Simple synthesis of pratosine and hippadine by intramolecular palladium-catalyzed cyclization and decarboxylation

Article abstract of DOI:10.3987/COM-11-12167

The palladium-catalyzed cyclization of dimethyl l-(2-bromo-4,5- dimethoxybenzyl)indole-2,3-dicarboxylate in the presence of tetrakis(triphenyl- phosphine)palladium(o) and potassium acetate in hot l,4-dioxane produced the 7H-pyrrolo[3,2,l-de]phenanthridine

Full text of DOI:10.3987/COM-11-12167

HETEROCYCLES, Vol. 83, No. 5, 2011
1111
HETEROCYCLES, Vol. 83, No. 5, 2011, pp. 1111 - 1119. © The Japan Institute of Heterocyclic Chemistry
Received, 8th February, 2011, Accepted, 15th March, 2011, Published online, 23rd March, 2011
DOI: 10.3987/COM-11-12167
SIMPLE SYNTHESIS OF PRATOSINE AND HIPPADINE BY
INTRAMOLECULAR PALLADIUM-CATALYZED CYCLIZATION AND
DECARBOXYLATION
Hideaki Umemoto, Masashi Dohshita, Hiromi Hamamoto, and Yasuyoshi
Miki*
School of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae,
Higashi-Osaka 577-8502, Japan
Abstract – The palladium-catalyzed cyclization of dimethyl 1-(2-bromo-4,5-
dimethoxybenzyl)indole-2,3-dicarboxylate in the presence of tetrakis(triphenyl-
phosphine)palladium(0) and potassium acetate in hot 1,4-dioxane produced the
7H-pyrrolo[3,2,1-de]phenanthridine derivative, which was converted to pratosine
by hydrolysis and decarboxylation. In a similar manner, hippadine was also
prepared.
7H-Pyrrolo[3,2,1-de]phenanthridine alkaloids, pratosine,1 hippadine,2 and kalbretorine,3 isolated from
various species of Amaryllidaceae have significant biological activities; for example, hippadine inhibits
fertility in male rats4 and kalbretorine has an antitumor activity.3 Pratosine and hippadine were mainly
synthesized by three methods from the 2-protected indole,5,6 indoline derivatives,7 or 7-haloindoles and
related compounds.8,9 In a previous paper, we reported the synthesis of pratosine and hippadine by the
palladium-catalyzed intramolecular cyclization of methyl 1-(2-bromo-4,5-dimethoxybenzyl)indole-
2-carboxylate protected 2-position of the indole moiety by an ester group.5 In this paper, we report the
simple synthesis of pratosine and hippadine by the palladium-catalyzed intramolecular cyclization of
dimethyl 1-(2-bromobenzyl)indole-2,3-dicarboxylates and decarboxylation.
4
1
11
N
N
N
N
O
O
O
O
8
OH
MeO
OMe
7H-pyrrolo[3,2,1-de]phenanthridine
MeO
O
O
O
O
OMe
pratosine
hippadine
kalbretorine

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HETEROCYCLES, Vol. 83, No. 5, 2011
Dimethyl 7-bromoindole-2,3-dicarboxylate (1)10 was converted to dimethyl 7-bromo-1-(3,4-dimethoxy-
benzyl)indole-2,3-dicarboxylate (2) by treatment with 3,4-dimethoxybenzyl chloride in the presence of
potassium carbonate. The treatment of 2 with a catalytic amount of tetrakis(triphenylphosphine)-
palladium(0) ((PPh3)4Pd) in the presence of potassium acetate in hot dioxane gave a mixture of dimethyl
7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) and dimethyl 7H-10,11-
dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4) in 35% and 3% yields, respectively
(Scheme 1).
Scheme 1
Cl
CO2Me
MeO
CO2Me
CO2Me
Pd(PPh3)4 / KOAc
dioxane
OMe
N
CO2Me
K2CO3 / MeCN
(59%)
Br
N
H
Br
MeO
OMe
1
2
CO2Me
CO2Me
CO2Me
CO2Me
+
N
N
MeO
MeO
MeO
OMe
3 (35%)
4 (3%)
Dimethyl 9,10-dimethoxy-7H-pyrrolo[3,2,1-de]phenanthridone-4,5-dicarboxylate (7) could not be
isolated by treatment of dimethyl 1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6), which
was prepared from dimethyl indole-2,3-dicarboxylate (5) and 2-bromo-4,5-dimethoxybenzoyl chloride, in
hot dioxane in the presence of Pd(PPh3)4 and potassium acetate. The starting material was recovered.
The treatment of 6 in N,N-dimethylformamide instead of dioxane at 100 °C afforded 5, which was
produced by the hydrolysis of 6, in low yield (Scheme 2).
Scheme 2
Cl
Br
CO2Me
CO2Me
CO2Me
CO2Me
O
Pd(PPh3)4
KOAc
CO2Me
CO2Me
MeO
OMe
N
N
Br
K2CO3 / MeCN
(quant.)
N
H
dioxane
O
O
MeO
MeO
5
OMe
OMe
7
6

HETEROCYCLES, Vol. 83, No. 5, 2011
1113
However, in a similar treatment described as 6, dimethyl 1-(2-bromo-4,5-dimethoxybenzyl)indole-2,3-
dicarboxylate (8), which was obtained from dimethyl indole-2,3-dicarboxylate (5) and 2-bromo-4,5-
dimethoxybenzyl bromide,11 produced dimethyl 9,10-dimethoxy-7H-pyrrolo[3,2,1-de]phenanthridine-4,5-
dicarboxylate (3) as the sole product in 76% yield (Scheme 3).
Scheme 3
Br
Br
CO2Me
CO2Me
CO2Me
CO2Me
Pd(PPh3)4
KOAc
MeO
CO2Me
CO2Me
OMe
N
N
Br
dioxane
(76%)
K2CO3 / MeCN
(78%)
N
H
MeO
MeO
5
OMe
OMe
8
3
In order to investigate the negative reactivity of 6 on palladium-catalyzed intramolecular cyclization via
Mizoroki-Heck reaction, 6 was subjected with phenylboronic acid in the presence of Pd(PPh3)4 and
potassium acetate in hot dioxane for 7 hours. In this case, the intermolecular coupling of 6 with
phenylboronic acid was occurred and dimethyl 1-(4,5-dimethoxy-2-phenylbenzoyl)indole-2,3-
dicarboxylate was obtained. Therefore, this result suggests that initial formation of the intermediate (9) is
proceeded in the presence of Pd(PPh3)4 and potassium acetate, but the following intramolecular
cyclization would not be occurred due to the steric hindrance. (Scheme 4) Even though the exact
reaction mechanism is still not clear, the difficulty of the palladium-catalyzed intramolecular cyclization
on C-7 position of 1-benzoylindole derivatives reported by Itahara may support the possibility of our
suggestions.12
Scheme 4
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Pd(PPh3)4
N
N
N
Br
PdLn
O
O
O
MeO
MeO
MeO
OMe
OMe
OMe
7
6
9
The hydrolysis of 3 with LiOH gave the corresponding dicarboxylic acid (10), which could be converted
into pratosine in 20% yield by treatment with copper chromite (CuO-Cr2O3) in hot quinoline (Scheme 5).

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HETEROCYCLES, Vol. 83, No. 5, 2011
Scheme 5
CO2Me
CO2Me
CO2H
CO2H
LiOH
2CuO-Cr2O3
N
N
N
dioxane-H2O
(99%)
quinoline
(20%)
O
MeO
MeO
MeO
OMe
OMe
OMe
pratosine
3
10
The reaction of dimethyl indole-2,3-dicarboxylate (5) with 2-bromo-4,5-methylenedioxybenzyl bromide13
afforded the dimethyl 1-(2-bromo-4,5-methylenedioxybenzyl)indole-2,3-dicarboxylate (11) (96%), which
was treated with a catalytic amount of (PPh3)4Pd in the presence of potassium acetate in hot dioxane to
produce dimethyl 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (12) (84%).
In a manner similar to the synthesis of pratosine, the hydrolysis of 12 with LiOH gave the corresponding
dicarboxylic acid (13) (85%), which could be converted into hippadine by the treatment with CuO-Cr2O3
in hot quinoline in 13% yield (Scheme 6).
Scheme 6
Br
Br
CO2Me
CO2Me
CO2Me
CO2Me
Pd(PPh3)4
KOAc
O
CO2Me
CO2Me
O
N
N
Br
dioxane
(84%)
K2CO3 / MeCN
(96%)
N
H
O
O
5
O
O
11
12
CO2H
2CuO-Cr2O3
LiOH
N
N
CO2H
dioxane-H2O
(85%)
quinoline
(13%)
O
O
O
O
O
hippadine
13
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (C) and also in part “High-Tech
Research Center Project” for Private Universities and a matching fund subsidy from the Ministry of
Education, Culture, Sports, Scientific and Technology-Japan (MEXT).
EXPERIMENTAL
Melting points were determined using a Yanagimoto micromelting point apparatus and are uncorrected.

HETEROCYCLES, Vol. 83, No. 5, 2011
1115
The 1H-NMR spectra were determined by a JEOL JNM-GSX 270 spectrometer using tetramethylsilane as
the internal standard. The IR spectra were recorded by a JASCO FT/IR-7000 spectrophotometer. The
high MS were recorded using a JEOL JMS-HX100 spectrometer. Column chromatography was
performed on E. Merck silica gel 60 (70-230 mesh or 230-400 mesh).
Dimethyl 7-Bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2)
A mixture of dimethyl 7-bromoindole-2,3-dicarboxylate (1)10 (281 mg, 0.9 mmol), 4,5-dimethoxybenzyl
chloride (202 mg, 1.1 mmol), and potassium carbonate (186 mg, 1.35 mmol) in acetone (3.6 mL) was
refluxed for 22 h. Water was added to the mixture and the aqueous mixture was extracted with CH2Cl2.
The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to
afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 7 : 1) to give
dimethyl 7-bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2) (245 mg, 59%).
Mp. 110.5-111 °C (Et2O). IR (CHCl3) cm-1: 1710, 1735. 1H-NMR (CDCl3) !: 3.76 (3H, s, OMe), 3.82 (3H,
s, OMe), 3.87 (3H, s, OMe), 3.92 (3H, s, OMe), 5.88 (2H, s, NCH2), 6.48 (1H, dd, J = 8.5, 2 Hz, H-6'),
6.60 (1H, d, J = 2 Hz, H-2'), 6.74 (1H, d, J = 8.5 Hz, H-5'), 7.14 (1H, t, J = 8 Hz, H-5), 7.50 (1H, dd, J =
8, 1 Hz, H-6), 8.19 (1H, dd, J = 8, 1 Hz, H-4). Anal. Calcd for C21H20BrNO6: C, 54.56; H, 4.36; N, 3.03.
Found: C, 54.80; H, 4.44; N, 2.99.
Intramolecular Cyclization of Dimethyl 7-Bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate
(2): Dimethyl 7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) and
7H-10,11-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4)
To a mixture of dimethyl 7-bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2) (46 mg, 0.1
mmol) and potassium acetate (10 mg, 0.1 mmol) in dioxane (1.5 mL) was added Pd(PPh3)4 (6 mg, 0.05
mmol). The mixture was refluxed for 10 h under argon in the dark. Water was added to the reaction
mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water,
dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by
column chromatography (n-hexane : AcOEt = 3 : 1) to give dimethyl 7H-9,10-dimethoxypyrrolo[3,2,1-de]-
phenanthridine-4,5-dicarboxylate (3) (13 mg, 35%) and 7H-10,11-dimethoxypyrrolo[3,2,1-de]-
phenanthridine-4,5-dicarboxylate (4) (1 mg, 3%).
Dimethyl 7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3): Mp 123-124 °C
(AcOEt). IR (CHCl3) cm-1: 1709. 1H-NMR (CDCl3) !: 3.91 (3H, s, OMe), 3.96 (3H, s, OMe), 3.99 (3H, s,
OMe), 4.02 (3H, s, OMe), 5.60 (2H, s, H-7), 6.66 (1H, s, H-8), 7.22 (1H, dd, J = 8, 7.5 Hz, H-2), 7.32
(1H, s, H-11), 7.47 (1H, dd, J = 7.5, 1 Hz, H-1), 7.78 (1H, dd, J = 8, 1 Hz, H-3). MS m/z: 381. HRMS
m/z: Calcd for C21H19NO6: 381.1212. Found: 381.1239. Anal. Calcd for C21H19NO6: C, 66.14; H, 5.02; N,
3.67. Found: C, 65.92; H, 5.08; N, 3.51.
7H-10,11-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4): IR (Nujol) cm-1: 1710.
1H-NMR (CDCl3) !: 3.93 (6H, s, OMe), 3.96 (3H, s, OMe), 4.02 (3H, s, OMe), 5.61 (2H, s, H-7), 6.90

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HETEROCYCLES, Vol. 83, No. 5, 2011
(1H, d, J = 8 Hz, H-8 or H-9), 6.96 (1H, d, J = 8 Hz, H-9 or H-8), 7.28 (1H, t, J = 8 Hz, H-2), 7.89 (1H, d,
J = 8 Hz, H-3), 8.46 (1H, d, J = 8 Hz, H-1). MS m/z : 381. HRMS m/z: Calcd for C21H19NO6: 381.1212.
Found: 381.1235.
Dimethyl 1-(2-Bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6)
A mixture of dimethyl indole-2,3-dicarboxylate (5) (350 mg, 1.5 mmol), 2-bromo-4,5-dimethoxybenzoyl
chloride (560 mg, 2 mmol), and potassium carbonate (311 mg, 2.25 mmol) in MeCN (7.5 mL) was
refluxed for 1 h. Water was added to the mixture and the aqueous mixture was extracted with CH2Cl2.
The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to
afford a residue, which was purified by column chromatography (CHCl3) to give dimethyl
1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6) (712 mg, quant.).
1
Mp 173-173.5 °C (n-hexane-AcOEt). IR (Nujol) cm-1: 1746, 1708. H-NMR (CDCl3) !: 3.83 (3H, s,
OMe), 3.85 (3H, s, OMe), 3.95 (3H, s, OMe), 3.98 (3H, s, OMe), 7.00 (1H, s, H-6'), 7.08 (1H, d, J = 8.5
Hz, H-7), 7.10 (1H, s, H-3'), 7.28 (1H, ddd, J = 7.7, 7.3, 1.5 Hz, H-5 or H-6), 7.37 (1H, ddd, J = 8.5, 7.7,
1 Hz, H-6 or H-5), 8.18 (1H, dd, J = 7.3, 1 Hz, H-4).
Attempt to Synthesize Dimethyl 7H-9,10-Dimethoxy-7-oxopyrrolo[3,2,1-de]phenanthridine-4,5-
dicarboxylate (7) by Intramolecular Cyclization of Dimethyl 1-(2-Bromo-4,5-dimethoxybenzoyl)-
indole-2,3-dicarboxylate (6)
To a mixture of dimethyl 1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6) (43 mg, 0.09
mmol) and potassium acetate (9 mg, 0.09 mmol) in dioxane (1.8 mL) was added Pd(PPh3)4 (5 mg, 0.05
mmol). The mixture was refluxed for 29 h under argon in the dark. Water was added to the reaction
mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried
over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column
chromatography (n-hexane : AcOEt = 8 : 1) to give 6 (12mg, 28%)
Dimethyl 1-(2-Bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8)
A mixture of dimethyl indole-2,3-dicarboxylate (5) (5.0 g, 22 mmol), 2-bromo-4,5-dimethoxybenzyl
bromide (6.7 g, 22 mmol) and potassium carbonate (4.5 g, 32 mmol) in MeCN (43 mL) was refluxed for
6 h. Water was added to the mixture and the aqueous mixture was extracted with CH2Cl2. The extracts
were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue,
which was purified by column chromatography (n-hexane : AcOEt = 20 : 1) to give dimethyl
1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8) (7.7 g, 78%).
Mp 108-109 °C (n-hexane-AcOEt). IR (CHCl3) cm-1: 1734, 1700. 1H-NMR (CDCl3) !: 3.52 (3H, s, OMe),
3.85 (3H, s, OMe), 3.95 (3H, s, OMe), 3.96 (3H, s, OMe), 5.44 (2H, s, NCH2), 6.25 (1H, s, H-6'), 7.04
(1H, s, H-3'), 7.25-7.34 (3H, m, arom), 8.12-8.18 (1H, m, H-4). Anal. Calcd for C21H20BrNO6: C, 54.56; H,
4.36; N, 3.03. Found: C, 54.79; H, 4.40; N, 2.79.
Intramolecular Cyclization of Dimethyl 1-(2-Bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate

HETEROCYCLES, Vol. 83, No. 5, 2011
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(8): Dimethyl 7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3)
To a mixture of dimethyl 1-(2-bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8) (2.9 g, 6.3
mmol) and potassium acetate (620 mg, 6.3 mmol) in dioxane (100 mL) was added Pd(PPh3)4 (364 mg,
0.32 mmol). The mixture was refluxed for 24 h under argon in the dark. Water was added to the reaction
mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried
over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column
chromatography
(CH2Cl2)
to
give
dimethyl
7H-9,10-dimethoxypyrrolo[3,2,1-de]-
phenanthridine-4,5-dicarboxylate (3) (1.82 g, 76%).
7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic Acid (10)
To a mixture of dimethyl 7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) (953
mg, 2.5 mmol) in a mixture of dioxane (15 mL) and water (15 mL) was added lithium hydroxide
monohydrate (420 mg, 10 mmol) and the mixture was refluxed for 2 h. The mixture was acidified with a
10% hydrochloric acid aqueous solution, and the precipitate was collected by filtration to afford
7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (10) (874 mg, 99%).
Mp 222 °C (decomp.) (THF). IR (Nujol) cm-1: 3474, 3362, 1729, 1704. 1H-NMR (DMSO-d6) !: 3.84 (3H,
s, OMe), 3.90 (3H, s, OMe), 5.86 (2H, s, H-7), 7.02 (1H, s, H-8), 7.24 (1H, dd, J = 8, 7.5 Hz, H-2), 7.56
(1H, s, H-11), 7.74 (1H, dd, J = 7.5, 0.5 Hz, H-3 or H-1), 7.99 (1H, dd, J = 8, 0.5 Hz, H-1 or H-3). MS
m/z: 353. HRMS m/z: Calcd for C19H15NO6: 353.0899. Found: 353.0903.
Pratosine
A mixture of 7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (10) (21 mg, 0.06
mmol) and copper chromite (2 mg) in quinoline (1 mL) was refluxed for 1 h. CHCl3 was added to the
mixture and the insoluble material was filtered through Celite to give a filtrate, which was washed with a
10% hydrochloric acid aqueous solution, then water and dried over Na2SO4. After filtration, the dried
CHCl3 solution was concentrated under reduced pressure to afford a residue, which was purified by
column chromatography (CHCl3) to give pratosine (3.3 mg, 20%).
Mp 234-235 °C (Et2O-MeOH) (lit.,1 232-233 °C); IR (Nujol) cm-1: 1670; 1H-NMR (CDCl3) !: 4.07 (3H, s,
OMe), 4.12 (3H, s, OMe), 6.90 (1H, d, J = 4 Hz, H-4), 7.48 (1H, t, J = 7.5 Hz, H-2), 7.64 (1H, s, H-8),
7.75 (1H, dd , J = 7.5, 0.5 Hz, H-3), 7.96 (1H, dd , J = 7.5, 0.5 Hz, H-1), 7.99 (1H, s, H-11), 8.05 (1H, d,
J = 4 Hz, H-5). HRMS m/z (M+) Anal. Calcd for C17H13NO3: 279.0895. Found: 279.0891.
Dimethyl 7H-9,10-Methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (12)
A mixture of dimethyl indole-2,3-dicarboxylate (5) (2.33 g, 10 mmol), 2-bromo-4,5-methylenedioxy-
benzyl bromide (3.54 g, 12 mmol), and potassium carbonate (2.07 g, 15 mmol) in MeCN (23 mL) was
refluxed for 2 h. The insoluble material was filtered through Celite to give a filtrate. The filtrate was
concentrated under reduced pressure to afford dimethyl 1-(2-bromo-4,5-methylenedioxybenzyl)-
indole-2,3-dicarboxylate (11) (4.26 g, 96%), which was used in next step without purification.

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HETEROCYCLES, Vol. 83, No. 5, 2011
1
IR (KBr) cm-1: 1733, 1708; H-NMR (CDCl3) !: 3.96 (3Hx2, s, CO2Me), 5.43 (2H, s, CH2), 5.88 (2H, s,
CH2), 6.05 (1H, s, arom), 7.04 (1H, s, arom), 7.2-7.35 (2H, m, arom), 8.2-8.3 (1H, m, arom).
To a mixture of dimethyl 1-(2-bromo-4,5-methylenedioxybenzyl)indole-2,3-dicarboxylate (11) (5.13 g,
11.5 mmol) and potassium acetate (1.35 g, 13.8 mmol) in dioxane (230 mL) was added Pd(PPh3)4 (0.66 g,
0.58 mmol). The mixture was refluxed for 6 h under argon in the dark. Water was added to the
reaction mixture and the aqueous mixture was extracted with CHCl3. The extracts were washed with
water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was
recrystallized from AcOEt to give dimethyl 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-
dicarboxylate (12) (3.54 g, 84%).
1
Mp 209-210 °C (AcOEt); IR (Nujol) cm-1: 1710, 1692; H-NMR (CDCl3) !: 3.95 (3H, s, CO2Me), 4.01
(3H, s, CO2Me), 5.60 (2H, s, NCH2), 6.02 (2H, s, O-CH2-O), 6.65 (1H, s, H-8 or H-11), 7.21 (1H, t, J = 7
Hz, H-2), 7.33 (1H, s, H-11 or H-8), 7.43 (1H, br d, J = 7 Hz, H-1), 7.78 (1H, br d, J = 7 Hz, H-3).
HRMS m/z (M+) Anal. Calcd for C20H15NO6: 366.0978. Found: 366.0965.
Hippadine
To a mixture of dimethyl 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (12)
(912 mg, 2.5 mmol) in a mixture of dioxane (12.5 mL) and water (12.5 mL) was added lithium hydroxide
monohydrate (525 mg, 12.5 mmol), and the mixture was refluxed for 5 h. The mixture was acidified
with a 10% hydrochloric acid aqueous solution and the precipitate was collected by filtration to afford
7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (13) (720 mg, 85%).
IR (KBr) cm-1: 1693; 1H-NMR (CDCl3) !: 5.82 (2H, s, CH2), 6.08 (2H, s, CH2), 6.99 (1H, s, H-8 or H-11),
7.21 (1H, t, J = 7 Hz, H-2), 7.65 (1H, s, H-11 or H-8), 7.69 (1H, d, J = 7 Hz, H-1 or H-3), 7.95 (1H, br d,
J = 7 Hz, H-3 or H-1). HRMS m/z (M+) Anal. Calcd for C18H12NO6: 338.0665. Found: 368.0675.
A mixture of 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (13) (51 mg,
0.15 mmol) and copper chromite (9 mg) in quinoline (1.5 mL) was heated at 220 °C for 2.5 h. CHCl3
was added to the mixture and the insoluble material was filtered through Celite to give a filtrate, which
was washed with a 10% hydrochloric acid aqueous solution, then water and dried over Na2SO4. After
filtration, the dried CHCl3 solution was concentrated under reduced pressure to afford a residue, which
was purified by column chromatography (n-hexane : AcOEt = 2 : 1) to give hippadine (5 mg, 13%).
1
Mp 215-216 °C (n-hexane-acetone) (lit.,2 209-210 °C); IR (Nujol) cm-1: 1673; H-NMR (CDCl3) !: 6.17
(2H, s, CH2), 6.90 (1H, d, J = 4 Hz, H-4), 7.48 (1H, t, J = 8 Hz, H-2), 7.66 (1H, s, H-8), 7.76 (1H, dd, J =
8, 0.5 Hz, H-3), 7.92 (1H, dd, J = 8, 0.5 Hz, H-1), 7.99 (1H, s, H-11), 8.04 (1H, d, J = 4 Hz, H-5).
HRMS m/z (M+) Anal. Calcd for C16H9NO3: 263.0582. Found: 263.0579.
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Br
Br
Pd(PPh3)4
KOAc
MeO
OMe
N
N
Br
OMe
OMe
NaH / DMF
(quant.)
dioxane
N
H
MeO
OMe
15
14
15. D. St. C. Black, P. A. Keller, and N. Kumar, Tetrahedron, 1993, 49, 151.