Agar-entrapped sulfonated DABCO: Agelly acidic catalyst for the acceleration of one-pot synthesis of 1,2,4-triazoloquinazolinone and some pyrimidine derivatives

Article abstract of DOI:10.1016/j.molstruc.2020.129336

In this project, a recently synthesized DABCO-based catalyst is entrapped in agar to reduce its moisture sensitivity leading to enhancement of its stability and catalytic activity. After preparation and identification this new reagent is used as an efficient and environmentally safe catalyst for the preparation of 1, 2, 4-triazoloquinazolinone and some pyrimidine derivatives. This method is accompanied with some superiorities such as, simple operation, mild and green conditions, use of low cost and non-hazardous natural material, short reaction times, easy preparation methods and simple work-up procedures. The prepared catalyst can be re-used for several times in all of the studied reactions without any appreciable loss in its activity.

Full text of DOI:10.1016/j.molstruc.2020.129336

Journal Pre-proof
Agar-entrapped sulfonated DABCO: A gelly acidic catalyst for the
acceleration of one-pot synthesis of 1,2,4-triazoloquinazolinone and
some pyrimidine derivatives
Issa Mousazadeh Moghaddampour , Farhad Shirini ,
Mohaddeseh Safarpoor Nikoo Langarudi
PII:
S0022-2860(20)31654-9
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2020.129336
MOLSTR 129336
To appear in:
Journal of Molecular Structure
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Revised date:
Accepted date:
12 July 2020
15 September 2020
24 September 2020
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Issa Mousazadeh Moghaddampour ,
Farhad Shirini ,
Mohaddeseh Safarpoor Nikoo Langarudi , Agar-entrapped sulfonated DABCO: A gelly acidic cat-
alyst for the acceleration of one-pot synthesis of 1,2,4-triazoloquinazolinone and some pyrimidine
derivatives, Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.129336
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Highlights:

Structurally functionalized 1,2,4-triazoloquinazolinone and some pyrimidine derivatives were
synthesized by agar-entrapped sulfonated DABCO as a non-metal catalyst.
The moisture-resistant property of the catalyst were investigated.
A simple purification step was performed to achieve high purity.



The reusability of the catalyst was investigated during three runs for all compounds.

Agar-entrapped sulfonated DABCO: A gelly acidic
catalyst for the acceleration of one-pot synthesis of 1,2,4-
triazoloquinazolinone and some pyrimidine derivatives
Issa Mousazadeh Moghaddampour a, Farhad Shirini, a,* Mohaddeseh Safarpoor
Nikoo Langarudi b
a Department of Chemistry, College of Science, University of Guilan, University Campus 2, Rasht, Iran.
b Department of Chemistry, College of Science, University of Guilan, Rasht, 41335-19141, Iran, Tel/Fax:
+981313233262; e-mail: shirini@guilan.ac.ir (and also fshirini@gmail.com).
Abstract: In this project, a recently synthesized DABCO-based catalyst is entrapped in agar to reduce its moisture
sensitivity leading to enhancement of its stability and catalytic activity. After preparation and identification this new reagent
is used as an efficient and environmentally safe catalyst for the preparation of 1, 2, 4-triazoloquinazolinone and some
pyrimidine derivatives. This method is accompanied with some superiorities such as, simple operation, mild and green
conditions, use of low cost and non-hazardous natural material, short reaction times, easy preparation methods and simple
work-up procedures. The prepared catalyst can be re-used for several times in all of the studied reactions without any
appreciable loss in its activity.
Keyword: DABCO, agar-entrapped catalyst, ionic liquids (ILs), triazole, uracile, quinazolinone, green chemistry,
gel-entrapped acidic catalyst (GEACs)
1. Introduction
Agar is a hydrophilic, colloidal substance consisting of the polysaccharides extracted from Gelidium
cartilogineumn Gaillon, Gracilaria confervoides Greville, and related red algae [1], probably existing in the form of its
calcium salt or a mixture of calcium and magnesium salts. It is a complex mixture of polysaccharides composed of
two major fractions agarose, a neutral polymer, and agaropectin, a charged, sulfated polymer. Agarose, the gelling
fraction, is a neutral linear molecule essentially free of sulfates, consisting of chains of repeating alternate units of β-
1,3-linked D-galactose and α-1,4-linked 3,6-anhydro-L-galactose. Agaropectin, the non-gelling fraction, is a sulfated
polysaccharide (3% to 10% sulfate), composed of agarose and varying percentages of ester sulfate, D-glucuronic acid,
and small amounts of pyruvic acid. Agarose normally represents at least two-thirds of the natural agar (Figure 1).
Because of their special structural characteristics, triazoles are considered as important class of heterocyclic
compounds showing interesting biological, pharmaceutical and therapeutic activities including antifungal [2],
antimicrobial [3-8], anti-cancer [9], anticonvulsant [10], antihypertensive [11], and anti-viral [12]. In this regard many

drugs containing triazole moiety are manufactured, which of them Ribavirin or Copegus (an antiviral), Alprazolam
(an anxiolytic), Letrozole (an anticancer), and Flusilazole (an organosilicon fungicide) [13] are examples (Figure 2a).
Uracil, as one of the four nucleobases in the nucleic acid, is a common and naturally occurring pyrimidine
derivative. In RNA uracil binds to adenine via two hydrogen bonds, and in DNA the uracil nucleobase is replaced by
thymine. This considerable interest is correlated with a huge range of biological activities such as, antitumor [14],
antifolate [15], antihypertensive [16], and cardio tonic (may be prescribed when the heart is not pumping enough
blood to supply other organs) [17]. A number of popular drugs including the uracil moiety are Sofosbuvir (a new
antiviral for COVID-19) [18], Uramustine (a chemotropic drug that damage DNA) [19] and Uridine monophosphate
(a nucleotide that is used as a monomer in RNA) [20] (Figure 2b). Recently the remedial effect in COVID-19 (human
coronavirus) patients was also observed that it has been proven by Ribavirin [21].
In recent years, a gel-entrapped-base catalysts (GEBCs), which in them the advantages of alkali and organic bases
with those of heterogeneous supports are combined with each other is going to become an attractive concept for
organic chemists. In this line, Salunkhe and co-workers reported the preparation of agar-agar entrapped-DABCO and
its applicability in the promotion of the synthesis of 2-amino-4H-chromenes [22]. This strategy causes to reduce the
amounts of the base used in the reactions and ease of the product isolation, along with making a cut in moisture
absorption by the catalyst [23].
Recently we have reported the preparation of [DABCO] (SO3H)2(Cl)2 as an acidic IL and its use in the
acceleration of some of the multi-component reactions [24], although the method is useful but its ability in the
adsorption of moisture causes that its efficiency to be reduced. For this reason we motivated to use the above
mentioned strategy to prepare, a gel entrapped acidic ionic liquid (GEAIL) by the entrapping of this reagent in agar
for the first time. After identification the effect of this method on the moisture adsorption and catalytic ability of this
reagent is studied in the synthesis of some triazole and uracil containing derivatives as an example.
2. Experimental
2.1. Materials and instruments
All solvents and materials, employed in this study, were purchased form Aldrich (Mumbai) and Merck Chemical
Companies (Munich) and utilized without any further purification. Solvents were stored in airtight containers and had
been distilled before being applied. To ensure about the purity of materials, they were checked with thin layer
chromatography (TLC) on silica-gel poly-gram SILG/UV 254 plates and their melting points were compared with
authenticated melting points in Merck and Aldrich indexes .

Melting points were determined by electro-thermal IA9100 melting point apparatus in capillary tubes. The melting
point range was input manually through keyboard and the material changes were visually monitored. FT-IR spectra
1
were recorded on a Perkin-Elmer spectrum BX series with KBr plates for solid samples. H NMR and 13C NMR
spectra were recorded on Bruker AV-400 and -500 using TMS (0.00 ppm) as internal standard and DMSO-d6 as the
solvent.
2.2. Preparation of [DABCO](SO3H)2(Cl)2
The acidic ionic liquid was precisely prepared according to the reported procedure in the article [24].
2.3. Preparation of Agar-entrapped IL
In a 150 mL flask, 5.0 g agar in 50 mL water was heated at boiling point to be completely dissolved (Figure 3-a).
Then a solution of 2.5 g of [DABCO](SO3H)2(Cl)2 (7.2 mmol, Figure 3-b), in warm water (50 mL) (Figure 3-c), was
added into preceding solution and stirred for 10 min. After that, the flask was poured into a petri dish and dried in
vacuum oven for 12 h to obtain agar-entrapped IL as rough brown crystals (Figure 3-d).
2.4. General procedure for the preparation of 1,2,4-triazoloquinazolinones
To a mixture of aromatic aldehyde 1 (1 mmol), 3-amino-1,2,4-triazole 2 (1 mmol), and β- diketone (dimedone 3 ,
methyl acetoacetate 4 or 1,3-cyclohexadione 5) (1mmol), agar-entrapped catalyst (0.03 g for 6, 0.02 g for 7 and 8) was
added in a 25 mL round-bottom flask. Then the mixture was stirred magnetically in the absence of solvent in an oil
bath (100 oC) for the appropriate time. The reaction process was carefully monitored by TLC (n-hexane: ethyl acetate;
8:3). After completion of the reaction, 5 mL water was poured into the reaction medium and filtered off to separate the
catalyst. Finally, the obtained precipitate was recrystallized from ethanol to afford the required product (6a-j, 7a-f, and
8a-g). The spectral data of new compounds are as follow:
Diethyl-7,7'-((butane-1,4-diyl-bis(oxy))bis(4,1-phenylene))bis(5-methyl-4,7-dihydro-[1,2,4]triazolo[1,5-
a]pyrimidine-6-carboxylate) (7e)
IR (KBr, ν/cm-1) ; 3422, 3135, 2934, 2871, 1692, 1642, 1581, 1510, 1473, 1427, 1383, 1248; 1H NMR (500 MHz,
DMSO-d6), δ = 1.04 (t, J = 7.1 Hz, 3H, CH3), 1.80 (br, 2H, CH2), 2.41 (s, 3H, CH3), 3.98 – 3.91 (m, 4H, 2CH2), 6.21
(s, 1H, CH), 6.83 (d, J = 8.6 Hz, 2H, 2CH), 7.11 (d, J = 8.6 Hz, 2H, 2CH), 7.63 (s, 1H, CH), 10.76 (s, 1H, NH); 13C
NMR (125 MHz, DMSO-d6), δ =14.3, 18.8, 25.7, 59.3, 59.7, 67.5, 114.6, 115.3, 128.6, 132.2, 146.8, 147.3, 150.4,
158.6, 165.6.
Diethyl-7,7'-((hexane-1,6-diyl-bis(oxy))bis(4,1-phenylene))bis(5-methyl-4,7-dihydro-[1,2,4]triazolo[1,5-
a]pyrimidine-6-carboxylate) (7f)

IR (KBr, ν/cm-1) ; 3381, 3097, 2987, 2867, 1695, 1653, 1591, 1510, 1489, 1415, 1370, 1266.; 1H NMR (500 MHz,
DMSO-d6), δ = 1.03 (t, J = 7.5 Hz, 3H, CH3), 1.43 (br, 2H, CH2), 1.67 (br, 2H, CH2), 2.40 (s, 3H, CH3), 3.93 – 4.05
(m, 4H, 2CH2) 6.20 (s, 1H, CH), 6.82 (d, J = 8.0 Hz, 2H, 2CH), 7.10 (d, J = 7.8 Hz, 2H, 2CH), 7.63 (s, 1H, CH),
10.76 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ =14.3, 18.8, 25.7, 29.0, 59.3, 59.7, 67.7, 114.5, 115.3, 128.6,
132.2, 146.8, 147.3, 150.4, 158.7, 165.6.
9-(2-Nitrophenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (8d)
IR (KBr, υ, cm−1) 3444, 3213, 2910, 1643, 1569, 1357; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 1.88–1.99 (2H,
m, CH2), 2.17–2.27 (2H, m, CH2), 2.64–2.67 (2H, m, CH2), 6.98 (1H, s, CH), 7.30 (1H, d, J = 1.2 Hz, CH-Ph), 7.49
(1H, dt, J1 = 7.6 Hz, J2 = 0.8 Hz, CH-Ph), 7.61 (1H, dt, J1 = 7.6 Hz, J2 = 1.2 Hz, CH-Ph), 7.73 (1H, s, CH-triazole),
7.86 (1H, dd, J1 = 8 Hz, J2 = 1.2 Hz, CH-Ph), 11.32 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 21.1, 26.8,
36.4, 53.4, 106.19, 124.4, 129.4, 129.8, 133.8, 135.3, 147.2, 149.0, 150.8, 153.7, 193.9.
9,9'-((Butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis(5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-
one) (8f)
1
IR (KBr, ν/cm-1) ; 3422, 3230, 2926, 2833, 1644, 1584, 1511, 1476, 1416, 1362, 1250; H NMR (500 MHz,
DMSO-d6), δ = 1.79 (s, 2H, CH2), 2.05 – 1.83 (m, 2H, CH2), 2.30 – 2.20 (m, 2H, CH2), 2.70 – 2.58 (m, 2H, CH2), 3.94
(t, J = 5.2 Hz, 2H, CH2), 6.17 (s, 1H, CH), 6.81 (d, J = 8.4 Hz, 2H, 2CH), 7.10 (d, J = 8.3 Hz, 2H, 2CH), 7.67 (s, 1H,
CH), 11.11 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6), δ =21.1, 25.8, 26.8, 36.8, 57.5, 67.5, 114.5, 115.3, 128.6,
134.1, 147.1, 150.3, 152.7, 158.5, 193.7.
9,9'-((Hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis(5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-
one) (8g)
1
IR (KBr, ν/cm-1); 3423, 3229, 2931, 2868, 1648, 1581, 1511, 1474, 1414, 1360, 1246; H NMR (500 MHz,
DMSO-d6), δ = 1.41 (br, 2H, CH2), 1.67 (br, 2H, CH2), 1.98 – 1.86 (m, 2H, CH2), 2.29 – 2.20 (m, 2H, CH2), 2.69 –
2.58 (m, 2H, CH2), 3.89 (t, J = 6.7 Hz, 2H, CH2), 6.16 (s, 1H, CH), 6.80 (d, J = 8.2 Hz, 2H, 2CH), 7.09 (d, J = 8.1 Hz,
2H, 2CH), 7.66 (s, 1H, CH), 11.10 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6), δ =21.1, 25.7, 26.8, 29.0, 36.8, 57.5,
67.7, 114.5, 115.3, 128.5, 134.0, 147.1, 150.3, 152.7, 158.6, 193.7.
2.5. General procedure for the preparation of 1, 2, 4-triazolo[4,3-a]pyrimidines
To a mixture of aromatic aldehyde 1 (1 mmol), 3-amino-1,2,4-triazole 2 (1 mmol), and malononitrile 9 (1 mmol),
in a 25 mL round-bottom flask, agar-entrapped catalyst (0.02 g) was added. Then the mixture was stirred magnetically
o
under solvent-free conditions in an oil bath (100 C) for the appropriate time. The progress of the reaction was

carefully monitored by TLC (n-hexane: ethyl acetate; 4:1). After completion of the reaction, 5 mL water was poured
into the reaction medium and then filtered off to separate the catalyst. Finally, the obtained precipitate was
recrystallized from ethanol to afford the required product (10a-f).
5-amino-7-(naphthalen-2-yl)-7,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile (10f)
1
M.p. 281-282 oC; IR (KBr, υ, cm−1) 3360, 3256, 3183, 2189, 1657, 1629, 1526; H NMR (400 MHz, DMSO-d6):
5.56 (d, J= 2 Hz, 1H, CH), 7.31 (d, J= 2.8 Hz, 2H, NH2), 7.50-7.55 (m, 3H, CH-Ph), 7.77 (d, J= 10.8 Hz, 2H, CH-
Ph), 7.90-7.97 (m, 3H, N=CH-N and CH-Ph), 8.88 (d, J= 2.4 Hz, 1H, NH); 13C NMR (100 MHz, DMSO-d6): 54.3,
119.0, 124.4, 124.6, 126.2, 126.5, 127.5, 127.6, 127.9, 128.7, 132.5, 132.6, 140.3, 147.0, 151.9, 153.9.
2.6. General procedure for the preparation of pyrido[4,5-b]quinolone
To a mixture of aromatic aldehyde 1 (1 mmol), 6-amino-1,3-dimethyluracil 11 (1 mmol), dimedone 3 (1 mmol) in
a 25 mL round-bottom flask, 0.02 g agar-entrapped catalyst was added and 5 mL of ethanol/water (2:1) was poured on
it. The mixture was stirred magnetically to dissolve all components at reflux temperature. The reaction process was
carefully checked by TLC (n-hexane: ethyl acetate; 4: 1). After completion, the mixture was filtered off to separate the
catalyst, which is solvated in the solvent. Recrystallization of the product from absolute ethanol led to the pure
product (12a-h).
2.7. General procedure for the preparation of pyrido[2,3-d]pyrimidines
Into a 25 mL round-bottom flask containing aldehyde 1 (1 mmol), 6-amino-1,3-dimethyluracil 11 (1 mmol), and
malononitrile 9 (1 mmol), 5 mL ethanol and 0.03 g agar-entrapped catalyst were added. The mixture was stirred
o
magnetically at 70 C to dissolve all components. The precipitate of the product is appeared in the reaction medium
after a short time. The reaction progress was traced to completion by TLC (n-hexane: ethyl acetate; 1: 4). After
completion of the reaction, the mixture was filtered off and the obtained residue was washed with water to remove the
catalyst. Finally, the crude product was recrystallized from ethanol if necessary (13a-i).
3. Results and discussion
3.1. Characterization of the catalyst
3.1.1. Fourier-Transform Infrared Spectroscopy (FT-IR)
When a molecule is entrapped in a linear polysaccharide through hydrogen bonding, it can be expected that the
number and intensity of the peaks of its functional groups be decreases due to a lock in the structure (Figure 4). This
phenomena can be seen by the comparison of the FT-IR spectra of free IL and agar-entrapped IL (Figure 5).

3.1.2. Scanning electron microscopy (SEM)
As shown in Figure 6, the morphology of DABCO changed going through the entrapping process. However,
DABCO has porous and irregular shape with tiny holes, it change to an aggregated particles due to hydrogen bonding
between hydroxyl groups of IL and agar.
3.1.3. Thermal gravimetric analysis (TGA)
TGA diagrams of agar, IL, and agar-entrapped IL are represented at Figure 7, As shown, the major weight loss
from agar-entrapped IL are happened between 369-681 oC (44.3 %) which is related to decomposition of the catalyst.
Before that, the weight loss (28.89%) between 219 and 312 oC is attributed to the thermal decomposition of IL which
is entrapped in agar. The weight loss from the catalyst between 62-157 oC is owing to the decomposition of agar and
the removal of physically adsorbed water and organic solvents, which were used in creating the catalyst.
3.2. Moisture-resistant property
In spite of great features of ionic liquids such as non-flammability, no miscibility with non-polar solvents, and
negligible vapor pressure, these compounds are very sensitive on exposure to air and moisture. Moisture adsorption
can be impacted on the properties of ILs; for example, can lead to a cut in the thermal stability or catalytic activity.
For this reason, finding a protocol which increases the moisture resistance can be thoroughly vital.
In order to show the effect of agar-trapping on the moisture adsorption of the selected IL, we carried out loss on
drying test for agar, IL, and agar-entrapped IL using Karl-Fischer method in 4 steps during 36 hours at a standard
temperature (23 oC) and 63 % relative humidity in the laboratory.
The obtained results show an acceptable decrease in the amount of the moisture which can be observed by IL after
its entrapping in agar (Figure 8). As shown, the moisture adsorption decreased when the IL trapped in agar. It can be
related to an increase in the H-bonding of catalyst with agar, as shown in Figure 4, which cause to a cut in the
positions which can H-bond with water [25].
3.3. Catalytic activity
After ensuring about the preparation of the catalyst, the catalytic activity of the entrapped IL was investigated in
the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[4,5-b]pyrimidine and 1,2,4-
triazoloquinazolinone derivatives.
At first, to gain the best conditions for the reactions, the synthesis of 4-cholorobenzaldehyde derivatives of these
types of compounds (6b, 8b, 10b, 12b, 13b) was investigated as models for all reactions. In the case of compounds 7a-

f the optimization studies were done on benzaldehyde as a selected model. The results are collected in Table 1. As
shown, different amounts of catalyst and various conditions were used to optimize the reaction conditions in accuracy.
Which is distinguished in the table, agar-entrapped IL is more effective when thermal conditions and protic solvents
were used (7a, 8b, 12b, and 13b). However, this catalyst was able to accelerate the synthesis of 6b and 10b in the
absence of solvent. On the basis of the obtained results the best conditions are determined as shown in Scheme 1.
After optimization of the reaction conditions, we have developed our studies by utilization of miscellaneous
aldehydes with withdrawal and/or donor functional groups. The obtained outcomes were collected in Table 2. These
results show that under the selected conditions the requested products can be obtained in high yields during accepteble
reaction times with no considerable effect of the substituents on the aromatic ring. Because that, in spite of the
aromatic aldehydes, a mixture of unidentified products were formed when aliphatic aldehydes were employed, the
related results were not included in Table 2. In this study some new triazole derivatives are prepared from bis-
aldehydes which their results are highlited in Table 2.
The mechanism starts from activation of aldehyde 1 via catalyst through H-bonding (intermadiate a). After that,
the route divides to two pathways. In route 1, activated 1,3-diketone (enol b) makes for intermadiate a comes to c
after loss water. If 3-amino-1,2,4-triazole 2 reacts with c through N2 or N3H2, the obtained products can be different. If
N2attacks to c, the products 6a-j, 7a-f, and 8a-g produce after intra-molecular cyclization (intermediate d) and
tautomerization. If intermediate c is attacked with N3H2, intermediate e produces which led to product A. But if it
happened, aliphatic –CH in ring, assigned with red circle, should be split as a doublet with J=2 Hz. This peak
1
appeared as a singlet in the H NMR spectra of 6h, 7e, 7f, 8f, and 8g which approves 3-amino-1,2,4-triazole 2
participates in reaction through N2. On the other hand, owing to the replacement of 3-amino-1,2,4-triazole 2 with 6-
amino-1,3-dimethyluracil 11, the products 12a-h were produced path through intermediate f.
In route 2, malononitrle 9 gets activated by catalyst to attack intermediate a and produce h as a key intermediate.
Then whether 3-amino-1,2,4-triazole 2 or 6-amino-1,3-dimethyluracil 11, products 10a-f or 13a-i can be produced,
going through intermediates i and k, respectively. But, by contrast, to produce product 10a-f, N3H2 from 3-amino-
1
1,2,4-triazole 2 should attack h, if not, product B prepares. The doublet peak about 5.5 ppm with J=2Hz in the H
NMR of 10f confirmed that the aliphatic –CH and –NH are in the neighborhood (Scheme 2)
A brilliant feature of a catalyst which changes it as a convenient one is its recyclability. For investigation of this
feature of our new catalyst, the synthesis of 4-chlorobenzaldehyde derivative in each reaction (6a, 8b, 10b, 12b, and
13b except 7a-f which benzaldehyde was used for the synthesis of 7a) is selected as model. After completion of the
o
reaction and separation of the product the solvent is removed under vacuum at 50 C. The obtained precipitate was

eluted by diethyl ether and used for another reaction. This study showed that the catalyst can be reused at least for 3
consecutive runs without considerable decrease in its activity (Figure 9).
In order to show the catalytic ability of the prepared reagent, the efficiency of agar-entrapped IL with some of the
other catalysts in the synthesis of 5-amino-7-(4-chlorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine and 7-
amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-
dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile,
is
compered in Table 3. This comparison implies that the selected reactions are carried out better using this new catalyst.
4. Conclusions
We have used agar-entrapped [DABCO](SO3H)2(Cl)2 as a novel, highly efficient and green catalyst for the multi-
component synthesis of 1,2,4-triazolo quinazolinone, 1,2,4-triazolo [4,3-a] pyrimidine, pyrido[4,5-b]quinolone and
pyrido [2,3-d]pyrimidine derivatives. This new catalyst has the least absorption of humidity leading to more stability
of the selected acidic ionic liquid. High yields, short reaction times, ease of separation, and stability and reusability of
the catalyst are some of the important advantages of the method.
We hope that this newly reported idea can be a useful way for the stabilization of other moisture sensitive reagents
leading to their broad range of applications in organic transformations.
Credit author statement
This article Agar-entrapped sulfonated DABCO: A gelly acidic catalyst for the acceleration of
one-pot synthesis of 1,2,4-triazoloquinazolinone and some pyrimidine derivatives
The main advantages of this method are: introduction of novel protocols for the synthesis of
1,2,4- triazoloquinazolinone and some pyrimidine derivatives in mild and green conditions.
Moreover, using small amounts of non-metal catalysts, high yields of products, no by-product
and simple work-up procedures are added advantages of these procedures. It should be
emphasized that the submission is original, not under consideration for publication elsewhere,
and that all authors are aware of the submission and agree to its publication.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We are thankful to the Research Council of University of Guilan for the partial support of this research.

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Figure 1. Agar/agarose structure and agar-entrapped sulfonated DABCO

Figure 2. The structures of some triazole (a) and uracil (b) containing drugs

Figure 3. Agar in heated water (a), [DABCO](SO3H)2(Cl)2 (b), ionic liquid in warm water (c) and agar-entrapped
ionic liquid (d).

Figure 4. Hydrogen bond probability of agar-entrapped IL

Agar-entrapped IL (d)
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
Agar (c)
IL (b)
DABCO (a)
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber cm-1
Figure 5. FT-IR spectra of DABCO (a), [DABCO] (SO3H)2Cl2 (b), agar (c) and agar-entrapped IL (d)

Figure 6. SEM of DABCO (a and b) and agar-entrapped IL (c and d)

Figure 7. TGA diagrams of agar (a) IL (b) and agar-entrapped IL (c)

Figure 8. A comparison between moisture resistant property of agar, IL, and agar-entrapped IL

Figure 9. Reusability of the catalyst in the synthesis of 1,2,4-triazoloquinazolinones (6b, 7a, 8b), 1,2,4-
triazolo[4,3-a]pyrimidines (10b), pyrido[4,5-b]quinolone (12b) and pyrido[2,3-d]pyrimidines (13b)

Scheme 1. Synthesis of 1,2,4-triazolo[4,3-a]pyrimidine, pyrido[2,3-d]pyrimidine and pyrido[4,5-b]pyrimidine,
and 1,2,4-triazoloquinazolinone derivatives

Scheme 2. The hypothesized mechanism for the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine, pyrido[2,3-d]pyrimidine
and pyrido[4,5-b]pyrimidine, and 1,2,4-triazoloquinazolinone derivatives in the presence of agar-entrapped IL

Table 1. Optimization of the reaction conditions for the synthesis of 6b (entries 1-10), 7a (entries 11-18), 8b
(entries 19-26), 10b (entries 27-35), 12b (entries 36-44), 13b (entries 45-52).
Ent
ry
Catalyst amount
(g)
Temp.
(oC)
r.t.
Reflux
r.t.
Reflux
Reflux
Reflux
Reflux
100
Time
(min.)
Conversion
Solvent
(Isolated yield %)
1
2
3
4
5
6
7
8
9
0.01
0.03
0.01
0.03
0.03
0.03
0.03
0.01
0.02
MeCN
MeCN
CH2Cl2
CH2Cl2
H2O
EtOH/H2O
EtOH
--
120
120
120
120
120
120
120
120
90
NRa
NRa
NRa
NRa
NCb
NCb
NCb
100 (70)
100 (90)
--
100
10
0.03
--
100
60
100
60
60
60
30
30
60
30
100
60
60
60
30
30
60
20
75
90
90
90
90
90
90
40
35
120
120
120
120
120
120
100
75
100 (91)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
0.20
0.20
0.20
0.20
0.20
0.20
0.10
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.10
0.20
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.02
0.03
0.02
0.03
0.03
0.03
0.02
0.03
H2O
MeCN
MeCN
CH2Cl2
CH2Cl2
H2O
r.t.
Reflux
Reflux
Reflux
Reflux
100
100
100
r.t.
Reflux
Reflux
Reflux
Reflux
100
100
100
Not NCb
NRa
NRa
NRa
NRa
100 (90)
100 (70)
100 (95)
NCb
EtOH/H2O
EtOH
H2O
MeCN
MeCN
CH2Cl2
CH2Cl2
H2O
EtOH/H2O
EtOH
MeCN
MeCN
EtOH
NRa
NRa
NRa
NRa
100 (90)
100 (70)
100 (95)
NRa
r.t.
Reflux
Reflux
Reflux
r.t.
Reflux
100
100
100
r.t.
Reflux
r.t.
Reflux
r.t.
Reflux
Reflux
Reflux
NRa
Trace
Trace
NCb
H2O
EtOH/H2O
EtOH/H2O
--
NCb
100 (90)
100 (90)
100 (98)
NRa
--
--
MeCN
MeCN
CH2Cl2
CH2Cl2
H2O
NRa
NCb
NCb
NCb
EtOH
100 (70)
100 (80)
100 (91)
EtOH/H2O
EtOH/H2O (2:1)
EtOH/H2O
(2:1)
44
0.02
Reflux
75
100 (92)
45
46
47
48
49
50
51
52
0.03
0.03
0.03
0.03
0.03
0.03
0.04
0.03
MeCN
MeCN
H2O
r.t.
120
120
120
120
120
40
NCb
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
NCb
NCb
EtOH/H2O
EtOH/H2O (2:1)
EtOH
NCb
NCb
100 (80)
100 (80)
100 (97)
EtOH
EtOH
40
55

a No reaction b Not completed
Table 2. preparation of 1,2,4-triazolo quinazolinone (entries 1-23) , 1,2,4-triazolo[4,3-a] pyrimidines (entries 24-
29), pyrido[4,5-b]quinolone (entries 30-37) and pyrido[2,3-d]pyrimidines (entries 38-46) in the presence of agar-
entrapped acidic IL as the catalyst
Melting point (oC)
Time
(min.)
95
60
85
90
80
90
100
110
115
110
30
60
45
60
60
80
20
20
35
45
40
60
65
30
35
40
40
30
50
55
75
Yield
(%)a
94
91
97
95
95
96
94
94
98
95
95
90
90
--
88
85
91
95
84
86
87
89
89
95
98
93
94
93
94
92
92
95
93
92
93
93
94
93.2
97
92
94
94
94
95
94
95
Entry
Ar
Subs.
Subs.
Pro.
Found
248-249
300-302
299-300
>300
Rep. [Ref.]
248-250 [26]
303-305 [27]
298-300 [28]
>300 [29]
C6H5-
4-ClC6H4-
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
triazole
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
uracil
DMb
DMb
DMb
DMb
DMb
DMb
DMb
DMb
DMb
DMb
MAAc
MAAc
MAAc
MAAc
MAAc
MAAc
CHe
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
7a
7b
7c
7d
7e
7f
8a
1
2
3
4
5
6
7
8
2-MeOC6H4-
4-OHC6H4-
2-Naphtaldehyde
4-NO3C6H4-
3-NO3C6H4-
2-NO3C6H4-
4-MeOC6H4-
3-MeOC6H4-
C6H5-
4-MeOC6H4-
4-NO3C6H4-
4-MeC6H4-
[(CH2)2OC6H4]2-
[(CH2)3OC6H4]2-
C6H5-
289-292
285-287
268-269
292-294
224-227
>300
287-290 [29]
284-286 [26]
266-269 [29]
290-292 [30]
222-224 [26]
>300 [31]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
193-194
233-234
257-258
Dec.d
193-194 [32]
233-235 [32]
257-258 [32]
--- [32]
>300
New
>300
New
299-300
294-295
298-299
>300
300-301 [31]
294-295 [33]
299-300 [31]
>300 [34]
4-ClC6H4-
CHe
8b
8c
8d
8e
8f
8g
3-NO3C6H4-
2-NO3C6H4-
4-MeOC6H4-
[(CH2)2OC6H4]2-
[(CH2)3OC6H4]2-
C6H5-
4-ClC6H4-
2-ClC6H4-
4-MeOC6H4-
2-NO3C6H4-
2-Naphtaldehyde
C6H5-
CHe
CHe
CHe
>300
>300 [31]
CHe
>300
New
CHe
>300
New
MNf
MNf
MNf
MNf
MNf
MNf
DMb
DMb
DMb
DMb
DMb
DMb
DMb
DMb
MNf
MNf
MNf
MNf
MNf
MNf
MNf
MNf
MNf
10a
10b
10c
10d
10e
10f
12a
12b
12c
12d
12e
12f
12g
12h
13a
13b
13c
13d
13e
13f
13g
13h
13i
>300
>300 [35]
256-257
264-266
220-223
247-248
281-282
270-271
288-289
224-226
223-224
>300
255-257 [35]
264-265 [35]
220-221 [35]
246-247 [35]
280-283 [36]
269-270 [37]
287-288 [38]
224-225 [37]
221-223 [37]
>300 [38]
4-ClC6H4-
4-NO3C6H4-
3-NO3C6H4-
2-ClC6H4-
2-NO3C6H4-
4-MeOC6H4-
2-MeOC6H4-
C6H5-
105
110
80
110
100
80
50
55
60
50
289-290
>300
287-290 [39]
>300 [38]
>300
>300 [38]
>300
>300 [40]
4-ClC6H4-
2-ClC6H4-
>300
>300 [41]
>300
>300 [41]
4-MeOC6H4-
4-NO3C6H4-
2-Naphtaldehyde
3-BrC6H4-
3-NO3C6H4-
2-NO3C6H4-
>300
>300 [40]
55
60
65
60
>300
>300 [42]
>300
>300 [43]
>300
>300 [41]
>300
>300 [41]
uracil
60
>300
>300 [42]
aIsolated yields, bDimedone,
fMalononitrile
cMethyl acetoacetate,
bDecomposition, eCyclohexadione

Table 3. Comparison of the activity of agar-entrapped IL with those of other reported catalysts in the synthesis of
5-amino-7-(4-chlorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine (10b, entries1–6) and 7-amino-5-(4-
chlorophenyl)-1,3-dimethyl-2,4- dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (13b, entries 7–11)
compared performance
Time
(min.)
30
60
15
40
50
35
15
Entry
Catalyst/Conditions [Ref.]
Yield(%)
NaOH/Reflux-EtOH [35]
NaOH/US-H2O [35]
82
88
90
95
96
98
90
92
92
95
97
1
2
3
4
5
6
7
8
9
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) / Reflux-EtOH [44]
[H2-DABCO][H2PO4]2/Solvent-free, 100 oC [36]
[H2-DABCO][ClO4]2/Solvent-free, 100 oC [36]
Agar entrapped [DABCO](SO3H)2Cl2 Solvent-free -100oC
Nano-MgO/H2O,80 oC [41]
Triethanolamine/H2O,80 oC [45]
120
720
50
Al-HMS-20/EtOH-r.t. [46]
[H2-DABCO][ClO4]2/EtOH, 70 oC [36]
Agar-entrapped [DABCO](SO3H)2Cl2/EtOH, 70 oC
10
11
55

Graphical abstract