A Highly Efficient Copper-Catalyzed Three-Component Synthesis of 4-Aminoquinazolines

Article abstract of DOI:10.1055/s-0036-1588727

A highly efficient copper-catalyzed one-pot protocol is developed for the synthesis of 4-aminoquinazolines from easily available 2-iodo- or 2-bromobenzimidamides, aldehydes, and sodium azide. This one-pot approach proceeds via consecutive copper-catalyzed S_NAr substitution, reduction, cyclization, oxidation and tautomerization. The corresponding target products (26 examples) are obtained in 50-90% yield.

Full text of DOI:10.1055/s-0036-1588727

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–I
paper
A
L. Yang et al.
Paper
Synthesis
A Highly Efficient Copper-Catalyzed Three-Component Synthesis
of 4-Aminoquinazolines
Lei Yang
NH
NH2
R1
R1
Honghua Luo
Yan Sun
NH2
CuBr, L-proline
DMF, 70 °C, 4 h
N
R2 CHO
+
NaN3
+
N
R2
X
Zhenyu Shi
Kaidong Ni
Fei Li
X = I, Br
26 examples; 50–90% yield
Simpler operation
Base-free conditions
Lower reaction temperature
Higher reaction rate
Dongyin Chen*
Department of Medicinal Chemistry, School of Pharmacy,
Nanjing Medical University, Nanjing 211166, P. R. of China
chendongyin@njmu.edu.cn
Received: 21.12.2016
Accepted after revision: 02.02.2017
Published online: 23.02.2017
Prazosin1d is a sympatholytic drug utilized to treat high
blood pressure, anxiety, and post-traumatic stress disorder,
acting as an inverse agonist at α1 adrenergic receptors (Fig-
ure 1). In addition, many 4-aminoquinazoline derivatives
are the key synthetic intermediates for the synthesis of bio-
logically active compounds, including opioid receptor like-1
antagonists,2a nociception receptor antagonists,2b capsaicin
receptor antagonists,2c C-C chemokine receptor 4 antago-
nists,2d human adenosine A3 receptor antagonists,2e recep-
tor tyrosine kinase inhibitors,2f aurora A/B kinase inhibi-
tors,2g and selective Toll-like receptor 4 ligands.2h
DOI: 10.1055/s-0036-1588727; Art ID: ss-2016-h0875-op
Abstract A highly efficient copper-catalyzed one-pot protocol is de-
veloped for the synthesis of 4-aminoquinazolines from easily available
2-iodo- or 2-bromobenzimidamides, aldehydes, and sodium azide. This
one-pot approach proceeds via consecutive copper-catalyzed SNAr sub-
stitution, reduction, cyclization, oxidation and tautomerization. The
corresponding target products (26 examples) are obtained in 50–90%
yield.
Key words copper, 2-halobenzimidamides, sodium azide, catalysis, 4-
In view of their great value, the synthesis of 4-amino-
quinazolines has gained much attention in the past de-
cade.3–8 The main synthetic methods toward this skeleton
are summarized in Scheme 1. Among these, a classical ap-
proach to these substances converged on the further deco-
ration of the existing quinazoline nucleus,3,4 including the
nucleophilic substitution reaction of amines with 4-halo-
or 4-mercaptoquinazolines,3 the reduction of 4-azido-
quinazolines,4a and the Suzuki–Miyaura coupling of 2-
chloro-4-aminoquinazolines.4b However, the commercially
unavailable quinazolines used as starting materials, the
aminoquinazolines
4-Aminoquinazoline, one of the most important nitro-
gen-containing heterocycles, is exemplified as a privileged
structure that exists in many pharmaceutical drugs and bi-
ologically active molecules.1,2 For example, gefitinib1a and
erlotinib1b are well-known drugs used to treat non-small
cell lung cancer, which act on the epidermal growth factor
receptor. Alfuzosin1c is an antagonist of the α1 adrenergic
receptor for the treatment of benign prostatic hyperplasia.
F
O
HN
N
Cl
HN
N
O
O
N
MeO
MeO
N
MeO
O
N
Gefitinib
Erlotinib
NH2
N
NH2
MeO
MeO
MeO
MeO
N
O
O
N
N
O
N
N
N
H
N
Me
O
Alfuzosin
Prazosin
Figure 1 Structures of selected 4-aminoquinazoline derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

B
L. Yang et al.
Paper
Synthesis
preparation of which required multistep routes from un-
common 2-aminobenzoic acid derivatives, has restricted
applications in synthetic chemistry. Therefore, increasing
efforts have been devoted to developing more efficient
methods for the generation of 4-aminoquinazolines, which
mainly involved the cyclization reactions of anthraniloni-
trile derivatives with different carbon and nitrogen sourc-
es,2e,5 the cyclization of 2-halobenzonitrile derivatives with
various amidines,6 and the aryl C–H amidination of N-aryl-
amidines with isonitriles.7 Recently, Wu and co-workers
developed a novel and efficient Fe/Cu-relay-catalyzed dom-
ino protocol for the synthesis of 2-phenyl-4-aminoquinazo-
lines from 2-halobenzonitriles, aromatic aldehydes, and so-
dium azide.8 Although these reactions provide efficient ac-
cess to various substituted 4-aminoquinazolines, their
applications are limited due to certain disadvantages, in-
cluding narrow substrate scope, tedious multistep proce-
dures, high reaction temperatures and complex reaction
conditions. Consequently, the development of simple, effec-
tive, mild and economic methods for the preparation of 4-
aminoquinazolines are still highly desirable.
recent studies on copper-catalyzed multicomponent syn-
theses of nitrogen-containing benzoheterocycles utilizing
NaN3 as the nitrogen source,8,11 herein we present a similar
protocol for the synthesis of 4-aminoquinazolines from
readily available 2-iodo- or 2-bromobenzimidamides, alde-
hydes and NaN3 (Scheme 1). Compared with the reported
methods,3–8 this approach is more suitable for synthesizing
multifarious 4-aminoquinazoline derivatives from readily
available substrates under mild conditions. Moreover, our
approach shows good tolerance of various alkyl aldehydes
and aromatic aldehydes, featuring simpler operations, a
lower reaction temperature and a higher reaction rate, be-
ing superior to the previously reported methodologies.6,8
Based on previous work,11c,12 we attempted to develop
an efficient synthetic protocol to construct 2-substituted
quinazolin-4-amines via copper-catalyzed consecutive re-
actions. Our investigation was carried out using 2-iodoben-
zimidamide (1a), benzaldehyde (2a) and NaN3 as model
substrates under different reaction conditions (Table 1). In
the presence of CuI (10 mol%) and L-proline (L-1) (20 mol%),
the reaction took place in N,N-dimethylformamide (DMF)
at 70 °C to give the desired product 3a in 57% yield (Table 1,
entry 1). Next, a series of copper catalysts was screened for
this reaction under the same reaction conditions (Table 1,
entries 2–8). When CuBr was used as the catalyst, the yield
Sodium azide (NaN3), as a convenient and inexpensive
nitrogen source, has been widely applied in various chemi-
cal transformations, such as 1,3-dipolar cycloadditions9 and
Cu-catalyzed SNAr reactions.10 Encouraged by the results of
Previous work
NH2
R1
N
X
N
Cl
R1
R1
CN
R2
Pd(OAc)2
B(OH)2
N
ref. 4b
C and N
sources
amines
or Pd/C, H2
N
R2
X = Cl, Br, SH, N3
NH2
R3
ref. 3, 4a
ref. 2e, 5
HN
R1
N
N
R2
NH
4-aminoquinazolines
NaN3
+
Ar
Fe, Cu
O
R2
NH2
R1
ref. 6
R1
ref. 8
R3 NC
Pd(OAc)2
CN
X
CN
X
ref. 7
R1
NH
X = F, Cl, Br, I
X = F, Cl, Br
N
R2
H
This work
NH
X
NH2
R1
R1
NH2
CuBr, L-proline
DMF, 70 °C, 4 h
N
R2 CHO
+
NaN3
+
N
R2
2
1
3
X = I, Br
Simpler operation
Base-free conditions
Lower reaction temperature
Higher reaction rate
Scheme 1 Synthetic routes to 4-aminoquinazoline derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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L. Yang et al.
Paper
Synthesis
was further improved to 81% (Table 1, entry 2). We then ex-
amined three other ligands including 1,10-phenanthroline
(L-2), picolinic acid (L-3) and N,N,N′,N′-tetramethyleth-
ylenediamine (L-4), however, the reaction yields decreased
significantly (Table 1, compare entries 2 and 9–11). Further
investigations indicated that both CuBr and L-proline were
necessary for this transformation (Table 1, entries 12 and
13). Moreover, replacing NaN3 with other nitrogen sources
such as ammonium acetate, ammonium hydroxide and am-
monium chloride, gave unsatisfactory results (Table 1, en-
tries 14–16). Subsequently, the effect of different solvents
was investigated, and DMF proved to be the optimum sol-
vent (Table 1, compare entries 2 and 17–21). It should be
noted that when H2O was used as the solvent, the desired
product 3a was obtained in a moderate 40% yield (Table 1,
entry 19), which suggests a potential application in green
chemistry. Increasing or decreasing the reaction tempera-
ture did not lead to any further improvement in the yield,
and a temperature of 70 °C gave the best result (Table 1,
compare entries 2, 22 and 23). In addition, an increase in
the amount of NaN3 (0.2 mmol) did not result in a higher
yield of the desired product (Table 1, compare entries 2 and
24). Finally, the optimized reaction conditions were deter-
mined as: 1a (0.4 mmol), 2a (1.2 equiv), NaN3 (2.0 equiv) as
the nitrogen source, CuBr (0.1 equiv) as the catalyst, L-pro-
line (0.2 equiv) as the ligand and DMF (3 mL) as the solvent
at 70 °C under an air atmosphere.
With optimized conditions in hand, we explored the
substrate scope of this copper-catalyzed, three-component
reaction, and the results are summarized in Scheme 2. We
first examined 2-bromobenzimidamide, 2-chlorobenzimid-
amide and 2-fluorobenzimidamide as substrates in reac-
tions with benzaldehyde (2a) and NaN3 under the standard
reaction conditions. 2-Bromobenzimidamide (1b) under-
went this transformation smoothly, and gave the desired
product 3a in a slightly lower yield. Unfortunately, other
ortho-halogenated benzimidamides such as 2-chlorobenz-
imidamides and 2-fluorobenzimidamides all had no reac-
tivity under the optimized conditions, despite increasing
the reaction temperature. The reactivity order is as follow:
aryl iodides > aryl bromides > aryl chlorides (fluorides). We
then further investigated the scope of this reaction using
different aldehydes. First, a variety of aromatic aldehydes
bearing different substituents reacted with 2-iodobenz-
imidamide (1a) to give the corresponding products 3a–j in
moderate to good yields (50−90%). The electronic effects of
the substituents on the aromatic ring, including electron-
neutral (H, 3a), electron-withdrawing (3-O2N, 3b; 4-Cl, 3c;
3,5-Cl2, 3g; 5-Br, 3h) and electron-donating (2-OH, 3d; 2-
Me, 3e; 5-t-Bu, 3i; 3-MeO; 3j) groups, did not lead to any
significant differences in reactivity. Much to our satisfac-
tion, the reactions with aromatic aldehydes containing 2-
phenolic hydroxy groups proceeded smoothly to afford the
corresponding products 3d and 3g–j in 70–90% yield, which
Table 1 Investigation of the Conditions for the Copper-Catalyzed Syn-
thesis of 2-Phenylquinazolin-4-amine (3a) Using 2-Iodobenzimidamide
(1a), Benzaldehyde (2a) and NaN3 as the Substratesa
NH
NH2
NH2
catalyst, ligand
solvent, T
N
NaN3
+
+
Ph CHO
2a
I
N
Ph
1a
3a
N
CO2H
N
N
N
CO2H
H
N
N
L-1
L-2
L-3
L-4
Entry
Cat.
Ligand
Solvent
Temp (°C) Yield (%)b
1
2
CuI
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-2
L-3
L-4
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
55
85
70
57
CuBr
CuCl
81
3
35
4
Cu2O
CuO
trace
N.R.
trace
N.R.
N.R.
30
5
6
CuBr2
CuCl2
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
–
7
8
9
10
11
12
13
14c
15d
16e
17
18
19
20
21
22
23
24f
25
23
20
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
trace
45
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
17
N.R.
66
DMSO
THF
52
H2O
40
DCE
trace
trace
57
toluene
DMF
DMF
DMF
75
78
a Reaction conditions: 1a (0.4 mmol), 2a (0.48 mmol), NaN3 (0.8 mmol), cat-
alyst (0.04 mmol), ligand (0.08 mmol), solvent (3 mL), under air, 4 h.
b Yield of isolated product. N.R. = no reaction.
c Ammonium acetate was used as the nitrogen source.
d Ammonium hydroxide was used as the nitrogen source.
e Ammonium chloride was used as the nitrogen source.
f NaN3 (0.2 mmol) was used.
provided the possibility for further functionalization. How-
ever, when using 2,6-dimethylbenzaldehyde as the cou-
pling partner under the optimized conditions, the corre-
sponding product 3f was obtained in a low yield (50%),
which indicated that the reaction was sensitive to the large
steric hindrance due to the substituents on the aromatic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

D
L. Yang et al.
Paper
Synthesis
ring. Better than the existing method,8 our approach
showed good tolerance toward alkyl aldehydes, and provid-
ed the corresponding products 3k–o in 50–84% yield.
Meanwhile, the optimized conditions were also found to be
suitable for 2-naphthaldehyde and 2-hydroxy-1-naphthal-
dehyde to give the desired products 3p,q in 74–80% yield.
Furthermore, 2-furanaldehyde, 2-thienaldehyde, and 3-
pyridinaldehyde were successfully applied to construct 2-
heteroaryl-4-aminoquinazolines 3r–t in good yields under
the optimized conditions. It was noticed that compound 3t
was a precursor for the synthesis of novel human adenosine
A3 receptor antagonists.2e
hydes as the reaction partners under the optimized condi-
tions. Generally, the reactions proceeded well with these
substrates to deliver the 2,6-disubstituted 4-aminoquinazo-
lines 3u–z in moderate to good yields. The results demon-
strated that the electronic features of the additional substit-
uent on the ortho-halogenated benzimidamide had limited
influence on this copper-catalyzed consecutive reaction.
Therefore, this approach showed high functional group tol-
erance and proved to be a quite general method for the
preparation of multifarious 4-aminoquinazoline derivatives
under mild conditions.
In order to explore the reaction mechanism for the syn-
thesis of 4-aminoquinazoline derivatives, some control ex-
periments were performed. First, 2-iodobenzimidamide
Next, we turned our attention to expand the scope of
the ortho-halogenated benzimidamides with benzalde-
NH
NH2
R1
R1
CuBr, L-proline
NH2
N
R2 CHO
+
+
NaN3
DMF, 70 °C
R2
X
N
1 X = I, Br
2
3
NH2
NH2
NH2
NH2
NH2
NH2
N
N
N
N
OH
N
N
NO2
N
N
N
N
N
N
Cl
3a (81%)a, (71%)b
3b (78%)a
NH2
3c (81%)a
3d (90%)a
3e (70%)a
3f (50%)a
NH2
NH2
N
NH2
N
NH2
N
NH2
N
N
OH
N
OH
OH
OH
Cl
N
N
N
OMe
N
N
N
Cl
Br
t-Bu
3g (83%)a
3h (85%)a
3i (75%)a
3j (70%)a
3k (84%)a
3l (73%)a
NH2
N
NH2
N
NH2
N
NH2
N
NH2
N
NH2
N
O
N
N
N
N
N
N
HO
3m (62%)a
3n (50%)a
3o (60%)a
3p (74%)a
3q (80%)a
3r (87%)a
NH2
N
NH2
N
NH2
N
NH2
N
NH2
N
NH2
N
F
F
MeO
MeO
OH
S
N
N
N
N
N
N
N
Cl
3s (83%)a
3t (75%)a
3u (71%)b
3v (70%)b
3w (75%)b
3x (87%)b
NH2
N
NH2
N
OH
N
N
3y (65%)b
3z (85%)b
Scheme 2 Scope of 2-halobenzimidamides and aldehydes. Reagents and conditions: 2-halobenzimidamide (0.4 mmol), aldehyde (0.48 mmol), NaN3
(0.8 mmol), CuBr (0.04 mmol), L-proline (0.08 mmol), DMF (3 mL), 70 °C, under air, 1–4 h. a Product was obtained from 2-iodobenzimidamide. b Prod-
uct was obtained from 2-bromobenzimidamide.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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L. Yang et al.
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Synthesis
(1a) was treated with NaN3 (2 equiv) in DMF in the pres-
ence of CuBr at 40 °C for two hours, giving 2-azidobenz-
imidamide (4) (m/z = 184.1, [M + Na]+) in 95% yield (Scheme
3, a). Next, when 4 was heated at 70 °C for two hours in
DMF in the presence of CuBr and L-proline (Scheme 3, b),
we fortunately observed the mass ion for 2-aminobenzimi-
damide (5) (m/z = 133.1, [M – 2 H]2–). Furthermore, the re-
action of 4 with benzaldehyde (2a) proceeded smoothly in
DMF at 70 °C using CuBr as the catalyst and L-proline as the
ligand to afford the target product 3a in 81% yield (Scheme
3, c). In this process, the MS spectrum after about 0.5 hours
reaction time showed the mass ion for Schiff base V, or pos-
sibly the cyclized intermediate VI (m/z = 246.1, [M + Na]+)
(see Scheme 4; R2 = Ph).
and the Cu(III) complex III,13 meanwhile releasing nitrogen.
Next, IV could easily condense with aldehyde 2, leading to
the formation of Schiff base V. Subsequently, intramolecu-
lar nucleophilic attack of the amidine nitrogen on the imine
carbon in V gives intermediate VI. Finally, VI undergoes oxi-
dative dehydrogenation and amine–imine tautomerization
to produce the target product 3.
In conclusion, we have developed an efficient and prac-
tical copper-catalyzed one-pot method for the synthesis of
4-aminoquinazoline derivatives under mild reaction condi-
tions, starting from readily available 2-iodo- or 2-bromo-
benzimidamides, aldehydes and NaN3. The reactions pro-
ceed via a consecutive process involving a copper-catalyzed
SNAr substitution, reduction, cyclization, oxidation and tau-
tomerization. It is hoped that the method will provide a
novel synthetic strategy for bioactive molecules containing
a 4-aminoquinazoline nucleus, and investigations on the
further utilization of this protocol to construct more com-
plex nitrogen-containing heterocycles are underway in our
laboratory.
NH
NH
NH2
CuBr, NaN3
NH2
(a)
DMF, 40 °C, 2 h
I
N3
1a
4 (95%)
NH
N3
NH
CuBr, L-proline
DMF, 70 °C, 2 h
NH2
NH2
(b)
All commercial materials and solvents were used directly without
further purification. Reactions were monitored by TLC on silica gel 60
F254 plates (Qingdao Ocean Chemical Company, China). Column
chromatography was carried out on silica gel (200–300 mesh, Qingd-
ao Ocean Chemical Company, China). Melting points were deter-
mined on an RY-1 melting point apparatus and are uncorrected. 1H
and 13C NMR spectra were measured on Bruker AV-300 or AV-500
spectrometers with tetramethylsilane (TMS) as the internal standard.
Low- and high-resolution mass spectra (LRMS and HRMS) were re-
corded in electron impact mode on Agilent 1100 LC/DAD/MSD or Q-
Tof Micro MS/MS spectrometers.
NH2
4
5
NH
N3
NH2
NH2
CuBr, L-proline, 2a
N
(c)
DMF, 70 °C, 1 h
N
Ph
4
3a (81%)
Scheme 3 Control experiments
Based on the above observations and the reported liter-
ature,8,11c,13 a possible mechanism for the copper-catalyzed
one-pot synthesis of 4-aminoquinazoline derivatives is pro-
posed in Scheme 4. First, the copper-catalyzed SNAr prod-
uct, 2-azidobenzimidamide I, is prepared from 2-halobenz-
imidamide 1 and NaN3. Then, with the aid of L-proline and
trace H2O in DMF, the copper-mediated denitrogenation of I
affords 2-aminobenzimidamide IV via the Cu(I) complex II
2-Halobenzimidamides (1); General Procedure
To a solution of 2-halobenzonitrile (4.0 mmol) in THF (1 mL) was add-
ed dropwise LiN(SiMe3)2 (4 mL, 1 M in anhydrous THF, 4.4 mmol) at
r.t. The reaction mixture was stirred overnight at the same tempera-
ture until the disappearance of the reactants (monitored by TLC), and
then concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc) to give the desired
products 1.
NH
NH
NH
N3
NH
NH
X
R1
R1
R1
R1
R1
H
H
NaN3
SNAr
CuBr
H2O
N
NH2
NH2
NH2
N H
CuIX(L)n
NH2
CuIIIX(L)n-1
L-proline
N
H
N
N2
CuBr, 1/2 O2
N2
1
I
II
III
IV
X = I, Br
NH2
N
NH
NH
H
R1
R1
R2 CHO
R1
N
[ O ]
tautomerism
NH
N
H
2
R2
H2O
N
R2
N
H
R2
V
VI
3
Scheme 4 Possible mechanism for the copper-catalyzed one-pot synthesis of 4-aminoquinazoline derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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L. Yang et al.
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Synthesis
2-Iodobenzimidamide (1a)14
1H NMR (300 MHz, DMSO-d6): δ = 8.44 (dd, J = 6.5, 3.0 Hz, 2 H), 8.22
(d, J = 8.1 Hz, 1 H), 7.79 (br s, 2 H), 7.74 (t, J = 5.7 Hz, 2 H), 7.40–7.53
(m, 4 H).
Yield: 0.93 g (95%); red oil.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 7.9 Hz, 1 H), 7.35 (d, J = 4.3
Hz, 2 H), 7.02–7.08 (m, 1 H), 5.45 (br s, 3 H).
MS (ESI): m/z = 222.1 [M + H]+.
MS (ESI): m/z = 247.0 [M + H]+.
2-(3-Nitrophenyl)quinazolin-4-amine (3b)8
Yield: 82 mg (78%); yellow solid; mp 237–239 °C.
2-Bromobenzimidamide (1b)15
1H NMR (300 MHz, CDCl3): δ = 9.22 (s, 1 H), 8.85 (d, J = 7.9 Hz, 1 H),
8.33 (d, J = 7.4 Hz, 1 H), 8.26 (d, J = 8.2 Hz, 1 H), 8.02 (br s, 2 H), 7.77–
7.81 (m, 3 H), 7.48–7.51 (m, 1 H).
Yield: 0.76 g (95%); yellow oil.
1H NMR (300 MHz, DMSO-d6): δ = 7.84 (d, J = 7.8 Hz, 1 H), 7.37–7.41
(m, 1 H), 7.28 (dd, J = 7.6, 1.6 Hz, 1 H), 7.06–7.12 (m, 1 H), 6.36 (br s, 3
H).
MS (ESI): m/z = 267.1 [M + H]+.
MS (ESI): m/z = 199.0 [M + H]+.
2-(4-Chlorophenyl)quinazolin-4-amine (3c)6d
Yield: 82 mg (81%); white solid; mp 151–153 °C.
2-Bromo-5-fluorobenzimidamide (1c)
1H NMR (300 MHz, DMSO-d6): δ = 8.44 (d, J = 8.5 Hz, 2 H), 8.23 (d, J =
8.1 Hz, 1 H), 7.88 (br s, 2 H), 7.69–7.79 (m, 2 H), 7.54 (d, J = 8.5 Hz, 2
H), 7.47 (t, J = 6.3 Hz, 1 H).
Yield: 0.81 g (93%); yellow oil.
1H NMR (500 MHz, DMSO-d6): δ = 7.92 (d, J = 8.9 Hz, 1 H), 7.70 (d, J =
6.9 Hz, 2 H), 6.90 (br s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 165.4, 161.6, 132.3, 132.2, 120.8,
MS (ESI): m/z = 256.1 [M + H]+.
115.7, 115.7.
MS (ESI): m/z = 217.0 [M + H]+.
HRMS: m/z [M + H]+ calcd for C7H7N2FBr: 216.9777; found: 216.9782.
2-(2-Hydroxyphenyl)quinazolin-4-amine (3d)
Yield: 86 mg (90%); yellow solid; mp 205–207 °C.
1H NMR (300 MHz, DMSO-d6): δ = 14.58 (br s, 1 H), 8.40–8.43 (m, 1
H), 8.26 (d, J = 8.1 Hz, 1 H), 8.21 (br s, 2 H), 7.77–7.87 (m, 1 H), 7.73 (d,
J = 8.2 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.31–7.36 (m, 1 H), 6.87–6.92
(m, 2 H).
2-Bromo-5-methoxybenzimidamide (1d)
Yield: 0.90 g (98%); white solid.
1H NMR (500 MHz, CDCl3): δ = 7.52 (d, J = 8.8 Hz, 1 H), 7.02 (d, J = 2.9
Hz, 1 H), 6.87 (dd, J = 8.8, 3.0 Hz, 1 H), 5.05 (br s, 3 H), 3.85 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.2, 158.5, 136.8, 133.9, 117.1,
113.9, 109.0, 55.2.
MS (ESI): m/z = 229.0 [M + H]+.
13C NMR (75 MHz, DMSO-d6): δ = 161.4, 160.9, 160.7, 147.5, 133.8,
132.2, 128.9, 126.1, 125.6, 123.8, 119.0, 118.0, 117.3, 112.8.
MS (ESI): m/z = 238.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C14H12N3O: 238.0980; found: 238.0986.
2-(2-Methylphenyl)quinazolin-4-amine (3e)8
HRMS: m/z [M
+
H]+ calcd for C8H10N2OBr: 228.9976; found:
228.9974.
Yield: 66 mg (70%); brown solid; mp 174–175 °C.
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 8.2 Hz, 1 H), 7.59–7.87 (m, 3
H), 7.48 (t, J = 7.4 Hz, 1 H), 7.29 (d, J = 11.5 Hz, 3 H), 6.07 (br s, 2 H),
2.52 (s, 3 H).
2-Bromo-5-methylbenzimidamide (1e)
Yield: 0.77 g (90%); red oil.
1H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 8.1 Hz, 1 H), 7.24 (d, J = 12.7
Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 6.63 (br s, 3 H), 2.28 (s, 3 H).
MS (ESI): m/z = 236.1 [M + H]+.
13C NMR (75 MHz, CDCl3): δ = 165.5, 137.5, 132.7, 132.01, 131.5,
2-(2,6-Dimethylphenyl)quinazolin-4-amine (3f)
129.3, 115.5, 20.2.
MS (ESI): m/z = 213.0 [M + H]+.
HRMS: m/z [M + H]+ calcd for C8H10N2Br: 213.0027; found: 213.0023.
Yield: 50 mg (50%); brown solid; mp 201–203 °C.
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 8.3 Hz, 1 H), 7.75–7.83 (m, 2
H), 7.52 (t, J = 7.5 Hz, 1 H), 7.14–7.24 (m, 1 H), 7.10 (d, J = 7.4 Hz, 2 H),
6.04 (br s, 2 H), 2.17 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 163.5, 161.0, 150.1, 139.2, 134.8, 132.8,
Quinazolin-4-amines (3); General Procedure
131.2, 128.2, 127.5, 127.1, 125.5, 121.0, 112.0, 19.2.
MS (ESI): m/z = 250.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C16H16N3: 250.1344; found: 250.1349.
To a solution of 2-iodo- or 2-bromobenzimidamide (1) (0.4 mmol) in
DMF (3 mL) was added an aldehyde (0.48 mmol), NaN3 (52 mg, 0.8
mmol), CuBr (5.7 mg, 0.04 mmol), and L-proline (9.2 mg, 0.08 mmol).
The reaction mixture was stirred at 70 °C under air. After the disap-
pearance of the reactants (monitored by TLC), H2O (30 mL) was added
and the mixture was then extracted with EtOAc (3 × 10 mL). The com-
bined extracts were washed with sat. NaCl solution, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (PE–EtOAc, 10:1
to 5:1) to give the desired product 3.
2-(3,5-Dichloro-2-hydroxyphenyl)quinazolin-4-amine (3g)
Yield: 101 mg (83%); yellow solid; mp 158–160 °C.
1H NMR (300 MHz, DMSO-d6): δ = 16.01 (s, 1 H), 8.44 (br s, 2 H), 8.35
(d, J = 2.6 Hz, 1 H), 8.29 (d, J = 8.2 Hz, 1 H), 7.76–7.90 (m, 2 H), 7.63 (d,
J = 2.6 Hz, 1 H), 7.56 (t, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 162.1, 159.5, 156.4, 147.1, 134.7,
131.7, 127.1, 126.9, 126.4, 124.4, 122.6, 121.6, 121.3, 113.5.
2-Phenylquinazolin-4-amine (3a)8
Yield: 71 mg (81%); yellow solid; mp 144–145 °C.
MS (ESI): m/z = 304.0 [M – H]–.
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L. Yang et al.
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HRMS: m/z [M – H]– calcd for C14H8N3OCl2: 304.0044; found:
304.0041.
1H NMR (300 MHz, DMSO-d6): δ = 8.14 (d, J = 6.6 Hz, 1 H), 7.66 (d, J =
6.7 Hz, 1 H), 7.51–7.59 (m, 3 H), 7.38 (d, J = 6.3 Hz, 1 H), 2.71–2.78 (m,
1 H), 1.77 (s, 1 H), 1.46 (s, 1 H), 1.19–1.21 (m, 5 H), 0.82 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 170.3, 161.9, 150.2, 132.3, 127.0,
2-(5-Bromo-2-hydroxyphenyl)quinazolin-4-amine (3h)
124.3, 123.3, 112.9, 42.2, 37.9, 20.3, 19.8, 14.0.
Yield: 106 mg (85%); white solid; mp 260–261 °C.
MS (ESI): m/z = 216.2 [M + H]+.
HRMS: m/z [M + H]+ calcd for C13H18N3: 216.1501; found: 216.1505.
1H NMR (300 MHz, DMSO-d6): δ = 14.72 (s, 1 H), 8.54 (d, J = 2.6 Hz, 1
H), 8.22–8.43 (m, 3 H), 7.72–7.88 (m, 2 H), 7.43–7.58 (m, 2 H), 6.89 (d,
J = 8.7 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.5, 159.9, 159.6, 147.2, 134.5,
2-Cyclopentylquinazolin-4-amine (3n)
134.0, 130.8, 126.1, 126.0, 123.8, 120.8, 119.7, 113.0, 109.2.
MS (ESI): m/z = 314.0 [M – H]–.
Yield: 43 mg (50%); yellow solid; mp 189–191 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.14 (d, J = 7.9 Hz, 1 H), 7.63–7.71
(m, 1 H), 7.57–7.59 (m, 3 H), 7.34–7.39 (m, 1 H), 3.07–3.12 (m, 1 H),
1.90–1.93 (m, 4 H), 1.72–1.74 (m, 2 H), 1.58–1.65 (m, 2 H).
HRMS: m/z [M
–
H]– calcd for C14H9N3OBr: 313.9929; found:
313.9924.
13C NMR (75 MHz, DMSO-d6): δ = 169.7, 161.9, 150.1, 132.4, 127.0,
124.3, 123.3, 112.9, 48.2, 31.9, 25.6.
2-[5-(tert-Butyl)-2-hydroxyphenyl]quinazolin-4-amine (3i)
MS (ESI): m/z = 214.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C13H16N3: 214.1344; found: 214.1350.
Yield: 88 mg (75%); yellow solid; mp 151–152 °C.
1H NMR (300 MHz, CDCl3): δ = 8.52 (d, J = 2.3 Hz, 1 H), 7.74–7.81 (m, 3
H), 7.43–7.45 (m, 2 H), 6.98 (d, J = 8.6 Hz, 1 H), 5.84 (s, 2 H), 1.38 (s, 9
H).
2-Cyclohexylquinazolin-4-amine (3o)16
13C NMR (75 MHz, CDCl3): δ = 162.1, 160.9, 159.1, 148.1, 141.0, 133.8,
130.1, 127.2, 125.9, 125.5, 121.7, 117.2, 34.2, 31.6.
MS (ESI): m/z = 292.1 [M – H]–.
HRMS: m/z [M – H]– calcd for C18H18N3O: 292.1450; found: 292.1453.
Yield: 55 mg (60%); white solid; mp 230–232 °C.
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 8.6 Hz, 1 H), 7.76–7.67 (m, 2
H), 7.42 (t, J = 7.6 Hz, 1 H), 5.70 (br s, 2 H), 2.79 (dd, J = 16.0, 7.6 Hz, 1
H), 1.99–2.04 (m, 2 H), 1.82–1.86 (m, 2 H), 1.62–1.74 (m, 4 H), 1.37–
1.51 (m, 2 H).
MS (ESI): m/z = 228.1 [M + H]+.
2-(3-Methoxy-2-hydroxyphenyl)quinazolin-4-amine (3j)
Yield: 75 mg (70%); yellow solid; mp 212–214 °C.
2-(Naphthalen-2-yl)quinazolin-4-amine (3p)8
1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 8.1 Hz, 1 H), 7.74–7.83 (m, 3
H), 7.45–7.50 (m, 1 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.87 (t, J = 8.0 Hz, 1 H),
5.77 (br s, 2 H), 3.95 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 161.5, 160.3, 151.3, 148.4, 147.3, 133.4,
126.6, 125.5, 121.2, 120.4, 118.7, 116.9, 113.7, 112.0, 55.7.
MS (ESI): m/z = 290.1 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C15H13N3O2Na: 290.0905; found:
Yield: 80 mg (74%); white solid; mp 150–151 °C.
1H NMR (300 MHz, DMSO-d6): δ = 9.00 (s, 1 H), 8.60 (d, J = 8.6 Hz, 1
H), 8.26 (d, J = 8.3 Hz, 1 H), 8.04–8.07 (m, 1 H), 7.99–8.02 (m, 1 H),
7.95–7.96 (m, 1 H), 7.86 (s, 2 H), 7.79 (dd, J = 8.3, 5.7 Hz, 2 H), 7.54–
7.58 (m, 2 H), 7.45–7.50 (m, 1 H).
MS (ESI): m/z = 272.1 [M + H]+.
290.0898.
2-(2-Hydroxynaphthalen-1-yl)quinazolin-4-amine (3q)
2-Propylquinazolin-4-amine (3k)6a
Yield: 92 mg (80%); yellow solid; mp 204–205 °C.
Yield: 63 mg (84%); yellow solid; mp 148–150 °C.
1H NMR (300 MHz, DMSO-d6): δ = 15.33 (s, 1 H), 9.62 (d, J = 8.7 Hz, 1
H), 8.29–8.33 (m, 3 H), 7.77–7.90 (m, 4 H), 7.47–7.57 (m, 2 H), 7.33 (t,
J = 7.3 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 162.1, 160.9, 160.3, 147.6, 133.8,
132.7, 128.3, 126.7, 126.3, 126.0, 125.6, 123.7, 122.4, 120.0, 112.2,
111.3.
1H NMR (300 MHz, CDCl3): δ = 7.82–7.91 (m, 2 H), 7.74–7.79 (m, 1 H),
7.46 (t, J = 7.6 Hz, 1 H), 6.04 (br s, 2 H), 2.86 (t, J = 6.3 Hz, 2 H), 1.90 (dt,
J = 15.2, 7.4 Hz, 2 H), 1.03 (t, J = 7.4 Hz, 3 H).
MS (ESI): m/z = 188.1 [M + H]+.
MS (ESI): m/z = 286.1 [M – H]–.
2-Butylquinazolin-4-amine (3l)
HRMS: m/z [M – H]– calcd for C18H12N3O: 286.0980; found: 286.0988.
Yield: 59 mg (73%); brown solid; mp 200–202 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.15 (d, J = 7.9 Hz, 1 H), 7.62–7.70
(m, 4 H), 7.37 (t, J = 7.5 Hz, 1 H), 2.65 (t, J = 7.3 Hz, 2 H), 1.67–1.76 (m,
2 H), 1.31 (dt, J = 14.4, 7.3 Hz, 2 H), 0.88 (t, J = 7.3 Hz, 3 H).
2-(Furan-2-yl)quinazolin-4-amine (3r)8
Yield: 73 mg (87%); black solid; mp 220–223 °C.
13C NMR (75 MHz, DMSO-d6): δ = 166.8, 161.8, 150.1, 132.4, 126.8,
124.3, 123.3, 38.7, 30.1, 22.0, 13.8.
MS (ESI): m/z = 202.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C12H16N3: 202.1344; found: 202.1349.
1H NMR (300 MHz, DMSO-d6): δ = 8.19 (d, J = 8.1 Hz, 1 H), 7.91 (br s, 2
H), 7.84 (s, 1 H), 7.67–7.78 (m, 2 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.19 (d, J =
3.2 Hz, 1 H), 6.64–6.65 (m, 1 H).
MS (ESI): m/z = 212.1 [M + H]+.
2-(Thiophen-2-yl)quinazolin-4-amine (3s)8
2-(Pentan-2-yl)quinazolin-4-amine (3m)
Yield: 75 mg (83%); brown solid; mp 178–181 °C.
Yield: 53 mg (62%); white solid; mp 162–164 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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L. Yang et al.
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1H NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 8.1 Hz, 1 H), 7.90 (s, 1 H),
7.89 (br s, 2 H), 7.78–7.70 (m, 1 H), 7.66 (d, J = 6.8 Hz, 2 H), 7.42 (t, J =
7.5 Hz, 1 H), 7.21–7.12 (m, 1 H).
1H NMR (300 MHz, DMSO-d6): δ = 14.63 (s, 1 H), 8.41 (dd, J = 8.2, 1.6
Hz, 1 H), 8.08 (s, 3 H), 7.63 (s, 2 H), 7.25–7.37 (m, 1 H), 6.81–6.95 (m, 2
H), 2.45 (s, 3 H).
MS (ESI): m/z = 228.0 [M + H]+.
13C NMR (75 MHz, DMSO-d6): δ = 161.0, 160.6, 160.2, 145.7, 135.3,
135.2, 132.0, 128.7, 125.9, 122.9, 119.1, 118.0, 117.2, 112.7, 21.0.
2-(Pyridin-3-yl)quinazolin-4-amine (3t)8
MS (ESI): m/z = 252.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C15H14N3O: 252.1137; found: 252.1143.
Yield: 67 mg (75%); brown solid; mp 216–218 °C.
1H NMR (300 MHz, DMSO-d6): δ = 9.55 (s, 1 H), 8.66–8.70 (m, 2 H),
8.25 (d, J = 8.0 Hz, 1 H), 7.92 (br s, 2 H), 7.77–7.82 (m, 2 H), 7.47–7.54
(m, 2 H).
Control Experiments
To a solution of 2-iodobenzimidamide (1a) (0.4 mmol) in DMF (3 mL)
were added NaN3 (52 mg, 0.8 mmol) and CuBr (5.7 mg, 0.04 mmol).
The reaction mixture was stirred at 40 °C under air for 2 h. H2O (30
mL) was added to the mixture followed by extraction with EtOAc
(3 × 10 mL). The combined extracts were washed with sat. NaCl solu-
tion, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on sil-
ica gel (PE–EtOAc, 5:1) to give azide 4 (m/z = 184.1, [M + Na]+) as a
black solid (61 mg, 95%).
MS (ESI): m/z = 223.1 [M + H]+.
6-Fluoro-2-phenylquinazolin-4-amine (3u)8
Yield: 68 mg (71%); yellow solid; mp 133–134 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.46–8.48 (m, 2 H), 8.35–8.38 (m, 1
H), 7.91 (br s, 2 H), 7.48–7.53 (m, 4 H), 7.38–7.42 (m, 1 H).
MS (ESI): m/z = 240.1 [M + H]+.
To a solution of 4 (61 mg, 0.38 mmol) in DMF (3 mL) were added CuBr
(5.4 mg, 0.038 mmol) and L-proline (8.7 mg, 0.076 mmol). The reac-
tion mixture was stirred at 70 °C under air for 2 h to give 2-amino-
benzimidamide 5 (m/z = 133.1, [M – 2 H]2–).
6-Fluoro-2-(4-chlorophenyl)quinazolin-4-amine (3v)
Yield: 76 mg (70%); yellow solid; mp 172–174 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.42 (d, J = 8.5 Hz, 2 H), 8.32 (dd, J =
8.9, 6.2 Hz, 1 H), 7.93 (s, 2 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.45 (d, J = 10.4
Hz, 1 H), 7.30–7.41 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 162.1, 158.7, 150.2, 137.4, 134.7,
133.0, 131.1, 129.5, 128.7, 128.2, 127.6, 125.3, 123.6, 113.2.
MS (ESI): m/z = 272.0 [M – H]–.
HRMS: m/z [M – H]– calcd for C14H8N3ClF: 272.0391; found: 272.0386.
To a solution of 4 (61 mg, 0.38 mmol) in DMF (3 mL) were added
benzaldehyde (2a) (49 mg, 0.46 mmol), CuBr (5.4 mg, 0.038 mmol)
and L-proline (8.7 mg, 0.076 mmol). The reaction mixture was stirred
at 70 °C under air. After the disappearance of the reactants (moni-
tored by TLC), H2O (30 mL) was added and the mixture was extracted
with EtOAc (3 × 10 mL). The combined extracts were washed with sat.
NaCl solution, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel (PE–EtOAc, 10:1) to give 3a as a yellow solid (68 mg,
81%).
6-Methoxy-2-phenylquinazolin-4-amine (3w)3b
Yield: 75 mg (75%); yellow solid; mp 146–148 °C.
1H NMR (500 MHz, CDCl3): δ = 8.52 (d, J = 6.9 Hz, 2 H), 7.95 (d, J = 9.1
Hz, 1 H), 7.48–7.54 (m, 4 H), 7.03 (d, J = 2.5 Hz, 1 H), 5.52 (br s, 2 H),
3.99 (s, 3 H).
Acknowledgment
MS (ESI): m/z = 252.1 [M + H]+.
This work was supported by the National Natural Science Foundation
of China (Grant No. 81602957), the Natural Science Foundation of
Jiangsu Province, China (Grant No. BK20161035), the Universities
Natural Science Research Project of Jiangsu Province (Grant No.
15KJB350002), and Nanjing Medical University Education Develop-
ment Foundation (Grant No. 2014NJMUZD019).
6-Methoxy-2-(2-hydroxyphenyl)quinazolin-4-amine (3x)
Yield: 93 mg (87%); yellow solid; mp 214–216 °C.
1H NMR (300 MHz, DMSO-d6): δ = 14.52 (s, 1 H), 8.40 (d, J = 7.9 Hz, 1
H), 8.07 (s, 2 H), 7.68–7.72 (m, 2 H), 7.44 (dd, J = 9.0, 1.5 Hz, 1 H), 7.31
(t, J = 7.6 Hz, 1 H), 6.86–6.90 (m, 2 H), 3.88 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 160.7, 160.4, 159.0, 157.0, 142.6,
131.7, 128.5, 127.7, 124.6, 119.2, 118.0, 117.1, 113.3, 103.5, 55.8.
MS (ESI): m/z = 268.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C15H14N3O2: 268.1086; found: 268.1090.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588727.
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References
Yield: 61 mg (65%); yellow solid; mp 156–158 °C.
(1) For selected papers, see: (a) Ciardiello, F.; Caputo, R.; Bianco, R.;
Damiano, V.; Pomatico, G.; De Placido, S.; Bianco, A. R.; Tortora,
G. Clin. Cancer Res. 2000, 6, 2053. (b) Shepherd, F. A.;
Rodrigues Pereira, J.; Ciuleanu, T.; Tan, E. H.; Hirsh, V.;
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Hz, 1 H), 7.87 (d, J = 8.6 Hz, 1 H), 7.58–7.63 (m, 1 H), 7.47–7.53 (m, 5
H), 2.54 (s, 3 H).
MS (ESI): m/z = 236.1 [M + H]+.
2-Hydroxy-6-methylphenylquinazolin-4-amine (3z)
Yield: 76 mg (85%); yellow solid; mp 225–226 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

I
L. Yang et al.
Paper
Synthesis
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