Synthesis of Polyfunctionalized Pyrroles via Green Chemical Methods

Article abstract of DOI:10.1002/jhet.3022

Water was found to be an excellent solvent for the one-pot synthesis of tetrasubstituted pyrrole derivatives under ultrasound involving the standard Knoevenagel condensation followed by the Michael type reaction. A new catalyst free system, excellent atom

Full text of DOI:10.1002/jhet.3022

Month 2017
Synthesis of Polyfunctionalized Pyrroles via Green Chemical Methods
Ramakanth Pagadalaa,b
and Sreenivasa Anuguc
*
aDepartment for Management of Science and Technology Development, Ton Duc Thang University,
Ho Chi Minh City, Vietnam
bFaculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
cMedicinal Chemistry Division, GVK Biosciences Pvt Ltd, Hyderabad, Telangana 500076, India
*
E-mail: ramakanth.pagadala@tdt.edu.vn
Received July 8, 2017
DOI 10.1002/jhet.3022
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Water was found to be an excellent solvent for the one-pot synthesis of tetrasubstituted pyrrole derivatives
under ultrasound involving the standard Knoevenagel condensation followed by the Michael type reaction.
A new catalyst free system, excellent atom economy, ultrasound in water medium, short reaction times, good
yields (88–93%), and ease of workup make this protocol more attractive and economically viable. The resulting
substituted pyrroles are characterized by 1H and 13C NMR, elemental analysis, and mass spectral data.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
with conventional method [5]. This ultrasound involving
energy saving and minimal waste generation is widely
accepted as a green chemistry approach [6].
Because of the increasing concern over the usage of
toxic reagents and volatile organic solvents, the pursuit of
novel synthetic methods that use water, the universal and
ubiquitous solvent, as the solvent to minimize the organic
waste has been gaining the momentum in the past decade
[1]. On the other hand, one pot preparations of synthetic
building blocks involving domino sequences and
multicomponent reactions to achieve atom economy have
also attracted considerable attention. Among these
approaches, the use of ultrasonic energy for the activation
of chemical transformations proved to be a safe and eco-
friendly technique. The sonochemistry of multicomponent
reactions “on-water” is becoming the mainstay of
the green chemistry for the sustainable industrial
development [2]. The sonochemistry of an organic
reaction has three components, that is the chemical
system, acoustics, and the bubbles [3,4]. There is
considerable evidence for the hypothesis that rather than
the acoustic energy of the sound wave, it is the cavitation
energy (resulting from the microbubble formation) that
actually supplies the activation energy to the chemical
system to induce chemical transformation. An ultrasonic
vibration not only reduces the reaction time but also
provides clean products in good to excellent yields, while
avoiding expensive and toxic reagents when compared
Syntheses of nitrogen containing heterocyclic analogues
are of great importance because of their abundance in
various synthetic as well as natural products that show
interesting biological activities [7]. The constructions of
C─N bond containing aromatic compounds are some of
the most important transformations and often pose
significant challenges to the synthetic medicinal chemists
[8]. Pyrrole is a ubiquitous moiety present in many
bioactive natural products like vitamin B12, heme,
chlorophyll, and various pyrrole alkaloids. Despite many
classical methods to prepare substituted pyrrole
derivatives [9], novel and greener synthetic methods to
prepare the pyrroles [10] are being sought for the eco-
friendly industrial processes. The construction of nitrogen
containing heterocycles in aqueous media, in particular
those performed under ultrasonication method, offers a
viable alternative to the usage of caustic reagents and
volatile solvents. Consequently, the design of new
approaches to prepare the privileged pyrrole scaffolds
using water as the reaction medium constitutes a very
important challenge in green chemistry [11]. With the
increasing demand for the environmentally friendly
protocols and considering their wide range of
applications, we realized the scope to develop improved
© 2017 Wiley Periodicals, Inc.

R. Pagadala and S. Anugu
Vol 000
and environmentally benign synthetic methodologies for
the synthesis of substituted pyrrole derivatives. As part of
our continuing research, we have developed one such
method where the metal free, one-pot synthesis of
substituted pyrroles utilizes water as solvent and
ultrasound as the energy source [12]. These results have
further inspired us to explore the viability of this new
method for the construction of other heteroaromatic cores.
Breslow’s hydrophobic effect [13]. The advantages of this
method for the formation of 5a, in terms of green
chemistry, were established (Table 1, entry 7). With the
optimized reaction conditions in hand, we next examined
the substrate scope of this sonication method for the
synthesis of tetrasubstituted pyrroles starting with
reactants containing a variety of substitutions, and the
results are shown in Table 2. The protocol was proven to
be efficient regardless of the electronic effects of the
substituents present in the reactants.
RESULTS AND DISCUSSION
The synthesized tetrasubstituted pyrroles were fully
1
characterized by FTIR, H NMR, 13C NMR, and mass
Development of multicomponent reactions based on the
reactive isocyanide has become an important research area
in the recent times [12]. As part of our continuing research
aimed at the development of new methods for the value-
added, metal-free, eco-compatible, and diversity-oriented
syntheses of biologically important heterocycles, we
investigated a four-component reaction protocol for the
synthesis of highly functionalized pyrroles in water using
ultrasound irradiation under catalyst-free conditions for
the first time.
spectrometry. The IR spectra of the products showed
symmetrical and unsymmetrical NH2 stretching in the
region between 3372 and 3279 cmÀ1, and the CN
stretching vibration of the nitrile group appeared in the
region between 2203 and 2289 cmÀ1. The 1H NMR
spectra in DMSO showed one singlet signal around
δ = 8.79 because of the ─NH2 protons, and all the
compounds were further examined by 15N NMR
(GHSQC) to confirm the presence of the ─NH2 group in
their structure (Supplementary data).
To validate the use of sonication for the multicomponent
reactions, a four-component reaction of malononitrile (1),
aromatic aldehyde (2a), morpholine (3a), and 3,4-
dichlorophenyl isocyanide (4a), in water (Scheme 1) was
performed under sonication as well as silent method at
variable temperature, and the results are shown in Table 1.
When the reaction was carried out at 80°C, under silent
method using acetonitrile, EtOH and water as the solvent,
the product formation was observed, but in low to good
yields (Table 1, entries 5, 4, 1, and 8). No product
formation was observed when the same reaction was
conducted at room temperature under silent reaction
conditions (Table 1, entries 2, 3, and 7). The same reaction
was performed in water under ultrasound irradiation at
room temperature. Impressively, the sonication method
yielded the desired product (5a) selectively in 90% yield
(Table 1, entry 7). The success of this reaction under
ultrasonic irradiation, when compared with silent
conditions, can be attributed to the possible activation
energy supplied by the phenomenon of cavitation and
When piperidine (6) was used as reactant in place
of morpholine (3a), it furnished the corresponding
polysubstituted pyrrole (7) in 90% yield (Scheme 2).
When Isocyanocyclohexane (8) was used as reactant
instead of 3,4-dichlorphenyl isocyanide under ultrasonic
irradiation, polysubstituted pyrrole (9) was formed in
88% yield (Scheme 3). The plausible mechanism for the
formation of tetrasubstituted pyrroles is described in
Scheme 4. By virtue of having an active methylene group,
malanonitrile readily condenses with aryl aldehyde to form
arylidenemalononitrile as a Knoevenagel product [14],
which undergoes conjugate addition by the carbon terminus
of isocyanide [15]. In the absence of the added base, the
secondary amine present in the reaction may be acting as
base to abstract the highly acidic proton from the active
methylene group. The resulting nitrilium ion is attacked by
the nucleophilic amine, which further undergoes
intramolecular cyclization followed by tautomerization to
form the stable 5 membered aromatic ring (Scheme 4).
CONCLUSION
Scheme 1. Model Reaction (5a–j). [Color figure can be viewed at
wileyonlinelibrary.com]
In summary, we have disclosed an efficient and greener
procedure involving
a multicomponent reaction to
prepare substituted pyrroles using water as a solvent
under ultrasonic irradiation. The salient features of this
protocol are the simple experimental procedure, cost
effectiveness, and its applicability for the synthesis of a
diverse set of tetrasubstituted pyrrole derivatives. This
new protocol is also tolerant of various substituents and
their electronic effects. Further extension of this
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
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Table 1
Optimization of reaction conditions for the synthesis of Pyrrole derivatives.
Conventional
Sonication
Entry
Product no.
Solvent
Time (h)
Temp (°C)
Yield a(%)
Time (h)
Temp (°C)
Yielda(%)
c
c
c
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
CH3CN
CH3CN
EtOH
EtOH
MeOH
MeOH
H2O
2.0
7.0
8.0
4.0
80
rt
rt
69.0
b
1.5
rt
75
b
4.0
rt
59
c
c
c
80
46.0
c
c
c
5.0
80
38
c
c
c
4.0
rt
50
b
9.0
1.5
rt
80
2.0
rt
90
c
c
c
H2O
75
rt = room temperature
aIsolated yields.
bProducts were not found.
cReaction was not performed.
Table 2
Synthesis of pyrroles under ultrasound irradiation and conventional method.
Conventional
Sonication
a
Entry
Product no.
R
Time (h)
Yield (%)
Time (h)
Yield a(%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
4-OH
3-OH
3,4-OH
2-NO2
2-OCH3
2,4-OCH3
2-Br
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
75.0
67.0
69.0
64.0
72.0
74.0
70.0
78.0
69.0
73.0
2.0
1.5
2.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
90.0
92.0
89.0
90.0
88.0
92.0
89.0
93.0
90.0
91.0
2-F
2,4-Cl
10
5j
aIsolated yields.
Scheme 2. Construction of Polysubstituted Pyrrole 7. [Color figure can
Scheme 3. Construction of Polysubstituted Pyrrole 9. [Color figure can
be viewed at wileyonlinelibrary.com]
be viewed at wileyonlinelibrary.com]
purification. 1H NMR and 13C NMR spectra were
recorded at 25°C on a Bruker-Avance (Switzerland) (400
MHz) and Varian-Gemini (Switzerland) (100MHz)
ultrasound process in water media to access various
biologically important heterocyclics is in progress.
instrument
respectively, using TMS as internal
EXPERIMENTAL
standard. Chemical shifts are given in parts per million.
The FT-IR spectroscopy of samples was carried out on a
Perkin Elmer Precisely 100 FT-IR spectrometer in the
400–4000 cmÀ1 region. LCMS mass spectra were
General Remarks.
All chemicals used were reagent
grade and were used as received without further
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Pagadala and S. Anugu
Vol 000
Scheme 4. Plausible mechanism for the formation of Polysubstituted Pyrrole. [Color figure can be viewed at wileyonlinelibrary.com]
recorded on a MASPEC low-resolution mass spectrometer
operating at 70 eV. Elemental analyses were carried out
using a Perkin Elmer Perkin Elmer (Maryland, USA),
CHNS Elemental Analyzer model 2400. Melting points
were recorded on a hot stage melting point apparatus
Ernst Leitz, Wetzlar, Germany, and were uncorrected.
The ultrasonic assisted reactions are carried out in a
“Spectralab model UMC 20 Ultrasonic cleaner” with a fre-
quency of 40 kHz and a nominal power 250 W. All the re-
actions and the purity of products were monitored using
thin layer chromatography (TLC) on aluminum-backed
plates coated with Merck Kieselgel 60 F254 silica gel, visu-
alizing the spots under ultraviolet light and iodine chamber.
2-Amino-1-(2,4-dichlorophenyl)-5-morpholin-4-yl-4-phenyl-
1H-pyrrole-3-parbonitrile (5a). Off-white solid: m.p. 192–
1
193°C; H NMR (400 MHz, DMSO) δ = 3.58 (8H, t,
J = 5.0 Hz), 7.41–7.47 (7H, m), 7.82 (1H, s), 8.79 (2H, s,
NH2); 13C NMR (100 MHz, DMSO): δ 44.04, 65.86,
108.05, 113.98, 117.06, 119.23, 120.35, 122.99, 125.59,
129.47, 130.13, 130.54, 132.94, 135.07, 137.68, 140.68,
154.56; IR (KBr, cm À 1): 2203 (CN), 3275 (NH2); MS
(ESI), m/z = 436 (M + Na, 100%); Anal. Calcd
(C21H18Cl2N4O): C 61.03, H 4.39, N 13.56%. Found: C
61.09, H 4.47, N 13.62%.
2-Amino-1-(2,4-dichlorophenyl)-4-(4-hydroxyphenyl)-5-
morpholin-4-yl-1H-pyrrole-3-carbonitrile (5b).
Off-white
solid: m.p. 215–216°C; 1H NMR (400 MHz, DMSO)
δ = 3.58 (8H, t, J = 5.0 Hz), 7.35–7.62 (7H, m), 7.82 (1H,
s), 8.79 (2H, s, NH2); 13C NMR (100 MHz, DMSO): δ
44.04, 65.86, 115.37, 116.07, 116.28, 119.23, 120.35,
122.99, 126.61, 127.37, 129.40, 129.95 130.13, 130.53,
131.17, 140.68, 154.56; IR (KBr, cm À 1): 2226 (CN),
3274 (NH2); MS (ESI), m/z = 430 (M + 1, 100%); Anal.
Calcd (C21H18Cl2N4O2): C 58.75, H 4.23, N 13.05%.
General Procedure for the Synthesis of Pyrrole Derivatives
Under Silent Conditions (5a–j). A mixture of aldehyde
(2.0 mmol) and malononitrile (2.0 mmol) in water was
magnetically stirred for 15 min at room temperature prior
to the addition of morpholine (2.0 mmol) and 3,4-
dichlorophenyl isocyanide (2.0 mmol). The reaction
mixture was heated at 80°C for the mentioned reaction
times (Tables 2). The reaction progress was monitored
using TLC. After completion of the reaction as judged by
TLC, the reaction mixture was cooled to room
temperature and the precipitated product was filtered,
washed with water and EtOH, and dried under vacuum.
Found: C 58.82, H 4.28, N 13.07%.
2-Amino-1-(2,4-dichlorophenyl)-4-(3-hydroxyphenyl)-5-
morpholin-4-yl-1H-pyrrole-3-carbonitrile (5c).
Off-white
solid: m.p. 202–203°C; 1H NMR (400 MHz, DMSO)
δ = 3.58 (8H, t, J = 5.0 Hz), 7.40–7.45 (5H, m), 7.81 (1H,
s), 8.41 (1H, s), 8.79 (2H, s, NH2), 10.13 (1H, s, OH); 13
C
General Procedure for the Synthesis of Pyrrole Derivatives
in Aqueous Medium Under Ultrasound Irradiation (5a–j).
NMR (100 MHz, DMSO): δ 44.04, 65.86, 108.10, 113.15,
114.23, 116.04, 119.22, 120.35, 121.76, 122.01, 122.90,
130.12, 130.54, 130.57, 132.35, 140.67, 154.56, 157.81,
161.58; IR (KBr, cm À 1): 2242 (CN), 3276 (NH2); MS
A 100 mL conical flask was charged with aldehyde
(2.0 mmol), malononitrile (2.0 mmol), morpholine
(2.0 mmol), and 3,4-dichlorophenyl isocyanide (2.0 mmol)
in water. The reaction flask was placed in the ultrasonic
bath, where the level of the reaction mass is slightly lower
than the level of water in the bath, and irradiated at room
(ESI), m/z
= 430 (M + 1, 100%); Anal. Calcd
(C21H18Cl2N4O2): C 58.75, H 4.23, N 13.05%. Found: C
58.84, H 4.32, N 13.09%.
temperature (25°C
5) for the reported reaction times
2-Amino-1-(2,4-dichlorophenyl)-4-(3,4-dihydroxy phenyl)-5-
(Tables 2). The reaction progress was monitored using
TLC. The reaction temperature of the ultrasonic bath was
controlled manually by addition or removal of small
amounts of water. The precipitated products were filtered,
washed with water and EtOH, and then dried under vacuum.
morpholin-4-yl-1H-pyrrole-3-carbonitrile (5d).
Off-white
solid: m.p. 227–228°C; 1H NMR (400 MHz, DMSO)
δ = 3.58 (8H, t, J = 5.0 Hz), 7.41–7.47 (4H, m), 7.81
(1H, s), 7.82 (1H, s), 8.79 (2H, s, NH2); 13C NMR
(100 MHz, DMSO): δ 44.04, 65.86, 107.58, 110.19,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Green Chemical Methods
113.50, 116.11, 119.23, 120.35, 122.99, 127.01, 128.91,
130.13, 130.53, 132.70, 136.25, 138.15, 140.67, 141.70,
154.56; IR (KBr, cm À 1): 2289 (CN), 3274 (NH2); MS
(ESI), m/z = 446 (M + 1, 100%); Anal. Calcd
(C21H18Cl2N4O3): C 56.64, H 4.07, N 12.58%. Found: C
NH2); 13C NMR (100 MHz, DMSO): δ 44.04, 65.86,
112.64, 113.69, 116.43, 116.64, 119.23, 119.47, 120.35,
122.99, 125.35, 125.38, 129.14, 130.13, 130.54, 136.49,
136.58, 140.67, 154.56; IR (KBr, cm À 1): 2229 (CN),
3273 (NH2); MS (ESI), m/z = 432 (M + 1, 100%); Anal.
Calcd (C21H17Cl2FN4O): C 58.48, H 3.97, N 12.99%.
56.71, H 4.16, N 12.65%.
2-Amino-1-(2,4-dichlorophenyl)-5-morpholin-4-yl-4-(2-
nitrophenyl)-1H–pyrrole-3-carbonitrile (5e). Off-white solid:
m.p. 181–182°C; H NMR (400 MHz, DMSO) δ = 3.58
Found: C 58.56, H 3.99, N 13.08%.
2-amino-4-(2,4-dichlorophenyl)-1-(3,4-dichlorophenyl)-
5-morpholino-1H-pyrrole-3-carbonitrile (5j). Off-white solid:
1
1
(8H, t, J = 5.0 Hz), 7.41–7.47 (6H, m), 7.81 (1H, s), 8.79
(2H, s, NH2); 13C NMR (100 MHz, DMSO): δ 44.04,
65.86, 111.75, 113.06, 116.32, 119.23, 120.35, 122.99,
125.39, 127.11, 130.13, 130.41, 130.53, 133.33, 135.02,
140.68, 146.75, 149.99, 154.56; IR (KBr, cm À 1): 2240
(CN), 3275 (NH2); MS (ESI), m/z = 459 (M + 1, 100%);
Anal. Calcd (C21H17Cl2N5O3): C 55.04, H 3.74, N 15.28%.
Found: C 55.09, H 3.81, N 15.37%.
m.p. 205–206°C; H NMR (400 MHz, DMSO) δ = 3.58
(8H, t, J = 5.0 Hz), 7.42–7.47 (4H, m), 7.82 (1H, s), 7.82
(1H, s), 8.79 (2H, s, NH2); 13C NMR (100 MHz, DMSO):
δ 44.04, 65.86, 108.05, 110.19, 112.08, 115.40, 119.22,
120.35, 122.99, 125.12, 126.77, 129.47, 130.12, 130.54,
132.22, 135.31, 137.20, 140.68, 154.56; IR (KBr, cm À 1):
2230 (CN), 3272 (NH2); MS (ESI), m/z = 483 (M + 1,
100%); Anal. Calcd (C21H16Cl4N4O): C 52.31, H 3.34, N
2-Amino-1-(2,4-dichlorophenyl)-4-(2-methoxyphenyl)-5-
11.62%. Found: C 52.39, H 3.43, N 11.68%.
morpholin-4-yl-1H-pyrrole-3-carbonitrile (5f).
Off-white
2-Amino-1-(3,4-dichlorophenyl)-4-phenyl-5-(piperidin-1-yl)-
solid: m.p. 208–209°C; 1H NMR (400 MHz, DMSO)
δ = 3.42 (3H, s), 3.58 (8H, t, J = 5.0 Hz), 7.41–7.45 (6H,
m), 7.82 (1H, s), 8.79 (2H, s, NH2); 13C NMR (100 MHz,
DMSO): δ 44.03, 56.26, 65.86, 112.19, 113.29, 119.23,
120.37, 123.03, 124.37, 128.37, 128.39, 130.02, 130.08,
130.56, 131.37, 133.49, 133.93, 134.72, 135.93, 154.57; IR
(KBr, cm À 1): 2227 (CN), 3275 (NH2); MS (ESI),
m/z = 444 (M + 1, 100%); Anal. Calcd (C22H20Cl2N4O2): C
59.60, H 4.55, N 12.64%. Found: C 59.67, H 4.59, N 12.72%.
2-Amino-1-(2,4-dichlorophenyl)-4-(2,4-dimethoxy phenyl)-
1H–pyrrole-3-carbonitrile (5k). Off-white solid: m.p. 188–
189°C; H NMR (400 MHz, DMSO) δ = 1.43–1.58 (6H,
1
m), 2.60–2.83 (4H, m), 7.41–7.47 (7H, m), 7.82 (1H, s),
8.79 (2H, s, NH2); 13C NMR (100 MHz, DMSO): δ
26.92, 28.34, 54.65, 108.05, 113.98, 117.06, 119.23,
120.35, 122.99, 125.59, 129.47, 130.13, 130.54, 132.94,
135.07, 137.68, 140.68, 154.56; IR (KBr, cm À 1): 2203
(CN), 3279 (NH2); MS (ESI), m/z = 412 (M + 1, 100%);
Anal. Calcd (C22H20Cl2N4): C 64.24, H 4.90, N 13.62%.
Found: C 64.32, H 4.97, N 13.65%.
5-morpholin-4-yl-1H-pyrrole-3-carbonitrile (5g).
Off-white
2-Amino-1-cyclohexyl-5-morpholino-4-phenyl-1H-pyrrole-3-
solid: m.p. 233–234°C; 1H NMR (400 MHz, DMSO)
δ = 3.58 (8H, t, J = 5.0 Hz), 3.89 (3H, s), 3.90 (3H, s),
7.41–7.47 (4H, m), 7.81 (1H, s), 8.23 (1H, s), 8.79 (2H, s,
NH2); 13C NMR (100 MHz, DMSO): δ 44.04, 56.08,
56.26, 65.86, 98.26, 107.67, 113.09, 114.16, 115.23,
119.22, 120.35, 122.99, 130.12, 130.46, 130.53, 136.50,
140.67, 153.83, 154.56, 161.30, 166.77; IR (KBr,
cm À 1): 2222 (CN), 3275 (NH2); MS (ESI), m/z = 474
(M + 1, 100%); Anal. Calcd (C23H22Cl2N4O3): C 58.36, H
1
carbonitrile (5l).
Off-white solid: m.p. 195–196°C; H
NMR (400 MHz, DMSO) δ = 1.47–1.52 (2H, m), 1.90–
1.98 (4H, m), 2.46–2.95 (5H, m), 3.58 (8H, t,
J = 5.0 Hz), 7.32–7.48 (5H, m), 8.78 (2H, s, NH2); 13C
NMR (100 MHz, DMSO): δ 23.72, 27.56, 34.79, 42.8,
44.04, 65.87, 108.76, 117.06, 119.23, 122.99, 125.59,
129.47, 130.54, 132.94, 137.68; IR (KBr, cm À 1): 2213
(CN), 3275 (NH2); MS (ESI), m/z = 351 (M + 1, 100%);
Anal. Calcd (C21H26N4O): C 71.97, H 7.48, N 15.99%.
Found: C 71.99, H 7.57, N 16.04%.
4.68, N 11.84%. Found: C 58.47, H 4.78, N 11.89%.
2-Amino-4-(2-bromophenyl)-1-(2,4-dichlorophenyl)-5-morpholin-
4-yl-1H-pyrrole-3-carbonitrile (5h). Off-white solid: m.p. 196–
1
197°C; H NMR (400 MHz, DMSO) δ = 3.57 (8H, t,
Acknowledgments. The authors are grateful to the authorities of
Ton Duc Thang University, Ho Chi Minh City, Vietnam, and
management of GVK Biosciences, Hyderabad, India, for the fa-
cilities and encouragement to carry out this work.
J = 5.0 Hz), 7.76–7.84 (6H, m), 8.55 (1H, s), 8.79 (2H, s,
NH2); 13C NMR (100 MHz, DMSO): δ 44.03, 65.86,
112.19, 113.29, 119.23, 120.37, 123.03, 124.37, 128.37,
128.39, 130.02, 130.08, 130.56, 131.37, 133.49, 133.93,
134.72, 135.93, 154.57; IR (KBr, cm À 1): 2232 (CN),
3274 (NH2); MS (ESI), m/z = 493 (M + 1, 100%); Anal.
Calcd (C21H17BrCl2N4O): C 51.24, H 3.48, N 11.38%.
REFERENCES AND NOTES
[1] (a) Price, B. K.; Tour, J. M. J Am Chem Soc 2006, 128,
12899; (b) Barbaro, P.; Gonsalvi, L.; Guerriero, A.; Liguori, F. Green
Chem 2012, 14, 3211; (c) Alberto, E. E.; Braga, A. L.; Detty, M. R. Tet-
rahedron 2012, 68, 10476.
[2] (a) Hu, Y.; Zou, Y.; Wu, H.; Shi, V. Ultrason Sonochem 2012,
19, 264; (b) Benjamin, H. R.; Serge, Z.; Vishal, R.; Andrei, K. Y. Chem
Rev 2014, 114, 8323; (c) Marc, O. S.; Chao, J. L. Chem Soc Rev 2012,
Found: C 51.35, H 3.58, N 11.44%.
2-Amino-1-(2,4-dichlorophenyl)-4-(2-fluorophenyl)-5-morpholin-
4-yl-1H-pyrrole-3-carbonitrile (5i). Off-white solid: m.p. 198–
1
199°C; H NMR (400 MHz, DMSO) δ = 3.58 (8H, t,
J = 5.0 Hz), 7.41–7.47 (6H, m), 8.57 (1H, s), 8.79 (2H, s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Pagadala and S. Anugu
Vol 000
41, 1415; (d) Pagadala, R.; Maddila, S.; Jonnalagadda, S. B. Ultrason
Sonochem 2014, 21, 472; (e) Zou, Y.; Wu, H.; Hu, Y.; Liu, H.;
Zhao, X.; Ji, H.; Shi, D. Ultrason Sonochem 2011, 18, 708.
[3] Margulis, M. A. Ultrasonics 1992, 30, 152.
[4] Martin-Aranda, R. M.; Ortega-Cantero, E.; Rojas-Cervantes,
M. L.; Vicente-Rodriguez, M. A.; Banares-Munoz, M. A. Catal Lett
2002, 84, 201.
[5] Yu, T.; Wang, Z.; Mason, T. J Ultrason Sonochem 2004, 11, 95.
[6] (a) Tabassum, S.; Govindaraju, S.; Khan, R.; Pasha, M. A.
Ultrason Sonochem 2015, 24, 1; (b) Cintas, P.; Luche, J.-L. Green Chem
1999, 1, 115.
(e) Madabhushi, S.; Vangipuram, V. S.; Reddy Mallu, K. K.;
Chinthala, N.; Beeram, C. R. Adv Synth Catal 2012, 354, 1413; (f) Zhang,
Z. H.; Li, J. J.; Li, T. S. Ultrason Sonochem 2008, 15, 673.
[10] Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F. Chem Rev 2008,
108, 264.
[11] (a) Moseley, J. D.; Kappe, C. O. Green Chem 2011, 13, 794;
(b) Ke, F.; Qu, Y.; Jiang, Z.; Li, Z.; Wu, D.; Zhou, X. Org Lett 2011, 13,
454; (c) Ma, N.; Jiang, B.; Zhang, G.; Tu, S.-J.; Wever, W.; Li, G. Green
Chem 2010, 12, 1357; (d) Ding, Q.; Cao, B.; Liu, X.; Zong, Z.; Peng, Y.-
Y. Green Chem 2010, 12, 1607; (e) Zhou, Y.; Zhai, Y.; Li, J.; Ye, D.;
Jiang, H.; Liu, H. Green Chem 2010, 12, 1397.
[12] (a) Domling, A.; Herdtweck, E.; Heck, S. Tetrahedron Lett
2006, 47, 1745; (b) Vlaar, T.; Ruijter, E.; Znabet, A.; Janssen, E.;
de Kanter, F. J. J.; Maes, B. U. W.; Orru, R. V. A. Org Lett 2011, 13,
6496; (c) Burchak, O. N.; Mugherli, L.; Ostuni, M.; Lacapere, J. J.;
Balakirev, M. Y. J Am Chem Soc 2011, 133, 10058; (d) Saha, B.;
Frett, B.; Wang, Y.; Li, H. Tetrahedron Lett 2013, 54, 2340;
(e) Khan, A. T.; Basha, R. S.; Lal, M.; Mir, M. H. RSC Adv 2012, 2,
5506.
[13] Gawande, M. B.; Bonifacio, V. D. B.; Luque, R.; Brancoa, P. S.;
Varma, R. S. Chem Soc Rev 2013, 42, 5522.
[14] Knoevenagel, E. Ber Dtsch Chem Ges 1898, 31, 2596.
[15] Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew Chem
1959, 71, 386.
[7] (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem Soc Rev
2011, 40, 5068; (b) Pagadala, R.; Gandhare, N. V.; Kusampally, U.;
Jetti, V.; Chopde, H. N.; Meshram, J. S.; Juneja, H. D. J Heterocycl Chem
2014, 51, 116; (c) Shabalala, N. G.; Pagadala, R.; Jonnalagadda, S. B.
Ultrason Sonochem 2015, 27, 423; (d) Pagadala, R.; Kommidi, D. R.;
Kankala, S.; Maddila, S.; Singh, P.; Moodley, B.; Koorbanally, N. A.;
Jonnalagadda, S. B. Org Biomol Chem 2015, 13, 1800; (e) Yulei, Z.;
Yang, Y.; Murong, X.; Zhong, Z.; Runhua, Z.; Yanzhong, L. Org Biomol
Chem 2017, 15, 6328.
[8] (a) Hili, R.; Yudin, A. K. Nat Chem Biol 2006, 2, 284;
(b) Kankala, S.; Pagadala, R.; Maddila, S.; Vasam, C. S.;
Jonnalagadda, S. B. RSC Adv 2015, 5, 105446; (c) Pagadala, R.; Maddila,
S.; Dasireddy, V. D. B. C.; Jonnalagadda, S. B. Cat Com 2014, 45, 148; (d)
Pagadala, R.; Maddila, S.; Rana, S.; Jonnalagadda, S. B. RSC Adv 2014, 4,
6602; (e) Mohammad, B.; Shima, N.; Behrouz, N. Tetrahedron 2017, 73,
1522; (f) Sanaz, M.; Alireza, H. Tetrahedron Lett 2017, 58, 2574.
[9] (a) Barton, D. H. R.; Zard, S. Z. J Chem Soc Chem Commun
1985 1098; (b) Palacios, F.; Aparico, D.; Santos, J. M.; Vicario, J. Tetrahe-
dron 2001, 57, 1961; (c) Manley, J. M.; Kalman, M. J.; Conway, B. G.;
Ball, C. C.; Havens, J. L.; Vaidyanathan, R. J Org Chem 2003, 68,
6447; (d) Shiner, C. M.; Lash, T. D. Tetrahedron 2005, 61, 11628;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet