In(OTf)3-catalysed one-pot versatile pyrrole synthesis through domino annulation of α-oxoketene-N,S-acetals with nitroolefins

Article abstract of DOI:10.1039/c4ob00781f

In(OTf)₃-catalyzed robust and sustainable one-pot access to previously unknown and synthetically demanding polysubstituted pyrroles via [3 + 2] annulation of α-oxoketene-N,S-acetals with β-nitrostyrenes has been achieved under solvent-free conditions. The merit of this domino Michael addition/cyclization sequence is highlighted by its operational simplicity, short reaction time (5-10 min), good to excellent yields, tolerance of a large variety of functional groups, and efficiency of producing two new (C-C and C-N) bonds and one highly functionalized pyrrole ring in a single operation, which make it an ideal alternative to existing methods. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00781f

Organic &
Biomolecular Chemistry
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In(OTf)3-catalysed one-pot versatile pyrrole
synthesis through domino annulation of
Cite this: Org. Biomol. Chem., 2014,
12, 5484
α-oxoketene-N,S-acetals with nitroolefins†
Abhijeet Srivastava,a Gaurav Shukla,a Anugula Nagaraju,a Girijesh Kumar Verma,a
Keshav Raghuvanshi,b Raymond C. F. Jonesc and Maya Shankar Singh*a
In(OTf)3-catalyzed robust and sustainable one-pot access to previously unknown and synthetically
demanding polysubstituted pyrroles via [3 + 2] annulation of α-oxoketene-N,S-acetals with β-nitrosty-
renes has been achieved under solvent-free conditions. The merit of this domino Michael addition/cycli-
zation sequence is highlighted by its operational simplicity, short reaction time (5–10 min), good to
excellent yields, tolerance of a large variety of functional groups, and efficiency of producing two new
(C–C and C–N) bonds and one highly functionalized pyrrole ring in a single operation, which make it an
ideal alternative to existing methods.
Received 15th April 2014,
Accepted 3rd June 2014
DOI: 10.1039/c4ob00781f
www.rsc.org/obc
Introduction
Pyrroles, one of the prominent and ubiquitous privileged
N-heterocyclic pharmacophores, exhibit diverse biological and
therapeutic activities,1 and constitute the core structural motif
of numerous natural products,2 medicinal agents,3 catalysts
and conducting polymers.4 Among the various pharmacological
profiles of pyrrole derivatives, their anti-bacterial,5a anti-inflam-
matory,5b,c anti-oxidant,5d,e anti-tumor,5f–h anti-fungal,5i–k and
immune suppressant activities5l seem to be well documented.
Chart 1 constitutes notable privileged medicinal scaffolds
having multiple substituted pyrroles.6 Furthermore, pyrrole
based derivatives have broad applications in molecular
optics,7a electronics,7b and as gas sensors for organic com-
pounds.7c Moreover, they are also widely employed as versatile
building blocks in organic synthesis.8
Chart 1 Selected
compounds.
examples
of
pyrrole-based
pharmaceutical
useful tools, most of them suffer from significant limitations
such as multiple steps, functional group compatibility, pre-
functionalized substrates, expensive catalysts/reagents, long
reaction times and harsh reaction conditions. Recently, a
number of strategies14–18 are employed for the synthesis of pyr-
roles. Rueping et al.19 reported the synthesis of pyrroles
through domino reaction of enaminones with β-bromonitro-
styrenes (Scheme 1). The above published protocols not only
showcase the power of advances in organic methodology but
also provide proof of the vibrant activity in this field. In spite
of these outstanding efforts, it is still challenging to prepare
polysubstituted pyrroles possessing diverse substituents
directly from readily available precursors in a single synthetic
operation in an environmentally benign fashion.
Traditional pyrrole syntheses9–11 generally require the
initial preparation of an intermediate that subsequently under-
goes a cyclization reaction. In general, pyrroles are prepared by
cycloaddition ([4 + 1] and [3 + 2]) reactions12 or intramolecular
cyclization reactions.13 Albeit the reported approaches are
aDepartment of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-
05, UP, India. E-mail: mssinghbhu@yahoo.co.in; Fax: +91-542-2368127;
Tel: +91-542-6702502
bInstitut für Organische und Biomolekulare Chemie, Georg-August-Universität,
Tammannstr. 2, 37077 Göttingen, Germany. E-mail: raghuvanshikeshav@gmail.com
cDepartment of Chemistry, Loughborough University, Loughborough, Leics,
LE11 3TU, UK. E-mail: r.c.f.jones@lboro.ac.uk
A possible retrosynthetic analysis for the construction of
pyrroles is given in Scheme 2, which comprises the use of
simple and easily available synthons such as binucleophilic
†Electronic supplementary information (ESI) available. CCDC 906650 and
946357. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob00781f
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Table 1 Optimization studies
Entry
Solvent
Catalyst (mol%)
T (°C)
Time
Yielda (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
MeOH
H2O
None
None
None
None
None
None
None
None
FeCl3 (10)
AlCl3 (10)
InBr3 (10)
CuBr2(10)
SbCl3 (10)
SnCl4 (10)
In(OTf)3 (10)
In(OTf)3 (5)
In(OTf)3 (15)
In(OTf)3 (10)
rt
55
Reflux
Reflux
Reflux
55
80
100
55
55
55
55
55
55
55
55
55
Reflux
72 h
11 h
9 h
20 h
22 h
8 h
55
64
68
55
50
55
40
15
80
55
82
63
85
82
92
76
92
74
None
None
None
None
None
None
None
None
None
None
None
None
EtOH
6 h
4 h
Scheme 1 Synthetic strategies for the construction of pyrroles.
9
30 min
20 min
15 min
40 min
20 min
15 min
5 min
10 min
5 min
5 min
10
11
12
13
14
15
16
17
18
a Isolated pure yields.
Scheme 2 A retrosynthetic disconnection approach for the synthesis
of pyrroles.
substrates under different conditions (Table 1). Initially, the
equimolar amount of 1a and 2a was treated in EtOH at room
temperature without any catalyst. The work up of the reaction
afforded 3-benzoyl-2-(methylthio)-1,4-diphenylpyrrole 3aa in
55% yield after 72 h (Table 1, entry 1). In an attempt to
increase the yield of 3aa, the above model reaction was further
investigated at 55 °C and in refluxing EtOH. The work up of
the reaction provided the desired pyrrole 3aa in 64% and 68%
yields, respectively, reducing the time significantly (Table 1,
entries 2 and 3). A brief screen of other protic solvents like
MeOH and H2O afforded 3aa in 55% and 50% yields, respect-
ively, taking more than double the time (Table 1, entries 4 and
5). Because of the increasing public concern for the harmful
effects of organic solvents over environment and human body,
we carried out the above model reaction under solvent-free
conditions at different temperatures. Notably, the reaction
proceeded smoothly at 55 °C furnishing the desired pyrrole 3aa
in 55% yield (Table 1, entry 6). Higher temperatures reduced
the yield of 3aa due to decomposition of the substrates
(Table 1, entries 7 and 8).
Scheme 3 One-pot synthesis of polysubstituted pyrroles.
α-oxoketene-N,S-acetals and bielectrophilic β-nitrostyrenes. In
continuation of our ongoing research for the development of
new methodologies for various heterocyclic systems by exploit-
ing the reactions of ketene-S,S/N,S-acetals,20,21 we envisioned
to explore α-oxoketene-N,S-acetals for the construction of
highly substituted pyrroles for the first time.
Herein, we report a rapid and efficient one-pot synthesis of
highly substituted pyrroles via coupling of α-oxoketene-N,S-
acetals with (E)-β-nitrostyrenes catalyzed by a Lewis acid under
solvent-free conditions at moderate temperature (Scheme 3).
With a view to optimize the reaction conditions for
maximum yield and lesser reaction time, the model reaction
was carried out in the presence of Lewis acid (LA) catalysts
such as FeCl3, AlCl3, InBr3, CuBr2, SbCl3, SnCl4 and In(OTf)3
under solvent-free conditions at 55 °C (Table 1, entries 9–15).
A radical change in reaction time was observed while using
various Lewis acids, and to our great pleasure 10 mol% of
Results and discussion
The feasibility of the coupling reaction was examined using In(OTf)3 catalyzed the reaction efficiently and afforded the
α-oxoketene-N,S-acetal 1a and (E)-β-nitrostyrene 2a as the test desired pyrrole 3aa in 92% yield within 5 min (Table 1, entry 15).
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Table 2 Scope of substrates for tetrasubstituted pyrroles
Table 3 Scope of N-substituted α-oxoketene-N,S-acetals
Time Yielda
Product (min) (%)
Time Yielda
Product (min) (%)
Entry R1
R3
Entry R1/R2
R3
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (2a)
4-MeC6H4 (2b)
4-OMeC6H4 (2c) 3ac
4-NO2C6H4 (2d) 3ad
4-NO2C6H4 (2d) 3bd
3aa
3ab
5
5
5
8
7
5
5
7
10
6
6
8
8
6
5
9
6
6
92
94
95
72
73
89
90
70
62
78
82
70
74
80
87
68
72
84
1
2
3
4-BrC6H4/Me (1h)
3-OHC6H4/n-butyl (1i) 4-OMeC6H4 (2c) 3ic
C6H5/cyclohexyl (1j) 4-OMeC6H4 (2c) 3jc
C6H5 (2a)
3ha
5
8
5
82
77
84
a Isolated pure yields.
4-MeC6H4 (1b)
4-OMeC6H4 (1c) C6H5 (2a)
4-OMeC6H4 (1c) 4-MeC6H4 (2b)
4-OMeC6H4 (1c) 4-NO2C6H4 (2d) 3cd
4-CF3C6H4 (1d)
4-PhC6H4 (1e)
4-PhC6H4 (1e)
4-PhC6H4 (1e)
2-Furyl (1f)
2-Furyl (1f)
2-Furyl (1f)
3ca
3cb
9
4-MeC6H4 (2b)
C6H5 (2a)
4-MeC6H4 (2b)
4-FC6H4 (2e)
C6H5 (2a)
4-MeC6H4 (2b)
4-OMeC6H4 (2c) 3fc
4-NO2C6H4 (2d) 3fd
3db
3ea
3eb
3ee
3fa
10
11
12
13
14
15
16
17
18
3fb
2-Furyl (1f)
2-Thienyl (1g)
2-Thienyl (1g)
C6H5 (2a)
4-MeC6H4 (2b)
3ga
3gb
a Isolated pure yields.
Scheme 4 Substrate functionalization on nitrostyrene. aIsolated pure
yields.
Next, reduction in the amount of LA catalyst resulted in lower
yield of the desired product, and increasing the catalyst
loading did not show any improvement (Table 1, entries 16
and 17). Finally, when the model reaction was carried out in
refluxing ethanol in the presence of 10 mol% of In(OTf)3, 3aa
was obtained in 74% yield in 5 h (Table 1, entry 18). Conse-
quently, the optimum reaction condition was achieved by
employing equimolar amounts of 1a and 2a in the presence of
10 mol% of In(OTf)3 at 55 °C under solvent-free conditions.
Having found an optimum reaction condition, we explored
the scope of the substrates and functional group tolerance by
synthesizing twenty-six new tetra- and penta-substituted pyr-
roles with high functionalities from different α-oxoketene-N,S-
acetals (1a–j) and (E)-β-nitrostyrenes (2a–h) as shown in Tables
2 and 3 and Schemes 4 and 5. In all products 2-thiomethyl
substituent that stem from α-oxoketene-N,S-acetals was kept
constant. The electron-donating groups at R3 of nitrostyrenes
(2b, 2c) gave a slightly higher yield of the product (Table 2,
entries 2, 3, 7, 9, 11, 14, 15, and 18) as compared to electron-
withdrawing groups at R3 of nitrostyrenes (2d, 2e) (Table 2,
entries 4, 5, 8, 12, and 16). Similarly, the electron-donating
group at R1 of α-oxoketene-N,S-acetal (1c) provides significantly
higher yield as compared with the electron-withdrawing group
(1d) (Table 2, entry 6 vs. entry 9).
Scheme 5 Synthesis of pentasubstituted pyrroles. aIsolated pure yields.
mized conditions to obtain the corresponding tetrasubstituted
pyrroles in 68–87% yields (Table 2, entries 10–18).
The scope of α-oxoketene-N,S-acetal is not limited to R2 as
phenyl only but various substituents have also been screened
as shown in Table 3. Methyl, n-butyl and cyclohexyl substitu-
ents also provided good yields under similar reaction con-
ditions (Table 3).
In order to further derivatise the pyrrole moiety, we pre-
pared functionally rich nitrostyrenes 2f and 2g from 2-ethynyl-
benzaldehyde and p-methoxycinnamaldehyde, respectively.
Treatment of α-oxoketene-N,S-acetals 1c and 1e with the nitro-
styrene 2f provided pyrroles 3cf and 3ef in 81% and 72%
yields, respectively. Treatment of α-oxoketene-N,S-acetal 1a
with (E)-β-nitrostyrene 2g gave pyrrole 3ag in 67% yield
To illustrate the broad synthetic utility and generality of our
developed methodology, we further treated α-oxoketene-N,S-
acetal bearing extended aromatic ring biphenyl (1e), and
heteroaryl groups like 2-furyl (1f) and 2-thienyl (1g) with
different (E)-β-nitrostyrenes separately under the above opti-
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(Scheme 4). These three examples also exhibited functional
group tolerance towards the Lewis acid catalyst.
Next, we turned our attention to expand the diversity of this
protocol for the synthesis of pentasubstituted pyrroles. Thus,
upon treatment of (E)-β-methyl-β-nitrostyrene 2h with α-oxo-
ketene-N,S-acetals 1d and 1f under previously described one-
pot optimised reaction conditions furnished pentasubstituted
pyrroles 3dh and 3fh in 66% and 79% yields, respectively
(Scheme 5).
Fig. 1 ORTEP diagrams of 3ga and 3eb.
Considering the high electronic efficacy exerted by the
various electron-rich and electron-deficient substituents, we
performed intermolecular competition experiments with two
different α-oxoketene-N,S-acetals, first containing an electron-
donating group 1c and second an electron-withdrawing group
1d with simple β-nitrostyrene 2a in an equimolar ratio. It has
been observed that the product pyrrole 3ca derived from α-oxo-
ketene-N,S-acetal 1c was major (70%) and 3da formed from 1d
was minor (30%) revealing an electron-rich substrate to be
more readily functionalized (Scheme 6a). In the next attempt,
we performed the reaction of α-oxoketene-N,S-acetal 1a with
two different (E)-β-nitrostyrenes 2c and 2d in an equimolar
ratio (Scheme 6b). Exclusively, we found only one pyrrole 3ac
in 92% yield derived from nitrostyrene with an electron-donat-
ing group 2c. Unused starting material 2d was recovered in
90% yield highlighting the electron-rich (E)-β-nitrostyrene to
be converted more preferentially.
Scheme 7 Plausible mechanism for formation of pyrroles 3.
The structures of all the newly synthesized pyrroles 3 were
deduced from their satisfactory spectral (IR, 1H &13C NMR,
and HRMS) studies and unequivocally established by the X-ray
single crystal diffraction analysis of two representative com-
pounds 3ga and 3eb (Fig. 1).22 The mass spectra of these com-
pounds displayed molecular ion peaks at the appropriate m/z
values.
On the basis of the above experimental results together
with the related reports, a plausible reaction scenario for
domino [3 + 2] heteroannulation is outlined in Scheme 7. We
speculate that the reaction occurs as a tandem Michael
addition/intramolecular ring closure/elimination process. The
first step in the mechanism is believed to be the Michael
addition of α-oxoketene-N,S-acetal 1 through its Lewis acid
activated enolate form A to β-nitrostyrene 2 to generate the
open-chain Michael adduct intermediate B. Next, the Michael
adduct intermediate B undergoes successive intramolecular
N-cyclization followed by elimination of H2O and nitroxyl
(HNO) via intermediate C leading to the desired pyrrole 3.
Conclusions
In summary, we have designed and developed an operationally
simple, highly efficient one-pot direct method for the synthesis
of tetra- and pentasubstituted pyrroles under solvent-free mild
reaction conditions. Further, we have shown α-oxoketene-N,S-
acetals to be suitable partners in (3 + 2) annulation with
β-nitrostyrenes. In(OTf)3 worked very efficiently with various
functional group-substituted α-oxoketene-N,S-acetals and
β-nitrostyrenes yielding highly functionalized pyrroles in good
to excellent yields. The scope and diversity of the tolerated sub-
strates in this work is rather broad in comparison with the
reported ones. These structurally unique molecules
synthesized in an environmentally benign manner may
reveal potential application in future drug discovery and
Scheme 6 Intermolecular competition reactions.
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development. A possible reaction mechanism was proposed to
account for the coupling reaction.
2-(Methylthio)-4-(4-nitrophenyl)-1-phenyl-3-(p-tolyl)pyrrole
(3bd). Yellow (crayola) sticky solid. Rf = 0.6 (19 : 1 hexane–ethyl
acetate). 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz,
2H), 7.79 (d, J = 7.8 Hz, 2H), 7.52 (m, 6H), 7.39 (d, J = 8.4 Hz,
2H), 7.16 (d, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.00 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ = 193.4, 145.9, 144.2, 140.8, 138.4, 135.7,
130.1, 129.19, 129.11, 128.9, 128.5, 127.6, 127.5, 126.5, 123.9,
Experimental section
General procedure for synthesis of 3
A 25 mL round bottom flask equipped with a magnetic stirrer 123.8, 21.7, 20.6. IR (KBr) (νmax/cm−1): 2931, 1653, 1559, 1495,
was charged with α-oxoketene-N,S-acetal (1.0 mmol), 1340, 1247. MS calcd for C25H20N2O3S, m/z: 428.1195, found
β-nitrostyrene 2 (1.0 mmol) and 10 mol% of In(OTf)3. The reac- 429.2 [(M + H)+].
1
tion mixture was heated on an oil bath at 55 °C for the stipu-
3-(4-Methoxybenzoyl)-2-(methylthio)-1,4-diphenylpyrrole
lated period of time (monitored through TLC). After (3ca). White solid, mp = 135–137 °C. Rf = 0.48 (19 : 1 hexane–
completion of the reaction, the reaction mixture was extracted ethyl acetate). 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J =
with EtOAc, washed with water (2 × 20 mL) followed by brine 8.8 Hz, 2H), 7.54–7.46 (m, 5H), 7.32–7.10 (m, 5H), 6.84 (d, J =
(1 × 20 mL), and dried over anhydrous sodium sulphate. The 8.8 Hz, 2H), 3.82 (s, 3H), 2.05 (s, 3H). 13C NMR (100 MHz,
solvent was evaporated under vacuum and the crude residue CDCl3): δ = 193.1, 163.3, 138.9, 134.0, 132.4, 131.5, 129.1,
thus obtained was purified by silica gel column chromato- 129.0, 128.4, 128.1, 127.4, 126.6, 126.3, 125.8, 125.6, 122.7,
graphy to give pure pyrrole 3.
113.3, 55.4, 20.8. IR (KBr) (νmax/cm−1): 3019, 2920, 1650, 1595,
3-Benzoyl-2-(methylthio)-1,4-diphenylpyrrole (3aa). Yellow 1494, 1262. HRMS (EI) calcd for C25H21NO2S, m/z: 399.1293,
sticky solid. Rf = 0.55 (19 : 1 hexane–ethyl acetate). 1H NMR found 400.1367 [(M + H)+].
(300 MHz, CDCl3): δ = 7.88 (d, J = 7.2 Hz, 2H), 7.51–7.38 (m,
3-(4-Methoxybenzoyl)-2-(methylthio)-1-phenyl-4-(p-tolyl) pyrrole
5H), 7.31–7.04 (m, 9H), 2.02 (s, 3H). 13C NMR (75 MHz, (3cb). White solid, mp = 109–111 °C. Rf = 0.35 (19 : 1 hexane–
CDCl3): δ = 194.1, 138.8, 138.5, 133.9, 132.6, 129.9, 129.0, ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J =
128.2, 128.1, 128.0, 127.6, 126.5, 126.2, 122.8, 20.8. IR (KBr) 8.7 Hz, 2H), 7.51–7.24 (m, 6H), 7.18–7.14 (m, 2H), 7.00–6.95
(νmax/cm−1): 2912, 1670, 1222. HRMS (EI) calcd for C24H19NOS, (m, 2H), 6.82 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 2.24 (s, 3H), 2.00
m/z: 369.1187, found 369.1193 [M+].
(s, 3H). 13C NMR (100 MHz, CDCl3): δ = 193.2, 163.3, 139.0,
3-Benzoyl-2-(methylthio)-1-phenyl-4-(p-tolyl)pyrrole
(3ab). 135.8, 132.4, 131.5, 131.0, 129.1, 129.0, 128.0, 127.3, 126.6,
Yellow sticky solid. Rf = 0.55 (19 : 1 hexane–ethyl acetate). 1H 126.3, 125.8, 125.2, 122.6, 113.6, 113.4, 55.4, 21.1, 20.8.
NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 7.2 Hz, 2H), 7.51–7.24 IR (KBr) (νmax/cm−1): 3010, 2933, 1650, 1575, 1482, 1254.
(m, 8H), 7.15–7.10 (m, 2H), 6.96 (d, J = 7.8 Hz, 2H), 2.23 (s, HRMS (ESI) calcd for C26H23NO2S, m/z: 413.1449, found
3H), 2.01 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 194.3, 138.9, 414.1522 [(M + H)+].
138.5, 135.8, 132.5, 130.9, 129.9, 128.9, 128.7, 128.3, 128.08,
3-(4-Methoxybenzoyl)-2-(methylthio)-4-(4-nitrophenyl)-1-phe-
128.00, 127.4, 127.0, 126.5, 126.19, 126.11, 125.2, 122.6, 20.9, nylpyrrole (3cd). Yellow sticky solid. Rf = 0.50 (19 : 1 hexane–
20.7. IR (KBr) (νmax/cm−1): 2920, 1656, 1595, 1496, 1225. HRMS ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 8.04 (d, J =
(ESI) calcd for C25H21NOS, m/z: 383.1344, found 384.1399 8.7 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.51–7.39 (m, 8H), 6.84 (d,
[(M + H)+].
J = 8.4 Hz, 2H), 3.83 (s, 3H), 2.02 (s, 3H). 13C NMR (75 MHz,
3-Benzoyl-4-(4-methoxyphenyl)-2-(methylthio)-1-phenylpyrrole CDCl3): δ = 194.3, 176.7, 173.7, 140.9, 132.3, 129.1, 128.5,
(3ac). Yellow sticky solid. Rf
=
0.48 (19 : 1 hexane–ethyl 127.5, 126.5, 123.9, 113.6, 55.4, 20.6. IR (KBr) (νmax/cm−1):
acetate). 1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 7.2 Hz, 3005, 2941, 1666, 1580, 1442, 1338, 1262, 1211. HRMS (EI)
2H), 7.55–7.45 (m, 6H), 7.35 (dd, J = 7.8, 7.2 Hz, 2H), 7.22 (d, calcd for C25H20N2O4S, m/z: 444.1144, found 444.1137 [M+].
J = 8.7 Hz, 2H), 7.11 (s, 1H), 6.75 (d, J = 8.7 Hz, 2H), 3.74 (s,
2-(Methylthio)-1-phenyl-4-(p-tolyl)-3-(4-trifluoromethyl) pyrrole
3H), 2.06 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 194.3, 158.1, (3db). White solid, mp = 105–107 °C. Rf = 0.60 (19 : 1 hexane–
138.8, 138.5, 132.5, 129.9, 128.9, 128.7, 127.9, 126.5, 126.1, ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 8.01 (d, J =
125.9, 122.3, 113.7, 55.1, 20.7. IR (KBr) (νmax/cm−1): 2922, 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.44–7.28 (m, 6H), 6.94 (d,
1650, 1340, 1229. HRMS (ESI) calcd for C25H21NO2S, m/z: J = 8.8 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H), 2.02 (s,
399.9293, found 438.1102 [(M + K)+].
3H). 13C NMR (75 MHz, CDCl3): δ = 184.3, 168.8, 143.4, 137.7,
3-Benzoyl-2-(methylthio)-4-(4-nitrophenyl)-1-phenylpyrrole 132.9, 132.48, 132.0, 131.6, 129.1, 127.3, 126.8, 125.3, 20.8,
(3ad). Yellow (crayola) sticky solid. Rf = 0.50 (19 : 1 hexane– 14.7. IR (KBr) (νmax/cm−1): 3077, 2921, 1557, 1537, 1480, 1386,
ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 1103. HRMS (EI) calcd for C26H20F3NOS, m/z: 451.1218, found
8.4 Hz, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.52–7.45 (m, 9H), 451.1229 [M+].
7.39–7.32 (m, 2H), 2.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ =
193.6, 146.0, 140.8, 138.4, 138.3, 133.1, 129.9, 129.2, 128.7, White crystalline solid, mp
1,4-Diphenyl-2-(methylthio)-3-(4-phenylbenzoyl)pyrrole (3ea).
103–105 °C, Rf 0.60
=
=
128.6, 128.3, 128.1, 127.8, 126.5, 124.2, 124.1, 123.8, 20.6. IR (19 : 1 hexane–ethyl acetate). 1H NMR (300 MHz, CDCl3): δ =
(KBr) (νmax/cm−1): 3064, 2922, 1651, 1595, 1513, 1341, 1228. 7.95 (d, J = 8.4 Hz, 2H), 7.58–7.08 (m, 18H), 2.05 (s, 3H). 13C
MS calcd for C24H17N2O3S, m/z: 414.1038, found 415.2 NMR (75 MHz, CDCl3): δ = 193.7, 145.1, 140.0, 138.8, 137.2,
[(M + H)+].
133.9, 130.6, 129.0, 128.8, 128.3, 128.1, 127.9, 127.6, 127.2,
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126.7, 126.5, 126.3, 126.2, 122.8, 20.8. IR (KBr) (νmax/cm−1): 8.7 Hz, 2H), 7.51–7.43 (m, 9H), 7.04 (d, J = 3.3 Hz, 1H), 6.42 (d,
3029, 2921, 1651, 1600, 1496, 1228. HRMS (ESI) calcd for J = 2.1 Hz, 1H), 2.08 (s, 3H). 13C NMR (75 MHz, CDCl3): δ =
C30H23NOS, m/z: 445.1500, found 446.1561 [(M + H)+].
180.0, 153.2, 146.7, 145.9, 141.0, 138.2, 129.1, 128.7, 128.6,
2-(Methylthio)-1-phenyl-3-(4-phenylbenzoyl)-4-(p-tolyl) pyrrole 127.5, 126.4, 124.0, 123.7, 120.0, 112.3, 20.6. IR (KBr) (νmax
/
(3eb). White crystalline solid, mp = 131–133 °C. Rf = 0.55 cm−1): 3100, 2915, 1665, 1555, 1465, 1421, 1224. HRMS (EI)
(19 : 1 hexane–ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = calcd for C22H16N2O4S, m/z: 404.0831, found 404.0830 [M+].
7.96 (d, J = 8.1 Hz, 2H), 7.58–7.35 (m, 12H), 7.23–7.12 (m, 3H),
1,4-Diphenyl-2-(methylthio)-3-(2-thienoyl)pyrrole
152–154 °C. Rf
(3ga).
0.45
6.98 (d, J = 7.8 Hz, 2H), 2.22 (s, 3H), 2.03 (s, 3H). 13C NMR White crystalline solid, mp
=
=
(75 MHz, CDCl3): δ = 193.8, 145.1, 140.0, 138.9, 137.2, 135.9, (19 : 1 hexane–ethyl acetate). 1H NMR (300 MHz, CDCl3): δ =
130.9, 130.6, 129.0, 128.9, 128.7, 128.0, 127.9, 127.4, 127.2, 7.54–7.41 (m, 8H), 7.31 (d, J = 7.2 Hz, 2H), 7.24–7.18 (m, 2H),
126.7, 126.5, 126.1, 122.6, 21.0, 20.8. IR (KBr) (νmax/cm−1): 7.11 (s, 1H), 6.90 (m, 1H), 2.08 (s, 3H). 13C NMR (75 MHz,
3030, 2926, 1643, 1602, 1495, 1446, 1229. HRMS (ESI) calcd for CDCl3): δ = 186.0, 145.6, 138.8, 134.9, 133.9, 129.0, 128.4,
C31H25NOS, m/z: 459.1657, found 460.1733 [(M + H)+].
4-(4-Fluorophenyl)-2-(Methylthio)-1-phenyl-3-(4-phenyl (νmax/cm−1): 3082, 2916, 1616, 1488, 1465, 1405, 1279, 1229.
benzoyl)pyrrole (3ee). Yellow crystalline solid, mp HRMS (EI) calcd for C22H17NOS2, m/z: 375.0752, found
149–152 °C. Rf = 0.55 (19 : 1 hexane–ethyl acetate). 1H NMR 375.0758 [M+].
128.1, 127.7, 127.5, 126.5, 126.3, 125.6, 122.8, 21.0. IR (KBr)
=
(300 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2H), 7.59–7.36 (m,
2-(Methylthio)-1-phenyl-3-(2-thienoyl)-4-(p-tolyl)pyrrole (3gb).
12H), 7.25–7.21(m, 2H), 7.11 (s, 1H), 6.90–6.85 (m, 2H), 2.04 (s, White crystalline solid, mp
= 157–159 °C. Rf = 0.40
3H). 13C NMR (75 MHz, CDCl3): δ = 193.6, 184.7, 166.5, 145.4, (19 : 1 hexane–ethyl acetate). 1H NMR (400 MHz, CDCl3): δ =
140.0, 138.8, 137.1, 130.5, 129.2, 129.0, 128.8, 128.2, 128.0, 7.57–7.53 (m, 5H), 7.51–7.46 (m, 2H), 7.25 (s, 1H), 7.13 (s, 1H),
127.2, 126.7, 126.5, 125.2, 122.8, 115.4, 115.1, 20.7. IR (KBr) 7.06 (d, J = 8 Hz, 2H), 6.95 (dd, J = 4.8, 4.0 Hz, 1H), 2.28 (s,
(νmax/cm−1): 2920, 1634, 1494, 1461, 1211. HRMS (EI) calcd for 3H), 2.10 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 186.3, 145.7,
C30H22FNOS, m/z: 463.1406, found 463.1426 [M+].
138.9, 136.0, 135.0, 134.0, 131.0, 129.2, 129.1, 128.9, 128.2,
1,4-Diphenyl-2-(methylthio)-3-(2-furoyl)pyrrole (3fa). White 127.9, 127.4, 126.6, 125.9, 125.6, 122.7, 22.7, 21.1. IR (KBr)
crystalline solid, mp = 148–150 °C. Rf = 0.40 (19 : 1 hexane– (νmax/cm−1): 3077, 2914, 1617, 1495, 1406, 1230. HRMS (EI)
ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 7.49–7.41 (m, calcd for C23H19NOS2, m/z: 389.0908, found 389.0902 [M+].
6H), 7.30 (d, J = 7.2 Hz, 2H), 7.24–7.09 (m, 4H), 6.93 (d, J =
3-(4-Bromobenzoyl)-4-phenyl-2-(methylthio)-1-methylpyrrole
0.48 (19 : 1 hexane–ethyl
3.3 Hz, 1H), 6.34 (d, J = 1.8 Hz, 1H), 2.10 (s, 3H). 13C NMR (3ha). Brown sticky solid. Rf
=
(75 MHz, CDCl3): δ = 180.7, 153.4, 146.4, 138.8, 134.1, 129.0, acetate). 1H NMR (300 MHz, CDCl3): δ = 7.61 (d, 2H, J =
128.3, 128.2, 127.9, 127.4, 127.2, 126.5, 126.2, 126.0, 122.8, 8.4 Hz), 7.36 (d, 2H, J = 8.4), 7.13–7.08 (m, 5H), 6.92 (s, 1H),
119.8, 112.0, 111.9, 20.9. IR (KBr) (νmax/cm−1): 3116, 2917, 3.80 (s, 3H), 2.30 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 192.8,
1633, 1492. HRMS (EI) calcd for C22H17NO2S, m/z: 359.0980, 137.4, 134.1, 131.3, 131.1, 128.2, 127.7, 127.3, 126.1, 125.8,
found 359.0973 [M+].
3-(2-Furoyl)-2-(methylthio)-1-phenyl-4-(p-tolyl)pyrrole (3fb). 385.0136, found 386.0219 [(M + H)+].
122.4, 34.0, 21.0. HRMS (EI) calcd for C19H16BrNOS, m/z:
Yellow amorphous, mp = 127–129 °C. Rf = 0.42 (19 : 1 hexane–
3-(3-Hydroxybenzoyl)-4-(4-methoxyphenyl)-2-(methylthio)-
ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 7.50–7.44 (m, 1-(n-butyl)pyrrole (3ic). Brown solid, mp = 114–116 °C. Rf =
1
6H), 7.20 (d, J = 7.8 Hz, 2H), 7.06–7.01 (m, 3H), 6.93 (d, J = 3.0 0.60 (19 : 1 hexane–ethyl acetate). H NMR (300 MHz, CDCl3):
Hz, 1H), 6.35 (dd, J = 1.8, 1.8 Hz, 1H), 2.27 (s, 3H), 2.09 (s, 3H). δ = 7.18–7.13 (m, 2H), 7.00–6.98 (m, 3H), 6.79–6.74 (m, 2H),
13C NMR (75 MHz, CDCl3): δ = 180.8, 153.5, 146.3, 138.8, 6.60–6.57 (d, 2H, J = 8.7 Hz), 4.32 (s, 0.35H), 4.04 (2H, dd, J =
135.8, 131.1, 129.0, 128.9, 128.1, 127.3, 126.9, 126.5, 125.9, 7.5, 7.2 Hz), 3.61 (s, 3H), 2.19(s, 3H), 1.73–1.71 (m, 2H),
122.6, 119.8, 112.0, 111.9, 20.9. IR (KBr) (νmax/cm−1): 3099, 1.37–1.18 (m, 2H), 0.93–0.80 (m, 3H). 13C NMR (75 MHz, CDCl3):
2972, 1656, 1442, 1202. HRMS (EI) calcd for C23H19NO2S, m/z: δ = 194.8, 157.9, 156.7, 155.7, 140.1, 132.1, 130.0, 129.0, 128.7,
373.1136, found 373.1139 [M+].
127.0, 126.2, 125.7, 123.0, 122.3, 120.7, 119.9, 116.0, 114.4,
3-(2-Furoyl)-4-(4-methoxyphenyl)-2-(methylthio)-1-phenyl pyrrole 113.6, 55.1, 46.7, 33.6, 21.5, 19.9, 13.6, 0.9. HRMS (EI) calcd for
(3fc). White solid, mp = 140–143 °C. Rf = 0.40 (19 : 1 hexane– C23H25NO3S, m/z: 395.1555, found 418.1480 [(M + Na)+].
ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 7.50–7.45 (m,
3-Benzoyl-4-(4-methoxyphenyl)-2-(methylthio)-1-cyclohexyl
7H), 7.23 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 3.6 Hz, 1H), 6.77 (d, J = pyrrole (3jc). Brown solid, mp = 111–113 °C. Rf = 0.60
8.4 Hz, 2H), 6.36 (dd, J = 1.65, 1.8 Hz, 1H), 3.75 (s, 3H), 2.09 (s, (19 : 1 hexane–ethyl acetate). 1H NMR (300 MHz, CDCl3): δ =
3H). 13C NMR (75 MHz, CDCl3): δ = 180.8, 158.2, 153.5, 146.4, 7.84–7.76 (m, 2H), 7.40–7.35 (m, 1H), 7.27–7.22 (m, 2H),
138.8, 129.0, 128.6, 128.1, 126.7, 126.5, 125.6, 122.5, 122.4, 7.11–7.08 (m, 2H), 6.94 (s, 1H), 6.66 (d, 2H, J = 8.1 Hz), 3.69 (s,
119.9, 113.8, 112.1, 112.0, 55.2, 20.9. IR (KBr) (νmax/cm−1): 3H), 2.26 (s, 3H), 2.07–1.91 (m, 4H), 1.80–1.56 (m, 2H),
3010, 2982, 1643, 1446, 1236. HRMS (EI) calcd for 1.52–1.20 (m, 4H). 13C NMR (75 MHz, CDCl3): δ = 194.5, 157.8,
C23H19NO3S, m/z: 389.1086, found 389.1076 [M+].
138.8, 132.2, 129.9, 128.8, 128.6, 127.8, 127.2, 126.9, 125.4,
3-(2-Furoyl)-2-(methylthio)-4-(4-nitrophenyl)-1-phenyl pyrrole 124.8, 117.7, 117.6, 113.5, 55.3, 34.7, 25.8, 25.3, 21.7. HRMS
(3fd). Brown solid, mp = 87–89 °C. Rf = 0.45 (19 : 1 hexane– (EI) calcd for C25H27NO2S, m/z: 405.1762, found 428.1689
ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 8.08 (d, J = [(M + Na)+].
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4-(2-Ethynylphenyl)-2-(methylthio)-3-(4-methoxyphenyl)-1-
phenylpyrrole (3cf). Yellow (crayola) sticky solid. Rf = 0.45
Acknowledgements
(19 : 1 hexane–ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = We gratefully acknowledge the generous financial support
7.72 (d, J = 7.8 Hz, 2H), 7.42–6.94 (m, 10H), 6.65 (d, J = 7.8 Hz, from the Science and Engineering Research Board (SB/S1/
2H), 3.66 (s, 3H), 3.01 (s, 1H), 1.98 (s, 3H). 13C NMR (75 MHz, OC-30/2013), the Council of Scientific and Industrial Research
CDCl3): δ = 191.9, 162.8, 138.8, 136.7, 133.3, 132.2, 131.3, (02(0072)/12/EMR-II), and the UGC-UKIERI Partnership-2013
129.9, 129.5, 128.8, 128.4, 127.9, 126.4, 126.1, 126.0, 124.79, (184-16/2013(IC), New Delhi. K. R. is highly grateful to DAAD
124.72, 123.8, 120.2, 112.9, 112.8, 83.5, 80.4, 55.2, 20.7. and George-August-Universität-Göttingen for financial support
IR (KBr) (νmax/cm−1): 3279, 2921, 1643, 1596, 1497, 1461, 1253. as DAAD fellowship.
HRMS (EI) calcd for C27H21NO2S, m/z: 423.1293, found
422.1182 [(M − H)+].
4-(2-Ethynylphenyl)-2-(methylthio)-1-phenyl-3-(4-phenyl
benzoyl)pyrrole (3ef). Yellow (crayola) sticky solid. Rf = 0.45
Notes and references
(19 : 1 hexane–ethyl acetate). 1H NMR (300 MHz, CDCl3): δ =
7.87 (d, J = 8.1 Hz, 2H), 7.51–7.27 (m, 14H), 7.16–7.09 (m, 2H),
7.01 (d, J = 7.2 Hz, 1H), 3.11 (s, 1H), 2.09 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ = 192.6, 144.5, 140.0, 138.8, 137.2, 136.8,
133.3, 130.5, 130.0, 129.2, 128.9, 128.8, 128.6, 128.5, 128.0,
127.8, 127.0, 126.4, 126.2, 126.1, 124.7, 124.2, 120.4, 83.5, 80.5,
20.7. IR (KBr) (νmax/cm−1): 3281, 3058, 2921, 1645, 1599, 1497,
1227. HRMS (ESI) calcd for C32H23NOS, m/z: 469.1500, found
470.1572 [(M + H)+].
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3-Benzoyl-4-((E)-(4-methoxystyryl))-2-(methylthio)-1-phenyl
pyrrole (3ag). Brown sticky solid. Rf = 0.45 (19 : 1 hexane–ethyl
acetate). 1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.5 Hz, 2H),
7.53–7.41 (m, 9H), 7.17 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.7 Hz,
2H), 6.72 (d, J = 10.2 Hz, 2H), 3.74 (s, 3H), 1.93 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ = 193.8, 158.7, 139.2, 138.7, 132.5, 130.3,
129.9, 128.9, 128.1, 127.1, 127.0, 126.5, 123.7, 121.9, 118.1,
113.8, 55.1, 20.5. IR (KBr) (νmax/cm−1): 2921, 1596, 1509, 1249.
MS calcd for C27H23NO2S, m/z: 425.1449, found 424.1 [M+].
4-(4-Methoxyphenyl)-5-methyl-2-(methylthio)-1-phenyl-3-(4-tri-
fluoromethyl)pyrrole (3dh). Brown solid, mp = 164–166 °C. Rf =
4 (a) A. Berlin, B. Vercelli and G. Zotti, Polym. Rev., 2008, 48,
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0.55 (19 : 1 hexane–ethyl acetate). H NMR (300 MHz, CDCl3):
δ = 7.83 (d, J = 8.1 Hz, 2H), 7.53–7.46 (m, 5H), 7.35 (d, J =
6.6 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H),
3.69 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ = 192.6, 158.0, 141.8, 137.7, 133.6, 133.2, 132.8,
132.3, 130.7, 130.0, 129.9, 129.1, 128.7, 128.5, 126.7, 126.4,
125.5, 125.1, 124.6, 123.0, 113.5, 55.1, 21.1, 12.0. IR (KBr)
(νmax/cm−1): 3058, 3043, 2921, 1643, 1557, 1482, 1386, 1212,
1172. HRMS (ESI) calcd for C27H22F3NO2S, m/z: 481.1323,
found 481.1326 [(M + Na)+].
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3-(2-Furoyl)-4-(4-methoxyphenyl)-5-methyl-2-(methylthio)-
1-phenylpyrrole (3fh). White solid, mp = 185–188 °C. Rf =
1
0.38 (19 : 1 hexane–ethyl acetate). H NMR (400 MHz, CDCl3):
δ = 7.53–7.49 (m, 3H), 7.39 (dd, J = 8.4, 6.8 Hz, 3H), 7.18 (d, J =
8.8 Hz, 2H), 6.93 (d, J = 3.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H),
6.35 (dd, J = 3.4, 1.6 Hz, 1H), 3.77 (s, 3H), 2.09 [s, 6H, {3H each
of 5-methyl and 2-methylthio}]. 13C NMR (100 MHz, CDCl3):
δ = 180.9, 157.8, 153.6, 146.1, 137.8, 130.5, 129.8, 129.1,
128.69, 128.64, 128.0, 127.2, 125.6, 122.3, 119.4, 113.6, 111.9,
55.2, 21.3, 12.2. IR (KBr) (νmax/cm−1): 2920, 1629, 1471, 1249.
HRMS (EI) calcd for C24H21NO3S, m/z: 403.1242, found
403.1250 [M+].
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5490 | Org. Biomol. Chem., 2014, 12, 5484–5491
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