Copper-catalyzed three-component one-pot synthesis of quinazolines

Article abstract of DOI:10.1016/j.tet.2012.09.035

Two efficient approaches to multi-substituted quinazolines by the three-component one-pot reaction of o-bromo aromatic ketones/aldehydes, ammonia water and aromatic aldehydes, or primary alcohols catalyzed by CuCl have been developed.

Full text of DOI:10.1016/j.tet.2012.09.035

Tetrahedron 68 (2012) 9364e9370
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed three-component one-pot synthesis of quinazolines
,
b
,
a
Jia Ju a, Ruimao Hua a , Ji Su
*
a Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Beijing 100084, China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2012
Received in revised form 1 September 2012
Accepted 7 September 2012
Available online 14 September 2012
Two efficient approaches to multi-substituted quinazolines by the three-component one-pot reaction of
o-bromo aromatic ketones/aldehydes, ammonia water and aromatic aldehydes, or primary alcohols
catalyzed by CuCl have been developed.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ammonia water
ortho-Bromo aromatic ketones
ortho-Bromo aromatic aldehydes
Aromatic aldehydes
Primary alcohols
Quinazolines
1. Introduction
report two protocols for the synthesis of multi-substituted qui-
nazoline derivatives via CuCl-catalyzed one-pot, three-component
Quinazoline and its derivatives are important compounds
found widespread in natural products and pharmaceuticals, which
show interesting biological and physiological activities, such as
antibacterial,1 antiviral,2 antitubercular,3 and anticancer activities.4
Therefore, a variety of synthetic methods have been developed to
synthesize such type of compounds including microwave-
promoted condensation of 2-aminoarylalkanone o-phenyl oximes
with aldehydes,5 condensation of 2-aminobenzophenone with
benzylic amines,6 condensation of 2-aminobenzylamines with al-
dehydes followed by subsequent oxidation with oxidants.7 Re-
cently, copper-catalyzed Ullmann N-arylations have made great
progress, and which has been applied to develop the synthetic
methods for quinazoline derivatives. For instance, copper-
catalyzed condensation of o-halo-benzaldehydes with amidine
hydrochlorides,8 condensation of substituted (2-bromophenyl)-
methylamines and amides under air via sequential Ullmann-type
coupling and aerobic oxidation reaction.9 However, all these
above-mentioned procedures require nitrogen-containing starting
materials, which are usually hard either to be available or to be
pre-prepared. In the continuation of our interest in development of
one-pot procedure to synthesize N-heterocyclic compounds using
cheap and easily available starting materials,10 in this paper, we
cyclocondensation with the use of ammonia water as a source of
nitrogen in the presence of oxidants.
2. Results and discussion
We initiated the study with the reaction of 20-bromoacetophe-
none (1a), benzaldehyde (2a), and ammonia water to optimize the
reaction conditions. As shown in Table 1, when a mixture of 1a
(0.50 mmol), 2a (0.55 mmol), and ammonia water (25% aqueous
ammonia, 1.0 mL) in NMP (0.5 mL) in a sealed tube under air was
heated at 80 ꢀC for 12 h, no desired product of 4-methyl-2-
phenylquinazoline (3a) formed at all (entry 1) by the analyses of
GC and GCeMS of the reaction mixture. Repeating the reaction in
the presence of CuCl in toluene gave a trace amount of 3a (entry 2),
and in CH3CN, DMSO and DMF, 3a was obtained in fair yields (en-
tries 3e5), in NMP, at 80 ꢀC or 100 ꢀC, the reaction afforded 3a in
good yields (entries 6e7). CuCl2 also showed good catalytic activity
for the formation of 3a at 80 ꢀC (entry 8). We screened other various
copper(I) catalysts, such as CuI, CuBr and Cu2O, and they showed
slightly lower catalytic activity compared to CuCl (entries 9e11).
Decreasing the reaction temperature to 60 ꢀC or performing the
reaction under nitrogen atmosphere led to significant decrease in
catalytic activity of CuCl (entries 12e13). Therefore we investigated
the scope of the present copper(I)-catalyzed three-component one-
pot reaction with the use of various o-bromo aromatic aldehydes/
* Corresponding author. Fax: þ86 10 62771149; e-mail address: ruimao@
mail.tsinghua.edu.cn (R. Hua).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.035

J. Ju et al. / Tetrahedron 68 (2012) 9364e9370
9365
ketones, aromatic aldehydes, and ammonia water under the re-
action conditions as indicated in entry 6.
As summarized in Table 2, the cyclocondensation of 1a and
ammonia water with a variety of aryl aldehydes bearing electron-
occurred predominantly for most cases, resulting in small
amount of quinazoline derivatives, only the reaction of trioxane
produced the corresponding 4-methylquinazoline (3p) in 49%
yield (Eq. 4).
O
S
N
S
(1)
Cl
CuCl (10 mol
)
2e + 25 NH3
+
N
3n 43
NMP, air
Br
80 oC for 12 h
1c
O
CHO
CuCl (10 mol
)
(2)
+ 25 NH3
3a
+
NMP, air
80 oC for 12 h
Cl
22
2a
1d
O
N
H
CuCl (10 mol
)
(3)
+ 2c + 25 NH3
N
3o 49
p-tolyl
NMP, air
Br
80 oC for 12 h
1e
N
CuCl (10 mol
)
1a
(4)
(CH2O)n
+
+ 25 NH3
NMP, air
80 oC for 12 h
N
3p 49
O
CuCl (10 mol
)
(5)
1a
+ 25 NH3
NMP, air
80 oC for 12 h
NH2
4a 45
donating or -withdrawing groups yielded the desired quinazoline
derivatives in fair to good yields, with an exception of 4-
nitrobenzaldehyde used, which showed low reactivity and selec-
tivity to form the corresponding quinazoline derivatives. In addi-
tion, the reaction of 20-bromo-40-fluoroacetophenone (1b) with
both electron-donating and electron-withdrawing groups
substituted aryl aldehydes occurred smoothly to afford the ex-
pected quinazoline derivatives in middle yields (37e51%).
Furthermore, the reactions of 2-acetyl-3-bromothiophene (1c)
with 2e and ammonia water afforded the interesting both sulfur
and nitrogen containing heterocyclic product of 2-(4-
chlorophenyl)-4-methylthieno[3,2-d]pyrimidine (3n) in 43% iso-
lated yield (Eq. 1). Notably, 20-chloroacetophenone (1d) (Eq. 2) and
2-bromobenzaldehyde (1e) (Eq. 3) also underwent the present
cyclocondensation, but relatively low yields were achieved com-
pare to 1a employed.
In order to elucidate the reaction mechanism for the for-
mation of quinazoline derivatives, the following control ex-
periments were performed. Firstly, the coupling reaction of (1a)
(0.5 mmol) with 25% ammonia water (0.5 mL) in the presence
of CuCl revealed that 20-aminoacetophenone (4a) was formed
in 45% yield (Eq. 5). Secondly, 4a could be transformed into 3a
in 92% yield under the standard conditions (Eq. 6). Thirdly, if
the reaction indicated in entry 6 of Table 1 was stopped in 6 h,
both 3a and 4a could be isolated from the reaction mixture in
47% and 12% yield, respectively (Eq. 7). On the basis of these
results, it is apparent that CuCl-catalyzed formation of 4a in
situ is the crucial intermediated for the formation of 3a.
Therefore, a proposed mechanism for the formation of quina-
zoline derivatives is shown in Scheme 1, it involves the
Ullmann-type amination reaction of o-halo-acetophenones (1)
with ammonia affording intermediate 4, cyclocondensation of 4
with aldehydes and ammonia followed by aerobic oxidation
reaction producing 3.
In the cases of aliphatic aldehydes used, unfortunately under
the reaction conditions, aldol condensation of aliphatic aldehydes

9366
J. Ju et al. / Tetrahedron 68 (2012) 9364e9370
could be also applied to the reaction of 1a or 1b, ammonia water
CuCl (10 mol
)
3a
4a
+ 2a + 25 NH3
(6)
and various primary alcohols to afford quinazoline derivatives in
fair to good yields (Table 4). It should be noted that the oxidation
cyclocondensation procedure was efficient not only for benzyl al-
cohols to give 2-aryl substituted quinazoline derivatives, but also
for aliphatic alcohols to produce 2-alkyl substituted quinazoline
derivatives (3o, 3q, 3r, 3s and 3v), which should be more applicable
to the synthesis of quinazoline derivatives.
In addition, the reaction of o-bromo benzyl alcohol, 5a and
ammonia water in the presence of DTBP (5.0 equiv) catalyzed
by CuCl was also examined. As shown in Eq. 8, the expected
product of 2-phenyl quinazolines (3w) was obtained in 16%
NMP, air
80 oC for 12 h
92
CuCl (10 mol
)
4a
3a
+
(7)
1a
+ 2a + 25 NH3
NMP, air
80 oC for 6 h
47
12
isolated yield after
6 h, indicating that both o-bromo-
As described above, under the standard reaction conditions, the
reaction of 20-bromoacetophenone, aliphatic aldehydes and am-
monia water could not yield the expected quinazoline derivatives
selectively due to the aldol condensation reaction. We assume that
benzaldehyde and 2a could be formed in situ, but it is a not
efficient reaction system for the formation of 2-substituted
quinazolines.
OH
N
CuCl (10 mol
)
25 NH3
(8)
+
5a
+
DTBP (5.0 equiv)
Br
N
3w 16
Ph
120 oC for 6 h
Table 1
Formation of 4-methyl-2-phenylquinazoline (3a) via the reaction of 20-bromoacetophenone (1a), benzaldehyde (2a), and aqueous ammoniaa
O
CHO
Cu catalyst
(10 mol )
solvent, air, 12 h
N
+ 25 NH3
+
N
Ph
Br
3a
2a
1a
Entry
Catalyst
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
d
NMP
Toluene
Acetonitrile
DMSO
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
80
80
80
80
80
80
100
80
80
80
80
60
80
0
<5
32
32
34
65(63)
66
60
54
58
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl2
Cul
CuBr
Cu2O
CuCl
CuCl
9
10
11
12
13c
59
43
22
a
Unless otherwise noted, the reactions were carried out with 0.5 mmol of 1a, 0.55 mmol of 2a, 0.5 mL of 25% aqueous ammonia, and 0.05 mmol of catalyst in 0.5 mL of
solvent in a sealed tube under air for 12 h.
b
GC yield based on the amount of 1a. Number in parenthesis is isolated yield.
Under nitrogen atmosphere.
c
if the concentration of aliphatic aldehydes can be controlled in
a low level, which might be the important factor to improve the
formation of quinazolines. Therefore, we conducted an oxidation
process of primary alcohol to aldehyde in the above-mentioned
cyclocondensation. As shown in Table 3, we first examined the
reaction of 1a, benzyl alcohol (5a) and ammonia water under the
similar reaction conditions as indicated in entry 6 of Table 1, in
either NMP or without organic solvent, 3a formed in 17% and 20%
GC yield, respectively (Table 3, entries 1e2). Extremely encouraged
by these results, we investigated the same reaction using 30%
aqueous hydrogen peroxide and di-tert-butyl peroxide (DTBP) as
oxidants under different reaction conditions, and it was found that
when 2.5 equiv of DTBP was used, 3a could be obtained in 66% GC
yield at 120 ꢀC for 6 h under organic solvent-free condition (Table 3,
entry 6). Furthermore, this oxidation cyclocondensation procedure
3. Conclusions
Insummary, we have developed the practical and efficient one-pot
CuCl-catalyzed synthesis of multi-substituted quinazolines by the
three-component reaction of either o-bromo aromatic ketones/alde-
hydes, aromatic aldehydes and ammonia water or o-bromo aromatic
ketones/aldehydes, primary alcohols and ammonia water. The most
significant features of the present catalytic systems include the use of
easily accessible o-bromo aromatic aldehydes/ketones, aromatic al-
dehydes or primary alcohols, and ammonia water as starting mate-
rials, and air or DTBP (in the case of primary alcohols used) as the
oxidants, as well as ammonia water as a source of nitrogen. The cat-
alytic system with the use of primary alcohols as the precursor of al-
dehydes has more extensively applicable scope as both aryl and alkyl
groups can be introduced at 2-position of quinazoline derivatives.

J. Ju et al. / Tetrahedron 68 (2012) 9364e9370
9367
Table 2
Synthesis of quinazoline derivatives
O
CHO
R
N
CuCl (10 mol
)
R'
R
+ 25 NH3
+
NMP, air
N
80 oC for 12 h
Br
R'
2
1
3
N
N
N
N
p-tolyl
N
N
N
3c 52
3b 64
3d 51
O
N
N
N
Cl
Cl
N
N
3g 51
3e 74
3f 57
Cl
N
N
N
N
N
F
N
Ph
3h 61
3i 17
3j 46
F
NO2
N
N
N
Cl
F
N
F
N
F
N
3k 44
3l 51
3m 37
O
Cl
resonance. GC analyses of organic compounds were performed on
an Agilent Technologies 1790 GC (with a TC-WAX capillary 25 m
column) instrument. Mass spectra were obtained on a Shimadzu
GC eMS-QP2010S, and HRMS was obtained on a micrOTOF-Q
10142.
O
O
R
R
NH3
R' CHO
N-arylation
+ NH3
Br
NH2
1
4
4.2. Typical experimental procedure for condensation of 20-
bromoacetophenone (1a), benzaldehyde (2a), and ammonia wa-
ter to afford 4-methyl-2-phenylquinazoline (3a) (Table 1, entry 6)
R
R
N
oxidation
N
N
20-Bromoacetophenone (1a) (100.0 mg, 0.5 mmol), benzalde-
hyde (2a) (58.0 mg, 0.55 mmol), CuCl (5.0 mg, 0.05 mmol), 25%
aqueous ammonia (0.5 mL), and NMP (0.5 mL) were placed in
a thick-walled Pyrex screw-cap tube (25 mL) under air atmosphere,
and the tube was capped and the mixture was heated in an oil bath
at 80 ꢀC with stirring for 12 h. After the reaction mixture was cooled
to room temperature, the crude reaction mixture was extracted
with EtOAc for three times (3.0 mLꢁ3). After removal of volatiles
under a reduced pressure, the residue was diluted with CH2Cl2
(4.0 mL) and then n-docosane (62.1 mg, 0.2 mmol) was added as an
internal standard for GC analysis. After GC and GCeMS analyses of
the reaction mixture, volatiles were removed under a reduced
pressure, and the residue was then subjected to silica gel column
chromatography [eluting with petroleum ether and then with
N
H
R'
R'
3
Scheme 1. Proposed mechanism for CuCl-catalyzed formation of quinazolines.
4. Experimental section
4.1. General methods
All organic starting materials are analytically pure and used
without further purification. 1H and 13C NMR spectra were recorded
on JOEL JNM-ECA300 spectrometers at 300 MHz and 75 MHz, re-
spectively. 1H NMR chemical shifts (
d
) were referenced to TMS and
13C NMR chemical shifts (
d) were referenced to internal solvent

9368
J. Ju et al. / Tetrahedron 68 (2012) 9364e9370
Table 3
a mixture of petroleum ether and ethyl acetate (100:1e50:1)] to
afford 4-methyl-2-phenylquinazoline (3a) (69.6 mg, 0.32 mmol,
63%) as white solid. The GC analysis of the reaction mixture dis-
closed the formation of 3a in 65% GC yield.
Formation of 3a via the reaction of 1a, benzyl alcohol (5a) and aqueous ammonia
under different conditionsa
CuCl (10 mol
oxidant
)
1a
+
+
25 NH3
Ph
OH
3a
5a
4.3. Typical experimental procedure for condensation of 20-
bromoacetophenone (1a), benzyl alcohol (5a), and ammonia
water to afford 4-methyl-2-phenylquinazoline (3a) (Table 3,
entry 6)
Entry
1c
2
3
4
5
6
7
Oxidant
Temp (ꢀC)
Time (h)
Yieldb (%)
Air
Air
80
80
18
18
12
6
6
6
6
6
6
17
20
30
43
30% H2O2 (2.5 equiv)
30% H2O2 (2.5 equiv)
30% H2O2 (2.5 equiv)
DTBP (2.5 equiv)
80
20-Bromoacetophenone (1a) (100.0 mg, 0.5 mmol), benzyl alcohol
(5a) (325.0 mg,1.5 mmol), CuCl (5.0 mg, 0.05 mmol), DTBP (365.0 mg,
1.25 mmol), and 25% aqueous ammonia (0.5 mL) were placed in
athick-walledPyrexscrew-captube(25mL), andthetubewascapped
and the mixture heated in an oil bath at 120 ꢀC with stirring for 6 h.
After thereaction mixturewascooled toroom temperature, thework-
up and isolation of the products were essentially similar to the pro-
cedure above-mentioned. Compound 3a was obtained as white solid
in 65% (71.5 mg, 0.33 mmol), and the GC analysis of the reaction
mixture disclosed the formation of 3a in 66% GC yield.
100
120
120
120
120
120
53
66(65)
65
DTBP (5.0 equiv)
DTBP (1.0 equiv)
DTBP (2.5 equiv)
8
30
65
9d
a
Unless otherwise noted, the reactions were carried out with 0.5 mmol of 1a,
1.5 mmol of 5a, 0.5 mL of 25% aqueous ammonia and oxidant in a sealed tube under
air for 12 h.
b
GC yield based on the amount of 1a. Number in parenthesis is isolated yield.
NMP (0.5 mL) was used.
Compound 5a (2.5 mmol) was used.
c
d
Table 4
Synthesis of quinazoline derivatives from primary alcohols
O
R
N
CuCl (10 mol
)
R
+ 25 NH3
OH
+
R'
DTBP (2.5 equiv)
N
R'
Br
N
120 oC for 6 h
5
1
3
N
N
N
N
p-tolyl
N
3c 62
3d 55
3e 81
O
Cl
N
N
N
N
N
N
N
N
3q 55
3i 61
3o 17
F
N
N
N
n-C6H13
F
N
Ph
Cl
3j 57
3r 51
3s 58
N
N
N
F
N
F
3k 52
3l 67
O
N
N
N
F
N
p-tolyl F
N
F
N
n-C6H13
3t 64
3u 60%
3v 53
F

J. Ju et al. / Tetrahedron 68 (2012) 9364e9370
9369
4.4. Characterization data for all products
(d, J2CꢂF¼21.7 Hz), 22.1; GCeMS m/z (% rel inten.) 238 (Mþ, 100),
223 (57), 197 (34), 76 (23).
4.4.1. 4-Methyl-2-phenylquinazoline (3a).11 White solid; 1H NMR
(300 MHz, CDCl3)
1H), 7.87 (dt, J¼8.3, 0.7 Hz, 1H), 7.71 (t, J¼7.6 Hz, 1H), 7.52e7.37 (m,
4H), 2.86 (s, 3H); 13C NMR (75 MHz, CDCl3)
168.1, 160.0, 150.2,
d
8.61 (dd, J¼7.6, 1.7 Hz, 2H), 7.98 (d, J¼8.6 Hz,
4.4.9. 4-Methyl-2-(4-nitrophenyl)quinazoline (3i).5b Yellow solid;
1H NMR (300 MHz, CDCl3)
d
8.76 (dt, J¼8.9, 2.1 Hz, 2H), 8.29 (dt,
d
J¼8.9, 2.1 Hz, 2H), 8.07 (t, J¼8.1 Hz, 2H), 7.89 (ddd, J¼8.3, 6.9, 1.2 Hz,
138.3, 133.3, 130.3, 129.1, 128.5, 128.4, 126.7, 124.8, 122.8, 21.9;
1H), 7.63 (ddd, J¼8.2, 6.9, 1.1, 1H), 3.00 (s, 3H); 13C NMR (75 MHz,
GCeMS m/z (% rel inten.) 220 (Mþ, 100), 205 (56), 179 (34).
CDCl3) d 168.8, 157.9, 150.2, 149.1, 144.2, 134.1, 129.5, 129.4, 128.0,
125.2, 123.7, 123.3, 22.1; GCeMS m/z (% rel inten.) 265 (Mþ, 100),
4.4.2. 4-Methyl-2-(naphthalen-2-yl)quinazoline (3b). Yellow solid;
219 (62).
mp 122.0e123.7 ꢀC; 1H NMR (300 MHz, CDCl3)
d 9.16 (s, 1H), 8.73
(dd, J¼8.6,1.4 Hz,1H), 8.09 (d, J¼8.6 Hz,1H), 8.05e8.01 (m, 2H), 7.96
4.4.10. 7-Fluoro-4-methyl-2-phenylquinazoline (3j). Yellow solid;
(d, J¼8.6 Hz, 1H), 7.91e7.80 (m, 2H), 7.57e7.48 (m, 3H), 3.01 (s, 3H);
mp 69.5e71.1 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.63e8.56 (m, 2H),
8.05e8.00 (m, 1H), 7.63 (dd, J¼10.0, 2.4 Hz, 1H), 7.54e7.48 (m, 3H),
7.32e7.24 (m, 1H), 2.94 (s, 3H); 13C NMR (75 MHz, CDCl3)
168.0,
13C NMR (75 MHz, CDCl3)
d 168.3, 160.2, 150.5, 135.8, 134.7, 133.6,
133.5, 129.4, 129.3, 128.9, 128.3, 127.8, 127.1, 127.0, 126.2, 125.6,
125.1, 123.1, 22.1; GCeMS m/z (% rel inten.) 270 (Mþ, 100), 255 (34),
127 (28); HRMS (ESI): calcd for C19H15N2 [MþH]þ: 271.1230; found:
271.1225.
d
165.6 (d, J1CꢂF¼254.3 Hz), 161.2, 152.4 (d, J3CꢂF¼13.7 Hz), 138.0,
130.8, 128.8, 128.7, 127.7 (d, J3CꢂF¼10.8 Hz), 120.3, 117.2 (d,
J2CꢂF¼25.3 Hz), 112.9 (d, J2CꢂF¼20.2 Hz), 22.2; GCeMS m/z (% rel
inten.) 238 (Mþ, 100), 223 (51), 197 (29), 77 (33); HRMS (ESI): calcd
for C15H12FN2 [MþH]þ: 239.0979; found: 239.0981.
4.4.3. 4-Methyl-2-p-tolylquinazoline
(3c). Yellow solid;
mp
99.0e101.2 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.51 (d, J¼7.9 Hz, 2H),
8.03e7.93 (m, 2H), 7.77 (ddd, J¼8.4, 7.0, 1.4 Hz, 1H), 7.49e7.42 (m,
4.4.11. 7-Fluoro-2-(4-methoxyphenyl)-4-methylquinazoline
1H), 7.30 (d, J¼7.9 Hz, 2H), 2.92 (s, 3H), 2.41 (s, 3H); 13C NMR
(3k). Yellow solid; mp 134.5e136.1 ꢀC; 1H NMR (300 MHz, CDCl3)
(75 MHz, CDCl3)
d
168.1,160.2,150.4,140.6,135.6,133.4,129.3, 129.1,
d
8.56 (d, J¼8.9 Hz, 2H), 8.04 (dd, J¼8.9, 5.9 Hz, 1H), 7.64e7.59 (m,
128.5, 126.6, 125.0, 122.9, 22.0, 21.6; GCeMS m/z (% rel inten.) 234
(Mþ, 100), 219 (43), 91 (16); HRMS (ESI): calcd for C16H15N2
[MþH]þ: 235.1230; found: 235.1240.
1H), 7.32e7.23 (m, 1H), 7.02 (d, J¼8.9 Hz, 2H), 3.89 (s, 3H), 2.95 (s,
3H); 13C NMR (75 MHz, CDCl3)
d
167.8, 165.6 (d, J1CꢂF¼254.3 Hz),
162.0, 161.0, 152.5 (d, J3CꢂF¼13.7 Hz), 130.7, 130.4, 127.7 (d,
J3CꢂF¼10.8 Hz), 120.1, 116.7 (d, J2CꢂF¼25.3), 114.0, 112.7 (d,
J2CꢂF¼20.2 Hz), 55.5, 22.2; GCeMS m/z (% rel inten.) 268 (Mþ, 100),
253 (46), 227 (6); HRMS (ESI): calcd for C16H14FN2O [MþH]þ:
269.1085; found: 269.1085.
4.4.4. 2-(4-Methoxyphenyl)-4-methylquinazoline
solid; 1H NMR (300 MHz, CDCl3)
8.58 (d, J¼8.9 Hz, 2H), 8.11e7.96
(m, 2H), 7.88e7.75 (m,1H), 7.58e7.45 (m,1H), 7.02 (d, J¼8.9 Hz, 2H),
3.87 (s, 3H), 2.96 (s, 3H); 13C NMR (75 MHz, CDCl3)
168.1, 161.7,
(3d).11 Yellow
d
d
159.9, 150.5, 133.5, 131.0, 130.2, 129.0, 126.4, 125.0, 122.7, 113.9, 55.4,
4.4.12. 2-(4-Chlorophenyl)-7-fluoro-4-methylquinazoline
(3l). Yellow solid; mp 158.8e160.0 ꢀC; 1H NMR (300 MHz, CDCl3)
22.1; GCeMS m/z (% rel inten.) 250 (Mþ, 100), 235 (48), 209 (9).
d
8.54 (d, J¼8.6 Hz, 2H), 8.06 (dd, J¼8.9, 6.0 Hz, 1H), 7.62 (dd, J¼10.0,
4.4.5. 2-(4-Chlorophenyl)-4-methylquinazoline (3e).11 Yellow solid;
2.4 Hz,1H), 7.46 (d, J¼8.6 Hz, 2H), 7.32 (dt, J¼8.7, 2.4 Hz,1H), 2.95 (s,
1H NMR (300 MHz, CDCl3)
d
8.51 (d, J¼8.3 Hz, 2H), 7.94 (t, J¼8.9 Hz,
3H); 13C NMR (75 MHz, CDCl3)
d
168.1, 165.7 (d, J1CꢂF¼255.0 Hz),
2H), 7.76 (t, J¼7.7 Hz, 1H), 7.52e7.38 (m, 3H), 2.88 (s, 3H); 13C NMR
160.2, 152.3 (d, J3CꢂF¼13.7 Hz), 137.0, 136.5, 130.1, 128.9, 127.8 (d,
J3CꢂF¼10.1 Hz), 120.4, 117.4 (d, J2CꢂF¼25.3 Hz), 113.0 (d,
J2CꢂF¼20.2 Hz), 22.2; GCeMS m/z (% rel inten.) 274 (35), 272 (Mþ,
100), 257 (46), 111 (19); HRMS (ESI): calcd for C15H11ClFN2 [MþH]þ:
273.0589; found: 273.0596.
(75 MHz, CDCl3) d 168.2, 158.9, 150.1, 136.7, 136.5, 133.6, 129.9, 129.1,
128.7, 127.0, 124.9, 122.9, 22.0; GCeMS m/z (% rel inten.) 256 (34),
254 (Mþ, 100), 239 (45), 213 (18), 102 (22), 76 (21).
4.4.6. 2-(3-Chlorophenyl)-4-methylquinazoline (3f). Yellow solid;
mp 100.8e101.7 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.62 (s, 1H),
4.4.13. 2-(2-Chlorophenyl)-7-fluoro-4-methylquinazoline
8.52e8.48 (m, 1H), 8.09e8.02 (m, 2H), 7.85 (t, J¼7.6 Hz, 1H), 7.58 (t,
(3m). Yellow oil; 1H NMR (300 MHz, CDCl3)
d
8.18 (dd, J¼9.1, 6.0 Hz,
J¼7.6 Hz, 1H), 7.46e7.41 (m, 2H), 2.99 (s, 3H); 13C NMR (75 MHz,
1H), 7.80e7.76 (m, 1H), 7.72 (dd, J¼9.6, 2.8 Hz, 1H), 7.55e7.50 (m,
CDCl3)
d 168.6, 158.9, 150.3, 140.2, 134.8, 133.8, 130.4, 129.9, 129.4,
1H), 7.47e7.37 (m, 3H), 3.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
128.7, 127.3, 126.7, 125.1, 123.2, 22.1; GCeMS m/z (% rel inten.) 256
(32), 254 (Mþ, 100), 239 (42), 76 (24); HRMS (ESI): calcd for
C15H12ClN2 [MþH]þ: 255.0684; found: 255.0694.
d
168.2, 165.8 (d, J1CꢂF¼256.5 Hz), 162.4, 152.0 (d, J3CꢂF¼13.7 Hz),
138.4, 133.0, 131.6, 130.7, 130.5, 127.9 (d, J3CꢂF¼10.1 Hz), 127.0,
120.1, 118.2 (d, J2CꢂF¼25.3 Hz), 113.1 (d, J2CꢂF¼20.2 Hz), 22.1;
GCeMS m/z (% rel inten.) 274 (14), 272 (Mþ, 44), 257 (24), 237 (100);
HRMS (ESI): calcd for C15H11ClFN2 [MþH]þ: 273.0589; found:
273.0594.
4.4.7. 2-(2-Chlorophenyl)-4-methylquinazoline (3g). Yellow solid;
mp 110.3e111.6 ꢀC; 1H NMR (300 MHz, CDCl3)
d 8.20e8.10 (m, 2H),
7.97e7.89 (m, 1H), 7.81e7.76 (m, 1H), 7.72e7.65 (m, 1H), 7.55e7.50
(m, 1H), 7.43e7.37 (m, 2H), 3.05 (s, 3H); 13C NMR (75 MHz, CDCl3)
4.4.14. 2-(4-Chlorophenyl)-4-methylthieno[3,2-d]pyrimidine
d
168.4, 161.3, 150.0, 138.7, 134.0, 132.9, 131.6, 130.6, 130.2, 129.3,
(3n). White solid; mp 142.6e143.6 ꢀC; 1H NMR (300 MHz, CDCl3)
127.8, 127.0, 125.1, 122.8, 22.0; GCeMS m/z (% rel inten.) 256 (18),
254 (Mþ, 56), 239 (35), 219 (100), 76 (28); HRMS (ESI): calcd for
C15H12ClN2 [MþH]þ: 255.0684; found: 255.0685.
d
8.48 (d, J¼8.6 Hz, 2H), 7.92 (d, J¼5.5 Hz, 1H), 7.55 (d, J¼5.5 Hz, 1H),
7.45 (d, J¼8.6 Hz, 2H), 2.83 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 161.5,
161.4, 160.3, 136.8, 136.4, 135.1, 129.7, 128.8, 125.2, 23.6; GCeMS m/z
(% rel inten.) 262 (39), 260 (Mþ, 100), 245 (32), 111 (22); HRMS
(ESI): calcd for C13H10ClN2S [MþH]þ: 261.0248; found: 261.0250.
4.4.8. 2-(4-Fluorophenyl)-4-methylquinazoline (3h).11 Yellow solid;
1H NMR (300 MHz, CDCl3)
d
8.69e8.56 (m, 2H), 8.10e8.00 (m, 2H),
7.83 (ddd, J¼8.3, 7.0, 1.2 Hz, 1H), 7.55 (ddd, J¼8.3, 6.9, 1.1 Hz, 1H),
4.4.15. 2-p-Tolylquinazoline (3o).9 White solid; 1H NMR (300 MHz,
CDCl3)
7.91e7.82 (m, 2H), 7.55 (ddd, J¼7.9, 6.9, 1.0 Hz, 1H), 7.22 (d, J¼7.9 Hz,
2H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3)
161.2, 160.5, 150.9,
7.22e7.14 (m, 2H), 2.97 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
168.4,
d
9.42 (s, 1H), 8.51 (d, J¼8.3 Hz, 2H), 8.08e8.03 (m, 1H),
164.7 (d, J1CꢂF¼250.0 Hz), 159.3, 150.5, 134.6 (d, J4CꢂF¼2.2 Hz),
133.7, 130.7 (d, J3CꢂF¼8.0 Hz), 129.2, 127.0, 125.1, 123.0, 115.5
d

9370
J. Ju et al. / Tetrahedron 68 (2012) 9364e9370
141.0, 135.4, 134.1, 129.5, 128.6, 127.2, 127.1, 123.6, 21.6; GCeMS m/z
J¼9.6, 2.4 Hz, 1H), 7.31 (dt, J¼8.6, 2.4 Hz, 1H), 3.03 (t, J¼7.9 Hz,
2H), 2.91 (s, 3H), 1.94e1.83 (m, 2H), 1.47e1.28 (m, 6H), 0.88 (t,
(% rel inten.) 220 (Mþ, 100), 219 (31), 193 (21), 91 (11), 76 (11).
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 168.4, 167.8, 165.5 (d,
4.4.16. 4-Methylquinazolin (3p).11 Yellow solid; 1H NMR (300 MHz,
J1CꢂF¼254.3 Hz), 151.9 (d, J3CꢂF¼13.7 Hz), 127.7 (d,
J3CꢂF¼10.8 Hz), 119.8, 116.9 (d, J2CꢂF¼24.6 Hz), 112.3 (d,
J2CꢂF¼20.2 Hz), 40.2, 31.8, 29.4, 29.1, 22.7, 21.9, 14.2; GCeMS m/
z (% rel inten.) 246 (Mþ, 9), 203 (14), 189 (29), 176 (100), 161 (7);
HRMS (ESI): calcd for C15H20FN2 [MþH]þ: 247.1605; found:
247.1610.
CDCl3)
d
9.18 (s, 1H), 8.10 (d, J¼8.6 Hz, 1H), 8.03 (d, J¼8.6 Hz, 1H),
7.92e7.85 (m,1H), 7.68e7.61 (m,1H), 2.96 (s, 3H); 13C NMR (75 MHz,
CDCl3)
d 168.3, 154.6, 149.6, 133.7, 129.1, 127.6, 125.1, 124.6, 21.9;
GCeMS m/z (% rel inten.) 144 (Mþ, 100), 129 (26), 103 (33), 76 (34).
4.4.17. 2,4-Dimethylquinazoline (3q).8a Yellow oil; 1H NMR
(300 MHz, CDCl3)
(ddd, J¼8.3, 6.9, 1.4 Hz, 1H), 7.55 (ddd, J¼8.3, 6.9, 1.0 Hz, 1H), 2.91 (s,
3H), 2.85 (s, 3H); 13C NMR (75 MHz, CDCl3)
168.1, 163.5, 149.8,
d
8.03 (d, J¼8.3 Hz,1H), 7.92 (d, J¼8.3 Hz,1H), 7.83
4.4.23. 2-Phenyl quinazoline (3w).8a Yellow oil; 1H NMR (600 MHz,
CDCl3)
d
9.46 (s, 1H), 8.62 (d, J¼6.9 Hz, 2H), 8.08 (d, J¼8.3 Hz, 1H),
d
7.92e7.87 (m, 2H), 7.59 (t, J¼7.2 Hz, 1H), 7.54e7.51 (m, 3H); 13C
133.6, 128.2, 126.6, 124.9, 122.2, 26.4, 21.7; GCeMS m/z (% rel inten.)
NMR (150 MHz, CDCl3) d 161.2, 160.6, 150.9, 138.2, 134.2, 130.7,
158 (Mþ, 100), 143 (59), 117 (47), 76 (19).
128.9, 128.8, 128.7, 127.4, 127.2, 123.7; GCeMS m/z (% rel inten.) 206
(Mþ, 100), 179 (56), 103 (34), 76 (53).
4.4.18. 2-Ethyl-4-methylquinazoline (3r). Yellow oil; 1H NMR
(300 MHz, CDCl3)
(t, J¼7.5 Hz, 1H), 7.56 (t, J¼7.5 Hz, 1H), 3.10 (q, J¼7.6 Hz, 2H), 2.93 (s,
3H), 1.46 (t, 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
168.2, 167.8,
150.0, 133.5, 128.5, 126.6, 125.0, 122.5, 33.3, 21.9, 13.2; GCeMS m/z
(% rel inten.) 172 (Mþ, 65), 171 (100), 144 (19), 129 (14), 76 (11);
HRMS (ESI): calcd for C11H13N2 [MþH]þ: 173.1073; found: 173.1072.
d
8.05 (d, J¼8.3 Hz,1H), 7.96 (d, J¼8.3 Hz,1H), 7.83
Acknowledgements
d
This project was supported by the National Natural Science
Foundation of China (21032004, 20972084), the Specialized Re-
search Fund for the Doctoral Program of Higher Education
(20110002110051) and the Bilateral Scientific Cooperation between
Tsinghua University & K.U. Leuven.
4.4.19. 2-Hexyl-4-methylquinazoline (3s). Yellow oil; 1H NMR
(300 MHz, CDCl3)
d
8.06 (d, J¼8.3 Hz, 1H), 7.96 (d, J¼8.3 Hz, 1H),
Supplementary data
7.87e7.80 (m, 1H), 7.56 (t, J¼7.4 Hz, 1H), 3.05 (t, J¼7.9 Hz, 2H), 2.93
Copies of 1H, and 13C NMR charts for all products are included in
Supplementary data. Supplementary data associated with this ar-
ticle can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2012.09.035.
(s, 3H), 1.95e1.84 (m, 2H), 1.50e1.27 (m, 6H), 0.88 (t, J¼7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3)
d 168.2, 167.2, 150.0, 133.6, 128.5, 126.6,
125.0, 122.5, 40.3, 31.9, 29.5, 29.3, 22.7, 21.9, 14.2; GCeMS m/z (% rel
inten.) 228 (Mþ, 9), 185 (14), 171 (29), 158 (100), 117 (8); HRMS
(ESI): calcd for C15H21N2 [MþH]þ: 229.1699; found: 229.1695.
References and notes
4.4.20. 7-Fluoro-4-methyl-2-p-tolylquinazoline (3t). Yellow solid;
mp 77.8e78.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.49 (d, J¼8.5 Hz, 2H),
8.05 (dd, J¼8.8, 5.9 Hz,1H), 7.64 (dd, J¼9.8, 2.4 Hz,1H), 7.34e7.28 (m,
3H), 2.96 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3)
167.8, 165.5
1. (a) Purohit, D. M.; Shah, V. H. Indian J. Heterocycl. Chem. 1999, 8, 213e216; (b)
Bedi, P. M. S.; Kumar, V.; Mahajan, M. P. Bioorg. Med. Chem. Lett. 2004, 14,
5211e5213.
2. (a) Chien, T.-C.; Chen, C.-S.; Yu, F.-H.; Chern, J.-W. Chem. Pharm. Bull. 2004, 52,
1422e1426; (b) Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.; Stamminger,
T.; Marschall, M. Antimicrob. Agents Chemother. 2004, 48, 4154e4162.
3. (a) Kunes, J.; Bazant, J.; Pour, M.; Waisser, K.; Slosarek, M.; Janota, J. Farmaco
2000, 55, 725e729; (b) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.;
Klimesova, V.; Kaustova, J. Farmaco 2001, 56, 803e807.
4. (a) Foster, B. A.; Coffey, H. A.; Mornin, M. J.; Rastinejad, F. Science 1999, 286,
2507e2510; (b) Doyle, L. A.; Ross, D. D. Oncogene 2003, 22, 7340e7358; (c)
Henderson, E. A.; Bavetsias, V.; Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A.
L. Bioorg. Med. Chem. 2006, 14, 5020e5042.
5. (a) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem. Commun. 2008,
2935e2937; (b) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org. Chem. 2009,
74, 4934e4942.
6. (a) Zhang, J.; Zhu, D.; Yu, C.; Wan, C.; Wang, Z. Org. Lett. 2010, 12, 2841e2843;
(b) Karnakar, K.; Shankar, J.; Murthy, S. N.; Ramesh, K.; Nageswar, Y. V. D. Synlett
2011, 1089e1096.
7. (a) Maheswari, C. U.; Kumar, G. S.; Venkateshwar, M.; Kumar, R. A.; Kantam, M.
L.; Reddy, K. R. Adv. Synth. Catal. 2010, 352, 341e346; (b) Han, B.; Yang, X.-L.;
Wang, C.; Bai, Y.-W.; Pan, T.-C.; Chen, X.; Yu, W. J. Org. Chem. 2012, 77,
1136e1142.
8. (a) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun. 2008, 6333e6335;
(b) Truong, V. L.; Morrow, M. Tetrahedron Lett. 2010, 51, 758e760.
9. Wang, C.; Li, S.; Liu, H.; Jiang, Y.; Fu, H. J. Org. Chem. 2010, 75, 7936e7938.
10. (a) Qi, C.; Zheng, Q.; Hua, R. Tetrahedron 2009, 65, 1316e1320; (b) Su, J.; Ju, J.;
Hua, R. Curr. Org. Synth. 2012, 9, 273e277.
d
(d, J1CꢂF¼254.3 Hz), 161.2, 152.3 (d, J3CꢂF¼13.7 Hz), 141.0, 135.2,
129.4,128.7,127.7 (d, J3CꢂF¼10.8 Hz),120.2,116.9 (d, J2CꢂF¼25.3 Hz),
112.8 (d, J2CꢂF¼20.2 Hz), 22.2, 21.6; GCeMS m/z (% rel inten.) 252
(Mþ, 100), 237 (38), 211 (12), 91 (18); HRMS (ESI): calcd for chemical
formula: C16H14FN2 [MþH]þ: 253.1136; found: 253.1130.
4.4.21. 7-Fluoro-2-(4-fluorophenyl)-4-methylquinazoline
(3u). Yellow solid; mp 147.4e148.7 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.63e8.56 (m, 2H), 8.05 (dd, J¼9.4, 5.9 Hz, 1H), 7.61 (dd, J¼9.6,
2.8 Hz, 1H), 7.34e7.26 (m, 1H), 7.21e7.14 (m, 2H), 2.95 (s, 3H); 13C
NMR (75 MHz, CDCl3)
d
168.1, 165.6 (d, J1CꢂF¼255.0 Hz), 164.8 (d,
J1CꢂF¼250.0 Hz), 160.2, 152.3 (d, J3CꢂF¼13.7 Hz), 134.1 (d,
J4CꢂF¼2.9 Hz), 130.9 (d, J3CꢂF¼8.7 Hz), 127.8 (d, J3CꢂF¼10.1 Hz),
120.2, 117.2 (d, J2CꢂF¼24.6 Hz), 115.6 (d, J2CꢂF¼21.7 Hz), 112.9 (d,
J2CꢂF¼19.5 Hz), 22.2; GCeMS m/z (% rel inten.) 256 (Mþ, 100), 241
(55), 215 (32), 95 (27), 75 (10); HRMS (ESI): calcd for C15H11F2N2
[MþH]þ: 257.0855; found: 257.0889.
4.4.22. 7-Fluoro-2-hexyl-4-methylquinazoline (3v). Yellow oil; 1H
NMR (300 MHz, CDCl3)
11. Alonso, R.; Caballero, A.; Campos, P. J.; Sampedro, D.; Rodriguez, M. A. Tetra-
hedron 2010, 66, 4469e4473.
d
8.07 (dd, J¼9.5, 5.9 Hz, 1H), 7.56 (dd,