Synthesis of 3-methoxyolivacine and olivacine by Friedel-Crafts reaction of indole-2,3-dicarboxylic anhydride with 2,4,6-trimethoxypyridine

Article abstract of DOI:10.1055/s-2004-831317

1-Benzylindole-2,3-dicarboxylic anhydride (1) was reacted with 2,4,6-trimethoxypyridine in the presence of titanium(IV) chloride to give 3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic acid (2) as the sole product in high yield, which could be converted

Full text of DOI:10.1055/s-2004-831317

2206
LETTER
Synthesis of 3-Methoxyolivacine and Olivacine by Friedel–Crafts Reaction of
Indole-2,3-dicarboxylic Anhydride with 2,4,6-Trimethoxypyridine
S
ynthesis of 3-Me
a
thoxyolivac
s
ine and
O
u
livacine yoshi Miki,* Yasuhiko Tsuzaki, Hajime Hibino, Yoshiyuki Aoki
Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Fax +81(6)67212332; E-mail: y_miki@phar.kindai.ac.jp
Received 5 June 2004
product, respectively.11 In this paper we report a simple
and useful synthesis of 3-methoxyolivacine and olivacine
by regioselective Friedel–Crafts reaction of 1 with 2,4,6-
trimethoxypyridine.
Abstract: 1-Benzylindole-2,3-dicarboxylic anhydride (1) was re-
acted with 2,4,6-trimethoxypyridine in the presence of titanium(IV)
chloride to give 3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic
acid (2) as the sole product in high yield, which could be converted
to olivacine.
1-Benzylindole-2,3-dicarboxylic anhydride (1)12,15 react-
ed with 2,4,6-trimethoxypyridine (2 equiv) in the
presence of titanium(IV) chloride (3 equiv) in dichloro-
methane to provide the corresponding 3-acylindole-2-car-
boxylic acid (2) in 97% yield, which was converted to
ketone 3 by treatment with copper chromite in quinoline
(180 °C) in 94% yield. The mixture of 3 with 47% hydro-
bromic acid in acetic acid was warmed at 50 °C to provide
4 in 94% yield as the sole product. Treatment of 1-hy-
droxy compound 4 with triflic anhydride (Tf2O) in the
presence of triethylamine gave triflate 5 (Scheme 1).
Keywords: indole, Friedel–Crafts reaction, Heck reaction, demeth-
ylation, olivacine
Olivacine is a member of the pyrido[4,3-b]carbazole alka-
loid family and possesses potent antitumor activity.1 Pyri-
do[4,3-b]carbazole alkaloids, ellipticine2 and olivacine
(Figure 1), are intercalating compounds and have high
DNA binding ability, which is responsible in part for their
pharmacological properties.3 Many methods to synthesize
olivacine have been developed including cyclization of
substituted carbazole derivatives,4 intramolecular cycliza-
tion of indole 2,3-quinodimethane5 or pyridine 3,4-quino-
dimethane,6 and intermolecular cyclization of pyridine
3,4-quinodimethane.7 Gribble reported an excellent syn-
thetic method of olivacine by the reaction of 2-lithioindole
and pyridine-3,4-dicarboxylic anhydride.8 Recently, some
synthesized olivacine derivatives also have been found to
have high antitumor activity.9
The triflate 5 could be converted to methyl derivative 6 by
reaction with MeMgBr13 in the presence of NiCl2 (dppe)2
in 79% yield. Selective demethylation of the 4-methoxy
group of 6 by treatment with boron tribromide was per-
formed to provide 4-hydroxy compound 7 in 99% yield,
which was changed by diborane reduction, followed by
treatment with Tf2O in the presence of triethylamine to
benzyl derivative 8. Benzyl derivative 8 was reacted with
(1-ethoxyvinyl)tributyltin in the presence of tet-
rakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] in re-
fluxing toluene, then 10% hydrochloric acid in
tetrahydrofuran to give 6-benzyl-3-methoxyolivacine (9)
in 84% yield (Scheme 2).
We showed a novel synthesis of ellipticine by a reaction
of 1-benzylindole-2,3-dicarboxylic anhydride (1) with 3-
bromo-4-lithiopyridine, but an application of this method
to the synthesis of olivacine by this method is difficult be-
cause introduction of the 1-methyl group of olivacine is
not easy.10
Debenzylation of 9 was performed by treatment with 47%
hydrobromic acid at 80 °C to provide 3-methoxyolivacine
(10), which was treated with hot 47% hydrobromic acid in
acetic acid gave 3-hydroxyolivacine (11) in 92% yield.
Hydrogenation of the triflate, which was prepared by
treatment with Tf2O and triethylamine (50%), with am-
monium formate in the presence of Pd(PPh3)4 in hot meth-
anol afforded olivacine14 in 67% yield (Scheme 3).
Me
Me
N
N
N
N
H
H
Me
Me
ellipticine
olivacine
Figure 1
References
Recently, we have reported that reaction of 1-benzylin-
dole-2,3-dicarboxylic anhydride (1) with anisoles gave 3-
benzoylindole-2-carboxylic acids, but 1-benzenesulfo-
nylindole-2,3-dicarboxylic anhydride with anisoles
afforded 2-benzoylindole-3-carboxylic acids as the sole
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(2) For reviews, see: (a) Gribble, G. W. Synlett 1991, 289.
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SYNLETT 2004, No. 12, pp 2206–2208
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1
.1
0
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0
4
Advanced online publication: 01.09.2004
DOI: 10.1055/s-2004-831317; Art ID: U16004ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Methoxyolivacine and Olivacine
2207
OMe
N
O
OMe
N
O
OMe
N
O
2CuO.Cr2O3
MeO
OMe
O
MeO
COOH
TiCl4
N
N
N
MeO
OMe
OMe
O
CH2Ph
CH2Ph
CH2Ph
1
2
3
O
OH
N
O
OTf
N
Tf2O / Et3N
47% HBr / AcOH
CH2Cl2
(94 %)
50 °C
(94%)
N
N
MeO
OMe
MeO
OMe
CH2Ph
CH2Ph
4
5
Scheme 1
Me
N
O
Me
O
BBr3
MeMgBr
N
5
CH2Cl2
NiCl2(dppe)2
(79%)
N
HO
OMe
N
MeO
OMe
(99%)
CH2Ph
CH2Ph
7
6
SnBu3
H2C
1)
/ Pd(PPh3)4
Me
Me
OEt
LiCl / (i-Pr)2NEt
1) BH3 / THF (73%)
2) Tf2O / Et3N (80%)
N
N
2) 10% HCl
N
N
TfO
CH2Ph
8
OMe
OMe
Me
(84%)
CH2Ph
9
Scheme 2
Me
Me
47% HBr / AcOH
47% HBr / AcOH
N
N
9
80°C
N
N
H
reflux
(92%)
OMe
OH
H
Me
(93%)
Me
11
10
Me
1) Tf2O /Et3N (50%)
2) HCOONH4 (67%)
N
N
H
Me
olivacine
Scheme 3
(3) Gribble, G. W. The Alkaloids, Vol. 39; Brossi, A., Ed.;
Academic Press: New York, 1990.
S. M. J. Chem. Soc., Chem. Commun. 1985, 86.
(h) Murakami, Y.; Yokoyama, Y.; Okuyama, N.
(4) (a) Narasimhan, N. S.; Gokhale, S. M. J. Indian Inst. Science
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Campos, A. M. F.; Queiroz, M. J. R. P.; Shannon, P. V. R. J.
Chem. Soc., Perkin Trans. 1 1992, 3439. (c) Hogan, I.;
Jenkins, P. D.; Sainsbury, M. Tetrahedron 1990, 46, 2943.
(d) Yokoyama, Y.; Okuyama, N.; Iwadate, S.; Momoi, T.;
Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1990, 1319.
(e) Bäckvall, J.-E.; Plobeck, N. A. J. Org. Chem. 1990, 55,
4528. (f) Naito, T.; Iida, N.; Ninomiya, I. J. Chem. Soc.,
Perkin Trans. 1 1986, 99. (g) Narasimhan, N. S.; Gokhale,
Tetrahedron Lett. 1983, 24, 2189. (i) Naito, T.; Iida, N.;
Ninomiya, I. J. Chem. Soc., Chem. Commun. 1981, 44.
(j) Oikawa, Y.; Yonemitsu, O. J. Chem. Soc., Perkin Trans.
1 1976, 1479. (k) Besselievre, R.; Husson, H.-P.
Tetrahedron Lett. 1976, 1873. (l) Kutney, J. P.; Grierson, D.
S. Heterocycles 1975, 3, 171. (m) Wenkert, E.; Dave, K. G.
J. Am. Chem. Soc. 1962, 84, 94. (n) Schmutz, J.; Wittwer,
H. Helv. Chim. Acta 1960, 43, 793.
(5) (a) Kutney, J. P.; Noda, M.; Lewis, N. G.; Monteiro, B.;
Mostowicz, D.; Worth, B. R. Can. J. Chem. 1982, 60, 2426.
(b) Bergman, J.; Carlsson, R. Tetrahedron Lett. 1978, 4055.
Synlett 2004, No. 12, 2206–2208 © Thieme Stuttgart · New York

2208
Y. Miki, et al.
LETTER
(6) Hibino, S.; Sugino, E. J. Heterocycl. Chem. 1990, 27, 1751.
(7) (a) Kametani, T.; Suzuki, T.; Ichikawa, Y.; Fukumoto, K. J.
Chem. Soc., Perkin Trans. 1 1975, 2102. (b) Kametani, T.;
Ichikawa, Y.; Suzuki, T.; Fukumoto, K. Heterocycles 1975,
3, 401.
(8) Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.;
Ketcha, D. M. J. Org. Chem. 1992, 57, 5891.
(9) (a) Haider, N.; Sotero, E. Chem. Pharm. Bull. 2002, 50,
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N.; Kraus-Berthier, L.; Léonce, S.; Michel, A.; Bisagni, E.;
Atassi, G. J. Med. Chem. 1999, 42, 2191.
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Trans. 1 2001, 2213. (b) Miki, Y.; Tada, Y.; Matsushita, K.
Heterocycles 1998, 48, 1593. (c) Miki, Y.; Tada, Y.;
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1996, 37, 7753.
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2002, 57, 1635.
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45, 1143.
H, s, 1-CH3), 7.21–7.26 (1 H, m, aromatic proton), 7.47–7.55
(2 H, m, aromatic protons), 7.79 (1 H, d, J = 6.0 Hz, H-4),
8.25 (1 H, d, J = 6.0 Hz, H-3), 8.35 (1 H, d, J = 7.5 Hz, H-
10), 8.89 (1 H, s, H-11), 11.20 (1 H, br s, NH). HRMS: m/z
[M+] calcd for C17H14N2: 246.1157. Found: 246.1138.
(15) Reaction of Anhydride (1) with 2,4,6-Trimethoxypyri-
dine: 1-Benzyl-3-(2,4,6-trimethoxynicotinoyl)-indole-2-
carboxylic Acid (2).
To a solution of 1-benzylindole-2,3-dicarboxylic anhydride
(1, 1.90 g, 7 mmol) and 2,4,6-trimethoxypyridine (2.40 g, 14
mmol) in CH2Cl2 (28 mL) was added titanium(IV) chloride
(21 mL of a 1 M CH2Cl2 solution, 21 mmol) and the mixture
was stirred for 18 h at r.t. To this reaction mixture H2O was
added and then the mixture was extracted with CH2Cl2. The
combined extracts were washed with H2O and dried over
Na2SO4, then concentrated under reduced pressure to give a
solid, which was purified by column chromatography (n-
hexane–EtOAc) to afford 1-benzyl-3-(2,4,6-trimethoxy-
nicotinoyl) indole-2-carboxylic acid (2, 3.02 g, 97%).
Analytical data of compound 2: mp 170–172 °C (n-hexane–
EtOAc). IR (nujol): 1722, 1593 cm–1. 1H NMR (CDCl3): d =
3.65 (3 H, s, OCH3), 3.78 (3 H, s, OCH3), 4.01 (3 H, s,
OCH3), 6.02 (1 H, s, H-5¢), 6.09 (2 H, s, CH2Ph), 7.08–7.34
(8 H, m, aromatics), 7.46 (1 H, d, J = 8.0 Hz, H-4). Anal.
Calcd for C25H22N2O6: C, 67.26; H, 4.95; N, 6.27. Found: C,
67.19; H, 5.01; N, 6.34.
(13) Sengupta, S.; Leite, M.; Razslan, D. S.; Quesnelle, C.;
Snieckus, V. J. Org. Chem. 1992, 57, 4066.
(14) Olivacine: mp >300 °C (MeOH) (lit.5n 318–326 °C). IR
(nujol): n = 3267 cm–1. 13C NMR (DMSO-d6): d = 158.0,
142.7, 144.2, 133.9, 132.8, 128.2, 126.0, 122.4, 121.6,
121.0, 119.7, 116.6, 116.2, 111.9, 111.2, 20.8, 12.3. 1H
NMR (270 MHz, CDCl3): d = 2.82 (3 H, s, 5-CH3), 3.03 (3
Synlett 2004, No. 12, 2206–2208 © Thieme Stuttgart · New York