Approach to the Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones Mediated by Ph3P-I2

Article abstract of DOI:10.1021/acs.joc.7b01322

Readily available N-substituted amides or their requisite carboxylic acids or acid chlorides have been used to construct 2,3-disubstituted-3H-quinazolin-4-ones in a one-pot procedure. Key transformation in this convergent approach involves Ph₃P-I₂-mediated formation of amidine upon condensation of an amide or the intermediate amide with methyl anthranilate. Cyclization of the amidine-tethered anthranilate then affords 2,3-disubstituted-3H-quinazolin-4-ones in good to excellent yields under mild conditions.

Full text of DOI:10.1021/acs.joc.7b01322

Article
pubs.acs.org/joc
Approach to the Synthesis of 2,3-Disubstituted‑3H‑quinazolin-4-ones
Mediated by Ph3P−I2
Wong Phakhodee,* Sirilak Wangngae, and Mookda Pattarawarapan
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang
Mai 50200, Thailand
S
* Supporting Information
ABSTRACT: Readily available N-substituted amides or their
requisite carboxylic acids or acid chlorides have been used to
construct 2,3-disubstituted-3H-quinazolin-4-ones in a one-pot
procedure. Key transformation in this convergent approach
involves Ph3P−I2-mediated formation of amidine upon
condensation of an amide or the intermediate amide with
methyl anthranilate. Cyclization of the amidine-tethered
anthranilate then affords 2,3-disubstituted-3H-quinazolin-4-ones in good to excellent yields under mild conditions.
chloride prepared by reacting lactam-HCl salts with POCl3
(Scheme 1).16
INTRODUCTION
■
Quinazoline-4(3H)-ones represent a unique class of hetero-
cycles that attracted considerable attention among organic and
medicinal chemists.1 Both naturally occurring and synthetic
quinazolinones, especially the 2,3-disubstituted derivatives, have
been shown to exhibit a broad spectrum of pharmacological
and biological activities, including antibacterial, antifungal,
antimalaria, antiviral, anti-inflammatory, antidiabetic, antituber-
culosis, and antitumor properties.2 Their potent inhibitory
effects on thymidylate synthase, poly(ADP-ribose) polymerase
(PARP), cholecystokinin, and thyrosine kinase have also been
reported.3
Although these methods have their own merits, most of them
still suffer from various limitations, such as requirement of
multistep procedure, costly and toxic reagents/or catalysts,
harsh reaction conditions, and long reaction times. Additionally,
some of the starting materials are not readily available and are
difficult to prepare, while the conditions are only applicable for
limited substrate scope. Considering the importance of this
class of molecules, the development of new mild and economic
methods that enable a convenient access to diverse quinazolin-
4(3H)-ones from simple and readily accessible precursors is
highly desirable.
Currently, several approved drugs with sedative, hypnotic,
and anxiolytic properties, such as methaqualone, mebroqu-
alone, mecloqualone, etaqualone, and piriqualone, are on the
market for treatment of insomnia and for use as a sedative and
muscle relaxant (Figure 1). Tryptanthrin is a plant alkaloid with
anti-inflammatory and anticancer activities. Idelalisib, ispinesib,
and raltitrexed have been in the market or are currently in
clinical trials for treatment of cancers.2
Owing to their remarkable properties as potential therapeutic
candidates, numeral synthetic methods have been developed
toward this compound class.2,4 Representative examples of
these methodologies include (i) condensation of 2-amino-
benzamides with aldehydes or 1,3-diketones;5 (ii) oxidation/
cyclization reaction of 2-aminobenzamides derived from isatoic
anhydride with aldehydes,6 benzyl halides,7 benzyl alcohols,8 or
orthoesters;9 (iii) amidation of benzoxazinones with aryl-
amines;10 (iv) reductive cyclization of 2-nitrobenzamides with
carbonyl compounds;11 (v) palladium-catalyzed cyclocarbony-
lation of o-haloanilines with N-toluenesulfonyl aldimines12 or
imidoyl chlorides;13 (vi) metal-catalyzed arylation of quinazo-
linones with aryl halides;14 (vii) intramolecular dehydrative
cyclization of the diamide derivatives of anthranilic acid;15 and
(viii) condensation of methyl anthranilate with an imidoyl
Recently, our group has reported that amidines could be
efficiently synthesized from amides using a combination of
triphenylphosphine (Ph3P) and iodine (I2) under mild
conditions.17 In a continuing study, this method was extended
toward the synthesis of 2,3-disubstituted-3H-quinazolin-4-ones
(Scheme 1). Although the Ph3P−I2 system has previously been
applied in the synthesis of quinazolinone derivatives from the
diamides of anthranilic acid (Scheme 1, route vii),15b−d to the
best of our knowledge, this reagent system has never been
applied in the condensation of readily available methyl
anthranilate and amides. We thus presented here a detailed
study of the reaction between amides and methyl anthranilate
mediated by the Ph3P−I2 system.
RESULTS AND DISCUSSION
■
First, the formation of 2,3-disubstituted-3H-quinazolin-4-one
was explored using N-methylbenzamide in reaction with methyl
anthranilate as model substrates. According to the previously
reported procedure for amidine synthesis,17 the reaction carried
out using Ph3P (1.5 equiv), I2 (1.5 equiv), and triethylamine (5
Received: May 30, 2017
© XXXX American Chemical Society
A
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Figure 1. Examples of bioactive 2,3-disubstituted quinazoline-4(3H)-ones.
Scheme 1. Reported Methods and the Present Strategy for the Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones
equiv) in dichloromethane was found to provide the
corresponding quinazolinone product in good yield at room
temperature (Table 1, Entry 1). The efficiency of the reaction
significantly decreased when replacing I2 with other halo-
genated additives, such as carbon tetrachloride, N-chlorosucci-
nimide (NCS), bromine, and N-bromosuccinimide (NBS)
(Table 1, Entries 2−5). Only trace amount of the product was
observed when the reaction was conducted with more polar
solvents including THF and acetonitrile (Table 1, Entries 6, 7).
Attempt to improve the product yield by increasing the reaction
temperatures in 1,2-dichloroethane or toluene also failed to give
satisfactory results possibly due to insolubility of polar
intermediates as well as their decomposition at elevated
temperature (Table 1, Entries 8, 9). Additionally, other
variation of the reactant and reagent quantities, addition
order, and reaction time did not lead to significant enhance-
ment of the final outcomes.
After having established the optimum reaction conditions,
the scope of the reaction was then examined using a variety of
N-aryl and N-alkyl substituted amides. These compounds were
subjected to our conditions without further modification.
According to Table 2, the reaction was applicable to a broad
range of amide substrates as several 2,3-disubstituted
quinazolinone derivatives were prepared in satisfactory yields.
In the reaction with N-methylbenzamide, anthranilate esters
containing -Cl or -I group were less reactive giving the
corresponding quinazolinones in lower yields than the parent
methyl anthranilate (Entries 1−3). Benzamide bearing N-aryl
B
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a
proton which make it difficult to form reactive intermediate
under the applied conditions.18
Table 1. Optimization of the Reaction Conditions
Multicomponent reactions have attracted considerable
interest for their high synthetic efficiency. In order to avoid
chromatographic purification of the requisite amide, a one-pot
three-component reaction toward quinazolinones was inves-
tigated. The in situ generated intermediate amide should
undergo activation with Ph3P−I2, before reacting with methyl
anthranilate to yield the 2,3-disubstituted quinazolin-4-ones.
Since no coupling reagent is necessary for the reaction of acid
chloride with an amine, the one-pot synthesis of quinazolinones
was carried out by sequentially mixing equimolar ratio of both
substrates to provide an amide, followed by coupling with
methyl anthranilate in the presence of Ph3P−I2. As shown in
Scheme 2, the reaction using different acid chlorides and
amines proceeded well to give the corresponding quinazoli-
nones in good yields. Remarkably, the sedative drug, methaqu-
alone, was directly obtained in 84% yield. This result is
comparable to the above-described method where amide was
obtained and purified from a separate step (Table 2, Entry 13)
indicating no interference from the first amide bond formation.
To our delight, the reaction could also be carried out starting
directly from a carboxylic acid. In this case, a one-pot procedure
toward quinazolinones was performed by increasing the
amount of the dehydrating agent. As shown in Scheme 3, the
three-component reaction of carboxylic acids, amines, and
methyl anthranilate proceeded smoothly to afford the
corresponding quinazoline-4(3H)-ones in reasonable yields.
By adding Ph3P (2.5 equiv), I2 (2.5 equiv), and 6 equiv of
triethylamine in one portion during the amide bond forming
step, the in situ generated N-benzyl benzamide reacted with
methyl anthranilate to provide the product 4a in good yield.
Nevertheless, the intermediate amide derived from an electron-
deficient nitro substituted acid gave low conversion toward 4b.
Noteworthy that 3-styrylquinazolinone derivative 4c, a carbon
analog of piriqualone, could be readily prepared in satisfactory
yield in one-pot. 2,3-Diaryl (3H)-quinazolin-4-one 4d was also
obtained in good yield from heteroaromatic acid.
The synthesis of 2,3-dialkyl-substituted quinazolinones
starting directly from a carboxylic acid was proven to be
much more difficult giving low to moderate yields of the
products 4e−4j. In these cases, amide bond forming step seems
to be the main problem. According to our previous study in the
Ph3P/I2-mediated synthesis of amides,19 the reaction between
aliphatic acids and aliphatic amines is generally slow with
incomplete conversion. Thus, the remained reactants from the
first amide bond forming may interfere with the following
reaction with methyl anthranilates. Indeed, compound 4e was
obtained in 63% yield when starting from the requisite amide
prepared and isolated from a separate step. It was also observed
that the yields were improved when the reagents were added in
two portions during the activation of a carboxylic acid to form
an amide and 30 min before treatment of the formed amide
with anthranilate.
entry
additive
solvent
temperature (°C)
yield (%)
1
2
3
4
5
6
7
8
9
I2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
25
25
25
25
25
25
80
110
84
CCl4
NCS
Br2
NBS
I2
48
NR
NR
NR
trace
trace
77
I2
CH3CN
DCE
I2
I2
toluene
18
a
Reaction conditions: N-methylbenzamide (0.28 mmol), methyl
anthranilate (0.34 mmol), Ph3P (0.42 mmol), additive (0.42 mmol),
and Et3N (1.4 mmol), solvent 2 mL, 0 °C−RT for 2 h. DCE = 1,2-
dichloroethane. NR = no reaction
substituent, such as benzanilide, also provided lower yield of the
cyclized product 2d possibly due to the low reactivity of the
arylamido nitrogen (Entry 4). In most of the cases, the reaction
of N-benzylbenzamide derivatives with methyl anthranilate
proceeded smoothly to give the cyclized products in good
yields (Entries 5−9). While the substrate bearing strong
electron-withdrawing nitro group gave low product yield (entry
6), other N-benzylbenzamides substituted with p-Br, (Entry 7),
o-Cl (Entry 8) as well as sterically hindered o-Me group (entry
9) provided the corresponding quinazolinones 2g−2i in high
yields. The reaction also proceeded smoothly with N-benzyl
amides containing conjugated cinnamyl group (Entry 10) or
alkyl moiety (Entries 11 and 12).
Further, the effect of substituents on the N-aryl ring of the
acetamides was investigated as shown in Entries 13−17.
Various N-arylacetamide substrates efficiently participated in
the reaction providing the products in good yields. The
presence of electron-donating groups in N-aryl substituent,
such as o-CH3 and p-OEt, gave higher yields of quinazolinones
(Entries 13 and 14) when comparing with the substrate having
an electron-withdrawing group, such as p-Cl (Entry 15). In the
case of N-(4-nitrophenyl)acetamide (Entry 16), no conversion
was observed which should be mainly due to the poor
nucleophilicity of the aryl amido group. The reaction condition
was compatible with the methyl ester group in N-arylacetamide
albeit with low yield due to incomplete cyclization of the
formed amidine intermediate (Entry 17). Nevertheless, the
isolation of this uncyclized product suggested that the
formation of amidine-tethered anthranilate is the key step
toward quinazolinone.
Evidently, both electronic and steric effects play crucial rule
in controlling amidine formation and the cyclization process.
The formation of intermediate amidine is less favorable when
the electron-withdrawing substituent is presented on the
aromatic ring of aryl amides, while its presence on N-aryl
group on the amide substrates makes the aryl amido nitrogen
less nucleophilic leading to ineffective cyclization. Sterically
hindered group also disfavors the ring closing reaction.
It is noted that attempt to use primary amides, such as
benzamide or acetanilide, to form quinazolinones failed to yield
the desired products. This may in part be due to low solubility
of these substrates as well as the low acidity of the amide
It should be noted that the reported conditions for synthesis
of 2,3-dialkyl-substituted quinazolinones often required ele-
vated temperatures and long reaction times.20 Low yield or no
product formation has been observed in several cases including
those metal-catalyzed reactions.13,14,21 Additionally, although
several one-pot three-component reactions toward substituted
quinazolinone have been reported,22 these methods still suffer
from harsh reaction conditions, expensive reagents, and/or
limited substrate scope. To the best of our knowledge, a mild
C
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Table 2. Synthesis of 2,3-Substituted-3H-quinazolin-4-ones Using Ph3P/I2/Et3N
a
Reaction conditions: amide (0.28 mmol), methyl anthranilates (0.34 mmol), Ph3P (0.42 mmol), iodine (0.42 mmol) and Et3N (1.4 mmol), CH2Cl2
b
2 mL, 0 °C−RT. Yield of noncyclized product.
method for direct access to broad scope of quinazolinone
derivatives in one-pot from readily available reactants is
unprecedented.
ppm corresponded to triphenylphosphonium iodide to 36.3
ppm. This result indicates the formation of a new phosphonium
species which could be resulted from the phosphorylation of
the amido oxygen. After treatment with triethylamine, this
signal rapidly disappeared with a release of Ph3PO (29.1
ppm)19 suggesting the formation of imidoyl iodide at this stage.
Subsequent adding with methyl anthranilate caused no
significant change in the 31P{1H} NMR spectrum excluding
the formation of other possible intermediates such as
aryliminophosphoranes which should appear at ca. 3−8 ppm.23
The 1H and 13C NMR spectra of crude reaction after 10 min
treatment with methyl anthranilate also provide useful
information (see Figure S2 in ESI). Four kinds of methyl
group including -NCH3 group of amides, -NCH3 group of
Based on the above results, it is highly likely that the amido
oxygen would undergo initial phosphorylation, followed by
converting to imidoyl iodide before reacting with methyl
anthranilate. To obtain more evidence for the formation of
phosphorus-containing intermediates as well as imidoyl iodide,
further experiments were conducted using NMR studies to
follow the progress of the reaction between N-methylbenza-
mide and methyl anthranilate.
According to 31P{1H} NMR spectra of the reaction mixture
(see Figure S1 in ESI), addition of N-methylbenzamide into the
Ph3P−I2 solution caused a significant shift of the signal at 44.4
D
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Scheme 2. Ph3P−I2-Mediated Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones from Acid Chlorides
a
Scheme 3. Ph3P−I2-Mediated Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones from Carboxylic Acids
a
The yield obtained from an amide was given in parentheses.
imidoyl iodide, -NCH3 of the desired quinazolinone product,
and -OCH3 of methyl anthranilate were observed at 2.96, 3.37,
3.49, 3.83 ppm, respectively. The 13C{1H} NMR spectrum
strongly supports the inclusion of imidoyl iodide intermediate
(CH3NCIPh) at 109.8 ppm.24
Scheme 4. Proposed Mechanism for the Ph3P−I2-Mediated
Synthesis of Substituted Quinazolinones
On the basis of these data, the mechanism for the formation
of quinazolinones was proposed as shown in Scheme 4.
Treatment of Ph3P with I2 provides reactive triphenylphos-
phonium iodide I. Phosphorylation at the oxygen atom of the
starting amide yields imidinium intermediate II. This species is
then converted into imidoyl iodide III in the presence of base.
Displacement of iodide of III with an amine function of methyl
anthranilate leads to the intermediate amidine IV before an
intramolecular cyclization to furnish quinazolinone product.
E
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HRMS calcd for C15H1237ClN2O (M+H)+ 273.0608, found 273.0614,
for C15H1635ClN2O (M+H)+271.0638, found 271.0637.
CONCLUSIONS
■
6-Iodo-3-methyl-2-phenylquinazolin-4(3H)-one.26 Table 2, entry
3, compound 2c; white solid; (0.0656 g, 74% yield); mp 137−138 °C;
In summary, we have developed a facile and cost-effective
method for convergent synthesis of 2,3-disubstituted-3H-
quinazolin-4-ones through Ph3P−I2-mediated amidine forma-
tion/cyclization sequence. A variety of quinazolinones could be
readily obtained in one-pot under mild conditions from readily
available starting materials and inexpensive reagents. This
convergent approach provides a useful alternative for
quinazolinone formation circumventing many issues associated
with previously reported processes.
1
Rf 0.23 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 8.64
(d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.6, 2.0 Hz, 1H), 7.62−7.48 (m, 5H),
7.45 (d, J = 8.6 Hz, 1H), 3.48 (s, 3H).
2,3-Diphenylquinazolin-4(3H)-one.13 Table 2, entry 4, compound
2d; yellow solid; (0.0604 g, 72% yield); mp 156−157 °C (lit.13 mp
1
158−159 °C); Rf 0.37 (20% EtOAc/hexanes); H NMR (400 MHz,
CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 7.85−7.78 (m, 2H), 7.53 (ddd, J =
8.0, 6.0, 2.0 Hz, 1H), 7.36−7.14 (m, 10H).
3-Benzyl-2-phenylquinazolin-4(3H)-one.6b Table 2, entry 5,
compound 2e; yellow solid; (0.0778 g, 89% yield and 0.0735 g, 84%
yield for 4a); mp 136−138 °C (lit.6b mp 137−139 °C); Rf 0.27 (20%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 7.6 Hz,
1H), 7.81−7.75 (m, 2H), 7.55−7.33 (m, 6H), 7.22−7.19 (m, 3H),
6.94−6.92 (m, 2H), 5.28 (s, 2H).
EXPERIMENTAL SECTION
■
Experimental Procedure. Material and Methods. All reagents
were purchased from Sigma-Aldrich Co., USA, and used without
further purification. The reaction was monitored by thin-layer
chromatography carried out on silica gel plates (60F254, MERCK,
Germany) and visualized under UV light (254 nm). Melting points
were determined using Mettler Toledo DSC equipment at a heating
rate of 6 °C/min and are uncorrected. NMR spectra were determined
3-Benzyl-2-(4-nitrophenyl)quinazolin-4(3H)-one.14a Table 2,
entry 6, compound 2f; yellow solid; (0.0350 g, 35% yield); mp
120−122 °C (lit.14a mp 121−123 °C); Rf 0.23 (20% EtOAc/hexanes;
1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 8.0, 1.6 Hz, 1H), 8.23 (d,
J = 8.8 Hz, 2H), 7.83 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.75 (dd, J = 8.0,
1.6 Hz, 1H), 7.59 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.49 (d, J = 8.8 Hz,
2H), 7.25−7.21 (m, 3H), 6.89−6.87 (m, 2H), 5.24 (s, 2H).
3-Benzyl-2-(4-bromophenyl)quinazolin-4(3H)-one.27 Table 2,
entry 7, compound 2g; white solid; (0.0901 g, 82% yield); mp 142−
143 °C (lit.27 mp 144−145 °C) ; Rf 0.35 (20% EtOAc/hexanes);1H
NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.81−7.73
(m, 2H), 7.56−7.51 (m, 3H), 7.24−7.20 (m, 5H), 6.94−6.92 (m, 2H),
5.25 (s, 2H).
1
using a Bruker AVANCE (400 MHz for H). Chemical shifts were
reported in parts per million (ppm, δ) downfield from TMS. Splitting
patterns are described as singlet (s), doublet (d), triplet (t), quartet
(q), quintet (qui), sextet (sex), multiplet (m), broad (br), doublet of
doublets (dd), triplet of doublets (td), and doublet of doublet of
doublets (ddd). High resolution mass spectra (HRMS) were recorded
using the LC-DAD-ESI-MS/MS system consisted of a Waters Alliance
2695 LC-DAD and a Q-TOF 2 (quadrupole mass filter-time-of-flight)
mass spectrometer with a Z-spray ES source.
General Procedure for the Synthesis of 2,3-Disubstituted-3H-
quinazolin-4-ones from Amides or Acid Chlorides. To a solution of
amide (0.28 mmol) in CH2Cl2 (2 mL) was added iodine (107 mg,
0.42 mmol) and triphenylphosphine (111 mg, 0.42 mmol) in one
portion at 0 °C. Triethylamine (0.20 mL, 1.40 mmol) was
subsequently added into the mixture with continuous stirring at 0
°C for 30 min. After that, methyl anthranilate (0.34 mmol) was added
and the reaction mixture was allowed to warm up to room temperature
and stirred until completion of the reaction. The crude mixture was
concentrated under reduced pressure then purified by column
chromatography (CC) using 5−20% ethyl acetate in hexane. A one-
pot method starting from acid chloride was also carried out according
to the above-described procedure except that acid chloride (0.28
mmol) was reacted with an amine (0.28 mmol) in CH2Cl2 (2 mL) to
generate amide in situ before treatment with Ph3P−I2 reagent.
General Procedure for the Synthesis of 2,3-Disubstituted-3H-
quinazolin-4-ones from Carboxylic Acids. To a solution of a
carboxylic acid (0.28 mmol) in CH2Cl2 (2 mL) was added an amine
(0.28 mmol), followed by iodine (178 mg, 0.70 mmol) and
triphenylphosphine (184 mg, 0.70 mmol) in one portion at 0 °C.
Triethylamine (0.23 mL, 1.68 mmol) was then added into the reaction
mixture which was allowed to stir at room temperature until the
disappearance of the acid as indicated by TLC. Subsequently, methyl
anthranilate (0.34 mmol) was added at 0 °C and the reaction mixture
was further stirred at room temperature until completion of the
reaction. The crude mixture was concentrated under reduced pressure
then purified by column chromatography (CC) using 5−20% ethyl
acetate in hexane.
3-Benzyl-2-(2-chlorophenyl)quinazolin-4(3H)-one. Table 2, entry
8, compound 2h; colorless oil; (0.0857 g, 88% yield); Rf 0.38 (20%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 8.2, 1.6
Hz, 1H), 7.82−7.75 (m, 2H), 7.56 (ddd, J = 8.2, 6.6, 1.6 Hz, 1H), 7.48
(dd, J = 8.0, 1.6 Hz, 1H), 7.41 (td, J = 8.0, 1.6 Hz, 1H), 7.23−7.13 (m,
4H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 6.87−6.85 (m, 2H), 5.77 (d, J =
15.2 Hz, 1H), 4.62 (d, J = 15.2 Hz, 1H).; 13C{1H}NMR (100 MHz,
CDCl3) δ 162.3, 153.7, 147.3, 136.3, 134.7, 134.4, 132.4, 131.2, 130.5,
129.7, 128.5, 127.8, 127.7, 127.6, 127.4, 127.3, 127.1, 121.3, 48.1;
TOF-HRMS calcd for C21H1637ClN2O (M+H)+ 349.0921, found
349.0913, for C21H1635ClN2O (M+H)+ 347.0951, found 347.0896.
3-Benzyl-2-(o-tolyl)quinazolin-4(3H)-one.14a Table 2, entry 9,
compound 2i; colorless solid; (0.0753 g, 82% yield); mp 110−111
°C (lit.14a mp 112−113 °C); Rf 0.40 (20% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.81−7.74 (m,
2H), 7.54 (ddd, J = 8.0, 6.6, 1.6 Hz, 1H), 7.37 (td, J = 7.6, 1.6 Hz, 1H),
7.24−7.12 (m, 6H), 6.86 (dd, J = 7.6, 1.6 Hz, 2H), 5.24 (d, J = 14.8
Hz, 1H), 5.09 (d, J = 14.8 Hz, 1H), 1.96 (s, 3H).
(E)-3-Benzyl-2-styrylquinazolin-4(3H)-one.28 Table 2, entry 10,
compound 2j; white solid; (0.0684 g, 72% yield); mp 138−139 °C
(lit.28 mp 138−140 °C); Rf 0.24 (10% EtOAc/hexanes); H NMR
1
(400 MHz, CDCl3) δ 8.35 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 15.6 Hz,
1H), 7.79−7.75 (m, 2H), 7.49−7.44 (m, 3H), 7.39−7.26 (m, 8H),
7.03 (d, J = 15.6 Hz, 1H), 5.52 (s, 2H).
2,3-Dibenzylquinazolin-4(3H)-one.20d Table 2, entry 11, com-
pound 2k; yellow solid; (0.0716 g, 78% yield); mp 168−169 °C (lit.20d
1
mp 167−168 °C); Rf 0.32 (10% EtOAc/hexanes); H NMR (400
MHz, CDCl3) δ 8.35 (dd, J = 8.0, 1.6 Hz, 1H), 7.82−7.75 (m, 2H),
7.51 (ddd, J = 8.0, 6.6, 1.6 Hz, 1H), 7.36−7.23 (m, 8H), 7.16 (d, J =
7.2 Hz, 2H), 5.27 (s, 2H), 4.11 (s, 2H).
3-Methyl-2-phenylquinazolin-4(3H)-one.25 Table 2, entry 1,
compound 2a; white solid; (0.0557 g, 84% yield); mp 132−133 °C
(lit.25 mp 131−132 °C); Rf 0.31 (20% EtOAc/hexanes); H NMR
1
3-Benzyl-2-methylquinazolin-4(3H)-one.29 Table 2, entry 12,
compound 2l; colorless solid; (0.0654 g, 93% yield); mp 120−121
°C (lit.29 mp 123−124 °C); Rf 0.28 (30% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.30 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 (t, J = 8.0
Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.34−7.24
(m, 3H), 7.19 (d, J = 7.2 Hz, 3H), 5.39 (s, 2H), 2.54 (s, 3H).
2-Methyl-3-(o-tolyl)quinazolin-4(3H)-one.29 Table 2, entry 13,
compound 2m; yellow solid; (0.0598 g, 85% yield and 0.0590 g, 84%
yield for 3d); mp 121−123 °C (lit.29 mp 119−121 °C) ; Rf 0.33 (30%
(400 MHz, CDCl3) δ 8.32 (d, J = 8.0 Hz, 1H), 7.77−7.71 (m, 2H),
7.58−7.47 (m, 6H), 3.49 (s, 3H).
6-Chloro-3-methyl-2-phenylquinazolin-4(3H)-one. Table 2, entry
2, compound 2b; white solid; (0.0541 g, 71% yield); mp 130−133 °C;
Rf 0.27 (10% EtOAc/hexanes);1H NMR (400 MHz, CDCl3) δ 8.25
(d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 2H), 7.56−7.50 (m, 5H), 3.48
(s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 161.8, 156.4, 145., 135.2,
134.8, 132.8, 130.3, 129.3, 129.0, 128.1, 126.1, 121.6, 34.5; TOF-
F
DOI: 10.1021/acs.joc.7b01322
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The Journal of Organic Chemistry
Article
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 8.0, 1.6
Hz, 1H), 7.77 (ddd, J = 8.2, 7.2, 1.6 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H),
7.47 (ddd, J = 8.2, 7.2, 1.6 Hz, 2H), 7.43−7.30 (m, 4H), 7.16 (d, J =
7.2 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H).
2-(2-Chloropyridin-3-yl)-3-(p-tolyl)quinazolin-4(3H)-one. Scheme
3, compound 4d; colorless crystal; (0.0762 g, 78% yield); mp 157−159
1
°C; Rf 0.23 (30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ
8.35 (dd, J = 8.0, 1.6 Hz, 1H), 8.28 (dd, J = 5.0, 1.6 Hz, 1H), 7.81 (m,
2H), 7.63 (dd, J = 7.6, 2.0 Hz, 1H), 7.56 (ddd, J = 8.0, 6.8, 1.6 Hz,
1H), 7.31 (d, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.6, 5.0 Hz, 1H), 7.12−
7.06 (m, 1H), 6.92 (br s, 1H), 2.25 (s, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ 161.9, 151.5, 150.3, 148.7, 147.2, 139.3, 139.0, 134.9, 133.7,
131.4, 130.2, 129.7, 128.5, 128.0, 127.9, 127.8, 127.3, 121.8, 121.5,
21.2; TOF-HRMS calcd for C20H1537ClN3O (M+H)+ 350.0874, found
350.0857, for C20H1535ClN3O (M+H)+ 348.0904, found 348.0896.
2-Benzyl-3-butylquinazolin-4(3H)-one.20b Scheme 3, compound
4e; colorless crystal; (0.0404 g, 49% yield); mp 125−127 °C (lit.20b
3-(4-Ethoxyphenyl)-2-methylquinazolin-4(3H)-one.30 Table 2,
entry 14, compound 2n; yellow solid; (0.0699 g, 89% yield); mp
146−147 °C (lit.30 mp 152−154 °C); Rf 0.26 (30% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 7.74 (t, J =
8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.14 (d,
J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.08 (q, J = 6.8 Hz, 2H),
2.24 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H).
3-(Chlorophenyl)-2-methylquinazolin-4(3H)-one.29 Table 2, entry
15, compound 2o; a white solid; (0.0631 g, 83% yield); mp 155−156
°C (lit.29 mp 157−158 °C); Rf 0.30 30% EtOAc/hexanes); H NMR
1
1
mp 127 °C); Rf 0.48 (20% EtOAc/hexanes); H NMR (400 MHz,
(400 MHz, CDCl3) 8.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (ddd, J = 8.0,
7.2, 1.6 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (d, J = 8.8 Hz,
2H), 7.46 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 2.24
(s, 3H).
CDCl3) δ 8.26 (dd, J = 8.2, 1.6 Hz, 1H), 7.76−7.69 (m, 2H), 7.46
(ddd, J = 8.2, 6.8, 1.6 Hz, 1H), 7.34−7.25 (m, 5H), 4.25 (s, 2H), 3.96
(t, J = 7.2 Hz, 2H), 1.54 (m, 2H), 1.34 (sex, J = 7.2 Hz, 2H), 0.90 (t, J
= 7.2 Hz, 3H).
Methyl 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)benzoate.31 Table
2, entry 17, compound 2q; yellow solid; (0.0306 g, 37% yield); mp
118−119 °C (lit.31 mp 114−115 °C) ; Rf 0.39 (30% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.4 Hz, 1H), 8.21 (d, J =
3-Benzyl-2-ethylquinazolin-4(3H)-one.20b Scheme 3, compound
4f; colorless crystal; (0.0296 g, 40% yield); mp 117−119 °C; Rf 0.44
1
(20% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 8.31 (dd, J =
8.0, 1.2 Hz, 1H), 7.74 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 7.68 (dd, J = 8.0,
1.2 Hz, 1H), 7.46 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 7.34−7.23 (m, 3H),
7.17 (d, J = 7.6 Hz, 1H), 5.42 (s, 3H), 2.77 (q, J = 7.2 Hz, 2H), 1.32 (t,
J = 7.2 Hz, 3H).
8.4 Hz, 1H), 7.78−7.68 (m, 3H), 7.60 (t, J = 7.6 Hz, 1H),7.44 (t, J =
7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 3.69 (s, 3H), 2.19 (s, 3H).
Methyl (Z)-2-(N′-(2-(methoxycarbonyl)phenyl)acetimidamido)-
benzoate. Table 2, entry 17, noncyclized product; yellow oil;
(0.0442 g, 48% yield); Rf 0.41 (30% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.74 (br s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.77
(d, J = 7.6 Hz, 1H), 7.30−7.24 (m, 3H), 6.98 (t, J = 7.6 Hz, 2H), 6.68
(d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 2.15 (s, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ 169.0, 167.6, 158.6, 149.7, 148.2,
2-Benzyl-3-(4-methoxybenzyl)quinazolin-4(3H)-one. Scheme 3,
compound 4g; colorless oil; (0.0473 g, 47% yield); Rf 0.44 (20%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 8.0, 1.6
Hz, 1H), 7.80−7.72 (m, 2H), 7.50 (ddd, J = 8.0, 6.8, 1.6 Hz, 1H),
7.36−7.23 (m, 5H), 7.11 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H),
5.19 (s, 2H), 4.14 (s, 2H), 3.78 (s, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ 162.9, 159.2, 155.6, 147.4, 135.4, 134.5, 129.2, 128.3, 128.2,
127.8, 127.5, 127.3, 127.2, 126.9, 120.7, 114.5, 55.4, 45.9, 42.3; TOF-
HRMS calcd for C23H21N2O2 (M+H)+ 357.1603, found 357.1596.
Methyl 2-(2-(4-methoxybenzyl)-4-oxoquinazolin-3(4H)-yl)-
acetate one. Scheme 3, compound 4h; brown solid; (0.0259 g, 27%
136.0, 133.0, 130.7, 130.5, 129.3, 123.16, 123.12, 123.07, 122.3, 121.4,
55.1, 52.1, 24.5; TOF-HRMS calcd for C18H19N2O4 (M+H)+
327.1345, found 327.1349.
3-(4-Methoxybenzyl)-2-phenylquinazolin-4(3H)-one.20d Scheme
2, compound 3a; white solid; (0.0818 g, 85% yield); mp 187−189
°C (lit.20d mp 187−189 °C); Rf 0.30 (20% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) δ 8.37 (d, J = 8.0 Hz, 1H), 7.78−7.73 (m, 2H),
7.53−7.35 (m, 6H), 6.85 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H),
5.21 (s, 2H), 3.73 (s, 3H).
1
yield); mp 112−114 °C; Rf 0.40 (30% EtOAc/hexanes); H NMR
(400 MHz, CDCl3) δ 8.25 (dd, J = 8.0,1.6 Hz, 1H), 7.78−7.74 (m,
2H), 7.48 (ddd, J = 8.0, 6.8, 1.6 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.85
(d, J = 8.8 Hz, 2H), 4.77 (s, 2H), 4.09 (s, 2H), 3.78 (s, 3H), 3.68 (s,
3H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.0, 162.3, 159.0, 154.7,
147.2, 134.6, 132.0. 129.4, 127.3, 127.0, 126.3, 120.2, 114.5, 55.3, 52.7,
44.9, 41.9; TOF-HRMS calcd for C19H19N2O4 (M+H)+ 339.1345,
found 339.1336.
3-Butyl-2-phenylquinazolin-4(3H)-one.13 Scheme 2, compound
3b; white solid; (0.0493 g, 63% yield); mp 113−114 °C (lit.13 mp
1
112−113 °C); Rf 0.44 (20% EtOAc/hexanes); H NMR (400 MHz,
CDCl3) δ 8.32 (d, J = 7.6 Hz, 1H), 7.77−7.71 (m, 2H), 7.54−7.47 (m,
6H), 3.97 (t, J = 7.6 Hz, 2H), 1.62−1.55 (m, 2H), 1.17 (sex, J = 7.6
Hz, 2H), 0.75 (t, J = 7.6 Hz, 3H).
6-Chloro-3-cyclopropyl-2-(2-methoxybenzyl)quinazolin-4(3H)-
one. Scheme 3, compound 4i; yellow solid; (0.0394 g, 41% yield); mp
1
160−162 °C; Rf 0.36 (20% EtOAc/hexanes); H NMR (400 MHz,
3-(4-(Diethylamino)phenyl)-2-ethylquinazolin-4(3H)-one.
CDCl3) δ 8.17 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.52
(d, J = 8.8 Hz, 1H), 7.26−7.22 (m, 1H), 7.08 (dd,, J = 7.6, 1.6 Hz,
1H), 6.88 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 4.41 (s, 2H),
3.79 (s, 3H), 2.75−2.69 (m, 1H), 1.26−1.23 (m, 2H), 0.94−0.89 (m,
2H); 13C{1H}NMR (100 MHz, CDCl3) δ 162.6, 158.8, 157.1, 145.7,
134.4, 132.1, 129.7, 128.7, 128.4, 126.0, 124.7, 122.3, 120.9, 110.6,
55.5, 36.2, 27.6, 10.6; TOF-HRMS calcd for C19H1837ClN2O2 (M+H)+
343.1027, found 343.1012, for C19H1835ClN2O2 (M+H)+ 341.1057,
found 341.1046.
Scheme 2, compound 3c; yellow solid; (0.0678 g, 75% yield); mp
165−167 °C; Rf 0.54 (20% EtOAc/hexanes); H NMR (400 MHz,
1
CDCl3) δ 8.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.75−7.68 (m, 2H), 7.42
(ddd, J = 8.0, 6.6, 1.6 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.74 (d, J =
9.0 Hz, 2H), 3.39 (q, J = 7.2 Hz, 4H), 2.53 (q, J = 7.2 Hz, 2H), 1.24−
1.19 (m, 9H); 13C{1H}NMR (100 MHz, CDCl3) δ 163.1, 159.3,
148.1, 147.7, 134.3, 128.8, 127.2, 127.0, 126.3, 124.5, 121.0, 112.0,
44.5, 29.5, 12.6, 11.5; TOF-HRMS calcd for C20H24N3O (M+H)+,
322.1919, found 322.1922.
3-Butyl-2-(4-nitrophenyl)quinazolin-4(3H)-one.21d Scheme 3,
compound 4b; yellow solid; (0.0347 g, 38% yield); mp 131−132 °C
3-Cyclopropyl-6-iodo-2-(4-methoxybenzyl)quinazolin-4(3H)-one.
Scheme 3, compound 4j; yellow solid; (0.0536 g, 44% yield); mp
1
(lit.21d mp 126−128 °C); Rf 0.21 (10% EtOAc/hexanes); H NMR
1
138−140 °C; Rf 0.23 (20% EtOAc/hexanes); H NMR (400 MHz,
CDCl3) δ 8.52 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.8, 2.4 Hz, 1H), 7.38
(d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H),
4.33 (s, 2H), 3.76 (s, 3H), 2.63−2.57 (m, 1H), 1.29−1.24 (m, 2H),
0.93−0.90 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 162.0, 158.8,
146.2, 142.8, 135.4, 129.6, 128.8, 127.2, 122.22, 114.3, 90.8, 55.3, 41.5,
27.4, 10.9; TOF-HRMS calcd for C19H18IN2O2 (M+H)+, 433.0413,
found 433.0406.
3-Butyl-2-(4-fluorobenzyl)-6-iodoquinazolin-4(3H)-one. Scheme
3, compound 4k; colorless oil; (0.0529 g, 43% yield); Rf 0.33 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.0 Hz,
1H), 7.98 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.23−
(400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 2H), 8.33 (dd, J = 8.0, 1.6
Hz, 1H), 7.80−7.73 (m, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.69 (dd, J =
8.0, 1.6 Hz, 1H), 7.53 (td, J = 8.0, 1.6 Hz, 1H), 3.94 (t, J = 7.2 Hz,
2H), 1.61−1.54 (m, 1H), 1.18 (sex, J = 7.2 Hz, 1H), 0.77 (t, J = 7.2
Hz, 2H).
(E)-2-styryl-3-(o-tolyl)quinazolin-4(3H)-one.28 Scheme 3, com-
pound 4c; brown solid; (0.0591 g, 62% yield); mp 160−162 °C
(lit.28 mp 162−164 °C); Rf 0.31 (30% EtOAc/hexanes); H NMR
1
(400 MHz, CDCl3) δ 8.33 (dt, J = 8.0, 1.2 Hz, 1H), 8.02 (d, J = 15.6
Hz, 1H), 7.83−7.80 (m, 2H), 7.51−7.40 (m, 3H), 7.34−7.28 (m, 5H),
7.23 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 15.6 Hz, 1H), 2.14 (s, 3H).
G
DOI: 10.1021/acs.joc.7b01322
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.20 (m, 2H), 7.04−6.98 (m, 2H), 4.17 (s, 2H), 4.03−3.73 (m, 2H),
3.93 (t, J = 7.6 Hz, 2H), 1.35 (sex, J = 7.6 Hz, 2H), 0.91 (t, J = 7.6 Hz,
3H); 13C{1H}NMR (100 MHz, CDCl3) δ 163.3, 160.9, 155.6, 146.4,
142.9, 135.6, 130.9, 129.8, 129.7, 129.0, 122.4, 116.1, 115.9, 91.0, 44.4,
41.6, 30.7, 20.2, 13.7; TOF-HRMS calcd for C19H19FIN2O (M+H)+
437.0526, found 437.0524.
(9) Kumar, D.; Jadhavar, P. S.; Nautiyal, M.; Sharma, H.; Meena, P.
K.; Adane, L.; Pancholia, S.; Chakraborti, A. K. RSC Adv. 2015, 5,
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M.; McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241. (b) Li,
X.; Lin, Q.; Wang, L. J. Iran. Chem. Soc. 2015, 12, 897. (c) Liu, J.-F.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01322.
Copies of 1H NMR of all products and 13C NMR spectra
for new compound (PDF)
(12) Okuro, K.; Alper, H. Tetrahedron Lett. 2012, 53, 2540.
(13) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829.
AUTHOR INFORMATION
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(14) (a) Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson,
T. Eur. J. Org. Chem. 2015, 2015, 7705. (b) Laclef, S.; Harari, M.;
Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.;
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(d) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432.
(e) Kshirsagar, U. A.; Mhaske, S. B.; Argade, N. P. Tetrahedron Lett.
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Corresponding Author
*E-mail: wongp2577@gmail.com; Fax: (+) 66-53-892277.
ORCID
Wong Phakhodee: 0000-0002-5489-9555
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from The Thailand Research Fund through
the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/
0206/2556) to S.W. and from the Center of Excellence for
Innovation in Chemistry (PERCH-CIC), Office of the Higher
Education Commission, Thailand, are gratefully acknowledged.
We also gratefully acknowledge Chulabhorn Research Institute
(CRI), Thailand, for assistance on ESI-MS analysis.
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DOI: 10.1021/acs.joc.7b01322
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DOI: 10.1021/acs.joc.7b01322
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