Copper-catalyzed aerobic oxidative decarboxylative amination of arylacetic acids: A facile access to 2-arylquinazolines

Article abstract of DOI:10.1039/c6ra04195g

An efficient copper-catalyzed oxidative decarboxylative amination of arylacetic acids with 2-aminobenzoketones and ammonium acetate under an oxygen atmosphere was first developed. This reaction represents a novel avenue for 2-arylquinazolines in good to e

Full text of DOI:10.1039/c6ra04195g

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Copper-catalyzed aerobic oxidative decarboxylative amination of
arylacetic acids: a facile access to 2-arylquinazolines
Yizhe Yan,a,b* Miaomiao Shi,a Bin Niua, Xiangping Menga, Changrui Zhua, Gengyao Liua, Ting Chena
and Yanqi Liua*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient copper-catalyzed oxidative decarboxylative amination of arylacetic acids with 2-aminobenzoketones and
ammonium acetate under oxygen atmosphere was first developed. This reaction represents a novel avenue for 2-
arylquinazolines in good to excellent yields via multiple C-N bond formations. This protocol features inexpensive copper as
the catalyst, molecular oxygen as the sole oxidant, H2O and CO2 as wastes, and broad substrate scope.
www.rsc.org/
SH
S
N
S
N
NH2
Introduction
Ar
C-N and C-S
C-N and C-O
Quinazolines are important structural units found in many
natural products and pharmaceuticals such as Lapatinib,
Prazosin, Iressa, Erlotinib and Linagliptin (Figure 1).1 Due to
their good biological activities, recently, a variety of substrates,
such as 2-aminobenzonitriles or anthranilic acids,2 2-
O
+
[N]
Ar
Ar
NH2
N
H
C
R1
R2
Ar
COOH
H2
N
S8
+
S
R1
C-H/C-C cleavage
C-N and C-S
Two C-N
Ar
N
R2
halobenzaldehyds,3
aminobenzylamines,5
2-halobenzylamines,4
N-arylamidines6
2-
2-
[N1
]
+
[N2
]
N1
and
Ar
N2
Our work
aminobenzoketones7 have been used as raw materials for the
synthesis of 2-arylquinazolines. However, these methods
usually required the use of either strongly acidic (or basic)
conditions or excess peroxide reagents. Therefore, the
development of more environmentally friendly methods
remains highly desirable.
Scheme 1 New strategies for C-N formation through oxidative decarboxylations of
arylacetic acids
In
the
past
decades,
transition-metal-catalyzed
decarboxylative couplings have emerged as important
strategies for direct C-X bond formations because of atom and
step economical advantages.8 Recently, the decarboxylative
reactions involving the cleavage of C(sp3)−COOH bonds were
reported for the construction of C-C,9 C-F(Cl),10 C-O,11 C-N,12 C-
P13 and C-S14. More recently, arylacetic acids as cheap and
available substrates were employed for single C-N bond
formation via oxidative decarboxylations (Scheme 1).15 To the
best of our knowledge, the construction of multiple C-N bonds
with arylacetic acids as substrates has rarely been reported.
Herein, we report a method for the synthesis of quinazolines
via copper-catalyzed oxidative decarboxylative amination of
arylacetic acids. Two C-N bonds were formed in a one-pot
reaction under oxygen conditions.
O
O
NH2
N
F
O
S
O
O
HN
F
N
HN
Cl
N
N
O
O
HN
Cl
O
N
N
N
N
O
N
Prazosin
Iressa
Lapatinib
NH2
O
N
O
N
N
N
HN
N
N
O
O
O
N
N
Lingaliptin
Erlotinib
Figure 1 Quinazolines as core structures in drugs
Results and discussion
Initially, 2-aminobenzophenone (1a) and 4-chlorophenylacetic
acid (2a) were chosen as model substrates to optimize the
reaction conditions. As depicted in Table 1, the catalyst,
oxidant, nitrogen source and solvent obviously affected the
efficiency of this reaction. First, the reaction of 1a (0.2 mmol),
2a (2.0 equiv) and ammonium acetate (2.0 equiv) in DMSO (1
a.School of Food and Biological Engineering, Zhengzhou University of Light Industry,
Zhengzhou, 450000, P. R. China. Email: yanyizhe@mail.ustc.edu.cn.
b.Collaborative Innovation Center of Food Production and Safety, Henan Province,
P. R. China.
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
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Table 1 Optimization of reaction conditionsa
Table 2 The scope of various arylacetic acids a
Yield(%)b
Entry
Ar
Product
Yield(%)b
Entry Cat
[N]
[O]
Solvent
1
4-Cl-Ph
Ph
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
97
88
95
82
97
93
99
75
17
89
85
74
52
65
80
1
Cu(OAc)2
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH3(aq)
NH4Cl
O2
DMSO
DMF
78
85
97
27
85
35
0
2
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
O2
3
4-F-Ph
4-Br-Ph
3-Cl-Ph
2-Cl-Ph
4-CF3-Ph
4-CN-Ph
3
O2
NMP
CH3CN
NMP
NMP
NMP
NMP
NMP
NMP
4
4
O2
5
5
O2
6
6
O2
7
2g
2h
2i
3ag
3ah
3ai
7
O2
8
8
NH4OAc
NH4OAc
NH4OAc
TBHPc
DTBPc
Air
40
41
78
9
4-NO2-Ph
4-Me-Ph
3-Me-Ph
2-Me-Ph
4-OMe-Ph
1-naphthyl
2-thienyl
9
10
11
12
13
14
15
2j
3aj
10
2k
2l
3ak
3al
11
12
13
14
15
16
Cu(OAc)2
Cu(OTf)2
CuBr2
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
N2
O2
O2
O2
O2
O2
NMP
NMP
NMP
NMP
NMP
NMP
trace
96
97
77
78
0
2m
2n
2o
3am
3an
3ao
CuI
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), NH4OAc (0.4 mmol), Cu(OAc)2
(0.04 mmol), NMP (1 mL), O2 (1atm), 120 °C, 20 h. b Isolated yield.
CuBr
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [N] (0.4 mmol), catalyst (0.04
mmol), solvent (1 mL), 120 °C, 20 h. b Isolated yield. c 4 equiv of peroxide reagent
was used under N2.
yields (Table 2, entries 1-13). It is noteworthy that phenylacetic
acids bearing electron-withdrawing groups (4-CF3, 4-F or 4-Cl)
gave the desired products in higher yields than electron-
donating groups (4-Me or 4-OMe) on the phenyl ring (Table 2,
entries 1,3 7, 10, and 13). Moreover, the position of the
substituents on the phenyl ring had some effect on yields
(Table 2, entries 1, 5-6 and 10-12). Ortho-substituted
substrates usually gave lower yields of the products compared
to meta- and para-substituted substrates, probably because of
steric hindrance. In addition, 1-naphthylacetic acid and 2-
thienyl acetic acid also gave the corresponding products in 65%
and 80% yields, respectively (Table 2, entries 14 and 15).
Subsequently, we investigated the scope of ortho-carbonyl-
substituted anilines under the optimized reaction conditions
(Table 3). First, the reaction of 1b-1g with an aryl group as R1
substituent and phenylacetic acid (2b) gave the corresponding
products 3bb-3gb in 92-97% yields (Table 3, entries 1-6).
Moreover, substrates 1h-1n with an aliphatic group as R1
substituent also gave the desired products 3hb-3nb in 10-90%
yields. It is noteworthy that substrates 1i and 1j gave a
unexpected 2-phenylquinazoline (3ib’ or 3jb’) by copper-
catalyzed C-C bond cleavage (Table 3, entries 8 and 9). Finally,
when 2-amino-5-chlorobenzophenone (1o) and 2-amino-5-
nitrobenzophenone (1p) were employed as the substrates, the
desired products 3ob and 3pb were obtained in 80% and 33%
yields, respectively (Table 3, entries 14 and 15). Notably, F, Cl,
Br, CN and NO2 group of the substrates remained intact during
all the reactions, providing an additional handle for further
derivatization.
mL) at 120 °C for 20 h using copper acetate (20 mol%) as
catalyst and oxygen as oxidant, gave 2-(4-chlorophenyl)-4-
phenylquinazoline (3aa) in 78% isolated yield (Table 1, entry
1). Among various solvents employed, NMP gave the highest
97% yield (Table 1, entries 2-4). When other nitrogen sources
such as ammonia (25% in water) and ammonium chloride were
used instead of ammonium acetate, no better result was
obtained (Table 1, entries 5 and 6). Expectedly, in the absence
of nitrogen source, no desired product 3a was detected (Table
1, entry 7). Subsequently, examination of various peroxides,
such as tert-butyl hydroperoxide (TBHP, 70% in water), di-tert-
butylperoxide (DTBP) or air, didn’t obtain better results (Table
1, entries 8-10). However, none of 3a was obtained under
nitrogen atmosphere, which indicated that molecular oxygen is
essential for this reaction (Table 1, entry 11). In addition,
When various copper catalysts, such as Cu(OTf)2, CuBr2, CuI
and CuBr, were used in this reaction, CuBr2 gave the same yield
with Cu(OAc)2 and other copper catalysts gave lower yields
than Cu(OAc)2 (Table 1, entries 12-15). In the absence of
copper catalyst, the reaction did not smoothly proceed (Table
1, entry 16). Thus, an optimal set of conditions are determined
as described in entry 3.
Under the optimal reaction conditions, we investigated the
scope of various arylacetic acids 2a-2o for the synthesis of
quinazolines (Table 2). First, when a variety of substituted
phenylacetic acids 2a-2m were employed in this reaction, the
corresponding products 3aa-3am could be obtained in 17-99%
To gain an insight into the reaction mechanism, several
control experiments were conducted (Scheme 2). Firstly, we
2 | J. Name., 2012, 00, 1-3
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observed that the reaction was completely inhibited in the
presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a
Table 3. The Scope of Various AminesOrtho-carbonyl anilinesa
Entry
1
R1
R2
H
Product
3bb
Yield(%)b
96
4-F-Ph
4-Cl-Ph
4-Br-Ph
3,5-di-F-Ph
4-Me-Ph
2-naphthyl
Me
1b
1c
1d
1e
1f
2
H
3cb
93
3
H
3db
94
Scheme 3. A Proposed Mechanism
4
H
3eb
97
5
H
3fb
92
On the basis of results described above and previous
reports,15 a plausible mechanism is proposed for the formation
of the quinazolines (Scheme 3). Initially, the coordination of 2b
to Cu(OAc)2 and subsequent ligand exchange generates a
6
H
1g
1h
1i
3gb
93
7
H
3hb
30
8
n-Bu
H
3ib(3ib’)
3jb(3jb’)
3kb
15(30)
10(35)
85
9
hexadecyl
i-Pr
H
1j
copper complex
of . Subsequently, oxygen insertion to
species , which is transformed into a copper species
the intermediate benzaldehyde via β-H elimination.
A
. Then
B
was formed though decarboxylation
gives a copper
and
in the
10
11
12
13
14
15
H
1k
1l
A
B
t-Bu
H
3lb
80
cyclopropyl
cyclopentyl
Ph
H
1m
1n
1o
3mb
3nb
90
C
D
H
85
D
5-Cl
3ob
80
presence of HOAc regenerates Cu(OAc)2. Then the
intermediate benzaldehyde and 4 which was generated by
condensation of 1a and nitrogen source, give the intermediate
5. Finally, the product 3ab is obtained via a tandem
intramolecular nucleophilic addition and condensation-
oxidative aromatization 5 in the presence of Cu( )/O2.15a
Ph
5-NO2 1p
3pb
33
a Reaction conditions: 1 (0.2 mmol), 2b (0.4 mmol), NH4OAc (0.4 mmol), Cu(OAc)2
(0.04 mmol), NMP (1 mL), O2 (1atm), 120 °C, 20 h. b Isolated yield. c Isolated yield
of 2-phenylquinazoline was given in parenthesis.
radical scavenger (Scheme 2a). This observation implied that
the reaction might proceed via a radical pathway. When
phenylacetic acid was performed under standard conditions,
benzaldehyde was obtainded in 35% yield (Scheme 2b). Then
when 1a and benzaldehyde, instead of 2b were carried out
under standard conditions, 3ab was obtained in 95% yield.
However, when other possible intermediates, such as toluene,
benzoic acid, benzonitrile, 2-oxo-2-phenylacetic acid and
benzamide were tested, 3ab was not detected (Scheme 2c).
These results indicated that benzaldehyde may be the
intermediate of this reaction.
Conclusions
In summary, we have developed a copper-catalyzed aerobic
decarboxylative amination of arylacetic acids with 2-
aminobenzoketones and ammonium acetate, affording 2-
arylquinazolines in moderate to excellent yields. Multiple C-N
bonds are formed in a one-pot process via C-H/C-C cleavage.
Compared with previous reports, this novel protocol is
distinguished by 1) cheap copper catalysis, 2) operational
simplicity, 3) molecular oxygen as the sole oxidant 4) H2O and
CO2 as wastes, and 5) a broad substrate scope. Further studies
are ongoing to expand the synthetic utility of this versatile
catalytic system.
Experimental
General information
Unless otherwise indicated, all commercial reagents and
solvents were used without additional purification. Chemical
shifts (in ppm) of 1H-NMR spectra were referenced to
tetramethylsilane (δ = 0 ppm) in CDCl3 as an internal standard.
13C-NMR spectra were calibrated with CDCl3 (δ = 77.16 ppm).
HRMS (EI) was recorded on a TOF mass analyzer.
General procedure for the synthesis of 2-arylquinazolines
Substrate
1 (0.2 mmol), 2 (0.4 mmol), NH4OAc (30.8 mg, 0.4
mmol), Cu(OAc)2 (8 mg, 0.04 mmol) and NMP (1.0 mL) were
successively added to a 10 mL of reaction tube with three-way
Scheme 2 Control experiments
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valve. After three times of oxygen displacement, the mixture = 32Hz), 130.3, 129.2, 129.1, 128.8, 127.8, 127.3, 125.7, 125.6
was stirred using oxygen balloon at 120 °C as monitored by TLC. (q, JC-F = 3.6Hz), 124.4 (q, JC-F = 270.6Hz), 122.0.
The solution was then cooled to r.t. and quenched by 4-(4-phenylquinazolin-2-yl)benzonitrile
(
3ah)6b: Yield: 75%
1
saturated NaHCO3 solution. The aqueous layers was extracted (46.0 mg); White solid; Mp: 197-199 °C; H NMR (400MHz,
with EtOAc (3x10 mL), the combined organic layers were dried CDCl3): δ 8.81 (dd, J1 = 6.8Hz, J2 = 2.0Hz, 2H), 8.19-8.15 (m, 2H),
over Na2SO4, filtered, and evaporated under vacuum. The 7.96-7.91 (m, 1H), 7.89-7.86 (m, 2H), 7.82-7.78 (m, 2H), 7.64-
residue was purified by column chromatography on silica gel 7.59 (m, 4H); 13C NMR (100MHz, CDCl3): δ 168.8, 158.4, 151.9,
(petroleum ether : ethyl acetate = 15:1) to afford the desired 142.5, 137.4, 134.1, 132.4, 130.34, 130.29, 129.5, 129.2, 128.8,
2-arylquinazolines
3
.
128.1, 127.3, 122.1, 119.1, 113.9.
2-(4-nitrophenyl)-4-phenylquinazoline (
3ai)7. White solid (11.0
Characterization Data for the Products
mg, 17%); Mp: 195-197 °C; 1H NMR (400MHz, CDCl3): δ 8.90 (d,
J = 8.8Hz, 2H), 8.37 (d, J = 9.2Hz, 2H), 8.23-8.17 (m, 2H), 7.99-
7.93 (m, 1H), 7.91-7.88 (m, 2H), 7.67-7.61 (m, 4H); 13C NMR
(100MHz, CDCl3): δ 169.0, 158.1, 151.9, 149.4, 144.2, 137.4,
134.2, 130.4, 130.3, 129.7, 129.5, 128.8, 128.2, 127.3, 123.8,
122.2.
2-(4-chlorophenyl)-4-phenylquinazoline
(
3aa)7: Yield: 97%
1
(61.4 mg); White solid; Mp
CDCl3): δ 8.65 (d J = 8.4Hz
7.85 (m 3H), 7.64-7.54 (m
NMR (100MHz, CDCl3 : δ 168.7, 159.3, 151.9, 137.6, 136.9,
136.7, 133.9, 130.3, 130.21, 130.18, 129.2, 128.9, 128.7
：
190-192 °C; H NMR (400MHz
2H), 8.18-8.12 (m 2H), 7.92-
4H), 7.48 (d
J = 8.4Hz, 2H); 13C
，
，
，
，
，
，
，
）
，
4-phenyl-2-(p-tolyl)quinazoline (
3aj)7: Yield: 89% (52.7 mg);
127.4
2,4-diphenylquinazoline
yellow solid; Mp
，127.2, 121.8.
1
(
3ab)7: Yield: 88% (49.6 mg); Light
White solid; Mp: 166-168 °C; H NMR (400MHz, CDCl3): δ 8.59
(d, J = 8.0Hz, 2H), 8.21 (d, J = 8.4Hz, 1H), 8.15 (d, J = 8.4Hz, 1H),
7.95-7.85 (m, 3H), 7.62-7.58 (m, 3H), 7.55-7.50 (m, 1H), 7.33 (d,
J = 8.0Hz, 2H), 2.44 (s, 3H); 13C NMR (100MHz, CDCl3): δ 168.5,
160.4, 152.0, 141.0, 137.9, 135.5, 133.7, 130.3, 130.1, 129.5,
129.1, 128.8, 128.7, 127.2, 127.0, 121.7, 21.7.
：
117-119 °C；
1H NMR (400MHz, CDCl3): δ
8.72-8.68 (m, 2H), 8.18-8.10 (m, 2H), 7.90-7.85 (m, 3H), 7.62-
7.56 (m, 3H), 7.55-7.47 (m, 4H); 13C NMR (100MHz, CDCl3): δ
168.5, 160.3, 152.0, 138.2, 137.8, 133.7, 130.7, 130.3, 130.1,
129.2, 128.8, 128.7, 127.15, 127.14, 121.8.
3ak)7: Yield: 85% (50.3 mg);
1H NMR (400MHz, CDCl3): δ
2-(4-fluorophenyl)-4-phenylquinazoline
mg); White solid; Mp: 153-155 °C
1H NMR (400MHz, CDCl3):
(
3ac)7: Yield: 95% (57
4-phenyl-2-(m-tolyl)quinazoline
White solid; Mp: 115-117 °C
(
；
；
8.21-8.15 (m, 2H), 8.00-7.97 (m, 1H), 7.94-7.89 (m, 1H), 7.88-
7.84 (m, 2H), 7.62-7.56 (m, 4H), 7.37-7.32 (m, 3H), 2.67 (s, 3H);
13C NMR (100MHz, CDCl3): δ 168.3, 163.4, 151.6, 138.8, 137.57,
137.55, 133.8, 131.4, 130.9, 130.3, 130.1, 129.4, 129.1, 128.7,
127.5, 127.1, 126.1, 121.1, 21.4.
δ 8.73-8.67 (m, 2H), 8.15-8.10 (m, 2H), 7.91-7.85 (m, 3H), 7.62-
7.58 (m, 3H), 7.57-7.52 (m, 1H), 7.23-7.16 (m, 2H); 13C NMR
(100MHz, CDCl3): δ 168.6, 164.8 (d, JC-F = 248.6Hz), 159.4,
152.0, 137.7, 134.5 (d, JC-F = 2.8Hz), 133.8, 130.9 (d, JC-F
=
8.6Hz), 130.3, 130.1, 129.2, 128.7, 127.2, 126.8, 121.7, 115.6
4-phenyl-2-(o-tolyl)quinazoline (
3al)7: Yield: 74% (43.8 mg);
(d, JC-F = 21.3Hz).
1
2-(4-bromophenyl)-4-phenylquinazoline
(
3ad)7: Yield: 82%
；
1H NMR (400MHz,
White solid; Mp: 72-74 °C; H NMR (400MHz, CDCl3): δ 8.22-
8.15 (m, 2H), 7.99-7.97 (m, 1H), 7.94-7.89 (m, 1H), 7.88-7.84
(m, 2H), 7.62-7.56 (m, 4H), 7.37-7.33 (m, 3H), 2.67 (s, 3H); 13C
NMR (100MHz, CDCl3): δ 168.3, 163.4, 151.5, 138.7, 137.54,
137.52, 133.9, 131.4, 130.9, 130.3, 130.1, 129.5, 129.0, 128.7,
127.5, 127.1, 126.1, 121.1, 21.4.
(59.2 mg); White solid; Mp: 192-194 °C
CDCl3): δ 8.60-8.56 (m, 2H), 8.16-8.11 (m, 2H), 7.92-7.86 (m,
3H), 7.67-7.50 (m, 6H); 13C NMR (100MHz, CDCl3): δ 168.6,
159.4, 152.0, 137.6, 137.2, 133.9, 131.8, 130.4, 130.3, 130.2,
129.2, 128.7, 127.4, 127.2, 125.5, 121.9.
2-(4-methoxyphenyl)-4-phenylquinazoline (
3am)7: Yield: 52%
2-(3-chlorophenyl)-4-phenylquinazoline
(61.4 mg); White solid; Mp
(
3ae)7: Yield: 97%
1
1
116-118 °C; H NMR (400MHz,
(32.4 mg); White solid; Mp: 158-160 °C; H NMR (400MHz,
CDCl3): δ 8.68-8.65 (m, 2H), 8.14 (d, J = 8.4Hz, 1H), 8.09 (dd, J1
= 8.4Hz, J2 = 0.8Hz, 1H), 7.90-7.84 (m, 3H), 7.62-7.58 (m, 3H),
7.53-7.50 (m, 1H), 3.89 (s, 3H); 13C NMR (100MHz, CDCl3): δ
168.5, 162.0, 160.1, 151.8, 137.8, 133.7, 130.7, 130.6, 130.3,
130.1, 128.8, 128.7, 127.2, 126.8, 121.1, 114.0, 55.5.
：
CDCl3): δ 8.70 (s, 1H), 8.61-8.58 (m, 1H), 8.19-8.12 (m, 2H),
7.93-7.86(m, 3H), 7.64-7.55 (m, 4H), 7.49-7.43 (m, 2H); 13C
NMR (100MHz, CDCl3): δ 168.7, 159.0, 151.9, 137.6, 134.8,
133.9, 130.6, 130.3, 130.2, 129.9, 129.3, 128.8, 128.7, 127.6,
127.2, 126.9, 122.0.
(
3an)7: Yield: 65%
7
2-(naphthalen-1-yl)-4-phenylquinazoline
2-(2-chlorophenyl)-4-phenylquinazoline
(
3af
)
:
Yield: 93%
(43.2 mg); Light yellow solid; Mp: 171-173 °C; 1H NMR
(400MHz, CDCl3): δ 8.76 (d, J = 8.0Hz, 1H), 8.35 (d, J = 8.4Hz,
1H), 8.27 (dd, J1 = 7.6Hz, J2 = 0.8Hz, 1H), 8.23 (d, J = 8.0Hz, 1H),
8.01-7.88 (m, 5H), 7.68-7.50 (m, 7H); 13C NMR (100MHz, CDCl3):
δ 169.1, 162.6, 151.1, 137.4, 134.33, 134.30, 131.4, 130.8,
130.4, 130.3, 130.2, 128.8, 128.7, 128.6, 127.9, 127.3, 127.0,
126.1, 126.0, 125.5, 125.0, 121.4.
(58.8 mg); White solid; Mp: 93-95 °C; 1H NMR (400MHz, CDCl3):
δ 8.27-8.19 (m, 2H), 7.98-7.86 (m, 4H), 7.67-7.62 (m, 1H), 7.60-
7.52 (m, 4H), 7.44-7.37 (m, 2H); 13C NMR (100MHz, CDCl3): δ
168.7, 161.2, 151.2, 138.2, 137.2, 134.2, 133.2, 132.0, 130.7,
130.5, 130.4, 130.3, 128.9, 128.8, 128.1, 127.2, 127.0, 121.5.
4-phenyl-2-(4-(trifluoromethyl)phenyl)quinazoline
(
3ag)7:
1
Yield: 99% (69.3 mg); White solid; Mp: 124-126 °C; H NMR
(400MHz, CDCl3): δ 8.82 (d, J = 8.0Hz, 2H), 8.21 (d, J = 8.4Hz,
1H), 8.15 (dd, J1 = 8.4Hz, J2 = 0.8Hz, 1H), 7.95-7.87 (m, 3H),
7.77 (d, J = 8.4Hz, 2H), 7.55-7.47 (m, 4H); 13C NMR (100MHz,
CDCl3): δ 168.9, 158.8, 151.7, 141.4, 137.5, 134.1, 132.2 (q, JC-F
4-phenyl-2-(thiophen-2-yl)quinazoline (3ao): Yield: 80% (46.0
1
mg); Light yellow solid; Mp: 151-153 °C; H NMR (400MHz,
CDCl3): δ 8.25-8.23 (m, 1H), 8.12-8.06 (m, 2H), 7.88-7.83 (m,
3H), 7.61-7.57 (m, 3H), 7.53-7.48 (m, 2H), 7.20-7.17 (m, 1H);
13C NMR (100MHz, CDCl3): δ 168.7, 157.2, 151.7, 144.1, 137.3,
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA04195G
Journal Name
134.0, 130.3, 130.22, 130.15, 129.7, 128.7, 128.4, 127.3, 126.9, 4-butyl-2-phenylquinazoline
ARTICLE
(
3ib)7:Yield:15% (7.8 mg); Light
121.6; HRMS (EI): calcd for C18H12N2S [M]+ 288.0721, found yellow solid; Mp: 45-47 °C; H NMR (400MHz, CDCl3): δ 8.66-
1
288.0710.
8.61 (m, 2H), 8.12-8.06 (m, 2H), 7.85-7.81 (m, 1H), 7.57-7.48
4-(4-fluorophenyl)-2-phenylquinazoline
(
3bb)7: Yield: 96% (m, 4H), 3.32 (t, J = 7.6Hz, 2H), 2.01-1.92 (m, 2H), 1.54 (sext, J =
(57.6 mg); White solid; Mp: 144-146 °C; H NMR (400MHz, 7.6Hz, 2H), 1.02 (t, J = 7.6Hz, 3H); 13C NMR (100MHz, CDCl3): δ
CDCl3): δ 8.70-8.66 (m, 2H), 8.18 (d, J = 8.4Hz, 1H), 8.11-8.08 171.7, 160.2, 150.8, 138.6, 133.4, 130.5, 129.5, 128.7, 128.6,
(m, 1H), 7.93-7.87 (m, 3H), 7.59-7.50 (m, 4H), 7.32-7.27 (m, 126.8, 124.7, 122.7, 34.4, 30.8, 22.9, 14.1.
1
2H); 13C NMR (100MHz, CDCl3): δ 167.4, 164.1 (d, J = 248.8Hz), 2-phenylquinazoline 3ib’)7:Yield: 30% (12.3 mg); Light yellow
(
1
160.3, 152.1, 138.1, 133.9 (d, J = 3.5Hz), 133.8, 132.4 (d, J = solid; Mp: 97-99 °C; H NMR (400MHz, CDCl3): δ 9.47 (s, 1H),
8.3Hz), 130.8, 129.4, 128.8, 128.7, 127.3, 126.9, 121.7, 115.8 8.64-8.61 (m, 2H), 8.10 (dd, J1 = 8.4Hz, J2 = 0.4 Hz, 1H), 7.94-
(d, J = 21.7Hz).
7.88 (m, 2H), 7.64-7.59 (m, 1H), 7.56-7.50 (m, 3H); 13C NMR
4-(4-chlorophenyl)-2-phenylquinazoline
(
3cb): Yield: 93% (100MHz, CDCl3): δ 161.2, 160.6, 150.9, 138.2, 134.3, 130.8,
1
(58.8 mg); White solid; Mp: 151-153 °C; H NMR (400MHz, 128.80, 128.79, 128.7, 127.4, 127.3, 123.8.
CDCl3): δ 8.69-8.66 (m, 2H), 8.16 (d, J = 8.4Hz, 1H), 8.16 (d, J1 = 4-hexadecyl-2-phenylquinazoline (
3jb)7: Yield: 10% (8.6 mg);
8.4Hz, J2 = 0.8Hz, 1H), 7.91-7.81 (m, 3H), 7.59-7.49 (m, 6H); 13
1
Light yellow solid; Mp: 66-68 °C; H NMR (400MHz, CDCl3): δ
C
NMR (100MHz, CDCl3): δ 167.2, 160.3, 152.1, 138.1, 136.4, 8.66-8.61 (m, 2H), 8.13-8.08 (m, 2H), 7.87-7.82 (m, 1H), 7.59-
136.2, 133.9, 131.7, 130.8, 129.4, 129.0, 128.8, 128.7, 127.4, 7.48 (m, 4H), 3.33 (t, J = 7.6Hz, 2H), 1.97 (quint, J = 7.6Hz, 2H),
126.7, 121.6; HRMS (EI): calcd for C20H13ClN2 [M]+ 316.0767, 1.54-1.47 (m, 2H), 1.44-1.36 (m, 2H), 1.27-1.20 (m, 22H), 0.88
found 316.0742.
(t, J = 7.2Hz, 3H); 13C NMR (100MHz, CDCl3): δ 171.8, 160.2,
4-(4-bromophenyl)-2-phenylquinazoline
1
(67.8 mg); White solid; Mp: 154-156 °C; H NMR (400MHz, 122.7, 34.8, 32.1, 29.85, 29.83, 29.75, 29.68, 29.5, 28.8, 22.8,
(
3db)7: Yield: 94% 150.8, 138.5, 133.5, 130.5, 129.5, 128.8, 128.7, 126.9, 124.8,
CDCl3): δ 8.69-8.66 (m, 2H), 8.16 (d, J = 8.4Hz, 1H), 8.16 (d, J = 14.3.
8.4Hz, 1H), 7.92-7.87 (m, 1H), 7.79-7.72 (m, 4H), 7.58-7.50 (m, 2-phenylquinazoline (
3jb’)7: Yield: 35% (14.4 mg); Light yellow
1
4H); 13C NMR (100MHz, CDCl3): δ 167.3, 160.3, 152.1, 138.0, solid; Mp: 97-99 °C; H NMR (400MHz, CDCl3): δ 9.47 (s, 1H),
136.6, 133.9, 131.94, 131.88, 130.8, 129.4, 128.8, 128.7, 127.4, 8.64-8.61 (m, 2H), 8.10 (dd, J1 = 8.4Hz, J2 = 0.4 Hz, 1H), 7.94-
7.88 (m, 2H), 7.64-7.59 (m, 1H), 7.56-7.50 (m, 3H); 13C NMR
126.7, 124.8, 121.5.
4-(3,5-difluorophenyl)-2-phenylquinazoline
(
3eb): Yield: 97% (100MHz, CDCl3): δ 161.2, 160.6, 150.9, 138.2, 134.3, 130.8,
1
(61.7 mg); White solid; Mp: 161-163 °C; H NMR (400MHz, 128.80, 128.79, 128.7, 127.4, 127.3, 123.8.
CDCl3): δ 8.69-8.65 (m, 2H), 8.19 (d, J = 8.4Hz, 1H), 8.08 (dd, J1 4-isopropyl-2-phenylquinazoline
3kb)7: Yield: 85% (42.1 mg);
(
1
= 8.4Hz, J2 = 0.8Hz, 1H), 7.95-7.90 (m, 1H), 7.62-7.51 (m
，4H), Light yellow solid; Mp: 64-66 °C; H NMR (400MHz, CDCl3): δ
7.44-7.41 (m, 2H), 7.08-7.02 (m, 1H); 13C NMR (100MHz, CDCl3): 8.71-8.68 (m, 2H), 8.14-8.09 (m, 2H), 7.84-7.79 (m, 1H), 7.56-
δ 165.9, 163.2 (dd, JC-F1 = 248.2Hz, JC-F2 = 12.4Hz), 160.3, 152.2, 7.48 (m, 4H), 3.93 (heptet, J = 7.2Hz, 1H), 1.50 (d, J = 7.2Hz,
140.8 (t, JC-F = 9.2Hz), 137.8, 134.2, 131.0, 129.5, 128.8, 127.7, 6H); 13C NMR (100MHz, CDCl3): δ 175.8, 160.0, 150.8, 138.5,
126.3, 121.3, 113.4 (dd, JC-F1 = 18.9Hz, JC-F2 = 7.4Hz), 105.5 (d, J 133.3, 130.6, 129.5, 128.6, 128.6, 126.8, 124.2, 121.8, 31.4,
= 25.0Hz); HRMS (EI): calcd for C20H12F2N2 [M]+ 318.0969, 21.9.
found 318.0949.
4-(tert-butyl)-2-phenylquinazoline (
3lb)7: Yield: 80% (41.9 mg);
1
2-phenyl-4-(p-tolyl)quinazoline (
3fb)7: Yield: 92% (54.5 mg); Light yellow solid; Mp: 70-72 °C; H NMR (400MHz, CDCl3): δ
White solid; Mp: 128-130 °C; 1H NMR (400MHz, CDCl3): δ 8.71- 8.70-8.67 (m, 2H), 8.46-8.43 (m, 1H), 8.13 (d, J = 8.4Hz, 1H),
8.68 (m, 2H), 8.16-8.11 (m
，2H), 7.89-7.81 (m, 1H), 7.78 (d, J = 7.83-7.78 (m, 1H), 7.56-7.48 (m，4H), 1.72 (s，
9H); 13C NMR
8.0Hz, 2H), 7.55-7.48 (m, 4H), 7.38 (d, J = 8.0Hz, 2H), 2.47 (s, (100MHz, CDCl3): δ 176.6, 159.0, 152.1, 138.6, 132.5, 130.5,
3H); 13C NMR (100MHz, CDCl3): δ 168.4, 160.3, 152.0, 140.3, 130.4, 128.7, 128.6, 126.7, 125.8, 121.7, 40.7, 30.8.
138.3, 135.0, 133.6, 130.6, 130.3, 129.4, 129.1, 128.7, 128.6, 4-cyclopropyl-2-phenylquinazoline
(
3mb)7: Yield: 90% (44.3
1
mg); Light yellow solid; Mp: 103-105 °C; H NMR (400MHz,
127.2, 127.0, 121.8, 21.6.
4-(naphthalen-2-yl)-2-phenylquinazoline
(3gb): Yield: 93% CDCl3): δ 8.61-8.58 (m, 2H), 8.30-8.27 (m, 1H), 8.08 (d, J =
1
(61.7 mg); White solid; Mp: 164-166 °C; H NMR (400MHz, 8.4Hz, 1H), 7.87-7.82 (m, 1H), 7.60-7.55 (m, 1H), 7.53-7.46 (m,
CDCl3): δ 8.75-8.71 (m, 2H), 8.34 (s, 1H), 8.22-8.16 (m, 2H), 3H), 2.84-2.77 (m, 1H), 1.58-1.53 (m, 2H), 1.28-1.23 (m, 2H);
8.07-7.94 (m, 4H), 7.92-7.86 (m, 4H), 7.62-7.50 (m, 6H); 13C 13C NMR (100MHz, CDCl3): δ 172.8, 159.9, 150.2, 138.4, 133.5,
NMR (100MHz, CDCl3): δ 168.5, 160.3, 152.0, 138.2, 135.1, 130.6, 129.2, 128.7, 128.6, 126.8, 124.5, 123.1, 29.8, 13.2, 12.4.
134.1, 133.8, 133.0, 130.8, 130.5, 129.2, 128.88, 128.86, 128.7, 4-cyclopentyl-2-phenylquinazoline
128.5, 128.0, 127.43, 127.36, 127.3, 127.2, 126.8, 122.0; HRMS mg); Light yellow solid; Mp: 79-81°C; 1H NMR (400MHz, CDCl3):
(
3nb)7: Yield: 85% (46.6
(EI): calcd for C24H16N2 [M]+ 332.1313, found 332.1299.
δ 8.68-8.65 (m, 2H), 8.18-8.15 (m, 1H), 8.07 (d, J = 8.0Hz, 1H),
4-methyl-2-phenylquinazoline
(
3hb)7: Yield: 30% (13.2 mg); 7.85-7.80 (m, 1H), 7.58-7.47 (m, 4H), 4.09-4.04 (m, 1H), 2.25-
1
Light yellow solid; Mp: 88-90 °C; H NMR (400MHz, CDCl3): δ 2.14 (m, 2H), 2.00-1.95 (m, 2H), 1.85-1.80 (m, 2H); 13C NMR
8.64-8.61 (m, 2H), 8.12-8.06 (m, 2H), 7.88-7.85 (m, 1H), 7.59- (100MHz, CDCl3): δ 174.5, 160.0, 151.0, 138.8, 133.1, 130.4,
7.48 (m, 4H), 3.01 (s, 3H); 13C NMR (100MHz, CDCl3): δ 168.6, 129.5, 128.7, 128.6, 126.6, 124.7, 122.6, 42.7, 32.7, 26.4.
160.2, 152.2, 138.2, 133.8, 130.6, 129.2, 128.8, 128.7, 127.1, 6-chloro-2,4-diphenylquinazoline (
3ob)7: Yield: 80% (50.6 mg);
125.1, 123.1, 22.2.
Light yellow solid; Mp: 190-192 °C; 1H NMR (400MHz, CDCl3): δ
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DOI: 10.1039/C6RA04195G
ARTICLE
Journal Name
and L. Liu, Sci. ChinaChem., 2011, 54, 1670; (d) W. I. Dzik, P.
P. Lange and L. J. Gooßen, Chem. Sci., 2012, , 2671; (e) C.
Shen, P. Zhang, Q. Sun, S. Bai, T. S. A. Hor and X. Liu, Chem.
Soc. Rev., 2015, 44, 291; (f) J. Xuan,; Z.-G. Zhang and W.-J.
Xiao, Angew. Chem., Int. Ed., 2015, 54, 15632.
(a) H.-P. Bi, L. Zhao, Y.-M. Liang and C.-J. Li, Angew. Chem.,
Int. Ed., 2009, 48, 792; (b) C. Zhang and D. Seidel, J. Am.
Chem. Soc., 2010, 132, 1798; (c) R. Shang, Z.-W. Yang, Y.
8.69-8.66 (m, 2H), 8.12-8.08 (m, 2H), 7.88-7.84 (m, 2H), 7.82-
7.79 (m, 1H), 7.63-7.59 (m, 3H), 7.56-7.49 (m, 3H), 2.25-2.14
(m, 2H), 2.00-1.95 (m, 2H), 1.85-1.80 (m, 2H); 13C NMR
(100MHz, CDCl3): δ 167.7, 160.5, 150.5, 137.8, 137.2, 134.7,
132.8, 130.96, 130.93, 130.4, 130.2, 128.9, 128.8, 128.7, 125.9,
122.3.
3
9
6-nitro-2,4-diphenylquinazoline (
3pb)7: Yield: 33% (21.6 mg);
Wang, S.-L. Zhang and L. Liu, J. Am. Chem. Soc., 2010, 132
,
Light yellow solid; Mp: 248-250 °C; 1H NMR (400MHz, CDCl3): δ
9.07 (d, J = 2.5Hz, 1H), 8.76-8.73 (m, 2H), 8.68-8.63 (m, 1H),
8.29 (d, J = 9.2Hz, 1H), 7.94-7.90 (m, 2H), 7.69-7.67 (m, 3H),
7.58-7.55 (m, 3H); 13C NMR (100MHz, CDCl3): δ 170.7, 163.0,
154.5, 145.6, 137.1, 136.5, 132.0, 131.2, 131.1, 130.4, 129.4,
129.2, 128.9, 127.2, 124.4, 120.6.
14391; (d) R. Shang, D.-S. Ji, L. Chu, Y. Fu and L. Liu, Angew.
Chem., Int. Ed., 2011, 50, 4470; (e) X. Liu, Z. Wang, X. Cheng
and C. Li, J. Am. Chem. Soc., 2012, 134, 14330.
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Soc., 2012, 134, 4258; (b) F. Yin, Z. Wang, Z. Li and C. Li, J.
Am. Chem. Soc., 2012, 134, 10401; (c) S. Ventre, F. R.
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Lett., 2014, 16, 4646; (b) K. Xu, Z. Wang, J. Zhang, L. Yu and J.
Tan, Org. Lett., 2015, 17, 4476.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21502177), Science and Technology Research Key
12 K. Kiyokawa, T. Kojima, Y. Hishikawa and S. Minakata, Chem.
Eur. J., 2015, 21, 15548.
Project of Department of Education of Henan Province 13 J. Hu, N. Zhao, B. Yang, G. Wang, L.-N. Guo, Y.-M. Liang and
S.-D. Yang, Chem. Eur. J., 2011, 17, 5516.
(15A150005) and the Doctoral Research Foundation of
Zhengzhou University of Light Industry (2014BSJJ032).
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8
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA04195G
Copper-catalyzed aerobic oxidative decarboxylative amination of
arylacetic acids: a facile access to 2-arylquinazolines
Yizhe Yan,a,b* Miaomiao Shi,a Bin Niua, Xiangping Menga, Changrui Zhua, Gengyao Liua, Ting Chena and
Yanqi Liua*
An efficient copper-catalyzed oxidative decarboxylative amination of arylacetic acids with
2-aminobenzoketones and ammonium acetate under oxygen atmosphere was first developed.