Copper-Catalyzed Cascade Synthesis of [1,2,4]-Triazoloquinazolinones

Article abstract of DOI:10.1055/s-0036-1591565

An efficient and practical method for the synthesis of 1,2,4-triazolo[5,1- b ]quinazolin-9(3 H)-ones has been developed via the copper-catalyzed domino reactions of readily available substituted N ′-acetyl-2-bromobenzohydrazides with cyanamide. The protocol uses inexpensive CuI as the catalyst, and no other ligand or additive was required. The target products were prepared in good to excellent yields with tolerance of various functional groups.

Full text of DOI:10.1055/s-0036-1591565

SYNLETT
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-
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2
1
4
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7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
Z. Lou et al.
Letter
Synlett
Copper-Catalyzed Cascade Synthesis of [1,2,4]-Triazoloquinazoli-
nones
Zhenbang Loua,b
Ningning Manb
Haijun Yangb
Changjin Zhua
O
O
H
N
R2
N
N
N
R2
copper-catalyzed
domino reaction
R1
R1
H
+
NH2CN
O
N
H
Y
N
Y
Br
24 examples
54–86% yield
Y = CH, N
Hua Fu*a,b
0
0
0
0
0-
0
0
1
7-
2
5
0
0-
0
5
3
R1 = H, Me, OMe, F, Cl, CF3
R2 = aryl, alkyl
a School of Chemistry and Chemical Engineering, Beijing Institute of
Technology, Beijing 100081, P. R. of China
fuhua@mail.tsinghua.edu.cn
b Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsing-
hua University, Beijing 100084, P. R. of China
Received: 04.02.2018
Accepted after revision: 12.03.2018
Published online: 20.04.2018
Table 1 Optimization of Conditions for Copper-Catalyzed Domino Re-
action of Acetophenone 2-Bromo-N′-(4-methylbenzoyl)benzohydrazide
(1b) with Cyanamide (2) Leading to 2-(p-Tolyl)-[1,2,4]triazolo[5,1-b]quin-
azolin-9(3H)-one (3b)a
DOI: 10.1055/s-0036-1591565; Art ID: st-2018-k0077-l
Abstract An efficient and practical method for the synthesis of 1,2,4-
triazolo[5,1-b]quinazolin-9(3H)-ones has been developed via the cop-
per-catalyzed domino reactions of readily available substituted N′-ace-
tyl-2-bromobenzohydrazides with cyanamide. The protocol uses inex-
pensive CuI as the catalyst, and no other ligand or additive was
required. The target products were prepared in good to excellent yields
with tolerance of various functional groups.
Me
O
H
N
N
H
O
O
Br
cat., base, solvent
120 °C, Ar, 12 h
1b
N
N
Me
+
N
H
N
NH2CN
Key words copper, domino reactions, [1,2,4]-triazoloquinazolinones,
cyanamide, synthetic method
3b
2
Entry
Cat.
Base
Solvent
Yield (%)b
1
2
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
dioxane
DMF
DMF
84
80
78
54
64
56
0
N-Heterocycles are widely found in natural products, bi-
ologically and pharmaceutically active molecules,1 and they
are privileged motifs in drug discovery.2 Quinazolinones
constitute an important class of N-heterocyclic compounds,
and they exhibit a wide range of biological and pharmaceu-
tical activities such as antimicrobial,3 antifungal,4 anti-in-
flammatory,5 anticancer6 and AMPA receptor antagonistic
activities.7 Similarly, N-heterocycles with the 1,2,4-triazole
unit show diverse biological functions. For example, they
are used as bactericidal, fungicidal, antitumor, anti-inflam-
matory and insecticidal agents.8 N-Fused compounds of
1,2,4-triazole and quinazolinone motifs, [1,2,4]-triazolo-
quinazolinones, have been reported to own excellent anti-
fungal, antirheumatic and antihistaminic activities.9 To the
best of our knowledge, the most common methods for the
synthesis of this kind of compounds are cyclization of 3-
amino-2-arylaminoquinazolin-4(3H)-ones with acyl chlo-
rides, carboxylic acids or aldehydes.10 However, it is difficult
to get the starting materials, 3-amino-2-arylamino-
quinazolin-4(3H)-ones. In 2004, Ding and co-workers de-
veloped the efficient synthesis of 1,2,4-triazolo[5,1-
CuBr
CuCl
Cu2O
Cu(OAc)2
CuCl2
–
3
4
5
6
7
8
CuI
81
80
83
84
42
84
25
9
CuI
K3PO4
10
11
12
13c
14d
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuI
CuI
CuI
CuI
a Reaction conditions: argon atmosphere, 2-bromo-N′-(4-methylbenzo-
yl)benzohydrazide (1b; 0.3 mmol), cyanamide (2; 0.45 mmol), catalyst
(0.03 mmol), base (0.3 mmol), solvent (3.0 mL), temperature (120 °C),
time (12 h) in a sealed Schlenk tube. DMA = N,N-Dimethylacetamide.
b Isolated yield.
c Reaction temperature was 130 °C.
d Reaction temperature was 100 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
Z. Lou et al.
Letter
Synlett
b]quinazolin-9(3H)-ones via a tandem Aza-Wittig/hetero-
cumulene-mediated annulation.11 Unfortunately, long pro-
cedures were required which is unfavorable for the con-
struction of diverse target molecules. Therefore, it is of im-
portance to develop a convenient and efficient approach to
this kind of compounds. Recently, copper-catalyzed cross-
couplings have received significant attention,12 and various
N-heterocycles have been prepared via the coupling reac-
O
H
O
N
R2
CuI, Cs2CO3, DMF
120 °C, Ar, 10–15 h
N
N
N
R1
R2
H
R1
+
NH2CN
O
N
H
Y
Br
Y
N
2
Y = CH, N
3
1
O
O
O
N
N
N
N
N
N
Me
N
N
H
N
N
N
N
H
H
3a (12 h, 82%)
3b (12 h, 84%)
3c (12 h, 81%)
O
O
O
N
N
N
N
N
N
Me
Cl
N
N
N
H
N
N
N
H
H
Me
Me
3d (12 h, 78%)
3e (12 h, 74%)
3f (12 h, 80%)
O
O
O
Me
N
N
N
N
N
N
Me
N
N
N
N
N
N
Me
Me
H
H
H
3g (10 h, 85%)
3h (10 h, 86%)
3i (10 h, 80%)
O
O
O
Me
MeO
MeO
N
N
N
N
N
N
Me
Me
N
N
N
N
N
N
H
H
H
3j (10 h, 81%)
3k (10 h, 81%)
3l (10 h, 84%)
O
O
O
MeO
MeO
F
F
N
N
N
N
N
N
Me
Me
N
N
N
N
N
N
H
H
H
3m (12 h, 74%)
3n (13 h, 64%)
3o (13 h, 67%)
O
O
O
Cl
N
N
N
N
N
N
Me
N
N
N
N
N
N
Cl
Cl
H
H
H
3p (12 h, 74%)
3q (12 h, 74%)
3r (12 h, 68%)
O
O
O
Cl
F3C
N
N
N
N
N
N
Me
Me
N
N
N
N
N
N
N
H
H
H
3s (12 h, 72%)
3t (14 h, 64%)
3u (15 h, 54%)
O
O
O
NHBoc
Me
N
N
N
N
N
N
Me
N
N
N
N
N
N
H
H
H
Me
3v (15 h, 68%)
3w (15 h, 67%)
3x (15 h, 56%, 98.1% ee)
Scheme 1 Copper-catalyzed cascade synthesis of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 3. Reaction conditions: argon atmosphere, substituted N′-
acetyl-2-bromobenzohydrazide 1 (0.3 mmol), cyanamide (2; 0.45 mmol), CuI (0.03 mmol), Cs2CO3 (0.3 mmol), DMF (3.0 mL), 120 °C, 10–15 h in a
sealed Schlenk tube. Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
Z. Lou et al.
Letter
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tions by us13 and other research groups.14 Herein, we report
a novel and efficient copper-catalyzed domino approach to
1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones.
0.21 g) under the standard conditions, and the target prod-
uct 3b was obtained in 81% yield. The result showed that
the method was very useful for the synthesis of [1,2,4]-tri-
azoloquinazolinones.
At first, the copper-catalyzed domino reaction of ace-
tophenone 2-bromo-N′-(4-methylbenzoyl)benzohydrazide
(1b) with cyanamide (2) leading to 2-(p-tolyl)-[1,2,4]triazo-
lo[5,1-b]quinazolin-9(3H)-one (3b) was selected as the
model reaction to optimize conditions including catalysts,
base, solvents, temperature and time. As shown in Table 1,
six catalysts were screened using Cs2CO3 as the base and
DMF as the solvent under argon atmosphere at 120 °C for
12 hours (Table 1, entries 1–6), and CuI provided the high-
est yield (Table 1, entry 1). No target product was observed
in the absence of copper catalyst (Table 1, entry 7). K2CO3
and K3PO4 were less efficient bases than Cs2CO3 (Table 1, en-
tries 8 and 9). The effect of solvent was investigated (com-
pare entries 1 and 10–12 in Table 1), and DMF was an opti-
mal choice. The reaction temperature was surveyed (com-
pare entries 1, 13 and 14 in Table 1), and a low yield was
observed for N-arylation of cyanamide (2) when the reac-
tion was performed at 100 °C, so 120 °C was a suitable tem-
perature. Therefore, the optimal conditions for the synthe-
sis of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones are as fol-
lows: 10 mol% CuI as the catalyst, Cs2CO3 as the base, and
DMF as the solvent under argon atmosphere.
After optimizing the reaction conditions, we investigat-
ed the substrate scope for the domino reactions of substi-
tuted N′-acetyl-2-bromobenzohydrazides 1 with cyana-
mide (2) leading to 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
ones 3 (Scheme 1).15 We first surveyed the reactivity of
substrates 1 with variation of substituents R1 when R2 was
an aromatic group, and the substrates containing electron-
donating R1 groups on the aromatic rings provided higher
yields than those containing electron-withdrawing R1
groups (see 3a–t). The substrates containing aliphatic sub-
stituents R2 were also effective (see 3v–x). In particular,
product 3x contains an amino acid residue, and its further
modification can afford diverse compounds after removal of
the Boc-protecting group. To confirm whether the present
method led to ee erosion of 3x, racemic rac-3′x was synthe-
sized under the standard conditions. Subsequently, HPLC
analysis of rac-3′x and 3x was performed with an OD-H chi-
ral column using n-hexane/isopropanol (90:10) as the mo-
bile phase (column pressure = 40 bar, flow rate = 1 mL/min),
and the results showed that the ee value of 3x was 98% (see
Supporting Information for the details). The copper-cata-
lyzed domino reactions exhibited tolerance of some func-
tional groups including ethers (see 3k–m), C–F bonds (see
3n and 3o), C–Cl bonds (see 3p–s), trifluoromethyl (see 3t),
amide (see 3x), and N-heterocycle (see 3u).
Me
O
H
N
N
H
O
Br
1b
O
3.36 mmol
1.12 g
CuI, Cs2CO3, DMF
120 °C, Ar, 12 h
N
N
Me
+
N
H
N
NH2CN
2
3b
5 mmol
0.21 g
2.71 mmol
0.748 g
81% yield
Scheme 2 Scale-up of the copper-catalyzed synthesis of 2-(p-tolyl)-
[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-one (3b) under the standard
conditions
Me
O
H
N
N
H
O
O
7
CuI, Cs2CO3, DMF
120 °C, Ar, 12 h
N
N
N
Me
+
H2N
NH2CN
8
2
no product
Scheme 3 Copper-catalyzed treatment of N′-benzoyl-4-methylbenzo-
hydrazide (7) with cyanamide (2)
To explore the mechanism of the copper-catalyzed
domino reaction, we investigated the treatment of N′-ben-
zoyl-4-methylbenzohydrazide (7) with cyanamide (2) un-
der the standard conditions (Scheme 3). No product 8 was
observed, which showed that the copper-catalyzed N-ary-
lation of cyanamide (2) with aryl bromide was the initial
step for the synthesis of 1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-ones 3. Therefore, a possible mechanism for the cop-
per-catalyzed domino reactions is proposed in Scheme 4
according to the present results and our previous re-
ports.13j,k First, copper-catalyzed N-arylation of cyanamide
(2) with substituted N′-acetyl-2-bromobenzohydrazide 1
affords I, and intramolecular nucleophilic addition of NH to
CN in I gives II. Isomerization of II leads to III, and intramo-
lecular nucleophilic attack of amino to carbonyl in III pro-
vides the target product 3 leaving water.
In summary, we have developed a novel, efficient, and
practical copper-catalyzed domino reaction of substituted
N′-acetyl-2-bromobenzohydrazides with cyanamide lead-
ing to 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones, and the
corresponding products were obtained in good to excellent
yields. The present method has some advantages including
inexpensive CuI as the catalyst, use of readily available
As shown in Scheme 2, we attempted to scale up the
synthesis of 2-(p-tolyl)-[1,2,4]triazolo[5,1-b]quinazolin-
9(3H)-one (3b) via copper-catalyzed domino reaction of ac-
etophenone
2-bromo-N′-(4-methylbenzoyl)benzohydra-
zide (1b; 3.36 mmol, 1.12 g) with cyanamide (2; 5.0 mmol,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
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O
O
H
N
H
copper-catalyzed
N-arylation
R2
+
N
R2
N
H
N
R1
R1
H
NH2CN
O
O
O
Br
N
H
CN
2
1
I
O
O
H
N
H
R2
N
R2
N
N
R1
R1
O
N
H
N
H2O
NH
NH2
III
II
O
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N
N
R2
R1
N
N
H
3
Scheme 4 A possible mechanism for the copper-catalyzed domino re-
action of substituted N′-acetyl-2-bromobenzohydrazides 1 with cyana-
mide (2)
starting materials, adoption of economical domino reac-
tions and tolerance of a broad range of functional groups.
Therefore, this domino strategy can be used in the synthesis
of other N-heterocycles.
Funding Information
(11) Ding, M.-W.; Chen, Y.-F.; Huang, N.-Y. Eur. J. Org. Chem. 2004,
3872.
Financial support from the National Natural Science Foundation of
China (Grant No. 21772108) is gratefully acknowledged.
N
oaitn
a
l
N
a
utra
l
S
ecin
c
e
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
7
7
2
1
0
8)
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Acknowledgments
We thank Dr. Haifang Li in Department of Chemistry at Tsinghua Uni-
versity for her great help in mass spectrometric analysis.
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S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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J. Org. Lett. 2006, 8, 4351. (g) Altenhoff, G.; Glorius, F. Adv. Synth.
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= 6.4 Hz, 3 H), 7.27 (s, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 2.47 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 161.6, 155.4, 151.5, 145.9,
139.5, 130.4, 130.1, 128.9 (2 × CH), 127.4, 126.7 (2 × CH), 124.4,
(15) General Procedures for the Preparation of Compounds 3a–w:
A Schlenk tube was charged with a mixture of CuI (0.03 mmol,
5.7 mg), Cs2CO3 (0.3 mmol, 98 mg), substituted N′-acetyl-2-bro-
mobenzohydrazide 1 (0.3 mmol), cyanamide (2; 0.45 mmol, 19
mg) and anhyd DMF (3.0 mL). After being evacuated and
recharged with Ar for three times, the tube was sealed and the
mixture was allowed to stir at 120 °C for 10–15 h. After comple-
tion of the reaction, the mixture was cooled to r.t., and H2O (20
mL) was added to the mixture. The solution was extracted with
CH2Cl2–MeOH (10:1; 3 × 10 mL), and the combined organic
layers were dried over anhyd Na2SO4. The solution was concen-
trated, and the residue was purified by silica gel column chro-
matography (CH2Cl2–MeOH = 30:1 or 20:1) providing the target
product (3a–x). Three representative examples are shown as
follows:
116.3, 111.3, 21.6. ESI–HRMS: m/z [M
16H12N4NaO: 299.0903; found: 299.0906.
+
Na]+ calcd for
C
7-Chloro-2-phenyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-
one (3r): eluent: CH2Cl2–MeOH = 30:1. Isolated yield: 68% (60.4
mg); white solid; mp 281–283 °C. 1H NMR (600 MHz, DMSO-
d6): δ = 8.14–8.19 (m, 3 H), 7.88 (dd, J = 8.8, 2.4 Hz, 1 H), 7.51–
7.58 (m, 4 H). 13C NMR (151 MHz, DMSO-d6): δ = 161.6, 155.0,
151.3, 139.1, 134.5, 131.1, 129.9, 128.3 (2 × CH), 127.9, 127.1,
126.5 (2 × CH), 122.4, 116.6. ESI–HRMS: m/z [M + H]+ calcd for
C
15H10ClN4O: 297.0538; found: 297.0540.
2-Methyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-one (3w):
eluent: CH2Cl2–MeOH = 30:1. Reaction time: 15 h. Isolated
yield: 67% (40.3 mg); white solid; mp 312–314 °C. 1H NMR (600
MHz, DMSO-d6): δ = 8.16 (d, J = 7.7 Hz, 1 H), 7.78 (t, J = 7.4 Hz, 1
H), 7.50 (d, J = 7.9 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 161.9, 155.2, 151.0, 139.7,
134.8, 127.3, 122.6, 117.2, 113.3, 14.4. ESI–HRMS: m/z [M + H]+
calcd for C10H9N4O: 201.0771; found: 201.0770.
6-Methyl-2-phenyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-
one (3e): eluent: CH2Cl2–MeOH = 30:1. Isolated yield: 85% (70.4
mg); white solid; mp 352–353 °C. 1H NMR (400 MHz, DMSO-
d6): δ = 8.16 (d, J = 6.5 Hz, 2 H), 8.11 (d, J = 8.2 Hz, 1 H), 7.54 (q, J
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E