One-pot synthesis of quinazolinones from anthranilamides and aldehydes via p -toluenesulfonic acid catalyzed cyclocondensation and phenyliodine diacetate mediated oxidative dehydrogenation

Article abstract of DOI:10.1055/s-0033-1338521

A variety of 4(3H)-quinazolinones are synthesized conveniently in one pot from 2-aminobenzamides and aldehydes, via cyclization catalyzed by p-toluenesulfonic acid followed by oxidative dehydrogenation mediated by the hypervalent iodine compound phenyliodine diacetate [PhI(OAc)₂, PIDA]. Highlights of the described method include the first synthesis of quinazolinones bearing an N-alkoxy substituent, a new application of phenyliodine diacetate as an efficient dehydrogenative oxidant, and mild reaction conditions. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338521

2998▌
PAPER
pOapnere-Pot Synthesis of Quinazolinones from Anthranilamides and Aldehydes
via p-Toluenesulfonic Acid Catalyzed Cyclocondensation and Phenyliodine
Diacetate Mediated Oxidative Dehydrogenation
One-Pot Synthesis of Quinazolinones
Ran Cheng, Tianjian Guo, Daisy Zhang-Negrerie, Yunfei Du,* Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, P. R. of China
Fax +86(22)27404031; E-mail: duyunfeier@tju.edu.cn; E-mail: kangzhao@tju.edu.cn
Received: 18.06.2013; Accepted after revision: 23.07.2013
hydes, which provides a convenient access to quinazoli-
Abstract: A variety of 4(3H)-quinazolinones are synthesized con-
nones through cyclocondensation followed by oxidative
veniently in one pot from 2-aminobenzamides and aldehydes, via
dehydrogenation in the presence of an oxidant. Significant
work has been devoted to the search for an efficient oxi-
cyclization catalyzed by p-toluenesulfonic acid followed by oxida-
tive dehydrogenation mediated by the hypervalent iodine com-
pound phenyliodine diacetate [PhI(OAc)2, PIDA]. Highlights of the dant for this process. For example, the use of 2,3-dichloro-
described method include the first synthesis of quinazolinones bear-
ing an N-alkoxy substituent, a new application of phenyliodine di-
acetate as an efficient dehydrogenative oxidant, and mild reaction
target molecules.5a Sodium hydrogen sulfite (NaHSO3)
conditions.
5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidant in
ethanol at reflux temperature has been reported to give the
has been employed as the dehydrogenating agent in N,N-
Key words: quinazolinones, cyclocondensation, dehydrogenation,
phenyliodine diacetate, one-pot synthesis
dimethylacetamide (DMAc) at 150 °C to realize the
synthesis of 2-aryl-4(3H)-quinazolinones.5b In 2007,
Bakavoli reported a one-pot strategy for the synthesis of
quinazolinones which involved oxidative heterocycliza-
tion using potassium permanganate (KMnO4) as the oxi-
The quinazolinone scaffold and its derivatives are found
in over 100 naturally occurring alkaloids isolated from a
dant in N,N-dimethylacetamide under microwave
irradiation.5h Mixtures of iodine and potassium iodide (I2–
KI) have also been identified as both an oxidizing agent
and catalyst to afford the corresponding quinazolin-
4(3H)-ones in aqueous medium at reflux temperature.5j
Compounds including transition metals, such as cop-
per(II) chloride (CuCl2), are also reported to act as the ox-
idizing agent for this oxidative dehydrogenation reaction,
together with tetrabutylammonium bromide (TBAB) as a
neutral ionic liquid catalyst under solvent-free conditions
at 100 °C.6 However, some of these methods suffer from
disadvantages including high temperatures, long reaction
times and/or tedious two-step procedures. Moreover, al-
most all the reported approaches have been utilized for the
preparation of N-unsubstituted, N-alkylated or N-arylated
quinazolinone derivatives. In contrast, there are only a
few examples describing the synthesis of N-alkoxyquin-
azolinones.7 It is known that specific biological activities
of some indole-based pharmaceutical agents can be im-
proved considerably by introducing a methoxy group at
the unsubstituted nitrogen atom.8 The work presented in
this paper serves to fill the void presented by the lack of
methods for the synthesis of N-alkoxyquinazolinones.
range of plant families, animals and microbial metabo-
lites, with many possessing a wide spectrum of pharmaco-
logical and biological activities.1 Pegamine, an important
alkaloid isolated from Peganum harmala, exhibits cyto-
toxic properties and belongs to the quinazolinone class of
compounds.2 The quinazolinone core can also be found in
pharmaceutical agents such as methaqualone, a hypnot-
ic/sedative drug that was used to treat insomnia until 1985
when it was banned and listed as an addictive drug,3 and
halofuginone, an ingredient of a traditional Chinese herb
that is used to treat malaria, cancer, fibrosis and various
inflammatory diseases (Figure 1).4
O
O
H
OH
Cl
Br
N
NH
N
O
N
O
HO
N
N
N
pegamine
halofuginone
methaqualone
Figure 1 Examples of quinazolinones in natural products and phar-
maceutical agents
Hypervalent iodine(III) regents, in particular phenylio-
dine bis(trifluoroacetate) (PIFA) and phenyliodine diace-
tate (PIDA), have been used widely in organic synthesis
as oxidants due to their non-toxic and environmentally be-
nign features.9 Mediated by hypervalent iodine oxidants,
various heterocycles have been constructed through oxi-
dative carbon–heteroatom,10 heteroatom–heteroatom11
and even carbon–carbon12 bond-forming reactions. In
continuation of our work on the synthesis of heterocycles
In view of the important properties associated with quin-
azolinones, numerous methods have been developed for
the synthesis of this valuable class of compounds.5
Among these is the reaction of anthranilamides with alde-
SYNTHESIS 2013, 45, 2998–3006
Advanced online publication: 15.08.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338521; Art ID: SS-2013-H0422-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Quinazolinones
2999
such as indoles,13 azirines,14 carbozolones15 and oxa- bis(trifluoroacetate) (PIFA) and iodosobenzene (PhIO),
zoles,16 mediated by hypervalent iodine reagents, we re- were also shown to be effective oxidants in this process,
port herein an efficient one-pot synthesis of 4(3H)- however, the yields were lower due to the formation of
quinazolinones from various anthranilamides and alde- unidentified by-products in each case (Table 1, entries 10
hydes using phenyliodine diacetate as the oxidant and 11). Further screening for appropriate oxidants indi-
(Scheme 1).
cated that 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
and iodine were inferior to phenyliodine diacetate, while
iron(III) chloride (FeCl3) and tert-butyl hydroperoxide
(TBHP) were both ineffective in this oxidative dehydro-
genation reaction (Table 1, entries 12–15).
O
O
O
OMe
OMe
Ph
OMe
Ph
PhCHO
I(III) oxidant
N
N
N
H
p-TsOH
NH2
1a
N
H
N
Table 1 Optimization of the Reaction Conditionsa
1a'
3a
O
Scheme 1 Proposed formation of N-methoxyquinazolinones from
anthranilamides and aldehydes via phenyliodine diacetate mediated
oxidative dehydrogenation
O
CHO
OMe
N
OMe
(i) catalyst, solvent
(ii) oxidant
N
+
H
N
NH2
1a
According to a known protocol,5a the reaction between 2-
amino-N-methoxybenzamide (1a) and benzaldehyde in
the presence of a catalytic amount of p-toluenesulfonic
acid (p-TsOH) affords 2,3-dihydroquinazolin-4(1H)-one
1a′. Next, we envisioned that an appropriate hypervalent
iodine reagent could be used as the oxidant to realize the
dehydrogenation step. To our pleasant surprise, treatment
of 2,3-dihydroquinazolin-4(1H)-one 1a′ with phenylio-
dine diacetate in dichloromethane at room temperature led
conveniently to the formation of the desired product 3a in
a very satisfactory yield of 80%. This result revealed that
a hypervalent iodine reagent can be employed as an effec-
tive oxidant to convert 1a′ into 3a via an oxidative dehy-
drogenation process. This new finding led us to believe
that a new approach for the construction of N-alkox-
ylquinazolinone from anthranilamides and aldehydes
through cyclization and the subsequent dehydrogenation
was on the horizon.
2a
3a
Entry Oxidant
(equiv)
Catalyst
Solvent
Time Yield
(h)b
(%)c
1
2
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIFA (1.5)
PhIO (2.5)
DDQ (1.5)
I2 (1.5)
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
AcOH
CH2Cl2
MeCN
EtOAc
toluene
MeOH
THF
THF
1
1
77
86
85
23
51
92
32
73
trace
70
75
55
47
0
3
1
4
1
5
1
6
1
7
1
8
TFA
THF
1
9
TfOH
THF
1
10
11
12
13
14
15
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
THF
1
Considering that both steps, namely, the acid-promoted
cyclization and the phenyliodine diacetate mediated oxi-
dative dehydrogenation, can be run in the same solvent,
we attempted to develop a one-pot protocol for this two-
step reaction. After the formation of 2,3-dihydroquinazo-
lin-4(1H)-one 1a′ via the cyclocondensation of 2-amino-
N-methoxybenzamide (1a) with benzaldehyde (2a) cata-
lyzed by p-toluenesulfonic acid in dichloromethane for 10
minutes, phenyliodine diacetate was added in a portion-
wise manner. We were pleased to find that the second ox-
idative dehydrogenation step was complete in one hour at
room temperature, and the desired product 3a was ob-
tained in 77% yield (Table 1, entry 1). Solvent screening
studies revealed that both acetonitrile and ethyl acetate
were also suitable solvents for this one-pot reaction (Table
1, entries 2 and 3), while the use of toluene and methanol
afforded poor yields of the quinazolinone (Table 1, entries
4 and 5). Further screening showed that tetrahydrofuran
was the best solvent, with product 3a being obtained in an
excellent 92% yield (Table 1, entry 6). Other acids
(AcOH, TFA and TfOH) were tested as catalysts (5 mol%
in each case), but none of them gave a better yield com-
pared to p-toluenesulfonic acid (Table 1, entries 7–9).
Two other hypervalent iodine(III) oxidants, phenyliodine
THF
3
THF
3
THF
12
7
FeCl3 (1.5)
TBHP (1.5)
THF
THF
12
0
a Reaction conditions: (i) 2-amino-N-methoxybenzamide (1a) (1.0
mmol), benzaldehyde (2a) (1.1 mmol), catalyst (5 mol%), solvent (10
mL); (ii) oxidant.
b Time refers to that required for the second step.
c Yield of isolated product.
Next, studies on the scope and generality of this new one-
pot protocol were carried out using the optimized condi-
tions (see Table 1, entry 6). Reactions with aryl aldehydes
bearing an electron-withdrawing group at the para or
meta position occurred smoothly to afford the correspond-
ing quinazolinones in excellent yields (Table 2, entries 2–
5). However, aryl aldehydes with an electron-withdraw-
ing group at the ortho position gave only moderate yields
of the expected quinazolinones (Table 2, entries 6 and 7).
Reactions of aldehydes possessing a para-methyl or meta-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2998–3006

3000
R. Cheng et al.
PAPER
product in an excellent 91% yield, which indicates that the
method is also compatible with aliphatic aldehydes (Table
2, entry 15). Furthermore, we found that the reaction was
well tolerant of the electronic properties of the substitu-
ents on the benzene ring of the 2-amino-N-alkoxybenz-
amides 1; the target quinazolinones 3p–t were all formed
in satisfactory yields, regardless of whether the starting
anthranilamide contained an electron-withdrawing or
electron-donating substituent (Table 2, entries 16–20).
Table 2 One-Pot Synthesis of 3-Alkoxy-4(3H)-quinazolinones 3
from Various Anthranilamides and Aldehydesa
O
O
OR2
+
OR2
R3
(i) p-TsOH, THF, r.t., 10 min
N
N
R1
H
R1
R3CHO
(ii) PIDA, r.t., 1 h
NH2
N
1
2
3
Entry R1
R2
R3
Product Yield
(%)b
The scope and applications of this method were further in-
vestigated by replacing the N-alkoxy moiety with other
substituents. The results showed that this convenient one-
pot protocol was equally applicable to the synthesis of
quinazolinones bearing N-alkyl and N-phenyl substituents
(Table 3, entries 1–3), as well as those with a free NH
moiety (Table 3, entries 4 and 5). Good to excellent yields
of quinazolinones 3u–y were obtained.
1
2
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
92
91
89
90
89
47
50
80
80
52
79
75
80
54
91
82
90
80
78
79
H
4-O2NC6H4
3-O2NC6H4
4-FC6H4
3
H
4
H
5
H
4-BrC6H4
6
H
2-F3CC6H4
2-BrC6H4
Table 3 One-Pot Synthesis of Quinazolinones 3 from Diverse
2-Aminobenzamides and Aldehydesa
7
H
3g
3h
3i
O
O
8
H
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
3,4-Cl2C6H3
3,4,5-MeO3C6H2
R2
R2
R3
N
N
(i) p-TsOH, THF, r.t.
R1
H
R1
R3CHO
+
9
H
(ii) PIDA, r.t.
NH2
N
10
11
12
13
14
15
16
17
18
19
20c
H
3j
1
2
3
H
3k
3l
Entry
R1
R2
R3
Product Yield (%)b
H
1
H
Me
Bn
Ph
H
Ph
Ph
Ph
Ph
Me
3u
3v
3w
3x
3y
92
75
87
95
91
H
2-O2N-4,5-MeO2C6H2 3m
2
H
H
2-furyl
n-Pr
Ph
3n
3o
3p
3q
3r
3s
3t
3
H
H
4
H
6-Cl
5-Br
4-O2N
5c
4-F
H
4-ClC6H4
Ph
a Reaction conditions: (i) benzamide 1 (1.0 mmol), aldehyde 2 (1.1
mmol), p-TsOH (5 mol%), THF (10 mL), 10 min; (ii) PIDA (1.5
mmol), 1 h.
b Yield of isolated product.
4-MeO Me
3-Me Bn
Ph
c Aldehyde (3.0 equiv) was used to enable complete conversion.
Ph
a Reaction conditions: (i) benzamide 1 (1.0 mmol), aldehyde 2 (1.1
mmol), p-TsOH (5 mol%), THF (10 mL), 10 min; (ii) PIDA (1.5
mmol), 1 h.
We propose the mechanism shown in Scheme 2 for the
phenyliodine diacetate mediated oxidative dehydrogena-
tion step: nucleophilic attack on the iodine center of phe-
nyliodine diacetate by the aryl amine moiety in 1a′ gives
the intermediate 3a′ accompanied by elimination of one
molecule of acetate (as AcOH). Next, cleavage of the N–
I bond in 3a′ occurs along with removal of a proton to fur-
nish the oxidized product 3.
b Yield of isolated product.
c PIDA was added 1 h later.
methoxy group gave the respective products in good
yields (Table 2, entries 8 and 9). A much lower yield of
the desired product was obtained when using p-methoxy-
benzaldehyde, which might be due to the formation of un-
identified by-products (Table 2, entry 10). Increasing the
number of substituents on the aryl aldehyde gave the cor-
responding products in satisfactory yields, despite the fact
that aldehyde 2m possessed an ortho substituent (Table 2,
entries 11–13). When the aryl aldehyde was replaced with
heterocyclic 2-furaldehyde, only a moderate 54% yield of
the desired product was achieved (Table 2, entry 14).
With n-butanal, the reaction afforded the desired cyclized
O
O
R2
R2
N
R1
N
PhI(OAc)2
– AcOH
R1
R3
3
– PhI
– AcOH
N
I
R3
H
Ph
N
H
AcO
1a'
3a'
Scheme 2 Proposed mechanistic pathway for the oxidative dehydro-
genation step
Synthesis 2013, 45, 2998–3006
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Quinazolinones
3001
over MgSO4, and concentrated under vacuum to afford the crude
product. Recrystallization from Et2O afforded the desired amide.
In summary, we have reported a new one-pot strategy for
the synthesis of 4(3H)-quinazolinones starting from 2-
aminobenzamides and various aldehydes. The process in-
volves a cyclocondensation reaction catalyzed by p-tolu-
enesulfonic acid followed by oxidative dehydrogenation
using phenyliodine diacetate as the oxidant. Compared to
existing procedures, the highlights of the present method
include the first synthesis of quinazolinones bearing an N-
2-Amino-N-methoxybenzamide (1a)18
Yield: 9.12 g (90%); brown solid; mp 110–111 °C.
IR (KBr): 3365, 3248, 2931, 1642, 1523, 1303, 876, 790, 757, 665
cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 11.38 (br s, 1 H), 7.31 (d,
J = 6.0 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H),
alkoxy substituent and the application of a hypervalent io- 6.49 (t, J = 7.5 Hz, 1 H), 6.29 (br s, 2 H), 3.68 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.5, 150.1, 132.6, 128.1,
116.8, 115.1, 112.7, 63.6.
HRMS (ESI): m/z [M + Na]+ calcd for C8H10N2NaO2: 189.0634;
found: 189.0635.
dine compound as an effective oxidant in an oxidative de-
hydrogenation reaction. Other advantages include the
general applicability, the mild reaction conditions and
simple work-up procedure.
2-Amino-6-chloro-N-methoxybenzamide (1b)
Toluene and CH2Cl2 were dried over CaH2 before use. Other re-
agents and solvents were purchased as reagent grade quality and
were used without further purification. All reactions were per-
formed in standard glassware (heated at 70 °C for 3 h before use).
TLC plates (Kangbinuo silica gel GF254, 20 × 50 mm) were made
visual by exposure to UV light. Flash column chromatography was
performed over Kangbinuo silica gel (200–300 mesh) using a mix-
ture of petroleum ether (PE) and EtOAc as the eluent. Petroleum
ether (PE) refers to the fraction boiling in the 60–90 °C range. Melt-
ing points were determined with a national micromelting point ap-
paratus and are uncorrected. IR spectra were recorded on a Nicolet
iS10 FT-IR spectrometer as KBr pellets. 1H and 13C NMR spectra
were recorded on a Bruker Avance III 600 MHz instrument (150
MHz or 100 MHz for 13C NMR) at 25 °C. Chemical shifts are given
in ppm and are referenced to TMS (set as 0.00 ppm) as the internal
standard. The multiplicities are defined as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets;
and td, triplet of doublets. The coupling constants (J) are reported in
Hertz (Hz). High-resolution mass spectra (HRMS) were obtained
on a Bruker micrOTOF-Q II microspectrometer.
Yield: 9.55 g (78%); pale yellow solid; mp 118–121 °C.
IR (KBr): 3480, 3386, 3218, 1652, 1625, 1509, 1448, 880, 783
cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 11.56 (br s, 1 H), 7.06 (t,
J = 7.3 Hz, 1 H), 6.65 (d, J = 8.2 Hz, 1 H), 6.59 (d, J = 7.9 Hz, 1
H), 5.25 (br s, 2 H), 3.72 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 161.8, 147.8, 131.0, 130.7,
118.0, 115.9, 113.7, 63.1.
HRMS (ESI): m/z [M + Na]+ calcd for C8H935ClN2NaO2: 223.0245;
found: 223.0250.
2-Amino-5-bromo-N-methoxybenzamide (1c)
Yield: 10.76 g (72%); white solid; mp 155–158 °C.
IR (KBr): 3458, 3348, 3310, 2938, 1636, 1617, 1580, 1488, 1256,
813 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 11.52 (br s, 1 H), 7.47 (d,
J = 1.9 Hz, 1 H), 7.29 (dd, J = 8.9, 2.2 Hz, 1 H), 6.70 (d, J = 8.8 Hz,
1 H), 6.44 (br s, 2 H), 3.68 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 165.5, 148.8, 134.5, 129.7,
118.4, 113.7, 104.9, 63.2.
HRMS (ESI): m/z [M + Na]+ calcd for C8H979BrN2NaO2: 266.9740;
found: 266.9735.
4-Methoxyisatoic Anhydride17
To a cooled (0 °C) soln of 4-methoxyanthranilic acid (1.29 g, 7.7
mmol) in THF (26 mL) was added triphosgene (0.80 g, 2.7 mmol)
portionwise over 20 min. After 30 min, the resulting mixture was
warmed to r.t., stirred for 1.5 h and then poured into ice-cold H2O
(150 mL). Additional H2O (50 mL) was added to facilitate the stir-
ring of the thick solid that formed. After stirring for 30 min, the mix-
ture was filtered to give a beige solid, which was washed with H2O,
air-dried, and then dried under high vacuum to give the title product
as a beige solid.
2-Amino-N-methoxy-4-nitrobenzamide (1d)
Yield: 12.50 g (97%); tan solid; mp 194–197 °C.
IR (KBr): 3480, 3367, 3217, 2932, 1655, 1630, 1511, 1356, 1270,
875, 734 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 11.74 (br s, 1 H), 7.60 (d,
J = 1.8 Hz, 1 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.28 (dd, J = 8.5, 1.8 Hz,
1 H), 6.73 (br s, 2 H), 3.72 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 165.1, 150.1, 149.6, 129.3,
117.5, 110.0, 108.3, 63.3.
Yield: 1.10 g (74%); mp 216–218 °C.
IR (KBr): 3222, 1787, 1736, 1625, 1600, 1350, 1289, 1208, 1109,
1027, 1001, 844, 751, 684 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 11.65 (br s, 1 H), 7.83 (d,
J = 8.8 Hz, 1 H), 6.83 (dd, J = 8.9, 2.4 Hz, 1 H), 6.58 (d, J = 2.3 Hz,
1 H), 3.86 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 165.8, 159.1, 147.3, 143.5,
130.9, 111.5, 102.7, 98.4, 55.8.
HRMS (ESI): m/z [M + Na]+ calcd for C8H9N3NaO4: 234.0485;
found: 234.0496.
2-Amino-N,4-dimethoxybenzamide (1e)
Yield: 10.53 g (88%); yellow solid; mp 72–73 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C9H7NNaO4: 216.0267;
found: 216.0264.
IR (KBr): 3471, 3353, 3177, 2967, 1627, 1585, 1499, 1352, 1226
cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.83 (br s, 1 H), 7.25 (d, J = 8.7
Hz, 1 H), 6.17 (dd, J = 8.8, 2.3 Hz, 1 H), 6.14 (d, J = 2.3 Hz, 1 H),
5.64 (br s, 2 H), 3.82 (s, 3 H), 3.76 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 168.7, 163.2, 151.2, 129.0, 105.9,
104.1, 100.5, 64.3, 55.1.
HRMS (ESI): m/z [M + Na]+ calcd for C9H12N2NaO3: 219.0740;
found: 219.0743.
Amides 1a–e; General Procedure
A modified version of the reported procedure was employed.18
A
soln of NaOH (2 M, 190 mmol) in H2O (100 mL) was added to a
25% aq soln of O-methylhydroxylamine hydrochloride (196 mmol)
at 5 °C, and then the appropriate isatoic anhydride (61 mmol) was
added in portions. The resulting suspension was stirred at 5 °C for
30 min, allowed to warm to r.t. (bubbling occurred), and then stirred
for 3 h. The mixture was extracted with EtOAc (3 × 200 mL), and
the combined organic layer washed with brine (3 × 50 mL), dried
© Georg Thieme Verlag Stuttgart · New York
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2-Amino-N-(benzyloxy)-3-methylbenzamide (1f)19
13C NMR (100 MHz, DMSO-d6): 171.8, 150.6, 132.4, 129.2, 116.9,
114.9, 114.2.
HRMS (ESI): m/z [M + H]+ calcd for C7H9N2O: 137.0709; found:
137.0707.
To a mixture of isatoic anhydride (10 g, 61.3 mmol) and O-benzyl-
hydroxylamine hydrochloride (11.74 g, 73.6 mmol) in anhyd THF
(100 mL) was added Et3N (12.39 g, 122.6 mmol). The mixture was
heated at reflux temperature for 6 h. After evaporation of the sol-
vent, EtOAc (150 mL) was added to the residue followed by H2O
(100 mL) with vigorous shaking. The organic layer was separated,
dried over anhyd Na2SO4, and concentrated to give a crude residue.
Purification by flash column chromatography (EtOAc–PE, 2:1)
gave benzamide 1f.
2-Amino-4-fluorobenzamide (1k)
Yield: 2.77g (60%); white solid; mp 134–135 °C.
IR (KBr): 3502, 3386, 3354, 3175, 1666, 1627, 1566, 1501, 1408,
1275, 1177, 1130 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 7.72 (br s, 1 H), 7.60 (m, 1 H),
7.06 (br s, 1 H), 6.89 (br s, 2 H), 6.44 (dd, J = 11.9, 2.5 Hz, 1 H),
6.28 (td, J = 8.5, 2.5 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 170.5, 164.5 (d, JC–F = 243.6
Hz), 152.6 (d, JC–F = 12.5 Hz), 131.3 (d, JC–F = 11.3 Hz), 110.4,
101.4 (d, JC–F = 19.8 Hz), 101.3 (d, JC–F = 21.5 Hz).
Yield: 10.9 g (74%); white crystals; mp 118–119 °C.
IR (KBr): 3487, 3369, 3228, 2937, 1618, 1585, 1484, 1256, 752,
740, 696 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 11.47 (br s, 1 H), 7.47 (d,
J = 7.3 Hz, 2 H), 7.43–7.36 (m, 3 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.09
(d, J = 7.1 Hz, 1 H), 6.47 (t, J = 7.5 Hz, 1 H), 6.11 (br s, 2 H), 4.93
(s, 2 H), 2.10 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C7H7FN2NaO: 177.0435;
found: 177.0438.
13C NMR (150 MHz, DMSO-d6): δ = 167.7, 147.5, 136.1, 132.9,
128.8, 128.3, 128.2, 125.6, 123.1, 114.6, 112.3, 77.0, 17.6.
2-Amino-N-phenylbenzamide (1i)23
A stirred soln of isatoic anhydride (3.26 g, 20 mmol) in DMF (10
mL) was heated to 80 °C, and then a soln of aniline (1.86 g, 20
mmol) in DMF (5 mL) was added dropwise over a period of 30 min.
After stirring at the same temperature for an additional 4 h, the mix-
ture was cooled and cold H2O (60 mL) was added with stirring. The
resulting precipitate was collected, washed with cold H2O (2 × 10
mL) and dried at 60 °C. Recrystallization from Et2O afforded benz-
amide 1i.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16N2NaO2: 279.1104;
found: 279.1105.
Amides 1g,h,j,k; General Procedure
A modified version of the reported procedure was employed.20 To a
soln of isatoic anhydride (30 mmol) and Et3N (60 mmol) in H2O (30
mL) was added a soln of the appropriate amine (60 mmol) in THF
(30 mL) over 30 min. The mixture was stirred for 2 h and then ex-
tracted with EtOAc (3 × 30 mL). The combined organic layer was
washed with H2O (3 × 30 mL) and brine (3 × 30 mL), then dried
over MgSO4, filtered and concentrated to yield the desired amide.
Yield: 3.34 g (79%); white solid; mp 130–131 °C.
IR (KBr): 3470, 3363, 3289, 1642, 1624, 1539, 1440, 1318, 1254,
750, 692 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.76 (br s, 1 H), 7.56 (d, J = 8.0
Hz, 2 H), 7.46 (d, J = 7.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 2 H), 7.25
(t, J = 8.0 Hz, 1 H), 7.14 (t, J = 7.5 Hz, 1 H), 6.72–6.69 (m, 2 H),
5.51 (br s, 2 H).24
2-Amino-N-methylbenzamide (1g)18
Yield: 3.73 g (82%); orange solid; mp 79–80 °C.
IR (KBr): 3451, 3346, 1625, 1581, 1538, 1411, 1264, 752, 659
cm–1.
13C NMR (100 MHz, CDCl3): δ = 167.7, 148.9, 137.9, 132.7, 129.1,
127.3, 124.5, 120.7, 117.6, 116.9, 116.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12N2NaO: 235.0842;
found: 235.0841.
1H NMR (600 MHz, CDCl3): δ = 7.29 (d, J = 8.0 Hz, 1 H), 7.19 (t,
J = 7.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 6.63 (t, J = 7.5 Hz, 1 H),
6.10 (br s, 1 H), 5.50 (br s, 2 H), 2.96 (d, J = 5.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.1, 148.5, 132.1, 127.3, 117.2,
116.6, 116.3, 26.5.
HRMS (ESI): m/z [M + Na]+ calcd for C8H10N2NaO: 173.0685;
Quinazolinones 3; General Procedure
To a soln of amide 1 (1 mmol) and p-TsOH (0.05 mmol) in THF (10
mL) was added aldehyde 2 (1.1 mmol). The mixture was stirred at
r.t. for 10 min (1 h for the reaction in entry 20, Table 2), and then
PIDA (1.5 mmol) was added portionwise over 5 min. After stirring
at r.t. for 1 h, the mixture was diluted with EtOAc (20 mL),
quenched with sat. aq NaHCO3 soln (20 mL), and then extracted
with EtOAc (3 × 20 mL). The combined organic layer was washed
with brine (3 × 30 mL), dried over anhyd Na2SO4 and concentrated
using a rotary evaporator. The crude residue was purified by flash
column chromatography (EtOAc–PE) to give the desired product.
found: 173.0690.
2-Amino-N-benzylbenzamide (1h)21
Yield: 5.23 g (77%); pale yellow solid; mp 123–125 °C.
IR (KBr): 3472, 3359, 3303, 1630, 1577, 1541, 1450, 1419, 1271,
753, 727, 695 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.36–7.34 (m, 4 H), 7.32–7.27 (m,
2 H), 7.20 (t, J = 7.5 Hz, 1 H), 6.69 (d, J = 8.2 Hz, 1 H), 6.62 (t,
J = 7.3 Hz, 1 H), 6.34 (br s, 1 H), 5.59 (br s, 2 H), 4.60 (d, J = 5.6
Hz, 2 H).
13C NMR (100 MHz, CDCl3): 169.3, 148.9, 138.4, 132.4, 128.8,
127.8, 127.5, 127.3, 117.3, 116.6, 115.9, 43.7.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14N2NaO: 249.0998;
3-Methoxy-2-phenylquinazolin-4(3H)-one (3a)
Yield: 224 mg (92%); white solid; mp 121–122 °C.
IR (KBr): 2954, 1696, 1562, 1471, 1354, 763, 695 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.35 (d, J = 8.0 Hz, 1 H), 7.91 (d,
found: 249.0995.
J = 8.2 Hz, 2 H), 7.82–7.77 (m, 2 H), 7.57–7.51 (m, 4 H), 3.77 (s, 3
H).
2-Aminobenzamide (1j)22
Yield: 3.43 g (83%); white solid; mp 113–114 °C.
13C NMR (150 MHz, CDCl3): δ = 158.0, 153.3, 146.5, 134.5, 131.9,
130.9, 129.5, 128.4, 127.9, 127.0, 126.8, 122.6, 64.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H12N2NaO2: 275.0791;
IR (KBr): 3411, 3323, 3196, 1660, 1628, 1586, 1544, 1401, 1316,
1258, 743, 628 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 7.71 (br s, 1 H), 7.52 (d,
J = 8.0 Hz, 1 H), 7.12 (t, J = 8.0 Hz, 1 H), 7.04 (br s, 1 H), 6.68 (d,
J = 8.0 Hz, 1 H), 6.55 (br s, 2 H), 6.47 (t, J = 7.5 Hz, 1 H).
found: 275.0793.
3-Methoxy-2-(4-nitrophenyl)quinazolin-4(3H)-one (3b)
Yield: 270 mg (91%); pale yellow solid; mp 195–196 °C.
IR (KBr): 1690, 1580, 1514, 1346, 770, 689 cm–1.
Synthesis 2013, 45, 2998–3006
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One-Pot Synthesis of Quinazolinones
3003
1H NMR (600 MHz, CDCl3): δ = 8.39–8.36 (m, 3 H), 8.13 (d,
J = 8.3 Hz, 2 H), 7.84–7.80 (m, 2 H), 7.58 (t, J = 7.0 Hz, 1 H), 3.82
(s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.6, 151.0, 149.1, 146.2, 137.8,
134.8, 130.8, 128.2, 127.8, 126.9, 123.5, 122.8, 64.5.
1H NMR (600 MHz, CDCl3): δ = 8.38 (d, J = 8.0 Hz, 1 H), 7.83–
7.80 (m, 2 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.58–7.55 (m, 1 H), 7.54
(dd, J = 7.6, 1.5 Hz, 1 H), 7.48 (td, J = 7.6, 0.8 Hz, 1 H), 7.41 (td,
J = 7.8, 1.6 Hz, 1 H), 3.85 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.7, 152.7, 146.3, 134.6, 134.1,
133.0, 131.4, 129.9, 128.1, 127.5, 127.3, 126.8, 123.1, 122.2, 64.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H1179BrN2NaO2:
HRMS (ESI): m/z [M + Na]+ calcd for C15H11N3NaO4: 320.0642;
found: 320.0640.
352.9896; found: 352.9899.
3-Methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3c)
Yield: 265 mg (89%); pale yellow solid; mp 173–175 °C.
3-Methoxy-2-(p-tolyl)quinazolin-4(3H)-one (3h)
Yield: 216 mg (80%); pale yellow solid; mp 153–154 °C.
IR (KBr): 2939, 1689, 1604, 1584, 1561, 1335, 782, 696 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.33 (d, J = 7.8 Hz, 1 H), 7.82 (d,
J = 7.7 Hz, 2 H), 7.80–7.76 (m, 2 H), 7.50 (t, J = 6.9 Hz, 1 H), 7.32
(d, J = 7.6 Hz, 2 H), 3.77 (s, 3 H), 2.45 (s, 3 H).
IR (KBr): 1686, 1587, 1556, 1525, 1476, 1358, 781, 748, 690 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.85 (s, 1 H), 8.43 (dd, J = 8.2, 1.4
Hz, 1 H), 8.36 (d, J = 7.8 Hz, 1 H), 8.30 (d, J = 7.7 Hz, 1 H), 7.85–
7.80 (m, 2 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.59–7.56 (m, 1 H), 3.84 (s,
3 H).
13C NMR (150 MHz, CDCl3): δ = 157.6, 150.7, 147.5, 146.2, 135.4,
13C NMR (150 MHz, CDCl3): δ = 158.1, 153.3, 146.7, 141.3, 134.4,
134.8, 133.5, 129.5, 128.1, 127.8, 126.9, 125.5, 124.9, 122.8, 64.5.
129.5, 129.1, 129.0, 127.9, 126.8, 126.7, 122.5, 64.0, 21.5.
HRMS (ESI): m/z [M + Na]+ calcd for C15H11N3NaO4: 320.0642;
HRMS (ESI): m/z [M + Na]+ calcd for C16H14N2NaO2: 289.0947;
found: 320.0641.
found: 289.0942.
2-(4-Fluorophenyl)-3-methoxyquinazolin-4(3H)-one (3d)
Yield: 242 mg (90%); white solid; mp 125–126 °C.
3-Methoxy-2-(3-methoxyphenyl)quinazolin-4(3H)-one (3i)
Yield: 226 mg (80%); white solid; mp 88–89 °C.
IR (KBr): 2949, 1702, 1605, 1564, 1513, 1474, 1353, 1235, 1156,
832, 772, 695, 624 cm–1.
IR (KBr): 2941, 2838, 1686, 1578, 1555, 1470, 1335, 1230, 801,
778, 715, 688 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.34 (d, J = 8.0 Hz, 1 H), 7.98–
7.95 (m, 2 H), 7.82–7.78 (m, 2 H), 7.54–7.52 (m, 1 H), 7.22 (t,
J = 8.5 Hz, 2 H), 3.78 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 164.3 (d, JC–F = 250.7 Hz), 157.9,
152.1, 146.5, 134.5, 131.9 (d, JC–F = 8.6 Hz), 128.1 (d, JC–F = 3.7
Hz), 127.9, 127.1, 126.8, 122.6, 115.5 (d, JC–F = 21.8 Hz), 64.0.
1H NMR (600 MHz, CDCl3): δ = 8.34 (d, J = 7.9 Hz, 1 H), 7.82–
7.78 (m, 2 H), 7.54–7.51 (m, 1 H), 7.49 (d, J = 7.7 Hz, 1 H), 7.44–
7.42 (m, 2 H), 7.10 (dd, J = 8.3, 2.0 Hz, 1 H), 3.88 (s, 3 H), 3.80 (s,
3 H).
13C NMR (150 MHz, CDCl3): δ = 159.4, 158.0, 153.1, 146.4, 134.5,
133.0, 129.5, 127.9, 127.1, 126.8, 122.6, 121.8, 117.0, 114.7, 64.2,
55.5.
HRMS (ESI): m/z [M + Na]+ calcd for C15H11FN2NaO2: 293.0697;
found: 293.0698.
HRMS (ESI): m/z [M + Na]+ calcd for C16H14N2NaO3: 305.0897;
found: 305.0899.
2-(4-Bromophenyl)-3-methoxyquinazolin-4(3H)-one (3e)
Yield: 293 mg (89%); white solid; mp 149–150 °C.
3-Methoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (3j)
Yield: 146 mg (52%); white solid; mp 132–133 °C.
IR (KBr): 1703, 1609, 1589, 1514, 1258, 827, 772 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.32 (d, J = 8.0 Hz, 1 H), 7.94 (d,
J = 8.5 Hz, 2 H), 7.77–7.75 (m, 2 H), 7.50–7.47 (m, 1 H), 7.02 (d,
J = 8.5 Hz, 2 H), 3.89 (s, 3 H), 3.78 (s, 3 H).
IR (KBr): 1699, 1598, 767, 694 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.33 (d, J = 7.8 Hz, 1 H), 7.83–
7.80 (m, 2 H), 7.79–7.77 (m, 2 H), 7.66 (d, J = 8.4 Hz, 2 H), 7.53
(t, J = 7.0 Hz, 1 H), 3.79 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.9, 152.1, 146.4, 134.6, 131.6,
131.1, 130.8, 128.0, 127.2, 126.8, 125.7, 122.6, 64.2.
13C NMR (150 MHz, CDCl3): δ = 161.8, 158.2, 152.8, 146.7, 134.4,
131.4, 127.8, 126.7, 126.6, 124.2, 122.4, 113.8, 63.9, 55.4.
HRMS (ESI): m/z [M + Na]+ calcd for C16H14N2NaO3: 305.0897;
HRMS (ESI): m/z [M + Na]+ calcd for C15H1179BrN2NaO2:
352.9896; found: 352.9899.
found: 305.0896.
3-Methoxy-2-[2-(trifluoromethyl)phenyl]quinazolin-4(3H)-one
(3f)
2-(3,4-Dichlorophenyl)-3-methoxyquinazolin-4(3H)-one (3k)
Yield: 253 mg (79%); white solid; mp 179–180 °C.
Yield: 151 mg (47%); pale yellow solid; mp 172–173 °C.
IR (KBr): 1701, 1585, 1471, 1353, 768, 695 cm–1.
IR (KBr): 2941, 1686, 1595, 1473, 1352, 1315, 1146, 1127, 774,
685, 652 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.38 (d, J = 8.1 Hz, 1 H), 7.84 (d,
J = 8.0 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.73–7.68 (m, 2 H), 7.63 (d,
J = 7.1 Hz, 1 H), 7.59–7.56 (m, 1 H), 3.81 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.5, 151.7, 146.1, 134.6, 131.6,
130.5, 130.4, 130.0, 129.0 (q, JC–F = 31.4 Hz), 128.0, 127.5, 126.9
(q, JC–F = 4.2 Hz), 126.7, 123.6 (q, JC–F = 272.2 Hz), 123.0, 64.0.
1H NMR (600 MHz, CDCl3): δ = 8.34 (d, J = 8.0 Hz, 1 H), 8.08 (s,
1 H), 7.82–7.78 (m, 3 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.54 (t, J = 7.2
Hz, 1 H), 3.82 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.7, 150.8, 146.2, 135.6, 134.7,
132.9, 131.61, 131.59, 130.4, 128.8, 128.0, 127.5, 126.9, 122.7,
64.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H1035Cl2N2NaO2:
343.0012; found: 343.0019.
HRMS (ESI): m/z [M + Na]+ calcd for C16H11F3N2NaO2: 343.0665;
found 343.0666.
3-Methoxy-2-(3,4,5-trimethoxyphenyl)quinazolin-4(3H)-one
2-(2-Bromophenyl)-3-methoxyquinazolin-4(3H)-one (3g)
Yield: 163.5 mg (50%); white solid; mp 201–203 °C.
(3l)
Yield: 257.5 mg (75%); white solid; mp 119–120 °C.
IR (KBr): 2936, 1686, 1599, 1471, 1351, 1246, 781, 767, 730, 694,
643 cm–1.
IR (KBr): 2939, 1688, 1572, 1506, 1468, 1414, 1363, 772 cm–1.
© Georg Thieme Verlag Stuttgart · New York
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PAPER
1H NMR (600 MHz, CDCl3): δ = 8.34 (d, J = 8.0 Hz, 1 H), 7.79 (d,
J = 3.6 Hz, 2 H), 7.54–7.50 (m, 1 H), 7.19 (s, 2 H), 3.94 (s, 6 H),
3.93 (s, 3 H), 3.82 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 156.8, 152.4, 145.3, 137.8, 137.5,
131.0, 130.0, 129.7, 129.3, 128.7, 123.9, 120.9, 64.2.
HRMS (ESI): m/z [M + Na]+ calcd for C15H1079Br35ClN2NaO2:
386.9506; found: 386.9501.
13C NMR (150 MHz, CDCl3): δ = 158.1, 153.0, 152.8, 146.5, 140.5,
134.5, 127.9, 127.0, 126.9, 126.8, 122.5, 107.0, 64.3, 61.0, 56.3.
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O5: 343.1288; found:
343.1290.
3-Methoxy-7-nitro-2-phenylquinazolin-4(3H)-one (3r)
Yield: 235.5 mg (80%); yellow solid; mp 143–145 °C.
IR (KBr): 1697, 1556, 1533, 1348, 1338, 742, 686 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.62 (d, J = 2.0 Hz, 1 H), 8.50 (d,
J = 8.8 Hz, 1 H), 8.26 (dd, J = 8.8, 2.1 Hz, 1 H), 7.95 (d, J = 7.3 Hz,
2 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 2 H), 3.81 (s, 3
H).
2-(4,5-Dimethoxy-2-nitrophenyl)-3-methoxyquinazolin-4(3H)-
one (3m)
Yield: 310 mg (80%); yellow solid; mp 181–183 °C.
IR (KBr): 2939, 1693, 1522, 1239, 1223, 773 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.37 (d, J = 8.0 Hz, 1 H), 7.82–
7.79 (m, 2 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.5 Hz, 1 H),
7.10 (s, 1 H), 4.05 (s, 3 H), 4.02 (s, 3 H), 3.82 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.5, 153.3, 151.4, 150.1, 146.4,
140.5, 134.6, 127.8, 127.4, 126.9, 123.1, 121.7, 112.3, 107.5, 64.4,
56.8, 56.7.
13C NMR (150 MHz, CDCl3): δ = 156.9, 155.3, 151.7, 147.1, 131.6,
131.2, 129.6, 128.7, 128.5, 126.6, 123.6, 120.5, 64.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H12N3O4: 298.0822; found:
298.0826.
3,7-Dimethoxy-2-phenylquinazolin-4(3H)-one (3s)
Yield: 220 mg (78%); white solid; mp 125–126 °C.
HRMS (ESI): m/z [M + H]+ calcd for C17H16N3O6: 358.1034; found:
358.1030.
IR (KBr): 2929, 1687, 1610, 1560, 1484, 1364, 774, 710, 690, 631
cm–1.
2-(Furan-2-yl)-3-methoxyquinazolin-4(3H)-one (3n)
1H NMR (600 MHz, CDCl3): δ = 8.23 (d, J = 8.9 Hz, 1 H), 7.89 (d,
J = 7.0 Hz, 2 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.52 (t, J = 7.3 Hz, 2 H),
7.18 (d, J = 2.4 Hz, 1 H), 7.09 (dd, J = 8.9, 2.5 Hz, 1 H), 3.92 (s, 3
H), 3.76 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 164.8, 157.6, 153.9, 148.7, 132.0,
130.9, 129.4, 128.4, 128.2, 117.4, 115.9, 108.4, 64.1, 55.8.
Yield: 130 mg (54%); yellow solid; mp 124–126 °C.
IR (KBr): 3107, 1708, 1584, 1537, 1452, 770, 762 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.30 (d, J = 7.9 Hz, 1 H), 7.85 (d,
J = 8.2 Hz, 1 H), 7.79–7.77 (m, 2 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.46
(d, J = 3.5 Hz, 1 H), 6.65 (d, J = 1.8 Hz, 1 H), 4.12 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.8, 146.6, 146.3, 143.8, 143.2,
134.6, 128.0, 126.9, 126.7, 122.1, 118.4, 112.6, 64.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O3: 283.1077; found:
283.1079.
HRMS (ESI): m/z [2 M + Na]+ calcd for C26H20N4NaO6: 507.1275;
found: 507.1276.
3-(Benzyloxy)-8-methyl-2-phenylquinazolin-4(3H)-one (3t)
Yield: 270 mg (79%); white solid; mp 162–163 °C.
3-Methoxy-2-propylquinazolin-4(3H)-one (3o)
IR (KBr): 1677, 1561, 1335, 771, 760, 695 cm–1.
Yield: 199.5 mg (91%); white solid; mp 55–56 °C.
1H NMR (600 MHz, CDCl3): δ = 8.22 (d, J = 7.9 Hz, 1 H), 7.84 (d,
J = 7.4 Hz, 2 H), 7.63 (d, J = 7.1 Hz, 1 H), 7.54 (t, J = 7.4 Hz, 1 H),
7.46 (t, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.3
Hz, 1 H), 7.21 (t, J = 7.6 Hz, 2 H), 7.03 (d, J = 7.4 Hz, 2 H), 4.92
(s, 2 H), 2.64 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 158.6, 152.1, 145.2, 136.7, 135.0,
132.9, 132.7, 130.6, 130.2, 130.1, 129.2, 128.4, 128.0, 126.7, 124.5,
122.7, 78.4, 17.5.
IR (KBr): 2963, 2936, 1693, 1597, 1471, 1240, 980, 772, 696 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.27 (dd, J = 8.0, 1.0 Hz, 1 H),
7.73 (td, J = 7.6, 1.4 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.45 (t,
J = 7.5 Hz, 1 H), 4.12 (s, 3 H), 2.87 (t, J = 7.7 Hz, 2 H), 1.93–1.87
(m, 2 H), 1.08 (t, J = 7.4 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.9, 156.2, 146.4, 134.2, 127.2,
126.6, 126.4, 122.5, 64.3, 34.5, 20.2, 13.9.
HRMS (ESI): m/z [M + Na]+ calcd for C22H18N2NaO2: 365.1260;
found: 365.1248.
HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O2: 219.1128; found:
219.1132.
3-Methyl-2-phenylquinazolin-4(3H)-one (3u)25
5-Chloro-3-methoxy-2-phenylquinazolin-4(3H)-one (3p)
Yield: 215 mg (92%); white solid; mp 132–134 °C.
Yield: 231 mg (82%); white solid; mp 137–138 °C.
IR (KBr): 1681, 1589, 1563, 1475, 1356, 764, 670 cm–1.
IR (KBr): 1705, 1592, 1551, 1456, 1353, 808, 697 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.33 (d, J = 7.9 Hz, 1 H), 7.77–
7.74 (m, 2 H), 7.57 (d, J = 7.9 Hz, 2 H), 7.53–7.49 (m, 4 H), 3.50
(s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 162.7, 156.1, 147.3, 135.4, 134.3,
130.1, 128.9, 128.0, 127.5, 127.0, 126.7, 120.6, 34.2.
HRMS (ESI): m/z [M + Na]+ calcd for C15H12N2NaO: 259.0842;
found: 259.0845.
1H NMR (600 MHz, CDCl3): δ = 7.91 (d, J = 7.8 Hz, 2 H), 7.68 (dd,
J = 8.2, 1.0 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 7.58–7.55 (m, 1 H),
7.53–7.49 (m, 3 H), 3.78 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 156.1, 153.9, 148.9, 134.2, 133.8,
131.6, 131.1, 129.6, 129.4, 128.4, 127.3, 119.6, 64.0.
HRMS (ESI): m/z [M + Na]+ calcd for C15H1135ClN2NaO2:
309.0401; found: 309.0402.
3-Benzyl-2-phenylquinazolin-4(3H)-one (3v)26
6-Bromo-2-(4-chlorophenyl)-3-methoxyquinazolin-4(3H)-one
(3q)
Yield: 233 mg (75%); pale yellow solid; mp 146–148 °C.
IR (KBr): 1678, 1585, 1568, 1378, 773, 704 cm–1.
Yield: 330 mg (90%); white solid; mp 207–210 °C.
IR (KBr): 1710, 1585, 1493, 1465, 823, 653 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.37 (d, J = 8.0 Hz, 1 H), 7.79–
7.76 (m, 2 H), 7.54–7.51 (m, 1 H), 7.46 (t, J = 7.4 Hz, 1 H), 7.39 (t,
J = 7.6 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.20–7.19 (m, 3 H),
6.93–6.92 (m, 2 H), 5.27 (s, 2 H).
1H NMR (600 MHz, CDCl3): δ = 8.45 (d, J = 2.2 Hz, 1 H), 7.89 (d,
J = 8.5 Hz, 2 H), 7.85 (dd, J = 8.7, 2.2 Hz, 1 H), 7.64 (d, J = 8.7 Hz,
1 H), 7.50 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H).
Synthesis 2013, 45, 2998–3006
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Quinazolinones
3005
13C NMR (150 MHz, CDCl3): δ = 162.5, 156.4, 147.2, 136.6, 135.3,
134.6, 129.9, 128.6, 128.5, 128.0, 127.6, 127.5, 127.2, 127.1, 127.0,
120.9, 48.8.
HRMS (ESI): m/z [M + Na]+ calcd for C21H16N2NaO: 335.1155;
found: 335.1160.
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Discovery Technol. 2008, 5, 250.
2,3-Diphenylquinazolin-4(3H)-one (3w)27
Yield: 261 mg (87%); white solid; mp 158–159 °C.
IR (KBr): 1686, 1554, 1470, 1343, 1272, 774, 701 cm–1.
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Rosales, M. E.; Urdaneta, N.; Godoy, M. V.; Charris, J. E.
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1H NMR (600 MHz, CDCl3): δ = 8.36 (d, J = 7.9 Hz, 1 H), 7.84–
7.79 (m, 2 H), 7.53 (t, J = 7.3 Hz, 1 H), 7.34–7.19 (m, 8 H), 7.15 (d,
J = 7.4 Hz, 2 H).
13C NMR (150 MHz, CDCl3): δ = 162.2, 155.2, 147.5, 137.7, 135.4,
134.7, 129.3, 129.1, 129.01, 128.99, 128.4, 128.0, 127.7, 127.3,
127.2, 121.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H14N2NaO: 321.0998;
found: 321.0994.
2-Phenylquinazolin-4(3H)-one (3x)5s
Yield: 210.5 mg (95%); white solid; mp 239–241 °C.
IR (KBr): 3196, 1669, 1603, 1561, 1482, 1297, 768, 694 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 12.56 (br s, 1 H), 8.21 (d,
J = 7.9 Hz, 2 H), 8.18 (dd, J = 7.9, 1.2 Hz, 1 H), 7.85 (t, J = 8.0 Hz,
1 H), 7.76 (d, J = 7.9 Hz, 1 H), 7.62–7.52 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.7, 152.8, 149.2, 135.0,
133.2, 131.8, 129.1, 128.2, 128.0, 127.0, 126.3, 121.5.
HRMS (ESI): m/z [M + Na]+ calcd for C14H10N2NaO: 246.0685;
found: 246.0683.
7-Fluoro-2-methylquinazolin-4(3H)-one (3y)
Yield: 161.5 mg (91%); white solid; mp 255 °C (dec.).
IR (KBr): 3035, 2910, 1678, 1620, 1460, 1300, 778 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 12.29 (br s, 1 H), 8.13 (t,
J = 7.6 Hz, 1 H), 7.35–7.29 (m, 2 H), 2.35 (s, 3 H).
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13C NMR (150 MHz, DMSO-d6): δ = 165.6 (d, JC–F = 248.7 Hz),
160.9, 155.9, 151.1, 128.7 (d, JC–F = 10.4 Hz), 117.6 (d, JC–F = 22.2
Hz), 114.3, 111.5 (d, JC–F = 22.7 Hz), 21.4.
HRMS (ESI): m/z [M + H]+ calcd for C9H8FN2O: 179.0615; found:
179.0616.
Acknowledgment
Y.D. acknowledges the National Natural Science Foundation of
China (#21072148), Cultivation Foundation (B) for Young Faculty
of Tianjin University (TJU-YFF-08B68), and the Innovation Foun-
dation of Tianjin University (2013XJ-0005) for financial support.
(6) Davoodnia, A.; Allameh, S.; Fakhari, A. R.; Tavakoli-
Hoseini, A. Chin. Chem. Lett. 2010, 21, 550.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 2998–3006
© Georg Thieme Verlag Stuttgart · New York