Imin-based synthesis of polyfunctionalized dihydro-2-oxypyrroles catalyzed by glycine amino acid via tandem Michael–Mannich cyclocondensation reaction under ambient temperature

Article abstract of DOI:10.1007/s11164-019-04072-z

An efficient and mild synthetic route to the convenient one-pot preparation of polyfunctionalized dihydro-2-oxypyrroles has been developed and catalyzed via glycine amino acid as a natural bio-based and biodegradable catalyst using imin-based four condensation domino reaction of amines, dialkyl acetylenedicarboxylates and formaldehyde via tandem Michael–Mannich cyclocondensation reaction under ambient temperature. The reactions complete in less time, but the products are obtained in outstanding yields. This environmentally friendly method includes the noticeable properties such as bio-based and green catalyst, direct workup without column chromatographic separation, cost-effective, mild and simple synthesis, one-pot procedure and high atom economy.

Full text of DOI:10.1007/s11164-019-04072-z

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-04072-z
Imin‑based synthesis of polyfunctionalized
dihydro‑2‑oxypyrroles catalyzed by glycine amino acid
via tandem Michael–Mannich cyclocondensation reaction
under ambient temperature
Farzaneh Mohamadpour1
Received: 27 September 2019 / Accepted: 30 December 2019
© Springer Nature B.V. 2020
Abstract
An efcient and mild synthetic route to the convenient one-pot preparation of poly-
functionalized dihydro-2-oxypyrroles has been developed and catalyzed via glycine
amino acid as a natural bio-based and biodegradable catalyst using imin-based four
condensation domino reaction of amines, dialkyl acetylenedicarboxylates and for-
maldehyde via tandem Michael–Mannich cyclocondensation reaction under ambi-
ent temperature. The reactions complete in less time, but the products are obtained
in outstanding yields. This environmentally friendly method includes the noticeable
properties such as bio-based and green catalyst, direct workup without column chro-
matographic separation, cost-efective, mild and simple synthesis, one-pot proce-
dure and high atom economy.
Keywords Polyfunctionalized dihydro-2-oxypyrroles · Glycine amino acid ·
Naturally bio-based and biodegradable catalyst · High atom economy · Imin-based
synthesis
Introduction
Biochemists and synthetic organic chemists have been fascinated by the struc-
tures comprising the pyrrole derivatives as a result of their biological and phar-
maceutical activities (Fig. 1). There are reports in the literature regarding pyrrole
derivatives as human cytomegalovirus protease (HCMV) [1] and human cytosolic
carbonic anhydrase isozymes [2]; they were utilized as PI-091 [3], as well as
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-04072-z) contains supplementary material, which is available to authorized users.
*
Farzaneh Mohamadpour
mohamadpour.f.7@gmail.com
1
School of Engineering, Apadana Institute of Higher Education, Shiraz, Iran
Vol.:(0123456789)
1 3

F. Mohamadpour
O
O
N
S
H
O
S
O
Me
N
H
O
O
HO
HO
N
H
O
HO
Me
OH
H
OH
O
HO
Me
UCS1025A
Thiomarinol A 4
H
O
NH
O
H
O
OH
H
O
NH
OH
O
Oteromycin
Fig. 1 Biologically active compounds with dihydro-2-oxypyrroles rings
Pyrrocidine A
cardiac cAMP phosphodiesterase [4]; most of the alkaloids possess pyrrole rings
[5]. Also, these rings have the same usage as oteromycin [6]. They exhibit various
biological activities, for example (imidazolylphenyl) pyrrol-2-one [4].
Considering the great prominence of pyrrole derivatives, recently, there are
some reports of synthesizing polyfunctionalized dihydro-2-oxypyrroles utilizing
reactions with multi-components in the existence of diferent catalysts such as I2
[7], InCl3 [8], [n-Bu4N][HSO4] [9], Al(H2PO4)3 [10], AcOH [11], Cu(OAc)2·H2O
[12], oxalic acid dihydrate [13], ZrCl4 [14], Fe3O4@ nano-cellulose–OPO3H
[15], ethylenediammonium diformate [16], maltose [17], BiFeO3 nanoparticles
[18], nano-Fe3O4@SiO2/SnCl4 [19], graphene oxide [20] and CoFe2O4@SiO2@
IRMOF-3 [21]. Each of the these methods has its own merits, but some of these
methods are limited in terms of the use of expensive catalysts, long reaction peri-
ods, low yields, harsh reaction conditions, tedious workup, and need of additional
quantities of catalysts or reagents and hazardous or toxic catalysts with column
chromatographic separation. Hence, fnding the mild environmentally friendly
and appropriate approaches for synthesizing these kinds of compounds is vital.
Since we partly aimed to develop efcient synthetic processes using green
catalyst [22–24] and due to the above considerations, preparation of various
1 3

Imin-based synthesis of polyfunctionalized…
Fig. 2 Structure of glycine
amino acid
biologically active polyfunctionalized dihydro-2-oxypyrroles is of considerable
interest and herein, we have reported glycine amino acid (Fig. 2) as a naturally
bio-based and biodegradable catalyst for synthesis of polyfunctionalized dihydro-
2-oxypyrroles through imin-based four condensation domino reaction of amines,
formaldehyde and dialkyl acetylenedicarboxylates in superb yields and short
reaction periods. The advantages of glycine in synthesis of organic compounds
are natural, green, easy control, low cost, trivial, simply accessible, non-toxic and
ecofriendly. Also, in the present paper, the products were found via simple flter-
ing and purifed just by washing with ethanol without requiring column chroma-
tographic separation.
Materials and methods
Materials
Utilizing an Electrothermal 9100 device, all compounds’ melting points were found.
Moreover, nuclear magnetic resonance, 1H NMR, spectra were recorded on a Bruker
DRX-400 and Bruker DRX-300 Avance tool with CDCl3.
Overall process of preparing (5a‑x)
A combination of amine 1 (1.0 mmol) and dialkyl acetylenedicarboxylate 2
(1.0 mmol) was agitated in MeOH (3 mL) for 15 min. Then, adding amine 3
(1.0 mmol) and formaldehyde 4 (1.5 mmol) and glycine amino acid (10 mol%), the
reaction was agitated for apposite period (Scheme 1). The combination was fltered
after completing the reaction (by thin-layer chromatography TLC), and then, the
solid was rinsed with EtOH without column chromatographic separation to obtain
pure compounds (5a-x). Comparing the spectroscopic information, the products
were categorized (1HNMR). Supporting Information associated with this article can
be found in the online version.
Results and discussion
Primarily, glycine amino acid’s catalytic activity was examined in a model system
in the four-element reaction between a combination of formaldehyde (1.5 mmol),
aniline (2 mmol) and dimethyl acetylenedicarboxylate (DMAD) (1 mmol). The
enhanced circumstances were defned by changing the solvents and number of
the catalyst equivalents. In the absence of a catalyst, only a trace of product was
obtained at rt for a reaction time of about 12h (Table 1, entry 1). Inserting 5 mol%
1 3

F. Mohamadpour
CO2R2
O
H
R1
NH2
+
N
R1
CO2R2
N Ar
H
1
Glycine amino acid (10 mol %)
MeOH, r.t.
R2O2C
H
2
5 a-x
O
H
Ar NH2
+
H
3
4
R1 = n-C4H9, PhCH2, C6H5, 4-Cl-C6H4, 4-Br-C6H4, 4-Et-C6H4, 4-OMe-C6H4, 4-F-C6H4,
4-Me-C6H4.
R2 = CH3, C2H5.
Ar = 4-Br-C6H4, 4-F-C6H4, 3,4-Cl2-C6H3, C6H5, 4-Cl-C6H4, 4-Et-C6H4, 4-OMe-C6H4, 4-
Me-C6H4.
Scheme 1 Synthesis of polyfunctionalized dihydro-2-oxypyrroles
Table 1 Optimizing the reaction circumstance in the existence of various quantities of glycine amino
acid
O
CO2Me
CO2Me
H
N
O
Ph
Ph NH2
+
Ph NH2
+
+
N
H
Ph
H
H
MeO2C
H
Entry
Glycine (mol %)
Solvent
Time (h)
Isolated yields (%)
1
2
3
4
5
6
7
8
Catalyst free
5
MeOH
MeOH
MeOH
H2O
12
5
3
7
4
6
6
4
4
10
9
4
10
Trace
67
93
17
56
44
32
45
50
16
21
39
13
94
10
10
10
10
10
10
10
10
10
10
10
15
EtOH
H2O/EtOH
Solvent free
DMF
THF
CHCl3
n-Hexane
CH3CN
CH2Cl2
MeOH
9
10
11
12
13
14
3
1 3

Imin-based synthesis of polyfunctionalized…
of the catalyst, a considerable progress was found by the reaction, completing in
around 5 h (Table 1, entry 2). When 10 mol% of catalyst was used, the reaction
efciently proceeded and completed in less reaction time (3h) (Table 1, entry 3). No
considerable enhancement in the product yield and reaction period was found by
additionally incrementing catalyst quantity (Table 1, entry 14). Some solvents like
H2O, MeOH, EtOH, H2O/EtOH, DMF, THF, CHCl3, n-hexane, CH3CN and CH2Cl2
were also examined with catalytic quantity of glycine (10 mol %) and from the envi-
ronmental and economic aspects; MeOH was chosen as medium for all additional
reactions (Table 1, entry 3). As observed in Table 2, it was indicated that this tech-
nique can work with various substrates. It should be noted that for purifying the
products (5a-x), a modest fltration and wash with ethanol are needed.
Recommended mechanism for synthesizing polyfunctionalized dihydro-2-ox-
ypyrroles is demonstrated in Fig. 2. Originally, in the existence of glycine, a reaction
happens between the amine 3 and formaldehyde 4 to create imine A. Furthermore,
enamine B is obtained by the Michael reaction between amine 1 and dialkyl acety-
lenedicarboxylate 2. Mannich kind of reaction happens between activated imine A
and enamine B to create intermediate C transforming to more stable tautomeric
form D. The intramolecular cyclization in intermediate D that in the fnal step, it
tautomerizes into the corresponding polyfunctionalized dihydro-2-oxypyrroles 5
(Scheme 2).
Table 3 represents the comparison of the catalytic capability of some catalysts
reported in the literature for synthesis of polyfunctionalized dihydro-2-oxypyrroles.
Within this work, it is revealed that glycine amino acid possesses its amazing poten-
tial as a substitute green, bio-based, biodegradable and inexpensive catalyst for the
one-pot mild synthesis of these naturally active heterocyclic compounds, and out-
standing yields and short reaction periods are the remarkable benefts of this current
procedure.
Conclusions
In conclusion, in the present work, it is demonstrated that a natural bio-based and
biodegradable catalyst, glycine amino acid, can be used as a greatly efcient and
available solid catalyst for one-pot mild imin-based 4-component synthesis of
polyfunctionalized dihydro-2-oxypyrroles under ambient temperature. The use of
the green, inexpensive and easy-to-handle catalyst, short reaction periods, excel-
lent yields, high catalytic efciency, mild reaction circumstances, simple workup,
1 3

F. Mohamadpour
Table 2 Glycine amino acid catalyzed synthesis of polyfunctionalized dihydro-2-oxypyrroles
H
H
O
O
N
N
N
H
Br
N
H
F
EtO2C
MeO2C
H
H
5b (2.5h, 91%)
Mp. 83-85 °C
Lit. 81-83 °C [16]
5a (4h, 82%)
Mp. 92-94 °C
Lit. 94-96 °C [10]
H
O
H
O
N
N
N
Cl
N
MeO2C
MeO2C
H
H
H
H
Cl
5d (3h, 84%)
Mp. 58-60 °C
Lit. 60 °C [7]
5c (4h, 80%)
Mp. 99-101 °C
Lit. 97-99 °C [10]
H
O
H
O
N
N
N
Cl
N
F
MeO2C
MeO2C
H
H
H
H
5e (3.5h, 88%)
Mp. 92-94 °C
Lit. 91-93 °C [16]
5f (3h, 86%)
Mp. 164-166 °C
Lit. 166-168 °C [10]
H
O
H
O
N
N
N
Br
N
Cl
MeO2C
MeO2C
H
H
H
H
5h (5h, 82%)
5g (4h, 85%)
Mp. 121-123 °C
Lit. 120-121 °C [7]
Mp. 146-148 °C
Lit. 147-148 °C [7]
H
O
H
O
N
N
N
N
EtO2C
MeO2C
H
H
H
H
5j (4h, 89%)
5i (4h, 86%)
Mp. 139-141 °C
Lit. 140-141 °C [11]
Mp. 128-130 °C
Lit. 130-132 °C [11]
1 3

Imin-based synthesis of polyfunctionalized…
Table 2 (continued)
H
H
O
O
N
N
N
N
H
EtO2C
MeO2C
H
H
H
5l (3h, 93%)
5k (3h, 90%)
Mp. 155-157 °C
Lit. 155-156 °C [7]
Mp. 137-139 °C
Lit. 138-140 °C [11]
H
O
H
O
N
N
Cl
Cl
N
H
Cl
N
Cl
EtO2C
MeO2C
H
H
H
5n (5h, 82%)
5m (5h, 80%)
Mp. 173-175 °C
Lit. 171-173 °C [9]
Mp. 169-171 °C
Lit. 168-170 °C [9]
H
O
H
O
N
N
Br
Br
N
Br
N
Br
EtO2C
MeO2C
H
H
H
H
5o (5.5h, 76%)
5p (5h, 79%)
Mp. 169-171 °C
Lit. 169-171 °C [11]
Mp. 173-175 °C
Lit. 175-177 °C [9]
H
H
O
N
O
N
N
Et
Et
Et
N
H
Et
EtO2C
MeO2C
H
H
H
5q (4h, 84%)
5r (4h, 82%)
Mp. 104-106 °C
Lit. 102-104 °C [15]
Mp. 123-125 °C
Lit. 124-125 °C [15]
H
H
O
O
N
N
N
MeO
MeO
N
H
OMe
OMe
EtO2C
MeO2C
H
H
H
5t (3h, 89%)
5s (3h, 91%)
Mp. 173-175 °C
Lit. 172-175 °C [9]
Mp. 151-153 °C
Lit. 152-154 °C [10]
1 3

F. Mohamadpour
Table 2 (continued)
H
H
O
N
O
N
N
F
F
F
N
H
F
EtO2C
MeO2C
H
H
H
5u (2h, 95%)
5v (2h, 96%)
Mp. 174-176 °C
Lit. 172-174 °C [9]
Mp. 162-164 °C
Lit. 163-165 °C [8]
H
H
O
N
O
N
N
Me
Me
Me
N
H
Me
EtO2C
MeO2C
H
H
H
5w (3h, 93%)
5x (3h, 92%)
Mp. 130-132 °C
Lit. 131-132 °C [11]
Mp. 178-180 °C
Lit. 177-178 °C [10]
R1
R1
O
O
HN
N
OR2
O
H
N
OR2
R2O
R2O
intramolecular
cyclization
R1
tautomerization
H
O
O
N
H
Ar
NH
Ar
NH
Ar
R2O2C
C
D
H
5
R1
O
H
CO2R2
N
:
..
OR2
R1 NH2
hydroamination
R2O
+
1
CO2R2
O
B
O
NH2
2
HO
mannich reaction
O
Ar
H
H
H
4
N
O
NH2
HO
H
H
O
O
H
H
H
O
Ar
NH2
HO
N
O
A
NH2
O
Ar NH2
3
H
H2O
N
H
O
Ar
Scheme 2 Recommended mechanistic path for synthesizing polyfunctionalized dihydro-2-oxypyrroles
convenient and expedient procedure are the notable advantages of this eco-safe and
simple protocol.
1 3

Imin-based synthesis of polyfunctionalized…
Table 3 Comparison of catalytic capability
Entry
Product
Catalyst
Conditions
Time/yield (%)
References
1
2
3
4
5
6
7
8
5k
5k
5k
5k
5k
5k
5k
5k
5k
5l
I2
InCl3
[n-Bu4N][HSO4]
Al(H2PO4)3
Cu(OAc)2∙H2O
ZrCl4
EDDF
Maltose
Glycine amino acid
I2
InCl3
[n-Bu4N][HSO4]
Al(H2PO4)3
Cu(OAc)2∙H2O
ZrCl4
EDDF
Maltose
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
EtOH, refux
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
EtOH, refux
MeOH, r.t.
MeOH, r.t.
1 h/81
3 h/85
4 h/86
5 h/80
5 h/85
3.5 h/83
3.5 h/84
6 h/73
3 h/90
1 h/82
3 h/85
4 h/88
5 h/81
6 h/91
4 h/84
3 h/89
3 h/82
3 h/93
[7]
[8]
[9]
[10]
[12]
[14]
[16]
[17]
This work
[7]
9
10
11
12
13
14
15
16
17
18
5l
[8]
[9]
5l
5l
[10]
[12]
[14]
[16]
[17]
This work
5l
5l
5l
5l
5l
Glycine amino acid
Acknowledgements We gratefully acknowledge fnancial support from the Research council of the
Apadana Institute of Higher Education.
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