A choline chloride-based deep eutectic solvent promoted three-component synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d] pyrimidinone (thione) derivatives

Article abstract of DOI:10.1016/j.molstruc.2019.127652

An efficient one-pot method for the synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone (thione) derivatives through a three-component reaction between aldehydes, malononitrile and enolizable C–H activated acidic compounds using a new deep eutectic solvent made of choline chloride, urea and thiourea as an environmentally benign catalyst has been reported. The structure of the catalyst was characterized using FT-IR, ¹H NMR, and ¹³C NMR. The present method exhibits some notable advantages such as ease of the preparation and handling of the catalyst, low cost, green reaction conditions, short reaction times, high yields, and simple work-up. Also, the catalyst could be recovered easily and recycled up to four times without significant loss of catalytic activity.

Full text of DOI:10.1016/j.molstruc.2019.127652

Journal Pre-proof
A choline chloride-based deep eutectic solvent promoted three-component
synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d] pyrimidinone (thione)
derivatives
Mohammad Biglari, Farhad Shirini, Nosrat O. Mahmoodi, Mehdi Zabihzadeh, Maryam
Mashhadinezhad
PII:
S0022-2860(19)31761-2
DOI:
https://doi.org/10.1016/j.molstruc.2019.127652
MOLSTR 127652
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Accepted Date:
21 September 2019
25 December 2019
Please cite this article as: Mohammad Biglari, Farhad Shirini, Nosrat O. Mahmoodi, Mehdi
Zabihzadeh, Maryam Mashhadinezhad, A choline chloride-based deep eutectic solvent promoted
three-component synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d] pyrimidinone (thione)
derivatives, Journal of Molecular Structure (2019), https://doi.org/10.1016/j.molstruc.2019.127652
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A choline chloride-based deep eutectic solvent promoted
three-component synthesis of tetrahydrobenzo[b]pyran and
pyrano[2,3-d] pyrimidinone (thione) derivatives
Mohammad Biglari,a Farhad Shirini,a,b*
a,b
b
Nosrat O. Mahmoodi, Mehdi Zabihzadeh,
Maryam Mashhadinezhad,b
aDepartment of Chemistry, College of Science, University of Guilan, University Campus 2, Rasht, Iran
bDepartment of Chemistry, College of Science, University of Guilan, Rasht, 41335-19141, Iran
E-mail: shirini@guilan.ac.ir (and also fshirini@gmail.com).

Journal Pre-proof
A choline chloride-based deep eutectic solvent promoted three-
component synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]
pyrimidinone (thione) derivatives
Mohammad Biglari,a Farhad Shirini,a,b*
a,b
b
Nosrat O. Mahmoodi, Mehdi Zabihzadeh, Maryam
Mashhadinezhadb
aDepartment of Chemistry, College of Science, University of Guilan, University Campus 2, Rasht, Iran
bDepartment of Chemistry, College of Science, University of Guilan, Rasht, 41335-19141, Iran
E-mail: shirini@guilan.ac.ir (and also fshirini@gmail.com).
Abstract— An efficient one-pot method for the synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone (thione) derivatives
through a three-component reaction between aldehydes, malononitrile and enolizable C–H activated acidic compounds using a new deep
eutectic solvent made of choline chloride, urea and thiourea as an environmentally benign catalyst has been reported. The structure of the
catalyst was characterized using FT-IR, 1H NMR, and 13C NMR. The present method exhibits some notable advantages such as ease of the
preparation and handling of the catalyst, low cost, green reaction conditions, short reaction times, high yields, and simple work-up. Also,
the catalyst could be recovered easily and recycled up to four times without significant loss of catalytic activity.
Keywords: Choline chloride, deep eutectic solvent, multicomponent reactions, tetrahydrobenzo[b]pyran, pyrano[2,3-
d]pyrimidinone.
1. Introduction
Recently, research on deep eutectic solvents (DESs) as a new generation of eco-friendly and sustainable solvent/catalyst systems
have attracted strong interest in organic synthesis. The concept of DES was first described by Abbott and co-workers in 2003 [1].
DESs are eutectic mixtures of two or more hydrogen-bond acceptors (HBA) (e.g. quaternary ammonium or phosphonium-based
salts) and hydrogen-bond donors (HBD) (e.g. alcohols, amines, acids or carbohydrates) in a certain molar ratio which combine via
hydrogen bond interactions with each other. The resulting DESs are characterized by their melting points, which are significantly
lower than that the melting point of the raw materials (HBD) and (HBA), separately [2-4]. The synthesis of DESs is often
straightforward, does not require further purification steps, and no by-products are formed. DESs have similar physicochemical
properties to conventional ionic liquids (ILs) such as thermal stability, low flammability, nonvolatility, and recyclability. Also, these
compounds exhibit bio-degradability, bio-compatibility, non-toxicity, and water-compatibility and can be prepared with 100 %
atom economy from easily accessible chemical materials [4-7]. Among the numerous DES components, choline chloride (ChCl)
(used as HBA) is the most frequently used salt. ChCl is non-toxic, bio-degradable, and cheap salt which can be synthesized from
fossil reserves or extracted from biomass [4, 8]. This compound is considered as an essential nutrient and is often regarded as a part
of the B complex vitamins [9]. In recent years, ChCl-based DESs have been extensively used in chemistry and chemical technology,
namely biotransformations, nanoscience, biodiesel preparation, polymer synthesis, and catalysis [10].
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4H-pyran-based heterocyclic scaffolds have been attracted considerable attention because of their various useful biological and
pharmacological activities such as anti-diabetic [11], anti-microbial [12], anti-oxidant [13], anti-fungal [14], anti-HIV [15],
cytotoxic [16], and anti-cancer [17] properties. In addition, they can be used as cognitive enhancers, for the treatment of
neurodegenerative disease, including Parkinson's disease, Huntington's disease, Alzheimer's disease, and Down's syndrome as well
as for the treatment of schizophrenia [18]. These compounds also are present in a variety of important natural compounds including
alkaloids, antibiotics, iridoids, and pheromones [19]. Figure 1 shows some of the 4H-pyran derivatives which display strong
pharmacological activities [20, 21]. Hence, design and development of novel synthetic methods to the synthesis of the libraries of
these compounds is an important field for many organic chemists. Among the known procedures for the synthesis of 4H-pyran
frameworks such as tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone (thione) derivatives, the most straightforward method
involves a multi-component reaction of aldehydes, malononitrile and diverse enolizable C–H activated acidic compounds. Multi-
component reactions (MCRs) have a major role in synthetic organic chemistry and pharmaceutical industry due to their advantages
such as high yields compared with multi-step reactions, minimization of time, cost, energy, and waste generation, better selectivity,
and simple performance [22]. Based on this, a large number of catalysts were introduced for the three-component synthesis of
tetrahydrobenzo[b]pyran and pyrano[2,3-d]-pyrimidinone (thione) derivatives under various conditions namely: NaN3 [23],
Fe3O4@SiO2@BenzIm-Fc[Cl]/NiCl2 nanoparticle [24], Fe3O4@MCM‐41@Zr‐piperazine‐MNPs [25], 2,2,2-trifluoroethanol [26],
MNP-DMAP [27], Urea [28], SO42-/MCM-41[29], DABCO [30], nano ZnO [31], [H2-DABCO][H2PO4]2 [32], Fe2O3@SiO2@VB1
[33], RHPrBPCl [34], Glutamic acid [35], [DABCO-PDO][CH3COO] [36], Al-HMS-20 [37], CaHPO4 [38], Choline
chloride.ZnCl2 [39], CuO/ZnO nanocatalyst [40], diammonium hydrogen phosphate [41], L-Proline [42],
Fe3O4@SiO2‐Propyl‐Pip‐SO3H.HSO4 [43], and Fe3O4@SiO2@(CH2)3-Urea-SO3H/HCl [44].
Considering the merit of all the above-mentioned catalysts and their methodologies, most of them suffer from several drawbacks
such as difficulties in the preparation of the catalyst, expensiveness of the reagent, long reaction times, need to use of excess
amounts of reagent or catalyst, moderate yields, and tedious work-up procedure. Thus, further efforts are needed to introduce more
efficient and cleaner methods using scalable low-cost materials for the synthesis of the aforementioned important target molecules.
As a part of our continuing interest on designing environmentally benign methods for various chemical transformations [25, 45-47],
herein we have described an efficient and more practical route for the synthesis 4H-pyran frameworks such as
tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone (thione) derivatives using a new deep eutectic solvent made of ChCl, urea,
and thiourea as a green catalyst.
2. Experimental
2.1. Materials
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All chemicals used in this study were purchased from Merck (Munich) and Sigma-Aldrich (Mumbai) Chemical Companies and
were used without further purification. The purity determination of the substrates and reaction monitoring were accomplished by
TLC on silica-gel polygram SILG/UV 254 plates. Yields refer to the isolated products. Products were characterized by their
physical constants, comparison with authentic samples, FT-IR and NMR spectroscopy.
2.2. Characterization techniques
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 were recorded on a PerkinElmer
1
spectrum BX series with KBr plates for solid samples. H NMR and 13C NMR spectra were recorded on Bruker 500 MHz using
TMS as internal standard and DMSO-d6 as solvent.
2.3. Synthesis of ChCl/urea/thiourea DES
A mixture of ChCl, urea, and thiourea in the ratio of 1:1:1 was heated in a round-bottomed flask (10 mL) at 80 oC under constant
stirring for 5 min until a clear and homogeneous liquid appeared. Then, the reaction was stopped and the prepared DES was
collected without any further purification. The characterization of the obtained DES was determined using FT-IR, 1H NMR and 13
NMR spectroscopic techniques.
C
Spectral data for ChCl/urea/thiourea DES:
1H NMR (500 MHz, DMSO-d6) δ = 3.13 (s, 9H); 3.42 (t, 2H), 3.81 (td, J = 5 Hz, 2H), 5.52 (t, OH), 5.58 (brs, NH), 7.25 (s, NH)
ppm. 13C NMR (125 MHz, DMSO-d6): δ 52.6, 54.5, 66.3, 159.3, 183.2 ppm. FT-IR (KBr, cm-1) 휐 = 3333, 3188, 1665, 1616, 1471,
1399, 1082, 954, 587, 483 cm–1.
2.4. General procedure for the synthesis of tetrahydrobenzo[b]pyran derivatives
In a round-bottomed flask (10 mL) a mixture of aldehyde (1 mmol), malanonitrile (1 mmol), dimedone (1 mmol), and DES (0.1 g,
36 mol%) was stirred and heated in an oil-bath at 100 oC for an appropriate period of time. The reaction progress was followed by
TLC (eluent: EtOAc : n-hexane). After completion of the reaction, water was added and the mixture was stirred for 10 min at 100
oC. Then, the precipitated product was filtered, dried, and subsequently recrystallized from ethanol if necessary.
2.5. General procedure for the synthesis of pyrano[2,3-d]pyrimidinone (thione) derivatives
A mixture of aldehyde (1 mmol), malanonitrile (1 mmol), barbituric or thiobarbituric acid (1 mmol), and DES (0.1 g, 36 mol%) was
stirred in refluxing water (2 mL) for an appropriate period of time. The reaction progress was followed by TLC (eluent: EtOAc : n-
hexane). After completion of the reaction, the mixture was diluted with water (4 mL) and filtered off. Finally, the solid product was
recrystallized from warm ethanol if necessary.
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2.6. Spectroscopic data of the selected previously introduced and new compounds
2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (Table 2, entry 2, 1b). yield 95%;
m.p. 210-212 oC; 1H NMR (400 MHz, DMSO-d6) 훿 (ppm) = 7.22 (d, 3JHH = 8.4 Hz, 2H), 7.18 (d, 3JHH = 8.4 Hz, 2H), 7.05 (s, 2H),
4.31 (s, 1H), 2.43-2.50 (m, 2H), 2.23 (d, 2JHH = 16 Hz, 1H), 2.15 (d, 2JHH = 16 Hz, 1H), 1.09 (s, 3H), 1.01 (s, 3H); FT-IR (KBr, cm-
1) 휐 = 3380, 3324, 2189, 1678, 1218 cm–1.
2-Amino-4-(4-(dimethylamino)phenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4Hchromene-3-carbonitrile (Table 2, entry 14, 1n).
o
1
3
3
yield 96%; m.p. 202-204 C; H NMR (400 MHz, DMSO-d6) 훿 (ppm) = 6.95 (d, JHH = 8.4 Hz, 2H), 6.82 (d, JHH = 8.4 Hz, 2H),
6.90 (s, 2H), 4.15 (s, 1H), 2.90 (s, 6H), 2.46-2.52 (m, 2H), 2.25 (d, 2JHH = 16.2 Hz, 1H), 2.09 (d, 2JHH = 16.2 Hz, 1H), 1.08 (s, 3H),
0.97 (s, 3H); FT-IR (KBr, cm-1) 휐 = 3374, 3235, 2196, 1671, 1609, 1216 cm–1.
7-Amino-5-(2-nitrophenyl)-4-oxo-2-thioxo1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (Table 2, entry 29, 2o).
o
1
yield 89%; m.p. 241-244 C; H NMR (400 MHz, DMSO-d6): 훿 (ppm) = 5.06 (s, 1H), 7.34 (s, 2H),7.48 (dt, J1 = 7.6 Hz, J2 = 1.6
Hz, 1H), 7.54 (dd, J1 = 8Hz, J2 = 1.2 Hz, 1H), 7.67 (dt, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.86 (dd, J1 = 8Hz, J2 = 1.2 Hz, 1H), 12.43
(NH, s, 1H), 13.67 (NH, s, 1H); FT-IR (KBr, cm-1) 휐 = 3426, 3062, 2197, 1675, 1573, 1518, 1349 cm–1.
7-Amino-5-(4-hydroxy-3-methoxy-5-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (Table
o
1
2, entry 25, 2k, new compound). yield 93%; m.p. 240-243 C; H NMR (500 MHz, DMSO-d6): 훿 (ppm) = 3.86 (s, 3H), 4.30 (s,
1H), 7.16 (s, 2H), 7.18 (s, 1H), 7.25 (s, 1H), 10.29 (s, NH), 11.07 (s, NH), 12.06 (s, OH) ppm. 13C NMR (125 MHz, DMSO-d6): 훿
(ppm) = 34.64, 56.14, 57.48, 87.05, 113.63, 115.26, 118.51, 134.38, 136.33, 140.76, 148.59, 148.97, 151.88, 157.17, 162.03 ppm.
FT-IR (KBr, cm-1) 휐 = 3429, 3332, 3196, 3116, 3023, 2197, 1711, 1661, 1550, 1521, 1398, 1271 cm–1.
3. Results and Discussion
The most famous employed example of ChCl-based DESs is the blend of ChCl and urea in a 1:2 molar ratio which is also the first
reported DES [1]. To date, ChCl/urea DES has been applied as an efficacious reaction medium or catalyst in many organic
transformations [48-51]. Nevertheless, despite the promising performance of this eutectic mixture, we have found its efficiency
could be significantly modified by adding thiourea as HBD.
3.1. Synthesis of ChCl/urea/thiourea DES and the characterization
As we have mentioned previously in continuation of our studies on the design, preparation and use of efficient and eco-friendly
catalytic systems, ChCl/urea/thiourea DES was prepared as an inexpensive and biodegradable eutectic mixture by mixing ChCl,
urea and thiourea using the heating method (Figure 2). For being certain about the purity of the product, it was checked by FT-IR,
1H NMR and 13C NMR.
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The FT-IR spectra of choline chloride (a), urea (b), thiourea (c) and the prepared DES (d) are presented in Figure 3. At first look, it
can be noted that the absorption bands related to the stretching modes of -NH2 (νas NH2 and νs NH2) in b and c moved towards the
lower wave number region and changed to broader bands in d. This maybe results from the forming of more hydrogen bonds
between choline chloride, urea and thiourea. In addition, the bands associated to ChCl, such as the rocking vibrations of CH3 (1471
cm-1), and CH2 groups (1082 cm-1), and the asymmetric stretching vibrations of CCO (954 cm-1) appeared in d which reveal that the
structure of Ch+ was not destroyed in the ChCl/urea/thiourea DES.
1
1H NMR and 13C NMR spectra of ChCl/urea/thiourea DES are presented in Figures 4 and 5. In the H NMR spectrum of
ChCl/urea/thiourea DES, six peaks related to six types of hydrogens are observed. The peaks at 3.13, 3.42, 3.81, and 5.52 ppm are
related to CH3, CH2 and OH associated to ChCl, respectively. Two singlet peaks at 5.58 and 7.25 ppm are related to NH2 groups of
thiourea and urea. Also the 13C NMR of the prepared DES properly showed five types of carbons.
3.2. Catalytic activity
The obtained data pointed out that ChCl/urea/thiourea DES was successfully synthesized, so in the next step, the catalytic efficacy
of this new DES was investigated. For this reason, this reagent was utilized as a catalyst in the synthesis of tetrahydrobenzo[b]pyran
and pyrano[2,3-d]pyrimidinone (thione) derivatives. The catalytic study commenced with the optimization of the three‐component
reaction of 4-chlorobenzaldehyde (1 mmol), malononitrile (1mmol) and dimedone (1 mmol) as a model reaction (Table 1, entries 1-
20). Preliminary trials revealed only a trace amount of the desired product was obtained when aprotic solvents like acetonitrile and
dichloromethane were used at room temperature and under reflux conditions. Next, the reaction was tested in green solvents, such
as water and EtOH. No significant product was observed when the mixture of the reaction was refluxed in EtOH. In contrast, when
water was used as a solvent, the product formation enhanced rapidly with 90% conversion in a short reaction time of 15 min, but the
reaction was not completed even after a prolonged reaction time of 120 min. Surprisingly, when the reaction was carried out under
solvent-free conditions, both reaction time and the yield were drastically improved. Finally, the best result was obtained using 36
mol % of DES under solvent-free conditions at 100 oC (Table 1, entry 17) (Scheme 1). Any further increase in the catalyst amounts
did not improve the reaction time and yield. To demonstrate the scope and generality of this protocol, a number of aromatic
aldehydes having substituents such as halogens, hydroxy, methoxy, nitro, and methyl, and aliphatic aldehydes such as
butaraldehyde and isobutaraldehyde were reacted with malononitrile and dimedone under the optimized reaction conditions to
obtain various tetrahydrobenzo[b]pyran derivatives. All reactions were proceeded smoothly with aromatic aldehydes, whereas using
aliphatic aldehydes led to a mixture of products. As a result, this procedure cannot be convenient for these substrates. The results are
depicted in Table 2.
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Next, the efficiency of the prepared DES for promoting the synthesis of pyrano[2,3-d]pyrimidinone (thione) derivatives was
investigated. Like above-mentioned model reaction, a one-pot, three-component system was designed containing 4-
chlorobenzaldehyde (1 mmol), malononitrile (1mmol) and barbituric acid (1 mmol). Control experiments on the model reaction
showed that the reaction was not completed under solvent-free conditions. Then, the reaction was studied in water. The progress of
the reaction at room temperature in water was slow, and became even slower as it proceeded; however, by carrying out the reaction
under reflux temperature the rate of it increased drastically. Finally, The best result was obtained using 36 mol % of DES in water
and under reflux conditions (Table 2, entry 24) (Scheme 2). Subsequently, to reveal the generality of this method, different
derivatives of pyrano[2,3-d]pyrimidinone (thione) were prepared and the results were summarized in Table 2. It should be
mentioned that although the conversion yields in all of the above-mentioned reactions were 100 %, a small amounts of the products
wasted through the work‐up procedure and the percentage yields got less than conversion yields.
The possibility of the recycling of ChCl/urea/thiourea DES was examined for the synthesis of product 1b (2-amino-4-(4-
chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile) under the optimized conditions. For this
purpose, after the completion of the reaction, (Monitored by TLC), water was added and the mixture was stirred for 10 min at 100
oC. The resulting precipitates of the crude solid product was filtered and the filtrate was evaporated under the reduced pressure. The
DES remained after evaporation of water was collected and used in the next cycles of the same synthesis. As Figure 6 shows, the
recovered catalyst could be reused at least for four runs without significant decrease in catalytic efficiency.
The postulated mechanism for the synthesis of pyran derivatives in the presence of ChCl/urea/thiourea DES is explained in Scheme
3 based on previous literatures [32, 45, 52]. According to this mechanism, initially, the aldehyde, malononitrile and β-dicarbonyl
could be activated by DES. Then the process could occur from two routes (routes 1 and 2). The activated aldehyde could be
attacked by the activated malononitrile (route 1) or β-dicarbonyl (route 2) through a Knoevenagel condensation reaction to generate
the intermediate a or the intermediate b. Both routes associated together in intermediate c which followed by intramolecular
cyclization produces the 4H-pyran derivatives.
The comparison of the catalytic activity of ChCl/urea/thiourea DES with other reported catalysts in the literature especially other
ChCl-based catalysts such as ChCl/urea DES (Table 3, entry 9) and ChCl/ZnCl2 (Table 3, entry 11) for the synthesis of
tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone (thione) derivatives of 4-chlorobenzaldehyde is depicted in Table 3. It is
clear that ChCl/urea/thiourea DES promoted the reaction in less time and more yield than other mentioned catalytic systems.
Moreover, the preparation of ChCl/urea/thiourea DES takes less time compared to ChCl/urea DES (Scheme 4) [53].
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4. Conclusion
In summary, the eutectic mixture of ChCl, urea and thiourea was found to be an efficacious and eco-friendly catalyst for the
synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3,d] pyrimidinone (thione) derivatives via one-pot three-component reaction of
aldehyde, malononitrile, and dimedone or (thio)barbituric acid. The simple and green experimental procedure both for preparation
of the catalyst and products, use of readily available, inexpensive, and biocompatible reagents for the synthesis of the catalyst, short
reaction times, easy work-up procedure needing no special separation methods, simple recovery of the catalyst from the reaction
mixture, high purity and high yields of the desired products are the considerable advantages of this protocol. Further studies are
currently on-going in our laboratories to identify additional transformations that can be mediated by this eutectic mixture.
Acknowledgements
We are thankful to the Research Council of the University of Guilan for the partial support of this research.
References
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Organomet. Chem. 32 (2018) e4371.
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tetrahydrobenzo[b]pyrans using 2,2,2-trifluoroethanol as a metal-free and reusable medium, J. Fluorine Chem. 141 (2012) 11-
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efficient and reusable solid acid catalyst, Reac. Kinet. Mech. Cat. 108 (2013) 213-229.
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application in the synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone derivatives, J. Mol. Liq. 234 (2017)
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2-c]chromene and dihydropyrano [4,3-b]pyran derivatives, Nanochem. Res. 1 (2016) 157-165.
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11

Journal Pre-proof
OMe
OMe
MeO
Br
N
N
O
O
O
CN
CN
CN
O
O
NH2
H2N
O
NH2
O
NH2
NH2
anticancer activity
anti-tubercular
antimicrobial
NMe2
O
O
OMe
O
CN
CN
NH2
CN
N
O
NH2
O
N
O
NH2
Ar
anti-tubercular
antibacterial
anti-tumor
Fig. 1. Selected examples of 4H-pyran-based biologically active molecules
12

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Fig. 2. Deep eutectic solvent preparation from choline chloride, urea and thiourea at 80 oC.
13

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Fig. 3. FT-IR spectra of ChCl (a), urea (b), thiourea (c), and prepared DES (d).
14

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Fig. 4. The 1H NMR spectrum of ChCl/urea/thiourea DES.
15

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Fig. 5. The 13C NMR spectrum of ChCl/urea/thiourea DES.
16

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Fig. 6. Recyclability of ChCl/urea/thiourea DES on the synthesis of 1b.
17

Journal Pre-proof
O
Ar
O
O
CN
DES (0.1 g, 36 mol%)
ArCHO
NC
CN
Sovent-free,100 oC
NH2
O
1a-n
Scheme 1. Synthesis of tetrahydrobenzo[b]pyran derivatives catalyzed by ChCl/urea/thiourea DES.
18

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O
O
Ar
O
CN
DES (0.1 g, 36 mol%)
HN
HN
ArCHO
NC
CN
H2O,Reflux
X
N
H
O
X
N
H
NH2
X = O, S
2a-o
Scheme 2. Synthesis of pyrano[2,3-d]pyrimidinone (thione) derivatives catalyzed by ChCl/urea/thiourea DES.
19

Journal Pre-proof
S
O
S
O
N
N
H
H
N
H
H
N
H
H
H
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
OH
OH
Cl
Cl
Cl
Cl
HO
HO
or
O
O
O
O
Ar
Ar
Ar
Ar
H
N
H
N
H
H
H
H
H
H
H
H
N
N
or
H
H
O
S
O
H
S
H
N
N
H
H
N
N
H
H
H
H
O
H
O
H
H
H
H
H
CN
CN
H
H
Route 1
NC
NC
Route 2
Knoevenagel
condensation
O
O
H2O
H2O
O
H
NC
CN
CN
H
O
H
Ar
CN
(a)
H
DES
DES
H
O
O
(b)
Ar
O
C
N
CN
DES
DES
OH
O
Ar
CN
N
O
N
H
H
C
N
H
N
H
OH
(c)
Cl
HO
DES:
H
DES
N
H
S
O
Ar
N
O
Ar
O
H
CN DES
NH
H
CN
O
NH2
(d)
Scheme 3. Plausible mechanism for the synthesis of pyran derivatives.
20

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S
N
H
H
O
S
N
H
N
H
Cl
+
HO
NH2
NH2
H2N
H2N
ChCl/urea/thiourea DES
H
N
80 oC / 5 min.
H
O
N
H
H
N
Cl
O
HO
N
H
H
N
H
N
H
O
Cl
HO
2
NH2
H2N
ChCl/urea DES
H
N
80 oC / 60 min.
H
O
N
H
H
Scheme 4. Synthesis of ChCl/urea/thiourea DES and ChCl/urea DES.
21

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Table 1. Optimization of the amounts of the catalyst, temperature and solvent in the synthesis of tetrahydrobenzo[b]pyran (entries
1-20) and pyrano[2,3-d]pyrimidinone (thione) (entries 21-26) derivatives of 4-chlorobenzaldehyde.
Entry
1
2
3
4
5
6
7
8
Amount of the catalyst (mol %) Solvent
Temp. (oC)
r.t.
100
Time (min.)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
8
120
120
7
120
120
120
17
Conversion yield (%)
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
---
---
18
18
72
36
36
72
---
36
72
36
36
72
36
36
18
36
72
36
72
36
36
72
36
---
---
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
C2H5OH
C2H5OH
C2H5OH
H2O
H2O
H2O
---
---
---
---
---
---
r.t.
Reflux
Reflux
r.t.
Reflux
Reflux
Reflux
r.t.
Reflux
r.t.
Reflux
Reflux
r.t.
100
100
70
100
100
100
r.t.
9
Trace
Trace
Trace
10
11
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Not completed
Not completed
Not completed
Not completed
100 (95)a
Not completed
Not completed
100 (93)a
Not completed
Not completed
Not completed
100 (93)a
---
H2O
H2O
H2O
Reflux
Reflux
70
15
120
100 (91)a
H2O
Not completed
a Isolated yields
22

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Table 2. Preparation of tetrahydrobenzo[b]pyran (entries 1-14) and pyrano[2,3-d]pyrimidinone (thione) (entries 15-29) derivatives
using ChCl/urea/thiourea DES as the catalyst.
M. P. (oC)
Found
Time
(min.)
Yield
(%)a
Entry Aldehyde
Product
Ref.
Rep.
O
1
2
C6H5CHO
1a
1b
12
90
95
226-228
210-212
227-229
[46]
CN
O
Cl
NH2
O
4-ClC6H4CHO
8
208-210
[32]
CN
O
NH2
Cl
O
O
3
4
3-ClC6H4CHO
2-ClC6H4CHO
1c
1d
11
14
91
93
230-232
215-217
229-232
216-218
[25]
[25]
CN
O
NH2
Cl
CN
O
NH2
Br
O
O
O
5
6
7
4-BrC6H4CHO
4-FC6H4CHO
4-NO2C6H4CHO
1e
1f
13
14
17
94
91
90
203-205
175-177
179-181
204-206
171-174
178-179
[46]
[32]
[25]
CN
O
F
NH2
CN
O
NO2
NH2
1g
CN
O
NH2
23

Journal Pre-proof
NO2
O
O
8
9
3-NO2C6H4CHO
2-NO2C6H4CHO
1h
1i
15
18
89
89
212-214
214-216
211-213
218-219
[46]
[25]
CN
O
NH2
NO2
CN
O
NH2
Me
O
10
11
12
4-MeC6H4CHO
4-OHC6H4CHO
4-OMeC6H4CHO
1j
1k
1l
21
23
21
91
93
91
215-217
205-207
200-202
211-214
208-210
200-203
[32]
[25]
[46]
CN
O
NH2
OH
O
CN
O
NH2
OMe
O
O
CN
O
NH2
OMe
CN
13
14
2-MeOC6H4CHO
1m
1n
27
19
90
96
200-202
202-204
198-203
199-203
[32]
[46]
O
NMe2
NH2
O
4-NMe2C6H4CHO
CN
O
NH2
24

Journal Pre-proof
O
15
16
17
18
C6H5CHO
2a
2b
2c
2d
21
17
21
19
91
93
91
95
220-223
241-243
211-215
225-227
219-222
238-240
209-214
225-227
[32]
[46]
[32]
[25]
CN
HN
O
N
H
O
NH2
Cl
O
4-ClC6H4CHO
2-ClC6H4CHO
4-BrC6H4CHO
CN
HN
O
N
H
O
NH2
O
Cl
CN
HN
O
N
H
O
NH2
Br
O
CN
HN
O
N
H
O
NH2
F
O
19
4-FC6H5CHO
2e
21
91
263-265
264-266
[46]
CN
NH2
HN
O
N
H
O
NO2
O
20
21
4-NO2C6H4CHO
2f
25
23
91
90
236-238
268-270
237-239
268-270
[32]
[46]
CN
HN
O
N
H
O
O
NH2
NO2
O
3-NO2C6H4CHO
2g
CN
HN
O
N
H
NH2
25

Journal Pre-proof
O
NO2
22
23
2-NO2C6H4CHO
2h
2i
25
23
88
91
254-256
249-251
[32]
[32]
CN
HN
O
N
H
O
NH2
OH
O
4-HOC6H4CHO
>300
>300
CN
HN
O
N
H
O
NH2
OMe
O
24
4-MeOC6H4CHO
2j
27
90
277-279
276-279
[32]
CN
HN
O
N
H
O
NH2
OH
O2N
O
OMe
4-OH-3-MeO-5-NO2-
C6H2CHO
25
26
2k
2l
15
22
93
90
240-243
223-226
---
New
[46]
CN
HN
O
N
H
O
NH2
O
C6H5CHO
220-224
CN
HN
S
N
H
O
NH2
Cl
O
27
28
4-ClC6H4CHO
2m
19
21
94
92
>300
>300
[32]
[32]
CN
HN
S
N
H
O
NH2
NO2
O
4-NO2C6H4CHO
2n
235-237
233-235
CN
HN
S
N
H
O
NH2
26

Journal Pre-proof
O
NO2
29
2-NO2C6H4CHO
2o
25
89
241-244
242-245
[46]
CN
HN
S
N
H
O
NH2
a Isolated yields
27

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Table 3. Comparison of catalytic activity of ChCl/urea/thiourea DES with some reported catalysts in the synthesis of 4-
chlorophenyl derivatives of tetrahydrobenzo[b]pyran (entrise 1-10) and pyrano[2,3,d] pyrimidinone (entries 11-18).
Time
(min.)
Yield
(%)a
Entry
Catalyst
Amount
Conditions
Ref.
1
2
3
4
5
6
7
8
9
SO42-/MCM-41
CaHPO4
25 mg
10 mol%
10 mol%
2 mL
EtOH /reflux
H2O/EtOH(4:1)/80 oC
H2O/reflux
60
120
120
300
10
40
80
180
60
80
92
94
95
90
91
78
87
92
[29]
[38]
[30]
[26]
[25]
[35]
[54]
[28]
[55]
This
Work
[39]
[28]
[38]
[37]
[56]
[43]
[56]
This
Work
DABCO
2,2,2-Trifluoroethanol
Fe3O4@MCM‐41@Zr‐Piperazine
Glutamic acid
Fructose
reflux
30 mg
H2O/EtOH(7:3)/reflux
EtOH/reflux
20 mol%
20 mol%
10 mol%
1 mL
H2O/EtOH(2:1)/40 oC
EtOH:H2O(1:1)/r.t.
80 oC
Urea
ChCl/urea
10
ChCl/urea/thiourea
36 mol%
Solvent-free/100 oC
8
95
11
12
13
14
15
16
17
ChCl/ZnCl2
Urea
CaHPO4
50 mol%
10 mol%
10 mol%
30 mg
20 mg
30 mg
EtOH/75 oC
EtOH:H2O(1:1)/r.t.
H2O/EtOH(4:1)/80 oC
EtOH/r.t.
2
82
86
92
92
89
95
85
840
120
720
60
20
110
Al-HMS-20
Nano-titania Sulfuric Acid
Fe3O4@SiO2‐Propyl‐Pip‐SO3H.HSO4
boric acid
EtOH:H2O(19:1)/ reflux
H2O/80 oC
10 mol%
THF:H2O(8:2)/ reflux
18
ChCl/urea/thiourea
36 mol%
H2O/reflux
17
93
28