Copper-catalyzed consecutive reaction to construct quinazolin-4(3H)-ones and pyrido[2,3-d]pyrimidin-4(3H)-ones

Article abstract of DOI:10.1016/j.tet.2015.12.059

An efficient and practical copper-catalyzed consecutive synthesis of quinazolin-4(3H)-ones and pyrido[2,3-d]pyrimidin-4(3H)-ones from easily available 2-halobenzamides (or 2-halonicotinamides), aldehydes, and sodium azide has been developed, which gave the corresponding target products in 50-95% yields for 29 examples. This remarkable consecutive process involved sequential copper-catalyzed S_NAr, reduction, cyclization, and oxidation. Notably, this work would provide a novel synthetic strategy for bioactive molecules containing quinazolinone class skeletons.

Full text of DOI:10.1016/j.tet.2015.12.059

Accepted Manuscript
Copper-catalyzed consecutive reaction to construct quinazolin-4(3H)-ones and
pyrido[2,3-d]pyrimidin-4(3H)-ones
Ting Li, Minglu Chen, Lei Yang, Zhengxin Xiong, Yongwei Wang, Fei Li, Dongyin
Chen
PII:
S0040-4020(15)30307-0
10.1016/j.tet.2015.12.059
TET 27385
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 October 2015
Revised Date: 7 December 2015
Accepted Date: 23 December 2015
Please cite this article as: Li T, Chen M, Yang L, Xiong Z, Wang Y, Li F, Chen D, Copper-catalyzed
consecutive reaction to construct quinazolin-4(3H)-ones and pyrido[2,3-d]pyrimidin-4(3H)-ones,
Tetrahedron (2016), doi: 10.1016/j.tet.2015.12.059.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Copper-catalyzed consecutive reaction to
construct quinazolin-4(3H)-ones and
pyrido[2,3-d]pyrimidin-4(3H)-ones
Leave this area blank for abstract info.
Ting Li, Minglu Chen, Lei Yang, Zhengxin Xiong, Yongwei Wang, Fei Li* and Dongyin Chen*
Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Copper-catalyzed consecutive reaction to construct quinazolin-4(3H)-ones and
pyrido[2,3-d]pyrimidin-4(3H)-ones
Ting Li, Minglu Chen, Lei Yang, Zhengxin Xiong, Yongwei Wang, Fei Li and Dongyin Chen
Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and practical copper-catalyzed consecutive synthesis of quinazolin-4(3H)-ones and
pyrido[2,3-d]pyrimidin-4(3H)-ones from easily available 2-halobenzamides (or 2-
halonicotinamides), aldehydes, and sodium azide has been developed, which gave the
corresponding target products in 50-95% yields for 29 examples. This remarkable consecutive
process involved sequential copper-catalyzed SNAr, reduction, cyclization, and oxidation.
Notably, this work would provide a novel synthetic strategy for bioactive molecules containing
quinazolinone class skeletons.
Available online
Keywords:
Copper
Consecutive reaction
2-Halobenzamide
Sodium azide
2015 Elsevier Ltd. All rights reserved
.
Quinazolin-4(3H)-ones
1. Introduction
starting materials; (iv) the copper-catalyzed expansion reaction of
2-arylindoles with amines using molecular oxygen as an
oxidant;8 (v) the copper-catalyzed N-arylation/condensation of 2-
halobenzonitriles and amides9. Although these reactions provided
efficient protocols to synthesize various substituted
quinazolinones, their applications are limited due to certain
disadvantages including tedious multi-step procedures, difficult-
to-prepare starting materials, the use of large excess oxidants,
long reaction time, and harsh reaction conditions. Therefore, the
development of a simple, effective, mild and economic method
for the preparation of quinazolinones is still highly desirable.
Quinazolin-4(3H)-ones (1) are one of the most important
fused nitrogen-containing heterocycles,1 broadly occurring in
many natural products and pharmaceutical drugs.2 (Fig. 1)
Various quinazolinone derivatives represent a wide range of
biological activities,3 such as anticancer3a, anti-inflammatory3b,
antibacterial3c,
antitubercular3d,
antihypertensive3e
and
anticonvulsant3f. As one of these quinazolinone analogs, the
pyrido[2,3-d]pyrimidin-4(3H)-ones (2) are also used as versatile
building blocks for the direct synthesis of biologically active
molecules.4 For example, a series of compounds containing
pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds have been developed
as microsomal prostaglandin E2 synthase-1 inhibitors.4a
In view of the great value of quinazolinones and their analogs,
various methodologies for their synthesis have been developed.5-9
The current synthetic methods of this skeleton are mainly
summarized as the following five types: (i) the condensation of
2-aminobenzamide with suitable carbonyl compounds (ketones5a,
aldehydes5b, acids5c, or acid chlorides5d), aryl halides5e,
methylarenes5f, and ketoalkynes5g under metal or metal-free
conditions; (ii) the copper-catalyzed domino reactions of 2-
halobenzamides with (aryl)methanamines6a,6d
,
amides6b, and
enaminones6c; (iii) the palladium-catalyzed insertion of carbon
monoxide (CO) with o-iodoanilines7a, N-arylamidines7b, N-(o-
Fig. 1. Structures of some selected natural products and drugs containing
quinazolinone moiety.
halophenyl)imidoyl chlorides7c or 2-aminobenzonitriles7d as
———
Corresponding authors. Tel.: +86-25-86868485; e-mail: chendongyin321@163.com (D. Y. Chen); kldlf@njmu.edu.cn (F. Li).

2
Tetrahedron
Recently, Guo and co-workers have developed a novel and
widely applied. Changed the reaction temperature did not lead to
ACCEPTED MANUSCRIPT
o
efficient route toward quinazolinone derivatives through copper-
catalyzed tandem reaction of 2-bromobenzamides with aldehydes
and aqueous ammonia (Scheme 1).10 However, this strategy
inevitably suffered from tedious operation, high reaction
temperature, long reaction time, and the addition of base (Cs2CO3)
due to the use of aqueous ammonia as nitrogen source in sealed
tube. Sodium azide (NaN3), as a convenient and inexpensive
nitrogen source, has been widely applied in organic synthesis,
mainly including 1,3-dipolar cycloaddition11 and copper-
catalyzed SNAr reactions12. Based on the recent report on copper-
catalyzed multicomponent synthesis of fused N-heterocycles
utilizing sodium azide as nitrogen source,13 herein we present a
similar strategy to construct quinazolin-4(3H)-ones and
pyrido[2,3-d]pyrimidin-4(3H)-ones from simple and readily
available 2-halobenzamides (or 2-halonicotinamides) and
aldehydes (Scheme 1). In this catalytic system, an integrated
consecutive process involved copper-catalyzed SNAr, reduction,
cyclization, and oxidation sequences. Compared with the
reported methods5-10, this approach is more smoothly applied to
synthesize multifarious 2-substituted, 3-substituted and 2,3-
disubstituted quinazolinone derivertives from readily available
substrates, featuring easy operation, high efficiency, and mild
condition.
any further improvement in the yield, and 80 C gave the best
result (Table 1, compare entries 3 and 17-19). When increasing
amount of CuBr and sodium azide, and adding a base such as
K2CO3, the reactions did not give higher yields (Table 1, compare
entries 3 and 20-22). Finally, the optimized reaction condition
was determined that 3a (2.0 mmol), 4a (1.1 equiv) and sodium
azide (2.0 equiv) were smoothly converted into 2-
phenylquinazolin-4(3H)-one (5a) in 75% yield with CuBr (0.1
equiv) as the catalyst, L-proline (0.2 equiv) as the ligand, and
DMSO as the solvent under an air atmosphere at 80 oC over 12 h
(Table 1, entry 3).
Table 1
Investigation of conditions for copper-catalyzed synthesis of 5a using 3a and
4a as the substratesa
T
Yield
(%)b
52
64
75
57
59
50
66
50
48
49
44
52
66
60
38
Entry
Catalyst
Ligand Solvent
(oC)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
100
80
80
80
1
2
3
4
5
6
7
8
CuI
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-2
L-3
L-4
-
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CuCl
CuBr
Cu2O
CuBr2
Cu(OAc)2
CuCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
1,4-dioxane
H2O
DCE
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
trace
55
71
70
73
Scheme 1. Copper-catalyzed multicomponent synthesis of quinazolinone
derivatives.
64
68
2. Results and discussion
a Reactions conditions: 3a (2.0 mmol), 4a (2.2 mmol), NaN3 (4.0
mmol), catalyst (0.2 mmol), ligand (0.4 mmol), solvent (3 mL),
under air for 12 h.
To optimize the reaction conditions, an initial experiment was
carried out using 2-iodobenzamide (3a), benzaldehyde (4a), and
sodium azide as model substrates. Various reaction parameters
were evaluated systematically, including catalysts, ligands,
solvents, and temperatures; all cases are shown in Table 1. First,
a series of copper catalysts were examined for this consecutive
reaction with 0.2 equiv of L-proline (relative to amount of 3a) as
b Isolated yield.
c Extra NaN3 (2.0 mmol) was added.
d Extra NaN3 (2.0 mmol) and K2CO3 (2.0 mmol) was added.
e Extra NaN3 (2.0 mmol) and CuBr (0.2 mmol) were added.
Under the optimized conditions, we first investigated CuBr-
catalyzed consecutive synthesis of quinazolinones 5 with 2-
halobenzamides 3 and aldehydes 4 as substrates. As shown in
Table 2, a variety of aromatic aldehydes bearing different
substituents reacted with 2-iodobenzamide (3a) to give the
corresponding products 5a−5j in moderate to good yields
(50%−95%). It was found that electron-neutral and electron-
donating groups on the aromatic ring of aldehydes 4 did not
impact the yields of the desired products. Much to our
satisfaction, reactions with aromatic aldehydes containing 2-
phenolic hydroxyl and 3,5-dihalo groups proceeded smoothly to
afford the corresponding products, which provided the possibility
for further functionalization. Notably, the optimized conditions
were also suitable enough for the transformation of sterically
o
the ligand and DMSO as the solvent at 80 C (Table 1, entries 1-
7), and CuBr showed the highest efficiency (Table 1, entry 3).
Then, other three ligands such as 1,10-phenanthroline, picolinic
acid and pentane-2,4-dione, were tested using 0.1 equiv CuBr
(relative to amount of 3a) as the catalyst in DMSO, and they
provided lower yields (Table 1, entries 8-10). In the absence of
ligand, the product was obtained in 44% yield (Table 1, entry
11), and the result showed significant effect of a suitable ligand
to the reaction system. Next, solvent effects on this consecutive
transformation in the presence of CuBr and L-proline at 80 °C
were investigated, and DMSO was found to be the optimal
solvent (Table 1, compare entries 3 and 12-16). It should be
noted that this transformation afforded desired product in a
moderate yield when using H2O as solvent (Table 1, entry 14),
suggesting that it had the potential of green chemistry to be
hindered
hydroxybenzaldehyde,
substrates
such
as
3,5-di-tert-butyl-2-
and 2,6-
2-methylbenzaldehyde

3
dimethylbenzaldehyde.
consecutive reactions had been successfully applied to synthesis
of 2-heteroaryl quinazolinones 5k-5m in 71%−79% yields, when
Meanwhile,
the
CuBr-catalyzed
neutral (4-H, 4-Et), electron-donating (4-OEt), and
ACCEPTED MANUSCRIPT
electron-withdrawing (4-NO2) groups of N-phenyl groups
showed no significant difference on the yields of
thiophene-2-carbaldehyde,
furan-2-carbaldehyde,
corresponding products 5u−5x (62%−72%). To our delight,
picolinaldehyde were employed as substrates respectively.
Furthermore, 2-iodobenzamide 3a showed higher reactivity to
provide the desirable product 5a in 75% yield, than the
corresponding 2-bromobenzamide (give 5a in 72% yield) and 2-
chlorobenzamide (give 5a in 33% yield). Beyond that, the
reactions showed good tolerance of alkylaldehydes including
formaldehyde and n-butylaldehyde, and provided quinazolin-
4(3H)-one (5n) in 71% yield and 2-propylquinazolin-4(3H)-one
(5o) in 65 % yield. Obviously, this is a quite general
methodology for the preparation of 2-alkyl, 2-aryl, and 2-
heteroaryl quinazolin-4(3H)-ones.
the reaction for synthesis of 5y containing N-(3-
bromo)phenyl group proceeded smoothly in a good yield
(92%), which allowed further modifications on the bromo
group by coupling reactions. However, when using N-(2,6-
dimethylphenyl)-2-iodobenzamide as substrate under the
optimized condition, the 2-azidobenzamide intermediate was
afforded as a main product (it’s structure was confirmed by
1H NMR and MS; see supporting information) and could not
be converted into the desired product, possibly due to the
large steric hindrance. Based on the above findings, except
for the steric effects, this approach showed high functional
group tolerance and proved to be
methodology for the preparation of multifarious 2-
substituted, 3-substituted and 2,3-disubstituted
quinazolinone derivertives.
a quite general
Table 2
Scope of 2-halobenzamides and aldehydesa
Besides that, we investigated the utility of this protocol for
preparation of some pyrido[2,3-d]pyrimidin-4(3H)-one class
compounds, which are structurally similar with quinazolin-
4(3H)-ones. (Table 3) By this protocol, the pyrido[2,3-
d]pyrimidin-4(3H)-ones 7a-7d were prepared successfully in
62−87% yield with 2-bromonicotinamides 6 and benzaldehyde
(4a) as starting materials. Therefore, the results gave us great
confidence to apply this method for the construction of some
novel quinazolinone analogues.
Table 3
Scope of 2-halonicotinamidesa
a
Reaction conditions: 2-bromonicotinamide (2.0 mmol),
benzaldehyde (2.2 mmol), NaN3 (4.0 mmol), CuBr (0.2 mmol),
and L-proline (0.4 mmol) in DMSO (3 mL) at 80 oC under air for
12 h.
In order to explore the reaction mechanism, some control
experiments were performed. Initially, 2-iodobenzamide
(
3a) reacted with sodium azide (2 equiv) in DMSO at 50 °C
for 4 h, giving 2-azidobenzamide in 83% yield (Scheme
2a). The structure of was confirmed by H NMR and MS.
Next,
was heated at 80 oC for 2 h in DMSO in the presence
of CuBr and L-proline (Scheme 2b), and we fortunately
observed the mass for 2-aminobenzamide m/z = 159.1,
[M + Na]+). Another experiment of
and benzaldehyde (4a
8
1
8
8
9
(
8
)
proceeded smoothly under standard conditions, and the
target product 5a was obtained in 84% yield (Scheme 2c).
Moreover, the MS spectrum after 1 h reaction time showed
a
Reaction conditions: 2-halobenzamide (2.0 mmol), aldehyde (2.2
mmol), NaN3 (4.0 mmol), CuBr (0.2 mmol), and L-proline (0.4
mmol) in DMSO (3 mL) at 80 oC under air for 5−12 h.
mass for Schi
intermediate VI
ff
’s base
V or possibly its cyclized
(
m/z = 247.1, [M + Na]+).
According to the above results and reported literature13-15, we
proposed a possible reaction mechanism for the copper-catalyzed
consecutive process. As shown in Scheme 3, copper-catalyzed
SNAr product 2-azidobenzamide I is first prepared from sodium
azide and 2-halobenzamide 3 despite the ortho-substituent
effect.14 Then, with the aid of L-proline and trace H2O in DMSO,
Next, the
iodobenzamides
mention that N-alkyl groups (methyl, ethyl and cyclohexyl)
and N-aryl groups (phenyl and substituted phenyl) were all
well-tolerated in this reaction, affording a series of 3-
e
ff
3
ects of the N-substituents of 2-
were explored. It is noteworthy to
substituented and 2,3-disubstituented quinazolinones 5p
in moderate to good yields (58%−92%). Further, electron-
−5y
the copper-mediated denitrogenation of
I
affords 2-

4
Tetrahedron
aminobenzamide IV via Cu(I) complex II and Cu(III) complex
point apparatus and were uncorrected. Reactions were
ACCEPTED MANUSCRIPT
III in turn,15 meanwhile releasing nitrogen. Next, IV could
easily condense with benzaldehyde 4, leading to the formation of
Schiff’s base V. Subsequently, intramolecular nucleophilic attack
of nitrogen in amide to carbon in imine in V gives intermediate
VI. Finally, VI undergoes oxidative dehydrogenation to produce
the target product 5.
monitored by TLC on silica gel 60 F254 plates (Qingdao
Ocean Chemical Company, China). Column
chromatography was carried out on silica gel (200−300
mesh, Qingdao Ocean Chemical Company, China).
4.2
．General procedure for preparation of quinazolin-
4(3H)-ones (5) and pyrido[2,3-d]pyrimidin-4(3H)-ones
(7)
To
a
solution of 2-iodobenzamide
(
3
)
or 2-
bromonicotinamide (
6
) (2.0 mmol) in DMSO (3 mL), was
added aldehyde (2.2 mmol), NaN3 (260 mg, 4.0 mmol),
CuBr (29 mg, 0.2 mmol), and L-proline (46 mg, 0.4 mmol).
The reaction mixture was stirred at 80 °C under air. After
disappearance of the reactant (monitored by TLC), water (30
mL) was added to the mixture, and then extracted with ethyl
acetate (15 mL) for three times. The extraction was washed
with saturated NaCl solution, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using
petroleum ether/ethyl acetate (10:1 to 3:1) as the eluent to
Scheme 2. Control experiments.
give the desired products
5 or 7.
4.2.1. 2-Phenylquinazolin-4(3H)-one (5a).6a White solid;
o
333 mg (75% yield); m.p. 228−229 C. 1H NMR (300 MHz,
DMSO-d6)
δ 10.78 (br s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.17-
8.19 (m, 2H), 7.79-7.89 (m, 2H), 7.59-7.61 (m, 3H), 7.49-
7.58 (m, 1H). ESI-MS m/z 221.1 [M - H]-.
5a
4.2.2. 2-(2-Hydroxyphenyl)quinazolin-4(3H)-one
(5b).
o
Light yellow solid, 386 mg (81% yield); m.p. 250-252 C.
1H NMR (300 MHz, DMSO-d6)
13.35 (br s, 1H), 12.40 (br
s, 1H), 8.23 (d, = 7.9 Hz, 1H), 8.01 (d, = 7.9 Hz, 1H),
7.83-7.88 (m, 1H), 7.76 (d, = 8.0 Hz, 1H), 7.54 (t, = 7.6
δ
J
J
J
J
Hz, 1H), 7.42-7.48 (m, 1H), 6.93-7.02 (m, 2H). ESI-MS m/z
237.1 [M - H]-.
4.2.3. 2-(2-Methoxyphenyl)quinazolin-4(3H)-one
Light brown solid, 414 mg (82% yield); m.p. 183-185 oC. 1H
NMR (300 MHz, DMSO-d6) 12.08 (br s, 1H), 8.15 (d,
7.7 Hz, 1H), 7.83 (t, = 7.0 Hz, 1H), 7.68-7.71 (m, 2H),
7.50-7.55 (m, 2H), 7.19 (d, = 8.3 Hz, 1H), 7.09 (t, = 7.4
Hz, 1H), 3.86 (s, 3H). ESI-MS m/z 275.1 [M + Na]+.
4.2.4. 2-(2-Hydroxy-3-methoxyphenyl)quinazolin-4(3H)-one
5d).17 Light yellow solid, 434 mg (81% yield); m.p. 283-
(
5c).16
δ
J =
J
J
J
Scheme 3. A possible mechanism.
(
o
1
284 C. H NMR (300 MHz, DMSO-d6)
12.44 (br s, 1H), 8.16 (d, = 7.8 Hz, 1H), 7.74-7.89 (m,
3H), 7.55 (t, = 7.6 Hz, 1H), 7.16 (d, = 7.9 Hz, 1H), 6.89
(t, = 8.2 Hz, 1H), 3.83 (s, 3H). ESI-MS m/z 291.1 [M +
Na]+.
δ 13.90 (br s, 1H),
3. Conclusion
J
J
J
In summary, we have developed a highly efficient and
practical copper-catalyzed reaction for the synthesis of
quinazolin-4(3H)-ones and pyrido[2,3-d]pyrimidin-4(3H)-ones,
starting from simple and readily available 2-halobenzamides (or
2-halonicotinamides), aldehydes, and sodium azide. The
reactions underwent a consecutive process, involved copper-
catalyzed SNAr, reduction, cyclization, and oxidation sequences.
It is worth mentioning that this protocol could provide diverse 2-
substituted, 3-substituted and 2,3-disubstituted quinazolinone
derivatives. Further utilizations of this protocol are underway to
construct more complex molecules in our laboratory.
J
4.2.5. 2-(2-Hydroxy-4-methoxyphenyl)quinazolin-4(3H)-one
(
5e
)
.17 Light yellow solid, 451 mg (84% yield); m.p. 283-284
1
oC. H NMR (300 MHz, DMSO-d6)
δ
13.40 (br s, 1H),
= 7.8 Hz, 1H), 7.86 (t, = 7.2
Hz, 1H), 7.74-7.77 (m, 2H), 7.52-7.57 (m, 1H), 6.96-7.09
12.59 (br s, 1H), 8.16 (d,
J
J
(m, 1H), 6.94 (d,
J = 8.9 Hz, 1H), 3.80 (s, 3H). ESI-MS m/z
269.1 [M + H]+.
4.2.6. 2-(3,5-Dichloro-2-hydroxyphenyl)quinazolin-4(3H)-
18
one (5f). Light yellow solid, 454 mg (74% yield); m.p. >
o
1
290 C. H NMR (300 MHz, DMSO-d6)
7.49-7.59 (m, 3H), 7.33 (d, = 7.9 Hz, 1H), 7.23 (t,
Hz, 1H). ESI-MS m/z 305.0 [M - H]-.
δ
7.72 (s, 1H),
4. Experimental section
J
J
= 7.5
4.1. General information
4.2.7. 2-(3,5-Dibromo-2-hydroxyphenyl)quinazolin-4(3H)-
one (5g).19 Light yellow solid, 436 mg (55% yield); m.p. >
All commercial materials and solvents were used directly
o
1
without further purification. H and 13C NMR spectra were
1
290 C. H NMR (300 MHz, DMSO-d6)
δ
15.55 (br s, 1H),
= 7.7 Hz, 1H), 7.99
J = 7.3 Hz, 1H). ESI-MS
12.87 (br s, 1H), 8.57 (s, 1H), 8.17 (d,
J
measured on a 300 MHz spectrometer using DMSO-d6 as
the solvent with tetramethylsilane (TMS) as the internal
standard. Mass spectra (MS) were recorded in electron
impact mode. Melting points were determined on a melting
(s, 1H), 7.84-7.92 (m, 2H), 7.59 (t,
m/z 394.9 [M - H]-.
4.2.8.
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)quinazolin-
4(3H)-one (5h).20 White solid, 666 mg (95% yield); m.p. >

5
o
1
290 C. H NMR (300 MHz, DMSO-d6)
δ
14.88 (br s, 1H),
Hz, 1H), 2.50-2.60 (m, 2H), 1.72-1.74 (m, 4H), 1.47-1.52
ACCEPTED MANUSCRIPT
12.78 (br s, 1H), 8.16 (d,
J
= 7.8 Hz, 1H), 8.04 (s, 1H), 7.76-
(d, J = 12.8 Hz, 1H), 1.02-1.19 (m, 1H), 0.77-0.90 (m, 2H).
7.87 (m, 2H), 7.53 (t,
J
= 7.3 Hz, 1H), 7.43 (s, 1H), 1.43 (s,
ESI-MS m/z 305.2 [M + H]+.
4.2.21. 2,3-Diphenylquinazolin-4(3H)-one
9H), 1.33 (s, 9H). ESI-MS m/z 351.2 [M + H]+.
(
5u).5f Light
o 1
4.2.9. 2-(o-Tolyl)quinazolin-4(3H)-one (5i).8 Light yellow
yellow solid, 370 mg (62% yield); m.p. 143-144 C. H
o
1
solid, 293 mg (62% yield); m.p. 223-224 C. H NMR (300
MHz, DMSO-d6) 12.41 (s, 1H), 8.15 (d, = 7.9 Hz, 1H),
7.82 (t, = 7.6 Hz, 1H), 7.67 (d, = 7.9 Hz, 1H), 7.48-7.55
NMR (300 MHz, DMSO-d6)
7.88-7.93 (m, 1H), 7.77 (d,
δ
8.20 (d,
J = 7.7 Hz, 1H),
J = 7.9 Hz, 1H), 7.58-7.63 (m,
1H), 7.36-7.39 (m, 2H), 7.28-7.32 (m, 4H), 7.21-7.24 (m,
δ
J
J
J
(m, 2H), 7.40-7.45 (m, 1H), 7.29-7.35 (m, 2H), 2.37 (s, 3H).
4H). ESI-MS m/z 299.1 [M + H]+.
ESI-MS m/z 259.1 [M + Na]+.
4.2.22.
(
3-(4-Ethylphenyl)-2-phenylquinazolin-4(3H)-one
5v). White solid, 457 mg (70% yield); m.p. 154-156 C. H
o 1
4.2.10. 2-(2,6-Dimethylphenyl)quinazolin-4(3H)-one (5j).21 Light
o
1
NMR (300 MHz, DMSO-d6)
δ 8.17-8.21 (m, 1H), 7.87-7.92
yellow solid, 250 mg (50% yield); m.p. 119-120 C. H NMR
(300 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H),
7.83 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.5
Hz, 1H), 7.24-7.33 (m, 1H), 7.15 (d, J = 7.6 Hz, 2H), 2.15 (s,
6H). ESI-MS m/z 273.1 [M + Na]+.
(m, 1H), 7.75 (d,
7.39 (m,
2.56 (t,
(75 MHz, DMSO-d6)
J
= 7.8 Hz, 1H), 7.57-7.62 (m, 1H), 7.35-
H), 7.19-7.26 (m, 5H), 7.13 (d, = 8.3 Hz, 2H),
= 7.6 Hz, 2H), 1.12 (t,
= 7.6 Hz, 3H). 13H NMR
161.4, 156.6, 155.3, 147.2, 143.6,
2
J
J
J
δ
135.7, 135.4, 134.7, 129.2, 128.8, 127.8, 127.4, 127.3, 127.1,
126.4, 27.6, 15.3. ESI-MS m/z 327.1 [M + H]+. HRMS calcd
for C22H18N2ONa [M + Na]+ 349.1317, found 349.1323.
4.2.11.
2-(Thiophen-2-yl)quinazolin-4(3H)-one
(
5k).6a
o
1
Yellow solid, 338 mg (74% yield); m.p. 137-139 C. H
NMR (300 MHz, DMSO-d6)
δ
12.64 (s, 1H), 8.23 (d,
J = 3.7
= 4.9 Hz, 1H),
4.2.23. 3-(4-Ethoxyphenyl)-2-phenylquinazolin-4(3H)-one
Hz, 1H), 8.12 (d, = 7.8 Hz, 1H), 7.86 (d,
J
J
o
(
5w).27 White solid, 493 mg (72% yield); m.p. 147-149 C.
7.78-7.83 (m, 1H), 7.65 (d,
J = 8.2 Hz, 1H), 7.46-7.51 (m,
1H NMR (300 MHz, DMSO-d6)
7.86-7.92 (m, 1H), 7.75 (d, = 7.8 Hz, 1H), 7.59 (t,
Hz, 1H), 7.36-7.39 (m, 2H), 7.18-7.26 (m, 5H), 7.54 (d,
δ
8.18 (d,
J
= 7.9 Hz, 1H),
= 7.1
1H), 7.22-7.25 (m, 1H). ESI-MS m/z 251.1 [M + Na]+.
J
J
4.2.12. 2-(Furan-2-yl)quinazolin-4(3H)-one (5l).6a Brown
J
=
o
1
solid, 335 mg (79% yield); m.p. 209-211 C. H NMR (300
MHz, DMSO-d6) 12.48 (s, 1H), 8.12 (d, = 7.9 Hz, 1H),
8.00 (s, 1H), 7.81 (t, = 7.5 Hz, 1H), 7.69 (d, = 8.0 Hz,
1H), 7.63 (d, = 3.3 Hz, 1H), 7.49 (t, = 1.5 Hz, 1H), 6.75
(s, 1H). ESI-MS m/z 235.1 [M + Na]+.
4.2.13. 2-(Pyridin-2-yl)quinazolin-4(3H)-one (5m).22 Brown
8.9 Hz, 2H), 3.92-3.99 (m, 2H), 1.26-1.29 (m, 3H). ESI-MS
m/z 365.1 [M + Na]+.
δ
J
J
J
4.2.24.
5x).27 Yellow solid, 460 mg (67% yield); m.p. 163-165 C.
1H NMR (300 MHz, DMSO-d6)
8.20 (d, = 7.7 Hz, 1H),
7.89-7.94 (m, 1H), 7.77 (d, = 8.1 Hz, 1H), 7.70 (s, 1H),
3-(4-Nitrophenyl)-2-phenylquinazolin-4(3H)-one
J
J
o
(
δ
J
J
o
1
solid, 317 mg (71% yield); m.p. 144-146 C. H NMR (300
MHz, DMSO-d6) 11.80 (s, 1H), 8.77 (d, = 4.3 Hz, 1H),
8.47 (d, = 7.9 Hz, 1H), 8.19 (d, = 7.9 Hz, 1H), 8.06-8.11
7.61 (t,
J = 7.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.34-7.41
(m, 2H), 7.23-7.28 (m, 5H). ESI-MS m/z 366.1 [M + Na]+.
δ
J
J
J
4.2.25. 3-(3-Bromophenyl)-2-phenylquinazolin-4(3H)-one
(m, 1H), 7.80-7.91 (m, 2H), 7.65-7.69 (m, 1H), 7.55-7.60
o
(m, 1H). ESI-MS m/z 246.1 [M + Na]+.
(
5y). Yellow solid, 694 mg (92% yield); m.p. 189-191 C.
1H NMR (300 MHz, DMSO-d6)
7.95 (m, 1H), 7.79 (d, = 8.0 Hz, 1H), 7.66-7.70 (m, 2H),
7.61-7.63 (m, 1H), 7.40 (d, = 7.0 Hz, 2H), 7.25-7.28 (m,
3H). 13H NMR (75 MHz, DMSO-d6)
161.1, 154.1, 147.1,
δ 8.16-8.23 (m, 3H), 7.91-
4.2.14. Quinazolin-4(3H)-one (5n).23 White solid, 208 mg
J
(71% yield); m.p. 205-207 oC. 1H NMR (300 MHz, DMSO-
J
d6)
δ 12.21 (br s, 1H), 8.09-8.14 (m, 2H), 7.79-7.84 (m, 1H),
δ
7.66 (d,
J = 8.1 Hz, 1H), 7.49-7.54 (m, 1H). ESI-MS m/z
146.7, 143.8, 135.1, 135.0, 131.2, 129.2, 128.9, 127.7, 127.5,
127.3, 126.4, 123.7, 120.6. ESI-MS m/z 400.1 [M + Na]+.
HRMS calcd for C20H13BrN2ONa [M + Na]+ 399.1317,
found 399.1321.
147.0 [M + H]+.
4.2.15. 2-Propylquinazolin-4(3H)-one (5o).23 White solid,
o
1
245 mg (65% yield); m.p. 189-190 C. H NMR (300 MHz,
DMSO-d6) 12.14 (br s, 1H), 8.08 (d, = 7.4 Hz, 1H), 7.74-
7.79 (m, 1H), 7.59 (d, = 8.1 Hz, 1H), 7.42 (t, = 7.7 Hz,
4.2.26. 2-Phenylpyrido[2,3-d]pyrimidin-4(3H)-one (7a).28
δ
J
White solid, 321 mg (72% yield); m.p. 178-180 oC. 1H NMR
J
J
1H), 2.50-2.60 (m, 2H), 1.68-181 (m, 2H), 0.85-0.96 (m,
(300 MHz, DMSO-d6)
δ
11.81 (s, 1H), 8.77 (d,
J = 4.3 Hz,
= 8.0 Hz, 1H), 8.09
J = 8.0 Hz, 1H), 7.80-7.91 (m, 2H), 7.65-7.69 (m, 1H),
3H). ESI-MS m/z 189.1 [M + H]+.
1H), 8.47 (d, = 3.9 Hz, 1H), 8.20 (d,
J
J
4.2.16. 3-Methylquinazolin-4(3H)-one (5p).24 White solid,
(t,
o
1
7.56-7.61 (m, 1H). ESI-MS m/z 246.1 [M + Na]+.
218 mg (68% yield); m.p. 58-60 C. H NMR (300 MHz,
DMSO-d6) 8.37 (s, 1H), 8.16 (d, = 7.9 Hz, 1H), 7.79-
δ
J
4.2.27. 3-Methyl-2-phenylpyrido[2,3-d]pyrimidin-4(3H)-one
7.84 (m, 1H), 7.67 (d,
J = 8.1 Hz, 1H), 7.51-7.56 (m, 1H),
(
7b).29 Light yellow solid, 294 mg (62% yield); m.p. 193-
o 1
3.50 (s, 3H). ESI-MS m/z 161.1 [M + H]+.
195 C. H NMR (300 MHz, DMSO-d6)
1H), 8.55-8.59 (m, 1H), 7.69-7.72 (m, 2H), 7.56-7.60 (m,
4H), 3.37 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
162.2,
δ 8.97-8.99 (m,
4.2.17. 3-Phenylquinazolin-4(3H)-one (5q).24 White solid, 324
o
1
mg (73% yield); m.p. 128-130 C. H NMR (300 MHz, DMSO-
d6) δ 8.34 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 8.0 Hz,
1H), 7.35 (d, J = 8.1 Hz, 1H), 7.49-7.63 (m, 6H). ESI-MS m/z
223.1 [M + H]+.
δ
159.1, 156.9, 156.0, 135.8, 135.0, 130.0, 128.4, 128.2, 122.5,
115.2, 34.1. ESI-MS m/z 260.1 [M + Na]+.
4.2.28. 3-Benzyl-2-phenylpyrido[2,3-d]pyrimidin-4(3H)-one
4.2.18.
White solid, 383 mg (81% yield); m.p. 112-114 oC. 1H NMR
(300 MHz, DMSO-d6) 8.18 (d, = 8.0 Hz, 1H), 7.82-7.87
3-Methyl-2-phenylquinazolin-4(3H)-one
(
5r).5f
o
(
7c).30 White solid, 545 mg (87% yield); m.p. 110-111 C.
1H NMR (300 MHz, DMSO-d6)
(d, = 7.9 Hz, 1H), 7.60-7.64 (m, 1H), 7.42-7.52 (m, 5H),
7.21-7.23 (m, 3H), 6.96 (d,
= 7.1 Hz, 2H), 5.19 (s, 2H). 13
NMR (75 MHz, DMSO-d6) 162.1, 159.3, 156.8, 156.3,
δ 9.01-9.03 (m, 1H), 8.60
δ
J
J
(t,
J = 7.3 Hz, 1H), 7.67-7.69 (m, 3H), 7.56-7.59 (m, 4H),
J
C
3.36 (s, 3H). ESI-MS m/z 237.1 [M + H]+.
δ
4.2.19. 3-Ethyl-2-phenylquinazolin-4(3H)-one (5s).25 White
156.1, 136.4, 136.2, 134.8, 130.0, 128.7, 128.4, 128.3, 128.1,
127.9, 127.2, 126.3, 122.9, 48.6. ESI-MS m/z 336.1 [M +
Na]+.
4.2.29. 3-(4-Chlorophenyl)-2-phenylpyrido[2,3-d]pyrimidin-
4(3H)-one (7d). White solid, 427 mg (64% yield); m.p. 217-
9.03 (s, 1H), 8.58
= 7.8 Hz, 1H), 7.60-7.65 (m, 1H), 7.38-7.42 (m, 6H),
7.28-7.30 (m, 3H). 13C NMR (75 MHz, DMSO-d6)
161.9,
157.9, 157.1, 156.2, 136.5, 136.1, 135.1, 132.9, 131.3, 129.3,
o
1
solid, 415 mg (83% yield); m.p. 122-124 C. H NMR (300
MHz, DMSO-d6) 8.20 (d, = 7.9 Hz, 1H), 7.82-7.87 (m,
1H), 7.63-7.67 (m, 3H), 7.54-7.62 (m, 4H), 3.86-3.93 (m,
δ
J
2H), 1.09 (t, J
= 7.0 Hz, 3H). ESI-MS m/z 251.1 [M + H]+.
218 oC. 1H NMR (300 MHz, DMSO-d6)
δ
4.2.20. 3-Cyclohexyl-2-phenylquinazolin-4(3H)-one (5t).26
o
(d,
J
Light yellow solid, 353 mg (58% yield); m.p. 113-115 C.
1H NMR (300 MHz, DMSO-d6)
δ
8.16 (d,
J
= 7.9 Hz, 1H),
= 11.8
δ
7.82 (t,
J
= 7.7 Hz, 1H), 7.51-7.64 (m, 7H), 3.74 (t, J

6
Tetrahedron
ACCEPTED MANUSCRIPT
256-262. (d) Lu, W.; Baig, I. A.; Sun, H. J.; Cui, C. J.; Guo, R.; Jung,
128.8, 128.6, 127.6, 122.8, 116.0. ESI-MS m/z 356.0 [M +
Na]+. HRMS calcd for C19H12ClN3ONa [M + Na]+ 356.1319,
found 349.1323.
I. P.; Wang, D.; Dong, M.; Yoon, M. Y.; Wang, J. G. Eur. J. Med.
Chem. 2015, 94, 298-305. (e) Abou-Seri, S. M.; Abouzid, K.; Abou
El Ella, D. A. Eur. J. Med. Chem. 2011, 46, 647-658. (f) Wolfe, J. F.;
Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D. J.
Med. Chem. 1990, 33, 161-166.
4.3
．Experimental procedure for control experiments
To a solution of 2-iodobenzamide (3a) (2.0 mmol) in DMSO
(3 mL), was added NaN3 (260 mg, 4.0 mmol) and CuBr (29 mg,
0.2 mmol). The reaction mixture was stirred at 50 °C under air
for 4 h. Water (30 mL) was added to the mixture, and then
extracted with ethyl acetate (15 mL) for three times. The
extraction was washed with saturated NaCl solution, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
using petroleum ether/ethyl acetate (8:1) as the eluent to give 8 as
a light brown solid (269 mg, 83% yield).
4. (a) Banerjee, A.; Pawar, M. Y.; Patil, S.; Yadav, P. S.; Kadam, P. A.;
Kattige, V. G.; Deshpande, D. S.; Pednekar, P. V.; Pisat, M. K.;
Gharat, L. A. Bioorg. Med. Chem. Lett. 2014, 24, 4838-4844. (b)
Farghaly, T. A.; Hassaneen, H. M. Arch. Pharm. Res. 2013, 36, 564-
572; (c) Deau, E.; Hédou, D.; Chosson, E.; Levacher, V.; Besson, T.
Tetrahedron Lett. 2013, 54, 3518-3521.
5. (a) Mohammed, S.; Vishwakarma, R. A.; Bharate, S. B. J. Org.
Chem. 2015, 80, 6915-6921. (b) Connolly, D. J.; Cusack, D.;
O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153-10202.
(c) Purandare, A. V.; Gao, A.; Wan, H.; Somerville, J.; Burke, C.;
Seachord, C.; Vaccaro, W.; Wityak, J.; Poss, M. A. Bioorg. Med.
Chem. Lett. 2005, 15, 2669-2672. (d) Potewar, T. M.; Nadaf, R. N.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Synth. Commun. 2005, 35,
231-241. (e) Jiang, X.; Tang, T.; Wang, J. M.; Chen, Z.; Zhu, Y. M.;
Ji, S. J. J. Org. Chem. 2014, 79, 5082-5087. (f) Zhao, D.; Wang, T.;
Li, J. X. Chem. Commun. 2014, 50, 6471-6474. (g) Yang, X.; Cheng,
G.; Shen, J.; Kuai, C.; Cui, X. Org. Chem. Front. 2015, 2, 366-368.
6. (a) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13,
1274-1277. (b) Xu, L.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 1150-
1153. (c) Songsichan, T.; Promsuk, J.; Rukachaisirikul, V.;
Kaeobamrung, J. Org. Biomol. Chem. 2014, 12, 4571-4575. (d)
Wang, L. X.; Xiang, J. F.; Tang, Y. L. Eur. J. Org. Chem. 2014,
2682-2685.
7. (a) Zheng, Z. Y.; Alper, H. Org. Lett. 2008, 10, 829-832. (b) Ma, B.;
Wang, Y.; Peng, J.; Zhu, Q. J. Org. Chem. 2011, 76, 6362-6366. (c)
Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. J. Org. Chem.
2012, 77, 9473-9486. (d) Li, H. Q.; He, L.; Neumann, H.; Beller, M.;
Wu, X. F. Green Chem. 2014, 16, 1336-1343.
8. Feng, Y. D.; Li, Y. D.; Cheng, G. L.; Wang, L. H.; Cui, X. L. J. Org.
Chem. 2015, 80, 7099-7107.
9. Chai, H. X.; Li, J. R.; Yang, L. P.; Lu, H. Y.; Qi, Z.; Shi, D. X. RSC
Adv. 2014, 4, 44811-44814.
To a solution of 8 (162 mg, 1.0 mmol) in DMSO (3 mL), was
added L-proline (23 mg, 0.2 mmol) and CuBr (15 mg, 0.1 mmol).
The reaction mixture was stirred at 80 °C under air for 2 h to give
2-aminobenzamide 9 (m/z = 159.1, [M + Na]+).
To a solution of 8 (162 mg, 1.0 mmol) in DMSO (3 mL), was
added benzaldehyde (4a) (117 mg, 1.1 mmol), L-proline (23 mg,
0.2 mmol) and CuBr (15 mg, 0.1 mmol). The reaction mixture
was stirred at 80 °C under air. After disappearance of the reactant
(monitored by TLC), water (30 mL) was added to the mixture,
and then extracted with ethyl acetate (15 mL) for three times. The
extraction was washed with saturated NaCl solution, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
using petroleum ether/ethyl acetate (10:1) as the eluent to give 5a
as a white solid (186 mg, 84% yield).
4.3.1. 2-Azidobenzamide (8).31 1H NMR (300 MHz, DMSO-d6) δ
7.75 (s, 1H), 7.54-7.59 (m, 2H), 7.49-7.52 (m, 1H), 7.32-7.35 (m,
1H), 7.21-7.26 (m, 1H). ESI-MS m/z 163.1 [M + H]+.
10. Guo, S. H.; Li, Y.; Tao, L.; Zhang, W. W.; Fan, X. S. RSC Adv. 2014,
4, 59289-59296.
11. For selected papers, see: (a) Zhang, Y.; Li, X.; Li, J.; Chen, J.; Meng,
X.; Zhao, M.; Chen, B. Org. Lett. 2012, 14, 26-29. (b) Quan, X. J.;
Ren, Z. H.; Wang, Y. Y.; Guan, H. Z. Org. Lett. 2014, 16, 5728-5731.
(c) Li, J.; Wang, D.; Zhang, Y.; Li, J.; Chen, B. Org. Lett. 2009, 11,
3024-3027. (d) Gawande, S. D.; Raihan, M. J.; Zanwar, M. R.;
Kavala, V.; Janreddy, D.; Kuo, C. W.; Chen, L. M.; Kuo, T. S.; Yao,
C. F. Tetrahedron 2013, 69, 1841-1848. (e) Kumar, S.; Dubey, S.;
Saxena, N.; Awasthi, S. K. Tetrahedron Lett. 2014, 55, 6034-6038. (f)
Mani, P.; Singh, A. K.; Awasthi, S. K. Tetrahedron Lett. 2014, 55,
1879-1882.
12. For selected papers, see: (a) Zhu, W.; Ma, D. Chem. Commun. 2004,
888-889. (b) Andersen, J.; Madsen, U.; Björkling, F.; Liang, X.
Synlett 2005, 2209-2213. (c) Markiewicz, J. T.; Wiest, O.; Helquist,
P. J. Org. Chem. 2010, 75, 4887-4890. (d) Zhao, H.; Fu, H.; Qiao, R.
J. Org. Chem. 2010, 75, 3311-3316. (e) Goriya, Y.; Ramana, C. V.
Tetrahedron 2010, 66, 7642-7650.
13. Jia, F. C.; Xu, C.; Zhou, Z. W.; Cai, Q.; Li, D. K.; Wu, A. X. Org.
Lett. 2015, 17, 2820-2823.
14. (a) Yang, D.; Wang, Y.; Yang, H.; Liu, T.; Fu, H. Adv. Synth. Catal.
2012, 354, 477-482. (b) Jia, F. C.; Xu, C.; Cai, Q.; Wu, A. X. Chem.
Commun. 2014, 50, 9914-9916.
15. (a) Zhang, H.; Zhao, L.; Wang, D. X.; Wang, M. X. Org. Lett. 2013,
15, 3836-3839. (b) Huang, H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.;
Jiang, H. Org. Lett. 2013, 15, 6254-6257. (c) Yu, D. G.; Suri, M.;
Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802-8805. (d) Dhar, D.;
Tolman, W. B. J. Am. Chem. Soc. 2015, 137, 1322-1329.
Acknowledgments
This work was supported by the Universities Natural Science
Research Project of Jiangsu Province (No. 15KJB350002),
Nanjing Medical University Education Development Foundation
(No. 2014NJMUZD019) and National Natural Science
Foundation of China (No. 21172108).
References and notes
1. For selected papers, see: (a) Kshirsagar, U. A. Org. Biomol. Chem.
2015, 13, 9336-9352. (b) He, L.; Li, H.; Chen, J.; Wu, X. F. RSC Adv.
2014, 4, 12065-12077. (c) Bowman, W. R.; Elsegood, M. R.; Stein,
T.; Weaver, G. W. Org. Biomol. Chem. 2007, 5, 103-113. (d)
Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153-10202. (e) Orfi, L.; Wáczek, F.; Pató, J.;
Varga, I.; Hegymegi-Barakonyi, B.; Houghten, R. A.; Kéri, G. Curr.
Med. Chem. 2004, 11, 2549-2553.
2. For selected papers, see: (a) Michael, J. P. Nat. Prod. Rep. 2008, 25,
166-187. (b) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62,
9787-9826. (c) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.;
Hecht, S. M. J. Am. Chem. Soc. 2003, 125, 13628-13629. (d) Moon,
T. C.; Murakami, M.; Kudo, I.; Son, K. H.; Kim, H. P.; Kang, S. S.;
Chang, H. W. Inflamm. Res. 1999, 48, 621-625. (e) Lannutti, B. J.;
Meadows, S. A.; Herman, S. E.; Kashishian, A.; Steiner, B.; Johnson,
A. J.; Byrd, J. C.; Tyner, J. W.; Loriaux, M. M.; Deininger, M.;
Druker, B. J.; Puri, K. D.; Ulrich, R. G.; Giese, N. A. Blood 2011,
117, 591-594. (f) van Meerbeeck, J. P.; Gaafar, R.; Manegold, C.;
Van Klaveren, R. J.; Van Marck, E. A.; Vincent, M.; Legrand, C.;
Bottomley, A.; Debruyne, C.; Giaccone, G. J. Clin. Oncol. 2005, 23,
6881-6889.
16. Gao, L. J.; Ji, H. L.; Rong, L. C.; Tang, D.; Zha, Y. Y.; Shi, Y. H.;
Tu, S. J. J. Heterocycl. Chem. 2011, 48, 957-960.
17. Rostamizadeh, S.; Nojavan, M.; Aryan, R.; Isapoor, E.; Azad, M. J.
Mol. Catal. A-Chem. 2013, 374, 102-110.
18. Potrawa, T. R. U.S. Patent 0094 038, 2012.
19. Deligeorgiev, T. G.; Kaloyanova, St.; Vasilev, A.; Vaquero, J. J.;
Alvarez-Builla, J.; Cuadro, Ana M. Color. Technol. 2010, 126, 24-30.
20. Zhan, D.; Li, T. B.; Zhang, X. P.; Dai, C.; Wei, H. D.; Zhang, Y. Y.;
Zeng, Q. L. Synthetic Commun. 2013, 43, 2493-2500.
21. Sharif, M.; Opalach, J.; Langer, P.; Beller, M; Wu, X. F. RSC Adv.
2014, 4, 8-17.
3. (a) Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang, G.
J.; Hamel, E. J. Med. Chem. 1990, 33, 1721-1728. (b) Ozaki, K.;
Yamada, Y.; Oine, T.; Ishizuka, T.; Iwasawa, Y. J. Med. Chem. 1985,
28, 568-576. (c) Grover, G.; Kini, S. G. Eur. J. Med. Chem. 2006, 41,
22. Li, Q.; Huang, Y.; Chen, T. Q.; Zhou, Y. B.; Xu, Q.; Yin, S. F.; Han,
L. B. Org. Lett. 2014, 16, 3672-3675.

7
23. Chen, X. L.; Chen, T. Q.; Zhou, Y. B.; Han, D. Q.; Han, L. B.; Yin, S.
F. Org. Biomol. Chem. 2014, 12, 3802-3807.
24. Rao, K. R.; Raghunadh, A.; Mekala, R.; Meruva, S. B.; Pratap, T. V.;
Krishna, T.; Kalita, D.; Laxminarayana, E.; Prasad, B.; Pal, M.
Tetrahedron Lett. 2014, 55, 6004-6006.
29. Chan, J.; Faul, M. Tetrahedron Lett. 2006, 47, 3361-3363.
ACCEPTED MANUSCRIPT
30. Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.;
Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17,
1700-1703.
31. Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.; Loukou, C.
Tetrahedron Lett. 2000, 41, 10107-10110.
25. Heidary, M.; Khoobi, M.; Ghasemi, S.; Habibi, Z.; Faramarzi, M. A.
Adv. Synth. Catal. 2014, 356, 1789-1794.
26. Liu, J. F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.;
McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241-1244.
27. Selvam, P.; Babu, P.; Rathore, P. R.; Witvrouw, M. Int. J. Chem. Sci.
2010, 8, 617-622.
Supplementary Material
1H NMR and 13C NMR copies of all synthesized compounds.
28. Huang, C.; Fu, Y.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Chem. Commun.
2008, 47, 6333-6335.

ACCEPTED MANUSCRIPT
Supporting Information
Copper-Catalyzed Consecutive Reaction To Construct Quinazolin-4(3H)-ones and
Pyrido[2,3-d]pyrimidin-4(3H)-ones
Ting Li, Minglu Chen, Lei Yang, Zhengxin Xiong, Yongwei Wang, Fei Li* and Dongyin Chen*
Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Table of Contents
Copies of NMR spectra of compound 5a-5y …………………………………………………………………. 2-15
Copies of NMR spectra of compound 7a-7d …………………………………………………………….....… 15-18
Copies of NMR spectra of compound 8 …………………………………………………………………………... 19
Copies of NMR and MS spectra of 2-azido-N-(2,6-dimethylphenyl)benzamide ……………………………... 19-20
1

ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
20