Caffeine as a naturally green and biodegradable catalyst promoted convenient and expedient synthetic route for the synthesis of polysubstituted dihydro-2-oxypyrroles

Article abstract of DOI:10.4314/bcse.v33i1.15

A green, convenient, high yielding and one-pot procedure for synthesis of high substituted dihydro-2-oxypyrroles by domino four-component condensation reaction between aromatic/aliphatic amines, dialkyl acetylenedicarboxylate and formaldehyde in the presence of a catalytic amount of caffeine as a green, natural, expedient and biodegradable catalyst under ambient temperature was studied. The salient features of this green approach are simplicity of operation and work-up procedures with no necessity of chromatographic purification steps, use of safe, non-volatile, non-corrosive and green catalyst, the availability and easy to handle of this solid catalyst, one-pot reaction, economical and clean synthesis.

Full text of DOI:10.4314/bcse.v33i1.15

Bull. Chem. Soc. Ethiop. 2019, 33(1), 149-158.
2019 Chemical Society of Ethiopia and The Authors
DOI: https://dx.doi.org/10.4314/bcse.v33i1.15
ISSN 1011-3924
Printed in Ethiopia

CAFFEINE AS A NATURALLY GREEN AND BIODEGRADABLE CATALYST
PROMOTED CONVENIENT AND EXPEDIENT SYNTHETIC ROUTE FOR THE
SYNTHESIS OF POLYSUBSTITUTED DIHYDRO-2-OXYPYRROLES
*
Farzaneh Mohamadpour
Young Researchers and Elite Club, Shiraz Branch, Islamic Azad University, Shiraz, Iran
(Received July 31, 2018; Revised January 10, 2019; Accepted January 16, 2019)
ABSTRACT. A green, convenient, high yielding and one-pot procedure for synthesis of high substituted
dihydro-2-oxypyrroles by domino four-component condensation reaction between aromatic/aliphatic amines,
dialkyl acetylenedicarboxylate and formaldehyde in the presence of a catalytic amount of caffeine as a green,
natural, expedient and biodegradable catalyst under ambient temperature was studied. The salient features of this
green approach are simplicity of operation and work-up procedures with no necessity of chromatographic
purification steps, use of safe, non-volatile, non-corrosive and green catalyst, the availability and easy to handle of
this solid catalyst, one-pot reaction, economical and clean synthesis.
KEY WORDS: Caffeine, Green catalyst, Polysubstituted dihydro-2-oxypyrroles, Ambient temperature, Simple
work-up
INTRODUCTION
Polyfunctionalized heterocyclic compounds are playing important roles in drug discovery
processes and in the analysis of drugs. In particular, pyrroles [1, 2] and their analogues have
been receiving attention owing to their biological and pharmacological properties [3] such as
human cytomegalovirus (HCMV) protease [4], human cytosolic carbonic anhydrase isozymes
[
5], they have been used as PI-091 [6], and cardiac cAMPphosphodiestrase [7], many of the
alkaloids have pyrrole rings [8]. Also, these rings have been utilized as Oteromycin [9]. They
exhibit various biological activities, for example (imidazolylphenyl) pyrrol-2-one [7] and
VEGF-R, a vascular endothelial growth factor receptor [10]. Some of them with biological
properties have been shown in Figure 1.
N
Me
N
OMe
OMe
OH
R2
MeO
C H
6
13
R1
HO
O
N
HO
O
Me
Me
N
HN
O
H
O
N
H
1
Me
R = Me, Et
2
R =H, Me
PI-091
(imidazolylphenyl) pyrrol-2-one
VEGF-R
Figure 1. Biologically active compounds with dihydro-2-oxypyrrole rings.
To date, methods for the synthesis of high substituted dihydro-2-oxypyrroles have been
reported using MCRs in the presence of various catalysts such as I [11], InCl [12], [n-
Bu N][HSO ] [13], Al(H PO [14], AcOH [15], Cu(OAc) .H O [16], oxalic acid dihydrate
17], ZrCl [18] and Fe @nano-cellulose–OPO H [19]. Some of these methods have
2
3
4
4
2
4
)
3
2
2
[
4
3
O
4
3
_
_________
*
Corresponding author. E-mail: mohamadpour.f.7@gmail.com
This work is licensed under the Creative Commons Attribution 4.0 International License

150
Farzaneh Mohamadpour
limitations such as long time reactions, low yields, the use of strongly acidic conditions, high
temperature, difficulty work-up, toxic and expensive catalysts.
The detection and measurement of caffeine (CAF) (Figure 2) or trimethylxanthine alkaloid,
as a central nervous system and metabolic stimulant [20], have attracted the attention of many
researchers. This compound is chemically related to the adenine and guanine bases of
deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). In the case of multifunctional
molecules, such as caffeine, there may be several sites for protonation (Figure 3). Proton affinity
(PA) is one of the most important thermodynamic quantities that link the thermochemistry of
ions to that of the neutral molecules [21].
O
CH3
N
H C
3
N
N
N
O
CH3
Figure 2. Structure of Caffeine.
O
CH3
H C
3
N
N
N
N
O
CH3
H
O
CH3
N
O
O
CH3
N
H C
3
CH3
N
H C
H C
3
3
N
N
N
N
H
N
O
N
H
N
H
N
N
O
O
CH
3
CH3
CH3
Figure 3. Protonation of caffeine.
The design of multi-component reactions (MCRs) [22-32] has received great attention from
research groups in medicinal chemistry, drug discovery and materials science due to their
significant advantages over conventional linear-type synthesis, including simple procedures,
environmental friendliness, atom economy, and the ability to generate architecturally complex
molecules in one synthetic step.
H
O
CO R
2
N
2
R1
N
H
Ar
R1 NH2
1
O
H
Caffeine (0.029 g)
MeOH, r.t.
+
+
H N Ar
+
2
R O C
2
2
H
CO R
2
3
H 4
2
5
a-t
2
Scheme 1. Synthesis of polysubstituted dihydro-2-oxypyrroles.
Finally, due to the above considerations and in continuation of our work on the development
of useful and green synthetic methodology for the preparation of biologically active heterocyclic
compounds using of caffeine as catalyst [33], we report herein, synthesis of polysubstituted
dihydro-2-oxypyrroles via one-pot, four condensation domino reaction between aromatic/
aliphatic amines (1 and 3), dialkyl acetylenedicarboxylate 2 and formaldehyde 4 in the presence
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Caffeine as a naturally green and biodegradable catalyst
151
of caffeine as a cost effective, green, biodegradable and readily catalyst under mild conditions
Scheme 1).
(
EXPERIMENTAL
Melting points all compounds were determined using an Electro thermal 9100 apparatus. Also,
1
nuclear magnetic resonance, H NMR spectra were recorded on a Bruker DRX-400 Avance
instrument with CDCl as solvent. All reagents and solvents were purchased from Merck, Fluka
3
and Acros chemical companies were used without further purification.
General procedure for preparation of substituted dihydro-2-oxypyrroles (5a-t)
A mixture of amine 1 (1.0 mmol) and dialkyl acetylenedicarboxylate 2 (1.0 mmol) was stirred in
MeOH (3 mL) for 15 min. Next, amine 3 (1.0 mmol) and formaldehyde 4 (1.5 mmol) and
caffeine (15 mol %, 0.029 g) were added and the reaction was stirred for appropriate time. After
completion of the reaction (by thin layer chromatography TLC), the mixture was separated by
filtration and the solid washed with ethanol (3×2 mL) with no column chromatographic
separation to give pure compounds (5a-t). The products were characterized by comparison of
1
spectroscopic data ( HNMR). Spectra data some of known products are represented below.
Methyl4-(4-fluoroyphenylamino)-1-(4-fluorophenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxy-
1
late (5c). Yield: 87%; m.p. 164-165 °C; H NMR (400 MHz, CDCl
3
): 3.79 (3H, s, OCH
3
), 4.52
(
2
2H, s, CH -N), 7.04 (2H, t, J=8.4 Hz, ArH), 7.08-7.16 (4H, m, ArH), 7.73-7.76 (2H, m, ArH),
8
.05 (1H, s, NH).
F
O
N
H
N
H
F
MeO C
2
H
Methyl4-(4-methoxyphenylamino)-1-(4-methoxyphenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carb-
1
oxylate (5g). Yield: 85%; m.p. 175-177 °C; H NMR (400 MHz, CDCl
3 3
): 3.77 (3H, s, CH ),
3
.83 (6H, s, 2OCH ), 4.50 (2H, s, CH -N), 6.89 (4H, d, J=17.6 Hz, ArH), 7.13 (1H, s, ArH)
3
2
,7.68 (1H, s, ArH), 8.03 (1H, s, NH).
OMe
O
N
C
H
N
H
OMe
MeO
2
H
Ethyl4-(4-methoxyphenylamino)-1-(4-methoxyphenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carbo-
1
xylate (5h). Yield: 87%; m.p. 150-152 °C; H NMR (400 MHz, CDCl
3
): 1.26 (3H, t, J = 7.2 Hz,
-N), 6.87
CH CH ), 3.83 (6H, s, 2OCH ), 4.23 (2H, q, J = 7.2 Hz, CH CH ), 4.50 (2H, s, CH
2
3
3
2
3
2
(
(
2H, d, J = 8.8 Hz, ArH), 6.93 (2H, d, J = 8.8 Hz, ArH), 7.12 (2H, d, J = 8.8 Hz, ArH), 7.69
2H, d, J = 8.8 Hz, ArH), 8.02 (1H, s, NH).
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Farzaneh Mohamadpour
OMe
O
N
H
N
H
OMe
EtO C
2
H
Methyl4-(4-methylphenylamino)-1-(4-methylphenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxy-
1
late (5k). Yield: 89%; m.p. 176-178 °C; H NMR (400 MHz, CDCl
3 3
): 2.36 (6H, s, 2CH ), 3.77
(
3H, s, OCH ), 4.52( 2H, s, CH -N), 7.06 (2H, d, J = 8.4 Hz, ArH), 7.14 (2H, d, J = 8.4 Hz,
3
2
ArH), 7.21(2H, d, J = 8.4 Hz, ArH), 7.68 (2H, d, J = 8.8 Hz, ArH), 8.03 (1H, s, NH).
Me
O
N
H
N
H
Me
MeO C
2
H
Ethyl4-(4-methylphenylamino)-1-(4-methylphenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate
1
(
5l): Yield: 86%; m.p. 132-134 °C; H NMR (400 MHz, CDCl
3
): 1.25 (3H, t, J=7.2 Hz,
CH CH ), 2.37 (6H, s, 2CH ), 4.23 (2H, q, J = 7.2 Hz, 2CH CH ), 4.53 (2H, s, CH -N),7.06
2
3
3
2
3
2
(
(
2H, d, J = 8.4 Hz, ArH), 7.14 (2H, d, J = 8.4 Hz, ArH), 7.21 (2H, d, J = 8.4 Hz, ArH), 7.69
2H, d, J = 8.4 Hz, ArH), 8.01 (1H, s, NH).
Me
O
N
H
N
H
Me
2
EtO C
H
Methyl4-(4-ethylphenylamino)-1-(4-ethylphenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3-carboxylate
1
(
2
5m). Yield: 82%; m.p. 126-128 °C; H NMR (400 MHz, CDCl
3
): 1.26 (6H, t, J=2.4 Hz,
-N),7.09
CH CH ), 2.67 (4H, q, J = 7.2 Hz, 2CH CH ), 3.76 (3H, s, 2OCH ), 4.53 (2H, s, CH
2
3
2
3
3
2
(
(
2H, d, J = 8.4 Hz, ArH), 7.17 (2H, d, J = 8.4 Hz, ArH), 7.24 (2H, d, J = 8.8 Hz, ArH), 7.70
2H, d, J = 8.8 Hz, ArH), 8.05(1H, s, NH).
Et
O
N
H
N
H
Et
MeO C
2
H
Ethyl4-(4-ethylphenylamino)-1-(4-ethylphenyl)-2,5-dihydro-5-oxo-1H-pyrrole-3carboxylate
1
(
5n). Yield: 84%; m.p. 102-104 °C; H NMR (400 MHz, CDCl
3
): 1.24 (9H, m, 3 CH
2
3
CH ), 2.67
(
4H, q, J = 7.2 Hz, 2CH CH ), 4.22 (2H, q, J = 7.2 Hz, CH CH
2
3
2
3
), 4.54 (2H, s, CH
2
-N), 7.09
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Caffeine as a naturally green and biodegradable catalyst
153
(
2H, d, J = 8.4 Hz, ArH), 7.16 (2H, d, J = 8.4 Hz, ArH), 7.24 (2H, d, J=8.4 Hz, ArH), 7.71 (2H,
d, J=8.8 Hz, ArH), 8.01 (1H, s, NH).
Et
O
N
H
N
H
Et
EtO C
2
H
Ethyl 1-(4-bromophenyl)-3-(butylamino)-2,5-dihydro-2-oxo-1H-pyrrole-4-carboxylate (5q).
1
Yield: 78%; m.p. 93-95 °C; H NMR (400 MHz, CDCl
3
): 0.97 (3H, t, J = 7.2 Hz, CH
3
), 1.35
(
3H, t, J = 7.2 Hz, OCH CH ), 1.43 (2H, sextet, J = 7.6 Hz, CH ), 1.61 (2H, quintet, J = 7.6 Hz,
2
3
2
2 2 2 3 2
CH ), 3.87 (2H, t, J = 7.2 Hz, CH -NH), 4.28 (2H, q, J = 7.2 Hz, OCH CH ), 4.40 (2H, s, CH -
N), 6.72 (1H, br s, NH), 7.52 (2H, d, J = 8.8 Hz, ArH), 7.70 (2H, d, J = 8.8 Hz, ArH).
H
O
N
N
H
Br
EtO C
2
H
RESULTS AND DISCUSSION
To generality of this transformation, we investigated caffeine catalyzed four-component reaction
between aniline (2 mmol), dimethyl acetylenedicarboxylate (DMAD) (1 mmol) and
formaldehyde (1.5 mmol) as a model reaction under mild conditions for the synthesis of
dihydro-2-oxypyrroles. The amount of catalyst was studied with this method and in the absence
of caffeine: a trace amount of this product was generated after 14 h (Table 1, entry 1). Good
yields were obtained in the presence of a catalyst. The best amount of catalyst was 15 mol %
(
Table 1, entry 4). The higher amount of catalyst did not increase the yields products (Table 1,
entry 11) and the results are summarized in Table 1. The effect of various solvents was
investigated for this protocol H O, CH Cl , CHCl , EtOH, MeOH and CH CN. Herein, the
2
2
2
3
3
reaction occurred efficiently to afford the corresponding polysubstituted dihydro-2-oxypyrroles
a
Table 1. Optimization of the reaction condition in the presence of different amounts of caffeine .
Entry
Caffeine (mol %)
Catalyst free
Solvent
MeOH
MeOH
MeOH
MeOH
EtOH
Time (h)
Isolated yields (%)
1
2
3
4
5
6
7
8
9
14
6
4
3
4
8
6
7
7
6
3
4
Trace
45
73
88
68
14
40
31
27
5
10
15
15
15
15
15
15
15
20
20
H
2
O
Solvent free
CH Cl
CHCl
CH CN
2
2
3
1
1
1
0
1
2
3
35
89
77
MeOH
EtOH
a
Reaction conditions: aniline (2 mmol), dimethyl acetylenedicarboxylate (1 mmol) and formaldehyde (1.5 mmol)
and caffeine in various solvents at room temperature.
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154
Farzaneh Mohamadpour
in 88 % yield when 15 mol% caffeine was used in MeOH at room temperature (Table 1, entry
). The efficiency of caffeine was demonstrated by synthesizing polysubstituted dihydro-2-
oxypyrroles via four-component condensation using a series aromatic/aliphatic amines (1 and 3,
mmol), dialkyl acetylenedicarboxylate (2, 1 mmol) and formaldehyde (4, 1.5 mmol) at
4
2
ambient temperature which results are shown in Table 2.
Table 2. Caffeine catalyzed synthesis of polysubstituted dihydro-2-oxypyrroles.
1
2
a
°
°
Entry
R
R
Ar
Ph
Ph
Product Time (h) Yield (%) M.p. C Lit. M.p. C
1
2
3
4
5
6
7
Ph
Ph
4-F-C
4-F-C
4-Br-C
4-Br-C
4-OMe-C
Me
Et
Me
Et
Me
Et
Me
5a
5b
5c
5d
5e
5f
3
3
88
86
87
88
80
78
85
154-156 155-156 [11]
140-141 138-140 [15]
164-165 163-165 [12]
173-174 172-174 [13]
177-180 175-177 [13]
168-170 169-171 [15]
175-177 172-175 [13]
6
H
H
4
4-F-C
4-F-C
6
H
H
4
2.5
2.5
4
6
4
6
4
6
H
4
4-Br-C
4-Br-C
4-OMe-C
6
H
4
6
H
4
6
H
4
5
3.5
6
H
4
6
H
4
5
g
8
9
4-OMe-C
6
H
4
Et
Me
Et
Me
Et
Me
Et
Me
4-OMe-C
6
H
4
5h
5i
5j
5k
5l
5m
5n
4.5
4
4.5
3
87
83
85
89
86
82
84
86
150-152 152-154 [14]
170-172 171-173 [13]
166-168 168-170 [13]
176-178 177-178 [14]
132-134 131-132 [15]
126-128 124-125 [19]
102-104 102-104 [19]
4-Cl-C
4-Cl-C
6
H
6
H
4
4-Cl-C
4-Cl-C
6
H
H
4
1
1
1
1
1
1
0
1
2
3
4
5
4
6
4
4-Me-C
4-Me-C
6
H
H
4
4-Me-C
4-Me-C
6
H
6
H
4
6
4
4
3
4-Et-C
4-Et-C
6
H
4
4-Et-C
4-Et-C
Ph
6
H
H
4
3.5
3.5
4
6
H
4
6
4
n-C
4
H
9
60-62
60 [11]
5
o
1
1
1
1
2
6
7
8
9
0
n-C
n-C
PhCH
PhCH
PhCH
4
4
H
H
9
9
2
2
2
Me
Et
Me
Me
Et
3,4-Cl
4-Br-C
Ph
2
-C
H
6 4
6
H
3
5p
5q
5r
5s
5t
4.5
5
3.5
3.5
4
80
78
84
85
82
96-98
93-95
140-142 140-141 [15]
166-167 166-168 [14]
130-132 130-132 [15]
97-99 [14]
94-96 [14]
4-F-C
6 4
H
Ph
a
Isolated yield.
Table 3. Comparison of catalytic ability some of catalysts reported in the literature for synthesis of
a
polysubstituted dihydro-2-oxypyrroles .
Entry Product
Catalyst
Conditions
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
Time/Yield (%)
1 h/82
3h/85
Reference
[11]
[12]
[13]
[14]
[16]
[18]
This work
[11]
[12]
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
5a
5h
5h
5h
5h
5h
5h
5h
I
2
InCl
[n-Bu
Al(H
Cu(OAc)
ZrCl
Caffeine
3
4
N][HSO
4
]
4 h/88
5 h/81
6 h/91
4 h/84
3h/88
2
PO
4
)
3
2
.H
2
O
4
I
2
1 h/81
3h/85
InCl
[n-Bu
Al(H
Cu(OAc)
ZrCl
Caffeine
3
1
0
1
2
3
4
4
N][HSO
4
]
4 h/86
5 h/80
5 h/85
3.5 h/83
3h/86
[13]
[14]
[16]
[18]
1
1
1
1
2
PO
.H
4
)
3
2
2
O
4
This work
a
Based on the four-component reaction of aniline, dimethylacetylenedicarboxylate, formaldehyde.
Proposed mechanism for the synthesis of polysubstituted dihydro-2-oxypyrroles is
illustrated in Scheme 2. Initially, the amine 3 reacts with formaldehyde 4 in the presence of
Bull. Chem. Soc. Ethiop. 2019, 33(1)

Caffeine as a naturally green and biodegradable catalyst
155
caffeine to form imine A. Also, the Michael reaction between amine
1
and
dialkylacetylenedicarboxylate 2 gives enamine B. Activated imine A undergoes a Mannich type
reaction with enamine B to generate intermediate C, which converts to more stable tautomeric
form D. The intramolecular cyclization in intermediate D that in the final step, it tautomerizes
into the corresponding polysubstituted dihydro-2-oxypyrroles 5.
Comparison of catalytic ability some of catalysts reported in the literature for synthesis of
polysubstituted dihydro-2-oxypyrroles are shown in Table 3. This study reveals that caffeine has
shown its extraordinary potential to be an alternative efficient, green, biodegradable and an
inexpensive catalyst for the one-pot clean synthesis of these biologically active heterocyclic
compounds, in addition to good to high yields is the notable advantages this present
methodology.
O
CH3
H C
3
N
N
N
N
O
H
CH3
R1
R1
R1
O
HN
O
N
O
NH
OR2
OR2
2
2
intramolecular R O
cyclization
R O
tautomerization
C
2
R O
H
O
O
O
N
NH
Ar
H
N
H
N
D
C
H
Ar
CH
Ar
O
5
3
CH3
O
N
H C
3
H C
N
N
N
3
O
N
O
N
CH3
N
R1
CH3
H
CO
2
R2
O
N:
.
.
OR2
hydroamination
1
O
2
+
R NH
2
CH3
N
O
R O
CH3
N
H
H C
O
2
1
3
H C
B
CO R
2
N
3
N
2
N
H
mannich reaction
N
N
O
N
O
CH3
O
CH3
O
Ar
H C
3
H
H
N
CH
3
4
N
N
H
N
O
N
H
H
CH3
O
H
O
H C
O
3
O
N
CH
N
3
H
H H
CH3
Ar H C
3
N
N
O
N
A
N
N
N
N
H C
O
3
Ar NH
2
CH3
3
H
H O
2
N
H
O
Ar
H C
3
N
H
N
O
N
O
CH3
N
H C
3
Scheme 2. Proposed mechanistic route for the synthesis of polysubstituted dihydro-2-
oxypyrroles.
Bull. Chem. Soc. Ethiop. 2019, 33(1)

156
Farzaneh Mohamadpour
CONCLUSION
In summary, a mild, convenient and efficient procedure for the one-pot synthesis of
polysubstituted dihydro-2-oxypyrroles by using of a catalytic amount of caffeine as a green
catalyst under ambient temperature is reported. The use of a natural, biodegradable and
inexpensive catalyst, along with simple work up, short reaction times and good to high yields,
provides a compelling method to prepare these biologically active compounds.
ACKNOWLEDGEMENT
We gratefully acknowledge financial support from Young Researchers and Elite Club, Shiraz
Branch, Islamic Azad University of Shiraz.
REFERENCES
1
2
. Jones, R.A.; Bean, G.P. The Chemistry of Pyrroles, 1st ed., Academic Press: London; 1977.
. Gossauer, A. In Methoden der Organichen Chemie (Houben-Weyl), 4th ed., Hetarene I, Teil
1
Pyrrole, Georg Thieme Verlag: New York; 1994; p 556-798.
3
4
. Khajuria, R.; Dham, S.; Kapoor, K.K. Active methylenes in the synthesis of pyrrole motif:
An imperative structural unit of Pharmaceuticals, Natural Products and Optoelectronic
materials. RSC Adv. 2016, 6, 37039-37066.
. Borthwick, A.D.; zzj.Crame, A.; Ertl, P.F.; Exall, A.M.; Haley, T.M.; Hart, G.J.; Mason,
A.M.; Pennell, A.M.K.; Singh, O.M.P.; Weingarten, G.G.; Woolven, J. Design and synthesis
of pyrrolidine-5,5-trans-lactams (5-oxohexahydropyrrolo[3,2-b]pyrroles) as novel
mechanism-based inhibitors of human cytomegalovirus protease. 2. Potency and chirality. J.
Med. Chem. 2002, 45, 1-18.
5
. Alp, C.; Ekinci, D.; Gultekin, M.S.; Senturk, M.; Sahin, E.; Kufrevioglu, O. A novel and
one-pot synthesis of new 1-tosyl pyrrol-2-one derivatives and analysis of carbonic anhydrase
inhibitory potencies. Bioorg. Med. Chem. 2010, 18, 4468-4474.
6
7
. Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. Total synthesis of PI-091. Tetrahedron Lett.
1
995, 36, 5551-5554.
. Lampe, Y.L.; Chou, R.G.; Hanna, R.G.; DiMeo, S.V.; Erhardt, P.W.; Hagedorn, A.A.;
Ingebretsen, W.R.; Cantor, E. (Imidazolylphenyl) pyrrol- 2-one inhibitors of cardiac cAMP
phosphodiesterase. J. Med. Chem. 1993, 36, 1041-1047.
8
9
1
. Chen, Y.; Zeng, D.X.; Xie, N.; Dang, Y.Z. Study on photochromism of diarylethenes with a
2
, 5-dihydropyrrole bridging unit: a convenient preparation of 3, 4-diarylpyrroles from 3,4-
diaryl-2,5-dihydropyrroles. J. Org. Chem. 2005, 70, 5001-5005.
. Singh, S.B.; Goetz, M.A.; Jones, E.T.; Billes, G.F.; Giacobbe, R.A.; Herranz, L.; Stevens-
Miles S.; Williams D.L. a novel antagonist of endothelin receptor. J. Org. Chem. 1995, 60,
7
040-7042.
0. Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.; Scha chtele, C.; Heidenreich, R.; Ro
cken, M.; Schollmeyer, D.; Laufer, S. Design, synthesis, and biological evaluation of novel
3-aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial growth
factor receptor (VEGF-R) inhibitors. J. Med. Chem. 2008, 51, 3814-3824.
1. Khan, A.T.; Ghosh, A.; Musawwer Khan, M. One-pot four-component domino reaction for
the synthesis of substituted dihydro-2-oxypyrrole catalyzed by molecular iodine.
Tetrahedron Lett. 2012, 53, 2622-2626.
2. Sajadikhah, S.S.; Maghsoodlou, M.T.; Hazeri, N. A simple and efficient approach to one-pot
synthesis of mono- and bis-N-aryl-3-aminodihidropyrrol-2-one-4-carboxylate catalyzed by
1
1
3
InCl . Chin. Chem. Lett. 2014, 25, 58-60.
Bull. Chem. Soc. Ethiop. 2019, 33(1)

Caffeine as a naturally green and biodegradable catalyst
157
1
1
3. Sajadikhah, S.S.; Hazeri, N. Coupling of amines, dialkyl acetylenedicarboxylaes and
formaldehyde promoted by [n-Bu N][HSO ]: An efficient synthesis of highly functionalized
dihydro-2-oxopyrrols and bis-dihydro-2-oxopyrroles. Res. Chem. Intermed. 2014, 40, 737-
48.
4. Sajadikhah, S.S.; Hazeri, N.; Maghsoodlou, M.T.; Habibi-Khorassani, S.M.; Beigbabaei,
A.; Willis, A.C. Al(H PO as an efficient and reusable catalyst for the multi-component
4
4
7
2
4 3
)
synthesis of highly functionalized piperidines and dihydro-2-oxypyrroles. 2013, J. Iran.
Chem. Soc. 10, 863-871.
1
1
1
1
1
2
5. Zhu, Q.; Jiang, H.; Li, J.; Liu, S.; Xia, C.; Zhang, M. Concise and versatile multicomponent
synthesis of multisubstituted polyfunctional dihydropyrroles. J. Comb. Chem. 2009, 11, 685-
6
96.
6. Lv, L.; Zheng, S.; Cai, X.; Chen, Z.; Zhu, Q.; Liu, S. Development of four-component
synthesis of tetra- and pentasubstituted polyfunctional dihydropyrroles: Free permutation
and combination of aromatic and aliphatic amines. J. ACS Comb. Sci. 2013, 15, 183-192.
7. Sajadikhah, S.S.; Hazeri, N.; Maghsoodlou, M.T. A one-pot multi-component synthesis of
N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates catalysed by oxalic acid dihydrate. J.
Chem. Res. 2013, 37, 40-42.
8. Sajadikhah, S.S.; Maghsoodlou, M.T.; Hazeri, N.; Mohamadian-Souri, S. ZrCl4 as an
efficient catalyst for one-pot four-component synthesis of polysubstituted dihydropyrrol-2-
ones. Res. Chem. Intermed. 2016, 42, 2805-2814.
9. Salehi, N.; Mirjalili, B.B.F. Synthesis of highly substituted dihydro-2-oxopyrroles using
3 4 3
Fe O @nano-cellulose–OPO H as a novel bio-based magnetic nanocatalyst. RSC Adv. 2017,
7
, 30303-30309.
0. Nehlig, A.; Daval, J.L.; Debry, G. Caffeine and the central nervous system: mechanisms of
action, biochemical, metabolic and psychostimulant effects. Brain Res. Rev. 1992, 17, 139-
1
70.
2
2
1. Bahrami, H.; Tabrizchi, M.; Farrokhpour, H. Protonation of caffeine: A theoretical and
experimental study. Chem. Phys. 2013, 415, 222-227.
2. Mohamadpour, F. Green and convenient one-pot access to polyfunctionalized piperidine
scaffolds via glutamic acid catalyzed Knoevenagel-intramolecular [4+2] aza-Diels-Alder
imin-based multi-component reaction under ambient temperature. Polycycl. Aromat. Comp.
2
018. DOI: 10.1080/10406638.2018.1472111.
2
3. Mohamadpour, F.; Maghsoodlou, M.T.; Heydari, R.; Lashkari, M. Copper(II) acetate
monohydrate: An efficient and eco-friendly catalyst for the one-pot multi-component
synthesis of biologically active spiropyrans and 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives under solvent-free conditions. Res. Chem. Intermed. 2016, 42, 7841-7853.
4. Zare Fekri, L.; Nikpassand, M.; Pourmirzajani, S.; Aghazadeh, B. Synthesis and
2
2 4
characterization of amino glucose-functionalized silica-coated NiFe O nanoparticles: A
heterogeneous, new and magnetically separable catalyst for the solvent-free synthesis of
pyrano[3,2-c]chromen-5(4H)-ones. RSC Adv. 2018, 8, 22313-22320.
2
2
5. Lashkari, M.; Heydari, R.; Mohamadpour, F. A facile approach for one-pot synthesis of 1H-
pyrazolo[1,2-b]phthalazine-5,10-dione derivatives catalyzed by ZrCl as an efficient catalyst
4
under solvent-free conditions. Iran. J. Sci. Technol. Trans. Sci. 2018, 42, 1191-1197.
6. Maghsoodlou, M.T.; Heydari, R.; Mohamadpour, F.; Lashkari, M. Fe O as an
2
3
environmentally benign natural catalyst for one-pot and solvent-free synthesis of spiro-4H-
pyran derivatives. Iran. J. Chem. Chem. Eng. 2017, 36, 31-38.
2
2
7. Nikpassand, M.; Zare Fekri, L. One-pot synthesis of 9-arylxanthenediones and 9-
pyrazoloxanthenediones using [DBU] OAc, Russ. J. Gen. Chem. 2017, 87, 816-820.
8. Zahedi, N.; Javid, A.; Mohammadi, M.K.; Tavakkoli, H. Microwave-promoted solvent free
one-pot synthesis of triazolo[1,2-a] indazole-triones catalyzed by silica-supported La0.5Ca
Bull. Chem. Soc. Ethiop. 2019, 33(1)

158
Farzaneh Mohamadpour
0
.5CrO nanoparticles as a new and reausable provskitetype oxide. Bull. Chem. Soc. Ethiop.
3
2
018, 32, 239-248.
+
3
2
3
3
3
9. Zare Fekri, L.; Nikpassand, M.; Movaghari, M. Fe -montmorillonite K10: As an effective
and reusable catalyst for the synthesis of 3, 4-dihydropyrimidin-2 (1H)-ones and–thiones.
Bull. Chem. Soc. Ethiop. 2017, 31, 313-321.
0. Zekavati, R.; Doulah, A.; Mohammadi, M.K.; Shirali, S. Solvent free synthesis of N-
alkylated imino indoline-2-ones derivatives under microwave irradiation. Bull. Chem. Soc.
Ethiop. 2018, 32, 393-398.
1. Bahrami, F.; Nikpassand, M. Potassium 2-oxoimidazolidine-1, 3-diide: An effective and
new catalyst for the grinding synthesis of (1H-indol-3-yl) methyl-2H-indan-1,3-diones. Bull.
Chem. Soc. Ethiop. 2018, 32, 399-405.
2. Maghsoodlou, M.T.; Heydari, R.; Lashkari, M.; Mohamadpour, F. Clean and one-pot
synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones/tiones derivatives using maleic acid as an
efficient and environmentally benign nature di-functional Brønsted acid catalyst under
solvent-free conditions. Indian. J. Chem. 56B 2017, 56B, 160-164.
3
3. Mohamadpour, F.; Lashkari, M. Three-component reaction of β-keto esters, aromatic
aldehydes and urea/thiourea promoted by caffeine: A green and natural, biodegradable
catalyst for eco-safe Biginelli synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/tiones
derivatives under solvent-free conditions. J. Serb. Chem. Soc. 2018, 83, 673-684.
Bull. Chem. Soc. Ethiop. 2019, 33(1)