Microwave-assisted facile synthesis of [a]-annelated pyrazolopyrroloindoles via intramolecular azomethine imine 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2014.03.134

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 stereoselective manner by using microwave irradiation is described. A one-pot strategy for the expedient synthesis of pyrazolopyrroloindoles has been developed.

Full text of DOI:10.1016/j.tetlet.2014.03.134

Tetrahedron Letters 55 (2014) 3064–3069
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted facile synthesis of [a]-annelated
pyrazolopyrroloindoles via intramolecular azomethine imine
1,3-dipolar cycloaddition
⇑
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,
⇑
Corresponding author. Tel./fax: +91 (40)23017058.
E-mail address: sharada@iith.ac.in (D.S. Sharada).
http://dx.doi.org/10.1016/j.tetlet.2014.03.134
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. H. Shinde et al. / Tetrahedron Letters 55 (2014) 3064–3069
3065
O
OCONH2
OMe
H2N
Me
N
N
NH
H
N
O
NMe2
O
mitomycine C
N
H
2
N
OH
O
N
NHMe
OH
O
OH
HN
flindrole C
isatisine A
1
3
N
H
H
N
OH
NHMe
isoborreverine
O
N
N
N
N
OH
OH
HN
N
O
N
5
O
S
H2N
S
O
HO
O
O
N
OH
N
CF3
HO
viagra
7
yuremamine
4
celecoxib
6
Figure 1. Representative examples of biologically active 1H-pyrrolo-[1,2-a]indole-based natural products and pyrazole-based drug molecules.
Me Me
Ph
N
N
H
Me
N-Allylation
Formylation
[3+2]
N
N
N
N
cycloaddition
Ph
CO2Me
MeO2C
Hydrazone
Formation
N
H
Scheme 1. Retrosynthetic strategy for the synthesis of [a]-annelated pyrazolopyrroloindoles.
Table 1
Me
Me
Me
Optimization of the reaction conditions for the synthesis of pyrazolopyrroloindole
12aa
O
CHO
CO2Me
N
N
N
Me
Me
POCl3/DMF
rt, overnight
H
8
CO2Me
OMe
TBAB
Br
CHO
CO2Me
9a
50% NaOH
PhMe, rt, 4h
N
N
N
N
PhNHNH2
additive
Ph
10a
(65%)
MeO2C
11a (85%)
PhNHNH2
Conditions
11a
Entry Solventb/additivec
12a
Condition
100 °C, 24 h
w, 100 °C, 1 h
% Yieldd
Me
Me
1
2
AcOH/H2O (1:3)
AcOH/H2O (1:3)
AcOH/H2O (1:3), NaOAc (0.3) 100 °C, 24 h
AcOH/H2O (1:3), NaOAc (0.3)
AcOH/H2O (1:3), NaOAc (0.3) ))), 38 °C, 2 h
40
42
38
1,3-dipolar
cycloaddition
N
N
H
l
N
N
N
3e
4e
5e
6
N
CO2Me
MeO2C
l
w , 100 °C, 1 h 43
28
40
nr
0
25
45
35
52
40
12a
AcOH/H2O (1:3), PPh3 (1)
100 °C, 18 h
0 °C, 3 h
60 °C, 24 h
80 °C, 24 h
80 °C, 24 h
80 °C, 24 h
Intermediate
7
DCM, BF3.(OEt)3
8
9
Toluene, I2 (2), DBU (2)
EtOH, HCl (5)f
Scheme 2. Synthesis of [a]-annelated pyrazolopyrroloindole.
10
11
12g
13
14
EtOH, HCl (10)f
EtOH, HCl (15)f
EtOH, HCl (10)f
l
l
l
w, 80 °C, 1 h
w , 65 °C, 1 h
Despite the importance of pyrroloindoles and pyrazoles, there
are no reports for the synthesis of pyrazolopyrroloindoles via
azomethine imine cycloaddition. Earlier, the synthesis of pyra-
zolopyrroloindoles was reported through nitrile imine cycloaddi-
tion but suffers from drawbacks like, use of the quantitative toxic
metal reagent, lead tetraacetate for generation of nitrile imine
dipole, tedious procedure and limited substrate scope.22 Herein,
we wish to report mild, metal-free synthesis of [a]-annelated
pyrazolopyrroloindoles containing ring junction quaternary center
via azomethine imine cycloaddition with simplified reaction
MeOH, HCl (10)f
n-BuOH, HCl (10)f
w , 120 °C, 1 h Complex mixture
a
Reaction conditions: 11a (0.2 mmol), PhNHNH2 (0.2 mmol), additive and 2 mL
of solvent.
b
Solvents ratio.
Equivalents of additive.
Isolated yield after column chromatography.
Instead of PhNHNH2, PhNHNH2ÁHCl has been used.
Concd HCl (37%) has been used.
Optimized condition.
c
d
e
f
g

3066
A. H. Shinde et al. / Tetrahedron Letters 55 (2014) 3064–3069
Table 2
Synthesis of variety of [a]-annelated pyrazolopyrrolo indoles 12a,b
Me
Me
CHO
N
PhNHNH2 / HCl
N
N
CO2Me
N
EtOH, µw, 80 oC, 1h
MeO2C
Ar
Ar
11
12
Me
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Me
Ph
Cl
MeO2C
MeO2C
MeO2C
MeO2C
Me
12c (51%)
12a (52%)
12b (55%)
Me
12d (43%)
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Cl
Ph
Ph
Cl
MeO 2C
MeO2C
MeO2C
MeO2C
Cl
Cl
Et
12e (45%)
Me
12f (37%)
12g (40%)
12h (56%)
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N Ph
Ph
Ph
Ph
Br
MeO2C
MeO2C
MeO2C
MeO2C
F
Br
iPr
12i (44%)
12j (54%)
12k (50%)
12l (37%)
Me
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
F
MeO2C
MeO2C
MeO2C
MeO2C
NO2
F
OMe
12p (-c)
Me
12m (50%)
Me
12n (42%)
12o (43%)
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
MeO2C
MeO2C
MeO2C
MeO2C
S
O
NO2
12q (-c)
O
12r (50%)
12s (43%)
12t (40%)
a
b
c
Reaction conditions: 11 (0.2 mmol), phenylhydrazine (0.2 mmol), concd HCl (37%) (2 mmol), EtOH (2 mL).
Isolated yields after column chromatography.
Complex reaction mixture formed.
procedure. Initially we envisaged that, Baylis–Hillman bromide
based N-allylated indole-2-carboxaldehyde can be exploited in
order to access the aforementioned tetracyclic framework through
in situ formation of azomethine imine ylide followed by an intra-
molecular 1,3-dipolar cycloaddition reaction according to the ret-
rosynthetic strategy shown in Scheme 1.
To manifest this, we started with (Z)-methyl 2-(bromomethyl)-
3-phenylacrylate 9a and reacted with 3-methylindole 8 to obtain
N-allylated indole 10a intermediate in good yield (65%). Further
formylation of the N-allylated indole intermediate under Vilsme-
ier–Haack conditions led to corresponding aldehyde 11a in excel-
lent yield (85%) (Scheme 2). In order to optimize the reaction

A. H. Shinde et al. / Tetrahedron Letters 55 (2014) 3064–3069
Me
CHO
3067
Me
N
PhNHNH2/HCl
N
N
N
R
Ph
EtOH, µw, 80 oC, 1h
R
R
R
11
12u
R= H, 49%
12v R= Me, 46%
Scheme 3. Synthesis of [a]-annelated pyrazolopyrroloindoles 12 from alkyl allyl systems 11.
the product (Table 1, entries 7 and 8). We have next examined,
the reaction in the presence of HCl additive in various alcoholic
solvents under conventional/microwave heating (Table 1, entries
9–14). Gratifyingly, the best result was obtained in the presence
of 10 equiv of HCl in ethanol under microwave heating at 80 °C
for 1 h to afford the desired product 12a in 52% yield (Table 1, entry
12).
With the optimized reaction condition in hand, next we synthe-
sized a series of substituted N-allylated indole-2-carboxaldehydes
to explore the generality of the reaction. We have successfully
extended the methodology to afford a variety of pyrazole-fused
pyrroloindole derivatives in moderate to good yields, as shown in
Table 2. It shows that the protocol is applicable to a wide range
of aryl allylic systems with strong donating as well as withdrawing
nature, except in the case of nitro-substituted allylic systems (12p
and 12q), which resulted in complex reaction mixtures (Table 2).
The present protocol is also applicable for alkyl substituted allylic
systems which afforded the products 12u and 12v in good yields
(Scheme 3).
Figure 2. Crystal structure of compound 12a (CCDC 976703).
The structure and regiochemistry of the cycloadducts were con-
firmed by spectral analysis. Although, the NMR spectroscopic data
support the formation of pyrazolopyrroloindoles 12, the structure
was unambiguously secured by an X-ray crystal structure analysis
of compound 12a (Fig. 2) (see SI for X-ray data of 12a).
Mechanistically, the formation of 12 can be rationalized by the
initial formation of hydrazone intermediate A by reaction of phen-
ylhydrazine with aldehyde 11 which can be facilitated under acid
catalysis.25 Then intramolecular 1,3-dipolar cycloaddition of
azomethine imine B20,26 (formed in situ in presence of HCl) yields
tetracyclic pyrazolidine C, which is spontaneously oxidized to pyr-
azolopyrroloindole 1227 (Scheme 4).
conditions for the synthesis of pyrazolopyrroloindole 12a, we
choose (E)-methyl 2-((2-formyl-3-methyl-1H-indol-1-yl) methyl)
-3-phenyl-acrylate 11a as a model substrate and performed the
reaction with phenylhydrazine (Table 1).
Initially, when we treated 11a with PhNHNH2/PhNHNH2ÁHCl in
the presence of AcOH/water (1:3) as a solvent system at various
temperatures by conventional/microwave/ultrasound heating, it
resulted in low to moderate yields of the desired product 12a
(Table 1, entries 1–6). A drastic reduction in the reaction time
was observed under microwave irradiation (Table 1, entries 2
23
and 4). Utilization of Lewis acids like BF3Á(OEt)3 and iodine,24
After having successfully developed the methodology, we were
keen to examine the feasibility of a sequential one-pot protocol for
which are known for the synthesis of pyrazole have failed to give
Me
Me
N
CHO
N
N
N
Ph
CO2Me
MeO2C
Ar
11
Ar
12
PhNHNH2/HCl
autoxidation
Me
Ph
Me
H
H
N
N
N
H
N
N
N Ph
CO2Me
MeO2C
Ar
A
Ar
Ph
N
H
N
Me
C
[3+2]
cycloaddition
HCl
Ar
N
CO2Me
azomethine imine B
Scheme 4. Plausible reaction mechanism for the synthesis of pyrazolo-pyrroloindole 12 from aldehyde 11.

3068
A. H. Shinde et al. / Tetrahedron Letters 55 (2014) 3064–3069
Table 3
References and notes
One-pot synthesis of [a]-annelated pyrazolopyrrolo-indoles 12a,b
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Me
Sequential one-pot
Me
, DMF/NaH, 0 oC, rt
POCl3/DMF, 60 o
1)
2)
N
N
N
9
C
N
H
MeO2C
PhNHNH2/HCl,
3)
EtOH, µw, 80 oC, 1h
8
R
N
12
Me
Me
Me
N
N
N
N
N
N
Ph
N
Ph
N
Ph
Br
MeO2C
MeO2C
12a
MeO2C
12j
12i
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27% (32%)
24% (31%)
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N
N
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12n
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20% (27%)
25% (26%)
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We have successfully developed a metal-free, facile intramolec-
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tetracyclic angularly fused [a]-annelated pyrazolopyrroloindoles
containing an all carbon quaternary center at the ring fusion by
using microwave irradiation. The important features of this proto-
col are rapid access to biologically relevant complex heterocyclic
scaffolds, wide substrate scope, and good yields. In addition, a
sequential one-pot synthesis of pyrazolopyrroloindole scaffolds
featuring concurrent construction of two rings with two C–C, three
C–N bond formations in good yields by avoiding tedious work-up
and isolation of intermediates has been developed. Further, studies
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Acknowledgments
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Financial support by the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, is gratefully acknowledged.
A.H.S. and V.C. thank UGC, New Delhi, India, for the award of
research fellowship.
Supplementary data
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26. Heating intermediate A (prepared separately) in absence of HCl failed to give
required product 12. However, heating in presence of HCl, resulted in product
12 with good yield, suggesting the role of HCl in the formation of azomethine
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