A simple one-pot synthesis of 2-substituted quinazolin-4(3 H)-ones from 2-nitrobenzamides by using sodium dithionite

Article abstract of DOI:10.1055/s-0033-1338854

A simple one-pot procedure for the preparation of 2-(het)arylquinazolin- 4(3H)-ones starting from readily available 2-nitrobenzamides and (het)aryl aldehydes is described. Sodium dithionite is used as the reducing agent for the nitro group, and its decomposition in situ in aqueous N,N-dimethylformamide leads to the final oxidation step that gives the desired heterocyclic compounds. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338854

PAPER
▌2043
paper
A Simple One-Pot Synthesis of 2-Substituted Quinazolin-4(3H)-ones from
2-Nitrobenzamides by Using Sodium Dithionite
One-Pot Synthesis of 2-Substituted Quinazolin-4(3H)-ones
Angel H. Romero, José Salazar, Simón E. López*
Laboratorio de Química Medicinal y Heterociclos, Departamento de Química, Edificio de Química y Procesos, Universidad Simón Bolívar,
Valle de Sartenejas, Apartado 89000, Baruta, Caracas 1080-A, Venezuela
Fax +58(212)9063961; E-mail: slopez@usb.ve
Received: 29.01.2013; Accepted after revision: 19.04.2013
availability of starting materials, the preparation of which
Abstract: A simple one-pot procedure for the preparation of 2-
can be laborious and time-consuming.
(het)arylquinazolin-4(3H)-ones starting from readily available 2-ni-
trobenzamides and (het)aryl aldehydes is described. Sodium dithi-
onite is used as the reducing agent for the nitro group, and its
decomposition in situ in aqueous N,N-dimethylformamide leads to
the final oxidation step that gives the desired heterocyclic com-
pounds.
2,3-Dihydroquinazolin-4(1H)-ones have also been syn-
thesized by a number of methods,31 but there are only a
few reports on their synthesis by one-pot proce-
dures.31c,g,h,n,o We therefore believed that it would be
worthwhile developing a concise, practical, and conve-
nient route to quinazolin-4(3H)-ones.
Sodium dithionite, a well-known reducing agent,32 has
been successfully used in the direct preparation of 2-aryl-
benzimidazoles by reduction of 2-nitroanilines in the
presence of benzaldehydes.33 This reaction is accelerated
by the addition of water.34
Key words: heterocycles, oxidations, dehydrogenations, reduc-
tions, amides, aldehydes
The quinazolin-4(3H)-one system1 has become an attrac-
tive core structure for the synthesis of new compounds
that exhibit interesting pharmacological properties.2–9
A
number of natural products, such as the alkaloids tryptan-
thrin (1)10 and deoxyvasicinone (2)11 and the antimalarials
febrifugine (3) and isofebrifugine (4),12,13 contain a quin-
azolin-4(3H)-one moiety (Figure 1).
We therefore sought a direct one-pot procedure for the
synthesis of 2-substituted quinazolin-4(3H)-one deriva-
Table 1 Optimization of the Conditions for the Preparation of
2-Phenylquinazolin-4(3H)-one (6a) from 2-Nitrobenzamide by Using
Sodium Dithionite
O
O
N
O
N
O
PhCHO
(1.2 equiv)
Na2S2O4
N
NH2
N
NH
2
O
air
1
NO2
5a
N
N
HO
N
O
O
O
6a
NH
HO
N
N
N
Entry Na2S2O4 Solvent
(equiv)
Temp Time Yield (%)
H
O
(°C)
(h)
of 6a
3
4
Figure 1
1
2
3.5
2.0
3.0
3.5
3.5
4.0
3.5
3.5
3.5
3.5
DMF
100
100
100
80
5
5
5
5
5
5
4
3
5
5
12
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
DMF–H2O (10:1)
10
Several reports describe methods for the preparation of
quinazolin-4(3H)-ones. These methods can be classified
on the basis of the starting aromatic materials that form
the A ring of the quinazolinone core. These include an-
thranilic acids,14–18 2-halobenzoic acids,19,20 acyl anthra-
nils or their derivatives,21,22 isatoic anhydride [3,1-
benzoxazine-2,4(1H)-dione],23 2-aminobenzamides,24–26
acylanilides,27 2-iodoanilines,28 or 2-halobenzamides29,30
(Scheme 1). Some of these methods suffer from problems
of low yields, long reaction times, harsh reaction condi-
tions, difficulties in workup, the use of expensive or envi-
ronmentally toxic catalysts, multistep procedures, or poor
3
70
4
40
5
90
79a
77
6
100
100
100
120
100
7
62b
47b
31c
78
8
9
10
a A similar yield (78%) was obtained when the reaction was carried
out under N2.
SYNTHESIS 2013, 45, 2043–2050
Advanced online publication: 14.06.2013
DOI: 10.1055/s-0033-1338854; Art ID: SS-2013-M0090-OP
© Georg Thieme Verlag Stuttgart · New York
b The 2,3-dihydroquinazolin-4(1H)-one intermediate 8a was detected
as a byproduct and removed by recrystallization (EtOH).
c Unreacted 2-nitrobenzamide was recovered.
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2044
A. H. Romero et al.
PAPER
1) R2CHO
2) CuCl2
CO2H
CO2H
NH2
NH
MeOH
+
MeO
R
NH2
CuI
CsCO3
CO2H
NR3
R2
R2NH2,
HC(OR)3
or HCO2H
+
CO2H
NH2
HY•H2N
X
O
R3NH2
HPA, MW
R1
O
FeCl3
CsCO3
CO2H
NH
R2
1) R2COCl
N
R1
CO2H
NH2
R1
CO2H
NH2
+
POCl3
2) R3NH2
H2N
R2
Br
NR3
DMF
EtOAc
mw
pyrrolidine
b
O
a
c
reflux
N
R2
CONHR3
O
CuI
K2CO3
NH
R3
+
R2
N
h
d
O
H2N
I
NH4OAc
HC(OEt)3
R1
A
B
N
O
CuBr
R2
CONH2
X
SiO2–H2SO4
K2CO3
R1
N
H
O
quinazolin-4(3H)-ones
+
H2N
R2
DMSO
air
e
g
f
CONH2
NH2
CONH2
Pd(OAc)2
Ph3P, CO
R2CHO
R1
R2CHO
NR3
I
NaHSO3
1) Pd(OAc)2
p-TsOH
CO, BQ
+
FeCl3•6H2O
NH2
Et3N
Cl
R2
H2O
NH2
R2
R1
CONH2
O
2) R3NH2
PCl3
Brönsted acid–IL
Cl
solvent free
N
O
+
H
R2
NH2
Scheme 1 General synthetic methods for the preparation of quinazolin-4(3H)-ones. a) Refs. 14–18; b) Refs. 19 and 20; c) Refs. 21 and 22; d)
Ref. 23; e) Refs. 24–26; f) Ref. 27; g) Ref. 28; h) Refs. 29 and 30.
tives by the reaction of 2-nitrobenzamides with aldehydes also proved to be useful for rapid and efficient synthesis
in the presence of sodium dithionite. The reaction condi- of the 6-pyrrolidino-2-aryl-quinazolin-4(3H)-ones 6t–u,
tions were optimized by studying the model reaction of 2- which are important cytotoxic antitumor compounds.24b,36
nitrobenzamide with benzaldehyde (Table 1). As shown,
Under aerobic conditions, sodium dithionite decomposes
water was required for optimal results at the temperatures
in water. This decomposition, which is accelerated at low-
tested. In the absence of water, the reaction gave a very
er pH values, generates sulfur dioxide (Scheme 2).38
low yield (12%) (entry 1). The chemical literature sug-
gests that at least two equivalents of water are required
NaHSO4 + NaHSO3
pH
Na2S2O4 + O2 + H2O
during the reduction of 2-nitroaryl amines by sodium di-
thionite,34 which clearly demonstrates that the reaction is
accelerated by the presence of water. Higher yields were
obtained with 3.5 equivalents of sodium dithionite at tem-
peratures of 90–100 °C for five hours (entries 2, 3, 5, and
10). Lower yields of the quinazolin-4(3H)-one were ob-
tained when the reaction time was reduced (entries 8 and
9). Higher temperatures probably led to decomposition of
the sodium dithionite in solution in the presence of water,
thereby diminishing its reducing power (entry 9).
3 SO2 + S + 2 H2O .
2 H2S2O4
Scheme 2 Decomposition of sodium dithionite in water under aero-
bic conditions with generation of sulfur dioxide in situ38
We therefore designed an experiment to examine the role
of sulfur dioxide in the formation of the 2-substituted
quinazolin-4(3H)-ones. An almost quantitative yield
(99%) (Table 3, entry 1) of the oxidation product 6k was
obtained in two hours when sulfur dioxide was bubbled
through a solution of the dihydro analogue 8k in 9:1 N,N-
dimethylformamide–water at 90 °C under aerobic condi-
tions. Control experiments without bubbling sulfur diox-
ide were carried out under air or under nitrogen at
atmospheric pressure. Virtually none of the compound 6k
was formed (entries 3 and 4). These experiments con-
firmed the role of sulfur dioxide as the dehydrogenating
agent.
Next we applied our optimized conditions in attempts to
the synthesize a series of 2-substituted quinazolin-4(3H)-
one derivatives 6a–w (Table 2). Aromatic aldehydes with
various electron-withdrawing or electron-donating groups
gave good yields of the corresponding 2-arylquinazolin-
4(3H)-ones (6a–k,m–r,t–w). The heteroaromatic 2-furyl
substituent was also successfully introduced (entry 18;
87% yield), but the aliphatic aldehyde propanal (entry 19)
failed to react, possibly because it might have been rapidly
reduced to the corresponding alcohol before it could react
with the 2-aminobenzamide intermediate.35 Our method
Synthesis 2013, 45, 2043–2050
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of 2-Substituted Quinazolin-4(3H)-ones
2045
Table 2 Results for One-Pot Syntheses of 2-Substituted Quinazolin-4(3H)-ones from 2-Nitrobenzamides by Using Sodium Dithionite
O
O
R1
Na2S2O4 (3.5 equiv)
R2CHO (1.2 equiv)
R1
NH2
NH
R2
NO2
5a–c
DMF–H2O (9:1)
90 °C, 5 h
N
6a–w
Entry
Product
R1
R2
Yield (%)
mp (°C) (Lit.)
1
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
79
70
69
75
84
92
90
82
65
72
73
234–235 (236–237)19
245–247 (247–248)30
260–262 (261–263)30
295–297 (299–301)30
264–266 (293–295)37a
>300 (296–297)37b
>300 (295–296)37b
292–294 (297–298)37c
208–209 (209–210)37b
209–211 (201–211)37b
242–244 (222–224)37c
–
2
4-MeOC6H4
4-Tol
3
4
4-ClC6H4
4-FC6H4
5
6
4-BrC6H4
3-BrC6H4
3-ClC6H4
3-MeOC6H4
3-Tol
7
6g
6h
6i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
6j
6k
6l
3-FC6H4
a
2-ClC6H4
2-MeOC6H4
2-HOC6H4
2,3-(MeO)2C6H3
3,4-(MeO)2C6H3
2-naphthyl
2-furyl
–
6m
6n
6o
6p
6q
6r
6s
66
79
66
70
76
87
201–203 (202–203)31m
>300 (301–302)37d
175–177 (177–179)37e
240–242 (240–242)37f
260–262 (212)37g
218–220 (218–220)17
–
b
Pr
–
6t
pyrrolidin-1-yl
3-MeOC6H4
3,4-(MeO)2C6H3
Ph
89
81
72
76
258–260 (261–263)24b
262–264 (263–264)24b
299–300 (295–296)30
>300
6u
6v
6w
pyrrolidin-1-yl
Cl
Cl
4-ClC6H4
a 2-(2-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (8l)37h was the sole product, even on extending the reaction time to 24 h.
b No quinazolinone product was detected; the reduced intermediate 2-aminobenzamide was recovered as the only product.
A possible mechanism for the one-pot reaction is shown quinazolin-4(3H)-one 6. A similar dehydrogenation pro-
in Scheme 3. The 2-nitro group of benzamide 5 is reduced cess has been observed in syntheses of several other het-
by the action of sodium dithionite in aqueous N,N-dimeth- erocycles by using sodium hydrogen sulfite.40,41
ylformamide to produce the 2-aminobenzamide interme-
diate 7. This reacts with the aldehyde (or more probably
its bisulfite adduct formed in situ) to give an imine-like in-
termediate that undergoes cyclization to the correspond-
In conclusion, we have developed an easy, practical, and
useful one-pot procedure for the preparation of 2-(het)ar-
ylquinazolin-4(3H)-one derivatives starting from readily
available 2-nitrobenzamides and aldehydes in the pres-
ing 2,3-dihydro 4(1H)-quinazolinone 8. The sulfur
ence of sodium dithionite. The method readily gives the
dioxide that is generated in situ might form the adduct 9
corresponding quinazolin-4(3H)-ones in good yields.
with the 2,3-dihydroquinazolin-4(1H)-one. Finally, this
adduct eliminates hyposulfurous acid to give the desired
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2043–2050

2046
A. H. Romero et al.
PAPER
further purification. 2-nitro-5-pyrrolidin-1-ylbenzamide (5b) and 2-
(3-fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (8k) were syn-
thesized according to the procedures described in the litera-
ture.24b,37c
Table 3 Study of the Dehydrogenation Reaction of a 2,3-Dihydro-
quinazolin-4(1H)-one Intermediate
O
O
NH
NH
2-Substituted Quinazolin-4(3H)-ones (6a–k,m–r,t–x); General
Procedure
F
F
DMF–H2O (9:1)
90 °C
N
H
N
A soln of the appropriate 2-nitrobenzamide 5 (1.0 mmol), substitut-
ed aldehyde (1.2 mmol), and Na2S2O4 (3.5 mmol) in 9:1 DMF–H2O
(3 mL) was stirred at 90 °C for 5 h then cooled to r.t. The mixture
was then poured into ice-water (10 mL) and the precipitated that
formed was collected by filtration, washed with cold water, dried
under vacuo, and crystallized (EtOH) when necessary.
6k
8k
Entry
Conditions
Time (h) Yield (%) of 6k
1
2
3
4
SO2, DMF–H2O (9:1), air a
2
3
3
3
99
99
–
a
SO2, DMF–H2O (9:1), N2
2-Phenylquinazolin-4(3H)-one (6a)
Pale-yellow solid; yield: 175 mg (79%); mp 234–235 °C (Lit.19
236–237 °C).
IR (KBr): 3310 (NH), 1660 (C=O) cm–1.
DMF–H2O (9:1), air
DMF–H2O (9:1), N2
–
1H NMR (400 MHz, DMSO-d6): δ = 12.55 (br s, 1 H, NH), 8.18 (m,
3 H, Ar-H), 7.85 (ddd, J = 1.5, 7.3, 7.7 Hz, 1 H, Ar-H), 7.75 (d,
J = 8.0 Hz, 1 H, Ar-H), 7.56 (m, 4 H, Ar-H).
a SO2 gas was generated by the reaction of Cu turnings with concd
H2SO4 in a separate vessel and continuously bubbled into the reaction
flask.39
13C NMR (68 MHz, DMSO-d6): δ = 163.0, 153.1, 149.1, 135.3,
133.2, 132.0, 129.2, 128.3, 127.8, 127.2, 126.4, 121.3.
O
O
Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C,
75.72; H, 4.49; N, 12.68.
Na2S2O4
DMF–H2O
R1
R1
NH2
NO2
NH2
NH2
reduction
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (6b)
Pale-yellow solid; yield: 177 mg (70%); mp 245–247 °C (Lit.30
247–248 °C).
IR (KBr): 3315 (NH), 1665 (C=O) cm–1.
5
7
CHO
R2
1H NMR (400 MHz, DMSO-d6): δ = 12.41 (br s, 1 H, NH), 8.19 (dd,
J = 2.0, 7.0 Hz, 2 H, Ar-H), 8.13 (dd, J = 1.1, 8.1 Hz, 1 H, Ar-H),
7.82 (ddd, J = 1.5, 7.7, 7.7 Hz, 1 H, Ar-H), 7.70 (dd, J = 1.1, 8.1 Hz,
1 H, Ar-H), 7.48 (ddd, J = 1.5, 7.7, 7.7 Hz, 1 H, Ar-H), 7.09 (dd,
J = 1.9, 7.0 Hz, 2 H, Ar-H), 3.85 (s, 3 H, OCH3).
O
O
R1
R1
in situ
SO2
NH
NH
oxidation
N
H
N
R2
R2
SO2H
13C NMR (68 MHz, DMSO-d6): δ = 163.0, 162.5, 152.7, 149.2,
9
8
135.2, 130.0, 127.6, 126.8, 126.4, 125.3, 121.1, 114.6.
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.36; H, 4.72; N, 11.18.
H2SO2
O
2-(4-Tolyl)quinazolin-4(3H)-one (6c)
Pale-yellow solid; yield: 163 mg (69%); mp 260–262 °C (Lit.30
261–263 °C).
IR (KBr): 3308 (NH), 1667 (C=O) cm–1.
R1
NH
N
R2
1H NMR (400 MHz, DMSO-d6): δ = 12.47 (br s, 1 H, NH), 8.14 (d,
J = 7.7 Hz, 1 H, Ar-H), 8.09 (d, JAB = 8.1 Hz, 2 H, Ar-H), 7.83 (dd,
J = 7.3, 7.3 Hz, 1 H, Ar-H), 7.72 (d, J = 7.7 Hz, 1 H, Ar-H), 7.51
(dd, J = 7.3, 7.3 Hz, 1 H, Ar-H), 7.35 (d, JAB = 8.1 Hz, 2 H, Ar-H),
2.39 (s, 3 H, CH3).
6
Scheme 3 Postulated pathway for the generation of 2-substituted
quinazolin-4(3H)-ones 6 by the reaction of 2-nitrobenzamide 5 with
(het)aryl aldehydes in the presence of sodium dithionite in aqueous
N,N-dimethylformamide
13C NMR (68 MHz, DMSO-d6): δ = 152.9, 149.4, 142.1, 135.1,
130.5, 129.8, 128.2, 127.8, 127.0, 126.4, 121.4, 21.5.
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.28; H, 5.15; N, 11.90.
Melting points were determined in duplicate using a Fischer-Johns
micro hot-stage apparatus and are uncorrected. IR spectra were re-
corded as KBr discs by using an FT-IR Nicolet Magna spectrome-
ter. 1H NMR spectra were recorded at 400 MHz on a JEOL Eclipse
spectrometer, and 13C NMR spectra were recorded at 68 MHz on an
Eclipse Plus spectrometer. DMSO-d6 was used as the solvent for all
NMR studies. Chemical shifts are reported in ppm relative to TMS
as an internal standard. Elemental analyses of synthesized com-
pounds were performed on a PerkinElmer 2400 CHN analyzer; re-
sults were within ±0.4% of the theoretical values. Silica gel plates
(ALUGRAM SIL G/UV254; Macherey-Nagel GmbH, Germany)
were used for TLC. Reagents were obtained from Aldrich (Milwau-
kee, MI, USA) or Merck (Darmstadt, Germany) and used without
2-(4-Chlorophenyl)quinazolin-4(3H)-one (6d)
Pale-yellow solid; yield: 193 mg (75%); mp 295–297 °C (Lit.30
299–301 °C).
IR (KBr): 3316 (NH), 1657 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.59 (br s, 1 H, NH), 8.16 (m,
3 H, Ar-H), 7.85 (ddd, J = 1.4, 7.5, 7.9 Hz, 1 H, Ar-H), 7.34 (d,
J = 8.0 Hz, 1 H, Ar-H), 7.62 (dd, J = 1.8, 8.4 Hz, 2 H, Ar-H), 7.54
(ddd, J = 1.4, 7.4, 8.0 Hz, 1 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ = 162.8, 152.0, 151.3, 149.0,
136.9, 135.2, 132.1, 130.2, 129.2, 127.9, 127.4, 126.4, 121.5.
Synthesis 2013, 45, 2043–2050
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 2-Substituted Quinazolin-4(3H)-ones
2047
Anal. Calcd for C14H9ClN2O: C, 75.66; H, 4.54; N, 12.60. Found:
C, 75.95; H, 4.60; N, 12.52.
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.50; H, 4.70; N, 11.04.
2-(4-Fluorophenyl)quinazolin-4(3H)-one (6e)
Pale-yellow solid; yield: 202 mg (84%); mp 264–266 °C (Lit.37a
293–295 °C).
2-(3-Tolyl)quinazolin-4(3H)-one (6j)
Pale-yellow solid; yield: 153 mg (65%); mp 209–211 °C (Lit.37b
201–211 °C).
IR (KBr): 3318 (NH), 1654 (C=O) cm–1.
IR (KBr): 3307 (NH), 1662 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.58 (br s, 1 H, NH), 8.25 (m,
2 H, Ar-H), 8.15 (dd, J = 1.5, 8.0 Hz, 1 H, Ar-H), 7.85 (ddd, J = 1.4,
7.5, 7.7 Hz, 1 H, Ar-H), 7.74 (d, J = 7.7 Hz, 1 H, Ar-H), 7.53 (ddd,
J = 1.4, 7.5, 7.7 Hz, 1 H, Ar-H), 7.39 (m, 2 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ = 166.5, 162.9, 152.1, 149.0,
135.2, 130.9 (d, J = 8.8 Hz, 1 C), 129.7, 127.8, 127.2, 126.4, 121.3,
116.1 (d, J = 22 Hz, 1 C).
1H NMR (270 MHz, DMSO-d6): δ = 12.35 (br s, 1 H, NH), 8.15 (d,
J = 7.7 Hz, 1 H, Ar-H), 8.03 (s, 1 H, Ar-H), 7.97 (d, J = 6.7 Hz, 1
H, Ar-H), 7.84 (dd, J = 7.5, 7.5 Hz, 1 H, Ar-H), 7.74 (d, J = 8.1 Hz,
1 H, Ar-H), 7.52 (dd, J = 7.5, 7.5 Hz, 1 H, Ar-H), 7.43 (m, 2 H, Ar-
H), 2.41 (s, 3 H, CH3).
13C NMR (68 MHz, DMSO-d6): δ = 162.8, 153.0, 149.3, 138.5,
135.1, 133.3, 132.5, 129.0, 128.8, 127.9, 127.0, 126.4, 125.4, 121.5,
21.5.
Anal. Calcd for C14H9FN2O: C, 69.99; H, 3.78; N, 11.66. Found: C,
70.09; H, 3.84; N, 11.71.
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.12; H, 5.07; N, 11.79.
2-(4-Bromophenyl)quinazolin-4(3H)-one (6f)
Pale-yellow solid; yield: 277 mg (92%); mp >300 °C (Lit.37b 296–
297 °C).
2-(3-Fluorophenyl)quinazolin-4(3H)-one (6k)
Pale-yellow solid; yield: 182 mg (76%); mp 222 °C (Lit.37c 267 °C).
IR (KBr): 3316 (NH), 1667 (C=O) cm–1.
IR (KBr): 3315 (NH), 1671 (C=O) cm–1.
1H NMR (270 MHz, DMSO-d6): δ = 12.47 (br s, 1 H, NH), 8.14 (m,
3 H, Ar-H), 7.83 (ddd, J = 1.2, 7.2, 7.2 Hz, 1 H, Ar-H), 7.74 (m, 3
H, Ar-H), 7.53 (ddd, J = 1.2, 7.2, 7.2 Hz, 1 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ = 162.7, 152.0, 149.1, 135.2,
132.5, 132.1, 130.3, 128.0, 127.3, 126.4, 125.7, 121.6.
1H NMR (400 MHz, DMSO-d6): δ = 12.55 (br s, 1 H, NH), 8.16 (d,
J = 7.3 Hz, 1 H, Ar-H), 8.03 (d, J = 7.3 Hz, 1 H, Ar-H), 7.98 (d,
J = 10.2 Hz, 1 H, Ar-H), 7.86 (dd, J = 7.3, 8.0 Hz, 1 H, Ar-H), 7.76
(d, J = 8.4 Hz, 1 H, Ar-H), 7.58 (m, 2 H, Ar-H), 7.44 (ddd, J = 2.6,
8.4, 8.8 Hz, 1 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ =162.8, 151.8, 148.8, 144.9,
139.1, 135.6, 135.4 (d, J = 7.3 Hz), 131.3 (d, J = 29.5 Hz), 128.1,
127.5, 126.4, 124.5, 121.6, 118.9, 118.6, 115.2, 114.9.
Anal. Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C,
55.96; H, 2.95; N, 9.35.
2-(3-Bromophenyl)quinazolin-4(3H)-one (6g)
Pale-yellow solid; yield: 195 mg (65%); mp >300 °C (Lit.37b 295–
296 °C).
Anal. Calcd for C14H9FN2O: C, 69.99; H, 3.78; N, 11.66. Found: C,
70.07; H, 3.84; N, 11.58.
IR (KBr): 3315 (NH), 1665 (C=O) cm–1.
2-(2-Methoxyphenyl)quinazolin-4(3H)-one (6m)
Pale-yellow solid; yield: 166 mg (66%); mp 201–203 °C (Lit.31m
202–203 °C).
IR (KBr): 3308 (NH), 1657 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.04 (br s, 1 H, NH), 8.15 (d,
J = 7.7 Hz, 1 H, Ar-H), 7.83 (ddd, J = 1.4, 7.7, 7.7 Hz, 1 H, Ar-H),
7.72 (m, 2 H, Ar-H), 7.54 (m, 2 H, Ar-H), 7.20 (d, J = 8.4, 1 H), 7.10
(dd, J = 7.7, 7.7 Hz, 1 H, Ar-H), 3.87 (s, 3 H, CH3).
13C NMR (68 MHz, DMSO-d6): δ = 183.0, 161.8, 157.8, 152.8,
149.5, 135.0, 132.9, 127.9, 127.1, 126.3, 123.1, 121.5, 121.1, 112.6,
56.5.
1H NMR (270 MHz, DMSO-d6): δ =12.49 (br s, 1 H, NH), 8.38 (s,
1 H, Ar-H), 8.17 (dd, J = 8.1, 8.1 Hz, 1 H, Ar-H), 7.79 (m, 3 H, Ar-
H), 7.51 (m, 3 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ =162.6, 151.5, 149.0, 135.5,
135.2, 134.6, 131.3, 130.9, 128.1, 127.4, 127.3, 126.4, 122.4, 121.7.
Anal. Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C,
55.94; H, 2.96; N, 9.38.
2-(3-Chlorophenyl)quinazolin-4(3H)-one (6h)
Pale-yellow solid; yield: 210 mg (82%); mp 292–294 °C (Lit.37c
297–298 °C).
IR (KBr): 3312 (NH), 1670 (C=O) cm–1.
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.33; H, 4.86; N, 11.03.
1H NMR (400 MHz, DMSO-d6): δ = 12.58 (br s, 1 H, NH), 8.24 (m,
1 H, Ar-H), 8.16 (m, 2 H, Ar-H), 7.85 (m, 1 H, Ar-H), 7.76 (m, 1 H,
Ar-H), 7.65 (d, J = 8.8 Hz, 1 H, Ar-H), 7.57 (m, 2 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ = 162.7, 151.6, 148.9, 135.3,
135.2, 134.1, 131.7, 131.1, 128.1, 128.0, 127.5, 126.9, 126.4, 121.7.
2-(2-Hydroxyphenyl)quinazolin-4(3H)-one (6n)
Pale-yellow solid; yield: 188 mg (79%); mp >300 °C (Lit.37d 301–
302 °C).
IR (KBr): 3400 (OH), 1633 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.37 (s, 1 H, OH), 8.10 (m, 2
H, Ar-H), 7.83 (dd, J = 7.0, 8.0 Hz, 1 H, Ar-H), 7.71 (d, J = 7.0 Hz,
1 H, Ar-H), 7.52 (dd, J = 7.0, 8.0 Hz, 1 H, Ar-H), 7.43 (dd, J = 7.0,
8.0 Hz, 1 H, Ar-H), 6.97 (m, 2 H, Ar-H).
Anal. Calcd for C14H9ClN2O: C, 75.66; H, 4.54; N, 12.60. Found:
C, 75.57; H, 4.47; N, 12.68.
2-(3-Methoxyphenyl)quinazolin-4(3H)-one (6i)
Pale-yellow solid; yield: 184 mg (73%); mp 208–209 °C (Lit.37b
209–210 °C).
13C NMR (68 MHz, DMSO-d6): δ = 159.9, 134.6, 135.7, 134.3,
128.1, 127.7, 126.6, 126.3, 123.5, 120.8, 119.9, 118.4, 118.3, 114.5.
IR (KBr): 3310 (NH), 1663 (C=O) cm–1.
Anal. Calcd for C14H10N2O3: C, 70.58; H, 4.23; N, 11.76. Found: C,
70.45; H, 4.16; N, 11.65.
1H NMR (400 MHz, DMSO-d6): δ = 12.39 (br s, 1 H, NH), 8.16 (d,
J = 8.3 Hz, 1 H, Ar-H), 7.82 (m, 2 H, Ar-H), 7.75 (m, 2 H, Ar-H),
7.53 (dd, J = 7.7, 7.7 Hz, 1 H, Ar-H), 7.46 (dd, J = 7.7, 7.7 Hz, 1 H.
Ar-H), 7.15 (dd, J = 2.2, 7.7 Hz, 1 H, Ar-H), 3.87 (s, 3 H, OCH3).
13C NMR (68 MHz, DMSO-d6): δ =159.9, 135.1, 134.6, 130.3,
128.1, 127.1, 126.2, 125.7, 121.4, 120.7, 118.2, 114.4, 113.3, 56.0.
2-(2,3-Dimethoxyphenyl)quinazolin-4(3H)-one (6o)
Pale-yellow solid; yield: 186 mg (66%); mp 175–177 °C (Lit.37e
177–179 °C).
IR (KBr): 3305 (NH), 1656 (C=O) cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2043–2050

2048
A. H. Romero et al.
PAPER
1H NMR (400 MHz, DMSO-d6): δ = 12.06 (br s, 1 H, NH), 8.16 (d,
J = 7.7 Hz, 1 H, Ar-H), 7.83 (dd, J = 7.0, 8.0 Hz, 1 H, Ar-H), 7.70
(d, J = 8.0 Hz, 1 H, Ar-H), 7.53 (dd, J = 7.3, 7.7 Hz, 1 H, Ar-H),
7.23 (m, 3 H, Ar-H), 3.88 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3).
13C NMR (68 MHz, DMSO-d6): δ =162.0, 153.0, 152.6, 149.3,
147.5, 135.2, 128.5, 127.9, 127.4, 126.3, 124.8, 121.9, 121.4, 115.9,
61.6, 56.6.
13C NMR (68 MHz, DMSO-d6): δ = 162.8, 160.0, 147.7, 146.9,
139.5, 135.0, 130.2, 129.2, 122.6, 120.8, 120.1, 117.3, 112.6, 104.6,
55.9, 48.1, 25.6.
Anal. Calcd for C19H19N3O2: C, 71.01; H, 5.96; N, 13.08. Found: C,
70.91; H, 5.99; N, 13.14.
2-(3,4-Dimethoxyphenyl)-6-pyrrolidin-1-ylquinazolin-4(3H)-
one (6u)
Pale-yellow solid; yield: 284 mg (81%); mp 262–264 °C (Lit.24b
263–264 °C).
Anal. Calcd for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C,
68.04; H, 4.97; N, 9.95.
IR (KBr): 3390 (NH), 1670 (C=O) cm–1.
2-(3,4-Dimethoxyphenyl)quinazolin-4(3H)-one (6p)
Pale-yellow solid; yield: 198 mg (70%); mp 240–242 °C (Lit.37f
240–242 °C).
IR (KBr): 3316 (NH), 1664 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.39 (br s, 1 H, NH), 8.14 (dd,
J = 1.5, 8.1 Hz, 1 H, Ar-H), 7.81 (m, 2 H, Ar-H), 7.87 (dd, J = 2.2,
8.4 Hz, 1 H, Ar-H), 7.81 (ddd, J = 1.5, 7.5, 7.9 Hz, 1 H, Ar-H), 7.72
(d, J = 8.1 Hz, 1 H, Ar-H), 7.49 (ddd, J = 0.8, 7.3, 7.7 Hz, 1 H, Ar-
H), 7.12 (d, J = 8.8 Hz, 1 H, Ar-H), 3.89 (s, 3 H, OCH3), 3.86 (s, 3
H, OCH3).
1H NMR (400 MHz, DMSO-d6): δ = 11.81 (br s, 1 H, NH), 7.78 (dd,
J = 1.8, 8.4 Hz, 1 H, Ar-H), 7.76 (d, J = 1.8 Hz, 1 H, Ar-H), 7.58 (d,
J = 9.1 Hz, 1 H, Ar-H), 7.14 (dd, J = 2.6, 8.9 Hz, 1 H, Ar-H), 7.08
(d, J = 8.4 Hz, 1 H, Ar-H), 7.05 (d, J = 2.9 Hz, 1 H, Ar-H), 3.88 (s,
3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.35 (m, 4 H, pyrrolid-H), 2.02
(m, 4 H, pyrrolid-H).
13C NMR (68 MHz, DMSO-d6): δ = 162.9, 151.4, 149.3, 147.6,
146.6, 141.9, 139.9, 128.8, 125.9, 122.1, 120.9, 120.8, 112.2, 111.1,
104.6, 56.3, 48.1, 25.6.
13C NMR (68 MHz, DMSO-d6): δ =162.9, 152.4, 149.3, 147.1,
141.0, 134.9, 126.6, 126.4, 125.4, 121.8, 121.0, 112.1, 111.5, 56.4.
Anal. Calcd for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C,
68.47; H, 5.97; N, 11.90.
Anal. Calcd for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C,
68.01; H, 4.97; N, 9.95.
6-Chloro-2-phenylquinazolin-4(3H)-one (6v)
White solid; yield: 185 mg (72%); mp 299–300 °C (Lit.30 295–
296 °C).
IR (KBr): 3385 (NH), 1668 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.73 (br s, 1 H), 8.15 (d,
J = 7.0 Hz, 2 H, Ar-H), 8.08 (d, J = 2.6 Hz, 1 H Ar-H), 7.84 (dd,
J =2.6, 8.8 Hz, 1 H, Ar-H), 7.76 (d, J = 8.8 Hz, 1 H, Ar-H), 7.61–
7.54 (m, 3 H, Ar-H).
2-(2-Naphthyl)quinazolin-4(3H)-one (6q)
Pale-yellow solid; yield: 207 mg (76%); mp 260–262 °C (Lit.37g
212 °C).
IR (KBr): 3308 (NH), 1666 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.62 (br s, 1 H, NH), 8.23 (d,
J = 7.7 Hz, 1 H, Ar-H), 8.16 (dd, J = 1.8, 8.0 Hz, 1 H, Ar-H), 8.13
(d, J = 8.0 Hz, 1 H, Ar-H), 8.05 (dd, J = 1.8, 8.0 Hz, 1 H, Ar-H),
7.87 (dd, J = 6.6, 7.7 Hz, 1 H, Ar-H), 7.80 (d, J = 7.0 Hz, 1 H, Ar-
H), 7.74 (d, J = 8.0 Hz, 1 H, Ar-H), 7.60 (m, 4 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ = 162.4, 154.3, 149.3, 135.1,
133.8, 132.3, 130.9, 130.8, 128.9, 128.2, 128.0, 127.6, 127.3, 126.9,
126.4, 125.7, 125.6, 121.8.
13C NMR (68 MHz, DMSO-d6): δ = 161.8, 153.6, 148.0, 135.1,
133.2, 132.0, 131.5, 130.1, 129.1, 128.4, 125.4, 122.8.
Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found:
C, 65.48; H, 3.55; N, 10.95.
6-Chloro-2-(4-chlorophenyl)quinazolin-4(3H)-one (6w)
White solid; yield: 221 mg (76%); mp >300 °C.
IR (KBr): 3390 (NH), 1665 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.18 (d, J = 8.8 Hz, 2 H, Ar-
H), 8.09 (d, J =2.6 Hz, 1 H, Ar-H), 7.83 (dd, J =2.6, 8.8 Hz, 1 H, Ar-
H), 7.76 (d, J =8.8 Hz, 1 H, Ar-H), 7.60 (d, J = 8.8 Hz, 2 H, Ar-H).
13C NMR (68 MHz, DMSO-d6): δ = 161.8, 152.6, 147.9, 137.2,
135.2, 132.0, 131.7, 130.2, 130.1, 129.2, 125.5, 122.9.
Anal. Calcd for C18H12N2O: C, 79.39; H, 4.44; N, 10.29. Found: C,
79.30; H, 4.37; N, 10.21.
2-(2-Furyl)quinazolin-4(3H)-one (6r)
Pale-yellow solid; yield: 184 mg (87%); mp 218–220 °C (Lit.17
218–220 °C).
IR (KBr): 3401 (NH), 1664 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.38 (br s, 1 H, NH), 8.12 (dd,
J = 1.10, 8.1 Hz, 1 H, Ar-H), 7.99 (d, J = 0.7 Hz, 1 H, furan-H), 7.82
(ddd, J = 1.4, 7.3, 7.7 Hz, 1 H, Ar-H), 7.69 (d, J = 8.1 Hz, 1 H, Ar-
H), 7.62 (d, J = 3.3 Hz, 1 H, furan-H), 7.50 (ddd, J = 1.4, 7.3, 7.7
Hz, 1 H, Ar-H), 6.75 (dd, J = 1.4, 3.3 Hz, 1 H, furan-H).
13C NMR (68 MHz, DMSO-d6): δ =162.1, 149.1, 147.0, 146.6,
144.9, 135.1, 127.6, 127.2, 126.4, 121.9, 114.9, 113.1.
Anal. Calcd for C14H8Cl2N2O: C, 57.76; H, 2.77; N, 9.62. Found: C,
57.80; H, 2.74; N, 9.65.
Dehydrogenation of 2-(3-Fluorophenyl)-2,3-dihydroquinazo-
lin-4(1H)-one (8k) by Sulfur Dioxide
A soln of dihydroquinazolinone 8k (0.242 g; 1.0 mmol) in 9:1
DMF–H2O (3 mL) was continuously stirred at 90 °C and bubbled
with SO2 gas for the indicated time under air or N2 (see Table 3).
The flow of the SO2 gas was stopped and the mixture was allowed
to cool to r.t then poured into ice-water (10 mL). The precipitate was
collected by filtration and washed with H2O to give 2-(3-fluorophe-
nyl)quinazolin-4(3H)-one (6k) almost quantitatively; yield: 0.237 g
(99%).
Anal. Calcd for C12H8N2O2: C, 67.92; H, 3.80; N, 13.20. Found: C,
67.85; H, 3.73; N, 13.12.
2-(3-Methoxyphenyl)-6-pyrrolidin-1-ylquinazolin-4(3H)-one
(6t)
Pale-yellow solid; yield: 286 mg (89%); mp 258–260 °C (Lit.24b
261–263 °C).
IR (KBr): 3417 (NH), 1666 (C=O) cm–1.
Acknowledgement
1H NMR (400 MHz, DMSO-d6): δ = 12.00 (br s, 1 H, NH), 7.74 (d,
J = 8.1 Hz, 1 H, Ar-H), 7.71 (d, J = 1.8 Hz, 1 H, Ar-H), 7.41 (dd,
J = 7.9, 8.1 Hz, 1 H, Ar-H), 7.15 (dd, J = 2.6, 8.9 Hz, 1 H, Ar-H),
7.07 (m, 3 H, Ar-H), 3.86 (s, 3 H, OCH3), 3.40 (m, 4 H, pyrrolid-H),
2.01 (m, 4 H, pyrrolid-H).
We thank Professor Jaime E. Charris (Faculty of Pharmacy, Univer-
sidad Central de Venezuela) and TSU Noelani Cigüela (NMR La-
boratory, Universidad Simón Bolívar) for the NMR spectra; we also
thank Dr. Ajoy Banerjee (Centro de Química, IVIC, Venezuela) and
Professor William R. Dolbier Jr. (Department of Chemistry, Uni-
Synthesis 2013, 45, 2043–2050
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 2-Substituted Quinazolin-4(3H)-ones
2049
versity of Florida, USA) for their careful revision of the manuscript.
S.L. and J.S. also thank Decanato de Investigación y Desarrollo
(Universidad Simón Bolívar) and Programa de Estímulo a la Inve-
stigación e Innovación (PEII) for financial aid. A.H.R. thanks the
Department of Chemistry of the Universidad Simón Bolívar for a
teaching assistantship and Decanato de Estudios de Postgrado, Uni-
versidad Simón Bolívar, for a fellowship.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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