RCM in indoles. A new entry to the mitosene skeleton

Article abstract of DOI:10.1016/S0040-4039(02)00909-7

The RCM metathesis reaction catalyzed by Grubbs' ruthenium catalyst is used with a series of 1,2-disubstituted indoles leading with excellent yields to tricyclic compounds. When applied to 1-allyl-2-vinylindoles this methodology allows a new entry to the mitosene skeleton.

Full text of DOI:10.1016/S0040-4039(02)00909-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4765–4767
RCM in indoles. A new entry to the mitosene skeleton
Patxi Gonza´lez-Pe´rez, Leticia Pe´rez-Serrano, Luis Casarrubios, Gema Dom´ınguez and
Javier Pe´rez-Castells*
Departamento de Qu´ımica, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo-CEU,
Urb. Montepr´ıncipe, Boadilla del Monte, 28668 Madrid, Spain
Received 16 April 2002; revised 30 April 2002; accepted 13 May 2002
Abstract—The RCM metathesis reaction catalyzed by Grubbs’ ruthenium catalyst is used with a series of 1,2-disubstituted indoles
leading with excellent yields to tricyclic compounds. When applied to 1-allyl-2-vinylindoles this methodology allows a new entry
to the mitosene skeleton. © 2002 Elsevier Science Ltd. All rights reserved.
RCM reactions catalyzed by ruthenium methylene com-
plexes have become an important tool in the synthesis
of natural products.1 Among the myriade of synthetic
applications reported to date, there are very few exam-
ples that use suitable functionalized indoles.2 Following
our project directed to the synthesis of polycycloindoles
related to natural alkaloids,3 we herein describe the
metathesis of 1-allylindoles bearing vinyl or alkenyl
The reaction of 2a with vinyl or allylmagnesiumbro-
mide gave the corresponding alcohols 4 and 5, which
decomposed partially when we tried to purify them by
chromatography. Thus, metathesis reactions were car-
ried out with the crude products and gave the pyrido-
and azepinoindoles 6 and 7 in excellent yields. Alterna-
tively, protection of the hydroxy group in 4 and 5 with
TBDMSCl gave compounds 8 and 9, which were
purified and submitted to RCM to give 10 and 11. This
three-step procedure gave lower overall yields (Scheme
chains at the
2 position. These reactions lead
to azepino[1,2-a]-, pyrido[1,2-a]- and pyrrolo[1,2-
a]indoles. The latter compounds have the skeleton of
mitosenes.
The mytomicine family is a group of metabolites from
Streptomices that have attracted much attention due to
their potent antitumoral and antibacterial activity (Fig.
1).3 Several synthesis of mitomycine and other mito-
senes have been reported.4 Access to the pyrrolo-
[1,2-a]indole skeleton which is common for these com-
pounds is generally carried out by radical cyclizations,5
metal carbene insertion,6 nitrone cycloadditions7 or
intramolecular cyclizations8 but until now the RCM
reaction has not been used.
Figure 1.
We have first obtained a series of indolic substrates
conveniently functionalized to give RCM reactions.
Thus, starting from indole-2-carboxylic acids 1a–b, the
1-allyl-2-indolecarbaldehydes 2a–b were obtained in
four steps with excellent global yield. Compound 2c
was obtained from 3-methylindole 3 by means of an
allylation and a Vilsmeier reaction (Scheme 1).
Keywords: indoles; mitosenes; ring closing metathesis; ruthenium.
* Corresponding author. Tel.: 34913724700; fax: 34913510475; e-mail:
jpercas@ceu.es
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00909-7

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P. Gonza´lez-Pe´rez et al. / Tetrahedron Letters 43 (2002) 4765–4767
2). We also used several reaction conditions. The best
solvent among toluene, benzene and DCM was the
latter and the amount of catalyst used was 5%. We
compared in particular the result with ruthenium cata-
lyst 12 and second generation catalyst 13. The results
with the four substrates depicted in Scheme 2 were
similar (87 and 90% yield for the obtention in one-pot
of 6 and 7, respectively, when using 5% of 13), and thus
commercial complex 12 was used for the rest of the
work.
In order to effect the synthesis of pyrrolo[1,2-a]indoles,
we submitted compound 2a to a Wittig reaction obtain-
ing 14a. This allylvinylindole was unstable and decom-
posed in hours although it could be purified by
chromatography on alumina. The RCM reaction of 14a
gave 15a with 34% global yield from 2a. We then tried
the tandem Wittig-metathesis reaction9 and succeeded
in obtaining pyrroloindole 15a in 65% yield. The
triphenylphosphine oxide present in the reaction did
not affect the metathesis process (Scheme 3). Com-
pounds 15b–c were obtained following this method.
Scheme 3. Reagents and conditions: (i) Ph3PꢀCH2; (ii) 5% 12.
DCM.
shown by the signal of the methyl that appears as a
doublet (J=7.1 Hz).10
In summary metathesis reactions of alkenylindoles lead
to interesting intermediates in the synthesis of alkaloids.
Some of the starting materials for these reactions are
unstable but this problem is circumvented by the use of
an efficient cascade Wittig-metathesis reaction. Use of
this methodology for the obtention of natural products
is underway.
As depicted in Scheme 3, the double bond emerging
from the metathesis reaction shifts towards the indole
nitrogen. This surprising behavior occurs in the three
examples. The structures of 15a–b were assigned
according to the NMR signal of the methylene (for 15a
1H: 3.80 ppm; 13C: 28.9 ppm), whereas in compounds
similar to the expected isomer, previously described in
the literature,5 this methylene appears at ca. 4.60 ppm.
Compound 2c, on the other hand, leads to 15c in
which the indolic double bond has shifted also, as
Acknowledgements
The authors are grateful to the DGES (MEC Spain,
PB98-0053) and the Universidad San Pablo-CEU (2/01)
for financial support. L.P.-S. gratefully acknowledges a
pre-doctoral fellowship from the USP-CEU.
OR
1)
MgBr
(85%)
N
2) 5% 12
6, R = H
10, R = TBDMS
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Scheme 2.

P. Gonza´lez-Pe´rez et al. / Tetrahedron Letters 43 (2002) 4765–4767
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the crude residue was dissolved in DCM (50 mL) and
Grubbs’ catalysts 12 was added (0.066 g, 0.08 mmol) and
the mixture was stirred at room temperature overnight.
The reaction was filtrated through Celite and the solvent
was evaporated in vacuum. The residue was purified by
column chromatography using hexane as eluent to give
0.24 g (1.58 mmol, 65%) of 15a as a white solid (mp
1
87–88°C). Spectroscopic data for 15a: H NMR (CDCl3)
l (ppm): 3.80 (s, 2H), 6.09–6.11 (m, 1H), 6.38 (dd, 1H,
J1=3.3 Hz, J2=2.8 Hz), 7.04–7.09 (m, 2H), 7.21–7.31 (m,
2H), 7.37 (d, 1H, J=7.2 Hz). 13C NMR (CDCl3) l
(ppm): 141.1, 135.4, 134.9, 127.3, 125.8, 122.9, 113.0,
109.7, 109.6, 101.6, 28.9. IR (KBr) w 2960, 1620, 1490
9. Experimental procedure for the synthesis of 15a is as
follows: To a suspension of methyltriphenylphosphonium
bromide (0.87 g, 2.43 mmol) in THF (20 mL), KHMDS
(0.5 M in toluene, 4.22 ml, 2.1 mmol) was added. The
resulting suspension was stirred vigorously at room tem-
perature and under argon for 30 min. The ylide was then
added dropwise via cannula to a solution of 2a (0.30 g,
1.60 mmol) in THF (15 mL). The mixture was stirred for
20 min at room temperature, and then poured to a
mixture of ether–H2O (1:1). The organic layer was dried
(MgSO4), filtrated and evaporated in vacuum. The
residue was purified by column chromatography of basic
alumina using hexane as eluent to give 0.20 g (68%) of
1-allyl-2-vinylindole 14a as a colorless oil. Alternatively,
cm−1
.
1
10. Spectroscopic data for 15c: H NMR (CDCl3) l (ppm):
1.50 (d, 3H, J1=7.1 Hz), 4.01 (q, 1H, J1=7.1 Hz),
6.08–6.09 (m, 1H), 6.36–6.38 (m, 1H), 7.04–7.05 (m, 1H),
7.10 (td, 1H, J1=7.7 Hz, J2=1.6 Hz), 7.23–7.31 (m, 2H),
7.36 (d, 1H, J=8.2 Hz). 13C NMR (CDCl3) l (ppm):
141.7, 140.7, 140.3, 127.4, 124.7, 123.1, 113.0, 109.6,
109.4, 100.8, 35.5, 19.0. IR (neat) w 2980, 2860, 1620,
1500 cm−1
.