A recyclable CuO-catalyzed synthesis of 4(3H)-quinazolinones

Article abstract of DOI:10.1039/c3ra41370e

This paper describes the synthesis of 2-substituted and 2,3-disubstituted 4(3H)-quinazolinones via a tandem reaction involving anthranilamides and aromatic aldehydes catalyzed by 3 mol% CuO powder under air atmosphere. This new method has several advantages: it uses recyclable and cheap CuO powder as the catalyst and air as the green oxidant, water is the only byproduct, and the solvent is recycled. It is easy to run, has a high atom economy and good to excellent yields. A mechanism for the CuO-catalyzed synthesis of the 4(3H)-quinazolinones is proposed.

Full text of DOI:10.1039/c3ra41370e

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A recyclable CuO-catalyzed synthesis of 4(3H)-
quinazolinones3
Cite this: DOI: 10.1039/c3ra41370e
Dan Zhan,a Tianbin Li,a Haidong Wei,a Wen Weng,b Khashayar Ghandic
and Qingle Zeng*a
This paper describes the synthesis of 2-substituted and 2,3-disubstituted 4(3H)-quinazolinones via a
tandem reaction involving anthranilamides and aromatic aldehydes catalyzed by 3 mol% CuO powder
under air atmosphere. This new method has several advantages: it uses recyclable and cheap CuO powder
as the catalyst and air as the green oxidant, water is the only byproduct, and the solvent is recycled. It is
easy to run, has a high atom economy and good to excellent yields. A mechanism for the CuO-catalyzed
synthesis of the 4(3H)-quinazolinones is proposed.
Received 13th December 2012,
Accepted 28th March 2013
DOI: 10.1039/c3ra41370e
www.rsc.org/advances
4(3H)-Quinazolinones are an important class of nitrogen-
containing heterocycles with various pharmacological and
therapeutic properties.1 They are used in anticancer,2 anti-
inflammatory,3 antibacterial4 and antihypertensive therapies,5
in addition to being vasopressin V3 receptor antagonists6 and
nonpeptide cholecystokinin B receptor antagonists.7 Hence,
the efficient synthesis of quinazolinone derivatives is impor-
tant.
Several methods for the synthesis of 4(3H)-quinazolinones
have been investigated in the past. Some common methods
include the condensation of 2-aminobenzamides and substi-
tuted benzoyl chlorides or their equivalents in ionic liquids,8
the tandem condensation and C–N cross coupling of 2-halo-
benzoic acids and amidines,9 the cyclization of o-acylamino-
benzamides,10 2-amino-benzonitrile,11 N-arylorthanilamides,12
and nitroenes,13 and aza-Wittig reactions of a-azido-substituted
aromatic imides.14 However, most of these procedures have
some drawbacks, as they have a poor atom economy, use
environmentally toxic reagents or media, use expensive
chemicals, and often involve harsh reaction conditions.
In addition, some three-component condensation reactions
involving isatoic anhydride–anthranilic acid, ortho esters and
amines have been reported,15 but these approaches again lack
a good atom economy. Very recently Adib developed an
efficient, one-pot three-component synthesis of 4(3H)-quina-
zolinones using benzyl halides, isatoic anhydride and primary
amines. However, benzyl chlorides are carcinogenic alkylating
agents and poisonous lachrymators and the base K2CO3 is
needed to neutralize the hydrochloride produced during the
reaction.16
Relatively recently, Fu reported a CuBr-catalyzed domino
synthesis of 2-aryl 4(3H)-quinazolinones via an Ullmann-type
coupling involing ortho-iodobenzamides and benzyl amines or
a-amino acids (decarboxylation of a-amino acids as the
substrates), and an aerobic oxidative C–H amidation.17 Very
recently, Ma developed a CuI–4-hydroxy-L-proline catalyzed
coupling involving N-substituted o-bromobenzamides and for-
mamide or other amides to afford 3-substituted quinazolinones
directly, or 2,3-disubstituted quinazolinones via a HMDS–ZnCl2
mediated condensative cyclization.18 Unfortunately, both
approaches lead to the generation of undesired byproducts,
such as hydrogen halide which consumes K2CO3 making the
overall process less efficient in terms of atom economy.
In 1994, Abdel-Jalil introduced a new synthetic protocol for
the production of 2-substituted 4(3H)-quinazolinones, i.e. a
cascade condensation of anthranilamide and aryl, alkyl, and
heteroaryl aldehydes and 3 equivalents of CuCl2 as the oxidant
and catalyst.19
Later, a similar approach was reported using 2 equivalents
of FeCl3 as the oxidant and catalyst.20 In 2010, Wang et al.
developed an iodine-catalyzed approach in ionic liquids with
the same class of substrates, that is, anthranilamide and
aldehydes, but the loading of iodine was not given in their
main paper or its supporting information, nor was any note
made in their general procedure for the synthesis of
2-arylquinazolin-4(3H)-one and (E)-2-arylideneaminobenza-
mide.21 Similar to this work, Dabiri et al. reported a one-pot
three-component route to synthesize 2,3-disubstituted 4(3H)-
quinazolinones in the presence of an equivalent amount of
iodine as the catalyst.22 All the aforementioned methods of
aInstitute of Green Catalysis and Synthesis, State Key Lab of Geohazard Prevention
and Geoenvironment Protection, College of Materials and Chemistry & Chemical
Engineering, Chengdu University of Technology, Chengdu 610059, China.
E-mail: qinglezeng@hotmail.com
bDepartment of Chemistry and Environmental Science, Zhangzhou Normal
University, Zhangzhou 363000, PR China
cDepartment of Chemistry and Biochemistry, Mount Allison University, Sackville, NB,
Canada
Electronic supplementary information (ESI) available: general experimental
3
details and characterisation data for compounds. See DOI: 10.1039/c3ra41370e
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Table 1 Screening of various reaction conditionsa
synthesis of 4(3H)-quinazolinones with anthranilamides and
aldehydes as substrates involve using stoichiometric amounts
of various chemical oxidants, such as CuCl2.
Copper salts have a wide variety of applications in organic
synthesis. The copper(II) ion itself can act as a stoichiometric
oxidant in the synthesis of 4(3H)-quinazolinones,19 and also
can be used as a good oxidation catalyst,23 even with air as the
oxidant.23a Of course, a heterogeneous, recyclable catalyst is
the best for a clean production. As an environmentally benign
and economic process, recyclable catalysis has shown a great
advancement over the past decades.24 The recyclable CuO
nanoparticle is a catalyst not only for the C–N cross coupling of
amines and iodobenzene,25 but also for the oxidation of
aldehydes to the corresponding carboxylic acids using mole-
cular oxygen.26 Commercial, inexpensive CuO could have
oxidation catalytic properties similar to CuO nanoparticles and
may also be recyclable.
As a continuation of our research in transition metal
catalyzed reactions,27 and in order to find a green and
recyclable catalytic system, CuO and some other insoluble,
nontoxic or low toxic metal oxides, such as Fe2O3, Cu2O, Al2O3
and TiO2, were adopted for the synthesis of 2-aryl-4(3H)-
quinazolinones. After our experimental exploration, we found
that CuO is a suitable green catalyst for this reaction.
Catalyst
(amount (mol%))
Temp.
(uC)
Time
(h)
Yieldb
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Al2O3 (5)
TiO2 (5)
Fe2O3 (5)
Cu2O (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (10)
CuO (3)
CuO (2)
CuO (3)
CuO (3)
CuO (3)
DMA
DMA
DMA
DMA
DMA
H2O
Ethanol
DMSO
DMF
DMA
DMA
DMA
DMA
DMA
DMA
120
120
120
120
120
100
80
120
120
120
120
120
100
80
24
24
24
24
24
24
24
24
24
24
24
24
24
24
20
51
55
78
92
98
5
21
89
79
91
97
75
24
trace
79
120
a
Reaction conditions: metal oxide, anthranilamide (1 mmol),
benzaldehyde (1 mmol), solvent (3 mL), in air. Isolated yield.
b
Herein we report an efficient recyclable CuO-catalyzed
synthesis of 4(3H)-quinazolinones (Scheme 1).
CuO-catalyzed synthesis of 2-phenyl-4(3H)-quinazolinone 3a
(entry 5).
In order to find a catalytic system for the synthesis of 4(3H)-
quinazolinones, anthranilamide (1a) and benzaldehyde (2a)
were used as the model substrates. Anthranilamide (1a) and
benzaldehyde (2a) and certain insoluble, nontoxic or low
toxicity metal oxides in the high boiling point, polar non-protic
solvent N,N-dimethylacetamide (DMA) were heated in air at
120 uC for 24 h. Several suitable metal oxides, such as Al2O3,
TiO2, Fe2O3, Cu2O and CuO were screened (Table 1). Among
the five metal oxides, when a 5 mol% amount of metal oxide
was used, Al2O3 and TiO2 gave moderate yields (Table 1,
entries 1 and 2), and Fe2O3 gave a slightly higher yield (entry
3), and Cu2O gave a high yield (entry 4). CuO gave the highest
yield, which was up to 98% (Table 1, entry 5).
Next, we screened the solvents. Water and ethanol are
green, inexpensive solvents, but they were proven to be poor
for dissolving anthranilamide and its product 2-phenyl-4(3H)-
quinazolinone (3a), and gave extremely poor yields at lower
temperatures (entries 6 and 7). When the reaction was
performed in DMSO, the reaction at 120 uC gave a lower yield
than that of the reaction in DMA (Table 1, entry 8 vs. entry 5).
DMF (N,N-dimethylformamide) afforded a poorer result with
79% yield (entry 9). Therefore, DMA is the best solvent for the
The amounts of the CuO catalyst were further screened. The
result shows that the higher CuO amount of 10 mol% did not
result in a higher yield (Table 1, entry 10), so perhaps the
excess CuO affected the efficient separation of the product. It
seems that 3 mol% CuO is enough for this reaction, as it
afforded nearly the same yield as 5 mol% CuO (Table 1, entry
11). However, when 2 mol% CuO was used, there was an
obvious decrease in the yield of 2-phenyl-4(3H)-quinazolinone
3a (Table 1, entry 12).
The further examination of reaction temperature demon-
strates that a lower reaction temperature sharply decreased the
yield due to the incomplete transformation of anthranilamide
and benzaldehyde (Table 1, entries 13 and 14); there was
almost no product when this reaction was performed at 80 uC.
Decreasing the reaction time also resulted in a sharp decrease
in the yield (Table 1, entry 15).
Therefore, the optimized procedure for the synthesis of
2-phenyl-4(3H)-quinazolinone 3a requires 3 mol% CuO, and
anthranilamide (1a) and benzaldehyde (2a) in DMA are heated
in air at 120 uC for 24 h.
With the optimized reaction conditions in hand, a series of
anthranilamides and aldehydes were investigated (Table 2,
Scheme 1). Under optimized conditions, the CuO-catalyzed
tandem condensation and aerobic oxidation of 4-methylben-
zaldehyde and anthranilamide afforded 2-(49-methylphenyl)-
4(3H)-quinazolinone (3b) in an excellent yield similar to that of
benzaldehyde (Table 2, entry 2 vs. entry 1).
Scheme 1 The CuO-catalyzed synthesis of 4(3H)-quinazolinones.
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Table 2 The synthesis of 2-substituted and 2,3-disubstituted 4(3H)-quinazoli-
nonesa
Table 3 The effect of recycled CuO on the reactiona
Entry
CuO
Yieldb (%)
1
2
3
4
5
5 mol%
98
94
91
88
85
Recycled first time
Recycled second time
Recycled third time
Recycled forth time
a
Yieldb (%)
Reaction conditions: CuO (0.05 mmol), anthranilamide (1 mmol),
Entry
R
R9
Product
b
benzaldehyde (1 mmol), DMA (3 mL), at 120 uC for 24 h. Isolated
yield.
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
97
97
89
95
77
93
86
88
85
90
86
78
81
52
87
4-CH3C6H4
3-CH3OC6H4
3,5-tBu2-2-(OH)C6H2
4-(CH3)2NC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
Furyl
Pentyl
Ph
Ph
Ph
We noticed that the black powder catalyst CuO precipitated
at the bottom of the vial when the reaction was complete and
the reaction mixture was cooled to room temperature. Keeping
the vial absolutely still, we removed the upper clear solution
using a pipette and deposited it into a flask. 3 mL DMA was
added into the vial and the upper clear solution was removed
again. The combined solution was condensed under vacuum
to afford the re-usable solvent DMA and the crude product,
which was purified using silica gel chromatography or
recrystallization from ethanol. The residual black CuO was
used as the first time recycled catalyst for the second synthesis
of 2-phenyl-4(3H)-quinazolinone 3a. The yield when using the
first time recycled CuO was still very high (Table 3, entry 2).
Repeated recycling of the CuO catalyst gave lower yields
(Table 3, entries 2 to 5). The yield was still reasonable (85%)
after the fourth reuse of CuO (Table 3, entry 5).
To account for the observed results, we reasoned that the
CuO-catalyzed reaction probably acts through a different
mechanistic pathway compared to those reported earlier
involving other catalytic systems and synthetic meth-
ods.15d,17a,21 The plausible mechanism of the CuO-catalyzed
synthesis of 4(3H)-quinazolinones is depicted in Scheme 2.
Firstly, condensation of the anthranilamide 1 and the
aldehyde 2 produces the imine 4, which is in equilibrium with
its tautomer 5. The coordination of tautomer 5 and CuO may
induce an intramolecular electron transfer. As a result, 2,3-
dihydroquinazolin-4(1H)-one 7 is obtained. A combination of
electron transfer and intramolecular rearrangement furnishes
the desired product 3 and Cu(0)?H2O, which should be more
stable then Cu(0) due to the coordination to H2O. Active
Cu(0)?H2O is facilely oxidized by oxygen in the air to restore
CuO, which enters the next catalytic cycle (Scheme 2).
9
10
11
12
13
14
15c
C3H7
CH2C6H5
H
a
Reaction conditions: CuO (0.03 mmol), anthranilamide (1 mmol;
R99 = H, unless otherwise mentioned), substituted benzaldehyde (1
mmol), DMA (3 mL), at 120 uC for 24 h. Isolated yield. R99 = 5-Cl.
b
c
This catalytic system tolerates various functional groups,
such as alkoxyl, halo, dimethylamino, and even hydroxyl, which
are suitable for the synthesis of 2-aryl-4(3H)-quinazolinone 3
(Table 2, entries 2 to 10). 3,5-Di-tert-butylsalicylaldehyde, with a
hydroxyl group on the aromatic cycle gave yields of up to 95%
(entry 4). However, N,N-dimethylaminobenzaldehyde afforded a
lower yield of 77% (Table 2, entry 5); and therefore, perhaps the
dimethylamino group inhibited this reaction slightly. All
substrates with various halo groups afforded good to excellent
yields (Table 2, entries 6 to 10). Interestingly, varying the
substituent positions through ortho-, meta- and para- on the
aromatic cycle had no apparent influence on the yields (Table 2,
entries 8 to 10).
Furthermore, the CuO-catalyzed cascade reaction involving
the heteroaromatic aldehyde furfural and anthranilamide gave
2-furyl-4(3H)-quinazolinone (3k) with a yield of up to 86%
(Table 2, entry 11).
The alphatic aldehyde pentanal also led to the correspond-
ing product in a good yield of 78% (Table 2, entry 12).
In addition to non-substituted anthranilamide, a substitu-
tion on the amide group of anthranilamide gave the desired
products in good yields with the exception of 2-amino-
N-benzylbenzamide (Table 2, entries 13 to 15). Perhaps due
to the steric hindrance, 2-amino-N-benzylbenzamide gave a
moderate yield of 2-phenyl-3-benzyl-4(3H)-quinazolinone (3n)
(Table 2, entry 14). However, this compound can be easily
synthesized via the benzylation of 2-phenyl-4(3H)-quinazoli-
none 3a.28
In conclusion, we have demonstrated for the first time that
recyclable copper(II) oxide powder could be used as an efficient
catalyst for the selective synthesis of 2-substituted and 2,3-
disubstituted 4(3H)-quinazolinones with air as the greenest
and least expensive oxidant. The prominent features of this
reaction include the use of environmentally friendly air as the
oxidant, the use of recyclable and inexpensive CuO powder
(only 3 mol%) as the catalyst, the recyclable nature of the
solvent, the ability to purify the crude product via recrystalliza-
tion, a high atom economy, good to excellent yields and an
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