Copper-catalyzed tandem N-arylation/condensation: Synthesis of quinazolin-4(3H)-ones from 2-halobenzonitriles and amides

Article abstract of DOI:10.1039/c4ra08031a

A novel, straightforward and practical copper-catalyzed domino protocol for synthesis of quinazolin-4(3H)-one derivatives from commercially available 2-halobenzonitriles and amides was successfully developed.

Full text of DOI:10.1039/c4ra08031a

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Copper-Catalyzed Tandem N-Arylation/Condensation:
Synthesis of Quinazolin-4(3H)-ones from 2-Halobenzo-
nitrile and Amides
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Hongxin Chaia, Jiarong Lia, Liupan Yangb, Hongyan Lua, Zhang Qia and Daxin Shia,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
1 A novel, straightforward and practical copper-catalyzed of the top priorities of both synthetic and medicinal chemists.
domino protocol for synthesis of quinazolin-4(3 )-one The traditional synthetic routes to quinazolin-4(3 )-one com-
derivatives from commercially available 2-halobenzonitriles pounds utilizing 2-aminobenzoic acid or its derivatives as
H
H
and amides was successfully developed.
starting materials suffer from several drawbacks such as tedious
multi-step procedures, long reaction time, and harsh refluxing
conditions.1,8 Domino reactions allow the concomitant
formation of two or more bonds with a rapid increase in
molecular complexity with minimized separation/purification
efforts.9 To overcome above problems and being inspired by
significant advantages of domino reactions, several groups have
applied metal catalyzed domino reactions for assembling
The quinazolin-4(3 )-one nucleus is a basic structural feature
H
which was found in many biologically active and pharm-
aceutically relevant natural products and synthetic analogues
(Figure 1).1 Till now, approximately 150 naturally occurring
alkaloids comprising the quinazolinone moiety have been
isolated from the plant, animals and microorganisms.1e In
substituted quinazolin-4(3
coupling reactions have made great progress and have been
employed for the assembling of important
-heterocycles.12
H
)-ones.10,11 Copper-catalyzed cross-
addition, substituted quinazolin-4(3H)-ones have been assigned
as privileged structures in drug discovery because of the wide
range of remarkable pharmacological activities including
anticancer,2 antifungal,3 antidiabetic,4 antiinflammatory,5 anti-
microbial,6 and many others.7
N
Typically, using 2-halobenzamides as the starting materials,
several copper-catalyzed domino synthesis of quinazolin-
4(3H)-one derivatives have been developed by Fu and other
research groups (scheme 1).11 The group of Wu has reported a
palladium-catalyzed CO insertion for the construction of
quinazolin-4(3
mediate.10b,10i During our studies on heterocycle synthesis via
-aminonitriles as strating materials13, we hypothesized that
H)-ones via N-(2-cyanoaryl)benzamides as inter-
o
amides could serve as suitable nucleophiles for coupling
reactions with more conveniently available 2-halobenzonitrile,
affording
N-(2-cyanoaryl)amides, which can yield the corres-
ponding quinazolinones through intramolecular cyclocon-
densation (Scheme 2).
Figure 1. Selected examples of biologically active quina-
zolinones.
Based on the above-mentioned remarkable importance of
quinazolin-4(3H)-ones, synthesis of the quinazolin-4(3H)-one
moieties with diverse substitution patterns has always been one
1 a School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing 100081, China
b Jiangsu Hengrui Medicine Co., Ltd., No.7 Kunlunshan Road, Lianyungang
Eco & Tech Development Zone, Jiangsu Province 222047, China
Fax: +86(10)68918012; E-mail: shidaxin@bit.edu.cn.
† Electronic Supplementary Information (ESI) available: See DOI:
10.1039/b000000x/.
Scheme 1 Methods for the synthesis of quinazolin-4(3H)-ones
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DOI: 10.1039/C4RA08031A
Table 2 Substrate scope for the copper-catalyzed domino
synthesis of quinazolin-4(3
H
)-ones a
Entry
1
1
2
Product Yield b (%)
Scheme 2. Synthetic route to 2-substituted quinazolin-4(3H)-ones
3a
3b
3c
3d
84
72
76
78
1a
2a
2b
Initially, 2-bromobenzonitrile (1a) and benzamide (2a) as
model substrates was performed. As expected, the desired 2-
2
3
4
1a
1a
1a
phenylquinazolin-4(3
treating 2 bromobenzonitrile (1a) (1.0 mmol) with benzamide
2a) (1.0 mmol) in the presence of CuI (5 mol%), NaOH (1.2
eq, relative to amount of 1a) in DMSO (5 mL) at 120 for 12
H)-one (3a) was isolated in 75% yield by
‑
(
℃
2c
h (Table 1, entry 2). Encouraged by this result, we further
optimized the reaction conditions by changing solvent, and
NMP was found to be the optimal solvent (Table 1, compared
entries 1, 2 and 8-11), the yield of 3a increased to 84% (Table 1,
entry 2). Other solvents, such as dioxane and DMF, gave lower
product yields (Table 1, entries 8 and 9). No desired 3a could
be detected when the reaction was carried out in toluene or H2O
(Table 1, entries 10 and 11). Compared with CuI, other
catalysts, such as Cu2O, Cu(OAc)2, showed less catalytic
activity. Among the examined bases, NaOH showed the best
activity (Table 1, compared entries 3-8). No significant
improvements in the yields were observed (Table 1, entries 7-9)
when increasing the amount of CuI or extending the reaction
2d
2e
5
6
1a
1a
3e
3f
75
83
2f
7
8
1a
1a
3g
3h
85
74
2g
2h
9
1a
3i
70
2i
time. On the other hand, 120
℃ was a better reaction
temperature compared to the others. (Table 1, entries 12-15).
10
11
12
13
14
15
16
2a
2h
2a
2g
2a
2h
2a
3j
3k
3l
65
62
61
55
83
78
80
1b
Table 1 Optimization of reaction conditions a
1b
1c
1d
1c
3m
3n
3o
3p
F
CN
Br
Entry
1
Cat.
CuI
Base
NaOH
NaOH
NaOH
NaOH
K2CO3
DBU
Solvent
DMSO
NMP
Temp (
120
120
120
120
120
120
120
120
120
110
)
Yield b (%)
℃
1d
75 (68c, 78d)
84 (72c, 87d)
F3C
CN
Br
2
CuI
3
Cu2O
Cu(OAc)2
CuI
NMP
57
1e
1f
4
NMP
23
17
18
19
1e
1f
2g
2a
2g
3q
—
—
77
0
5
NMP
0
6
CuI
NMP
35
0
7
CuI
Cs2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NMP
0
8
CuI
Dioxane
DMF
73 (62c, 76d)
20
21
2a
2a
3r
3a
67
62
42 (30c, 45d)
1g
9
CuI
10
11
12
13
14
15
CuI
Toluene
H2O
0
0
CuI
reflux
120
100
80
1h
84e, 85f
22
23
24
25
1h
1h
1h
1h
2b
2f
3b
3f
56
52
56
63
CuI
NMP
CuI
NMP
82
2h
2i
3h
3i
CuI
NMP
63
CuI
NMP
140
83
26
2a
3a
86
a Reaction conditions: 1a (1.0 mmol), 2e (1.0 mmol), catalyst (0.05
mmol), base (1.2 mmol), solvent (5.0 ml), 120 ℃, 12 h, under an air
1i
27
28
1i
1i
2g
2i
3g
3i
78
80
c
f
atmosphere. b Isolated yield. Time: 8 h. d Time: 24 h. e 0.1 mmol.
0.2 mmol.
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a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), CuI (0.05 mmol),
NaOH (1.2 mmol), NMP (5.0 ml), 120 ℃, 12 h, under an air
atmosphere. b Isolated yield
indicated that hydrolysis of intermediate
likely.
I (Pathway A) is less
The scope of copper-catalyzed domino reactions of
substituted 2-halobenzonitriles with amides was investigated
under the optimized conditions (using 5 mol% of CuBr as the
catalyst, 1.2 equiv of NaOH as the base, and NMP as the
solvent). Initially, 2-bromobenzonitrile was chosen as a model
substrate to react with a range of amides. For aromatic amides,
in general, no significant difference of reactivity was observed
for the examined substituted aryl amides with varied electronic
properties, including electron-rich, electron-poor, and neutral
substrates. All aliphatic amides tested furnished the
Scheme 4 Mechanistic studies
In conclusion, we demonstrate for the first time a novel and
efficient copper-catalyzed domino protocol for synthesis of
quinazolin-4(3H)-one derivatives by using commercially
available 2-halobenzonitriles and amides as starting materials,
inexpensive CuI as the catalyst and cheap inorganic base as a
promoter. This methodology does not require any special
equipment and protection measures, besides, it also tolerates
various functional groups and the corresponding quinazolinones
prepared in moderate to good yields without any ligand or
additive under air condition. Therefore, the present method
provides a complementary strategy for construction of diverse
corresponding quinazolin-4(3H)-ones in good yields (Table 2,
entries 4-8). Moreover, the copper-catalyzed domino synthesis
of quinazolinones showed good tolerance of the functional
groups in the substrates including the methyl, methoxy, a C-F
bond and trifluoromethyl in the substituted 2-halobenzonitriles,
the 2-bromobenzonitriles containing electron withdrawing
groups provided higher yields than the ones containing
electron-donating groups, while those with strong electron-
withdrawing groups like nitro, no product was observed.
N-heterocyclic compounds and will have a wide application in
both academic and industrial research.
Financial support from the International S&T Cooperation
Program of
acknowledged.
China (2012DFR40240) is gratefully
Furthermore, o-iodobenzonitriles showed higher reactivity than
the corresponding 2-bromobenzonitriles and 2-chlomobenzo-
nitriles.
A possible mechanism for domino reactions of substituted 2-
halobenzonitrile and amides is suggested in Scheme 3. The
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