Rapid synthesis of 2,3-disubstituted-quinazolin-4-ones enhanced by microwave-assisted decomposition of formamide

Article abstract of DOI:10.1016/j.tetlet.2007.07.114

An efficient methodology for the preparation of a series of 2,3-disubstituted-quinazolin-4(3H)-ones is described via a three step reaction from anthranilic acid. The obtained results also reveal that microwave-assisted rapid decomposition of formamide under controlled conditions of power, temperature and time is a very convenient source of ammonia for the synthesis of 2-substituted-quinazolin-4(3H)-ones and other rings.

Full text of DOI:10.1016/j.tetlet.2007.07.114

Tetrahedron Letters 48 (2007) 6609–6613
Rapid synthesis of 2,3-disubstituted-quinazolin-4-ones enhanced
by microwave-assisted decomposition of formamide
Ioannis K. Kostakis,a Abdelhakim Elomri,a Elisabeth Seguin,a Mauro Iannellib and
Thierry Bessona,*
aUMR CNRS 6014, Groupe de Chimie Pharmaceutique, Universite´ de Rouen, UFR Me´decine-Pharmacie,
22 Boulevard Gambetta, F-76183 Rouen Cedex, France
bMilestone S.r.l., Via Fatebenefratelli, 1/5, 24010 Sorisole (BG), Italy
Received 4 June 2007; revised 17 July 2007; accepted 20 July 2007
Available online 27 July 2007
Abstract—An efficient methodology for the preparation of a series of 2,3-disubstituted-quinazolin-4(3H)-ones is described via a
three step reaction from anthranilic acid. The obtained results also reveal that microwave-assisted rapid decomposition of formam-
ide under controlled conditions of power, temperature and time is a very convenient source of ammonia for the synthesis of 2-substi-
tuted-quinazolin-4(3H)-ones and other rings.
Ó 2007 Elsevier Ltd. All rights reserved.
The quinazolinone moiety is a building block for
approximately 150 naturally occurring alkaloids1 such
as glycosminine,2 echinozolinone,3 deoxyvasicinone,4
rutaecarpine5 and drugs like methaqualone6 (Fig. 1).
The natural quinazolinones and their synthetic analo-
gous, possess a variety of biological activities, including
antimalarial,7 anticonvulsant,8 antibacterial,9 antidia-
betic10 and anticancer.11 Thus, due to the diverse range
of the pharmacological activities of quinazolinones and
their derivatives, there are numerous methods available
for their synthesis.12 Among them, the main synthetic
routes employ 2-aminobenzoic acid, 2-aminobenzamide,
isatoic anhydride, N-arylnitrilium salts and 3,1-benzox-
azinones as appropriate precursors.
In these compounds, an alkyl group was inserted into
the quinazolinone ring in position 2 with the aim to elu-
cidate the structural requirements and thus contribute to
structure–activity studies.
The advantages of using microwave dielectric heating
for performing organic reactions are well known14
(e.g., remarkable reduction of reaction time, improved
yields and cleaner reactions than the ones performed
under conventional thermal heating). Therefore, we
wish to report here the microwave-assisted synthesis of
substituted quinazolin-4-ones via activation and decom-
position of formamide. The experiments were performed
under pressurized conditions using the novel ‘hybrid’
microwave platform MultiSYNTHÒ (Milestone S.r.l.,
Italy).15 The reported microwave conditions were opti-
mized varying applied power and temperature.
In previous works we have synthesized a series of novel
heterocycles where the quinazolinone ring was fused
with a thiazole, indole or benzimidazole core.13 Contin-
uing our studies on this class of compounds, we consid-
ered to prepare 2,3-disubstituted-quinazolin-4(3H)-one
derivatives that can be employed as intermediates in
the synthesis of functional bioactive molecules.
The synthesis of the desired quinazolin-4(3H)-ones 6a–e
and 7a–e was performed in three steps starting from
anthranilic acid (1) and using 3,1-benzoxazinones 2 and
3 as intermediates (Scheme 1). This approach was in-
spired by the previous works of Dabiri et al.12d and Liu
et al.12h who described 2,3-disubstituted-quinazolines
prepared under microwaves via similar intermediates.
Our work exploits the dielectric properties of the mole-
cules and their capacity to react specifically under the
microwaves in order to reduce the number of reactants
involved and then to develop eco-compatible methods.
Keywords: Microwave-assisted chemistry; Quinazolin-4-ones; Benzox-
azin-4-ones; Formamide.
*
Corresponding author. Tel.: +33 (0)235148399; fax: +33
(0)235148423; e-mail: thierry.besson@univ-rouen.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.114

6610
I. K. Kostakis et al. / Tetrahedron Letters 48 (2007) 6609–6613
O
N
O
O
R2
R1
H
N
N
N
N
N
Quinazolin-4-one core
Methaqualone
Glycosminine
O
O
O
OH
N
N
N
N
N
N
N
H
Echinozolinone
Deoxyvasicinone
Rutaecarpine
Figure 1. Structure of the quinazoline core and various natural and synthetic alkaloids.
O
N
NHR2
O
O
N
R2
R1
CO2H
NH2
a
O
N
c
b
H
N
R1
R1
O
1
2, R1 = Me
3, R1 = Et
4a-e, R1 = Me
5a-e, R1 = Et
6a-e, R1 = Me
7a-e, R1 = Et
(anthranilic acid)
Scheme 1. Reagents and conditions: (a) (R1 = Me): acetic anhydride, MW (200 W), 130 °C, 10 min; (R1 = Et): propionic anhydride, MW (200 W),
160 °C, 10 min; (b) aliphatic amine (R2–NH2) (2 equiv), CH2Cl2, rt, 10–40 min; (c) formamide, MW (200 W), 170 °C, 10 min.
The first synthetic step involved the condensation of
anthranilic acid (1) with acetic or propionic anhydride
to afford the desired benzoxazinones (2 and 3, respec-
tively) in quantitative yields. After evaporation of the
excess of anhydride under reduced pressure, the crude
product was used without any further purification. In
fact, the methyl analogue is very moisture sensitive
and could be easily hydrolyzed into the N-acylanthrani-
lic acid.16
in reaction time), the isolation of the products in pure
form was very difficult due to the large presence of
decomposition products probably due to the highly at-
tained temperature (200 °C).
The use of formamide as the reaction solvent gave the
most satisfactory results. The best results were obtained
using a programmed irradiation at 200 W and a fixed
temperature of 170 °C. Complete conversion was
achieved within 10 min in good yields (see Table 1 for
overall yields from anthranilic acid). As comparison,
diamide 4a was also subjected to the same reaction con-
ditions (170 °C and formamide as solvent) under con-
ventional thermal heating in a preheated oil bath.
After a reaction time of 110 min, the overall yield of
the cyclized product (6a) dropped to 76% (compared
to 84% after 10 min under microwave irradiation, see
Table 1).
Intermediates 2 and 3 were then totally converted into
4a–e and 5a–e through treatment with an excess of the
appropriate aliphatic amine. Finally, the obtained dia-
mides were subjected to microwave-assisted cyclocon-
densation to give the desired quinazolinones 6a–e and
7a–e in good yields (Table 1).
According to the literature, this final step usually in-
volves long heating (several hours) of the diamide inter-
mediates in various solvents such as acetic acid, xylene or
dimethylformamide (DMF).17 In preliminary experi-
ments with many different solvents (e.g., acetic acid, N-
methylpyrrolidone (NMP), methanesulfonic acid, acetic
anhydride, xylene and formamide), we observed that
the most favourable one was formamide. The complete
conversion to quinazolin-4(3H)-ones using acetic acid
and acetic anhydride was achieved only with prolonged
reaction times (50 min or more). Performing the reaction
in NMP afforded the desired product in low yields (at
temperatures above 190 °C, the reaction yielded compli-
cated mixtures of carbonaceous compounds and impuri-
ties), while the use of xylene was inconvenient due to its
weak microwave absorbing character.
Through optimization runs it was possible to observe
that working at a temperature of 200 °C, the desired
quinazolinones 6a–e and 7a–e were formed as the major
products accompanied by minor amounts of the non-
alkylated quinazolin-4(3H)-ones (8 and 9, respectively,
see Scheme 2).
The thermal decomposition of formamide was already
described in the literature18 and there are a few examples
where it was not used only as a solvent.19,20 According
to these results, we can suggest that formamide could
be, under the applied reaction conditions, the source
of the ammonia that generates the unexpected mono-
2-substituted-4(3H)-quinazolinones 8 and 9.
Although, methanesulfonic acid afforded good results,
especially with the methyl analogues (striking reduction
This simple procedure for the synthesis of the monosub-
stituted quinazolinones would obviously be of great

I. K. Kostakis et al. / Tetrahedron Letters 48 (2007) 6609–6613
Table 1. Synthesis of 3H-quinazolin-4-ones from anthranilic acid
6611
Starting compound
R2NH2 (equiv)
Product
R1
R2
Yielda (%)
2
2
2
2
6a
6b
Me
Me
Me
n-Bu
84
75
N
2
2
2
2
6c
6d
Me
Me
77
83
N
2
2
6e
Me
77
O
N
3
3
2
2
7a
7b
Et
Et
Me
n-Bu
87
74
3
3
2
2
2
7c
7d
7e
Et
Et
Et
85
86
87
N
N
3
O
N
a Overall yield from anthranilic acid.
O
O
O
N
H
formamide
N
R1
R1
N
(200 W
MW
a
), 200 °C, 10min
2, R1 = Me
3, R1 = Et
8, R1 = Me (84% - 85% from 2)
9, R1 = Et (83 - 86% from 3)
b
NH2
O
H
N
R1
O
10, R1 = Me
11, R1 = Et
Scheme 2. Reagents and conditions: (a) NH3 20% aq (8 equiv), THF, rt; 10–20 min; (b) NaOH 5% aq, MW (100 W), 90 °C, 4 min.
interest for synthetic chemists. In fact, formamide could
be a cheap and easy to handle ammonia source for the
introduction of N-3 in the quinazolinone ring. To the
best of our knowledge, there are no reports on the use
of formamide as an ammonia synthon for the synthesis
of heterocyclic compounds under microwave irradiation.
dure for the disubstituted quinazolinones, the benzoxazi-
nones (2 and 3) were first converted to the corresponding
acylanthranilamides. The reaction took place at room
temperature in 20% aqueous ammonia solution to afford
products 10 and 11 (Scheme 2). The microwave-assisted
cyclocondensation with a preset power of 100 W and a
fixed temperature of 90 °C allowed ring closure of the
intermediate diamides 10 and 11 and provided the target
mono-2-substituted-quinazolin-4(3H)-ones 8 and 9 in
85% and 86% yields, respectively (Scheme 2). The overall
yields of the two methods are comparable, nevertheless,
the procedure with formamide as an ammonia source, is
simpler and more convenient, and requires only two syn-
thetic steps from anthranilic acid.
According to the previous observations, 10 min of irradi-
ation at 200 W (200 °C) of a mixture of 3,1-benzoxazi-
nones (2 or 3) and formamide, afforded the expected
mono-2-substituted-4(3H)-quinazolinones 8 and 9 in
very good yields (84% and 83%, respectively) (Scheme 2).
With the aim to confirm our results, we reinvestigated,
using microwave irradiation, the traditional conditions
described in the literature for the synthesis of 2-substi-
tuted-4(3H)-quinazolinones via treatment of the appro-
priate 3,1-benzoxazinones with aqueous ammonia
(8 equiv).21 By analogy to the above mentioned proce-
In conclusion, we have developed an efficient and novel
methodology for the preparation of a series of 2,3-disub-
stituted-quinazolin-4(3H)-ones via a three step reaction
from anthranilic acid and 3,1-benzoxazinones as inter-

6612
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mediates, with formamide as the solvent. Considering
that the synthesis of these molecules is a well established
procedure by conventional methods,22 the proposed
synthetic strategy could be a general method for the syn-
thesis of 2,3-dialkyl-quinazolin-4(3H)-ones.
As we have previously shown in our study of the micro-
wave-assisted decomposition of DMSO, and its use in
Pictet–Spengler heterocyclization,23 reactants may have
different behaviours under microwaves, depending on
the power input, the temperature reached, and also, on
the pressure obtained in the vials. Then, we have demon-
strated here that microwave-assisted rapid decomposi-
tion of formamide can be controlled under well
established conditions of power, temperature and time.
This phenomenon is a very convenient source of ammo-
nia for the synthesis of mono-2-substituted-quinazolin-
4(3H)-ones. Because it may also avoid the use of expen-
sive or difficult to handle reagents, it can be simply and
efficiently extended to the synthesis of various hetero-
cyclic derivatives.
14. For recent reviews see: (a) Lidstro¨m, P.; Tierney, J.;
Wathey, B.; Westmam, J. Tetrahedron 2001, 57, 9225–
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Acknowledgement
We wish to thank Milestone S.r.l. for support on micro-
wave experiments.
15. The ‘hybrid’ microwave platform MultiSYNTHÒ (Mile-
stone S.r.l.), is a novel dedicated microwave system for
synthetic applications. It allows a fast reaction optimiza-
tion providing high energy density in a single-mode like
configuration and an efficient scale-up (maximum working
volume 300 ml) through parallel synthesis in a multi-mode
configuration. The instrument features a special shaking
system that ensures high homogeneity of the reaction
mixtures. It is equipped with an indirect pressure-control
through pre-calibrated springs at the bottom of the vessels
shields and with both, contact-less infrared pyrometer
(IRT) and fibre-optic contact thermometer (FO) for
accurate temperature measurement. It is noteworthy that
the IRT can be calibrated directly on the temperature read
by the FO to ensure the highest accuracy and reproduc-
ibility. A complete description of this system is available at
www.milestonesrl.com.
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