Synthesis of 3-methoxyellipticine andellipticine by friedel-crafts reaction of indole-2,3-dicarboxylic anhydride and selective demethylation

Article abstract of DOI:10.3987/COM-05-10522

Reaction of 1-benzylindole-2,3-dicarboxylic anhydride with 2,4,6-trimethoxypyridine in the presence of a Lewis acid gave 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic acid as the sole product in high yield, which could be changed to 1-benzyl-3-(2,4,6-trimethynicotinoyl)indole. 1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)indole was converted to 3-methoxyellipticine and ellipticine by selective demethylation and triflation of the methoxy group.

Full text of DOI:10.3987/COM-05-10522

HETEROCYCLES, Vol. 65, No. 11, 2005
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HETEROCYCLES, Vol. 65, No. 11, 2005, pp. 2693 - 2703
Received, 25th July, 2005, Accepted, 26th August, 2005, Published online, 26th August, 2005
SYNTHESIS
OF
3-METHOXYELLIPTICINE
AND
ELLIPTICINE BY FRIEDEL-CRAFTS REACTION OF
INDOLE-2,3-DICARBOXYLIC
SELECTIVE DEMETHYLATION
ANHYDRIDE
AND
Yasuyoshi Miki,* Yoshiyuki Aoki, Yasuhiko Tsuzaki, Misako Umemoto, and
Hajime Hibino
Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae,
Higashi-Osaka 577-8502, Japan
Abstract - Reaction of 1-benzylindole-2,3-dicarboxylic anhydride with 2,4,6-
trimethoxypyridine in the presence of a Lewis acid gave 1-benzyl-3-(2,4,6-
trimethoxynicotinoyl)indole-2-carboxylic acid as the sole product in high yield,
which could be changed to 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole.
1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)indole was converted to 3-methoxy-
ellipticine and ellipticine by selective demethylation and triflation of the methoxy
group.
Antitumor pyridocarbazole alkaloid ellipticine, isolated from the leaves of Ochrasia elliptica1 and many
of its derivatives showed potent antitumor activities.2,3 A large number of useful syntheses of
ellipticine have been developed.4 We also have shown a new synthetic method of ellipticine by using
a reaction of indole-2,3-dicarboxylic anhydride with (3-bromo-4-pyridyl)triisopoxytitanium5 or 4-lithio-
3-bromo-pyridine,6 but in this reaction a severe dry condition was required. Recently, we reported a
novel synthesis of 3-(4-methoxybenzoyl)indoles by a reaction of 1-benzylindole-2,3-dicarboxylic
anhydride (1) with anisoles in the presence of a Lewis acid7 and its application to the synthesis of
olivacine.8
Me
N
N
H
Me
ellipticine

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HETEROCYCLES, Vol. 65, No. 11, 2005
In this paper we show in detail a simple and useful synthesis of 3-methoxyellipticine and ellipticine by
regioselective Friedel-Crafts reaction of 1-benzylindole-2,3-dicarboxylic anhydride with 2,4,6-
trimethoxypyridine.
Reaction of 1-benzylindole-2,3-dicarboxylic anhydride (1)9 (1 equivalent) with 4-methoxypyridine (2a)
or 2,4-dimethoxypyridine (2b) (1 equivalent) in CH2Cl2 in the presence of titanium chloride (IV) (2
equivalents) at room temperature resulted in recovery of the starting material (Entries 1, 2), but with
2,4,6-trimethoxypyridine (2c)10 gave 1-benzyl-3-(2,4,6-trimethoxyisonicotinoyl)indole-2-carboxylic acid
(3c) in 25% yield (Entry 3). Many attempts to attain 3c under various conditions were less than
satisfactory (Entries 4, 5). However, treatment of 1 (1 equivalent) with 2c (2 equivalents) in the
presence of titanium chloride(IV) (3 equivalents) afforded 3c in 98% yield (Entry 6). In a similar
manner, 3d was obtained from 1 and 2,6-dimethoxypyridine (2d) (Entry 7) (Scheme 1) (Table 1). The
carboxylic acid (3c) was converted to ketone (4) by treatment with copper chromite in hot quinoline
(180°C) in 94% yield.
Scheme 1
R1
N
R1
O
OMe
N
O
O
R2
R3
2CuO.Cr2O3
(94%)
2
N
O
TiCl4
R3
N
N
N
MeO
OMe
R2
COOH
O
CH2Ph
CH2Ph
CH2Ph
1
3
4
Table 1
2
(Equiv.)
TiCl
(Equiv.)
4
1
2
3
2
a
b
c
c
c
c
d
R
R
R
Entry
Yield (%)
H
OMe
OMe
OMe
OMe
OMe
OMe
H
H
1
2
3
4
5
6
7
1
1
1
1
2
2
2
2
2
2
4
2
3
3
recovered
recovered
25
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
mixture
26
98
75
Treatment of ketone (4) with boron tribromide gave a mixture of 4-hydroxy (5) and 2-hydroxy derivative
(6) in 37% and 47% yields, respectively, but a mixture of 4 and 47% hydrobromic acid in acetic acid

HETEROCYCLES, Vol. 65, No. 11, 2005
2695
warmed to 50°C to provided 6 in 93% yield as the sole product. Reaction of the 4-hydroxy derivative
(5) with triflic anhydride (Tf2O) in the presence of triethylamine gave the corresponding triflate, which
could be changed to 2,6-dimethoxy compound (7) by reduction with ammonium formate in the presence
of 10% Pd-C in hot methanol in 92% yield. In a similar manner, 6 was led to 2,4-dimethoxy compound
(8) in 82% yield. 7 was also obtained by decarboxylation of the carboxylic acid (3d) in the presence of
copper chromite in quinoline (170-180°C) in 74% yield. (Scheme 2)
Scheme 2
O
OMe
N
O
OH
OMe
N
O
BBr3
N
+
or
N
N
OMe
MeO
N
MeO
OMe
OMe
HO
47% HBr
CH2Ph
CH2Ph
CH2Ph
5
4
6
1) Tf2O / Et3N
2) HCOONH4
Pd(PPh3)4
1) Tf2O / Et3N
2) HCOONH4
Pd(PPh3)4
O
OMe
N
O
O
OMe
N
2CuO.Cr2O3
(74%)
N
N
N
N
OMe
COOH
OMe
MeO
OMe
CH2Ph
CH2Ph
CH2Ph
8
3d
7
Selective demethylation of the 4-methoxy group of 8 was performed by treatment with boron tribromide
to provide 4-hydroxy compound (9) in 88% yield, which was changed by reaction with Ph3P=CH2 and
catalytic reduction in the presence of PtO2, followed by treatment with Tf2O in the presence of
triethylamine to give the corresponding triflate. The triflate was reacted with (1-ethoxyvinyl)tributyltin
in the presence of tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) in refluxing toluene to provide
the ethoxyvinyl compound, which was treated with 10% hydrochloric acid in tetrahydrofuran to give 6-
benzyl-3-methoxyellipticine (10) in 81% yield.
Debenzylation of 10 was performed by treatment with 47% hydrobromic acid at 80°C to provide
3-methoxyellipticine (11) (98%). When 11 was treated with boron tribromide at room temperature for 24
h, 11 was recovered, but reaction of 11 with hot 47% hydrobromic acid in acetic acid gave 3-hydroxy-
ellipticine in 63% yield. Triflation of 3-hydroxyellipticine was performed by treatment with Tf2O in
the presence of triethylamine to provide the corresponding triflate and subsequent hydrogenation of the

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HETEROCYCLES, Vol. 65, No. 11, 2005
triflate with ammonium formate in the presence of Pd(PPh3)4 in hot methanol afforded ellipticine5 in
68% yield. (Scheme 3)
Scheme 3
1) Ph3P=CH2 (72%)
2) H2 / PtO2 (68%)
Me
Me
O
BBr3
N
N
8
(88%)
N
3) Tf2O / Et3N (88%)
HO
N
OMe
OMe
4) (ethoxyvinyl)tributyltin / Pd(PPh3)4,
then 10% HCl (81%)
CH2Ph
CH2Ph
10
9
Me
Me
Me
1) 47% HBr (63%)
2) Tf2O / Et3N (53%)
N
N
47% HBr
80°C
(98%)
(68%)
3) HCOONH4 / Pd(PPh3)4
N
H
N
H
OMe
Me
11
ellipticine
EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected.
The 1H-NMR spectra were determined on a JEOL JNM-GSX 270 spectrometer using tetramethylsilane as
an internal standard and CDCl3 as solvent. The IR spectra were recorded with a JASCO FT/IR-7000
spectrophotometer. The high MS spectra were recorded on a JOEL JMS-HX100 spectrometer.
Column chromatography was performed on E. Merck silica gel 60 (70-230 mesh or 230-400 mesh).
Thin-layer (TLC) and preparative thin-layer chromatography (PLC) were performed on E. Merck silica
gel 60 F254. Tetrahydrofuran (THF) was distilled from sodium and benzophenone prior to use.
Dichloromethane (CH2Cl2) was distilled from calcium hydride prior to use.
Reaction of 1-Benzylindole-2,3-dicarboxylic Anhydride (1) with Methoxypyridines (2): General
procedure
1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic Acid (3c)
To a solution of 1-benzylindole-2,3-dicarboxylic anhydride (1)9 (4.16 g, 15 mmol) and 2,4,6-
trimethoxypyridine (2c)10 (5.07 g, 30 mmol) in dichloromethane (60 mL) was added 1.0 M titanium (IV)
chloride in dichloromethane solution (45 mL, 45 mmol) and the mixture was stirred for 18 h at rt.
Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The
combined extracts were washed with water and dried over Na2SO4, then concentrated under reduced

HETEROCYCLES, Vol. 65, No. 11, 2005
2697
pressure. The residue was purified by column chromatography on silica gel (CHCl3 : MeOH = 10 : 1)
to give 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic acid (3c) (6.58 g, 98%), mp 164-
-1
1
168°C (from n-hexane-acetone). IR (Nujol) ν: 1723, 1596 cm ; H-NMR (CDCl3) δ: 3.65 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 4.01 (3H, s, OCH3), 6.02 (1H, s, H-5'), 6.02 (2H, s, CH2Ph), 7.08-7.34 (8H,
m, aromatic protons), 7.46 (1H, d, J = 8.0 Hz, H-4). Anal. Calcd for C22H22N2O6: C, 67.26; H, 4.97; N,
6.27. Found: C, 67.19; H, 4.95; N, 6.34.
1-Benzyl-3-(2,6-dimethoxynicotinoyl)indole-2-carboxylic Acid (3d)
Using a procedure similar to that described for the preparation of 3c, 3d (75%) was obtained from 1, mp
157-159 °C (from n-hexane-acetone). IR (CHCl3) ν: 1716, 1592 cm-1; 1H-NMR (CDCl3) δ: 3.77 (3H, s,
OCH3), 4.04 (3H, s, OCH3), 6.07 (2H, s, CH2Ph), 6.44 (1H, d, J = 8.0 Hz, H-5'), 7.00-7.36 (8H, m,
aromatic protons), 7.47 (1H, d, J = 8.0 Hz, H-4'), 7.84 (1H, d, J = 8.0 Hz, H-4). HRMS m/z (M+) calcd
for C24H20N2O2 , 416.1372. Found 416.1350.
1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)indole (4)
A mixture of 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic acid (3c) (3.70 g, 8.3 mmol)
and copper chromite (0.33 g) in quinoline (83 mL) was heated at 180°C for 0.5 h and the insoluble
material was removed by filtration through Celite. Water was added to the filtrate and the mixture was
extracted with CHCl3. The combined extracts were washed with water, then with 5% hydrochloric acid
and water. The solution was dried over Na2SO4 and evaporated off to give a residue, which was
purified by column chromatography (n-hexane : AcOEt = 2 : 1) to yield 1-benzyl-3-(2,4,6-
trimethoxynicotinoyl)indole (4) (3.10 g, 94%), mp 175-176 °C (from AcOEt). IR (Nujol) ν: 1625 cm-1;
1H-NMR (CDCl3) δ: 3.71 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.95 (3H, s, OCH3), 5.30 (2H, s, CH2Ph),
5.95 (1H, s, H-5'), 7.08-7.35 (8H, m, aromatic protons), 7.51 (1H, s, H-2), 8.31-8.37 (1H, m, H-4).
Anal. Calcd for C24H22N2O4: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.60; H, 5.50; N, 7.03.
Demethylation of 1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)indole (4)
1. By Boron Tribromide
To a solution of 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole (4) (20 mg, 0.05 mmol) in
dichloromethane (2 mL) was added 1.0 M boron tribromide in dichloromethane solution (0.6 mL, 0.06
mmol) at 0°C and the mixture was stirred for 2 h.
Water was added to the reaction mixture and the
mixture was neutralized with saturated sodium hydrogen carbonate solution. The solution was extracted
with dichloromethane and the combined extracts were washed with water and dried over Na2SO4, then

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HETEROCYCLES, Vol. 65, No. 11, 2005
concentrated under reduced pressure. The residue was purified by column chromatography on silica gel
(CHCl3 : MeOH = 10 : 1) to give 1-benzyl-3-(4-hydroxy-2,6-dimethoxynicotinoyl)indole (5) (7 mg, 37%)
and 1-benzyl-3-(2-hydroxy-4,6-dimethoxynicotinoyl)indole (6) (9 mg, 47%).
-1
1
5; IR (CHCl3) ν: 1623 cm ; H-NMR (CDCl3) δ: 3.65 (3H, s, OCH3), 3.93 (3H, s, OCH3), 5.33 (2H, s,
CH2Ph), 5.95 (1H, s, H-5'), 7.16-7.40 (8H, m, aromatic protons), 7.72 (1H, s, H-2), 8.19 (1H, m, H-4),
12.58 (1H, s, OH).
-1
1
6; mp 240-242°C (from MeOH). IR (CHCl3) ν: 1634 cm ; H-NMR (CDCl3) δ: 3.51 (3H, s, OCH3),
3.99 (3H, s, OCH3), 5.34 (2H, s, CH2Ph), 5.83 (1H, s, H-5'), 7.16-7.40 (8H, m, aromatic protons), 7.62
(1H, s, H-2), 8.14 (1H, m, H-4). Anal. Calcd for C23H20N2O4: C, 71.12; H, 5.19; N, 7.21. Found: C,
71.20; H, 5.25; N, 7.22.
2. By 47% Hydrobromic Acid in Acetic Acid
A mixture of 4 (404 mg, 1 mmol), 47% hydrobromic acid (5 mL) and acetic acid (2 mL) was heated at
50°C for 8 h and the reaction mixture was neutralized by saturated sodium hydrogen carbonate solution.
The solution was extracted with CHCl3. The combined extracts were washed with water and dried over
Na2SO4, then concentrated under reduced pressure to give a residue, which was purified by column
chromatography (CHCl3 : MeOH = 30 : 1) to yield 6 (362 mg, 93%).
1-Benzyl-3-(2,6-dimethoxynicotinoyl)indole (7)
1. In the Presence of Copper Chromite in Hot Quinoline
A mixture of 1-benzyl-3-(2,6-dimethoxynicotinoyl)indole-2-carboxylic acid (3d) (710 mg, 1.7 mmol) and
copper chromite (0.68 mg) in quinoline (17 mL) was heated at 180°C for 1 h and the insoluble material
was removed by filtration through Celite. Water was added to the filtrate and the mixture was extracted
with CHCl3. The combined extracts were washed with water, then with 5% hydrochloric acid and water.
The solution was dried over Na2SO4 and evaporated off to give a residue, which was purified by column
chromatography (n-hexane : AcOEt = 3 : 2) to yield 1-benzyl-3-(2,6-dimethoxynicotinoyl)indole (7) (469
mg, 74%).
2. By Reduction of the Triflate with Ammonium Formate in the Presence of Pd(PPh3)4
Triflic anhydride (0.016 mL, 0.096 mmol) was added to a mixture of 1-benzyl-3-(4-hydroxy-2,6-
dimethoxynicotinoyl)indole (5) (30 mg, 0.08 mmol) and triethylamine (0.027 mL, 0.8 mmol) in
dichloromethane (1 mL) and the mixture was stirred for 1 h at rt. Water was added to the reaction

HETEROCYCLES, Vol. 65, No. 11, 2005
2699
mixture and the mixture was extracted with dichloromethane. The combined extracts were washed with
water and dried over Na2SO4, then concentrated under reduced pressure to give a residue (35 mg).
A suspension of the residue (31 mg, 0.06 mmol)), ammonium formate (23 mg, 0.36 mmol), and
Pd(PPh3)4 (13 mg, 0.012 mmol) in MeOH (1 mL) was refluxed for 2 h. Water was added to the reaction
mixture and the mixture was extracted with CHCl3. The combined extracts were washed with water and
dried over Na2SO4, then concentrated under reduced pressure to give a residue, which was purified by
column chromatography (n-hexane : AcOEt = 5 : 1) to afford 7 (18 mg, 92%), mp 178°C (from AcOEt);
-1
1
IR (CHCl3) ν: 1619 cm ; H-NMR (CDCl3) δ: 3.89 (3H, s, OCH3), 3.98 (3H, s, OCH3), 5.33 (2H, s,
CH2Ph), 6.36 (1H, d, J = 8.0 Hz, H-5'), 7.10-7.36 (8H, m, aromatic protons), 7.53 (1H, s, H-2), 7.78 (1H,
d, J = 8 Hz, H-4'), 8.35-8.41 (1H, m, H-4). Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52.
Found: C, 74.19; H, 5.49; N, 7.58.
1-Benzyl-3-(4,6-dimethoxynicotinoyl)indole (8)
Triflic anhydride (0.81 mL, 4.8 mmol) was added to a mixture of 1-benzyl-3-(2-hydroxy-4,6-
dimethoxynicotinoyl)indole (6) (1.56 g, 4.0 mmol) and triethylamine (1.1 mL, 8.0 mmol) in
dichloromethane (20 mL) and the mixture was stirred for 1 h at rt. Water was added to the reaction
mixture and the mixture was extracted with CHCl3. The combined extracts were washed with water and
dried over Na2SO4, then concentrated under reduced pressure to give a residue, which was purified by
column chromatography (n-hexane : AcOEt = 3 : 2) to yield 1-benzyl-3-(4,6-dimethoxy-2-
-1
1
trifluoromethanesulfonyloxynicotinoyl)indole (1.97 g, 94%). IR (Nujol) ν: 1627 cm ; H-NMR
(CDCl3) δ: 3.80 (3H, s, OCH3), 3.95 (3H, s, OCH3), 5.32 (2H, s, CH2Ph), 6.30 (1H, s, H-5'), 7.12-7.35
(8H, m, aromatic protons), 7.52 (1H, s, H-2), 8.37-8.41 (1H, m, H-4).
A suspension of 1-benzyl-3-(4,6-dimethoxy-2-trifluoromethanesulfonyloxynicotinoyl)indole (2.08 g, 4.0
mmol), ammonium formate (1.51 g, 24 mmol), and Pd(PPh3)4 (0.93 g, 0.8 mmol) in MeOH (20 mL) was
refluxed for 2 h. Water was added to the reaction mixture and the mixture was extracted with CHCl3.
The combined extracts were washed with water and dried over Na2SO4, then concentrated under reduced
pressure to give a residue, which was purified by column chromatography (n-hexane : AcOEt = 2 : 1) to
afford 1-benzyl-3-(4,6-dimethoxynicotinoyl)indole (8) (1.28 g, 85%), mp 161-162°C (from n-hexane-
-1
AcOEt). IR (Nujol) ν: 1624 cm ; H-NMR (CDCl3) δ: 3.80 (3H, s, OCH3), 3.98 (3H, s, OCH3), 5.33
1
(2H, s, CH2Ph), 6.29 (1H, s, H-5'), 7.10-7.36 (8H, m, aromatic protons), 7.53 (1H, s, H-2), 8.20 (1H, s,

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HETEROCYCLES, Vol. 65, No. 11, 2005
H-2'), 8.41-8.47 (1H, m, H-4). Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C,
74.15; H, 5.39; N, 7.55.
1-Benzyl-3-(4-hydroxy-6-methoxynicotinoyl)indole (9)
To a suspension of 1-benzyl-3-(4,6-dimethoxynicotinoyl)indole (8) (781 mg, 2.1 mmol) in
dichloromethane (11 mL) was added 1.0 M boron tribromide in dichloromethane solution (3.7 mL, 3.7
mmol) at -20°C and the mixture was stirred for 2 h. Water was added to the reaction mixture. The
mixture was neutralized with saturated sodium hydrogen carbonate solution, extracted with
dichloromethane, and the combined extracts were washed with water and dried over Na2SO4, then
concentrated under reduced pressure. The residue was purified by column chromatography on silica gel
(n-hexane : AcOEt = 5 : 1) to give 1-benzyl-3-(4-hydroxy-6-methoxynicotinoyl)indole (9) (658 mg,
88%), mp 148-149°C (from n-hexane-AcOEt). IR (CHCl3) ν: 1628 cm-1; 1H-NMR (CDCl3) δ: 3.98 (3H,
s, OCH3), 5.41 (2H, s, CH2Ph), 6.33 (1H, s, H-2'), 7.12-7.40 (8H, m, aromatic protons), 7.78 (1H, s, H-2),
8.27-8.34 (1H, m, H-4), 8.71 (1H, s, H-2'), 12.67 (1H, s, OH). Anal. Calcd for C22H18N2O3: C, 73.73;
H, 5.06; N, 7.82. Found: C, 73.72; H, 5.11; N, 7.83.
6-Benzyl-3-methoxyellipticine (10)
A solution of 1-benzyl-3-(4-hydroxy-6-methoxynicotinoyl)indole (9) (644 mg, 1.8 mmol) in THF (9
mL) was added to
a
solution of methylenetriphenylphosphorane [prepared from
methyltriphenylphosphonium bromide (1.90 g, 5.4 mol) and 1.56 M n-butyllithium in n-hexane solution
(3.5 mL, 5.4 mmol) in THF (9 mL) at rt] at 0°C under argon and the mixture was stirred for 4 h. The
reaction mixture was acidified with saturated ammonium chloride solution and extracted with CHCl3.
The organic extracts were washed with water, dried over Na2SO4, and concentrated. The residue was
purified by column chromatography (n-hexane : AcOEt = 1 : 2) to give 1-(1-benzyl-3-indolyl)-1-(4-
hydroxy-6-methoxy-3-pyridinyl)ethene (461 mg, 72%) as a white solid. IR (CHCl3) ν: 3472, 1625 cm-
1
1
; H-NMR (CDCl3) δ: 3.93(3H, s, OCH3), 5.27 (2H, s, CH2Ph), 5.32 (2H, d, J= 1.3 Hz, C=CH2), 6.28
(1H, s, H-5'), 7.04 (1H, s, H-2), 7.05-7.36 (8H, m, aromatic protons), 7.78 (1H, m, H-4), 8.05 (1H, s, H-
2').
A suspension of 1-(1-benzyl-3-indolyl)-1-(4-hydroxy-6-methoxy-3-pyridinyl)ethene (461 mg, 1.29
mmol) and platinum(IV) oxide (46 mg) in EtOH (7 mL) was stirred for 6 h under hydrogen. The
catalyst was removed by filtration through Celite and the filtrate was evaporated off. The residue was
purified by column chromatography (CHCl3 : MeOH = 20 : 1) to yield 1-(1-benzyl-3-indolyl)-1-(4-

HETEROCYCLES, Vol. 65, No. 11, 2005
2701
hydroxy-6-methoxy-3-pyridinyl)ethane (314 mg, 68%) as a pale yellow solid. IR (CHCl3) ν: 3422 cm-1;
1H-NMR (CDCl3) δ: 1.63 (3H, d, J = 7.2 Hz, CH3), 3.71 (3H, s, OCH3), 4.60 (1H, q, J = 7.2 Hz, Ar-
CH(CH3)-Ar), 5.26 (2H, s, CH2Ph), 6.10 (1H, s, H-5'), 6.92-7.43 (8H, m, aromatic protons), 7.44-7.54
(1H, br s, OH).
Triflic anhydride (0.161 mL, 0.96 mmol) was added to a mixture of 1-(1-benzyl-3-indolyl)-1-(4-hydroxy-
6-methoxy-3-pyridinyl)ethane (286 mg, 0.8 mmol) and triethylamine (0.233 mL, 1.6 mmol) in
dichloromethane (20 mL) and the mixture was stirred for 1 h at -78°C. Water was added to the reaction
mixture and the mixture was extracted with CHCl3. The combined extracts were washed with water and
dried over Na2SO4, then concentrated under reduced pressure to give a residue, which was purified by
column chromatography (n-hexane : AcOEt = 5 : 1) to yield 1-(1-benzyl-3-indolyl)-1-(6-methoxy-4-
-1
1
trifluoromethanesulfonyloxy-3-pyridinyl)ethane (345 mg, 88%). IR (Nujol) ν: 1622 cm ; H-NMR
(CDCl3) δ: 1.65 (3H, d, J = 7.2 Hz, CH3), 3.81 (3H, s, OCH3), 4.62 (1H, q, J = 7.2 Hz, Ar-CH(CH3)-Ar),
5.24 (2H, s, CH2Ph), 6.81 (1H, s, H-5'), 6.94-7.46 (8H, m, aromatic protons).
A mixture of 1-(1-benzyl-3-indolyl)-1-(6-methoxy-4-trifluoromethanesulfonyloxy-3-pyridinyl)ethane
(167 mg, 0.34 mmol), (1-ethoxyvinyl)tributyltin (0.115 mL, 0.34 mmol), diisopropylethylamine (0.071
mL, 0.41 mmol), lithium chloride (43 mg, 1.0 mmol), and Pd(PPh3)4 (20 mg, 0.017 mmol) in toluene (4
mL) was refluxed for 2 h under argon. The insoluble material was filtered off and the filtrate was
concentrated to give a residue.
A mixture of the residue and 10% hydrochloric acid (3 mL) in THF (3
mL) was stirred for 16 h at rt. The reaction mixture was neutralized by addition of 5% sodium hydrogen
carbonate solution and extracted with CHCl3. The organic extracts were washed with water, dried over
Na2SO4, and concentrated. The residue was purified by column chromatography (CHCl3) to give
6-benzyl-3-methoxyellipticine (10) (100 mg, 81%) as a greenish yellow solid, mp 229-230°C (from
-1
1
AcOEt). IR (CHCl3) ν: 1614 cm ; H-NMR (DMSO-d6) δ: 2.74 (3H, s, CH3), 3.26 (3H, s, CH3), 4.00
(3H, s, OCH3), 5.86 (2H, s, CH2Ph), 7.08-7.53 (7H, m, aromatic protons), 8.34 (1H, d, J = 8.0 Hz, H-10),
9.48 (1H, s, H-1). Anal. Calcd for C25H22N2O: C, 81.94; H, 6.05; N, 7.65. Found: C, 81.92; H, 6.10;
N, 7.61.
3-Methoxyellipticine (11)
A solution of 6-benzyl-3-methoxyellipticine (10) (84 mg, 0.23 mmol) in 47% hydrobromic acid (3 mL)
and acetic acid (3 mL) was heated at 80°C for 15 min. Water was added to the reaction mixture and
the precipitated solid was collected by filtration to give 3-methoxyellipticine (11) (62 mg, 98%) as an

2702
HETEROCYCLES, Vol. 65, No. 11, 2005
orange solid, mp >300°C (from MeOH). IR (CHCl3) ν: 1614 cm-1; 1H-NMR (DMSO-d6) δ: 2.74 (3H, s,
CH3), 3.24 (3H, s, CH3), 4.09 (3H, s, OCH3), 7.20-7.58 (4H, m, aromatic protons), 8.33 (1H, d, J = 8.0
Hz, H-10), 9.47 (1H, s, H-1), 11.32 (1H. br s, NH). Anal. Calcd for C18H16N2O: C, 78.23; H, 5.84; N,
10.14. Found: C, 78.21; H, 5.79; N, 10.08.
Ellipticine
A solution of 3-methoxyellipticine (11) (17 mg, 0.06 mmol) in 47% hydrobromic acid (1 mL) and
acetic acid (1 mL) was refluxed for 28 h. Water was added to the reaction mixture and the
precipitated solid was collected by filtration to give 3-hydroxyellipticine (10 mg, 63%). 1H-NMR
(DMSO-d6) δ: 2.64 (3H, s, CH3), 3.17 (3H, s, CH3), 7.01 (1H, s, H-4), 7.16-7.52 (3H, m, aromatic
protons), 8.26 (1H, d, J = 8.0 Hz, H-10), 9.27 (1H, s, H-1), 11.10 (1H. br s, NH).
Triflic anhydride (0.06 mL, 0.036 mmol) was added to a mixture of 3-hydroxyellipticine (8.0 mg, 0.03
mmol) and triethylamine (0.083 mL, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was
stirred for 1 h at 0°C. Water was added to the reaction mixture and the mixture was extracted with
CHCl3. The combined extracts were washed with water and dried over Na2SO4, then concentrated
under reduced pressure to give a residue, which was purified by PLC (CHCl3) to yield
3-trifluoromethanesulfonyloxyellipticine (6.4 mg, 53%). 1H-NMR (CDCl3) δ: 2.65 (3H, s, CH3), 3.11
(3H, s, CH3), 7.28-7.61 (3H, m, Ar), 7.65 (1H, s, H-4), 8.02 (1H. br s, NH), 8.29 (1H, d, J = 8.0 Hz, H-
10), 9.29 (1H, s, H-1).
A suspension of 3-trifluoromethanesulfonyloxyellipticine (6.0 mg, 0.015 mmol), ammonium formate (5.7
mg, 0.09 mmol), and Pd(PPh3)4 (3.5 mg, 0.003 mmol) in MeOH (1 mL) was refluxed for 5 h. Water
was added to the reaction mixture and the mixture was extracted with CHCl3. The combined extracts
were washed with water and dried over Na2SO4, then concentrated under reduced pressure to give a
residue, which was purified by PLC (CHCl3) to give ellipticine5 (2.5 mg, 68%), mp >300 °C (from
MeOH).
1H-NMR (DMSO-d6) δ: 2.80 (3H, s, CH3), 3.27 (3H, s, CH3), 7.22-7.33 (1H, m, aromatic
protons), 7.49-7.61 (2H, m, aromatic protons), 7.91 (1H, d. J = 6.0 Hz, H-4), 8.36 (1H, d, J = 8.0 Hz, H-
10), 8.43 (1H, d, J = 6 Hz, H-3), 9.69 (1H, s, H-1), 11.25 (1H, s, NH). HRMS m/z (M+) calcd for
C17H14N2: 246.1157. Found: 246.1185.
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