Copper-catalyzed aerobic oxidative cyclization protocol for the synthesis of quinazolines via amination of C(sp3)-H bonds of methylazaarenes

Article abstract of DOI:10.1016/j.tet.2019.130783

A new aerobic copper-catalyzed three-component synthesis of azaaryl-substituted quinazolines has been developed, which featured inexpensive methylazaarenes as C1 sources, easily available copper salts as the catalysts and O₂ as a sole oxidant. The transformation had very good substrate applicability towards methylazaarenes, and various azaaryl-substituted quinazolines were obtained in moderate to good yields.

Full text of DOI:10.1016/j.tet.2019.130783

Journal Pre-proof
Copper-catalyzed aerobic oxidative cyclization protocol for the synthesis of
3
quinazolines via amination of C(sp )-H bonds of methylazaarenes
En Liang, Yinrong Wu, Jiewen Chen, Wei Xiong, Jinwu Zhao, Xingang Yao, Xiaodong
Tang
PII:
S0040-4020(19)31179-2
https://doi.org/10.1016/j.tet.2019.130783
TET 130783
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 September 2019
Revised Date: 31 October 2019
Accepted Date: 8 November 2019
Please cite this article as: Liang E, Wu Y, Chen J, Xiong W, Zhao J, Yao X, Tang X, Copper-catalyzed
3
aerobic oxidative cyclization protocol for the synthesis of quinazolines via amination of C(sp )-H bonds
of methylazaarenes, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130783.
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Graphical Abstract
Copper-catalyzed aerobic oxidative
Leave this area blank for abstract info.
cyclization protocol for the synthesis of
3
quinazolines via amination of C(sp )-H bonds
of methylazaarenes
En Liang, Yinrong Wu, Jiewen Chen, Wei Xiong, Jinwu Zhao,* Xingang Yao and Xiaodong Tang*
1
1
R
R
R2
R2
[
Cu]/O2
O
N
+
N
+ NH4OAc
NH2
N
N
3
1 examples
up to 88% yield

1
Tetrahedron
journal homepage: www.elsevier.com
Copper-catalyzed aerobic oxidative cyclization protocol for the synthesis of
3
quinazolines via amination of C(sp )-H bonds of methylazaarenes
a
a
a
a
b,*
a
a,∗
En Liang , Yinrong Wu , Jiewen Chen , Wei Xiong , Jinwu Zhao , Xingang Yao and Xiaodong Tang
a
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1023 South Shatai Road,
Baiyun District, Guangzhou 510515, P. R. China
b
School of Pharmacy, Guangdong Medical University, Dongguan 523808, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A new aerobic copper-catalyzed three-component synthesis of azaaryl-substituted
quinazolines has been developed, which featured inexpensive methylazaarenes as C1
Received in revised form
Accepted
Available online
2
sources, easily available copper salts as the catalysts and O as a sole oxidant. The
transformation had very good substrate applicability towards methylazaarenes, and
various azaaryl-substituted quinazolines were obtained in moderate to good yields.
2
019 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
Aerobic oxidation
Cyclization
Quinazolines
Methylazaarenes
1
. Introduction
The methylazaarenes are inexpensive and easily available raw
materials. Therefore, the transformation of methylazaarenes as a
potential functional group into other target molecules is a good
and green procedure. In recent years, utlizing methylazaarenes
directly to construct carbon-carbon and carbon-heteroatom bonds
have attracted increasing attention. These reported protocols
include acid-catalyzed nucleophilic addition to unsaturated
Quinazolines are an important kind of aromatic N-
heterocycles with diverse therapeutic and pharmacological
properties such as anti-cancer, anti-bacterial, anti-virus, anti-
hypertension, anti-diabetes etc. Owing to the importance of this
class of compounds, various synthetic methods have been
developed to construct this class of compounds, such as
cyclization between ortho-acyl-arylamines, nitrogen sources and
aldehydes, oxidative cyclocondensation of 2-aminobenzyl
alcohols with nitriles or benzylamines, intramolecular oxidative
amination reaction, and so on. Whereas, the azaaromatic
aldehydes, nitriles or benzylamines were unavailable and
expensive reagants which were usually produced from
corresponding methylazaarenes by multi-step reactions with toxic
reagents under harsh reaction conditions. To this day, few
azaaryl-substituted quinazolines were obtained. On the other
hand, azaaryl-substituted quinazolines were
biheteroaryls, which were widely used in organic functional
materials, pharmaceuticals, natural products, and metals
ligands. Thus, it is of great importance to develop an efficient
and convenient approach for the synthesis of various azaaryl-
substituted quinazolines which may have many potential
applications.
1
10
11
bond,
cyclization.
ox12idation coupling reaction,
and
oxidative
Among them, oxidative cyclization of
2
methylazaarenes is considered as an ideal strategy to access
3
aromatic N-heterocycle. In 2015, Yang reported a Cu-catalyzed
4
5
3
C(sp )-H bond oxidative functionalization of methylazaarenes to
12a
isoxazoline derivatives with K S O as oxidants. Deng's group
2
2
8
presented procedures for the synthesis of 1,2,4-thiadiazoles and
benzothiazoles from methylazaarenes, sulfur powder , anilines or
6
amidines, in which sulfur powder was not only as substrate but
12b,c
also as an oxidant.
Although Cu/O system as an ideal
2
a
kind of
oxidative reaction system has made great progress in these
13
years, applying this system to construct
heterocycles with methylazaarenes remains scarce.
aromatic N-
7
8
9
12d-f
In our previous work, we have disclosed a copper-catalyzed
aerobic oxidative carboamination of methylazaarenes for
14a
synthesis of pyrrolo[1,2-a]quinoxalines (Scheme 1a). We have
also reported a direct alkenylation of methylazaarenes with
1
4b
—
——
aldehydes through synergistic catalysis (Scheme 1b). Inspired
∗
Corresponding author. e-mail: tangxdong@smu.edu.cn (X. Tang),
jwzhao@gdmu.edu.cn (J. Zhao)

2
Tetrahedron
by these interesting works, herein, we report a one-pot method
for the synthesis of 2-azaaryl quinazolines from 2-aminophenyl
ketones, methylazaarenes and ammonium acetate with dioxygen
as the oxidant through Cu-catalyzed cascade oxidative
cyclization (Scheme 1c).
Cu(OTf)2
CuBr
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMSO
toluene
DMF
DMA
DMF
DMF
DMF
DMF
DMF
DMF
37
41
40
49
45
44
36
35
38
84
43
<10
17
<10
14
0
9
2
1
0
CuBr
CuCl
11
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
CuI
Cu(OAc)
2
3 2
Cu(NO )
CuCl
CuCl
CuCl
CuCl
2
2
2
2
b
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
2
0
1
2
3
c
d
e
f
2
2
2
2
Scheme 1. Our previous works and this work about transformation of
4
methylazaarenes
g
51
2
5
2
. Results and discussion
-Aminobenzophenone (1a), 2-methylquinoline (2a) and
a
Reaction conditions (unless otherwise specified): all reactions were
performed with 1a (0.3 mmol), 2a (0.6 mmol), NH OAc (0.6 mmol), [Cu] (20
mol%), Acid (50 mol %l) in solvent (2 mL), at 120 C under O
Isolated yield. TFA = trifluoroacetic acid, PivOH = trimethylacetic acid,
TsOH = p-toluenesulfonic acid, NMP = N-methyl pyrrolidone, DMA = N,N-
dimethylacetamide.
4
2
o
2
for 24 h.
NH OAc as a nitrogen source were chosen as the model
4
substrates for this investigation, and the results are shown in
Table 1. Initially, different Brønsted acids were screened under
o
O atmosphere at 120 C with CuCl as catalyst and NMP as a
b
c
d
2
2
2 2
The reaction was used H O (0.9 mmol ) as oxidant.
solvent (Table 1, entries 1-6), and TFA provided the best result
with the desired product 3a obtained in 61% yield (Table 1, entry
2 2 8
The reaction was used K S O (0.9 mmol ) as oxidant.
2
). Expectedly, in the absence of copper salts or Brønsted acids,
The reaction was used tert-butyl hydroperoxide (70% in water) (0.9 mmol )
as oxidant.
no desired product 3a was detected and most of raw materials
were recovered (Table 1, entries 7-8). Other copper salts such as
Cu(OTf) , CuBr , CuBr, CuCl, CuI, Cu(OAc) , Cu(NO ) were
e
The reaction was used 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.9 mmol )
as oxidant.
2
2
2
3 2
then examined and the results indicated that they were all inferior
f
2
The reaction was conducted under N .
to CuCl (Table 1, entries 9-15). Various solvents were next
2
g
o
The reaction was conducted at 100 C.
probed (Table 1, entries 16-19). As shown in entry 18, the target
compound was isolated in 84% yield when the three-component
reaction proceeded in DMF (Table 1, entry 18). The yields
decreased sharply when the reaction was run with other oxidants
With the optimized reaction conditions in hand, we first
investigated the scope of 2-aminophenyl ketones and the results
are summarized in Table 2. When the R groups were various
substituted phenyl, the corresponding quinazolines were isolated
in moderate to good yields (Table 2, 3aa-3ea). Notably, among
them, strongly electron-withdrawing group CF3 was well
tolerated (3ea). However, substrates with an aliphatic group like
1
(
Table 1, entries 20-23). In addition, control experiment without
dioxygen was performed for this reaction, and no desired product
was detected (Table 1, entry 24). Finally, our experimental result
o
suggested that decreasing the reaction temperature from 120 C
o
1
to 100 C had a negative effect (Table 1, entry 25).
methyl as R substituent failed to yield the desired heterocycles.
a
We then evaluated the influence of the substituent in the aniline
ring of 2-aminobenzophenones. Our experimental results showed
Table 1. Optimization of the reaction conditions
that 2-aminobenzophenones substituted by F, Cl, Br, CH , or
3
OCH in the aniline ring could all go through the oxidative
3
cyclization reaction smoothly (Table 2, 3fa-3la). Also, 2-amino-
2
',5-dichlorobenzophenone also gave the expected cyclization
product 3ma in 67% yield.
Entry
[Cu]
Acid
Ph PO
TFA
Solvent
Yield( % )
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
H
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
28
61
48
<10
<10
50
0
1
2
3
4
5
6
7
8
2
2
2
2
2
TsOH
PivOH
HOAc
PhCOOH
TFA
---
CuCl
2
---
0

3
a
a
Table 2. Substrate scope of 2-aminophenyl ketones
Table 3. Substrate scope of methylazaarenes
R1
R1
N
Ph
Ph
CuCl2 ( 20 mol % )
TFA ( 50 mol % )
CuCl
2
( 20 mol % )
TFA ( 50 mol % )
O
N
O
N
R2
+
+
NH4OAc
+
N
+
NH OAc
4
N
N
O2, DMF (2 mL)
2
O , DMF (2 mL)
NH2
R2
NH2
N
3
1
20 oC, 24 h
20 oC, 24 h
1
N
1
2a
3
1a
2
F
Cl
Ph
N
Ph
N
Ph
N
Br
N
N
N
N
N
N
N
N
N
N
N
3ab, 54%
3
ac, 60%
Ph
3ad, 61 %
N
N
F
Cl
N
N
N
N
N
3da, 65 %
Ph
Ph
3
aa, 84%
3ba, 78 %
3ca, 70 %
N
N
N
N
N
N
N
N
N
N
Cl
CF3
3ae, 66%
3af, 57%
3ag, 73%
Br
O
F
Cl
N
N
Ph
Ph
Ph
N
N
N
N
N
N
N
Cl
N
N
N
N
N
N
3
ea, 61 %
3fa, 60 %
3ga, 63 %
N
N
3ah, 65%
3
ai, 81%
3aj, 78%
Ph
Ph
Ph
N
N
N
N
Br
N
N
N
N
N
H3CO
N
N
N
N
N
N
N
N
N
3ak, 56%a , 77%b
3al, 80%b
3am, 52%b
3ha, 54 %
3ia, 88 %
3ja, 51%
Ph
Ph
Ph
Cl
N
N
N
N
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
F
O
N
N
3ao, 79%b
Ph
b
3
an, 71%b
Ph
CN
3ap, 62%
3
ka, 52 %
3la, 47 %
3ma, 67 %
Ph
N
N
N
N
N
N
a
N
S
Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), NH
4
OAc (0.6 mmol),
atmosphere at
CuCl (20 mol %), TFA (50 mol %), DMF (2.0 mL) under O
1
2
2
N
N
S
N
3aq, 34%b
3ar, 79%b
3as, 42%b
o
20 C for 24 h. Isolated yields.
a
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), NH
4
OAc (0.6 mmol),
atmosphere at
The reaction scope with respect to methylazaarenes was next
examined (Table 3). Firstly, series of substituted 2-
methylquinoline were examined under the optimized conditions,
and corresponding products 3ab-3ah were produced in 54-81%
yields. Notably, the 1-methylisoquinoline and 4-methylquinoline
showed good reactivity and provided the products in 81% and
CuCl (20 mol %), TFA (50 mol %), DMF (2.0 mL) under O
1
2
2
a
o
b
20 C for 24 h. Isolated yields. TFA (100 mol %) was used.
To gain some mechanistic information, we conducted several
control experiments (Scheme 2). When the reaction of 2-
aminobenzophenone (1a), quinoline-2-carbaldehyde and
7
8%, respectively (Table 3, 3ai, 3aj). To our delight, we found 2-
NH OAc was carried out under the standard conditions, and the
4
methylpyridine afforded the desired product 3ak in 56% yield
and the yield could be raised to 77% with 1 equivalent TFA
added. Subsequently, various methylpyridines were examined.
As demonstrated in Table 3, substituted 2-methylpyridines and
product 3aa was produced in 86% yield. [Eq. (1)]. Only a trace
amount of 3aa was obtained with the addition of radical
scavengers [2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or
butylated hydroxytoluene (BHT)] in the standard reaction, which
revealed that this transformation should proceed through the
radical pathway [Eq. (2)]. When the substrate 1a and compound
4 were reacted in standard conditions, 3aa was not detected. This
result suggested that the compound 4 was not the intermediate in
the transformation [Eq. (3)]. Based on the above experimental
4
-methylpyridine were also able to give the expected cyclization
products (Table 3, 3al-3ao). However, 3-methylpyridine could
not go across this transformation at all under the optimized
reaction conditions. It was noteworthy that methylazaarenes
containing multiple heteroatoms such as 2-methylpyrazine, 4-
methylpyrimidine, 2-methylthiazole and 2-methylbenzothiazole
were also suitable substrates for this transformation, generating
the corresponding azaaryl-substituted quinazolines in 34-69%
yields (Table 3, 3ap-3as).
12e,12f,15
results and previous reports,
a tentative reaction pathway
is depicted in Scheme 2. Firstly, the enamine intermediate A is
15
formed via isomerization of 1a with acid. Subsequently,
intermediate A combined with copper salts and O generates
intermediate B, which goes through intramolecular
2
12e,12f,15
rearrangement to give intermediate C.
Then, quinoline-2-
carbaldehyde was produced from intermediate C, followed by
reacting with intermediate D to generate imine intermediate E via
acid-catalyzed dehydration. Finally, cyclization and oxidation of
12f
intermediate E provides the final product 3aa.

4
Tetrahedron
4
-Phenyl-2-(quinolin-2-yl)quinazoline (3aa): Yellow Solid
o 1
(84.0 mg, 84%); m.p.=157~158 C. H NMR (400 MHz, CDCl )
3
δ 8.86 (d, J = 8.6 Hz, 1H), 8.43 (dd, J = 17.6, 8.5 Hz, 2H), 8.34
d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.94 (t, J = 6.9 Hz,
(
3
7
1
1
3
H), 7.87 (d, J = 7.4 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.66 –
13
.55 (m, 5H). C NMR (100 MHz, CDCl ) δ 168.9, 159.2, 155.4,
3
52.0, 148.3, 137.3, 136.9, 133.7, 130.9, 130.3, 130.0, 129.5,
28.5, 128.5, 128.0, 127.4, 127.3, 126.9, 122.2, 121.5. IR (KBr):
-
1
044, 2925, 1743, 1536, 760, 688 cm . HRMS (ESI) m/z: calcd
+
for C H N [M+H] , 334.1339; found, 334.1331.
23
16
3
4
-(4-Fluorophenyl)-2-(quinolin-2-yl)quinazoline
(3ba):
o
1
Yellow solid (82.2 mg, 78%); m.p.=207~208 C. H NMR (400
MHz, CDCl ) δ 8.85 (d, J = 8.5 Hz, 1H), 8.44 (dd, J = 18.6, 8.4
3
Hz, 2H), 8.35 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.96
(
7
s, 3H), 7.88 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.66-
.58 (m, 2H), 7.31 (t, J = 8.3 Hz, 2H). C NMR (100 MHz,
13
CDCl ) δ 167.6, 163.9 (d, J = 248.9 Hz), 159.0, 155.1, 151.9,
3
1
1
48.2, 136.8, 133.7, 133.3, 132.3, 132.2, 130.7, 129.9, 129.5,
28.4, 128.1, 127.3, 126.5, 121.9, 121.3, 115.6 (d, J = 21.5 Hz).
1
9
F NMR (376 MHz, CDCl ) δ -110.4. IR (KBr): 3055, 2924,
3
-
1
1
683, 1603, 1537, 1493, 1083, 767, 627 cm . HRMS (ESI) m/z:
+
calcd for C H FN [M+H] , 352.1245; found, 352.1238.
23
15
3
Scheme 2. Control experiments and possible reaction mechanism
4
-(4-Chlorophenyl)-2-(quinolin-2-yl)quinazoline
1
(3ca):
3
. Conclusion
o
Yellow solid (77.1 mg, 70%); m.p.=202~203 C. H NMR (400
MHz, CDCl ) δ 8.83 (d, J = 8.6 Hz, 1H), 8.45-8.39 (m, 2H), 8.33
3
In conclusion, we have disclosed a direct method for the
synthesis of 2-azaaryl quinazolines via copper-catalyzed aerobic
oxidative cyclization from 2-aminophenyl ketones,
methylazaarenes and ammonium acetate. This method provided
various azaaryl-substituted quinazolines in moderate to good
yields, which were rarely synthesized by previous methods. The
protocol featured available materials, green oxidants, mild
conditions, simple operation and good substrate applicability.
Further study about effective transformation of methylazaarenes
are ongoing in our laboratory.
(d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.95 (t, J = 7.6 Hz,
1
H), 7.87 (t, J = 7.3 Hz, 3H), 7.76 (t, J = 7.5 Hz, 1H), 7.65-7.58
13
(m, 4H). C NMR (100 MHz, CDCl ) δ 167.5, 159.0, 155.1,
3
1
1
3
52.0, 148.2, 136.9, 136.4, 135.6, 133.8, 131.5, 130.7, 130.0,
29.5, 128.8, 128.4, 128.2, 127.3, 126.4, 121.9, 121.3. IR (KBr):
-
1
056, 2923, 1740, 1537, 756, 673 cm . HRMS (ESI) m/z: calcd
+
for C H ClN [M+H] , 368.0949; found, 368.0941.
23 15
3
4
-(4-Bromophenyl)-2-(quinolin-2-yl)quinazoline
(3da):
o
1
Yellow solid (80.4 mg, 65%); m.p.=195~196 C. H NMR (400
MHz, CDCl ) δ 8.84 (d, J = 8.5 Hz, 1H), 8.49 – 8.39 (m, 2H),
3
4
. Experimental section
8
.35 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.96 (t, J = 7.5
4
.1. General methods
Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.85 – 7.74 (m, 5H), 7.66-7.59
13
(
m, 2H). C NMR (101 MHz, CDCl ) δ 167.8, 159.1, 155.1,
3
1
13
H and C NMR spectra were recorded on BRUKER DRX-
1
52.1, 148.3, 137.4, 137.0, 136.2, 133.9, 131.8, 130.8, 130.2,
1
4
00 spectrometer with CDCl as the solvent. H shifts were
3
129.6, 128.5, 128.3, 127.4, 127.4, 126.5, 124.8, 122.0, 121.4. IR(
13
-
1
referenced to CDCl at 7.26 ppm. C shifts were referenced to
CDCl at 77 ppm. IR spectra were obtained with an infrared
3
KBr): 3047, 2924, 1733, 1544, 1345, 757, 675 cm . HRMS (ESI)
+
3
m/z: calcd for C H BrN [M+H] , 412.0444; found, 412.0437.
23
15
3
spectrometer on either potassium bromide pellets or liquid films
between two potassium bromide pellets. GC-MS data were
obtained using electron ionization. HRMS was carried out on a
high-resolution mass spectrometer (LCMS-IT-TOF). TLC was
performed using commercially available 100−400 mesh silica gel
plates (GF254). Unless otherwise stated, all reagents and solvents
were purchased from commercial suppliers and used without
further purification.
2
-(Quinolin-2-yl)-4-(4-(trifluoromethyl)phenyl)quinazoline
o 1
(
3ea): Light yellow solid (73.5 mg, 61%); m.p.=215~216 C. H
NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.6 Hz, 2H), 8.12 (d, J =
.5 Hz, 2H), 7.95 (s, 2H), 7.85 – 7.79 (m, 4H), 7.73 (ddd, J = 8.4,
.9, 1.4 Hz, 2H), 7.56 – 7.49 (m, 2H). C NMR (100 MHz,
CDCl ) δ 167.5, 159.4, 155.1, 152.1, 148.3, 140.8, 137.1, 134.1,
32.0 (q, J = 32.1 Hz), 130.9, 130.6, 130.3, 129.7, 128.6, 128.5,
27.5, 127.4, 126.4, 125.6 (q, J = 3.7 Hz), 122.1, 121.4. F NMR
3
8
6
13
3
1
1
9
4
.2. General procedure towards quinazolines 3
(376 MHz, CDCl ) δ -62.7. IR (KBr): 3038, 2921, 1740, 1533,
3
-
1
+
7
4
61, 686 cm . HRMS (ESI) m/z: calcd for C H F N [M+H] ,
23 15 3 3
2
-aminophenyl ketones 1 (0.3 mmol), methylazaarenes 2 (0.6
02.1213; found, 402.1203.
-Fluoro-4-phenyl-2-(quinolin-2-yl)quinazoline (3fa): Light
mmol), NH OAc (0.6 mmol), CuCl2 (20 mol %), TFA (50
mol %), DMF (2.0 mL) were added to a 25 mL Schlenk tube
under O atmosphere with magnetic stirrer bar. The reaction
mixture was stirred at 120 °C (oil bath temperature) for 24 h.
After the reaction was finished (monitored by TLC), the mixture
was cooled to room temperature, quenched with solution of
NaHCO (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over anhydrous MgSO and
4
6
o
1
yellow solid (63.2 mg, 60%); m.p.=198~199 C. H NMR (400
MHz, CDCl ) δ 8.85 (d, J = 8.6 Hz, 1H), 8.48 – 8.41 (m, 2H),
2
3
8
7
.35 (d, J = 8.5 Hz, 1H), 7.93-7.87 (m, 3H), 7.84 – 7.70 (m, 3H),
13
.64 – 7.57 (m, 4H). C NMR (100 MHz, CDCl ) δ 168.4, 161.0
3
(
(
d, J = 249.9 Hz), 158.9, 155.1, 149.3, 148.2, 137.1, 136.9, 132.8
d, J = 8.6 Hz), 130.8, 130.3, 130.0, 129.7, 128.8, 128.6, 127.5,
3
4
1
1
27.4, 124.2(d, J = 25.7 Hz), 122.9 (d, J = 9.1 Hz), 121.4,
the solvent was removed under vacuum. The crude product was
purified by column chromatography (EtOAc/hexanes) on silica
gel.
19
10.4(d, J = 23.2 Hz). F NMR (376 MHz, CDCl ) δ -108.8. IR
3
-
1
(
KBr): 3048, 2923, 1722, 1532, 1157, 759, 684 cm . HRMS

5
+
(
3
ESI) m/z: calcd for C H FN [M+H] , 352.1244; found,
52.1436.
117.7, 107.6, 55.9. IR (KBr): 3039, 2921, 2846, 1731, 1543,
23
15
3
-1
1339, 758, 676 cm . HRMS (ESI) m/z: calcd for C H N O
2
4
18
3
+
[
M+H] , 364.1444; found, 364.1434.
6
-Chloro-4-phenyl-2-(quinolin-2-yl)quinazoline
Yellow solid (69.5 mg, 63%); m.p.=204~205 C. H NMR (400
MHz, CDCl ) δ 8.86 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 8.3 Hz,
(3ga):
o
1
6-Chloro-4-(2-chlorophenyl)-2-(quinolin-2-yl)quinazoline
o
1
(3ma): Light yellow solid (80.9 mg, 67%); m.p.=215~216 C. H
3
1
7
H), 8.36 (d, J = 6.1 Hz, 2H), 8.17 (s, 1H), 7.88-7.93 (m, 4H),
.78 (t, J = 7.8 Hz, 1H), 7.67 – 7.59 (m, 4H). C NMR (100
NMR (400 MHz, CDCl ) δ 8.78 (d, J = 8.6 Hz, 1H), 8.43 (d, J =
3
13
8.5 Hz, 1H), 8.36 (t, J = 10.2 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H),
13
MHz, CDCl ) δ 168.3, 159.5, 155.0, 150.6, 148.4, 137.0, 136.8,
7.77 (t, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.63 – 7.50 (m, 5H). C
3
1
1
1
34.8, 133.9, 131.8, 130.9, 130.4, 130.2, 129.7, 128.8, 128.6,
27.5, 127.4, 125.8, 122.8, 121.5. IR (KBr): 3056,2925, 1676,
NMR (100 MHz, CDCl ) δ 166.9, 159.7, 154.9, 150.0, 148.3,
3
137.1, 135.6, 135.2, 134.0, 132.9, 131.6, 131.2, 131.0, 130.9,
130.1, 129.7, 128.6, 127.5, 127.4, 127.1, 125.5, 123.4, 121.6. IR
-
1
537, 1082, 767, 628 cm .HRMS (ESI) m/z: calcd for
+
-1
C H ClN [M+H] , 368.0949; found, 368.0944.
(KBr): 3047, 2922, 1737, 1647, 1539, 1071, 838, 757 cm .
23
15
3
+
HRMS (ESI) m/z: calcd for C H Cl N [M+H] , 402.0559;
23
14
2
3
6
-Bromo-4-phenyl-2-(quinolin-2-yl)quinazoline (3ha). Light
o 1
found, 402.0554.
yellow solid (67 mg, 54% ); m.p.=248~249 C. H NMR (400
MHz, CDCl3) δ 8.86 (d, J = 8.6 Hz, 1H), 8.50 (d, J = 8.5 Hz,
2-(6-Methylquinolin-2-yl)-4-phenylquinazoline (3ab): Light
yellow solid (56.3 mg, 54%); m.p.=192~193 C. H NMR (400
o
1
1
=
H), 8.38 (d, J = 8.6 Hz, 1H), 8.35 – 8.27 (m, 2H), 8.03 (dd, J
8.9, 2.2 Hz, 1H), 7.96 – 7.88 (m, 3H), 7.81 – 7.76 (m, 1H),
MHz, CDCl ) δ 8.85 (d, J = 8.6 Hz, 1H), 8.41 (dd, J = 13.0, 8.7
3
1
3
7
1
1
1
7
4
.67 – 7.60 (m, 4H). C NMR (100 MHz, CDCl ) δ 168.1,
Hz, 2H), 8.27 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.99 –
3
13
59.2, 154.8, 150.8, 148.0, 137.4, 136.8, 131.9, 130.7, 130.4,
30.2, 129.9, 129.1, 128.8, 128.7, 127.7, 127.4, 123.3, 122.1,
21.5. IR (KBr): 3055, 2921, 2845, 1595, 1495, 1244, 1027, 825,
7.92 (m, 3H), 7.67 – 7.60 (m, 6H), 2.57 (s, 3H). C NMR (101
MHz, CDCl ) δ 168.9, 159.2, 154.5, 152.1, 146.7, 137.6, 137.4,
3
136.5, 133.7, 132.0, 130.5, 130.3, 130.2, 130.1, 128.7, 128.6,
128.0, 127.0, 126.3, 122.3, 121.6, 21.7. IR (KBr): 3045, 2921,
-
1
+
50 cm . HRMS (ESI) m/z: calcd for C H B N [M+H] ,
12.0444; found, 412.0450.
23
15
r
3
-
1
1748,1540, 1353, 759, 679 cm . HRMS (ESI) m/z: calcd for
+
C H N [M+H] , 348.1492; found, 348.1489.
2
4
18
3
6
-Methyl-4-phenyl-2-(quinolin-2-yl)quinazoline (3ia): Yellow
o
1
solid (91.7 mg, 88%); m.p.=191~192 C. H NMR (400 MHz,
2-(6-Fluoroquinolin-2-yl)-4-phenylquinazoline (3ac): Light
o 1
yellow solid (63.2 mg, 60%); m.p.=177~178 C. H NMR (400
CDCl ) δ 8.84 (d, J = 8.6 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.30
3
(d, J = 8.5 Hz, 2H), 7.91 (d, J = 6.1 Hz, 3H), 7.84 (d, J = 8.1 Hz,
MHz, CDCl ) δ 8.87 (d, J = 8.2 Hz, 1H), 8.44 (s, 1H), 8.39 (d, J
3
1
H), 7.74 (t, J = 7.9 Hz, 2H), 7.63 – 7.52 (m, 4H), 2.50 (s, 3H).
= 8.0 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H),
1
3
13
C NMR (100 MHz, CDCl ) δ 168.0, 158.6, 155.5, 150.6, 148.2,
7.92 (s, 3H), 7.65 – 7.41 (m, 6H). C NMR (10 MHz, CDCl ) δ
3
3
1
1
2
38.3, 137.5, 136.8, 135.9, 130.8, 130.1, 129.8, 129.7, 129.4,
28.4, 127.3, 127.1, 125.4, 122.1, 121.4, 21.9. IR (KBr): 3050,
169.0, 161.1 (d, J = 264.6 Hz), 159.0, 154.9, 152.0, 145.4, 137.3,
136.3, 136.2, 133.8, 133.4 (d, J = 9.3 Hz), 130.3, 130.1, 130.0,
129.2 (d, J = 10.1 Hz), 128.6, 128.1, 127.0, 122.3, 119.9 (d, J =
-
1
923, 2850, 1745, 1538, 1408, 1341, 768, 697 cm . HRMS (ESI)
+
19
m/z: calcd for C H N [M+H] , 348.1495; found, 348.1489.
25.9 Hz), 110.4 (d, J = 21.5 Hz). F NMR (376 MHz, CDCl3) δ
24
18
3
-
1
-
111.8. IR (KBr): 3045, 2921, 1743, 1534, 1065, 763, 689 cm .
6
-Methoxy-4-phenyl-2-(quinolin-2-yl)quinazoline
(3ja):
+
o
1
HRMS (ESI) m/z: calcd for C23
found, 352.1239.
H15FN [M+H] , 352.1245;
3
Yellow solid (55.6 mg, 51%); m.p.=228~229 C. H NMR (400
MHz, CDCl ) δ 8.85 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H),
3
8
7
1
.35 (dd, J = 8.9, 3.4 Hz, 2H), 7.96 (dd, J = 7.5, 2.0 Hz, 2H),
.88 (dd, J = 8.1, 1.4 Hz, 1H), 7.77 (ddd, J = 8.5, 6.8, 1.4 Hz,
H), 7.66 – 7.56 (m, 5H), 7.45 (d, J = 2.8 Hz, 1H), 3.88 (s, 3H).
2-(6-Chloroquinolin-2-yl)-4-phenylquinazoline (3ad): Yellow
o 1
solid (67.3 mg, 61%); m.p.=202~203 C. H NMR (400 MHz,
CDCl ) δ 8.87 (d, J = 8.6 Hz, 1H), 8.38 (dd, J = 8.7, 3.4 Hz, 2H),
3
13
C NMR (101 MHz, CDCl ) δ 167.0, 158.9, 155.4, 148.3, 137.7,
8.23 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.98 – 7.89 (m,
3H), 7.84 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 9.0, 1.9 Hz, 1H), 7.66
3
1
1
2
37.1, 131.7, 130.7, 130.0, 129.9, 129.6, 128.7, 128.5, 127.4,
27.3, 126.5, 123.3, 121.4, 104.2, 55.7. IR (KBr): 3046, 2921,
13
– 7.58 (m, 4H). C NMR (100 MHz, CDCl ) δ 169.0, 158.8,
3
-
1
841, 1740, 1530, 1224, 760, 694, 574 cm . HRMS (ESI) m/z:
155.7, 152.0, 146.6, 137.2, 135.9, 133.8, 133.1, 132.4, 130.5,
130.2, 130.1, 130.0, 129.0, 128.6, 128.2, 127.0, 126.1, 122.4,
+
calcd for C H N O [M+H] , 364.1444; found, 364.1434.
24
18
3
-
1
1
22.2. IR (KBr): 3082, 2925, 1642, 1537, 1070, 758, 682 cm .
7
-Fluoro-4-phenyl-2-(quinolin-2-yl)quinazoline (3ka): Yellow
+
o
1
HRMS (ESI) m/z: calcd for C23
found, 368.0943.
H15ClN [M+H] , 368.0949;
3
solid (54.8 mg, 52%); m.p.=91~92 C. H NMR (400 MHz,
CDCl ) δ 8.20 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 8.5 Hz, 2H), 7.98
3
(
s, 2H), 7.84 (t, J = 8.9 Hz, 4H), 7.74 (t, J = 7.7 Hz, 2H), 7.54 (t,
2-(6-Bromoquinolin-2-yl)-4-phenylquinazoline (3ae): Light
o 1
yellow solid (81.6 mg, 66%); m.p.=214~215 C. H NMR (400
13
J = 7.5 Hz, 2H). C NMR (101 MHz, CDCl ) δ 168.8, 165.6 (d,
3
J = 255.1 Hz), 160.2, 155.2, 154.1, 148.3, 137.1 (d, J = 8.5 Hz),
MHz, CDCl ) δ 8.89 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H),
3
1
1
30.9, 130.3, 130.3, 129.9, 129.8, 129.7, 128.7, 128.6, 127.6,
8.31 (d, J = 8.9 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.3
Hz, 1H), 8.04 (s, 1H), 7.98 – 7.90 (m, 3H), 7.83 (d, J = 8.9 Hz,
19
27.4, 121.6, 118.6 (d, J = 25.0 Hz), 113.7 (d, J = 20.5 Hz).
F
13
NMR (376 MHz, CDCl ) δ -102.1. IR (KBr): 3051, 2920, 1745,
1
for C H FN [M+H] , 352.1244; found, 352.1234.
1H), 7.67 – 7.60 (m, 4H). C NMR (100 MHz, CDCl ) δ 168.9,
3
3
-
1
683, 1551, 1400, 1175, 765, 686 cm . HRMS (ESI) m/z: calcd
159.0, 156.2, 152.1, 144.7, 137.4, 137.3, 134.7, 133.8, 130.37,
130.1, 130.0, 129.9, 129.8, 128.5, 128.2, 127.2, 126.9, 126.6,
+
23
15
3
1
22.3, 122.2. IR (KBr): 3049, 2924,1717, 1537, 1352, 758, 683
7
-Methoxy-4-phenyl-2-(quinolin-2-yl)quinazoline (3la): Light
-
1
+
o
1
cm . HRMS (ESI) m/z: calcd for C23
found, 412.0436.
H15BrN [M+H] , 412.0444;
3
yellow solid (51.2 mg, 47%); m.p.=138~140 C. H NMR (400
MHz, CDCl ) δ 8.86 (d, J = 8.6 Hz, 1H), 8.48 (d, J = 8.5 Hz,
3
1
7
=
H), 8.35 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.96 –
2-(6-Methoxyquinolin-2-yl)-4-phenylquinazoline (3af):Yellow
o 1
.86 (m, 3H), 7.81 – 7.71 (m, 2H), 7.64 – 7.59 (m, 4H), 7.23 (d, J
solid (62.1 mg, 57%); m.p.=158~159 C. H NMR (400 MHz,
13
2.5 Hz, 1H), 4.03 (s, 3H). C NMR (100 MHz, CDCl ) δ
CDCl ) δ 8.85 (d, J = 8.5 Hz, 1H), 8.39 (dd, J = 15.5, 8.9 Hz,
3
3
1
1
67.7, 163.9, 159.7, 155.5, 154.6, 148.2, 137.5, 137.0, 130.8,
30.2, 129.9, 129.6, 128.5, 128.3, 127.4, 127.3, 121.5, 121.4,
2H), 8.24 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.95 (s,
3H), 7.61 (s, 4H), 7.42 (d, J = 8.9 Hz, 1H), 7.14 (s, 1H), 3.97 (s,

6
Tetrahedron
13
3
H). C NMR (101 MHz, CDCl ) δ 168.9, 158.6, 153.0, 152.1,
130.1, 129.3, 128.6, 127.9, 127.0, 122.2, 121.9, 119.7, 24.5. IR
3
-1
1
1
3
44.3, 137.5, 135.7, 133.7, 132.3, 131.3, 130.3, 130.1, 129.8,
28.6, 127.9, 127.0, 122.6, 122.2, 121.9, 104.8, 55.6. IR (KBr):
055, 2925, 2842, 1695, 1532, 1233, 759, 682, 517 cm . HRMS
(KBr): 3054, 2923, 1737, 1537, 1387, 761, 691, 508 cm . HRMS
(ESI) m/z: calcd for C H N [M+H] , 298.1339; found,
298.1332.
+
20
16
3
-
1
+
(ESI) m/z: calcd for C H N O [M+H] , 364.1444; found,
24 18 3
2
-(5-Methylpyridin-2-yl)-4-phenylquinazoline (3am): Light
3
64.1433.
-(7-Chloroquinolin-2-yl)-4-phenylquinazoline (3ag): Light
o
1
yellow solid (46.4 mg, 52%); m.p.=101~102 C. H NMR (400
MHz, CDCl ) δ 8.74 (s, 1H), 8.66 (d, J = 7.9 Hz, 1H), 8.35 (d, J
= 8.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.94 – 7.86 (m, 3H), 7.68
(d, J = 7.6 Hz, 1H), 7.58 (s, 4H), 2.44 (s, 3H). C NMR (101
2
3
o
1
yellow solid (80.6 mg, 73%); m.p.=166~167 C. H NMR (400
MHz, CDCl ) δ 8.86 (d, J = 8.5 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J
13
3
=
8.4 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H),
MHz, CDCl ) δ 168.7, 159.2, 152.7, 152.0, 150.7, 137.4, 137.4,
3
7
4
1
1
1
.99 – 7.92 (m, 3H), 7.81 (d, J = 8.6 Hz, 1H), 7.68 – 7.60 (m,
134.6, 133.7, 130.2, 129.9, 129.8, 128.5, 127.6, 126.9, 123.9,
122.1, 18.5. IR (KBr): 3049, 2921, 1735, 1540, 1266, 759, 691,
13
H), 7.54 (d, J = 8.6 Hz, 1H). C NMR (100 MHz, CDCl ) δ
3
-
1
+
69.0, 158.9, 156.4, 152.0, 148.6, 137.2, 136.8, 135.4, 133.9,
30.3, 130.1, 130.0, 129.6, 128.6, 128.4, 128.2, 127.0, 126.8,
22.3, 121.7. IR (KBr): 3052, 2924, 1728, 1541, 1083, 766, 692
509 cm . HRMS (ESI) m/z: calcd for C H N [M+H] ,
20 16 3
298.1339; found, 298.1334.
6-(4-Phenylquinazolin-2-yl)nicotinonitrile (3an): White solid
-
1
+
cm . HRMS (ESI) m/z: calcd for C H ClN [M+H] , 368.0949;
found, 368.0944.
o
1
23
15
3
(
65.7 mg, 71%); m.p.=215~216 C. H NMR (400 MHz, CDCl )
3
δ 9.17 (s, 1H), 8.92 (d, J = 8.2 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H),
2
-(8-Chloroquinolin-2-yl)-4-phenylquinazoline (3ah): Yellow
8.23 – 8.14 (m, 2H), 7.98 (t, J = 7.7 Hz, 1H), 7.88 (dd, J = 3.9,
o
1
13
solid (71.7 mg, 65%); m.p.=160~161 C. H NMR (400 MHz,
2.5 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.64 – 7.59 (m, 3H).
C
CDCl ) δ 8.88 (d, J = 8.5 Hz, 1H), 8.39 – 8.35 (m, 2H), 8.20 (d, J
NMR (100 MHz, CDCl ) δ 169.2, 158.4, 157.5, 152.8, 151.8,
3
3
=
8.4 Hz, 1H), 7.95 (d, J = 4.3 Hz, 3H), 7.89 (d, J = 7.3 Hz, 1H),
140.2, 137.0, 134.3, 130.3, 130.1, 129.9, 128.8, 128.7, 127.1,
124.0, 122.5, 116.7, 110.4. IR (KBr): 3031, 2923, 2200, 1743,
7
1
1
1
3
.81 (d, J = 8.4 Hz, 1H), 7.66-7.60 (m, 4H), 7.50 (t, J = 7.7 Hz,
H). C NMR (100 MHz, CDCl ) δ 168.9, 159.0, 156.1, 152.0,
44.6, 137.4, 137.3, 134.6, 133.8, 130.3, 130.1, 130.0, 129.8,
29.7, 128.5, 128.2, 127.2, 126.9, 126.6, 122.3, 122.2. IR (KBr):
922, 1743, 1538, 1086, 759, 682 cm . HRMS (ESI) m/z: calcd
13
-1
1639, 1529, 757, 683 cm . HRMS (ESI) m/z: calcd for C H N
[M+H] , 309.1135; found, 309.1128.
3
20 13
4
+
2a
-
1
4-Phenyl-2-(pyridin-4-yl)quinazoline (3ao) : Light yellow
o
1
+
solid (67.1 mg, 79%); m.p.=158~159 C. H NMR (400 MHz,
for C H ClN [M+H] , 368.0949; found, 368.0941.
23
15
3
CDCl ) δ 8.81 (s, 2H), 8.54 (d, J = 5.8 Hz, 2H), 8.19 (t, J = 8.3
3
2
-(Isoquinolin-1-yl)-4-phenylquinazoline (3ai): Light yellow
Hz, 2H), 7.95 (dd, J = 11.2, 4.2 Hz, 2H), 7.91 – 7.86 (m, 2H),
o
1
13
solid (81.0 mg, 81%); m.p.=165~166 C. H NMR (400 MHz,
7.63 (dd, J = 9.9, 6.4 Hz, 4H). C NMR (100 MHz, CDCl ) δ
3
CDCl ) δ 8.75 (d, J = 5.2 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.30
168.8, 158.1, 151.8, 150.3, 145.7, 137.2, 133.9, 130.2, 130.2,
129.4, 128.6, 128.1, 127.1, 122.5, 122.3. IR (KBr): 3038, 2921,
1740, 1533, 1340, 761, 686 cm .
3
(d, J = 8.4 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.96 (t, J = 7.6 Hz,
-1
1
H), 7.89 (d, J = 5.5 Hz, 3H), 7.77 (d, J = 5.1 Hz, 1H), 7.70-7.64
13
(m, 2H), 7.60-7.55 (m, 4H). C NMR (100 MHz, CDCl ) δ
3
4
-Phenyl-2-(pyrazin-2-yl)quinazolineo (3ap): Light yellow
1
1
1
68.8, 160.9, 156.7, 151.5, 142.3, 137.1, 137.0, 133.9, 130.1,
30.0, 130.0, 129.4, 128.5, 128.1, 127.6, 127.3, 127.0, 126.9,
26.9, 121.9, 121.7. IR (KBr): 3050, 2923, 1743, 1541, 762, 690
1
solid (52.9 mg, 62%); m.p.=182~183 C. H NMR (400 MHz,
CDCl ) δ 9.96 (s, 1H), 8.86 (s, 1H), 8.71 (s, 1H), 8.37 (d, J = 8.5
3
-
1
-1
Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.97 (t, J = 7.7 Hz, 1H), 7.91 –
cm . IR (KBr): 3033, 2921, 1727, 1538, 761, 684 cm . HRMS
13
+
7.87 (m, 2H), 7.69 – 7.59 (m, 4H). C NMR (100 MHz, CDCl
3
)
(ESI) m/z: calcd for C H N [M+H] , 334.1339; found,
23 16 3
δ 169.2, 157.5, 151.8, 150.7, 146.0, 145.2, 144.6, 137.0, 134.1,
30.2, 130.2, 129.7, 128.6, 128.4, 127.1, 122.4. IR (KBr): 3058,
3
34.1332.
-Phenyl-2-(quinolin-4-yl)quinazoline (3aj): Light yellow
1
-
1
4
2919, 1736, 1540, 1090, 765, 689 cm . HRMS (ESI) m/z: calcd
for C H N [M+H] , 285.1135; found, 285.1128.
o
1
+
solid (78.0 mg, 78%); m.p.=164~165 C. H NMR (400 MHz,
18
13
4
CDCl ) δ 9.09 (d, J = 4.4 Hz, 1H), 8.89 (d, J = 8.1 Hz, 1H), 8.24
3
4
-Phenyl-2-(pyrimidin-4-yl)quinazoline (3aq): Yellow solid
o 1
(t, J = 9.0 Hz, 3H), 8.16 (d, J = 4.4 Hz, 1H), 8.01 – 7.95 (m, 1H),
(
29.0 mg, 34%); m.p.=179~180 C. H NMR (400 MHz, CDCl )
3
7
.89 (dd, J = 6.6, 2.9 Hz, 2H), 7.79 – 7.74 (m, 1H), 7.71 – 7.57
13
δ 9.50 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.65 (d, J = 5.1 Hz, 1H),
.35 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.94 (t, J = 7.7
Hz, 1H), 7.87 – 7.82 (m, 2H), 7.64 (t, J = 7.7 Hz, 1H), 7.59 –
(m, 5H). C NMR (100 MHz, CDCl ) δ 168.8, 160.5, 151.5,
3
8
1
1
50.0, 149.1, 144.0, 137.0, 134.1, 130.2, 130.1, 129.8, 129.3,
28.7, 128.3, 127.2, 127.1, 126.3, 126.0, 122.8, 121.6. HRMS
13
+
7.56 (m, 3H). C NMR (100 MHz, CDCl
3
) δ 169.1, 162.1, 159.5,
58.3, 157.3, 151.7, 136.9, 134.1, 130.2, 130.1, 129.9, 128.8,
28.6, 127.0, 122.7, 120.4. IR (KBr): 3045, 2925, 1732, 1551,
(ESI) m/z: calcd for C H N [M+H] , 334.1339; found,
23
16
3
1
1
3
34.1331.
4
a
-1
4
-Phenyl-2-(pyridin-2-yl)quinazoline (3ak) : Light yellow
1362,763, 690 cm . HRMS (ESI) m/z: calcd for C H N
18 13 4
+
o
1
solid (65.4 mg, 77%); m.p.=178~179 C. H NMR (400 MHz,
[M+H] , 285.1135; found, 285.1129.
CDCl ) δ 8.91 (s, 1H), 8.75 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 8.4
3
2
-(4-Phenylquinazolin-2-yl)benzo[d]thiazole (3ar): Light
Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.97 – 7.84 (m, 4H), 7.60 –
o
1
13
yellow solid (80.4 mg, 79%); m.p.=214~215 C. H NMR (400
MHz, CDCl ) δ 8.38 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 7.9 Hz,
H), 8.20 (d, J = 8.3 Hz, 1H), 8.00-7.92 (m, 4H), 7.70 – 7.60 (m,
4H), 7.54 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H). C NMR
100 MHz, CDCl ) δ 169.2, 168.0, 155.2, 154.6, 151.8, 136.9,
7
.57 (m, 4H), 7.43 – 7.38 (m, 1H). C NMR (100 MHz, CDCl3)
3
δ 168.8, 159.0, 155.3, 152.0, 150.2, 137.3, 136.9, 133.7, 130.1,
1
1
3
29.9, 129.9, 128.5, 127.8, 126.9, 124.6, 124.3, 122.2. IR (KBr):
048, 2923, 1743, 1543, 1088, 765, 696 cm .
13
-
1
(
3
2
-(4-Methylpyridin-2-yl)-4-phenylquinazoline (3al): Light
136.7, 134.3, 130.3, 129.9, 128.7, 128.6, 127.3, 126.4, 126.2,
124.9, 122.8, 121.8. IR (KBr): 3033, 2920, 1743, 1533, 760, 688
o
1
yellow solid (71.4 mg, 80%); m.p.=108~109 C. H NMR (400
MHz, CDCl ) δ 8.66 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 8.32 (d, J
-
1
+
cm . HRMS (ESI) m/z: calcd for C H N S [M+H] , 340.0903;
3
21 14 3
=
5.2 Hz, 1H), 8.16 (dd, J = 11.4, 8.5 Hz, 2H), 7.95 – 7.84 (m,
found, 340.0895.
13
3
H), 7.61-7.56 (m, 4H), 2.69 (s, 3H). C NMR (100 MHz,
CDCl ) δ 168.6, 158.9, 158.3, 151.7, 149.5, 145.8, 137.2, 133.9,
3

7
4
374; (c) Reux, B.; Nevalainen, T.; Raitio, K. H.; Koskinen, A.
M. P. Bioorg. Med. Chem. 2009, 17, 4441–4447.
Wu, J.-S.; Cheng, S.-W.; Cheng, Y.-J.; Hsu, C.-S. Chem. Soc. Rev.
015, 44, 1113–1154.
2
-(4-Phenylquinazolin-2-yl)thiazole (3as): Light yellow solid
o 1
(
36.5 mg, 42%); m.p.=171~172 C. H NMR (400 MHz, CDCl )
δ 8.27 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.09 (d, J =
.1 Hz, 1H), 7.93 – 7.84 (m, 3H), 7.62 – 7.51 (m, 5H). C NMR
100 MHz, CDCl ) δ 169.1, 167.7, 155.1, 151.7, 145.2, 136.7,
34.1, 130.2, 129.6, 128.5, 128.0, 127.1, 122.9, 122.5. IR (KBr):
051, 2918, 1733, 1535, 1058, 762, 689 cm . HRMS (ESI) m/z:
calcd for C H N S [M+H] , 290.0746; found, 290.0737.
3
7
8
.
.
2
13
3
(
1
3
(a) Kuo, G.-H.; Prouty, C.; Wang, A.; Emanuel, S.; DeAngelis, A.;
Zhang, Y.; Song, F.; Beall, L.; Connolly, P. J.; Karnachi, P.; Chen,
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Middleton, S. A.; Jolliffe, L.; Murray, W. V. J. Med. Chem. 2005,
48, 4892–4909; (b) Vasta, J. D.; Raines, R. T. Biochemistry 2016,
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-1
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17
12
3
5
5, 3224–3233.
9
1
.
Hughes, R. A.; Moody, C. J. Angew. Chem. Int. Ed. 2007, 46,
7930–7954
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This work was supported by the National Natural Science
Foundation of China (21702096), Natural Science Foundation of
Guangdong Province (2017A030310546), and the High-level
Talent Introduction Foundation of Southern Medical University
7
343–7346; (d) Gao, X.; Zhang, F.; Deng, G.; Yang, L. Org. Lett.,
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►
►
►
copper-catalyzed cascade oxidative cyclization
O as a sole oxidant
2
available starting materials, good functional group tolerance

Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.