Synthesis of ellipticine by reaction of 1-(4-methoxybenzyl)indole-2,3-dicarboxylic anhydride with (3-bromo-4-pyridyl)-triisopropoxytitanium

Article abstract of DOI:10.1039/b105116b

The synthesis of ellipticine by the reaction of 1-(4-methoxybenzyl)indole-2,3-dicarboxylic anhydride with (3-bromo-4-pyridyl)-triisopropoxytitanium was reported. The reaction involved the deprotection of the 1-(4-methoxybenzyl) group of the 2-acylindole-3-carboxylic acid by treatment with perchloric acid in acetic acid to afford 2-(3-bromoisonicotinoyl)indole, which was then converted to ellipticine. The effect of different reagents and conditions on the reaction was observed and infrared spectrometry was performed on the products.

Full text of DOI:10.1039/b105116b

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Synthesis of ellipticine by reaction of 1-(4-methoxybenzyl)indole-
2,3-dicarboxylic anhydride with (3-bromo-4-pyridyl)-
triisopropoxytitanium
1
Yasuyoshi Miki,* Hiroko Hachiken and Norihide Yanase
Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka,
577-8502, Japan
Received (in Cambridge, UK) 8th June 2001, Accepted 19th July 2001
First published as an Advance Article on the web 28th August 2001
Reaction of 1-benzyl- and 1-(4-methoxybenzyl)indole-2,3-dicarboxylic anhydride with (3-bromo-4-
pyridyl)triisopropoxytitanium gave the corresponding 2-acylindole-3-carboxylic acids as the sole product.
Deprotection of the 1-(4-methoxybenzyl) group of the 2-acylindole-3-carboxylic acid was performed by treatment
with perchloric acid in acetic acid to afford 2-(3-bromoisonicotinoyl)indole, which was converted to ellipticine.
Ellipticine, 5,11-dimethyl-6H-pyrido[4,3-b]carbazole, has potent
antitumor activity1 and many useful methods for its synthesis
have been developed.2 In a previous paper we described the
synthesis of ellipticine,3 but in this synthesis debenzylation
of the 1-benzyl-2-(3-bromoisonicotinoyl)indole resulted in low
yield. However, recently, we have shown that the 4-methoxy-
benzyl and 3,4-dimethoxybenzyl groups are suitable for the
protection of the nitrogen in an indole and deprotection of
the 4-methoxybenzyl and 3,4-dimethoxybenzyl groups was
performed by treatment with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) or trifluoroacetic acid depending on
the substituents of the indoles.4 In this paper we report the
detailed synthesis of ellipticine by the reaction of 1-benzyl-3,5
and 1-(4-methoxybenzyl)indole-2,3-dicarboxylic anhydride (1
and 10) with (3-bromo-4-pyridyl)triisopropoxytitanium.
Results and discussion
Reaction of 1-benzylindole-2,3-dicarboxylic anhydride 16 with
3-bromo-4-lithiopyridine (2, M = Li) in THF at Ϫ96 ЊC gave
1-benzyl-2-(3-bromoisonicotinoyl)indole-3-carboxylic acid 3 in
42% yield (Scheme 1).5 Many attempts to obtain 3 under various
conditions were less than satisfactory (Table 1 entry 1, 2). How-
ever, treatment of 1 with (3-bromo-4-pyridyl)triisopropoxy-
titanium (2, M = Ti(OPr-i)3)7 afforded 3 in 86% yield (Table 1,
entry 3, 4).
Debenzylation of the carboxylic acid 3 by treatment with
AlCl3 and anisole8 resulted in recovery of 3. However, after
removal of the carboxy group from 3 with 20% hydrochloric
acid in acetic acid, debenzylation of the 1-benzyl-2-(3-bromo-
isonicotinoyl)indole 4 was performed by treatment of AlCl3
and anisole to give 2-(3-bromoisonicotinoyl)indole 5 in 42%
yield, but the yield was still low.
Scheme 1 Reagents and conditions: i. 2, in THF, Ϫ96 ЊC; ii, 20%
HClO4 in AcOH, reflux (94%); iii, AlCl3 in anisole, 100 ЊC (42%); iv,
Table 1 Reaction of the anhydride 1 with 4-metalated 3-bromo-
pyridine 2
Ph3P᎐CH2 in THF (66%); v, PtO2 in EtOH (83%); vi, AlCl3 in anisole,
᎐
100 ЊC 8 (28%) and 9 (27%).
Entry
M
2 (equiv.)
Yield of 3 (%)
Finally, we examined the effect of the 2-substituents on the
indole ring on the reactivity of 1-benzyl-2-(4-pyridylmethyl)-
indole derivative 7 compared with that of the 2-acylindole
5. Compound 5 was changed to 7 by treatment with methyl-
1
2
3
4
Li
Li
1.2
2.0
1.2
2.0
42
25
60
86
Ti(OPr-i)3
Ti(OPr-i)3
enetriphenylphosphorane (Ph P᎐CH ), followed by catalytic
᎐
3
2
DOI: 10.1039/b105116b
J. Chem. Soc., Perkin Trans. 1, 2001, 2213–2216
This journal is © The Royal Society of Chemistry 2001
2213

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hydrogenation. Compound 7 was treated with AlCl3 and anisole
at 100 ЊC to afford a mixture of the debenzylated product
8 and 3-benzyl derivative 9 in 28 and 27% yields, respectively.
These results show that debenzylation of 3, 4, and 7 was dif-
ficult. Therefore, we investigated the utility of the 4-methoxy-
benzyl group as a protecting group of an indole nitrogen in the
synthesis of ellipticine.
Column chromatography was performed on E. Merck silica gel
60 (70–230 mesh or 230–400 mesh). Tetrahydrofuran (THF)
was distilled from sodium and benzophenone prior to use.
Dichloromethane (CH2Cl2) was distilled from calcium hydride
prior to use.
1-Benzyl-2-(3-bromoisonicotinoyl)indole 4
1-(4-Methoxybenzyl)indole-2,3-dicarboxylic anhydride 10
was reacted with (3-bromo-4-pyridyl)triisopropoxytitanium (2,
M = Ti(OPr-i)3) in THF at Ϫ96 ЊC to provide 1-(4-methoxy-
benzyl)-2-(3-bromoisonicotinoyl)indole-3-carboxylic acid 11 in
61% yield (Scheme 2). Removal of both the 4-methoxybenzyl
and carboxy groups was performed by treatment with 20%
perchloric acid in acetic acid to provide 5 in 81% yield.
A suspension of 1-benzyl-2-(3-bromoisonicotinoyl)indole-3-
carboxylic acid 35 (435 mg, 1.0 mmol) in 20% perchloric acid
(10 cm3) and acetic acid (5 cm3) was refluxed for 3 h. The reac-
tion mixture was neutralized by addition of saturated sodium
hydrogen carbonate solution and extracted with CHCl3. 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 = 10 : 1) to give 1-benzyl-2-(3-bromoisonico-
tinoyl)indole 4 (368 mg, 94%), mp 103–104 ЊC (from n-hexane);
νmax(Nujol)/cmϪ1 1652; δH (CDCl3) 5.97 (2H, s, CH2Ph), 6.87
(1H, d, J 1, 3-H), 7.12–7.48 (9H, m, Ar), 7.65 (1H, dt, J 8, 1,
4-H), 8.66 (1H, d, J 5, 6Ј-H), 8.83 (1H, s, 2Ј-H) (Calcd. for
C21H15BrN2O: C, 64.46; H, 3.86; N, 7.16. Found: C, 64.36;
H, 4.06; N, 7.17%).
2-(3-Bromoisonicotinoyl)indole 5
A mixture of 1-benzyl-2-(3-bromoisonicotinoyl)indole 4 (587
mg, 1.5 mmol) and aluminium() chloride (998 mg, 7.5 mmol)
in anisole (15 cm3) was stirred for 1.5 h at 100 ЊC. Alumin-
ium() chloride (599 mg, 4.5 mmol) was added to the mixture
and the mixture was stirred for another 2.5 h at 100 ЊC. The
reaction mixture was neutralized by addition of saturated
sodium hydrogen carbonate solution and extracted with
CHCl3. 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 (CH2Cl2–AcOEt = 10 : 1) to give 2-(3-bromoisonicotinoyl)-
indole 5 (188 mg, 42%), mp 220–221 ЊC (from MeOH);
νmax(CHCl3)/cmϪ1 3454, 1643; δH (CDCl3) 6.88 (1H, dd, J 2.5, 1,
3-H), 7.18 (1H, ddd, J 8, 7, 1, 5-H), 7.42 (1H, ddd, J 8, 7, 1,
6-H), 7.42 (1H, d, J 5, 5Ј-H), 7.49 (1H, dd, J 8, 1, 7-H), 7.68
(1H, dd, J 8, 1, 4-H), 8.69 (1H, d, J 5, 6Ј-H), 8.89 (1H, s, 2Ј-H),
9.23 (1H, br s, NH) (Calcd. for C14H9BrN2O: C, 55.84; H, 3.01;
N, 9.30. Found: C, 55.80; H, 3.14; N, 9.24%).
From 11
Using a procedure similar to that described for the preparation
of 4, 5 (17 mg, 81%) was obtained from 1-(4-methoxybenzyl)-
2-(3-bromoisonicotinoyl)indole-3-carboxylic acid 11 (33 mg,
0.07 mmol).
Scheme 2 Reagents and conditions: i. 2 (M = Ti(OPr-i)3) in THF,
Ϫ96 ЊC (61%); ii, 20% HClO4 in AcOH, reflux (81%); iii, Ph3P᎐CH2 in
᎐
THF (63%); iv, PtO2 in EtOH (73%); v, (ethoxyvinyl)tributyltin in
toluene, reflux (97%); vi, 10% HCl in THF, rt (87%).
1-(1-Benzyl-2-indolyl)-1-(3-bromo-4-pyridyl)ethene 6
In a similar conversion to 7 from 4, 5 was converted to 8 by
treatment with methylenetriphenylphosphorane (Ph P᎐CH ),
᎐
3
2
A solution of 1-benzyl-2-(3-bromoisonicotinoyl)indole 4 (391
mg, 1 mmol) in THF (1.5 cm3) was added to a solution of
methylenetriphenylphosphorane [prepared from methyltri-
phenylphosphonium bromide (430 mg, 1.2 mmol) and 1.56 M
n-butyllithium in n-hexane solution (5.8 cm3, 9 mmol) for 30
min at rt] in THF (2.5 cm3) at 0 ЊC and the mixture was stirred
for 22 h under argon. The reaction mixture was acidified with
10% hydrochloric acid and extracted with CH2Cl2. The organic
extracts were washed with water, dried over Na2SO4, and con-
centrated. The residue was purified by column chromatography
(n-hexane–AcOEt = 10 : 1) to give 1-(1-benzyl-2-indolyl)-1-(3-
bromo-4-pyridyl)ethene 6 (258 mg, 66%), mp 102–103 ЊC (from
n-hexane); δH (CDCl3) 5.38 (2H, s, CH2Ph), 5.51 (1H, s, vinyl),
5.63 (1H, s, vinyl), 6.35 (1H, s, 3-H), 6.96–7.35 (9H, m, Ar),
7.56–7.64 (1H, m, 4-H), 8.43 (1H, d, J 5, 6Ј-H), 8.66 (1H,
s, 2Ј-H) (Calcd. for C22H17BrN2: C, 67.88; H, 4.40; N, 7.20.
Found: C, 67.79; H, 4.50; N, 7.18%).
followed by catalytic hydrogenation. Treatment of 8 with
(1-ethoxyvinyl)tributyltin in the presence of tetrakis(triphenyl-
phosphine)palladium(0) in refluxing toluene gave the corre-
sponding ethoxyvinyl derivative 13, which was converted to
ellipticine9,10 in 87% yield by treatment with 10% hydrochloric
acid.
Experimental
Melting points were determined on a Yanagimoto micromelting
1
point apparatus and are uncorrected. The H-NMR spectra
were determined on a JEOL JNM-GSX 270 spectrometer using
tetramethylsilane as an internal standard and CDCl3 as solvent
and J values are given in Hz. The IR spectra were recorded with
a JASCO FT/IR-7000 spectrophotometer. The high resolution
MS were recorded on a JEOL JMS-HX100 spectrometer.
2214
J. Chem. Soc., Perkin Trans. 1, 2001, 2213–2216

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1-(1-Benzyl-2-indolyl)-1-(3-bromo-4-pyridyl)ethane 7 and
1-(1-benzyl-2-indolyl)-1-(4-pyridyl)ethane
cm3, 2.4 mmol), and 1.56 M n-butyllithium in n-hexane solution
(1.6 cm3, 2.4 mmol) in THF (5 cm3) at room temperature]
was added 1.0 M chlorotitanium triisopropoxide in n-hexane
solution (2.4 cm3, 2.4 mmol) at Ϫ96 ЊC. A solution of 1-(4-
methoxybenzyl)indole-2,3-dicarboxylic anhydride 10 (368 mg,
1.2 mmol) in THF (5 cm3) was added to the dark suspension at
Ϫ96 ЊC and the mixture was stirred for 1 h. The reaction mix-
ture was quenched by addition of 10% hydrochloric acid and
extracted with CHCl3. 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 (CHCl3–MeOH = 20 : 1) to give 11 (343 mg, 61%),
mp 232–233 ЊC (from acetone); νmax(Nujol)/cmϪ1 1679; δH
(DMSO-d6) 3.68 (3H, s, OMe), 5.50 (2H, s, CH2Ph), 6.78–6.84
(2H, m, Ar), 7.04–7.12 (2H, m, Ar), 7.17 (1H, d, J 5, 5Ј-H), 7.31
(1H, ddd, J 8, 6.5, 1.5, 5-H), 7.41 (1H, ddd, J 8, 6.5, 1.5, 6-H),
7.72 (1H, d, J 8, H-7), 8.03–8.08 (1H, m, 4-H), 8.53 (1H, d,
J 5, 6Ј-H), 8.83 (1H, s, 2Ј-H) (Calcd. for C23H17BrN2O4: C,
59.40; H, 3.68; N, 6.02. Found: C, 59.29; H, 3.81; N, 5.91%)
(HRMS m/z Calcd. for C23H17BrN2O4: M, 464.0372. Found:
Mϩ, 464.0397).
A suspension of 1-(1-benzyl-2-indolyl)-1-(3-bromo-4-pyridyl)-
ethene 6 (389 mg, 1 mmol) and PtO2 (45 mg) in AcOEt (20 cm3)
was stirred for 8 h under hydrogen. The catalyst was removed by
filtration through Celite and the filtrate was evaporated off. The
residue was purified by column chromatography (n-hexane–
AcOEt = 4 : 1) to yield 1-(1-benzyl-2-indolyl)-1-(3-bromo-4-
pyridyl)ethane 7 (326 mg, 83%) as an oil; δH (CDCl3) 1.61 (3H,
d, J 7, CHCH3), 4.53 (1H, q, J 7, CHCH3), 4.89 (1H, d, J 17,
CH2Ph), 5.16 (1H, d, J 17, CH2Ph), 6.68 (1H, s, 3-H), 6.75–
6.83 (2H, m, Ar), 6.85 (1H, d, J 5, 5Ј-H), 7.08–7.72 (6H, m, Ar),
7.65–7.72 (1H, m, 4-H), 8.19 (1H, d, J 5, 6Ј-H), 8.57 (1H, s, 2Ј-
H) (HRMS m/z Calcd. for C22H19BrN2: M, 390.0732. Found:
Mϩ, 390.0755). 1-(1-Benzyl-2-indolyl)-1-(4-pyridyl)ethane (4.5
mg, 10%) as an oil; δH (CDCl3) 1.64 (3H, d, J 7, CHCH3), 4.06
(1H, q, J 7, CHCH3), 4.89 (1H, d, J 17, CH2Ph), 5.21 (1H, d,
J 17, CH2Ph), 6.62 (1H, s, 3-H), 6.76–6.84 (2H, m, Ar), 7.02
(2H, d, J 5, 3Ј-H and 5Ј-H), 7.09–7.24 (6H, m, Ar), 7.63–7.71
(1H, m, 4-H), 8.44 (2H, d, J 5, 2Ј-H and 6Ј-H) (HRMS
m/z Calcd. for C22H20N2: M, 312.1626. Found: Mϩ, 312.1629).
1-(2-Indolyl)-1-(3-bromo-4-pyridyl)ethene 12
1-(2-Indolyl)-1-(3-bromo-4-pyridyl)ethane 8 and 1-(3-benzyl-
2-indolyl)-1-(3-bromo-4-pyridyl)ethane 9
A solution of 2-(3-bromoisonicotinoyl)indole 5 (60 mg, 0.2
mmol) in THF (1.5 cm3) was added to a solution of methylene-
triphenylphosphorane [prepared from methyltriphenylphos-
phonium bromide (157 mg, 0.44 mmol) and 1.56 M n-
butyllithium in n-hexane solution (0.28 cm3, 0.44 mmol) for 30
min at rt] in THF (1 cm3) at 0 ЊC and the mixture was stirred for
18 h under argon. The reaction mixture was acidified with 10%
hydrochloric acid and extracted with CH2Cl2. The organic
extracts were washed with water, dried over Na2SO4, and con-
centrated. The residue was purified by column chromatography
(CH2Cl2–AcOEt = 50 : 1) to give 1-(2-indolyl)-1-(3-bromo-4-
pyridyl)ethene 12 (38 mg, 63%), mp 171–172 ЊC (from MeOH);
νmax(CHCl3)/cmϪ1 3472; δH (CDCl3) 5.26 (1H, s, one of CH2),
5.26 (1H, s, one of CH2), 6.16 (1H, d, J 2, 3-H), 7.08 (1H, ddd,
J 8, 7, 1, 5-H), 7.21 (1H, ddd, J 8.5, 7, 1.5, 6-H), 7.32 (1H, dd,
J 5, 0.5, 5Ј-H), 7.36 (1H, dd, J 8.5, 1, 7-H), 7.52 (1H, br d, J 8,
4-H), 8.31 (1H, br s, NH), 8.58 (1H, d, J 5, 6Ј-H), 8.81 (1H, d,
J 0.5, 2Ј-H) (Calcd. for C15H11BrN2: C, 60.22; H, 3.71; N, 9.37.
Found: C, 60.16; H, 3.86; N, 9.24%).
Using a procedure similar to that described for the preparation
of 5, 1-(2-indolyl)-1-(3-bromo-4-pyridyl)ethane 8 (8 mg, 28%)
and 1-(3-benzyl-2-indolyl)-1-(3-bromo-4-pyridyl)ethane 9 (11
mg, 27%) were obtained from 1-(1-benzyl-2-indolyl)-1-(3-
bromo-4-pyridyl)ethane 7 (39 mg, 0.1 mmol).
8: mp 117–119 ЊC (from n-hexane–AcOEt); νmax(CHCl3)/
cmϪ1 3464; δH (CDCl3) 1.69 (3H, d, J 7, CHCH3), 4.68 (1H, q,
J 7, CHCH3), 6.47–6.50 (1H, m, 3-H), 7.00 (1H, d, J 5, 5Ј-H),
7.06–7.30 (3H, m, Ar), 7.56–7.62 (1H, m, 4-H), 7.98 (1H, br s,
NH), 8.34 (1H, d, J 5, 6Ј-H), 8.69 (1H, s, 2Ј-H) (HRMS
m/z Calcd. for C15H13BrN2: M, 300.0262. Found: Mϩ, 300.0267).
9: oil; νmax(CHCl3)/cmϪ1 3436; δH (CDCl3) 1.64 (3H, d, J 7,
CHCH3), 4.02 (2H, s, –CH2Ph), 4.75 (1H, q, J 7, CHCH3),
7.00–7.22 (8H, m, Ar), 7.35 (1H, d, J 8.5, 7-H), 7.44 (1H, d, J 8,
4-H), 7.94 (1H, s, NH), 8.32 (1H, d, J 5, 6Ј-H), 8.61 (1H, s,
2Ј-H) (HRMS m/z Calcd. for C22H19BrN2: M, 390.0732. Found:
Mϩ, 390.0733).
1-(4-Methoxybenzyl)indole-2,3-dicarboxylic anhydride 10
To a suspension of sodium hydride (1.20 g, 60% assay, 30
mmol) in N,N-dimethylformamide (6 cm3) was added indole-
2,3-dicarboxylic acid (1.23 g, 6 mmol), then 4-methoxybenzyl
chloride (2.44 cm3, 18 mmol) at 0 ЊC. After the mixture
was stirred for 24 h at room temperature, the mixture was
poured into water and washed with Et2O. The aqueous layer
was acidified (pH = 1) with concentrated hydrochloric acid to
give a precipitate, which was collected by filtration to afford
1-(4-methoxybenzyl)indole-2,3-dicarboxylic acid (1.35 g, 69%).
A suspension of 1-(4-methoxybenzyl)indole-2,3-dicarboxylic
acid (650 mg, 2 mmol) and trifluoroacetic anhydride (0.85 cm3,
6 mmol) in CH2Cl2 (20 cm3) was stirred for 4 h at room tem-
perature. The reaction mixture was evaporated off to afford a
solid, which was washed with n-hexane–CHCl3 (3 : 1) to give
1-(4-methoxybenzyl)indole-2,3-dicarboxylic anhydride 10 (473
mg, 77%), mp 177–179 ЊC (from THF); νmax(Nujol)/cmϪ1 1825,
1766; δH (DMSO-d6) 3.69 (3H, s, OMe), 5.81 (2H, s, CH2Ph),
6.82 (2H, d, J 9, 2Ј-H and 6Ј-H), 7.09 (2H, d, J 9, 3Ј-H and
5Ј-H), 7.15–7.28 (2H, m, Ar), 7.50 (1H, d, J 8.5, 7-H), 8.28 (1H,
d, J 8.5, 4-H) (HRMS m/z Calcd. for C18H13NO4: M, 307.0845.
Found: Mϩ, 307.0823).
1-(2-Indolyl)-1-(3-bromo-4-pyridyl)ethane 8
A suspension of 1-(2-indolyl)-1-(3-bromo-4-pyridyl)ethene 12
(60 mg, 0.2 mmol) and PtO2 (9 mg) in AcOEt (4 cm3) was
stirred for 8 h under hydrogen. The catalyst was removed by
filtration through Celite and the filtrate was evaporated off. The
residue was purified by column chromatography (CH2Cl2–
AcOEt = 20 : 1) to yield 1-(2-indolyl)-1-(3-bromo-4-pyridyl)-
ethane 8 (44 mg, 73%).
1-(2-Indolyl)-1-[3-(1-ethoxyvinyl)-4-pyridyl]ethane 13
A solution of 1-(2-indolyl)-1-(3-bromo-4-pyridyl)ethane 8 (36
mg, 0.12 mmol), (1-ethoxyvinyl)tributyltin (0.061 cm3, 0.18
mmol), and tetrakis(triphenylphosphine)palladium(0) (3 mg,
0.0024 mmol) in toluene (2 cm3) was refluxed for 1 h under
argon. The insoluble material was filtered off and the filtrate
was concentrated to give a residue, which was purified by
column chromatography (n-hexane–AcOEt = 5 : 1) to yield
1-(2-indolyl)-1-[3-(1-ethoxyvinyl)-4-pyridyl]ethane 13 (34 mg,
97%) as an oil; νmax(CHCl3)/cmϪ1 3426; δH (CDCl3) 1.47 (3H,
t, J 7, OCH CH ), 1.70 (3H, d, J 7, ᎐CHCH ), 4.04 (2H, q,
᎐
2
3
3
J 7, OCH2CH3), 4.41 (1H, d, J 2.5, vinyl), 4.48 (1H, q, J 7,
1-(4-Methoxybenzyl)-2-(3-bromoisonicotinoyl)indole-
3-carboxylic acid 11
᎐CHCH ), 4.52 (1H, d, J 2.5, vinyl), 6.46–6.49 (1H, m, 3-H),
᎐
3
7.02–7.21 (4H, m, Ar), 7.55–7.61 (1H, m, 4-H), 8.41 (1H, d, J 5,
6Ј-H), 8.41 (1H, br, NH), 8.55 (1H, s, 2Ј-H) (HRMS m/z Calcd.
for C19H20N2O: M, 292.1576. Found: Mϩ, 292.1602).
To a solution of 3-bromo-4-lithiopyridine [prepared from 3-
bromopyridine (0.23 cm3, 2.4 mmol), diisopropylamine (0.34
J. Chem. Soc., Perkin Trans. 1, 2001, 2213–2216
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2 For reviews, see G. W. Gribble, Synlett, 1991, 289; G. W. Gribble, in
Advances in Heterocyclic Natural Product Synthesis, ed.W. Pearson,
Jai Press Inc., London, 1990, vol. 1, p. 43; V. K. Kansal and P. Potier,
Tetrahedron, 1986, 42, 2389; G. W. Gribble and M. G. Saulnier,
Heterocycles, 1985, 23, 1277; M. J. E. Hewlins, A.-M. O.-Campos
and P. V. R. Shannon, Synthesis, 1984, 289; M. Sainsbury, Synthesis,
1977, 437.
3 Y. Miki, Y. Tada, N. Yanase, H. Hachiken and K. Matsushita,
Tetrahedron Lett., 1996, 37, 7753 and references therein.
4 Y. Miki, H. Hachiken, Y. Kashima, W. Sugimura and N. Yanase,
Heterocycles, 1998, 48, 1.
5 Y. Miki, Y. Tada, N. Yanase and K. Matsushita, Heterocycles, 1998,
48, 1593.
6 Y. Miki, H. Hachiken and I. Yoshikawa, Heterocycles, 1997, 45,
1143.
7 B. Weidmann, L. Wilder, A. G. Olivero, C. D. Maycock and
D. Seebach, Helv. Chim. Acta, 1981, 64, 357.
8 T. Watanabe, A. Kobayashi, M. Nishiura, H. Takahashi, T. Usui,
I. Kamiyama, N. Mochizuki, K. Noritake, Y. Yokoyama and Y.
Murakami, Chem. Pharm. Bull., 1991, 39, 1152.
Ellipticine
A
solution of 1-(2-indolyl)-1-[3-(1-ethoxyvinyl)-4-pyridyl]-
ethane 13 (29 mg, 0.1 mmol) and 10% hydrochloric acid (0.2
cm3) in THF (0.8 cm3) was stirred for 16 h at rt. The reaction
mixture was neutralized by addition of 5% sodium hydrogen
carbonate solution and extracted with CHCl3–MeOH (10 : 1).
The organic extracts were washed with water, dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography (CH2Cl2–AcOEt = 40 : 1) to give ellipticine (22
mg, 87%), mp >300 ЊC (from MeOH) [lit.9 312–314 ЊC (dec.)].
δH (DMSO-d6) 2.80 (3H, s, CH3), 3.27 (3H, s, CH3), 7.22–7.33
(1H, m, Ar), 7.49–7.61 (2H, m, Ar), 7.91 (1H, d, J 6, 4-H), 8.36
(1H, d, J 8, 10-H), 8.43 (1H, d, J 6, 3-H), 9.69 (1H, s, 1-H),
11.25 (1H, s, NH) (HRMS m/z Calcd. for C17H14N2: M,
246.1157. Found: Mϩ, 246.1185).
9 C. May and C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 1988,
247.
10 For a recent synthesis of ellipticine, see M. Ishikura, A. Hino,
T. Yaginuma, I. Agata and N. Katagiri, Tetrahedron, 2000, 56, 193.
References
1 L. K. Dalton, S. Demerac, B. C. Elmes, J. W. Loder, J. M. Swan
and T. Teitei, Aust. J. Chem., 1967, 20, 2715.
2216
J. Chem. Soc., Perkin Trans. 1, 2001, 2213–2216