First example of regiospecific intermolecular C-H insertion reactions of cyclic rhodium carbenoids: Novel synthesis of 3-indol-3′-yloxindoles

Article abstract of DOI:10.1039/b200412g

Facile regiospecific intermolecular C-H insertion reactions of cyclic rhodium carbenoids have been achieved using diazo carbonyl compounds 1 and indole or N-substituted indoles to afford 1,3-dihydro-1′H-[3,3′]biindolyl-2-ones, 3a-o in an excellent yield.

Full text of DOI:10.1039/b200412g

First example of regiospecific intermolecular C–H insertion reactions of
cyclic rhodium carbenoids: novel synthesis of 3-indol-3A-yloxindoles
Sengodagounder Muthusamy,* Chidambaram Gunanathan, Srinivasarao Arulananda Babu,
Eringathodi Suresh and Parthasarathi Dastidar
Silicates and Catalysis Discipline, Central Salt and Marine Chemicals Research Institute, Bhavnagar 364
002, India. E-mail: salt@csir.res.in; Fax: +91 278 567562; Tel: +91 278 567760
Received (in Cambridge, UK) 11th January 2002, Accepted 6th March 2002
First published as an Advance Article on the web 18th March 2002
Facile regiospecific intermolecular C–H insertion reactions
of cyclic rhodium carbenoids have been achieved using diazo
carbonyl compounds 1 and indole or N-substituted indoles to
afford 1,3-dihydro-1AH-[3,3A]biindolyl-2-ones, 3a–o in an
excellent yield.
1b–e with 2a–c were completed within 1 h and the chromato-
graphic purification of the reaction mixtures resulted the
respective pure products 3.§ Reactions that yielded products
3c,f,i,l,o, were followed by IR spectroscopy (disappearance of
the characteristic diazo peak), due to the identical Rf value of
Oxindole derivatives are known to possess a variety of
biological activities.1 Oxindole systems having indole 3-sub-
stituents are present in various marine microorganisms such as
sponge Hyrtios altum.2 Interestingly, polybromo 3,3A-biindoles
are also present in the blue–green alga rivularia firma.3 In
continuation of our work4 on reactions of diazo carbonyl
compounds with indoles, we focused our attention on the
synthesis of indolyloxindoles using cyclic rhodium carbenoids.
The reaction of a-diazo carbonyl compounds with rhodium(II
)
carboxylates is a well described method to generate the rhodium
carbenoids, which can undergo an array of reactions such as
cyclopropanations, C–H or heteroatom-H insertions and ylide
formations.5 Insertion reactions of carbenes into C–H bonds
have gained significant attention since the first discovery by
Meerwein, Rathjen and Werner.6 The insertion process can
proceed either by an intermolecular or intramolecular pathway.7
A number of reports are available in the chemical literature,
which describe the intramolecular insertion of metal-stabilized
carbenoids to the C–H bonds for the construction of five
membered carbocyclic and heterocyclic systems.8 Apparently,
the intermolecular C–H insertions are believed to be synthet-
ically not useful because of the low selectivity and competitive
intramolecular reactions.5b,7 A few literature reports are
available on the intermolecular C–H insertion of metallo-
carbenoids, which reveal the formation of a mixture of products
without any selectivity.9 To the best of our knowledge, there is
no report in which the intermolecular C–H insertion reaction of
cyclic metallo-carbenoids is achieved although these inter-
mediates always have a propensity to afford cycloadducts10 via
1,3-dipolar cycloaddition reactions. We have been extensively
involved in developing new synthetic strategies11 using diazo
carbonyl compounds. Consequent to these efforts, herein we
report the novel and regiospecific intermolecular C–H insertion
reactions of 3-diazooxindoles with substituted/unsubstituted
indoles in the presence of a Rh2(OAc)4 catalyst.
We investigated the rhodium(II)-catalyzed behavior of cyclic
diazo carbonyl compounds† 1 with indoles 2 in an inter-
molecular fashion. The reaction of 3-diazooxindole (1a) and
indole (2a) with 0.3 mol% rhodium(II) acetate dimer catalyst
afforded biindole 3a in 81% yield (Scheme 1) with re-
giospecificity. The regiochemistry of the product 3a was
unequivocally corroborated by single-crystal X-ray (Fig. 1)
analysis.‡
Subsequently, we investigated the rhodium(II)-catalyzed
reaction of cyclic diazo carbonyl compound 1a with N-methyl
or N-benzylindole which furnished the C–H insertion products
3b,c respectively in very good yields (Table 1) with re-
giospecificity.
Scheme 1
Fig. 1 Crystal structure (ORTEP representation) of 3a.
Table 1 Regiospecific C–H insertion of diazo compounds 1 with indoles 2
catalyzed by rhodium(II) acetate.a
Biindole 3
R1
R2
Time
Yieldb(%)
mp/°C
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
H
H
H
CH3
CH3
CH3
CH2Ph
CH2Ph
CH2Ph
Allyl
Allyl
Allyl
COPh
COPh
COPh
H
10 h
81
85
87
176–178
180–182
186–188
162–164
127–129
105–107
166–168
95–97
155–157
131–133
119–121
101–103
147–149
114–116
133–135
CH3
CH2Ph
H
CH3
CH2Ph
H
CH3
CH2Ph
H
CH3
CH2Ph
H
10 h
10 h
60 min
60 min
60 min
60 min
30 min
30 min
60 min
30 min
30 min
5 min
7 min
7 min
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
63
CH3
CH2Ph
66
73
a Reactions were carried out as follows: a catalytic amount of Rh2(OAc)4
(0.3 mol%) was added to a stirred solution of cyclic diazo compound 1 (1
mmol) and indole 2 (1.2 mmol) in freshly prepared dry DCM at rt under an
argon atmosphere. After completion of the reaction, the solvent was
evaporated in vacuo and the residue purified by chromatography. b Yields
(unoptimized) refer to isolated and chromatographically pure compounds of
3.
Encouraged by these results obtained in the above reactions,
we were further interested to carry out the reactions of
substituted cyclic diazo carbonyl compounds 1b–e. Surpris-
ingly, the rhodium(II)-catalyzed reactions of diazooxindoles
824
CHEM. COMMUN., 2002, 824–825
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N-alkylation of 3-diazooxindole (1a) with methyl iodide, benzyl bromide or
allyl bromide using 10% ethanolic KOH solution. The N-benzoyl-
3-diazooxindole (1e) was synthesized by N-benzoylation of 1a with benzoyl
chloride using n-butyllithium at 270 °C.
‡ Crystal data for 3a: C16H12N2O, M = 248.3, colorless prism 0.18 3 0.12
3 0.10 mm, monoclinic, P21/n, a = 11.137(4), b = 4.6810(10), c =
23.871(6) Å, b = 95.85(2)°, V = 1238.0(6) Å3, T = 293(2) K, Z = 4, Dc
= 1.332 Mg m23, F(000) = 520, m = 0.085 mm21, l = 0.7107 Å, 2178
reflections were collected on
independent (I ! 2s(I)). Final R1 = 0.0465, wR2 = 0.1315 observed data.
The largest difference peak and hole
0.196 and 20.230 eÅ23
a CAD-4 diffractometer, 1507 were
=
respectively. The solid-state supramolecular arrangement of compound 3a
shows that the molecules are arranged in layers along the a-axis by
alignment of the adjacent screw type molecules with three types of
hydrogen bonding interactions, namely C–H…O, N–H…O and N–H…N.
The structure was solved and refined using G. M. Sheldrick, SHELX97
program, University of Göttingen, Germany, 1997. CCDC 177615. See
http://www.rsc.org/suppdata/cc/b2/b200412g/ for crystallographic data in
cif or other electronic format.
§ All new compounds exhibited spectral data consistent with their
structures.
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Scheme 2
starting materials in TLC. These reactions led to the facile
synthesis of substituted and unsubstituted biindoles 3 in
quantitative yield evidently from many examples (Table 1).
Surprisingly, the diazo carbonyl compound having an electron-
withdrawing group (1e) underwent reaction with indoles 2a–c
in short duration, but the yield was reduced when compared
with other reactions.
In all reactions, the regiospecific biindoles were obtained
exclusively as a result of the C–H insertion of diazo ketones 1
to the 3-position of indoles in the presence of 0.3 mol% of
Rh2(OAc)4 catalyst. We have not obtained any products
resulting from the potential competitive intermolecular N–H
insertion13 reaction (where R2 = H) of the rhodium carbenoids.
A plausible mechanism for the reactions of cyclic diazo
carbonyl compounds 1 with indoles 2 in the presence of
rhodium(II) acetate may be proposed as given in Scheme 2. The
initially formed transient rhodium carbenoid 4 underwent
insertion to the nucleophilic indole 3-position to produce
zwitterion 5 followed by a proton transfer to furnish product 3.
The ring closure of zwitterion 5 did not furnish any anticipated
cycloadducts 6.10
In summary, we have demonstrated the facile synthesis of N-
substituted and unsubstituted 3-indol-3A-yloxindoles from cy-
clic diazo carbonyl compounds 1 and indoles 2 via inter-
molecular C–H insertion. This methodology forms the first
regiospecific synthesis using an intermolecular rhodium carbe-
noid C–H insertion process. Further exploration of this strategy
with other heterocyclic systems and approach towards the
naturally existing molecules is currently in progress.
This research was supported by Young Scientist Scheme,
CSIR, New Delhi. We thank P. K. Ghosh, Director and R. V.
Jasra, Head of the division, for their encouragement shown in
this work. C. G. and S. A. B. thank CSIR, New Delhi for a
Fellowship.
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Notes and references
† The cyclic diazo carbonyl compound 1a was obtained by the literature
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method.12 The N-substituted-3-diazooxindoles (1b–d) were synthesized by
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