Catalyst-free Synthesis of Pyrano[2,3-d]pyrimidine Scaffolds via Knoevenagel-Michael Cyclocondensation Using PEG-400 as a Green Promoting Medium

Full text of DOI:10.1080/00304948.2020.1796158

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Catalyst-free Synthesis of Pyrano[2,3-d]pyrimidine
Scaffolds via Knoevenagel-Michael
Cyclocondensation Using PEG-400 as a Green
Promoting Medium
Farzaneh Mohamadpour
To cite this article: Farzaneh Mohamadpour (2020): Catalyst-free Synthesis of
Pyrano[2,3-d]pyrimidine Scaffolds via Knoevenagel-Michael Cyclocondensation Using PEG-400
as a Green Promoting Medium, Organic Preparations and Procedures International, DOI:
10.1080/00304948.2020.1796158
To link to this article: https://doi.org/10.1080/00304948.2020.1796158
Published online: 26 Oct 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1796158
EXPERIMENTAL PAPER
Catalyst-free Synthesis of Pyrano[2,3-d]pyrimidine Scaffolds
via Knoevenagel-Michael Cyclocondensation Using PEG-400
as a Green Promoting Medium
Farzaneh Mohamadpour
School of Engineering, Apadana Institute of Higher Education, Shiraz, Iran
ARTICLE HISTORY Received 25 March 2020; Accepted 1 June 2020
Recently, much attention has been given to examining polyethylene glycol 400 (PEG-400)
as a green and financially viable alternative to conventional solvents. Its favorable features
include non-corrosiveness, stability, and useful solubility for organic compounds. PEG-
400 has been used as a convenient green reaction environment for a number of organic
reactions.1–4 Pyrano[2,3-d]pyrimidines feature significant pharmacological properties,
including antihypertensive,5 cardiotonic,6 bronchodilator,7 antibronchitic8 and antitumor
activities.9 There are numerous approaches for synthesizing these compounds using such
promoters as DABCO-based ionic liquids,10 L-proline,11 iron ore pellets,12 nano-sawdust-
OSO3H,13 Al-HMS-20,14 TSA/B(OH)3,15 Mn/ZrO2,16 cellulose-based nanocomposites,17
DBA,18 TBAB,19 Fe3O4@SiO2@(CH2)3-Urea-SO3H/HCl,20 Et3N-ultrasound,21 ZnFe2O4
nanoparticles,22 microwave irradiation,23 nickel nanoparticles,24 CaHPO4,25
26
Zn[(L)proline]2 and theophylline.27 It was shown that these reported procedures lead to
the desired products, but some of them have undesirable features. Among these we might
note expensive reagents, environmental hazards, long reaction times, or the use of homo-
geneous catalysts that are difficult to separate from the reaction mixture. Given these facts
and our own current focus on environmentally benign protocols,28–32 we investigated the
catalyst-free green synthesis of pyrano[2,3-d]pyrimidines using PEG-400 as a reusable pro-
moting medium (Scheme 1). The preparation takes place via tandem Knoevenagel-
Michael cyclocondensation.
As a model, the multicomponent reaction among malononitrile (1 mmol), benzalde-
hyde (1 mmol), and barbituric acid (1 mmol) was studied in several solvents under cata-
lyst-free circumstances at different temperatures, and the outcomes are provided in
Table 1. An outstanding yield of 94% resulted by using PEG-400 as a medium with no
catalyst at 100 ꢀC for 80 min (entry 6). With the best conditions in hand, we then
applied them to the preparation of a variety of pyrano[2,3-d]pyrimidines (Table 2) and
found the method broadly applicable, with very good yields (range 76-95%, mean 87%).
It is worthy of note that all reactants are soluble in PEG-400, providing a nearly trans-
parent solution at the start of the reaction. By way of contrast, all the products in our
study are insoluble in PEG-400. As the reaction takes place, the products are deposited
gradually from the reaction mixture.
CONTACT Farzaneh Mohamadpour
mohamadpour.f.7@gmail.com
School of Engineering, Apadana Institute of
Higher Education, Shiraz, Iran
ß 2020 Taylor & Francis Group, LLC

2
F. MOHAMADPOUR
Scheme 1. Synthesis of pyrano[2,3-d]pyrimidine scaffolds.
Scheme 2 shows the suggested mechanism for synthesizing pyrano[2,3-d]pyrimidines,
a key feature of which is the creation of an inclusion complex between PEG-400 and
reactants. Thus, the intermediate ylidenemalononitrile (cyano olefin) A may be gener-
ated in situ from the Knoevenagel condensation between PEG-400 solubilized arylalde-
hyde 1 and active methylene compound 2. PEG-400 may also catalyze the creation of
the enolic form of barbituric acid (or 1,3-dimethylbarbituric acid) 3 by hydrogen bond-
ing. Michael addition to form C, followed by cyclizing and tautomerizing, affords the
target product 4.
The recovery and reusability of PEG-400 was investigated in several recurrent runs.
After following the optimized protocol for the preparation of 4e (see Experimental sec-
tion), the aqueous filtrate containing the PEG-400 was distilled at 100 ꢀC to eliminate
water to give PEG-400. The recovered PEG-400 was effectively utilized in five consecu-
tive runs with only minor decreases in yield (92, 91, 88, 86 and 82% respectively) and
with insignificant PEG-400 loss.
Summing up, we have demonstrated that pyrano[2,3-d]pyrimidines may be conveni-
ently prepared using PEG-400 as an effective green medium. The reactions occur in
very good yields (mean 87%) and the yields do not appear to be very dependent on
substituents. The reaction occurs without the need for any additional catalyst. It is
hoped that the simplicity of the method will encourage further synthesis and study of
these highly useful heterocyclic systems.
Experimental section
Utilizing an Electro thermal 9100 device, all compounds’ melting points were found and
1
they are uncorrected. H NMR spectra were obtained on Bruker DRX-400 and Bruker
DRX-300 Avance instruments with DMSO-d6 as solvent. All solvents and reagents were
bought from Acros, Merck, and Fluka chemical companies and were utilized with no
additional purification.
Overall process for preparing pyrano[2,3-d]pyrimidines (4a-u)
To a mixture of malononitrile (2, 1.0 mmol), aryl aldehyde (1, 1.0 mmol), barbituric
acid (or 1,3-dimethylbarbituric acid) (3, 1.0 mmol) was added PEG-400 (3 mL). Then

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Scheme 2. Proposed mechanistic route for the synthesis of pyrano[2,3-d]pyrimidine scaffolds.
the mixture was heated in an oil-bath (100ꢀC) (Scheme 1). The reaction progress was moni-
tored by TLC (silica gel) utilizing EtOAc/n-hexane (1:3) as an eluent. The reaction mass was
chilled to room temperature after completing the reaction and then poured into cold water.
The solid which resulted was filtered, rinsed with water; and the crude solid was recrystal-
lized from ethanol to provide the pure material without requiring more purification. The
aqueous filtrate was refined at 100 ꢀC to eliminate water to give PEG-400 which was used
for the next run under similar reaction conditions. The polyethylene glycol (PEG-400) was
reused through several further runs with little activity loss. All of the pyrano[2,3-d]pyrimi-
dines were known compounds and were identified by matching their melting points with

4
F. MOHAMADPOUR
Table 1. Optimizing the preparation of 4e.
Entry
Solvent (3 mL)
PEG-400
Temp (ꢀC)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
rt
420
360
180
120
95
80
80
29
46
58
73
85
94
95
76
82
68
57
61
44
<5
<5
<5
<5
<5
<5
<5
<5
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-200
PEG-600
H2O
EtOH
H2O/EtOH (1:1)
MeOH
Solvent-free
DMSO
CH3CN
40 ꢀC
60 ꢀC
80 ꢀC
90 ꢀC
100 ꢀC
110 ꢀC
100 ꢀC
100 ꢀC
Reflux
Reflux
Reflux
Reflux
100 ꢀC
100 ꢀC
Reflux
Reflux
Reflux
Reflux
100 ꢀC
100 ꢀC
85
80
9
10
11
12
13
14
15
16
17
18
19
20
21
360
360
360
360
420
480
480
480
480
480
480
480
CHCl3
THF
DCM
DMF
Toluene
aIsolated yields.
Table 2. Catalyst-free synthesis of pyrano[2,3-d]pyrimidines.
(continued)

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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6
F. MOHAMADPOUR
those reported in the literature cited (see Table 2). For the sake of completeness, the
1HNMR data of several examples are presented below.
7-Amino-5-(4-methoxyphenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimi-
dine-6-carbonitrile (4h)
1H NMR (300 MHz, DMSO-d6): 3.57 (3H, s, OCH3), 4.46 (1H, s, CHAr), 7.49-8.19 (6H,
m, ArH & NH2), 10.73 (1H, s, NH), 11.80 (1H, s, NH).
7-Amino-5-(4-nitrophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-
d]-pyrimidine-6-carbonitrile (4l)
1H NMR (400 MHz, DMSO-d6): 3.04 (3H, s, CH3), 3.07 (3H, s, CH3), 4.53 (1H, s,
CHAr), 7.57 (2H, d, J ¼ 8.8 Hz, ArH), 7.76 (2H, s, NH2), 8.16 (2H, d, J ¼ 8.8 Hz, ArH).
7-Amino-5-(2,4-di-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimi-
dine-6-carbonitrile (4p)
1H NMR (300 MHz, DMSO-d6): 4.24 (1H, s, CHAr), 7.26-7.51 (5H, m, ArH & NH2),
10.56 (1H, s, NH), 11.81 (1H, s, NH).
Acknowledgments
We gratefully acknowledge financial support from the Research Council of the Apadana Institute
of Higher Education.
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