Synthesis of 3-aryl-4(3H)-quinazolinones from anthranilic acids and triethyl orthoformate

Article abstract of DOI:10.1080/00397910802026584

A one-step, convenient approach to the synthesis of 3-aryl-4(3H)- quinazolinones by the reaction of anthranilic acid with triethyl orthoformate in the presence of a catalytic amount of concentrated sulfuric acid has been developed. The possible reaction pathway was proposed. Copyright Taylor & Francis Group, LLC.

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Synthesis of 3-Aryl-4(3H)-
quinazolinones from
Anthranilic Acids and Triethyl
Orthoformate
Sheng-Li Cao a , Mei Zhang a , Yu-Ping Feng b , Yu-
Yang Jiang c & Nan Zhang c
a Department of Chemistry, Capital Normal
University, Beijing, China
b Department of Chemistry, Tsinghua University,
Beijing, China
c Key Laboratory of Chemical Biology, Guangdong
Province; Graduate School at Shenzhen, Tsinghua
University, Shenzhen, China
Published online: 18 Aug 2008.
To cite this article: Sheng-Li Cao , Mei Zhang , Yu-Ping Feng , Yu-Yang Jiang & Nan
Zhang (2008): Synthesis of 3-Aryl-4(3H)-quinazolinones from Anthranilic Acids and
Triethyl Orthoformate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:13, 2227-2236
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Synthetic Communications1, 38: 2227–2236, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802026584
Synthesis of 3-Aryl-4(3H)-quinazolinones from
Anthranilic Acids and Triethyl Orthoformate
Sheng-Li Cao,1 Mei Zhang,1 Yu-Ping Feng,2 Yu-Yang Jiang,3 and
Nan Zhang3
1Department of Chemistry, Capital Normal University, Beijing, China
2Department of Chemistry, Tsinghua University, Beijing, China
3Key Laboratory of Chemical Biology, Guangdong Province;
Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
Abstract: A one-step, convenient approach to the synthesis of 3-aryl-4(3H)-qui-
nazolinones by the reaction of anthranilic acid with triethyl orthoformate in the
presence of a catalytic amount of concentrated sulfuric acid has been developed.
The possible reaction pathway was proposed.
Keywords: 2-Amino-5-methylbenzoic acid; Anthranilic acid; 3-Aryl-4(3H)-quina-
zolinone; Heterocyclization; Triethyl orthoformate
INTRODUCTION
4(3H)-Quinazolinones bearing substituents on either C-2 or N-3 or both
C-2 and N-3 display a wide range of biological activities such as antitu-
mor,[1] anti-inflammatory,[2] antibacterial,[3] anticonvulsive,[4] and antihy-
pertensive activities.[5] Therefore, many methods for the synthesis of
4(3H)-quinazolinones have been developed and reported in the literature,
which had been reviewed recently by Connolly et al.[6] As for N-3-substi-
tuted 4(3H)-quinazolinones, the most popular synthetic approach
involves the amidation of (4H)-3,1-benzoxazin-4-ones with alkyl or aryl
amines.[7] Recently, Majo and Perumal described a novel dimerization
reaction by treating 5-substitued-2-aminobenzoic acid with Vilsmeier
Received August 17, 2007
Address correspondence to Sheng-Li Cao, Department of Chemistry, Capital
Normal University, Beijing, China. E-mail: sl_cao@sohu.com
2227

2228
S.-L. Cao et al.
reagent, a combination of N, N-dimethylformamide (DMF) and POCl3,
to furnish 3-substitued-4(3H)-quinazolinones.[8]
In our attempt to prepare pure N-monoalkylated derivatives of 2-
amino-5-methylbenzoic acid 1a, such as 5-methyl-2-(methylamino)ben-
zoic acid, and 2-(ethylamino)-5-methylbenzoic acid, which would be used
as starting material for the synthesis of N-1 substituted 4(3H)-quinazoli-
nones, a dimerization of 1a forming 3-aryl-4(3H)-quinazolinone was
observed. We report here this unexpected reaction and its application.
RESULTS AND DISCUSSION
Heating 3-methylaniline with triethyl orthoformate in the presence of a
catalytic amount of concentrated sulfuric acid, while removing ethanol
formed by distillation, affords N-ethyl-N-formyl-3-methylaniline, which
followed by acidic hydrolysis gives pure N-ethyl-3-methylaniline.[9] How-
ever, the reaction of 2-amino-5-methylbenzoic acid 1a under the same
condition did not yield the desired compound 2, but rather 3a
(Scheme 1). Interestingly, treating 1a with trimethyl orthoformate gave
the same product 3a. The structure of 3a was confirmed by means of
1H NMR, electrospray ionization mass spectrum (ESI-MS), and elemen-
tal analysis. Furthermore, a single crystal of 3a was obtained and its
structure was solved by X-ray diffraction (Figure 1).
[X-ray crystal data for 3a: CCDC deposit no. 642545; empirical for-
mula: C17H14N2O3; formula weight: 294.30; T ¼ 293(2) K; k ¼ 0.71073
˚
A; crystal system ¼ monoclinic; space group: P2(1)=n; unit cell dimen-
˚
sions: a ¼ 9.841(2), b ¼ 10.901(2), c ¼ 13.791(3) A, a ¼ 90.00,
ꢀ
3
b ¼ 95.17(3), c ¼ 90.00 ; V ¼ 1473.5(5) A ; Z ¼ 4; Dcal ¼ 1.327 g cmꢁ3
;
˚
ꢀ
m ¼ 0.093 mmꢁ1; h range for data collection: 2.39–25.02 ; reflections
Scheme 1. The unexpected reation of 1a.

3-Aryl-4(3H)-quinazolinones
2229
Figure 1. Molecular structure of 5-methyl-2-(6-methyl-4-oxoquinazolin-3(4H)-
yl)benzoic acid 3a.
used: 9408; independent reflections: 2602 [R(int) ¼ 0.0364]; refinement
method: full-matrix least-squares on F2; R1 ¼ 0.0650, wR2 ¼ 0.1048
[I > 2r (I)]. Structure solution and refinement were achieved using
SHELXS98 and SHELXL98(10)].
To investigate whether the formation of 3a involves the heterocycli-
zation of 2-amino-5-methylbenzoic acid 1a with triethyl orthoformate,
and amidation of resultant 6-methyl-4H-3,1-benzoxazin-4-one with
unreacted 1a, 1a was heated with triethyl orthoformate (molar
ratio ¼ 1:2) under reflux for 1.5 h, without distilling to remove the low
boiling-point substances that formed. Consequently, the intermediate
amidine 4 instead of 6-methyl-4H-3,1-benzoxazin-4-one as described in
literature[11,12] was obtained (Scheme 2), which may cyclodehydrate to
provide the final product 3a. In fact, adding 2 drops of concentrated sul-
furic acid into the mixture after treating 1a with triethyl orthoformate
under reflux for 1.5 h and refluxing for 1 h further afforded 3a eventually.
Therefore, the presence of concentrated sulfuric acid could promote the
formation of imidic ester, the precursor of amidine 4, as well as the cyclo-
dehydration of 4 to give 3a.
For optimizing the reaction conditions, acid, solvent, and the relative
molar ratio of 1a to triethyl orthoformate were varied, and the results are
Scheme 2. Reaction of 1a with triethyl orthoformate in the absence of concen-
trated H2SO4.

2230
S.-L. Cao et al.
Table 1. Yields of 3a in the reaction of 1a with HC(OEt)3 under various
ꢀ
conditions after 1 h at 154–156 Ca
Molar ratio
[1a=HC(OEt)3]
Yield of
3a (%)b
Entry
Acid
Solvent
1
2
3
4
5
6
7
8
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
TsOH
Solvent-free
Solvent-free
DMF
1:1
1:1.5
1:1
1:1.25
1:1.5
1:1.75
1:2
69
65
73
76
91
79
27
45
DMF
DMF
DMF
DMF
DMF
1:1.5
aThe low boiling-point substance formed was removed by distillation.
bYields of pure isolated products.
listed in Table 1. Although the reaction under solvent-free conditions
could give 3a in moderate yield, the use of DMF as solvent, especially
increasing the molar ratio of 1a to triethyl orthoformate, could obviously
improve the yield. Nevertheless, when the molar ratio of 1a to triethyl
orthoformate was more than 1:1.5, the yield decreased drastically. More-
over, the replacement of concentrated sulfuric acid with 4-methylbenze-
nesulfonic acid (TsOH) decreased the yield from 91% to 45%.
Under the optimized conditions, a range of anthranilic acids with
various substituents (1a–j) were treated with triethyl orthoformate, pro-
viding 3-aryl-4(3H)-quinazolinons 3a–i (Scheme 3 and Table 2). As seen
from Table 2, most anthranilic acids with electron-donating substituents
underwent the reaction in fairly high yields, whereas the anthranilic acid
1i with electron-withdrawing substituent (4-carboxyl) converted into 3i
only in 65% yield. In the case of 2-amino-5-nitrobenzoic acid 1j, the
expected product was not obtained, but imidic ester 5 was isolated in
39% yield instead (Scheme 4).
Scheme 3. For R1, R2 and R3, see Table 2.

3-Aryl-4(3H)-quinazolinones
2231
Table 2. Synthesis of 3-aryl-4(3H)-quinazolinone 3a–i
Entry
3
R1
R2
R3
Yield (%)a
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
H
Me
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
CO2H
Me
H
OH
Cl
H
Br
AcNH
H
91
85
96
80
92
78
67
85
65
3g
3h
3i
H
aYields of isolated products.
Although the reaction of 2-amino-5-nitrobenzoic acid 1j with triethyl
orthoformate could not yield the heterocyclized product, the isolated
intermediate imidic ester 5 is helpful in outlining the possible reaction
pathway. Rad-Moghadam and Mohseni[13] reported that the reaction
of anthranilic acid and orthoesters in the presence of ammonium acetate
under microwave conditions produced 2-substituted quinazolin-4(3H)-
ones, and the reaction was thought to proceed through the intermediate
amidine. Considering together with the intermediate amidine 4 obtained
in the reaction of 1a with triethyl orthoformate, we supposed that the
whole reaction proceeded in three steps: condensation of anthranilic acids
with triethyl orthoformate promoted by sulfuric acid gave imidic ester
(for example, 5); the intermediate imidic ester undergoes necleophilic
attack by the amino group in remaining anthranilic acid to produce ami-
dine (for example, 4); and cyclization of amidine through the elimination
of a molecule of H2O to form the final product 3-aryl-4(3H)-quinazoli-
nones (Scheme 5). Thus, anthranilic acids with electron-donating substi-
tuents underwent the reaction smoothly in each step, whereas those with
electron-withdrawing groups (for instance 1i) could not efficiently attack
the intermediate imidic ester because of the poor necleophility of amino
group, so the yield was relatively low (65%). As for anthranilic acid 1j
with strong electron-withdrawing nitro group, the reaction rested on
Scheme 4. Reaction of 1j with triethyl orthoformate in the presence of
concentrated H2SO4.

2232
S.-L. Cao et al.
Scheme 5.
the stage of imidic ester 5, and neither heterocyclized product nor ami-
dine intermediate was obtained.
In summary, we have described a simple and efficient synthesis of 3-
aryl-4(3H)-quinazolinones from anthranilic acids. The methodology was
suitable for a range of substituted anthranilic acids except for 5-nitro
anthranilic acid, which gave the intermediate imidic ester. The structures
of the final products and the intermediates isolated have been confirmed
1
by MS, H NMR, elemental analysis, or HRMS, which enabled us to
elaborate the possible reaction pathway.
EXPERIMENTAL
Melting points were determined on an X-6 microscopic melting-point
1
apparatus and are uncorrected. H NMR spectra were recorded on a
Bruker AC-200P spectrometer at 200 MHz using tetramethylsilane
(TMS) as internal standard. Chemical ionization (CI) mass spectrum
was recorded on a Finnigan Trace DSQ mass spectrometer. Low-resol-
ution electrospray ionization (ESI) mass spectra were recorded on a Bru-
ker Daltonics Esquire-LC 00136 mass spectrometer, and high-resolution
electrospray ionization (HR-ESI) mass spectra were recorded on a Bru-
ker Apex II FT-ICR mass spectrometer. High-resolution electron impact
(HR-EI) mass spectrum was recorded on a Micromass GCT mass spec-
trometer. Elemental analyses were performed by the Institute of Chemis-
try, Chinese Academy of Science, on a Flash EA 1112 elemental analyzer.
Column chromatography was carried out on silica gel (200–300 mesh). 2-
Amino-5-methylbenzoic acid was prepared according to the reported
method.[14] Triethyl orthoformate was distilled before using, and other
commercially available reagents were used without further purification.

3-Aryl-4(3H)-quinazolinones
2233
Selected Data for Compound 4
Mp: 266–267 ꢀC; 1H NMR (200 MHz, DMSO-d6): d ¼ 2.32 (s, 6 H, CH3),
7.43 (d, J ¼ 8.1 Hz, 2 H, Ar-H), 7.68 (d, J ¼ 8.1 Hz, 2 H, Ar-H), 7.80
þ
=
(s, 2 H, Ar-H), 8.84 (s, 1 H, CH N); ESI-MS: m=z ¼ 313 [M þ H] .
HRMS (ESI): m=z calcd. for C17H16N2O4: 311.1037 [M ꢁ H]ꢁ; found:
311.1036.
General Procedure for the Preparation of 3-Aryl-4(3H)-quinazolinones
3a–i
To a stirred solution of triethyl orthoformate (1.48 g, 10 mmol), concen-
trated H2SO4 (2 drops) in DMF (5 mL) was added along with anthranilic
acid 1 (6.67 mmol), and the mixture was heated carefully. As the tem-
perature rose, some low-boiling-point substances formed,ꢀwhich were
removed by distillation. After the temperature rose to 154 C, the reac-
ꢀ
tion mixture was stirred at 154–156 C for another 1 h. The mixture
was cooled to room temperature and poured into ice water (20 mL)
under stirring. The separated solid was collected by filtration and was
recrystallized from DMF-H2O to give 3-aryl-4(3H)-quinazolinones 3a–i
(Table 1).
Data
Compound 3a: 5-Methyl-2-(6-methyl-4-oxoquinazolin-3(4H)-yl)benzoic
ꢀ
acid, mp: 269–270 C; 1H NMR (200 MHz, DMSO-d6): d ¼ 2.45 (s,
3 H, CH3), 2.46 (s, 3 H, CH3), 7.45 (d, J ¼ 8.0 Hz, 1 H, Ar-H), 7.60 (d,
J ¼ 7.9 Hz, 1 H, Ar-H), 7.69 (m, 2 H, Ar-H), 7.89 (s, 1 H, Ar-H), 7.96
(s, 1 H, Ar-H), 8.21 (s, 1 H, Ar-H); ESI-MS: m=z ¼ 295 [M þ H]þ. Anal.
calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.28; H,
4.83; N, 9.33.
Compound 3b: 3-Methyl-2-(8-methyl-4-oxoquinazolin-3(4H)-yl)ben-
ꢀ
1
zoic acid, mp: 254–255 C; H NMR (200 MHz, DMSO-d6): d ¼ 2.13 (s,
3 H, CH3), 2.60 (s, 3 H, CH3), 7.48 (t, J ¼ 7.6 Hz, 1 H, Ar-H), 7.59 (t, J ¼
7.7 Hz, 1 H, Ar-H), 7.73 (d, J ¼ 7.2 Hz, 1 H, Ar-H), 7.77 (d, J ¼ 7.1 Hz,
1 H, Ar-H), 7.96 (d, J ¼ 7.6 Hz, 1 H, Ar-H), 8.03 (d, J ¼ 8.0 Hz, 1 H,
Ar-H), 8.25 (s, 1 H, Ar-H); ESI-MS: m=z ¼ 295 [M þ H]þ. Anal. Calcd.
for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.14; H, 4.83;
N, 9.58.
Compound 3c: 5-Hydroxy-2-(6-hydroxy-4-oxoquinazolin-3(4H)-
yl)benzoic acid, mp: >300 ꢀC; 1H NMR (200 MHz, DMSO-d6):
d ¼ 7.10 (dd, J ¼ 8.5, 2.7 Hz, 1 H, Ar-H), 7.32 (m, 2 H, Ar-H), 7.44

2234
S.-L. Cao et al.
(m, 2 H, Ar-H), 7.60 (d, J ¼ 8.7 Hz, 1 H, Ar-H), 8.03 (s, 1 H, Ar-H); ESI-
MS: m=z ¼ 299 [M þ H]þ, Anal. Calcd. for C15H10N2O5ꢂH2O: C, 56.96;
H, 3.82; N, 8.86. Found: C, 57.23; H, 3.76; N, 8.59.
Compound 3d: 5-Chloro-2-(6-chloro-4-oxoquinazolin-3(4H)-yl)ben-
ꢀ
1
zoic acid, mp: >300 C; H NMR (200 MHz, DMSO-d6): d ¼ 7.70 (d,
J ¼ 8.4 Hz, 1 H, Ar-H), 7.79 (d, J ¼ 8.7 Hz, 1 H, Ar-H), 7.89–7.96 (m,
2 H, Ar-H), 8.06 (d, J ¼ 2.3 Hz, 1 H, Ar-H), 8.11 (d, J ¼ 2.1 Hz, 1 H,
Ar-H), 8.38 (s, 1 H, Ar-H), 13.52 (br s, 1 H, OH); CI-MS: m=z ¼ 355
[M þ H]þ. Anal. Calcd. for C15H8Cl2N2O3: C, 53.76; H, 2.41; N, 8.36.
Found: C, 53.47; H, 2.52; N, 8.20.
Compound 3e: 4-Chloro-2-(7-ꢀchloro-4-oxoquinazolin-3(4H)-yl)ben-
ꢀ
1
zoic acid, mp: >300 C (lit.: 298 C)[15]; H NMR (200 MHz, DMSO-
d6): d ¼ 7.65 (dd, J ¼ 8.5, 2.0 Hz, 1 H, Ar-H), 7.78 (dd, J ¼ 8.4, 2.1 Hz,
1 H, Ar-H), 7.84 (d, J ¼ 2.0 Hz, 1 H, Ar-H), 7.88 (d, J ¼ 2.1 Hz, 1 H,
Ar-H), 8.10 (d, J ¼ 8.4 Hz, 1 H, Ar-H), 8.17 (d, J ¼ 8.5 Hz, 1 H, Ar-H),
8.42 (s, 1 H, Ar-H); ESI-MS: m=z ¼ 335 [M þ H]þ. Anal. Calcd. for
C15H8Cl2N2O3: C, 53.76; H, 2.41; N, 8.36. Found: C, 53.81; H, 2.53;
N, 8.46.
Compound 3f: 5-ꢀBromo-2-(6-bromo-4-oxoquinazolin-3(4H)-yl)ben-
1
zoic acid, mp: >300 C; H NMR (200 MHz, DMSO-d6): d ¼ 7.38 (d,
J ¼ 8.4 Hz, 1 H, Ar-H), 7.67 (d, J ¼ 8.7 Hz, 1 H, Ar-H), 7.73 (dd,
J ¼ 8.4, 2.0 Hz, 1 H, Ar-H), 7.95 (s, 1 H, Ar-H), 8.01 (dd, J ¼ 8.7,
2.3 Hz, 1 H, Ar-H), 8.18 (s, 1 H, Ar-H), 8.22 (d, J ¼ 2.3 Hz, 1 H, Ar-
H); ESI-MS: m=z ¼ 423 [M þ H]þ; HRMS (ESI): m=z calcd. for
C15H8Br2N2O3: 420.8829 [M ꢁ H]ꢁ; found: 420.8825.
Compound 3g: 5-Acetamido-2-(6-acetamido-4-oxoquinazolin-3(4H)-
yl)benzoic acid, mp: 246–248 ꢀC; 1H NMR (200 MHz, DMSO-d6):
d ¼ 2.11 (s, 3 H, COCH3), 2.12 (s, 3 H, COCH3), 7.51 (d, J ¼ 8.6 Hz,
1 H, Ar-H), 7.72 (m, 2 H, Ar-H), 7.99 (m, 2 H), 8.21 (s, 1 H, Ar-H),
8.32 (d, J ¼ 2.5 Hz, 1 H, Ar-H), 8.45 (m, 2 H); ESI-MS: m=z ¼ 381
[M þ H]þ. Anal. Calcd. for C19H16N4O5ꢂH2O: C, 57.28; H, 4.55; N,
14.06. Found: C, 57.32; H, 4.55; N, 13.72.
Compound 3h: 2-(4-Oxoquinazolin-3(4H)-yl)benzoic acid, mp: 287–
ꢀ
ꢀ
1
288 C (lit.: 283 C)[15]; H NMR (200 MHz, DMSO-d6): d ¼ 7.55–7.93
(m, 6 H, Ar-H), 8.08 (dd, J ¼ 7.6, 1.4 Hz, 1 H, Ar-H), 8.17 (dd, J ¼ 7.9,
1.0 Hz, 1 H, Ar-H), 8.32 (s, 1 H, Ar-H); ESI-MS: m=z ¼ 267 [M þ H]þ.
Anal. Calcd. for C15H10N2O3: C, 67.67; H, 3.79; N, 10.52. Found: C,
67.32; H, 3.89; N, 10.49.
Compound 3i: 2-(7ꢀ-Carboxy-4-oxoquinazolin-3(4H)-yl)benzene-1,4-
1
dioic acid, mp: >300 C; H NMR (200 MHz, DMSO-d6): d ¼ 7.95–
8.29 (m, 6 H, Ar-H), 8.40 (s, 1 H, Ar-H); ESI-MS: m=z ¼ 355 [M þ H]þ,
HRMS (EI): m=z calcd. for C17H10N2O7: 354.0488 [Mþ]; found:
354.0490.

3-Aryl-4(3H)-quinazolinones
2235
The reaction of 5-nitro-2-aminobenzoic acid 1j was carried out
according to this general procedure. Column chromatography (eluent:
petroleum ether-AcOEt, 3:2) of the product gave 2-(N-ethoxymethylene-
amino)-5-nitrobenzoic acid 5 as a yellow solid, yield: 39%, mp: 100–102
ꢀC; 1H NMR (200 MHz, CDCl3): d ¼ 1.48 (t, J ¼ 7.1 Hz, 3 H,
OCH2CH3), 4.48 (q, J ¼ 7.1 Hz, 2 H, OCH2CH3), 8.39 (dd, J ¼ 9.3,
=
2.7 Hz, 1 H, Ar-H), 8.62 (s, 1 H, N CH), 8.94 (m, 2 H, Ar-H), 11.39
(br s, 1 H, OH); ESI-MS: m=z ¼ 239 [M þ H]þ, Anal. Calcd. for
C10H10N2O5: C, 50.42; H, 4.23; N, 11.76. Found: C, 50.74; H, 4.38;
N, 12.12.
ACKNOWLEDGMENTS
We are grateful to the Natural Science Foundation of Beijing City (Pro-
ject No. 7042006) and the Education Committee of Beijing City (Project
No. KM200710028008) for financial support.
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