Synthesis of arnoamine B

Article abstract of DOI:10.3987/COM-09-11804

The synthesis of arnoamine B (2), which inhibits the catalytic activity of topoisomerase II and exhibits selective cytotoxicity against human tumor cell lines, was achieved in six steps from 5-methoxy-6-nitroindole (3) in 33 % overall yield.

Full text of DOI:10.3987/COM-09-11804

HETEROCYCLES, Vol. 81, No. 1, 2010
145
HETEROCYCLES, Vol. 81, No. 1, 2010, pp. 145 - 148. © The Japan Institute of Heterocyclic Chemistry
Received, 29th July, 2009, Accepted, 6th November, 2009, Published online, 9th November, 2009
DOI: 10.3987/COM-09-11804
SYNTHESIS OF ARNOAMINE B
Shinsuke Nakahara,＊ Toshiyuki Sadachi, and Akinori Kubo
Meiji Pharmaceutical University, 2-552-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Abstract – The synthesis of arnoamine B (2), which inhibits the catalytic activity of
topoisomerase II and exhibits selective cytotoxicity against human tumor cell lines,
was achieved in six steps from 5-methoxy-6-nitroindole (3) in 33 % overall yield.
Over the last decade, a series of structurally interesting and biologically active fused
polycyclic aromatic alkaloids containing a pyrido[2,3,4-kl]acridine subunit has been
isolated from marine sources.1 The pyridoacridine system is of interest, as the skeleton
contains an indole ring.2
N
Arnoamine A (1) and B (2),2a which have relatively simple structures, were obtained in
1998 from the brownish-purple ascidian Cystodytes sp., collected near Arno Atoll in the
Republic of the Marshall Islands. The structures of 1 and 2 were proposed on the basis
of spectroscopic data, particularly those obtained from HMBC and NOE NMR
experiments.
N
OR
1 R = H
2 R =Me
In 2000, the first synthesis of arnoamines A (1) and B (2) was accomplished by Delfourne and co-workers
using thermolysis of arylaminomethylene Meldrum’s acid derivative, biaryl cross coupling reaction, and the
Fisher indole synthesis. Starting from commercially available 2-methoxy-5-nitroaniline, arnoamine B (2)
was obtained in 12 steps with a 5% overall yield.3 In 2006, Radchenko and co-workers reported a simple
and effective approach to the synthesis of the pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton of the
arnoamines starting from a known indole.4 In 2007, we reported the synthesis of arnoamine B (2) from
4-bromo-8-methoxy-6-methyl-5-nitroquinoline in four steps via biaryl cross coupling reaction. The indole
moiety of 2 was introduced by the Leimgruber-Batcho indole synthesis.5 The yield of the pyrrole ring was
low, and the overall yield was 12% from 4-bromo-8-methoxy-6-methyl-5-nitroquinoline.
In this study we report a simple and convenient synthesis of arnoamine B (2) using N-arylation,
thermolysis of arylaminomethylene Meldrum’s acid derivative and intramolecular radical cyclization.
N-Arylation of 5-methyl-6-nitroindole (3)6 with iodobenzene in toluene gave the 5-methyl-6-nitro-1-
phenylindole (4) in 80% yield.7 Enamine (5) was prepared by catalytic hydrogenation of 4 over 10% Pd-C
in methanol, followed by reaction with Meldrum’s acid in trimethyl orthoformate in 66% yield.8
N-Phenylpyrrolo[2,3-f]quinoline (6) was prepared in 68% yield by cyclization of 5 via unstable

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HETEROCYCLES, Vol. 81, No. 1, 2010
aminoketene in refluxing diphenyl ether for 20 min, followed by reaction with phosphorus oxychloride at
75 C for 3.5 h. Compound 6 was also prepared in 70% yield under microwave irradiation9 of 5 at 45 C for
20 min. In the reaction with phosphorus oxybromide, monobromoquinoline was not prepared but
tribromoquinoline10 was obtained under microwave irradiation. Finally, intramolecular radical cyclization11
of 6 with tri-n-butyltin hydride (30 equiv) and azobisisobutyronitrile (AIBN: 15 equiv) in toluene at 115 C
for 2.5 h afforded arnoamine B (2) in 90% yield, but the reaction did not go to completion with
tri-n-butyltin hydride (4 equiv) and AIBN (2 equiv). The spectroscopic data of synthetic 2 matched those of
authentic samples in all respects.
O
O
O
NR
Cl
N
NR
NR
c
d
O
b
2
66%
90%
70%
N
H
NO2
OMe
OMe
OMe
a
3 R = H
4 R = C6H5
5 R = C6H5
6 R = C6H5
80%
a) C6H5I, CuI, (CH2NHMe)2, K3PO4, toluene, 115℃, 48 h b) i Pd-C, H2, MeOH, 1h ii Meldrum's acid, HC(OMe3)3, 100℃, 2 h
c) i (C6H5)2O, reflux, 20 min
ii POCl , MW, 45℃, 20 min
d) AIBN, Bu3SnH, toluene, 115℃, 2.5 h
3
In summary, arnoamine B (2) was synthesized in six steps from a known compound in 33% overall yield.
Microwave irradiation was useful at the chlorination step.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micromelting point apparatus and are uncorrected.
1H-NＭR spectra at 270 MHz were measured in CDCl3 with tetramethylsilane as an internal standard.
Anhydrous sodium sulfate was used for drying organic solvent extracts, and the solvent was removed with a
rotary evaporator and finally under high vacuum. Column chromatography (flash chromatography) was
performed with silica gel 60 (Merck, 230-400 mesh).
5-Methoxy-6-nitro-1-phenylindole (4). To a solution of 5-methoxy-6-nitroindole (3) (231 mg, 1.2 mmol)
in toluene (2.2 mL) were added iodobenzene (612 mg, 3 mmol), capper (I) iodide (28.5 mg, 15 mol %),
N,N’-dimethylethylenediamine (52.8 mg, 60 mol %), and K3PO4 (679 mg, 3.2 mmol) and were heated at
115 ℃ in sealed tube for 2 days. The reaction mixture was cooled and diluted with CHCl3 (5 mL), and
filtered through a plug of silica gel, eluting with EtOAc (20 mL). The filtrate was concentrated. The residue
was chromatographed (eluting with hexane-EtOAc 5 : 1) to afford 4 (257 mg, 80%). mp 107-108 ℃ (light
yellow needles from CHCl3-hexane). HRMS Calcd for C15H12N2O5: 268.0848, Found: 268.0854. Ms m/z
(%): 268(M+, 100), 253(9), 221(15), 192(30), 191(28). IR(KBr) cm-1: 1594, 1504, 1469, 1266, 1162.

HETEROCYCLES, Vol. 81, No. 1, 2010
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1H-NMR（CDCl3）δ: 3.99(3H, s), 6.65(1H, dd, J=3.3, 0.7 Hz), 7.25(1H, s), 7.38-7.46(3H, m,),
7.50-7.57(3H, m), 8.11(1H, d, J=0.7 Hz). 13C-NMR (100 MHz, CDCl3) δ: 57.02, 103.42, 104.06, 109.22,
124.26, 127.46, 129.04, 130.01, 133.37, 136.55, 138.56, 148.28.
5-[(5-Methoxy-1-phenylindol-6-ylamino)methylene]-2,2-dimethyl-4,6-dione-1,3-dioxane (5).
5-Methoxy-6-nitro-1-phenylindole (4) (616 mg, 2.3 mmol) in MeOH (100 mL) was hydrogenated for 1 h
using 10% Pd-C (330 mg) as a catalyst under H2 atomsphere. The catalyst was filtered off and the solvent
was removed. A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (346 mg, 2.4 mmol) in methyl orthoformate
(5 mL) was refluxed for 2 h and the crude aminoindole was immediately added. The mixture was stirred at
100 ℃ for another 2 h. After the reaction mixture was cooled, the precipitated crystals were collected by
filtration and recrystallized from CHCl3-hexane to give 5 (596 mg, 66%) as yellow needles. mp 216-217 ℃.
HRMS Calcd for C22H20N2O5: 392.1372, Found: 392.1368. Ms m/z (%): 392(M+, 23), 290(22), 275(11),
-1
１
259(100). IR(KBr) cm : 1719, 1673, 1612, 1449, 1318, 1279. H-NMR（CDCl3）δ: 1.74(6H, s), 4.00(3H,
s), 6.62(1H, dd, J=3.3, 0.7 Hz), 7.20(1H, s), 7.33(1H, d, J=3.3 Hz), 7.40-7.47(4H, m,), 7.54-7.61(2H, m),
8.59(1H, d, J=14.5 Hz), 11.77(1H,br d, J=14.5 Hz). 13C-NMR (100 MHz, CDCl3) δ: 26.97, 56.43, 86.72,
97.77, 102.46, 103.24, 104.83, 124.06, 124.53, 127.26, 127.51, 129.63, 130.08, 130.60, 139.16, 145.23,
150.62, 164.11, 165.37.
9-Chloro-5-methoxy-1-phenylpyrrolo[2,3-f]quinoline (6).
Method A) A mixture of 5 (346 mg, 0.8 mmol) and diphenyl ether (5 mL) was refluxed for 20 min. The
reaction mixture was cooled and diluted with hexane (45 mL). The precipitated crystals were collected by
filtration, washed with hexane (3 x 5 mL). A mixture of the crude pyrroloquinolone and POCl3 (1.5 mL)
was stirred at 75 ℃ for 3.5 h, poured into cold water (10 mL) and adjusted to pH 7 with saturated aqueous
NaHCO3 solution. The precipitated crystals were collected by filtration and chromatographed (eluting with
hexane-EtOAc 5 : 1) to afford 6 (168 mg, 68%). mp 115.5-116.5 ℃ (yellow crystals from Et2O-hexane).
HRMS Calcd for C18H13N2ClO: 308.0716, Found: 308.0717. Ms m/z (%): 310(M++2, 34), 308(M+, 100),
1
279(15), 271(38), 243(13). IR(KBr) cm-1: 1601, 1499, 1460, 1390, 1274, 1240, 1193, 761. H-NMR
(CDCl3)δ: 4.15(3H, s), 6.80(1H, d, J=3.3 Hz), 7.18-7.23(2H, m,), 7.26-7.42(6H, m), 8.69(1H, d, J=4.6 Hz).
13C-NMR (100 MHz, CDCl3) δ: 56.26, 102.68, 105.79, 118.10, 122.39, 122.52, 122.82, 126.24, 128.88,
129.60, 133.33, 137.47, 141.08, 144.69, 145.52, 150.82.
Method B) A mixture of 5 (157 mg, 0.4 mmol) and diphenyl ether (3 mL) was refluxed for 20 min. The
reaction mixture was cooled and diluted with hexane (25 mL). The precipitated crystals were collected by
filtration, washed with hexane (3 x 3 mL). A mixture of the crude pyrroloquinolone and POCl3 (1.5 mL)
was heated at 45 ℃ for 20 min in a sealed tube of microwave reactor, poured into cold water (10 mL) and
adjusted to pH 7 with saturated aqueous NaHCO3 solution. The precipitated crystals were collected by
filtration and chromatographed (eluting with hexane- EtOAc 5 : 1) to afford 6 (86 mg, 70%).
Arnoamine B (2) 9-Chloro-5-methoxy-1-phenylpyrrolo[2,3-f]quinoline (6) (30.9 mg, 0.1 mmol) was

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HETEROCYCLES, Vol. 81, No. 1, 2010
dissolved in deoxygenated toluene (3 mL), heated at 115 ℃ and tri-n-butyltin hydride (873 mg, 3 mmol)
and AIBN (246 mg, 1.5 mmol) added in five portions over 2.5 h under N2 with stirring. The resulting brown
solution was cooled and chromatographed (eluting with EtOAc) to afford 2 (24.5 mg, 90%) mp 236-237 ℃
(yellow prisms from CHCl3-hexane) HRMS Calcd for C18H12N2O: 272.0949, Found: 272.0943. Ms m/z
(%): 272(M+, 100), 271(84), 257(10), 243(27), 242(31), 229(8). IR(KBr) cm-1: 1610, 1474, 1389, 1361,
１
1284. H-NMR（CDCl3）δ: 4.20(3H, s), 7.10(1H, d, J=3.0 Hz), 7.43(1H, ddd, J=8.3, 7.3, 1.0 Hz), 7.51(1H,
s), 7.68(1H, ddd, J=8.3, 7.3, 1.3 Hz), 7.91(1H, dd, J=8.0, 1.0 Hz), 7.96(1H, d, J=5.0 Hz), 8.04(1H, d, J=3.0
Hz), 8.40(1H, dd, J=8.3, 1.3 Hz), 9.09(1H, d, J=5.0 Hz). 13C-NMR (100 MHz, CDCl3) δ: 56.30, 102.41,
107.21, 110.67, 113.98, 115.08, 116.68, 116.96, 120.09, 121.51, 123.92, 125.57, 130.93, 132.56, 134.68,
138.81, 147.35, 150.35.
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+
１
62), 508(M , 21), 431(59), 429(100), 427(47), 401(20), 322(16). H-NMR（CDCl3）δ: 4.19(3H, s),
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