(2024) 18:120
Monem et al. BMC Chemistry
https://doi.org/10.1186/s13065-024-01227-x

BMC Chemistry

RESEARCH

Open Access

The new phthalic acid‑based deep eutectic
solvent as a versatile catalyst for the synthesisof pyrimido[4,5‑d]pyrimidines and pyrano[3,2‑c]chromenes
Arezo Monem1, Davood Habibi1*, Abdolhamid Alizadeh2 and Hadis Goudarzi1

Abstract
A new DES (MTPPBr-PHTH-DES) was prepared from a mixture of methyltriphenyl-phosphonium bromide (MTPPBr) and phthalic acid (PHTH). The eutectic point phase diagram showed that a one-to-one molar ratio of MTPPBr
to PHTH is the optimal molar ratio for the synthesis of new DES. Then, it was characterized with various techniquessuch as FT-IR, TGA/DTA, densitometer, eutectic point, and NMR and used as a novel acid catalyst in the synthesisof pyrimido[4,5-d]pyrimidines and pyrano[3,2-c]chromes in solvent-free condition. Short reaction time, low temperature, high efficiency, green condition, and easy recycling and separation of the DES catalyst are among the mostimportant features of the presented method.
Keywords Methyltriphenylphosphonium bromide, Phthalic acid, DES, Pyrimidopyrimidines, Pyrano-chromenes
Introduction
The importance of environmental protection has recently
been seriously emphasized, and green chemistry has followed a smooth path to achieving these goals. Targeted
use of solvents and catalysts is a fundamental solution to
pursue environmental goals [1, 2]. Green environment
solvents must meet various criteria such as availability,
non-toxicity, recyclability, thermal stability, renewableability, non-flammability, low vapor pressure, economy,
and biodegradability [3, 4].
DESs have been developed in line with the goalsof green chemistry as a suitable alternative to ionic*Correspondence:
Davood Habibi
davood.habibi@gmail.com; dhabibi@basu.ac.ir
1
Department of Organic Chemistry and Petroleum Chemistry, Facultyof Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran2
Department of Organic Chemistry, Faculty of Chemistry, Alzahra
University, Tehran 1993893973, Iranliquids (ILs) and have found many applications in various research fields [5]. DESs are often cheap and safe andusually consist of mixing two or three ionic compounds
where each component has a high melting point, butwhen they are combined, the melting point of the prepared DES is lower than either component [6–8]. DESs
have countless advantages over conventional solvents, as
they not only comply with the principles of green chemistry but also act as catalysts, depending on their properties and they do not need to be separated and purified.
The use of DESs as acid catalysts has several advantages,
including nontoxicity, catalytic efficiency comparable toor better than that of the acid itself, and the possibilityof recovery and reuse without significant loss of activity[9–11].
A multicomponent reaction (MCR) is a reaction inwhich three or more reagents are added simultaneously
to a reaction flask and mixed in a one-pot process. These
reactions have several advantages over conventional synthesis protocols, including fewer steps, and no need to© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
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Monem et al. BMC Chemistry(2024) 18:120

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Scheme 1 Structure of pyrimidine containing drugs

separate reaction intermediates, resulting in fewer purification steps. Since most of the carbon atoms are present
in the final product, MCR can be considered as a good
atom-economical process [12–14].
Since pyrimidine moieties are present in the structureof many natural compounds, they have been studied formore than a century for their chemical and biologicalimportance, including anti-oxidant, anti-inflammatory,
immunomodulatory, anti-bacterial, anti-viral, antihypertensive, anti-cancer, anti-thyroid, anti-parasitic,
anti-malarial, anti-HIV, anti-viral, antifungal, anti-Leishmania, anti-HCV, anti-tumor, and urease inhibitory
activities [15–26].
Below are some compounds that have a pyrimidine ringin their structure and are used in medicine. For example,
Minoxidil acts directly on the smooth muscles of the vascular wall and reduces peripheral vascular resistance andblood pressure [27]. Cytarabine is easily converted into
nucleotides inside the cells, inhibits DNA synthesis, andhas a strong effect of suppressing the immune system
and anticancer [22]. Propylthiouracil inhibits the synthesis of thyroid hormones and has antithyroid activity[23]. Primethamine has anti-infective and anti-malarial
activity [24]. Lamivudine is an antiseptic drug and isused for HIV infections [25]. Trimethoprim is an antibiotic with a wide application range, which is used in thetreatment of infections, especially urinary infections [25].
(Scheme 1).
Barbituric acids (BAs) are an important class of pyrimidines that have many medicinal uses and are usedas hypnotics, sedatives, anti-convulsant, anesthetics,
and anti-fungal. The most commonly used barbiturate
drugs include butalbital, phenobarbital, barbital, andthialbarbital, and multicomponent reactions are thegood method for the synthesis of heterocyclic compounds. High efficiency, short reaction time, energy
saving, and simple operation are the advantages ofmulticomponent reactions [28–31].
Chromenes are an important group of heterocyclic
compounds that are the result of the fusion of a benzene ring with a pyran ring. As an important class ofcompounds, they are widely present in plants, including edible vegetables and fruits, and as drugs havesignificant effects, including anticancer, anti-HIV, antiviral, anticoagulant, anti-anaphylaxis, spasmolytic, anddiuretic [32–37] (Scheme 2).
Continuing our research on the preparation of novel
catalytic systems, we would like to report here thepreparation and characterization of the novel DES (3)by mixing one mole of MTPPBr (1) and one mole of
PHTH (2) (Scheme 3).
Then, it was used as a novel DES catalyst in the synthesis of two sets of the following compounds at 70 °C
in solvent‐free condition:• Pyrimido[4,5-d]pyrimidines 4(a–p) from the reaction of aldehydes (1), BA (2), urea (3), and• Pyrano[3,2-c]chromenes 7(a–j) from the reactionof 4-hydroxycoumarin (5), malononitrile (6), andaldehydes (1) (Scheme 4).

Monem et al. BMC Chemistry(2024) 18:120

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Scheme 2 Structure of drugs containing chromenes

Scheme 3 Synthesis of MTPPBr-PHTH-DES

Scheme 4 Synthesis of 4(a–p) and 7(a–j) by DES

Results and discussion
Characterization of MTPPBr‑PHTH‑DES

Characterization by FT‑IR
1

The new DES was characterized by FT-IR, H NMRTGA-DTA, densitometer, and eutectic points.

Figure 1 shows the IR spectra of MTPP-Br (a), PHTH (b),the fresh DES (c), and the recovered DES (d). In spectrum(a), the peaks at about 2900–3100 ­cm−1 are related to theMonem et al. BMC Chemistry(2024) 18:120

Page 4 of 17and (b) spectra, which confirm the structure of the DES
catalyst.
To confirm the structure of the recovered DES (d), thecorresponding IR spectrum was obtained which showsthat there is no significant difference between the fresh(c) and the recovered IR spectra.
Characterization by 1H NMR
The 1H NMR spectrum of MTPPBr

Figure 2 shows the 1H NMR spectrum of MTPPBr. Peaks
at 3.18–3.24 (d, 3H), and 7.79–7.63 (m, 15H) ppm are
related to the C­ H3 hydrogens, and the three phenyl ringhydrogens of MTPPBr, respectively.
Fig. 1 The FT-IR spectra of (a–d)

aromatic and aliphatic hydrogens, and the peaks at about
750 and 1480 ­cm−1 are related to the C-P bonds, respectively. In spectrum (b), the peak in1700 ­cm−1 is related
to the C=O group, and the broad peak in the region of
2400–3100 ­cm−1 is related to the OH of COOH. In spectrum (c), the indicated peaks can be seen in both (a)Fig. 2 The 1H NMR of MTPPBr

The 1H NMR spectrum of PHTH

Figure 3 shows the 1H NMR spectrum of PHTH. The
peak at 13.04 (s, 1H) belongs to a hydrogen of the –COOH group. The peaks at 7.52–7.54 (d, 2H) and 7.61–
7.63 (d, 2H) ppm are related to the four hydrogens of aphenyl ring.
The 1H NMR spectrum of MTPPBr‑PHTH‑DES

Figure 4 shows the 1H NMR spectrum of MTPPBrPHTH-DES. Peaks at 3.10–3.13 (d, 3H), 7.71 (dt,Monem et al. BMC Chemistry(2024) 18:120

Page 5 of 17

Fig. 3 The 1H NMR of PHTH

J = 10.0, 3.7 Hz, 15H), 7.61 (dq, J = 7.9, 4.1 Hz, 2H),
7.53 (dt, J = 5.9, 3.6 Hz, 2H) and 13.05 (s, 2H) ppm are
related to the C­ H3 hydrogens, three phenyl ring hydrogens, the phenyl ring of PHTH, and the acid groups,
respectively. When DES is formed, the signal intensity of hydrogens weakens and shifts towards the low
field. These observations indicate the presence of the
new hydrogen bond interactions between MTPPBr
and PHTH [38], confirming the structure of the newly
formed DES.
Characterization by TGA‑DTA

To investigate the stability and thermal behavior of the
new DES, the TGA-DTA analysis was performed whichshows three breaks (Fig. 5). The first failure in the area
below 200 °C is related to the absorbed vapors during
preparation of the catalyst. The second break in the area
below 400 °C is probably related to the breaking of hydrogen bonds in the DES structure and removal of the acidic
group, and the break at 600 °C is related to the decomposition of MTPPBr.

Characterization by densitometer

DESs usually have a density of 1.0 to 1.35 g/cm3, so a certain weight of DES was mixed with a certain volume ofwater, and its density was calculated using the relevant
formula, which is about 1.33013 g/ml [39].
Characterization by eutectic points

To check the best ratio of MTPPBr to PHTH, the eutectic point experiment was performed, and different ratiosof MTPPBr to PTHT were prepared. The eutectic point
phase diagram (Fig. 6) showed that the best ratio for thenovel DES formation is one mole of MTPPBr to one moleof PHTH.
The melting points of MTPPBr and PHTH are 230 and
210 °C, respectively, but when a novel DES was prepared,
its melting point decreased to 60 °C.
Optimization of the reaction conditions for the synthesisof 4h

To check the performance of the catalyst to find theappropriate solvent ­(H2O, EtOH, H­ 2O/EtOH, EtOAc,
n-hexane, and solvent-free condition), temperature

Monem et al. BMC Chemistry(2024) 18:120

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Fig. 4 The 1H NMR of DES(50, 60, 70, 80, 90, and 100 °C), and amount of the catalyst (0.25, 0.5, 0.75, 1.0, 1.25, and 1.5 mol), the reaction
between 4-chloro-benzaldehyde (1), BA (2), urea (3), andwas chosen as a model reaction for the synthesis of 4h(Scheme 5).
The best result was found to be the 1:1:1 molar ratio ofBA, urea, and 4-chloro-benzaldehyde with 1.0 mmol of
the novel DES catalyst at 70 °C in solvent-free condition(Table 1).
Synthesis of 4(a–p)

Based on the obtained results from the model reaction,
pyrimido[4,5-d]pyrimidines were synthesized under
optimal reaction condition (Table 2). Short reaction
times and high yields are important features of the proposed method.
Proposed mechanism for the synthesis of 4(a–p)

The possible mechanism for the synthesis of 4(a–p) is
shown in Scheme 6. First, the carbonyl group of an aldehyde is activated by the DES catalyst to be susceptible tothe nucleophilic attack of BA to form (I). By removing

water, (II) will be formed, and its condensation withurea yields (III). Then, by internal cyclization of (III) andremoving water, the final product (IV) is formed.
Reusability of DES in synthesis of 4(a–p)

Catalyst reusability and recovery is an essential parameter to be considered. Therefore, after completion of thereaction (TLC) under optimal condition, it was stopped,
and the resulting mixture was washed with ethanol toseparate the catalyst. Ethanol was removed from the filtrate and the separated DES was dried and used in further four reaction runs. The efficiency of reactions was
about 92, 90, 86 and 79%, respectively which confirms thestability of the prepared DES catalyst (Fig. 7).
Comparison of the catalyst activities

Table 3 shows the comparison of different methods forthe synthesis of 4(a–p). Green condition, short reaction
time, low temperature, easy separation of the DES catalyst and high efficiency are the advantages of our proposed method.

Monem et al. BMC Chemistry(2024) 18:120

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Fig. 5 The TGA-DTA pattern of DES

Optimization of the reaction conditions for the synthesisof 7cFig. 6 The Eutectic points phase diagram pattern of DES

Scheme 5 Synthesis of 4h by DES

To check the performance of the catalyst to find an
appropriate solvent ­(H2O, EtOH, H­ 2O/EtOH, EtOAc,
n-hexane, and solvent-free condition), temperature(50, 60, 70, 80, 90, and 100 °C), and amount of the catalyst (0.25, 0.5, 0.75, 1.0 1.25, and 1.5 mol), the reaction
between 4-chlorobenzaldehyde (1), 4-hydroxy-coumarin(5), and malononitrile (6), was chosen as a model reaction for the synthesis of 3c (Scheme 7).
The best result was found to be the 1:1:1 mol ratio ofBA, urea, and 4-chloro-benzaldehyde with 1.0 mmol ofMonem et al. BMC Chemistry(2024) 18:120

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Table 1 Optimization of the reaction conditions
Entry

Catalyst (mmol)

Temp. (°C)

Solvent

Yield (%)

1

0.25

70

–

87

2

0.50

70

–

91

3

0.75

70

–

93

4

1.25

70

–

90

5

1.50

70

–

91

6

1.0

50

–

90

7

1.0

60

–

89

8

1.0

80

–

86

9

1.0

90

–

83

10

1.0

100

–

76

11

1.0

Reflux

EtOH

85

12

1.0

RefluxH2O/EtOH

69

13

1.0

Reflux

H2O

52

14

1.0

Refluxn-Hexane

71

15

1.0

Reflux

EtOAc

82

16

1.0

70

–

92

time, low temperature, easy separation of the DES catalyst and high efficiency are the advantages of our proposed method.

Experimental section
Materials and methods

All chemicals were provided by the foreign chemicalcompanies and used as received. Progress of the reactions
was monitored by the TLC-silica gel 60 F-254 plates.
The Fourier Transform Infrared (FT-IR) spectra wererecorded by the Perkin-Elmer Spectrum Version 10.02.00
using KBr pellets. The NMR spectra were recorded on
a 250 MHz Bruker spectrometer. Melting points were
determined on a BUCHI 510 melting point apparatus.
The density of the DES catalyst was determined by the
AND-HR200 instrument. Thermo-Gravimetric-Analysis
Differential-Thermal-Analysis (TGA-DTA) was done by
the SDT-Q600 device.
General procedure for preparation of MTPPBr‑PHTH‑DES

the novel DES catalyst at 60 °C in solvent-free condition(Table 4).
Synthesis of 7(a–j)

Table 5 shows the synthesis of diverse pyrano[3,2-c]chromenes under optimal condition in short reaction
times and high yields.
Proposed mechanism for the synthesis of pyrano[3,2‑c]chromenes

The possible mechanism for the synthesis of 7(a–j) isshown in Scheme 8. First, the carbonyl group of an aldehyde is activated by the DES catalyst to be susceptible
to the nucleophilic attack of malononitrile to form (I).
By removing water, (II) will be formed which condenses
with 4-hydroxy-coumarin to yield (III). Then, by internal
cyclization of (III), (IV) is formed, and the final product(V) will be formed by rearrangement of (IV).
Reusability of DES in the synthesis of pyrano[3,2‑c]chromenes

After completion of the reaction (TLC) under optimal
condition, it was stopped, and the resulting mixture waswashed with ethanol to separate the catalyst. Ethanol was
removed from the filtrate and the separated DES wasdried and used in further four reaction runs. The efficiency of reactions was about 96, 95, 91 and 88%, respectively which confirms the stability of the prepared DES
catalyst (Fig. 8).
Comparison of the catalyst activities

Table 6 shows the comparison of different methods forthe synthesis of 7(a–j). Green condition, short reaction

The mixture of MTPPBr and PHTH (molar ratio 1:1) was
stirred at 60 °C in solvent-free condition until a homogeneous liquid was obtained. When it was cooled slowly
at room temperature, it turned into a transparent solid(DES) which dissolves well in water or ethanol.
General procedure for the synthesis of pyrimido[4,5‑d]pyrimidines 4(a–p)

BA (1 mmol, 128 mg), urea (1 mmol, 60.06 mg), aldehyde(1.0 mmol), and DES catalyst (1 mmol, 0.523 g) weremixed and stirred at 70 °C in solvent‐free condition for
an appropriate time. After completion of the reaction(TLC), the resulting mixture was washed with ethanol toseparate the catalyst (the DES catalyst is soluble in ethanol and the reaction mixture is insoluble). Ethanol was
removed from the filtrate and the separated DES was
kept for further reactions.
A solid precipitate was washed several times with ethanol and characterized with comparison of their FT-IR, 1
HNMR, 13C NMR, Mass spectra, and melting points withauthentic samples.
Spectral data of the 4(a–p)

5‑(4‑Isopropylphenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrim‑
idine‑2,4,7(1H,3H,6H)‑trione (4a) Yellow solid, M.P.:
228–230 °C; IR (KBr) ν = 3202, 3089, 2957, 2868, 1751,
1703, 1673, 1578, 1440, 1414, 1343, 1307, 1212, 1196,
1136, 1077, 1045, 1021, 837, 813, 794, 634 and 545 ­cm−1.
1
H NMR (250 MHz, DMSO-d6) δ = 11.34 (s, 1H), 11.19(s, 1H), 8.24 (s, 1H), 7.72 (dd, J = 187.4, 7.9 Hz, 5H), 5.47(s, 1H). 2.93 (h, J = 6.7 Hz, 1H), 1.21 (d, J = 6.8 Hz, 6H).
13
C NMR (62.5 MHz, DMSO-d6) δ = 164.0, 162.2, 155.3,

Monem et al. BMC Chemistry(2024) 18:120

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Table 2 Synthesis of 4(a-p) by DES

Entry

Aldehyde

Product

Time (min)Yield (%)

M.P. °C
Found, literature

TON

TOF

1

4a

35

93

228–230, NEW

93

2.65

2

4b

40

86

296–300, NEW

86

2.15

3

4c

35

94

217–220, NEW

94

2.68

4

4d

35

95

257–259, NEW

95

2.71

5

4e

45

79

223–225, NEW

79

1.75

6

4f

40

88

245–248,
241–244 [40]

88

2.20

7

4g

60

85

275–278,
282–284 [41]

85

1.41

8

4h

25

92

297–300,
292–295 [40]

92

3.68

9

4i

50

87

240–243,
239–240 [40]

87

1.74

Monem et al. BMC Chemistry(2024) 18:120

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Table 2 (continued)

Entry

Aldehyde

Product

Time (min)Yield (%)

M.P. °C
Found, literature

TON

TOF

10

4j

40

83

247–250,
199–202 [40]

83

2.07

11

4k

45

81

236–239,
221–224 [40]

81

1.80

12

4l

50

87

264–267,
251–254 [40]

87

1.74

13

4m

40

83

296–299,
284–287 [40]

83

2.07

14

4n

25

80

282–285,
271–273 [42]

80

3.20

15

4o

30

89

282–286
272–274 [43]

89

2.96

16

4p

40

75

221–224
215–216 [44]

75

1.87

154.3, 150.6, 134.5, 133.7, 130.7, 126.6, 125.6, 124.8, 118.3,
34.0, 32.0, 26.6, 23.8.
4‑(2,5,7‑Trioxo‑1,2,3,4,5,6,7,8‑octahydropyrimido[4,5‑d]pyrimidin‑4‑yl)benzoic acid (4b) Yellow solid, M.P.:
296–300 °C; IR (KBr) ν = 3271, 3247, 3131, 2874, 1777,
1766, 1734, 1705, 1599, 1417, 1366, 1322, 1289, 1252, 1218,
1059, 1041, 966, 772, 744, 685 and 502 ­cm−1. 1H NMR(250 MHz, DMSO-d6) δ = 11.57 (s, 1H), 11.47–11.18 (m,2H), 10.98–10.81 (m, 2H), 7.85–7.81 (m, 2H), 7.73–7.69(m, 1H), 7.54–7.52 (m, 1H), 6.23 (s, 1H). 13C NMR (62.5
MHz, DMSO-d6) δ = 169.5, 162.7, 150.8, 134.5, 134.4,
133.3, 129.4, 129.4, 127.5, 125.5, 123.2, 78.9, 51.1. MS:
m/z = 302.1 ­[M]+, Base peak: m/z = 231.2.
5‑(4‑(Diethylamino)phenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimidine‑2,4,7(1H,3H,6H)‑trione (4c) Yellow solid,
M.P.: 217–220 °C; IR (KBr) ν = 3445, 3271, 3208, 3027,
1736, 1684, 1652, 1608, 1449, 1443, 1391, 1345, 1311,
1187, 1153, 1075, 1011, 795, 677 and 518 ­cm−1. 1H NMR

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Scheme 6 Proposed mechanism for the synthesis of 4(a–p)

155.7, 152.6, 150.8, 142.8, 139.9, 120.1, 111.3, 111.3, 109.3,
44.6, 12.9.; MS: m/z = 329.2 ­[M]+, Base peak: m/z = 272.1.

Fig. 7 Reusability of DES(250 MHz, DMSO-d6) δ = 11.04 (s, 1H), 10.91 (s, 1H),
8.41 (s, 1H), 8.11 (s, 1H), 7.80–5.86 (m, 4H), 5.44 (s, 1H),
3.49–3.42 (m, 4H), 1.12 (t, J = 7.6 Hz, 6H).13C NMR (62.5
MHz, DMSO-d6) δ = 165.2, 165.2, 163.2, 160.1, 155.7,

5‑(3‑Ethoxy‑4‑hydroxyphenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimidine2,4,7(1H,3H,6H)‑trione (4d) Yellow solid,
M.P.: 257–259 °C; IR (KBr) ν = 3512, 3205, 3039, 2842,
1761, 1701, 1652, 1543, 1505,1405, 1349, 1277, 981, 793,
753, 513 and 407 ­cm−1. 1H NMR (250 MHz, DMSO-d6)
δ = 11.22 (d, J = 6.9 Hz, 1H), 11.10 (d, J = 6.8 Hz, 1H), 10.45(d, J = 7.3 Hz, 1H), 8.46 (d, J = 5.9 Hz, 1H), 8.18 (d, J = 7.6
Hz, 1H), 7.76–6.83 (m, 3H), 5.39 (s, 1H), 4.09–4.03 (m,2H), 1.38–1.32 (m, 3H). 13C NMR (62.5 MHz, DMSO-d6)
δ = 165.1, 164.6, 162.9, 156.4, 153.7, 150.6, 146.5, 132.9,
124.6, 119.4, 115.8, 114.3, 64.2, 15.0.; MS: m/z = 318.2­[M]+, Base peak: m/z = 276.1.
5‑(2,3‑Dihydroxyphenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimidine‑2,4,7(1H,3H,6H)‑trione (4e) Yellow solid,
M.P.: 223–225 °C; IR (KBr) ν = 3600, 3438, 3361, 3223,
3096, 1748, 1712, 1635, 1474, 1456, 1347, 1216, 1149,

Table 3 Comparison of DES with the other catalysts
Entry

Catalyst

Condition

Time (min)Yield (%)

Ref

1

MnCoFe2O4@ovalbumin

Solvent-free, 80 °C

10–25

80–96

[40]

2

CoFe2O4/TMU‐17‐NH2

Solvent-free, 80 °C

30

95–98

[41]

3

Catalyst freeRefluxing methanol

720

75–80

[42]

4

β-CD/H2O

60–65 °C

–

76–89

[43]

5

(α-Fe2O3)-MCM-41-DAIL

Solvent-free, 120 °C

180–480

91–98

[45]

6

CuI NPs

H2O, r.t

240–360

91–98

[46]

7

[H2-DABCO][ClO4]2

H2O, 75 °C

15–55

85–95

[47]

8

MTPP-Br/PHTH-DES

Solvent-free, 60 °C

43

85–95

Our work

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Scheme 7 Synthesis of 7c by DES

845, 781, 496 and 419 ­cm−1. 1H NMR (250 MHz, DMSOd6) δ = 11.89 (s, 1H), 11.24 (s, 1H), 11.15–11.08 (m, 1H),
10.95 (s, 1H), 10.12–10.00 (m, 1H), 7.00–6.79 (m, 2H),
6.50 (d, J = 7.3 Hz, 1H), 5.42 (s, 1H), 4.64 (s, 1H). 13C NMR(62.5 MHz, DMSO-d6) δ = 164.0, 160.1, 151.0, 149.9,
145.9, 138.4, 125.6, 122.2, 117.7, 116.1, 85.5, 53.5.; MS:m/z = 290.1 ­[M]+, Base peak: m/z = 230.
5‑Phenyl‑5,8‑dihydropy rimido[4,5‑d]py rimi‑
dine‑2,4,7(1H,3H,6H)‑trione (4f ) Yellow solid, M.P.:
262–265 °C; IR (KBr) ν = 3215, 3069, 2836, 1743, 1677,
1582, 1566, 1451, 1405, 1341, 1297, 1203, 1033, 864, 763,
680, 526 and 419 c­ m−1.
5‑(2‑Chlorophenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrim‑
idine‑2,4,7(1H,3H,6H)‑trione (4g) Yellow solid, M.P.:
215–218 °C; IR (KBr) ν = 3487, 3450, 3210, 3051, 2819,
1766, 1678, 1611, 1431, 1383, 1275, 1228, 1049, 943, 806,
789, 754, 609, 525, 505, and 435 c­ m−1.

Table 4 Optimization of the reaction conditions
Entry

Catalyst (mmol)

Temp. (°C)

Solvent

Yield (%)

1

0.25

60

–

89

2

0.50

60

–

90

3

0.75

60

–

91

4

1.25

60

–

94

5

1.50

60

–

89

6

1.0

50

–

95

7

1.0

70

–

94

8

1.0

80

–

86

9

1.0

90

–

79

10

1.0

100

–

76

11

1.0

Reflux

EtOH

86

12

1.0

RefluxH2O/EtOH

76

13

1.0

Reflux

H2O

70

14

1.0

Reflux

CH3CN

65

15

1.0

RefluxCH2Cl2

42

16

1.0

60

–

96

5‑(4‑Chlorophenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrim‑
idine‑2,4,7(1H,3H,6H)‑trione (4h) Yellow solid, M.P.:
297–300 °C; IR (KBr) ν = 3212, 3087, 2845, 1755, 1704,
1673, 1574, 1554, 1443, 1413, 1344, 1289, 1202, 1092,
1019, 882, 838, 809, 793, 550 and 423 c­ m−1.
5‑(2,4‑Dichlorophenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimidine‑2,4,7(1H,3H,6H)‑trione (4i) Yellow solid,
M.P.: 270–273 °C; IR (KBr) ν = 3211, 3074, 2832, 1759,
1722, 1691, 1578, 1439, 1379, 791 and 509 c­ m−1.
5‑(3‑Nitrophenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimi‑
dine‑2,4,7(1H,3H,6H)‑trione (4j) Yellow solid, M.P.:
247–250 °C; IR (KBr) ν = 3409, 3083, 2963, 2778, 1755,
1725, 1688, 1650, 1526, 1409, 1380, 1352, 1246, 1218,
1080, 1009, 909, 843, 809, 728, 499 and 417 c­ m−1.
5‑(4‑Nitrophenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimi‑
dine‑2,4,7(1H,3H,6H)‑trione (4k) Yellow solid, M.P.:
246–249 °C; IR (KBr) ν = 3343, 3269, 3078, 2995, 2837,
1721, 1650, 1519, 1419, 1379, 1349, 1292, 1238, 1109,
1013, 860, 778, 697, 657, 550 and 534 c­ m−1.
5 ‑ ( p ‑To l y l) ‑ 5 , 8 ‑ di hy dr o p y r imi d o [ 4 , 5 ‑ d] p y r imi ‑dine‑2,4,7(1H,3H,6H)‑trione (4l) Yellow solid, M.P.:
270–275 °C; IR (KBr) ν = 3467, 3210, 3081, 2839, 1752,
1675, 1556, 1430, 1344, 1296, 1192, 822, and 523 c­ m−1.
5‑(4‑Methoxyphenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimidine‑2,4,7(1H,3H,6H)‑trione (4m) Yellow solid,
M.P.: 297–300 °C; IR (KBr) ν = 3208, 3070, 2841, 1729,
1673, 1550, 1508, 1435, 1401, 1308, 1271, 1180, 1015,
837, 794, 628, 519 and 421 c­ m−1.
5‑(3,4‑Dimethoxyphenyl)‑5,8‑dihydropyrimido[4,5‑d]pyrimidine‑2,4,7(1H,3H,6H)‑trione (4n) Yellow solid,
M.P.: 320–324 °C; IR (KBr) ν = 3226, 3146, 3076, 2950,
1740, 1696, 1655, 1541, 1496, 1424, 1390, 1276, 1148,
1011, 798, 524 and 483 (­ cm−1).

Monem et al. BMC Chemistry(2024) 18:120

Page 13 of 17

Table 5 Synthesis of 7(a–j) by MTPPBr-PHTH-DES

Entry

Aldehyde

Product

Time
(min)

Yield
(%)

M.P. °C
Found, literature

TON

TOF

1

7a

10

95

262-265,
256-257 [48]

95

9.50

2

7b

15

97

263-267,
266–268 [49]

97

6.46

3

7c

10

96

259-262,264-267 [49]

96

9.60

4

7d

20

93

260-263,
256-258 [49]

93

4.65

5

7e

10

92

256-258,261-263 [49]

92

9.20

6

7f

10

90

273-275,259-261 [49]

90

9.00

7

7g

20

91

234-236,230-233 [50]

91

4.55

8

7h

25

85

230-233,
233-236 [50]

85

3.40

Monem et al. BMC Chemistry(2024) 18:120

Page 14 of 17

Table 5 (continued)

Entry

Aldehyde

Product

Time
(min)

Yield
(%)

M.P. °C
Found, literature

TON

TOF

9

7i

20

88

248-252,
260–263 [51]

88

4.40

10

7j

25

89

220-224,226-230 [48]

89

3.56

Scheme 8 Proposed mechanism for the synthesis of 7(a–j)

5‑(Furan‑2‑yl)‑5,8‑dihydropyrimido[4,5‑d]pyrimi‑
dine‑2,4,7(1H,3H,6H)‑trione (4o) Yellow solid, M.P.:
323–325 °C; IR (KBr) ν = 3512, 3205, 3121, 3037, 2842,
1741, 1761, 1698, 1651, 1543, 1499, 1441, 1276, 1163,
972, 793, 753, and 515 (­ cm−1).

Fig. 8 Reusability of DES

5‑(Thiophen‑2‑yl)‑5,8‑dihydropyrimido[4,5‑d]pyrimi‑
dine‑2,4,7(1H,3H,6H)‑trione (4p) Yellow solid, M.P.:
330–333 °C; IR (KBr) ν = 3226, 3146, 3076, 2950, 1740,
1696, 1655, 1541, 1496, 1424, 1390, 1276, 1148, 1011,
798, 524 and 483 (­ cm−1).

Monem et al. BMC Chemistry(2024) 18:120

Page 15 of 17

Table 6 Comparison of DES with the other catalysts
Entry Catalyst

Condition

Time (min) Yield (%) Refs.

1

H2O/EtOH,
Reflux

8–12

90–95

[49]

SBPPSP

2

TBAB

Water

45–62

85–93

[50]

3

[TETA]TFA

H2O/EtOH,
Reflux

5–240

50–94

[51]

4

Nano ­Al2O3 EtOH

300

75–89

[52]

5

TRUE

Water

8–25

88–94

[53]

6

DBU

Water/Reflux

5–20

81–94

[54]

7

H5BW12O40 H2O/EtOH,
Reflux

195–270

85–98

[55]
[56]

8

DABCO

Neat

30

87–97

9

(CH2)6N4

EtOH, Reflux

7–80

89–95

[57]

10

DES

Solvent-free,
60 °C

10–25

85–97

Our work

General procedure for the synthesis of pyrano[3,2‑c]chromenes 7(a–j)

4-Hydroxycoumarin (1 mmol, 162 mg), malononitrile(1 mmol, 66 mg), aldehyde (1.0 mmol), and the DES catalyst (1 mmol, 0.523 mg) were mixed and stirred at 70 °C
in solvent‐free condition for an appropriate time. Aftercompletion of the reaction (TLC), the resulting mixture
was washed with ethanol to separate the catalyst (theDES catalyst is soluble in ethanol and the reaction mixture is insoluble). Ethanol was removed from the filtrate
and the separated DES was kept for further reactions.
A solid precipitate was washed several times with ethanol and characterized with comparison of their FT-IR,
1
HNMR spectra, and melting points with authentic
samples.
Spectral data of the 7(a–j)

2 ‑ Am i n o ‑ 5 ‑ o x o ‑ 4 ‑ p h e n y l ‑ 4 H , 5 H ‑ p y ra n o [ 3 , 2 ‑ c ]chromene‑3‑carbonitrile (7a) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3376, 3285, 3065, 2198, 1709, 1675,
1605, 1638, 1382, 1211, 1113, 1058, 956, 758, 706 and 522­(cm−1).
2‑Amino‑4‑(2‑chlorophenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7b) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3402, 3284, 3180, 3086, 2192, 1710,
1675, 1602, 1458, 1382, 1174, 1063, 958, 904, 756 and 522.
­(cm−1).
2‑Amino‑4‑(4‑chlorophenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7c) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3382, 3307, 3291, 2193, 1714, 1676,
1603, 1562, 1458, 1378, 1213, 1092, 1061, 906, 845, 765
and 513 (­ cm−1).

2‑Amino‑4‑(2,4‑dichlorophenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7d) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3323, 3204, 2195, 1720, 1668, 1601,
1512, 1381, 1264, 1143, 1095, 762 and 481 (­ cm−1).
2‑Amino‑4‑(3‑nitrophenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7e) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3322, 3193, 3093, 2994, 2203, 1703,
1672, 1606, 1531, 1381, 1347, 1176, 1058, 898, 762 and 709­(cm−1).
2‑Amino‑4‑(4‑nitrophenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7f ) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3369, 3335, 3073, 2195, 1717, 1671,
1606, 1505, 1347, 1370, 1055, 765 and 459 (­ cm−1).
2‑Amino‑4‑(3,4‑dimethoxyphenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7g) White solid, M.P.:
234–236 °C; IR (KBr) ν = 3406, 3326, 3261, 2196, 1709,
1673, 1378, 1048 and 760. 1H NMR (250 MHz, DMSO-d6)
δ = 7.87 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.45
(t, J = 9.3 Hz, 2H), 7.35 (s, 2H), 6.85 (d, J = 12.4 Hz, 2H),
6.72 (d, J = 8.3 Hz, 1H), 4.38 (s, 1H), 3.69 (s, 6H). 13C NMR(62.5 MHz, DMSO-d6) δ = 158.4, 152.5, 149, 149, 136.3,
133.3, 125.1, 122.9, 120.1, 119.8, 117, 112.3, 112, 104.5,
58.5, 55.9, 40.9, 40.6, 40.3, 39.9, 39.6, 39.3, 38.9, 36.9.
2‑Amino‑4‑(4‑isopropylphenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7h) White solid, M.P.: 230–
233 °C; IR (KBr) ν = 3390, 3304, 3205, 2202, 1713, 1672,
1375, 1050 and 769. (­ cm−1).
2‑Amino‑4‑(4‑hydroxyphenyl)‑5‑oxo‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7i) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3504, 3410, 3287, 3184, 3068, 2879,
2197, 1697, 1674, 1610, 1513, 1460, 1382, 1266, 1071, 844,
760, 562 and 524 ­(cm−1).
2‑Amino‑5‑oxo‑4‑(thiophen‑2‑yl)‑4H,5H‑pyrano[3,2‑c]chromene‑3‑carbonitrile (7j) White solid, M.P.: 228–
230 °C; IR (KBr) ν = 3368, 3279, 3177, 3070, 2200, 1709,
1668, 1601, 1564, 1308, 1056, 760 and 705 (­ cm−1).

Conclusion
In conclusion, the new DES (MTPPBr-PHTH-DES) was
prepared, characterized and used as a novel catalyst in
the synthesis of pyrimido[4,5-d]pyrimidines 4(a–p) andpyrano[3,2-c]chromenes 7(a–j). The newly synthesized
DES catalyst can be synthesized simply by mixing andheating the starting materials, which does not require any
additional purification steps, and a simple filtration is sufficient to separate it from the reaction mixture. It can beMonem et al. BMC Chemistry(2024) 18:120

used not only as a moderate, inexpensive, and environmentally safe solvent, but also as recyclable and reusableorganocatalyst to facilitate organic transformations.

Page 16 of 17

8.
9.

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s13065-​024-​01227-x.

10.

Supplementary Material 1.
11.
Acknowledgements
The authors are grateful to the Bu-Ali Sina University for the support of thiswork.
Author contributions
Arezo Monem did the lab experiment. Davood Habibi wrote the main manuscript text. Hadis Goudarzi is a co-author. Abdolhamid Alizadeh is a co-author.
All authors reviewed the manuscript.
Funding
This study was financially supported by the Bu-Ali Sina University, Hamedan
Iran, and had no role in the design of the study and collection, analysis, andinterpretation of data and in writing the manuscript.

12.
13.
14.
15.
16.

Availability of data and materials
All the methods carried out in this project are in accordance with relevant
local/national/ international institutional guidelines and regulations. All data
generated or analyzed during this study are not publicly available due to DATANOT PUBLIC but are available from the corresponding author on reasonable
request.

17.
18.
19.

Declarations

20.

Ethics approval and consent to participate
Not applicable.

21.

Consent for publication
Not applicable.

22.

Competing interests
The authors declare that they have no competing interests.

23.

Received: 17 February 2024 Accepted: 13 June 2024

24.
25.

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