A simple and efficient approach to quinazolinones under mild copper-catalyzed conditions

Article abstract of DOI:10.1002/anie.200804675

(Chemical Equation Presented) Cop some rings: A simple and highly efficient copper-catalyzed method for the synthesis of quinazolinone derivatives through the reaction of substituted 2-halobenzoic acids with amidines or guanidines under mild conditions ha

Full text of DOI:10.1002/anie.200804675

Communications
DOI: 10.1002/anie.200804675
Homogeneous Catalysis
A Simple and Efficient Approach to Quinazolinones under Mild
Copper-Catalyzed Conditions**
Xiaowei Liu, Hua Fu,* Yuyang Jiang, and Yufen Zhao
Quinazolinone (Q) is a key core structure that occurs in
natural products such as luotonin A from Peganum nigellas-
trum,[1a] 2-methyl-4(3H)-quinazolinone from Bacillus cer-
eus,[1b] 2-(4-hydroxybutyl)quinazolin-4-one from Dichroa
febrifuga,[1c] and bouchardatine from Bouchardatia neuro-
cocca (Figure 1).[1d] Quinazolinone derivatives are now
acid derivatives. Some of the starting materials are also
sometimes difficult to prepare. Recently, progress has been
made on the copper-catalyzed Ullmann N-arylations,[7] and
they have been used to make N-heterocycles.[8] Unfortu-
nately, these methods are not useful for constructing some
quinazolinone molecules because the reaction temperatures
are too high. Therefore, it is desirable to develop milder
copper-catalyzed coupling methods. Recently, Shafir and
Buchwald[9] and ourselves[10] have developed copper-cata-
lyzed N-arylations at room temperature, and the results
showed that the efficiency of the copper-catalyzed coupling
reactions was highly dependent on the involvement of
suitable ligands. To the best of our knowledge, there is no
example of constructing N-heterocycles under ligand-free
copper catalysis at room temperature. Herein, we report a
simple, practical, and efficient strategy for the synthesis of
quinazolinone derivatives by using mild copper-catalyzed
conditions in the absence of ligands or additives.
2-Bromobenzoic acid (1a) and acetamidine hydrochloride
(2a) were chosen as the model substrates for the optimization
of the reaction conditions, which include the catalyst, base,
and solvent. As shown in Table 1, four copper catalysts were
tested at room temperature by using two equivalents of
Cs2CO3 as the base (relative to amount of 1a) in DMF
Figure 1. Quinazolinone (Q) and examples of related natural products.
known to have useful biological and medicinal activities;
they can be used as hypnotic, sedative, analgesic, anticonvul-
sant, antitussive, antibacterial, antidiabetic, anti-inflamma-
tory, and antitumor agents.[2,3] Additionally, some therapeutic
agents containing this core structure have been on the market
or are in clinical trials for the treatment of cancer.[4]
Table 1: Copper-catalyzed coupling of 2-bromobenzoic acid with acet-
amidine hydrochloride: Optimization of the reaction conditions.[a]
Although some methods for the synthesis of quinazoli-
none derivatives[2,5,6] have been developed, they depend on
the availability of the requisite ortho-amino- or -nitrobenzoic
Entry
Catalyst
Base
Solvent
Yield [%][b]
[*] X. Liu, Prof. Dr. H. Fu, Prof. Dr. Y. Jiang, Prof. Dr. Y. Zhao
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
1
2
3
4
5
6
7
8
Cu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
dioxane
DMSO
DMF
19
23
75
CuSO4
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
Fax: (+86)10-6278-1695
E-mail: fuhua@mail.tsinghua.edu.cn
81
57[c]
74
Prof. Dr. Y. Jiang
K3PO4
69
trace
62
Key Laboratory of Chemical Biology (Guangdong Province)
Graduate School of Shenzhen, Tsinghua University
Shenzhen (China)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
59
[**] Financial support was provided by the National Natural Science
Foundation of China (Grant No. 20672065), Chinese 863 Project
(Grant No. 2007AA02Z160), the Program for New Century Excellent
Talents in University (NCET-05-0062), and Changjiang Scholars and
Innovative Research Team in University (PCSIRT) (No. IRT0404) in
China and the Key Subject Foundation from the Beijing Department
of Education (XK100030514).
trace[d]
trace[e]
CuI
DMF
[a] Reaction conditions: 2-bromobenzoic acid (0.5 mmol), acetamidine
hydrochloride (0.75 mmol), catalyst (0.1 mmol), base (1 mmol), solvent
(3 mL) at room temperature (ca. 258C) under a nitrogen atmosphere.
[b] Yield of isolated product. [c] Base (0.5 mmol). [d] No addition of
catalyst. [e] Without nitrogen atmosphere. DMSO=dimethylsulfoxide;
DMF=N,N-dimethylformamide.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804675.
348
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Chemie
Table 2: Copper-catalyzed synthesis of quinazolinone derivatives.[a]
(Table 1, entries 1–4). CuI
showed the best activity
(Table 1, entry 4) and the
coupling yield decreased as
the amount of base was
reduced (Table 1, entry 4
versus 5). Several bases
such as Cs2CO3, K2CO3,
and K3PO4 were screened
and Cs2CO3 proved to be
the most effective base
Entry
1
Product
Yield [%][b]
2
1
2
1a
2a
2b
3a 81
(Table 1, entries 4 and
6
versus 7). The effect of the
solvent was also investi-
gated (Table 1, entries 4,
and 8–10), and DMF was
found to be the best choice
(Table 1, entry 4). Only
trace amounts of quinazo-
line 3a were observed when
the reaction was run either
in the absence of the cata-
lyst (Table 1, entry 11) or
the nitrogen atmosphere
(Table 1, entry 12).
1a
1a
3b 79
3c 84
3
4
2c
2d
1a
3d 85
5
6
1b
2a
2b
3e 69
The scope of copper-
catalyzed cascade reactions
of the substituted 2-halo-
benzoic acids with amidines
was investigated under the
optimized conditions. As
shown in Table 2, most of
the substrates examined
provided good to excellent
yields at room temperature.
For the substituted 2-halo-
benzoic acids, their relative
reactivity was in the order
of aryl iodides > aryl bro-
mides > aryl chlorides. The
reactions of 2-iodo- and 2-
bromobenzoic acids with
amidines produced quina-
zolinones in good to excel-
lent yields at room temper-
ature, and 2-chlorobenzoic
acid gave lower yields
under the same reaction
conditions. Notably, the
yields of the target products
were greatly improved as
the reaction temperature
was increased; for example,
2-chlorobenzoic acid pro-
vided the target products
in more than 80% yield at
808C (Table 2, entries 20
and 21). In fact, aryl chlor-
ides are weak substrates in
1b
1b
3 f 65 (89[c])
7
8
2c
2d
3g 68
1b
3h
79
9
1c
2a
2b
3i
3j
83
87
10
1c
1c
11
2c
3k 75
12
13
1c
2d
2b
3l
66
1d
3m 40[c] (49[d])
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349

Communications
Table 2: (Continued)
quinazolinones
were
Entry
1
Product
Yield [%][b]
obtained in good yields
when temperature was
raised to 808C (Table 2,
entries 18 and19).
2
14
15
1d
2d
2a
3n 61
Quinazolinones can be
readily transformed into
the corresponding quinazo-
lines, which have various
biological and medicinal
activities,[11] so the present
method provides a novel
strategy for synthesis of a
diverse array of quinazoli-
1e
3a
89
16
17
1e
1e
2b
2d
3b
3d
90
97
18
19
1e
1e
2e
2 f
3o 59[c] (72[d])
none
and
quinazoline
derivatives.
Given that suitable
ortho substituents promote
Ullmann-type couplings,[12]
a mechanism for the for-
mation of quinazolinones is
proposed in Scheme 1. This
proposal is based on the
results discussed herein
and on the other experi-
mental evidence (see the
Supporting Information for
details). The coordination
of substituted 2-haloben-
3p 45[c] (70[d])
20
21
1 f
2b
2d
3b
3d
40[c] (81[d])
43[c] (85[d])
1 f
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), CuI (0.1 mmol), Cs2CO3 (1 mmol), DMF (3 mL) at room
temperature (ca. 258C) under nitrogen atmosphere. [b] Yield of isolated product. [c] Reaction temperature of
408C. [d] Reaction temperature of 808C.
the previously reported copper-catalyzed N-arylations,[7–11]
and the result above demonstrates that an ortho-substituent
effect is present during the N-arylation and is derived from
the coordination of the carboxyl group (Scheme 1). The
reaction of 2-bromo-5-chlorobenzoic acid (1c) with amidines
zoic acid to CuI forms I in the presence of the base
(Cs2CO3). Oxidative addition of I and complexation of
copper with the amidine provides II, which then undergoes
reductive elimination to give the N-arylation product III and
releases the copper catalyst. The coupling of the carboxyl and
amino groups in III affords target product 3.[13]
In summary, we have developed a simple and highly
efficient method for the synthesis of quinazolinone deriva-
tives. The coupling reactions of 2-bromo- and iodobenzoic
acid derivatives with amidines performed well at room
temperature without the addition of a ligand or an additive.
The target products were also obtained in higher yields from
the nonactive substrates, such as 2-chlorobenzoic acid (1 f) or
guanidines, when the reaction temperature was raised to
808C. The present method is economical and practical, and
the starting materials are readily available. These advantages,
relative to previous methods, provide an opportunity for the
construction of diverse and useful molecules within organic
and medicinal chemistry.
À
took place at the C Br bond ortho to the carboxyl group and
À
not at the C Cl bond, again demonstrating an the presence of
an ortho-substituent effect. The substituted 2-halobenzoic
acids containing electron-rich groups showed slightly weaker
reactivity than those containing electron-neutral or electron-
deficient groups; for example, 6-bromo-1,3-benzodioxole-5-
carboxylic acid (1d) provided lower yields (Table 2, entries 13
and 14). In general, amidines are good substrates, but the
couplings of guanidines with 2-halobenzoic acids did not
perform well at room temperature. The corresponding
Received: September 24, 2008
Published online: December 3, 2008
Keywords: copper · cyclization · guanidines · heterocycles ·
.
quinazolinone
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quinazolinones.
350
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