L-Proline based ionic liquid: A highly efficient and homogenous catalyst for synthesis of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and pyrano[2,3-d] pyrimidine diones under ultrasonic irradiation

Article abstract of DOI:10.1080/00397911.2020.1811987

A catalytic, practical, efficient procedure for the synthesis of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and pyrano[2,3-d] pyrimidine diones at room temperature was developed using L-Proline nitrate ionic liquid under ultrasonic irradiation. The L-Proline nitrate is homogeneous and green catalyst easy to prepare by mixing L-Proline and nitric acid possess excellent catalytic activity under standard ultrasonic bath at room temperature for the synthesis of pyrimidine core. This adequate procedure offers some advantages like the use of green solvent H₂O, environmentally green benign procedure, excellent yields, simple procedure, short reaction times, no need for column chromatographic separation and reusability of catalyst for five subsequent reaction.

Full text of DOI:10.1080/00397911.2020.1811987

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
L-Proline based ionic liquid: A highly
efficient and homogenous catalyst
for synthesis of 5-benzylidene-1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and
pyrano[2,3-d] pyrimidine diones under ultrasonic
irradiation
Paresh G. Patil , Yuvraj Satkar & Dhananjay H. More
To cite this article: Paresh G. Patil , Yuvraj Satkar & Dhananjay H. More (2020): L-Proline
based ionic liquid: A highly efficient and homogenous catalyst for synthesis of 5-benzylidene-1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and pyrano[2,3-d] pyrimidine diones under ultrasonic
irradiation, Synthetic Communications, DOI: 10.1080/00397911.2020.1811987
To link to this article: https://doi.org/10.1080/00397911.2020.1811987
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https://doi.org/10.1080/00397911.2020.1811987
L-Proline based ionic liquid: A highly efficient and
homogenous catalyst for synthesis of 5-benzylidene-1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and pyrano[2,3-
d] pyrimidine diones under ultrasonic irradiation
Paresh G. Patila, Yuvraj Satkara, and Dhananjay H. Moreb
aPostgraduate and, Research Recognized Department of Chemistry, S.P.D.M. College Shirpur, Shirpur,
b
India; School of Chemical Sciences, Kavayitri Bahinabai Chaudhari North Maharashtra University,
Jalgaon, India
ABSTRACT
ARTICLE HISTORY
Received 29 May 2020
A catalytic, practical, efficient procedure for the synthesis of 5-benzyli-
dene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and pyrano[2,3-d]
pyrimidine diones at room temperature was developed using
L-Proline nitrate ionic liquid under ultrasonic irradiation. The
L-Proline nitrate is homogeneous and green catalyst easy to prepare
by mixing L-Proline and nitric acid possess excellent catalytic activ-
ity under standard ultrasonic bath at room temperature for the syn-
thesis of pyrimidine core. This adequate procedure offers some
advantages like the use of green solvent H2O, environmentally
green benign procedure, excellent yields, simple procedure, short
reaction times, no need for column chromatographic separation and
reusability of catalyst for five subsequent reaction.
KEYWORDS
Amino acid ionic liquid; e5-
benzylidene-1,3-dimethyl-
pyrimidine-2,4,6(1H,3H,5H)-
trione; L-Proline nitrate;
pyrano[2,3-d] pyrimidine
diones; ultrasonic irradiation
GRAPHICAL ABSTRACT
Introduction
Ionic liquids (ILs) have attracted extensive interest in organic synthesis, in recent
years[1] because of their supreme values in organic synthesis. Basically, ionic liquid
exists in synthetic quaternary nitrogen organic salts due to their high selectivity which
added green treasure in ongoing organic research.[2] High thermal stability, low volatil-
ity, recyclability, non-flammability, negligible vapors pressure, ability to dissolve many
organic and inorganic substances and miscibility with water and organic solvents are
CONTACT D. H. More
dhmore@rediffmail.com
School of Chemical Sciences, Kavayitri Bahinabai Chaudhari North
Maharashtra University, Jalgaon, MS, India.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
P. G. PATIL ET AL.
Scheme 1. Synthesize of L-Proline nitrate ionic liquid.
key features of the ionic liquid.[3] L-Proline-NO3 ionic liquids are an important class of
amino acid ionic liquids (AAILs) easily derived from naturally occurring precursors. L-
Proline nitrate ILs are green ILs obtained from natural, bio-compatible and nontoxic
materials and additionally they can be easily synthesized from commercially available
material.[4] Being inspired by these common advantages and demand of AAIL-mediated
reactions for synthetic organic chemists for the synthesis of biologically active mole-
cules, we have synthesized L-Proline nitrate ionic liquid with previous reported proced-
ure in our lab (Scheme 1).
5-Benzylidene barbituric acids and their derivatives are pharmacologically important
because compounds containing these structural motifs possess, antibacterial, antile-
protics,[5] sedative-hypnotic, anticonvulsant, and local anesthetic drugs,[6] antitumor[7]
activities. 5-benzylidene barbituric acids and their 2-thio derivatives are seem to be
important class of compounds found as intermediate in preparation of heterocyclic
compounds,[8] oxathiazolidines,[9] benzyl barbituric derivatives,[10] and unsymmetrical
desulfated[11]. 5-benzylidene barbituric acids are easily synthesized via Knoevenagel con-
densation reaction of barbituric acid derivatives with aromatic aldehydes. Literature
search displays several described methods for synthesis of various 5-benzylidene barbitu-
ric acids derivatives. Such as nickel nanoparticles,[12] nano Fe3O4,[13] DABCO-based
polymer,[14] piperidine,[15] aq KOH.[16] Pyran frameworks are common structural subu-
nits in natural products such as alkaloids, carbohydrates, polyether antibiotics, phero-
mones, and iridoids.[17]
Pyrano[2,3-d] pyrimidine is unsaturated six-membered heterocycle which is framed
by a combination of pyran and pyrimidine rings together, comprising two nitrogen
atoms at position number 1,3 and one oxygen atom present at position number 8.
Pyrano[2,3-d] pyrimidine possesses remarkable therapeutic applications and biological
activities such as antitumor, anticancer, antifungal, antioxidant, and antihypertensive.[18]
Therefore, for the preparation of the important pyrimidine and their derivatives large
assays have been occurred. Figure 1 represents some of the bioactive pyrimidine-annu-
lated heterocyclic compounds exhibiting a diverse kind of pharmaceutical potentials.
Between the known procedures for the synthesis of pyrano[2,3-d] pyrimidine diones
derivatives, the most simple and straightforward protocol for synthesis of pyrano[2,3-d]
pyrimidine diones via three-component condensation of 1,3 dimethyl barbituric acid,
malononitrile, and aromatic aldehyde. To date, wide variety of catalyst have been
reported for the synthesis of pyrano[2,3-d] pyrimidine compounds, such as
(NH4)2HPO4,[19]
SBA-Pr-SO3H,[20]
TMU-16-NH2,[21]
KF,[22]
ZnFe2O4,[23]
fFe3O4@SiO2@(CH2)3-Urea-SO3H/HClg magnetic nanoparticle,[24] Et3N,[25] and ZnO
nano powder.[26] However, the methods go through one or more drawbacks, such as

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Figure 1. Some bioactive pyrimidine-annulated heterocyclic compounds.
longer reaction time, unsatisfactory yield, harsh reaction condition, expensive reagents,
tedious workup, use of toxic, and volatile organic solvents. Therefore, this encourages
us to develop efficient clean, high-yielding, and environmentally friendly methodology
for the synthesis of pyrimidine.
Thus, the researcher is compelled to search an efficient, environmentally friendly
approach for the synthesis of these heterocyclic compounds with impressive yields. In
continuation of our previous literature studies, we wish to report the applicability of L-
Proline-NO3 ionic liquid in promoting the synthesis of pyrano[2,3-d] pyrimidine diones.
All reaction is carried out in mild reaction condition with high yield and comparatively
in short reaction time.
Previous work
This work

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P. G. PATIL ET AL.
Table 1. Optimization of reaction condition for synthesis of 5-(4-chlorobenzylidene)-1, dimethylpyri-
midine-2,4,6(1H,3H,5H)-trione by L-Proline Nitratea.
Entry
Catalyst (mole%)
Solvent
Temp. ꢀC
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
–
Solvent free
Solvent free
n-Hexane
CH2Cl2
CH3CN
C2H5–OH
H2O
RT
RT
6 h
2 h
80
80
60
30
08
20
10
08
08
02
Traces
<20
60
75
78
86
94
80
86
20
20
20
20
20
20
5
10
15
25
15
Reflux
Reflux
Reflux
Reflux
Reflux
50
50
50
50
RT
H2O
H2O
H2O
H2O
9
10d
11
12c
94
94
94
H2O
aReaction conditions: 4-chloro benzaldehyde (1 mmol), 1,3 dimethyl barbituric acid (1 mmol), solvent (0.15 M), open
c
flask, dMethod A¼ conventional method, Method B ¼ ultrasonication, and bIsolated yield.
Best yield are shown by bold.
Results and discussion
Recently, our group publish the activation of aromatic aldehyde using Chitosan–SO3H
catalyst.[27] Those results encouraged us also, ILs reports on multicomponent type reac-
tion. We hypothesized that using an ionic liquid, such as L-Proline-NO3 could give rise
to 1–11 and 12–22 type of compound activating aromatic aldehyde via nucleophilic
addition of 1,3 dimethyl barbituric acid. In the beginning, we focused our attention for
the synthesis of pyrimidine motif to search optimal reaction condition the condensation
of 4-chlorobenzaldehyde (1 mmol) with 1,3 dimethyl barbituric acid (1 mmol) was
selected as a model reaction and the optimization assay including the method of reac-
tion, amount of catalyst, solvent and temperature were examined, the results of which
are tabulated in (Table 1).
We first studied the reaction at room temperature in the and presence of L-Proline-
NO3 catalyst under solvent-free in 6 and 2 h respectively, which gave product 5 in trace
and <20% yield, respectively (Entries 1–2). These experiments validated our hypothesis
and confirmed that the presence of L-Proline-NO3 was able to increase yield. These
results inspired us for further optimization. In fathered optimization, we carried out the
reaction with different nonpolar and polar hexane, CH2Cl2, CH3CN, EtOH, H2O with
20 mole% of L-Proline-NO3 catalyst product 5 yields in 60, 75, 78, 86, and 94%, respect-
ively (Entries 3–7).
Next, we decided to decrease the catalyst loading for these purposes, hence analyzed
the model reaction in water as solvent at temperature 50 ꢀC in different amount of cata-
lyst at 5 mole%, 10 mole%, 15 mole%, and 25 mole% affording 80, 86, 94, and 94% prod-
ucts yield, respectively (Entries 8–11). Then, further increase in the amount of catalyst

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5
d
aReaction conditions: aromatic aldehyde (1 mmol), 1,3 dimethyl barbituric acid (1 mmol), Method. Method A=
Conventional method, cMethod B= Ultra sonication, Isolated yield.
Scheme 2. Synthesis of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives under
optimized conditions.
beyond 15 mole% had no additional effect on the increase in the yield of product 5.
After optimizing catalyst loading and solvent condition, an additional optimization reac-
tion was performed using method B in the presence of ultrasound irradiation.
Gratifyingly, the best yields were obtained using method B of 96% and time was
reduced to 2 min (Entry 12). Among the various tested conditions, Entries 10 and 12
show the more appropriate condition for this reaction (Scheme 2).
With the optimal reaction condition in hand, we proceeded to explore the scope of
this new protocol with respect to changes in the aryl unit with 1,3-dimethyl barbituric
acid (Scheme 2). A range of electron-donating and electron-withdrawing aromatic alde-
hyde substrate was tested as well as some of their heterocyclic derivatives. Thus,

6
P. G. PATIL ET AL.
benzaldehyde treated with 1,3-dimethyl barbituric acid in an optimized condition leads
to 1 in 93%. Remarkably, gram-scale reactions were achieved providing 1 in 86% this
reaction proved scalability and efficiency of our procedure. 4-Methyl benzaldehyde and
4 methoxy benzaldehyde treated with 1,3-dimethyl barbituric acid 86 and 88% yields
were obtained for 2 and 3, respectively. The [1,10-biphenyl]-4carbaldehyde in the same
reaction condition yielded an excellent 88% to get 4. Encouraged by excellent results of
electron-donating aldehyde derivative, in further scope for reaction was tested for elec-
tron deactivating aromatic aldehyde derivatives. The 4-chlorobenzaldehyde and 4-bro-
mobenzaldehyde treated with 1,3-dimethyl barbituric acid 96 and 92% yields were
obtained for 5 and 6, respectively. Also, strong electron –NO2 leads to the formation of
7 in 94% yield which revels the excellent efficiency of our protocol toward the strongly
electron-withdrawing group. 2 hydroxy benzaldehyde and 4 hydroxy benzaldehyde
treated with 1,3-dimethyl barbituric acid yielded 86 and 88% for 8 and 9, respectively.
It shows that free –OH group did not influence for the formation of the corresponding
product and allowed reaction to proceed. In the case of heterocyclic aldehyde, substrate
thiophene-2-carbaldehyde gave rise to corresponding product 10 in 80% yield, also
fused aromatic aldehyde substrate alpha naphthaldehyde gives corresponding product
11 in good yield of 82%. Thus, we denied that heterocyclic aldehyde and fused aromatic
aldehyde affect yield. Interestingly, the catalyst also efficiently promoted the reaction of
1,3-dimethyl barbituric acid with various electron-donating, electron-withdrawing and
heteroaromatic as well as fused aromatic aldehyde to furnish corresponding product in
high to excellent yields and in short reaction times.
After our first successful synthesis of 5-benzylidene-1,3-dimethylpyrimidine 2,4,6
(1H, 3H, and 5H)-trione, we were inspired to achieve an advantage for another reac-
tion synthesis for a synthesis of pyrano[2,3-d] pyrimidinones derivative. We initially
require validation of our hypothesis using 4-chlorobenzaldehyde, malononitrile, 1,3
dimethyl barbituric acid using L-Proline-NO3 selected as a model reaction. The illus-
trative optimization assays are summarized in Table 2. Initially attempt carried out
were performed based on our previously developed conditions for the synthesis of
pyrimidine (Table 1) in the absence of catalyst at room temperature under solvent-
free condition after 6 h observed that starting material remains unreacted (Entry 1).
Then, we carry out reaction with L-Proline-NO3 (20 mol%) at room temperature
under solvent-free condition to form product 14 in <10% (Entry 2), it shows that
our another hypothesis also work using L-Proline-NO3 catalyst further for optimiza-
tion solvent were examined under reflux condition. Using different polar and non-
polar solvent, such as n-Hexane, CH2Cl2, CH3CN, EtOH, H2O with (20 mole%) cata-
lyst product led product 14 yields in 55, 70, 75, 86, and 92%, respectively (Entries
3–7), it shows moderate to excellent yield.
Also, for the conventional method, we optimized assay in order to check the opti-
mized reaction for varying temperature and catalyst loading; the model reaction was
carried at 50 ꢀC in H2O and 80 ꢀC with (10 mole%), (15 mole%), (20 mole%), and
(25 mol%) product 14 yield in 70, 84, 92, and 92%, respectively (Entries 8 and 12–14).
After optimizing some entries for a conventional method by variating parameters such
as temperature, solvent, and catalyst loading, we moved to optimized reaction assay for
method B in the presence of ultrasound irradiation, which led to the formation of 14 in

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Table 2. Optimization of reaction condition for the synthesis of 7-amino-5-(4-chlorophenyl)-2,3,4,5-
tetrahydro-1,3-dimethyl-2,4-dioxo-1H-pyrano(2,3-d) pyrimidine-6-carbonitrile catalyzed by L-Proline-
a
NO3 .
Entry
Catalyst (mole %)
Solvent
Temperature ꢀC
Time (min)
Yield %b
1
2
3
4
5
6
7
8
–
Solvent free
Solvent free
n-Hexane
CH2Cl2
CH3CN
C2H5-OH
H2O
RT
RT
6 h
3 h
90
90
90
25
15
60
10
04
04
20
15
20
n. r.
<10
55
70
75
86
92
70
84
94
94
84
92
20
20
20
20
20
20
20
10
15
20
10
15
25
Reflux
Reflux
Reflux
Reflux
Reflux
50
RT
RT
RT
80
H2O
H2O
H2O
H2O
H2O
H2O
H2O
9c
10c
11c
12d
13d
14d
80
80
92
aReaction conditions: 4-chlorobenzaldehyde (1 mmol), Malononitrile (1 mmol), 1,3 di methyl barbituric acid (1 mmol),
solvent (0.15 M), open flask. n.r. ¼ no reaction observed. Method: dMethod A ¼ Conventional method, cMethod
B ¼ ultrasonication, bIsolated yield.
94% and reduced to 4 min (Entry 10). It is concluded that our hypothesis also works
for L-Proline-NO3 catalyst under ultrasound irradiation with an excellent yield.
In further optimization assay, we varied catalyst lodging (20 moles %) (10 moles %),
which led to Product 14 yield in 94% and 84%, respectively (Entries 9 and 11).
Further increase or decrease in the amount of catalyst loading did not significantly
change in the yield of Product 14. After all this optimization assay with various tested
conditions, it concludes that Entries 10 and 13 show that the more appropriate condi-
tion for this reaction are methods A and B. With the optimal reaction condition in
hand, we proceeded to explore the scope (Scheme 3).
After established optimal reaction condition, we developed a broad scope for this
protocol with different electronic environment, such as electron rich, electron deficient,
and fused aryl aldehyde. Benzaldehyde treated with malononitrile and 1,3-dimethyl
barbituric acid in standard optimized condition leads 12 in 90% yield. To examine elec-
tronic effect with different electron-withdrawing aldehyde, 2-chlorobenzaldehyde,
4-chlorobenzaldehyde, and 4-bromobenzaldehyde treated with malononitrile and 1,3-
dimethyl barbituric yielded 92, 94, and 92% of 13, 14, and 15, respectively, showing an
excellent yield. Also, strong electron-withdrawing group 2-nitrobenzaldehyde and 3-
nitrobenzaldehyde, yielded 94% and 95% of products 16 and 17. The above results con-
clude that our protocol tolerates the electron-withdrawing substituent leading to an

8
P. G. PATIL ET AL.
aReaction conditions: aromatic aldehyde (1 mmol), Malanonitrile, (1 mmol) and 1,3 di methyl barbituric acid (1
mmol), d Method A= Conventional method, cMethod B= Ultra sonication, Open flask. Isolated yield.
Scheme 3. Synthesis of pyrano[2,3-d] pyrimidine diones derivatives under optimized conditions.
excellent yield in the corresponding product. These results clearly clarify that the use of
electronically deactivating substituent at ortho, meta, and para positions have no signifi-
cant effect on the yield. In the further scope some electron-donating aldehyde was
treated, with the electron-releasing 4-methylbenzaldehyde and 4-methoxybenzaldehyde
86 and 88% yields were obtained for 18 and 19, respectively. In general, excellent yields
were observed for electron-donating and electron-withdrawing aldehyde, afterwards we
tested the scope of this procedure with free –OH and fused aromatic aldehyde. In this
protocol, 2-hydroxybenzaldehyde and 4-hydroxybenzaldehyde also produced expected
products 20 and 21 in 88 and 90% yields, respectively. The presence of free –OH group
in aromatic aldehyde was well tolerated by our procedure. In the case of fused aromatic
aldehyde, 1-Napthaldehyde results yielded 86% of Product 22. They do not have any

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9
Scheme 4. Experimental study on the thermal stability and reactivity of the L-Proline-NO3 for our
developed procedure.
negative impact on the reaction yield, it accomplished that our protocol was also useful
for fused aromatic aldehyde. Also, we could not observe any decomposition of the prod-
uct during reaction and recrystallization of the product.
At this point, it is important to focus on some following points on our protocol: (1)
We obtained product using ultrasonication method as well as a conventional method,
(2) ionic liquid catalyzed, (3) use of green solvent H2O, (4) the absence of an inert
atmosphere, (5) reusability of catalyst, (6) no need of column purification, (7) easily
recrystallized in ethanol, (8) high yielding, and (9) short reaction time. However, we
overcame many literature limitations: (1) long reaction time, (2) low yields, (3) hard
conditions for the catalyst preparation, and (4) in some cases no or low reusability
of catalyst.
We carried out the synthesis and characterization of ionic liquid catalyst L-Proline-
NO3 in our lab with the reported procedure. Also, to carry out study for the possible
thermal and sensitivity of the catalyst, we carried out the synthesis of pyrano[2,3-d] pyr-
imidine diones over the period of one month by comparing two storage temperature 23
and 4 ꢀC (Scheme 4).
In this study, we used a standard reaction condition for Method B. On the same day,
93% of product 12 was yielded at 23 ꢀC. This reaction was carried out the day after the
synthesis of the reagent, which was stored at 4 ꢀC before use. When the reaction was
attempted with a reagent stored at 23 ꢀC for one day, we obtained a slightly lower yield
(90 and 92%) of product 12. In general, L-Proline-NO3 stored at 4 ꢀC gave essentially
high yields (90–88%) of product 12 even after one month of storage. In the reactions
carried out with the reagent stored at 23 ꢀC, notably diminished but still encouraging
yields (90–89%) of Product 12 were observed over a period of one month. All these
experimental data conclude that the thermal stability and reactivity of the L-Proline-
NO3 does not change over a period of one month at different temperature conditions.
The characterization IR and synthesis of catalyst L-Proline-NO3 are provided in the
Supplementary material.

10
P. G. PATIL ET AL.
We also investigated the regeneration and reusability of the catalyst, the reaction between
4-chlorobenzaldehyde, malononitrile and 1,3-dimethyl barbituric acid was studied in stand-
ard optimized reaction conditions. After completion of the reaction, the mixture was filtered
and catalyst was recovered from the evaporation of solvent under vacuum at 70ꢀC. The
recovered catalyst was washed with diethyl ether and dried under vacuum. The recovered
catalyst could be used up to five times without any appreciable loss in activity, as shown in
Figure 2. After a deep analysis of previous literature, our protocol provides excellent reus-
ability of catalysts and also thermal stability and reactivity.
To gain more understanding toward the chemoselectivity of our protocol, we decided
to carry out the synthesis with ketone, acid, and ester functional group to correspond
for the synthesis of pyrano[2,3-d] pyrimidine diones derivatives, as we cannot observe
any reaction with standard reaction conditions.
The sets of reactions in Eqs. (1–3) concluded that our protocol has an excellent
chemo-selectivity aldehyde functional group.
Plausible mechanism
Here, we propose a plausible mechanistic path for our protocols, which is represented
in (Schemes 5 and 6), respectively, According to the mechanism in the formation of 5-
benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione, L-Proline NO3 acts as a
proton donor which increases the electrophilic character of aldehyde as well as acceler-
ate enolization of 1,3-dimethyl barbituric acid. Next, the enolized 1,3-dimethyl barbitu-
ric acid easily leads to Knoevenagel condensation with an aldehyde to form

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11
Reaction Cycle
96
90
86
81
100
80
60
40
20
0
76
2
2
2
2
2
Time(Min)
1
2
3
4
5
Time(Min)
Yield
Figure 2. Reusability of catalysts for the synthesis of Product 14.
Scheme 5. Plausible mechanistic pathway for Scheme 2.
intermediate I followed by the elimination of water molecule, resulting in the formation
of Product II.
Also, for the proposed mechanism of the formation of pyrano[2,3-d] pyrimidine dio-
nes is shown in Scheme 6. Initially, electrophilic activation of the carbonyl group of aro-
matic aldehyde takes place in the presence of L-Proline NO3 which triggered a
nucleophilic attack of activated malanonitrile followed by the loss of water molecule in
Knoevenagel condensation to form 2-arylidenemalanonitrile (IV). In the next step, the
presence of L-Proline NO3 enolized 1,3-dimethyl barbituric acid undergoes Michael
type of addition leading to form V followed by intramolecular cyclization, which further
leads to the formation of intermediate VI. In a final step, intermediate VI undergoes an

12
P. G. PATIL ET AL.
Scheme 6. Plausible mechanistic pathway for Scheme 3.
Table 3. Comparison of the results obtained from the synthesis of pyrano[2,3-d] pyrimidine diones.
Product
Catalyst
Time
Yield
References
[24]c
Product 14
Urea based ionic liquid fFe3O4@SiO2@(CH2)3-Urea-SO3H/HClg
30 min
60 min
25 min
40 min
2.5 h
97
90
87
90
86
[21]a
TMU-16-NH2. Reflux, H2O
[25]a,d
[28]a
Et3N, ultrasonication
Tungustophosphoric acid H3PW12O40, EtOH Reflux
ZnO Nanopowder
[26]a,b
Literature limitations: long reaction time blow yields, hard conditions for the catalyst preparation, and dultrasonication.
a
c
imine-enamine tautomerism which resulted in the formation of a desired product VII
(Table 3).
Conclusions
In summary, our experiment suggests a new route for a promising synthesis of 5-benzy-
lidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione and pyrano[2,3-d] pyrimidine
diones using L-Proline-NO3 catalyst under ultrasonication method. L-Proline-NO3 was
found to be effective and applied to a broad range of different arenas including aro-
matic, fused aromatic, and heteroaromatic derivatives. Mild reaction condition, oper-
ationally simple, eco-friendly catalyst, recyclability of catalyst, good tolerance with
electron donating, no need of column chromatography, electron withdrawing aldehyde,
and clean reaction profile are key advantages of the present protocol. The above result
describes ultrasonication replaces the classical method in terms of short reaction time,
simple work up, and high isolated product yield.
Experimental section
General procedure for the preparation of of 5-benzylidene-1,3-dimethylpyrimidine-
2,4,6(1H, 3H, and 5H)-trione
Method A: A 25 mL oven-dried round-bottom flask was filled with a mixture of aro-
matic aldehyde (1 mmol), 1,3 dimethyl barbituric acid (1 mmol), and L-Proline Nitrate

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13
(15 mol%, 0.15 mmol) in 10 mL water as solvent. The resulting mixture was heated in
an oil bath for the appropriate time as mentioned in Table 1. The progress of the reac-
tion was monitored by TLC using n-hexane:ethyl acetate in the ratio of 7:3. After the
completion of reaction, crude product was filtered off, washed with water and recrystal-
lized from ethanol to give the desired product.
Method B: A 25 mL oven-dried round-bottom flask was filled with a mixture of aro-
matic aldehyde (1 mmol), 1,3 dimethyl barbituric acid (1 mmol), and L-Proline Nitrate
(15 mol%, 0.15 mmol) in 10 mL water as solvent. The resulting mixture was sonicated in
an ultrasonic bath at room temperature for the appropriate time as mentioned in Table
1. The progress of the reaction was monitored by TLC using n-hexane:ethyl acetate in
the ratio of 7:3. After completion of the reaction, crude product was filtered off, washed
with water, and recrystallized from ethanol to give the desired product.
General procedure for the preparation of pyrano[2,3-d] pyrimidinones
Method A: A 25 mL oven-dried round-bottom flask was filled with a mixture of aro-
matic aldehyde (1 mmol), malononitrile (1 mmol), 1,3 dimethyl barbituric acid
(1 mmol), and L-Proline Nitrate (15 mol%, 0.15 mmol) in 10 mL water as solvent. The
resulting mixture was heated in an oil bath for the appropriate time as mentioned in
Table 2. The progress of reaction was monitored by TLC using n-hexane:ethyl acetate
in the ratio of 8:2. After completion of reaction, crude product was filtered off, washed
with water, and recrystallized from ethanol to give the desired product.
Method B: A 25 mL oven-dried round-bottom flask was filled with a mixture of aro-
matic aldehyde (1 mmol), malononitrile (1 mmol), 1,3 dimethyl barbituric acid
(1 mmol), and L-Proline Nitrate (15 mol%, 0.15 mmol) in 10 mL water as solvent. The
resulting mixture was sonicated in an ultrasonic bath at room temperature for the
appropriate time as mentioned in Table 2. The progress of reaction was monitored by
TLC using n-hexane:ethyl acetate in the ratio of 8:2. After completion of reaction, crude
product was filtered off, washed with water, and recrystallized from ethanol to give the
desired product.
Acknowledgments
The authors are thankful to BCUD K.B.C.N.M.U Jalgaon for providing financial support. We
also gratefully acknowledgment to School of Chemical Science K.B.C.N.M.U Jalgaon for provid-
ing all necessary facilities.
Disclosure statement
The authors declare no competing financial interest.
Funding
This work was supported by Board of College and University Development,
K.B.C.N.M.U. Jalgaon.

14
P. G. PATIL ET AL.
References
[1] (a) Poliakoff, M.; Fitzpatrick, J. M.; Farren, T. R.; Anastas, P. T. Green Chemistry: Science
and Politics of Change. Science 2002, 297, 807–810. DOI: 10.1126/science.297.5582.807.
(b) Kirchner, B.; Clare, B. Ionic Liquids. Springer Science & Business Media: Berlin,
Germany, 2009.(c) Santra, S.; Majee, A.; Hajra, A. Task-Specific Ionic Liquid-Catalyzed
Efficient Couplings of Indoles with 1,3-Dicarbonyl Compounds: An Efficient Synthesis of
3-Alkenylated Indoles. Tetrahedron Lett. 2011, 52, 3825–3827. DOI: 10.1016/j.tetlet.2011.
05.069.
[2] (a) Handy, S. T. Greener Solvents: Room Temperature Ionic Liquids from Biorenewable
Sources. Chem. Eur. J. 2003, 9, 2938–2944. DOI: 10.1002/chem.200304799. (b) List, B.
Asymmetric Aminocatalysis. Synlett 2001, 2001, 1675–1686. DOI: 10.1055/s-2001-18074.
[3] (a) Shirini, F.; Langarudi, M. S. N.; Daneshvar, N.; Jamasbi, N.; Irankhah-Khanghah, M.
M. Preparation and Characterization of [H2-DABCO][ClO4]2 as a New Member of
DABCO-Based Ionic Liquids for the Synthesis of Pyrimido[4,5-b]-Quinoline and
Pyrimido[4,5-d]Pyrimidine Derivatives. J. Mol. Struct. 2018, 1161, 366–382. DOI: 10.1016/
j.molstruc.2018.02.069. (b) Nabinia, N.; Shirini, F.; Tajik, H.; Mashhadinezhad, M.;
Langarudi, M. S. N. An Affordable DABCO-Based Ionic Liquid Efficiency in the Synthesis
of 3-Amino-1-Aryl-1H-Benzo[f] Chromene-2-Carbonitrile, 1-(Benzothiazolylamino)
Phenylmethyl-2-Naphthol, and 1-(Benzoimidazolylamino) Phenylmethyl-2-Naphthol
Derivatives. J. Iran. Chem. Soc. 2018, 15, 2147–2157. DOI: 10.1007/s13738-018-1408-x.(c)
Shirini, F.; Langarudi, M. S. N.; Goli-Jolodar, O. Synthesis of 2H-Indazolo[2,1-
b]Phthalazine-1,6,11(13H)-Triones Using 1,4-Disulfo-1,4-Diazabicyclo[2.2.2]Octane-1,4-
Diium Dihydrogen Sulfate fDABCO(HSO3)2(HSO4)2g as a New Ionic Liquid Catalyst.
Dye. Pigment 2015, 123, 186–195. DOI: 10.1016/j.dyepig.2015.07.036.(d) Das, S.; Santra, S.;
Mondal, P.; Majee, A.; Hajra, A. Zwitterionic Imidazolium Salt: Recent Advances in
Organocatalysis. Synthesis 2016, 48, 1269–1285. DOI: 10.1055/s-0035-1561336.
[4] (a) Bahekar, S. P.; Sarode, P. B.; Wadekar, M. P.; Chandak, H. S. Simple and Efficient
Synthesis of 3,4-Dihydropyrimidin-2(1H)-Thiones Utilizing L-Proline Nitrate as
a
Proficient, Recyclable and Eco-Friendly Catalyst. J. Saudi Chem. Soc. 2017, 21, 415–419.
DOI: 10.1016/j.jscs.2015.09.004. (b) Bahekar, S. P.; Agrawal, N. R.; Sarode, P. B.; Agrawal,
A. R.; Chandak, H. S. L-Proline Nitrate: An Amino Acid Ionic Liquid for Green and
Efficient Conjugate Addition of Thiols to Sulfonamide Chalcones. Chem. Select 2017, 2,
9326–9329. DOI: 10.1002/slct.201701891.
[5] Levina, R. Y.; Velichko, F. K. Advances in the Chemistry of Barbituric Acid. Russ. Chem.
Rev. 1960, 29, 437–459. DOI: 10.1070/RC1960v029n08ABEH001245.
[6] Singh, P.; Paul, K. A Simple Synthesis of 5-Spirobarbituric Acids and Transformations of
Spirocyclopropanobarbiturates to 5-Substituted Barbiturates. Indian J. Chem. Sect. B Org.
Med. Chem. 2006, 45, 247–251. DOI: 10.1002/chin.200618154.
[7] Morgan, L. R.; Jursic, B. S.; Hooper, C. L.; Neumann, D. M.; Thangaraj, K.; LeBlanc, B.
Anticancer Activity for 4,40-Dihydroxybenzophenone-2,4-Dinitrophenylhydrazone (A-007)
Analogues and Their Abilities to Interact with Lymphoendothelial Cell Surface Markers.
Bioorganic Med. Chem. Lett. 2002, 12, 3407–3411. DOI: 10.1016/S0960-894X(02)00725-4.
ꢀ
[8] Bojarski, J. T.; Mokrosz, J. L.; Barton, H. J.; Paluchowska, M. H. Recent Progress in
Barbituric Acid Chemistry. Adv. Heterocycl. Chem. 1985, 38, 229–297. DOI: 10.1016/
S0065-2725(08)60921-6.
[9] Figueroa-Villar, J. D.; Cruz, E. R.; Lucia dos Santos, N. Synthesis of Oxadeazaflavines
from Barbituric Acid and Aromatic Aldehydes. Synth. Commun. 1992, 22, 1159–1164.
DOI: 10.1080/00397919208021101.
[10] Frangin, Y.; Guimbal, C.; Wissocq, F.; Zamarlink, H. Symthesis of Substituted Barbituric
Acids via Organozinc Reagents. Synthesis 1986, 12, 1046–1050.
[11] Tanaka, K.; Chen, X.; Yoneda, F. Oxidation of Thiol with 5-Arylidene-1,3-
Dimethylbarbituric Acid: Application to Synthesis of Unsymmetrical Disulfide1.
Tetrahedron 1988, 44, 3241–3249. DOI: 10.1016/S0040-4020(01)85957-3.

R
SYNTHETIC COMMUNICATIONSV
15
[12] Khurana, J. M.; Vij, K. Nickel Nanoparticles Catalyzed Knoevenagel Condensation of
Aromatic Aldehydes with Barbituric Acids and 2-Thiobarbituric Acids. Catal. Lett. 2010,
138, 104–110. DOI: 10.1007/s10562-010-0376-2.
[13] Fattahi, M.; Davoodnia, A.; Pordel, M. Efficient One-Pot Synthesis of Some New
Pyrimido[50,40:5,6]Pyrido[2,3-d]Pyrimidines Catalyzed by Magnetically Recyclable Fe3O4
Nanoparticles. Russ. J. Gen. Chem. 2017, 87, 863–867. DOI: 10.1134/S1070363217040326.
[14] Ziyaei Halimehjani, A.; Barati, V.; Karimi, M. Synthesis of a Novel Tetracationic Acidic
Organic Salt Based on DABCO and Its Applications as Catalyst in the Knoevenagel
Condensation Reactions in Water. Synth. Commun. 2019, 49, 724–734. DOI: 10.1080/
00397911.2019.1570268.
[15] Pałasz, A. Three-Component One-Pot Synthesis of Fused Uracils - Pyrano[2,3-d]-
Pyrimidine-2,4-Diones. Monatsh. Chem. 2008, 139, 1397–1404. DOI: 10.1007/s00706-008-
0935-z.
[16] Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. Fe-Catalyzed Allylic C–C-Bond Activation:
Vinylcyclopropanes as Versatile A1,A3,D5-Synthons in Traceless Allylic Substitutions and
[3 þ 2]-Cycloadditions. J. Am. Chem. Soc. 2012, 134, 5048–5051. DOI: 10.1021/ja300294a.
[17] Tietze, L. F.; Kettschau, G. Hetero Diels-Alder Reactions in Organic Chemistry. In
Stereoselective Heterocyclic Synthesis, Peter Metz, Ed.; Springer: Berlin, Heidelberg,
Germany, 1997; Vol. 189, pp 1–120.
[18] (a) Aly, H. M.; Kamal, M. M. Efficient One-Pot Preparation of Novel Fused
Chromeno[2,3-d]Pyrimidine and Pyrano[2,3-d]Pyrimidine Derivatives. Eur. J. Med. Chem.
2012, 47, 18–23. DOI: 10.1016/j.ejmech.2011.09.040.. . (b) Paliwal, P. K.; Jetti, S. R.; Jain,
S. Green Approach towards the Facile Synthesis of Dihydropyrano(c)Chromene and
Pyrano[2,3-d]Pyrimidine Derivatives and Their Biological Evaluation. Med. Chem. Res.
2013, 22, 2984–2990. DOI: 10.1007/s00044-012-0288-3.(c) Bedair, A. H.; Emam, H. A.; El-
Hady, N. A.; Ahmed, K. A. R.; El-Agrody, A. M. Synthesis and Antimicrobial Activities of
Novel Naphtho[2,1-b]Pyran, Pyrano[2,3-d]Pyrimidine and Pyrano[3,2-e][1,2,4]Triazolo[2,
3-c]-Pyrimidine Derivatives. Farmaco 2001, 56, 965–973. DOI: 10.1016/S0014-
827X(01)01168-5.(d) Daneshvar, N.; Nasiri, M.; Shirzad, M.; Safarpoor Nikoo Langarudi,
M.; Shirini, F.; Tajik, H. The Introduction of Two New Imidazole-Based Bis-Dicationic
€
Bronsted Acidic Ionic Liquids and Comparison of Their Catalytic Activity in the Synthesis
of Barbituric Acid Derivatives. New J. Chem. 2018, 42, 9744–9756. DOI: 10.1039/
C8NJ01179F.
[19] Balalaie, S.; Abdolmohammadi, S.; Bijanzadeh, H. R.; Amani, A. M. Diammonium
Hydrogen Phosphate as a Versatile and Efficient Catalyst for the One-Pot Synthesis of
Pyrano[2,3-d]Pyrimidinone Derivatives in Aqueous Media. Mol. Divers. 2008, 12, 85–91.
DOI: 10.1007/s11030-008-9079-7.
[20] Ziarani, G. M.; Faramarzi, S.; Asadi, S.; Badiei, A.; Bazl, R.; Amanlou, M. Three-
Component Synthesis of Pyrano[2,3-d]-Pyrimidine Dione Derivatives Facilitated by
Sulfonic Acid Nanoporous Silica (SBA-Pr-SO3H) and Their Docking and Urease
Inhibitory Activity. Daru 2013, 21, 3–13. DOI: 10.1186/2008-2231-21-3.. .
[21] Beheshti, S.; Safarifard, V.; Morsali, A. Isoreticular Interpenetrated Pillared-Layer
Microporous Metal-Organic Framework as a Highly Effective Catalyst for Three-
Component Synthesis of Pyrano[2,3-d]. Pyrimidines. Inorg. Chem. Commun. 2018, 94,
80–84. DOI: 10.1016/j.inoche.2018.06.002.
[22] Elinson, M. N.; Ryzhkov, F. V.; Merkulova, V. M.; Ilovaisky, A. I.; Nikishin, G. I. Solvent-
Free Multicomponent Assembling of Aldehydes, N,N0-Dialkyl Barbiturates and
Malononitrile: Fast and Efficient Approach to Pyrano[2,3-d]Pyrimidines. Heterocycl.
Commun. 2014, 20, 281–284. DOI: 10.1515/hc-2014-0114.
[23] Khazaei, A.; Ranjbaran, A.; Abbasi, F.; Khazaei, M.; Moosavi-Zare, A. R. Synthesis,
Characterization and Application of ZnFe2O4 Nanoparticles as a Heterogeneous Ditopic
Catalyst for the Synthesis of Pyrano[2,3-d] Pyrimidines. RSC Adv. 2015, 5, 13643–13647.
DOI: 10.1039/C4RA16664G.

16
P. G. PATIL ET AL.
[24] Zolfigol, M. A.; Ayazi-Nasrabadi, R.; Baghery, S. The First Urea-Based Ionic Liquid-
Stabilized Magnetic Nanoparticles: An Efficient Catalyst for the Synthesis of
Bis(Indolyl)Methanes and Pyrano[2,3-d]Pyrimidinone Derivatives. Appl. Organometal.
Chem. 2016, 30, 273–281. DOI: 10.1002/aoc.3428.
[25] Azarifar, D.; Nejat-Yami, R.; Sameri, F.; Akrami, Z. Ultrasonic-Promoted One-Pot
Synthesis of 4 H -Chromenes, Pyrano [2, 3- d] Pyrimidines, and 4 H -Pyrano [2, 3-c]. Lett.
Organic Chem. 2012, 9, 435–439. DOI: 10.2174/157017812801322435.
[26] Maleki, N.; Shakarami, Z.; Jamshidian, S.; Nazari, M. Clean Synthesis of Pyrano[2,3-
D]Pyrimidines Using ZnO Nano-Powders. Acta Chem. Iasi. 2016, 24, 20–28. DOI: 10.
1515/achi-2016-0002.
[27] Patil, P. G.; Sehlangia, S.; More, D. H. Biodegradable Polymeric Catalyst for the Synthesis
Amidoalkyl- b -Naphthol’s. Synth. Commun. 2020, 50, 1696–1711. DOI: 10.1080/
00397911.2020.1753078.
[28] Gholipour, S.; Davoodnia, A.; Moghaddam, M. N. 12-Tungstophosphoric Acid
(H3PW12O40): an Efficient and Reusable Catalyst for One-Pot Synthesis of Pyrano[2,3-
d]Pyrimidines. Der Pharm. Chem. 2015, 7, 368–372.