Ammonium chloride-catalyzed one-pot synthesis of 4(3H)-quinazolinones under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2013.873467

Ammonium chloride, which is a very inexpensive and readily available reagent, can efficiently catalyze three-component, one-pot condensation reactions of 2-amino-benzoic acid esters, ortho esters, and aromatic amines to afford the corresponding 4(3H)-quinazolinones in good to excellent yields under solvent-free conditions.

Full text of DOI:10.1080/00397911.2013.873467

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Ammonium Chloride–Catalyzed One-Pot
Synthesis of 4(3H)-Quinazolinones Under
Solvent-Free Conditions
Guoli Huang a , Bo Liu a , Mingyu Teng a & Yegao Chen a
a School of Chemistry and Chemical Engineering, Yunnan Normal
University , Kunming , China
Published online: 14 May 2014.
To cite this article: Guoli Huang , Bo Liu , Mingyu Teng & Yegao Chen (2014) Ammonium
Chloride–Catalyzed One-Pot Synthesis of 4(3H)-Quinazolinones Under Solvent-Free Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:12, 1786-1794, DOI: 10.1080/00397911.2013.873467
To link to this article: http://dx.doi.org/10.1080/00397911.2013.873467
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Synthetic Communications1, 44: 1786–1794, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.873467
AMMONIUM CHLORIDE–CATALYZED ONE-POT
SYNTHESIS OF 4(3H)-QUINAZOLINONES UNDER
SOLVENT-FREE CONDITIONS
Guoli Huang, Bo Liu, Mingyu Teng, and Yegao Chen
School of Chemistry and Chemical Engineering, Yunnan Normal University,
Kunming, China
GRAPHICAL ABSTRACT
Abstract Ammonium chloride, which is a very inexpensive and readily available reagent, can
efficiently catalyze three-component, one-pot condensation reactions of 2-amino-benzoic
acid esters, ortho esters, and aromatic amines to afford the corresponding 4(3H)-
quinazolinones in good to excellent yields under solvent-free conditions.
Keywords Ammonium chloride; one-pot condensation; 4(3H)-quinazolinones; solvent-
free
INTRODUCTION
It is well known that 4(3H)-quinazolinones are fused heterocycles and exhibit a
wide range of biological activities such as antimalarial, antitumor, anticonvulsant,
anti-inflammatory, fungicidal, antimicrobial, antihypertensive, anti-parkinsonism,
antihistaminic, and calcilytic activities.[1] In addition, a small number of quinazoli-
none core units such as 3-aryl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-diones,[2]
3-arylquinazoline-2,4(1H,3H)-diones, and quinazolinone derivatives[3] are potent
chemotherapeutic agents in the treatment of tuberculosis. Recently, many synthetic
methods for the preparation of this class of compounds have been reported. The
most direct procedure includes the condensation of anthranilic acid, ortho
esters, and amines in the presence of various catalysts such as Yb(OTf)3,[4] SiO2-
NaHSO4 or Amberlyst-15,[5] Yb(III)-resin,[6] Bi(TFA)3-[nbp]FeCl4 ionic liquid,[7]
Received August 1, 2013.
Address correspondence to Guoli Huang, School of Chemistry and Chemical Engineering, Yunnan
Normal University, Kunming 650500, China. E-mail: hgli2005@126.com
1786

SYNTHESIS OF 4(3H)-QUINAZOLINONES
1787
Scheme 1. Synthesis of 4(3H)-quinazolinones catalyzed by NH4Cl.
La(NO3)3 ꢀ 6H2O or p-toluenesulfonic acid,[8] SiO2-FeCl3,[9] Keggin-type
heteropolyacid,[10] iodine,[11] Ce(CH3SO3)3 ꢀ 2H2O,[12] ceric ammonium nitrate
(CAN),[13] SrCl2 ꢀ 6H2O,[14] Zn(ClO4)2,[15] SiO2-BF3,[16] and Al(NO3)3 ꢀ 9H2O.[17]
However, some of these methods are associated with certain drawbacks such as
long reaction time (20 h), harmful organic solvent, and use of metal salts. Indeed,
anthranilic acid is a precursor chemicals and not readily available. Therefore, the
discovery of a new and inexpensive catalyst for the preparation of 4(3H)-
quinazolinones under neutral and mild conditions is of prime importance. Recently,
Vasu reported a novel, efficient, and greener one-pot method for the synthesis of
4(3H)-quinazolinones by the reaction of methyl anthranilate, N,N-dimethyl forma-
mide dimethyl acetal, and anilines.[18]
In this regard, ammonium chloride is very inexpensive, easily available, and
efficient catalyst in organic synthesis. It can effectively promote reactions such as
four-component synthesis of pyrrolo[3,4-b]pyridinones,[19] Ugi four-component,
five-center reactions,[20] and three-component synthesis of 5-iminooxazoline.[21]
Moreover, ammonium chloride was used as an efficient catalyst for reactions
such as reduction of nitrophenols under ultrasound,[22] Biginelli synthesis of 3,4-
dihydropyrimidinones under solvent-free conditions,[23] one-pot synthesis of diindo-
lylmethanes under solvent-free conditions,[24] and thia-Michael addition reaction of
carbon–sulfur bond formation in water.[25]
Herein we report the synthesis of 3-aryl-4(3H)-quinazolinones by the three-
component condensation of 2-amino-benzoic acid esters, ortho esters, and aromatic
amines in the presence of NH4Cl as a very inexpensive, easily available, and efficient
catalyst under solvent-free conditions (Scheme 1).
RESULTS AND DISCUSSION
The one-pot condensation reaction of 2-amino-benzoic acid esters (1a), tri-
methyl orthofomate (2a), and aniline (3a) was chosen as a model system to determine
the optimum reaction conditions, and the results are summarized in Table 1. The
initial study was conducted by examining the suitable ammonium salts including
organic and inorganic ones in the model reaction. First, the model reaction pro-
ceeded in the presence of NH4OAc and generated the desired product 4a in 90% yield
(entry 1). Further, other ammonium salts, such as (NH4)2(CO2)2, (NH4)2SO4, and
(NH4)2Fe(SO4)2 ꢀ 6H2O, showed less reactivity than NH4Cl (entries 2–5), which gave
the greatest yield (99%). We investigated the effect of the amount of NH4Cl on the
reaction. Reducing the catalyst loading from 40 to 20 and 10 mol% lowered the con-
version from 99 to 85 and 71%, respectively (entries 5–7). In the absence of the
catalyst, the trace product was observed after a long reaction time (6 h) (entry 8).

1788
G. HUANG ET AL.
Table 1. Synthesis of 4(3H)-quinazolinones under solvent-free conditionsa
Amount of
catalyst (mol%)
Temperature
(ꢁC)
Time
(h)
Yield of
4a (%)b
Entry
Catalyst
1
2
NH4OAc
(NH4)2(CO2)2
(NH4)2SO4
(NH4)2Fe(SO4)2 ꢀ 6H2O
NH4Cl
40
40
40
40
40
20
10
—
40
40
40
40
100
100
100
100
100
100
100
100
80
2
90
20
2
3
2
31
10
99 (81)c
85
71
4
2
5
2
6
NH4Cl
NH4Cl
2
7
2
8
—
NH4Cl
2
<5
67
9
2
10
11
12
NH4Cl
NH4Cl
NH4Cl
60
2
44
81
100
100
1
0.5
60
aReaction conditions: 2-amino-benzoic acid ester (1.0 mmol), aniline (1.2 mmol), trimethyl orthofomate
(1.5 mmol).
bDetermination from 1H NMR.
cThe molar ratio of 2-amino-benzoic acid esters, aniline, and trimethyl orthofomate is 1.0:1.2:1.2.
It is evident that the amount of catalyst has remarkable effect on this reaction. The
effect of temperature has also been investigated. The reaction could proceed
smoothly at 100 ꢁC. However, lowering the temperature from 100 to 80 and 60 ꢁC
significantly reduced the conversion from 99 to 67 and 44% (entries 9 and 10). We
have tried to shorten the reaction time from 2 to 1 and 0.5 h, but the conversion
was obviously lowered from 99 to 81 and 60%, respectively (entries 11 and 12).
Hence, the optimal reaction conditions were 2-amino-benzoic acid esters (1.0 equiv),
ortho esters (1.5 equiv), and aromatic amines (1.2 equiv) at 100 ꢁC for 2 h under
solvent-free conditions.
After establishing the optimal reaction conditions, a wide range of structurally
varied 2-amino-benzoic acid esters, ortho esters, and aromatic amines were examined
in the presence of NH4Cl under solvent-free conditions, and the results are summar-
ized in Table 2. In all cases, the three-component reaction proceeded rapidly to
afford the corresponding 4(3H)-quinazolinones in excellent yields. In addition to
2-amino-benzoic acid ester (1a), 8-bromo-2-amino-benzoic acid ester was subjected
to the condensation reactions. The position of substituent groups on the 2-amino-
benzoic acid esters did not significantly affect the reaction rates and yields (entries
1 and 7). In addition, equally good results were obtained for trimethyl and triethyl
orthoformates, but triethyl orthoformate gave slightly greater yields than trimethyl
orthoformate under the optimized conditions (entries 1 vs 2, 3 vs 4, 7 vs 8, 12 vs
13, 18 vs 19). A variety of substituent groups of the aromatic amines were well

SYNTHESIS OF 4(3H)-QUINAZOLINONES
1789
Table 2. Synthesis of 4(3H)-quinazolinones catalyzed by NH4Cl under solvent-free conditionsa
Entry
X
R
Ar
Product (yield %)b
1
2
H
Me
Et
Ph
Ph
4a (92) (99)c
4a (94)
4b (95)
4b (96)
4c (91)
4d (89)
4e (93)
4e (95)
4f (95)
4g (97)
4h (91)
4i (96)
H
3
H
Me
Et
4-MeC6H4
4-MeC6H4
1-Naphthyl
2-MeC6H4
Ph
4
H
5
H
Me
Me
Me
Et
6
H
7
Br
Br
Br
Br
Br
H
8
Ph
9
Me
Me
Me
Me
Et
1-Naphthyl
4-MeC6H4
2-MeC6H4
4-MeOC6H4
4-MeOC6H4
3,4-Cl2C6H3
4-MeCOC6H4
4-NO2C6H4
4-HO2CC6H4
4-MeOC6H4
4-MeOC6H4
4-MeCOC6H4
3,4-Cl2C6H3
2-BrC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
H
4i (97)
4j (91)
H
Me
Me
Me
Me
Me
Et
H
4k (86)
4l (75)
H
H
4m (70)
4n (95)
4n (97)
4o (90)
4p (84)
4q (82)
Br
Br
Br
Br
Br
Me
Me
Me
aReaction conditions: 2-amino-benzoic acid esters (1.0 mmol), aromatic amines (1.2 mmol), ortho esters
(1.5 mmol).
bIsolated yields.
cDetermination from 1H NMR.
tolerated. In general, reaction substrates with electron-donating groups (such as
methoxy and methyl, entries 3, 6, and 12) on the aniline system gave greater yields
than those with electron-withdrawing groups (such as chloro, acetyl, nitro, carboxyl
and bromo, entries 14–17, and 22), possibly due to the increased electron density of
aromatic system. Furthermore, the positions of substituent groups on the aniline sys-
tem also affected the reaction rates and yields under the optimized conditions. The
yield of product with ortho-substituted anilines was lower than that with para posi-
tions (entries 3 vs 6, 10 vs 11).
We propose a mechanism similar to that of Errede[26] and Wang[4] for the reac-
tion (Scheme 2). In the first step of this reaction, NH4Cl facilitates the reaction of
ortho esters 2 with 2-amino-benzoic acid ester 1 or aromatic amines 3 to give imidic
ester 5 or 7, which are very prone to react immediately with amine (3 or 1) to form an
amidine intermediate 6 that is further activated by NH4Cl. Subsequently, the

1790
G. HUANG ET AL.
Scheme 2. Possible reaction mechanism for NH4Cl-catalyzed synthesis of 4(3H)-quinazolinones.
reaction proceeds via 6 by an intramolecular attack of the nitrogen nucleophile at
carbonyl carbon to produce the corresponding cyclized product 4.
CONCLUSION
In summary, we have developed an economical and environmentally friendly
procedure for the synthesis of 4(3H)-quinazolinones via a three-component, one-pot
condensation of 2-amino-benzoic acid esters, ortho esters, and aromatic amines in
excellent yields. This involves the use of NH4Cl as a very inexpensive and easily
available catalyst, solvent-free conditions, and reduced reaction time.
EXPERIMENTAL
2-Amino-3-bromobenzoic acid methyl ester was synthesized by stirring 2-
aminobenzoic acid methyl ester with N-bromosuccinimide (NBS) in AcOH (see
the supplemental material). The commercially available reagents and solvents were
used without further purification unless otherwise noted. Column chromatography
was performed with silica gel (200–300 mesh). 1H and 13C NMR spectra were
recorded on a Bruker Avance III 500-MHz spectrometer for solution in CDCl3 or
DMSO-d6. High-resolution mass spectra (HRMS) were obtained from Agilent
6538 UHD accurate-mass Q-TOF. All the products (except 4e–4h and 4n–4q) are
1
known compounds,[4,7,8,11–14,18,27] which were characterized by H and 13C NMR
spectral data (see the supplemental material).
General Experimental Procedure for the Preparation of Compounds
4a–q
A mixture of 2-amino-benzoic acid esters (1.0 mmol), aromatic amines
(1.2 mmol), ortho esters (1.5 mmol), and NH4Cl (0.021 g, 0.4 mmol) was heated with
stirring at 100 ꢁC for 2 h. After cooling, H2O was added and the product was
extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated, and
the residue was recrystallized from EtOH–hexane to afford the pure product.

SYNTHESIS OF 4(3H)-QUINAZOLINONES
1791
8-Bromo-3-phenyl-4(3H)-quinazolinone (4e)
White solid. 1H NMR (CDCl3) d ¼ 8.50 (s, 1H), 8.13 (s, 1H), 7.88 (d,
J ¼ 8.6 Hz, 1H), 7.65 (d, J ¼ 8.6 Hz, 1H), 7.58–7.50 (m, 3H), 7.42 (d, J ¼ 7.6 Hz,
2H). 13C NMR (CDCl3) d ¼ 159.7, 146.9, 146.8, 137.9, 137.3, 129.9, 129.8, 129.5,
129.4, 127.0, 123.9, 121.4. HRMS (EI): calcd. for C14H9BrN2O [MHþ]: 302.1455;
found 302.1459.
8-Bromo-3-(1-naphthyl)-4(3H)-quinazolinone (4f)
1
White solid. H NMR (CDCl3) d ¼ 8.53 (d, J ¼ 1.9 Hz, 1H), 8.10 (s, 1H), 8.04
(d, J ¼ 8.3 Hz, 1H), 7.98 (d, J ¼ 8.1 Hz, 1H), 7.93 (dd, J ¼ 8.7, 2.1 Hz, 1H), 7.72 (d,
J ¼ 8.7 Hz, 1H), 7.65–7.47 (m, 5H). 13C NMR (CDCl3) d ¼ 160.0, 147.3, 147.1,
138.0, 134.5, 133.9, 130.6, 129.9, 129.7, 129.6, 128.8, 128.0, 127.1, 126.0, 125.6,
123.9, 121.9, 121.5. HRMS (EI): calcd. for C18H11BrN2O [MHþ]: 352.2041; found
352.2044.
8-Bromo-3-(4-methylphenyl)-4(3H)-quinazolinone (4g)
1
White solid. H NMR (CDCl3) d ¼ 8.49 (d, J ¼ 2.0 Hz, 1H), 8.11 (s, 1H), 7.87
(dd, J ¼ 8.6, 2.1 Hz, 1H), 7.63 (d, J ¼ 8.6 Hz, 1H), 7.35 (d, J ¼ 8.0 Hz, 2H), 7.29 (d,
J ¼ 8.2 Hz, 2H), 2.44 (s, 3H). 13C NMR (CDCl3) d ¼ 159.8, 146.9, 146.7, 139.6,
137.8, 134.7, 130.4, 129.8, 129.5, 126.7, 123.9, 121.3, 21.3. HRMS (EI): calcd. for
C15H11BrN2O [MHþ]: 316.1720; found 316.1715.
8-Bromo-3-(2-methylphenyl)-4(3H)-quinazolinone (4h)
White solid. 1H NMR (CDCl3) d ¼ 8.51 (s, 1H), 8.00 (s, 1H), 7.90 (dd, J ¼ 5.4,
1.8 Hz, 1H), 7.67 (d, J ¼ 7.1 Hz, 1H), 7.40 (d, J ¼ 18.6 Hz, 3H), 2.20 (s, 3H). 13C
NMR (CDCl3) d ¼ 159.4, 147.1, 146.8, 137.9, 136.4, 135.8, 131.5, 130.0, 129.8,
129.6, 127.8, 127.5, 123.9, 121.4, 17.8. HRMS (EI): calcd. for C15H11BrN2O
[MHþ]: 316.1720; found 316.1726.
8-Bromo-3-(4-methoxyphenyl)-4(3H)-quinazolinone (4n)
1
White solid. H NMR (CDCl3) d ¼ 8.48 (d, J ¼ 1.8 Hz, 1H), 8.10 (s, 1H), 7.86
(dd, J ¼ 8.6, 2.0 Hz, 1H), 7.63 (d, J ¼ 8.6 Hz, 1H), 7.32 (d, J ¼ 8.8 Hz, 2H), 7.04 (d,
J ¼ 8.8 Hz, 2H), 3.87 (s, 3H). 13C NMR (125 MHz, CDCl3) d 160.2, 146.9, 146.8,
137.8, 129.9, 129.8, 129.5, 128.2, 123.9, 121.3, 115.0, 55.7. HRMS (EI): calcd. for
C15H11BrN2O2 [MHþ]: 332.1714; found 332.1717.
8-Bromo-3-(4-acetylphenyl)-4(3H)-quinazolinone (4o)
Yellow solid. 1H NMR (CDCl3) d ¼ 8.49 (d, J ¼ 2.0 Hz, 1H), 8.15 (d,
J ¼ 8.4 Hz, 2H), 8.12 (s, 1H), 7.90 (dd, J ¼ 8.6, 2.1 Hz, 1H), 7.66 (d, J ¼ 8.6 Hz,
1H), 7.55 (d, J ¼ 8.4 Hz, 2H), 2.67 (s, 3H). 13C NMR (CDCl3) d ¼ 196.8, 159.4,

1792
G. HUANG ET AL.
146.7, 145.6, 141.0, 138.2, 137.6, 129.9 (2C), 129.6, 127.2, 123.7, 121.8, 26.9. HRMS
(EI): calcd. for C16H11BrN2O2 [MHþ]: 344.1821; found 344.1824.
8-Bromo-3-(3,4-dichlorophenyl)-4(3H)-quinazolinone (4p)
1
White solid. H NMR (CDCl3) d ¼ 8.47 (s, 1H), 8.06 (s, 1H), 7.95–7.86 (m,
1H), 7.64 (dd, J ¼ 8.6, 2.5 Hz, 2H), 7.57 (s, 1H), 7.29 (dd, J ¼ 8.4, 1.7 Hz, 1H). 13C
NMR (CDCl3) d ¼ 159.4, 146.6, 145.4, 138.3, 136.3, 134.1, 134.0, 131.5, 129.9,
129.7, 129.2, 126.4, 123.6, 121.9. HRMS (EI): calcd. for C14H7BrCl2N2O [NHþ]
371.0356; found 371.0350.
8-Bromo-3-(3-bromophenyl)-4(3H)-quinazolinone (3q)
1
White solid. H NMR (CDCl3) d ¼ 8.49 (d, J ¼ 2.3 Hz, 1H), 7.94 (s, 1H), 7.90
(dd, J ¼ 8.7, 2.0 Hz, 1H), 7.83–7.77 (m, 1H), 7.67 (d, J ¼ 8.7 Hz, 1H), 7.52 (t,
J ¼ 7.4 Hz, 1H), 7.44–7.20 (m, 2H). 13C NMR (CDCl3) d ¼ 159.1, 147.0, 146.3,
138.0, 136.5, 134.1, 131.5, 130.0, 129.9, 129.7, 129.0, 124.0, 122.5, 121.5. HRMS
(EI): calcd. for C14H8Br2N2O [NHþ] 381.0415; found 381.0410.
FUNDING
We thank the Applied Basic Research Projects of Yunnan Province (No.
2013FZ043, 2014FZ042) and the Scientific Research Fund of Yunnan Education
Department (No. 22012Z017, 2013Y431) for the financial support.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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