Heterogenized tungsten complex: An efficient and high yielding catalyst for the synthesis of structurally diverse tetra substituted pyrrole derivatives via four-component assembly

Article abstract of DOI:10.1016/j.tetlet.2013.08.016

An efficient, high yielding, and expeditious method has been developed for the synthesis of diversity oriented pyrrole derivatives via a four component, one-pot cyclocondensation reaction of amines, aldehydes, α-methylene ketones, and nitroalkanes using silica supported tungstic acid as a heterogeneous catalyst for the first time. The scope of the domino reaction is successfully explored toward synthesis of highly aryl-substituted pyrroles. The reaction was conveniently promoted by silica supported tungstic acid and the catalyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The advantageous features of this methodology are high atom-economy, operational simplicity, shorter reaction time, convergence, and facile automation.

Full text of DOI:10.1016/j.tetlet.2013.08.016

Accepted Manuscript
Heterogenized Tungsten Complex: an efficient and high yielding catalyst for
the synthesis of structurally diverse tetra substituted pyrrole derivatives via four-
component assembly
Amol B. Atar, Yeon Tae Jeong
PII:
S0040-4039(13)01356-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.016
TETL 43376
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 June 2013
29 July 2013
1 August 2013
Please cite this article as: Atar, A.B., Jeong, Y.T., Heterogenized Tungsten Complex: an efficient and high yielding
catalyst for the synthesis of structurally diverse tetra substituted pyrrole derivatives via four-component assembly,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.016
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Heterogenized Tungsten Complex: an efficient and
high yielding catalyst for the synthesis of structurally
diverse tetra substituted pyrrole derivatives via
four-component assembly
Leave this area blank for abstract info.
Amol B. Atar, Yeon Tae Jeong
Department of Image Science and Engineering,
Pukyong National University, Busan 608-737,
Republic of Korea
O
O
O
H
O
R1
R4
R3
R2 NH2
2
NO2
4
R3
R1
1
R4
Reflux, 4-6 Hrs
3
N
R2
R1=Aromatic, Heteroaromatic, aliphatic
R2= Aryl, Alkyl
5
24 examples
OC(CH ) , OCH CH
3
R3=
3 3
3,
R4= CH3, CH2-CH3
Fonts or abstract dimensions should not be changed or altered.

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Heterogenized Tungsten Complex: an efficient and high yielding catalyst for the
synthesis of structurally diverse tetra substituted pyrrole derivatives via four-
component assembly
Amol B. Atar , Yeon Tae Jeong ∗
Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient, high yielding, and expeditious method has been developed for the
synthesis of diversity oriented pyrrole derivatives via a four component, one-pot
cyclocondensation reaction of amines, aldehydes, α-methylene ketones and
nitroalkanes using Silica supported tungstic acid as a heterogeneous catalyst for the
first time. The scope of the domino reaction is successfully explored toward synthesis
of highly aryl-substituted pyrroles. The reaction was conveniently promoted by Silica
supported tungstic acid and the catalyst could be recovered easily after the reaction
and reused without any loss of its catalytic activity. The advantageous features of this
methodology are high atom-economy, operational simplicity, shorter reaction time,
convergence, and facile automation.
Available online
Keywords:
Silica supported tungstic acid
Heterogeneous catalyst
Tetra-substituted pyrroles
Four-component reaction
2009 Elsevier Ltd. All rights reserved.
———
∗ Corresponding author. Tel.: +82-51-629-6411; fax: +82-51-629- 6408; e-mail: ytjeong@pknu.ac.kr

2
Tetrahedron
bonds in a single operation and offer remarkable
advantages like convergence, operational
Introduction
Pyrroles and their derivatives are one of the most
important classes of heterocyclic compounds.1
They
simplicity, facile automation, and reduction in the
number of work-up, extraction, and purification
processes, and hence minimize waste generation,
rendering the transformations green.18-20
exhibit
extensive
biological
and
pharmacological properties.2 Many pyrrole
derivatives have shown interesting biological
properties
such
as
antibacterial,3
anti-
inflammatory,4 antioxidant,5 antitumor, antifungal6
and immune suppressant activities.7 Furthermore,
they are also extensively used in material science.8
Highly functionalized pyrroles are subunits of
heme, chlorophyll, bile pigments, vitamin B12 and
pyrrole alkaloids isolated from marine source.9
Pyrroles are very important building blocks in
organic synthesis as well as in the drug discovery.
A good example for this case is atorvastatin
calcium, the active material of famous drug named
as “Atorvastatin” (produced by Pfizer drug
company) (Figure 1). Atrovastatin (Lipitor) is a
drug for lowering cholesterol.10
Recently a four-component reaction of amines,
aldehydes, diketones and nitroalkanes is reported to
give diversity oriented pyrroles by using FeCl3,21
NiCl2.6H2O,22
iodine22 and
Ionic
liquid
[Hbim]BF4.23 But unfortunately, all four reports use
homogenous catalysts and ionic liquid. The use of
homogeneous catalysts has received little attention
as alternatives in alleviating some of the
limitations. Thus, the search for an inexpensive,
readily available, and convenient catalyst is
desirable. The usage of heterogeneous metal Lewis
acid catalyst instead of traditional homogeneous
metal Lewis and Brønsted acid catalysts could
possess
a
more environmentally friendly
alternative. The development of environmentally
friendly solid catalysts for the synthesis of fine
chemicals and pharmaceuticals is becoming an area
of growing interest because the use of
heterogeneous catalytic processes allows easier
separation, recovery, and recycling of the catalysts
from the reaction mixtures.24 Solid catalysts
provide numerous opportunities for recovering and
recycling catalysts from reaction environments.
Among the various heterogeneous catalysts,
particularly, silica gel-supported tungstic acid
(STA) has the advantages of low cost, ease of
preparation, environmentally friendly, highly
efficient, and catalyst recycling. It is evident from
the previous literature that silica gel-supported
tungstic acid has invoked enormous interest as a
green and a potential acid catalyst to construct
carbon–carbon and carbon–heteroatom bonds in
various organic transformations. 25
O
NH
Ca2+.3H20
N
F
HO
HO
O
O
Figure 1. Atorvastatin calcium
The classic synthetic approaches to pyrrole include
the Knorr,11 Paal–Knorr,12 and Hantzsch13
syntheses, which routinely involve multistep
synthetic operations and suffer from the substrate
scope limitation. Recently, many efforts have been
devoted to develop novel and highly efficient
synthetic protocols for pyrrole synthesis, such as
multi-component coupling reactions,14 transition
metal catalyzed cyclizations,15 cross-metatheses16
and [3+2] cycloadditions.17 Many of these reactions
have various drawbacks such as harsh reaction
conditions, availability of the starting materials,
regiospecificity, prolonged reaction time, functional
group compatibility. In the midst of them
multicomponent coupling reactions (MCRs) offer
significant advantages over classical stepwise
methods, because they allow the creation of several
In continuation of our ongoing effort to
development of new environmentally benign
methodology for the synthesis of a useful precursor
in the field of biology, industry, and key
intermediate for the multistep synthesis,26 we
decided to investigate the efficiency of supported
silica tungstic acid catalyst for the synthesis of
functionalized pyrroles. So herein we wish to report
the multicomponent reaction for the synthesis of
diversity oriented pyrrole derivatives from amines,
aldehydes, diketones and nitroalkanes using silica

3
8
tungstic acid as a reusable catalyst in quantitative
yield (Scheme 1). The reaction is easy to perform
BF3·SiO2
STA
4
4
56
88
86
82
85
86
82
85
9
and
allows
synthesizing
various
multi
10
11
12
13
14
15
STA
10
8
functionalized derivatives. These reaction work-up
procedures were simple and we can isolate products
with high purity and yields.
FeCl3·SiO2
FeCl3·SiO2
STA
24
24
4
O
O
O
H
O
R1
R4
R3
STA (05mol%)
STA (20mol%)
R2 NH2
2
NO2
4
R3
R1
1
R4
Reflux, 4-6 Hrs
4
N
3
R2
aAll reactions were carried out using aldehyde (1
mmol), amine (1.5 mmol), and active methylene
compounds (1 mmol) with nitromethane (1 mL)
under reflux. bYield obtained after column
chromatography.
5
Scheme 1
Result and discussion-
Initially, in search of the best catalytic system for
this one-pot synthesis, optimization of various
reaction parameters like different metal Lewis acid
catalysts, temperature, and solvent was carried out
(Table 1) with the standard reaction of anisidine, 4-
isopropylbenzaldehyde, tert butyl acetoacetate and
nitromethane. In order to establish the real
effectiveness of the catalyst for the synthesis of
tetra substituted pyrroles, a test reaction was
performed without catalyst using model reaction at
reflux condition. It was found that only a trace
amount of product 5a was obtained in the absence
of catalyst even after 24 h (Table 1, entry 1).
In search of effective, eco-friendly, and efficient
reusable catalytic system for this reaction, same test
reaction was performed with different supported
metal Lewis acid catalysts such as Cu–Sn (200
mesh, 100 mg), Cu(OTf)2·SiO2, Zn(OTf)2·SiO2,
TiO2·SiO2, BF3·SiO2, and ZnCl2·SiO2 (Table 1). To
study the role of SiO2, the reaction was tested with
SiO2 (100 mg) only, and we observed comparable
good yield as compared to catalyst free reaction
(Table 1, entry 2). Among all screened catalysts
STA gave the best result in view of yield and
reaction time (Table 1, entry 9). In contrast
ZnCl2·SiO2, BF3·SiO2, and TiO2·SiO2 did not afford
the desired product 5a in good yields (Table 1,
entries 3, 7, and 8). The supported Lewis acid
catalyst FeCl3·SiO2 shows effective, but required
time for the completion of the reaction which is
more as compared with STA catalyst with slightly
lower yield (Table 1, entry 11, 12). Careful analysis
of screened supported Lewis acid catalyst, shows
that silica supported metal triflates such as
Cu(OTf)2·SiO2, Zn(OTf)2·SiO2 were effective, but
promising results were obtained with silica
supported tugstic acid catalyst in lesser time with
better yield (Table 1, entry 5,6,9). The reaction was
also studied in various solvents such as
tetrahydrofuran, dichloromethane, dichloroethane,
and toluene; however, the yield of the desired
product was decreased. So, in this reaction
nitroalkane was used both as a solvent and as one
of the reactants as well.
Table 1. Four-Component Coupling Reactions
under Various Catalytic Conditionsa
O
O
H
O
NH2
O
O
3
N
Catalyst
NO2
O
Reflux, 4-24 Hrs
OMe
2
OMe
5a
1
4
Entry
Catalyst
(10mol%)
Time (h)
Yieldb
(%)
1
2
3
---
24
10
10
Trace
38
SiO2
ZnCl2·SiO2
46
4
CuSn(200mesh,
100mg)
Zn(OTf)2·SiO2
6
55
Once found best catalyst and solvent condition, we
studied the effect of varying amounts of STA
catalyst for this one-pot multicomponent system. In
order to evaluate the appropriate catalyst loading, a
model reaction was carried out using 5 and 20 mol
5
6
7
6
4
6
60
65
48
Cu(OTf)2·SiO2
TiO2·SiO2

4
Tetrahedron
% of STA at reflux (Table 1, entries 14 and 15). It
the yield nor shortens the conversion time. So, 10
mole % of catalyst were found to be the optimal
quantity and sufficient to push the reaction forward.
was found that 10 mol % of catalyst shows
maximum yield in minimum time. A larger loading
amount of the catalyst (20 mol %) neither increases
Table 2. STA-Catalyzed Four-Component Coupling Synthesis of Functionalized Pyrrolesa.
O
O
O
H
O
R1
R4
R3
R2 NH2
2
NO2
4
R3
R1
1
R4
Reflux, 4-6 Hrs
N
3
R2
5a-5y
Entry
R1
R2
R3
R4
Reaction Products Yieldb
time (h)
(%)
88
87
85
82
85
87
86
68
84
80
82
83
86
60
80
85
79
81
77
86
87
85
72
80
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-CH(CH3)2-C6H4
4-F-C6H4
4-OMe-C6H4
3,4-OMe-C6H3
4-OMe-C6H4
3,4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
3,4-OMe-C6H4
4-OMe-C6H4
4-CH3-C6H4
-C6H5
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
-CH2C6H5
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OC(CH3)3
OCH3
OCH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4
4.5
4
5
5.5
4
4.5
6
4
5.5
4
4.5
4
6
5
4.5
5
5.5
6
4
4.5
4
6
5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
2-F-C6H4
-C6H5
4-CH3-C6H4
2-Cl 6-F-C6H3
4-CH(CH3)2-C6H4
2-Thiophen
4-CH(CH3)2-C6H4
-C6H5
4-Cl-C6H4
4-Br-C6H4
4-Cl-C6H4
4-Cl-C6H4
-(CH2)2CH3
-4-Cl-C6H4
-C6H5
-4-CH3-C6H4
4-OCH3-C6H4
4-NO2-C6H4
4-F-C6H4
4-Br-C6H4
2-Thiophen
4-Cl-C6H4
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
5s
5t
5u
5w
5x
5y
OCH3
OCH3
OCH3
OCH3
-CH(CH3)2
OCH3
aAll reactions were carried out using aldehydes (1 mmol), amines (1.5 mmol), and active methylene
compounds (1 mmol) with nitroalkanes (1 mL) under reflux. bYield obtained after column chromatography.
With the optimized conditions in hand, we next
concentrated on the generality of the reaction with electron-deficient
various amines, aldehydes and active methylene corresponding products in good to excellent yields
summarized in Table 2. Both electron-rich and
aldehydes afforded the
ketones by using nitroalkanes as a solvent as well
as reactant at refluxed condition, the results are
(Table 2, entries 1-24). Clearly, the electronic effect
played an important role, with electron-rich

5
substituents on the benzene ring of aldehyde
affording the products in lower yields than the
corresponding strong electron-withdrawing groups.
Due to these successful results, various aromatic
aldehydes having substituents such as CH(CH3)2,
MeO, Me, NO2, F, Cl and Br in the aromatic ring
were examined with amines and active methylene
compounds in the presence of the same amount of
catalyst in similar reaction conditions and the
products 5a–y (Table 2, entries 1-24) were obtained
in good yields. The same methodology was further
extended with heteroaromatic aldehyde namely 2-
formylthiophene and the desired products 5h and
5x were isolated in 68% and 72% yields,
respectively (Table 2, entries 8 and 20). A possible
mechanism of this one pot reaction is expected on
the basis of reported literature.22
3
4
IIIrd cycle
IVth cycle
87
86
The reported as well as synthesized novel
compounds were further characterized by their
spectral properties (1H, 13C NMR, and HRMS).
Conclusion
In summary, an efficient, expeditious, operationally
simple, economical, and environmentally friendly
method has been developed for the synthesis of
tetra-substituted pyrroles via a four component;
one-pot reaction of amines, aldehydes, active
methylenes compounds and nitroalkanes using
Silica supported tungstic acid as heterogeneous
catalyst. The main advantage of this present
methodology is the simple work-up, easy recovery
of catalyst, no need for anhydrous condition, no
base or any additional activator required. To the
best of our knowledge this is the first report for the
synthesis of tetra-substituted pyrroles by using
Silica supported tungstic acid as heterogeneous
catalyst.
R2
O
O
NH
O
O
R1
STA
STA
R3
O
R2 NH2
NO2
H
R3
R3
O
N
OH
N
N
O
R1
H
O
R2
O
O
O
R1
O
R1
H
R3
R1
R3
N
R3
OH
OH
N
N
R2
H
NH
R2
N
OH
R2
Experimental section
Scheme 2. Plausible mechanism for the formation
of substituted pyrrole derivatives.
General Procedure for the Synthesis of silica
tungstic acid: A silica tungstic acid was prepared
by adopting the literature precedent B. Karami et
The reusability of the STA catalyst was also
examined. The catalyst was reused four times and
the results show that silica supported tungstic acid
(STA) can be reused as such without a significant
loss in yield (Table 3). The reusability of the
catalyst reduces the cost of the production.
Accordingly, after the first fresh run with 88%
yield, the catalyst was removed by filtration. The
recovered catalyst was dried under vacuum at 120
0C for 12 h and tested up to three more reaction
cycles. Recycling and reuse of the catalyst showed
minimal decreases in yields. The product 5a was
obtained in 88%, 88%, 87%, and 86% yields after
successive cycles. (Table 3, entries 1–4), thus
proving the catalyst’s reusability. Careful analysis
of Table 3 shows that there is no significant loss of
catalytic activity of this supported catalyst.
25
all. To a mixture of silica chloride (6.00 g) and
sodium tungstic (7.03 g) was added n-hexane (10
mL). The reaction mixture was stirred under
refluxing conditions for 4 h. After completion of
the reaction, the reaction mixture was filtered and
washed with distilled water, and dried and then
stirred in the presence of 0.1 N HCl (40 mL) for an
hour. Finally, the mixture was filtered, washed with
distilled water, and dried to afford STA.
General Procedure for the Synthesis of Pyrrole:
To a mixture of an amine (1 mmol) and b-ketoester
(1 mmol) in nitroalkane (1 mL) was added 10 mol
% STA and kept for stirring at room temperature.
The solid precipitate appeared after 10 minutes and
then aromatic aldehyde (1 mmol) was added into it.
Subsequently, the reaction mixture was kept for
refluxing in a heated oil-bath with constant stirring.
After completion of the reaction as monitored by
TLC, the reaction mixture was brought to room
temperature and the excess nitroalkane was
Table 3. The reusability of STA in the synthesis of
compound 5a
Entry
1
2
Reaction cycle
Ist (Fresh run)
IInd cycle
Yielda (%)
88
88

6
Tetrahedron
m/z): Calcd for C23H24FNO3 (m/z) 381.174; found:
removed on a rotary evaporator. Then, the crude
381.174.
residue was dissolved in 25 mL of dichloromethane
and the solid particle was removed by filtration.
The precipitate was further washed with 2 mL of
dichloromethane. The filtrate was washed with
water and dried over anhydrous sodium sulfate. The
organic extract was concentrated and the crude
residue was finally purified through a silica gel
column chromatography. The final product was
obtained by eluting with ethyl acetate and hexane
mixture (5:95)
Tert-butyl
phenyl-1H-pyrrole-3-carboxylate
1-(3,4-dimethoxyphenyl)-2-methyl-4-
(5d) Brown
1
sticky liquid; H NMR (400 MHz, CDCl3) δ 1.35
(s, 9H), 2.41 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 6.66
(s, 1H), 6.81-6.80 (d, J = 2.2 Hz, 1H), 6.88-6.85
(dd, J = 2.32 Hz, 8.4 Hz, 1H), 6.93-6.91 (d, J = 8
Hz, 1H), 7.26-7.24 (t, J = 8 Hz, 1H), 7.34-7.31 (m,
13
2H), 7.41-7.39 (m, 2H) ppm; C NMR (100 MHz,
CDCl3) δ 12.61, 28.30, 56.28, 56.32, 79.87, 110.30,
111.22, 113.20, 118.81, 120.91, 126.30, 126.37,
127.76, 129.47, 132.28, 136.18, 136.46, 149.00,
149.42, 165.43 ppm. HRMS (ESI, m/z): Calcd for
C24H27NO4 (m/z) 393.194; found: 393.194.
Tert-butyl
4-(4-isopropylphenyl)-1-(4-
methoxyphenyl)-2-methyl-1H-pyrrole-3-
1
carboxylate (5a) Brown sticky liquid; H NMR
(400 MHz, CDCl3) δ 1.27-1.27 (d, J = 6.96 Hz,
6H), 1.35 (s, 9H), 2.39 (s, 3H), 2.93-2.88 (m, 1H),
3.84 (s, 3H), 6.62 (s, 1H), 6.97-6.95 (d, J = 8.76
Hz, 2H), 7.20-7.18 (d, J = 8.08 Hz, 2H), 7.24-7.22
(d, J = 6.96 Hz, 2H), 7.32-7.30 (d, J = 8.08 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 12.61, 24.30,
28.27, 34.03, 55.72, 79.74, 113.23, 114.56, 120.75,
125.78, 126.34, 127.70, 129.39, 132.23, 133.63,
136.30, 146.85, 159.31, 165.54 ppm. HRMS (ESI,
m/z): Calcd for C23H31NO3 (m/z) 405.2304; found:
405.2301.
Tert-butyl
1-(4-methoxyphenyl)-2-methyl-4-p-
tolyl-1H-pyrrole-3-carboxylate (5e) Brown sticky
1
liquid; H NMR (400 MHz, CDCl3) δ 1.38 (s, 9H),
2.35 (s, 3H), 2.38 (s, 3H), 3.83 (s, 3H), 6.61 (s, 1H),
6.94 (s, 1H), 6.97 (s, 1H), 7.15-7.13 (d, J = 8 Hz,
1H), 7.23-7.19 (m, 2H), 7.30-7.28 (d, J = 8 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 12.65, 21.34,
28.34, 55.71, 79.82, 113.12, 114.55, 126.29,
127.71, 128.46, 129.29, 132.20, 133.12, 135.76,
136.27, 159.32, 165.50 ppm. HRMS (ESI, m/z):
Calcd for C24H27NO3 (m/z) 377.1991; found:
377.1989.
Tert-butyl
4-(4-fluorophenyl)-1-(3,4-
dimethoxyphenyl)-2-methyl-1H-pyrrole-3-
carboxylate (5b) Brown sticky liquid; H NMR
1
(400 MHz, CDCl3) δ 1.37 (s, 9H), 2.41 (s, 3H),
3.88 (s, 3H), 3.93 (s, 3H), 6.63 (s, 1H), 6.80-6.79
(d, J = 2.2 Hz, 1H), 6.87-6.85 (dd, J = 2.2 Hz, 8.44
Hz, 1H), 6.93-6.91 (d, J = 8.6 Hz, 1H), 7.04-7.00
(m, 2H), 7.37-7.33 (m, 2H) ppm; 13C NMR (100
MHz, CDCl3) δ 13.60, 29.28, 57.21, 80.88, 111.18,
112.08, 115.35, 115.55, 119.72, 121.87, 126.21,
131.78, 131.86, 133.05, 137.62, 149.95, 150.35,
161.60, 166.20 ppm. HRMS (ESI, m/z): Calcd for
C24H26FNO4 (m/z) 411.1846; found: 411.1848.
Tert-butyl
methoxyphenyl)-2-methyl-1H-pyrrole-3
4-(2-chloro-6-fluorophenyl)-1-(4-
carboxylate (5f) Brown sticky liquid; 1H NMR (400
MHz, CDCl3) δ 1.54 (s, 9H), 2.14 (s, 3H), 3.86 (s,
1H), 6.17-6.19 (d, J = 8 Hz, 1H), 6.97-6.93 (m,
2H), 7.02-7.00 (d, J = 8 Hz, 2H), 7.12-7.08 (m, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 19.63, 28.61,
55.74, 80.56, 96.70, 115.13, 115.45, 124.03,
128.33, 130.98, 143.04, 152.28, 159.76, 166.79
ppm. HRMS (ESI, m/z): Calcd for C23H23FClNO3
(m/z) 415.135; found: 415.135.
Tert-butyl
4-(2-fluorophenyl)-1-(4-
methoxyphenyl)-2-methyl-1H-pyrrole-3-
1
carboxylate (5c) Brown sticky liquid; H NMR
(400 MHz, CDCl3) δ 1.32 (s, 9H), 2.41 (s, 3H),
3.84 (s, 3H), 6.65 (s, 1H), 6.97-6.95 (d, J = 8.8 Hz,
1H), 7.12-7.04 (m, 2H), 7.24-7.21 (m, 4H) ppm;
13C NMR (100 MHz, CDCl3) δ 12.47, 28.17, 55.71,
79.70, 113.92, 114.57, 115.07, 115.29, 119.19,
121.35, 123.53, 124.45, 127.71, 128.17, 131.42,
132.04, 136.45, 159.38, 165.19 ppm. HRMS (ESI,
Tert-butyl
4-(4-isopropylphenyl)-1-(3,4-
dimethoxyphenyl)-2-methyl-1H-pyrrole-3-
carboxylate (5g) Brown sticky liquid; H NMR
(400 MHz, CDCl3) δ 1.27-1.25 (d, J = 8 Hz, 6H),
1.35 (s, 9H), 2.41 (s, 3H), 2.93-2.88 (m, 1H), 3.87
(s, 3H), 3.93 (s, 3H), 6.64 (s, 1H), 6.81-6.80 (d, J =
4 Hz, 1H), 6.88-6.85 (dd, J = 4 Hz, 8 Hz, 1H),
6.93-6.91 (d, J = 8 Hz, 1H), 7.20-7.18 (d, J = 8 Hz,
1

7
2H), 7.33-7.31 (d, J = 8 Hz, 2H) ppm; 13C NMR CDCl3) δ 12.83, 50.81, 55.75, 110.99, 114.66,
(100 MHz, CDCl3) δ 12.65, 24.30, 28.27, 34.03, 121.48, 125.38, 127.73, 127.97, 130.85, 131.84,
56.25, 56.29, 79.78, 110.26, 111.17, 113.26, 132.28, 134.30, 137.57, 159.56, 166.25 ppm.
HRMS (ESI, m/z): Calcd for C20H18ClNO3 (m/z)
355.0975; found: 355.0972.
118.77, 120.77, 125.80, 126.36, 129.37, 132.33,
133.55, 136.26, 146.90, 148.92, 149.36, 165.48
ppm. HRMS (ESI, m/z): Calcd for C27H33NO4 (m/z)
435.241; found: 435.241.
Methyl 4-(4-bromophenyl)-1-(4-methoxyphenyl)-2-
methyl-1H-pyrrole-3-carboxylate (5l) Brown sticky
1
liquid; H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H),
Tert-butyl
1-(4-methoxyphenyl)-2-methyl-4-
(5h)
3.70 (s, 3H), 3.85 (s, 3H), 6.64 (s, 3H), 6.98-6.96
(d, J = 8 Hz, 2H), 7.22-7.20 (d, J = 8 Hz, 2H), 7.25
(s, 1H), 7.28 (s, 1H), 7.45-7.43 (d, J = 8 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 12.82, 50.81,
55.74, 110.94, 114.65, 120.43, 121.43, 125.36,
127.71, 130.89, 130.93, 131.81, 134.77, 137.59,
159.55, 166.22 ppm. HRMS (ESI, m/z): Calcd for
C20H18BrNO3 (m/z) 399.0473; found: 399.0472.
(thiophen-2-yl)-1H-pyrrole-3-carboxylate
Brown sticky liquid; 1H NMR (400 MHz, CDCl3) δ
1.44 (s, 9H), 2.37 (s, 3H), 3.85 (s, 3H), 6.74 (s, 1H),
6.97-6.95 (d, J = 8 Hz, 2H), 7.02-7.00 (d, J = 8 Hz,
1H), 7.11-7.10 (d, J = 4 Hz, 1H), 7.21-7.18 (q, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 12.75, 28.43,
55.75, 80.07, 114.62, 121.19, 123.89, 126.20,
126.88, 127.76, 131.89, 136.11, 136.45, 159.49,
165.08 ppm. HRMS (ESI, m/z): Calcd for
C21H23NO3S (m/z) 369.1399; found: 369.1399.
Methyl 4-(4-chlorophenyl)-1-isopropyl-2-methyl-
1H-pyrrole-3-carboxylate (5u) Brown sticky liquid;
1H NMR (400 MHz, CDCl3) δ 1.42-1.41 (d, J = 4
Hz, 6H), 2.54 (s, 3H), 3.65 (s, 3H), 4.37-4.32 (m,
1H), 6.61 (s, 1H), 7.36-7.34 (d, J = 8 Hz, 2H), 7.22-
7.20 (d, J = 8 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 11.03, 23.07, 47.05, 50.32, 115.20,
124.81, 127.52, 130.19, 131.63, 134.65, 135.64,
166.14 ppm. HRMS (ESI, m/z): Calcd for
C16H18ClNO2 (m/z) 291.1026; found: 291.1026.
Tert-butyl
4-(4-isopropylphenyl)-2-methyl-1-p-
tolyl-1H-pyrrole-3-carboxylate (5i) Brown sticky
liquid; 1H NMR (400 MHz, CDCl3) δ 1.27-1.25 (d,
J = 8 Hz, 6H), 1.35 (s, 9H), 2.40 (s, 3H), 2.42 (s,
3H), 2.93-2.88 (m, 1H), 6.65 (s, 1H), 7.09-7.08 (d,
J = 4 Hz, 1H), 7.11 (s, 2H), 7.21-7.18 (dd, J = 4 Hz,
8 Hz, 2H), 7.28-7.27 (d, J = 4 Hz, 1H), 7.33-7.31
(q, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 13.38,
22.25, 25.22, 29.18, 34.93, 80.70, 114.45, 121.44,
124.44, 126.69, 130.31, 136.89, 140.47, 147.79,
166.45 ppm. HRMS (ESI, m/z): Calcd for
C26H31NO2 (m/z) 389.2355; found: 389.2356.
Acknowledgments
This work was supported by the Pukyong National
University Research Abroad Fund in 2012(PS-
2012-0910). The authors also thanks to Snehal H.
Dhotre.
Tert-butyl
2-methyl-1,4-diphenyl-1H-pyrrole-3-
carboxylate (5j) Brown sticky liquid; 1H NMR (400
MHz, CDCl3) δ 1.35 (s, 9H), 2.43 (s, 3H), 6.67 (s,
1H), 7.25-7.23 (d, J = 8 Hz, 2H), 7.34-7.29 (q, 4H),
7.46-7.45 (d, J = 4 Hz, 2H), 7.55-7.52 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 28.29, 79.90,
120.64, 126.31, 126.47, 127.75, 129.31, 129.48,
129.57, 132.31, 136.14, 137.32, 139.21, 165.43
ppm. HRMS (ESI, m/z): Calcd for C22H23NO2 (m/z)
333.1729; found: 333.1729.
References-
1. Black, D. StC.; '1H-Pyrroles', in Science of
synthesis, hetarenes and related ring systems.
Thieme Verlag, Stuttgart. 2001, 9, 441 – 552.
2. Bellur, E.; Langer, P. Tetrahedron Lett. 2005,
47, 2151-2154.
3. Daidone, G.; Maggio, B.; Schillaci, D.
Pharmazie. 1990, 45, 441-442.
Methyl 4-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-
4. a) Kimura, T.; Kawara, A.; Nakao, A.;
Ushiyama, S.; Shimozato, T.; Suzuki, K. PCT
Int Appl.CODEN:PIXXD2 WO 2000001688 A1,
200001132000, 173; b) Kaiser, D. G.; Glenn, E.
M. J. Pharm. Sci. 1972, 61, 1908-1911.
5. Demir, A. S.; Akhmedov, I. M.; Sesenoglu, O.
methyl-1H-pyrrole-3-carboxylate
(5k)
Brown
1
sticky liquid; H NMR (400 MHz, CDCl3) δ 2.40
(s, 3H), 3.70 (s, 3H), 3.86 (s, 3H), 6.64 (s, 1H),
6.99-6.97 (d, J = 8 Hz, 2H), 7.23-7.20 (dd, J = 4
Hz, 8 Hz, 2H), 7.30-7.28 (d, J = 8 Hz, 2H), 7.35-
7.33 (d, J = 8 Hz, 2H) ppm; 13C NMR (100 MHz,

8
Tetrahedron
Tetrahedron 2002, 58, 9793-9799.
4402-4421; (b) Hong, D.; Zhu, Y.; Li, Y.; Lin,
X.; Lu, P.; Wang, Y. Org. Lett. 2011, 13,
4668-4671; (c) Attanasi, O. A.; Favi, G.;
Mantellini, F.; Moscatelli, G.; Santeusanio, S.
J. Org. Chem. 2011, 76, 2860-2866; (d)
Galliford, C. V.; Scheidt, K. A. J. Org. Chem.
2007,72, 1811; (e) Lamande-Langle, S.;
Abarbri, M.; Thibonnet, J.; Duchene, A.;
Parrain, J. –L. Chem. Commun. 2010, 46, 5157-
5159.
6. Meshram, H. M.; Prasad, B. R. V.; Kumar, D.
A. Tetrahedron Lett. 2010, 51, 3477–3480.
7. Davis, F. A.; Bowen, K. A.; Xu, H.; Velvadapu,
V. Tetrahedron 2008, 64, 4174-4182.
8. For a review, see: (a) Higgins, S. J. Chem. Soc.
Rev. 1997, 26, 247-257; (b) Groenendaal, L.;
Meijer, E. W.; Vekemans, J. A. J. M. In
Electronic Materials: The Oligomer Approach;
Mullen, K., Wegner, G., Eds.; Wiley-VCH:
Weinheim, 1997; (c) Domingo, V. M.; Aleman,
C.; Brillas, E.; Julia, L. J. Org. Chem. 2001, 66,
4058–4061; (d) Novak, P.; Muller, K.;
15 (a) Bauer, I.; Knolker, H.; Top. Curr. Chem.
2012, 309, 203-253; (b) Cadierno, V.; Crochet,
P. Curr. Org. Synth. 2008, 5, 343-364; (c) Liu,
W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12,
312-315.
Santhanam, K. S. V.; Hass, O. Chem. Rev. 1997,
97, 207–282; (e) Ramanavicius, A.;
Ramanaviciene, A.; Malinauskas, A.
16 Donohoe, T. J.; Bower, J. F.; Chan, L. K. M.
Org. Biomol. Chem. 2012, 10, 1322-1328.
17 (a) Padwa, A.; Pearson, W. H. The Chemistry
of Heterocyclic Compounds, ed. E. C. Taylor
and P. Wipf, John Wiley & Sons, Inc. New
York, 2002, 59; (b) Larionov, O. V.; Meijere,
A. D. Angew. Chem., Int. Ed. 2005, 44, 5664-
5667; (c) Kamijo, S.; Kanazawa, C.;
Electrochem. Acta. 2006, 51, 6025–6037; (f)
Langley, P. J.; Davis, F. J.; Mitchell, G. R. J.
Chem. Soc., Perkin Trans. 1997, 2, 2229–2240;
(g) Li, X.-G.; Chen, R.-F.; Huang, M. R.; Zhu,
M. Z.; Chen, Q. J. Polym Sci., PartA: Polym.
Chem. 2004, 42, 2073–2092; (h) Kiskan, B.;
Akar, A.; Kizilcan, N.; Ustamehmetoglu, B. J.
Appl. Polym. Sci. 2005, 96,1830–1834.
Yamamoto,Y. J. Am, Chem. Soc. 2005, 127,
9260-9266; (d) Laia, F. M. R.; Pinho e Melo,
T. M. V. D. Tetrahedron Lett. 2009, 50, 6180-
6182; (e) Misra, N. C.; Panda, K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2007, 72, 1246-
1251; (f) Shi, F.; Luo, S. W.; Tao, Z. L.; He,
L.; Yu, J.; Tu, S. J.; Gong, L. Z. Org. Lett.
2011, 13, 4680-4683; (g) St-Cyr, D. J.; Morin,
M. S. T.; Belanger-Gariepy, F.; Arndtsen, B.
A.; Krenske, E. H.; Houk, K. N. J. Org. Chem.
2010, 75, 4261-4273; (h) Morin, M. S. T.; St-
Cyr, D. J.; Arndtsen, B. A. Org. Lett. 2010, 12,
4916-4919; (i) Galliford, C. V.; Scheidt, K. A.
J. Org.Chem. 2007, 72, 1811-1813.
9. Reisser, M.; Maas, G. J. Org. Chem. 2004, 69,
4913-4924.
10. Kappelle, P. J. W. H.; Dallinga-Thie, G. M.;
Dullaart, R. P.F.; Biochimica et Biophysica
Acta. 2010, 1801,89–94.
11. For selected examples of the Knorr synthesis:
(a) Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.;
Bolourtchian, M.; Saidi, M. R. Synlett, 2009,
2245-2248; (b)Alberola, A.; Ortega, A. G.;
Sadaba, M. L.; Sanudo, C. Tetrahedron 1999,
55, 6555-6566; (c) Shiner, C. M.; Lash, T.
D. Tetrahedron 2005, 61, 11628-11640.
12 For recent examples of the Paal–Knorr
synthesis: (a) Rahmatpour, A. J. Organomet.
Chem. 2012, 712, 15-19; (b) Aghapoor, K.;
Ebadi-Nia, L.; Mohsenzadeh, F.; Morad, M. M.;
Balavar, Y.; Darabi, H. R. J. Organomet.
Chem. 2012, 708–709, 25-30; (c) Minetto, G.;
Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J.
Org. Chem. 2005, 5277-5288; (d) Azizi, N.;
Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian,
M.; Saidi, M. R. Synlett. 2009, 2245-2248.
13 (a) Trautwein, A. W.; Submuth, R. D.; Jung, G.
Bioorg. Med. Chem. Lett. 1998, 8, 2381-2384;
(b) Herath, A.; Cosford, N. D. P. Org. Lett.
2010, 12, 5182-5185.
18. (a) Toure, B. B.; Hall, D. G. Chem. Rev. 2009,
109, 4439-4486; (b) Sunderhaus, J. D.; Martin,
S. F. Chem. Eur. J. 2009, 15, 1300-1308; (c)
Ganem, B. Acc. Chem. Res. 2009, 42, 463-472;
(d) Ismabert, N.; Lavilla, R. Chem. Eur. J. 2008,
14, 8444-8454; (e) D’Souza, D. M.; Muller, T.
J. J. Chem. Soc.Rev. 2007, 36, 1095-1108; (f)
Jang, B.; Shi, F.; Tu, S. T. Curr. Org. Chem.
2010, 14, 357-361; (g) Jiang, B.; Rajale, T.;
Wever, W.; Tu, S.-J.; Li, G. Chem. Asian J.
2010, 5, 2318-2335.
19. (a) Bannwarth, W.; Felder, E. Combinatorial
Chemistry; Wiley-VCH: Weinheim, 2000, 1,
209-237; (b) Zhu, J.; Bienayme, H.
14 For review: (a) Estevez, V.; Villacampa, M.;
Menendez, J. C. Chem. Soc. Rev. 2010, 39,
Multicomponent Reactions; Wiley-VCH:

9
Weinheim, 2005, 76-92 (c) Domling, A. Chem.
Rev. 2006, 106, 17; (d) Yu, J.; Shi, F.; Gong, L.
Z. Acc.Chem. Res. 2011, 44, 1156-1171; (e)
Domling, A.; Wang, W.; Wang, K. Chem. Rev.
2012, 112, 3083-3135; (f) Eckert, H.
701; d) Dindulkar, S. D.; Parthiban, P.; Jeong,
Y. T. Monatsh. Chem. 2012, 143, 113-118.
Molecules. 2012, 17, 1074-1102; See also the
Chemical Society Reviews issue on the rapid
formation of molecular complexity in organic
synthesis. Chem. Soc. Rev. 2009, 38, 2969-
3276.
20. (a) Balme, G.; Bossharth, E.; Monteiro, N. Eur.
J. Org. Chem. 2003, 4101-4111; (b) Orru, R. V.
A.; Greef, M. De. Synthesis 2003, 1, 471-1499;
(c) Bienayme, H.; Hulme, C.; Oddon, G.;
Schmitt,P. Chem. Eur. J. 2000, 6, 3321-3329;
(d) Grondal, C.; Jeanty, M.; Enders, D. Nat.
Chem. 2010, 2, 167-178; (e) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134-7186.
21. Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem.
2010, 75, 1674-1683.
22. (a)Khan, A. T.; Lal, M.; Bagdi, P. R.; Basha, R.
S.; Saravanan, P.; Patra, S. Tetrahedron Lett.
2012, 53, 4145-4150; (b) Reddy, G. R.;
Reddy,T. R.; Joseph, S. C.; Reddy, K. S.;
Pal, M. RSC Adv. 2012, 2, 3387-3395.
23. Meshram H.M. ; Babu B.M.; Kumar G.S.;
Thakur P.B.; Bangade V.M. Tetrahedron
Lett. 2013, 54, 2296-2302.
24.(a) Andrews, S. P.; Stepan, A. F.; Tanaka, H.;
Ley, S. V.; Smith, M. D. Adv. Synth. Catal.
2005, 347, 647-654; (b) Miao, T.; Wang, L.
Tetrahedron Lett. 2007, 48, 95-99; (c) Amali,
A. J.; Rana, K. R. Green Chem. 2009, 11, 1781-
1786; (d) Cai, M.; Zheng, G.; Zha, L.; Peng, J.
Eur. J.Org. Chem. 2009, 1585-1589; (e)
Trzeciak, A. M.; Mieczynska, E.; Ziolkowski, J.
J.; Bukowski, W.; Bukowska, A.; Noworol, J.;
Okal, J. New J. Chem. 2008, 32, 1124-1130; (f)
Ma, X.; Zhou, Y.; Zhang, J.; Zhu, A.; Jiang, T.;
Han, B. Green Chem. 2008, 10, 59-66; (g)
Mennecke, K.; Kirschning, A. Beilstein J. Org.
Chem. 2009, 5, 3762-3765.
25. a) Karami, B.; Ghashghaee, V.; Khodabakhshi,
S. Catal. Commun. 2012, 20, 71-75 b)
Khodabakhshi, S.; Karami, B. Catal. Sci.
Technol. 2012, 2, 1940-1944.
26. a) Atar, A. B.; Jeong, Y.T. Tetrahedron Lett.
2013, 54, 1302--1306; b) Reddy, M.V.; Reddy,
C.S.; Jeong, Y. T. Tetrahedron. 2012, 68,
6820-6828; c) Atar, A. B.; Dindulkar, S. D.;
Jeong, Y.T. Monatsh. Chem. 2013, 144, 695-

10
Tetrahedron
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Heterogenized Tungsten Complex: an efficient and
high yielding catalyst for the synthesis of structurally
diverse tetra substituted pyrrole derivatives via
four-component assembly
Leave this area blank for abstract info.
Amol B. Atar, Yeon Tae Jeong
Department of Image Science and Engineering,
Pukyong National University, Busan 608-737,
Republic of Korea
O
O
O
H
O
R1
R4
R3
R2 NH2
2
NO2
4
R3
R1
1
R4
Reflux, 4-6 Hrs
3
N
R2
R1=Aromatic, Heteroaromatic, aliphatic
R2= Aryl, Alkyl
5
24 examples
OC(CH ) , OCH CH
3
R3=
3 3
3,
R4= CH3, CH2-CH3
Fonts or abstract dimensions should not be changed or altered.