Screening of natural deep eutectic solvents for green synthesis of 2-methyl-3-substituted quinazolinones and microwave-assisted synthesis of 3-aryl quinazolinones in ethanol

Article abstract of DOI:10.5562/CCA3597

In this study, two fast and efficient protocols for green synthesis of 3-substituted quinazolinones were perfomed. A synthesis of 2-methyl-3-substituted quinazolinones was performed in natural deep eutectic solvents, while 3-aryl quinazolinones were obtained by using microwave assisted synthesis. Benzoxazinone, which was used as an intermediate in the synthesis of 2-methyl-3-substituted quinazolinones, was prepared conventionally from anthranilic acid and acetic anhydride. In order to find the most appropriate synthetic path, twenty natural deep eutectic solvents were applied as a solvent in these syntheses. Choline chloride:urea (1: 2) was found to be the most efficient solvent and was further used in the synthesis of 2-methyl quinazolinone derivatives (2–12). 3-Aryl quinazolinones (13–17), on the other hand, were synthesized in one-pot microwave-assisted reaction of anthranilic acid, different amines and trimethyl orthoformate. All compounds were synthesized in good to excellent yields, characterized by LC-MS/MS spectrometry and ¹H- and ¹³C-NMR spectroscopy.

Full text of DOI:10.5562/CCA3597

O R I G I NA L S C I E N T I F I C P A P E R
Croat. Chem. Acta 2019, 92(4), 511–517
Published online: March 28, 2020
DOI: 10.5562/cca3597
Screening of Natural Deep Eutectic Solvents for Green
Synthesis of 2-methyl-3-substituted Quinazolinones
and Microwave-Assisted Synthesis of 3-aryl
Quinazolinones in Ethanol
Mario Komar,1 Maja Molnar,1,* Anastazija Konjarević2
1
Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology, F. Kuhača 20, HR-31000 Osijek, Croatia
Croatian Veterinary Institute-Branch Veterinary Institute Vinkovci, J. Kozarca 24, HR-32100 Vinkovci, Croatia
Corresponding author’s e-mail address: maja.molnar@ptfos.hr
2
*
RECEIVED: November 7, 2019
REVISED: December 26, 2019
ACCEPTED: December 28, 2019
Abstract: In this study, two fast and efficient protocols for green synthesis of 3-substituted quinazolinones were perfomed. A synthesis of
2-methyl-3-substituted quinazolinones was performed in natural deep eutectic solvents, while 3-aryl quinazolinones were obtained by using
microwave assisted synthesis. Benzoxazinone, which was used as an intermediate in the synthesis of 2-methyl-3-substituted quinazolinones,
was prepared conventionally from anthranilic acid and acetic anhydride. In order to find the most appropriate synthetic path, twenty natural
deep eutectic solvents were applied as a solvent in these syntheses. Choline chloride:urea (1 : 2) was found to be the most efficient solvent
and was further used in the synthesis of 2-methyl quinazolinone derivatives (2–12). 3-Aryl quinazolinones (13–17), on the other hand, were
synthesized in one-pot microwave-assisted reaction of anthranilic acid, different amines and trimethyl orthoformate. All compounds were
synthesized in good to excellent yields, characterized by LC-MS/MS spectrometry and 1H- and 13C-NMR spectroscopy.
Keywords: natural deep eutectic solvents, microwave-assisted synthesis, quinazolinones, anthranilic acid, amine.
this manner, in the past few decades, a great attention is
INTRODUCTION
given to the design of the new solvents. Low-melting mix-
UINAZOLINONES are widely used heterocyclic com-
pounds of a great pharmaceutical interest. Due to
tures based on the naturally acceptable species, also called
natural deep eutectic solvents (NADESs), are a novel gener-
ation of solvents in organic chemistry. They are often char-
acterized as environmentally friendly and sustainable
mixtures of nontoxic and cheap compounds, with low vapor
pressure, non-flammability and biodegradability, where
components form a eutectic mixture. Often, hydrogen
bond acceptors (HBAs; quaternary ammonium salts) are
combined with hydrogen bond donors (HBDs; ureas, poly-
ols, dicarboxylic acids) in different ratios, to obtain DES with
desirable physical and chemical characteristics.[12,13]
Q
their structural diversity, they possess various biological ac-
tivities, including antihelmintic,[1,2] antibacterial,[3–5] anti-in-
flammatory,[6] anticancer,[7,8] antihyperlipidemic[9] and
antioxidant.[10] Their biological activities have been recog-
nized by pharmaceutical industry and today many com-
monly available drugs contain different quinazolinones as
an active ingredient (Figure 1). Therefore, they are synthe-
sized on a daily basis in many laboratories these days, and
improving their synthesis in terms of making these
processes “greener” is of a great importance.
So far, we have successfully applied DESs in different
Modern synthetic methods with green pathways are
able to eliminate harmful solvents and they usually use mild
conditions. Green synthetic methods are tending to comply
with as many green chemistry principles as possible.[11] In
organic synthetic routes, like in the Knoevenagel condensa-
tion of rhodanine derivatives with different aldehydes,[14]
synthesis of triazoles,[15] Schiff bases[16] and 2-mercap-
toquinazolinones.[17] There are some extensive reviews
This work is licensed under a Creative Commons Attribution 4.0 International License.

512
M. KOMAR et al.: Screening of Natural Deep Eutectic Solvents …
describing the physico-chemical properties of the DESs,[18–22]
as well as their application in other synthetic routes.[23–25]
Apart from our report on the synthesis of 2-mercap-
toquinazolinones in DESs,[17] the synthesis of quinazolinone
derivatives in DESs was also described by other authors.
Lobo et al. (2012) synthesized 2,3-dihydroquinazolin-4(1H)-
one derivatives using choline chloride/malonic acid DES as
a catalyst,[26] while Zhang et al. (2012) used sugar/urea salt
mixture as a solvent in the synthesis of quinazolinone
derivatives.[27] Ghosh et al. (2016) synthesized substituted
quinazolinones and dihydroquinazolinones using L-(+)-
tartaric acid/dimethyl urea DES,[28] and Arafa et al. (2019)
synthesized bis-quinazolin-4-one derivatives in L-(+)-
tartaric acid/choline chloride DES.[29]
The aim of our work was to perform a synthesis of 3-
substituted quinazolinones using deep eutectic solvents.
This method was applied for the synthesis of 2-methyl-3-
substituted quinazolinones. Since it was observed that the
reaction of anthranilic acid and different orthoformates
yielded no 3-substituted quinazolinones in DESs, a micro-
wave-assisted synthesis was proposed for this reaction.
Microwaves are often characterized as one of the green
chemistry methods, due to the reduced reaction time,
increase in the product yield and elimination of unwanted
reaction pathways. The use of microwave-assisted synthe-
sis is manifested in a huge increase of publications in the
last decade, and a large number of quinazolinone deriva-
tives have been synthesized, for the application in medicine
and pharmacy.[30–33] Therefore, in this paper we report two
green protocols for the synthesis of 3-substituted and
2-methyl-3-substituted quinazolinones: a) deep eutectic
solvents, and b) microwave induced synthesis, using
anthranilic acid as a starting material.
EXPERIMENTAL
All chemicals were obtained from commercial suppliers. All
reactions were monitored by thin-layer chromatograhpy
(TLC) using aluminium plates silica gel coated with
flourescent indicator F254 (Kieselgel 60) in benzene : acetic
acid : acetone (8 : 1 : 1) as a solvent system. Microwave-
assisted synthesis was performed in Milestone flexiWAVE
(Milestone Srl, Sorisole (BG), Italy) microwave system,
equipped with rotating carousel with 15 positions for PTFE
high-pressure vessels. Melting points were determined
using capillary Electrothermal IA9100 digital melting point
apparatus. The mass spectra were recorded on the Agilent
UPLC Infinity 1290 s QQQ 6460 Triple Quad LC/MS/MS, ESI,
USA. All NMR spectra were recorded on a Bruker ultrashield
Avance, working at 300 and 600 MHz and chemical shifts
are expressed as ppm in respect to the internal standard
tetramethylsilane (TMS).
Preparation of 2-Methyl-4H-
benzo[d][1,3]oxazin-4-one
A mixture of anthranilic acid (0.1 mol) and acetic anhydride
(0.2 mol) was refluxed for 4 hours. The excess of acetic
anhydride and acetic acid was evaporated under vacuum.
The pale-yellow solid was washed with petroleum ether
and used in the synthesis of 2–12.
Preparation of NADES
Choline chloride based DES were prepared as described by
previous reports.[15,35] A mixture of choline chloride (7.5 g,
53.7 mmol) and different hydrogen bond donors (HBDs,
Table 1) was stirred at 80 °C until colorless liquid of NADES
was obtained.
O
O
General Procedure for the Synthesis of
3-(4-Chlorophenyl)-2-methylquinazolin-
4(3H)-one (1) and
3-Aryl-2-methylquinazolin-4(3H)-one
Derivatives (2–12)
N
N
N
COO
H
N
N
-
-
-
-
oxo u nazo
n
enzo c ac
id
)
PIRI UALONE
2
4
(
q
i
li 3 4H yl b
i
Q
(
d
)
-
se
d
a
ve
no
c
t
i
)
an en o ox c
t
i
hyp
t
i
t
i
(
(
)
To the prepared DES containing molecular sieves (1 g), 2-
methyl-4H-benzo[d][1,3]oxazin-4-one (5 mmol) and 4-chlo-
roaniline (5 mmol) or other amine (5 mmol; 2.5 mmol of
pyridine-2,6-dicarbohydrazide) were added. The reaction
was stirred at 80 °C, monitored by TLC, and after the com-
pletion of the reaction, water was added. Molecular sieves
were removed and crude product was collected by filtra-
tion. The desired product was recrystallized from ethanol.
O
O
N
N
N
N
N
HN
LUOTONIN A
an umor
t t
RUTAEA ARPINE
C
-
,
ana es c an
er ens ve an
n
or
t
d COX 2 i hibi
)
t
t
i
lg
i
ihyp
i
(
)
(
O
O
H
N
H
2NO2NS
N
N
General Procedure for the Synthesis of
3-Substituted Quinazolin-4(3H)-one
Derivatives (13–17)
O
N
HO
Cl
N
METOLAZONE
ure
FEBRIFU INE
G
an ma ar a
l l
i
)
c
i
)
t
di
(
t
i
(
Anthranilic acid (5 mmol), trimethyl orthoformate (6 mmol)
and amine (6 mmol) were mixed together and reaction was
Figure 1. Several important quinazolinones in pharmacy.[34]
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DOI: 10.5562/cca3597

M. KOMAR et al.: Screening of Natural Deep Eutectic Solvents …
513
carried out by a microwave irradiation for 30 min at 120 °C.
After the completion of the reaction, the mixture was
poured over crushed ice and water. The crude product was
collected by filltration and washed with cold water.
139.7, 135.2, 134.1, 131.6, 129.6, 129.2, 128.0, 127.2,
126.9, 126.8, 120.9, 120.4, 24.5; MS: m / z: 270.90 (M+)
(270.71).
2-(2-METHYL-4-OXOQUINAZOLIN-3(4H)-YL)-
BENZOIC ACID (6)
3-(4-CHLOROPHENYL)-2-METHYLQUINAZOLIN-
4(3H)-ONE (1)[34]
Yield: 49 %; Mp= 244–247 °C; Rf = 0.41; 1H-NMR (600 MHz,
ppm, DMSO-d6) 2.11 (s, 3 H), 7.51 (t, J=6.97 Hz, 1H, arom.),
7.57 (d, J=8.07 Hz, 1H, arom.), 7.65–7.70 (m, 2H, arom.),
7.78–7.87 (m, 2H, arom.), 8.06–8.14 (m, 1H, arom.); 13C-
NMR (DMSO-d6) δ (ppm): 165.7, 161.3, 154.2, 147.5, 137.5,
134.5, 133.6, 131.5, 130.2, 129.5, 128.9, 126.6, 126.2,
120.4, 23.7; MS: 281.00 m / z: (M+) (280.28).
Yield: 89 %; Mp = 159–161 °C (lit. 159–160 °C) ; Rf = 0.70 ;
1H-NMR (300 MHz, ppm, DMSO-d6): 2.14 (s, 3H, CH3), 7.51–
7.54 (m, 3H, arom.), 7.63–7.68 (m, 3H, arom.), 7.85 (m, 1H,
arom.), 8.08 (dd, J = 7.91, 1. 5 Hz, 1H, arom); 13C-NMR
(DMSO-d6) δ (ppm): 161.92, 154.6, 147.8, 137.2, 135.1,
134.1, 130.9, 130.1, 127.1, 126.9, 126.8, 120.9, 24.5; MS:
m / z: 271.20 (M+) (270.71).
2-METHYL-3-PHENYLQUINAZOLIN-4(3H)-ONE (7)
Yield: 74 %; Mp= 127–128 °C; Rf = 0.62; 1H-NMR (600 MHz,
ppm, DMSO-d6): 2.13 (s, 3H, CH3), 7.43–7.47 (m, 2H, arom.),
7.49–7.54 (m, 2H, arom.), 7.55–7.60 (m, 2H, arom.), 7.67 (d,
J=8.07 Hz, 1H, arom.), 7.82–7.86 (m, 1H, arom.), 8.10 (dd,
J=8.07, 1.47 Hz, 1H, arom.); 13C-NMR (DMSO-d6) δ (ppm):
161.3, 154.4, 147.3, 137.9, 136.5, 129.5, 128.9, 128.4,
126.6, 126.4, 126.3, 120.5, 24.0; MS: m / z: 237.00 (M+)
(236.27).
3-(4-METHOXYPHENYL)-2-METHYLQUINAZOLIN-
4(3H)-ONE (2)[34]
Yield: 71 %; Mp =170-173 °C (lit.167–170 °C) Rf = 0.62; 1H-
NMR (300 MHz, ppm, DMSO-d6): 2.15 (s, 3H, CH3), 3.85 (s,
3H, OCH3), 7.01–7.12 (m, 2H, arom.), 7.34–7.37 (m, 2H,
arom.), 7.51 (m, 1H, arom.), 7.66 (m, 1H, arom.), 7.84 (m,
1H, arom.), 8.09 (dd, 1H, J = 8.10, 1.32, arom); 13C-NMR
(DMSO-d6) δ (ppm): 162.0, 159.7, 155.5, 147.9, 134.9,
130.8, 129.9, 127.1, 126.8, 115.2, 55.9, 24.5; MS: m / z:
267.10 (M+) (266.29).
3-(4-METHOXYPHENYL)-2-METHYL-6-NITROQUINAZOLIN-
4(3H)-ONE (8)
3-(4-BROMOPHENYL)-2-METHYLQUINAZOLIN-
4(3H)-ONE (3)[34]
Yield: 84 %; Mp = 229–230 °C; Rf = 0.70 ; 1H-NMR (300 MHz,
ppm, DMSO-d6): 2.20 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.11–
7.14 (d, 2H, J = 9.04, arom.), 7.40–7.43 (d, 2H, J = 8.67,
arom.), 7.83 (d, 1H, J = 9.04, arom.), 8.55 (dd, 1H, J = 9.04,
2.64, arom.), 8.76 (s, 1H, arom.); 13C-NMR (DMSO-d6)
δ (ppm): 161.3, 160.0, 159.7, 152.0, 145.1, 130.2, 129.9,
128.9, 122.9, 121.1, 115.3, 55.9, 24.9; MS: m / z: 312.20
(M+) (311.29).
Yield: 53 %; Mp = 170–173 °C (lit. 168–169 °C) Rf = 0.69 ; 1H-
NMR (300 MHz, ppm, DMSO-d6): 2.14 (s, 3H, CH3), 7.51–
7.54 (m, 3H, arom.), 7.63–7.68 (m, 3H, arom.), 7.85 (m, 1H,
arom.), 8.08 (dd, J = 7.91, 1. 5 Hz, 1H, arom); 13C-NMR
(DMSO-d6) δ (ppm): 161.92, 154.6, 147.8, 137.2, 135.1,
134.1, 130.9, 130.1, 127.1, 126.9, 126.8, 120.9, 24.5; MS:
m / z: 314.80 (M−) (315.16).
6-IODO-3-(4-METHOXYPHENYL)-2-METHYLQUINAZOLIN-
4(3H)-ONE (9)
3-(2-BROMO-4-METHYLPHENYL)-2-METHYLQUINAZOLIN-
4(3H)-ONE (4)
Yield: 63 %; Mp= 141–143 °C; Rf = 0.69; 1H-NMR (300 MHz,
ppm, DMSO-d6): 2.12 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.04–
7.15 (m, 2H, arom.), 7.28–7.38 (m, 2H, arom.), 7.44 (d,
J=8.67 Hz, 1H, arom.), 8.11 (dd, J=8.48, 2.07 Hz, 1H, arom.),
8.35 (d, J=2.26 Hz, 1H, arom.); 13C-NMR (DMSO-d6) δ (ppm):
160.7, 159.8, 156.3, 147.1, 143.3, 135.0, 130.6, 129.9,
129.3, 122.9, 115.2, 115.1, 91.5, 55.6, 24.7; MS: m / z:
393.00 (M+) (392.19).
Yield: 68 %; Mp= 116–118 °C; Rf = 0.75; 1H-NMR (300 MHz,
ppm, DMSO-d6): 2.11 (s, 3H, CH3) 2.41 (s, 3H, CH3) 7.41 (d,
J=7.16 Hz, 1H, arom.) 7.47–7.59 (m, 2H, arom.) 7.62–7.75
(m, 2H, arom.) 7.80–7.93 (m, 1H, arom.) 8.12 (dd, J=7.91,
1.13 Hz, 1H, arom.); 13C-NMR (DMSO-d6) δ (ppm): 161.0,
154.4, 147.7, 141.9, 135.4, 134.0, 130.6, 130.4, 127.3,
127.2, 126.9, 122.2, 120.7, 100.0, 23.9, 20.9; MS: m / z:
329.19 (M+) (330.90).
2-((4-METHYL-2-OXO-2H-CHROMEN-7-YL)OXY)-N-(2-
METHYL-4-OXOQUINAZOLIN-3(4H)-YL)ACETAMIDE (10)
Yield: 75 %; Mp = 230 °C; Rf = 0.28; 1H-NMR (600 MHz, ppm,
DMSO-d6): 2.11 (s, 3H, CH3), 2.36 (s, 3H, CH3), 5.01 (s, 2H,
CH2), 6.20 (s, 1H; C-3 coum.),6.83 (dd, J = 8.80, 2.2 Hz, 1H,
arom.), 6.93 (s, 1H, arom.), 7.54 (d, J = 8.07 Hz, 1H, arom.),
7.61 (d, J = 8.80 Hz, 1H, arom.), 7.66 (m, 1H, arom.), 7.76
3-(3-CHLOROPHENYL)-2-METHYLQUINAZOLIN-
4(3H)-ONE (5)
Yield: 51 %; Mp= 113–115 °C; 1H-NMR (300 MHz, ppm,
DMSO-d6): 2.15 (s, 3 H, CH3), 7.42–7.73 (m, 6H, arom.),
7.79–7.90 (m, 1H, arom.), 8.10 (d, J=7.53 Hz, 1H,
arom.); 13C-NMR (DMSO-d6) δ (ppm): 161.8, 154.4, 147.8,
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M. KOMAR et al.: Screening of Natural Deep Eutectic Solvents …
(m, 1H, arom.), 8.05 (m, 1H, arom.); 13C-NMR (DMSO-d6) δ
(ppm): 165.5, 160.2, 159.9, 154.3, 153.2, 152.8, 149.4,
133.3, 132.4, 131.4, 130.4, 129.6, 129.4, 126.3, 113.6,
112.2, 111.44, 101.6, 60.5, 18.1, 10.4; MS: m / z: 392.20
(M+) (391.38).
=CH), 8.20 (s, 1H, C-2); 13C-NMR (DMSO-d6) δ (ppm): 160.2,
149.1, 148.4, 135.1, 127.8, 126.8, 122.5, 116.0, 115.8,
113.9, 56.7, 56.2; MS: m / z: 282.90 (M+) (282.29).
3-PHENYLQUINAZOLIN-4(3H)-ONE (16)[37]
Yield: 12 %; Mp= 143–145 °C (lit. 139 °C); Rf = 0.73; 1H-NMR
(300 MHz, ppm, DMSO-d6): 7.55-7.63 (m, 6H, arom.), 7.75
(m, 1H, arom.), 7.86 (dd, J = 6.97, 1.3 Hz, 1H, arom.), 8.21
(dd, J = 8.10, 0.9 Hz,1H, arom.), 8.36 (s, 1H, C-2).; 13C-NMR
(DMSO-d6) δ (ppm): 160.44, 148.2, 147., 138.1, 135.1,
129.7, 129.2, 127.9, 127.8, 127.7, 126.9, 122.43; MS: m / z:
221.10 (M−) (222.24).
2-(7-HYDROXY-2-OXO-2H-CHROMEN-4-YL)-N-(2-METHYL-
4-OXOQUINAZOLIN-3(4H)-YL)ACETAMIDE (11)
Yield: 79 %; Mp = 200–204 °C; Rf = 0.30; 1H-NMR (300 MHz,
ppm, DMSO-d6): 2.36 (s, 3H, CH3), 4.02 (s, 2H, -CH2-), 6.39
(s, 1H, coum.), 6.75 (s, 1H, arom.), 6.83 (m, 1H, arom.), 7.53
(m, 1H, arom.), 7.63 (d, 1H, J = 7.91, arom.), 7.73 (d, 1H, J =
8.67, arom.), 7.85 (m, 1H, arom.), 8.10 (dd, 1H, J = 7.91,
1.13, arom); 13C-NMR (DMSO-d6) δ (ppm): 168.4, 161.8,
160.6, 159.3, 156.3, 155.5, 150.1, 147.0, 135.5, 120.9,
113.4, 112.8, 111.7, 102.9, 37.1, 21.5; MS: m / z: 376.20
(M−) (377.35).
3-(3-CHLOROPHENYL)QUINAZOLIN-4(3H)-ONE (17)
Yield: 57 %; Mp= 155–157 °C; Rf = 0.731NMR (600 MHz,
ppm, DMSO-d6): 7.54–7.57 (m, 1H, arom.), 7.59–7.62 (m,
3H, arom.), 7.74–7.77 (m, 2H, arom.), 7.87–7.92 (m, 1H,
arom.), 8.21 (dd, J=8.07, 1.47 Hz, 1H, arom.), 8.37 (s, 1H, C-
2); 13C-NMR (DMSO-d6) δ (ppm): 159.9, 149.7, 146.8, 138.9,
134.7, 134.6, 133.2, 130.8, 128.8, 127.8, 127.5, 127.3,
126.4, 123.3, 121.8, 118.7; MS: m / z: 257.39 (M+) (256.69).
N,N'-BIS(2-METHYL-4-OXOQUINAZOLIN-3(4H)-
YL)PYRIDINE-2,6-DICARBOXAMIDE (12)
Yield: 31 %; Mp= 225–228 °C; Rf = 0.20; 1H-NMR (300 MHz,
ppm, DMSO-d6): 2.53 (s, 3H, CH3), 2.55 (s, 3H, CH3), 7.59 (t,
J=7.54 Hz, 2H, aom.), 7.73 (d, J=8.29 Hz, 2H, arom.), 7.91 (t,
J=7.54 Hz, 2H, arom.), 8.10–8.23 (m, 2H, arom.), 8.36–8.50
(m, 3H, arom.); 13C-NMR (DMSO-d6) δ (ppm): 162.9, 162.8,
159.5, 156.5, 147.2, 147.1, 147.0, 141.2, 135.8, 127.6,
127.0, 120.8, 21.7; MS: m / z: 482.10 (M+) (481.46).
RESULTS AND DISCUSSION
Deep eutectic solvents have found a great application in
organic synthesis. Among many, choline chloride based
deep eutectic solvents have proven to be very effective in
various organic transformations. When choline chloride is
combined with various HBDs, a great number of DESs is
formed, all differing in their chemical and physical
properties. Therefore, in order to find the most suitable
DES for desired chemical reaction, the best way is to
perform a screening of different DESs on a model
reaction.
In order to find the most efficient reaction media for
green synthesis of different quinazolinones, the model re-
action of benzoxazinone and 4-chloroaniline (Figure 2) was
performed, in twenty choline chloride based deep eutectic
solvents (Table 2.). It was found that DESs are not suitable
for the synthesis of the intermediate benzoxazionone,
3-(4-(TRIFLUOROMETHOXY)PHENYL)QUINAZOLIN-
4(3H)-ONE (13)
Yield: 48 %; Mp = 138–139 °C; Rf = 0.76; 1H-NMR (600 MHz,
ppm, DMSO-d6): 7.56-7.60 (m, 3H, arom.), 7.70–7.74
(m, 3H, arom.), 7.86–7.89 (m, 1H, arom.), 8.19 (m, 1H,
arom.), 8.36 (s, 1H, C-2); 13C-NMR (DMSO-d6) δ (ppm):
159.9, 147.7, 136.5, 134.7, 129.7, 127.5, 127.3, 126.4,
121.8;MS: m / z: 307.10 (M+) (306.24).
2-(4-OXOQUINAZOLIN-3(4H)-YL)BENZOIC ACID (14)[36]
Yield: 35 %; Mp= 295–297 °C (lit. 287–288 °C); Rf = 0.48; 1H-
NMR (600 MHz, ppm, DMSO- d6): 7.68–7.72 (m, 2H, arom.),
7.77 (m, 1H, arom.), 7.84 (m, 1H, arom.), 7.88–7.92 (m, 1H,
arom.), 7.98 (m, 1H, arom.), 8.18 (dd, J = 8.07, 1.4 Hz,1H,
arom.), 8.27 (dd, J = 8.07, 1.4 Hz,1H, arom.), 8.42 (s, 1H, C-
2), 13.18 (br.s., 1H, OH); 13C-NMR (DMSO-d6) δ (ppm):
165.8, 160.3, 147.9, 147.1, 137.1, 134.6, 133.4, 131.1,
129.5, 129.2, 127.2, 126.3, 121.9; MS: m / z: 267.00 (M+)
(266.25).
O
H
COO
Cl
c
O
A
2O
+
NH2
N
H2N
°
;
DE
S 80
C
Cl
O
3-(2,5-DIMETHOXYPHENYL)QUINAZOLIN-4(3H)-ONE (15)
Yield: 54 %; Mp = 159–161 °C; Rf = 0.71; 1H-NMR (300 MHz,
ppm, DMSO-d6): 3.72 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 7.11
(m, 1H, arom.), 7.15–7.21 (m,2H, arom.), 7.60 (t, J = 6.97
Hz, 1H, arom.), 7.76 (d, J = 8.29 Hz, 1H, arom.), 7.89 (m, 1H,
N
N
1
Figure 2. Model reaction for the synthesis of benzoxazinone.
Croat. Chem. Acta 2019, 92(4), 511–517
DOI: 10.5562/cca3597

M. KOMAR et al.: Screening of Natural Deep Eutectic Solvents …
515
because only N-acetylanthranilic acid was obtained. There-
fore, benzoxazinone was prepared conventionally,[38] via
condensation reaction of anthranilic acid and acetic anhy-
dride under reflux for 4 hours. The product was obtained
after evaporation of the excess of acetic anhydride and ace-
tic acid, washed with petroleum ether and immediately
used for all further reactions. The reaction optimization
was performed with 4-chloroaniline in DESs in the presence
of molecular sieves during 2-4 hours at 80 °C. The results
are tabulated in Table 1.
1H and 13C NMR spectra elucidated structures of all
the synthesized compounds. Methyl protons of all 2-
methylquinazolinone derivatives show characteristic
singlet peak at 2.11–2.36 ppm. Aromatic protons are visible
at 7.01-8.76 ppm. All characteristic peaks for phenyl ring
substituents are also present; methoxy protons for com-
pound 2 at 3.85 ppm, methyl protons for compound 4 at
2.41 ppm, methoxy protons for compound 8 at 3.85 ppm
and for compound 9 at 3.83 ppm. Phenyl ring substituents
influenced the product yields, where the highest yield was
obtained with 4-chlorophenyl aniline, and the lowest in
compound 12, with dipicolinic acid hydrazide as a starting
compound. Compounds 10 and 11 were successfully
synthesized, although the starting amino compounds were
bulky molecules, thus forming a quinazolinone-coumarin
hybrids. For compound 10 coumarin proton of C-3 peaked
at 6.20 ppm, while two -CH2- protons are found at
5.01 ppm. For compound 11 coumarin C-3 proton is
found at 6.39 ppm, while two –CH2-protons are found at
4.02 ppm.
Second part of this research involved the synthesis
of 3-aryl quinazolinones (13–17), starting from anthranilic
acid, trimethyl orthoformate and different aromatic amines
(Figure 4).
These reactions demanded higher temperatures,
120 °C, respectively, which cannot be accomplished in
DESs, due to their degradation at higher temperatures.
Therefore, DES could not be efficiently employed for their
synthesis. Here we decided to apply microwaves, in order
to maintain the green character of the process. So far, there
are several examples of 3-aryl quinazolinone synthesis from
O
NH2
H
COO
O
c
A
2O
+
Table 1. Choline chloride based deep eutectic solvents with
different HBDs in green synthesis of 3-(4-chlorophenyl)-2-
methylquinazolinone (1).
NH2
N
N
R2
O
N
r
A
:
h l U
C C
Ratio
HBD : HBA
-
=
R1
=
=
:
:
:
:
:
:
:
:
°
2
3
4
5
6
7
8
9
R1 H; R2 4 OCH3
Entry
HBD
Ref.
Yield / %
80
C
-
=
r
r
R1 H; R2 4 B
-
- -
H
=
=
=
=
=
=
=
=
=
-
R1
R1
R1
R1
H
H
H
H
; R
; R
; R
; R
2
B
4 C
2
2
2
2
3
2 12
-
1
Urea
1 : 2
18
18
89
73
3 C
l
-
2 COO
H
=
O
R1
H
2
N-methylurea
1 : 3
1 : 2
H
=
R1
H
-
-
=
NH
O
R1 5 NO2
; R
4 OC
H
3
H
2
3
:
11
-
-
=
; R
4 OC
2
1,3-
dimethylurea
=
:
:
10
H
N
R1 5 I
3
39
87
O
N
O
O
HO
O
O
4
Thiourea
Acetamide
Butane-1,4-diol
Ethane-1,2-diol
Glycerol
1 : 2
1 : 2
1 : 3
1 : 2
1 : 2
1 : 1
1 : 1
2 : 1
2 : 1
1 : 1
1 : 1
1 : 1
1 : 2
1 : 2
1 : 1
1 : 1
1 : 1
18
18
40
18
41
39
41
41
41
39
42
41
39
43
41
41
44
64
62
=
R1
H
12
5
H
H
N
N
O
O
6
57
7
42
Figure 3. Synthesis of 2-methyl-3-substituted- quinazoli-
nones.
8
36
9
Xylitol
44
Table 2. Reaction time and yield of synthesized compounds.
10
11
12
13
14
15
16
17
18
19
20
Sorbitol
64
Comp. Time / min Yield / % Comp. Time / min Yield / %
Glucose
in traces
in traces
in traces
55
1
2
3
4
5
6
7
8
9
120
150
150
150
150
180
180
240
240
89
71
53
68
51
49
74
84
63
10
11
12
13
14
15
16
17
240
240
240
30
75
79
31
48
35
54
12
57
Fructose
Citric acid
Tartaric acid
Oxalic acid
Levulinic acid
Lactic acid
Malic acid
Malonic acid
Maleic acid
62
30
in traces
50
30
30
71
30
79
61
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516
M. KOMAR et al.: Screening of Natural Deep Eutectic Solvents …
H
+
NH2
COO
O
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