Multicomponent synthesis of 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin- 4(3 H)-one derivatives

Article abstract of DOI:10.1080/00397911.2011.558968

A novel, one-pot, three-component reaction for the synthesis of novel 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one derivatives using the Huisgen 1,3-dipolar cycloaddition reaction of organic azides and in situ-prepared terminal alkynes in good to excellent yields is reported.

Full text of DOI:10.1080/00397911.2011.558968

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Multicomponent Synthesis of
1,2,3-Triazol-4-yl-methylthio-3-
arylquinazolin-4(3H)-one Derivatives
Majid Koohshari a , Minoo Dabiri a , Peyman Salehi b & Mahboobeh
Bahramnejad a
a Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Tehran, Iran
b Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute, Shahid Beheshti University, Tehran, Iran
Accepted author version posted online: 15 Dec 2011. Version of
record first published: 14 May 2012
To cite this article: Majid Koohshari, Minoo Dabiri, Peyman Salehi & Mahboobeh Bahramnejad (2012):
Multicomponent Synthesis of 1,2,3-Triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:16, 2415-2422
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Synthetic Communications1, 42: 2415–2422, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.558968
MULTICOMPONENT SYNTHESIS OF 1,2,3-TRIAZOL-4-
YL-METHYLTHIO-3-ARYLQUINAZOLIN-4(3H)-ONE
DERIVATIVES
Majid Koohshari,1 Minoo Dabiri,1 Peyman Salehi,2 and
Mahboobeh Bahramnejad1
1Department of Chemistry, Faculty of Science, Shahid Beheshti University,
Tehran, Iran
2Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A novel, one-pot, three-component reaction for the synthesis of novel 1,2,3-
triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one derivatives using the Huisgen 1,3-
dipolar cycloaddition reaction of organic azides and in situ–prepared terminal alkynes in
good to excellent yields is reported.
Keywords Azide; click chemistry; propargyl bromide; quinazolinone; 1,2,3-triazole
INTRODUCTION
The quinazolinone moiety is a widely researched and important scaffold in
medicinal chemistry because of the variety of pharmacological properties associated
with the compounds bearing this heterocycle.[1] Although their importance in cancer
chemotherapy is unparalleled,[l,2] these heterocyclic systems also exhibit activities
such as kinase inhibition,[3] anticancer,[4] antimalarial,[5,6] antidiabetes, and antiobe-
sity[7] activities. Quinazoline derivatives are well-known natural alkaloids that are
widely distributed in the plant and animal kingdoms.[8] Many biologically active
molecules with quinazoline or quinazolinone structures have been reported in the
literature.[9]
Received August 16, 2010.
Address correspondence to Minoo Dabiri or Peyman Salehi, Department of Chemistry, Faculty of
Science, Shahid Beheshti University, G. C., Evin, Tehran, Iran. E-mail: m-dabiri@sbu.ac.ir; p-salehi@
sbu.ac.ir
2415

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M. KOOHSHARI ET AL.
‘‘Click chemistry,’’ introduced by Kolb et al., has emerged as a fast and
efficient approach for the synthesis of novel heterocyclic compounds.[10] Click chem-
istry has been defined as reactions that are modular, wide in scope, high-yielding,
free from offensive by-products, stereospecific, simple to perform, and require
benign or no solvent.[11]
The Cu(I)-catalyzed reaction of terminal alkynes with organic azides via Huisgen
1,3-dipolar cycloaddition reaction to give a regioselective formation of 1,4-disubstituted
1,2,3-triazoles is one of the most useful examples of click chemistry.[12]
1,2,3-Triazoles are potential targets for drug discovery because of their wide
range of biological properties such as antibacterial, antiviral, antiepileptic, and
antiallergic[13] activities. They are also used as optical brighteners, light stabilizers,
fluorescent whiteners, and corrosion retarding agents.[14]
Recently, many multicomponent reactions have been reported that involved click
reactions such as Huisgen 1,3-dipolar cycloaddition.[15] In addition to these improve-
ments, optimization of the reaction conditions was reported by varying the number of
equivalents of propargyl bromide, azides, and 3-phenyl-2-thioxoquinazolinone in the
presence of different amounts of Cu(OAc)2 and sodium ascorbate.[16]
In nature, many biological processes occur in aqueous environments, and these
fascinating in vivo reactions should prompt organic chemists to explore the potential
of water as a medium for organic reactions. In addition to scientific interest in aque-
ous reaction media, social pressure to find environmentally benign alternatives to
current organic chemical processes has made these reactions attractive from an eco-
logical point of view. The field of aqueous organic synthesis has been regularly and
comprehensively reviewed.[17] In addition, recent reviews focusing on microwave-
assisted organic synthesis in water,[18] reactions in near-critical water,[19] and bio-
catalysts in water[20] have been also published.
In view of our current studies on multicomponent reactions (MCRs),[21] herein
we describe the synthesis of 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one
derivatives 4a–l via a condensation reaction among 2-thioxoquinazolinone 1 (pre-
pared by the treatment of 2-aminobenzoic acids with isothiocyanides,)[22] propargyl
bromide 2, and azide 3[23] in good to excellent yields at 80 ꢀC (Scheme 1).
In a pilot experiment, the treatment of 2-thioxoquinazolinone, propargyl
bromide and 4-nitrophenylazide afforded 2-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-
yl)methylthio)-3-phenylquinazolin-4(3H)-one 4d in 82% yield. In the same manner,
various 2-thioxoquinazolinones and azides were condensed with propargyl bromide
in a one-pot operation at 80 ꢀC in H2O=EtOH to give the corresponding 1,2,3-
triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one derivatives 4a–l in good to
excellent yields.
Scheme 1. Synthesis of 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one derivatives 4a—l.

1,2,3-TRIAZOL-4-YL-METHYLTHIO-3-ARYLQUINAZOLIN-4(3H)-ONE
2417
Figure 1. Structures of 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-one 4a–l.
Copper acetate in the presence of sodium ascorbate was used as the catalyst of
the reaction. The results shown in Fig. 1 clearly indicate the scope and generality of
the reaction with respect to various starting materials.
Compounds 4a–l were stable solids, and their structures were corroborated by
1
infrared (IR), H and 13C NMR spectroscopy, mass spectrometry, and elemental
analysis.
In summary, we have developed a mild and straightforward procedure for the
synthesis of a new class of substituted 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin-
4(3H)-one derivatives from a MCR of 2-thioxoquinazolinone, propargyl bromide,
and azide in H2O=EtOH in good to excellent yields.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9100 apparatus and were
not corrected. IR spectra were recorded on a Fourier transform (FT)-IR 10MB

2418
M. KOOHSHARI ET AL.
BOMEM spectrometer. Mass spectra were documented on a Finnigan-MAT8430
mass spectrometer operating at an ionizationpotential of 70 eV. The elemental analy-
ses were performed with an Elementar Analysensysteme GmbH VarioEL instru-
1
ment. H and 13C NMR spectra were recorded on a Bruker DRX-300 Avance
spectrometer at 300.13 and 75.47 MHz. NMR spectra were obtained on solutions
in CDCl3 and dimethylsulfoxide [DMSO (d6]) using tetramethylsilane (TMS) as
internal standard. The chemicals used in this work were purchased from Merck
and Fluka chemical companies.
General Procedure for the Preparation of 1,2,3-Triazolyl-methylthio-
quinazolin-4-ones 4a–l
A mixture of a 2-thioxoquinazolinone (1 mmol), propargyl bromide (1 mmol),
azide (1 mmol), sodium ascorbate (20 mol%), and Cu(OAc)2 (10 mol%) in 2 ml of
H2O=EtOH (1:1) was stirred for 8 h at 80 ꢀC. After completion of the reaction, as
indicated by thin-layer chromatography (TLC; ethyl acetate=n-hexane, 2=1), the pro-
duct was then precipitated by the addition of NH3 (2 ml). The product was isolated
by filtration and then washed with H2O (2 ꢁ 10 ml). Finally, the pure product was
obtained after recrystallization from CHCl3 to give products 4a–l.
Compound Characterization Data
2-((1-Benzyl-1H-1,2,3-triazol-4-yl)methylthio)-3-phenylquinazolin-4(3-
H)-one (4a). Light yellow solid, dec ¼ 167–170 ꢀC. IR (KBr) (tmax=cmꢂ1): 1689,
1
1544, 1468. H NMR (300 MHz, DMSO-d6): dH ¼ 8.19 (s, 1H), 8.08–8.11 (d, 1H),
7.84–7.89 (m, 1H), 7.68–7.71 (m, 1H), 7.54–7.60 (m, 3H), 7.40–7.52 (m, 3H),
7.25–7.35 (m, 5H), 5.55 (s, 2H), 4.44 (s, 2H). 13C NMR (75 MHz, DMSO-d6):
dC ¼ 161.2, 157.1, 147.6, 142.9, 136.4, 136.2, 135.4, 130.4, 130.0, 129.9, 129.2,
128.6, 128.4, 127.0, 126.7, 126.5, 124.7, 120.0, 53.2, 27.3. Anal. calcd for
C23H17N5OS: C, 67.13; H, 4.16; N, 17.02. Found: C, 67.07; H, 4.24; N, 17.12.
2-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-phenylquina-
zolin-4(3H)-one (4b). Light yellow solid, dec ¼ 227–230 ꢀC. IR (KBr) (tmax=cmꢂ1):
1688, 1594, 1548, 1496. 1H NMR (300 MHz, DMSO-d6): dH ¼ 8.78 (s, 1H), 7.90–8.24
(m, 1H), 7.89 (d, J ¼ 8.1 Hz, 2H), 7.70–8.84 (m, 2H), 7.64 (d, J ¼ 8.0 Hz, 2H),
7.51–7.58 (m, 3H), 7.44–7.51 (m, 3H), 4.53 (s, 2H). 13C NMR (75 MHz, DMSO-
d6): dC ¼ 161.2, 156.9, 147.7, 144.4, 136.2, 135.7, 135.4, 133.4, 130.4, 130.3, 130.0,
129.9, 127.0, 126.7, 126.5, 122.7, 122.1, 120.1, 27.0. MS (EI, 70 eV): m=z (%) 416
(mþ ꢂ28, 10). Anal. calcd. for C22H14ClN5OS: C, 61.18; H, 3.27; N, 16.22. Found:
C, 61.26; H, 3.45; N, 16.41.
2-((1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-phenylquinazo-
lin-4(3H)-one (4c). Yellow solid, dec ¼ 167–170 ꢀC. IR (KBr) (tmax=cmꢂ1): 1683,
1
1575, 1550, 1467. H NMR (300 MHz, DMSO-d6): dH ¼ 8.99 (s, 1H), 8.65 (s, 1H),
8.28–8.35 (m, 2H), 8.07–8.09 (d, J ¼ 7.7 Hz, 2H), 7.77–7.86 (m, 2H), 7.48–7.57 (m,
6H), 4.54 (s, 2H). 13C NMR (75 MHz, DMSO-d6): dC ¼ 161.2, 156.8, 148.9, 147.7,
147.5, 144.6, 137.5, 136.1, 132.0, 130.5, 130.4, 130.0, 129.9, 127.0, 126.7, 126.5,

1,2,3-TRIAZOL-4-YL-METHYLTHIO-3-ARYLQUINAZOLIN-4(3H)-ONE
2419
123.6, 123.1, 27.0. Anal. calcd. for C23H16N6O3S: C, 60.52; H, 3.53; N, 18.41. Found:
C, 60.48; H, 3.55; N, 18.50.
2-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-phenylquina-
zolin-4(3H)-one (4d). Yellow solid, dec ¼ 166–168 ꢀC; IR (KBr) (tmax=cmꢂ1):
1
1681, 1600, 1548, 1524. H NMR (300 MHz, DMSO- d6): dH ¼ 8.95 (s, 1H), 8.39–
8.41 (d, J ¼ 6.2 Hz, 2H), 8.15–8.17 (d, J ¼ 6.7 Hz, 2H), 8.06–8.08 (d, J ¼ 5.9 Hz,
1H), 7.78–7.84 (m, 2H), 7.47–7.54 (m, 6H), 4.54 (s, 2H). 13C NMR (75 MHz,
DMSO-d6): dC ¼ 161.2, 156.8, 147.7, 147.1, 144.9, 141.2, 136.1, 135.4, 130.4, 130.0,
129.9, 127.0, 126.7, 126.5, 126.0, 123.0, 121.0, 120.1, 26.9. Anal. calcd. for
C23H16N6O3S: C, 60.52; H, 3.53; N, 18.41. Found: C, 60.33; H, 3.56; N, 18.49.
2-((1-Benzyl-1H-1,2,3-triazol-4-yl)methylthio)-3-(4-chlorophenyl)quina-
zolin-4(3H)-one (4e). Light yellow solid, dec ¼ 191–193 ꢀC. IR (KBr) (tmax=cmꢂ1):
1
1689, 1545, 1497. H NMR (300 MHz, DMSO-d6): dH ¼ 8.17 (s, 1H), 8.07–8.09 (d,
J ¼ 7.0 Hz, 1H), 7.83–7.85 (m, 1H), 7.61–7.69 (m, 3H), 7.50–7.52 (m, 3H),
7.20–7.50 (m, 5H), 5.53 (s, 2H), 4.44 (s, 2H). 13C NMR (75 MHz, DMSO-d6):
dC ¼ 161.1, 156.7, 147.6, 136.4, 135.4, 135.1, 131.9, 130.1, 129.2, 128.6, 128.3,
127.0, 126.7, 126.6, 124.6, 120.0, 53.2, 27.3. Anal. calcd. for C24H18ClN5OS: C,
62.67; H, 3.94; N, 15.23; S, 6.97. Found: C, 62.43; H, 3.98; N, 15.09.
3-(4-Chlorophenyl)-2-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl-
thio)quinazolin-4(3H)-one (4f). Light yellow solid, dec ¼ 213–215 ꢀC. IR (KBr)
1
(tmax=cmꢂ1): 1690, 1546, 1497, 1468. H NMR (300 MHz, DMSO-d6): dH ¼ 8.76
(s, 1H), 7.61–8.05 (m, 12H), 4.53 (s, 2H). 13C NMR (75 MHz, DMSO-d6):
dC ¼ 161.2, 157.6, 147.6, 135.8, 135.2, 135.1, 133.4, 133.1, 132.0, 131.9, 130.3,
130.1, 127.1, 127.0, 126.7, 126.0, 122.1, 122.0, 27.1. Anal. calcd. for C23H15Cl2N5OS:
C, 57.51; H, 3.15; N, 14.58. Found: C, 57.42; H, 3.22; N, 14.59.
3-(4-Chlorophenyl)-2-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl-
thio)quinazolin-4(3H)-one (4g). Yellow solid, dec ¼ 160–164 ꢀC. IR (KBr)
1
(tmax=cmꢂ1): 1691, 1545, 1498, 1469. H NMR (300 MHz, DMSO-d6): dH ¼ 8.97
(s, 1H), 8.41–8.44 (d, J ¼ 9.0 Hz, 2H), 8.16–8.19 (d, J ¼ 9.0 Hz, 2H), 8.07–8.09 (d,
J ¼ 7.8 Hz, 1H), 7.83–7.87 (m, 3H), 7.47–7.67 (m, 4H), 4.59 (s, 2H). 13C NMR
(75 MHz, DMSO-d6): dC ¼ 161.1, 155.8, 147.5, 147.1, 135.5, 135.3, 134.9, 131.9,
130.1, 129.1, 128.4, 128.3, 127.0, 126.7, 126.6, 126.0, 121.0, 120.0, 27.0. Anal. calcd.
for C23H15ClN6O3S: C, 56.27; H, 3.08; N, 17.12. Found: C, 56.20; H, 3.21; N, 17.09.
6-Chloro-2-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-phe-
nylquinazolin-4(3H)-one (4h). Light yellow solid, dec ¼ 202–205 ꢀC. IR (KBr)
1
(tmax=cmꢂ1): 1687, 1569, 1545, 1499. H NMR (300 MHz, DMSO-d6): dH ¼ 8.77
(s, 1H), 7.85–7.98 (m, 5H), 7.46–7.61 (m, 7H), 4.50 (s, 2H). 13C NMR (75 MHz,
DMSO-d6): dC ¼ 160.3, 157.8, 146.4, 144.2, 135.9, 135.7, 135.4, 133.4, 130.5, 130.3,
130.0, 129.8, 128.9, 125.9, 122.7, 122.2, 121.4, 27.1. Anal. calcd. for C23H15Cl2N5OS:
C, 57.51; H, 3.15; N, 14.58. Found: C, 57.38; H, 3.31; N, 14.37.
6-Chloro-2-((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-phe-
nylquinazolin-4(3H)-one (4i). Yellow solid, mp ¼ 162–164 ꢀC. IR (KBr) (tmax
=
1
cmꢂ1):1685, 1570, 1538, 1466, 1349. H NMR (300 MHz, DMSO-d6): dH ¼ 8.98 (s,
1H), 8.64 (s, 1H), 8.31 (m, 2H), 7.84–7.99 (m, 5H), 7.47–7.55 (m, 6H), 4.54 (s,

2420
M. KOOHSHARI ET AL.
2H). 13C NMR (75 MHz, DMSO-d6): dC ¼ 160.3, 157.7, 148.9, 146.4, 135.9, 135.4,
132.0, 130.5, 130.0, 129.8, 129.2, 129.0, 126.5, 125.9, 123.6, 123.1, 115.2, 62.3,
27.1. MS (EI, 70 eV): m=z (%) 462 (mþ ꢂ28, 12). Anal. calcd. for C22H13ClN6O3S:
C, 55.41; H, 2.75; N, 17.62. Found: C, 55.37; H, 2.54; N, 17.69.
6-Chloro-2-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-phe-
nylquinazolin-4(3H)-one (4j). Yellow solid, dec ¼ 170–174 ꢀC, IR (KBr) (tmax
=
cmꢂ1): 1692, 1598, 1570, 1544. H NMR (300 MHz, DMSO-d6): dH ¼ 8.96 (s, 1H),
8.21–8.60 (m, 2H), 8.10–8.19 (m, 2H), 7.90–8.10 (m, 1H), 7.71–7.90 (m, 3H),
7.25–7.75 (m, 6H), 4.53 (s, 2H). 13C NMR (75 MHz, DMSO-d6): dC ¼ 160.2,
157.7, 147.1, 146.4, 141.2, 135.4, 134.7, 132.0, 130.5, 130.0, 129.8, 129.0, 126.0,
125.9, 123.0, 121.4, 121.0, 27.0. Anal. calcd. for C22H13ClN6O3S: C, 55.41; H,
2.75; N, 17.62. Found: C, 55.36; H, 2.55; N, 17.69.
1
2-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-6,7-dimethoxy-
3-phenylquinazolin-4(3H)-one (4k). Light yellow solid, dec ¼ 232–235 ꢀC. IR
(KBr) (tmax=cmꢂ1): 1685, 1612, 1546, 1499. 1H NMR (300 MHz, DMSO-d6):
dH ¼ 8.81 (s, 1H), 7.86–7.89 (d, J ¼ 6.8 Hz, 2H), 7.61–7.64 (d, J ¼ 7.3 Hz, 2H),
7.49–7.55 (m, 3H), 7.20–7.49 (m, 4H), 4.51 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H). 13C
NMR (75 MHz, DMSO-d6): dC ¼ 160.6, 155.5, 154.7, 148.5, 144.2, 144.0, 136.4,
135.7, 133.4, 130.3, 129.9, 122.8, 122.1, 112.7, 107.7, 106.8, 56.7, 56.2, 26.9. Anal.
calcd. for C25H20ClN5O3S: C, 59.34; H, 3.98; N, 13.84. Found: C, 60.86; H, 3.99;
N, 13.85.
6,7-Dimethoxy-2-((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-
phenylquinazolin-4(3H)-one (4l). Yellow solid, dec ¼ 178–182 ꢀC. IR (KBr)
1
(tmax=cmꢂ1): 1678, 1612, 1548, 1496. H NMR (300 MHz, DMSO-d6): dH ¼ 8.99
(s, 1H), 8.62 (s, 1H), 8.12–8.34 (m, 3H), 7.21–8.33 (m, 7H), 4.52 (s, 2H), 3.90 (s,
3H), 3.82 (s, 3H). 13C NMR (75 MHz, DMSO-d6): dC ¼ 160.5, 155.4, 154.6, 148.5,
144.4, 144.2, 136.2, 135.6, 133.4, 130.4, 130.0, 129.0, 126.5, 125.9, 123.6, 123.1,
112.7, 107.6, 106.1, 56.5, 56.2, 26.9. Anal. calcd. for C25H20N6O5S: C, 58.13; H,
3.90; N, 16.27. Found: C, 58.07; H, 4.11; N, 16.32.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of
Shahid Beheshti University and the Catalyst Center of Excellence (CCE).
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