Synthesis of quinazolinones from o-aminobenzamides and benzyl amines under metal-free conditions

Article abstract of DOI:10.1016/j.cclet.2015.08.003

A convenient and transition-metal free protocol for quinazolinones synthesis with o-aminobenzamides and benzyl amines as substrates has been developed. Using H₂O₂ as the oxidant, various quinazolinones were obtained in moderate to good yields under metal- and additive-free conditions.

Full text of DOI:10.1016/j.cclet.2015.08.003

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Chinese Chemical Letters xxx (2015) xxx–xxx
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
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Original article
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4
Synthesis of quinazolinones from o-aminobenzamides and benzyl
amines under metal-free conditions
Q1 Xin-Xin Qi a, Zhen-Zhen Song a, Jin-Long Gong a, Zheng-Yu Fang b, Xiao-Feng Wu a,c,
*
5
6
7
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a Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campous, Hangzhou 310018, China
b Department of Anal-colorectal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
c
¨
Leibniz-Institut fu¨r Katalyse e.V. an der Universitat Rostock, 18059 Rostock, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient and transition-metal free protocol for quinazolinones synthesis with o-aminobenzamides
and benzyl amines as substrates has been developed. Using H2O2 as the oxidant, various quinazolinones
were obtained in moderate to good yields under metal- and additive-free conditions.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 27 May 2015
Received in revised form 2 July 2015
Accepted 7 July 2015
Available online xxx
Keywords:
Quinazolinones
Metal-free
Benzyl amine
H2O2
9
10
1. Introduction
autoxidation of benzyl amines and applied in heterocycles 30
synthesis was developed as well [14a]. Five examples of 31
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Quinazolinones represent a high value class of compounds in
organic chemistry, which has a wide range of biological and
pharmacological activities [1], including anti-bacterial [2], anti-
cancer [3], anti-inflammatory [4], anti-microbial [5], anti-tuber-
cular [6], anti-ulcer [7], and so on [8]. Additionally, they are
Q3 important intermediates in natural products preparation [9] and
applied as structural scaffold in drug discovery [1c].
quinazolinones were prepared in moderate yields under 150 8C 32
with 40% AcOH as the additive. Meanwhile, we reported a 33
procedure for the transformation of benzyl amines to the 34
corresponding imines [15]. Various imines were produced in 35
good to excellent yields under metal-free conditions and with 36
H2O2 as the green oxidant. From mechanistic point of view, the 37
oxidation of benzyl amines to the corresponding benzaldehydes 38
should be the first step and then followed by condensation to give 39
the imines. Hence, we believe a procedure for quinazolinones 40
preparation with o-aminobenzamides and benzylamines as the 41
substrates without metal catalysts and using H2O2 as the green 42
oxidant should be highly realizable. Under this context, we 43
developed this interesting metal-free and additive-free procedure 44
for the synthesis of quinazolinones from o-aminobenzamides and 45
Owing to their diverse bioactivity and privileged sub-structure
for drug design, the synthetic methodologies development
becomes attractive and many synthetic routes have been devel-
oped [10a]. For example, copper-catalyzed Ullmann-type coupling
reactions [10b], redox condensation between o-substituted
nitrobenzenes with amines in the presence of iron and cobalt as
catalysts [11], one-pot synthesis of quinazolinones from benzyl
alcohols by iridium or ruthenium catalysts [12]. In these reactions,
metal-salts turned out to be indispensable, and many metal wastes
were generated. Besides, condensation between o-aminobenza-
mides and aldehydes with additional oxidants is also a typical
method to prepare quinazolinones [13]. Recently, a procedure on
benzyl amines.
46
2. Experimental
47
A 15 mL tube was added 2-aminobenzamide (1 mmol), benzyl 48
amine (1.5 mmol), and a stir bar. Then H2O2 (30 wt% in H2O, 49
5 equiv.) was added by a syringe at room temperature under open 50
air. The tube was closed and kept at 120 8C for 20 h. The conversion 51
and yield were determined by GC and GC–MS using hexadecane 52
*
Corresponding author at: Department of Chemistry, Zhejiang Sci-Tech
Q2
University, Xiasha Campous, Hangzhou 310018, China.
(0.1 mmol) as the internal standard.
53
E-mail address: xiao-feng.wu@catalysis.de (X.-F. Wu).
http://dx.doi.org/10.1016/j.cclet.2015.08.003
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: X.-X. Qi, et al., Synthesis of quinazolinones from o-aminobenzamides and benzyl amines under metal-
free conditions, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.003

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X.-X. Qi et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Table 1
Screening of the reaction conditions.a
O
O
NH2
NH2
NH
.
NH2
N
1a
2a
3a
Entry
Oxidant (equiv.)
Solvent (2 mL)
Temp. (8C)
Yield (%)b
1
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (3)
H2O2 (8)
H2O2 (5)
H2O2 (5)
DMSO
DMF
DMA
dioxane
THF
H2O
C2H5OH
CH3CN
CH3NO2
DCE
–
100
100
100
100
100
100
100
100
100
100
100
100
100
120
80
25
0
2
3
0
4
<5
<5
<5
20
20
0
5
6
7
8
9
10
11
12
13
14
15
35
50
30
<10
71
46
–
–
–
–
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), oxidant, solvent (2 mL), 20 h.
b
GC yield, with hexadecane as the internal standard.
Table 2
Synthesis of quinazolinones: substrates testing.a
O
N
O
R3
N
NH
NH2
NH2
H2O2 (5 equiv.)
120 °C
H
.
R2
R1
R1
R2
1
2
3
Entry
1
1
2
3
Yield 3 (%)b
71
O
N
O
NH2
NH
NH2
2a
NH2
1a
3aa
2
59
O
O
NH2
NH2
NH2
1a
NH
2b
N
3ab
3
69
O
N
O
NH2
NH
NH2
NH2
1a
2c
3ac
4
44
O
O
N
NH2
NH2
NH2
1a
NH
O
2d
2e
O
3ad
5
50
O
N
O
NH2
NH
NH2
NH2
1a
F3C
CF3
3ae
Please cite this article in press as: X.-X. Qi, et al., Synthesis of quinazolinones from o-aminobenzamides and benzyl amines under metal-
free conditions, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.003

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X.-X. Qi et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Table 2 (Continued )
Entry
1
2
3
Yield 3 (%)b
6
45
O
O
N
NH2
NH2
NH2
1a
NH
F
2f
F
O
3af
NH2
NH2
1a
7
40
O
N
NH2
NH
Cl
Br
2g
2h
Cl
Br
3ag
NH2
8
44
O
N
O
NH
NH2
NH2
1a
O
3ah
N
NH2
NH2
NH2
1a
9
65
O
N
2i
2j
NH
N
3ai
10
45
O
O
N
H
NH
NH2
NH2
1a
N
3aa
11
40
O
O
N
NH2
NH2
NH2
NH2
NH
F3C
2k
Cl
Cl
1b
CF3
3bk
12
40
O
O
2c
NH
NH2
N
NH2
1c
3cc
13
50
O
O
N
NH2
NH2
NH
2a
2a
NH2
1c
3ca
14
65
O
O
NH2
NH2
NH2
NH
N
1d
3da
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), H2O2 (5 equiv.), 120 8C, 20 h.
GC yield.
b
Please cite this article in press as: X.-X. Qi, et al., Synthesis of quinazolinones from o-aminobenzamides and benzyl amines under metal-
free conditions, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.003

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X.-X. Qi et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
oxidants under metal-free and solvent-free conditions, a variety of
quinazolinones were generated in moderate to good yields.
104
105
Acknowledgments
106
The authors thank the financial supports from NSFC (No. Q4 107
21472174), Education Department of Zhejiang Province (No.
Y201432060) and Zhejiang Sci-Tech University (Nos. 1206838-Y
and 14062015-Y). X.-F. Wu appreciates the general support from
Matthias Beller in LIKAT.
108
109
110
111
Scheme 1. Proposed reaction mechanism.
References
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3. Results and discussion
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At the beginning, substrates 1a and 2a were chosen as the
starting materials. The reaction was conducted with 5 equiv. of
H2O2 (30 wt% in H2O) at 100 8C in DMSO, fortunately, 25% yield of
the target product 3aa was obtained (Table 1, entry 1). Encouraged
by this result, we continued with the studies of different solvents
which did not improve the yield significantly (Table 1, entries 2–
10). However, when we tried the reaction without solvent, the
yield raised to 50% (Table 1, entry 11). Furthermore, the amount of
H2O2 was examined, less and more H2O2 all decreased the yield
(Table 1, entries 12 and 13). Notably, reaction temperature was
found hold great influence for this transformation. 80 8C resulted in
46% yield (Table 1, entry 15), while 120 8C resulted in 71% yield
(Table 1, entry 14). No better yield can be obtained under higher
reaction temperature.
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entries 2 and 3). However, as an electron-rich group, para-
methoxybenzylamine decreased the yield of the desired product to
44% (Table 2, entry 4). A moderate product yield was generated
when the substrate decorated with electron-deficient group, such
as trifluoromethyl moiety (Table 2, entry 5). Moreover, benzyl
amines bearing fluoro, chloro, and bromo provided the desired
products with slightly lower yields (Table 2, entries 6–8). It is
noteworthy that heteroaromatic substrate can also be tolerated
under the standard condition, resulted the corresponding product
in 65% yield (Table 2, entry 9). In addition, N-substituted
benzylamine was also examined, affording the product 3aa in
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the target products in moderate yields.
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has been proposed in Scheme 1. First, benzyl amine 1 was oxidized
to benzaldehyde in the presence of H2O2. Then, the condensation of
the in situ formed aldehyde with o-aminobenzamide 2 occurred.
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In conclusion, we have developed an environmental friendly
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free conditions, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.003

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Please cite this article in press as: X.-X. Qi, et al., Synthesis of quinazolinones from o-aminobenzamides and benzyl amines under metal-
free conditions, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.003