Facile and inexpensive entry to indeno[2,1-b]indol-6-one nucleus

Article abstract of DOI:10.1081/SCC-200063981

Starting from simple indole, a straightforward and inexpensive four-step synthetic approach to indeno[2,1-b]indol-6-one nucleus is described. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200063981

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Facile and Inexpensive Entry
to Indeno[2,1‐b]indol‐6‐one
Nucleus
Giorgio Abbiati a , Valentina Canevari a , Elisabetta
Rossi a & Alberto Ruggeri a
a Istituto di Chimica Organica “Alessandro
Marchesini,” Facoltà di Farmacia, Università degli
Studi di Milano, Milan, Italy
Published online: 15 Aug 2006.
To cite this article: Giorgio Abbiati , Valentina Canevari , Elisabetta Rossi & Alberto
Ruggeri (2005) Facile and Inexpensive Entry to Indeno[2,1‐b]indol‐6‐one Nucleus,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:13, 1845-1850, DOI: 10.1081/SCC-200063981
To link to this article: http://dx.doi.org/10.1081/SCC-200063981
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Synthetic Communicationsw, 35: 1845–1850, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063981
Facile and Inexpensive Entry to
Indeno[2,1-b]indol-6-one Nucleus
Giorgio Abbiati, Valentina Canevari, Elisabetta Rossi, and
Alberto Ruggeri
`
Istituto di Chimica Organica “Alessandro Marchesini,” Facolta di
`
Farmacia, Universita degli Studi di Milano, Milan, Italy
Abstract: Starting from simple indole, a straightforward and inexpensive four-step
synthetic approach to indeno[2,1-b]indol-6-one nucleus is described.
Keywords: Indeno[2,1-b]indol-6-ones, polycyclic indoles, Ullmann coupling
INTRODUCTION
Indeno[2,1-b]indol-6-ones are an interesting class of compounds structurally
related to ellipticine,[1] a natural alkaloid characterized by a significant
antitumor activity.[2,3] Recently, some hydroxy indeno[2,1-b]indol-6-one
derivatives were investigated for their potential antioxidative properties,[4]
and a patent concerning these compounds was recently filed.[5]
The synthesis of some indeno-indolones was previously achieved by
means of a Japp–Klingemann reaction combined with the Fischer indole
synthesis,[6] through two different palladium-catalyzed intramolecular
reactions (the cyclisation of 2-(2-bromobenzoyl)-1-methyl-indole[7] and the
cyclocarbonylation of 2-iodo-3-phenyl-indoles[8]), and finally by a double
lithiation of 3-phenyl-indoles followed by treatment with ethyl N,N-dimethyl-
carbamate.[9] Despite the usefulness and neatness of these approaches, some of
them suffer from a few drawbacks, such as the high cost of the reagents
Received in Poland February 14, 2005
Address correspondence to Giorgio Abbiati, Istituto di Chimica Organica
`
`
“Alessandro Marchesini,” Facolta di Farmacia, Universita degli Studi di Milano, Via
Venezian 21-20133, Milan, Italy. Tel.: þ39 þ2 50.31.44.74; Fax: þ39 þ2
50.31.44.76; E-mail: giorgio.abbiati@unimi.it
1845

1846
G. Abbiati et al.
Scheme 1.
employed, multistep procedures, and less-than-satisfactory overall reaction
yields. In connection with our ongoing interest in the synthesis of polycyclic
indole derivatives,[10] in this article we present an alternative, simple, and inex-
pensive approach to the indeno[2,1-b]indol-6-one nucleus starting from indole.
RESULTS
The 3-iodo-1-phenylsulfonylindole 1 was prepared in good yields according
to Sakamoto’s procedure,[11] sequential alkaline iodination/nitrogen protec-
tion of indole (Scheme 1). The product was easily purified by crystallization
with a mixture of petroleum ether/ethyl acetate.
The derivative 1 was transformed in the intermediate 3 by lithiation with
lithium diisopropylamide (LDA) in THF at 2608C followed by reaction with
the 2-iodo-benzoic acid-anhydride 2; after the usual workup, the reaction
mixture was purified by flash chromatography over silica gel, yielding the diio-
doderivative 3 in 84% yield (Scheme 2). The anhydride 2 was prepared in 90%
yields by treatment of 2-iodobenzoic acid with dicyclohexyl-carbodiimide
(DCC) in diethyl ether.
Scheme 2.

Synthesis of Indeno[2,1-b]indol-6-one
1847
The cyclisation of derivative 3 was performed through a Ullmann-type
coupling[12] in the presence of activated copper in DMF at 1408C, yielding
quantitatively the N-protected indeno-indolone 4. Finally, the desired
product 5 was obtained in almost quantitative yields through alkaline hydroly-
sis of 4 in ethanol/dimethylsulfoxide at 508C and purifying the reaction crude
by flash chromatography over silica gel (Scheme 3). All structures were
assigned on the basis of analytical and spectral data.
In summary, we developed an alternative synthetic route to indeno[2,1-
b]indol-6-one nucleus starting from simple indole. The method offer several
advantages, such as relatively cheap reagents, effortless experimental
operation, and high overall process yield.
EXPERIMENTAL
All chemicals and solvents are commercially available and were used after
distillation or treatment with drying agents. Fluka silica gel F254 thin-layer
plates were employed for thin-layer chromatography (TLC). Davisil silica
gel LC 60A was employed for flash column chromatography. Melting
points, measured with a Stuart Scientific SMP3 apparatus, are uncorrected.
Infrared spectra were recorded on a FT-IR Perkin Elmer Spectrum One
spectrophotometer using KBr tablets. Proton and carbon NMR spectra
were recorded at room temperature, on Varian-Gemini 200 spectrometer.
The APT or DEPT sequences were used to distinguish the methine and
methyl carbon signals from those resulting from methylene and quaternary
carbons. “PE” refers to the fraction of petroleum ether with boiling point
of 40–608C. “EtOAc” means ethyl acetate. Indole and 2-iodobenzoic acid
were purchased respectively from Lancaster Synthesis Ltd. and Avocado
Research Chemical Ltd.
3-Iodo-1-phenylsulfonylindole 1: To a well-stirred mixture of indole (2.95 g,
25.2 mmol) and powdered potassium hydroxide (5.65 g, 100.7 mmol) in DMF
(13 mL) a solution of iodine (6.71 g, 26.5 mmol) in DMF (13 mL) was added
dropwise. The reaction mixture was stirred at room temperature for 15 min
Scheme 3.

1848
G. Abbiati et al.
and than poured into a stirred mixture of sodium bisulfite (2.00 g, 10.7 mmol)
and 2% aqueous ammonia (350 mL). The light precipitate obtained was
rapidly filtered off and added to a mixture of 20% aqueous sodium
hydroxide (60 mL) and tetrabutylammonium bromide (0.8 g, 2.5 mmol). A
solution of benzenesulfonylchloride (5.33 g, 30.2 mmol) in benzene (40 ml)
was slowly added and the reaction mixture was vigorously stirred at room
temperature for 2 h. After that, the organic layer was separated, washed
with water (1 ꢀ 40 mL), dried over sodium sulfate, and filtered, and the
solvent removed at reduced pressure. The resulting crude was recrystallized
from PE/EtOAc, yielding the 3-iodo-1-phenylsulfonylindole 1 as a pale
1
yellow solid (8.1 g, 84%). Mp: 1268C (lit.[10] 127–128). H NMR (CDCl3,
200 MHz): d ¼ 7.32–7.60 (m, 6H, arom.), 7.73 (s, 1H, C2-H arom.), 7.89–
8.02 (m, 3H, arom.) ppm.
2-Iodo-benzoic acid-anhydride 2: A mixture of 2-iodobenzoic acid (2.00 g,
8.06 mmol) and DCC (0.832 g, 4.03 mmol) in dry diethyl ether (10 mL) was
vigorously stirred at rt for 2 h under a nitrogen atmosphere. The white precipi-
tate was filtered off over a double layer of filter paper and washed with cold, dry
diethyl ether (2 ꢀ 10 mL). The ethereal phase was evaporated under reduced
pressure, yielding the 2-iodo-benzoic acid-anhydride 2 as a white solid
(1.73 g, 90%). Mp: 68–728C (lit.[11] 71–75). IR: n ¼ 1792 (C55O), 987 (C–
1
O) cm21. H NMR (CDCl3, 200 MHz): d ¼ 7.24 (dt, 1H, arom., J ¼ 8.1,
1.8 Hz), 7.47 (dt, 1H, arom., J ¼ 7.5, 1.1 Hz), 8.01 (dd, 1H, arom., J ¼ 8.1,
1.8 Hz), 8.10 (dd, 1H, arom., J ¼ 7.5, 1.1 Hz) ppm. 13C NMR (CDCl3, 200
MHz): d ¼ 128.5, 132.5, 134.4, 142.4 (C-H arom.), 95.6, 132.7 (C quat.
arom.), 161.5 (C55O) ppm. ESI-MS m/z (%): 478 [Mþ] (20), 477 (100).
(1-Benzenesulfonyl-3-iodo-1H-indol-2-yl)-(2-iodo-phenyl)-methanone 3:
LDA (0.78 mL, 2 M solution in heptane/THF/ethylbenzene, 1.56 mmol)
was slowly added to a well-stirred solution of 3-iodo-1-phenylsulfonylindole
1 (0.30 g, 0.78 mmol) in dry THF at 2608C under a nitrogen atmosphere. The
solution was stirred for 1.5 h, and after that a solution of 2-iodo-benzoic acid–
anhydride 2 (0.75 mg, 1.56 mmol) in dry THF (3 ml) was added dropwise. The
reaction mixture was allowed to warm at room temperature and the stirring
was proceeded until no more starting product was detectable by TLC
analysis. After 36 h the reaction mixture was concentred under reduced
pressure, poured into water (40 mL), and extracted with dichloromethane
(2 ꢀ 25 mL). The combined organic layers, dried over sodium sulfate, were
evaporated to dryness and the crude purified by flash chromatography over
a silica-gel column (PE/CH2Cl2 ¼ 8 : 2), yielding 3 as a light yellow
solid (0.41 g, 84%). Mp: 195–2008C (dec.). IR: n ¼ 1662 (C55O), cm21
.
1H NMR (CDCl3, 200 MHz): d ¼ 7.21 (dt, 1H, arom., J ¼ 7.3, 1.5 Hz),
7.32–7.60 (m, 9H, arom.), 7.97–8.14 (m, 3H, arom.) ppm. 13C NMR
(CDCl3, 200 MHz): d ¼ 115.1, 123.8, 125.2, 127.8, 128.2, 128.3, 129.5,
133.2, 133.6, 134.5, 142.3 (C-H arom.), 95.2, 110.9, 132.1, 136.4, 137.4,

Synthesis of Indeno[2,1-b]indol-6-one
1849
137.5, 140.1 (C quat. arom.), 188.4 (C55O) ppm. ESI-MS m/z (%): 636
[Mþ þ Na] (100).
5-Benzenesulfonyl-5H-indeno[2,1-b]indol-6-one 4: A stirred solution of 3
(0.20 g, 0.32 mmol) and activated copper powder[13] (0.060 g, 0.96 mmol) in
DMF (6 mL) was heated at 1408C for 3 h. After cooling, the reaction
mixture was poured into water (200 mL) and extracted with diethyl ether
(2 ꢀ 50 mL). The organic layers were dried over sodium sulfate, filtered,
and evaporated to dryness to afford crude 4 as a dark orange solid (0.116 g,
100%). NMR analysis demonstrated that the product obtained was sufficiently
pure to be used without further purification. Mp: 1988C. IR: n ¼ 1709 (C55O),
cm21. 1H NMR (CDCl3, 200 MHz): d ¼ 7.15 (dt, 1H, arom., J ¼ 7.0, 1.5 Hz),
7.22–7.60 (m, 8H, arom.), 7.73 (d, 1H, arom., J ¼ 7.3), 8.15 (d, 2H, arom.,
J ¼ 7.5), 8.31 (d, 1H, arom., J ¼ 8.4) ppm. 13C NMR (CDCl3, 200 MHz):
d ¼ 115.8, 120.3, 122.0, 124.3, 125.1, 127.5, 128.8, 129.2, 129.6, 133.9,
134.6 (C-H arom.), 122.9, 134.8, 136.0, 137.1, 138.5, 142.8, 142.9 (C quat.
arom.), 180.5 (C55O) ppm. ESI-MS m/z (%): 382 [Mþ þ Na] (100).
5H-Indeno[2,1-b]indol-6-one 5: To a solution of 4 (0.100 g, 0.28 mmol) in
EtOH (10 mL) and DMSO (1.5 mL), 10% aq. NaOH (0.6 mL) was slowly
added. The reaction mixture was stirred at 508C for 40 min. Thus, the
reaction mixture was concentrated at reduced pressure, poured into water
(100 mL), and extracted with EtOAc (3 ꢀ 30 mL). The combined organic
layers, dried over sodium sulfate, were filtered and evaporated to dryness.
The crude was purified by flash chromatography over a silica-gel column
(PE/CH2Cl2 ¼ 3 : 1), yielding 5 as a dark red solid (0.060 g, 98%). Mp:
1
257–2598C. IR: n ¼ 1694 (C55O), 3434 (NH) cm21. H NMR (DMSO,
200 MHz): d ¼ 7.00 (dt, 1H, arom., J ¼ 7.2, 1.7 Hz), 7.09–7.38 (m, 6H,
arom.), 7.80 (d, 1H, arom., J ¼ 8.1), 12.04 (bs, 1H, NH) ppm. 13C NMR
(DMSO, 200 MHz): d ¼ 115.0, 120.1, 122.1, 122.4, 123.8, 126.9, 127.4,
134.9 (C-H arom.), 121.3, 134.6, 137.1, 137.2, 140.8, 143.7 (C quat. arom.),
184.3 (C55O) ppm. APCI( þ )-MS m/z (%): 220 [Mþ þ Na] (100).
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