A novel, chemoselective one-pot procedure for the preparation of 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives via oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles

Article abstract of DOI:10.1016/j.tetlet.2013.10.156

A one-pot, efficient and chemoselective procedure for the synthesis of new 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives has been developed which involves room temperature oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles themselves synthesized from the reaction of ninhydrin and enaminones in 30% ethanol. A reasonable mechanism is proposed for the oxidation reaction based on the results of this study and our previous related work.

Full text of DOI:10.1016/j.tetlet.2013.10.156

Tetrahedron Letters 55 (2014) 1967–1970
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel, chemoselective one-pot procedure for the preparation
of 3H-spiro[isobenzofuran-1,20-pyrrole]-3,30(10H)-dione derivatives
via oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles
b
b
Gholam Hossein Mahdavinia a, Mohammad R. Mohammadizadeh b, , Noushin Ariapour , Maryam Alborz
⇑
a Department of Chemistry, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
b Chemistry Department, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
A one-pot, efficient and chemoselective procedure for the synthesis of new 3H-spiro[isobenzofuran-1,20-
pyrrole]-3,30(10H)-dione derivatives has been developed which involves room temperature oxidative
cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles themselves synthesized from the reaction of ninhydrin
and enaminones in 30% ethanol. A reasonable mechanism is proposed for the oxidation reaction based on
the results of this study and our previous related work.
Article history:
Received 1 August 2013
Revised 14 October 2013
Accepted 31 October 2013
Available online 7 November 2013
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Chemoselective
One-pot
Oxidative cleavage
Indenopyrroles
Spiroisobenzofuranopyrroles
Spirocyclic compounds represent an important class of
naturally occurring substances with highly pronounced biological
properties.1 Isobenzofuranones2 are an important class of O-het-
erocyclic compounds. They possess anti-oxidant, antimicrobial,
antiplatelet, and cytotoxic activities along with anti-arrhythmic ef-
fects.3–6 Pyrrole derivatives7 are valuable N-heterocycles, which
have become increasingly important in medicinal chemistry and
organic synthesis. They are also substructures in important biolog-
ically active compounds such as indolizidine alkaloids, unsaturated
or Ph substituents, spiro[isobenzofuran-1,20-pyrrole] derivatives 2
were the exclusive products.12
As part of our continuing interest on the development of new
synthetic methods for heterocyclic compounds,9–12 and guided
by the observation that the presence of two or more different het-
erocyclic moieties in a single molecule often enhances remarkably
the biological properties,14 and in continuation of our previous
work on the oxidation of cyclic diols12 and with the aim to estab-
lish a plausible mechanism, we have studied the oxidation of the
title compounds 1 with periodic acid in aqueous medium.
When cyclic dihydroxyindeno[1,2-b]pyrroles 1, which were
formed from the reaction of ninhydrin 4 and enaminones 5, were
exposed to H5IO6 at room temperature, 3H-spiro[isobenzofuran-
c
-lactams, and bicyclic lactams.8
While isobenzofuranone and pyrrole derivatives have attracted
significant attention, the preparation of spiroheterocyclic com-
pounds incorporating isobenzofuranone and pyrrole motifs has
not been the subject of as much research.9–13
1,20-pyrrole]-3,30(10H)-dione
derivatives
2
were
formed
Recently we reported that room temperature oxidation of
3a,8b-dihydroxyindeno[1,2-b]pyrrol-4-ones 1 with Pb(OAc)4 in
acetic acid resulted in the chemoselective formation of spiro[iso-
(Scheme 2).
The oxidation step is very fast and involves a simple procedure
followed by isolation and purification. In order to establish the
scope of the procedure various aromatic and aliphatic substituted
enaminones were employed. The results (Table 1) show that the
desired products were obtained in good to excellent yields.
The structures of products 2 were characterized unambiguously
by elemental and spectroscopic analysis. The IR spectra showed
characteristic peaks at 1792, 1784, 1683, and 1653 cmꢀ1 corre-
sponding to the asymmetric and symmetric stretching vibrations
of the carbonyl groups. The 1H NMR spectrum of 2k in CDCl3 exhib-
ited a triplet and a quartet at 1.32 and 4.28 ppm, respectively,
(both with J of 6.4 Hz) which were attributed to the ethyl group
benzofuran-1,20-pyrrole] derivatives
2 and isobenzofurans 3
(Scheme 1). The chemoselectivity of the reaction depended on
the nature of the R1 group of dihydroxyindeno[1,2-b]pyrroles 1.
When R1 was H, the isobenzofuran derivatives 3 were isolated
from the reaction mixture and characterized unambiguously from
their NMR and X-ray crystallographic data, whereas for R1 = CO2Me
⇑
Corresponding author. Tel./fax: +98 7714541494.
E-mail addresses: mrmohammadizadeh@pgu.ac.ir, mrmohamadizadeh@gmail.
com (M.R. Mohammadizadeh).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.156

1968
G. H. Mahdavinia et al. / Tetrahedron Letters 55 (2014) 1967–1970
O
O
O
O
O
O
O
OH
O
O
O
R2
HO
R2
Pb(OAc)4, AcOH
r.t., 4 h
R2
+
R1
O
HN
N
N
R1
R1
Ar
Ar
Ar
O
1
2
3
R1= CO2Me or Ph 80-84%
not formed
82-92%
R1= H
not formed
Scheme 1. Our previous work on the chemoselective preparation of spiro[isobenzofuran-1,20-pyrrole] derivatives 2 and isobenzofurans 3.
O
O
O
O
O
O
O
OH
N
O
O
R2
R2
OH
OH
HO
H5IO6
EtOH (30%)
r.t., 3 h
+
R2
R1
HN
(CH2)n
R1
N
r.t., 1 h
R1
(CH2)n
Ar
Ar
(CH2)n
Ar
n= 0, 1, 2
5a
4
1a-1; not isolated
-1
2a
-1
Scheme 2. One-pot chemoselective synthesis of spiro[isobenzofuran-1,20-pyrrole]-3,30(10H)-diones 2.
Table 1
One-pot chemoselective synthesis of 3H-spiro[isobenzofuran-1,20-pyrrole]-3,30(10H)-diones 2a–l
Entry
Enaminone 5
Product 2
Yielda (%)
Entry
Enaminone 5
Product 2
Yielda (%)
O
O
O
O
O
O
O
O
O
O
O
Ph
a
84
g
87
HN
Ph
N
N
HN
HN
Ph
Ph
C6H4-4-Cl
Ph
Ph
C6H4-4-Cl
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
Ph
Ph
b
c
80
80
h
93
90
HN
Ph
N
N
C6H4-4-OMe
C6H4-4-OMe
C6H4-4-OMe
C6H4-4-OMe
O
O
O
O
O
O
O
O
OMe
OMe
i
HN
HN
N
OMe
OMe
N
N
H
O
Ph
Ph
Ph
Ph
O
O
O
Bu-t
O
O
O
O
O
O
O
O
OMe
Bu-t
Bu-t
H
O
HN
O
N
d
90
j
OMe
90
N
C6H4-4-Me
O
Bu-t
H
H
C6H4-4-Me
Ph
Ph
O
O
O
O
H
O
O
O
O
O
O
O
Ph
OEt
HN
e
f
84
85
k
90
85
HN
OEt
Ph
N
N
Ph
O
C6H4-2-Cl
O
C6H4-2-Cl
Ph
O
O
O
O
O
O
OEt
H
3
HN
l
HN
Ph
OEt
C6H4-2-OMe
N
N
C6H4-2-OMe
H
Ph
a
Isolated yields.

G. H. Mahdavinia et al. / Tetrahedron Letters 55 (2014) 1967–1970
1969
δ-
δ+
O
O
O
O
O
OH
N
R2
R2
H5IO6/EtOH
HO
δ+
R1
R1
N
H2O
1
O
X-Ar
X-Ar
6
R2
R2
R1
H
R1
N
OH
O
O
X-Ar
O
O
O
N
O
HO
Path I
O
X-Ar
H
O
R
O
H
O
O
N
R2
OH
H
R1
Ar-X
(7b)
O
O
(7a)
CH3COOH
R1
Path II
8
R2
O
O
O
O
O
O
O
X-Ar
N
CH
H
3
R2
N
O
R1
Ar-X
O
2
3
O
Scheme 3. Plausible mechanism for the synthesis of 3H-spiro[isobenzofuran-1,20-pyrrole]-3,30(10H)-diones 2 and isobenzofuran 3 in acetic acid and aqueous media.
of the ester, in addition to an AB quartet for the diastereotopic ben-
zylic protons at 4.49 ppm (J = 12 Hz). It also exhibited one single
sharp peak at 8.76 ppm which was readily recognized as arising
from the methine proton of the pyrrole moiety along with multi-
plets at 6.96–7.91 ppm for the aromatic protons. The 1H-decoupled
13C NMR spectrum of 2k showed 21 distinct resonances in agree-
ment with the proposed structure. The methyl and methylene car-
bons resonated at 14.4 and 60.4 ppm while the carbonyl carbon
signals were observed at 167.3, 172.0, and 187.8 ppm. The reso-
nance signal corresponding to the spiro carbon was present at
94.4 ppm. The mass spectrum of 2k displayed a molecular ion peak
at m/z = 397.07 (12%). Both the mass spectrum and elemental anal-
ysis established the molecular formula of 2k as C21H16ClNO5.
Concerning these results and those obtained from the previous
related work,12 two important features can be summarized: (1)
when the oxidation was run under Pb(OAc)4/acetic acid conditions,
the type of product was dependent on the R1 group (R1 = H, com-
pounds 3; R1 = other groups, compounds 2 were obtained); (2)
using H5IO6/ethanol (30%) conditions the products are indepen-
dent of the nature of the R1 group (spiro[isobenzofuran-1,20-pyr-
role] derivatives 2 were the exclusive products).
esterification of intermediate 8 is prevented and pathway II occurs
to give products 2.
In summary, we have developed an efficient and
chemoselective one-pot synthesis of 3H-spiro[isobenzofuran-1,20-
pyrrole]-3,30(10H)-dione derivatives by oxidative cleavage of
dihydroxyindeno[1,2-b]pyrroles. A significant and attractive fea-
ture of this method is the assembly of two biologically valuable
heterocyclic frameworks into one structure. New mechanistic
features of the reaction have been explained by comparison of
the products from a variety of substituted dihydroxyindeno-
[1,2-b]pyrroles under two sets of reaction conditions.
General procedure for the one-pot preparation of 3H-
spiro[isobenzofuran-1,20-pyrrole]-3,30(10H)-dione derivatives 2
A mixture of enaminone 5 (2 mmol), ninhydrin (4) (2 mmol),
and EtOH:H2O (30:70, 5 mL) was stirred at r.t. for 3 h. Then,
H5IO6 (2 mmol) was added, and the mixture was stirred for an
additional 1 h. Products 2a–l precipitated and were separated from
the reaction mixture by filtration and further purified by recrystal-
lization from EtOH.
A plausible mechanism is shown in Scheme 3. It is reasonable to
propose that enaminone
5 adds to ninhydrin (4) to form
Supplementary data
dihydroxyindeno[1,2-b]pyrrole derivatives 1. Subsequently, oxida-
tion of 1 gave the corresponding benz[c]azocine-1,5,6-trione 6,
that was hydrolyzed to give benzoic acid 7, which might equili-
brate into forms 7a and 7b. When R1 = H, the tautomer 7a is more
stable than 7b, because of the occurrence of highly efficient intra-
molecular hydrogen bonding,12 and there is no repulsion between
the R1 and R2 groups. In contrast, when R1 is a larger group there is
relatively high repulsion between R1 and R2 and consequently, 7b
is more stable than 7a. In acetic acid, if R1 = H, compounds 3 were
formed as the major products via intramolecular cyclization of 7a
(Path I) to give 3-hydroxyisobenzofuran-1-one derivatives 8, fol-
lowed by esterification with AcOH. When R1 is a larger group,
products 2 are formed preferentially via intramolecular cyclization
of 7b (Path II).12 When the reaction was run in aqueous medium,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013
.10.156.
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