MHz) spectrometer unless otherwise stated. NMR
data are reported in ppm downfield from tetramethylsilane as
an internal standard (δ 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 (Merck,
silica gel 60, No. 9385) or aluminium oxide (Wako, about 300
mesh). All experiments were carried out in an argon atmos-
phere and the extract was washed with brine, dried over
anhydrous 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 concentrated to
dryness to give purified Pd(OAc)2.28
J. Chem. Soc., Perkin Trans. 1, 2001, 523–528
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2-Iodo-N-methoxymethyl-N-phenylbenzamide (5b)
was stirred for 3 h at rt. The reaction mixture was concentrated
to dryness and diluted with CHCl3, then washed with 10% HCl,
aqueous 5% NaOH solution and brine. The residue was
dissolved in benzene and the solution was subjected to column
chromatography on silica gel. Elution with hexane–AcOEt
(6 : 1) gave 11a (3.12 g, 74%) as colorless needles, mp 149–
152 ЊC (from ether); νmax/cmϪ1 3280 and 1660; δH (200 MHz)
6.04 (2H, s, OCH2O), 7.03 (1H, s, 3-H), 7.13 (1H, s, 6-H), 7.16
(1H, t, J 7.8, 4Ј-H), 7.37 (2H, t, J 7.8, 3Ј-H and 5Ј-H), 7.62 (2H,
d, J 7.8, 2Ј-H and 6Ј-H) and 7.78 (1H, br s, NH). Found: C,
52.3; H, 3.2; N, 4.3%. Calcd for C14H10BrNO3: C, 52.5; H, 3.2;
N, 4.4%.
To a stirred solution of amide 5a (200 mg, 0.619 mmol) in dry
CHCl3 (12 cm3) was added dimethoxymethane (14 cm3, 158
mmol) and phosphorus pentaoxide (2.0 g), and the mixture was
stirred for 5 h at rt. The mixture was poured into aqueous 5%
Na2CO3 solution and extracted with ether. The residue was
dissolved in benzene and subjected to column chromatography
on alumina. Elution with benzene–hexane (2 : 1) afforded 5b
(141 mg, 62%) as an oil; νmax/cmϪ1 1670; δH (60 MHz) 3.55 (3H,
br s, OCH3), 5.28 (2H, br s, NCH2O) and 6.96–7.79 (9H, m,
aromatic protons); m/z (FAB) 368 (M+ + 1). Found: C, 49.2; H,
3.9; N, 3.6%. Calcd for C15H14INO2: C, 49.1; H, 3.8; N, 3.8%.
N-(2-Iodophenyl)-3,4-methylenedioxybenzamide (11b)
N-(2-Iodophenyl)-N-methoxymethylbenzamide (6b)
Oxalyl chloride (3.05 g, 24.1 mmol) was added to a solution of
piperonylic acid (9b) (2.0 g, 12.0 mmol) in dry THF (100 cm3)
containing ten drops of dry DMF at 10 ЊC. The stirred mixture
was refluxed for 2.5 h, and concentrated to dryness under
reduced pressure. To this residue was added a solution of 2-
iodoaniline (10b) (2.63 g, 12.0 mmol) in dry THF (50 cm3) and
dry NEt3 (2.01 cm3, 14.4 mmol) and the mixture was stirred for
3 h at rt. The reaction mixture was concentrated to dryness and
diluted with AcOEt, then washed with 10% HCl, aqueous 5%
NaOH solution and brine. The residue was dissolved in benzene
and subjected to column chromatography on silica gel. Elution
with hexane–AcOEt (5 : 1) gave 11b (3.53 g, 80%) as colorless
needles, mp 122–124.5 ЊC (from ether); νmax/cmϪ1 3260 and
1650; δH (200 MHz) 6.08 (2H, s, OCH2O), 6.88 (1H, ddd, J 7.9,
7.8 and 1.6, 4Ј-H), 6.92 (1H, d, J 8.2, 5-H), 7.40 (1H, ddd, J 7.8,
7.8 and 1.6, 5Ј-H), 7.45 (2H, d, J 1.8, 2-H), 7.52 (1H, dd, J 8.2
and 1.8, 6-H), 7.81 (1H, dd, J 7.8 and 1.6, 6Ј-H), 8.16 (1H, br s,
NH) and 8.42 (1H, dd, J 7.9 and 1.6, 3Ј-H). Found: C, 45.7; H,
3.0; N, 3.7%. Calcd for C14H10INO3: C, 45.8; H, 2.7; N, 3.8%.
To a stirred solution of amide 6a (200 mg, 0.619 mmol) in dry
CHCl3 (12 cm3) was added dimethoxymethane (14 cm3, 158
mmol) and phosphorus pentaoxide (2.0 g), and the reaction
mixture was stirred for 46 h at rt. The mixture was poured into
aqueous 5% Na2CO3 solution and extracted with ether. The
residue dissolved in benzene was subjected to column chrom-
atography on alumina. Elution with benzene afforded 6b (194
mg, 85%) as colorless prisms, mp 70–71.5 ЊC (from hexane);
νmax/cmϪ1 1650; δH (60 MHz) 3.46 (3H, s, OCH3), 4.63 (1H, d,
J 10.0, NCHAHBO), 5.70 (1H, br d, J 10.0, NCHAHBO) and
6.95–7.90 (9H, m, aromatic protons); m/z (EI) 367 (M+). Found:
C, 49.0; H, 4.2; N, 3.8%. Calcd for C15H14INO2: C, 49.1; H, 3.8;
N, 3.8%.
General procedure for the cyclization reaction of N-methoxy-
methylbenzanilides 5b and 6b by palladium reagent
Reaction of benzanilide (36.7 mg, 0.1 mmol) with Pd(OAc)2, a
phosphine ligand, and a base in dry DMF (4 cm3) was carried
out using Pd(OAc)2 and the ligand in a ratio of 1 : 2 and 2 mol
equivalents of base under reflux and under the reaction con-
ditions indicated in Table 1. The reaction mixture was diluted
with benzene and the precipitates were removed by filtration.
The filtrate was washed with brine. The residue dissolved
in benzene was subjected to column chromatography on silica
gel. Elution with hexane–AcOEt (4 : 1) gave 5-methoxymethyl-
phenanthridin-6(5H)-one (7b) as colorless prisms, mp 93–94 ЊC
(from ether); νmax/cmϪ1 1670; δH (60 MHz) 3.48 (3H, s, OCH3),
5.83 (2H, s, NCH2O) and 7.27–8.62 (8H, m, aromatic protons).
Found: C, 75.5; H,5.5; N, 5.8%. Calcd for C15H13NO2: C, 75.3;
H, 5.5; N, 5.9%.
2-Bromo-N-methoxymethyl-4,5-methylenedioxy-N-phenyl-
benzamide (12a)
To a suspension of 11a (1.0 g, 3.12 mmol) and NaH (360 mg,
63% dispersion in mineral oil, 9.37 mmol) in dry DMF (50 cm3)
was added chloromethyl methyl ether (378 mg, 4.69 mmol).
After stirring for 5 h at rt, the reaction mixture was diluted with
ether and washed with aqueous sat. NaHCO3 solution and
brine. The residue was dissolved in CHCl3 and subjected to
column chromatography on alumina. Elution with hexane–
AcOEt (4 : 1) gave 12a (955 mg, 84%) as an oil; νmax(CHCl3)/
cmϪ1 1640; δH (60 MHz) 3.52 (3H, s, OCH3), 5.20 (2H, s,
NCH2O), 5.91 (2H, s, OCH2O), 6.63 (1H, s, 3-H), 6.87 (1H, s,
6-H) and 7.26 (5H, br s, aromatic protons); m/z (FAB) 364
(M+ + 1).
Phenanthridine (8)
LiAlH4 (68.3 mg, 1.80 mmol) was added to a solution of 7b
(144 mg, 0.60 mmol) in dry THF (7 cm3) and the mixture was
stirred for 2 h at rt. Excess hydride was decomposed with wet
ether and the organic layer was decanted. The residue in THF
(3 cm3) was treated with 6 M HCl (3 cm3) for 1 h under reflux.
The reaction mixture was poured into aqueous sat. Na2CO3
solution and extracted with CHCl3. The residue in CHCl3 was
subjected to chromatography on silica gel. Elution with
hexane–AcOEt (6 : 1) gave 8 (58 mg, 54%) as colorless prisms,
mp 103–105 ЊC (from EtOH–hexane) (lit.22 mp 104–105 ЊC);
m/z (EI) 170 (M+). Found: C, 87.1; H, 5.4; N, 7.8%. Calcd for
C13H9N: C, 87.1; H, 5.1; N, 7.8%.
N-(2-Iodophenyl)-N-methoxymethyl-3,4-methylenedioxbenz-
amide (12b)
To a suspension of 11b (300 mg, 0.82 mmol) and NaH (94 mg,
63% dispersion in mineral oil, 2.45 mmol) in dry THF (12 cm3)
was added chloromethyl methyl ether (99 mg, 1.23 mmol). After
stirring for 1.5 h at rt, the reaction mixture was diluted with
ether and washed with aqueous sat. NaHCO3 solution and
brine. The residue was dissolved in CHCl3 and subjected to
column chromatography on alumina. Elution with hexane–
AcOEt (4 : 1) gave 12b (283 mg, 84%) as pale yellow prisms, mp
77–79 ЊC (from ether); νmax(CHCl3)/cmϪ1 1640; δH (60 MHz)
3.45 (3H, s, OCH3), 4.63 (1H, d, J 10.0, NCHAHBO), 5.60 (1H,
br d, J 10.0, NCHAHBO), 5.92 (2H, s, OCH2O) and 6.55–7.92
(7H, m, aromatic protons). Found: C, 47.0; H, 3.3; N, 3.3%.
Calcd for C16H14INO4: C, 46.7; H, 3.4; N, 3.4%.
2-Bromo-4,5-methylenedioxy-N-phenylbenzamide (11a)
Oxalyl chloride (3.33 g, 26.3 mmol) was added to a solution of
6-bromopiperonylic acid (9a) (3.0 g, 13.1 mmol) in dry THF
(120 cm3) containing twenty drops of dry DMF at 10 ЊC. The
stirred mixture was refluxed for 3 h, and then concentrated
to dryness under reduced pressure. To this residue was added
a solution of aniline (10a) (1.21 g,13.1 mmol) in dry THF
(60 cm3) and dry NEt3 (2.18 cm3, 15.7 mmol) and the mixture
General procedure for the cyclization reaction of bromo-N-
methoxymethylbenzanilide (12a) by palladium reagent
Reaction of 12a (180 mg, 0.5 mmol) with Pd(OAc)2, a phos-
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phine ligand, and a base in dry DMF (12 cm3) was carried out
using Pd(OAc)2 and ligand in a ratio of 1 : 2 and 2 mol equiv-
alents of base under reflux and under the reaction conditions
indicated in Table 2. The reaction mixture was diluted with
ether–AcOEt (1 : 1) and the precipitates were removed by fil-
tration. The filtrate was washed with brine. The residue was
dissolved in benzene and subjected to column chromatography
on silica gel. Elution with hexane–AcOEt (6 : 1) gave 5-meth-
oxymethyl-8,9-methylenedioxyphenanthridin-6(5H)-one (13)
as colorless needles, mp 180–182 ЊC (from AcOEt); νmax/cmϪ1
1640; δH (200 MHz) 3.46 (3H, s, OCH3), 5.82 (2H, s, NCH2O),
6.12 (2H, s, OCH2O), 7.30 (1H, ddd, J 8.2, 7.0 and 1.4, 2-H),
7.48 (1H, ddd, J 8.1, 7.0 and 1.4, 3-H), 7.59 (1H, s, 10-H), 7.60
(1H, dd, J 8.1 and 1.4, 4-H), 7.87 (1H, s, 7-H) and 8.04 (1H, dd,
J 8.2 and 1.4, 1-H). Found: C, 67.6; H, 4.4; N, 4.9%. Calcd for
C16H13NO4: C, 67.8; H, 4.6; N, 5.0%.
(1H, d, J 8.5, 5-H) and 7.03–7.65 (5H, m, aromatic protons);
m/z (FAB) 522 (M+ + 1). Found: C, 50.7; H, 3.8; N, 2.7%. Calcd
for C22H20INO6: C, 50.7; H, 3.9; N, 2.7%.
General procedure for the cyclization reaction of iodo-N-meth-
oxymethylbenzanilide (18) by palladium reagent
Reaction of 18 (260 mg, 0.5 mmol) with Pd(OAc)2, a phosphine
ligand, and a base in dry DMF (15 cm3) was carried out using
Pd(OAc)2 and ligand in a ratio 1 : 2 and 2 mol equivalents of
base under reflux and under the reaction conditions indicated in
Table 4. The reaction mixture was diluted with benzene and the
precipitates were removed by filtration. The filtrate was washed
with brine. The residue was dissolved in benzene and sub-
jected to column chromatography on silica gel. Elution with
hexane–AcOEt (2 : 1) gave 9,10-dimethoxy-7-methoxymethyl-
1,2-methylenedioxynaphtho[1,8-cd][2]benzazepin-8(7H)-one
(20) and successive elution with the same solvent gave 7,8-
dimethoxy-5-methoxymethyl-2,3-methylenedioxybenzo[c]phen-
anthridin-6(5H)-one (19).
General procedure for the cyclization reaction of iodo-N-meth-
oxymethylbenzanilide (12b) by palladium reagent
Reaction of 12b (100 mg, 0.24 mmol) with Pd(OAc)2 (5.5 mg,
0.025 mmol), triphenylphosphine (12.9 mg, 0.05 mmol), and
two mol equivalents of base as indicated in Table 3 in dry DMF
(3 cm3) was carried out for 2 h. The reaction mixture was
diluted with ether and the precipitates were removed by filtra-
tion. The filtrate was washed with brine. The residue was
dissolved in CHCl3 and subjected to column chromatography
on alumina. Elution with hexane–iPr2O (2 : 1) gave 13, mp 178–
179 ЊC and successive elution with the same solvent gave 5-
methoxymethyl-9,10-methylenedioxyphenanthridin-6(5H)-one
(14) as colorless needles, mp 183–185 ЊC (from CHCl3–hexane);
νmax(CHCl3)/cmϪ1 1600; δH (500 MHz) 3.47 (3H, s, OCH3), 5.81
(2H, br s, NCH2O), 6.27 (2H, s, OCH2O), 7.09 (1H, d, J 8.5,
8-H), 7.30 (1H, ddd, J 8.2, 8.2 and 1.3, 2-H), 7.50 (1H, ddd,
J 8.2, 8.2 and 1.4, 3-H), 7.59 (1H, dd, J 8.2 and 1.3, 4-H), 8.19
(1H, d, J 8.5, 7-H) and 8.62 (1H, dd, J 8.2 and 1.4, 1-H). Found:
C, 67.9; H, 4.8; N, 4.9%. Calcd for C16H13NO4: C, 67.8; H, 4.6;
N, 5.0%.
Compound 20: mp 178–179 ЊC (from ether–hexane) as color-
less prisms; νmax/cmϪ1 1660; δH (200 MHz) 3.47 (3H, s, OCH3),
3.88 (3H, s, OCH3), 4.04 (3H, s, OCH3), 6.12 (2H, br s,
OCH2O), 6.94 (1H, d, J 8.8, 11-H), 6.98 (1H, s, 3-H), 7.25 (1H,
dd, J 7.6 and 7. 4, 5-H), 7.38 (1H, d, J 8.8, 12-H), 7.38 (1H, dd,
J 7.4 and 1.4, 4-H) and 7.56 (1H, dd, J 7.6 and 1.4, 6-H);
(500 MHz, d6-DMSO, 80 ЊC) 3.21 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 3.88 (3H, s, OCH3), 5.00 (2H, br s, NCH2O), 6.23 (2H,
br s, OCH2O), 7.13 (1H, d, J 9.0, 11-H), 7.19 (1H, s, 3-H),
7.29 (1H, dd, J 8.0 and 7.5, 5-H), 7.41 (1H, d, J 9.0, 12-H), 7.47
(1H, dd, J 7. 5 and 1.0, 4-H) and 7.49 (1H, dd, J 8.0 and 1.0,
6-H). Found: C, 67.2; H, 5.0; N, 3.5%. Calcd for C22H19NO6: C,
67.2; H, 4.9; N, 3.6%.
Compound 19: mp 199–200 ЊC (from ether–hexane) as color-
less prisms; νmax/cmϪ1 1665; δH (500 MHz) 3.75 (3H, s, OCH3),
3.98 (3H, s, OCH3), 4.07 (3H, s, OCH3), 5.35 (2H, s, NCH2O),
6.09 (2H, s, OCH2O), 7.12 (1H, s, 1-H), 7.38 (1H, d, J 8.5, 9-H),
7.50 (1H, d, J 8.5, 12-H), 7.95 (1H, d, J 8.5, 9-H) and 8.38 (1H,
s, 4-H). Found: C, 67.2; H, 5.1; N, 3.6%. Calcd for C22H19NO6:
C, 67.2; H, 4.9; N, 3.6%.
The ratio of products was determined by HPLC (column,
chemosorb 5Si; eluent, hexane–AcOEt (1 : 3); flow rate, 1.0 ml
minϪ1; wavelength, 254 nm; tR for 13 = 7.2 min; tR for 14 = 6.4
min).
Norchelerythrine (4)
LiAlH4 (43.4 mg, 1.14 mmol) was added to a solution of 19
(149 mg, 0.38 mmol) in dry THF (15 cm3) and the mixture was
stirred for 30 min at rt. Excess hydride was decomposed with
wet ether and the organic layer was decanted. A solution of
residue in THF (10 cm3) and 10% HCl (25 cm3) was stirred for
1 h at rt. The reaction mixture was poured into aqueous sat.
NaHCO3 solution and extracted with CHCl3. The organic layer
was washed with brine. The residue was recrystallized from
benzene–hexane to provide 4 (116 mg, 92%) as pale yellow
prisms, mp 217–219 ЊC (from hexane) (lit.25a mp 212–214 ЊC,
lit.25c mp 213–215 ЊC).
Trisphaeridine (3)
LiAlH4 (59.4 mg, 1.57 mmol) was added to a solution of 13 (89
mg, 0.31 mmol) in dry THF (9 cm3) and the mixture was stirred
for 3 h at rt. Excess hydride was decomposed with wet ether and
the organic layer was decanted. A solution of the residue in
10% HCl (3 cm3) was stirred for 1 h at 80 ЊC. The reaction
mixture was poured into aqueous 5% NaOH solution and
extracted with CHCl3. The organic layer was washed with brine.
The residue in CHCl3 was subjected to chromatography on
alumina. Elution with CHCl3 gave 3 (38 mg, 54%) as colorless
prisms, mp 142.5–144 ЊC (from hexane) (lit.23e mp 144.5–
145 ЊC); m/z (FAB) 224 (M+ ϩ 1). Found: C, 69.6; H, 4.7; N,
5.8%. Calcd for C14H9NO2·H2O: C, 69.7; H, 4.6; N, 5.8%.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific
Research (No. 11672103) from the Ministry of Education, Sci-
ence, Sports, and Culture. The authors are indebted to Dr J.
Bastida, University of Barcelona, Faculty of Pharmacy, for
providing us with copies of spectral data for trisphaeridine and
to the SC-NMR Laboratory of Okayama University for the
NMR experiments.
6-Iodo-2,3-dimethoxy-N-methoxymethyl-N-(6,7-methylenedi-
oxy-1-naphthyl)benzamide (18)
A suspension of 17 (1.0 g, 2.1 mmol) and NaH (380 mg, 63%
dispersion in mineral oil, 6.3 mmol) in dry DMF (30 cm3) was
stirred for 2 h at rt and then chloromethyl methyl ether (254 mg,
3.2 mmol) was added to the reaction mixture. After stirring for
2 h at rt, the reaction mixture was diluted with ether and
washed with brine. The residue was dissolved in benzene and
subjected to column chromatography on silica gel. Elution with
hexane–AcOEt (2 : 1) gave 18 (951 mg, 87%) as colorless
prisms, mp 152–153 ЊC (from ether–hexane); νmax/cmϪ1 1660;
δH (60 MHz) 3.19–4.89 (11H, m, 3 × OCH3 and NCH2O,
rotamer), 6.05 (2H, s, OCH2O), 6.76 (1H, d, J 8.5, 4-H), 7.58
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