Aerobic photooxidative synthesis of 2-aryl-4-quinazolinones from aromatic aldehydes and aminobenzamide using catalytic amounts of molecular iodine

Article abstract of DOI:10.1039/c5ra07275a

This study reports a safe, mild, and environmentally benign synthetic method toward 2-aryl-4-quinazolinones from aromatic aldehydes and aminobenzamides through a cyclization-oxidation sequence using a catalytic amount of iodine, which serves as both a Lewis acid and an oxidant, harmless visible light irradiation, and molecular oxygen as the terminal oxidant.

Full text of DOI:10.1039/c5ra07275a

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Aerobic photooxidative synthesis of 2-aryl-4-quinazolinones from
aromatic aldehydes and aminobenzamide using catalytic amounts
of molecular iodine
Received 00th January 20xx,
Accepted 00th January 20xx
Y. Nagasawa,a Y. Matsusaki,a T. Nobuta,a N. Tada,a T. Miura,b and A. Itoh*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
This study reports a safe, mild, and environmentally benign synthetic require transition metals or thermal condition.15 As such, we
method toward 2-aryl-4-quinazolinones from aromatic aldehydes and developed an aerobic photooxidative synthesis of 2-aryl-4-
aminobenzamides through
a
cyclization–oxidation sequence using
a
quinazolinones from aromatic aldehydes and aminobenzamide
catalytic amount of iodine, which serves as both a Lewis acid and an using a catalytic amount of iodine with more mild condition
oxidant, harmless visible light irradiation, and molecular oxygen as the (Scheme 1). Herein we describe this reaction in detail.
terminal oxidant.
O
O
O2, hν (VIS)
cat. I2
4-Quinazolinones are well-known compounds with a variety of
biological and pharmacological activities, such as anticancer,
anti-inflammatory, and antidiuretic, and are assigned as
privileged structures in drug discovery.1 As such, many
methods have been reported for the synthesis of 4-
quinazolinones.2 Among those reported, oxidation of cyclic
aminal intermediates obtained from 2-aminobenzamides and
aldehydes with I2,3 DDQ (dichlorodicyanobenzoquinone),4
CuCl2,5 CuBr,6 MnO2,7 KMnO4,8 FeCl3•6H2O,9 or microwave
irradiation conditions10,4b are reliable methods; however, they
require stoichiometric amounts of reagents, transition metals,
or involve a complicated procedure.
NH2
NH2
NH
Ar
ArCHO
+
N
Scheme 1. Catalytic aerobic photooxidative syntheses of 4-quinazolinones
We selected 2-aminobenzamide (1) and benzaldehyde (2a)
as the test substrates for optimization of the reaction
conditions (Table 1). Although we examined the reaction
conditions with various halogen sources, the yields of 2-
phenyl-4-quinazolinone (3a) were unsatisfactory, except for
those using molecular iodine (entries 1–6). In this reaction,
addition of K2CO3 or Na2SO4 had only a marginal effect (entries
13 and 14), while addition of AcOH decreased the yield of 3a
to 17% (entry 15). Further study of the solvent, amount of
benzaldehyde, and reaction time revealed that using iodine
(0.05 equiv) and benzaldehyde (1.0 equiv) in EtOAc for 1 h
gave the best yield (entry 17). The fact that 3a was not
obtained or was obtained only in low yield without iodine,
molecular oxygen, or photoirradiation shows the necessity of
these conditions for this reaction (entries 18–20). Under these
In recent times, iodine source catalyzed C–H oxidation with
various stoichiometric oxidants, such as H2O2 or tert-BuOOH,
and has attracted great interest because iodine sources have
low toxicity and are inexpensive compared with transition
metal catalysts.11 Furthermore, iodine serves as both a Lewis
acid and an oxidant.12 Therefore, in multi-step syntheses,
iodine is able to accelerate stoichiometric or catalytic domino
reactions.13
conditions,
1 and the cyclized intermediate (2,3-dihydro-2-
From the perspective of green chemistry, various aerobic
photooxidative reactions using catalytic amounts of iodine
sources with molecular oxygen as the terminal oxidant under
visible light irradiation have been developed in our
laboratory.14 The methods to synthesize the quinazolinones
using molecular oxygen were recently reported but they
phenyl-4(1H)-quinazolinone: 4a) were obtained in low yields.
Table 2 shows the results of the scope and limitations of
photooxidative synthesis of 2-aryl-4-quinazolinones from
various aromatic aldehydes under the optimized conditions. In
general, the corresponding 2-aryl-4-quinazolinones were
obtained in moderate to high yields regardless of the electron
donating or weak electron withdrawing groups on the benzene
ring of the aldehydes (entries 1–8). In contrast, 4-cyano and 4-
nitrobenzaldehyde bearing strong electron withdrawing
a.Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan.
b.Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
groups gave moderate and low yields of
3. Unfortunately,
aliphatic aldehydes such as cyclohexanecarboxaldehyde and
dodecyl aldehyde were poor substrates.
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Table 1. Optimization of the reaction conditions for the synthesis of 2-aryl-4-
Table 2. Catalytic aerobic photooxidative synthesis of 2-aryl-4-quinazolinones
quinazolinones
entry
1
R’
time (h)
product
3a
yield (%) a
86
entry halogen source
additive
solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
MeOH
i-Pr2O
Hexane
H2O
yield (%) a
H
2a
2b
2c
2d
2e
2f
1
5
1
KI
LiI
CaI2
ZnI2
I2
-
0
2
4-OH
4-OMe
3-OMe
4-Me
3-Me
4-tBu
4-F
3b
3c
80
2
-
0
3
1
75
3
-
0
6
4
1
3d
3e
81
4
-
5
5
76
5
-
86
6
10
3
3f
93
6
I2
-
74
7
2g
2h
2i
3g
83
7
I2
-
24
8
15
15
15
15
5
3h
3i
85
8
I2
-
22
9
4-Cl
88
9
I2
-
11
10
11
12
13
4-Br
2j
3j
82
10
11
12
13
14
15 b
16 d
17 e
18 f
I2
-
MeCN
Acetone
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
6
4-CF3
4-CN
4-NO2
2k
2l
3k
76
I2
-
0
3l
66
I2
K2CO3
76
2m
5
3m
69
I2
Na2SO4
73
a The reaction conditions: 1 (0.3 mmol), 2 (1.0 equiv), and I2 (0.05 equiv) in EtOAc
(5 mL) was stirred and irradiated with fluorescent lamp under O2 atmosphere.
Isolated yields .
I2
AcOH
17
85 (86) c
I2
-
-
-
-
-
0
I2
0
I2
trace
a The reaction conditions: 1 (0.3 mmol), 2a (1.5 equiv), and halogen sources (0.05
equiv) in solvent (5 mL) was stirred and irradiated with fluorescent lamp under O2
atmosphere for 30 min. 1H NMR yields. b Reaction was conducted for 1h and
conducted with 1.0 equivalent of benzaldehyde. c The number in the parentheses
is the isolated yield. d 1 (26%) was recoverd with 4a (16%). e Reaction was
conducted under argon. 1 (36%) was recovered with 4a (18%). f Reaction was
conducted in the dark. 1 (18%) was recovered with 4a (28%).
To clarify the reaction mechanism, several control
experiments were examined. When one equivalent of
molecular iodine was used in the absence of molecular oxygen
and visible light irradiation, 3a was obtained in low yield and
many by-products were formed (Scheme 2, equation 1). This
result indicated that the reaction required irradiation with
visible light and the presence of molecular oxygen. When 4a
was used as a substrate under the optimal conditions, 3a was
obtained in good yield (Scheme 2, equation 2). In contrast, no
3a was obtained in the absence of iodine (Scheme 2, equation
3). These results and entries 18–20 in Table 2 suggest that 4a is
the reaction intermediate and molecular oxygen, iodine, and
visible light are all required for the oxidation of 4a. Hypoiodous
acid (IOH) may be the active species in the final step of the
oxidation because it is easily prepared from an iodine source
and a peroxide.16
Scheme 2. Control experiments to investigate reaction mechanism.
I2
O
O
O
O
N
H
Ar
NH2
NH2
2
NH
Ar
NH2
Ar
imine
formation
N
H
4
1
I2
O
O2, h , I2
NH
Ar
O2, h
2HI
I2
-2HI
N
3
Scheme 3 shows a plausible path for this reaction. The
Scheme 3. Plausible pathway of photooxidative synthesis of 2-aryl-4-quinazolinones
intermediates (
2-aminobenzamides
molecular iodine as a Lewis acid. Intermediate
transformed to 4-quinazolinones by oxidation with
molecular iodine, molecular oxygen, and visible light. In
addition, hydrogen iodide, generated by the oxidation of , is
4
) are formed through condensation between
and aldehydes ), catalyzed by
is then
(
1)
(2
4
(3)
Conclusions
In conclusion, we have developed an environmentally benign
synthesis of 2-aryl-4-quinazolinones with a catalytic amount of
iodine under photooxidative conditions. This method is of
4
reoxidized to molecular iodine under the aerobic
photooxidative conditions.
2 | J. Name., 2012, 00, 1-3
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