Conversion of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones to N(3)-unsubstituted 2-(het)arylquinazolin-4(3H)-ones by copper-mediated Pd-catalysed cross-coupling reactions

Article abstract of DOI:10.3987/COM-15-S(T)12

With the purpose of searching for new heterocyclic building blocks, a new method to access N(3)-unsubstituted 2-(het)arylquinazolin-4(3H)-ones from 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives was developed. The synthetic protocol was based on the copper-mediated palladium-catalysed cross-coupling reactions of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones with (het)arylstannanes or their S-benzylated derivatives with (het)arylboronic acids, using CuBr·Me₂S and CuMeSal as promoters, respectively. A similar transformation was applied for the preparation of 2-aryl[1]benzothieno[3,2-d]pyrimidin-4(3H)-ones.

Full text of DOI:10.3987/COM-15-S(T)12

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HETEROCYCLES, Vol. 93, No. 1, 2016
HETEROCYCLES, Vol. 93, No. 1, 2016, pp. 150 - 163. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 9th August, 2015, Accepted, 2nd October, 2015, Published online, 20th October, 2015
DOI: 10.3987/COM-15-S(T)12
CONVERSION OF 2-THIOXO-2,3-DIHYDROQUINAZOLIN-4(1H)-ONES
TO N(3)-UNSUBSTITUTED 2-(HET)ARYLQUINAZOLIN-4(3H)-ONES BY
COPPER-MEDIATED Pd-CATALYSED CROSS-COUPLING
REACTIONS
Vilija Kriščiūnienė,a Gita Matulevičiūtė,a Osvaldas Paliulis,a Patrick Rollin,b
and Algirdas Šačkusꢀa
a Institute of Synthetic Chemistry, Kaunas University of Technology, Radvilėnų pl.
b
19, LT-50254 Kaunas, Lithuania. Université d’Orléans et CNRS, ICOA, UMR
7311, BP 6759, F-45067 Orléans, France. E-mail: algirdas.sackus@ktu.lt
Dedicated to Professor Dr. Lutz F. Tietze on the occasion of his 75th birthday
Abstract – With the purpose of searching for new heterocyclic building blocks, a
new method to access N(3)-unsubstituted 2-(het)arylquinazolin-4(3H)-ones from
2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives was developed. The
synthetic protocol was based on the copper-mediated palladium-catalysed
cross-coupling reactions of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones with
(het)arylstannanes or their S-benzylated derivatives with (het)arylboronic acids,
using CuBr·Me2S and CuMeSal as promoters, respectively. A similar
transformation
was
applied
for
the
preparation
of
2-aryl[1]benzothieno[3,2-d]pyrimidin-4(3H)-ones.
INTRODUCTION
The quinazolin-4(3H)-one ring system is an important structural unit of many synthetically produced or
naturally occurring1,2 biologically active compounds, with some well-known drugs among them.3,4
Examples include the E-glucuronidase enzyme inhibitor 2-(3,4-dimethoxyphenyl)quinazolin-4(3H)-one
(1)5 and 2,3-disubstituted derivatives of quinazolin-4(3H)-one such as Diproqualone (2), which exhibits
sedative and analgesic properties,6 as well as Afloqualone (3), which is known for its muscle-relaxant
effects.7-9 Tiprinast (4), which is based on the isosteric thieno[2,3-d]pyrimidin-4(3H)-one ring system, is a
potent non-steroidal anti-allergy agent.10 Moreover, the [1]benzothieno[3,2-d]pyrimidin-4(3H)-one 5,
which is structurally related to compound 4
, has been screened as an inhibitor for the Pim family of kinases.11

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151
The most common approach for the construction of the quinazolin-4(3H)-one ring system is based on
cyclization reactions of various 2-aminobenzoic acid derivatives including 2-aminobenzamides.12,13 The
recent examples for the synthesis of 3-substituted quinazolin-4(3H)-ones from 2-aminobenzamides
comprise coupling the latter amide with benzaldehydes,5 acid chlorides,14 aryl halides in the presence of
isocyanide,15 and methylarenes.16 Another recently developed synthetic pathway is based on the
Pd-catalysed cyclization reaction of 2-halobenzoates with amidines.17
We have recently shown18,19 that N(3)-benzyl 2-substituted quinazolin-4(3H)-one derivatives easily form
with good yields when N(3)-benzyl 2-(benzylsulfanyl)quinazolin-4(3H)-ones are subjected to Suzuki-type
Liebeskind-Srogl copper 3-methylsalicylate (CuMeSal) mediated palladium-catalysed cross-coupling
reactions,20 while the corresponding Stille-type reactions with (het)aryl tri-n-butylstannanes, are
successfully completed in the presence of copper(I) thiophene-2-carboxylate (CuTC). However, the
presence of a benzyl substituent at the N(3) atom of the products obtained, potentially prevents further
functionalization of the heterocyclic system at this site of the molecule. Therefore, the main aim of the
present work was to develop a method to access N(3)-unprotected 2-(het)arylquinazolin-4(3H)-ones from
2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives. Such a synthetic protocol could also be useful in
the preparation of diverse fused-pyrimidine libraries,21,22 while it would provide a method for the
convenient conversion of the 2-thioxo-2,3-dihydroquinazolin-4(1H)-one structural unit to the
2-substituted quinazolin-4(3H)-one moiety.
OCH3
OCH3
F
N
N
CH3
OH
H2N
N
CH3
NH
N
N
OH
O
O
O
1
2
3
a b-glucuronidase inhibitor
Diproqualone
Afloqualone
HO
H
N
S
O
N
N
O
S
N
OH
N
CH3
H3C
H3C
O
O
N
NH
NH CH3
S
6
Altanserin
H3C
O
5
4
an inhibitor of Pim kinases
F
Tiprinast
Figure 1. Biologically active molecules derived from quinazolin-4(3H)-one and its thieno-analogues
It has to be mentioned that 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones are easily accessible compounds.

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HETEROCYCLES, Vol. 93, No. 1, 2016
Examples of their synthesis include the base-catalysed intramolecular cyclization of
2-[(carbamothioyl)amino]benzoates18 and 1-(2-haloaroyl)-3-aryl thioureas,23 the reaction of
2-aminobenzamides with phenyl isothiocyanate,24 or aromatic ring annulation onto 2-thiobarbituric acid.25
It was also shown that various derivatives of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one exhibit
interesting biological activities and have found practical applications as diacylglycerol kinases inhibitors26
and serotonin antagonists.27-29 For example, the [18F]-form of Altanserin 6 is the preferred radiotracer for
in vivo labelling of serotonin 2A receptors by positron emission tomography (PET).30
RESULTS AND DISCUSSION
The synthetic pathway for the preparation of the starting 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones 9a,b
is depicted in Scheme 1. The required precursor methyl 2-isothiocyanatobenzoate 8a was obtained in
good yield by reacting the corresponding methyl anthranilate 7a with thiophosgene as previously
reported.18 The 4-chloro derivative 8b was analogously prepared. Stirring of 8a,b in toluene saturated
with gaseous ammonia resulted in the formation of compounds 9a,b in 96% and 93% yield, respectively.
H
R
NH2
OMe
R
NCS
OMe
R
N
S
i
ii
NH
O
O
O
8a (93%)
8b (91%)
9a (96%)
9b (93%)
7a,b
a R = H;
b R = Cl
Scheme 1. Reagents and conditions: (i) CSCl2, CHCl3, NaHCO3, H2O, rt, 40 min, then corresponding
amine, rt, 8 h; (ii) NH3, toluene, pyridine, -34 C to rt, 2 bar, 1 h
Having the key precursor 9a in hand, we further tested its Suzuki-type cross-coupling under
Liebeskind-Srogl Pd-catalysed reaction conditions.20 4-Methoxyphenylboronic acid was selected as a
coupling counterpart, for the reason that the expected 2-(4-methoxyphenyl)quinazolin-4(3H)-one 10a is
known as a potent -glucuronidase enzyme inhibitor.5 However, the reaction of compound 9a with
4-methoxyphenylboronic acid in the presence of Pd(PPh3)4 as catalyst and CuMeSal as promoter 31 in
THF gave the target product 10a in only a low isolated yield of 18% (Table 1, entry 1). Heating of the
reaction mixture under microwave irradiation (MW) did not significantly improve the yield (Table 1,
entry 2).

HETEROCYCLES, Vol. 93, No. 1, 2016
153
Scheme 2. Reagents and conditions: see Table 1
Table 1. Pd-catalysed reaction conditions using various coupling agents
Entry
Starting
substrate
Coupling
counterpart
Reaction
Product
Yield
conditions*
1.
2.
i
18%
24%
9a
9a
10a
10a
ii
3.
4.
5.
i
i
i
96%
66%
73%
11a
11b
11a
10a
10b
10c
6.
7.
i
95%
97%
11a
11a
10d
10a
ii
8.
ii
ii
93%
49%
79%
29%
80%
91%
11a
11a
9a
10e
10f
10f
10f
10f
10g
9.
10.
11.
12.
13.
iii
iii
iv
iv
11a
11a
11a
*(i) Coupling counterpart (2.2 eqiv.), Pd(PPh3)4 (0.01 eqiv.), CuMeSal (2.2 eqiv.), THF, reflux, 48 h; (ii)
coupling counterpart (2.2 eqiv.), CuMeSal (2.2 eqiv.), Pd(PPh3)4 (0.01 eqiv.), THF, MW, 100 ºC, 1 h; (iii)
coupling counterpart (2.2 eqiv.), CuBr·Me2S (2.2 eqiv.), Pd(PPh3)4 (0.01 eqiv.), THF, reflux, 48 h; (iv)
coupling counterpart (2.2 eqiv.), CuBr·Me2S (2.2 eqiv.), Pd(PPh3)4 (0.01 eqiv.), THF, MW, 100 ºC, 1 h

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HETEROCYCLES, Vol. 93, No. 1, 2016
Next, we decided to activate the starting substrate by S-benzylation thereby forming the benzylsulfanyl
moiety as a more effective leaving group, which was the strategy used in our previous work on the arylation
of N(3)-protected 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones.18,19 However, it is worth noting that the
applicability of this two-step approach for the arylation of 9a,b was uncertain due to the recent findings of
Guillaumet et al. showing that the Suzuki-type Liebeskind-Srogl reaction of thiouracils with phenylboronic
acid provides a successful outcome only for the corresponding N(3)-protected substrates.32
To prepare the required starting N(3)-unprotected 2-(benzylsulfanyl)quinazolin-4(3H)-ones 11a,b as
coupling substrates, we investigated the reaction of compounds 9a,b with benzyl bromide. Recently,
Sanchez et al. reported that the reaction of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one 9a with benzyl
bromide in dry DMF in the presence of K2CO3 at rt afforded the S-benzylated product 11a.33 However, it
was previously reported by Yun et al. that a similar benzylation 9a, carried out in the presence of KOH,
provided
a
mixture
of
S-
and
N-benzylated
products.34
When
we
treated
7-chloro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one 9b with benzyl bromide according to Sanchez’s
protocol (DMF, K2CO3, rt),33 the formation of a complex mixture of S-monoalkylated, S/N-dialkylated and
S/O-dialkylated products (NMR spectroscopy data) took place, from which the required 11b could only be
separated in a poor yield of 3%. However, when replacing DMF by dioxane and using sodium hydride as
the base, the benzylation furnished 7-chloro-2-(benzylsulfanyl)quinazolin-4(3H)-one 11b as the sole
product in 96% isolated yield. Subsequently, compound 11a was similarly obtained in 97% yield.
Treatment of 2-(benzylsulfanyl)quinazolin-4(3H)-ones 11a,b with 4-methoxyphenylboronic acid in the
presence of Pd(PPh3)4 and CuMeSal in refluxing THF for 48 h, afforded the target compounds 10a,b in
96% and 66% yield, respectively (Table 1, entries 3 and 4). The coupling of 11a with 3-chlorophenyl-
and 2-naphthylboronic acids afforded 2-arylquinazolin-4(3H)-ones 10c and 10d (Table 1, entries 5 and 6).
An excellent yield (97%) of compound 10a was also obtained when the corresponding reaction mixture
was heated in a closed vessel at 100 C under MW irradiation, allowing the reaction time to be
significantly reduced (Table 1, entry 7).
Next, we explored the Pd-catalysed Suzuki-type coupling of 2-(benzylsulfanyl)quinazolin-4(3H)-one 11a
with 3- and 2-thienylboronic acids. The MW-assisted reaction of 11a with 3-thienylboronic acid was
carried out in analogous conditions to those for the aforementioned couplings with arylboronic acids and
furnished product 10e in 93% yield (Table 1, entry 8), while the reaction with 2-thienylboronic acid
afforded the target product 10f in only 49% yield (Table 1, entry 9). To increase the yield of 10f, we decided
to investigate cross-coupling reactions of substrates 9a and 11a with 2-(tributylstannyl)thiophene under
Stille reaction conditions. Guillaumet et al. have recently shown that 2-thiouracil derivatives displaying an
unprotected acyl thiourea moiety underwent a Stille-type palladium-catalysed cross-coupling with
(het)arylstannanes when copper(I) bromide-dimethyl sulphide complex (CuBr.Me2S) was used as

HETEROCYCLES, Vol. 93, No. 1, 2016
155
promoter.32 Indeed, treatment of substrate 9a with 2-(tributylstannyl)thiophene in the presence of
Pd(PPh3)4 and CuBr·Me2S as metal cofactor in refluxing THF gave the desired compound 10f with an
acceptable yield of 79% (Table 1, entry 10). The yield of the analogous coupling of the S-benzylated
substrate 11a was less than 30% (Table 1, entry 11), but it could be increased to 80% by MW irradiation
heating of the reaction mixture (Table 1, entry 12). The MW-assisted reaction of 11a with
tributylphenylstannane provided 2-phenylquinazolin-4(3H)-one 10g with a good yield of 91% (Table 1,
entry 13).
To estimate the synthetic versatility of those methods, we further moved our attention to a Suzuki arylation
of 2-thioxo-2,3-dihydro[1]benzothieno[3,2-d]pyrimidin-4(1H)-ones 14a,b. The starting compounds 12a
and 12b were obtained by reacting methyl 2-mercaptoacetate with 2-nitrobenzonitrile or
4-chloro-2-fluorobenzonitrile, respectively, according to published methods.11,35 The reaction of 12a with
thiophosgene in acetone as described in the literature36 gave 13a in 70% yield. However, when carried out
in the presence of NaHCO3 in a binary chloroform–water mixture, the reaction of 12a,b with thiophosgene
afforded the isothiocyanates 13a and 13b with yields of 88% and 79%, respectively. Treatment of 13a and
13b with ammonia under pressure in a mixture of pyridine and toluene at rt afforded the target compounds
14a,b in 91% and 89% yield, respectively.
R
R
R
H
N
NH2
OMe
S
i
NCS
OMe
ii
NH
S
S
S
O
O
O
12a,b
13a (88%)
13b (79%)
14a (91%)
14b (89%)
a R = H;
b R = Cl
R
R
OMe
N
O
SBn
N
O
iii
iv
NH
NH
S
S
15a (93%)
15b (91%)
16a (59%)
16b (51%)
Scheme 3. Reagents and conditions: (i) CSCl2, CHCl3, NaHCO3, H2O, rt, 24 h; (ii) NH3, pyridine,
toluene, -34 C to rt, 2 bar, 1 h; (iii) BnBr, NaH, dioxane, rt, 1 h; (iv) 4-methoxyphenylboronic acid,
Pd(PPh3)4, CuMeSal, THF, reflux, 48 h
The
conversion
of
compounds
14a,b
to
the
corresponding
2-aryl[1]benzothieno[3,2-d]pyrimidin-4(3H)-ones was tested using the synthetic protocol described above.

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HETEROCYCLES, Vol. 93, No. 1, 2016
Thioxo derivatives 14a,b were selectively alkylated to the corresponding S-benzyl derivatives 15a,b by
reaction with benzyl bromide in dioxane solution in the presence of NaH. The
2-(benzylsulfanyl)[1]benzothieno[3,2-d]pyrimidin-4(3H)-ones 15a,b were further submitted to the
cross-coupling reaction with 4-methoxyphenylboronic acid in the presence of Pd(PPh3)4 and CuMeSal in
refluxing THF (Scheme 3). Flash column chromatography purification of crude products was not feasible,
due to their low solubility in common organic solvents. However, pure target compounds 16a,b could be
readily obtained via sublimation under high vacuum.
In summary, we have demonstrated that N(3)-unsubstituted 2-arylquinazolin-4(3H)-ones can be directly
obtained from 2-thioxo-2,3-dihydroquinazolin-4(1H)ones in good to excellent yields by Stille-type
CuBr·Me2S promoted Liebeskind-Srogl reactions with (het)arylstannanes or by a two-step procedure via
their S-benzylated derivatives applying CuMeSal promoted Suzuki-type Liebeskind-Srogl reactions with
arylboronic acids. Selective S-benzylation of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones can be
performed with excellent yields by their reaction with benzyl bromide in dioxane in the presence of
sodium hydride.
EXPERIMENTAL
Uncorrected melting points (ºC) were determined using a Büchi Melting Point M-560 apparatus.
Elemental analysis was performed with an Exeter Analytical CE-440 elemental analyser. IR spectra (KBr
disk or neat) were measured on a Perkin-Elmer Paragon 1000 PC or a Bruker Vertex V70
spectrophotometer. NMR spectra were recorded on a 300 MHz Varian Unity Inova instrument, a 400
MHz Bruker Avance spectrometer or a 700 MHz Bruker Avance spectrometer using TMS as the internal
standard. Chemical shifts are reported in parts per million (ppm). Low-resolution mass spectra were
recorded on a Perkin-Elmer Micromass ZQ System apparatus for the positive chemical ionization (APCI)
mode, or a Shimadzu LCMS-2020 spectrometer for the positive electrospray ionization (ESI) mode.
High-resolution mass spectra (HRMS) were recorded with a Bruker microTOF-QIII spectrometer in the
ESI mode. Analytical thin layer chromatography (TLC) was performed on aluminum foil backed plates
(Merck Kieselgel 60 F254). Visualization of the compounds was effected by UV light (254 nm). Column
chromatography was performed using silica gel SI 60 (43-60 μm, E. Merck). Microwave reactions were
conducted using a CEM Discover Synthesis Unit (CEM Corp., Matthews, NC). The machine consists of a
continuous focused microwave power delivery system with operator-selectable power output from 0 to
150 W. The reaction was performed in glass vessels (capacity 10 mL) sealed with a septum. The pressure
was controlled by a load cell connected to the vessel. The temperature of the contents of the vessel was
monitored using a calibrated infrared temperature control mounted under the reaction vessel. All
experiments were performed using a stirring option whereby the contents of the vessel are stirred by

HETEROCYCLES, Vol. 93, No. 1, 2016
157
means of a rotating magnetic plate located below the floor of the microwave cavity and a Teflon coated
magnetic stirring bar in the vessel.
Starting Materials. Compounds 8a18, 12a,b11,35 and 13a18 were prepared according to previously
reported procedures. All other starting chemicals used in this study were commercially available.
Methyl 4-chloro-2-isothiocyanatobenzoate (8b). A solution of thiophosgene (0.84 mL, 11.03 mmol) in
CHCl3 (10 mL) was treated dropwise with a solution of NaHCO3 (0.72 g, 8.62 mmol) in water (5 mL)
over 30 min at room temperature. After 10 min vigorous stirring, a solution of methyl
5-chloroanthranilate (1.60 g, 8.62 mmol) in CHCl3 (15 mL) was added, followed by 8 h stirring at room
temperature. The workup consisted of a dilution with CHCl3 (50 mL) followed by washing sequentially
with water (250 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered,
and concentrated in vacuo. Purification by flash chromatography on silica gel (eluent: Hex/EtOAc 97:3)
1
provided product 8b (1.96 g, 91%) as white needles; mp 7578 ºC (EtOH). H NMR (300 MHz,
DMSO-d6):  3.88 (s, 3H, OCH3), 7.52 (dd, 1H, J = 1.8, 8.6 Hz, H-5), 7.35 (d, 1H, J = 1.8 Hz, H-3), 7.93
13
(d, 1H, J = 8.6 Hz, H-6). C NMR (75 MHz, DMSO-d6):  52.7 (OCH3), 124.6, 127.8, 127.9 (CH-Ar),
130.4, 132.7, 134.8 (CIV-Ar), 138.1 (C=S), 163.5 (C=O). IR (KBr): ν 3096, 2148 (NCS), 1710 (C=O),
1591, 1430, 1289, 1112 cm-1. MS (APCI): m/z 228 [M + H]+. Anal. Calcd for C9H6ClNO2S: C, 47.48; H,
2.66; N, 6.15. Found: C, 47.41; H, 2.77; N, 6.11.
2-Thioxo-2,3-dihydroquinazolin-4(1H)-one (9a). A solution of methyl 2-isothiocyanatobenzoate (8a)
(2.15 g, 11.16 mmol) in dry toluene (10 mL) and pyridine (1.35 mL, 16.74 mmol) was placed in a 15 mL
pressure tube (reactor) under argon atmosphere. After the solution was cooled to -34 ºC, ammonium gas
was added in excess at a rate that kept the solution below -34 ºC. The tube was carefully sealed, and the
solution was stirred at rt for 1 h (pressure 2 bar). The white precipitate obtained was collected by filtration,
washed with toluene, and recrystallized from MeOH to afford compound 9a (1.91 g, 96%) as white
needles; mp 296297 ºC (lit.37 mp 300 ºC).
7-Chloro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (9b). Prepared from isothiocyanate 8b (2.13 g,
9.35 mmol) as described for the preparation of 9a; yield 1.85 g (93%); white needles; mp 305306 ºC
(MeOH). 1H NMR (400 MHz, DMSO-d6):  7.327.36 (m, 2H), 7.91 (d, 1H, J = 8.3 Hz), 12.56 (br s, 1H,
13
NH), 12.72 (br s, 1H, NH). C NMR (100 MHz, DMSO-d6):  115.2, 115.3, 124.4, 128.9, 139.7, 141.3,
159.0 (C=O), 174.8 (C=S). IR (KBr): ν 3086 (br, 2NH), 1710 (C=O), 1618, 1561, 1426, 1289, 1166 cm-1.
Anal. Calcd for C8H5ClN2OS: C, 45.18; H, 2.37; N, 13.17. Found: C, 45.37; H, 2.39; N, 13.49.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (10a). Method A. Thermal heating. To a solution of 9a
(0.14 g, 0.79 mmol) or 11a (0.12 g, 0.45 mmol) in dry THF (6 mL), CuMeSal (0.37 g, 1.73 mmol or 0.21 g,
0.98 mmol, respectively) and p-methoxyphenylboronic acid (0.26 g, 1.73 mmol or 0.15 g, 0.98 mmol,

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HETEROCYCLES, Vol. 93, No. 1, 2016
respectively) were added. After stirring at rt for 10 min, tetrakis(triphenylphosphine) palladium (9 mg,
0.0079 mmol or 5 mg, 0.0045 mmol, respectively) was added, then the mixture was stirred under reflux for
48 h. After removal of the solvent in vacuo, the crude product was purified via column chromatography
(eluent: Hex/EtOAc 7:3). The obtained white solid was recrystallized from MeOH to afford compound 10a
(0.03 g, 18% or 0.11 g, 96%, respectively); white needles; mp 247248 ºC (lit.37 mp 245247 ºC).
Method B. Microwave heating. To a solution of compound 9a (0.12 g, 0.67 mmol) or compound 11a
(0.12 g, 0.45 mmol) in dry THF (6 mL), CuMeSal (0.32 g, 1.48 mmol or 0.21 g, 0.98 mmol, respectively)
and p-methoxyphenylboronic acid (0.22 g, 1.48 mmol or 0.15 g, 0.98 mmol, respectively) were added.
After stirring at rt for 10 min, tetrakis(triphenylphosphine) palladium (8 mg, 0.007 mmol or 5 mg,
0.0045 mmol, respectively) was added, then the mixture was heated in a microwave reactor at 100 °C for 1
h. After removal of the solvent in vacuo, the crude product was purified via column chromatography
(eluent: Hex/EtOAc 7:3). The obtained white solid was recrystallized from MeOH to afford compound 10a
(0.04 g, 24% or 0.11 g, 97%, respectively) as white needles.
7-Chloro-2-(4-methoxyphenyl)quinazolin-4(3H)-one (10b). This compound was prepared from 11b
(0.11 g, 0.37 mmol) in a similar manner as described for the preparation of 10a (method A); yield 0.07 g
1
(66%); white needles; mp 316317 ºC (MeOH); (lit.38 mp 310312 ºC). H NMR (300 MHz,
CDCl3:CF3COOD, 1:1):  3.78 (s, 3H, OCH3), 7.03 (d, 2H, J= 9.0 Hz), 7.55 (dd, 1H, J = 1.8 Hz, J = 8.6 Hz),
7.71 (d, 1H, J = 1.8 Hz), 8.85 (d, 2H, J = 9.0 Hz), 8.14 (d, 1H, J = 8.6 Hz), 11.57 (br s, 1H, NH). 13C NMR
(75 MHz, CDCl3:CF3COOD, 1:1):  56.3 (OCH3), 114.5, 116.0, 116.9 (2CH), 120.0, 129.8, 131.4 (2CH),
131.6, 138.9, 146.7, 157.4, 161.7, 168.1 (C=O). IR (Neat): ν 3173 (NH), 1664 (C=O), 1598, 1250, 1186
cm-1. MS (APCI): m/z 287 [M + H]+. Anal. Calcd for C15H11ClN2O2: C, 62.84; H, 3.87; N, 9.77. Found: C,
62.98; H, 3.90; N, 9.82.
2-(3-Chlorophenyl)quinazolin-4(3H)-one (10c). Prepared from 11a (0.16 g, 0.60 mmol) as described for
the preparation of 10a (method A); yield (0.11 g, 73%); white needles; mp 297300 ºC (lit.39 mp
297298 ºC). 1H NMR (700 MHz, DMSO-d6): δ 7.39 (d, 1H, J = 7.0 Hz), 7.66 (d, 1H, J = 7.0 Hz),
7.767.78 (m, 1H), 7.86 (t, 1H, J = 7.0 Hz), 8.09–8.14 (m, 1H), 8.15–8.17 (m, 2H), 8.25 (d, 1H, J = 2.1 Hz),
13
12.62 (s, 1H, NH). C NMR (176 MHz, DMSO-d6): δ 118.9, 126.3, 126.9, 128.0, 128.2, 129.2, 131.0,
131.9, 132.0, 135.2, 136.7, 149.0, 151.5, 160.2 (C=O). IR (KBr): ν 3162 (NH), 1678 (C=O), 1610, 1450,
1230 cm-1. HRMS (ESI): m/z [M + H]+ calcd for C14H10ClN2O: 257.0476, found: 257.0476.
2-(Naphthalen-2-yl)quinazolin-4(3H)-one (10d). Prepared from 11a (0.20 g, 0.74 mmol) as described
for the preparation of 10a (method A); yield 0.19 g (95%); pale yellow needles; mp 284.5285.4 ºC
1
(MeOH); (lit.40 mp 212 ºC). H NMR (700 MHz, DMSO-d6): δ 7.55 (t, 1H, J = 7.0 Hz), 7.62–7.66 (m,
2H), 7.80 (d, 1H, J = 7.0 Hz), 7.87 (t, 1H, J = 7.0 Hz), 8.01 (d, 1H, J = 7.0 Hz), 8.06–8.08 (m, 2H),

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159
8.18–8.19 (m, 1H), 8.32–8.33 (m, 1H), 8.82 (s, 1H), 12.66 (s, 1H, NH). 13C NMR (176 MHz, DMSO-d6):
δ 121.5, 125.0, 126.4 (2xCH), 127.1, 127.4, 128.0, 128.1, 128.6, 128.7, 129.4, 130.4, 132.8, 134.6, 135.1,
149.3, 152.7, 162.7 (C=O). IR (KBr): ν 3193 (NH), 1671 (C=O), 1603, 1562, 1470, 1305 cm-1. MS (ESI):
m/z 273 [M + H]+.
2-(Thiophen-3-yl)quinazolin-4(3H)-one (10e). Prepared from 11a (0.12 g, 0.45 mmol) as described for
the preparation of 10a (method B); yield 0.09 g (93%); pale yellow needles; mp 259261 ºC (MeOH). 1H
NMR (700 MHz, DMSO-d6): δ 7.50 (t, 1H, J = 7.0 Hz), 7.68–7.73 (m, 2H), 7.82 (t, 1H, J = 7.0 Hz), 7.88 (d,
1H, J = 7.0 Hz), 8.13 (d, 1H, J = 7.0 Hz), 8.60 (d, 1H, J = 1.7 Hz), 12.46 (s, 1H, NH). 13C NMR (176 MHz,
DMSO-d6): δ 121.0, 125.5, 126.4, 127.0, 127.4, 127.7, 128.6, 134.6, 135.4, 148.3, 148.9, 162.0 (C=O). IR
(KBr): ν 3172 (NH), 1669 (C=O), 1597, 1468, 1287 cm-1. HRMS (ESI): m/z [M + H]+ calcd for
C12H9N2OS: 229.0430, found: 229.0430.
2-(Thiophen-2-yl)quinazolin-4(3H)-one (10f). Method A. Prepared from 11a (0.12 g, 0.45 mmol) as
described for the preparation of 10a (method B); yield 0.50 g (49%); pale yellow needles; mp 285287 ºC
(MeOH); (lit.41 mp 275276 ºC).
Method B. To a solution of compound 9a (0.20 g, 1.12 mmol) or compound 11a (0.15 g, 0.56 mmol) in dry
THF (10 mL), CuBr·Me2S (0.51 g, 2.47 mmol or 0.25 g, 1.23 mmol, respectively) and
2-(tributylstannyl)thiophene (0.78 mL, 2.47 mmol or 0.39 mL, 1.23 mmol, respectively) were added. After
stirring at rt for 10 min, tetrakis(triphenylphosphine)palladium (13 mg, 0.011 mmol or 6 mg, 0.005 mmol,
respectively) was added, then the mixture was stirred under reflux for 48 h. After removal of the solvent in
vacuo, the crude product was purified via column chromatography (eluent: Hex/EtOAc 7:3 → 1:1). The
obtained white solid was recrystallized from MeOH to afford compound 10f (0.20 g, 79% or 0.04 g, 29%,
respectively).
Method C. To a solution of compound 11a (0.15 g, 0.56 mmol) in dry THF (10 mL), CuBr/Me2S (0.25 g,
1.23 mmol) and 2-(tributylstannyl)thiophene (0.39 mL, 1.23 mmol) were added. After stirring at rt for 10
min, tetrakis(triphenylphosphine) palladium (6 mg, 0.005 mmol) was added, then the mixture was heated in
a microwave reactor at 100 ºC for 1 h. After removal of the solvent in vacuo, the crude product was purified
via column chromatography (eluent: Hex/EtOAc 7:3 → 1:1). The obtained white solid was recrystallized
from methanol to afford compound 10f (0.10 g, 80%).
2-Phenylquinazolin-4(3H)-one (10g). Prepared from 11a (0.12 g, 0.45 mmol) as described for the
preparation of 10f (method B); yield 10g (0.09 g, 91%); white needles; mp 218222 ºC (MeOH); (lit.42 mp
220–222 ºC). The NMR data are in good agreement with the literature.37,42 HRMS (ESI): m/z [M + H]+
calcd. for C14H11N2O 223.0866, found 223.0866.
2-(Benzylsulfanyl)quinazolin-4(3H)-one (11a). To a solution of 2-thioxo-2,3-dihydroquinazolin-4(1H)-

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one (9a) (0.50 g, 2.81 mmol) in dry dioxane (12 mL) were added NaH (0.12 g, 3.09 mmol) and benzyl
bromide (0.33 mL, 0.48 g, 2.81 mmol) and the reaction mixture was stirred at rt for 1 h under argon
atmosphere. After removal of the solvent in vacuo, the crude was recrystallized from methanol to afford
compound 11a (0.73 g, 97%) as white needles; mp 216218 ºC (lit.34 mp 212213 ºC). 1H NMR (300
MHz, CDCl3:DMSO-d6, 1:1):  4.47 (s, 2H, SCH2), 7.187.39 (m, 4H, 7-H, Ar-H), 7.44 (d, 2H, J = 7.2
Hz, Ar-H), 7.55 (d, 1H, J = 8.1 Hz, 8-H), 7.577.74 (m, 1H, 6-H), 8.01 (d, 1H, J = 8.0 Hz, 5-H), 12.47
(br s, 1H, NH). 13C NMR (75 MHz, CDCl3:DMSO-d6, 1:1):  33.6 (SCH2), 99.4, 120.0, 125.3, 125.7,
125.9, 127.0, 128.2 (2CH), 128.9 (2CH), 134.2, 137.1, 148.2, 161.3 (C-2). IR (neat): ν 3156 (NH),
1666 (C=O) 1577, 1468, 1263, 1169 cm-1. MS (APCI): m/z 291 [M + Na]+. Anal. Calcd for C15H12N2OS:
C, 67.14; H, 4.51; N, 10.44. Found: C, 66.89; H, 4.67; N, 10.39.
2-(Benzylsulfanyl)-7-chloroquinazolin-4(3H)-one (11b). Prepared from 10b (0.20 g, 0.93 mmol) as
described for the preparation of 11a; yield 0.27 g (96%); white needles; mp 195196 ºC (MeOH). 1H NMR
(300 MHz, DMSO-d6):  4.48 (s, 2H, SCH2), 7.227.34 (m, 3H, Ar-H), 7.44 (dd, 1H, J = 2.0 Hz, J = 8.5 Hz,
6-H), 7.48 (d, 2H, J = 6.8 Hz, Ar-H), 7.65 (d, 1H, J = 2.0 Hz, 8-H), 8.00 (d, 1H, J = 8.5 Hz, 5-H), 12.73 (br
s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):  33.6 (SCH2), 118.8, 125.2, 125.9, 127.3, 128.1, 128.5
(2CH), 129.3 (2CH), 137.3, 139.2, 149.3, 157.2 (C=O), 160.6 (C-2). IR (neat): ν 3025 (NH), 1657 (C=O),
1604, 1572, 1446, 1261, 116 cm-1. MS (APCI): m/z 303 [M + H]+. Anal. Calcd for C15H11ClN2OS: C,
59.50; H, 3.66; N, 9.25. Found: C, 59.62; H, 3.91; N, 9.12.
Methyl 5-chloro-3-isothiocyanato[1]benzothiophene-2-carboxylate (13b). Prepared from 12b (0.20 g,
0.80 mmol) as described for the preparation of 8b. Purification of the crude product by flash
chromatography on silica gel (eluent: Hex/EtOAc 95:5) provided compound 13b (0.18 g, 79%) as white
needles; mp 146147 ºC (CHCl3). 1H NMR (300 MHz, DMSO-d6):  3.91 (s, 3H, CH3), 7.65 (dd, 1H, J=
2.1, 8.7 Hz, 6-H), 7.89 (d, 1H, J = 2.1 Hz, 4-H), 8.12 (d, 1H, J = 8.7 Hz, 7-H). 13C NMR (75 MHz,
DMSO-d6):  53.7 (CH3), 100.2, 122.4, 124.9, 126.3, 128.2, 129.7, 132.1, 135.6, 136.5 (C=S), 161.3
(C=O). IR (KBr): ν 2134 (NCS), 1721 (C=O), 1524, 1431, 1353, 1267, 1142 cm-1; MS (APCI): m/z 283.5
[M + H]+. Anal. Calcd for C11H6ClNO2S2: C, 46.56; H, 2.13; N, 4.94. Found: C, 46.73; H, 2.35; N, 4.89.
2-Thioxo-2,3-dihydro[1]benzothieno[3,2-d]pyrimidin-4(1H)-one (14a). Prepared from 13a (0.20 g,
0.80 mmol) as described for the preparation of 9a; yield 0.17 g (91%); white needles; mp 318319 ºC
(MeOH). 1H NMR (400 MHz, DMSO-d6):  7.547.60 (m, 1H, 8-H), 7.66 (t, 1H, J = 7.5 Hz, 7-H), 8.13 (d,
1H, J = 8.1 Hz, 9-H), 8.61 (d, 1H, J = 7.9 Hz, 6-H), 12.80 (br s, 1H, NH), 13.65 (br s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6):  115.0, 124.0 (2xC), 125.6, 127.9, 129.3, 140.4, 141.9, 157.2 (C=O), 175.1 (C=S).
IR (KBr): ν 3053 (NH), 1669 (C=O), 1556, 1181 cm-1. MS (APCI): m/z 235 [M + H]+. Anal. Calcd for
C10H6N2OS2: C, 51.26; H, 2.58; N, 11.96. Found: C, 50.98; H, 2.61; N, 11.65.

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8-Chloro-2-thioxo-2,3-dihydro[1]benzothieno[3,2-d]pyrimidin-4(1H)-one (14b). Prepared from 13b
(0.20 g, 0.71 mmol) as described for the preparation of 9a; yield 0.17 g (89%); white needles; mp > 320 ºC
(dec.). 1H NMR (400 MHz, DMSO-d6):  7.70 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz, 7-H), 8.19 (d, 1H, J = 8.8 Hz,
6-H), 8.76 (d, 1H, J = 2.0 Hz, 9-H), 12.86 (s, 1H, NH), 13.61 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
 99.5, 116.7, 123.4, 125.8, 129.3, 130.6, 138.9, 140.9, 157.1 (C=O), 175.1 (C=S). IR (KBr): ν 3377 (NH),
3046 (NH), 1682 (C=O), 1559, 1423, 1169, 1152 cm-1. MS (ESI): m/z 269 [M + H]+. Anal. Calcd for
C10H5ClN2OS2: C, 44.69; H, 1.88; N, 10.42. Found: C, 44.87; H, 1.93; N, 10.05.
2-(Benzylsulfanyl)[1]benzothieno[3,2-d]pyrimidin-4(3H)-one (15a). Prepared from 14a (0.20 g, 0.86
mmol) as described for the preparation of 11a; yield 0.26 g (93%); white needles; mp 280282 ºC (MeOH).
1H NMR (400 MHz, DMSO-d6):  4.60 (s, 2H, SCH2), 7.24 (t, 1H, J = 7.2 Hz, 7-H), 7.297.34 (m, 2H,
Ar-H), 7.54 (d, 2H, J = 7.3 Hz, Ar-H), 7.587.69 (m, 2H, Ar-H, 8-H), 8.12 (d, 1H, J = 7.7 Hz, 9-H), 8.32 (d,
1H, J = 7.2 Hz, 6-H), 13.11 (br s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):  34.0 (SCH2), 118.9, 120.0,
123.4, 123.9, 125.6, 127.3, 128.5 (2CH), 129.2 (2CH), 133.7, 137.5, 140.4, 152.4, 158.3, 158.4 (C-2). IR
(KBr): ν 3061 (NH), 1659 (C=O), 1538, 1211 cm-1. MS (APCI): m/z 325 [M + H]+, 347 [M + Na]+. Anal.
Calcd for C17H12N2OS2: C, 62.94; H, 3.73; N, 8.63. Found: C, 62.94; H, 3.91; N, 8.76.
2-(Benzylsulfanyl)-8-chloro[1]benzothieno[3,2-d]pyrimidin-4(3H)-one (15b). Prepared from 14b (0.20
g, 0.73 mmol) as described for the preparation of 11a; yield 0.24 g, (91%); white needles; mp 278281 ºC
(MeOH). 1H NMR (400 MHz, DMSO-d6):  4.62 (s, 2H, SCH2), 7.317.35 (m, 3H, Ar-H), 7.53 (d, 2H, J =
7.2 Hz, Ar-H), 7.70 (dd, 1H, J = 2.1 Hz, J = 8.7 Hz, 7-H), 8.19 (d, 1H, J = 8.7 Hz, 6-H), 8.30 (d, 1H, J = 2.1
Hz, 9-H), 13.17 (br s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):  34.5 (SCH2), 123.0, 126.3, 127.2, 127.8,
128.9 (2CH), 129.6 (2CH), 129.7, 131.1, 135.5, 137.8, 139.3, 151.8, 158.6, 159.1 (C-2). IR (KBr): ν
3061 (NH), 1673 (C=O), 1538, 1495, 1211, 1077 cm-1. MS (ESI): m/z 359 [M + H]+, 381 [M + Na]+. Anal.
Calcd for C17H11ClN2OS2: C, 56.90; H, 3.09; N, 7.81. Found: C, 57.20; H, 3.28; N, 7.63.
2-(4-Methoxyphenyl)[1]benzothieno[3,2-d]pyrimidin-4(3H)-one (16a). Prepared from 15a (0.11 g, 0.33
mmol) as described for the preparation of 10a (method A). The crude product was purified by sublimation
(200 oC, 0.2 mbar), then the obtained solid was recrystallized from MeOH; yield 0.06 g (59%); white
needles; mp 295297 ºC. 1H NMR (400 MHz, DMSO-d6):  3.87 (s, 3H, OCH3), 7.13 (d, 2H, J = 8.9 Hz,
2-H, 6-H), 7.597.69 (m, 2H, 7-H, 8-H), 8.16 (d, 1H, J = 7.5 Hz, 6-H), 8.28 (d, 2H, J = 8.9 Hz, 3-H, 5-H),
8.35 (d, 1H, J = 7.3 Hz, 9-H), 12.89 (br s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):  55.5 (OCH3), 114.1
(2CH), 120.0, 123.4, 123.9 (2CH), 124.4, 125.4, 129.1, 129.6, 134.3, 140.5, 153.3, 154.6, 159.1, 161.9
(C=O). IR (neat): ν 3152 (NH), 1662 (C=O), 1502, 1259, 1180 cm-1. HRMS [M + H]+ calcd for
C17H13N2O2S: 309.0692, found: 309.0695.

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8-Chloro-2-(4-methoxyphenyl)[1]benzothieno[3,2-d]pyrimidin-4(3H)-one (16b). Prepared from 15b
(0.10 g, 0.29 mmol) as described for the preparation of 10a (method A). The crude product was purified by
sublimation (200 oC, 0.2 mbar), then the obtained solid was recrystallized from MeOH; yield 0.05 g (51%);
white crystals. 1H NMR (300 MHz, DMSO-d6):  3.89 (s, 3H, OCH3), 7.15 (d, 2H, J = 8.9 Hz, 2-H, 6-H),
7.74 (dd, 1H, J = 2.2 Hz, J = 8.7 Hz, 7-H), 8.23 (d, 1H, J = 8.7 Hz, 6-H), 8.33 (d, 1H, J = 2.2 Hz, 9-H), 8.50
(d, 2H, J = 8.9 Hz, 3-H, 5-H), 12.91 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):  55.6 (OCH3), 114.2
(2CH), 120.4, 123.6, 123.6 (2CH), 124.0, 125.5, 129.2, 129.7, 134.4, 140.6, 153.3, 154.7, 159.2, 162.0
(C=O). IR (KBr): ν 3158 (NH), 1672 (C=O), 1579, 1263, 1186 cm-1; MS (APCI): m/z 343 [M + H]+. Anal.
Calcd for C17H11ClN2O2S: C, 59.56; H, 3.23; N, 8.17. Found: C, 59.89; H, 3.32; N, 8.01.
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