Highly efficient copper-catalyzed cascade synthesis of quinazoline and quinazolinone derivatives

Article abstract of DOI:10.1039/b814011a

We have developed a general and highly efficient copper-catalyzed method for synthesis of quinazoline and quinazolinone derivatives, the target products were obtained in good to excellent yields via cascade reactions of amidine hydrochlorides with substituted 2-halobenzaldehydes, 2-halophenylketones, or methyl 2-halobenzoates, and the method is of simple, economical and practical advantages. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b814011a

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Highly efficient copper-catalyzed cascade synthesis of quinazoline
and quinazolinone derivativesw
Cheng Huang,ab Yuan Fu,a Hua Fu,*a Yuyang Jiang*ab and Yufen Zhaoa
Received (in Cambridge, UK) 12th August 2008, Accepted 22nd September 2008
First published as an Advance Article on the web 24th October 2008
DOI: 10.1039/b814011a
We have developed a general and highly efficient copper-
catalyzed method for synthesis of quinazoline and quinazolinone
derivatives, the target products were obtained in good to ex-
cellent yields via cascade reactions of amidine hydrochlorides
with substituted 2-halobenzaldehydes, 2-halophenylketones, or
methyl 2-halobenzoates, and the method is of simple, economical
and practical advantages.
2-Bromobenzaldehyde and acetamidine hydrochloride were
firstly chosen as the model substrates to optimize reaction
conditions including optimization of the catalysts, ligands,
bases and solvents under nitrogen atmosphere. As shown in
Table 1, five ligands were tested at 110 1C using 10 mol% CuI as
the catalyst and 3 equiv. Cs2CO3 as the base (relative to the
amount of 2-bromobenzaldehyde) in DMF (entries 1–5), and
L-proline showed the best activity (entry 2). No quinazoline 3a
was formed in the absence of ligand (entry 6). When reaction
temperature was lowered to 80 1C, only 30% yield was provided
(entry 7). CuBr was used as the catalyst in place of CuI, and it
showed weaker activity than CuI (entry 8). The effect of
solvents was also investigated (compare entries 2, 9–11), and
DMF was the best choice (entry 2). Several bases, Cs2CO3,
Na2CO3 and K3PO4, were also tested, and Cs2CO3 proved to be
the most effective base (compare entries 2, 12 and 13).
Quinazoline and quinazolinone derivatives have attracted much
attention for their various biological and medicinal properties.
For example, quinazoline derivatives act as powerful inhibitors
of the epidermal growth factor (EGF) receptors of tyrosine
kinase,1 and some of them show remarkable activity as antic-
ancer,2 antiviral,3 and antitubercular agents.4 They are also
used as ligands for benzodiazepine and GABA receptors in the
CNS system5 or as DNA binders.6 Quinazolinone is a building
block for approximately 150 naturally occurring alkaloids
isolated to date from a number of families of the plant king-
dom, from animals and from microorganisms, such as luotonin
A from Peganum nigellastrum,7a 2-methyl-4(3H)-quinazolinone
from Bacillus cereus,7b 2-(4-hydroxybutyl)quinazolin-4-one
from Dichroa febrifuga,7c bouchardatine from Bouchardatia
neurococca.7d Quinazolinones and their derivatives are now
known to have a wide range of useful biological properties,
such as hypnotic, sedative, analgesic, anti-convulsant, anti-
tussive, anti-bacterial, anti-diabetic, anti-inflammatory, anti-
tumor.8,9 Although some methods for the syntheses of
quinazoline10 and quinazolinone derivatives8,11,12 have been
developed, it is highly desirable to search for a more convenient
and efficient approach. Recently, copper-catalyzed Ullmann
N-arylations have made great progress;13 some research groups,13
and we,14 have developed efficient copper catalyst systems to
perform aminations of aryl halides, and the N-arylation
strategy has been used to construct N-heterocycles.15 Herein,
we report highly efficient copper-catalyzed cascade reactions
of amidines with substituted o-carbonylaryl halides to synthe-
size quinazoline and quinazolinone derivatives.
After the optimization process for catalysts, ligands, sol-
vents and bases, the various quinazoline derivatives were
synthesized under our standard conditions: 10 mol% CuI as
the catalyst, 20 mol% L-proline as the ligand, 3 equiv. of
Cs2CO3 as the base (relative to 2-bromobenzaldehydes or
Table 1 Copper-catalyzed cascade coupling of 2-bromobenzaldehyde
with acetamidine hydrochloride: optimization of conditionsa
Entry
Catalyst
Ligand
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
—
L2
L2
L2
L2
L2
L2
L2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
DMF
DMF
68
75
50
65
30
0
30
50
0
55
40
72
69
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
Dioxane
THF
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing, 100084, P. R. China.
9
10
11
12
13
E-mail: fuhua@mail.tsinghua.edu.cn; Fax: +86 10 62781695;
Tel: +86 10 62797186
DMF
DMF
b Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University, Shenzhen,
518057, P. R. China
a
Reaction conditions: under nitrogen atmosphere, reaction tempera-
ture (80 1C for for entry 7, reflux in THF for entry 11, 110 1C for
others), time (16 h for entry 12, 24 h for others). 2-bromobenzaldehyde
(1 mmol), acetamidine hydrochloride (1.1 mmol), catalyst (0.1 mmol),
w Electronic supplementary information (ESI) available: General pro-
cedure for copper-catalyzed synthesis of quinazoline and quinazoli-
none derivatives, characterization data for compounds 3a–j, 5a–h and
6b, references, and 1H and 13C NMR spectra of compounds 3a–j, 5a–h
and 6b. See DOI: 10.1039/b814011a
b
ligand (0.2 mmol), base (3 mmol), solvent (10 mL). Isolated yield.
ꢀc
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Table 3 Copper-catalyzed synthesis of quinazolinone derivativesa
Table 2 Copper-catalyzed synthesis of quinazoline derivativesa
Entry
1
4
Time/h
16
Product
Yield (%)b
91
Entry
1
1
Time/h
24
Product
Yield (%)b
75
2
4a
16
74
2
3
1a
1a
24
24
82
55
22
89
3
4
4a
16
16
4
5
6
20
20
20
92
95
89
87
1b
1b
5
6
4b
4b
16
16
95
86
7
8
9
20
20
24
84
86
81
1c
7
8
20
20
90
77
4c
61c
18
10
1d
24
a
Reaction conditions: under nitrogen atmosphere, 1(1 mmol), 2
(1.1 mmol), CuI (0.1 mmol), L-proline (0.2 mmol), Cs2CO3 (3 mmol),
9
4c
20
20
20
86
82
76
b
DMF (10 mL). Isolated yield. CuI (0.2 mmol), L-proline (0.4 mmol).
c
10
2-bromophenylketones) and DMF as the solvent at 110 1C. As
shown in Table 2, all the substrates examined provided good
to excellent yields. In general, 2-bromobenzaldehydes showed
higher reactivity than 2-bromophenylketones, 6-bromo-1,3-
benzodioxole-5-carboxaldehyde (1b) was more effective than
2-bromobenzaldehyde (1a), and 20-bromoacetophenone (1c)
gave higher yields than 2-bromobenzophenone (1d). Reactive
activity of aliphatic amidines were better than aromatic ones,
their order is butyramidine 4 acetamidine 4 benzamidine.
11
4d
a
Reaction conditions: under nitrogen atmosphere, 4 (1 mmol), 2
(1.1 mmol), CuI (0.1 mmol), L-proline (0.2 mmol), Cs2CO3 (3 mmol),
b
DMF (10 mL). Isolated yield.
ꢀc
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Subject Foundation from Beijing Department of Education
(XK100030514).
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15 For recent studies on the synthesis of N-heterocycles through
Ullmann-type couplings, see: (a) A. Klapars, S. Parris,
K. W. Anderson and S. L. Buchwald, J. Am. Chem. Soc., 2004,
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Scheme 1 Plausible formation mechanism of quinazolinones.
We also attempted cascade reactions of substituted methyl
2-halobenzoates with amidine hydrochlorides to synthesize
various quinazolinone derivatives under our standard catalytic
conditions. As shown in Table 3, all the examined substrates
gave the corresponding quinazolines in good to excellent
yields. Interestingly, methyl 2-chlorobenzoate (4c) and methyl
2-bromobenzoate (4a) almost provided the same yields (com-
pare entries 1–3, 7–9), and methyl 2-chloronicotinate (4d) also
afforded the corresponding target products (5g,h) in good
yields (entries 10 and 11). In fact, aryl chlorides are weak
substrates in the previous copper-catalyzed N-arylations,13,14
and the results above could show an ortho-effect during
N-arylations (see reaction mechanism). Further, N-arylation
selectively occurred at the ortho-site of the ester group in
methyl 2-bromo-5-chlorobenzoate (4b) (entries 4–6). It is
worthwhile to note that reaction of electron-rich butyramidine
with methyl 2-bromobenzoate (4a) or methyl 2-chlorobenzoate
(4c) gave a minor quinozoline (6b) besides the major quina-
zolinone (5b) (entries 2 and 8). In addition, reactive activity of
amidines also showed similar results to Table 2.
Since the suitable ortho-substituents could promote
Ullmann-type couplings,16 a plausible formation mechanism
of quinazolinones was proposed in Scheme 1 according to the
results in Table 3. Coordination of L-proline with CuI in the
presence of base (Cs2CO3) first forms I (CuL). Substitution
reaction of methyl 2-halobenzoate with amidine hydrochloride
yields amide II in the presence of Cs2CO3, and treatment of II
with CuL (I) gives complex III, in which one nitrogen of the
amidine group may coordinate with the copper center to
provide additional stabilization. Oxidation addition of III
provides coordinate IV, and reduction elimination of IV
affords the target product 5 releasing the copper catalyst.
In summary, we have developed a general and highly
efficient method for synthesis of quinazoline and quinazoli-
none derivatives via copper-catalyzed cascade couplings of
amidine hydrochlorides with substituted 2-halobenzaldehydes,
2-halophenylketones and methyl 2-halobenzoates under mild
conditions. The present method shows simple, economical and
practical advantages over the previous methods, so it can
provide diverse molecules for organic chemistry and medicinal
chemistry.
This work was supported by the National Natural Science
Foundation of China (Grant No. 20672065), Chinese 863
Project (Grant No. 2007AA02Z160). Programs for New Cen-
tury Excellent Talents in University (NCET-05-0062) and
Changjiang Scholars and innovative Research Team in Uni-
versity (PCSIRT) (No. IRT0404) in China and the Key
16 (a) K. C. Nicolaou, C. N. C. Boddy, S. Natarajar, T.-Y. Yue,
H. Li, S. Brase and J. M. Ramanjulu, J. Am. Chem. Soc., 1997,
¨
119, 3421; (b) Q. Cai, B. Zou and D. Ma, Angew. Chem., Int. Ed.,
2006, 45, 1276.
ꢀc
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Chem. Commun., 2008, 6333–6335 | 6335