Synthesis of 1-substituted 4(1H)-quinazolinones under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2011.566407

(Chemical Equation Presented) Heating a mixture of 2-(N-alkylamino)benzoic acids, triethyl orthoformate, and ammonium acetate under solvent-free conditions generated 1-substituted 4(1H)- quinazolinones in 73-99% yields. Moreover, a possible reaction pathway was proposed. Copyright Taylor & Francis Group, LLC.

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Synthesis of 1-Substituted 4(1H)-
Quinazolinones Under Solvent-Free
Conditions
Yao Wang a , Mei Zhang a , Shengli Cao a b , Huihui Lin a , Man Gao a
& Zhongfeng Li a
a Department of Chemistry, Capital Normal University, Beijing, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking
University, Beijing, China
Accepted author version posted online: 31 Oct 2011.Published
online: 29 May 2012.
To cite this article: Yao Wang , Mei Zhang , Shengli Cao , Huihui Lin , Man Gao & Zhongfeng Li
(2012) Synthesis of 1-Substituted 4(1H)-Quinazolinones Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:18, 2715-2727, DOI: 10.1080/00397911.2011.566407
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Synthetic Communications1, 42: 2715–2727, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.566407
SYNTHESIS OF 1-SUBSTITUTED 4(1H)-
QUINAZOLINONES UNDER SOLVENT-FREE
CONDITIONS
Yao Wang,1 Mei Zhang,1 Shengli Cao,1,2 Huihui Lin,1
Man Gao,1 and Zhongfeng Li1
1Department of Chemistry, Capital Normal University, Beijing, China
2State Key Laboratory of Natural and Biomimetic Drugs, Peking University,
Beijing, China
GRAPHICAL ABSTRACT
Abstract Heating a mixture of 2-(N-alkylamino)benzoic acids, triethyl orthoformate,
and ammonium acetate under solvent-free conditions generated 1-substituted 4(1H)-
quinazolinones in 73ꢀ99% yields. Moreover, a possible reaction pathway was proposed.
Keywords Cyclization; 4(1H)-quinazolinone; solvent-free; triethyl orthoformate
INTRODUCTION
4-Quinazolinone and its derivatives, such as 2-substituted, 3-substituted, and
2,3-disubstituted 4-quinazolinones, exhibit a wide variety of biological activities,
the synthetic methodologies of which have attracted intense attention.[1–3] In fact,
many naturally occurring or synthetic 1-substituted 4(1H)-quinazolinones also
present attractive biological activities. For example, 1-methyl-4(1H)-quinazolinone,
commonly named glycorine, isolated from Glycosmis arborea, is an alkaloid with
anti-inflammatory activity,[4,5] some 1-alkenyl-4(1H)-quinazolinones have analgesic
effects equal to or better than that of codeine, and 1-allyl-4(1H)-quinazolinone
was selected for clinical trials.[6] However, few methods for the synthesis of 1-substi-
tuted 4(1H)-quinazolinones have been reported until now.[6–9]
The Niementowski ring closure was shown to be applicable to the formation of
1-substituted 4(1H)-quinazolinones. For instance, N-aryl-substituted anthranilic
acids and excess formamide reacted in a sealed tube at 150–160 ꢁC or under atmos-
pheric pressure at 170–180 ꢁC to give 1-substituted 4(1H)-quinazolinones in 20–40%
Received December 8, 2010.
Address correspondence to Shengli Cao, Department of Chemistry, Capital Normal University,
Beijing 100048, China. E-mail: sl_cao@sohu.com
2715

2716
Y. WANG ET AL.
yields.[7] However, only the N-methylanthranilic acid salt of 1-methyl-4(1-
H)-quinazolinone was isolated in very poor low yield as N-methylanthranilic acid
was heated with formamide.[8] For the synthesis of 1-alkenyl-4(1H)-quinazolinones,
Vincent and coworkers prepared 2-(N-alkenylamino)benzamides either through the
reaction of 2-aminobenzamides with alkenyl bromide or through the ammonolysis of
the N-alkenyl isatoic anhydrides, which were heated in boiling triethyl orthoformate
for 35 h while distilling off the ethanol formed, and then the reactions were continued
at room temperature for another 15 h.[6] However, no yield was stated by the
authors. Kametani et al. described another method in which N-methylsulphinamide
anhydride, prepared from the reaction of N-methylanthranilic acid with thionyl
chloride, was treated with formamide to form 1-methyl-4(1H)-quinazolinone hydro-
chloride in 47% yield.[9] The aforementioned methods for the synthesis of 1-substi-
tuted 4(1H)-quinazolinones have some drawbacks such as unsatisfactory yields,
long reaction times, and complicated procedures. Herein, we report one-step method
to synthesize 1-substituted 4(1H)-quinazolinones under solvent-free conditions in
good to excellent yields.
RESULTS AND DISCUSSION
In an attempt to prepare 1-substituted 4(1H)-quinazolinones as intermediates
for the synthesis of new anticancer agents, we heated 5-methyl-2-(N-methylamino)-
benzoic acid (3f) in excess formamide according to the Niementowski reaction, but
the cyclized product desired was hardly obtained because it was difficult to be sepa-
rated from formamide. Inspired by the reaction of anthranilic acids with orthoesters
and ammonium acetate under microwave irradiation to afford 2-substituted-4(3-
H)-quinazolinones,[10] we heated 5-methyl-2-(N-methylamino)benzoic acid (3f),
triethyl orthoformate and ammonium acetate under solvent-free condition, generat-
ing 1,6-dimethyl-4(1H)-quinazolinone (4f) as expected (Scheme 1). As presumed by
Rad-Moghadam et al.,[10] the reaction of anthranilic acid with orthoesters first gen-
erated 4H-benzo[d][1,3]oxazin-4-ones, which then interacted with ammonium acetate
and were converted into 2-(N-acylamino)benzamides, followed by cyclization
through the elimination of a molecule of H2O to give 4(3H)-quinazolinones
(Scheme 2).
As for the reaction of 3f with triethyl orthoformate, it was impossible to form
an intermediate like 4H-benzo[d][1,3]oxazin-4-one as supposed by Rad-Moghadam
et al. because of the substituent linked at the nitrogen atom of 3f. Therefore, we reck-
oned that 3f was alkylated first by triethyl orthoformate to form the N-alkylated
Scheme 1. Reaction of 3f with triethyl orthoformate and ammonium acetate.

1-SUBSTITUTED 4(1H)-QUINAZOLINONES
2717
Scheme 2. Synthesis of 2-substituted 4(3H)-quinazolinone by Rad-Moghadam et al.[10]
product 5, as shown in Scheme 3. One of ethoxy groups in 5 was protonated, and
then the formed intermediate 6 underwent elimination to lose a molecule of EtOH.
Subsequently, the hydroxyl added to the double bond of the formed intermediate 7
generated 8. The polarized carbonyl in 8 was nucleophilly attacked by ammonia
released from heated ammonium acetate to generate 9, followed by the elimination
of EtOH to form the protonated N-formyl intermediate 10. The intramolecular
addition of amino onto the protonated formyl group formed the cyclized product
11, which lost a molecule of H2O and a proton to give the final product 4f (Scheme 3).
To search for the optimal reaction conditions from 3f to 4f, the effects of tem-
perature, solvent, and the relative molar ratio of 3f to triethyl orthoformate and
ammonium acetate on the yield were investigated, and the results are listed in
Table 1. The mixture of 3f, HC(OEt)3, and AcONH4 in a molar ratio of 1:5:3 was
refluxed in ethanol within 3h, giving 4f in only 46% yield. Replacing ethanol by
N,N-dimethylformamide (DMF) and increasing the temperature to 90–95 ꢁC obvi-
ously enhanced the yield to 83%. However, the yield decreased drastically when
the reaction temperature was further increased to 120–130 ꢁC. Interestingly, the reac-
tion was carried out in the absence of solvent at 80–85 ꢁC, affording the product in
82% yield, and the yield was even enhanced to 97% if the temperature was raised to
90–95 ꢁC. However, the decreasing molar ratio of 3f, HC(OEt)3, and AcONH4 to
1:3:2 would lower the yield to 88% (entry 6). Thus, it could be concluded that the
treatment of 3f, HC(OEt)3, and AcONH4 in the molar ratio of 1:5:3 at 90–95 ꢁC
under solvent-free conditions is the most suitable choice to obtain 4f.
To further investigate the application scope of this method, 2-(N-substituted
amino)benzoic acids (3a–e) were prepared starting from isatin (1a) (Scheme 4). As
far as we know, the substituents at the C6 position of quinazolinones are of impor-
tance for their biological activities, and moreover, 6-methyl-quinazolinones are the
Scheme 3. Possible reaction pathway of 3f to 4f.

2718
Y. WANG ET AL.
Table 1. Yields of 4f in the reaction of 3f with HC(OEt)3 and AcONH4 under various conditions
Entry
Temperature (ꢁC)
Solvent
EtOH
DMF
Molar ratio [3f=HC(OEt)3=AcONH4]
Yield (%)a,b
1
2
3
4
5
6
75–80
90–95
120–130
80–85
90–95
90–95
1:5:3
1:5:3
1:5:3
1:5:3
1:5:3
1:3:2
46
83
45
82
97
88
DMF
Solvent-free
Solvent-free
Solvent-free
aYields of pure isolated products.
bReaction time: 3 h.
key intermediates in the synthesis of the folate analogs as anticancer agents.[11–13]
Therefore, 2-(N-substituted amino)benzoic acids (3f–t) bearing CH3, F or Cl at
the C5 position were also chosen and prepared in this research. Thus, N-alkylation
of isatins 1a–d was undertaken first to generate the alkylated products 2a–t accord-
ingly, which were subjected to the cycle-opening reaction to furnish 3a–t in satisfac-
tory yields. Furthermore, 20 2-(N-alkyl, alkenyl, or benzylamino)benzoic acids (3a–t)
were treated with triethyl orthoformate and ammonium acetate under optimized
conditions, generating the corresponding 1-substituted 4(1H)-quinazolinones (4a–t)
(Scheme 4). The reaction proceedings were monitored by thin-layer chromatography
(TLC) to determine their reaction times, and the results are summarized in Table 2.
As shown in Table 2, the reactions were completed within 3–4h in moderate to
excellent yields, when R1 is a hydrogen or methyl group. Nevertheless, it could be
seen that the yields decreased as the R2 groups became bulky, which could be
ascribed to the steric hindrance effect on the cyclization. In the cases when R1 are
electronegative atoms, namely fluorine or chlorine atoms, the yields were still as
good as when R1 are hydrogen or methyl groups, although longer reaction times
were required.
It is worth mentioning that Susse and Johne synthesized quinazolin-4-on-1-
¨
ylacetic acid esters in a similar way, using 3,1-benzoxaine-2,4-diones as starting mate-
rials treated with ammonia to give the intermediates 2-aminobenzamides, which is
different from the present procedure. Subsequent cyclization of 2-aminobenzamides
with triethyl orthoformate gave 4-quinazolion-1-yl-acetic acid esters in 60–78%
yields.[14] Recently, Nikpour and Paibast reported that the treatment of 2-(methyla-
mino)benzoic acid with urea in N,N-dimethylacetamide or H2O under microwave
Scheme 4. Reagents and conditions: (a) R2X, K2CO3, DMF, rt, 2.5–6.5 h or 50–100 ꢁC, 1–6 h; (b) (i)
H2O2=NaOH, (ii) AcOH; and (c) HC(OEt)3, AcONH4, 90–95 ꢁC.

1-SUBSTITUTED 4(1H)-QUINAZOLINONES
2719
Table 2. Synthesis of 1-substituted 4(1H)-quinazolinones 4a–t
Entry
Compound
R1
R2
Time (h)
Mp (ꢁC)
Yield (%)a
1
2
4a
4b
4c
4d
4e
4f
H
CH3
CH2CH3
3
3
133–135 (lit.[8] 136–137)
128–129
148–149
134–136 (lit.[6] 136–137)
206–207
192–193
99
94
88
81
84
97
92
85
82
73
92
91
87
89
85
99
88
85
83
88
H
3
H
CH2CH2CH3
=
CH2CH CH2
3
4
H
3
5
H
CH2Ph
CH3
3
6
CH3
CH3
CH3
CH3
CH3
Cl
3
7
4g
4h
4i
CH2CH3
CH2CH2CH3
3
188–189
143–144
133–135 (lit.[6] 135–137)
166–167
225–226
8
3
=
9
CH2CH CH2
CH2Ph
CH3
4
10
11
12
13
14
15
16
17
18
19
20
4j
4
4k
4l
10
10
10
10
14
7
Cl
Cl
CH2CH3
CH2CH2CH3
190–191
138–140
127–129 (lit.[6] 126–128)
144–145
201–202
4m
4n
4o
4p
4q
4r
4s
4t
=
Cl
Cl
CH2CH CH2
CH2Ph
CH3
F
F
CH2CH3
CH2CH2CH3
7
175–176
129–131
102–103 (lit.[6] 104–105)
166–167
F
7
=
F
CH2CH CH2
CH2Ph
7
F
7
aYields of pure isolated products.
irradiation gave 1-methyl-2,4(1H,3H)-quinazolinedione in good yield.[15] However,
their product has a different structure from 1-substituted 4(1H)-quinazolinones.
In summary, we have developed a convenient and efficient method for the syn-
thesis of 1-substituted 4(1H)-quinazolinones from isatins via three steps. The new
method possesses the advantages of readily available starting materials, mild reac-
tion conditions, simple workup procedure, and good yield. It will be useful for the
synthesis of 4(1H)-quinazolinone derivatives as either synthetic intermediates or bio-
logically active compounds.
EXPERIMENTAL
Melting points were determined on an X-6 or XT5B microscopic melting-point
apparatus and are uncorrected. 1H NMR spectra were recorded on a Bruker
AC-200P spectrometer at 200 MHz or a Varian VNMRS-600 spectrometer at
600 MHz using tetramethylsilane (TMS) as internal standard. 13C NMR spectra
were recorded on a Varian VNMRS-600 spectrometer at 150 MHz using tetra-
methylsilane (TMS) as internal standard. Electron impact (EI) mass spectrum was
recorded on a Shimadzu GCMS-QP2010 Plus mass spectrometer. Low-resolution
electrospray ionization (ESI) mass spectra were recorded on a Bruker Daltonics
Esquire-LC 00136 mass spectrometer, and high-resolution electrospray ionization
(HR-ESI) mass spectra were recorded on an Agilent LC=SMD TOF mass spec-
trometer. Elemental analyses were performed by the Institute of Chemistry, Chinese
Academy of Science, on a Flash EA 1112 elemental analyzer. Column chromato-
graphy was carried out on silica gel (200–300 mesh). 2-Amino-5-methylbenzoic acid

2720
Y. WANG ET AL.
was prepared according to the reported method.[16] Triethyl orthoformate was dis-
tilled before use, and other commercially available reagents were used without
further purification.
2-(N-Substituted Amino)Benzoic Acids 3a–t
General procedure. Finely powered potassium carbonate (1 g, 7.2 mmol) and
alkyl halide (30 mmol) were added to a solution of isatin (1) (10 mmol) in DMF
(10 mL). After reacting at room temperature for 2.5–6.5 h or heating at 50–100 ꢁC
for 1–6 h (monitored by TLC), the mixture was poured into ice water. The precipi-
tate was filtered and dried to give compounds 2a–t, which were directly used in the
next step.
A solution of sodium hydroxide (0.84 g, 21 mmol) in water (10 mL) was cooled
in an ice-water bath. After the temperature was below 30 ꢁC, compound 2 (7.0 mmol)
was added and dissolved with stirring. The temperature of the reaction mixture was
kept below 15 ꢁC, while a 30% aqueous solution of hydrogen peroxide (1.8 g,
52.8 mmol) was added dropwise. Stirring was continued at 15–20 ꢁC for 0.5–2 h
(monitored by TLC). The mixture was cooled in an ice bath and adjusted to pH
5–6 with glacial acetic acid. After several hours in a refrigerator, the precipitate
was collected by filtration, washed with ice water three times, and dried in air to give
the pure products 3a, 3f, 3g, 3i, 3j, 3k, and 3m–t. Otherwise, purification by recrys-
tallization from methanol=H2O (3:1) afforded compounds 3b–e, 3h, and 3l.
2-(Methylamino)benzoic acid (3a). Yield (two steps, hereinafter the same):
64%; yellowish solid; mp 150–152 ꢁC (lit.[17] mp 159–171 ꢁC).1H NMR (600 MHz,
CDCl3): d 2.94 (s, 3 H, CH3), 6.62 (t, J ¼ 7.8 Hz, 1 H, Ph-H), 6.69 (d, J ¼ 7.8 Hz,
1 H, Ph-H), 7.43 (t, J ¼ 7.8 Hz, 1 H, Ph-H), 7.97 (d, J ¼ 7.8 Hz, 1 H, Ph-H), 11.50
(br s, 1 H, COOH). MS (EI): m=z 151 [Mþ].
2-(Ethylamino)benzoic acid (3b). Yield: 34%; yellowish solid; mp
141–143 ꢁC (lit.[18] mp 152.0–155.0 ꢁC). 1H NMR (600 MHz, CDCl3): d 1.33 (t,
J ¼ 7.2 Hz, 3 H, CH2CH3), 3.26 (q, J ¼ 7.2 Hz, 2 H, CH2CH3), 6.60 (t, J ¼ 7.8 Hz,
1 H, Ph-H), 6.69 (d, J ¼ 7.8 Hz, 1 H, Ph-H), 7.39 (t, J ¼ 7.8 Hz, 1 H, Ph-H), 7.98
(d, J ¼ 7.8 Hz, 1 H, Ph-H), 12.0 (br s, 1 H, COOH). MS (EI): m=z 165 [Mþ].
2-(Propylamino)benzoic acid (3c). Yield: 52%; yellowish solid; mp
1
114–115 ꢁC. H NMR (600 MHz, CDCl3): d 1.04 (t, J ¼ 7.2 Hz, 3 H, CH2CH3),
1.72 (m, 2 H, CH2CH3), 3.18 (t, J ¼ 7.2 Hz, 2 H, CH2CH2), 6.59 (t, J ¼ 7.8 Hz, 1
H, Ph-H), 6.69 (d, J ¼ 7.8 Hz, 1 H, Ph-H), 7.38 (t, J ¼ 7.8 Hz, 1 H, Ph-H), 7.98 (d,
J ¼ 7.8 Hz, 1 H, Ph-H), 12.10 (br s, 1 H, COOH). MS (EI): m=z 179 [Mþ].
HRMS-ESI: m=z [M þH]þ calcd. for C10H14NO2: 180.1025; found: 180.1018.
2-(Allylamino)benzoic acid (3d). Yield: 39%; yellowish solid; mp
1
115–117 ꢁC. H NMR (600 MHz, CDCl3): d 3.91 (d, 2 H, J ¼ 4.2 Hz, NCH2) 5.20
(d, J ¼ 10.2 Hz, 1 H, ¼CHH), 5.30 (d, J ¼ 16.8 Hz, 1 H, ¼CHH), 5.96 (m, 1 H,
CH ¼), 6.63 (t, J ¼ 7.8 Hz, 1 H, Ph-H), 6.68 (d, J ¼ 7.8 Hz, 1 H, Ph-H), 7.39 (t,
J ¼ 7.8 Hz, 1 H, Ph-H), 7.78 (br s, 1 H, NH), 7.99 (d, J ¼ 7.8 Hz, 1 H, Ph-H),
11.80 (br s, 1 H, COOH). MS (EI): m=z 177 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd.
for C10H12NO2: 178.0868; found: 178.0860.

1-SUBSTITUTED 4(1H)-QUINAZOLINONES
2721
2-(Benzylamino)benzoic acid (3e). Yield: 73%; yellowish solid; mp
1
170–171 ꢁC; (lit.[18] mp 170.0–173.0 ꢁC). H NMR (600 MHz, CDCl3): d 4.49 (s, 2
H, NCH2), 6.62 (t, J ¼ 7.8 Hz, 1 H, Ph-H), 6.64 (d, J ¼ 7.8 Hz, 1 H, Ph-H),
7.27–7.36 (m, 6 H, Ph-H and Bz-H), 7.99 (d, J ¼ 7.8 Hz, 1 H, Ph-H), 8.09 (br s, 1
H, NH), 11.20 (br s, 1 H, COOH). MS (EI): m=z 227 [Mþ]. HRMS-ESI: m=z [M
þH]þ calcd. for C14H14NO2: 228.1025; found: 228.1024.
5-Methyl-2-(methylamino)benzoic acid (3f). Yield: 62%; yellowish solid;
1
mp 148–149 ꢁC (lit.[18] mp 146.0–148.5 ꢁC). H NMR (200 MHz, CDCl3): d 2.26 (s,
3 H, CH3), 2.92 (s, 3 H, NCH3), 6.63 (d, J ¼ 8.6 Hz, 1 H, Ph-H), 7.27 (dd, J ¼ 8.6,
2.0 Hz, 1 H, Ph-H), 7.79 (d, J ¼ 2.0 Hz, 1 H, Ph-H), 9.50 (br s, 1 H, NH). MS
(ESI): m=z 166 [M þH]þ.
2-(Ethylamino)-5-methylbenzoic acid (3g). Yield: 60%; yellowish solid; mp
158–159 ꢁC. 1H NMR (200 MHz, CDCl3): d 1.31 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 2.24
(s, 3 H, CH3), 3.24 (q, J ¼ 7.2 Hz, 2 H, CH2CH3), 6.63 (d, J ¼ 8.6 Hz, 1 H, Ph-H),
7.23 (d, J ¼ 8.6 Hz, 1 H, Ph-H), 7.78 (s, 1H, Ph-H). MS (ESI): m=z 180 [M þH]þ.
HRMS-ESI: m=z [M þH]þ calcd. for C10H14NO2: 180.1025; found: 180.1012.
5-Methyl-2-(propylamino)benzoic acid (3h). Yield: 76%; yellowish solid;
1
mp 108–109 ꢁC. H NMR (200 MHz, CDCl3): d 1.03 (t, J ¼ 7.2 Hz, 3 H, CH2CH3),
1.71 (m, 2 H, CH2CH3), 2.24 (s, 3 H, CH3), 3.17 (t, J ¼ 7.2 Hz, 2 H, NCH2), 6.63 (d,
J ¼ 8.6 Hz, 1 H, Ph-H), 7.23 (d, J ¼ 8.6 Hz, 1 H, Ph-H), 7.78 (s, 1 H, Ph-H). MS
(ESI): m=z 194 [M þH]þ. HRMS-ESI: m=z [M þH]þ calcd. for C11H16NO2:
194.1181; found: 194.1173.
2-(Allylamino)-5-methylbenzoic acid (3i). Yield: 51%; yellowish solid; mp
1
117–118 ꢁC. H NMR (600 MHz, CDCl3): d 2.24 (s, 3 H, CH3), 3.88 (d, J ¼ 4.8 Hz,
Hz, 2 H, NCH2), 5.18 (d, J ¼ 10.2 Hz, 1 H, ¼CHH), 5.29 (d, J ¼ 16.8 Hz, 1 H,
¼CHH), 5.95 (m, 1 H, CH ¼), 6.61 (d, J ¼ 8.4 Hz, 1 H, Ph-H), 7.21 (d, J ¼ 8.4 Hz,
1 H, Ph-H), 7.79 (s, 1 H, Ph-H). 13C NMR (150 MHz, CDCl3): d 20.1, 45.3,
108.6, 111.9, 116.0, 123.9, 132.2, 134.7, 136.7, 149.7, 173.9. MS (ESI): m=z 192 [M
þH]þ. HRMS-ESI: m=z [M þH]þ calcd. for C11H14NO2: 192.1025; found: 192.1015.
2-(Benzylamino)-5-methylbenzoic acid (3j). Yield: 81%; yellowish solid;
1
mp 152–153 ꢁC. H NMR (200 MHz, DMSO-d6): d 2.15 (s, 3 H, CH3), 4.43 (s, 2
H, NCH2), 6.59 (d, J ¼ 8.6 Hz, 1 H, Ph-H), 7.13 (d, J ¼ 8.6 Hz, 1 H, Ph-H), 7.32
(m, 5 H, Bz-H), 7.61 (s, 1 H, Ph-H). MS (ESI): m=z 242 [M þH]þ. HRMS-ESI:
m=z [M þH]þ calcd. for C15H16NO2: 242.1181; found: 242.1172.
5-Chloro-2-(methylamino)benzoic acid (3k). Yield: 45%; yellowish solid;
1
mp 174–176 ꢁC (lit.[18] mp 178.0–181.0 ꢁC). H NMR (600 MHz, CDCl3): d 2.91 (s,
3 H, CH3), 6.62 (d, J ¼ 9.0 Hz, 1 H, Ph-H), 7.35 (dd, J ¼ 9.0, 2.4 Hz, 1 H, Ph-H),
7.91 (d, J ¼ 2.4 Hz, 1 H, Ph-H). MS (EI): m=z 185, 187 [Mþ]. HRMS-ESI: m=z [M
þH]þ calcd. for C8H9ClNO2: 186.0322; found: 186.0312.
5-Chloro-2-(ethylamino)benzoic acid (3l). Yield: 69%; yellowish solid; mp
102–103 ꢁC. 1H NMR (600 MHz, CDCl3): d 1.32 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 3.24
(q, J ¼ 7.2 Hz, 2 H, CH2CH3), 6.63 (d, J ¼ 9.0 Hz, 1 H, Ph-H), 7.32 (dd, J ¼ 9.0,

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Y. WANG ET AL.
2.4 Hz, 1 H, Ph-H), 7.93 (d, J ¼ 2.4 Hz, 1 H, Ph-H). MS (EI): m=z 199, 201 [Mþ].
HRMS-ESI: m=z [M þH]þ calcd. for C9H11ClNO2: 200.0478; found: 200.0473.
5-Chloro-2-(propylamino)benzoic acid (3m). Yield: 72%; yellowish solid;
1
mp 154–156 ꢁC. H NMR (600 MHz, CDCl3): d 1.03 (t, J ¼ 7.2 Hz, 3 H, CH2CH3),
1.71 (m, 2 H, CH2CH2CH3), 3.16 (t, J ¼ 7.2 Hz, 2 H, NCH2CH2), 6.64 (d, J ¼ 9.0 Hz,
1 H, Ph-H), 7.31 (dd, J ¼ 9.0, 2.4 Hz, 1 H, Ph-H), 7.92 (d, J ¼ 2.4 Hz, 1 H, Ph-H). MS
(EI): m=z 213, 215 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd. for C10H13ClNO2:
214.0635; found: 214.0631.
2-(Allylamino)-5-chlorobenzoic acid (3n). Yield: 37%; yellowish solid; mp
1
102–104 ꢁC. H NMR (600 MHz, CDCl3): d 3.89 (d, J ¼ 4.8 Hz, 2 H, NCH2CH),
5.22 (dd, J ¼ 10.2, 1.2 Hz, 1 H, ¼CHH), 5.28 (dd, J ¼ 17.4, 1.2 Hz, 1 H, ¼CHH),
5.93 (m, 1 H, CH ¼), 6.62 (d, J ¼ 9.0 Hz, 1 H, Ph-H), 7.31 (dd, J ¼ 9.0, 2.4 Hz, 1
H, Ph-H), 7.74 (br s, 1 H, NH), 7.94 (d, J ¼ 2.4 Hz, 1 H, Ph-H), 11.92 (br s, 1 H,
COOH). 13C NMR (150 MHz, CDCl3): d 45.3, 109.5, 113.3, 116.5, 119.5, 131.6,
133.9, 135.5, 150.2, 173.0. MS (EI): m=z 211, 213 [Mþ]. HRMS-ESI: m=z [M
þH]þ calcd. for C10H11ClNO2: 212.0478, 214.0449; found: 212.0478, 214.0446.
2-(Benzylamino)-5-chlorobenzoic acid (3o). Yield: 79%; yellowish solid;
mp 154–155 ꢁC. 1H NMR (600 MHz, CDCl3): d 4.47 (s, 2 H, NCH2), 6.58 (d,
J ¼ 9.0 Hz, 1 H, Ph-H), 7.27 (m, 2 H, Ph-H), 7.34 (m, 4 H, Ph-H), 7.94 (d, J ¼ 2.4 Hz,
Hz, 1 H, Ph-H), 8.10 (br s, 1 H, NH). MS (EI): m=z 261, 263 [Mþ]. HRMS-ESI: m=z
[M þH]þ calcd. for C14H13ClNO2: 262.0635; found: 262.0632.
5-Fluoro-2-(methylamino)benzoic acid (3p). Yield: 49%; yellowish solid;
1
mp 139–142 ꢁC. H NMR (600 MHz, DMSO-d6): d 2.83 (s, 3 H, NCH3), 6.69 (dd,
J ¼ 9.6, 4.2 Hz, 1 H, Ph-H), 7.29 (td, J ¼ 9.6, 3.0 Hz, 1 H, Ph-H), 7.49 (dd, J ¼ 9.6,
3.0 Hz, 1 H, Ph-H). 13C NMR (150 MHz, DMSO-d6): d 30.0, 110.3 (d, J ¼ 6.2 Hz),
112.6 (d, J ¼ 7.2 Hz), 116.8 (d, J ¼ 22.8 Hz), 122.4 (d, J ¼ 22.8 Hz), 149.2, 152.4 (d,
J ¼ 229.2 Hz), 169.4. MS (EI): m=z 169 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd.
for C8H9FNO2: 170.0617; found: 170.0613.
2-(Ethylamino)-5-fluorobenzoic acid (3q). Yield: 73%; yellowish solid; mp
90–93 ꢁC. 1H NMR (600 MHz, CDCl3): d 1.32 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 3.24 (q,
J ¼ 7.2 Hz, 2 H, CH2CH3), 6.64 (dd, J ¼ 9.0, 4.2 Hz, 1 H, Ph-H), 7.16 (m, 1 H, Ph-H),
7.65 (dd, J ¼ 9.6, 3.0 Hz, 1 H, Ph-H). 13C NMR (150 MHz, CDCl3): d 14.5, 37.8,
108.1, 112.6 (d, J ¼ 6.8 Hz), 117.4 (d, J ¼ 22.8 Hz), 123.6 (d, J ¼ 23.0 Hz), 148.7,
152.3 (d, J ¼ 213.9 Hz), 172.89. MS (EI): m=z 183 [Mþ]. Anal. calcd. for
C9H10FNO2: C, 59.01; H, 5.50; N, 7.65. Found: C, 59.25; H, 5.68; N, 7.70.
5-Fluoro-2-(propylamino)benzoic acid (3r). Yield: 74%; yellowish solid;
1
mp 98–100 ꢁC. H NMR (600 MHz, CDCl3): d 1.03 (t, J ¼ 7.2 Hz, 3 H, CH2CH3),
1.71 (m, 2 H, CH2CH2CH3), 3.16 (t, J ¼ 7.2 Hz, 2 H, NCH2CH2), 6.63 (dd,
J ¼ 9.0, 4.2 Hz, 1 H, Ph-H), 7.15 (m, 1 H, Ph-H), 7.65 (dd, J ¼ 9.6, 3.0 Hz, 1 H,
Ph-H). 13C NMR (150 MHz, CDCl3): d 11.7, 22.4, 45.1, 108.1, 112.6 (d, J ¼ 6.8 Hz),
), 117.4 (d, J ¼ 22.8 Hz), 123.6 (d, J ¼ 23.0 Hz), 148.9, 152.8 (d, J ¼ 232.1 Hz), 173.2.
MS (EI): m=z 197 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd. for C10H13FNO2:
198.0930; found: 198.0923.

1-SUBSTITUTED 4(1H)-QUINAZOLINONES
2723
2-(Allylamino)-5-fluorobenzoic acid (3s). Yield: 49%; yellowish solid; mp
1
107–109 ꢁC. H NMR (600 MHz, CDCl3): d 3.89 (d, J ¼ 4.8 Hz, 2 H, NCH2CH),
5.21 (dd, J ¼ 10.2, 1.2 Hz, 1 H, ¼CHH), 5.29 (dd, J ¼ 17.4, 1.2 Hz, 1 H, ¼CHH),
5.94 (m, 1 H, CH ¼), 6.62 (dd, J ¼ 9.0, 1.2 Hz, 1 H, Ph-H), 7.15 (m, 1 H, Ph-H),
7.66 (dd, J ¼ 9.6, 3.0 Hz, 1 H, Ph-H). 13C NMR (150 MHz, CDCl3): d 45.5, 108.5
(d, J ¼ 6.6 Hz), 113.0 (d, J ¼ 6.8 Hz), 116.3, 117.4 (d, J ¼ 23.4 Hz), 123.5 (d,
J ¼ 22.8 Hz),134.3, 148.5, 153.0 (d, J ¼ 232.5 Hz), 173.1. MS (EI): m=z 195 [Mþ].
HRMS-ESI: m=z [M þH]þ calcd. for C10H11FNO2: 196.0774; found: 196.0773.
2-(Benzylamino)-5-fluorobenzoic acid (3t). Yield: 79%; yellowish solid; mp
1
97–99 ꢁC. H NMR (600 MHz, CDCl3): d 4.44 (s, 2 H, NCH2), 6.56 (dd, J ¼ 9.0,
4.2 Hz, 1 H, Ph-H), 7.06 (m, 1 H, Ph-H), 7.27 (m, 1 H, Ph-H), 7.32 (m, 4 H,
Ph-H), 7.66 (dd, J ¼ 9.0, 3.0 Hz, 1 H, Ph-H). 13C NMR (150 MHz, CDCl3): d
29.7, 47.2, 113.2 (d, J ¼ 6.8 Hz), 117.5 (d, J ¼ 23.4 Hz), 123.4 (d, J ¼ 25.7 Hz),
126.9, 127.3, 128.8, 138.5, 148.4, 153.2 (d, J ¼ 233.1 Hz), 172.8. MS (EI): m=z 245
[Mþ]. HRMS-ESI: m=z [M þH]þ calcd. for C14H13FNO2: 246.0830; found:
246.0930.
1-Substituted 4(1H)-Quinazolinone 4a–t
General procedure. A mixture of 2-(N-substituted amino)benzoic acid 3
(3 mmol), ammonium acetate (9 mmol) and triethyl orthoformate (15 mmol) was stir-
red at 90–95 ꢁC for 3–14 h (monitored by TLC). Most of excess triethyl orthoformate
was removed by rotary evaporation, and the residue was applied to a silica-gel col-
umn and eluted with dichloromethane=methanol (95:5) to give compounds 4a–t.
1-Methylquinazolin-4(1H)-one (4a). 1H NMR (600 MHz, CDCl3): d 3.78 (s,
3 H, CH3), 7.35 (d, J ¼ 8.4 Hz, 1 H, 8-H), 7.51 (t, J ¼ 7.8 Hz, 1 H, 6-H), 7.77 (t,
J ¼ 8.4 Hz, 1 H, 7-H), 8.22 (s, 1 H, 2-H), 8.35 (d, J ¼ 7.8 Hz, 1 H, 5-H). 13C NMR
(150 MHz, CDCl3): d 37.4, 114.6, 120.5, 126.7, 128.9, 134.0, 139.9, 153.3, 169.2.
MS (EI): m=z 160 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd. for C9H9N2O:
161.0715; found: 161.0704.
1-Ethylquinazolin-4(1H)-one (4b). 1H NMR (600 MHz, CDCl3): d 1.54 (t,
J ¼ 7.2 Hz, 3 H, CH2CH3), 4.20 (q, J ¼ 7.2 Hz, 2 H, CH2CH3), 7.38 (d, J ¼ 8.4 Hz,
1 H, 8-H), 7.50 (t, J ¼ 7.8 Hz, 1 H, 6-H), 7.76 (t, J ¼ 8.4 Hz, 1 H, 7-H), 8.27 (s, 1
H, 2-H), 8.38 (d, J ¼ 7.8 Hz, 1 H, 5-H). 13C NMR (150 MHz, CDCl3): d 14.6,
45.3, 114.5, 120.8, 126.4, 129.2, 133.8, 138.8, 152.7, 169.1. MS (EI): m=z 174 [Mþ].
HRMS-ESI: m=z [M þH]þ calcd. for C10H11N2O: 175.0871; found: 175.0864.
1-Propylquinazolin-4(1H)-one (4c). 1H NMR (600 MHz, CDCl3): d 1.04 (t,
J ¼ 7.2 Hz, 3 H, CH2CH3), 1.92 (m, 2H, CH2CH2CH3), 4.09 (t, J ¼ 7.2 Hz, 2 H,
CH2CH2), 7.36 (d, J ¼ 8.4 Hz, 1 H, 8-H), 7.49 (t, J ¼ 7.8 Hz, 1 H, 6-H), 7.75 (t,
J ¼ 8.4 Hz, 1 H, 7-H), 8.23 (s, 1 H, 2-H), 8.38 (d, J ¼ 7.8 Hz, 1 H, 5-H). 13C NMR
(150 MHz, CDCl3): d 11.0, 22.0, 52.0, 114.7, 120.8, 126.4, 129.1, 133.8, 139.0,
153.1, 169.4. MS (EI): m=z 188 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd. for
C11H13N2O: 189.1028; found: 189.1023.

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Y. WANG ET AL.
1-Allylquinazolin-4(1H)-one (4d). 1H NMR (600 MHz, CDCl3): d 4.75 (m, 2
H, NCH2), 5.24 (d, J ¼ 17.4 Hz, 1 H, ¼CHH), 5.38 (d, J ¼ 10.8 Hz, 1 H, ¼CHH),
6.01 (m, 1 H, CH ¼), 7.33 (d, J ¼ 8.4 Hz, 1 H, 8-H), 7.48 (t, J ¼ 7.8 Hz, 1 H, 6-H),
7.72 (t, J ¼ 8.4 Hz, 1 H, 7-H), 8.24 (s, 1 H, 2-H), 8.36 (d, J ¼ 7.8 Hz, 1 H, 5-H).
13C NMR (150 MHz, CDCl3): d 52.2, 115.2, 119.6, 120.7, 126.5, 129.1, 130.5,
133.8, 139.2, 153.1, 169.3. MS (EI): m=z 186 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd.
for C11H11N2O: 187.0871; found: 187.0868.
1-Benzylquinazolin-4(1H)-one (4e). 1H NMR (600 MHz, CDCl3): d 5.31 (s,
2 H, NCH2), 7.22 (m, 3 H, Ar-H), 7.37 (m, 3 H, Ar-H), 7.46 (t, J ¼ 7.8 Hz, 1 H, 6-H),
7.61 (t, J ¼ 7.8 Hz, 1 H, 7-H), 8.37 (s, 1 H, 2-H), 8.39 (d, J ¼ 7.8 Hz, 1 H, 5-H). 13C
NMR (150 MHz, CDCl3): d 53.9, 115.5, 120.8, 126.2, 126.6, 128.8, 129.1, 129.5,
133.8, 133.9, 139.3, 153.5, 169.3. MS (ESI): m=z 237 [M þH]þ. HRMS-ESI: m=z
[M þH]þ calcd. for C15H13N2O: 237.1028; found: 237.1022.
1,6-Dimethylquinazolin-4(1H)-one (4f). 1H NMR (600 MHz, DMSO-d6): d
2.43 (s, 3 H, CH3), 3.74 (s, 3H, CH3), 7.52 (d, J ¼ 8.4 Hz, 1 H, 8-H), 7.67 (d,
J ¼ 8.4 Hz, 1 H, 7-H), 7.88 (s, 1 H, 5-H), 8.43 (s, 1 H, 2-H). 13C NMR (150 MHz,
DMSO-d6): d 23.7, 40.0, 119.1, 122.8, 129.8, 137.9, 138.8, 141.2, 156.9, 171.6. MS
(ESI): m=z 175 [M þH]þ. Anal. calcd. for C10H10N2O ꢂ 0.1H2O: C, 68.24; H, 5.84;
N, 15.92. Found: C, 68.06; H, 5.83; N, 15.88.
1-Ethyl-6-methylquinazolin-4(1H)-one (4g). 1H NMR (200 MHz, CDCl3):
d 1.52 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 2.46 (s, 3 H, CH3), 4.19 (q, J ¼ 7.2 Hz, 2 H,
CH2CH3), 7.29 (d, J ¼ 8.6 Hz, 1 H, 8-H), 7.56 (d, J ¼ 8.6 Hz, 1 H, 7-H), 8.16 (s, 1
H, 5-H), 8.23 (s, 1 H, 2-H). 13C NMR (150 MHz, CDCl3): d 14.7, 21.0, 45.4,
114.5, 120.7, 128.6, 135.0, 136.6, 136.7, 152.2, 169.6. MS (EI): m=z 188 [Mþ]. Anal.
calcd. for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 69.93; H, 6.44; N,
14.87.
6-Methyl-1-propylquinazolin-4(1H)-one (4h). 1H NMR (600 MHz,
CDCl3): d 1.03 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 1.90 (m, 2 H, CH2CH2CH3), 2.47 (s,
3 H, CH3), 4.06 (t, J ¼ 7.2 Hz, 2 H, NCH2CH2), 7.26 (d, J ¼ 8.4 Hz, 1 H, 8-H),
7.55 (d, J ¼ 8.6 Hz, 1 H, 7-H), 8.18 (s, 2 H, 5-H and 2-H). 13C NMR (150 MHz,
CDCl3): d 11.0, 21.0, 22.0, 51.9, 114.6, 120.6, 128.6, 134.9, 136.5, 136.9, 152.5,
169.5. MS (ESI): m=z 203 [M þH]þ. Anal. calcd. for C12H14N2O ꢂ H2O: C, 65.43;
H, 7.32; N, 12.72. Found: C, 65.60; H, 7.23; N, 12.50.
1-Allyl-6-methylquinazolin-4(1H)-one (4i). 1H NMR (600 MHz, CDCl3): d
2.46 (s, 3 H, CH3), 4.71 (d, J ¼ 4.8 Hz, 2 H, NCH2CH), 5.22 (d, J ¼ 16.8 Hz, 1 H,
¼CHH), 5.37 (d, J ¼ 10.8 Hz, 1 H, ¼CHH), 5.99 (m, 1 H, CH ¼), 7.22 (d, J ¼ 8.4 Hz,
Hz, 1 H, 8-H), 7.53 (d, J ¼ 8.4 Hz, 1 H, 7-H), 8.17 (s, 1 H, 5-H), 8.20 (s, 1 H, 2-H).
13C NMR (150 MHz, CDCl3): d 21.0, 52.2, 115.1, 119.4, 120.4, 128.4, 130.6, 135.0,
136.8, 137.1, 152.6, 169.5. MS (ESI): m=z 201 [M þH]þ. HRMS-ESI: m=z [M
þH]þ calcd. for C12H13N2O: 201.1028; found: 201.1013.
1-Benzyl-6-methylquinazolin-4(1H)-one (4j). 1H NMR (200 MHz, CDCl3):
d 2.42 (s, 3 H, CH3), 5.30 (s, 2 H, NCH2), 7.10-7.43 (m, 7 H, Ar-H), 8.17 (s, 1 H,
5-H), 8.36 (s, 1 H, 2-H). 13C NMR (150 MHz, CDCl3): d 21.0, 53.9, 115.5, 120.6,
126.2, 128.4, 128.6, 129.4, 134.1, 135.0, 136.8, 137.2, 153.0, 169.5. MS (ESI): m=z

1-SUBSTITUTED 4(1H)-QUINAZOLINONES
2725
251 [M þH]þ. Anal. calcd. for C16H14N2O ꢂ 0.5H2O: C, 74.11; H, 5.83; N, 10.80.
Found: C, 73.83; H, 5.93; N, 10.61.
6-Chloro-1-methylquinazolin-4(1H)-one (4k). 1H NMR (600 MHz,
CDCl3): d 3.77 (s, 3 H, CH3), 7.30 (d, J ¼ 9.0 Hz, 1H, 8-H), 7.71 (dd, J ¼ 9.0,
2.4 Hz, 1H, 7-H), 8.19 (s, 1 H, 2-H), 8.32 (d, J ¼ 2.4 Hz, 1 H, 5-H). 13C NMR
(150 MHz, CDCl3): d 37.5, 116.3, 121.5, 128.5, 132.6, 134.2, 138.4, 153.2, 168.2.
MS (EI): m=z 194, 196 [Mþ]. Anal. calcd. for C9H7ClN2O ꢂ 0.4H2O: C, 53.56; H,
3.90; N, 13.88. Found: C, 53.95; H, 3.89; N, 13.52.
6-Chloro-1-ethylquinazolin-4(1H)-one (4l). 1H NMR (600 MHz, CDCl3): d
1.53 (t, J ¼ 7.8 Hz, 3 H, CH2CH3), 4.19 (q, J ¼ 7.8 Hz, 2 H, CH2CH3), 7.33 (d,
J ¼ 9.0 Hz, 1H, 8-H), 7.71 (dd, J ¼ 9.0, 2.4 Hz, 1 H, 7-H), 8.23 (s, 1 H, 2-H), 8.34
(d, J ¼ 2.4 Hz, 1 H, 5-H). 13C NMR (150 MHz, CDCl3): d 14.6, 45.5, 116.3, 121.9,
128.7, 132.3, 134.2, 137.3, 152.7, 168.2. MS (EI): m=z 208, 210 [Mþ]. Anal. calcd.
for C10H9ClN2O: C, 57.57; H, 4.35; N, 13.43. Found: C, 57.61; H, 4.43; N, 13.03.
6-Chloro-1-propylquinazolin-4(1H)-one (4m). 1H NMR (600 MHz,
CDCl3): d 1.05 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 1.91 (m, 2 H, CH2CH3), 4.10 (t,
J ¼ 7.2 Hz, 2 H, CH2CH2), 7.32 (d, J ¼ 9.0 Hz, 1 H, 8-H), 7.70 (dd, J ¼ 9.0, 2.4 Hz,
1 H, 7-H), 8.32 (s, 1 H, 2-H), 8.36 (d, J ¼ 2.4 Hz, 1 H, 5-H). 13C NMR (150 MHz,
CDCl3): d 11.0, 22.0, 52.1, 116.5, 121.8, 128.6, 132.3, 134.1, 137.5, 153.1, 168.3.
MS (EI): m=z 222, 224 [Mþ]. Anal. calcd. for C11H11ClN2O: C, 59.33; H, 4.98; N,
12.58. Found: C, 59.29; H, 5.00; N, 12.36.
1-Allyl-6-chloroquinazolin-4(1H)-one (4n). 1H NMR (600 MHz, CDCl3): d
4.77 (d, J ¼ 4.8 Hz, 2 H, NCH2CH), 5.24 (d, J ¼ 17.4 Hz, 1 H, ¼CHH), 5.40 (d,
J ¼ 10.2 Hz, 1 H, ¼CHH), 6.00 (m, 1 H, CH ¼), 7.31 (d, J ¼ 9.0 Hz, 1 H, 8-H),
7.65 (dd, J ¼ 9.0, 1.8 Hz, 1 H, 7-H), 8.24 (d, J ¼ 1.8 Hz, 1 H, 5-H), 8.26 (s, 1 H,
2-H). 13C NMR (150 MHz, CDCl3): d 52.4, 117.3, 119.8, 121.5, 128.2, 130.2,
132.4, 134.1, 137.6, 153.3, 168.2. MS (EI): m=z 220, 222 [Mþ]. HRMS-ESI: m=z
[M þH]þ calcd. for C11H10ClN2O: 221.0482; found: 221.0470.
1-Benzyl-6-chloroquinazolin-4(1H)-one (4o). 1H NMR (600 MHz,
CDCl3): d 5.32 (s, 2 H, CH2Ph), 7.19 (m, 3 H, Ar-H), 7.38 (m, 3 H, Ar-H), 7.55
(dd, J ¼ 9.0, 2.4 Hz, 1 H, 7-H), 8.35 (d, J ¼ 2.4 Hz, 1 H, 5-H), 8.45 (s, 1 H, 2-H).
13C NMR (150 MHz, CDCl3): d 54.1, 117.4, 121.8, 126.2, 128.4, 128.9, 129.5,
132.5, 133.5, 134.2, 137.7, 153.6, 168.1. MS (EI): m=z 270, 272 [Mþ]. Anal. calcd.
for C15H11ClN2O ꢂ 0.2H2O: C, 65.68; H, 4.19; N, 10.21. Found: C, 65.81; H, 4.12;
N, 9.96.
6-Fluoro-1-methylquinazolin-4(1H)-one (4p). 1H NMR (600 MHz,
CDCl3): d 3.78 (s, 3 H, CH3), 7.36 (dd, J ¼ 9.0, 3.6 Hz, 1 H, 8-H), 7.51 (m, 1 H,
7-H), 8.02 (dd, J ¼ 8.4, 3.0 Hz, 1 H, 5-H), 8.19 (s, 1 H, 2-H). 13C NMR (150 MHz,
CDCl3): d 37.6, 114.4 (d, J ¼ 23.0 Hz), 117.0 (d, J ¼ 7.8 Hz), 122.1 (d, J ¼ 6.6 Hz),
122.3 (d, J ¼ 24.6 Hz), 136.4, 153.0, 160.6 (d, J ¼ 247.5 Hz), 168.7. MS (EI): m=z
178 [Mþ]. Anal. calcd. for C9H7FN2O ꢂ 0.6H2O: C, 57.20; H, 4.37; N, 14.82. Found:
C, 57.09; H, 4.39; N, 14.78.

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Y. WANG ET AL.
1-Ethyl-6-fluoroquinazolin-4(1H)-one (4q). 1H NMR (600 MHz, CDCl3): d
1.54 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 4.21 (q, J ¼ 7.2 Hz, 2 H, CH2CH3), 7.40 (dd,
J ¼ 9.0, 4.2 Hz, 1 H, 8-H), 7.49 (m, 1 H, 7-H), 8.04 (dd, J ¼ 7.8, 3.0 Hz, 1 H, 5-H),
8.29 (s, 1 H, 2-H). 13C NMR (150 MHz, CDCl3): d 14.6, 45.6, 114.4 (d, J ¼ 23.0 Hz),
116.9 (d, J ¼ 7.8 Hz), 122.2 (d, J ¼ 24.6 Hz), 122.6 (d, J ¼ 7.4 Hz), 152.4, 135.3, 160.4
(d, J ¼ 245.9 Hz), 168.7. MS (EI): m=z 192 [Mþ]. Anal. calcd. for C10H9FN2O: C,
62.49; H, 4.72; N, 14.58. Found: C, 62.67; H, 4.80; N, 14.57.
6-Fluoro-1-propylquinazolin-4(1H)-one (4r). 1H NMR (600 MHz, CDCl3):
d 1.05 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 1.91 (m, 2 H, CH2CH2CH3), 4.10 (t, J ¼ 7.2 Hz,
2 H, CH2CH2), 7.38 (dd, J ¼ 9.6, 4.2 Hz, 1 H, 8-H), 7.48 (m, 1 H, 7-H), 8.02 (dd,
J ¼ 7.8, 3.0 Hz, 1 H, 5-H), 8.22 (s, 1 H, 2-H). 13C NMR (150 MHz, CDCl3): d
11.0, 22.1, 52.2, 114.2 (d, J ¼ 23.0 Hz), 117.1 (d, J ¼ 7.8 Hz), 122.2 (d, J ¼ 24.6 Hz),
122.5 (d, J ¼ 6.6 Hz), 135.5, 152.8, 160.4 (d, J ¼ 247.5 Hz), 168.7. MS (EI): m=z
206 [Mþ]. Anal. calcd. for C11H11FN2O: C, 64.07; H, 5.38; N, 13.58. Found: C,
64.16; H, 5.32; N, 13.55.
1-Allyl-6-fluoroquinazolin-4(1H)-one (4s). 1H NMR (600 MHz, CDCl3): d
4.74 (d, J ¼ 4.8 Hz, 2 H, NCH2CH), 5.25 (d, J ¼ 17.4 Hz, 1 H, ¼CHH), 5.41 (d,
J ¼ 10.2 Hz, 1 H, ¼CHH), 6.00 (m, 1 H, CH ¼), 7.35 (dd, J ¼ 9.6, 4.2 Hz, 1 H,
8-H), 7.45 (m, 1 H, 7-H), 8.03 (dd, J ¼ 7.8, 3.0 Hz, 1 H, 5-H), 8.26 (s, 1 H, 2-H).
13C NMR (150 MHz, CDCl3): d 52.5, 114.1 (d, J ¼ 22.8 Hz), 117.7 (d, J ¼ 7.8 Hz),
119.8, 122.1 (d, J ¼ 24.6 Hz), 122.3, 130.3, 135.7, 152.9, 160.4 (d, J ¼ 248.3 Hz),
168.7. MS (EI): m=z 204 [Mþ]. HRMS-ESI: m=z [M þH]þ calcd. for C11H10FN2O:
205.0777; found: 205.0763.
1-Benzyl-6-fluoroquinazolin-4(1H)-one (4t). 1H NMR (600 MHz, CDCl3):
d 5.35 (s, 2 H, NCH2), 7.20 (d, J ¼ 7.2 Hz, 2 H, Ar-H), 7.25 (dd, J ¼ 9.6, 4.2 Hz, 1 H,
8-H), 7.31–7.40 (m, 4 H, Ar-H), 7.96 (dd, J ¼ 7.8, 3.0 Hz, 1 H, 5-H), 8.37 (s, 1 H,
2-H). 13C NMR (150 MHz, CDCl3): d 54.2, 114.0 (d, J ¼ 22.8 Hz), 118.1 (d,
J ¼ 7.4 Hz), 122.2 (d, J ¼ 24.6 Hz), 122.4 (d, J ¼ 7.2 Hz), 126.2, 128.9, 129.5, 133.6,
135.7, 153.3, 160.4 (d, J ¼ 248.3 Hz), 168.7. MS (EI): m=z 254 [Mþ]. Anal. calcd.
for C15H11FN2O ꢂ 0.5H2O: C, 68.43; H, 4.59; N, 10.64. Found: C, 68.52; H, 4.57;
N, 10.35.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (No. 20972099) and the Beijing Municipal Commission of Education (No.
KZ201210028035).
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