One-pot synthesis of quinazolinone and benzamide derivatives using SBA-Pr-SO3H as a nanoporous heterogeneous acid catalyst

Article abstract of DOI:10.13005/ojc/290443

A series of quinazolinone and benzamide derivatives have been efficiently synthesized in good to excellent yields via the reaction of 2-aminobenzamide and aromatic benzoyl chlorides under solvent-free conditions using SBA-Pr-SO ₃H as a nano solid acid catalyst.

Full text of DOI:10.13005/ojc/290443

ISSN: 0970-020 X
CODEN: OJCHEG
2013, Vol. 29, No. (4):
Pg. 1597-1603
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
One-pot Synthesis of Quinazolinone and Benzamide
Derivatives Using SBA-Pr-SO3H as a Nanoporous
Heterogeneous Acid Catalyst
MONIREH SHAKIBA NAHAD and GHODSI MOHAMMADI ZIARANI*
Department of Chemistry, Alzahra University, Vanak Square, Tehran, Iran.
*Corresponding author E-mail: gmziarani@hotmail.com, gmohammadi@alzahra.ac.ir
http://dx.doi.org/10.13005/ojc/290443
(Received: July 25, 2013; Accepted: October 09, 2013)
ABSTRACT
A series of quinazolinone and benzamide derivatives have been efficiently synthesized in
good to excellent yields via the reaction of 2-aminobenzamide and aromatic benzoyl chlorides under
solvent-free conditions using SBA-Pr-SO3H as a nano solid acid catalyst.
Key words: Quinazolinones, benzamide, SBA-Pr-SO3H, nano-reactor, green synthesis.
INTRODUCTION
naturally occurring alkaloids have quinazolinone
skeleton. Methaqualone, the most well-known
synthetic quinazolinone drug synthesized for the
first time in 1951, has sedative–hypnotic effects
(Fig. 1)7.
Quinazolines are an important class of
heterocycles with a wide range of pharmacological
and biological activities such as anticancer, antiviral,
anti-tubercular agents, treatment of diabetes
and obesity, anti-inflammatory, insecticidal, anti-
microbial1, anticonvulsant, antiulcer, hypolipidemic
activity, potent chemotherapeutic agents in the
treatment of tuberculosis2, potent and selective ALK5
inhibitors3. These compounds also have sedative,
tranquilizer, analgesic, anesthetic, antihypertensive,
In the most common approach for
the synthesis of quinazolinone compounds,
2-aminobenzoic acid or its derivatives,
2-aminobenzamide, 2-aminobenzonitrile, isatoic
anhydride, 2-carbomethoxyphenylisocyanate,
N-arylnitrilium salts, and 4H-3,1-benzoxazinones as
appropriate precursors were used. Other methods
involve the reaction of anthranilic acid and the
appropriately substituted imidate in a facile one-
pot procedure, cycloaddition of anthranilic acid
iminoketene to methylbutyrolactam (via sulfonamide
diuretic, and muscle relaxant properties4-5
.
Quinazolinone moiety is a building block
for approximately 150 naturally occurring alkaloids6.
Luotonin A, Bouchardatine1, and Febrifugine as

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NAHAD & zIARANI, Orient. J. Chem., Vol. 29(4), 1597-1603 (2013)
anhydride), reactions of anthranilic acid derivatives General Procedure for the Synthesis of
with a wide range of substrates including imidates Quinazolinone Derivatives (4a-d)
and imino halides, and microwave-promoted reaction
The SBA-Pr-SO3H (0.01 g) was activated
of anthranilic acid with amines and formic acid (or its in vacuum at 100 °C and then after cooling to room
ortho ester) and isatoic anhydride2, 7-8
.
temperature, 2-aminobenzamide (3 mmol, 0.41
g) and benzoyl chlorides (3 mmol) were added
Various catalysts such as pentameth to it. The mixture was stirred at 130 °C under
ylcycloopentadienyliridium(III) chloride dimer solvent free conditions as reported time in Table
([Cp*IrCl2]2 (Cp*=pentamethylcyclo-pentadienyl)9, 3. After completion of reaction that was indicated
1
12
montmorillonite K-1010, I211, InCl3 , Ga(OTf)3
,
by TLC (n-hexane/EtOAc, 1/1), the crude product
[Et3NH]3PW12O4013, carbon based-solid acid5, and was dissolved in hot convenient crystallization
tetrabutylammonium bromide (TBAB)7 were used in solvent (Table 3), the heterogeneous solid catalyst
the synthesis of quinazolinone derivatives.
was removed easily by simple filtration and after
evaporation of excess solvent, corresponding
In continuation of our previous studies14- products were obtained. The acid catalyst can be
16, in this paper we want to report the application reactivated by simple washing subsequently with
of SBA-Pr-SO3H as a highly active nanoporous diluted acid solution, water and acetone, dried under
heterogeneous acid catalyst in the preparation vacuum and re-used for several times without loss
of quinazolinone derivatives. The heterogeneous of significant activity.
catalysts can suitably be removed from the reaction
mixture, making the experimental procedure simple
and eco friendly. SBA-Pr-SO3H has mesoporous
silica structure with porous texture which is uniform in
RESULTS AND DISCUSSION
In this paper, condensation of
size (2–10 nm range) that can act as a nano-reactor 2-aminobenzamide 1 with benzoyl chlorides 2 in
in organic synthesis17.
the presence of SBA-Pr-SO3H as a heterogeneous
and reusable nano catalyst for the synthesis of
benzamide derivatives 3 and some quinazolinone
derivatives 4 was studied (Scheme 1).
ExPERIMENTAL
Materials and Methods
All chemicals were obtained commercially
At first, the reaction of 2-aminobenzamide
and used without further purification. GC-Mass 1 and 3,5-dinitro benzoyl chloride 2 was examined
analysis was performed on a GC-Mass model: 5973 as a model experiment in various solvents such as
network mass selective detector, GC 6890 Agilent.IR polar protic (H2O, EtOH) and polar aprotic (MeCN,
spectra were obtained with a Brucker 500 scientific EtOAc,THF) solvents under reflux condition to get an
spectrometer.The 1H NMR was run on a Bruker DPX, insight into the solvent effect on the yield of reaction.
250 MHz. Melting points were measured using the As shown results in Table 1, it can be seen that yield
capillary tube method with an electro thermal 9200 of products 3 were increased in polar aprotic solvents
apparatus.SEM analysis was performed on a Philips (Table 1, entries 1-4) while in polar protic solvents,
XL-30 field-emission scanning electron microscope the product was formed in slightly lower yield (Table
operated at 16 kV, while TEM was carried out on a 1, entries 5-6). As shown results in Table 1, among
Tecnai G2 F30 at 300 kV.
the tested solvents, the best result was obtained
in MeCN under reflux conditions in excellent yield.
SBA-15 Nanoporous Silica Synthesis and Therefore, MeCN under reflux condition was selected
Functionalization
as optimized condition and developed to synthesis
The nanoporous compound SBA-15 was other derivatives (Table 2, Method A).
synthesized and functionalized according to our
previous report18 and the modified SBA-15-Pr-SO3H
GC-MSS analysis of condensation products
was used as nanoporous solid acid catalyst in the of 2-aminobenzamide 1 with various benzoyl
following reaction.
chlorides 2 in the presence of SBA-Pr-SO3H under

NAHAD & zIARANI, Orient. J. Chem., Vol. 29(4), 1597-1603 (2013)
1599
reflux conditions in MeCN as solvent (Method
A), indicated that this optimum condition was not
applicable for all benzoyl chlorides. The effect of
temperature in this reaction was also studied by
carrying out the same model of reaction under
solvent-free conditions (Method B). As shown in
Table 2, the progress of the reaction for the synthesis
of quinazolinone derivatives 4 at 130 °C is greater.
Therefore, it was observed that the yield of products
is a function of temperature and the yield increased
as the reaction temperature was raised.
Table 1: Solvent effect on the synthesis of benzamide derivatives 3
Entry Solvent Temp. (°C) Time (min) Yield of 3f (%)
MeCN r.t 45 94
1
2
3
4
5
6
MeCN
EtOAc
THF
EtOH
H2O
reflux
reflux
reflux
reflux
reflux
3
4
3
3
5
100
98
86
83
80
Table 2: Ratio of products in condensation of 2-aminobenzamide 1 with
various benzoyl chlorides 2 under reflux and solvent-free conditions
Method Aa
Ratiob
Time
(h)
Method B
Ratiob
Entry
x
3 (%)
4 (%)
3 (%)
4 (%)
1
2
3
4
5
6
7
2-Cl
3-Cl
4-Cl
2,4-(Cl)2
2-Me
27
50
70
37
100
100
100
73
50
30
63
-
2
18
22
12
-
25
100
100
82
78
88
100
75
-
2.5
1.5
1
4
4
4-NO2
3,5-(NO2)2
-
-
2.5
-
Method A: SBA-Pr-SO3H, reflux, MeCN. Method B: SBA-Pr-SO3H, 130 °C, solvent-free conditions.
aThe time of reactions is 1 sec (immediately).
baccording to GC-MSS analysis
Table 3: Synthesis of quinazolinone derivatives 4a-d under solvent-free conditions
Entry
x
Producta Yield (%)
Crys. Solventb
m.p (°C)
m.p (Lit.)
1
2
3
4
3-Cl
4-Cl
2,4-(Cl)2
2-Me
4a
4b
4c
4d
76
82
50
75
EtOH/DMF
EtOH/DMF
EtOH
297-300
301-304
255-257
212-214
296-2981
306-3081
252-25319
21820
EtOH
a Reactions times are according to the Table 2.
bCrystallization solvent

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NAHAD & zIARANI, Orient. J. Chem., Vol. 29(4), 1597-1603 (2013)
Table 4: Synthesis of benzamide
derivatives 3a-g under reflux conditions in MeCN
Entry
x
Producta
Yield (%)
m.p (°C)
m.p (Lit.)
1
2
3
4
5
6
7
2-Cl
4-Cl
3a
3b
3c
3d
3e
65
60
55
91
79
70
52
205-206
199-200
196-197
237-240
238-239
283-285
236-237
200-20221
200.522
2,4-(Cl)2
2-Me
4-NO2
3,5-(NO2)2 3f
3-NO2 3g
New
217-21822
235-23622
New
Not Reported
a Reactions times are according to the Table 2.
In this regard, different substituted
Suggested mechanism for the synthesis
quinazolinones 4a-d were synthesized under solvent- of benzamides 3 and quinazolinones 4 was shown
free conditions at 130 °C (Table 3). Results in the in Scheme 2. SBA-Pr-SO3H as a nano acid catalyst
synthesis of various substituted benzamides 3a-g protonates the carbonyl group of benzoyl chloride.
are summarized in Table 4.
Then, the nucleophilic attack of amino group of
O
NH2
SBA-Pr-SO3H
NH
Reflux, MeCN
O
O
O
X
NH2
NH2
Cl
X
3
O
2
1
NH
SBA-Pr-SO3H
N
Solvent-free
X
130 °C
4
Scheme 1: Synthesis of benzamide 3 and quinazolinones 4
Scheme 2: Plausible mechanism for synthesis of quinazolinones 4a-d

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NAHAD & zIARANI, Orient. J. Chem., Vol. 29(4), 1597-1603 (2013)
Fig. 1: Synthetic and natural quinazolinone compounds
Fig. 2: SBA-Pr-SO3H acts as a nano-reactor
Fig. 3: Schematic representation of SBA-Pr-SO3H

NAHAD & zIARANI, Orient. J. Chem., Vol. 29(4), 1597-1603 (2013)
1602
2-aminobenzamide to carbonyl group of benzoyl
chloride resulted in the formation of benzamides 3.
The following nucleophilic attack of NH2 to carbonyl
group of compound 3 and subsequent dehydration
afforded quinazolinone derivatives 4 (Scheme 2)23.
preparation of SBA-Pr-SO3H was shown in Fig. 3.
First, the calcined SBA-15 silica was functionalized
with (3-mercaptopropyl)trimethoxysilane (MPTS)
and then, the thiol groups were oxidized to sulfonic
acid by hydrogen peroxide (Fig. 3).
SBA-Pr-SO3H with its distinct features such
as the pore size of 6 nm, acts as an efficient nano-
reactor in this reaction (Fig. 2). Fig. 2 also illustrates
the SEM and TEM images of SBA-Pr-SO3H. SEM
image (Fig.2, a) shows uniform particles about 1µm.
The same morphology was observed for SBA-15. It
can be concluded that morphology of solid was saved
without change during the surface modifications.On
the other hand, the TEM image (Fig. 2, b) reveals
the parallel channels, which resemble the pores
configuration of SBA-15.This indicates that the pore
of SBA-Pr-SO3H was not collapsed during two-steps
reactions.
CONCLUSION
In conclusion, we have developed an
efficient and mild procedure for the synthesis
of a series of quinazolinone derivatives via the
reaction of corresponding benzoyl chlorides and
2-aminobenzamide. The use of SBA-Pr-SO3H in
this reaction has the advantages of being reusable
and environmentally benign nano-reactor that the
reaction proceeds easily in its nano-pores.
ACKNOWLEDGEMENTS
We gratefully acknowledge for financial
support from the Research Council of Alzahra
University.
The sulfonic acid functionalized SBA-15
was usually synthesized through direct synthesis
or post-grafting24-25. A schematic illustration for the
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