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
Soheilizad, Mehdi
