Y(OTf)3-catalyzed heterocyclic formation via aerobic oxygenation: An approach to dihydro quinazolinones and quinazolinones

Article abstract of DOI:10.1016/j.cclet.2015.07.026

The Y(OTf)₃-catalyzed aerobic oxidative cyclization reaction for the selective synthesis of dihydroquinazolinones and quinazolinones has been developed. This method provides a practical, effective and green synthetic approach to dihydroquinazolinones and quinazolinones which both are important units in many biologically active compounds.

Full text of DOI:10.1016/j.cclet.2015.07.026

Chinese Chemical Letters 26 (2015) 1355–1358
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Y(OTf) -catalyzed heterocyclic formation via aerobic oxygenation:
3
An approach to dihydro quinazolinones and quinazolinones
Ying-Hui Shang, Li-Yan Fan *, Xiang-Xiong Li, Meng-Xia Liu
Department of Chemistry, Tongji University, Shanghai 200092, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The Y(OTf) -catalyzed aerobic oxidative cyclization reaction for the selective synthesis of dihydroqui-
3
Received 26 May 2015
nazolinones and quinazolinones has been developed. This method provides a practical, effective and
Received in revised form 23 June 2015
Accepted 7 July 2015
green synthetic approach to dihydroquinazolinones and quinazolinones which both are important units
in many biologically active compounds.
Available online 11 August 2015
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Aerobic oxygenation
Yttrium-catalyzed reaction
Dihydroquinazolinones
Quinazolinones
1
. Introduction
2
phosphoric acids [12], HCl [13] and SmI [14]. Many of the reported
synthetic protocols suffered from unsatisfactory product yields,
critical product isolation procedures, volatile organic solvents and
harsh reaction conditions such as high reaction temperatures,
strong acidic media and prolonged reaction time.
In addition, there is a paucity of synthetic route to implement the
selectivity of two such compounds [15]. Many of the reported
methods are associated with the use of extra-oxidant to complete
the fusion of the quinazolin-4(3H)-ones. Traditionally, at least a
Heterocyclic compounds widely exist in the nature with
widespread biological activities and they also have been assigned
as privileged structures in drug development. For example, 2,3-
dihydroquinazolin-4(1H)-ones are an important class of hetero-
cycles with a broad spectrum of biological and pharmaceutical
activities, such as anticancer, analgesic, antitumor and diuretic.
Some 2,3-dihydro-4(1H)-quinazolinones are herbicides and plant
growth regulators [1,2]. Furthermore, they could be oxidized to 2-
substituted-4(1H)-quinazolinones [3], which exhibit many central
nervous system effects, cardiovascular and anti-inflammatory
activity, and act as psychotropic, hypnotic, cardiotonic and
antihistamine agents. Quinazolinones are potent antibacterial,
antifungal, antiviral, antimycobacterial and antimalarial sub-
stances. They are also used as inhibitors of various enzymes
including monoamine oxidase, aldose reductase, tumor necrosis
factor R and thymidylate synthase [4].
stoichiometric amount of toxicoxidants, suchas DDQ [16], CuCl
2
[17],
MnO [18], KMnO [19], K (S ) [20] and PhI(OAc) [21] were used
2
4
2
O
2 8
2
with possible uncontrollable explosive danger yielding almost the
same amount of oxidant-derived waste. On the other hand, aerobic
oxidation is interestingin keepingwiththenotion of green chemistry,
since molecular oxygen is a cleaner and larger atom-efficient oxidant
than other oxidants. Furthermore, molecular oxygen theoretically
produces only water as the by-product after oxidation.
Herein, we report a versatile procedure for the fabrication of
quinazolin-4(3H)-ones and 2,3-dihydroquinazolin-4(1H)-ones
As a result, a number of synthetic strategies have been developed
for the preparation of 2,3-dihydroquinazolin-4(1H)-ones or quina-
zolin-4(3H)-ones. The most common approach involves condensa-
tion of 2-anthranilamide with structurally diverse aldehydes or
ketones in the presence of various catalysts, such as 2-morpholi-
3
selectively catalyzed by Y(OTf) (Scheme 1). This methodology
utilizes oxygen in air as oxidant in terms of green chemistry and
atom economy and two target compounds were obtained by
employing different solvent. We also demonstrate that yttrium is
mild catalyst to efficiently activate the oxygen.
3 4 2
noethanesulfonic acid [5], p-TSA/NaHSO [6], TiCl /Zn [7], CuCl [8],
ionic liquid water [9], TFA [10], ammonium chloride [11], chiral
2. Experimental
1
13
*
Corresponding author.
H NMR and C NMR spectra were made on Bruker ARX 400
for proton and carbon using DMSO-d or CDCl as the solvent with
E-mail address: fanly@tongji.edu.cn (L.-Y. Fan).
6
3
http://dx.doi.org/10.1016/j.cclet.2015.07.026
001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
1

1
356
Y.-H. Shang et al. / Chinese Chemical Letters 26 (2015) 1355–1358
Table 2
a
Screening of solvent for the synthesis of 3a.
b
Entry
Solvent
Temp (8C)
Time (h)
Yield (%)
1
2
3
4
Toluene
MeCN
EtOH
80
80
80
r.t.
1.5
1.5
1.5
1.5
89
86
95
93
EtOH
a
Anthranilamid (1.1 equiv.), benzaldehyde (1.0 equiv.), catalyst (5 mol%).
Isolated yield.
b
Scheme 1. The process to dihydroquinazolinone and quinazolinone derivatives.
tetramethylsilane as an internal standard at room temperature. All
reagents were obtained from commercial sources and used as
received.
alcohol with altered catalysts, and the results are summarized in
Table 1. It turned out that in the absence of the catalyst only trace
product was obtained for even longer time (Table 1, entry 1). In the
A general procedure for preparation of dihydroquinazolinones
2 2 3
presence of Lewis catalysts, such as ZnCl , CuCl , FeCl , the yields
3
: Y(OTf)
3
(0.0268 g, 0.05 mmol) were dissolved in 10 mL EtOH and
were dramatically improved (Table 1, entries 2–4). Interestingly,
the reaction appears to work more efficiently using rare earth
chlorides (Table 1, entries 5–9). Among the eight selected catalysts,
stirred until the solid dissolved completely, then anthranilamide
1
a
(0.1498 g, 1.1 mmol) and benzaldehyde 2a (0.101 mL,
1
.0 mmol) was added into the reaction mixture. After 1.5 h, the
3
Y(OTf) has proved to be the most effective (Table 1, entry 8).
reaction was completed which was determined by TLC analysis.
Water (15 mL) was added to the reaction mixture, and the
crystalline products were collected by filtration to give the crude
product. The crude products thus obtained were crystallized from
EtOH to give pure products 3a.
To determine the effect of solvents, next we examined our
reaction in different solvents as depicted in Table 2. Among all the
solvents screened, it was found that alcohol was the most suitable
solvent forthis reaction(Table2, entry3). Interestingly, thereaction
also proceeds in good yield at room temperature (Table 2, entry 4),
which was chosen as the optimal condition for further work.
Encouraged by the above experiments, we further explored the
synthetic protocol and the scope by employing different kinds of
aldehydes functionalized with electron-rich and electron-deficient
groups to form a series of dihydroquinazolinones. The results were
summarized in Table 3. Clearly, all reactions worked well
A general procedure for preparation of quinazolinones 4:
Y(OTf)
3
(0.0268 g, 0.05 mmol) were dissolved in 10 mL DMSO and
stirred until the solid dissolved completely, then anthranilamide
1
a
(0.1498 g, 1.1 mmol) and benzaldehyde 2a (0.101 mL,
1
.0 mmol) was added into the reaction mixture. Then the mixture
was heated to 110 8C under air atmosphere. After completion of the
reaction monitored by TLC, the reaction mixture was cooled to
room temperature. Water (15 mL) was added to the reaction
mixture, and the crystalline products were collected by filtration to
give the crude product. The crude products thus obtained were
Table 3
a
3
One-pot synthesis of dihydroquinazolinones catalyzed by Y(OTf) .
1
crystallized from EtOH to give pure products 4a. All H NMR and
13
C NMR results were summarized in Supporting information.
3
. Results and discussion
Initially, we examined the model cyclocondensation reaction
between anthanilamide (1) and benzaldehyde (2a) at 80 8C in
b
Entry
Aldehyde
Product
Yield (%)
1
1
2
3
4
5
6
7
8
9
R = 4-H
3a
3b
3c
3d
3e
3f
93
91
88
92
97
95
93
75
98
89
99
85
82
1
R = 4-F
1
Table 1
R = 4-Cl
a
1
Catalyst-screen for the synthesis of 3a.
R = 4-OCH
3
3
3
1
R = 3-OCH
1
R = 2-OCH
1
R = 4-CH
3
3g
3h
3i
1
R = 4-NO
2
1
R = 3-NO
2
1
1
0
1
R = 4-OH
3j
1
1
R = 3-OH
3k
3l
b
1
Entry
Catalyst
None
Time (h)
Yield (%)
12
R = 2-OH
13
CHO
3m
1
2
3
4
5
6
7
8
9
3
Trace
59
OH
OH
ZnCl
CuCl
2
3
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
75
HO
FeCl
LaCl
GdCl
3
70
1
1
4
5
3n
3o
99
99
3
79
3
78
OHC
S
OH
YCl
Y(OTf)
ScCl
3
87
3
95
CHO
3
84
a
a
Anthranilamid (1.1 equiv.), benzaldehyde (1.0 equiv.), catalyst (5 mol%).
Isolated yield.
Anthranilamid (1.1 equiv.), benzaldehyde (1.0 equiv.), Y(OTf)
Isolated yield.
3
(5 mol%).
b
b

Y.-H. Shang et al. / Chinese Chemical Letters 26 (2015) 1355–1358
1357
Table 4
Table 5
a
a
One-pot synthesis of quinazolinones catalyzed by Y(OTf)
3
.
Effect of atmosphere and catalyst in the formation of 3a and 4a.
.
2
b
Entry
Aldehyde
R
Product
Yield (%)
1
1
2
3
4
5
6
7
8
9
R =4-H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
90
88
91
94
88
93
88
91
86
93
90
82
1
R =4-F
1
R =4-Cl
1
R =4-Br
1
R =4-OCH
3
3
3
1
Entry
Catalyst
Atmosphere
Yield
R =3-OCH
1
b
b
R =2-OCH
4g
4h
4i
3a (%)
4a (%)
1
R =4-CH
3
1
1
2
3
Y(OTf)
Y(OTf)
None
3
3
N
2
89
Trace
90
R =4-OH
1
Air
Air
Trace
9
1
1
1
0
1
2
R =3-OH
4j
1
Trace
R =2-OH
4k
4l
a
o-Aminothiophenols (1.1 equiv.), aldehyde (1.0 equiv.), catalyst (5 mol%).
b
Isolated yield.
1
3
H
4m
89
1
14
15
16
17
18
R =4-H
Cl
Cl
Cl
Cl
H
4n
4o
4p
4q
4r
87
92
92
80
85
1
R =4-OMe
1
R =2-OMe
1
R =2-OH
a
Anthranilamid (1.1 equiv.), benzaldehyde (1.0 equiv.), Y(OTf)
Isolated yield.
3
(5 mol%).
b
Scheme 2. Proposed reaction mechanism for the synthesis of 3a and 4a.
irrespective of substiuents on the aldehydes substrates (Table 3,
entries 1–14). Heteroaromatic aldehyde was also readily intro-
duced into the quinazolinone skeleton at 2-position, and desired
product was formed in excellent yield (Table 3, entry 15).
During the above reaction, trace of dihydroquinazolinones
could be transformed to quinazolinones. The unexpected results
According to the aforementioned observations, a tentative
reaction mechanism is outlined in Scheme 2. The present reaction
consists of Schiff base formation, intramolecular cyclization,
dioxygen activation and heterocyclic compounds oxidation.
Condensation of 1a and 2a generates the corresponding Schiff
prompted us to focus on the synthesis of quinazolin-4(3H)-one 4
ꢀ
using different oxidant such as H
PhI(OAc)
improve the yield, this reaction proceeded in DMSO with the
presence of Y(OTf) . As expected, 4a was obtained in good yield
2
O
2
, AATEMPOBF
4
, NHPI,
3
base A with Y(OTf) as an accelerant. The oxidative cyclization of
2
, but with relatively unsatisfactory yield. To further
Schiff base A could be envisioned to form heterocycle 3a which
then undergoes Y(OTf) -catalyzed aerobic oxidation to yield the
3
desired product 4a.
3
while a trace amount of 3a was generated.
Then various aldehydes with either electron-donating or
electron-withdrawing groups on aromatic ring were investigated
in DMSO, and the results were listed in Table 4. It is noteworthy
that various aldehydes were observed to be well tolerated under
optimized conditions furnishing the product in good yields.
Moreover, the reaction with nonaromatic aldehyde (Table 4, entry
4
. Conclusion
In conclusion, we have developed a green and efficient method
to selectively synthesize dihydroquinazolinones and quinazoli-
nones catalyzed by Y(OTf) via regulating solvents. This method
3
1
8) also afforded the product in excellent yield.
Then the roles of air and catalyst in the reaction were
provides a simple, compatible and potentially powerful synthetic
protocol for the modular construction of quinazolinones and
dihydroquinazolinones, which are important units of biologically
active molecules. The usage of molecular oxygen in air renders this
protocol very attractive and practical. Furthermore, our results
demonstrated that the rare earth catalysts play a decisive role in
aerobic oxidation. A detailed study on the scope of our synthetic
methodology is ongoing in our laboratory.
explored. Under nitrogen atmosphere, in the presence of
Y(OTf) , only a trace amount of quinazolinones 4a was detected
3
whereas the dihydroquinalzolinone 3a was obtained in good
yield (Table 5, entry 1). When the same reaction was carried out
in air, the yield of 4a reached nearly 100% (Table 5, entry 2). It
can therefore be deduced that oxygen in air as an oxidant
promotes the transformation of 3a to product 4a. In the absence
of catalyst, compound 3a was produced only in 9% yield while
Acknowledgment
4
a in trace yield in air, indicating that the catalyst plays an
important role not only in the condensation process but also the
oxidation.
We gratefully acknowledge the National Natural Science
Foundation of China (No. 20802052) for financial support.

1
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