One-pot tandem approach for the synthesis of quinazolinones from ortho-aminobenzamides, benzyl halides and benzyl alcohols

Article abstract of DOI:10.3184/174751912X13505766800606

A one-pot tandem procedure is described for the synthesis of quinazolinones from benzyl halides or benzyl alcohols and ortho-aminobenzamides leading to the production of quinazolinones with high yields under mild conditions in DMSO without requiring an additional oxidant. According to the current method benzyl chlorides, benzyl bromides and benzyl alcohols bearing a range of substituents are suitable substrates.

Full text of DOI:10.3184/174751912X13505766800606

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 701
DECEMBER, 701–702
One-pot tandem approach for the synthesis of quinazolinones from
ortho-aminobenzamides, benzyl halides and benzyl alcohols
Kourosh Motevallia*, Roghieh Mirzazadehb and Zahra Yaghoubic
aDepartment of Applied Chemistry, Faculty of Science, Islamic Azad University, SouthTehran Branch, Tehran, Iran
bDepartment of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
cIndustrial Faculty, Islamic Azad University, SouthTehran Branch, 4 Islamic Azad University, Tehran, Iran
A one-pot tandem procedure is described for the synthesis of quinazolinones from benzyl halides or benzyl alcohols
and ortho-aminobenzamides leading to the production of quinazolinones with high yields under mild conditions in
DMSO without requiring an additional oxidant. According to the current method benzyl chlorides, benzyl bromides
and benzyl alcohols bearing a range of substituents are suitable substrates.
Keywords: quinazolinones, ortho-aminobenzamides, benzyl halides, benzyl alcohol, one-pot tandem synthesis, nitrogenated
heterocycles
Quinazolinones have emerged as an important class of
nitrogenated heterocycles because of their pharmacological
and therapeutic properties ranging from anticancer, diuretic,
anti-inflammatory, anticonvulsant and antihypertensive activi-
ties.1–4 There are a variety of procedures for producing quina-
zolinone scaffolds.5 2-Aryl/alkyl-4(3H)-quinazolinones are
most commonly prepared using amidation of anthranilonitrile,
anthranilic acid, or anthranilamide prior to cyclisation of the
intermediate.6–8 Methods involving condensation of imidates
with anthranilic acid have also been reported.9,10 Other
approaches include using hetero Diels–Alder reaction of
1-aryl-4-dimethylamino-2-phenyl-1,3-diaza-1,3-butadienes
and phenyl isocyanate,11 or reaction of nitriles with lithiated
anthranilamides.12 Thermolysis of 3-arylideneamino-1,2,3-
benzotriazin-4-ones,13 and direct condensation of aldehydes
and anthranilamide derivatives in the presence of CuCl2 have
also been reported.14 One of the most frequently encountered
heterocycles in medicinal chemistry is 4(3H)-quinazolinone.
A literature survey revealed that there are many new routes
affording corresponding quinazolinones. For example,
Pd(II)-catalysed intramolecular C(sp2)–H carboxamidation of
N-arylamidines,15 CuI/4-hydroxy-l-proline catalysed coupling
of N-substituted o-bromobenzamides with formamide,16
Pd-catalysed benzylic C–H amidation with benzyl alcohols,17
palladium-catalysed N-monoarylation of amidines,18 I2/KI
catalysed oxidative cyclocondensation of o-aminobenzamide
with various aldehydes,19 tetra-butylammonium bromide
catalysed cyclocondensation of 2-aminobenzamide with
aldehydes,20 cellulosesulfonic acid catalysed condensation of
2-aminobenzamide with aldehydes or ketones,21 chiral phos-
phoric acid catalysed transformation of 2-aminobenzamides
with imines22 and Zn[(L)-proline]2 catalysed cyclocondensa-
tion of 2-aminobenzamides with aryl aldehydes23 are examples
of these methods. In addition, an interesting multi-component
reaction based on the use of isatoic anhydride as one of the
starting materials for the synthesis of 2-arylquinazolin-4(3H)-
ones has been reported.24 By another approach, a tandem
reaction between isatoic anhydride, a primary aniline or ammo-
nium acetate, and triethylorthoacetate in the presence of imid-
azolium trifluoroacetate [Hmim]TFA has been reported.25
Most of the commonly used multi-step procedures suffer
from shortcomings such as requiring long times for the reac-
tion to be completed, low yields, harsh reaction conditions,
difficult workups, and requiring expensive and toxic catalysts,
media and reactants.
benzyl alcohols 2 is used to afford 4(3H)-quinazolinones 3 in
good yields of 78–86% (Scheme 1).
Results and discussion
The reactions were performed at 90 °C by mixing the two
components and were completed within 3 hours (Table 1). The
1
structures of the products were established by H NMR, 13C
NMR spectroscopy and by comparison of their spectral data
and melting point values with those of the authentic samples
reported in the literature.26–28
The procedure develops the known reaction, while not limit-
ing one of the substrates to be an aldehyde. According to the
mechanism of the reaction (Scheme 2), benzylic substrate 1 in
DMSO is converted into the corresponding aldehyde 4 in the
presence of K2CO3 at 90 °C under mild Kornblum oxidation
conditions.29–30 Subsequently the in situ prepared aldehyde is
condensed with the ortho-aminobenzamides at 90 °C to yield
the corresponding 4(3H)-quinazolinones 3 in 78–86% yields.
Conclusion
In summary, it can be concluded that an expedient and facile
approach for the synthesis of 4(3H)-quinazolinones based on
the feasibility of the use of the benzylic substrates has been
developed. Benzyl chlorides, benzyl bromides and benzyl
alcohols were found to be suitable substrates in this reaction,
affording a range of 4(3H)-quinazolinones with good yields
without having to use any additional oxidants.
Experimental
Chemicals and solvents were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification.
Melting points were measured on a Barnstead electrothermal melting
point apparatus and were not corrected. 1H NMR and 13C NMR
spectra were determined in DMSO-d6 on a Bruker 500MHz NMR
machine and chemical shifts were expressed in ppm downfield from
tetramethylsilane.
Synthesis of 2-phenylquinazolin-4(3H)-one (entry a, Table 1); general
procedure
A mixture of benzyl chloride (0.126 g, 1 mmol) and K2CO3 (1.5 mmol)
in DMSO (1 mL) was stirred for 4 h at 90 °C. ortho-Aminobenzamide
We now report a novel and efficient one pot method for the
synthesis of 4(3H)-quinazolinones. According to this method,
a mixture of ortho-aminobenzamides 1 and benzyl halides or
* Correspondent. E-mail: k_motevalli@azad.ac.ir
Scheme 1

702 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Synthesis of 4(3H)-quinazolinones derivatives 3a–l
Received 27 July 2012; accepted 9 October 2012
Paper 1201433 doi: 10.3184/174751912X13505766800606
Published online: 5 December 2012
3
Ar
X
R
Yield/% M.p./°C Lit. m.p./°C
a
b
c
d
e
f
g
h
i
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
C6H5
C6H5
C6H5
4-MeOC6H4 Br
Br
Cl
H
H
82
80
84
80
86
81
85
86
78
82
85
80
236–238 235–23727
236–238 235–23727
238–2240 238–24027
238–2240 238–24027
238–2240 238–24027
288–290 287–28927
288–290 287–28927
284–286 284–28627
246–248 245–24626
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(0.136 g, 1 mmol) was added to the reaction mixture and stirring was
continued at 90 °C for 2 h. The reaction mixture was cooled to room
temperature and water (5 mL) was added. Stirring was continued
for 1 h at ambient temperature. The resulting white precipitate was
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