Copper-catalyzed domino synthesis of quinazolin-4(3 H)-ones from (Hetero)arylmethyl halides, bromoacetate, and cinnamyl bromide

Article abstract of DOI:10.1055/s-0033-1340040

Alkyl halides, including heteroarylmethyl and arylmethyl halides, bromoacetate, and cinnamyl bromide, are readily prepared via halogenation from basic raw materials, even using green processes. It is essential to replace their downstream products with them to prepare medicinally important heterocycles quinazolin-4(3H)-ones. Copper(I) bromide catalyzed domino reaction of alkyl halides and anthranilamides under air affords 2-substituted quinazolin-4(3H)-ones in good to excellent yields and with wide functional group tolerance. A mechanism for a copper(I) bromide involved organometal-catalyzed reaction via a four-step domino reaction is proposed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340040

PAPER
▌3349
paper
Copper-Catalyzed Domino Synthesis of Quinazolin-4(3H)-ones from
(Hetero)arylmethyl Halides, Bromoacetate, and Cinnamyl Bromide
Copper-Catalyzed Domino Synthesis of Quinazolin-4(3H)-ones
Haidong Wei,a Tianbin Li,b Yue Zhou,a Lihong Zhou,a Qingle Zeng*a
a
Institute of Green Catalysis and Synthesis, College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology,
Chengdu 610059, P. R. of China
Fax +86(28)84079074; E-mail: qinglezeng@hotmail.com
b
State Key Lab of Geohazard Prevention and Geoenvironment Protection, Chengdu University of Technology, Chengdu 610059, P. R. of China
Received: 21.08.2013; Accepted after revision: 23.09.2013
Generally, three-component condensation reactions are
composed of isatoic anhydride, ammonium acetate (or
amines), and benzaldehydes,21 or composed of isatoic an-
hydride, orthoesters, and amines.22 One of the three com-
Abstract: Alkyl halides, including heteroarylmethyl and arylmeth-
yl halides, bromoacetate, and cinnamyl bromide, are readily pre-
pared via halogenation from basic raw materials, even using green
processes. It is essential to replace their downstream products with
them to prepare medicinally important heterocycles quinazolin- ponents is a benzaldehyde or an orthoester (i.e.,
4(3H)-ones. Copper(I) bromide catalyzed domino reaction of alkyl
halides and anthranilamides under air affords 2-substituted quinaz-
olin-4(3H)-ones in good to excellent yields and with wide function-
(triethoxymethyl)benzene), which are also downstream
products of arylmethyl halides.
The synthesis of 2-substituted quinazolin-4(3H)-ones us-
ing basic organic raw materials instead of their down-
stream products shortens the synthetic route, reduces
environmental pollution, and lowers production costs,
thus it is fundamental in industrial production and mean-
ingful for academic research. Arylmethyl halides and het-
eroarylmethyl halides are readily prepared via
halogenation from basic organic raw materials, methylar-
enes and heteromethylarenes,23 even using green process-
es,24 and thus a number of this type of chemicals are
readily available and less expensive.
al group tolerance. A mechanism for a copper(I) bromide involved
organometal-catalyzed reaction via a four-step domino reaction is
proposed.
Key words: copper, condensation, tandem reaction, oxygenation,
quinazolin-4(3H)-ones
2-Substituted quinazolin-4(3H)-ones are an important
class of nitrogen-containing heterocycle that occur widely
in natural products,1 such as luotonin alkaloids2 and rutae-
carpine.3 They have are of importance for their bioactivity
and medical value,1 e.g. for their anticancer,4 anti-inflam-
matory,5 antibacterial,6 antihypertensive,7 and antimalari-
al activity,8 and as an antituberculosis agent,9 vasopressin
V3 receptor antagonist,10 and nonpeptide cholecystokinin
B receptor antagonist.11
It is commonly known, and experimental results confirm,
that anthranilamides are facilely benzylated with benzyl
halides in the presence of the weak base potassium car-
bonate. Since N-benzylanilines can be oxidized into N-
benzylideneanilines under 1 atm oxygen in the presence
of cobalt Schiff base complex25 or Ru2(OAc)4Cl,26 then 2-
(benzylamino)benzamide may be turned into 2-
phenylquinazolin-4(3H)-ones under air in the presence of
a suitable catalyst.
The importance of 2-substituted quinazolin-4(3H)-ones
promotes the development of methods for their synthe-
sis.1,2 These are commonly divided into two-component
synthesis and three-component synthesis. In two-compo-
nent synthesis, some typical pairs of two-component reac-
tions are composed of: 2-aminobenzamides and benzoyl
chlorides or their equivalents;12 2-halobenzoic acids or es-
ters and arylamidines;13 α-azido-substituted aromatic
imides;14 o-iodobenzamides and benzylamines;15 anthra-
nilamide and (hetero)aryl aldehydes;16 anthranilamide
and benzyl alcohols;17 lithium 2-(diethylaminocarbon-
yl)anilide and (hetero)arylnitriles;18 2-aminobenzoic acids
and benzimidates;19 1-aryl-4-(dimethylamino)-2-phenyl-
1,3-diazabuta-1,3-dienes and phenyl isocyanate.20 One of
two components in each reaction, such as arylamidines,
benzoyl chlorides, benzylamines, benzyl alcohols, and
(hetero)arylnitriles, are downstream products of aryl-
methyl halides.
During the initial study, we found that copper(I) bromide
directly transformed 2-(benzylamino)benzamide to 2-
phenylquinazolin-4(3H)-ones under air at 120 °C. Further
research showed that copper(I) bromide could directly
turn anthranilamides and (hetero)arylmethyl halides into
2-(hetero)arylquinazolin-4(3H)-ones under air and in the
presence of a weak base (Scheme 1).
As our ongoing research on synthesis of quinazolin-
4(3H)-ones16a and transition-metal-catalyzed reactions,27
we describe in this paper the copper(I) bromide catalyzed
cascade synthesis of 2-(hetero)aryl-substituted quinazo-
lin-4(3H)-ones from (hetero)arylmethyl halides and an-
thranilamides (Scheme 1).
SYNTHESIS 2013, 45, 3349–3354
Advanced online publication: 18.10.2013
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DOI: 10.1055/s-0033-1340040; Art ID: SS-2013-F0579-OP
© Georg Thieme Verlag Stuttgart · New York

3350
H. Wei et al.
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O
N
When 5 mol% copper(II) oxide was examined, surprising-
ly 56% yield of the desired product 2-phenylquinazolin-
4(3H)-one (3a) was obtained (entry 1). Further screening
of various copper salts demonstrated that copper(I) bro-
mide was the best catalyst for this cascade reaction (en-
tries 1–6). 2-Phenylquinazolin-4(3H)-one (3a) was
obtained in 89% yield in N,N-dimethylacetamide (DMA)
under air atmosphere (entry 4), which means that oxygen
in the air and copper(I) bromide fulfill the oxidation of the
cascade reaction. Screening various bases (entries 7 and 8
vs. 4) and amounts (entries 9 and 10 vs. 4) did not give
higher yields. Both shortening and prolonging the reaction
time gave lower yields (entries 11 and 12 vs. 4). Investi-
gation of the solvent indicates that dimethyl sulfoxide was
better than N,N-dimethylacetamide and N,N-dimethyl-
formamide (entries 4, 13, and 14). Lowering the amount
of copper(I) bromide to 1 mol% caused a decrease in the
O
NH
R2
NH2
CuBr, K2CO3
R2
X
+
DMSO, 120 °C, 24 h
R1
R1
NH2
1
2
3
Scheme 1 Copper-catalyzed domino synthesis of quinazolin-4(3H)-
ones
To begin with, we took anthranilamide and benzyl bro-
mide as the model substrates (Table 1). Considering that
inexpensive and less toxic copper salts are both good oxi-
dation catalysts with air as the oxidant28 and based on our
earlier study of copper(II) oxide as an efficient catalyst for
the synthesis of quinazolin-4(3H)-ones,16a we initially
chose copper(II) oxide as the catalyst to explore this new
protocol.
Table 1 Optimization of Conditions for the Reaction of Anthranilamide (1a) and Benzyl Bromide (2a)a
Entry
Catalyst (mol%)
Base
Solvent
Time (h)
Temp (°C)
Yieldb (%) of 3a
1
CuO (5)
Cu2O (5)
CuI (5)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
24
24
24
24
24
24
24
24
24
24
10
36
24
24
24
24
24
24
24
24
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
56
66
62
89
81
73
47
60
66
59
63
68
58
93
72
97
95
trace
71
79
2
3
4
CuBr (5)
CuCl (5)
CuCl2(5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (1)
CuBr (2)
CuBr (3)
5
6
7
8
9c
10d
11
12
13
14
15
16
17
18
19
20
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
e
–
CuBr (2)
CuBr (2)
a Reaction conditions: anthranilamide (1 mmol), BnBr (1 mmol), K2CO3 (1.0 equiv), copper source (0.02 equiv), solvent, temperature, time,
unless otherwise mentioned.
b Isolated yield.
c K2CO3 (1.2 equiv).
d K2CO3 (0.8 equiv).
e No catalyst was added and the major product is 2-(benzylamino)benzamide (86% yield).
Synthesis 2013, 45, 3349–3354
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Domino Synthesis of Quinazolin-4(3H)-ones
3351
yield (entries 14 vs. 15). Further screening of the amount substituted groups, such as fluoro, nitro, cyano, ethoxy-
of copper(I) bromide showed that 2 mol% afforded the carbonyl, methoxy, only slightly influenced the yields of
highest yield of 97% (entries 14–17). The absence of cop- 3e,h,i,l (entries 5, 8, 9 vs. 12). It seems that ethyl 4-(4-
per(I) bromide in the reaction gave mainly 2-(benzylami- oxo-3,4-dihydroquinazolin-2-yl)benzoate (3k) contains
no)benzamide and only trace amounts of the desired an ester group that was not hydrolyzed during the weak
product (entry 18). Both increasing and lowering the tem- basic reaction conditions and the workup process (entry
perature resulted in lower yields (entries 19 and 20).
11), and is an intermediate of a series of drug candidates
with cytotoxic activities.29
With the optimized conditions in hand, we continued to
investigate the reaction of (hetero)arylmethyl halides with Surprisingly, heteroaryl bromide, i.e., 2-(bromometh-
anthranilamide (Table 2). 4-Methylbenzyl bromide gave a yl)pyridine afforded 2-(2-pyridyl)quinazolin-4(3H)-one
slightly higher yield for 3b than the yield of 3a from ben- (3m) (entry 13), a compound similar to a series of bioac-
zyl bromide (entries 2 vs. 1). The effect of the 2-, 3-, and tive natural products luotonins,2 rutaecarpine,3 and drug
4-methyl-substitution on benzyl bromide produced mar- candidates.1a Interestingly, 4-(chloromethyl)pyridine also
ginal effects on their yields and 3b–d were all obtained in gave the desired 2-(4-pyridyl)quinazolin-4(3H)-one (3n),
excellent yields (entries 2–4). However, 2-fluorobenzyl whose derivative has a promising hypnotic effect,30 but
bromide gave 3f in about 10% lower yield than that the with a lower yield due to the lower reactivity of 4-(chlo-
yield of 3e from 3-fluorobenzyl bromide (entries 5 vs. 6). romethyl)pyridine (entry 14).
Moreover, the yield of 3g from a 2,6-difluoro-substituted
For 3-(trifluoromethyl)benzyl chloride, it seems that sub-
benzyl bromide sharply decreased (entries 7 vs. 6 and 5).
stitution of chloro or bromo group on benzyl position did
Interestingly, 4-(trifluoromethyl)benzyl bromide and eth-
not obviously affect the reactions (entries 15 vs. 10).
yl 4-(bromomethyl)benzoate gave 3j and 3k, respectively,
However, benzyl chloride gave a much lower yield of 3a
in slightly lower yields (entries 10 and 11) and the
than benzyl bromide due to its low reactivity (entries 16
electron-withdrawing or -donating properties of p- or m-
vs. 1).
Table 2 Reactions of Heteroaryl- or Arylmethyl Halides 2 and Anthranilamide (1a, R1 = H) (Scheme 1)a
Entry
R2CH2X 2
X
R2 in 3
Product
Yield (%)
1
benzyl bromide
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Br
Br
Ph
3a
3b
3c
3d
3e
3f
97
99
91
94
87
71
58
89
89
75
79
86
80
55
71
39
77
79
2
4-methylbenzyl bromide
2-methylbenzyl bromide
3-methylbenzyl bromide
3-fluorobenzyl bromide
2-fluorobenzyl bromide
2,6-difluorobenzyl bromide
4-nitrobenzyl bromide
3-cyanobenzyl bromide
4-(trifluoromethyl)benzyl bromide
ethyl 4-(bromomethyl)benzoate
4-methoxybenzyl bromide
2-(bromomethyl)pyridine
4-(chloromethyl)pyridine
3-(trifluoromethyl)benzyl chloride
benzyl chloride
4-MeC6H4
2-MeC6H4
3-MeC6H4
3-FC6H4
3
4
5
6
2-FC6H4
7
2,6-F2C6H3
4-O2NC6H4
3-NCC6H4
4-F3CC6H4
4-EtO2CC6H4
4-MeOC6H4
2-pyridyl
4-pyridyl
3-F3CC6H4
Ph
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
18
3j
3k
3l
3m
3n
3o
3a
3p
3q
ethyl bromoacetate
CO2H
cinnamyl bromide
CH=CHPh
a Reaction conditions: anthranilamide (1 mmol), benzyl bromide (1 mmol), K2CO3 (1.0 equiv), CuBr (0.02 equiv), DMSO, 120 °C, 24 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3349–3354

3352
H. Wei et al.
PAPER
Interestingly, ethyl bromoacetate was able to react with We propose a mechanism for copper(I) bromide catalyzed
anthranilamide to produce 4-oxo-3,4-dihydroquinazoline- cascade reaction via SN2 substitution of benzyl halides,
2-carboxylic acid (3p), another valuable compound,1 in- aerobic oxidation of N-benzyl-substituted anthranil-
stead of 2-(ethoxycarbonyl)quinazolin-4(3H)-one.
amides into N-benzylidene-substituted anthranilamides,
intramolecular addition, and aerobic oxidation of 2-aryl-
2,3-dihydroquinazolin-4(3H)-ones into 2-arylquinazolin-
4(3H)-one. The plausible mechanism is depicted in
Scheme 2.
Furthermore, cinnamyl bromide also reacted with anthra-
nilamide and produced 2-styrylquinazolin-4(3H)-one
(3q) (entry 18), whose derivatives are a class of antimitot-
ic anticancer agents that inhibit tubulin polymerization,4
and whose analogues containing pyridine structure are po- Under basic condition, SN2 nucleophilic substitution of
tent noncompetitive α-amino-3-hydroxy-5-methylisoxa- anthranilamide 1 and arylmethyl halide 2 (or ethyl bromo-
zole-4-propionic acid receptor antagonists.31 Moreover, acetate, or cinnamyl bromide) occurs and produces 2-[(ar-
2-styrylquinazolin-4(3H)-one (3q) can be further trans- ylmethyl)amino]benzamide 4, which was isolated and
formed into a number of potential medicinal com- verified by NMR and could be transformed into the de-
pounds.1a
sired product under the same conditions. Next, compound
4 is oxidized by oxygen in the air under the catalysis of
copper(I) bromide to produce N-arylmethylidene-substi-
tuted anthranilamide 5 due to its special structure. Intra-
molecular addition of the latter occurs promptly in the
presence of copper(I) bromide to afford 2,3-dihydroquin-
azolin-4(3H)-one 6. Compound 6 is oxidized under air at-
mosphere with the assistance of copper(I) bromide to
afford the desired product, 2-arylquinazolin-4(3H)-one 3.
Next we investigated the reaction of a few anthranil-
amides and arylmethyl bromides (Table 3). Reactions of
5-chloroanthranilamide and various arylmethyl bromides
all gave good yields (entries 1 to 4). 3-Aminobenzofuran-
2-carboxamide reacted with 3-methyl- and 3-fluorobenzyl
bromides to afford the desired products 3v and 3w, re-
spectively, (entries 5 and 6), which are promising candi-
dates for use as medicines. Cascade reaction of 2-
aminobenzanilide and arylmethyl bromides produced the In conclusion, copper(I) bromide catalyzed synthesis of 2-
2,3-diarylquinazolin-4(3H)-ones 3x,y in good yields (en- arylquinazolin-4(3H)-ones, a class of heterocycles with
tries 7 and 8).
extensive pharmacological effects, from heteroarylmethyl
Table 3 Reactions of Anthranilamides 1 and Arylmethyl Bromides 2 (Scheme 2)a
Entry
Substrate
Arylmethyl bromide 2
Product
Yield (%)
1
2
3
4
5
6
7
8
5-chloroanthranilamide
5-chloroanthranilamide
5-chloroanthranilamide
5-chloroanthranilamide
3-aminobenzofuran-2-carboxamide
3-aminobenzofuran-2-carboxamide
2-aminobenzanilide
benzyl bromide
3r
3s
87
79
82
75
77
82
83
89
2-fluorobenzyl bromide
4-(trifluoromethyl)benzyl bromide
4-methylbenzyl bromide
3-methylbenzyl bromide
3-fluorobenzyl bromide
benzyl bromide
3t
3u
3v
3w
3x
3y
2-aminobenzanilide
4-methylbenzyl bromide
a Reaction conditions: anthranilamide (1.0 mmol), benzyl bromide (1.0 mmol), K2CO3 (1.0 equiv), CuBr (0.02 equiv), DMSO, 120 °C, 24 h.
O
O
O
R2
R3
R2
R3
R2
K2CO3
N
CuBr, air
N
N
R3CH2X
H
H
+
H
R1
R1
N
H
N
R1
NH2
1
2
4
5
O
O
R2
R2
CuBr
N
CuBr, air
N
R3
R3
R1
R1
N
N
H
6
3
Scheme 2 A proposed mechanism
Synthesis 2013, 45, 3349–3354
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Domino Synthesis of Quinazolin-4(3H)-ones
3353
1H NMR (300 MHz, DMSO-d6): δ = 12.73 (s, 1 H), 8.31 (d, J = 8.0
Hz, 2 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.11 (s, 1 H), 7.89 (dd, J = 19.2,
8.0 Hz, 2 H), 7.82–7.72 (m, 1 H), 7.56 (t, J = 7.4 Hz, 1 H), 4.41–
4.33 (m, 2 H), 1.34 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 165.1, 162.1, 148.5, 136.8,
134.7, 132.0, 129.1 (J = 24 Hz), 128.1, 127.6, 127.0, 126.2, 125.9,
121.1, 61.1, 14.1.
or arylmethyl halides, ethyl bromoacetate, or cinnamyl
bromide and anthranilamides via a one-pot cascade reac-
tion has been developed. This process is inexpensive and
simple, and it has a wide functional group tolerance. All
bromides and partial halides examined (except 4-(chloro-
methyl)pyridine and benzyl chloride) afford good to ex-
cellent yields. A mechanism for the copper-catalyzed
synthesis of 2-arylquinazolin-4(3H)-ones via a four-step
cascade reaction containing SN2 substitution, aerobic oxi-
dation, addition, and aerobic oxidation was proposed.
Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.54; H, 4.53; N, 9.78.
6-Chloro-2-(2-fluorophenyl)quinazolin-4(3H)-one (3s)
White solid; yield 0.216 g (79%); mp 205–207 °C.
IR (KBr): 3420, 2071, 1635, 1389, 1084, 546 cm–1.
Chemicals were purchased from Aldrich, Alfa Aesar, Acros,
Aladdin, and Kelong Chemical Companies, and used without fur-
ther purification. Reactions were monitored using TLC on commer-
cial silica gel plates. Visualization of the developed plates was
performed under UV light (254 nm). Flash column chromatography
was performed on silica gel. The purity of all the synthesized com-
pounds was checked by TLC using various combinations of non-
aqueous organic solvents as eluent. Melting points were measured
on an Electrothermal digital melting point apparatus without correc-
1H NMR (300 MHz, DMSO-d6): δ = 12.78 (s, 1 H), 8.11 (s, 1 H),
7.87–7.91 (m, 1 H), 7.75–7.80 (m, 2 H), 7.60–7.65 (m, 1 H), 7.35–
7.43 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 160.5, 150.4, 147.4, 134.7,
133.1, 131.2, 131.0, 129.7 (J = 2 Hz), 124.7, 124.6, 124.5, 122.4,
116.3, 116.1.
Anal. Calcd for C14H8ClFN2O: C, 61.22; H, 2.94; N, 10.20. Found:
C, 61.50; H, 2.83; N, 10.12.
1
tions. H and 13C NMR spectra were recorded on a Bruker 300 or
400 MHz spectrometer; referenced to internal TMS standard or the
deuterated solvent CDCl3, acetone-d6, or DMSO-d6. All IR spectra
were taken on a Bruker Tensor-27 infrared spectrophotometer with
an OPUS workstation. Combustion analyses are performed on a
Euro EA-3000 elemental analyzer (Leeman Labs Inc.). Compounds
3a,16a 3b,16a 3c,32 3d,32 3e,18 3f,18 3g,33 3h,34 3j,18 3l,34 3m,35 3n,13
3o,18 3p,36 3q,37 3r,16a 3u,38 3x,23 and 3y23 have been previously de-
scribed in the literature.
6-Chloro-2-[4-(trifluoromethyl)phenyl]quinazolin-4(3H)-one
(3t)
White solid; yield 0.266 g (82%).
IR (KBr): 3412, 2084, 1675, 1638, 1469, 1393, 1324, 1184, 1121,
1085, 992, 946, 839, 550 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 12.94 (s, 1 H), 8.37 (d, J = 8.2
Hz, 2 H), 8.11 (d, J = 2.1 Hz, 1 H), 7.87–7.94 (m, 3 H), 7.80 (d,
J = 8.7 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 161.4, 151.9, 147.2, 136.5,
134.7, 131.3, 131.2, 129.8, 128.8, 125.5 (J = 4 Hz), 125.3, 124.9,
122.5.
2-Phenylquinazolin-4(3H)-one (3a) by Copper-Catalyzed Cas-
cade Reaction of Anthranilamide (1a) and Benzyl Bromide (2a);
Typical Procedure
To a 20-mL ground-in test tube equipped with a magnetic stirrer bar
were added anthranilamide (1 mmol), CuBr (0.02 mmol), K2CO3 (1
mmol), DMSO (3 mL), and BnBr (1 mmol). The test tube was put
in an oil bath preheated at 120 °C and kept stirring under air. After
24 h, the test tube was removed from the oil bath and cooled to r.t.
The reaction was quenched with H2O (2 mL) and then extracted
with EtOAc (5 × 15 mL). The combined organic layer was washed
with H2O (2 × 10 mL) and dried (anhyd Na2SO4). The filtrate was
condensed on a vacuum rotary evaporator. The residual was puri-
fied by column chromatography (silica gel, gradient petroleum
ether–EtOAc) to give 3a as a white solid; yield: 215.3 mg (97%).
Anal. Calcd for C15H8ClF3N2O: C, 55.49; H, 2.48; N, 8.63. Found:
C, 55.34; H, 2.68; N, 8.85.
2-(m-Tolyl)benzofuro[3,2-d]pyrimidin-4(3H)-one (3v)
White solid; yield 0.213 g (77%); mp 291–293 °C.
IR (KBr): 3560, 2076, 1637, 1391, 1085, 991, 546 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 13.0 (s, 1 H), 8.12 (d, J = 7.7
Hz, 1 H), 7.93–7.99 (m, 2 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.66–7.72
(m, 1 H), 7.52–7.54 (m, 1 H), 7.17–6.93 (m, 1 H), 2.42 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 156.3, 154.5, 153.4, 138.0
(J = 10 Hz), 131.9, 129.9, 129.1, 128.6 (J = 7 Hz), 128.1, 127.7,
125.4, 125.1, 124.4, 122.4, 121.4, 113.0, 20.9.
3-(4-Oxo-3,4-dihydroquinazolin-2-yl)benzonitrile (3i)
White solid; yield 0.220 g (89%); mp 273–275 °C.
IR (KBr): 3419, 2396, 1677, 1619, 1472, 1315, 879, 771 cm–1.
Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38; N, 10.14. Found: C,
73.78; H, 4.71; N, 10.26.
1H NMR (300 MHz, DMSO-d6): δ = 12.75 (s, 1 H), 8.60 (s, 1 H),
8.49 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.07 (d, J = 8.0
Hz, 1 H), 7.86 (t, J = 7.4 Hz, 1 H), 7.82–7.72 (m, 2 H), 7.56 (t,
J = 7.5 Hz, 1 H).
2-(3-Fluorophenyl)benzofuro[3,2-d]pyrimidin-4(3H)-one (3w)
White solid; yield 0.230 g (82%).
IR (KBr): 3499, 2075, 1637, 1391, 1086, 543 cm–1.
13C NMR (101 MHz, DMSO-d6): δ = 162.5, 151.3, 148.2, 136.6,
134.6, 132.5, 131.5, 129.9, 127.5 (C1′), 126.9, 125.9, 121.1, 118.3,
111.7, 108.9.
1H NMR (300 MHz, DMSO-d6): δ = 13.21 (s, 1 H), 8.14 (d, J = 7.5
Hz, 1 H), 8.11–7.94 (m, 2 H), 7.86 (t, J = 9.0 Hz, 1 H), 7.77–7.59
(m, 2 H), 7.60–7.33 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 163.3, 161.1, 160.8, 156.3,
153.2, 134.1, 130.8 (J = 8 Hz), 130.0, 124.5, 124.2 (J = 3 Hz),
122.3, 121.4, 118.2 (J = 21 Hz), 117.3, 114.8 (J = 24 Hz), 113.0.
Anal. Calcd for C15H9N3O: C, 72.87; H, 3.67; N, 16.99. Found: C,
72.62; H, 3.79; N, 16.72.
Ethyl 4-(4-Oxo-3,4-dihydroquinazolin-2-yl)benzoate (3k)
White solid; yield 0.232 g (79%); mp 279–281 °C.
Anal. Calcd for C16H9FN2O2: C, 68.57; H, 3.24; N, 10.00. Found:
C, 68.69; H, 3.48; N, 9.87.
IR (KBr): 3423, 2925, 2397, 2295, 1629 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3349–3354

3354
H. Wei et al.
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Acknowledgment
We appreciate the National Natural Science Foundation of China
(No. 21372034), the Science and Technology Bureau of Sichuan
(Grant No. 2011HH0016), the Incubation Program for Excellent In-
novation Team of Chengdu University of Technology and the Ope-
ning Fund of State Key Laboratory of Geohazard Prevention and
Geoenvironment Protection (No. SKLGP2012K005) for financial
support.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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