Tetrahedron Letters
Microwave-assisted facile synthesis of [a]-annelated
pyrazolopyrroloindoles via intramolecular azomethine imine
1,3-dipolar cycloaddition
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Anand H. Shinde, Shinde Vidyacharan, Duddu S. Sharada
Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram 502 205, Medak District, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of [a]-annelated pyrazolopyrroloindoles via intramolecular 1,3-dipolar cycloaddition of
in situ generated azomethine imine from N-allylated indole-2-carboxaldehyde, in regio- and stereoselec-
tive manner by using microwave irradiation is described. A one-pot strategy for the expedient synthesis
of pyrazolopyrroloindoles has been developed.
Received 12 February 2014
Revised 28 March 2014
Accepted 28 March 2014
Available online 5 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted
1,3-Dipolar cycloaddition
Azomethine imine
Pyrazolopyrroloindole
Stereoselective
The chemistry of fused biheterocycles has been the fascinating
field of investigation in medicinal chemistry, as they have been
found to exhibit enhanced biological profile.1 Heterocyclic com-
pounds play an important role in medicinal chemistry and natural
products. Among them, [a]-annelated indole is a unique structural
feature, present in a wide range of heterocyclic compounds. Pyrrol-
o[1,2-a]-indole2,3 scaffold is a primary target for synthetic chemists
due to its structural diversity. The biological significance of these
motifs has been clearly exemplified by natural products and syn-
thetic compounds, such as flinderole C (1),4 mitomycin C (2),5 isat-
isine A (3),6 yuremamine (4)7 and so forth (Fig. 1). Owing to the
importance of pyrroloindole scaffolds, there has been continuous
interest to develop new synthetic methods such as N-heterocyclic
carbene catalyzed domino reaction between 1H-indole-2-carbal-
dehydes and formylcyclopropane 1,1-diesters,3b nitrile oxide
cycloaddition,3c palladium catalyzed cyclization,3d–g and radical
cyclization.3h
anti-inflammatory,9 anti-microbial,10 anti-anxiolytic,11 herbi-
cidal,12a and insecticidal activities.12b For instance Celecoxib (6), a
pyrazole derivative is used as an analgesic. They have a rich chem-
istry because of their ready reductive cleavage13 and susceptibility
to ring transformations.14 Among various literature methods,15
1,3-dipolar cycloaddition of azomethine imine is the well-known
strategy for the synthesis of pyrazoles and its derivatives.16 Azo-
methine imines are less common than other 1,3-dipoles but are
known to react with alkene in inter-17 or intramolecular18 fashion
to construct variety of ring-fused pyrazolidines.19 Cyclic azome-
thine imines are widely explored dipoles in cycloaddition reactions
with various dipolarophiles leading to a wide variety of pyrazole
fused heterocyclic compounds. In contrast, acyclic azomethine imi-
nes have gained little attention due to requisite harsh reaction con-
ditions. However, generation of stabilized acyclic azomethine
imines has been facilitated by acid additives.20
Microwave-assisted organic synthesis (MAOS)21 has become an
effective and popular tool in synthetic chemistry due to advantages
such as drastic acceleration of sluggish transformations, enhanced
yields, cleaner reactions, and rapid generation of diverse complex
molecules in environmentally benign manner. As mentioned, when
one biodynamic heterocyclic system is coupled with another, a
molecule with enhanced biological activity can be produced. Keep-
ing in view the high potential of pyrroloindoles and pyrazoles as
drug candidates, the synthesis of angularly fused pyrazolopyrro-
loindole derivatives was undertaken.
1,3-Dipolar cycloaddition is one of the important methods for
the synthesis of five-membered heterocyclic compounds in a
regio- and stereocontrolled manner.8 Five-membered heterocyclic
compounds form an integral part of natural products and
bioactive molecules, specifically pyrazoles are known to possess
a broad spectrum of biological activities, such as anti-tumor,
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0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.