An Expedient, Direct, Three-Component Approach for the Synthesis of 4-Thioarylpyrroles

Article abstract of DOI:10.1055/s-0039-1690024

A three-component strategy for the synthesis of 4-thioarylpyrroles from 1,4-enediones, thiols, and ammonium formate in one-pot has been developed. The reaction proceeds through the sequential thiol-Michael/Paal-Knorr reaction of 1,4-enediones with the for

Full text of DOI:10.1055/s-0039-1690024

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
paper
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en
V. Rajeshkumar et al.
Paper
Synthesis
An Expedient, Direct, Three-Component Approach for the Synthesis
of 4-Thioarylpyrroles
Venkatachalam Rajeshkumar*
Chinnaraj Neelamegam
Sambandam Anandan
0
0
0
0-0
0
0
2-
3
0
7
5-4
2
0
4
R3
O
SH
R2
S
COR2
HCOONH4
+
AcOH, 120 °C
O
O
R3
R1
Department of Chemistry, National Institute of Technology
Tiruchirappalli, Tamil Nadu-620015, India
orgrajeshkumar@gmail.com
R
N
H
R1
R
vrajesh@nitt.edu
One-pot thiol-Michael and Paal–Knorr reaction
Formation of one C–S and two C–N bonds
Gram-scale synthesis
29 Examples, up to 97% yield
Received: 24.06.2019
Accepted after revision: 20.07.2019
Published online: 15.08.2019
O
O
O
S
X
N
NH
DOI: 10.1055/s-0039-1690024; Art ID: ss-2019-n0171-op
N
X = O, CH2, NMe
N
F
F
Abstract A three-component strategy for the synthesis of 4-thio-
arylpyrroles from 1,4-enediones, thiols, and ammonium formate in
one-pot has been developed. The reaction proceeds through the se-
quential thiol-Michael/Paal–Knorr reaction of 1,4-enediones with the
formation of one new C–S and two C–N bonds. The operationally sim-
ple protocol provides direct access to the highly functionalized 4-thio-
arylpyrroles with free-NH in good to excellent yields. The synthetic ap-
plication of resulting 4-thioarylpyrroles was demonstrated by oxidation
of the sulfur atom to the corresponding sulfoxide and sulfone.
HO
HO
HO
HO
COO–Na+
CO2H
Atorvastatin
anti-hyperlipidemic
4-Sulfamoyl pyrroles
anti-hyperlipidemic
Figure 1 Representative examples of pyrrole-containing bioactive
molecules
Key words metal-free synthesis, 1,4-enediones, 4-thioarylpyrroles,
thiol-Michael reaction, C–S bond formation
been developed for the synthesis of pyrroles, which include
transition-metal-mediated reactions,6 multicomponent
coupling reactions,7 and cycloaddition reactions.8 Recently,
iodine-mediated synthetic transformations have emerged
as a potential tool for the construction of various heterocy-
clic systems.9 In this context, various research groups have
reported the iodine-mediated synthesis of polysubstituted
pyrroles from readily available substrates.10 Very recently,
Gandon and Sahoo demonstrated the use of yne-ynamides
as precursors for the synthesis of 4-sulfinylated pyrroles11a
and 4-thioarylpyrroles11b via Au(I)-catalyzed cycloisomeri-
zation and sulfur radical-triggered cyclization approaches,
respectively (Scheme 1a). However, these methods involve
multistep synthesis of starting materials. Herein, we de-
scribe a new approach to synthesize 4-thioarylpyrroles
through the combination of thiol-Michael and Paal–Knorr
reactions of 1,4-enediones (Scheme 1b).
Pyrrole is a prominent heterocyclic motif that is found
extensively in numerous natural products, bioactive drug
molecules, and functional organic materials.1 Its derivatives
exhibit a broad range of biological action such as antibacte-
rial, antifungal, anti-inflammatory, and anticancer activi-
ties.2–3 For instance, Atorvastatin4a–d is a pyrrole-based top-
selling drug molecule that is widely used as a cholesterol-
lowering agent that acts by inhibiting HMG-CoA reductase.
Interestingly, the corresponding 4-sulfamoyl pyrroles4e also
display potential activity as antihypolipidemic agents,
which illustrates the importance of sulfur substitution in
diversifying the statins (Figure 1).
Owing to the prominence of these molecules, the devel-
opment of efficient and practical protocols for the con-
struction of highly functionalized pyrrole rings has been an
attractive area of research. In general, classical methods
such as Hantzsch, Knorr, and Paal–Knorr are widely used for
the synthesis of pyrroles.5 However, these methods offer
limited access to pyrrole ring with different functionalities
because of the restricted availability of starting materials.
Over the past decades, a variety of elegant methods have
On the other hand, the reduction followed by Paal–
Knorr cyclization of methylthio-substituted 1,4-enediones
was observed for the synthesis of methylthio-substituted
pyrroles.11c Furthermore, the prevalence of organosulfur
compounds in bioactive molecules and pharmaceuticals
has inspired the scientific community to develop valuable
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
V. Rajeshkumar et al.
Paper
Synthesis
Table 1 Optimization of Reaction Conditionsa
a) Previous methods for preparing 4-sulfinylated and 4-thioarylpyrroles
"Gandon" and "Sahoo"
R2
O
S
R2
R
XPhosAuNTf2
acetone, 80 °C
O
R3
O
R1
SH
OEt
N
R1
R3
S
CO2Et
N
H
HCOONH4
+
S
O
O
R
O
O
N
H
Ar1
O
R3
1a
2b
3ab
SH
S
Ar1
20 mol%
N OH
O
R2
+
Yield (%)b
R2
Entry
Solvent (mL)
Temp (°C)
Time (h)
N
R1
Ar2
N
R1
CH2Cl2, 70 °C, 36 h
R3
Ar2
1
2
3
4
5
6
7
8
toluene
toluene/AcOH (2:1)
AcOH
110
120
120
120
120
120
100
120
24
18
24
42
36
36
48
48
trace
85
92
26
68
0
b) This work: One-pot thiol-Michael and Paal–Knorr reactions
O
R2
R1
S
COR1
Ar2
SH
HCOONH4
Ar1
Ar2
+
Ar1
HCOOH
TFA
AcOH, 120 °C
N
O
O
H
R2
Scheme 1 Methods for the synthesis of polysubstituted pyrroles
CF3SO3H
AcOH
83
76c
new synthetic routes to access these compounds.12 During
the last decade, transition-metal-catalyzed coupling reac-
tions have become efficient tools to build C–S bonds and
they are utilized extensively in the synthesis of valuable
products.13 To avoid use of metal catalyst and to construct
C–S bonds, recently, iodine-mediated sulfenylation of elec-
tron-rich aromatic systems such as indoles, benzofurans,
pyrazolones, naphthols, and naphthylamines have been de-
veloped by using sulfonyl hydrazides as sulfenylating
agents.14 Despite the advances made, most of these meth-
ods have shortcomings such as substrate availability or they
are limited to electron-rich systems. Thus, the development
of an alternative route for the construction of aryl thio-
ethers is highly desirable. In this perspective, here, we re-
port a practical route for the synthesis of 4-thioarylpyrroles
from readily accessible starting materials such as 1,4-enedi-
ones and thiols under metal-free reaction conditions
(Scheme 1b).
We started by examining the reaction conditions for the
formation of 4-thioarylpyrrole 3ab with the model sub-
strates 1,4-enedione 1a and thiol 2b, with ammonium for-
mate as nitrogen source (Table 1). The initial attempt at the
formation 4-thioarylpyrrole 3ab was unsuccessful when
the reaction was carried out in toluene at 110 °C for 24 h.
However, we achieved a satisfactory yield of 85% of the de-
sired product 3ab when we performed the reaction in a
mixture of toluene/AcOH (2:1) as solvent (entry 2). Further-
more, the yield of the reaction was enhanced to 92% when
the reaction was carried out in acetic acid as the sole sol-
vent at 120 °C for 24 h (entry 3). The screening of other ac-
ids such as formic acid (HCOOH), trifluoroacetic acid (TFA)
and trifluoromethanesulfonic acid (CF3SO3H) as reaction
solvent for the present transformation was not efficient
(entries 4–6). Decreasing the temperature of the reaction or
reducing the amount of ammonium formate resulted in
lower yields (entries 7 and 8).
AcOH
a Reaction conditions: 1a (100 mg, 0.324 mmol), 2b (44 mg, 0.356 mmol),
HCOONH4 (51 mg, 0.811 mmol), solvent (2 mL), sealed tube.
b Isolated yield.
c Ammonium formate (1 equiv) was used.
After the optimal reaction conditions for the formation
of 4-thioarylpyrrole had been established, the scope and
generality of this protocol were explored. As shown in
Scheme 2, numerous 4-thioarylpyrroles were synthesized
in good to high yields by treating various 1,4-enediones
with thiols under the standard reaction conditions. Initially,
we employed simple 1,4-enedione 1a to react with various
thiols bearing different substituents. The electron-donating
groups on the thiols such as 2a–d underwent reaction with
1a to afford 4-thioarylpyrroles 3aa–ad in 71–92% yields.
The thiols equipped with halogen substitutions also reacted
efficiently to produce the corresponding products 3ae–af in
good yields (66–69%). It is noteworthy that the reaction
proceeded smoothly in the case of thiols bearing strong
electron-withdrawing groups such as trifluoromethyl (CF3)
and nitro (NO2), to give the desired products 3ag–ah in 76
and 85% yield, respectively. 1,4-Enedione 1b, containing a
dimethoxy group, reacted efficiently to afford the product
3ai in 80% yield. Next, 1,4-enedione 1c, possessing a chloro
substituent, underwent the reaction to give the product 3aj
in 71% yield. The substrate 1e, containing a dimethyl group,
reacted with p-thiocresol to give the product 3ak in 85%
yield. 1,4-Enedione 1f, bearing a highly electron-withdraw-
ing NO2 group, was compatible with the present reaction,
delivering various products 3al–ap in good yields (72–86%).
Furthermore, the 1,4-enedione substrates 1g–i, containing
both electron-donating (Me, OMe) and electron-withdraw-
ing (NO2) groups, were investigated for this protocol. These
substrates reacted with various thiols efficiently and fur-
nished 4-thioarylpyrroles 3aq–at in 82–97% yields. Next,
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

C
V. Rajeshkumar et al.
Paper
Synthesis
the 1,4-enedione 1j, having two nitro groups, was also tol-
erated in the reaction, affording the desired product 3au in
83% yield.
Encouraged by the good tolerance of a variety of 1,4-
enedione substrates, we further turned our attention to in-
vestigate the scope of the reaction with 1,4-enediones pos-
sessing a keto group instead of an ester group (Scheme 2).
The substrates 1k–l, having a keto group, reacted with dif-
ferent thiols to give the 4-thioarylpyrroles 3ba–bc in good
to excellent yields. In addition, the scope of the reaction
was also examined with alkyl thiols. Notably, the alkyl thi-
ols 2l–m proved to be a good substrates for the present re-
action to afford the products 3ca–cd in 65–79% yield. Fur-
thermore, substrate 1n, without having either a keto or es-
ter group in the system, also reacted efficiently to afford the
product 3da in 75% yield.
R3
O
R2
SH
S
COR2
HCOONH4
+
AcOH, 120 °C
O
O
N
H
R1
R3
R
R1
R
1a–n
2a–m
3aa–da
OMe
F
Br
COOEt
COOEt
S
S
COOEt
S
S
COOEt
S
COOEt
S
COOEt
N
N
H
N
H
N
H
N
H
N
H
H
3aa
76%, 24 h
3ab
92%, 24 h
3ac
78%, 24 h
3ad
71%, 21 h
3ae
66%, 36 h
3af
69%, 36 h
CF3
NO2
Br
F
S
COOEt
S
COOEt
S
COOEt
S
COOEt
COOEt
COOEt
S
S
MeO
N
H
N
N
H
N
H
N
H
N
H
H
NO2
MeO
Cl
3ag
76%, 24 h
3ah
84%, 12 h
3ai
80%, 21 h
3aj
71%, 36 h
3ak
85%, 24 h
3al
72%, 24 h
Br
Cl
Br
Br
Cl
COOEt
COOEt
COOEt
S
S
COOEt
COOEt
S
S
COOEt
S
S
N
N
H
N
H
N
H
N
H
N
H
NO2
H
NO2
NO2
NO2
NO2
NO2
MeO
3am
86%, 12 h
3an
79%, 15 h
3ao
78%, 15 h
3ap
74%, 9 h
3aq
94%, 12 h
3ar
89%, 12 h
Cl
Cl
F
O
O
S
COOEt
S
S
COOEt
COOEt
S
S
MeO
MeO
N
H
N
H
N
H
N
N
H
MeO
H
NO2
NO2
MeO
NO2
O2N
3as
97%, 9 h
3at
82%, 14 h
3au
83%, 8 h
3ba
92%, 13 h
3bb
75%, 24 h
O
O
O
O
O
O
O
O
O
O
S
COOEt
S
COOEt
S
S
S
COOEt
S
N
H
N
H
N
H
N
H
N
H
N
H
Cl
NO2
Br
Br
3bc
85%, 7 h
3ca
70%, 36 h
3cb
65%, 36 h
3cc
77%, 29 h
3cd
79%, 6 h
3da
75%, 21 h
Scheme 2 Substrate scope for the synthesis of 4-thioarylpyrroles. Reagents and conditions: 1a–n (100 mg), 2a–m (1.1 equiv), HCOONH4 (2.5 equiv),
acetic acid (2 mL), 120 °C for the time indicated. Isolated yields are reported.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

D
V. Rajeshkumar et al.
Paper
Synthesis
Considering the importance of pyrroles and thio com-
pounds in pharmaceutical industries and in biological sci-
ences,2–4,12 a larger scale reaction was carried out to high-
light the synthetic potential of the current protocol. The re-
action worked well with 1,4-enedione 1a (1.71 g, 5.6 mmol)
and 4-methylbenzenethiol 2b (758 mg, 6.1 mmol) under
the standard reaction conditions to produce 4-thioarylpyr-
role 3ab in 86% yield (Scheme 3).
S
COOEt
m-CPBA
(1 equiv)
DCM, rt, 5 h
m-CPBA
(3 equiv)
DCM, rt, 5 h
N
H
3ab
O
O
S
COOEt
COOEt
S
O
N
N
H
H
O
SH
OEt
4; 93%
S
CO2Et
5; 96%
HCOONH4
+
AcOH
120 °C, 24 h
O
O
Scheme 4 Conversion of 4-thioarylpyrrole 3ab into the corresponding
sulfoxide 4 and sulfone 5
N
H
1a; 1.76 g, 5.6 mmol
2b
3ab; 1.98 g, 86%
Scheme 3 Gram-scale synthesis of 4-thioarylpyrrole 3ab
substituted 1,4-diketone 6 in 80% yield.17 Next, we treated
the resulting 1,4-diketone 6 with ammonium formate in
acetic acid. The product 3da was obtained in 86% yield.
These results clearly show that the present protocol pro-
ceeds through the sequential thiol-Michael and Paal–Knorr
reaction to provide 4-thioarylpyrroles. In addition to this,
the Paal–Knorr reaction of methylthio-substituted dike-
tones were absorbed to form the methylthio-substituted
pyrroles.11c
All the compounds were characterized by IR, 1H, and 13
NMR spectroscopy and by HRMS (ESI) analysis. In addition,
the structure of compound 3ap was confirmed by single-
crystal X-ray analysis (Figure 2).15
C
SH
(1)
O
S
AcOH
+
120 °C, 2 h
O
O
O
1n
2b
6, 80%
S
(2)
S
HCOONH4
AcOH, 120 °C, 19 h
N
H
O
O
Figure 2 X-ray crystal structure of compound 3ap (CCDC 1895966)
6
3da, 86%
Scheme 5 Control experiments
A synthetic application of this protocol was demonstrat-
ed by the oxidation of 4-thioarylpyrrole 3ab using m-CPBA
(Scheme 4). Upon treatment of compound 3ab with one
equivalent of m-CPBA, the sulphenyl group was oxidized to
the corresponding sulfoxide 4 in 93% yield. Similarly, sul-
fone 5 was obtained in 96% yield when three equivalents of
m-CPBA were used.16
Control experiments were carried out in order to better
understand the mechanism. First, the reaction of 1,4-enedi-
one 1n with 4-methylbenzenethiol 2b was performed un-
der the standard reaction conditions in the absence of am-
monium formate (Scheme 5). Interestingly, the thiol-Mi-
chael addition proceeded efficiently to form thioaryl
Based on our experimental results and on previous re-
ports,18 a reaction mechanism for the formation of 4-thio-
arylpyrrole is proposed as shown in Scheme 6.
1,4-Enediones 1 react with thiols to form thio-tethered
diketones A through thiol-Michael addition. Subsequently,
the imine intermediate B is formed by the reaction of A
with NH3, which is generated in situ by decomposition of
ammonium formate under the reaction conditions. Intra-
molecular nucleophilic attack of the amino group of enam-
ine C on the keto group then results in the formation of a
new C–N bond to produce cyclic intermediate E, which un-
dergoes dehydration and aromatization to give 4-thio-
arylpyrrole 3.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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V. Rajeshkumar et al.
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Synthesis
HCOONH4
HCOOH
Ar3
S
H
Ar3
Ar1
R
H
R S
Ar3
Ar1
R
S
Ar3
Ar1
H
R
S
NH3
Ar
Ar
Ar1
thiol-Michael
addition
Ar
Ar
NH
O
O
O O
NH2
O
O
A
B
C
1
H
S
R
S
Ar3
Ar1
R
Ar3
Ar1
OH2
S
Ar3
Ar3
H
Ar3
Ar1
S
R
S
R
R
H
Ar
Ar1
Ar1
Ar
Ar
Ar
Ar
N
H
N
H
N
H
N
OH
NH2
OH
H
3
G
F
D
E
Scheme 6 Reaction mechanism
In conclusion, we have developed a one-pot thiol-
Michael/Paal–Knorr reaction for the synthesis of 4-thio-
arylpyrroles from readily available starting materials such
as 1,4-enediones, thiols, and ammonium formate. This pro-
tocol is operationally simple and avoids the use of metal
catalysts for C–S bond formation. A wide range of structur-
ally diverse 4-thioarylpyrroles were obtained in good to ex-
cellent yields. Furthermore, the synthetic transformation of
4-thioarylpyrrole was demonstrated for the synthesis of
sulfoxide and sulfone moieties by simple oxidation in excel-
lent yields.
Ethyl 2,5-Diphenyl-4-(phenylthio)-1H-pyrrole-3-carboxylate (3aa)
Yield: 99 mg (76%); yellow solid; mp 103–104 °C.
FTIR (KBr): 3230, 3061, 2974, 1673, 1479, 1259, 1149, 764, 689 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.82 (s, 1 H), 7.56 (dd, J = 12.0, 7.6 Hz,
4 H), 7.41–7.29 (m, 6 H), 7.24–7.14 (m, 4 H), 7.06 (t, J = 6.8 Hz, 1 H),
4.03 (q, J = 7.0 Hz, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.55, 140.06, 137.33, 137.13,
131.61, 130.83, 128.58 (2C), 128.54, 128.47, 128.30, 128.18, 127.72,
125.57, 124.41, 116.94, 107.72, 60.10, 13.60.
HRMS (ESI): m/z [M + H]+ calcd for C25H22NO2S: 400.1371; found:
400.1363.
Ethyl 2,5-Diphenyl-4-(p-tolylthio)-1H-pyrrole-3-carboxylate (3ab)
Yield: 122 mg (91%); white solid; mp 116–117 °C.
FTIR (KBr): 3228, 2974, 2923, 1675, 1479, 1260, 1150, 764, 689 cm–1
Commercially available chemicals were purchased from Alfa Aesar or
Sigma–Aldrich and used as received. Thin-layer chromatography
(TLC) was performed using Merck silica gel 60 F254 precoated plates
(0.25 mm) and visualized with a UV lamp for reaction monitoring. Sil-
ica gel for column chromatography (particle size 100–200 mesh) was
purchased from Avra Synthesis Private Ltd India. 1H and 13C NMR
spectra were recorded with Bruker 300 & 400 MHz instruments.
Chemical shifts were recorded in parts per million (ppm) relative to
tetramethylsilane ( = 0.00 ppm) or chloroform ( = 7.26 ppm). 1H
NMR splitting patterns are designated as s (singlet), d (doublet), t
(triplet), q (quartet), dd (doublet of doublets), m (multiplet), etc. 13C
NMR spectral values were reported relative to CDCl3 ( = 77.00 ppm)
and DMSO-d6 ( = 39.51 ppm). FTIR spectra were recorded with a JAS-
CO spectrometer and are reported in frequency of absorption (cm−1).
High-resolution mass spectra were obtained with a Waters Q-Tof Pre-
mier Spectrometer.
.
1H NMR (400 MHz, CDCl3):  = 8.93 (s, 1 H), 7.59–7.53 (m, 2 H), 7.48
(dd, J = 7.7, 1.4 Hz, 2 H), 7.37–7.24 (m, 6 H), 7.02 (dd, J = 21.9, 8.2 Hz,
4 H), 4.01 (q, J = 7.2 Hz, 2 H), 2.25 (s, 3 H), 0.94 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.69, 137.19, 136.98, 136.38,
134.04, 131.56, 130.83, 129.33, 128.47, 128.46, 128.29, 128.16,
128.00, 127.70, 125.69, 116.77, 108.07, 60.06, 20.84, 13.60.
HRMS (ESI): m/z [M + H]+ calcd for C26H24NO2S: 414.1528; found:
414.1528.
Ethyl 4-{[4-(tert-butyl)phenyl]thio}-2,5-diphenyl-1H-pyrrole-3-
carboxylate (3ac)
Yield: 115 mg (78%); white solid; mp 128–129 °C.
FTIR (KBr): 3229, 2959, 2866, 1675, 1479, 1323, 1258, 1144, 764,
689 cm–1
.
4-Thioarylpyrroles 3aa–da; General Procedure
1H NMR (300 MHz, CDCl3):  = 8.65 (s, 1 H), 7.65–7.55 (m, 4 H), 7.48–
7.31 (m, 6 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.11 (d, J = 8.6 Hz, 2 H), 4.06 (q,
J = 7.1 Hz, 2 H), 1.26 (s, 9 H), 0.92 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.73, 147.41, 137.17, 137.02, 136.34,
131.60, 130.89, 128.49, 128.45, 128.29, 128.16, 127.97, 127.78,
125.57, 125.52, 116.75, 108.17, 60.02, 34.20, 31.26, 13.47.
To an oven-dried sealed tube equipped with a magnetic stir bar was
added 1,4-enedione 1a–n (100 mg), thiol 2a–m (1.1 equiv), ammoni-
um formate (2.5 equiv) and acetic acid (2 mL). The tube was then
sealed with a screw-type cap and the resulting reaction mixture was
placed in an oil bath at 120 °C with stirring. The progress of the reac-
tion was monitored by TLC. Upon completion of the reaction, the re-
action mixture was cooled to r.t. and extracted with EtOAc (3 × 15
mL). The extract was then washed with aqueous brine solution. After
drying over Na2SO4 and evaporation, the crude product was purified
by column chromatography on silica gel (eluent: petroleum
ether/EtOAc) to afford the corresponding 4-thioarylpyrrole 3aa–da.
HRMS (ESI): m/z [M + H]+ calcd for C29H30NO2S: 456.1997; found:
456.2006.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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V. Rajeshkumar et al.
Paper
Synthesis
Ethyl 4-[(4-Methoxyphenyl)thio]-2,5-diphenyl-1H-pyrrole-3-car-
Ethyl 4-[(4-Nitrophenyl)thio]-2,5-diphenyl-1H-pyrrole-3-carbox-
boxylate (3ad)
ylate (3ah)
Yield: 99 mg (71%); white solid; mp 90–91 °C.
Yield: 121 mg (84%); pale-yellow solid; mp 124–125 °C.
FTIR (KBr): 3235, 2978, 1674, 1494, 1322, 1246, 1143, 1041, 764,
FTIR (KBr): 3272, 3064, 2977, 2926, 1684, 1578, 1511, 1338, 1242,
670 cm–1
.
762, 694 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.73 (s, 1 H), 7.58 (dd, J = 25.9, 6.6 Hz,
4 H), 7.48–7.28 (m, 6 H), 7.13 (d, J = 7.8 Hz, 2 H), 6.77 (d, J = 7.8 Hz,
2 H), 4.09 (q, J = 6.5 Hz, 2 H), 3.74 (s, 3 H), 1.01 (t, J = 6.7 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.59, 157.35, 136.84, 136.68,
131.63, 130.89, 130.44, 128.54, 128.41, 128.38, 128.27, 128.07,
127.85, 127.71, 116.87, 114.32, 109.34, 60.08, 55.23, 13.70.
1H NMR (300 MHz, CDCl3):  = 8.82 (s, 1 H), 8.09 (d, J = 8.8 Hz, 2 H),
7.60 (d, J = 6.1 Hz, 2 H), 7.52 (d, J = 6.2 Hz, 2 H), 7.42 (dd, J = 19.3,
6.7 Hz, 6 H), 7.28 (d, J = 9.0 Hz, 1 H), 4.07 (q, J = 7.0 Hz, 2 H), 0.95 (t, J =
7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.09, 150.74, 144.66, 138.01, 131.23,
130.21, 128.76, 128.71, 128.69, 128.62, 128.28, 127.67, 124.97,
123.81, 116.32, 105.16, 60.21, 13.61.
HRMS (ESI): m/z [M + H]+ calcd for C26H24NO3S: 430.1477; found:
430.1483.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2O4S: 445.1222; found:
445.1225.
Ethyl 4-[(4-Fluorophenyl)thio]-2,5-diphenyl-1H-pyrrole-3-car-
boxylate (3ae)
Ethyl 4-[(4-Bromophenyl)thio]-5-(3,4-dimethoxyphenyl)-2-phe-
nyl-1H-pyrrole-3-carboxylate (3ai)
Yield: 90 mg (66%); white solid; mp 129–130 °C.
Yield: 117 mg (80%); yellow solid; mp 111–112 °C.
FTIR (KBr): 3281, 2977, 2927, 1685, 1487, 1225, 1156, 1044, 802, 761,
694 cm–1
.
FTIR (KBr): 3246, 2995, 2935, 1673, 1499, 1251, 1133, 1027, 767,
689 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.84 (s, 1 H), 7.61–7.47 (m, 4 H), 7.44–
7.29 (m, 6 H), 7.12 (ddd, J = 8.3, 5.1, 2.6 Hz, 2 H), 6.90 (t, J = 8.7 Hz,
2 H), 4.06 (q, J = 7.1 Hz, 2 H), 0.97 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.53, 161.89, 159.47, 137.16 (d,
JC–F = 14.0 Hz), 134.93 (d, JC–F = 3.18 Hz), 131.54, 130.73, 128.61,
1H NMR (400 MHz, CDCl3):  = 8.93 (s, 1 H), 7.56 (d, J = 7.5 Hz, 2 H),
7.40 (dt, J = 12.3, 6.2 Hz, 3 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.10–7.01 (m,
4 H), 6.84 (d, J = 8.3 Hz, 1 H), 4.08 (q, J = 7.0 Hz, 2 H), 3.84 (s, 3 H), 3.64
(s, 3 H), 0.99 (t, J = 7.1 Hz, 3 H).
128.51, 128.30, 128.25, 127.73, 127.52, 127.45, 115.62 (d, JC–F
22.09 Hz), 115.51, 108.24, 60.15, 13.68.
HRMS (ESI): m/z [M + H]+ calcd for C25H21FNO2S: 418.1277; found:
418.1269.
=
13C NMR (101 MHz, CDCl3):  = 164.46, 149.14, 149.12, 148.71,
139.81, 137.69, 136.74, 136.72, 131.55, 128.58, 128.50, 128.28,
126.94, 123.37, 119.85, 117.80, 116.90, 111.28, 111.07, 60.17, 55.82,
55.55, 13.69.
HRMS (ESI): m/z [M + H]+ calcd for C27H25BrNO4S: 538.0688; found:
538.0696.
Ethyl 4-[(4-Bromophenyl)thio]-2,5-diphenyl-1H-pyrrole-3-car-
boxylate (3af)
Ethyl 5-(4-Chlorophenyl)-4-[(4-fluorophenyl)thio]-2-phenyl-1H-
pyrrole-3-carboxylate (3aj)
Yield: 107 mg (69%); white solid; mp 113–114 °C.
FTIR (KBr): 3230, 2976, 1676, 1473, 1323, 1259, 1149, 765, 689 cm–1
.
Yield: 94 mg (71%); white solid; mp 162–163 °C.
1H NMR (400 MHz, CDCl3):  = 8.94 (s, 1 H), 7.52 (t, J = 5.8 Hz, 4 H),
7.39–7.27 (m, 8 H), 7.02 (d, J = 8.4 Hz, 2 H), 4.03 (q, J = 7.2 Hz, 2 H),
0.95 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.45, 139.51, 137.53, 137.34,
131.51, 131.41, 130.56, 128.59, 128.54, 128.52, 128.29, 128.24,
127.68, 127.06, 117.86, 116.61, 106.94, 60.16, 13.63.
FTIR (KBr): 3262, 2989, 1683, 1488, 1226, 1166, 1090, 696 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.78 (s, 1 H), 7.59–7.48 (m, 4 H), 7.46–
7.38 (m, 3 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.16–7.08 (m, 2 H), 6.92 (t, J =
8.7 Hz, 2 H), 4.08 (q, J = 7.2 Hz, 2 H), 0.99 (t, J = 7.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3/DMSO-d6 = 3:1):  = 163.75, 159.66 (d, J =
241.69 Hz), 137.00, 135.60, 134.40 (d, J = 3.01 Hz), 132.52, 131.09,
128.88, 128.81, 128.45, 127.41, 127.33, 127.06, 126.41 (d, J = 7.65 Hz),
115.82, 114.80 (d, J = 21.6 Hz), 106.50, 58.99, 12.91.
HRMS (ESI): m/z [M + H]+ calcd for C25H21BrNO2S: 478.0476; found:
478.0469.
HRMS (ESI): m/z [M + H]+ calcd for C25H20ClFNO2S: 452.0887; found:
452.0890.
Ethyl 2,5-Diphenyl-4-{[4-(trifluoromethyl)phenyl]thio}-1H-pyr-
role-3-carboxylate (3ag)
Yield: 115 mg (76%); white solid; mp 137–138 °C.
FTIR (KBr): 3225, 2982, 1671, 1605, 1325, 1259, 1114, 766, 689 cm–1
Ethyl 2,5-Di-p-tolyl-4-(p-tolylthio)-1H-pyrrole-3-carboxylate
(3ak)
.
1H NMR (300 MHz, CDCl3):  = 8.74 (s, 1 H), 7.57 (ddd, J = 13.2, 7.8,
1.6 Hz, 4 H), 7.50–7.34 (m, 8 H), 7.26 (d, J = 8.2 Hz, 2 H), 4.07 (q, J =
7.1 Hz, 2 H), 0.94 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.32, 145.54, 137.78, 137.61, 131.40,
130.48, 128.68, 128.65, 128.61, 128.45, 128.30, 127.69, 126.42 (q, J =
32.3 Hz), 125.41 (q, J = 3.8 Hz), 125.14, 122.53, 116.64, 106.13, 60.18,
13.53.
Yield: 112 mg (85%); yellow solid; mp 78–79 °C.
FTIR (KBr): 3434, 2957, 2924, 2855, 1728, 1608, 1491, 1171, 1035,
820 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.54 (s, 1 H), 7.47 (dd, J = 7.7, 5.2 Hz,
4 H), 7.21 (dd, J = 14.8, 8.0 Hz, 4 H), 7.05 (dd, J = 18.9, 8.1 Hz, 4 H), 4.07
(q, J = 7.1 Hz, 2 H), 2.40 (s, 3 H), 2.35 (s, 3 H), 2.27 (s, 3 H), 0.99 (t, J =
7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.70, 138.31, 137.99, 137.14, 136.92,
136.61, 133.95, 129.32, 129.26, 128.97, 128.83, 128.35, 128.11,
127.55, 125.71, 116.56, 107.69, 59.99, 21.28, 21.22, 20.85, 13.70.
HRMS (ESI): m/z [M + H]+ calcd for C26H21F3NO2S: 468.1245; found:
468.1258.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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V. Rajeshkumar et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C28H28NO2S: 442.1841; found:
HRMS (ESI): m/z [M + H]+ calcd for C25H20ClN2O4S: 479.0832; found:
422.1193.
479.0828.
Ethyl 2-(4-Nitrophenyl)-5-phenyl-4-(phenylthio)-1H-pyrrole-3-
Ethyl 4-[(4-Bromophenyl)thio]-2-(4-nitrophenyl)-5-phenyl-1H-
carboxylate (3al)
pyrrole-3-carboxylate (3ap)
Yield: 90 mg (72%); yellow solid; mp 128–129 °C.
Yield: 109 mg (74%); yellow solid; mp 171–172 °C.
FTIR (KBr): 3251, 2927, 2853, 1673, 1512, 1479, 1344, 854, 693 cm–1
.
FTIR (KBr): 3250, 2995, 2976, 2926, 1683, 1602, 1513, 1471, 1150,
854, 693 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.34 (s, 1 H), 8.22–8.08 (m, 2 H), 7.71–
7.54 (m, 4 H), 7.34 (d, J = 5.6 Hz, 3 H), 7.21 (t, J = 7.6 Hz, 2 H), 7.16–
7.04 (m, 3 H), 4.04 (q, J = 7.1 Hz, 2 H), 0.95 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.56, 146.93, 139.50, 139.07, 137.71,
133.93, 130.29, 129.06, 128.67, 128.56, 127.95, 125.62, 124.86,
124.68, 123.43, 118.91, 108.74, 60.62, 13.57.
1H NMR (400 MHz, CDCl3):  = 9.25 (s, 1 H), 8.16 (d, J = 8.9 Hz, 2 H),
7.71–7.63 (m, 2 H), 7.54 (dd, J = 7.3, 2.2 Hz, 2 H), 7.38 (ddd, J = 7.2, 4.4,
1.6 Hz, 3 H), 7.34–7.29 (m, 2 H), 7.02–6.97 (m, 2 H), 4.08 (q, J = 7.2 Hz,
2 H), 0.99 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.29, 147.08, 139.14, 138.82,
137.51, 134.04, 131.65, 129.98, 129.05, 128.83, 128.72, 127.79,
127.17, 123.51, 118.75, 118.25, 108.22, 60.74, 13.66.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2O4S: 445.1222; found:
445.1212.
HRMS (ESI): m/z [M + K]+ calcd for C25H19BrKN2O4S: 560.9886; found:
560.9857.
Ethyl 2-(4-Nitrophenyl)-5-phenyl-4-(p-tolylthio)-1H-pyrrole-3-
carboxylate (3am)
Ethyl 4-[(4-Bromophenyl)thio]-2-(4-nitrophenyl)-5-(p-tolyl)-1H-
pyrrole-3-carboxylate (3aq)
Yield: 111 mg (86%); yellow solid; mp 195–196 °C.
FTIR (KBr): 3256, 2925, 1678, 1519, 1345, 1264, 854, 693 cm–1
.
Yield: 138 mg (94%); yellow solid; mp 184–185 °C.
1H NMR (400 MHz, CDCl3):  = 8.90 (s, 1 H), 8.26 (d, J = 8.8 Hz, 2 H),
7.73 (d, J = 8.9 Hz, 2 H), 7.61 (dd, J = 8.0, 1.4 Hz, 2 H), 7.45–7.33 (m,
3 H), 7.04 (q, J = 8.4 Hz, 4 H), 4.10 (q, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 1.01
(t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, DMSO):  = 164.53, 146.87, 139.26, 137.85,
136.08, 134.59, 133.79, 130.58, 129.94, 129.84, 128.80, 128.77,
128.67, 125.69, 123.72, 119.09, 107.71, 60.56, 20.72, 13.86.
FTIR (KBr): 3228, 2925, 2853, 1683, 1514, 1347, 1235, 813 cm–1
.
1H NMR (300 MHz, CDCl3):  = 9.01 (s, 1 H), 8.25 (d, J = 8.7 Hz, 2 H),
7.73 (d, J = 8.8 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 7.33 (d, J = 8.5 Hz,
2 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.02 (d, J = 8.5 Hz, 2 H), 4.11 (q, J =
7.1 Hz, 2 H), 2.37 (s, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.22, 147.15, 139.36, 139.01, 137.65,
133.78, 131.64, 129.48, 129.05, 127.68, 127.20, 123.58, 118.86,
118.19, 107.94, 60.67, 21.30, 13.70.
HRMS (ESI): m/z [M + H]+ calcd for C26H23N2O4S: 459.1379; found:
459.1370.
HRMS (ESI): m/z [M + H]+ calcd for C26H22BrN2O4S: 537.0484; found:
537.0471.
Ethyl 4-[(4-Chlorophenyl)thio]-2-(4-nitrophenyl)-5-phenyl-1H-
pyrrole-3-carboxylate (3an)
Ethyl 4-[(4-Bromophenyl)thio]-5-(4-methoxyphenyl)-2-(4-nitro-
phenyl)-1H-pyrrole-3-carboxylate (3ar)
Yield: 107 mg (79%); yellow solid; mp 143–144 °C.
FTIR (KBr): 3230, 2926, 1677, 1600, 1518, 1475, 1344, 855, 694 cm–1
.
Yield: 129 mg (89%); yellow solid; mp 188–189 °C.
1H NMR (400 MHz, CDCl3):  = 9.32 (s, 1 H), 8.18 (d, J = 8.2 Hz, 2 H),
7.68 (d, J = 8.5 Hz, 2 H), 7.59–7.53 (m, 2 H), 7.41–7.34 (m, 3 H), 7.20–
7.15 (m, 2 H), 7.09–7.04 (m, 2 H), 4.09 (q, J = 7.2 Hz, 2 H), 1.00 (t, J =
7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.28, 147.11, 139.11, 138.13,
137.57, 134.03, 130.48, 130.05, 129.08, 128.80, 128.78, 128.71,
127.83, 126.91, 123.52, 118.81, 108.44, 60.72, 13.68.
FTIR (KBr): 3235, 2977, 2922, 1673, 1519, 1346, 1267, 1163, 834,
694 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.84 (s, 1 H), 8.27 (d, J = 8.7 Hz, 2 H),
7.74 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.33 (d, J = 8.5 Hz,
2 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.93 (d, J = 8.7 Hz, 2 H), 4.12 (q, J =
7.2 Hz, 2 H), 3.82 (s, 3 H), 1.01 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.32, 158.55, 145.55, 138.73, 138.67,
136.99, 132.70, 130.37, 128.89, 128.44, 125.91, 122.28, 121.92,
117.42, 116.53, 112.56, 105.04, 59.09, 54.16, 12.64.
HRMS (ESI): m/z [M + H]+ calcd for C25H20ClN2O4S: 479.0832; found:
479.0839.
HRMS (ESI): m/z [M + H]+ calcd for C26H22BrN2O5S: 553.0433; found:
553.0438.
Ethyl 4-[(3-Chlorophenyl)thio]-2-(4-nitrophenyl)-5-phenyl-1H-
pyrrole-3-carboxylate (3ao)
Yield: 106 mg (78%); yellow solid; mp 125–126 °C.
Ethyl 5-(3,4-Dimethoxyphenyl)-2-(4-nitrophenyl)-4-(p-tolylthio)-
1H-pyrrole-3-carboxylate (3as)
FTIR (KBr): 3238, 2979, 2926, 2853, 1701, 1600, 1577, 1518, 1343,
855, 771, 695 cm–1
.
Yield: 112 mg (97%); yellow solid; mp 150–151 °C.
1H NMR (400 MHz, CDCl3):  = 9.10 (s, 1 H), 8.25 (dd, J = 8.7, 2.8 Hz,
2 H), 7.74 (dd, J = 8.8, 2.2 Hz, 2 H), 7.57 (d, J = 6.9 Hz, 2 H), 7.44–7.36
(m, 3 H), 7.14 (dd, J = 14.2, 6.3 Hz, 2 H), 7.05 (t, J = 7.2 Hz, 2 H), 4.11 (q,
J = 7.0 Hz, 2 H), 0.99 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.35, 147.07, 141.77, 139.25, 137.48,
134.65, 134.18, 129.94, 129.69, 129.08, 128.80, 128.68, 127.81,
125.17, 124.87, 123.66, 123.46, 118.70, 107.73, 60.73, 13.58.
FTIR (KBr): 3245, 2932, 2833, 1677, 1598, 1518, 1493, 1341, 1255,
1026, 849, 699 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.90 (s, 1 H), 8.26 (d, J = 8.7 Hz, 2 H),
7.74 (d, J = 8.8 Hz, 2 H), 7.20–6.99 (m, 6 H), 6.88 (d, J = 8.3 Hz, 1 H),
4.14 (q, J = 7.2 Hz, 2 H), 3.88 (s, 3 H), 3.64 (s, 3 H), 2.27 (s, 3 H), 1.04 (t,
J = 7.2 Hz, 3 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

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V. Rajeshkumar et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3):  = 164.58, 149.22, 148.67, 146.89, 138.98,
137.79, 136.02, 134.43, 133.01, 129.48, 128.86, 125.65, 123.48,
123.14, 119.98, 119.42, 111.52, 111.05, 108.42, 60.65, 55.81, 55.53,
20.83, 13.71.
HRMS (ESI): m/z [M + H]+ calcd for C28H27N2O6S: 519.1590; found:
519.1595.
1H NMR (400 MHz, CDCl3):  = 8.89 (s, 1 H), 7.73 (d, J = 7.3 Hz, 2 H),
7.68 (d, J = 7.3 Hz, 2 H), 7.36 (tt, J = 14.7, 7.3 Hz, 6 H), 7.25–7.15 (m,
3 H), 7.06–6.94 (m, 2 H), 6.94–6.80 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 193.52, 158.98 (d, J = 245.21 Hz),
138.15, 137.34, 134.47, 132.56, 130.71 (d, J = 19.51 Hz), 129.83,
128.720 (d, J = 4.05 Hz), 128.55, 128.55, 128.20, 127.98, 127.86,
127.39, 127.30, 126.39, 126.32, 126.24, 125.80, 124.20 (d, J = 3.31 Hz),
114.94 (d, J = 21.35 Hz), 106.51.
Ethyl 4-[(4-Chlorophenyl)thio]-5-(3,4-dimethoxyphenyl)-2-(4-ni-
trophenyl)-1H-pyrrole-3-carboxylate (3at)
HRMS (ESI): m/z [M + H]+ calcd for C29H21FNOS: 450.1328; found:
450.1321.
Yield: 107 mg (82%); yellow solid; mp 120–121 °C.
FTIR (KBr): 3084, 2980, 1708, 1481, 1283, 1028, 765, 698 cm–1
.
Phenyl[2-phenyl-5-(p-tolyl)-4-(p-tolylthio)-1H-pyrrol-3-yl]meth-
anone (3bc)
1H NMR (400 MHz, CDCl3):  = 9.11 (s, 1 H), 8.23 (d, J = 8.8 Hz, 2 H),
7.73 (d, J = 8.8 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H), 7.14–7.05 (m, 4 H),
6.86 (d, J = 8.2 Hz, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.86 (s, 3 H), 3.66 (s,
3 H), 1.03 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.30, 149.43, 148.75, 147.03, 139.25,
138.45, 137.66, 133.47, 130.43, 129.04, 128.80, 126.70, 123.50,
122.83, 120.12, 119.08, 111.36, 111.13, 107.38, 60.71, 55.84, 55.58,
13.71.
Yield: 110 mg (85%); yellow solid; mp 180–181 °C.
FTIR (KBr): 3250, 2956, 2923, 2853, 1636, 1489, 1234, 908, 712,
693 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.74 (s, 1 H), 7.73 (d, J = 7.3 Hz, 2 H),
7.60 (d, J = 8.1 Hz, 2 H), 7.37 (dd, J = 9.4, 7.6 Hz, 4 H), 7.22 (dd, J = 7.6,
4.1 Hz, 6 H), 6.93 (q, J = 8.3 Hz, 4 H), 2.37 (s, 3 H), 2.21 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C27H24ClN2O6S: 539.1044; found:
539.1050.
13C NMR (75 MHz, CDCl3):  = 193.81, 138.32, 137.97, 137.02, 135.63,
134.48, 133.78, 132.38, 131.04, 129.91, 129.38, 129.30, 128.63,
128.02, 127.77, 127.35, 127.28, 127.20, 126.59, 125.70, 108.66, 21.24,
20.84.
Ethyl 4-[(4-Chlorophenyl)thio]-2,5-bis(4-nitrophenyl)-1H-pyr-
role-3-carboxylate (3au)
HRMS (ESI): m/z [M + H]+ calcd for C31H26NOS: 460.1735; found:
460.1747.
Yield: 109 mg (83%); yellow solid; mp 197–198 °C.
FTIR (KBr): 3190, 2924, 2852, 1673, 1596, 1520, 1343, 1164, 854 cm–
.
1
Ethyl 5-(4-Chlorophenyl)-4-{[3-oxo-3-(pentyloxy)propyl]thio}-2-
phenyl-1H-pyrrole-3-carboxylate (3ca)
1H NMR (300 MHz, CDCl3/DMSO-d6 = 3:1):  = 12.26 (s, 1 H), 8.17 (dd,
J = 19.8, 8.9 Hz, 4 H), 7.80 (dd, J = 20.1, 8.9 Hz, 4 H), 7.12 (d, J = 8.6 Hz,
2 H), 7.01 (d, J = 8.6 Hz, 2 H), 4.04 (q, J = 7.1 Hz, 2 H), 0.94 (t, J = 7.2 Hz,
3 H).
13C NMR (75 MHz, CDCl3/DMSO-d6 = 3:1):  = 163.69, 146.81, 146.46,
137.36, 137.32, 136.50, 136.02, 135.46, 130.21, 129.56, 128.54,
128.49, 126.57, 123.06, 122.73, 119.10, 109.78, 60.17, 13.35.
Yield: 102 mg (70%); white solid; mp 98–99 °C.
FTIR (KBr): 3320, 2952, 2871, 1710, 1481, 1225, 1046, 840, 697 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.76 (s, 1 H), 7.63 (d, J = 8.5 Hz, 2 H),
7.47 (dd, J = 7.3, 1.6 Hz, 2 H), 7.42–7.33 (m, 3 H), 4.20 (q, J = 7.2 Hz,
2 H), 3.90 (t, J = 6.8 Hz, 2 H), 2.98 (t, J = 7.4 Hz, 2 H), 2.40 (t, J = 7.4 Hz,
2 H), 1.59–1.46 (m, 2 H), 1.37–1.21 (m, 4 H), 1.16 (t, J = 7.2 Hz, 3 H),
0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 172.11, 164.78, 136.95, 135.05, 133.68,
131.77, 129.61, 129.35, 128.60, 128.54, 128.38, 128.15, 116.84,
111.26, 64.73, 60.18, 34.21, 31.49, 28.11, 27.91, 22.24, 13.90, 13.89.
HRMS (ESI): m/z [M + H]+ calcd for C25H19ClN3O6S: 524.0683; found:
524.0692.
(2,5-Diphenyl-4-(p-tolylthio)-1H-pyrrol-3-yl)(phenyl)methanone
(3ba)
HRMS (ESI): m/z [M + H]+ calcd for C27H31ClNO4S: 500.1662; found:
500.1662.
Yield: 120 mg (92%); yellow solid; mp 162–163 °C.
FTIR (KBr): 3242, 2918, 2856, 1633, 1489, 1233, 906, 689 cm–1
.
Ethyl 5-(4-Bromophenyl)-4-{[3-oxo-3-(pentyloxy)propyl]thio}-2-
phenyl-1H-pyrrole-3-carboxylate (3cb)
1H NMR (400 MHz, CDCl3):  = 9.28 (s, 1 H), 7.75–7.63 (m, 4 H), 7.35–
7.26 (m, 6 H), 7.15 (t, J = 7.7 Hz, 2 H), 7.10 (dd, J = 4.8, 2.2 Hz, 3 H),
6.90 (dd, J = 22.5, 8.2 Hz, 4 H), 2.17 (s, 3 H).
Yield: 91 mg (65%); white solid; mp 100–101 °C.
FTIR (KBr): 3321, 2961, 2870, 1710, 1474, 1355, 1225, 1046, 787,
13C NMR (101 MHz, CDCl3):  = 193.98, 138.23, 136.89, 135.54,
134.45, 134.27, 132.38, 130.87, 130.82, 129.89, 129.27, 128.51,
128.48, 127.85, 127.74, 127.68, 127.44, 127.28, 126.53, 125.53,
108.84, 20.80.
HRMS (ESI): m/z [M + H]+ calcd for C30H24NOS: 446.1579; found:
446.1577.
698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.69 (s, 1 H), 7.56 (q, J = 8.6 Hz, 4 H),
7.48 (d, J = 6.5 Hz, 2 H), 7.39 (d, J = 7.0 Hz, 3 H), 4.21 (q, J = 7.0 Hz,
2 H), 3.91 (t, J = 6.8 Hz, 2 H), 2.99 (t, J = 7.3 Hz, 2 H), 2.41 (t, J = 7.3 Hz,
2 H), 1.58–1.48 (m, 2 H), 1.29 (dd, J = 15.7, 8.6 Hz, 4 H), 1.16 (t, J =
7.1 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 172.09, 164.74, 136.99, 135.04, 131.77,
131.58, 130.06, 129.59, 128.55, 128.43, 128.19, 121.92, 116.94,
111.38, 64.74, 60.20, 34.23, 31.51, 28.13, 27.93, 22.26, 13.91, 13.90.
HRMS (ESI): m/z [M + H]+ calcd for C27H31BrNO4S: 544.1157; found:
544.1147.
{4-[(2-Fluorophenyl)thio]-2,5-diphenyl-1H-pyrrol-3-yl}(phe-
nyl)methanone (3bb)
Yield: 99 mg (75%); yellow solid; mp 170–171 °C.
FTIR (KBr): 3234, 2932, 1624, 1615, 1469, 1212, 910, 695 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

I
V. Rajeshkumar et al.
Paper
Synthesis
Ethyl 2-(4-Nitrophenyl)-4-{[3-oxo-3-(pentyloxy)propyl]thio}-5-
phenyl-1H-pyrrole-3-carboxylate (3cc)
washed with brine (30 mL), dried (Na2SO4), and concentrated. The
crude material was purified by flash chromatography on silica gel
(eluent: petroleum ether/EtOAc) to provide product 4.
Yield: 111 mg (77%); yellow solid; mp 98–99 °C.
Yield: 97 mg (93%); white solid; mp 128–129 °C.
FTIR (KBr): 3309, 2958, 2928, 1698, 1601, 1518, 1345, 1223, 1149,
857, 693 cm–1
.
FTIR (KBr): 3084, 2980, 2924, 1708, 1490, 1488, 1238, 1028, 765,
698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.33 (s, 1 H), 8.16 (dd, J = 8.7, 1.8 Hz,
2 H), 7.71–7.65 (m, 2 H), 7.62 (d, J = 8.9 Hz, 2 H), 7.38 (dt, J = 24.7,
7.3 Hz, 3 H), 4.25 (q, J = 7.2 Hz, 2 H), 3.88 (t, J = 6.8 Hz, 2 H), 2.93 (t, J =
7.5 Hz, 2 H), 2.39 (t, J = 7.5 Hz, 2 H), 1.57–1.46 (m, 2 H), 1.34–1.24 (m,
4 H), 1.22 (t, J = 7.2 Hz, 3 H), 0.88 (t, J = 7.0 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 172.10, 164.67, 146.90, 137.99,
137.87, 133.24, 130.60, 128.94, 128.50, 128.31, 128.20, 123.41,
118.81, 111.86, 64.76, 60.67, 34.28, 31.51, 28.07, 27.90, 22.22, 13.98,
13.89.
1H NMR (300 MHz, CDCl3):  = 9.27 (s, 1 H), 7.60–7.44 (m, 4 H), 7.43–
7.28 (m, 8 H), 7.12 (d, J = 8.2 Hz, 2 H), 4.14–3.83 (m, 2 H), 2.32 (s, 3 H),
1.06 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.80, 141.32, 139.26, 138.37, 137.73,
130.76, 129.63, 129.44, 128.97, 128.88, 128.62, 128.44, 128.03,
127.96, 124.98, 121.35, 112.71, 60.21, 21.13, 13.74.
HRMS (ESI): m/z [M + H]+ calcd for C26H24NO3S: 430.1477; found:
430.1478.
HRMS (ESI): m/z [M + H]+ calcd for C27H31N2O6S: 511.1903; found:
511.1902.
Ethyl 2,5-Diphenyl-4-tosyl-1H-pyrrole-3-carboxylate (5)
To a round-bottom flask containing a solution of 3ab (100 mg, 0.242
mmol) in CH2Cl2 (5 mL) was added m-chloroperoxybenzoic acid (m-
CPBA) (125.0 mg, 0.725 mmol). The reaction mixture was stirred at r.t.
for 5 h and the progress of the reaction was monitored by TLC. Upon
completion of the reaction, the mixture was washed with aq. NaOH
solution and the layers were separated. The aq. layer was further ex-
tracted with CH2Cl2 (2 × 20 mL) and the combined organics were
washed with brine (30 mL), dried (Na2SO4), and concentrated. The
crude material was purified by flash chromatography on silica gel
(eluent: petroleum ether/EtOAc) to provide product 5.
3-Phenylpropyl 3-{[4-benzoyl-2-(4-bromophenyl)-5-phenyl-1H-
pyrrol-3-yl]thio}propanoate (3cd)
Yield: 117 mg (79%); yellow solid; mp 94–95 °C.
FTIR (KBr): 3296, 2924, 2853, 1732, 1712, 1639, 1471, 1230, 1009,
908, 695 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.66 (s, 1 H), 7.84–7.78 (m, 2 H), 7.69
(d, J = 8.6 Hz, 2 H), 7.57 (d, J = 8.6 Hz, 2 H), 7.42 (dd, J = 14.2, 6.9 Hz,
1 H), 7.33–7.26 (m, 5 H), 7.26–7.10 (m, 7 H), 3.92 (t, J = 6.6 Hz, 2 H),
2.83 (t, J = 7.3 Hz, 2 H), 2.59 (t, J = 7.3 Hz, 2 H), 2.36 (t, J = 7.3 Hz, 2 H),
1.90–1.76 (m, 2 H).
Yield: 103 mg (96%); white solid; mp 92–93 °C.
13C NMR (75 MHz, CDCl3):  = 193.94, 171.79, 141.12, 138.31, 134.94,
134.32, 132.71, 131.78, 130.83, 130.04, 129.97, 129.18, 128.64,
128.37, 128.35, 128.06, 127.97, 127.32, 125.97, 125.93, 121.94,
111.56, 63.87, 34.12, 32.02, 31.92, 29.97.
FTIR (KBr): 3259, 3059, 2979, 2925, 1721, 1480, 1382, 1302, 1237,
1139, 696 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.62 (s, 1 H), 7.69 (d, J = 8.3 Hz, 2 H),
7.52–7.30 (m, 10 H), 7.17 (d, J = 8.2 Hz, 2 H), 4.30 (q, J = 7.2 Hz, 2 H),
2.36 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C35H31BrNO3S: 624.1208; found:
13C NMR (75 MHz, CDCl3):  = 165.28, 143.08, 140.38, 136.48, 132.26,
130.01, 129.88, 129.60, 129.19, 129.05, 128.59, 128.44, 127.93,
127.31, 127.09, 120.56, 115.06, 61.48, 21.46, 13.77.
624.1214.
2,5-Di-p-tolyl-3-(p-tolylthio)-1H-pyrrole (3da)
Yield: 105 mg (75%); white solid; mp 121–122 °C.
HRMS (ESI): m/z [M + H]+ calcd for C26H24NO4S: 446.1426; found:
446.1419.
FTIR (KBr): 3454, 2922, 2854, 1502, 1490, 1463, 808 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.60 (s, 1 H), 7.54 (d, J = 8.2 Hz, 2 H),
7.40 (d, J = 8.2 Hz, 2 H), 7.19 (dd, J = 8.2, 2.5 Hz, 4 H), 7.10 (d, J =
8.3 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 2 H), 6.61 (d, J = 2.8 Hz, 1 H), 2.36 (s,
3 H), 2.35 (s, 3 H), 2.27 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 137.25, 136.60, 136.38, 135.85, 134.42,
132.35, 129.66, 129.53, 129.35, 128.97, 128.83, 126.73, 126.15,
123.67, 113.61, 108.08, 21.20, 21.14, 20.85.
1,4-Di-p-tolyl-2-(p-tolylthio)butane-1,4-dione (6)
To an oven-dried sealed tube equipped with a magnetic stir bar was
added (E)-1,4-di-p-tolylbut-2-ene-1,4-dione (1n; 200 mg, 0.757
mmol), 4-methylbenzenethiol (2b; 103 mg, 0.832 mmol) and acetic
acid (5 mL). The tube was then sealed with a screw-type cap and the
resulting reaction mixture was placed in the oil bath at 120 °C with
stirring. The progress of the reaction was monitored by TLC. Upon
completion of the reaction, the mixture was cooled to r.t. and extract-
ed with EtOAc (3 × 25 mL). The extract was then washed with aque-
ous brine solution. After drying over Na2SO4 and evaporation, the
crude product was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc) to afford product 6.
HRMS (ESI): m/z [M + H]+ calcd for C25H24NS: 370.1629; found:
370.1630.
Ethyl 2,5-Diphenyl-4-(p-tolylsulfinyl)-1H-pyrrole-3-carboxylate
(4)
To a round-bottom flask containing a solution of 3ab (100 mg, 0.242
mmol) in CH2Cl2 (5 mL) was added m-chloroperoxybenzoic acid (m-
CPBA) (41.73 mg, 0.242 mmol). The reaction mixture was stirred at r.t.
for 5 h and the progress of the reaction was monitored by TLC. Upon
completion of the reaction, the mixture was washed with aq. NaOH
solution and the layers were separated. The aq. layer was further ex-
tracted with CH2Cl2 (2 × 20 mL) and the combined organics were
Yield: 234 mg (80%); pale-yellow solid; mp 91–92 °C.
FTIR (KBr): 3060, 2921, 1673, 1604, 1322, 1183, 812 cm–1
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 8.1 Hz, 2 H), 7.85 (d, J =
8.1 Hz, 2 H), 7.27 (dd, J = 14.7, 7.0 Hz, 6 H), 7.12 (d, J = 7.9 Hz, 2 H),
5.11 (dd, J = 9.4, 4.3 Hz, 1 H), 3.86 (dd, J = 17.9, 9.4 Hz, 1 H), 3.47 (dd,
J = 18.0, 4.4 Hz, 1 H), 2.45 (s, 3 H), 2.42 (s, 3 H), 2.35 (s, 3 H).
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

J
V. Rajeshkumar et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3):  = 197.22, 194.54, 144.15, 143.77,
139.29, 135.25, 133.82, 133.25, 129.83, 129.21 (2C), 128.92, 128.22,
127.40, 45.84, 40.71, 21.65 (2C), 21.20.
HRMS (ESI): m/z [M + H]+ calcd for C25H25O2S: 389.1575; found:
389.1583.
A.; Vacondio, F.; Arosio, D.; Bianchini, F.; Zanardi, F. J. Med.
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Steinbaugh, B. A.; Sun, K.; Tait, B. D.; Kowala, M. C.; Trivedi, B. K.;
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2,5-Di-p-tolyl-3-(p-tolylthio)-1H-pyrrole (3da)
To an oven-dried sealed tube equipped with a magnetic stir bar was
added 1,4-di-p-tolyl-2-(p-tolylthio)butane-1,4-dione
6 (100 mg,
0.257 mmol), ammonium formate (41 mg, 0.643 mmol) and acetic
acid (2 mL). The tube was then sealed with a screw-type cap and the
resulting reaction mixture was placed in an oil bath at 120 °C with
stirring. The progress of the reaction was monitored by TLC. Upon
completion of the reaction, the reaction mixture was cooled to r.t. and
extracted with EtOAc (3 × 15 mL). The extract was then washed with
aqueous brine solution. After drying over Na2SO4 and evaporation, the
crude product was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc) to afford 3da (82 mg, 86%).
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Funding Information
We thank the Department of Science and Technology (DST), New Del-
hi, India for the financial support for this work under a DST-INSPIRE
faculty scheme (DST/INSPIRE/04/2016/000295).
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Acknowledgment
We thank the National Institute of Technology Tiruchirappalli for the
use of infrastructures and facilities.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690024.
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(15) CCDC 1895966 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
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(17) The intermediate compound 6 was completely characterized by
1H and 13C NMR spectroscopy and HRMS. For details, see the
Supporting Information.
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