Hexamethylenetetramine-based ionic liquid/MIL-101(Cr) metal-organic framework composite: a novel and versatile tool for the preparation of pyrido[2,3-d:5,6-d′]dipyrimidines

Article abstract of DOI:10.1039/d0ra09054a

In the current paper, a hexamethylenetetramine-based ionic liquid immobilized on the MIL-101(Cr) metal-organic framework was successfully synthesized as a novel, efficient, and recoverable catalyst for the synthesis of pyrido[2,3-d:5,6-d′]dipyrimidine derivativesviathe reaction of barbituric acid derivatives, 6-aminouracil/6-amino-1,3-dimethyl uracil, and aromatic aldehydes under solvent-free conditions. Characterization of the catalyst was carried out using various methods such as field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectrophotometry (FT-IR), and Brunauer-Emmett-Teller (BET). Efficient transformation, short reaction times, excellent yields, easy product isolation, mild conditions, and the potential high recyclability of the organocatalyst are the main features of this protocol.

Full text of DOI:10.1039/d0ra09054a

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Hexamethylenetetramine-based ionic liquid/MIL-
101(Cr) metal–organic framework composite:
a novel and versatile tool for the preparation of
pyrido[2,3-d:5,6-d0]dipyrimidines†
b
Cite this: RSC Adv., 2021, 11, 364
Boshra Mirhosseini-Eshkevari,ab Mohammad Ali Ghasemzadeh,
*
a
Manzarbanoo Esnaashari and Saeed Taghvaei Ganjalia
*
In the current paper, a hexamethylenetetramine-based ionic liquid immobilized on the MIL-101(Cr) metal–
organic framework was successfully synthesized as a novel, efficient, and recoverable catalyst for the
synthesis of pyrido[2,3-d:5,6-d0]dipyrimidine derivatives via the reaction of barbituric acid derivatives, 6-
aminouracil/6-amino-1,3-dimethyl uracil, and aromatic aldehydes under solvent-free conditions.
Characterization of the catalyst was carried out using various methods such as field emission scanning
electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD),
thermogravimetric analysis (TGA), Fourier transform infrared spectrophotometry (FT-IR), and Brunauer–
Emmett–Teller (BET). Efficient transformation, short reaction times, excellent yields, easy product
isolation, mild conditions, and the potential high recyclability of the organocatalyst are the main features
of this protocol.
Received 23rd October 2020
Accepted 8th December 2020
DOI: 10.1039/d0ra09054a
rsc.li/rsc-advances
MOFs), merging several nuclei, organic, and linker character-
istics into a framework.11–13 Some other cases regarding carbon–
1. Introduction
carbon bond formation, oxidation reactions, and catalytic
activity of MOFs have also been reported.14,15 The reusable rigid
acid catalysts have recently been substantially replaced in
industrial operations by dangerous homogeneous acid cata-
lysts.16,17 By ltering or centrifuging, acidic heterogeneous
catalyzing agents may be isolated efficiently from the reaction
blend without a need for particular treatments, thus providing
a promising ecological process and reducing the handling cost.18
The reusability is another advantage of the heterogeneous cata-
lyst.19,20 Ionic liquids (ILs), consisting of ions, may have certain
features; therefore, they are used broadly in different organic
synthesis and catalytic reactions. ILs have further been allocated as
a group of environmental materials owing to their non-ammable
features, besides low vapor pressure.21 Cases of their uses as
catalysts in Biginelli reaction have also recently been discussed,
showing excellent catalytic activity.22,23 Although ample prospects
are in using MOFs as solid supports of ILs, ILs/MOFs composites
have revealed signicant features due to the ILs nano sizing than
the bulk ionic liquid, indicating the typical freezing or melting
features.24 Therefore, preparing and exploring the use of chemi-
cally connement ILs-MOFs for catalysis for the rst time is very
substantial. One of the most efficient strategies of synthesization
of organic and medicinal chemistry products is multicomponent
reactions (MCRs).25 A substantial group of annulated uracils is
derivatives of pyridopyrimidine that, with a wide variety of
medicinal, pharmacological, and biological features, have recently
Currently, inorganic clusters or metal ions (usually transition
metal) are used to make solid compounds that are crystalline in
structure, connecting to two or multifunctional organic
elements for providing metal–organic frameworks (MOFs).1
Metal–organic frameworks have, in past years, been useful
resources for their applications in preparing different catalysts,
fuel cells, electronics, sensors, and extensive industrial prod-
ucts, together with their other use in drug delivery, selective
separation, adsorption, and petrochemistry.2–4 High surface
area and thermal stability are some benets of these porous and
nanoscopic materials.5–8 MIL-101 is one of the most promising
porous materials for future energy and environmental applica-
tions, owing to its superior physicochemical properties
including high hydrothermal/chemical stability and desirable
textural properties.9 MIL-101 is a member of the large family of
MOFs with the largest Langmuir surface area (4500 m2 gꢀ1),
10
˚
˚
pore size (29–34 A), and cell volume (702.000 A). Several
probabilities to model the porous complexity of MOFs in
a logical method have been offered by multivariate MOFs (MTV-
aDepartment of Chemistry, North Tehran Branch, Islamic Azad University, Post Box:
1913674711, Tehran, I. R. Iran. E-mail: Mb_esnaashari@yahoo.com
bDepartment of Chemistry, Qom Branch, Islamic Azad University, Post Box: 37491-
13191, Qom, I. R. Iran. E-mail: Ghasemzadeh@qom-iau.ac.ir; Fax: +98-253-
7780001; Tel: +98-253-7780001
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra09054a
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Scheme 1 Synthesis of pyrido[2,3-d:5,6-d0]dipyrimidine derivatives using HMTA-BAIL@MIL-101(Cr) under solvent-free conditions.
Scheme 2 Preparation of MIL-101(Cr).
gained signicant attention.26,27 Pyrido [2,3-d:6,5-d0]dipyrimidines liquid, highly efficient and reusable catalyst for the synthesis of
is synthesized by various catalysts like piperidine,28 SBA-Pr-SO3H,29 pyrido[2,3-d:5,6-d0]dipyrimidine derivatives via the one-pot
P2O5 (ref. 30) and MWCNTs@L-His/Cu(II).31
three-component condensation reaction of 6-aminouracil or 6-
These protocols have some advantages including high product amino-1,3-dimethyl uracil, barbituric acid derivatives and
yields, short reaction times, and mild reaction conditions while aromatic aldehydes under solvent-free conditions (Scheme 1).
they have some drawbacks such as high production costs, low
chemical and thermal stability, and tedious work-up. Therefore,
there is a considerable attempt to build an appropriate catalytic
2. Experimental
2.1 Materials and instrumentation
system to synthesize pyrido[2,3-d:5,6-d0]dipyrimidine. Recently, we
have reported various synthetic methods for the preparation of
several heterocycle compounds using nanocatalysts.32–36 In exper-
imental and industrial research, it is essential to decrease toxic
waste and reaction process time to protect the environment.
In this research, we decided to investigate the application of
HMTA-BAIL@MIL-101(Cr) as a novel Brønsted acidic ionic
The high purities chemicals were bought from Sigma-Aldrich and
Merck. The substances with the commercial reagent grades were
utilized with no more purifying. The melting point was unmodied
and dened in a capillary tube over a melting point microscope
(Boetius). 1H NMR and 13C NMR spectra were attained on Bruker 250
MHz spectrometer with DMSO-d6 as a solvent and utilizing TMS as
Scheme 3 Preparation of HMTA-BAIL.
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Scheme 4 Preparation of HMTA-BAIL@MIL-101(Cr).
an internal standard. Recording FT-IR spectra was performed on a previously used procedure with minor modication.37 To this
Magna-IR, spectrometer 550. The elemental analyses (H, C, N) were end, a combination of 5.4 g of Cr(NO3)3$9H2O, 1.5 g of tereph-
conducted using a Carlo ERBA Model EA 1108 analyzer. Powder XRD thalic acid (BDC), 45 mL of deionized water, and 0.6 mL of
(X-ray diffraction) was performed on a Philips diffractometer (X'pert hydrouoric acid (5 mol Lꢀ1) was sonicated for 10 min and then
˚
Co.) with Cu Ka mono chromatized radiation (l ¼ 1.5406 A). The the mixture was transferred to a Teon-lined stainless steel
microscopic morphology of the products was observed through SEM autoclave for 8 h at 220 ꢁC. Subsequent to cooling down the
(LEO, 1455VP). Recording the mass spectra was based on a Joel D-30 autoclave to ambient temperature, the reaction mixture was
tool at an ionizing potential of 70 eV. The energy dispersive analysis subjected to ltration and washing by distilled water. The
ꢁ
of X-ray was used to perform compositional analysis (EDX, Kevex, resultant solid was dehydrated in an 80 C oven nightlong and
Delta Class 1). A Mettler Toledo TGA was considered to perform denoted as crude MIL-101(Cr) crystals.
thermogravimetric analysis (TGA), under argon and heating was
performed to 825 ꢁC from room temperature. A Belsorp mini auto-
2.3 Preparation of HMTA-BAIL
matic adsorption tool was used to measure nitrogen adsorption–
desorption isotherms at 196 ꢁC followed by degassing the specimens
HMTA-BAIL was prepared based on the previous method with
for 5 h at 150 ꢁC. The sample weight was estimated as 10 mg in the
TG test with heating at 10 ꢁC per minute.
a slight modication.38 A mixture of hexamethylenetetramine
(0.01 mol) and 1,4-butane sultone (0.08 mol) was stirred at room
temperature for 72 h under solvent-free conditions. The
produced white solid zwitterion (HMTA-BAIL precursor) was
ltered out and washed repeatedly by diethyl ether. An ionic
2.2 Preparation of MIL-101(Cr)
Scheme 2 illustrates the synthesis procedure of the MIL-101(Cr), liquid was formed through adding a stoichiometric quantity of
which was performed under hydrothermal conditions based on sulfuric acid to the zwitterion and then stirring the produced
Fig. 1 The EDS spectra of MIL-101(Cr) (a) and HMTA-BAIL@MIL-101(Cr) (b).
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Fig. 2 FE-SEM images of MIL-101(Cr) (a) and HMTA-BAIL@MIL-101(Cr) (b).
admixture at 90 ꢁC for 8 h. Lastly, washing the BAIL phase was d: 3.01 (s, 3H, CH3), 3.66 (s, 3H, CH3), 4.22 (s, 1H, CH), 6.96–6.99 (d,
performed for different times by diethyl ether and toluene for 1H, J ¼ 7.4 Hz, ArH), 7.07 (s, 1H, ArH), 7.30–7.33 (d, 1H, J ¼ 7.8 Hz,
removing non-ionic remains, and then dehydrating was per- ArH), 9.27 (s, 1H, OH), 10.40 (s, 1H, NH), 10.64 (s, 1H, NH), 11.58
formed at 100 ꢁC under vacuum (Scheme 3).
(s, 1H, NH); 13C NMR (62.9 MHz, DMSO-d6) d: 27.49, 31.76, 50.39,
82.52, 97.14, 114.97, 118.79, 123.66, 129.29, 131.61, 135.34, 146.33,
150.33, 151.57, 152.85, 157.33, 162.33. FT-IR (KBr): 3365, 3172,
3051, 1705, 1674, 1591 cmꢀ1; anal. calcd. For C17H14BrN5O4S: C
50.80, H 3.62, Br 7.50, N 17.77, O 13.53, S 6.78. Found C 50.76, H
3.61, Br 7.53, N 17.74, O 13.46, S 6.64.; MS (EI) (m/z): 462.99 (M+).
5-(2-Hydroxy-5-nitrophenyl)-1,3-dimethyl-8-thioxo-5,8,9,10-
tetrahydropyrido[2,3-d:6,5-d0]dipyrimidine-2,4,6(1H,3H,7H)-tri-
one (4p). White solid; mp: >300 ꢁC.$1H NMR (250 MHz, DMSO-d6)
d: 3.09 (s, 3H, CH3), 3.22 (s, 3H, CH3), 4.13 (s, 1H, CH), 6.73 (d, 1H, J
¼ 7.4 Hz, ArH), 7.11 (d, 1H, J ¼ 7.7 Hz, ArH), 7.19 (d, 1H, J ¼ 7.8 Hz,
ArH), 9.12 (s, 1H, OH); 9.18 (s, 1H, NH), 10.28 (s, 1H, NH), 11.12 (s,
1H, NH); 13C NMR (62.9 MHz, DMSO-d6) d: 27.64, 33.24, 50.53,
82.52, 97.68, 116.51, 121.32, 123.53, 126.94, 128.65, 135.82, 146.86,
150.74, 151.57, 152.43, 157.24, 162.45. FT-IR (KBr): 3456, 3444,
3107, 2951, 1693, 1668, 1597 cmꢀ1; anal. calcd. For C17H14N6O6S: C
47.44, H 3.28, N 19.53, O 22.30, S 7.45. Found C 47.42, H 3.31, N
19.51, O 22.32, S 7.42.; MS (EI) (m/z): 430.07 (M+).
2.4 Preparation of HMTA-BAIL@MIL-101(Cr)
Scheme 4 displays the preparing procedure of the new and vigorous
¨
Bronsted acidic ionic liquid functionalized MIL-101(Cr) MOF. In
brief, dehydration of MIL-101(Cr) (1.0 g) was done under vacuum at
110 ꢁC for 12 h. A suspension of MIL-101(Cr) in anhydrous toluene
(30 mL) was prepared in a round bottom ask, and hexamethy-
lenetetramine (5 mmol) was added aerward. The reaction combi-
nations were reuxed through stirring for 12 h at 80 ꢁC. To separate
the solvent, it was ltrated upon the termination of the reaction, and
then washed by toluene to remove the extra hexamethylenetetra-
mine. Thereaer, the product was dissipated in 30 mL of anhydrous
toluene. Throughout stirring vigorously, an equal molar ratio 1,4-
butane sultone (5 mmol) was incorporated into the solution, fol-
lowed by reuxing the admixture for 12 h at 80 ꢁC. Finally, the solid
was harvested via ltration and dehydrated under vacuum for 3 h at
110 ꢁC. A suspension of the solid was then made in 20 mL of ethanol
simultaneously an equivalent amount of concentrated H2SO4 (98%)
was added dropwise for 24 h at 50 ꢁC. In the end, the catalyst was
isolated by ltration and desiccated under vacuum for 12 h at 50 ꢁC.
3. Results and discussion
The prepared catalyst was analyzed through some characterization
methods such as EDS, FE-SEM, XRD, FT-IR, BET, and TGA.
2.5 General procedure for the synthesis of pyrido[2,3-d:5,6-
d0]dipyrimidine(4a–4p)
A combination of 6-aminouracil/6-amino-1,3-dimethyl uracil (1
mmol), barbituric acid derivatives (1 mmol), aldehyde (1 mmol),
and HMTA-BAIL@MIL-101(Cr) (0.008 g) was heated at 80 ꢁC for
10–15 min. Followed by completing the reaction based on the
TLC (hexane/ethyl acetate, 4 : 1) (thin layer chromatography),
cooling the reaction combination was performed to room
temperature and the achieved solid was dissolved within
dichloromethane. Then, the catalyst was not soluble in CH2Cl2
and was separated through simple ltration. Evaporating the
solvent was performed and recrystallizing the residue from
ethanol was performed to obtain the pure product.
Spectral data of the new products are given below.
5-(5-Bromo-2-hydroxyphenyl)-7,9-dimethyl-8-thioxo-5,8,9,10-
tetrahydropyrido[2,3-d:6,5-d0]dipyrimidine-2,4,6(1H,3H,7H)-tri-
one (4o). White solid; mp: >300 ꢁC. 1H NMR (250 MHz, DMSO-d6) Fig. 3 XRD patterns of MIL-101(Cr) and HMTA-BAIL@MIL-101(Cr).
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Fig. 4 The FT-IR spectra of MIL-101(Cr) and HMTA-BAIL@MIL-101(Cr).
main diffraction peaks regarding the pure MIL-101(Cr) and
simulated pattern (Fig. 3). Such ndings showed that the MIL-
101(Cr) materials' crystalline structures were unaffected and
remained intact over the BAIL functionalization procedure. The
reection planes equivalent to the Miller indices (201), (311),
(440), (402), (333), (531), (606), (753), (666), and (600) are
indexed for the MIL-101 consistent with the reported values.37,39
It is found that there is a good consistency between the repre-
sentative peaks of the synthesized HMTA-BAIL@MIL-101(Cr)
materials and MIL-101(Cr). There is also an agreement
between the observations and the one reported in the studies.40
3.1 EDS analysis
Fig. 1 illustrates the elemental analysis of the MIL-101(Cr) and
HMTA-BAIL@MIL-101(Cr) obtained from EDS. The results
conrmed the existence of C, O, Cr, F and N as the only elementary
components of MIL-101(Cr) MOF (Fig. 1a). In EDS spectrum of
HMTA-BAIL@MIL-101(Cr), C, O, Cr, F, N and S elements were
observed (Fig. 1b). The presence of the S element in the Fig. 1b
conrmed the successful functionalization of the ionic liquid.
3.2 FE-SEM analysis
To distinguish the particle size and surface morphology of the
synthesized HMTA-BAIL@MIL-101(Cr) SEM was studied. Fig. 2a
and b show an FE-SEM micrograph of the as-synthesized
MIL-101(Cr) and HMTA-BAIL@MIL-101(Cr) representing a char-
acteristic octahedral shape form.
3.4 Infrared spectroscopy
The FT-IR spectra of the BAIL-functionalized MIL-101(Cr) and
bare MIL-101(Cr) nanostructure are represented in Fig. 4. FT-IR
3.3 Powder X-ray diffraction
The PXRD (powder X-ray diffraction) patterns of the BAIL
functionalized MIL-101(Cr) substances represent nearly all the
Fig. 5 The N2 adsorption–desorption isotherms at 77 K of MIL-101(Cr) Fig. 6 TGA curves of the MIL-101(Cr) and HMTA-BAIL@MIL-101(Cr)
and HMTA-BAIL@MIL-101(Cr).
under Ar atmosphere.
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Scheme 5 The model reaction for the synthesis pyrido[2,3-d:5,6-d0]dipyrimidine 4j.
1.42 cm3 gꢀ1 and 2473 m2 gꢀ1, these values are close to the
reported values (pore volume and BET surface area were 1.19
cm3 gꢀ1 and 2338 m2 gꢀ1, respectively) for MIL-101(Cr).42 The
HMTA-BAIL@MIL-101(Cr) exhibited corresponding values
(pore volume and BET surface area) of 1.06 cm3 gꢀ1 and 1921 m2
gꢀ1. The reduced porosity for HMTA-BAIL@MIL-101(Cr) in
comparison with MIL-101(Cr) may be related to the pore
blockage of MIL-101(Cr) via the BAIL groups.
3.6 TGA analysis
Fig. 7 The optimization of the solvent in the model study.
The thermogravimetric analysis curves for MIL-101(Cr) and
HMTA-BAIL@MIL-101(Cr) show two-step weight losses at 30 to
100 ꢁC and >300 ꢁC to 400 ꢁC, respectively (Fig. 6). The rst loss
can be related to the solvent loss in the framework. The
subsequent loss can be attributed to decomposing the immo-
bilized ionic liquid moieties into the MIL-101(Cr) nanocages,
causing the collapse of frameworks.
In the next step of our research, we decided to evaluate the
catalytic activity of the prepared novel catalyst for synthesizing pyrido
[2,3-d:5,6-d0]dipyrimidines. For achieving this purpose, the reaction
conditions (solvent, catalyst, and amount of catalyst) were rst opti-
mized, while selecting the reaction between 6-aminouracil, barbituric
acid, and 4-chlorobenzaldehyde as a model reaction (Scheme 5).
To discover the effects of solvent in preparing pyrido[2,3-
d:5,6-d0]dipyrimidine 4j, we conducted the model reaction using
HMTA-BAIL@MIL-101(Cr) by different solvents as well as
solvent-free conditions at various temperatures. As illustrated in
Fig. 7, it concluded that solvent-free conditions with high
temperatures have great effects on the reaction accelerating. The
best ndings (98% yield within 10 min) were attained without
using any toxic solvent at 80 ꢁC for this multicomponent reaction.
spectrum of MIL-101(Cr) shows the absorption bands at 1381
and 1663 cmꢀ1 related to symmetric and asymmetric stretching
vibrations of COO–.41 Moreover, Cr–O bonds are appeared around
550 and 663 cmꢀ1. In addition, the contribution of HMTA-BAIL in
the HMTA-BAIL@MIL-101(Cr) composite was veried with the
existence of the absorption bands corresponding to hexamethy-
lenetetramine ring and sulfonyl groups. As indicated in FT-IR
spectrum of HMTA-BAIL@MIL-101(Cr), the absorption bands at
1155 and 1185 cmꢀ1 are corresponding to stretching vibrations of
S–O and C–N bonds, respectively. Moreover, the stretching vibra-
tions of O]S]O is appeared at 1452 cmꢀ1 conrming that the
incorporation of HMTA-BAIL into the MIL-101(Cr).
3.5 BET analysis
The N2 adsorption–desorption isotherm of MIL-101(Cr) and
HMTA-BAIL@MIL-101(Cr) was shown in Fig. 5. For the bare
MIL-101(Cr) an overall pore volume and BET surface area were
Fig. 8 The effect of various catalysts on model reaction.
Fig. 9 The effect of catalyst amount on the model reaction.
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Table 1 Synthesis of pyrido[2,3-d:5,6-d0]dipyrimidines using HMTA-BAIL@MIL-101(Cr) catalyst
Entry
R1
R2
R3
X
Product
Time(min)
Yielda (%)
Mp ꢁ
C
Lit. Mp ꢁ
C
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
CH3
H
H
4-Cl
4-NO2
4-CH3
H
O
O
O
O
O
O
O
O
O
O
S
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
20
14
15
16
12
20
10
18
17
10
14
16
13
15
17
19
91
95
97
88
92
87
90
89
93
98
93
96
91
93
95
89
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
>300 ꢁ
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
>300 ꢁC28
4-Cl
4-NO2
4-CH3
H
4-Cl
H
4-Cl
H
4-Cl
5-Br, 2-OH
2-OH, 5-NO2
9
10
11
12
13
14
15
16
S
S
S
S
b
CH3
H
—
b
S
—
a
Isolated yield. b New products.
Table 2 Comparison on the efficiency of HMTA-BAIL@MIL-101(Cr) for the synthesis of pyrido[2,3-d:5,6-d0]dipyrimidinesa
Entry
Catalyst
Conditions
Time/yield (%)
References
1
2
3
4
5
Piperidine
SBA-Pr-SO3H
P2O5
MWCNTs@L-His/Cu(II)
HMTA-BAIL@MIL-101(Cr)
H2O/60 ꢁC/U. S.
Solvent-free/140 ꢁ
EtOH/reux
1 h/81–91
1.5 h/65–90
2 h/80–88
1 h/78–92
10 min/87–98
28
29
30
31
C
EtOH/reux
Solvent-free, 80 ꢁC
This work
a
Based on the three-component reaction of 6-aminouracil, barbituric acid, 4-chlorobenzaldehyde.
A temperature increase in this reaction represented no signicant BAIL@MIL-101(Cr) was made to be a highly efficient nano-
impacts on time and product yield.
structure for the synthesis of pyrido[2,3-d:5,6-d0]dipyrimidines.
The catalytic performance and efficiency of HMTA-
Furthermore, to assess the effects of diverse catalysts, the
catalytic performance of seven types of catalysts like KOH, CaO, BAIL@MIL-101(Cr) were compared with several previous
MgO, ZnO, HMTA, MIL-101(Cr), HMTA-BAIL@CaO and HMTA- approaches to synthesize the pyrido[2,3-d:5,6-d0]dipyrimidines,
BAIL@MIL-101(Cr) was examined on the model reaction under presented in Table 2. As indicated, HMTA-BAIL@MIL-101(Cr)
solvent-free conditions (Fig. 8). The results of this study nanocomposite is greater based on the reported catalysts
exhibited that HMTA-BAIL@MIL-101(Cr) was afforded pyrido regarding reaction time, yield, and conditions. Our method has
[2,3-d:5,6-d0]dipyrimidine 4j in superior yield within short the advantages of short reaction time, mild conditions, and
reaction time compared to the other catalysts.
good to superior yields (Table 2).
To continue our study, we ran the reaction of 6-aminouracil,
barbituric acid, and 4-chlorobenzaldehyde using different
amounts of HMTA-BAIL@MIL-101(Cr) nanocatalyst under
solvent-free conditions. According to Fig. 9, the optimum
concentration of HMTA-BAIL@MIL-101(Cr) was attained at
0.008 g. The time and yield of the reaction are not altered by
a value of higher than 0.008 g.
3.7 Recycling and reusing of the catalyst
The recovery and recyclability of the HMTA-BAIL@MIL-101(Cr)
were also controlled by taking the condensation reaction for the
Aer examining different conditions on the reaction prog-
ress, we found the general applicability of the HMTA-BAIL@MIL-
101(Cr) catalyst with aryl aldehydes comprising electron with-
drawing or donating substituents, barbituric acid/thiobarbituric
acid/1,3-dimethylbarbituric acid and 6-aminouracil or 6-amino-
1,3-dimethyl uracil. According to Table 1, all of the derivatives
with electron withdrawing or donating groups were afforded the
products in good to the superior yields. The total HMTA-
Fig. 10 Reusability of the HMTA-BAIL@MIL-101(Cr) catalyst.
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Fig. 11 FT-IR spectrum (a) and XRD pattern (b) of the recovered HMTA-BAIL@MIL-101(Cr) after 6 runs.
model reaction. Followed by completing the reaction (based on BAIL@MIL-101(Cr) nanocomposite (1.26 mmol gꢀ1). These
TLC), dissolving the residues was performed in CH2Cl2, while facts prove that the efficiency, appearance and structure of
ltering the catalyst. According to Fig. 10, this catalyst could be HMTA-BAIL@MIL-101(Cr) catalyst remained intact in recycles
reused over six runs with no considerable loss of its catalytic and there was no considerable deformation or leaching aer 6
activity.
The chemical structure of recovered HMTA-BAIL@MIL-
runs.
A plausible mechanism for the synthesis of pyrido[2,3-d:5,6-
101(Cr) was veried using XRD pattern and FT-IR spectrum. d0]dipyrimidines utilizing HMTA-BAIL@MIL-101(Cr) as the
There is no signicant difference between the XRD and FT-IR of catalyst is represented in Scheme 6. The ndings were experi-
the fresh and recovered nanocomposite (Fig. 11(a and b)). Also, mentally studied based on the literature.29,30 It is likely that
the acid sites (1.23 mmol gꢀ1) of the catalyst aer 6 times reused HMTA-BAIL@MIL-101(Cr) acts as a Brønsted acid and incre-
had no dramatic changes based on the acid–base titration ments the carbonyl group's electrophilicity on the aldehyde by
measurement, in comparison with acid sites of the fresh HMTA- release proton. Firstly, barbituric acid 3 has a reaction with
Scheme 6 Proposed mechanism for the synthesis of pyrido[2,3-d:5,6-d0]dipyrimidines.
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aromatic aldehydes 2 to create standard Knoevenagel conden- 12 F. Wei, Q. Ren and Z. Liang, ChemistrySelect, 2019, 4, 5755–
sation product I. The succeeding Michael-type adding of the 6- 5762.
aminouracil 1 with Knoevenagel product I aer cyclization 13 M. Nasrabadi, M. A. Ghasemzadeh and M. R. Zand
provides the intermediate II giving desired product 4 on
dehydration.
Monfared, New J. Chem., 2019, 43, 16033–16040.
14 W. Chaikittisilp, K. Ariga and Y. Yamauchi, J. Mater. Chem.,
2013, 1, 14–19.
15 N. L. Torad, M. Hu, Sh. Ishihara, H. Sukegawa, A. A. Belik,
M. Imura, K. Ariga, Y. Sakka and Y. Yamauchi, Small,
2014, 10, 2096–2107.
4. Conclusions
¨
In conclusion, we have reported a new Bronsted acidic ionic
16 S. A. Hassan, A. M. Al-Sabagh, N. H. Shalaby, S. A. Hana and
H. A. Hassan, Egypt. J. Pet., 2013, 22, 179–188.
17 H. M. Hassan, M. A. Betiha, S. K. Mohamed, E. El-Sharkawy
and E. A. Ahmed, Appl. Surf. Sci., 2017, 412, 394–404.
18 Y. C. Sharma, B. Singh and J. Korstad, Biofuels, Bioprod.
Bioren., 2011, 5, 69–92.
liquid immobilized on MIL-101(Cr) MOF as an efficient nano-
porous and heterogeneous catalyst for the synthesis of pyrido
[2,3-d:5,6-d0]dipyrimidine derivatives under solvent-free condi-
tions. The new catalyst was characterized by EDS, SEM, XRD,
FT-IR, BET and TGA. The main benets of this work are the
short reaction time, facile workup, reusability of the catalyst,
and high yield of products. The highly reactive and heteroge-
neity nature of this catalyst offers a wide application in
heterocyclic synthesis and medicinal chemistry applications.
19 H. C. Zhou, J. R. Long and O. M. Yaghi, Chem. Rev., 2012,
112, 673–674.
20 H. M. Hassan, M. A. Betiha, S. K. Abd El Rahman, M. Mostafa
and M. Gallab, J. Porous Mater., 2016, 23, 1339–1351.
21 W. R. Mohamed, S. S. Metwally, H. A. Ibrahim, E. A. El-
Sherief, H. S. Mekhamer, I. M. Moustafa and
E. M. Mabrouk, J. Mol. Liq., 2017, 236, 9–17.
22 H. M. Savanur, R. G. Kalkhambkar, G. Aridoss and
K. K. Laali, Tetrahedron Lett., 2016, 57, 3029–3035.
23 R. Kore and R. Srivastava, J. Mol. Catal. A: Chem., 2011, 345,
117–126.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The author gratefully acknowledges the nancial support of this
work by the Research Affairs Office of the Islamic Azad
University, Qom Branch, Qom, I. R. Iran [grant number 2019-
2898] and Department of Chemistry, North Tehran Branch,
Islamic Azad University, Tehran, Iran.
24 R. L. Vekariya, J. Mol. Liq., 2017, 227, 44–60.
¨
25 A. Domling and I. Ugi, Chem. Eng. [Int. Ed.], 2000, 39, 3168–
3210.
26 D. A. Ibrahim and A. M. El-Metwally, Eur. J. Med. Chem.,
2010, 45, 1158–1166.
27 M. J. Aliaga, D. J. Ramon and M. Yus, Org. Biomol. Chem.,
2010, 8, 43–46.
28 M. H. Mosslemin and M. R. Nateghi, Ultrason. Sonochem.,
2010, 17, 162–167.
29 G. M. Ziarani, P. Ghlamzadeh, A. Badiei, S. H. Asadi and
A. A. Soorki, J. Chil. Chem. Soc., 2015, 60, 2975–2978.
References
1 Z. Hong-Cai, J. R. Long and O. M. Yaghi, Chem. Rev., 2012,
112, 673–674.
2 M. E. Davis, Nature, 2002, 417, 813–821.
3 K. Ariga, A. Vinu, Y. Yamauchi, Q. Ji and J. P. Hill, Bull. Chem. 30 K. T. Patil, P. P. Warekar, P. T. Patil, S. S. Undare,
Soc. Jpn., 2012, 85, 1–11.
4 Y. Yamauchi, N. Suzuki, L. Radhakrishnan and L. Wang,
Chem. Rec., 2009, 9, 321–339.
5 M. A. Ghasemzadeh, B. Mirhosseini-Eshkevari, M. Tavakoli
and F. Zamani, Green Chem., 2020, 22, 7265–7300.
G. B. Kolekar and P. V. Anbhule, J. Heterocycl. Chem., 2018,
55, 154–160.
31 H. Saeidiroshan and L. Moradi, J. Organomet. Chem., 2019,
893, 1–10.
32 I. Yavari and M. Esnaashari, Synthesis, 2005, 7, 1049–1051.
6 H. M. A. Hassan, M. A. Betiha, S. K. Mohamed, E. A. El- 33 M. A. Ghasemzadeh, M. H. Abdollahi-Basr and
Sharkawy and E. A. Ahmed, J. Mol. Liq., 2017, 236, 385–394.
7 M. Samy El-Shall, V. Abdelsayed, A. El R. S. Khder,
B. Mirhosseini-Eshkevari, Green Chem. Lett. Rev., 2018, 11,
47–53.
H. M. A. Hassan, H. M. El-Kaderi and E. T. Reich, J. Mater. 34 M. A. Ghasemzadeh, B. Mirhosseini-Eshkevari and
Chem., 2009, 19, 7625–7631.
8 H. M. A. Hassan, M. A. Betiha, S. K. Mohamed, E. A. El-
M. H. Abdollahi-Basr, Appl. Organomet. Chem., 2018, 33,
4679–4687.
Sharkawy and E. A. Ahmed, Appl. Surf. Sci., 2017, 412, 394– 35 B. Mirhosseini-Eshkevari, M. A. Ghasemzadeh and J. Safaei-
404.
Ghomi, Res. Chem. Intermed., 2015, 41, 7703–7715.
9 V. I. Isaeva and L. M. Kustov, Pet. Chem., 2010, 50, 167–180. 36 M. A. Ghasemzadeh, M. Azimi-Nasrabad, S. Farhadi and
10 P. D. Du, H. T. M. Thanh, T. C. To, H. S. Thang, M. X. Tinh,
T. N. Tuyen, T. T. Hoa and D. Q. Khieu, J. Nanomater., 2019,
2019, 1–15.
B. Mirhosseini-Eshkevari, J. Organomet. Chem., 2019, 900,
120935–120942.
´
37 C. Ferey, C. Mellot-Draznieks, F. Serre, J. Millange,
11 T. B. Faust and D. M. D'Alessandro, RSC Adv., 2014, 4, 17498–
17512.
S. S. Dutour and I. A Margiolaki, Science, 2005, 309, 2040–
2042.
372 | RSC Adv., 2021, 11, 364–373
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
38 X. Liang and J. Yang, Green Chem., 2010, 12, 201–204.
39 H. Wei, B. Teo, A. Chakraborty and S. Kayal, Appl. Therm.
Eng., 2016, 101, 891–900.
40 T. Hu, Q. Jia, S. He, S. Shan, H. Su, Y. Zhi and L. He, J. Alloys
Compd., 2017, 727, 114–122.
41 C. P. Cabello, G. Berlier, G. Magnacca, P. Rumori and
G. T. Palomino, CrystEngComm, 2015, 17, 430–437.
42 X. Huang, Q. Hu, L. Gao, Q. Hao, P. Wang and D. Qin, RSC
Adv., 2018, 8, 27623–27630.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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