Eco-friendly rapid synthesis of 3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones in choline chloride based deep eutectic solvent

Article abstract of DOI:10.1080/00397911.2017.1291815

A series of 3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones and 6-iodo-3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones were synthesized in choline chloride/urea deep eutectic solvent. Substituted 2-mercapto-4(3H)-quinazolinones were synthesized from anthranilic acid or 5-iodoanthranilic acid and appropriate isothiocyanates in good to excellent yields. Isolation of final product was easy and required no further purification. Synthesis of these compounds was rapid, selective, and catalyst free, while preparation of deep eutectic solvent was easy, components are readily available, cheap, and environmentally friendly.

Full text of DOI:10.1080/00397911.2017.1291815

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Eco-Friendly Rapid Synthesis of 3-Substituted-2-
Thioxo-2,3-Dihydroquinazolin-4(1H)-Ones in
Choline Chloride Based Deep Eutectic Solvent
Maja Molnar, Jelena Klenkar & Tena Tarnai
To cite this article: Maja Molnar, Jelena Klenkar & Tena Tarnai (2017): Eco-Friendly Rapid
Synthesis of 3-Substituted-2-Thioxo-2,3-Dihydroquinazolin-4(1H)-Ones in Choline Chloride Based
Deep Eutectic Solvent, Synthetic Communications, DOI: 10.1080/00397911.2017.1291815
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1291815
View supplementary material
Accepted author version posted online: 13
Feb 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [The UC San Diego Library]
Date: 13 February 2017, At: 11:42

Eco-Friendly Rapid Synthesis of 3-Substituted-2-Thioxo-2,3-Dihydroquinazolin-
4(1H)-Ones in Choline Chloride based Deep Eutectic Solvent
Maja Molnar1, Jelena Klenkar1, Tena Tarnai1
1Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology Osijek,
Osijek, Croatia
Corresponding author Maja Molnar E-mail: maja.molnar@ptfos.hr
Abstract
A series of 3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones and 6-iodo-3-
substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones were synthesized in choline
chloride/urea deep eutectic solvent. Substituted 2-mercapto-4(3H)-quinazolinones were
synthesized from anthranilic acid or 5-iodoanthranilic acid and appropriate
isothiocyanates in good to excellent yields. Isolation of final product was easy and
required no further purification. Synthesis of these compounds was rapid, selective and
catalyst free, while preparation of deep eutectic solvent was easy, components are readily
available, cheap and environmentally friendly.
Graphical Abstract
KEYWORDS: deep eutectic solvents, 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones,
anthranilic acid, 5-iodoanthranilic acid, isothiocyanate
1

INTRODUCTION
4(3H)-Quinazolinones are a class of compounds with well-known potent biological
activity and are very popular in drug discovery. There are numerous drugs containing
quinazolinone moiety available on the market, including Afloqualone, Balaglitazone,
Halofuginone, etc.[1] Efforts are made on daily bases to make structural changes in
quinazolinone core to increase their biological activity. For this purpose 2-mercapto-
4(3H)-quinazolinones, bearing thiol group can serve as a good substrate for introducing
various moieties to quinazolinone core.[2,3] Li and coworkers synthesized such mercapto
derivatives by refluxing anthranilic acid or substituted anthranilic acid and 2-
methoxyphenyl or phenyl isothiocyanate in ethanol for 5 hours and used column
chromatography for purification.[4] The same was done by El-Azab and coworkers on
condensation of 5-iodoanthranilic acid with appropriate isothiocyanate.[3] Butler and
Partridge synthesized 2-mercapto-3-methyl-4(3H)-quinazolinone by reacting anthranilic
acid and corresponding isothiocyanate in acetic acid[5] and Kavalek and coworkers
prepared the same compound from methyl anthranilate and methyl isothiocyanate at
room temperature, solvent free, but the reaction took 3 days to be completed.[6] These
compounds can also be prepared via cyclisation of ethyl 2-nitrobenzoates with
isothiocyanates or isothiocyanates using TiCl4/Zn system,[7] or from isatoic anhydride in
reaction with anililne in the first step, then with phenylisothiocyanate in the presence of
heteropolyacids.[8] Alafeefy synthesized 6-iodo-2-mercapto-3-substituted derivatives,
starting from 5-iodoanthranilic acid and appropriate isothiocyanate, using triethylamine
in ethanol.[9] Most of these methods use organic compounds, either as solvents, catalysts
or for further purification of final products.
2

In our ongoing work on synthesis of quinazolinones in choline chloride (CC) based deep
eutectic solvents (DES) we found an easy, effective, selective and high yielded route for
synthesis of 3-substituted-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones, also from
anthranilic or 5-iodo anthranilic acid and appropriate isothiocyanate with no or minimal
need for further purification of final products.
DESs are known as environmentally friendly substitution for conventional organic
solvents, being non-toxic, biodegradable and inexpensive, especially those choline
chloride based.[10,11] They are usually made of choline chloride and hydrogen bond
donors, such as urea, glycerol or carboxylic acids,[12] a natural compounds which are
environmentally acceptable and biodegradable.[13] Their use as green solvents is being
more and more prominent these days, not only for their ecological aspect, but for their
effectiveness in synthetic routes[14-16] of various compounds as well as their use in
extraction of biologically active natural compounds.[17]
DISCUSSION
In our attempt to synthesize some quinazolinone derivatives, we observed fast formation
of 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3c) in DES made of choline
chloride/urea (CC/U) (1:2), without any need for further purification. This compound was
synthesized from anthranilic acid and phenyl isothiocyanate, and although some authors
were using catalysts, we noticed that there is no need for one. The reaction mixture was
heated to 90°C and the product was formed in 15 minutes, but it took up to 3 hours for
3

reactants to be consumed completely by TLC monitoring. The isolation of final products
was easy since it required addition of water and filtration of the products. A synthesis of
the same product was also performed in DES made of CC/malonic acid (1:1) but the
yield was much lower and the reaction time was prolonged. This fact agrees with findings
of Mancuso and coworkers[18] that the nature of DES has a great impact on outcome of
the reaction.
In track changes and Compound 3c was characterized by specific 1H NMR peaks,
aromatic (7.97-7.27 ppm) and for NH group (13.01 ppm).
After a successful synthesis of compound 3c, other derivatives of 3-substituted-2-thioxo-
2,3-dihydroquinazolin-4(1H)-ones were synthesized in CC/U DES, without any catalysts
(Figure 1). Anthranililc acid was combined with methylisothicyanate, ethyl
isothiocyanate, 4-chlorophenylisothiocyanate and allyl isothiocyanate to form compounds
3a, 3b, 3d and 3e. Compound 3a showed characteristic peaks (3.66 ppm) for methyl
group on 1H NMR spectra, which for compound 3b were identified as ethyl group peaks
(1.2-1.25 and 4.41-4.48 ppm). Compound 3d showed characteristic aromatic peaks (7.97-
7.33 ppm), and 3e for allyl substituent (5.86-5.93 and 5.04-5.20 ppm).
As seen from Table 1, we obtained most of the products in high isolated yields, except for
allyl derivatives, with melting points of the known ones matching the literature.
4

Since cyclization of anthranilic acid was very successful, the same reactions were
performed on 5-iodoanthranilic acid (Figure 2).
First anthranilic acid was iodinated following the literature procedure.[19] Procedure of
synthesis 6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives (4a-e) in CC/U
DES was the same as for anthranilic acid. Derivatives of 6-iodo-2-thioxo-2,3-
dihydroquinazolin-4(1H)-ones were synthesized by reacting 5-iodoanthranilic acid and
appropriate isothiocyanate, at 90 °C and isolated by addition of water to reaction mixture.
Depending on the substituent i.e. corresponding isothiocyanate, reaction was finished in
2-4 hours, monitored on TLC until full consumption of reactants. 1H NMR spectra
showed characteristic peaks for each of compounds. For 4a methyl protons (3.64 ppm),
compound 4b ethyl group (5.41 and 3.12 ppm), 4c and 4d aromatic protons (7.22-8.18
ppm) and for allyl substituent in compound 4e (5.85 and 5.13-5.19 ppm). Isolated yields
of iodinated compounds were lower than those described above, derived from anthranilic
acid. Product yields of all compounds presented in Table 1 and Table 2 are isolated
yields. Since all the reactions were stopped upon full consumption of reactants, the
isolated yield of the final product depends sollely on its solubility in water. In order to
increase an isolated yield of the products, extraction with dichloromethane can be
performed.
Structures of all synthesized compounds were also confirmed by mass spectra and 13C
NMR. These compounds usually exist as thiole or thione tautomers (Figure 3), and shifts
5

on 1H NMR clearly show a peak at for –NH proton at 12.86-13.15 ppm confirming that
they exist in thione form.
EXPERIMENTAL
All solvents and reagents were purchased from commercial suppliers and used without
further purification. Reactions were monitored by TLC, using benzene : acetone : acetic
acid (8:1:1) mixture as eluent and spots were identified under 254 and 365 nm UV lamp.
Melting points were obtained using Electrothermal melting point apparatus
(Electrothermal, Rochford, Great Britain). NMR spectra were recorded on a Bruker
Avance 600 MHz NMR Spectrometer (Bruker Biospin GmbH, Rheinstetten, Germany) at
293 K in DMSO-d6. The MS spectra were recorded on LCMS/MS API 2000 (Applied
Biosystems/MDS SCIEX, CA, USA) using electrospray ionization (ESI) source.
GENERAL PROCEDURE FOR PREPARATION OF DEEP EUTECTIC
SOLVENT (DES)[12]
Cholin chloride based deep eutectic solvents were prepared by mixing choline chloride
with urea (1:2) and malonic acid (1:1). Mixtures were heated with stirring until a clear
solution formed. The deep eutectic solvent was cooled and used in all reactions without
any purification.
GENERAL PROCEDURE FOR SYNTHESIS OF 2-MERCAPTO-3-
SUBSTITUTED-4(3H)-QUINAZOLINONES
6

A mixture of anthranilic acid 1 (1.37 g, 0.01 mol) or 5-iodoanthranilic acid 2 (2.63 g,
0.01 mol) and appropriate isothiocyanate was (0.01 mol) stirred in DES at 90 °C for 2-4
hours. After the completion of reaction, water was added to the mixture and precipitated
product was filtered and dried. Compounds 4e and 4b were extracted from the mixture
with DCM.
Spectral Data For Selected Compounds
3-Phenyl-2-Thioxo-2,3-Dihydroquinazolin-4(1H)-One (3c)
Yield 90 %; Mp = 312 °C; Rf (benzene:acetone:acetic acid 8:1:1) 0.73; 1H NMR (300
MHz DMSO-d6) 13.01 (1H, br.s., NH), 7.97-7.27 (9H, m, arom); 13C NMR (75 MHz,
CDCl3) 176.6, 160.5, 140.1, 139.8, 136.0, 129.5, 129.4, 128.6, 127.9, 124.8, 116.7,
116.2; m/z 252.90 (M-H+); Anal. calcd. for C14H10N2OS: C, 66.12; H, 3.96; N, 11.02; O,
6.29; S, 12.61%. Found: C, 66.03; H, 3.77; N, 11.12; %.
Literature data (Capuano and Zander, 1966)[21]: Mp =295 °C; Lakhan and Srivastava
(1993) [20]: Mp =302 °C; 1H NMR: 7.19-8.09 (m, 9H, Ar-H), 13.0 (s, 1H, NH).
6-Iodo-3-Phenyl-2-Thioxo-2,3-Dihydroquinazolin-4(1H)-One (4c)
Yield 91%; Mp = >300 °C; Rf (benzene:acetone:acetic acid 8:1:1) 0.79; 1H NMR (600
MHz DMSO-d6) 13.1 (1H, br.s., NH), 8.18-7.24 (8H, m, J=1.88, J=8.67, J=2.26, arom.);
13C NMR (75 MHz, CDCl3) 176.6, 159.1, 144.1, 139.6, 139.5, 135.7, 129.5, 129.4,
129.3, 128.7, 118.7, 118.4, 88.1; m/z 379.10 (M-H+); Anal. calcd. for C14H9IN2OS: C,
44.23; H, 2.39; I, 33.38; N, 7.37; O, 4.21; S, 8.43 %. Found: C, 44.42; H, 2.19; N, 7.27%.
7

Literature data (Lakhan and Srivastava, 1993)[20]: Mp = 295 °C .
Supporting information: Full experimetnal detail, 1H NMR and 13C NMR spectra. This
material can be found via the „Supplementary Content“ section of this article's webpage.
REFERENCES
[1]
Tiwary, B. K.; Pradhan, K.; Nanda, A.K.; Chakraborty, R. J. Chem. Biol. Ther.
2015, 1, 1-7.
[2]
Kadi, A. A.; El-Azab, A. S.; Alafeefy, A. M.; Abdel-Hamide, S. G. Ar. J. Pharm.
Sci. 2009, 34, 135-155.
[3]
[4]
El-Azab, A. S. Phosphorus Sulfur Silicon Relat Elem. 2007, 182, 333-348.
Li, H.; Wang, J. P.; Yang, F.; Liu, T.; Qiu, J. Y.; Li, J.; Tang, J. Heterocycles
2012, 85, 1897-1911.
[5]
[6]
Butler, K.; Partridge, M. W. J. Chem. Soc. 1959, 1512-1521.
Kavalek, J.; Kotyk, M.; El Bahaie, S.; Šterba, V. Collect. Czech. Chem. Commun.
1981, 46, 246-255.
[7]
Dou, G. L.; Wang, M. M.; Huang, Z. B.; Shi, D. Q. J. Heterocyclic Chem. 2009,
46, 645-649.
[8]
Allameh, S.; Heravi, M. M.; Hashemi, M. M.; Bamoharram, F. F. Chin. Chem.
Lett. 2011, 22, 131-134.
[9]
Alafeefy, A. M. J. Saudi Chem. Soc. 2011, 15, 337-343.
[10] Khandelwal, S.; Tailor, Y. K.; Kumar, M. J. Mol. Liq. 2016, 215, 345-386.
8

[11] Singh, B.; Lobo, H.; Shankarling, G. Catal. Lett. 2011, 141, 178-182.
[12] Lobo, H. R.; Singh, B. S.; Shankarling, G. S. Catal. Comm. 2012, 27, 179-183.
[13] Dai, Y.; van Spronsen, J.; Witkamp, G. J.; Verpoorte, R.; Choi, Y. H. Anal. Chim.
Acta 2013, 766, 61-68.
[14] Zhang, Q.; De Oliveira Vigier, K.; Royer, S.; Jerome, F. Chem. Soc. Rev. 2012,
41, 7108-7146.
[15] Massolo, E.; Palmieri, S.; Benaglia, M.; Capriati, V.; Perna, F. M. Green Chem.
2016, 18, 792-797.
[16] Martinez, R.; Berbegal, L.; Guillena, G.; Ramon, D. J. Green Chem. 2016, 18,
1724-1730.
[17] García, A.; Rodríguez-Juan, E.; Rodríguez-Gutiérrez, G.; Rios, J. J.; Fernández-
Bolaños, J. Food Chem. 2016, 197, 554-561.
[18] Mancuso, R.; Maner, A.; Cicco, L.; Perna, F. M.; Capriati, V. Tetrahedron 2016,
72, 4239-4244.
[19] Singh, T.; Sharma, S.; Srivastava, V. K.; Kumar, A. Ind. J. Chem. 2006, 45B,
2558-2565.
[20] Lakhan, R.; Srivastava, M. Proc. Indian Acad. Sci. (Chem. Sci.) 1993, 105, 11-17.
[21] Capuano, L.; Zander, M. Chem. Ber. 1966, 99, 3085-3096.
[22] Reddy, C. K.; Reddy, P. S. N.; Ratnam, C. V. Indian J. Chem. 1987, 26B, 882.
9

Table 1. Synthesized 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives.
entry compound
3a
yield (%)
68
3b
3c
72
90
3d
3e
75
35
10

Table 2. Synthesized 6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives.
entry compound
4a
yield (%)
73
4b
4c
10
91
4d
4e
40
20
11

Figure 1. Synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives.
12

Figure 2. Synthesis of 6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives.
13

Figure 3. Thiole-thione tautomers of synthesized compounds.
14