One-pot three-component synthesis of quinazolines: Via a copper-catalysed oxidative amination reaction

Article abstract of DOI:10.1039/c6ob00625f

A copper-catalysed three-component reaction for constructing a series of quinazoline derivatives has been developed. In this system, solvents act as the reactants and different functional groups are well tolerated to obtain corresponding products in moderate to good yields.

Full text of DOI:10.1039/c6ob00625f

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One-pot three-component synthesis of quinazolines via a
copper-catalysed oxidative amination reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Tiantian Duana, Tianran Zhai a, Huanhuan Liua, Zilong Yana, Yue Zhaoa, Lei Fenga, Chen
Ma*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A copperꢀcatalysed threeꢀcomponent reaction for constructing a series of quinazoline derivatives
has been developed. In this system, solvents are acted as the reactants and different functional
groups are well tolerated to give corresponding products in moderate to good yields.
Introduction
Quinazolines are
a kind of important Nꢀfused heterocyclic
compounds with extensive biological and pharmacological activities,
which are widely applied in the fields of pesticide, medicine, and
pharmacy.1ꢀ2 Because of their anticancer,3 antiviral,4 antitubercular5
and antioxidant6 activities, numerous quinazoline derivatives have
been developed to available drugs, such as bactericide
fluquinconazole, insecticide fenazaquin and anticancer drugs iressa.5
Owing to their wide applications in pharmaceutical area, more and
more attention has been paid on the synthesis of quinazoline
derivatives. Numerous work has been reported in the past years, but
some problems still exist in the research, such as the use of volatile
solvents,7 high temperature,8 expensive metal catalysts9 and multiꢀ
step reactions.10 Recently, Wang developed a I2ꢀcatalyzed strategy
from 2ꢀformylpyrroles and αꢀamino acids to construct quinazoline
derivatives (Scheme 1a).11 Next, the same group reported a method
for the formation of quinazoline derivatives via an iodineꢀcatalysed
intermolecular oxidative amination of a C(sp3)ꢀH bond adjacent to
the nitrogen or oxygen atom of Nꢀalkylamides with orthoꢀcarbonylꢀ
substituted anilines in 2011. (Scheme 1b).12 Li proposed a KIꢀ
catalysed protocol via amination of benzylic CꢀH bonds of
methylarenes to form quinazoline derivatives (Scheme 1c).13 In these
transformations, peroxides which were excessive and easily
exploded at high temperature were used as oxidant. Thus, it is highly
desirable to develop a simple, efficient, and lowꢀtoxic approach for
the synthesis of quinazolines.
Scheme 1. preparation of quinazoline derivatives.
In recent years, more and more reports about copperꢀcatalysed14
CꢀH bond activation15 and CꢀN16 bond formation are abundantly
present. The main reason is that copper salts have some advantages
such as inexpensive, handleꢀeasily and generally efficient.17 In
addition, dimethylsulfoxide (DMSO) is usually used as a polar
solvent. Besides, DMSO is recognized as carbon source in numerous
copperꢀcatalyzed transformations in last few years.18 Based on our
previous work19 and other research20 on construction of various
aKey Laboratory of Special Functional Aggregated Materials, Ministry of
Education, School of Chemistry and Chemical Engineering, Shandong
University, Jinan, 250100, P. R. China.
bState Key Laboratory of Bioactive Substance and Function of Natural
Medicines, Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing, 100050, P. R.
China.Eꢀmail:chenma@sdu.edu.cn
heterocyclic compounds, we report
a copperꢀcatalysed threeꢀ
component reaction to produce quinazoline derivatives. DMSO and
Nꢀalkylamides are selected as sp3 carbon source, NH4OAc is used as
cheap nitrogen source,21 and molecular oxygen is chosen as clean
and green oxidant (Scheme 1).
†
Electronic supplementary information (ESI) available: The NMR spectra
of all synthesized new compounds. See DOI: 10.1039/b000000x/
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Journal Name
Results and discussion
Table 1. Optimization of reaction conditionsa
Yield/
%
Entry
1
R1
H
R2
Product
b
Phenyl
85
Yieldb
/%
3a
Entry
Cat.
CuCl
—
N source
Acid
AcOH
AcOH
—
T/oC
110
110
110
NH3·H2
O
NH3·H2
O
NH3·H2
O
NH4OAc
NH4I
NH4Cl
1
2
3
84
62
46
2
3
4
H
H
H
4ꢀFluorophenyl
4ꢀChlorophenyl
pꢀTolyl
77
3b
CuCl
80
4
5
6
7
8
9
10
11
CuCl
CuCl
CuCl
CuCl
CuCl
AcOH
AcOH
AcOH
110
110
110
110
110
110
110
110
85
56
46
79
70
68
70
84
3c
NH4OAc TsOH·H2O
70
NH4OAc
NH4OAc
NH4OAc
NH4OAc
Ph2PO2H
AcOH
AcOH
CuI
CuBr
3d
Cu(OAc)2
Cu(NO3)2·
3H2O
CuSO4
CuCl2·2H2O
Cu2O
AcOH
5
6
H
H
Cyclopentyl
Cycloprotyl
33
12
NH4OAc
AcOH
110
77
3e
13
14
15
16
17
18
19
NH4OAc
NH4OAc
NH4OAc
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
110
110
110
110
110
90
80
83
80
41
3f
Cu2(OH)2CO3 NH4OAc
79
CuCl
CuCl
CuCl
NH4OAc
NH4OAc
NH4OAc
76c
trace
78
7
8
4ꢀNitro
4ꢀChloro
4ꢀBromo
4ꢀChloro
Phenyl
Phenyl
73
3g
130
aReaction conditions: 1a (0.5 mmol), 2a (2 mL), N source (1.0
mmol), catalyst (10 mol %), acid (0.5 mmol), O2 (1 atm), 110 oC,
bIsolated yields. cAir atmosphere.
77
3h
9
Phenyl
69
Initially, we chose 2ꢀaminobenzophenone 1a, dimethyl sulfoxide
2a and aqueous ammonia as model substrates (Table 1). When the
reaction was carried out in the following condition: CuCl as catalyst,
AcOH as acid, 110 oC and under O2, desired compound 3a was
obtained in 84% yield (entry 1). Without adding copper salts,
moderate yield (62%) of 3a was obtained (entry 2). Then 46% yield
of 3a was afforded without acid (entry 3). It’s obvious that copper
salts and acid played important roles in the process. Next, various
inorganic ammonium salts as N source were tested and NH4OAc
gave the best result (entries 4ꢀ6). Therefore, N source had an
important impact on the reaction. Among the examination of various
acids, acetic acid performed best in the reaction (entries 7ꢀ8).
Different copper catalysts were tested and CuCl was proved to be
most suitable in this transformation (entries 9ꢀ16). When the reaction
was conducted under air atmosphere, the compound 3a was obtained
in 76% yield (entry 17). As illustrated in entries 18ꢀ19, either high or
low temperature gave inferior results.
3i
10
2ꢀChlorophenyl
87
3j
4,5ꢀ
Dimethoyl
11
12
Phenyl
Phenyl
92
3k
4ꢀPhenyl
75
3l
4ꢀPhenylꢀ
2'ꢀ
13
14
Phenyl
H
95
methylthi
o
3m
H
36
3n
Table 2. Substrate scope of 2ꢀaminophenyla
2 | J. Name., 2012, 00, 1ꢀ3
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aReaction conditions: 1 (0.5 mmol), 2a (2 mL), NH4OAc (1.0
o
mmol), CuCl (10 mol %), AcOH (0.5 mmol), O2 (1 atm), 110 C,
12 h. bIsolated yields.
With the optimal condition in hand, the scope of substrate 2ꢀ
aminophenyl was investigated and most substrates could afford
desired compounds in moderate to good yields (Table 2). Firstly, 1b
and 1c which R2 groups were haloꢀbenzenes could give
corresponding products 3d and 3c in good yields. However substrate
1d with electronꢀdonating groups on the phenyl ring afforded 3d in a
little lower yield than 3b and 3c. When R2 were aliphatic substituents,
the yields of 3e, 3f decreased substantially. Moreover, when Cl, Br,
and NO2 groups were introduced at 5ꢀposition of 2ꢀ
aminobenzophenone, the products 3gꢀ3i were obtained in good yield.
Notably, CꢀF, CꢀCl and CꢀBr bonds in the products remained intact,
which provided an additional handle for further derivatization (3bꢀ3c,
3hꢀ3j). 1j could also afford corresponding product 3j in good yield
of 87%. In addition, Substrates bearing donating groups were well
tolerated to provide good yields from 70% to 95% (entries 11ꢀ13).
Finally, 2ꢀAminobenzaldehyde was chosen as substrate and 2ꢀ
(quinazolinꢀ2ꢀyl)aniline 3n was obtained in 36% instead of desired
compound quinazoline. Because 2ꢀAminobenzaldehyde occured
selfꢀreaction to produce shiff base, then NH4OAc reacted with
formyl group of shiff base and intramolecular cycloaddition and
oxidation led to obtain 2ꢀ(quinazolinꢀ2ꢀyl)aniline 3n (entry 14).
Subsequently, the scope of carbon source was investigated. As
shown in Table 3, to our delight, N, NꢀDimethylformamide
(DMF),18b N, Nꢀdimethylacetamide (DMA)20 as carbon source were
both effective in the transformation, and the reaction with DMA
gave a higher yield than that of DMF (entries 1ꢀ3). Next, Nꢀ
methylacetamide 2d was tested as a carbon source and the yield of
desired compound 3a decreased in 54% yield. However Nꢀ
ethylacetamide 2e afforded trace of 3a, and 2ꢀmethylꢀ4ꢀ
phenylquinazoline 3o was obtained in 40% yield (entries 4ꢀ5). Nꢀ
benzylethanamide 2f and N, Nꢀdimethylꢀ1ꢀphenylmethanamine 2g
were examined in the process, only a little trace of 3a were obtained
but 45% and 50% yield of 2, 4ꢀdiphenylquinazoline 3p were
provided respectively (entries 6ꢀ7). In addition, N1, N1, N2, N2ꢀ
tetramethylethaneꢀ1, 2ꢀdiamine (TMEDA) and N1, N2ꢀ
dimethylethaneꢀ1, 2ꢀdiamine (DMEDA)21c exhibited less efficiency
in this reaction, which afforded the desired product 3a in 39% and
35% yields, respectively (entries 8ꢀ9). Nꢀmethylꢀ2ꢀpyrrolidone
(NMP) was also tolerated in this transformation (entry 10).
Entry
1
Carbon source
Yield/%b
85
2a
2
3
82
73
2b
2c
2d
2e
4
5
54
tracec
6
7
8
traced
tracee
39
2f
2g
2h
9
35
38
2i
10
2j
aReaction conditions: 1a (0.5 mmol),
2
(2 mL), NH4OAc (1.0
o
mmol), CuCl (10 mol %), AcOH (0.5 mmol), O2 (1 atm), 110 C,
12 h. bIsolated yields. c40% yield of 2ꢀmethylꢀ4ꢀphenylquinazoline
d
was obtained. 45% yield of 2, 4ꢀdiphenylquinazoline was obtained.
e50% yield of 2, 4ꢀdiphenylquinazoline was obtained.
On the basis of all these preliminary results and previous
reports,18a,
25
a plausible mechanism of this transformation was
To gain a further insight into the mechanism, several control
experiments were carried out. At first, DMSOꢀd6 was employed as
carbon source, the products dꢀ3a and 3a were obtained in 78% yield
with the ratio of 4.3/1. This result indicated that the carbon atom in
the products was primarily derived from DMSO (Scheme 2a). Next,
the reaction of 2ꢀaminobenzophenone (1a) with 1 mL DMSO (2a)
was tested in the presence of 8 equiv. of radicalꢀcapturing species
TEMPO (2, 2, 6, 6ꢀtetramethylpiperidineꢀ1ꢀoxy) to capture methyl
radicals. The yield of 3a was decreased to 15% and compound i and
ii were detected by HRMS (see Supporting Information for details),
illustrated in Scheme 3. Initially, NH4OAc reacted with substrate 1
to give intermediate A under acid condition. Dimethyl sulfoxide
(DMSO) produced a methyl radical via a single electron transfer
process in the presence of Cu2+ and O2. Subsequently, peroxy radical
was formed by trapping O2 and was converted into formaldehyde
B.26 DMSO could also give formaldehyde and methanethiol at high
temperature.27 Next formaldehyde with A were reacted to deliver
imine species C. Then an intramolecular nucleophilic addition was
occurred to provide D. Finally further oxidation of D afforded
desired product 3. Compared with previous report,28 although the
mechanism in our work was similar to the previous work, DMSO
was used as formaldehyde source in our method. Thus a series of 2ꢀ
unsubstituted derivatives were afforded in our work. However,
aromatic aldehydes and primary alcohols were served as carbon
sources to produce corresponding 2ꢀaryl and 2ꢀalkyl quinazolines in
indicating that
a radical process might be involved in this
transformation (Scheme 2b).24
Table 3. Substrate scope of C sourcea
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the preceding literature. Because quinazolines were important Substrates (1d
Journal Name
ꢀ
1f
,
1i
,
1k-1m) were prepared according to
skeleton in the field of pharmaceutical chemistry, the method that we literature procedures12. Others chemicals were commercially
proposed would be an alternative way for synthesis these structures.
available and were used without further purification. All
reactions were monitored by thinꢀlayer chromatography (TLC).
1H NMR spectra were recorded on a Bruker Avance 400 or 300
spectrometer at 400 or 300 MHz, using CDCl3 and DMSOꢀd6
as solvent and tetramethylsilane (TMS) as internal standard. 13C
NMR spectra were run in the same instrument at 100 or 75
MHz. HRMS spectra were determined on a QꢀTOF6510
spectrograph (Agilent). Melting points were determined on an
XDꢀ4digital micro melting point apparatus.
General experimental procedure for 3a
2ꢀaminophenyl
1 (0.5 mmol), NH4OAc (1.0 mmol), CuCl (10
mol %), AcOH (0.5 mmol) were added to a 25 mL Schlenk
tube, and oxygen gas was flushed after vacuum, followed by
addition of
2
(2 mL). The mixture was stirred at 110 oC for 12 h.
After completion of the reactions, the solution was cooled to
room temperature, extracted with ethyl acetate (15 mL × 3).
The combined organic layers were dried with MgSO4, filtered
and evaporated in vacuo to obtain the residue. The residue was
Scheme 2. Control experiments for investigation of the reaction.
purified by column chromatography on silica gel to afford 3a
.
4-Phenylquinazoline(3a)
1
Light yellow solid (85%). Mp 95ꢀ97
CDCl3):
7.79ꢀ7.77 (m, 2H), 7.57ꢀ7.56 (m, 4H); 13C NMR (100 MHz,
CDCl3): 168.35, 154.66, 151.10, 137.10, 133.65, 130.03,
°
C. H NMR (400 MHz,
δ
9.39 (s, 1H), 8.14ꢀ8.10 (m, 2H), 7.92ꢀ7.88 (m, 1H),
δ
129.93, 128.89, 128.61, 127.69, 127.07, 123.13; HRMS calcd
for C14H10N2 (M+H)+ 207.0917; found: 207.0937.
4-(4-Fluorophenyl)quinazoline (3b)
1
Light yellow solid (77%). Mp 91ꢀ93
CDCl3): 9.37 (s, 1H),8.14 (t,
1H), 7.82ꢀ7.79 (m, 2H), 7.66ꢀ7.62(m, 1H), 7.30ꢀ7.262 (m, 2H);
13C NMR (100 MHz, CDCl3):
167.23, 165.24 (d, = 199.0
Hz, 1C), 154.62, 151.18, 133.79, 133.25 (d, = 3.0 Hz, 1C),
°
C. H NMR (400 MHz,
δ
J = 8.24 Hz 2H), 7.95ꢀ7.91 (m,
Scheme 3. A proposed mechanism for formation of quinazoline
δ
J
derivatives.
J
132.06 (d,
115.94 (d,
J
J
= 9.0 Hz, 1C), 129.05, 127.89, 126.77, 123.06,
= 22.0 Hz, 1C); HRMS calcd for C14H9FN2
Conclusions
(M+H)+ 225.0823; found: 225.0855.
In conclusion, a oneꢀpot threeꢀcomponent synthetic protocol
to construct quinazoline derivatives via copperꢀcatalysed
procedure has been developed. Several types of solvents were
acted as the carbon source, and clean oxygen was selected as
oxidant instead of peroxides and iodides in the process. The
approach is simple, efficient, environmentalꢀfriendly, and
atom–economical. Different functional groups were well
tolerated to give corresponding products in moderate to good
yields. Further studies on the application of this reaction system
in pharmaceuticals is in progress.
4-(4-Chlorophenyl)quinazoline (3c)
Light yellow solid (80%). Mp 116ꢀ118°
C. 1H NMR (400 MHz,
CDCl3):
7.76ꢀ7.73 (m, 2H), 7.65ꢀ7.62 (m, 1H), 7.58ꢀ7.55 (m, 2H); 13C
NMR (100 MHz, CDCl3): 167.14, 154.61, 151.14, 136.49,
δ 9.38 (s, 1H), 8.14ꢀ8.08 (m, 2H), 7.96ꢀ7.92 (m, 1H),
δ
135.52, 133.88, 131.32, 129.06, 128.97, 127.98, 126.65, 122.97;
HRMS calcd for C14H10N2Cl (M+H)+ 241.0527; found:
241.0551.
Experimental
4-(p-Tolyl)quinazoline (3d)
1
General information
Light yellow oil (70%). H NMR (300 MHz, CDCl3):
δ
9.36 (s,
1H), 8.17 (d,
J
= 8.4 Hz, 1H), 8.12 (d,
J
= 8.4 Hz, 1H), 7.92ꢀ
4 | J. Name., 2012, 00, 1ꢀ3
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1
7.87 (m, 1H), 7.71(d,
J
= 8.1 Hz, 2H), 7.62ꢀ7.57 (m, 1H), 7.39 Light yellow solid (87%). Mp 78ꢀ80
°
C. H NMR (300 MHz,
(d,
J
= 8.1Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6):
δ
167.88, CDCl3):
δ
9.43 (s, 1H), 8.28 (d,
2 = 2.4 Hz, 1H), 7.64ꢀ7.58 (m, 2H), 7.56ꢀ7.43 (m, 3H);
166.36, 154.80, 149.05, 135.38,
J = 9.0 Hz, 1H), 7.88 (dd, J1 =
154.82, 150.92, 140.34, 134.46, 134.33, 130.37, 129.59, 128.85, 9.0 Hz,
J
128.58, 127.21, 122.76, 21.41; HRMS calcd for C14H9N3O2 13C NMR (100 MHz, CDCl3):
δ
(M+H)+ 221.1073; found: 221.1065.
135.12, 133.76, 132.66, 131.07,130.80, 130.62, 130.16, 127.16,
125.59, 124.37; HRMS calcd for C14H8N2Cl2 (M+H)+ 275.0137;
found: 275.0140.
4-Cyclopentylquinazoline (3e)
1
Light yellow oil (73%). H NMR (400 MHz, CDCl3):
δ 9.6 (s,
6,7-dimethoxy-4-phenylquinazoline (3k)
1H), 8.25 (d,
J = 8.4 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.94ꢀ
7.90 (m, 1H), 7.70ꢀ7.65 (m, 1H), 4.11ꢀ3.93 (m, 1H), 2.24ꢀ2.10 Light yellow solid (92%). Mp 154ꢀ155
(m, 4H), 2.08ꢀ1.92 (m, 2H), 1.90ꢀ1.74 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 9.23 (s, 1H), 7.82ꢀ7.99 (m, 2H), 7.60ꢀ7.59 (m,
MHz, CDCl3):
175.35, 154.21, 149.27, 133.63, 128.74, 3H), 7.43 (s, 1H), 7.36 (s, 1H), 4.11 (s, 3H), 3.93 (s, 3H); 13C
°
C. 1H NMR (400
δ
127.54, 124.71, 124.02, 42.53, 32.81, 26.25; HRMS calcd for NMR (100 MHz, CDCl3): δ 165.10, 155.84, 153.56, 150.42,
C14H9N3O2 (M+H)+ 199.1230; found: 199.1240.
149.14, 137.70, 129.77, 129.52, 128.72, 118.78, 107.01,
103.99, 55.45, 55.12; HRMS calcd for C16H14N2O2 (M+H)+
267.1128; found: 267.1128.
4-Cyclopropylquinazoline (3f)
Light yellow oil (73%). 1H NMR (400 MHz, CDCl3):
δ 9.09 (s,
4, 6-diphenylquinazoline (3l)
1H), 8.32 (d,
J = 8.4 Hz, 1H), 8.02 (d, J = 8.44 Hz, 1H), 7.88ꢀ
1
7.84 (m, 1H), 7.65ꢀ7.62 (m, 1H), 2.80ꢀ2.74 (m, 1H), 1.44ꢀ1.40 Light yellow solid (75%). H NMR (400 MHz, CDCl3):
δ 9.39
(m, 2H), 1.28ꢀ1.22 (m, 2H); 13C NMR (100 MHz, CDCl3):
172.33, 154.73, 149.50, 133.24, 129.05, 127.19, 124.47, 124.34, 2H), 7.62ꢀ7.58 (m, 5H), 7.49ꢀ7.45 (m, 2H), 7.41ꢀ7.39 (m, 1H);
12.79, 12.07; HRMS calcd for C11H10N2 (M+H)+ 171.0917; 13C NMR (100 MHz, CDCl3):
168.51, 154.58, 150.50, 140.70,
δ
(s, 1H), 8.293ꢀ8.289 (m, 1H), 8.18ꢀ8.17 (m, 2H), 7.84ꢀ7.82 (m,
δ
found: 171.0917.
139.79, 137.18, 133.45, 130.14, 129.98, 129.39, 129.11, 128.77,
128.15, 127.48, 124.58, 123.38; HRMS calcd for C20H14N2
(M+H)+ 283.1230; found: 283.1231.
6-Nitro-4-phenylquinazoline (3g)
Light yellow solid (73%). Mp 130ꢀ132 °
C. 1H NMR (300 MHz,
6-(2-(methylthio)phenyl)-4-phenylquinazoline (3m)
CDCl3):
9.3 Hz,
2H), 7.69ꢀ7.64 (m, 3H); 13C NMR (100 MHz, CDCl3):
157.22, 153.43, 146.07, 135.78, 131.15, 131.11, 130.11, 129.19, 1H), 7.85ꢀ7.83 (m, 2H), 7.57ꢀ7.53 (m, 3H), 7.38ꢀ7.35 (m, 1H),
127.03, 124.21, 122.06;HRMS calcd for C14H9N3O2 (M+H)+ 7.33 (d, = 7.6 Hz, 1H), 7.23ꢀ7.22 (m, 2H), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3): 168.50, 154.75, 150.51, 140.10,
δ
9.53 (s, 1H), 9.09 (d,
J = 2.4 Hz, 1H), 8.71 (dd, J1 =
1
J2 = 2.4 Hz, 1H), 8.29 (d,
J
= 9.3 Hz, 1H), 7.84ꢀ7.80 (m, Light yellow solid (95%). H NMR (400 MHz, CDCl3):
δ
9.40
δ
170.61, (s, 1H), 8.18ꢀ8.16 (m, 2H), 8.02 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz,
J
252.0768; found: 252.0788.
δ
139.48, 137.27, 137.06, 135.56, 130.16, 130.11, 130.07, 128.67,
128.62, 127.36, 125.79, 125.10, 122.91, 16.17; HRMS calcd for
C21H16N2S (M+H)+ 329.1107; found: 329.1109.
6-Chloro-4-phenylquinazoline (3h)
Light yellow solid (77%). Mp 134ꢀ136 °
C. 1H NMR (400 MHz,
CDCl3):
9.0 Hz, 1H), 7.87 (dd,
δ
9.38 (s, 1H), 8.11 (d,
J
= 2.24 Hz, 1H), 8.09 (d,
J =
2-(quinazolin-2-yl)aniline (3n)
J1 = 8.92 Hz,
J2 = 2.24 Hz, 1H), 7.78ꢀ
7.76 (m,2H), 7.62ꢀ7.60 (m, 3H); 13C NMR (100 MHz, CDCl3): Light yellow oil (36%). H NMR (300 MHz, CDCl3):
δ 9.43(d, J =
1
δ
167.66, 154.81, 149.59, 136.54, 134.72, 133.54, 130.68, 0.3 Hz, 1H), 8.65 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 7.99ꢀ7.96 (m,
130.40, 129.86, 128.87, 125.83, 123.70; HRMS calcd for 1H), 7.89ꢀ7.83 (m, 2H), 7.59ꢀ7.54 (m, 1H), 7.28ꢀ7.23 (m, 1H), 6.85ꢀ
C14H9N2Cl (M+H)+ 241.0527; found: 241.0527.
6.77 (m, 2H), 6.56 (s, br, 2H); 13C NMR (75 MHz, CDCl3):
δ 162.50,
159.74, 149.64, 148.93, 134.02, 131.75, 131.40, 127.89, 127.13,
126.84, 122.51, 119.06, 117.11, 116.94; HRMS calcd for C14H11N3
(M+H)+ 222.1026; found: 222.1033.
6-Bromo-4-phenylquinazoline (3i)
Light yellow solid (69%). Mp 144ꢀ146
CDCl3): 9.39 (s, 1H), 8.28 (d, = 1.12 Hz, 1H), 7.99ꢀ7.98 (m,
2H), 7.78ꢀ7.75 (m, 2H), 7.61ꢀ7.59 (m, 3H); 13C NMR (100
MHz, CDCl3):
°
C. 1H NMR (400 MHz,
δ
J
2-methyl-4-phenylquinazoline (3o)
δ
167.53, 154.86, 149.79, 137.25, 136.52, Light yellow oil (40%). 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J =
130.73, 130.40, 129.87, 129.15, 128.87, 124.16, 121.60; HRMS 8.8 Hz, 2H), 7.88ꢀ7.84 (m, 1H), 7.76ꢀ7.74 (m, 2H), 7.58ꢀ7.49 (m,
calcd for C14H9N2Br (M+H)+ 285.0022; found: 285.0025.
4H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.59, 163.83,
151.41, 137.29, 133.63, 129.85, 128.61, 128.14, 127.03, 126.72,
121.02, 26.63; HRMS calcd for C15H12N2 (M+H)+ 221.1073; found:
221.1100.
6-Chloro -4-(2-chlorophenyl)quinazoline (3j)
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DOI: 10.1039/C6OB00625F
ARTICLE
Journal Name
Kupfer, T. Stamminger and M. Marschall, Antimicrob. Agents
Chemother., 2004, 48, 4154ꢀ4162.
2, 4-diphenylquinazoline (3p)
1
Light yellow solid. Mp 117ꢀ118 °C. H NMR (400 MHz, CDCl3): δ
8.71 (dd, J1 = 3.72 Hz, J2 = 1.8 Hz, 2H), 8.15ꢀ8.01 (m, 2H), 7.89ꢀ
7.83 (m, 3H), 7.59ꢀ7.57 (m, 3H), 7.54ꢀ7.48 (m, 4H); 13C NMR (100
MHz, CDCl3): δ 168.32, 160.27, 152.03, 138.26, 137.73, 133.54,
130.53, 130.22, 129.94, 129.21, 128.71, 128.56, 127.02, 121.72;
HRMS calcd for C20H14N2 (M+H)+ 283.1230; found: 283.1256.
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Light yellow oil (50%). 1H NMR (400 MHz, CDCl3): δ 7.60ꢀ7.58(m,
2H), 7.48ꢀ7.41 (m, 3H), 6.91 (s, 1H), 6.24 (s, br, 2H), 6.19 (s, 1H),
3.86 (s, 3H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.10,
155.50, 148.68, 140.73, 139.69, 130.57, 128.66, 128.09, 116.74,
109.96, 99.26, 56.60, 55.85; HRMS calcd for C15H15NO3 (M+H)+
258.1125; found: 258.1147.
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56505.
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(4-amino-[1,1'-biphenyl]-3-yl)(phenyl)methanone (1l)
12. Y. Yan, Y. Zhang, C. Feng, Z. Zha and Z. Wang, Angew. Chem., Int. Ed.,
2012, 51, 8077ꢀ8081.
Yellow solid (60%). Mp 112ꢀ113 °C. 1H NMR (400 MHz, CDCl3): δ
7.70ꢀ7.67 (m, 3H), 7.56ꢀ7.49 (m, 2H), 7.46ꢀ7.39 (m, 4H), 7.35ꢀ7.31
(m, 2H), 7.24 (d, J = 7.28 Hz, 1H), 6.80 (d, J = 8.56 Hz, 1H), 6.0 (s,
br, 2H); 13C NMR (100 MHz, CDCl3): δ 199.07, 150.25, 140.33,
140.00, 133.04, 132.64, 131.34, 129.30, 128.83, 128.65, 128.27,
126.56, 126.23, 118.42, 117.64; HRMS calcd for C19H15NO (M+H)+
274.1226; found: 274.1252.
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Tetrahedron Letters, 2015, 56, 3066ꢀ30. (c) D. Talukdar, S. Borah and
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Chem. Int. Ed., 2015, 54, 4669ꢀ4672. (e) S. Guo, Y. Yuan and J. Xiang,
New J. Chem., 2015, 39, 3093ꢀ3097. (f) H. Wang, W. Xu, Z. Wang, L.
Yu and K. Xu, J. Org. Chem., 2015, 80, 2431ꢀ2435. (g) D. Chandra
Mohan, S. Nageswara Rao, C. Ravi and S. Adimurthy, Org. Biomol.
Chem., 2015, 13, 5602ꢀ5607.(h) N. Khatun, A. Banerjee, S. K. Santra,
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Soc., 2012, 134, 3679ꢀ3682.(c) G. Li, C. Jia, Q. Chen, K. Sun, F. Zhao,
H. Wu, Z. Wang, Y. Lv and X. Chen, Adv. Synth. Catal., 2015, 357,
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(4-amino-2'-(methylthio)-[1,1'-biphenyl]-3-yl)(phenyl)methanone
(1m)
1
Yellow oil (70%). H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 6.8
Hz, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.53ꢀ7.42 (m, 4H), 7.32ꢀ7.29 (m,
2H), 7.20ꢀ7.18 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.21 (s, br, 2H),
2.42(s, 3H); 13C NMR (100 MHz, CDCl3): δ 199.02, 150.45, 140.13,
139.96, 137.36, 135.39, 135.12, 131.16, 130.00, 129.33, 128.16,
127.86, 127.74, 125.39, 124.87, 117.73, 116.92, 16.12; HRMS calcd
for C20H17NOS (M+H)+ 320.1104; found: 320.1111.
Acknowledgements
We are grateful to the National Science Foundation of China
(No.21572117) and State Key Laboratory of Bioactive Substance
and Function of Natural Medicines, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical
College (No. GTZK 201405) for financial support of this research.
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