Synthesis of 4-(Dimethylamino)quinazoline via Direct Amination of Quinazolin-4(3 H)-one Using N, N -Dimethylformamide as a Nitrogen Source at Room Temperature

Article abstract of DOI:10.1055/s-0034-1380550

An efficient direct amination of quinazolin-4(3H)-ones using N,N-dimethylformamide as a nitrogen source is described that affords the corresponding 4-(dimethylamino)quinazolines in high yields. This transformation proceeds through efficient 4-toluenesulfo

Full text of DOI:10.1055/s-0034-1380550

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2055–2062
paper
2055
X. Chen et al.
Paper
Synthesis
Synthesis of 4-(Dimethylamino)quinazoline via Direct Amination
of Quinazolin-4(3H)-one Using N,N-Dimethylformamide as a
Nitrogen Source at Room Temperature
Xin Chenb
Qin Yangb
Yirong Zhoub
Zhihong Dengb
Xuechun Maob
Yiyuan Peng*a,b
O
NMe2
1) TsCl, Na2CO3
THF
NH
N
R2
R2
R1
N
R1
2) DMF, KOt-Bu
r.t., 1 h
N
R1 = aryl, heteroaryl
2 = Me, Br
60–89%
R
a National Research Center for Carbohydrate Synthesis and Key Laboratory of Small
Functional Organic Molecules, Ministry of Education, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. of China
yypeng@jxnu.edu.cn
yiyuanpeng@yahoo.com
b Key Laboratory of Green Chemistry, Jiangxi Province College of Chemistry, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. of China
Received: 17.01.2015
Accepted after revision: 18.03.2015
Published online: 22.04.2015
F
DOI: 10.1055/s-0034-1380550; Art ID: ss-2015-h0036-op
O
HN
N
Cl
N
O
Abstract An efficient direct amination of quinazolin-4(3H)-ones using
N,N-dimethylformamide as a nitrogen source is described that affords
the corresponding 4-(dimethylamino)quinazolines in high yields. This
transformation proceeds through efficient 4-toluenesulfonyl chloride
mediated C–OH bond activation at room temperature.
N
MeO
gefitnib (Iressa)
Figure 1 The structure of gefitinib (Iressa)
Key words amination, quinazolin-4(3H)-one, 4-aminoquinazoline
Quinazoline heterocycles are important scaffolds in me-
dicinal chemistry. They are recognized as exhibiting a broad
range of biological activity, such as anti-inflammatory, anti-
convulsant, vasodilator, antihypertensive, antibiosis, and fi-
brinogen receptor antagonistic activity.1 In particular, 4-
aminoquinazolines have attracted widespread attention in
recent years because of their potential pharmacological ac-
tivity.2 For example, gefitinib (Iressa), developed from 4-
aminoquinazoline, is approved and marketed for non-small
cell lung cancer treatment (Figure 1).3 The most common
route for the preparation of 4-aminoquinazolines is
through acid- or base-mediated SNAr substitution of 4-chlo-
roquinazolines with amines.4 However, the common meth-
od for the preparation of 4-chloroquinazolines is the chlori-
nation of quinazolin-4(3H)-ones, which often requires acid-
ic and harsh conditions using thionyl chloride or
phosphoryl chloride as the chlorination reagent (Scheme
1).
then reacted it with primary and secondary amines to pro-
vide 4-aminoquinazolines in good yields (Scheme 1).6 How-
ever, the reaction required two discrete steps to complete
the reaction.
We have developed direct sulfanylations of 4-hydroxy-
coumarins7 and quinazolin-4(3H)-ones8 via C–OH bond ac-
tivation. Prompted by our continued interest in 4-toluene-
sulfonyl chloride mediated C–OH bond activation, we envi-
sioned that a small library of 4-aminoquinazolines could be
constructed starting from quinazolin-4(3H)-ones.
In parallel, chemists have achieved important develop-
ments in the field of organic synthesis by employing N,N-
dimethylformamide as a reaction precursor. Because of its
specific structure, N,N-dimethylformamide can participate
in many reactions by serving as a multipurpose building
block for various units, such as CO, NMe2, CONMe2, Me,
CHO, etc.9 Substitution reactions of benzyl and (hetero)aryl
halides leading to amines at high temperatures have been
carried out using N,N-dimethylformamide as the solvent
and reactant.10 Shao and Chen also disclosed that amides
could be used as the nitrogen source in palladium-cata-
lyzed reactions with aryl chlorides.11 In this paper, as part
of our ongoing study on novel and green coupling process-
es,7,12 we report the one-pot direct amination of
Recently, a particular emphasis has been placed on
cross-coupling reactions via C–OH bond activation of tau-
tomerizable heterocycles, where phosphonium salts or 4-
toluenesulfonyl chloride are recognized as efficient activa-
tion reagents.5 Lockman et al. isolated 2-methyl-4-(tosyl-
oxy)quinazoline from 2-methylquinazolin-4(3H)-one and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2056
X. Chen et al.
Paper
Synthesis
common route
R2
R3
N
N
N
Cl
O
R2R3NH
SOCl2 or POCl3
N
NH
acid or base
R1
R1
N
R1
N
Lockman`s route
O
R1
R2
N
N
N
OTs
TsCl, Et3N
DMAP–CH2Cl2
R1R2NH
N
NH
Me
overnight
i-PrOH, CH2Cl2
Me
N
Me
N
present one-pot route
Me
Me
N
O
N
N
TsCl, DMF, KOt-Bu
r.t., 1 h
NH
N
Ar
Ar
Scheme 1 Routes for the preparation of 4-aminoquinazolines
Table 1 Influence of the Reaction Conditions on the Direct Amination
of Quinazolinone 1a Using N,N-Dimethylformamidea
quinazolin-4(3H)-ones using N,N-dimethylformamide as
the nitrogen source via a 4-toluenesulfonyl chloride medi-
ated C–OH bond activated procedure (Scheme 1).
O
NMe2
N
At the outset, 2-p-tolylquinazolin-4(3H)-one (1a) and
N,N-dimethylformamide were selected as the model sub-
strates to optimize the reaction conditions. We reasoned
that the presence of 4-toluenesulfonyl chloride would en-
able in situ activation of 2-p-tolylquinazolin-4(3H)-one
(1a). Based on these considerations, different bases and sol-
vents were screened, and the results are given in Table 1.
In initial experiments, the reaction was performed in
N,N-dimethylformamide with triethylamine or 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (3.0 equiv) as the base at ambient
temperature, but no product was detected (Table 1, entries
1 and 2). Gratifyingly, the desired product 4-(dimethylami-
no)-2-p-tolylquinazoline (2a) was isolated in 60% yield us-
ing an inorganic base, sodium carbonate (entry 3). Slightly
higher yields were obtained when potassium carbonate,
potassium hydroxide, or sodium tert-butoxide were em-
ployed as the base (entries 4–6). Further evaluation showed
that potassium tert-butoxide was the best base for this
transformation because it afforded the desired product 2a
in 85% yield (entry 7). Other solvents (DMSO, DCE, THF, 1,4-
dioxane, toluene, and cyclohexane) were subsequently
screened, and N,N-dimethylformamide proved to be the
most efficient solvent (entries 8–13). A control experiment
showed that no reaction occurred without the addition of
4-toluenesulfonyl chloride (entry 14).
NH
TsCl, DMF
base, solvent
r.t.
N
N
Me
Me
2a
1a
Entry
Base
Solvent
Yieldb (%)
1
2
Et3N
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DCE
–
–
3
Na2CO3
K2CO3
60
67
72
75
85
63
73
78
75
75
70
–
4
5
KOH
6
NaOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
7
8
9
10
11
12
13
14c
THF
1,4-dioxane
toluene
cyclohexane
DMF
a Reaction conditions: 1a (0.5 mmol), DMF (2.5 mmol), TsCl (0.5 mmol),
base (3.0 equiv), solvent (3 mL), r.t., 1–12 h, air.
b Isolated yield.
c Without the addition of TsCl.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2057
X. Chen et al.
Paper
Synthesis
The generality and scope of this reaction were then in-
vestigated under the optimized conditions [TsCl (1.0 equiv),
KOt-Bu (3.0 equiv), DMF (3 mL), r.t.]; the results are sum-
marized in Scheme 2.
In most cases the corresponding products were ob-
tained in good to excellent yields when 2-arylquinazolin-
4(3H)-ones were used as substrates. 2-Arylquinazolin-
4(3H)-one with electron-donating groups or electron-with-
drawing groups on the aryl group were all good partners
under the optimum conditions, which afforded the desired
product 2a–l in excellent yields. For example, 2-m-
tolylquinazolin-4(3H)-one reacted with N,N-dimethylform-
amide to provide 2b in 88% yield. A slightly lower yield
(70%) was obtained for 4-aminoquinazoline 2l. Additional-
ly, other quinazolinones 1 incorporated methyl and bromo
on the quinazolinone ring were examined in the reactions,
which provided the expected products 2p–t in good yields.
2-(1-Naphthyl)- and 2-heteroarylquinazolin-4(3H)-ones
O
NMe2
TsCl, DMF, KOt-Bu
r.t., 1 h
NH
N
R2
R2
R1
N
R1
N
1
2
NMe2
N
NMe2
N
NMe2
NMe2
N
NMe2
N
N
Me
Me
N
N
N
N
N
Me
OMe
2a, 85%
2b, 88%
2c, 80%
2d, 80%
2e, 85%
NMe2
N
NMe2
N
NMe2
N
NMe2
N
NMe2
N
OMe
OMe
N
N
N
N
N
NMe2
Cl
Br
2f, 72%
2g, 84%
2h, 66%
2i, 78%
2j, 80%
Cl
NMe2
N
NMe2
N
NMe2
NMe2
N
NMe2
N
N
O
N
N
N
N
N
N
CN
CF3
2k, 76%
2l, 70%
2m, 86%
2n, 65%
2o, 90 %
NMe2
NMe2
N
NMe2
N
NMe2
N
NMe2
Br
Cl
Br
N
Br
N
Me
N
Me
N
N
N
N
Me
Cl
2p, 88%
2q, 63%
2r, 90%
2s, 60%
2t, 73%
NMe2
NMe2
N
N
N
N
2u, trace
2w, trace
Scheme 2 Direct amination of quinazolin-4(3H)-ones with N,N-dimethylformamide. Reagents and conditions: 1 (0.5 mmol), TsCl (1.0 equiv), KOt-Bu
(3.0 equiv), DMF (3 mL), r.t., 1 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2058
X. Chen et al.
Paper
Synthesis
X
N
O
H
O
TsCl (1.0 equiv)
N
NH
N
+
N
X
KOt-Bu (3.0 equiv)
N
r.t.
Me
Me
1a
(3 mL)
2x, X = C, 56%
2y, X = O, 65%
NMe2
N
O
Me
O
TsCl (1.0 equiv)
NH
+
N
Me
Me
KOt-Bu (3.0 equiv)
N
N
r.t.
(3 mL)
1a
Me
Me
2a, 55%
Scheme 3 Direct amination of 4-quinazolinone 1a with piperidine-1-carbaldehyde, morpholine-4-carbaldehyde, and N,N-dimethylacetamide
also afforded 2m–o in moderate to high yields. However,
similar to our previous reports8 the reaction was unsuc-
cessful with 2-unsubstituted quinazolin-4(3H)-one and 2-
cyclohexylquinazolin-4(3H)-one even with a prolonged re-
action time.
As N,N-dimethylformamide is a readily available source
of dimethylamine in amination reactions, we also explored
whether this reaction could be extended to other amides.
When piperidine-1-carbaldehyde and morpholine-4-carb-
aldehyde were employed in the direct amination of 2-p-
tolylquinazolin-4(3H)-one (1a), the expected products 2x
and 2y were obtained in 56% and 65% yields, respectively
(Scheme 3). Interestingly, N,N-dimethylacetamide also
works well in the amination with 1a to produce 2a in 55%
yield (Scheme 3).
Table 2 Using 2-p-Tolyl-4-(tosyloxy)quinazoline (3) with Varying
Amine Sources
OTs
N
NR1R2
KOt-Bu
(3.0 equiv)
r.t.
N
N
+
R1R2NH
N
Tol
Tol
3
Entry
Amine
DMF
Product
Yielda,b (%)
1
2
3
2a
2a
2a
90
60
12
aq Me2NH
Me2NH·HCl
NEt2
To explore the mechanism of this direct amination reac-
tion, several control experiments were performed (Table 2).
First, the key intermediate, tosylate 2-p-tolyl-4-(tosyl-
oxy)quinazoline (3) was isolated, and it was treated with
N,N-dimethylformamide under the reaction conditions to
provide 2a in 90% yield (entry 1). The reaction of 3 and di-
methylamine (5.0 equiv in water) gave 2a in 60% yield (en-
try 2). However when the reactions proceed under the con-
ditions of Lockman et al., the corresponding products were
obtained in 12% and 28% yields (entries 3 and 4). In the case
of cyclic secondary amines, like morpholine and piperidine,
the corresponding products were obtained in 58% and 37%
yields (entries 5 and 6). Stirring 3 and diethylamine (5.0
equiv), N,N-dimethylformamide (5.0 equiv), and potassium
tert-butoxide (3.0 equiv) in tetrahydrofuran (3.0 mL) at
room temperature did not give the SNAr substitution prod-
uct of diethylamine and only 2a (15%) was obtained
(Scheme 4). These results indicated that in this catalytic
system, formamide had higher reactivity compared to the
corresponding simple aliphatic amine.
4
Et2NH·HCl
28
Tol
O
O
N
N
N
5
58
N
H
Tol
N
N
N
6
37
N
H
Tol
a Reaction conditions: 3 (0.5 mmol), amine (5.0 mmol), base (3.0 equiv),
THF (3 mL), r.t., 1–12 h, air.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2059
X. Chen et al.
Paper
Synthesis
2-alkylquinazolines. While our method is efficient for the
preparation of 4-aminated 2-arylquinazolines. Hence, these
two reaction systems complement each other.
H
N
NEt2
N
Et
Et
KOt-Bu
(3.0 equiv)
(5.0 equiv)
2a
+
3
+
In conclusion, we have described a facile and efficient
route for the synthesis of 2-aryl-4-(dimethylami-
no)quinazoline via direct amination of 2-arylquinazolin-
4(3H)ones with N,N-dimethylformamide under mild condi-
tions. Notably, by using the inexpensive and easy to handle
4-toluenesulfonyl chloride as the C–OH bond activation re-
agent, this cost-effective methodology will be attractive for
further library construction.
THF, r.t.
DMF
(5.0 equiv)
N
Tol
15%
only product
not detected
Scheme 4
Based on these experiments and other work,10,13 a pos-
sible mechanism is proposed in Scheme 5. Quinazolinone 1
could isomerize to quinazolin-4-ol A. Treatment of
quinazolinone with 4-toluenesulfonyl chloride in the pres-
ence of base (KOt-Bu) leads to the formation of tosylate B,
which attacks N,N-dimethylformamide to form successive
intermediates C, D, E, and F; hydrolysis of F gives the final
product 2. When R is H or alkyl group, only traces of ex-
pected products were obtained probably because the inter-
mediates C or D are difficult to form without the delocaliza-
tion effect of the 2-aryl group.
Unless otherwise stated, all commercial reagents were used as re-
ceived. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using sili-
ca gel (60-Å pore size, 32–63 μm, standard grade). Analytical TLC was
performed using glass plates precoated with 0.25 mm 230–400 mesh
silica gel impregnated with a fluorescent indicator (254 nm). TLC
plates were visualized by exposure to ultraviolet light. Organic solu-
tions were concentrated on rotary evaporators at ~27 mbar at 25–
35 °C. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruker
DRX-400 spectrometer operating at 400 MHz and 100 MHz, respec-
tively. HRMS were obtained on a micrOTOF II Instrument.
Me
Me
N
Me
Me
N
N
N
O
O
NH
H2O
one-pot
H
4-(Dimethylamino)quinazolines 2; General Procedure
N
R
N
R
N
R
Quinazolinone (0.5 mmol) and KOt-Bu (1.5 mmol) in DMF (3.0 mL)
were added to a round-bottom flask. The mixture was stirred for 2
min, TsCl (0.5 mmol) was added, and the mixture was stirred at r.t. for
1 h. When the reaction was complete (TLC), the mixture was
quenched with sat. NaCl solution and extracted with EtOAc, and the
combined extracts were dried (Na2SO4). The crude product was puri-
fied by chromatography (silica gel, PE–EtOAc, 15:1–10:1) to provide
the corresponding product 2.
1
2
F
OH
N
Me
Me
N
N
N
O
N
H
R
R
4-(Dimethylamino)-2-p-tolylquinazoline (2a)14
A
E
TsCl
KOt-Bu
White solid; yield: 112.2 mg (85%); mp 153.5–154.5 °C.
IR (KBr): 2923, 1609, 1334, 765, 740 cm–1
.
Me
Me
N
Me
Me
Me
O
Me
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 3.41 (s, 6 H), 7.28 (d, J =
8.0 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.92 (d, J =
8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 8.45 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 41.8, 114.9, 123.9, 125.5, 128.4,
128.6, 129.0, 132.0, 136.2, 140.1, 153.0, 159.4, 163.9.
N
TsO
N
OTs
OTs
O
O
H
N
N
H
N
H
R
N
R
N
N
R
B
C
D
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3: 264.1501; found:
264.1497.
Scheme 5 Proposed mechanism
4-(Dimethylamino)-2-m-tolylquinazoline (2b)14
Finally, in order to compare the results of Lockman et
al., a serial of control experiments were performed. The re-
actions of 4-(tosyloxy)quinazolines (intermediates) B with
several amines were studied under the conditions of Lock-
man et al.; the results revealed that when the substituent at
the 2-position of the quinazoline is methyl or hydrogen the
reactions gave good yields but when it is aryl the yields
were poor (see the Supporting Information). These results
showed that the procedure of Lockman et al. can only be
applied to the synthesis of 4-aminated 2-unsubstituted or
Milky solid; yield: 116.2 mg (88%); mp 77.2–78.8 °C.
IR (KBr): 2916, 1608, 1283, 769, 733 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H), 3.40 (s, 6 H), 7.26 (d, J =
7.6 Hz, 1 H), 7.31–7.39 (m, 2 H), 7.66 (t, J = 8.4 Hz, 1 H), 7.93 (d, J = 8.0
Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 8.36 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 41.8, 115.0, 124.0, 125.5, 125.6,
128.2, 128.7, 128.9, 130.8, 137.8, 137.9, 153.0, 159.5, 163.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3: 264.1501; found:
264.1500.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2060
X. Chen et al.
Paper
Synthesis
4-(Dimethylamino)-2-o-tolylquinazoline (2c)14
2-(4-Chlorophenyl)-4-(dimethylamino)quinazoline (2h)14
Yellow solid; yield: 93.7 mg (66%); mp 124.3–126.6 °C.
IR (KBr): 2923, 1640, 1579, 1331, 688 cm–1
Brown oil; yield: 105.6 mg (80%).
IR (KBr): 2924, 1610, 1348, 767, 734 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3 H), 3.38 (s, 6 H), 7.25–7.32
(m, 3 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.69 (t, J = 8.4 Hz, 1 H), 7.89–7.94 (m,
2 H), 8.03 (d, J = 8.4 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 3.43 (s, 6 H), 7.37 (t, J = 7.6 Hz, 1 H),
7.44 (d, J = 8.8 Hz, 2 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 1 H),
8.02 (d, J = 8.4 Hz, 1 H), 8.51 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3 41.9, 114.4, 124.2, 125.4, 125.7,
13C NMR (100 MHz, CDCl3): δ = 41.8, 114.9, 124.3, 125.5, 128.4, 128.6,
128.6, 130.4, 131.0, 131.9, 137.2, 139.6, 152.7, 162.5, 163.6.
129.8, 130.9, 132.2, 137.3, 152.7, 158.2, 163.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3: 264.1501; found:
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClN3: 284.0954; found:
264.1494.
284.0949.
4-(Dimethylamino)-2-phenylquinazoline (2d)14
2-(3-Chlorophenyl)-4-(dimethylamino)quinazoline (2i)
Flavescent solid; yield: 100.0 mg (80%); mp 60.2–61.5 °C.
Milky solid; yield: 110.8 mg (78%); mp 69.3–70.2 °C.
IR (KBr): 2922, 1613, 1349, 760, 741 cm–1
.
IR (KBr): 2924, 1611, 1325, 801, 729, 672 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 6 H), 7.34 (t, J = 8.2 Hz, 1 H),
7.36–7.50 (m, 3 H), 7.67 (t, J = 8.2 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H),
7.99 (d, J = 8.4 Hz, 1 H), 8.56 (d, J = 8.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 3.45 (s, 6 H), 7.33–7.41 (m, 2 H), 7.57
(d, J = 6.8 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 8.03
(d, J = 7.6 Hz, 1 H), 8.51 (d, J = 8.0 Hz, 1 H), 8.70 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 41.8, 115.0, 124.0, 125.5, 128.2, 128.4,
13C NMR (100 MHz, CDCl3): δ = 41.8, 115.0, 122.5, 124.4, 125.5, 127.0,
128.7, 130.0, 132.0, 139.0, 153.0, 159.3, 163.9.
128.7, 129.7, 131.4, 132.2, 132.9, 141.0, 152.7, 157.7, 163.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3: 250.1334; found:
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClN3: 284.0954; found:
250.1338.
284.0940.
4-(Dimethylamino)-2-(4-methoxyphenyl)quinazoline (2e)
2-(4-Bromophenyl)-4-(dimethylamino)quinazoline (2j)
White solid; yield: 119.0 mg (85%); mp 109.5–111.3 °C.
Yellow solid; yield: 131.2 mg (80%); mp 108.2–110.6 °C.
IR (KBr): 2932, 1606, 1351, 841.2, 765, 740 cm–1
.
IR (KBr): 2925, 1635, 1568, 1330, 578 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.38 (s, 6 H), 3.86 (s, 3 H), 6.99 (d, J =
8.4 Hz, 2 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.65 (t, J = 7.2 Hz, 1 H), 7.89 (d, J =
8.4 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 8.52 (d, J = 8.4 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 6 H), 7.35 (t, J = 8.2 Hz, 1 H),
7.58 (d, J = 8.8 Hz, 2 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 1 H),
7.98 (d, J = 8.4 Hz, 1 H), 8.43 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.8, 55.3, 113.6, 114.8, 123.7, 125.5,
13C NMR (100 MHz, CDCl3): δ = 41.8, 115.0, 124.2, 124.5, 125.5, 128.7,
128.5, 130.0, 131.6, 131.9, 153.1, 159.1, 161.4, 163.9.
130.0, 131.3, 132.0, 138.0, 152.9, 158.3, 163.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O2: 280.1450; found:
HRMS (ESI): m/z [M + H]+ calcd for C16H15BrN3: 328.0449; found:
280.1442.
328.0440.
2-(3,4-Dimethoxyphenyl)-4-(dimethylamino)quinazoline (2f)
4-(Dimethylamino)-2-[4-(trifluoromethyl)phenyl]quinazoline (2l)
Flavescent solid; yield: 111.6 mg (72%); mp 89.7–90.3 °C.
Milky solid; yield: 120.8 mg (76%); mp 83.6–85.1 °C.
IR (KBr): 2933, 1601, 1344, 1262, 1089, 766 cm–1
.
IR (KBr): 2929, 1621, 1354, 1316, 856, 760 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.43 (s, 6 H), 3.95 (s, 3 H), 4.04 (s, 3 H),
6.97 (d, J = 8.4 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.68 (t, J = 7.8 Hz, 1 H),
7.92 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 8.17–8.20 (m, 2 H).
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 6 H), 7.36 (t, J = 7.2 Hz, 1 H),
7.66–7.72 (m, 3 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H),
8.65 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.7, 56.0, 110.8, 111.6, 114.8, 121.7,
123.7, 125.5, 128.5, 131.9, 148.9, 151.1, 153.0, 159.0, 163.9.
13C NMR (100 MHz, CDCl3): δ = 41.7, 115.1, 124.4, 125.1, 125.5, 128.7,
131.3 (JC-F = 32 Hz), 131.6, 132.1, 142.4, 152.8, 157.8, 163.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H20N3O2: 310.1556; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H15F3N3: 318.1218; found:
310.1546.
318.1223.
4-(Dimethylamino)-2-[4-(dimethylamino)phenyl]quinazoline
(2g)14
4-N,N-Dimethylamino-2-(4-cyanophenyl)quinazoline (2k)
Colorless flakes; yield: 96.3 mg (70%); mp 184.5–185.2 °C.
Yellow solid; yield: 123.1 mg (84%); mp 138.6–141.5 °C.
IR (KBr): 2923, 2231, 1618, 1316, 760 cm–1
.
IR (KBr): 2919, 1604, 1335, 1270, 766 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.44 (s, 6 H), 7.41 (t, J = 7.6 Hz, 1 H),
7.70–7.75 (m, 3 H), 7.93 (d, J = 8.4 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H),
8.65 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.8, 113.1, 115.1, 119.1, 124.8, 125.5,
128.8, 132.0, 132.3, 143.2, 152.8, 157.3, 163.8.
1H NMR (400 MHz, CDCl3): δ = 2.94 (s, 6 H), 3.30 (s, 6 H), 6.71 (d, J =
9.2 Hz, 2 H), 7.19 (t, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.79 (d, J =
8.4 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.38 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 40.3, 41.7, 111.7, 114.7, 123.1, 125.5,
126.9, 128.3, 129.7, 131.7, 152.0, 153.2, 159.7, 163.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N4: 293.1766; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H15N4: 275.1297; found:
275.1310.
293.1750.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2061
X. Chen et al.
Paper
Synthesis
4-(Dimethylamino)-2-(naphthalen-1-yl)quinazoline (2m)
HRMS (ESI): m/z [M + H]+ calcd for C17H17N3: 298.1111; found:
298.1110.
Flavescent solid; yield: 129.0 mg (86%); mp 106.5–108.2 °C.
IR (KBr): 2955, 1613, 1344, 857, 769 cm–1
.
6-Bromo-4-(dimethylamino)-2-phenylquinazoline (2r)
1H NMR (400 MHz, CDCl3): δ = 3.38 (s, 6 H), 7.31 (t, J = 7.2 Hz, 1 H),
7.67–7.49 (m, 2 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.84–7.87 (m, 1 H), 7.92 (d,
J = 8.8 Hz, 1 H), 7.95–8.02 (m, 3 H), 8.69 (d, J = 8.4 Hz, 1 H), 9.07 (s, 1
H).
13C NMR (100 MHz, CDCl3): δ = 41.8, 115.0, 124.1, 125.6, 125.8, 125.9,
126.6, 127.7, 127.8, 128.4, 128.7, 129.2, 132.1, 133.4, 134.5, 136.4,
153.1, 159.2, 163.9.
Flavescent solid; yield: 147.6 mg (90%); mp 75.2–77.0 °C.
IR (KBr): 2922, 1619, 1344, 828, 707, 539 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.36 (s, 6 H), 7.45–7.47 (m, 3 H), 7.70
(dd, J = 2.0, 8.8 Hz, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 8.09 (s, 1 H), 8.52 (dd,
J = 1.6, 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.8, 116.1, 116.8, 127.9, 128.3, 128.4,
130.2, 130.5, 135.2, 138.6, 151.8, 159.5, 162.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H18N3: 300.1501; found:
HRMS (ESI): m/z [M + H]+ calcd for C16H15BrN3: 328.0449; found:
300.1502.
328.0476.
4-(Dimethylamino)-2-(furan-2-yl)quinazoline (2n)
Tan oil; yield: 78.0 mg (65%).
6-Bromo-4-(dimethylamino)-2-p-tolylquinazoline (2s)
IR (KBr): 2927, 1612, 1331, 766, 684 cm–1
.
Brown solid; yield: 102.6 mg (60%); mp 105.6–108.8 °C.
IR (KBr): 2923, 1599, 1340, 832, 739, 540 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.38 (s, 6 H), 6.54 (dd, J = 1.6, 3.2 Hz 1
H), 7.31–7.36 (m, 2 H), 7.62 (s, 1 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.97 (d, J =
8.4 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.42 (s, 6 H), 7.28 (d, J =
8.0 Hz, 2 H), 7.74–7.78 (m 2 H), 8.14 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 8.0
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.7, 111.7, 112.7, 115.0, 124.1, 125.4,
13C NMR (100 MHz, CDCl3): δ = 21.5, 41.8, 116.0, 116.6, 127.9, 128.4,
129.1, 130.4, 135.2, 135.8, 140.4, 151.8, 159.7, 162.9.
128.6, 132.1, 144.4, 152.5, 152.7, 153.3, 163.9.
HRMS (ESI): m/z [M + H]+ calcd for C14H14N3O: 240.1137; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H17BrN3: 342.0606; found:
240.1114.
342.0624.
4-(Dimethylamino)-2-(pyridin-4-yl)quinazoline (2o)14
Yellow solid; yield: 113.0 mg (90%); mp 111.3–113.5 °C.
6-Bromo-2-(4-chlorophenyl)-4-(dimethylamino)quinazoline (2t)
IR (KBr): 2923, 1608, 1330, 772, 681 cm–1
.
Yellow solid; yield: 132.1 mg (73%); mp 162.2–163.5 °C.
IR (KBr): 2924, 1622, 1319, 786, 649, 573 cm–1
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 6 H), 7.42 (d, J = 8.8 Hz, 2 H),
7.72–7.77 (m, 2 H), 8.12 (d, J = 1.2 Hz, 1 H), 8.46 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.8, 116.0, 117.0, 127.9, 128.5, 129.7,
130.4, 135.4, 136.4, 137.0, 151.6, 158.5, 162.7.
.
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 6 H), 7.38 (t, J = 7.6 Hz, 1 H),
7.69 (t, J = 7.8 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H),
8.36 (d, J = 4.8 Hz, 2 H), 8.73 (d, J = 4.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 41.7, 115.3, 122.3, 124.9, 125.5, 128.9,
132.2, 144.4, 150.0, 152.7, 157.1, 163.8.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N4: 251.1297; found:
251.1281.
HRMS (ESI): m/z [M + H]+ calcd for C16H14BrClN3: 362.0060; found:
362.0089.
4-(Dimethylamino)-7-methyl-2-phenylquinazoline (2p)
4-Piperidino-2-p-tolylquinazoline (2x)
Milky solid; yield: 116.2 mg (88%); mp 102.6–104.8 °C.
Yellow solid; yield: 85.0 mg (56%); mp 112.3–114.6 °C.
IR (KBr): 2923, 1623, 1344, 775, 705 cm–1
.
IR (KBr): 2929, 1606, 1566, 1350, 792 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H), 3.40 (s, 6 H), 7.18 (d, J =
7.2 Hz, 1 H), 7.43–7.49 (m, 3 H), 7.73 (s, 1 H), 7.90 (d, J = 8.4 Hz, 1 H),
8.55 (d, J = 6.8 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 1.79–1.83 (m, 6 H), 2.42 (s, 3 H), 3.79
(s, 4 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.69 (dd, J =
7.2, 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 8.45
(d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.7, 41.7, 112.9, 125.3, 126.0, 128.0,
13C NMR (100 MHz, CDCl3): δ = 21.5, 24.9, 26.1, 51.0, 115.4, 124.4,
125.1, 128.4, 128.5, 129.1, 132.2, 135.8, 140.3, 152.5, 159.5, 165.1.
128.2, 128.3, 129.9, 139.1, 142.5, 153.3, 159.4, 163.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3: 264.1501; found:
HRMS (ESI): m/z [M + H]+ calcd for C20H22N3: 304.1814; found:
264.1485.
304.1798.
2-(4-Chlorophenyl)-4-(dimethylamino)-7-methylquinazoline (2q)
Flavescent solid; yield: 93.9 mg (63%); mp 132.1–134.0 °C.
4-Morpholino-2-p-tolylquinazoline (2y)
IR (KBr): 2922, 1599, 1354, 1316, 856, 760 cm–1
.
Yellow solid; yield: 99.4 mg (65%); mp 142.8–144.5 °C.
IR (KBr): 3030, 2917, 1606, 1563, 1350, 1125, 765 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H), 3.40 (s, 6 H), 7.18 (d, J =
8.4 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.70 (s, 1 H) 7.89 (d, J = 8.8 Hz, 1
H), 8.49 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.7, 41.8, 112.8, 125.3, 126.2, 127.9,
128.4, 129.7, 135.9, 137.5, 142.7, 153.1, 158.3 163.6.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.84 (d, J = 4.4 Hz, 4 H),
4.93 (t, J = 4.2 Hz, 4 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 1 H),
7.71 (t, J = 7.6 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H),
8.44 (d, J = 8.4 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062

2062
X. Chen et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 21.5, 50.4, 66.8, 115.3, 124.6, 124.9,
128.4, 129.0, 129.1, 132.5, 136.8, 140.4, 152.8, 159.6, 164.9.
HRMS (ESI): m/z [M + H]+ calcd for C19H20N3O: 306.1606; found:
306.1605.
Yoshimoto, R.; Ohyama, S.; Sasaki, K.; Chiba, M.; Ohtake, N.;
Nagata, Y.; Eiki, J.; Nishimura, T. Bioorg. Med. Chem. Lett. 2009,
19, 5531.
(3) Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.; Barlow, J.
J.; Healy, M. P.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.;
Scarlett, L.; Henthorn, L.; Richards, L. Bioorg. Med. Chem. Lett.
2001, 11, 1911.
(4) (a) Zhang, Y. D.; Xu, C. L.; Houghten, R. A.; Yu, Y. P. J. Comb.
Chem. 2007, 9, 9. (b) Wissner, A.; Floyd, M. B.; Johnson, B. D.;
Fraser, H.; Ingalls, C.; Nittoli, T.; Dushin, R. G.; Discafani, C.;
Nilakantan, R.; Marini, J.; Ravi, M.; Cheung, K.; Tan, X. Z.; Musto,
S.; Annable, T.; Siegel, M. M.; Loganzo, F. J. Med. Chem. 2005, 48,
7560. (c) Hennequin, L. F.; Allen, J.; Breed, J.; Curwen, J.; Fennell,
M.; Green, T. P.; Brempt, C. L. V. D.; Morgentin, R.; Norman, R. A.;
Olivier, A.; Otterbein, L.; Ple, P. A.; Warin, N.; Costello, G. J. Med.
Chem. 2006, 49, 6465.
Acknowledgment
We are grateful to the National Natural Science Foundation of China
(grant nos. 21162012 and 21362014), Jiangxi Provincial Department
of Science and Technology (for Jiangxi’s Key Laboratory of Green
Chemistry, and no. 20122BAB203007), the Science Foundation of Ed-
ucation Department of Jiangxi province (grant no. GJJ10386) and the
open project program of National Research Center for Carbohydrate
Synthesis (grant no. GJDTZX-KF-2014XX) for their financial support.
(5) (a) Kumar, R.; Van der Eycken, E. V. Chem. Soc. Rev. 2013, 42,
1121; and references therein. (b) Kang, F.-A.; Sui, Z.; Murray, W.
V. J. Am. Chem. Soc. 2008, 130, 11300. (c) Luo, Y.; Wu, J. Tetrahe-
dron Lett. 2009, 50, 2103. (d) Luo, Y.; Wu, J. Tetrahedron 2009,
65, 6810. (e) Hu, Y.; Ding, Q.; Ye, S.; Peng, Y.; Wu, J. Tetrahedron
2011, 67, 7258. (f) Qiu, G.; Huang, P.; Yang, Q.; Lu, H.; Xu, J. S.;
Deng, Z.; Zhang, M.; Peng, Y. Y. Synthesis 2013, 45, 3131.
(6) Lockman, J. W.; Klimova, Y.; Anderson, M. B.; Willardsen, J. A.
Synth. Commun. 2012, 42, 1715.
(7) Peng, Y.-Y.; Wen, Y.; Mao, X.; Qiu, G. Tetrahedron Lett. 2009, 50,
2405.
(8) Peng, Y.; Qiu, G.; Yang, Q.; Yuan, J.; Deng, Z. Synthesis 2012, 44,
1237.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380550.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References
(1) (a) Havera, H. J.; Vidrio, H. J. J. Med. Chem. 1979, 22, 1548.
(b) Hori, M.; Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.;
Ohtaka, H. Chem. Pharm. Bull. 1990, 38, 681. (c) Liverton, N. J.;
Armstrong, D. J.; Claremon, D. A.; Remy, D. C.; Bardwin, J. J.;
Lynch, R. J.; Zhang, G.; Gould, R. J. Bioorg. Med. Chem. Lett. 1998,
8, 483. (d) Kung, P. P.; Casper, M. D.; Cook, K. L.; Wilson-Ling-
ardo, L.; Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt,
J. R.; Cook, P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705.
(e) Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson,
D. A.; Cottam, H. B. J. Med. Chem. 1999, 42, 3860. (f) Brunton, S.
A.; Stibbard, J. H. A.; Rubin, L. L.; Kruse, L. I.; Guicherit, O. M.;
Boyd, E. A.; Price, S. J. Med. Chem. 2008, 51, 1108.
(2) (a) Barlaam, B.; Ballard, P.; Bradbury, R. H.; Ducray, R.; Germain,
H.; Hickinson, D. M.; Hudson, K.; Kettle, J. G.; Klinowska, T.;
Magnien, F.; Ogilvie, D. J.; Olivier, A.; Pearson, S. E.; Scott, J. S.;
Suleman, A.; Trigwell, C. B.; Vautier, M.; Whittaker, R. D.; Wood,
R. Bioorg. Med. Chem. Lett. 2008, 18, 674. (b) Smits, R. A.; de
Esch, I. J. P.; Zuiderveld, O. P.; Broeker, J.; Sansuk, K.; Guaita, E.;
Coruzzi, G.; Adami, M.; Haaksma, E.; Leurs, R. J. Med. Chem.
2008, 51, 7855. (c) Sirisoma, N.; Pervin, A.; Zhang, H.; Jiang, S.
C.; Willardsen, J. A.; Anderson, M. B.; Mather, G.; Pleiman, C. M.;
Kasibhatla, S.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2009,
52, 2341. (d) Iino, T.; Sasaki, Y.; Bamba, M.; Mitsuya, M.; Ohno,
A.; Kamata, K.; Hosaka, H.; Maruki, H.; Futamura, M.;
(9) (a) Muzart, J. Tetrahedron 2009, 65, 8313. (b) Ding, S.; Jiao, N.
Angew. Chem. Int. Ed. 2012, 51, 9226.
(10) (a) Kadish, K. M.; Han, B. C.; Franzen, M. M.; Araullo-McAdams,
C. J. Am. Chem. Soc. 1990, 112, 8364. (b) Agarwal, A.; Chauhan, P.
M. S. Synth. Commun. 2004, 34, 2925. (c) Watanabe, T.; Tanaka,
Y.; Sekiya, K.; Akita, Y.; Ohta, A. Synthesis 1980, 39. (d) D’Amico,
J. J.; Webster, S. T.; Campbell, R. H.; Twine, C. E. J. Org. Chem.
1965, 30, 3618. (e) Čechová, L.; Jansa, P.; Šála, M.; Dračínský, M.;
Holý, A.; Janeba, Z. Tetrahedron 2011, 67, 866. (f) Samadi, A.;
Silva, D.; Chioua, M.; do Carmo Carreiras, M.; Marco-Contelles, J.
Synth. Commun. 2011, 41, 2859. (g) Li, Y.; Xie, Y.; Zhang, R.; Jin,
K.; Wang, X.; Duan, C. J. Org. Chem. 2011, 76, 5444. (h) Wang, J.;
Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2011, 47,
3652.
(11) Chen, W.-X.; Shao, L.-X. J. Org. Chem. 2012, 77, 9236.
(12) (a) Peng, Y.-Y.; Liu, J.; Lei, X.; Yin, Z. Green Chem. 2010, 12, 1072.
(b) Ding, Q.; Cao, B.; Liu, X.; Zong, Z.; Peng, Y.-Y. Green Chem.
2010, 12, 1607. (c) Liu, J.-B.; Zhou, H.-P.; Peng, Y.-Y. Tetrahedron
Lett. 2014, 55, 2872.
(13) Kodimuthali, A.; Mungara, A.; Prasunamba, P. L.; Pal, M. J. Braz.
Chem. Soc. 2010, 21, 1439.
(14) Zielinski, W.; Mazik, M. Pol. J. Chem. 1994, 68, 489.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2055–2062