CuBr-catalysed one-pot multicomponent synthesis of 3-substituted 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives

Article abstract of DOI:10.1002/aoc.4635

A novel methodology is presented for the synthesis of 3-substituted 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives based on an efficient tandem multicomponent reaction using copper bromide as catalyst. This methodology is based on the multicomponent one-pot reaction of methyl 2-bromobenzoate, phenylisothiocyanate derivatives and sodium azide in the presence of copper bromide and l-proline under basic conditions. To show the generality of the method, various phenylisothiocyanates bearing electron-donating or electron-withdrawing functionalities were used and the desired products were obtained in high isolated yields.

Full text of DOI:10.1002/aoc.4635

Received: 19 June 2018
DOI: 10.1002/aoc.4635
Revised: 11 September 2018
Accepted: 18 September 2018
F U L L P A P E R
CuBr‐catalysed one‐pot multicomponent synthesis of
3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one
derivatives
Mohammad Hosein Sayahi1 | Seyyed Jafar Saghanezhad2
Mohammad Mahdavi4
| Saeed Bahadorikhalili3 |
1 Department of Chemistry, Payame Noor
A novel methodology is presented for the synthesis of 3‐substituted 2‐thioxo‐
2,3‐dihydroquinazolin‐4(1H)‐one derivatives based on an efficient tandem mul-
ticomponent reaction using copper bromide as catalyst. This methodology is
based on the multicomponent one‐pot reaction of methyl 2‐bromobenzoate,
phenylisothiocyanate derivatives and sodium azide in the presence of copper
bromide and L‐proline under basic conditions. To show the generality of the
method, various phenylisothiocyanates bearing electron‐donating or electron‐
withdrawing functionalities were used and the desired products were obtained
in high isolated yields.
University (PNU), PO Box 19395‐3697,
Tehran, Iran
2 ACECR‐Production Technology
Research Institute, Ahvaz, Iran
3 Iranian Space Research Center, Institute
of Mechanics, Shiraz, Iran
4 Endocrinology and Metabolism Research
Center, Endocrinology and Metabolism
Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran
14176, Iran
Correspondence
KEYWORDS
Mohammad Hosein Sayahi, Department
of Chemistry, Payame Noor University
(PNU), PO Box 19395‐3697, Tehran, Iran.
Email: sayahymh@pnu.ac.ir
2‐thioxoquinazolinone, CuBr, methyl 2‐bromobenzoate, multicomponent reaction, one‐pot reaction
Mohammad Mahdavi, Endocrinology and
Metabolism Research Center,
Endocrinology and Metabolism Clinical
Sciences Institute, Tehran University of
Medical Sciences, Tehran 14176, Iran.
Email: momahdavi@sina.tums.ac.ir
1 | INTRODUCTION
and JNK inhibitors.[9] They also are novel orally active
5‐HT3 antagonists[10] and thymidylate synthase inhibi-
Quinazolinone and its derivatives have attracted interest
due to their unique biological properties, which have
led to their wide applications in research and clinical
treatment. The valuable properties of quinazolinone
derivatives, such as antitumour,[1] anticonvulsant,[2]
anti‐inflammatory[3] and epidermal growth factor recep-
tor tyrosine kinase inhibitory activities,[4] have attracted
a great deal of attention. Also, they have been well known
as peptidomimetic scaffolds.[5] These compounds also
exhibit various biological and medicinal activities such
as antihypertensive activity[6] and act as melatonin MT1
and MT2 receptor agonists,[7] Rho‐kinase inhibitors[8]
tors,[11] and are applied for the treatment of stomach
tumours and diseases of human brain cells.[12,13]
Quinazolinone derivatives also have good cytotoxic
activity.[14]
Regarding the outstanding biological activities of
quinazolinones, finding a synthetic method for these
compounds that is efficient, simple and fast has become
a challenge for researchers.[15,16] A very common strategy
for the synthesis of quinazolinone derivatives is the
reaction of aldehydes with aminobenzoic acid derivatives
such as 2‐aminobenzamide,[17,18] 2‐aminobenzonitrile[19]
and 2‐aminobenzoic acid.[20] Reactions of 2‐
Appl Organometal Chem. 2018;e4635.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
1 of 8
https://doi.org/10.1002/aoc.4635

2 of 8
SAYAHI ET AL.
aminobenzamide with primary alcohols in the presence
of Pt[21] and Pd[22] catalysts have also been reported for
the synthesis of quinazolinones. In addition, 2‐
halobenzamide[23,24] and 2‐haloaniline[25] derivatives
have been used for this synthesis. Among various
quinazolinone derivatives, 3‐substituted 2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐ones are significant, due to
their wide biological activities. Regarding their impor-
tance from pharmaceutical, industrial and synthetic
points of view, a number of synthetic pathways have been
reported for the preparation of this class of com-
pounds.[26–28] Regarding the importance of this family of
organic compounds, developing a method that is simple,
efficient, high‐yielding and environmentally friendly is
an aim.
Tandem reactions are regarded as very efficient for
the synthesis of complex organic compounds.[29–32] Tan-
dem reactions have attracted interest; using these
methods, the number of laboratory operations will be
decreased, which leads to a decrease in time, chemicals
and solvents.[33–36] Several catalysts are used in tandem
reactions to increase the reaction efficiency and the yields
of products. Among various catalysts, copper is widely
used due to its unique properties, such as high efficiency,
sufficient activity and simple applicability.[37–39]
L‐proline. For obtaining the optimal reaction conditions,
the reaction of phenylisothiocyanate with other species
was selected as the model reaction and the effect of the
different variables on the isolated yields of the desired
product was investigated. For this purpose, the reaction
was performed in various solvents to find the best solvent
for the reaction. It is proposed that the ligand has a key
role in the mechanism of the reaction. Therefore, four dif-
ferent ligands were also applied and the effect of the
ligands on the isolated yields of the products was studied.
The structures of the different ligands are shown in
Scheme 2. Finally, the reaction was performed at various
temperatures and the effect of temperature on the reac-
tion was investigated.
The results in Table 1 show that the best solvent for
the reaction performance is dimethylsulfoxide (DMSO).
SCHEME 2 Structures of ligands
TABLE 1 Investigation of various conditionsa
Extending the chemistry of quinazolinone and its
derivatives[40–46] and the use of copper as catalyst in the
reactions[47–50] have been a goal of our research group.
Following our ongoing efforts for the synthesis of
quinazolinone derivatives, herein we report a method
for the synthesis of 3‐substituted 2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one derivatives based on a tan-
dem reaction through the reaction of methyl 2‐
bromobenzoate, phenylisothiocyanate and sodium azide
in the presence of copper bromide and L‐proline
(Scheme 1).
Temperature
(°C)
Yield
(%)b
Entry Catalyst Ligand Solvent
1
2
3
4
5
6
7
CuI
L‐1
L‐1
L‐1
L‐1
L‐1
L‐1
L‐1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
70
70
70
70
70
70
60
71
24
CuBr
CuCl
Cu2O
CuO
Trace
Trace
Trace
No
CuBr2
CuCl2
reaction
8
Cu
L‐1
DMF
70
Trace
(OAc)2
2 | RESULTS AND DISCUSSION
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
L‐2
L‐3
L‐4
L‐1
L‐1
L‐1
L‐1
L‐1
L‐1
DMF
DMF
DMF
70
70
70
17
10
11
12
13
14
15
16
17
25
As can be seen in Scheme 1, 3‐substituted 2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one derivatives have been
prepared in one step from the reaction of the correspond-
ing methyl 2‐bromobenzoate, phenylisothiocyanate and
sodium azide in the presence of copper bromide and
20
DMSO 70
64
THF
DCE
70
70
32
Trace
Trace
56
Toluene 70
DMSO 55
DMSO 85
78
aReaction
conditions:
methyl
2‐bromobenzoate
(1
mmol),
phenylisothiocyanate(1 mmol), sodium azide (1 mmol), copper catalyst
(0.05 mmol), K2CO3 (0.5 mmol), ligand (0.1 mmol) and solvent (3 ml).
bIsolated yield.
SCHEME
dihydroquinazolin‐4(1H)‐one
1
Synthesis
of
3‐substituted
2‐thioxo‐2,3‐

SAYAHI ET AL.
3 of 8
In other solvents such as dimethylformamide (DMF), tol-
uene and dichloroethane, the reaction leads to lower iso-
lated yields. The reaction was conducted in the presence
of various copper catalytic agents. Various Cu(I) and Cu
(II) reagents were applied as catalysts. Cu(II) agents did
not produce the desired product and no activity in the
reaction was observed (Table 1, entries 5–8). Using
Cu(I) halides led to desired products, but the best isolated
yield was observed in the presence of CuBr. Use of vari-
ous ligands also produced the desired 3‐phenyl‐2‐thioxo‐
2,3‐dihydroquinazolin‐4(1H)‐one, but the highest isolated
yield was obtained when L‐proline was used as the ligand
in the reaction.
substrates under the optimal reaction conditions. As is evi-
dent, a wide range of phenylisothiocyanate derivatives can
efficiently produce the desired 3‐substituted 2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐ones using this methodology.
Phenylisothiocyanates possessing electron‐rich as well as
electron‐poor substituents underwent the reaction with
methyl 2‐bromobenzoate and sodium azide in the pres-
ence of copper bromide and L‐proline in DMSO. The struc-
tures of the synthesized products as well as the
corresponding isolated yields of the desired 3‐substituted
2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐ones are presented
in Table 2.
For a better insight into the reaction performance, a
possible mechanism is suggested, which is shown in
Scheme 3. In the suggested mechanism, sodium azide
reacts with methyl 2‐bromobenzoate in the presence of
activated copper bromide with L‐proline as ligand, to
form methyl 2‐azidobenzoate (5). Afterwards, the azide
We investigated the scope of the multicomponent syn-
thesis of 3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐
4(1H)‐one derivatives under the optimized conditions. As
evident from Table 2, the corresponding products were
obtained in moderate to good yields for various examined
TABLE 2 Substrate scope explorationa
Entry
Compound
4a
Product
Yield (%)b
1
73
2
3
4b
4c
75
71
4
5
6
4d
4e
4f
75
70
69
(Continues)

4 of 8
SAYAHI ET AL.
TABLE 2 (Continued)
Entry
Compound
4g
Product
Yield (%)b
7
61
8
9
4h
4i
74
76
10
11
12
13
4j
4k
4l
75
69
70
68
4m
14
4n
74
aReaction conditions: methyl 2‐bromobenzoate (1 mmol), phenylisothiocyanate (1 mmol), sodium azide (1 mmol),CuBr (0.05 mmol), K2CO3 (0.5 mmol), L‐pro-
line (0.1 mmol) and DMSO (3 ml).
bIsolated yield.
group is reduced to amine in the presence of copper cat-
alyst and water. A nitrogen molecule is released from this
step and methyl 2‐aminobenzoate (6) is formed. In the
next step, methyl 2‐(3‐phenylthioureido)benzoate (7) is
prepared from the reaction of methyl 2‐aminobenzoate
and phenylisothiocyanate (3). Finally, an intermolecular
reaction between the amine and the carbonyl group leads
to the product (4).
3 | CONCLUSIONS
In summary, we have developed an efficient method for
the synthesis of 3‐substituted 2‐thioxo‐2,3‐
SCHEME 3 Proposed mechanism for synthesis of 3‐substituted
2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one

SAYAHI ET AL.
5 of 8
dihydroquinazolin‐4(1H)‐one derivatives. This methodol-
ogy is based on the tandem and multicomponent reaction
of methyl 2‐bromobenzoate, phenylisothiocyanate and
sodium azide in the presence of copper bromide as cata-
lyst and L‐proline as ligand in DMSO as solvent.
Performing the model reaction under various conditions
showed that the best yields can be obtained when L‐pro-
line is applied as ligand and DMSO is used as solvent at
125.8, 126.5, 128.9, 131.5, 134.4, 148.8, 152.4, 162.3. MS
(70 eV): m/z = 297.09 (M+).
4.2.2 | 3‐(2‐Methoxyphenyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4b)
White solid; m.p. 213–215°C. IR (KBr, ν, cm−1): 3312,
1
3025, 1669, 1537, 1484. H NMR (500.1 MHz, DMSO‐d6,
85°C. Performing
the reaction
with various
δ, ppm): 3.88 (3H, s, OCH3), 7.08 (1H, t, J = 7.0 Hz),
7.19 (1H, d, J = 8.5 Hz), 7.50–7.55 (2H, m), 7.70 (1H, d,
J = 8.0 Hz), 7.49 (1H, d, J = 7.5 Hz), 7.82 (1H, t,
J = 7.5 Hz), 8.16 (1H, d, J = 7.5 Hz), 12.00 (1H, s, NH).
13C NMR (125.8 MHz, DMSO‐d6, δ, ppm): 55.7, 111.8,
120.3, 120.9, 122.5, 125.7, 126.4, 127.3, 130.3, 132.1,
134.2, 148.9, 152.2, 157.1, 161.1. MS (70 eV):
m/z = 284.06 (M+).
phenylisothiocyanate derivatives with different electron‐
donating or electron‐withdrawing functionalities resulted
in products in high yields. This method is simple and effi-
cient, and no tedious purification steps are needed for
product isolation. In addition, the tandem‐type reaction
that is used in this method for the synthesis of 3‐
substituted
2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one
derivatives makes this an efficient method for the synthe-
sis of desired products.
4.2.3 | 3‐(4‐Methoxyphenyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4c)
4 | EXPERIMENTAL
White solid; m.p. 245–247°C. IR (KBr, ν, cm−1): 3310,
3028, 1671, 1535, 1487. H NMR (500.1 MHz, DMSO‐d6,
4.1 | General procedure for preparation of
3‐substituted
1
δ, ppm): 3.85 (s, 3H), 7.08 (d, J = 8.5 Hz, 2H), 7.49 (t,
J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.79 (t,
J = 7.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 8.21 (d,
J = 8.5 Hz, 2H), 12.33 (s, 1H). 13C NMR (125.8 MHz,
DMSO‐d6, δ, ppm): 55.4, 114.0, 120.7, 124.8, 125.7,
126.0, 127.2, 129.4, 134.4, 148.9, 151.9, 161.8, 162.2. MS
(70 eV): m/z = 284.06 (M+).
2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one
derivatives
A solution containing methyl 2‐bromobenzoate (1 mmol),
NaN3 (1 mmol), CuBr (0.05 mmol), K2CO3 (0.5 mmol)
and L‐proline (0.1 mmol) in dry DMSO (3 ml) was stirred
in a round‐bottom flask for 3 h at 85°C. Then,
phenylisothiocyanate (1 mmol) was added and stirred for
more 2 h. After reaction completion, monitored by TLC,
the reaction mixture was cooled to room temperature, and
water (20 ml) was added to quench the reaction. The prod-
uct was extracted with EtOAc (3 × 20 ml) and washed with
30% (v/v) NaCl solution, dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified
by column chromatography using petroleum ether–ethyl
acetate (3:1) as eluent to afford the pure product 4d.
4.2.4 | 3‐(2‐Methylphenyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4d)
White solid; m.p. 229–231°C. IR (KBr, ν, cm−1): 3247,
3028, 1668, 1623, 1527, 1490. 1H NMR (500.1 MHz,
DMSO‐d6, δ, ppm): 3.88 (s, 3H), 7.09 (t, J = 7.0 Hz, 1H),
7.10 (d, J = 8.5 Hz, 1H), 7.59–7.51 (m, 2H), 7.70 (d,
J = 8.0 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.81 (t,
J = 7.5 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 12.00 (s, 1H).
13C NMR (125.8 MHz, DMSO‐d6, δ, ppm): 55.8, 111.9,
120.4, 121.0, 122.6, 125.8, 126.5, 127.4, 130.4, 132.0,
134.2, 149.0, 152.3, 157.2, 161.1. MS (70 eV): m/
z = 268.06 (M+).
4.2 | Spectral data of products
4.2.1 | 3‐(4‐(Dimethylamino)phenyl)‐2‐
thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one (4a)
White solid; m.p. 217–219°C. IR (KBr, ν, cm−1): 3251,
3030, 1666, 1620, 1532, 1491. 1H NMR (500 MHz,
DMSO‐d6, δ, ppm): 3.03 (s, 6H), 6.80 (d, J = 8.5 Hz,
2H), 7.43 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H),
7.72 (t, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.12
(d, J = 8.5 Hz, 2H), 12.22 (s, 1H). 13C NMR (125.8 MHz,
DMSO‐d6, δ, ppm): 39.6, 111.4, 118.5, 120.3, 125.4,
4.2.5 | 3‐Phenyl‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4e)
White solid; m.p. 234–235°C. IR (KBr, ν, cm−1): 3247,
3031, 1664, 1622, 1530, 1488. 1H NMR (500 MHz,
DMSO‐d6, δ, ppm): 7.26–7.28 (m, 2H), 7.35 (t,
J = 7.8 Hz, 1H), 7.42–7.50 (m, 4H), 7.78 (td, J = 7.8,

6 of 8
SAYAHI ET AL.
1.1 Hz, 1H), 7.96 (dd, J = 8.0, 1.1 Hz, 1H), 13.03 (s, 1H).
13C NMR (125 MHz, DMSO‐d6, δ, ppm): 115.5, 116.2,
124.2, 127.5, 128.1, 128.9, 129.0, 135.4, 139.4, 139.7,
159.8, 175.1. MS (70 eV): m/z = 254.05 (M+).
10.90 (s, 1H). 13C NMR (125 MHz, DMSO‐d6, δ, ppm):
11.2, 20.1, 48.4, 114.6, 116.2, 125.0, 128.5, 135.3, 138.4,
159.6, 175.7. MS (70 eV): m/z = 220.07 (M+).
4.2.10 | 2,3‐Dihydro‐3‐isopropyl‐2‐
thioxoquinazolin‐4(1H)‐one (4j)
4.2.6 | 3‐(2‐Chlorophenyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4f)
White crystals; m.p. 204–205°C (202–204°C[45]). IR (KBr,
White solid; m.p. 246–247°C. IR (KBr, ν, cm−1): 3180,
3030, 1696, 1648, 1623, 1537, 1488. 1H NMR
(500.1 MHz, DMSO‐d6, δ, ppm): 7.50 (t, J = 8.0 Hz, 1H),
7.75–7.62 (m, 3H), 7.67 (d, J = 7.5 Hz, 1H), 7.71 (d,
J = 8.0 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 8.20 (d,
J = 8.0 Hz, 1H), 12.59 (s, 1H). 13C NMR (125.8 MHz,
DMSO‐d6, δ, ppm): 121.2, 125.7 (2C), 126.9, 127.1, 127.4,
129.5, 130.7, 131.4, 133.7, 134.4, 148.5, 152.1, 161.3. MS
(70 eV): m/z = 288.01 (M+).
ν, cm−1): 3188, 3054, 1691, 1628, 1625, 1535, 1481. H
1
NMR (500 MHz, DMSO‐d6, δ, ppm): 1.03 (d, J = 7.0 Hz,
6H, (CH3)2CHN), 6.06 (q, J = 7.0 Hz, 1H, (CH3)2CHN),
7.32 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.67
(td, J = 8.0, 1.3 Hz, 1H), 8.15 (dd, J = 8.0, 1.3 Hz, 1H),
12.87 (s, 1H, NH). 13C NMR (125 MHz, DMSO‐d6, δ,
ppm): 18.5, 52.5, 115.3, 116.7, 124.4, 126.9, 135.2, 138.8,
159.4, 175.2. MS (70 eV): m/z = 220.07 (M+).
4.2.11 | 3‐(2‐Chlorobenzyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4k)
4.2.7 | 3‐(4‐Chlorophenyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4g)
White crystals; m.p. 230–232°C (231–233°C[45]). IR (KBr,
1
White solid, m.p. 216–219°C. IR (KBr, ν, cm−1): 3172,
3032, 1687, 1209. 1HNMR (500 MHz, DMSO‐d6, δ,
ppm): 5.16 (s, 2H), 7.16–7.79 (m, 8H), 12.02 (s, 1H).
13CNMR (125 MHz, DMSO‐d6, δ, ppm): 46.4, 115.8,
122.4, 125.0, 126.7, 127.7, 130.6, 133.2, 134.5, 140.8,
145.8, 157.1, 172.3. MS (70 eV): m/z = 288.01 (M+).
ν, cm−1): 3182, 3033, 1690, 1620, 1540, 1488. H NMR
(500 MHz, CDCl3, δ, ppm): 5.88 (s, 2H, NCH2), 6.97 (d,
J = 7.5 Hz, 1H), 7.13–7.17 (m, 2H), 7.20 (t, J = 7.7 Hz,
1H), 7.36 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H),
7.70 (t, J = 7.7 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H), 10.12
(s, 1H, NH). 13C NMR (125 MHz, CDCl3, δ, ppm): 48.0,
114.4, 125.2, 125.9, 126.8, 128.2, 128.9, 129.7, 131.1,
132.9, 135.0, 135.8, 138.3, 159.5, 176.2. MS (70 eV):
m/z = 302.03 (M+).
4.2.8 | 3‐(4‐Fluorophenyl)‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4h)
White solid; m.p. 207–209°C. IR (KBr, ν, cm−1): 3182,
3028, 1697, 1647, 1621, 1535, 1482. 1H NMR
(500.1 MHz, DMSO‐d6, δ, ppm): 7.38 (t, J = 9.0 Hz, 2H),
7.52 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.83 (t,
J = 7.5 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.26 (dd,
J = 9.0, 5.5 Hz, 2H), 12.53 (s, NH, 1H). 13C NMR
4.2.12 | 3‐[(Furan‐2‐yl)methyl]‐2,3‐
dihydro‐2‐thioxoquinazolin‐4(1H)‐one (4l)
White crystals; m.p. 230–232°C (233–234°C[45]). IR (KBr,
ν, cm−1): 3246, 3044, 1658, 1621, 1533, 1488. H NMR
1
(500 MHz, DMSO‐d6, δ, ppm): 5.65 (s, 2H, NCH2), 6.34
(dd, J = 3.2, 0.7 Hz, 1H, furan), 6.37 (dd, J = 3.2,
1.8 Hz, 1H, furan), 7.34 (t, J = 7.5 Hz, 1H, H6), 7.39 (d,
J = 7.5 Hz, 1H, H8), 7.53–7.54 (m, 1H, furan), 7.73 (td,
J = 7.5, 1.3 Hz, 1H, H7), 7.97 (dd, J = 7.5, 1.3 Hz, 1H,
H5), 13.03 (s, 1H, NH). 13C NMR (125 MHz, DMSO‐d6,
δ, ppm): 42.2, 108.3, 110.5, 115.3, 115.7, 124.6, 127.3,
135.7, 136.0, 139.0, 142.0, 159.0, 175.0. MS (70 eV): m/z
(%) = 258.05 (M+).
2
(125.8 MHz, DMSO‐d6, δ, ppm): 115.4 (d, JC‐
= 22.6 Hz), 120.8, 125.7, 126.5, 127.1, 129.2, 130.1 (d,
F
3JC‐F
= 8.9 Hz), 134.4, 148.5, 151.3, 162.5 (d,
1JC‐F = 104.2 Hz), 164.9. MS (70 eV): m/z = 272.04 (M+).
4.2.9 | 3‐Propyl‐2‐thioxo‐2,3‐
dihydroquinazolin‐4(1H)‐one (4i)
White solid; m.p. 172–174°C. IR (KBr, ν, cm−1): 3190,
1
3052, 1699, 1648, 1626, 1535, 1481. H NMR (500 MHz,
4.2.13 | 3‐Benzyl‐2‐thioxo‐2,3‐
DMSO‐d6, δ, ppm): 1.04 (t, J = 7.5 Hz, 3H), 1.86 (sextet,
J = 7.5 Hz, 2H), 4.50 (t, J = 7.5 Hz, 2H), 7.23 (d,
J = 7.7 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.67 (td,
J = 7.7, 1.3 Hz, 1H), 8.15 (dd, J = 7.7, 1.3 Hz, 1H),
dihydroquinazolin‐4(1H)‐one (4m)
White solid; m.p. 245–246°C (247–248°C[45]), IR (KBr, ν,
cm−1): 3178, 3029, 1694, 1645, 1621, 1533, 1486. 1H

SAYAHI ET AL.
7 of 8
[12] S. H. Hwang, A. Rait, K. F. Pirollo, Q. Zhou, V. M. Yenugonda,
G. M. Chinigo, M. L. Brown, E. H. Chang, Mol. Cancer Ther.
2008, 7, 559.
NMR (500 MHz, DMSO‐d6, δ, ppm): 5.24 (s, 2H), 7.19–
7.27 (m, 7H), 7.74–781 (m, 2H), 12.01 (brs, 1H). 13C
NMR (125 MHz, DMSO‐d6, δ, ppm): 50.4, 116.3, 116.6,
124.9, 126.1, 127.8, 129.3, 140.8, 127.9, 135.8, 140.6,
159.7, 175.2. MS (70 eV): m/z = 268.07 (M+).
[13] M. A. DeJonge, H. Dumez, J. Verweij, S. Yarkoni, D. Snyder, D.
Lacombe, S. Marreaud, Eur. J. Cancer 2006, 42, 1768.
[14] G. Marzaro, A. Guiotto, A. Chilin, Expert Opin. Ther. Pat. 2012,
22, 223.
4.2.14 | 3‐(Pyridin‐2‐ylmethyl)‐2‐thioxo‐
2,3‐dihydroquinazolin‐4(1H)‐one (4n)
[15] L. He, H. Li, J. Chen, X. Wu, RSC Adv. 2014, 4, 12065.
[16] X. Yang, M. Wu, S. Sun, C. Huang, H. Guo, J. Wang, J. Lee, Y.
Xing, Mol. Divers. 2016, 20, 551.
White crystals; m.p. 262–264°C (265–268°C[45]). IR (KBr,
1
ν, cm−1): 3268, 3071, 1664, 1623, 1596, 1532, 1481. H
[17] R. J. Abdel‐Jalil, W. Voelter, M. Saeed, Tetrahedron Lett. 2004,
45, 3475.
NMR (500 MHz, DMSO‐d6, δ, ppm): 5.77 (s, 2H, NCH2),
7.22 (t, J = 7.5 Hz, 1H, H6), 7.27 (d, J = 7.2 Hz, 1H,
H30), 7.36 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H,
H8), 7.71 (t, J = 7.2 Hz, 1H, H40), 7.78 (t, J = 7.5 Hz,
1H, H7), 7.96 (d, J = 7.5 Hz, 1H), 8.41 (t, J = 7.2 Hz,
1H), 13.04 (s, 1H, NH). 13C NMR (125 MHz, DMSO‐d6,
δ, ppm): 50.0, 115.4, 115.7, 120.7, 121.9, 124.5, 127.4,
135.6, 136.5, 139.2, 148.8, 155.4, 159.4, 175.6. MS
(70 eV): m/z (%) = 269.06 (M+).
[18] M. Hour, L. Huang, S. Kuo, Y. Xia, K. Bastow, Y. Nakanishi, E.
Hamel, K. Lee, J. Med. Chem. 2000, 43, 4479.
[19] D. J. Connolly, D. Cusack, T. P. O'Sullivan, P. J. Guiry, Tetrahe-
dron 2005, 61, 10153.
[20] A. S. El‐Azab, M. A. Al‐Omar, A. Alaa, N. I. Abdel‐Aziz, A.
Magda, A. M. Aleisa, M. M. Sayed‐Ahmed, S. Abdel‐Hamide,
Eur. J. Med. Chem. 2010, 45, 4188.
[21] S. H. Siddiki, K. Kon, A. S. Touchy, K. Shimizu, Catal. Sci.
Technol. 2014, 4, 1716.
[22] M. Sharif, J. Opalach, P. Langer, P. Beller, X. Wu, RSC Adv.
2014, 4, 8.
ORCID
Seyyed Jafar Saghanezhad
9163-388X
http://orcid.org/0000-0001-
[23] W. Xu, Y. Jin, H. Liu, Y. Jiang, H. Fu, Org. Lett. 2011, 13, 1274.
[24] L. Xu, Y. Jiang, D. Ma, Org. Lett. 2012, 14, 1150.
[25] K. Natte, H. Neumann, X. Wu, Catal. Sci. Technol. 2015, 5,
4474.
REFERENCES
[26] M. Wang, G. Dou, D. Shi, J. Heterocycl. Chem. 2010, 47, 939.
[1] I. Al‐Suwaidan, A. Amer, M. Alanazi, A. M. Alaa, A.
Menshawy, A. S. El‐Azab, Bioorg. Med. Chem. Lett. 2013, 23,
3935.
[27] G. Dou, M. Wang, Z. Huang, D. Shi, J. Heterocycl. Chem. 2009,
46, 645.
[2] V. Jatav, P. Mishra, S. Kashaw, J. P. Stables, Eur. J. Med. Chem.
2008, 43, 1945.
[28] S. Allameh, M. M. Heravi, M. M. Hashemi, F. F. Bamoharram,
Chin. Chem. Lett. 2011, 22, 131.
[3] A. M. Alaa, L. A. Abou‐Zeid, K. Eldin, H. ElTahir, A.
Menshawy, A. Mohamed, A. El‐Enin, A. S. El‐Azab, Bioorg.
Med. Chem. 2016, 24, 3818.
[29] J. Zhou, Chem. Asian J. 2010, 5, 422.
[30] Z. J. Jia, H. Jiang, J. L. Li, B. Gschwend, Q. Z. Li, X. Yin, J.
Grouleff, Y. C. Chen, K. A. Jørgensen, J. Am. Chem. Soc.
2011, 133, 5053.
[4] J. B. Smaill, A. J. Gonzales, J. A. Spicer, H. Lee, J. E. Reed, K.
Sexton, I. W. Althaus, J. Med. Chem. 2016, 59, 8103.
[31] H. Pellissier, H. Pellissier, Tetrahedron 2013, 35, 7171.
[5] U. A. Kshirsagar, S. B. Mhaske, N. P. Argade, Tetrahedron Lett.
2007, 48, 3243.
[32] Y. B. Huang, J. Liang, X. S. Wang, R. Cao, Chem. Soc. Rev. 2017,
46, 126.
[6] V. Alagarsamy, U. S. Pathak, Bioorg. Med. Chem. 2007, 15,
[33] Y. Liu, J. P. Wan, Org. Biomol. Chem. 2011, 9, 6873.
[34] R. A. Bunce, Tetrahedron 1995, 51, 13103.
3457.
[7] A. Palomer, M. Príncep, A. Guglietta, Annu. Rep. Med. Chem.
2007, 42, 63.
[35] R. Yao, H. Liu, Y. Wu, M. Cai, Appl. Organometal. Chem. 2013,
27, 109.
[8] X. Fang, Y. T. Chen, E. H. Sessions, S. Chowdhury, T.
Vojkovsky, Y. Yin, J. R. Pocas, Bioorg. Med. Chem. Lett. 2011,
21, 1844.
[36] W. Fu, M. Zhu, G. Zou, Appl. Organometal. Chem. 2010, 24,
499.
[37] Z. M. Chen, W. Bai, S. H. Wang, B. M. Yang, Y. Q. Tu, F. M.
[9] M. E. Noble, J. A. Endicott, L. N. Johnson, Science 2004, 303,
Zhang, Angew. Chem. 2013, 125, 9963.
1800.
[38] S. Kamijo, Y. Sasaki, Y. Yamamoto, Tetrahedron Lett. 2004,
45, 35.
[10] A. Asagarasu, T. Matsui, H. Hayashi, S. Tamaoki, Y. Yamauchi,
K. Minato, M. Sato, J. Med. Chem. 2010, 53, 7549.
[11] D. S. Theti, V. Bavetsias, L. A. Skelton, J. Titley, D. Gibbs, G.
[39] Q. Cai, F. Zhou, T. Xu, L. Fu, K. Ding, Org. Lett. 2010, 13,
Jansen, A. L. Jackman, Cancer Res. 2003, 63, 3612.
340.

8 of 8
SAYAHI ET AL.
[40] M. Mahdavi, V. Lotfi, M. Saeedi, E. Kianmehr, A. Shafiee, Mol.
Divers. 2016, 20, 677.
[47] S. E. Sadat‐Ebrahimi, S. M. Haghayegh‐Zavareh, S.
Bahadorikhalili, A. Yahya‐Meymandi, M. Mahdavi, M. Saeedi,
Synth. Commun. 2017, 47, 2324.
[41] M. Mahdavi, R. Hassanzadeh, M. Soheilizad, S. Golshani, S.
Moghimi, L. Firoozpour, A. Shafiee, A. Foroumadi, Tetrahe-
dron Lett. 2016, 57, 3770.
[48] M. Mahdavi, H. Lijan, S. Bahadorikhalili, L. Ma'mani, P. R.
Ranjbar, A. Shafiee, RSC Adv. 2016, 6, 28838.
[49] S. Bahadorikhalili, L. Ma'mani, H. Mahdavi, A. Shafiee,
[42] Z. Arasteh‐Fard, K. A. Dilmaghani, M. Saeedi, M. Mahdavi, A.
Shafiee, Helv. Chim. Acta 2016, 99, 539.
Micropor. Mesopor. Mater. 2018, 262, 207.
[50] S. Bahadorikhalili, A. Ashtari, L. Ma'mani, P. R. Ranjbar, M.
Mahdavi, Appl. Organometal. Chem. 2018, 32, e4212.
[43] M. Mahdavi, M. Asadi, M. Saeedi, Z. Rezaei, H. Moghbel, A.
Foroumadi, A. Shafiee, Synlett 2012, 23, 2521.
[44] S. Bahadorikhalili, M. Mahdavi, L. Ma'mani, A. Shafiee, H.
How to cite this article: Sayahi MH,
Mahdavi, T. Akbarzadeh, New J. Chem. 2018, 42, 5499.
Saghanezhad SJ, Bahadorikhalili S, Mahdavi M.
CuBr‐catalysed one‐pot multicomponent synthesis
of 3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐
4(1H)‐one derivatives. Appl Organometal Chem.
2018;e4635. https://doi.org/10.1002/aoc.4635
[45] M. Asadi, A. Masoomi, S. M. Ebrahimi, M. Mahdavi, M. Saeedi,
A. Shafiee, A. Foroumadi, Monatsh. Chem. 2014, 145, 497.
[46] Z. Najafi, M. Saeedi, M. Mahdavi, R. Sabourian, M. Khanavi,
M. Barazandeh, F. M. Moghadam, Bioorg. Chem. 2016, 67, 84.