Catalyst-free synthesis of quinazolinones by oxidative cyclization under visible light in the absence of additives

Article abstract of DOI:10.1002/jhet.4275

A general metal-free oxidative cyclization route was developed to synthesize quinazolinones under visible light. A series of substituted 2-aminobenzamides were reacted with aldehydes or ketones to produce the desired quinazolinones in good yields. Most importantly, the reaction did not require excess oxidant or high temperatures.

Full text of DOI:10.1002/jhet.4275

Received: 24 January 2021
DOI: 10.1002/jhet.4275
Revised: 31 March 2021
Accepted: 16 April 2021
A R T I C L E
Catalyst-free synthesis of quinazolinones by oxidative
cyclization under visible light in the absence of additives
Jiangnan Yang1,2 | Zongbo Xie1,2
Qian Li1,2 | Zhanggao Le1,2
| Zhongsheng Chen1,2 | Liang Jin1,2
|
1Jiangxi Province Key Laboratory of
Abstract
Synthetic Chemistry, East China
University of Technology, Nanchang,
China
2School of Chemistry, Biology and
Material Science, East China University of
Technology, Nanchang, China
A general metal-free oxidative cyclization route was developed to synthesize
quinazolinones under visible light. A series of substituted 2-aminobenzamides
were reacted with aldehydes or ketones to produce the desired quinazolinones
in good yields. Most importantly, the reaction did not require excess oxidant or
high temperatures.
Correspondence
Zhanggao Le and Zongbo Xie,
Department of applied chemistry, East
China University of Technology,
No. 418, Guanglan Avenue, Economic
Development Zone, 330013, Nanchang,
China.
Email: zhgle@ecut.edu.cn and
zbxie@ecut.edu.cn
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21966003;
Science and Technology Projects of
Jiangxi, Grant/Award Number:
20181BBH80007
1 | INTRODUCTION
2-aminobenzamide (1a) and aldehyde [5]. More
recently, the reaction of 1a with alcohols has been
Quinazolinones are an important heterocyclic system in
nature and are present in approximately 150 natural alka-
loids, some of which exhibit important biological and
pharmacological activities (Figure 1) [1]. For instance,
methaqualone exhibits significant anticonvulsant activ-
ity [2]; (À)-vasicinone exhibits antitumor, bronchodilating,
hypotensive, anthelmintic, and antianaphylactic activities
[3]; and febrifugine is a new lead compound as a type of
antimalarial drug [4].
There has been a long-standing concern about the
development of new methods for the synthesis of
quinazolinones, primarily because of their significant
biological and pharmacological activities. To date,
the most common method for the synthesis of
quinazolinones is the condensation reaction between
explored by chemists for the synthesis of quinazolinones
[2,6]. Nevertheless, aldehydes synthesized by the oxida-
tion of readily available alcohols are chemically unsta-
ble, and a stoichiometric or large excess of oxidants such
as KMnO4 [7], CuCl2 [8], I2 [9], and t-BuOOH [10] are
required for the oxidation. In addition, the oxidation
reaction commonly requires high temperatures [11].
Therefore, aldehydes were selected as starting materials.
From the viewpoint of green chemistry, the field of bio-
catalysis is attracting increasing attention. Enzymes are
green and efficient biocatalysts [12], we have reported
several studies on the synthesis of quinazolinone deriva-
tives using pepsin [13], and alkaline [14] protease as cat-
alysts. Thus, it is necessary to explore newer synthetic
strategies for quinazolinones.
J Heterocyclic Chem. 2021;1–6.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
YANG ET AL.
FIGURE 1 Structures of natural
quinazolinones
SCHEME 1 Synthesis of quinazolinone from 2-aminobenzo-amide and benzaldehyde using DMSO as an oxidant
TABLE 1 Optimization of reaction
conditionsa
Entry
Catalyst
Solvent
DMSO
DMSO
Molar ratio [1a:2a]
Time [h]
Yield [%]b
88%
1
2
–
1:2
1:2
24
24
[Ru(bpy)3]Cl2Á
85%
6H2O
3
Rose Red
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
EtOH
1:2
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
15
18
20
50%
4
Eosin Y
1:2
78%
5
Eosin B
1:2
63%
6c
7d
8e
9
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1:2
None
88%
1:2
1:2
51%
1:2
Trace
Trace
<5%
None
None
Trace
Trace
76%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1:2
Dioxane
H2O
1:2
1:2
DCE
1:2
DCM
1:2
THF
1:2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1:1.5
1:2.5
1:3
99%
99%
1:4
95%
1:2.5
1:2.5
1:2.5
1:2.5
57%
72%
99%
98%
aReaction conditions: 1a (0.2 mmol), solvent (1.5 ml), blue LED, air, r.t.
bYield of the isolated product.
cDark conditions.
dO2 atmosphere.
eN2 atmosphere.

YANG ET AL.
3
Visible light is a clean source of energy and has
conditions were further optimized at a molar ratio of
1:2.5. Besides, when the reaction time was decreased to
12 h (Table 1, entries 20–23), the yield decreased to 57%.
The yield improved with increasing reaction time and
reached 72% in 15 h. 1a could be completely converted in
18 h with 99% product yield. No remarkable increase
in the yield was observed when the reaction time was
increased to 20 h.
received increasing attention from chemists [15]. Over
the years, researchers have developed various organic
reactions that can be initiated by visible light irradiation
[16]. Metal catalysts including those based on Pd [17], Ru
[18], or Ir [19] are usually applied in photocatalysis. In
this study, the cyclization reaction of 2-aminobenzamide
derivative
and
benzaldehyde
to
synthesize
quinazolinones was initiated by visible light, and the use
of metal catalysts or other unfriendly catalysts could be
avoided in the process. We also found that dimethyl sulf-
oxide (DMSO) efficiently facilitated the oxidation of
aminal intermediates to quinazolinones under visible
light (Scheme 1).
With the optimized reaction conditions in hand, the
synthesis of various quinazolinones (Table 2) was
explored using different aldehydes and 1a as the starting
materials (Table 1, entry 22).
First, various substituted aldehydes were subjected to
the above conditions; both aromatic and aliphatic alde-
hydes were smoothly converted to 2-substituted
quinazolinones (Table 2, 3a–3k) upon reaction with
2-aminobenzamide, and excellent yields were obtained.
Steric effects hardly influenced the quinazolinone yields
(Table 2, 3b–3d). When substrates with the electron-
donating group were used, higher yields of
quinazolinones were obtained. The yields of
2 | RESULTS AND DISCUSSION
2-Aminobenzamide (1a) and benzaldehyde (2a) were
employed as the model substrates to optimize the reac-
tion conditions such as catalysts, solvents, molar ratio,
and reaction time. The results are summarized in
Table 1.
quinazolinones
substituted
with
the
electron-
withdrawing group were slightly lower than those of
quinazolinones substituted with the electron-donating
group. Notably, heterocycle-bearing quinazolinones
could be prepared in high yields (Table 2, 3f–3h). The
It is evident that the reaction of 1a and 2a easily gen-
erated the desired product 3a in 88% yield under blue
LED, even without a catalyst (Table 1, entry 1). To iden-
tify a suitable photocatalyst, a series of catalysts were
screened (Table 1, entries 2–5). However, there was no
effective increase in the product yield in the presence of a
photocatalyst. Thus, a blue LED, in the absence of
a photocatalyst, was chosen to activate the reaction, and
this avoided pollution. Surprisingly, no product was
obtained under dark conditions (Table 1, entry 6),
suggesting that the blue LED was necessary to stimulate
this reaction. Under O2 and N2 atmospheres, the
quinazolinone yields were 88% and 51%, respectively
(Table 1, entries 7–8). This indicated that O2 was not
essential for this reaction, and a component within the
reaction medium promoted the oxidation. Next, the reac-
tion medium was screened (Table 1, entries 9–15). When
DMSO was replaced with other solvents (such as MeCN,
EtOH, and DCM), only a trace amount of the product
was obtained or no product was obtained. Therefore, the
solvent was an important factor affecting the reaction.
Thus, DMSO was used as the solvent to optimize the
molar ratio (Table 1, entries 16–19). When the ratio of 1a
to 2a was 1:1.5, the yield was 76% (Table 1, entry 16); the
yield increased to 90% (Table 1, entry 5) and 99%
(Table 1, entry 17) when the substrate ratios were
decreased to 1:2 and 1:2.5, respectively. When the sub-
strate ratios were further decreased to 1:3 and 1:4, the
yields were not remarkably different from that at a ratio
of 1:2.5 (Table 1, entries 17–18). Therefore, the reaction
TABLE 2 Synthesis of 2-substituted quinazolinones in
DMSOa,b
O
N
O
N
O
N
O
N
NH
NH
NH
NH
3c , 95%
3b , 95%
3d , 95%
3a , 99%
O
O
O
O
NH
N
NH
NH
N
NH
S
O
N
N
S
Cl
3h c , 72%
3g , 93 %
3e , 75%
3f , 71%
O
O
N
N
O
O
NH
N
NH
NH
N
N
3i , 94%
3k , 55%
3l , 32%
3j , 90%
O
O
O
O
Br
Cl
NH
NH
NH
NH
N
N
N
H
3o , 84%
N
H
3m , 73%
3n , 73%
3p d , 91%
O
NH
N
H
3q d , 41%
aReaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), DMSO (1.5 ml), blue LED,
air, r.t., 18 h.
bIsolated yield.
cReaction performed for 24 h.
dKetone (0.5 ml), DMSO (1.0 ml), reaction performed for 18 h.

4
YANG ET AL.
(a)
(b)
(c)
(d)
(e)
SCHEME 2 Control experiments and plausible reaction pathway
scope of this reaction for various 2-aminobenzamide sub-
strates was further explored (Table 2, 3l–3n). Benzalde-
hyde reacted efficiently with electron-withdrawing
groups on the benzene ring. The yields of 3m and 3n
were 73%. Ketones were also found to be an effective sub-
strate in this reaction (Table 2, 3o–3q).
Furthermore, to elucidate the reaction pathway from
1a and 2a to 3a, some control experiments were con-
ducted. We refined the reaction time and found that
cyclic intermediate 4a was formed in 2 h, which was
further converted to 3a in 5 h (Scheme 2A). Intermediate
4a is formed during this process, then 3a is obtained in
different solvents (Table 1, entries 9–15). Consequently,
the oxidation of cyclic amino intermediates to
quinazolinones is very important during the synthesis of
quinazolinones. Based on the use of DMSO in oxidation
reactions, it might be assumed that DMSO has some ben-
eficial effects on this oxidative cyclization reaction too.
As evident from Table 3, the yield increased when DMSO
was added into the reaction system as a mixed solvent

YANG ET AL.
5
TABLE 3 Effect of solvent on the reactiona
behaved as an oxidant, and the reaction proceeded effi-
ciently at room temperature under mild conditions even
in the absence of a catalyst. Functional groups were well
tolerated in this reaction. These features establish this
reaction as a potential method for the practical synthesis
of biologically important heterocyclic compounds.
Entry
Catalyst
Solvent
Yield [%]b
68%
1
–
–
–
–
–
–
–
–
–
–
DMSO + MeCN
DMSO + EtOH
DMSO + dioxane
DMSO + H2O
DMSO + DCE
DMSO + DCM
DMSO + THF
MeCN + dibutyl sulfoxide
MeCN + sulfolane
MeCN
2
78%
3
30%
4
Trace
80%
5
4 | EXPERIMENTAL SECTION
4.1 | Instruments and reagents
6
78%
7
58%
8c
9c
10d
90%
None
19%
All major chemicals and solvents were obtained from
commercial sources and used without further purifica-
1
tion. H NMR and 13C NMR spectra were recorded on a
aReaction conditions: 1a (0.2 mmol), benzaldehyde (0.4 mmol), solvent
(DMSO [1.0 ml] + another solvent [0.5 ml]), blue LED, air, r.t., 24 h.
bIsolated yield.
cSolvent (MeCN [1.0 ml] + another solvent [0.5 ml]).
dIn the presence of K2S2O8 (1 eq).
Bruker Avance III-500 spectrometer (Swiss Bruker,
Switzerland).
4.2 | General methods for the synthesis
of quinazolinones derivatives
(Table 3, entries 1–7). When DMSO was replaced with a
similar polar solvent such as dibutyl sulfoxide and
sulfolane (Table 3, entries 8–9), the oxidative cyclization
can occur in the former to give 3a. Simultaneously, the
yield was only 19% using acetonitrile instead of DMSO
and adding K2S2O8 to the reaction system as oxidant.
However, no product was obtained in sulfolane. There-
fore, DMSO and other sulfoxide solvents play a key role
in this reaction. To study the photocatalytic process,
TEMPO was added to the reaction system under opti-
mized conditions. The reaction was found to be
completely inhibited (Scheme 2B), suggesting that a free
radical is probably involved in this reaction. To further
prove the role of blue LED, the intermediate 4a was pre-
pared by controlling the reaction time under blue light.
After the formation of 4a, the system was transferred to
the dark condition, in which 3a was not produced
(Scheme 2C). Meanwhile, 1a and 2a did not produce
intermediate 4a under dark conditions (Scheme 2D).
Therefore, it was concluded that a blue LED was needed
for the whole process.
2-Aminobenzamide (0.2 mmol) and aldehyde (0.5 mmol)
were added to a tube dried in an oven, and then DMSO
(1.5 ml) was added to this mixture, and irradiated at
room temperature with an 18 W blue LED for 18 h. The
progress of the reaction was monitored by thin-layer
chromatography (petroleum ether/ethyl acetate = 2:1,
v/v). After the reaction reached completion, the solution
was diluted with EtOAc (3 ml), washed with H2O
(3 Â 5 ml), and concentrated under reduced pressure.
Then purified by column chromatography (PE:
EtOAc = 2:1).
ACKNOWLEDGMENTS
This project was supported by the National Natural Sci-
ence Foundation of China (No. 21966003) and the
Science
and
Technology
Projects
of
Jiangxi
(No. 20181BBH80007).
DATA AVAILABILITY STATEMENT
Based on the above results and previous reports, an
oxidation reaction was proposed in the reaction pathway
(Scheme 2E). First, 2a reacts with 1a to form intermedi-
ate 4a. Following this, 3a was oxidized by DMSO dehy-
drogenation in the presence of blue LED.
The data that support the findings of this study are avail-
able from the corresponding author upon reasonable
request.
ORCID
Zongbo Xie https://orcid.org/0000-0002-6957-6433
3 | CONCLUSION
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Yang J, Xie Z, Chen Z,
Jin L, Li Q, Le Z. Catalyst-free synthesis of
quinazolinones by oxidative cyclization under
visible light in the absence of additives.
J Heterocyclic Chem. 2021;1–6. https://doi.org/10.
1002/jhet.4275
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