Efficient copper-catalyzed synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline derivatives

Article abstract of DOI:10.1055/S-0029-1218530

We have developed an efficient copper-catalyzed method for the synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline derivatives via reactions of substituted 2-bromobenzonitriles with amidines or guanidine, and the method is of economical and practic

Full text of DOI:10.1055/S-0029-1218530

LETTER
A
Efficient Copper-Catalyzed Synthesis of 4-Aminoquinazoline and
2,4-Diaminoquinazoline Derivatives
S
ynthesis of 4-A
m
i
inoquin
a
azoline
a
n
o
d 2,4-Diamin
b
oquinazolin
o
D
erivatives Yang,a,b Hongxia Liu,c Hua Fu,*a Renzhong Qiao,*b Yuyang Jiang,c Yufen Zhaoa
a
b
c
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering,
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, P. R. of China
E-mail: qiaorz@mail.buct.edu.cn
Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University,
Shenzhen 518057, P. R. of China
Received 21 September 2009
and anti-hypertensive agents.10 2,4-Diaminoquinazoline
derivatives have also shown unique biological and medic-
inal functions. For example trimetrexate (B)11 and piri-
trexim (C)12 in Figure 1, two lipophilic agents originally
developed against cancer,13 are now used in clinic as sec-
ond-line therapy in moderate to severe PCP.14 Some 2,4-
diaminoquinazoline derivatives have been used as dihy-
drofolate reductase inhibitors,15 potent and selective in-
hibitors of the leishmanial and trypanosomal enzymes and
SMN2 promoter activators (such as D and E in Figure 1)
for the potential treatment of spinal muscular atrophy.16
Some of them have exhibited potent growth inhibition of
the clinically relevant life-cycle stage of the intact
parasite17 and antitumor activity (such as F in Figure 1).18
For the synthesis of 4-aminoquinazoline derivatives, most
of them start from reactions of cyanophenyltriazenes,19
o-azidobenzonitriles with nitriles,20 aromatic nitriles with
2-aminobenzonitriles,21 and 2-aminobenzonitrile and
orthoesters with ammonium acetate.22 The preparation of
2,4-diaminoquinazoline derivatives commonly uses reac-
tion of substituted 2-fluorobenzonitriles with guanidine
carbonate,16 substituted 2-aminobenzonitriles with guani-
Abstract: We have developed an efficient copper-catalyzed meth-
od for the synthesis of 4-aminoquinazoline and 2,4-diamino-
quinazoline derivatives via reactions of substituted 2-bromo-
benzonitriles with amidines or guanidine, and the method is of eco-
nomical and practical advantage.
Key words: copper, Ullmann-type reaction, cross-coupling,
quinazoline, synthetic method
Nitrogen-containing heterocycles are ubiquitous in nature
and are well-represented among the desirable structures of
modern medicinal chemistry. Quinazoline derivatives
have been used as powerful inhibitors of the epidermal
growth factor (EGF) receptors of tyrosine kinase,1 ligands
for benzodiazepine and GABA receptors in the CNS
system2 or as DNA binders,3 and some of quinazoline de-
rivatives have shown remarkable activity as anticancer,4
antiviral,5 and antitubercular agents.6 The quinazoline de-
rivatives with different substituted groups show different
biological and medicinal activity. 4-Aminoquinazoline
derivatives (A in Figure 1) have been applied as fungi-
cides,7 anti-inflammatory,8 anti-cancer,9 anti-microbial,
OMe
OMe
OMe
NH2
OMe
NH2
N
NH2
N
N
N
H
N
R'
H2N
N
N
H2N
R
N
OMe
trimetrexate (B)
piritrexim (C)
A
Cl
O
COOH
NH2
N
N
(CH2)3
NH
NH2
S
NH2
O
H
N
N
N
H2N
O
H2N
N
H2N
N
COOH
E
D
F
Figure 1 4-Aminoquinazoline and 2,4-diaminoquinazoline derivatives with important biological and medicinal activity
SYNLETT 2009, No. x, pp 000A–000F
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Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1218530; Art ID: W15209ST
© Georg Thieme Verlag Stuttgart · New York

B
X. Yang et al.
LETTER
dine hydrochloride15c and chloroformamidine hydrochlo-
ride.23 Although the previous methods for the synthesis of
2-aminoquinazoline and 2,4-aminoquinazoline deriva-
tives are efficient, the starting materials often are not
readily available or difficult to prepare. Recently, copper-
catalyzed Ullmann-type N-arylations have made great
progress,24 and the N-arylation strategy has been used to
make N-heterocycles.25 We have also developed some
copper-catalyzed methods for synthesis of N-heterocycles
via the Ullmann-type coupling.26 Herein, we report a sim-
ple, convenient one-pot copper-catalyzed cascade method
for the synthesis of 2-aminoquinazoline and 2,4-amino-
quinazoline derivatives under mild conditions.
Table 1 Copper-Catalyzed Coupling of 2-Bromobenzonitrile with
Butyramidine Hydrochloride: Optimization of Conditionsa
NH2
cat., base, ligand
solvent, temp
CN
Br
HN
NH2⋅HCl
N
+
N
1a
2b
3b
COOH
H2N
NH2
Me NH HN Me
N
H
L3
N
COOH
H
L1
L2
L4
OH
OH
Initially, 2-bromobenzonitrile and butyramidine hydro-
chloride were chosen as the model substrates to optimize
reaction conditions including the catalysts, bases, and sol-
vents under nitrogen atmosphere. As shown in Table 1,
five copper catalysts were tested at 80 °C using 20 mol%
N,N¢-dimethylethylenediamine (DMEDA) as the ligand, 2
equiv of K2CO3 as the base (relative to amount of 2-bro-
mobenzonitrile) in DMF (entries 1–5), and CuI showed
the best activity (entry 1). We attempted other ligands (en-
tries 6–10), and N,N¢-dimethylethylenediamine was
proved to be the most effective. Only small amount of the
target product was obtained in the absence of ligand (entry
11). The effect of bases was investigated, and K2CO3 dis-
played the best results (compare entries 1, 12–14). Several
solvents, DMF, DMSO, and toluene, were screened, and
DMF was found to be the most effective (compare entries
1, 15, and 16). Reaction temperature was also changed,
high temperature (more than 100 °C) led to small amount
of unknown byproducts, but lower temperature (<60 °C)
provided lower yields.
N
N
L6
L5
Entry Cat.
Ligand Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
Yield (%)b
79
1
2
CuI
CuBr
CuCl
CuCl2
Cu
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
–
K2CO3
K2CO3
63
3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
64
4
46
5
33
6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
32
7
21
8
64
9
63
10
11
12
13
14
15
16
42
The scope of copper-catalyzed reactions of the substituted
2-bromobenzonitriles with amidines was investigated un-
der the optimized conditions (10 mol% CuI, 20 mol%
DMEDA, 2 equiv of K2CO3).27 As shown in Table 2, most
of the substrates examined provided good yields at 80 °C
within 3–12 hours. For the substituted 2-bromobenzoni-
triles, the electron effect of the substituent groups could
affect the reactivity of the substrates. For example, 2-bro-
mo-4-nitrobenzonitrile showed higher reaction rates than
the substrates containing electron-rich or electron-neutral
groups. Aliphatic and aromatic amidines provided higher
yields. Couplings of the substituted 2-bromobenzonitriles
with guanidine almost quantitatively transferred into the
corresponding 2,4-diaminoquinazolines, and only moder-
ate to good isolated yields were obtained because of high
polarity of the target products (entries 11–13 in Table 2).
21
L1
L1
L1
L1
L1
32
57
19
53
trace
a Reaction conditions: 2-bromobenzonitrile (1 mmol), butyramidine
hydrochloride (1.2 mmol), catalyst (0.1 mmol), base (2 mmol), sol-
vent (3 mL), 80 °C, nitrogen atmosphere, 12 h.
b Isolated yield.
NH2
N
CN
HN
NH2
N
CuI, L, base
HBr
R1
+
R1
R1
R2
R2
Br
N
NH2
N
1
2
3
I
R2
Scheme 1 Possible formation mechanism of 4-aminoquinazoline derivatives
Synlett 2009, No. x, A–F © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Aminoquinazoline and 2,4-Diaminoquinazoline Derivatives
C
Table 2 Copper-Catalyzed Synthesis of 4-Aminoquinazoline and 2,4-Diaminoquinazoline Derivatives via Reactions of Substituted 2-Bromo-
benzonitriles with Amidines or Guanidinea
NH2
N
HN
HN
NH2⋅HCl
R1
N
R2
R2
CN
Br
or
CuI, L, base
DMF, 80 °C
R1
or
NH2⋅HCl
+
NH2
1
N
R1
NH2
N
NH2
Me NH HN Me
L =
2
3
CN
Br
CN
CN
O2N
Br
Br
1c
1a
1b
Entry
1
2
Time (h)
Product (3)
Yield (%)b
69
NH2
HN
2a
NH2•HCl
NH2•HCl
N
12
12
N
3a
3b
NH2
HN
N
2
3
79
72
N
2b
NH2
HN
NH2•HCl
N
12
12
N
2c
3c
NH2
HN
NH2•HCl
N
4
85
N
2d
2a
3d
3e
3f
NH2
N
5
6
12
12
75
79
N
NH2
N
2b
2c
N
NH2
N
7
12
55
N
3g
Synlett 2009, No. x, A–F © Thieme Stuttgart · New York

D
X. Yang et al.
LETTER
Table 2 Copper-Catalyzed Synthesis of 4-Aminoquinazoline and 2,4-Diaminoquinazoline Derivatives via Reactions of Substituted 2-Bromo-
benzonitriles with Amidines or Guanidinea (continued)
NH2
N
HN
HN
NH2⋅HCl
R1
N
R2
R2
CN
Br
or
CuI, L, base
DMF, 80 °C
R1
or
NH2⋅HCl
+
NH2
1
N
R1
NH2
N
NH2
Me NH HN Me
L =
2
3
CN
Br
CN
CN
O2N
Br
Br
1c
1a
1b
Entry
8
2
Time (h)
Product (3)
Yield (%)b
NH2
N
2d
12
67
N
3h
NH2
N
9
10
11
12
13
2a
2b
3
3
63
76
66
57
85
O2N
N
3i
NH2
N
O2N
N
3j
NH2
HN
NH2•HCl
NH2
N
12
12
8
N
NH2
2e
3k
NH2
N
2e
2e
N
NH2
3l
NH2
N
O2N
N
NH2
3m
a Reaction conditions: substituted 2-bromobenzonitrile (1 mmol), amidine hydrochloride (1.2 mmol), CuI (0.1 mmol), DMEDA (0.2 mmol),
base (2 mmol, Cs2CO3 for acetamidine hydrochloride; K2CO3 for others), DMF (3 mL), 80 °C, nitrogen atmosphere.
b Isolated yield.
A possible formation mechanism of 4-aminoquinazoline of CuI in the presence of base (K2CO3 or Cs2CO3). In-
derivatives was proposed in Scheme 1. The Ullmann-type tramolecular nucleophilic attack of amino group to ortho-
coupling reaction of the substituted 2-bromobenzonitrile cyano group in I affords the target product 3.
with amidine first provides intermediate I under catalysis
Synlett 2009, No. x, A–F © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Aminoquinazoline and 2,4-Diaminoquinazoline Derivatives
E
(12) Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichol,
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In summary, we have developed a simple and efficient
method for the synthesis of 2-aminoquinazoline and 2,4-
diaminoquinazoline derivatives. The couplings of substi-
tuted 2-bromobenzonitriles with amidines or guanidine
were performed well under mild conditions, and the target
products were obtained in good yields when reaction tem-
perature was raised to 80 °C. The present method shows
economical, practical, and starting material readily avail-
able advantages over the previous methods, so it will pro-
vide opportunity for construction of diverse and useful
molecules in organic chemistry and medicinal chemistry.
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Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065, 20732004, 20872010,
20972083), Chinese 863 Project (Grant No. 2007AA02Z160,
2006DFA43030), and the Key Subject Foundation from Beijing
Department of Education (XK100030514).
Thosteinsdottir, M.; Bjornsson, J. M.; Coovert, D. D.;
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X. Yang et al.
LETTER
and the combined filtrate was concentrated by the rotary
evaporator, and the residue was purified by column
chromatography on silica gel using CHCl3–MeOH (40:1 to
5:1) as eluent to give the desired product.
(27) General Procedure for the Synthesis of Compounds
3a–m
A 25 mL round-bottom flask was charged with a magnetic
stirrer and DMF (3 mL), substituted 2-bromobenzonitrile (1,
1 mmol), amidine hydrochloride (2, 1.2 mmol), DMEDA
(0.2 mmol, 18 mg), and K2CO3 (2 mmol, 138 mg) [2 mmol
(656 mg) of Cs2CO3 were used for acetamidine hydro-
chloride] after stirring of the mixture for 15 min under
nitrogen atmosphere, and CuI (0.1 mmol, 19 mg) was added
to the flask. The mixture was stirred at 80 °C for the time
indicated in Table 2. The resulting mixture was cooled to r.t.
and filtered. The solid was washed with DMF (2 × 3 mL),
Cyclopropyl-4-aminoquinazoline (3c)
Eluent CHCl3–MeOH (40:1). Yield 134 mg (72%). White
solid; mp 198–200 °C. 1H NMR (300 MHz, DMSO-d6): d =
8.12 (d, 1 H, J = 7.9 Hz), 7.58 (m, 4 H), 7.34 (t, 1 H, J = 7.4
Hz), 1.99 (m, 1 H, J = 7.5 Hz), 1.05–0.87 (m, 4 H). 13C NMR
(75 MHz, DMSO-d6): d = 167.6, 162.3, 150.5, 133.2, 126.9,
124.5, 124.0, 113.4, 18.4, 9.4. HRMS: m/z calcd for
C11H11N3 [M + H]+: 186.1031; found: 186.1037.
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