Nitro-facilitated '5-exo-dig' intramolecular cyclisation of 2-(2-nitrophenylethynyl)benzoic acids: A new total synthesis of indeno[1,2-b]indoles

Article abstract of DOI:10.1055/s-2002-31896

2-(2′-Nitrophenylethynyl)benzoic acid esters, obtained by Sonagashira coupling of o-bromobenzoates to 2-(2′-nitrophenyl)acetylenes, were converted into indeno[1,2-b]indoles by a two-step sequence, through the corresponding 2-nitrophenyl-1,3-indandiones.

Full text of DOI:10.1055/s-2002-31896

LETTER
999
Nitro-facilitated ‘5-Exo-dig’ Intramolecular Cyclisation of 2-(2-Nitrophenyl-
ethynyl)benzoic Acids: A New Total Synthesis of Indeno[1,2-b]indoles
A
New Total
S
r
ynthesis
a
of Indeno[
n
1, 2-
b
]indole
c
s
isco J. Reboredo, Mónica Treus, Juan C. Estévez, Luis Castedo, Ramón J. Estévez*
Departamento de Química Orgánica and Unidade Asociada (C.S.I.C.), Universidade de Santiago, 15782 Santiago de Compostela, Spain
Fax +34(981)591085; E-mail: qorjec@usc.es
Received 15 April 2002
iodobenzoic acid esters 1 and o-nitrophenylacetylenes 2
Abstract: 2-(2 -Nitrophenylethynyl)benzoic acid esters, obtained
(Scheme 1).
by Sonagashira coupling of o-bromobenzoates to 2-(2 -nitrophe-
nyl)acetylenes, were converted into indeno[1,2-b]indoles by a two-
step sequence, through the corresponding 2-nitrophenyl-1,3-indan-
diones.
R
R
CO2Me
R
CO2Me
Key words: alkynes, carboxylic acids, cyclizations, indoles, palla-
I
1: a) R=H
b) R=OMe
dium, rearrangements
R
R'
R'
PdCl2(PPh3)2, CuI
THF, Et3N
rt, 3.5 h
O2N
R'
R'
The intramolecular addition of an anionic centre to a car-
bon-carbon triple bond is a topic of current interest on ac-
count of its usefulness for the construction of ring systems
in natural product syntheses.1 The ring size of the result-
ing reaction product can usually be predicted by Bald-
win’s rules.2 For the intramolecular cyclisation of 2-
ethynylbenzoic acids, the ‘6-endo-dig’ or the ‘5-exo-dig’
closures are allowed by Baldwin’s rules and both closure
modes have been observed. This allows the preparation of
3-subtituted isocoumarins or 3-alkylidenephthalides, re-
spectively, although sometimes mixtures of both com-
pounds are obtained.3,4 The direction of the favoured
cyclisation is greatly influenced by both the nature of the
substituents at the multiple bond and the reaction condi-
tions. A reliable way to predict the regiochemistry of these
reactions is not currently known.
3:
a) R=R'=H
b) R=H, R'=OMe
(78%)
(90%)
O2N
2: a) R'=H
b) R'=OMe
c) R=OMe, R'=H (29%)
Scheme 1 Sonogashira coupling reaction of methyl o-iodobenzo-
ates to o-nitrophenylacetylenes
Methyl benzoate 3a was subjected to basic hydrolysis in
order to promote transformation of its benzoate 4a into ni-
trobenzylidenephthalide 5a by intramolecular attack of
the carboxylate group to the acetylenic functionality
(Scheme 2). Much to our surprise, however, this treatment
gave the nitrophenylindandione 7a directly in very good
yield, as deduced from analytical and spectroscopic data.8
A plausible mechanism for this transformation is outlined
below: the resonance effect of the nitro-substituent may
promote the 5-exo-dig cyclisation of benzoate of 4a to
give nitrobenzylidenephthalide 5a, which is in equilibri-
um with the corresponding ketoacid 6a. Under the basic
reaction conditions compound 6a could spontaneously
undergo a mixed Claisen condensation to afford indandi-
one 7a. This mechanism is supported by the well-known
rearrangement of 1-benzylidenephthalides to 2-phenyl-
1,3-indandiones.6,9
We describe here the new ‘5-exo-dig’ intramolecular cy-
clisation of o-nitrophenylethynylbenzoic acid salts (4)
and nitrobenzylidenephthalides (6) and the subsequent
transformation of the resulting compounds into inde-
no[1,2-b]indoles (10). This latter family of indoles has re-
cently been reported to be capable of inhibiting radical
chain reactions in disease processes, with some members
of this family being among the most potent antioxidants
known.5 As far as we are aware, this method of cyclisation
of compounds of type 4 has not yet been investigated in
any detail and only one example, carried out in our la-
boratories, of a related synthesis6 of indeno[1,2-b]indoles
has been undertaken.
In a similar way, benzoic acid esters 3b and 3c were di-
rectly converted into the corresponding nitrophenylindan-
diones 7b and 7c, respectively.
Subsequent catalytic hydrogenation of nitrophenylindan-
dione 7a yielded indenoindole 10a in moderate yield
(50%), probably by intramolecular amino-carbonyl con-
densation of aminophenylindandione 8a and subsequent
reduction of indoleindanone 9a in the reaction medium.
As expected, nitrophenylindandiones 7b and 7c were sim-
ilarly transformed into indenoindoles 10b (40% yield) and
10c (25% yield), respectively.
Our present study was carried out with model com-
pounds 3a, 3b and 3c, which were easily obtained by a
Sonogashira coupling7 reaction between appropriate o-
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0999,1001,ftx,en;D06102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1000
F. J. Reboredo et al.
LETTER
O
O
O
O
R
R
R
O
O
NaOH
R
MeOH
rt
5,5-48 h
3
R'
R'
R'
R'
N
O
4
N
O
O
O
R
R
R
R
O
O
R'
OH NO2
O
R
R'
R'
R'
R
O
R'
X
O2N
R'
5
6
H
2 (1 atm), Pd/C
7: X=NO2 (90-98%)
8: X=NH2
n-PrOH/i-PrOH (5:1)
rt, 13-18 h
O
R
R
R'
R'
R'
R
R
N
H
R'
N
H
9
10 (25-50%)
a) R=R'=H; b) R=H, R'=OMe; c) R=OMe, R'=H
Scheme 2 Transformation of 2-(2-nitrophenylethynyl)benzoic acids into indeno[1,2-b]indoles
In summary, we present a new contribution regarding the References
usefulness of diphenylacetylenes in the synthesis of natu-
(1) See: Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.;
Kasano, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
2000, 4339; and references cited therein.
(2) (a) Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L.
J. Org. Chem. 1977, 42, 3846. (b) Johnson, C. D. Acc.
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(3) (a) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org.
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(4) For recent references, see: (a) Liau, H.-Y.; Cheng, C.-H. J.
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A. Synthesis 1999, 1145. (c) Bellina, F.; Ciucci, D.;
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(d) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.;
Mannina, L. Tetrahedron Lett. 2000, 41, 5281.
ral products. This utility is illustrated by the development
of the total synthesis of o-nitrophenylethynylbenzoic acid
esters 3 and their nitro-promoted regiospecific ‘5-exo-dig’
intramolecular cyclisation to nitrobenzylidenephthalides
5, which in basic media spontaneously rearrange to give
nitrophenyl-1,3-indandiones 7. The subsequent direct
transformation of compounds 7 into indeno[1,2-b]indoles
(10) allowed us to develop a new, general synthesis for
these target compounds that is shorter and more efficient
than previous routes.5a
Work is now in progress to improve this short general syn-
thesis of indeno[1,2-b]indoles. In addition, we have em-
barked on a project aimed at the extension of this
potentially wide-ranging synthetic methodology to the
synthesis of natural products related to indenoindoles 10,
including benzo[c]phenanthridines, benzo[b]carbazoles
and pyrido[4,3-b]carbazoles, some of which (e.g. ellipti-
cine) show pronounced anticancer activity.10
(5) (a) Brown, D. W.; Mahon, M. F.; Ninan, A.; Sainsbury, M.;
Shertzer, H. G. Tetrahedron 1993, 49, 8919. (b) Sainsbury,
M.; Shertzer, H. G. Eur. Pat. Appl. EP 91-309445 19911015,
1992. (c) Shertzer, H. G.; Sainsbury, M. Food Chem.
Toxicol. 1991, 29, 391. (d) Brown, D. W.; Graupner, P. R.;
Sainsbury, M.; Shertzer, H. G. Tetrahedron 1991, 47, 4383.
(6) Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron Lett.
1993, 34, 6479.
Acknowledgement
We thank the Ministry of Education and Culture (DGES) and the
Xunta de Galicia for financial support and the latter organisation for
a grant for Mónica Treus. We also thank Jacobo Cruces and Carme
Pampín for their contribution to this paper.
(7) Sonogashira, K.; Ohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(8) All new compounds gave satisfactory analytical and
spectroscopic data. Selected physical and spectroscopic data
follow. Compound 3a. Mp 90–91 °C(hexane). 1H NMR
(ppm, CDCl3): = 3.96 (s, 3 H), 7.38–7.63 (m, 4 H), 7.71
(dd, J = 7.4 Hz, J = 0.9 Hz, 1 H), 7.78 (dd, J = 7.5 Hz,
Synlett 2002, No. 6, 999–1001 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
J = 1.2 Hz, 1 H), 7.99 (dd, J = 7.8 Hz, J = 0.9 Hz, 1 H), 8.06
A New Total Synthesis of Indeno[1,2-b]indoles
1001
J = 7.8 Hz, 1 H), 7.68 (t, J = 7.4 Hz, 1 H), 8.15 (d, J = 8.1
Hz, 1 H). MS: m/z (%) = 327(10) [M+], 164(100). Compound
10a. Mp 242–245 °C(methanol). 1H NMR (ppm, CDCl3/
CD3SOCD3): = 3.61 (s, 2 H), 7.01–7.20 (m, 3 H), 7.32 (t,
J = 7.1 Hz, 1 H), 7.62 (m, 4 H), 11.51 (s, 1 H). MS (CI): m/
z (%) = 246(17) [M + 1]+, 205(100). Compound 10b. Mp
205–207 °C (ethyl acetate/hexane). 1H NMR (ppm,
CD3SOCD3): = 3.68 (s, 2 H), 3.94 (s, 3 H), 3.97 (s, 3 H),
6.96 (s, 1 H), 7.09 (s, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.30 (t,
J = 7.5 Hz, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.51 (d, J = 7.2
Hz, 1 H), 8.17 (s, 1 H). MS (CI): m/z (%) = 265 [100) [M +
1]+. Compound 10c. Mp 245–250 °C (methanol/dichloro-
methane). 1H NMR (ppm, CDCl3/CD3SOCD3): = 3.66 (s,
2 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 7.06 (s, 1 H), 7.10–7.20 (m,
3 H), 7.40–7.44 (m, 1 H), 7.60–7.65 (m, 1 H), 8.30 (bs, 1 H).
MS: m/z (%) = 265(100) [M+].
(dd, J = 8.2 Hz, J = 0.9 Hz, 1 H). MS: m/z (%) = 262(1)
[M+], 163(100). Compound 3b. Mp 110–113 °C(methanol).
1H NMR (ppm, CDCl3): = 3.96 (s, 6 H), 3.99 (s, 3 H), 7.14
(s, 1 H), 7.40 (t, J = 6.3 Hz, 1 H), 7.50 (t, J = 6.3 Hz, 1 H),
7.64 (s, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.80 (d, J = 7.5 Hz,
1 H). MS: m/z (%, CI) = 342(37) [M + 1]+, 312(100).
Compound 3c. Mp 130–133 °C (methanol/dichloro-
methane). 1H NMR (ppm, CDCl3): = 3.96 (s, 3 H), 3.97 (s,
3 H), 3.99 (s, 3 H), 7.16 (s, 1 H), 7.47 (t, J = 6.9 Hz, 1 H),
7.53 (s, 1 H), 7.62 (t, J = 6.9 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1
H), 8.10 (d, J = 8.2 Hz, 1 H). MS m/z (%) = 341(4) [M+],
223(100). Compound 7a. Mp 178–180 °C(chloroform). 1H
NMR (ppm, CDCl3): = 4.67 (s, 0.5 H), 7.46 (dd, J = 7.9
Hz, J = 1.4 Hz, 1 H), 7.58 (td, J = 7.4 Hz, J = 1.3 Hz, 1 H),
7.72 (td, J = 7.4 Hz, J = 1.4 Hz, 1 H), 7.90–8.10 (m, 4 H),
8.21 (dd, J = 6.4 Hz, J = 1.4 Hz, 1 H). MS: m/z (%) = 267
(0.5) [M+], 104(100). Compound 7b. Mp 196–198
(9) Steigel, A.; Veith, R. W.; Braun, M. Liebigs Ann. Chem.
1989, 1, 99.
(10) (a) Cheng, C. C. Structural Aspects of Antineoplastic
Agents-A New Approach, In Progress in Medicinal
Chemistry, Vol. 25; Ellis, G. P.; West, G. B., Eds.; Elsevier
Science Publisher, B. V. (Biomedical Division):
°C(methanol). 1H NMR (ppm, CDCl3): = 3.98 (s, 3 H),
4.02 (s, 3 H), 4.51 (s, 1 H), 6.82 (s, 1 H), 7.80 (s, 1 H), 7.90
(dd, J = 5.6 Hz, J = 3.1 Hz, 2 H), 8.04 (dd, J = 5.6 Hz,
J = 3.4 Hz, 2 H). MS (FAB): m/z (%) = 327(9) [M + 1]+,
104(100). Compound 7c. Mp 210–213 °C (decomp.,
Amsterdam, 1988, 35. (b) Thomson, R. H. Naturally
Occurring Quinones, 4th ed.; Chapman and Hall: London,
New York, 1997.
methanol/dichloromethane). 1H NMR (ppm, CDCl3):
4.03 (s, 6 H), 4.74 (s, 1 H), 7.39–7.44 (m, 3 H), 7.55 (t,
=
Synlett 2002, No. 6, 999–1001 ISSN 0936-5214 © Thieme Stuttgart · New York