Solvent-free copper-catalyzed three-component synthesis of 2-substituted quinazolin-4(3H)-ones

Article abstract of DOI:10.1007/s00706-016-1804-9

Abstract: A novel and efficient approach for the synthesis of quinazoline-4(3H)-ones through a one-pot copper-catalyzed three-component reaction of isatoic anhydrides, aryl nitriles, and ammonium acetate under solvent-free conditions in good yields is described. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1804-9

Monatsh Chem
DOI 10.1007/s00706-016-1804-9
ORIGINAL PAPER
Solvent-free copper-catalyzed three-component synthesis
of 2-substituted quinazolin-4(3H)-ones
Mehdi Soheilizad1 Shakiba Soroosh2 Rahim Pashazadeh1
•
•
Received: 26 April 2016 / Accepted: 13 June 2016
Ó Springer-Verlag Wien 2016
Abstract A novel and efficient approach for the synthesis
of quinazoline-4(3H)-ones through a one-pot copper-cat-
alyzed three-component reaction of isatoic anhydrides, aryl
nitriles, and ammonium acetate under solvent-free condi-
tions in good yields is described.
antidiabetic [7], anti-ulcer [8], anti-bacterial [9, 10], anti-
convulsant [11, 12], anti-virus [13], and anti-cytotoxin [14].
Due to a wide range of medicinal applications, the
development of novel and efficient protocols for the syn-
thesis of quinazoline-4(3H)-ones has been made more
valuable. As a result, numerous synthetic routes for the
preparation of quinazolinone derivatives reported in the
literature include the reaction of isatoic anhydride with
amidoximes catalyzed by FeCl3 [15], domino reaction of
alkyl halides and anthranilamides catalyzed by CuBr [16],
p-TSA-catalyzed cyclization of 2-aminobenzamides and
aldehydes followed by oxidative dehydrogenation with
PhI(OAc)2 [17], reaction of 2-nitrobenzamides with alde-
hydes via in situ reduction of nitro group by Na2S2O4 [18],
the C–C bond cleavage of 2,2-disubstituted 1,2,3,4-te-
trahydroquinazolinone by CuBr/air catalytic system [19],
three-component reaction of isatoic anhydride, primary
amines, and benzyl halides under Kornblum oxidation
conditions [20], copper-catalyzed domino Ullmann-type
coupling and aerobic oxidative C–H amidation of
2-halobenzamides and (aryl)methanamines [21], cou-
pling/condensative cyclization of 2-haloarylcarbox-amides
with imidamides catalyzed by CuI [22], Pd-catalyzed
cyclocarbonylation of 2-iodoanilines with imidoyl chlo-
rides [23], condensation of anthranilic acids, carboxylic
acids, and amines under microwave conditions [24], reac-
tion of isatoic anhydride, orthoesters, and primary amines
catalyzed by silica sulfuric acid [25], CuO nanoparticle-
catalyzed three-component reaction of isatoic anhydride,
aldehydes, and amine or ammonium under ultrasound
irradiation [26], and reaction between 2-aminobenzamides
and aryl halides via a palladium-catalyzed isocyanide
insertion/cyclization sequence [27], and so on [28–33].
Albeit the reported procedures are useful approaches for
the synthesis of quinazolinones, most of them suffer from
Graphical abstract
Keywords Ammonium acetate Á Copper (I) iodide Á
Isatoic anhydride Á Nitriles Á Quinazoline-4(3H)-one
Introduction
Quinazoline-4(3H)-one core is an important class of bio-
logically active nitrogen-containing heterocyclic scaffold
with ample medicinal activities, including anti-inflamma-
tory [1, 2], anti-microbial [3, 4], anticancer [5, 6],
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1804-9) contains supplementary
material, which is available to authorized users.
& Mehdi Soheilizad
m.soheilizad@yahoo.com
1
School of Chemistry, College of Science, University of
Tehran, PO Box 14155-6455, Tehran, Iran
2
Department of Chemistry, Faculty of Science, Central Tehran
Branch, Islamic Azad University, Tehran, Iran
123

M. Soheilizad et al.
remarkable limitations, such as harsh reaction conditions,
long reaction times, low yields of the products, difficult
work-up and use of expensive and toxic catalysts, reagents,
or media. Therefore, the development of simple and effi-
cient approaches for the synthesis of quinazolinone
derivatives is strongly favorable. Hence, we herein
describe a novel and straightforward protocol for the syn-
examined by 5 and 15 mol % of CuI (entries 7 and 8), and
finally, we found that 10 mol % of CuI gave the best result
(entry 5). Also, other Cu source catalysts, such as
Cu(OAc)2, CuO, Cu2O, CuCl2, and CuBr, could not
enhance the yield of desire product (entries 9–13). Then, to
choice of the best ammonium source, the model reaction
was examined by various ammonium salts, such as
HCO2NH4, NH4NO3, NH4Cl, NH4I, and NH4HCO3 (en-
tries 14–18). As shown in Table 1, among various
ammonium salts examined, NH4OAc turned out to be the
best choice, while others were less or none effective. Next ,
to optimize the time, we observed that decreasing the
reaction time from 4 to 2 h reduces the yield of 3a to 68 %
(entry 19). Also, when the reaction time increased up to
6 h, no significant impact was seen in the yield (87 %) of
desired product 3a (entry 20). Then, to examine of reaction
temperature, we tested the model reaction in both high and
low temperatures of 120 °C, includes 140 and 100 °C. The
isolated yields of 3a were 65 and 52 %, respectively (en-
tries 21 and 22). Finally, to evaluate of reaction medium,
the effect of the several solvents, such as H2O, DMSO, and
PhCH3, was investigated, that for H2O and DMSO, 3a was
detected in 38 and 52 % yield (entries 23 and 24),
respectively, and the reaction was ineffective by toluene as
solvent (entry 25).
thesis of quinazoline-4(3H)-ones through
a copper-
catalyzed three-component condensation of isotaic anhy-
drides, aryl nitriles, and ammonium acetate. Although a
large number of functional groups and modifications have
been successfully explored, to the best of our knowledge,
there has been no report concerning the use of nitriles as
the starting materials for the preparation of quinazoline-
4(3H)-ones.
Result and discussion
In continuation of our studies on preparation of nitrogen-
containing organic compounds [34–38], herein, we report a
novel and efficient solvent-free approach for the synthesis
of quinazoline-4(3H)-ones 3, through a three-component
condensation of isatoic anhydride 1, aryl nitriles 2, and
ammonium acetate in the present of CuI as catalyst under
solvent-free conditions (Scheme 1).
With the optimized reaction conditions in hand, the
scope of the protocol was investigated for the reaction of a
series of substituted benzonitriles 2a–2n, isatoic anhydride
(1a), and NH4OAc, in the present of CuI, as the repre-
sentative example (Table 2). First, the effect of the
substituents at the ortho, meta, and para-position of ben-
zonitriles was examined. Electron-donating groups (3-Me,
4-Me, 2-OMe, 3-OMe, 4-OMe, and 4-NMe2) on benzoni-
trile were well tolerated leading to the desired quinazolines
3b–3g in yields of 70–82 % (entries 2–7). In addition,
electron-withdrawing groups (2-Cl, 4-Cl, 4-F, 2-NO2, and
3-NO2) readily underwent reaction to afford the target
products 3h–3l in yields of 82–88 % (entries 8–12). Next,
we used the 6-chloroisatoic anhydride 1b, with benzonitrile
(2a) and 4-methylbenzonitrile (2c) in optimal conditions
that gave corresponding products 3m, 3n in good yields
(entries 13 and 14). Finally, the reaction of the heterocyclic
nitriles, furyl-2-nitrile (2m) and thienyl-2-nitrile (2n), with
isatoic anhydride (1a) was used to afford the target prod-
ucts 3o, 3p in 77 and 81 % yield, respectively (entries 15
and 16).
In begin our r esearch, preparation of 2-phenylquina-
zolin-4(3H)-one (3a) was investigated as model reaction
(Table 2, entry 1). Also, the influence of various factors,
such as the ammonium salts, catalyst, temperature, time,
and reaction medium, was evaluated (Table 1). First, to
find a convenient reaction conditions, the model reaction
was carried out using 1 equivalent of NH4OAc, in the
absence and presence of CuI as catalyst, at 120 °C under
solvent-free conditions (entries 1 and 2). As shown in
Table 1, in the absence of CuI, no product was formed
(entry 1), but in the presence of CuI (10 mol %), the
reaction took place with 27 % yield (entry 2). Next, to
optimize the amount of NH4OAc, the model reaction was
carried out using two to five equivalents of NH4OAc, and
CuI (10 mol %), at 120 °C under solvent-free conditions
(entries 3–6). The best yield of 3a (87 %) was obtained
with 4 equivalent of NH4OAc (entry 5). Then, to find the
best amount of CuI catalyst, the model reaction was
Scheme 1
The plausible mechanism for the formation of the
quinazoline-4(3H)-ones 3 is suggested in Scheme 2. It is
reasonable to assume that the anthranilamide (4) undergoes
a decarboxylation, formed by nucleophilic addition of
isatoic anhydride 1 with ammonia. Next, the prepared
anthranilamide (4) is condensed by intermediate 5, which is
in situ prepared by coordination of nitrile 2 with CuI, to
123

Solvent-free copper-catalyzed three-component synthesis of 2-substituted quinazolin-4(3H)-ones
Table 1 Effect of different reaction conditions on synthesis of 2-phenylquinazolin-4(3H)-one
Entry
NH4X (eq.)
Cat.
Temp./°C
Time/h
Yielda/%
1
NH4OAc (1)
NH4OAc (1)
NH4OAc (2)
NH4OAc (3)
NH4OAc (4)
NH4OAc (5)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
HCO2NH4 (4)
NH4NO3 (4)
NH4Cl (4)
–
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
100
120
120
120
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
2
6
4
4
4
4
4
NR
27
46
68
87
85
66
85
63
75
55
68
82
64
55
NR
NR
60
68
87
65
52
38
52
NR
2
CuI
3
CuI
4
CuI
5
CuI
6
CuI
7b
8c
9
CuI
CuI
Cu(OAc)2
CuO
Cu2O
CuCl2
CuBr
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24e
25f
CuI
CuI
NH4I (4)
CuI
NH4HCO3 (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
NH4OAc (4)
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Highlighted values represent the best reaction condition
Reaction conditions Isatoic anhydride (1 mmol), Benzonitrile (1 mmol)
NR no reaction
a
Isolated yield
b
CuI (5 mol%)
c
CuI (15 mol%)
H2O (2 cm3) as solvent employed
d
e
DMSO (2 cm3) as solvent employed
f
Toluene (2 cm3) as solvent employed
form the intermediate 6. Then, intramolecular cyclization
of intermediate 6, followed by libration of ammonia, leads
to the formation of the corresponding quinazoline-4(3H)-
ones 3 (Scheme 2).
a one-pot copper-catalyzed three-component condensation
of isatoic anhydrides, aryl nitriles, and ammonium acetate
under solvent-free conditions. The simplicity of the starting
materials, one-pot procedure, as well as solvent-free con-
ditions and good yields of the products are the main
advantages of the reported method.
In summary, we have developed novel and efficient
approach for the preparation of quinazoline-4(3H)-ones via
123

M. Soheilizad et al.
Table 2 The substrate scope of quinazolin-4(3H)-one derivatives
Entry
X
1
Ar
2
Yielda/
%
Product
M.p./°C
Observed
Reported
1
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1a
1a
Ph
2a
2b
2c
2d
2e
2f
87
80
82
70
77
75
72
83
84
88
82
83
80
78
77
81
3a
3b
3c
3d
3e
3f
233–235
204–206
260–262
208–210
206–208
246–248
236–238
290–292
195–197
291–293
349–352
208–210
288–290
296–297
214–216
273–275
234–235 [21]
210–212 [31]
261–263 [21]
209–212 [29]
209–210 [28]
247–248 [21]
236–238 [26]
293–295 [27]
196–197 [28]
296–298 [21]
352–354 [20]
208–210 [26]
295–296 [21]
300–302 [21]
210–212 [31]
275–276 [21]
2
3-Me-Ph
4-Me-Ph
2-OMe-Ph
3-OMe-Ph
4-OMe-Ph
4-NMe2-Ph
4-F-Ph
3
4
5
6
7
2g
2h
2i
3g
3h
3i
8
9
2-Cl-Ph
4-Cl-Ph
2-NO2-Ph
3-NO2-Ph
Ph
10
11
12
13
14
15
16
2j
3j
2k
2l
3k
3l
2a
2c
2m
2n
3m
3n
3o
3p
4-Me-Ph
2-Furyl
2-Thienyl
Reaction conditions Isatoic anhydride (1.0 mmol), Aryl nitrile (1.0 mmol), NH4OAc (4.0 mmol), CuI (0.1 mmol), 120 °C, 4 h
a
Isolated yield
Scheme 2
FT-IR spectrometer. 1H and 13C NMR spectra were
Experimental
recorded on a Bruker Avance 500-MHz NMR spectrometer
using tetramethylsilane (TMS) as internal standard. Melt-
ing points were determined in a capillary tube. The
progress of reaction was followed with TLC using silica
All chemicals were purchased from Merck and Fluka
companies. All yields refer to isolated products. IR spectra
of the compounds were obtained on a Perkin Elmer GX
123

Solvent-free copper-catalyzed three-component synthesis of 2-substituted quinazolin-4(3H)-ones
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