Highly efficient regioselective synthesis of pyrroles via a tandem enamine formation-Michael addition-cyclization sequence under catalyst- and solvent-free conditions

Article abstract of DOI:10.1039/c5gc00365b

A convenient catalyst-free, three-component procedure was developed for the synthesis of tetrasubstituted pyrroles under solvent-free conditions and in green solvents glycerol, PEG-200 and water. A sequential enamine-formation, Michael addition and intram

Full text of DOI:10.1039/c5gc00365b

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Highly efficient regioselective synthesis of pyrroles via
a tandem enamine formation-Michael addition-
cyclization sequence under catalyst- and solvent-free
conditions
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Thavaraj Vivekanand,a Perumal Vinoth,a B. Agieshkumar,b Natarajan Sampath,a
Arumugam Sudalai,c J. Carlos Menéndez,d and Vellaisamy Sridharan*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A convenient catalystꢀfree, threeꢀcomponent procedure was developed for the synthesis of
tetrasubstituted pyrroles under solventꢀfree conditions and in green solvents glycerol, PEGꢀ200
and water. A sequential enamineꢀformation, Michael addition and intramolecular cyclization of
primary amines, 1,3ꢀdicarbonyl compounds and isatinꢀderived Michael acceptors afforded 3ꢀ
(1Hꢀpyrrolꢀ3ꢀyl)indolinꢀ2ꢀones in excellent yields. In this simple oneꢀpot transformation the
requirement of column chromatography purification of the products was completely avoided.
Besides, the method is highly environmentally benign and atomꢀeconomical, and the only side
product of this reaction was two molecules of water. A comparative study for the four
developed conditions showed that the solventꢀfree condition was superior regardless of the
nature of the starting materials, and the green solvents were effective for alkyl and
benzylamines affording higher yields compared to arylamines. The preliminary in vitro
cytotoxic studies of a representative compound against Ehrlich’s ascites carcinoma (EAC)
tumor cells showed significant activity with a CTC50 value of 15.64 µM.
Introduction
The majority of natural and synthetic drugs, agrochemicals and other
biologically significant molecules are heterocyclic compounds,
predominantly nitrogen heterocycles, as evident that the majority of
top ten bestꢀselling brand name drugs, headed by the antipsychotic
aripiprazole (Abilify®) and the antiulcer esomeprazole (Nexium®)
contain at least one heterocyclic ring, and most of them are nitrogen
heterocycles.1 In particular, pyrrole is one of the simplest nitrogen
heterocycles and a very significant structural motif found in
numerous biologically significant compounds including the marine
natural compounds lamellarins 1 and lukianols 2.2 Moreover, pyrrole
is the key structural fragment of porphyrins, corrins and chlorins
found in, respectively, heme, vitamin B12 and chlorophyll. Besides, a
large number of pyrrole derivatives serve as potential drugs for many
diseases represented by the multiꢀtargeted receptor tyrosine kinase
inhibitors sunitinib 3a and toceranib 3b and the nonꢀsteroidal antiꢀ
inflammatory drug zomepirac 4 (Fig. 1).3 Other notable pyrroleꢀ
derived drugs include the topꢀselling cholesterolꢀlowering agent
atorvastatin, the anticancer drug tallimustine, the anthelmintic agent
pyrvinium and the antiꢀinflammatory drug tolmetin among many
others. Additionally, pyrroleꢀderived compounds are also known to
exhibit remarkable biological activities including antitumoral,4,5 antiꢀ
HIV,6 antibacterial,7 antifungal,8 antimalarial,9 antioxidant10 and
several others. In addition to biological significance pyrroles have
found broad application in organic synthesis as building blocks and
in materials science. Similarly oxindoles have drawn much
Fig.
compounds.
1. Representative pyrrole natural products and bioactive
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o
interest owing to their versatile pharmacological activities.11 2). The reaction rate was increased at elevated temperature (70 C)
Consequently, we envisioned to synthesize tetrasubstituted pyrroles without significantly improving the yield (entry 3). Addition of CAN
o
bearing an oxindole moiety, anticipating added biological activities, catalyst (10 mol%) reduced the reaction time to 3 h at 25 C with
and to perform preliminary cytotoxicity studies.
almost identical yield.23 In order to make the protocol greener,
The fundamental assets of an ideal synthesis, defined by Wender subsequently, we optimized the reaction conditions in readily
and coꢀworkers, include ready and cheap availability of starting available green solvents glycerol, PEGꢀ200, lactic acid and water. At
o
materials, high conversion and yield, simple, safe, often oneꢀpot, 25 C, in glycerol, the reaction was completed only after 14 hours
environmentally friendly operation, step and atom economy.12 In allowing 81% of the product (entry 5). It is likely that the poor
contemporary organic synthesis, the construction of complex solubility of compound 7a and high viscosity of the solvent are
molecules starting from simple and readily available materials, by responsible for the diminished reaction rate. Change of solvent
creating molecular diversity and complexity by means of the quantity neither decreased the reaction time nor improved the yield
generation of several bonds and rings in a single operation, is an (entries 6 and 7). Intriguingly, the reaction rate was increased manyꢀ
essential and challenging task. Oneꢀpot, multiꢀbond forming fold at elevated temperatures; indeed, the reaction was completed
processes, including multicomponent13 and domino reactions,14 are just in one hour affording 86% of the product at 70 oC (entries 8 and
the best choice to attain atom and step economy and thus to develop 9).
ideal synthetic procedures for complex molecules. In the past two
decades synthetic chemists have shown significant interest in the
development of environmentally friendly organic processes
involving green chemistry that comprises the use of green solvents,
catalysts and techniques including microwave and ultrasonic
synthesis etc.15,16 The development of solventꢀfree protocols remains
the most promising approach for environmentally friendly organic
synthesis avoiding the use of toxic solvents and minimizing waste
generation despite the difficulties often associated with their largeꢀ
scale efficacy owing to the physical properties of the starting
materials and nature of the reactions.17 On the other hand, the use of
readily available green solvents including water, glycerol,
polyethylene glycol and lactic acid would overcome the drawbacks
of the solventꢀfree reactions.18 From the green chemistry point of
view, the ideal reaction would be one involving the exclusion of
catalysts19 and column chromatography for purification.
Results and Discussion
With all these points in mind, we envisioned to develop an efficient
green protocol for the synthesis of 3ꢀ(1Hꢀpyrrolꢀ3ꢀyl)indolinꢀ2ꢀones
8 comparing solventꢀfree conditions with the use of the green
solvents glycerol, PEGꢀ200 and water, starting from readily
available primary amines 5, 1,3ꢀdicarbonyl compounds 6 and isatinꢀ
derived Michael acceptors 7 in the absence of any catalyst. βꢀ
Enaminone intermediates generated from various precursors are
known to undergo regioselective Michael additions with compounds
Scheme 1. Reactivity of (E)ꢀ3ꢀ(2ꢀoxoꢀ2ꢀarylethylidene)indolinꢀ2ꢀone 7
7 followed by regioselective intramolecular cyclization to afford
diverse products depending on the nature of the starting materials
(Scheme 1). For instance, the enaminones derived from arylamines
and cyclic 1,3ꢀdiketones afforded indolo[2,3ꢀb]quinolines 9 in the
presence of base under microwave irradiation (Scheme 1A).20 On the
other hand Alizadeh and Mokhtari reported the synthesis of spiroꢀ
indolineꢀ3,4'ꢀpyridines 10 starting from enamines derived from
amines and acyclic 1,3ꢀdicarbonyl compounds and in situ generated
7 (Scheme 1B).21 Nevertheless, we reinvestigated the structural
elucidation of their products and confirmed that they are pyrroles 8
and not the reported spiroꢀindolineꢀ3,4'ꢀpyridines 10 (vide infra).
The third type of reactivity of enamines, generated in situ from
arylamines and acetylenedicarboxylates, and compounds 7 involves
the formation of 3ꢀ(1Hꢀpyrrolꢀ3ꢀyl)indolinꢀ2ꢀones 8 under acidic
conditions (Scheme 1C).22
In spite of this diverse reactivity of enaminones we started our
optimization studies by using butylamine 5a (0.65 mmol), ethyl
acetoacetate 6a (0.5 mmol) and compound 7a (0.5 mmol) under
various reaction conditions (Table 1). At the outset, we carried out
the reaction in ethanol at 25 oC in the absence of any catalyst. To our
delight, 64% of pyrrole 8a was obtained in two hours (entry 1) and at
elongated reaction time (7 h) the yield was improved to 80% (entry
with ꢀenaminones
β
A similar trend was observed in PEGꢀ200, however, it took
two hours to allow the maximum yield of 84% at 70 oC (entries
11ꢀ15). With an aim to achieve maximum yield at ambient
temperature, we employed a few common Lewis acids as
catalysts. Although the use of InCl3, Sc(OTf)3, Yb(OTf)3 and
CAN at ambient temperature increased the rate of the reaction
notably, the yield was not improved remarkably (entries 16ꢀ19).
InCl3 was the most effective to afford 78% yield in 5 h.
Replacement of glycerol or PEGꢀ200 with another green
solvent, namely lactic acid, was inefficient at 25 C, furnishing
only 21% yield even after 15 h; nonetheless, the yield was
increased to 72% at 70 C, although a longer reaction time was
needed (entries 20 and 21). After identifying suitable reaction
conditions in glycerol and PEGꢀ200, our attention turned
towards the use of the ideal green solvent i.e. water. It is
apparent from entries 22ꢀ24 that water was the best solvent to
o
o
o
this point, as the maximum yield of 92% was obtained at 70 C
in one hour. Here again the addition of a Lewis acid played no
significant role at 25 oC (entry 25). Finally, as the greenest
2 | J. Name., 2012, 00, 1-3
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Table 1. Reaction Optimizationa
arylamines (
o
ꢀ,
m
ꢀ and
p
ꢀsubstituted) bearing electronꢀdonating
and withdrawing substituents and benzylamine (entries 1ꢀ8).
Gratifyingly, irrespective of the nature of the amines, our
solventꢀfree conditions afforded the products in excellent yields
(up to 93%). However, the aliphatic and benzylamines reacted
in higher rates than that of the aromatic ones in all the three
green solvents (entries 4, 7 and 8). The lower yields and longer
reaction times could be attributed to the reactivity of the
arylamines in the enamine formation step compared to the
aliphatic amines as evidenced by the fact that the electronꢀrich
arylamine afforded relatively higher yields than that of
electronꢀdeficient analog (entries 7 and 8). It is also apparent
that the rate of the reaction was slow for amino alcohols both in
PEGꢀ200 and water (entries 2 and 3).
S.
No.
1
2
Solvent
Catalyst
Temp.
(oC)
25
Reaction
time (h)
2
7
Yield of
8a (%)b
64
EtOH
EtOH
ꢀ
ꢀ
25
80
The reaction also tolerated the bromoꢀ and methoxyꢀ
substituents on the oxindole moiety, and the reaction times and
yields were similar to those observed for unsubstituted system
3
4
EtOH
EtOH
ꢀ
70
25
25
25
25
50
70
25
25
25
25
50
70
25
25
1
3
14
14
14
3
82
79
81
69
71
82
86
82
85
77
83
79
84
78
74
71
85
21
72
77
90
92
82
CAN
ꢀ
ꢀ
ꢀ
ꢀ
-
CAN
ꢀ
ꢀ
ꢀ
ꢀ
-
InCl3
Sc(OTf)3
Yb(OTf)3 25
CAN
ꢀ
ꢀ
ꢀ
ꢀ
5
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
PEGꢀ200
PEGꢀ200
PEGꢀ200
PEGꢀ200
PEG-200
PEGꢀ200
PEGꢀ200
PEGꢀ200
PEGꢀ200
Lactic acid
Lactic acid
H2O
6c
(entries 9ꢀ12). Similar to
βꢀketoesters, βꢀdiketones were also
7d
effective to afford the products under solventꢀfree conditions
(entries 13ꢀ15). Here again, lower yields and higher reaction
times were observed in green solvents for arylamines (entry
13). In the case of 1ꢀphenylbutaneꢀ1,3ꢀdione, only 73% yield
was obtained even after 15 hours under solventꢀfree conditions,
and the other three reaction conditions did not show any
8
9
1
10
11
12c
13d
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
10
17
17
17
5
2
5
8
8
13
15
9
13
2
1
10
6
2
improvement (entry 16). Additionally, the Nꢀbenzyl substituted
pyrrole derivative 8q was also prepared under optimized
conditions in good yield (entry 17). Finally, the role of the
nature of the aryl substituents on substrate
7 was investigated.
We introduced four different aryl units including electronꢀrich
and deficient aryls, heteroaryl and naphthyl, and no significant
difference in reactivity was observed under neat conditions
(entries 18ꢀ25). Substrates bearing methylꢀ and chloroꢀ
25
25
70
25
50
70
25
50
70
100
H2O
H2O
H2O
Neat
Neat
Neat
substituents reacted smoothly with alkyl and arylamines, and
βꢀ
-
ketoesters to afford 3ꢀ(1Hꢀpyrrolꢀ3ꢀyl)indolinꢀ2ꢀones in high
8
CAN
yields under all four optimized conditions (entries 18ꢀ21). In
the case of 2ꢀthienylꢀ and 2ꢀnaphthylꢀsubstituted analogues,
good yields were obtained under solventꢀfree conditions,
however, the green solvent conditions were not equally
effective (entry 22). A systematic comparison led to a
conclusion that the use of solventꢀfree conditions is superior to
ꢀ
-
ꢀ
89 (78)e
91
88
1
a Reaction conditions: unless otherwise noted, all reactions were carried
out with 5a (0.65 mmol, 1.3 equiv), 6a (0.5 mmol, 1 equiv) and 7a (0.5
mmol, 1 equiv) in 3 mL solvent. b Isolated yield. 1.5 mL of solvent
c
d
e
was used. 5 mL of solvent was used. Yield in parenthesis was the other methods affording high yields with alkyl, benzyl and
obtained from the reaction at 25 oC with occasional grinding for 15 h.
arylamines. On the other hand, green solvent conditions are
effective for alkyl and benzylamines.
possible option, we carried out the reaction under catalystꢀ and
solventꢀfree conditions. To our surprise, the reaction progressed
efficiently to afford 89% of the product in a span of six hours at
o
50 C (entry 26). As shown in entries 27 and 28, a further
increase of temperature reduced the reaction time and improved
o
o
the yield (70 C, 2 h, 91% and 100 C, 1 h, 88%). The reaction
was also carried out at room temperature under neat conditions
with occasional grinding to afford 78% product after 15 h
(entry 26). It should be highlighted that the purification of the
products was achieved through simple crystallization in
ethanol, without use of column chromatography, in all the four
developed conditions. It is also worth mentioning that the
reaction was completely regioselective and the competitive
regioisomeric products indolo[2,3ꢀb]quinolines 9 or the spiroꢀ
indolineꢀ3,4'ꢀpyridines 10 were not obtained in any case.
With optimized conditions in hand (glycerol, PEGꢀ200,
water or solventꢀfree, 70 oC), we explored the scope and
limitations of the threeꢀcomponent protocol, and the results are
summarized in Table 2. The reaction showed a broad scope and
Fig. 2. ORTEP diagram of compound 8t
.
it allowed to employ a wide variety of primary amines
5
including alkyl amines, amino alcohols, naphthylamine,
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Table 2. Synthesis of 3ꢀ(1Hꢀpyrrolꢀ3ꢀyl)indolinꢀ2ꢀones 8a
S.
Product 8
Neat condition
Glycerol
PEGꢀ200
Water
No.
Reaction
time (h)
2
5
5
5
2
3
2
3
3
3
2
2
3
3
4
15
2
4
3
2
4
2
1
4
3
2
5
18
18
Yield
(%)b
91 (84)c
88
83
93
89
89
78
73
87
91
77
81
84
74
79
73
86
89
75
83
79
80
78
63
Reaction
time (h)
Yield
(%)b
86
85
83
51
81
ꢀ
67
57
80
87
ꢀ
Reaction
time (h)
2
4
4
10
1
Yield
(%)b
84
82
80
54
83
ꢀ
71
56
84
89
ꢀ
Reaction
time (h)
Yield
(%)b
92
75
ꢀ
59
85
ꢀ
65
58
79
83
ꢀ
1
2
3
4
5
6
7
8
R2 = H, R5 = OEt, R4 = nBu, 8a
R2 = H, R5 = OEt, R4 = ꢀ(CH2)2OH, 8b
R2 = H, R5 = OEt, R4 = ꢀ(CH2)3OH, 8c
R2 = H, R5 = OEt, R4 = Ph, 8d
R2 = H, R5 = OEt, R4 = Bn, 8e
R2 = H, R5 = OEt, R4 = 1ꢀnaph, 8f
R2 = H, R5 = OEt, R4 = 4ꢀMeC6H4, 8g
R2 = H, R5 = OEt, R4 = 4ꢀClC6H4, 8h
R2 = Br, R5 = OEt, R4 = nBu, 8i
R2 = Br, R5 = OEt, R4 = Bn, 8j
R2 = OMe, R5 = OEt, R4 = nBu, 8k
R2 = OMe, R5 = OEt, R4 = Ph, 8l
R2 = H, R5 = Me, R4 = Ph, 8m
R2 = H, R5 = Me, R4 = 4ꢀClC6H4, 8n
R2 = Br, R5 = Me, R4 = 1ꢀnaph, 8o
R2 = H, R5 = Ph, R4 = Ph, 8p
1
1
1
10
1
ꢀ
10
10
1
1
ꢀ
1
8
ꢀ
10
1
ꢀ
10
10
1
1
ꢀ
ꢀ
10
10
1
1
ꢀ
ꢀ
8
ꢀ
ꢀ
15
10
1
ꢀ
1
ꢀ
10
ꢀ
ꢀ
ꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26d
27e
28f
29g
ꢀ
8
ꢀ
ꢀ
66
ꢀ
ꢀ
78
ꢀ
ꢀ
8
ꢀ
ꢀ
69
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
15
10
1
ꢀ
1
ꢀ
10
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
50
58
83
ꢀ
78
ꢀ
65
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
54
45
79
ꢀ
75
ꢀ
63
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
22
26
15
10
1
ꢀ
2
ꢀ
10
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
55
55
80
ꢀ
74
ꢀ
59
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
R3 = Ph, R1 = Bn, R4 = Ph, 8q
R3 = 4ꢀMeC6H4, R1 = H, R4 = nBu, 8r
R3 = 4ꢀMeC6H4, R1 = H, R4 = 3ꢀMeC6H4, 8s
R3 = 4ꢀClC6H4, R1 = H, R4 = Bn, 8t
R3 = 4ꢀClC6H4, R1 = H, R4 = Ph, 8u
R3 = 2ꢀthienyl, R1 = H, R4 = Ph, 8v
R3 = 2ꢀthienyl, R1 = H, R4 = 2ꢀMeC6H4, 8w
R3 = 2ꢀnaph, R1 = H, R4 = Ph, 8x
R3 = 2ꢀnaph, R1 = H, R4 = ꢀ(CH2)3OH, 8y
R3 = Me, R1 = H, R4 = nBu, 8z
R3 = Me, R1 = H, R4 = Ph, 8aa
8ab
74
78
ꢀ
ꢀ
18
18
81
8h
8ac
10h
ꢀ
ꢀ
ꢀ
ꢀ
a
Reaction conditions: unless otherwise noted, all reactions were carried out with
arylamines), (0.5 mmol, 1 equiv) and
(0.5 mmol, 1 equiv) under solventꢀfree conditions or in 3 mL of solvent at 70 oC. b Isolated yield. c Yield
in parenthesis refers to the reaction between isolated enaminone
rotamers with 1:0.68 ratio was obtained. f Two rotamers with 1:0.23 ratio was obtained. g Two rotamers with 1:0.37 ratio was obtained. h Unreacted
starting material was recovered.
5 (0.65 mmol, 1.3 equiv for alkylamines; 0.5 mmol, 1 equiv for
6
7
d
e
A
and compound 7a
.
Two rotamers with 1:0.7 ratio was obtained. Two
7
A detailed spectral analysis of the synthesized compounds not the quaternary spiro carbon from DEPT experiments.
proved that they are pyrroles and not the spiro compounds 10 Finally, the structure was unequivocally assigned by single
Thus, the singlet at 4.11 ppm in proton NMR of compound 8a crystal Xꢀray analysis of compound 8t24 (Fig. 2). It is also
8
.
crucial to mention that we have also synthesized a previously
reported compound (8e) and carried out a systematic structural
analysis and proved that the structure was wrongly assigned as
can be attributed to the Hꢀ3 of the oxindole moiety. This
δ
value is too low to account for the olefinic hydrogen of the
dihydropyridine of the spiro compound. Moreover the Cꢀ3
carbon at 45.1 ppm is confirmed as the Cꢀ3 methine carbon and
the spiro compound 10 instead of pyrrole 8 21
Another
.
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interesting structural feature of these compounds is their that Shanthi and Perumal have reported a mechanistically
tendency to exist as conformer mixtures owing to restricted different (Michael addition/PaalꢀKnorr condensation), InCl3ꢀ
rotation around the pyrroleꢀoxindole bond. For most of our catalyzed procedure for the synthesis of related compounds
compounds (R3 = Ph) the rotamer ratio is ca. 95:5. In the case albeit with a limited substrate scope, since it is restricted only to
of compounds 8z and 8aa (R3 = Me) the rotamer ratios were ammonium acetate.26
1:0.7 and 1:0.68 respectively, and for pyrroles derived from
A representative 3ꢀ(1Hꢀpyrrolꢀ3ꢀyl)indolinꢀ2ꢀone derivative
cyclic 1,3ꢀdiketones (8ab and 8ac) 1: 0.23 and 1:0.37 rotameric 8a was evaluated for in vitro cytotoxicity against Ehrlich’s
ratios were observed. Computational studies agree well with ascites carcinoma (EAC) tumor cells using tryphan blue
these observations, since both possible conformations of the exclusion method. The compound induced 100% cell death at a
compounds arising from the methyl ketone have almost concentration of 200 µg/mL with a CTC50 of 15.64 µM (Table
3). With this encouraging preliminary result, screening of other
identical energies (ꢀ
E 0.09 kJ.molꢀ1), while for the compounds
where R3 = Ph there is a difference of 1.8 kJ/mol that explains
why almost a single compound is observed.
pyrroles
8 bearing a wide range of substitutions are under
investigation to identify a potential lead compound for an
antitumor drug discovery program. Studies to understand the
mechanism of the cytotoxic action will also be undertaken.
The formation of pyrrole
8 can be visualized through an
enamine formationꢀMichael additionꢀintramolecular cyclization
domino sequence. The initial reaction between primary amines
Table 3. Cytotoxicity of compound 8a against EAC tumor cells
5
and 1,3ꢀdicarbonyl compounds
6
should afford the enaminone
. Successive regioselective Michael addition of
to compounds followed by regioselective
intermediate
enaminone
A
Compound
Conc. (µg/mL)
% GIa
100
95
CTC50b (µM)
A
7
200
100
50
intramolecular cyclocondensation would furnish pyrroles
8
through the intermediacy of species
B and C after a final
8a
78
15.64
dehydration (Scheme 2).25 The regioselective Michael addition can
be explained by steric hindrance, and the regioselective
intramolecular cyclization is due to the competition between the
amide carbonyl and ketone carbonyl of intermediate B. In order to
confirm the proposed enaminone formationꢀinitiated
20
52
10
40
a
%
Growth inhibition (GI)
=
100−[{(CelltotalꢀCelldead)×100}/
b
Celltotal].
percentage growth.
CTC50 = Cytotoxic concentration inhibiting 50 % of
mechanism, we synthesized enaminone
butylamine and ethyl acetoacetate and treated it with compound
under optimized solventꢀfree condition. As expected, the
A starting from
Conclusions
7
product 8a was isolated in 84% yield, supporting the proposed
reaction sequence. The reaction was completely regioselective
and the other possible Michael additionꢀcyclization modes that
would afford indolo[2,3ꢀb]quinolines 9 and spiroꢀindolineꢀ3,4'ꢀ
pyridines 10 were not observed. It is relevant to mention here
We have developed an efficient, environmentally benign and
atomꢀeconomical procedure for the synthesis of 3ꢀ(1Hꢀpyrrolꢀ3ꢀ
yl)indolinꢀ2ꢀones from readily available starting materials. This
oneꢀpot, threeꢀcomponent reaction between primary amines,
1,3ꢀdicarbonyl compounds and isatinꢀderived Michael
acceptors afforded the products in high yields via an enamine
formationꢀMichael
additionꢀintramolecular
cyclization
sequence. The reaction was carried out under perfect green
conditions, since our protocol excludes the use of catalyst,
solvent and column chromatography. Some green solvents such
as glycerol, PEGꢀ200 and water were also effective for a set of
substrates to furnish the products in high yields. This simple
protocol allowed the formation of two CꢀN and a CꢀC bonds in
a single operation affording two molecules of water as the only
side product. One of the synthesized compounds showed
significant in vitro cytotoxicity against Ehrlich’s ascites
carcinoma (EAC) tumor cells.
Experimental
General
All reagents and solvents were purchased from commercial
suppliers (Avra, Alfa Aesar, SigmaꢀAldrich, CDH) and used
without further purification. The reactions were monitored by
thinꢀlayer chromatography using Merck silica gel 60 F254 and
visualized by UV detection or using pꢀanisaldehyde stain or
molecular iodine. Melting points were recorded on a melting
1
point apparatus in capillaries and are uncorrected. Hꢀ and 13Cꢀ
NMR spectra were recorded in CDCl3 or DMSOꢀd6 at room
temperature on a Bruker Avance 300 spectrometer operating at
300 MHz for H and 75 MHz for 13C. Chemical shifts (δ) are
expressed in ppm using TMS as internal standard and coupling
constants (J) are given in Hz. Infrared (IR) spectra were
1
Scheme 2. Mechanistic proposal involving enamine formationꢀMichael
additionꢀintramolecular cyclization sequence.
obtained in an Agilent Cary630 FTIR spectrometer with a
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Green Chemistry
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ARTICLE
Journal Name
DOI: 10.1039/C5GC00365B
diamond ATR accessory for solid and liquid samples, requiring 3.80 (q, J = 6.6 Hz, 2H), 4.31 (s, 1H), 6.81ꢀ6.97 (m, 3H), 7.11ꢀ7.39
no sample preparation and the major frequencies were reported (m, 11H), 10.38 (s, 1H); 13C NMR (DMSOꢀd6,75 MHz)* δ 12.4,
in cmꢀ1. Elemental analyses were determined at the CAI de 13.8, 45.1,58.2, 108.7, 109.9, 115.2, 120.8, 122.6, 127.1, 127.7,
Microanálisis Elemental, Universidad Complutense, by using a 128.1, 128.3, 128.5, 129.1, 130.6, 131.2, 135.6, 137.1, 137.2, 142.7,
Leco 932 CHNS combustion microanalyzer.
163.9, 178.3; Anal Calcd for C28H24N2O3: C, 77.04; H, 5.54; N,
6.42. Found: C, 76.76; H, 5.41; N, 6.30. *one sp2 carbon merged
with others.
General procedure for the synthesis of 3-(1H-pyrrol-3-
yl)indolin-2-ones 8
Ethyl 1-benzyl-2-methyl-4-(2-oxoindolin-3-yl)-5-phenyl-1H-
o
pyrrole-3-carboxylate (8e).21 Offꢀwhite solid, mp. 207ꢀ209 C; IR
(Neat): 3245, 2973, 1710, 1691, 1618, 1468, 1329, 1272, 1119 cmꢀ1;
1H NMR (DMSOꢀd6, 300 MHz) δ 0.82 (t, J = 6.9 Hz, 3H), 2.37 (s,
3H), 3.74 (q, J = 6.9 Hz, 2H), 4.20 (s, 1H), 5.14 (t, J = 2.7 Hz, 2H),
6.79ꢀ6.91 (m, 5H), 7.12 (t, J = 7.2 Hz, 1H), 7.23ꢀ7.41 (m, 8H), 10.34
(s, 1H); 13C NMR (DMSOꢀd6, 75 MHz)* δ 16.6, 19.0, 50.4, 52.4,
63.3, 113.9, 114.8, 120.2, 126.1, 127.7, 130.8, 132.3, 132.4, 133.8,
133.9, 135.6, 135.9, 136.6, 140.8, 142.0, 142.8, 147.9, 169.1, 183.6.
Anal Calcd for C29H26N2O3: C, 77.31; H, 5.82; N, 6.22. Found: C,
76.97; H, 5.77; N, 6.31. *one sp2 carbon merged with others.
Solvent-free conditions: All the reactions were carried out in a
clean and dry open RB flask fitted with a glass rod. To a
mixture of primary amine
arylamines: 0.5 mmol) and 1,3ꢀdicarbonyl compound
mmol) was added compound (0.5 mmol). The mixture was
5
(alkyl amines: 0.65 mmol,
6
(0.5
7
o
kept at 70 C with occasional stirring with the glass rod for the
time periods specified in Table 2. After completion of the
reaction, as indicated by TLC, the crude product was
precipitated by adding a minimum amount of 5:1 petroleum
etherꢀDCM mixture. The solid was recrystallized in ethanol to
afford the pure products
In green solvents: A mixture of primary amines
amines: 0.65 mmol, arylamines: 0.5 mmol) and 1,3ꢀdicarbonyl
8.
Ethyl
4-(5-bromo-2-oxoindolin-3-yl)-1-butyl-2-methyl-5-
5
(alkyl
phenyl-1H-pyrrole-3-carboxylate (8i). Offꢀwhite solid, mp. 184ꢀ
187 oC; IR (Neat): 3102, 2960, 1688, 1617, 1528, 1471, 1324, 1235,
1168, 1093 cmꢀ1; H NMR (DMSOꢀd6, 300 MHz) δ 0.70 (t, J = 6.9
1
compound
6 (0.5 mmol) in glycerol or PEGꢀ200 or H2O (3 mL)
was stirred at 25 oC. After 30 minutes, compound
7 (0.5 mmol)
Hz, 3H), 0.87 (t, J = 6.6 Hz, 3H), 1.05ꢀ1.13 (m, 2H), 1.41ꢀ1.46 (m,
2H), 2.54 (s, 3H), 3.75ꢀ3.82 (m, 4H), 4.16 (s, 1H), 6.75ꢀ6.90 (d, J =
8.1 Hz, 1H), 7.02 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.50ꢀ7.51 (m,
5H), 10.46 (s, 1H); 13C NMR (DMSOꢀd6, 75 MHz) δ 11.3, 13.2,
13.9, 19.1, 31.8, 43.4, 45.1, 58.0, 108.6, 110.5, 112.4, 114.0, 124.9,
128.5,128.7, 129.6, 130.6, 131.0, 134.0,135.1, 136.3, 142.1, 163.8,
177.8. Anal Calcd for C26H27Br N2O3: C, 63.03; H, 5.49; N, 5.65.
Found: C, 62.74; H, 5.55; N, 5.58.
o
was added and stirring was continued at 70 C for the time
periods specified in Table 2. After completion of reaction, as
indicated by TLC, the mixture was diluted with water (10 mL)
and extracted with ethyl acetate (3 x 5 mL). The combined
organic layer was washed with water followed by brine and
dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure and the residue was recrystallized in
ethanol to afford the pure products 8. In the case of aromatic
Ethyl
1-butyl-4-(5-methoxy-2-oxoindolin-3-yl)-2-methyl-5-
amines (entries 4, 7, 8, 13, 16, 17, 22, 28 and 29 Table 2),
where the reactions were incomplete, double recrystallization or
column chromatography was required to separate the products
completely from the unreacted starting materials, while under
solventꢀfree conditions all the products were purified by
recrystallization in ethanol except entries 28 and 29.
phenyl-1H-pyrrole-3-carboxylate (8k). Offꢀwhite solid, mp. 155ꢀ
157 oC; IR (Neat): 3175, 2980, 1692, 1621, 1543, 1338, 1251, 1144,
1
1079 cmꢀ1; H NMR (CDCl3, 300 MHz) δ 0.78 (t, J = 7.5 Hz, 3H),
0.97 (t, J = 7.2 Hz, 3H), 1.11ꢀ1.20 (m, 2H), 1.47ꢀ1.57 (m, 2H), 2.60
(s, 3H), 3.74 (s, 3H), 3.78 (m, 2H), 3.89 (q, J = 13.8 Hz, 2H), 4.39
(s, 1H), 6.51ꢀ6.76 (m, 3H), 7.42ꢀ7.52 (m, 5H), 8.01 (s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 6.6, 8.2, 8.9, 14.6, 27.4, 39.0, 41.0, 50.5,
53.5, 104.1, 104.2, 105.6, 105.7, 109.1, 123.3, 125.8, 126.0, 126.2,
128.0, 129.9, 130.3, 131.8, 150.2, 159.6, 175.4. Anal Calcd for
C27H30 N2O4: C, 72.62; H, 6.77; N, 6.27. Found: C, 72.33; H, 6.65;
N, 6.19.
Ethyl
1-butyl-2-methyl-4-(2-oxoindolin-3-yl)-5-phenyl-1H-
pyrrole-3-carboxylate (8a). Offꢀwhite solid, mp. 177ꢀ179 oC; IR
(Neat): 3142, 3084, 2959, 1689, 1619, 1528, 1469, 1262, 1195 cmꢀ1;
1H NMR (DMSOꢀd6, 300 MHz) δ 0.70 (t, J = 7.5 Hz, 3H), 0.81 (t, J
= 7.2 Hz, 3H), 1.05ꢀ1.12 (m, 2H), 1.40ꢀ1.47 (m, 2H), 2.56 (s, 3H),
3.71 (q, J = 7.5 Hz, 2H), 3.82 (t, J = 7.2 Hz, 2H), 4.11 (s, 1H), 6.76ꢀ
6.82 (m, 3H), 7.07ꢀ7.12 (m, 1H), 7.48ꢀ7.54 (m, 5H), 10.29 (s, 1H);
13C NMR (DMSOꢀd6, 75 MHz) δ 11.3, 13.2, 13.8, 19.1, 31.9, 43.4,
45.1, 57.8, 108.6, 108.9, 114.7, 120.8, 122.4, 126.9, 128.5, 128.7,
130.9, 131.0, 131.2, 134.8, 136.2, 142.7, 163.9, 178.4. Anal Calcd
for C26H28N2O3: C, 74.97; H, 6.78; N, 6.73. Found: C, 74.67; H,
6.69; N, 6.82.
3-(4-Acetyl-5-methyl-1-(naphthalen-1-yl)-2-phenyl-1H-
pyrrol-3-yl)-5-bromoindolin-2-one (8o). Pale brown solid, mp.
o
258ꢀ260 C; IR (Neat): 3281, 3054, 1721, 1632, 1473, 1405, 1367,
1
1206, 1104 cmꢀ1; H NMR (DMSOꢀd6, 300 MHz) δ 2.18 (s, 3H),
2.29 (s, 3H), 4.29 (s, 1H), 6.78ꢀ7.29 (m, 8H), 7.58ꢀ7.76 (m, 5H),
7.90ꢀ7.99 (m, 2H), 10.46 (s, 1H); 13C NMR (DMSOꢀd6, 75 MHz) δ
13.4, 30.4, 45.3, 110.6, 112.4, 114.9,119.9, 121.9, 122.1, 124.6,
125.4, 126.8, 127.7, 128.0, 128.3, 128.5, 129.3, 129.7, 130.1, 130.3,
130.6, 130.8, 133.4, 133.5, 133.6, 137.0, 142.8, 177.3, 192.6. Anal
Calcd for C31H23BrN2O2: C, 69.54; H, 4.33; N, 5.23. Found: C,
69.31; H, 4.28; N, 5.08.
Ethyl 1-(2-hydroxyethyl)-2-methyl-4-(2-oxoindolin-3-yl)-5-
phenyl-1H-pyrrole-3-carboxylate (8b). Pale brown solid, mp. 202ꢀ
204 oC; IR (Neat): 3469, 3241, 2952, 1709, 1663, 1618, 1467, 1273,
1
1192, 1124 cmꢀ1; H NMR (DMSOꢀd6, 300MHz) δ 0.80 (t, J = 6.9
Hz, 3H), 2.54 (s, 3H), 3.70 (q, J = 6.9 Hz, 2H), 3.89 (t, J = 6.3 Hz,
2H), 4.06 (s, 1H), 4.95 (t, J = 5.4 Hz, 2H), 6.76ꢀ6.82 (m, 3H), 7.06ꢀ
7.12 (m, 1H), 7.40ꢀ7.55 (m, 5H), 10.27 (s, 1H); 13C NMR (DMSOꢀ
d6, 75 MHz) δ 11.5, 13.8, 45.1, 46.1, 57.8, 59.9, 108.6, 108.8, 114.7,
120.7, 122.5, 126.9, 128.5, 128.7, 130.8, 131.2, 131.3, 134.9, 137.0,
142.6, 163.9, 178.4. Anal Calcd for C24H24N2O4: C, 71.27; H, 5.98;
N, 6.93. Found: C, 70.98; H, 5.90; N, 6.93.
3-(4-Benzoyl-5-methyl-1,2-diphenyl-1H-pyrrol-3-yl)indolin-
2-one (8p). Offꢀwhite solid, mp. 151ꢀ154 oC; IR (Neat): 3188, 3029,
1
1713, 1635, 1596, 1414, 1261, 1211, 1076 cmꢀ1; H NMR (DMSOꢀ
d6, 300 MHz) δ 1.71 (s, 3H), 4.33 (s, 1H), 6.65ꢀ6.72 (m, 2H), 6.92ꢀ
7.50 (m, 17H), 10.28 (s, 1H); 13C NMR (DMSOꢀd6, 75 MHz)* δ
13.5, 44.6, 108.7, 116.6,120.3, 120.6, 122.7, 125.2, 127.1, 127.5,
128.1, 128.3, 128.4, 129.1, 129.7, 130.2, 130.6, 131.8, 134.3, 137.3,
140.0, 142.9, 178.1,192.0. Anal Calcd for C32H24N2O2: C, 82.03; H,
5.16; N, 5.98. Found: C, 81.79; H, 5.26; N, 5.84. *two sp2 carbons
merged with others.
Ethyl
2-methyl-4-(2-oxoindolin-3-yl)-1,5-diphenyl-1H-
pyrrole-3-carboxylate (8d). Offꢀwhite solid, mp. 225ꢀ227 oC; IR
(Neat): 3151, 2981, 1698, 1620, 1471, 1262, 1139, 1099 cmꢀ1; H
1
NMR (DMSOꢀd6, 300 MHz) δ 0.85 (t, J = 6.6 Hz, 3H), 2.29 (s, 3H),
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 9
Journal Name
Green Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5GC00365B
Ethyl 4-(1-benzyl-2-oxoindolin-3-yl)-2-methyl-1,5-diphenyl-
1H-pyrrole-3-carboxylate (8q). Offꢀwhite solid, mp. 166ꢀ168 C;
2. For a review on pyrroleꢀderived marine alkaloids, see: H. Fan, J. Peng,
M. T. Hamann and J.ꢀF. Hu, Chem. Rev., 2008, 108, 264ꢀ267.
3. For selected reviews of pyrroles, see: (a) V. Estévez, M. Villacampa and
J. C. Menéndez, Chem. Soc. Rev., 2014, 43, 4633ꢀ4657; (b) A. V.
Gulevich, A. S. Dudnik, N. Chernyak and V. Gevorgyan, Chem. Rev.,
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Menéndez, Chem. Soc. Rev., 2010, 39, 4402ꢀ4421; (d) C. T. Walsh, S.
GarneauꢀTsodikova, A. R. HowardꢀJones, Nat. Prod. Rep., 2006, 23,
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Mikhaleva, Chem. Rev., 2004, 104, 2481ꢀ2506; (f) Sundberg, R. J. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Scriven, E.
F. V., Rees, C. W., Eds.; Elsevier: Oxford, 1996; Vol. 2, pp 119ꢀ206.
4. For reviews of antitumor pyrrole derivatives, see: (a) C. R. Prakash, P.
Theivendren and S. Raja, Pharmacol. Pharm., 2012, 3, 62ꢀ71; (b) N. R
Williamson, P. C. Fineran, T. Gristwood, S. R. Chawrai, F. J. Leeper and
G. P. Salmond, Future Microbiol., 2007, 2, 605ꢀ618; (c) V. M.
Dembitsky, T. A. Gloriozova and V. V. Poroikov, Mini-Rev. Med.
Chem., 2005, 5, 319ꢀ336.
o
IR (Neat): 3055, 2980, 1698, 1612, 1495, 1258, 1081 cmꢀ1; 1H NMR
(DMSOꢀd6, 300 MHz) δ 0.78 (t, J = 6.9 Hz, 3H), 2.30 (s, 3H), 3.60
(m, J = 6.9 Hz, 1H), 3.82 (m, J = 6.9 Hz, 1H), 4.52 (s, 1H), 4.79 (d,
J = 15.6 Hz, 1H), 5.15 (d, J = 15.6 Hz, 1H), 6.87ꢀ6.96 (m, 4H), 7.07
(d, J = 7.2 Hz, 3H), 7.14ꢀ7.19 (m, 2H), 7.25ꢀ7.34 (m, 5H), 7.36ꢀ7.44
(m, 5H); 13C NMR (DMSOꢀd6, 75 MHz) δ 12.6,13.9, 43.1, 44.6,
58.3, 108.2, 109.8, 115.0, 121.7, 122.5, 127.1,127.2, 127.4, 127.8,
128.2, 128.3, 128.5, 128.6, 129.1, 130.3, 130.5, 130.7, 135.8,136.8,
137.1, 137.2, 143.3, 163.8, 176.4. Anal Calcd for C35H30N2O3: C,
79.82; H, 5.74; N, 5.32. Found: C, 79.51; H, 5.60; N, 5.24.
Ethyl 2-methyl-4-(2-oxoindolin-3-yl)-1-phenyl-5-(thiophen-2-
yl)-1H-pyrrole-3-carboxylate (8v). Offꢀwhite solid, mp. 126ꢀ128
oC; IR (Neat): 3231, 3091, 2935, 1700, 1618, 1484, 1216, 1088 cmꢀ1;
1H NMR (DMSOꢀd6, 300 MHz) δ 0.87 (t, J = 6.9 Hz, 3H), 2.27 (s,
3H), 3.80 (q, J = 6.9 Hz, 2H), 4.46 (s, 1H), 6.83 (d, J = 7.8 Hz, 1H),
6.89 (d, J = 7.5 Hz, 1H), 6.95ꢀ7.02 (m, 3H), 7.15 (d, J = 7.5 Hz, 1H),
7.33ꢀ7.35 (m, 2H), 7.45ꢀ7.51 (m, 4H), 10.40 (s, 1H); 13C NMR
(DMSOꢀd6, 75 MHz)* δ 12.5, 13.8, 45.2, 58.6, 108.7, 110.1, 117.6,
120.9, 122.7, 127.0, 127.1, 128.0, 128.5, 128.8, 129.2, 129.9, 130.8,
131.0, 136.8, 138.1, 142.8, 163.6, 177.9. Anal Calcd for
C26H22N2O3S: C, 70.57; H, 5.01; N, 6.33; S, 7.25. Found: C, 70.39;
H, 4.93; N, 6.26; S, 7.15. *one sp2 carbon merged with others.
5. For selected references, see: (a) F. Basit, S. Cristofanon and S. Fulda,
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Acknowledgements
Financial support from the Department of Science and
Technology, DST (No. SB/FT/CSꢀ006/2013) and the Council
of Scientific and Industrial Research, CSIR (No.
02(0219)/14/EMRꢀII) is gratefully acknowledged. JCM
acknowledges financial support from MICINN, grant
CTQ2012ꢀ33272ꢀBQU.
7. (a) N. R. Williamson, H. T. Simonsen, R. A. Ahmed, G. Goldet, H.
Slater, L. Woodley, F. J. Leeper and G. P. Salmond, Mol. Microbiol.,
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6814,699, 1968; Chem. Abstr. 1969, 70, 87560z and 8b.
Notes and references
Organic Synthesis Group, Department of Chemistry, School of Chemical
a
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and Biotechnology, SASTRA University, Thanjavur 613401, Tamil Nadu,
India. Eꢀmail: vsridharan@scbt.sastra.edu, vesridharan@gmail.com
b
Department of Biotechnology, School of Chemical and Biotechnology,
SASTRA University, Thanjavur 613401, Tamil Nadu, India.
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c
Chemical Engineering and Process Development Division, National
Chemical Laboratory, Pashan Road, Pune 411 008, India.
d
Departamento de Química Orgánica y Farmacéutica, Facultad de
Farmacia, Universidad Complutense, 28040 Madrid, Spain.
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Electronic Supplementary Information (ESI) available: Starting material
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8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5GC00365B
Graphical abstract for Table of contents entry
An efficient three-component, catalyst-, solvent-, and column chromatography-free
procedure was developed for the synthesis of 3-(1H-pyrrol-3-yl)indolin-2-ones